CN1871231A - Pyrazine derivatives and pharmaceutical use thereof - Google Patents

Pyrazine derivatives and pharmaceutical use thereof Download PDF

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Publication number
CN1871231A
CN1871231A CN200480031570.1A CN200480031570A CN1871231A CN 1871231 A CN1871231 A CN 1871231A CN 200480031570 A CN200480031570 A CN 200480031570A CN 1871231 A CN1871231 A CN 1871231A
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compound
salt
amino
propyl
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余西敏
青木敏
松岛雄司
赤羽厚
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Astellas Pharma Inc
Yamanouchi Pharmaceutical Co Ltd
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Yamanouchi Pharmaceutical Co Ltd
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Abstract

A pyrazine derivative of the following formula (I): or a salt thereof. The pyrazine compound (I) and a salt thereof of the present invention are adenosine antagonists and are useful for the prevention and/or treatment of depression, dementia (e.g. Alzheimer's disease, cerebrovascular dementia, dementia accompanying Parkinson's, disease, etc.), Parkinson's disease, anxiety, pain, cerebrovascular disease (e.g. stroke), etc.), heart failure and the like.

Description

Pyrazines derivatives and medicinal use thereof
Technical field
The present invention relates to a kind of novel pyrazines derivatives and salt thereof, it can be used as medicine.
Background technology
Adenosine is ubiquitous biochemical courier.Adenosine connects and activates 7 strides film G-protein-coupled receptor, causes various physiological response.It (is A that Adenosine Receptors is divided into four kinds of known hypotypes 1, A 2a, A 2bAnd A 3).That these receptor subtypes transmit is different, opposite effect sometimes.For example, adenosine A 1The activation of acceptor improves kidney blood vessel resistance, and adenosine A 2aThe activation of acceptor causes the reduction of kidney blood vessel resistance.Therefore, adenosine antagonist can be used for preventing and/or treating multiple disease, comprises degenerative disease, respiratory disease, and the multiple disease that is suitable for diuretic therapy of cardiovascular disorder, central nervous system.
The 2-aminopyridine compounds (WO02/14282, WO 01/25210 etc.) of more known demonstration Adenosine Receptors antagonistic actions, also known 2-aminopyrimidine compounds (US2001/0027196 etc.).
Yet generally to make the pyrazine that four kinds of different substituents replace, for example existing people's report form A pyrazine compound is synthetic:
Figure A20048003157000091
In the formula, Ar and Ar ' are identical or different aryl independently; And
R, R ' and M be independently hydrogen or suitably substituting group (as (1) J.Org.Chem., 40, 2341 (1975)., (2) J.Heterocyclic Chem., 15665 (1978), (3) J.Chem.Soc., Perkin Trans.1,885 (1994)., (4) Synthesis, 931 (1994)., (5) WO-02/088084 etc.), however its Ar and Ar ' are identical and as far as our knowledge goes, the selectivity that does not show the pyrazine compound A that its Ar and Ar ' are different is synthetic, and 2-amino-6-aryl-5-aryl-5-(6-oxo-1,6-dihydro-pyridin-3-yl)-pyrazine compound and derivative thereof be novel, therefore still has nothing to do in any knowledge of these compounds for order so far.And, have both adenosine A 1And A 2aIt all is unknown suppressing active any pyrazines derivatives.
Summary of the invention
The present invention relates to a kind of novel pyrazines derivatives and pharmaceutically acceptable salt thereof, this derivative can be used as medicine nontoxic or low toxicity (particularly convulsibility toxicity); The manufacture method of pyrazines derivatives and salt thereof; A kind of pharmaceutical composition comprises described pyrazines derivatives or its pharmaceutically acceptable salt as effective constituent; Described pyrazines derivatives or its pharmaceutically acceptable salt are as the purposes of medicament; And use described pyrazines derivatives or its pharmaceutically acceptable salt to reach the method for therapeutic purpose, comprise the described pyrazines derivatives of human or animal's administration or its pharmaceutically acceptable salt.
This pyrazines derivatives and salt thereof are adenosine antagonist (A particularly 1Acceptor and A 2(A especially 2a) acceptor binary antagonist); and have various different pharmacological actions, as catalepsy effect, cognitive promoter action, analgesic effect, motion effect, antidepressant effect, diuretic properties, cardioprotection, cardiotonic, vasorelaxation action (as the cerebral vasodilation effect etc.), increase the effect of kidney blood flow, kidney provide protection, renal function improvement effect, steatolysis enhancement, supersensitivity tracheae and shrink restraining effect, Regular Insulin and discharge booster action, increase the effect that erythropoietin produces, the effect of anticoagulant etc.
They can be used as cognitive promotor, anxiolytic, the dementia resisting medicine, psychostimulant, pain killer, heart protective agent, antidepressive, and circulation activator, tranquillizer, the heart failure therapy medicine, cardiotonic drug, hypotensive agent, renal failure (renal function deficiency) curative, the renal toxicity curative, the kidney protective material, the renal function activator, diuretic(s), the edema therapeutic medicine, antiobesity agent, anti-asthma agent, tracheae diastole agent, curative suffocates, gout therapertics, the hyperuricemia curative, burst infant death syndrome (SIDS) curative, adenosine immunosuppressive action activator, antidiabetic, the ulcer treatment medicine, the pancreatitis curative, auditory vertigo syndrome curative, the treatment for anemia medicine, the thrombus treatment medicine, the treatment of myocardial infarction medicine, block curative, the atherosclerosis obliterans curative, the thrombophlebitis curative, the cerebral infarction therapy medicine, temporary transient ischemic stroke curative, angina pectoris treatment medicine etc.; And can be used for preventing and/or treating dysthymia disorders, dementia (as Alzheimer's disease, cerebrovascular dementia, follow Parkinson's disease dementia etc.), Parkinson's disease, anxiety disorder, pain, cerebrovascular disease (as apoplexy etc.), heart failure; Hypertension (as essential hypertension, nephrogenic hypertension etc.); By the circulatory function deficiency (acute circulatory function deficiency) that causes as ischemia/reperfusion injury (as myocardial ischemia, Cerebral Ischemia damage, peripheral blood vessel ischemia/reperfusion injury etc.), shock (as endotoxin shock, hemorrhagic shock etc.), operative procedure etc.; Asystolia after reviving; The rhythm of the heart low; Dynamo-electric disassociation, Hemodynamics depletion; SIRS (general inflammatory response syndrome); Multiple organ failure; Renal failure (renal insufficiency) (as acute renal failure etc.), renal toxicity are [as because of cis-platinum, gentamicin, FR=900506 (being disclosed in EP-0184162), the renal toxicity that cyclosporins medicines such as (e.g. Sandimmunes) and glycerine etc. cause], nephrosis, ephritis, oedema (after one's own heart swollen, the spontaneous oedema of oedema, renal edema, edema due to dysfunction of the liver, medicine oedema, acute vascular neuropathic edema, heredity nervus vasculairs characteristic of disease oedema, carninomatosis ascites, stomach oedema etc.); The hypertension that obesity, bronchial asthma, gout, high blood Aciduria, sudden infant death syndrome, immunosuppression, glycosuria disease, ulcer such as digestive tract ulcer (as stomach ulcer, duodenal ulcer etc.), pancreatitis, auditory vertigo syndrome, anaemia, dialysis are brought out, constipation, ischemia large intestine disease, intestinal obstruction (as institutional intestinal obstruction, the hard resistance of unable property intestines etc.); Reach myocardial infarction, thrombus (as arterial thrombus, cerebral thrombosis etc.), obstruction, atherosclerosis obliterans, thrombophlebitis, cerebral infarction, temporary transient ischemic stroke, stenocardia etc.
Novel pyrazines derivatives of the present invention or its salt, availablely represent with following formula (I):
Figure A20048003157000111
In the formula
R 1Be
In the formula
R 6Be hydrogen, or the optional low alkyl group that replaces;
R 7Be hydrogen or halogen;
R 8Be low alkyl group;
R 2Be hydrogen; Hydroxyl; Halogen; Cyano group; Or each low alkyl group, low-grade alkenyl, alkynyl of low-grade chain, lower alkoxy, aryloxy, arylthio, acyl group, aryl, heterocyclic radical or amino that all randomly has substituting group to replace;
R 3And R 4Be hydrogen, low alkyl group or acyl group independently; And
R 5Be each low alkyl group, low-grade alkenyl, low-grade alkynyl, cyano group, aryl or heterocyclic radical that all randomly has substituting group to replace;
Or its salt.
The preferable embodiment of the pyrazine compound of the present invention of general formula I representative is as follows.
(1) pyrazine compound of general formula (I)
Wherein
R 1For
Figure A20048003157000121
In the formula
R 6Be hydrogen, low alkyl group, aryl (rudimentary) alkyl, heteroaryl (rudimentary) alkyl;
R 7Be hydrogen or halogen;
R 2For hydrogen, halogen, cyano group, randomly have the low alkyl group of replacement, randomly low-grade alkynyl, lower alkoxy, aryloxy, arylthio, formamyl, carboxyl, the shielded carboxyl of replacement or the amino of replacement is randomly arranged arranged;
R 3And R 4Be hydrogen or low alkyl group independently; And
R 5Be aryl or the heteroaryl that randomly has one or more substituting groups to replace separately;
Or its salt.
(2) pyrazine compound of above (1),
Wherein
R 2Be hydrogen, halogen, cyano group, hydroxylation (rudimentary) alkyl, low-grade alkynyl, lower alkoxy, aryloxy, arylthio, carboxyl, esterifying carboxyl group, formamyl, amidation carboxyl, amino or single or two (rudimentary) alkylamino radical;
R 3And R 4Be hydrogen independently;
R 5Be aryl or heteroaryl, each all randomly has one or more substituting groups that are selected from halogen and lower alkoxy to replace;
R 6Be hydrogen or low alkyl group; And
R 7Be hydrogen;
Or its salt.
(3) pyrazine compound of above (2),
Wherein
R 2Be hydrogen, bromine, cyano group, methylol, hydroxyethyl, hydroxypropyl, ethynyl, methoxyl group, oxyethyl group, propoxy-, phenoxy group, thiophenyl, carboxyl, formamyl, list or dimethylin carbonyl, picolyl aminocarboxyl, hydroxyl methylamino carbonyl or list or dimethylin;
R 3And R 4Be hydrogen independently;
R 5Be phenyl, pyridyl, furyl, thienyl, pyrryl or pyrazolyl, each all randomly has one or more substituting group replacements that are selected from fluorine, chlorine, reach methoxyl group;
R 6Be hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl or the tertiary butyl; And
R 7Be hydrogen;
Or its salt.
(4) pyrazine compound of above (3),
Wherein
R 2Be hydrogen, cyano group, ethynyl, methoxyl group, phenoxy group, thiophenyl, carboxyl, formamyl or methylamino; And
R 5Be phenyl, furyl or thienyl, each all randomly have one or more be selected from fluorine, chlorine, and the substituting group of methoxyl group replace;
Or its salt.
(5) pyrazine compound of above (4),
Wherein,
R 2Be hydrogen, cyano group, carboxyl, formamyl or methylamino;
R 5Be the phenyl that randomly has one or more fluorine to replace; And
R 6Be hydrogen, methyl, ethyl or sec.-propyl;
Or its salt.
Target compound of the present invention (I) and salt thereof can be with following method manufacturings.
Method 1
Figure A20048003157000141
Method 2
Method 3
Method 4
Method 5
Method 6
Figure A20048003157000153
Method 7
Figure A20048003157000154
Method 8
Figure A20048003157000161
Wherein, R 1, R 2, R 3, R 4, R 5And R 8And each is as above definition;
R 9Be cyano group, formamyl or carboxyl;
R 10Be the optional low alkyl group that replaces;
R 11And R 12Be hydrogen, low alkyl group, lower alkoxy or ring (rudimentary) alkyl independently, each all randomly has substituting group to replace; Or R 11And R 12Represent a nitrogen heterocycle that replacement is randomly arranged together with the nitrogen-atoms that they connected;
R 13Be low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, aryloxy, arylthio, acyl group, aryl, heterocyclic radical or amino, each all randomly has substituting group to replace;
Y is a leavings group;
Hal is a halogen atom; And
Z is hydrogen, basic metal (as lithium, sodium, potassium etc.), SnBu 3, BW 2, or Met-Hal; Wherein BW2 is the part of organoboron compound, as B (OH) 2, B (CHCH 3CH (CH 3) 2) 2, tetramethyl--1,3, assorted dicyclo [3.3.1] nonyl of 2-dioxo bora penta ring-2-base, 9-boron etc.; And
Met-Hal is the part of metal halide, as MgBr, and ZnCl etc.
Can prepare initial compounds or its salt by following reaction process.
Method A
Method B
Figure A20048003157000172
Method C
Figure A20048003157000173
Method D
Method E
R wherein 1, R 2, R 3, R 4, R 10, Y and Hal are respectively as above definition.
In addition to the above methods, target compound (I) and salt thereof can be according to as in this specification sheetss Real Execute exampleDescribed step or mode similar with it prepare.
Initial compounds can be according in this specification sheets PreparationDescribed step or mode similar with it prepare.
Target compound (I) and salt thereof can according to PreparationOr EmbodimentDescribed in method or mode similar with it prepare.
The solvation form (as hydrate etc.) and any crystallized form of compound (I) that also are noted that compound (I) all comprise within the scope of the invention.
Be noted that also radiolabeled compound (I) derivative that is suitable for biological study is also included within the scope of the invention.
The suitable salt of target compound (I) is acceptable salt on the known drug, comprise metal-salt, as an alkali metal salt (as sodium salt, sylvite etc.) and alkaline earth salt (as calcium salt, magnesium salts etc.), ammonium salt, organic alkali salt is (as trismethylamine salt, triethyl amine salt, pyridinium salt, picoline salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt etc.), organic acid salt is (as acetate, trifluoroacetate, maleate, tartrate, fumarate, mesylate, benzene sulfonate, formate, tosylate etc.), inorganic acid salt (example hydrochloric acid salt, hydrobromate, hydriodate, vitriol, phosphoric acid salt etc.), amino acid is (as arginine, aspartic acid, L-GLUTAMICACID) salt etc.
Present invention resides in its scope, and this specification sheets above-mentioned and following in the suitable example and illustrating of various definition of appearance be explained as follows in detail.
This term means " do not have replacement or replacement is arranged " " replacement randomly ".
" rudimentary " this term means 1-6 carbon atom person, unless point out in addition.
Suitable " low alkyl group " reaches " (low alkyl group) " segment in " single or two (paper level) alkylamino radical " this term, can comprise straight chain or branched chain wherein is preferably methyl, ethyl or sec.-propyl as methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group, hexyl etc.
Suitable " low alkyl group that replacement is randomly arranged " can comprise the low alkyl group that randomly has suitable substituting group such as lower alkoxy, hydroxyl, aryloxy, ring (rudimentary) alkyl, amino, aryl, heterocyclic radical or acyl group etc. to replace.
That suitable " lower alkoxy " can comprise straight chain or branched chain, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, pentyloxy, hexyloxy etc.
The lower alkoxy of replacements such as suitable " lower alkoxy that replacement is randomly arranged " can comprise randomly suitable substituting group such as hydroxyl, ring (low alkyl), amino, aryl, heterocyclic radical, acyl group.
Suitable " ring (low) alkyl " can be ring (C 3-C 8) alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc., wherein be preferably cyclohexyl.
That suitable " low-grade alkenyl " can comprise straight chain or branched chain, as vinyl, propenyl, allyl group, pseudoallyl, butenyl, pentenyl, hexenyl etc., wherein be preferably vinyl.
Suitable " the replacement low-grade alkenyl is randomly arranged " can comprise the low-grade alkenyl that randomly has suitable substituting group to replace, and suitably substituting group is for example lower alkoxy, hydroxyl, ring (rudimentary) alkyl, amino, aryl, heterocyclic radical, acyl group etc.
That suitable " low-grade alkynyl " can comprise straight chain or branched chain, as ethynyl, proyl, butynyl, pentynyl, hexin base etc., wherein be preferably ethynyl.
Suitable " low-grade alkynyl that replacement is randomly arranged " can comprise the low-grade alkynyl that randomly has suitable substituting group to replace, and suitable substituting group is for example lower alkoxy, hydroxyl, ring (rudimentary) alkyl, amino, aryl, heterocyclic radical, acyl group etc.
" aryl " segment that suitable " aryl " reaches in " aryloxy " or " arylthio " can comprise phenyl, naphthyl, indenyl, anthryl etc., wherein is preferably C 6-C 10Aryl is more preferred from phenyl.
Suitable " aryl (rudimentary) alkyl " can comprise phenyl (rudimentary) alkyl (as benzyl, styroyl etc.), phenylbenzene (rudimentary) alkyl (as diphenyl-methyl etc.), triphenyl (rudimentary) alkyl (as trityl etc.), naphthalene (rudimentary) alkyl, indenes (paper level) alkyl or anthracene (rudimentary) alkyl etc., wherein be preferably benzene (rudimentary) alkyl, be more preferred from benzene (C 1-C 4) alkyl.
Suitable " aryl that replacement is randomly arranged " can comprise the aryl that randomly has suitable substituting group to replace, and suitable substituting group is preferably 1-3 substituting group, as low alkyl group, lower alkoxy, hydroxyl, halogen etc.Randomly there is the suitable example of the aryl of replacement to comprise lower alkyl phenyl, rudimentary alkoxyphenyl radical, reaches the halobenzene base.
Suitable " heterocyclic radical " can be and contain at least one and be selected from oxygen, sulphur, and the heteroatomic saturated or undersaturated monocycle of nitrogen or encircle heterocyclic radical more.
The good especially example of described heterocyclic radical can comprise: the unsaturated heteromonocyclic group of 3-8 person that contains 1-4 nitrogen-atoms, as pyrryl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and N-oxide compound thereof, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (as 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazyl (as 1H-tetrazyl, 2H-tetrazyl etc.) dihydrogen triazine base (4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl etc.) etc.;
The saturated heteromonocyclic group of 3-8 person that contains 1-4 nitrogen-atoms is as azetidinyl, pyrrolidyl, imidazolidyl, piperidyl (as piperidino-(1-position only)), piperazinyl etc.;
The unsaturated annelated heterocycles base that contains 1-5 nitrogen-atoms, as indyl, pseudoindoyl, indolizine base, benzimidazolyl-, quinolyl, isoquinolyl, indazolyl, benzotriazole base, tetrazolo pyridyl, tetrazolo pyridazinyl (as tetrazolo [1,5-b] pyridazinyl etc.), dihydro Triazolopyridazines base etc.;
The unsaturated heteromonocyclic group of 3-8 person that contains 1 or 2 Sauerstoffatom and 1-3 nitrogen-atoms is as  azoles base, different  azoles base,  di azoly (as 1,2,4- di azoly, 1,3,4- di azoly, 1,2,5- di azoly etc.) etc.;
The saturated heteromonocyclic group of 3-8 person that contains 1 or 2 Sauerstoffatom and 1-3 nitrogen-atoms is as morpholinyl,  oxazolidinyl (as 1,3- oxazolidinyl etc.) etc.;
The unsaturated annelated heterocycles base that contains 1 or 2 Sauerstoffatom and 1-3 nitrogen-atoms is as benzoxazol base, benzo  di azoly etc.;
The unsaturated heteromonocyclic group of 3-8 person that contains 1 or 2 sulphur atom and 1-3 nitrogen-atoms, as thiazolyl, isothiazolyl, thiazolinyl, thiadiazolyl group (as 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,2,3-thiadiazolyl group etc.) etc.;
The saturated heteromonocyclic group of 3-8 person that contains 1 or 2 sulphur atom and 1-3 nitrogen-atoms is as thiazolidyl etc.;
The unsaturated heteromonocyclic group of 3-8 person that contains 1 sulphur atom is as thienyl etc.;
The unsaturated annelated heterocycles base of 3-8 person that contains 1 or 2 sulphur atom and 1-3 nitrogen-atoms is as benzothiazolyl, diazosulfide base etc.;
The 3-8 person's unsaturated heterocycle base that contains 1 or 2 Sauerstoffatom is as furyl, pyranyl, dioxolyl etc.;
The saturated heteromonocyclic group of 3-8 person that contains 1 or 2 Sauerstoffatom is as oxa-cyclohexyl, THP trtrahydropyranyl (as tetrahydrochysene-2H-pyrans-2-base etc.), dioxacyclohexyl etc.; And
The unsaturated heterocyclic radical that contracts of 3-8 person that contains 1 or 2 Sauerstoffatom is as isobenzofuran-base, chromenyl (as 2H-chromene-3-base etc.), dihydro chromenyl (as 3,4-dihydro-2H-chromene-4-base etc.) etc.
Suitable " heterocycle that replacement is randomly arranged " can comprise the heterocyclic radical that randomly has suitable substituting group to replace, and is preferably 1-3 substituting group and replaces, and suitably substituting group is such as low alkyl group, lower alkoxy, hydroxyl, halogen etc.
Suitable " nitrogen heterocycle " can be above-mentioned " heterocyclic radical ", wherein said group comprises at least 1 nitrogen-atoms in its ring members, as pyrryl, pyrrolinyl, imidazolyl, pyrazolyl, triazolyl, tetrazyl, dihydrogen triazine base, azelidinyl, pyrrolidyl, imidazolidyl, piperidyl, piperazinyl, indyl, pseudoindoyl, indazolyl, benzotriazole base, dihydro Triazolopyridazines base, morpholinyl,  oxazolidinyl, thiazolinyl, thiazolidyl etc.
" heteroaryl " segment that suitable " heteroaryl " reaches in " heteroaryl (low alkyl group) " this term can be above-mentioned " heterocyclic radical ", wherein be categorized as aromatic heterocyclic radical, as pyrryl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazyl, the dihydrogen triazine base, indyl, pseudoindoyl, the indolizine base, benzimidazolyl-, quinolyl, isoquinolyl, indazolyl, the benzotriazole base, the tetrazolo pyridyl, the tetrazolo pyridazinyl, dihydro Triazolopyridazines base,  azoles base, different  azoles base, the  di azoly, the benzoxazol base, benzo  di azoly, thiazolyl, isothiazolyl, thiazolinyl, thiadiazolyl group, thienyl, benzothiazolyl, the diazosulfide base, furyl, pyranyl, dioxacyclohexyl, isobenzofuran-base, chromenyl, dihydro chromenyl etc.
Suitable " acyl group " can comprise lower alkane acyl group, aroyl, carboxyl, protected carboxyl etc.
Suitable " lower alkane acyl group " example can be formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, valeryl, caproyl etc., and wherein the preferably can be (C 1-C 4) alkyloyl.
Suitable " aroyl " can be benzoyl, toluyl etc.
Suitable described " protected carboxyl " can be
I) esterifying carboxyl group, wherein suitable esterifying carboxyl group can comprise lower alkoxycarbonyl (as methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, butoxy carbonyl, tertbutyloxycarbonyl, penta oxygen carbonyl, own oxygen carbonyl etc.), aryl (rudimentary) carbalkoxy (as carbobenzoxy-(Cbz), benzene ethoxycarbonyl, the 2-phenyl third oxygen carbonyl, 4-phenyl butoxy carbonyl, 4-phenyl penta oxygen carbonyl, 1, the own oxygen carbonyl of 3-phenylbenzene etc.) etc.;
Ii) amidation carboxyl; wherein suitable amidation carboxyl can comprise formamyl; N-(rudimentary) alkyl-carbamoyl is (as N-methylamino formyl radical; N-ethylamino formyl radical; N-sec.-propyl formamyl; N-butyl formamyl; N-amyl group formamyl; N-hexyl formamyl etc.); N; N-two (rudimentary) alkyl-carbamoyl is [as N; the N-formyl-dimethylamino; N; N-diethylamino formyl radical; N-methyl-N-ethylamino formyl radical; N; N-dipropyl formamyl; N, N-two (tertiary butyl) formamyl; N-amyl group-N-hexyl formamyl etc.]; N-low alkyl group-N-aryl (rudimentary) alkyl-carbamoyl (as N-methyl-N-benzylamino formyl radical etc.) etc.
Suitable " halogen " can be fluorine, chlorine, bromine, iodine.
Suitable " leavings group " can comprise acyloxy such as halogen, hydroxyl, alkanoyloxy (as acetoxyl group, propionyloxy etc.) or sulfonyloxy (as mesyloxy, tosyloxy etc.) etc.
Suitable " amino that replacement is randomly arranged " can comprise amino, list or two (rudimentary) alkylamino radical (as methylamino, dimethylin, methyl ethyl-amine base etc.), amide group (as rudimentary alcoxyl carbonyl amido (as methoxy carbonyl amido, ethoxy carbonyl amido etc.), sulfoamido (as the methylsulfonyl amido etc.), urea groups etc.) etc.
The preparation method of purpose pyrazine compound (I) is explained as follows in detail.
Method 1
Make compound (II) or its salt and compound (III) or its salt carry out coupled reaction and can prepare compound (I) or its salt.
This reaction is carried out in known solvent usually, this solvent comprises for example water, acetone, two  alkane, acetonitrile, 1,2-glycol dimethyl ether, chloroform, methylene dichloride, 1,2-ethylene dichloride, tetrahydrofuran (THF), ethyl acetate, N, dinethylformamide, methyl alcohol, ethanol, diethyl ether, 1,3-dimethyl-2-imidazolidone, N-Methyl pyrrolidone, N, N-dimethyl allene urea, its mixture or any other organic solvent that this reaction is not caused harmful effect.
This reaction has some preferablely to carry out in the presence of organic bases or mineral alkali, and this alkali for example comprises basic metal (as sodium, potassium etc.), alkaline-earth metal (as magnesium, calcium etc.), its hydride or oxyhydroxide or alkoxide or carbonate or supercarbonate or paraffinic acid, trialkylamine (as triethylamine, Trimethylamine 99 etc.), hydrazine, pyridine compounds (as pyridine, lutidine, picoline, 4-dimethylamino pyridine etc.), quinoline etc.
This reaction has some preferablely to carry out in the presence of catalyzer such as acid chloride (II), four (triphenyl phosphine) palladium (0) etc.
Temperature of reaction is unimportant, the reaction usually normal temperature, heat or heat under carry out.
Method 2
Make compound (Ia) or its salt hydrolysis can prepare compound (Iba) or its salt.
This reaction is carried out according to currently known methods.
Hydrolysis is carried out preferable comprising in the presence of the Lewis acid in alkali or acid.
Suitable alkali comprises mineral alkali and organic bases, as basic metal (as sodium, potassium etc.), alkaline-earth metal (as magnesium, calcium etc.), its oxyhydroxide or carbonate or supercarbonate, trialkylamine (as triethylamine, Trimethylamine 99 etc.), hydrazine, pyridine compounds (as pyridine, lutidine, picoline, 4-dimethylamino pyridine etc.), 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, quinoline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene etc.
Suitable acid comprises organic acid (as formic acid, acetate, propionic acid, trichoroacetic acid(TCA), trifluoroacetic acid etc.) and mineral acid (example hydrochloric acid, Hydrogen bromide, sulfuric acid, hydrogenchloride, hydrogen bromide etc.).
Use Lewis acid, in the presence of positively charged ion trapping agent (as phenylmethylether, phenol etc.), carry out as the elimination effect of boron tribromide, boron trichloride, boron trifluoride, aluminum chloride etc. is preferable.
Hydrolysis in the case comprises in the presence of the Lewis acid in acid usually to be carried out, and these acid comprise that Lewis acid can mixture uses, and hydrolysis point or numerical value can different because of condition (seeing embodiment part (embodiment 2,7,10,15) for details).
This reaction is usually at solvent such as water, alcohol (as methyl alcohol, ethanol, Virahol etc.), tetrahydrofuran (THF), two  alkane, toluene, methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide, N,N-dimethylacetamide or any this reaction not being caused in other organic solvent of harmful effect or its mixture are carried out.
Liquid alkali or acid also can be used as this solvent.
Temperature of reaction is unimportant, and reaction is carried out being cooled under the heating usually.
Method 3
Make compound (Ib) or its salt and compound (IV) or its salt generation alkylation, can prepare compound (Ic) or its salt.
The salt of suitable compound (IV) may be preferably those that enumerate for compound (I).
This reaction is carried out in solvent usually, as water, phosphate buffered saline buffer, acetone, chloroform, acetonitrile, oil of mirbane, methylene dichloride, 1,2-ethylene dichloride, methane amide, N, dinethylformamide, methyl alcohol, ethanol, sec-butyl alcohol, amylalcohol, diethyl ether, two  alkane, 1,2-glycol dimethyl ether, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) or any other organic solvent that this reaction is not caused harmful effect are preferably and have strong polarity person.In these solvents, hydrophilic solvent can mix use with water.When compound (IV) when being liquid, also available its as solvent.This reaction is preferablely carried out in the presence of alkali, as mineral alkali such as alkali metal hydroxide, alkali metal alcoholates (as potassium tert.-butoxide), alkaline carbonate, alkali metal hydrocarbonate, alkalimetal hydride (as sodium hydride etc.) or organic bases as three alkanamines (triethylamine etc.) or basic resin etc.
Temperature of reaction is unimportant, the reaction usually normal temperature, heat or heat under carry out.
Preferable in the presence of alkali metal halide, carry out (as sodium iodide, the potassiumiodide etc.) etc. of this reaction.
When Y be-during OH, may wait with triphenyl phosphine etc. and azo-2-carboxylic acid two (rudimentary) alkane ester (as diethylazodicarboxylate, diisopropyl azo-2-carboxylic acid etc.) OH is activated.
Method 4
Compound (Id) or its salt use alkali or acid hydrolysis can prepare compound (Ie) or its salt.This reaction can be carried out as the hydrolysis of using alkali described in the preceding method 2, and therefore reagent that will use and reaction conditions (as solvent, temperature of reaction etc.) can be with reference to those of step 2.
Method 5
Decarboxylic reaction by compound (Ie) or its salt can prepare compound (If) or its salt.
This reaction is carried out with currently known methods such as thermal decomposition method, acid decomposition etc.; Suitably the person is a thermal decomposition method in this case.
This reaction is usually at known inert solvent such as quinoline, dichlorobenzene, , dodecane, Dowtherm (phenylate-biphenyl eutectic mixture) or any this reaction not being caused in other organic solvent of harmful effect or its mixture are carried out; More suitable in this case person is 1, the 2-dichlorobenzene.
Temperature of reaction is unimportant, and reaction is carried out under 100-200 ℃ of heating condition usually.
Method 6
The amidation of compound (Ie) or its salt can prepare compound (Ig) or its salt.
This reaction is usually at known solvent such as water, acetone, two  alkane, acetonitrile, chloroform, methylene dichloride, 1,2-ethylene dichloride, tetrahydrofuran (THF), ethyl acetate, N, dinethylformamide, pyridine or any other organic solvent that this is not reacted the generation harmful effect, or carry out in its mixture.
This reacts preferable and carries out in the presence of known condensing agent, as N, N '-dicyclohexyl carbodiimide, N-cyclohexyl-N '-morpholino ethyl carbodiimide, N-cyclohexyl-N '-(4-diethylin cyclohexyl) carbodiimide, N, N '-di-isopropyl carbodiimide, N-ethyl-N '-(3-dimethylamino-propyl) carbodiimide, N, N-carbonyl diurethane (glyoxal ethyline), pentamethylene ketenes base-N-U-4527, phenylbenzene ketenes base-N-cyclohexyl imines, oxyethyl group acetylene, 1-alkoxyl group-1-vinylchlorid, tricresyl phosphite alkane ester, the polyphosphoric acid isopropyl ester, Phosphorus Oxychloride (phosphoryl chloride), trichlorine phosphoric acid, thionyl chloride, oxalyl chloride, triphenyl phosphine, 2-ethyl-different  the azoles of 7-hydroxy benzo  salt, the different  azoles  of hydroxide 2-ethyl-5-(sulfophenyl) molecule inner salt, 1-(to the chlorobenzene sulfonyloxy)-6-chloro-1H-benzotriazole, by N, dinethylformamide and thionyl chloride, phosgene, the what is called of prepared in reaction such as Phosphorus Oxychloride is taken this Mil's reagent (Vilismeier reagent); Deng.
This reaction also can be carried out in the presence of mineral alkali or organic bases, as alkali metal hydrocarbonate, three (rudimentary) alkanamine, pyridine, N-(rudimentary)-alkyl morpholine, N, and N-two (rudimentary) alkane benzylamine etc.
Temperature of reaction is unimportant, and reaction is carried out being cooled under the heating usually.
Method 7
Make compound (If) or its salt and halogenating agent such as N-halo succinimide (as N-chlorosuccinimide, N-bromosuccinimide etc.) etc. carry out halogenation, can prepare compound (Ih) or its salt.
This reaction is usually at solvent such as tetrahydrofuran (THF), two  alkane, toluene, methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide, N,N-dimethylacetamide or any organic solvent that this reaction is not caused harmful effect, or carry out in its mixture.
Method 8
Make compound (Ih) or its salt and compound (V) or its salt carry out coupled reaction and can prepare compound (Ij) or its salt.
This reaction can identical mode be carried out as the coupled reaction in the preceding method 1, reagent that therefore will use and reaction conditions (as solvent, temperature of reaction etc.) but reference method 1.
Method A
Compound (VI) or its salt can prepare compound (VII) or its salt with acid hydrolysis (as step 1 illustration).This reaction can with preceding method 2 in use the identical mode of the hydrolysis of acid to carry out, therefore reagent that will use and reaction conditions (as solvent, temperature of reaction etc.) but reference method 2.
Make compound (VII) or its salt and compound (IV) or its salt carry out alkylating (as step 2 illustration), can prepare target compound (VIII).This reaction can be carried out with identical mode in the preceding method 3, therefore reagent that will use and reaction conditions (as solvent, temperature of reaction etc.) but reference method 3.
Method B
Acetylizing (as step 1 illustration) from compound (IX) can prepare compound (X) or its salt with disclosed method in the aftermentioned preparation example 1 or mode similar with it.
Making compound (X) or its salt carry out in the preparation example 2 as described later oxime open or mode similar with it forms reaction and can prepare target compound (XI).
Method C
Make compound (XI) or its salt and amino propane dinitrile or its reactant salt can prepare compound (XII) or its salt.
This reacts preferable and carries out in the presence of catalyzer such as tosic acid etc.
This reaction is usually at known solvent such as water, acetone, two  alkane, acetonitrile, 1,2-glycol dimethyl ether, chloroform, methylene dichloride, 1,2-ethylene dichloride, tetrahydrofuran (THF), ethyl acetate, N, dinethylformamide, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, diethyl ether, isopropyl ether or any this reaction not being caused in other organic solvent of harmful effect or its mixture are carried out.
Temperature of reaction is unimportant, the reaction usually normal temperature, heat or heat under carry out.
This reaction can be undertaken by disclosed method in the aftermentioned preparation example 3 or mode similar with it.
Method D
Make compound (XIII) or its salt can prepare compound (XVI) or its salt with acid hydrolysis.
Method E
Compound (XV) or its salt and compound (XVI) or its salt are reacted to prepare compound (H) or its salt.
This reaction is usually at known solvent such as acetone, two  alkane, acetonitrile, 1,2-glycol dimethyl ether, chloroform, methylene dichloride, 1,2-ethylene dichloride, tetrachloro furans, ethyl acetate, N, dinethylformamide, diethyl ether, isopropyl ether or any this reaction not being caused in other organic solvent of harmful effect or its mixture are carried out.
This reaction can be carried out according to disclosed method in the aftermentioned preparation example 4 or mode similar with it.
Above method, all parent materials and product compound all can be salt.The compound of above method all can be converted into salt according to currently known methods.
Target compound of the present invention (I) is an adenosine antagonist, has the various pharmacotoxicological effects of as above claiming.
Embodiment
In order to manifest the availability of The compounds of this invention (I), below show the pharmacology test result of representative compounds of the present invention.
Test 1:
The adenosine antagonistic activity
[I] testing method
With the radioligand combination technology, use 8-cyclopentyl-1,3-dipropyl xanthine, [dipropyl-2,3- 3H (N)] ([ 3H] DPCPX, 4.5nM) be used for people A 1Acceptor, and [ 3H] CGS21680 (20nM) is used for people A 2aAcceptor, the adenosine antagonistic activity [Ki (nM)] of examination test compounds.
[II] test compounds
3-amino-6-(1-ethyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides (embodiment 4)
3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine nitrile (embodiment 11)
3-amino-5-(3, the 4-difluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine nitrile (embodiment 39)
3-amino-N-(cyanogen methyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides (embodiment 46)
5-[5-amino-6-(methylol)-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (embodiment 47)
3-amino-N-(2-hydroxyethyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides (embodiment 49)
5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-3-bromo-1-sec.-propyl-2 (1H)-pyridone (embodiment 53)
5-[5-amino-3-(2-thienyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (embodiment 115)
5-[5-amino-3-(3, the 5-difluorophenyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (embodiment 129)
5-[5-amino-6-bromo-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (embodiment 141)
5-[5-amino-6-(2-furyl)-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (embodiment 144)
5-(5-amino-6-phenoxy group-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (embodiment 151)
[III] test result
Table 1
Test compounds (embodiment number) Adenosine Receptors is in conjunction with (Ki:nM)
A 1 A 2a
4 11 39 46 47 49 53 115 129 141 144 151 5.09 22.47 23.99 5.25 22.27 6.07 0.93 4.89 10.71 0.61 1.78 1.57 2.34 2.35 6.52 1.49 7.52 1.69 0.91 0.84 3.90 0.23 0.54 0.32
Test 2: catalepsy activity in the mouse body
[I] testing method
To ddy mouse (n=7) this test compounds of oral administration (3.2mg/kg).Then, behind this compound administration 30 minutes through intraperitoneal injection haloperidol (0.32mg/kg) 30 minutes.Inject the catalepsy reaction of measuring mouse in back 30 minutes.The forelimb of every mouse is placed on the wide horizon bar of 3cm height, 3mm, the time length of measuring the catalepsy posture, reaches 30 seconds most.
[II] test compounds
3-amino-6-(1-ethyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides (embodiment 4)
3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine nitrile (embodiment 11)
3-amino-5-(3, the 4-difluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine nitrile (embodiment 39)
3-amino-N-(cyanogen methyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides (embodiment 46)
5-[5-amino-6-(methylol)-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (embodiment 47)
3-amino-N-(2-hydroxyethyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides (embodiment 49)
5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-3-bromo-1-sec.-propyl-2 (1H)-pyridone (embodiment 53)
5-[5-amino-3-(2-thienyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (embodiment 115)
5-[5-amino-3-(3, the 5-difluorophenyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (embodiment 129)
5-[5-amino-6-bromo-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (embodiment 141)
5-[5-amino-6-(2-furyl)-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (embodiment 144)
5-(5-amino-6-phenoxy group-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (embodiment 151)
[III] test result
Table 2
Test compounds (embodiment number) Catalepsy occurrence rate (mouse quantity)
4 11 39 46 47 49 53 115 129 141 144 151 0/7 0/7 0/7 0/7 1/7 1/7 0/7 0/7 0/7 0/7 0/7 0/7
Pyrazine compound of the present invention (I) and salt thereof can be used as adenosine antagonist (A particularly 1Acceptor and A 2(especially be A 2a) acceptor binary antagonist), be used to prevent and/or treat dysthymia disorders, dementia (as Alzheimer's disease, cerebrovascular dementia disease, follow the dementia of parkinsonism etc.), Parkinson's disease, anxiety, pain, cerebrovascular disease, heart failure, hypertension, circulatory function deficiency, recovery back asystolia, the rhythm of the heart low, dynamo-electric disassociation, Hemodynamics depletion, SIRS (condensation of general inflammatory response is levied); Multiple organ failure; The hypertension that renal failure (renal insufficiency), renal toxicity, nephrosis, ephritis, oedema, obesity, bronchial asthma, gout, high blood Aciduria, sudden infant death syndrome, immunosuppression, diabetes, ulcer, pancreatitis, auditory vertigo syndrome, anaemia, dialysis are brought out, constipation, ischemia large intestine disease, intestinal obstruction, myocardial infarction, thrombus, obstruction, atherosclerosis obliterans, thrombophlebitis, cerebral infarction, temporary transient ischemic stroke, stenocardia etc.
Adenosine antagonist and L-3,4-Dihydroxyphenylalanine (L-DOPA) co-administered and be used for parkinsonism, this medicine is the most general curative of parkinsonism (R.Grondin et al., Neurology, 521673 (1999)).Therefore the combination of pyrazine compound of the present invention (I) and salt and L-DOPA also can be used for treating and/or preventing parkinsonism, the side effects such as onset of dyskinesia that reduction or minimizing cause as long-term application L-DOPA etc.
And then from using the viewpoint of these bonded as the field of medicine, these compounds should have the persistence of certain degree.The time length of pyrazine compound of the present invention (I) and salt thereof is contemplated to long-lasting.
Pharmaceutical composition of the present invention can use with pharmaceutical dosage forms, for example be solid, semisolid or liquid form, contain pyrazine compound (I) or its pharmaceutically acceptable salt as effective constituent, with the blending of organic or inorganic carrier or vehicle, be fit to per-rectum, through (via intranasal application or oral cavity suck) of lung, via intranasal application, through eye, external application (part), per os or parenteral (comprise through subcutaneous, through intravenously and through intramuscular) administration or be blown into.This effective constituent can be for example with nontoxic, medicine usually on can accept carrier and cooperate and be used for tablet, pill, lozenge, capsule, suppository, creme, ointment, aerosol, suction with powder agent, solution, emulsion agent, suspension liquor and any other fit for service form.In addition, adjuvant, stablizer, thickening material, tinting material and flavouring agent can use where necessary.Pyrazine compound (I) or its pharmaceutically acceptable salt are contained in the pharmaceutical composition with sufficient quantity, so that the lysis or the state of an illness are produced desirable above-mentioned medical effect.
For said composition is applied on the mankind or the animal, preferable with through intravenously, through intramuscular, through lung or oral administration or suction.Though the treatment significant quantity dosage of pyrazine compound (I) because of age of the individual patients that will treat, and the state of an illness different, but for preventing and/or treating above-mentioned disease, people under the situation of intravenous administration or animal per Kg body weight dosage every day is 0.01-100mg pyrazine compound (I), people under the situation of intramuscular administration or animal per Kg body weight dosage every day is 0.1-100mg pyrazine compound (I), and people or animal per Kg body weight dosage every day are 0.5-100mg pyrazine compound (I) under peroral administration situation.
Following preparation example and embodiment are used to be described in more detail purpose of the present invention.The shortenings, symbol and the term that use among preparation and the embodiment have following implication.
AcOH acetate
CHCl 3Chloroform
CH 2Cl 2Methylene dichloride
DME 1, the 2-glycol dimethyl ether
DMF N, dinethylformamide
The DMSO dimethyl sulfoxide (DMSO)
The EtOAc ethyl acetate
EtOH ethanol
The IPA Virahol
The IPE isopropyl ether
MeOH methyl alcohol
The MeCN acetonitrile
The NMP N-Methyl pyrrolidone
The THF tetrahydrofuran (THF)
HCl hydrochloric acid
NEt 3Triethylamine
The t-BuOK potassium tert.-butoxide
K 2CO 3Salt of wormwood
MgSO 4Sal epsom
The NaOAc sodium acetate
Na 2CO 3Yellow soda ash
The NaH sodium hydride
NaHCO 3Sodium bicarbonate
NaOH sodium hydroxide
The EtI iodoethane
The MeI methyl iodide
N-PrBr bromine n-propane
The different propane of i-PrI iodine
CuI cuprous iodide (cupric iodide (I))
PdCl 2(PPh 3) 2Dichloro two (triphenyl phosphine) palladium (II)
Pd (OAc) 2Acid chloride (II)
Pd (PPh 3) 4Four (triphenyl phosphine) palladium (II)
Aq. the aqueous solution
Conc. dense
Sat. saturated
Preparation 1
2-methoxyl group pyridinium bromide (25g) and normal-butyl Vinyl Ether (66.6g) are dissolved among the DMF (250ml).In this solution, add 1 under the nitrogen atmosphere, 3-two (diphenyl phosphine) propane (3.62g) and Pd (OAc) 2(896mg) and aq.K 2CO 3Stirred this reaction mixture 2 hours at 100-120 ℃.Mixture is cooled to 25 ℃.In this solution, add 1N aq.HCl (625ml).Stirred this solution 1 hour at 25-30 ℃.This solution distributes between EtOAc and water.Separate organic layer.Water layer extracts with EtOAc.The organic solution that merges is used MgSO with water and salt solution washing 4Dry.Evaporating solvent in the vacuum obtains the oily residue.(EtOAc: normal hexane=1: 5 v/v), obtains solid state 2-methoxyl group-5-acetylpyridine (12.14g) with silica gel chromatography purifying residue.
1H-NMR(DMSO-d 6δ)：2.56(3H，s)，3.95(3H，s)，6.92(1H，d，J＝8.4Hz)，8.17(1H，dd，J＝2.4，8.4Hz)，8.30(1H，d，J＝2.4Hz)
MS(ESI +)：152[M+H] +
Preparation 2
2-methoxyl group-5-the acetylpyridine (12.1g) and the nitric acid tert-butyl ester (9.92g) are dissolved among the THF (120ml).This solution is cooled to 0-5 ℃.In this solution, add t-BuOK (10.8g) at 5-25 ℃.Stirred this reaction mixture 2 hours at 25 ℃.In this mixture, add 1N HCl (105ml).This solution distributes between EtOAc and water.Separate organic layer.Water layer extracts with EtOAc.The organic layer that merges with 10%aq.NaOAc and salt solution washing, is used MgSO successively 4Dry.Evaporating solvent in the vacuum.Solid residue is with IPE (150ml) spraying powdered.The crystal of separating out filters to be collected, and obtains solid state (1E)-(6-methoxyl group-3-pyridyl) (oxo) ethylidenehydroxylamine (5.45g) (trans, cis mixture (anti-: suitable=1: 1)).Evaporated filtrate obtains residue.Residue grinds with IPE.The crystal of separating out filters to be collected, and obtains solid state (1E)-(6-methoxyl group-3-pyridyl) (oxo) ethylidenehydroxylamine (2.5g) (trans, cis mixture (anti-: suitable=1: 1)).
Trans
1H-NMR(DMSO-d 6δ)：3.95(3H，s)，6.95(1H，d，J＝8.4Hz)，8.00(1H，s)，8.23(1H，dd，J＝2.4，8.4Hz)，8.85(1H，d，J＝2.4Hz)，12.7(1H，s)
MS(ESI +)：181[M+H] +，203[M+Na] +
Cis
1H-NMR(DMSO-d 6δ)：3.96(3H，s)，7.00(1H，d，J＝8.4Hz)，7.59(1H，s)，8.09(1H，dd，J＝2.4，8.4Hz)，8.64(1H，d，J＝2.4Hz)，11.8(1H，s)，
MS(ESI +)：181[M+H] +，203[M+Na] +
Preparation 3
Make (1E)-(6-methoxyl group-3-pyridyl) (oxo) ethylidenehydroxylamine (5.4g) and amino propane dinitrile tosilate (7.6g) are suspended in the 2-propyl alcohol (108ml) and in 25 ℃ of stirrings.In this mixture, add tosic acid (5.71g).Heated these mixtures 2 hours, 1 hour at normal temperatures then at 50 ℃.Above-mentioned reaction mixture concentrates in a vacuum.In this concentrated solution, add sat.aq.NaOAc.Separate out crystal, stirred this suspension 15 hours at 20 ℃.Filter and collect this crystal, vacuum-drying obtains Powdered 3-amino-6-(6-methoxyl group-3-pyridyl)-2-pyrazine nitrile-4-oxide compound (6.65g).
1H-NMR(DMSO-d 6δ)：3.90(3H，s)，6.92(1H，d，J＝8.6Hz)，8.06(2H，brs)，8.23(1H，dd，J＝2.4，8.6Hz)，8.74(1H，d，J＝2.4Hz)，9.21(1H，s)
MS(ESI +)：244[M+H] +，
IR(KBr)：3386，3186，2238，1639，1610，1489，1189cm -1
Preparation 4
Make 3-amino-6-(6-methoxyl group-3-pyridyl)-2-pyrazine nitrile-4-oxide compound (6.65g) be dissolved in DMF (133ml).In this solution, add Phosphorus Oxychloride (12.6g) at 25 ℃.Normal temperature stirred this mixture 2 hours down.In this mixture, add entry (520ml).This solution was stirred 15 hours at 20-25 ℃.Filter and collect the crystal of separating out, vacuum-drying obtains Powdered 3-amino-5-chloro-6-(6-methoxyl group-3-pyridyl)-2-pyrazine nitrile (4.6g).With EtOAc extraction filtrate.Organic layer is used MgSO with water and salt solution washing 4Dry.Vacuum evaporating solvent obtains the oily residue.(EtOAc: normal hexane=1: 1 v/v), obtains Powdered 3-amino-5-chloro-6-(6-methoxyl group-3-pyridyl)-2-pyrazine nitrile (1.0g) with silica gel chromatography purifying residue.
1H-NMR(DMSO-d 6δ)：3.93(3H，s)，6.92(1H，d，J＝8.6Hz)，7.88(2H，s)，7.95(1H，dd，J＝2.4，8.6Hz)，8.43(1H，d，J＝2.4Hz)
MS(ESI +)：262[M+H] +，284(M+Na] +
IR(KBr)：3384，3187，2227，1656，1610，1475，1209cm -1
Preparation 5
2-methoxyl group-5-bromopyridine (615g) is dissolved among the 6N HCl (3l).This solution is 99-105 ℃ of heating.This mixture refluxes and stirred 5 hours.Above-mentioned reaction mixture is cooled to 5 ℃.Adjust pH value to 6.5 with 10%aq.NaOH.Filter and collect the crystal of separating out, with water (500ml) washing, vacuum-drying obtains crystalloid 5-bromo-2 (1H)-pyridones (570g).
1H-NMR (DMSO-d 6δ): 6.36 (1H, d, J=9.8Hz), 7.55 (1H, dd, J=2.8,9.8Hz), 7.69 (1H, d, J=2.4Hz), 11.7 (1H, s) MS (ESI +): 196 and 198[M+Na] +
Preparation 6
T-BuOK (32.2g) is added in the suspension of 5-bromo-2 (1H)-pyridones (50g) in DME (500ml).Mixture was stirred 30 minutes.In this mixture, add K 2CO 3(27.8g) with 2-iodopropane (81.6g).This mixture refluxes and stirred 3 hours.Said mixture is cooled to 20-25 ℃.Filter and remove the salt of separating out, wash with DME (100ml).Vacuum evaporating solvent obtains solid residue.Make residue be dissolved in CHCl 3(150ml).Wash this solution with 0.1N HCl and salt solution, use MgSO 4Dry.Vacuum evaporating solvent obtains solid residue.In residue, add normal hexane (150ml), grind residue.Filter and collect this throw out, vacuum-drying obtains 5-bromo-1-sec.-propyl-2 (1H)-pyridone (41.2g).
1H-NMR(DMSO-d 6δ)：1.29(6H，d，J＝6.8Hz)，4.99(1H，m)，6.36(1H，d，J＝9.6Hz)，7.48(1H，dd，J＝2.4，9.6Hz)，7.96(1H，d，J＝2.4Hz)
MS (ESI +): 216 and 218[M+H] +, 238 and 240[M+Na] +
Preparation 7
5-bromo-1-sec.-propyl-2 (1H)-pyridone (50g) is dissolved in the normal-butyl Vinyl Ether (250ml), in this solution, adds 1,3-two (diphenylphosphine) propane (6.3g) and Powdered K at 25 ℃ 2CO 3(38.2g) with Pd (OAc) 2(1.56g).This mixture was 90-95 ℃ of heating, stirring 8 hours.Make reaction mixture be cooled to 25-30 ℃.In this cooling mixture, add CHCl 3(125ml).Filter and remove the salt of separating out, with CHCl 3(125ml) washing.Solvent in the vacuum-evaporation filtrate obtains the oily residue.This residue is dissolved in CHCl 3(125ml).In this solution, add and go up 1N HCl (125ml).This reaction mixture stirred 1 hour at 25-30 ℃.Separate organic layer.Water layer is with CHCl 3(100ml) extraction.The organic layer that merges is with 10%aq.NaHCO 3(50ml) MgSO is used in washing 4(25g) with silica gel (25g) drying.Filter and remove MgSO 4With silica gel, with CHCl 3Washing.Solvent in the vacuum in the evaporated filtrate obtains the oily residue, with normal hexane (500ml) crystallization.Filter and collect crystallization,, obtain 5-ethanoyl-1-sec.-propyl-2 (1H)-pyridone (32.35g) 40 ℃ of vacuum-dryings.
1H-NMR(DMSO-d 6δ)：1.37(6H，d，J＝6.8Hz)，2.47(3H，s)，5.02(1H，m)，6.44(1H，d，J＝9.6Hz)，7.82(1H，dd，J＝2.6，9.6Hz)，8.41(1H，d，J＝2.6Hz)
MS(ESI +)：180[M+H] +，202[M+Na] +
Preparation 8
Make 5-ethanoyl-1-sec.-propyl-2 (1H)-pyridone be dissolved in CH 2Cl 2(300ml).Cool off this solution to-30～-25 ℃.In this cooling solution, add 4N hydrogenchloride two  alkane (55.3mol) solution and nitrite tert-butyl (10.4g) at-30～-25 ℃.The temperature that improves reaction mixture is to 20-25 ℃.This mixture stirred 3 hours at uniform temp.Filter and collect the crystal of separating out, air-dry at normal temperature, obtain (1E)-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl) (oxo) ethylidenehydroxylamine (14.0g).
1H-NMR(DMSO-d 6δ)：1.35(6H，d，J＝6.8Hz)，5.02(1H，m)，6.47(1H，d，J＝9.6Hz)，7.89(1H，dd，J＝2.4，9.6Hz)，8.00(1H，s)，8.69(1H，d，J＝2.4Hz)，12.65(1H，brs)
MS(ESI +)：209[M+H] +，231[M+Na] +
IR(KBr)：3129，1660，1617，1529，1018cm -1
Preparation 9
75-80 ℃ of heating (1E)-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl) (oxo) ethylidenehydroxylamine (14g) stirred 2 hours down with the mixture of amino propane dinitrile tosilate (17g) with IPA (210ml), uniform temp.This reaction mixture is cooled to 0-5 ℃, stirred 2 hours.Filter the collecting precipitation thing, dry in the vacuum, obtain 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine nitrile 4-oxo thing (9.2g).
1H-NMR(DMSO-d 6δ)：1.36(6H，d，J＝6.8Hz)，5.09(1H，m)，6.48(1H，d，J＝9.6Hz)，7.92-7.99(3H，m)，8.28(1H，d，J＝2.6Hz)，9.25(1H，s)
MS(ESI +)：293[M+Na] +
IR(KBr)：3122，2200，1656，1598，1531，1174cm -1
Preparation 10
Make 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine nitrile 4-oxide compound (9g) be dissolved in 25% Hydrogen bromide/AcOH solution (90ml) at 20-25 ℃.Reaction mixture normal temperature stirred 2 hours down.In reaction mixture, add two  alkane (180ml).Suspension normal temperature stirred 2 hours down.Filter the collecting precipitation thing, with the washing of two  alkane, normal temperature is air-dry.Above-mentioned powder suspends in water (90ml).Adjust this pH of suspension value to 8-8.5 with 1H NaOH (70ml).This suspension of stirring at normal temperature.Filter the collecting precipitation thing, with water washing, 50 ℃ of vacuum-dryings obtain 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides 4-oxide compound (8.80g).
1H-NMR(DMSO-d 6δ)：1.39(6H，d，J＝6.8Hz)，5.10(1H，m)，6.46(1H，d，J＝9.4Hz)，7.88(2H，s)，7.89(1H，s)，8.32(1H，dd，J＝2.4，9.4Hz)，8.41(1H，d，J＝2.4Hz)，8.51(1H，s)，9.15(1H，s)
MS(ESI +)：312[M+Na] +
IR(KBr)：3440，1660，1596，1554，1186cm -1
Preparation 11
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides 4-oxide compound (8g) is dissolved among the DMF (80ml).This solution is cooled to-30 ℃.In this cooling solution, drip phosphoryl chloride (12.7g) at-30～-40 ℃.After phosphoryl chloride added, reaction mixture temperature was increased to-10～-5 ℃.Mixture stirred 1 hour down at-10～-5 ℃.In reaction mixture, add water (400ml).Stirred this suspension 15 hours at 30～35 ℃.The pH value of adjusting this suspension is 4.5.Cool off this suspension to 0-5 ℃, uniform temp stirred 2 hours down.Filter the collecting precipitation thing, dry under the 40-50 ℃ of vacuum with water washing, obtain 3-amino-5-chloro-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides (7.1g).
1H-NMR(DMSO-d 6δ)：1.34(6H，d，J＝7.0Hz)，5.09(1H，m)，6.44(1H，d，J＝9.4Hz)，7.74(1H，s)，7.85(1H，dd，J＝2.4，9.4Hz)，7.85(2H，s)，8.13(1H，d，J＝2.4Hz)，8.13(1H，s)
MS (ESI +): 330 and 332[M+Na] +
IR(KBr)：3284，1673，1604，1461，1187cm -1
Preparation 12
Make 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides 4-oxide compound (29.1g) be dissolved in DMF (290ml).Cool off this solution to-30 ℃.In this cooling solution, drip phosphoryl chloride (46.3g) at-30～-40 ℃.After adding phosphoryl chloride, reaction mixture temperature is increased to 40-45 ℃.This mixture stirred 1 hour down at 40-45 ℃.In reaction mixture, add entry (1160ml).Stirred this suspension 15 hours at 30-35 ℃.Adjust this pH of suspension value to 7 with 12%aq.NaOH (400ml).Cool off this suspension to 0-5 ℃, uniform temp stirred 2 hours down.Filter the collecting precipitation thing, dry under the 40-50 ℃ of vacuum with water washing, obtain 3-amino-5-chloro-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine nitrile (17.2g).
1H-NMR(DMSO-d 6δ)：1.34(6H，d，J＝7.0Hz)，5.09(1H，m)，6.44(1H，d，J＝9.4Hz)，7.74(1H，s)，7.85(1H，dd，J＝2.4，9.4Hz)，7.85(2H，s)，8.13(1H，d，J＝2.4Hz)，8.13(1H，s)
MS(ESI +)：330[M+Na] +
IR(KBr)：3291，1662，1600，1465，1182cm -1
Preparation 13
The ice bath cooling adds sodium hydride in the 1-(diphenyl-methyl) in DMF (25ml)-3-azetidin alcohol hydrochloride (5.0g) solution down.Stirring makes this mixture go up to 25 ℃ under the equality of temperature after 10 minutes, stirs then 15 hours.EtOAc (500ml) is poured in this mixture with water (200ml).Separate organic layer,, use MgSO with water and salt solution washing 4Drying, decompression goes down to desolventize.Residue is with column chromatography purifying (silica gel; 200ml, toluene: EtOAc=15: 1-8: 1), obtain 1-(diphenyl-methyl)-3-methoxyl group azetidine (3.41g).
1H-NMR(DMSO-d 6δ)：2.7-2.9(2H，m)，3.12(3H，s)，3.3-3.5(2H，m)，3.99(1H，m)，4.40(1H，s)，7.1-7.4(6H，m)，7.3-7.5(4H，m)
MS(ESI +)：254[M+H] +
Preparation 14
Add 20% palladium hydroxide/charcoal (0.7g) in 1-(diphenyl-methyl) in MeOH (35ml)-3-methoxyl group azetidine (3.4g) solution.Under nitrogen atmosphere, stirred this mixture 2.5 hours then.In this mixture, add 1N HCl (20ml), filter then and remove catalyzer, wash with 1N HCl.Decompression goes down to desolventize.EtOAc and water are poured in the residue, separate water layer, wash with EtOAc.Decompression goes down to desolventize residue and EtOH azeotropic, vacuum-drying.Normal hexane is poured in the residue, the filtering separation crystallization, with the normal hexane washing, vacuum-drying obtains 3-methoxyl group azetidine hydrochloride (1.58g).
1H-NMR(DMSO-d 6δ)：3.21(3H，s)，3.6-3.9(2H，m)，4.0-4.4(3H，m)
MS (ESI +): 88[M+H] +(free state)
Preparation 15
5-bromo-2 (1H)-pyridone (200g) in 80 ℃ of heating DME (21) and MeI (324g) and K 2CO 3Mixture (318g) stirred 2 hours.Cool off this mixture to room temperature.Filter and remove the salt of separating out, wash with DME.Solvent in the vacuum-evaporation filtrate obtains the oily residue.Residue is allocated between EtOAc and the water.Separate organic layer.Water layer is with the EtOAc extracting twice.Use MgSO 4The dry organic solution that merges.Vacuum evaporating solvent obtains crystalline residue.Residue with IPE and normal hexane (1: 3,1000ml) spraying powdered.Filter collecting precipitation, vacuum-drying obtains white powder 5-bromo-1-methyl-2 (1H)-pyridone (182.5g).
1H-NMR(DMSO-d 6δ)：3.40(3H，s)，6.36(1H，d，J＝9.6Hz)，7.51(1H，dd，J＝2.8，9.6Hz)，8.03(1H，d，J＝2.8Hz)
MS (ESI +): 210 and 212[M+Na] +
Preparation 16
Make 5-bromo-1-methyl-2 (1H)-pyridone (150g) be dissolved in DMF (1500ml).In this solution, add 1,3-two (diphenyl phosphine) propane (21.7g), normal-butyl Vinyl Ether (400g), with 3M aq. salt of wormwood (262.5ml) and Pd (OAc) 2(10.2g).80 ℃ of these mixtures of heating stirred 3 hours under the equality of temperature.Reaction mixture is poured among the 1N HCl (1485ml) to 25-30 ℃.30-40 ℃ was stirred this mixture 2 hours down.Extract this solution with EtOAc (1500ml, three times).Water layer is with CH 2Cl 2(1000ml, three times) extraction.The organic solution MgSO that collects 4Dry.Evaporating solvent obtains solid residue, with IPA (150ml) and IPE (1500ml) spraying powdered.This suspension is statically placed in refrigerator overnight.Filter the collecting precipitation thing, vacuum-drying, ethanoyl-1-methyl-2 (1H)-pyridone is white powder (128g) to obtain 5-.
1H-NMR(DMSO-d 6δ)：2.41(3H，s)，3.52(3H，s)，6.42(1H，d，J＝9.6Hz)，7.84(1H，dd，J＝2.4，9.6Hz)，8.66(1H，d，J＝2.4Hz)
MS(ESI +)：152[M+H] +，174[M+Na] +
Preparation 17
(1E)-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl) (oxo) ethylidenehydroxylamine title compound is to obtain in the mode that is similar to preparation 8.
1H-NMR(DMSO-d 6δ)：3.57(3H，s)，6.47(1H，d，J＝9.6Hz)，7.93(1H，dd，J＝2.4，9.6Hz)，8.03(1H，s)，8.76(1H，d，J＝2.4Hz)，12.62(1H，s)
MS(ESI +)：203[M+Na] +
Preparation 18
3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine nitrile 4-oxide compound title compound is to obtain in the mode that is similar to preparation 9.
1H-NMR(DMSO-d 6δ)：3.50(3H，s)，6.47(1H，d，J＝9.6Hz)，7.96(2H，s)，7.96-8.02(1H，m)，8.43(1H，d，J＝2.4Hz)，9.04(1H，s)
MS(ESI +)：244[M+Na] +
Preparation 19
At 25-30 ℃ 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine nitrile 4-oxide compound (97g) is added 25% hydrogen bromide AcOH solution (700ml).Normal temperature stirred this mixture 2 hours down.In this mixture, add 12%aq.NaOH (2100ml) and water (1000ml).Stir this mixture overnight in the refrigerator.Filter and collect the crystallization that gained is separated out, with water washing, vacuum-drying obtains 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides 4-oxide powder (52g).
1H-NMR(DMSO-d 6δ)：3.52(3H，s)，6.45(1H，d，J＝9.6Hz)，7.82(2H，s)，7.92(1H，s)，8.26(1H，dd，J＝2.6，9.6Hz)，8.54(1H，s)，8.72(1H，d，J＝2.6Hz)，8.97(1H，s)
MS(ESI +)：262[M+H] +，284[M+Na] +
Preparation 20
3-amino-5-chloro-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine nitrile title compound is to obtain in the mode that is similar to preparation 12.
1H-NMR(DMSO-d 6δ)：3.25(3H，s)，6.45(1H，d，J＝9.4Hz)，7.70(1H，dd，J＝2.6，9.4Hz)，7.83(2H，s)，8.06(1H，d，J＝2.6Hz)
MS (ESI +): 262 and 263[M+H] +, 284 and 286[M+Na] +
Preparation 21
In-40 ℃ of suspension, add phosphorus trichloride (1.07ml) with 20 fens clock times 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides 4-oxide compound (1.0g) in DMF.Allow this reaction mixture go up, stirred 1 hour to-10 ℃.In this solution, add entry (40ml), stirred 14 hours at 40 ℃.The pH that adjusts obtained aqueous solution with 12%aq.NaOH is 6-7.Filter the collecting precipitation thing, with water washing, amino-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides (263mg) is a yellow powder to 5-chloro-6-to obtain 3-.
MS(ESI) +：280[M+H] +
Embodiment 1
Make 3-amino-5-chloro-6-(6-methoxyl group-3-pyridyl)-2-pyrazine nitrile (1.35g) be dissolved in two  alkane (135ml).At 25 ℃ of phenyl-boron dihydroxides (1.89g) and Pd (PPh that in this solution, add in the entry (27ml) 3) 4(179mg) and Na 2CO 3(2.19g).Heated these reaction mixtures 2 hours at 80 ℃, then normal temperature is following 3 hours.Said mixture distributes between EtOAc and water.Separate organic layer, with aq.Na 2CO 3And the salt solution washing, use MgSO 4Dry.Vacuum evaporating solvent obtains the oily residue, and (EtOAc: normal hexane=1: 1, v/v), obtaining 3-amino-6-(6-methoxyl group-3-pyridyl)-5-phenyl-2-pyrazine nitrile is yellow powder, the EtOAc crystallization (1.15g) of latter's usefulness with the silica gel chromatography purifying.
1H-NMR(DMSO-d 6δ)：3.81(3H，s)，6.73(1H，d，J＝8.6Hz)，7.35(5H，s)，7.51(2H，s)，7.54(1H，dd，J＝2.4，8.6Hz)，7.99(1H，d，J＝2.4Hz)
MS(ESI +)：304[M+H] +，326[M+Na] +
IR(KBr)：3357，3183，2238，1648，1598，1544，1195cm -1
m.p.：201-205℃(IPE)
Embodiment 2
3-amino-6-(6-methoxyl group-3-pyridyl)-5-phenyl-2-pyrazine nitrile (500mg) is dissolved among two  alkane (10ml) and the conc.HCl (5ml).Stirred this solution 5 hours at 80 ℃.Cool off this reaction mixture to 25-30 ℃, vacuum concentration obtains residue.In residue, add water, adjust aqueous mixture pH to 6-7 with 1N NaOH.Filter and collect the crystallization of separating out, vacuum-drying obtains 3-amino-6-(6-oxo-1,6-two-hydrogen-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides (390mg).
1H-NMR(DMSO-d 6δ)：6.16(1H，d，J＝9.4Hz)，7.26-7.70(10H，m)，8.23(1H，s)，11.66(1H，s)
MS(ESI +)：330[M+Na] +
MS(ESI -)：306[M-H] -
IR(KBr)：3309，1656，1610，1544，1201cm -1
m.p.：215-220℃(H 2O)
Embodiment 3
3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides (61.4mg) is dissolved among the DMF (1ml).1M MeI (0.22ml) solution in this solution among the adding DMF and the 0.1M t-BuOK solution (2.2ml) among the DMF.20-30 ℃ was stirred this mixture 2 hours.Reaction mixture distributes between EtOAc and water.Separate organic layer.With the EtOAc aqueous layer extracted.With the organic solution that the salt solution washing merges, use MgSO 4Dry.Evaporating solvent obtains the oily residue.With this residue of silica gel chromatography purifying (independent EtOAc-EtOAc: MeOH=93: 7, v/v), obtain 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides, the latter is with EtOAc crystallization (20mg).
1H-NMR(DMSO-d 6δ)：3.45(3H，s)，6.12(1H，d，J＝9.4Hz)，6.97(1H，dd，J＝2.4，9.4Hz)，7.41-7.62(8H，m)，8.14(1H，d，J＝2.4Hz)，8.29(1H，s)
MS(ESI +)：344[M+Na] +
IR(KBr)：3353，1664，1599，1531，1438cm -1
m.p.：＞250℃(EtOAc)
Embodiment 4
3-amino-6-(1-ethyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides
Title compound is to obtain in the mode that is similar to embodiment 3.
1H-NMR(DMSO-d 6δ)：1.12(3H，t，J＝7.0Hz)，3.84(2H，q，J＝7.0Hz)，6.18(1H，d，J＝9.4Hz)，7.21(1H，dd，J＝2.4，9.4Hz)，7.40-7.72(8H，m)，7.89(1H，d，J＝2.4Hz)，8.27(1H，s)
MS(ESI +)：336[M+H] +，358[M+Na] +
IR(KBr)：3154，1679，1597，1535，1444cm -1
m.p.：＞250℃(EtOAc)
Embodiment 5
3-amino-6-(6-oxo-1-propyl group-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides
Title compound is to obtain in the mode that is similar to preparation example 3.
1H-NMR(DMSO-d 6δ)：0.77(3H，t，J＝7.4Hz)，1.52(2H，m)，3.76(2H，t，J＝7.2Hz)，6.20(1H，d，J＝9.4Hz)，7.34-7.47(8H，m)，7.66-7.72(2H，m)，8.19(1H，s)
MS(ESI +)：350[M+H] +，372[M+Na] +
IR(KBr)：3421，1650，1571，1515，1417cm -1
m.p.：＞250℃(EtOAc)
Embodiment 6
3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides (92.1mg) is dissolved among the DMF (1ml).In this solution, add among the DMF 0.1M t-BuOK solution (3.3ml) in the 1M i-PrI solution (0.33ml) and DMF.Stirred this mixture 2 hours at 20-30 ℃.Reaction mixture distributes between EtOAc and water.Separate organic layer.Water layer extracts with EtOAc.The organic solution that merges is washed with salt solution, uses MgSO 4Dry.Evaporating solvent obtains the oily residue.With this residue of silica gel chromatography purifying (independent EtOAc-EtOAc: MeOH=96: 4, v/v), obtain 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides (18mg) and 3-amino-6-(6-isopropoxy-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides (42mg).
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.97(6H，d，J＝6.8Hz)，4.90(1H，m)，6.20(1H，d，J＝9.4Hz)，7.34-7.47(8H，m)，7.66-7.72(2H，m)，8.19(1H，s)
MS(ESI +)：350[M+H] +，372[M+Na] +
IR(KBr)：3417，1664，1591，1533，1450cm -1
m.p.：240-245℃(EtOAc)
3-amino-6-(6-isopropoxy-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.26(6H，d，J＝6.8Hz)，5.20(1H，m)，6.60(1H，d，J＝8.6Hz)，7.42.(5H，s)，7.60-7.67(3H，m)，8.17(2H，s)
MS(ESI +)：350[M+H] +，372[M+Na] +
IR(KBr)：3471，1683，1656，1600，1488cm -1
Embodiment 7
Make 3-amino-6-(6-methoxyl group-3-pyridyl)-5-phenyl-2-pyrazine nitrile (800mg) be dissolved in two  alkane and conc.HCl.Stirred this solution 15 hours at 80 ℃.Evaporative removal two  alkane.Reaction mixture is to room temperature, and vacuum concentration obtains residue.In residue, add 1NNaOH, adjust this aqueous mixture pH to 6-7.Filter and collect crystallization, vacuum-drying, 3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid is powder (600mg) in acquisition.
1H-NMR(DMSO-d 6δ)：6.18(1H，d，J＝9.4Hz)，7.25-7.65(9H，m)，11.8(2H，brs)
MS(ESI -)：307[M-H] -
Embodiment 8
3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid (154mg) is dissolved among the DMF (5ml).In this solution, add EtI (86.1mg) and t-BuOK (61.9mg).Stirred this mixture 2 hours at 20-30 ℃.This reaction mixture distributes between EtOAc and water.Separate organic layer.Water layer extracts with EtOAc.The organic solution that merges is washed with salt solution, uses MgSO 4Dry.Evaporating solvent obtains the oily residue.With this residue of silica gel chromatography purifying (independent EtOAc-EtOAc: MeOH=95: 5, v/v), obtain 3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid, ethyl ester (84mg) and 3-amino-6-(1-ethyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid, ethyl ester (28mg).
3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid, ethyl ester
1H-NMR(DMSO-d 6δ)：1.34(3H，t，J＝7.0Hz)，4.37(2H，q，J＝7.0Hz)，6.23(1H，d，J＝9.4Hz)，7.19(1H，d，J＝2.4Hz)，7.25(1H，dd，J＝2.4，9.4Hz)，7.40-7.52(5H，m)
MS(ESI +)：359[M+Na] +
IR(KBr)：3400，1697，1614，1434，1130cm -1
m.p.：230-238℃(EtOAc)
3-amino-6-(1-ethyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid, ethyl ester
1H-NMR(DMSO-d 6δ)：1.00(3H，t，J＝7.0Hz)，1.34(3H，t，J＝7.0Hz)，3.76(2H，q，J＝7.0Hz)，4.37(2H，q，J＝7.0Hz)，6.32(1H，d，J＝9.4Hz)，7.32(1H，dd，J＝2.6，9.4Hz)，7.36-7.5(8H，m)
MS(ESI +)：365[M+H] +，387[M+Na] +
IR(KBr)：3400，1662，1600，1440，1122cm -1
m.p.：175-179℃(EtOAc)
Embodiment 9
3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid (283mg) is dissolved among the DMF (10ml).In this solution, add i-PrI (172mg) and t-BuOK (114mg).Stirred this mixture 2 hours at 20-30 ℃.This reaction mixture is allocated between EtOAc and the water.Separate organic layer.Water layer extracts with EtOAc.The organic solution that merges is washed with salt solution, uses MgSO 4Dry.Evaporating solvent obtains the oily residue.With this residue of silica gel chromatography purifying (independent EtOAc-EtOAc: MeOH=96: 4, v/v) obtain 3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid isopropyl, be yellow crystal (64mg).
1H-NMR(DMSO-d 6δ)：1.35(6H，d，J＝6.2Hz)，5.20(1H，m)，6.23(1H，d，J＝9.4Hz)，7.19(1H，d，J＝2.2Hz)，7.22(1H，dd，J＝2.2，9.4Hz)，7.40(5H，m)，11.6(1H，s)
MS(ESI +)：351[M+H] +，373[M+Na] +
IR(KBr)：3425，1666，1612，1434，1101cm -1
m.p.：250-256℃(EtOAc)
Embodiment 10
Make 3-amino-6-(6-methoxyl group-3-pyridyl)-5-phenyl-2-pyrazine nitrile (370mg) be dissolved in 1, in the 2-ethylene dichloride (37ml).In this solution, add CH 2Cl 2In 1M boron tribromide solution (12.2ml).Stirred this mixture 24 hours at 80 ℃.Cool off this mixture to 20-25 ℃, be allocated between EtOAc and the water.Separate organic layer.Water layer extracts with EtOAc.The organic solution that merges is washed with salt solution, uses MgSO 4Dry.Vacuum evaporating solvent obtains the red solid residue.With broken this residue of water mill, 3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine nitrile is powder (254mg) in acquisition.
1H-NMR(DMSO-d 6δ)：6.21(1H，d，J＝9.4Hz)，7.20-7.98(7H，m)，11.6(1H，s)
MS(ESI +)：312[M+Na] +
IR(KBr)：3326，2221，1656，1610，1544，1201cm -1
m.p.：243-248℃(H 2O)
Embodiment 11
3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine nitrile (58mg) is dissolved among the DMF (1ml).In this solution, add among the DMF 0.1M t-BuOK solution (2.2ml) in the 1M MeI solution (0.22ml) and DMF.Stirred this mixture 2 hours at 20-30 ℃.This reaction mixture is allocated between EtOAc and the water.Separate organic layer.Water layer extracts with EtOAc.The organic solution that merges is washed with salt solution, uses MgSO 4Dry.Evaporating solvent obtains the oily residue.With this residue of silica gel chromatography purifying (independent EtOAc-EtOAc: MeOH=93: 7, v/v), obtain 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine nitrile, the latter is with EtOAc crystallization (18mg).
1H-NMR(DMSO-d 6δ)：3.40(3H，s)，6.17(1H，d，J＝9.4Hz)，6.97(1H，dd，J＝2.6，9.4Hz)，7.40-7.50(7H，m)，7.81(1H，d，J＝2.6Hz)
MS(ESI +)：304[M+H] +，326[M+Na] +
IR(KBr)：3386，2221，1670，1590，1542，1205cm -1
m.p.：＞250℃(EtOAc)
Embodiment 12
3-amino-6-(1-ethyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine nitrile
Title compound is to obtain in the mode that is similar to embodiment 11.
1H-NMR(DMSO-d 6δ)：1.03(3H，t，J＝7.0Hz)，3.79(2H，q，J＝7.0Hz)，6.25(1H，d，J＝9.4Hz)，7.19(1H，dd，J＝2.6，9.4Hz)，7.44-7.47(7H，m)，7.58(1H，d，J＝2.6Hz)
MS(ESI +)：318[M+H] +，340[M+Na] +
IR(KBr)：3180，2221，1657，1587，1535，1203cm -1
m.p.：193-199℃(IPE)
Embodiment 13
3-amino-6-(6-oxo-1-propyl group-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine nitrile (17mg)
Title compound is to obtain in the mode that is similar to embodiment 11.
1H-NMR(DMSO-d 6δ)：0.71(3H，t，J＝7.4Hz)，1.44(2H，m)，3.73(2H，t，J＝7.2Hz)，6.26(1H，d，J＝9.4Hz)，7.20(1H，dd，J＝2.6，9.4Hz)，7.38-7.47(7H，m)，7.54(1H，d，J＝2.6Hz)
MS(ESI +)：332[M+H] +，354[M+Na] +
IR(KBr)：3311，2220，1658，1536，1463，1201cm -1
m.p.：180-183℃(IPE)
Embodiment 14
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine nitrile
Title compound is to obtain in the mode that is similar to embodiment 11.
1H-NMR(DMSO-d 6δ)：0.94(6H，d，J＝6.8Hz)，4.85-4.92(1H，m)，6.35(1H，d，J＝9.4Hz)，7.28(1H，d，J＝2.4Hz)，7.38-7.49(8H，m)
MS(ESI +)：332[M+H] +，354[M+Na] +
IR(KBr)：3426，2225，1664，1621，15521，1106cm -1
M.p.:204.5 ℃ (95%aq.2-propyl alcohol)
Embodiment 15
Make 3-amino-6-(6-methoxyl group-3-pyridyl)-5-phenyl-2-pyrazine nitrile (100mg) be dissolved in 30% hydrogen bromide solution (1ml) among the AcOH.25-30 ℃ was stirred this solution 3 hours.In this solution, add entry.Adjust the pH to 6-7 of aqueous mixture with 12%aq.NaOH.Separate out crystallization.Stirred this suspension 3 hours at 25-30 ℃, in refrigerator, left standstill 10 hours.Filter and collect crystallization, vacuum-drying obtains 3-amino-6-(6-methoxyl group-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides (92.5mg).
1H-NMR(DMSO-d 6δ)：3.82(3H，s)，6.69(1H，d，J＝6.6Hz)，7.39(5H，s)，7.64-7.70(3H，m)，8.17(2H，s)
MS(ESI +)：322[M+H] +，344[M+Na] +
IR(KBr)：3411，3276，1689，1598，1496，1286cm -1
m.p.：208-212℃(H 2O)
Below 24 compounds all obtain in the mode that is similar to embodiment 1.
Embodiment 16
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.97(6H，d，J＝6.8Hz)，4.90(1H，m)，6.32(1H，d，J＝9.4Hz)，7.34-7.46(6H，m)，7.66-7.72(4H，m)，8.19(1H，s)
MS(ESI +)：350[M+H] +，372[M+Na] +
IR(KBr)：3417，1664，1590，1533，1450cm -1
mp：245℃(IPA-H 2O)
Embodiment 17
3-amino-5-(2-fluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.93(6H，d，J＝6.8Hz)，4.89(1H，m)，6.35(1H，d，J＝9.4Hz)，7.22-7.81(9H，m)，8.22(1H，s)
MS(ESI +)：368[M+H] +，390[M+Na] +
IR(KBr)：3367，1664，1600，1446，1205cm -1
mp：251.7℃(IPA-H 2O)
Embodiment 18
3-amino-5-(3-fluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.01(6H，d，J＝6.8Hz)，4.93(1H，m)，6.35(1H，d，J＝9.4Hz)，7.21-7.71(9H，m)，8.22(1H，s)
MS(ESI +)：368[M+H] +，390[M+Na] +
IR(KBr)：3394，1658，1590，1533，1452cm -1
mp：258.8℃(IPA-H 2O)
Embodiment 19
3-amino-5-(4-fluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.97(6H，d，J＝6.8Hz)，4.90(1H，m)，6.32(1H，d，J＝9.4Hz)，7.34-7.46(6H，m)，7.66-7.72(3H，m)，8.19(1H，s)
MS(ESI +)：390[M+Na] +
IR(KBr)：3293，1660，1583，1450，1153cm -1
mp：235.6℃(IPA-H 2O)
Embodiment 20
3-amino-5-(2-chloro-phenyl-)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.90(6H，m)，4.87(1H，m)，6.34(1H，d，J＝9.4Hz)，7.16(1H，d，J＝2.4Hz)，7.48-7.68(6H，m)，7.73(1H，s)，7.82(1H，dd，J＝2.4，9.4Hz)，8.24(1H，s)
MS(ESI +)：384[M+H] +，406[M+Na] +
IR(KBr)：3367，1666，1604，1454，1157cm -1
mp：254.5℃(IPA-H 2O)
Embodiment 21
3-amino-5-(3-chloro-phenyl-)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.01(6H，d，J＝6.8Hz)，4.93(1H，m)，6.35(1H，d，J＝9.4Hz)，7.35-7.46(5H，m)，7.49(2H，s)，7.57-7.72(3H，m)，8.21(1H，s)
MS(ESI +)：384[M+H] +，406[M+Na] +
IR(KBr)：3396，1658，1589，1452，1250cm -1
mp：232.6℃(IPA-H 2O)
Embodiment 22
3-amino-5-(4-chloro-phenyl-)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.02(6H，d，J＝6.8Hz)，4.94(1H，m)，6.34(1H，d，J＝9.4Hz)，7.40(1H，d，J＝2.4Hz)，7.49(6H，s)，7.65(1H，dd，J＝2.4，9.4Hz)，7.70(1H，s)，8.21(1H，s)
MS(ESI +)：406[M+Na] +
IR(KBr)：3278，1664，1587，1450，1093cm -1
mp：246.2℃(IPA-H 2O)
Embodiment 23
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-p-methoxy-phenyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.89-1.05(6H，m)，3.48(3H，s)，4.88(1H，m)，6.32(1H，d，J＝9.4Hz)，6.99-7.13(2H，m)，7.22(1H，d，J＝2.4Hz)，7.37-7.65(2H，m)，7.59(2H，brs)，7.66(1H，s)，7.75(1H，dd，J＝2.4，9.4Hz)，8.16(1H，s)
MS(ESI +)：380[M+H] +，402[M+Na] +
IR(KBr)：3259，1662，1596，1452，1259cm -1
mp：263.1℃(IPA-H 2O)
Embodiment 24
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(3-p-methoxy-phenyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.01(6H，d，J＝6.8Hz)，3.71(3H，s)，4.90(1H，m)，6.33(1H，d，J＝9.4Hz)，6.94-7.02(3H，m)，7.30-7.39(2H，m)，7.65-7.71(3H，m)，8.19(1H，s)
MS(ESI +)：380[M+H] +，402[M+Na] +
IR(KBr)：3442，1660，1581，1444，1268cm -1
IR(KBr)：3442，1660，1581，1444，1268cm-1
mp：192.3℃(IPA-H 2O)
Embodiment 25
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(4-p-methoxy-phenyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.05(6H，d，J＝6.8Hz)，3.77(3H，s)，4.94(1H，m)，6.32(1H，d，J＝9.4Hz)，6.97(2H，d，J＝8.8Hz)，7.42(2H，d，J＝8.8Hz)，7.45-7.64(5H，m)，8.15(1H，s)
MS(ESI +)：380[M+H] +，402[M+Na] +
IR(KBr)：3266，1664，1600，1448，1255cm -1
mp：243.9℃(IPA-H 2O)
Embodiment 26
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-[2-(trifluoromethoxy) phenyl]-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.90(6H，m)，4.88(1H，m)，6.34(1H，d，J＝9.4Hz)，7.20(1H，d，J＝2.4Hz)，7.34-7.39(1H，m)，7.54-7.78(7H，m)，8.24(1H，s)
MS(ESI +)：434[M+H] +，456[M+Na] +
IR(KBr)：3386，1662，1596，1257，1162cm -1
mp：206.5℃(IPA-H 2O)
Embodiment 27
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-[3-(trifluoromethoxy) phenyl]-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.98(6H，d，J＝6.8Hz)，4.88(1H，m)，6.35(1H，d，J＝9.4Hz)，7.37-7.81(9H，m)，8.22(1H，s)
MS(ESI +)：434[M+H] +，456[M+Na] +
IR(KBr)：3403，1660，1592，1452，1263cm -1
mp：265.5℃(IPA-H 2O)
Embodiment 28
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-[4-(trifluoromethoxy) phenyl]-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.98(6H，d，J＝6.8Hz)，4.91(1H，m)，6.37(1H，d，J＝9.4Hz)，7.30(1H，d，J＝2.4Hz)，7.42(2H，d，J＝8.2H z)，7.58(2H，d，J＝8.2Hz)，7.70(3H，m)，7.78(1H，dd，J＝2.4，9.4Hz)，8.21(1H，s)
MS(ESI +)：434[M+H] +，456[M+Na] +
IR(KBr)：3403，1660，1592，1452，1263cm -1
mp：264.0℃(IPA-H 2O)
Embodiment 29
3-amino-5-(3, the 4-difluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.05(6H，d，J＝6.8Hz)，4.96(1H，m)，6.35(1H，d，J＝9.2Hz)，7.28(1H，d，J＝6.4Hz)，7.46-7.65(6H，m)，7.71(1H，s)，8.21(1H，s)
MS(ESI +)：386[M+H] +，408[M+Na] +
IR(KBr)：3382，1662，1602，1444，1191cm -1
mp：225.8℃(IPA-H 2O)
Embodiment 30
3-amino-5-(3, the 5-difluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.05(6H，d，J＝6.8Hz)，4.95(1H，m)，6.37(1H，d，J＝9.4Hz)，7.14-7.37(3H，m)，7.46(1H，d，J＝2.4Hz)，7.66(1H，dd，J＝2.4，9.4Hz))，7.73(3H，m)，8.23(1H，s)
MS(ESI +)：408[M+Na] +
IR(KBr)：3284，1664，1587，1446，1120cm -1
mp：248.8℃(IPA-H 2O)
Embodiment 31
3-amino-5-(4-benzonitrile base)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.98(6H，d，J＝6.8Hz)，4.92(1H，m)，6.35(1H，d，J＝9.4Hz)，7.38(1H，d，J＝2.4Hz)，7.65(2H，d，J＝8.4Hz)，7.65-7.69(4H，m)，7.74(1H，s)，7.90(1H，d，J＝8.4Hz)，8.24(1H，s)
MS(ESI +)：397[M+Na] +
IR(KBr)：3432，2223，1671，1606，1450cm -1
mp：292℃(IPA-H 2O)
Embodiment 32
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine nitrile
1H-NMR(DMSO-d 6δ)：0.94(6H，d，J＝6.8Hz)，4.89(1H，m)，6.35(1H，d，J＝9.4Hz)，7.28(1H，d，J＝2.4Hz)，7.39-7.49，(8H，m)
MS(ESI +)：332[M+H] +，354[M+Na] +
IR(KBr)：3357，2219，1652，1579，1465，1203cm -1
mp：205.4℃(IPA-H 2O)
Embodiment 33
3-amino-5-(2-fluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine nitrile
1H-NMR(DMSO-d 6δ)：0.91(6H，d，J＝6.8Hz)，4.87(1H，m)，6.37(1H，d，J＝9.4Hz)，7.18-7.63(8H，m)
MS(ESI +)：350[M+H] +，372[M+Na] +
IR(KBr)：3366，2214，1615，1516，1200cm -1
mp：210.6℃(IPA-H 2O)
Embodiment 34
3-amino-5-(3-fluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine nitrile
1H-NMR(DMSO-d 6δ)：0.98(6H，d，J＝6.8Hz)，4.92(1H，m)，6.37(1H，d，J＝9.4Hz)，7.22-7.53(8H，m)
MS(ESI +)：350[M+H] +，372[M+Na] +
IR(KBr)：3360，2214，1660，1570，1205cm -1
mp：210.6℃(IPA-H 2O)
Embodiment 35
3-amino-5-(4-fluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine nitrile
1H-NMR(DMSO-d 6δ)：0.98(6H，d，J＝6.8Hz)，4.92(1H，m)，6.37(1H，d，J＝9.4Hz)，7.22-7.68(8H，m)
MS(ESI +)：350[M+H] +
IR(KBr)：3364，2214，1660，1572，1200cm -1
mp：207.0℃(IPA-H 2O)
Embodiment 36
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-p-methoxy-phenyl)-2-pyrazine nitrile
1H-NMR(DMSO-d 6δ)：0.97(6H，brs)，3.46(3H，s)，4.86(1H，m)，6.34(1H，d，J＝9.4Hz)，6.99(1H，d，8.2Hz)，7.10(1H，t，7.6Hz)，7.18(1H，d，2.5Hz)，7.37-7.50(5H，m)
MS(ESI +)：362[M+H] +，384[M+Na] +
IR(KBr)：3266，2214，1600，1448，1255cm -1
mp：222.6℃(IPA-H 2O)
Embodiment 37
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(3-p-methoxy-phenyl)-2-pyrazine nitrile
1H-NMR(DMSO-d 6δ)：0.98(6H，d，J＝6.8Hz)，3.69(3H，s)，4.91(1H，m)，6.35(1H，d，J＝9.4Hz)，6.95-6.97(1H，m)，7.00(2H，s)，7.30-7.47(5H，m)
MS(ESI +)：362[M+H] +，384[M+Na] +
IR(KBr)：3360，2215，1655，1570，1205cm -1
mp：192.3℃(IPA-H 2O)
Embodiment 38
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(4-p-methoxy-phenyl)-2-pyrazine nitrile
1H-NMR(DMSO-d 6δ)：1.02(6H，d，J＝6.8Hz)，3.76(3H，s)，4.93(1H，m)，6.35(1H，d，J＝9.4Hz)，6.98(2H，d，7.2Hz)，7.38-7.43(6H，m)
MS(ESI +)：362[M+H] +，384[M+Na] +
IR(KBr)：3357，2218，1650，1570，1200cm -1
mp：243.9℃(IPA-H 2O)
Embodiment 39
3-amino-5-(3, the 4-difluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine nitrile
1H-NMR(DMSO-d 6δ)：1.02(6H，d，J＝6.8Hz)，4.95(1H，m)，6.38(1H，d，J＝9.0Hz)，7.26(1H，m)，7.38-7.58(6H，m)，
MS(ESI +)：368[M+H] +，390[M+Na] +
IR(KBr)：3166，2210，1658，1461，1201cm -1
mp：180℃(IPA-H 2O)
Embodiment 40
3-amino-5-(4-fluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides (30g) is suspended among two  alkane (60ml) and the 2N aq.NaOH (600ml).At 90 ℃ of these mixtures of heating, stirred 4 hours.Cool off this reaction mixture to 25-30 ℃.Adjust this pH of suspension value to 2.5 with 35%HCl (105ml).Filter the collecting precipitation thing,,, obtain 3-amino-5-(4-fluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid, be yellow powder (29.6g) 50 ℃ of vacuum-dryings 15 hours with water washing.
1H-NMR(DMSO-d 6δ)：1.00(6H，d，J＝6.8Hz)，4.93(1H，m)，6.37(1H，d，J＝9.4Hz)，7.22-7.36(3H，m)，7.48-7.68(5H，m)，13.00(1H，s)
IR(KBr)：3266，1725，1662，1600，1455cm -1
mp：222.2℃(IPA-H 2O)
Embodiment 41
Make 3-amino-5-(4-fluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid (25g) be suspended in 1,2-dichlorobenzene (125ml).At 165-170 ℃ of this suspension of heating, stirred 4 hours.Cool off this reaction mixture to 20-25 ℃.In this cooling mixture, add IPE (250ml).This suspension stirred 3 hours at 25-30 ℃.Filter the collecting precipitation thing, vacuum-drying.Above-mentioned dried throw out is with CHCl 3: it is refining that MeOH (9: 1,21) elutriant carries out silica gel (500g) chromatography.Vacuum evaporating solvent obtains the yellow crystal residue, and the latter obtains 5-[5-amino-3-(4-fluorophenyl)-2-pyrazinyl with 70%EtOH (322ml) recrystallization]-1-sec.-propyl-2 (1H)-pyridone is yellow crystal (19.4g).
1H-NMR(DMSO-d 6δ)：1.00(6H，d，J＝6.8Hz)，4.93(1H，m)，6.33(1H，d，J＝9.2Hz)，6.63(2H，s)，7.17-7.26(3H，m)，7.38-7.46(3H，m)，7.93(1H，s)
MS(ESI +)：325[M+H] +，347[M+Na] +
IR(KBr)：3166，1666，1604，1533，1467，1222cm -1
mp：257.7℃(IPA-H 2O)
Embodiment 42
Stir CH at 25 ℃ 2Cl 23-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid (70mg), methylamine hydrochloride (14.8mg), 1-ethyl-3-[3 '-(dimethylin) propyl group (0.7ml)]-carbodiimide (34.1mg), with the mixture of I-hydroxybenzotriazole (29.7mg) 4 hours.Water and EtOAc are poured in this mixture.Separate organic layer, with water, sat.aq.NaHCO 3, and salt solution washing, use MgSO 4Dry.Decompression goes down to desolventize.(normal hexane-EtOAc is CH then with silica gel column chromatography for residue 2Cl 2-MeOH) refining, use the MeOH-IPE crystallization then, obtain 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-N-methyl-5-phenyl-2-pyrazine carboxylic acid amides (40mg).
1H-NMR(DMSO-d 6δ)：0.93(6H，d，J＝6.8Hz)，2.84(3H，d，J＝4.8Hz)，4.89(1H，qq，J＝6.8，6.8Hz)，6.38(1H，d，J＝9.4Hz)，7.26(1H，d，J＝2.5Hz)，7.42(5H，m)，7.62(2H，brs)，7.79(1H，dd，J＝2.5，9.4Hz)，8.69(1H，m)
MS(ESI +)：364[M+H] +
Below 4 kinds of compounds all obtain in the mode that is similar to embodiment 42.
Embodiment 43
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-N, N-dimethyl-5-phenyl-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.93(6H，d，J＝6.7Hz)，3.04(3H，s)，3.10(3H，s)，4.89(1H，qq，J＝6.7，6.7Hz)，6.36(1H，d，J＝9.4Hz)，6.73(2H，brs)，7.21(1H，d，J＝2.5Hz)，7.3-7.6(6H，m)
MS(ESI -)：376[M-H] -
Embodiment 44
5-[5-amino-6-(4-morpholine carbonyl)-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：0.95(6H，d，J＝6.8Hz)，3.63(4H，brs)，3.70(4H，brs)，4.86(1H，qq，J＝6.8，6.8Hz)，6.36(1H，d，J＝9.4Hz)，6.78(2H，brs)，7.24(1H，d，J＝2.4Hz)，7.3-7.5(6H，m)
MS(ESI +)：420[M+H] +
Embodiment 45
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-N-(2-pyridylmethyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.94(6H，d，J＝6.8Hz)，4.64(2H，d，J＝6.0Hz)，4.87(1H，qq，J＝6.8，6.8Hz)，6.39(1H，d，J＝9.4Hz)，7.1-7.9(12H，m)，8.52(1H，distorted d，J＝4.1Hz)，9.37(1H，t，J＝6.0Hz)。
MS(ESI +)：441[M+H] +
Embodiment 46
3-amino-N-(cyanogen methyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.92(6H，d，J＝6.8Hz)，4.34(2H，d，J＝5.9Hz)，4.88(1H，qq，J＝6.8，6.8Hz)，6.41(1H，d，J＝9.4Hz)，7.24(1H，d，J＝2.4Hz)，7.3-7.5(5H，m)，7.61(2H，brs)，7.83(1H，dd，J＝2.4，9.4Hz)，9.27(1H，brt，J＝5.9Hz)
MS(ESI +)：389[M+H] +，411[M+Na] +
Embodiment 47
Under ice bath cooling to 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid (70mg) and NEt 3(40.4mg) and add isobutyl chlorocarbonate (32.7mg) in the mixture of THF (0.7ml).Stir under the equality of temperature after 1.5 hours, this mixture is poured under ice bath in the mixture of THF (0.7ml) and water (1.4ml) and sodium borohydride (30.2mg), stirs 2.5 hours under the equality of temperature, dilute this mixture with water and EtOAc, separate organic layer then,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue is with silica gel column chromatography purifying (CH 2Cl 2-MeOH=25: 1-10: 1).Desirable fraction is developed with IPE, is obtained 5-[5-amino-6-(methylol)-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (24mg).
1H-NMR(DMSO-d 6δ)：0.95(6H，d，J＝6.8Hz)，4.59(2H，d，J＝5.6Hz)，4.90(1H，qq，J＝6.8，6.8Hz)，5.34(1H，t，J＝5.6Hz)，6.3-6.4(3H，m)，7.20(1H，d，J＝2.4Hz)，7.2-7.5(5H，m)，7.50(1H，dd，J＝2.4，9.4Hz)
MS(ESI +)：337[M+H] +，359[M+Na] +
Below 3 kinds of compounds all obtain in the mode that is similar to embodiment 42.
Embodiment 48
5-[5-amino-6-(1-azelidinyl carbonyl)-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：0.92(6H，d，J＝6.8Hz)，2.25(2H，m)，4.09(2H，t，J＝7.6Hz)，4.70(2H，t，J＝7.6Hz)，4.91(1H，qq，J＝6.8，6.8Hz)，6.36(1H，d，J＝9.4Hz)，7.29(1H，d，J＝2.4Hz)，7.3-7.6(6H，m)，7.62(2H，brs)
MS(ESI +)：390[M+H] +
Embodiment 49
3-amino-N-(2-hydroxyethyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxamide
1H-NMR(DMSO-d 6δ)：0.93(6H，d，J＝6.8Hz)，3.4-3.5(2H，m)，3.5-3.6(2H，m)，4.7-5.0(2H，m)，6.39(1H，d，J＝9.4Hz)，7.26(1H，2.4Hz)，7.3-7.5(5H，m)，7.63(2H，brs)，7.75(1H，dd，J＝2.4，9.4Hz)，8.63(1H，t，J＝5.8Hz)
MS(ESI +)：394[M+H] +，416[M+Na] +
Embodiment 50
3-amino-N-cyclopropyl-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxamide
1H-NMR(DMSO-d 6δ)：0.6-0.8(4H，m)，0.93(6H，d，J＝6.8Hz)，2.84(1H，m)，4.89(1H，qq，J＝6.8，6.8Hz)，6.37(1H，d，J＝9.4Hz)，7.29(1H，d，J＝2.4Hz)，7.3-7.5(5H，m)，7.61(2H，brs)，7.75(1H，dd，J＝2.4，9.4Hz)，8.57(1H，t，J＝4.2Hz)
MS(ESI +)：390[M+H] +，412[M+Na] +
Embodiment 51
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid
Title compound obtains in the mode that is similar to embodiment 40.
1H-NMR(DMSO-d 6δ)：0.95(6H，d，J＝6.8Hz)，4.90(1H，qq，J＝6.8，6.8Hz)，6.37(1H，d，J＝9.4Hz)，7.31(1H，d，J＝2.4Hz)，7.2-7.6(7H，m)，7.59(1H，dd，J＝2.4，9.4Hz)，13.0(1H，brs)
MS(ESI -)：349[M-H] -
Embodiment 52
5-(5-amino-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H) pyridone
Title compound obtains in the mode that is similar to embodiment 41.
1H-NMR(DMSO-d 6δ)：0.95(6H，d，J＝6.8Hz)，4.90(1H，qq，J＝6.8，6.8Hz)，6.32(1H，d，J＝9.4Hz)，6.60(2H，brs)，7.21(1H，d，J＝2.4Hz)，7.2-7.5(6H，m)，7.93(1H，s)
MS(ESI +)：307[M+H] +，329[M+Na] +
Embodiment 53
The mixture of 5-(5-amino-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (100mg) and N-bromine succinimide (87.1mg) stirred 20 minutes in 50 ℃ of heating DMF.With Sat.aq.NaHCO 3Pour in this mixture with EtOAc.Separate organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue is with silica gel column chromatography purifying (normal hexane: EtOAc=10: 1-2: 1).With the IPE recrystallization, vacuum-drying obtains 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-3-bromo-1-sec.-propyl-2 (1H)-pyridone (57mg) with desirable product.
1H-NMR(DMSO-d 6δ)：0.94(6H，d，J＝6.8Hz)，4.89(1H，qq，J＝6.8，6.8Hz)，6.97(2H，brs)，7.24(1H，d，J＝2.4Hz)，7.2-7.6(5H，m)，7.92(1H，d，J＝2.4Hz)
MS(ESI +)：463[M+H] +
Embodiment 54
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-N-methoxyl group-N-methyl-5-phenyl-2-pyrazine carboxylic acid amides
Title compound obtains in the mode that is similar to embodiment 42.
1H-NMR(DMSO-d 6δ)：0.94(6H，d，J＝6.8Hz)，3.36(3H，s)，3.75(3H，s)，4.89(1H，qq，J＝6.8，6.8Hz)，6.36(1H，d，J＝9.3Hz)，6.79(2H，brs)，7.24(1H，d，J＝2.4Hz)，7.3-7.6(6H，m)
MS(ESI +)：394[M+H] +
Embodiment 55
5-(5-amino-6-chloro-3-phenyl-2-pyrazinyl)-3-chloro-1-sec.-propyl-2 (1H)-pyridone
Title compound obtains in the mode that is similar to embodiment 53.
1H-NMR(DMSO-d 6δ)：0.95(6H，d，J＝6.8Hz)，4.90(1H，qq，J＝6.8，6.8Hz)，7.05(2H，brs)，7.22(1H，d，J＝2.4Hz)，7.2-7.6(5H，m)，7.74(1H，d，J＝2.4Hz)
MS(ESI +)：375[M+H] +，397[M+Na] +
Embodiment 56
5-{5-amino-6-[(3-methoxyl group-1-azelidinyl) carbonyl]-3-phenyl-2-pyrazinyl }-1-sec.-propyl-2 (1H)-pyridone
Title compound obtains in the mode that is similar to embodiment 1.
1H-NMR(DMSO-d 6δ)：1.00(6H，d，J＝6.8Hz)，3.24(3H，s)，3.8-4.0(1H，m)，4.2-4.5(2H，m)，4.4-4.6(1H，m)，4.8-5.1(2H，m)，6.35(1H，J＝9.2Hz)，7.3-7.5(7H，m)，7.62(2H，brs)
MS(ESI +)：420[M+H] +
Embodiment 57
Under the ice bath cooling, (the 1-sec.-propyl-6-oxo-1 of 3-amino-6-in THF (4.0ml), 6-dihydro-3-pyridyl)-suspension of N-methoxyl group-N-methyl-5-phenyl-2-pyrazine carboxylic acid amides (200mg) in, drip 3.0M methyl chloride magnesium solution (0.85ml) among the THF.Synthermal this mixture of stirring down 5 hours.Pour this mixture into sat.aq ammonium chloride (20ml),,, use MgSO with water and salt solution washing with EtOAc (50ml) extraction organic layer 4Dry.Decompression goes down to desolventize.Residue is with silica gel column chromatography purifying (CH 2Cl 2-MeOH=50: 1-15: 1).Desirable fraction MeOH recrystallization, vacuum-drying obtains 5-(6-ethanoyl-5-amino-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (111mg).
1H-NMR(DMSO-d 6δ)：0.95(6H，d，J＝6.8Hz)，2.66(3H，s)，4.91(1H，qq，J＝6.8，6.8Hz)，6.41(1H，d，J＝9.4Hz)，7.30(1H，d，J＝2.4Hz)，7.3-7.6(5H，m)，7.61(1H，dd，J＝2.4，9.4Hz)，7.81(2H，brs)
MS(ESI +)：249[M+H] +，371[M+Na] +
Embodiment 58
3-amino-N-[2-(dimethylin) ethyl]-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid amides
Title compound obtains in the mode that is similar to embodiment 42.
1H-NMR(DMSO-d 6δ)：0.97(6H，d，J＝6.8Hz)，2.20(6H，s)，2.42(2H，t，J＝6.6Hz)，3.3-3.5(2H，m)，4.91(1H，qq，J＝6.8，6.8Hz)，6.37(1H，d，J＝9.4Hz)，7.31(1H，d，J＝2.4Hz)，7.3-7.5(5H，m)，7.66(1H，dd，J＝2.4，9.4Hz)，8.62(1H，t，J＝5.7Hz)
MS(ESI +)：421[M+H] +
Embodiment 59
3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine nitrile
Title compound obtains in the mode that is similar to embodiment 1.
1H-NMR(DMSO-d 6δ)：3.40(3H，s)，6.17(1H，d，J＝9.4Hz)，6.97(1H，dd，J＝2.6，9.4Hz)，7.40-7.49(7H，m)，7.81(1H，d，J＝2.6Hz)
MS(ESI +)：304[M+H] +，326[M+Na] +
IR(KBr)：3386，2221，1670，1590，1542，1205cm -1
Embodiment 60
Make 3-amino-5-chloro-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides (500mg), (4-p-methoxy-phenyl) boric acid (740mg), with Pd (PPh 3) 4(56.3mg) at 2M aq.Na 2CO 3(3.25ml) with two  alkane (20ml) in mixture refluxed 3 hours.In this reaction mixture, pour water (40ml) and EtOAc (30ml) into, with EtOAc extraction water-soluble solution.Organic layer is used MgSO with water and salt solution washing 4Dry.After the filtration, decompression goes down to desolventize.Solid residue on silicagel column with CHCl 3-MeOH (25: 1) elution.Evaporation of eluate with IPE suspension residue, is filtered and is obtained 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(4-p-methoxy-phenyl)-2-pyrazine carboxylic acid amides (512mg), is yellow powder.
1H-NMR(DMSO-d 6δ)：1.05(6H，d，J＝7.0Hz)，4.94(1H，sept，J＝7.0Hz)，6.32(1H，d，J＝9.5Hz)，6.98(2H，d，J＝9.0Hz)，7.39-7.64(7H，m)，8.15(1H，brs)
MS(ESI +)：380[M+H] +，421[M+H+MeCN] +
Below 18 kinds of compounds all obtain in the mode that is similar to embodiment 60.
Embodiment 61
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-p-methoxy-phenyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.89(6H，brs)，3.48(3H，s)，4.88(1H，sept，J＝6.8Hz)，6.32(1H，d，J＝9.5Hz)，7.00-7.13(2H，m)，7.22(1H，d，J＝2.5Hz)，7.37-7.79(6H，m)，8.16(1H，brs)
Embodiment 62
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(3-p-methoxy-phenyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.00(6H，d，J＝7.0Hz)，3.71(3H，s)，4.92(1H，sept，J＝7.0Hz)，6.33(1H，d，J＝9.5Hz)，6.94-7.02(3H，m)，7.30-7.39(2H，m)，7.65-7.71(4H，m)，8.20(1H，brs)
Embodiment 63
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-aminomethyl phenyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.88(6H，d，J＝7.0Hz)，1.99(3H，s)，4.85(1H，sept，J＝7.0Hz)，6.33(1H，d，J＝9.5Hz)，7.11(1H，d，J＝2.5Hz)，7.32(4H，brs)，7.70(3H，brs)，7.89(1H，dd，J＝2.5，9.5Hz)，8.23(1H，brs)
MS(ESI +)：364[M+H] +，405[M+H+MeCN] +
Embodiment 64
3-amino-5-(2, the 3-difluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.97(6H，d，J＝7.0Hz)，4.92(1H，sept，J＝7.0Hz)，6.37(1H，d，J＝9.0Hz)，7.34-7.79(8H，m)，8.26(1H，brs)
MS(ESI +)：386[M+H] +，427[M+H+MeCN] +
Embodiment 65
3-amino-5-(2,4 difluorobenzene base)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.99(6H，d，J＝6.8Hz)，4.93(1H，sept，J＝6.8Hz)，6.36(1H，d，J＝9.0Hz)，7.24-7.35(3H，m)，7.65-7.77(5H，m)，8.23(1H，brs)
MS(ESI +)：386[M+H] +，427[M+H+MeCN] +
Embodiment 66
3-amino-5-(2, the 5-difluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.99(6H，d，J＝7.0Hz)，4.92(1H，sept，J＝7.0Hz)，6.37(1H，d，J＝9.5Hz)，7.24-7.40(3H，m)，7.48-7.79(5H，m)，8.25(1H，brs)
MS(ESI +)：386[M+H] +，427[M+H+MeCN] +
Embodiment 67
3-amino-5-(2-furyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.25(6H，d，J＝6.8Hz)，5.07(1H，sept，J＝6.8Hz)，6.39(1H，d，J＝9.0Hz)，6.61(1H，dd，J＝1.1，3.5Hz)，6.79(1H，d，J＝3.5Hz)，7.55(1H，dd，J＝2.5，9.5Hz)，7.66(3H，brs)，7.79(2H，brs)，8.09(1H，brs)
MS(ESI +)：340[M+H] +，381[M+H+MeCN] +
Embodiment 68
3-amino-5-(3-furyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.25(6H，d，J＝6.8Hz)，5.07(1H，sept，J＝6.8Hz)，6.39(1H ，d，J＝9.0Hz)，6.62(1H，dd，J＝2.0，3.5Hz)，6.79(1H，d，J＝3.5Hz)，7.55(1H，dd，J＝2.5，9.5Hz)，7.66(3H，brs)，7.99(2H，s)，8.09(1H，brs)
MS(ESI +)：340[M+H] +，381[M+H+MeCN] +
Embodiment 69
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-thienyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.23(6H，d，J＝6.8Hz)，5.07(1H，sept，J＝6.8Hz)，6.42(1H，d，J＝9.5Hz)，7.04-7.06(1H，m)，7.16-7.17(1H，m)，7.49(1H，d，J＝2.5Hz)，7.54(1H，d，J＝2.5Hz)，7.65(2H，brs)，7.69(1H，d，J＝5.5Hz)，7.87(1H，d，J＝2.5Hz)，8.06(1H，brs)
MS(ESI +)：356[M+H] +，397[M+H+MeCN] +
Embodiment 70
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(3-thienyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.12(6H，d，J＝7.0Hz)，4.98(1H，sept，J＝7.0Hz)，6.36(1H，d，J＝9.0Hz)，7.12(1H，dd，J＝1.3，5.0Hz)，7.54-7.71(7H，m)，8.14(1H，brs)
MS(ESI +)：356[M+H] +，397[M+H+MeCN] +
Embodiment 71
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(5-methyl-2-thienyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.26(6H，d，J＝6.5Hz)，2.44(3H，s)，5.08(1H，sept，J＝6.8Hz)，6.41(1H，d，J＝9.5Hz)，6.76(1H，d，J＝2.5Hz)，6.98(1H，d，J＝3.5Hz)，7.47(1H，d，J＝2.5Hz)，7.52(1H，d，J＝2.5Hz)，7.61(2H，brs)，7.89(1H，d，J＝2.5Hz)，8.01(1H，brs)
MS(ESI +)：370[M+H] +，411[M+H+MeCN] +
Embodiment 72
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(1H-pyrazoles-4-yl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.23(6H，d，J＝7.0Hz)，5.06(1H，sept，J＝7.0Hz)，6.40(1H，d，J＝9.5Hz)，7.50(1H，dd，J＝2.5，9.5Hz)，7.57(5H，brs)，7.80(1H，d，J＝2.5Hz)，8.01(1H，brs)，13.06(1H，brs)
MS(ESI +)：362[M+Na] +，701[2M+Na] +
Embodiment 73
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-[(E)-2-styryl]-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.32(6H，d，J＝6.5Hz)，5.12(1H，sept，J＝6.5Hz)，6.50(1H，d，J＝9.5Hz)，7.20-7.43(5H，m)，7.59-7.83(6H，m)，7.90(1H，d，J＝2.5Hz)，8.10(1H，brs)
MS(ESI +)：398[M+Na] +，773[2M+Na] +
Embodiment 74
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-[3-pyridyl]-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：0.98(6H，d，J＝7.0Hz)，4.93(1H，sept，J＝7.0Hz)，6.36(1H，d，J＝9.5Hz)，7.37-7.46(3H，m)，7.66-7.75(4H，m)，8.26(1H，brs)，8.61-8.64(2H，m)
MS(ESI +)：351[M+H] +，392[M+H+MeCN] +
Embodiment 75
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(4-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：1.00(6H，d，J＝7.0Hz)，4.93(1H，sept，J＝7.0Hz)，6.35(1H，d，J＝9.5Hz)，7.42-7.89(7H，m)，8.23(1H，brs)，8.57(1H，dd，J＝2.0，5.0Hz)，8.64(1H，d，J＝2.0Hz)
MS(ESI +)：351[M+H] +，392[M+H+MeCN] +
Embodiment 76
3-amino-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：3.46(3H，s)，6.17(1H，d，J＝9.5Hz)，7.00(1H，dd，J＝2.5，9.5Hz)，7.25(2H，t，J＝9Hz)，7.51-7.73(5H，m)，8.15(1H，d，J＝2.5Hz)，8.27(1H，brs)
MS(ESI +)：362[M+Na] +，701[2M+Na] +
Embodiment 77
3-amino-5-(2-furyl)-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：3.50(3H，s)，6.33(1H，d，J＝9.0Hz)，6.63(1H，dd，J＝1.8，3.5Hz)，6.83(1H，d，J＝3.5Hz)，7.28(1H，dd，J＝2.5，9.5Hz)，7.69-7.79(4H，m)，8.10(1H，d，J＝2.5Hz)，8.16(1H，brs)
MS(ESI +)：334[M+Na] +
Embodiment 78
3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-thienyl)-2-pyrazine carboxylic acid amides
1H-NMR(DMSO-d 6δ)：3.50(3H，s)，6.35(1H，d，J＝9.5Hz)，7.04-7.09(1H，m)，7.19-7.21(1H，m)，7.35(1H，dd，J＝2.5，9.5Hz)，7.66(1H，brs)，7.70-7.72(3H，m)，8.12-8.13(2H，m)
MS(ESI +)：350[M+Na] +
Embodiment 79
3-amino among the DMF (2ml)-5-chloro-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides (200mg), Phenylacetylene (331mg), NEt 3(658mg), triphenyl phosphine (17mg), CuI (6.2mg) and PdCl 2(PPh 3) 2Mixture (23mg) was 80 ℃ of heating 18 hours.Water (20ml) is poured in this reaction mixture with EtOAc (20ml), with EtOAc extraction water solution.Organic layer is used MgSO with water and salt solution washing 4Dry.After the filtration, decompression goes down to desolventize.Solid residue places on the silicagel column, with CHCl 3-MeOH (97: 3) elution.Evaporation of eluate with IPE suspension residue, is filtered and is obtained 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(phenylacetylene base)-2-pyrazine carboxylic acid amides (218mg), is yellow powder.
MS(ESI +)：396[M+Na] +，769[2M+Na] +
Embodiment 80
3-amino-5-chloro-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides (200mg), 2-(tributyl tin) pyridine (311mg), with Pd (PPh 3) 4Toluene solution (22.5mg) refluxed 5 hours.Water (20ml) is poured in this reaction mixture with EtOAc (15ml), with EtOAc extraction water solution.Organic layer is used MgSO with water and salt solution washing 4Dry.After the filtration, decompression goes down to desolventize.Solid residue places silicagel column, with CHCl 3-MeOH=97: 3 elutions.Evaporation of eluate with IPE suspension residue, is filtered and is obtained 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-pyridyl)-2-pyrazine carboxylic acid amides (64mg), is yellow powder.
1H-NMR(DMSO-d 6δ)：1.01(6H，d，J＝6.5Hz)，4.93(1H，sept，J＝6.5Hz)，6.30(1H，d，J＝9.5Hz)，7.35-7.46(2H，m)，7.59-7.75(5H，m)，7.96(1H，dt，J＝1.7，7.8Hz)，8.24(1H，brs)，8.55(1H，d，J＝4.5Hz)
MS(ESI +)：351[M+H] +
Embodiment 81
(2M 4ml), makes this solution 100 ℃ of heating 4 hours to add aq NaOH in 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-the pyridyl)-suspension of 5-(4-p-methoxy-phenyl)-2-pyrazine carboxylic acid amides (210mg) in two  alkane (2ml).Cool off this reaction mixture to room temperature, the pH value of adjusting this solution with 2N aq.HCl is 2.5.Filter the collecting precipitation thing,, obtain 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(4-p-methoxy-phenyl)-2-pyrazine carboxylic acid (203mg), be yellow powder with water washing.
1H-NMR(DMSO-d 6δ)：1.03(1H，d，J＝7Hz)，3.77(3H，s)，4.94(1H，sept，J＝7.0Hz)，6.36(1H，d，J＝9.5Hz)，6.98(2H，d，J＝9.0Hz)，7.41-7.56(6H，m)，12.91(1H，brs)
MS(ESI +)：381[M+H] +，422[M+H+MeCN] +
Below 24 kinds of compounds obtain in the mode that is similar to embodiment 81.
Embodiment 82
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-p-methoxy-phenyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：0.91(6H，brs)，3.48(3H，s)，4.87(1H，sept，J＝6.8Hz)，6.35(1H，d，J＝9.5Hz)，7.01(1H，d，J＝8Hz)，7.10(1H，t，J＝7.5Hz)，7.19(1H，d，J＝2.5Hz)，7.38-7.49(4H，m)，7.62(1H，dd，J＝2.5，9.0Hz)，12.93(1H，brs)
MS(ESI +)：381[M+H] +，422[M+H+MeCN] +
Embodiment 83
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(3-p-methoxy-phenyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：0.99(6H，d，J＝7Hz)，3.70(3H，s)，4.92(1H，sept，J＝7.0Hz)，6.37(1H，d，J＝9.5Hz)，6.95-7.04(3H，m)，7.30-7.38(2H，m)，7.50(2H，brs)，7.58(1H，dd，J＝2.5，9.0Hz)，13(1H，brs)
MS(ESI +)：381[M+H] +，422[M+H+MeCN] +
Embodiment 84
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-aminomethyl phenyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：0.88(6H，d，J＝7.0Hz)，1.99(3H，s)，4.85(1H，t，J＝7.0Hz)，6.37(1H，d，J＝9.5Hz)，7.09(1H，d，J＝2.5Hz)，7.26-7.40(4H，m)，7.49(2H，brs)，7.73(1H，dd，J＝2.5，9.5Hz)，13.05(1H，brs)
Embodiment 85
3-amino-5-(2, the 3-difluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：0.95(6H，d，J＝3.5Hz)，4.92(1H，sept，J＝3.5Hz)，6.40(1H，d，J＝4.7Hz)，7.30(1H，d，J＝1.1Hz)，7.34-7.63(6H，m)，13.20(1H，brs)
MS(ESI +)：387[M+H] +，428[M+H+MeCN] +
Embodiment 86
3-amino-5-(2,4 difluorobenzene base)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：0.97(6H，d，J＝3.4Hz)，4.92(1H，sept，J＝3.4Hz)，6.39(1H，d，J＝4.8Hz)，7.26-7.33(3H，m)，7.56(2H，brs)，7.61(1H，dd，J＝1.3，4.8Hz)，7.68-7.74(1H，m)，13.15(1H，brs)
MS(ESI +)：387[M+H] +，428[M+H+MeCN] +
Embodiment 87
3-amino-5-(2, the 5-difluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：0.97(6H，d，J＝3.5Hz)，4.92(1H，sept，J＝3.5Hz)，6.4(1H，d，J＝4.8Hz)，7.25-7.38(3H，m)，7.51-7.55(1H，m)，7.58(2H，brs)，7.62(1H，dd，J＝1.3，4.8Hz)，13.19(1H，brs)
MS(ESI +)：387[M+H] +，428[M+H+MeCN] +
Embodiment 88
3-amino-5-(2-furyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：1.24(6H，d，J＝6.5Hz)，5.09(1H，sept，J＝6.5Hz)，6.43(1H，d，J＝9Hz)，6.62(1H，dd，J＝2，3.5Hz)，6.77(1H，d，J＝3Hz)，7.45-7.51(3H，m)，7.75-7.82(2H，m)
Embodiment 89
3-amino-5-(3-furyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：1.21(6H，d，J＝3.5Hz)，5.06(1H，sept，J＝3.5Hz)，6.43(1H，d，J＝4.8Hz)，6.54(1H，d，J＝0.9Hz)，7.44(2H，brs)，7.48(1H，dd，J＝1.3，4.8Hz)，7.72-7.77(3H，m)，12.95(1H，brs)
MS(ESI +)：341[M+H] +，382[M+H+MeCN] +
Embodiment 90
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-thienyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：1.22(6H，d，J＝7.0Hz)，5.08(1H，sept，J＝7.0Hz)，6.46(1H，d，J＝9.0Hz)，7.05-7.09(1H，m)，7.2(1H，dd，J＝1.0，4.0Hz)，7.42-7.48(3H，m)，7.73(1H，dd，J＝1.0，5.0Hz)，7.83(1H，d，J＝2.5Hz)，13.00(1H，brs)
MS(ESI +)：357[M+H] +，398[M+H+MeCN] +
Embodiment 91
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(3-thienyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：1.10(6H，d，J＝6.5Hz)，4.98(1H，sept，J＝6.5Hz)，6.37-6.43(1H，m)，7.13(1H，dd，J＝1.5，5.0Hz)，7.46-7.60(5H，m)，7.72(1H，dd，J＝1.3，3Hz)
MS(ESI +)：357[M+H] +，398[M+H+MeCN] +
Embodiment 92
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(5-methyl-2-thienyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：1.25(6H，d，J＝7.0Hz)，5.09(1H，sept，J＝7.0Hz)，2.44(3H，s)，6.45(1H，d，J＝9.5Hz)，6.77-6.78(1H，m)，7.01(1H，d，J＝3.5Hz)，7.40-7.46(3H，m)，7.85(1H，d，J＝2.5Hz)，12.98(1H，brs)
MS(ESI +)：371[M+H] +，412[M+H+MeCN] +
Embodiment 93
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(1H-pyrazoles-4-yl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：1.23(1H，d，J＝7.0Hz)，5.07(1H，sept，J＝7.0Hz)，6.44(1H，d，J＝9.0Hz)，7.37(2H，brs)，7.43(1H，dd，J＝2.5，9.0Hz)，7.66(2H，s)，7.77(1H，d，J＝2.5Hz)，12.99(1H，brs)
MS(ESI -)：339[M-H] -
Embodiment 94
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-[(E)-2-styryl]-2-pyrazine carboxylic acid.
MS(ESI -)：375[M-H] -
Embodiment 95
3-amino-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：3.43(3H，s)，6.22(1H，d，J＝9.5Hz)，7.05(1H，dd，J＝2.8，9.5Hz)，7.26(2H，t，J＝8.8Hz)，7.50(2H，brs)，7.55(2H，dd，J＝5.5，9.0Hz)，7.92(1H，d，J＝2.5Hz)
Embodiment 96
3-amino-5-(2-furyl)-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid
MS(ESI -)：311[M-H] -
Embodiment 97
3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-thienyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：3.49(3H，s)，6.40(1H，d，J＝9.5Hz)，7.08(1H，dd，J＝4.0，5.0Hz)，7.22(1H，dd，J＝1.0，4.0Hz)，7.36(1H，dd，J＝2.8，9.5Hz)，7.48(2H，brs)，7.74(1H，dd，J＝1.0，5.0Hz)，7.97(1H，d，J＝2.5Hz)
Embodiment 98
3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(phenylacetylene base)-2-pyrazine carboxylic acid
MS(ESI -)：373[M-H] -
Embodiment 99
3-amino-5-(2-fluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：0.92(1H，d，J＝7.0Hz)，4.88(1H，sept，J＝7.0Hz)，6.38(1H，d，J＝9.5Hz)，7.18-7.69(8H，m)，13.12(1H，brs)
MS(ESI +)：369[M+H] +，410[M+H+MeCN] +
Embodiment 100
3-amino-5-(3-fluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：0.99(6H，d，J＝6.5Hz)，4.93(1H，t，J＝6.5Hz)，6.38(1H，d，J＝9.0Hz)，7.22-7.60(8H，m)，13.07(1H，brs)
MS(ESI +)：369[M+H] +，410[M+H+MeCN] +
Embodiment 101
3-amino-5-(3-chloro-phenyl-)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：0.99(1H，d，J＝7.0Hz)，4.94(1H，sept，J＝7.0Hz)，6.39(1H，d，J＝9.5Hz)，7.37-7.62(8H，m)，13.06(1H，brs)
MS(ESI +)：385[M+H] +，426[M+H+MeCN] +
Embodiment 102
3-amino-5-(4-chloro-phenyl-)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：1.00(6H，d，J＝7.0Hz)，4.94(1H，t，J＝7.0Hz)，6.38(1H，d，J＝9.5Hz)，7.34-7.59(8H，m)，13.04(1H，brs)
MS(ESI +)：385[M+H] +，426[M+H+MeCN] +
Embodiment 103
3-amino-5-(3, the 4-difluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：1.03(6H，d，J＝7.0Hz)，4.96(1H，sept，J＝6.8Hz)，6.39(1H，d，J＝9.0Hz)，7.30-7.61(7H，m)，13.06(1H，brs)
MS(ESI +)：387[M+H] +，428[M+H+MeCN] +
Embodiment 104
3-amino-5-(3, the 5-difluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：1.03(1H，d，J＝6.5Hz)，4.97(1H，sept，J＝6.5Hz)，6.40(1H，d，J＝9.5Hz)，7.16-7.59(7H，m)，13.16(1H，brs)
MS(ESI +)：387[M+H] +，428[M+H+MeCN] +
Embodiment 105
3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylic acid
1H-NMR(DMSO-d 6δ)：3.42(3H，s)，6.18(1H，d，J＝9.0Hz)，7.03(1H，dd，J＝2.8，9.0Hz)，7.38-7.53(7H，m)，7.91(1H，d，J＝2.5Hz)
Embodiment 106
1, the suspension (3ml) of 3-amino-6-in the 2-benzene dichloride (1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(4-p-methoxy-phenyl)-2-pyrazine carboxylic acid was 200 ℃ of heating, stirring 4 hours.This reaction mixture is cooled to room temperature.In this solution, add IPE, stirred 1 hour under the room temperature.Filter the collecting precipitation thing, wash with IPE.Solid residue places on the silicagel column, with CHCl 3-MeOH (20: 1) elution.Evaporation of eluate, residue obtain 5-[5-amino-3-(4-p-methoxy-phenyl)-2-pyrazinyl with EtOH-water recrystallizing and refining]-1-sec.-propyl-2 (1H)-pyridone (88mg), be filbert crystallization.
1H-NMR(DMSO-d 6δ)：1.02(6H，d，J＝7.0Hz)，3.75(3H，s)，4.94(1H，sept，J＝7.0Hz)，6.31(1H，d，J＝9.5Hz)，6.55(2H，brs)，6.94(2H，d，J＝9.0Hz)，7.29-7.42(4H，m)，7.87(1H，s)
MS(ESI +)：337[M+H] +，378[M+H+MeCN] +
Below 24 kinds of compounds obtain in the mode that is similar to embodiment 106.
Embodiment 107
5-[5-amino-3-(2-p-methoxy-phenyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：0.91(6H，brs)，3.48(3H，s)，4.87(1H，sept，J＝6.8Hz)，6.31(1H，d，J＝9.0Hz)，6.51(2H，brs)，6.97-7.10(3H，m)，7.33-7.51(3H，m)，7.90(1H，s)
MS(ESI +)：337[M+H] +，378[M+H+MeCN] +
Embodiment 108
5-[5-amino-3-(3-p-methoxy-phenyl)-2-pyrazinyl 1-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：0.98(6H，d，J＝7.0Hz)，3.69(3H，s)，4.92(1H，sept，J＝7.0Hz)，6.32(1H，d，J＝9.5Hz)，6.61(2H，brs)，6.89-6.95(3H，m)，7.24-7.33(3H，m)，7.43(1H，dd，J＝2.5，9.5Hz)，7.92(1H，s)
Embodiment 109
5-[5-amino-3-(2-tolyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：0.88(6H，d，J＝6.5Hz)，1.97(3H，s)，4.84(1H，sept，J＝6.5Hz)，6.32(1H，d，J＝9.0Hz)，6.58(2H，brs)，7.02(1H，d，J＝2.5Hz)，7.27(4H，brs)，7.56(1H，dd，J＝2.5，9.0Hz)，7.95(1H，s)
Embodiment 110
5-[5-amino-3-(2, the 3-difluorophenyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：0.96(6H，d，J＝7Hz)，4.91(1H，sept，J＝7Hz)，6.36(1H，d，J＝9.5Hz)，6.75(2H，brs)，7.2(1H，d，J＝2.5Hz)，7.3-7.51(4H，m)，8.01(1H，s)
MS(ESI +)：343[M+H] +，484[M+H+MeCN] +
Embodiment 111
5-[5-amino-3-(2,4 difluorobenzene base)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：0.97(6H，d，J＝7.0Hz)，4.92(1H，t，J＝7.0Hz)，6.35(1H，d，J＝9.0Hz)，6.7(2H，brs)，7.19-7.30(3H，m)，7.47(1H，dd，J＝2.8，9.0Hz)，7.56-7.68(1H，m)，7.97(1H，s)
MS(ESI +)：343[M+H] +，384[M+H+MeCN] +
Embodiment 112
5-[5-amino-3-(2, the 5-difluorophenyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：0.97(6H，d，J＝6.8Hz)，4.91(1H，sept，J＝6.8Hz)，6.36(1H，d，J＝9.5Hz)，6.73(2H，brs)，7.21-7.30(3H，m)，7.44-7.52(2H，m)，7.99(1H，s)
MS(ESI +)：343[M+H] +，384[M+H+MeCN] +
Embodiment 113
5-[5-amino-3-(2-furyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.22(6H，d，J＝7.0Hz)，5.06(1H，sept，J＝7.0Hz)，6.38(1H，d，J＝9.0Hz)，6.56(1H，dd，J＝1.8，3.5Hz)，6.65-6.66(1H，m)，7.36(3H，dd，J＝2.8，9.5Hz)，7.58(2H，d，J＝2.5Hz)，7.70(1H，m)，7.87(1H，s)
MS(ESI +)：297[M+H] +，338[M+H+MeCN] +
Embodiment 114
5-[5-amino-3-(3-furyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.19(6H，d，J＝6.5Hz)，5.04(1H，sept，J＝6.5Hz)，6.4(1H，d，J＝12.0Hz)，6.42(1H，brs)，6.54(2H，brs)，7.39(1H，dd，J＝2.5，9.5Hz)，7.59(1H，d，J＝2.5Hz)，7.65-7.69(2H，m)，7.84(1H，brs)
MS(ESI +)：297[M+H] +，338[M+H+MeCN] +
Embodiment 115
5-[5-amino-3-(2-thienyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.20(6H，d，J＝6.5Hz)，5.06(1H，sept，J＝6.5Hz)，6.4(1H，d，J＝9.5Hz)，6.63(2H，brs)，6.99-7.04(2H，m)，7.36(1H，dd，J＝2.5，9.5Hz)，7.59(1H，dd，J＝2.0，4.5Hz)，7.68(1H，d，J＝2.0Hz)，7.84(1H，s)
MS(ESI +)：313[M+H] +，354[M+H+MeCN] +
Embodiment 116
5-[5-amino-3-(3-thienyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.09(6H，d，J＝6.5Hz)，4.97(1H，sept，J＝6.5H z)，6.35(1H，d，J＝9.5Hz)，6.56(2H，brs)，7.04(1H，dd，J＝1.3，5.0Hz)，7.38-7.44(2H，m)，7.51-7.58(2H，m)，7.87(1H，s)
MS(ESI +)：313[M+H] +，354[M+H+MeCN] +
Embodiment 117
5-[5-amino-3-(5-methyl-2-thienyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.22(6H，d，J＝6.5Hz)，2.41(3H，s)，5.07(1H，sept，J＝6.5Hz)，6.40(1H，d，J＝9.5Hz)，6.57(2H，brs)，6.69-6.70(1H，m)，6.84(1H，d，J＝3.5Hz)，7.35(1H，dd，J＝2.5，9.0Hz)，7.70(1H，d，J＝2.5Hz)，7.79(1H，s)
MS(ESI +)：327[M+H] +，368[M+H+MeCN] +
Embodiment 118
5-[5-amino-3-(1H-pyrazoles-4-yl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.20(6H，d，J＝6.5Hz)，5.05(1H，sept，J＝6.5Hz)，6.38(1H，d，J＝9.0Hz)，6.45(2H，brs)，7.34(1H，dd，J＝2.5，9.0Hz)，7.50-7.62(3H，m)，7.77(1H，s)，12.92(1H，brs)
MS(ESI +)：319[M+Na] +，615[2M+Na] +
Embodiment 119
5-{5-amino-3-[(E)-the 2-styryl]-the 2-pyrazinyl }-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.30(6H，d，J＝7.0Hz)，5.13(1H，sept，J＝7.0Hz)，6.49(1H，d，J＝9.5Hz)，6.58(2H，brs)，7.16(1H，d，J＝15.6Hz)，7.29-7.40(3H，m)，7.53-7.65(4H，m)，7.74(1H，d，J＝2.0Hz)，7.88(1H，s)
MS(ESI +)：333[M+H] +，355[M+Na] +，687[2M+Na] +
Embodiment 120
5-[5-amino-3-(4-fluorophenyl)-2-pyrazinyl]-1-methyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：3.40(3H，s)，6.20(1H，d，J＝9.5Hz)，6.62(2H，brs)，7.01(1H，dd，J＝2.5，9.5Hz)，7.21(1H，t，J＝8.5Hz)，7.46(1H，dd，J＝5.5，8.5Hz)，7.74(1H，d，J＝2.5Hz)，7.90(1H，s)
MS(ESI +)：297[M+H] +，319[M+Na] +，615[2M+Na] +
Embodiment 121
5-[5-amino-3-(2-furyl)-2-pyrazinyl]-1-methyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：3.46(3H，s)，6.33(1H，d，J＝9.5Hz)，6.57(1H，dd，J＝1.5，3.5Hz)，6.65-6.68(3H，m)，7.22(1H，dd，J＝2.5，9.5Hz)，7.69(1H，s)，7.78(1H，d，J＝2.5Hz)，7.85(1H，s)
MS(ESI +)：269[M+H] +，291[M+Na] +，559[2M+Na] +
Embodiment 122
5-[5-amino-3-(2-thienyl)-2-pyrazinyl]-1-methyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：3.46(3H，s)，6.36(1H，d，J＝9.5Hz)，6.64(2H，brs)，6.99-7.07(2H，m)，7.28(1H，dd，J＝2.5，9.5Hz)，7.60(1H，d，J＝3.5Hz)，7.82(1H，s)，7.85(1H，d，J＝2.5Hz)
MS(ESI +)：307[M+Na] +，591[2M+Na] +
Embodiment 123
5-[5-amino-3-(phenylacetylene base)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.26(6H，d，J＝7.0Hz)，5.06(1H，t，J＝7.0Hz)，6.49(1H，d，J＝9.5Hz)，6.75(2H，brs)，7.43-7.54(5H，m)，7.91(1H，dd，J＝2.5，9.5Hz)，7.95(1H，s)，8.17(1H，d，J＝2.5Hz)
MS(ESI +)：331[M+H] +，353[M+Na] +，683[2M+Na] +
Embodiment 124
5-[5-amino-3-(2-fluorophenyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：0.92(6H，d，J＝7.0Hz)，4.88(1H，sept，J＝7.0Hz)，6.34(1H，d，J＝9.5Hz)，6.67(2H，brs)，7.15-7.60(6H，m)，7.97(1H，s)
MS(ESI +)：325[M+H] +，366[M+H+MeCN] +
Embodiment 125
5-[5-amino-3-(3-fluorophenyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.00(6H，d，J＝6.8Hz)，4.94(1H，sept，J＝6.8Hz)，6.35(1H，d，J＝9.0Hz)，6.68(2H，brs)，7.28-7.48(6H，m)，7.95(1H，s)
MS(ESI +)：341[M+H] +，382[M+H+MeCN] +
Embodiment 126
5-[5-amino-3-(3-chloro-phenyl-)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.00(6H，d，J＝6.8Hz)，4.94(1H，sept，J＝6.8Hz)，6.35(1H，d，J＝9.0Hz)，6.68(2H，brs)，7.28-7.48(6H，m)，7.95(1H，s)
MS(ESI +)：341[M+H] +，382[M+H+MeCN] +
Embodiment 127
5-[5-amino-3-(4-chloro-phenyl-)-2-pyrazinyl 1-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.00(6H，d，J＝6.8Hz)，4.93(1H，sept，J＝6.8H z)，6.34(1H，d，J＝9.5Hz)，6.65(2H，brs)，7.25(1H，d，J＝2.5Hz)，7.38-7.48(5H，m)，7.93(1H，s)
MS(ESI +)：341[M+H] +，382[M+H+MeCN] +
Embodiment 128
5-[5-amino-3-(3, the 4-difluorophenyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.03(6H，d，J＝6.8Hz)，4.96(1H，sept，J＝6.8Hz)，6.35(1H，d，J＝9.5Hz)，6.68(2H，brs)，7.20-7.53(6H，m)，7.95(1H，s)
MS(ESI +)：343[M+H] +，384[M+H+MeCN] +
Embodiment 129
5-[5-amino-3-(3, the 5-difluorophenyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.04(6H，d，J＝6.8Hz)，4.96(1H，sept，J＝6.8Hz)，6.37(1H，d，J＝9.0Hz)，6.72(2H，brs)，7.07-7.46(5H，m)，7.97(1H，s)
MS(ESI +)：343[M+H] +，384[M+H+MeCN] +
Embodiment 130
5-(5-amino-3-phenyl-2-pyrazinyl]-1-methyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：3.38(3H，s)，6.16(1H，d，J＝4.8Hz)，6.60(2H，brs)，6.99(1H，dd，J＝1.4，4.8Hz)，7.36-7.42(5H，m)，7.72(1H，d，J＝1.4Hz)，7.90(1H，s)
Embodiment 131
(2M, 1ml), this solution heated 4 hours down at 100 ℃ to add aq.NaOH in 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-the pyridyl)-suspension of 5-(2-pyridyl)-2-pyrazine carboxylic acid amides (52mg) in two  alkane (0.5ml).This reaction mixture is cooled to room temperature, adjusts this pH value of solution value to 2.5 with 2N aq.Hcl.Decompression is this solution of evaporation down, obtains yellow solid.1, the suspension in the 2-benzene dichloride (2ml) stirred 4 hours at 200 ℃ of these yellow solids of heating.This reaction mixture is cooled to room temperature.In this solution, add IPE, stirred 1 hour under the room temperature.Filter the collecting precipitation thing, wash with IPE.Solid residue places on the silicagel column, with CHCl 3-MeOH-28%aq. ammonia (15: 1: 0.1) elution.Evaporation of eluate, residue obtain 5-[5-amino-3-(2-pyridyl)-2-pyrazinyl with the EtOH-IPE recrystallization]-1-sec.-propyl-2-(1H)-pyridone (5mg), be faint yellow crystallization.
1H-NMR(DMSO-d 6δ)：1.13(6H，d，J＝7.0Hz)，5.18(1H，t，J＝7.0Hz)，6.48(1H，d，J＝9.0Hz)，7.29-7.38(3H，m)，7.46(1H，d，J＝7.5Hz)，7.75(1H，dt，J＝1.7，7.5Hz)，8.09(1H，s)，8.71(1H，d，J＝4.5Hz)
MS(ESI +)：308[M+H] +，349[M+H+MeCN] +
Below 2 kinds of compounds obtain in the mode that is similar to embodiment 131.
Embodiment 132
5-[5-amino-3-(3-pyridyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：0.98(6H，d，J＝7.0Hz)，4.92(1H，t，J＝7.0Hz)，6.35(1H，d，J＝9.5Hz)，6.71(2H，brs)，7.3(1H，d，J＝2.5Hz)，7.38-7.46(2H，m)，7.79(1H，dt，J＝2.5，4.0Hz)，7.97(1H，s)，8.51(1H，dd，J＝1.5，5.0Hz)，8.56(1H，d，J＝1.5Hz)
MS(ESI +)：308[M+H] +，349[M+H+MeCN] +
Embodiment 133
5-[5-amino-3-(4-pyridyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：0.96(6H，d，J＝7.0Hz)，4.92(1H，t，J＝7.0Hz)，6.36(1H，d，J＝9.5Hz)，6.74(2H，brs)，7.25(1H，d，J＝2.5Hz)，7.36-7.48(3H，m)，7.99(1H，brs)，8.56-8.59(2H，m)
MS(ESI +)：308[M+H] +，349[M+H+MeCN] +
Embodiment 134
Make 2M aq.Na 2CO 3(3.25ml) with two  alkane (20ml) in 3-amino-5-chloro-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazine carboxylic acid amides (500mg), (4-p-methoxy-phenyl) boric acid (740mg) and Pd (PPh 3) 4(56.3mg) refluxed 3 hours.Water (40ml) is poured in this reaction mixture with EtOAc (30ml), and the aqueous solution extracts with EtOAc.Organic layer is used the MgSO4 drying with water and salt solution washing.After the filtration, decompression goes down to desolventize.Residual solid places on the silicagel column, with CHCl 3-MeOH (97: 3) elution.Evaporation of eluate with IPE suspension residue, is filtered and is obtained yellow powder.In the suspension in the suspension of this yellow powder in two  alkane (0.5ml), (2M, 1ml), this solution of heat is 4 hours in 100 ℃ to add aq.NaOH.Cool off this reaction mixture to room temperature, adjust this pH value of solution value to 2.5 with 2N aq.HCl.Decompression is this solution of evaporation down, obtains yellow solid.1, the suspension in the 2-dichlorobenzene (2ml) stirred 4 hours at 200 ℃ of these yellow solids of heating.Cool off this reaction mixture to room temperature.In this solution, add IPE, stirred 1 hour under the room temperature.Filter the collecting precipitation thing, wash with IPE.Residual solid places on the silicagel column, with CHCl 3-MeOH (97: 3) elution.Evaporation of eluate, residue is refining at GPC (gel permeation chromatography), obtain 5-[5-amino-3-(5-chloro-2-thienyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (25mg) and 5-[5-amino-3-(5 '-chloro-2,2 '-bithiophene-5-yl)-the 2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (26mg), be yellow powder.
5-[5-amino-3-(5-chloro-2-thienyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.24(6H，d，J＝7.0Hz)，5.08(1H，sept，J＝7.0Hz)，6.43(1H，d，J＝9.0Hz)，6.7(2H，brs)，6.86(1H，d，J＝11.4Hz)，7.02(1H，d，J＝4.0Hz)，7.38(1H，dd，J＝2.5，9.0Hz)，7.77(1H，d，J＝2.5Hz)，7.85(1H，brs)
MS(ESI +)：347[M+H] +，388[M+H+MeCN] +
5-[5-amino-3-(5 '-chloro-2,2 '-bithiophene-5-yl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
1H-NMR(DMSO-d 6δ)：1.24(6H，d，J＝6.5Hz)，5.09(1H，sept，J＝6.5Hz)，6.44(1H，d，J＝9.5Hz)，6.69(2H，brs)，6.93(1H，d，J＝3.5Hz)，7.12-7.21(3H，m)，7.40(1H，dd，J＝2.5，9.5Hz)，7.78(1H，d，J＝2.5Hz)，7.85(1H，s)
MS(ESI +)：429[M+H] +，470[M+H+MeCN] +
Embodiment 135
3-amino-5-(4-fluorophenyl)-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-N-methyl-2-pyrazine carboxylic acid amides
Title compound obtains in the mode that is similar to preparation 42.
1H-NMR(DMSO-d 6δ)：0.98(6H，d，J＝7.0Hz)，2.84(3H，d，J＝5.0Hz)，4.92(1H，sept，J＝7.0Hz)，6.39(1H，d，J＝9.0Hz)，7.21-7.78(8H，m)，8.68(1H，d，J＝5.0Hz)
MS(ESI +)：382[M+H] +，404[M+Na] +，785[2M+Na] +
Embodiment 136
In 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-the pyridyl)-5-phenyl-suspension of 2-pyrazine carboxylic acid (350mg) in MeOH (7.0ml), under the ice bath cooling, drip thionyl chloride (0.146m).Under equality of temperature, stir after 1 hour, make this mixture go back up to room temperature.This mixture stirred 6 hours, refluxed then and stirred 15 hours.After the cooling, decompression goes down to desolventize.Water is poured in the residue, adjusted mixture pH value to 10 with 1N aq.NaOH.Filter collecting precipitation, with water washing, vacuum-drying obtains 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylate methyl ester (244mg).
1H-NMR(DMSO-d 6δ)：0.91(6H，d，J＝6.8Hz)，3.89(3H，s)，4.89(1H，qq，J＝6.8，6.8Hz)，6.41(1H，d，J＝9.3Hz)，7.21(1H，d，J＝2.4Hz)，7.30-7.50(7H，m)，7.56(1H，dd，J＝2.4，9.3Hz)
MS(ESI +)：365[M+H] +，387[M+Na] +
Embodiment 137
Under the ice bath cooling, (3M solution is 0.46ml) in 3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carboxylate methyl ester (100mg) suspension among the adding THF (10ml) with methylmagnesium-chloride.Stir after 7.5 hours under the equality of temperature, (1ml) pours in this mixture with saturated aqueous ammonium chloride.Water and EtOAc are poured in this mixture, separated organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue obtains 5-[5-amino-6-(1-hydroxyl-1-methylethyl)-3-phenyl-2-pyrazinyl with MeOH-IPE recrystallization, drying under reduced pressure]-1-sec.-propyl-2 (1H)-pyridone (41mg).
1H-NMR(DMSO-d 6δ)：0.93(6H，d，J＝6.8Hz)，1.56(6H，s)，4.89(1H，qq，J＝6.8，6.8Hz)，5.76(1H，brs)，6.37(1H，d，J＝9.3Hz)，6.59(2H，brs)，7.17(1H，d，J＝2.4Hz)，7.20-7.50(5H，m)，7.53(1H，dd，J＝2.4，9.3Hz)
MS(ESI +)：365[M+H] +
Embodiment 138
THF-MeOH (1: 1, add sodium borohydride (8.9mg) in the solution of 5-(6-ethanoyl-5-amino-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (82mg) in 2.0ml).Mixture at room temperature stirred 4 hours.1N HCl (0.05ml) is poured in this mixture.Water and EtOAc are poured in this mixture, separated organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue is with the column chromatography purifying.Desirable product EtOH recrystallization, vacuum-drying obtains 5-[5-amino-6-(1-hydroxyethyl)-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (16mg).
1H-NMR(DMSO-d 6δ)：0.93(3H，d，J＝6.7Hz)，0.94(3H，d，J＝6.7Hz)，1.46(3H，d，J＝6.5Hz)，4.70-5.00(2H，m)，5.57(1H，d，J＝5.4Hz)，6.35(1H，d，J＝9.4Hz)，6.40(2H，brs)，7.18(1H，d，J＝2.5Hz)，7.40(5H，m)，7.53(1H，dd，J＝2.5，9.4Hz)
MS(ESI +)：351[M+H] +
Embodiment 139
Under ice bath cooling, with NaH (60% purity 18mg) adds 5-[5-amino-6-(methylol) among the DMF (1.0ml)-3-phenyl-2-pyrazinyl]-suspension of 1-sec.-propyl-2 (1H)-pyridone (100mg) in.After stirring in 10 minutes, in mixture, add MeI (127mg).Synthermal stirring down allowed this mixture go up to 25 ℃ after 10 minutes.3.5 after hour stirring, water and EtOAc are poured in this mixture, separate organic layer, with water and salt solution washing, use MgSO 4Dry.Decompression goes down to desolventize.Residue is with the column chromatography purifying, and with the IPE development, vacuum-drying obtains 5-[5-amino-6-(methoxymethyl)-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (40mg).
1H-NMR(DMSO-d 6δ)：0.93(6H，d，J＝6.7Hz)，3.36(3H，s)，4.53(2H，s)，4.89(1H，qq，J＝6.7，6.7Hz)，6.36(1H，d，J＝9.4Hz)，6.41(1H，brs)，7.17(1H，d，J＝2.5Hz)，7.2-7.5(4H，m)，7.50(1H，dd，J＝2.5，9.4Hz)
MS(ESI +)：351[M+H] +，373[M+Na] +
Embodiment 140
5-[5-amino-6-[(benzyloxy) methyl]-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
Title compound is made in the mode that is similar to embodiment 139.
1H-NMR(DMSO-d 6δ)：0.93(6H，d，J＝6.8Hz)，4.62(2H，s)，4.67(2H，s)，4.89(1H，qq，J＝6.8，6.8Hz)，6.35(1H，d，J＝9.4Hz)，6.45(2H，brs)，7.18(1H，d，J＝2.4Hz)，7.20-7.40(10H，m)，7.49(1H，dd，J＝2.4，9.4Hz)
MS(ESI +)：427[M+H] +，449[M+Na] +
Embodiment 141
Under the ice bath cooling, in 5-(5-amino-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (3.0g) solution among N-bromine succinimide (1.83g) the adding DMF (90ml).Stirred the mixture under synthermal 2 hours.With water and CH 2Cl 2Pour in this mixture, separate organic layer, with saturated aqueous sodium thiosulfate, saturated NaHCO 3MgSO is used in the aqueous solution, water, and salt solution washing 4Dry.Decompression goes down to desolventize.(vacuum-drying obtains 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (3.0g) to residue for silica gel, toluene-EtOAc), use the EtOAc recrystallization with the column chromatography purifying.
1H-NMR(DMSO-d 6δ)：0.93(6H，d，J＝6.8Hz)，4.88(1H，qq，J＝6.8，6.8Hz)，6.35(1H，d，J＝9.4Hz)，6.89(2H，brs)，7.20(1H，d，J＝2.5Hz)，7.30-7.50(6H，m)
MS(ESI +)：385[M+H] +，407[M+Na] +
Embodiment 142
To 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (100mg) and Pd (PPh 3) 4(15mg) add in the suspension in THF (1.0ml) methyl chloride zinc among the THF (2.0M, 0.75ml).Stirred this mixture 7.5 hours at 25 ℃, then 60 ℃ of heating 1.5 hours.After the cooling, water and EtOAc are poured in this mixture, separated organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue MeOH-IPE crystallization, vacuum-drying obtains 5-(5-amino-6-methyl-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (95mg).
1H-NMR(DMSO-d 6δ)：0.94(6H，d，J＝6.8Hz)，2.38(3H，s)，4.89(1H，qq，J＝6.8，6.8Hz)，6.33(1H，d，J＝9.4Hz)，6.38(2H，s)，7.15(1H，d，J＝2.4Hz)，7.20-7.50(5H，m)，7.49(1H，dd，J＝2.4，9.4Hz)
MS(ESI +)：321[M+H] +，343[M+Na] +
Embodiment 143
At 90 ℃ of heating 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridones (100mg), phenyl-boron dihydroxide (79mg), Pd (PPh 3) 4(9mg), Na 2CO 3(110mg) mixture of solution in water (0.8ml) and two  alkane (2.0ml) stirred 1 hour.After the cooling, water and EtOAc are poured in this mixture, separated organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue MeOH-IPE recrystallization, vacuum-drying obtains 5-(5-amino-3,6-phenylbenzene-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (84mg).
1H-NMR(DMSO-d 6δ)：0.94(6H，d，J＝6.8Hz)，4.90(1H，qq，J＝6.8，6.8Hz)，6.30-6.40(3H，m)，7.24(1H，d，J＝2.0Hz)，7.30-7.70(9H，m)，7.80-7.90(2H，m)
MS(ESI +)：383[M+H] +，405[M+Na] +
Embodiment 144
5-[5-amino-6-(2-furyl)-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
Title compound obtains in the mode that is similar to embodiment 143.
1H-NMR(DMSO-d 6δ)：0.95(6H，d，J＝6.8Hz)，4.91(1H，qq，J＝6.8，6.8Hz)，6.38(1H，d，J＝9.4Hz)，6.60-6.80(3H，m)，7.19(1H，d，J＝3.4Hz)，7.27(1H，d，J＝2.4Hz)，7.30-7.50(5H，m)，7.59(1H，dd，J＝2.4，9.4Hz)，7.89(1H，d，J＝1.1Hz)
MS(ESI +)：373[M+H] +，395[M+Na] +
Embodiment 145
5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (100mg), acrylamide (55mg), Pd (OAc) 2(3mg), three (2-tolyl) phosphines (8mg), NEt 3(0.11ml), with the mixture of DMF (1.0ml) 60 ℃ of heated and stirred 1 hour, then 90 ℃ of heated and stirred 5 hours.After the cooling, water and EtOAc are poured in this mixture, separated organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue EtOAc recrystallization, vacuum-drying obtains (2E)-3-[3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinyl] acrylamide (70mg).
1H-NMR(DMSO-d 6δ)：0.93(6H，d，J＝6.8Hz)，4.90(1H，qq，J＝6.8，6.8Hz)，6.40(1H，d，J＝9.4Hz)，6.81(2H，brs)，7.08(1H，d，J＝14.9Hz)，7.10-7.20(2H，m)，7.20-7.50(5H，m)，7.62(1H，dd，J＝2.5，9.3Hz)，7.70(1H，brs)，7.75(1H，d，J＝14.9Hz)
MS(ESI +)：376[M+H] +，398[M+Na] +
Embodiment 146
(2E)-3-[3-amino-6-(1-sec.-propyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinyl]-N,N-DMAA
Title compound obtains in the mode that is similar to embodiment 145.
1H-NMR(DMSO-d 6δ)：0.96(6H，d，J＝6.7Hz)，2.96(3H，s)，3.16(3H，s)，4.92(1H，qq，J＝6.7，6.7Hz)，6.36(1H，d，J＝9.4Hz)，6.84(2H，brs)，7.30-7.60(8H，m)，7.79(1H，d，J＝14.6Hz)
MS(ESI +)：404[M+H] +，426[M+Na] +
Embodiment 147
Under the ice bath cooling, to 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (500mg), ethynyl trimethyl silane (255mg), PdCl 2(PPh 3) 2(46mg), CuI (12mg) and CH 2Cl 2Add NEt in the mixture (10ml) 3(0.2ml).This mixture is gone up to 25 ℃, stirred 15 hours.Water and EtOAc are poured in this mixture, separated organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue is with column chromatography purifying (silica gel; CH 2Cl 2-MeOH), use the EtOH recrystallization, vacuum-drying obtains 5-{5-amino-3-phenyl-6-[(trimethyl silyl) ethynyl]-the 2-pyrazinyl }-1-sec.-propyl-2 (1H)-pyridone (373mg).
1H-NMR(DMSO-d 6δ)：0.29(9H，s)，0.94(6H，d，J＝6.7Hz)，4.89(1H，qq，J＝6.7，6.7Hz)，6.34(1H，d，J＝9.4Hz)，6.70(2H，brs)，7.21(1H，d，J＝2.4Hz)，7.30-7.50(5H，m)，7.47(1H，dd，J＝2.5，9.4Hz)
MS(ESI +)：403[M+H] +，425[M+Na] +
Embodiment 148
Stir 5-{5-amino-3-phenyl-6-[(trimethyl silyl among the MeOH (4.5ml) at 25 ℃) ethynyl]-the 2-pyrazinyl }-1-sec.-propyl-2 (1H)-pyridone (300mg) and sat.K 2CO 3Mixture 3 hours.Water and EtOAc are poured in this mixture, separated organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue is with column chromatography purifying (silica gel; CH 2Cl 2), use the EtOH recrystallization, obtain 5-{5-amino-6-ethynyl-3-phenyl-2-pyrazinyl }-1-sec.-propyl-2 (1H)-pyridone (100mg).
1H-NMR(DMSO-d 6δ)：0.95(6H，d，J＝6.8Hz)，4.71(1H，s)，4.89(1H，qq，J＝6.8，6.8Hz)，6.34(1H，d，J＝9.3Hz)，6.75(2H，brs)，7.22(1H，d，J＝2.5Hz)，7.30-7.50(6H，m)
MS(ESI +)：331[M+H] +，353[M+Na] +
Embodiment 149
5-{5-amino-6-bromo-3-phenyl-2-pyrazinyl in 100 ℃ of heating NMP (1.0ml) }-mixture of 1-sec.-propyl-2 (1H)-pyridone (100mg), sodium methylate (70mg), CuI (5mg) 2.5 hours.After the cooling, water and EtOAc are poured in this mixture, separated organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue obtains 5-(5-amino-6-methoxyl group-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (58mg) with the MeOH-IPE recrystallization.
1H-NMR(DMSO-d 6δ)：0.94(6H，d，J＝6.7Hz)，3.98(3H，s)，4.90(1H，qq，J＝6.7，6.7Hz)，6.35(1H，d，J＝9.4Hz)，6.49(2H，brs)，7.19(1H，d，J＝9.4Hz)，7.20-7.40(5H，m)，7.52(1H，dd，J＝2.5，9.4Hz)
MS(ESI +)：337[M+H] +，359[M+Na] +
Embodiment 150
100 ℃ of heated and stirred 5-(5-amino-6-methoxyl group-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (80mg), dense HCl (0.8ml), with the mixture of two  alkane (1.6ml) 3 hours, after the cooling, adjust the pH value to 8 of this mixture, filter and collect the precipitation that produces, vacuum-drying obtains 5-(5-amino-6-hydroxyl-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (36mg).
1H-NMR(DMSO-d 6δ)：1.08(6H，d，J＝6.8Hz)，4.94(1H，qq，J＝6.8，6.8Hz)，6.26(1H，d，J＝9.4Hz)，6.76(2H，brs)，7.13(1H，dd，J＝2.2，9.4Hz)，7.1-7.3(5H，m)，7.46(1H，d，J＝2.2Hz)，11.91(1H，brs)
MS(ESI +)：323[M+H] +，345[M+Na] +
Embodiment 151
Under the ice bath cooling, add 60%NaH (52mg) in phenol (147mg) solution in NMP (1.0ml).After stirring in 5 minutes, synthermal 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (the 1H)-pyridone (100mg) that in this mixture, adds down.This mixture was 100 ℃ of heating down, stirring 5.5 hours then.After the cooling, water and EtOAc are poured in this mixture, separated organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue MeOH-IPE recrystallization obtains 5-(5-amino-6-phenoxy group-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (88mg).
1H-NMR(DMSO-d 6δ)：0.90(6H，d，J＝6.8Hz)，4.86(1H，qq，J＝6.8，6.8Hz)，6.23(1H，d，J＝10.1Hz)，7.15(2H，m)，7.20-7.50(10H，m)
MS(ESI +)：399[M+H] +，421[M+Na] +
Embodiment 152
Under 100 ℃, in sealed tube, heated and stirred 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (100mg) and methylamine/THF solution (2.0M, mixture 1.0ml) 20 hours.After the cooling, decompression is removed this solvent down, and residue MeOH-IPE recrystallization obtains 5-[5-amino-6-(methylamino)-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (13mg).Concentrated filtrate in the vacuum, residue obtain desirable product (60mg) with the MeOH-IPE rinsing.
1H-NMR(DMSO-d 6δ)：0.94(6H，d，J＝6.7Hz)，2.93(3H，d，J＝4.4Hz)，4.90(1H，qq，J＝6.7，6.7Hz)，6.11(2H，brs)，6.33(1H，d，J＝9.3Hz)，6.49(1H，m)，7.19(1H，d，J＝2.4Hz)，7.10-7.40(5H，m)，7.52(1H，dd，J＝2.4，9.4Hz)
MS(ESI +)：336[M+H] +，358[M+Na] +
Embodiment 153
At 150 ℃ with 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (100mg), morpholine (113mg), stirred one day with the mixture heating up of NMP (1.0ml).After the cooling, water and EtOAc are poured in this mixture, separated organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue is with the MeOH-IPE recrystallization, and vacuum-drying obtains 5-(5-amino-6-(4-morpholinyl)-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (84mg).
1H-NMR(DMSO-d 6δ)：0.94(6H，d，J＝6.7Hz)，3.10-3.20(4H，m)，3.70-3.90(4H，m)，4.90(1H，qq，J＝6.7，6.7Hz)，6.22(2H，brs)，6.35(1H，d，J＝9.4Hz)，7.19(1H，d，J＝2.4Hz)，7.20-7.40(5H，m)，7.54(1H，dd，J＝2.4，9.4Hz)
MS(ESI +)：392[M+H] +，414[M+Na] +
Embodiment 154
At 150 ℃ of heated and stirred 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (100mg), dimethylamine hydrochloride (106mg), N, the mixture of N-diisopropylethylamine (201mg) in NMP (1.0ml) 65 hours.After the cooling, water and EtOAc are poured in this mixture, separated organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue is with the MeOH-IPE recrystallization, and vacuum-drying obtains 5-[5-amino-6-(dimethylin)-3-phenyl-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (8mg).
1H-NMR(DMSO-d 6δ)：0.94(6H，d，J＝7.0Hz)，2.83(6H，s)，4.90(1H，qq，J＝7.0，7.0H2)，6.16(2H，brs)，6.34(1H，d，J＝9.5Hz)，7.20(1H，d，J＝2.5Hz)，7.20-7.40(5H，m)，7.54(1H，dd，J＝2.5，9.5Hz)
MS(ESI +)：350[M+H] +，372[M+Na] +
Embodiment 155
Under the ice bath cooling, add 60%NaH (52mg) in pyrazoles (106mg) solution in NMP (1.0ml).After stirring in 5 minutes, in this mixture, add 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (1H)-pyridone (100mg).This mixture was 100 ℃ of following heated and stirred 2 hours then.After the cooling, water and EtOAc are poured in this mixture, separated organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue is with the MeOH recrystallization, and vacuum-drying obtains 5-[5-amino-3-phenyl-6-(1H-pyrazol-1-yl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (60mg).
1H-NMR(DMSO-d 6δ)：0.98(6H，d，J＝6.8Hz)，4.92(1H，qq，J＝6.8，6.8Hz)，6.38(1H，d，J＝9.4Hz)，6.68(1H，m)，7.3-7.5(6H，m)，7.5-7.7(3H，m)，7.94(1H，m)，8.78(1H，m)
MS(ESI -)：371[M-H] -
Embodiment 156
5-[5-amino-3-phenyl-6-(1H-pyrroles-1-yl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone
Title compound obtains in the mode that is similar to preparation example 155.
1H-NMR(DMSO-d 6δ)：0.95(6H，d，J＝6.8Hz)，4.90(1H，qq，J＝6.8，6.8Hz)，6.3-6.4(3H，m)，6.49(2H，brs)，7.28(1H，d，J＝2.4Hz)，7.30-7.50(7H，m)，7.53(1H，dd，J＝2.4，9.4Hz)
MS(ESI +)：372[M+H] +，394[M+Na] +
Embodiment 157
The ice bath cooling adds thiophenol (143mg) in 60%NaH (52mg) suspension in NMP (1.0ml) down.After stirring in 10 minutes, synthermal 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-sec.-propyl-2 (the 1H)-pyridone (100mg) that in this mixture, adds down.Synthermal this mixture of stirring down 10 minutes makes it go up to 25 ℃ then.After stirring in 2 hours, make this mixture 100 ℃ of heating 1 hour.After the cooling, water and EtOAc are poured in this mixture, separated organic layer,, use MgSO with water and salt solution washing 4Dry.Decompression goes down to desolventize.Residue MeOH-IPE recrystallization obtains 5-[5-amino-3-phenyl-6-(thiophenyl)-2-pyrazinyl]-1-sec.-propyl-2 (1H)-pyridone (93mg).
1H-NMR(DMSO-d 6δ)：0.93(6H，d，J＝6.8Hz)，4.87(1H，qq，J＝6.8，6.8Hz)，6.18(1H，d，J＝9.4Hz)，6.62(2H，brs)，7.06(1H，dd，J＝2.4，9.4Hz)，7.17(1H，d，J＝2.4Hz)，7.3-7.5(8H，m)，7.5-7.6(2H，m)
MS(ESI +)：415[M+H] +，437[M+Na] +

Claims (17)

1. with a kind of pyrazines derivatives of following formula (I) expression:
In the formula
R 1Be
Figure A2004800315700002C2
Or
Figure A2004800315700002C3
In the formula
R 6Be hydrogen, or the optional low alkyl group that replaces;
R 7Be hydrogen or halogen;
R 8Be low alkyl group;
R 2Be hydrogen; Hydroxyl; Halogen; Cyano group; Or each low alkyl group, low-grade alkenyl, alkynyl of low-grade chain, lower alkoxy, aryloxy, arylthio, acyl group, aryl, heterocyclic radical or amino that all randomly has substituting group to replace;
R 3And R 4Be hydrogen, low alkyl group or acyl group independently; And
R 5Be each low alkyl group, low-grade alkenyl, low-grade alkynyl, cyano group, aryl or heterocyclic radical that all randomly has substituting group to replace;
Or its salt.
2. the compound of claim 1, wherein
R 1For
Figure A2004800315700002C4
In the formula
R 6Be hydrogen, low alkyl group, aryl (rudimentary) alkyl, heteroaryl (rudimentary) alkyl;
R 7Be hydrogen or halogen;
R 2For hydrogen, halogen, cyano group, randomly have the low alkyl group of replacement, randomly low-grade alkynyl, lower alkoxy, aryloxy, arylthio, formamyl, carboxyl, the shielded carboxyl of replacement or the amino of replacement is randomly arranged arranged;
R 3And R 4Be hydrogen or low alkyl group independently; And
R 5Be aryl or the heteroaryl that randomly has one or more substituting groups to replace separately;
Or its salt.
3. the compound of claim 2, wherein
R 2Be hydrogen, halogen, cyano group, hydroxylation (rudimentary) alkyl, low-grade alkynyl, lower alkoxy, aryloxy, arylthio, carboxyl, esterifying carboxyl group, formamyl, amidation carboxyl, amino or single or two (rudimentary) alkylamino radical;
R 3And R 4Be hydrogen independently;
R 5Be aryl or heteroaryl, each all randomly has one or more substituting groups that are selected from halogen and lower alkoxy to replace;
R 6Be hydrogen or low alkyl group; And
R 7Be hydrogen;
Or its salt.
4. the compound of claim 3, wherein
R 2Be hydrogen, bromine, cyano group, methylol, hydroxyethyl, hydroxypropyl, ethynyl, methoxyl group, oxyethyl group, propoxy-, phenoxy group, thiophenyl, carboxyl, formamyl, list or dimethylin carbonyl, picolyl aminocarboxyl, hydroxyl methylamino carbonyl or list or dimethylin;
R 3And R 4Be hydrogen independently;
R 5Be phenyl, pyridyl, furyl, thienyl, pyrryl or pyrazolyl, each all randomly has one or more substituting group replacements that are selected from fluorine, chlorine, reach methoxyl group;
R 6Be hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl or the tertiary butyl; And
R 7Be hydrogen;
Or its salt.
5. the compound of claim 4, wherein
R 2Be hydrogen, cyano group, ethynyl, methoxyl group, phenoxy group, thiophenyl, carboxyl, formamyl or methylamino; And
R 5Be phenyl, furyl or thienyl, each all randomly have one or more be selected from fluorine, chlorine, and the substituting group of methoxyl group replace;
Or its salt.
6. the compound of claim 5, wherein
R 2Be hydrogen, cyano group, carboxyl, formamyl or methylamino;
R 5Be the phenyl that randomly has one or more fluorine to replace; And
R 6Be hydrogen, methyl, ethyl or sec.-propyl;
Or its salt.
7. one kind as shown in the formula the pyrazine compound shown in (I) or the preparation method of its salt,
Figure A2004800315700004C1
Wherein, R 1, R 2, R 3, R 4And R 5Separately with the definition of claim 1; This method comprises
(1) make the reaction of formula (II) compound or its salt and formula (III) compound or its salt, provide formula (I) compound or its salt,
Figure A2004800315700004C2
R wherein 1, R 2, R 3And R 4Separately with above definition, and Hal is a halogen atom;
R 5-Z (III) is R wherein 5With above definition, and
Z is hydrogen, basic metal (as lithium, sodium, potassium etc.), SnBu 3, BW 2Or Met-Hal; BW wherein 2Be the part of organoboron compound, as B (OH) 2, B (CHCH 3CH (CH 3) 2) 2, tetramethyl--1,3, assorted dicyclo [3.3.1] nonyl of 2-dioxo bora penta ring-2-base, 9-boron etc.; And
Met-Hal is the part of metal halide, as MgBr, ZnCl etc.;
Wherein, R 1, R 2, R 3, R 4And R 5Separately with above definition;
(2) make the hydrolysis of formula (Ia) compound or its salt, provide formula (Iba) compound or its salt,
Wherein, R 3, R 4And R 5Separately with above definition, R 8With the definition in the claim 1,
Figure A2004800315700005C2
R wherein 3, R 4And R 5Separately with above definition, R 9Be cyano group, formamyl or carboxyl;
(3) nitrogen-atoms that makes formula (Ib) compound or its salt is provided formula (Ic) compound or its salt by the alkylation of formula (IV) compound or its salt,
R wherein 2, R 3, R 4And R 5Separately with above definition;
R 10-Y (IV)
R wherein 10Be low alkyl group, aryl (rudimentary) alkyl or heteroaryl (rudimentary) alkyl, each all randomly has one or more suitable substituting groups to replace; And
Y is a leavings group;
R wherein 2, R 3, R 4, R 5And R 10Separately with above definition;
(4) make the hydrolysis of formula (Id) compound or its salt, provide formula (Ie) compound or its salt,
Figure A2004800315700006C1
R wherein 1, R 3, R 4And R 5Separately with above definition,
Figure A2004800315700006C2
Wherein, R 1, R 3, R 4And R 5Separately with above definition;
(5) make formula (Ie) compound or its salt decarboxylation, provide formula (If) compound or its salt,
Figure A2004800315700006C3
Wherein, R 1, R 3, R 4And R 5Separately with above definition;
(6) make above compound (If) or its salt halogenation, provide formula (Ih) compound or its salt,
Figure A2004800315700006C4
Wherein, R 1, R 3, R 4, R 5With Hal separately with above definition;
(7) make the reaction of above compound (Ih) or its salt and formula V compound or its salt, provide formula (Ij) compound or its salt,
R 13-Z (V)
Wherein Z is with above definition, and
R 13Be low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, aryloxy, arylthio, acyl group, aryl, heterocyclic radical or amino, each all randomly has substituting group to replace,
Wherein, R 1, R 3, R 4, R 5And R 13Separately with above definition;
(8) make the reaction of formula (XI) compound or its salt and amino propane dinitrile, provide formula (XII) compound or its salt,
R wherein 1As above definition,
R wherein 1With R 2Separately with above definition;
(9) make formula (XV) compound or its salt and formula (XVI) compound carry out halogenating reaction, provide formula (II) compound or its salt,
Figure A2004800315700007C4
Wherein, R 1, R 2, R 3And R 4Separately with above definition;
PO(Hal) 3 (XVI)
Wherein the same definition of Hal.
8. pharmaceutical composition, comprise the compound of claim 1 or its drug acceptable salt and with medicine on can accept the carrier blending.
9. prevention or treatment are selected from the method for following disease: dysthymia disorders, dementia, Parkinson's disease, anxiety, pain, cerebrovascular disease, heart failure, hypertension, circulatory function deficiency, recovery back asystolia, the rhythm of the heart low, dynamo-electric disassociation, Hemodynamics depletion, SIRS (condensation of general inflammatory response is levied); Multiple organ failure; Renal failure (renal insufficiency), renal toxicity, nephrosis, ephritis, oedema, fat, bronchial asthma, gout, high blood Aciduria, sudden infant death syndrome, immunosuppression, diabetes, ulcer, pancreatitis, auditory vertigo syndrome, anaemia, the hypertension that dialysis is brought out, constipation, the ischemia large intestine disease, intestinal obstruction, myocardial infarction, thrombus, block, atherosclerosis obliterans, thrombophlebitis, cerebral infarction, temporary transient ischemic stroke and stenocardia, this method comprises the compound of human or animal's administration claim 1 or its pharmaceutically acceptable salt.
10. prevention or treatment are selected from the method for following disease: dysthymia disorders, disease are slow-witted, Parkinson's disease, anxiety, pain, cerebrovascular disease, auditory vertigo syndrome and cerebral infarction, and this method comprises any one compound or its pharmaceutically acceptable salt in human or animal's administration claim 1～7.
11. prevention or treatment are selected from the method for following disease: dysthymia disorders, dementia, Parkinson's disease and anxiety, this method comprise the compound of human or animal's administration claim 1 or its pharmaceutically acceptable salt.
12. the compound of claim 1 or its drug acceptable salt are as the purposes of medicament.
13. the compound of claim 1 or its drug acceptable salt are as the purposes of adenosine antagonist.
14. the compound of claim 1 or its drug acceptable salt are as A 1Acceptor and A 2The purposes of acceptor binary antagonist.
15. comprising, a preparation of drug combination method, this method can accept the carrier blending on the compound that makes claim 1 or its drug acceptable salt and the medicine.
16. the compound of claim 1 or the purposes of its drug acceptable salt are used to make the treatment of diseases pharmaceutical composition that adenosine antagonist can effectively be treated.
17. an adenosine antagonist appraisal procedure, this method comprise compound or its drug acceptable salt that uses claim 1.
CN200480031570.1A 2003-10-27 2004-10-25 Pyrazine derivatives and pharmaceutical use thereof Pending CN1871231A (en)

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CN102791703A (en) * 2009-10-30 2012-11-21 詹森药业有限公司 Pyrazines as delta opioid receptor modulators
CN102822150A (en) * 2010-02-05 2012-12-12 赫普泰雅治疗有限公司 1,2,4-triazine-4-amine derivatives
WO2015120800A1 (en) * 2014-02-17 2015-08-20 四川百利药业有限责任公司 Nitrogen heterocyclic compound, preparation method therefor and use thereof
CN110240593A (en) * 2018-03-09 2019-09-17 四川科伦博泰生物医药股份有限公司 Substituted aromatic amines compound and its preparation method and application
WO2020035052A1 (en) * 2018-08-17 2020-02-20 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Pyrazine compounds and uses thereof
CN111747954A (en) * 2018-08-17 2020-10-09 迪哲（江苏）医药有限公司 Pyrazine compounds and uses thereof
CN112279837A (en) * 2018-08-17 2021-01-29 迪哲(江苏)医药股份有限公司 Pyrazine compounds and uses thereof
CN113166109A (en) * 2018-12-28 2021-07-23 四川科伦博泰生物医药股份有限公司 Aminopyridine compound and preparation method and application thereof

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102791703A (en) * 2009-10-30 2012-11-21 詹森药业有限公司 Pyrazines as delta opioid receptor modulators
CN102791703B (en) * 2009-10-30 2014-07-09 詹森药业有限公司 Pyrazines as delta opioid receptor modulators
CN102822150A (en) * 2010-02-05 2012-12-12 赫普泰雅治疗有限公司 1,2,4-triazine-4-amine derivatives
CN102822150B (en) * 2010-02-05 2014-12-03 赫普泰雅治疗有限公司 1,2,4-triazine-4-amine derivatives
WO2015120800A1 (en) * 2014-02-17 2015-08-20 四川百利药业有限责任公司 Nitrogen heterocyclic compound, preparation method therefor and use thereof
CN110240593A (en) * 2018-03-09 2019-09-17 四川科伦博泰生物医药股份有限公司 Substituted aromatic amines compound and its preparation method and application
US10898481B2 (en) 2018-08-17 2021-01-26 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Pyrazine compounds and uses thereof
CN111747954A (en) * 2018-08-17 2020-10-09 迪哲（江苏）医药有限公司 Pyrazine compounds and uses thereof
WO2020035052A1 (en) * 2018-08-17 2020-02-20 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Pyrazine compounds and uses thereof
CN112279837A (en) * 2018-08-17 2021-01-29 迪哲(江苏)医药股份有限公司 Pyrazine compounds and uses thereof
CN111747954B (en) * 2018-08-17 2021-08-24 迪哲(江苏)医药股份有限公司 Pyrazine compounds and uses thereof
CN112279837B (en) * 2018-08-17 2022-08-09 迪哲(江苏)医药股份有限公司 Pyrazine compounds and uses thereof
CN115181092A (en) * 2018-08-17 2022-10-14 迪哲(江苏)医药股份有限公司 Pyrazine compounds and uses thereof
US11571420B2 (en) 2018-08-17 2023-02-07 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Pyrazine compounds and uses thereof
CN115181092B (en) * 2018-08-17 2024-05-03 迪哲(江苏)医药股份有限公司 Pyrazine compounds and uses thereof
CN113166109A (en) * 2018-12-28 2021-07-23 四川科伦博泰生物医药股份有限公司 Aminopyridine compound and preparation method and application thereof
CN113166109B (en) * 2018-12-28 2024-01-02 四川科伦博泰生物医药股份有限公司 Aminopyridine compound and preparation method and application thereof

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