CN101044141B - Purine derivatives for use as adenosin A-2A receptor agonists - Google Patents
Purine derivatives for use as adenosin A-2A receptor agonists Download PDFInfo
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- CN101044141B CN101044141B CN200580036010XA CN200580036010A CN101044141B CN 101044141 B CN101044141 B CN 101044141B CN 200580036010X A CN200580036010X A CN 200580036010XA CN 200580036010 A CN200580036010 A CN 200580036010A CN 101044141 B CN101044141 B CN 101044141B
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Abstract
Compounds of formula (I) in free or salt form, wherein R<1>, R<2> and R<3> have the meanings as indicated in the specification, are useful for treating conditions mediated by activation of the adenosine A2A receptor, especially inflammatory or obstructive airways diseases. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.
Description
The present invention relates to organic compound, their preparation and as the purposes of medicine.
On the one hand, the invention provides the formula I compound of free or salt form,
Wherein
R
1Be hydrogen, optional by R
4Replace-C (=O)-C (=O)-NH-C
1-C
8-alkyl, C
1-C
8-alkyl-carbonyl, C
3-C
8-naphthene base carbonyl ,-SO
2-C
1-C
8-alkyl or C
7-C
14-aromatic alkyl carbonyl;
R
2Be hydrogen or optional by C
6-C
10The C that-aryl replaces
1-C
8-alkyl;
R
3Be hydrogen, halogeno-group, C
2-C
8-thiazolinyl or C
2-C
8-alkynyl,
Perhaps R
3Be optional by C
3-C
8The amino of-cycloalkyl substituted, wherein C
3-C
8-cycloalkyl is optional to be replaced by amino,
Perhaps R
3Be optional by hydroxyl, C
6-C
10-aryl or R
5The C that replaces
1-C
8-alkylamino,
Perhaps R
3Be optional by amino or-NH-C (=O)-NH-R
7The R that replaces
6,
Perhaps R
3Be optional quilt-NH-C (=O)-NH-R
7Replace-NH-R
6,
Perhaps R
3Be C
1-C
8-alkyl amino-carbonyl or C
3-C
8-cycloalkyl amino carbonyl, optional by amino, C
1-C
8-alkylamino, two (C
1-C
8-alkyl) amino or-NH-C (=O)-NH-R
8Replace;
R
4, R
5And R
6Be 5-or the 6-unit heterocycle that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur independently, described 5-or 6-unit heterocycle are alternatively by halogeno-group, cyano group, oxo base, hydroxyl, carboxyl, amino, nitro, C
1-C
8-alkyl, C
1-C
8-alkyl sulphonyl, aminocarboxyl, C
1-C
8-alkyl-carbonyl or the optional C that is replaced by aminocarboxyl
1-C
8-alkoxyl group replaces;
R
7And R
8Be 5-or the 6-unit heterocycle that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur independently, described 5-or 6-unit heterocycle are alternatively by halogeno-group, cyano group, oxo base, hydroxyl, carboxyl, amino, nitro, C
1-C
8-alkyl, C
1-C
8-alkyl sulphonyl, aminocarboxyl, C
1-C
8-alkyl-carbonyl, the optional C that is replaced by aminocarboxyl
1-C
8-alkoxyl group or 5-or 6-unit heterocyclic substituted, described 5-or 6-unit heterocycle contain at least one and are selected from the ring hetero atom of nitrogen, oxygen and sulphur and alternatively by halogeno-group, cyano group, oxo base, hydroxyl, carboxyl, amino, nitro, C
1-C
8-alkyl, C
1-C
8-alkyl sulphonyl, aminocarboxyl, C
1-C
8-alkyl-carbonyl, the optional C that is replaced by aminocarboxyl
1-C
8-alkoxyl group replaces.
The term that is used in the specification sheets has following meanings:
" optional being substituted " relates to can be in one or more positions, the preferred group that replaced by the listed thereafter group of any one or arbitrary combination of one or two position.
" halogeno-group " used herein or " halogen " can be fluorine, chlorine, bromine or iodine.Preferably, halogeno-group is a chlorine.Work as R
3When being halogeno-group, it is chlorine preferably.Work as R
3By-NH-C (=O)-NH-R
7The R that replaces
6The time, R wherein
7By 5-that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or 6-unit heterocycle that halogeno-group replaces, this heterocycle is replaced by chlorine two positions.
" C used herein
1-C
8-alkyl " expression has the straight or branched alkyl of 1 to 8 carbon atom.Preferably, C
1-C
8-alkyl is C
1-C
6-alkyl.Work as R
2Be optional by C
6-C
10The C that-aryl replaces
1-C
8During-alkyl, R
2Preferably unsubstituted C
1-C
6-alkyl, especially amyl group or hexyl, more specifically-CH (C
2H
5)
2Or-CH
2CH
2C (CH
3)
2, perhaps R
2By C
6-C
10The C that-aryl replaces
1-C
5-alkyl, especially a position by naphthyl substituted or the C that replaced by phenyl two positions
2-C
5-alkyl (more specifically amyl group).
" C used herein
2-C
8-thiazolinyl " expression straight or branched hydrocarbon chain, it contains 2 to 8 carbon atoms and one or more carbon-to-carbon double bond.Preferably, C
2-C
8-thiazolinyl is C
2-C
4-thiazolinyl.
" C used herein
2-C
8-alkynyl " expression straight or branched hydrocarbon chain, it contains 2 to 8 carbon atoms and one or more carbon-to-carbon, three key and optional one or more carbon-to-carbon double bond.Preferably, C
2-C
8-alkynyl is C
2-C
6-alkynyl.Work as R
3Be C
2-C
8During-alkynyl, it is C preferably
2-C
6-alkynyl, hexin base especially, more specifically-C ≡ C-C
4H
9
" C used herein
1-C
8-alkoxyl group " expression has the straight or branched alkoxyl group of 1 to 8 carbon atom.Preferably, C
1-C
8-alkoxyl group is C
1-C
4-alkoxyl group.
" C used herein
3-C
8-cycloalkyl " expression has a cycloalkyl of 3 to 8 carbon atoms, monocyclic groups for example, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group, any can be by one or more, one or two C usually in them
1-C
4-alkyl replaces, perhaps bicyclic groups, for example two suberyl or two ring octyl groups.Preferably, C
3-C
8-cycloalkyl is C
3-C
6-cycloalkyl.Work as R
2By C
3-C
8During-cycloalkyl substituted amino, C
3-C
8-cycloalkyl is C preferably
3-C
6-cycloalkyl, more specifically cyclohexyl.
" C used herein
1-C
8-alkylamino " and " two (C
1-C
8-alkyl) amino " expression is respectively by one or two C as defined above
1-C
8The amino that-alkyl replaces, alkyl can be identical or different.Preferably, C
1-C
8-alkylamino and two (C
1-C
8-alkyl) amino is respectively C
1-C
4-alkylamino and two (C
1-C
4-alkyl) amino.Work as R
3Alternatively by C
1-C
8When-alkylamino replaces, C
1-C
8-alkylamino is C preferably
1-C
4-alkylamino, the especially ethylamino or third amino.
" C used herein
1-C
8-alkyl-carbonyl " and " C
1-C
8-alkoxy carbonyl " difference that is connected with carbonyl by carbon atom of expression C as defined above
1-C
8-alkyl or C
1-C
8-alkoxyl group.Preferably, C
1-C
8-alkyl-carbonyl and C
1-C
8-alkoxy carbonyl is respectively C
1-C
4-alkyl-carbonyl and C
1-C
4-alkoxy carbonyl.
" C used herein
3-C
8-naphthene base carbonyl " C as defined above that is connected with carbonyl by carbon atom of expression
3-C
8-cycloalkyl.Preferably, C
3-C
8-naphthene base carbonyl is C
3-C
5-naphthene base carbonyl.Work as R
1Be C
3-C
8During-naphthene base carbonyl, it is C preferably
3-C
5-naphthene base carbonyl, especially cyclopropyl carbonyl or cyclobutyl carbonyl.
" C used herein
3-C
8-cycloalkyl amino " expression is by the nitrogen-atoms as defined above C that be connected of carbon atom with amino
3-C
8-cycloalkyl.Preferably, C
3-C
8-cycloalkyl amino is C
3-C
5-cycloalkyl amino.
" C used herein
6-C
10-aryl " expression monovalence carbocyclic aromatic group, it contains 6 to 10 carbon atoms, for example can be monocyclic groups, for example phenyl, perhaps bicyclic groups, for example naphthyl.Preferably, C
6-C
10-aryl is a phenyl or naphthyl.Work as R
2By C
6-C
10The C that-aryl replaces
1-C
8During-alkyl, C
6-C
10-aryl is phenyl or naphthyl preferably.
" C used herein
7-C
14-aralkyl " expression is by C as defined above
6-C
10The alkyl as defined above that-aryl replaces, for example C
1-C
4-alkyl.Preferably, C
7-C
14-aralkyl is C
7-C
10-aralkyl, for example phenyl-C
1-C
4-alkyl, especially benzyl.
" C used herein
1-C
8-alkyl amino-carbonyl " and " C
3-C
8-cycloalkyl amino carbonyl " difference that is connected with carbonyl by carbon atom of expression C as defined above
1-C
8-alkylamino and C
3-C
8-cycloalkyl amino.Preferably, C
1-C
8-alkyl amino-carbonyl and C
3-C
8-cycloalkyl amino carbonyl is respectively C
1-C
4-alkyl amino-carbonyl and C
3-C
8-cycloalkyl amino carbonyl.Work as R
3Be C
1-C
8During-alkyl amino-carbonyl, it is C preferably
1-C
3-alkyl amino-carbonyl, especially third aminocarboxyl.
" C used herein
6-C
10-aryl carbonyl " and " C
7-C
14-aromatic alkyl carbonyl " difference that is connected with carbonyl by carbon atom of expression C as defined above
6-C
10-aryl and C
7-C
14-aralkyl.Preferably, C
6-C
10-aryl carbonyl and C
7-C
14-aromatic alkyl carbonyl is respectively C
6-C
8-aryl carbonyl and C
7-C
10-aromatic alkyl carbonyl.Work as R
1Be C
7-C
14During-aromatic alkyl carbonyl, it is C preferably
7-C
10-aromatic alkyl carbonyl, especially benzyloxycarbonyl group, i.e. phenyl kharophen.
" 5-or the 6-unit heterocycle that contain at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur " used herein for example can be furans, pyrroles, tetramethyleneimine, pyrazoles, imidazoles, triazole, different triazole, tetrazolium, thiadiazoles, isothiazole, oxadiazole, pyridine, piperidines, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, tetramethyleneimine, morpholino, triazine, oxazine or thiazole.Preferred heterocycle comprises piperazine, tetramethyleneimine, morpholino, imidazoles, different triazole, pyrazoles, tetrazolium, thiazole, thiadiazoles, pyridine, piperidines, pyrazine, furans, oxazole, isoxazole, oxadiazole and azetidine.5-or 6-unit heterocycle can be unsubstituted, and perhaps it can be in one or more positions, preferably one or two position is replaced by following group: halogeno-group, cyano group, oxo base, hydroxyl, carboxyl, amino, nitro, C
1-C
8-alkyl, C
1-C
8-alkyl sulphonyl, aminocarboxyl, C
1-C
8-alkyl-carbonyl or can be selected in one or more positions, the preferred C that replaced by aminocarboxyl of one or two position
1-C
8-alkoxyl group.Especially preferred substituting group comprises methyl, ethyl, propyl group and amino.Work as R
3Be optional by R
5The C that replaces
1-C
8During-alkylamino, R
5Preferably unsubstituted imidazolyl, unsubstituted piperidyl or a position by C
1-C
3The imidazolyl that-alkyl replaces.Work as R
3Be optional quilt-NH-C (=O)-NH-R
7The R that replaces
6The time, R
6Preferably pyrrolidyl, piperidyl or piperazinyl, relevant R
7Preferably unsubstituted thienyl, unsubstituted pyridine base, unsubstituted pyrrolidyl, by chlorine Disubstituted pyridine base, the piperidyl that replaces by methyl substituted piperazinyl, at a position pyridyl a position or the piperidyl that replaces at a position pyridyl.Work as R
3Be optional quilt-NH-C (=O)-NH-R
7Replace-NH-R
6The time, R
6Preferably unsubstituted pyrrolidyl, perhaps R
6Be a position quilt-NH-C (=O)-NH-R
7The pyrrolidyl that replaces, wherein R
7It is the unsubstituted pyridine base.Work as R
3By-NH-C (=O)-NH-R
8The C that replaces
1-C
8During-alkyl amino-carbonyl, R
8Preferably unsubstituted piperidyl, the piperidyl that is replaced by methyl sulphonyl a position, the piperidyl that replaces at a position pyridyl or the pyrrolidyl that replaces at a position pyridyl.
Unless context has needs in addition, the word that spreads all over this specification sheets and following claims " comprises " or such as " including " or variants such as " comprising " will being understood that to hint integer or step or integer or the step group that comprises defined, but does not get rid of other integers or step or integer or step group arbitrarily.
Preferred formula I compound free or salt form comprises as follows, wherein
R
1Be optional by R
4Replace-C (=O)-C (=O)-NH-C
1-C
8-alkyl, C
1-C
8-alkyl-carbonyl, C
3-C
8-naphthene base carbonyl ,-SO
2-C
1-C
8-alkyl or C
7-C
14-aromatic alkyl carbonyl;
R
2Be hydrogen or optional by C
6-C
10The C that-aryl replaces
1-C
8-alkyl;
R
3Be halogeno-group or C
2-C
8-alkynyl,
Perhaps R
3Be optional by C
3-C
8The amino of-cycloalkyl substituted, wherein C
3-C
8-cycloalkyl is optional to be replaced by amino,
Perhaps R
3Be optional by hydroxyl, C
6-C
10-aryl or R
5The C that replaces
1-C
8-alkylamino,
Perhaps R
3Be optional by amino or-NH-C (=O)-NH-R
7The R that replaces
6,
Perhaps R
3Be optional quilt-NH-C (=O)-NH-R
7Replace-NH-R
6,
Perhaps R
3Be optional quilt-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl;
R
4, R
5And R
6Be 5-or the 6-unit heterocycle that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur independently, described 5-or 6-unit heterocycle are alternatively by C
1-C
8-alkyl replaces; And
R
7And R
8Be 5-or the 6-unit heterocycle that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur independently, described 5-or 6-unit heterocycle are alternatively by halogeno-group, C
1-C
8-alkyl, C
1-C
8-alkyl sulphonyl or contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or 6-unit heterocyclic substituted.
Especially preferred formula I compound free or salt form comprises as follows, wherein
R
1Be alternatively a position by R
4Replace-C (=O)-C (=O)-NH-C
1-C
4-alkyl, C
1-C
4-alkyl-carbonyl, C
3-C
5-naphthene base carbonyl ,-SO
2-C
1-C
4-alkyl or C
7-C
10-aromatic alkyl carbonyl;
R
2Be hydrogen, unsubstituted C
1-C
6-alkyl or a position by C
6-C
10The C that-aryl replaces
1-C
5-alkyl;
R
3Be halogeno-group or C
2-C
6-alkynyl,
Perhaps R
3Be alternatively a position by the C that is replaced by amino a position alternatively
3-C
6The amino of-cycloalkyl substituted,
Perhaps R
3Be by hydroxyl, phenyl or R in one or two position
5The C that replaces
1-C
4-alkylamino,
Perhaps R
3Be alternatively a position by amino or-NH-C (=O)-NH-R
7The R that replaces
6,
Perhaps R
3Be alternatively a position quilt-NH-C (=O)-NH-R
7Replace-NH-R
6,
Perhaps R
3Be a position quilt-NH-C (=O)-NH-R
8The C that replaces
1-C
4-alkyl amino-carbonyl;
R
4, R
5And R
6Be to contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or 6-unit heterocycle independently, described 5-or 6-unit heterocycle alternatively a position by C
1-C
4-alkyl replaces; And
R
7And R
8Be to contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or 6-unit heterocycle independently, described 5-or 6-unit heterocycle alternatively in one or two position by halogeno-group, C
1-C
4-alkyl, C
1-C
4-alkyl sulphonyl or 5-or the 6-N-of unit heterocyclic substituted.
Second aspect the invention provides formula I compound, wherein
R
1Be hydrogen, optional by R
4Replace-C (=O)-C (=O)-NH-C
1-C
8-alkyl, C
1-C
8-alkyl-carbonyl, C
3-C
8-naphthene base carbonyl ,-SO
2-C
1-C
8-alkyl or C
7-C
14-aromatic alkyl carbonyl;
R
2Be hydrogen or optional by C
6-C
10The C that-aryl replaces
1-C
8-alkyl;
R
3Be hydrogen, halogeno-group, C
2-C
8-thiazolinyl or C
2-C
8-alkynyl,
Perhaps R
3Be optional by C
3-C
8The amino of-cycloalkyl substituted, wherein C
3-C
8-cycloalkyl is optional to be replaced by amino,
Perhaps R
3Be optional by hydroxyl, C
6-C
10-aryl or R
5The C that replaces
1-C
8-alkylamino,
Perhaps R
3Be optional by amino or-NH-C (=O)-NH-R
7The R that replaces
6,
Perhaps R
3Be C
1-C
8-alkyl amino-carbonyl or C
3-C
8-cycloalkyl amino carbonyl, optional by amino, C
1-C
8-alkylamino, two (C
1-C
8-alkyl) amino or-NH-C (=O)-NH-R
8Replace;
R
4, R
5And R
6Be 5-or the 6-unit heterocycle that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur independently; And
R
7And R
8Be 5-or the 6-unit heterocycle that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur independently, described 5-or 6-unit heterocycle are contained the 5-or the 6-unit heterocyclic substituted of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur alternatively.
Preferred formula I compound free or salt form comprises as follows, wherein
R
1Be optional by R
4Replace-C (=O)-C (=O)-NH-C
1-C
8-alkyl, C
1-C
8-alkyl-carbonyl, C
3-C
8-naphthene base carbonyl ,-SO
2-C
1-C
8-alkyl or C
7-C
14-aromatic alkyl carbonyl;
R
2Be hydrogen or optional by C
6-C
10The C that-aryl replaces
1-C
8-alkyl;
R
3Be halogeno-group or C
2-C
8-alkynyl,
Perhaps R
3Be optional by C
3-C
8The amino of-cycloalkyl substituted, wherein C
3-C
8-cycloalkyl is optional to be replaced by amino,
Perhaps R
3Be optional by hydroxyl, C
6-C
10-aryl or R
5The C that replaces
1-C
8-alkylamino,
Perhaps R
3Be optional by amino or-NH-C (=O)-NH-R
7The R that replaces
6,
Perhaps R
3Be optional quilt-NH-C (=O)-NH-R
7Replace-NH-R
6,
Perhaps R
3Be optional quilt-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl;
R
4, R
5And R
6Be 5-or the 6-unit heterocycle that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur independently; And
R
7And R
8Be 5-or the 6-unit heterocycle that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur independently, described 5-or 6-unit heterocycle are contained the 5-or the 6-unit heterocyclic substituted of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur alternatively.
Especially preferred formula I compound free or salt form comprises as follows, wherein
R
1Be alternatively a position by R
4Replace-C (=O)-C (=O)-NH-C
1-C
4-alkyl, C
1-C
4-alkyl-carbonyl, C
3-C
6-naphthene base carbonyl ,-SO
2-C
1-C
4-alkyl or C
7-C
10-aromatic alkyl carbonyl;
R
2Be hydrogen or optional by C
6-C
10The C that-aryl replaces
1-C
6-alkyl;
R
3Be halogeno-group or C
2-C
5-alkynyl,
Perhaps R
3Be optional by C
3-C
8The amino of-cycloalkyl substituted, wherein C
3-C
8-cycloalkyl is optional to be replaced by amino,
Perhaps R
3Be optional by hydroxyl, C
6-C
8-aryl or R
5The C that replaces
1-C
4-alkylamino,
Perhaps R
3Be optional by amino or-NH-C (=O)-NH-R
7The R that replaces
6,
Perhaps R
3Be optional quilt-NH-C (=O)-NH-R
7Replace-NH-R
6,
Perhaps R
3Be optional quilt-NH-C (=O)-NH-R
8The C that replaces
1-C
4-alkyl amino-carbonyl;
R
4, R
5And R
6Be 5-or the 6-unit heterocycle that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur independently; And
R
7And R
8Be 5-or the 6-unit heterocycle that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur independently, described 5-or 6-unit heterocycle are contained the 5-or the 6-unit heterocyclic substituted of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur alternatively.
Especially preferred concrete formula I compound be following embodiment described those.
Compound by formula I representative can generate acid salt, particularly pharmaceutically-acceptable acid addition.The pharmaceutically-acceptable acid addition of formula Ia compound comprises mineral acid and those salt of organic acid, and mineral acid is haloid acid such as hydrofluoric acid, spirit of salt, Hydrogen bromide or hydroiodic acid HI, nitric acid, sulfuric acid, phosphoric acid for example; Organic acid is aliphatic monocarboxylic acid such as formic acid for example, acetate, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxide radical acid is as lactic acid, citric acid, tartrate or oxysuccinic acid, di-carboxylic acid such as toxilic acid or succsinic acid, aromatic carboxylic acid such as phenylformic acid, right-chloro-benzoic acid, diphenyl acetic acid, right-biphenyl phenylformic acid or triphenylacetic acid, aromatic hydroxy acid such as neighbour-hydroxy-benzoic acid, right-hydroxy-benzoic acid, 1-hydroxyl naphthalene-2-carboxylic acid or 3-hydroxyl naphthalene-2-carboxylic acid, cinnamic acid such as 3-(2-naphthyl) vinylformic acid, right-methoxy cinnamic acid or right-tolyl acrylic acid and sulfonic acid such as methylsulfonic acid or Phenylsulfonic acid.These salt can be by known salify technology from formula I compound.
The formula I compound that contains acidic-group, for example carboxyl also can generate salt with alkali, particularly pharmaceutically acceptable alkali, for example well known in the art those; The salt that this class is fit to comprises metal-salt, particularly basic metal or alkaline earth salt, for example sodium, potassium, magnesium or calcium salt, the perhaps salt of ammonia or pharmaceutically acceptable organic amine or heterocyclic bases, for example thanomin, benzylamine or pyridine.These salt can be by known salify technology from formula Ia compound.
Exist therein in those compounds of unsymmetrical carbon, these compounds exist with discrete optically active isomeric form or its mixture, for example the diastereo-isomerism mixture.The present invention contain discrete optically active R and S isomer with and composition thereof.
The present invention provides the method for the free or salt form Ia compound of preparation formula on the other hand, comprises that (i) (A) with regard to the preparation of formula I compound, in the presence of alkali, makes formula II compound
R wherein
2And R
3As defined above,
With the formula III compound
R
1-X
a III
Or the reaction of formula III a compound,
R wherein
1Be hydrogen, C
1-C
8-alkyl-carbonyl, C
3-C
8-naphthene base carbonyl or C
7-C
14-aromatic alkyl carbonyl, X
aBe leavings group, K is hydrogen, C
1-C
8-alkyl or C
1-C
8-alkoxyl group;
(B) with regard to regard to the preparation of I compound, R wherein
3By the optional C that is replaced by amino
3-C
8The amino of-cycloalkyl substituted, perhaps R
3Be optional by hydroxyl, C
6-C
10-aryl or R
5The C that replaces
1-C
8-alkylamino, perhaps R
3Be optional by amino or-NH-C (=O)-NH-R
7The R that replaces
6, make formula IV compound
R wherein
1And R
2As defined above, X is a halogeno-group,
With formula Va or the reaction of formula Vb compound,
H
2N-R
3a Va
R wherein
3aBe optional by the amino C that replaces
3-C
8-cycloalkyl, perhaps R
3Be optional by hydroxyl, C
6-C
10-aryl or R
5The C that replaces
1-C
8-alkyl, wherein R
5As defined above, R
3bAnd R
3cConstitute 5-or 6-unit heterocycle together, it contain one or more nitrogen-atoms and alternatively by amino or-NH-C (=O)-NH-R
7Replace, wherein R
7As defined above;
(C) with regard to the preparation of formula I compound, in the presence of alkali, make formula VI compound
R wherein
1And R
3As defined above, X is a halogeno-group,
With the reaction of formula VII compound,
H
2N-R
2 VII
R wherein
2As defined above;
(D) with regard to the preparation of formula I compound, formula VIII compound is gone protection,
R wherein
1, R
2And R
3As defined above, L is C
1-C
8-alkyl;
(E) with regard to regard to the preparation of I compound, R wherein
3By-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl or C
3-C
8-cycloalkyl amino carbonyl, wherein R
8As defined above, in the presence of alkali, make formula IX compound
R wherein
1And R
2As defined above, Y is C
1-C
8-alkyl or C
3-C
8-cycloalkyl is with formula X compound
Or the reaction of formula XI compound,
O＝C＝N-R
8 XI
Wherein T is C
6-C
10-aryloxy or contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or 6-unit heterocycle, R
8As defined above;
(F) R wherein just
3Be C
2-C
8The preparation of the formula I compound of-alkynyl,
In the presence of alkali and catalyzer, make wherein R
1And R
2Formula IV compound and formula XII compound reaction as defined above,
R
x-C≡C-H XII
R wherein
xBe C
1-C
8-alkyl;
(G) with regard to regard to the preparation of I compound, R wherein
3Be optional quilt-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl,
In the presence of alkali, make formula XIIa compound alternatively
R wherein
1And R
2As defined above, R
yBe C
1-C
8-alkyl,
With the reaction of formula XIIb compound,
R wherein
zBe C
1-C
8-alkyl ,-NH-C (=O)-NH-R
8As defined above; Perhaps
(H) with regard to regard to the preparation of I compound, R wherein
3By-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl, wherein R
8Be 5-or the 6-unit heterocycle that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur, this encircles by C
1-C
8-alkyl sulphonyl replaces,
In the presence of alkali, make wherein R
3By-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl, R wherein
8Be 5-or 6-unit's heterocyclic formula I compound and the sulfonyl agent reaction that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur;
(I) with regard to regard to the preparation of I compound, R wherein
3By-NH-C (=O)-NH-R
7The R that replaces
6, R wherein
7As defined above,
Make formula XIIc compound
R wherein
1And R
2As defined above, R
6Be to contain at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur, the 5-that is replaced by amino a position or 6-unit heterocycle,
With formula Xa compound
Or the reaction of formula XIa compound,
O＝C＝N-R
7 XIa
Wherein T is C
6-C
10-aryloxy or contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or 6-unit heterocycle, R
8As defined above;
(J) with regard to regard to the preparation of I compound, R wherein
3By-NH-C (=O)-NH-R
7The R that replaces
6, R wherein
7As defined above,
Make formula XIId or XIIe compound or its protected form
R wherein
1, R
2And R
6As defined above, T is C
6-C
10-aryloxy or contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or 6-unit heterocycle,
With the reaction of formula XIIf compound,
R wherein
3dAnd R
3eConstitute the 5-or the 6-N-of the unit heterocycle that contain at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur together, described 5-or 6-unit heterocycle are alternatively by halogeno-group, cyano group, oxo base, hydroxyl, carboxyl, amino, nitro, C
1-C
8-alkyl, C
1-C
8-alkyl sulphonyl, aminocarboxyl, C
1-C
8-alkyl-carbonyl, the optional C that is replaced by aminocarboxyl
1-C
8-alkoxyl group or contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or 6-unit heterocyclic substituted; Perhaps
(K) with regard to regard to the preparation of I compound, R wherein
3By-NH-C (=O)-NH-R
7The R that replaces
6, R wherein
7As defined above,
Make wherein R
1, R
2And R
6As defined above, T is C
6-C
10-aryloxy or contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or the 6-heterocyclic formula XIId of unit or XIIe compound react with formula XIIg compound,
H
2N-R
7 XIIg
R wherein
7As defined above; With
(ii) remove any blocking group, reclaim the formula Ia compound of the free or salt form of gained.
Method variant (A) can utilize and become known for making amine and carboxylic acid halides, acid anhydrides or mixed acid anhydride such as carboxylic acid and anhydride of carbonic acid (or its acid amides-generative nature derivative, for example carboxylic acid) or sulfonic acid halide as the technology of methylsulfonyl halogen reaction or be similar to hereinafter and carry out as described in the embodiment.Leavings group can be the leavings group that is fit to arbitrarily, for example halogeno-group ,-SO
2-C
1-C
8-alkyl or-SO
2-C
6-C
10-aryl.Reaction is aptly with an organic solvent as tetrahydrofuran (THF) (THF), carry out in the presence of alkali such as diisopropylethylamine (DIPEA).The temperature of reaction that is fit to is 10 ℃ to 40 ℃, preferred room temperature.
Method variant (B) can utilize the technology that becomes known for making halogenide, especially aromatic halide and amine reaction or be similar to that hereinafter embodiment is described carries out.Reaction is aptly with an organic solvent as dichlorobenzene, dimethyl sulfoxide (DMSO), acetonitrile or N-Methyl pyrrolidone (NMP) or its mixture, carry out in the presence of catalyzer such as sodium iodide and alkali such as triethylamine alternatively.The temperature of reaction that is fit to is 100 ℃ to 250 ℃, preferably between 120 ℃ to 220 ℃, especially about 170 ℃, for example uses carry out microwave radiation heating.
Method variant (C) can utilize the technology that becomes known for making halogenide and amine reaction or be similar to that hereinafter embodiment is described carries out.Reaction aptly with an organic solvent as tetrahydrofuran (THF), preferably in inert atmosphere such as argon, in the presence of alkali such as diisopropylethylamine, carry out alternatively.The temperature of reaction that is fit to is 0 ℃ to 70 ℃, preferably between 40 ℃ to 60 ℃, and especially about 50 ℃.
Method variant (D) can utilize the technology that becomes known for the cracking ester bond, for example use organic acid such as trifluoroacetic acid to carry out.Reaction is with an organic solvent carried out as methylene dichloride (DCM) aptly.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Method variant (E) can utilize and become known for making the technology of amine and acylimidazole or isocyanate reaction or be similar to that hereinafter embodiment is described carries out.T among the formula X is imidazolyl preferably.Reaction is with an organic solvent carried out as toluene and/or Virahol aptly.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Method variant (F) can utilize the technology that becomes known for making halogenide and alkynes reaction or be similar to that hereinafter embodiment is described carries out.Catalyzer is palladium catalyst (with CuI salt) preferably, and alkali is butylamine preferably.Reaction is with an organic solvent carried out as dimethyl formamide (DMF) aptly.The temperature of reaction that is fit to is 40 ℃ to 200 ℃, preferred 80 ℃ to 160 ℃, and especially about 120 ℃.
Method variant (G) can utilize the technology that becomes known for making alkyl carboxylates and amine reaction or be similar to that hereinafter embodiment is described carries out.Alkali is imidazoles preferably.With an organic solvent as 1,2-ethylene dichloride, Virahol or its mixture carry out aptly in reaction.The temperature of reaction that is fit to is a room temperature to 250 ℃, preferred 50 ℃ to 100 ℃.
Method variant (H) can utilize and become known for sulfonylation heterocyclic technology or be similar to that hereinafter embodiment is described carries out.Sulfonyl agent is heteroaryl-alkylsulfonyl halides preferably, for example methylsulfonyl chloride.Alkali is triethylamine preferably.Reaction is aptly with an organic solvent as dimethyl formamide (DMF), preferably carry out in inert atmosphere.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Method variant (I) can utilize the technology that becomes known for making amine and acylimidazole, isocyanic ester or aryl carbamate reaction or be similar to that hereinafter embodiment is described carries out.T among the formula X is imidazolyl preferably.Reaction is aptly with an organic solvent as tetrahydrofuran (THF) or N-Methyl pyrrolidone (NMP), preferably carry out in the presence of alkali such as triethylamine.When making amine and acylimidazole or isocyanate reaction, suitable temperature of reaction is 0 ℃ to 40 ℃, preferred room temperature.When making amine and aryl carbamate such as carboxylamine phenylester when reaction, suitable temperature of reaction is a room temperature to 120 ℃, preferred 80 ℃ to 110 ℃, and especially about 110 ℃.
Method variant (J) can utilize the technology that becomes known for making N-heterocycle and acylimidazole, isocyanic ester or aryl carbamate reaction or be similar to that hereinafter embodiment is described carries out.T among the formula XIIe is imidazolyl preferably.Reaction is with an organic solvent carried out as tetrahydrofuran (THF) or N-Methyl pyrrolidone (NMP) aptly.When making N-heterocycle and acylimidazole or isocyanate reaction, suitable temperature of reaction is 0 ℃ to 40 ℃, preferred room temperature.When making N-heterocycle and aryl carbamate such as carboxylamine phenylester when reaction, suitable temperature of reaction is a room temperature to 120 ℃, preferred 80 ℃ to 110 ℃, and especially about 110 ℃.
Method variant (K) can utilize the technology that becomes known for making amine and acylimidazole, isocyanic ester or aryl carbamate reaction or be similar to that hereinafter embodiment is described carries out.Reaction is with an organic solvent carried out as tetrahydrofuran (THF) aptly.When making amine and acylimidazole or isocyanate reaction, suitable temperature of reaction is 0 ℃ to 40 ℃, preferred room temperature.When making amine and aryl carbamate such as carboxylamine phenylester when reaction, suitable temperature of reaction is a room temperature to 120 ℃, preferred 80 ℃ to 110 ℃, and especially about 110 ℃.
When this paper mentioned protected functional group or blocking group, blocking group can be selected according to the attribute of functional group, Protective Groups in Organic Synthesis for example, T.W.Greene and P.G.M.Wuts, John Wiley ﹠amp; C Sons Inc, the third edition, 1999 is described, and the document has also been described the technology that is suitable for hydrogen displacement blocking group.
Formula II compound can utilize the technology that becomes known for the cracking ester bond by going protection XIII compound, perhaps is similar to the hereinafter described preparation of embodiment,
R wherein
2And R
3As defined above, each L is C
1-C
8-alkyl.Preferably, reaction uses organic acid such as trifluoroacetic acid to carry out.Each L is the tertiary butyl preferably.Reaction is with an organic solvent carried out as methylene dichloride aptly.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula III or IIIa compound be commercially available to be got or can prepare the technology of this compounds or be similar to the described acquisition of this paper embodiment by becoming known for.
Formula IV compound can be prepared as follows: in the presence of alkali, make wherein R
3Be the formula II compound of halogeno-group and R wherein
1As defined above, X is a leavings group, preferably halogeno-group, K are hydrogen or C
1-C
8The formula III of-alkyl or the reaction of IIIa compound perhaps are similar to the described preparation of this paper embodiment.Reaction is with an organic solvent carried out as tetrahydrofuran (THF) aptly.Alkali is diisopropylethylamine preferably.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula Va or formula Vb compound be commercially available to be got or can prepare the technology of this compounds or be similar to the described acquisition of this paper embodiment by becoming known for.
Formula VI compound can be prepared as follows: in the presence of alkali, make formula XIV compound
R wherein
3As defined above, X is a halogeno-group, with formula III or the reaction of IIIa compound, wherein R
1As defined above, X is a leavings group, preferred halogeno-group, and K is hydrogen or C
1-C
8-alkyl perhaps is similar to the described preparation of this paper embodiment.Reaction is aptly with an organic solvent as tetrahydrofuran (THF), preferably carry out in the presence of alkali such as diisopropylethylamine.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula VII compound is commercially available to be got or can prepare the technology of this compounds or be similar to the described acquisition of this paper embodiment by becoming known for.
Formula VIII compound can be prepared as follows: make formula XV compound
R wherein
1, R
2And R
3As defined above, L is C
1-C
8-alkyl is with dihydroxy agent such as perosmic anhydride (OsO
4) with the reaction of stoichiometric quantity or catalytic amount, preferably with reoxidize agent such as N-methylmorpholine N-oxide compound (NMO) reacts, perhaps select as an alternative to use AD-mix-α or AD-mix-β, perhaps be similar to the described preparation of this paper embodiment.L is the tertiary butyl preferably.Reaction is with an organic solvent carried out as THF aptly.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula IX compound can be prepared as follows: make formula XVI compound
R wherein
1And R
2As defined above, L is C
1-C
8-alkyl, with the reaction of formula XVII compound,
Wherein Y is C
1-C
8-alkyl or C
3-C
8-cycloalkyl perhaps is similar to the described preparation of this paper embodiment.The temperature of reaction that is fit to is 80 ℃ to 130 ℃, preferred 90 ℃ to 120 ℃, and especially about 105 ℃.
Formula X, Xa, XI or XIa compound be commercially available to be got or can prepare the technology of this compounds or be similar to the described acquisition of this paper embodiment by becoming known for.
Formula XII compound is commercially available to be got or can prepare the technology of this compounds or be similar to the described acquisition of this paper embodiment by becoming known for.
Formula XIIa compound can utilize this paper about the described method of preparation formula XVI compound or be similar to the described preparation of this paper embodiment.
Formula XIIb compound is commercially available to be got or can prepare the technology of this compounds or be similar to the described acquisition of this paper embodiment by becoming known for.
Formula XIIc compound can utilize this paper about preparing wherein R
3Be R
6The described method of formula I compound or be similar to the described preparation of this paper embodiment.
Formula XIId or XIIe compound can be by making wherein R
3The R that is replaced by amino
6Formula I compound with the acylation reaction that is fit to or be similar to the described preparation of this paper embodiment.
Formula XIIf or XIIg compound be commercially available to be got or can prepare the technology of this compounds or be similar to the described acquisition of this paper embodiment by becoming known for.
Formula XIII compound can be prepared as follows: make formula XVIII compound
R wherein
2And R
3As defined above, each L is C
1-C
8-alkyl or benzyl are with hydroxylating agent such as perosmic anhydride (OsO
4) with the reaction of stoichiometric quantity or catalytic amount, preferably with reoxidize agent such as N-methylmorpholine N-oxide compound (NMO) reacts, perhaps select as an alternative to use AD-mix-α or AD-mix-β, perhaps be similar to the described preparation of this paper embodiment.L
1And L
2The tertiary butyl preferably.Reaction is with an organic solvent carried out as tetrahydrofuran (THF) aptly.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XIV compound can be prepared as follows: make formula XIX compound
R wherein
3With X as defined above, each L is C
1-C
8-alkyl or benzyl react with organic acid such as trifluoroacetic acid, perhaps are similar to the described preparation of this paper embodiment.Each L is the tertiary butyl preferably.Reaction is with an organic solvent carried out as methylene dichloride aptly.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XV compound can be prepared as follows: make formula XX compound
R wherein
3As defined above, X is a halogeno-group, and L is C
1-C
8-alkyl or benzyl are with R wherein
2Formula VII compound reaction as defined above perhaps is similar to the described preparation of this paper embodiment.Reaction is aptly with an organic solvent as tetrahydrofuran (THF), preferably carry out in inert atmosphere such as argon.The temperature of reaction that is fit to is 30 ℃ to 70 ℃, preferred 40 ℃ to 60 ℃, and especially about 50 ℃.
Formula XVI compound can be prepared as follows: make formula XXI compound
R wherein
2As defined above, L ' is C
1-C
8-alkyl or benzyl, but preferable methyl are with formula III or the reaction of IIIa compound, wherein R
1As defined above, X is a leavings group, preferred halogeno-group, and K is hydrogen or C
1-C
8-alkyl perhaps is similar to the described preparation of this paper embodiment.Reaction is aptly with an organic solvent as tetrahydrofuran (THF), preferably carry out in the presence of alkali such as diisopropylethylamine.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XVII compound is commercially available to be got or can prepare the technology of this compounds or be similar to the described acquisition of this paper embodiment by becoming known for.
Formula XVIII compound can be prepared as follows: preferably catalyzer as the catalyzer that derives from four (triphenyl phosphine) palladiums and triphenyl phosphine in the presence of, make formula XXII compound
R wherein
2And R
3As defined above, L " be C
1-C
8-alkyl, preferable methyl or ethyl, with the reaction of formula XXIII compound,
Wherein each L is C
1-C
8-alkyl or benzyl, preferred benzyl perhaps is similar to the described preparation of this paper embodiment.Preferably, each L is the tertiary butyl or benzyl.Reaction is aptly in inert environments such as argon, with an organic solvent carry out as the deoxidation tetrahydrofuran (THF).The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XIX compound can be prepared as follows: make formula XXIV compound
R wherein
3With X as defined above, each L is C
1-C
8-alkyl or benzyl are with hydroxylating agent such as perosmic anhydride (OsO
4) with the reaction of stoichiometric quantity or catalytic amount, preferably with reoxidize agent such as N-methylmorpholine N-oxide compound (NMO) reacts, perhaps select as an alternative to use AD-mix-α or AD-mix-β, perhaps be similar to the described preparation of this paper embodiment.Each L is the tertiary butyl preferably.Reaction is with an organic solvent carried out as tetrahydrofuran (THF) aptly.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XX compound can be prepared as follows: preferably catalyzer as the catalyzer that derives from four (triphenyl phosphine) palladiums and triphenyl phosphine in the presence of, make formula XXV compound
R wherein
3As defined above, L " be C
1-C
8-alkyl, with the reaction of formula XXVa compound,
R wherein
1As defined above, L is C
1-C
8-alkyl or benzyl perhaps are similar to the described preparation of this paper embodiment.Preferably, L is the tertiary butyl or benzyl.Reaction is aptly in inert environments such as argon, with an organic solvent carry out as the deoxidation tetrahydrofuran (THF).The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XXI compound can be prepared as follows: utilize the technology that becomes known for the cracking ester bond, make formula XXVI compound
R wherein
2As defined above, each L is C
1-C
8-alkyl or benzyl, L ' are C
1-C
4-alkyl reacts with strong acid such as spirit of salt, perhaps is similar to the described preparation of this paper embodiment.Preferably, each L is the tertiary butyl or benzyl, L
aBe methyl or ethyl.Reaction is aptly in inert environments such as argon, with an organic solvent carry out as diox.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XXII compound can be prepared as follows: in the presence of alkali such as Diisopropylamine and catalyzer such as 4-Dimethylamino pyridine (DMAP), make formula XXVII compound
R wherein
2And R
3As defined above, with acylating agent such as carboxylic acid C
1-C
8-alkyl ester, for example 3-oxygen base-benzotriazole-1-formic acid ethyl ester reaction perhaps are similar to the described preparation of this paper embodiment.Reaction is aptly in inert environments such as argon, with an organic solvent carry out as deoxidation THF.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XXIII compound is commercially available to be got or can prepare the technology of this compounds or be similar to the described acquisition of this paper embodiment by becoming known for.
Formula XXIV compound can be prepared as follows: preferably catalyzer as the catalyzer that derives from four (triphenyl phosphine) palladiums and triphenyl phosphine in the presence of, make formula XXVIII compound
R wherein
3With X as defined above, L " be C
1-C
8-alkyl, with each L wherein be C
1-C
8The formula XXIII compound reaction of-alkyl or benzyl perhaps is similar to the described preparation of this paper embodiment.Preferably, each L is the tertiary butyl or benzyl.Reaction is aptly in inert environments such as argon, with an organic solvent carry out as the deoxidation tetrahydrofuran (THF).The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XXV compound can be prepared as follows: in the presence of alkali such as Diisopropylamine and catalyzer such as 4-Dimethylamino pyridine (DMAP), make formula XXIX compound
R wherein
3With X as defined above, with acylating agent such as carboxylic acid C
1-C
8-alkyl ester, for example 3-oxygen base-benzotriazole-1-formic acid ethyl ester reaction perhaps are similar to the described preparation of this paper embodiment.Reaction is aptly in inert environments such as argon, with an organic solvent carry out as the deoxidation tetrahydrofuran (THF).The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XXVa compound is commercially available get or can by the technology that becomes known for preparing this compounds for example people such as Ken-ichi Takana in Chem.Pharm.Bull.1988,36,3125 described technologies or be similar to the described acquisition of this paper embodiment.
Formula XXVI compound can be prepared as follows: make formula XXX compound
R wherein
2As defined above, each L is C
1-C
8-alkyl, L ' are C
1-C
4-alkyl or benzyl, preferred benzyl are with hydroxylating agent such as perosmic anhydride (OsO
4) with the reaction of stoichiometric quantity or catalytic amount, preferably with reoxidize agent such as N-methylmorpholine N-oxide compound (NMO) reacts, perhaps select as an alternative to use AD-mix-α or AD-mix-β, perhaps be similar to the described preparation of this paper embodiment.Preferably, each L is the tertiary butyl, L
aBe methyl or ethyl.Reaction is with an organic solvent carried out as tetrahydrofuran (THF) aptly.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XXVII compound can be prepared as follows: make formula XXXI compound
R wherein
2And R
3As defined above, with (1S, 4R)-cis-4-acetoxyl group-2-cyclopentenes-1-alcohol alkali such as sodium hydride and catalyzer as the catalyzer that derives from four (triphenyl phosphine) palladiums and triphenyl phosphine in the presence of reaction, perhaps be similar to the described preparation of this paper embodiment.Reaction is aptly in inert environments such as argon, with an organic solvent carry out as deoxidation tetrahydrofuran (THF) or dimethyl sulfoxide (DMSO) (DMSO).The temperature of reaction that is fit to is 40 ℃ to 60 ℃, preferred about 50 ℃.
Formula XXVIII compound can be prepared as follows: in the presence of alkali such as Diisopropylamine and catalyzer such as 4-Dimethylamino pyridine (DMAP), make wherein R
3With X formula XXIX compound and acylating agent such as carboxylic acid C as defined above
1-C
8-alkyl ester, for example 3-oxygen base-benzotriazole-1-formic acid ethyl ester reaction perhaps are similar to the described preparation of this paper embodiment.Reaction is aptly in inert environments such as argon, with an organic solvent carry out as THF.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XXIX compound can be prepared as follows: make formula XXXII compound
R wherein
3With X as defined above, with (1S, 4R)-cis-4-acetoxyl group-2-cyclopentenes-1-alcohol alkali such as sodium hydride and catalyzer as the catalyzer that derives from four (triphenyl phosphine) palladiums and triphenyl phosphine in the presence of reaction, perhaps be similar to the described preparation of this paper embodiment.Reaction is aptly in inert environments such as argon, with an organic solvent carry out as deoxidation tetrahydrofuran (THF) or dimethyl sulfoxide (DMSO) (DMSO).The temperature of reaction that is fit to is 40 ℃ to 60 ℃, preferred about 50 ℃.
Formula XXX compound can be prepared as follows: make formula XXXIII compound
R wherein
2As defined above, L " be C
1-C
8-alkyl or benzyl, L ' are C
1-C
4Alkyl, with each L wherein be C
1-C
8The reaction of the formula XXIII compound of-alkyl is preferably reacted in the presence of as the catalyzer that derives from four (triphenyl phosphine) palladiums and triphenyl phosphine at catalyzer, perhaps is similar to the described preparation of this paper embodiment.Preferably, each L " be the tertiary butyl or benzyl, L ' is methyl or ethyl.Reaction is aptly in inert environments such as argon, with an organic solvent carry out as the deoxidation tetrahydrofuran (THF).The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XXXI compound can be prepared as follows: make wherein R
3As defined above, X is the formula XXXII compound of halogeno-group and R wherein
2Formula VII compound reaction as defined above perhaps is similar to the described preparation of this paper embodiment.Reaction is aptly in inert environments such as argon, with an organic solvent carry out as tetrahydrofuran (THF).The temperature of reaction that is fit to is 40 ℃ to 60 ℃, preferred about 50 ℃.
Formula XXXII compound is commercially available to be got or can prepare the technology of this compounds or be similar to the described acquisition of this paper embodiment by becoming known for.
Formula XXXIII compound can be prepared as follows: make formula XXXIV compound
R wherein
2And L ' is as defined above, with the reaction of formula XXXV compound,
L wherein " be C
1-C
8-alkyl, preferable methyl or ethyl, X are halogeno-groups, preferred chlorine perhaps is similar to the described preparation of this paper embodiment.Reaction aptly in inert environments such as argon, with an organic solvent as the deoxidation tetrahydrofuran (THF), preferably in the presence of alkali such as pyridine, carry out.The temperature of reaction that is fit to is 0 ℃ to 40 ℃, preferred room temperature.
Formula XXXIV compound can be prepared as follows: make formula XXXVI compound
R wherein
2As defined above, L ' is C
1-C
4Alkyl, preferable methyl or ethyl, with (1S, 4R)-cis-4-acetoxyl group-2-cyclopentenes-1-alcohol alkali such as sodium hydride and catalyzer as the catalyzer that derives from four (triphenyl phosphine) palladiums and triphenyl phosphine in the presence of reaction, perhaps be similar to the described preparation of this paper embodiment.Reaction is aptly in inert environments such as argon, with an organic solvent carry out as deoxidation tetrahydrofuran (THF) or dimethyl sulfoxide (DMSO).The temperature of reaction that is fit to is 60 ℃ to 100 ℃, preferred about 80 ℃.
Formula XXXV compound is commercially available to be got or can prepare the technology of this compounds or be similar to the described acquisition of this paper embodiment by becoming known for.
Formula XXXVI compound can be prepared as follows: make wherein R
3As defined above, L is C
1-C
8The formula XXXVI salt compound of-alkyl and silane-based agent perhaps are similar to the described preparation of this paper embodiment as (N, two (trimethyl silyl) ethanamides of O-) reaction.Reaction is aptly in inert environments such as argon, with an organic solvent carry out as anhydrous chloroform.The temperature of reaction that is fit to is 60 ℃ to 100 ℃, preferred about 80 ℃.The silylation intermediate that is generated is handled with methyl alcohol, obtained free alkali.
In a usual manner, the free form of formula I compound can be converted into salt form, and vice versa.Free or the salt form of compound can or contain the solvate forms that is useful on the crystalline solvent with hydrate and obtain.Formula I compound can reclaim also purifying in a usual manner from reaction mixture.Isomer, for example steric isomer can obtain in a usual manner, for example fractional crystallization or from raw material asymmetric synthesis corresponding asymmetric replacement, for example optically active.
Formula I compound and their pharmacy acceptable salt useful as drug.Definite, they activate adenosine A
2AAcceptor, promptly they serve as A
2AReceptor stimulant.They are as A
2AThe character of agonist can be utilized people such as L.J.Murphree, Molecular Pharmacology 61, and the described method of 455-462 (2002) is proved.
Hereinafter the embodiment compound has the K that is lower than 1.0 μ M in the said determination method
iValue.For example, embodiment 1,2,4,6,12,14,20,33,38,39,42,47,55 and 61 compounds have the K of 0.582,0.018,0.057,0.008,0.003,0.690,0.008,0.052,0.002,0.003,0.002,0.002,0.004 and 0.009 μ M respectively
iValue.
In view of they to adenosine A
2AThe activation of acceptor, hereinafter is called " promoting agent of the present invention " in addition at the free or pharmacy acceptable salt form of formula I compound, can be used for treatment in response to adenosine A
2AThe illness of receptor activation, particularly inflammatory or allergic conditions.According to treatment of the present invention can be that suit the medicine to the illness or preventative.
Therefore, promoting agent of the present invention can be used for treating inflammatory or obstructive airway diseases, causes for example tissue injury, airway inflammation, bronchial hyperreactivity, reproduces or the alleviating of progression of disease.Inflammatory that the present invention is suitable for or obstructive airway diseases and illness comprise acute lung injury (ALI), adult/adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary, air flue or lung disease (COPD, COAD or COLD), comprise chronic bronchitis or relevant with it expiratory dyspnea, pulmonary emphysema, and the deterioration of the airway hyperreactivity after other drug therapy, particularly other imbedibility pharmacotherapys.The present invention also can be used for treating the bronchitis of which kind of type no matter or origin, for example comprises acute, Semen arachidis hypogaeae imbedibility, Catarrhal, croup, chronic or phthinoid bronchitis.Other inflammatories that the present invention is suitable for or obstructive airway diseases comprise that the pneumoconiosis of which kind of type no matter or origin (inflammatory, is generally occupational lung disease, often with obstruction of the air passage, chronic or acutely all can, cause by sucking dust repeatedly), for example comprise aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, arc-welder's disease, silicosis, tabacism (tobacosis) and byssinosis.
Other inflammatories that the present invention is suitable for or obstructive airway diseases comprise the asthma of which kind of type no matter or origin, comprise endogenous (anallergic) asthma and exogenous (allergy) asthma, slight asthma, moderate bronchial asthma, serious asthma, segmental bronchus inflammatory asthma, temper the asthma of bringing out behind (exercise-induced) asthma, occupational asthma and the infectation of bacteria that brings out.Treatment of asthma for example also is understood that to contain 4 or the treatment of curee below 5 years old, show the symptom of stridulating, diagnosed or diagnosable for " asthma child (wheezy infant) ", this is the patient who obtains confirming of a class medical circle common concern, often is accredited as initial stage or early stage asthma now.(for for simplicity, this specific asthma situation is called as " asthma child's syndrome ".)
Preventive effect in the treating asthma will reduce by the frequency or the seriousness of paresthesia epilepsy, for example acute asthma or bronchoconstriction outbreak, pulmonary function improves or the airway hyper-reaction property improvement proves.Can also be further obtain proof, i.e. the therapy that when paresthesia epilepsy, is used for or attempts to limit or end, for example (for example reflunomide) of anti-inflammatory or bronchiectasis by the needs that reduce other symptomatiatrias.Prevention beneficial effect in the asthma is obvious especially in the curee that " the daystart pulmonary function descends (morning dipping) " tendency is arranged." decline of daystart pulmonary function " is a kind of generally acknowledged asthma syndrome, and most of common by asthmatic patient is being feature away from the asthma attack of the time of asthma therapies to the ill that was given any before usually promptly between 4 o'clock to 6 o'clock in the morning for example.
In view of their anti-inflammatory activity, particularly relate to eosinophilic granulocyte activatory restraining effect, promoting agent of the present invention also can be used for treating eosinophilic granulocyte dependency illness, eosinophilia for example, the eosinophilic granulocyte dependency illness of air flue (the ill eosinophilic granulocyte that for example involves lung tissue soaks into) particularly, comprise that eosinophilic granulocyte is too much, because it influences air flue and/or lung, and for example be secondary to or occur together in the eosinophilic granulocyte dependency illness of the air flue of loeffler syndrome, the eosinophilic granulocyte pneumonia, parasite (particularly metazoan) is infected (comprising tropical eosinophilia), bronchopneumonic aspergillosis, polyarteritis nodosa (comprising Churg-Strauss syndrome), eosinophilic granuloma and the eosinophilic granulocyte dependency illness that influences air flue that causes by medicine-reaction.
Promoting agent of the present invention also can be used for treating the inflammatory or the allergic conditions of skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, hickie, allergic angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, and other skin inflammatory or allergic conditions.
Promoting agent of the present invention also can be used for the treatment of other diseases or illness, particularly has the disease or the illness of inflammatory factor, for example treats the disease and the illness of eyes, for example conjunctivitis, keratoconjunctivitis sicca and spring conjunctivitis; Influence the disease of nose, comprise rhinallergosis; Wherein involve the inflammatory diseases that autoimmune response is arranged or have the autoimmunization factor or the cause of disease, comprise autoimmunity hematology illness (hemolytic anemia for example, aplastic anemia, pure red-cell anemia and spontaneous thrombopenia), systemic lupus erythematous, polychondritis, scleroderma, wegner's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, spontaneous sprue, autoimmunization inflammatory bowel disease (for example ulcerative colitis and regional ileitis), endocrine ophthalmopathy, the Ge Leifushi disease, sarcoidosis, alveolitis, the chronic anaphylaxis pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (behind before the room and the room), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with do not have nephrotic syndrome, for example comprise spontaneous nephrotic syndrome or MCN).
Can comprise diabetes with the other diseases or the illness of promoting agent treatment of the present invention, for example type i diabetes (juvenile onset diabetes) and type ii diabetes, the retinopathy of diarrhoea property disease, ischemia/reperfusion injury, retinopathy such as diabetic retinopathy or hyperbaric oxygen-bring out, raise or the aqueous humor secretion is the illness such as the glaucoma of feature with intraocular pressure, from dabbling ischemic tissue/organ damage again, and bedsore.
The validity of promoting agent of the present invention in suppressing inflammatory conditions, for example airway inflammatory disease can be proved in the animal model of airway inflammation or other inflammatory conditions, for example mouse or rat model, people such as Szarka for example, J.Immunol. Methods (1997) 202:49-57; People such as Renzi, Am.Rev.Respir.Dis. (1993) 148:932-939; People such as Tsuyuki, J.Clin.Invest. (1995) 96:2924-2931; People such as Cernadas, people (2002) European Journal of Pharmacological 438 such as (1999) Am.J.Respir.Cell Mol.Biol.20:1-8 and Fozard, 183-188 is described.
Promoting agent of the present invention also can be used as auxiliary therapeutical agent, be used for uniting use with the other drug material, for example anti-inflammatory, bronchiectasis, antihistamine or cough suppressing medicine material, particularly in the treatment of obstructive or airway inflammatory disease, for example mentioned above those, for example as the active reinforcer of this class pharmacological agent or as the required dosage that reduces this class medicine or the means of potential side effect.Promoting agent of the present invention can be blended in the fixed pharmaceutical composition with the other drug material, and perhaps it can separate with the other drug material, before, use simultaneously or afterwards.
Therefore, the present invention includes the combination of the invention described above promoting agent and anti-inflammatory, bronchiectasis, antihistamine or cough suppressing medicine material, described promoting agent of the present invention and described drug substance are in the identical or different pharmaceutical composition.
The antiphlogiston that is fit to comprises steroid, glucocorticosteroid particularly, budesonide for example, beclomethasone dipropionate, Fluticasone Propionate, ring shrinkage porosite or furancarboxylic acid Mo Meitasong, the described steroid of perhaps following document: WO 02/88167, WO 02/12266, WO 02/100879, (especially embodiment 3 for WO 02/00679,11,14,17,19,26,34,37,39,51,60,67,72,73,90, those of 99 and 101), WO 03/35668, WO 03/48181, WO 03/62259, WO03/64445, WO 03/72592, WO 04/39827 and WO 04/66920; The non-steroidal glucocoricoid receptor agonist, for example following document described those: DE 10261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03/82787, WO 03/86294, WO 03/104195, WO 03/101932, WO 04/05229, WO 04/18429, WO 04/19935 and WO04/26248; The LTB4 antagonist, for example BIIL 284, CP-195543, DPC11870, LTB4 glycollic amide, LY 293111, LY 255283, CGS025019C, CP-195543, ONO-4057, SB 209247, SC-53228 and US 5451700 described those; LTD4 antagonist, as comprise Singulair, pranlukast, Zafirlukast, Accolate, SR2640, Wy-48,252, ICI 198615, MK-571, LY-171883, Ro 24-5913 and L-648051; PDE4 inhibitor, for example cilomilast (Ariflo
GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID (TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (KyowaHakko Kogyo) and be disclosed in the following document those: WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/104204, WO 03/104205, WO 03/39544, WO 04/000814, WO04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/018431, WO 04/018449, WO 04/018450, WO04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607 and WO 04/037805; Adenosine A
2BReceptor antagonist, for example WO 02/42298 described those; And β-2 adrenoreceptor agonists, for example Aerolin (salbutamol), Orciprenaline, terbutaline, Salmeterol, Partusisten, procaterol, especially formoterol, Ka Moteluo (carmoterol) and pharmacy acceptable salt thereof, with the formula I compound of quoting at this WO 00/75114 as a reference (free or salt or solvate forms), preferred embodiment compound, especially following formula: compound
And pharmacy acceptable salt, and the formula I compound of WO 04/16601 (free or salt or solvate forms), also have the compound of following document: EP 1440966, JP 05025045, WO93/18007, WO 99/64035, US 2002/0055651, US 2005/0133417, US2005/5159448, WO 01/42193, WO 01/83462, WO 02/66422, WO 02/70490, WO 02/76933, WO 03/24439, WO 03/42160, WO 03/42164, WO 03/72539, WO 03/91204, WO 03/99764, WO 04/16578, WO 04/22547, WO 04/32921, WO 04/33412, WO 04/37768, WO 04/37773, WO 04/37807, WO 04/39762, WO 04/39766, WO 04/45618, WO 04/46083, WO 04/80964, EP1460064, WO 04/087142, WO 04/089892, EP 01477167, US 2004/0242622, US2004/0229904, WO 04/108675, WO 04/108676, WO 05/033121, WO05/040103, WO 05/044787, WO 05/058867, WO 05/065650, WO 05/066140 and WO 05/07908.
The bronchodilator that is fit to comprises anticholinergic or muscarine antagonist, ipratropium bromide particularly, Oxitropium Bromide, tiotropium (tiotropium) salt and CHF 4226 (Chiesi), and Glycopyrronium Bromide, and following document described those: EP 424021, US 3714357, US 5171744, US2005/171147, US 2005/182091, WO 01/04118, WO 02/00652, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422, WO 04/05285 and WO 05/077361.
The dual anti-inflammatory and the bronchodilator that are fit to comprise dual beta-2 adrenoreceptor agonists/muscarine antagonist, for example are disclosed in the following document those: US 2004/0167167, US2004/0242622, US 2005/182092, WO 04/74246 and WO 04/74812.
The antihistamine drug substances that is fit to comprises cetrizine hcl, paracetamol, clemastine fumarate, promethazine, Loratadine, desloratidine, diphenhydramine, hydrochloric acid Fei Suonading, activastine, astemizole, nitrogen
Si Ting, Ai Basi pyridine, epinastine, mizolastine and terfenadine (tefenadine), and be disclosed among JP 2004107299, WO 03/099807 and the WO04/026841 those.
The useful combination of other of promoting agent of the present invention and antiphlogiston is the combination with chemokine receptor anagonists, CCR-1 for example, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CCR-5 antagonist particularly, Schering-Plough antagonist SC-351125 for example, SCH-55700 and SCH-D, Takeda antagonist such as N-[[4-[[[6,7-dihydro-2-(4-aminomethyl phenyl)-5H-benzo-suberene-8-yl] carbonyl] amino] phenyl]-methyl] tetrahydrochysene-N, N-dimethyl-2H-pyrans-4-ammonium chloride (TAK-770) and the described CCR-5 antagonist of following document: US 6166037 (particularly claim 18 and 19), WO 00/66558 (particularly claim 8), WO 00/66559 (particularly claim 9), WO 04/018425 and WO 04/026873.
According to above-mentioned, the present invention also provides treatment in response to adenosine A
2AThe method of the illness of receptor activation, for example inflammatory or allergic conditions, particularly inflammatory or obstructive airway diseases, this method comprises free form or the pharmacy acceptable salt form of the curee that needs are arranged, particularly human subject being used formula I compound.On the other hand, the invention provides the free form or the pharmacy acceptable salt form of the formula I compound that is used in the medication preparation, this medicine is used for the treatment of in response to adenosine A
2AThe illness of receptor activation, particularly inflammatory or obstructive airway diseases.
Promoting agent of the present invention can be by any suitable administration, and is for example oral, for example tablet or capsular form; Parenteral, for example intravenously; Suck, for example in the treatment of inflammatory or obstructive airway diseases; In the nose, for example in the treatment of rhinallergosis; Local skin is for example in the treatment of atopic dermatitis; Perhaps rectum is for example in the treatment of inflammatory bowel disease.
Advance on the one hand, the present invention also provides pharmaceutical composition, comprises the free form or the pharmacy acceptable salt form of formula I compound, alternatively and pharmaceutically acceptable diluent or carrier.Composition can contain auxiliary therapeutical agent, for example above-mentioned anti-inflammatory, bronchiectasis, antihistamine or antitussive.This based composition can utilize conventional thinner or the known technology of vehicle and galenical field to be prepared.Thereby oral dosage form can comprise tablet and capsule.Local administration preparation can be taked the form of creme, ointment, gel or transdermal delivery system, for example patch.Composition for inhalation can comprise aerosol or other aerosolizable preparation or dry powder formulations.
When composition constitutes aerosol, it preferably contains for example hydro fluoroalkanes (HFA) propelling agent, for example HFA134a or HFA227 or these mixture, and can contain one or more solubility promoters known in the art, ethanol (20 weight % at the most) for example, and/or one or more tensio-active agents, for example oleic acid or sorbitan trioleate, and/or one or more weighting agents, for example lactose.When composition constitutes dry powder formulations; it for example preferably contains particle diameter 10 microns formula I compound at the most; alternatively and the diluent or carrier of required size distribution such as lactose and the compound such as the Magnesium Stearate that help the protection product performance not to be damaged because of moisture.When composition constituted atomization preparation, it preferably contained the formula I compound that for example is dissolved or suspended in the carrier, and described carrier contains water, solubility promoter such as ethanol or propylene glycol and stablizer (it can be a tensio-active agent).
The present invention includes the sucked form of (A) formula I compound, for example aerosol or other aerosolizable compositions or the particulate that can suck, for example micronization form; (B) medicine that can suck comprises the sucked form of formula I compound; (C) medicament production comprises the sucked form of formula I compound and the device that can suck; (D) suction apparatus contains the sucked form of formula I compound.
The dosage that is used to implement formula I compound of the present invention certainly will be different because of the particular disorder of for example being treated, required effect and administering mode.Generally speaking, be suitable for inhalation every day dosage in 0.005 to 10mg rank, and be suitable for oral administration every day dosage in 0.05 to 100mg rank.
The following example is set forth the present invention.
Embodiment
Preferred formula I compound
Comprise shown in the following table 1 those.The method for preparing this compounds is as mentioned below.Form also shows mass spectrum MH
+(ESMS) data.These embodiment are free forms, and except embodiment 1-3,7-11 and the 17-37, they are trifluoroacetates.
Table 1
Further preferred formula I compound is as shown in table 2 below.The method for preparing this compounds is as mentioned below.Form also shows mass spectrum MH
+(ESMS) data.These embodiment compounds are trifluoroacetates, except embodiment 41,48,52 and 53 compounds are that free form and embodiment 44 compounds are the hydrochloride.
Table 2
Further preferred formula I compound is as shown in table 3 below.The method for preparing this compounds is as mentioned below.Form also shows mass spectrum MH
+(ESMS) data.These embodiment compounds are trifluoroacetates, except embodiment 76 compounds are that free form and embodiment 79 compounds are the hydrochloride.
Table 3
The preparation of midbody compound
Used abbreviation is as follows: CDI is 1,1 '-carbonyl dimidazoles, DCM are methylene dichloride, and DIPEA is a diisopropylethylamine, DMAP is the 4-Dimethylamino pyridine, DMF is a dimethyl formamide, and DMSO is a dimethyl sulfoxide (DMSO), and LCMS is a liquid chromatography mass, TEA is a triethylamine, TFA is a trifluoroacetic acid, and THF is a tetrahydrofuran (THF), and TLC is a thin-layer chromatography.
3-oxygen base-benzotriazole-1-formic acid ethyl ester
By Wuts, people such as Peter G M, Organic Letters (2003), 5 (9), the technology of 1483-1485 prepares this compound from I-hydroxybenzotriazole.
1H?nmr(CDCl
3，400MHz)；8.20(d，1H)，8.00(d，1H)，7.75(t，1H)，7.55(t，1H)，4.60(q，2H)，1.55(t，3H)。
2-(1-sec.-propyl-1H-imidazol-4 yl)-ethylamine
By Rahul Jain and Louis A.Cohen Tetrahedron, 1996,52,5363 technology, from 2-sec.-propyl-5-oxo-5,6,7,8-tetrahydrochysene-imidazo [1,5-c] pyridine-2-iodide prepare this compound.
1H?nmr(MeOD，400MHz)；7.60(s，1H)，6.95(s，1H)，4.40(m，1H)，2.90(t，2H)，2.70(t，2H)，1.45(d，6H)。
Propionyl-carboxylamine tertiary butyl ester
Utilize people such as Ken-ichi Takana in Chein.Pharm.Bull.1988,36,3125 described technologies prepare title compound from propyl group-carboxylamine tertiary butyl ester.
1H?nmr(CDCl
3，400MHz)；725(br?s，1H)，2.75(q，2H)，1.50(s，9H)，1.15(t，3H)。
Two-(4-methoxyl group-phenyl)-ketoxime
With 4,4 '-(25g 103mmol) is suspended in ethanol (150ml) and the pyridine (30ml) the dimethoxy benzophenone.(21.50g 310mmol), makes reaction mixture refluxed to add oxammonium hydrochloride.The TLC demonstration reacts completely after 3 hours.Make the reaction mixture cooling, remove in a vacuum and desolvate.Resistates is distributed between ethyl acetate (500ml) and water (500ml).With organic layer through MgSO
4Drying is filtered, and removes in a vacuum and desolvates.From ethyl acetate/hexanaphthene, after the crystallization, obtain title compound.
1H?nmr(CDCl
3，400MHz)；7.70(s，1H)，7.40(dd，4H)，6.95(0，2H)，6.85(d，2H)，3.85(s，3H)，3.80(s，3H)。
C, C-pair-(4-methoxyl group-phenyl)-methylamine
Will be two-(20g 77.82mmol) is suspended in ammonia .880 (450ml) and the ethanol (90ml) (4-methoxyl group-phenyl)-ketoxime.Add ammonium acetate (3.00g, 38.91mmol), succeeded by by part add a zinc powder (25.29g, 389.10mmol).In case add fully, reaction mixture slowly be heated to 50 ℃.After effervesce stops, making reaction mixture refluxed.The TLC demonstration reacts completely after 4 hours.Make the reaction mixture cooling, add ethyl acetate (250ml).Reaction mixture by diatomite filtration, is separated each phase.With organic layer through MgSO
4Drying is filtered, and removes in a vacuum and desolvates, and obtains title compound.
1H?nmr(CDCl
3，400MHz)；7.25(d，4H)，6.80(d，4H)，5.10(s，1H)，3.75(s，6H)。
1,3-two (R)-tetramethyleneimine-3-base-urea
(a) 1,3-pair-((R)-1-benzyl-tetramethyleneimine-3-yl)-urea:
With (R)-1-benzyl-tetramethyleneimine-3-base amine (5.0g, DCM 28.4mmol) (10ml) solution with CDI (2.3g 14.2mmol) handles, with reaction mixture stirring at room 48 hours.Remove in a vacuum and desolvate, the gained resistates is dissolved in ethyl acetate.With this part water, succeeded by the salt water washing, dry (MgSO
4), concentrate in a vacuum, obtain title compound, be greenish orange look solid.
(b) 1,3-two (R)-tetramethyleneimine-3-base-urea:
Under the inert atmosphere of argon, to 1,3-pair-((R)-1-benzyl-tetramethyleneimine-3-yl)-urea (5.34g, palladium hydroxide carbon (1.07g) is draped over one's shoulders in the adding of ethanol 14.1mmol) (80ml) solution.Reaction mixture is purified with argon, be placed on nitrogen atmosphere following two days, then mixture is filtered the catalyzer washing with alcohol.Merge organic moiety, concentrate in a vacuum, obtain title compound, be white solid.
Imidazoles-1-formic acid (3,4,5,6-tetrahydrochysene-2H-[1.2 '] dipyridyl-4-yl)-acid amides
Go through the CDI that 30 fens clockwise stirring (1.1g, DCM 6.77mmol) (100ml) solution drips 3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-base amine (WO 99/65895, and EP 21973) (1g, the 50ml DCM solution of 5.64mmol).Reaction mixture stirring at room 15 minutes, is obtained title compound, be the DCM solution of 10mg/ml.In subsequent reaction, use the solution of compound.This solution composition committee: imidazoles-urea intermediate (C) and corresponding isocyanic ester of variable quantity and imidazoles, its under reaction conditions from the reversibly hot cancellation gained of imidazoles.In step subsequently, use this solution, because imidazoles-urea intermediate and isocyanic ester intermediate are suitable as the precursor of urea equally.
1-(2-amino-ethyl)-3-((S)-1-pyridine-2-base-tetramethyleneimine-3-yl)-urea
(a) ((S)-1-pyridine-2-base-tetramethyleneimine-3-yl)-carboxylamine tertiary butyl ester:
With (S)-tetramethyleneimine-3-base-carboxylamine tertiary butyl ester of stirring (2.0g, 10.7mmol), (1.7g, 10.7mmol) (1.1g, DMF 10.7mmol) (40ml) solution is heated to 80 ℃ and reaches 50 hours the 2-bromopyridine with TEA.Remove in a vacuum and desolvate, thick resistates is used ethyl acetate through the silicon-dioxide chromatogram purification: hexane wash-out (being incremented to 1: 4 at 1: 9), obtain title compound, and be white solid.
(b) (S)-1-pyridine-2-base-tetramethyleneimine-3-base amine dihydrochloride:
To ((S)-1-pyridine-2-base-tetramethyleneimine-3-yl)-carboxylamine tertiary butyl ester (0.221g, 0.84mmol) De diox (4ml) adds 4M HCl (dioxane solution with methyl alcohol (1ml) solution) (0.525ml, 2.1mmol), with reaction mixture in stirred overnight at room temperature.The gained suspension is filtered, and the washing of Yong diox (3 * 1ml), obtain title compound.
(c) imidazoles-1-formic acid ((S)-1-pyridine-2-base-tetramethyleneimine-3-yl)-acid amides:
Will ((S)-1-pyridine-2-base-tetramethyleneimine-3-base amine dihydrochloride (0.242g, 1.02mmol), (0.364g 2.26mmol) handles the mixture of TEA (0.2ml) in DCM (10.2ml) with CDI.Reaction mixture stirring at room 2 hours, is obtained title compound, be the DCM solution of 0.1M.This solution composition is: imidazoles-urea intermediate and corresponding isocyanic ester of variable quantity and imidazoles.In step subsequently, use this solution, because imidazoles-urea intermediate and isocyanic ester intermediate are suitable as the precursor of urea equally.
(d) 1-(2-amino-ethyl)-3-((S)-1-pyridine-2-base-tetramethyleneimine-3-yl)-urea:
To imidazoles-1-formic acid ((S)-1-pyridine-2-base-tetramethyleneimine-3-yl)-acid amides (the 0.1M DCM solution of 9.9ml, Virahol 0.99mmol) (1ml) solution add ethyl-1, the 2-diamines (2ml, 37mmol).Stirring at room 4 hours, utilize continuous liquid-liquid extraction system to extract then reaction mixture, obtain title compound with DCM, for 1: 4 molar mixture of imidazoles.
1-(2-amino-ethyl)-3-((R)-1-pyridine-2-base-tetramethyleneimine-3-yl)-urea
Be similar to intermediate D and prepare title compound, replace (S)-tetramethyleneimine-3-base-carboxylamine tertiary butyl ester, replace the 2-bromopyridine with the 2-chloropyridine with (R)-tetramethyleneimine-3-base-carboxylamine tertiary butyl ester.
[(1S, 2R, 3S, 4R)-and 4-(2,6-two chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-propionyl-amino first
The acid tertiary butyl ester
Be similar to 9-[(1R; 2S; 3R; 4S)-4-(tertbutyloxycarbonyl-propionyl-amino)-2; 3-dihydroxyl-cyclopentyl]-6-(2; 2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester (embodiment 38) preparation title compound; with [(1S; 4R)-4-(2; 6-two chloro-purine-9-yl)-ring penta-2-thiazolinyl]-propionyl-carboxylamine tertiary butyl ester replacement 9-[(1R; 4S)-4-(tertbutyloxycarbonyl-propionyl-amino)-ring penta-2-thiazolinyl]-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester.
N-{ (3aR, 4S, 6R, 6aS)-6-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-and purine-9-yl]-2,2-dimethyl-tetrahydrochysene-cyclopenta [1.3] Dioxol-4-yl }-propionyl
Amine
A) (R)-1-[9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-yl]-tetramethyleneimine-3-yl }-the carboxylamine benzyl ester:
With (R)-tetramethyleneimine-3-base-carboxylamine benzyl ester hydrochloride (0.88g, DCM solution 3.45mmol) with sodium hydrogen carbonate solution free-alkalization (free based), obtain (R)-tetramethyleneimine-3-base-carboxylamine benzyl ester (0.487g, 2.22mmol).This amine is joined N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 4) (0.5g, 0.96mmol) and TEA (0.224g, 2.22mmol) in, be dissolved in NMP (7ml) then.At Personal Chemistry Emrys
TMOptimize in the microwave reactor, utilize microwave radiation 190 ℃ of heating 1 hour reaction mixture.The gained mixture is through the silicon-dioxide chromatogram purification, and the DCM eluant solution with 5%MeOH obtains title compound.
B) (R)-1-[9-((3aS, 4R, 6S, 6aR)-2,2-dimethyl-6-propionamido-tetrahydrochysene-cyclopenta [1,3] Dioxol-4-yl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-yl]-tetramethyleneimine-3-yl }-the carboxylamine benzyl ester:
Will (R)-1-[9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-yl]-tetramethyleneimine-3-yl }-carboxylamine benzyl ester (0.63g, acetone 0.89mmol) (10ml) and 2,2-Propanal dimethyl acetal (5ml) solution is handled with toluenesulphonic acids (about 60mg), then in stirred overnight at room temperature.Mixture is alkalized with ammonium hydroxide, remove in a vacuum and desolvate.Crude product is distributed, with organic moiety salt water washing, through MgSO between DCM and water
4Drying is filtered, and removes in a vacuum and desolvates, and obtains title compound.[MH+745].
C) N-{ (3aR, 4S, 6R, 6aS)-6-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,2-dimethyl-tetrahydrochysene-cyclopenta [1,3] Dioxol-4-yl }-propionic acid amide:
Under the inert atmosphere of argon, to (R)-1-[9-((3aS, 4R, 6S, 6aR)-2,2-dimethyl-6-propionamido-tetrahydrochysene-cyclopenta [1,3] Dioxol-4-yl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-yl]-tetramethyleneimine-3-yl }-(0.598g, palladium hydroxide carbon (10mg) is draped over one's shoulders in the adding of ethanol 0.79mmol) (7.5ml) solution to the carboxylamine benzyl ester.Reaction mixture is purified with argon, be placed under the nitrogen atmosphere and spend the night.Mixture is filtered, and through the silicon-dioxide chromatogram purification, the DCM eluant solution with 5%MeOH obtains title compound.[MH+611]。
The preparation of specific embodiment:
Embodiment 1
N-[(1S, 2R, 3S, 4R)-and 4-(6-amino-2-chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl-1-methane-sulphur
The acid amides trifluoroacetate
Two-(4-methoxyl group-phenyl)-methyl]-(2-chloro-9H-purine-6-yl)-amine
Under argon atmospher, with 2, (9.50g 50.29mmol) is dissolved in THF (200ml) to the 6-dichloropurine.Add Diisopropylamine (7.14g, 55.32mmol), succeeded by C, C-is two-(4-methoxyl group-phenyl)-methylamine (referring to the preparation of intermediate) (12.22g, 50.29mmol), with reaction mixture 50 ℃ of stirrings.The LCMS demonstration reacts completely after 5 days.Remove in a vacuum and desolvate, replace with MeOH (250ml).Leach the gained precipitation, drying obtains title compound.
1H?nmr(d
6-DMSO，400MHz)；8.20(br?s，1H)，7.25(d，4H)，6.90(d，4H)，3.75(s，6H)，3.15(m，1H)，MS(ES+)m/e?396(MK
+)。
(1S, 4R)-4-(6-{[pair-(4-methoxyl group-phenyl)-methyl]-amino }-2-chloro-purine-9-yl)-ring penta-2-alkene
Alcohol
With two-(4-methoxyl group-phenyl)-methyl]-(13g 32.87mmol) is placed under the argon atmospher through in the flask of oven drying (2-chloro-9H-purine-6-yl)-amine.Add the THF (100ml) and the anhydrous DMSO (2ml) of no water deoxygenation, suspension is cooled off on ice bath.Slowly add then sodium hydride 95% (0.79g, 32.87mmol), with solution stirring at room 30 minutes.Will (1S, 4R)-cis-4-acetoxyl group-2-cyclopentenes-1-alcohol (4.9g, 34.5mmol) and triphenyl phosphine (1.36g 5.17mmol) is placed under the argon atmospher and passes through in the flask of oven drying.Add no water deoxygenation THF (50ml).This solution is joined in the anion solutions via syringe.Add then four (triphenyl phosphine) palladium (0) (2g, 1.73mmol), with mixture 50 ℃ of stirrings.The LCMS demonstration reacts completely after 2 hours.Make the reaction mixture cooling, remove in a vacuum and desolvate.Resistates is dissolved in methyl alcohol (50ml), leaches the gained precipitation, drying obtains title compound.
1H?nmr(CDCl
3，400MHz)；9.10(m，1H)，8.10(m，1H)，7.30(d，4H)，6.90(d，4H)，6.55(d，1H)，6.20(m，1H)，5.95(m，1H)，5.40(m，1H)，5.30(d，1H)，4.70(m，1H)，3.70(s，6H)，2.90(m，1H)，1.70(m，1H)，MS(ES+)m/e?478(MH
+)。
Carbonic acid (1S, 4R)-4-(6-{[pair-(4-methoxyl group-phenyl)-methyl]-amino }-2-chloro-purine-9-yl)-ring penta
-2-alkenyl esters ethyl ester
Will (1S, 4R)-4-(6-{[pair-(4-methoxyl group-phenyl)-methyl]-amino }-2-chloro-purine-9-yl)-(8.00g 16.75mmol) is placed under the argon atmospher through in the flask of oven drying ring penta-2-enol.Add anhydrous pyridine (80ml), succeeded by Diisopropylamine (16ml).Add the DMAP of catalytic amount, succeeded by 3-oxygen base-benzotriazole-1-formic acid ethyl ester (6.94g, 33.50mmol is referring to the preparation of intermediate).With reaction mixture in stirring at room.The TLC demonstration reacts completely after 18 hours.Remove in a vacuum and desolvate, resistates is distributed between ethyl acetate (500ml) and 2M HCl (200ml).With organic layer water (150ml) and salt solution (150ml) washing, through MgSO
4Drying is filtered, and removes in a vacuum and desolvates.Behind flash column chromatography purifying (silicon-dioxide, methylene chloride 50: 1), obtain title compound.
1H?nmr(CDCl
3，400MHz)；7.80(s，1H)，7.25(dd，4H)，6.85(dd，4H)，6.65(m，1H)，6.50(m，1H)，6.35(m，1H)，6.15(m，1H)，5.65(m，2H)，4.25(q，2H)，3.80(s，6H)，3.10(m，1H)，1.95(m，1H)，1.35(t，3H)。
[two-(4-methoxyl group-phenyl)-methyl]-2-chloro-9-[(1R, 4S)-4-(two-Boc-amino)-ring penta-2-alkene
Base]-9H-purine-6-yl }-amine
With carbonic acid (1S, 4R)-4-(6-{[pair-(4-methoxyl group-phenyl)-methyl]-amino }-2-chloro-purine-9-yl)-ring penta-2-alkenyl esters ethyl ester (2.00g, 3.64mmol), iminodiformic acid di-t-butyl ester (0.87g, 4.00mmol) and triphenyl phosphine (0.14g 0.55mmol) is placed under the argon atmospher through in the flask of oven drying.Add no water deoxygenation THF (20ml), succeeded by four (triphenyl phosphine) palladium (0) (0.21g, 0.18mmol), with mixture in stirring at room.The LCMS demonstration reacts completely after 3 hours.Remove in a vacuum and desolvate, behind flash column chromatography purifying (silicon-dioxide, isohexane/ethyl acetate 4: 1), obtain title compound.
1H?nmr(CDCl
3，400MHz)；8.20(s，1H)，7.25(d，4H)，6.85(d，4H)，6.60(m，1H)，6.35(m，1H)，6.10(m，1H)，5.80(m，1H)，5.65(m，1H)，5.35(m，1H)，3.80(s，6H)，3.15(m，1H)，2.10(m，1H)，1.55(s，18H)。
(1R, 2S, 3R, 5S)-3-(6-{[pair-(4-methoxyl group-phenyl)-methyl]-amino }-2-chloro-purine-9-yl)-5-(two
-Boc-amino)-and pentamethylene-1, the 2-glycol
With [two-(4-methoxyl group-phenyl)-methyl]-2-chloro-9-[(1R, 4S)-4-(two-Boc-amino)-ring penta-2-thiazolinyl]-9H-purine-6-yl-(0.75g 1.11mmol) is dissolved in THF (15ml) to amine.Add N-methylmorpholine N-oxide compound (0.26g, 2.22mmol), succeeded by perosmic anhydride (1.5ml, 4% aqueous solution).With reaction mixture in stirring at room.The LCMS demonstration reacts completely after 18 hours.Remove in a vacuum and desolvate, behind flash column chromatography purifying (silicon-dioxide, methylene chloride 50: 1), obtain title compound.
1H?nmr(CDCl
3，400MHz)；7.75(s，1H)，7.25(m，4H)，6.85(m，4H)，6.60(m，2H)，5.70(m，1H)，4.70(m，2H)，4.60(m，1H)，4.45(m，1H)，3.80(s，6H)，3.70(m，1H)，3.40(m，1H)，3.25(m，1H)，2.65(m，1H)，2.50(m，1H)，1.55(s，18H)。
(1S, 2R, 3S, 5R)-and 3-amino-5-(6-amino-2-chloro-purine-9-yl)-pentamethylene-1,2-glycol trifluoroacetic acid
Salt
Will (1R, 2S, 3R, 5S)-3-(6-{[pair-(4-methoxyl group-phenyl)-methyl]-amino }-2-chloro-purine-9-yl)-5-(two-Boc-amino)-pentamethylene-1, (600mg 0.84mmol) is dissolved in methylene dichloride (4ml) to the 2-glycol.Add TFA (2ml), with reaction mixture in stirring at room.The LCMS demonstration reacts completely after 18 hours.Remove in a vacuum and desolvate, through reversed-phase column chromatography purifying (Isolute
TMBehind the C18,0-100% acetonitrile solution-0.1%TFA), obtain title compound.
1H?nmr(MeOD，400MHz)；8.10(s，1H)，4.80(m，1H)，4.60(m，1H)，4.30(m，1H)，3.60(m，1H)，2.85(m，1H)，2.30(m，1H)。MS(ES+)m/e?285(MH
+)。
N-[(1S, 2R, 3S, 4R)-and 4-(6-amino-2-chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-methane-sulphonyl
The amine trifluoroacetate
Will (1S, 2R, 3S, 5R)-and 3-amino-5-(6-amino-2-chloro-purine-9-yl)-pentamethylene-1,2-glycol trifluoroacetate (20mg, 39 μ mol) and diisopropylethylamine (25mg, 190 μ mol) are placed in the flask that contains anhydrous THF (1ml).Add methylsulfonyl chloride (4.5mg, 39 μ mol), with reaction mixture in stirring at room.The LCMS demonstration reacts completely after 3 hours.Remove in a vacuum and desolvate, through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1% TFA) after, obtain title compound.MS(ES+)m/e?363(MH
+)。
Embodiment 2
N-[(1S, 2R, 3S, 4R)-and 4-(6-amino-2-styroyl amino-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-
The propionic acid amide trifluoroacetate
N-[(1S, 2R, 3S, 5R)-and 4-(6-amino-2-chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-propionic acid amide three
Fluoroacetate
With (1S, 2R, 3S, 5R)-3-amino-5-(6-amino-2-chloro-purine-9-yl)-pentamethylene-1,2-glycol trifluoroacetate (intermediate of preparation embodiment 1) (20mg, 39 μ mol) and diisopropylethylamine (25mg, 190 μ mol) are placed in the flask that contains anhydrous THF (1ml).Add propionyl chloride (3.6mg, 39 μ mol), with reaction mixture in stirring at room.The LCMS demonstration reacts completely after 3 hours.Remove in a vacuum and desolvate, obtain title compound, can pass through reversed-phase column chromatography purifying (Isolute
TMC18, the 0-100% acetonitrile solution-0.1%TFA).
1H?nmr(MeOD，400MHz)；8.10(s，1H)，4.75(m，1H)，4.60(m，1H)，4.20(m，1H)，4.00(m，1H)，3.75(m，1H)，3.25(m，1H)，2.85(m，1H)，2.40(q，2H)，2.10(m，1H)，1.20(t，3H)，MS(ES+)m/e?341(MH
+)。
N-[(1S, 2R, 3S, 4R)-and 4-(6-amino-2-styroyl amino-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-
The propionic acid amide trifluoroacetate
With the N-[(1S that does not have purifying directly to obtain in the back, 2R, 3S, 4R)-4-(6-amino-2-chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-propionic acid amide (10.6mg, 31 μ mol) and styroyl-amine (19mg, 150 μ mol) is placed in the 0.5-2.5ml microwave bottle.Add dichlorobenzene (0.5ml), at PersonalChemistry Emrys
TMOptimize in the microwave reactor reaction mixture in 240 ℃ of microwave treatment.Liquid chromatography-mass spectrography after 1 hour (LCMS) demonstration reacts completely.Remove in a vacuum and desolvate, through reversed-phase column chromatography purifying (Isolute
TMBehind the C18,0-100% acetonitrile solution-0.1%TFA), obtain title compound.
1H?nmr(MeOD，400MHz)；8.05(s，1H)，7.40-715(m，5H)，4.70(m，1H)，4.55(m，1H)，4.10(m，2H)，3.70(m，4H)，3.15(m，1H)，2.95(m，4H)，2.70(m，1H)，2.20(m，2H)，2.00(m，1H)，1.20(t，3H)，MS(ES+)m/e?426(MH
+)。
Embodiment 3
N-[(1S, 2R, 3S, 4R)-and 4-(6-amino-2-oneself-1-alkynyl-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-third
The acid amides trifluoroacetate
With N-[(1S, 2R, 3S, 4R)-and 4-(6-amino-2-chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-propionic acid amide (10.6mg, 31 μ mol), 1-hexin (25.4mg, 310 μ mol), cupric iodide (I) (1.5mg, 7.75 μ mol), two (triphenyl phosphine) palladiums (II) (5.5mg, 7.75 μ mol) of dichloro, triphenyl phosphine (4.0mg, 15.5 μ mol), diethylamine (0.4ml) and DMF (0.2ml) are placed in the 0.5-2.5ml microwave bottle.At Personal Chemistry Emrys
TMOptimize in the microwave reactor reaction mixture in 120 ℃ of microwave treatment.The LCMS demonstration reacts completely after 1 hour.Remove in a vacuum and desolvate, through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1% TFA.) after, obtain title compound.MS(ES+)m/e?387(MH
+)。
Embodiment 4
N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2, the 3-dihydroxyl-
Cyclopentyl }-propionic acid amide
(1S, 4R)-4-(2,6-two chloro-purine-9-yl)-ring penta-2-enol
Under argon atmospher, with 2,6-dichloropurine (10g, 52.90mmol), (1S, 4R)-cis-4-acetoxyl group-2-cyclopentenes-1-alcohol (10g, 70.40mmol), three (dibenzalacetones), two palladiums (0) (3.20g, 3.50mmol) and the triphenyl phosphine (3mmol/g of polymkeric substance carrying, 11.60g, 35.00mmol) be placed on through in the flask of oven drying.Add no water deoxygenation THF (80ml), reaction mixture was stirred 5 minutes gently.Add triethylamine (20ml), with reaction mixture 50 ℃ of stirrings.The LCMS demonstration reacts completely after 1 hour.Make the reaction mixture cooling, filter, remove in a vacuum and desolvate.Behind flash column chromatography purifying (silicon-dioxide, methylene chloride 25: 1), obtain title compound.
1H?nmr(CDCl
3，400MHz)；8.30(s，1H)，6.40(m，1H)，5.90(m，1H)，5.50(m，1H)，4.95(m，1H)，3.05(m，1H)，2.10(m，1H)，MS(ES+)m/e?271(MH
+)。
Carbonic acid (1S, 4R)-4-(2,6-two chloro-purine-9-yl)-ring penta-2-alkenyl esters ethyl ester
Under argon atmospher, will (1S, 4R)-(9.5g 35.05mmol) is placed on through in the flask of oven drying 4-(2,6-two chloro-purine-9-yl)-ring penta-2-enol.Add anhydrous THF (200ml), succeeded by anhydrous pyridine (5.54g, 70.1mmol).Slow adding Vinyl chloroformate (15.21g, 140.2mmol), so that temperature does not rise to more than 40 ℃.With reaction mixture in stirring at room.The LCMS demonstration reacts completely after 1 hour.Remove in a vacuum and desolvate, resistates (is distributed between 200ml and the water (200ml) at methylene dichloride.With organic layer water (150ml) and salt solution (150ml) washing, through MgSO
4Drying is filtered, and removes in a vacuum and desolvates.From methyl alcohol, after the crystallization, obtain title compound.
1Hnmr(CDCl
3，400MHz)；8.20(s，1H)，6.45(m，1H)，6.23(m，1H)，5.75(m，1H)，5.70(m，1H)，4.25(q，2H)，3.20(m，1H)，2.05(m，1H)，1.35(t，3H)，MS(ES+)m/e?343(MH
+)。
Two-Boc-[(1S, 4R)-4-(2,6-two chloro-purine-9-yl)-ring penta-2-thiazolinyl]-amine
Under argon atmospher, with carbonic acid (1S, 4R)-4-(2,6-two chloro-purine-9-yl)-ring penta-2-alkenyl esters ethyl ester (2.5g, 7.29mmol), iminodiformic acid di tert butyl carbonate (1.74g, 8.02mmol), three (dibenzalacetones), two palladiums (0) (0.33g, 0.36mmol) and triphenyl phosphine (0.29g 1.09mmol) is placed on through in the flask of oven drying.Add no water deoxygenation THF (30ml), with reaction mixture in stirring at room.The LCMS demonstration reacts completely after 3 hours.Remove in a vacuum and desolvate, behind flash column chromatography purifying (silicon-dioxide, ethyl acetate/isohexane 4: 1), obtain title compound.
1H?nmr(CDCl
3，400MHz)；8.70(s，1H)，6.20(m，1H)，5.85(m，1H)，5.80(m，1H)，5.40(m，1H)，3.20(m，1H)，2.15(m，1H)，1.55(s，18H)，MS(ES+)m/e?470(MH
+)。
(1S, 2R, 3S, 5R)-and 3-(two-Boc-amino)-5-(2,6-two chloro-purine-9-yl)-pentamethylene-1, the 2-glycol
Utilization is similar to preparation (1R, 2S, 3R, 5S)-3-(6-{[pair-(4-methoxyl group-phenyl)-methyl]-amino }-2-chloro-purine-9-yl)-5-(two-Boc-amino)-pentamethylene-1, the technology of 2-glycol, from two-Boc-[(1S, 4R)-4-(2,6-two chloro-purine-9-yl)-ring penta-2-thiazolinyl]-amine prepares title compound.
1Hnmr(CDCl
3，400MHz)；8.35(s，1H)，4.80(m，1H)，4.70(m，1H)，4.50(m，1H)，3.85(m，1H)，3.75(m，1H)，3.10(m，1H)，2.75(m，1H)，2.55(m，1H)，1.55(s，18H)，MS(ES+)m/e?504(MH
+)。
(1S, 2R, 3S, 5R)-and 3-amino-5-(2,6-two chloro-purine-9-yl)-pentamethylene-1,2-glycol trifluoroacetate
Utilization is similar to preparation (1S among the embodiment 1,2R, 3S, 5R)-3-amino-5-(6-amino-2-chloro-purine-9-yl)-pentamethylene-1, the technology of 2-glycol trifluoroacetate, from (1S, 2R, 3S, 5R)-3-(two-Boc-amino)-5-(2,6-two chloro-purine-59-yl)-and pentamethylene-1, the 2-glycol prepares title compound.MS(ES+)m/e?304(MH
+)。
N-[(1S, 2R, 3S, 4R)-and 4-(2,6-two chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-propionic acid amide
Utilization is similar among the embodiment 2 and prepares N-[(1S, 2R, 3S, 4R)-4-(6-amino-2-chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-technology of propionic acid amide trifluoroacetate, from (1S, 2R, 3S, 5R)-3-amino-5-(2,6-two chloro-purine-9-yl)-and pentamethylene-1,2-glycol trifluoroacetate and propionyl chloride prepare title compound.MS(ES+)m/e?360(MH
+)。
N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2, the 3-dihydroxyl-
Cyclopentyl }-propionic acid amide
Under argon atmospher, with N-[(1S, 2R, 3S, 4R)-and 4-(2,6-two chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-(160mg 0.44mmol) is dissolved in THF (5ml) to propionic acid amide.Add Diisopropylamine (69mg, 0.53mmol), succeeded by 2, the 2-diphenyl-ethylamine (96mg, 0.49mmol), with reaction mixture 50 ℃ of stirrings.The LCMS demonstration reacts completely after 2 hours.Remove in a vacuum and desolvate, through reversed-phase column chromatography purifying (Isolute
TMBehind the C18,0-100% acetonitrile solution-0.1%TFA), obtain title compound.
1H?nmr(MeOD，400MHz)；8.00(s，1H)，7.40-7.15(m，10H)，4.75(m，1H)，4.60(m，1H)，4.50(m，1H)，4.20(m，3H)，3.95(m，1H)，2.85(m，1H)，2.40(q，2H)，2.10(m，1H)，1.20(t，3H)，MS(ES+)m/e?521(MH
+)。
Final embodiment 4 compounds also can utilize following process preparation:
2-chloro-9-[(1R, 4S)-4-(two-Boc-amino)-ring penta-2-thiazolinyl]-9H-purine-6-yl }-(2,
The 2-phenylbenzene-
Ethyl)-amine
Under argon atmospher, will (1S, 2R, 3S, 5R)-and 3-(two-Boc-amino)-5-(2,6-two chloro-purine-9-yl)-pentamethylene-1, (13.0g 27.66mmol) is dissolved in THF (250ml) to the 2-glycol.Add Diisopropylamine (4.28g, 33.19mmol), succeeded by 2, the 2-diphenyl-ethylamine (6.0g, 30.43mmol), with reaction mixture 50 ℃ of stirrings.The LCMS demonstration reacts completely after 18 hours.Remove in a vacuum and desolvate, reaction mixture is distributed between methylene dichloride (250ml) and 0.1M HCl (250ml).With organic layer water (200ml) and salt solution (200ml) washing, through MgSO
4Drying is filtered, and removes in a vacuum and desolvates, and obtains title compound.
1H?nmr(CDCl
3，400MHz)；8.05(s，1H)，7.30-7.10(m，10H)，6.00(m，1H)，5.70(m，2H)，5.60(m，1H)，5.20(m，1H)，4.30(m，1H)，4.20(m，1H)，3.65(m，1H)，3.05(m，1H)，2.00(m，1H)，1.70(m，1H)，1.40(s，18H)，MS(ES+)m/e?631(MH
+)。
(1R, 2S, 3R, 5S)-3-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-5-(two-Boc-ammonia
Base)-and pentamethylene-1, the 2-glycol
Utilization is similar to the technology of preparation example 11, from 2-chloro-9-[(1R, 4S)-4-(two-Boc-amino)-ring penta-2-thiazolinyl]-9H-purine-6-yl }-(2,2-phenylbenzene-ethyl)-amine prepares title compound.
1H?nmr(MeOD，400MHz)；8.05(s，1H)，7.35-7.15(m，10H)，4.70-4.55(m，4H)，4.50(m，1H)，4.35(m，1H)，4.20(m，2H)，2.55(m，1H)，2.45(m，1H)，1.60(s，18H)。
(1S, 2R, 3S, 5R)-3-amino-5-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-pentamethylene
-1,2-glycol trifluoroacetate
Will (1R, 2S, 3R, 5S)-3-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-5-(two-Boc-amino)-pentamethylene-1, (10.3g 15.50mmol) is dissolved in methylene dichloride (50ml) to the 2-glycol.Add TFA (25ml), with reaction mixture in stirring at room.The LCMS demonstration reacts completely after 2 hours.Remove in a vacuum and desolvate, obtain title compound.
1H?nmr(MeOD，400MHz)；7.90(s，1H)，7.30-7.10(m，10H)，4.65(m，1H)，4.50(m，1H)，4.40(m，1H)，4.20(m，1H)，4.10(m，2H)，3.50(m，1H)，2.75(m，1H)，2.15(m，1H)，MS(ES+)m/e?465(MH
+)。
N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2, the 3-dihydroxyl-
Cyclopentyl }-propionic acid amide
With (1S, 2R, 3S, 5R)-3-amino-5-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-pentamethylene-1,2-glycol trifluoroacetate (9.50g, 16.42mmol) and diisopropylethylamine (6.36g 49.27mmol) is placed in the flask that contains anhydrous THF (150ml).Drip propionyl chloride (1.52g, 16.42mmol), with reaction mixture in stirring at room.The LCMS demonstration reacts completely after 1 hour.Remove in a vacuum and desolvate, resistates is distributed between methylene dichloride (250ml) and water (250ml).With organic layer water (200ml) and salt solution (200ml) washing, through MgSO
4Drying is filtered, and removes in a vacuum and desolvates.Make solid from 1, recrystallization in the 2-ethylene dichloride obtains title compound.
1H?nmr(MeOD，400MHz)；8.00(s，1H)，7.40-7.15(m，10H)，4.75(m，1H)，4.60(m，1H)，4.50(m，1H)，4.20(m，3H)，3.95(m，1H)，2.85(m，1H)，2.40(q，2H)，2.10(m，1H)，1.20(t，3H)，MS(ES+)m/e?521(MH
+)。
Embodiment 5
N-{ (1S, 2R, 3S, 4R)-4-[2-(4-amino-cyclohexyl amino)-6-(2,2-phenylbenzene-ethylamino)-purine
-9-yl]-2,3-dihydroxyl-cyclopentyl }-the propionic acid amide trifluoroacetate
Make N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (the final compound of embodiment 4) and hexanaphthene-1, the 4-diamine reactant utilizes the technology that is similar to preparation embodiment 2 compounds.MS(ES+)m/e?599(MH
+)。
Following generation free alkali: with N-{ (1S, 2R, 3S, 4R)-4-[2-(4-amino-cyclohexyl amino)-S-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-(300mg 0.50mmol) is loaded into DOWEX to the propionic acid amide trifluoroacetate
50WX2-200 ion exchange resin (water in advance washing).Wash deresination with water until neutral pH, use methyl alcohol then: ammonia .880 (1: 1) wash-out free alkali.
1H?nmr(MeOD，400MHz)；7.65(s，1H)，7.40-7.20(m，10H)，4.60(m，1H)，4.50(m，2H)，4.20(m，3H)，4.05(m，1H)，3.70(m.1H)，2.70(m，2H)，2.30(q，2H)，2.20(m，2H)，2.00(m，1H)，1.95(m，2H)，1.30(m，4H)，1.20(t，3H)，MS(ES+)m/e?599(MH
+)。
Embodiment 6
N-{ (1S, 2R 3S, 4R)-4-[6-(2,2-phenylbenzene-ethylamino)-2-oneself-1-alkynyl-purine-9-yl]-2,3-
Dihydroxyl-cyclopentyl }-propionic acid amide
Utilization is similar to the technology of preparation embodiment 3 compounds, from N-[(1S, 2R, 3S, 4R)-4-(2,6-two chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-propionic acid amide prepares title compound.
Embodiment 7
N-{ (1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[2-(1H-imidazol-4 yl)-ethyl ammonia
Base]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl }-propionic acid amide
In the technology that is similar to preparation embodiment 5 compounds, use histamine,, 2R, 3S, 4R)-4-(2,6-two chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl from N-[(1S]-propionic acid amide prepares this compound.
Embodiment 8
N-{ (1S, 2R, 3S, 4R)-and 4-[6-(2,2-phenylbenzene-ethylamino)-2-(2-piperidines-1-base-ethylamino)-fast
Purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide
In the technology that is similar to preparation embodiment 5 compounds, use N-(amino-ethyl) piperidines, the preparation title compound.
Embodiment 9
N-((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-methyl isophthalic acid H-imidazol-4 yl)-
Ethylamino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the propionic acid amide trifluoroacetate
With N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 4 compounds) (20mg, 38 μ mol) and 2-(1-methyl isophthalic acid H-imidazol-4 yl)-ethylamine (24mg, 190 μ mol) be placed in the 0.5-2.5ml microwave bottle.Add dichlorobenzene (0.5ml), at Personal Chemistry Emrys
TMOptimize in the microwave reactor, utilize microwave radiation in 200 ℃ of heating reaction mixture.The LCMS demonstration reacts completely after 2 hours.Remove in a vacuum and desolvate, through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1% TFA) after, obtain title compound.
1H?nmr(MeOD，400MHz)；
*.80(s，1H)，8.15(s，1H)，7.40-7.20(m，11H)，4.75(m，2H)，4.50(m，2H)，4.30(m，1H)，4.10(m，2H)，3.85(s，3H)，3.75(m，2H)，3.10(m，3H)，2.70(m，1H)，2.25(q，2H)，1.95(m，1H)，1.30(m，4H)，1.15(t，3H)，MS(ES+)m/e?610(MH
+)。
Embodiment 10
N-((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-ethyl-1H-imidazol-4 yl)-
Ethylamino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide
Utilization is similar to the technology of embodiment 21, from N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 4 compounds) and 2-(1-ethyl-1H-imidazol-4 yl)-ethylamine prepare this compound.MS(ES+)m/e?624(MH
+)。
Embodiment 11
N-((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-sec.-propyl-1H-imidazoles-4-
Base)-ethylamino]-purine-9-yl)-2,3-dihydroxyl-cyclopentyl)-propionic acid amide
Utilization is similar to the technology of embodiment 9 about required salt, from N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 4 compounds) and 2-(1-sec.-propyl-1H-imidazol-4 yl)-ethylamine prepare this compound.MS(ES+)m/e638(MH
+)。
Embodiment 12 and 13
Utilization is similar to prepared the cyclopropane-carboxylic acid { (1S of embodiment 4; 2R, 3S, 4R)-4-[2-chloro-6-(2; 2-phenylbenzene-ethylamino)-and purine-9-yl]-2; 3-dihydroxyl-cyclopentyl }-acid amides and N-{ (1S, 2R, 3S; 4R)-4-[2-chloro-6-(2; 2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-butyramide, wherein replace propionyl chloride with suitable acylating agent.
Embodiment 14
N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-ring penta
Base]-propionic acid amide
[(1S, 4R)-4-(2,6-two chloro-purine-9-yl)-ring penta-2-thiazolinyl]-propionyl-carboxylamine tertiary butyl ester
Utilization is similar to two-Boc-[(1S; 4R)-4-(2; 6-two chloro-purine-9-yl)-ring penta-2-thiazolinyl]-technology of amine (intermediates of another kind of preparation embodiment 4 compounds); from carbonic acid (1S; 4R)-4-(2,6-two chloro-purine-9-yl)-ring penta-2-alkenyl esters ethyl ester (intermediates of preparation embodiment 4 compounds) and propionyl-carboxylamine tertiary butyl ester (referring to the preparation of intermediate) preparation title compound.
1H?nmir(CDCl
3，400MHz)；8.70(s，1H)，6.15(m，1H)，5.85(m，1H)，5.80(m，1H)，5.60(m，1H)，3.15(m，1H)，2.75(q，2H)，2.10(m，1H)，1.55(s，9H)，1.15(t，3H)，MS(ES+)m/e?426(MH
+)。
(1S, 4R)-4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-ring penta-2-thiazolinyl }-propionyl-ammonia
Base formic acid tertiary butyl ester
Under argon atmospher, will [(1S, 4R)-4-(2,6-two chloro-purine-9-yl)-ring penta-2-thiazolinyl]-(700mg 1.64mmol) is dissolved in THF (15ml) to propionyl-carboxylamine tertiary butyl ester.Add 3-amyl group-amine (315mg, 3.61mmol), with reaction mixture 50 ℃ of stirrings.The LCMS demonstration reacts completely after 18 hours.Reaction mixture is distributed between methylene dichloride (50ml) and 0.1M HCl (50ml).With organic layer water (20ml) and salt solution (20ml) washing, through MgSO
4Drying is filtered, and removes in a vacuum and desolvates, and obtains title compound.
1H?nmr(CDCl
3，400MHz)；8.10(s，1H)，6.00(m，1H)，5.70(m，1H)，5.60(m，2H)，5.45(m，1H)，4.20(m，1H)，3.65(m，1H)，3.00(m，1H)，2.65(m，3H)，1.95(m，1H)，1.60(m，3H)，1.45(s，9H)，1.10(m，4H)，0.85(t，6H)，MS(ES+)m/e?477(MH
+)。
(1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-ring penta
Base }-propionyl-carboxylamine tertiary butyl ester
Utilization be similar to (1R, 2S, 3R, 5S)-3-(6-{[is two-(4-methoxyl group-phenyl)-methyl]-amino-2-chloro-purine-9-yl)-5-(two-Boc-amino)-pentamethylene-1, the technology of 2-glycol (referring to embodiment 1).Through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1% TFA), from (1S, 4R)-4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-ring penta-2-thiazolinyl }-propionyl-carboxylamine tertiary butyl ester prepares title compound.
1H?nmr(MeOD，400MHz)；8.10(s，1H)，4.80(m，1H)，4.65(m，1H)，4.35(m，1H)，4.20(m，1H)，2.85(m，2H)，2.60(m，1H)，2.35(m，1H)，1.70(m，2H)，1.65(s，9H)，1.60(m，2H)，1.15(t，3H)，0.95(t，6H)。
N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-ring penta
Base }-propionic acid amide
Will (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-(300mg 0.59mmol) is dissolved in methylene dichloride (5ml) to propionyl-carboxylamine tertiary butyl ester.Add TFA (2ml), with reaction mixture in stirring at room.The LCMS demonstration reacts completely after 1 hour.Remove in a vacuum and desolvate, make resistates at methylene dichloride (50ml) and saturated NaHCO
3Distribute (50ml).With organic layer water (20ml) and salt solution (20ml) washing, through MgSO
4Drying is filtered, and removes in a vacuum and desolvates, and obtains title compound.
1H?nmr(MeOD，400MHz)；8.05(s，1H)，4.75(m，1H)，4.60(m，1H)，4.20(m，2H)，4.00(m，1H)，2.90(m，1H)，2.40(q，2H)，2.10(m，1H)，1.70(m，2H)，1.60(m，2H)，1.20(t，3H)，0.95(t，6H)，MS(ES+)m/e?411(MH
+)。
Embodiment 15
N-{ (1S, 2R, 3S, 4R)-4-[6-(1-ethyl-propyl group amino)-2-oneself-1-alkynyl-purine-9-yl]-2, the 3-dihydroxy
Base-cyclopentyl }-propionic acid amide
Utilization is similar to the technology of embodiment 3, from (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionyl-carboxylamine tertiary butyl ester prepares this compound.
Embodiment 16
N-{ (1S, 2R, 3S, 4R)-4-[6-(2,2-phenylbenzene-ethylamino)-2-((S)-1-methylol-2-phenyl-ethyl
Amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide
N-{ (1S with embodiment 4,2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (46.8mg, 90 μ mol), L-phenylalaninol (alaninol) (271mg, 1.80mmol) and sodium iodide (6.75mg, 45 μ mol) be placed in the 0.5-2.5ml microwave bottle.Add acetonitrile (0.25ml) and NMP (0.25ml), at Personal ChemistryEmrys
TMOptimize in the microwave reactor, utilize microwave radiation in 200 ℃ of heating reaction mixture.The LCMS demonstration reacts completely after 1 hour.Through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1% TFA) after, obtain title compound.MS(ES+)m/e?636(MH
+)。
Embodiment 17
N-{ (1S, 2R, 3S, 4R)-4-[6-(1-ethyl-propyl group amino)-2-(2-piperidines-1-base-ethylamino)-purine
-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide
Utilization is similar to the technology of embodiment 9, makes N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 14 compounds) and 1-(2-amino-ethyl)-piperidines reaction, obtain title compound.MS(ES+)m/e?503(MH
+)。
Embodiment 18
N-{ (1S, 2R, 3S, 4R)-4-[2-[2-(1-ethyl-1H-imidazol-4 yl)-ethylamino]-6-(1-hydroxyl-ring penta
Base }-propionic acid amide
Utilization is similar to the technology of embodiment 9, makes N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl cyclopentyl }-propionic acid amide (embodiment 14 compounds) and 2-(1-ethyl-1H-imidazol-4 yl)-ethylamine reaction, obtain title compound.MS(ES+)m/e?514(MH
+)。
Embodiment 19
N-{ (1S, 2R, 3S, 4R)-4-[2-[2-(1-sec.-propyl ethyl-1H-imidazol-4 yl)-ethylamino]-6-(1-hydroxyl
Base-cyclopentyl }-propionic acid amide
Utilization is similar to the technology of embodiment 9, make N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 14 compounds) and 2-(1-sec.-propyl ethyl-1H-imidazol-4 yl)-ethylamine reaction, obtain title compound.MS(ES+)m/e?528(MH
+)。
Embodiment 20
N-{ (1S, 2R 3S, 4R)-4-[2-(4-amino-cyclohexyl amino)-6-(1-ethyl-propyl group amino)-purine-9-
Base]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide
Utilization is similar to the technology of embodiment 9, makes N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 14 compounds) and anti-form-1, the reaction of 4-diamino-cyclohexane obtains title compound.MS(ES+)m/e?489(MH
+)。
Embodiment 21
N-((1S, 2R, 3S, 4R)-4-{6-amino-2-[2-(1-ethyl-1H-imidazol-4 yl)-ethylamino]-purine-9-
Base]-2,3-dihydroxyl-cyclopentyl }-isobutyramide
N-[(1S, 2R, 3S, 4R)-and 4-(6-amino-2-chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-isobutyramide
Utilization is similar to the technology of embodiment 1, make (1S, 2R, 3S, 5R)-and 3-amino-5-(6-amino-2-chloro-purine-9-yl)-pentamethylene-1,2-glycol trifluoroacetate (intermediate of preparation embodiment 1 compound) and different propionyl chloride reaction obtain title compound.MS(ES+)m/e?355(MH
+)。
N-((1S, 2R, 3S, 4R)-4-{6-amino-2-[2-(1-ethyl-1H-imidazol-4 yl)-ethylamino]-purine-9-
Base }-2,3-dihydroxyl-cyclopentyl)-isobutyramide
Utilization is similar to the technology of embodiment 9, makes N-[(1S, 2R, and 3S, 4R)-and 4-(6-amino-2-chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-isobutyramide and 2-(1-ethyl-1H-imidazol-4 yl)-ethylamine reaction, obtain title compound.MS(ES+)m/e?458(MH
+)。
Embodiment 22
Cyclopropane-carboxylic acid ((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-sec.-propyl-1H-
Imidazol-4 yl)-ethylamino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the acid amides trifluoroacetate
(2-chloro-9H-purine-6-yl)-(2,2-phenylbenzene-ethyl)-amine
Under argon atmospher, with 2, (20.00g 106mmol) is dissolved in THF (250ml) to the 6-dichloropurine.Add Diisopropylamine (16.38g, 127mmol), succeeded by 2, the 2-diphenyl-ethylamine (25.00g, 127mmol), with reaction mixture 50 ℃ of stirrings.The LCMS demonstration reacts completely after 6 hours.Remove 50% solvent in a vacuum, replace with MeOH.Leach the gained precipitation, drying obtains title compound.
1Hnmr(d
6-DMSO，400MHz)；8.05(br?s，1H)，7.35-7.10(m，10H)，4.55(m，1H)，4.10(m，2H)，MS(ES+)m/e?350(MH
+)。
(1S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-ring penta-2-enol
Under argon atmospher, (12.92g 36.97mmol) is placed on through in the flask of oven drying with (2-chloro-9H-purine-6-yl)-(2,2-phenylbenzene-ethyl)-amine.Add no water deoxygenation THF (100ml) and anhydrous DMSO (2ml), suspension is cooled off on ice bath.Slowly add then sodium hydride 95% (0.89g, 36.97mmol), with solution stirring at room 30 minutes.Under argon atmospher, will (1S, 4R)-cis-4-acetoxyl group-2-cyclopentenes-1-alcohol (5.00g, 35.20mmol) and triphenyl phosphine (1.38g 5.28mmol) is placed on and passes through in the flask of oven drying.Add no water deoxygenation THF (50ml).This solution is joined in the anion solutions.Add four (triphenyl phosphine) palladium (0) (2.03g, 1.76mmol), with reaction mixture 50 ℃ of stirrings.The LCMS demonstration reacts completely after 3 hours.Make the reaction mixture cooling, remove in a vacuum and desolvate.Resistates is dissolved in methylene dichloride (50ml), pours in the diethyl ether (300ml) that vigorous stirring.Leach precipitation, get filtrate, remove in a vacuum and desolvate, obtain title compound.
1H?nmr(CDCl
3，400MHz)；7.65(m，1H)，7.35-7.15(m，10H)，6.35(m，1H)，5.90(m，1H)，5.80(m，1H)，5.50(m，1H)，5.25(d，1H)，4.85(t，1H)，4.35(t，1H)，4.25(m，2H)，2.95(m，1H)，2.15(d，1H)，MS(ES+)m/e?432(MH
+)。
Carbonic acid (1S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-ring penta-2-alkenyl esters second
The base ester
Under argon atmospher, will (1S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-(3.00g 6.95mmol) is placed on through in the flask of oven drying ring penta-2-enol.Add anhydrous THF (100ml), succeeded by anhydrous pyridine (1.10g, 13.90mmol).Slowly add Vinyl chloroformate (3.02g, 27.80mmol), with reaction mixture in stirring at room.The TLC demonstration reacts completely after 4 hours.Remove in a vacuum and desolvate, resistates is distributed between methylene dichloride (200ml) and 10% citric acid (200ml).With organic layer water (150ml) and salt solution (150ml) washing, through MgSO
4Drying is filtered, and removes in a vacuum and desolvates.Behind flash column chromatography purifying (silicon-dioxide, isohexane/ethyl acetate 2: 1), obtain title compound.
1H?nmr(CDCl
3，400MHz)；7.70(br?s，1H)，7.35-7.15(m，10H)，6.35(m，1H)，6.15(m，1H)，5.80(m，1H)，5.65(m，2H)，4.35(t，1H)，4.25(m，2H)，4.20(q，2H)，3.10(m，1H)，1.95(d，1H)，1.30(t，3H)，MS(ES+)m/e?504(MH
+)。
9-((1R, 4S)-4-(two-(tertbutyloxycarbonyl))-amino-ring penta-2-thiazolinyl)-2-chloro-9H-purine-6-
Base]-(2,2-phenylbenzene-ethyl)-amine
Under argon atmospher, with carbonic acid (1S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-ring penta-2-alkenyl esters ethyl ester (3.2g, 6.3mmol), iminodiformic acid di tert butyl carbonate (1.5g, 7.0mmol) and triphenyl phosphine (250mg, 0.95mmol) be dissolved in the degassing THF (30ml).(291mg 0.32mmol), heats mixture 1.5 hours at 40 ℃ to add three (dibenzalacetones), two palladiums (0).Reaction mixture is cooled to room temperature, under reduced pressure removes and desolvate.Resistates is through silica gel chromatography, and use ethyl acetate: isohexane (0: 100 volume ratio) gradually becomes ethyl acetate: the gradient system wash-out of isohexane (20: 80 volume ratios) obtains title compound.LCMS (electron spray(ES)): m/z[MH
+] 631.32.
(1S, 2R, 3S, 5R)-3-(two-(tertbutyloxycarbonyl))-amino-5-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-
Purine-9-yl]-pentamethylene-1, the 2-glycol
With 9-((1R, 4S)-4-(two-(tertbutyloxycarbonyl))-amino-ring penta-2-thiazolinyl)-2-chloro-9H-purine-6-yl]-(2,2-phenylbenzene-ethyl)-amine (2.9g, 4.6mmol) THF (60ml) solution with 4-methylmorpholine N-oxide compound (1.1g, 9.3mmol) and perosmic anhydride (4% aqueous solution) (6ml) handle, with mixture stirring at room 48 hours.Under reduced pressure remove and desolvate, resistates is through silica gel chromatography, and use methyl alcohol: methylene dichloride (0: 100 volume ratio) gradually becomes methyl alcohol: the gradient system wash-out of methylene dichloride (4: 96 volume ratios) obtains title compound.LCMS (electron spray(ES)): m/z[MH
+] 665.34.
(1S, 2R, 3S, 5R)-3-amino-5-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-ring
Pentane
-1, the 2-diol hydrochloride
(1S, 2R, 3S, 5R)-3-(two-(tertbutyloxycarbonyl))-amino-5-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-pentamethylene-1,2-glycol (1.9g, 2.9mmol) (4M 1 to be dissolved in hydrogen chloride solution, the 4-dioxane solution) (13ml, 51.2mmol), with mixture stirring at room 1 hour.Under reduced pressure remove and desolvate, resistates is through the reverse-phase chromatography purifying, with acetonitrile (0.1%HCl): water (0.1%HCl) (0: 100 volume ratio) gradually becomes acetonitrile (0.1%HCl): the gradient system wash-out of water (0.1%HCl) (100: 0 volume ratios) obtains title compound.LCMS (electron spray(ES)): m/z[MH
+] 465.20.
Cyclopropane-carboxylic acid (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-
Base]-2,3-dihydroxyl-cyclopentyl }-acid amides
With (1S, 2R, 3S, 5R)-3-amino-5-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-pentamethylene-1,2-diol hydrochloride (200mg, 0.4mmol) anhydrous THF (2.5ml) solution with diisopropylethylamine (0.35ml, 2mmol) and cyclopropanecarbonyl chloride (0.036ml 0.4mmol) handles, with mixture stirring at room 48 hours.Under reduced pressure remove and desolvate, resistates is through the reverse-phase chromatography purifying, with acetonitrile (0.1%TFA): water (0.1%TFA) (0: 100 volume ratio) gradually becomes acetonitrile (0.1%TFA): the gradient system wash-out of water (0.1%TFA) (100: 0 volume ratios) obtains title compound.LCMS (electron spray(ES)): m/z[MH
+] 533.25.
1H?nmr(MeOD，400MHz)；8.00(s，1H)，7.40-7.25(m，8H)，7.25-7.20(m，2H)，4.75(m，1H)，4.60(m，1H)，4.50(m，1H)，4.20(m，2H)，4.00(m，1H)，2.85(m，1H)，2.10(m，1H)，1.85(m，1H)，0.95-0.80(m，4H)。
Cyclopropane-carboxylic acid ((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-sec.-propyl-1H-
Imidazol-4 yl)-ethylamino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the acid amides trifluoroacetate
With cyclopropane-carboxylic acid { (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-acid amides (20mg, 0.04mmol) NMP: acetonitrile (1: 1) (0.5ml) solution with 2-(1-sec.-propyl-1H-imidazol-4 yl)-ethylamine (30mg, 0.2mmol) and sodium iodide (6mg 0.04mmol) handles, at Personal Chemistry Emrys
TMOptimize in the microwave reactor, mixture was heated 30 minutes in 200 ℃.Reaction mixture is through the reverse-phase chromatography purifying, and with acetonitrile (0.1%TFA): water (0.1%TFA) (0: 100 volume ratio) gradually becomes acetonitrile (0.1%TFA): the gradient system wash-out of water (0.1%TFA) (100: 0 volume ratios) obtains title compound.LCMS (electron spray(ES)): m/z[MH
+] 650.22.
Embodiment 23
Cyclobutane formate ((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-sec.-propyl-1H-
Imidazol-4 yl)-ethylamino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the acid amides trifluoroacetate
Cyclobutane formate (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-
Base]-2,3-dihydroxyl-cyclopentyl }-acid amides:
With (1S, 2R, 3S, 5R)-3-amino-5-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-pentamethylene-1,2-diol hydrochloride (intermediate of preparation embodiment 22) (100mg, 0.2mmol) anhydrous THF (1ml) solution with diisopropylethylamine (0.17ml, 1mmol) and the tetramethylene formyl chloride (0.023ml 0.2mmol) handles, with mixture stirring at room 48 hours.Under reduced pressure remove and desolvate.Resistates is through the reverse-phase chromatography purifying, with acetonitrile (0.1%TFA): water (0.1%TFA) (0: 100 volume ratio) gradually becomes acetonitrile (0.1%TFA): the gradient system wash-out of water (0.1%TFA) (100: 0 volume ratios) obtains title compound (51mg).LCMS (electron spray(ES)): m/z[MH
+] 547.26.
1H?nmr(MeOD，400MHz)；8.00(s，1H)，7.40-7.25(m，8H)，7.20-7.15(m，2H)，4.70(m，1H)，4.50(m，2H)，4.20(m，2H)，3.95(m，1H)，2.85(m，1H)，2.30(m，2H)，2.20(m，2H)，2.05(m，2H)，1.90(m，1H)。
Cyclobutane formate ((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-sec.-propyl-1H-
Imidazol-4 yl)-ethylamino]-purine-9-yl]-2,3-dihydroxyl-cyclopentyl)-the acid amides trifluoroacetate
Utilization is similar to the method for preparing embodiment 22 compounds, use cyclobutane formate { (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl cyclopentyl }-acid amides, 2-(1-sec.-propyl-1H-imidazol-4 yl)-ethylamine (referring to the preparation of intermediate) (30mg, 0.2mmol) and sodium iodide (6mg, 0.04mmol), the preparation title compound.LCMS (electron spray(ES)): m/z[MH
+] 664.44.
Embodiment 24
N-((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-sec.-propyl-1H-imidazoles-4-
Base)-ethylamino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the butyramide trifluoroacetate
N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2, the 3-dihydroxyl-
Cyclopentyl }-butyramide
By with cyclobutane formate { (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl)-method that acid amides is identical prepares title compound, from (1S, 2R, 3S, 5R)-3-amino-5-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-pentamethylene-1,2-diol hydrochloride (intermediates of preparation embodiment 22 compounds) and butyryl chloride begin, and obtain title compound (48mg).LCMS (electron spray(ES)): m/z[MH
+] 535.26.
1H?nmr(MeOD，400MHz)；8.00(s，1H)，7.40-7.30(m，8H)，7.25-7.15(m，2H)，4.75(m，1H)，4.60(m，1H)，4.50(m，1H)，4.20(m，2H)，3.95(m，1H)，2.85(m，1H)，2.35(m，2H)，2.05(m，1H)，1.70(m，2H)，1.00(m，3H)。
N-((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-sec.-propyl-1H-imidazoles-4-
Base)-ethylamino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the butyramide trifluoroacetate
Utilization is similar to the method for preparing embodiment 22 compounds, use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-butyramide, 2-(1-sec.-propyl-1H-imidazol-4 yl)-ethylamine (referring to the preparation of intermediate) (30mg, 0.2mmol) and sodium iodide (6mg, 0.04mmol), the preparation title compound.LCMS (electron spray(ES)): m/z[MH
+] 652.44.
Embodiment 25
N-((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-sec.-propyl-1H-imidazoles-4-
Base)-ethylamino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the isobutyramide trifluoroacetate
N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2, the 3-dihydroxyl-
Cyclopentyl }-isobutyramide
By with cyclobutane formate { (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl)-method that acid amides is identical prepares title compound, from (1S, 2R, 3S, 5R)-3-amino-5-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-pentamethylene-1,2-diol hydrochloride (intermediates of preparation embodiment 22 compounds) and isobutyryl chloride begin, and obtain title compound.LCMS (electron spray(ES)): m/z [MH
+] 535.26.
1H?nmr(MeOD，400MHz)；8.00(s，1H)，7.40-7.30(m，8H)，7.25-7.15(m，2H)，4.75(m，1H)，4.60(m，1H)，4.50(m，1H)，4.20(m，2H)，3.95(m，1H)，2.85(m，1H)，2.70(m，1H)，2.10(m，1H)，1.20(m，6H)。
N-((1S, 2R, 3S, 4R)-4-(6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-sec.-propyl-1H-imidazoles-4-
Base)-ethylamino]-purine-9-yl)-2,3-dihydroxyl-cyclopentyl)-the isobutyramide trifluoroacetate
Utilization is similar to the method for preparing embodiment 22 compounds, use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-isobutyramide, 2-(1-sec.-propyl-1H-imidazol-4 yl)-ethylamine (referring to the preparation of intermediate) (30mg, 0.2mmol) and sodium iodide (6mg, 0.04mmol), the preparation title compound.LCMS (electron spray(ES)): m/z[MH
+] 652.44.
Embodiment 26
N-((1S, 2R, 3S, 4R)-4-(6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-sec.-propyl-1H-imidazoles-4-
Base)-ethylamino]-purine-9-yl]-2,3-dihydroxyl-cyclopentyl)-2-phenyl-ethanamide trifluoroacetate
N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2, the 3-dihydroxyl-
Cyclopentyl }-2-phenyl-ethanamide
With (1S, 2R, 3S, 5R)-3-amino-5-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-pentamethylene-1,2-diol hydrochloride (intermediates of preparation embodiment 22 compounds) (100mg, 0.2mmol) anhydrous THF (1ml) solution with diisopropylethylamine (0.17ml, 1mmol) and phenyllacetyl chloride (0.026ml 0.2mmol) handles, with mixture stirring at room 18 hours.Under reduced pressure remove and desolvate, resistates is dissolved in methylene dichloride (2ml), with dilute hydrochloric acid (2ml) washing.Separate organic layer, vapourisation under reduced pressure obtains title compound (114mg).LCMS (electron spray(ES)): m/z[MH
+] 583.27.
N-((1S, 2R, 3S, 4R)-4-(6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-sec.-propyl-1H-imidazoles-4-
Base)-ethylamino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-2-phenyl-ethanamide trifluoroacetate
Utilization is similar to the method for preparing embodiment 22 compounds, use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-2-phenyl-ethanamide, 2-(1-sec.-propyl-1H-imidazol-4 yl)-ethylamine (referring to the preparation of intermediate) (30mg, 0.2mmol) and sodium iodide (6mg, 0.04mmol), the preparation title compound.LCMS (electron spray(ES)): m/z[MH
+] 700.45.
Embodiment 27
Cyclobutane formate (1S, 2R, 3S, 4R)-4-[6-(2,2-phenylbenzene-ethylamino)-2-(2-piperidines-1-base-second
Base is amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl]-the acid amides trifluoroacetate
Utilization is similar to the method for preparing embodiment 22 compounds, use cyclobutane formate { (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl cyclopentyl }-acid amides (preparation embodiment 23 intermediate), 1-(2-amino-ethyl) piperidines (0.057ml, 0.4mmol) and sodium iodide (6mg, 0.04mmol), the preparation title compound.LCMS (electron spray(ES)): m/z[MH
+] 639.45.
Embodiment 28
N-{ (1S, 2R, 3S, 4R)-and 4-[6-(2,2-phenylbenzene-ethylamino)-2-(2-piperidines-1-base-ethylamino)-fast
Purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-the butyramide trifluoroacetate
Utilization is similar to the method for preparing embodiment 22 compounds, use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-butyramide (preparation embodiment 24 intermediate), 1-(2-amino-ethyl)-piperidines (0.057ml, 0.4mmol) and sodium iodide (6mg, 0.04mmol), the preparation title compound.LCMS (electron spray(ES)): m/z[MH
+] 627.44.
Embodiment 29
N-{ (1S, 2R, 3S, 4R)-and 4-[6-(2,2-phenylbenzene-ethylamino)-2-(2-piperidines-1-base-ethylamino)-fast
Purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-the isobutyramide trifluoroacetate
Utilization is similar to the method for preparing embodiment 22 compounds, use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-isobutyramide (preparation embodiment 25 intermediate), 1-(2-amino-ethyl)-piperidines (0.057ml, 0.4mmol) and sodium iodide (6mg, 0.04mmol), the preparation title compound.LCMS (electron spray(ES)): m/z[MH
+] 627.44.
Embodiment 30
N-{ (1S, 2R, 3S, 4R)-and 4-[6-(2,2-phenylbenzene-ethylamino)-2-(2-piperidines-1-base-ethylamino)-fast
Purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-2-phenyl-ethanamide trifluoroacetate
Utilization is similar to the method for preparing embodiment 22 compounds, use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-2-phenyl-ethanamide (intermediate of embodiment 26), 1-(2-amino-ethyl)-piperidines (0.057ml, 0.4mmol) and sodium iodide (6mg, 0.04mmol), the preparation title compound.LCMS (electron spray(ES)): m/z[MH
+] 675.47.
Embodiment 31
N-{ (1S, 2R, 3S, 4R)-and 4-[6-(2,2-phenylbenzene-ethylamino)-2-(2-piperidines-1-base-ethylamino)-fast
Purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-N '-(2-piperidines-1-base-ethyl)-oxamide
Isoxazole-5-formic acid (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-
Base]-2,3-dihydroxyl-cyclopentyl }-acid amides
By with cyclobutane formate { (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-method that acid amides is identical prepares title compound, from (1S, 2R, 3S, 5R)-3-amino-5-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-pentamethylene-1, (the intermediate) of preparation embodiment 22 compounds is with isoxazole-5-carbonyl chloride obtains title compound to the 2-diol hydrochloride.LCMS (electron spray(ES)): m/z[MH
+] 560.28.
N-{ (1S, 2R, 3S, 4R)-and 4-[6-(2,2-phenylbenzene-ethylamino)-2-(2-piperidines-1-base-ethylamino)-fast
Purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-N '-(2-piperidines-1-base-ethyl)-oxamide
Utilization is similar to the method for preparing embodiment 22 compounds, use isoxazole-5-formic acid { (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-acid amides, 1-(2-amino-ethyl)-piperidines (51mg, 0.4mmol) and sodium iodide (6mg, 0.04mmol), the preparation title compound.LCMS (electron spray(ES)): m/z[MH
+] 739.55.
Embodiment 32
Cyclopropane-carboxylic acid ((1S, 2R, 3S, 4R)-4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-second
Base is amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-acid amides
Utilization is similar to the method for preparing embodiment 22 compounds and prepares title compound, use cyclopropane-carboxylic acid { (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-acid amides (preparation embodiment 22 intermediate), (R)-tetramethyleneimine-3-base amine (34mg, 0.4mmol) and sodium iodide (6mg 0.04mmol) obtains the mixture of two kinds of regional isomers, through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1% TFA), obtain product, be mainly cyclopropane-carboxylic acid { (1S, 2R, 3S, 4R)-and 4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-acid amides.LCMS (electron spray(ES)): m/z[MH
+] 583.42.
Embodiment 33
Cyclobutane formate (1S, 2R, 3S, 4R)-4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-second
Base is amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl)-acid amides
Utilization is similar to the method for preparing embodiment 22 compounds and prepares title compound, use cyclobutane formate { (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-acid amides (preparation embodiment 23 intermediate), (R)-tetramethyleneimine-3-base amine (34mg, 0.4mmol) and sodium iodide (6mg, 0.04mmol), obtain the mixture of two kinds of regional isomers, through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1% TFA), obtain product, be mainly cyclobutane formate { (1S, 2R, 3S, 4R)-4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,, 2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-acid amides.LCMS (electron spray(ES)): m/z[MH
+] 597.45.
Embodiment 34
N-{ (1S, 2R, 3S, 4R)-4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-
Purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-2-phenyl-ethanamide
Utilization is similar to the method for preparing embodiment 22 compounds and prepares title compound, use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-2-phenyl-ethanamide (preparation embodiment 26 intermediate), (R)-tetramethyleneimine-3-base amine (34mg, 0.4mmol) and sodium iodide (6mg 0.04mmol) obtains the mixture of two kinds of regional isomers, through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1% TFA), obtain product, be mainly N-{ (1S, 2R, 3S, 4R)-and 4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-2-phenyl-ethanamide.LCMS (electron spray(ES)): m/z[MH
+] 633.46.
Embodiment 35
N-((1S, 2R, 3S, 4R)-4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-
Purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-3-phenyl-propionic acid amide
N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2, the 3-dihydroxyl-
Cyclopentyl }-3-phenyl-propionic acid amide
With (1S, 2R, 3S, 5R)-3-amino-5-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-pentamethylene-1,2-diol hydrochloride (intermediates of preparation embodiment 22 compounds) (100mg, 0.2mmol) anhydrous THF (1ml) solution with diisopropylethylamine (0.17ml, 1mmol) and 3-phenyl-propionyl chloride (0.03ml 0.2mmol) handles, with mixture stirring at room 18 hours.Under reduced pressure remove and desolvate, resistates is dissolved in methylene dichloride (2ml), with dilute hydrochloric acid (2ml) washing.Separate organic layer, vapourisation under reduced pressure obtains title compound.LCMS (electron spray(ES)): m/z[MH
+] 597.32.
N-{ (1S, 2R, 3S, 4R)-4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-
Purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-3-phenyl-propionic acid amide
Utilization is similar to the method for preparing embodiment 22 compounds and prepares title compound, use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-3-phenyl-propionic acid amide, (R)-tetramethyleneimine-3-base amine (34mg, 0.4mmol) and sodium iodide (6mg 0.04mmol) obtains the mixture of two kinds of regional isomers, through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1% TFA), obtain product, be mainly N-{ (1S, 2R, 3S, 4R)-and 4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-2-phenyl-ethanamide.LCMS (electron spray(ES)): m/z[MH
+] 647.47.
Embodiment 36a and 36b
N-{ (1S, 2R, 3S, 4R)-4-[2-((1S, 3R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethyl ammonia
The base)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide and
N-{ (1S, 2R, 3S, 4R)-and 4-[6-(2,2-phenylbenzene-ethylamino)-2-((R)-tetramethyleneimine-3-base-amino)-fast
Purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide
Embodiment 36a embodiment 36b
Utilization is similar to the method for preparing embodiment 22 compounds and prepares these compounds, use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (intermediate of preparation embodiment 16), (R)-tetramethyleneimine-3-base amine (34mg, 0.4mmol) and sodium iodide (6mg, 0.04mmol), obtain the mixture of two kinds of regional isomers, be N-{ (1S, 2R, 3S, 4R)-4-[2-((1S, 3R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 36a) and N-{ (1S, 2R, 3S, 4R)-4-[6-(2,2-phenylbenzene-ethylamino)-2-((R)-tetramethyleneimine-3-base-amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 36b), through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1% TFA), obtain product, be mainly N-{ (1S, 2R, 3S, 4R)-and 4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide.LCMS (electron spray(ES)): m/z[MH
+] 571.41.
Embodiment 37a and 37b
N-[(1S, 2R, 3S, 4R)-4-(6-(2,2-phenylbenzene-ethylamino)-2-{ (1S, 3R)-3-[3-(3,4,5, the 6-tetrahydrochysene
-2H-[1,2 '] dipyridyl-4-yl)-urea groups]-tetramethyleneimine-1-yl }-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-
Propionic acid amide and
(R)-3-[9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-second
Base is amino)-9H-purine-2-base is amino]-tetramethyleneimine-1-formic acid (3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-
Base)-acid amides
Embodiment 37a embodiment 37b
With N-{ (1S, 2R, 3S, 4R)-4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-(30mg 0.04mmol) is dissolved in toluene (2ml) and iPrOH (1ml) to propionic acid amide.Add N-[1-(2-pyridyl)-4-piperidyl]-1H-imidazoles-1-acid amides (utilizing International Patent Application WO 01/94368 described prepared) (12mg, dichloromethane solution 0.044mmol).With reaction mixture in stirring at room.The LCMS demonstration reacts completely after 24 hours.Remove in a vacuum and desolvate.Title compound exists with the mixture of two kinds of regional isomers, be N-[(1S, 2R, 3S, 4R)-4-(6-(2,2-phenylbenzene-ethylamino)-2-{ (1S, 3R)-3-[3-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl)-urea groups]-tetramethyleneimine-1-yl }-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-propionic acid amide (embodiment 37a) and (R)-3-[9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-base is amino]-tetramethyleneimine-1-formic acid (3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl)-acid amides (embodiment 37b), separate (Isolute through flash column chromatography
TMC18, the 0-100% acetonitrile solution).LCMS (electron spray(ES)): m/z[MH
+] 596.42.
Utilize secondary isotope effect in the NMR spectrum to determine the structure of embodiment 37a and 37b compound.Isotopic effect is the mature technology (B.A.Bernheim and H.Batiz-Hernandez, Prog.Nucl-Magn.Reson.Spectrosc.3,63-85[1967]) in the NMR spectrum.Primary isotope effect has broad research (people such as L.J.Altman, Am.Chem.Soc.100,8264-8266[1978]), but the secondary isotope drift provides important structural information just.At the part deuterium for compound
1H or X-nuclear are (usually
13C) observe these secondary isotope effects in the NMR spectrum, this technology is called as SIMPLE (the secondary isotope multiplet of part mark-up entity).The part deuterium of replaceable proton is for the different isotropic substance bodies that allow direct viewing to measure under slow permutizer condition in the molecule, separates according to analyzing resonance line for contributive pair of key of secondary isotope effect of deuterium-bring out with three key isotopic effect.For example, observe signal from single carbon atom, as a series of multiplets, its strength ratio along with
1H:
2H ratio and quantitatively changing.The amplitude of two keys and three bonding effect is along with the replacement of the configuration of carbon and these displaceable group and hydrogen bond and change.Utilize multiple formation of these signals and isotopic effect amplitude clearly to determine and confirm the structure of embodiment 37a and embodiment 37b just.
Based on the structure that is proposed, determine the proton and the carbon spectrum of two kinds of molecules by standard 1-and 2-D technology.Two allophanyls have the drift of 157.38ppm and 156.34ppm respectively in embodiment 37a and embodiment 37b.Two carbonyl fragments all are bonded to two nitrogen-atoms, but crucial difference is that embodiment 37a is bonded to two NH groups, and the carbonyl of equal value among the embodiment 37b is bonded to the full replacement nitrogen of a NH group and proline(Pro) ring.
To two duplicate samples titration deuterium oxide carefully, cause about 50: 50 replaceable fragment of protonated and deuterate.By
1H NMR monitoring titration process is adding 1 μ l D
2Measure the integration of replaceable proton after the O aliquots containig.Then two duplicate samples are carried out high resolving power
13The C spectroscopic analysis.The carbonyl of embodiment 37a connects and shows the triplet structure, this may be only since in two keys two part deuteriums for exist (triplet is made up of NHCONH, [NDCONH/NDCONH] and NDCOND carbon resonance) of group.But, the carbon of equal value among the embodiment 37b is made up of dual structure, has confirmed that this carbonyl connection only is bonded to a NH group, thereby has confirmed its structure.
Embodiment 38
9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-formic acid 2-[3-(3,4,5,6-tetrahydrochysene-2H-[1,2] dipyridyl-4-yl) urea groups]-ethyl }-acyl
Amine
6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester
Under argon atmospher, (35g 85.3mmol) is placed in the flask with 6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester hydrochloride (utilizing International Patent Application WO 2001/94368 described prepared).Add anhydrous CHCl
3(300ml) and N, two (trimethyl silyl) ethanamides (61ml) of O-made reaction mixture refluxed 1 hour.Make the reaction mixture cooling, remove volatile matter in a vacuum.Add MeOH (300ml) to gained oil.The gained white solid is filtered, and (2 * 200ml), drying in vacuum drying oven obtains title compound then with the MeOH washing.
1H?NMR(DMSO，400MHz).
6-(2,2-phenylbenzene-ethylamino)-9-((1R, 4S)-4-hydroxyl-ring penta-2-thiazolinyl)-9H-purine-2-formic acid
Methyl ester
Under argon atmospher, (5g 13.4mmol) adds no water deoxygenation tetrahydrofuran (THF) (100ml) and anhydrous dimethyl sulphoxide (2ml) to 6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester.Add then sodium hydride 95% (0.32g, 13.4mmol), with solution 40 ℃ of stirrings.Separately to (1S, 4R)-cis-4-acetoxyl group-2-cyclopentenes-1-alcohol (1.89g, 13.4mmol) and triphenyl phosphine (0.53g, 2.0mmol) no water deoxygenation tetrahydrofuran (THF) (20ml) solution add three (dibenzalacetones), two palladiums (0) (0.69g, 0.67mmol), with mixture stirring at room 10 minutes.This solution is joined in the anion solutions via syringe, then with the gained mixture 80 ℃ of stirrings.The LCMS demonstration reacts completely after 2 hours.Make the reaction mixture cooling, add methyl alcohol, cross filter solid.Concentrated filtrate in a vacuum, precipitation obtains title compound from dichloromethane/hexane.
1H?NMR(MeOD，400MHz)；8.15(s，1H)，7.40-7.15(m，10H)，6.20(m，1H)，5.95(m，1H)，5.50(m，2H)，4.75(m，2H)，4.55(m，1H)，4.10(m，2H)，3.90(s，2H)，3.80(s，1H)，2.9(m，1H)，1.75(m，1H)。
6-(2,2-phenylbenzene-ethylamino)-9-((1R, 4S)-4-ethoxycarbonyl-oxygen base-ring penta-2-thiazolinyl)-the 9H-purine
-2-formic acid methyl ester
Under argon atmospher, ((2.80g 6.14mmol) is placed on through in the flask of oven drying (1R, 4S)-4-hydroxyl-ring penta-2-thiazolinyl)-9H-purine-2-formic acid methyl ester with 6-(2,2-phenylbenzene-ethylamino)-9-.Add anhydrous tetrahydro furan (30ml), succeeded by anhydrous pyridine (0.97g, 12.3mmol).Slowly add Vinyl chloroformate (2.66g, 24.6mmol), with reaction mixture in stirring at room.The LCMS demonstration reacts completely after 3 hours.Remove in a vacuum and desolvate, resistates (is distributed between 2 * 200ml) at methylene dichloride (200ml) and 1M HCl.With organic layer with saturated sodium bicarbonate solution (2 * 200ml), water (2 * 100ml), salt solution (2 * 100ml) washing, through MgSO
4Drying is filtered, and removes in a vacuum and desolvates.Behind flash column chromatography purifying (silicon-dioxide, the dichloromethane solution of 4%MeOH), obtain title compound.MS(ES+)m/e?528.3(MH
+)。
9-((1R, 4S)-4-two-t-butoxycarbonyl amino-ring penta-2-thiazolinyl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-formic acid methyl ester
((1R, 4S)-4-ethoxycarbonyl-oxygen base-ring penta-2-thiazolinyl)-(2.2g 4.2mmol) is dissolved in the deoxidation tetrahydrofuran (THF) to 9H-purine-2-formic acid methyl ester with 6-(2,2-phenylbenzene-ethylamino)-9-.Gained solution is stirred under the room temperature argon atmospher.Add the iminodiformic acid di tert butyl carbonate (0.9g, 4.2mmol), triphenyl phosphine (0.16g, 0.63mmol) and triethylamine (0.42g, 4.2mmol), succeeded by three (dibenzalacetones), two palladiums (0) (0.22g, 0.21mmol).Then reaction mixture was stirred 4 hours at 45 ℃, be cooled to room temperature, add methyl alcohol, filter reaction mixture.Concentrated filtrate in a vacuum.Gained oil obtains title compound through column chromatography purifying (silicon-dioxide, the hexane solution of 80% ether).MS(ES+)m/e536.4(MH
+)。
9-((1R, 2S, 3R, 4S)-and 4-two-t-butoxycarbonyl amino-2,3-dihydroxyl-cyclopentyl)-6-(2, the 2-phenylbenzene-
Ethylamino)-9H-purine-2-formic acid methyl ester
Utilization is similar to (1R, 2S, 3R, 5S)-3-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-5-(two-Boc-amino)-pentamethylene-1, the technology of 2-glycol is from 9-((1R, 4S)-4-two-t-butoxycarbonyl amino-ring penta-2-thiazolinyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester prepares title compound.MS(ES+)m/e?689.4(MH
+)。
9-((1R, 2S, 3R, 4S)-and 4-amino-2,3-dihydroxyl-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-
Purine-2-formic acid methyl ester
((1R, 2S, 3R, 4S)-4-two-t-butoxycarbonyl amino-2,3-dihydroxyl-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-(0.5g 0.73mmol) is dissolved in diox to 9H-purine-2-formic acid methyl ester, stirs under argon atmospher with 9-.(3.68ml 14.5mmol), with gained solution stirring 20 hours, concentrates then in a vacuum to add 4M HCl De dioxane solution.Handle (Isolute through flash column chromatography
TMC18, the 0-100% acetonitrile solution), obtain title compound.MS(ES+)m/e?489.3(MH
+)。
9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-formic acid methyl ester
((1R, 2S, 3R, 4S)-4-amino-2,3-dihydroxyl-cyclopentyl)-(200mg 0.36mmol) is dissolved in tetrahydrofuran (THF) (5ml) to 6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester hydrochloride with 9-.Add diisopropylethylamine (0.16ml, 0.9mmol), with solution stirring 10 minutes.Add propionyl chloride (33mg, 0.36mmol), with reaction mixture stirring at room 1 hour.With methyl alcohol cancellation reaction, handle (Isolute through flash column chromatography
TMC18, the 0-100% acetonitrile solution), obtain title compound.MS(ES+)m/e?545.3(MH
+)。
9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-formic acid (2-amino-ethyl)-acid amides
With 9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester (and 62mg, 1.0mmol) be dissolved in quadrol (3.4ml, 51mmol), with solution 105 ℃ of stirrings.The LCMS demonstration reacts completely after 45 minutes.Concentrated reaction mixture passes through reversed-phase column chromatography purifying (Isolute in a vacuum
TMC18, the 0-100% acetonitrile solution) after, obtain title compound.MS(ES+)m/e?573.4(MH
+)。
9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-formic acid 2-[3-(3,4,5,6-tetrahydrochysene-2H-[1.2] dipyridyl-4-yl) urea groups]-ethyl }-acyl
Amine
((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-(25mg 0.044mmol) is dissolved in toluene (2ml) and iPrOH (1ml) to 6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid (2-amino-ethyl)-acid amides with 9-.Add N-[1-(2-pyridyl)-4-piperidyl]-1H-imidazoles-1-acid amides (utilizing International Patent Application WO 01/94368 described prepared) (12mg, dichloromethane solution 0.044mmol).With reaction mixture in stirring at room.The LCMS demonstration reacts completely after 24 hours.Remove in a vacuum and desolvate.Handle (Isolute through flash column chromatography
TMC18, the 0-100% acetonitrile solution), obtain title compound.MS(ES+)m/e?388.7(MH
+)。
The alternative method of preparation embodiment 38 compounds is described below:
9-[(1R, 4S)-4-(tertbutyloxycarbonyl-propionyl-amino)-ring penta-2-thiazolinyl]-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-formic acid methyl ester
This compound is the trifluoroacetate of embodiment 37 final compounds; utilization is similar to preparation 9-((1R; 4S)-4-two-t-butoxycarbonyl amino-ring penta-2-thiazolinyl)-6-(2; 2-phenylbenzene-ethylamino)-and the preparation of the method for 9H-purine-2-formic acid methyl ester, wherein replace the iminodiformic acid di tert butyl carbonate with propionyl-carboxylamine tertiary butyl ester.
9-[(1R, 2S, 3R, 4S)-and 4-(tertbutyloxycarbonyl-propionyl-amino)-2,3-dihydroxyl-cyclopentyl]-6-(2,2-
Phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester
To the 9-[(1R that is stirring; 4S)-4-(tertbutyloxycarbonyl-propionyl-amino)-ring penta-2-thiazolinyl]-6-(2; 2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester (6.6g; 10.82mmol), (1.03g 10.82mmol) adds perosmic anhydride (3ml 4% aqueous solution) with the suspension of AD-mix-α (16.23g) in the trimethyl carbinol (40ml) and water (40ml) to Toluidrin.With reaction mixture vigorous stirring 36 hours.Reaction mixture is distributed, with organic moiety drying (MgSO between ethyl acetate and water
4), concentrate in a vacuum.From methyl alcohol, be settled out title product.Through the silicon-dioxide chromatography, use DCM: methyl alcohol (25: 1) wash-out obtains more product from mother liquor.
(1S, 2R, 3S, 4R)-4-[2-(2-amino-ethyl carbamyl-6-(2,2-phenyl-ethylamino)-purine
-9-yl]-2,3-dihydroxyl-cyclopentyl }-the carboxylamine tertiary butyl ester
Be similar to 9-((1R; 2S; 3R; 4S)-2; 3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid (2-amino-ethyl)-acid amides prepares this compound, wherein uses 9-[(1R; 2S; 3R, 4S)-4-(tertbutyloxycarbonyl-propionyl-amino)-2,3-dihydroxyl-cyclopentyl]-6-(2; 2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester replacement 9-((1R; 2S, 3R, 4S)-2; 3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester.
(1S, 2R, 3S, 4R)-4-(6-(2,2-phenylbenzene-ethylamino)-2-(2-[3-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] connection
Pyridin-4-yl)-urea groups]-the ethyl carbamyl }-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-carboxylamine
Tertiary butyl ester
Be similar to 9-((1R, 2S, 3R; 4S)-2; 3-dihydroxyl-4-propionamido-cyclopentyl)-(2,2-phenylbenzene-ethylamino)-{ 2-[3-(3,4 for 9H-purine-2-formic acid for 6-; 5; 6-tetrahydrochysene-2H-[1,2] urea groups dipyridyl-4-yl)]-ethyl }-acid amides prepares this compound, wherein uses { (1S; 2R; 3S, 4R)-4-[2-(2-amino-ethyl carbamyl)-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2; 3-dihydroxyl-cyclopentyl }-carboxylamine tertiary butyl ester replacement 9-((1R; 2S, 3R, 4S)-2; 3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid (2-amino-ethyl)-acid amides.
9-((1R, 2S, 3R, 4S)-and 4-amino-2,3-dihydroxyl-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-
Purine-2-formic acid 2-[3-(3,4,5,6-tetrahydrochysene-2H-[1.2 '] dipyridyl-4-yl)-urea groups]-ethyl }-acid amides two
Hydrochloride
Be similar to 9-((1R, 2S, 3R; 4S)-4-amino-2; 3-dihydroxyl-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester prepares this compound, wherein uses (1S; 2R; 3S, 4R)-4-(6-(2,2-phenylbenzene-ethylamino)-2-{2-[3-(3; 4; 5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl)-urea groups]-the ethyl carbamyl }-purine-9-yl)-2; 3-dihydroxyl-cyclopentyl]-carboxylamine tertiary butyl ester replacement 9-((1R; 2S, 3R, 4S)-4-two-t-butoxycarbonyl amino-2; 3-dihydroxyl-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester.
9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-formic acid 2-[3-(3,4,5,6-tetrahydrochysene-2H-[1,2] dipyridyl-4-yl) urea groups]-ethyl }-acyl
The amine trifluoroacetate
Be similar to 9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester prepares this compound, wherein uses 9-((1R, 2S, 3R, 4S)-4-amino-2,3-dihydroxyl-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-{ 2-[3-(3 for 9H-purine-2-formic acid, 4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl)-urea groups]-ethyl }-acid amides dihydrochloride replacement 9-((1R, 2S, 3R, 4S)-4-amino-2,3-dihydroxyl-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester hydrochloride.
Embodiment 39
N-((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[(R)-3-((R)-3-tetramethyleneimine-3-base
Urea groups)-tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the propionic acid amide trifluoroacetate
Be similar to embodiment 22 these compounds of preparation, wherein use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide replacement cyclopropane-carboxylic acid { (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-acid amides, with 1,3-two (R)-tetramethyleneimine-3-base-urea replaces 2-(1-sec.-propyl-1H-imidazol-4 yl)-ethylamine.
Embodiment 40
Cyclobutane formate [(1S, 2R, 3S, 4R)-4-(6-(2,2-phenylbenzene-ethylamino)-2-{ (R)-3-[3-(3,4,5,6-
Tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl)-urea groups]-tetramethyleneimine-1-yl }-purine-9-yl)-2,3-dihydroxyl-ring
Amyl group]-the acid amides trifluoroacetate
With cyclobutane formate { (1S, 2R, 3S, 4R)-4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-the acid amides dihydrochloride (0.02g, 0.03mmol), TEA (0.09ml, 0.06mmol) mixture in Virahol (0.5ml) is with imidazoles-1-formic acid (3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl)-acid amides (0.03mmol) handle by the 10mg/ml DCM solution of 0.04ml.Reaction mixture after stirred overnight at room temperature, is removed in a vacuum and desolvates, and crude product is through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1%TFA), obtain title product.
Embodiment 41
9-[(1R, 2S, 3R, 4S)-and 4-(tetramethylene carbonyl-amino)-2,3-dihydroxyl-cyclopentyl]-6-(2, the 2-phenylbenzene-
Ethylamino)-9H-purine-2-formic acid (2-[3-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl)-urea groups]-
Ethyl }-acid amides
Be similar to 9-((1R, 2S, 3R; 4S)-2; 3-dihydroxyl-4-propionyl-amino-cyclopentyl)-(2,2-phenylbenzene-ethylamino)-{ 2-[3-(3,4 for 9H-purine-2-formic acid for 6-; 5; 6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl) urea groups]-ethyl }-acid amides prepares this compound, wherein uses 9-((1R; 2S; 3R, 4S)-4-amino-2,3-dihydroxyl-cyclopentyl)-6-(2; 2-phenylbenzene-ethylamino)-{ 2-[3-(3 for 9H-purine-2-formic acid; 4,5,6-tetrahydrochysene-2H-[1; 2 '] dipyridyl-4-yl)-urea groups]-ethyl }-acid amides dihydrochloride replacement (1S; 2R, 3S, 5R)-3-amino-5-[2-chloro-6-(2; 2-phenylbenzene-ethylamino)-purine-9-yl]-pentamethylene-1, the 2-diol hydrochloride.
Embodiment 42
9-((1R, 2S, 3R, 4S)-and 4-acetylaminohydroxyphenylarsonic acid 2,3-dihydroxyl-cyclopentyl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-formic acid 2-[3-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl)-urea groups]-ethyl }-
The acid amides trifluoroacetate
With 9-((1R, 2S, 3R, 4S)-4-amino-2,3-dihydroxyl-cyclopentyl)-(2,2-phenylbenzene-ethylamino)-{ 2-[3-(3,4 for 9H-purine-2-formic acid for 6-, 5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl)-urea groups]-ethyl }-acid amides dihydrochloride (0.02g, 25 μ mol), TEA (0.013g, 125 μ mol) mixture in THF (2ml) is handled with Acetyl Chloride 98Min. (0.003g, 40 μ mol).Reaction mixture after stirred overnight at room temperature, is removed in a vacuum and desolvates, and crude product is through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1%TFA), obtain title product.
Embodiment 43
9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-formic acid (2-[3-((R)-1-pyridine-2-base-tetramethyleneimine-3-yl)-urea groups]-ethyl]-acid amides
Trifluoroacetate
With 9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-(0.01g is 0.018mmol) with 1-(2-amino-ethyl)-3-((R)-1-pyridine-2-base-tetramethyleneimine-3-yl)-urea (1: 5 molar mixture of 0.022g and imidazoles for 6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid methyl ester, 0.04mmol) 1,2-ethylene dichloride: Virahol (1: 1 mixture of 0.2ml) solution heating 70 hours under refluxing.Remove in a vacuum and desolvate, crude product is through reversed-phase column chromatography purifying (Isolute
TMC18,0-65% acetonitrile solution-0.1%TFA), obtain title product.
Embodiment 44
N-{ (1S, 2R, 3S, 4R)-4-[2-(4-amino-piperadine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-purine-9-
Base]-2,3-dihydroxyl-cyclopentyl }-the propionic acid amide dihydrochloride
1-[9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-yl]-piperidin-4-yl }-carboxylamine tertiary butyl ester trifluoroacetate
Be similar to cyclopropane-carboxylic acid ((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-sec.-propyl-1H-imidazol-4 yl)-ethylamino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the acid amides trifluoroacetate prepares this compound, wherein use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide replacement cyclopropane-formic acid { (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-acid amides, replace 2-(1-sec.-propyl-1H-imidazol-4 yl)-ethylamine with piperidin-4-yl-carboxylamine tertiary butyl ester.
N-{ (1S, 2R, 3S, 4R)-4-[2-(4-amino-piperadine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-purine-9-
Base]-2,3-dihydroxyl-cyclopentyl }-the propionic acid amide dihydrochloride
With { 1-[9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethyl-amino)-9H-purine-2-yl]-piperidin-4-yl }-(0.02g 0.03mmol) is dissolved in HCl (1ml 1.25M methanol solution) to carboxylamine tertiary butyl ester trifluoroacetate, places in room temperature and spends the night.Remove in a vacuum and desolvate, obtain title compound.
Embodiment 45 and 46
These compounds are N-{ (1S, 2R, 3S, 4R)-4-[6-(2,2-phenylbenzene-ethylamino)-and 2-tetramethyleneimine-1-base-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide trifluoroacetate and N-{ (1S, 2R, 3S, 4R)-4-[6-(2,2-phenylbenzene-ethylamino)-and 2-piperazine-1-base-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-the propionic acid amide trifluoroacetate, be similar to cyclopropane-carboxylic acid ((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[2-(1-sec.-propyl-1H-imidazol-4 yl)-ethylamino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the acid amides trifluoroacetate prepared, and wherein uses N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide replacement cyclopropane-carboxylic acid { (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-acid amides, replace 2-(1-sec.-propyl-1H-imidazol-4 yl)-ethylamine with suitable amine.
Embodiment 47
9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-formic acid 2-[3-((S)-1-pyridine-2-base-tetramethyleneimine-3-yl)-urea groups]-ethyl }-acid amides
Trifluoroacetate
Be similar to 9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid { 2-[3-((R)-1-pyridine-2-base-tetramethyleneimine-3-yl)-urea groups]-ethyl }-acid amides trifluoroacetate prepares this compound, wherein uses 1-(2-amino-ethyl)-3-((S)-1-pyridine-2-base-tetramethyleneimine-3-yl)-urea to replace 1-(2-amino-ethyl)-3-((R)-1-pyridine-2-base-tetramethyleneimine-3-yl)-urea.
Embodiment 48
9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-formic acid [2-(3-piperidin-4-yl-urea groups)-ethyl-acid amides
4-[3-(2-{[9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2, the 2-phenylbenzene-
Ethylamino)-9H-purine-2-carbonyl]-amino }-ethyl)-urea groups]-piperidines-1-formic acid benzyl ester
To 9-((1R; 2S; 3R; 4S)-2; 3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2; 2-phenylbenzene-ethylamino)-(0.1g, chloroform 174mmol) (5ml) solution add 4-isocyanide acyl group-Z-piperidines (0.045g, chloroform 0.174mmol) (5ml) solution to 9H-purine-2-formic acid (2-amino-ethyl)-acid amides.Reaction mixture in stirred overnight at room temperature, is added methyl alcohol then with any residual isocyanic ester of cancellation.Remove in a vacuum and desolvate, obtain title compound, need not to be further purified and promptly can be used for next step.
9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-formic acid [2-(3-piperidin-4-yl-urea groups)-ethyl]-acid amides
Under argon atmospher, with 4-[3-(2-{[9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-carbonyl]-amino }-ethyl)-urea groups]-piperidines-1-formic acid benzyl ester (0.145g, 0.174mmol) methyl alcohol (1ml) solution handle with draping over one's shoulders palladium hydroxide carbon (0.054g, 20%w/w carbon).Reaction mixture is placed under the nitrogen atmosphere,, filters then stirring at room 72 hours.Concentrated filtrate obtains title compound in a vacuum, is the oil of green.
Embodiment 49
9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethyl ammonia
Base)-9H-purine-2-formic acid 2-[3-(1-methylsulfonyl-piperidin-4-yl)-urea groups]-ethyl }-acid amides trifluoro second
Hydrochlorate
Under argon atmospher, to 9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-formic acid [2-(3-piperidin-4-yl-urea groups)-ethyl]-acid amides (0.01g, 0.0143mmol) DMF (1ml) solution add triethylamine (TEA) (0.003g, 0.0286mmol), succeeded by methylsulfonyl chloride (0.0016g, 0.0143mmol).After the room temperature placement is spent the night, remove in a vacuum and desolvate, crude product is through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1% TFA), obtain title product.
Embodiment 50
N-((1S, 2R, 3S, 4R)-4-{2-chloro-6-[(naphthalene-1-ylmethyl)-amino]-purine-9-yl }-2,3-dihydroxyl-ring
Amyl group)-the propionic acid amide trifluoroacetate
With [(1S; 2R; 3S; 4R)-and 4-(2,6-two chloro-purine-9-yl)-2,3-dihydroxyl-cyclopentyl]-propionyl-carboxylamine tertiary butyl ester (0.5g; 1.1mmol), DIPEA (0.227ml; 1.3mmol), 1-naphthalene methylamine (0.175ml, 1.2mmol) 1,2-two chloro-ethane (3ml) solution are 50 ℃ of heated overnight.Add hydrochloric acid (10ml 0.1M solution) to reaction mixture, after stirring, separate organic moiety, handle with TFA (1ml).After room temperature is placed 2 hours, remove in a vacuum and desolvate, obtain title compound.
Embodiment 51-53
These compounds promptly
N-{ (1S, 2, R, 3S, 4R)-and 4-[2-chloro-6-(3,3-dimethyl-butyl amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide trifluoroacetate (embodiment 51),
N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 52),
N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(3,3-phenylbenzene-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 53),
Be similar to N-((1S, 2R, 3S, 4R)-4-{2-chloro-6-[(naphthalene-1-ylmethyl)-amino]-purine-9-yl-2,3-dihydroxyl-cyclopentyl)-the propionic acid amide trifluoroacetate prepared, and wherein replaces 1-naphthalene methylamine with suitable amine.Also embodiment 53 and 54 usefulness salt of wormwood/methyl alcohol are handled, obtain the free form of product.
Embodiment 54
N-((1S, 2R, 3S, 4R)-4-{6-(1-ethyl-propyl group amino)-2-[(R)-3-((R)-3-tetramethyleneimine-3-base urea groups)
Tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the propionic acid amide trifluoroacetate
With N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (0.02g, 0.03mmol) with 1, (0.03g, DMSO 0.15mmol) (0.2ml) solution is heated to 100 ℃ and reaches 24 hours 3-two (R)-tetramethyleneimine-3-base-urea.The preparation type LC-MS that utilizes quality to point to carries out purifying, and use acetonitrile: water: the trifluoroacetic acid wash-out obtains title compound.
Embodiment 55
N-((1S, 2R, 3S, 4R)-2,3-dihydroxyl-4-{6-[(naphthalene-1-ylmethyl)-amino]-2-[(R)-3-((R)-3-pyrrole
Cough up alkane-3-base urea groups)-tetramethyleneimine-1-yl]-purine-9-yl }-cyclopentyl)-the propionic acid amide trifluoroacetate
Be similar to N-((1S, 2R, 3S, 4R)-4-{6-(1-ethyl-propyl group amino)-2-[(R)-3-((R)-3-tetramethyleneimine-3-base urea groups)-tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the propionic acid amide trifluoroacetate prepares this compound, wherein use N-((1S, 2R, 3S, 4R)-4-{2-chloro-6-[(naphthalene-1-ylmethyl)-amino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate replacement N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide.
Embodiment 56
N-{ (1S, 2R, 3S, 4R)-4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(1-ethyl-propyl group amino)-purine
-9-yl]-2,3-dihydroxyl-cyclopentyl }-the propionic acid amide trifluoroacetate
With N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (0.02g, 0.03mmol), (3R)-3-(BOC-amino) tetramethyleneimine (0.028g, 0.15mmol) and sodium iodide (0.004g 0.03mmol) is placed in the 0.5-2.5ml microwave bottle.Add acetonitrile (0.25ml) and NMP (0.25ml), at Personal Chemistry Emrys
TMOptimize in the microwave reactor, utilize microwave radiation in 160 ℃ of heating 30 minutes reaction mixture.Add DCM (3ml) and water (3ml) to reaction mixture, after stirring, separate organic moiety, handle with TFA (0.5ml).After the room temperature placement is spent the night, the preparation type LC-MS purifying that utilizes quality to point to, use acetonitrile: water: the trifluoroacetic acid wash-out obtains title compound.
Embodiment 57
N-((1S, 2R, 3S, 4R)-and 4-{2-((R)-3-amino-tetramethyleneimine-1-yl)-6-[(naphthalene-1-ylmethyl) amino]-fast
Purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the propionic acid amide trifluoroacetate
Be similar to N-{ (1S, 2R, 3S, 4R)-and 4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-the propionic acid amide trifluoroacetate prepares this compound, wherein use N-((1S, 2R, 3S, 4R)-4-{2-chloro-6-[(naphthalene-1-ylmethyl)-amino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate replacement N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide.
Embodiment 58 and 59
These compounds are N-((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-propyl group amino)-2-[(R)-3-((R)-3-tetramethyleneimine-3-base urea groups)-tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate (embodiment 58) and N-((1S, 2R, 3S, 4R)-4-{6-(3,3-phenylbenzene-propyl group amino)-2-[(R)-3-((R)-3-tetramethyleneimine-3-base urea groups)-tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate (embodiment 59), be similar to N-((1S, 2R, 3S, 4R)-4-{6-(1-ethyl-propyl group amino)-2-[(R)-3-((R)-3-tetramethyleneimine-3-base urea groups)-tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the propionic acid amide trifluoroacetate prepared, wherein replace N-{ (1S with suitable raw material, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide, the preparation of raw material is as described herein.
Embodiment 60 and 61
These compounds are N-((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-propyl group amino)-2-[2-(1-ethyl-1H-imidazol-4 yl)-ethylamino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate (embodiment 60) and N-((1S, 2R, 3S, 4R)-4-{6-(3,3-phenylbenzene-propyl group-amino)-2-[2-(1-ethyl-1H-imidazol-4 yl)-ethylamino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate (embodiment 61), be similar to N-{ (1S, 2R, 3S, 4R)-and 4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-the propionic acid amide trifluoroacetate prepared, wherein use 2-(1-ethyl-1H-imidazol-4 yl)-ethylamine to replace (3R)-3-(BOC-amino) tetramethyleneimine, replace N-{ (1S with suitable raw material, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide, the preparation of raw material is as described herein.
Embodiment 62
N-((1S, 2R, 3S, 4R)-4-{6-(3,3-dimethyl-butyl amino)-2-[(R)-3-((R)-3-tetramethyleneimine-3-base
Urea groups)-tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the propionic acid amide trifluoroacetate
Be similar to N-((1S, 2R, 3S, 4R)-4-{6-(1-ethyl-propyl group amino)-2-[(R)-3-((R)-3-tetramethyleneimine-3-base urea groups)-tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the propionic acid amide trifluoroacetate prepares title compound, wherein use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(3,3-dimethyl-butyl amino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide trifluoroacetate replacement N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide.
Embodiment 63
N-{ (1S, 2R, 3S, 4R)-4-[6-(1-ethyl-propyl group amino)-2-((S)-1-methylol-2-phenyl-ethyl ammonia
Base)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-the propionic acid amide trifluoroacetate
Be similar to N-{ (1S, 2R, 3S, 4R)-4-[6-(2,2-phenylbenzene-ethylamino)-and 2-((S)-1-methylol-2-phenyl-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 16) prepares this compound, wherein uses N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 14) replacement N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 4).
Embodiment 64
N-((1S, 2R, 3S, 4R)-4-{6-(1-ethyl-propyl group amino)-2-[((R)-1-ethyl-tetramethyleneimine-2-Ji Jia
Base)-amino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the propionic acid amide trifluoroacetate
Be similar to N-{ (1S, 2R, 3S, 4R)-4-[6-(2,2-phenylbenzene-ethylamino)-and 2-((S)-1-methylol-2-phenyl-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 16) prepares this compound, wherein use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 14) replacement N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 4), replace (S)-2-amino-3-phenyl-third-1-alcohol with C-((R)-1-ethyl-tetramethyleneimine-2-yl)-methylamine.
Embodiment 65
N-{ (1S, 2R, 3S, 4R)-4-[6-amino-2-((S)-1-methylol-2-phenyl-ethylamino)-purine-9-
Base]-2,3-dihydroxyl-cyclopentyl }-the propionic acid amide trifluoroacetate
N-((1S, 2R, 3S, 4R)-and 4-{2-chloro-6-[(9H-fluorenes-9-ylmethyl) amino]-purine-9-yl }-2, the 3-dihydroxyl
-cyclopentyl)-propionic acid amide
Be similar to N-((1S, 2R, 3S, 4R)-4-{2-chloro-6-[(naphthalene-1-ylmethyl)-amino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate (embodiment 50) prepares this compound, wherein uses C-(9H-fluorenes-9-yl)-methylamine to replace 1-naphthalene methylamine.
N-{ (1S, 2R, 3S, 4R)-4-[6-amino-2-((S)-1-methylol-2-phenyl-ethylamino)-purine-9-
Base]-2,3-dihydroxyl-cyclopentyl }-the propionic acid amide trifluoroacetate
Be similar to N-{ (1S, 2R, 3S, 4R)-4-[6-(2,2-phenylbenzene-ethylamino)-and 2-((S)-1-methylol-2-phenyl-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 16) prepares this compound, wherein uses N-((1S, 2R, 3S, 4R)-4-{2-chloro-6-[(9H-fluorenes-9-ylmethyl)-amino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide replacement N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 4).
Embodiment 66
N-((1S, 2R, 3S, 4R)-2,3-dihydroxyl-4-[6-[(naphthalene-1-ylmethyl)-amino]-2-(2-piperidines-1-base-second
Base is amino)-purine-9-yl]-cyclopentyl }-the propionic acid amide trifluoroacetate
Be similar to N-{ (1S, 2R, 3S, 4R)-4-[6-(2,2-phenylbenzene-ethylamino)-and 2-((S)-1-methylol-2-phenyl-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 16) prepares this compound, wherein use N-((1S, 2R, 3S, 4R)-4-{2-chloro-6-[(naphthalene-1-ylmethyl)-amino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate (embodiment 50) replacement N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 4), replace (S)-2-amino-3-phenyl-third-1-alcohol with 2-piperidines-1-base-ethylamine.
Embodiment 67-69
These compounds promptly
N-((1S, 2R, 3S, 4R)-4-{2-(4-amino-cyclohexyl amino)-6-[(naphthalene-1-ylmethyl)-amino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate (embodiment 67),
N-((1S, 2R, 3S, 4R)-2,3-dihydroxyl-4-{2-[2-(1H-imidazol-4 yl)-ethylamino]-6-[(naphthalene-1-ylmethyl)-amino]-purine-9-yl-cyclopentyl)-propionic acid amide trifluoroacetate (embodiment 68) and
N-((1S, 2R, 3S, 4R)-4-{2-[((R)-1-ethyl-tetramethyleneimine-2-ylmethyl)-amino]-6-[(naphthalene-1-ylmethyl)-amino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate (embodiment 69),
Be similar to N-{ (1S, 2R, 3S, 4R)-2,3-dihydroxyl-4-[6-[(naphthalene-1-ylmethyl)-amino]-2-(2-piperidines-1-base-ethylamino)-purine-9-yl]-cyclopentyl }-propionic acid amide trifluoroacetate (embodiment 66) prepared, and wherein replaces 2-piperidines-1-base-ethylamine with suitable amine.
Embodiment 70
These compounds promptly
N-{ (1S, 2R, 3S, 4R)-and 4-[2-(4-amino-cyclohexyl amino)-6-(3,3-dimethyl-butyl amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide trifluoroacetate (embodiment 70),
N-((1S, 2R, 3S, 4R)-4-{6-(3,3-dimethyl-butyl amino)-2-[2-(1H-imidazol-4 yl)-ethylamino]-purine-9-yl-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate (embodiment 71) and
N-((1S, 2R, 3S, 4R)-4-{6-(3,3-dimethyl-butyl amino)-2-[((R)-1-ethyl-tetramethyleneimine-2-ylmethyl)-amino]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate (embodiment 72),
Be similar to N-{ (1S, 2R, 3S, 4R)-and 4-[6-(2,2-phenylbenzene-ethylamino)-2-((S)-1-methylol-2-phenyl-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 16) prepared, wherein use N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(3,3-dimethyl-butyl amino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide trifluoroacetate (embodiment 51) replacement N-{ (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 4), replace the L-phenylalaninol with suitable amine.
Embodiment 73
N-[(1S, 2R, 3S, 4R)-4-(2-{ (R)-3-[3-(2,6-two chloro-pyridin-4-yls)-urea groups]-tetramethyleneimine-1-
Base }-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoro second
Hydrochlorate
With N-{ (1S; 2R; 3S, 4R)-4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethyl-amino)-purine-9-yl]-2; 3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 36) (23mg; 40 μ mol) THF (1ml) solution is handled with TEA (7.3mg, 72 μ mol), joins 2 then; in 6-two chloro-4-isocyanide acyl group-pyridines (6.8mg, 36 μ mol).Reaction mixture is shaken in room temperature, place then and spend the night.Remove in a vacuum and desolvate, through the preparation type LC-MS purifying that quality is pointed to, use acetonitrile: water: the trifluoroacetic acid wash-out obtains title compound.
Embodiment 74
N-((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[(R)-3-(3-thiophene-2-base-urea groups)-
Tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the propionic acid amide trifluoroacetate
Be similar to N-{ (1S; 2R; 3S; 4R)-4-[2-{ (R)-3-[3-(2; 6-two chloro-pyridin-4-yls)-urea groups]-tetramethyleneimine-1-yl }-6-(2,2-phenylbenzene-ethylamino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide trifluoroacetate (embodiment 73) prepares this compound; wherein replace 2,6-two chloro-4-isocyanide acyl group-pyridines with 2-thienyl isocyanic ester.
Embodiment 75
N-((1S, 2R, 3S, 4R)-4-(6-(2,2-phenylbenzene-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-urea groups)-
Tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the propionic acid amide trifluoroacetate
Be similar to 9-((1R; 2S; 3R; 4S)-and 4-acetylaminohydroxyphenylarsonic acid 2,3-dihydroxyl-cyclopentyl)-(2,2-phenylbenzene-ethylamino)-{ 2-[3-(3 for 9H-purine-2-formic acid for 6-; 4; 5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl)-urea groups]-ethyl }-acid amides trifluoroacetate (embodiment 42) prepares this compound; wherein use N-{ (1S; 2R, 3S, 4R)-4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2; 2-phenylbenzene-ethylamino)-and purine-9-yl]-2; 3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 36) replacement 9-((1R, 2S, 3R; 4S)-4-amino-2; 3-dihydroxyl-cyclopentyl)-(2,2-phenylbenzene-ethylamino)-{ 2-[3-(3,4 for 9H-purine-2-formic acid for 6-; 5; 6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl)-urea groups]-ethyl }-acid amides dihydrochloride (intermediate of preparation embodiment 38), with 3-isocyanide acyl group-pyridine replacing acetyl chloride.
Embodiment 76
Cyclobutane formate ((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[(R)-3-((R)-3-pyrrole
Cough up alkane-3-base urea groups)-tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-acid amides
Be similar to N-((1S, 2R, 3S, 4R)-4-{6-(1-ethyl-propyl group amino)-2-[(R)-3-((R)-3-tetramethyleneimine-3-base urea groups)-tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate (embodiment 54) prepares this compound, wherein use cyclobutane formate { (1S, 2R, 3S, 4R)-4-[2-chloro-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-acid amides (being used to prepare the intermediate of embodiment 23) replacement N-{ (1S, 2R, 3S, 4R)-and 4-[2-chloro-6-(1-ethyl-propyl group amino)-purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 14).
Embodiment 77
4-methyl-piperazine-1-formic acid (R)-1-[9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-ring penta
Base)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-yl]-tetramethyleneimine-3-yl }-the acid amides trifluoroacetate
Imidazoles-1-formic acid ((R)-1-[9-((3aS, 4R, 6S, 6aR)-2,2-dimethyl-6-propionamido-tetrahydrochysene-ring penta
Diene is [1,3] Dioxol-4-yl also)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-yl]-pyrrole
Cough up alkane-3-yl }-acid amides
With N-{ (3aR, 4S, 6R, 6aS)-6-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,2-dimethyl-tetrahydrochysene-cyclopenta [1,3] Dioxol-4-yl }-propionic acid amide (referring to the preparation of intermediate) (0.24g, 0.39mmol) (0.275g, 1.7mmol) mixture in DCM was stirring at room 3 hours with CDI.The gained mixture is through the silicon-dioxide chromatogram purification, and the DCM eluant solution with 0-5%MeOH obtains title compound, is xanchromatic oil.This compound exists with the mixture of imidazoles-urea intermediate and corresponding isocyanic ester of variable quantity and imidazoles, and they are suitable as the precursor of urea equally.
4-methyl-piperazine-1-formic acid (R)-1-[9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-ring penta
Base)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-yl]-tetramethyleneimine-3-yl }-the acid amides trifluoroacetate
With imidazoles-1-formic acid (R)-1-[9-((3aS, 4R, 6S, 6aR)-2,2-dimethyl-6-propionamido-tetrahydrochysene-cyclopenta [1,3] Dioxol-4-yl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-yl]-tetramethyleneimine-3-yl }-acid amides (25mg, 40 μ mol) DCM (1ml) solution joins in the 1-methylpiperazine (4mg, 40 μ mol), with reaction mixture in stirred overnight at room temperature.Remove in a vacuum and desolvate, with crude product with the processing of 1: 1 TFA/ water (1ml), stirring at room 3 hours.Concentrated reaction mixture passes through the preparation type LC-MS purifying that quality is pointed in a vacuum, and use acetonitrile: water: the trifluoroacetic acid wash-out obtains title compound.
Embodiment 78
N-((1S, 2R, 3S, 4R)-4-{6-(2,2-phenylbenzene-ethylamino)-2-[(R)-3-(3-pyridine-2-base-urea groups)-
Tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-the propionic acid amide trifluoroacetate
Be similar to 4-methyl-piperazine-1-formic acid (R)-1-[9-((1R, 2S, 3R, 4S)-2,3-dihydroxyl-4-propionamido-cyclopentyl)-6-(2,2-phenylbenzene-ethylamino)-9H-purine-2-yl]-tetramethyleneimine-3-yl }-acid amides trifluoroacetate (embodiment 77) prepares this compound, wherein replaces the 1-methylpiperazine with the 2-aminopyridine.
Embodiment 79
N-((1S, 2R, 3S, 4R)-4-(6-(2,2-phenylbenzene-ethylamino)-2-[(R)-3-(3-pyridin-4-yl-urea groups)-
Tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionamide hydrochloride
With N-{ (1S, 2R, 3S, 4R)-4-[2-((R)-3-amino-tetramethyleneimine-1-yl)-6-(2,2-phenylbenzene-ethylamino)-and purine-9-yl]-2,3-dihydroxyl-cyclopentyl }-propionic acid amide (embodiment 36) (16.6mg, 29 μ mol) with pyridin-4-yl-carboxylamine phenylester (according to Journal of Medicinal Chemistry (2005), 48 (6), the prepared that 1857-1872 reported) (6.9mg, 32 μ mol) mixture in NMP (0.5ml) is 100 ℃ of heating 1 hour, then in stirred overnight at room temperature.Product is through reversed-phase column chromatography purifying (Isolute
TMC18,0-100% acetonitrile solution-0.1% HCl), obtain title compound.[MH+691]。
Embodiment 80
N-((1S, 2R, 3S, 4R)-4-{6-amino-2-[(R)-3-(3-pyridin-3-yl-urea groups)-tetramethyleneimine-1-yl]-purine
-9-yl }-2,3-dihydroxyl-cyclopentyl }-propionic acid amide
Be similar to N-((1S, 2R, 3S, 4R)-4-{6-(1-ethyl-propyl group amino)-2-[(R)-3-((R)-3-tetramethyleneimine-3-base urea groups)-tetramethyleneimine-1-yl]-purine-9-yl }-2,3-dihydroxyl-cyclopentyl)-propionic acid amide trifluoroacetate (embodiment 54) prepares this compound.
Claims (11)
1. the formula I compound of free or salt form,
Wherein
R
1Be hydrogen, optional by R
4Replace-C (=O)-C (=O)-NH-C
1-C
8-alkyl, C
1-C
8-alkyl-carbonyl, C
3-C
8-naphthene base carbonyl ,-SO
2-C
1-C
8-alkyl or C
7-C
14-aromatic alkyl carbonyl;
R
2Be hydrogen or optional by C
6-C
10The C that-aryl replaces
1-C
8-alkyl;
R
3Be hydrogen, halogeno-group, C
2-C
8-thiazolinyl or C
2-C
8-alkynyl,
Perhaps R
3Be optional by C
3-C
8The amino of-cycloalkyl substituted, wherein C
3-C
8-cycloalkyl is optional to be replaced by amino,
Perhaps R
3Be optional by hydroxyl, C
6-C
10-aryl or R
5The C that replaces
1-C
8-alkylamino,
Perhaps R
3Be optional by amino or-NH-C (=O)-NH-R
7The R that replaces
6,
Perhaps R
3Be optional quilt-NH-C (=O)-NH-R
7Replace-NH-R
6,
Perhaps R
3Be optional by amino, C
1-C
8-alkylamino, two (C
1-C
8-alkyl) amino or-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl or C
3-C
8-cycloalkyl amino carbonyl;
R
4, R
5And R
6Be 5-or 6-unit heterocycle independently, contain the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur, described 5-or 6-unit heterocycle are alternatively by halogeno-group, cyano group, oxo base, hydroxyl, carboxyl, amino, nitro, C
1-C
8-alkyl, C
1-C
8-alkyl sulphonyl, aminocarboxyl, C
1-C
8-alkyl-carbonyl or the optional C that is replaced by aminocarboxyl
1-C
8-alkoxyl group replaces;
R
7And R
8Be 5-or 6-unit heterocycle independently, contain the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur, described 5-or 6-unit heterocycle are alternatively by halogeno-group, cyano group, oxo base, hydroxyl, carboxyl, amino, nitro, C
1-C
8-alkyl, C
1-C
8-alkyl sulphonyl, aminocarboxyl, C
1-C
8-alkyl-carbonyl, the optional C that is replaced by aminocarboxyl
1-C
8-alkoxyl group or 5-or 6-unit heterocyclic substituted, described 5-or 6-unit heterocycle contain the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur, and alternatively by halogeno-group, cyano group, oxo base, hydroxyl, carboxyl, amino, nitro, C
1-C
8-alkyl, C
1-C
8-alkyl sulphonyl, aminocarboxyl, C
1-C
8-alkyl-carbonyl, the optional C that is replaced by aminocarboxyl
1-C
8-alkoxyl group replaces;
Condition is: R
1, R
2And R
3At least one be not hydrogen.
2. according to the compound of claim 1, wherein
R
1Be optional by R
4Replace-C (=O)-C (=O)-NH-C
1-C
8-alkyl, C
1-C
8-alkyl-carbonyl, C
3-C
8-naphthene base carbonyl ,-SO
2-C
1-C
8-alkyl or C
7-C
14-aromatic alkyl carbonyl;
R
2Be hydrogen or optional by C
6-C
10The C that-aryl replaces
1-C
8-alkyl;
R
3Be halogeno-group or C
2-C
8-alkynyl,
Perhaps R
3Be optional by C
3-C
8The amino of-cycloalkyl substituted, wherein C
3-C
8-cycloalkyl is optional to be replaced by amino,
Perhaps R
3Be optional by hydroxyl, C
6-C
10-aryl or R
5The C that replaces
1-C
8-alkylamino,
Perhaps R
3Be optional by amino or-NH-C (=O)-NH-R
7The R that replaces
6,
Perhaps R
3Be optional quilt-NH-C (=O)-NH-R
7Replace-NH-R
6,
Perhaps R
3Be optional quilt-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl;
R
4, R
5And R
6Be 5-or 6-unit heterocycle independently, contain the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur, described 5-or 6-unit heterocycle are alternatively by C
1-C
8-alkyl replaces; And
R
7And R
8Be 5-or 6-unit heterocycle independently, contain the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur, described 5-or 6-unit heterocycle are alternatively by halogeno-group, C
1-C
8-alkyl, C
1-C
8-alkyl sulphonyl or contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or 6-unit heterocyclic substituted.
3. according to the compound of claim 1, wherein
R
1Be alternatively a position by R
4Replace-C (=O)-C (=O)-NH-C
1-C
4-alkyl, C
1-C
4-alkyl-carbonyl, C
3-C
5-naphthene base carbonyl ,-SO
2-C
1-C
4-alkyl or C
7-C
10-aromatic alkyl carbonyl;
R
2Be hydrogen, unsubstituted C
1-C
6-alkyl or a position by C
6-C
10The C that-aryl replaces
1-C
5-alkyl;
R
3Be halogeno-group or C
2-C
6-alkynyl,
Perhaps R
3Be alternatively a position by C
3-C
6The amino of-cycloalkyl substituted, wherein C
3-C
6-cycloalkyl is replaced by amino a position alternatively,
Perhaps R
3Be by hydroxyl, phenyl or R in one or two position
5The C that replaces
1-C
4-alkylamino,
Perhaps R
3Be alternatively a position by amino or-NH-C (=O)-NH-R
7The R that replaces
6,
Perhaps R
3Be alternatively a position quilt-NH-C (=O)-NH-R
7Replace-NH-R
6,
Perhaps R
3Be a position quilt-NH-C (=O)-NH-R
8The C that replaces
1-C
4-alkyl amino-carbonyl;
R
4, R
5And R
6Be 5-or 6-unit heterocycle independently, contain the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur, described 5-or 6-unit heterocycle alternatively a position by C
1-C
4-alkyl replaces; And
R
7And R
8Be 5-or 6-unit heterocycle independently, contain the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur, described 5-or 6-unit heterocycle alternatively in one or two position by halogeno-group, C
1-C
4-alkyl, C
1-C
4-alkyl sulphonyl or 5-or the 6-N-of unit heterocyclic substituted.
4. according to the compound of claim 1, wherein
R
1Be hydrogen, optional by R
4Replace-C (=O)-C (=O)-NH-C
1-C
8-alkyl, C
1-C
8-alkyl-carbonyl, C
3-C
8-naphthene base carbonyl ,-SO
2-C
1-C
8-alkyl or C
7-C
14-aromatic alkyl carbonyl;
R
2Be hydrogen or optional by C
6-C
10The C that-aryl replaces
1-C
8-alkyl;
R
3Be hydrogen, halogeno-group, C
2-C
8-thiazolinyl or C
2-C
8-alkynyl,
Perhaps R
3Be optional by C
3-C
8The amino of-cycloalkyl substituted, wherein C
3-C
8-cycloalkyl is optional to be replaced by amino,
Perhaps R
3Be optional by hydroxyl, C
6-C
10-aryl or R
5The C that replaces
1-C
8-alkylamino,
Perhaps R
3Be optional by amino or-NH-C (=O)-NH-R
7The R that replaces
6,
Perhaps R
3Be optional by amino, C
1-C
8-alkylamino, two (C
1-C
8-alkyl) amino or-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl or C
3-C
8-cycloalkyl amino carbonyl;
R
4, R
5And R
6Be 5-or 6-unit heterocycle independently, contain the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur; And
R
7And R
8Be 5-or 6-unit heterocycle independently, contain the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur, described 5-or 6-unit heterocycle are contained the 5-or the 6-unit heterocyclic substituted of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur alternatively;
Condition is: R
1, R
2And R
3At least one be not hydrogen.
5. according to the compound of claim 4, wherein
R
1Be optional by R
4Replace-C (=O)-C (=O)-NH-C
1-C
8-alkyl, C
1-C
8-alkyl-carbonyl, C
3-C
8-naphthene base carbonyl ,-SO
2-C
1-C
8-alkyl or C
7-C
14-aromatic alkyl carbonyl;
R
2Be hydrogen or optional by C
6-C
10The C that-aryl replaces
1-C
8-alkyl;
R
3Be halogeno-group or C
2-C
8-alkynyl,
Perhaps R
3Be optional by C
3-C
8The amino of-cycloalkyl substituted, wherein C
3-C
8-cycloalkyl is optional to be replaced by amino,
Perhaps R
3Be optional by hydroxyl, C
6-C
10-aryl or R
5The C that replaces
1-C
8-alkylamino,
Perhaps R
3Be optional by amino or-NH-C (=O)-NH-R
7The R that replaces
6,
Perhaps R
3Be optional quilt-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl;
R
4, R
5And R
6Be 5-or 6-unit heterocycle independently, contain the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur; And
R
7And R
8Be 5-or 6-unit heterocycle independently, contain the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur, described 5-or 6-unit heterocycle are contained the 5-or the 6-unit heterocyclic substituted of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur alternatively.
6. according to the compound of claim 5, wherein
R
1Be optional by R
4Replace-C (=O)-C (=O)-NH-C
1-C
4-alkyl, C
1-C
4-alkyl-carbonyl, C
3-C
6-naphthene base carbonyl ,-SO
2-C
1-C
4-alkyl or C
7-C
10-aromatic alkyl carbonyl;
R
2Be hydrogen or optional by C
6-C
10The C that-aryl replaces
1-C
6-alkyl;
R
3Be halogeno-group or C
2-C
5-alkynyl,
Perhaps R
3Be optional by C
3-C
8The amino of-cycloalkyl substituted, wherein C
3-C
8-cycloalkyl is optional to be replaced by amino,
Perhaps R
3Be optional by hydroxyl, C
6-C
8-aryl or R
5The C that replaces
1-C
4-alkylamino,
Perhaps R
3Be optional by amino or-NH-C (=O)-NH-R
7The R that replaces
6,
Perhaps R
3Be optional quilt-NH-C (=O)-NH-R
8The C that replaces
1-C
4-alkyl amino-carbonyl;
R
4, R
5And R
6Be 5-or 6-unit heterocycle independently, contain the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur; And
R
7And R
8Be 5-or 6-unit heterocycle independently, contain the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur, described 5-or 6-unit heterocycle are contained the 5-or the 6-unit heterocyclic substituted of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur alternatively.
7. according to the formula I compound of claim 1, R wherein
1, R
2And R
3As shown in the table:
8. pharmaceutical composition comprises the compound any according to claim 1 to 7 as activeconstituents, alternatively and pharmaceutically acceptable diluent or carrier.
9. be used for the treatment of by adenosine A in preparation according to any one compound of claim 1 to 7
2APurposes in the medicine of the illness of receptor activation mediation.
10. be used for the treatment of purposes in the medicine of inflammatory or obstructive airway diseases according to any one compound of claim 1 to 7 in preparation.
Dissociate or the method for the formula I compound of salt form 11. preparation as claim 1 be defined, comprise
(i) (A) with regard to the preparation of formula I compound, in the presence of alkali, make formula II compound
R wherein
2And R
3As defined above, with the formula III compound
R
1-X
a III
Or the reaction of formula III a compound,
R wherein
1Be hydrogen, C
1-C
8-alkyl-carbonyl, C
3-C
8-naphthene base carbonyl or C
7-C
14-aromatic alkyl carbonyl, X
aBe leavings group, K is hydrogen, C
1-C
8-alkyl or C
1-C
8-alkoxyl group;
(B) with regard to regard to the preparation of I compound, R wherein
3By the optional C that is replaced by amino
3-C
8The amino of-cycloalkyl substituted, perhaps R
3Be optional by hydroxyl, C
6-C
10-aryl or R
5The C that replaces
1-C
8-alkylamino, perhaps R
3Be optional by amino or-NH-C (=O)-NH-R
7The R that replaces
6, make formula IV compound
R wherein
1And R
2Such as claim 1 definition, X is a halogeno-group,
With formula Va or the reaction of formula Vb compound,
H
2N-R
3a Va
R wherein
3aBe optional by the amino C that replaces
3-C
8-cycloalkyl, perhaps R
3Be optional by hydroxyl, C
6-C
10-aryl or R
5The C that replaces
1-C
8-alkyl, wherein R
5Such as claim 1 definition, R
3bAnd R
3cConstitute 5-or 6-unit heterocycle together, its contain one or more nitrogen-atoms and alternatively by amino or-NH-C (=O)-NH-R
7Replace, wherein R
7Such as claim 1 definition;
(C) with regard to the preparation of formula I compound, in the presence of alkali, make formula VI compound
R wherein
1And R
3Such as claim 1 definition, X is a halogeno-group, with formula VII compound reaction,
H
2N-R
2 VII
R wherein
2Such as claim 1 definition;
(D) with regard to the preparation of formula I compound, formula VIII compound is gone protection,
R wherein
1, R
2And R
3Such as claim 1 definition, L is C
1-C
8-alkyl;
(E) with regard to regard to the preparation of I compound, R wherein
3By-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl or C
3-C
8-cycloalkyl amino carbonyl, wherein R
8Such as claim 1 definition, in the presence of alkali, make formula IX compound
R wherein
1And R
2Such as claim 1 definition, Y is C
1-C
8-alkyl or C
3-C
8-cycloalkyl,
With formula X compound
Or the reaction of formula XI compound,
O＝C＝N-R
8 XI
Wherein T is C
6-C
10-aryloxy or contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or 6-unit heterocycle, R
8Such as claim 1 definition;
(F) with regard to regard to the preparation of I compound, R wherein
3Be C
2-C
8-alkynyl,
In the presence of alkali and catalyzer, make wherein R
1And R
2As the defined formula IV compound of claim 1
With the reaction of formula XII compound,
R
x-C≡C-H XII
R wherein
xBe C
1-C
8-alkyl;
(G) with regard to regard to the preparation of I compound, R wherein
3Be optional quilt-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl,
In the presence of alkali, make formula XIIa compound alternatively
R wherein
1And R
2Such as claim 1 definition, R
yBe C
1-C
8-alkyl,
With the reaction of formula XIIb compound,
R wherein
zBe C
1-C
8-alkyl ,-NH-C (=O)-NH-R
8Such as claim 1 definition; Perhaps
(H) with regard to regard to the preparation of I compound, R wherein
3By-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl, wherein R
8Be 5-or the 6-unit heterocycle that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur, this encircles by C
1-C
8-alkyl sulphonyl replaces,
In the presence of alkali, make wherein R
3By-NH-C (=O)-NH-R
8The C that replaces
1-C
8-alkyl amino-carbonyl, R wherein
8Be 5-or 6-unit's heterocyclic formula I compound and the sulfonyl agent reaction that contains at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur;
(I) with regard to regard to the preparation of I compound, R wherein
3By-NH-C (=O)-NH-R
7The R that replaces
6, R wherein
7Such as claim 1 definition,
Make formula XIIc compound
R wherein
1And R
2Such as claim 1 definition, R
6Be to contain at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur, the 5-that is replaced by amino a position or 6-unit heterocycle,
With formula Xa compound
Or the reaction of formula XIa compound,
O＝C＝N-R
7 XIa
Wherein T is C
6-C
10-aryloxy or contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or 6-unit heterocycle, R
8Such as claim 1 definition;
(J) with regard to regard to the preparation of I compound, R wherein
3By-NH-C (=O)-NH-R
7The R that replaces
6, R wherein
7Such as claim 1 definition,
Make formula XIId or XIIe compound or its protected form
R wherein
1, R
2And R
6Such as claim 1 definition, T is C
6-C
10-aryloxy or contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or 6-unit heterocycle,
With the reaction of formula XIIf compound,
R wherein
3dAnd R
3eConstitute the 5-or the 6-N-of the unit heterocycle that contain at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur together, described 5-or 6-unit heterocycle are alternatively by halogeno-group, cyano group, oxo base, hydroxyl, carboxyl, amino, nitro, C
1-C
8-alkyl, C
1-C
8-alkyl sulphonyl, aminocarboxyl, C
1-C
8-alkyl-carbonyl, the optional C that is replaced by aminocarboxyl
1-C
8-alkoxyl group or contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or 6-unit heterocyclic substituted; Perhaps
(K) with regard to regard to the preparation of I compound, R wherein
3By-NH-C (=O)-NH-R
7The R that replaces
6, R wherein
7As defined above,
Make wherein R
1, R
2And R
6Such as claim 1 definition, T be C
6-C
10-aryloxy or contain the 5-of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur or the 6-heterocyclic formula XIId of unit or XIIe compound react with formula XIIg compound,
H
2N-R
7 XIIg
R wherein
7Such as claim 1 definition; With
(ii) remove any blocking group, reclaim the formula Ia compound of the free or salt form of gained.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0423551A GB0423551D0 (en) | 2004-10-22 | 2004-10-22 | Organic compounds |
| GB0423551.1 | 2004-10-22 | ||
| GB0514619A GB0514619D0 (en) | 2005-07-15 | 2005-07-15 | Organic compounds |
| GB0514619.6 | 2005-07-15 | ||
| PCT/EP2005/011344 WO2006045552A1 (en) | 2004-10-22 | 2005-10-21 | Purine derivatives for use as adenosin a-2a receptor agonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101044141A CN101044141A (en) | 2007-09-26 |
| CN101044141B true CN101044141B (en) | 2010-08-04 |
Family
ID=33485073
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|---|---|---|---|
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Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101044141B (en) |
| GB (1) | GB0423551D0 (en) |
| ZA (1) | ZA200702635B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1365361A (en) * | 1999-07-02 | 2002-08-21 | 卫材株式会社 | Fused imiazole compounds and remedies for diabetes mellitus |
-
2004
- 2004-10-22 GB GB0423551A patent/GB0423551D0/en not_active Ceased
-
2005
- 2005-10-21 CN CN200580036010XA patent/CN101044141B/en not_active Expired - Fee Related
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2007
- 2007-03-29 ZA ZA200702635A patent/ZA200702635B/en unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1365361A (en) * | 1999-07-02 | 2002-08-21 | 卫材株式会社 | Fused imiazole compounds and remedies for diabetes mellitus |
Non-Patent Citations (5)
| Title |
|---|
| Cowart M. et al.Synthesis of Novel CarbocyclicAdenosineAnaloguesasInhibitors of Andenosine Kinase.J. Org. Chem.vol. 64 7.1999,vol. 64(7),2240-2249. * |
| Cowart M.et al.Synthesis of Novel CarbocyclicAdenosineAnaloguesasInhibitors of Andenosine Kinase.J.Org.Chem.vol.64 7.1999,vol. 64(7),2240-2249. * |
| Yang M. M. et al.Amino substitued derivatives of 5＇-amino-5＇-deoxy-5＇-noraristeromycine..Bioorganic & Medicinal Chemistryvol. 13 3.2005,vol. 13(3),877-882. * |
| 同上.全文. * |
| 同上.全文.;Yang M.M.et al.Amino substitued derivatives of 5＇-amino-5＇-deoxy-5＇-noraristeromycine..Bioorganic & Medicinal Chemistryvol.13 3.2005,vol.13(3),877-882. * |
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| ZA200702635B (en) | 2008-07-30 |
| GB0423551D0 (en) | 2004-11-24 |
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