AU2004283990A1

AU2004283990A1 - Pyrazine derivatives and pharmaceutical use thereof

Info

Publication number: AU2004283990A1
Application number: AU2004283990A
Authority: AU
Inventors: Atsushi Akahane; Satoshi Aoki; Yuji Matsushima; Satoshi Yonishi
Original assignee: Astellas Pharma Inc
Current assignee: Astellas Pharma Inc
Priority date: 2003-10-27
Filing date: 2004-10-25
Publication date: 2005-05-06

Description

WO 2005/040151 PCT/JP2004/016193 DESCRIPTION PYRAZINE DERIVATIVES AND PHARMACEUTICAL USE THEREOF TECHNICAL FIELD The present invention relates to a novel pyrazine 5 derivative and a salt thereof, which are useful as medicaments. BACKGROUND ART Adenosine is a ubiquitous biochemical messenger. Adenosine binds to and activates seven-transmembrane 10 spanning G-protein coupled receptors, eliciting a variety of physiological responses. Adenosine receptors are divided into four known subtypes (i.e., Al, A2a, A2b, and

A

3 ). These receptor subtypes mediate different, and sometimes opposing, effects. Activation of the adenosine 15 A 1 receptor, for example, elicits an increase in renal vascular resistance, while activation of the adenosine A2a receptor elicits a decrease in renal vascular resistance. Accordingly, adenosine antagonists are useful in the prevention and/or treatment of numerous diseases, 20 including cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, and many diseases for which diuretic treatment is suitable. Some 2-aminopyridine compounds to exhibit adenosine 25 receptor antagonism are known (WO 02/14282, WO 01/25210, 1 WO 2005/040151 PCT/JP2004/016193 etc.), anrid some 2-aminopyrimidine compounds are also known (US 2001/0027196, etc.). However, it is generally difficult to produce a pyrazine which is substituted by four different 5 substituents, and for example the synthesis of a pyrazine compound of the formula A : Ar N M 1 1"R (A) Ar N NR R 10 wherein Ar and Ar' are independently same or different aryl; and R, R' and M are independently hydrogen or suitable substituent; is reported (e.g. (1)J. Org. Chem., 40, 2341 (1975)., (2)J. 15 Heterocyclic Chem., 15, 665 (1978), (3)J. Chem. Soc., Perkin Trans. 1, 885 (1994)., (4)Synthesis, 931 (1994)., (5)WO-02/088084, etc.), however the Ar and Ar' thereof are same, and the selective synthesis of a pyrazine compound A wherein Ar and Ar' are different is not shown as far as 20 we know, and 2-amino-6-aryl-5-(6-oxo-l,6 dihydro-pyrid-3-yl)-pyrazine compounds and derivatives thereof are novel, so there has been no knowledge about these compounds, so far. In addition, any pyrazine derivatives having both of adenosine A, and A 2 a inhibitory 25 activities are not known.

WO 2005/040151 PCT/JP2004/016193 DISCLOSURE OF INVENTION The present invention relates to a novel pyrazine derivative anda pharmaceutically acceptable salt thereof, which are useful as medicaments with no or less toxicity 5 (particularly the convulsive toxicity); processes for preparing the preparation of pyrazine derivative and a salt thereof; a pharmaceutical composition comprising, as an active ingredient, said pyrazine derivative or a pharmaceutically acceptable salt thereof; a use of said 10 pyrazine derivative or a pharmaceutically acceptable salt thereof as a medicament; and a method for using said pyrazine derivative or a pharmaceutically acceptable salt thereof for therapeutic purposes, which comprises administering said pyrazine derivative or a 15 pharmaceutically acceptable salt thereof to a human being or an animal. The pyrazine derivatives and a salt thereof are adenosine antagonists (especially, A, receptor and A 2 (particularly A2a) receptor dual antagonists) and possess 20 various pharmacological actions such as anticatalepsy action, cognitive enhancing action, analgesic action, locomotor action, antidepressant action, diuretic action, cardioprotective action, cardiotonic action, vasodilating action (e.g. cerebral vasodilating action, etc.), the 25 action of increasing the renal blood flow, renal protective 3 WO 2005/040151 PCT/JP2004/016193 action, improvement action of renal function, enhancing action of lipolysis, inhibition action of anaphylactic bronchoconstriction, acceleration action of the insulin release, the action of increasing the production of 5 erythropoietin, inhibiting action ofplatelet aggregation, or the like. They are useful as cognitive enhancer, antianxiety drug, antidementia drug, psychostimulant, analgesic, cardioprotective agent, antidepressant, ameliorants of 10 cerebral circulation, tranquilizer, drug for heart failure, cardiotonic agent, antihypertensive agent, drug for renal failure (renal insufficiency), drug for renal toxicity, renal protective agent, drug for improvement of renal function, diuretic, drug for edema, antiobesity, 15 antiasthmatic, bronchodilator, drug for apnea, drug for gout, drug for hyperuricemia, drug for sudden infant death syndrome (SIDS), ameliorants of immunosuppressive action of adenosine, antidiabetic agent, drug for ulcer, drug for pancreatitis, drug forHeniere's syndrome, drug for anemia; 20 drug for thrombosis, drug for myocardial infarction, drug for obstruction, drug for arteriosclerosis obliterans, drug for thrombophlebitis, drug for cerebral infarction, drug for transient ischemic attack, drug for angina pectoris, or the like; and useful for the prevention and/or 25 treatment of depression, dementia (e.g. Alzheimer's 4 WO 2005/040151 PCT/JP2004/016193 disease, cerebrovascular dementia, dementia accompanying Parkinson's disease, etc.), Parkinson's disease, anxiety, pain, cerebrovascular disease (e.g. stroke, etc.), heart failure; hypertension (e.g. essential hypertension, 5 nephrogenous hypertension, etc.); circulatory insufficiency (acute circulatory insufficiency) causedby, for example, ischemia/reperfusion injury (e.g. myocardial ischemia/reperfusion injury, cerebral ischemia/reperfusion injury, peripheral 10 ischemia/reperfusion injury, etc.), shock (e.g. endotoxin shock, hemorrhagic shock, etc.), surgical procedure, or the like; post-resuscitation asystole; bradyarrhythmia; electro-mechanical dissociation; hemodynamic collapse; SIRS (systemic inflammatory response syndrome); multiple 15 organ failure; renal failure (renal insufficiency) (e.g. acute renal failure, etc.), renal toxicity [e.g. renal toxicity induced by a drug such as cisplatins, gentamicin, FR-900506 (disclosed in EP-0184162), cyclosporin (e.g. cyclosporin A) or the like; glycerol, etc.], nephrosis, 20 nephritis, edema (e.g. cardiac edema, nephrotic edema, hepatic edema, idiopathic edema, drug edema, acute angioneurotic edema, hereditary angioneurotic edema, carcinomatous ascites, gestational edema, etc.); obesity, bronchial asthma, gout, hyperuricemia, sudden infant death 25 syndrome, immunosuppression, diabetes, ulcer such as 5 WO 2005/040151 PCT/JP2004/016193 peptic ulcer (e.g. gastric ulcer, duodenal ulcer, etc.), pancreatitis, Meniere's syndrome, anemia, dialysis-induced hypotension, constipation, ischemic bowel disease, ileus (e.g. mechanical ileus, adynamicileus, 5 etc.); and myocardial infarction, thrombosis (e.g. arterial thrombosis, cerebral thrombosis, etc.), obstruction, arteriosclerosis obliterans, thrombophlebitis, cerebral infarction, transient ischemic attack, angina pectoris, or the like. 10 The novel pyrazine derivative or a salt thereof of the present invention can be shown by the following formula (I): R' N R 15 R N N, R (I)

R

4 wherein

R

6 I R is or R 20 R wherein R6 is hydrogen, or optionally substituted lower alkyl; R is hydrogen or halogen; 25 R 8 is lower alkyl; 6 WO 2005/040151 PCT/JP2004/016193 R- is hydrogen; hydroxy; halogen; cyano; or lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, aryloxy, arylthio, acyl, aryl, heterocyclic group or amino, each of which is optionally substituted by 5 substituent(s); R and R 4 are independentlyhydrogen, lower alkyl or acyl; and

R

5 is lower alkyl, lower alkenyl, lower alkynyl, cyano, aryl or heterocyclic group, each of which is 10 optionally substituted by substituent(s); or a salt thereof. The preferred embodiments of the pyrazine compound of the present invention represented by the general formula 15 (1) are as follows. (1) The pyrazine compound of the general formula (I) wherein

RP

6 R, is 0 "--' N 20 R wherein R6 is hydrogen, lower alkyl, aryl(lower)alkyl, heteroaryl(lower)alkyl;

R

7 is hydrogen or halogen; 25 R 2 is hydrogen, halogen, cyano, optionally substituted 7 WO 2005/040151 PCT/JP2004/016193 lower alkyl,. optionally substituted lower alkynyl, lower alkoxy, afyloxy, arylthio, carbamoyl, carboxy, protected carboxy or optionally substituted amino; 5 R 3 and R 4 are independently hydrogen or lower alkyl; and

R

5 is aryl or heteroaryl each of which is optionally substituted by one or more substituent(s); or a salt thereof. 10 (2) The pyrazine compound of (1) above wherein

R

2 is hydrogen, halogen, cyano, hydroxylated(lower)alkyl, lower alkynyl, lower alkoxy, aryloxy, arylthio, carboxy, esterified 15 carboxy, carbamoyl, amidated carboxy, amino or mono- or di-(lower)alkylamino;

R

3 and R 4 are independently hydrogen;

R

5 is aryl or heteroaryl, each of which is optionally substituted by one or more substituent(s) selected 20 from the group consisting of halogen and lower alkoxy;

R

6 is hydrogen or lower alkyl; and

R

7 is hydrogen; or a salt thereof. 25 (3) The pyrazine compound of (2) above 8 WO 2005/040151 PCT/JP2004/016193 wherein R is hydrogen, brormor, cyano, hydroxymethyl, hydroxyethyl, hydroxypropyl, ethynyl, methoxy, ethoxy, propoxy, phenyloxy, phenylthio, carboxy, 5 carbamoyl, mono- or di-methylaminocarbonyl, pyridylmethylaminocarbonyl, hydroxymethylaminocarbonyl or mono- or di-methylamino;

R

3 and R 4 are independently hydrogen; 10 R 5 is phenyl, pyridyl, furyl, thienyl, pyrrolyl or pyrazolyl, each of which is optionally substituted by one or more substituent(s) selected from the group consisting of fluoro, chloro and methoxy; R6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, 15 n-butyl or t-butyl ; and

R

7 is hydrogen; or a salt thereof. (4) The pyrazine compound of (3) above wherein 20 R 2 is hydrogen, cyano, ethynyl, methoxy, phenyloxy, phenylthio, carboxy, carbamoyl or methylamino; and

R

5 is phenyl, furyl or thienyl, each of which is optionally substituted by one or more 25 substituent(s) selected from the group consisting 9 WO 2005/040151 PCT/JP2004/016193 of fluoro, chloro and methoxy; or a salt thereof. (5) The pyrazine compound of (4) above wherein 5 R 2 is hydrogen, cyano, carboxy, carbamoyl or methylamino;

R

5 is phenyl which is optionally substituted by one or more fluoro; and

R

6 is hydrogen, methyl, ethyl or isopropyl; 10 or a salt thereof. The object compound (I) and a salt thereof of the present invention can be prepared by the following processes. 15 Process 1 R1 N R 2 R N R 2 I Rp + R-Z R Hal N N RS N N R (I ) (III) (I)R 20 or a salt thereof or a salt thereof or a salt thereof Process 2

R

8 10* N H N CN N R' 25 RON R

R

5

N

(Ia) (Iba) or a salt thereof or a salt thereof 10 WO 2005/040151 PCT/JP2004/016193 Process 3 H

R

i o C NN ONN N R +_R_- _ O R 5 R4p4 R R (Ib) (IV) (Ic) or a salt thereof or a salt thereof or a salt thereof Process 4 10 NH, OH 10R R 5 I 5

R

5 W NR N NM' (Id) (Ie) or a salt thereof or a salt thereof 15 Process 5 OH. R 1 1 R 3 R SR 5 1 N N

R

5 N N 20 (le) (If) or a salt thereof or a salt thereof Process 6 OH

R

1 1

R

1 2 25 R' N- R I N 25 0 3 R N 5 N1 N R 5 N N R R (le) (Ig) or a salt thereof or a salt thereof 30 11 WO 2005/040151 PCT/JP2004/016193 Process 7 RP N R N Hal R N ' R 5 N N

R

4 5 (If) (Ih) or a salt thereof or a salt thereof Process 8

R

1 N Hal R'1 N R 13 10 RS TN NR 3 + R 3- Z R N NR 3

R

4 R 4 (Ih) (Ij) or a salt thereof or a salt thereof (V) 15 or a salt thereof [wherein R', R 2 , R , R , R' and R 8 are each as defined above;

R

9 is cyano, carbamoyl or carboxy;

R

10 i is optionally substituted lower alkyl; 20 R' 1 and R 1 2 are independently hydrogen, lower alkyl, lower alkoxy or cyclo(lower)alkyl, each of which is optionally substituted by substituent(s); or R 11 and R 1 2, together with the nitrogen atom to which they are 25 attached, represent a optionally substituted N-containing heterocyclic group;

R

13 is lower alkyl, lower alkenyl, lower alkynyl, 12 WO 2005/040151 PCT/JP2004/016193 lower alkoxy, aryloxy, arylthio, acyl, aryl, heterocyclic grou or amino, each of which is optionally substituted by substituent(s); Y is a leaving group; 5 Hal is a halogen atom; and Z is hydrogen, an alkali metal (e.g. lithium, sodium, potassium, etc.), SnBu 3 , BW 2 or Met-Hal; wherein BW 2 is a part of organoboron compound such as

B(OH)

2 , B(CHCH 3

CH(CH

3 ) 2) 2 , 10 tetramethyl-l,3,2-dioxaborolan- 2 -yl, 9-borabicyclo[3.3.1]nonanyl, or the like; and Met-Hal is a part of metalhalide compound such asMgBr, ZnCl, orthelike. ] 15 The starting compounds or a salt thereof can be prepared, for example, by the following reaction schemes. Process A R10 20 MeO N H I , Step 1 0 N Step 20 N Hal Hal

R

0 -Y Hal (VI) (VII) (VIII) or a salt thereof or a salt thereof or a salt tebreof (IV) 25 or a salt thereof 13 WO 2005/040151 PCT/JP2004/016193 Process B RHal Step 1 Step 2 ' ' H "Hal -tep - - - i q O O (IX) (X) (XI) 5 or a salt thereof or a salt thereof or a salt thereof Process C

R

1 N R 2 R / OH aminomalonitrile N H N NH O2 0 or a salt thereof 100 (XI) (XII) or a salt thereof or a salt thereof Process D O 15 R1 N CN P 1 N "NHX H N NH 2 NH, NoNo 0 (XIII) (XIV) 20 or a salt thereof or a salt thereof Process E

R

1 N R 2 R. N R 2 1N + PO(Hal) 3 Hal N N R 25 R R (XV) (XVI) (II) or a salt thereof or a salt thereof or a salt thereof 1 2 3 4 1 30 [wherein R ,

R

2 , R , R R, R , Y and Hal are each as defined 14 WO 2005/040151 PCT/JP2004/016193 above. In addition'to the processes as mentioned above, the object compound (I) and a salt thereof can be prepared, for 5 example, according to the procedures as illustrated in Examples in the present specification or in a manner similar thereto. The starting compounds can be prepared, for example, according to the procedures as illustrated in Preparations 10 in the present specificationor in a manner similar thereto. The object compound (I) and a salt thereof can be prepared according to the methods as shown in Preparations or Examples, or in a manner similar thereto. It is also to be noted that the solvating form of the 15 compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention. It is also to be noted that radiolabelled derivatives of the compound (I), which are suitable for biological 20 studies, are included within the scope of the present invention. Suitable salts of the object compound (I) are conventional pharmaceutically acceptable ones and include a metal salt such as an alkali metal salt (e.g. sodium salt, .25 potassium salt, etc.) andanalkalineearthmetal salt (e.g. 15 WO 2005/040151 PCT/JP2004/016193 calcium salt, magnesium salt, etc.), an armmonium salt, an organic base salt (e.g. trimethylamine salt, triethylarmine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid 5 salt (e.g. acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydriodide, sulfate, phosphate, etc.), a salt with an amino acid (e.g. arginine, 10 aspartic acid, glutamic acid, etc.), and the like. Suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof and which appear in the above and following description in the present specification are explained in 15 detail as follows. The term "optionally substituted" refers to "unsubstituted or substituted". The term "lower" is intended to mean 1 to 6 carbon atom(s) unless otherwise indicated. 20 Suitable "lower alkyl" and "(lower)alkyl" moiety in the term of " mono- or di-(lower)alkylamino" may include straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl or the like, in which the preferred one may be methyl, ethyl or 25 isopropyl. 16 WO 2005/040151 PCT/JP2004/016193 Suitable "optionally substituted lower alkyl" may include lower alkyl which is optionally substituted by suitable substituent (s) such as lower alkoxy, hydroxy, aryloxy, cyclo(lower)alkyl, amino, aryl, heterocyclic 5 group, acyl or the like. Suitable "lower alkoxy" may include straight or branched ones such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy or the like. Suitable "optionally substituted lower alkoxy" may 10 include lower alkoxy which is optionally substituted by suitable substituent(s) such as hydroxy, cyclo(lower)alkyl, amino, aryl, heterocyclic group, acyl or the like. Suitable "cyclo(lower)alkyl" may be cyclo(C3-C8)alkyl such as cyclopropyl, cyclobutyl, 15 cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or the like, in which the preferred one may be cyclohexyl. Suitable "lower alkenyl" may include straight or branched ones such as vinyl, propenyl, allyl, isopropenyl, butenyl, pentenyl, hexenyl or the like, in which the 20 preferred one may be vinyl. Suitable "optionally substituted lower alkenyl" may include lower alkenyl which is optionally substituted by suitable substituent(s) such as lower alkoxy, hydroxy, cyclo(lower)alkyl, amino, aryl, heterocyclic group, acyl 25 or the like. 17 WO 2005/040151 PCT/JP2004/016193 Suitable "lower alkynyl" may include straight or branched ones such as etiynyl, propynyl, butynyl, pentynyl, hexynyl or the like, in which the preferred one may be ethynyl. 5 Suitable "optionally substituted lower alkynyl" may include lower alkynyl which is optionally substituted by suitable substituent(s) such as lower alkoxy, hydroxy, cyclo(lower)alkyl, amino, aryl, heterocyclic group, acyl or the like. 10 Suitable "aryl" and "aryl" moiety in the term of "aryloxy" or "arylthio" may include phenyl, naphthyl, indenyl, anthryl, or the like, in which the preferred one may be (C6-C10) aryl, and the more preferred one may be phenyl. 15 Suitable "aryl(lower)alkyl" may include phenyl(lower)alkyl (e.g. benzyl, phenethyl, etc.), diphenyli(lower)alkyl (e.g. benzhydryl, etc.), triphenyl(lower)alkyl (e.g. trityl, etc..), naphthyl(lower)alkyl, indenyl(lower)alkyl or 20 anthryl(lower)alkyl and the like, in which the preferred one may be phenyl(lower)alkyl, and the more preferred one may be phenyl(Cl-C4)alkyl. Suitable "optionally substituted aryl" may include aryl which is optionally substituted by suitable 25 substituent(s), preferably 1 to 3 substituent(s), such as 18 WO 2005/040151 PCT/JP2004/016193 lower alkyl, lower alkoxy, hydroxy, halogen, etc. Suitable examples of optionally substituted aryl include lower alkylphenyl, lower alkoxyphenyl and halophenyl. Suitable "heterocyclic group" may be saturated or 5 unsaturated monocyclic or polycyclic heterocyclic groups containing at least one heteroatom selected from among oxygen, sulfur and nitrogen. The particularly preferred example of said heterocyclic group may include 10 3- through 8-membered unsaturated heteromonocyclic groups containing 1 through 4 nitrogen atom(s), such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-l,2,4-triazolyl, IH-l,2,3-triazolyl, 15 2H-l,2,3-triazolyl, etc.), tetrazolyl (e.g. IH-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g. 4,5-dihydro-l,2,4-triazinyl, 2 ,5-dihydro-1l,2,4-triazinyl, etc.), etc.; 3- through 8-membered saturated heteromonocyclic 20 groups containing 1 through 4 nitrogen atom(s), such as azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl (e.g. piperidino, etc.), piperazinyl, etc.; unsaturated condensed heterocyclic groups containing 1 through 5 nitrogen atom(s), such as indolyl, 25 isoindolyl, indolizinyl, benzimidazolyl, quinolyl, 19 WO 2005/040151 PCT/JP2004/016193 isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g. tetrazololl,5-b]pyridazinyl etc.), dihydrotriazolopyridazinyl, etc.; 3- through 8-membered unsaturated heteromonocyclic 5 groups containing 1 or 2 oxygen atoms and 1 through 3 nitrogen atom(s), such as oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.; 3- through 8-membered saturated heteromonocyclic 10 groups containing 1 or 2 oxygen atom(s) and 1 through 3 nitrogen atoms, such as morpholinyl, oxazolidinyl (e.g. 1,3-oxazolidinyl etc.), etc.; unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atom(s) and 1 through 3 nitrogen 15 atom(s), such as benzoxazolyl, benzoxadiazolyl, etc.; 3- through 8-membered unsaturated heteromonocyclic groups containing 1 or 2 sulfur atom(s) and 1 through 3 nitrogen atom(s), such as thiazolyl, isothiazolyl, thiazolinyl, thiadiazolyl (e.g. 1,2,4-thiadiazolyl, 20 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1, 2 ,3-thiadiazolyl), etc.; 3- through 8-membered saturated heteromonocyclic groups containing 1 or 2 sulfur atom(s) and 1 through 3 nitrogen atom(s), such as thiazolidinyl etc.; 25 3- through 8-membered unsaturated heteromonocyclic 20 WO 2005/040151 PCT/JP2004/016193 groups containing 1 sulfur atom, such as thienyl etc.; unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atoms and 1 through 3 nitrogen atom(s), such as benzothiazolyl, benzothiadiazolyl, etc.; 5 3- through 8-membered unsaturated heteromonocyclic groups containing 1 or 2 oxygen atom(s), such as furyl, pyranyl, dioxolyl, etc.; 3- through 8-membered saturated heteromonocyclic groups containing 1 or 2 oxygen atom(s), such as oxolanyl, 10 tetrahydropyranyl (e.g. tetrahydro-2H-pyran-2-yl etc.), dioxolanyl, etc.; and unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atom(s), such as isobenzofuranyl, chromenyl (e.g. 2H-chromen-3-yl etc.), dihydrochromenyl 15 (e.g. 3,4-dihydro-2H-chromen-4-yl etc.), etc. Suitable "optionally substituted heterocyclic group" may include heterocyclic group which is optionally substituted by suitable substituent(s), preferably 1 to 3 substituent(s), such as loweralkyl, loweralkoxy, hydroxy, 20 halogen, or the like. Suitable "N-containing heterocyclic group" may be aforesaid "heterocyclic group", in which said group contains at least one N atom in its ring members, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, triazolyl, 25 tetrazolyl, dihydrotriazinyl, azetidinyl, pyrrolidinyl, 21 WO 2005/040151 PCT/JP2004/016193 imidazolidinyl, piperidyl, piperazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, dihydrotriazolopyridazinyl, morpholinyl, oxazolidinyl, thiazolynyl, thiazolidinyl, etc. 5 Suitable '"heteroaryl" and "hetercaryl" moiety in the term of "heteroaryl(lower)alkyl" may be aforesaid "heterocyclic group", in which those categorized as an aromatic heterocyclic group, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, 10 pyridazinyl, triazolyl, tetrazolyl, dihydrotriazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl, dihydrotriazolopyridazinyl, oxazolyl, isoxazolvi, 15 oxadiazolyl, benzoxazolyl, benzoxadiazolyl, thiazolyl, isothiazolyl, thiazolinyl, thiadiazolyl, thienyl, benzothiazolyl, benzothiadiazolyl, furyl, pyranyl, dioxolyl, isobenzofuranyl, chromenyl, dihydrochromenyl, etc. 20 Suitable "acyl" may include lower alkanoyl, aroyl, carboxy, protected carboxy, and the like. Suitable examples of aforesaid "lower alkanoyl" may be formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, or the like, in which the preferred one 25 may be (Cl-C4)alkanoyl. 22) WO 2005/040151 PCT/JP2004/016193 Suitable examples of aforesaid "aroyl" maybe berizoyl, toluoyl, or the like. Suitable examples of afbresaid "protected carboxy" may be 5 i) esterified car.boxy , in which suitable esterified carboxy may include lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), aryl(lower)alkoxycarbonyl (e.g. 10 benzyloxycarbonyl, phenethyloxycarbonyl, 2 -phenylpropoxycarbonyl, 4 -phenylbutoxycarbonyl, 4 -phenylpentyloxycarbonyl, 1,3-diphenylhexyloxycarbonyl, etc.), and the like; ii) amidated carboxy, in which suitable amidated 15 carboxy may include carbamoyl, N-(lower)alkylcarbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-pentylcarbamoyl, N-hexylcarbamoyl, etc.), N,N-di(lower)alkylcarbamoyl [e.g. N,N-dimethylcarbamoyl, 20 N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-di(t-butyl)carbamoyl, N-pentyl-N-hexylcarbamoyl, etc.], N-lower alkyl-N-aryl(lower)alkylcarbamoyl (e.g. N-methyl-N-benzylcarbamoyl, etc), and the like. 25 Suitable "halogen" may be fluoro, chloro, bromo and 23 WO 2005/040151 PCT/JP2004/016193 iodo. ,Suitable "a leaving'group" may include halogen, hydroxy, acyloxy such as alkanoyloxy (e.g. acetoxy, propionyloxy, etc.) or sulfonyloxy (e.g. mesyloxy, 5 tosyloxy, etc.), or the like. Suitable "optionally substituted amino" may include amino, mono- or di-(lower)alkylamino (e.g. methylamino, dimethylamino, methylethylamino, etc.), acylamino (e.g. lower alkoxycarbonylamino (e.g. methoxycarbonylamino, 10 ethoxycarbonylamino, etc.), sulfonylamino (e.g. mesylamino, etc.), ureido, etc.), or the like. The processes for preparing the object pyrazine compound (I) are explained in detail in the following. 15 Process 1 The compound (I) or a salt thereof can be prepared by subjecting the compound (II) or a salt thereof to coupling reaction with the compound (III) or a salt thereof. 20 This reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, 1,2-dimethoxyethane, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, methanol, ethanol, 25 diethyl ether, 1,3-dimethyl-2-imidazolidinone, 24 WO 2005/040151 PCT/JP2004/016193 N-methylpyrrolidone, N,N'-dimethylpropyleneurea, a mixture thereof or any other organic solvent which does not adversely affect the reaction. Some of the present reaction is preferably carried 5 out in the presence of an organic or inorganic base such as an alkali metal (e.g. sodium, potassium, etc.), an alkaline earth metal (e.g. magnesium, calcium, etc.), the hydride or hydroxide or alkoxide or carbonate or hydrogencarbonate or alkanoic acid thereof, trialkylamine 10 (e.g. triethylamine, trimethylamine, etc.), hydrazine, pyridine compound (e.g. pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), quinoline, and the like. Some of the present reaction is preferably carried out in the presence of a catalyst such as palladium(II) 15 acetate, tetrakis(triphenylphosphine) palladium(0), and the like. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or heating. 20 Process 2 The compound (Iba) or a salt thereof can be prepared by subjecting the compound (la) or a salt thereof to hydrolysis. This reaction is carried out in accordance with a 25 conventional method. 25 WO 2005/040151 PCT/JP2004/016193 The hydrolysis is preferably carried out in the presence of a base or an'acid including Lewis acid. Suitable base includes an inorganic base and an organic base such as an alkali metal (e.g. sodium, potassium, 5 etc.), an alkaline earth metal (e.g. magnesium, calcium, etc.), the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine (e.g. triethylamine, trimethylamine, etc.), hydrazine, pyridine compound (e.g. pyridine, lutidine, picoline, 4-dimethylaminopyridine, 10 etc.), 1,5-diazabicyclo[4.3.0]non-5-ene, quinoline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like. Suitable acid includes an organic acid (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, 15 trifluoroacetic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.). The elimination using Lewis acid such as boron tribromide, borontrichloride, borontrifluoride, aluminum 20 chloride or the like is preferably carried out in the presence of cation trapping agents (e.g. anisole, phenol, etc.). The hydrolysis in this case usually carried out in the presence of an acid including Lewis acid, and these 25 acid(s) including Lewis acid(s) can be used in the mixture, 26 WO 2005/040151 PCT/JP2004/016193 and the point(s) or the number of being hydrolyzed can be different by the condition (see the example part (examples 2, 7, 10 and 15) in detail). The reaction is usually carried out in a solvent such 5 as water, an alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, dichloromethane, 1,2-dichloroethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvent which does not adversely affect the 10 reaction, or a mixture thereof. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating. Process 3 15 The compound (Ic) or a salt thereof can be prepared by subjecting the compound (Ib) or a salt thereof to the alkylation with the compound (IV) or a salt thereof. Suitable salt of the compound (IV) can be referred ones as exemplified for the compound (I). 20 This reaction is carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, dichloromethane, 1,2-dichloroethane, formamide, N,N-dimethylformamide, methanol, ethanol, sec-butanol, amyl alcohol, diethyl ether, dioxane, 25 1,2-dimethoxyethane, tetrahydrofuran, dimethyl sulfoxide, 27 WO 2005/040151 PCT/JP2004/016193 or any other organic solvent which does not adversely affect the reaction, preferably in ones having strong polarities. Among the solvents, hydrophilic solvents may be used in a mixture with water. When the compound (IV) is in a liquid 5 state, it can also be used as a solvent. The reaction is preferably conducted in thepresence of a base, for example, inorganic base such as alkali metal hydroxide, alkali metal alkoxide (e.g. potassium t-butoxide), alkali metal carbonate, alkali metal bicarbonate, alkali metal hydride 10 (e.g. sodium hydride, etc.), or organic base such as trialkylamine (e.g. triethylamine, etc.), or basic resin, and the like. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, 15 under warming or heating. The present reaction is preferably carried out in the presence of alkali metal halide (e.g. sodium iodide, potassium iodide, etc.), or the like. When Y is -OH, activation of OH with 20 triphenylphosphine, or the like, and di (lower) alkyl azodicarboxylate (e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.), or the like, may be necessary. Process 4 25 The compound (Ie) or a salt thereof can be prepared 28 WO 2005/040151 PCT/JP2004/016193 by subjecting the compound (Id) or a salt thereof to hydrolysis using a base or an acid. This reaction can be carried out in the same manner as the aforementioned hydrolysis using a base in Process 5 12, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 2. Process 5 The compound (If) or a salt thereof can be-prepared 10 by decarboxylation of the compound (Ie) or a salt thereof. This reaction is carried out in accordance with a conventional method such as thermal decomposition, acid decomposition and the like; more suitable one in this case is thermal decomposition. 15 The reaction is usually carried out in a conventional inactive solvent such as quinoline, dichlorobenzene, mesitylene, dodecane, Dowtherm® (phenyl ether-biphenyl eutectic mixture) or any other organic solvent which does not adversely affect the reaction, or a mixture thereof; 20 more suitable one in this case is 1,2-dichlorobenzene. The reaction temperature is not critical, and the reaction is usually carried out. on 100 0 C-200 0 C heating condition. Process 6 25 The compound (Ig) or a salt thereof can be prepared 29 WO 2005/040151 PCT/JP2004/016193 by amidation of the compound (le) or a salt thereof. The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, 5 tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction, or a mixture thereof. The reaction is preferably carried out in the presence of a conventional condensing agent such as 10 N,N'-dicyclohexylcarbodiimide; N-cyclohexyl N'-morpholinoethyl-carbodiimide; N-cyclohexyl N'-(4-diethylaminocyclohexyl)-carbodiimide; N,N'-diisopropylcarbodiimide; N-ethyl N'-(3-dimethylaminopropyl)carbodiimide; N,N-carbonyl 15 bis-(2-methylimidazole); pentamethyleneketene N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; l-alkoxy-1-chloroethylene; trialkyl phosphite; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus 20 trichloride; thionyl chloride; oxalyl chloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy) 6-chloro-1H-benzotriazole; so-called Vilsmeier reagent 25 prepared by the reaction of N,N-dimethylformamide with 30 WO 2005/040151 PCT/JP2004/016193 thionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like. The reaction may also be carried out in the presence of an organic or inorganic base such as an alkali metal 5 bicarbonate, tri(lower)alkylamine, pyridine, N-(lower) alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating. 10 Process 7 The compound (Ih) or a salt thereof can be prepared by subjecting the compound (If) or a salt thereof to halogenation with a halogenating agent such as N-halosuccinimide (e.g. N-chlorosuccinimide, 15 N-bromosuccinimide, etc.), or the like. The reaction is usually carried out in a solvent such as tetrahydrofuran, dioxane, toluene, dichloromethane, 1,2-dichloroethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvent which 20 does not adversely affect the reaction, or a mixture thereof. Process 8 The compound (Ij) or a salt thereof can be prepared by subjecting the compound (Ih) or a salt thereof to 25 coupling reaction with the compound (V) or a salt thereof. 31 WO 2005/040151 PCT/JP2004/016193 This reaction can be carried out in the same manner as the aforementioned coupling reaction in Process 1, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can 5 be referred to those of Process 1. Process A The compound (VII) or a salt thereof can be prepared by subjecting the compound (VI) or a salt thereof to hydrolysis using an acid (exemplified by Step 1). This 10 reaction can be carried out in the same manner as the aforementioned hydrolysis using an acid in Process 2, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 2. 15 And the object compound (VIII) can be prepared by subjecting the compound (VII) or a salt thereof to the alkylation with the compound (IV) or a salt thereof (exemplified by Step 2). This reaction can be carried out in the same manner as in the aforementioned Process 3, and 20 therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 3. Process B The compound (X) or a salt thereof can be prepared 25 from the acetylation of the compound (IX) (exemplified by 32 WO 2005/040151 PCT/JP2004/016193 Step 1) by the methods disclosed in Preparation 1 mentioned later or the similar manner thereto. And the object compound (XI) can be prepared by subjecting the compound (X) to the oxime-formation reaction 5 (exemplified by Step 2) that disclosed in Preparation 2 mentioned later or the similar manners thereto. Process C The compound (XII) or a salt thereof can be prepared by reacting the compound (XI) or a salt thereof with 10 aminomalonitrile or a salt thereof. The present reaction is preferably carried out in the presence of a catalyst such as p-toluenesulfonic acid, and the like. This reaction is usually carried out in a 15 conventional solvent such as water, acetone, dioxane, acetonitrile, 1,2-dimethoxyethane, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, methanol, ethanol, isopropanol, t-butanol, diethyl ether, isopropyl ether, a 20 mixture thereof or any other organic solvent which does not adversely affect the reaction. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or heating. 25 This reaction can be carried out by the method 33 WO 2005/040151 PCT/JP2004/016193 disclosed in Preparation 3 mentioned later or the similar manner thereto. Process D The compound (XVI) or a salt thereof can be prepared 5 by subjecting the compound (XII) or a salt thereof to hydrolysis using an acid. Process E The compound (II) or a salt thereof can be prepared by reacting the compound (XV) or a salt thereof with the 10 compound (XVI) or a salt thereof. This reaction is usually carried out in a conventional solvent such as acetone, dioxane, acetonitrile, 1,2-dimethoxyethane, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 15 ethyl acetate, N,N-dimethylformamide, diethyl ether, isopropyl ether, a mixture thereof or any other organic solvent which does not adversely affect the reaction. This reaction can be carried out by the method disclosed in Preparation 4 mentioned later or the similar 20 manner thereto. Above processes, all starting materials and product compounds may be salts. The compounds of above processes can be converted to salts according to a conventional 25 method. 34 WO 2005/040151 PCT/JP2004/016193 The object compound (I) of the present invention is an adenosine antagonist and possesses the various pharmacological actions as stated before. 5 In order to show the usefulness of the compound (I) of the present invention, the pharmacological test result of the representative compound of the present invention is shown in the following. 10 Test 1 : Adenosine antagonistic activity [I] Test method The adenosine antagonistic activity [Ki(nM)] of the test compound was examined by radioligand binding techniques using 8-cyclopentyl-l,3-dipropylxanthine, 15 [dipropyl-2,3- 3 H(N)] ([ 3 H]DPCPX, 4.5nM) for human A, receptor and [ 3 HJCGS 21680 (20nM) for human A 2 a receptor. [II] Test compound 3-Amino-6-(1-ethyl-6-oxo-l,6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarboxamide (Example 4) 20 3 -Amino-6-(l-methyl-6-oxo-l,6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarbonitrile (Example 11) 3-Amino-5-(3,4-difluorophenyl)-6-(1-isopropyl 6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarbonitrile (Example 39) 25 3-Amino-N-(cyanomethyl)-6-(l-isopropyl-6-oxo 35 WO 2005/040151 PCT/JP2004/016193 1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (Example 46) 5-[5-amino-6-(hydroxymethyl)-3-phenyl 2-pyrazinyl]-1-ispropyl- 2 ( iH)-pyridone (Example 47) 5 3-Amino-N-(2-hydroxyethyl)-6- (1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (Example 49) 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-3-bromo l-isopropyl-2(1H)-pyridone (Example 53) 10 5-[5-Amino-3-(2-thienyl)-2-pyrazinyl]-l-isopropyl 2(1H)-pyridone (Example 115) 5-[5-Amino-3-(3,5-difluorophenyl)-2-pyrazinyl] -1 isopropyl-2(lH)-pyridone (Example 129) 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl) -1 15 isopropyl-2(lH)-pyridone (Example 141) 5-[5-Amino-6-(2-furyl)-3-phenyl-2-pyrazinyl] -1 isopropyl-2(lH)-pyridone (Example 144) 5-(5-amino-6-phenoxy-3-phenyl-2-pyrazinyl) -1 isopropyl-2(lH)-pyridone (Example 151) 20 25 36 WO 2005/040151 PCT/JP2004/016193 [III] Test result Table 1 Adenosine receptor binding Test compound (Ki:nM) (Example No.)

A

1 A2a 4 5.09 2.34 5 11 22.47 2.35 39 23.99 6.52 46 5.25 1.49 47 22.27 7.52 49 6.07 1.69 10 53 0.93 0.91 115 4.89 0.84 129 10.71 3.90 141 0.61 0.23 144 1.78 0.54 15 151 1.57 0.32 Test 2 : Anticatalepsy activity in Mouse [I Test method The test compound (3.2mg/kg) was administered orally 20 with ddY mice(n=7). Then, haloperidol (0.32mg/kg) was injected intraperitoneally 30 min. after the 37 WO 2005/040151 PCT/JP2004/016193 administration of the compound. Thirty min. after the injection, the cataleptic'responses of mice were measured. The forelimbs of each mouse were placed on a 3 cm high, 3 mm wide horizontal bar, and the duration of cataleptic 5 posture was measured for up to 30 sec. [II] Test compound 3-Amino-6-(l-ethyl-6-oxo-l,6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarboxamide (Example 4) 3-Amino-6-(l-methyl-6-oxo-1,6-dcihydro-3-pyridyl) 10 5-phenyl-2-pyrazinecarbonitrile (Example 11) 3-Amino-5-(3,4-difluorophenyl)-6-(1-isopropyl 6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarbonitrile (Example 39) 3-Amino-N-(cyanomethyl)-6-(1-isopropyl-6-oxo 15 1,6-dihydro- 3 -pyridyl)-5-phenyl-2-pyrazinecarboxamide (Example 46) 5-[5-amino-6-(hydroxymethyl)-3-phenyl 2 -pyrazinyl]-l-isopropyl-2(1H)-pyridone (Example 47) 3 -Amino-N-(2-hydroxyethyl)-6-(l-isopropyl-6-oxo 20 1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (Example 49) 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-3-bromo l-isopropyl-2(1H)-pyridone (Example 53) 5-[5-Amino-3-(2-thienyl)-2-pyrazinyl]-1-isopropyl 25 2(1H)-pyridone (Example 115) 38 WO 2005/040151 PCT/JP2004/016193 5- [5-Amino--3- (3, 5-dcifluorophenji) -2-pyrazinyl] -1 isopropyl-2 (1H) -pyridone -(Example 129) 5- (5-amino-6--bromo-3-phenyl1-2-pyrazin 1) -1 isopropyl-'2 (11)-pyridone (Example 141) 5 5- [5-Amin-o-'6- (2-furyl) -3-ph-enyl-2-pyraziny71-1 isopropyl-2 (PH) -pyridone (Example 144) 5- (5-amino--6-phenoxy-3-penyl-2-pyrazinyl) -1 isopropyl-2 (1H)-pyricione (Example 151) 10 15 20 25 39 WO 2005/040151 PCT/JP2004/016193 [III] Test result Table 2 Manifestation rate of Test compound Catalepsy (Example No.) (number of mouse) 4 0/7 11 0/7 5 39 0/7 46 0/7 47 1/7 49 1/7 53 0/7 10 115 0/7 129 0/7 141 0/7 144 0/7 151 0/7 15 The pyrazine compound (I) and a salt thereof of this invention are useful as adenosine antagonists (especially, A, receptor and A 2 (particularly A29a) receptor dual antagonists) and for the prevention and/or the treatment 20 of depression, dementia (e.g. Alzheimer's disease, cerebrovascular dementia, dementia accompanying 40 WO 2005/040151 PCT/JP2004/016193 Parkinson's disease, etc.), Parkinson's disease, anxiety, pain, cerebrovasculardisdase, heart failure, hypertension, circulatory insufficiency, post-resuscitation, asystole, bradyarrhythmia, electro-mechanical dissociation, 5 hemodynamiccollapse, SIRS (systemic inflammatory response syndrome), multiple organ failure, renal failure (renal insufficiency), renal toxicity, nephrosis, nephritis, edema, obesity, bronchial asthma, gout, hyperuricemia, sudden infant death syndrome, immunosuppression, diabetes, 10 ulcer, pancreatitis, Meniere's syndrome, anemia, dialysis-induced hypotension, constipation, ischemic bowel disease, ileus, myocardial infarction, thrombosis, obstruction, arteriosclerosis obliterans, thrombophlebitis, cerebral infarction, transient ischemic 15 attack, angina pectoris, and the like. Adenosine antagonists can be useful for Parkinson's disease by co-administrating with L-3,4-dihidroxy-phenylalanine(L-DOPA), which is the most popular drug for Parkinson's disease(R. Grondin et al., 20 Neurology, 52, 1673 (1999)). So the combination use of the pyrazine compound (I) and a salt thereof of this invention with L-DOPA may be also useful for treatment and/or prevention of Parkinson's disease with decreasing or reducing the side effect such as the onset of dyskinesia 25 eliciting by the long-team application of'L-DOPA, and so 41 WO 2005/040151 PCT/JP2004/016193 on. Further, in view of-the field using these compounds for as a medicament, these compounds should be durable to some degree. And the duration time of the pyrazine compound 5 (I) or a salt thereof of this invention are expected to be long-lasting. The pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in a solid, semisolid or liquid form, which 10 contains the pyrazine compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal orbuccal inhalation), nasal, ocular, external (topical), oral or parenteral 15 (including subcutaneous, intravenous and intramuscular) administrations or insufflation. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, 20 aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use. In addition, auxiliary, stabilizing agents, thickening agents, coloring agents and perfumes-may be used where necessary. The pyrazine compound (I) or a pharmaceutically acceptable 25 salt thereof is included in a pharmaceutical composition 42 WO 2005/040151 PCT/JP2004/016193 in an amount sufficient to produce the desired aforesaid pharmaceutical effect up6n the process or condition of diseases. For applying the composition to a human being or an 5 animal, it is preferable to apply it by intravenous, intramuscular, pulmonary or oral administration, or insufflation. While'the dosage of therapeutically effective amount of the pyrazine compound (1) varies depending on the age and condition of each individual 10 patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 100mg of the pyrazine compound (I) per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.1 - 100 mg of the pyrazine compound (I) per kg weight 15 of a human being or an animal, and in case of oral administration, a daily dose of 0.5 - 100mg of thepyrazine compound (I) per kg weight of a human being or an animal is generally given for the prevention and/or treatment of the aforesaid diseases. 20 25 43 WO 2005/040151 PCT/JP2004/016193 The following preparations and examples are given for the purpose of illustrating the present invention in more detail. 5 The abbreviations, symbols and terms used in the preparations and examples have the following meanings. AcOH acetic acid CHC1 3 chloroform

CH

2 C1 2 dichloromethane 10 DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMS.0 dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol 15 IPA isopropyl alcohol IPE isopropyl ether MeOH methanol MeCN acetonitrile NMP N-methylpyrrolidone 20 THF tetrahydrofuran HCl hydrochloric acid NEt 3 triethylamine t-BuOK potassium tert-butoxide

K

2

CO

3 potassium carbonate 25 MgSO 4 magnesium sulfate 44 WO 2005/040151 PCT/JP2004/016193 NaOAc sodium acetate I,,Ia 2 CO3 sodium carbonate 1NaiH sodium hydride NaHCO 3 sodium bicarbonate 5 NaOH sodium hydroxide EtI ethyl iodide Mel methyl iodide n-PrBr n-propyl bromide i-PrI isopropyl iodide 10 CuI cuprous iodide (copper(I) iodide) PdC12(PPh3) 2 dichlorobis(triphenylphosphine) *palladium(II) Pd(OAc) 2 palladium(II) acetate Pd(PPh 3 ) 4 tetrakis(triphenylphosphine) 15 palladium(II) aq. aqueous conc. concentrated sat. saturated 20 Preparation 1 2-Methoxybromopyridine (25 g) 'and n-butyl vinyl ether (66.6 g) were dissolved in DMF (250 ml). To the solution were added 1,3-bis(diphenylphosphino)propane (3.62 g)and Pd(OAc) 2 (896 mg) and aq. K 2

CO

3 under nitrogen 25 atmosphere. The reaction mixture was stirred for 2 hours 45 WO 2005/040151 PCT/JP2004/016193 at 100-120CC. The mixture was cooled to 25 0 C. To the solution was added IN aq. HCI (625 rml) The solution was stirred for 1 hour at 25-30°C. The solution was portioned to EtOAc and water. The organic layer was separated. The aqueous layer 5 was extracted with EtOAc. The combined organic solution was washed with water and brine, and dried over MgSO 4 . Evaporation of solvent in vacuo gave oily residue. The residue was purified by chromatography on silica gel (EtOAc : n-Hexane=1 : 5, v/v) to give 10 2-methoxy-5-acetylpyridine as a solid (12.14 g). 2H-NMR(DMSO-d 5) : 2.56 (3H, s), 3.95 (3H, s), 6.92 (1H, d, J=8.4 Hz), 8.17 (1H, dd, J=2.4, 8.4 Hz), 8.30 (IH, d, J=2.4 Hz)

MS(ESIT

+

) : 152[M+H]) 15 Preparation 2 2-Methoxy-5-acetylpyridine (12.1 g) and t-butyl nitrite (9.92 g) were dissolved in THF (120 ml). The solution was cooled at 0-5 0 C. To the solution was added t-BuOK (10.8 g) at 5-25 0 C. The reaction mixture was stirred 20 at 25 0 C for 2 hours. To the mixture was added 1N HCI (105 ml). The solution was portioned to EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with 10% aq. NaOAcandbrine successively, dried over 25 MgSO4. Evaporation of solvent in vacuo gave solid residue. 46 WO 2005/040151 PCT/JP2004/016193 The residue was pulverized with IPE (150 ml). The precipitated crystals were collectedby filtration, to give (iE)-(6-methoxy-3-pyridyl) (oxo)acetaldehyde oxime as a solid (5.45 g) (anti, syn mixture (anti : syn=l:1)) 5 Evaporation of solvent in the filtrate gave a residue. The residue was pulverized with IPE. The precipitated crystals were collected by filtration, to give (lE)-(6-methoxy 3-pyridyl) (oxo) acetaldehyde oxime as a solid (2.5 g) (anti, syn mixture (anti : syn=1:1)). 10 anti form 1 H-NMR(DMSO-d6 5) : 3.95 (3H, s), 6.95 (IH, d, J=8.4 Hz), 8.00 (IH, s), 8.23 (1H, dd, J=2.4, 8.4 Hz), 8.85 (IH, d, J=2.4 Hz), 12.7 (IH, s)

MS(ESI

+

) : 181[M+H]

+

, 203[M+Na] + 15 syn form 'H-NMR(DMSO-d 6 5) : 3.96 (3H, s), 7.00 (IH, d, J=8.4 Hz), 7.59 (1H, s), 8.09 (1H, dd, J=2.4, 8.4 Hz), 8.64 (IH, d, J=2.4 Hz), 11.8 (IH, s), MS(ESI 4 ) : 181[M+H]

+

, 203(H[M+Naj* 20 Preparation 3 (lE)-(6-Methoxy-3-pyridyl)(oxo)acetaldehyde oxime (5.4 g) and aminomalonitrile p-toluenesulfonate (7.6 g) were suspended in 2-propanol (108 ml) and stirred at 25 0 C. To the mixture was added p-toluenesulfonic acid (5.71 g) 25 The mixture was heated at 50'C for 2 hours, then at ambient 47 WO 2005/040151 PCT/JP2004/016193 temperature for 1 hour. The above reaction mixture was concentrated in vacuo. To the concentrated solution was added sat. aq. NaOAc. Crystals were precipitated. The suspension was stirred at 20 0 C for 15 hours. The crystals 5 were collected by filtration, and dried in vacuo to give 3-amino-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile 4-oxide as powder (6.65 g). 1 H-NMR(DMSO-ds 6) : 3.90 (3H, s), 6.92 (11H, d, J=8.6 Hz), 8.06 (2H, brs), 8.23 (1H, dd, J=2.4, 8.6 Hz), 8.74 (1H, d, 10 J=2.4 Hz), 9.21 (IH, s) MS(ESI-) : 244[M+H] , IR(KBr) : 3386, 3186, 2238, 1639, 1610, 1489, 1189 cm Preparation 4 3-Amino-6- (6-methoxy-3-pyridyl) 15 2-pyrazinecarbonitrile 4-oxide (6.65 g) was dissolved in DMF (133 ml). To the solution was added phosphorus oxychloride (12.6 g) at 25 0 C. The mixture was stirred at ambient temperature for 2 hours. To the mixture was added water (520 ml). The solution was stirred at 20-25 0 C for 15 20 hours. The precipitated crystals were collected by filtration and dried in vacuo, to give 3-amino-5-chloro 6- (6-methoxy-3-pyridyl) - 2 -pyrazinecarbonitrile as powder (4.6 g). The filtrate was extracted with EtOAc. The organic solution was washed with brine, dried over MgSO 4 . 25 Evaporation of solvent in vacuo gave oily residue. The 48 WO 2005/040151 PCT/JP2004/016193 residue was purified by chromatography on silica gel (EtOAc : n-Hexane=l : 1, v/v) to give 3-amino-5-chloro 6-(6-methoxy-3-pyridyl) -2-pyrazinecarbonitrile as powder (1.0 g). 5 'H-NMR(DMSO-d 6 5) : 3.93 (3H, s), 6.92 (1H, d, J=8.6 Hz), 7.88 (2H, s), 7.95 (1H, dd, J=2.4, 8.6 Hz), 8.43 (1H, d, J=2.4 Hz) MS(ESI ) : 262[M+H] , 284[M+Nal] IR(KBr) : 3384, 3187, 2227, 1656, 1610, 1475, 1209 cm 10 Preparation 5 2-Methoxy-5-bromo-pyridine (615 g) was dissolved in 6N HCl (3 1). The solution was heated at 99-105 0 C. The mixture was refluxed and stirred for 5 hours. The above reaction mixture was cooled to 5 0 C. The pH of the solution 15 was adjusted to 6.5 with 10% aq. NaOH. The precipitated crystal was collected by filtration and washed with water (500 ml), and dried in vacuo, to give 5-bromo-2(1H) pyridone (570 g) as crystal. 'H-NMR(DMSO-d 6 5) : 6.36 (1H, d, J=9.8 Hz), 7.55 (IH, dd, 20 J=2.8, 9.8 Hz), 7.69 (IH, d, J=2.4 Hz), 11.7 (1H, s)

MS(ESI

+

) : 196 and 198[M+Na) Preparation 6 t-BuOK (32.2 g) was added to the suspension of 5-bromo-2(iH})-pyridone (50 g) in DME (500 ml). The mixture 25 was stirred for 30 minutes. To the mixture was added K 2 CO3 49 WO 2005/040151 PCT/JP2004/016193 (27.8 g) and 2-iodopropane (81.6 g). The reaction mixture was refluxed with stirring-for 3 hours. The above mixture was cooled to 20-25cC. The precipitated salt was removed by filtration and washed with DME (100 ml) . Evaporation of 5 solvent in vacuo gave solidly residue. The residue was dissolved in CHC1 3 (150 ml). The solution was washed with 0.1N HCl and brine, and dried over MgSO 4 . Evaporation of solvent in vacuo gave solidly residue. To the residue was added n-hexane (150 ml) to pulverize the residue. The 10 precipitate was collected by filtration and dried in vacuo to give 5-bromo-l-isopropyl-2(IH)- pyridone (41.2 g). H-NMR(DMSO-dG 5) : 1.29 (6H, d, J=6.8 Hz), 4.99 (IH, m), 6.36 (1H, d, J=9.6 Hz), 7.48 (1H, dd, J=2.4, 9.6 Hz), 7.96 (IH, d, J=2.4 Hz) 15 MS(ESTI

+

) : 216 and 218[M+H] , 238 and 240[M+Na]l Preparation 7 5-Bromo-l-isopropyl-2(lH)-pyridone (50 g) was dissolved in n-butyl vinyl ether (250 ml). To the solution were added 1,3-bis(diphenylphosphino)propane (6.3 g) and 20 powdered K 2

CO

3 (38.2 g) and Pd(OAc) 2 (1.56 g) at 25 0 C. The mixture was heated at 90-950C with stirring for 8 hours. The reaction mixture was cooled to 25-30 0 C. To the cooled mixture was added CHC1 3 (125 ml) . The precipitated salt was removed by filtration and washed with CHC1 3 (125 ml). 25 Evaporation of solvent in the filtrate in vacuo gave oily 50 WO 2005/040151 PCT/JP2004/016193 residue. The residue was dissolved in CHC1 3 (125 ml). To the solution was added INHCI1 (125 ml). The reaction mixture was stirred at 25-30 0 C for 1 hour. The organic layer was separated. The aqueous layer was extracted with CHC1 3 (100 5 ml). The combined organic layer was washed with 10% aq. NaHCO 3 (50 ml) and dried over MgSO 4 (25 g) and silica gel (25 g). MgSO 4 and silica gel were removed by filtration and washed with CHC1 3 .Evaporation of solvent in the filtrate in vacuo gave oily residue, which was crystallized from 10 n-hexane (500 ml) . The crystal was collected by filtration and dried in vacuo at 40 0 C, to give 5-acetyl-l-isopropyl-2(lH)-pyridone (32.35 g). IH-NMR(DMSO-dG 5) : 1.37 (6H, d, J=6.8 Hz), 2.47 (3H, s), 5.02 (IH, m), 6.44 (H13, d, J=9.6 Hz), 7.82 (1H, dd, J=2.6, 15 9.6 Hz), 8.41 (IH, d, J=2.6 Hz)

MS(ESI

+

) 180[MI+H]-, 202[M+Na] + Preparation 8 5-Acetyl-1-isopropyl-2(iH)-pyridone was dissolved in CHeCl 2 (300 ml). The solution was cooled to -30~-25 0 C. 20 To the cooled solution were added 4N hydrogen chloride in dioxane (55.3 ml) and t-butyl nitrite (10.4 g) at -30~-25 0 C. The temperature of the reaction mixture was raised to 20-25 0 C. The mixture was stirred at the same temperature for 3 hours. The precipitated crystal was collected by 25 filtration, and dried in the air at ambient temperature, 51 WO 2005/040151 PCT/JP2004/016193 to give (iE)-(1-isopropyl-6-oxo-1,6 dihydro-3-pyridyl)(oxo)acetaldehyde oxime (14.0 g). H-NMR(DMSO-d6 5) : 1.35 (6H, d, J=6.8 Hz), 5.02 (IH, m), 6.47 (1H, d, J=9.6 Hz), 7.89 (1H, dd, J=2.4, 9.6 Hz), 8.00 5 (1Hr s), 8.69 (1H, d, J=2.4 Hz), 12.65 (1H, brs)

MS(ESI

+

) : 209[M+H]', 231[M+Na] IR(KBr) : 3129, 1660, 1617, 1529, 1018 cm -1 Preparation 9 Themixtureof (iE)-(1-isopropyl-6-oxo-1,6-dihydro 10 3 -pyridyl)(oxo)acetaldehyde oxime (14 g) and aminomalonitrilep-toluenesulfonate (17 g) and IPA (210ml) was heated at 75-80 0 C and stirred for 2 hours at the same temperature. The reaction mixture was cooled to 0-5 0 C and stirred for 2 hours. The precipitate was collected by 15 filtration, and dried in vacuo, to give 3-amino 6-(l-isopropyl-6-oxo-1,'6-dihydro-3-pyridyl) 2 -pyrazinecarbonitrile 4-oxide (9.2 g). H-NMR(DMSO-d 6 5) : 1.36 (6H, d, J=6.8 Hz), 5.09 (1H, m), 6.48 (1H, d, J=9.6Hz), 7.92-7.99 (3H, m), 8.28 (1H, d, J=2.6 20 Hz), 9.25 (1H, s) MS(ESI) : 293(M+Na] + IR(KBr) : 3122, 2200, 1656, 1598, 1531, 1174 cm -1 Preparation 10 3-Amino-6-(l-isopropyl-6-oxo-l, 6-dihydro 25 3 -pyridyl)-2-pyrazinecarboniitrile 4-oxide (9 g) was 52 WO 2005/040151 PCT/JP2004/016193 dissolved in 25% hydrogen bromide solution of AcOH (90 ml) at 20-25 0 C. The reaction mixture was stirred for 2 hours at ambient temperature. To the reaction mixture was added dioxane (180 ml). The suspension was stirred for 2 hours 5 at ambient temperature. The precipitate was collected by filtration and washed with dioxane, and dried in the air at ambient temperature. The above powder was suspended in water (90ml). ThepHof the suspension was adjusted to 8-8.5 with 1NNaOH (70 ml). The suspension was stirred at ambient 10 temperature. The precipitate was collected by filtration and washed with water, and dried in vacuo at 50'C, to give 3-amino- 6-(l-isopropyl-6-oxo-l,6-dihydro-3-pyridyl) 2 -pyrazinecarboxamide 4-oxide (8.80 g). 'H-NMR(DMSO-d, 5) : 1.39 (6H, d, J=6.8 Hz), 5.10 (IH, m), 15 6.46 (1H, d, J=9.4 Hz), 7.88 (2H, s), 7.89 (1H, s), 8.32 (1H, dd, J=2.4, 9.4 Hz),8.41 (1H, d, J=2.4 Hz), 8.51 (1H, s), 9.15 (IH, s) MS(ESI ) : 312[M+Na]* IR(KBr) : 3440, 1660, 1596, 1554, 1186 cm

-

1 20 Preparation 11 3 -Amino-6-(l-isopropyl-6-oxo-l,6-dihydro 3 -pyridyl)-2-pyrazinecarboxamide 4-oxide (8 g) was dissolved in DMF (80 ml). The solution was cooled to -300C. To the cooled solution was added phosphoryl chloride (12.7 25 g) dropwise at -30~-40'C. After addition of phosphoryl 53 WO 2005/040151 PCT/JP2004/016193 chloride, the temperature of the reaction mixture was raised to -10~-5 0 C. The mixture was stirred at -10~-5'C for 1 hour. To the reaction mixture was added water (400 ml) The suspension was stirred at 30-350C for 15 hours. The pH 5 of the suspension was adjusted to 4.5. The suspension was cooled to 0-50C and stirred at the same temperature for 2 hours. The precipitate was collected by filtration and washed with water, and dried in vacuo at 40-50 0 C, to give 3 -amino-5-chloro-6-(1-isopropyl-6-oxo-1, 6-dihydro 10 3-pyridyl)-2-pyrazinecarboxamide (7.1 g). 2 H-NMR(DMSO-d, 5) : 1.34 (6H, d, J=7.0 Hz), 5.09 (IH, m), 6.44 (1H, d, J=9.4 Hz)r 7.74 (IH, s), 7.85 (1H, dd, J=2.4, 9.4 Hz), 7.85 (2H, s), 8.13 (IH, d, J=2.4 Hz), 8.13 (1H, s) 15 MS(ESI ) : 330 and 332[M+Na) + IR(KBr) : 3284, 1673, 1604, 1461, 1187 cm

-

2 Preparation 12 3-Amino-6-(l-isopropyl-6-oxo-1,6-dihydro 3 -pyridyl)-2-pyrazinecarboxamide 4-oxide (29.1 g) was 20 dissolved in DMF (290 ml) . The solution was cooled to -30 0 C. To the cooled solution was added phosphoryl chloride (46.3 g) dropwise at -30~-400C. After addition of phosphoryl chloride, the temperature of the reaction mixture was raised to 40-45 0 C. The mixture was stirred at 40-45 0 C for 25 1 hour. To the reaction mixture was added water (1160 ml) 54 WO 2005/040151 PCT/JP2004/016193 The suspension was stirred at 30-35 0 C for 15 hours. The pH of the suspension was adjusted to 7 with 12% aq. NaOH (400 ml). The suspension was cooled to 0-5 0 C and stirred at the same temperature for 2 hours. The precipitate was collected 5 by filtration and washed with water, and dried in vacuo at 40-50 0 C, to give 3-amino-5-chloro-6-(l-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarbonitrile (17.2 g). iH-NMR(DMSO-d 6 5) : 1.34 (6H, d, J=7.0 Hz), 5.09 (1H, m), 6.44 (1H, d, J=9.4 Hz), 7.74 (IH, s), 7.85 (IH, dd, J=2.4, 10 9.4 Hz), 7.85 (2H, s), 8.13 (IH, d, J=2.4 Hz), 8.13 (IH, s) MS(ESI) 330[M+Na]* IR(KBr) : 3291, 1662, 1600, 1465, 1182 cm -1 Preparation 13 15 To a solution of 1-(diphenylmethyl)-3-azetidinol hydrochloride (5.0 g) in DMF (25 ml), was added sodium hydride under ice-bath cooling. After 10 minute stirring at the same temperature, the mixture was allowed to warm to 25 0 C and then stirred for 15 hours. EtOAc (500 ml) and 20 water (200 ml) were poured into the mixture. The organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel; 200 ml, toluene : EtOAc=15 : 1- 8 : 1) to give 25 l-(diphenylmethyl)-3-methoxyazetidine (3.41 g). 55 WO 2005/040151 PCT/JP2004/016193 iH-NMR(DNMSO-d, 6) : 2.7-2.9 (2H, m), 3.12 (3H, s), 3.3-3.5 (2H, m), 3.99 (1H, m), 4.40 (IH, s), 7.1-7.4 (6H, m), 7.3-7.5 (4H, m) MS(ESI ) : 254[H+H] + 5 Preparation 14 To a solution of 1-(diphenylmethyl)-3-methoxy azetidine (3.4 g) in MeOH (35 ml), was added 20% palladium hydroxide on carbon (0.7 g). And then the mixture was stirred under hydrogen atmosphere for 2.5 hours. 1NHCl (20 10 ml) was added to the mixture and the catalyst was removed by filtration and washed with IN HC1. The solvent was removed under reduced pressure. Water and EtOAc were poured into the residue, and the aqueous layer was separated, washed with EtOAc. The solvent was removed under reduced 15 pressure and the residue was azeotroped with EtOH and dried in vacuo. n-Hexane was poured into the residue and a crystal was isolated by filtration, washed with n-hexane, and dried in vacuo togive 3-methoxyazetidine hydrochloride (1.58 g). 'H-NMR(DMSO-d, 5) : 3.21 (3H, s), 3.6-3.9 (2H, m), 4.0-4.4 20 (3H, m)

MS(ESI

+

) : 88[M+H] + (free form) Preparation 15 Themixtureof 5-bromo-2(IH)-pyridone (200 g) andMel (324 g) and K 2

CO

3 (318 g) in DME (2 1) was heated at 80 0 C 25 with stirring for 2 hours. The above mixture was cooled to 56 WO 2005/040151 PCT/JP2004/016193 room temperature. The precipitated salt was removed by filtration and washed with-DME. Evaporation of solvent in the filtrate in vacuo gave oily residue. The residue was portioned to EtOAc and water. The organic layer was 5 separated. Aqueous layer was extracted with EtOAc twice. The combined organic solution was dried over MgSO 4 . Evaporation of solvent in vacuo gave crystal residue. The residue was pulverized with IPE and n-hexane (1 : 3, 1000 ml) . The precipitate was collected by filtration and dried 10 in vacuo to give 5-bromo-l-methyl- 2(1H)-pyridone as white powder (182.5 g). H-NMR(DMSO-dG 5) : 3.40 (3H, s), 6.36 (lH, d, J=9.6 Hz), 7.51 (1H, dd, J=2.8, 9.6 Hz), 8.03 (IH, d, J=2.8 Hz)

MS(ESI

) : 210 and 212[M+Na] 4 15 Preparation 16 5-Bromo-l-methyl-2(iH)-pyridone (150 g) was dissolved in DMF (1500 ml). To the solution were added 1, 3 -bis(diphenylphosphino)propane (21.7 g), n-butyl vinyl ether (400 g), and 3M aq. potassium carbonate (262.5 ml) 20 and Pd(OAc) 2 (10.2 g). The mixture was heated at 80 0 C and stirred for 3 hours at the same temperature. The reaction mixture was cooled to 25-30 0 C and poured to IN HC1 (1485 ml). The mixture was stirred for 2 hours at 30-40 0 C. The solution was extracted with EtOAc (1500 ml, three times) 25 The aqueous layer was extracted with CH 2 C1 2 (1000 ml, three 57 WO 2005/040151 PCT/JP2004/016193 times). The collected organic solution was dried overMgSO 1 . Evaporation of solvent gave solidly residue, which was pulverized with IPA (150 ml) and IPE (1500 ml). The suspension was stood in the refrigerator overnight. The 5 precipitate was collected by filtration, dried in vacuo, to give 5-acetyl-l-methyl-2(lH)-pyridone as white powder (128 g). 'H-NMR(DMSO-d 6 6) : 2.41 (3H, s), 3.52 (3H, s), 6.42 (1H, d, J=9.6 Hz), 7.84 (1H, dd, J=2.4, 9.6 Hz), 8.66 (1H, d, 10 J=2.4 Hz) MS(ESI ) : 152[M+H] , 174[M+Na] + Preparation 17 (1E)-(1-Methyl-6-oxo-l,6-dihydro-3-pyridyl)(oxo) acetaldehyde oxime 15 The title compound was obtained in a similar manner to that of Preparation 8. 2 H-NMR(DMSO-d 6 5) : 3.57 (3H, s), 6.47 (1H, d, J=9.6 Hz), 7.93 (1H, dd, J=2.4, 9.6 Hz), 8.03 (iH, s), 8.76 (1H, d, J=2.4 Hz), 12.62 (1H, s) 20 MS(ESI

+

) : 203[M+Na] + Preparation 18 3-Amino-6- (1-methyl-6-oxo-1,6-dihydro-3-pyridyl) 2-pyrazinecarbonitrile 4-oxide The title compound was obtained in a similar manner 25 to that of Preparation 9. 58 WO 2005/040151 PCT/JP2004/016193 'H-NMR(DMSO-dE 5) : 3.50 (3H, s), 6.47 (1H, d, J=9.6 Hz), 7.96 (2H, s), 7.96-8.02 (IH, m), 8.43 (1H, d, J=2.4 Hz), 9.04 (IH, s) MS(ESI ) : 244M [+Na] 5 Preparation 19 3-Amino-6- (l-methyl-6-oxo-1,6-dihydro 3-pyridyl)-2-pyrazinecarbonitrile 4-oxide (97 g) was added to 25% hydrogen bromide solution of AcOH (700ml) at 25-30 0 C. The mixture was stirred for 2 hours at ambient temperature. 10 To the mixture was added 12% aq. NaOH (2100 ml) and water (1000 ml). The mixture was stirred overnight at the refrigerator. The resultant precipitated crystals were collected by filtration, and washed with water, and dried in vacuo, to give 3-amino-6-(l-methyl-6-oxo-1,6-dihydro 15 3-pyridyl)-2-pyrazinecarboxamide 4-oxideaspowder (52 g). 2H-NMR(DMSO-d6 5) : 3.52 (3H, s), 6.45 (IH, d, J=9.6 Hz), 7.82 (2H, s), 7.92 (IH, s), 8.26( IH, dd, J=2.6, 9.6 Hz), 8.54 (1H, s), 8.72 (1H, d, J=2.6 Hz), 8.97 (1H, s)

MS(ESI

+

) : 262[M+H]*, 284[M+Na] + 20 Preparation 20 3-Amino-5-chloro-6- (l-methyl-6-oxo-1,6-dihydro 3-pyridyl) -2-pyrazinecarbonitrile The title compound was obtained in a similar manner to that of Preparation 12. 25 H-NMR(DMSO-d 6 5) : 3.25 (3H, s), 6.45 (IH, d, J=9.4 Hz), 59 WO 2005/040151 PCT/JP2004/016193 7.70 (IH, dd, J=2.6, 9.4 Hz), 7.83 (2H, s), 8.06 (1H, d, J=2.6 Hz) MS(ESI') : 262 and 263[M+H]

+

, 284 and 286[M+Na] 4 Preparation 21 5 To a suspension of 3-amino-6-(l-methyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 4-oxide (1.0 g) in DMF was added phosphoric trichloride (1.07 ml) at -40 0 C for 20 minutes. This reaction mixture was warmed to -10 0 C and stirred for 1 hour. To this solution was added 10 water (40 ml) and stirred at 40 0 C for 14 hours. The pH of the resulting suspension was adjusted to 4.5 with 30% The pH of the aqueous mixture was adjusted to 6-7 with 12% aq. .NaOH. The precipitate was collected by filtration and washed with water to give 3-amino-5-chloro-6-(l-methyl 15 6-oxo-l,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (263 mg) as a yellow powder. MS(ESI ) : 280[M+H]+ Example 1 3-Amino-5-chloro-6-(6-methoxy-3-pyridyl) 20 2-pyrazinecarbonitrile (1.35 g) was dissolved in dioxane (135 ml). To the solution were added phenylboronic acid (1.89 g) and Pd(PPh 3 )4 (179 mg) and Na 2

CO

3 (2.19 g) in water (27 ml) at 25 0 C. The reaction mixture was heated at 800C for 2 hours, then at ambient temperature for 3 hours. The 25 above mixture was portioned to EtOAc and water. The organic 60 WO 2005/040151 PCT/JP2004/016193 layer was separated and washed with aq. NazCO 3 and brine, and dried over MgSO 4 . Evaporation of solvent in vacuo gave oily residue, which was purified by chromatography on silica gel (EtOAc : n-Hexane=l : 1, v/v) to give 5 3-amino-6-(6-methoxy-3-pyridyl)-5-phenyl-2 pyrazinecarbonitrile as yellow crystal which was crystallized from EtOAc (1.15 g). 2 H-NIMR(DMSO-d 6 5) : 3.81 (3H, s), 6.73 (1H, d, J=8.6 Hz), 7.35 (5H, s), 7.51 (2H, s), 7..54 (1H, dd, J=2.4, 8.6 Hz), 10 7.99 (1H, d, J=2.4 Hz) MS(ESI), : 304[M+H]j, 326[M+Na]j + IR(KBr) : 3357, 3183r 2238, 1648, 1598, 1544, 1195 cm m.p. : 201-205 0 C (IPE) Example 2 15 3-Amino-6-(6-methoxy-3-pyridyl)-5-phenyl 2-pyrazinecarbonitrile (500 mg) was dissolved in dioxane (10 ml) and conc. HCl (5 ml). The solution was stirred at 80 0 C for 5 hours. The reaction mixture was cooled to 25-30'C and concentrated in vacuo to give a residue. To the residue 20 was added water and 1NNaOH to adjust the pH of the aqueous mixture to 6-7. The precipitated crystals were collected by filtration dried in vacuo to give 3-amino-6-(6-oxo 1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (390 mg). 25 'H-NMR(DMSO-d 6 5) : 6.16 (1H, d, J=9.4 Hz), 7.26-7.70 (10H, 61 WO 2005/040151 PCT/JP2004/016193 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, 1201 cm ~ 5 m.p. : 215-2200C

(H

2 0) Example 3 3-Amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl 2 -pyrazinecarboxamide (61.4 mg) was dissolved in DMF (1 ml) To the solution were added IM Mel solution in DMF (0.22 ml) 10 and 0.1M t-BuOK solution in DMF (2.2 ml). The mixture was stirred at 20-30 0 C for 2 hours. The reaction mixture was portioned EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine and dried over MgSO 4 . 15 Evaporation of solvent gave oily residue. The above residue was purified by chromatography on silica gel (EtOAc only - EtOAc : MeOH=93 : 7, v/v) to give 3-amino 6- (l-methyl-6-oxo-l, 6-dihydro-3-pyridyl)-5-phenyl 2 -pyrazinecarboxamide, which was crystallized from EtOAc 20 (20 mg). H-NMR(DMSO-d 6 5) : 3.45 (3H, s), 6.12 (IH, d, J=9.4 Hz), 6.97 (1H, dd, J=2.4, 9.4 Hz), 7.41-7.62 (BH, m), 8.14 (IH, d, J=2.4 Hz), 8.29 (IH, s) MS(ESI') : 344[M+Na] + 25 IR(KBr) : 3353, 1664, 1599, 1531, 1438 cm 62 WO 2005/040151 PCT/JP2004/016193 m.p. : >250 0 C (EtOAc) Example 4 3-Amino-6- (1-ethyl-6-oxo1, 6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarboxamide 5 The title compound was obtained in a similar manner to that of Example 3. 1 H-NMR(DMSO-d 6 5) : 1.12 (3H, t, J=7.0 Hz), 3.84 (2H, q, J=7.0 Hz),6.18 (1H, d, J=9.4 Hz), 7.21 (IH, dd, J=2.4, 9.4 Hz), 7.40-7.72 (8H, m), 7.89 (1H, d, J=2.4 Hz), 8.27 (1H, 10 s) MS(ESI') : 336[M+H] , 358[M+Na]* IR(KBr) : 3154, 1679, 1597, 1535, 1444 cm

-

1 m.p. : >250 0 C (EtOAc) Example 5 15 3-Amino-6-(6-oxo-l1-propyl-1,6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarboxamide The title compound was obtained in a similar manner to that of Preparation 3. 1 H-NMR(DMSO-d6 5) : 0.77 (3H, t, J=7.4 Hz), 1.52 (2H, m), 20 3.76 (2H, t, J=7.2 Hz), 6.20 (1H, d, J=9.4 Hz), 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 0 C (EtOAc) 25 Example 6 63 WO 2005/040151 PCT/JP2004/016193 3-Amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl 2-pyrazinecarboxamide (92.1 mg) was dissolved in DMF (1 ml). To the solution were added IM i-PrI solution in DMF (0.33 ml) and 0.1M t-BuOK solution in DMF (3.3 ml). The mixture 5 was stirred at 20-30 0 C for 2 hours. The reaction mixture was portioned EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine and dried over MgSO 4 . Evaporation of solvent gave oily residue. The 10 above residue was purified by chromatography on silica gel (EtOAc only - EtOAc : MeOH=96 : 4, v/v) to give 3-amino-6-(l-isopropyl-6-oxo-l,6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarboxamide (18 mg) and 3-amino 6-(6-isopropoxy-3-pyridyl)-5-phenyl-2-pyrazine 15 carboxamide (42 mg). 3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarboxamide 2H-NMR(DMSO-d 6 5) : 0.97 (6H, d, J=6.8 Hz), 4.90 (IH, m), 6.20 (1H, d, J=9.4 Hz), 7.34-7.47 (8H, m), 7.66-7.72 (2H, 20 m), 8.19 (IH, s)

MS(ESI

+

) : 350 [M+H] , 372 [M+Na] IR(KBr) : 3417, 1664, 1591, 1533, 1450 cm

-

i m.p. : 2410-245 0 C (EtQAc) 3-Amino-6-(6-isopropoxy-3-pyridyl)-5-phenyl-2-pyrazine 25 carboxamide 64 WO 2005/040151 PCT/JP2004/016193 2 H-NMR(DMSO-ds 5) : 1.26 (6H, d, J=6.8 Hz), 5.20 (1H, m), 6.60 (IH, d, J=8.6 Hz), 7.42 (5H, s), 7.60-7.67 (3H, m), 8.17 (2H, s) MS(ESI 4 ) : 350 [M+H], 372 [M+Na] 5 IR(KBr) : 3471, 1683, 1656, 1600, 1488 cm Example 7 3-Amino-6-(6-methoxy-3-pyridyl)-5-phenyl 2-pyrazinecarbonitrile (800 mg) was dissolved in dioxane and conc. HCl. The solution was stirred at 80 0 C for 15 hours. 10 Dioxane was evaporated out. The reaction mixture was cooled to room temperature and concentrated in vacuo to give residue. To the residue was added IN NaOH to adjust the pH of the aqueous mixture to 6-7. The crystals were collected by filtration, and dried in vacuo to give 3-amino-6-(6-oxo 15 1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylic acid as powder (600 mg). IH-NMR(DMSO-d 6 6) : 6.18 (1H, d, J=9.4 Hz), 7.25-7.65 (9H, m), 11.8 (2H, brs) MS(ESI-) : 307[M-H] 20 Example 8 3-Amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl 2-pyrazinecarboxylic acid (154 mg) was dissolved in DMF(5 ml). To the solution were added EtI (86.1 mg) and t-BuOK (61.9 mg). The mixture was stirred at 20-30 0 C for 2 hours. 25 The reaction mixture was portioned EtOAc and water. The 65 WO 2005/040151 PCT/JP2004/016193 organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine and dried over MgSO 4 . Evaporation of solvent gave oily residue. The above residue was purified 5 by chromatography on silica gel (EtOAc only - EtOAc : MeOH=95 : 5, v/v) to give ethyl 3-amino-6-(6-oxo 1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylate (84 mg) and ethyl 3-amino-6-(l-ethyl-6-oxo-1,6-dihydro 3-pyridyl)-5-phenyl-2-pyrazinecarboxylate (28 mg). 10 Ethyl 3-amino-6-(6-oxo-l, 6-dihydro-3-pyridyl)-5-phenyl 2-pyrazinecarboxylate H-NMR(DMSO-d6 5) : 1.34 (3H, t, J=7.0 Hz), 4.37 (2H, q, J=7.0 Hz), 6.23 (IH, d, J=9.4 Hz), 7.19 (1H, d, J=2.4 Hz), 7.25 (IH, dd, J=2.4, 9.4 Hz), 7.40-7.52 (5H, m) 15 MS(ESI 4 ) : 359[M+Na] IR(KBr) : 3400, 1697, 1614, 1434, 1130 cm m.p. : 230-238 0 C (EtOAc) Ethyl 3-amino-6-(l-ethyl-6-oxo-l,6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarboxylate 20 'H-NMR(DMSO-dG 5) : 1.00 (3H, t, J=7.0 Hz), 1.34 (3H, t, J-7.0 Hz), 3.76 (2H, q, J=7.0 Hz), 4.37 (2H, q, J=7.0 Hz), 6.32 (IH, d, J=9.4 Hz), 7.32 (1H, dd, J=2.6, 9.4 Hz), 7.36-7.5 (8H, m) MS(ESI ) : 365[M+H] , 387[M+Na] 25 IR(KBr) : 3400, 1662, 1600, 1440, 1122 cm 66 WO 2005/040151 PCT/JP2004/016193 m.p. : 175-1790C (EtOAc) Example 9 3-Amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl 2-pyrazinecarboxylic acid (283mg) was dissolved in DMF (10 5 ml). To the solution were added i-PrI (172 mg) and t-BuOK (114 mg). The mixture was stirred at 20-30 0 C for 2 hours. The reaction mixture was portioned EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was 10 washed with brine and dried over MgSO4. Evaporation of solvent gave oily residue. The above residue was purified by chromatography on silica gel (EtOAc only - EtOAc : MeOH=96 : 4, v/v) to give isopropyl 3-amino-6-(6-oxo 1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylate 15 as yellow crystal (64mg). 2H-NMR(DMSO-d, 5) : 1.35 (6H, d, J=6.2 Hz), 5.20 (1H, m), 6.23 (1H, d, J=9.4Hz), 7.19 (1H, d, J=2.2 Hz), 7.22 (1iH, dd, J=2.2, 9.4 Hz), 7.40 (5H, m), 11.6 (1H, s)

MS(ESI

)

: 351[M+H] + , 373[M+Na]4 20 IR(KBr) : 3425, 1666, 1612, 1434, 1101 cm - 1 m.p. : 250-256 0 C (EtOAc) Example 10 3-Amino-6-(6-methoxy-3-pyridyl)-5-phenyl 2-pyrazinecarbonitrile (370 mg) was dissolved in 25 1,2-dichloroethane (37 ml). To the solution was added 1M 67 WO 2005/040151 PCT/JP2004/016193 boron tribromide solution in CH-.C1 2 (12.2 ml). The mixture was stirred at 80 0 C for 24 hours. The mixture was cooled to 20-25 0 C, and portioned to EtOAc and water. The organic layer was separated. The aqueous layer was extracted with 5 EtOAc. The combined organic layer was washed with brine, and dried over MgSO 4 .Evaporation of solvent in vacuo gave reddish solid residue. The residue was pulverized with water, to give 3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarbonitrile as powder (254 mg). 10 'H-NMR(DMSO-d 6 5) : 6.21 (1H, d, J=9.4 Hz), 7.20-7.98 (7H, m), 11.6 (1H, s)

MS(ESI

4 ) : 312[M+Na] IR(KBr) : 3326, 2221, 1656, 1610, 1544, 1201 cm ~ m.p. : 243-248 0 C (H 2 0) 15 Example 11 3-Amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl 2-pyrazinecarbonitrile (58 mg) was dissolved in DMF (1 ml) To the solution were added IMMeI solution in DMF (0.22 ml) and 0.1M t-BuOK solution in DMF (2.2 ml). The mixture was 20 stirred at 20-30 0 C for 2 hours. The reaction mixture was portioned EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine and dried over MgSO 4 . Evaporation of solvent gave oily residue. The above residue 25 was purified by chromatography on silica gel (EtOAc only 68 WO 2005/040151 PCT/JP2004/016193 - EtOAc : HeOH=93 : 7, v/v) to give 3-amino-6-(1-methyl 6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazine carbonitrile, which was crystallized from EtOAc (18 mg). H-NMR(DMSO-d 6 15) : 3.40 (3H, s), 6.17 (1H, d, J=9.4 Hz), 5 6.97 (1H, dd, J=2.6, 9.4 Hz:), 7.40-7.50 (7H, m), 7.81 (IH, d, J=2.6 Hz) MS(ESI ) : 304[1M+H] 4 , 326[M+Na] + IR(KBr) : 3386, 2221, 1670, 1590, 1542, 1205 cm m.p. : >250 0 C (EtOAc) 10 Example 12 3-Amino-6- (1-ethyl-6-oxo-1,6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarbonitrile The title compound was obtained in a similar manner to that of Example 11. 15 'H-NMR(DMSO-d 6 5) : 1.03 (3H, t, J=7.0 Hz), 3.79 (2H, q, J=7.0 Hz), 6.25 (1H, d, J=9.4 Hz), 7.19 (1H, dd, J=2.6, 9.4 Hz), 7.44-7.47 (7H, m), 7.58 (1H, d, J=2.6 Hz)

MS(ESI

+

) : 318[M+H] , 340[M+Na] + IR(KBr) : 3180, 2221, 1657, 1587, 1535, 1203 cm - 1 20 m.p. : 193-1990C (IPE) Example 13 3-Amino-6- (6-oxo-1-propyl-1, 6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarbonitrile (17 mg) The title compound was obtained in a similar manner 25 to that of Example 11. 69 WO 2005/040151 PCT/JP2004/016193 'H-NMR(DMSO-d 6 6) : 0.71 (3H, t, J=7.4 Hz), 1.44 (2H, m), 3.73 (2H, t, J=7.2 Hz), 6.26 (1H, d, J=9.4 Hz), 7.20 (IH, dd, J=2.6, 9.4 Hz), 7.38-7.47 (7H, m), 7.54 (1H, d, J=2.6 Hz) 5 MS(ESI ) : 332[M+H]

*

', 354[M+Na) IR(KBr) : 3311, 2220, 1658, 1536, 1463, 1201 cm

-

' m.p. : 180-183 0 C (IPE) Example 14 3-Amino-6- (1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 10 5-phenyl-2-pyrazinecarbonitrile The title compound was obtained in a similar manner to that of Example 11. 'H-NMR(DMSO-d 6 5) : 0.94 (6H, d, J=6.8 Hz), 4.85-4.92 (1H, m), 6.35 (1H, d, J=9.4 Hz), 7.28 (1H, d, J=2.4 Hz), 7.38-7.49 15 (SH, m) MS(ESI 4 ) : 332[M+H] , 354[M+Na] + IR(KBr) : 3426, 2225, 1664, 1621, 15521, 1106 cm -I m.p. : 204.5 0 C (95% aq.2-propanol) Example 15 20 3-Amino-6-(6-methoxy-3-pyridyl)-5-phenyl 2-pyrazinecarbonitrile (100 mg) was dissolved in 30% hydrogen bromide solution in AcOH (1 ml). The solution was stirred at 25-30 0 C for 3 hours. To the solution was added water. The pH of the aqueous mixture was adjusted to 6-7 25 with 12% aq. NaOH. The crystals were precipitated. The 70 WO 2005/040151 PCT/JP2004/016193 suspension was stirred at 25-300C for 3 hours, and stood for 10 hours in refrigerator. The crystals was collected by filtration and dried in vacuo, to give 3-amino 6-(6-methoxy-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide 5 (92.5 mg). H-NMR(DMSO-d 6 5) : 3.82 (3H, s), 6.69 (IH, d, J=6.6 Hz), 7.39 (5H, s), 7.64-7.70 (3H, m), 8.17 (2H, s)

MS(ESI

+

) : 322[M+H]

+

, 344[M+Na] 4 IR(KBr) : 3411, 3276, 1689, 1598,1496,1286 cm 10 m.p. : 208-212 0 C (H 2 0) The following 24 compounds were obtained in a similar manner to that of Example 1. Example 16 3-amino-6- (1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 15 5-phenyl-2-pyrazinecarboxamide IH-NMR(DMSO-d 6 6) : 0.97 (6H, d, J=6.8 Hz), 4.90 (IH, m), 6.32 (IH, d, J=9.4 Hz), 7.34-7.46 (6H, m), 7.66-7.72 (4H, m), 8.19 (IH, s)

MS(ESI

+

) : 350[M+H]+, 372[M+Na] + 20 IR(KBr) : 3417, 1664, 1590, 1533, 1450 cm mp : 245 0 C (IPA-H 2 0) Example 17 3-Amino-5-(2-fluorophenyl)-6-(l-isopropyl-6-oxo 1,6-dihydro-3-pyridyl) -2-pyrazinecarboxamide 25 'H-NMR(DMSO-d 6 5) : 0.93 (6H, d, J=6.8 Hz), 4.89 (1H, m), 71 WO 2005/040151 PCT/JP2004/016193 6.35 (1H, dc, J=9.4 Hz), 7.22-7.81 (9H, m), 8.22 (1H, s) MS(ESI') : 368[M+H]

+

, 390[M+Na] IRP(KBr) : 3367, 1664, 1600, 1446, 1205 cm mp : 251.70C (IPA-H 2 0) 5 Example 18 3-Amino-5-(3-fluorophenyl)-6-(1-isopropyl-6-oxo 1,6-dihydro-3-pyridcyl) -2-pyrazinecarboxamide 1 H-NMR(DMSO-d 6 5) : 1.01 (6H, d, J=6.8 Hz), 4.93 (1H, m), 6.35 (1H, d, J=9.4 Hz), 7.21-7.71 (9H, m), 8.22 (1H, s) 10 MS(ESI

+

) : 368[M+H] 4 , 390[M+Na] + IR(KBr) : 3394, 1658, 1590, 1533, 1452 cm mp : 258.8 0 C (IPA-H 2 0) Example 19 3-Amino-5-(4-fluorophenyl)-6-(l-isopropyl-6-oxo 15 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 'H-NMR(DMSO-d 6 5) : 0.97 (6H, d, J=6.8 Hz), 4.90 (IH, m), 6.32 (1H, d, J=9.4 Hz), 7.34-7.46 (6H, m), 7.66-7.72 (3H, m), 8.19 (1H, s) MS(ESI 4 ) : 390[M+Na]+ 20 IR(KBr) : 3293, 1660, 1583, 1450, 1153 cm mp : 235.6 0 C (IPA-H 2 0) Example 20 3-Amino-5- (2-chlorophenyl) -6- (1-isopropyl- 6 -oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 25 'H-NMR(DMSO-d 6 6) : 0.90 (6H, m), 4.87 (1H, m), 6.34 (IH, 72 WO 2005/040151 PCT/JP2004/016193 d, J=9.4 Hz),7.16 (1H, d, J=2.4 Hz), 7.48-7.68 (6H, m), 7.73 (1H, s), 7.82 (1H, dd, J=2.4, 9.4 Hz), 8.24 (IH, s) MS(ESI ): 384[M+HJ , 406[M+Na]+ IR(KBr) : 3367, 1666, 1604, 1454, 1157 cm 5 mp: 254.50C (IPA-H 2 0) Example 21 3-Amino-5-(3-chlorophenyl)-6- (1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide IH-NMR(DMSO-d 6 5) : 1.01 (6H, d, J=6.8 Hz), 4.93 (1H, m), 10 6.35 (1H, d, J=9.4 Hz), 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, 1250 cm

-

1 mp: 232.6 0 C (IPA-H 2 0) 15 Example 22 3-Amino-5-(4-chlorophenyl)-6- (1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide IH-NMR(DMSO-d 6 5) : 1.02 (6H, d, J=6.8 Hz), 4.94 (1H, m), 6.34 (1H, d, J=9.4 Hz), 7.40 (1H, d, J=2.4Hz), 7.49 (6H, 20 s), 7.6 5(1H, dd, J=2.4, 9.4 Hz), 7.70 (1H, s), 8.21 (1H, s) MS(ESI ) : 406[M+Naj + IR(KBr) : 3278, 1664, 1587, 1450, 1093 cm 1 mp: 246.2 0 C (IPA-H 2 0) 25 Example 23 73 WO 2005/040151 PCT/JP2004/016193 3-Amino-6- (1-isopropyl-6-oxo-l, 6-dihydro-3-pyridyl) 5-(2-mrnethoxyphenyl)-2-pyrazinecarboxamide H-NMR(DMSO-d 6 5) : 0.89-1.05 (6H, m), 3.48 (3H, s), 4.88 (1H, m), 6.32 (IH, d, J=9.4 Hz), 6.99-7.13 (2H, m), 7.22 5 (IH, d, J=2.4 Hz), 7.37-7.65 (2H, m), 7.59 (2H, brs), 7.66 (IH, s), 7.75 (IH, dd, J=2.4, 9.4 Hz), 8.16 (1H, s)

MS(ESI

+

) : 380[M+H]3, 402[M+Na]* IR(KBr) : 3259, 1662, 1596, 1452, 1259 cm

-

i mp : 263.1 0 C (IPA-H 2 0) 10 Example 24 3-Amino-6- (1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-(3-methoxyphenyl)-2-pyrazinecarboxamide 1H-NMR(DMSO-d 6 5) : 1.01 (6H, d, J=6.8 Hz), 3.71 (3H, s), 4.90 (1H, m), 6.33 (1H, d, J=9.4 Hz), 6.94-7.02 (3H, m), 15 7.30-7.39 (2H, m), 7.65-7.71 (3H, m), 8.19 (1H, s)

MS(ESI

+

) : 380[M+H] , 402[M+Nai* IR(KBr) : 3442, 1660, 1581, 1444, 1268 cm IR(KBr) : 3442, 1660, 1581, 1444, 1268 cm-1 mp : 192.3'C (IPA-H 2 0) 20 Example 25 3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-(4-methoxyphenyl)-2-pyrazinecarboxamide H-NMR(DHSO-d 6 5) : 1..05 (6H, d, J=6.8 Hz), 3.77 (3H, s), 4.94 (1H, m), 6.32 (IH, d, J=9.4 Hz), 6.97 (2H, d, J=8.8 25 Hz), -7.42 (2H, d, J=8.8 Hz), 7.45-7.64 (5H, m), 8.15 (1H, 74 WO 2005/040151 PCT/JP2004/016193 S) MlrS(ESI 4 ') 380[H+H] 4 , 402flA[-+Na]+ IR(K~r) 3266, 1664, 1600, 1443, 1255 cm rnp :243.9'C (TPA-H 2 0O) 5 Example 26 3-Amino--6- (l-isopropyl-6-oxo-1, 6-dihydro-3-pyriciyl) 5-[2-(trifluoromethoxy)phenyll-2?-pyrazinecar-oxanide 'H-111R(DMSO-d, 5) :0.90 (6H, mn), 4.83 (1H, in), 6.34 (1H, d, J=9.4 Hz),7.20 (1H, d, J=2.4 Hz), 7.34-7.39 (1H, mn), 10 7.54-7.78 (7H, mn), 3.24 (1H-, s)

MS(ESI

4 ) 434[H- -H]+, 456 [MNBN] 4 IR(KBr) 3336, 1662, 1596, 1257, 1162 cnf' mp : 206.5"C (TPA-H 2 O) Example 27 15 3-Amino-6-(1-isopropyl-6-cxo-1,6-dihydro-3-pyridyl) 5-t3- (trifluoromethoxy)phenyl] -2-pyrazinecarboxamicle 'H-NMR(DMSQ-a 6 5) :0.98 (6H, d, J=6.8 Hz), 4.88 (1H, mn), 6.35 (1H-, d, J=9.4 Hz), 7.37-7.81 (9H-, in), 8.22 (1H,s) MS(ESI+) :434[M+H] 4 , 456[M+Na]+ n0 IR(KBr) :3403, 1660, 2592, 1452, 1263 cm mp :265.50C (IPA-H 2 0O) Example 28 3-Amino-6- (1-isopropyl-6-oxo-1, 6-dihydro-3--pyridyl) 5-{4-(trifluoronethoxy)phenyl]-2'-pyrazinecaroxanide 25 1 H-NMR(DMSO-d 6 5) :0.98 (6H, d, J=6.8 Hz), 4.91 (1H, in), 75 WO 2005/040151 PCT/JP2004/016193 6.37 (1H, d, J=9.4 Hz),7.30 (1H, d, J=2.4Hz), 7.42 (2H, d, J=8.2Hz), 7.58 (2H, d, J=8.2Hz), 7.70 (3H, im), 7.78 (1H, dd, J=2.4, 9.4Hz), 8.21 (1H,s)

MS(ESI

) : 434[M+H] , 456[M+Na) 4 5 IR(KBr) : 3403, 1660, 1592, 1452, 1263 cm~ mp : 264.00C (IPA-H20) Example 29 3-Amino-5-(3,4-difluorophenyl)-6- (1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 10 'H-NHR(DMSO-d 6 5) : 1.05 (6H, d, J=6.8 Hz), 4.96 (1H, m), 6.35 (1H, d, J=9.2 Hz), 7.28 (1H, d, J=6.4 Hz), 7.46-7.65 (6H, m), 7.71 (1H, S)r 8.21 (IH, s)

MS(ESI

+

) : 386[M+H]

+

, 408[M+Na) IR(KBr) : 3382, 1662, 1602, 1444, 1191 cm ~ 15 mp : 225.8 0 C (IPA-H 2 0) Example 30 3-Amino-5-(3,5-difluorophenyl)-6-(1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide H-NMR(DMSO-ds 5) : 1.05 (6H, d, J=6.8 Hz), 4.95 (1H, m), 20 6.37 (1H, d, J=9.4 Hz), 7.14-7.37 (3H, m), 7.46 (1H, d, J=2.4Hz), 7.66 (IH, 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, 1120 cm 25 mp : 248.8 0 C (IPA-HzO) 76 WO 2005/040151 PCT/JP2004/016193 Example 31 3-Amino-5-(4-cyanophenyl) -6-(1-isopropyl-6-oxo-1, 6 dihydro-3-pyridyl)-2-pyrazinecarboxamide H-NMR(DMSO-d 6 5) : 0.98 (6H, d, J=6.8 Hz), 4.92 (1H, m), 5 6.35 (1H, d, J=9.4 Hz), 7.38 (1H, d, J=2.4 Hz), 7.65 (2H, d, J=8.4 Hz), 7.65-7.69 (4H, m), 7.74 (1H, s), 7.90 (1H, d, J=8.4 Hz), 8.24 (1H, s) MS(ESI ) : 397[M+Na] 4 IR(KBr) : 3432, 2223, 1671, 1606, 1450 cm 10 mp : 2920C (IPA-H20) Example 32 3-Amino-6- (1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarbonitrile 'H-NMR(DMSO-d 6 5) : 0.94 (6H, d, J=6.8 Hz), 4.89 (1iH, m), 15 6.35 (1H, d, J=9.4 Hz), 7.28 (1H, d, J 2.4 Hz), 7.39-7.49 (8H, nm) MS(ESI ) : 332[M+H] 4 , 354[M+Na]) IR(KBr) : 3357, 2219, 1652, 1579, 1465, 1203 cm mp : 205.4 0 C (IPA-H 2 0) 20 Example 33 3-Amino-5-(2-fluorophenyl)-6- (1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarbonitrile H-NMR(DMSO-d 6) : 0.,91 (6H, d, J=6.8 Hz), 4.87 (1H, m), 6.37 (1H, d, J=9.4 Hz), 7.18-7.63 (8H, m) 25 MS(ESI

+

) : 350[M+H] 4 , 372[M+Na] + 77 WO 2005/040151 PCT/JP2004/016193 IR(KBr) : 3366, 2214, 1615, 1516, 1200 cm

-

' mp : 210.6 0 C (IPA-H 2 0) Example 34 3-Amino-5-(3-fluorophenyl)-6-(1-isopropyl-6-oxo 5 1,6-dihydro-3-pyridyl)-2-pyrazinecarbonitrile aH-NMR(DMSO-d6 5) : 0.98 (6H, dc, J=6.8 Hz), 4.92 (1H, m), 6.37 (IH, d, J=9.4 Hz), 7.22-7.53 (SH, m) MS(ESI') : 350[M+H]*, 372[M+Na]l IR(KBr) : 3360, 2214, 1660, 1570, 1205 cm 10 mp : 210.6 0 C (IPA-H 2 0) Example 35 3-Amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl) -2-pyrazinecarbonitrile H-NMR(DMSO-d6 5) : 0.98 (6H, d, J=6.8 Hz), 4.92 (1H, m), 15 6.37 (1H, d, J=9.4 Hz), 7.22-7.68 (8H, m)

MS(ESI

+

) : 350[M+H] + IR(KBr) : 3364, 2214, 1660, 1572, 1200 cm - 2 mp : 207.0 0 C (IPA-H 2 0) Example 36 20 3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-(2-methoxyphenyl) -2-pyrazinecarbonitrile 'H-NMR(DMSO-d 6 5) : 0.97 (6H, brs), 3.46 (3H, s), 4.86 (IH, m), 6.34 (1H, d, J=9.4 Hz), 6.99 (1H, d, 8.2 Hz), 7.10 (IH, t, 7.6 Hz), 7.18 (1H, d, 2.5 Hz), 7.37-7.50 (5H, m) 25 MS(ESI

+

) : 362[M+H] , 384[M+Na) 78 WO 2005/040151 PCT/JP2004/016193 IR(KBr) : 3266, 2214, 1600, 1448, 1255 cm mp : 222.6 0 C (IPA-H 2 0) Example 37 3-Amino-6- (1-isopropyl-6-oxo-l, 6-dihydro-3-pyridyl) 5 5-(3-methoxyphenyl)-2-pyrazinecarbonitrile 2H-NMR(DMSO-dG 5) : 0.98 (6H, d, J=6.8 Hz), 3.69 (3H, s), 4.'91 (1H, m), 6.35 (1H, d, J=9.4 Hz), 6.95-6.97 (IH, m), 7.00 (2H, s), 7.30-7.47 (5H, m)

MS(ESI

+

) : 362[M+H] 4 , 384[M+Na] 10 IR(KBr) : 3360, 2215, 1655, 1570, 1205 cm -1 mp : 192.3 0 C (IPA-H 2 0) Example 38 3-Amino-6- (1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-(4-methoxyphenyl)-2-pyrazinecarbonitrile 15 'H-NMR(DMSO-d 6 5) : 1.02 (6H, d, J=6.8 Hz), 3.76 (3H, s), 4.93 (1H, m), 6.35 (1H, d, J=9.4 Hz), 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, 1200 cm 20 mp : 243.9 0 C (IPA-H 2 0) Example 39 3-Amino-5-(3,4-difluorophenyl)-6- (l-isopropyl-6-oxo 1, 6-dihydro-3-pyridyl)-2-pyrazinecarbonitrile IH-NMR(DMSO-d 6 5) : 1.02 (6H, d, J=6.8 Hz), 4.95 (1H, m), 25 6.38 (1H, d, J=9.0 Hz), 7.26 (IH, m), 7.38-7.58 (6H, m), 79 WO 2005/040151 PCT/JP2004/016193 IMS(ESI) : 368 [M4H] 4 , 390 [M+Na] IR(KBr) : 3166, 2210, 1658, 1461, 1201 cm

-

1 mp : 180 0 C (IPA-H 2 ,0) Example 40 5 3 -Amino-5-(4-fluorophenyl)-6-(l-isopropyl-6-oxo 1, 6 -dihydro-3-pyridyl)-2-pyrazinecarboxamide (30 g) was suspended in dioxane (60 ml) and 2N1 aq. NaOH (600 ml) . The mixture was heated at 900C with stirring for 4 hours. The above reaction mixture was cooled to 25-30 0 C. The pH of the 10 suspension was adjusted to 2.5 with 35% HC1 (105 ml). The precipitate was collected by filtration and washed with water and dried in vacuo at 50 0 C for 15 hours to give 3-amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo-l,6 dihydro-3-pyridyl)-2-pyrazinecarboxylic acid as yellow 15 powder. (29.6 g) 'IH-NMR(DMSO-d, 5) : 1.00 (6H, d, J=6.8 Hz), 4.93 (1H, m), 6.37 (1H, d, J=9.4 Hz), 7.22-7.36 (3H, m), 7.48-7.68 (SH, m), 13.00 (1H, s) IR(KIBr) : 3266, 1725, 1662, 1600, 1455 cm -1 20 mp : 222.2 0 C (IPA-H 2 0) Example 41 3-Amino-5-(4-fluorophenyl)-6-(1l-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxylic acid (25 g) was suspended in 1,2-dichlorobenzene (125 ml). The 25 suspension was heated at 165-170 0 C with stirring for 4 hours. 80 WO 2005/040151 PCT/JP2004/016193 The reaction mixture was cooled to 20-25 0 C. To the cooled mixture was added IPE (250 ml). The suspension was stirred at 25-30 0 C for 3 hours. The precipitate was collected by filtration and dried in vacuo. The above dried precipitate 5 waspurifiedbychromatographyon silica gel (500 g) eluting with CHC1l : MeOH (9 : 1, 2 1). Evaporation of solvent in vacuo gave yellowish crystal residue, which was recrystallized from 70% EtOH (322 ml) to give 5-[S-amino 3-(4-fluorophenyl)- 2 -pyrazinyl]-1-isopropyl-2(lH) 10 pyridone as yellowish crystal (19.4 g). H-NNR(DMSO-d 6 5) : 1.00 (6H, d, J=6.8 Hz), 4.93 (IH, m), 6.33 (IH, d, J=9.2 Hz), 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) 15 IR(KBr) : 3166, 1666, 1604, 1533, 1467, 1222 cm

-

1 mp : 257.7 0 C (IPA-H 2 0) Example 42 A mixture of 3-amino-6-(1-isopropyl-6-oxo-1,6 dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylic acid 20 (70 mg), methylamine hydrochloride (14.8 mg), l-ethyl- 3

-[

3 '-(dimethylamino)propyl]-carbodiimide (34.1 mg), and 1-hydroxy-benzotriazole (29.7 mg) in CH 2 C1 2 (0.7 ml) was stirred at 250C for 4 hours. Water and EtOAc were poured into the mixture. The organic layer was separated, 25 washed with water, sat. aq. NaHCO 3 , and brine, and dried 81 WO 2005/040151 PCT/JP2004/016193 over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane - EtOAc then CHzCl 2 - MeOH) and then crystallized from MeOH-IPE to give 5 3-amino-6- (1-isopropyl 6-oxo-1,6-dihydro-3-pyridyl)-N--methyl-5-phenyl 2-pyrazinecarboxamide (40 mg). 1 WH-NMR(DMSO-d 6 5) : 0.93 (6H, d, J=6.8 Hz), 2.84 (3H, d, J=4.8 Hz), 4.89 (1H, qq, J=6.8, 6.8 Hz), 6.38 (IH, d, J=9.4 10 Hz), 7.26 (1H, d, J=2.5 Hz), 7.42 (5H, m), 7.62 (2H, brs), 7.79 (1H, dd, J=2.5, 9.4 Hz), 8.69 (1H, m) MS(ESI) : 364[M+H] + The following 4 compounds were obtained in a similar manner to that of Example 42. 15 Example 43 3-Amino-6-(l-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) N,N-dimethyl-5-phenyl-2-pyrazinecarboxamide 1 H-NMR(DMSO-d, 5) : 0.93 (6H, d, J=6.7 Hz), 3.04 (3H, s), 3.10 (3H, s), 4.89 (IH, qq, J=6.7, 6.7 Hz), 6.36 (1H, d, 20 J=9.4 Hz), 6.73 (2H, brs), 7.21 (1H, d, J=2.5 Hz), 7.3-7.6 (6H, m) MS(ESI-) : 376[M-H] Example 44 5-[5-Amino-6-(4-morpholinylcarbonyl)-3-phenyl 25 2-pyrazinyl] -1-isopropyl-2 (IH)-pyridone 82 WO 2005/040151 PCT/JP2004/016193 H-NMR(DMSO-dF, 6) : 0.95 (6H, d, J=6.8 Hz), 3.63 (4H, brs), 3.70 (4H, brs), 4.86 (1H, qq, J=6.8, 6.8 Hz), 6.36 (IH, d, J=9.4 Hz), 6.78 (2H, brs), 7.24 (1H, d, J=2.4 Hz), 7.3-7.5 (6H, m) 5 MS(ESIT) : 420[M+H]* Example 45 3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-phenyl-N-(2-pyridylmet-ihyl)-2-pyrazinecarboxamide 'H-NMR(DMSO-d6 6) : 0.94 (6H, d, J=6.8 Hz), 4.64 (2H, d, 10 J=6.0 Hz), 4.87 (1H, qq, J=6.8, 6.8 Hz), 6.39 (1H, d, J=9.4 Hz), 7.1-7.9 (12H, m), 8.52 (1H, distorted d, J=4.1 Hz), 9.37 (1H, t, J=6.0 Hz)

MS(ESI

'

) : 441[M+H] + Example 46 15 3-Amino-N-(cyanomethyl)-6- (1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide. 1 H-NMR(DMSO-d 6 5) : 0.92 (6H, d, J=6.8 Hz), 4.34 (2H, d, J=5.9 Hz), 4.88 (1H, qq, J=6.8, 6.8 Hz), 6.41 (IH, d, J=9.4 Hz), 7.24 (1H, d, J=2.4 Hz), 7.3-7.5 (5H, m), 7.61 (2H, brs), 20 7.83 (IH, dd, J=2.4, 9.4 Hz), 9.27 (1H, brt, J=5.9 Hz) MS(ESI) : 389[M+H]

+

, 411[M+Na] Example 47 To a mixture of 3-amino-6-(1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylic 25 acid (70 mg) and NEt 3 (40.4 mg) in THF (0.7 ml), was added 83 WO 2005/040151 PCT/JP2004/016193 isobutyl chloroformate (32.7 mg) under ice-bath cooling. After 1.5 hours stirring at the same temperature,.the mixture was poured into a mixture of sodium borohydride (30.2 mg) in a mixture of THF (0.7 ml) and water (1.4 ml) 5 under ice-bath cooling. After 2.5 hours stirring at the same temperature, the mixture was diluted with water and EtOAc, and then the organic layer was separated, washed with water and brine, and dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by 10 silica-gel column chromatography (CH 2 C1 2 : MeOH=25 : 1 10 : 1). A desired fraction was triturated with IPE to give 5-[5-amino-6-(hydroxymethyl)-3-phenyl 2-pyrazinyl]-l-isopropyl-2(1H)-pyridone (24 mg). iH-NMR(DMSO-d, 5) : 0.95 (6H, d, J=6.8 Hz), 4.59 (2H, d, 15 J=5.6 Hz), 4.90 (1H, qq, J=6.8, 6.8 Hz), 5.34 (IH, t, J=5.6 Hz), 6.3-6.4 (3H, m), 7.20 (1H, d, J=2.4 Hz), 7.2-7.5 (5H, m), 7.50 (IH, dd, J=2.4, 9.4 Hz) MS(ESI ) : 337[M+H]

+

, 359[M+Na] The following 3 compounds were obtained in a similar manner 20 to that of Example 42. Example 48 5-[5-Amino-6- (1-azetidinylcarbonyl)-3-phenyl 2-pyrazinyl] -l-isopropyl-2 (1H)-pyridone 'H-NMR(DMSO-d, 5) : 0.92 (6H, d, J=6.8 Hz), 2.25 (2H, m), 25 4.09 (2H, t, J=7.6 Hz), 4.70 (2H, t, J=7.6 Hz), 4.91 (IH, 84 WO 2005/040151 PCT/JP2004/016193 qq, J=6.8, 6.8 Hz), 6.36 (1H, d, J=9.4 Hz), 7.29 (1H, d, J=2.4 Hz), 7.3-7.6 (6H, m), 7.62 (2H, brs) MS(ESI ) : 390[M+H] Example 49 5 3-Amino-N-(2-hydroxyethyl)-6-(1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide 'H-NMR(DMSO-dG 8) : 0.93 (6H, d, J=6.8 Hz), 3.4-3.5 (2H, m), 3.5-3.6 (2H, m), 4.7-5.0 (2H, m), 6.39 (IH, d, J=9.4 Hz), 7.26 (1H, 2.4 Hz), 7.3-7.5 (5H, m), 7.63 (2H, brs), 10 7.75 (1H, dd, J=2.4, 9.4 Hz), 8.63 (IH, t, J=5.8 Hz) MS(ESI) : 394[M+H], 416[M+Nal' Example 50 3-Amino-N-cyclopropyl-6-(l-isopropyl-6-oxo-l, 6-dihydro 3-pyridyl)-5-phenyl-2-pyrazinecarb.oxamide 15 'H-NMR(DMSO-d6 ) : 0.6-0.8 (4H, m), 0.93 (6H, d, J=6.8 Hz), 2.84 (1H, m), 4.89 (IH, qq, J=6.8, 6.8 Hz), 6.37 (IH, d, J=9.4 Hz), 7.29 (1H, d, J=2.4 Hz), 7.3-7.5 (SH, m), 7.61 (2H, brs), 7.75 (1H, dd, J=2.4, 9.4 Hz), 8.57 (IH, t, J=4.2 Hz) 20 MS(ESI ) : 390[M+H]*, 412[M+Na] + Example 51 3-Amino-6-(l-isopropyl-6-oxo-l, 6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarboxylic acid The title compound was obtained in a similar manner 25 to that of Example 40. 85 WO 2005/040151 PCT/JP2004/016193 H-NMR(DMSO-de 8) : 0.95 (6H, d, J=6.8 Hz), 4.90 (1E, qq, J=6.8, 6.8 Hz), 6.37 (IH, d, J=9.4 Hz), 7.31 (IH, d, J=2.4 Hz), 7.2-7.6 (7H, m), 7.59 (1H, dd, J=2.4, 9.4 Hz), 13.0 (IH, brs) 5 MS(ESI-) : 349[M-H] Example 52 5-(5-Amino-3-phenyl-2-pyrazinyl) -1-isopropyl 2(1H) -pyridone The title compound was obtained in a similar manner 10 to that of Example 41. H-NMR(DMSO-d 6 5) : 0.95 (6H, d,. J=6.8 Hz), 4.90 (1H, qq, J=6.8, 6.8 Hz), 6.32 (1H, d, J=9.4 Hz), 6.60 (2H, brs), 7.21 (1Hr d, J=2.4 Hz), 7.2-7.5 (6H, m), 7.93 (IH, s) MS(ESI) : 307[M+H] 4 , 329[M+Na]+ 15 Example 53 A mixture of 5-(5-amino-3-phenyl-2-pyrazinyl) 1-isopropyl-2(1H)-pyridone (100 mg) and N-bromosuccinimide (87.1 mg) in DMF was heated at 50 0 C with stirring for 20 minutes. Sat. aq. NaHCO 3 and EtOAc were 20 poured into the mixture. The organic layer was separated, washed with water and brine, and dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane : EtOAc-10 : 1 - 2 : 1). A desired product was recrystallized 25 with IPE and dried in vacuo to give 86 WO 2005/040151 PCT/JP2004/016193 5-(5-amino-6-bromo-3-phenyl-2-pyrazinryl)-3-br omrno l-isopropyl-2(1H)-pyridone (57 mg). H-NMR(DMSO-d 6 5) : 0.94 (6H, d, J=6.8 Hz), 4.89 (IH, qq, J=6.8, 6.8 Hz), 6.97 (2H, brs), 7.24 (1H, d, J=2.4 Hz), 5 7.2-7.6 (5H, m), 7.92 (IH, d, J=2.4 Hz)

MS(ESI

+

) : 463[M+H] Example 54 3-Amino-6-(l-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) N-methoxy-N-methyl-5-phenyl-2-pyrazinecarboxamide 10 The title compound was obtained in a similar manner to that of Example 42. H-NMR(DMSO-ds 5) : 0.94 (6H, d, J=6.8 Hz), 3.36 (3H, s), 3.75 (3H, s), 4.89 (1H, qq, J=6.8, 6.8 Hz), 6.36 (1H, d, J=9.3 Hz), 6.79 (2H, brs), 7.24 (1H, d, J=2.4 Hz), 7.3-7.6 15 (6H, m) MS(ESIT) : 394[M+Hj Example 55 5-(5-Amino-6-chloro-3-phenyl-2-pyrazinyl)-3-chloro l-isopropyl-2 (IH)-pyridone 20 The title compound was obtained in a similar manner to that of Example 53. 'H-NMR(DMSO-d, 6) : 0:95 (6H, d, J=6.8 Hz), 4.90 (1H, qq, J=6.8, 6.8 Hz), 7.05 (2H, brs), 7.22 (1H, d, J=2.4 Hz), 7.2-7.6 (5H, m), 7.74 (1H, d, J=2.4 Hz) 25 NS(ESI

+

) : 375[M+H] , 397[M+Na] + 87 WO 2005/040151 PCT/JP2004/016193 Example 56 5-{5-Amino-6- [ (3-rmethoxy-l-azetidinyl) carbonyl] 3-phenyl-2-pyrazinyl)}-l-isopropyl-2 (1H)-pyridone The title compound was obtained in a similar manner 5 to that of Example 1. 2 H-NMR(DMSO-ds 6) : 1.00 (6H, d, J=6.8 Hz), 3.24 (3H, s), 3.8-4.0 (1H, m), 4.2-4.5 (2H, m), 4.4-4.6 (IH, m), 4.8-5.1 (2H, m), 6.35 (1H, J=9.2 Hz), 7.3-7.5 (7H, m), 7.62 (2H, brs) 10 MS(ESI

+

) : 420[M+H]j Example 57 Under ice-bath cooling, to a suspension of 3 -amino-6-(l-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) N-methoxy-N-methyl-5-phenyl-2-pyrazinecarboxamide (200 15 mg) in THF (4.0 ml) was added 3.0M solution of methylmagnesium chloride in THF (0.85 ml) dropwise. The mixture was stirred at the same temperature for 5 hours. The mixture was poured into sat. aq ammonium chloride (20 ml) and an organic layer was extracted with EtOAc (50 ml), 20 washed with water and brine, and dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by silica-gel column chromatography (CH 2 C1 2 MeOH=50 : 1 - 15 : 1). The desired fraction was recrystallized from MeOH and dried in vacuo to give 25 5-(6-acetyl-5-amino- 3-phenyl-2-pyrazinyl)-l-isopropyl 88 WO 2005/040151 PCT/JP2004/016193 2(1H)-pyridone (111 mg) H-NMR(DMSO-ds 5) : 0.95 (6H, d, J=6.8 Hz), 2.66 (3H, s), 4.91 (1H, qq, J=6.8, 6.8 Hz), 6.41 (1H, d, J=9.4 Hz), 7.30 (1H, d, J=2.4 Hz), 7.3-7.6 (5H, m), 7.61 (1H, dd, J=2.4, 5 9.4 Hz), 7.81 (2H, brs)

MS(ESI

+

) : 249[M+H] 4 , 371[M+Na] + Example 58 3-Amino-N-[2-(dimethylamino)ethyl]-6- (1-isopropyl 6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl 10 2-pyrazinecarboxamide The title compound was obtained in a similar manner to that of Example 42. 1 H-NMR(DMSO-d 6 5) : 0.97 (6H, d, J=6.8 Hz), 2.20 (6H, s), 2.42 (2H, t, J=6.6 Hz), 3.3-3.5 (2H, m), 4.91 (IH, qq, J=6.8, 15 6.8 Hz), 6.37 (1H, d, J=9.4 Hz), 7.31 (1H, d, J=2.4 Hz), 7.3-7.5 (5H, m), 7.66 (2H, dd, J=2.4, 9.4 Hz), 8.62 (1H, t, J=5.7 Hz) MS(ESI ) : 421[M+H] + Example 59 20 3-Amino-6-(l-methyl-6-oxo-l, 6-dihydro-3-pyridyl) 5-phenyl-2-pyrazinecarbonitrile The title compound was obtained in a similar manner to that of Example 1. H-NMR(DMSO-d 6 5) : 3.40 (3H, s), 6.17 (1H, d, J=9.4 Hz), 25 6.97 (1H, dd, J=2.6, 9.4 Hz), 7.40-7.49 (7H, m), 7.81 (IH, 89 WO 2005/040151 PCT/JP2004/016193 d, J=2.6 Hz) MS(ESI) : 304[M+HJ', 326[M+Na] IR(KBr) : 3386, 2221, 1670, 1590, 1542, 1205 cm - 1 Example 60 5 Amixture of 3-amino-5-chloro-6-(l-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (500 mg), (4-methoxyphenyl)boronic acid (740mg), and Pd(PPh 3

)

4 (56.3 mg) in 2M aq. NaZCO 3 (3.25 ml) and dioxane (20 ml) was refluxed for 3 hours. Water (40 ml) and of EtOAc (30 ml) 10 were poured into the reaction mixture and the aqueous solution was extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSOI. After filtration, the solvent was removed under reduced pressure. The residual solid was placed on a column of silica-gel and 15 elutedwithCHCl 3 :MeOH (25 : 1). The eluentwas evaporated and the residue was suspended with IPE and filtrated to give 3-amino-6-(l-isopropyl-6-oxo-l, 6-dihydro-3-pyridyl) 5-( 4 -methoxyphenyl)-2-pyrazinecarboxamide (512 mg) as a yellow powder. 20 'H-NMR(DMSO-d 6 5) : 1.05 (6H, d, J=7.0 Hz), 4.94 .(1H, sept, J=7.0 Hz), 6.32 (1H, d, J=9.5 Hz), 6.98 (2H, d, J=9.0 Hz), 7.39-7.64 (7H, m), 8.15(IH, brs) MS(ESI') : 380[M+H] ,.421[M+H+MeCN] + The following 18 compounds were obtained in a similar manner 25 to that of Example 60. 90 WO 2005/040151 PCT/JP2004/016193 Example 61 3-Amino-6-(l-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-(2-methoxyphenyl)- 2 -pyrazinecarboxamide 1 H-NMR(DMSO-d6 6) : 0.89 (6H, brs), 3.48 (3H, s), 4.88 (1H, 5 sept, J=6.8 Hz), 6.32 (1H, d, J=9.5 Hz), 7.00-7.13 (2H, m), 7.22 (1iH, d, J=2.5 Hz), 7.37-7.79 (6H, m), 8.16 (1H, brs) Example 62 3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-(3-methoxyphenyl)- 2 -pyrazinecarboxamide 10 2 H-NMR(DMSO-d6 5) : 1.00 (6H, d, J=7.0 Hz), 3.71 (3H, s), 4.92 (IH, sept, J=7.0Hz), 6.33 (IH, d, J=9.5 Hz ), 6.94-7.02 (3H, m), 7.30-7.39 (2H, m), 7.65-7.71 (4H, m), 8.20 (IH, brs) Example 63 15 3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-(2-methylphenyl) -2-pyrazinecarboxamide IH-NMR(DMSO-dG 5) : 0.88 (6H, d, J=7.0 Hz), 1.99 (3H, s), 4.85 (1H, sept, J=7.0 Hz), 6.33 (IH, d, J=9.5 Hz), 7.11 (IH, d, J=2.5 Hz), 7.32 (4H, brs), 7.70 (3H, brs), 7.89 (1H, dd, 20 J=2.5, 9.5 Hz), 8.23 (1H, brs)

MS(ESI

+

) : 364 [M+H], 405[M+H+MeCN] + Example 64 3-Amino-5-(2,3-difluorophenyl)-6-(l-isoprpyl-6-oxo 1,6-dihydro-3-pyridyl)- 2 -pyrazinecarboxamide 25 H-NMR(DMSO-d, 5) : 0.97 (6H, d, J=7.0 Hz), 4.92 (IH, sept, 91 WO 2005/040151 PCT/JP2004/016193 J=7.0 Hz), 6.37 (1H, d, J=9.0 Hz), 7.34-7.79 (8H, nm), 8.26 (1H, brs)

MS(ESI

+

) : 386[M+H]

+

, 427[M+H+MeCN] + Example 65 5 3-Amino-5-(2,4-difluorophenyl)-6-(1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide H-NMR(DMSO-dG 6) : 0.99 (6H, d, J=6.8 Hz), 4.93 (1H, sept, J=6.8 Hz), 6.36 (1H, d, J=9.0 Hz), 7.24-7.35 (3H, m), 7.65-7.77 (5H, m), 8.23 (1H, brs) 10 MS(ESI

+

) : 386[M+H]

+

, 427[M+H+MeCN]+ Example 66 3-Amino-5-(2, 5-difluorophenyl)-6- (1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide H-NMR(DMSO-de 6) : 0.99 (6H, d, J=7.0 Hz), 4.92 (IH, sept, 15 J=7.0 Hz), 6.37 (1H, d, J=9.5 Hz), 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] 4 Example 67 3-Amino-5-(2-furyl)-6- (1-isopropyl-6-oxo-1,6-dihydro 20 3-pyridyl) -2-pyrazinecarboxamide H-NMR(DMSO-d 6 5) : 1.25 (6H, d, J=6.8 Hz), 5.07 (1H, sept, J=6.8 Hz), 6.39 (1H, d, J=9.0 Hz), 6.61 (1H, dd, J=1.1, 3.5 Hz), 6.79 (1H, d, J=3..5 Hz), 7.55 (1H, dd, J=2.5, 9.5 Hz), 7.66 (3H, brs), 7.79 (2H, brs), 8.09 (1H, brs) 25 MS(ESI

+

) : 340[M+H]

+

, 381[M+H+MeCN] + 92 WO 2005/040151 PCT/JP2004/016193 Example 68 3-Amino-5-(3-furyl)-6- (1-isopropyl-6-oxo-1,6-dihydro 3-pyridyl)-2-pyrazinecarboxamide IH-NIMR(DMSO-d 6 5) : 1.25 (6H, d, J=6.8 Hz), 5.07 (1H, sept, 5 J=6.8 Hz), 6.39 (1H, d, J=9.0 Hz), 6.62 (1H, dd, J=2.0, 3.5 Hz), 6.79 (1H, d, J=3.5 Hz), 7.55(1H, dd, J=2.5, 9.5 Hz), 7.66 (3H, brs), 7.99 (2H, s), 8.09 (1H, brs)

MS(ESI

) : 340[M+H], 381[M+H+MeCN] Example 69 10 3-Amino-6- (1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-(2-thienyl)-2-pyrazinecarboxamide 'H-NMR(DMSO-d, 5) : 1.23 (6H, d, J=6.8 Hz), 5.07 (1H, sept, J=6.8 Hz), 6.42 (1H, d, J=9.5 Hz), 7.04-7.06 (IH, m), 7.16-7.17 (1H,m), 7.49 (1H,d, J=2.5 Hz), 7.54 (IH, d, J=2.5 15 H.z), 7.65 (2H, brs), 7.69 (1H, d, J=5.5 Hz), 7.87 (1H, d, J=2.5 Hz), 8.06 (1H, brs) MS(ESI) : 356[M+H]*, 397[M+H+MeCN] Example 70 3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 20 5-(3-thienyl)-2-pyrazinecarboxamide 1 H-NMR(DMSO-d 6 5) : 1.12 (6H, d, J=7.0 Hz), 4.98 (1H, sept, J=7.0 Hz), 6.36 (1H, d, J=9.0 Hz), 7.12 (1H, dd, J=1.3, 5.0 Hz), 7.54-7.71 (7H, m), 8.14 (1H, brs) MS(ESI ) : 356[M+H] , 397[M+H+MeCN] + 25 Example 71 93 WO 2005/040151 PCT/JP2004/016193 3-Amino-6- (l-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-(5-mrethyl-2-thienyl)-2-pyrazinecarboxamide H-NMR(DMSO-d 6 5) : 1.26 (6H, d, J=6. 5 Hz), 2. 44 (3H, s), 5.08 (1H, sept, J=6.8 Hz), 6.41 (1H, d, J=9.5 Hz), 6.76 ( 1H, 5 dc, J=2.5 Hz), 6.98 (1H, d, J=3.5 Hz), 7.47 (1H, d, J=2.5 Hz), 7.52 (1H, d, J=2.5 Hz), 7.61 (2H, brs), 7.89 (1H, d, J=2.5 Hz), 8.01 (1H, brs) MS(ESI 4 ) : 370[M+H]

+

, 411[M+H+MeCN] t Example 72 10 3 -Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-(1H-pyrazol-4-yl)-2-pyrazinecarboxamide H-NMR(DMSO-do 5) : 1.23 (6H, d, J=7.0 Hz), 5.06 (1H, sept, J=7.0 Hz), 6.40 (1H, d, J=9.5 Hz), 7.50 (IH, dd, J=2.5, 9.5 Hz), 7.57 (5H, brs), 7.80 (1H, d, J=2.5 Hz), 8.01 (1H, brs), 15 13.06 (1H, brs)

MS(ESI

+

) : 362[M+Na]

+

, 701[2M+Na] Example 73 3-Amino-6- (1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5- [ (E) - 2 -phenylvinyl]l-2-pyrazinecarboxamide 20 'H-NMR(DMSO-d 6 5) : 1.32 (6H, d, J=6.5 Hz), 5.12 (1H, sept, J=6.5 Hz), 6.50 (IH, d, J=9.5 Hz), 7.20-7.43 (5H, m), 7.59-7.83 (6H, m), 7.90 (1H, d, J=2.5 Hz), 8.10 (1H, brs)

MS(ESI

+

) : 398[M+Na], 773[2M+Na] + Example 74 25 3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 94 WO 2005/040151 PCT/JP2004/016193 5-(3-pyridyl)- 2 -pyrazinecarboxamide H-NMR(DMSO-d. 5) : 0.98 (6f, d, J=7.0 Hz), 4.93 (1H, sept, J=7.0 Hz), 6.36 (1H, d, J=9.5 Hz), 7.37-7.46 (3H, m), 7.66-7.75 (4H, m), 8.26 (1H, brs), 8.61-8.64 (2H, m) 5 MS(ESI') : 351[M+H] 4 , 392[M+H+MeCN]* Example 75 3-Amino-6-(l-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-(4-pyridyl)- 2 -pyrazinecarboxamide 1H-NMR(DMSO-d 6 6) : 1.00 (6H, d, J=7.0 Hz), 4.93 (IH, sept, 10 J=7.0 Hz), 6.35 (IH, dc, J=9.5 Hz), 7.42-7.89 (7H, m), 8.23 (1H, brs), 8.57 (1H, dd, J=2.0, 5.0 Hz), 8.64 (1H, d, J=2.0 Hz) MS(ESI ) : 351[M+H]), 392[M+H+MeCNJ Example 76 15 3 -Amino-5-(4-fluorophenyl)-6-(1-methyl-6-oxo-, 6 dihydro-3-pyridyl)- 2 -pyrazinecarboxamide 1H-NMR(DMSO-d, 6) : 3.46 (3H, s), 6.17 (1H, d, J=9.5 Hz), 7.00 (1H, dd, J=2.5, 9.5 Hz), 7.25 (2H, t, J=9 Hz), 7.51-7.73 (5H, m), 8.15 (1H, d, J=2.5 Hz), 8.27 (1H, brs) 20 MS(ESI) : 362[M+Na]

+

, 701[2M+Na]+ Example 77 3-Amino-5-(2-furyl)-6- (1-methyl-6-oxo-1,6-dihydro 3-pyridyl) - 2 -pyrazinecarboxamide 1 H-NMR(DMSO-d 6 5) : 3.50 (3H, s), 6.33 (1H, d, J=9.0 Hz), 25 6.63 (IH, dd, J=1.8, 3.5 Hz), 6.83 (1H, d, J=3.5 Hz), 7.28 . 95 WO 2005/040151 PCT/JP2004/016193 (1H, dId, J=2.5, 9.5 Hz), 7.69-7.79 (4H, mn), 8.10 (1H, d, J=2.5 Hz), 8.16 (1H, brs)

MS(ESI

) : 334[M+Na] Example 78 5 3-Amino-6-(l-methyl-6-oxo-1, 6-dihydro-3-pyridyl) 5- (2-thienyl)-2-pyrazinecarboxamide IH-NMR(DMSO-d 6 5) : 3.50 (3H, s), 6.35 (IH, d, J=9.5 Hz), 7.04-7.09 (1H, m), 7.19-7.21 (IH, m), 7.35 (1H, dd, J=2.5, 9.5 Hz), 7.66 (IH, brs), 7.70-7.72 (3H, m), 8.12-8.13 (2H, 10 m) NS(ES 4) : 350[M+Na] + Example 79 Amixture of 3-amino-5-chloro-6-(1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (200 mg), 15 ethynylbenzen (331 mg), NEt 3 (658 mg), triphenylphosphine (17 mg), Cul (6.2 mg), and PdC1 2 (PPh 3

)

2 (23 mg) in DMF (2 ml) was heated at 80 0 C for 18 hours. Water (20 ml) and EtOAc (20 ml) were poured into the reaction mixture and the aqueous solution was extracted with EtOAc. The organic 20 layer was washed with water and brine, and dried over MgSO 4 . After filtration, the solvent was removed under reduced pressure. The residual solid was placed on a column of silica-gel and eluted with CHC13 -NeOH (97 : 3). The eluent was evaporated and the residue was suspended with IPE and 25 filtrated to give 3-amino-6-(l-isopropyl-6-oxo 96 WO 2005/040151 PCT/JP2004/016193 1,6-dihydro-3-pyridyl)-5-(phenylethynyl) 2-pyrazinecarboxamide (218 mg) as a yellow powder. MS(ESI ) : 396[M+Na] , 769[2M+Na]) + Example 80 5 A toluene solution of 3-amino-5-chloro 6-(l-isopropyl-6-oxo-1, 6-dihydro-3-pyridyl) 2-pyrazinecarboxamide (200 mg), 2-(tributylstannyl)pyridine (311 mg), and Pd(PPh3) 4 (22.5 mg) was refluxed for 5 hours. Water (20 ml) and EtOAc (15 10 ml) were poured into the reaction mixture and the aqueous solution was extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSO 4 . After filtration, the solvent was removed under reduced pressure. The residual solid was placed on a column of silica-gel and 15 eluted with CHC1 3 - MeOH (97 : 3) . The eluent was evaporated and the residue was suspended with IPE and filtrated to give 3-amino-6- (1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-( 2 -pyridyl)-2-pyrazinecarboxamide (64 mg) as a yellow powder. 20 'H-NMR(DMSO-d 6 5) : 1.01 (6H, d, J=6.5 Hz), 4.93 (1H, sept, J=6.5 Hz), 6.30 (1H, d, J=9.5 Hz), 7.35-7.46 (2H, m), 7.59-7.75 (5H, m), 7.96 (IH, dt, J=1.7, 7.8 Hz), 8.24 (IH, brs), 8.55 (IH, d, J=4.5 Hz)

MS(ESI

4 ) : 351[M+H] 25 Example 81 97 WO 2005/040151 PCT/JP2004/016193 To a suspention of 3-amino-6-(l-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-5-(4-methoxyphenyl) 2-pyrazinecarboxamide (210 mg) in dioxane (2 ml) was added an aq. NaOH (2M, 4 ml) and this solution was heated at 100 0 C 5 for 4 hours. This reaction mixture was cooled to room temperature and the pH of this solution was adjusted to 2.5 with 2Naq. HCl. The precipitate was collectedby filtration and washed with water to give 3-amino-6-(l-isopropyl 6-oxo-l, 6-dihydro-3-pyridyl) -5- (4-methoxyphenyl) 10 2-pyrazinecarboxylic acid (203 mg) as a yellow powder. 'H-NMR(DMSO-d 6) : 1.03 (1H, d, J=7 Hz), 3.77. (3H, s), 4.94 (IH, sept, J=7.0 Hz), 6.36 (IH, d, J=9.5 Hz), 6.98 (2H, d, J=9.0 Hz), 7.41-7.56 (6H, m), 12.91 (1H, brs) MS(ESI ) : 381[M+H] , 422[M+H+MeCN] 15 The following 24 compounds were obtained in a similar manner to that of Example 81. Example 82 3-Amino-6- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridyl) 5-(2-methoxyphenyl)-2-pyrazinecarboxylic acid 20 H-NMR(DMSO-d 6 6) : 0.91 (6H, brs), 3.48 (3H, s), 4.87 (IH, sept, J=6.8 Hz), 6.35 (IH, d, J=9.5 Hz), 7.01 (IH, d, J=8 Hz), 7.10 (IH, t, J=7.5 Hz), 7.19 (1H, d, J=2.5 Hz), 7.38-7.49 (4H, m), 7.62 (IH, dd, J=2.5, 9.0 Hz), 12.93 (1H, brs) 25 MS(ESI

+

) : 381[M+H] 4 , 422[M+H+MeCN] 98 WO 2005/040151 PCT/JP2004/016193 Example 83 3-Amino-6-(1-isopropyl-6-bxo-1,6-dihydro-3-pyridyl) 5-(3-methoxyphenyl)-2-pyrazinecarboxylic acid 1 H-NMR(DMSO-d 6 5) : 0.99 (6H, d, J=7 Hz), 3.70 (3H, s), 4.92 5 (IH, sept, J=7.0 Hz), 6.37 (1H, d, J=9.5 Hz), 6.95-7.04 (3H, m), 7.30-7.38 (2H, m), 7.50 (2H, brs), 7.58 (1H, dd, J=2.5, 9.0 Hz), 13 (1H, brs) MS(ESI ) : 381[M+H]f, 422[M+H+MeCN]+ .Example 84 10 3-Amino-6- (1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-(2-methylphenyl)-2-pyrazinecarboxylic acid 'H-NMR(DMSO-dG 5) : 0.88 (6H, d, J=7.0 Hz), 1.99 (3H, s), 4.85 (IH, t, J=7.0 Hz), 6.37 (1H, d, J=9.5 Hz), 7.09 (IH, d, J=2.5 Hz), 7.26 - 7.40 (4H, m), 7.49 (2H, brs), 7.73 (1H, 15 dd, J=2.5, 9.5 Hz), 13.05 (IH, brs) Example 85 3-Amino-5-(2,3-difluorophenyl)-6- (l-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxylic acid 'H-NMR(DMSO-d 6 5) : 0.95 (6H, d, J=3.5 Hz), 4.92 (1H, sept, 20 J=3.5 Hz), 6.40 (1H, d, J=4.7 Hz), 7.30 (1H, d, J=1.1 Hz), 7.34-7.63 (6H, m), 13.20 (1H, brs)

MS(ESI

+

) : 387[M+H]1 , 428[M+H+MeCN] + Example 86 3-Amino-5-(2,4-difluorophenyl)-6- (1-isopropyl-6-oxo 25 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxylic acid 99 WO 2005/040151 PCT/JP2004/016193 H-NMR(DMSO-d 5) : 0.97 (6H, d, J=3.4 Hz), 4.92 (1H, sept, J=3.4 Hz), 6.39 (1H, d, J=4.8 Hz), 7.26-7.33 (3H, m), 7.56 (2H, brs), 7.61 (1H, dd, J=1.3, 4.8 Hz), 7.68-7.74 (1H, m), 13.15 (1H, brs) 5 MS(ESI

+

) : 387[M+-H] , 428[M+H+MeCN] + Example 87 3-Amino-5-(2,5-difluorophenyl)-6- (l-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxylic acid H-NMR(DMSO-d 6 5) : 0.97 (6H, d, J=3.5 Hz), 4.92 (1H, sept, 10 J=3.5 Hz), 6.4 (IH, d, J=4.8 Hz), 7.25-7.38 (3H, m), 7.51-7.55 (1H, m), 7.58 (2H, brs), 7.62 (1H, dd, J=1.3, 4.8 Hz), 13.19 (1H, brs) MS(ESI ) : 387[M+H]

+

, 428[M+H+MeCN] 4 Example 88 15 3-Amino-5-(2-furyl)-6- (1-isopropyl-6-oxo-1,6-dihydro 3-pyridyl) - 2 -pyrazinecarboxylic acid 2 H-NMR(DMSO-d, 5) : 1.24 (6H, d, J=6.5 Hz), 5.09 (1H, sept, J=6.5 Hz), 6.43 (1H, d, J=9 H:), 6.62 (1H, dd, J=2, 3.5 Hz), 6.77 (1H, d, J=3 Hz), 7.45-7.51 (3H, m), 7.75-7.82 (2H, m) 20 Example 89 3-Amino-5-(3-furyl)-6-(1-isopropyl-6-oxo-1,6-dihydro 3-pyridyl)- 2 -pyrazinecarboxylic acid IH-NMR(DMSO-d 6 5) : 1.21 (6H, d, J=3.5 Hz), 5.06 (1H, sept, J=3.5 Hz), 6.43 (1H, d, J=4.8 Hz), 6.54 (1H, d, J=0.9 Hz), 25 7.44 (2H, brs), 7.48 (1H, dd, J=1.3, 4.8 Hz), 7.72-7.77 (3H, 100 WO 2005/040151 PCT/JP2004/016193 m), 12.95 (1H, brs) MS(ESI) : 341[M+H] 4 , 382[M+H+MeCN] Example 90 3-Amino-6-(l-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5 5-(2-thienyl)-2-pyrazinecarboxylic acid 'H-NMR(DMSO-d 6 5) : 1.22 (6H, d, J=7.0 Hz), 5.08 (1H, sept, J=7.0 Hz), 6.46 (1H, d, J=9.0 Hz), 7.05-7.09 (IH, m), 7.2 (1H, dd, J=1.0, 4.0 Hz), 7.42-7.48 (3H, m), 7.73 (1H, dd, J=1.0, 5.0 Hz), 7.83 (IH, d, J=2.5 Hz), 13.00 (1H, brs) 10 MS(ESI ) : 357[M+H]I , 398[M+H+MeCN] + Example 91 3-Amino-6- (1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-(3-thienyl)-2-pyrazinecarboxylic acid IH-NMR(DMSO-d 6 5) : 1.10 (6H, d, J=6.5 Hz), 4.98 (1H, sept, 15 J=6.5 Hz), 6.37-6.43 (1H, m), 7.13 (1H, dd, J=1.5, 5.0 Hz), 7.46-7.60 (5H, m), 7.72 (IH, dd, J=1.3, 3 Hz)

MS(ESI

4 ) : 357[M+H]i, 398[M+H-+MHeCN] Example 92 3-Amino-6- (1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 20 5-(5-methyl-2-thienyl)-2-pyrazinecarboxylic acid 'H-NMR(DMSO-d 6 5) : 1.25 (6H, d, J=7.0 Hz), 5.09 (1H, sept, J=7.0 Hz), 2.44 (3H, s), 6.45 (1H, d, J=9.5 Hz), 6.77-6.78 (1H, m), 7.01 (IH, d, J=3.5 Hz), 7.40-7.46 (3H, m), 7.85 (1H, d, J=2.5 Hz), 12.98 (1H, brs) 25 MS(ESI

+

) : 371[M+H]

+

, 412[M+H+MeCN] + 101 WO 2005/040151 PCT/JP2004/016193 Example 93 3-amino-6- (1-isopropyl-6-oxo-l, 6-dihydro-3-pyridyl) 5-(1H-pyrazol-4-yl)-2-pyrazinecarboxylic acid H-NMR(DMSO-d6 5) : 1.23 (1H, d, J=7.0 Hz), 5.07 (1H, sept, 5 J=7.0 Hz), 6.44 (1H, d, J=9.0 Hz), 7.37 (2H, brs), 7.43 (1H, dd, J=2.5, 9.0 Hz), 7.66 (2H, s), 7.77 (1iH, d, J=-2.5 Hz), 12.99 (1H, brs) MS(ESI-) : 339[M-H] Example 94 10 3-Amino-6-(l-isopropyl-6-oxo-1,6-dihydro-3-pyridyl) 5-[(E)-2-phenylvinyl]-2-pyrazinecarboxylic acid MS(ESI-) : 375[M-H] Example 95 3-Amino-5-(4-fluorophenyl)-6- (1-methyl-6-oxo-1,6 15 dihydro-3-pyridyl)-2-pyrazinecarboxylic acid IH-NMR(DMSO-d 6 5) : 3.43 (3H, s), 6.22 (1H, d, J=9.5 Hz), 7.05 (1H, dd, J=2.8, 9.5 Hz), 7.26 (2H, t, J=8.8 Hz), 7.50 (2H, brs), 7.55 (2H, dd, J=5.5, 9.0 Hz), 7.92 (1H, d, J=2.5 Hz) 20 Example 96 3-Amino-5-(2-furyl)-6- (1-methyl-6-oxo-l, 6-dihydro 3-pyridyl)-2-pyrazinecarboxylic acid MS(ESI-) : 311[M-H] Example 97 25 3-Amino-6- (I-methyl-6-oxo-l, 6-dihydro-3-pyridyl) 102 WO 2005/040151 PCT/JP2004/016193 5-(2-thienyl)-2-pyrazinecarboxylic acid 'H-NMR(DMSO-d, 6) : 3.49 (3H, s), 6.40 (1H, d, J=9.5 Hz), 7.08 (IH, dd, J=4.0, 5.0 Hz), 7.22 (1H, dd, J=1.0, 4.0 Hz), 7.36 (1H, dd, J=2.8, 9.5 Hz), 7.48 (2H, brs), 7.74 (1H, dd, 5 J=1.0, 5.0 Hz), 7.97 (1H, d, J=2.5 Hz) Example.98 3-Amino-6- (1-isopropyl-6-oxo-l, 6-dihydro-3-pyridyl) 5-(phenylethynyl)-2-pyrazinecarboxylic acid MS(ESI-) : 373[M-H] 10 Example 99 3-Amino-5-(2-fluorophenyl)-6- (1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxylic acid H-NMR(DMSO-d 6 ) : 0.92 (1H, d, J=7.0 Hz), 4.88 (1H, sept, J=7.0 Hz), 6.38 (IH, d, J=9.5 Hz), 7.18-7.69 (8H, m), 13.12 15 (1H, brs)

MS(ESI

+

) : 369[M+H]*, 41O[M+H+MeCN] + Example 100 3-Amino-5-(3-fluorophenyl)-6- (1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxylic acid 20 H-NMR(DMSO-d 6 5) : 0.99 (6H, d, J=6.5 Hz), 4.93 (1H, t, J=6.5 Hz), 6.38 (1H, d, J=9.0 Hz), 7.22-7.60 (8H, m), 13.07 (1H, brs)

MS(ESI

+) : 369[M+H] ,.410[M+H+MeCN] Example 101 25 3-Amino-5-(3-chlorophenyl)-6- (1-isopropyl-6-oxo 103 WO 2005/040151 PCT/JP2004/016193 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxylic acid IH-NMR(DMSO-dE 5) : 0.99 (iH, d, J=7.0 Hz), 4.94 (1H, sept, J=7.0 Hz), 6.39 (1H, d, J=9.5 Hz), 7.37-7.62 (8H, m), 13.06 (1H, brs) 5 MS(ESI) : 385[H+H] , 426[M+H+MeCN] Example 102 3-Amino-5-(4-chlorophenyl)-6- (1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxylic acid H-NMR(DMSO-d6 5) : 1.00 (6H, d, J=7.0 Hz ), 4.94 (1H, t, 10 J=7.0 Hz), 6.38 (1H, d, J=9.5 Hz), 7.34-7.59 (8H, m), 13.04 (1H, brs) MS(ESI ) : 385[M+H] , 426[M+H+MeCN] + Example 103 3-Amino-5-(3,4-difluorophenyl)-6- (1-isopropyl-6-oxo 15 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxylic acid H-NMR(DMSO-d 6 5) : 1.03 (6H, d, J=7.0 Hz), 4.96 (1H, sept, J=6.8 Hz), 6.39 (1H, d, J=9.0 Hz), 7.30-7.61 (7H, m), 13.06 (IH, brs)

MS(ESI

+

) : 387[M+H]+, 428[M+H+MeCN]J + 20 Example 104 3-Amino-5-(3,5-difluorophenyl)-6- (1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-2-pyrazinecarboxylic acid 1 H-NMR(DMSO-d6 5) : 1..03 (1H, d, J=6.5 Hz), 4.97 (1H, sept, J=6.5 Hz), 6.40 (1H, d, J=9.5 Hz), 7.16-7.59 (7H, m), 13.16 25 (1H, brs) 104 WO 2005/040151 PCT/JP2004/016193

MS(ESI

) : 387 [M+H1~, 428[M+H+MIeCN] Example 105 3-Amino-6- (1-methyl-6-oxo-1,6-dihydro-3-pyridyl) 5-phenyl- 2 -pyrazinecarboxylic acid 5 'H-NMR(DMSO-d 6 5) : 3.42 (3H, s), 6.18 (1H, d, J=9.0 Hz), 7.03 (1H, dd, J=2.8, 9.0 Hz), 7.38-7.53 (7H, m), 7.91 (1H, d, J=2.5 Hz) Example 106 A suspention of 3-amino-6-(l-isopropyl-6-oxo-1,6 10 dihydro-3-pyridyl)-5-(4-methoxyphenyl)-2 pyrazinecarboxylic acid in 1,2-dichlorobenzen (3 ml) was heated at 200 0 C and stirred for 4 hours. This reaction mixture was cooled to room temperature. To this solution was added IPE and stirred at room temperature for 1 hour. 15 The precipitate was collected by filtration and washed with IPE. The residual solid was placed on a column of silica-gel and eluted with CHCl 3 - MeOH (20 : 1). The eluent was evaporated and the residue was purified by recrystallization from EtOH - water to give 5-[5-amino 20 3 -(4-methoxyphenyl)-2-pyrazinyl]-1-isopropyl-2(1H) pyridone (88 mg) as a pale brown crystal. 'H-NMR(DMSO-d 6 6) : 1.02 (6H, d, J=7.0 Hz), 3.75 (3H, s), 4.94 (1H, sept, J=7.0.Hz), 6.31 (1H, d, J=9.5 Hz), 6.55 (2H, brs), 6.94 (2H, d, J=9.0 Hz), 7.29-7.42 (4H, m), 7.87 (1H, 25 s) 105 WO 2005/040151 PCT/JP2004/016193

MS(ESI

) : 337[M+H] , 378[M+H4+MeCN] The following 24 compounds were obtained in a similar manner to that of Example 106. Example 107 5 5- [5-Amino-3-(2-methoxyphenyl)-2-pyrazinyll] -1 isopropyl-2 (lH)-pyridone H-NMR(DSO-d6 5) : 0.91 (6H, brs), 3.48 (3H, s), 4.87 (IH, sept, J=6.8 Hz), 6.31 (1H, d, J=9.0 Hz), 6.51 (2H, brs), 6.97-7.10 (3H, m), 7.33-7.51 (3H, m), 7.90 (1H, s) 10 MS(ESI

+

) : 337[M+H]', 378[M+H+MeCN] + Example 108 5-[5-Amino-3-(3-methoxyphenyl) -2-pyrazinyl] -1 isopropyl-2(1H)-pyridone 'H-NMR(DMSO-d 6 5) : 0.98 (6H, d, J=7.0 Hz), 3.69 (3H, s), 15 4.92 (1H, sept, J=7.0 Hz), 6.32 (1H, d, J=9.5 Hz), 6.61 (2H, brs), 6.89-6.95 (3H, m), 7.24-7.33 (3H, m), 7.43 (IH, dd, J=2.5, 9.5 Hz), 7.92 (1H, s) Example 109 5-[5-Amino-3-(2-methylphenyl)-2-pyrazinyl] -1 20 isopropyl-2 (1H) -pyridone 1H-NMR(DMSO-d6 5) : 0.88 (6H, d, J=6.5 Hz), 1.97 (3H, s), 4.84 (1H, sept, J=6.5 Hz), 6.32 (1H, d, J=9.0 Hz), 6.58 (2H, brs), 7.02 (1H, d, J=2.5 Hz), 7.27 (4H, brs), 7.56 (1H, dd, J=2.5, 9.0 Hz), 7.95 (IH, s) 25 Example 110 106 WO 2005/040151 PCT/JP2004/016193 5-[5-Amino-3-(2,3-difluorophenyl)-2-pyrazinyl]-2 isopropyl-2 (1H)-pyridone aH-NMR(DMSO-d 6 5) : 0.96 (6H, d, J=7 Hz), 4.91 (1H, sept, J=7 Hz), 6.36 (1H, d, J=9.5 Hz), 6.75 (2H, brs), 7.2 (1H, 5 d, J=2.5 Hz), 7.3-7.51 (4H, m), 8.01 (IH, s)

MS(ESI

+

) : 343[M+H] , 484[M+H+MeCN] + Example 111 5-[5-Amino-3-(2,4-difluorophenyl)-2-pyrazinyl] -1 isopropyl-2 (1H)-pyridone 10 aH-NMR(DMSO-d 6 5) : 0.97 (6H, d, J=7.0 Hz), 4.92 (1H, t, J=7.0 Hz), 6.35 (1H, d, J=9.0 Hz), 6.7 (2H, brs), 7.19-7.30 (3H, m), 7.47 (IH, dd, J=2.8, 9.0 Hz), 7.56-7.68 (1H, m), 7.97 (1H, s) MS(ESI ) : 343[M+H] 4 , 384[M+H+MeCN] + 15 Example 112 5-[5-Amino-3-(2,5-difluorophenyl)-2-pyrazinyll] -1 isopropyl-2 (1H)-pyridone 1 H-NMR(DMSO-d 6 5) : 0.97 (6H, d, J=6.8 Hz), 4.91 (1H, sept, J=6.8 Hz), 6.36 (IH, d, J=9.5 Hz), 6.73 (2H, brs), 20 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]+ Example 113 5-[5-Amino-3-(2-furyl) -2-pyrazinyl] -1-isopropyl-2 (1H) pyridone 25 'H-NMR(DMSO-d6 5) : 1.22 (6H, d, J=7.0 Hz), 5.06 (1H, sept, 107 WO 2005/040151 PCT/JP2004/016193 J=7.0 Hz), 6.38 (1H, d, J=9.0 Hz), 6.56 (1H, dd, J=1.8, 3.5 Hz), 6.65-6.66 (1H, m), 7.36 (3H, dd, J=2.8, 9.5 Hz), 7.58 (2H, d, J=2.5 Hz), 7.70 (1H, m), 7.87 (1H, s)

MS(ESI

+

) : 297[M+H]

+

, 338[M+H+MeCN] + 5 Example 114 5-[5-Amino-3-(3-furyl)-2-pyrazinyl]-1-isopropyl-2(1H) pyridone 'H-NMR(DMSO-d6 6) : 1.19 (6H, d, J=6.5 Hz), 5.04 (1H, sept, J=6.5 Hz), 6.4 (1H, d, J=12.0 Hz), 6.42 (1H, brs), 6.54 (2H, 10 brs), 7.39 (1H, dd, J=2.5, 9.5 Hz), 7.59 (1H, d, J=2.5 Hz), 7.65-7.69 (2H, m), 7.84 (IH, brs)

MS(ESI

+

) : 297[M+H] , 338[M+H+MeCN]' Example 115 5-[5-Amino-3- (2-thienyl)-2-pyrazinyl] -1-isopropyl 15 2(1H)-pyridone 2 H-NMR(DMSO-d 6 5) : 1.20 (6H, d, J=6.5 Hz), 5.06 (1H, sept, J=6.5 Hz), 6.4 (1H, d, J=9.5 Hz), 6.63 (2H, brs), 6.99-7.04 (2H, m), 7.36 (1H, dd, J=2.5, 9.5 Hz), 7.59 (1H, dd, J=2.0, 4.5 Hz), 7.68 (1H, d, J=2.0 Hz), 7.84 (1H, s) 20 MS(ESI

+

) : 313[M+H]+, 354[M+H+MeCN] + Example 116 5-[5-Amino-3-(3-thienyl)-2-pyrazinyl] -1-isopropyl 2 (1H) -pyridone H-NMR(DMSO-d 6 5) : 1.09 (6H, d, J=6.5 Hz), 4.97 (1H, sept, 25 J=6.5 Hz), 6.35 (1H, d, J=9.5 Hz), 6.56 (2H, brs), 7.04 (1H, 108 WO 2005/040151 PCT/JP2004/016193 dd, J=1.3, 5.0 Hz), 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]' Example 117 5 5-[5-Amino-3-(5-methyl-2-thienyl)-2-pyrazinyl]-l isopropyl-2 (1H)-pyridone IH-NMR(DMSO-ld 5) : 1.22 (6H, d, J=6.5 Hz), 2.41 (3H, s), 5.07 (1H, sept, J=6.5 Hz), 6.40 (1H, d, J=9.5 Hz), 6.57 (2H, brs), 6.69-6.70 (1H, m), 6.84 (1H, d, J=3.5 Hz), 7.35 (IH, 10 dd, J=2.5, 9.0 Hz), 7.70 (1H, d, J=2.5 Hz), 7.79 (1H, s) MS(ESI) : 327[M+H]

+

, 368[M+H+MeCN] Example 118 5-[5-Amino-3-(1H-pyrazol-4-yl)-2-pyrazinyl]-l isopropyl-2 (1H)-pyridone 15 'H-NMR(DMSO-d 6 5) : 1.20 (6H, d, J=6.5 Hz), 5.05 (1H, sept, J=6.5 Hz), 6.38 (1H, d, J=9.0 Hz), 6.45 (2H, brs), 7.34 (1H, dd, J=2.5, 9.0 Hz), 7.50-7.62 (3H, m), 7.77 (IH, s), 12.92 (1H, brs)

MS(ESI

+

) : 319[M+Na]

+

, 615[2M+Na] 20 Example 119 5-{ 5-Amino-3- [ (E)-2-phenylvinyl] -2-pyrazinyl}-l isopropyl-2 (1H) -pyridone 'H-NMR(DMSO-d 6 6) : 1..30 (6H, d, J=7.0 Hz), 5.13 (1H, sept, J=7.0 Hz), 6.49 (1H, d, J=9.5 Hz), 6.58 (2H, brs), 7.16 (1H, 25 d, J=15.6 Hz), 7.29-7.40 (3H, m), 7.53-7.65 (4H, m), 7.74 109 WO 2005/040151 PCT/JP2004/016193 (1H, d, J=2.0 Hz), 7.88 (1H, s) MS(ESI ) : 333[MH] , 355[M+Na] , 687[2M+Na] Example 120 5-[5-Amino-3-(4-fluorophenyl) -2-pyrazinyl] -1-methyl 5 2(1H)-pyridone IH-NMR(DMSO-d6 5) : 3.40 (3H, s), 6.20 (1H, d, J=9.5 Hz), 6.62 (2H, brs), 7.01 (1H, dd, J=2.5, 9.5 Hz), 7.21 (1H, t, J=8.5 Hz), 7.46 (1H, dd, J=5.5, 8.5 Hz), 7.74 (1H, d, J=2.5 Hz), 7.90 (1H, s) 10 MS(ESI ) : 297[M+H]

+

, 319[M+Na]

+

, 615[2M+Na] + Example 121 5- [5-Amino-3- (2-furyl)-2-pyrazinyl] -1-methyl-2 (1H) pyridone IH-NMR(DMSO-d 6 6) : 3.46 (3H, s), 6.33 (1H, d, J=9.5 Hz), 15 6.57 (1H, dd, J=1.5, 3.5 Hz), 6.65-6.68 (3H, m), 7.22 (1H, dd, J=2.5, 9.5 Hz), 7.69 (1H, s), 7.78 (1H, d, J=2.5 Hz), 7.85 (1H, s)

MS(ESI

+

) : 269[M+H]

+

, 291[M+Na]

+

, 559[2M+Nal + , Example 122 20 5-[5-Amino-3-(2-thienyl)-2-pyrazinyl]-1-methyl-2(lH) pyridone H-NMR(DMSO-d6 6) : 3.46 (3H, s), 6.36 (1H, d, J=9.5 Hz), 6.64 (2H, brs), 6.99-,7.07 (2H, m), 7.28 (1H, dd, J=2.5, 9.5 Hz), 7.60 (1H, d, J=3.5 Hz), 7.82 (1H, s), 7.85 (1H, d, J=2.5 25 Hz) 110 WO 2005/040151 PCT/JP2004/016193 MS(ESI 4 ) : 307[M+Na] , 591[2M+Na] Example 123 5-[5-Amino-3-(phenylethynyl)-2-pyrazinyl] -.1-isopropyl 2 (1H)-pyridone 5 H-NMR(DMSO-d 6 6) : 1.26 (6H, d, J=7.0 Hz), 5.06 (1H, t, J=7.0 Hz) , 6.49 (1H, d, J=9.5 Hz), 6.75 (2H, brs), 7.43-7.54 (5H, m), 7.91 (1H, dd, J=2.5, 9.5 Hz), 7.95 (1H, s), 8.17 (1H, d, J=2.5 Hz) MS(ESI ) : 331[M+H]

+

, 353[M+Na] 4 , 683[2M+Na] + 10 Example 124 5-[5-Amino-3-(2-fluorophenyl)-2-pyrazinyl]-l-isopropyl 2 (1H)-pyridone H-NMR(DMSO-d 6 5) : 0.92 (6H, d, J=7.0 Hz), 4.88 (IH, sept, J=7.0 Hz) , 6.34 (1H, d, J=9.5 Hz), 6.67 (2H, brs), 7.15-7.60 15 (6H, m), 7.97 (1H, s)

MS(ESI

+

) : 325[M+H]j, 366[M+H+MeCN] + Example 125 5-[5-Amino-3-(3-fluorophenyl)-2-pyrazinyl] -1-isopropyl 2 (1H)-pyridone 20 H-NMR(DMSO-d, 5) : 1.00 (6H, d, J=6.8 Hz), 4.94 (18, sept, J=6.8 Hz), 6.35 (1H, d, J=9.0 Hz), 6.68 (2H, brs), 7.28-7.48 (6H, m), 7.95 (1H, s) MS(ESI') : 341[M+H],. 382[M+H+MeCN] + Example 126 25 5-[5-Amino-3-(3-chlorophenyl)-2-pyrazinyl]-l-isopropyl 111 WO 2005/040151 PCT/JP2004/016193 2 (IH) -pyridone 1H-NMR(DMSO-d 6 5) : 1.00 (6H, d, J=6.8 Hz), 4.94 (IH, sept, J=6.8 Hz), 6.35 (1H, d, J=9.0 Hz), 6.68 (2H, brs), 7.28-7.48 (6H, m), 7.95 (1H, s) 5 MS(ESI ) : 341[M+H]

+

, 382[M+H+MeCN]+ Example 127 5-[5-Amino-3-(4-chlorophenyl)-2-pyrazinyl] -1-isopropyl 2 (1H)-pyridone 'H-NMR(DMSO-d 6 5) : 1.00 (6H, d, J=6.8 Hz), 4.93 (IH, sept, 10 J=6.8 Hz), 6.34 (1H, d, J=9.5 Hz), 6.65 (2H, brs), 7.25 (1H, d, J=2.5 Hz), 7.38-7.48 (5H, m), 7.93 (1H, s)

MS(ESI

+

) : 341[M+H]

+

, 382[M+H+MeCN] + Example 128 5-[5-Amino-3-(3,4-difluorophenyl)-2-pyrazinyll] -1 15 isopropyl-2 (1H) -pyridone 'H-NMR(DMSO-d 6 5) : 1.03 (6H, d, J=6.8 Hz), 4.96 (IH, sept, J=6.8 Hz), 6.35 (1H, d, J=9.5 Hz), 6.68 (2H, brs), 7.20-7.53 (6Hr m), 7.95 (1H, s) MS(ESI ) : 343[M+H]+, 384[M+H+MeCN] 20 Example 129 5-[5-Amino-3-(3,5-difluorophenyl)-2-pyrazinyl] -1 isopropyl-2 (H)-pyridone 'H-NMR(DMSO-d 6 5) : 1.04 (6H, d, J=6.8 Hz), 4.96 (IH, sept, J=6.8 Hz), 6.37 (1H, d, J=9.0 Hz), 6.72 (2H, brs), 7.07-7.46 25 (5H, m), 7.97 (1H, s) 112 WO 2005/040151 PCT/JP2004/016193

MS(ESI

4 ) : 343[M+H] 4 , 384[M+H+MeCN] Example 130 5-(5-Amino-3-phenyl-2-pyrazinyl)-1-methyl-2 (IH) pyridone 5 'H-NMR(DMSO-dE ) : 3.38 (3H, s), 6.16 (1IH, d, J=4.8 Hz), 6.60 (2H, brs), 6.99 (1H, dd, J=l.4, 4.8 Hz), 7.36-7.42 (5H, m), 7.72 (1H, d, J=1.4 Hz), 7.90 (1H, s) Example 131 To a suspention of 3-amino-6-(l-isopropyl-6-oxo 10 1,6-dihydro-3-pyridyl)-5-(2-pyridyl)-2 pyrazinecarboxamide (52 mg) in dioxane (0.5 ml) was added an aq. NaOH (2M, 1 ml) and this solution was heated at 100 0 C for 4 hours. This reaction mixture was cooled to room temperature and the pH of this solution was adjusted to 2.5 15 with 2Naq. HCl. This solution was evaporated under reduced pressure to give yellow solid. A suspension of this yellow solid in 1,2-dichlorobenzene (2 ml) was heated at 200 0 C and stirred for 4 hours. This reaction mixture was cooled to room temperature. To this solution was added IPEand stirred 20 at room temperature for 1 hour. The precipitate was collected by filtration and washed with IPE. The residual solid was placed on a column of silica-gel and eluted with CHCl 3 - MeOH - 28% aq.. ammonia (15 : 1 : 0.1) . The eluent was evaporated and the residue was purified by 25 recrystallization from EtOAc - IPE to give 5-[5-amino 113 WO 2005/040151 PCT/JP2004/016193 3-(2-pyridyl)-2-pyrazinyl]-l-isopropyl-2(1H)-pyridone (5 mg) as a pale yellow crystal. IH-NMR(DMSO-d 6 5) : 1.13 (6H, d, J=7.0 Hz), 5.18 (1H, t, J=7.0 Hz), 6.48 (1H, d, J=9.0 Hz), 7.29-7.38 (3H, m), 7.46 5 (1H, d, J=7.5 Hz), 7.75 (1H, dt, J=l.7, 7.5 Hz), 8.09 (1H, s), 8.71 (1H, d, J=4.5 Hz) MS(ESI ) : 308[M+H]

+

, 349[M+H+MeCN] + The following 2 compounds were obtained in a similar manner to that of Example 131. 10 Example 132 5- [5-Amino-3-(3-pyridyl)-2-pyrazinyl ] -1-isopropyl 2 (1H)-pyridone H-NMR(DMSO-d 6 6) : 0.98 (6H, d, J=7.0 Hz), 4.92 (IH, t, J=7.0 Hz), 6.35 (IH, d, J=9.5 Hz), 6.71 (2H, brs), 7.3 (1H, 15 d, J=2.5 Hz), 7.38-7.46 (2H, m), 7.79 (1H, dt, J=2.5, 4.0 Hz), 7.97 (1H, s), 8.51 (1H, dd, J=l.5, 5.0 Hz), 8.56 (1H, d, J=1.5 Hz)

MS(ESI

+

) : 308[M+H]

+

, 349[M+H+MeCN] + Example 133 20 5-[5-Amino-3-(4-pyridyl)-2-pyrazinyl]-1-isopropyl 2 (1H)-pyridone H-NMR(DMSO-d 5 : 0.96 (6H, d, J=7.0 Hz), 4.92 (1H, t, J=7.0 Hz), 6.36 (IH, d, J=9.5 Hz), 6.74 (2H, brs), 7.25 (1H, d, J=2.5 Hz), 7.36-7.48 (3H, m), 7.99 (1H, brs), 8.56-8.59 25 (2H, m) 114 WO 2005/040151 PCT/JP2004/016193

MS(ESI

4 ) : 308[MA+H]

+

, 349[M+H+MeCN] Example 134 3-Amino-5-chloro-6-(1-isopropyl-6-oxo-l,6 dihydro-3-pyridyl)-2-pyrazinecarboxamide (500 mg), 5 (4-methoxyphenyl)boronic acid (740mg), andPd(PPh 3

)

4 (56.3 mg) in 2M aq. Na 2

CO

3 (3.25 ml) and dioxane (20 ml) was refluxed for 3 hours. Water (40 ml) and EtOAc (30 ml) were poured into the reaction mixture and the aqueous solution was extracted with EtOAc. The organic layer was washed with 10 water and brine, and dried over MgSO 4 . After filtration, the solvent was removed under reduced pressure. The residual solid was placed on a column of silica-gel and elutedwithCHCl3 -MeOH (97 : 3). The eluent was evaporated and the residue was suspended with IPE and filtrated to give 15 yellow powder. To a suspension of this yellow powder in dioxane (0.5 ml) was added an aq. NaOH (2M, 1 ml) and this solution was heated at 100'C for 4 hours. This reaction mixture was cooled to room temperature and the pH of this solution was adjusted to 2.5 with 2Naq. HCl. This solution 20 was evaporated under reduced pressure to give yellow solid. A suspension of this yellow solid in 1,2-dichlorobenzen (2 ml) was heated at 200 0 C and stirred for 4 hours. This reaction mixture was cooled to room temperature. To this solution was added IPE and stirred at room temperature for 25 1 hour. The precipitate was collected by filtration and 115 WO 2005/040151 PCT/JP2004/016193 washed with IPE. The residual solid was placed on a column of silica-gel and eluted with CHCl 3 - MeOH (97 : 3). The eluent was evaporated and the residue was purified by GPC (Gel Permeation Chromatography) to give 5-[5-amino 5 3-(5-chloro-2-thienyl)-2-pyrazinyl]-1-isopropyl 2(1H)-pyridone (25 mg) and 5-[5-amino-3-(5'-chloro-2,2' bithien-5-yl) -2-pyrazinyl] -l-isopropyl-2 (lIH)-pyridone (26 mg) as yellow powder. 5-[5-Amino-3-(5-chloro-2-thienyl)-2-pyrazinyl] -1 10 isopropyl-2 (IH)-pyridone H-NMR(DMSO-d 6 5) : 1.24 (6H, d, J=7.0 Hz), 5.08 (1H, sept, J=7.0 Hz), 6.43 (IH, d, J=9.0 Hz), 6.7 (2H, brs), 6.86 (1H, d, J=11.4 Hz), 7.02 (IH, d, J=4.0 Hz), 7.38 (1H, dd, J=2.5, 9.0 Hz), 7.77 (IH, d, J=2.5 Hz), 7.85 (1H, brs) 15 MS(ESI

+

) : 347[M+H]', 388[M+H+MeCN] 5-[S-Amino-3-(5'-chloro-2,2'-bithien-5-yl)-2 pyrazinyl]-l-isopropyl-2(lH)-pyridone H-NMR(DMSO-di 5) : 1.24 (6H, d, J=6.5 Hz), 5.09 (1H, sept, J=6.5 Hz), 6.44 (1H, d, J=9.5 Hz), 6.69 (2H, brs), 6.93 (1H, 20 d, J=3.5 Hz), 7.12-7.21 (3H, m), 7.40 (1H, dd, J=2.5, 9.5 Hz), 7.78 (1H, d, J=2.5 Hz), 7.85 (1H, s)

MS(ESI

+

) : 429[M+H] , 470[M+H+MeCN] Example 135 3-Amino-5-(4-fluorophenyl)-6- (1-isopropyl-6-oxo-1,6 25 dihydro-3-pyridyl)-N-methyl-2-pyrazinecarboxamide 116 WO 2005/040151 PCT/JP2004/016193 The title compound was obtained in a similar manner to that of Preparation 42. 1 H-NMR(DMSO-d 6 5) : 0.98 (6H, d, J=7.0 Hz), 2.84 (3H, d, J=5.0 Hz), 4.92 (1H, sept, J=7.0 Hz), 6.39 (IH, d, J=9.0 5 Hz), 7.21-7.78 (8H, m), 8.68 (IH, d, J=5.0 Hz) MS(ESI ) : 382[M+H] , 404[M+Na] , 785[2M+Na] Example 136 To a suspension of 3 -amino-6-(1-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylic 10 acid (350 mg) in MeOH (7.0 ml), was added thionyl chloride (0.146 m) dropwise under ice-bath cooling. After 1 hour stirring at the same temperature, the mixture was allowed to warm to room temperature. The mixture was stirred for 6 hours and then refluxed with stirring for 15 hours. After 15 cooling, the solvent was removed under reduced pressure. Water was poured into the residue and the pH of the mixture was adjusted to 10 with 1N aq. NaOH. A precipitate was isolated by filtration, washed with water, and dried in vacuo to give methyl 3 -amino-6-(1-isopropyl-6-oxo-1,6 20 dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylate (244 mg). IH-NMR(DMSO-dG 5) : 0.91 (6H, d, J=6.8 Hz), 3.89 (3H, s), 4.89 (1H, qq, J=6.8, 6.8 Hz), 6.41 (1H, d, J=9.3 Hz), 7.21 (1H, d, J=2.4 Hz), 7.30-7.50 (7H, m), 7.56 (1H, dd, J=2.4, 25 9.3 Hz) 117 WO 2005/040151 PCT/JP2004/016193 MS(ESI') : 365[M+H] +, 387[M+Na) Example 137 Under ice-bath cooling, methylmagnesium chloride (3M solution, 0.46 ml) was added to a suspension of methyl 5 3-amino-6-(1-isopropyl-6-oxo-1, 6-dihydro-3-pyridyl)-5 phenyl-2-pyrazinecarboxylate (100mg) in THF (10ml). After 7.5 hours stirring at the same temperature, sat. aq. ammonium chloride solution (1 ml) was poured into the mixture. Water and EtOAc were poured into the mixture and 10 the organic layer was separated, washed with water and brine, and dried over MgSO 4 .The solvent was removed under reduced pressure. The residue was recrystallized fromMeOH-IPE and dried under reduced pressure to give 5-[5-amino 6-(l-hydroxy-l-methylethyl)-3-phenyl-2-pyrazinyl]-1 15 isopropyl-2(IH)-pyridone (41 mg). 1 H-NMR(DMSO-d 6 5) : 0.93 (6H, d, J=6.8 Hz), 1.56 (6H, s), 4.89 (1H, qq, J=6.8, 6.8 Hz), 5.76 (1H, brs), 6.37 (1H, d, J=9.3 Hz), 6.59 (2H, brs), 7.17 (1H1, d, J=2.4 Hz), 7.20-7.50 (5H, m), 7.53 (IH, dd, J=2.4, 9.3 Hz) 20 MS(ESI ) : 365[M+H] + Example 138 To a solution of 5-(6-acetyl-5-amino-3-phenyl 2-pyrazinyl)-l-isopropyl-2(1H)-pyridone (82 mg) in THF MeOH (1 : 1, 2.0 ml), was added sodiumborohydride (8.9mg). 25 The mixture was stirred st room temperature for 4 hours. 118 WO 2005/040151 PCT/JP2004/016193 INHCI (0.05 ml) was poured into the mixtre. Water and EtOAc were poured into the mixture and the organic layer was separated, washed with water and brine, and dried overMgSO. The solvent was removed under reduced pressure. The residue 5 was purified by column chromatography. The desired product was recrystallized from EtOH and dried in vacuo to give 5-[5-amino-6- (l-hydroxyethyl)-3-phenyl-2-pyrazinyl] -1 isopropyl-2(1H)-pyridone (16 mg). 'H-NMR(DMSO-d, 5) : 0.93 (3H, d, J=6.7 Hz), 0.94 (3H, d, 10 J=6.7 Hz), 1.46 (3H, d, J=6.5 Hz), 4.70-5.00 (2H, m), 5.57 (IH, d, J=5.4 Hz), 6.35 (1H, d, J=9.4 Hz), 6.40 (2H, brs), 7.18 (1H, d, J=2.5 Hz), 7.40 (5H, m), 7.53 (IH, dd, J=2.5, 9.4 Hz) MS(ESI) : 351[M+H] + 15 Example 139 Under ice-bath cooling, NaH (60% pure, 18 mg) was added to a suspension of 5-[5-amino-6-(hydroxymethyl) 3-phenyl-2-pyrazinyl]-l-isopropyl-2(1H)-pyridone (100 mg) in DMF (1.0 ml) . After 10 minute stirring, MeI (127 mg) 20 was added to the mixture. After 10 minutes stirring at the same temperature, the mixture was allowed to warm to 250C. After 3.5 hours stirring, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO 4 .The solvent was 25 removed under reduced pressure and the residue was purified 119 WO 2005/040151 PCT/JP2004/016193 by column chromatography, triturated with IPE , and dried in vacuo to give 5-[5-amino-6-(methoxymethyl)-3-phenyl 2-pyrazinyl]-l-isopropyl-2(1H)-pyridone (40 mg). IH-NMR(DMSO-d 6 5) : 0.93 (6H, d, J=6.7 Hz), 3.36 (3H, s), 5 4.53 (2H, s), 4.89 (1H, qq, J=6.7, 6.7 Hz), 6.36 (IH, d, J=9.4 Hz), 6.41 (1H, brs), 7.17 (IH, d, J=2.5 Hz), 7.2-7.5 (4H, m), 7.50 (1H, dd, J=2.5, 9.4 Hz) MS(ESI') : 351[M+H] , 373[M+Na] 4 Example 140 10 5-{5-Amino-6-[(benzyloxy)methyl]-3-phenyl-2-pyrazinyl} 1-isopropyl-2 (1H)-pyridone The title compound was obtained in 'a similar manner to that of Preparation 139. 1 H-NMR(DMSO-d6 5) : 0.93 (6H, d, J=6.8 Hz), 4.62 (2H, s), 15 4.67 (2H, s), 4.89 (1H, qq, J=6.8, 6.8 Hz), 6.35 (1H, d, J=9.4 Hz), 6.45 (2H, brs), 7.18 (1H, d, J=2.4 Hz), 7.20-7.40 (10H, m), 7.49 (IH, dd, J=2.4, 9.4 Hz)

MS(ESI

+

) : 427[M+H]

+

, 449[M+Na]+ Example 141 20 Under ice-bath cooling, N-bromosuccinimide (1.83 g) was added to a solution of 5-(5-amino-3-phenyl 2-pyrazinyl)-l-isopropyl-2(1H)-pyridone (3.0 g) inDMF (90 ml). The mixture was stirred at the same temperature for 2 hours. Water and CH 2 Cl 2 were poured into the mixture and 25 the organic layer was separated, washed with sat. aq. sodium 120 WO 2005/040151 PCT/JP2004/016193 thiosulfate solution, sat. aq. NaHCO3 solution, water, and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica-gel, toluene - EtOAc), 5 recrystallized from EtOH, and dried in vacuo to give 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl 2(lH)-pyridone (3.0 g). 'H-NMR(DMSO-d6 5) : 0.93 (6H, d, J=6.8 Hz), 4.88 (1H, qq, J=6.8, 6.8 Hz), 6.35 (1H, d, J=9.4 Hz), 6.89 (2H, brs), 7.20 10 (1H, d, J=2.5 Hz), 7.30-7.50 (6H, m) MS(ESI ) : 385[M+H] , 407[M+Na] Example 142 To a suspension of 5-(5-amino-6-bromo-3-phenyl 2-pyrazinyl)-l-isopropyl-2(IH)-pyridone (100 mg) and 15 Pd(PPh 3

)

4 (15 mg) in THF (1.0 ml), was added a solution of methylzinc chloride in THF (2. 0M, 0.75 ml). The mixture was stirred at 250C for 7.5 hours and then heated at 600C for 1.5 hours. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed 20 with water and brine, and dried over MgSO 4 .The solvent was removed under reduced pressure. The residue was crystallized form MeOH - IPE and dried in vacuo to give 5-(5-amino-6-methyl-3-phenyl-2-pyrazinyl)-l-isopropyl 2(iH)-pyridone (95 mg). 25 H-NMR(DMSO-d 6 6) : 0.94 (.6H, d, J=6.8 Hz), 2.38 (3H, s), 121 WO 2005/040151 PCT/JP2004/016193 4.89 (1H, qq, J=6.8, 6.8 Hz), 6.33 (1H, d, J=9.4 Hz), 6.38 (2H, s), 7.15 (1H, d, J=2.4 Hz), 7.20-7.50 (5H, m), 7.49 (1H, dd, J=2.4, 9.4 Hz)

MS(ESI

+

) : 321[M+H] 4 , 343[M+Na] 5 Example 143 A mixture of 5-(5-amino-6-bromo-3-phenyl 2-pyrazinyl)-1-isopropyl-2(IH)-pyridone (100 mg), phenylboronic acid (79 mg), Pd(PPh 3

)

4 (9 mg), a solution of Na 2

CO

3 (110 mg) in water (0.8 ml) and dioxane (2.0 ml) 10 was heated at 90 0 C with stirring for 1 hour. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgS04. The solvent was removed under reduced pressure. The residue was recrystallized from MeOH - IPE 15 and dried in vacuo to give 5-(5-amino-3,6-diphenyl 2-pyrazinyl)-l1-isopropyl-2(iH)-pyridone (84 mg). IH-NMR(DMSO-dG 5) : 0.94 (6H, d, J=6.8 Hz), 4.90 (IH, qq, J=6.8, 6.8 Hz), 6.30-6.40 (3H, m), 7.24 (dH, d, J=2.0 Hz), 7.30-7.70 (9H, m), 7.80-7.90 (2H, m) 20 MS(ESI

+

) : 383[M+H]

+

, 405[M+Na] + Example 144 5-[5-Amino-6-(2-furyl)-3-phenyl-2-pyrazinyl] -1 isopropyl-2 (lH)-pyridone The title compound was obtained in a similar manner 25 to that of Preparation 143. 122 WO 2005/040151 PCT/JP2004/016193 2 H-NMR(DMSO-d 6 6) : 0.95 (6H, d, J=6.8 Hz), 4.91 (1H, qq, J=6.8, 6.8 Hz), 6.38 (IH, d, J=9.4 Hz), 6.60-6.80 (3H, m), 7.19 (1H, d, J=3.4 Hz), 7.27 (IH, d, J=2.4 Hz), 7.30-7.50 (5H, m), 7.59 (IH, dd, J=2.4, 9.4 Hz), 7.89 (1H, d, J=1.l 5 Hz) MS(ESI) : 373[M+H] 4 , 395[M+Na] Example 145 A mixture of 5-(5-amino-6-bromo-3-phenyl 2 -pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg), 10 acrylamide (55 mg), Pd(OAc) 2 (3 mg), tris(2-methylphenyl)phosphine (8 mg), NEt 3 (0.11 ml), and DMF (1.0 ml) was heated with stirring at 60 0 C for 1 hour and then at 90 0 C for 5 hours. After cooling, EtOAc and water were poured into the mixture, and the organic layer was 15 separated, washed with water and brine, and dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was recrystallized from EtOAc and dried in vacuo to give (2E)-3-[3-amino-6-(l-isopropyl-6-oxo 1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinyl]acrylamide 20 (70 mg). IH-NMR(DMSO-d 6 5) : 0.93 (6H, d, J=6.8 Hz), 4.90 (IH, qq, J=6.8, 6.8 Hz), 6.40 (IH, d, J=9.4 Hz), 6.81 (2H, brs), 7.08 (1H, d, J=14.9 Hz), 7.10-7.20 (2H, m), 7.20-7.50 (5H, m), 7.62 (1H, dd, J=2.5, 9.3 Hz), 7.70 (IH, brs), 7.75 (IH, d, 25 J=14.9 Hz) 123 WO 2005/040151 PCT/JP2004/016193 MS(ESI') : 376[M+H]

+

, 398[M+Na]j Example 146 (2E)-3-[3-amino-6-(l-isopropyl-6-oxo-1, 6-dihydro-3 pyridyl)-5-phenyl-2-pyrazinyl] -N, N-dimethylacrylamide 5 The title compound was obtained in a similar manner to that of Preparation 145. H-NMR(DMSO-d 6 6) : 0.96 (6H, d, J=6.7 Hz), 2.96 (3H, s), 3.16 (3H, s), 4.92 (1H, qq, J=6.7, 6.7 Hz), 6.36 (IH, d, J=9.4 Hz), 6.84 (2H, brs), 7.30-7.60 (8H, m), 7.79 (1H, d, 10 J=14.6 Hz) MS(ESI) : 404[M+H]

+

, 426[M+Na] + Example 147 To a mixture of 5-(5-amino-6-bromo-3-phenyl 2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (500 mg), 15 ethynyl(trimethyl)silane (255 mg), PdCl 2 (PPh 3

)

2 (46 mg), CuI (12 mg), and CH 2 C1 2 (10 ml), was addedNEt 3 (0.2ml) under ice-bath cooling. The mixture was allowed to warm to 25 0 C and stirred for 15 hours. Water and EtOAc were poured into the mixture, and the organic layer was separated, washed 20 with water and brine, and dried over MgSO 4 .The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica-gel; CH 2 C1 2 - MeOH), recrystallized from EtOH, and dried in vacuo to give 5-({5-amino-3-phenyl-6-[(trimethylsilyl)ethynyl] 25 2 -pyrazinyll-l-isopropyl-2(IH)-pyridone (373 mg). 124 WO 2005/040151 PCT/JP2004/016193 'H-NMR(DMSO-ds ) : 0.29 (9H, s), 0.94 (6H, d, J=6.7 Hz), 4.89 (1H, qq, J=6.7, 6.7 Hz), 6.34 (1H, d, J=9.4 Hz), 6.70 (2H, brs), 7.21 (1H, d, J=2.4 Hz), 7.30-7.50 (5H, m), 7.47 (1H, dd, J=2.5, 9.4 Hz) 5 MS(ESI ) : 403[M+H] 4 , 425[M+Na]* Example 148 A mixture of 5-{5-amino-3-phenyl 6-[(trimethylsilyl)ethynyl]-2-pyrazinyl}-l-isopropyl 2(1H)-pyridone (300 mg) and sat. K 2

CO

3 in MeOH (4.5 ml) was 10 stirred at 25 0 C for 3 hours. Water and EtOAc were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by short column (silica-gel; CH 2

CI

2 ) and 15 recrystallized from EtOH to give 5-(5-amino-6-ethynyl 3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg). 'H-NMR(DMSO-dE 5) : 0.95 (6H, d, J=6.8 Hz), 4.71 (1H, s), 4.89 (1H, qq, J=6.8, 6.8 Hz), 6.34 (1H, d, J=9.3 Hz), 6.75 20 (2H, brs), 7.22 (IH, d, J=2.5 Hz), 7.30-7.50 (6H, m) MS(ESI ) : 331[M+H]

+

, 353[M+Na]' Example 149 A mixture of 5-(5-amino-6-bromo-3-phenyl 2 -pyrazinyl)-l-isopropyl-2(H)-pyridone (100 mg), sodium 25 methoxide (70 mg), Cul (5 mg) in NMP (1.0 ml) was heated 125 WO 2005/040151 PCT/JP2004/016193 at 100 0 C for 2.5 hours. After cooling, EtOAc and water were poured into the mixture, and theorganiclayer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was 5 recrystallized from MeOH - IPE to give 5-(5-amino 6-methoxy-3-phenyl-2-pyrazinyl) -1l-isopropyl 2(IH)-pyridone (58 mg). H-NMR(DMSO-dE 5) : 0.94 (6H, d, J=6.7 Hz), 3.98 (3H, s), 4.90 (1H, qq, J=6.7, 6.7 Hz), 6.35 (1H, d, J=9.4 Hz), 6.49 10 (2H, brs), 7.19 (1H, d, J=9.4 Hz), 7.20-7.40 (5H, m), 7.52 (1H, dd, J=2.5, 9.4 Hz) MS(ESI ) : 337[M+H]', 359[M+Na] + Example 150 A mixture of 5-(5-amino-6-methoxy-3-phenyl 15 2-pyrazinyl)-l-isopropyl-2(lH)-pyridone (80 mg), conc. HCl (0.8 ml), and dioxane (1.6 ml) was heated with stirring at 1000C for 3 hours. After cooling, the pH of the mixture was adjusted to 8 and a generated precipitate was isolated by filtration and dired in vacuo to give 5-(5-amino 20 6-hydroxy-3-phenyl-2-pyrazinyl) -1-isopropyl 2(1H)-pyridone (36 mg). 1H-NMR(DMSO-d 6 6) : 1.08 (6H, d, J=6.8 Hz), 4.94 (1H, qq, J=6.8, 6.8 Hz), 6.26 (IH, d, J=9.4 Hz), 6.76 (2H, brs), 7.13 (1H, dd, J=2.2, 9.4 H:), 7.1-7.3 (5H, m), 7.46 (1H, d, J=2.2 25 Hz), 11.91 (IH, brs) 126 WO 2005/040151 PCT/JP2004/016193

MS(ESI

4 ) : 323[M+H] , 345[M+NIla] Example 151 To absolution of phenol (147 mg) in NMP (1.0 ml), was added 60% NaH (52 mg) under ice-bath cooling. After 5 5 minutes stirring, 5-(5-amino-6-bromo-3-phenyl 2-pyrazinyl)-1l-isopropyl-2(1H)-pyridone (100 mg) was added to the mixture at the same temperature. And then the mixture was heated at 100 0 C with stirring for 5.5 hours. Aftercooling, EtOAc andwaterwere poured intothemixture, 10 and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was recrystallized from MeOH - IPE to give 5- (5-amino-6-phenoxy-3-phenyl-2-pyrazinyl) l-isopropyl-2(1H)-pyridone (88 mg). 15 1 H-NMR(DMSO-d 6 5)': 0.90 (6H, d, J=6.8 Hz), 4.86 (1H, qq, J=6.8, 6.8 Hz), 6.23 (1H, d, J=10.1 Hz), 7.15 (2H, m), 7.20-7.50 (10H, m)

MS(ESI

+

) : 399[M+H]+, 421[M+Na] 4 Example 152 20 A mixture of 5-(5-amino-6-bromo-3-phenyl 2-pyrazinyl)-1-isopropyl-2(iH)-pyridone (100 mg) and a solution of methylamine in THF (2.0M, 1.0 ml) was heated at 100'C with stirring for 20 hours in a sealed tube. After cooling, the solvent was removed under reduced pressure and 25 the residue was recrystallized from MeOH - IPE to give 127 WO 2005/040151 PCT/JP2004/016193 5-[5-amino-6-(methylamino)-3-phenyl-2-pyrazinyl] -1 isopropyl-2(1IH)-pyridone (13 mg). The filtrate was concentrated in vacuo, and the residue was rinsed with MeOH - IPE to give the desired product (60 mg). 5 'H-NMR(DMSO-d6 5) : 0.94 (6H, d, J=6.7 Hz), 2.93 (3H, d, J=4.4 Hz), 4.90 (1H, qq, J=6.7, 6.7 Hz), 6.11 (2H, brs), 6.33 (1H, d, J=9.3 Hz), 6.49 (IH, m), 7.19 (IH, d, J=2.4 Hz), 7.10-7.40 (5H, m), 7.52 (1H, dd, J=2.4, 9.4 Hz)

MS(ESI

+

) : 336[M+H]

+

, 358[M+Na] + 10 Example 153 A mixture of 5-(5-amino-6-bromo-3-phenyl 2 -pyrazinyl)-1-isopropyl-2(lH)-pyridone (100 mg), morpholine (113 mg), and NMP (1.0 ml) was heated at 150'C with stirring for 1 day. After cooling, EtOAc and water were 15 poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO 4 . The solvent was removed under reduced pressure, and the residue was recrystallized from MeOH - IPE and dried in vacuo to give 5-[5-amino-6-(4-morpholinyl)-3-phenyl 20 2-pyrazinyl]-l-isopropyl-2(lH)-pyridone (84 mg). 'H-NMR(DMSO-d 6 5) : 0.94 (6H, d, J=6.7 Hz), 3.10-3.20 (4H, m), 3.70-3.90 (4H, m), 4.90 (1H, qq, J=6.7, 6.7 Hz), 6.22 (2H, brs), 6.35 (1H, d, J=9.4 Hz), 7.19 (IH, d, J=2.4 Hz), 7.20-7.40 (5H, m), 7.54 (1H, dd, J=2.4, 9.4 Hz) 25 MS(ESI

+

) : 392[M+H]

+

, 414[M+Na] 128 WO 2005/040151 PCT/JP2004/016193 Example 154 A mixture of 5-(5-amino-6-bromo-3-phenyl 2-pyrazinyl)-l-isopropyl-2(1H)-pyridone (100 mg), dimethylamine hydrochloride (106 mg), 5 N,N-diisopropylethylamine (201 mg) in NMP (1.0 ml) was heated at 1500C with stirring for 65 hours. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSOq. The solvent was removed under reduced 10 pressure. The residue was recrystallized from MeOH - IPE and dried in vacuo to give 5-[5-amino-6-(dimethylamino) 3-phenyl-2-pyrazinyl]-l-isopropyl-2(lH)-pyridone (8 mg). 1 H-NMR(DMSO-d 6 5) : 0.94 (6H, d, J=7.0 Hz), 2.83 (6H, s), 4.90 (1H, qq, J=7.0, 7.0 Hz), 6.16 (2H, brs), 6.34 (IH, d, 15 J=9.5 Hz), 7.20 (IH, d, J=2.5 Hz), 7.20-7.40 (5H, m), 7.54 (IH, dd, J=2.5, 9.5 Hz) MS(ESI+).: 350[M+H] 4 , 372[M+Na] Example 155 To a solution of pyrazole (106 mg) in NMP (1.0 ml), 20 was added 60% NaH (52 mg) under ice-bath cooling. After 5 minutes stirring, 5-(5-amino-6-bromo-3-phenyl 2-pyrazinyl)-1-isopropyl-2(IH)-pyridone (100 mg) was added to the mixture.. And then the mixture was heated at 1000C with stirring for 2 hours. After cooling, EtOAc and 25 water were poured into the mixture, and the organic layer 129 WO 2005/040151 PCT/JP2004/016193 was separated, washed with water and brine, and dried over MgSO 4 .The solvent was removed under reduced pressure, and the residue was recrystallized from MeOH and dried in vacuo to give 5-[5-amino-3-phenyl-6-(1H-pyrazol-l-yl) 5 2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (60 mg). 1 H-NMR(DMSO-d 6 5) : 0.98 (6H, d, J=6.8 Hz), 4.92 (1H, qq, J=6.8, 6.8 Hz), 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] 10 Example 156 5-[5-amino-3-phenyl-6-(IH-pyrrol-l-yl)-2-pyrazinyl] l-isopropyl-2 (lH)-pyridone The title compound was obtained in a similar manner to that of Preparation 155. 15 'H-NMR(DMSO-d 6 5) : 0.95 (6H, d, J=6.8 Hz), 4.90 (1H, qq, J=6.8, 6.8 Hz), 6.3-6.4 (3H, m), 6.49 (2H, brs), 7.28 (IH, d, J=2.4 Hz), 7.30-7.50 (7H, m), 7.53 (1H, dd, J=2.4, 9.4 Hz)

MS(ESI

+

) : 372[M+H]*, 394[M+Na] + 20 Example 157 To a suspension of 60% NaH (52 mg) in NMP (1.0 ml), was added thiophenol (143 mg) under ice-bath cooling. After 10 minute stirring, 5-(5-amino-6-bromo-3-phenyl 2-pyrazinyl)-l-isopropyl-2(iH)-pyridone (100 mg) was 25 added to the mixture at the same temperature. The mixture 130 WO 2005/040151 PCT/JP2004/016193 was stirred at the same temperature for 10 minutes and then allowed to warm to 250C. After 2 hours stirring, the mixture was heated at 100 0 C for 1 hour. After cooling, EtOAc and water were poured into the mixture, and the organic layer 5 was separated, washed with water and brine, and dried over MgSO 4 .The solvent was removed under reduced pressure. The residue was recrystallized from MeOH - IPE to give 5-[5-amino-3-phenyl-6-(phenylthio) -2-pyrazinyl] l-isopropyl-2(lH)-pyridone (93 mg). 10 'H-NMR(DMSO-d 6 5) : 0.93 (6H, d, J=6.8 Hz), 4.87 (1H, qq, J=6.8, 6.8 Hz), 6.18 (1H, d, J=9.4 Hz), 6.62 (2H, brs), 7.06 (1H, dd, J=2.4, 9.4 Hz), 7.17 (1H, d, J=2.4 Hz), 7.3-7.5 (8H, m), 7.5-7.6 (2H, m) MS(ESI ) : 415[M+H]

+

, 437[M+Na] 15 131

Claims

1. A pyrazine derivative shown by the following formula (I): R 1 N R 2 5 s - N R (I) R 5 N NR (T) I R 4 wherein R 6

10.R is orRO 10 R wherein R is hydrogen, or optionally substituted lower alkyl; R 7 is hydrogen or halogen; 15 R 8 is lower alkyl; R 2 is hydrogen; hydroxy; halogen; cyano; or lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, aryloxy, arylthio, acyl, aryl, heterocyclic group or amino, each of which is optionally substituted by 20 substituent(s); R 3 and R are independently hydrogen, lower alkyl oracyl; and R 5 is lower alkyl, lower alkenyl, lower alkynyl, cyano, aryl or heterocyclic group, each of which is 25 optionally substituted by substituent(s); 132 WO 2005/040151 PCT/JP2004/016193 or a salt thereof. 2. The compound of claim 1, wherein R 6 R is R R wherein R 6 is hydrogen, lower alkyl, aryl(lower)alkyl, heteroaryl(lower)alkyl; R 7 is hydrogen or halogen; 10 R 2 is hydrogen, halogen, cyano, optionally substituted lower alkyl, optionally substituted lower alkynyl, lower alkoxy, aryloxy, arylthio, carbamoyl, carboxy, protected carboxy or optionally substituted amino; 15 R 3 and R 4 are independently hydrogen or lower alkyl; and R s is aryl or heteroaryl each of which is optionally substituted by one or more substituent(s); or a salt thereof. 20 3. The compound of claim 2, wherein R is hydrogen, halogen, cyano, hydroxylated(lower)alkyl, lower alkynyl, lower alkoxy, aryloxy, arylthio, carboxy, esterified carboxy, carbamoyl, amidated carboxy, amino or 25 mono- or di-(lower)alkylamino; 133 WO 2005/040151 PCT/JP2004/016193 R 3 and R' are independently hydrogen; R 5 is aryl or heteroaryl, each of which is optionally substituted by one or more substituent(s) selected from the group consisting of halogen and lower 5 alkoxy; R 6 is hydrogen or lower alkyl; and R 7 is hydrogen; or a salt thereof. 4. The compound of claim 3, wherein 10 R is hydrogen, bromo, cyano, hydroxymethyl, hydroxyethyl, hydroxypropyl, ethynyl, methoxy, ethoxy, propoxy, phenyloxy, phenylthio, carboxy, carbamoyl, mono- or di-methylaminocarbonyl, pyridylmethylaminocarbonyl, 15 hydroxymethylaminocarbonyl or mono- or di-methylamino; R 3 and R 4 are independently hydrogen; R 5 is phenyl, pyridyl, furyl, thienyl, pyrrolyl or pyrazolyl, each of which is optionally substituted 20 by one or more substituent(s) selected from the group consisting of fluoro, chloro and methoxy; R 6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl ; and R 7 is hydrogen; 25 or a salt thereof. 134 WO 2005/040151 PCT/JP2004/016193 5. The compound of claim 4, wherein R 2 is hydrogen, cyano, ethynyl, methoxy, phenyloxy, phenylthio, carboxy, carbamoyl or methylamino; and 5 R 5 is phenyl, furyl or thienyl, each of which is optionally substituted by one or more substituent(s) selected from the group consisting of fluoro, chloro and methoxy; or a salt thereof. 10 6. The compound of claim 5, wherein R 2 is hydrogen, cyano, carboxy, carbamoyl or methylamino; R 5 is phenyl which is optionally substituted by one or more fluoro; and 15 R 6 is hydrogen, methyl, ethyl or isopropyl; or a salt thereof. 7. A process for preparing the pyrazine compound of the following formula (I): R IN R 2 20 R 5 N NR (I) 1~ 4 R wherein R , R', R , R and Rs are each as defined in claim 1, or a salt thereof; which comprises 25 (1) reacting of a compound of the formula (II): 135 WO 2005/040151 PCT/JP2004/016193 RN R 2 Hal N N R (I I) 1 2 3 wherein R , R 2 , R and R 4 are each as defined above, and 5 Hal is a halogen atom; or a salt thereof, with a compound of the formula (III) : R 5 -Z (III) wherein 10 R is as defined above, and Z is hydrogen, an alkali metal (e.g. lithium, sodium, potassium, etc.), SnBu 3 , BW 2 or Met-Hal; wherein BW 2 is a part of organoboron compound such as B(OH) 2 , B(CHCH 3 CH(CH 3 ) 2 ) 2 , 15 tetramethyl-l,3,2-dioxaborolan-2-yl, 9-borabicyclo[3.3.1]nonanyl, or the like; and Met-Hal is a part of metalhalide compound such as MgBr, ZnCl, or the like; 20 or a salt thereof, to give a compound of the formula (I): R . N R 2 R 5 N N R (I) 25 wherein R , R , R , R and R 5 are each as defined above, 136 WO 2005/040151 PCT/JP2004/016193 or a salt thereof, (2) hydrolyzing of a compound of the formula (Ia) R 8 0 ",-N N CN "N R 3 (Ta) R N N, 5. wherein R 3 , R 4 and R 5 are each as defined above, and R 8 is as defined in claim 1, or a salt thereof, to give a compound of the formula (Iba): H o N 10 N R' (Iba) P3 .R 5 N N' wherein R , R and R 5 are each as defined above, and R 9 is cyano, carbamoyl or carboxy; or a salt thereof, 15 (3) alkylating to a nitrogen atom of a compound of the formula (Ib): H O N N R 2 (Ib) R ,,, N ] .R 3 R 5 N NR R 4 20 wherein R 2 , R , R and R are each as defined above, or a salt thereof, with a compound of the formula (IV): R 0 -Y (IV) wherein R1 0 is lower alkyl, aryl(lower)alkyl or 25 heteroaryl(lower)alkyl, each of which is 137 WO 2005/040151 PCT/JP2004/016193 optionally substituted by one or more suitable substituent(s), and Y is a leaving group; or a salt thereof, 5 to give a compound of the formula (Ic): R 10 io O N 0 R ' (Ic) N R4 10 wherein R 2 , R 3 , , R 5 R and R1o are each as defined above,or a salt thereof, (4) hydrolyzing of a compound of the formula (Id): NH 2 RO N R 3 (Id) R N N 15 R wherein R 1 , R , R 4 and R 5 are each as defined above, or a salt thereof, to give a compound of the formula (le): OH 20 13 (le) R 5 N) N O RR wherein R 1 , R , R and R 5 are each as defined above,or a salt thereof, (5) decarboxylating of a compound (Ie) or a salt thereof 25 above to give a compound of the formula (If): 138 WO 2005/040151 PCT/JP2004/016193 P3 R2 N RS N NR (If) wherein RP', R 3 , R 4 and R 5 are each as defined above,or a 5 salt thereof, (6) halogenating of a compound (If) or a salt thereof above to give a compound of the formula (Ih): R 1 N Hal R 1N N R (Ih) R N N 10 wherein RP 1 , R 3 , R 4 , R 5 and Hal are each as defined above,or a salt thereof, (7) reacting of a compound (Ih) or a salt thereof above with a compound of the formula (V): 15 R13-Z (V) wherein Z is defined above, and R 13 is lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, aryloxy, arylthio, acyl, aryl, heterocyclic group or amino, each of which is 20 optionally substituted by substituent(s); or a salt thereof, to give a compound of the formula (Ij): R 1 N R13 I5" -X N R 3 (lj) R N NR 25 4 139 WO 2005/040151 PCT/JP2004/016193 wherein R, R, , R R 5 and R are each as defined above, or a salt thereof, (8) reacting of a compound of the formula (XI): R1 1OH 5 0 (Xl) wherein R I is as defined above, or a salt thereof, with aminomalonitrile, to give a compound of the formula (XII): 1 RN R 10 (XII) N NHq O 0 wherein R' and R2 are each as defined above, or a salt thereof, (9) halogenating of a compound of the formula (XV): 15 R I N R 2 ""N' N' R (XV) O wherein R', R 2 , R 3 and R 4 are each as defined above, or a salt thereof, 20 with a compound of the formula (XVI): PO(Hal) 3 (XVI) wherein Hal is as defined above, to give a compound (II) or a salt thereof above. 8. A pharmaceutical composition comprising the compound 25 of claim 1 or a pharmaceutically acceptable salt thereof 140 WO 2005/040151 PCT/JP2004/016193 in admixture with a pharmaceutically acceptable carrier. 9. Amethod for preventing or treating a disease selected from the group consisting of depression, dementia, Parkinson's disease, anxiety, pain, cerebrovascular 5 disease, heart failure, hypertension, circulatory insufficiency, post-resuscitation, asystole, bradyarrhythmia, electro-mechanical dissociation, hemodynamic collapse, SIRS (systemic inflammatory response syndrome), multiple organ failure, renal 10 failure (renal insufficiency), renal toxicity, nephrosis, nephritis, edema, obesity, bronchial asthma, gout, hyperuricemia, sudden infant death syndrome, immunosuppression, diabetes, ulcer, pancreatitis, Meniere's syndrome, anemia, dialysis-induced 15 hypotension, constipation, ischemic bowel disease, ileus, myocardial infarction, thrombosis, obstruction, arteriosclerosis obliterans, thrombophlebitis, cerebral infarction, transient ischemic attack and angina pectoris, which comprises administering the 20 compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal. 10. Amethod for preventing or treating a disease selected from the group consisting of depression, dementia, Parkinson's disease, anxiety, pain, cerebrovascular 25 disease, Meniere's syndrome and cerebral infarction, 141 WO 2005/040151 PCT/JP2004/016193 which comprises administering any of the compound of claim 1 to 7 or a pharmaceutically acceptable salt thereof to a human being or an animal.

11. Amethod for preventing or treating a disease selected 5 from the group consisting of depression, dementia, Parkinson's disease and anxiety, which comprises administering any of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal 10 12. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof as a medicament.

13. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof as an adenosine antagonist.

14. Use of the compound of claim 1 or a pharmaceutically 15 acceptable salt thereof as an A, receptor and A 2 receptor dual antagonist.

15. A process for preparing a pharmaceutical composition which comprises admixing the compound of claim 1 or a pharmaceutically acceptable salt thereof with a 20 pharmaceutically acceptable carrier.

16. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical composition for the therapy of diseases on which an adenosine antagonist is therapeutically 25 effective. 142 WO 2005/040151 PCT/JP2004/016193

17. A method for evaluation of adenosine antagonism which comprises use of compound of claim 1 or a I pharmaceutically acceptable salt thereof. 143