CN101282976A - Xanthine derivatives as selective HM74A agonists - Google Patents
Xanthine derivatives as selective HM74A agonists Download PDFInfo
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- CN101282976A CN101282976A CNA2006800374272A CN200680037427A CN101282976A CN 101282976 A CN101282976 A CN 101282976A CN A2006800374272 A CNA2006800374272 A CN A2006800374272A CN 200680037427 A CN200680037427 A CN 200680037427A CN 101282976 A CN101282976 A CN 101282976A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
Abstract
The present invention relates to compounds1 of formula (I) which are xanthine derivatives, processes for the manufacture of said derivatives, pharmaceutical formulations containing these, compounds and the use of the compounds in therapy, for example, in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial.
Description
The present invention relates to compound for xanthine derivative, the method for preparing described derivative, contain the pharmaceutical preparation of described compound and described compound in treatment, for example in treatment by the caused disease of HM74A receptor activation deficiency (under-activation) or benefit from purposes in the disease that activates the HM74A acceptor.
Hyperlipemia (dyslipidaemia) is the general designation that is used to describe individual lipoprotein abnormalities.Clinically, the main compound type that is used for the treatment of the patient of the cardiovascular disorder danger of suffering from hyperlipemia and causing thus is the special class (fibrates) of Statins (statins), chlorine shellfish, bile acide binding resin (bile acidbinding resin) and nicotinic acid.Nicotinic acid (Niacin, vitamins B) is used for the treatment of the patient surplus in the of 40 year who suffers from multi-form hyperlipemia clinically.The main binding mode of nicotinic acid is by suppressing the triglyceride lipase (HSL) to hormone-sensitive, make blood plasma non-esterified fatty acid (NEFA) reduce, change the liver fat metabolism successively, thereby reduce LDL and VLDL (low-density lipoprotein and vldl) generation.It is believed that the VLDL level reduces can reducing cholesterol fat transfer protein (CETP) activity, causes HDL (high-density lipoprotein (HDL)) level to raise, and this may be to observe cardiovascular benefited reason.Therefore, nicotinic acid has produced the change of making us very satisfied to lipoprotein; VLDL and LDL level have been reduced and the HDL level that raise simultaneously.Confirm also that in addition nicotinic acid has the benefit of alleviating disease, in a plurality of tests, alleviate the deterioration of atherosclerotic lesion and promote it to restore, and reduced the number of times that causes cardiovascular event.
Adopting nicotinic acid to treat viewed HSL restraining effect is to reduce by cAMP in the cell (cAMP) to regulate, and cAMP (cAMP) minimizing is what to be caused by the protein mediated adenylate cyclase enzyme inhibition of G-in the cell.Recently, the acceptor HM74 of G-albumen coupling and acceptor (the PCT patent application WO02/84298 that HM74A is nicotinic acid have been identified; People .J Biol Chem. such as Wise, 2003,278 (11), 9869-9874).The dna sequence dna of people HM74A can find in Genbank; Accession number AY148884.Other two pieces of papers have been supported above-mentioned discovery (people .Nature Medicine such as Tunaru, 2003,9 (3), people such as 352-255 and Soga .Biochem Biophys Res Commun., 2003,303 (1) 364-369), still wherein used name has nuance.In the paper of Tunaru, they claim the people HM74, and we claim HM74A, and in the paper of Soga, HM74b is exactly HM74A.The cell of transfection expression HM74A and/or HM74 has obtained initiation G after being exposed to nicotinic acid
iThe ability of the protein mediated response of G-.In the mouse that lacks HM74A (m-PUMA-G) homologue, nicotinic acid can not reduce plasmal NE FA level.
Some xanthine derivative is synthetic and open in the prior art.For example, EP0389282 discloses the xanthine derivative as the potential mediator of cerebrovascular disease.A series of xanthine derivatives are by .in J.Med.Chem. such as Jacobson, and 1993,36,2639-2644 is defined as adenosine receptor antagonists.
We find a class xanthine derivative at present, and it is the selective agonist of niacin receptor HM74A, thereby it is in treatment, prevention with to suppress to be activated by this receptor not enough caused disease or benefit from the disease that activates this receptor be useful.
Summary of the invention
The invention provides xanthine derivative and described derivative in treatment, for example treatment by the HM74A receptor activation not enough caused disease or benefit from purposes in the disease that activates this receptor.For example; treatment lipid metabolism disease comprises hyperlipemia or hyperlipoproteinemia for example diabetes hyperlipemia and mixing hyperlipemia (mixed dyslipidaemia); in heart failure; hypercholesterolemia (hypercholesteraemia), cardiovascular disorder comprises atherosclerosis, arteriosclerosis and hypertriglyceridemia.The compounds of this invention can also be used as coronary artery disease equally, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease and apoplexy, and the therapeutical agent of the cardiovascular indications relevant with type ii diabetes, type i diabetes, insulin resistant, hyperlipidaemia, anorexia nervosa, obesity.The compounds of this invention also can be used for treating various inflammatory diseasess or illness as described below.
Various intermediate as herein described, preparation, method and step have constituted the present invention on the other hand.
Detailed description of the invention
According to an aspect of the present invention, we provide at least a compound chemistry individuality that is selected from formula (I)
And pharmaceutically acceptable derivates, wherein
R
1Expression-(alkylidene group)
m-X-(alkylidene group)
n-Y;
Wherein X represents A, A1, A2 or directly connects;
A represents to be selected from following group:
Cycloalkylidene, inferior cycloalkenyl group, aryl, heteroaryl, heterocyclic radical and-CH
2-OC (O)-;
A1 represents to be selected from following group:
-CH
2-O-(CH
2)
qAryl-O-,-CH
2-O-(CH
2)
wN (R
5) C (O) O-,-CH
2-N (R
5) C (O) O-,-CH
2-N (R
5) C (O)-,-CH
2-(O)
p-(CH
2)
qC (O) NR
5-,-CH
2-N (R
5) C (O) N (R
5)-,-CH
2-C (O) N ((CH
2)
wOH)-,-CH
2-NR
5-S (O)
2-, CH
2-S (O)
2NR
5-,-CH
2-C (O) O-,-O-,-NR
5-and-S-;
A
2Expression-CH (OH)-;
When X was A, A1 or A2, Y represented to be selected from following group:
Heteroaryl, heterocyclic radical, aryl, cycloalkyl, cycloalkenyl group ,-the NH-aryl ,-O (CH
2)
n-aryl ,-the O-heteroaryl ,-OR
5,-C (O) OR
5,-C (O) O-C6 aryl ,-OC (O) R
4,-CH (aryl)
2,-CH (heteroaryl)
2With-C
1-6Haloalkyl;
When X is that A1 and Y are selected from:
-O (CH
2)
n-aryl ,-the O-heteroaryl ,-OR
5,-OC (O) R
4During with-NH-aryl,
N is selected from 2,3,4 and 5 integer;
When X is that A1 and Y are-C
1-6During haloalkyl, or when X was A2, n was selected from 1,2,3,4 and 5 integer;
When X is when directly connecting, (m+n) be the integer that is selected from 2-10;
When X is directly to connect and (m+n) is that Y represents to be selected from when being selected from the integer of 3-10:
-C (O) (CH
2)
qOR
4,-C (O)-aryl ,-C (O)-heteroaryl ,-C (O)-heterocyclic radical, heteroaryl, heterocyclic radical, aryl, 3 or 4 rings condense system ,-CH (aryl)
2,-CH (heteroaryl)
2,-OR
5,-NR
5R
6,-NR
5C (O) OR
7,-(O)
pC (O) NR
5R
7With-NR
5C (O) R
7Group;
When X directly connects and (m+n) when being 2, Y represents to be selected from:
-OR
5,-NH
2With-NR
5C (O) OR
8Group;
When Y introduced ring, this ring can be optional by one or more C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, halogen ,-(CH
2)
qNR
5R
7,-(CH
2)
q-(O)
p-(CH
2)
q-N (R
5) C (O) OR
8,-(CH
2)
q-N (R
5) C (O) R
8,-(CH
2)
q-(O)
p-(CH
2)
q-C (O) NR
5R
6,-(CH
2)
q-N (R
5) C (O) N (R
5) R
6,-(CH
2)
q-C (O) N ((CH
2)
mOH) R
5,-(CH
2)
q-N (R
5)-S (O)
2R
8,-CH
2-S (O)
2N (R
5) R
6,-C
1-6Haloalkyl ,-OCF
3,-OCH (F)
2,-OCH
2F ,-C (O) OR
5,-OR
5,-R
8CN ,-CN ,-SO
2R
9,-(CH
2)
nHeteroaryl ,-(CH
2)
nHeterocyclic radical ,-(CH
2)
nCycloalkyl ,-(CH
2)
nCycloalkenyl group and-(CH
2)
nAryl replaces;
Condition be when X be A1, A1 is-during ring that O-and Y are replaced by aryl or heteroaryl, m is selected from 3,4 and 5 integer so;
R
2Be selected from hydrogen, C
1-10Alkyl, C
2-10Alkenyl, C
2-10Alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, its each can be optionally to be replaced by one or more group, described group is independently selected from: C
1-10Alkyl, C
2-10Alkenyl, C
2-10Alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-6Haloalkyl, halogen ,-CN ,-OR
4,-(CH
2)
nCOR
4,-C (O) OR
4,-OCOR
4,-(CH
2)
nNR
5R
6,-(NH)
pCONR
5R
6,-OCONR
5R
7With-NR
5C (O) OR
7
R
3Expression is selected from the group of halogen and CN;
R
4Be selected from hydrogen, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl ,-(CH
2)
nCycloalkyl ,-(CH
2)
nCycloalkenyl group ,-(CH
2)
nHeterocyclic radical ,-(CH
2)
nAryl and-(CH
2)
nHeteroaryl;
R
5And R
6Be independently selected from hydrogen and C
1-4Alkyl;
R
7Expression is selected from H, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl ,-(CH
2)
tCycloalkyl ,-(CH
2)
nCycloalkenyl group ,-(CH
2)
tHeterocyclic radical ,-(CH
2)
tAryl and-(CH
2)
tThe group of heteroaryl;
R
8Expression is selected from C
1-4The group of alkyl;
R
9Expression is selected from C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl ,-(CH
2)
nCycloalkyl ,-(CH
2)
nCycloalkenyl group ,-(CH
2)
nHeterocyclic radical ,-(CH
2)
nAryl ,-(CH
2)
nThe group of heteroaryl and CN;
M represents to be selected from 1,2,3,4 and 5 integer;
N represents to be selected from 0,1,2,3,4 and 5 integer;
P represents to be selected from 0 and 1 integer;
Q represents to be selected from 0,1 and 2 integer;
T represents to be selected from 1 and 2 integer; With
W represents to be selected from 2,3 and 4 integer.
The compounds of this invention can be used for treating by the not enough caused disease of HM74A receptor activation or benefits from the disease that activates this receptor.For example comprise hyperlipemia or hyperlipoproteinemia for example diabetes hyperlipemia and mixing hyperlipemia in the lipid metabolism disease; in heart failure; hypercholesterolemia disease, cardiovascular disorder comprise in the treatment of atherosclerosis, arteriosclerosis and hypertriglyceridemia.The compounds of this invention can also be used as and coronary artery disease equally, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease and apoplexy, and the therapeutical agent of the cardiovascular indications relevant with type ii diabetes, type i diabetes, insulin resistant, hyperlipidaemia, anorexia nervosa, obesity.The compounds of this invention equally also can be as agonist or the partial agonist of HM74A.
According to another aspect of the present invention, we provide at least one to be selected from the compound chemistry individuality of formula (I)
And pharmaceutically acceptable derivates, wherein
R
1Expression-(alkylidene group)
m-X-(alkylidene group)
n-Y;
Wherein X represents A, A1, A2 or directly connects;
A represents to be selected from following group
Cycloalkylidene, inferior cycloalkenyl group, aryl, heteroaryl, heterocyclic radical and-CH
2-OC (O)-;
A
1Expression is selected from following group:
-CH
2-O-(CH
2)
qAryl-O-,-CH
2-O-(CH
2)
wN (R
5) C (O) O-,-CH
2-N (R
5) C (O) O-,-CH
2-N (R
5) C (O)-,-CH
2-(O)
p-(CH
2)
qC (O) NR
5-,-CH
2-N (R
5) C (O) N (R
5)-,-CH
2-C (O) N ((CH
2)
wOH)-,-CH
2-NR
5-S (O)
2-, CH
2-S (O)
2NR
5-,-CH
2-C (O) O-,-O-,-NH-and-S-;
A
2Expression:
-CH(OH)-；
When X was A, A1 or A2, Y represented to be selected from following group:
Heteroaryl, heterocyclic radical, aryl, cycloalkyl, cycloalkenyl group ,-the NH-aryl ,-O (CH
2)
n-aryl ,-the O-heteroaryl ,-OR
5,-C (O) OR
5,-C (O) O-C6 aryl ,-OC (O) R
5,-CH (aryl)
2,-CH (heteroaryl)
2With-C
1-6Haloalkyl;
When X is that A1 and Y are selected from:
-O (CH
2)
n-aryl ,-the O-heteroaryl ,-OR
5,-OC (O) R
5During with-NH-aryl,
N is selected from 2,3,4 and 5 integer;
When X is that A1 and Y are-CF
3The time, or when X was A2, n was selected from 1,2,3,4 and 5 integer;
When X is when directly connecting, (m+n) be the integer that is selected from 2-10;
When X is directly to connect and (m+n) is when being selected from the integer of 3-10 that Y represents to be selected from-C (O) (CH
2)
qOR
5,-C (O)-aryl ,-C (O)-heteroaryl ,-C (O)-heterocyclic radical, heteroaryl, heterocyclic radical, aryl, 3 or 4 rings condense system ,-CH (aryl)
2,-CH (heteroaryl)
2,-OR
5,-NR
5R
6,-NC (O) OR
8,-(O)
pC (O) NR
5R
6With-NR
5C (O) R
8Group;
When X directly connects and (m+n) when being 2, Y represents to be selected from
-OR
5,-NH
2With-NC (O) OR
8Group;
When Y introduced ring, this ring can be chosen wantonly by one or more C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, halogen ,-NH
2,-(CH
2)
q-(O)
p-(CH
2)
q-N (R
5) C (O) OR
8,-(CH
2)
q-N (R
5) C (O) R
8,-(CH
2)
q-(O)
p-(CH
2)
q-C (O) NR
5R
6,-(CH
2)
q-N (R
5) C (O) N (R
5) R
6,-(CH
2)
q-C (O) N ((CH
2)
mOH) R
5,-(CH
2)
q-N (R
5)-S (O)
2R
8,-CH
2-S (O)
2N (R
5) R
6,-C
1-6Haloalkyl ,-OCF
3,-OCH (F)
2,-OCH
2F ,-C (O) OR
5,-OR
5,-(R
8)
pCN ,-SO
2R
9,-(CH
2)
nHeteroaryl ,-(CH
2)
nHeterocyclic radical ,-(CH
2)
nCycloalkyl ,-(CH
2)
nCycloalkenyl group and-(CH
2)
nAryl replaces;
Condition be when X be A1, A1 is-during ring that O-and Y are replaced by aryl or heteroaryl, m is selected from 3,4 and 5 integer so;
R
2Be selected from hydrogen, C
1-10Alkyl, C
2-10Alkenyl, C
2-10Alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, its each can be optionally to be replaced by one or more group, described group is independently selected from: C
1-10Alkyl, C
2-10Alkenyl, C
2-10Alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-6Haloalkyl, halogen ,-CN ,-OR
4,-(CH
2)
nCOR
4,-C (O) OR
4,-OCOR
4,-(CH
2)
nNR
5R
6,-(NH)
pCONR
5R
6,-OCONR
5R
7With-NHC (O) OR
7
R
3Expression is selected from the group of halogen and CN;
R
4Be selected from hydrogen, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl ,-(CH
2)
nCycloalkyl ,-(CH
2)
nCycloalkenyl group ,-(CH
2)
nHeterocyclic radical ,-(CH
2)
nAryl and-(CH
2)
nHeteroaryl;
R
5And R
6Be independently selected from hydrogen and C
1-4Alkyl;
R
7Expression is selected from H, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl ,-(CH
2)
tCycloalkyl ,-(CH
2)
nCycloalkenyl group ,-(CH
2)
tHeterocyclic radical ,-(CH
2)
tAryl and-(CH
2)
tThe group of heteroaryl;
R
8Expression is selected from C
1-4The group of alkyl;
R
9Expression is selected from C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl ,-(CH
2)
nCycloalkyl ,-(CH
2)
nCycloalkenyl group ,-(CH
2)
nHeterocyclic radical ,-(CH
2)
nAryl and-(CH
2)
nThe group of heteroaryl, CN;
M represents to be selected from 1,2,3,4 and 5 integer;
N represents to be selected from 0,1,2,3,4 and 5 integer;
P represents to be selected from 0 and 1 integer;
Q represents to be selected from 0,1 and 2 integer;
T represents to be selected from 1 and 2 integer; With
W represents to be selected from 2,3 and 4 integer.
In one embodiment, X represents A or A1.In another embodiment, A is selected from heteroaryl, heterocyclic radical, and A1 is selected from CH
2-O-(CH
2)
wN (R
5) C (O) O-, for example CH
2O (CH
2)
2NHC (O) O-, CH
2-N (R
5) C (O) O-CH for example
2-NHC (O) O, CH
2-N (R
5) C (O)-for example, CH
2-NHC (O)-, CH
2-(O)
p-(CH
2)
qC (O) NR
5-CH for example
2C (O) NCH
3-, CH
2-N (R
5) C (O) N (R
5The CH of)-for example
2-NHC (O) NCH
3-, CH
2-C (O) N ((CH
2)
mOH)-for example CH
2-C (O) N ((CH
2)
2OH)-, CH
2-NR
5-S (O)
2-CH for example
2-NH-S (O)
2-, CH
2-S (O)
2NR
5-CH for example
2-S (O)
2NCH
3-, and CH
2-C (O) O-.In another embodiment, X represents that A and A represent heteroaryl.In another embodiment, A represents nitrogenous heteroatomic heteroaryl, for example, and triazolyl, furazan Ji, oxadiazole base, tetrazyl, imidazolyl or pyrazolyl.
In one embodiment, Y represents that the optional group that replaces is selected from: aryl, phenyl or naphthyl for example, heteroaryl, for example pyridyl, thiazolyl, thienyl, benzofuryl or indyl, and O-aryl, for example O-phenyl.
In another embodiment, Y is replaced by one or more following groups that are selected from: OR
5For example OH or OCH
3, halogen, for example F or Cl, aryl, phenyl for example, C
1-6Haloalkyl is CF for example
3Or CH
2CF
3, OCF
3, (R
8)
pCN is CN for example, (CH
2)
q-N (R
5)-S (O)
2R
8, NHSO for example
2CH
3And SO
2R
9, SO for example
2CH
3
In also having other embodiment, Y is by one or more OR that are selected from
5, halogen, C
1-6Haloalkyl and-(CH
2)
q-N (R
5) C (O) R
8Group replace.
In another embodiment, Y is by one or more halogen and C of being selected from
1-6The group of haloalkyl replaces.
In also having other embodiment, wherein Y is a ring, and it is not substituted.
In one embodiment of the present invention, when X represents A or A1, and A representative ring alkyl, cycloalkenyl group, aryl, heteroaryl or heterocyclic radical, and A1 represents-CH
2-O-(CH
2)
wN (R
5) C (O) O-,-CH
2-N (R
5) C (O) O-,-CH
2-N (R
5) C (O)-,-CH
2-(O)
p-(CH
2)
qC (O) NR
5-,-CH
2-N (R
5) C (O) N (R
5)-or-CH
2-C (O) N ((CH
2)
mOH)-, and Y representative ring, for example when X Biao Shi oxadiazole base, tetrazyl or pyrazolyl, and Y is when representing phenyl, pyridyl or thienyl, m is selected from 3 and 4 integer and n to be selected from 0 and 1 integer, for example m be 4 and n be 0, or m be 3 and n be 1;
In one embodiment, R
2Expression C
1-10Alkyl, it can be chosen wantonly by one or more following groups and replace: cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-6Haloalkyl, halogen ,-CN ,-OR
4,-(CH
2)
nCOR
5,-C (O) OR
4,-OCOR
4,-(CH
2)
nNR
5R
6With-(NH)
pCONR
5R
6In another embodiment, R
2Be selected from C
1-10Alkyl, it can be chosen wantonly by one or more following groups and replace: cycloalkyl, aryl, heteroaryl, C
1-6Haloalkyl, halogen ,-CN ,-OR
4,-(CH
2)
nCOR
5,-C (O) OR
4With-OCOR
4In also having another embodiment, R
2Be selected from C
1-6Alkyl, it can be chosen wantonly by one or more following groups and replace: cycloalkyl, C
1-6Haloalkyl, halogen ,-CN or-OR
4In also having another kind of other embodiment, R
2Be selected from C
3-6Alkyl, for example butyl or amyl group.
In one embodiment, R
3The expression halogen.In another embodiment, R
3Be selected from: chlorine and bromine.In another embodiment, R
3Expression chlorine.
About steric isomer, the compound of formula (I) can have one or more unsymmetrical carbons and can exist with racemic modification, racemic mixture and independent enantiomer or the form of diastereomer.All these isomeric forms, comprise that their mixture comprises within the scope of the present invention.
If the compound of formula (I) contains alkenyl or alkenylene, cis (Z) and trans (E) isomery also may appear.The present invention includes each steric isomer of The compounds of this invention, and if suitable, its each tautomeric form, and their mixture.
The separation of diastereomer or genial trans isomer can obtain by routine techniques, for example pass through fractional crystallization, chromatogram or the HPLC of reagent three-dimensional heterogeneous mixture, also can be from corresponding optical purity intermediate or by splitting preparation, as use the HPLC of the corresponding racemic modification of suitable chiral support, or by fractional crystallization by the diastereomeric salt that corresponding racemic modification and suitable optical activity acid or alkali reaction form, depend on the circumstances.
In addition, some crystal formations of formula (I) compound can exist with the form of polymorphic form, and it comprises within the scope of the present invention.A kind of crystal formation may have advantage than another kind of crystal formation, and for example a kind of crystal formation may have the stability of improvement with respect to another kind of crystal formation.
Be appreciated that any combination that the present invention includes specific embodiments and comprise aforesaid concrete substituent all combinations.
The wording of using in the whole text in this specification sheets and claims " contains " and " comprising " and various modification thereof are meant and are included in the interior meaning.That is to say that under the situation that context allows, these wording mean that can contain other does not have clear and definite indicated element or integer.
Term as used herein " alkyl " (when the part in being used as group or group is used) is meant unless otherwise defined, is meant the straight or branched hydrocarbon chain that contains the carbon atom that specifies number.For example, C
3-C
10Alkyl is meant and contains at least 3, the straight or branched hydrocarbon chain of 10 carbon atoms at the most.The employed examples of alkyl of this paper includes but not limited to methyl (Me), ethyl (Et), n-propyl and sec.-propyl.
Term used herein " alkylidene group " is meant that straight chain is connected base with side chain or cyclic saturated hydrocarbon.The example of alkylidene group comprises methylene radical (CH
2-), ethylidene (CH
2CH
2-), vinylidene (CH=CH-) or cyclopropylidene etc.For example, this paper employed-(alkylidene group)
n-, wherein n is 3 expression-(CH
2)
3-,-C (CH
3)
2-,-CH
2CH=CH-or-cyclopropylidene-etc.For example this paper employed-(alkylidene group)
m-wherein m is 4 expression-(CH
2)
4-,-CH
2C (CH
3)
2-,-CH
2CH=CHCH
2-or-CH
2Cyclopropylidene-etc.
Term as used herein " alkenyl " is meant and contains the carbon atom that specifies number, the straight or branched hydrocarbon chain that contains one or more pairs of keys.
Term as used herein " alkynyl " is meant and contains the carbon atom that specifies number, contains one or more triple-linked straight or branched hydrocarbon chains.
" cycloalkyl " is meant the saturated mono cyclic hydrocarbon ring of 3-8 carbon atom at this employed term.The example of these groups comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group etc.
Term as used herein " cycloalkylidene " is meant that 3-8 carbon connects the saturated monocyclic hydrocarbon ring of base.This examples of groups comprises cyclopropylidene, inferior cyclobutyl, cyclopentylidene, cyclohexylidene, inferior suberyl or inferior ring octyl group etc.
Term as used herein " cycloalkenyl group " is meant the monocyclic hydrocarbon ring of the unsaturated non-fragrance of 3 to 8 carbon atoms that contain one or more carbon-to-carbon double bonds.This examples of groups comprises cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctene base etc.
Term as used herein " inferior cycloalkenyl group " is meant the monocyclic hydrocarbon ring of the unsaturated non-fragrance of 3 to 8 carbon linking groups that contain one or more carbon-to-carbon double bonds.This examples of groups comprises inferior cyclopropenyl radical, inferior cyclobutene base, cyclopentenylidene, phenylidene, inferior cycloheptenyl or inferior cyclooctene base etc.
Term as used herein " aryl " is meant C
6-12Monocycle, dicyclo or tricyclic hydrocarbon ring, wherein at least one ring is fragrant.These examples of groups comprise phenyl, naphthyl or tetralyl etc.
Term as used herein " heteroaryl " is meant 5-6 unit's monocycle aromatic nucleus or condenses 8-10 unit Bicyclic ring that wherein monocycle or dicyclo contain 1-4 heteroatoms that is selected from oxygen, nitrogen and sulphur.On described ring carbon atom, have one or more optional oxo substituting groups.The example of these monocyclic aromatic rings comprises thienyl, furyl, furazan base, pyrryl, triazolyl, tetrazyl, imidazolyl, oxazolyl, thiazolyl, oxadiazole base, isothiazolyl, isoxazolyl, thiadiazolyl group, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, tetrazine base etc.The example of these fused aromatic rings comprises quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, pteridyl, the cinnolines base, phthalazinyl, naphthyridinyl, indyl, pseudoindoyl, the azaindole base, the indolizine base, indazolyl, purine radicals, pyrrolopyridinyl, the furo pyridyl, benzofuryl, isobenzofuran-base, benzothienyl, benzimidazolyl-benzoxazolyl, the benzoisoxazole base, benzothiazolyl, benzisothiazole base Ben Bing oxadiazole base, diazosulfide base etc.
Term as used herein " heterocyclic radical " is meant 4-7 unit monocycle or condenses 8-12 unit dicyclo, and it can be saturated or part is undersaturated, and wherein monocycle or dicyclo contain 1-4 heteroatoms that is selected from oxygen, nitrogen or sulphur.On described ring carbon atom, have one or more optional oxo substituting groups.These monocyclic examples comprise pyrrolidyl, azetidinyl, pyrazolidyl oxazolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, thiazolidyl, the glycolylurea base, the Valerolactim base, the oxirane base, oxetanyl, dioxolanyl alkyl dioxin, oxygen thia cyclopentyl, oxygen thia cyclohexyl, the dithiane base, the dihydrofuran base, tetrahydrofuran base, dihydro pyranyl, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro-thienyl, tetrahydro thiapyran base, Diazesuberane base (diazepanyl), azepan base etc.The example of these dicyclos comprises indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydrochysene-1H-3-benzo-aza
, tetrahydro isoquinolyl etc.
Term as used herein " 3 or 4 rings condense system " is meant condensed 12-18 unit three ring or Fourth Rings, and it contains the heteroatoms of 1 to 4 N, and wherein at least one ring is aromatic ring.On ring carbon atom, can have one or more optional oxo substituting groups.The example of this condensed aromatic ring comprises carbazyl, acenaphthenyl, naphthothiazoles base etc.
Term as used herein " halogen " or " halo " are meant fluorine, chlorine, bromine and iodine.
Term as used herein " C
1-6Haloalkyl " is meant as defined C in the literary composition
1-6Alkyl, wherein at least one hydrogen atom is replaced by halogen.This examples of groups comprises fluoro ethyl, trifluoromethyl or trifluoroethyl etc.
In this article, when certain group is known as by another group " replacement " or has " one or more substituting group ",, should be appreciated that described substituting group may reside on the optional position of this group unless spelt out described substituent particular location.
Term as used herein " pharmaceutically acceptable derivates " is meant any pharmaceutically acceptable derivates of The compounds of this invention, for example salt, solvate or ester, it can (directly or indirectly) provide this compound or its active metabolite after delivering medicine to Mammals such as people.These derivatives are conspicuous to those skilled in the art, do not need the over-drastic experiment, and with reference to Burger ' sMedicinal Chemistry And Drug Discovery, the 5th edition, the instruction of Vol 1:Principles andPractice, it is hereby incorporated by.
This paper is employed, employed term " pharmaceutically acceptable " (wherein said composition can be included in the pharmaceutical preparation that gives the patient) aspect composition (activeconstituents, thinner, vehicle or carrier), be meant with this point that is present in any other composition compatibility in the described pharmaceutical preparation on be acceptable and the recipient do not had the component of poisoning.
Term as used herein " solvate " is meant by what solute (being formula (I) compound, its salt or its pharmaceutically acceptable derivates in the present invention) and solvent formed to have a variable stoichiometric mixture.This kind solvent that satisfies the object of the invention can not disturb the biological activity of described solute.Solvent for use can be pharmaceutically acceptable solvent.The example of suitable pharmaceutically acceptable solvent comprises water, ethanol and acetate.The example of spendable solvent is a water, and in this case, described solvate can be called the hydrate of the solute that comes into question.
Should be appreciated that for pharmaceutical application above-mentioned " salt or solvate " can be pharmacy acceptable salt or solvate.Yet other salt or solvate can be used in the preparation of formula (I) compound for example or its pharmacy acceptable salt or solvate.
Pharmacy acceptable salt comprises Berge, Bighley and Monkhouse, J.Pharm.Sci., 1977,66, the salt described in the 1-19.Suitable pharmacy acceptable salt comprises by adding for example an alkali metal salt that forms of alkali metal hydroxide of alkali metal base.The example of suitable an alkali metal salt is sodium salt or sylvite.Other suitable pharmacy acceptable salt comprises alkaline earth salt for example calcium salt and magnesium salts, ammonium salt; Or with the organic bases salt that forms of thanomin, trolamine, quadrol, triethylamine, choline and meglumine for example; Perhaps with the amino acid salt that forms of arginine, Methionin and Histidine for example.
Ester itself can be active, and/or is hydrolyzable under the condition in vivo in human body.Hydrolyzable ester group is included in those that resolve into parent acid or its salt in the human body easily in the suitable pharmaceutically acceptable body.Ester can form at carboxylic acid (C (O) OH) group place, comprises by means commonly known in the art and corresponding alcohol reaction.For example, ester can be C
1-6Alkyl ester, for example methyl esters, ethyl ester etc.
Term as used herein " compound of the present invention " is meant formula I compound and pharmaceutically acceptable derivates thereof.Term " compound of the present invention " is meant any of The compounds of this invention as defined above.
Term as used herein " at least a chemical entity (entity) " is meant at least a chemical substance of the compound of the compound that is selected from formula I and pharmaceutically acceptable derivates thereof.
On the one hand, the invention provides the 3-butyl of crystalline state-8-chloro-1-{4-[5-(2-pyridyl)-1,2 basically, 4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone crystal formation 1.In another aspect, the invention provides the 3-butyl of crystalline state-8-chloro-1-{4-[5-(2-pyridyl)-1,2 basically, 4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone crystal formation 2.
To the 3-butyl of crystalline state-8-chloro-1-{4-[5-(2-pyridyl)-1,2 basically, 4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone crystal formation 1 and 2 sample carry out heat analysis.Therefore, the invention provides the 3-butyl of crystalline state-8-chloro-1-{4-[5-(2-pyridyl)-1 basically, 2,4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone (crystal formation 1 or crystal formation 2), it is measured to have respectively by DSC and originates in 160 ℃ or bigger and 147 ℃ or bigger fusing point (± 0.5 ℃).
Basically the 3-of crystalline state butyl-8-chloro-1-{4-[5-(2-pyridyl)-1,2,4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone crystal formation 1 and 3-butyl-8-chloro-1-{4-[5-(2-pyridyl)-1,2,4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2, the sample of 6-diketone crystal formation 2, preparation as described below obtains the X-ray powder diffraction pattern of Fig. 1-2.Described x-ray diffraction pattern is unique to described crystal formation.Described crystal formation basically shows diffractogram, its have unique diffraction peak group and can with 2 θ angles (°) expression.
The position at various peaks in the 2 θ diffraction angle explanation x-ray diffraction pattern.Based on employed specific diffractometer and analyst's sample preparation technology, can expect the slight variation at observed 2 θ angles.
Basically the 3-of crystalline form butyl-8-chloro-1-{4-[5-(2-pyridyl)-1,2,4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2, the 6-diketone can be confirmed by there being feature 2 θ horns, or confirm by a plurality of feature 2 θ angles of specific crystal formation of reasonably representing.In order to determine the 3-butyl of crystalline state-8-chloro-1-{4-[5-(2-pyridyl)-1,2 basically, 4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone (crystal formation 1), these peaks are in column position existence down, represent (± 0.1 degree) with 2 θ angles: 5.4,6.7,9.7,11.1,12.9,14.0,15.6,16.3,16.7,23.1 degree.In order to determine the 3-butyl of crystalline state-8-chloro-1-{4-[5-(2-pyridyl)-1,2 basically, 4-oxadiazole-3-yl] butyl }-3, there are column position down in 7-dihydro-1H-purine-2,6-diketone (crystal formation 2), these peaks, represent (± 0.1 degree) with 2 θ angles: 5.2,6.6,10.4,11.2,13.4,15.6,18.1,19.5,20.9 degree.In one embodiment, use in the 2 θ angles above at least one to determine the 3-butyl of crystalline state-8-chloro-1-{4-[5-(2-pyridyl)-1 basically, 2,4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone crystal formation 1 and the 3-butyl of crystalline state-8-chloro-1-{4-[5-(2-pyridyl)-1 basically, 2,4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone crystal formation 2.In other embodiments, at least 2,3,4 or 5 (if suitable) using 2 θ angles above are to determine the 3-butyl of crystalline state-8-chloro-1-{4-[5-(2-pyridyl)-1 basically, 2,4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone crystal formation 1, basically the 3-of crystalline state butyl-8-chloro-1-{4-[5-(2-pyridyl)-1,2,4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone crystal formation 2.
There are some limit of error in each 2 θ angle.For above-mentioned each peak value, the limit of error at above-mentioned 2 θ angles is ± 0.1 degree approximately.
Owing to might have some limit of error in the numerical value at 2 θ angles, relatively the X-ray powder diffraction pattern is that X-ray powder diffraction pattern with unknown crystal formation is folded on the X-ray powder diffraction pattern of known crystal formation so that determine the preferred method of specific crystal formation.For example, those skilled in the art can superimposedly not identify the 3-butyl-8-chloro-1-{4-[5-(2-pyridyl)-1 of crystal formation, 2,4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2, the X-ray powder diffraction pattern of 6-diketone, use method as herein described to obtain, referring to Fig. 3 for example, and easily judge do not identify crystal formation x-ray diffraction pattern whether basically with the 3-butyl of crystalline state-8-chloro-1-{4-[5-(2-pyridyl)-1,2 basically, 4-oxadiazole-3-yl] butyl-3,7-dihydro-1H-purine-2,6-diketone crystal formation 1 or 2 described X-ray powder diffraction pattern are identical.If described X-ray powder diffraction pattern basically with Fig. 1-2 identical shown in any one, the crystal formation of front can easily and accurately be identified so.
Term as used herein " crystalline state basically " is meant that it is substantially free of unbodied 3-butyl-8-chloro-1-{4-[5-(2-pyridyl)-1,2,4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone.Term " do not have basically " to be meant contain less than 50% amorphous, on the one hand less than 20% amorphous, in another aspect less than 10% amorphous, in another aspect less than 5% amorphous, in another aspect less than 2% amorphous, in another aspect less than 1% amorphous.
The invention provides the 3-butyl-8-chloro-1-{4-[5-(2-pyridyl)-1,2 of preparation crystalline state basically as described herein, 4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2, the method for 6-diketone crystal formation.
Formula (I) compound is in treatment and alleviate in many lipid metabolism disease symptomses and have the potential result of treatment; described disease comprises hyperlipemia or hyperlipoproteinemia for example diabetes hyperlipemia and mixing hyperlipemia; heart failure, hypercholesterolemia disease, cardiovascular disorder comprises atherosclerosis, arteriosclerosis and hypertriglyceridemia; type ii diabetes; type i diabetes, insulin resistant, hyperlipidaemia; anorexia nervosa, obesity.The compounds of this invention equally also can be used as the therapeutical agent of coronary artery disease, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease and apoplexy.
HM74 and HM74A acceptor and inflammation-related (WO02084298) according to reports.Inflammation has been represented a series of blood vessels, cell and the neural response for wound.For example monocyte, neutrophilic granulocyte and granulocyte move to in-house inflammation can be described as inflammatory cell.This is accompanied by usually, and the endothelial barrier effect reduces and the interior oedema of tissue.Be commonly referred to as chronic inflammatory diseases with the inflammation of disease-related.This class chronic inflammatory diseases can show by disease symptoms.Therefore, the purpose of anti-inflammatory treatment is to alleviate chronic inflammatory diseases, makes that the physiology step of healing and tissue repair is carried out.
The inflammatory diseases that The compounds of this invention was suitable for or the example of illness comprise arthritis disease or illness, for example sacroiliitis (rheumatoid arthritis for example, osteoarthritis, pseudarthrosis malfunctioning (prosthetic jointfailure)), perhaps gastrointestinal tract inflammation (ulcerative colitis for example, Crohn disease, and other inflammatory bowel and gastrointestinal illness, the gastritis and the mucosal inflammation that cause by infection, the enteropathy that causes by nonsteroidal anti-inflammatory drug), lung inflammation (adult respiratory distress syndrome for example, asthma, cystic fibrosis, or chronic obstructive pulmonary disease), heart inflammation (for example myocarditis), inflammation of neuronal tissue (for example multiple sclerosis), pancreas inflammation (for example relevant inflammation) with diabetes and complication thereof, kidney inflammation (for example glomerulonephritis), chafing (dermatitis for example, psoriasis, eczema, urticaria, burn), eye inflammation (for example glaucoma), and transplant organ (for example rejection) and many organ diseases (systemic lupus erythematosus for example, Sepsis), inflammatory sequela with virus or infectation of bacteria, and the inflammation relevant with atherosclerosis and next appear at brain for example or ischemic heart disease in hypoxic or ischemia (ischaemic) wound (comprising or do not comprise perfusion again).
A kind of embodiment, The compounds of this invention can be used for treatment and preventing inflammation, diabetes and cardiovascular disorder or illness, comprise atherosclerosis, arteriosclerosis, hypertriglyceridemia and mix hyperlipemia.
Nicotinic acid has significant side effects, and this may be because its cause according to high level (the gram quantity of every day (gram quantities)) administration.Modal side effect is the intensive skin rubefaction.In certain embodiments of the invention, The compounds of this invention demonstrates the side effect of reduction for nicotinic acid.Identified that HM74A is the high-affinity receptor of nicotinic acid, and HM74 is a low-affinity receptor.The compounds of this invention demonstrates the higher avidity of comparison HM74 to HM74A, therefore finds the HM74A agonist or the partial agonist of The compounds of this invention useful as selective.
The usefulness of formula (I) compound activating HM74A can adopt following external full raji cell assay Raji to be confirmed:
Vitro test
In order to carry out transient transfection, HEK293T cell (the antigenic HEK293 cell of the big T-of stably express SV40) is remained among the DMEM that contains 10% foetal calf serum and 2mM glutamine.Cell inoculation grows to 60-80% and converges (confluence) (18-24 hour) in the 90mm culture dish before transfection.With people HM74A (GenBank
TMAccession number AY148884) subclone is at mammalian expression vector (pcDNA3; Invitrogen) in, use Lipofectamine reagent to carry out transfection.In order to carry out transfection, 9 μ g DNA and 30 μ l Lipofectamine are mixed among the 0.6ml Opti-MEM (LifeTechnologies Inc.), at room temperature hatched 30 minutes, add 1.6ml Opti-MEM then.Cell is exposed to the Lipofectamine/DNA mixture following 5 hours, adds the DMEM solution of 6ml 20% (v/v) foetal calf serum then.48 hours collecting cells after transfection.By with 50ngml
-1Toxins, pertussis is appended in the substratum, carry out Toxins, pertussis and handled 16 hours.All transient transfection research relates to acceptor and G
I/oG albumen, G
O1The cotransfection of α.
In order to generate stable cell strain, the transfection of use aforesaid method is seeded in the six hole wares and grows to the 30% CHO-K1 cell that converges.These cells are remained in the DMEM F-12HAM substratum (available from Invitrogen) that contains 10% foetal calf serum and 2mM glutamine.After the transfection 48 hours, (G418 Gibco), carries out antibiotic tolerance cell and selects to append the Geneticin of 400 μ g/ml in substratum.After adding nicotinic acid, the clone CHO-K1 cell strain of stably express HM74A by [
35S]-GTP γ S confirmed in conjunction with measuring.
P2 membrane prepare-prepare the plasma membrane (plasma membrane) that contains the P2 particulate fraction by the cell mass (cell paste) that is frozen under-80 ℃ after collecting.Overall Steps carries out under 4 ℃.Cell precipitation (pellet) is suspended in 10mM Tris-HCl and the 0.1mM EDTA of 1ml once more, among the pH 7.5 (buffer A), uses 20 seconds of Ultra Turrax homogenate, then by (5 times) 25-pin.With cell lysate (lysates) in Eppendorf centrifuge, 1, under the 000g centrifugal 10 minutes, make nucleus and not damaged cell precipitation, and the P2 particulate fraction is by 16, microcentrifugation reclaimed in 30 minutes under the 000g.The P2 particulate fraction is suspended in the buffer A once more, is stored under-80 ℃ when being required.
[
35S]-combination-(K.H. (1994) Methods Enzymol.237 3-13) measures in the 384-orifice plate at room temperature GTP γ S for Wieland, T. and Jakobs according to previous described method.Briefly, the diluent of preparation standard or test compounds is that 10 μ l add in the 384-orifice plate with volume then.Film (HM74A or HM74) is diluted in assay buffer (20mM HEPES, 100mMNaCl, 10mM MgCl
2, pH7.4) in, appended saponin(e (60 μ g/ml), Leadseeker WGA pearl (Amersham in the described damping fluid; 250 μ g/ holes) and 10 μ M GDP, make the 20 μ l volumes that are added in each hole contain 5 μ g films.Will [
35S]-(1170Ci/mmoL, Amersham) dilution (1: 1500) adds 20 μ l to GTP γ S in each hole in assay buffer.Add after the radioligand, with the plate sealing, pulse rotation (pulse spun), and at room temperature hatched 4 hours.When incubation period, finish, at Leadseeker machine (VIEWLUX PLUS; Perkin-Elmer) read plate on, measure specificity in conjunction with level.
Improve these tests by reducing final test volume to 10 μ l.For the test of this 10 μ l, use the scheme of revising.This comprises standard substance or the test compounds of only using in each hole of 384-orifice plate to 100nl, and 1.5 μ g films and 100 μ g Leadseeker WGA pearls.For low volume scheme, with film, pearl and [
35S]-GTP γ S is admixed together, and then this mixture of 10 μ l is assigned in each hole.Hatching of 10 μ l and 50 μ l test with to read plate identical.
With all exemplary compounds above-mentioned one or two [
35S]-GTP γ S tests in (i.e. the test of 10 μ l and 50 μ l) in conjunction with test.
Use the XC50 software package, with four parameter logical equatiions carry out curve fitting (2 points of deletion maximum from arbitrary curve) come analytical data.Use pEC
50Render a service with % and to represent the specificity combination with respect to nicotinic acid bonded peak response.
In vivo test
With at least 12 hours male Spague-Dawley rat (200-250g) of fasting test HM74A agonist before the research.Compound is with the dosage intravenously administrable of 1mg/kg or 3mg/kg (5ml/kg) or with the dosage gastric infusion of 1-30mg/kg (10ml/kg).Three time points before administration and after the administration (from time period of 15 minutes to 6 hours after the administration) blood sample collection (0.3ml tail vein blood).Each blood sample is transferred in the heparin test tube (Becton Dickinson Microtainer, PST LH), and centrifugal (10,000g, 5 minutes) obtain plasma sample.The test kit that use is purchased (Randox) is measured non-esterified fatty acid (NEFA) level of this plasma sample.Employing is for inhibition (with respect to the level before the administration) the expression HM74A agonist activity of plasmal NE FA level.
In order to determine whether the HM74A compound demonstrates rubescent reply (flushingresponse) relevant with nicotinic acid, it can be delivered medicine to clear-headed cavy.Before testing, make male Dunkin Hartley cavy (300-600g; N=10-20 only/group) fasting 12 hours, but be no more than 24 hours.Under restorative anesthesia (3.5% isoflurane that contains other O2 (1L/min)), from every animal, gather the preceding blood sample (0.5ml) of research by cardiac puncture.Place infrared temperature sensor at the left ear place of every animal and carry out ear temperature mensuration.In preceding 5 minutes of administration timed interval of 30 minutes to the administration, temperature measurement result of each minute record.After administration 2 hours then, temperature measurement result of 15 minutes records at interval.Animal is accepted test compounds (5ml/kg) by irritating stomach.Under lethality (terminal) anesthesia, by cardiac puncture blood sample collection (0.5ml).After administration 0.5,1,2,3 and 4 hour from each animal blood sample collection so that data to be provided.All blood samples are placed blood cylinder (roller) last 5 minute, preserve on ice then until research and finish.Centrifugation (12000g, 5min) after, blood plasma is transferred in the new test tube, and is preserved down until measuring NEFA concentration at-20 ℃.
Synthetic compound (referring to following synthetic embodiment) according to formula (I), and above-mentioned [
35S]-GTP γ S in conjunction with the test in test.
Some compounds of formula (I) comprise:
3-butyl-8-chloro-1-[3-(dimethylamino) propyl group]-3,7-dihydro-1H-purine-2,6-diketone;
8-chloro-3-(3, the 3-dimethylbutyl)-1-[2-(ethyl oxygen base) ethyl]-3,7-dihydro-1H-purine-2,6-diketone;
3-butyl-8-chloro-1-[3-(5-phenyl-1,2,4-oxadiazole-3-yl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone;
1-[3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group]-1H-naphtho-[2,3-d] [1,2,3] triazole-4, the 9-diketone;
2-(4-[3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group] and phenyl } the oxygen base) ethyl acetate.
In other compound of preparation formula (I), can be used as intermediate.
Detect these compounds aforesaid [
35S]-GTPS is in conjunction with in the test, illustrational compound (embodiment 1-894) has 4.3 (+/-0.3log unit) or bigger pEC
50And 30% or the effectiveness of bigger (with respect to nicotinic acid).
The test following compounds and find than 4.3 (+/-0.3log unit) low active and aforesaid [
35S]-GTPS is in conjunction with the effectiveness that has in the test less than 30% (with respect to nicotinic acid), and they are tested therein.
8-chloro-1-(3-{3-[(2,4-difluorophenyl) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3-[2-(piperidino) ethyl]-3,7-dihydro-1H-purine-2,6-diketone;
8-chloro-1-(3-{3-[(2,4-difluorophenyl) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3-[2-(six hydrogen-1H-azepine
-1-yl) ethyl]-3,7-dihydro-1H-purine-2,6-diketone;
8-chloro-1-(3-{3-[(2,4-difluorophenyl) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3-[2-(1-pyrrolidyl) ethyl]-3,7-dihydro-1H-purine-2,6-diketone;
8-chloro-1-(3-{3-[(2,4-difluorophenyl) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3-[2-(dimethylamino)-2-methyl-propyl]-3,7-dihydro-1H-purine-2,6-diketone;
8-chloro-1-(3-{3-[(2,4-difluorophenyl) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3-[3-(dimethylamino) propyl group]-3,7-dihydro-1H-purine-2,6-diketone;
8-chloro-1-(3-{3-[(2,4-difluorophenyl) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3-[3-(4-methyl isophthalic acid-piperazinyl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone;
8-chloro-1-(3-{3-[(2,4-difluorophenyl) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3-[2-(dimethylamino) ethyl]-3,7-dihydro-1H-purine-2,6-diketone.
General purifying and analytical procedure:
LC/MS: method
Analyze HPLC at Supelcosil
TM(3 μ m 3.3cmx4.6mmID) go up enforcement to ABZ+PLUS post (Supelco), use 0.1%HCO
2H and 0.01M ammonium acetate solution (solvent orange 2 A) and 95%MeCN and 5% water (contain 0.5%HCO
2H) (solvent B) wash-out uses following gradient 0-0.7min 0%B, 0.7-4.2min 0 → 100%B, and 4.2-4.6min 100%B, 4.6-4.8min 100 → 0%B is with the flow velocity of 3ml/min.Carrying out diode array UV in the 215-330nm scope detects.Mass spectrum (MS) is recorded on the Waters ZQ mass spectrograph, and [(ES+ve is to obtain MH to use the ionization of electron spray(ES) positive electricity subtype
+And M (NH
4)
+Molion] or the ionization of electron spray(ES) negatron [(ES-ve is to obtain (M-H)
-Molion] mode.Only mark main isotopic parent ion.
1H NMR spectrum is used Bruker DPX 400MHz spectrograph record, uses the tetramethyl-silicomethane as standard.
Biotage
TMChromatography is meant that purification system (Flash 40i or Flash 150i) that use is sold by Biotage AB and the post of using KPSil (silicon-dioxide) to load in advance carry out purifying.
Companion
TMSystem is meant Teledyne Isco Combiflash Companion
TMPurification system.This is a kind of gradient control purification system, has whole, variable wavelength UV and detects, and it has the function that causes automatic fraction collection by the UV threshold value.
The directed automated preparation of quality (Mass directed autoprep) is meant a kind of like this method: wherein material passes through high performance liquid chromatography, goes up the solvent orange 2 A that uses suitable gradient: 0.1%HCO at Supelcosil ABZ+5 μ m post (10cmx20mm i.d.) or Supelcosil ABZ+10 μ m post (15cmx30mm i.d.)
2The aqueous solution of H, and solvent B:95%MeCN, 5% water (contain 0.5%HCO
2H) carry out purifying.Waters 2767 injection/collectors cause making interested part detect (using Micromass MassLynx software) by on the MicroMass ZQ mass spectrograph.
Preparation HPLC (preparing HPLC or preparation automatically automatically) is meant method, and wherein said material is gone up at Supelcosil ABZ+5 μ m post (10cmx21.2mm i.d.) with high performance liquid chromatography and purified, with the 0.1%HCO of suitable gradient
2The H aqueous solution and MeCN (contain 0.5%HCO
2H).Gilson 233 run tanks detect by UV and cause.
SPE (Solid-Phase Extraction) is meant and uses the polyethylene post that its sorbent material that is used to purify is loaded in advance.The sorbent material that is included in these cylinders will be specific.Employed example is elaborated below:
C18 SPE is meant the pre-pillar of loading of silica adsorbent (being sold by Varian Inc.) that uses with 40 μ M C18 functionalization.Generally compound is loaded among 50: 50 DMSO/MeOH, join conform with MeCN in advance and the post with the 5%MeCN aqueous equilibrium on.Described product is with the 0.1%HCO of suitable gradient
2The H aqueous solution and MeCN (0.5%HCO
2H) wash-out.
Aminopropyl SPE or post are meant and use with the pre-pillar of loading of the functionalized silicon-dioxide of 40 μ m-120 μ m aminopropyls (being sold by Varian Inc.).Generally described crude product is loaded in the DCM/MeOH mixture, joins then in advance on the post that conforms with MeOH.Neutral component is used the eluent wash-out that contains a certain proportion of AcOH (2-20%) usually with MeOH and/or DCM (3 or 4 times of column volumes) wash-out, acidic components.
Oasis
TMPost/Oasis
TMSPE ' s is meant and uses the SPE cylinder of being loaded by the polymeric adsorbant of Waters company preparation.These general MeOH with 3 times of column volumes before load sample conform and watering balance.Salt and inorganics water wash-out, described product are generally with MeOH or MeCN wash-out.
GreenHouse
TMBeing meant can be from RDT Ltd, the parallel synthesizer platform of 24 reactions that UK obtains.
As mentioned above, the compound of formula (I) can be used for people or veterinary science, for example in the treatment of hyperlipemia and hyperlipoproteinemia as the activator of HM74A.
Therefore, as another embodiment of the present invention, the invention provides compound or its pharmaceutically acceptable derivates of at least a formula (I), it is used for people or veterinary science, for example comprise in the treatment of hyperlipemia and hyperlipoproteinemia in the lipid metabolism disease, diabetes hyperlipemia and mix hyperlipemia for example, heart failure, hypercholesterolemia, cardiovascular disorder comprise atherosclerosis, arteriosclerosis and hypertriglyceridemia, type ii diabetes, type i diabetes, insulin resistant, hyperlipidaemia, anorexia nervosa, obesity.Described compound also is provided for treating in coronary artery disease, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease and the apoplexy.
As another embodiment of the present invention, the invention provides compound or its pharmaceutically acceptable derivates of at least a formula (I), be used for preparing medicine people or veterinary science, described medicine for example is used for the treatment of the lipid metabolism disease and comprises hyperlipemia and hyperlipoproteinemia, diabetes hyperlipemia and mix hyperlipemia for example, in heart failure, hypercholesterolemia, cardiovascular disorder comprises atherosclerosis, arteriosclerosis and hypertriglyceridemia, type ii diabetes, type i diabetes, insulin resistant, hyperlipidaemia, anorexia nervosa, obesity.Described compound also is provided for treating in coronary artery disease, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease and the apoplexy.
Be appreciated that treatment described herein extends to prevention and the inhibition of symptom and the illness that treatment is determined of prevention, recurrence.
In one embodiment of the present invention, the invention provides compound or its pharmaceutically acceptable derivates of at least a formula (I), it is used for the treatment of the lipid metabolism disease and comprises in hyperlipemia and the hyperlipoproteinemia.For example, the invention provides the compound of at least a formula (I) or its pharmaceutically acceptable derivates at treatment diabetic hyperlipemia, mix hyperlipemia, heart failure, hypercholesterolemia, type ii diabetes, type i diabetes, insulin resistant, hyperlipidemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, stenocardia, chronic renal failure, apoplexy and cardiovascular disorder and comprise purposes in atherosclerosis, arteriosclerosis and the hypertriglyceridemia.
Be appreciated that this embodiment of the present invention comprises the combination of any specific embodiments and comprises concrete substituent all combinations of aforesaid formula (I) compound.
In addition, the invention provides the compound or the purposes of its pharmaceutically acceptable derivates in the preparation medicine of at least a formula (I), described medicine is used for the treatment of arthritis disease or illness, for example sacroiliitis (rheumatoid arthritis for example, osteoarthritis, pseudarthrosis malfunctioning (prosthetic joint failure)), perhaps gastrointestinal tract inflammation (ulcerative colitis for example, Crohn disease, and other inflammatory bowel and gastrointestinal illness, the gastritis and the mucosal inflammation that cause by infection, the enteropathy that causes by nonsteroidal anti-inflammatory drug), lung inflammation (adult respiratory distress syndrome for example, asthma, cystic fibrosis, or chronic obstructive pulmonary disease), heart inflammation (for example myocarditis), inflammation of neuronal tissue (for example multiple sclerosis), pancreas inflammation (for example relevant inflammation) with diabetes and complication thereof, kidney inflammation (for example glomerulonephritis), chafing (dermatitis for example, psoriasis, eczema, urticaria, burn), eye inflammation (for example glaucoma), and transplant organ (for example rejection) and many organ diseases (systemic lupus erythematous for example, Sepsis), inflammatory sequela with virus or infectation of bacteria, and the inflammation relevant with atherosclerosis and next appear at brain for example or ischemic heart disease in hypoxic or ischemia (ischaemic) wound (comprising or do not comprise perfusion again).
In other or another embodiments, the invention provides treatment human or animal patient by the not enough caused disease of HM74A receptor activation or benefit from the method for the disease that activates this receptor, described method comprises formula (I) compound or its pharmaceutically acceptable derivates that delivers medicine to described human or animal patient's significant quantity.
Once more, be appreciated that this embodiment of the present invention comprises the combination of any specific embodiments and comprises concrete substituent all combinations of aforesaid formula (I) compound.
In one embodiment, the invention provides the method that treatment lipid metabolism disease comprises hyperlipemia and hyperlipoproteinemia, for example diabetic hyperlipemia and mixing hyperlipemia, heart failure, hypercholesterolemia, cardiovascular disorder comprise atherosclerosis, arteriosclerosis and hypertriglyceridemia, type ii diabetes, type i diabetes, insulin resistant, hyperlipidemia, anorexia nervosa and obesity, and described method comprises compound or its pharmaceutically acceptable derivates of at least a formula (I) that gives described human or animal experimenter's significant quantity.In addition, these compounds also find to treat the method for coronary artery disease, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease and apoplexy, and described method comprises compound or its pharmaceutically acceptable derivates of at least a formula (I) that gives described human or animal experimenter's significant quantity.
To depend on a number of factors in order to reach required formula (I) compound of required biological effect or the amount nature of its pharmaceutically acceptable derivates, for example, administering mode and recipient's accurate clinical disease.Usually, per daily dose will be in the scope of 0.1mg-1g/kg, generally in the scope of 0.1-100mg/kg.Intravenous dosages for example can be within the 0.01mg-0.1g/kg scope, generally within the 0.01mg-10mg/kg scope, its can be easily with the form administration of 0.1 μ g-1mg per minute transfusion.The transfusion liquid that is suitable for this purposes can contain, for example, and every milliliter of 0.01g-0.1mg.Unitary dose can contain, for example, and the The compounds of this invention of 0.01 μ g-1g.Therefore, the injection ampulla can contain, for example, 0.01 μ g-0.1g, and oral administration unit dose formulations, for example tablet or capsule can contain, for example, 0.1mg-1g, for example 5mg-50mg.
Formula (I) compound or its pharmaceutically acceptable derivates itself can be used for treating by the not enough caused disease of HM74A receptor activation or benefit from the disease that activates this receptor, the example be with The compounds of this invention with can accept the form of carrier and exist with pharmaceutical preparation.Certainly, described carrier can must be acceptable aspect other components compatibility in the preparation, simultaneously must be nontoxic to the recipient.Described carrier can be that solid or liquid or both have concurrently, The compounds of this invention can be prepared into the unit dose formulations form, and tablet for example wherein can contain the The compounds of this invention of 0.05 weight %-95 weight %.
Described preparation comprises that those are fit to the preparation of oral, rectum, part, oral cavity (for example hypogloeeis) and parenteral (for example subcutaneous, intramuscular, intracutaneous or intravenously) administration.
Also providing the method for preparing this class pharmaceutical composition, described method to comprise according to the present invention mixes various compositions.
The preparation that is fit to oral administration can exist with the discrete unit form, for example contains formula (I) compound of predetermined amount or capsule, cachet, lozenge or the tablet of its pharmaceutically acceptable derivates separately; Pulvis or granule form; Solution in water or on-aqueous liquid or suspensoid form; Perhaps oil-in-water or water-in-oil emulsion form.In general, by the solid carrier of formula (I) compound or its pharmaceutically acceptable derivates and liquid or segmentation or both are had concurrently carry out even and fine and close mixed, then if necessary, make formed product, can prepare above-mentioned preparation like this.For example, tablet can be by with the powder of formula (I) compound or its pharmaceutically acceptable derivates or particle is optional prepares with one or more ancillary component compactings or moulding.Compressing tablet can be by preparing for example optional the compacting with tackiness agent, lubricant, inert diluent and/or surfactant/dispersant blended powder or particle of the The compounds of this invention of unrestricted flow (free-flowing) form in suitable machine.Molded (Moulded) tablet can be by carrying out molded preparing with the wetting powder compound of inert liquid diluent in suitable machine.
Can contain conventional excipients in the tablet of oral administration and the capsule, tackiness agent for example is as syrup, gum arabic, gelatin, Sorbitol Powder, tragakanta, starch mucus or polyvinylpyrrolidone; Weighting agent is as lactose, Microcrystalline Cellulose, sugar, W-Gum, calcium phosphate or Sorbitol Powder; Lubricant is as Magnesium Stearate, stearic acid, talcum powder, polyoxyethylene glycol or silicon-dioxide; Disintegrating agent is as yam starch, croscarmellose sodium or primojel; Perhaps wetting agent is as sodium lauryl sulphate.Tablet can be according to method dressing well known in the art.Oral liquid can be for example water-based or oiliness suspensoid, solution, emulsion, syrup or elixir form, perhaps also can be the drying products form that constitutes (constitution) before use with water or other appropriate carrier.This liquid preparation for example can contain conventional additives: suspending agent, as Sorbitol Powder syrup, methylcellulose gum, glucose/table sugar syrup, gelatin, Walocel MT 20.000PV, hypromellose, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat; Emulsifying agent is as Yelkin TTS, dehydrated sorbitol mono-fatty acid ester or gum arabic; Nonaqueous carrier (wherein can contain edible oil) is as Prunus amygdalus oil, fractionated coconut oil (fractionated coconut oil), oily ester, propylene glycol or ethanol; Perhaps sanitas is as methyl p-hydroxybenzoate or propylparaben or Sorbic Acid.If be fit to, can also contain buffering salt, seasonings, tinting material and/or sweeting agent (for example N.F,USP MANNITOL) in the preparation.
The preparation that is fit to oral cavity (hypogloeeis) administration is included in the lozenge that contains The compounds of this invention in the flavoured base (being generally sucrose and gum arabic or tragakanta) and for example contains the pastille of The compounds of this invention in gelatin and glycerine or sucrose and the gum arabic at inert base.
The preparation of the present invention that is fit to administered parenterally generally includes the aseptic aqueous solution preparation of formula (I) compound or its pharmaceutically acceptable derivates, and described preparation can ooze with the intravital blood of expection recipient etc.These preparations can pass through intravenous administration, though also can realize by subcutaneous, intramuscular or intradermal injection.This class preparation usually can be by mixing formula (I) compound or its pharmaceutically acceptable derivates and water, then with resulting solution sterilization and make it and blood etc. oozes and prepares easily.Usually contain 0.1-5%w/w formula (I) compound or its pharmaceutically acceptable derivates according to Injectable composition of the present invention.
Therefore, the preparation of the present invention that contains the suitable administered parenterally of formula (I) compound or its pharmaceutically acceptable derivates can be mixed with by injecting (bolus injection) or continuous infusion fast and carry out the form of administered parenterally, and can exist with unit dosage form, for example ampoule, bottle (vials), small volume transfusion or prefilled syringe form, perhaps the multi-dose container form with sanitas with interpolation exists.Described composition can be taked for example solution, suspensoid or the emulsion form in water or nonaqueous carrier (vehicles), and can contain various formulated for example antioxidant, buffer reagent, biocide and/or toxicity conditioning agent.The examples of formulations that is suitable for oral administration comprises compound or the preparation of its pharmaceutically acceptable derivates in the sterile saline solution of 10%DMSO and 90% sodium bicarbonate that comprises formula (I).The examples of formulations that is suitable for intravenous administration comprise the compound that comprises formula (I) or its pharmaceutically acceptable derivates 5% or the aseptic aqueous solution of 10%DMSO and 95% or 90% sodium bicarbonate in preparation.Perhaps, described therapeutic active agents can be the powder type that constituted with for example aseptic pyrogen-free water of appropriate carrier before using.Described drying solid preparation can be by preparing aseptic the inserting in the independent sterile chamber of sterilized powder, perhaps by inserting in each container sterile solution is aseptic, and then freeze-drying and preparing.
The preparation that is fit to rectal administration can exist with the unitary dose suppository form.Described unitary dose suppository can by with formula (I) compound or its pharmaceutically acceptable derivates and one or more conventional solid carriers for example cocoa butter or glyceryl ester mix, and then make resulting mixture forming and prepare.
Be fit to topical application to the preparation of skin and can take ointment, emulsion, lotion, paste, gelifying agent, sprays, aerosol or finish form.Spendable carrier comprises Vaseline, lanolin, polyoxyethylene glycol, alcohols and two or more mixture wherein.Described formula (I) compound or its pharmaceutically acceptable derivates exist with the concentration that accounts for composition 0.1-15%w/w, for example 0.5-2%w/w usually.
The employed topical of this paper comprises and being blown into and inhalation.The various types of formulation examples that are used for topical comprise ointment, emulsion, lotion, pulvis, vaginal suppository, sprays, aerosol, the capsule that is used for sucker or insufflator or cartridge case or drops (for example eye drops or nasal drop).
Ointment and emulsion can add the preparation of suitable thickening material and/or jelling agent and/or solvent and obtain simultaneously by for example making use or oleaginous base.Therefore, this class matrix can for example comprise for example Albolene or vegetables oil peanut oil or Viscotrol C or solvent polyoxyethylene glycol for example for example of water and/or oil.Spendable thickening material comprises soft wax, aluminum stearate, cetostearyl alcohol (cetostearylalcohol), polyoxyethylene glycol, Microcrystalline Wax and beeswax.
Lotion can make use or oleaginous base preparation obtain, and in general, can also contain one or more emulsifying agents, stablizer, dispersion agent, suspending agent or thickening material.
The pulvis that is used for external application can be by means of for example talcum powder, lactose or the starch formation of any suitable powder matrix.Drops can make use or the preparation of non-aqueous matrix obtain, and can contain one or more dispersion agents, solubilizing agent or suspending agent.
Spray composite can be formulated into for example aqueous solution agent or suspensoid form or by the aerosol of sending by suitable propelling agent in the pressurized package, for example Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, 1 of propelling agent wherein, 1,1,2,3,3,3-heptafluoro-propane, 1,1,1,2-Tetrafluoroethane, carbonic acid gas or other suitable gas.
Can be mixed with and comprise for example powdered mixture of lactose or starch of The compounds of this invention and suitable powder matrix being used for the capsule of sucker or insufflator and cartridge case (for example gelatin).
Can also be used in combination with other therapeutical agent according to pharmaceutical composition of the present invention, for example the hyperlipemia medicine (for example Statins, the special class of chlorine shellfish, bile acide binding resin or nicotinic acid) with other type is used in combination.
The compounds of this invention can be used in combination with one or more other therapeutic activity agent, for example the hyperlipemia drug regimen with other type uses, as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (Statins) or the special class of chlorine shellfish or bile acide binding resin or nicotinic acid.Therefore the present invention provides described on the other hand and has been combined in treatment by the not enough caused disease of HM74A receptor activation or benefit from purposes in the disease that activates this receptor; and formula (I) compound or its pharmaceutically acceptable derivates are used for combination therapy (combination therapy) lipid metabolism obstacle in preparation and comprise for example diabetes hyperlipemia and mix hyperlipemia of hyperlipemia or hyperlipoproteinemia; in heart failure; hypercholesterolemia; cardiovascular disorder comprises atherosclerosis; arteriosclerosis and hypertriglyceridemia; type ii diabetes; type i diabetes; insulin resistant; hyperlipidaemia, the purposes in the medicine of anorexia nervosa or obesity.
When The compounds of this invention and other therapeutic activity agent were used in combination, these compounds can be by any conventional route together or separately, successively or administration simultaneously.
The alleged combination in front can exist by the form of using pharmaceutical preparation easily, therefore contains aforesaid combination and optional pharmaceutically acceptable carrier or the pharmaceutical preparation of vehicle and has constituted another embodiment of the present invention.Independent component in the combination of this class can with separately or the pharmaceutical dosage forms that merges together or separately, successively or administration simultaneously.
In the time of in being combined in same preparation, should be appreciated that these two kinds of components must be stable, and compatible each other and with preparation in other component compatibility, and can prepare and be used for administration.When preparing respectively, they can provide with conventional formulation form (normally this area is at the known mode of this compounds) arbitrarily.
When second therapeutical agent with the antagonism same disease made up, the dosage of every kind of component can be different with the dosage that compound uses separately.Appropriate dosage those skilled in the art can understand at an easy rate.
Therefore, in another embodiment, the invention provides and contain the combination of at least a formula (I) compound or its pharmaceutically acceptable derivates with other therapeutic activity agent.
The alleged combination in front can exist by the form of using pharmaceutical preparation easily, and the pharmaceutical preparation that therefore contains aforesaid combination and pharmaceutically acceptable carrier thereof has been represented another embodiment of the present invention.
The compounds of this invention and pharmaceutically acceptable derivative thereof can be according to hereinafter described method preparations, and this has constituted another embodiment of the present invention.
In one embodiment, the invention provides method by suitable starting material (for example compound of formula (II)) preparation formula (I) compound:
PG=protecting group wherein, this method comprises:
(i) carry out alkylation at the protected xanthic N1 of N7 place;
(ii) carry out alkylation at the protected xanthic N3 of N7 place;
(iii) carry out halogenation at the C8 place; And
The (iv) deprotection of N7;
Above-mentioned steps is carried out with any order, and condition is to carry out deprotection after the alkylation.
Method 1:
The method of preparation formula of the present invention (I) compound, wherein R1 introduces cycloalkyl, heterocyclic radical, cycloalkenyl group, heteroaryl or aryl.
I) with allyl bromide 98 to the guanine alkylation
Ii) use Sodium Nitrite diazotization, then hydrolysis is with the preparation xanthine
Iii) chlorination
The iv) alkylation at N3 place
The v) alkylation at N1 place
Vi) allyl group is removed in palladium catalysis
Wherein L represents leavings group, for example halogen.
Method 2:
The method of preparation formula of the present invention (I) compound, wherein R1 introduces acid amides, carbamate or urea
Wherein L represents leavings group, halogen for example, d represent (m-1) (be d with the front methylene radical=m), R represents-(alkylidene group)
n-Y and Q can exist or can not exist, and represent O or NR5 if present.
Method 3:
The method of preparation formula of the present invention (I) compound, wherein R1 introduces one ' reverse ' carbamate or urea
Wherein L represents leavings group, halogen for example, and d represents (m-1), and R represents-(alkylidene group)
n-Y.
Method 4:
The method of preparation formula of the present invention (I) compound, wherein R1 introduces ester or acid amides
Wherein L represents leavings group, halogen for example, and d represents (m-1), and R represents-NR
5R
7Or-OR
5
Method 5:
The method of preparation formula of the present invention (I) compound, wherein R1 introduces pyrazoles, imidazoles or tetrazolium.
Wherein L represents leavings group, halogen for example, and d represents (m-1), and R represents-(alkylidene group)
n-Y.
Method 6:
The method of preparation formula of the present invention (I) compound, wherein R1 Yin Ru oxadiazole.
Wherein L represents leavings group, halogen for example, and d represents (m-1), and R represents alkyl and R ' expression-(alkylidene group)
n-Y.
Method 7:
The method of preparation formula of the present invention (I) compound, wherein R1 Yin Ru oxadiazole.
Wherein L represents leavings group, halogen for example, and d represents (m-1), and R represents alkyl and R ' expression-(alkylidene group)
n-Y.
Method 8:
The method of preparation formula of the present invention (I) compound, wherein R
3Be CN, comprise the step (i) of method 1 and (ii), then:
The iii) alkylation at N3 place
The iv) alkylation at N1 place
V), then use the DMF cancellation by generating aldehyde with the LiHMDS lithiumation at the C8 place
Vi) described aldehyde is converted into nitrile
Vii) allyl group is removed in palladium catalysis
Wherein L represents leavings group.
Method 9:
The method of preparation formula of the present invention (I) compound, wherein R
3Be Cl or Br, comprise the step (i)-(iv) of method 8, then:
I) use NCS or NBS in the halogenation of C8 place
Ii) allyl group is removed in palladium catalysis
Method 10:
The method of preparation formula of the present invention (I) compound, wherein R
3Be CN, comprise the step (i)-(iv) of method 8, then:
V) generate ester
Vi) this methyl esters of hydrolysis
Vii) described acid is converted into acid amides.
Viii) described acid amides is converted into nitrile
Ix) allyl group is removed in palladium catalysis
Method 11:
The method of preparation formula of the present invention (I) compound, wherein R
3Be Cl, comprise:
I) alkylation at N3 place
The ii) alkylation at N1 place
Iii) debenzylation
The iii) chlorination at C8 place
Wherein L represents leavings group
Method 12:
The method of preparation formula of the present invention (I) compound, wherein R
1Be different from R
2And R
3Be Cl, comprise the step (i) of method 1-(v) (R of method 1 wherein
2SEM or MEM specifically), then:
Vi) cracking MEM or SEM protecting group
Vii) N3 alkylation, then allyl group is removed in palladium catalysis
Wherein L represents leavings group
Method 13:
The method of preparation formula of the present invention (I) compound, wherein R
3Be Cl, Br or I, comprise the step (i)-(iv) of method 8, then:
V) allyl group is removed in palladium catalysis
Vi) use NCS, NBS or NIS in the halogenation of C8 place
Method 14:
The method of preparation formula of the present invention (I) compound comprises:
I) generate pyrimidine dione
The ii) alkylation at N1 place
Iii) nitrosification
Iv) use Na
2S
2O
4Or similarly reductive agent reduction
V) generate xanthine
Vi) use NCS in the halogenation of C8 place
Wherein L represents leavings group
Method 15:
The method of preparation formula of the present invention (I) compound:
Wherein L represents leavings group.
The additional step of aforesaid general method, particularly use in the preparation of embodiment below, the method that several purification gained compounds are arranged, wherein one or more can be with in the present invention, for example use MDAP, with one or more suitable solvent recrystallization for example ethyl acetate, straight alcohol, acetonitrile or methyl alcohol, or use scavenging tower for example Silica Redisep post and subsequently with suitable solvent as containing the methylene dichloride wash-out of ethyl acetate.
If desired or necessary words, as the final step in any one above-mentioned synthetic method, resulting formula (I) compound can be converted into the pharmacy acceptable salt form, perhaps vice versa, perhaps a kind of salt form is converted into another kind of pharmacy acceptable salt form.
Abbreviation
AcOH acetate
The atm normal atmosphere
Br wide (NMR)
The CDI carbonyl dimidazoles
D doublet (NMR)
DBAD azo-2-carboxylic acid di-t-butyl ester
The DCM methylene dichloride
The DIPEA diisopropylethylamine
The DMSO methyl-sulphoxide
DMF N, dinethylformamide
The EtOAc ethyl acetate
EtOH ethanol
H hour
The IPA Virahol
M multiplet (NMR)
The directed automated preparation method (Mass directed autoprep) of MDAP quality
The MeCN acetonitrile
MeOH methyl alcohol
Min minute
The NCS N-chloro-succinimide
NBS N-bromine succinimide
NIS N-iodine succinimide
Q quartet (NMR)
The rt room temperature
The RT retention time
S unimodal (NMR)
The SPE solid-phase extraction column
T triplet (NMR)
The TFA trifluoroacetic acid
The THF tetrahydrofuran (THF)
The DMEM DMEM
HEPES 4-(2-hydroxyethyl) piperazine-1-ethyl sulfonic acid
LiHMDS hexamethyl dimethyl silanyl lithium amide
The Δ heating
SEM 2-(trimethyl silyl) ethoxyl methyl
MEM 2-methoxy ethoxy methyl
The Boc tertbutyloxycarbonyl
The THP tetrahydropyrans
Brief description of drawings
Fig. 1: the 3-of crystalline state butyl-8-chloro-1-{4-[5-(2-pyridyl)-1,2 basically, 4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2, the XRPD data of 6-diketone crystal formation 1.
Fig. 2: the 3-of crystalline state butyl-8-chloro-1-{4-[5-(2-pyridyl)-1,2 basically, 4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2, the XRPD data of 6-diketone crystal formation 2.
Fig. 3: the 3-of crystalline state butyl-8-chloro-1-{4-[5-(2-pyridyl)-1,2 basically, 4-oxadiazole-3-yl] butyl }-3,7-2 hydrogen-1H-purine-2, the XRPD data of 6-diketone crystal formation 1 and crystal formation 2 superimposed.
Following non-limitative example is used for illustrating the present invention:
Synthetic embodiment
Should be noted that (Z) that sets forth in the illustrational below compound-stereochemical not data acknowledgement by experiment of arranging.Those skilled in the art also will know, can change mutually between E and Z isomer.(Dondoni，Alessandro；Lunazzi，Lodovico；Giorgianni，Patrizia；Macciantelli，Dante.Carbon-nitrogen?rotational?barrier?as?a?stereochemicalprobe?of?benzamidoximes.Journal?of?Organic?Chemistry(1975)，40(20)，2979-80)
Embodiment 1:8-chloro-1-(2-hydroxyethyl)-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-1-(2-hydroxyethyl)-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
With 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (1.5g, 5.1mmol), Cs
2CO
3(1.8g, 5.6mmol) and ethylene chlorhydrin (509 μ l, 7.7mmol) together in DMF (20ml) at 60 ℃ of following reaction 18h.Reaction is cooled to room temperature, and mixture adds nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(428mg 0.37mmol), then outgases mixture once more.(2.1ml 24.7mmol), then stirs 3h with mixture in nitrogen, distribute between 2MHCl (aq) and EtOAc then to add morpholine.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Resistates is dissolved among the MeOH, then by the aminopropyl post, product 3%AcOH/MeOH wash-out.Merge the product cut, concentrate, purify with the EtOAc recrystallization then.Filter and collect the gained solid,, obtain the title compound (713mg, 47%) of white solid form with the EtOAc washing.
LC/MS：m/z?301[MH]
+，RT?2.7min.
1H?NMR(DMSO-d
6)δ：0.86(t，3H，J＝7Hz)，1.22-1.36(m，4H)，1.63(m，2H)，3.50(br?t，2H，J＝6Hz)，3.90(t，2H，J＝7.5Hz)，3.95(t，2H，J＝6.5Hz)，4.75(br?s，1H)，14.5(br?s，1H).
B) 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
To 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (100mg, 0.44mmol) add in the solution in dry DMF (3ml) yellow soda ash (0.051g, 0.484mmol).After at room temperature stirring 10min, (0.063ml 0.484mmol), at room temperature continues to stir 18h in nitrogen to add amyl iodide.Extract with reaction mixture water (25ml) dilution and with EtOAc (2x25ml).With the organic extract liquid drying (MgSO that merges
4), filter and evaporation.(Si 5g) purifies, and with 4: 1 EtOAc/ hexanaphthene wash-outs, obtains the title compound (96mg, 74%) of white solid form by SPE.
LC/MS：m/z?297[MH]
+.
C) 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
To 7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone) (10.52g, 54.7mmol) add in the solution in dry DMF (60ml) NCS (8.04g, 60.2mmol).Reaction mixture is stirred 6h down at 20 ℃ in nitrogen.Reaction mixture concentrates in a vacuum, obtains a kind of amber oil.Add MeOH and leave standstill 18h.The gained resistates is filtered also drying in a vacuum, obtain title compound (7.69g, 62%).
LC/MS：m/z?227[MH]
+.
D) 7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
With 2-amino-7-(2-propylene-1-yl)-1, (40g, 0.209mol) mixture in acetate (900ml) and water (100ml) heats under 55 ℃ 7-dihydro-6H-purine-6-one.Drip Sodium Nitrite (57.74g, water 0.837mol) (100ml) solution.Carefully; Toxic smog.Finish back (about 25min), reaction mixture is cooled to envrionment temperature, be concentrated into about 1/3 of its initial volume then.Add entry (500ml), filter and collect the gained precipitation.Resistates washes with water, then under 50 ℃ at P
2O
5In and under vacuum dry 2h, obtain title compound (17.20g).Then, concentrated aqueous cut then adds entry (100ml).The gained solid is filtered and drying once more.Obtain more title compound (2.31g) like this.The product (19.52g, 49%) that merges.
LC/MS：m/z?193[MH]
+.
E) 2-amino-7-(2-propylene-1-yl)-1,7-dihydro-6H-purine-6-one
With guanosine (20g, 0.071mol), allyl bromide 98 (14.7ml, 0.169mol) and the mixture of anhydrous DMSO (100ml) in nitrogen, at room temperature stir 18h.The dense HCl of disposable adding (50ml, 37%) stirs 45min with mixture, is poured into then among the MeOH (600ml).Described methanol solution filters and collects the gained white precipitate with the neutralization of 2MNaOH (aq) solution.White solid is dry in a vacuum 18h under 50 ℃, obtains title compound (16g), and it is not having just use under the situation of further purifying.
LC/MS：m/z?192[MH]
+.
Embodiment 2:8-chloro-3-(2-cyclobutyl ethyl)-1-(2-hydroxyethyl)-3,7-dihydro-1H-purine-2,6-
Diketone
7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (575mg 2.54mmol) (254mg) stirs with 2-cyclobutyl ethanol (c.73mol%, all the other 1-butanols) in anhydrous THF (20ml) the 6-diketone together.(94%, 1.57g 4.95mmol), is cooled to 0 ℃ with mixture, then drips triphenylphosphine (1.302g, 4.97mmol) solution in anhydrous THF (10ml) to add azo-2-carboxylic acid's dibenzyl ester.Mixture stirs 30min down at 0 ℃ in nitrogen, at room temperature stir 18h then.Steaming desolventizes, and resistates is gone up in Biotage system (100g) and purified, with EtOAc-hexanaphthene (2: 3) wash-out.Thus obtained material (0.53g) is a required compound, and the mixture of corresponding normal-butyl analogue and hydrazine dicarboxylic acid dibenzyl ester is not then having to carry out alkylation under the situation of further purifying.
With this mixture (256mg) and Cs
2CO
3(326mg 1mmol) stirs in dry DMF (5ml).(80.5mg 1mmol), then stirs mixture down and heating 65h at 55 ℃ to add ethylene chlorhydrin.After the cooling, it is fully outgased, add tetrakis triphenylphosphine palladium (O) (200mg) and morpholine (0.7ml), then mixture is stirred 6h.Add EtOAc and 2M HCl, then mixture is filtered, organic phase salt water washing, dry (Na
2SO
4) and evaporation, resistates separates with nonacid material by aminopropyl SPE (5g, MeOH-THF and MeOH washing are with the MeOH wash-out of the extra acetate of DCM-5%).The material that obtains from pickling (105mg) is further purified with MDAP, obtains title compound (42.7mg).
LC/MS：m/z?313[MH]
+，RT?2.58min.
1H?NMR(DMSO-d
6)δ：1.53-1.64(m，2H)，1.71-1.84(m，4H)，1.94-2.02(m，2H)，2.21-2.30(m，1H)，3.47-3.53(m，2H)，3.84(t，2H，J＝7Hz)，3.95(t，2H，J＝7Hz)，4.76(br?s，1H)，14.45(br?s，1H)
Embodiment 3:8-chloro-1-[3-(2-furyl) propyl group]-3-amyl group-3,7-dihydro-1H-purine-2, the 6-diketone,
Sodium salt
The GreenHouse of agitator is being housed
TMThe 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3 of the 0.25ml aliquots containig of packing in the pipe, 7-dihydro-1H-purine-2, the 0.54M solution of 6-diketone (0.13mmol) in THF.In this mixture, add 3-(2-furyl)-1-propyl alcohol (21mg, 0.16mmol, 1.2eq) THF (0.25ml) solution, (E)-1 that then adds the 0.25ml aliquots containig, 2-diazene dicarboxylic acid two (1, the 1-dimethyl ethyl) the 0.71M solution of ester (0.18mmol) in THF adds the 0.71M solution of triphenylphosphine (0.18mmol) in THF of 0.25ml aliquots containig then.Described solution is at GreenHouse
TMIn under nitrogen, stir 16h.(E)-1 that in this mixture, adds other 0.25ml aliquots containig, 2-diazene dicarboxylic acid two (1, the 1-dimethyl ethyl) the 1.4M solution of ester (0.36mmol) in THF adds the 1.4M solution of triphenylphosphine (0.36mmol) in THF of other 0.25ml aliquots containig then.Mixture is stirred 16h under nitrogen gas stream.
With tetrakis triphenylphosphine palladium (O) (16mg, 0.014mmol) and morpholine (0.12ml 1.35mmol) joins in the mixture, and described mixture stirs 16h under nitrogen gas stream.Reaction mixture concentrates in nitrogen, with thick material be dissolved in the NaOH aqueous solution (0.5ml, 2M) in.Gained solution uses aminopropyl SPE (with DCM and the MeOH eluant solution of AcOH) to purify.Use C18 SPE (water, ammoniacal liquor and MeCN mixture) further to purify, obtain clarifying gelationus title compound (22mg, 45%).
LC/MS：m/z?365[MH]
+，RT?3.48min.
1H NMR (DMSO-d
6) δ: 0.85 (t, 3H, J=7Hz), 1.35-1.19 (m, 4H), 1.62 (m, 2H), 1.79 (m, 2H), 2.59 (t, 2H, J=8Hz), 3.93-3.80 (m, 4H), 6.14 (d, 1H, J=3Hz), 6.32 (dd, 1H, J=3 and 2Hz), 7.48 (d, 1H, J=2Hz).
Embodiment 4:5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-[(3-
Aminomethyl phenyl) methyl] valeramide
A) methyl 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-[(3-aminomethyl phenyl)] valeramide
(50mg, 0.14mmol) (27mg 0.17mmol) handles the mixture in DCM (3ml) 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeric acid, then at room temperature stirs 1h with CDI.(25 μ l 0.20mmol), and then stir 1h to [adding (3-aminomethyl phenyl) methyl] amine.Mixture concentrates, and purifies with aminopropyl SPE then.Title compound 2-3%AcOH/MeOH wash-out concentrates then, obtains the title compound (56mg, 87%) of white solid form.
LC/MS：m/z?460[MH]
+，RT?3.3min.
B) 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeric acid
With 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) methyl valerate (8.40g, 0.023mol), LiOH (1.63g, 0.068mol), the mixture of MeOH (150ml) and water (10ml) stirs 64h at ambient temperature.Mixture distributes between water and EtOAc, then acidified aqueous solution.Separate organic layer, the aqueous solution extracts with EtOAc once more.The extraction liquid salt water washing that merges, dry (MgSO
4) and concentrate, obtain the title compound (9.09g) of pale solid form.
LC/MS：m/z?357[MH]
+，RT?3.0min.
C) 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) methyl valerate
8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (2.0g, 6.7mmol) the solution Cs in dry DMF (40ml)
2CO
3(2.42g, 7.4mmol) (1.16ml 8.1mmol) handles with the 5-bromo pentane acid A ester.Mixture is heated 18h down at 50 ℃, be cooled to room temperature then, in the vacuum of gentleness, outgas, introduce nitrogen then.Repeat twice of this process.Add Pd (PPh
3)
4(779mg 0.67mmol), then outgases mixture once more.(5.9ml 67mmol), at room temperature stirs 3h then to add morpholine.Mixture distributes between 2M HCl (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate, obtain a kind of yellow residue/oil (5.16g).Resistates is dissolved among the MeOH, is divided into two equal portions, each equal portions is used the MeOH wash-out by aminopropyl SPE (20g) then, then uses the 5%AcOH/MeOH wash-out, uses the 10%AcOH/MeOH wash-out then, uses the 15%AcOH/MeOH wash-out at last.Merge the product cut, concentrate, obtain the title compound (2.28g, 91%) of pale solid form.
LC/MS：m/z?371[MH]
+，RT?3.1min.
Embodiment 5:5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-[(3-
Ethylphenyl) methyl] valeramide
(50mg, 0.14mmol) (27mg 0.17mmol) handles the mixture in DCM (3ml) 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeric acid, then at room temperature stirs 1h with CDI.(25 μ l 0.20mmol), and then stir 1h to add [(3-ethylphenyl) methyl] amine.Mixture concentrates, and purifies on aminopropyl SPE then.Title compound 2-3%AcOH/MeOH wash-out obtains a kind of white solid (61mg, 92%).
LC/MS：m/z?474[MH]
+，RT?3.5min.
Embodiment 6:5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-[(4-
Fluoro-3-aminomethyl phenyl) methyl] valeramide
5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeric acid (50mg, 0.14mmol) and the mixture of DCM (3ml) (27mg 0.17mmol) handles, and then at room temperature stirs 1h with CDI.Add 1-(4-fluoro-3-aminomethyl phenyl) methylamine (27mg, 0.20mmol) and DIPEA (24 μ l, 0.14mmol).Behind the 1h, enriched mixture is dissolved in resistates then and also passes through aminopropyl SPE product 2%AcOH/MeOH wash-out among the MeOH, then further purifies with MDAP, obtains the title compound (15mg, 22%) of solid form.
LC/MS：m/z?478[MH]
+，RT?3.4min.
Embodiment 7:5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeric acid benzene
The base methyl esters
(50mg, 0.14mmol) (27mg 0.17mmol) handles the mixture in DCM (3ml) 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeric acid, then at room temperature stirs 1h with CDI.(21 μ l 0.20mmol), and then stir 1h to add benzylalcohol.Concentrated reaction mixture adds DMF (3ml), heats 2h down at 50 ℃ then.Enriched mixture is purified with MDAP then, obtains the title compound (33mg, 53%) of white solid form.
LC/MS：m/z?447[MH]
+，RT?3.7min.
Embodiment 8:[3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group]
Carboxylamine (3-aminomethyl phenyl) methyl esters
A) [3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group] carboxylamine (3-aminomethyl phenyl) methyl esters
(16 μ l, 0.13mmol) (24mg 0.15mmol) handles the solution in DCM (3ml) the 3-xylyl alcohol, then at room temperature stirs 1h with CDI.Add 1-(3-aminopropyl)-8-chloro-3-amyl group-3,7-dihydro-1H-purine-2, (50mg, 0.16mmol), (28 μ l 0.16mmol), heat 56h down at 50 ℃ to 6-diketone trifluoroacetate then then to add DIPEA.Concentrated reaction mixture is dissolved among the MeOH resistates also with aminopropyl SPE purification.Title compound 2%AcOH/MeOH wash-out is collected and is obtained a kind of white solid (40mg, 58%).
LC/MS：m/z?462[MH]
+，RT?3.6min.
B) 1-(3-aminopropyl)-8-chloro-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone trifluoroacetate
[3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group] carboxylamine 1,1-dimethyl ethyl ester (1.59g, 4.38mmol) solution in DCM (16ml) handles with TFA (16ml), then at room temperature stirs 2h, concentrate in a vacuum then.By remove remaining TFA, resistates Et then with the DCM azeotropic
2O develops, and obtains the title compound (1.48g, quantitative) of solid form.
LC/MS：m/z?314[MH]
+，RT?2.1min.
C) [3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group] carboxylamine 1,1-dimethyl ethyl ester
At room temperature in nitrogen, (3-hydroxypropyl) carboxylamine 1,1-dimethyl ethyl ester (1.0ml, 6.1mmol) solution in THF (40ml) is with 8-chloro-3-amyl group-1-[3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) propyl group]-3,7-dihydro-1H-purine-2, the 6-diketone (1.5g, 5.1mmol) and PPh
3(1.73g 6.6mmol) handles.Disposable adding DBAD (1.52g, 6.6mmol) and stir 18h.Mixture is introduced nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(586mg 0.51mmol), then outgases mixture once more.(4.4ml 50.7mmol), then stirs 3h with mixture in nitrogen, distribute between 2MHCl (aq) and EtOAc then to add morpholine.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate, obtain a kind of yellow oil.Add MeOH, then by aminopropyl SPE, product 2-3%AcOH/MeOH wash-out.Merge the product cut, concentrate, obtain clarifying the title compound (1.59g, 75%) of colloidal solid form.
LC/MS：m/z?414[MH]
+，RT?3.4min.
Embodiment 9:[3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group]
Carboxylamine phenyl methyl esters
At 1-(3-aminopropyl)-8-chloro-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone trifluoroacetate (50mg, in DCM 0.12mmol) (3ml) solution with DIPEA (51 μ l, 0.29mmol) and benzyl chloroformate (20 μ l, 0.14mmol) processing.Behind the 1h, concentrated reaction mixture is then purified on aminopropyl SPE.Title compound 2%AcOH/MeOH wash-out is collected and is obtained a kind of white solid (35mg, 67%).
LC/MS：m/z?448[MH]
+，RT?3.4min.
Embodiment 10:[3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group]
Carboxylamine (2-fluorophenyl) methyl esters
In nitrogen, (2-fluorophenyl) methyl alcohol (11 μ l, (3ml) solution of DCM 0.10mmol) and CDI (17mg, 0.11mmol) reaction 1h.Add 1-(3-aminopropyl)-8-chloro-3-amyl group-3,7-dihydro-1H-purine-2, (50mg, 0.16mmol), (20 μ l 0.12mmol), heat 18h to 6-diketone trifluoroacetate then under refluxing then to add DIPEA.Add THF (3ml), then heat 5h down at 75 ℃.After the cooling, mixture concentrates in a vacuum, then purifies with MDAP, obtains the title compound (21mg, 39%) of solid form.
LC/MS：m/z?466[MH]
+，RT?3.4min.
Embodiment 11:[3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group]
Carboxylamine (2,4 difluorobenzene base) methyl esters
In nitrogen, (2,4 difluorobenzene base) methyl alcohol (11 μ l, (3ml) solution of DCM 0.10mmol) and CDI (17mg, 0.11mmol) reaction 1h.Add 1-(3-aminopropyl)-8-chloro-3-amyl group-3,7-dihydro-1H-purine-2, (50mg, 0.16mmol), (20 μ l 0.12mmol), heat 18h to 6-diketone trifluoroacetate then under refluxing then to add DIPEA.Add THF (3ml), then heat 5h down at 75 ℃.After the cooling, mixture concentrates in a vacuum, then purifies with MDAP, obtains the title compound (29mg, 21%) of solid form.
LC/MS：m/z?484[MH]
+，RT?3.4min.
Embodiment 12:[3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group]
Carboxylamine 2-(3-pyridyl) ethyl ester
A) [3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group] carboxylamine 2-(3-pyridyl) ethyl ester
CDI (21mg, 0.13mmol) solution in THF (2ml) is with 2-(3-pyridyl) ethanol (16mg, 0.13mmol) handle, then under refluxing, heat 1h, add 1-(3-aminopropyl)-8-chloro-3-amyl group-3 then, 7-dihydro-1H-purine-2,6-dione hydrochloride (50mg, 0.14mmol) and DIPEA (25 μ l, 0.14mmol).Reaction backflow 18h concentrates then, purifies with MDAP, obtains the title compound (30mg, 24%) of solid form.
LC/MS：m/z?463[MH]
+，RT?2.6min.
B) 1-(3-aminopropyl)-8-chloro-3-amyl group-3,7-dihydro-1H-purine-2,6-dione hydrochloride
With [3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group] carboxylamine 1,1-dimethyl ethyl ester (5.19g, 12.5mmol) and 4M HCl 1, the mixture in the 4-diox (80ml) at room temperature stirs 3h.Mixture concentrates in a vacuum, and is dry in a vacuum, obtains the title product (4.49g, quantitative) of white solid form.
LC/MS：m/z?314[MH]
+，RT?2.2min.
Embodiment 13:[3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group]
Carboxylamine 2-(3-fluorophenyl) ethyl ester
CDI (21mg, 0.13mmol) solution in THF (2ml) is with 2-(3-fluorophenyl) ethanol (16 μ l, 0.13mmol) handle, then under refluxing, heat 1h, add 1-(3-aminopropyl)-8-chloro-3-amyl group-3 then, 7-dihydro-1H-purine-2,6-dione hydrochloride (50mg, 0.14mmol) and DIPEA (25 μ l, 0.14mmol).Reaction backflow 18h concentrates then, purifies with MDAP, obtains the title compound (27mg, 39%) of solid form.
LC/MS：m/z?480[MH]
+，RT?3.5min.
Embodiment 14:[3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group]
Carboxylamine 2-(2-thienyl) ethyl ester
CDI (21mg, 0.13mmol) solution in THF (2ml) is with 2-(2-thienyl) ethanol (15 μ L, 0.13mmol) handle, then under refluxing, heat 1h, add 1-(3-aminopropyl)-8-chloro-3-amyl group-3 then, 7-dihydro-1H-purine-2,6-dione hydrochloride (50mg, 0.14mmol) and DIPEA (25 μ L, 0.14mmol).Reaction backflow 18h concentrates then, purifies with MDAP, obtains the title compound (34mg, 51%) of solid form.
LC/MS：m/z?468[MH]
+，RT?3.4min.
Embodiment 15:(1-phenycyclopropyl) carboxylamine 3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-
Tetrahydrochysene-1H-purine-1-yl) propyl ester
A) (1-phenycyclopropyl) carboxylamine 3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl diester
8-chloro-1-(3-hydroxypropyl)-3-amyl group-3,7-dihydro-1H-purine-2, (50mg, (28mg 0.18mmol) handles solution 0.16mmol) the 6-diketone, then at room temperature stirs 1h with CDI.(30mg 0.20mmol), then heats 18h with mixture under refluxing in nitrogen to add 1-benzyl ring propylamine.(30mg 0.20mmol), then adds THF (3ml) to add the 1-benzyl ring propylamine of another five equilibrium.Be reflected at 75 ℃ of down heating 18h, concentrate then and purify with MDAP.This obtains the title compound (13mg, 18%) of white solid form.
LC/MS：m/z?474[MH]
+，RT?3.5min.
B) 8-chloro-1-(3-hydroxypropyl)-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-3-amyl group-1-[3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) propyl group]-3,7-dihydro-1H-purine-2,6-diketone (5.87g, 14.8mmol) pTsOH (2.8g of the solution in EtOH (100ml), 14.8mmol) handle, then at room temperature stir 18.5h.Mixture distributes between 1M HCl (aq) and EtOAc.Separate organic layer, water layer extracts once more.The extraction liquid water (x5), the salt water washing that merge, dry then (MgSO
4) and concentrate, obtain a kind of light yellow solid.Solid Et
2The O washing is filtered collection and is obtained a kind of white solid (2.42g, 52%).
LC/MS：m/z?315[MH]
+，RT?2.7min.
C) 8-chloro-3-amyl group-1-[3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) propyl group]-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (5.0g, 16.8mmol), Cs
2CO
3(6.0g, 18.5mmol) and 2-(3-bromine propoxy-) tetrahydrochysene-2H-pyrans (3.4ml, 20mmol) in DMF (100ml) under 50 ℃ in nitrogen the 24h that reacts.Reaction is cooled to room temperature, and mixture adds nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(1.4g 1.2mmol), then outgases mixture once more.(14.7ml 170mmol), then stirs 3h with mixture in nitrogen, distribute between 2M HCl (aq) and EtOAc then to add morpholine.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate, obtain a kind of yellow residue (5.16g).Add MeOH, then by aminopropyl SPE, product 5%AcOH/MeOH wash-out.Merge the product cut, concentrate, obtain the title compound (5.97g, 89%) of light yellow solid form.
LC/MS：m/z?399[MH]
+，RT?3.3min.
Embodiment 16:(phenyl methyl) carboxylamine 3-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene
-1H-purine-1-yl) propyl ester
8-chloro-1-(3-hydroxypropyl)-3-amyl group-3,7-dihydro-1H-purine-2, the 6-diketone (50mg, 0.16mmol) solution in THF (3ml) with triphosgene (47mg, 0.16mmol) and pyridine (13 μ L, 0.16mmol) processing.Behind the 30min, (217 μ l 2.0mmol), follow restir 30min to add benzylamine.Mixture distributes between 2M HCl (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Resistates is dissolved among the MeOH, purifies product 2-5%AcOH/MeOH wash-out with aminopropyl SPE.Obtain the title compound (67mg, 94%) of pale solid form.
LC/MS：m/z?448[MH]
+，RT?3.2min.
Embodiment 17:[(3-aminomethyl phenyl) methyl] carboxylamine 3-(8-chloro-2,6-dioxo-3-amyl group
-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl ester
8-chloro-1-(3-hydroxypropyl)-3-amyl group-3,7-dihydro-1H-purine-2, (50mg, 0.16mmol) (31mg 0.19mmol) handles the solution in DCM (3ml) the 6-diketone, then at room temperature stirs 1h with CDI.(26 μ l 0.21mmol), then heat 18h under refluxing to add the 3-methylbenzylamine.(4 μ l, 0.03mmol), 4h then refluxes mixture to add the methylbenzylamine of another equal portions.Enriched mixture is dissolved among the MeOH then also by aminopropyl SPE.Product 2%AcOH/MeOH wash-out is further purified by MDAP then.Obtain the title compound (42mg, 57%) of white solid form like this.
LC/MS：m/z?462[MH]
+，RT?3.5min.
Embodiment 18:8-chloro-1-(3-{1-[(2-chloro-6-fluorophenyl) methyl]-1H-pyrazoles-4-yl } propyl group)-3-penta
Base-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-1-(3-{1-[(2-chloro-6-fluorophenyl) methyl]-1H-pyrazoles-4-yl } propyl group)-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-3-amyl group-7-(2-propylene-1-yl)-1-[3-(1H-pyrazoles-4-yl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone (61mg, 0.15mmol) dry DMF (2ml) solution and yellow soda ash (64mg, 0.6mmol) and 2-chloro-6-fluoro benzyl bromide (134mg 0.6mmol) stirs together and heat 18h under 45 ℃ in nitrogen.After being cooled to room temperature, mixture is by vacuumize degassing and nitrogen injection again, with tetrakis triphenylphosphine palladium (O) (35mg, 0.303mmol) and morpholine (0.13ml) stir 5.5h together.Mixture distributes between EtOAc and 2M HCl, separate organic phase and evaporation, resistates aminopropyl SPE purification (5g, wash with THF-MeOH (1: 1), pure then MeOH washing, at last with containing DCM-MeOH (1: the 1) wash-out of 5%AcOH), obtain the title compound (57mg) of solid form.
LC/MS：m/z?507[MH]
+，RT?3.64min.
B) 8-chloro-3-amyl group-7-(2-propylene-1-yl)-1-[3-(1H-pyrazoles-4-yl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone
3-amyl group-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (5g, 16.86mmol) and 3-(1H-pyrazoles-4-yl) third-1-alcohol (2.12g 16.8mmol) stirs under 3 ℃ in anhydrous THF (150ml).(10.05g 33.7mmol), then drips triphenylphosphine (8.83g, anhydrous THF (70ml) solution 33.7mmol) to add azo-2-carboxylic acid's dibenzyl ester.Mixture is warmed to room temperature, stirs 18h then.Add entry (1ml), then with solvent evaporation.Resistates is dissolved in Et
2Among the O (200ml), crystallization goes out a kind of white solid, and major part is a triphenylphosphine oxide, then filters.Filtrate concentrates, and goes out other by product with ether-hexanaphthene crystallization.Residual filtrate is concentrated (19.2g), at Biotage
TMSystem (400g) goes up purifies, and with EtOAc-hexanaphthene (2: 1) wash-out, obtains the title compound (2.89g) of white solid form.
LC/MS：m/z?405[MH]
+，RT?3.19min.
Following compounds (table 1) uses the method that is similar to embodiment 18 to be prepared by corresponding benzyl halogenide.
Table 1
*After further purifying by MDAP.
The NMR details of the embodiment that selects from table 1
Embodiment 19:8-chloro-3-amyl group-1-(3-{1-[(2,4,6-trifluorophenyl) methyl]-1H-pyrazoles-4-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(DMSO-d
6)δ：0.85(t，3H，J＝7Hz)，1.20-1.40(m，4H)，1.60-1.70(m，2H)，1.70-1.82(m，2H)，2.39(t，2H，J＝8Hz)，3.83-3.94(m，4H)，5.24(s，2H)，7.18-7.30(m，3H)，7.57(s，1H).
Embodiment 23:8-chloro-1-(3-{1-[(2,4-difluorophenyl) methyl]-1H-pyrazoles-4-yl } propyl group)-3-penta
Base-3,7-dihydro-1H-purine-2,6-diketone
With 8-chloro-3-amyl group-7-(2-propylene-1-yl)-1-[3-(1H-pyrazoles-4-yl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone (81mg, 0.2mmol) and yellow soda ash (85mg, 0.8mmol) in dry DMF (2ml) with 2, (166mg 0.8mmol) stirs 18h down at 45 ℃ to the 4-difluoro benzyl bromide together.The mixture degassing, then with tetrakis triphenylphosphine palladium (O) (46mg, 0.04mmol) and morpholine (176mg 2mmol) at room temperature stirs 6h together.Post-reaction treatment is then purified (5g, with THF-MeOH (1: 1) washing, pure then MeOH washing is at last with DCM-MeOH (1: the 1) wash-out that contains 5%AcOH) with aminopropyl SPE, obtains the title compound (37.7mg) of solid form.
LC/MS：m/z?491[MH]
+，RT?3.42min.
1H?NMR(d
6DMSO)0.85(3H，t，J＝7Hz)，1.21-1.34(4H，m)，1.58-1.68(2H，m)，1.71-1.80(2H，m)，2.41(2H，t，J＝8Hz)，3.84-3.93(4H，m)，5.26(2H，s)，7.02-7.09(1H，m)，7.15-7.29(2H，m)，7.31(1H，s)，7.61(1H，s).
Following compounds (table 1) uses the method that is similar to embodiment 23 to be prepared by corresponding benzyl halogenide.
Table 2
*After further purifying by MDAP.
The NMR details of the embodiment that selects from table 2
Embodiment 24:8-chloro-3-amyl group-1-{3-[1-(phenyl methyl)-1H-pyrazoles-4-yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone;
1H NMR (DMSO-d
6) δ: 0.87 (t, 3H, J=7Hz), 1.20-1.36 (m, 4H), 1.60-1.70 (m, 2H), 1.72-1.85 (m, 2H), 2.42 (t, 2H, J=8Hz), 3.83-3.95 (m, 4H), 5.24 (s, 2H), 7.13-7.38 (m, 6H), 7.61 (s, 1H).
Embodiment 28:8-chloro-1-(3-{1-[(2-chloro-phenyl-) methyl]-1H-pyrazoles-4-yl } propyl group)-the 3-amyl group
-3,7-dihydro-1H-purine-2,6-diketone
By being used to prepare 8-chloro-1-(3-{1-[(2,4-difluorophenyl) methyl]-1H-pyrazoles-4-yl propyl group)-3-amyl group-3,7-dihydro-1H-purine-2, the preparation of the method for 6-diketone, but with 2-chlorine bromotoluene (164mg, 0.8mmol).But, in order to finish deprotection steps, add other tetrakis triphenylphosphine palladium (O) (40mg) and morpholine (0.15ml), then continue to stir other 5.5h.By purifying, obtain the title compound (42mg) of solid form as above-mentioned aminopropyl SPE.
LC/MS：m/z?489[MH]
+，RT?3.67min.
Embodiment 29:3-butyl-8-chloro-1-{3-[1-(phenyl methyl)-1H-imidazol-4 yl] propyl group }-3,7-two
Hydrogen-1H-purine-2, the 6-diketone
A) 3-butyl-8-chloro-1-{3-[1-(phenyl methyl)-1H-imidazol-4 yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
3-butyl-8-chloro-1-[4-(1H-imidazol-4 yl) butyl]-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (300mg, 0.77mmol) bromotoluene (144mg of the solution in anhydrous THF (5ml), 0.84mmol) and DIPEA (147 μ l, 0.84mmol) processing.Mixture at room temperature stirred 4 days in nitrogen.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Thick material is purified with silicon-dioxide SPE post, uses the 0.5-5%MeOH/DCM gradient elution.Merge the product cut, then under high vacuum, concentrate.Product is dissolved among the THF (5ml), adds Pd (PPh then
3)
4(88mg, 0.077mmol) and morpholine (670 μ l 7.67mmol), then at room temperature stir 3h with mixture in nitrogen.Pd (the PPh that adds 88mg
3)
4(0.077mmol), then mixture is at room temperature stirred 16h in nitrogen.Mixture is at EtOAc and H
2Distribute between the O.Separate organic layer, water layer extracts (x2) with EtOAc.Merge organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Crude product is purified with MDAP, obtains the title compound (9mg, 2%) of white solid form.
LC/MS：m/z?441[MH]
+，RT?2.50min.
1H NMR (DMSO-d
6) δ: 0.89 (t, 3H, J=7.5Hz), 1.28 (m, 2H), 1.60 (m, 2H), 1.79 (m, 2H), 2.48 (t and DMSO are overlapping, 2H, J=7.5Hz), 3.89 (m, 4H), 5.17 (s, 2H), 7.08 (s, 1H), 7.31, (m, 6H), 8.03 (s, 1H).
B) 3-butyl-8-chloro-1-[3-(1H-imidazol-4 yl) propyl group]-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (2.8g, 9.9mmol) 3-(1H-imidazol-4 yl)-1-propyl alcohol (1.5g, 12mmol) anhydrous THF (10ml) solution and the PPh of the solution in anhydrous THF (60ml)
3(3.4g 13mmol) handles.(2.9g, 13mmol), mixture at room temperature stirs 18h to disposable adding DBAD in nitrogen.Mixture is at EtOAc and H
2Distribute between the O.Water layer extracts and washing with EtOAc.Merge organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Crude product is purified with silicon-dioxide SPE post, with MeOH/EtOAc gradient elution (0.5%-7%MeOH).Merge the product cut, concentrate, obtain the title compound (2.16g, 55%) of white solid form.
LC/MS：m/z?391[MH]
+，RT?2.40min.
C) 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
To 3-butyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (3.34g, (1.97g 14.8mmol), then at room temperature stirs 22h to the 6-diketone in nitrogen 13.4mmol) to add NCS in the solution in dry DMF (19ml).Mixture concentrates in a vacuum, obtains a kind of yellow solid, this yellow solid is filtered and with the MeOH washing, obtain gathering in the crops for the first time.Filtrate is concentrated into solid,, obtains after-crop, and repeat twice again, obtain title compound with the MeOH washing.After the washing, (Si, 20g) further purify, and uses EtOAc: hexanaphthene (1: 1) wash-out by post with SPE for filtrate at last.The solid that merges is dry in a vacuum, obtain title compound (2.42g, 64%).
LC/MS：m/z?283[MH]
+.
Embodiment 30:3-butyl-8-chloro-1-(3-{1-[(2,3-difluorophenyl) methyl]-the 1H-imidazol-4 yl } third
Base)-3,7-dihydro-1H-purine-2,6-diketone
3-butyl-8-chloro-1-[4-(1H-imidazol-4 yl) butyl]-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (150mg, 0.38mmol) solution in dry DMF (3ml) is with 1-(brooethyl)-2,4-two fluorobenzene (54 μ l, 0.42mmol) and DIPEA (73 μ l, 0.42mmol) processing.Mixture at room temperature stirred 3 days in nitrogen.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Crude product is purified on silicon-dioxide SPE post, with DCM described material is loaded on the post, and flush away impurity uses the 0-5%MeOH/DCM gradient with the wash-out compound then.Merge the product cut, concentrate, then resistates is dissolved in the dry DMF (3ml).With this solution degassing, add Pd (PPh then
3)
4(39mg, 0.034mmol) and morpholine (200 μ l 2.3mmol), then at room temperature stir 3h with mixture in nitrogen.Crude product is purified with aminopropyl SPE, with MeOH described compound is loaded on the post, and flush away impurity uses the 0-5%AcOH/MeOH gradient with eluted product then.Merge the product cut, high vacuum concentrates, and obtains the title compound (14mg, 7%) of white solid form.
LC/MS：m/z?477[MH]
+，RT?2.54min.
Embodiment 31:3-butyl-8-chloro-1-[3-(1-{[2-(trifluoromethyl) phenyl] methyl }-1H-imidazoles-4-
Base) propyl group]-3,7-dihydro-1H-purine-2,6-diketone
3-butyl-8-chloro-1-[4-(1H-imidazol-4 yl) butyl]-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (150mg, 0.38mmol) solution in dry DMF (3ml) is with 1-(chloromethyl)-2-(trifluoromethyl) benzene (61 μ l, 0.42mmol) and DIPEA (73 μ l, 0.42mmol) processing.Mixture at room temperature stirred 3 days in nitrogen.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Crude product is purified on silicon-dioxide SPE post, with DCM described material is loaded on the post, and flush away impurity uses the 0-5%MeOH/DCM gradient with the wash-out compound then.Merge the product cut, concentrate, then resistates is dissolved in the dry DMF (3ml).With the described solution degassing, add Pd (PPh then
3)
4(35mg, 0.030mmol) and morpholine (174 μ l 2.0mmol), then at room temperature stir 3h with mixture in nitrogen.Crude product is purified with aminopropyl SPE, with MeOH described compound is loaded on the post, and flush away impurity uses the 0-5%AcOH/MeOH gradient with eluted product then.Merge the product cut, high vacuum concentrates, and obtains the title compound (50mg, 26%) of white solid form.
LC/MS：m/z?509[MH]
+，RT?2.64min.
Embodiment 32:3-butyl-8-chloro-1-[3-(1-{[3-(trifluoromethyl) phenyl] methyl }-1H-imidazoles-4-
Base) propyl group]-3,7-dihydro-1H-purine-2,6-diketone
3-butyl-8-chloro-1-[4-(1H-imidazol-4 yl) butyl]-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (150mg, 0.38mmol) solution in dry DMF (3ml) is with 1-(chloromethyl)-3-(trifluoromethyl) benzene (65 μ l, 0.42mmol) and DIPEA (73 μ l, 0.42mmol) processing.Mixture at room temperature stirred 3 days in nitrogen.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Crude product is purified on silicon-dioxide SPE post, with DCM described material is loaded on the post, and flush away impurity uses the 0-5%MeOH/DCM gradient with the wash-out compound then.Merge the product cut, concentrate, then resistates is dissolved in the dry DMF (3ml).The solution degassing adds Pd (PPh then
3)
4(30mg, 0.027mmol) and morpholine (156 μ l 1.8mmol), then at room temperature stir 3h with mixture in nitrogen.Crude product is purified with aminopropyl SPE, with MeOH described compound is loaded on the post, and flush away impurity uses the 0-5%AcOH/MeOH gradient with eluted product then.Merge the product cut, high vacuum concentrates, and obtains the title compound (18mg, 9%) of white solid form.
LC/MS：m/z?509[MH]
+，RT?2.78min.
Embodiment 33:3-butyl-8-chloro-1-{3-[3-(phenyl methyl)-1H-1,2, the 4-triazol-1-yl] third
Base }-3,7-dihydro-1H-purine-2,6-diketone
A) 3-butyl-8-chloro-1-{3-[3-(phenyl methyl)-1H-1,2, the 4-triazol-1-yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
3-butyl-8-chloro-1-{3-[3-(phenyl methyl)-1H-1,2, the 4-triazol-1-yl] propyl group }-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (669mg, 1.39mmol) solution in THF (7ml) is introduced nitrogen by vacuum outgas to the 6-diketone then.Add Pd (PPh
3)
4(160mg 0.14mmol), then outgases mixture once more.(1.2ml 13.9mmol), then stirs 18h with mixture in nitrogen, distribute between the HCl of 2M (aq) and EtOAc then to add morpholine.Separate organic layer, water layer extracts with EtOAc once more.The extraction liquid salt water washing that merges, dry (MgSO
4) and concentrate, obtain a kind of yellow residue.Add MeOH, then by aminopropyl SPE, product 2-3%AcOH/MeOH wash-out.Merge the product cut, concentrate, obtain a kind of light yellow solid (380mg).About 1/4th material is purified with preparation HPLC automatically, and all the other use MeOH: DMSO (1: 1) crystallization obtains the title compound (125mg, 31%) of white solid form.
LC/MS：m/z?442[MH]
+，RT?3.0min.
1H?NMR(DMSO-d
6)δ：0.89(t，3H，J＝7Hz)，1.30(m，2H)，1.62(m，2H)，2.07(m，2H)，3.90(m，6H)，4.13(t，2H，J＝7Hz)，7.24(m，5H)，8.36(1H，s)，14.5(brs，1H).
B) 3-butyl-8-chloro-1-{3-[3-(phenyl methyl)-1H-1,2, the 4-triazol-1-yl] propyl group }-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
3-(phenyl methyl)-1H-1,2, the 4-triazole (2.1g, 13.2mmol) solution in MeOH (40ml) is with MeOH (29ml) solution-treated of the NaOMe of 0.5M, and then with 1,3-dibromopropane (1.7ml) is handled.Behind 50 ℃ of stirring 5h, mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate, obtain a kind of oily resistates (1.0g).In this resistates, add butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (917mg, 3.2mmol) and Cs
2CO
3(1.2g, 3.6mmol).Add DMF (15ml), then mixture is stirred 20h down at 50 ℃, between the HCl of 2M (aq) and EtOAc, distribute then.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Gained oil (1.52g) is by silicon-dioxide SPE (50g) post, with EtOAc/ hexanaphthene mixture wash-out.Obtain two kinds of isomerized products of triazole, it is 2: 1 a mixture, and title compound is more, is yellow mashed prod (697mg, 67% ratio based on isomer of the present invention).
LC/MS：m/z?482[MH]
+，RT?3.3min.
Embodiment 34:8-chloro-3-amyl group-1-{3-[5-(phenyl methyl)-2H-tetrazolium-2-yl] propyl group }-3,7-two
Hydrogen-1H-purine-2, the 6-diketone
5-benzyl-1H-tetrazolium (1.0g, 6.24mmol) solution in MeOH (5ml) with 1-chloro-3-iodopropane (1.0ml, 9.36mmol) and MeOH (4.7ml, 9.36mmol) solution-treated of 0.5M NaOMe.Be reflected at the heating 18h down that refluxes, between the HCl of 2M (aq) and EtOAc, distribute then.Separate organic layer, water layer extracts with EtOAc once more.The extraction liquid salt water washing that merges, dry (MgSO
4) and concentrate, obtain a kind of yellow solid (796mg).This material of 700mg and 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (732mg, 2.47mmol) and Cs
2CO
3(967mg 3.0mmol) reacts 24h down at 75 ℃ in DMF (20ml).Reaction is cooled to room temperature, and mixture adds nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(428mg 0.37mmol), then outgases mixture once more.(2.1ml 24.7mmol), then stirs 3h with mixture in nitrogen, distribute between the HCl of 2M (aq) and EtOAc then to add morpholine.Separate organic layer, water layer extracts once more.The extraction liquid that merges concentrates, and obtains a kind of yellow residue.Add MeOH, then by aminopropyl SPE, product 2-3%AcOH/MeOH wash-out.Merge the product cut, concentrate, purify with MDAP then, obtain the title compound (35mg, 3%) of white solid form.
LC/MS：m/z?457[MH]
+，RT?3.5min.
1H?NMR；(DMSO-d
6)δ：0.85(t，3H，J＝7Hz)，1.21-1.34(m，4H)，1.62(m，2H)，2.22(m，2H)，3.88(t，2H，J＝7Hz)，3.97(t，2H，J＝7Hz)，4.17(s，2H)，4.67(t，2H，J＝7Hz)，7.20-7.32(m，5H)，14.5(br?s，1H).
Embodiment 35:3-butyl-8-chloro-1-{3-[5-(phenyl methyl)-2H-tetrazolium-2-yl] propyl group }-3,7-two
Hydrogen-1H-purine-2, the 6-diketone
5-benzyl-1H-tetrazolium (1.8g, 11.2mmol) solution in MeOH (30ml) is with 1, and (5.7ml 56.2mmol) and MeOH (31.5ml) solution-treated of the NaOMe of 0.5M, stirs 60h to the 3-dibromopropane then in nitrogen under 40 ℃.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.By SPE (20g silicon-dioxide, hexanaphthene/EtOAc mixture) with pass through Companion
TMSystem's (silicon-dioxide SPE, hexanaphthene/EtOAc mixture) part is purified, and obtains a kind of oil (2: 1,2-(3-bromopropyl)-5-(phenyl methyl)-2H-tetrazolium was more for 1.98g, 62% isomer mixture), and it directly uses with thick material in next step.
With 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (1.74g, 6.1mmol), thick 2-(3-bromopropyl)-5-(phenyl methyl)-2H-tetrazolium) (1.9g, 6.8mmol), Cs
2CO
3(2.2g, 6.8mmol) and the mixture of DMF (60ml) under 45 ℃, in nitrogen, stir 24h.Mixture is introduced nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(705mg 0.61mmol), then outgases mixture once more.(5.4ml 61.4mmol), then stirs 4h with mixture in nitrogen, distribute between the HCl of 2M (aq) and EtOAc then to add morpholine.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate, obtain a kind of yellow residue.Add MeOH, then by the aminopropyl post, product 2%AcOH/MeOH wash-out.Product is further used Companion
TMSystem purifies, with EtOAc/ hexanaphthene mixture wash-out.The gained solid is at boiling Et
2Stir among the O, then be cooled to the room temperature after-filtration.Collection obtains the title compound (1.01g, 37%) of white solid form, then carries out drying under 50 ℃ in a vacuum.
LC/MS：m/z?443[MH]
+，RT?3.3min.
1H?NMR(DMSO-d
6)δ：0.89(t，3H，J＝7Hz)，1.29(m，2H)，1.61(m，2H)，2.22(m，2H)，3.89(t，2H，J＝7Hz)，3.97(t，2H，J＝7Hz)，4.17(s，2H)，4.67(t，2H，J＝7Hz)，7.20-7.32(m，5H)，14.5(br?s，1H).
Embodiment 36:8-chloro-1-(3-{5-[(4-fluorophenyl) methyl]-2H-tetrazolium-2-yl } propyl group)-3-(4,4,4-
The trifluoro butyl)-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-1-(3-{5-[(4-fluorophenyl) methyl]-2H-tetrazolium-2-yl } propyl group)-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2,6-diketone
The 5-[(4-fluorophenyl) methyl]-the 1H-tetrazolium (75mg, 0.4mmol) with salt of wormwood (100mg, 0.7mmol) and DMF (3ml) processing.Described mixture methylsulfonic acid 3-[8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-3-(4,4,4-trifluoro butyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] propyl diester (100mg, 0.2mmol) solution-treated in DMF (0.5ml).Heated 3 hours down with the mixture stirring and at 60 ℃, cool off then and evaporate.Resistates is at chloroform (4ml) and water (2cm
3) between distribute.With 1cm
3Saturated sodium bicarbonate aqueous solution (3ml) join every kind.With mixture separation, the evaporation organic phase.Resistates is dissolved among the anhydrous THF (3ml), and mixture outgases by careful vacuum and the nitrogen pressure of using continuously.Mixture with tetrakis triphenylphosphine palladium (O) (10mg, 0.008mmol) and morpholine (0.2ml, 2.3mmol) processing, in nitrogen atmosphere, stir 2h then.With the mixture evaporation, then between chloroform (4ml) and saturated aqueous ammonium chloride (3ml), distribute.Separating mixture, water are used chloroform extraction again.The evaporation organic phase then is dissolved in resistates among the MeOH (3ml).This solution is joined the top of 2g aminopropyl SPE, then with MeOH (15ml) washing.Required product is by the pillar eluant solution of 3%v/vAcOH in MeOH (20ml).Merge and to contain the cut product, evaporation, resistates is by flash chromatography purify (with 10: 1 hexanaphthene/EtOAc gradient elution to EtOAc).Merge and contain the product cut, evaporate, obtain the product of colorless oil.In minimum ether, grind, cause product to solidify,, obtain the title compound (18.7mg, 18%) of white solid form then with this solid product thorough drying.
LC/MS：m/z?515[MH]
+，RT?3.31min.
1H?NMR(CDCl
3)δ：2.06(m，2H)，2.21(m，2H)，2.45(m，2H)，4.17(m，4H)，4.24(t，2H，J＝7.0Hz)，4.70(t，2H，J＝7.2Hz)，6.96(m，2H)，7.25(m，2H).
B) methylsulfonic acid 3-[8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-3-(4,4,4-trifluoro butyl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] propyl diester
8-chloro-1-(3-hydroxypropyl)-7-(2-propylene-1-yl)-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2,6-diketone (0.82g, 2.1mmol) triethylamine (0.42ml of the solution in DCM (20ml), 3.1mmol) and methylsulfonic acid acid anhydride (0.40g, 2.3mmol) processing.Behind the 1h, mixture is handled with saturated sodium bicarbonate aqueous solution (20ml).Separating mixture is with organic phase drying (MgSO
4), to filter, evaporation obtains title compound (0.91g), and it just uses under the situation that does not have further purification.
LC/MS：m/z?473[MH]
+，RT?3.17min.
C) 8-chloro-1-(3-hydroxypropyl)-7-(2-propylene-1-yl)-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-7-(2-propylene-1-yl)-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2,6-diketone (1.0g, 3.0mmol) cesium carbonate (1.16g of the solution in DMF (15ml), 3.6mmol) and 3-bromo-1-propyl alcohol (0.3ml, 3.3mmol) processing.Mixture heats 4h down at 60 ℃, cools off then and evaporates.Resistates distributes between EtOAc (50ml) and water (50ml).With organic phase drying (MgSO
4), filter and evaporation.Product is purified with flash chromatography, with the gradient elution of hexanaphthene to EtOAc.Merge and contain the product cut, evaporate, obtain the title compound (0.82g, 75%) of colorless oil.
LC/MS：m/z?395[MH]
+，RT?2.90min.
D) 8-chloro-7-(2-propylene-1-yl)-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (2.0g, 8.8mmol) (1.15g, 10.8mmol) with 4-bromo-1,1, (1.86g 9.7mmol) handles 1-trifluoro butane the solution in DMF (20ml) the 6-diketone with yellow soda ash.Mixture stirs 18h down at 50 ℃, cools off then and evaporates.Resistates distributes between EtOAc (100ml) and saturated sodium bicarbonate aqueous solution (50ml).With organic phase drying (MgSO
4), filter and evaporation.Resistates grinds in the mixture of ether and hexanaphthene, and product leaches then, and drying obtains the title compound (1.18g, 40%) of white solid form.
LC/MS：m/z?337[MH]
+，RT?2.83min.
E) methyl 5-[(4-fluorophenyl)]-the 1H-tetrazolium
Triethyl ammonium chloride (4.14g, 30mmol) and sodiumazide (1.95g, (1.35g 10mmol) handles in the solution of toluene (14ml), then mixture is stirred and at 100 ℃ of heating 5h down with (4-fluorophenyl) acetonitrile for 30mmol) mixture.Cooled mixture water (10ml) is handled, then separating mixture.Stir water and drip concentrated hydrochloric acid, till product precipitates from solution.Leach sedimentary product, wash with water, drying obtains the title compound (1.27g, 72%) of white solid form.
LC/MS：m/z?179[MH]
+，RT?2.24min.
Compound in the table 3 uses and is similar to embodiment 36:8-chloro-1-(3-{5-[(4-fluorophenyl) methyl]-2H-tetrazolium-2-yl } propyl group)-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2, the method of 6-diketone is with suitable methanesulfonates tetrazolium preparation.Use MDAP with those pure inadequately compounds after normal-phase chromatography is purified of further purification.
Methanesulfonates intermediate and their precursor alcohols prepare according to the following step:
Methylsulfonic acid 3-[8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-3-propyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] propyl diester
8-chloro-1-(3-hydroxypropyl)-7-(2-propylene-1-yl)-3-propyl group-3,7-dihydro-1H-purine-2,6-diketone (1.99g, 6.1mmol) triethylamine (1.2ml of the solution in DCM (50ml), 8.6mmol) and methylsulfonic acid acid anhydride (1.2g, 6.9mmol) processing.1.5h after, mixture water (50ml) is handled.Separating mixture, water extracts (25ml), the organic phase drying (MgSO of merging with DCM
4), filter, evaporate, obtain the title compound (2.38g) of light yellow oily, it just uses under the situation that does not have further purification.
LC/MS：m/z?405[MH]
+，RT?2.93min.
Methylsulfonic acid 3-[3-butyl-8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] propyl diester
According to being used for preparing methylsulfonic acid 3-[8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-3-propyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] method of propyl diester, obtain the title compound (2.44g) of light yellow oily.
LC/MS：m/z?419[MH]
+，RT?3.14min.
8-chloro-1-(3-hydroxypropyl)-7-(2-propylene-1-yl)-3-propyl group-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-7-(2-propylene-1-yl)-3-propyl group-3,7-dihydro-1H-purine-2, (3.0g, 11.1mmol) (3.7g, 11.4mmol) (1.6g 11.5mmol) handles the solution in DMF (20ml) the 6-diketone with 3-bromo-1-propyl alcohol with cesium carbonate.Mixture heats 4h down at 60 ℃, cools off then and evaporates.Resistates distributes between EtOAc (60ml) and saturated sodium bicarbonate aqueous solution (50ml).Water is extracted the organic phase drying (MgSO of merging with EtOAc (60ml)
4), filter and evaporation.Product Companion
TMSystem is purified, with the gradient elution of hexanaphthene to EtOAc.Merge and contain the product cut, evaporate, obtain the title compound (2.6g) of colorless oil.
LC/MS：m/z?327[MH]
+，RT?2.62min.
3-butyl-8-chloro-1-(3-hydroxypropyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
According to being used for preparing 8-chloro-1-(3-hydroxypropyl)-7-(2-propylene-1-yl)-3-propyl group-3,7-dihydro-1H-purine-2, the method for 6-diketone obtains the title compound (2.3g) of colorless oil.
LC/MS：m/z?341[MH]
+，RT?2.85min.
Table 3
The NMR details of the embodiment that selects from table 3:
Embodiment 37:8-chloro-1-(3-{5-[(4-fluorophenyl) methyl]-2H-tetrazolium-2-yl } propyl group)-3-propyl group-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(CDCl
3)δ：0.99(t，3H，J＝7.5Hz)，1.80(m，2H)，2.46(m，2H)，4.06(m，2H)，4.18(s，2H)，4.25(t，2H，J＝7Hz)，4.70(t，2H，J＝7.5Hz)，6.96(m，2H)，7.26(m，2H)，13.15(br?s，1H).
Embodiment 40:8-chloro-3-(4,4,4-trifluoro butyl)-1-(3-{5-[(2,4,6-trifluorophenyl) methyl]-2H-tetrazolium-2-yl } propyl group)-3,7-dihydro-1H-purine-2, the 6-diketone:
1H NMR (CDCl
3) δ: 2.07 (m, 2H), 2.21 (m, 2H), 2,44 (m, 2H), 4.18 (t, 2H, J=7.1Hz), 4.20 (s, 2H), 4.24, (t, 2H, J=6.8Hz), 4.68 (t, 2H, J=7.3Hz), 6.67 (t, 2H, J=8.1Hz), 13.04 (br s, 1H).
Embodiment 41:
1H NMR (CDCl
3): 2.03-2.10 (m, 2H), 2.16-2.28 (m, 2H), 2.43-2.50 (m, 2H), 4.16-4.19 (m, 2H), 4.17 (s, 2H), 4.24 (t, 2H, J=7.1Hz), 4.71 (t, 2H, J=7.1Hz), 7.00-7.13 (m, 3H), 13.06 (bs, 1H).
Embodiment 44:
1H NMR (CDCl
3): 0.99 (t, 3H, J=7.5Hz), 1.76-1.86 (m, 2H), 2.40-2.47 (m, 2H), 4.05-4.09 (m, 2H), 4.23-4.26 (m, 2H), 4.54 (s, 2H), 4.65-4.69 (m, 2H), 7.14-7.18 (m, 1H), 7.31-7.33 (m, 2H), 13.18 (bs, 1H).
Embodiment 45:
1H NMR (CDCl
3): 0.97 (t, 3H, J=7.5Hz), 1.36-1.46 (m, 2H), and 1.71-1.79 (m, 2H), 2.42-2.49 (m, 2H), and 4.08-4.11 (m, 2H), 4.25 (s, 2H), and 4.24-4.27 (m, 2H), 4.68-4.71 (m, 2H), and 7.02-7.09 (m, 2H), 7.20-7.26 (m, 2H), 13.14 (bs, 1H).
Embodiment 46:
1H NMR (CDCl
3): 0.97 (t, 3H, J=7.5Hz), 1.36-1.45 (m, 2H), 1.71-1.79 (m, 2H), 2.42-2.49 (m, 2H), 4.09 (t, 2H, J=7.5Hz), 4.26 (t, 2H, J=7.5Hz), 4.34 (s, 2H), 4.70 (t, 2H, J=7.3Hz), 7.18-7.21 (m, 2H), 7.25-7.27 (m, 1H), 7.35-7.37 (m, 1H), 13.34 (bs, 1H).
Embodiment 47:3-butyl-8-chloro-1-(3-{5-[(3-fluorophenyl) methyl]-2H-tetrazolium-2-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(CDCl
3)δ：0.97(t，3H，J＝7Hz)，1.40(m，2H)，1.75(m，2H)，2.46(m，2H)，4.10(t，2H，J＝7.5Hz)，4.21(s，2H)，4.26(t，2H，J＝6.5Hz)，4.70(t，2H，J＝7.5Hz)，6.90(m，1H)，6.99(m，1H)，7.07(m，1H)，7.25(m，1H)，13.25(br?s，1H).
Embodiment 48:
1H NMR (CDCl
3): 0.99 (t, 3H, J=7.5Hz), 1.38-1.48 (m, 2H), 1.73-1.81 (m, 2H), 2.44-2.51 (m, 2H), 4.12 (t, 2H, J=7.5Hz), 4.20 (s, 2H), 4.27 (t, 2H, J=7.5Hz), 4.70 (t, 2H, J=7.3Hz), 6.95-7.00 (m, 2H), 7.26-7.30 (m, 2H), 13.35 (bs, 1H).
Embodiment 49:3-butyl-8-chloro-1-(3-{5-[(4-fluorophenyl) methyl]-2H-tetrazolium-2-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(CDCl
3)δ：0.99(t，3H，J＝7Hz)，1.43(m，2H)，1.77(m，2H)，2.48(m，2H)，4.12(t，2H，J＝7.5Hz)，4.20(s，2H)，4.27(t，2H，J＝7Hz)，4.72(t，2H，J＝7.5Hz)，6.98(m，2H)，7.27(m，2H)，13.35(br?s，1H).
Embodiment 50:3-butyl-8-chloro-1-(3-{5-[(4-chloro-phenyl-) methyl]-2H-tetrazolium-2-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(CDCl
3)δ：1.02(t，3H，J＝7.5Hz)，1.45(m，2H)，1.79(m，2H)，2.50(m，2H)，4.14(t，2H，J＝7.5Hz)，4.22(s，2H)，4.29(t，2H，J＝7Hz)，4.75(t，2H，J＝7.5Hz)，7.27(s，4H)，13.35(br?s，1H).
Embodiment 55:3-butyl-8-chloro-1-{3-[5-(1-phenycyclopropyl)-2H-tetrazolium-2-yl] propyl group }-3,7-dihydro-1H-purine-2, the 6-diketone:
1H NMR (CDCl
3) δ: 0.93 (t, 3H, J=7.3Hz), 1.36 (m, 4H), 1.55 (m, 2H), 1.71 (m, 2H), 2.38 (m, 2H), 4.06 (t, 2H, J=7.5Hz), 4.20 (t, 2H, J=6.7Hz), 4.59 (t, 2H, J=7.5Hz), 7.25 (m, 3H), 7.36 (m, 2H), 13.30 (br s, 1H).
Embodiment 67:8-chloro-1-(3-{5-[(2,4-difluorophenyl) methyl]-2H-tetrazolium-2-yl } propyl group)-3-propyl group-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(CDCl
3)δ：0.99(t，3H，J＝7.5Hz)，1.80(m，2H)，2.45(m，2H)，4.06(m，2H)，4.20(s，2H)，4.25(t，2H，J＝7Hz)，4.70(t，2H，J＝7.5Hz)，6.80(m，2H)，7.23(m，1H).
Embodiment 70:8-chloro-3-propyl group-1-(3-{5-[(2,4,6-trifluorophenyl) methyl]-2H-tetrazolium-2-yl } propyl group)-3,7-dihydro-1H-purine-2, the 6-diketone:
1H NMR (CDCl
3): 0.99 (t, 3H, J=7.3Hz), 1.80 (m, 2H), 1.98 (m, 2H), 2.01 (m, 2H), 4.20 (s, 2H), 4.25 (t, 2H, J=6.5Hz), 4.67 (t, 2H, J=7.3Hz), 6.68 (t, 2H, J=8.1Hz).
Embodiment 71:
1H NMR (CDCl
3): 0.99 (t, 3H, J=7.3Hz), 1.76-1.85 (m, 2H), 2.39-2.46 (m, 2H), 4.05-4.08 (m, 2H), 4.24 (t, 2H, J=7.1Hz), 4.39 (s, 2H), 4.64 (t, 2H, J=7.1Hz), 7.29-7.32 (m, 1H), 7.38-7.44 (m, 1H), 7.49-7.51 (m, 1H), 13.17 (bs, 1H).
Embodiment 78:
1H NMR (CDCl
3): 0.99 (t, 3H, J=7.6Hz), 1.36-1.45 (m, 2H), and 1.71-1.79 (m, 2H), 2.42-2.49 (m, 2H), 4.09 (t, 2H, J=7.5Hz), 4.17 (s, 2H), 4.24 (t, 2H, J=7.5Hz), 4.71 (t, 2H, J=7.3Hz), 7.00-7.14 (m, 3H), 13.07 (bs, 1H).
Embodiment 80:
1H NMR (CDCl
3): 0.96 (t, 3H, J=7.2Hz), 1.32-1.47 (m, 2H), 1.68-1.80 (m, 2H), 2.40-2.51 (m, 2H), 4.06-4.12 (m, 2H), 4.22 (s, 2H), 4.22-4.27 (m, 2H), 4.67-4.73 (m, 2H), 6.84-7.04 (m, 3H), 13.05 (bs, 1H).
Embodiment 83:3-butyl-8-chloro-1-(3-{5-[(2,4,6-trifluorophenyl) methyl]-2H-tetrazolium-2-yl } propyl group)-3,7-dihydro-1H-purine-2, the 6-diketone:
1H NMR (CDCl
3) δ: .0.97 (t, 3H, J=7.3Hz), 1.41 (m, 2H), 1.75 (m, 2H), 2.44 (m, 2H), 4.10 (t, 2H, J=7.5Hz), 4.20 (s, 2H), 4.25 (t, 2H, J=6.5Hz), 4.67 (t, 2H, J=7.4Hz), 6.67 (t, 2H, J=8.0Hz), 13.25 (br s, 1H).
Embodiment 87:8-chloro-3-amyl group-1-{3-[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] propyl group }-3,7-
Dihydro-1H-purine-2, the 6-diketone
A) 8-chloro-3-amyl group-1-{3-[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
3-[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl]-1-propyl alcohol (88mg, 0.4mmol) solution in THF (4ml) in nitrogen with 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, and the 6-diketone (100mg, 0.34mmol) and PPh
3(115mg 0.44mmol) handles.(101mg 0.44mmol), then reacts 5h to a collection of adding DBAD.Mixture is introduced nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(39mg 0.034mmol), then outgases mixture once more.(294 μ l 3.4mmol), then stir 3h with mixture in nitrogen to add morpholine.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.After the MDAP purification, obtain the title compound (64mg, 42%) of white solid form.
LC/MS：m/z?457[MH]
+，RT?3.4min.
1H?NMR(DMSO-d
6)δ：0.85(t，3H，J＝7Hz)，1.22-1.34(m，4H)，1.62(m，2H)，2.02(m，2H)，2.91(t，2H，J＝7Hz)，3.88(t，2H，J＝7Hz)，3.95-4.00(m，4H)，7.22-7.33(m，5H)，14.5(br?s，1H).
B) 3-[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl]-the 1-propyl alcohol
Gamma-butyrolactone (223 μ l, 2.9mmol), the benzenyl amidine oxime (480mg, 3.2mmol), EtOH (1.3ml) solution of 21%NaOEt and EtOH (3ml) in microwave at 140 ℃ of heating 10min down.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Title product is purified in silicon-dioxide, uses Companion
TMSystem obtains a kind of light yellow oil (143mg, 23%).
LC/MS：m/z?219[MH]
+，RT?2.4min.
Embodiment 88:8-chloro-1-(3-{3-[(4-chloro-phenyl-) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3-penta
Base-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-1-(3-{3-[(4-chloro-phenyl-) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-1-(3-{3-[(4-chloro-phenyl-) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (0.18g, 0.34mmol) solution in DMF (5ml) passes through the continuous vacuumize degassing of flask, and input nitrogen (x3) and morpholine (0.5ml, 5.8mmol), then add Pd (PPh
3)
4(80mg, 0.068mmol).Solution stirring 72h concentrates then, with MeOH resistates is loaded on the aminopropyl SPE (10g).Use the MeOH wash-out, then use the 5%AcOH/MeOH wash-out, obtain the title compound of light yellow solid form, it washs with ether, obtains a kind of white solid (0.053g, 32%).
LC/MS：m/z?491[MH]
+，RT?3.69min
B) 8-chloro-1-(3-{3-[(4-chloro-phenyl-) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
I) with gamma-butyrolactone (8ml, 104mmol), (3.0g, 16.25mmol), MeOH (5ml) solution of 30%NaOMe and the mixture backflow 30h of MeOH (80ml), cooling also concentrates 4-spanon oxime.Resistates is purified with the flash chromatography on silica gel method, with DCM/EtOH/0.88 ammoniacal liquor (200: 8: 1) wash-out, obtains a kind of yellow oil (13g).This material is dissolved among the DCM (150ml), with 2M sodium hydroxide (100ml) washing, separation of organic substances, drying, concentrate, obtain the 3-{3-[(4-chloro-phenyl-) methyl]-1,2,4-oxadiazole-5-yl }-the 1-propyl alcohol, be a kind of toughening oil (3.95g, 96%) that it is used for next step.
Ii) to 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (0.10g, 0.34mmol), the 3-{3-[(4-chloro-phenyl-) methyl]-1,2,4-oxadiazole-5-yl }-1-propyl alcohol (0.086g, 0.34mmol) and triphenylphosphine (0.186g, 0.69mmol) add in the solution in THF (5ml) azo-2-carboxylic acid's dibenzyl ester (0.204g, 0.68mmol), then with solution stirring 18h.Then, with solution concentration, (20g SPE), originally uses the DCM wash-out to resistates, uses DCM/Et then with the silica gel chromatography separation
2O mixture wash-out obtains by the title compound of azo-2-carboxylic acid's dibenzyl ester by-product contamination (0.18g).Thick material is used for deprotection steps.
LC/MS：m/z?531[MH]
+，RT?3.83min.
Embodiment 89:8-chloro-3-amyl group-1-{3-[3-(2-phenylethyl)-1,2,4-oxadiazole-5-yl] third
Base }-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-3-amyl group-1-{3-[3-(2-phenylethyl)-1,2,4-oxadiazole-5-yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
3-[3-(2-phenylethyl)-1,2,4-oxadiazole-5-yl]-1-propyl alcohol (150mg, 0.65mmol) solution in THF (6ml) in nitrogen with 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, and the 6-diketone (160mg, 0.54mmol) and PPh
3(183mg 0.70mmol) handles.(161mg 0.70mmol), then reacts 18h to disposable adding DBAD.Mixture is introduced nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(39mg 0.034mmol), then outgases mixture once more.(294 μ l 3.4mmol), then stir 3h with mixture in nitrogen to add morpholine.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Resistates is dissolved among the MeOH, purifies product 2-5%AcOH/MeOH wash-out with aminopropyl SPE.Obtain the title compound (185mg, 73%) of pale solid form.
LC/MS：m/z?471[MH]
+，RT?3.6min.
1H?NMR；(DMSO-d
6)δ：0.85(t，3H，J＝7Hz)，1.23-1.34(m，4H)，1.63(m，2H)，2.06(m，2H)，2.87(m，4H)，2.93(t，2H，J＝7Hz)，3.89(t，2H，J＝7Hz)，4.00(t.2H，J＝6.5Hz)，7.16-7.29(m，5H)，14.5(br?s，1H).
B) 3-[3-(2-phenylethyl)-1,2,4-oxadiazole-5-yl]-the 1-propyl alcohol
Gamma-butyrolactone (426 μ l, 5.5mmol), styroyl amidine oxime (1.0g, 6.1mmol), the mixture of EtOH (2ml) solution of 21%NaOEt and EtOH (3ml) in microwave at 140 ℃ of heating 10min down.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Title product is purified with Si-SPE, with EtOAc/ hexanaphthene mixture wash-out, obtains the title compound (390mg, 31%) of light yellow oily.
LC/MS：m/z?233[MH]
+，RT?2.5min.
Embodiment 90:8-chloro-1-{3-[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] propyl group }-3-propyl group-3,7-
Dihydro-1H-purine-2, the 6-diketone
A) 8-chloro-1-{3-[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] propyl group }-3-propyl group-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-7-(2-propylene-1-yl)-3-propyl group-3,7-dihydro-1H-purine-2, the 6-diketone (200mg, 0.74mmol) solution in THF (4ml) is with 3-[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl]-the 1-propyl alcohol (195mg, 0.89mmol) and PPh
3(254mg 0.96mmol) handles.(223mg, 0.96mmol), mixture at room temperature stirs 18h to disposable adding DBAD in nitrogen.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Crude product is purified with silicon-dioxide SPE post, with 0-70% hexanaphthene/EtOAc gradient elution.Merge the product cut, concentrate, then further purify, with 0-60% hexanaphthene/EtOAc gradient elution with silicon-dioxide SPE post.Merge the product cut, concentrate, then resistates is dissolved among the anhydrous THF (4ml).Solution adds Pd (PPh then by high vacuum degassing
3)
4(86mg, 0.074mmol) and morpholine (644 μ l 7.4mmol), then at room temperature stir mixture 1 day in nitrogen.Mixture distributes between HCl (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrated by high vacuum.Crude product is purified with aminopropyl SPE, with MeOH described compound is loaded on the post, and flush away impurity uses the 2-4%AcOH/MeOH gradient with eluted product then.Merge the product cut, high vacuum concentrates, and obtains the title compound (74mg, 23%) of white solid form.
LC/MS：m/z?429[MH]
+，RT?3.14min.
1H NMR; (DMSO-d
6) δ: 0.87 (t, 3H, J=7.5Hz), 1.65 (m, 2H), 2.02 (m, 2H), 2.91 (t, 2H, J=7.5Hz), 3.86 (t, 2H, J=7Hz), 3.97 (s, t is overlapping, 4H), 7.27 (m, 5H), 14.46 (s, 1H).
B) 8-chloro-7-(2-propylene-1-yl)-3-propyl group-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (1.5g, 6.6mmol), propyl iodide (1.2g, 6.9mmol) and yellow soda ash (0.9g, 8.5mmol) mixture in DMF (40ml) is at 50 ℃ of following heating 18h.Reaction mixture concentrates in a vacuum, and resistates water (60ml) is handled, then with EtOAc (3x80ml) extraction.With the organic extract liquid drying (MgSO that merges
4), filter and evaporation.Resistates leaches solid with ether/hexanaphthene development, and drying obtains title compound (0.82g, 46%).
LC/MS：m/z?269[MH]
+.
Embodiment 91:8-chloro-3-amyl group-1-{3-[3-(3-thienyl methyl)-1,2,4-oxadiazole-5-yl] third
Base }-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-3-amyl group-1-{3-[3-(3-thienyl methyl)-1,2,4-oxadiazole-5-yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
With 4-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl butyrate (70mg, 0.19mmol), N-hydroxyl-2-(3-thienyl) ethanamidine (36mg, 0.23mmol), the EtOH of 21%NaOEt (78 μ l, 0.21mmol) mixture of solution and EtOH (1.5ml) in microwave at 140 ℃ of heating 10min down.After the cooling, be reflected between the HCl (aq) of 2M and the EtOAc and distribute.Separate organic layer, water layer extracts with EtOAc once more.The extraction liquid that merges is concentrated and purify with MDAP.Title compound is from 1, and lyophilize in the 4-diox obtains a kind of white solid (27mg, 31%).
LC/MS：m/z?463[MH]
+，RT?3.4min.
B) 4-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl butyrate
8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (3.0g, 10.1mmol) the solution Cs in dry DMF (35ml)
2CO
3(3.6g, 11.1mmol) (1.6ml 11.1mmol) handles with 4-bromo-butyric acid ethyl ester.Mixture is at room temperature stirred 18h, in the vacuum of gentleness, outgas then, introduce nitrogen then.Repeat twice of this process.Add Pd (PPh
3)
4(1.17g 1.0mmol), then outgases mixture once more.(8.8ml 101mmol), at room temperature stirs 3h then to add morpholine.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate, obtain a kind of yellow solid (5.16g).Resistates is dissolved among the MeOH, is divided into two equal portions, each equal portions is used the MeOH wash-out by aminopropyl SPE (20g) then, then uses the 5%AcOH/MeOH wash-out.Merge the product cut, concentrate, obtain the title compound (3.01g, 80%) of near-white solid form.
LC/MS：m/z?371[MH]
+，RT?3.2min.
Embodiment 92:8-chloro-3-amyl group-1-{3-[3-(1-phenylethyl)-1,2,4-oxadiazole-5-yl] third
Base }-3,7-dihydro-1H-purine-2,6-diketone
4-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl butyrate (70mg, 0.19mmol), N-hydroxyl-2-phenyl third amidine (38mg, 0.23mmol), the EtOH of 21%NaOEt (78 μ l, 0.21mmol) mixture of solution and EtOH (1.5ml) in microwave at 140 ℃ of heating 10min down.After the cooling, be reflected between the HCl (aq) of 2M and the EtOAc and distribute.Separate organic layer, water layer extracts with EtOAc once more.The extraction liquid that merges is concentrated and purify with MDAP.Title compound is with 1, and the lyophilize of 4-diox obtains a kind of white solid (44mg, 49%).
LC/MS：m/z?471[MH]
+，RT?3.6min.
Embodiment 93:3-butyl-8-chloro-1-{3-[3-(2, the 3-difluorobenzyl)-1,2,4-oxadiazole-5-yl] third
Base }-3,7-dihydro-1H-purine-2,6-diketone
A) 3-butyl-8-chloro-1-{3-[3-(2, the 3-difluorobenzyl)-1,2,4-oxadiazole-5-yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
With 2, (23mg 0.15mmol) is dissolved among the EtOH (1ml) 3-difluorophenyl acetonitrile.Add oxammonium hydrochloride (14mg, 0.20mmol), then add entry (0.5ml) and salt of wormwood (41mg, 0.3mmol).Mixture is heated overnight under refluxing, and cooling then distributes between EtOAc and salt solution then.With the organic phase evaporation, thus obtained thick amidoxim is dissolved among the EtOH (1ml).Add 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl butyrate (43mg, 0.12mmol) and the sodium ethylate (0.067ml of 21wt.%, 0.18mmol), then mixture is heated 10min down at 140 ℃ in microwave reactor.Mixture distributes between the HCl of EtOAc and 2M, the organic phase evaporation, and product is purified with MDAP, obtains the title compound (13mg) of solid form.
LC/MS：m/z?479[MH]
+，RT?3.52min.
1H?NMR(MeOH-d
4)δ：0.96(t，3H，J＝7Hz)，1.34-1.45(m，2H)，1.65-1.75(m，2H)，2.13-2.22(m，2H)，2.97(t，2H，J＝7Hz)，4.00(t，2H，J＝7Hz)，4.05(s，2H)，4.12(t，2H，J＝7Hz)，7.03-7.25(m，3H).
B) 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl butyrate
To 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (6.0g adds Cs in dry DMF 21.24mmol) (100ml) solution to the 6-diketone
2CO
3(7.62g, 23.36mmol), then add 4-bromo-butyric acid ethyl ester (4.556g, 23.36mmol).At 55 ℃ of following heating 18h, cooling then vacuumizes repeatedly then and adds the nitrogen degassing with mixture.(14.9g, 171mmol), (4.0g 3.46mmol), then stirs 4h with mixture then to add tetrakis triphenylphosphine palladium (O) to add morpholine.The HCl (150ml) and the water (100ml) that add EtOAc (300ml) and 2M then separate organic phase, with salt solution (3x100ml) washing, then filter.Filtrate drying (Na
2SO
4), then evaporation.Crude product (10g) is purified with aminopropyl SPE (3x 20g), be loaded among the THF/MeOH (1: 1), with THF/MeOH (1: 1) and pure MeOH washing, product obtains title compound (5.08g) with DCM/MeOH (1: the 1) wash-out that contains 5% extra AcOH.
LC/MS：m/z?357[MH]
+，RT?3.06min.
1H?NMR(d
4MeOH)0.96(3H，t，J＝7Hz)，1.33-1.42(2H，m)，1.64-1.74(2H，m)，2.12-2.21(2H，m)，2.95(2H，t，J＝8Hz)，3.99(2H，t，J＝7Hz)，4.03(2H，s)，4.11(2H，t，J＝7Hz)，7.03-7.21(3H，m).
Embodiment 94:3-butyl-8-chloro-1-{3-[3-(2-benzyl chloride base)-1,2,4-oxadiazole-5-yl] propyl group }-3,7-
Dihydro-1H-purine-2, the 6-diketone
With 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl butyrate (53mg, 0.15mmol) and (1Z)-2-(2-chloro-phenyl-)-N-hydroxyl acetamidine (30mg, 0.18mmol; Clauses and subclauses 1, table 7) (0.083ml 0.22mmol) heats 10min down at 140 ℃ together with 21% sodium ethylate in EtOH (0.75ml).Then, mixture distributes between the HCl of EtOAc and 2M, then organic phase is evaporated.Product is purified with MDAP, obtains the title compound (34.8mg) of solid form.
LC/MS：m/z?477[MH]
+，RT?3.59min.
1H?NMR(d
6?DMSO)0.89(3H，t，J＝8Hz)，1.24-1.34(2H，m)，1.56-1.65(2H，m)，1.98-2.07(2H，m)，2.92(2H，t，J＝7Hz)，3.89(2H，t，J＝7Hz)，3.98(2H，t，J＝7Hz)，4.09(2H，s)，7.28-7.48(4H，m).
Embodiment 95:3-butyl-8-chloro-1-{3-[3-(4-luorobenzyl)-1,2,4-oxadiazole-5-yl] propyl group }-3,7-
Dihydro-1H-purine-2, the 6-diketone
From (1Z)-2-(4-fluorophenyl)-N-hydroxyl acetamidine (28mg, 0.18mmol; Clauses and subclauses 2, table 7) begin, obtain the title compound (10.0mg) of solid form similarly.
LC/MS：m/z?461[MH]
+，RT?3.49min.
Embodiment 96:3-butyl-8-chloro-1-{3-[3-(2, the 3-dichloro benzyl)-1,2,4-oxadiazole-5-yl] third
Base }-3,7-dihydro-1H-purine-2,6-diketone
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl butyrate (53mg, 0.15mmol) and (1Z)-2-(2, the 3-dichlorophenyl)-N-hydroxyl acetamidine (36mg, 0.165mmol; Clauses and subclauses 3, table 7) and 21% sodium ethylate (0.083ml, 0.22mmol) together in EtOH (0.75ml) heating in microwave reactor at 140 ℃ of heating 10min down.Then, mixture distributes between the HCl of EtOAc and 2M, and organic phase is separated, evaporation, and product is purified with MDAP, obtains the title compound (42.1mg) of solid form.
LC/MS:m/z 511,513,515 (isotropic substance) [MH]
+, RT 3.66min.
Following compounds (table 4) is used the method preparation be similar to embodiment 96, uses suitable amidoxim, (except that embodiment 110 (table 4), during aftertreatment, before extracting with EtOAc with pH regulator to 5; And under the situation of embodiment 111 (table 4), crude product stirs 18h with the NaOH (0.5ml) of EtOH (1ml) and 2M, embodiment 112 (table 4) stirs 18h with the NaOH (0.5ml) of EtOH (0.75ml) and 2M, then repeats aftertreatment and purifies with MDAP).
Table 4
| S, 2S)-the 2-phenycyclopropyl]-1,2,4-oxadiazole-5-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone |
The NMR details of the embodiment that selects from table 4
Embodiment 97:3-butyl-8-chloro-1-{3-[3-(3-luorobenzyl)-1,2,4-oxadiazole-5-yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(DMSO-d
6)δ：0.90(t，3H，J＝7Hz)，1.25-1.36(m，2H)，1.56-1.67(m，2H)，2.0-2.1(m，2H)，2.94(t，2H，J＝7Hz)，3.90(t，2H，J＝7Hz)，3.98(t，2H，J＝7Hz)，4.02(s，2H)，7.05-7.15(m，3H)，7.32-7.40(m，1H).
Embodiment 98:3-butyl-8-chloro-1-{3-[3-(3, the 4-difluorobenzyl)-1,2,4-oxadiazole-5-yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(DMSO-d
6)δ：0.89(t，3H，J＝7.5Hz)，1.25-1.34(m，2H)，1.56-1.65(m，2H)，1.99-2.07(m，2H)，2.92(t，2H，J＝7Hz)，3.89(t，2H，J＝7Hz)，3.98(t，2H，J＝7Hz)，4.02(s，2H)，7.10-7.15(m，1H)，7.32-7.39(m，2H)，14.45(br?s，1H).
Embodiment 100:3-butyl-8-chloro-1-{3-[3-(1-phenycyclopropyl)-1,2,4-oxadiazole-5-yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(MeOH-d
4)δ：0.95(t，3H，J＝7Hz)，1.25-1.30(m，2H)，1.30-1.45(m，4H)，1.64-1.75(m，2H)，2.15-2.25(m，2H)，2.94(t，2H，J＝7Hz)，3.98(t，2H，J＝7Hz)，4.10(t，2H，J＝7Hz)，7.20-7.37(m，5H).
Embodiment 102:1-{3-[3-(1,3-benzo dioxole-5-ylmethyl)-1,2,4-oxadiazole-5-yl] propyl group }-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(DMSO-d
6)δ：0.90(t，3H，J＝7Hz)，1.25-1.36(m，2H)，1.58-1.68(m，2H)，1.98-2.09(m，2H)，2.92(t，2H，J＝7Hz)，3.88-3.95(m，4H)，3.99(t，2H，J＝7Hz)，5.98(s，2H)，6.70-6.86(m，3H).
Embodiment 110:3-butyl-8-chloro-1-{3-[3-(1H-indol-3-yl methyl)-1,2,4-oxadiazole-5-yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(DMSO-d
6)δ：0.89(t，3H，J＝7Hz)，1.23-1.36(m，2H)，1.56-1.67(m，2H)，1.96-2.08(m，2H)，2.90(t，2H，J＝7Hz)，3.90(t，2H，J＝7Hz)，3.99(t，2H，J＝7Hz)，4.04(s，2H)，6.92-7.50(m，5H)，10.95(s，1H).
Embodiment 111:3-butyl-8-chloro-1-(3-{3-[(3-hydroxy phenyl) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(DMSO-d
6)δ：0.90(t，3H，J＝7Hz)，1.25-1.38(m，2H)，1.57-1.68(m，2H)，1.96-2.07(m，2H)，2.92(t，2H，J＝7Hz)，3.86(s，2H)，3.89(t，2H，J＝7Hz)，3.99(t，2H，J＝7Hz)，6.58-6.68(m，3H)，7.08(m，1H)，9.40(s，1H).
Embodiment 112:N-[3-(5-[3-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group] and-1,2,4-oxadiazole-3-yl } methyl) phenyl] Toluidrin
1H?NMR(DMSO-d
6)δ：0.89(t，3H，J＝7.5Hz)，1.24-1.34(m，2H)，1.56-1.65(m，2H)，1.97-2.06(m，2H)，2.91(t，2H，J＝7.5Hz)，2.97(s，3H)，3.90(t，2H，J＝7.5Hz)，3.96(s，2H)，3.97(t，2H，J＝7Hz)，6.96-6.99(m，1H)，7.06-7.13(m，2H)，7.26(t，1H，J＝8Hz)，9.75(s，1H)，14.45(br?s，1H).
Embodiment 114:3-butyl-8-chloro-1-(3-{3-[(3,4-dichlorophenyl) methyl]-1,2,4-oxadiazole-5-
Base } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl butyrate (71mg, 0.2mmol), (1Z)-2-(3, the 4-dichlorophenyl)-N-hydroxyl acetamidine (48mg, 0.22mmol) and the sodium ethylate of 21wt.% (0.111ml, 0.3mmol) together in EtOH (1ml) in microwave reactor at 140 ℃ of heating 10min down.Then, mixture distributes between the HCl of EtOAc and 2M, separates organic phase, evaporation, and crude product is purified with MDAP, obtains the title compound (48.8mg) of solid form.
LC/MS：m/z?511，513[MH]
+，RT?3.65min.
Following compounds (table 5) is used the method preparation that is similar to embodiment 114, uses suitable amidoxim (except that embodiment 115 and embodiment 125, add 0.185ml, 21% sodium ethylate (0.5mmol) is so that described amidoxim is a hydrochloride).
Table 5
The NMR details of the embodiment that selects from table 5
Embodiment 115:
1H NMR (d
6DMSO) 0.88 (3H, t, J=7Hz), 1.24-1.33 (2H, m), 1.56-1.65 (2H, m), 1.98-2.06 (2H, m), 2.92 (2H, t, J=7Hz), 3.89 (2H, t, J=7Hz), 3.97 (2H, t, J=7Hz), 4.14 (2H, s), 7.52-7.70 (4H, m).
Embodiment 117:3-butyl-8-chloro-1-{3-[3-(1-phenylethyl)-1,2,4-oxadiazole-5-yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(DMSO-d
6)δ：0.89(t，3H，J＝7Hz)，1.22-1.35(m，2H)，1.52(d，3H，J＝8Hz)，1.56-1.68(m，2H)，1.95-2.08(m，2H)，2.91(t，2H，J＝7Hz)，3.89(t，2H，J＝7Hz)，3.95(t，2H，J＝7Hz)，4.18(q，1H，J＝8Hz)，7.17-7.32(m，5H).
Embodiment 119:3-butyl-8-chloro-1-(3-{3-[(4-chloro-phenyl-) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(DMSO-d
6)δ：0.89(t，3H，J＝7Hz)，1.23-1.37(m，2H)，1.55-1.67(m，2H)，1.97-2.09(m，2H)，2.90(t，2H，J＝7Hz)，3.88(t，2H，J＝7Hz)，3.97(t，2H，J＝7Hz)，4.00(s，2H)，7.27-7.40(m，4H).
Embodiment 122:3-butyl-8-chloro-1-(3-{3-[(4-hydroxy phenyl) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(DMSO-d
6)δ：0.90(t，3H，J＝7Hz)，1.23-1.37(m，2H)，1.57-1.68(m，2H)，1.96-2.08(m，2H)，2.90(t，2H，J＝7Hz)，3.82(s，2H)，3.90(t，2H，J＝7Hz)，3.98(t，2H，J＝7Hz)，6.68(d，2H，J＝9Hz)，7.04(d，2H，J＝9Hz)，9.32(s，1H).
Embodiment 123:3-butyl-8-chloro-1-[3-(3-{[3-(trifluoromethyl)-1H-pyrazol-1-yl] methyl }-1,2,4-oxadiazole-5-yl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(DMSO-d
6)δ：0.90(t，3H，J＝7Hz)，1.23-1.36(m，2H)，1.57-1.69(m，2H)，1.95-2.08(m，2H)，2.95(t，2H，J＝7Hz)，3.91(t，2H，J＝7Hz)，3.97(t，2H，J＝7Hz)，5.62(s，2H)，6.79(s，1H)，8.10(s，1H).
Embodiment 125:3-butyl-8-chloro-1-(3-{3-[1-(4-chloro-phenyl-) ethyl]-1,2,4-oxadiazole-5-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
1H?NMR(DMSO-d
6)δ：0.90(t，3H，J＝7Hz)，1.23-1.38(m，2H)，1.51(d，3H，J＝6Hz)，1.55-1.69(m，2H)，1.96-2.10(m，2H)，2.92(t，2H，J＝7Hz)，3.89(t，2H，J＝7Hz)，3.98(t，2H，J＝7Hz)，4.24(q，1H，J＝6Hz)，7.27-7.40(m，4H).
Embodiment 126:3-butyl-8-chloro-1-[3-(3-{[3-(ethyl oxygen base)-4-hydroxy phenyl] methyl }-1,2,4-
Oxadiazole-5-yl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl butyrate (53mg, 0.15mmol) and (1Z)-2-[3-(ethyl oxygen base)-4-hydroxy phenyl]-N-hydroxyl acetamidine (35mg, 0.165mmol; Clauses and subclauses 11, table 7) in EtOH (0.75ml), mix.(21wt.%, 0.083ml 0.22mmol), then down heat 10min at 140 ℃ with mixture in microwave to add sodium ethylate.Then, add the NaOEt solution of other 0.055ml (0.15mmol), follow mixture at 140 ℃ of following reheat 10min.Mixture distributes between the HCl of EtOAc and 2M, the evaporation organic phase, and product is purified with MDAP, obtains the title compound (29.6mg) of solid form.
LC/MS：m/z?503[MH]
+，RT?3.15min.
Following compounds (table 6) is used the method preparation that is similar to embodiment 126, use suitable amidoxim (except that embodiment 127 (table 6), described crude product spends the night with EtOH (1ml) and 2MNaOH (0.5ml) stirring after aftertreatment, so that the initial ester of hydrolysed residue is purified in repetition HCl aftertreatment with MDAP then).
Table 6
The NMR details of the embodiment that selects from table 6
Embodiment 129:N-[3-(5-[3-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propyl group] and-1,2,4-oxadiazole-3-yl } methyl) phenyl] ethanamide
1H?NMR(DMSO-d
6)δ：0.90(t，3H，J＝7Hz)，1.25-1.38(m，2H)，1.57-1.68(m，2H)，1.95-2.07(m，5H)，2.92(t，2H，J＝7Hz)，3.91(t，2H，J＝7Hz)，3.94(s，2H)，3.98(m，2H)，6.88-7.50(m，4H)，9.90(s，1H).
Embodiment 130:3-butyl-8-chloro-1-(3-{3-[(2-chloro-4-fluorophenyl) methyl]-1,2,4-oxadiazole-5-
Base } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl butyrate (100mg, 0.28mmol) and (1Z)-(62.4mg, 0.308mmol) (0.157ml 0.42mmol) heats 10min down at 140 ℃ to 2-(2-chloro-4-fluorophenyl)-N-hydroxyl acetamidine together in microwave reactor in EtOH (1.5ml) with the 21wt.% sodium ethylate.Mixture carries out aftertreatment by distributing between the HCl of EtOAc and 2M.With the organic phase evaporation, purify with MDAP, obtain the title compound (73mg) of solid form.
LC/MS：m/z?495[MH]
+，RT?3.55min.
Embodiment 131:8-chloro-3-ethyl-1-{3-[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] third
Base }-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-3-ethyl-1-{3-[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-3-ethyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (150mg, 0.59mmol) solution in anhydrous THF (4ml) is with 3-[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl]-the 1-propyl alcohol (154mg, 0.71mmol) and triphenylphosphine (200mg 0.76mmol) handles.(162mg, 0.71mmol), mixture at room temperature stirs 18h to disposable adding DBAD in nitrogen.Mixture adds Pd (PPh then by high vacuum degassing
3)
4(68mg, 0.059mmol) and morpholine (515 μ l, 5.9mmol).Mixture is at room temperature stirred 3h in nitrogen.Mixture distributes between the HCl of EtOAc and 2M (aq).Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrated by high vacuum.Thick material is purified with aminopropyl SPE, with MeOH described compound is loaded on the post, and flush away impurity uses 2%AcOH/MeOH with the wash-out compound then.Merge the UV active fractions, then under high vacuum, concentrate.Product is purified with MDAP again.Merge the product cut, concentrate, obtain the title compound (61mg, 25%) of white solid form.
LC/MS：m/z?415[MH]
+，RT?3.01min
1H?NMR；(DMSO-d
6)δ：1.19(t，3H，J＝7Hz)，2.93(m，2H)，2.91(t，2H，J＝7.5Hz)，3.96(m，6H)，7.27(m，5H)14.46(s，1H).
B) 8-chloro-3-ethyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (10g, 0.044mol) solution in dry DMF (100ml) with iodoethane (5.4ml, 0.068mol) and Na
2CO
3(4.9g 0.046mol) handles.Reaction mixture at room temperature stirred 2 days in nitrogen.(0.35ml 0.0044mol), then at room temperature stirred mixture 1 day to add iodoethane.Mixture distributes between the HCl of EtOAc and 2M.Separate organic layer, use saturated sodium bisulfite solution and salt water washing successively, dry (MgSO
4), then concentrate.Thick solid Et
2O washs, and obtains the title compound (8.37g, 75%) of white solid form.
LC/MS：m/z?255[MH]
+，RT?2.35min.
Embodiment 132:8-chloro-3-amyl group-1-(3-{3-[(1S, 2S)-the 2-phenycyclopropyl]-1,2,4-oxadiazole-5-
Base } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
(70mg 0.19mmol) is dissolved among the EtOH (1.5ml) Valeric acid ethylester with 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl).Described solution with the EtOH of 21%NaOEt (78 μ l, 0.21mmol) solution and (1S, 2S)-(37mg 0.21mmol) handles N-hydroxyl-2-benzyl ring propane carbonamidine.Be reflected in the microwave and heat 10min down at 140 ℃.Mixture distributes between the HCl of EtOH and 2M (aq).Separate organic layer and concentrated, the gained crude product is purified with MDAP.Merge the product cut, concentrate, obtain the title compound (35mg, 38%) of white solid form.
LC/MS：m/z?483[MH]
+，RT?3.67min.
Embodiment 133:8-chloro-1-(3-{3-[(3-chloro-phenyl-) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3-
Amyl group-3,7-dihydro-1H-purine-2,6-diketone
(70mg 0.19mmol) is dissolved among the EtOH Valeric acid ethylester with 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl).(78 μ l, 0.21mmol) solution and (1Z)-(38mg 0.21mmol) handles 2-(3-chloro-phenyl-)-N-hydroxyl acetamidine with the EtOH of 21%NaOEt for described solution.Be reflected in the microwave and heat 10min down at 140 ℃.Mixture distributes between the HCl of EtOH and 2M (aq).Pour out organic layer, then concentrate.Crude product is purified with MDAP.Merge the product cut, concentrate, obtain the title compound (46mg, 49%) of white solid form.
LC/MS：m/z?491[MH]
+，RT?3.64min.
1H?NMR(DMSO-d
6)δ：0.85(t，3H，J＝7Hz)，1.27(m，4H)，1.62(m，2H)，2.02(m，2H)，2.92(t，2H，J＝7.5Hz)，3.88(t，2H，J＝7Hz)，3.97(t，2H，J＝6.5Hz)，4.02(s，2H)，7.23(d，1H，J＝7Hz)，7.34(m，3H).
Embodiment 134:8-chloro-1-(3-{3-[(3,4-dichlorophenyl) methyl]-1,2,4-oxadiazole-5-yl } third
Base)-and 3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
(70mg 0.19mmol) is dissolved among the EtOH Valeric acid ethylester with 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl).(78 μ l, 0.21mmol) solution and (1Z)-(46mg 0.21mmol) handles 2-(3, the 4-dichlorophenyl)-N-hydroxyl acetamidine with the EtOH of 21%NaOEt for described solution.Be reflected in the microwave and heat 10min down at 140 ℃.Mixture distributes between the HCl of EtOH and 2M (aq).Pour out organic layer, then concentrate.Crude product is purified with MDAP.Merge the product cut, concentrate, obtain the title compound (66mg, 66%) of white solid form.
LC/MS：m/z?527[MH]
+，RT?3.80min.
Embodiment 135:8-chloro-1-(3-{3-[(2,6-dichlorophenyl) methyl]-1,2,4-oxadiazole-5-yl } third
Base)-and 3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
(70mg 0.19mmol) is dissolved among the EtOH Valeric acid ethylester with 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl).(78 μ l, 0.21mmol) solution and (1Z)-(46mg 0.21mmol) handles 2-(2, the 6-dichlorophenyl)-N-hydroxyl acetamidine with the EtOH of 21%NaOEt for described solution.Be reflected in the microwave and heat 10min down at 140 ℃.Mixture distributes between the HCl of EtOH and 2M (aq).Pour out organic layer, then concentrate by the nitrogen exhaust.Crude product is purified with MDAP.Merge the product cut, concentrate, obtain the title compound (80mg, 80%) of white solid form.
LC/MS：m/z?526[MH]
+，RT?3.6min.
Embodiment 136:8-chloro-1-(3-{3-[(2-chloro-4-fluorophenyl) methyl]-1,2,4-oxadiazole-5-yl } third
Base)-and 3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
(70mg 0.19mmol) is dissolved among the EtOH Valeric acid ethylester with 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl).(78 μ l, 0.21mmol) solution and (1Z)-(42mg 0.21mmol) handles 2-(2-chloro-4-fluorophenyl)-N-hydroxyl acetamidine with the EtOH of 21%NaOEt for described solution.Be reflected in the microwave and heat 10min down at 140 ℃.Mixture distributes between the HCl of EtOH and 2M (aq).Pour out organic layer, then concentrate.Crude product is purified with MDAP.Merge the product cut, concentrate, obtain the title compound (65mg, 67%) of white solid form.
LC/MS：m/z?509[MH]
+，RT?3.63min.
Embodiment 137:3-butyl-8-chloro-1-{3-[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] third
Base }-3,7-dihydro-1H-purine-2,6-diketone
3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (205mg, 0.73mmol) solution in anhydrous THF (4ml) is with 3-[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl]-the 1-propyl alcohol (190mg, 0.87mmol) and PPh
3(247mg 0.94mmol) handles.(217mg, 0.94mmol), mixture at room temperature stirs 18h to disposable adding DBAD in nitrogen.Mixture adds Pd (PPh then by high vacuum degassing
3)
4(84mg, 0.073mmol) and morpholine (636 μ l, 7.3mmol).Mixture at room temperature stirs 3h in nitrogen.Mixture distributes between the HCl of EtOAc and 2M, separates organic layer, uses the salt water washing, dry (MgSO
4), then concentrate.Thick material is purified with the aminopropyl post, with MeOH described compound is loaded on the post, flush away impurity, then with the 2-4%AcOH/MeOH gradient elution from post, to remove compound.Further purify by MDAP, obtain the title compound (75mg, 23%) of white solid form.
LC/MS：m/z?443[MH]
+，RT?3.37min.
1H?NMR；(DMSO-d
6)δ：0.89(t，3H，J＝7.5Hz)，1.29(m，2H)，1.61(m，2H)，2.02(m，2H)，2.91(t，2H，J＝7.5Hz)，3.89(t，2H，J＝7Hz)，3.97(m，4H)，7.27(m，5H)14.46(s，1H).
Embodiment 138:8-chloro-1-(3-{3-[(4-hydroxy phenyl) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3-
Amyl group-3,7-dihydro-1H-purine-2,6-diketone
5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) Valeric acid ethylester (29mg, 0.078mmol) and (1Z)-(14mg, 0.084mmol) (0.043ml 0.117mmol) heats 10min down at 140 ℃ to N-hydroxyl-2-(4-hydroxy phenyl) ethanamidine together under microwave radiation with 21% sodium ethylate in EtOH (1ml).Mixture distributes between the HCl of EtOAc and 2M, then organic phase is evaporated.This material is stirred 18h with the NaOH (0.5ml) of EtOH (1ml) and 2M, then carry out aftertreatment by between the HCl of EtOAc and 2M, distributing once more.Purify by MDAP, obtain title compound (6.5mg).
LC/MS：m/z?473[MH]
+，RT?3.34min.
1H?NMR(MeOH-d
4)δ：0.92(t，3H，J＝7Hz)，1.25-1.45(m，4H)，1.68-1.78(m，2H)，2.11-2.21(m，2H)，2.93(t，2H，J＝7Hz)，3.82(s，2H)，3.98(t，2H，J＝7Hz)，4.10(t，2H，J＝7Hz)，6.70(d，2H，J＝10Hz)，7.02(d，2H，J＝10Hz).
Embodiment 139:3-butyl-8-chloro-1-(3-{3-[(phenoxy group) methyl]-1,2,4-oxadiazole-5-yl } third
Base)-3,7-dihydro-1H-purine-2,6-diketone
To 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl butyrate (26mg, 0.073mmol) and (1Z)-(16mg adds 21%wt. alcohol sodium solution (0.068mL to N-hydroxyl-2-(phenoxy group) B amidine hydrochloric acid salt in EtOH 0.079mmol) (1ml) solution, 0.183mmol), then described mixture is heated 10min down at 140 ℃ under microwave radiation.Mixture distributes between the HCl of EtOAc and 2M, organic phase drying (Na
2SO
4), evaporation is purified with MDAP, obtains gelationus title compound, solidifies when it grinds with ether (5.9mg).
LC/MS：m/z?459[MH]
+，RT?3.39min.
1H?NMR(DMSO-d
6)δ：0.90(t，3H，J＝8Hz)，1.22-1.36(m，2H)，1.57-1.68(m，2H)，2.02-2.14(m，2H)，3.00(t，2H，J＝8Hz)，3.90(t，2H，J＝7Hz)，4.00(t，2H，J＝7Hz)，5.18(s，2H)，6.95-7.35(m，5H).
Embodiment 140:3-butyl-8-chloro-1-(3-{3-[(3,5-dichlorophenyl) methyl]-1,2,4-oxadiazole-5-
Base } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
To 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl butyrate (185mg, 0.52mmol) and (1Z)-2-(3, the 5-dichlorophenyl)-N-hydroxyl acetamidine (126mg, 0.58mmol; Clauses and subclauses 23, table 7) add in anhydrous EtOH (2ml) solution 21%wt. alcohol sodium solution (0.29ml, 0.78mmol), then mixture by microwave at 140 ℃ of heating 10min down.Reaction is carried out aftertreatment by distributing between the HCl of EtOAc and 2M, then evaporate organic phase.Purify by MDAP, obtain the title compound (135mg) of solid form.
LC/MS：m/z?511[MH]
+，RT?3.71min.
Embodiment 141:3-butyl-8-chloro-1-(3-{3-[(2,4,6-trifluorophenyl) methyl]-1,2,4-oxadiazole-5-
Base } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
From (1Z)-N-hydroxyl-2-(2,4, the 6-trifluorophenyl) ethanamidine (119mg, 0.58mmol; Clauses and subclauses 24, table 7) beginning, carry out similar preparation, obtain the yield of 135mg.
LC/MS：m/z?497[MH]
+，RT?3.39min.
1H?NMR(DMSO-d
6)δ：0.90(t，3H，J＝7Hz)，1.24-1.36(m，2H)，1.55-1.66(m，2H)，1.96-2.06(m，2H)，2.91(t，2H，J＝8Hz)，3.91(t，2H，J＝8Hz)，3.94-4.02(m，4H)，7.18-7.28(m，2H).
The amidoxim class:
These can obtain by the method that describes in detail below and illustrate by the analogue in the table 7.
Table 7 (intermediate)
Method A
(0.08ml 1.3mmol) stirs and at 65 ℃ of heating 4.5h down corresponding nitrile (0.5mmol) together with 50% aqueous hydroxylamine in EtOH (1.5ml).After the cooling, described crude product mixture is loaded into SCX SPE post (2g) goes up and wash, the described then amidoxim product MeOH eluant solution of 2M ammonia with MeOH.
Method B
Be similar to method A, except that product crystallization from crude product mixture is separated out and by filtering rather than separating by SCX.
Method C
Be similar to method A, except that product purifying on the 5g SCX post.
Method D
Be similar to method C, except that being heat-up time the 18h.
Method E
Be similar to method C, except that described quantity is the nitrile of 0.753mmol.
Method F
Be similar to method A, except that described quantity is the nitrile of 1.5mmol and purifying on the 10g SCX post.
Method G
Be similar to method A, except that being heat-up time that 2.75h and described quantity are the nitrile of 0.25mmol.
Should be noted that above-mentioned (Z)-stereochemical arranging do not confirmed by experimental data.Those skilled in the art also will know, can change (Dondoni, Alessandro between E and Z isomer mutually; Lunazzi, Lodovico; Giorgianni, Patrizia; Macciantelli, Dante.Carbon-nitrogenrotational barrier as a stereochemical probe of benzamidoximes.Journal ofOrganic Chemistry (1975), 40 (20), 2979-80).
Embodiment 142:3-butyl-8-chloro-1-(3-{5-[(3-chloro-phenyl-) methyl]-1,2,4-oxadiazole-3-yl } third
Base)-3,7-dihydro-1H-purine-2,6-diketone
A) 3-butyl-8-chloro-1-(3-{5-[(3-chloro-phenyl-) methyl]-1,2,4-oxadiazole-3-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
(3-chloro-phenyl-) acetate (0.1mmol), N-[3-(dimethylamino) propyl group]-N '-ethyl-carbodiimide hydrochloride (21mg, 0.11mmol) and 1H-1,2, (15mg 0.11mmol) stirs in 1-Methyl-2-Pyrrolidone (1ml) 3-benzotriazole-1-alcohol.(34mg 0.1mmol), then at room temperature stirs 17h with mixture, stirs 24h down at 80 ℃ then to add (1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl fourth amidine in this.Reaction mixture is purified, and does not further change, and by preparation HPLC (preparation automatically), obtains title compound (13mg, 27%).
LC/MS：m/z?477，479[MH]
+，RT?3.5min.
1H?NMR(CDCl
3)δ：0.96(t，3H，J＝7Hz)，1.32-1.47(m，2H)，1.68-1.80(m，2H)，2.12-2.24(m，2H)，2.83(t，2H，J＝7.5Hz)，4.05-4.24(m，6H)，7.16-7.30(m，4H).
B) (1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl fourth amidine
(1g 0.0032mol) stirs in EtOH (3.5ml) and water (1.8ml) 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) butyronitrile.Add oxammonium hydrochloride (344mg, 0.0049mol) and salt of wormwood (652mg 0.0049mol), then heats mixture 3 days down at 80 ℃.After the cooling, crude product mixture is evaporated.Crude product is soluble in water, be neutralized to pH7 with HCl, then load to Oasis
TMOn the post (2g).The water wash-out removes and desalts, and uses the MeOH wash-out then, obtains title compound (957mg, 86%).
LC/MS：m/z?343，345[MH]
+，RT?2.04min.
C) 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) butyronitrile
4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] (2.1g 6mmol) stirs in the mixture of the DCM (20ml) of the nitrogen degassing and AcOH (2ml) butyronitrile.Add tetrakis triphenylphosphine palladium (675mg, 0.6mmol) and phenyl silane (7.4ml 60mmol), follows mixture and at room temperature stirs 2d.Then, evaporation, the resistates ether: the mixture of hexanaphthene (1: 1) is developed, and obtains the title compound (1.47g, 60%) of white solid form.
LC/MS：m/z?310[MH]
+，RT?2.66min.
D) 4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] butyronitrile
At 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (2.0g adds Cs in anhydrous MeCN (20ml) solution 0.0072mol) to the 6-diketone
2CO
3(4.68g, 0.0144mol), then add the bromine butyronitrile (1.38g, 0.0094mol).Mixture is at 80 ℃ of heating 18h, then with its cooling.The reaction mixture evaporation, crude product distributes between EtOAc and HCl (2N).Organic phase separated and use salt water washing, drying (MgSO
4), evaporation obtains crude product.This head product is purified with silica gel SPE (50g), and use hexanaphthene: (2: 1-1: 1) wash-out obtains clarifying buttery title compound (2.1g, 85%) to ethyl acetate.
LC/MS：m/z?350[MH]
+，RT?3.10min.
Following compounds (table 8) is used the method preparation be similar to embodiment 142, by corresponding acid and (1Z)-and 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl fourth amidine.
Table 8
The NMR details of the embodiment that selects from table 8
Embodiment 145:
1H NMR (CDCl
3) 0.96 (3H, t, J=7.5Hz), 1.32-1.47 (2H, m), 1.65-1.81 (2H, m), 2.12-2.25 (2H, m), 2.84 (2H, t, J=7.5Hz), 4.02 (2H, t, 7.5Hz), 4.22 (2H, t, 7Hz), 4.24 (2H, s), 7.40-7.62 (4H, m).
Embodiment 152:8-chloro-3-amyl group-1-{3-[5-(phenyl methyl)-1,2,4-oxadiazole-3-yl] third
Base }-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-3-amyl group-1-{3-[5-(phenyl methyl)-1,2,4-oxadiazole-3-yl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-3-amyl group-7-(2-propylene-1-yl)-3 under stirring, 7-dihydro-1H-purine-2,6-diketone (0.20,0.67mmol) add 3-[5-(phenyl methyl)-1,2,4-oxadiazole-3-yl in the solution in THF (5ml)]-1-propyl alcohol (0.162g, 0.74mmol), DBAD (0.186g, 0.81mmol) and triphenylphosphine (0.212g, 0.81mmol), then with described solution stirring 18h.In described solution, add Pd (PPh
3)
4(75mg, 0.067mmol) and morpholine (600 μ l 6.7mmol), then at room temperature stir 3h again in nitrogen.Pd (the PPh that adds 75mg
3)
4, then with described mixture restir 3h.Mixture distributes between the HCl of EtOAc and 2M (aq).Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Thick material is purified with aminopropyl SPE, with MeOH described compound is loaded on the post, and flush away impurity uses 2-4%AcOH/MeOH with the described compound of wash-out then.Merge the product cut, concentrate, further purify with MDAP then.Merge the product cut, concentrate, obtain the title compound (51mg, 20%) of white solid form.
LC/MS：m/z?457[MH]
+，RT?3.54min.
B) 3-[5-(phenyl methyl)-1,2,4-oxadiazole-3-yl]-the 1-propyl alcohol
(1E)-4,4-two (ethyl oxygen base)-N-hydroxyl fourth amidine (3.2g, 16.8mmol), Phenylacetic acid ethylester (2.3ml, 14.4mmol) and sodium ethylate (21% EtOH solution, mixture 6.4ml) in microwave at 140 ℃ of following heating 10min.Those of the described material and second reaction (use (1E)-4 of 1.2g, 4-two (ethyl oxygen base)-N-hydroxyl fourth amidine also carries out as above-mentioned) mix, and then distribute between the HCl of 1M solution and EtOAc.Separate organic layer, use the salt water washing, drying concentrates, and obtains 5-[3,3-two (ethyl oxygen base) propyl group]-5-(phenyl methyl)-1,2, the 4-oxadiazole, it is not having just to be used for next step under the situation of purifying.
With thick 3-[3,3-two (ethyl oxygen base) propyl group]-5-(phenyl methyl)-1,2,4-oxadiazole (5.63g, 19.4mmol) EtOH (75ml) solution and tosic acid (0.738g 3.9mmol) stirs 21h together, then mixture is distributed between EtOAc and water.Separate organic phase, water and salt water washing, drying concentrates, and obtains a kind of reddish oil.This material contains a large amount of acetals, therefore described oil is dissolved in the HCl solution-treated 2h that also uses 2M among the THF (15ml), distributes between EtOAc and water then.The salt water washing of organism after the separation, drying concentrates, and obtains 3-[5-(phenyl methyl)-1,2,4-oxadiazole-3-yl] propionic aldehyde, be redness/brown oil (3.77g) that it uses thick material to be used for next step.
With thick 3-[5-(phenyl methyl)-1,2,4-oxadiazole-3-yl] propionic aldehyde (3.76g, 17.4mmol) solution in MeOH (60ml) is cooled to 0 ℃, then in 30min, add in batches sodium borohydride (0.724g, 19.1mmol).Remove cooling bath,, between the HCl of 1M and EtOAc, distribute then solution restir 1h.Separate organic layer, hydrate is extracted with EtOAc.The extraction liquid salt water washing that merges, dry and concentrated, obtain a kind of orange liquid.This liquid is purified on 50g silica gel SPE, with hexanaphthene/EtOAc (20%-80% gradient elution) wash-out, obtains the title compound (2.24g) of yellow oily.
LC/MS：m/z?210[MH]
+.
C) (1E)-4,4-two (ethyl oxygen base)-N-hydroxyl fourth amidine
With 3-cyano group propionic aldehyde diethyl acetal (6.12g, 39mmol), oxammonium hydrochloride (4.06g, 58.4mmol), salt of wormwood (10.76g, 77.9mmol) the mixture backflow 24h in water (20ml) and EtOH (40ml).With the mixture cooling, between water and EtOAc, distribute then.Separate organic layer, water extracts with EtOAc.The organic fraction salt water washing that merges, drying concentrates, and obtains the title compound of colorless oil, and it is polluted (6.03g, 81%) by about 20% initial nitrile.
LC/MS：m/z?191[MH]
+.
Embodiment 153:8-chloro-1-{3-[5-(phenyl methyl)-1,2,4-oxadiazole-3-yl] propyl group }-the 3-propyl group
-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-7-(2-propylene-1-yl)-3-propyl group-3,7-dihydro-1H-purine-2, the 6-diketone (200mg, 0.74mmol) solution in THF (4ml) is with 3-[5-(phenyl methyl)-1,2,4-oxadiazole-3-yl]-the 1-propyl alcohol (195mg, 0.89mmol) and PPh
3(254mg 0.96mmol) handles.(223mg, 0.96mmol), mixture at room temperature stirs 18h to disposable adding DBAD in nitrogen.Mixture distributes between the HCl of EtOAc and 2M (aq).Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrated by high vacuum.Crude product is purified on silicon-dioxide SPE post, with 0-70% hexanaphthene/EtOAc gradient elution.Merge the product cut, high vacuum concentrates, and then purifies on silicon-dioxide SPE post, with 0-60% hexanaphthene/EtOAc gradient elution.Merge the product cut, concentrate, then be dissolved among the anhydrous THF (4ml).Solution adds Pd (PPh then by high vacuum degassing
3)
4(61mg, 0.053mmol) and morpholine (460 μ l 5.3mmol), then at room temperature stir mixture 1 day in nitrogen.Mixture distributes between the HCl of EtOAc and 2M (aq).Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrated by high vacuum.Crude product is purified with aminopropyl SPE, with MeOH described compound is loaded on the post, and flush away impurity uses the 2-4%AcOH/MeOH gradient with eluted product then.Merge the product cut, concentrate, obtain the title compound (36mg, 11%) of white solid form.
LC/MS：m/z?429[MH]
+，RT?3.14min.
1H?NMR(DMSO-d
6)δ：0.86(t，3H，J＝7.5Hz)，1.65(m，2H)，1.93(m，2H)，2.70(t，2H，J＝7.5Hz)，3.86(t，2H，J＝7Hz)，3.96(t，2H，J＝7Hz)，4.28(s，2H)，7.32(m，5H).
Embodiment 154:3-butyl-8-chloro-1-{3-[5-(phenyl methyl)-1,2,4-oxadiazole-3-yl] third
Base }-3,7-dihydro-1H-purine-2,6-diketone
3-[5-(phenyl methyl)-1,2,4-oxadiazole-3-yl]-1-propyl alcohol (594mg, 2.7mmol) solution in THF (25ml) in nitrogen with 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, and the 6-diketone (700mg, 2.48mmol) and PPh
3(779mg 2.97mmol) handles.(684mg 2.97mmol), then reacts 60h to disposable adding DBAD.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.MeOH is joined in the resistates, then by the aminopropyl post, product 2-4%AcOH/MeOH wash-out.Merge the product cut, concentrate.Canescence resistates EtOAc: hexanaphthene (1: 1) recrystallization obtains the title compound (696mg, 63%) of white solid form.
LC/MS：m/z?443[MH]
+，RT?3.4min.
1H?NMR(DMSO-d
6)δ：0.89(t，3H，J＝7Hz)，1.29(m，2H)，1.61(m，2H)，1.93(m，2H)，2.70(t，2H，J＝7.5Hz)，3.90(t，2H，J＝7Hz)，3.96(t，2H，J＝7Hz)，4.28(2H，s)，7.31(m，5H)，14.4(br?s，1H).
Embodiment 155:3-butyl-8-chloro-1-(3-{5-[(3-chloro-4-hydroxy phenyl) methyl]-1,2, the 4-oxadiazole
-3-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
(24mg, 0.13mmol) (21mg 0.13mmol) handles the solution in DMSO (1ml) 3-chloro-4-hydroxyphenyl acetic acid, then reacts 30min with CDI.(50mg 0.15mmol), then down heats 15min at 120 ℃ with mixture in microwave to add (1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl fourth amidine.Described solution is directly purified with MDAP, obtains the title compound (12mg, 17%) of white solid form.
LC/MS：m/z?493[MH]
+，RT?3.2min.
Embodiment 156:3-butyl-8-chloro-1-[3-(5-{[3-chloro-2-(methoxyl group) phenyl] methyl }-1,2,4-Evil two
Azoles-3-yl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone
(32mg, 0.16mmol) (26mg 0.16mmol) handles the mixture in DMF (1.5ml) [3-chloro-2-(methoxyl group) phenyl] acetate, then reacts 45min with CDI.(60mg 0.18mmol), then down heats 15min at 140 ℃ with mixture in microwave to add (1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl fourth amidine.After the cooling, be reflected between the HCl (aq) of 2M and the EtOAc and distribute.Separate organic layer, concentrate then, then purify with MDAP.Obtain the title compound (25mg, 28%) of white solid form.
LC/MS：m/z?507[MH]
+，RT?3.5min.
Embodiment 157:3-butyl-8-chloro-1-(3-{5-[(3-fluoro-4-hydroxy phenyl) methyl]-1,2, the 4-oxadiazole
-3-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
(27mg, 0.16mmol) (26mg 0.16mmol) handles the mixture in DMF (1.5ml) (3-fluoro-4-hydroxy phenyl) acetate, then reacts 45min with CDI.(60mg 0.18mmol), then down heats 15min at 140 ℃ with mixture in microwave to add (1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl fourth amidine.After the cooling, be reflected between the HCl (aq) of 2M and the EtOAc and distribute.Separate organic layer, concentrate then and purify with MDAP.Obtain the title compound (10mg, 12%) of white solid form.
LC/MS：m/z?477[MH]
+，RT?3.2min.
Embodiment 158:8-chloro-3-amyl group-1-[4-(5-phenyl-1,2,4-oxadiazole-3-yl) butyl]-3, the 7-dihydro
-1H-purine-2, the 6-diketone
A) 8-chloro-3-amyl group-1-[4-(5-phenyl-1,2,4-oxadiazole-3-yl) butyl]-3,7-dihydro-1H-purine-2, the preparation of 6-diketone
Phenylformic acid (18mg 0.15mmol) uses 1H-1, and 2,3-benzotriazole-1-alcohol hydrate (25mg, 0.19mmol) solution-treated in DMSO (0.3ml).In this, add N-[3-(dimethylamino) propyl group]-N '-ethyl-carbodiimide hydrochloride (29mg, 0.15mmol) solution/suspension in DMSO (0.3ml), then add 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine (55mg, 0.15mmol) solution in DMSO (0.3ml).Mixture heats 1h down at 40 ℃, then 80 ℃ of heating 5h, then coolings down.Mixture is purified by MDAP.Contain the product cut and dry up, obtain the title compound (17.2mg, 25%) of white solid form by nitrogen.
LC/MS：m/z?457[MH]
+，RT?3.67min.
1H?NMR(CDCl
3)δ：0.90(t，3H，J＝6.8Hz)，1.35(m，4H)，1.76(m，2H)，1.89(m，4H)，2.88(t，2H，J＝7.2Hz)，4.08(t，2H，J＝7.5Hz)，4.17(t，2H，J＝6.7Hz)，7.50(m，2H)，7.57(m，1H)，8.08，(d，2H，J＝7.3Hz).
B) 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine
5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeronitrile (3.0g, 8.9mmol) solution with water (15ml) in EtOH (30ml), salt of wormwood (1.48g, 10.7mmol) and oxammonium hydrochloride (0.74g, 10.7mmol) handle, then 70 ℃ of following heated overnight.Carefully with other salt of wormwood (1.5g, 10.9mmol) and oxammonium hydrochloride (1.0g 14.5mmol) joins in the mixture, is heated 90 ℃ then, 24h.With the mixture cooling, then concentrate in a vacuum, to remove most EtOH.Residual mixture water (30ml) is handled, and by careful adding 2M aqueous hydrochloric acid it is acidified to pH 7.The solid of filtering-depositing washes with water, and then with ether washing, thorough drying obtains the title compound (2.80g, 85%) of white solid form.
LC/MS：m/z?371[MH]
+，RT?2.27min.
C) 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeronitrile
8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (4.0g, 13.5mmol) (4.83g, 14.8mmol) (1.73ml 14.8mmol) handles the solution in DMF (100ml) the 6-diketone with 5-bromine valeronitrile with cesium carbonate.Mixture heats 19h in nitrogen atmosphere under 50 ℃, then cooling.Then, mixture adds nitrogen pressure then by repeating to use continuously vacuum outgas.Then, mixture with tetrakis triphenylphosphine palladium (O) (1.1g, 0.94mmol) and morpholine (11.8ml, 136mmol) processing.Mixture stirs 3h in nitrogen atmosphere, distribute between EtOAc and 2M aqueous hydrochloric acid then.Separate organic layer, use the salt water washing, dry (MgSO
4) and the concentrated yellow oily resistates that obtains.This resistates is dissolved among the MeOH, divides equally four parts, every part is applied to 20g aminopropyl SPE, and it washs with MeOH then.Required product is by the pillar eluant solution of 5%v/vAcOH in MeOH.Merge and contain the product cut, concentrate, obtain the title compound (4.03g, 88%) of light yellow solid form.
LC/MS：m/z?338[MH]
+，RT?3.05min.
Following compounds uses the method be similar to embodiment 158 (8-chloro-3-amyl group-1-[4-(5-phenyl-1,2,4-oxadiazole-3-yl) butyl]-3,7-dihydro-1H-purine-2,6-diketone) by corresponding acid preparation:
Table 9
Embodiment 159 in addition, 8-chloro-3-amyl group-1-{4-[5-(2-pyridyl)-1,2,4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2, the 6-diketone has following spectroscopic data:
1H NMR (CDCl
3) δ: 0.89 (t, 3H, J=6.9Hz), 1.75 (m, 4H), 1.89 (m, 6H), 2.92 (t, 2H, J=7.1Hz), 4.07 (t, 2H, J=7.4Hz), 4.16 (t, 2H, J=6.9Hz), 7.52 (m, 1H), 7.92 (m, 1H), 8.18 (m, 1H), 8.83 (m, 1H), 13.40 (br s, 1H).
Embodiment 163:8-chloro-1-{4-[5-(4-hydroxy phenyl)-1,2,4-oxadiazole-3-yl] butyl }-the 3-propyl group
-3,7-dihydro-1H-purine-2,6-diketone
The 4-hydroxy-benzoic acid (18mg, 0.13mmol) and CDI (24mg 0.15mmol) at room temperature stirs 1h in anhydrous DMSO (0.9ml).Add (1Z)-5-(8-chloro-2,6-dioxo-3-propyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine (50mg, 0.15mmol; The mode to be similar to (1Z)-5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine described in embodiment 158 (b) prepares), then mixture is stirred 2h down at 90 ℃.Reaction mixture is purified with MDAP.Merge the product cut, under high vacuum, concentrate, obtain the title compound (7mg, 11%) of white solid form.
LC/MS：m/z?443[MH]
+，RT?3.28min.
Embodiment 164:3-butyl-8-chloro-1-{4-[5-(2, the 6-difluorophenyl)-1,2,4-oxadiazole-3-yl] fourth
Base }-3,7-dihydro-1H-purine-2,6-diketone
2, the 6-difluoro-benzoic acid (40mg, 0.25mmol) and CDI (45mg 0.28mmol) at room temperature stirs 1h in anhydrous DMSO (0.9ml).(100mg 0.28mmol), then stirs 16h with mixture down at 90 ℃ to add (1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine.Reaction mixture is purified with MDAP.Merge the product cut, concentrate, obtain the title compound (18mg, 15%) of white solid form.
LC/MS：m/z?479[MH]
+，RT?3.40min.
Embodiment 165:3-butyl-8-chloro-1-{4-[5-(2-fluorophenyl)-1,2,4-oxadiazole-3-yl] fourth
Base }-3,7-dihydro-1H-purine-2,6-diketone
The 2-fluorobenzoic acid (36mg, 0.25mmol) and CDI (45mg 0.28mmol) at room temperature stirs 1h in anhydrous DMSO (0.9ml).(100mg 0.28mmol), then stirs 16h with mixture down at 90 ℃ to add (1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine.Mixture is purified with MDAP.Merge the product cut, concentrate, obtain the title compound (33mg, 29%) of white solid form.
LC/MS：m/z?461[MH]
+，RT?3.44min.
Embodiment 166:3-butyl-8-chloro-1-{4-[5-(4-chloro-2-pyridyl)-1,2,4-oxadiazole-3-yl] fourth
Base }-3,7-dihydro-1H-purine-2,6-diketone
4-chloro-2-Pyridinecarboxylic Acid (40mg, 0.25mmol) and CDI (45mg 0.28mmol) at room temperature stirs 1h in anhydrous DMSO (0.9ml).(100mg 0.28mmol), then stirs 16h with mixture down at 90 ℃ to add (1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine.Reaction mixture is purified with MDAP.Merge the product cut, concentrate, obtain the title compound (13mg, 11%) of white solid form.
LC/MS：m/z?478[MH]
+，RT?3.31min.
1H NMR (DMSO-d
6) δ
H14.4 (br.s, 1H), 8.79 (d, 1H, J=6Hz), 8.24 (d, 1H, J=2Hz), (7.88 dd, 1H, J=6Hz and 2Hz), 3.91 (m, 4H), 2.85 (t, 2H, J=7.5Hz), 1.56-1.76 (m, 6H), 1.28 (m, 2H), 0.87 (t, 3H, J=7.5Hz) ppm.
Embodiment 167:3-butyl-8-chloro-1-{4-[5-(3-methyl-2-pyridyl)-1,2,4-oxadiazole-3-yl]
Butyl }-3,7-dihydro-1H-purine-2,6-diketone
3-methyl-2-Pyridinecarboxylic Acid (35mg, 0.25mmol) and CDI (45mg 0.28mmol) at room temperature stirs 1h in anhydrous DMSO (0.9ml).(100mg 0.28mmol), then stirs 16h with mixture down at 90 ℃ to add (1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine.Reaction mixture is purified with MDAP.Merge the product cut, concentrate, obtain the title compound (14mg, 12%) of white solid form.
LC/MS：m/z?458[MH]
+，RT?3.13min.
Embodiment 168:3-butyl-8-chloro-1-{4-[5-(2-pyridyl)-1,2,4-oxadiazole-3-yl] fourth
Base }-3,7-dihydro-1H-purine-2,6-diketone
Method A
2-Pyridinecarboxylic Acid (31mg, 0.25mmol) and CDI (45mg 0.28mmol) at room temperature stirs 1h in anhydrous DMSO (0.5ml).(100mg, the 0.28mmol) solution in DMSO (0.4ml) then stir 16h with mixture down at 90 ℃ to add (1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine.Reaction mixture is directly purified by MDAP.Merge the product cut, concentrate, obtain the title compound (14mg, 12%) of white solid form.
LC/MS：m/z?444[MH]
+，RT?3.01min.
1H NMR (DMSO-d
6) δ: 0.87 (t, 3H, J=7Hz), 1.27 (m, 2H), 1.65 (m, 6H), 2.84 (t, 2H, J=7Hz), 3.91 (m, 4H), 7.70 (dd 1H, J=5 and 7Hz), 8.07 (m, 1H), 8.19 (d, 1H, J=8Hz), 8.81 (d, 1H, J=5Hz), 14.5 (br.s, 1H).
Method B
2-Pyridinecarboxylic Acid (675mg, 5.3mmol) and CDI (909mg 5.6mmol) at room temperature stirs 90mins in nitrogen in dry DMF (30ml).Add (1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine (2.0g, 5.6mmol) and DMF (10ml), then with mixture at 100 ℃ of stirring 20h down.Reaction mixture is cooled to room temperature, then at saturated NH
4Distribute between Cl (aq) solution and the EtOAc.Separate organic layer, the aqueous solution extracts with EtOAc.The extraction liquid salt water washing that merges, dry MgSO
4And concentrate, obtain a kind of orange liquid.This liquid is used Companion
TMSystem is purified, and obtains two kinds of identical white solid (649mg; 240mg).
LC/MS：m/z?444[MH]
+，RT?3.04min.
Method C
12-L, round-bottomed flask are equipped with temperature sensor, condenser and the nitrogen inlet interconnecting device of suspention mechanical stirrer, band J-KEM temperature regulator.Pack in the described flask pyridine carboxylic acid (0.180kg, 1.46mol), MIBK (4.0L), 1,1 '-carbonyl dimidazoles (0.23kg, 1.42mol) and more MIBK (0.66L).Mixture is stirred and in about 1 hour, be warmed to 50 ℃, then temperature is risen to 56 ℃.Be heated to during 50 ℃, the solid dissolving, and produce carbonic acid gas.At 50 ℃ after 1 hour, (3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-(0.467kg 1.31mol) joins in the described reaction N-hydroxyl penta amidine with (1Z)-5-.Then, in 1 hour, mixture is warmed to 90 ℃.After 5.5 hours, the described reaction of HPLC analysis revealed of reaction is finished 90 ℃ of heating.Disconnect heating, then add 1.0N hydrochloric acid soln (2.33L).Temperature is dropped to 61 ℃.After stirring is spent the night, separate out described product, then filter.The filter cake water (1x2.23L, 1x2.43L) and heptane (1.40L) washing.Wet cake descended dry 22 hours at 50 ℃ in vacuum drying oven, obtained the product (68%) of 396g, and it is 97.7% (AUC) t that HPLC analyzes
R=18.6min.
Method D
3-butyl-8-chloro-1-{4-[5-(2-pyridyl)-1,2,4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2, the preparation of 6-diketone crystal formation 1
3-butyl-8-chloro-the 1-{4-[5-(2-pyridyl)-1,2 that in described reaction vessel, packs into, 4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone (1wt), acetone (20vol) and water (0.6vol).Described mixture is stirred and be warmed to 50-60 ℃, then stirred at least 1 hour.Form a kind of solution, it is filled in second reaction vessel by 1 micron filter under this temperature and clarifies.Described solution at about 3 hours internal cooling to 33-38 ℃, and under this temperature with 3-butyl-8-chloro-1-{4-[5-(2-pyridyl)-1,2,4-oxadiazole-3-yl] butyl-3,7-dihydro-1H-purine-2, the 6-diketone (crystal formation 1,0.01wt) plant brilliant.Described thin suspension was stirred 1 hour under this temperature at least, be cooled to 20-25 ℃ and under this temperature, kept at least 12 hours then.The suspension that forms thus is cooled to 13-17 ℃, then under this temperature, kept at least 1 hour.Then, to this suspension sampling
*, then in the laboratory, filter and collect described solid.Analyze to check crystal formation with this solid drying and by xrpd/DSC.If described crystal formation is needed (crystal formation 1), filter this batch of material, washing (2x3vol acetone) is also dry down at 50 ℃ in vacuum drying oven.In case analysis revealed solvent (acetone, water) reaches acceptable level, takes out described batch of material.
Expection yield (75-80%w/w).
If
*The sample crystal formation of sampling is proved to be the crystal formation 1 that is not pure, so
*With described batch of material reheat to 35-45 ℃ and under this temperature, stirred at least 1 hour.Then, described thin suspension is cooled to 20-25 ℃ and under this temperature, kept at least 12 hours.Then, the suspension that forms thus is cooled to 13-17 ℃ and under this temperature, kept at least 1 hour.Then, to this suspension sampling, then in the laboratory, filter and collect described solid.Analyze to check crystal formation with this solid drying and by xrpd/DSC.If described crystal formation is required (crystal formation 1), so as described above described batch of material is filtered washing, drying.If described form is not pure crystal formation 1, repeat so from
*Begin to circulate, till obtaining satisfactory result.
X-ray powder diffraction (XRPD)
X-ray powder diffraction (XRPD) data are illustrated among Fig. 1-3.Described data are at PANalyticalX ' Pert Pro powder diffractometer, and the PW3040/60 type obtains on sequence number DY1850 use X ' the Celerator detector.Acquisition condition is: radiation: Cu K α, producer voltage: 40kV, producer electric current: 45mA, initial angle: 2.0 ° of 2 θ, end angle: 40.0 ° of 2 θ, step-length: 0.0167 ° of 2 θ, per time in step: 31.75 seconds.By on Si plate (no reflection events) specimen holder, putting several milligrams sample sample preparation, produce the skim powder.
Embodiment 169:3-butyl-8-chloro-1-{4-[5-(4-hydroxy phenyl)-1,2,4-oxadiazole-3-yl] fourth
Base }-3,7-dihydro-1H-purine-2,6-diketone
The 4-hydroxy-benzoic acid (35mg, 0.25mmol) and CDI (45mg 0.28mmol) at room temperature stirs 1h in anhydrous DMSO (0.9ml).(100mg 0.28mmol), then stirs 16h with mixture down at 90 ℃ to add (1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine.Mixture is purified with MDAP, obtains the title compound (5mg, 4%) of white solid form.
LC/MS：m/z?459[MH]
+，RT?3.24min.
Embodiment 170:8-chloro-1-[4-(5-phenyl-1,2,4-oxadiazole-3-yl) butyl]-3-propyl group-3, the 7-dihydro
-1H-purine-2, the 6-diketone
Phenylformic acid (9mg, 0.074mmol) and CDI (13mg 0.081mmol) at room temperature stirs 1h in anhydrous DMSO (0.9ml).(28mg 0.081mmol), then stirs 4h with mixture down at 80 ℃ to add (1Z)-5-(8-chloro-2,6-dioxo-3-propyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine.Mixture is purified with MDAP, obtains the title compound (0.6mg, 2%) of white solid form.
LC/MS：m/z?429[MH]
+，RT?3.21min.
1H NMR (MeOH-d
4) δ: 0.93 (t, 3H, J=7.5Hz), 1.74 (m, 4H), 1.84 (m, 2H), 2.84 (t, 2H, J=7Hz), 3.97 (t, 2H, J=7.5Hz), 4.08 (t, 2H, J=7Hz), 7.57 (dd, 2H, J=7 and 7.5Hz), 7.65 (dd, 1H, J=7 and 7.5Hz), 8.08 (d, 2H, J=7.5Hz).
Embodiment 171:3-butyl-8-chloro-1-{4-[5-(2-chloro-6-fluorophenyl)-1,2,4-oxadiazole-3-yl] fourth
Base }-3,7-dihydro-1H-purine-2,6-diketone
2-chloro-6-fluorobenzoic acid (44mg, 0.25mmol) and CDI (45mg 0.28mmol) at room temperature stirs 1h in anhydrous DMSO (0.9ml).(100mg 0.28mmol), then stirs 16h with mixture down at 90 ℃ to add (1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine.Mixture is purified with MDAP.Merge the product cut, concentrate, obtain the title compound (6.4mg, 5%) of white solid form.
LC/MS：m/z?495[MH]
+，RT?3.58min.
Embodiment 172:3-butyl-8-chloro-1-{4-[5-(5-hydroxyl-2-pyridyl)-1,2,4-oxadiazole-3-yl]
Butyl }-3,7-dihydro-1H-purine-2,6-diketone
5-hydroxyl-2-Pyridinecarboxylic Acid (24mg, 0.17mmol) and CDI (31mg 0.19mmol) at room temperature stirs 1h in anhydrous DMSO (0.9ml).(68mg 0.19mmol), then stirs 16h with mixture down at 90 ℃ to add (1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine.Mixture is purified with MDAP, and the product cut concentrates, and obtains the title compound (19mg, 24%) of white solid form.
LC/MS：m/z?459[MH]
+，RT?3.03min.
Embodiment 173:8-chloro-3-amyl group-1-{4-[5-(3-thienyl)-1,2,4-oxadiazole-3-yl] fourth
Base }-3,7-dihydro-1H-purine-2,6-diketone
(1Z)-5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine (50mg, 0.13mmol) EtOH (55 μ l, 0.21mmol) solution and 3-thiophene carboxylate (18 μ l, 0.13mmol) processing of 21%NaOEt of the solution in EtOH (1ml).Mixture heats 10min down at 150 ℃ in microwave.After the cooling, be reflected between the HCl (aq) of 2M and the EtOAc and distribute.Separate organic layer, water layer extracts with EtOAc once more.The extraction liquid that merges is concentrated and purify with MDAP.Obtain the title compound (20mg, 32%) of pale solid form.
LC/MS：m/z?463[MH]
+，RT?3.6min.
Embodiment 174:8-chloro-3-amyl group-1-{4-[5-(2-thienyl)-1,2,4-oxadiazole-3-yl] fourth
Base }-3,7-dihydro-1H-purine-2,6-diketone
(14mg 0.11mmol) is dissolved among the NMP (0.9ml), and then (18mg 0.11mmol) handles with CDI with 2-Thiophene Carboxylic Acid.Behind the 1h, (50mg 0.13mmol), then down heats 15min at 150 ℃ with mixture in microwave to add (1Z)-5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine.Solution is directly purified with MDAP, obtains title compound, and it is with 1 then, and the lyophilize of 4-diox obtains the title compound (19mg, 31%) of white solid form.
LC/MS：m/z?463[MH]
+，RT?3.5min.
Embodiment 175:8-chloro-3-amyl group-1-{4-[5-(1,3-thiazoles-2-yl)-1,2,4-oxadiazole-3-yl] fourth
Base }-3,7-dihydro-1H-purine-2,6-diketone
(1Z)-5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine (50mg, 0.13mmol) EtOH (50 μ l, 0.13mmol) solution and 1 of 21%NaOEt of the solution in EtOH (1.5ml), (18mg 0.11mmol) handles 3-thiazole-2-carboxylic acid, ethyl ester.Mixture heats 10min down at 170 ℃ in microwave.After the cooling, be reflected between the HCl (aq) of 2M and the EtOAc and distribute.Separate organic layer, concentrate then, then purify with MDAP.Obtain the title compound (13mg, 21%) of white solid form.
LC/MS：m/z?464[MH]
+，RT?3.3min.
1H?NMR(DMSO-d
6)δ：0.83(t，3H，J＝7Hz)，1.21-1.32(m，4H)，1.60-1.77(m，6H)，2.84(t，2H，J＝7Hz)，3.91(m，4H)，8.23(d，1H，J＝3Hz)，8.27(d，1H，J＝3Hz)，14.4(br?s，1H).
Embodiment 176:3-butyl-8-chloro-1-{4-[3-(2-pyridyl)-1,2,4-oxadiazole-5-yl] fourth
Base }-3,7-dihydro-1H-purine-2,6-diketone
A) 3-butyl-8-chloro-1-{4-[3-(2-pyridyl)-1,2,4-oxadiazole-5-yl] butyl }-3,7-dihydro-1H-purine-2, the preparation of 6-diketone
To 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) Valeric acid ethylester (120mg, 0.32mmol) and N-hydroxyl-2-picolyl ether (50mg 0.36mmol) adds the EtOH (0.225ml of 21% (w/v) sodium ethylate in the mixture in EtOH (2ml), 0.62mmol) solution, in the sealing phial, in microwave oven, heat 10min down then at 140 ℃.Cooled mixture is evaporated to dried, resistates distributes between chloroform (5ml) and saturated aqueous ammonium chloride (5ml).Organic phase is evaporated to dried, crude product is purified by MDAP.Merge and contain the product cut, be evaporated to dried.Described product is grinding to form solid in a small amount of ether, drying obtains the title compound (44mg, 31%) of white solid form.
LC/MS：m/z?444[MH]
+，RT?3.03min.
1H?NMR(CDCl
3)δ：0.96(t，3H，J＝7.3Hz)，1.40(m，2H)，1，74(m，2H)，1.88(m，2H)，1.99(m，2H)，3.07(t，2H，J＝7.5Hz)，4.09(t，2H，J＝7.5Hz)，4.17(t，2H，J＝7.0Hz)，7.43(m，1H)，7.64(m，1H)，8.10(m，1H)，8.79(m，1H).
B) preparation of N-hydroxyl-2-picolyl ether
To 2-pyridine nitrile (3g, 29mmol) and salt of wormwood (4.1g 30mmol) adds entry (15ml) in the mixture in EtOH (30ml), and (2.9g 42mmol), heats 6h then under refluxing, cool off and be evaporated to dried then to add oxammonium hydrochloride carefully.Resistates water (100ml) is handled, and leaches the suspended solids product, washes with water and drying, obtains the title compound (2.28g, 57%) of white solid form.
1H?NMR(DMSO-d
6)δ：5.85(br?s，2H)，7.40(m，1H)，7.79(m，1H)，7.86(m，1H)，8.55(m，1H)，9.92(s，1H)
Embodiment 177:3-butyl-8-chloro-1-[4-(3-phenyl-1,2,4-oxadiazole-5-yl) butyl]-3, the 7-dihydro
-1H-purine-2, the 6-diketone
Method A
A) 3-butyl-8-chloro-1-[4-(3-phenyl-1,2,4-oxadiazole-5-yl) butyl]-3,7-dihydro-1H-purine-2,6-diketone
With 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) Valeric acid ethylester (74mg, 0.2mmol) and benzamidoxime (30mg 0.22mmol) is suspended among the anhydrous EtOH (1ml), then add sodium ethylate (21%wt., 0.111ml, 0.3mmol).Mixture is leniently warm, till the solid dissolving, in microwave reactor, heat 10min down then at 140 ℃.Then, mixture distributes between the HCl of EtOAc and 2M, then with organic phase drying (Na
2SO
4) and evaporation.Purify by MDAP, obtain pure title compound (40.7mg).
LC/MS：m/z?443[MH]
+，RT?3.67min.
1H?NMR(DMSO-d
6)δ：0.89(t，3H，J＝7Hz)，1.22-1.34(m，2H)，1.57-1.75(m，4H)，1.75-1.86(m，2H)，3.05(t，2H，J＝7Hz)，3.88-3.98(m，4H)，7.52-7.63(m，3H)，7.95-8.0(m，2H).
B) 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) Valeric acid ethylester
To 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (1.5g adds Cs in dry DMF 5.31mmol) (25ml) solution to the 6-diketone
2CO
3(1.905g, 5.84mmol), then add 5-bromine Valeric acid ethylester (1.46g, 6.99mmol).Mixture is at 55 ℃ of following heating 18h, allows its cooling then.By find time repeatedly and again nitrogen injection outgas, add then morpholine (3.70ml, 42.5mmol) and tetrakis triphenylphosphine palladium (O) (1.0g 0.865mmol), then stirs 5h with mixture.Add HCl (40ml) and the water (20ml) of EtOAc (75ml), 2M, then separate organic phase,, filter to remove some undissolved yellow solids, dry (Na with salt water washing (3x25ml)
2SO
4) and evaporation.Resistates (2.5g) is purified with aminopropyl SPE (20g), is loaded into THF-MeOH (1: 1) lining, with the MeOH washing and with DCM-MeOH (1: the 1) eluted product that contains 5% extra AcOH, obtains title compound (1.53g).
LC/MS：，m/z?371?MH
+，RT?3.18min
Method B
A) 3-butyl-8-chloro-1-[4-(3-phenyl-1,2,4-oxadiazole-5-yl) butyl]-3,7-dihydro-1H-purine-2,6-diketone
(0.98g, (1.89g is 5.5mmol) in the solution in DMF (15ml) and stir 1.5h in nitrogen 6.1mmol) to join 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeric acid with CDI.(0.91g 6.1mmol), then stirs described mixture down at 110 ℃ and spends the night to add benzamidoxime.Reaction mixture distributes between the HCl of EtOAc and 2M.Separate organic layer, use the salt water washing, dry (MgSO
4) and evaporation.The crude product methanol crystallization is used Companion then
TMSystem is further purified, with the gradient elution of hexanaphthene-EtOAc.Merge and contain the product cut, evaporate, obtain the title compound (850mg) of white solid form.
LC/MS：m/z?443[MH]
+，RT?3.52min.
1H?NMR(MeOH-d
4)δ：0.94(t，3H，J＝7.5Hz)，1.31-1.41(m，2H)，1.65-1.73(m，2H)，1.75-1.83(m，2H)，1.87-1.96(m，2H)，3.04(t，2H，J＝7.5Hz)，4.01(t，2H，J＝7.5Hz)，4.06(t，2H，J＝7Hz)，7.46-7.55(m，3H)，7.98-8.02(m，2H).
B) 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeric acid
5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) Valeric acid ethylester (2.8g, 7.55mmol), LiOH (542mg, 22.7mmol), the mixture of water (2.5ml) and methyl alcohol (50ml) at room temperature stirs 60h.Mixture distributes between water and EtOAc, and then the pH value with water is adjusted to pH 4-5.Separate organic layer, use the salt water washing, dry (MgSO
4) and evaporate, obtain the title compound (2.18g) of white solid form.
LC/MS：m/z?343[MH]
+，RT?2.69min.
Embodiment 178:8-chloro-3-amyl group-1-[4-(3-phenyl-1,2,4-oxadiazole-5-yl) butyl]-3, the 7-dihydro
-1H-purine-2, the 6-diketone
With 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) methyl valerate (50mg, 0.13mmol), the benzenyl amidine oxime (20mg, 0.15mmol) and the EtOH of 21%NaOEt (76 μ l, 0.20mmol) mixture of solution in EtOH (1.5ml) in microwave at 140 ℃ of heating 10min down.After the cooling, be reflected between the HCl (aq) of 2M and the EtOAc and distribute.Separate organic layer, dry (MgSO
4) and concentrate.Purify by MDAP, obtain the title compound (25mg, 41%) of white solid form.
LC/MS：m/z?457[MH]
+，RT?3.7min.
1H?NMR(DMSO-d
6)δ：0.82(t，3H，J＝7Hz)，1.25(m，4H)，1.66(m，4H)，1.79(m，2H)，3.04(t，2H，J＝7Hz)，3.92(4H，m)，7.57(m，3H)，7.97(m，2H)，14.5(brs，1H).
Embodiment 179:3-butyl-8-chloro-1-{4-[3-(3-hydroxy phenyl)-1,2,4-oxadiazole-5-yl] fourth
Base }-3,7-dihydro-1H-purine-2,6-diketone
5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) Valeric acid ethylester (50mg, 0.13mmol), N, 3-dihydroxy-benzene carbonamidine (25mg, 0.16mmol), the EtOH of 21%NaOEt (55 μ l, 0.15mmol) mixture of solution and EtOH (1.5ml) in microwave at 180 ℃ of heating 10min down.Add another aliquot 21%NaOEt EtOH (55 μ l, 0.21mmol) solution, then with mixture in microwave at 175 ℃ of heating 30min down.After the cooling, be reflected between the HCl (aq) of 2M and the EtOAc and distribute.Separate organic layer, concentrate, then purify with MDAP.Obtain the title compound (20mg, 32%) of pale solid form.
LC/MS：m/z?459[MH]
+，RT?3.3min.
Embodiment 180:8-chloro-1-{4-[3-(4-hydroxy phenyl)-1,2,4-oxadiazole-5-yl] butyl }-the 3-amyl group
-3,7-dihydro-1H-purine-2,6-diketone
(50mg, 0.14mmol) (23mg 0.14mmol) handles the solution in DMF (2ml) 5-(8-chloro-2,6-dioxo-3-amyl group-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeric acid, then at room temperature stirs 30min with CDI.Add N, (26mg 0.17mmol), then down heats 15min at 120 ℃ with mixture to 4-dihydroxy-benzene carbonamidine in microwave.After the cooling, be reflected between the HCl (aq) of 2M and the EtOAc and distribute.Separate organic layer, concentrate, then purify with MDAP.Obtain the title compound (17mg, 26%) of pale solid form.
LC/MS：m/z?473[MH]
+，RT?3.5min.
Embodiment 181:3-butyl-8-chloro-1-[4-(5-phenyl-2H-tetrazolium-2-yl) butyl]-3,7-dihydro-1H-
Purine-2, the 6-diketone
Methylsulfonic acid 4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] and butyl ester (50mg, 0.12mmol), Cs
2CO
3(45mg, 0.14mmol) and the mixture of DMF (3ml) (20mg 0.14mmol) handles, and then stirs 60h down at 50 ℃ with 5-phenyl-1H-tetrazolium.After the cooling, mixture is introduced nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(20mg 0.017mmol), then outgases mixture once more.(150 μ l 1.7mmol), then stir 18h with mixture in nitrogen, distribute between the HCl of 2M (aq) and EtOAc then to add morpholine.Separate organic layer, water layer extracts with EtOAc once more.The extraction liquid that merges is concentrated, obtain yellow residue.Add MeOH, pass through NH then
2-propyl group post, product 2%AcOH/MeOH wash-out.Further purify by MDAP, obtain the title compound (15mg, 29%) of pale solid form.
LC/MS：m/z?443[MH]
+，RT?3.4min.
1H?NMR(DMSO-d
6)δ：0.86(t，3H，J＝7Hz)，1.26(m，2H)，1.59(m，4H)，1.97(m，2H)，3.90(m，4H)，4.76(t，2H，J＝7Hz)，7.54(m，3H)，8.02(m，2H)，14.4(brs，1H).
Embodiment 182:3-butyl-8-chloro-1-[4-(5-oxo-4-phenyl-4,5-dihydro-1H-tetrazolium-1-yl)
Butyl]-3,7-dihydro-1H-purine-2,6-diketone
Methylsulfonic acid 4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] and butyl ester (50mg, 0.12mmol), Cs
2CO
3(45mg, 0.14mmol) and the mixture of DMF (3ml) with 1-phenyl-1, (23mg 0.14mmol) handles 2-dihydro-5H-tetrazolium-5-ketone, then stirs 60h down at 50 ℃.After the cooling, mixture is introduced nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(20mg 0.017mmol), then outgases mixture once more.(150 μ l 1.7mmol), then stir 18h with mixture in nitrogen, distribute between the HCl of 2M (aq) and EtOAc then to add morpholine.Separate organic layer, water layer extracts with EtOAc once more.The extraction liquid that merges is concentrated, obtain yellow residue.Add MeOH, then by the aminopropyl post, product 2%AcOH/MeOH wash-out.Further purify by MDAP, obtain the title compound (27mg, 51%) of pale solid form.Note existing the alkylating material of about 10%O-.
LC/MS：m/z?459[MH]
+，RT?3.1min.
1H?NMR(DMSO-d
6)δ：0.88(t，3H，J＝7Hz)，1.28(m，2H)，1.62(m，4H)，1.79(m，2H)，3.91(m，4H)，4.03(m，2H)，7.44(m，1H)，7.57(m，2H)，7.85(m，2H)，14.5(br?s，1H).
Embodiment 183:3-butyl-8-chloro-1-[4-(4-methyl-2,5-dioxo-3-phenyl-1-imidazolidyl)
Butyl]-3,7-dihydro-1H-purine-2,6-diketone
A) 3-butyl-8-chloro-1-[4-(4-methyl-2,5-dioxo-3-phenyl-1-imidazolidyl) butyl]-3,7-dihydro-1H-purine-2,6-diketone
Methylsulfonic acid 4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] and butyl ester (88mg, 0.20mmol), Cs
2CO
3(80mg, 0.24mmol) and the mixture of DMF (2ml) with 5-methyl isophthalic acid-phenyl-2, (46mg 0.24mmol) handles the 4-imidazolidimedione, then stirs 18h down at 70 ℃.After the cooling, mixture is introduced nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(25mg 0.022mmol), then outgases mixture once more.(174 μ l 2.0mmol), then stir 5h with mixture in nitrogen, distribute between the HCl of 2M (aq) and EtOAc then to add morpholine.Separate organic layer, water layer extracts with EtOAc once more.The extraction liquid that merges is concentrated, obtain yellow residue.Add MeOH, then by aminopropyl SPE, product 2%AcOH/MeOH wash-out.Further purify by MDAP, obtain the title compound (70mg, 71%) of solid form.
LC/MS：m/z?487[MH]
+，RT?3.2min.
B) methylsulfonic acid 4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] butyl ester
3-butyl-8-chloro-1-(4-hydroxyl butyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (1.30g, 3.66mmol) solution in DCM (10ml) is with triethylamine (0.77ml, 5.50mmol) handle, then add in batches the methylsulfonic acid acid anhydride (702mg, 4.03mmol).Carefully, boiling.Reaction mixture at room temperature stirs 10min, then at saturated NaHCO
3(aq) distribute between solution and the DCM.Separate organic layer, then, use the salt water washing then with HCl (aq) washing of 1M.Dry (MgSO
4), concentrate, obtain thickness buttery title compound (1.60g, quantitative).
LC/MS：m/z?433[MH]
+，RT?3.3min.
C) 3-butyl-8-chloro-1-(4-hydroxyl butyl)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6 diketone
3-butyl-8-chloro-7-(2-propylene-1-yl)-3 under stirring, 7-dihydro-1H-purine-2,6-diketone (5.0g, 17.7mmol) the solution Cs in DMF (100ml)
2CO
3(6.3g, 19.5mmol) (3.0ml 21.2mmol) handles with 4-bromo-1-butanols.Mixture heats 5h down at 50 ℃, distributes between the HCl of 2M (aq) and EtOAc then.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate, obtain a kind of yellow solid.Purify by silicon-dioxide SPE (EtOAc/ hexanaphthene mixture is as eluent), pass through Companion then
TMSystem (the IPA/DCM mixture is as eluent) is purified, and obtains the title compound (1.35g, 21%) of colorless oil.
LC/MS：m/z?355[MH]
+，RT?2.9min.
Embodiment 184:8-chloro-1-{4-[4-(cyclopentyl alkylsulfonyl) phenyl] butyl }-3-amyl group-3, the 7-dihydro
-1H-purine-2, the 6-diketone
With 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (100mg 0.34mmol) is dissolved among the DMF (1ml) and uses 4-[4-(cyclopentyl alkylsulfonyl) phenyl successively]-the 1-butanols (105mg, 0.37mmol), PPh
3(the DMF solution of the 1M of 404 μ l) and DBAD (the DMF solution of the 1M of 404 μ l) handle.Stir 24h in nitrogen after, mixture is introduced nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(39mg 0.034mmol), then outgases mixture once more.(297 μ l 3.4mmol), then stir 63h with mixture in nitrogen, distribute between the HCl of 2M (aq) and EtOAc then to add morpholine.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate, obtain a kind of yellow residue.Add MeOH, then by aminopropyl SPE, product 2%AcOH/MeOH wash-out.Product is further purified with MDAP, obtains the title compound (5mg, 3%) of beige solid form.
LC/MS：m/z?521[MH]
+，RT?3.7min.
Embodiment 185:8-chloro-1-{4-[4-(methoxyl group) phenyl] butyl }-3-amyl group-3,7-dihydro-1H-purine
-2, the 6-diketone
4-(4-brombutyl) methyl-phenoxide (88mg, 0.36mmol) solution in DMF (3ml) and 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (90mg, 0.30mmol) and Cs
2CO
3(109mg 0.33mmol) reacts 5h down at 50 ℃.Mixture is introduced nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(35mg 0.030mmol), then outgases mixture once more.(0.26ml 3.0mmol), then stirs 3h with mixture in nitrogen to add morpholine.Add another aliquot Pd (PPh
3)
4(35mg 0.030mmol), follows restir 3h.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, water layer extracts with EtOAc once more.The extraction liquid that merges is concentrated, obtain yellow residue.Add MeOH, then by aminopropyl SPE, product 3%AcOH/MeOH wash-out.Product is further purified with MDAP, obtains the title compound (2mg, 1.5%) of solid form.
LC/MS：m/z?419[MH]
+，RT?3.7min.
1H?NMR；(MeOH-d
4)δ：0.90(t，3H，J＝7Hz)，1.28-1.40(m，4H)，1.57-1.75(m，6H)，2.57(t，2H，J＝7Hz)，3.73(s，3H)，3.97-4.02(4H，m)，6.77(m，2H)，7.06(m，2H).
Embodiment 186:8-chloro-3-amyl group-1-{3-[3-(methoxyl group) phenyl] propyl group }-3,7-dihydro-1H-purine
-2, the 6-diketone
A) 8-chloro-3-amyl group-1-{3-[3-(methoxyl group) phenyl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone b)
With 8-chloro-3-amyl group-1-{3-[3-(methoxyl group) phenyl] propyl group }-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (2.94g) is dissolved among the anhydrous THF (40ml).Described solution purges 6 degassings with nitrogen/vacuum.Add tetrakis triphenylphosphine palladium (0.66g), then add morpholine (5ml).After stirring 18hr, reaction mixture dilutes with EtOAc, and then HCl and the salt solution (x2) with 1N washs, dry (MgSO
4) and evaporation in a vacuum.This thick material is gone up purification at aminopropyl SPE (70g), use the MeOH wash-out,, obtain the title compound (1.56g) of light yellow solid form then with the MeOH wash-out that contains 3%AcOH.
LC/MS：m/z?405[MH]
+，RT?3.51min.
B) 8-chloro-3-amyl group-1-{3-[3-(methoxyl group) phenyl] propyl group }-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
In nitrogen atmosphere with 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (1.76g, 5.94mmol) and 3-[3-(methoxyl group) phenyl]-(1.00g 6.04mmol) is dissolved among the anhydrous THF (50ml) the 1-propyl alcohol.Behind the 5min, and the adding triphenylphosphine (1.87g, 7.12mmol).Behind 5min, and adding azo-2-carboxylic acid di tert butyl carbonate (1.64g, 7.1mmol).This solution is at room temperature stirred 20h.Turbid solution concentrates in a vacuum, goes up at 50g silicon-dioxide II SPE (IST) and purifies, and uses BiotageFlashMaster
TMPersonal, with 5: 1 wash-outs of hexanaphthene/EtOAc, suitable cut concentrates in a vacuum, obtains containing the shallow cream-colored buttery title compound (2.94g) of small amount of impurities.
LC/MS：，m/z?445[MH]
+，RT?3.88min.
Embodiment 187:8-chloro-1-[3-(3-hydroxy phenyl) propyl group]-3-amyl group-3,7-dihydro-1H-purine-2,6-
Diketone
Under-73 ℃, to 8-chloro-3-amyl group-1-{3-[3-(methoxyl group) phenyl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone (1.52g, 3.86mmol) slow DCM (4.6ml) solution that adds the 1N boron tribromide in the suspension in anhydrous DCM (40ml).Reaction mixture stirred 2 hours down at-70 ℃, at room temperature stirred 96h then.Reaction mixture cools off in ice, then adds entry (6.8ml) lentamente.Reaction mixture dilutes with EtOAc and water then, organic phase saturated sodium bicarbonate (x3) and salt water washing, dry then (MgSO
4) and evaporation in a vacuum.This thick material (90mg) of a part is purified with MDAP, after the lyophilize, obtains the title compound (40mg) of white solid form.
LC/MS：，m/z?391[MH]
+，RT?3.43min.
1H?NMR(DMSO-d
6)δ：0.85(t，3H，J＝7Hz)；1.27(m，4H)；1.63(m，2H)；1.80(m，2H)；2.50(m，2H)；3.89(m，4H)；6.57(m，3H)；7.02(t，1H，J＝8Hz)；9.22(s，1H)；14.39(s，1H)
Embodiment 188:3-butyl-8-chloro-1-{4-[3-(4-hydroxy phenyl)-1,2,4-oxadiazole-5-yl] fourth
Base }-3,7-dihydro-1H-purine-2,6-diketone
(100mg, 0.29mmol) (52mg 0.32mmol) handles the solution in DMF (4ml) 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeric acid under stirring with CDI.Behind the 1h, add N, 4-dihydroxy-benzene carbonamidine then heats 6h with mixture down at 100 ℃.After the cooling, reaction mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Purify by MDAP, obtain the title compound (72mg) of light gray solid form.
LC/MS：m/z?459[MH]
+，RT?3.27min.
Following compounds (table 10) uses the method that is similar to embodiment 177 by suitable amidoxim preparation.
Table 10
Embodiment 192:3-butyl-8-chloro-1-{3-[3-(1-benzyl ring amyl group)-1,2,4-oxadiazole-5-yl] third
Base }-3,7-dihydro-1H-purine-2,6-diketone
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl butyrate (53mg, 0.15mmol), N-hydroxyl-1-benzyl ring pentane carbonamidine (34mg, 0.165mmol) and sodium methylate (20mg 0.37mmol) heats 10min in microwave reactor under 140 ℃ in anhydrous MeOH (0.75ml).Then, mixture distributes between the HCl of ethyl acetate and 2M, the organic phase evaporation, and product is purified with MDAP, obtains the title compound (29.1mg) of solid form.
LC/MS：m/z?497[MH]
+，RT?3.76min.
Following compounds (table 11) is used the method preparation that is similar to embodiment 192, and [except that following: embodiment 210,211 and 212, and EtOH is used as reaction solvent to use suitable amidoxim; For embodiment 210,211 and 212, described reaction is by adding the HCl aftertreatment of 2M, and till neutrality, then steaming desolventizes; For embodiment 206, described quantity is the initial ethyl ester of 32mg; For embodiment 208, described quantity is the initial ethyl ester of 42mg].
Table 11
Embodiment 210:3-butyl-8-chloro-1-[3-(3-{[4-(methoxyl group) phenyl] methyl }-1,2,4-oxadiazole-5-
Base) propyl group]-3,7-dihydro-1H-purine-2,6-diketone
Use is similar to the method preparation of embodiment 93, except that extra last purification step is used the HPLC.Yield 6.0mg.
LC/MS：m/z?473[MH]
+，RT?3.27min.
Following compounds (table 12) is used the method preparation be similar to embodiment 96, and [except following: the quantity of embodiment 211 is 0.12mmol rather than 0.15mmol to use suitable amidoxim; For embodiment 216, EtOAc/HCl aftertreatment then commonly used and MDAP are spent the night in NaOH (0.5ml) stirring with 2M in EtOH (0.75ml) of described crude product; Embodiment 218 separates from the preparation of embodiment 219 as impurity and separates with embodiment 219 by HPLC; For embodiment 221,222 and 223, during moisture aftertreatment, before extraction, described pH regulator is arrived about 5; In addition, behind MDAP, embodiment 223 further uses silicon-dioxide SPE (2g, DCM-MeOH 40: 1 20: 1 then) to purify].
Table 12
Following compounds (table 13) is used the method preparation that is similar to embodiment 114, and [except that following: embodiment 226 carries out on half scale of embodiment 114 and during aftertreatment, water neutralized before extraction to use suitable amidoxim; Embodiment 227 is carrying out on half scale of embodiment 114 and crude product stirs 5h with the NaOH (0.5ml) of 2M in EtOH (1ml), then aftertreatment and MDAP; For embodiment 232, use the 21%NaOEt of 0.185ml (0.5mmol)].
Table 13
Embodiment 237:3-butyl-8-chloro-1-(3-{3-[(2-oxo-2,3-dihydro-1H-benzoglyoxaline-5-yl)
Methyl]-1,2,4-oxadiazole-5-yl } propyl group)-3,7-dihydro-1H-purine-2,6-diketone
Synthetic by the method that is similar to embodiment 126, to remove and use other 2 normal 21% sodium ethylates (0.11ml), be 20min extra heat-up time, outside product then grinds with hot MeOH by filtering separation.Yield 14.5mg.
LC/MS：m/z?499[MH]
+，RT?2.78min.
The method preparation of following compounds (table 14) by being similar to embodiment 18 [but except following: embodiment 238-243 is all by 8-chloro-3-amyl group-7-(2-propylene-1-yl)-1-[3-(1H-pyrazoles-4-yl) propyl group of 50mg]-3,7-dihydro-1H-purine-2, synthetic on the scale of 6-diketone; Embodiment 241,243,245,246 and 247 further purifies with MDAP behind aminopropyl SPE; Embodiment 242 further purifies with the MeOH recrystallization behind aminopropyl SPE; For embodiment 248, use the yellow soda ash of 128mg (1.2mmol); During aftertreatment, before extraction, described water is adjusted to pH6; And described product purifies with MDAP, further purifies by HPLC then; For embodiment 241, before SPE, the solid of separating out during aftertreatment mixes with the EtOAc extraction liquid].
Table 14
Embodiment 249:8-chloro-1-(3-{1-[(4-chloro-phenyl-) methyl]-1H-pyrazoles-4-yl } propyl group)-the 3-amyl group
-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-3-amyl group-7-(2-propylene-1-yl)-1-[3-(1H-pyrazoles-4-yl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone (50mg, 0.123mmol) dry DMF (1.5ml) solution and yellow soda ash (75mg, 0.708mmol) and 4-chlorine bromotoluene (150mg 0.73mmol) stirs down 18h at 40 ℃ together.Mixture distributes between EtOAc and water, then with organic phase salt water washing, and dry and evaporation.Product is purified (Companion system, EtOAc-hexanaphthene gradient) with the silica gel normal-phase chromatography, obtains a kind of oil (44mg).In the nitrogen with this oil the degassing dry DMF (1ml) in and tetrakis triphenylphosphine palladium (O) (19mg) and morpholine (0.072ml) stir 6h together.Mixture distributes between the HCl of EtOAc and 2M, then purifies with the organic phase evaporation and with aminopropyl SPE method commonly used.Yield 21.0mg.
LC/MS：m/z?489[MH
+]，RT?3.59min.
Following compounds (table 15) prepares [except that following: for embodiment 250, add the Pd (PPh of second section behind 5h by the method that is similar to embodiment 23
3)
4, continue to stir and spend the night, and realize last the purification by HPLC; For embodiment 252, need be by the additional purification of MDAP; Embodiment 257 need be by carrying out extra purification with the MeOH recrystallization; Embodiment 258 need carry out extra purification by grinding with MeOH].
Table 15
| Triazol-1-yl) phenyl] methyl }-1H-pyrazoles-4-yl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone |
Embodiment 259:8-chloro-3-amyl group-1-[3-(1-amyl group-1H-pyrazoles-4-yl) propyl group]-3,7-dihydro-1H-
Purine-2, the 6-diketone
8-chloro-3-amyl group-7-(2-propylene-1-yl)-1-[3-(1H-pyrazoles-4-yl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone (61mg, 0.15mmol) and yellow soda ash (32mg, 0.3mmol) (238mg 1.2mmol) heats 25min down at 120 ℃ together in microwave reactor with n-amyl iodide in dry DMF (1.5ml).After the cooling, with the mixture degassing and with tetrakis triphenylphosphine palladium (O) (40mg, 0.0346mmol) and morpholine (0.2ml) stir 7h together.Then, the Pd (PPh that adds other 20mg
3)
4, then continue to stir to spend the night.Mixture stirs 1h with the HCl of EtOAc and 2M, then organic phase is separated and evaporation.Product is purified with aminopropyl SPE (5g), and with MeOH-THF (1: 1) washing, with the MeOH washing, then product obtains title compound (25mg) with DCM-MeOH (1: the 1) wash-out that contains 5% extra AcOH then.
LC/MS：m/z?435[MH]
+，RT?3.65min.
The method preparation [but except that following: described compound with MDAP purify and for embodiment 261, total heat-up time in microwave reactor be 50min] of following compounds (table 16) by being similar to embodiment 259.
Table 16
Embodiment 264:8-chloro-3-amyl group-1-{3-[1-(2-phenylethyl)-1H-pyrazoles-4-yl] propyl group }-3,7-
Dihydro-1H-purine-2, the 6-diketone
8-chloro-3-amyl group-7-(2-propylene-1-yl)-1-[3-(1H-pyrazoles-4-yl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone (81mg, 0.2mmol), yellow soda ash (42mg, 0.4mmol) and (2-iodine ethyl) benzene (0.174ml, 1.2mmol) together in dry DMF (1ml) under microwave radiation at 120 ℃ of following heating 25min.(46mg 0.04mmol) and morpholine (0.174ml), then stirs 6h with mixture to add tetrakis triphenylphosphine palladium (O).These reagent that add other quantity (46mg and 0.174ml), and continue to stir 60h again.As embodiment in the table 16, carry out aftertreatment and purification, obtain title compound (15.5mg).
LC/MS：m/z?469[MH]
+，RT?3.60min.
Embodiment 265:8-chloro-3-amyl group-1-(3-{1-[2-(1-pyrrolidyl) ethyl]-1H-pyrazoles-4-yl }
Propyl group)-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-3-amyl group-7-(2-propylene-1-yl)-1-[3-(1H-pyrazoles-4-yl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone (61mg, 0.15mmol), yellow soda ash (159mg, 1.5mmol) and 1-(2-chloroethyl) pyrrolidine hydrochloride (127mg, 0.75mmol) together in dry DMF (2ml) at 80 ℃ of following heating 65h.(55mg 0.15mmol), then continues heating 18h again to add tetrabutylammonium iodide.1-(2-chloroethyl) pyrrolidine hydrochloride (127mg that adds greater amt, 0.75mmol), then mixture is heated down at 120 ℃ by microwave, add 1-(2-chloroethyl) pyrrolidine hydrochloride (100mg) of C grade portions then, under 120 ℃, in microwave, heat 25min again.Mixture distributes between water and EtOAc, and organic phase is separated, with salt water washing and evaporation.This material is distributed between the HCl of EtOAc and 2M.Water after separating is alkalized to pH9, saturated and with EtOAc extraction (x2) with NaCl.With extraction liquid evaporation, resistates (28mg) in the DMF of no water degasification (1.5ml) with tetrakis triphenylphosphine palladium (O) (50mg) and morpholine (0.2ml) stir 6h.Mixture distributes between the HCl of EtOAc and 2M, and water filters, and uses the EtOAc extracting twice, then is evaporated to dried.Resistates is purified with aminopropyl SPE method, and then MDAP obtains title compound (1.9mg).
LC/MS：m/z?462[MH]
+，RT?2.46min.
Embodiment 266:8-chloro-1-(3-{1-[(5-chloro-2-thienyl) methyl]-1H-pyrazoles-4-yl } propyl group)-3-
Amyl group-3,7-dihydro-1H-purine-2,6-diketone
Under-78 ℃, in nitrogen, to 8-chloro-3-amyl group-7-(2-propylene-1-yl)-1-[3-(1H-pyrazoles-4-yl) propyl group]-3,7-dihydro-1H-purine-2, the 6-diketone (61mg, (1M is in THF, 0.15ml) to add potassium tert.-butoxide in anhydrous THF (1ml) solution 0.15mmol), then add 2-chloro-5-(chloromethyl) thiophene (25mg, 0.15mmol).Continue down to stir 15min at-78 ℃, at room temperature stir 1h then, stir 18h down at 60 ℃ at last.With the solution degassing, add morpholine (0.13ml) and tetrakis triphenylphosphine palladium (O) (35mg), then continue to stir 6h.Add other quantity (0.2ml morpholine, 50mg Pd (PPh
3)
4), then continue to stir to spend the night.Carry out aftertreatment by between the HCl of EtOAc and 2M, distributing, purify, then purify, obtain the title compound (5.1mg) of white solid form with MDAP with the organic phase evaporation and with standard aminopropyl SPE method.
LC/MS：m/z?495[MH]
+，RT?3.68min.
Embodiment 267:8-chloro-3-amyl group-1-[3-(1H-pyrazoles-4-yl) propyl group]-3,7-dihydro-1H-purine
-2,6-diketone acetate
8-chloro-3-amyl group-7-(2-propylene-1-yl)-1-[3-(1H-pyrazoles-4-yl) propyl group]-3,7-dihydro-1H-purine-2,6-diketone (50mg, 0.124mmol) no water degasification THF (1.5ml) solution and tetrakis triphenylphosphine palladium (O) (29mg, 0.025mmol) and morpholine (0.108ml) in nitrogen, stir 5h together.Mixture distributes between EtOAc and 0.5M citric acid, then organic phase is separated.Carry out twice EtOAc extraction again, with the organism evaporation that merges, product uses aminopropyl SPE (2g) to purify, and loads and with THF-MeOH (1: 1) washing, with the MeOH washing, follows with DCM-MeOH (1: the 1) wash-out that contains 5%AcOH then.Yield 28.3mg.
LC/MS：m/z?365[MH]
+，RT?2.89min.
Embodiment 268:8-chloro-3-hexyl-1-(2-hydroxyethyl)-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-3-hexyl-1-(2-hydroxyethyl)-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-3-hexyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, and the 6-diketone (100mg, 0.322mmol), cesium carbonate (126mg, 0.387mmol) and ethylene chlorhydrin (29.8mg, 0.37mmol) in dry DMF (3ml) together in nitrogen at 55 ℃ of following heating 42h.Cooled mixture fully outgas and with tetrakis triphenylphosphine palladium (O) (74mg) and morpholine (0.28ml) stir 5h.Reaction is carried out aftertreatment by distributing between the HCl of EtOAc and 2M, organic phase is separated and evaporation.Resistates is loaded on the aminopropyl SPE (5g) among the THF-MeOH (1: 1), with identical solvent wash, then with pure MeOH washing, follows described product with DCM-MeOH (1: the 1) wash-out that contains AcOH (2.5% rises to 5%).Thus obtained product is further purified with MDAP, obtains title compound (38mg).
LC/MS：m/z?315[MH]
+，RT?2.79min.
B) 8-chloro-3-hexyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
To 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (226mg, 1mmol) and yellow soda ash (117mg, add in dry DMF 1.1mmol) (7ml) solution 1-iodohexane (223mg, 1.05mmol).Mixture stirs and heated 2 days down at 50 ℃.After the cooling, mixture distributes between EtOAc and water, and organic phase salt water washing is at Na
2SO
4Middle dry and evaporation.Crude product EtOAc-hexanaphthene (1: 2) recrystallization.Yield 146mg.
LC/MS：m/z?311[MH]
+，RT?3.12min.
Following compounds (table 17) is by being similar to the method preparation of embodiment 268, except that following: for embodiment 270, described scale is reduced to precursor 8-chloro-3-(3-cyclopropyl propyl group)-7-(2-propylene-1-yl)-3 of 75mg (0.243mmol), 7-dihydro-1H-purine-2,6-diketone.
Table 17
Described intermediate removes 8-chloro-3-(3-cyclopropyl propyl group)-7-(2-propylene-1-yl)-3 according to the method preparation of embodiment 268b, 7-dihydro-1H-purine-2, and the 6-diketone is with silicon-dioxide SPE (5g) purification and with beyond EtOAc-hexanaphthene (2: the 3) wash-out.
Embodiment 271:3-butyl-8-chloro-1-{3-[5-(phenyl methyl)-1,3,4-oxadiazole-2-yl] third
Base }-3,7-dihydro-1H-purine-2,6-diketone
To 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (99mg, 0.35mmol) dry DMF (2ml) solution in add cesium carbonate (137mg, 0.42mmol), then add 2-(3-chloropropyl)-5-(phenyl methyl)-1,3,4-oxadiazole (99mg, 0.42mmol) solution in dry DMF (1ml).Mixture stirs in nitrogen and heats 2.5h down at 55 ℃, at room temperature stirs then and spends the night.Mixture is by finding time repeatedly and import the nitrogen degassing, add then tetrakis triphenylphosphine palladium (O) (81mg, 0.07mmol) and morpholine (0.305ml, 3.5mmol), then continue to stir 5h, add the HCl of EtOAc and 2M, then mixture is stirred 20min, filter then.Organic phase is separated and evaporation, and product aminopropyl SPE (5g) purification with THF-MeOH (1: 1) washing, with the MeOH washing, is followed acid product DCM-MeOH (1: the 1) wash-out that contains 5% extra AcOH then.Thus obtained product is further purified with MDAP, obtains title compound (92mg).
LC/MS：m/z?443[MH]
+，RT?3.18min.
Following compounds (table 18) is by being similar to the method preparation of embodiment 271, except that embodiment 279 usefulness HPLC further purify.
Table 18
Carry out chloropropyl 1,3 by table 18,4-oxadiazole intermediate synthetic:
2-[(2-chloro-4-fluorophenyl) methyl]-5-(3-chloropropyl)-1,3, the 4-oxadiazole
2-(3-chloropropyl)-5-[(2, the 4-difluorophenyl) methyl]-1,3, the 4-oxadiazole
2-(3-chloropropyl)-5-(phenyl methyl)-1,3, the 4-oxadiazole
Diacyl hydrazide (500mg, synthetic below) stirs in dry toluene (4ml), then adds phosphorus oxychloride (4ml).Mixture is at 90 ℃ of following heating 2h, allows its cooling then, then steams to desolventize.Resistates is dissolved in the dry toluene, and evaporation is then at EtOAc and NaHCO
3Distribute between the aqueous solution.Organic phase salt water washing is at Na
2SO
4Middle dry, evaporate, obtain the Suo Xu oxadiazole of water white oil form.These do not have the xanthine reaction of further purifying just direct and above-mentioned.
The preparation of 4-chloro-N '-(phenylacetyl) daminozide
At room temperature, to the 4-chlorobutanoylchloride (1.12ml, in 40min, drip in anhydrous DCM (10ml) solution 10mmol) the phenyl acethydrazide (1.5g, 10mmol) and DIPEA (1.77ml, 10.2mmol) mixture in anhydrous DCM (40ml).Generate thick white precipitate.Behind 20min.Add the HCl (30ml) of 2M, leach title compound (white solid), wash with water and dry (2.24g).
LC/MS：m/z?255[MH]
+，RT?2.20min.
The preparation of 4-chloro-N '-[(2-chloro-4-fluorophenyl) ethanoyl] daminozide
(i) solution of 2-chloro-4-fluorophenyl Acetyl Chloride 98Min. (10mmol) in anhydrous DCM (15ml) is joined tert-butyl carbazate (t-butyl carbazate) (1.32g in 20min, 10mmol) and DIPEA (1.77ml is 10.2mmol) in the mixture in anhydrous DCM (20ml).Behind the restir 2h, mixture is used NaHCO then with the HCl washing of 1M
3Solution washing.Separate out white solid this moment, this solid is leached, and water and DCM washing, dry then, obtain 2-[(2-chloro-4-fluorophenyl) ethanoyl] and hydrazine carboxylic acid 1,1-dimethyl ethyl ester (1.94g).
(ii) (1.92g 6.34mmol) is suspended in the diox (2ml), then adds HCl De diox (5ml) solution of 4M with this compound.Generate thick white precipitate.Behind the 1h, mixture is at EtOAc and saturated NaHCO
3Distribute organic phase salt water washing, dry (Na between the aqueous solution
2SO
4), evaporate, obtain 2-(the 2-chloro-4-fluorophenyl) acethydrazide (1.07g) of white solid form.
(iii) in 20min, with 2-(2-chloro-4-fluorophenyl) acethydrazide (909mg, 4.5mmol) and DIPEA (0.817ml, 4.7mmol) mixture in anhydrous DCM (65ml) join 4-chlorobutanoylchloride in anhydrous DCM (5ml) (0.505ml, 4.5mmol) in.1.5h after, the HCl of adding 2M filters 4-chloro-N '-[(the 2-chloro-4-fluorophenyl) ethanoyl] daminozide of separating out, and washes with water and dry (1.24g).
LC/MS：m/z?307[MH]
+，RT?2.61min.
2-(3-chloropropyl)-5-[(2, the 4-difluorophenyl) methyl]-1,3, the preparation of 4-oxadiazole
(i) in 10min, the solution of 2,4 difluorobenzene base Acetyl Chloride 98Min. (10mmol) in anhydrous DCM (15ml) joined tert-butyl carbazate (1.32g, 10mmol) and DIPEA (1.77ml is 10.2mmol) in the mixture in anhydrous DCM (20ml).After stirring 1.5h, mixture is used NaHCO then with the HCl washing of 1M
3Solution washing.Organic phase is evaporated, and obtains the 2-[(2 of white solid form, the 4-difluorophenyl) ethanoyl] hydrazine carboxylic acid 1,1-dimethyl ethyl ester.
(ii) 2-[(2, the 4-difluorophenyl) ethanoyl] hydrazine carboxylic acid 1, (10mmol) De diox (5ml) solution stirs 1.5h with HCl De diox (8ml) solution of 4M to 1-dimethyl ethyl ester.Mixture is at EtOAc and saturated NaHCO
3Distribute between the aqueous solution, then with organic phase salt water washing, dry (Na
2SO
4) and evaporation.Reaction is incomplete, so resistates stirs 2.5h with HCl De diox (10ml) solution of 4M once more.As above aftertreatment obtains 2-(2,4 difluorobenzene base) acethydrazide (570mg) of solid form.
(iii) in 15min, with 2-(2,4 difluorobenzene base) acethydrazide (570mg, 3.06mmol) and DIPEA (0.553ml, 3.2mmol) mixture in anhydrous DCM (30ml) joins the 4-chlorobutanoylchloride (0.343ml is in anhydrous DCM (5ml) solution 3.06mmol).Form a kind of precipitation of white immediately.After stirring 1h, add the HCl (20ml) of 2M, cross filter solid 2-(3-chloropropyl)-5-[(2, the 4-difluorophenyl) methyl]-1,3, the 4-oxadiazole washes with water and dry (726mg).
LC/MS：m/z?291[MH]
+，RT?2.45min.
Embodiment 280:3-butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl) butyl]-3,7-dihydro-1H-
Purine-2, the 6-diketone
A) 3-butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl) butyl]-3,7-dihydro-1H-purine-2,6-diketone
In nitrogen, with 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (100mg, 0.354mmol) and 4-(3-phenyl-5-isoxazolyl)-1-butanols (77mg 0.355mmol) is dissolved among the anhydrous THF (4ml).Adding azo-2-carboxylic acid dibenzyl ester (94%, 224mg, 0.708mmol) solution in anhydrous THF (2ml).Mixture is cooled to 0 ℃, adds triphenylphosphine (185mg, 0.708mmol) solution in anhydrous THF (1ml).Mixture is stirred 20min down at 0 ℃, at room temperature stir then and spend the night.Then, with the mixture degassing, (82mg) stir 4.5h with morpholine (0.308ml) and tetrakis triphenylphosphine palladium (O).The tetrakis triphenylphosphine palladium (O) that adds 60mg more then continues to stir to spend the night.Be reflected to distribute between the HCl of EtOAc and 2M and carry out aftertreatment, the organic phase evaporation is also purified with aminopropyl SPE (5g), with THF-MeOH (1: 1) washing, with the MeOH washing, then uses DCM-MeOH (1: the 1) wash-out that contains 5% extra AcOH then.Further purify by MDAP, obtain title compound (56mg).
LC/MS：m/z?442[MH]
+，RT?3.59min.
B) 4-(3-phenyl-5-isoxazolyl)-1-butanols
To N-hydroxybenzene auxotox radical chlorine (N-hydroxybenzenecarboximidoyl chloride) (622mg, add in anhydrous DCM (6ml) solution 4mmol) 5-hexin-1-alcohol (431mg, 4.4mmol).Mixture is cooled to 0 ℃ in nitrogen, then in 10min, drip triethylamine (0.612ml, 4.4mmol).Stir 20min down at 0 ℃ again, at room temperature stir then and spend the night.Mixture is washed with water the organic phase evaporation.Product is purified with silicon-dioxide SPE (20g), with EtOAc-hexanaphthene (1: 2,3: 1 then) wash-out, obtains white waxy solid (443mg).
LC/MS：m/z?218[MH]
+，RT?2.74min.
Embodiment 281:3-butyl-8-chloro-1-{3-[3-(phenyl methyl)-5-isoxazolyl] propyl group }-3, the 7-dihydro
-1H-purine-2, the 6-diketone
A) 3-butyl-8-chloro-1-{3-[3-(phenyl methyl)-5-isoxazolyl] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
Similar 3-butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl) butyl]-3,7-dihydro-1H-purine-2,6-diketone (embodiment 280) is prepared, use the molar weight of half, from 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (50mg, 0.177mmol) and 3-[3-(phenyl methyl)-5-isoxazolyl]-1-propyl alcohol (38.4mg, 0.177mmol) beginning.Yield 24.2mg, LC/MS:m/z 442[MH]
+, RT 3.43min.
B) 3-[3-(phenyl methyl)-5-isoxazolyl]-the 1-propyl alcohol
(3-phenyl-5-isoxazolyl)-the 1-butanols is the same synthetic with 4-, use N-hydroxyl-2-phenyl second imino-chlorine (253mg, 1.5mmol) and 4-pentyne-1-alcohol (139mg, 1.65mmol).Obtain the light yellow oil of 61mg.
LC/MS：m/z?218[MH]
+，RT?2.62min.
Embodiment 282:3-butyl-8-chloro-1-{3-[(3-phenyl-1,2,4-oxadiazole-5-yl) sulphur] propyl group }-3,7-
Dihydro-1H-purine-2, the 6-diketone
A) 3-butyl-8-chloro-1-{3-[(3-phenyl-1,2,4-oxadiazole-5-yl) sulphur] propyl group }-3,7-dihydro-1H-purine-2,6-diketone
By 3-butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl) butyl]-3; 7-dihydro-1H-purine-2; the method preparation of 6-diketone is from 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2; 6-diketone (100mg; 0.354mmol) and 3-[(3-phenyl-1,2,4-oxadiazole-5-yl) sulphur]-1-propyl alcohol (83.5mg; 0.354mmol) beginning, except that the adding second aliquot 250mg tetrakis triphenylphosphine palladium (O) during the deprotection steps.Yield 19.6mg
LC/MS：m/z?461[MH]
+，RT?3.75min.
B) 3-[(3-phenyl-1,2,4-oxadiazole-5-yl) sulphur]-the 1-propyl alcohol
To 3-phenyl-1,2,4-oxadiazole-5 (2H)-thioketones (178mg, add in anhydrous THF (3ml) solution 1mmol) DIPEA (0.174ml, 1mmol) and 3-bromo-1-propyl alcohol (139mg, 1mmol).Continue to stir 65h, mixture distributes between EtOAc and water then.Organic phase salt water washing, dry (Na
2SO
4) and evaporation, obtain buttery title compound (235mg).
LC/MS：m/z?237[MH]
+，RT?2.94min.
Embodiment 283:3-butyl-8-chloro-1-{2-[(3-phenyl-1,2,4-oxadiazole-5-yl) sulphur] ethyl }-3,7-
Dihydro-1H-purine-2, the 6-diketone
A) 3-butyl-8-chloro-1-{2-[(3-phenyl-1,2,4-oxadiazole-5-yl) sulphur] ethyl }-3,7-dihydro-1H-purine-2,6-diketone
By be similar to embodiment 270 (3-butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl) butyl]-3,7-dihydro-1H-purine-2, the 6-diketone) method preparation, from 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (141mg, 0.5mmol) and 2-[(3-phenyl-1,2,4-oxadiazole-5-yl) sulphur] ethanol (111mg, 0.5mmol) beginning.Single part tetrakis triphenylphosphine palladium (O) is used for deprotection steps, still, continues to stir 6h.Purify by aminopropyl SPE, then purify, obtain the title compound (33.1mg) of white solid form by MDAP.
LC/MS：m/z?447[MH]
+，RT?3.67min.
B) 2-[(3-phenyl-1,2,4-oxadiazole-5-yl) sulphur] ethanol
Can be by similar 3-[(3-phenyl-1,2,4-oxadiazole-5-yl) sulphur]-mode of 1-propyl alcohol obtains title compound by ethylene bromohyrin, purifies after the reaction times and by silicon-dioxide SPE (ethyl acetate-hexanaphthene 1: 1) at 24h.Yield 176mg.
LC/MS：m/z?223[MH]
+，RT?2.98min.
Embodiment 284:3-butyl-8-chloro-1-(2-{[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] amino }
Ethyl)-3,7-dihydro-1H-purine-2,6-diketone
A) 3-butyl-8-chloro-1-(2-{[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] amino } ethyl)-3,7-dihydro-1H-purine-2,6-diketone
3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (64.4mg, 0.228mol), 2-{[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] amino } (50mg is 0.228mmol) with azo-2-carboxylic acid's dibenzyl ester (136mg for ethanol, 0.456mmol) in anhydrous THF (3ml), drip triphenylphosphine (119mg, anhydrous THF (1ml) solution 0.456mmol) down at 0 ℃.Mixture is stirred 10min down at 0 ℃.At room temperature stirring 2 then spends the night.The fully degassing, (53mg 0.046mmol) stirs 5h together with morpholine (0.2ml) and tetrakis triphenylphosphine palladium (O).Then, add the catalyzer of other 53mg, then continue to stir and spend the night.Be reflected to distribute between the HCl of EtOAc and 2M and carry out aftertreatment, the organic phase evaporation is also purified with aminopropyl SPE (5g), with THF-MeOH (1: 1) washing, with the MeOH washing, then uses DCM-MeOH (1: the 1) wash-out that contains 5%AcOH then.Further purify by MDAP, obtain title compound (11.8mg).
LC/MS：m/z?444[MH]
+，RT?3.12min.
B) 2-{[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] amino } ethanol
With 3-(phenyl methyl)-5-(trichloromethyl)-1,2, (140mg, dry DMF 0.505mmol) (2ml) solution stirs 1.5h with thanomin (0.25ml) to the 4-oxadiazole.Mixture distributes between EtOAc and water, organic phase water, salt water washing, dry (Na
2SO
4) and evaporation, obtain white waxy solid (87mg).
LC/MS：m/z?220[MH]
+，RT?2.22min.
Embodiment 285:3-butyl-8-chloro-1-(2-{[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] sulphur } second
Base)-3,7-dihydro-1H-purine-2,6-diketone
A) 3-butyl-8-chloro-1-(2-{[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] sulphur } ethyl)-3,7-dihydro-1H-purine-2,6-diketone
With 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, and the 6-diketone (150mg, 0.531mmol) and 2-{[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] sulphur } ethanol (125mg, anhydrous THF (4ml) solution 0.530mmol) is cooled to 0 ℃, adds azo-2-carboxylic acid's dibenzyl ester (94%, 336mg, 1.06mmol) anhydrous THF (2ml) solution, then add triphenylphosphine (278mg, 1.06mmol).Mixture is stirred 15min down at 0 ℃.At room temperature stirring 2 then spends the night.(250mg 0.216mmol) joins in the de-gassed solution, behind the 5h, adds the Pd (PPh of other 100mg with morpholine (1g) and tetrakis triphenylphosphine palladium (O)
3)
4, then continue to stir 3 whole night.Be reflected to distribute between the HCl of EtOAc and 2M and carry out aftertreatment, the organic phase evaporation is also purified with aminopropyl SPE (5g), with THF-MeOH (1: 1) washing, with the MeOH washing, then uses DCM-MeOH (1: the 1) wash-out that contains 5%AcOH then.Further purify by MDAP, obtain title compound (26mg).
LC/MS：m/z?461[MH]
+，RT?3.47min.
B) 2-{[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] sulphur } ethanol
To 3-(phenyl methyl)-1,2,4-oxadiazole-5 (2H)-thioketones (384mg, add in anhydrous THF (5ml) solution 2mmol) DIPEA (0.348ml, 2mmol) and ethylene bromohyrin (250mg, 2mmol).Mixture at room temperature stirs and spends the night, and distributes between the HCl of EtOAc and 1M then.Organic phase salt water washing, drying, evaporation is purified with silicon-dioxide SPE (10g), with EtOAc-hexanaphthene (1: 2) wash-out, obtains the title compound (315mg) of colorless oil.
LC/MS：m/z?237[MH]
+，RT?2.74min.
Embodiment 286:3-butyl-8-chloro-1-{[3-(3-phenyl propyl)-1,2,4-oxadiazole-5-yl] first
Base }-3,7-dihydro-1H-purine-2,6-diketone
A) 3-butyl-8-chloro-1-{[3-(3-phenyl propyl)-1,2,4-oxadiazole-5-yl] methyl }-3,7-dihydro-1H-purine-2,6-diketone
(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl acetate (66mg, 0.2mmol) and (1Z)-N-hydroxy-4-phenyl fourth amidine (39mg, 0.22mmol) in dehydrated alcohol (1ml) with sodium ethylate (21%wt solution, 0.111ml, 0.3mmol) stir together, then under microwave radiation, heat 10min down at 140 ℃.The refrigerative mixture distributes between ethyl acetate and 2M hydrochloric acid, and organic phase is separated and evaporation.Product is purified with MDAP, obtains the title compound (31.5mg) of solid form.
LC/MS：m/z?443[MH]
+，RT?3.56min.
B) (3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl acetate
3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (1.5g, 5.31mmol) and cesium carbonate (1.903g 5.84mmol) stirs in dry DMF (25ml).(0.648ml 5.84mmol), then stirs mixture down at 55 ℃ and spends the night to add ethyl bromoacetate.Cooled mixture use the nitrogen degassing and with tetrakis triphenylphosphine palladium (O) (1g) and morpholine (3.73ml) stir 4.5h.Mixture distributes between the HCl of ethyl acetate (80ml) and 2M (50ml).Organic phase is filtered, at Na with the water washing of 3x80ml salt
2SO
4Middle dry and evaporation.Product aminopropyl SPE (20g) purification with THF-MeOH (1: 1) washing, with pure MeOH washing, is followed product DCM-MeOH (1: the 1) wash-out that contains acetate (2.5% rises to 5%) then, and it obtains pure title compound (1.16g).
LC/MS：m/z?329[MH]
+，RT?2.87min.
Embodiment 287:3-butyl-8-chloro-1-{[3-(2-phenylethyl)-1,2,4-oxadiazole-5-yl] first
Base }-3,7-dihydro-1H-purine-2,6-diketone
Synthetic by the method that is similar to embodiment 286, from (1Z)-N-hydroxyl-3-phenyl third amidine.Yield 22.6mg.
LC/MS：m/z?429[MH]
+，RT?3.43min.
Embodiment 288:3-butyl-8-chloro-1-{2-[3-(2-phenylethyl)-1,2,4-oxadiazole-5-yl] second
Base }-3,7-dihydro-1H-purine-2,6-diketone
Synthetic by the method that is similar to embodiment 286, begin from (1Z)-N-hydroxyl-3-phenyl third amidine and 3-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl propionate.Yield 23.3mg.
LC/MS：m/z?443[MH]
+，RT?3.40min.
Embodiment 289:3-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) propionic acid
Ethyl ester
About (3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) ethyl acetate is synthetic, from 3-ethyl bromide (0.749ml, 5.84mmol) beginning, except following, after initial heated overnight, add other 3-ethyl bromide (1.5ml), again reheat 4h, add the cesium carbonate (1.903g) of part in addition then, behind the 2h, add the 3-ethyl bromide (1.5ml) of third part.Continue heating second whole night down at 55 ℃ then, then as above-mentioned aftertreatment and the deprotection of carrying out.Yield 0.404g.
LC/MS：m/z?343[MH]
+，RT?2.90min.
Following compounds (table 19) is by being similar to the method preparation of embodiment 3, and wherein any change is illustrated among the method A-F.
Table 19
Method A: be similar to embodiment 3
Method B: be similar to method A, except that material is used preparation HPLC purification automatically after using aminopropyl SPE purification.
Method C: be similar to method A, after purifying with aminopropyl SPE except that material washes with water the purification.
Method D: be similar to method A, except that material after purifying with aminopropyl SPE with the MDAP purification.
Method E: be similar to method A, remove material after at first purifying, outside purifying with SCXSPE with aminopropyl SPE.
Method F: be similar to method A, remove material and purify, use outside the Zorbax phenyl post with preparation property HPLC.
Embodiment 321:8-chloro-1-[3-(ethyl oxygen base) ethyl]-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-
Purine-2, the 6-diketone
A) 8-chloro-1-[3-(ethyl oxygen base) ethyl]-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-diketone
In the greenhouse pipe that agitator is housed, add cesium carbonate (85mg, 0.26mmol), then add 8-chloro-7-(2-propylene-1-yl)-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-diketone (69mg, 0.22mmol) solution in dry DMF (1ml), add 1-bromo-3-(ethyl oxygen base) ethane (60mg, 0.39mmol) solution in dry DMF (1ml) then.Mixture is heated to 80 ℃ in nitrogen, 5h allows its cool to room temperature 16h then.Reaction mixture uses traditional vacuum to concentrate.THF (2.5ml) is joined in the mixture, then add Pd (PPh
3)
4(30mg, 0.026mmol) and morpholine (190uL 2.2mmol), at room temperature stirs 72h with mixture then in nitrogen.Mixture distributes between the HCl of 2N (2ml) and chloroform (4ml), uses the hydrophobic glass material that organic layer is separated, and water layer extracts with chloroform (2x4ml).The organic layer that merges under reduced pressure concentrates, and is loaded into then on 1: 1 aminopropyl SPE (5g) among the DCM/MeOH, with DCM/MeOH washing in 1: 1, then uses 1 of 20%-80% acetate: the 1DCM/MeOH eluant solution.Under reduced pressure remove and desolvate, obtain the title compound (70mg, 93%) of solid form.
1H?NMR(MeOD)δ：1.11(t，3H，J＝7Hz)，3.51(q，2H，J＝7Hz)，3.64(t，2H，J＝6Hz)，4.18(t，2H，J＝6Hz)，4.73(q，2H，J＝9Hz).
LC/MS：m/z?341[MH]
+，RT?2.72min.
B) 8-chloro-7-(2-propylene-1-yl)-3-(2,2, the 2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-diketone
At 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (1.5g, 6.62mmol) dry DMF (50ml) solution and yellow soda ash (980mg, 9.25mmol) and 1,1, (1.2g 5.71mmol) at room temperature stirs 18h to 1-three fluoro-2-iodoethane together in nitrogen.Mixture heats 6h down at 50 ℃, is cooled to room temperature and restir 10h then.Mixture heats 4h down at 120 ℃, adds 1,1 again, and (426mg 2.03mmol), then heats 3h with reaction mixture down at 120 ℃ to 1-three fluoro-2-iodoethane again.Reaction mixture is under reduced pressure concentrated.
The 8-chloro-7-of quantity (2-propylene-1-yl)-3 in addition, 7-dihydro-1H-purine-2,6-diketone (3.8g, 16.8mmol) dry DMF (125ml) solution and yellow soda ash (2.5g, 23.1mmol) and 1,1,1-three fluoro-2-iodoethane (4.1g, 19.5mmol) stir together, then reaction mixture is heated 16h under 120 ℃ in nitrogen.This reaction mixture and thick material before merge, and then under reduced pressure concentrate.Resistates is developed with DCM, and mixture is filtered, and filtrate under reduced pressure concentrates, and is dissolved in then among the DCM (20ml).This material of 10ml is purified with silicon-dioxide chromatogram, use the 100g silica column, this title compound is with the ethyl acetate/hexanaphthene wash-out of suitable gradient.Remaining 10ml uses silicon-dioxide RediSep post (130g) to purify on Companion, and this title compound is with the ethyl acetate/hexanaphthene wash-out of suitable gradient.The cut that contains title compound of two kinds of purification modes is merged, under reduced pressure concentrate, obtain the title compound (1.6g, 22% total recovery) of white solid form.
LC/MS：m/z?309[MH]
+，RT?2.59min.
Embodiment 322:8-chloro-1-[3-(2, the 6-dichlorophenyl) propyl group]-3-amyl group-3,7-dihydro-1H-purine
-2,6-diketone, sodium salt
To 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (40mg, 0.14mmol) go into cesium carbonate (49mg in the solution that in dry DMF (0.25ml), adds, 0.15mmol), then add 2-(3-bromopropyl)-1,3-dichlorobenzene (54mg, 0.20mmol) solution in dry DMF (0.25ml).Mixture stirs 16h down at 60 ℃, adds Pd (PPh then
3)
4(16mg, 0.014mmol), (118uL 1.4mmol), and then stirs 16h with mixture then to add morpholine.Use vacuum centrifuge to remove and desolvate, sample is dissolved among the DMSO (0.25ml), be loaded into then on the C18SPE (5g).The NaOH (0.5ml) that adds 2N, with the ammonia/water/MeCN of suitable gradient with this product of wash-out.Separate the title compound (52mg, 83%) that obtains solid form.
1H NMR (DMSO-d
6) δ: 0.84 (t, 3H, J=7Hz), 1.18-1.36 (m, 4H), 1.55-1.69 (m, 2H), 1.69-1.85 (m, 2H), 2.78-2.89 (m, 2H), 3.85 (t, 2H, J=7Hz), 3.95 (t, 2H, J=7Hz), 7.23 (dd, 1H, J=9 and 7Hz), 7.41 (d, 2H, J=7Hz).
LC/MS：m/z?445[MH]
+，RT?4.05min.
Following compounds (table 20) uses the method that is similar to embodiment 322 to be prepared by corresponding haloalkane:
Table 20
Method A: be similar to embodiment 3
Method B: be similar to method A, but after concentrating by traditional vacuum, material distributes between the HCl of 2M and DCM, and water layer separates, and purifies in the mode described in the method A with C18SPE then.
Method C: be similar to method A, but after concentrating by traditional vacuum, material distributes between the HCl of 2M and DCM, prepare HPLC automatically after, product separates from organic layer.
Method D: be similar to method A, but product separates with aminopropyl SPE.
Method E: be similar to method A, but material water/MeOH/MeCN/TFA with suitable gradient on phenyl HPLC purifies further, prepare HPLC then automatically, with the water/acetonitrile of suitable gradient.
Following compounds (table 21) is used the method preparation be similar to embodiment 142, by corresponding acid and (1Z)-and 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl fourth amidine.
Table 21
Embodiment 353:3-butyl-8-chloro-1-(2-{[4-(2-thienyl) phenyl] the oxygen base } ethyl)-3, the 7-dihydro
-1H-purine-2, the 6-diketone
Contain the 2-thienyl boric acid (16mg that packs in the microwave phial of magnetic stirring bar, 0.125mmol), the 1-{2-[(4-bromophenyl) the oxygen base] ethyl-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-diketone (50mg, 0.113mmol), aqueous sodium carbonate (1ml, 1M solution) and glycol dimethyl ether (1ml).This mixture outgases with nitrogen, adds Pd (PPh then
3)
2Cl
2(4mg, 5.6x10
-6Mol).Cover reaction mixture, under 140 ℃, in microwave, heat 15min (pressure arrives 7 crust).(2M, 1.5ml) acidifying with chloroform (2x1ml) washing, then separate each phase to crude product mixture with HCl.With the organism evaporation that merges, crude product is purified with MDAP, obtains title compound (10mg).
LC/MS：m/z?445[MH]
+，RT?3.76min
Embodiment 354:3-butyl-8-chloro-1-(2-{[4-(4-methyl-2-thienyl) phenyl] the oxygen base } second
Base)-3,7-dihydro-1H-purine-2,6-diketone
Contain (4-methyl-2-thienyl) boric acid (18mg that packs in the microwave phial of magnetic stirring bar, 0.125mmol), the 1-{2-[(4-bromophenyl) the oxygen base] ethyl-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-diketone (50mg, 0.113mmol), aqueous sodium carbonate (1ml, 1M solution) and glycol dimethyl ether (1ml).This mixture outgases with nitrogen, adds Pd (PPh then
3)
2Cl
2(4mg, 0.0056mmol).Cover reaction mixture, under 140 ℃, in microwave, heat 15min (pressure arrives 7 crust).(2M, 1.5ml) acidifying with chloroform (2x1ml) washing, then separate each phase to crude product mixture with HCl.With the organism evaporation that merges, crude product is purified with MDAP, obtains title compound (17mg).
LC/MS：m/z?459[MH]
+，RT?3.9min
Embodiment 355:1-{2-[(4-bromophenyl) oxygen base] ethyl }-3-butyl-8-chloro-3,7-dihydro-1H-purine
-2, the 6-diketone
A) oxygen base 1-{2-[(4-bromophenyl)] ethyl }-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-diketone
The 1-{2-[(4-bromophenyl) oxygen base] ethyl }-3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (2.3g 4.8mmol) stirs in the mixture of the DCM (40ml) of the nitrogen degassing and AcOH (4ml) the 6-diketone.Add tetrakis triphenylphosphine palladium (1.1g, 0.896mmol) and phenyl silane (5.9ml 48mmol), follows mixture and at room temperature stirs 2h.Then, with this evaporation, the resistates ether: the mixture of hexanaphthene (1: 2) is developed, and obtains the title compound (1.02g, 49%) of white solid form.
LC/MS：m/z?441/443[MH]
+，RT?3.6min
B) oxygen base 1-{2-[(4-bromophenyl)] ethyl }-3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
At 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (2.8g adds Cs in dry DMF 9.8mmol) (50ml) solution to the 6-diketone
2CO
3(6.4g, 19.6mmol), then add 2-brooethyl 4-bromophenyl ether (3.6g, 13mmol).Mixture heats 17h down at 80 ℃, then with its cooling.The reaction mixture evaporation, crude product distributes between EtOAc and HCl (2N).Organic phase separated and use salt water washing, drying (MgSO
4), evaporation obtains crude product.This crude product is purified with silicon-dioxide SPE (50g), use hexanaphthene: (10: 1-1: 1) wash-out obtains the title compound (2.9g, 62%) of beige solid form to ethyl acetate.
LC/MS：m/z?381/483[MH]
+，RT?3.87min.
Embodiment 356:1,1 '-(1,4-fourth two bases) two (3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-diketone)
A) 1,1 '-(1,4-fourth two bases) two (3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-diketone)
1,1 '-(24mg 0.039mmol) stirs in the mixture of the DCM (2ml) of the nitrogen degassing and AcOH (0.2ml) (1,4-fourth two bases) two [3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone].Add tetrakis triphenylphosphine palladium (38mg, 0.033mmol) and phenyl silane (42uL 0.39mmol), follows mixture and at room temperature stirs 2h.Then, with mixture evaporation, crude product is with reverse-phase chromatography purify (5-95% gradient, H
2O: CH
3CN), obtain title compound (2mg).
LC/MS：m/z?539[MH]
+，RT?3.33min
B) 1,1 '-(1,4-fourth two bases) two [3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone]
At 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (60mg adds Cs in dry DMF 0.212mmol) (1ml) solution to the 6-diketone
2CO
3(207mg 0.636mol), then adds 1, and 4-two iodo butane (16ul, 0.106mmol).Mixture heats 17h down at 80 ℃, then with its cooling.Reaction mixture distributes between DCM and HCl (2M).Organic phase separated and use salt water washing, drying (MgSO
4), evaporation obtains crude product.This crude product is purified with MDAP, obtain the title compound (24mg) of beige solid form.
LC/MS：m/z?619[MH]
+，RT?3.95min.
Following compounds (table 22) is used the method preparation that is similar to embodiment 356.
Table 22
Embodiment 359:8-chloro-1-[2-(ethyl oxygen base) ethyl]-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-
Purine-2, the 6-diketone
8-chloro-7-(2-propylene-1-yl)-3-(4,4,4-trifluoro butyl)-3,7-dihydro-1H-purine-2,6-diketone (84mg, 0.25mmol) cesium carbonate (163mg of the solution in DMF (1ml), 0.5mmol) and 1-bromo-2-(ethyl oxygen base) ethane (42mg, 0.275mmol) processing.Mixture is 80 ℃ of heating 4h, coolings then down.
Reaction mixture outgases with nitrogen, and (29mg 0.025mmol) handles, and then stirs 4h to use morpholine (220uL) and tetrakis triphenylphosphine palladium then.Reaction mixture distributes between chloroform and HCl (2M).Organic phase is separated and evaporation.Crude product is loaded on the aminopropyl SPE.The non-acidic impurities mixture wash-out of DCM and MeOH, the required product DCM eluant solution of 10%AcOH.Evaporation obtains title compound (77mg).
LC/MS：m/z?369[MH]
+，RT?1.96min.
Embodiment 360:8-chloro-3-propyl group-1-{4-[3-(2-pyridyl)-1,2,4-oxadiazole-5-yl] fourth
Base }-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-3-propyl group-1-{4-[3-(2-pyridyl)-1,2,4-oxadiazole-5-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-7-(2-propylene-1-yl)-1-{4-[3-(2-pyridyl)-1,2,4-oxadiazole-5-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone (40mg, 0.09mmol) solution in DMF (3ml) with salt of wormwood (15mg, 0.11mmol) and propyl iodide (19mg, 0.11mmol) processing.Mixture heats 3h down at 40 ℃, then at 70 ℃ of following reheat 3h.Mixture cooling and by using vacuum and nitrogen to outgas successively.Then, mixture with tetrakis triphenylphosphine palladium (O) (10mg, 0.009mmol) and morpholine (0.1ml, solution-treated 1.2mmol), then the stirring spend the night.The mixture evaporation also distributes between chloroform (2ml) and water (2ml).Water is further used chloroform (2ml) extraction, and the organism evaporation of merging is dissolved in resistates in the methyl alcohol (2ml).Solution is applied on the 1g aminopropyl SPE, uses methanol-eluted fractions, use the methanol solution wash-out of 5% acetate then.Merge and contain the product cut, evaporation, product is further purified with MDAP, obtains the 8-chloro-3-propyl group-1-{4-[3-(2-pyridyl)-1,2 of white solid form, 4-oxadiazole-5-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone (1.4mg).
LC/MS：m/z?430[MH]
+，RT?2.84min.
B) 8-chloro-7-(2-propylene-1-yl)-1-{4-[3-(2-pyridyl)-1,2,4-oxadiazole-5-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone
(1.15g, 8.4mmol) (0.38g 7.0mmol) handles the suspension in anhydrous THF (20ml) N-hydroxyl-2-picolyl ether, then mixture is stirred 5min with sodium methylate.This mixture 5-[8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] (2g 5.6mmol) handles Valeric acid ethylester, follows stir about 5min, till the total material dissolving.Then, with the mixture sealing, heat 15min down at 120 ℃ in microwave, cooling then distributes between ethyl acetate (100ml) and saturated sodium bicarbonate aqueous solution (50ml) then.Water is used ethyl acetate (50ml) extraction again, with the organism drying (MgSO that merges
4), filter and evaporation.Product is purified with flash chromatography, with 1: 9 ethyl acetate/hexanaphthene-ethyl acetate gradient elution, obtains 8-chloro-7-(2-propylene-1-the yl)-1-{4-[3-(2-pyridyl)-1 of white solid form, 2,4-oxadiazole-5-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone (1.49g).
LC/MS：m/z?428[MH]
+，RT?2.70min.
Preparation is 8-chloro-1-(3-{3-[(2 similarly, the 4-difluorophenyl) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone, with 4-[8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] ethyl butyrate.
LC/MS：m/z?463[MH]
+，RT?3.09min.
C) the 5-[8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] Valeric acid ethylester
8-chloro-7-(2-propylene-1-yl)-3-({ [2-(trimethyl silyl) ethyl] oxygen base } methyl)-3,7-dihydro-1H-purine-2,6-diketone (10g, 28mmol) salt of wormwood (the 4.8g of the solution in DMF (10ml), 35mmol) with 5-bromine Valeric acid ethylester (6.5g, 31mmol) handle, be heated to 70 ℃ of 3h then, cooling and evaporation.Resistates distributes between ethyl acetate (100ml) and water (50ml).Organic phase drying (MgSO
4), filter and evaporation, described thick intermediate is dissolved in the methylene dichloride (90ml), handle with trifluoroacetic acid (17ml), then mixture is stirred at ambient temperature and spend the night.Add toluene (50ml), then mixture is evaporated to dried.Product is purified with flash chromatography, with hexanaphthene-ethyl acetate gradient elution, obtains the 5-[8-chloro-2 of the 8.65g of white solid form, 6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] Valeric acid ethylester.
LC/MS：m/z?355[MH]
+，RT?2.75min.
Preparation is a 4-[8-chloro-2 similarly, 6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] ethyl butyrate.
LC/MS：m/z?341[MH]
+，RT?2.61min.
D) 8-chloro-7-(2-propylene-1-yl)-3-({ [2-(trimethyl silyl) ethyl] oxygen base } methyl)-3,7-dihydro-1H-purine-2,6-diketone
To 8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (5g 22.1mmol) adds 2-2-(trimethyl silyl) ethoxyl methyl chlorine (4.3ml to the 6-diketone in the solution in DMF (80ml), 24.2mmol) and yellow soda ash (2.6g, 24.2mmol).At room temperature stir spend the night after, adds other 2-2-(trimethyl silyl) ethoxyl methyl chlorine (4.3ml, 24.2mmol) and yellow soda ash (1.3g, 12.1mmol), then continuation stirring 2h.Then, reaction mixture distributes between the 5%LiCl aqueous solution and ethyl acetate.Separate organic extract liquid, use the salt water washing, dry (MgSO
4) and concentrate.Pass through Biotage
TMChromatogram is purified, and uses silica column, and with 1: 4-1: 2 ethyl acetate/hexanaphthene wash-out obtain title compound (3.14g, 40%).
m/z?374[MNH
4 +]
Following compounds (table 23) is by being similar to the method preparation of embodiment 360, with 8-chloro-7-(2-propylene-1-yl)-1-{4-[3-(2-pyridyl)-1,2,4-oxadiazole-5-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone and suitable alkylating reagent.
Table 23
Following compounds (table 24) is by being similar to the method preparation of embodiment 360, with 8-chloro-1-(3-{3-[(2,4-difluorophenyl) methyl]-1,2,4-oxadiazole-5-yl } propyl group)-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone and suitable alkylating reagent.
Table 24
Embodiment 398:1-[3-(3-bromophenyl) propyl group]-8-chloro-3-amyl group-3,7-dihydro-1H-purine-2,6-two
Ketone
3-(3-bromophenyl)-third-1-alcohol (1.627g, 7.56mmol) solution in THF (65ml) is used 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3 in nitrogen, 7-dihydro-1H-purine-2, (2.04g 6.87mmol) handles the 6-diketone.Behind the 2min, with PPh
3(2.164g 8.25mmol) joins in the mixture under stirring, passes through 6min again, and disposable adding DBAD (1.9g, 8.25mmol).Mixture stirs 2.5h, reacts 16h then.Mixture is introduced nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(794mg 0.69mmol), then outgases mixture once more.(6ml 68.8mmol), then stirs 6h with mixture in nitrogen to add morpholine.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Resistates is dissolved among the MeOH, purifies product 2-5%AcOH/MeOH wash-out with aminopropyl SPE.Obtain the title compound (2.48g, 79%) of pale solid form.
LC/MS：m/z?455，453[MH]
+，RT?3.85min.
Embodiment 399:8-chloro-1-{2-[(3-hydroxy phenyl) oxygen base] ethyl }-3-amyl group-3,7-dihydro-1H-is fast
Purine-2,6-diketone and embodiment 400:8-chloro-1-(2-{[3-(the 2-[(3-hydroxy phenyl) and the oxygen base] ethyl } the oxygen base) benzene
Base] the oxygen base } ethyl)-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
2-(2-hydroxyethyl)-Resorcinol (1.156g, 7.5mmol) solution in THF (60ml) is used 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3 in nitrogen, 7-dihydro-1H-purine-2, (2.016g 6.79mmol) handles the 6-diketone.Behind the 4min, with PPh
3(2.138g 8.15mmol) joins in the mixture under stirring, passes through 8min again, and disposable adding DBAD (1.88g, 8.16mmol).Mixture stirs 1h50min, reacts 16h then.Mixture is introduced nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(785mg 0.68mmol), then outgases mixture once more.(5.9ml 67.7mmol), then stirs 4.5h with mixture in nitrogen to add morpholine.Mixture distributes between the HCl of 2M (aq) and EtOAc.Separate organic layer, use the salt water washing, dry (MgSO
4) and concentrate.Resistates is dissolved among the MeOH, purifies product 2-5%AcOH/MeOH gradient elution with aminopropyl SPE.The evaporation of product cut be will contain, a kind of light yellow foam (2.39g) and a kind of light yellow gluey thing (213mg) obtained.Described foam is dissolved in the methylene dichloride (50ml), then by the hydrophobic glass material.Solution evaporation, dry in a vacuum, obtain the 8-chloro-1-{2-[(3-hydroxy phenyl of white solid form) the oxygen base] ethyl }-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone (1.919g, contain 15%8-chloro-1-(2-{[3-({ 2-[(3-hydroxy phenyl) oxygen base] ethyl } the oxygen base) phenyl] the oxygen base } ethyl)-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone).
Described jelly is purified with MDAP, obtains the 8-chloro-1-{2-[(3-hydroxy phenyl of white solid form) the oxygen base] ethyl }-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone (126mg).
LC/MS：m/z?393[MH]
+，RT?3.23min
And
The 8-chloro-1-of light yellow solid form (2-{[3-(the 2-[(3-hydroxy phenyl) and the oxygen base] ethyl } the oxygen base) phenyl] the oxygen base } ethyl)-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone (38mg).
LC/MS：m/z?529[MH]
+，RT?3.62min.
Following compounds (table 25) is used and is similar to top 8-chloro-1-{2-[(3-hydroxy phenyl) the oxygen base] ethyl }-3-amyl group-3,7-dihydro-1H-purine-2, the method preparation of 6-diketone is by corresponding alcohol preparation.
Table 25
Embodiment 403:8-chloro-1-(3-{3-[(3-chloro-phenyl-) oxygen base] phenyl } propyl group)-3-amyl group-3, the 7-dihydro
-1H-purine-2, the 6-diketone
With 1-[3-(3-bromophenyl) propyl group]-8-chloro-3-amyl group-3,7-dihydro-1H-purine-2, (100mg 022mmol) is dissolved in the diox (0.75ml) the 6-diketone.Cuprous iodide (1) (9mg, 0.05mmol), N, the N-dimethyl glycine hydrochloride (9mg, 0.06mmol), (215mg, 0.66mmol) (52mg 0.4mmol) joins in the described solution cesium carbonate with the 3-chlorophenol.Mixture heats 10min down at 200 ℃ under microwave radiation,, then the refrigerative mixture is filtered resistates EtOAc and MeOH washing then at 200 ℃ of following reheat 10min.Merging filtrate and washing lotion are under reduced pressure steamed and are removed, and obtain a kind of redness/brown solid.Solid is distributed between DCM and water.Separate each phase by the hydrophobic glass material, the organic phase vapourisation under reduced pressure obtains a kind of solid.Described solid is purified with MDAP, obtains yellow solid/gelationus title compound (27mg, 24%).
LC/MS：m/z?501[MH]
+，RT?4.25min.
Embodiment 404:8-chloro-3-amyl group-1-{3-[3-(phenoxy group) phenyl] propyl group }-3,7-dihydro-1H-purine
-2, the 6-diketone
With 1-[3-(3-bromophenyl) propyl group]-8-chloro-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone (100mg, 0.22mmol), cuprous iodide (1) (4mg, 0.02mmol), N, the N-dimethyl glycine hydrochloride (9mg, 0.06mmol), cesium carbonate (144mg, 0.44mmol) and phenol (31mg 0.33mmol) is put in the diox (0.44ml).Then, described mixture heats 3.3min down at 150 ℃ in microwave, then with the cesium carbonate (72mg of other quantity, 0.22mmol), cuprous iodide (1) (6mg, 0.03mmol) He diox (0.44ml) join in this mixture, then in microwave, heat 10min down, then at 200 ℃ of following reheat 10min at 170 ℃.The refrigerative mixture is filtered, and resistates washs with EtOAc.Merging filtrate and washing lotion are under reduced pressure steamed and are removed, and obtain a kind of dun coloring agent.Described glue is purified with MDAP, obtains the title compound (44mg, 42%) of shallow cream-colored solid form.
LC/MS：m/z?467[MH]
+，RT?4.14min.
Embodiment 405:8-chloro-1-[3-(3 '-chloro-3-xenyl) propyl group]-3-amyl group-3,7-dihydro-1H-purine
-2, the 6-diketone
1-[3-(3-bromophenyl) propyl group]-8-chloro-3-amyl group-3,7-dihydro-1H-purine-2, (100mg, 0.22mmol) (35mg, mixture 0.22mmol) stir in Virahol (0.35ml) the 6-diketone with the 3-chlorophenylboronic acid.(70mg, 0.66mmol) solution in water (0.35ml) joins in this mixture, then adds 10% palladium/carbon (6mg, Degussa type E101NE/W) with yellow soda ash.Mixture heats 10min down at 160 ℃ in microwave, filter (glass fiber filter paper) then, and then resistates washs with IPA.Merging filtrate and washing lotion are under reduced pressure steamed and are removed, and obtain a kind of glue.Glue is distributed between DCM and water.Organic phase is separated, and water extracts with EtOAc.With the organic phase drying (MgSO that merges
4), concentrate, obtain a kind of foam.Described foam is purified with MDAP, obtains colourless gelationus title compound (40mg, 37%).
LC/MS：m/z?485[MH]
+，RT?4.27min.
Following compounds (table 26) is used and to be similar to top 8-chloro-1-[3-(3 '-chloro-3-xenyl) propyl group]-3-amyl group-3,7-dihydro-1H-purine-2, the method preparation of 6-diketone (embodiment 405), by corresponding boric acid, but 2-chloro-phenyl-analogue heats 10min twice down at 160 ℃ in microwave, use simultaneously and carry out aftertreatment in 1M hydrochloric acid rather than in water.In addition, omit the EtOAc extraction.
Table 26
Embodiment 408:3-butyl-8-chloro-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2,6-diketone
A) 3-butyl-8-chloro-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2,6-diketone
3-butyl-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2, the 6-diketone (100mg, 0.31mmol) and NCS (41mg 0.31mmol) is suspended among the MeCN (5ml), is then heating 10min under 120 ℃ under microwave radiation.Reaction mixture under reduced pressure concentrates, and title compound uses HPLC to separate.
1H?NMR(CDCl
3)δ：0.96(3H，t)，1.37-1.43(2H，m)，1.70-1.78(2H，m)，2.00-2.09(2H，m)，2.73(2H，t)，4.08(2H，t)，4.14(2H，t)，7.13-7.26(5H，m)，12.6(1H，br.s).
LC/MS：m/z?361[MH]
+.
B) 3-butyl-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2,6-diketone
With 3-butyl-7-(phenyl methyl)-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2, (0.6g 1.44mmol) is dissolved in the acetate (35ml) the 6-diketone, add 20% palladium hydroxide/carbon (0.366g), then with this mixture shaken over night in hydrogen (50psi).Pass through Celite
Remove by filter catalyzer, then wash with acetate.Filtrate under reduced pressure concentrates, and uses HPLC to separate title compound (0.385g, 82%).
LC/MS：m/z?327[MH]
+.
C) 3-butyl-7-(phenyl methyl)-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2,6-diketone
7-benzyl-3-butyl-3,7-dihydro-1H-purine-2, the 6-diketone (0.5g, 1.68mmol) and salt of wormwood (0.347g 2.5mmol) is suspended among the DMF (20ml), add (3-bromopropyl) benzene (390mg, 1.96mmol).Reaction mixture stirred at ambient temperature spend the night.Reaction mixture is evaporated to dried, and resistates distributes between ethyl acetate and water.Organic layer washes with water, then uses the salt water washing, and is dry in anhydrous sodium sulphate, under reduced pressure concentrates, and obtains title compound.
1H?NMR(CDCl
3)δ：0.95(3H，t)，1.34-1.43(2H，m)，1.68-1.76(2H，m)，1.98-2.07(2H，m)，2.71(2H，t)，4.05-4.10(4H，m)，5.49(2H，s)，7.19-7.24(5H，m)，7.33-7.38(5H，m)，7.52(1H，s).
LC/MS：m/z?417[MH]
+.
D) 7-benzyl-3-butyl-3,7-dihydro-1H-purine-2,6-diketone
7-benzyl-3,7-dihydro-1H-purine-2, the 6-diketone (17.14g, 70.8mmol) [SyntheticCommunications, 20 (16), 2459-2467,1990] and salt of wormwood (11.43g, 82.8mmol) at 40 ℃ of low suspensions in DMF (400ml).Stir after 30 minutes, (8.76ml 77.0mmol), stirs mixture down at 40 ℃ then and spends the night to add butyl iodide.Add 50% acetic acid aqueous solution (60ml), then solution under reduced pressure concentrates.Resistates is suspended in the water (500ml), then product is extracted in the chloroform.Collect organism, concentrate, product uses flash chromatography to separate, with methylene dichloride (9.49g, the 45%) wash-out that contains 1% methyl alcohol.
1H?NMR(CDCl
3)δ：0.95(3H，t)，1.34-1.41(2H，m)，1.70-1.78(2H，m)，4.05(2H，t)，5.46(2H，s)，7.31-7.40(5H，m)，7.56(1H，s)，8.21(1H，br.s).
LC/MS：m/z?299[MH]
+.
Embodiment 409:3-butyl-8-chloro-1-[2-(phenoxy group) ethyl]-3,7-dihydro-1H-purine-2,6-diketone
A) 3-butyl-8-chloro-1-[2-(phenoxy group) ethyl]-3,7-dihydro-1H-purine-2,6-diketone
Title compound uses 3-butyl-8-chloro-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2, the method preparation of 6-diketone is with 3-butyl-1-[2-(phenoxy group) ethyl]-3,7-dihydro-1H-purine-2,6-diketone and NCS.
1H?NMR(CDCl
3)δ：0.95(3H，t)，1.36-1.45(2H，m)，1.71-1.79(2H，m)，4.11(2H，t)，4.29(2H，t)，4.54(2H，t)，6.87-6.94(3H，m)，7.21-7.27(2H，m)，13.10(1H，br.s).
LC/MS：m/z?363[MH]
+.
B) 3-butyl-1-[2-(phenoxy group) ethyl]-3,7-dihydro-1H-purine-2,6-diketone
Title compound uses 3-butyl-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2, the listed method preparation of 6-diketone is with 3-butyl-7-(phenyl methyl)-1-[2-(phenoxy group) ethyl]-3,7-dihydro-1H-purine-2,6-diketone.
LC/MS：m/z?329[MH]
+.
C) 3-butyl-7-(phenyl methyl)-1-[2-(phenoxy group) ethyl]-3,7-dihydro-1H-purine-2,6-diketone
Title compound uses 3-butyl-7-(phenyl methyl)-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2, and the method preparation that the 6-diketone is listed is with 7-benzyl-3-butyl-3,7-dihydro-1H-purine-2,6-diketone and 2 bromoethyl benzene base ether.
1H?NMR(CDCl
3)δ：0.95(3H，t)，1.35-1.44(2H，m)，1.69-1.78(2H，m)，4.07-4.11(2H，m)，4.26(2H，t)，4.434(2H，t)，5.49(2H，s)，6.87-7.38(10H，m)，7.55(1H，s).
LC/MS：m/z?419[MH]
+.
Embodiment 410:8-chloro-3-methyl isophthalic acid-(3-phenyl propyl)-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-3-methyl isophthalic acid-(3-phenyl propyl)-3,7-dihydro-1H-purine-2,6-diketone
Title compound uses 3-butyl-8-chloro-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2, and the listed method preparation of 6-diketone is with 3-methyl isophthalic acid-(3-phenyl propyl)-3,7-dihydro-1H-purine-2,6-diketone and NCS.
1H?NMR(CDCl
3)δ：2.01-2.12(2H，m)，2.74(2H，t)，3.57(3H，s)，4.14(2H，t)，6.99-7.24(5H，m)，12.5(1H，br.s).
LC/MS：m/z?319[MH]
+.
B) 3-methyl isophthalic acid-(3-phenyl propyl)-3,7-dihydro-1H-purine-2,6-diketone
Title compound uses 3-butyl-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2, and the listed method preparation of 6-diketone is with 3-methyl-7-(phenyl methyl)-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2,6-diketone.
LC/MS：m/z?285[MH]
+.
C) 3-methyl-7-(phenyl methyl)-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2,6-diketone
Title compound uses 3-butyl-7-(phenyl methyl)-1-(3-phenyl propyl)-3,7-dihydro-1H-purine-2, and the listed method preparation of 6-diketone, with 3-methyl-7-(phenyl methyl)-3,7-dihydro-1H-purine-2,6-diketone and (3-bromopropyl) benzene.
LC/MS：m/z?375[MH]
+.
D) 3-methyl-7-(phenyl methyl)-3,7-dihydro-1H-purine-2,6-diketone
Title compound uses 7-benzyl-3-butyl-3,7-dihydro-1H-purine-2, and the described method preparation of 6-diketone, the use methyl-iodide (0.28ml, 4.46mmol).Purify by grinding.Product (0.334g, 57%) is insoluble to chloroform and water with isolated in solid form.
1H?NMR(DMSO-d
6)δ：3.34(3H，s)，5.44(2H，s)，7.26-7.37(5H，m)，8.21(1H，s)，11.13(1H，s).
LC/MS：m/z?257[MH]
+.
Embodiment 411:8-chloro-3-amyl group-1-{[1-(phenyl methyl)-1H-indoles-5-yl] methyl }-3, the 7-dihydro
-1H-purine-2, the 6-diketone
A) 8-chloro-3-amyl group-1-{[1-(phenyl methyl)-1H-indoles-5-yl] methyl }-3,7-dihydro-1H-purine-2,6-diketone
In nitrogen with 8-chloro-3-amyl group-3,7-dihydro-1H-purine-2, the 6-diketone (156mg 0.5mmol) is dissolved among the anhydrous THF (5ml), then add [1-(phenyl methyl)-1H-indoles-5-yl] methyl alcohol (138mg, 0.58mmol).Behind the several minutes, add triphenylphosphine (168mg, 0.63mmol), behind the 5-10min, then add DBAD (155mg, 0.67mmol), then with solution stirring 18h.Mixture is introduced nitrogen then by vacuum outgas.Add Pd (PPh
3)
4(63mg 0.054mmol), then outgases mixture once more.(0.461ml 5.3mmol), then stirs 24h with mixture in nitrogen to add morpholine.Pd (the PPh that adds greater amt
3)
4(58mg 0.05mmol), then stirs 96h with mixture in nitrogen.Mixture dilutes with EtOAc, with HCl (5ml) washing of 2M, uses salt solution (15ml) washing then, dry (MgSO
4) and concentrate.Thick material aminopropyl SPE purification (eluent MeOH uses the 3-4%AcOH/MeOH wash-out then with washing impurity).Merge the product cut, concentrate, obtain the title compound (43mg, 17%) of white solid form.
LC/MS：m/z?476[MH]
+，RT?3.78min.
B) [1-(phenyl methyl)-1H-indoles-5-yl] methyl alcohol
In nitrogen, (1.17g 4.4mmol) is dissolved among the anhydrous THF, then is cooled to-5 ℃ with 1-(phenyl methyl)-1H-indole-5-carboxylic acid methyl esters.Ether (4.0ml) solution that adds the 1M lithium aluminum hydride lentamente.Remove cooling bath, reaction mixture is at room temperature spent the night.Reaction by add successively entry (0.15ml), 15%NaOH (0.15ml), then water (0.45ml), ethyl acetate is carried out quencher then, adds sodium sulfate, then mixture is stirred 0.5h.Leach insoluble substance, use the ethyl acetate thorough washing.Filtrate concentrates in a vacuum, obtains the title compound of cream-colored solid form, its darken when leaving standstill (1.04g, 100%).
LC/MS：m/z?238[MH]
+，RT?3.03min.
Following alcohol can prepare by the corresponding methyl esters of reduction in a similar manner:
[1-(phenyl methyl)-1H-indoles-4-yl] methyl alcohol
LC/MS：m/z?238[MH]
+，RT?3.03min.
[2-(phenyl methyl)-1,3-benzoxazole-4-yl] methyl alcohol
LC/MS：m/z?240[MH]
+，RT?2.02min.
C) 1-(phenyl methyl)-1H-indole-5-carboxylic acid methyl esters
(1.0g 5.7mmol) is dissolved in the dry DMF, then is cooled to 2 ℃ with 1H-indole-5-carboxylic acid methyl esters in nitrogen.Add sodium hydride (60% in paraffin for 0.25g, 6.3mmol).0.5h after, (0.75ml 6.0mmol), then at room temperature stirs 4hr with reaction mixture, allows it spend the night then to add bromotoluene.Reaction mixture is poured in water (50ml) and the ethyl acetate (10ml).Water extracts with ethyl acetate (50ml).The organic phase that merges is washed with weak ammonia, uses the salt water washing then, dry (MgSO
4) and concentrate in a vacuum.Crude product on 50g Si SPE, purify (gradient elution, cyclohexane/ethyl acetate 8%-16%).Relevant cut concentrates in a vacuum, obtains the title compound (1.17g, 77%) of white solid form
LC/MS：m/z?266[MH]
+，RT?3.60min.
Can prepare 1-(phenyl methyl)-1H-indole-4-carboxylic acid methyl esters in a similar manner
LC/MS：m/z?266[MH]
+，RT?3.58min.
2-(phenyl methyl)-1,3-benzoxazole-5-carboxylate methyl ester
(1.34g 6.8mmol) is dissolved in the methyl alcohol (2ml), and (0.56g 3.35mmol), adds concentrated hydrochloric acid (9.1ml) then then to add 3-amino-methyl hydroxybenzoate with benzyl orthoformic acid trimethylammonium ester.Mixture stirs 4.75h under refluxing, allow its cooling also evaporate in a vacuum.Resistates distributes between the NaOH solution (5ml) of ether (10ml) and 2M.Ether (10ml) extraction is used in organic phase water (5ml) washing, the water of merging again.Organic phase drying (the MgSO that merges
4), concentrate in a vacuum, obtain a kind of orange oil (1.37g).Crude product is gone up at silicon-dioxide (40g SPE, gradient elution, cyclohexane/ethyl acetate 0-100%) and is purified, and obtains the title compound (0.72g, 80%) of white solid form.
LC/MS：m/z?268[MH]
+，RT?3.27min.
3-[3-(phenyl methyl) phenyl]-the 1-propyl alcohol
In nitrogen with 3-[3-(phenylcarbonyl group) phenyl] (491mg 1.96mmol) is dissolved among the anhydrous THF propionic acid, then is cooled to 0 ℃.The LiAlH that adds 1M lentamente
4Diethyl ether solution (2.13ml), then reaction mixture is at room temperature stirred 20h.Be reflected in the ice and cool off, add the diethyl ether solution (2.2ml) of the LiAlH4 of tetrahydrofuran (THF) (5ml) and 1M.Reaction mixture heats 7hr under refluxing, be allowed to condition at then under the room temperature to keep 3 days.React water (0.16ml), 15%NaOH (0.16ml) and water (0.47ml) cancellation successively, with the ethyl acetate dilution, then use dried over sodium sulfate then.Leach insoluble substance, use the ethyl acetate thorough washing.Filtrate concentrates in a vacuum, obtains White-opalescent buttery 3-{3-[hydroxyl (phenyl) methyl] phenyl }-1-propyl alcohol (0.42g, 90%)
LC/MS：m/z?243[MH]
+，RT?2.71min.
With above-mentioned substance (200mg 0.82mmol) is dissolved in the anhydrous methylene chloride (5ml), add triethyl silicane (0.53ml, 3.2mmol), then add trifluoroacetic acid (0.36ml, 4.1mmol).Reaction mixture stirs 1h, washs with saturated sodium bicarbonate solution then.Organic phase is filtered by the hydrophobic glass material, then concentrates in a vacuum.Crude product is gone up at silicon-dioxide (4g SPE, gradient elution, cyclohexane/ethyl acetate 0-30%) and is purified, and obtains the title compound (68mg, 37%) of colorless oil.
LC/MS：m/z?227[MH]
+，RT?3.25min.
Following compounds (table 27) is used and is similar to 8-chloro-3-amyl group-1-{[1-(phenyl methyl)-1H-indoles-5-yl] methyl }-3,7-dihydro-1H-purine-2, the method preparation of 6-diketone is by corresponding pure as mentioned above.
Table 27
Embodiment 415:8-chloro-1-(2-hydroxyl-6-phenyl hexyl)-3-amyl group-3,7-dihydro-1H-purine-2,6-
Diketone
A) 8-chloro-1-(2-hydroxyl-6-phenyl hexyl)-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
With 8-chloro-1-(2-hydroxyl-6-phenyl hexyl)-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (0.084g, 0.18mmol) and Pd (PPh
3)
4((0.25ml 2.8mmol), then stirs mixture and spends the night to add morpholine then for 0.042g, the 0.035mmol) degassing of the solution in THF (5ml) (vacuumize continuously and then add nitrogen x3).Solution is loaded on the aminopropyl SPE (5g), to remove by product, uses the 5%AcOH/MeOH wash-out then, after concentrating, obtain a kind of oil (0.022g, 29%) to separate title compound with the MeOH wash-out.
LC/MS：m/z?433[MH]
+
B) 8-chloro-1-(2-hydroxyl-6-phenyl hexyl)-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
To 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (0.107g, 0.36mmol) and 1-chloro-6-phenyl-2-hexanol (0.107g, 0.5mmol) add cesium carbonate (0.24g in the solution in DMF (5ml), 0.74mmol), then mixture is heated 3h down at 60 ℃, then add the cesium carbonate of other 80mg and continue heating 18h down at 100 ℃.Cooling solution concentrates, and resistates obtains the title compound (0.085mg, 53%) of yellow oily with silicon-dioxide chromatogram purification 20g (SPE at first uses the DCM wash-out, uses DCM/10% ether wash-out then).
LC/MS：m/z?473[MH]
+
Embodiment 416:8-chloro-1-{4-[2-oxo-3-(phenyl methyl)-1-pyrrolidyl] butyl }-the 3-amyl group
-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-1-{4-[2-oxo-3-(phenyl methyl)-1-pyrrolidyl] butyl }-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
8-chloro-1-{4-[2-oxo-3-(phenyl methyl)-1-pyrrolidyl] butyl }-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (0.35g, 0.67mmol), Pd (PPh
3)
4(0.082g, 0.07mmol) and morpholine (0.6ml, 6.7mmol) 4h is stirred in the solution in THF (10ml) degassing (vacuumize continuously and then add nitrogen x3) then.Then, described solution is loaded on the aminopropyl SPE (5g), at first uses the MeOH wash-out, then with the 5%AcOH/MeOH wash-out to obtain containing the title compound of small amount of impurities.(10g SPE, gradient elution, ether/ethyl acetate 1: 0-0: 1) further purify, obtain a kind of clarified oil (0.10g, 31%) in silicon-dioxide.
LC/MS：m/z?486[MH]
+
B) 8-chloro-1-{4-[2-oxo-3-(phenyl methyl)-1-pyrrolidyl] butyl }-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone
As preparation 8-chloro-1-(2-hydroxyl-6-phenyl hexyl)-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the situation of 6-diketone is the same, as alkylating reagent, salt of wormwood heats 18h down as alkali and at 50 ℃ with 1-(4-brombutyl)-3-(phenyl methyl)-2-Pyrrolidone.Yield 86%.
LC/MS：m/z?526[MH]
+
C) 1-(4-brombutyl)-3-(phenyl methyl)-2-Pyrrolidone
(0.23g, 1.3mmol) with 1, (0.57g, (0.151g 1.6mmol), follows described solution stirring 18h the 4-dibromobutane 4.2mmol) to add sodium tert-butoxide in the solution in DMF (5ml) to 3-(phenyl methyl)-2-Pyrrolidone.With solution concentration, resistates is purified (20g SPE at first uses the hexanaphthene wash-out, uses the DCM wash-out then) with the silicon-dioxide chromatogram, obtains containing the title compound (0.25g, 61%) of micro-DMF.
LC/MS：m/z?311[MH]
+
Embodiment 417:8-chloro-1-{4-[2-oxo-1-(phenyl methyl)-3-pyrrolidyl] butyl }-the 3-amyl group
-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-1-{4-[2-oxo-1-(phenyl methyl)-3-pyrrolidyl] butyl }-3-amyl group-3,7-dihydro-1H-purine-2,6-diketone
To 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (0.086g, 0.29mmol) and 3-(4-brombutyl)-1-(phenyl methyl)-2-Pyrrolidone (0.17g, 0.55mmol, mixture contained 2-(phenyl methyl)-2-azaspiro [4.4] nonane-1-ketone in 1: 1) add in the solution in THF (5ml) salt of wormwood (0.08g, 0.58mmol), then with described mixture 50 ℃ of heating and stir 18h down.Cooling solution, the degassing (vacuumize continuously and then add nitrogen x3) then adds Pd (PPh
3)
4(0.09g, 0.077mmol), (0.2ml 2.2mmol), stirs 18h with solution then at ambient temperature then to add morpholine.Solution separates between ethyl acetate and rare HCl, and organism salt water washing is dry and concentrated.Resistates is purified with aminopropyl SPE (5g), at first uses the MeOH wash-out, uses the 5%AcOH/MeOH wash-out then, obtains the title compound of yellow oily, crystallization when it leaves standstill in ether (0.031g, 22%).
LC/MS：m/z?486[MH]
+
B) 3-(4-brombutyl)-1-(phenyl methyl)-2-Pyrrolidone
Under-78 ℃, in 5min, (0.47g 2.7mmol) adds hexamethyl dimethyl silanyl azine lithium (2.8ml, 2.7mmol, 1M solution) in the solution in THF (10ml) to 1-(phenyl methyl)-2-Pyrrolidone.Behind the 15min, add 1, (0.32ml 2.7mmol), then reaches envrionment temperature with solution to the 4-dibromobutane in 2h, and then stirs 18h.Solution separates between ethyl acetate and water, and separating organic matters is dry and concentrated.Silicon-dioxide (20g SPE) chromatogram is purified, and uses the hexanaphthene wash-out, uses the DCM wash-out then, uses the ether wash-out at last, obtains a kind of clarified oil, and it is 1: 1 mixture (0.17g) of title compound and 2-(phenyl methyl)-2-azaspiro [4.4] nonane-1-ketone.This crude product does not have further purification just to be used for next step.
LC/MS：m/z?310，312[MH]
+
Embodiment 418:8-chloro-1-(5-{5-[(3,4-dichlorophenyl) methyl]-2H-tetrazolium-2-yl } amyl group)-3-
Amyl group-3,7-dihydro-1H-purine-2,6-diketone
To 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, (0.18g 0.61mmol) adds 5-{5-[(3 in the solution in THF (5ml) to the 6-diketone, the 4-dichlorophenyl) methyl]-2H-tetrazolium-2-yl }-1-amylalcohol (0.191g, 0.61mmol; Prepare in the mode that is similar to embodiment 35), triphenylphosphine (0.36g, 1.3mmol) and last azo-2-carboxylic acid's dibenzyl ester (0.40g, 1.3mmol).With solution stirring 18h, then add Pd (PPh
3)
4(0.16g, 0.137mmol), (0.75ml 8.3mmol), stirs 6h at ambient temperature with solution to add morpholine then.Described solution is loaded on the aminopropyl SPE (5g), at first uses the MeOH wash-out, then with the 5%AcOH/MeOH wash-out to obtain containing the title compound of small amount of impurities.Further (silicon-dioxide SPE 20g), uses the ether wash-out to chromatographic separation, obtains the title compound (0.061g, 18%) of white solid form.
LC/MS：m/z?553[MH]
+
Embodiment 419:8-chloro-3-amyl group-1-{5-[3-(phenyl methyl)-1,2,4-oxadiazole-5-yl] penta
Base }-3,7-dihydro-1H-purine-2,6-diketone
To 8-chloro-3-amyl group-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2, the 6-diketone (0.093g 0.3mmol) adds 5-[3-(phenyl methyl)-1,2 in the solution in THF (5ml), 4-oxadiazole-5-yl]-1-amylalcohol (0.077g, 0.3mmol; Prepare in the mode that is similar to embodiment 87b), triphenylphosphine (0.17g, 0.6mmol) and last azo-2-carboxylic acid's dibenzyl ester (0.20g, 0.6mmol).Solution stirring 18h, the degassing adds Pd (PPh thereafter
3)
4(0.08g, 0.07mmol), (0.35ml 3.9mmol), stirs 6h with described solution then at ambient temperature then to add morpholine.Described solution is loaded on the aminopropyl SPE (5g), at first uses the MeOH wash-out, then with the title compound (0.051g, 34%) of 5%AcOH/MeOH wash-out to obtain cream-colored solid form.
LC/MS：m/z?485[MH]
+
Embodiment 420:8-chloro-1-{3-[5-(4-chloro-phenyl-)-1H-pyrazole-3-yl] propyl group }-3-amyl group-3,7-two
Hydrogen-1H-purine-2, the 6-diketone
As 8-chloro-1-(5-{5-[(3,4-dichlorophenyl) methyl]-2H-tetrazolium-2-yl } amyl group)-3-amyl group-3,7-dihydro-1H-purine-2, the situation preparation of 6-diketone is with 3-[5-(4-chloro-phenyl-)-1H-pyrazole-3-yl]-the 1-propyl alcohol.Final product washs with ether, obtains the title compound (30%) of cream-colored solid form.
LC/MS：m/z?475[MH]
+
Embodiment 421:3-butyl-8-chloro-1-{4-[5-(1-methyl isophthalic acid H-1,2,3-triazole-4-yl)-1,2,4-Evil two
Azoles-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone
1-methyl isophthalic acid H-1,2, (18mg, 0.14mmol) solution in DMF (0.5ml) is at room temperature used CDI (23mg, 0.14mmol) processing 1h to 3-triazole-4-carboxylic acid.With (1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-(50mg, 0.14mmol) solution in DMSO (0.4ml) joins in the described mixture N-hydroxyl penta amidine, is heated to 100 ℃ of 18h then.Reaction mixture is purified with MDAP, obtains the title compound (18mg) of white solid form.
LC/MS：m/z?448[MH]
+，RT?2.86min.
Following compounds (table 28) uses the method that is similar to embodiment 421 by suitable carboxylic acid preparation.
Table 28
Embodiment 465:1-{4-[1,3-benzoxazole-2-base (methyl) amino] butyl }-8-chloro-3-ethyl-3,7-
Dihydro-1H-purine-2, the 6-diketone
2-chloro-1, (0.46g, 3mmol) (0.26g 3mmol) handles the solution in THF (20ml) the 3-benzoxazole, then reaction mixture is heated 6h under refluxing, and cools off then and is evaporated to dried with the 1-crassitude.Flash chromatography is purified [Isco Companion, 12g Redisep post is with hexanaphthene-hexanaphthene/ether (3: 2) gradient elution], obtains N-(4-the chlorobutyl)-N-methyl isophthalic acid of the colorless oil of 0.52g (73% yield), 3-benzoxazole-2-amine.LC/MS：m/z?239[MH]
+，RT?3.12min.
8-chloro-3-ethyl-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (0.112g, 0.44mmol) solution in DMF (10ml) is with salt of wormwood (0.08g, 0.6mmol) and N-(4-chlorobutyl)-N-methyl isophthalic acid, (0.12g 0.5mmol) handles 3-benzoxazole-2-amine.Reaction mixture heats 18h down at 75 ℃, is cooled to envrionment temperature then.Mixture then outgases with the nitrogen backfill by repeating to apply vacuum, use then tetrakis triphenylphosphine palladium (O) (0.03g, 0.026mmol) and morpholine (0.5ml 5.7mmol) handles.Stir 4h at ambient temperature in nitrogen atmosphere, then described mixture is evaporated to driedly, resistates distributes between chloroform (40ml) and saturated aqueous ammonium chloride (40ml).Organic phase is evaporated to dried, resistates is dissolved in the methyl alcohol (5ml), then joins among the 5g aminopropyl SPE, and it uses methanol wash subsequently, and described product is with the methanol solution wash-out that contains 5% acetate.Be evaporated to the product cut that contains that merges dried, product is purified with MDAP, obtains the title compound (0.043g, 23%) of white solid form.
LC/MS：m/z?417[MH]
+，RT?2.91min.
Following compounds (table 29) is by being similar to the method preparation of embodiment 465.
Table 29
Embodiment 468:3-butyl-8-chloro-1-[5-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) penta
Base]-3,7-dihydro-1H-purine-2,6-diketone
3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (0.5g, 1.8mmol) solution in DMF (20ml) with salt of wormwood (0.3g, 2.1mmol) and pentamethylene bromide (1.2ml, 8.9mmol) handle, heat 2h down at 50 ℃ then.With the mixture cooling, then be evaporated to dried.Resistates distributes between ethyl acetate (30ml) and saturated sodium bicarbonate aqueous solution (30ml).Water is used ethyl acetate (30ml) extraction again, and the organism that merges is dry in sal epsom, filters and be evaporated to dried.Product is with flash chromatography [the Isco Companion that purifies, 40g Redisep carteidge, gradient elution is from hexanaphthene-cyclohexane/ethyl acetate (1: 1)], obtain 1-(5-bromine the amyl group)-3-butyl-8-chloro-7-(2-propylene-1-yl)-3 of the colorless oil of 0.663g (87%), 7-dihydro-1H-purine-2, the 6-diketone.LC/MS：m/z431/433[MH]
+，RT?3.76min.
To 1-(5-bromine amyl group)-3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (0.642g, 1.5mmol) add potassium phthalimide (0.303g in the solution in DMF (10ml), 1.6mmol), then described mixture is heated 2h, cooling then down at 50 ℃.Mixture then outgases with the nitrogen backfill by repeating to apply vacuum, use then tetrakis triphenylphosphine palladium (O) (0.173g, 0.15mmol) and morpholine (1.3ml 15mmol) handles.Mixture leaves standstill 18h at ambient temperature under nitrogen, with the mixture evaporation, resistates distributes between chloroform (30ml) and saturated aqueous ammonium chloride (30ml) thereafter.Water is used chloroform (30ml) extraction again, and the organism that merges is dry in sal epsom, filters and be evaporated to dried.Resistates is dissolved in the methyl alcohol (5ml), then joins in the 10g aminopropyl SPE post, it uses methanol wash subsequently, the described product methanol solution wash-out that contains 5% acetate.Contain the evaporation of product cut, purify by MDAP then, obtain N-[5-(the 3-butyl-8-chloro-2 of white solid form, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) amyl group]-2-(4-morpholinyl carbonyl) benzamide (0.137g, LC/MS:m/z 545[MH]
+, RT 2.77min) and obtain the title compound (0.239g, 35%) of white solid form.
LC/MS：m/z?458[MH]
+，RT?3.33min.
Embodiment 469:8-chloro-1-{4-[3-(2,4 difluorobenzene base)-1,2,4-oxadiazole-5-yl] butyl }-3-second
Base-3,7-dihydro-1H-purine-2,6-diketone
A) 8-chloro-1-{4-[3-(2,4 difluorobenzene base)-1,2,4-oxadiazole-5-yl] butyl }-3-ethyl-3,7-dihydro-1H-purine-2,6-diketone
(0.05g, 0.16mmol) (0.029g 0.18mmol) handles the solution in DMSO (1ml) 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeric acid, then this mixture is at room temperature stirred 1h with CDI.Subsequently, this mixture is with 2, and (0.03g 0.18mmol) handles 4-difluoro benzyl amidoxime, is heated to 120 ℃ of 30min then.Product is purified with MDAP by crude mixture.Use nitrogen will contain the evaporation of product cut, gained does not have coloring agent and grinds in ether, and drying obtains the title compound (50mg, 70%) of white solid form.
LC/MS：m/z?451[MH]
+，RT?2.23min.
B) 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeric acid
5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) Valeric acid ethylester (2.3g, 6.7mmol) solution with water (3ml) and the lithium hydroxide (0.481g in methyl alcohol (75ml), 20.1mmol) handle, then this mixture is stirred 17h down at 40 ℃.Described mixture is evaporated to dried, resistates is with 50ml ethyl acetate and 50ml water treatment.Separate two-phase, water is adjusted to pH5 with the 2M aqueous hydrochloric acid.The product that filtration is separated out, drying obtains 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6, the 7-tetrahydrochysene-1H-purine-1-yl) valeric acid (1.99g, 95%) of white solid form.
LC/MS：m/z?315[MH]
+，RT?2.34min.
C) 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) Valeric acid ethylester
8-chloro-7-(2-propylene-1-yl)-3-ethyl-3,7-dihydro-1H-purine-2,6-diketone (3g, 11.8mmol) solution in DMF (40ml) is with salt of wormwood (1.9g, 14.1mmol) and 5-bromine Valeric acid ethylester (2.24ml, 14.1mmol) handle, then this mixture is heated 5h, cooling then down at 70 ℃ in nitrogen atmosphere.Mixture then outgases with the nitrogen backfill by repeating to apply vacuum, use then tetrakis triphenylphosphine palladium (O) (1.36g, 1.1mmol) and morpholine (10.3ml 118mmol) handles.Mixture stirs 4h in nitrogen atmosphere, be evaporated to dried then.Described resistates is distributed between 100ml ethyl acetate and 100ml water.Water extracts with the 100ml ethyl acetate again, and the organism that merges is dry in sal epsom, filters and evaporation.Resistates grinds in ether, filters and drying, obtains 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) the Valeric acid ethylester compound (2.3g, 57%) of white solid form.
LC/MS：m/z?343[MH]
+，RT?2.73min.
Following compounds (table 30) is by being similar to the method preparation of embodiment 469.
Table 30
Following compounds (table 31) uses the method that is similar to embodiment 158 by suitable acid preparation.
Table 31
Following compounds (table 32) is used the method preparation that is similar to embodiment 36, uses suitable tetrazolium and methylsulfonic acid 3-[3-alkyl-8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] propyl diester.Use MDAP with those pure inadequately compounds after normal-phase chromatography is purified of further purification.
Table 32
Embodiment 597:1-[5-(1,3-benzoxazole-2-yl) amyl group]-8-chloro-3-ethyl-3,7-dihydro-1H-is fast
Purine-2, the 6-diketone
A) 1-[5-(1,3-benzoxazole-2-yl) amyl group]-8-chloro-3-ethyl-3,7-dihydro-1H-purine-2,6-diketone
A) 3-ethyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (0.095g, 0.37mmol) solution in DMF (10ml) is with salt of wormwood (0.0615g, 0.45mmol) and 2-(5-chlorine amyl group)-1, (0.091g 0.41mmol) handles the 3-benzoxazole, then described mixture is heated 4.5h down at 70 ℃.Mixture is cooled off, reuse vacuum and the gas of filling nitrogen qi exhaustion subsequently by reaction mixture, use then tetrakis triphenylphosphine palladium (O) (0.043g, 0.037mmol) and morpholine (0.32ml, 3.7mmol) handle, then described mixture is stirred 4h in nitrogen atmosphere.Described mixture is evaporated to dried, resistates distributes between 25ml ethyl acetate and 25ml salt solution.Water extracts with the 25ml ethyl acetate again, and the organism that merges is dry in sal epsom, filters and evaporation.Resistates is dissolved in the 5ml methyl alcohol, then joins among the 5g aminopropyl SPE, it uses methanol wash subsequently, the described product methanol solution wash-out that contains 5% acetate.Merge and to contain the product cut, evaporation obtains a kind of no coloring agent, and it is developed with ether, and drying obtains the title compound (0.0538g, 36%) of white solid form.
LC/MS：m/z?402[MH]
+，RT?3.06min
B) 2-(5-chlorine amyl group)-1, the 3-benzoxazole
(0.95g, (0.05g 0.26mmol) handles 6-chloro-N-(2-hydroxy phenyl) hexanamide, follows described mixture and heat 1h down at 160 ℃ in microwave, cools off then and evaporates 3.9mmol) to use toluene (20ml) and 4-toluenesulphonic acids monohydrate.Described resistates is distributed between 25ml ethyl acetate and 25ml saturated sodium bicarbonate aqueous solution.Water 25ml ethyl acetate extracting twice again, the organism that merges is dry in sal epsom, filter and be evaporated to dried.Then, product is purified with flash chromatography, and (gradient elution: hexanaphthene-cyclohexane/ethyl acetate 1: 1), obtain the 2-(5-chlorine amyl group)-1 of colorless oil, the 3-benzoxazole leaves standstill after fixing (0.47g, 53%).
LC/MS：m/z?224[MH]
+，RT?3.32min
C) 6-chloro-N-(2-hydroxy phenyl) hexanamide
The 2-amino-phenol (0.5g 4.6mmol) stirs in ethyl acetate (15ml), drip 6-chlorine caproyl chloride (0.664ml, 5.5mmol), drip then triethylamine (0.95ml, 6.9mmol).Behind the 1h, mixture is with the washing of the saturated sodium bicarbonate aqueous solution of 2x25ml, and organic phase is dry in sal epsom, filters, and is evaporated to driedly, obtains 6-chloro-N-(2-hydroxy phenyl) hexanamide (0.05g, 86%) of light brown solid form.
LC/MS：m/z?242[MH]
+，RT?2.95min.
Following compounds (table 33) is used the method preparation that is similar to embodiment 597.
Table 33
Embodiment 601:1-[5-(1,3-benzothiazole-2-yl) amyl group]-3-butyl-8-chloro-3,7-dihydro-1H-is fast
Purine-2, the 6-diketone
A) 1-[5-(1,3-benzothiazole-2-yl) amyl group]-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-diketone
3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (0.053g, 0.19mmol) solution in DMF (5ml) is with salt of wormwood (0.026g, 0.19mmol) and 2-(5-chlorine amyl group)-1, (0.0498g 0.21mmol) handles the 3-benzothiazole, and then this mixture heated 3 days down at 60 ℃.With mixture cooling, by reusing vacuum and the gas of filling nitrogen qi exhaustion subsequently, use then tetrakis triphenylphosphine palladium (O) (0.0294g, 0.025mmol) and morpholine (0.164ml, 1.9mmol) processing then stirs 18 with described mixture in nitrogen atmosphere.Described mixture is evaporated to dried, resistates distributes between 25ml ethyl acetate and 25ml saturated sodium bicarbonate aqueous solution.Organic phase is dry in sal epsom, filter and evaporation.Resistates is dissolved in the 5ml methyl alcohol, then joins among the 5g aminopropyl SPE, it uses methanol wash subsequently, the described product methanol solution wash-out that contains 5% acetate.Merge and contain the product cut, evaporation, resistates is purified by MDAP, obtains the title compound (0.0101g, 12%) of white solid form.
LC/MS：m/z?446[MH]
+，RT?3.55min.
B) 2-(5-chlorine amyl group)-1, the 3-benzothiazole
(0.376ml, 3.54mmol) (0.62ml 3.54mmol) handles the solution under ice-cooled in anhydrous THF (5ml) the 2-aminothiophenol, and then (0.36ml 2.95mmol) handles with 6-chlorine caproyl chloride with diisopropylethylamine.Mixture stirs 2h at ambient temperature, heats 19h then under refluxing, and cooling then is then with DCM (10ml) dilution.Solution 2M aqueous hydrochloric acid, the 2M aqueous sodium hydroxide solution of 10ml and the salt water washing of 10ml of 10ml; Dry in sal epsom, filter and evaporation, obtain the light yellow oil of 0.4122g.Product is purified with flash chromatography, with hexanaphthene-cyclohexane/ethyl acetate (7: 3) gradient elution, obtains the 2-(5-chlorine amyl group)-1 of water white oil form, 3-benzothiazole (0.0541g, 6%).
LC/MS：m/z?240[MH]
+，RT?3.48min.
Embodiment 602:3-butyl-8-chloro-1-{3-[4-(phenyl methyl)-1-piperazinyl] propyl group }-3, the 7-dihydro
-1H-purine-2, the 6-diketone
Methylsulfonic acid 3-[3-butyl-8-chloro-2,6-dioxo-7-(2-propylene-1-yl)-2,3,6,7-tetrahydrochysene-1H-purine-1-yl] and propyl diester (0.08g, 0.19mmol) (0.08g is 0.6mmol) with 1-benzyl diethylenediamine (0.04g with salt of wormwood for the solution in DMF (5ml), 0.23mmol) handle, heat 2h down at 70 ℃ then.With mixture cooling, be evaporated to driedly, then between the water of the DCM of 10ml and 10ml, distribute.Organic phase is evaporated to dried, then resistates is dissolved among the anhydrous THF (5ml).With solution by reusing vacuum and the gas of filling nitrogen qi exhaustion subsequently, use then tetrakis triphenylphosphine palladium (O) (0.010g, 0.009mmol) and morpholine (0.200ml, 2.3mmol) processing is then stirred 2h with described mixture in nitrogen atmosphere.With the mixture evaporation, resistates imports in the 5ml methyl alcohol, then joins in the 2g aminopropyl SPE post, uses methanol wash then, the product methanol solution wash-out that contains 3% acetate.Merge and contain the product cut, be evaporated to dried.Then, product is purified with flash chromatography, and with DCM/2% acetate-DCM/20%MeOH/2% acetate gradient elution, final product is from 1, and freeze-drying in the 4-diox obtains the title compound (0.021g, 24%) of white solid form.
LC/MS：m/z?459[MH]
+，RT?2.37min.
Following compounds (table 34) is by suitable as mentioned above general method preparation.
Table 34
Embodiment 837:3-butyl-8-chloro-1-{4-[5-(2-fluoro-4-hydroxy phenyl)-1,2,4-oxadiazole-3-yl]
Butyl }-3,7-dihydro-1H-purine-2,6-diketone
A) 3-butyl-8-chloro-1-{4-[5-(2-fluoro-4-hydroxy phenyl)-1,2,4-oxadiazole-3-yl] butyl }-3,7-dihydro-1H-purine-2,6-diketone
With CDI (45mg, anhydrous DMSO (0.5ml) solution 0.28mmol) join 2-fluoro-4-hydroxy-benzoic acid (40mg, 0.25mmol) in, then at room temperature stir 2h.(100mg, DMSO 0.28mmol) (0.4ml) solution then heat 18h with the gained mixture down at 90 ℃ to add 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine.Purify by MDAP, obtain the title compound (38mg, 28%) of solid form.
LC/MS：m/z?477[MH]
+，RT?3.39min.
1H?NMR(DMSO-d
6)δ：0.87(t，3H，J＝7Hz)，1.27(m，2H)，1.56-1.78(m，6H)，2.77(t，2H，J＝7Hz)，3.90(m，4H)，6.80(m，2H)，7.91(t，1H，J＝9Hz)，11.01(s，1H)，14.45(br?s，1H).
B) 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl)-N-hydroxyl penta amidine
(8.5g 26mmol) is dissolved among the EtOH (100ml) valeronitrile with 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl).Add azanol (50% aqueous solution; 2.6ml, 39mmol), then mixture is heated 48h down at 80 ℃ in nitrogen.Reaction mixture concentrates in a vacuum, gained solid methanol wash, and drying obtains the title compound (5.9g, 47%) of solid form.
LC/MS：m/z?357[MH]
+，RT?2.17min.
C) 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-1-yl) valeronitrile
With 5-bromine valeronitrile (4.54ml, 39mmol) and cesium carbonate (12.7g) join 3-butyl-8-chloro-7-(2-propylene-1-yl)-3,7-dihydro-1H-purine-2,6-diketone (10g, 35mmol) in the solution in DMF (100ml), then described mixture is stirred down at 40 ℃ in nitrogen and spend the night, then allow its cooling.
Then, mixture adds nitrogen pressure then by repeating to use continuously vacuum outgas.Then, mixture with tetrakis triphenylphosphine palladium (O) (2.86g, 2.5mmol) and morpholine (30.8ml, 350mmol) processing.Mixture stirs 3h in nitrogen atmosphere, distribute between EtOAc and 2M aqueous hydrochloric acid then.Separate organic layer, water layer extracts (x2) with EtOAc.The organic phase that merges concentrates in a vacuum, obtains a kind of solid, and this solid is washed with ether, filters then dry.Concentrated filtrate is purified by the aminopropyl post, uses the MeOH wash-out, then uses the 3%AcOH/MeOH wash-out.Merge and contain the product cut, concentrate, obtain a kind of solid, it mixes with filtering product.Obtain the title compound (10.5g, 93%) of solid form.
LC/MS：m/z?324[MH]
+，RT?2.75min.
Following compounds (table 35) uses the method that is similar to embodiment 837 by suitable carboxylic acid preparation.
At these whole publications of being quoted in this specification sheets, include, but are not limited to various patents and patent application and be incorporated herein by reference, just look like every piece of full content in the independent publication by specifically with independently be incorporated herein by reference the same.
Claims (19)
1. at least a chemical entity, it is selected from formula (I) compound
With its pharmacy acceptable derivates, wherein
R
1Expression-(alkylidene group)
m-X-(alkylidene group)
n-Y;
Wherein X represents A, A1, A2 or direct key;
A represents to be selected from following group:
Ring alkylidene group, ring alkenylene, aryl, heteroaryl, heterocyclic radical and-CH
2-OC (O)-;
A1 represents to be selected from following group:
-CH
2-O-(CH
2)
qAryl-O-,-CH
2-O-(CH
2)
wN (R
5) C (O) O-,-CH
2-N (R
5) C (O) O-,-CH
2-N (R
5) C (O)-,-CH
2-(O)
p-(CH
2)
qC (O) NR
5-,-CH
2-N (R
5) C (O) N (R
5)-,-CH
2-C (O) N ((CH
2)
wOH)-,-CH
2-NR
5-S (O)
2-, CH
2-S (O)
2NR
5-,-CH
2-C (O) O-,-O-,-NR
5-and-S-;
A2 represents-CH (OH)-;
When X was A, A1 or A2, Y represented to be selected from following group:
Heteroaryl, heterocyclic radical, aryl, cycloalkyl, cycloalkenyl group ,-the NH-aryl ,-O (CH
2)
n-aryl ,-the O-heteroaryl ,-OR
5,-C (O) OR
5,-C (O) O-C
6Aryl ,-OC (O) R
4,-CH (aryl)
2,-CH (heteroaryl)
2, and-C
1-6Haloalkyl;
When X was A1, Y was selected from:
-O (CH
2)
n-aryl ,-the O-heteroaryl ,-OR
5,-OC (O) R
4, and-the NH-aryl,
N is selected from 2,3,4 and 5 integer;
When X is that A1 and Y are-C
1-6Haloalkyl, or when X was A2, n was selected from 1,2,3,4 and 5 integer;
When X is direct key, (m+n) for being selected from the integer of 2-10;
When X is a direct key and (m+n) when being selected from the integer of 3-10, Y represents to be selected from following group:
-C (O) (CH
2)
qOR
4,-C (O)-aryl ,-C (O)-heteroaryl ,-C (O)-heterocyclic radical, heteroaryl, heterocyclic radical, aryl, 3 or 4 rings condense system ,-CH (aryl)
2,-CH (heteroaryl)
2,-OR
5,-NR
5R
6,-NR
5C (O) OR
7,-(O)
pC (O) NR
5R
7, and-NR
5C (O) R
7
When X is a direct key and (m+n) when being 2, Y represents to be selected from following group
-OR
5,-NH
2, and-NR
5C (O) OR
8
When Y introduced ring, this ring is optional to be replaced by one or more following groups: C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, halogen ,-(CH
2)
qNR
5R
7,-(CH
2)
q-(O)
p-(CH
2)
q-N (R
5) C (O) OR
8,-(CH
2)
q-N (R
5) C (O) R
8,-(CH
2)
q-(O)
p-(CH
2)
q-C (O) NR
5R
6,-(CH
2)
q-N (R
5) C (O) N (R
5) R
6,-(CH
2)
q-C (O) N ((CH
2)
mOH) R
5,-(CH
2)
q-N (R
5)-S (O)
2R
8,-CH
2-S (O)
2N (R
5) R
6,-C
1-6Haloalkyl ,-OCF
3,-OCH (F)
2,-OCH
2F ,-C (O) OR
5,-OR
5,-R
8CN ,-CN ,-SO
2R
9,-(CH
2)
nHeteroaryl ,-(CH
2)
nHeterocyclic radical ,-(CH
2)
nCycloalkyl ,-(CH
2)
nCycloalkenyl group and-(CH
2)
nAryl;
Condition is, when X is A1, A1 is-O-and Y be ring, and when this ring was replaced by aryl or heteroaryl, m was selected from 3,4 and 5 integer so;
R
2Be selected from hydrogen, C
1-10Alkyl, C
2-10Alkenyl, C
2-10Alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, each can be chosen wantonly by one or more following group replacement: C that are independently selected from them
1-10Alkyl, C
2-10Alkenyl, C
2-10Alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-6Haloalkyl, halogen ,-CN ,-OR
4,-(CH
2)
nCOR
4,-C (O) OR
4,-OCOR
4,-(CH
2)
nNR
5R
6,-(NH)
pCONR
5R
6,-OCONR
5R
7, and-NR
5C (O) OR
7
R
3Expression is selected from the group of halogen and CN;
R
4Be selected from hydrogen, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl ,-(CH
2)
nCycloalkyl ,-(CH
2)
nCycloalkenyl group ,-(CH
2)
nHeterocyclic radical ,-(CH
2)
nAryl and-(CH
2)
nHeteroaryl;
R
5And R
6Be independently selected from hydrogen and C
1-4Alkyl;
R
7Expression is selected from following group: H, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl ,-(CH
2)
tCycloalkyl ,-(CH
2)
nCycloalkenyl group ,-(CH
2)
tHeterocyclic radical ,-(CH
2)
tAryl and-(CH
2)
tHeteroaryl;
R
8Expression is selected from C
1-4The group of alkyl;
R
9Expression is selected from following group: C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl ,-(CH
2)
nCycloalkyl ,-(CH
2)
nCycloalkenyl group ,-(CH
2)
nHeterocyclic radical ,-(CH
2)
nAryl ,-(CH
2)
nHeteroaryl and CN;
M represents to be selected from 1,2,3,4 and 5 integer;
N represents to be selected from 0,1,2,3,4 and 5 integer;
P represents to be selected from 0 and 1 integer;
Q represents to be selected from 0,1 and 2 integer;
T represents to be selected from 1 and 2 integer; With
W represents to be selected from 2,3 and 4 integer.
2. at least a chemical entity of claim 1, wherein X is selected from A and A1.
3. claim 1 or 2 at least a chemical entity, wherein R
2Be selected from C
3-6Alkyl.
4. at least a chemical entity of above-mentioned each claim, wherein X is selected from A and A1, and A represents to be selected from the group of heteroaryl and heterocyclic radical, and A1 represents to be selected from CH
2-O-(CH
2)
wN (R
5) C (O) O-, CH
2-N (R
5) C (O) O-, CH
2-N (R
5) C (O)-, CH
2-(O)
p-(CH
2)
qC (O) NR
5-, CH
2-N (R
5) C (O) N (R
5)-, CH
2-C (O) N ((CH
2)
mOH)-, CH
2-NR
5-S (O)
2-, CH
2-S (O)
2NR
5-and CH
2The group of-C (O) O-.
5. at least a chemical entity of claim 4, wherein X represents that A and A represent to be selected from the group of heteroaryl.
6. at least a chemical entity of claim 5, wherein A represents to be selected from the group of the heteroaryl that comprises nitrogen heteroatom.
7. at least a chemical entity of above-mentioned each claim, wherein Y represents to be selected from the group of aryl, heteroaryl and O-aryl.
8. at least a chemical entity of above-mentioned each claim, wherein R
3The expression halogen.
9. at least a chemical entity of above-mentioned each claim, wherein R
3Expression chlorine.
10. at least a chemical entity of above-mentioned each claim, it is used for people's medication or veterinary drug.
11. each at least a chemical entity among the claim 1-9, it is used for the treatment of the lipid metabolism obstacle and comprises hyperlipemia and hyperlipoproteinemia and/or inflammatory diseases or illness.
12. each at least a chemical entity among the claim 1-9, it is used for the treatment of diabetes hyperlipemia, mixes hyperlipemia, heart failure, hypercholesterolemia, cardiovascular disorder comprise atherosclerosis, arteriosclerosis and hypertriglyceridemia, type ii diabetes, type i diabetes, insulin resistant, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, stenocardia, chronic renal failure, peripheral vascular disease or apoplexy.
13. at least a chemical entity of claim 1-9 in each is used for preparation treatment diabetes hyperlipemia, mixes hyperlipemia, heart failure, hypercholesterolemia, cardiovascular disorder comprise atherosclerosis, arteriosclerosis and hypertriglyceridemia, type ii diabetes, type i diabetes, insulin resistant, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, stenocardia, the purposes in the medicine of chronic renal failure or apoplexy.
14. treatment has by the not enough caused illness of HM74A receptor activation or benefits from the method for human or animal's object of the illness that activates the HM74A acceptor, described method comprises at least a chemical entity in each to the claim 1-9 of described human or animal's object effective dosage.
15. according to the method for claim 14, wherein said human or animal patient suffers from the lipid metabolism obstacle and comprises hyperlipemia or hyperlipoproteinemia or inflammatory diseases or illness.
16. pharmaceutical preparation, it contains among the with good grounds claim 1-9 each at least a chemical entity and at least a pharmaceutically acceptable thinner, vehicle or carrier.
17. be used for together or separately, successively or the combination of administration simultaneously with alone or in combination pharmaceutical dosage forms, described combination comprises according to each at least a chemical entity and other therapeutic activity agent among the claim 1-9.
18. pharmaceutical preparation, it contains:
(i) each at least a chemical entity among the claim 1-9;
(ii) one or more are selected from the therapeutic activity agent in Statins, the special class of chlorine shellfish, bile acide binding resin and the nicotinic acid; And
(iii) one or more pharmaceutically acceptable thinners, vehicle or carrier.
19. prepare each the method for at least a chemical entity of claim 1-9, wherein R by suitable starting material
3Be halogen, described starting material is the compound of formula (II) for example:
PG=protecting group wherein, described method comprises:
(i) carry out alkylation at the protected xanthic N1 of N7 place;
(ii) carry out alkylation at the protected xanthic N3 of N7 place;
(iii) carry out halogenation at the C8 place; And
The (iv) deprotection of N7;
Above-mentioned steps is carried out with any order, and condition is to carry out deprotection after the alkylation.
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| GB0516464A GB0516464D0 (en) | 2005-08-10 | 2005-08-10 | Novel compounds |
| GB0607736.6 | 2006-04-19 | ||
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| CN102276610A (en) * | 2011-05-04 | 2011-12-14 | 北京工业大学 | Method for preparing N7-guanine alkylate |
| CN103180314A (en) * | 2010-08-16 | 2013-06-26 | 贝林格尔.英格海姆国际有限公司 | Oxadiazole inhibitors of leukotriene production |
| CN110461838A (en) * | 2017-03-07 | 2019-11-15 | 豪夫迈·罗氏有限公司 | Oxadiazoles transient receptor potential channel inhibitor |
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| CA3155338A1 (en) * | 2019-09-25 | 2021-04-01 | Goldfinch Bio, Inc. | Xanthine cb1 inhibitors |
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| GB0319124D0 (en) * | 2003-08-14 | 2003-09-17 | Smithkline Beecham Corp | Chemical compounds |
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| CN103180314A (en) * | 2010-08-16 | 2013-06-26 | 贝林格尔.英格海姆国际有限公司 | Oxadiazole inhibitors of leukotriene production |
| CN102276610A (en) * | 2011-05-04 | 2011-12-14 | 北京工业大学 | Method for preparing N7-guanine alkylate |
| CN110461838A (en) * | 2017-03-07 | 2019-11-15 | 豪夫迈·罗氏有限公司 | Oxadiazoles transient receptor potential channel inhibitor |
| CN114874209A (en) * | 2017-03-07 | 2022-08-09 | 豪夫迈·罗氏有限公司 | Oxadiazole transient receptor potential channel inhibitors |
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| CN101282977B (en) | 2011-07-27 |
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