JP2006232849A - Nitrogenous fused-ring compound and use thereof as hiv integrase inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new nitrogen-containing fused-ring compound usable as an anti-HIV agent or a pharmaceutically acceptable salt. <P>SOLUTION: The nitrogen-containing fused-ring compound represented by general formula [I], or the pharmaceutically acceptable salt thereof, and the anti-HIV agent containing such compound are provided. 2-(3,4-Dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride is cited as a concrete example. The compound has an HIV integrase inhibitory activity, and is useful as an agent for the prophylaxis or treatment of AIDS, or as an anti-HIV agent. In addition, by the combined use with other anti-HIV agents such as a protease inhibitor, a reverse transcriptase inhibitor and the like, it can be a more effective anti-HIV agent. Because it shows integrase-specific high inhibitory activity, the compound can be a pharmaceutical agent safe on human body, which causes only a fewer side effects. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a novel nitrogen-containing fused ring compound useful as an anti-HIV agent or a pharmaceutically acceptable salt thereof. The present invention also relates to a novel use of certain nitrogen-containing fused ring compounds or pharmaceutically acceptable salts thereof as anti-HIV agents. More particularly, the present invention relates to an anti-HIV agent containing a nitrogen-containing fused ring compound or an pharmaceutically acceptable salt thereof that exhibits an anti-HIV action due to an integrase inhibitory activity.

  HIV (Human Immunodeficiency Virus (type 1): human immunodeficiency virus) belonging to a retrovirus is a causative virus of AIDS (Acquired Immunodeficiency Syndrome).

  HIV targets a group of CD4 positive cells such as helper T cells, macrophages, and dendritic cells, destroys these immunocompetent cells, and causes immunodeficiency.

  Therefore, for the treatment or prevention of AIDS, a drug that eradicates HIV in vivo or suppresses its growth is effective.

  HIV has two RNA genes in the shell, and the shell is covered with a coat protein. RNA encodes a plurality of virus-specific enzymes (protease, reverse transcriptase, integrase, etc.), etc. There are translated reverse transcriptase and integrase in the nucleus, and protease inside and outside the nucleus.

  HIV contacts and invades the host cell, then undergoes shelling and releases a complex such as RNA and integrase into the cytoplasm. From this RNA, DNA is transcribed by reverse transcriptase to produce full-length double-stranded DNA. The DNA moves into the host cell nucleus and is incorporated into the host cell DNA by integrase. The incorporated DNA is converted into mRNA by the host cell polymerase, and various proteins necessary for virus formation are synthesized from the mRNA by HIV protease and the like, and finally virus particles are formed, budding and releasing.

  These virus-specific enzymes are essential for the growth of HIV, attracting attention as a target for the development of antiviral agents, and several anti-HIV agents have already been developed.

  For example, zidovudine, didanosine, lamivudine and the like are already commercially available as reverse transcriptase inhibitors, and indinavir, nelfinavir and the like are already commercially available as protease inhibitors.

  In addition, multi-drug combination therapy using these drugs is also used, for example, a combination of two reverse transcriptase inhibitors (zidovudine and didanosine), reverse transcriptase inhibitor (zidovudine and lamivudine) and protease inhibitor (nelfinavir) These three-drug combinations have become the mainstream of AIDS treatment (Folia Pharmacologica Japonica, 118, 131-134, 2001).

  However, some of these drugs have known side effects such as liver dysfunction and central nervous system disorders such as dizziness, and acquisition of resistance to the drug is also a problem. In addition, the emergence of HIV showing multidrug resistance to multidrug combination therapy is also known.

  Under such circumstances, the development of further new drugs, particularly the development of anti-HIV drugs by a new mechanism, is desired, and the integrase characteristic of retroviruses is an enzyme essential for the growth of HIV. Development of anti-HIV agents having integrase inhibitory activity is expected.

  However, no effective integrase inhibitor has yet been found.

  Next, known compounds that are relatively similar to the anti-HIV agent of the present invention will be described.

  WO 01/96283 describes the following compound [A] and the like as an anti-HIV agent having integrase inhibitory activity (see WO 01/96283, page 176, compound 70).

  WO 03/016266 describes the following compound [B] and the like as an anti-HIV agent having integrase inhibitory activity (see WO 03/016266, page 159, Example No. 3-17).

  WO01 / 95905 describes the following compound [C] and the like as an anti-HIV agent having integrase inhibitory activity (see WO01 / 95905, page 109, Example E-2).

  In addition, WO03 / 047564 describes the following compound [D] and the like as an anti-HIV agent having integrase inhibitory activity (see WO03 / 047564, page 73, Example 11).

  In addition, WO02 / 30930 and WO02 / 55079 describe the following compounds [E], [F] and the like as anti-HIV agents having integrase inhibitory activity (WO02 / 30930, page 171, respectively). Example 1; see WO02 / 55079, page 79, Example 1). Similar compounds are also disclosed in WO 02/30426, WO 02/30931 and WO 02/36734.

  WO03 / 031413 describes the following compound [G] and the like as an anti-HIV agent having integrase inhibitory activity (see WO03 / 031413, page 21, compound 8).

  WO03 / 035076 and WO03 / 035077 describe the following compounds [H], [i] and the like as anti-HIV agents having integrase inhibitory activity (WO03 / 035076, page 188, respectively). Example 1; WO 03/035077, page 146, Example 22).

  However, these publications do not disclose the nitrogen-containing fused ring compound included in the present invention, and there is no description suggesting it.

  WO 2004/24078 describes the following compound [J] and the like as an anti-HIV agent having integrase inhibitory activity.

In this publication, the following formula is described as the general formula (I) of claim 1 and tautomers thereof. However, the compound described in the publication clearly shows the present invention in that a hydroxyl group or an oxo group is essential at the position corresponding to R ^y1 of Y ² in the general formula [I] of the nitrogen-containing fused ring compound of the present invention. It is different from the compound. Further, the publication does not suggest any compound having no hydroxyl group or oxo group at the position.

  Further, from page 46 to page 113 of the publication, disclosure of a method for producing the compound of the general formula (I) can be seen, but depending on the specific production method disclosed herein, it is included in the present invention. A nitrogen-fused ring compound cannot be produced, and no specific method for producing the compound is mentioned.

  From the findings obtained from previous studies and clinical results, anti-HIV agents are effective in preventing and treating AIDS, and in particular, compounds having an integrase inhibitory action can be effective anti-HIV agents.

  Therefore, an object of the present invention is to provide a drug having an anti-HIV action, particularly a drug having an integrase inhibitory action.

  As a result of intensive studies to find a compound having an anti-HIV action, particularly an integrase inhibitory action, the present inventors have completed the present invention.

  More specifically, it is as shown in the following [1] to [38].

[1] A nitrogen-containing fused ring compound represented by the following general formula [I] or a pharmaceutically acceptable salt thereof.

[Where:
R ¹ is
(1) a C1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the following group A;
(2) a C2-6 alkenyl group which may be substituted with 1 to 3 substituents selected from group A below, or
(3) Formula

(Where Z is
(1 ') join,
(2 ') C1-6 alkylene,
(3 ') C2-6 alkenylene, or
(4 ') * - (CH 2) m -Q- (CH 2) n -
{Where Q is
(1 '')-O-,
(2 '')-NR ^5-
(Wherein R ⁵ is a hydrogen atom or a C 1-6 alkyl group),
(3``) -CO-,
(4``) -SO-,
_{(5 '') - SO 2} -, or,
(6 '') **-CO-NR ^6-
(Wherein R ⁶ is a hydrogen atom or a C 1-6 alkyl group, and ** represents the side bonded to (CH ₂ ) _m ),
m represents 0 or an integer of 1 to 4;
n represents 0 or an integer of 1 to 4,
* Indicates the side bonded to the nitrogen atom of ring A. },
Ring D is
(1 ′) a C3-10 carbocyclic group which may be substituted with 1 to 3 substituents selected from the following group B, or
(2 ′) a heterocyclic group which may be substituted with 1 to 3 substituents selected from the following group B (wherein the heterocyclic group is at least one selected from a nitrogen atom, an oxygen atom and a sulfur atom) Contains heteroatoms). )
X is
(1) -C (R ^x1 ) (R ^x2 )-#,
(2) -C (R ^x1 ) (R ^x2 ) -C (R ^x3 ) (R ^x4 )-#,
(3) -C (R ^x1 ) (R ^x2 ) -C (R ^x3 ) (R ^x4 ) -C (R ^x5 ) (R ^x6 )-#,
(4) -C (R ^x7 ) = C (R ^x8 )-#,
(5) -C (R ^x1 ) (R ^x2 ) -C (R ^x7 ) = C (R ^x8 )-#,
(6) -C (R ^x7 ) = C (R ^x8 ) -C (R ^x1 ) (R ^x2 )-#,
(7) -N = C (R ^x9 )-#, or
(8) −C (R ^{× 10} ) = N− #
(Wherein # represents the side of ring B bonded to Y ¹ , R ^x1 to R ^x10 are each independently selected from the following group C, R ^x1 and R ^x2 , R ^x3 and R ^x4 , R ^x5 and ^Rx6 may each independently form a C3-8 cycloalkyl together with adjacent carbon atoms.)
Of ring B

Is
(1) C = C (R ^y1 ) −N (R ^y2 ),
(2) N-C (R ^y1 ) = N,
(3) N-C (R ^y1 ) = C (R ^y2 ),
(4) C = N-N (R ^y2 ), or
(5) N-N = C (R ^y3 )
(Where R ^y1 to R ^y3 are each independently selected from the following group C):

Is N-C (R ^y1 ) = C (R ^y2 ), ring B is condensed with the benzene ring

(In the formula, R ⁴ is selected from the following group C).
R ² is
(1) hydrogen atom,
(2) C1-6 alkyl group,
(3) C6-14 aryl C1-6 alkyl group, or
(4) -SO ₂ R ^d1
Here, R ^d1 is a hydrogen atom, a C 1-7 alkyl group which may be substituted with 1 to 3 substituents selected from the following group A, or a C 6-14 aryl group.
Group A:
(1) a halogen atom,
(2) a cyano group,
(3) -OR ^a1 ,
(4) -SR ^a1 ,
(5) -CO ₂ R ^a1 ,
(6) -CONR ^a2 R ^a3 ,
(7) -COR ^a4 ,
_{^{(8) -SO 2 NR a2 R}} a3,
(9) -SO ₂ R ^a4 ,
(10) C6-14 aryloxy group,
(11) C6-14 aryl C1-6 alkyloxycarbonyl group,
(12) a C1-6 alkylcarbonyloxy group which may be substituted with a halogen atom,
(13) 1 to 3 substitutions selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C1-6 alkylsulfonyl group, a di (C1-6 alkyl) amino group, and a C1-6 alkylcarbonylamino group A C6-14 aryl group optionally substituted with a group, and
(14) A heterocyclic group which may be substituted with a C1-6 alkyloxy group.
Here, R ^a1 , R ^a2 , R ^a3 and R ^a4 are each independently a hydrogen atom or a C 1-6 alkyl group.

Group B:
(1) a halogen atom,
(2) a cyano group,
(3) C1-6 alkyl group,
(4) a halo C1-6 alkyl group,
(5) -OR ^b1 ,
(6) -SR ^b1 ,
₍₇₎ -CO ^{2 R b1,}
(8) -CONR ^b2 R ^b3 ,
(9) -COR ^b4 ,
(10) -SO ₂ NR ^b2 R ^b3 ,
(11) -SO ₂ R ^b4 ,
(12) C6-14 aryloxy group,
(13) C6-14 aryl C1-6 alkyloxycarbonyl group,
(14) a C6-14 aryl C1-6 alkyloxy group, and
(15) -NR ^b5 COR ^b6 .
Here, R ^b1 , R ^b2 , R ^b3 , R ^b4 , R ^b5 and R ^b6 are each independently a hydrogen atom or a C 1-6 alkyl group.

Group C:
(1) hydrogen atom,
(2) C3-8 cycloalkyl C1-6 alkyl group,
(3) a cyano group,
(4) a halogen atom,
(5) C1-7 alkyl group,
(6) C2-6 alkenyl group,
(7) C2-6 alkynyl group,
(8) C6-14 aryl group,
(9) Heterocyclic group (wherein the heterocyclic group is a saturated or unsaturated monocyclic 5-membered or 6-membered heterocycle containing at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom) Or a condensed ring of these heterocyclic rings, or a condensed ring of a carbocyclic ring selected from benzene, cyclopentane or cyclohexane and the heterocyclic ring).
(10) C1-6 alkyloxy group,
(11) C6-14 aryl C1-6 alkyl group,
(12) C6-14 aryl C1-6 alkyloxy group,
(13) -CO ₂ R ^c1 ,
(14) -CONR ^c2 R ^c3 ,
(15) -COR ^c4 ,
(16) -SO ₂ NR ^c2 R ^c3 ,
(17) C6-14 arylcarbonyl group,
(18) -NR ^c4 R ^c5 ,
(19) -NR ^c6 COR ^c7 ,
(20) -NR ^c8 SO ₂ R ^c9 ,
(21) -SR ^c10 ,
(22) -SOR ^c11 ,
(23) -SO ₂ R ^c12 ,
(24) -NR ^c13 CONR ^c14 R ^c15 ,
(25) -NR ^c16 CO ₂ R ^c17 , and
(26) -NR ^c18 COCOR ^c19 .
^{Here, R c1, R c2, R} c3, R c4, R c5, R c6, R c7, R c8, R c9, R c10, R c11, R c12, R c13, R c14, R c15, R c16 , R ^c17 , R ^c18 and R ^c19 are each independently
(1 ') hydrogen atom,
(2 ′) a C 1-7 alkyl group which may be substituted with 1 to 3 substituents selected from Group A above;
(3 ′) a C6-14 aryl group which may be substituted with 1 to 3 substituents selected from Group B above,
(4 ′) a heterocyclic group which may be substituted with 1 to 3 substituents selected from Group B, or
(5 ') a C3-8 cycloalkyl group,
R ^c2 and R ^c3 may be combined with an adjacent nitrogen atom to form a nitrogen-containing heterocycle, and the nitrogen-containing heterocycle is substituted with 1 to 3 substituents selected from Group B above. Also good.
The C1-7 alkyl group, C1-6 alkyl moiety, C2-6 alkenyl group, and C2-6 alkynyl group of Group C are substituted with 1 to 3 substituents selected from Group A or a heterocyclic group. You can,
The C6-14 aryl group, the C6-14 aryl moiety and the heterocyclic group of the group C may be substituted with 1 to 3 substituents selected from the group B. ]

[2] of ring B

Is C = C (R ^y1 ) —N (R ^y2 ), N—C (R ^y1 ) = N, N—C (R ^y1 ) = C (R ^y2 ), or C = N—N (R ^y2). (Wherein each symbol is as described in [1].) The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to [1].
[3] The nitrogen-containing fused ring compound according to [2] represented by the following general formula [I] -1 or a pharmaceutically acceptable salt thereof.

(In the formula, each symbol is as described in [1].)
[4] The nitrogen-containing fused ring compound of [2] represented by the following general formula [I] -2 or a pharmaceutically acceptable salt thereof.

(In the formula, each symbol is as described in [1].)
[5] The nitrogen-containing fused ring compound according to [2] represented by the following general formula [I] -3 or a pharmaceutically acceptable salt thereof.

(In the formula, each symbol is as described in [1].)
[6] The nitrogen-containing fused ring compound of [2] represented by the following general formula [I] -4 or a pharmaceutically acceptable salt thereof.

(In the formula, each symbol is as described in [1].)
[7] X ^{is, -C (R x1) (R} x2) -C (R x3) (R x4) - #, - C (R x1) (R x2) -C (R x3) (R x4) - C ( ^Rx5 ) ( ^Rx6 )-#, -C ( ^Rx7 ) = C ( ^Rx8 )-#, -N = C ( ^Rx9 )-#, or -C ( ^Rx10 ) = N- # (Here, each symbol is as described in [1].) The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [6].
[8] X is -C ( ^Rx1 ) ( ^Rx2 ) -C ( ^Rx3 ) ( ^Rx4 )-# or -C ( ^Rx7 ) = C ( ^Rx8 )-# (where each The symbol is as described in [1].) The nitrogen-containing fused ring compound according to [7] or a pharmaceutically acceptable salt thereof.
[9] As described in [8], X is —C (R ^x1 ) (R ^x2 ) —C (R ^x3 ) (R ^x4 ) — # (where each symbol is as described in [1]). A nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof.
[10] The nitrogen-containing fused ring compound or pharmaceutical according to [8], wherein X is -C (R ^x7 ) = C (R ^x8 )-# (wherein each symbol is as described in [1]). Its acceptable salt.
[11] R ¹ is a formula

(Where, Z is, C1-6 alkylene, _{or, * - (CH 2) m} -Q- (CH 2) n - and is, and other symbols are as [1], wherein.) The group represented by The nitrogen-containing fused ring compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.
[12] The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to [11], wherein Z is C1-6 alkylene.
[13] The nitrogen-containing fused ring compound according to [11], wherein Ring D is a C3-10 carbocyclic group which may be substituted with 1 to 3 substituents selected from Group B, or a pharmaceutically acceptable product thereof salt.
[14] R ^{x1 to} R ^x10 are independently selected from the following groups, and R ^x1 and R ^x2 , R ^x3 and R ^x4 , R ^x5 and R ^x6 are each independently selected from adjacent carbon atoms The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [6], which may form C3-8 cycloalkyl together.
Hydrogen atom,
C3-8 cycloalkyl C1-6 alkyl group,
A cyano group,
C1-7 alkyl group,
C6-14 aryl group,
C6-14 aryl C1-6 alkyl group,
-CO ₂ R ^c1,
-CONR ^c2 R ^c3 , and
-COR ^c4
(Wherein the C1-7 alkyl group and the C1-6 alkyl moiety may be substituted with 1 to 3 substituents selected from group A or heterocyclic groups, and other symbols are described in [1]. Street.)
[15] The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to [14], wherein R ^{x1 to} R ^x10 are hydrogen atoms.
[16] The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [6], wherein R ^y1 is selected from the following group.
Hydrogen atom,
C1-7 alkyl group,
C6-14 aryl group,
-CO ₂ R ^c1,
-CONR ^c2 R ^c3 ,
-COR ^c4 and
C6-14 arylcarbonyl group (wherein the C1-7 alkyl group may be substituted with 1 to 3 substituents selected from group A, or a heterocyclic group; It may be substituted with 1 to 3 substituents selected from Group B, and other symbols are as described in [1].)
[17] The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to [16], wherein R ^y1 is a hydrogen atom.
[18] The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [6], wherein R ^y2 is selected from the following group.
Hydrogen atom,
A halogen atom,
C1-7 alkyl group C6-14 aryl group,
A heterocyclic group,
-CO ₂ R ^c1,
-CONR ^c2 R ^c3 ,
-COR ^c4 ,
-NR ^c4 R ^c5 ,
-NR ^c6 COR ^c7 ,
-NR ^c8 SO ₂ R ^c9 ,
-SR ^c10 ,
-SO ₂ R ^c12,
-NR ^c13 CONR ^c14 R ^c15 ,
-NR ^c16 CO ₂ R ^c17 and,
-NR ^c18 COCOR ^c19
(Wherein the C1-7 alkyl group may be substituted with 1 to 3 substituents selected from group A, or a heterocyclic group; the C6-14 aryl group and heterocyclic group may be substituted with group B; And may be substituted with 1 to 3 substituents selected from the above, and other symbols are as described in [1].)
[19] The nitrogen-containing condensation according to [18], wherein R ^y2 is a heterocyclic group (wherein the heterocyclic group may be substituted with 1 to 3 substituents selected from group B). A ring compound or a pharmaceutically acceptable salt thereof.
[20] R ^y2 is a heterocyclic group bonded to Y ^{3 by} a carbon atom, and in the heterocyclic group, at least one of the α-positions of the carbon atom is from a nitrogen atom, an oxygen atom, and a sulfur atom. A nitrogen-containing fused ring compound according to [19], wherein the heterocyclic group may be substituted with 1 to 3 substituents selected from Group B, or a pharmaceutically acceptable group. Its salt.
[21] The nitrogen-containing condensation according to [18], wherein R ^y2 is selected from —CO ₂ R ^c1 , —CONR ^c2 R ^c3 , and —COR ^c4 (wherein each symbol is as described in [1]). A ring compound or a pharmaceutically acceptable salt thereof.
[22] R ^y2 is —NR ^c4 R ^c5 , —NR ^c6 COR ^c7 , —NR ^c8 SO ₂ R ^c9 , —NR ^c13 CONR ^c14 R ^c15 , —NR ^c16 CO ₂ R ^c17 , and —NR ^c18 COCOR ^c19 (Here, each symbol is as described in [1].) The nitrogen-containing fused ring compound according to [18] or a pharmaceutically acceptable salt thereof.
[23] R ^y2 is —NR ^c6 COR ^c7 , —NR ^c8 SO ₂ R ^c9 , —NR ^c13 CONR ^c14 R ^c15 , —NR ^c16 CO ₂ R ^c17 , and —NR ^c18 COCOR ^c19 (where each symbol Is as described in [1].) The nitrogen-containing fused ring compound according to [22] or a pharmaceutically acceptable salt thereof.
[24] The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [6], wherein R ² is a hydrogen atom.

[25] 2- (3,4-Dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 1),
2- (3,4-Dichlorobenzyl) -10-hydroxy-2,3,4,5-tetrahydropyrido [1,2-a] [1,4] diazepine-1,9-dione (Example 2) ,
2- (3,4-dichlorobenzyl) -9-hydroxy-3-methyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 3),
2- (3,4-dichlorobenzyl) -9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 4),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-hydroxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 5),
2- (3,4-Dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carboxylic acid (Examples) 6),
2- (3,4-Dichlorobenzyl) -6- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione ( Example 7),
2- (3,4-dichlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 8),
2- (3,4-dichlorobenzyl) -9-hydroxy-3-methyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 9),
2- (3-Chlorobenzyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 10),
2- [3- (2,6-dichlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 11),
2- (3,4-dichlorobenzyl) -9-hydroxy-2H-pyrazino [1,2-c] pyrimidine-1,8-dione hydrochloride (Example 12),
2- (3,4-dichlorobenzyl) -9-hydroxy-4-methyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 13),
4-benzyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 14),
2- (3,4-dichlorobenzyl) -9-hydroxy-4-phenyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 15),
4-butyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 16),
2- (3,4-dichlorobenzyl) -9-hydroxy-4-isopropyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 17),
2- (3,4-dichlorobenzyl) -9-hydroxy-3,3-dimethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 18),
2- (3,4-Dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-4-spiro-1′-cyclopentane-1,8-dione Example 19),
2- (3,4-Dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-4-spiro-1′-cyclohexane-1,8-dione (Examples) 20),

2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-4-carboxylic acid methyl ester ( Example 21),
2- (3,4-Dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-4-carboxylic acid (Examples) 22),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-methoxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 23),
N, N-dimethyl-2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6 Carboxamide (Example 24),
3-benzyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 25),
3-butyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 26),
N, N-dimethyl-2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-4 Carboxamide (Example 27),
2- (3,4-dichlorobenzyl) -9-hydroxy-4-hydroxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 28),
2- (3,4-dichlorobenzyl) -9-hydroxy-4-methoxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 29),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-methylsulfanylmethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 30),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-methanesulfonylmethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 31),
2- (3,4-Dichlorobenzyl) -9-hydroxy-4- (2-methanesulfonylethyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Example 32),
2- (3,4-Dichlorobenzyl) -9-hydroxy-4- (2-methylsulfanylethyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Example 33),
2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carboxylic acid methyl ester ( Example 34),
6-acetyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 35),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isopropylsulfanylmethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 36),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isopropylsulfonylmethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 37),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isopropoxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 38),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isobutoxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 39),
2- (3,4-Dichlorobenzyl) -9-hydroxy-6- (1-hydroxyethyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Examples) 40),

2- (3,4-dichlorobenzyl) -9-hydroxy-6-phenoxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 41),
2- (4-fluorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 42),
2- (3-chlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 43),
2-Benzyl-9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 44),
2- (4-chlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 45),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isopropyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 46),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isobutyryl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 47),
2- (3,4-Dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carbaldehyde (Examples) 48),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-phenyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 49),
9-hydroxy-2- (3-phenylpropyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 50),
2- (3-chloro-2-fluorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 51),
9-hydroxy-2-phenethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 52),
2- (3,4-Dichlorobenzyl) -9-hydroxy-6- (1-hydroxy-2-methylpropyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione (Example 53),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isobutyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 54),
2- (3,4-Dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carboxamide (Example 55) ),
N-methyl-2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carboxamide (Example 56),
2- (4-chloro-3-fluorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 57),
6-benzoyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 58),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-propionyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 59),
2- (3,4-dichlorobenzyl) -9-hydroxy-6-methyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 60),

N, N-diethyl-2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6 Carboxamide (Example 61),
N-isopropyl-N-methyl-2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -6-carboxamide (Example 62),
N-ethyl-N-methyl-2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -6-carboxamide (Example 63),
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 64),
2- (2-chlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 65),
2- (3,5-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 66),
6-tert-butyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 67),
2- (3,4-dichlorobenzyl) -9-hydroxy-6- (1-hydroxy-2,2-dimethylpropyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1, 8-dione (Example 68),
3-benzyl-9-hydroxy-2-methyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 69),
2- [3- (4-chlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 70),
2- [3- (2-chlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 71),
2- (3,4-dichlorobenzyl) -9-hydroxy-4-methyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 72),
2- (3-Chloro-4-methoxybenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 73),
9-hydroxy-2-methyl-3-phenethyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 74),
[2- (3,4-Dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazin-6-yl] acetonitrile ( Example 75),
2- [3- (3-chlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 76),
9-hydroxy-2-methyl-3- (3-phenylpropyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 77),
2- (3,4-dichlorobenzyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 78),
2- [3- (3,4-dichlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 79),
2- [3- (3,5-dichlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 80),

[2- (3,4-Dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazin-6-yl] acetic acid benzyl Ester (Example 81),
2- [2- (3,4-Dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazin-6-yl] -3-phenylpropionic acid benzyl ester (Example 82),
2- (3,4-Dichlorobenzyl) -9-hydroxy-6- (2-hydroxyethyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Examples) 83),
2- (3,4-dichlorobenzyl) -9-hydroxy-4-propyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 84),
2- (3,4-dichlorobenzyl) -4-ethyl-9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 85),
2- (3,4-dichlorobenzyl) -9-hydroxy-4-hydroxymethyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 86),
2- (3,4-dichlorobenzyl) -9-hydroxy-4-isobutyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 87),
2- (3-Chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 88),
2- (3,4-Dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-4-carboxylic acid methyl ester (Example 89) ,
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 90),
2- [3- (2,3-dichlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 91),
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 92),
2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-4-carboxylic acid methyl ester (Example 93),
7-bromo-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 94),
2- [3- (2-chloro-6-fluorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 95),
2- (3-Chlorobenzyl) -9-hydroxy-7-phenyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 96),
N, N-dimethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-4-carboxamide (Example 97) ),
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-4-carboxylic acid (Example 98),
3- (3-chlorobenzyl) -5-hydroxy-3H-pyrazino [1,2-a] quinoline-4,6-dione hydrochloride (Example 99),
2- (3-chlorobenzyl) -9-hydroxy-2H-pyrazino [1,2-c] pyrimidine-1,8-dione hydrochloride (Example 100),

2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-4-carbaldehyde (Example 101),
2- (3-Chlorobenzyl) -9-hydroxy-4-hydroxymethyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 102),
2- (3-chlorobenzyl) -9-hydroxy-4- (1-hydroxyethyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 103),
2- (3-Chlorobenzyl) -9-hydroxy-7-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 104),
4-acetyl-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 105),
2- (3-chlorobenzyl) -8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (Example 106),
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-4-carbonitrile (Example 107),
2- (3-chlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrazino [1,2-c] pyrimidine-1,8-dione (Example 108),
Methanesulfonic acid 7-bromo-2- (3-chlorobenzyl) -1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-9-yl ester (Example 109),
7-bromo-2- (3-chlorobenzyl) -3,9-dihydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 110),
3- (3-chlorobenzyl) -5-hydroxy-2,3-dihydro-1H-pyrazino [1,2-a] quinoline-4,6-dione (Example 111),
2- (3-chlorobenzyl) -7- (3-chlorophenyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 112),
2- (3-chlorobenzyl) -7- (4-chlorophenyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 113),
2- (3-Chlorobenzyl) -7- (2-chlorophenyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 114),
2- (3-chlorobenzyl) -9-hydroxy-7- (pyridin-3-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 115),
2- (3-Chlorobenzyl) -9-hydroxy-7- (pyridin-4-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 116),
2- (3-chlorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 117),
2- (3-Chlorobenzyl) -9-hydroxy-7- (1-hydroxy-2,2-dimethylpropyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Examples) 118),
2- (3-chlorobenzyl) -4-cyclohexylmethyl-9-hydroxy-7-phenyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 119),
2- (3-chlorobenzyl) -7- (furan-2-yl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 120),

2- (3,4-dichlorobenzyl) -8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (Example 121),
2- [3- (2-Chloro-6-fluorophenyl) propyl] -8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (Examples) 122),
6- (3-chlorobenzyl) -4-hydroxy-2-methyl-2,6,7,8-tetrahydropyrido [4,3-c] pyridazine-3,5-dione (Example 123),
7- (Benzofuran-2-yl) -2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 124),
2- (3-chlorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 125),
2- (3-Chlorobenzyl) -7- (2,2-dimethylpropyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 126),
2- (3-Chlorobenzyl) -9-hydroxy-7- (2-trifluoromethylphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 127),
2- (3-chlorobenzyl) -9-hydroxy-7- (3-methoxyphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 128),
7-bromo-2- (3-chlorobenzyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 129),
2- (3-chlorobenzyl) -7- (2-fluorophenyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 130),
2- (3-Chlorobenzyl) -9-hydroxy-4-isopropyl-7-phenyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 131),
2- (3-Chlorobenzyl) -9-hydroxy-7- (2-methoxyphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 132),
2- (3-Chlorobenzyl) -9-hydroxy-7- (4-methoxyphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 133),
2- (3-Chlorobenzyl) -7-ethyl-9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 134),
2- (3-Chlorobenzyl) -7- (2,6-dimethylphenyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 135),
2- (3-chlorobenzyl) -9-hydroxy-7- (3-hydroxyphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 136),
7-benzoyl-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 137),
2- (3-chlorobenzyl) -7- (2-ethylphenyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 138),
2- (3-chlorobenzyl) -7- (3-chlorophenyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 139),
7-benzyl-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 140),

2- (3-chlorobenzyl) -9-hydroxy-7- (2-hydroxyphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 141),
2- (3-chlorobenzyl) -9-hydroxy-7- (4-hydroxyphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 142),
8-hydroxy-6-methyl-2- (3-trifluoromethylbenzyl) -2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (Example 143),
8-hydroxy-2- (3-methoxybenzyl) -6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (Example 144),
6- (3-chlorobenzyl) -4-hydroxy-2-methyl-2,6-dihydropyrido [4,3-c] pyridazine-3,5-dione (Example 145),
3- (3-chlorobenzyl) -5-hydroxy-3H-pyrido [2,1-f] [1,2,4] triazine-4,6-dione (Example 146),
2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid methyl ester hydrochloride (Example 147) ,
2- (3-Chlorobenzyl) -9-hydroxy-7- (1-methyl-1H-imidazol-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (implemented) Example 148),
2- (3-Chlorobenzyl) -9-hydroxy-7-isobutyryl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 149),
2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid isopropyl ester (Example 150),
2- (4-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 151),
2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid hydrochloride (Example 152),
N, N-dimethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 153) ),
2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid isopropylamide (Example 154),
N-methyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 155),
N, N-diethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 156) ),
2- (4-Bromobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 157),
2- (3-bromobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 158),
2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid 2,2-dimethylpropyl ester Example 159),
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid cyclohexyl ester (Example 160),

7-amino-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 161),
2- (3-Chlorobenzyl) -9-hydroxy-4-methyl-2H-pyrido [1,2-d] [1,2,4] triazine-1,8-dione hydrochloride (Example 162),
2- (3-Chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 163),
2- (3-Chlorobenzyl) -9-hydroxy-7- (4H-1,2,4-triazol-3-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 164),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide (Example 165) ,
2- (4-Chloro-2-methoxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 166),
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 167),
2- (3-Chloro-2-methoxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 168),
2- [2- (2-chlorophenoxy) ethyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 169),
2- (3-Chlorobenzyl) -9-hydroxy-7- (pyrimidin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 170),
N-propyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 171),
N-butyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 172),
N-isobutyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 173),
{[2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carbonyl] amino} acetic acid methyl ester Example 174),
N-ethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 175),
N- (2-methoxyethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide ( Example 176),
Trifluoroacetic acid 2-{[2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carbonyl] amino} Ethyl ester (Example 177),
N- (2-hydroxyethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide ( Example 178),
2- (3-Chloro-2-hydroxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 179),
N-benzyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 180),

N- (2,2,2-trifluoroethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide (Example 181),
N-butyl-N-methyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (implemented) Example 182),
N- (2-methoxyethyl) -N-methyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine- 7-carboxamide (Example 183),
2- (3-chlorobenzyl) -9-hydroxy-7- (pyrrolidine-1-carbonyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 184),
2- (3-chlorobenzyl) -9-hydroxy-7- (morpholine-4-carbonyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 185),
2- (4-Chloro-3-methoxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 186),
[2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetic acid methyl ester (Example 187) ,
2- (3-chlorobenzyl) -9-hydroxy-7- (1H-tetrazol-5-yl) -2H-pyrido [1,2-a] pyrazin-1,8-dione hydrochloride (Example 188),
2- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -N-methylacetamide ( Example 189),
2- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -N, N-dimethyl Acetamide (Example 190),
[2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetic acid (Example 191),
N- (2-hydroxypropyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide hydrochloride Salt (Example 192),
{[2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carbonyl] amino} acetic acid (Example 193) ),
N-dimethylcarbamoylmethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 194) ),
N-methylcarbamoylmethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 195) ),
N-phenyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide hydrochloride (Example 196) ),
2- (3-Chlorobenzyl) -9-hydroxy-7- (oxazol-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 197),
2- (3-Chlorobenzyl) -9-hydroxy-7- (3-hydroxypyrrolidine-1-carbonyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 198) ,
N- (2-oxopropyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide ( Example 199),
2- (9-hydroxy-1,8-dioxo-1,8-dihydro-pyrido [1,2-a] pyrazin-2-yl) -N-phenylacetamide hydrochloride (Example 200),

2- (3-chlorobenzyl) -9-hydroxy-7- (3-oxopyrrolidine-1-carbonyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 201),
2- (5-chloro-2-methoxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 202),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] methanesulfonamide (Examples) 203),
7-acetyl-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 204),
2- (3-Chlorobenzyl) -9-hydroxy-7-propionyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 205),
9-hydroxy-2- (3-phenylallyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 206),
N-methyl-2- (3-chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (implemented) Example 207),
N, N-dimethyl-2- (3-chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 208),
N- (2-methanesulfonylethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 209),
N- [2- (2-oxopyrrolidin-1-yl) ethyl] -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2 -A] pyrazine-7-carboxamide (Example 210),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -N-methylmethanesulfone An amide (Example 211),
2- (3-Chloro-5-methoxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 212),
N- (pyridin-4-ylmethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 213),
N- (4-fluorobenzyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide ( Example 214),
2- (3-Chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 215) ),
2- (3-chlorobenzyl) -9-hydroxy-7-hydroxymethyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 216),
2- (3-Chloro-4-fluorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example) 217),
2- (3-chlorobenzyl) -9-hydroxy-7- (thiazol-5-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 218),
2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid methylamide (Example 219) ),
N, N-dimethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 220),

2- (3-Chloro-4-fluorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride (Example 221),
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-4-hydroxymethyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid Methylamide hydrochloride (Example 222),
2- (3-Chlorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride ( Example 223),
2- (4-Chloro-2-hydroxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 224),
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 225),
2- (9-hydroxy-1,8-dioxo-1,8-dihydro-pyrido [1,2-a] pyrazin-2-yl) -N-methyl-N-phenylacetamide hydrochloride (Example 226),
N-methyl-2- (3-chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7 Carboxamide (Example 227),
N, N-dimethyl-2- (3-chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide (Example 228),
Acetic acid 3- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2,2- Dimethyl-3-oxopropyl ester hydrochloride (Example 229),
2- (3-Chlorobenzyl) -9-hydroxy-7- (3-hydroxy-2,2-dimethylpropionyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Examples) 230),
2- (3-Chlorobenzyl) -9-hydroxy-7- (pyrazin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 231),
2- (3-Chlorobenzyl) -9-hydroxy-7- (2-methyl-2H-1,2,4-triazol-3-yl) -2H-pyrido [1,2-a] pyrazine-1,8 -Dione hydrochloride (Example 232),
N- (2-fluoroethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide ( Example 233),
N-benzyl-N-methyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (implemented) Example 234),
2- (3-chlorobenzyl) -9-hydroxy-7-phenylsulfanyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 235),
7-benzenesulfinyl-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 236),
7-benzenesulfonyl-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 237),
2- (3,4-Dichlorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione ( Example 238),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] isobutyramide (Example 239) ),
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide ( Example 240),

2- (3-Chloro-4-fluorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-4-hydroxymethyl-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 241),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] propionamide (Example 242) ),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-phenylacetamide ( Example 243),
7-acetyl-2- (3-chloro-4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 244),
2- (3-chlorobenzyl) -9-hydroxy-7-methylsulfanyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 245),
2- (3-chlorobenzyl) -9-hydroxy-7-methanesulfonyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 246),
2- (3-chlorobenzyl) -9-hydroxy-7-methanesulfinyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 247),
2- (3-Chlorobenzyl) -9-hydroxy-7- (5-methylthiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione ( Example 248),
2- (3,4-Dichlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Example 249),
2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 250),
7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 251),
2- (4-Fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 252),
N-methyl-2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 253),
2- [3- (2-Chloro-6-fluorophenyl) propyl] -7- (2,2-dimethylpropionyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 254),
2- (3-Chlorobenzyl) -9-hydroxy-7- (4-methylthiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione ( Example 255),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] butyramide (Example 256) ,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] benzamide (Example 257) ,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -3-phenylpropionamide (Example 258),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -N-methylacetamide ( Example 259),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-methoxyacetamide ( Example 260),

2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid methyl ester (Examples) 261),
3- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -1,1-dimethyl Urea (Example 262),
[2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] carbamic acid methyl ester (Example 263) ),
2- [3- (2-Chloro-6-fluorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine- 1,8-dione (Example 264),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-oxopropionamide (Example 265),
N-benzyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (implemented) Example 266),
2- (3-Chlorobenzyl) -9-hydroxy-7- (1H-pyrazol-3-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Example 267),
2- (3-Chlorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 268) ),
N- (Naphthalen-1-ylmethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide (Example 269),
N-benzhydryl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (implemented) Example 270),
2- (3-Chlorobenzyl) -9-hydroxy-7- (pyrimidin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride Example 271),
2- (3-Chlorobenzyl) -9-hydroxy-7- (2-methyl-2-phenylpropionyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione ( Example 272),
N- (4-tert-butylbenzyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] Pyrazine-7-carboxamide (Example 273),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] cyclopentanecarboxamide (Examples) 274),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2- (4- Fluorophenyl) acetamide (Example 275),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2,2-dimethyl Propionamide (Example 276),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-phenylisobutyramide (Example 277),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -4-fluorobenzamide ( Example 278),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] pyridine-2-carboxamide Tri Fluoroacetate (Example 279),
2- (3-chlorobenzyl) -9-hydroxy-7-isopropylamino-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 280),

2- (3-chlorobenzyl) -7-diethylamino-9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 281),
2- (3-Chlorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (implemented) Example 282),
2- (3-Chlorobenzyl) -9-hydroxy-7-isobutylamino-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 283),
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-isopropyl-3 -Methylbutyramide (Example 284),
2- (3-chlorobenzyl) -7-ethylamino-9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 285),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] nicotinamide trifluoroacetate (Example 286),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] isonicotinamide trifluoroacetic acid Salt (Example 287),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] furan-2-carboxamide ( Example 288),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] thiophene-2-carboxamide ( Example 289),
2- (3-Chlorobenzyl) -9-hydroxy-7- (pyridazin-3-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride Example 290),
2- (3,4-Difluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Example 291),
2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 292),
2- (4-Chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 293) ),
2- (4-Chloro-3-fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 294),
2- (4-Chloro-2-methoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 295),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -1-methyl-1H -Pyrrole-2-carboxamide (Example 296),
2- [3- (4-Chlorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 297),
2- [3- (2-Chlorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 298),
2- [3- (3-Chlorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 299),
2- (3-Chlorobenzyl) -9-hydroxy-7- (3-methyl-1,2,4-thiadiazol-5-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine -1,8-dione hydrochloride (Example 300),

5-Fluoro-2- [9-hydroxy-1,8-dioxo-7- (thiazol-2-yl) -1,3,4,8-tetrahydro-pyrido [1,2-a] pyrazin-2-ylmethyl ] -N-methylbenzamide (Example 301),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -N-isobutylacetamide ( Example 302),
N- [2- (4-Fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide (Example 303) ,
N- [2- (4-Fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] benzamide (Example 304) ,
N- [2- (4-Fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] methanesulfonamide (Examples) 305),
2- (4-Fluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione trifluoroacetate (Example 306),
2- (2-Fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 307) ),
2- (3-Fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 308) ),
2- (4-Fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 309) ),
2- (2-Chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 310) ),
9-hydroxy-2- (naphthalen-2-ylmethyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Examples) 311),
2- [3- (3-Chloro-2-fluorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine- 1,8-dione (Example 312),
2- [3- (4-Chloro-3-fluorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine- 1,8-dione (Example 313),
2- [3- (4-Fluorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione (Example 314),
2- [3- (3-Fluorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione (Example 315),
9-hydroxy-2- (3-phenylpropyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (implemented) Example 316),
2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 317),
N- [2- (4-Fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-methoxyacetamide ( Example 318),
N- [2- (4-Fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-propanesulfonamide (Example 319),
N- [2- (4-Fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] nicotinamide trifluoroacetate (Example 320),

N- [2- (4-Fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] isobutyramide (Example 321) ),
N- (2-methoxyethyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide ( Example 322),
N-ethyl-2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 323),
N- {2- [3- (2-Chloro-6-fluorophenyl) propyl] -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7 -Yl} acetamide (Example 324),
N- [2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide hydrochloric acid Salt (Example 325),
5-Fluoro-2- [9-hydroxy-1,8-dioxo-7- (thiazol-2-yl) -1,3,4,8-tetrahydro-pyrido [1,2-a] pyrazin-2-ylmethyl Benzoic acid methyl ester (Example 326),
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 327),
2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-7- (pyridin-3-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 328),
2- [3- (2-Chloro-6-fluorophenyl) propyl] -9-hydroxy-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine- 1,8-dione hydrochloride (Example 329),
2- (Benzofuran-2-ylmethyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Examples) 330),
N- (1,2-diphenylethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] Pyrazine-7-carboxamide (Example 331),
N- [2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] acetamide (Example 332),
2- [3- (2-Fluorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione (Example 333),
N- (1,3-diphenylpropyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] Pyrazine-7-carboxamide (Example 334),
5-Fluoro-2- {3- [9-hydroxy-1,8-dioxo-7- (thiazol-2-yl) -1,3,4,8-tetrahydro-pyrido [1,2-a] pyrazine- 2-yl] propyl} -N-methylbenzamide (Example 335),
2- [3- (2-Chloro-6-fluorophenyl) propyl] -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine -1,8-dione (Example 336),
2- (3-chlorobenzyl) -9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 337),
9-hydroxy-2- (4-phenylbutyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (implemented) Example 338),
9-hydroxy-2-pentyl-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 339),
2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-7- (pyridin-4-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 340),

2- (4-Fluorobenzyl) -9-hydroxy-7- (pyridin-4-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 341),
2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -2H-pyrido [1,2-a] pyrazin-1,8-dione trifluoroacetate Example 342),
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-7- (2-methyl-2H-1,2,4-triazol-3-yl) -3,4-dihydro-2H-pyrido [1 , 2-a] pyrazine-1,8-dione (Example 343),
7-acetyl-2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 344),
2- (4-Fluorobenzyl) -9-hydroxy-7-isobutyryl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 345),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazin-7-yl] isonicotine Amide hydrochloride (Example 346),
2- (4-fluorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 347),
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-7- (pyrazin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 348),
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] isobutyramide (Example 349),
2- (4-Chloro-2-hydroxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 350),
9-Hydroxy-2- (3-phenylbutyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride Example 351),
N- [2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] nicotinamide hydrochloride (Example 352),
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] methanesulfonamide (Example 353),
2- (3-Chloro-4-propoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 354),
2- (3-Chloro-4-isopropoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride (Example 355),
2- (4-Benzyloxy-3-chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride (Example 356),
2- (4-Chloro-2-propoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 357),
2- (4-Chloro-2-isopropoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride (Example 358),
2- (2-Benzyloxy-4-chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride (Example 359),
2- (4-Fluorobenzyl) -9-hydroxy-7- (2-methyl-2H-1,2,4-triazol-3-yl) -2H-pyrido [1,2-a] pyrazine-1,8 -Dione hydrochloride (Example 360),

N-methyl-2- (3-chloro-2-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7 Carboxamide (Example 361),
2- (3-Chlorobenzyl) -7- (2,2-dimethylbutyryl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Example 362),
2- (4-Fluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (implemented) Example 363),
2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 364) ),
2- (3-Fluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 365),
N- {5-Fluoro-2- [9-hydroxy-1,8-dioxo-7- (thiazol-2-yl) -1,3,4,8-tetrahydro-pyrido [1,2-a] pyrazine- 2-ylmethyl] phenyl} acetamide hydrochloride (Example 366),
2- (3-Chloro-2-fluorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride (Example 367),
5-Fluoro-2- [9-hydroxy-1,8-dioxo-7- (thiazol-2-yl) -1,3,4,8-tetrahydro-pyrido [1,2-a] pyrazin-2-ylmethyl Benzoic acid hydrochloride (Example 368),
2- (3,4-difluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 369),
N-benzyl-N-methyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7 Carboxamide hydrochloride (Example 370),
N- (pyridin-3-ylmethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide hydrochloride (Example 371),
N- (pyridin-2-ylmethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide hydrochloride (Example 372),
2- (3,4-Dichlorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione trifluoro Acetate (Example 373),
N- (2-oxopropyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine- 7-carboxamide hydrochloride (Example 374),
2- (3-Fluorobenzyl) -9-hydroxy-7- (pyridin-4-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 375),
7- (2,2-dimethylpropionyl) -2- (3-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 376),
N- (2-fluorobenzyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine- 7-carboxamide (Example 377),
N- (4-fluorobenzyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine- 7-carboxamide (Example 378),
N-methyl-2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (implemented) Example 379),
N-benzyl-2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (implemented) Example 380),

N-methyl-2- (4-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (implemented) Example 381),
7- (2,2-dimethylbutyryl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 382),
2- (3,4-Dichlorobenzyl) -9-hydroxy-7- (pyrazin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 383),
2- (3,4-dichlorobenzyl) -9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 384),
2- (4-fluorobenzyl) -9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 385),
7- (2,2-Dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Examples) 386),
2- (4-fluorobenzyl) -9-hydroxy-7- (3-methylbutyryl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 387),
N-methyl-2- (3,4-difluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide (Example 388),
2- (4-Fluorobenzyl) -9-hydroxy-7- (3-methoxy-2,2-dimethylpropionyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione (Example 389),
9-benzyloxy-7-bromo-2- (3-chlorobenzyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 390),
2- (3-Chlorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 391),
2- (4-Fluorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride Example 392),
2- (4-Chlorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride Example 393),
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 394),
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 395) ),
2- (3-Chloro-5-propoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride (Example 396),
2- (3-Chloro-5-isopropoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride (Example 397),
2- (3-Benzyloxy-5-chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride (Example 398),
2- (4-chlorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -2H-pyrido [1,2-a] pyrazin-1,8-dione hydrochloride (Example 399),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2- (pyridine- 3-yl) acetamide hydrochloride (Example 400),

N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2- (pyridine- 4-yl) acetamide hydrochloride (Example 401),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2- (pyridine- 2-yl) acetamide hydrochloride (Example 402),
2- (3-Fluorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 403),
2- (3-Fluorobenzyl) -9-hydroxy-7- (pyrazin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 404),
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-7- (2-methyl-2H-1,2,4-triazol-3-yl) -2H-pyrido [1,2-a] pyrazine -1,8-dione hydrochloride (Example 405),
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] -3,3-dimethylbutyramide (Example 406),
2- (3-Fluorobenzyl) -9-hydroxy-4-methyl-7- (pyridin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 407) ),
7- (2,2-Dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-4-methyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example) 408),
7- (2,2-Dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-6-methoxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8 -Dione hydrochloride (Example 409),
N- (pyridin-2-ylmethyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide hydrochloride (Example 410),
N- (furan-2-ylmethyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide hydrochloride (Example 411),
7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1, 8-dione hydrochloride (Example 412),
7-Bromo-2- (4-fluorobenzyl) -9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (implemented) Example 413),
2- (4-Fluorobenzyl) -9-hydroxy-4,4-dimethyl-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8 -Dione hydrochloride (Example 414),
N- (4-dimethylaminobenzyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide hydrochloride (Example 415),
2- (3-Chlorobenzyl) -9-hydroxy-7- (pyrazin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride Example 416),
2- (4-Fluorobenzyl) -9-hydroxy-7- (pyrazin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride Example 417),
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] benzenesulfonamide (Example 418),
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] benzylsulfonamide (Example 419),
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] -2-thiophenesulfonamide (Example 420),

N- (4-Methanesulfonylbenzyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide hydrochloride (Example 421),
2- (4-Fluorobenzyl) -9-hydroxy-6- (2-hydroxy-3,3-dimethylbutyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride (Example 422),
N- [2- (3-Chlorobenzyl) -9-hydroxy-4-methyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide ( Example 423),
2- (4-Fluorobenzyl) -9-hydroxy-6-methoxymethyl-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride (Example 424),
2- (4-Fluorobenzyl) -9-hydroxy-7- (3-methoxy-2,2-dimethylpropionyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Examples) 425),
N- (4-methoxypyrimidin-2-ylmethyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2- a] Pyrazine-7-carboxamide hydrochloride (Example 426),
6- (3,3-Dimethyl-2-oxobutyl) -7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1, 2-a] pyrazine-1,8-dione hydrochloride (Example 427),
N- (4-acetylaminobenzyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide (Example 428),
2- (3,4-dichlorobenzyl) -9-hydroxy-4- (2-hydroxyethyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 429),
2- (3,4-dichlorobenzyl) -9-hydroxy-4- (1-hydroxypropyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 430),
2- (3,4-dichlorobenzyl) -9-hydroxy-4- (3-hydroxypropyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 431),
2- (3,4-Dichlorobenzyl) -9-hydroxy-4- (1-hydroxy-2-methylpropyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 432) ,
2- (3,4-dichlorobenzyl) -9-hydroxy-4-phenethyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 433),
2- (4-fluorobenzyl) -9-hydroxy-2H-pyrazino [1,2-c] pyrimidine-1,8-dione hydrochloride (Example 434),
2- (3,4-dichlorobenzyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (Example 435),
2- (3-chlorobenzyl) -9-hydroxy-4-methyl-2H-pyrido [1,2-d] [1,2,4] triazine-1,8-dione (Example 436),
2- (3-Chlorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (Examples) 437),
7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione (Example 438),
7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione sodium salt (Example 439),
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide sodium salt (Examples) 440), and 2- (3-chlorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione sodium salt (Example 441)
The nitrogen-containing fused ring compound according to [1] or a pharmaceutically acceptable salt thereof selected from the group consisting of:

[26] A pharmaceutical composition comprising the nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [25], and a pharmaceutically acceptable carrier.

[27] An anti-HIV agent comprising the nitrogen-containing fused ring compound according to any one of [1] to [25] or a pharmaceutically acceptable salt thereof as an active ingredient.

[28] An integrase inhibitor comprising, as an active ingredient, the nitrogen-containing fused ring compound according to any one of [1] to [25] or a pharmaceutically acceptable salt thereof.

[29] An antiviral agent comprising the nitrogen-containing fused ring compound according to any one of [1] to [25] or a pharmaceutically acceptable salt thereof as an active ingredient.

[30] An anti-HIV composition comprising the nitrogen-containing fused ring compound according to any one of [1] to [25] or a pharmaceutically acceptable salt thereof, and one or more other anti-HIV active substances as active ingredients object.

[31] The nitrogen-containing fused ring compound according to any one of [1] to [25] or a pharmaceutically acceptable salt thereof as an active ingredient for multi-drug combination therapy with other anti-HIV agents Anti-HIV agent.

[32] Use of the nitrogen-containing fused ring compound according to any one of [1] to [25] or a pharmaceutically acceptable salt thereof for producing an anti-HIV agent.

[33] Use of the nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [25] for producing an integrase inhibitor.

[34] Use of the nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [25] for producing an antiviral agent.

[35] A method for preventing or treating HIV infection, comprising administering an effective amount of the nitrogen-containing fused ring compound according to any one of [1] to [25] or a pharmaceutically acceptable salt thereof to a mammal. .

[36] The method for preventing or treating HIV infection according to [35], further comprising administering an effective amount of at least one other anti-HIV active substance to the mammal.

[37] A method for inhibiting integrase, comprising administering an effective amount of the nitrogen-containing fused ring compound according to any one of [1] to [25] or a pharmaceutically acceptable salt thereof to a mammal.

[38] A method for preventing or treating a viral infection, comprising administering an effective amount of the nitrogen-containing fused ring compound according to any one of [1] to [25] or a pharmaceutically acceptable salt thereof to a mammal. .

  The compound of the present invention can be an effective drug for preventing or treating AIDS as an anti-HIV agent having HIV integrase inhibitory activity. Moreover, it can become a more effective anti-HIV agent by using together with other anti-HIV agents such as protease inhibitors and reverse transcriptase inhibitors. In addition, having high inhibitory activity specific to integrase can be a safe drug with few side effects for the human body.

  “Coupled” means direct connection. For example, in Z—Ph, when Z is “coupled”, N—Ph is meant.

  The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.

  In group A, a fluorine atom is more preferable, in group B, more preferably a fluorine atom or a chlorine atom, and in group C, a bromine atom is more preferable.

  The “C 1-6 alkyl group” represents a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a tert-pentyl group, and a hexyl group.

In R ⁶ , R ^b2 , R ^b3 , R ^b4 , R ^b5 and R ^b6 , a methyl group is preferable. R ^b1 is preferably a methyl group, a propyl group, or an isopropyl group. In group B, a methyl group, an ethyl group and a tert-butyl group are preferable.

  The “C 1-7 alkyl group” represents a linear or branched alkyl group having 1 to 7 carbon atoms, preferably a linear or branched alkyl group having 1 to 4 carbon atoms. Specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, tert-pentyl group, hexyl group, 1-isopropyl- Examples include 2-methylpropyl group.

  The “C 2-6 alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 2-methyl- 1-propenyl group, 1-butenyl group, 2-butenyl group, 1,3-butadienyl group, 3-methyl-2-butenyl group, 4-methyl-2-pentenyl group, 4-methyl-3-pentenyl group, 1 -Methyl-2-butenyl group etc. are mentioned.

  The “C2-6 alkynyl group” is a linear or branched alkynyl group having 2 to 6 carbon atoms, and specifically includes ethynyl group, 1-propynyl group, 2-propynyl group, 3-butynyl group and the like. Can be mentioned.

“C 1-6 alkylene” represents a straight or branched alkylene having 1 to 6 carbon atoms, and includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, —CH (CH ₃ ) —, C (CH ₃ ) ₂ —, —CH (CH ₃ ) — (CH ₂ ) ₂ — and the like can be mentioned.

  Preferred are methylene, ethylene, trimethylene and tetramethylene, and more preferred is methylene.

The "C2-6 alkenylene" represents a straight-chain or branched-chain alkenylene of 2 to 6 carbon atoms, vinylene, propenylene, 1-butenylene, _{1,3-butadienylene, -CH (CH 3) -CH =} CH- , etc. Is mentioned. Preferably, it is propenylene.

  The “halo C1-6 alkyl group” is a group in which the “C1-6 alkyl group” defined above is substituted with the “halogen atom” defined above, and preferably the alkyl moiety is a straight chain having 1 to 4 carbon atoms. A haloalkyl group which is a chain or branched chain alkyl group. Specifically, fluoromethyl group, difluoromethyl group, trifluoromethyl group, bromomethyl group, chloromethyl group, 1,2-dichloroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoroethyl Groups and the like. Preferably, it is a trifluoromethyl group.

  The “C 1-6 alkyloxy group” is an alkyl-oxy group whose alkyl moiety is the “C 1-6 alkyl group” defined above, and preferably the alkyl moiety is linear or branched having 1 to 4 carbon atoms. It is an alkyl-oxy group which is an alkyl group of a chain. Specific examples include a methoxy group, an ethoxy group, a propoxy group, an isopropyloxy group, a butoxy group, an isobutyloxy group, a tert-butyloxy group, a pentyloxy group, and a hexyloxy group.

  The “C6-14 aryl group” is an aromatic hydrocarbon group having 6 to 14 carbon atoms, specifically, phenyl group, naphthyl group, anthryl group, indenyl group, azulenyl group, fluorenyl group, phenanthryl group, etc. Preferably, it is a phenyl group.

  The “C6-14 aryloxy group” is an aryl-oxy group whose aryl moiety is the “C6-14 aryl group” defined above, specifically, a phenoxy group, a naphthyloxy group, an anthryloxy group, An indenyloxy group, an azulenyloxy group, a fluorenyloxy group, a phenanthryloxy group and the like can be mentioned, and a phenoxy group is preferable.

  “C6-14 aryl C1-6 alkyl group” means an aryl-alkyl group whose alkyl moiety is “C1-6 alkyl group” as defined above and whose aryl moiety is “C6-14 aryl group” as defined above. It is. Preferably, the alkyl moiety is a linear or branched alkyl group having 1 to 4 carbon atoms, and the aryl moiety is an aryl-alkyl group which is a phenyl group. Specifically, a benzyl group, a phenethyl group, 3- A phenylpropyl group, 2-phenylpropyl group, 4-phenylbutyl group, etc. are mentioned.

R ² is particularly preferably a benzyl group.

  The “C6-14 aryl C1-6 alkyloxy group” is an aryl-alkyl-oxy group in which the C6-14 aryl C1-6 alkyl moiety is the “C6-14 aryl C1-6 alkyl group” defined above. . Preferably, the alkyl moiety is a linear or branched alkyl group having 1 to 4 carbon atoms, and the aryl moiety is an aryl-alkyl-oxy group that is a phenyl group. Specifically, a benzyloxy group, phenethyloxy, and the like. Group, 3-phenylpropyloxy group, 2-phenylpropyloxy group, 4-phenylbutyloxy group and the like.

  “C 6-14 aryl C 1-6 alkyloxycarbonyl group” means an aryl-alkyl-oxy-carbonyl in which the C 6-14 aryl C 1-6 alkyl moiety is the “C 6-14 aryl C 1-6 alkyl group” defined above. It is a group. Preferably, the alkyl moiety is a linear or branched alkyl group having 1 to 4 carbon atoms, and the aryl moiety is an aryl-alkyl-oxy-carbonyl group having a phenyl group, specifically, a benzyloxycarbonyl group Phenethyloxycarbonyl group, 3-phenylpropyloxycarbonyl group, 2-phenylpropyloxycarbonyl group, 4-phenylbutyloxycarbonyl group and the like.

  A benzyloxycarbonyl group is preferred.

  The “C6-14 arylcarbonyl group” is an aryl-carbonyl group whose aryl moiety is the “C6-14 aryl group” defined above. Specific examples include benzoyl group, 1-naphthoyl group, 2-naphthoyl group, anthrylcarbonyl group, indenylcarbonyl group, azulenylcarbonyl group, fluorenylcarbonyl group, phenanthrylcarbonyl group, and the like. Is a benzoyl group.

  The “C 3-10 carbocyclic group” is a saturated or unsaturated cyclic hydrocarbon group having 3 to 10 carbon atoms, and means an aryl group, a cycloalkyl group, a cycloalkenyl group, or a condensed ring thereof.

  Specific examples of the “aryl group” include a phenyl group, a naphthyl group, a pentarenyl group, and an azulenyl group, preferably a phenyl group and a naphthyl group, and more preferably a phenyl group.

  Specific examples of the “cycloalkyl group” include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, an adamantyl group, a norbornanyl group, and the like, preferably a cyclopentyl group, a cyclohexyl group, and A cycloheptyl group, particularly preferably a cyclopentyl group and a cyclohexyl group.

  The “cycloalkenyl group” includes at least one, preferably one or two double bonds, and specifically includes a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexenyl group ( 2,4-cyclohexadien-1-yl group, 2,5-cyclohexadien-1-yl group, etc.), cycloheptenyl group, cyclooctenyl group and the like.

  Specific examples of the ring in which these “aryl group”, “cycloalkyl group” and “cycloalkenyl group” are condensed include indenyl group, indanyl group, 1,4-dihydronaphthyl group, 1,2,3,4-tetrahydro Examples thereof include a naphthyl group (1,2,3,4-tetrahydro-2-naphthyl group, 5,6,7,8-tetrahydro-2-naphthyl group, etc.), a perhydronaphthyl group and the like. Preferred is a condensed ring of a phenyl group and another ring, such as indenyl group, indanyl group, 1,4-dihydronaphthyl group, 1,2,3,4-tetrahydronaphthyl group and the like.

  The “heteroaryl group” is a 5- or 6-membered ring heteroaryl group containing at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom as an atom constituting the ring. .

  Specifically, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, 1,3,5-triazinyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group (1,2,3-triazolyl group, 1,2 , 4-triazolyl group), tetrazolyl group, thienyl group, furyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, oxadiazolyl group (1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, 1 , 2,5-oxadiazolyl group), thiadiazolyl group (1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-thiadiazolyl group) and the like.

  The “heterocyclic group” is saturated or unsaturated (partially unsaturated) including at least one selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms, preferably 1 to 4 heteroatoms. And a monocyclic 5-membered or 6-membered heterocyclic ring, a condensed ring of these heterocyclic rings, or a condensed ring of a carbocyclic ring and a heterocyclic ring selected from benzene, cyclopentane, or cyclohexane. means.

  Examples of the "saturated monocyclic heterocyclic group" include pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, imidazolidinyl group, pyrazolidinyl group, 1,3-dioxolanyl group, 1,3-oxathiolanyl group, oxazolidinyl group, thiazolidinyl group , Piperidinyl group, piperazinyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, dioxanyl group, morpholinyl group, thiomorpholinyl group, 3-hydroxypyrrolidinyl group, 2-oxopyrrolidinyl group, 3-oxopyrrolidinyl group , 2-oxopiperidinyl group, 4-oxopiperidinyl group, 2,6-dioxopiperidinyl group and the like. Preferable are pyrrolidinyl group, piperidinyl group and morpholinyl group.

  Examples of the “unsaturated monocyclic heterocyclic group” include pyrrolyl group, furyl group, thienyl group, imidazolyl group, 1,2-dihydro-2-oxoimidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group , Isothiazolyl group, 1,2,4-triazolyl group, 1,2,3-triazolyl group, tetrazolyl group, 1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-thiadiazolyl Group, 1,2,4-thiadiazolyl group, furazanyl group, pyridyl group, pyrimidinyl group, 3,4-dihydro-4-oxopyrimidinyl group, pyridazinyl group, pyrazinyl group, 1,3,5-triazinyl group, imidazolinyl group, Pyrazolinyl group, oxazolinyl group (2-oxazolinyl group, 3-oxazolinyl group, 4-oxazolin group Le group), isoxazolinyl group, thiazolinyl group, isothiazolinyl group, pyranyl group, 2-Okisopiraniru group and the like. Preferably imidazolyl group, pyrazolyl group, isoxazolyl group, thiazolyl group, 1,2,4-triazolyl group, tetrazolyl group, 1,3,4-oxadiazolyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, oxazolinyl group is there.

  Examples of the “heterocyclic group which is a condensed ring” include indolyl group, isoindolyl group, 1,3-dihydro-1,3-dioxoisoindolyl group, benzimidazolyl group, indazolyl group, benzothiazolyl group, benzofuranyl group, isobenzo group. Furanyl group, indolizinyl group, quinolyl group, isoquinolyl group, 1,2-dihydro-2-oxoquinolyl group, quinazolinyl group, quinoxalinyl group, cinnolinyl group, phthalazinyl group, quinolidinyl group, purinyl group, pteridinyl group, indolinyl group, isoindolinyl group 5,6,7,8-tetrahydroquinolyl group, 1,2,3,4-tetrahydroquinolyl group, 2-oxo-1,2,3,4-tetrahydroquinolyl group, 1,3-benzodi Oxolyl group, 3,4-methylenedioxypyridyl group, 4,5-ethylenedio Shi pyrimidinyl group, chromenyl group, chromanyl group, isochromanyl group, 1,2,4-benzotriazinyl group and the like. Preferred are indolyl group, benzofuranyl group, quinolyl group, benzothiazolyl group, 1,2,3,4-tetrahydroquinolyl group, 1,3-benzodioxolyl group and 1,2,4-benzotriazinyl group .

  The “heterocyclic group” in which the C 1-7 alkyl group, C 1-6 alkyl moiety, C 2-6 alkenyl group and C 2-6 alkynyl group of Group C are substituted is preferably a 2-oxopyrrolidin-1-yl group .

  The “C 3-8 cycloalkyl group” is a cycloalkyl group having 3 to 8 carbon atoms, and specifically includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. is there.

R ^c7 of group C is preferably a cyclopentyl group.

  The “C 3-8 cycloalkyl C 1-6 alkyl group” is a cycloalkyl-alkyl group in which the “C 1-6 alkyl group” defined above is substituted with the “C 3-8 cycloalkyl group” defined above. The C1-6 alkyl moiety is preferably a linear alkyl group having 1 to 4 carbon atoms, and the C3-8 cycloalkyl is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

  Specific examples of the “C 3-8 cycloalkyl C 1-6 alkyl group” include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a 2-cyclohexylethyl group, and a 3-cyclohexylpropyl group. It is done.

  The group C is preferably a cyclohexylmethyl group.

  The “C 1-6 alkylsulfonyl group” is an alkyl group in which the C 1-6 alkyl moiety is a “C 1-6 alkyl group” as defined above, preferably a linear or branched alkyl group having 1 to 4 carbon atoms. A sulfonyl group.

  Specifically, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, isopentylsulfonyl group, Examples thereof include a tert-pentylsulfonyl group and a hexylsulfonyl group.

  In group A, a methylsulfonyl group is preferable.

  The “di (C1-6 alkyl) amino group” is a “C1-6 alkyl group” whose C1-6 alkyl moiety is as defined above, preferably a linear or branched alkyl group having 1 to 4 carbon atoms. It is a certain di (alkyl) -amino group.

  Specific examples include dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, N-ethyl-N-methylamino group, N-isopropyl-N-methylamino group and the like.

  In group A, a dimethylamino group is preferable.

  “C1-6 alkylcarbonylamino group” is an alkyl whose C1-6 alkyl moiety is a “C1-6 alkyl group” as defined above, preferably a linear or branched alkyl group having 1 to 4 carbon atoms. -A carbonyl-amino group.

  Specific examples include an acetylamino group, a propionylamino group, a butyrylamino group, an isobutyrylamino group, and a pivaloylamino group.

  In group A, an acetylamino group is preferable.

  “C1-6 alkylcarbonyloxy group optionally substituted with a halogen atom” means that the C1-6 alkyl moiety is a “C1-6 alkyl group” as defined above, and is substituted by a “halogen atom” as defined above An alkyl-carbonyl-oxy group which may be substituted. It contains an unsubstituted C1-6 alkylcarbonyloxy group, and preferably has an alkyl moiety of a linear or branched alkyl group having 1 to 4 carbon atoms. Here, the halogen atom is preferably a fluorine atom.

  Specifically, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, pivaloyloxy group, fluoromethylcarbonyloxy group, trifluoromethylcarbonyloxy group, 2,2,2-trifluoroethylcarbonyloxy group Can be mentioned.

  Group A is preferably an acetyloxy group and a trifluoromethylcarbonyloxy group.

  “1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C1-6 alkylsulfonyl group, a di (C1-6 alkyl) amino group, and a C1-6 alkylcarbonylamino group The “optionally substituted C6-14 aryl group” means “C6-14 aryl group” as defined above, preferably phenyl group, “halogen atom” as defined above, and “C1-6 alkyl group” as defined above. 1 to 3 selected from the group consisting of “C1-6 alkylsulfonyl group” as defined above, “di (C1-6 alkyl) amino group” as defined above, and “C1-6 alkylcarbonylamino group” as defined above. It may be substituted with three substituents and includes an unsubstituted aryl group.

  “1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C1-6 alkylsulfonyl group, a di (C1-6 alkyl) amino group, and a C1-6 alkylcarbonylamino group Specific examples of the optionally substituted C6-14 aryl group include phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-bromophenyl group, 2 , 4-Difluorophenyl group, 3,5-dichlorophenyl group, 4-methylphenyl group, 4-isopropylphenyl group, 4-tert-butylphenyl group, 4-dimethylaminophenyl group, 4-methylsulfonylphenyl group, 4- An acetylaminophenyl group etc. are mentioned.

  Group A is preferably a phenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 4-tert-butylphenyl group, 4-dimethylaminophenyl group, 4-methylsulfonylphenyl group and 4-acetylaminophenyl group. is there.

  The “heterocyclic group optionally substituted with a C1-6 alkyloxy group” is one in which the “heterocyclic group” defined above may be substituted with the “C1-6 alkyloxy group” defined above. And an unsubstituted heterocyclic group.

  A monocyclic 5-membered or 6-membered heterocyclic group is preferable.

  Specific examples of the “heterocyclic group optionally substituted with a C 1-6 alkyloxy group” include pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, pyrrolyl group, furyl group, imidazolyl group, pyrazolyl group, 1,2 , 4-triazolyl group, tetrazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, 3-methoxypyridin-2-yl group, 6-methoxypyridin-2-yl group, 5-isopropyloxypyridin-3-yl Group and 4-methoxypyrimidin-2-yl group and the like.

  Group A is preferably 2-pyridyl group, 3-pyridyl group, 2-furyl group, 6-methoxypyridin-2-yl group and 4-methoxypyrimidin-2-yl group.

“Group A” is the following substituent group.
(Here, R ^a1 , R ^a2 , R ^a3 and R ^a4 are each independently a hydrogen atom or a “C 1-6 alkyl group” as defined above.)
“Halogen atom” as defined above,
A cyano group,
-OR ^a1 (for example, hydroxyl group, methoxy group, ethoxy group, propoxy group, isopropyloxy group, butoxy group, isobutyloxy group, tert-butyloxy group, etc.),
-SR ^a1 (for example, mercapto group, methylsulfanyl group, ethylsulfanyl group, isopropylsulfanyl group, etc.),
-CO ₂ R ^a1 (for example, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, isopropyloxycarbonyl group, tert-butoxycarbonyl group, etc.),
-CONR ^a2 R ^a3 (for example, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, isopropylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, diisopropylcarbamoyl group, di-tert-butylcarbamoyl group, N-ethyl-N-methyl Carbamoyl group, N-isopropyl-N-methylcarbamoyl group, etc.),
-COR ^a4 (for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, etc.),
—SO ₂ NR ^a2 R ^a3 (for example, sulfamoyl group, methylsulfamoyl group, ethylsulfamoyl group, isopropylsulfamoyl group, dimethylsulfamoyl group, diethylsulfamoyl group, diisopropylsulfamoyl group, di- -Tert-butylsulfamoyl group, N-ethyl-N-methylsulfamoyl group, N-isopropyl-N-methylsulfamoyl group, etc.),
-SO ₂ R ^a4 (e.g., methylsulfonyl group, ethylsulfonyl group, isopropylsulfonyl group, such as tert- butylsulfonyl group),
"C6-14 aryloxy group" as defined above,
"C6-14 aryl C1-6 alkyloxycarbonyl group" defined above,
“C1-6 alkylcarbonyloxy group optionally substituted with halogen atom” as defined above,
1 to 3 selected from the group consisting of “halogen atom, C1-6 alkyl group, C1-6 alkylsulfonyl group, di (C1-6 alkyl) amino group, and C1-6 alkylcarbonylamino group” as defined above. A C6-14 aryl group optionally substituted with a substituent ", and
“Heterocyclic group optionally substituted with a C1-6 alkyloxy group” as defined above.

  The “C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from group A” means that “C 1-6 alkyl group” as defined above is selected from “group A” as defined above. It may be substituted with 1 to 3 substituents and includes an unsubstituted alkyl group.

  Specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, tert-pentyl group, neopentyl group, 1-ethyl Propyl group, hexyl group, trifluoromethyl group, cyanomethyl group, 2-cyanoethyl group, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group, 1-hydroxy -1-methylethyl group, 1-hydroxypropan-2-yl group, 1,3-dihydroxypropan-2-yl group, 1-hydroxy-2-methylpropan-2-yl group, 1-hydroxy-2-methyl Propyl, 1-hydroxy-2,2-dimethylpropyl, methoxymethyl, 2-methyl Xyethyl group, isopropyloxymethyl group, isobutyloxymethyl group, mercaptomethyl group, methylsulfanylmethyl group, isopropylsulfanylmethyl group, 2-methylsulfanylethyl group, carboxymethyl group, ethoxycarbonylmethyl group, 2-carboxyethyl group, 2 -Ethoxycarbonylethyl group, carbamoylmethyl group, methylcarbamoylmethyl group, formylmethyl group, acetylmethyl group, isobutyrylmethyl group, pivaloylmethyl group, sulfamoylmethyl group, 2-sulfamoylethyl group, methylsulfamoyl group Examples include a methyl group, a methylsulfonylmethyl group, an isopropylsulfonylmethyl group, a 2-methylsulfonylethyl group, a phenoxymethyl group, and a benzyloxycarbonylmethyl group.

R ¹ is preferably a methyl group, an ethyl group, a propyl group, or a pentyl group, and particularly preferably a methyl group or a pentyl group.

  The “C1-7 alkyl group optionally substituted with 1 to 3 substituents selected from group A” is selected from the above-defined “group A” as defined above. It may be substituted with 1 to 3 substituents and includes an unsubstituted alkyl group.

  Specific examples include the substituents mentioned in “C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from group A”.

R ² is preferably a methyl group. Group C is preferably methyl group, ethyl group, propyl group, isobutyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, cyanomethyl group, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group. 3-hydroxypropyl group, 1-hydroxypropyl group, 1-hydroxy-2-methylpropyl group, methoxymethyl group, isopropyloxymethyl group, isobutyloxymethyl group, 2,2-dimethylpropyl group, 2,2-dimethyl -1-hydroxypropyl group, 3,3-dimethyl-2-hydroxybutyl group, carboxymethyl group, methoxycarbonylmethyl group, methylcarbamoylmethyl group, dimethylcarbamoylmethyl group, methylsulfanylmethyl group, 2- (methylsulfanyl) ethyl Group Rusulfonylmethyl group, isopropylsulfonylmethyl group, 2- (methylsulfonyl) ethyl group, isopropylsulfanylmethyl group, pivaloylmethyl group, benzyl group, phenethyl group, 3-phenylpropyl group, phenoxymethyl group, and benzyloxycarbonylmethyl group Is mentioned.

  The “C 2-6 alkenyl group optionally substituted with 1 to 3 substituents selected from group A” is selected from the “group A” defined above as defined in “C 2-6 alkenyl group” as defined above. It may be substituted with 1 to 3 substituents and includes an unsubstituted alkenyl group.

  Specifically, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 1-butenyl group, 2-butenyl group, 1,3-butadienyl group, 3-methyl-2 -Butenyl group, 4-methyl-2-pentenyl group, 4-methyl-3-pentenyl group, 1-methyl-2-butenyl group, carboxyvinyl group, carbamoylvinyl group and the like can be mentioned.

  The “C 2-6 alkynyl group optionally substituted with 1 to 3 substituents selected from group A” means that “C 2-6 alkynyl group” defined above is selected from “group A” defined above. It may be substituted with 1 to 3 substituents and includes an unsubstituted alkynyl group.

  Specific examples include ethynyl group, 1-propynyl group, 2-propynyl group, 3-butynyl group, carboxyethynyl group, carbamoylethynyl group and the like.

“Group B” is a group selected from the following substituent group.
(Here, R ^b1 , R ^b2 , R ^b3 , R ^b4 , R ^b5 and R ^b6 are each independently a hydrogen atom or a “C 1-6 alkyl group” as defined above.)
“Halogen atom” as defined above,
A cyano group,
“C1-6 alkyl group” as defined above,
“Halo C1-6 alkyl group” as defined above,
-OR ^b1 (for example, hydroxyl group, methoxy group, ethoxy group, propoxy group, isopropyloxy group, butoxy group, isobutyloxy group, tert-butyloxy group, etc.),
-SR ^b1 (for example, mercapto group, methylsulfanyl group, ethylsulfanyl group, isopropylsulfanyl group, etc.),
-CO ₂ R ^b1 (e.g., carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, isopropyloxycarbonyl group, tert- butoxycarbonyl group and the like),
-CONR ^b2 R ^b3 (for example, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, isopropylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, diisopropylcarbamoyl group, di-tert-butylcarbamoyl group, N-ethyl-N-methyl Carbamoyl group, N-isopropyl-N-methylcarbamoyl group, etc.),
-COR ^b4 (for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, etc.),
—SO ₂ NR ^b2 R ^b3 (for example, sulfamoyl group, methylsulfamoyl group, ethylsulfamoyl group, isopropylsulfamoyl group, dimethylsulfamoyl group, diethylsulfamoyl group, diisopropylsulfamoyl group, di- -Tert-butylsulfamoyl group, N-ethyl-N-methylsulfamoyl group, N-isopropyl-N-methylsulfamoyl group, etc.),
-SO ₂ R ^b4 (e.g., methylsulfonyl group, ethylsulfonyl group, isopropylsulfonyl group, such as tert- butylsulfonyl group),
"C6-14 aryloxy group" defined above, and
"C6-14 aryl C1-6 alkyloxycarbonyl group" defined above
-NR ^b5 COR ^b6 (for example, acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, pivaloylamino group, etc.).

  "C3-10 carbocyclic group optionally substituted with 1 to 3 substituents selected from group B" means "C3-10 carbocyclic group" as defined above, preferably phenyl group as defined above. Which may be substituted with 1 to 3 substituents selected from “Group B” of ## STR4 ## and includes an unsubstituted C3-10 carbocyclic group.

  Specifically, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 3,4-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl Group, 4-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group, 3,4- Dichlorophenyl group, 3,5-dichlorophenyl group, 3,4-dibromophenyl group, 3-chloro-2-fluorophenyl group, 2-chloro-3-fluorophenyl group, 4-chloro-3-fluorophenyl group, 3- Chloro-4-fluorophenyl group, 2-chloro-6-fluorophenyl group, 2-methylphenyl group, 3-methyl Phenyl group, 4-methylphenyl group, 4-ethylphenyl group, 4-propylphenyl group, 3-isopropylphenyl group, 4-isopropylphenyl group, 3-butylphenyl group, 3-isobutylphenyl group, 4-isobutylphenyl group 3- (2-methyl-1-propenyl) phenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 3,5-bistrifluoromethylphenyl group, 2 -Methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-ethoxyphenyl group, 3-ethoxyphenyl group, 4-ethoxyphenyl group, 2-isopropyloxyphenyl group, 3-isopropyloxyphenyl group, 4 -Isopropyloxyphenyl group, 3-phenoxyphe Group, 4-phenoxyphenyl group, 3-methylthiophenyl group, 4-methylthiophenyl group, 3-carboxyphenyl group, 4-carboxyphenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 3-acetylphenyl group 4-acetylphenyl group, 3-isobutyrylphenyl group, 4-isobutyrylphenyl group, 3-carbamoylphenyl group, 4-carbamoylphenyl group, 3- (methylcarbamoyl) phenyl group, 4- (methylcarbamoyl) Phenyl group, 3- (isopropylcarbamoyl) phenyl group, 4- (isopropylcarbamoyl) phenyl group, 3- (butylcarbamoyl) phenyl group, 3- (N-ethyl-N-methylcarbamoyl) phenyl group, 3- (dimethylcarbamoyl) ) Phenyl group, 4- (dimethylcarbamoyl) fur Enyl group, 3- (diethylcarbamoyl) phenyl group, 4- (diethylcarbamoyl) phenyl group, 3- {N-methyl-N- (3-methylbutyl) carbamoyl} phenyl group, 4- {N-methyl-N- ( 3-methylbutyl) carbamoyl} phenyl group, 3-sulfamoylphenyl group, 4-sulfamoylphenyl group, 3- (methylsulfamoyl) phenyl group, 4- (methylsulfamoyl) phenyl group, 3- ( Ethylsulfamoyl) phenyl group, 4- (ethylsulfamoyl) phenyl group, 3- (isopropylsulfamoyl) phenyl group, 3- (butylsulfamoyl) phenyl group, 3- (dimethylsulfamoyl) phenyl Group, 4- (dimethylsulfamoyl) phenyl group, 3- (diethylsulfamoyl) phenyl group, 4- (di Tylsulfamoyl) phenyl group, 3- (N-ethyl-N-methylsulfamoyl) phenyl group, 3- (methylsulfonyl) phenyl group, 4- (methylsulfonyl) phenyl group, 3- (ethylsulfonyl) phenyl group 4- (ethylsulfonyl) phenyl group, 3- (isopropylsulfonyl) phenyl group, 4- (isopropylsulfonyl) phenyl group, 4-chloro-3-carboxyphenyl group, 4-chloro-3-dimethylcarbamoylphenyl group, 3 -Chloro-4-methylphenyl group, 3-chloro-2-hydroxyphenyl group, 3-chloro-4-hydroxyphenyl group, 3-chloro-2-methoxyphenyl group, 3-chloro-4-methoxyphenyl group, 3 -Chloro-4-propyloxyphenyl group, 3-chloro-4-isopropyloxyphene Group, 3-chloro-4-benzyloxyphenyl group, 3-chloro-5-methoxyphenyl group, 3-chloro-6-methoxyphenyl group, 3-chloro-4-ethoxyphenyl group, 3-chloro-4- Isopropyloxyphenyl group, 4-chloro-2-methoxyphenyl group, 4-chloro-3-methoxyphenyl group, 4-chloro-2-hydroxyphenyl group, 4-chloro-2-isopropyloxyphenyl group, 4-chloro- 2-propyloxyphenyl group, 4-chloro-2-benzyloxyphenyl group, 3-carboxy-5-trifluoromethylphenyl group, 3-dimethylcarbamoyl-5-trifluoromethylphenyl group, 4-dimethylcarbamoyl-2- Fluorophenyl group, 4-carboxy-3-chlorophenyl group, 3-chloro-4-methylcarb Vamoylphenyl group, 3-chloro-4-dimethylcarbamoylphenyl group, 3-chloro-4-diethylcarbamoylphenyl group, 4-carbamoyl-3-chlorophenyl group, 3-chloro-4-acetylphenyl group, 3-chloro- 4-pivaloylphenyl group, 3-chloro-5-dimethylcarbamoylphenyl group, 3-hydroxy-4-dimethylcarbamoylphenyl group, 3-hydroxy-5-dimethylcarbamoylphenyl group, 3-cyano-5-dimethylcarbamoylphenyl Group, 3-carboxy-5-methoxyphenyl group, 3-carboxy-5-ethoxyphenyl group, 3-carboxy-5-isopropyloxyphenyl group, 3-carboxy-5-cyanophenyl group, 3,5-dicarboxyphenyl Group, 3,4-dicarboxyphenyl group, 3- Ruboxy-5-dimethylcarbamoylphenyl group, 3-carboxy-4-methoxyphenyl group, 3-carboxy-4-ethoxyphenyl group, 3-carboxy-4-isopropyloxyphenyl group, 3-carboxy-4-cyanophenyl group, 3-carbamoyl-5-dimethylcarbamoylphenyl group, 3-dimethylcarbamoyl-5-methylcarbamoylphenyl group, 4-carboxy-3-methoxyphenyl group, 4-carboxy-2-methoxyphenyl group, 4-carboxy-3-ethoxy Phenyl group, 4-carboxy-3-isopropyloxyphenyl group, 4-carboxy-3-cyanophenyl group, 4-carbamoyl-2-methoxyphenyl group, 4-methylcarbamoyl-3-methoxyphenyl group, 4-dimethylcarbamoyl- 3-methoxy Phenyl group, 3,5-bis (dimethylcarbamoyl) phenyl group, 3-carbamoyl-5-cyanophenyl group, 3-carboxy-4-methylphenyl group, 3-dimethylcarbamoyl-4-methylphenyl group, 4-methyl- 3-methylcarbamoylphenyl group, 3-dimethylsulfamoyl-4-methylphenyl group, 4-fluoro-3-chlorophenyl group, 4-fluoro-2-carboxyphenyl group, 4-fluoro-2-methoxycarbonylphenyl group, 4-fluoro-2-methylcarbamoylphenyl group, 4-fluoro-2-acetylaminophenyl group, 3,5-dichloro-4-hydroxyphenyl group, 3,5-dichloro-4-methoxyphenyl group, 1-naphthyl group 2-naphthyl group, 1-bromonaphthalen-2-yl group, 6-bromonaphthalene N-2-yl group, 7-cyanonaphthalen-2-yl group, 7-methoxynaphthalen-2-yl group, 5-bromo-6-methoxynaphthalen-2-yl group, cyclopentyl group, 1-methylcyclopentyl group, 1-ethylcyclopentyl group, 1-isopropylcyclopentyl group, 2,5-dimethylcyclopentyl group, 2,2-dimethylcyclopentyl group, cyclohexyl group, 1-methylcyclohexyl group, 1-ethylcyclohexyl group, 1-isopropylcyclohexyl group, 2 , 6-dimethylcyclohexyl group, cycloheptyl group, 1-methylcycloheptyl group, 1-ethylcycloheptyl group, 1-isopropylcycloheptyl group and the like.

The ring D of R ¹ is preferably a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 3,4-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4- Chlorophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2,3-dichlorophenyl group, 2,6-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 3-chloro-2-fluoro Phenyl group, 4-chloro-3-fluorophenyl group, 2-chloro-6-fluorophenyl group, 3-trifluoromethylphenyl group, 3-methoxyphenyl group, 3-chloro-2-hydroxyphenyl group, 3-chloro 2-methoxyphenyl group, 3-chloro-4-methoxyphenyl group, 3-chloro-4-propylio Xiphenyl group, 3-chloro-4-isopropyloxyphenyl group, 3-chloro-4-benzyloxyphenyl group, 3-chloro-5-methoxyphenyl group, 3-chloro-6-methoxyphenyl group, 4-chloro-2 -Methoxyphenyl group, 4-chloro-3-methoxyphenyl group, 4-chloro-2-hydroxyphenyl group, 4-chloro-2-isopropyloxyphenyl group, 4-chloro-2-propyloxyphenyl group, 4-chloro 2-benzyloxyphenyl group, 4-fluoro-3-chlorophenyl group, 4-fluoro-2-carboxyphenyl group, 4-fluoro-2-methoxycarbonylphenyl group, 4-fluoro-2-methylcarbamoylphenyl group, 4 -Fluoro-2-acetylaminophenyl group and 2-naphthyl group.

  The “heterocyclic group optionally substituted by 1 to 3 substituents selected from group B” means that “heterocyclic group” defined above is 1 to 3 selected from “group B” defined above. The above-mentioned substituents may be substituted and include unsubstituted heterocyclic groups.

  Specifically, 2-imidazolyl group, 5-methylpyrazol-3-yl group, 5-methylisoxazol-3-yl group, 2-furyl group, 2-thiazolyl group, 4-methylthiazol-2-yl group 5-methylthiazol-2-yl group, 5-thiazolyl group, 2-oxazolyl group, 1-methylimidazol-2-yl group, 3-pyrazolyl group, 1,2,4-triazol-3-yl group, 2 -Methyl-1,2,4-triazol-3-yl group, 5-methyl-1,2,4-triazol-3-yl group, 5-ethyl-1,2,4-triazol-3-yl group, 1-ethyl-1,2,4-triazol-3-yl group, 1,5-dimethyl-1,2,4-triazol-3-yl group, 4-methyl-1,2,4-triazole-3- Yl group, 4-ethyl-1,2,4- Riazol-3-yl group, 5-tetrazolyl group, 5-ethyl-1,2,4-oxadiazol-3-yl group, 5-ethyl-1,3,4-oxadiazol-2-yl group, 3-methyl-1,2,4-thiadiazol-5-yl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 4-methoxypyridin-2-yl group, 6-methylpyridin-2-yl Group, 2-pyrimidinyl group, 4-pyrimidinyl group, 4-methylpyrimidin-2-yl group, 4-ethylpyrimidin-2-yl group, 4-isopropylpyrimidin-2-yl group, 4-butylpyrimidin-2-yl Group, 4-sec-butylpyrimidin-2-yl group, 4-carboxypyrimidin-2-yl group, 4-methoxypyrimidin-2-yl group, 4-ethoxypyrimidin-2-yl group, 4-isopro Ruoxypyrimidin-2-yl group, 4-tert-butyloxypyrimidin-2-yl group, 5-methylpyrimidin-2-yl group, 5-ethylpyrimidin-2-yl group, 5-isopropylpyrimidin-2-yl Group, 5-butylpyrimidin-2-yl group, 5-sec-butylpyrimidin-2-yl group, 5-carboxypyrimidin-2-yl group, 5-methoxypyrimidin-2-yl group, 5-ethoxypyrimidine-2 -Yl group, 5-isopropyloxypyrimidin-2-yl group, 5-tert-butyloxypyrimidin-2-yl group, 3-pyridazinyl group, 2-pyrazinyl group, 2-quinazolinyl group, 2-oxazolin-2-yl Group, 5-ethyl-2-oxazolin-2-yl group, 4,4-dimethyloxazolin-2-yl group, 2-quinolyl group, 6-quinolyl group Noryl group, 2-benzothiazolyl group, 1,2,4-triazin-3-yl group, 1,3,5-triazin-2-yl group, 1,2,3,4-tetrahydroquinolin-1-yl group, 5-indolyl group, 1-methylindol-2-yl group, 2-benzimidazolyl group, 2-benzofuranyl group, 1,3-benzodioxol-5-yl group, 1,2,4-benzotriazine-3 -Yl group, 4-piperidyl group, 4-methylpiperidin-4-yl group, 4-ethylpiperidin-4-yl group, 4-isopropylpiperidin-4-yl group, 4-tetrahydropyranyl group, 4-methyltetrahydro Pyran-4-yl group, 4-ethyltetrahydropyran-4-yl group, 4-isopropyltetrahydropyran-4-yl group, 3,5-dimethyltetrahydropyran-4-i Group, 4-tetrahydrothiopyranyl group, 4-methyl-tetrahydrothiopyran-4-yl group, 4-ethyl tetrahydrothiopyran-4-yl group, 4-isopropyl tetrahydrothiopyran-4-yl group and the like.

The ring D of R ¹ is preferably a 2-benzofuranyl group.

  Group C is preferably 2-furyl group, 2-thiazolyl group, 4-methylthiazol-2-yl group, 5-methylthiazol-2-yl group, 5-thiazolyl group, 2-oxazolyl group, 1-methylimidazole 2-yl group, 3-pyrazolyl group, 1,2,4-triazol-3-yl group, 2-methyl-1,2,4-triazol-3-yl group, 5-tetrazolyl group, 3-methyl- 1,2,4-thiadiazol-5-yl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 2-pyrazinyl group, 3-pyridazinyl group, and 2-benzofuranyl group.

  The “C 6-14 aryl group optionally substituted with 1 to 3 substituents selected from group B” is selected from the “group B” defined above as “C 6-14 aryl group” defined above. It may be substituted with 1 to 3 substituents and includes an unsubstituted C6-14 aryl group.

  Specifically, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 3,4-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl Group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 3,4-dibromophenyl group, 3-chloro-2-fluorophenyl group, 2-chloro- 3-fluorophenyl group, 4-chloro-3-fluorophenyl group, 3-chloro-4-fluorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,6-dimethylphenyl Group, 2-ethylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 4-propylphenyl group, 3- Sopropylphenyl group, 4-isopropylphenyl group, 3-butylphenyl group, 3-isobutylphenyl group, 4-isobutylphenyl group, 3- (2-methyl-1-propenyl) phenyl group, 2-trifluoromethylphenyl group 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 3,5-bistrifluoromethylphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-methoxyphenyl group 3-methoxyphenyl group, 4-methoxyphenyl group, 2-ethoxyphenyl group, 3-ethoxyphenyl group, 4-ethoxyphenyl group, 2-isopropyloxyphenyl group, 3-isopropyloxyphenyl group, 4-isopropyloxyphenyl Group, 3-phenoxyphenyl group, -Phenoxyphenyl group, 3-methylthiophenyl group, 4-methylthiophenyl group, 3-carboxyphenyl group, 4-carboxyphenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 3-acetylphenyl group, 4-acetyl Phenyl group, 3-isobutyrylphenyl group, 4-isobutyrylphenyl group, 3-carbamoylphenyl group, 4-carbamoylphenyl group, 3- (methylcarbamoyl) phenyl group, 4- (methylcarbamoyl) phenyl group, 3 -(Isopropylcarbamoyl) phenyl group, 4- (isopropylcarbamoyl) phenyl group, 3- (butylcarbamoyl) phenyl group, 3- (N-ethyl-N-methylcarbamoyl) phenyl group, 3- (dimethylcarbamoyl) phenyl group, 4- (dimethylcarbamoyl) phenyl group , 3- (diethylcarbamoyl) phenyl group, 4- (diethylcarbamoyl) phenyl group, 3- {N-methyl-N- (3-methylbutyl) carbamoyl} phenyl group, 4- {N-methyl-N- (3- Methylbutyl) carbamoyl} phenyl group, 3-sulfamoylphenyl group, 4-sulfamoylphenyl group, 3- (methylsulfamoyl) phenyl group, 4- (methylsulfamoyl) phenyl group, 3- (ethylsulfuryl) Famoyl) phenyl group, 4- (ethylsulfamoyl) phenyl group, 3- (isopropylsulfamoyl) phenyl group, 3- (butylsulfamoyl) phenyl group, 3- (dimethylsulfamoyl) phenyl group, 4- (dimethylsulfamoyl) phenyl group, 3- (diethylsulfamoyl) phenyl group, 4- (diethyls Famoyl) phenyl group, 3- (N-ethyl-N-methylsulfamoyl) phenyl group, 3- (methylsulfonyl) phenyl group, 4- (methylsulfonyl) phenyl group, 3- (ethylsulfonyl) phenyl group, 4 -(Ethylsulfonyl) phenyl group, 3- (isopropylsulfonyl) phenyl group, 4- (isopropylsulfonyl) phenyl group, 4-chloro-3-carboxyphenyl group, 4-chloro-3-dimethylcarbamoylphenyl group, 3-chloro -4-methylphenyl group, 3-chloro-4-hydroxyphenyl group, 3-chloro-4-methoxyphenyl group, 3-chloro-4-ethoxyphenyl group, 3-chloro-4-isopropyloxyphenyl group, 3- Carboxy-5-trifluoromethylphenyl group, 3-dimethylcarbamoyl-5 Trifluoromethylphenyl group, 4-dimethylcarbamoyl-2-fluorophenyl group, 4-carboxy-3-chlorophenyl group, 3-chloro-4-methylcarbamoylphenyl group, 3-chloro-4-dimethylcarbamoylphenyl group, 3- Chloro-4-diethylcarbamoylphenyl group, 4-carbamoyl-3-chlorophenyl group, 3-chloro-4-acetylphenyl group, 3-chloro-4-pivaloylphenyl group, 3-chloro-5-dimethylcarbamoylphenyl group 3-hydroxy-4-dimethylcarbamoylphenyl group, 3-hydroxy-5-dimethylcarbamoylphenyl group, 3-cyano-5-dimethylcarbamoylphenyl group, 3-carboxy-5-methoxyphenyl group, 3-carboxy-5- Ethoxyphenyl group, 3-carboxy -5-isopropyloxyphenyl group, 3-carboxy-5-cyanophenyl group, 3,5-dicarboxyphenyl group, 3,4-dicarboxyphenyl group, 3-carboxy-5-dimethylcarbamoylphenyl group, 3-carboxy -4-methoxyphenyl group, 3-carboxy-4-ethoxyphenyl group, 3-carboxy-4-isopropyloxyphenyl group, 3-carboxy-4-cyanophenyl group, 3-carbamoyl-5-dimethylcarbamoylphenyl group, 3 -Dimethylcarbamoyl-5-methylcarbamoylphenyl group, 4-carboxy-3-methoxyphenyl group, 4-carboxy-2-methoxyphenyl group, 4-carboxy-3-ethoxyphenyl group, 4-carboxy-3-isopropyloxyphenyl Group, 4-carboxy-3-sia Phenyl group, 4-carbamoyl-2-methoxyphenyl group, 4-methylcarbamoyl-3-methoxyphenyl group, 4-dimethylcarbamoyl-3-methoxyphenyl group, 3,5-bis (dimethylcarbamoyl) phenyl group, 3-carbamoyl -5-cyanophenyl group, 3-carboxy-4-methylphenyl group, 3-dimethylcarbamoyl-4-methylphenyl group, 4-methyl-3-methylcarbamoylphenyl group, 3-dimethylsulfamoyl-4-methylphenyl Group, 3,5-dichloro-4-hydroxyphenyl group, 3,5-dichloro-4-methoxyphenyl group, 1-naphthyl group, 2-naphthyl group, 1-bromonaphthalen-2-yl group, 6-bromonaphthalene 2-yl group, 7-cyanonaphthalen-2-yl group, 7-methoxynaphthalene 2-yl group, and 5-bromo-6-methoxynaphthalene-2-yl group.

  Group C is preferably a phenyl group, 2-fluorophenyl group, 2-ethylphenyl group, 2,6-dimethylphenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, and 2-trifluoromethylphenyl group.

  “Heteroaryl group optionally substituted by 1 to 3 substituents selected from group B” means that “heteroaryl group” defined above is 1 to 3 selected from “group B” defined above And may be substituted with an unsubstituted heteroaryl group.

  Specifically, 2-imidazolyl group, 5-methylpyrazol-3-yl group, 5-methylisoxazol-3-yl group, 2-thiazolyl group, 1,2,4-triazol-3-yl group, 5 -Methyl-1,2,4-triazol-3-yl group, 5-ethyl-1,2,4-triazol-3-yl group, 1-ethyl-1,2,4-triazol-3-yl group, 1,5-dimethyl-1,2,4-triazol-3-yl group, 4-methyl-1,2,4-triazol-3-yl group, 4-ethyl-1,2,4-triazole-3- Yl group, 5-tetrazolyl group, 5-ethyl-1,2,4-oxadiazol-3-yl group, 5-ethyl-1,3,4-oxadiazol-2-yl group, 2-pyridyl group 4-methoxypyridin-2-yl group, 6-methylpyridine- -Yl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 4-methylpyrimidin-2-yl group, 4-ethylpyrimidin-2-yl group, 4-isopropylpyrimidin-2-yl group, 4-butylpyrimidine-2 -Yl group, 4-sec-butylpyrimidin-2-yl group, 4-carboxypyrimidin-2-yl group, 4-methoxypyrimidin-2-yl group, 4-ethoxypyrimidin-2-yl group, 4-isopropyloxy Pyrimidin-2-yl group, 4-tert-butyloxypyrimidin-2-yl group, 5-methylpyrimidin-2-yl group, 5-ethylpyrimidin-2-yl group, 5-isopropylpyrimidin-2-yl group, 5-butylpyrimidin-2-yl group, 5-sec-butylpyrimidin-2-yl group, 5-carboxypyrimidin-2-yl group, 5 Methoxypyrimidin-2-yl group, 5-ethoxypyrimidin-2-yl group, 5-isopropyloxypyrimidin-2-yl group, 5-tert-butyloxypyrimidin-2-yl group, 3-pyridazinyl group, 2-pyrazinyl group Groups and the like.

“Group C” is a group selected from the following substituent group.
(1) hydrogen atom,
(2) "C3-8 cycloalkyl C1-6 alkyl group" defined above,
(3) a cyano group,
(4) `` Halogen atom '' as defined above,
(5) "C1-6 alkyl group" as defined above,
(6) "C2-6 alkenyl group" as defined above,
(7) "C2-6 alkynyl group" defined above,
(8) “C6-14 aryl group” as defined above,
(9) Heterocyclic group (wherein the heterocyclic group is a saturated or unsaturated monocyclic 5-membered or 6-membered heterocycle containing at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom) Or a condensed ring of these heterocyclic rings, or a condensed ring of a carbocyclic ring selected from benzene, cyclopentane or cyclohexane and the heterocyclic ring).
(10) "C1-6 alkyloxy group" defined above,
(11) "C6-14 aryl C1-6 alkyl group" defined above,
(12) "C6-14 aryl C1-6 alkyloxy group" defined above,
(13) -CO ₂ R ^c1 (for example, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, isopropyloxycarbonyl group, tert-butoxycarbonyl group, 2,2-dimethylpropyloxycarbonyl group, cyclohexyloxycarbonyl, etc.),
(14) -CONR ^c2 R ^c3 (for example, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, butylcarbamoyl group, isobutylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, diisopropylcarbamoyl group, Di-tert-butylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N-isopropyl-N-methylcarbamoyl group, N-butyl-N-methylcarbamoyl group, 2-fluoroethylcarbamoyl group, 2-hydroxyethylcarbamoyl group Group, 2-methoxyethylcarbamoyl group, N-methyl-N- (2-methoxyethyl) carbamoyl group, 2-oxopropylcarbamoyl group, 2-hydroxypropylcarbamoyl group, carbo Cymethylcarbamoyl group, methoxycarbonylmethylcarbamoyl group, 2,2,2-trifluoroethylcarbamoyl group, 2- (trifluoroacetyloxy) ethylcarbamoyl group, methylcarbamoylmethylcarbamoyl group, dimethylcarbamoylmethylcarbamoyl group, 2- ( Methylsulfonyl) ethylcarbamoyl group, phenylcarbamoyl group, benzylcarbamoyl group, N-benzyl-N-methylcarbamoyl group, 2-fluorobenzylcarbamoyl group, 4-fluorobenzylcarbamoyl group, 4-tert-butylbenzylcarbamoyl group, 4- (Dimethylamino) benzylcarbamoyl group, 4- (methylsulfonyl) benzylcarbamoyl group, 4- (acetylamino) benzylcarbamoyl group, 1-naphthylmethylcarbamoy Group, diphenylmethylcarbamoyl group, 1,2-diphenylethylcarbamoyl group, 1,3-diphenylpropylcarbamoyl group, 2-pyridylmethylcarbamoyl group, 3-pyridylmethylcarbamoyl group, 4-pyridylmethylcarbamoyl group, 2-furyl Methylcarbamoyl group, 4-methoxypyrimidin-2-ylmethylcarbamoyl group, 2- (2-oxopyrrolidin-1-yl) ethylcarbamoyl group, 1-pyrrolidinylcarbonyl group, 3-hydroxypyrrolidin-1-ylcarbonyl group , 3-oxopyrrolidin-1-ylcarbonyl group, morpholinocarbonyl group, etc.)
(15) -COR ^c4 (for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, benzoyl group, 3-methylbutyryl group, 2,2-dimethylbutyryl group, 2,2-dimethyl- 1-hydroxypropionyl group, 2,2-dimethyl-1-methoxypropionyl group, 1-acetyloxy-2,2-dimethylpropionyl group, 2-methyl-2-phenylpropionyl group, etc.),
(16) —SO ₂ NR ^c2 R ^c3 (for example, sulfamoyl group, methylsulfamoyl group, ethylsulfamoyl group, isopropylsulfamoyl group, dimethylsulfamoyl group, diethylsulfamoyl group, diisopropylsulfamoyl group) Group, di-tert-butylsulfamoyl group, N-ethyl-N-methylsulfamoyl group, N-isopropyl-N-methylsulfamoyl group, etc.),
(17) "C6-14 arylcarbonyl group" as defined above,
(18) -NR ^c4 R ^c5 (for example, amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, dimethylamino group, diethylamino group, diisopropylamino group, di-amino group) -Tert-butylamino group, N-ethyl-N-methylamino group, N-isopropyl-N-methylamino group, etc.),
(19) -NR ^c6 COR ^c7 (for example, acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, pivaloylamino group, benzoylamino group, 4-fluorobenzoylamino group, 3-methylbutyrylamino group, 3,3-dimethylbutyrylamino group, (methoxyacetyl) amino group, 2-isopropyl-3-methylbutyrylamino group, 2,2-dimethyl-1-hydroxypropionylamino group, 2,2-dimethyl-1- Methoxypropionylamino group, 1-acetyloxy-2,2-dimethylpropionylamino group, 2-methyl-2-phenylpropionylamino group, N-acetyl-N-methylamino group, N-acetyl-N-isobutylamino group, Benzylcarbonylamino group, 4-fluorobenzylcarbonylamino Group, 3-phenylpropionylamino group, cyclopentylcarbonylamino group, 2-pyridylcarbonylamino group, 3-pyridylcarbonylamino group, 4-pyridylcarbonylamino group, 2-furylcarbonylamino group, 2-thienylcarbonylamino group, 1-methylpyrrol-2-ylcarbonylamino group, etc.)
(20) -NR ^c8 SO ₂ R ^c9 (for example, methylsulfonylamino group, ethylsulfonylamino group, isopropylsulfonylamino group, phenylsulfonylamino group, benzylsulfonylamino group, N-methyl-N- (methylsulfonyl) amino group N-methyl-N- (ethylsulfonyl) amino group, N-methyl-N- (isopropylsulfonyl) amino group, 4-pyridylsulfonylamino group, 2-furylsulfonylamino group, 2-thienylsulfonylamino group, 1- Methylpyrrol-2-ylsulfonylamino group, etc.)
(21) -SR ^c10 (for example, methylsulfanyl group, ethylsulfanyl group, isopropylsulfanyl group, phenylsulfanyl group, etc.),
(22) -SOR ^c11 (eg, methylsulfinyl group, ethylsulfinyl group, isopropylsulfinyl group, phenylsulfinyl group, etc.),
(23) —SO ₂ R ^c12 (eg, methylsulfonyl group, ethylsulfonyl group, isopropylsulfonyl group, phenylsulfonyl group, etc.),
(24) -NR ^c13 CONR ^c14 R ^c15 (for example, methylcarbamoylamino group, dimethylcarbamoylamino group, diethylcarbamoylamino group, diisopropylcarbamoylamino group, N-ethyl-N-methylcarbamoylamino group, etc.),
(25) -NR ^c16 CO ₂ R ^c17 (eg, methoxycarbonylamino group, ethoxycarbonylamino group, isopropyloxycarbonylamino group, phenoxycarbonylamino group, etc.), and
(26) -NR ^c18 COCOR ^c19 (for example, 2- ^{oxopropionylamino} group, 2-oxobutyrylamino group, 3-methyl-2-oxobutyrylamino group, 2-oxo-2- (pyridin-2-yl) ) Acetylamino group and the like.
Here, R ^c1 , R ^c2 , R ^c3 , R ^c4 , R ^c5 , R ^c6 , R ^c7 , R ^c8 , R ^c9 , R ^c10 , R ^c11 , R ^c12 , R ^c13 , R ^c14 , R ^c15 , R ^c16 , R ^c17 , R ^c18 and R ^c19 are each independently
(1 ') hydrogen atom,
(2 ′) a C 1-7 alkyl group which may be substituted with 1 to 3 substituents selected from Group A above;
(3 ′) a C6-14 aryl group which may be substituted with 1 to 3 substituents selected from Group B above,
(4 ′) a heterocyclic group which may be substituted with 1 to 3 substituents selected from Group B, or
(5 ') a C3-8 cycloalkyl group,
R ^c2 and R ^c3 may ^combine with an adjacent nitrogen atom to form a nitrogen-containing heterocycle, and the nitrogen-containing heterocycle may contain an ether moiety or a carbonyl moiety. It may be substituted with 1 to 3 substituents selected from

  The C1-7 alkyl group, the C1-6 alkyl moiety, the C2-6 alkenyl group and the C2-6 alkynyl group of the group C may contain 1 to 3 substituents selected from the group A or a carbonyl moiety. It may be substituted with a nitrogen heterocyclic group, specifically, “C1-7 alkyl group optionally substituted with 1 to 3 substituents selected from group A” as defined above, “group” as defined above A C2-6 alkenyl group which may be substituted with 1 to 3 substituents selected from A ", and a C2-6 alkynyl group which may be substituted with 1 to 3 substituents selected from Group A as defined above. Group ”and an oxy group substituted by“ C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from group A ”as defined above.

  The C6-14 aryl group, the C6-14 aryl moiety and the heterocyclic group of the group C may be substituted with 1 to 3 substituents selected from the group B, specifically, the “ A C6-14 aryl group which may be substituted with 1 to 3 substituents selected from group B ", or a heterocyclic group which may be substituted with 1 to 3 substituents selected from group B, as defined above; A “C 1-6 alkyl group” defined above substituted by a “C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from group B”, defined above, and a “group defined above” "C1-6 alkyloxy group" defined above substituted with "C6-14 aryl group optionally substituted with 1 to 3 substituents selected from B", and "1 to 3 selected from Group B" C6-14 aryl optionally substituted by 1 substituent It contains a carbonyl group substituted by ".

  In addition, the “C 6-14 aryl C 1-6 alkyl group” of the group C is substituted with the “C 6-14 aryl group optionally substituted with 1 to 3 substituents selected from the group B” defined above. In which the alkyl group part of the “C 1-6 alkyl group” is substituted with 1 to 3 substituents selected from “Group A” as defined above, specifically, a carbamoylphenylmethyl group, Examples include 1-carboxy-2-phenylethyl group, 1-hydroxymethyl-2-phenylethyl group, 1-carboxymethyl-2-phenylethyl group, 1-benzyloxycarbonyl-2-phenylethyl group, and the like.

  Further, the “C 6-14 aryl C 1-6 alkyloxy group” of the group C is defined by the “C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group B” defined above. Also included are those in which the alkyl group part of the substituted “C 1-6 alkyloxy group” is substituted with 1 to 3 substituents selected from “Group A” defined above, specifically, carbamoylphenylmethyl Oxy group, 1-carboxy-2-phenylethyloxy group, 1-hydroxymethyl-2-phenylethyloxy group, 1-carboxymethyl-2-phenylethyloxy group, 1-benzyloxycarbonyl-2-phenylethyloxy group Etc. )

R ^c2 and R ^c3 may form a “nitrogen-containing heterocycle together with an adjacent nitrogen atom”, and the “nitrogen-containing heterocycle” means at least one nitrogen atom in the “heterocyclic group”. And a bond extends from a nitrogen atom. The “nitrogen-containing heterocycle” may further contain a heteroatom selected from an oxygen atom and a sulfur atom in addition to a nitrogen atom.

  A 1-pyrrolidinyl group, a 3-hydroxypyrrolidin-1-yl group, a 3-oxopyrrolidin-1-yl group, and a morpholino group are preferable.

X ^{is, -C (R x1) (R} x2) - #, - C (R x1) (R x2) -C (R x3) (R x4) - #, - C (R x1) (R x2) - ^{C (R x3) (R x4} ) -C (R x5) (R x6) - #, - C (R x1) (R x2) -C (R x7) = C (R x8) - #, or, - Carbon in which R ^x1 and R ^x2 , R ^x3 and R ^x4 , or R ^x5 and R ^x6 are adjacent when C (R ^x7 ) = C (R ^x8 ) −C (R ^x1 ) (R ^x2 ) − # X in the case of forming C3-8 cycloalkyl together with an atom is, for example,

Examples of the cycloalkyl moiety include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

  The cycloalkyl moiety is preferably a cyclopentyl group or a cyclohexyl group.

R ¹ is preferably

And
Z is preferably “C 1-6 alkylene” as defined above or * — (CH ₂ ) _m —Q— (CH ₂ ) _n —, more preferably “C 1-6 alkylene” as defined above. is there.

Ring D is preferably “C3-10 carbocyclic group optionally substituted with 1 to 3 substituents selected from group B” as defined above, and more preferably from “Group B” as defined above. A phenyl group which may be substituted with 1 to 3 selected substituents, more preferably a halogen atom and —OR ^b1 (wherein R ^b1 is a hydrogen atom or a C 1-6 alkyl group); It is a phenyl group which may be substituted with 1 to 3 selected substituents.

R ¹ is preferably a “C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from group A” as defined above, and more preferably a “C 1-6 alkyl group” as defined above. "Base".

R ² is preferably a hydrogen atom, a C 6-14 aryl C 1-6 alkyl group, or —SO ₂ R ^{d 1} , and more preferably a hydrogen atom.

The preferred ^{X, -C (R x1) (} R x2) -C (R x3) (R x4) - #, - C (R x1) (R x2) -C (R x3) (R x4) -C ( ^Rx5 ) ( ^Rx6 )-#, -C ( ^Rx7 ) = C ( ^Rx8 )-#, -N = C ( ^Rx9 )-#, or -C ( ^Rx10 ) = N- # More preferably -C ( ^Rx1 ) ( ^Rx2 ) -C ( ^Rx3 ) ( ^Rx4 )-# or -C ( ^Rx7 ) = C ( ^Rx8 )-#.

One of the more preferred embodiments is -C ( ^Rx1 ) ( ^Rx2 ) -C ( ^Rx3 ) ( ^Rx4 )-#, and the other is -C ( ^Rx7 ) = C ( ^Rx8 )-#. It is.

  Of ring B

Preferably, C═C (R ^y1 ) —N (R ^y2 ), N—C (R ^y1 ) = N, N—C (R ^y1 ) = C (R ^y2 ), or C═N—N ( R ^y2 ), and more preferably N—C (R ^y1 ) ═C (R ^y2 ).

  Preferred embodiments of the general formula [I] include the following general formulas [I] -1, [I] -2, [I] -3, and [I] -4.

(In the formula, each symbol is as described above.)
As R ^{x1 to} R ^x10 ,
Hydrogen atom,
C3-8 cycloalkyl C1-6 alkyl group,
A cyano group,
C1-7 alkyl group,
C6-14 aryl group,
C6-14 aryl C1-6 alkyl group,
-CO ₂ R ^c1,
-CONR ^c2 R ^c3 , and
-COR ^c4
(The meaning of each symbol and substituent is as described above.)

It is also preferred when R ^x3 and R ^x4 are taken together with adjacent carbon atoms to form C3-8 cycloalkyl.

Specific examples of R ^{x1 to} R ^x10 include hydrogen atom, cyano group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, hydroxymethyl group, 1-hydroxyethyl group, and 2-hydroxyethyl group. 1-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxy-2-methylpropyl group, methoxymethyl group, 2-methylsulfanylethyl group, 2-methylsulfonylethyl group, phenyl group, benzyl group, phenethyl group, 3-phenylpropyl group, carboxyl group, methoxycarbonyl group, formyl group, acetyl group, dimethylcarbamoyl group and the like, or, R ^x3 and R ^x4 is a cyclopentyl group or a cyclohexyl group together with the adjacent carbon atoms Can be mentioned.

R ^{x1 to} R ^x10 are more preferably a hydrogen atom.

As R ^y1 ,
Hydrogen atom,
C1-7 alkyl group,
C6-14 aryl group,
-CO ₂ R ^c1,
-CONR ^c2 R ^c3 ,
-COR ^c4 and
It is selected from C6-14 arylcarbonyl groups (each symbol, meaning of substituent is as described above).

Specific examples of R ^y1 include a hydrogen atom, methyl group, isopropyl group, isobutyl group, tert-butyl group, cyanomethyl group, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxy-2- Methylpropyl group, 1-hydroxy-2,2-dimethylpropyl group, methoxymethyl group, isopropyloxymethyl group, isobutyloxymethyl group, 2-hydroxy-3,3-dimethylbutyl group, methylsulfanylmethyl group, isopropylsulfanylmethyl Group, methylsulfonylmethyl group, isopropylsulfonylmethyl group, pivaloylmethyl group, phenoxymethyl group, benzyloxycarbonylmethyl group, phenyl group, carboxyl group, methoxycarbonyl group, carbamoyl group, methylcarbamoyl group, dimethyl group Rubamoyl group, diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N-isopropyl-N-methylcarbamoyl group, formyl group, acetyl group, propionyl group, isobutyryl group, pivaloyl group, benzoyl group, 1- (benzyloxy And carbonyl) -2-phenylethyl group.

These substituents are particularly preferred when X is —C (R ^x1 ) (R ^x2 ) —C (R ^x3 ) (R ^x4 ) — #.

R ^y1 is particularly preferably a hydrogen atom.

R ^y2 is preferably
Hydrogen atom,
A halogen atom,
C1-7 alkyl group,
C6-14 aryl group,
A heterocyclic group,
-CO ₂ R ^c1,
-CONR ^c2 R ^c3 ,
-COR ^c4 ,
-NR ^c4 R ^c5 ,
-NR ^c6 COR ^c7 ,
-NR ^c8 SO ₂ R ^c9 ,
-SR ^c10 ,
-SO ₂ R ^c12,
-NR ^c13 CONR ^c14 R ^c15 ,
-NR ^c16 CO ₂ R ^c17 and,
-NR ^c18 COCOR ^c19
(The meaning of each symbol and substituent is as described above.)

One preferred embodiment of R ^y2 is a heterocyclic group.

More preferably, R ^y2 is a heterocyclic group bonded to Y ³ with a carbon atom, and in the heterocyclic group, at least one of the α-positions of the carbon atom is a nitrogen atom, an oxygen atom, and a sulfur atom. And the heterocyclic group is a heterocyclic group which may be substituted with 1 to 3 substituents selected from Group B, specifically 2-thiazolyl Group, 4-methyl-thiazol-2-yl group, 5-methyl-thiazol-2-yl group, 5-thiazolyl group, 2-oxazolyl group, 1-methyl-imidazol-2-yl group, 3-pyrazolyl group, 1,2,4-triazol-3-yl group, 2-methyl-1,2,4-triazol-3-yl group, 5-tetrazolyl group, 3-methyl-1,2,4-thiadiazol-5-yl Group, 2-pyridyl group, 2-pi Examples include a rimidinyl group, a 4-pyrimidinyl group, a 2-pyrazinyl group, a 3-pyridazinyl group, and a 2-benzofuranyl group.

As another preferred embodiment of R ^y2 ,
—CO ₂ R ^c1 (specifically, a carboxyl group, a methoxycarbonyl group, an isopropyloxycarbonyl group, a 2,2-dimethylpropyloxycarbonyl group, and a cyclohexyloxycarbonyl group).
-CONR ^c2 R ^c3 (specifically, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, butylcarbamoyl group, isobutylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, N-butyl- N-methylcarbamoyl group, 2-fluoroethylcarbamoyl group, 2-hydroxyethylcarbamoyl group, 2-methoxyethylcarbamoyl group, N-methyl-N- (2-methoxyethyl) carbamoyl group, 2-oxopropylcarbamoyl group, 2 -Hydroxypropylcarbamoyl group, carboxymethylcarbamoyl group, methoxycarbonylmethylcarbamoyl group, 2,2,2-trifluoroethylcarbamoyl group, 2- (trifluoroacetyloxy) ester Tylcarbamoyl group, methylcarbamoylmethylcarbamoyl group, dimethylcarbamoylmethylcarbamoyl group, 2- (methylsulfonyl) ethylcarbamoyl group, phenylcarbamoyl group, benzylcarbamoyl group, N-benzyl-N-methylcarbamoyl group, 2-fluorobenzylcarbamoyl group 4-fluorobenzylcarbamoyl group, 4-tert-butylbenzylcarbamoyl group, 4- (dimethylamino) benzylcarbamoyl group, 4- (methylsulfonyl) benzylcarbamoyl group, 4- (acetylamino) benzylcarbamoyl group, 1-naphthyl Methylcarbamoyl group, diphenylmethylcarbamoyl group, 1,2-diphenylethylcarbamoyl group, 1,3-diphenylpropylcarbamoyl group, 2-pyridylmethylcarbamo Group, 3-pyridylmethylcarbamoyl group, 4-pyridylmethylcarbamoyl group, 2-furylmethylcarbamoyl group, 4-methoxypyrimidin-2-ylmethylcarbamoyl group, 2- (2-oxopyrrolidin-1-yl) ethylcarbamoyl Group, 1-pyrrolidinylcarbonyl group, 3-hydroxypyrrolidin-1-ylcarbonyl group, 3-oxopyrrolidin-1-ylcarbonyl group, and morpholinocarbonyl group).
-COR ^c4 (specifically, acetyl group, propionyl group, 2,2-dimethyl-3-hydroxypropionyl group, 2-methyl-2-phenylpropionyl group, 2,2-dimethyl-3-methoxypropionyl group, 3 -Acetyloxy-2,2-dimethylpropionyl group, isobutyryl group, 2,2-dimethylbutyryl group, pivaloyl group, 3-methylbutyryl group, 2,2-dimethylbutyryl group, and benzoyl group. Is mentioned.
More preferably, -COR ^c4 (wherein R ^c4 is more preferably an unsubstituted C 1-6 alkyl group).

As ^still another preferred embodiment of R ^y2 ,
-NR ^c4 R ^c5 (e.g., amino group, ethylamino group, isopropylamino group, isobutylamino group, and include diethylamino group.)
-NR ^c6 COR ^c7 (for example, acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, pivaloylamino group, benzoylamino group, 4-fluorobenzoylamino group, 3,3-dimethylbutyrylamino group, ( Methoxyacetyl) amino group, 2-isopropyl-3-methylbutyrylamino group, 2-methyl-2-phenylpropionylamino group, N-acetyl-N-methylamino group, N-acetyl-N-isobutylamino group, benzyl A carbonylamino group, a 4-fluorobenzylcarbonylamino group, a 3-phenylpropionylamino group, a cyclopentylcarbonylamino group, a 2-pyridylcarbonylamino group, a 3-pyridylcarbonylamino group, and a 4-pyridylcarbonylamino group).
—NR ^c8 SO ₂ R ^c9 (for example, methylsulfonylamino group, phenylsulfonylamino group, benzylsulfonylamino group, 2-thienylsulfonylamino group, and N-methyl-N- (methylsulfonyl) amino group may be mentioned. ),
-NR ^c13 CONR ^c14 R ^c15 (for example, a dimethylcarbamoylamino group),
-NR ^c16 CO ₂ R ^c17 (for example, methoxycarbonylamino group), and
-NR ^c18 COCOR ^c19 (for example, a 2- ^{oxopropionylamino} group is mentioned).

R ^y2 is more preferably —NR ^c6 COR ^c7 , —NR ^c8 SO ₂ R ^c9 , —NR ^c13 CONR ^c14 R ^c15 , —NR ^c16 CO ₂ R ^c17 , and —NR ^c18 COCOR ^c19 , particularly preferably —NR ^c6 COR ^c7 (wherein R ^c6 is more preferably a hydrogen atom, and R ^c7 is more preferably an unsubstituted C 1-6 alkyl group).

  “Pharmaceutically acceptable salts thereof” are non-toxic to the compounds represented by the above general formulas [I], [I] -1, [I] -2, [I] -3 and [I] -4. Any salt can be used, for example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid; or oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid Organic acids such as acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, benzylsulfonic acid; or sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, etc. Inorganic bases; or methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, guanidine, choline, cinchoni Organic bases and the like; or lysine, can be obtained by reacting arginine, with the amino acid alanine, and the like. In the present invention, a hydrate or hydrate or solvate of each compound is also included.

  In the present invention, prodrugs and metabolites of each compound are also included.

  A “prodrug” is a derivative of the compound of the present invention having a group that can be chemically or metabolically decomposed, restored to the original compound after administration to a living body, and exhibiting its original medicinal effect, and is a covalent bond Non-conforming complexes and salts.

  Prodrugs are used, for example, for improving absorption in oral administration or for targeting to a target site.

  Examples of the modified site include highly reactive functional groups such as a hydroxyl group, a carboxyl group, an amino group, and a thiol group in the compound of the present invention.

  Specific examples of the hydroxyl modifying group include a methyl group, a benzyl group, a trimethylsilyloxymethyl group, an acetyl group, a propionyl group, an isobutyryl group, a pivaloyl group, a benzoyl group, a 4-methylbenzoyl group, a dimethylcarbamoyl group, and a sulfo group. Can be mentioned. Specific examples of the modifying group for the carboxyl group include an ethyl group, a pivaloyloxymethyl group, a 1- (acetyloxy) ethyl group, a 1- (ethoxycarbonyloxy) ethyl group, and a 1- (cyclohexyloxycarbonyloxy) ethyl group. Carboxylmethyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group, phenyl group, o-tolyl group and the like. Specific examples of the amino group-modifying group include hexylcarbamoyl group, 3-methylthio-1- (acetylamino) propylcarbonyl group, 1-sulfo-1- (3-ethoxy-4-hydroxyphenyl) methyl group, (5 -Methyl-2-oxo-1,3-dioxol-4-yl) methyl group and the like.

  Preferably, in the general formulas [I], [I] -1, [I] -2, [I] -3 and [I] -4, the hydroxyl group on the ring B is a methyl group, a benzyl group or trimethylsilyl. And prodrugs modified with an oxymethyl group.

  The compound of the present invention can be administered to mammals (human, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, etc.) as an anti-HIV agent, integrase inhibitor, antiviral agent and the like. .

  When the compound of the present invention is used as a pharmaceutical preparation, it is usually a pharmaceutically acceptable carrier, excipient, diluent, extender, disintegrant, stabilizer, preservative, buffer, emulsifier, fragrance, coloring. Agents, sweeteners, thickeners, flavoring agents, solubilizing agents, other additives, specifically water, vegetable oils, alcohols such as ethanol or benzyl alcohol, polyethylene glycol, glycerol triacetate, gelatin, lactose, starch and other carbohydrates Tablets, pills, powders, granules, suppositories, injections, eye drops, solutions, capsules, troches, aerosols, elixirs, etc., mixed with magnesium stearate, talc, lanolin, petrolatum, etc. Can be administered systemically or topically, orally or parenterally, in the form of suspensions, emulsions, syrups, etc. That.

  The dosage varies depending on age, body weight, symptoms, therapeutic effects, administration method, etc., but is usually in the range of 0.01 mg to 1 g per adult, once or several times a day, orally or intravenously. It is administered in a dosage form such as an injection.

  As a preferred embodiment of the compound of the present invention, a compound having a strong pharmacological activity (for example, a compound having a strong inhibitory activity against HIV integrase, a compound having a strong anti-HIV (for example, HIV-1 IIIB strain) activity, or a drug resistant virus is hardly generated. Compounds, compounds that are effective against multidrug-resistant viruses, compounds with good bioavailability (eg, compounds with high oral absorption, compounds with high permeability to cell membranes (eg, Caco2), and stable to metabolic enzymes (eg, S9) A compound that is maintained in blood for a long time (for example, a high blood concentration after 8 hours of administration) or a protein (for example, human plasma protein, human serum albumin, α1-acid glycoprotein) A compound having a low rate), a compound having high safety (for example, a compound having a low inhibitory activity on P450 (CYP), and the like).

  In general, anti-HIV agents are required not only to temporarily suppress virus growth but also to maintain their effects so that the virus does not grow again. Therefore, long-term administration is required, and in order to maintain the effect for a long time such as at night, it is often necessary to increase the dose once. These long-term and large doses increase the risk of side effects.

  Accordingly, one of the particularly preferred embodiments of the nitrogen-containing fused ring compound of the present invention is one having high absorbability by oral administration, and one in which the blood concentration of the administered compound is maintained for a long time. Can be mentioned.

  Furthermore, a compound that has strong anti-HIV activity, high absorbability by oral administration, and long-term maintenance of blood concentration is desirable.

  In an in vitro test, a compound having little influence upon addition of serum (for example, human serum, fetal bovine serum, horse serum) and maintaining strong integrase inhibitory activity and strong anti-HIV activity is also one preferred embodiment.

  “Prevention of AIDS” means, for example, the administration of a drug to a person who has HIV detected by examination or the like and has no AIDS symptoms, or the symptoms are improved after AIDS treatment Administration of a drug to a person who has not been eradicated of HIV and is concerned about recurrence of AIDS, and administration of the drug before HIV infection is concerned because of the danger of infection.

  Examples of "other anti-HIV agents" used in combination therapy include anti-HIV antibodies, HIV vaccines, immune enhancers such as interferons, HIV ribozymes, HIV antisense agents, reverse transcriptase inhibitors, protease inhibitors, viruses And host cell binding receptors (such as CD4, CXCR4, CCR5, etc.) and viral binding inhibitors.

  Specific examples of HIV reverse transcriptase inhibitors include Retrovir (R) (zidovudine), Epivir (R) (lamivudine), Zelit (R) (sanilvudine), Videx (R) (didanocin), Hibid (R) ( Sarcitabine), Ziagen (R) (Abacavir sulfate), Viramune (R) (Nevirapine), Stockrin (R) (Efavirenz), Rescrypter (R) (Delavirdin mesylate), Combivir (R) (Zidovudine + Lamivudine), Trizivir (R) (abacavir sulfate + lamivudine + zidovudine), Coactinon (R) (emivirin), Phosphovir (R), Coviracil (R), alovudine (3'-fluoro-3'-deoxythymidine), Thiovir (Thiovir) Gi ), Kalababilin (5-[(3,5-dichlorophenyl) thio] -4-isopropyl-1- (4-pyridylmethyl) imidazole-2-methanol carbamic acid), Tenofovir disoproxil fumarate ((R)-[[ 2- (6-Amino-9H-purin-9-yl) -1-methylethoxy] methyl] phosphonic acid bis (isopropoxycarbonyloxymethyl) ester fumarate), DPC-083 ((4S) -6-chloro -4-[(1E) -cyclopropylethenyl] -3,4-dihydro-4-trifluoromethyl-2 (1H) -quinazolinone), DPC-961 ((4S) -6-chloro-4- (cyclo Propylethynyl) -3,4-dihydro-4- (trifluoromethyl) -2 (1H) -quinazolinone), DAPD ((−)-Β-D-2,6-diaminopurine dioxolane), Immunocal, MSK-055, MSA-254, MSH-143, NV-01, TMC-120, DPC-817 and the like. Here, (R) indicates a registered trademark (the same applies hereinafter), and other drug names indicate general names.

  Specific examples of HIV protease inhibitors include Crixiban (R) (Indinavir sulfate adduct), Saquinavir, Inbilase (R) (Saquinavir mesylate), Novia (R) (Ritonavir), Viracept (R) (Mesyl) Nelfinavir acid), lopinavir, prose (R) (amprenavir), karetra (R) (ritonavir + lopinavir), and mozenavir dimesylate ([4R- (4α, 5α, 6β)]-1,3-bis [( 3-aminophenyl) methyl] hexahydro-5,6-dihydroxy-4,7-bis (phenylmethyl) -2H-1,3-diazepin-2-one dimethanesulfonate), tipranavir (3 ′-[( 1R) -1-[(6R) -5,6-dihydro-4-hydroxy-2-oxy So-6-phenylethyl-6-propyl-2H-pyran-3-yl] propyl] -5- (trifluoromethyl) -2-pyridinesulfonic acid amide), lasinavir (N- [5 (S)-(tert -Butoxycarbonylamino) -4 (S) -hydroxy-6-phenyl-2 (R)-(2,3,4-trimethoxybenzyl) hexanoyl] -L-valine 2-methoxyethyleneamide), KNI-272 ( (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-N-[(R) -2-N- (isoquinolin-5-yloxyacetyl) amino-3-methylthio Propanoyl] amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide), GW-433908, TMC-126 DPC-681, buckminsterfullrene, MK-944A (MK944 (N- (2 (R) -hydroxy-1 (S) -indanyl) -2 (R) -phenylmethyl-4 (S) -hydroxy-5- [4- (2-benzo [b] furanylmethyl) -2 (S)-(tert-butylcarbamoyl) piperazin-1-yl] pentanamide) + indinavir sulfate), JE-2147 ([2 (S) -oxo-4-phenylmethyl -3 (S)-[(2-methyl-3-oxy) phenylcarbonylamino] -1-oxabutyl] -4-[(2-methylphenyl) methylamino] carbonyl-4 (R) -5,5-dimethyl -1,3-thiazole), BMS-232632 ((3S, 8S, 9S, 12S) -3,12-bis (1,1-dimethylethyl) ) -8-hydroxy-4,11-dioxo-9- (phenylmethyl) -6-[[4- (2-pyridinyl) phenyl] methyl] -2,5,6,10,13-pentaazatetradecanedicarboxylic Acid dimethyl ester), DMP-850 ((4R, 5S, 6S, 7R) -1- (3-amino-1H-indazol-5-ylmethyl) -4,7-dibenzyl-3-butyl-5,6-dihydroxy Perhydro-1,3-diazepin-2-one), DMP-851 and the like.

  Moreover, as HIV integrase inhibitor, S-1360, etc., DNA polymerase inhibitor or DNA synthesis inhibitor as foscavir (R), ACH-126443 (L-2 ′, 3′-didehydro-dideoxy-5-fluorocytidine ), Entecavir ((1S, 3S, 4S) -9- [4-hydroxy-3- (hydroxymethyl) -2-methylenecyclopentyl] guanine), calanolide A ([10R- (10α, 11β, 12α)]-11 , 12-dihydro-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-2H, 6H, 10H-benzo [1,2-b: 3,4-b ′: 5,6-b ''] Tripyran-2-one), calanolide B, NSC-674447 (1,1′-azobisformamide), Iscador (vi cum album extract), HITV-43, GEM-92, etc., anti-HIV antibodies or other antibodies such as NM-01, PRO-367, KD-247, Cytolin (R), TNX- 355 (CD4 antibody), AGT-1, PRO-140 (CCR5 antibody), etc., as HIV vaccine or other vaccines, ALVAC®, AIDSVAX®, Remune®, HIV gp41 vaccine, HIV gp120 vaccine, HIV gp140 vaccine, HIV gp160 vaccine, HIV p17 vaccine, HIV p24 vaccine, HIV p55 vaccine, AlphaVax Vector System, canarypox gp160 vaccine, AntiTat, MVA-F6 Nef vaccine, IVrev vaccine, C4-V3 peptide, p2249f, VIR-201, HGP-30W, TBC-3B, PARTICLE-3B, etc. Antiferon (interferon-α vaccine), etc., interferon or interferon agonists such as Sumiferon (R), MultiFeron (R ), Interferon-τ, Reticulose, etc., SCH-351125, etc. as CCR5 antagonists, PG-21399 (1,4,4) as HIV fusion inhibitors, such as GPG-NH2 (glycyl-prolyl-glycinamide), etc., as drugs acting on HIVp24 -Bis [3-[(2,4-dichlorophenyl) carbonylamino] -2-oxo-5,8-disodiumsulfonyl] naphthyl-2,5-dimethoxyphenyl-1,4-dihydrazone , T-1249, Synthetic Polymeric Construction No3, pentafuside, etc., IL-2 agonist or antagonist, interleukin-2, immunose (R), Proleukin (R), Multikine (R), Ontak (R), etc., TNF-α antagonist As Thalamide (R) (thalidomide), Remicade (R) (infliximab), sulfated curdlan, α-glucosidase inhibitors, Bucast (R), etc., purine nucleoside phosphorylase inhibitors as perdecine (2-amino- 4-oxo-3H, 5H-7-[(3-pyridyl) methyl] pyrrolo [3,2-d] pyrimidine) and the like, as an apoptosis agonist or inhibitor, Arkin Z (R), Panavir (R), Coenzyme Q10 (2-deca (3-methyl-2-butenylene) -5,6-dimethoxy-3-methyl-p-benzoquinone) and the like, as a cholinesterase inhibitor, Cognex (R) and the like, as an immunomodulator, Immunox ( R), Prokine (R), Met-enkephalin (6-de-L-arginine-7-de-L-arginine-8-de-L-valinamide-adrenorphine), WF-10 (tetrachlorodecaoxide 10-fold diluted solution), Perthon, PRO-542 and the like.

  In addition, Neurotropin (R), Lydacol (R), Answer 20 (R), Ampligen (R), Anticort (R), Inactivin (R), PRO-2000, RevM10 gene, HIV-specific cytotoxic T cells (CTL immunotherapy, ACTG protocol 080 treatment, CD4-ζ gene therapy), SCA binding protein, RBC-CD4 complex and the like.

  The “other anti-HIV agent” used in the multi-drug combination therapy with the compound of the present invention is preferably a reverse transcriptase inhibitor and a protease inhibitor. Two or three or more drugs can be used in combination, and at this time, a combination of drugs having different action mechanisms is one of the preferred embodiments. In addition, selection of drugs that do not have side effects are preferred. Specific drug combinations include efavirenz, indinavir, nelfinavir, ritonavir + indinavir, ritonavir + lopinavir, ritonavir + saquinavir, didanosine + lamivudine, zidovudine + didanosine, stavudine + didanosine, zidovudine + lamivudine, (Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. August 13,2001). Particularly preferred is inbilase (R) (saquinavir mesylate).

  Next, an example of the manufacturing method of the compound used for implementation of this invention is demonstrated. However, the manufacturing method of this invention compound is not limited to these.

  Even if there is no description in this production method, a protective group is introduced into the functional group as necessary, and deprotection is performed in the post-process. The functional group is treated as a precursor in each step, and converted into a desired functional group at an appropriate stage. Efficient production may be performed by devising such as changing the order of each manufacturing method and process.

  In each step, post-reaction treatment may be carried out by a commonly performed method, and isolation and purification may be performed by crystallization, recrystallization, distillation, liquid separation, column chromatography, thin layer chromatography as necessary. A commonly used method such as preparative HPLC may be appropriately selected and combined.

  The meanings of the abbreviations used in this specification are as follows. Me is methyl group, Et is ethyl group, Bn is benzyl group, n-Bu (or Bu) is butyl group, t-Bu is tert-butyl group, Ac is acetyl group, Boc is tert-butoxycarbonyl group, MOM is A methoxymethyl group and Ms represent a methanesulfonyl group.

Manufacturing method 1
Manufacturing method 1-1

(Wherein L ¹ is a leaving group such as a chlorine atom, a bromine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a toluenesulfonyloxy group, etc., and W ¹ is an acetyl group, a benzoyl group, a benzyl group, a methoxy group, It is a protective group such as ethoxymethyl group or tert-butyldimethylsilyl group, or a hydrogen atom, and other symbols are as described above.)

  Compound [1] is dissolved in an organic solvent such as tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, tert-butanol, isopropanol, sodium hydride, lithium diisopropyl. Compound [I] can be synthesized by reacting at room temperature or under cooling in the presence of a base such as amide, lithium bis (trimethylsilyl) amide, potassium tert-butoxide, triethylamine, diisopropylethylamine and the like.

When a compound in which R ² is a hydrogen atom is desired, the reaction may be performed by a conventional method under the condition that W ¹ is eliminated. In addition, when a compound in which R ² is a C 1-6 alkyl group, a C 6-14 aryl C 1-6 alkyl group, or —SO ₂ R ^d1 is desired, the reaction is carried out under mild conditions in which these substituents are not eliminated. (The same applies to the following manufacturing method).

Manufacturing method 1-2

(In the formula, L ² —X ¹ — represents C (R ^x7 ) (OMe) ₂ —CH (R ^x8 ) — or C (R ^x7 ) (OMe) ₂ —CH (R ^x8 ) —C (R ^x1 ) ( ^Rx2 )-(wherein each symbol is as described above),
Here, when L ² -X ¹ -is C (R ^x7 ) (OMe) ₂ -C (R ^x8 )-, -X ² -is -C (R ^x7 ) = C (R ^x8 )-#. , ^L 2 -X ¹ - when, -X ² - - is _{^{C (R x7) (OMe)}} 2 -CH (R x8) -C (R x1) (R x2) is ^{-C (R} x7) = C (R ^x8 ) -C (R ^x1 ) (R ^x2 )-#,
Other symbols are as described above. )

  The compound represented by the general formula [I-1] can be synthesized by ring-closing the compound [2] under acidic conditions in a solvent or in the absence of a solvent at room temperature to heating.

  Examples of acids used include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and polyphosphoric acid, organic acids such as acetic acid, trifluoroacetic acid, camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid, pyridinium p- Examples include acidic salts such as toluene sulfonate, etc. Solvents include ether solvents such as tetrahydrofuran, dioxane, and diethyl ether, benzene solvents such as benzene, toluene, chlorobenzene, and dichlorobenzene, and alcohols such as ethanol, isopropanol, and tert-butanol. Examples of the solvent include halogenated hydrocarbon solvents such as methylene chloride, chloroform and dichloroethane, but the combination of an organic acid and a benzene solvent often gives good results. Also preferred are conditions for carrying out the reaction without using a solvent using an acid such as phosphoric acid, polyphosphoric acid, sulfuric acid, etc., and conditions for adding hydrochloric acid water to this using acetic acid or trifluoroacetic acid as a solvent. Illustrated as one of the options.

Manufacturing method 2

(W ² is an alkyl group such as a methyl group or an ethyl group, or a hydrogen atom, and the other symbols are as described above.)

  Compound [I] can be synthesized by ring-closing Compound [3] under acidic or basic conditions at room temperature or under heating.

When W ² is a hydrogen atom, for example, a condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, carbonyldiimidazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, etc. In the presence or absence of a condensation additive, an ether solvent such as tetrahydrofuran, dioxane or diethyl ether, a benzene solvent such as benzene or toluene, a hydrocarbon solvent such as cyclohexane, dimethylformamide, dimethylacetamide, 1,3 -Ring-closing reaction is achieved by reacting in an amide solvent such as dimethylimidazolidinone, a ketone solvent such as acetone or 2-butanone, or a halogenated hydrocarbon solvent such as methylene chloride or chloroform.

When W ² is an alkyl group, in the presence of an acid catalyst such as camphorsulfonic acid and p-toluenesulfonic acid or a base catalyst such as dimethylaminopyridine, in a solvent such as benzene and toluene, particularly at room temperature to under heating, The ring closure reaction can be achieved preferably by carrying out the reaction under heating.

Manufacturing method 3
Production method 3-1

(In the formula, each symbol is as described above.)
Compound [4] can be prepared in an organic solvent such as tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, tert-butanol, isopropanol, ethanol, or these and water. In a mixed solvent of the compound [I] in the presence or absence of an organic base such as triethylamine or diisopropylethylamine, or a carbonate base such as sodium carbonate, potassium carbonate or sodium hydrogencarbonate, at room temperature to under heating. -2] can be synthesized.

Manufacturing method 3-2

(In the formula, each symbol is as described above.)

  Compound [I-2] can be synthesized by subjecting compound [5] to the same reaction procedure as in Production Method 1-1.

Manufacturing method 3-3

(Wherein, ^-X 3 -L ^{3 is, -CH (R x7) -C (} R x8) (OMe) 2 or ^{-C (R x1) (R x2} ) -CH (R x7) -C (R x8 ) (OMe) ₂ (where each symbol is as described above),
Here, when ^-X 3 -L ³ is ^{-CH (R x7) -C (R} x8) (OMe) 2, -X 2 - is ^{-C (R x7) = C (} R x8) - Yes in # ,
-X ³ -L ³ is ^{-C (R x1) (R x2} ) -CH (R x7) -C (R x8) (OMe) 2 when -X ² - is ^{-C (R x1) (R x2} ) -C ( ^Rx7 ) = C ( ^Rx8 )-#, and other symbols are as described above. )

  Compound [I-2] can be synthesized by subjecting compound [6] to the same reaction procedure as in Production Method 1-2.

Manufacturing method 3-4

(In the formula, -X ⁴ -L ⁴ represents -CH (R ^x7 ) -C (= O) (R ^x8 ) or -C (R ^x1 ) (R ^x2 ) -CH (R ^x7 ) -C ( = O) (R ^x8 ) (where each symbol is as described above),
Here, when ^-X 4 -L ⁴ is ^{-CH (R x7) -C (=} O) (R x8), -X 2 - is ^{-C (R x7) = C (} R x8) - Yes in # ,
When -X ⁴ -L ⁴ is ^-C of ^{(R x1) (R x2)} -CH (R x7) -C (= O) (R x8), -X 2 - is ^{-C (R} x1) (R ^x2 ) -C (R ^x7 ) = C (R ^x8 )-#,
Other symbols are as described above. )

  Compound [I-3] can be obtained by ring-closing compound [7] in the same manner as in Production method 3-3.

Manufacturing method 4

(In the formula, each symbol is as described above.)

  Compound [4], Compound [5], Compound [6] and Compound [7] can be obtained by conducting a condensation amidation reaction in the same manner as in Production Method 2, respectively.

  Moreover, the method of converting a carboxyl group into an acid halide and then condensing it is highly versatile and often gives good results. Specifically, the starting compound is thionyl chloride or oxalyl chloride in a halogenated hydrocarbon solvent such as methylene chloride or chloroform or in a benzene solvent such as benzene or toluene in the presence or absence of a catalytic amount of dimethylformamide. The condensation reaction is accomplished by reacting with the like and then in the presence of a base. Examples of the base to be used include potassium carbonate, sodium carbonate, sodium hydrogen carbonate, triethylamine, pyridine and the like. In many cases, good results are obtained when an organic base such as triethylamine or pyridine is used.

In carrying out these reactions, if there are other reactive sites, these are protected in advance and deprotected after the reaction, or a condensation reaction is performed as a stable precursor and then converted into the desired form, etc. In many cases, better results are obtained by using a method commonly used in ordinary organic reactions. Specifically, when there are two nitrogen atoms, the method in which the reaction is not desired is protected, or in order to avoid the reaction of the nitrogen atoms with the leaving groups L ¹ to L ³ , the leaving group site is a hydroxyl group. Examples thereof include a method in which a condensation reaction is performed using a certain compound, and then a hydroxyl group is converted into a leaving group.

  Compound [8], Compound [10] and Compound [13] are described in JP-A-2-502281 (WO88 / 06588), WO03 / 016275, J. Med. Chem., 42, 4814-4823, 1999, etc. It can be prepared by the methods described or by methods in accordance therewith.

  In addition, compound [9], compound [11], compound [12] and compound [14] are prepared by a conventional method as a secondary amine.

Manufacturing method 5

(In the formula, L ⁵ is a leaving group such as a chlorine atom, a bromine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a toluenesulfonyloxy group, and the other symbols are as described above.)

  Compound [17] can be obtained by reacting compound [15] or compound [18] in the same manner as in Production Method 3, respectively. In carrying out these reactions, as described in production method 4, if there are other reactive sites, these are protected in advance and deprotected after the reaction, or after performing a condensation reaction as a stable precursor, In many cases, better results are obtained by using a method commonly used in ordinary organic reactions such as conversion to a desired form.

When the amide moiety (R ¹ —HNCO—) of compound [15] or compound [18] is a carboxylic acid or a carboxylic acid ester (W ² —OCO—), L ⁵ may be R ¹ —NH—. good.

L ⁵ —X— is C (R ^x7 ) (OMe) ₂ —CH (R ^x8 ) — or C (R ^x7 ) (OMe) ₂ —CH (R ^x8 ) —C (R ^x1 ) ( R ^x2 ) − (where each symbol is as described above).

Manufacturing method 6

(In the formula, each symbol is as described above.)
Compound [15] and Compound [18] can be obtained by conducting a condensation amidation reaction in the same manner as in Production Method 2, respectively.

Manufacturing method 7

In general formula [I],

However, compound [I] -1 which is ^NC ( ^Ry1 ) = C ( ^Ry2 ) is compoundable by the manufacturing method mentioned above (however, except manufacturing method 3-4).

(In the formula, L ⁶ is L ¹ or L ² , L ⁷ is L ¹ or L ³ , and other symbols are as described above. The manufacturing method of each step is the same as the above-described manufacturing method described in the formula You can do the same.)

Compound [10 ′] can be obtained by reacting compound [8 ′] with NH ₃ .

In the production of compound [I] -1, a good result may be obtained by introducing R ^y2 or a precursor thereof using a compound in which R ^y2 is a hydrogen atom in any of the above steps.

  Specific examples are given below.

Manufacturing method 7-1

(In the formula, each symbol is as described above.)

Production of compounds wherein R ^y2 is a bromine atom

  Compound [8′-2] can be obtained by reacting compound [8′-1] with a brominating reagent such as bromine or phenyltrimethylammonium tribromide.

  As the solvent, chloroform is highly versatile, but acetic acid, toluene, chlorobenzene, and the like may be used. Furthermore, these solvents may be used in combination with an alcoholic solvent such as methanol or ethanol.

R ^y2 is a C1-7 alkyl group, a C3-8 cycloalkyl C1-6 alkyl group, a C6-14 aryl C1-6 alkyl group, a C1-6 alkyloxy group, a C6-14 aryl C1-6 alkyloxy group, a C6- 14 aryl group, a heterocyclic group, a cyano _{^{group, -CO 2 R c1, -CONR c2}} R c3, -SO 2 NR c2 R c3, C6-14 arylcarbonyl ^{group, -NR c4 R c5, -NR c6} COR c7, Compound [8′-3] which is —NR ^c8 SO ₂ R ^c9 , —NR ^c13 CONR ^c14 R ^c15 , —NR ^c16 CO ₂ R ^c17 , or —NR ^c18 COCOR ^c19 (wherein each symbol is as defined above) .) Production of the compound

Using compound [8′-2]
a) Handbook of Palladium-Catalyzed Organic Reactions: Synthetic Aspects and Catalytic Cycles. Jean-Luc Malleron et al. (1997) Academic Pr.
b) Palladium in Heterocyclic Chemistry: A Guide for the Synthetic Chemist (Tetrahedron Organic Chemistry Series, V. 20). Jie Jack Li et al. (2000) Elsevier Science Ltd.
c) Handbook of Organopalladium Chemistry for Organic Synthesis. Ei-Ichi Negishi et al. (2002) John Wiley & Sons Inc. In accordance with the method described in the above, it is synthesized by subjecting it to a coupling reaction using palladium as a catalyst.
More specifically, the following method is mentioned.

Production of compounds wherein R ^y2 is a C6-14 aryl group or a heterocyclic group

For example, the compound [8′-2] and R ^y2 —SnBu ₃ are heated in dioxane in the presence of a catalytic amount of tetrakis (triphenylphosphine) palladium (0) to thereby yield the corresponding compound [8′-3. ] Can be obtained.

In carrying out this reaction, good results are often obtained even when R ^y2 —B (OH) ₂ is used instead of R ^y2 —SnBu ₃ . Further, many options of useful palladium catalysts are described in the above-mentioned references, and an example of the options is a combination of palladium (II) acetate and 1,3-bis (diphenylphosphino) propane. Solvents that can be used are not limited to those described above, and a relatively wide range of solvents such as tetrahydrofuran and toluene are used as long as the reaction is not particularly inhibited. Furthermore, in carrying out this reaction, good results are often obtained when the reaction is carried out under an inert gas in order to avoid interference with oxygen and moisture.

Production of compounds wherein R ^y2 is a C1-7 alkyl group, a C3-8 cycloalkyl C1-6 alkyl group, or a C6-14 aryl C1-6 alkyl group

For example, the desired compound [8′-3] can be obtained by reacting the compound [8′-2] with R ^y2 -SnBu ₃ in the same manner as described above.

Here, R ^y2 is R ^{y2 ′} -CX ⁵ H—CY ⁵ H— (where X ⁵ and Y ⁵ are lower alkyl groups such as a methyl group and an ethyl group, and R ^{y2 ′} is a C 1-7 alkyl group) In the case of a compound which is a group obtained by removing the CX ⁵ H-CY ⁵ H part from the alkyl moiety of a C 3-8 cycloalkyl C 1-6 alkyl group or C 6-14 aryl C 1-6 alkyl group), R ^{y2 '} -CX ⁵ = CY ⁵ -SnBu ₃ was used, and after obtaining compound [8'-3] where R ^y2 was R ^y2' -CX ⁵ = CY ^5- , this was subjected to catalytic hydrogen reduction, and R ^y2 In many cases, better results can be obtained by obtaining the compound [8′-3] in which is R ^{y2 ′} —CX ⁵ H—CY ⁵ H—.

Production of compounds wherein R ^y2 is a C1-6 alkyloxy group or a C6-14 aryl C1-6 alkyloxy group

For example, a compound [8′-2] and R ^{y2 ′} ONa (where R ^{y2 ′} is a C1-6 alkyl group or a C6-14 aryl C1-6 alkyl group) in toluene with bis ( Dibenzylideneacetone) palladium (0) and 1,1′-bis (diphenylphosphino) ferrocene are reacted in the presence of the desired compound [8′-3].

Production of compounds in which R ^y2 is a cyano group

  For example, the corresponding compound [8′-3] is obtained by heating the compound [8′-2] and dicyanozinc in dimethylformamide in the presence of a catalytic amount of tetrakis (triphenylphosphine) palladium (0). be able to.

Production of compounds wherein R ^y2 is —CO ₂ R ^c1 or —CONR ^c2 R ^c3

For example, the compound [8′-2] is heated in dimethyl sulfoxide in the presence of R ^c1 OH, triethylamine, palladium (II) acetate, and 1,3-bis (diphenylphosphino) propane in a carbon monoxide atmosphere. Thus, a compound [8′-3] in which R ^y2 is —CO ₂ R ^c1 can be obtained.

By using methanol as R ^c1 OH and obtaining compound [8′-3] wherein R ^y2 is —CO ₂ CH ₃ , this is hydrolyzed by a commonly used method such as aqueous sodium hydroxide / tetrahydrofuran. A compound [8′-3] in which R ^y2 is —CO ₂ H can be obtained.

Can be further ^{R y2} by condensing this compound with ^NHR c2 ^{R c3} get ^-CONR c2 ^{R c3,} Compound [8'-3]. Here, the condensation reaction can be carried out according to production method 2 and production method 4 described above.

Preparation of a compound in which R ^y2 is —NR ^c4 R ^c5

For example, compound [8′-2] and HNR ^c4 R ^c5 are mixed with cesium carbonate, a catalytic amount of palladium (II) acetate, and 2,2′-bis (di-tert-butylphosphino) -1,1 ′. -Desired compound [8'-3] can be obtained by heating in benzene in the presence of binaphthyl.

^Preparation of a compound in which R ^y2 is —NR ^c6 COR ^c7 , —NR ^c8 SO ₂ R ^c9 , —NR ^c13 CONR ^c14 R ^c15 , —NR ^c16 CO ₂ R ^c17 , or —NR ^c18 COCOR ^c19

For example, compound [8′-2] and HNR ^c6 COR ^c7 in toluene in the presence of sodium tert-butoxide, catalytic amounts of palladium (II) acetate, and 1,1′-bis (diphenylphosphino) ferrocene To obtain compound [8′-3] in which R ^y2 is —NR ^c6 COR ^c7 .

Similarly, a compound [8′-3] in which R ^y2 is —NR ^c8 SO ₂ R ^c9 , —NR ^c13 CONR ^c14 R ^c15 , —NR ^c16 CO ₂ R ^c17 , or —NR ^c18 COCOR ^c19 is also synthesized. However, good results may be obtained when the reaction is carried out stepwise. That is, first, NH ₂ CO ₂ t-Bu and compound [8′-2] are subjected to the same reaction as described above to obtain compound [8′-3] in which R ^y2 is —NHCO ₂ t-Bu. be able to. By treating this with trifluoroacetic acid or hydrochloric acid-dioxane according to a conventional method, a compound [8′-5] in which R ^y2 is —NH ₂ can be obtained.

The obtained compound [8′-5] was prepared from the corresponding carboxylic acid (for example, R ^c7 CO ₂ H), carboxylic acid anhydride (for example, R ^c7 CO ₂ COR ^c7 ) as described in the above Production Method 2 and Production Method 4. Or, acid chloride (for example, R ^c7 COCl), chlorocarbonate (R ^c17 OCOCl), isocyanate (R ^c14 -NCO), chlorocarbonic acid amide (R ^c14 R ^c15 NCOCl), sulfonyl chloride (R ^c9 SO ₂ Cl) and the like By reacting, the corresponding compound [8′-3] can be synthesized.

Prior to carrying out the above reaction, R ^c6 , R ^c8 , R ^c13 , R ^c16 , R ^c18 may be introduced into —NH ₂ by a conventional method, or may be introduced after the reaction.

Production of compounds in which R ^y2 is an amino group

  Compound [8′-4] can be obtained by reacting compound [8′-1] with nitric acid, fuming nitric acid, nitronium tetrafluoroborate or the like.

  As the solvent to be used, acetic acid, chloroform and the like are generally used, but various conditions widely known as aromatic ring nitration conditions may be used.

  [8'-4] can be obtained by catalytic hydrogen reduction, reduction with a metal powder such as iron or zinc, or reduction with a metal ion such as tin chloride.

  In the case of reduction with metal powder, the solvent is generally a solvent such as acetic acid, hydrochloric acid-alcohol, hydrochloric acid-tetrahydrofuran, and in the case of reduction using tin chloride, methanol and ethanol are common.

The introduction of Br and the conversion to R ^y2 are not limited to the compound [8]. In the production method described above, the introduction of Br can be performed at a desired and appropriate timing in all steps. And conversion to R ^y2 may be performed in a separate step. In particular, when Br is introduced with the compound [5], [6], [10], [17], [18], [10] or [I-1], good results may be obtained.

Manufacturing method 7-2

(In the formula, E is a functional group derived from an electrophile corresponding to R ^y2 such as ^{—COR c4} , —COOH, and —SR ^c10 , and other symbols are as described above.)

  As another method for introducing a functional group, a method of reacting compound [15′-1] with a base and then reacting with an electrophile can be mentioned.

  Specific examples of the electrophile include esters, aldehydes, ketones, disulfides and carbon dioxide.

Examples of the base to be used include lithium diisopropylamide, potassium hexamethyldisilamide, and n-butyllithium. Examples of the solvent include tetrahydrofuran, diethyl ether, dimethoxyethane, and the like. When lithium diisopropylamide is used in tetrahydrofuran. Often gives good results. As the reaction temperature, good results are often obtained when the reaction is carried out at room temperature or under cooling. The functional group thus introduced can be converted into a desired and appropriate R ^y2 by various known reactions.

  The following manufacturing method is mentioned as a specific example.

Production of compounds wherein R ^y2 is —COR ^c4

Compound [15′- wherein R ^y2 is —CH (OH) R ^c4 by adding R ^c4 —CHO as an electrophile to compound [15′-1] treated with lithium diisopropylamide at −78 ° C. in tetrahydrofuran. 2] can be obtained.

The resulting compound [15′-2], wherein R ^y2 is —CH (OH) R ^c4 , is sulfur trioxide in a solvent that does not itself inhibit the reaction in the presence of triethylamine and dimethyl sulfoxide, for example, chloroform. By treating with -pyridine complex, R ^y2 can be converted to compound [15′-2] in which —COR ^c4 . This oxidation reaction is not limited to the above conditions, and 1,1,1-tris (acetoxy) -1,1-dihydro-1,2-benzoiodoxol-3- (1H)-in chloroform Conditions using ON (Dess-Martin reagent) as the oxidizing agent often also give good results. Under either condition, the reaction is carried out at room temperature or under cooling, but a range of 0 ° C. to room temperature is more preferred.

Production of compounds wherein R ^y2 is —COOH, —SR ^c10 , —SOR ^c11 , or —SO ₂ R ^c12

By using carbon dioxide and disulfide (such as R ^c10 SSR ^c10 ) as the electrophile, a compound [15′-2] in which R ^y2 is —COOH and —SR ^c10 can be obtained. Here, by treating the compound [15′-2] in which R ^y2 is —SR ^c10 with a peracid such as m-chloroperbenzoic acid in chloroform, R ^y2 is —SOR ^c11 or —SO ₂ R ^c12 . A certain compound [15′-2] can be obtained.

The introduction of E by the electrophile and the conversion to R ^y2 are not limited to the compound [15], and can be carried out at a desired and appropriate timing in all steps in the production method described above. And conversion to R ^y2 may be performed in separate steps.

  However, introduction of E by an electrophile in the presence of a base is often better avoided in compounds [3], [8], and [10] in order to control side reactions.

Manufacturing method 8
Manufacturing method 8-1

(In the formula, each symbol is as described above.)

Compound [I-5] can be obtained by converting compound [10 ′] to compound [19] and then condensing with compound represented by R ^x9 —CH (OMe) ₂ .

Here, the conversion from the compound [10 ′] to the compound [19] was performed according to the method described in the production method 6 using R ¹ —NHNH—W (W is an amino protecting group) instead of R ¹ —NH _2. Is done.

  In the presence of an acid catalyst such as hydrochloric acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, the condensation reaction from compound [19] to compound [I-5] is carried out in a benzene solvent such as benzene, toluene or chlorobenzene. Or in an alcoholic solvent such as methanol or ethanol at room temperature or under heating.

Manufacturing method 8-2

(In the formula, each symbol is as described above.)

Compound [I-6] can be obtained by converting compound [8 ′] to compound [20] and subsequently condensing with compound represented by R ^x10 —CH (OMe) ₂ .

Here, the conversion from the compound [8 ′] to the compound [20] was performed by using W—NH—NH ₂ (W is an amino protecting group) instead of L ⁵ —X—NH ₂ , and the reaction described in Production Method 5. Is carried out according to The condensation reaction from compound [20] to compound [I-6] is achieved under acidic conditions, as in production method 8-1.

Manufacturing method 3-5

(In the formula, each symbol is as described above.)

  Compound [I] -2 is a part of the compound represented by the general formula [I], and is produced by the method described above. Among them, a preferable result is often obtained when this production method is followed.

That is, the compound [22] is a compound prepared by a method described in the literature (Breslow, DS, et al., J. Am. Chem. Soc., 1946, 68, 1232) or a method based thereon. 21] and R ^y1 —C (NH ₂ ) ═NH are synthesized by reacting them under acidic conditions or basic conditions. Examples of the acid to be used include hydrochloric acid, p-toluenesulfonic acid and the like, which are usually provided as a salt of amidine, but may be further added as necessary. Examples of the base include sodium methoxide and potassium carbonate, and examples of the solvent include methanol, ethanol, dioxane, tetrahydrofuran and the like. Although this reaction can be achieved in such a solvent that does not inhibit the reaction under a relatively wide pH condition, a preferable method is to use sodium methoxide as a base in methanol and under heating. Illustrated.

  The subsequent steps of producing compound [I] -2 from compound [22] via compound [23] are carried out according to the aforementioned production method 4 and production method 3, respectively. Prior to this conversion, it is necessary to hydrolyze compound [22] to a carboxylic acid using sodium hydroxide or the like in a solvent such as alcohol or tetrahydrofuran.

Manufacturing method 3-6

(In the formula, each symbol is as described above.)

  The production of compound [I] -3 often gives favorable results when this process is followed.

  That is, the compound [24] derived from an amino acid is reacted with methyl orthoformate in methanol or in the absence of a solvent in the presence of an acid catalyst such as hydrochloric acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, and the like. By protecting, compound [25] can be obtained.

  Compound [26] can be obtained by reacting compound [25] with methyl chloroglyoxylate in the presence of a base such as pyridine or triethylamine in a solvent such as chloroform, toluene or tetrahydrofuran or without solvent. This reaction often gives good results when carried out under cooling.

Compound [27] can be obtained by reacting compound [26] with W ² -OAc. In carrying out this reaction, first, W ² -OAc is treated with a base such as lithium diisopropylamide or lithium hexamethyldisilamide in a solvent such as tetrahydrofuran to give an enolate, and then reacted with compound [26]. Often gives results. The reaction is carried out at room temperature or under cooling, but often gives favorable results especially when it is carried out at 0 ° C. or lower.

  Compound [28] can be obtained by hydrolyzing compound [27] under acidic conditions. The acid used is preferably 4N or less hydrochloric acid, and is carried out in tetrahydrofuran or dioxane.

  Compound [29] can be obtained by treating compound [28] with a base. Examples of the base used include metal salts such as potassium carbonate and sodium carbonate, metal amides such as lithium diisopropylamide and potassium hexamethyldisilamide, and organic bases such as triethylamine, ethyldiisopropylamine and pyridine, but triethylamine and ethyldiisopropylamine. In many cases, good results are obtained when the above is used. The choice of the solvent is wide, and examples include chloroform, tetrahydrofuran, dioxane, methanol, ethanol, toluene and the like, but it is obvious that there are limitations depending on the type of base used.

  The step of producing compound [I] -3 from compound [29] via compound [30] can be carried out according to production method 5 and production method 1-1 or 1-2 described above.

Manufacturing method 3-7

(In the formula, each symbol is as described above.)

Compound [31] and Compound H prepared according to or according to the methods described in the literature (Micovic, IV et al., J. Chem. Soc., Perkin Trans. 1 (1996) 16, 2041) Compound [32] can be synthesized by reacting ₂ N—NH—R ^y2 in a solvent such as methanol, ethanol, tetrahydrofuran, dioxane, toluene, or the like at room temperature or under heating.

  Compound [I] -4 is obtained by reacting compound [32] with oxalyl chloride in the presence of an organic base such as triethylamine, ethyldiisopropylamine or pyridine in a solvent such as chloroform, tetrahydrofuran, dioxane or toluene. Can do. The reaction temperature is not limited, but often gives good results when carried out under cooling to room temperature.

  Next, the nitrogen-containing fused ring compound represented by the general formula [I] or the pharmaceutically acceptable salt thereof and the production method thereof according to the present invention will be specifically described with reference to examples. However, the present invention is not limited to these examples.

Example 1
Synthesis of 2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

Process 1
3-Benzyloxy-4-oxo-4H prepared according to the method described in the literature (Japanese National Publication No. 2-502281 (WO88 / 06588), J. Med. Chem., 1999, 42, 4814-4823) -Oxalyl chloride (0.21 ml) and dimethylformamide (0.01 ml) were added to a chloroform (30 ml) solution of pyran-2-carboxylic acid (0.4 g), and the mixture was stirred at room temperature for 30 minutes. After the reaction solvent was distilled off under reduced pressure, toluene was added and the mixture was concentrated, and dissolved in chloroform (5 ml). Under ice-cooling, 3,4-dichlorobenzylamine (0.23 ml) and triethylamine (0.34 ml) were sequentially added, and the mixture was stirred for 20 minutes under ice-cooling. A 5% aqueous potassium hydrogen sulfate solution was added to the resulting reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 8), and N- (3,4- Dichlorobenzyl) -3-benzyloxy-4-oxo-4H-pyran-2-carboxamide (0.43 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 9.15 (t, 1H, J = 6.0 Hz), 8.19 (d, 1H, J = 5.8 Hz), 7.54 (s, 1H), 7. 53 (d, 1H, J = 8.4 Hz), 7.31-7.20 (m, 5H), 6.51 (d, 1H, J = 5.8 Hz), 5.17 (s, 2H), 4.46 (d, 1H, J = 6.0 Hz).

Process 2
N- (3,4-dichlorobenzyl) -3-benzyloxy-4-oxo-4H-pyran-2-carboxamide obtained in the previous step in tetrahydrofuran (1 ml), ethanol (1 ml), water (0.2 ml) Ethanolamine (0.05 ml) and 2N aqueous sodium carbonate solution (0.06 ml) were sequentially added to the solution, and the mixture was stirred at room temperature for 1 hour and then stirred at 35 ° C. for 4 hours. The solvent was distilled off, and the resulting crystals were washed successively with ethyl acetate and water, dried, and N- (3,4-dichlorobenzyl) -3-benzyloxy-1- (2-hydroxyethyl) -4. -Oxo-1,4-dihydropyridine-2-carboxamide (0.142 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 9.46 (t, 1H, J = 5.8 Hz), 7.60 (d, 1H, J = 7.7 Hz), 7.56 (d, 1H, J = 2.1 Hz), 7.32 (d, 1H, J = 8.3 Hz), 7.30-7.27 (m, 5H), 7.25 (dd, 1H, J = 2.1, 8. 3 Hz), 6.24 (d, 1H, J = 7.7 Hz), 5.05 (s, 2H), 5.06-5.01 (m, 1H), 4.41 (d, 1H, J = 5.8 Hz), 3.88-3.81 (m, 2H), 3.65-3.57 (m, 2H).

Process 3
N- (3,4-dichlorobenzyl) -3-benzyloxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxamide (0.142 g) obtained in the previous step To the mixture was added dry tetrahydrofuran (2 ml), and the mixture was cooled to 0 ° C. under an argon atmosphere. Diisopropylethylamine (0.026 ml) and methanesulfonyl chloride (0.009 ml) were successively added dropwise at the same temperature, and the mixture was stirred at room temperature for 1 hour, and then again diisopropylethylamine (0.053 ml) and methanesulfonyl chloride at 0 ° C. (0.019 ml) was successively added dropwise and stirred at room temperature for 1 hour. To the resulting reaction solution was added 1N aqueous hydrochloric acid under ice cooling, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine. After drying with sodium sulfate, the crude product obtained by evaporating the solvent was dissolved in dry tetrahydrofuran (4 ml), sodium hydride (60%) (8 mg) was added, and the mixture was heated at 80 ° C. Sodium hydride (60%) (8 mg) was added every 30 minutes. After adding 5 times in total, 1N hydrochloric acid was added under ice-cooling, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine. did. After drying over sodium sulfate, the solvent was distilled off and the residue was purified by thin layer chromatography (ethyl acetate: methanol = 5: 2), and 9-benzyloxy-2- (3,4-dichlorobenzyl) -3,4 -Dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (22 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.64 (d, 1H, J = 7.4 Hz), 7.62-7.56 (m, 2H), 7.51-7.46 (m, 2H) ), 7.34-7.22 (m, 4H), 6.26 (d, 1H, J = 7.4 Hz), 5.08 (s, 2H), 4.67 (s, 2H), 4. 17-4.08 (m, 2H), 3.63-3.55 (m, 2H).

Process 4
Acetic acid was added to 9-benzyloxy-2- (3,4-dichlorobenzyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (12 mg) obtained in the previous step. (0.75 ml) and concentrated hydrochloric acid (0.15 ml) were added, and the mixture was stirred at 90 ° C. for 20 minutes. The solvent was distilled off, and the resulting residue was crystallized from hexane: ethyl acetate = 1: 2 to give 2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1, 2-a] pyrazine-1,8-dione hydrochloride (8 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.96 (d, 1H, J = 7.2 Hz), 7.67 (d, 1H, J = 1.9 Hz), 7.62 (d, 1H, J = 8.4 Hz), 7.36 (dd, 1 H, J = 1.9, 8.4 Hz), 6.73 (d, 1 H, J = 7.2 Hz), 4.74 (s, 2 H), 4 .42-4.36 (m, 2H), 3.79-3.74 (m, 2H).

Example 2
Synthesis of 2- (3,4-dichlorobenzyl) -10-hydroxy-2,3,4,5-tetrahydropyrido [1,2-a] [1,4] diazepine-1,9-dione

Process 1
N- (3,4-dichlorobenzyl) -3-benzyloxy-4-oxo-4H-pyran-2-carboxamide (60 mg) obtained in the same manner as in Step 1 of Example 1 was added to tetrahydrofuran (0.5 ml). , Ethanol (0.5 ml) and water (0.1 ml), 3-amino-1-propanol (0.0226 ml) and sodium carbonate (8 mg) were sequentially added, and the mixture was stirred at room temperature for 7 hours. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 4: 1), and N- (3,4-dichlorobenzyl) -3-benzyloxy- 1- (3-hydroxypropyl) -4-oxo-1,4-dihydropyridine-2-carboxamide (43 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 9.47 (t, 1H, J = 6.0 Hz), 7.65 (d, 1H, J = 7.4 Hz), 7.57 (d, 1H, J = 1.9 Hz), 7.34-7.25 (m, 7H), 6.26 (d, 1H, J = 7.4 Hz), 5.05 (s, 2H), 4.65 (t, 1H) , J = 4.9 Hz), 4.42 (d, 2H, J = 6.0 Hz), 3.86 (dd, 2H, J = 7.2, 7.2 Hz), 3.35 (dd, 2H, J = 6.3, 10.9 Hz), 1.84-1.77 (m, 2H).

Process 2
N- (3,4-dichlorobenzyl) -3-benzyloxy-1- (3-hydroxypropyl) -4-oxo-1,4-dihydropyridine-2-carboxamide (30 mg) obtained in the previous step was added to tetrahydrofuran (30 mg). 1.5 ml) and cooled to 0 ° C. under an argon atmosphere. Diisopropylethylamine (0.034 ml) and methanesulfonyl chloride (0.0065 ml) were successively added dropwise at the same temperature, and the mixture was stirred at room temperature for 2 hours, and then again diisopropylethylamine (0.017 ml) and methanesulfonyl chloride at 0 ° C. (0.005 ml) was successively added dropwise and stirred at room temperature for 1.5 hours. To the resulting reaction solution was added 1N aqueous hydrochloric acid under ice-cooling, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over sodium sulfate, the crude product obtained by evaporating the solvent was dissolved in tetrahydrofuran (1.5 ml), sodium hydride (60%) (5 mg) was added at room temperature, and sodium hydride was added every 30 minutes. (60%) (8 mg) was added, and the mixture was added 3 times in total. Then, 1N aqueous hydrochloric acid was added under ice-cooling, and the mixture was extracted twice with ethyl acetate. Washed sequentially. After drying over sodium sulfate, the solvent was distilled off, and the resulting residue was purified by thin layer chromatography (ethyl acetate: methanol = 2: 1), and 10-benzyloxy-2- (3,4-dichlorobenzyl). ) -2,3,4,5-tetrahydropyrido [1,2-a] [1,4] diazepine-1,9-dione (23 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.49-7.46 (m, 3H), 7.39 (d, 1H, J = 8.3 Hz), 7.30-7.26 (m, 3H), 7.22 (dd, 1H, J = 2.3, 8.3 Hz), 7.09 (d, 1H, J = 7.5 Hz), 6.46 (d, 1H, J = 7.5 Hz), 5 .69 (d, 1H, J = 10.9 Hz), 5.06 (d, 1H, J = 10.9 Hz), 4.71 (d, 1H, J = 14.7 Hz), 4.48 (d, 1H, J = 14.7 Hz), 3.82-3.77 (m, 2H), 3.07 (dd, 1H, J = 6.8, 15.5 Hz), 2.96-2.85 (m , 1H), 1.92-1.79 (m, 1H), 1.74-1.61 (m, 1H).

Process 3
10-Benzyloxy-2- (3,4-dichlorobenzyl) -2,3,4,5-tetrahydropyrido [1,2-a] [1,4] diazepine-1,9 obtained in the previous step -Dione (15 mg) was dissolved in trifluoroacetic acid (1.0 ml), stirred at room temperature for 30 minutes, and then stirred at 60 ° C for 1.5 hours. After distilling off the solvent, toluene was added and concentrated three times, ethyl acetate was added and concentrated twice, and the resulting residue was crystallized from ethyl acetate / hexane to give 2- (3, 4-Dichlorobenzyl) -10-hydroxy-2,3,4,5-tetrahydropyrido [1,2-a] [1,4] diazepine-1,9-dione (11 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.79 (brs, 1H), 7.66 (d, 1H, J = 8.3 Hz), 7.65 (d, 1H, J = 2.3 Hz), 7.38 (dd, 1H, J = 2.3, 8.3 Hz), 6.50 (brs, 1H), 4.68 (brs, 2H), 4.10 (brs, 2H), 3.33 ( bt, 2H, J = 6.4 Hz), 1.94 (bt, 2H, J = 6.4 Hz).

Example 3
Synthesis of 2- (3,4-dichlorobenzyl) -9-hydroxy-3-methyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione

Process 1
N- (3,4-dichlorobenzyl) -3-benzyloxy-4-oxo-4H-pyran-2-carboxamide (50 mg) obtained in the same manner as in Step 1 of Example 1 was added to tetrahydrofuran (0.5 ml). , Ethanol (0.5 ml), water (0.1 ml), DL-1-amino-2-propanol (0.0191 ml) and sodium carbonate (7 mg) were sequentially added, and the mixture was stirred overnight at room temperature. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 4: 1), and N- (3,4-dichlorobenzyl) -3-benzyloxy- 1- (2-hydroxypropyl) -4-oxo-1,4-dihydropyridine-2-carboxamide (34 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 9.43 (t, 1H, J = 6.3 Hz), 7.57 (s, 1H), 7.57 (d, 1H, J = 7.4 Hz), 7.36 (d, 1H, J = 8.1 Hz), 7.31-7.26 (m, 6H), 6.23 (d, 1H, J = 7.4 Hz), 5.08 (d, 1H) , J = 10.9 Hz), 5.04 (d, 1H, J = 10.9 Hz), 5.02 (d, 1H, J = 6.3 Hz), 4.44 (dd, 1H, J = 6. 3, 14.8 Hz), 4.37 (dd, 1 H, J = 6.3, 14.8 Hz), 3.81 (brs, 1 H), 3.69 (dd, 1 H, J = 3.7, 14 .4 Hz), 3.60 (dd, 1 H, J = 8.8, 14.4 Hz), 0.94 (d, 3 H, J = 6.3 Hz).

Process 2
N- (3,4-dichlorobenzyl) -3-benzyloxy-1- (2-hydroxypropyl) -4-oxo-1,4-dihydropyridine-2-carboxamide (34 mg) obtained in the previous step was added to tetrahydrofuran (34 mg). 1.5 ml) and cooled to 0 ° C. under an argon atmosphere. Diisopropylethylamine (0.0385 ml) and methanesulfonyl chloride (0.0074 ml) were successively added dropwise at the same temperature, and the mixture was stirred at room temperature for 1 hour, and then again diisopropylethylamine (0.0385 ml) and methanesulfonyl chloride at 0 ° C. (0.0074 ml) was sequentially added dropwise and stirred at room temperature for 1.5 hours. To the resulting reaction solution was added 1N aqueous hydrochloric acid under ice-cooling, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over sodium sulfate, the crude product obtained by evaporating the solvent was dissolved in tetrahydrofuran (1.5 ml), sodium hydride (60%) (5 mg) was added at room temperature, and hydrogenated every 30 minutes. Sodium (60%) (8 mg) was added, and the mixture was added 3 times in total. Under ice-cooling, 1N hydrochloric acid was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were saturated sodium bicarbonate aqueous solution and saturated brine. And washed sequentially. After drying over sodium sulfate, the solvent was distilled off, and the resulting residue was purified by thin layer chromatography (ethyl acetate: methanol = 2: 1) to give 9-benzyloxy-2- (3,4-dichlorobenzyl). ) -3-Methyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (8 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.62-7.59 (m, 2H), 7.45-7.42 (m, 2H), 7.35-7.27 (m, 3H), 7. 20 (dd, 1H, J = 2.3, 8.3 Hz), 7.13 (d, 1H, J = 7.5 Hz), 6.52 (d, 1H, J = 7.5 Hz), 5.58 (D, 1H, J = 10.2 Hz), 5.25 (d, 1H, J = 14.7 Hz), 5.24 (d, 1H, J = 10.2 Hz), 4.09 (dd, 1H, J = 3.8, 12.8 Hz), 3.97 (d, 1H, J = 14.7 Hz), 3.62-3.58 (m, 2H), 1.04 (d, 3H, J = 6) .8 Hz).

Process 3
9-Benzyloxy-2- (3,4-dichlorobenzyl) -3-methyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione obtained in the previous step ( 8 mg) was dissolved in trifluoroacetic acid (1.0 ml) and stirred at 60 ° C. for 1.5 hours. After distilling off the solvent, toluene was added and concentrated three times, ethyl acetate was added and concentrated twice, and the resulting residue was crystallized from ethyl acetate / hexane to give 2- (3, 4-Dichlorobenzyl) -9-hydroxy-3-methyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (6 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.84 (brs, 1H), 7.70 (d, 1H, J = 1.9 Hz), 7.63 (d, 1H, J = 8.4 Hz), 7.40 (dd, 1H, J = 1.9, 8.4 Hz), 6.57 (brs, 1H), 5.03 (d, 1H, J = 15.3 Hz), 4.45 (d, 1H) , J = 15.3 Hz), 4.42-4.39 (m, 1H), 4.22-4.19 (m, 1H), 4.00 (m, 1H), 1.18 (d, 3H) , J = 6.5 Hz).

Example 4
Synthesis of 2- (3,4-dichlorobenzyl) -9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione

Process 1
2-tert-Butoxycarbonylamino-2-methylpropionic acid (2 g) was dissolved in tetrahydrofuran (20 ml), 3,4-dichlorobenzylamine (1.2 ml), 1-hydroxybenzotriazole (1.81 g), 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide (2.26 g) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, 5% aqueous potassium hydrogen sulfate solution and saturated brine, and then dried over sodium sulfate. The solvent was distilled off, and the resulting solid was washed with ethyl acetate / hexane and collected by filtration. Crude crystals of [1- (3,4-dichlorobenzylcarbamoyl) -1-methylethyl] carbamic acid tert-butyl ester (2.98 g) was obtained.

Process 2
The crude crystals (1.0 g) of [1- (3,4-dichlorobenzylcarbamoyl) -1-methylethyl] carbamic acid tert-butyl ester obtained in the previous step were dissolved in tetrahydrofuran (5 ml). And cooled to 0 ° C. Borane-tetrahydrofuran complex (1.0 M / tetrahydrofuran solution) (15 ml) was added dropwise at the same temperature. After removing the ice bath and stirring at room temperature for 2 hours, borane-tetrahydrofuran complex (1.0 M / tetrahydrofuran solution every 30 minutes). ) (5 ml) was added twice. Methanol (10 ml) was added to the resulting reaction solution under ice cooling, and then the solvent was distilled off. The obtained residue was dissolved in tetrahydrofuran (10 ml) and 1N aqueous sodium hydroxide solution (4 ml), and the mixture was stirred at 90 ° C. for 1 hour. The obtained reaction solution was extracted twice with toluene, and the combined organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain [2- (3,4-dichlorobenzylamino) -1,1-dimethylethyl]. Carbamic acid tert-butyl ester (290 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.59 (d, 1H, J = 1.9 Hz), 7.56 (d, 1H, J = 8.3 Hz), 7.31 (dd, 1H, J = 1.9, 8.3 Hz), 6.20 (brs, 1H), 3.69 (brs, 2H), 2.48 (brs, 2H), 2.17 (brs, 1H), 1.35 ( s, 9H), 1.16 (s, 6H).

Process 3
To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (150 mg) obtained in the same manner as in Step 1 of Example 1 in chloroform (3 ml), oxalyl chloride (0.069 ml), dimethylformamide (0.005 ml) was added and stirred at room temperature for 1 hour. The reaction solvent was distilled off under reduced pressure, toluene was added and the mixture was concentrated twice and dissolved in chloroform (2 ml). This solution was cooled to [2- (3,4-dichlorobenzylamino) -1,1-dimethylethyl] carbamic acid tert-butyl ester (192 mg), triethylamine (0.11 ml) obtained in Step 2 under ice cooling. Was added dropwise to a chloroform solution (3 ml) and stirred for 1 hour under ice-cooling. A 5% aqueous potassium hydrogen sulfate solution was added to the resulting reaction solution, and the mixture was extracted with chloroform. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, evaporated, and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), crude { 2- [N- (3-Benzyloxy-4-oxo-4H-pyran-2-carbonyl) -N- (3,4-dichlorobenzyl) amino] -1,1-dimethylethyl} carbamic acid tert-butyl ester (270 mg) was obtained.

Process 4
Crude {2- [N- (3-benzyloxy-4-oxo-4H-pyran-2-carbonyl) -N- (3,4-dichlorobenzyl) amino] -1,1-dimethyl obtained in the previous step Ethyl} carbamic acid tert-butyl ester (90 mg) was dissolved in 4N hydrochloric acid / dioxane solution (2 ml) and stirred at room temperature for 30 minutes. After the solvent was distilled off, chloroform azeotropy was performed three times. The obtained residue was dissolved in ethanol (3 ml) and saturated aqueous sodium carbonate solution (1.5 ml), and the mixture was stirred at 50 ° C. for 30 minutes. Water was added to the obtained reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over sodium sulfate, the solvent was evaporated, and the obtained residue was purified by thin layer chromatography (ethyl acetate: methanol = 3: 2). Benzyloxy-2- (3,4-dichlorobenzyl) -4,4-dimethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (50 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.65 (dd, 2H, J = 1.5, 7.9 Hz), 7.46 (d, 1H, J = 1.9 Hz), 7.45 (d, 1H , J = 8.3 Hz), 7.37-7.29 (m, 4H), 7.22 (dd, 1H, J = 1.9, 8.3 Hz), 6.50 (d, 1H, J = 7.5 Hz), 5.37 (s, 2H), 4.65 (s, 2H), 3.26 (s, 2H), 1.39 (s, 6H).

Process 5
9-Benzyloxy-2- (3,4-dichlorobenzyl) -4,4-dimethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- obtained in the previous step Dione (30 mg) was dissolved in trifluoroacetic acid (2.0 ml) and stirred at 65 ° C. for 2 hours. After distilling off the solvent, the operation of adding toluene and concentrating this was repeated three times, and the operation of adding ethyl acetate and concentrating this was performed twice. The resulting residue was crystallized from diisopropyl ether, and 2- (3,4- Dichlorobenzyl) -9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (22 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.96 (bd, 1H, J = 7.9 Hz), 7.68 (d, 1H, J = 1.9 Hz), 7.65 (d, 1H, J = 8.1 Hz), 7.40 (dd, 1H, J = 1.9, 8.1 Hz), 6.49 (brs, 1H), 4.74 (s, 2H), 3.67 (s, 2H) ), 1.44 (s, 6H).

Example 5
Synthesis of 2- (3,4-dichlorobenzyl) -9-hydroxy-6-hydroxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione

Process 1
N- (2-aminoethyl) carbamic acid tert-butyl ester (1.51 g) was dissolved in chloroform (20 ml), and 3,4-dichlorobenzaldehyde (1.65 g), acetic acid (0.54 ml), Sodium acetoxyborohydride (2.6 g) was added and stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction solution, and the mixture was stirred and extracted three times with chloroform. The combined organic layers were washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1), and [2- (3,4-dichlorobenzylamino) ethyl] carbamic acid tert-butyl ester ( 2.1 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.59 (d, 1H, J = 1.9 Hz), 7.56 (d, 1H, J = 8.3 Hz), 7.31 (dd, 1H, J = 1.9, 8.3 Hz), 6.73 (brs, 1H), 3.67 (brs, 2H), 3.00 (bdd, 2H, J = 6.0, 12.4 Hz), 2.47. (M, 2H), 2.27 (brs, 1H), 1.37 (s, 9H).

Process 2
Kojic acid (5 g) was dissolved in chloroform (50 ml), triethylamine (7.4 ml) and dimethylaminopyridine (5 mg) were added, and then tert-butyldimethylsilyl chloride (5.3 g) was added under ice cooling. Stir at temperature for 1 hour. A 5% aqueous potassium hydrogen sulfate solution was added to the resulting reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The solvent was distilled off, the resulting residue was dissolved in chloroform (50 ml), diisopropylethylamine (8.0 ml) was added, chloromethyl methyl ether (3.2 ml) was added under ice cooling, and the mixture was stirred for 30 minutes. The ice bath was removed and the mixture was stirred overnight at room temperature. A 5% aqueous potassium hydrogen sulfate solution was added to the resulting reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 2: 1) to give 5- (tert-butyldimethylsilyloxy) -2-methoxymethoxymethyl. -4H-pyran-4-one (5.5 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.19 (s, 1H), 6.41 (s, 1H), 4.66 (s, 2H), 4.39 (s, 2H), 3.28 (S, 3H), 0.92 (s, 9H), 0.16 (s, 6H).

Process 3
5- (tert-Butyldimethylsilyloxy) -2-methoxymethoxymethyl-4H-pyran-4-one (5.5 g) obtained in the previous step was dissolved in tetrahydrofuran (30 ml), and tetra (n -Butyl) ammonium fluoride (1.0 M / tetrahydrofuran solution) (19.2 ml) was added and stirred for 30 minutes. To the obtained reaction solution, 5% aqueous potassium hydrogen sulfate solution was added to adjust the pH to 3, and extraction was performed 4 times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over sodium sulfate. The solvent was distilled off and the resulting solid was washed with ethyl acetate / hexane. The obtained solid (2.3 g) was dissolved in water (20 ml), 1N aqueous sodium hydroxide solution (12.7 ml), 36% aqueous formaldehyde solution was added at room temperature, and the mixture was stirred for 6 hours. A 5% aqueous potassium hydrogen sulfate solution was added to the resulting reaction solution to adjust the pH to 3, sodium chloride was added, and the mixture was extracted 5 times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the resulting residue was dissolved in dimethylformamide (10 ml), potassium carbonate (1.97 g) was added, benzyl chloride (0.82 ml) was added at room temperature, and the mixture was stirred overnight. To the obtained reaction solution, 5% aqueous potassium hydrogen sulfate solution was added to adjust the pH to 3, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 4) to give 3-benzyloxy-2-hydroxymethyl-6-methoxymethoxymethyl- 4H-pyran-4-one (783 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.47-7.32 (m, 5H), 6.43 (s, 1H), 5.48 (t, 1H, J = 6.0 Hz), 5. 03 (s, 2H), 4.68 (s, 2H), 4.40 (s, 2H), 4.28 (d, 2H, J = 6.0 Hz), 3.29 (s, 3H).

Process 4
3-Benzyloxy-2-hydroxymethyl-6-methoxymethoxymethyl-4H-pyran-4-one (783 mg) obtained in the previous step was added to acetone (8.0 ml) and saturated aqueous sodium hydrogen carbonate solution (8.0 ml). Dissolve in potassium bromide (30 mg), 2,2,6,6-tetramethylpiperidine 1-oxyl, free radical (39 mg) and add 6% aqueous sodium hypochlorite solution (3.4 ml) under ice cooling. After dropwise addition and stirring for 30 minutes, a 6% aqueous sodium hypochlorite solution (3.3 ml) was further added dropwise and the mixture was further stirred for 30 minutes. Water was added to the obtained reaction solution, and the mixture was washed twice with ethyl acetate. A 5% aqueous potassium hydrogen sulfate solution was added to the aqueous layer to adjust to pH = 3, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain 3-benzyloxy-6-methoxymethoxymethyl-4-oxo-4H-pyran-2-carboxylic acid (710 mg).
¹ H-NMR (DMSO-d ₆ ) δ 7.44-7.30 (m, 5H), 6.54 (s, 1H), 5.11 (s, 2H), 4.65 (s, 2H) 4.43 (s, 2H), 3.27 (s, 3H).

Process 5
3-Benzyloxy-6-methoxymethoxymethyl-4-oxo-4H-pyran-2-carboxylic acid (658 mg) obtained in Step 4 was dissolved in dimethylformamide (5 ml) and obtained in Step 1 at room temperature. [2- (3,4-Dichlorobenzylamino) ethyl] carbamic acid tert-butyl ester (596 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (429 mg), 1-hydroxybenzotriazole (343 mg) And stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 15: 1), and crude {2- [N- (3-benzyloxy-6-methoxymethoxymethyl-4- Oxo-4H-pyran-2-carbonyl) -N- (3,4-dichlorobenzyl) amino] ethyl} carbamic acid tert-butyl ester (1.12 g) was obtained.

Step 6
Crude {2- [N- (3-benzyloxy-6-methoxymethoxymethyl-4-oxo-4H-pyran-2-carbonyl) -N- (3,4-dichlorobenzyl) amino] obtained in the previous step Ethyl} carbamic acid tert-butyl ester (1.12 g) was dissolved in 4N hydrochloric acid / dioxane solution (10 ml) and stirred at room temperature for 30 minutes. After distilling off the solvent, toluene was added and the mixture was concentrated three times. The obtained residue was dissolved in ethanol (40 ml) and saturated aqueous sodium carbonate solution (10 ml), and stirred at 50 ° C. for 30 minutes. The solvent was distilled off, and the resulting crystals were washed with 5% aqueous potassium hydrogen sulfate solution and a small amount of ethyl acetate, and then collected by filtration. 9-Benzyloxy-2- (3,4-dichlorobenzyl) -6-hydroxymethyl- 3,4-Dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (433 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.64 (d, 1H, J = 1.5 Hz), 7.63 (d, 1H, J = 8.3 Hz), 7.51 (dd, 2H, J = 1.5, 8.3 Hz), 7.37-7.29 (m, 4H), 6.40 (s, 1H), 5.67 (t, 1H, J = 5.7 Hz), 5.08 (S, 2H), 4.68 (s, 2H), 4.43 (d, 2H, J = 5.7 Hz), 4.10-4.04 (m, 2H), 3.63-3.57 (M, 2H).

Step 7
9-Benzyloxy-2- (3,4-dichlorobenzyl) -6-hydroxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione obtained in the previous step (15 mg) was dissolved in trifluoroacetic acid (1 ml) and stirred at room temperature for 1 hour. After distilling off the solvent, toluene was added and concentrated three times, ethyl acetate was added and concentrated twice, and the resulting residue was crystallized from ethyl acetate / diisopropyl ether to give 2- (3 , 4-dichlorobenzyl) -9-hydroxy-6-hydroxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (12 mg).
¹ H-NMR (DMSO-d ₆ ) δ 12.20 (brs, 1H), 7.66 (d, 1H, J = 1.9 Hz), 7.62 (d, 1H, J = 8.1 Hz), 7.36 (dd, 2H, J = 1.9, 8.1 Hz), 6.25 (s, 1H), 5.65 (t, 1H, J = 5.6 Hz), 4.71 (s, 2H) ), 4.41 (d, 2H, J = 5.6 Hz), 4.15-4.13 (m, 2H), 3.68-3.65 (m, 2H).

Example 6
Synthesis of 2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carboxylic acid

Process 1
9-Benzyloxy-2- (3,4-dichlorobenzyl) -6-hydroxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1 obtained in Step 6 of Example 5 , 8-dione (100 mg) in acetone (1.6 ml), saturated aqueous sodium hydrogen carbonate (1.0 ml), potassium bromide (3 mg), 2,2,6,6-tetramethylpiperidine 1-oxyl, Free radicals (3 mg) were added, 6% aqueous sodium hypochlorite solution (3.4 ml) was added dropwise under ice cooling, and the mixture was stirred for 15 minutes. The ice bath was removed and the mixture was stirred at room temperature for 4 hours. Furthermore, 6% sodium hypochlorite aqueous solution (0.1 ml) was added dropwise and stirred for 1.5 hours. The obtained reaction solution was poured into a 5% aqueous potassium hydrogen sulfate solution and stirred for 30 minutes. The crystals were collected by filtration, and 9-benzyloxy-2- (3,4-dichlorobenzyl) -1,8-dioxo-1,3. , 4,8-Tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carboxylic acid (94 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.64 (d, 1H, J = 1.9 Hz), 7.62 (d, 1H, J = 8.4 Hz), 7.49 (dd, 2H, J = 1.9, 8.4 Hz), 7.36-7.29 (m, 4H), 6.70 (s, 1H), 5.11 (s, 2H), 4.67 (s, 2H), 4.26-4.24 (m, 2H), 3.59-3.56 (m, 2H).

Process 2
9-Benzyloxy-2- (3,4-dichlorobenzyl) -1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine- obtained in the previous step 6-carboxylic acid (25 mg) was dissolved in trifluoroacetic acid (2 ml) and stirred at room temperature for 1 hour. After distilling off the solvent, toluene was added and concentrated three times, methanol and ethyl acetate were added and concentrated once, and the resulting residue was crystallized from methanol / ethyl acetate. (3,4-Dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carboxylic acid (20 mg) was obtained. It was.
¹ H-NMR (DMSO-d ₆ ) δ 7.69 (d, 1H, J = 2.2 Hz), 7.64 (d, 1H, J = 8.4 Hz), 7.39 (dd, 2H, J = 2.2, 8.4 Hz), 6.58 (s, 1H), 4.73 (s, 2H), 4.44-4.41 (m, 2H), 3.71-3.68 (m) , 2H).

Example 7
Of 2- (3,4-dichlorobenzyl) -6- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Composition

Process 1
9-Benzyloxy-2- (3,4-dichlorobenzyl) -6-hydroxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1 obtained in Step 6 of Example 5 , 8-dione (860 mg) in chloroform (80 ml) was added Dess-Martin reagent (843 mg). After stirring at room temperature for 1 hour, the solvent was distilled off, chloroform (50 ml) was added to the resulting residue, and the solid was filtered off. The filtrate was concentrated and purified by silica gel column chromatography (chloroform: acetone = 1: 2), and 9-benzyloxy-2- (3,4-dichlorobenzyl) -1,8-dioxo-1,3,4 , 8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carbaldehyde (621 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 9.58 (s, 1H), 7.62-7.55 (m, 2H), 7.46-7.40 (m, 2H), 7.37-7. 26 (m, 3H), 7.16 (dd, 1H, J = 2.0, 8.1 Hz), 6.97 (s, 1H), 5.39 (s, 2H), 4.65 (s, 2H), 4.43-4.37 (m, 2H), 3.43-3.36 (m, 2H).

Process 2
9-Benzyloxy-2- (3,4-dichlorobenzyl) -1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine- obtained in the previous step A solution of 6-carbaldehyde (205 mg) in dry tetrahydrofuran (40 ml) was cooled in a dry ice-acetone bath. At the same temperature, tert-butylmagnesium chloride (2.0 M / diethyl ether solution) (0.448 ml) was added dropwise. After stirring for 30 minutes, 5% aqueous potassium hydrogen sulfate solution was added to adjust to pH = 2, and the mixture was extracted with ethyl acetate. . The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. Purification by silica gel column chromatography (chloroform: methanol = 12: 1), crude 9-benzyloxy-2- (3,4-dichlorobenzyl) -6- (1-hydroxy-2,2-dimethylpropyl)- 3,4-Dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (220 mg) was obtained.

Crude 9-benzyloxy-2- (3,4-dichlorobenzyl) -6- (1-hydroxy-2,2-dimethylpropyl) -3,4-dihydro-2H-pyrido [1,2-a] Dessmartin reagent (65 mg) was added to a solution of pyrazine-1,8-dione (132 mg) in chloroform (4 ml). After stirring at room temperature for 20 minutes, a saturated aqueous sodium hydrogen carbonate solution and sodium sulfite were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. Purification by silica gel column chromatography (ethyl acetate: chloroform = 4: 1), 9-benzyloxy-2- (3,4-dichlorobenzyl) -6- (2,2-dimethylpropionyl) -3,4- Dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (38 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.63-7.57 (m, 2H), 7.46-7.38 (m, 2H), 7.37-7.26 (m, 3H), 7. 15 (dd, 1H, J = 2.1, 8.1 Hz), 6.42 (s, 1H), 5.38 (s, 2H), 4.63 (s, 2H), 3.69-3. 61 (m, 2H), 3.43-3.36 (m, 2H), 1.27 (s, 9H).

Process 3
9-Benzyloxy-2- (3,4-dichlorobenzyl) -6- (2,2-dimethylpropionyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine obtained in the previous step Trifluoroacetic acid (4 ml) was added to -1,8-dione (36 mg), and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent, toluene was added and the mixture was concentrated twice. The obtained residue was crystallized from ethyl acetate: diisopropyl ether = 1: 4 to give 2- (3,4-dichlorobenzyl) -6- (2,2-Dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (26 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 12.40 (brs, 1H), 7.68 (d, 1H, J = 2.1 Hz), 7.62 (d, 1H, J = 8.4 Hz), 7.38 (dd, 1H, J = 2.1, 8.4 Hz), 6.15 (s, 1H), 4.71 (s, 2H), 3.92-3.85 (m, 2H), 3.67-3.59 (m, 2H), 1.22 (s, 9H).

Example 8
Synthesis of 2- (3,4-dichlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione

Process 1
N- (3,4-dichlorobenzyl) -3-benzyloxy-4-oxo-4H-pyran-2-carboxamide (49 mg) in tetrahydrofuran (0.5 ml) obtained in the same manner as in Step 1 of Example 1. Aminoacetaldehyde dimethyl acetal (0.026 ml) and sodium carbonate (6.4 mg) were sequentially added to a solution of ethanol (0.5 ml) and water (0.1 ml), and the mixture was stirred at room temperature for 1 hour and then stirred at 45 ° C. for 4 hours. The mixture was stirred at 60 ° C. for 20 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 5: 1), and N- (3,4-dichlorobenzyl) -3-benzyloxy-1- (2, 2-Dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxamide (30 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.35 (d, 1H, J = 2.0 Hz), 7.30-7.20 (m, 7H), 7.09 (t, 1H, J = 6.3 Hz) ), 7.05 (dd, 1H, J = 2.0, 8.0 Hz), 6.33 (d, 1H, J = 7.4 Hz), 5.20 (s, 2H), 4.51 (t , 1H, J = 5.1 Hz), 4.32 (d, 2H, J = 6.3 Hz), 3.86 (d, 1H, J = 5.1 Hz), 3.31 (s, 6H).

Process 2
N- (3,4-dichlorobenzyl) -3-benzyloxy-1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxamide (30 mg) obtained in the previous step Camphorsulfonic acid (15 mg) was added to a toluene (3 ml) solution, and the mixture was stirred at 110 ° C. for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. 9-Benzyloxy-2- (3,4-dichlorobenzyl) -2H-pyrido [1,2-a] pyrazine was purified by silica gel column chromatography (ethyl acetate: methanol = 5: 1 to 4: 1). -1,8-dione (17 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.63 (d, 1H, J = 7.4 Hz), 7.43 (d, 1H, J = 8.4 Hz), 7.39 (d, 1H, J = 2) 0.0 Hz), 7.38-7.25 (m, 5H), 7.15 (dd, 1H, J = 2.0, 8.4 Hz), 6.70 (d, 1H, J = 7.4 Hz) 6.41 (d, 1H, J = 6.3 Hz), 6.20 (d, 1H, J = 6.3 Hz), 5.39 (s, 2H), 4.89 (s, 2H).

Process 3
Trifluoroacetic acid (2 ml) was added to 9-benzyloxy-2- (3,4-dichlorobenzyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione (16 mg) obtained in the previous step. The mixture was further stirred at room temperature for 1 hour. After distilling off the solvent, toluene was added and the mixture was concentrated twice. The obtained residue was crystallized from diisopropyl ether, and 2- (3,4-dichlorobenzyl) -9-hydroxy-2H-pyrido [1 , 2-a] pyrazine-1,8-dione (9 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.11 (d, 1H, J = 7.3 Hz), 7.71 (d, 1H, J = 1.8 Hz), 7.66 (d, 1H, J = 8.4 Hz), 7.40 (dd, 1 H, J = 1.8, 8.4 Hz), 7.35 (d, 1 H, J = 6.2 Hz), 7.03 (d, 1 H, J = 6.2 Hz), 6.76 (d, 1H, J = 7.3 Hz), 4.99 (s, 2H).

Example 9
Synthesis of 2- (3,4-dichlorobenzyl) -9-hydroxy-3-methyl-2H-pyrido [1,2-a] pyrazine-1,8-dione

Process 1
N- (3,4-dichlorobenzyl) -3-benzyloxy-4-oxo-4H-pyran-2-carboxamide (0.04 g) obtained in the same manner as in Step 1 of Example 1 in tetrahydrofuran (3 ml) To the solution were added 1-amino-2-propanol (0.224 g) and saturated aqueous sodium hydrogen carbonate solution (1 ml), and the mixture was stirred at 60 ° C. for 4 hours. The reaction solvent was evaporated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with 1N aqueous hydrochloric acid and saturated brine. After drying over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1), and N- (3,4-dichlorobenzyl) -3-benzyloxy-1- (2 -Hydroxypropyl) -4-oxo-1,4-dihydropyridine-2-carboxamide (0.334 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 9.45 (t, 1H), 7.58-7.56 (m, 2H), 7.37-7.23 (m, 7H), 6.62 ( d, 1H, J = 5.7 Hz), 5.09-5.05 (m, 3H), 4.50-4.31 (m, 4H), 3.81-3.42 (m, 4H), 0.92 (d, 3H, J = 5.7 Hz).

Process 2
N- (3,4-dichlorobenzyl) -3-benzyloxy-1- (2-hydroxypropyl) -4-oxo-1,4-dihydropyridine-2-carboxamide (0.250 g) obtained in the previous step was used. Dissolved in chloroform (10 ml), desmartin reagent (0.5 g) was added, and the mixture was stirred at room temperature overnight. The resulting reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution. After drying over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1), and N- (3,4-dichlorobenzyl) -3-benzyloxy-4-oxo- Crude crystals (0.304 g) of 1- (2-oxopropyl) -1,4-dihydropyridine-2-carboxamide were obtained. The crude crystals were dissolved in tetrahydrofuran-toluene (5: 2, 7 ml), p-toluenesulfonic acid (0.03 g) was added, and the mixture was stirred at 80 ° C. for 10 hours. The obtained reaction solution was purified by silica gel column chromatography (chloroform: methanol = 10: 1), and 9-benzyloxy-2- (3,4-dichlorobenzyl) -3-methyl-2H-pyrido [1, 2-a] pyrazine-1,8-dione (0.063 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.93 (d, 1H, J = 5.7 Hz), 7.84-7.69 (m, 4H), 7.32-7.20 (m, 4H) ), 7.03 (s, 1H), 6.62 (d, 1H, J = 5.7 Hz), 5.12 (s, 2H), 5.07 (s, 2H), 2.01 (s, 3H).

Process 3
9-Benzyloxy-2- (3,4-dichlorobenzyl) -3-methyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (0.063 g) obtained in the previous step was trimethylated. Dissolved in fluoroacetic acid (2 ml) and stirred at room temperature for 3 hours. Thereafter, the reaction solution was azeotroped three times with toluene. Crystallization with ethyl acetate-diisopropyl ether gave 2- (3,4-dichlorobenzyl) -9-hydroxy-3-methyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (0.05 g). )
¹ H-NMR (DMSO-d ₆ ) δ 8.19 (d, 1H, J = 10 Hz), 7.64-7.61 (m, 2H), 7.44 (s, 1H), 7.33 ( dd, 1H, J = 7.3, 11.2 Hz), 7.05 (d, 1H, J = 9.6 Hz), 5.21 (s, 2H), 2.12 (s, 3H).

Example 10
Synthesis of 2- (3-chlorobenzyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

Process 1
Oxalyl chloride (2.00 g) and dimethylformamide (50 μl) were added to a chloroform (30 ml) solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (3.00 g) for 30 minutes at room temperature. Stir. After distilling off the solvent from the reaction solution, an operation of adding toluene and concentrating it was performed to obtain acid chloride. Triethylamine (1.85 g) was added to a chloroform (30 ml) solution of 3-chlorobenzylamine (1.90 g), and the above-mentioned acid chloride in chloroform (30 ml) was added dropwise with stirring at 0 ° C. After stirring at 0 ° C. for 30 minutes, a saturated aqueous sodium hydrogen carbonate solution (40 ml) was added to the reaction solution to return to room temperature, and the organic layer was separated. The aqueous layer was extracted with chloroform, and the organic layers were combined and washed with saturated brine. After drying over sodium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 2) to give 3-benzyloxy-4-oxo-4H-pyran-2. -Carboxylic acid 3-Chlorobenzylamide (3.90 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.08 (brs, 1H), 7.84 (d, 1H, J = 5.5 Hz), 7.37-7.20 (m, 7H), 7.15 ( m, 1H), 7.05 (m, 1H), 5.38 (s, 2H), 4.37 (d, 2H, J = 5.8 Hz).

Process 2
To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (1.20 g) obtained in the previous step in toluene (120 ml), pyridinium p-toluenesulfonate (815 mg) and 2-Amino-3-methylbutanol (702 mg) was added and stirred at 110 ° C. for 15 hours. 2-Amino-3-methylbutanol (833 mg) was added, and the mixture was further stirred at 110 ° C. for 30 hr. The solvent was distilled off from the reaction solution, saturated aqueous sodium carbonate solution (30 ml) was added, and the mixture was extracted twice with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. N- (3-chlorobenzyl) -3-benzyloxy-1- (1-hydroxymethyl-2-methylpropyl) -4 was purified by silica gel column chromatography (ethyl acetate to chloroform: methanol = 10: 1). A crude product mainly composed of -oxo-1,4-dihydropyridine-2-carboxamide was obtained. The crude product was used in the next step without further purification.

Process 3
Crude formation of N- (3-chlorobenzyl) -3-benzyloxy-1- (1-hydroxymethyl-2-methylpropyl) -4-oxo-1,4-dihydropyridine-2-carboxamide obtained in the previous step Triethylamine (1.60 g) and sulfur trioxide pyridine complex (900 mg) were sequentially added to a solution of the product in dimethyl sulfoxide (8.5 ml), and the mixture was stirred at room temperature for 20 minutes. To the reaction solution was added 1M hydrochloric acid (50 ml), and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated. Purification by silica gel column chromatography (chloroform: methanol = 100: 1 to 20: 1), 9-benzyloxy-2- (3-chlorobenzyl) -3-hydroxy-4-isopropyl-3,4-dihydro- 2H-pyrido [1,2-a] pyrazine-1,8-dione (202 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.70 (d, 1H, J = 7.4 Hz), 7.53-7.46 (m, 3H), 7.40-7.27 (m, 5H) ), 6.83 (d, 1H, J = 5.6 Hz), 29 (d, 1H, J = 7.4 Hz), 5.12-5.02 (m, 4H), 4.31 (d, 1H) , J = 14.6 Hz), 3.83 (dd, 1H, J = 10.0, 1.5 Hz), 1.41 (m, 1H), 0.66 (d, 3H, J = 6.7 Hz) , 0.55 (d, 3H, J = 6.5 Hz).

Process 4
9-Benzyloxy-2- (3-chlorobenzyl) -3-hydroxy-4-isopropyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- obtained in the previous step Acetic acid (5 ml) and concentrated hydrochloric acid (5 ml) were sequentially added to dione (200 mg), and the mixture was stirred at 90 ° C. for 15 hours. After distilling off the solvent from the reaction solution, toluene was added to concentrate it. Crystallization with diisopropyl ether-ethyl acetate gave 2- (3-chlorobenzyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (164 mg) Got.
¹ H-NMR (DMSO-d ₆ ) δ 13.0 (brs, 1H), 8.52 (d, 1H, J = 7.4 Hz), 7.50 (s, 1H), 7.43-7. 35 (m, 3H), 7.25 (m, 1H), 7.22 (s, 1H), 5.13 (s, 2H), 3.25 (Hept, 1H, J = 6.7 Hz), 1 .25 (d, 6H, J = 6.7 Hz).

Example 11
Synthesis of 2- [3- (2,6-dichlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione

Process 1
Lithium aluminum hydride (1.31 g) was suspended in tetrahydrofuran (30 ml), and 3- (2,6-dichlorophenyl) acrylic acid (4.62 g) was added dropwise over about 20 minutes under ice cooling. During the dropwise addition, tetrahydrofuran (20 ml) was added. After stirring at 0 ° C. for 3.5 hours, the mixture was stirred at room temperature for 18 hours. A 4N aqueous potassium hydroxide solution was added to the reaction solution, and the solid component was separated by filtration. The filtrate was concentrated under reduced pressure, 1N aqueous hydrochloric acid solution was added to the residue, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine. After drying with sodium sulfate, the solvent was distilled off to obtain a crude product (5.40 g) of 3- (2,6-dichlorophenyl) propan-1-ol.

Process 2
Triphenylphosphine (6.14 g), phthalimide (3.44 g), 3- (2,6-dichlorophenyl) propan-1-ol obtained in the previous step (crude product: 5.40 g) in tetrahydrofuran (90 ml) Under ice-cooling, diethyl azodicarboxylate (40% toluene solution) (10.19 g) was added dropwise to the solution. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, the precipitated solid component was filtered off, and the filtrate was concentrated. Diethyl ether was again added to the obtained residue, the solid component was filtered off, the filtrate was concentrated, and purified by silica gel column chromatography (chloroform to hexane: ethyl acetate = 4: 1) to give 2- [3- ( A crude product (4.28 g) of 2,6-dichlorophenyl) propyl] isoindole-1,3-dione was obtained.

Process 3
Hydrazine monohydrate was added to a solution of 2- [3- (2,6-dichlorophenyl) propyl] isoindole-1,3-dione (crude product: 4.28 g) obtained in the previous step in ethanol (50 ml). (2.79 ml) was added and the mixture was heated to reflux for 1 hour. The reaction solution was cooled to room temperature, 10% aqueous sodium carbonate solution (90 ml) was added, and the mixture was extracted with chloroform (100 ml × 2). The organic layer was washed with water and dried over sodium sulfate, and then the solvent was distilled off to obtain a crude product (3.20 g) of 3- (2,6-dichlorophenyl) propylamine.

Process 4
Oxalyl chloride (0.13 ml) and dimethylformamide (0.01 ml) were added to a suspension of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (0.30 g) in chloroform (10 ml) at room temperature. For 30 minutes. After the reaction solvent was distilled off under reduced pressure, toluene was added and the mixture was concentrated, and chloroform (5 ml) was added. Under ice-cooling, a solution of 3- (2,6-dichlorophenyl) propylamine (0.31 g) obtained in the previous step in chloroform (1 ml) and triethylamine (0.21 ml) were sequentially added, and the mixture was added under ice-cooling. Stir for minutes. A 1N aqueous hydrochloric acid solution was added to the resulting reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 2), and N- [3- (2,6-dichlorophenyl) Propyl] -3-benzyloxy-4-oxo-4H-pyran-2-carboxamide (0.24 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.81 (d, 1H, J = 5.6 Hz), 7.79 (br, 1H), 7.39-7.26 (m, 7H), 7.08 ( dd, 1H, J = 7.6, 8.6 Hz), 6.49 (d, 1H, J = 5.6 Hz), 5.40 (s, 2H), 3.31 (dt, 2H, J = 5) .2, 7.2 Hz), 2.82 (dd, 2H, J = 7.9, 8.1 Hz), 1.62-1.57 (m, 2H).

Process 5
N- [3- (2,6-dichlorophenyl) propyl] -3-benzyloxy-4-oxo-4H-pyran-2-carboxamide (0.24 g) obtained in the previous step was added to tetrahydrofuran (1.8 ml), Ethanol (1.8 ml) and aminoacetaldehyde dimethyl acetal (0.012 ml) were added, and the mixture was stirred at 60 ° C. for 46 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0-10: 1), and N- [3- (2,6-dichlorophenyl) propyl] -3-benzyloxy-1- (2,2-Dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxamide (0.24 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.35-7.24 (m, 8H), 7.07 (dd, 1H, J = 7.6, 8.1 Hz), 6.42 (d, 1H, J = 7.5 Hz), 6.25 (br, 1H), 5.28 (s, 2H), 4.57 (dd, 1H, J = 3.1, 5.1 Hz), 3.89 (d, 2H) , J = 4.8 Hz), 3.41-3.36 (m, 6H), 3.29 (m, 2H), 2.85 (dd, 2H, J = 7.2, 8.6 Hz), 1 71-1.62 (m, 2H).

Step 6
N- [3- (2,6-dichlorophenyl) propyl] -3-benzyloxy-1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxamide obtained in the previous step (237 mg) in toluene (20 ml) was added camphorsulfonic acid (106 mg) and stirred at 110 ° C. for 5 hours. After stirring at room temperature for 15 hours, camphorsulfonic acid (21 mg) was added, and the mixture was stirred at 110 ° C. for 3 hours. Triethylamine (1 ml) was added to the reaction solution at room temperature, and the precipitated solid was filtered off. The filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1 to 5: 1), thin layer chromatography (ethyl acetate: methanol = 5: 1), and 9-benzyloxy-2- [3- (2,6-Dichlorophenyl) propyl] -2H-pyrido [1,2-a] pyrazine-1,8-dione (120 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.64 (d, 2H, J = 7.9 Hz), 7.38 (d, 1H, J = 7.4 Hz), 7.38-7.23 (m, 5H) ), 7.08 (dd, 1H, J = 7.7, 8.4 Hz), 6.71 (d, 1H, J = 7.4 Hz), 6.43 (d, 1H, 5.8 Hz), 6 .28 (d, 1H, J = 6.0 Hz), 5.35 (s, 2H), 3.89 (t, 2H, J = 7.4 Hz), 2.98 (dd, 2H, J = 7. 2,8.4 Hz), 1.99 (m, 2H).

Step 7
9-Benzyloxy-2- [3- (2,6-dichlorophenyl) propyl] -2H-pyrido [1,2-a] pyrazine-1,8-dione (120 mg) obtained in the previous step was added to trifluoroacetic acid. (1 ml) was added and left at room temperature for 1 hour. After distilling off the solvent, toluene was added and the mixture was concentrated twice. The obtained crystals were washed with diisopropyl ether to give 2- [3- (2,6-dichlorophenyl) propyl] -9-hydroxy-2H. -Pyrid [1,2-a] pyrazine-1,8-dione (92 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.16 (d, 1H, J = 7.3 Hz), 7.46 (d, 2H, J = 7.7 Hz), 7.41 (d, 1H, J = 6.2 Hz), 7.28 (m, 1 H), 7.11 (d, 1 H, J = 5.9 Hz), 6.85 (d, 1 H, J = 7.7 Hz), 4.43 (br , 1H), 3.92 (t, 2H, J = 7.0 Hz), 2.93 (dd, 2H, J = 7.7, 8.4 Hz), 1.92 (m, 2H).

Example 12
Synthesis of 2- (3,4-dichlorobenzyl) -9-hydroxy-2H-pyrazino [1,2-c] pyrimidine-1,8-dione hydrochloride

Process 1
Sodium methoxide (1.28 g) and formamidine hydrochloride (953 mg) were added to a solution of 2-benzyloxy-3-hydroxy-2-butenedicarboxylic acid dimethyl ester (3.0 g) in methanol (60 ml) under ice cooling. In addition, the mixture was stirred at 70 ° C. for 1.5 hours. After the reaction solvent was distilled off under reduced pressure, water was added to the residue to dissolve it. A 5% aqueous potassium hydrogen sulfate solution was added, and the precipitated solid was collected by filtration, washed with water, and dried to give 5-benzyloxy-6-hydroxypyrimidine-4-carboxylic acid methyl ester (1.1 g).
¹ H-NMR (DMSO-d ₆ ) δ 13.1 (brs, 1H), 8.01 (s, 1H), 7.2-7.5 (m, 5H), 5.12 (s, 2H) , 3.75 (s, 3H).

Process 2
Methanol (6 ml) and 1N aqueous sodium hydroxide solution (2.5 ml) were added to 5-benzyloxy-6-hydroxypyrimidine-4-carboxylic acid methyl ester (530 mg) obtained in the previous step, and the mixture was stirred at room temperature for 1 hour. . After adding 2N hydrochloric acid (2.5 ml) to the reaction solution, methanol was distilled off under reduced pressure. The precipitate was collected by filtration, washed with water and dried to obtain 5-benzyloxy-6-hydroxypyrimidine-4-carboxylic acid (253 mg).
¹ H-NMR (DMSO-d ₆ ) δ 13.5 (brs, 1H), 13.0 (brs, 1H), 8.00 (s, 2H), 7.2-7.5 (s, 2H) .

Process 3
5-Benzyloxy-6-hydroxypyrimidine-4-carboxylic acid (103 mg) obtained in the previous step was dissolved in acetonitrile / tetrahydrofuran (2 ml), carbonyldiimidazole (88 mg) was added, and the mixture was stirred at room temperature for 30 minutes. This was added to a solution of N- (3,4-dichlorobenzyl) -N- (2,2-dimethoxyethyl) amine obtained in the same manner as in Step 1 of Example 5 in acetonitrile (2 ml) and stirred at room temperature overnight. did. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform and washed with saturated brine. After drying over magnesium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2-ethyl acetate) to obtain an oil (210 mg). This was dissolved in dioxane (5 ml), pyridinium p-toluenesulfonic acid (22 mg) was added, and the mixture was heated to reflux overnight. The reaction solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, and then washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate: methanol = 9: 1) to obtain an oil (40 mg). This was dissolved in acetic acid (600 μl) and concentrated hydrochloric acid (200 μl) and stirred at 100 ° C. for 1.5 days. The reaction solvent was distilled off under reduced pressure, toluene was added to the residue and the mixture was concentrated twice, and then crystallized from methanol. The crystals were collected by filtration and dried to give 2- (3,4-dichlorobenzyl) -9-hydroxy-2H-pyrazino [1,2-c] pyrimidine-1,8-dione hydrochloride (12 mg).
¹ H-NMR (DMSO-d ₆ ) δ 1.08 (brs, 1H), 8.48 (s, 1H), 7.68 (d, 1H, J = 4 Hz), 7.63 (d, 1H, J = 8 Hz), 7.3-7.4 (m, 2H), 7.16 (d, 1H, J = 8 Hz), 6.80 (d, 1H, J = 8 Hz), 4.90 (s, 2H).

Examples 13-92
The compounds of Examples 13 to 92 shown in the table below were obtained by the same or similar methods as in Examples 1 to 12 and conventional methods.

Example 118
Synthesis of 2- (3-chlorobenzyl) -9-hydroxy-7- (1-hydroxy-2,2-dimethylpropyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

Process 1
3-Benzyloxy-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (300 mg) and 2,2-dimethylpropionaldehyde (9 ml) tetrahydrofuran obtained in Step 1 of Example 10 ( 9M), 1.5M lithium diisopropylamide-tetrahydrofuran / cyclohexane solution (4.5ml) was added dropwise at -78 ° C under nitrogen. After stirring at the same temperature for 2 hours, the cooling bath was removed, 1N aqueous hydrochloric acid (15 ml) and ethyl acetate (25 ml) were immediately added, and the temperature was raised to room temperature. The organic layer was separated and extracted from the aqueous layer with ethyl acetate (25 ml). The combined organic layers were dried and concentrated, and then purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give 3-benzyloxy-5- (1-hydroxy-2,2-dimethylpropyl) -4. -Oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (0.22 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.07 (brt, 1H, J = 5.8 Hz), 7.82 (s, 1H), 7.35-7.18 (m, 7H), 7.15 ( s, 1H), 7.05 (d, 1H, J = 7.0 Hz), 5.33 (s, 2H), 4.43 (d, 1H, J = 7.2 Hz), 4.39 (d, 2H, J = 5.8 Hz), 3.61 (d, 1H, J = 7.2 Hz), 0.96 (s, 9H).

Process 2
3-Benzyloxy-5- (1-hydroxy-2,2-dimethylpropyl) -4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (0.22 g) in tetrahydrofuran (1.5 ml)- Aminoacetaldehyde dimethyl acetal (0.16 ml) was added to an ethanol (1.5 ml) solution, and the mixture was stirred at 60 ° C. for 24 hours. After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to ethyl acetate) to give 3-benzyloxy-1- (2,2-dimethoxyethyl) -5- (1-hydroxy -2,2-dimethylpropyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (198 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.73 (brdd, 1H, J = 6.2, 5.8 Hz), 7.33-7.10 (m, 10H), 5.76 (brd, 1H, J = 7.4 Hz), 5.17 (d, 1 H, J = 11.0 Hz), 5.01 (d, 1 H, J = 11.0 Hz), 4.50 (t, 1 H, J = 5.0 Hz) , 4.39 (dd, 1H, J = 6.2, 15.1 Hz), 4.23 (dd, 1H, J = 5.8, 15.1 Hz), 4.14 (d, 1H, J = 7) .4 Hz), 3.29 (s, 3H), 3.27 (s, 3H), 0.89 (s, 9H).

Process 3
3-Benzyloxy-1- (2,2-dimethoxyethyl) -5- (1-hydroxy-2,2-dimethylpropyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide Concentrated hydrochloric acid (0.55 ml) was added to a solution of (60 mg) in dioxane (0.55 ml), and the mixture was stirred at 90 ° C. for 2 hours. After distilling off the solvent, toluene was added and the mixture was concentrated twice, crystallized from ethyl acetate-diisopropyl ether, and 2- (3-chlorobenzyl) -9-hydroxy-7- (1-hydroxy-2 , 2-dimethylpropyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (44 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.30 (s, 1H), 7.70 (d, 1H, J = 6.2 Hz), 7.50 (s), 7.44-7.34 ( m, 3H), 7.26 (d, 1H, J = 6.2 Hz), 5.09 (d, 1H, J = 14.9 Hz), 4.99 (d, 1H, J = 14.9 Hz), 4.76 (s, 1H), 0.87 (s, 9H).

Example 125
Synthesis of 2- (3-chlorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

Process 1
3-Benzyloxy-1- (2,2-dimethoxyethyl) -5- (1-hydroxy-2,2-dimethylpropyl) -4-oxo-1,4-dihydropyridine obtained in Step 2 of Example 118 2-Carboxylic acid Triethylamine (1.1 ml) and sulfur trioxide / pyridine complex (450 mg) were added to a solution of 3-chlorobenzylamide (120 mg) in dimethyl sulfoxide (5 ml), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 ml). The combined ethyl acetate layers were washed with water, dried and concentrated, then purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3), and 3-benzyloxy-1- (2,2-dimethoxyethyl) -5. -(2,2-Dimethylpropionyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (104 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.27 (brt, 1H, J = 6.0 Hz), 7.26-7.14 (m, 8H), 7.06 (t, 1H, J = 7.7 Hz) ), 5.08 (s, 2H), 4.54 (t, 1H, J = 5.1 Hz), 4.34 (d, 2H, J = 6.0 Hz), 3.81 (d, 2H, J = 5.1 Hz), 3.28 (s, 6H), 1.20 (s, 9H).

Process 2
3-Benzyloxy-1- (2,2-dimethoxyethyl) -5- (2,2-dimethylpropionyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (100 mg) Concentrated hydrochloric acid (1 ml) was added to the dioxane (1 ml) solution, and the mixture was stirred at 90 ° C. for 2 hours. After distilling off the solvent, toluene was added and the mixture was concentrated twice, and crystallized from ethyl acetate-diisopropyl ether to give 2- (3-chlorobenzyl) -7- (2,2-dimethylpropionyl) -9. -Hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (71 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.09 (s, 1H), 7.48 (s, 1H), 7.43-7.32 (m, 3H), 7.22 (d, 1H, J = 6.2 Hz), 6.94 (d, 1H, J = 6.2 Hz), 4.98 (s, 2H), 1.19 (s, 9H).

Example 161
Synthesis of 7-amino-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

Process 1
Bromine (1.5 ml) was added to a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (5.13 g) obtained in Step 1 of Example 10 in chloroform (100 ml). ) In chloroform (50 ml) was added, and the mixture was heated and stirred for 2 hours under reflux. Further, a chloroform (1.0 ml) solution of bromine was added and the mixture was heated and stirred for 16 hours, and then the solvent was distilled off. Toluene was added to the residue, and this was concentrated twice to give 5-bromo-3-hydroxy-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide as a crude product. The obtained crude product was dissolved in dimethylformamide (50 ml), potassium carbonate (3.87 g) and benzyl bromide (2.75 ml) were added thereto, and the mixture was stirred at room temperature for 1 hour. Water (100 ml) and 1N aqueous hydrochloric acid (50 ml) were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (200 ml each). The ethyl acetate layer was washed, dried and concentrated, and then purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid. The acid 3-chlorobenzylamide (3.31 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.21 (s, 1H), 8.01 (brt, 1H, J = 5.9 Hz), 7.41-7.20 (m, 7H), 7.15 ( s, 1H), 7.05 (d, 1H, J = 7.3 Hz), 5.38 (s, 2H), 4.39 (d, 2H, J = 5.9 Hz).

Process 2
3-Benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid To a solution of 3-chlorobenzylamide (1.50 g) in tetrahydrofuran (10 ml) -ethanol (10 ml) was added aminoacetaldehyde dimethyl acetal (0 .73 ml) was added and stirred at 60 ° C. for 1 hour. After the solvent was distilled off, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 2) to give 3-benzyloxy-5-bromo-1- (2,2-dimethoxyethyl) -4. -Oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (1.35 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.03 (brt, 1H, J = 6.2 Hz), 7.65 (s, 1H), 7.33-7.11 (m, 9H), 5.04 ( s, 2H), 4.53 (t, 1H, J = 5.1 Hz), 4.34 (d, 2H, J = 6.2 Hz), 3.83 (d, 2H, J = 5.1 Hz), 3.30 (s, 6H).

Process 3
3-Benzyloxy-5-bromo-1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (3.89 g) in dimethyl sulfoxide (26 ml) -Palladium (II) acetate (0.16 g), 1,3-bis (diphenylphosphino) propane (0.3 g) and triethylamine (2 ml) were added to a methanol (13 ml) solution, and the mixture was heated to 70 ° C under carbon monoxide. And stirred for 24 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted twice with ethyl acetate (200 ml each). The ethyl acetate layer was washed with water, dried and concentrated to give 5-benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4-oxo-1,4 as a crude product. -Dihydropyridine-3-carboxylic acid methyl ester (4.12 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.50 (brs, 1H), 7.95 (s, 1H), 7.29-7.12 (m, 9H), 4.97 (s, 2H), 4 .56 (t, 1H, J = 5.1 Hz), 4.46 (d, 2H, J = 6.3 Hz), 3.83 (d, 2H, J = 5.1 Hz), 3.73 (s, 3H), 3.27 (s, 6H).

Process 4
5-Benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-3-carboxylic acid methyl ester (2.0 g) in tetrahydrofuran (2.0 g) To a 20 ml) -methanol (10 ml) solution was added 4N aqueous lithium hydroxide solution (1.5 ml), and the mixture was stirred at 70 ° C. for 1 hour. The precipitated solid was removed with a thin layer of celite and washed with methanol. After distilling off the solvent, 1N aqueous hydrochloric acid (6.5 ml) and water (50 ml) were added, and the mixture was extracted twice with ethyl acetate (75 ml each). The ethyl acetate layer was dried, concentrated and crystallized from ethyl acetate-diisopropyl ether to give 5-benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4-oxo-1 , 4-dihydropyridine-3-carboxylic acid (1.2 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.35 (s, 1H), 7.42-7.09 (m, 9H), 6.55 (brs, 1H), 5.34 (s, 2H), 4 .50 (t, 1H, J = 4.4 Hz), 4.40 (d, 2H, J = 5.9 Hz), 4.10 (d, 2H, J = 4.4 Hz), 3.31 (s, 6H).

Process 5
Dimethylformamide (0.3 ml) of 5-benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-3-carboxylic acid (50 mg) ) To the solution were added triethylamine (0.07 ml) and diphenylphosphoryl azide (0.054 ml). After stirring at room temperature for 1 hour, tert-butanol (0.3 ml) was added, heated to 100 ° C. and stirred for 1 hour. After cooling to room temperature, saturated aqueous ammonium chloride solution (5 ml) and water (5 ml) were added, and the mixture was extracted twice with ethyl acetate (15 ml each). The ethyl acetate layer was washed with water, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain [5-benzyloxy-6- (3-chlorobenzylcarbamoyl). ) -1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridin-3-yl] carbamic acid tert-butyl ester (40 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.39 (s, 1H), 7.70 (s, 1H), 7.36-7.08 (m, 9H), 6.43 (brt, 1H, J = 6.2 Hz), 5.27 (s, 2 H), 4.52 (t, 1 H, J = 5.1 Hz), 4.37 (d, 2 H, J = 6.2 Hz), 4.06 (d, 2H, J = 5.1 Hz), 3.28 (s, 6H), 1.55 (s, 9H).

Step 6
[5-Benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridin-3-yl] carbamic acid tert-butyl ester (40 mg) Was dissolved in acetic acid (0.4 ml), concentrated hydrochloric acid (0.4 ml) was added thereto, and the mixture was stirred at 90 ° C. for 5 hours. After concentrating the reaction solution, toluene was added to the residue, and this was concentrated twice. Methanol was further added, and this was concentrated twice, and crystallized from ethyl acetate-methanol-diisopropyl ether. -Amino-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (23 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 12.29 (brs, 1H), 7.99 (s, 1H), 7.78 (d, 1H, J = 6.0 Hz), 7.58 (d, 1H, J = 6.0 Hz), 7.49 (s, 1H), 7.43-7.33 (m, 3H), 5.10 (s, 2H).

Example 165
Synthesis of N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide

The 7-amino-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (23 mg) obtained in Example 161 was converted to pyridine (0 0.1 ml) and acetic anhydride (0.0123 ml) was added. After stirring at room temperature for 1 hour, water (3 ml) was added to the reaction mixture, and the mixture was extracted twice with chloroform (6 ml each). The chloroform layer was dried and concentrated, and then crystallized from chloroform-methanol-diisopropyl ether to obtain 22 mg of a solid. This solid was suspended in tetrahydrofuran (0.4 ml) -methanol (1 ml) -chloroform (1 ml), 2N aqueous sodium hydroxide solution (0.043 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, 1N aqueous hydrochloric acid (6 ml) was added, and the mixture was extracted 3 times with chloroform (8 ml each). The chloroform layer was dried, concentrated, crystallized from chloroform-methanol-diisopropyl ether, and N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [ 1,2-a] pyrazin-7-yl] acetamide (18 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 11.59 (bs, 1H), 9.44 (s, 1H), 9.08 (s, 1H), 7.49 (s, 1H), 7.47 (D, 1H, J = 6.0 Hz), 7.42-7.32 (m, 3H), 6.95 (d, 1H, J = 6.0 Hz), 4.97 (s, 2H), 2 .17 (s, 3H).

Example 94
Synthesis of 7-bromo-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

3-Benzyloxy-5-bromo-1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide obtained in Step 2 of Example 161 ( 50 mg) was subjected to the same reaction operation as in Step 6 of Example 161, crystallized from ethyl acetate-methanol-diisopropyl ether, and 7-bromo-2- (3-chlorobenzyl) -9-hydroxy-2H- Pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (30 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.63 (s, 1H), 7.48 (s, 1H), 7.44-7.33 (m, 3H), 7.21 (d, 1H, J = 6.2 Hz), 6.95 (d, 1H, J = 6.2 Hz), 4.98 (s, 2H).

Example 96
Synthesis of 2- (3-chlorobenzyl) -9-hydroxy-7-phenyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

Process 1
3-Benzyloxy-5-bromo-1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide obtained in Step 2 of Example 161 ( To a solution of 70 mg) in dimethoxyethane (1.4 ml) -water (0.7 ml), phenylboronic acid (32 mg), tetrakis (triphenylphosphine) palladium (0) (31 mg) and sodium carbonate (42 mg) were sequentially added. Stir at 80 ° C. for 2 hours. After cooling to room temperature, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 1), and 3-benzyloxy-1- (2,2-dimethoxyethyl) -4-oxo-5- Phenyl-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (56 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.27 (brs, 1H), 7.50 (s, 1H), 7.40-7.09 (m, 14H), 5.15 (s, 2H), 4 .55 (t, 1H, J = 5.1 Hz), 4.16 (d, 2H, J = 6.0 Hz), 3.85 (d, 2H, J = 5.1 Hz), 3.28 (s, 6H).

Process 2
3-Benzyloxy-1- (2,2-dimethoxyethyl) -4-oxo-5-phenyl-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (52 mg) in acetic acid (0.5 ml) Dissolved, concentrated hydrochloric acid (0.5 ml) was added thereto, and the mixture was stirred at 90 ° C. for 2 hr. After concentrating the reaction solution, the operation of adding toluene to the residue and concentrating it was performed twice. Further, methanol was added and the mixture was concentrated and crystallized from ethyl acetate-diisopropyl ether to give 2- (3-chlorobenzyl) -9. -Hydroxy-7-phenyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (39 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.50 (s, 1H), 7.73 (d, 2H, J = 7.0 Hz), 7.53 to 7.36 (m, 8H), 7. 10 (d, 1H, J = 6.2 Hz), 5.04 (s, 2H).

Example 104
Synthesis of 2- (3-chlorobenzyl) -9-hydroxy-7-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

Process 1
3-Benzyloxy-5-bromo-1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide obtained in Step 2 of Example 161 ( Tributyl-2-propenyltin (245 mg) and tetrakis (triphenylphosphine) palladium (0) (60 mg) were added to a solution of 138 mg) in dioxane (2.5 ml), and the mixture was stirred at 100 ° C. for 4 hours. After the solvent was distilled off, toluene was added, and this was concentrated again. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give 3-benzyloxy-1- (2, 2-Dimethoxyethyl) -5-isopropenyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (89 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.75 (brt, 1H, J = 6.0 Hz), 7.31-7.09 (m, 10H), 5.80 (d, 2H, J = 2.3 Hz) ), 5.19 (dq, 1H, J = 2.3, 1.4 Hz), 5.09 (s, 2H), 4.52 (t, 1H, J = 5.1 Hz), 4.31 (d , 2H, J = 6.0 Hz), 3.82 (d, 2H, J = 5.1 Hz), 3.29 (s, 6H), 2.05 (brs, 3H).

Process 2
3-Benzyloxy-1- (2,2-dimethoxyethyl) -5-isopropenyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid To a solution of 3-chlorobenzylamide (60 mg) in methanol (1 ml) 5% Palladium carbon (20 mg) was added, and the mixture was stirred for 16 hours under normal pressure of hydrogen. After filtering off the solid, the filtrate was concentrated and 1- (2,2-dimethoxyethyl) -3-hydroxy-5-isopropyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide ( 43 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.89 (brt, 1H, J = 5.8 Hz), 7.38-7.24 (m, 5H), 4.63 (d, 2H, J = 5.8 Hz) ), 4.60 (d, 1H, J = 4.9 Hz), 4.51 (d, 2H, J = 4.9 Hz), 3.23 (sep, 1H, J = 6.8 Hz), 1.23 (D, 6H, J = 6.8 Hz).

Process 3
1- (2,2-dimethoxyethyl) -3-hydroxy-5-isopropyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid Step 6 of Example 161 using 3-chlorobenzylamide (42 mg) The same reaction procedure as above was followed by crystallization from ethyl acetate-methanol-diisopropyl ether, recrystallization from ethyl acetate-methanol, and 2- (3-chlorobenzyl) -9-hydroxy-7-isopropyl-2H-pyrido. [1,2-a] pyrazine-1,8-dione hydrochloride (18 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.27 (s, 1H), 7.51-7.45 (m, 2H), 7.42-7.31 (m, 3H), 7.17 ( brd, 1H, J = 6.2 Hz), 5.04 (s, 2H), 3.23 (sep, 1H, J = 7.0 Hz), 1.19 (d, 6H, J = 7.0 Hz).

Example 187
Synthesis of [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetic acid methyl ester

Process 1
3-Benzyloxy-5-bromo-1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide obtained in Step 2 of Example 161 ( 300 mg) in a toluene solution, tributyltin fluoride (518 mg), tris (dibenzylideneacetone) dipalladium (0) -chloroform solvate (58 mg), 1,1′-bis (diphenylphosphino) ferrocene ( 64 mg) and 1- (tert-butyldimethylsilyloxy) -1-methoxyethane (525 mg) were added, and the mixture was stirred at 100 ° C. for 15 hours. After cooling to room temperature, sodium bicarbonate water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The extract was dried and concentrated, then purified by silica gel column chromatography (ethyl acetate), and [5-benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4- Oxo-1,4-dihydropyridin-3-yl] acetic acid methyl ester (184 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.38 (s, 1H), 7.32-7.07 (m, 9H), 6.76 (brt, 1H, J = 6.0 Hz), 5.24 ( s, 2H), 4.52 (t, 1H, J = 5.1 Hz), 4.37 (d, 2H, J = 6.0 Hz), 3.90 (d, 2H, J = 5.1 Hz), 3.72 (s, 3H), 3.48 (s, 2H), 3.31 (s, 6H).

Process 2
[5-Benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridin-3-yl] acetic acid methyl ester (30 mg) in trifluoro Dissolved in acetic acid (1 ml) and stirred at 70 ° C. for 4 hours. After cooling and concentration, the operation of adding toluene to the residue and concentrating it again was performed twice, and further crystallized from ethyl acetate-diisopropyl ether to give [2- (3-chlorobenzyl) -9-hydroxy-1,8. -Dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetic acid methyl ester (17 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 11.50 (brs, 1H), 8.05 (s, 1H), 7.48 (s, 1H), 7.42-7.31 (m, 3H) 7.18 (d, 1H, J = 6.1 Hz), 6.86 (d, 1H, J = 6.1 Hz), 4.96 (s, 2H), 3.59 (s, 3H), 3 .47 (s, 2H).

Example 191
Synthesis of [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetic acid

Process 1
[5-Benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridin-3-yl] obtained in Step 1 of Example 187 A 4N aqueous sodium hydroxide solution (0.11 ml) was added to a solution of acetic acid methyl ester (150 mg) in tetrahydrofuran (1.5 ml) -methanol (1.5 ml), and the mixture was stirred at 70 ° C. for 30 minutes. After returning to room temperature, 1N aqueous hydrochloric acid (0.5 ml) and water (15 ml) were added, and the mixture was extracted twice with ethyl acetate (30 ml each). The ethyl acetate layer was washed with water, dried, concentrated and crystallized from ethyl acetate-diisopropyl ether to give [5-benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4. -Oxo-1,4-dihydropyridin-3-yl] acetic acid (116 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.42 (s, 1H), 7.43-7.08 (m, 9H), 6.81 (brt, 1H, J = 5.8 Hz), 5.27 ( s, 2H), 4.51 (t, 1H, J = 4.6 Hz), 4.39 (d, 2H, J = 5.8 Hz), 4.01 (d, 2H, J = 4.6 Hz), 3.55 (s, 2H), 3.30 (s, 6H).

Process 2
[5-Benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridin-3-yl] acetic acid (20 mg) according to Example 187 The reaction was carried out in the same manner as in Step 2 and crystallized from ethyl acetate-diisopropyl ether to give [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [ 1,2-a] pyrazin-7-yl] acetic acid (13 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 12.40 (brs, 1H), 11.52 (brs, 1H), 8.05 (s, 1H), 7.48 (s, 1H), 7.42 −7.31 (m, 3H), 7.19 (d, 1H, J = 6.3 Hz), 6.87 (d, 1H, J = 6.3 Hz), 4.96 (s, 2H), 3 .40 (s, 2H).

Example 189
Of 2- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -N-methylacetamide Composition

Process 1
[5-Benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridin-3-yl] obtained in Step 1 of Example 191 ] To a solution of acetic acid (25 mg) in dimethylformamide (0.2 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (19 mg), 1-hydroxybenzotriazole hydrate (15 mg), methylamine (2M tetrahydrofuran solution) (0.073 ml) was sequentially added, and the mixture was stirred at room temperature for 2 hours. The obtained reaction solution was directly subjected to silica gel thin layer chromatography (chloroform: methanol = 10: 1), further crystallized from ethyl acetate-diisopropyl ether, and 3-benzyloxy-1- (2,2-dimethoxyethyl). ) -5-methylcarbamoylmethyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (22 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.48 (s, 1H), 7.45 (brd, 1H, J = 4.8 Hz), 7.34-7.05 (m, 9H), 6.38 ( brt, 1H, J = 6.0 Hz), 5.27 (s, 2H), 4.49 (t, 1H, J = 4.8 Hz), 4.36 (d, 2H, J = 6.0 Hz), 3.95 (d, 2H, J = 4.8 Hz), 3.40 (s, 2H), 3.30 (s, 6H), 2.73 (d, 3H, J = 4.8 Hz).

Process 2
3-Benzyloxy-1- (2,2-dimethoxyethyl) -5-methylcarbamoylmethyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-Chlorobenzylamide (21 mg) as in Example 187 The reaction was carried out in the same manner as in Example 2, and crystallized from ethyl acetate-diisopropyl ether to give 2- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido. [1,2-a] pyrazin-7-yl] -N-methylacetamide (11 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 11.44 (brs, 1H), 8.01 (s, 1H), 7.77 (s, 1H), 7.47 (s, 1H), 7.43 −7.31 (m, 3H), 7.23 (d, 1H, J = 6.0 Hz), 6.87 (d, 1H, J = 6.0 Hz), 4.96 (s, 2H), 3 .27 (s, 2H), 2.55 (d, 3H, J = 4.6 Hz).

Example 390
Synthesis of 9-benzyloxy-7-bromo-2- (3-chlorobenzyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione

Process 1
3-Benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (2.0 g) obtained in Step 1 of Example 161 in tetrahydrofuran (10 ml) -ethanol (10 ml) ) 2-Aminoethanol (0.33 ml) was added to the solution and stirred at room temperature and 50 ° C. for 30 minutes, respectively. After the solvent was distilled off, the residue was crystallized from ethyl acetate-diisopropyl ether to give 3-benzyloxy-5-bromo-1- (2-hydroxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3 -Chlorobenzylamide (1.95 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 9.44 (brt, 1H, J = 5.8 Hz), 8.19 (s, 1H), 7.39-7.16 (m, 9H), 5. 08 (t, 1H, J = 5.1 Hz), 5.05 (s, 2H), 4.43 (d, 2H, J = 5.8 Hz), 3.92 (t, 2H, J = 5.1 Hz) ), 3.62 (q, 2H, J = 5.1 Hz).

Process 2
3-Benzyloxy-5-bromo-1- (2-hydroxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (1.75 g) was suspended in tetrahydrofuran (50 ml). N, N-diisopropylethylamine (3.72 ml) and methanesulfonyl chloride (1.38 ml) were added. After stirring at room temperature for 1 hour, 0.5N aqueous hydrochloric acid (40 ml) was added, and the mixture was extracted twice with ethyl acetate (100 ml each). The ethyl acetate layer was washed with aqueous sodium bicarbonate, dried and concentrated. The obtained residue was dissolved in dimethylformamide (50 ml), and 60% sodium hydride was added little by little at room temperature with stirring. After confirming the completion of the reaction by thin layer chromatography (TLC), the reaction solution was ice-cooled, 0.33N aqueous hydrochloric acid (300 ml) was added, and the mixture was extracted twice with ethyl acetate (250 ml each). The ethyl acetate layer was washed with water, dried, concentrated, crystallized from ethyl acetate-hexane, and 9-benzyloxy-7-bromo-2- (3-chlorobenzyl) -3,4-dihydro-2H-pyrido [1 , 2-a] pyrazine-1,8-dione (1.58 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.66 (d, 2H, J = 6.7 Hz), 7.56 (s, 1H), 7.37-7.25 (m, 6H), 7.16 ( m, 1H), 5.32 (s, 2H), 4.62 (s, 2H), 3.94-3.88 (m, 2H), 3.52-3.45 (m, 2H).

Example 244
Synthesis of 7-acetyl-2- (3-chloro-4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

Process 1
3-Benzyloxy-5-bromo-1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid prepared in the same manner as the compound described in Step 2 of Example 161 To a solution of acid 3-chloro-4-fluorobenzylamide (150 mg) in toluene (2 ml), tris (dibenzylideneacetone) dipalladium (0) -chloroformate (14 mg), 1,1′-bis under a stream of argon. (Diphenylphosphino) ferrocene (15 mg) and tributyl (1-ethoxyvinyl) tin (189 mg) were added, and the mixture was stirred at 90 ° C. for 4 hours. After cooling to room temperature, the reaction solution was concentrated and purified by silica gel thin layer chromatography twice (ethyl acetate: hexane = 2: 1) (toluene: acetone = 3: 1) to give 5-acetyl-3-benzyl. Oxy-1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chloro-4-fluorobenzylamide (60 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.07 (s, 1H), 7.34-7.25 (m, 6H), 7.09-6.96 (m, 2H), 6.67 (brt, 1H, J = 6.0 Hz), 5.25 (s, 2H), 4.48 (t, 1H, J = 4.7 Hz), 4.31 (d, 2H, J = 6.0 Hz), 4. 03 (d, 2H, J = 4.7 Hz), 3.31 (s, 6H), 2.73 (s, 3H).

Process 2
5-acetyl-3-benzyloxy-1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chloro-4-fluorobenzylamide (59 mg) was The same reaction procedure as in step 2 was performed, crystallized from ethyl acetate-diisopropyl ether, and 7-acetyl-2- (3-chloro-4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2- a] Pyrazine-1,8-dione hydrochloride (35 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.48 (s, 1H), 7.65 (m, 1H), 7.43-7.40 (m, 2H), 7.38 (d, 1H, J = 6.3 Hz), 6.93 (d, 1H, J = 6.3 Hz), 4.92 (s, 2H), 2.61 (s, 3H).

Example 251
Synthesis of 7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

Process 1
3-Benzyloxy-4-oxo-4H-pyran-2-carboxylic acid 4-fluorobenzylamide (0.6 g) and 2,2-dimethyl prepared by a method similar to that described in Step 1 of Example 10 A 1.5M lithium diisopropylamide-tetrahydrofuran / cyclohexane solution (14.9 ml) was added dropwise to a solution of propionaldehyde (1.88 ml) in tetrahydrofuran (6 ml) at −78 ° C. under nitrogen. After stirring at the same temperature for 2 hours, the cooling bath was removed, 2N aqueous hydrochloric acid (15 ml) and ethyl acetate were immediately added, and the temperature was raised to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried and concentrated, and then purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2-ethyl acetate) to give 3-benzyloxy-5- (1-hydroxy-2,2-dimethylpropyl). ) -4-Oxo-4H-pyran-2-carboxylic acid 4-fluorobenzylamide (0.27 g) was obtained. This whole amount was dissolved in chloroform (3 ml), and 1,1,1-tris (acetoxy) -1,1-dihydro-1,2-benzoiodoxol-3- (1H) -one (Dess-Martin) at room temperature. Reagent) (291 mg) was added and stirred for 2.5 hours. After adding 2-propanol and stirring for 30 minutes, sodium bicarbonate water and sodium sulfite aqueous solution were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried and concentrated. The obtained residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 1) to give 3-benzyloxy-5- (2 , 2-Dimethylpropionyl) -4-oxo-4H-pyran-2-carboxylic acid 4-fluorobenzylamide (0.13 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.00 (m, 1H), 7.80 (s, 1H), 7.40-6.93 (m, 9H), 5.34 (s, 2H), 4 .39 (d, 2H, J = 5.76 Hz), 1.24 (s, 9H).

Process 2
3-Benzyloxy-5- (2,2-dimethylpropionyl) -4-oxo-4H-pyran-2-carboxylic acid 4-fluorobenzylamide (0.13 g) in tetrahydrofuran (0.5 ml) -ethanol (0. To the solution, aminoacetaldehyde dimethyl acetal (0.033 ml) was added and stirred at 70 ° C. for 3 days. After cooling to room temperature, the solvent was distilled off to give 3-benzyloxy-1- (2,2-dimethoxyethyl) -5- (2,2-dimethylpropionyl) -4-oxo-1,4-dihydropyridine-2- Carboxylic acid 4-fluorobenzylamide (157 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.08 (m, 1H), 7.31-7.15 (m, 8H), 6.84-6.78 (m, 2H), 5.06 (s, 2H), 4.55 (t, 1H, J = 5.1 Hz), 4.35 (d, 2H, J = 6.0 Hz), 3.82 (d, 2H, J = 5.1 Hz), 3. 30 (s, 6H), 1.21 (s, 9H).

Process 3
3-Benzyloxy-1- (2,2-dimethoxyethyl) -5- (2,2-dimethylpropionyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 4-fluorobenzylamide (157 mg). Dissolved in acetic acid (1.5 ml), concentrated hydrochloric acid (0.5 ml) was added thereto, and the mixture was stirred at 90 ° C. for 3 hours. The reaction mixture was concentrated and crystallized from ethyl acetate to give 7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1 , 8-dione hydrochloride (92 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.07 (s, 1H), 7.46-7.41 (m, 2H), 7.22-7.16 (m, 3H), 6.91 ( d, 1H, J = 6.0 Hz), 4.93 (s, 2H), 1.18 (s, 9H).

Example 223
Of 2- (3-chlorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride Composition

Process 1
3-Benzyloxy-5- (1-hydroxy-2,2-dimethylpropyl) -4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide obtained in the same manner as in Step 118 of Example 118 To a solution of (0.22 g) in chloroform (2 ml), 1,1,1-tris (acetoxy) -1,1-dihydro-1,2-benzoiodoxol-3- (1H) -one (0.23 g) Was added. After stirring at room temperature for 30 minutes, aqueous sodium hydrogen carbonate and aqueous sodium sulfite were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, concentrated, and 3-benzyloxy-5- (2,2-dimethylpropionyl) -4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (225 mg). )
¹ H-NMR (CDCl ₃ ) δ 8.02 (1H, t, J = 6.0 Hz), 7.81 (1H, s), 7.36-7.16 (7H, m), 7.14 ( 1H, s), 7.04 (1H, d, J = 7.0 Hz), 5.36 (2H, s), 4.39 (2H, d, J = 6.0 Hz), 1.26 (9H, s).

Process 2
3-Benzyloxy-5- (2,2-dimethylpropionyl) -4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (113 mg) in tetrahydrofuran (0.7 ml) -ethanol (0.7 ml) To the solution, 2-aminoethanol (0.015 ml) was added and stirred at 60 ° C. for 11 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to give 3-benzyloxy-5- (2,2-dimethylpropionyl) -1- (2- Hydroxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (91 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.37 (1H, t, J = 6.0 Hz), 7.36 (1H, s), 7.30 (1H, s), 7.28-7.07 ( 8H, m), 4.94 (2H, s), 4.76 (1H, br s), 4.28 (2H, d, J = 6.0 Hz), 4.03-3.95 (2H, m ), 3.84-3.76 (2H, m), 1.15 (9H, s).

Process 3
3-Benzyloxy-5- (2,2-dimethylpropionyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (91 mg) in tetrahydrofuran (91 mg) 3 ml), N, N-diisopropylethylamine (0.187 ml) was added to the solution, and the mixture was ice-cooled. Under stirring, methanesulfonyl chloride (0.07 ml) was added over 30 minutes at the same temperature. After confirming the completion of the reaction by thin layer chromatography, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with brine, aqueous sodium bicarbonate and brine, dried and concentrated. The obtained residue was dissolved in dimethylformamide (2 ml), and 60% sodium hydride (50 mg) was added little by little at room temperature with stirring. After stirring for 30 minutes, the reaction solution was ice-cooled, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried and concentrated. The obtained residue was purified by silica gel thin layer chromatography (ethyl acetate) to give 9-benzyloxy-2- (3-chlorobenzyl) -7-. (2,2-Dimethylpropionyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (44 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.61-7.59 (2H, m), 7.29-7.22 (8H, m), 5.39 (2H, s), 4.68 (2H, s), 3.96-3.92 (2H, m), 3.52-3.46 (2H, m), 1.32 (9H, s).

Process 4
9-Benzyloxy-2- (3-chlorobenzyl) -7- (2,2-dimethylpropionyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (43 mg ) Was dissolved in trifluoroacetic acid (2 ml) and stirred at room temperature for 1 hour. After the solvent was distilled off, toluene was added, and this was concentrated again, followed by addition of an appropriate amount of hydrochloric acid / ethyl acetate solution and concentration again. Ethyl acetate (0.6 ml) -diisopropyl ether (1 ml) was added to the resulting residue, and the resulting solid was collected by filtration to give 2- (3-chlorobenzyl) -7- (2,2-dimethylpropionyl)- 9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (25.6 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.73 (1H, s), 7.45-7.30 (4H, m), 4.71 (2H, s), 4.25 (2H, t, J = 5.6 Hz), 3.72 (2H, t, J = 5.6 Hz), 1.20 (9H, s).

Example 154
Synthesis of 2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid isopropylamide

5-Benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-3-carboxylic acid obtained in Step 4 of Example 161 Triethylamine (0.021 ml) and thionyl chloride (0.0056 ml) were added successively to a solution of (25.4 mg) in tetrahydrofuran (0.3 ml) at 0 ° C. with stirring, and the mixture was stirred at room temperature for 10 minutes, and then ice-cooled again. Then isopropylamine (0.0086 ml) was added. After stirring at room temperature for 30 minutes, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried and concentrated. Trifluoroacetic acid was added to the resulting residue and stirred at 70 ° C. for 5.5 hours. After distilling off trifluoroacetic acid, toluene was added and this was concentrated twice and crystallized from ethyl acetate (2 ml) to give 2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo- 1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid isopropylamide (13.6 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 11.79 (1H, s), 10.10 (1H, d, J = 7.9 Hz), 8.74 (1H, s), 7.51-7. 49 (2H, m), 7.40-7.34 (3H, m), 7.01 (1H, d, J = 6.5 Hz), 4.96 (2H, s), 4.05 (1H, sept, J = 6.5 Hz), 1.18 (6H, d, J = 6.5 Hz).

Example 249
Synthesis of 2- (3,4-dichlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione

Process 1
9-Benzyloxy-2- (3,4-dichlorobenzyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione obtained in Step 3 of Example 1 ( To a solution of 3.8 g) in chloroform (90 ml) -methanol (60 ml), phenyltrimethylammonium tribromide (5.0 g) was added and stirred at room temperature for 13 hours. A sodium sulfite aqueous solution was added to the reaction solution, and the mixture was extracted twice with chloroform. The combined extracts were washed with brine, and then purified as they were by silica gel column chromatography (chloroform-methanol = 19: 1 to 10: 1) to give 9-benzyloxy-7-bromo-2- (3,4- Dichlorobenzyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (2.44 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.36 (s, 1H), 7.6-7.7 (m, 2H), 7.5-7.6 (m, 2H), 7.2 7.4 (m, 4H), 5.08 (s, 2H), 4.68 (s, 2H), 4.1-4.3 (m, 2H), 3.6-3.8 (m, 2H).

Process 2
9-Benzyloxy-7-bromo-2- (3,4-dichlorobenzyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (150 mg) in dioxane (5 ml) ) To the solution, tris (dibenzylideneacetone) dipalladium (0) -chloroform solvate (63 mg), tri-2-furylphosphine (57 mg) and (2-thiazolyl) tributyltin (0.285 ml) were added under a stream of argon. Then, the macrowave was irradiated at 80 W for 1 hour in a sealed state. The obtained reaction solution was concentrated and subsequently purified by silica gel column chromatography (chloroform: methanol = 40: 1), and 9-benzyloxy-2- (3,4-dichlorobenzyl) -7- (thiazole- 2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (95 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.49 (s, 1H), 7.85 (d, 1H, J = 3.3 Hz), 7.6-7.8 (m, 2H), 7.1- 7.5 (m, 7H), 5.47 (s, 2H), 4.64 (s, 2H), 4.11 (t, 2H, J = 5.4 Hz), 3.56 (t, 2H, J = 5.4 Hz).

Process 3
9-Benzyloxy-2- (3,4-dichlorobenzyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione ( 93 mg) was dissolved in trifluoroacetic acid (2 ml), allowed to stand at room temperature for 1.5 hours, and then concentrated. Toluene was added to the residue and this was concentrated again twice, and then ethyl acetate was added and the solid was collected by filtration to give 2- (3,4-dichlorobenzyl) -9-hydroxy-7- (thiazole-2- Yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (53 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 12.25 (brs, 1H), 8.71 (s, 1H), 7.89 (d, 1H, J = 3.2 Hz), 7.69 (d, 1H, J = 2 Hz), 7.6-7.65 (m, 2H), 7.39 (dd, 1H, J = 8.4 Hz, 2 Hz), 4.74 (s, 2H), 4.4- 4.5 (m, 2H), 3.75-3.85 (m, 2H).

Example 219
Synthesis of 2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid methylamide

Process 1
9-Benzyloxy-7-bromo-2- (3-chlorobenzyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1 prepared by a method similar to Step 1 of Example 249 , 8-dione (600 mg) was subjected to the same reaction procedure as in Step 161 of Example 161 to give 9-benzyloxy-2- (3-chlorobenzyl) -1,8-dioxo-1,3,4,8- Tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid methyl ester and 2- (3-chlorobenzyl) -1,8-dioxo-9-hydroxy-1,3,4,8-tetrahydro- A mixture of 2H-pyrido [1,2-a] pyrazine-7-carboxylic acid methyl ester was obtained. This mixture was dissolved in dimethylformamide (17 ml), treated with benzyl bromide (1.36 g) and potassium carbonate (1.75 g), and then purified by silica gel column chromatography (ethyl acetate to chloroform: methanol = 10: 1). 9-Benzyloxy-2- (3-chlorobenzyl) -1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid methyl ester ( 480 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.02 (s, 1H), 7.66 (d, 2H, J = 6 Hz), 7.2-7.4 (m, 6H), 7.1-7. 2 (m, 1H), 5.33 (s, 2H), 4.62 (s, 2H), 3.94 (t, 2H, J = 5.3 Hz), 3.91 (s, 3H), 3 .50 (t, 2H, J = 5.3 Hz).

Process 2
9-Benzyloxy-2- (3-chlorobenzyl) -1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid methyl ester (420 mg ) Was dissolved in tetrahydrofuran (8 ml) -water (2 ml), and 4N aqueous lithium hydroxide solution (0.58 ml) was added with stirring. After stirring at 70 ° C. for 1 hour, the mixture was concentrated, and water (5 ml) was added with stirring, followed by 5% aqueous potassium hydrogen sulfate solution (15 ml). The precipitated crystals were collected by filtration, and 9-benzyloxy-2- (3-chlorobenzyl) -1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine- 7-carboxylic acid (352 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.70 (brs, 1H), 7.2-7.6 (m, 9H), 5.16 (s, 2H), 4.72 (s, 2H) , 4.3-4.6 (m, 2H), 3.6-3.8 (m, 2H).

Process 3
9-Benzyloxy-2- (3-chlorobenzyl) -1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid (350 mg) was added. The reaction was conducted in the same manner as in Example 154 to give 2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a]. Pyrazine-7-carboxylic acid methylamide (182 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 12.28 (s, 1H), 9.8-10.0 (m, 1H), 8.38 (s, 1H), 7.46 (s, 1H) , 7.25-7.4 (m, 3H), 4.72 (s, 2H), 4.40 (t, 2H, J = 5.5 Hz), 3.75 (t, 2H, J = 5. 5 Hz), 2.83 (d, 3H, J = 4.9 Hz).

Example 362
Synthesis of 2- (3-chlorobenzyl) -7- (2,2-dimethylbutyryl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione

Process 1
9-Benzyloxy-2- (3-chlorobenzyl) -1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] obtained in Step 2 of Example 219 Pyrazine-7-carboxylic acid (200 mg) was suspended in tetrahydrofuran (6 ml), and triethylamine (0.07 ml) and thionyl chloride (0.037 ml) were added with stirring at room temperature. After stirring at room temperature for 10 minutes, the mixture was cooled to -78 ° C, and 1.0 M 1,1-dimethylpropylmagnesium chloride / ether solution was added dropwise. After further stirring for 20 minutes at the same temperature, 5% aqueous potassium hydrogen sulfate solution (5 ml) and ethyl acetate (6 ml) were added, and water (5 ml) was further added, followed by ethyl acetate-tetrahydrofuran (1: 1, 30 ml each). Extracted twice. After drying and concentration of the organic layer, ethyl acetate was added to the residue, and the resulting solid was collected by filtration, and 9-benzyloxy-2- (3-chlorobenzyl) -7- (2,2-dimethylbutyryl)- 3,4-Dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (59 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.63-7.59 (m, 2H), 7.36-7.17 (m, 8H), 5.89 (s, 2H), 4.68 (s, 2H), 3.97-3.91 (m, 2H), 3.51-3.46 (m, 2H), 1.78 (q, 2H, J = 7.6 Hz), 1.28 (s, 6H), 0.83 (t, 3H, J = 7.6 Hz).

Process 2
9-benzyloxy-2- (3-chlorobenzyl) -7- (2,2-dimethylbutyryl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione ( 55 mg) was dissolved in trifluoroacetic acid (0.5 ml) and stirred at room temperature for 30 minutes. After distilling off the solvent, toluene was added, and this was concentrated twice and crystallized from chloroform-diisopropyl ether to give 2- (3-chlorobenzyl) -7- (2,2-dimethylbutyryl)- 9-Hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (32 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 12.08 (bs, 1H), 7.70 (s, 1H), 7.46 (s, 1H), 7.44-7.32 (m, 3H) 4.72 (s, 2H), 4.30-4.22 (m, 2H), 3.76-3.69 (m, 2H), 1.65 (q, 2H, J = 7.4 Hz). 1.16 (s, 6H), 0.77 (t, 3H, J = 7.4 Hz).

Example 205
Synthesis of 2- (3-chlorobenzyl) -9-hydroxy-7-propionyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

Process 1
5-Benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine obtained in Step 4 of Example 161 in tetrahydrofuran (7 ml). -3-carboxylic acid (517 mg) and triethylamine (0.43 ml) were added, followed by thionyl chloride (0.098 ml) at 0 ° C. After stirring at room temperature for 3 minutes, the reaction solution was cooled to −78 ° C., and a 1M lithium aluminum hydride / tetrahydrofuran solution (1.55 ml) was added dropwise. After stirring at the same temperature for 3 minutes, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated, and then purified by silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 20: 1) to give 3-benzyloxy-1- (2,2-dimethoxyethyl) -5-hydroxy. Methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (240 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.33-7.15 (8H, m), 7.11 (1H, d, J = 7.4 Hz), 6.88 (1H, t, J = 6.0 Hz) ), 5.23 (2H, s), 4.54-4.35 (3H, m), 4.34 (2H, d, J = 6.0 Hz), 3.93 (2H, d, J = 5) .1 Hz), 3.32 (6H, s).

Process 2
3-Benzyloxy-1- (2,2-dimethoxyethyl) -5-hydroxymethyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-Chlorobenzylamide (235 mg) was prepared in Step 1 of Example 223. To 3-benzyloxy-1- (2,2-dimethoxyethyl) -5-formyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (197 mg) Got.
¹ H-NMR (CDCl ₃ ) δ 10.28 (1H, s), 7.89 (1H, s), 7.31-7.19 (8H, m), 7.11 (1H, d, J = 7.9 Hz), 6.72 (1H, t, J = 6.0 Hz), 5.29 (2H, s), 4.49 (1H, t, J = 4.9 Hz), 4.37 (2H, d, J = 6.0 Hz), 3.99 (2H, d, J = 4.9 Hz), 3.30 (6H, s).

Process 3
To a solution of 3-benzyloxy-1- (2,2-dimethoxyethyl) -5-formyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (168 mg) in tetrahydrofuran (6 ml), 0.89 M ethylmagnesium bromide (1.09 ml) was added dropwise at −78 ° C. with stirring. After stirring at the same temperature for 10 minutes, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried and concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1 to 4: 1) to give 3-benzyloxy-1 -(2,2-Dimethoxyethyl) -5- (1-hydroxypropyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (137 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.30-7.16 (8H, m), 7.10 (1H, d, J = 7.4 Hz), 6.78 (1H, t, J = 5.1 Hz) ), 5.23 (2H, s), 4.56 (1H, d, J = 7.4 Hz), 4.49 (1H, t, J = 4.9 Hz), 4.46 (1H, dd, J = 7.4, 10.2 Hz), 4.35 (2H, d, J = 5.1 Hz), 3.92 (2H, d, J = 4.9 Hz), 3.30 (3H, s), 3 .29 (3H, s), 1.83 (2H, dq, J = 7.2, 10.2 Hz), 0.94 (3H, t, J = 7.2 Hz).

Process 4
3-Benzyloxy-1- (2,2-dimethoxyethyl) -5- (1-hydroxypropyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (102 mg) The same reaction procedure as in Step 1 of 223 was carried out to give 3-benzyloxy-1- (2,2-dimethoxyethyl) -4-oxo-5-propionyl-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzyl Amide (92 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.09 (1H, s), 7.28-7.21 (8H, m), 7.08 (1H, d, J = 7.4 Hz), 6.54 ( 1H, d, J = 6.0 Hz), 5.27 (2H, s), 4.47 (1H, t, J = 5.1 Hz), 4.34 (2H, d, J = 6.0 Hz), 4.04 (2H, d, J = 5.1 Hz), 3.29 (6H, s), 3.21 (2H, q, J = 7.1 Hz), 1.16 (3H, t, J = 7) .1 Hz).

Process 5
3-Benzyloxy-1- (2,2-dimethoxyethyl) -4-oxo-5-propionyl-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (89 mg) was combined with step 2 of Example 96. The same reaction operation was performed to obtain 2- (3-chlorobenzyl) -9-hydroxy-7-propionyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (56 mg).
¹ H-NMR (DMSO-d ₆ ) δ 8.48 (1H, s), 7.47 (1H, s), 7.44-7.29 (4H, m), 6.93 (1H, d, J = 6.0 Hz), 4.94 (2H, s), 3.10 (3H, q, J = 7.2 Hz), 1.03 (3H, t, J = 7.2 Hz).

Example 242
Synthesis of N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] propionamide

Process 1
5-Benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-3-carboxylic acid obtained in Step 4 of Example 161 Triethylamine (0.61 ml) and diphenylphosphoryl azide (0.47 ml) were added to a solution of (1 g) in tetrahydrofuran (15 ml) -toluene (15 ml), and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off, the residue was dissolved in tetrahydrofuran (8 ml), and triethylamine (0.61 ml) and diphenylphosphoryl azide (0.47 ml) were added again. After further 2 hours and 3 hours, triethylamine (1.22 ml, 0.61 ml) and diphenylphosphoryl azide (0.94 ml, 0.47 ml) were added and stirring was continued. After confirming disappearance of the raw materials, 9-fluorenylmethanol (7.7 g) and toluene (10 ml) were added, and the mixture was heated and stirred under reflux. After 20 minutes, triethylamine (2.5 ml) was added, and heating and stirring were continued for 1.5 hours. After concentration, water was added to the residue and extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried and concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1 to chloroform: methanol = 15: 1) to give 5-amino-3. -Benzyloxy-1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (886 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.41-7.18 (m, 8H), 7.15-7.12 (m, 2H), 6.96 (s, 1H), 5.15 (s, 2H), 4.53 (t, 1H, J = 5.0 Hz), 4.32 (d, 2H, J = 5.8 Hz), 3.93 (brs, 2H), 3.86 (d, 2H, J = 5.0 Hz), 3.29 (s, 6H).

Process 2
To a solution of 5-amino-3-benzyloxy-1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (55 mg) in chloroform (1 ml), Triethylamine (0.033 ml) and propanoyl chloride (0.012 ml) were added at 0 ° C. After stirring at the same temperature for 20 minutes, sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated, and then purified by silica gel thin layer chromatography (chloroform: methanol = 10: 1) to give N- [5-benzyloxy-6- (3-chlorobenzylcarbamoyl) -1- (2 , 2-dimethoxyethyl) -4-oxo-1,4-dihydropyridin-3-yl] propionamide (55 mg). 51 mg of the obtained compound was subjected to the same reaction procedure as in Step 2 of Example 187, and N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro- 2H-pyrido [1,2-a] pyrazin-7-yl] propionamide (27 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 11.59 (s, 1H), 9.34 (s, 1H), 9.12 (s, 1H), 7.50-7.45 (m, 2H) 7.41-7.33 (m, 3H), 6.96 (d, 1H, J = 6.0 Hz), 4.98 (s, 1H), 2.50 (q, 2H, J = 7. 5 Hz), 1.06 (t, 3H, J = 7.5 Hz).

Example 382
Synthesis of 7- (2,2-dimethylbutyryl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

Process 1
5-Benzyloxy-6- (4-fluorobenzylcarbamoyl) -1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine- obtained by the same production method as in Step 4 of Example 161 3-Carboxylic acid (100 mg) was subjected to the same reaction procedure as in Step 1 of Example 362 and purified by silica gel thin layer chromatography (chloroform: acetone = 3: 1) to give 3-benzyloxy-1- (2 , 2-dimethoxyethyl) -5- (2,2-dimethylbutyryl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 4-fluorobenzylamide (40 mg).
¹ H-NMR (CDCl ₃ ) δ 7.86 (br, 1H), 7.29-7.18 (m, 8H), 6.84 (dd, 2H, J = 8.7 Hz, 8.7 Hz), 5.10 (s, 2H), 4.54 (t, 1H, J = 5.0 Hz), 4.35 (d, 2H, J = 5.8 Hz), 3.83 (d, 2H, J = 5) .0Hz), 3.30 (s, 6H), 1.65 (q, 2H, J = 7.5Hz), 1.19 (s, 6H), 0.83 (t, 3H, J = 7.5Hz) ).

Process 2
3-Benzyloxy-1- (2,2-dimethoxyethyl) -5- (2,2-dimethylbutyryl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 4-fluorobenzylamide (40 mg) Was subjected to the same reaction operation as in Step 161 of Example 161 to give 7- (2,2-dimethylbutyryl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a Pyrazine-1,8-dione hydrochloride (25 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.01 (s, 1H), 7.43 (dd, 2H, J = 9.0 Hz, 5.5 Hz), 7.22 (d, 1H, J = 6) .3 Hz), 7.19 (dd, 2H, J = 9.0 Hz, 9.0 Hz), 6.90 (d, 1H, J = 6.3 Hz), 1.60 (q, 2H, J = 7. 5 Hz), 1.13 (s, 6H), 0.77 (t, 3H, J = 7.5 Hz).

Example 283
Synthesis of 2- (3-chlorobenzyl) -9-hydroxy-7-isobutylamino-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

Process 1
5-Amino-3-benzyloxy-1- (2,2-dimethoxyethyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide obtained in Step 1 of Example 242 ( To a solution of 65 mg) in chloroform (1 ml), isobutyraldehyde (0.025 ml), acetic acid (0.016 ml) and sodium triacetoxyborohydride were sequentially added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated brine (10 ml), and the mixture was extracted twice with chloroform (10 ml each). The organic layer was dried and concentrated, and then purified by silica gel thin layer chromatography (chloroform: methanol = 10: 1) to give 3-benzyloxy-1- (2,2-dimethoxyethyl) -5-isobutylamino-4- Oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (68 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.26-7.20 (8H, m), 7.10 (1H, d, J = 7.4 Hz), 6.80 (1H, t, J = 6.0 Hz) ), 6.63 (1H, s), 5.22 (2H, s), 4.55 (1H, t, J = 5.1 Hz), 4.34 (2H, d, J = 6.0 Hz), 3.99 (2H, d, J = 5.1 Hz), 3.31 (6H, s), 2.82 (2H, d, J = 7.0 Hz), 1.93 (1H, dt, J = 6) .5, 7.0 Hz), 1.01 (6H, d, J = 6.5 Hz).

Process 2
3-Benzyloxy-1- (2,2-dimethoxyethyl) -5-isobutylamino-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-Chlorobenzylamide (66 mg) was prepared in Step 6 of Example 161. To 2- (3-chlorobenzyl) -9-hydroxy-7-isobutylamino-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (43.5 mg) Got.
¹ H-NMR (DMSO-d ₆ ) δ 8.07 (1H, s), 7.64 (1H, d, J = 6.0 Hz), 7.50-7.30 (5H, m), 5. 09 (2H, s), 2.99 (2H, d, J = 7.0 Hz), 1.95 (1H, dt, J = 6.0, 7.0 Hz), 0.91 (6H, d, J = 7.0 Hz).

Example 302
Of N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -N-isobutylacetamide Composition

2- (3-Chlorobenzyl) -9-hydroxy-7-isobutylamino-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (23 mg) was added to chloroform (2 ml) and 0 ° C. Then, pyridine (0.062 ml) and acetyl chloride (0.024 ml) were sequentially added, and the mixture was stirred at room temperature for 2 hours. A 5% aqueous potassium hydrogen sulfate solution was added to the resulting reaction solution, and the mixture was extracted with ethyl acetate. The residue obtained by evaporating the solvent was dissolved in tetrahydrofuran (0.5 ml) -methanol (0.1 ml), 1N aqueous sodium hydroxide solution (0.084 ml) was added, and the mixture was stirred at room temperature for 30 min. 2N aqueous hydrochloric acid (0.056 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried and concentrated, and then crystallized from ethyl acetate-diisopropyl ether to give N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo- 1,8-Dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -N-isobutylacetamide (18.2 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.27 (1H, s), 7.49 (1H, s), 7.39-7.32 (3H, m), 7.18 (1H, d, J = 6.0 Hz), 6.92 (1H, d, J = 6.0 Hz), 4.97 (2H, s), 3.53 (1H, dd, J = 13.7, 8.6 Hz), 3.12 (1H, dd, J = 13.7, 7.2 Hz), 1.76 (3H, s), 1.62 (1H, ddt, J = 7.2, 8.6, 6.5 Hz) , 0.82 (6H, d, J = 6.5 Hz).

Example 349
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- [Il] isobutyramide

Process 1
9-Benzyloxy-7-bromo-2- (3-chloro-4-fluorobenzyl) -3,4-dihydro-2H-pyrido [1,2-a] prepared by a method similar to step 1 of Example 249 ] A solution of pyrazine-1,8-dione (170 mg) in dioxane (1.7 ml), carbamic acid tert-butyl ester (49 mg), tris (dibenzylideneacetone) dipalladium (0) -chloroform hydrate under an argon stream. (1.8 mg), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (3 mg) and cesium carbonate (158 mg) were added, and the mixture was stirred at 100 ° C. After 10 hours, carbamic acid tert-butyl ester (49 mg), tris (dibenzylideneacetone) dipalladium (0) -chloroform solvate (18 mg), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene ( 30 mg) was added, followed by heating and stirring for 18 hours. After cooling to room temperature, insolubles were removed by Celite filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: acetone = 2: 1), and [9-benzyloxy-2- (3-chloro -4-Fluorobenzyl) -1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazin-7-yl] carbamic acid tert-butyl ester (156 mg) was obtained. It was.
¹ H-NMR (CDCl ₃ ) δ 8.31 (s, 1H), 7.80 (s, 1H), 7.62 (m, 2H), 7.38-7.10 (m, 5H), 7 .12 (dd, 1H, J = 8.3, 8.3 Hz), 5.33 (s, 2H), 4.65 (s, 2H), 4.38 (br, 1H), 4.02-3 .98 (m, 2H), 3.50-3.47 (m, 2H), 1.50 (s, 9H).

Process 2
[9-Benzyloxy-2- (3-chloro-4-fluorobenzyl) -1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazin-7-yl A 4N hydrochloric acid / dioxane solution (2 ml) was added to a dioxane (2 ml) solution of carbamic acid tert-butyl ester (179 mg), and the mixture was stirred at room temperature for 3.5 hours. To the residue obtained by distilling off the solvent was added sodium bicarbonate water, and the mixture was extracted with chloroform. The chloroform layer was dried and concentrated, and then purified by silica gel column chromatography (ethyl acetate: methanol = 5: 1) to give 7-amino-9-benzyloxy-2- (3-chloro-4-fluorobenzyl) -3. , 4-Dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (88 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.66-7.64 (m, 2H), 7.35-7.24 (m, 4H), 7.19-7.15 (ddd, 1H, J = 1) .9, 4.4, 8.6 Hz), 7.10 (dd, 1 H, J = 8.3, 8.6 Hz), 6.96 (s, 1 H), 5.27 (s, 2 H), 4 .59 (s, 2H), 3.91-3.88 (m, 2H), 3.45-3.42 (m, 2H), 2.42 (br, 2H).

Process 3
7-amino-9-benzyloxy-2- (3-chloro-4-fluorobenzyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (29 mg) in chloroform To the (0.6 ml) solution, pyridine (0.0082 ml) and isobutyryl chloride (0.01 ml) were added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution was added 5% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was dried and concentrated, and then purified by silica gel thin layer chromatography (chloroform: methanol = 10: 1) to give N- [9-benzyloxy-2- (3-chloro-4-fluorobenzyl). ) -1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazin-7-yl] isobutyramide (29 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.80 (s, 1H), 8.62 (s, 1H), 7.66-7.64 (m, 2H), 7.39 (dd, 1H, J = 2.3, 6.7 Hz), 7.36-7.30 (m, 3H), 7.21 (ddd, 1H, J = 2.3, 4.6, 8.4 Hz), 7.14 (dd , 1H, J = 8.3, 8.8 Hz), 5.35 (s, 2H), 4.66 (s, 2H), 4.03-4.00 (m, 2H), 3.52-3 .50 (m, 2H), 2.63 (sept, 1H, J = 7.0 Hz), 1.25 (d, 6H, J = 7.0 Hz).

Process 4
N- [9-Benzyloxy-2- (3-chloro-4-fluorobenzyl) -1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7 -Yl] isobutyramide (27 mg) was subjected to the same reaction procedure as in Step 4 of Example 223 to give N- [2- (3-chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1 , 3,4,8-Tetrahydro-2H-pyrido [1,2-a] pyrazin-7-yl] isobutyramide (17 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 11.91 (br, 1H), 9.13 (s, 1H), 8.71 (s, 1H), 7.64 (dd, 1H, J = 1. 6, 7.9 Hz), 7.43-7.39 (m, 2H), 4.70 (s, 2H), 4.30-4.26 (m, 2H), 3.74-3.71 ( m, 2H), 2.88 (sept, 1H, J = 6.7 Hz), 1.07 (d, 6H, J = 6.7 Hz).

Example 353
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- [Il] Methanesulfonamide

7-Amino-9-benzyloxy-2- (3-chloro-4-fluorobenzyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine- obtained in Step 2 of Example 349 1,8-dione (29 mg) was subjected to a reaction procedure according to the method described in steps 3 and 4 of Example 349 except that methanesulfonyl chloride was used instead of isobutyryl chloride, and N- [2- ( 3-chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazin-7-yl] methanesulfonamide ( 4.7 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 12.08 (br, 1H), 8.83 (br, 1H), 7.78 (s, 1H), 7.63 (dd, 1H, J = 1. 7, 7.7 Hz), 7.42-7.40 (m, 2H), 4.71 (s, 2H), 4.30-4.27 (m, 2H), 3.74-3.72 ( m, 2H), 2.97 (s, 3H).

Example 222
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-4-hydroxymethyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid Synthesis of methylamide hydrochloride

Process 1
3-Benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid 3-chloro-4-fluorobenzylamide (380 mg) and 2-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid obtained by a method similar to step 1 of Example 161 Amino-3-methoxymethoxy-1-propanol (275 mg) was dissolved in tetrahydrofuran (2 ml) -ethanol (2 ml) and stirred at 60 ° C. for 1 hour. The reaction mixture was concentrated and purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 3-benzyloxy-5-bromo-1- (1-hydroxy-3-methoxymethoxy-2-propyl)- 4-Oxo-1,4-dihydropyridine-2-carboxylic acid 3-chloro-4-fluorobenzylamide (410 mg) was obtained.

Process 2
To a solution of oxalyl chloride (0.245 ml) in methylene chloride (1 ml) was added dropwise a solution of dimethyl sulfoxide (0.269 ml) in methylene chloride (1 ml) at −78 ° C. under a nitrogen stream, and the mixture was stirred for 10 minutes. 3-Benzyloxy-5-bromo-1- (1-hydroxy-3-methoxymethoxy-2-propyl) -4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chloro-4-fluoro at the same temperature A solution of benzylamide (410 mg) in methylene chloride (16 ml) was added over 5 minutes. After stirring for another 10 minutes after completion of the dropwise addition, triethylamine (1.37 ml) was added, and the temperature was raised to room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated, water was added, and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with saturated brine, dried and concentrated. The obtained crude product was dissolved in chloroform (8 ml), and N, N-diisopropylethylamine (0.734 ml) and methanesulfonyl chloride (0.101 ml) were successively added under ice cooling. After stirring at room temperature for 2 hours, methanesulfonyl chloride (0.05 ml) was added, and the mixture was further stirred for 1 hour. The reaction mixture was concentrated, aqueous sodium bicarbonate was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with saturated brine, dried, concentrated, purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2-ethyl acetate), and 9-benzyloxy-7-bromo-2. -(3-Chloro-4-fluorobenzyl) -4- (methoxymethoxy) methyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (163 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.35 (s, 1H), 7.69-7.65 (m, 2H), 7.37-7.16 (m, 5H), 7.13 (dd, 1H, J = 8.7 Hz, 8.7 Hz), 6.32 (s, 1H), 5.37 (s, 2H), 4.88 (s, 2H), 4.68 (s, 2H), 4 .46 (s, 2H), 3.42 (s, 3H).

Process 3
9-Benzyloxy-7-bromo-2- (3-chloro-4-fluorobenzyl) -4- (methoxymethoxy) methyl-2H-pyrido [1,2-a] pyrazine-1,8-dione (125 mg) Was subjected to the same reaction procedure as in Step 3 of Example 161, and 9-benzyloxy-2- (3-chloro-4-fluorobenzyl) -4- (methoxymethoxy) methyl-1,8-dioxo-1,8 -Dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid methyl ester (28 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.68 (s, 1H), 7.69-7.65 (m, 2H), 7.38-7.18 (m, 5H), 7.13 (dd, 1H, J = 8.5 Hz, 8.5 Hz), 6.32 (s, 1H), 5.39 (s, 2H), 4.87 (s, 2H), 4.69 (s, 2H), 4 .46 (s, 2H), 3.96 (s, 3H), 3.41 (s, 3H).

Process 4
9-Benzyloxy-2- (3-chloro-4-fluorobenzyl) -4- (methoxymethoxy) methyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine- 7-Carboxylic acid methyl ester (27 mg) was hydrolyzed in the same manner as in Step 161 of Example 161, followed by treatment according to Example 154 to give 2- (3-chloro-4-fluorobenzyl). -9-hydroxy-4-hydroxymethyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid methylamide hydrochloride (2.2 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 12.22 (s, 1H), 9.97 (s, 1H), 8.83 (s, 1H), 7.69-7.66 (m, 1H) , 7.44-7.41 (m, 2H), 7.16 (s, 1H), 5.68 (t, 1H, J = 5.3 Hz), 4.96 (s, 2H), 4.50 (D, 2H, J = 5.3 Hz), 2.85 (d, 3H, J = 4.6 Hz).

Example 316
Synthesis of 9-hydroxy-2- (3-phenylpropyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride

Process 1
3-Benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (6.82 g) was suspended in methanol (20 ml) -tetrahydrofuran (50 ml), and 2M (trimethylsilyl) diazomethane / hexane solution ( 25.8 ml) was added dropwise, followed by stirring at room temperature for 1.5 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in chloroform (50 ml), bromine (14.2 ml) was added thereto, and the mixture was stirred at 75 ° C. for 2 days. After returning to room temperature, the mixture was concentrated under reduced pressure, hexane was added to the residue, and the precipitated solid was collected by filtration. The obtained solid was dissolved in dimethylformamide (40 ml), potassium carbonate (4.59 g) and benzyl bromide (3.62 ml) were added, and the mixture was stirred at 80 ° C. for 40 minutes. To the residue obtained by evaporating the solvent was added 1N aqueous hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with saturated brine, dried, concentrated, purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 1: 1), and the eluate was concentrated to precipitate. The crystals were collected by filtration to give 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid methyl ester (4.69 g).
¹ H-NMR (CDCl ₃ ) δ 8.10 (s, 1H), 7.47-7.44 (m, 2H), 7.38-7.32 (m, 3H), 5.32 (s, 2H), 3.88 (s, 3H).

Process 2
To a solution of 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid methyl ester (2.3 g) in dioxane (25 ml) was added tetrakis (triphenylphosphine) palladium (0) under a stream of argon. (1.57 g) and (2-thiazolyl) tributyltin (5.08 g) were added, and the mixture was stirred at 100 ° C. for 1.5 hours. The resulting reaction solution was concentrated and subsequently purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 1: 2) to give 3-benzyloxy-4-oxo-5- (thiazole-2- Yl) -4H-pyran-2-carboxylic acid methyl ester (1.47 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.98 (s, 1H), 7.92 (d, 1H, J = 3.2 Hz), 7.53-7.48 (m, 3H), 7.48- 7.25 (m, 3H), 5.41 (s, 2H), 3.91 (s, 3H).

Process 3
3-Benzyloxy-4-oxo-5- (thiazol-2-yl) -4H-pyran-2-carboxylic acid methyl ester (1.47 g) was suspended in ethanol (15 ml) -dioxane (15 ml), 2-Aminoethyl) carbamic acid tert-butyl ester (0.816 ml) was added. After stirring at 70 ° C. for 1.5 hours, the solvent was distilled off, and 4N hydrochloric acid / dioxane solution (70 ml) and chloroform (10 ml) were added to the residue. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue were added saturated aqueous sodium hydrogen carbonate (20 ml) and methanol (50 ml), and the mixture was stirred for 2 hours. The solid obtained by distilling off the solvent was collected by filtration, washed well with water, and 9-benzyloxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a]. Pyrazine-1,8-dione (1.07 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.84 (s, 1H), 8.66 (brt, 1H, J = 3.7 Hz), 7.93 (d, 1H, J = 3.2 Hz), 7.68 (d, 1H, J = 3.2 Hz), 7.59 (d, 2H, J = 6.8 Hz), 7.40-7.30 (m, 3H), 5.17 (s, 2H) ), 4.41-4.36 (m, 2H), 3.54-3.48 (m, 2H).

Process 4
9-Benzyloxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (30 mg) and 3-phenylpropyl bromide (0 0.02 ml) was added to dimethyl sulfoxide (1 ml) and sodium hydride (7 mg) was added with stirring. After stirring for 20 minutes, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted twice with ethyl acetate. The ethyl acetate layer was washed with brine, dried and concentrated, then purified by silica gel thin layer chromatography (chloroform-methanol = 15: 1), and 9-benzyloxy-2- (3-phenylpropyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (27 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.50 (s, 1H), 7.86 (d, 1H, J = 3.2 Hz), 7.69-7.65 (m, 2H), 7.42 ( d, 1H, J = 3.2 Hz), 7.36-7.16 (m, 8H), 5.45 (s, 2H), 4.11-4.07 (m, 2H), 3.62- 3.53 (m, 4H), 2.70 (t, 2H, J = 7.5 Hz), 1.96 (tt, 2H, J = 7.5 Hz, 7.5 Hz).

Process 5
9-Benzyloxy-2- (3-phenylpropyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (27 mg) Concentrated aqueous hydrochloric acid (0.5 ml) was added to an acetic acid (1 ml) solution, and the mixture was stirred at 90 ° C. for 2 hours. The solvent was distilled off, ethyl acetate was added to the residue, and the resulting solid was collected by filtration to give 9-hydroxy-2- (3-phenylpropyl) -7- (thiazol-2-yl) -3,4-dihydro -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride (25 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.72 (s, 1H), 7.89 (d, 1H, J = 3.1 Hz), 7.63 (d, 1H, J = 3.1 Hz), 7.30-7.14 (m, 5H), 4.45-4.40 (m, 2H), 3.82-3.77 (m, 2H), 3.55 (t, 2H, J = 7 .1 Hz), 2.64 (t, 2H, J = 7.7 Hz), 1.91 (tt, 2H, J = 7.1 Hz, 7.7 Hz).

Example 291
Synthesis of 2- (3,4-difluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione

Process 1
The method described in Step 3 of Example 316 from 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid methyl ester (1.2 g) obtained in Step 1 of Example 316 According to the above, 9-benzyloxy-7-bromo-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (1.05 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.61 (brt, 1H, J = 4.0 Hz), 8.37 (s, 1H), 7.53 (dd, 2H, J = 8.4 Hz, 1 .7 Hz), 7.37-7.26 (m, 3H), 5.05 (s, 2H), 4.20-4.15 (m, 2H), 3.46-3.41 (m, 2H) ).

Process 2
According to the method described in Step 4 of Example 316 from 9-benzyloxy-7-bromo-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (50 mg). 9-Benzyloxy-7-bromo-2- (3,4-difluorobenzyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (60 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.67-7.64 (m, 2H), 7.57 (s, 1H), 7.37-7.29 (m, 3H), 7.18-7. 10 (m, 2H), 7.04-6.99 (m, 1H), 5.33 (s, 2H), 4.61 (s, 2H), 3.96-3.92 (m, 2H) 3.53-3.48 (m, 2H).

Process 3
From 9-benzyloxy-7-bromo-2- (3,4-difluorobenzyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (60 mg), examples 9-benzyloxy-2- (3,4-difluorobenzyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] by a method according to Step 2 of H.249. Pyrazine-1,8-dione (35 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.50 (s, 1H), 7.85 (d, 1H, J = 3.3 Hz), 7.69-7.65 (m, 2H), 7.42 ( d, 1H, J = 3.3 Hz), 7.38-7.30 (m, 3H), 7.20-7.12 (m, 2H), 7.07-7.02 (m, 1H), 5.47 (s, 2H), 4.66 (s, 2H), 4.14-4.09 (m, 2H), 3.59-3.54 (m, 2H).

Process 4
9-Benzyloxy-2- (3,4-difluorobenzyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione ( 35 mg) was dissolved in trifluoroacetic acid (1 ml) and stirred at room temperature for 3 hours. Toluene was added to the residue obtained by distilling off trifluoroacetic acid under reduced pressure, and this was concentrated twice. Further, ethyl acetate was added, and the resulting solid was collected by filtration to give 2- (3,4-difluorobenzyl. ) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione (14 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 12.30 (s, 1H), 8.71 (s, 1H), 7.89 (d, 1H, J = 3.2 Hz), 7.63 (d, 1H, J = 3.2 Hz), 7.52-7.40 (m, 2H), 7.28-7.22 (m, 1H), 4.72 (s, 2H), 4.49-4. 43 (m, 2H), 3.81-3.76 (m, 2H).

Example 106
Synthesis of 2- (3-chlorobenzyl) -8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

Process 1

To a solution of (N-benzyloxycarbonyl-N-methylamino) acetic acid (15 g) in tetrahydrofuran (150 ml) was added carbonyldiimidazole (16.3 g) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Separately, a suspension of magnesium chloride (6.21 g) and ethyl potassium malonate (17.2 g) in tetrahydrofuran (250 ml) stirred at 50 ° C. for 7 hours was ice-cooled, and the above solution was stirred over 30 minutes. It was dripped down. After stirring for 12 hours, the solvent was distilled off under reduced pressure, and ethyl acetate and 5% aqueous potassium hydrogen sulfate solution were added to the residue and stirred. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give an oil (16.8 g). This was dissolved in tetrahydrofuran (120 ml) / ethanol (180 ml), and sodium borohydride (6.5 g) was added under ice cooling. After 20 minutes, calcium chloride (9.54 g) was added, and the mixture was stirred at room temperature for 1 hour. 1N aqueous hydrochloric acid and ethyl acetate were added to the reaction solution. The separated organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give an oil (12.48 g). This was dissolved in dimethylformamide (100 ml), tert-butyldiphenylchlorosilane (12.81 ml) and imidazole (6.71 g) were added under ice cooling, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, subsequently dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3), and N- [4- (tert-butyldiphenylsilanyloxy) -2-hydroxybutyl] -N-methylcarbamic acid benzyl ester (12 .84 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.67 (4H, d, J = 7.0 Hz), 7.48-7.28 (11H, m), 5.14 (2H, s), 4.14 ( 1H, br s), 3.89 (2H, br s), 3.47-3.27 (2H, m), 3.04 (3H, s), 1.79-1.60 (2H, m) , 1.07 (9H, s).

Process 2

A solution of N- [4- (tert-butyldiphenylsilanyloxy) -2-hydroxybutyl] -N-methylcarbamic acid benzyl ester (12.84 g) in chloroform (150 ml) under ice-cooling was 1,1,1-tris. (Acetoxy) -1,1-dihydro-1,2-benzoiodoxol-3- (1H) -one (Dess-Martin reagent) (15.50 g) was added and stirred for 1 hour. The reaction solution was washed successively with a saturated aqueous sodium hydrogen carbonate solution, a saturated aqueous sodium sulfite solution, and saturated brine, and then dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give N- [4- (tert-butyldiphenylsilanyloxy) -2-oxobutyl] -N-methylcarbamic acid benzyl ester. (10.92 g) was obtained. Methyl orthoformate (70 ml) and pyridinium p-toluenesulfonate (4.08 g) were added to a methanol (70 ml) solution of the obtained compound (7.95 g), and the mixture was heated and stirred at 60 ° C. for 18 hours. The reaction mixture was concentrated, ethyl acetate was added to the residue, the precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5), and N- [4- (tert-butyldiphenylsilanyloxy) -2,2-dimethoxybutyl] -N-methylcarbamic acid benzyl ester (2.25 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.74-7.62 (4H, m), 7.45-7.22 (11H, m), 5.07 (1H, brs), 4.96 (1H , D, J = 10.0 Hz), 3.79 (2H, brs), 3.41 (2H, brs), 3.12 (6H, brs), 2.95 (3H, s), 1 .99 (2H, s), 1.06 (9H, s).

Process 3

10% palladium carbon was added to a methanol (60 ml) solution of N- [4- (tert-butyldiphenylsilanyloxy) -2,2-dimethoxybutyl] -N-methylcarbamic acid benzyl ester (3.22 g) in a hydrogen atmosphere. (3 atm) and stirred for 2.5 hours. Palladium on carbon was filtered off, and the filtrate was concentrated to give an oil (2.44 g). This was dissolved in pyridine (30 ml), methyl chloroglyoxylate (0.839 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the residue obtained by evaporating the solvent, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give an oil (2.968 g). Separately, the above oily substance was added to a solution of lithium enolate in tetrahydrofuran (60 ml) prepared at −78 ° C. from lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 12.14 ml) and benzyl acetate (1.753 ml) at −78 ° C. And stirred at the same temperature for 20 minutes. Acetic acid (1.04 ml), water and ethyl acetate were sequentially added to the reaction solution, and the mixture was warmed to room temperature and separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Dioxane (50 ml) and 2N aqueous hydrochloric acid solution (5 ml) were added to the residue. After stirring at room temperature for 1 hour, the solvent was distilled off, followed by addition of toluene and concentration again. The obtained residue was dissolved in chloroform (40 ml) and triethylamine (20 ml), stirred for 1 hour, and then the solvent was distilled off. The residue was dissolved in pyridine (60 ml), benzoyl chloride (1.41 ml) was added under ice cooling, and the mixture was stirred for 1 hour, and then the solvent was distilled off. Water was added to the residue, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) and 3-benzoyloxy-5- [2- (tert-butyldiphenylsilanyloxy) ethyl] -1-methyl-2-oxo -1,2-Dihydropyridine-4-carboxylic acid benzyl ester (2.519 g) was obtained. This was dissolved in methanol (75 ml), 7.5% palladium carbon was added, and the mixture was stirred under a hydrogen atmosphere (1 atm) for 1 hour. After the palladium carbon was filtered off, the filtrate was concentrated and crystallized with ethyl acetate / hexane to give 3-benzoyloxy-5- [2- (tert-butyldiphenylsilanyloxy) ethyl] -1-methyl-2- Oxo-1,2-dihydropyridine-4-carboxylic acid (1.32 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.15 (2H, d, J = 8.3 Hz), 7.62-7.56 (5H, m), 7.49-7.36 (8H, m), 7.07 (1H, s), 3.83 (2H, t, J = 6.0 Hz), 3.52 (3H, s), 2.70 (2H, t, J = 6.0 Hz), 1. 06 (9H, s).

Process 4

3-Benzoyloxy-5- [2- (tert-butyldiphenylsilanyloxy) ethyl] -1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.956 g) in dimethylformamide (10 ml ) 1-hydroxybenzotriazole hydrate (HOBT) (0.395 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) (0.495 g), 3-chlorobenzylamine (0.274 ml) was added and stirred at room temperature for 2 hours. Water was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) and benzoic acid 5- [2- (tert-butyldiphenylsilanyloxy) ethyl] -4- (3-chlorobenzylcarbamoyl) -1 -Methyl-2-oxo-1,2-dihydropyridin-3-yl ester (0.615 g) was obtained. This was dissolved in tetrahydrofuran (20 ml), acetic acid (0.259 ml) and tetrabutylammonium fluoride (0.474 g) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel thin layer chromatography (chloroform: methanol = 10: 1) to give 4- (3-chlorobenzylcarbamoyl) -5- (2-hydroxyethyl) -1-methyl benzoate. 2-Oxo-1,2-dihydropyridin-3-yl ester (0.213 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 8.04 (2H, d, J = 7.4 Hz), 7.64 (1H, t, J = 7.4 Hz), 7.46 (2H, t, J = 7) .9 Hz), 7.22 (1 H, s), 7.15 (1 H, s), 6.99 (2 H, d, J = 7.9 Hz), 6.86 (1 H, t, J = 7.9 Hz) ), 6.67 (1H, t, J = 6.5 Hz), 4.43 (2H, d, J = 6.0 Hz), 3.86-3.78 (2H, m), 2.69 (2H) , T, J = 6.0 Hz), 2.67 (1H, br s).

Process 5

A solution of benzoic acid 4- (3-chlorobenzylcarbamoyl) -5- (2-hydroxyethyl) -1-methyl-2-oxo-1,2-dihydropyridin-3-yl ester (0.1 g) in tetrahydrofuran (4 ml) Under ice cooling, diisopropylethylamine (0.119 ml) and methanesulfonyl chloride (0.035 ml) were sequentially added. After 20 minutes, diisopropylethylamine (0.119 ml) and methanesulfonyl chloride (0.035 ml) were further added, and the mixture was stirred for 20 minutes under ice cooling. Water was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate / hexane and collected by filtration to obtain crystals (0.15 g). This was dissolved in dimethylformamide (3 ml), sodium hydride (0.09 g, 60%) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate and 2N aqueous hydrochloric acid solution were added for extraction, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (ethyl acetate to chloroform: methanol = 6: 1), crystallized from ethyl acetate / hexane, and the crystals were collected by filtration to give 2- (3-chlorobenzyl) -8- Hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (0.029 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 12.75 (1H, s), 7.33-7.29 (3H, m), 7.24-7.19 (1H, m), 6.61 (1H, s), 4.71 (2H, s), 3.57 (3H, s), 3.46 (2H, t, J = 6.4 Hz), 2.73 (2H, t, J = 6.4 Hz) .

Example 123
Synthesis process 1 of 6- (3-chlorobenzyl) -4-hydroxy-2-methyl-2,6,7,8-tetrahydropyrido [4,3-c] pyridazine-3,5-dione

An ethanol solution of ethyl acrylate (11.5 ml) was added dropwise to a solution of 3-chlorobenzylamine (15 g) in ethanol (150 ml) at room temperature and stirred overnight. Chloroform (500 ml), pyridine (50 ml) and 4-dimethylaminopyridine (3.9 g) were added to the residue obtained by concentrating the reaction solution under reduced pressure. Ethylmalonyl chloride (13.6 ml) was added dropwise to the mixture under ice cooling. After stirring for 1 hour under ice cooling and further for 1 hour at room temperature, the reaction mixture was washed with 2N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1 to 3: 2) to obtain an oil (25.6 g). A solution of this oil (25.6 g) in toluene (50 ml) was added dropwise to a suspension of potassium carbonate (50 g) and 18-crown-6 (1.9 g) in toluene (250 ml) with heating under reflux. For 12 hours. After cooling to room temperature, the reaction solution was poured into ice water, 6N aqueous hydrochloric acid was added to adjust the pH of the reaction solution to 1 or less, and the mixture was extracted three times with chloroform. A 10% aqueous oxalic acid solution (200 ml) was added to the residue obtained by drying and concentrating the chloroform layer, and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled, extracted three times with chloroform, and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 3 to 1: 2) to give 1- (3-chlorobenzyl) piperidine-2,4. -Dione (6.2 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.1-7.4 (4H, m), 4.67 (2H, s), 3.51 (2H, t, J = 6.3 Hz), 3.44 ( 2H, s), 2.58 (2H, t, J = 6.3 Hz).

Process 2

1- (3-Chlorobenzyl) piperidine-2,4-dione (1.2 g) was dissolved in ethanol (25 ml), methylhydrazine (0.5 ml) was added thereto, and the mixture was heated to reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 95: 1) to give 1- (3-chlorobenzyl) -4- (methylhydrazono) piperidine-2. -On (1.05 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ 7.1-7.4 (4H, m), 4.2-4.8 (3H, m), 3.2-3.5 (4H, m), 2. 95 (3H, s), 2.3-2.7 (2H, m).

Process 3

1- (3-Chlorobenzyl) -4- (methylhydrazono) piperidin-2-one (1.05 g) was dissolved in chloroform (20 ml), and triethylamine (1.2 ml), methyloxalyl chloride ( 0.735 ml) was added sequentially. After stirring at room temperature for 2 hours, the reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 3-ethyl acetate to chloroform: methanol = 90: 10) to obtain an oily substance (200 mg). It was. This was dissolved in tetrahydrofuran (4 ml), sodium hydride (27 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 30 min. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 90: 10) to give 6- (3-chlorobenzyl) -4-hydroxy-2-methyl-2,6. , 7,8-tetrahydropyrido [4,3-c] pyridazine-3,5-dione (92 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 13.41 (1H, s), 7.39-7.33 (4H, m), 4.70 (2H, s), 3.64-3.56 ( 5H, m), 2.85 (2H, t, J = 6.5 Hz).

Example 438
7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8- obtained in the same manner as in Example 251. Dione hydrochloride (7.5 g) was suspended in ethyl acetate (1.5 L), and saturated aqueous sodium hydrogen carbonate (500 ml) was added with stirring. After the suspension dissolved, the aqueous layer was separated and extracted with a small amount of ethyl acetate. The combined ethyl acetate layers were washed with saturated brine, dried over sodium sulfate, and concentrated. Acetone-ethyl acetate was added to the obtained residue, and the obtained crystal was collected by filtration, and 7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1 , 2-a] pyrazine-1,8-dione (6.38 g).
¹ H-NMR (DMSO-d ₆ ) δ 11.65 (1H, br), 8.04 (1H, s), 7.44 (2H, dd, J = 8.8, 5.1 Hz), 7. 19 (2H, dd, J = 8.8, 8.8 Hz), 7.18 (1H, d, J = 6.0 Hz), 6.88 (1H, d, J = 6.0 Hz), 4.92 (2H, s), 1.17 (9H, s).

Example 439
7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione obtained in Example 438 ( 100 mg) was suspended in tetrahydrofuran-methanol (3: 1) (4 ml). 1M aqueous sodium hydroxide solution (270 μl) was added and stirred for 24.5 hours. The precipitate was collected by filtration, washed with tetrahydrofuran, and dried under reduced pressure at 50 ° C. to give 7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido. [1,2-a] pyrazine-1,8-dione sodium salt (94 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 7.48 (1H, s), 7.37 (2H, dd, J = 8.8, 5.6 Hz), 7.12 (2H, t, J = 8) .8 Hz), 6.86 (1 H, d, J = 6.3 Hz), 6.57 (1 H, d, J = 6.3 Hz), 4.78 (2 H, s), 1.21 (9 H, s) ).

Sodium salt, potassium salt, hydrochloride, trifluoroacetate, methanesulfonate, benzenesulfonate, and toluenesulfonate were obtained from the compound of Example 165 by a conventional method.
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide sodium salt (Examples) 440)
¹ H-NMR (DMSO-d ₆ ) δ 8.92 (1H, brs), 8.54 (1H, s), 7.41-7.26 (4H, m), 6.97 (1H, brs) , 6.60 (1H, brs), 4.83 (2H, s), 2.08 (3H, s).

A free compound and a sodium salt were obtained from the compound of Example 223 by a conventional method.
2- (3-Chlorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione sodium salt ( Example 441)
¹ H-NMR (DMSO-d ₆ ) δ 7.39-7.24 (5H, m), 4.65 (2H, s), 4.17-4.05 (2H, m), 3.54- 3.47 (2H, m), 1.23 (9H, s).

  The free form, sodium salt, potassium salt and benzenesulfonate were obtained from the compound of Example 251 by a conventional method.

Examples 93-437
Examples 1 to 12, 118, 125, 161, 165, 94, 96, 104, 187, 191, 189, 390, 244, 251, 223, 154, 249, 219, 362, 205, 242, 382, 283, 302, 349, 353, 222, 316, 291, 106, 123, 438, 439 The compounds of Examples 93 to 437 other than those described above were obtained in the same or similar manner and in the usual manner.

  Tables 1 to 37 show chemical structural formulas and physical property data of the Example compounds.

Test example 1
Next, a method for evaluating the HIV integrase inhibitory activity of the compound of the present invention will be described.
(I) Construction of recombinant integrase gene expression system The 185th phenylalanine of the full-length HIV integrase gene (J. Virol., 67, 425-437 (1993)) was replaced with histidine, and plasmid pET21a (+) (Novagen) In the restriction enzyme NdeI and XhoI sites of the integrase expression vector pET21a-INH.

(Ii) Production and purification of integrase protein The recombinant Escherichia coli BL21 (DE3) transformed with the plasmid pET21a-INH obtained in (i) was cultured in a liquid medium containing ampicillin at 37 ° C. with shaking, and logarithmically. At the time of the growth phase, the expression of the integrase gene was promoted by the addition of isopropyl-β-D-thiogalactopyranoside (isopropyl-β-D-thiogalactopyranoside). Subsequently, the cells were cultured for 3 hours to promote the accumulation of integrase protein, and the recombinant E. coli was collected as a pellet by centrifugation and stored at −80 ° C.
This Escherichia coli is suspended in a Lysis buffer solution (20 mM HEPES (pH 7.5), 5 mM DTT, 10 mM CHAPS, 10% glycerol) containing 1 M sodium chloride, and repeatedly subjected to pressurization and decompression treatment. The water-soluble fraction (supernatant) was collected by centrifugation at 000 × g for 60 minutes. This was diluted 10-fold with a Lysis buffer containing no sodium chloride, mixed with SP-Sepharose (Pharmacia), and stirred at 4 ° C. for 30 minutes to adsorb the integrase protein to the resin. The resin was washed with a Lysis buffer containing 100 mM sodium chloride, and then the integrase protein was eluted with a Lysis buffer containing 1 M sodium chloride.

The eluted integrase protein solution was applied to a Superdex 75 (Pharmacia) column and subjected to gel filtration. The protein was eluted with Lysis buffer containing 1M sodium chloride.
Fractions of the obtained integrase protein were collected and stored at -80 ° C.

(Iii) Preparation of DNA solution The following DNA synthesized in the Greiner is dissolved in TE buffer (10 mM Tris-hydrochloric acid (pH 8.0), 1 mM EDTA), donor DNA, target DNA, and complementary strands (+ And -chain) are mixed to 1 μM, heated at 95 ° C. for 5 minutes, 80 ° C. for 10 minutes, 70 ° C. for 10 minutes, 60 ° C. for 10 minutes, 50 ° C. for 10 minutes, and 40 ° C. for 10 minutes. The double-stranded DNA was obtained by incubating at 25 ° C. and used.

Donor DNA (-strand has biotin added at the 5 'end)
Donor + strand: 5′-Biotin-ACC CTT TTA GTC AGT GTG GAA AAT CTC TAG CA-3 ′ (SEQ ID NO: 1)
Donor-chain: 5'-ACT GCT AGA GAT TTT CCA CAC TGA CTA AAA G-3 '(SEQ ID NO: 2)
Target DNA (with digoxigenin added to the 3 'end for both + and-strands)
Target + chain: 5′-TGA CCA AGG GCT AAT TCA CT-Dig-3 ′ (SEQ ID NO: 3)
Target-chain: 5′-AGT GAA TTA GCC CTT GGT CA-Dig-3 ′ (SEQ ID NO: 4)

(Iv) Measurement of enzyme (HIV integrase) inhibitory activity The donor DNA was diluted to 10 nM with TE buffer, and 50 μl was added to each well of a microtiter plate (manufactured by Roche) coated with streptavidin. Adsorption was carried out at 60 ° C. for 60 minutes. Next, after washing with a phosphate buffer solution (Dulbecco PBS, manufactured by Sanko Junyaku Co., Ltd.) containing 0.1% Tween 20 and a phosphate buffer solution, a reaction solution (70 μl) having the following composition and a test substance diluted with the reaction solution ( 10 μl) and 100 μg / ml integrase protein (10 μl) were added to each well and reacted at 37 ° C. for 60 minutes.
Composition of reaction solution: 30 mM MOPS (3-morpholinopropanesulfonic acid), 5 mM magnesium chloride, 3 mM DTT (dithiothreitol), 0.1 mg / ml BSA (bovine serum albumin), 5% glycerol, 10% DMSO (dimethylsulfoxide) ), 0.01% Tween 20.

  Subsequently, 50 nM target DNA (10 μl) was added and reacted at 37 ° C. for 10 minutes, and then washed with a phosphate buffer containing 0.1% Tween 20 to stop the reaction.

  Subsequently, a 100 mU / ml peroxidase-labeled anti-digoxigenin antibody solution (Roche, 100 μl) was added, reacted at 37 ° C. for 60 minutes, and then washed with a phosphate buffer containing 0.1% Tween 20.

  Next, a peroxidase coloring solution (Bio-Rad, 100 μl) was added and reacted at room temperature for 4 minutes, 1N sulfuric acid (100 μl) was added to stop color development, and the absorbance at 450 nm was measured.

The HIV integrase inhibitory activity (IC ₅₀ ) of the compound of the present invention was calculated from the inhibition rate determined from the following formula.

Inhibition rate (%) = [1- (Object-Blank) / (Control-Blank)] × 100
Object; Absorbance control of well in the presence of test compound; Absorbance of well in the absence of test compound Blank; Absorbance of well in the absence of test compound and in the absence of integrase protein

The results are shown in Table 38 to Table 46. IC ₅₀ shows the following ranges.
+: 1 μM or more and less than 10 μM ++: 0.1 μM or more and less than 1 μM +++: 0.01 μM or more and less than 0.1 μM +++++: less than 0.01 μM

Test Example 2 Evaluation of Antiviral Activity The combined effect of the compound of the present invention and a known anti-HIV agent can be measured as follows.

  For example, existing nucleoside reverse transcriptase inhibitors (zidovudine, lamivudine, tenofovir), non-nucleoside reverse transcriptase inhibitors (efavirenz) or protease inhibitors (indinavir, nelfinavir) and test substance A, etc. Are evaluated by the XTT method using CEM-SS cells infected with HIV-1 IIIB.

  Moreover, the triple agent combined use with test substance A, zidovudine, and lamivudine, or the triple agent combined use effect with test substance A, tenofovir, and lamivudine, etc. are evaluated.

Prior to the combination test, the IC ₅₀ and CC ₅₀ of each drug alone are measured. The combination of 5 concentrations of drug A and 9 concentrations of drug B determined from this result is used to evaluate the combined effect of 2 drugs. In the case of a combination of three drugs, a high concentration of drug B and drug C are mixed, and drug A and the concentration are combined and evaluated.

Analyze the test results of the test substance and concomitant drugs alone or in combination using the programs of Prichard and Shipman MacSynergy II version 2.01 and Deltagraph version 1.5d. A three-dimensional plot was made with 95% (or 68%, 99%) confidence limits from the inhibition rate at the concentration of each combined drug obtained from three experiments, and from the value of μM ² % calculated therefrom Determine the combined effect. Judgment criteria are shown below.
Definition of interaction μM ² %
Strong synergy> 100
Slight synergy +51 to +100
Additive action +50 to -50
Slight antagonism -51 to -100
Strong antagonism <-100

  As is clear from the above results, the compound of the present invention exhibits high inhibitory activity against HIV integrase.

  Therefore, these compounds can be effective drugs for preventing or treating AIDS as anti-HIV agents having HIV integrase inhibitory activity. Moreover, it can become a more effective anti-HIV agent by using together with other anti-HIV agents such as protease inhibitors and reverse transcriptase inhibitors. In addition, having high inhibitory activity specific to integrase can be a safe drug with few side effects for the human body.

Although the example of a formulation is given to the following, it is not limited to this.
Formulation Example (a) 10 g of the compound of Example 1
(B) Lactose 50g
(C) Corn starch 15g
(D) Sodium carboxymethyl cellulose 44 g
(E) Magnesium stearate 1g
The whole amount of (a), (b), (c) and 30 g of (d) are kneaded with water, and after vacuum drying, granulation is performed. This granulated powder is mixed with 14 g of (d) and 1 g of (e), and tableted with a tableting machine to produce 1000 tablets containing 10 mg of (a) per tablet.

  The present invention relates to a novel nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof useful as an anti-HIV agent, a novel nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof as a novel anti-HIV agent. More particularly, it relates to an anti-HIV agent containing a nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof that exhibits an anti-HIV action by integrase inhibitory activity, and is effective in preventing and treating AIDS development. In particular, by having an integrase inhibitory action, it can be an effective anti-HIV agent, and a drug having an anti-HIV action, particularly a drug having an integrase inhibitory action, can be provided.

SEQ ID NO: 1 Donor for measuring HIV integrase activity + strand SEQ ID NO: 2 Donor for measuring HIV integrase activity-Strand SEQ ID NO: 3 Target for measuring HIV integrase activity + Strand SEQ ID NO: 4 Target-strand for measuring HIV integrase activity

  This application is based on patent application Nos. 2003-293117 and 2004-134896 filed in Japan, the contents of which are included in this specification.

Claims (38)

A nitrogen-containing fused ring compound represented by the following general formula [I] or a pharmaceutically acceptable salt thereof.

[Where:
R ¹ is
(1) a C1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the following group A;
(2) a C2-6 alkenyl group which may be substituted with 1 to 3 substituents selected from group A below, or
(3) Formula

(Where Z is
(1 ') join,
(2 ') C1-6 alkylene,
(3 ') C2-6 alkenylene, or
(4 ') * - (CH 2) m -Q- (CH 2) n -
{Where Q is
(1 '')-O-,
(2 '')-NR ^5-
(Wherein R ⁵ is a hydrogen atom or a C 1-6 alkyl group),
(3``) -CO-,
(4``) -SO-,
_{(5 '') - SO 2} -, or,
(6 '') **-CO-NR ^6-
(Wherein R ⁶ is a hydrogen atom or a C 1-6 alkyl group, and ** represents the side bonded to (CH ₂ ) _m ),
m represents 0 or an integer of 1 to 4;
n represents 0 or an integer of 1 to 4,
* Indicates the side bonded to the nitrogen atom of ring A. },
Ring D is
(1 ′) a C3-10 carbocyclic group which may be substituted with 1 to 3 substituents selected from the following group B, or
(2 ′) a heterocyclic group which may be substituted with 1 to 3 substituents selected from the following group B (wherein the heterocyclic group is at least one selected from a nitrogen atom, an oxygen atom and a sulfur atom) Contains heteroatoms). )
X is
(1) -C (R ^x1 ) (R ^x2 )-#,
(2) -C (R ^x1 ) (R ^x2 ) -C (R ^x3 ) (R ^x4 )-#,
(3) -C (R ^x1 ) (R ^x2 ) -C (R ^x3 ) (R ^x4 ) -C (R ^x5 ) (R ^x6 )-#,
(4) -C (R ^x7 ) = C (R ^x8 )-#,
(5) -C (R ^x1 ) (R ^x2 ) -C (R ^x7 ) = C (R ^x8 )-#,
(6) -C (R ^x7 ) = C (R ^x8 ) -C (R ^x1 ) (R ^x2 )-#,
(7) -N = C (R ^x9 )-#, or
(8) −C (R ^{× 10} ) = N− #
(Wherein # represents the side of ring B bonded to Y ¹ , R ^x1 to R ^x10 are each independently selected from the following group C, R ^x1 and R ^x2 , R ^x3 and R ^x4 , R ^x5 and ^Rx6 may each independently form a C3-8 cycloalkyl together with adjacent carbon atoms.)
Of ring B

Is
(1) C = C (R ^y1 ) −N (R ^y2 ),
(2) N-C (R ^y1 ) = N,
(3) N-C (R ^y1 ) = C (R ^y2 ),
(4) C = N-N (R ^y2 ), or
(5) N-N = C (R ^y3 )
(Where R ^y1 to R ^y3 are each independently selected from the following group C):

Is N-C (R ^y1 ) = C (R ^y2 ), ring B is condensed with the benzene ring

(In the formula, R ⁴ is selected from the following group C).
R ² is
(1) hydrogen atom,
(2) C1-6 alkyl group,
(3) C6-14 aryl C1-6 alkyl group, or
(4) -SO ₂ R ^d1
Here, R ^d1 is a hydrogen atom, a C 1-7 alkyl group which may be substituted with 1 to 3 substituents selected from the following group A, or a C 6-14 aryl group.
Group A:
(1) a halogen atom,
(2) a cyano group,
(3) -OR ^a1 ,
(4) -SR ^a1 ,
(5) -CO ₂ R ^a1 ,
(6) -CONR ^a2 R ^a3 ,
(7) -COR ^a4 ,
_{^{(8) -SO 2 NR a2 R}} a3,
(9) -SO ₂ R ^a4 ,
(10) C6-14 aryloxy group,
(11) C6-14 aryl C1-6 alkyloxycarbonyl group,
(12) a C1-6 alkylcarbonyloxy group which may be substituted with a halogen atom,
(13) 1 to 3 substitutions selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C1-6 alkylsulfonyl group, a di (C1-6 alkyl) amino group, and a C1-6 alkylcarbonylamino group A C6-14 aryl group optionally substituted with a group, and
(14) A heterocyclic group which may be substituted with a C1-6 alkyloxy group.
Here, R ^a1 , R ^a2 , R ^a3 and R ^a4 are each independently a hydrogen atom or a C 1-6 alkyl group.
Group B:
(1) a halogen atom,
(2) a cyano group,
(3) C1-6 alkyl group,
(4) a halo C1-6 alkyl group,
(5) -OR ^b1 ,
(6) -SR ^b1 ,
₍₇₎ -CO ^{2 R b1,}
(8) -CONR ^b2 R ^b3 ,
(9) -COR ^b4 ,
(10) -SO ₂ NR ^b2 R ^b3 ,
(11) -SO ₂ R ^b4 ,
(12) C6-14 aryloxy group,
(13) C6-14 aryl C1-6 alkyloxycarbonyl group,
(14) a C6-14 aryl C1-6 alkyloxy group, and
(15) -NR ^b5 COR ^b6 .
Here, R ^b1 , R ^b2 , R ^b3 , R ^b4 , R ^b5 and R ^b6 are each independently a hydrogen atom or a C 1-6 alkyl group.
Group C:
(1) hydrogen atom,
(2) C3-8 cycloalkyl C1-6 alkyl group,
(3) a cyano group,
(4) a halogen atom,
(5) C1-7 alkyl group,
(6) C2-6 alkenyl group,
(7) C2-6 alkynyl group,
(8) C6-14 aryl group,
(9) Heterocyclic group (wherein the heterocyclic group is a saturated or unsaturated monocyclic 5-membered or 6-membered heterocycle containing at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom) Or a condensed ring of these heterocyclic rings, or a condensed ring of a carbocyclic ring selected from benzene, cyclopentane or cyclohexane and the heterocyclic ring).
(10) C1-6 alkyloxy group,
(11) C6-14 aryl C1-6 alkyl group,
(12) C6-14 aryl C1-6 alkyloxy group,
(13) -CO ₂ R ^c1 ,
(14) -CONR ^c2 R ^c3 ,
(15) -COR ^c4 ,
(16) -SO ₂ NR ^c2 R ^c3 ,
(17) C6-14 arylcarbonyl group,
(18) -NR ^c4 R ^c5 ,
(19) -NR ^c6 COR ^c7 ,
(20) -NR ^c8 SO ₂ R ^c9 ,
(21) -SR ^c10 ,
(22) -SOR ^c11 ,
(23) -SO ₂ R ^c12 ,
(24) -NR ^c13 CONR ^c14 R ^c15 ,
(25) -NR ^c16 CO ₂ R ^c17 , and
(26) -NR ^c18 COCOR ^c19 .
^{Here, R c1, R c2, R} c3, R c4, R c5, R c6, R c7, R c8, R c9, R c10, R c11, R c12, R c13, R c14, R c15, R c16 , R ^c17 , R ^c18 and R ^c19 are each independently
(1 ') hydrogen atom,
(2 ′) a C 1-7 alkyl group which may be substituted with 1 to 3 substituents selected from Group A above;
(3 ′) a C6-14 aryl group which may be substituted with 1 to 3 substituents selected from Group B above,
(4 ′) a heterocyclic group which may be substituted with 1 to 3 substituents selected from Group B, or
(5 ') a C3-8 cycloalkyl group,
R ^c2 and R ^c3 may be combined with an adjacent nitrogen atom to form a nitrogen-containing heterocycle, and the nitrogen-containing heterocycle is substituted with 1 to 3 substituents selected from Group B above. Also good.
The C1-7 alkyl group, C1-6 alkyl moiety, C2-6 alkenyl group, and C2-6 alkynyl group of Group C are substituted with 1 to 3 substituents selected from Group A or a heterocyclic group. You can,
The C6-14 aryl group, the C6-14 aryl moiety and the heterocyclic group of the group C may be substituted with 1 to 3 substituents selected from the group B. ] Of ring B

Is C = C (R ^y1 ) —N (R ^y2 ), N—C (R ^y1 ) = N, N—C (R ^y1 ) = C (R ^y2 ), or C = N—N (R ^y2). (Wherein each symbol is as defined in claim 1), the nitrogen-containing fused ring compound according to claim 1 or a pharmaceutically acceptable salt thereof. The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to claim 2, represented by the following general formula [I] -1.

(In the formula, each symbol is as defined in claim 1.) The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to claim 2, represented by the following general formula [I] -2.

(In the formula, each symbol is as defined in claim 1.) The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to claim 2, represented by the following general formula [I] -3.

(In the formula, each symbol is as defined in claim 1.) The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to claim 2, represented by the following general formula [I] -4.

(In the formula, each symbol is as defined in claim 1.) X ^{is, -C (R x1) (R} x2) -C (R x3) (R x4) - #, - C (R x1) (R x2) -C (R x3) (R x4) -C (R ^x5 ) ( ^Rx6 )-#, -C ( ^Rx7 ) = C ( ^Rx8 )-#, -N = C ( ^Rx9 )-#, or -C ( ^Rx10 ) = N- # (where And each symbol is as defined in claim 1.) The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6. X is -C ( ^Rx1 ) ( ^Rx2 ) -C ( ^Rx3 ) ( ^Rx4 )-# or -C ( ^Rx7 ) = C ( ^Rx8 )-# (where each symbol is a claim 8. The nitrogen-containing fused ring compound according to claim 7 or a pharmaceutically acceptable salt thereof. 9. The nitrogen-containing condensation according to claim 8, wherein X is -C ( ^Rx1 ) ( ^Rx2 ) -C ( ^Rx3 ) ( ^Rx4 )-# (wherein each symbol is as defined in claim 1). A ring compound or a pharmaceutically acceptable salt thereof. 9. The nitrogen-containing fused ring compound or the pharmaceutically acceptable product according to claim 8, wherein X is -C ( ^Rx7 ) = C ( ^Rx8 )-# (wherein each symbol is as defined in claim 1). Its salt. R ¹ is the formula

(Where, Z is, C1-6 alkylene, _{or, * - (CH 2) m} -Q- (CH 2) n - and is, the other symbols as in Claim 1 wherein.) The group represented by The nitrogen-containing fused ring compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.   The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to claim 11, wherein Z is C1-6 alkylene.   The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to claim 11, wherein ring D is a C3-10 carbocyclic group which may be substituted with 1 to 3 substituents selected from group B. R ^{x1 to} R ^x10 are each independently selected from the following group, and R ^x1 and R ^x2 , R ^x3 and R ^x4 , R ^x5 and R ^x6 are each independently combined with an adjacent carbon atom. The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which may form C3-8 cycloalkyl.
Hydrogen atom,
C3-8 cycloalkyl C1-6 alkyl group,
A cyano group,
C1-7 alkyl group,
C6-14 aryl group,
C6-14 aryl C1-6 alkyl group,
-CO ₂ R ^c1,
-CONR ^c2 R ^c3 , and
-COR ^c4
(Wherein the C1-7 alkyl group and the C1-6 alkyl moiety may be substituted with 1 to 3 substituents selected from group A, or a heterocyclic group; Street.) The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to claim 14, wherein R ^{x1 to} R ^x10 are a hydrogen atom. The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R ^y1 is selected from the following group.
Hydrogen atom,
C1-7 alkyl group,
C6-14 aryl group,
-CO ₂ R ^c1,
-CONR ^c2 R ^c3 ,
-COR ^c4 and
C6-14 arylcarbonyl group (wherein the C1-7 alkyl group may be substituted with 1 to 3 substituents selected from group A or a heterocyclic group, and the C6-14 aryl group is It may be substituted with 1 to 3 substituents selected from group B, and other symbols are as defined in claim 1.) The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to claim 16, wherein R ^y1 is a hydrogen atom. The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R ^y2 is selected from the following group.
Hydrogen atom,
A halogen atom,
C1-7 alkyl group C6-14 aryl group,
A heterocyclic group,
-CO ₂ R ^c1,
-CONR ^c2 R ^c3 ,
-COR ^c4 ,
-NR ^c4 R ^c5 ,
-NR ^c6 COR ^c7 ,
-NR ^c8 SO ₂ R ^c9 ,
-SR ^c10 ,
-SO ₂ R ^c12,
-NR ^c13 CONR ^c14 R ^c15 ,
-NR ^c16 CO ₂ R ^c17 and,
-NR ^c18 COCOR ^c19
(Wherein the C1-7 alkyl group may be substituted with 1 to 3 substituents selected from group A, or a heterocyclic group; the C6-14 aryl group and heterocyclic group may be substituted with group B; And may be substituted with 1 to 3 substituents selected from the above, and other symbols are as defined in claim 1.) 19. The nitrogen-containing fused ring compound according to claim 18, wherein R ^y2 is a heterocyclic group (wherein the heterocyclic group may be substituted with 1 to 3 substituents selected from group B). A pharmaceutically acceptable salt thereof. R ^y2 is a heterocyclic group bonded to Y ³ with a carbon atom, and in the heterocyclic group, at least one of the α-positions of the carbon atom is selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. 20. The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to claim 19, which is a selected hetero atom, and the heterocyclic group may be substituted with 1 to 3 substituents selected from group B. . The nitrogen-containing condensed ring compound according to claim 18, wherein R ^y2 is selected from -CO ₂ R ^c1 , -CONR ^c2 R ^c3 , and -COR ^c4 (wherein each symbol is as defined in claim 1). A pharmaceutically acceptable salt thereof. R ^y2 represents —NR ^c4 R ^c5 , —NR ^c6 COR ^c7 , —NR ^c8 SO ₂ R ^c9 , —NR ^c13 CONR ^c14 R ^c15 , —NR ^c16 CO ₂ R ^c17 , and —NR ^c18 COCOR ^c19 And each symbol is as defined in claim 1.) The nitrogen-containing fused ring compound according to claim 18 or a pharmaceutically acceptable salt thereof. R ^y2 is —NR ^c6 COR ^c7 , —NR ^c8 SO ₂ R ^c9 , —NR ^c13 CONR ^c14 R ^c15 , —NR ^c16 CO ₂ R ^c17 , and —NR ^c18 COCOR ^c19 (where each symbol is claimed) 23. The nitrogen-containing fused ring compound according to claim 22 or a pharmaceutically acceptable salt thereof selected from the group consisting of 1). The nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R ² is a hydrogen atom. 2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3,4-dichlorobenzyl) -10-hydroxy-2,3,4,5-tetrahydropyrido [1,2-a] [1,4] diazepine-1,9-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-3-methyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3,4-dichlorobenzyl) -9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-6-hydroxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carboxylic acid,
2- (3,4-dichlorobenzyl) -6- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-3-methyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chlorobenzyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- [3- (2,6-dichlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-2H-pyrazino [1,2-c] pyrimidine-1,8-dione hydrochloride,
2- (3,4-dichlorobenzyl) -9-hydroxy-4-methyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
4-benzyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-4-phenyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
4-butyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-4-isopropyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-3,3-dimethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-4-spiro-1′-cyclopentane-1,8-dione;
2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-4-spiro-1′-cyclohexane-1,8-dione;
2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-4-carboxylic acid methyl ester,
2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-4-carboxylic acid,
2- (3,4-dichlorobenzyl) -9-hydroxy-6-methoxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
N, N-dimethyl-2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6 -Carboxamide,
3-benzyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
3-butyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
N, N-dimethyl-2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-4 -Carboxamide,
2- (3,4-dichlorobenzyl) -9-hydroxy-4-hydroxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-4-methoxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3,4-dichlorobenzyl) -9-hydroxy-6-methylsulfanylmethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3,4-dichlorobenzyl) -9-hydroxy-6-methanesulfonylmethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-4- (2-methanesulfonylethyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3,4-dichlorobenzyl) -9-hydroxy-4- (2-methylsulfanylethyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carboxylic acid methyl ester,
6-acetyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isopropylsulfanylmethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isopropylsulfonylmethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isopropoxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isobutoxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3,4-dichlorobenzyl) -9-hydroxy-6- (1-hydroxyethyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-6-phenoxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (4-fluorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2-benzyl-9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (4-chlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isopropyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isobutyryl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carbaldehyde,
2- (3,4-dichlorobenzyl) -9-hydroxy-6-phenyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
9-hydroxy-2- (3-phenylpropyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chloro-2-fluorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
9-hydroxy-2-phenethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3,4-Dichlorobenzyl) -9-hydroxy-6- (1-hydroxy-2-methylpropyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Zeon,
2- (3,4-dichlorobenzyl) -9-hydroxy-6-isobutyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carboxamide;
N-methyl-2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6-carboxamide ,
2- (4-chloro-3-fluorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
6-benzoyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3,4-dichlorobenzyl) -9-hydroxy-6-propionyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-6-methyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
N, N-diethyl-2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-6 -Carboxamide,
N-isopropyl-N-methyl-2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -6-carboxamide,
N-ethyl-N-methyl-2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -6-carboxamide,
2- (3-chloro-4-fluorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (2-chlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,5-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
6-tert-butyl-2- (3,4-dichlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-6- (1-hydroxy-2,2-dimethylpropyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1, 8-dione,
3-benzyl-9-hydroxy-2-methyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- [3- (4-chlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- [3- (2-chlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-4-methyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chloro-4-methoxybenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
9-hydroxy-2-methyl-3-phenethyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
[2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazin-6-yl] acetonitrile,
2- [3- (3-chlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione,
9-hydroxy-2-methyl-3- (3-phenylpropyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- [3- (3,4-dichlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- [3- (3,5-dichlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione,
[2- (3,4-Dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazin-6-yl] acetic acid benzyl ester,
2- [2- (3,4-Dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazin-6-yl] -3-phenylpropionic acid benzyl ester,
2- (3,4-dichlorobenzyl) -9-hydroxy-6- (2-hydroxyethyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-4-propyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -4-ethyl-9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-4-hydroxymethyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-4-isobutyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3,4-dichlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-4-carboxylic acid methyl ester,
2- (3-chloro-4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- [3- (2,3-dichlorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chloro-4-fluorobenzyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-4-carboxylic acid methyl ester,
7-bromo-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- [3- (2-chloro-6-fluorophenyl) propyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7-phenyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N, N-dimethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-4-carboxamide,
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-4-carboxylic acid,
3- (3-chlorobenzyl) -5-hydroxy-3H-pyrazino [1,2-a] quinoline-4,6-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-2H-pyrazino [1,2-c] pyrimidine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-4-carbaldehyde,
2- (3-chlorobenzyl) -9-hydroxy-4-hydroxymethyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chlorobenzyl) -9-hydroxy-4- (1-hydroxyethyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chlorobenzyl) -9-hydroxy-7-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
4-acetyl-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chlorobenzyl) -8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione,
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-4-carbonitrile,
2- (3-chlorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrazino [1,2-c] pyrimidine-1,8-dione,
Methanesulfonic acid 7-bromo-2- (3-chlorobenzyl) -1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-9-yl ester,
7-bromo-2- (3-chlorobenzyl) -3,9-dihydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
3- (3-chlorobenzyl) -5-hydroxy-2,3-dihydro-1H-pyrazino [1,2-a] quinoline-4,6-dione,
2- (3-chlorobenzyl) -7- (3-chlorophenyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -7- (4-chlorophenyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -7- (2-chlorophenyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (pyridin-3-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (pyridin-4-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (1-hydroxy-2,2-dimethylpropyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -4-cyclohexylmethyl-9-hydroxy-7-phenyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -7- (furan-2-yl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3,4-dichlorobenzyl) -8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione,
2- [3- (2-chloro-6-fluorophenyl) propyl] -8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione,
6- (3-chlorobenzyl) -4-hydroxy-2-methyl-2,6,7,8-tetrahydropyrido [4,3-c] pyridazine-3,5-dione,
7- (benzofuran-2-yl) -2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -7- (2,2-dimethylpropyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (2-trifluoromethylphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (3-methoxyphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
7-bromo-2- (3-chlorobenzyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -7- (2-fluorophenyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-4-isopropyl-7-phenyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (2-methoxyphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (4-methoxyphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -7-ethyl-9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -7- (2,6-dimethylphenyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (3-hydroxyphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione,
7-benzoyl-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -7- (2-ethylphenyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -7- (3-chlorophenyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
7-benzyl-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (2-hydroxyphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chlorobenzyl) -9-hydroxy-7- (4-hydroxyphenyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione,
8-hydroxy-6-methyl-2- (3-trifluoromethylbenzyl) -2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione,
8-hydroxy-2- (3-methoxybenzyl) -6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione,
6- (3-chlorobenzyl) -4-hydroxy-2-methyl-2,6-dihydropyrido [4,3-c] pyridazine-3,5-dione,
3- (3-chlorobenzyl) -5-hydroxy-3H-pyrido [2,1-f] [1,2,4] triazine-4,6-dione,
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid methyl ester hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (1-methyl-1H-imidazol-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7-isobutyryl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid isopropyl ester,
2- (4-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid hydrochloride,
N, N-dimethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide,
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid isopropylamide,
N-methyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N, N-diethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
2- (4-bromobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-bromobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid 2,2-dimethylpropyl ester,
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid cyclohexyl ester,
7-amino-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-4-methyl-2H-pyrido [1,2-d] [1,2,4] triazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-Chlorobenzyl) -9-hydroxy-7- (4H-1,2,4-triazol-3-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride ,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide,
2- (4-chloro-2-methoxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide,
2- (3-chloro-2-methoxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- [2- (2-chlorophenoxy) ethyl] -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (pyrimidin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N-propyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N-butyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N-isobutyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
{[2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carbonyl] amino} acetic acid methyl ester,
N-ethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N- (2-methoxyethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
Trifluoroacetic acid 2-{[2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carbonyl] amino} Ethyl ester,
N- (2-hydroxyethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
2- (3-chloro-2-hydroxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N-benzyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N- (2,2,2-trifluoroethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide,
N-butyl-N-methyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N- (2-methoxyethyl) -N-methyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine- 7-carboxamide,
2- (3-chlorobenzyl) -9-hydroxy-7- (pyrrolidine-1-carbonyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chlorobenzyl) -9-hydroxy-7- (morpholine-4-carbonyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (4-chloro-3-methoxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
[2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetic acid methyl ester,
2- (3-chlorobenzyl) -9-hydroxy-7- (1H-tetrazol-5-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -N-methylacetamide,
2- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -N, N-dimethyl Acetamide,
[2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetic acid,
N- (2-hydroxypropyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide hydrochloride salt,
{[2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carbonyl] amino} acetic acid,
N-dimethylcarbamoylmethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N-methylcarbamoylmethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N-phenyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (oxazol-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (3-hydroxypyrrolidine-1-carbonyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N- (2-oxopropyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
2- (9-hydroxy-1,8-dioxo-1,8-dihydro-pyrido [1,2-a] pyrazin-2-yl) -N-phenylacetamide hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (3-oxopyrrolidine-1-carbonyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (5-chloro-2-methoxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] methanesulfonamide,
7-acetyl-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7-propionyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
9-hydroxy-2- (3-phenylallyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione,
N-methyl-2- (3-chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N, N-dimethyl-2- (3-chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide ,
N- (2-methanesulfonylethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide ,
N- [2- (2-oxopyrrolidin-1-yl) ethyl] -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2 -A] pyrazine-7-carboxamide,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -N-methylmethanesulfone Amide,
2- (3-chloro-5-methoxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N- (pyridin-4-ylmethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide ,
N- (4-fluorobenzyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
2- (3-chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3-chlorobenzyl) -9-hydroxy-7-hydroxymethyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chloro-4-fluorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (thiazol-5-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid methylamide;
N, N-dimethyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide ,
2- (3-Chloro-4-fluorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride,
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-4-hydroxymethyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid Methylamide hydrochloride,
2- (3-chlorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (4-chloro-2-hydroxybenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione ,
2- (9-hydroxy-1,8-dioxo-1,8-dihydro-pyrido [1,2-a] pyrazin-2-yl) -N-methyl-N-phenylacetamide hydrochloride,
N-methyl-2- (3-chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7 -Carboxamide,
N, N-dimethyl-2- (3-chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide,
Acetic acid 3- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2,2- Dimethyl-3-oxopropyl ester hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (3-hydroxy-2,2-dimethylpropionyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (pyrazin-2-yl) -2H-pyrido [1,2-a] pyrazin-1,8-dione hydrochloride,
2- (3-Chlorobenzyl) -9-hydroxy-7- (2-methyl-2H-1,2,4-triazol-3-yl) -2H-pyrido [1,2-a] pyrazine-1,8 -Dione hydrochloride,
N- (2-fluoroethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N-benzyl-N-methyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
2- (3-chlorobenzyl) -9-hydroxy-7-phenylsulfanyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
7-benzenesulfinyl-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione,
7-benzenesulfonyl-2- (3-chlorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] isobutyramide,
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide,
2- (3-Chloro-4-fluorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-4-hydroxymethyl-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] propionamide,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-phenylacetamide,
7-acetyl-2- (3-chloro-4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7-methylsulfanyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chlorobenzyl) -9-hydroxy-7-methanesulfonyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chlorobenzyl) -9-hydroxy-7-methanesulfinyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chlorobenzyl) -9-hydroxy-7- (5-methylthiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (4-fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N-methyl-2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
2- [3- (2-Chloro-6-fluorophenyl) propyl] -7- (2,2-dimethylpropionyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (4-methylthiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] butyramide,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] benzamide,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -3-phenylpropionamide ,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -N-methylacetamide,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-methoxyacetamide,
2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxylic acid methyl ester,
3- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -1,1-dimethyl urea,
[2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] carbamic acid methyl ester,
2- [3- (2-Chloro-6-fluorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine- 1,8-dione,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-oxopropionamide ,
N-benzyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
2- (3-chlorobenzyl) -9-hydroxy-7- (1H-pyrazol-3-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chlorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
N- (Naphthalen-1-ylmethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide,
N-benzhydryl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
2- (3-chlorobenzyl) -9-hydroxy-7- (pyrimidin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (2-methyl-2-phenylpropionyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
N- (4-tert-butylbenzyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] Pyrazine-7-carboxamide,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] cyclopentanecarboxamide;
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2- (4- Fluorophenyl) acetamide,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2,2-dimethyl Propionamide,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-phenylisobutyramide ,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -4-fluorobenzamide,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] pyridine-2-carboxamide Tri Fluoroacetate,
2- (3-chlorobenzyl) -9-hydroxy-7-isopropylamino-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -7-diethylamino-9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7-isobutylamino-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-isopropyl-3 -Methylbutyramide,
2- (3-chlorobenzyl) -7-ethylamino-9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] nicotinamide trifluoroacetate ,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] isonicotinamide trifluoroacetic acid salt,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] furan-2-carboxamide;
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] thiophene-2-carboxamide;
2- (3-chlorobenzyl) -9-hydroxy-7- (pyridazin-3-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3,4-difluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione ,
2- (4-chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (4-Chloro-3-fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione ,
2- (4-Chloro-2-methoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione ,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -1-methyl-1H -Pyrrole-2-carboxamide,
2- [3- (4-Chlorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
2- [3- (2-Chlorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
2- [3- (3-Chlorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
2- (3-Chlorobenzyl) -9-hydroxy-7- (3-methyl-1,2,4-thiadiazol-5-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine -1,8-dione hydrochloride,
5-Fluoro-2- [9-hydroxy-1,8-dioxo-7- (thiazol-2-yl) -1,3,4,8-tetrahydro-pyrido [1,2-a] pyrazin-2-ylmethyl ] -N-methylbenzamide,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -N-isobutylacetamide,
N- [2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide,
N- [2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] benzamide,
N- [2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] methanesulfonamide,
2- (4-fluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione trifluoroacetate salt,
2- (2-fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (3-fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (4-fluorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- (2-chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
9-hydroxy-2- (naphthalen-2-ylmethyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
2- [3- (3-Chloro-2-fluorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine- 1,8-dione,
2- [3- (4-Chloro-3-fluorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine- 1,8-dione,
2- [3- (4-Fluorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Zeon,
2- [3- (3-Fluorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Zeon,
9-hydroxy-2- (3-phenylpropyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
N- [2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-methoxyacetamide,
N- [2- (4-Fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2-propanesulfonamide ,
N- [2- (4-Fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] nicotinamide trifluoroacetate ,
N- [2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] isobutyramide,
N- (2-methoxyethyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N-ethyl-2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N- {2- [3- (2-Chloro-6-fluorophenyl) propyl] -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazine-7 -Yl} acetamide,
N- [2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide hydrochloric acid salt,
5-Fluoro-2- [9-hydroxy-1,8-dioxo-7- (thiazol-2-yl) -1,3,4,8-tetrahydro-pyrido [1,2-a] pyrazin-2-ylmethyl ] Methyl benzoate,
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-7- (pyridin-3-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
2- [3- (2-Chloro-6-fluorophenyl) propyl] -9-hydroxy-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine- 1,8-dione hydrochloride,
2- (benzofuran-2-ylmethyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione;
N- (1,2-diphenylethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] Pyrazine-7-carboxamide,
N- [2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] acetamide,
2- [3- (2-Fluorophenyl) propyl] -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Zeon,
N- (1,3-diphenylpropyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] Pyrazine-7-carboxamide,
5-Fluoro-2- {3- [9-hydroxy-1,8-dioxo-7- (thiazol-2-yl) -1,3,4,8-tetrahydro-pyrido [1,2-a] pyrazine- 2-yl] propyl} -N-methylbenzamide,
2- [3- (2-Chloro-6-fluorophenyl) propyl] -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine -1,8-dione,
2- (3-chlorobenzyl) -9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
9-hydroxy-2- (4-phenylbutyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
9-hydroxy-2-pentyl-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-7- (pyridin-4-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
2- (4-fluorobenzyl) -9-hydroxy-7- (pyridin-4-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chloro-2-fluorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -2H-pyrido [1,2-a] pyrazin-1,8-dione trifluoroacetate salt,
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-7- (2-methyl-2H-1,2,4-triazol-3-yl) -3,4-dihydro-2H-pyrido [1 , 2-a] pyrazine-1,8-dione,
7-acetyl-2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (4-fluorobenzyl) -9-hydroxy-7-isobutyryl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazin-7-yl] isonicotine Amide hydrochloride,
2- (4-fluorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-7- (pyrazin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione ,
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] isobutyramide,
2- (4-Chloro-2-hydroxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
9-hydroxy-2- (3-phenylbutyl) -7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N- [2- (3-Chloro-2-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Ill] nicotinamide hydrochloride,
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] methanesulfonamide,
2- (3-Chloro-4-propoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
2- (3-Chloro-4-isopropoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride,
2- (4-Benzyloxy-3-chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride,
2- (4-Chloro-2-propoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
2- (4-Chloro-2-isopropoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride,
2- (2-Benzyloxy-4-chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride,
2- (4-Fluorobenzyl) -9-hydroxy-7- (2-methyl-2H-1,2,4-triazol-3-yl) -2H-pyrido [1,2-a] pyrazine-1,8 -Dione hydrochloride,
N-methyl-2- (3-chloro-2-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7 -Carboxamide,
2- (3-chlorobenzyl) -7- (2,2-dimethylbutyryl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (4-fluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chloro-2-fluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-fluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N- {5-Fluoro-2- [9-hydroxy-1,8-dioxo-7- (thiazol-2-yl) -1,3,4,8-tetrahydro-pyrido [1,2-a] pyrazine- 2-ylmethyl] phenyl} acetamide hydrochloride,
2- (3-Chloro-2-fluorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride,
5-Fluoro-2- [9-hydroxy-1,8-dioxo-7- (thiazol-2-yl) -1,3,4,8-tetrahydro-pyrido [1,2-a] pyrazin-2-ylmethyl ] Benzoic acid hydrochloride,
2- (3,4-difluorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N-benzyl-N-methyl-2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7 -Carboxamide hydrochloride,
N- (pyridin-3-ylmethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide hydrochloride,
N- (pyridin-2-ylmethyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide hydrochloride,
2- (3,4-Dichlorobenzyl) -9-hydroxy-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione trifluoro Acetate,
N- (2-oxopropyl) -2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine- 7-carboxamide hydrochloride,
2- (3-fluorobenzyl) -9-hydroxy-7- (pyridin-4-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
7- (2,2-dimethylpropionyl) -2- (3-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N- (2-fluorobenzyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine- 7-carboxamide,
N- (4-fluorobenzyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine- 7-carboxamide,
N-methyl-2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N-benzyl-2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
N-methyl-2- (4-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide;
7- (2,2-dimethylbutyryl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3,4-Dichlorobenzyl) -9-hydroxy-7- (pyrazin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride ,
2- (3,4-dichlorobenzyl) -9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (4-fluorobenzyl) -9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (4-fluorobenzyl) -9-hydroxy-7- (3-methylbutyryl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N-methyl-2- (3,4-difluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7-carboxamide ,
2- (4-Fluorobenzyl) -9-hydroxy-7- (3-methoxy-2,2-dimethylpropionyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Zeon,
9-benzyloxy-7-bromo-2- (3-chlorobenzyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3-chlorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -2H-pyrido [1,2-a] pyrazin-1,8-dione hydrochloride,
2- (4-fluorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (4-chlorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
2- (3-chloro-4-fluorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-Chloro-5-propoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione Hydrochloride,
2- (3-Chloro-5-isopropoxybenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride,
2- (3-Benzyloxy-5-chlorobenzyl) -9-hydroxy-7- (thiazol-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride,
2- (4-chlorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -2H-pyrido [1,2-a] pyrazin-1,8-dione hydrochloride,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2- (pyridine- 3-yl) acetamide hydrochloride,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2- (pyridine- 4-yl) acetamide hydrochloride,
N- [2- (3-Chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] -2- (pyridine- 2-yl) acetamide hydrochloride,
2- (3-fluorobenzyl) -9-hydroxy-7- (pyrimidin-4-yl) -2H-pyrido [1,2-a] pyrazin-1,8-dione hydrochloride,
2- (3-fluorobenzyl) -9-hydroxy-7- (pyrazin-2-yl) -2H-pyrido [1,2-a] pyrazin-1,8-dione hydrochloride,
2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-7- (2-methyl-2H-1,2,4-triazol-3-yl) -2H-pyrido [1,2-a] pyrazine -1,8-dione hydrochloride,
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] -3,3-dimethylbutyramide,
2- (3-fluorobenzyl) -9-hydroxy-4-methyl-7- (pyridin-2-yl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-4-methyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
7- (2,2-Dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-6-methoxymethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8 -Dione hydrochloride,
N- (pyridin-2-ylmethyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide hydrochloride,
N- (furan-2-ylmethyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide hydrochloride,
7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1, 8-dione hydrochloride,
7-bromo-2- (4-fluorobenzyl) -9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (4-Fluorobenzyl) -9-hydroxy-4,4-dimethyl-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8 -Dione hydrochloride,
N- (4-dimethylaminobenzyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-7- (pyrazin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (4-fluorobenzyl) -9-hydroxy-7- (pyrazin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] benzenesulfonamide,
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] benzylsulfonamide,
N- [2- (3-Chloro-4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine-7- Yl] -2-thiophenesulfonamide,
N- (4-Methanesulfonylbenzyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide hydrochloride,
2- (4-Fluorobenzyl) -9-hydroxy-6- (2-hydroxy-3,3-dimethylbutyl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride,
N- [2- (3-chlorobenzyl) -9-hydroxy-4-methyl-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide,
2- (4-Fluorobenzyl) -9-hydroxy-6-methoxymethyl-7- (pyridin-2-yl) -3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8- Dione hydrochloride,
2- (4-fluorobenzyl) -9-hydroxy-7- (3-methoxy-2,2-dimethylpropionyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
N- (4-methoxypyrimidin-2-ylmethyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2- a] pyrazine-7-carboxamide hydrochloride,
6- (3,3-Dimethyl-2-oxobutyl) -7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1, 2-a] pyrazine-1,8-dione hydrochloride,
N- (4-acetylaminobenzyl) -2- (4-fluorobenzyl) -9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido [1,2-a] pyrazine -7-carboxamide,
2- (3,4-dichlorobenzyl) -9-hydroxy-4- (2-hydroxyethyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3,4-dichlorobenzyl) -9-hydroxy-4- (1-hydroxypropyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-4- (3-hydroxypropyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-4- (1-hydroxy-2-methylpropyl) -2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (3,4-dichlorobenzyl) -9-hydroxy-4-phenethyl-2H-pyrido [1,2-a] pyrazine-1,8-dione,
2- (4-fluorobenzyl) -9-hydroxy-2H-pyrazino [1,2-c] pyrimidine-1,8-dione hydrochloride,
2- (3,4-dichlorobenzyl) -9-hydroxy-4-isopropyl-2H-pyrido [1,2-a] pyrazine-1,8-dione hydrochloride,
2- (3-chlorobenzyl) -9-hydroxy-4-methyl-2H-pyrido [1,2-d] [1,2,4] triazine-1,8-dione,
2- (3-chlorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione,
7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione,
7- (2,2-dimethylpropionyl) -2- (4-fluorobenzyl) -9-hydroxy-2H-pyrido [1,2-a] pyrazine-1,8-dione sodium salt,
N- [2- (3-chlorobenzyl) -9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido [1,2-a] pyrazin-7-yl] acetamide sodium salt, and
2- (3-Chlorobenzyl) -7- (2,2-dimethylpropionyl) -9-hydroxy-3,4-dihydro-2H-pyrido [1,2-a] pyrazine-1,8-dione sodium salt
The nitrogen-containing fused ring compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of:   A pharmaceutical composition comprising the nitrogen-containing fused ring compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.   An anti-HIV agent comprising the nitrogen-containing fused ring compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof as an active ingredient.   An integrase inhibitor comprising as an active ingredient the nitrogen-containing fused ring compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.   An antiviral agent comprising the nitrogen-containing fused ring compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof as an active ingredient.   An anti-HIV composition comprising the nitrogen-containing fused ring compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and one or more other anti-HIV active substances as active ingredients.   An anti-HIV agent comprising the nitrogen-containing fused ring compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof as an active ingredient for multi-drug combination therapy with another anti-HIV agent.   Use of the nitrogen-containing fused ring compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof for producing an anti-HIV agent.   Use of the nitrogen-containing fused ring compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof for producing an integrase inhibitor.   Use of the nitrogen-containing fused ring compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof for producing an antiviral agent.   A method for preventing or treating HIV infection, comprising administering an effective amount of the nitrogen-containing fused ring compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof to a mammal.   36. The method of preventing or treating HIV infection according to claim 35, further comprising administering to the mammal an effective amount of at least one other anti-HIV active substance.   A method for inhibiting integrase, comprising administering an effective amount of the nitrogen-containing fused ring compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof to a mammal.   A method for preventing or treating a viral infection, comprising administering an effective amount of the nitrogen-containing fused ring compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof to a mammal.