JP2005002092A - 4-oxoquinoline compound and its use as hiv integrase inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an anti-HIV agent that has the HIV integrase inhibitory activity. <P>SOLUTION: This invention relates to an anti-HIV agent that includes 4-oxoquinoline compound represented by general formula [I] or its pharmaceutically acceptable salts and relates to the anti-HIV agent including these compounds. The compound according to this invention has the action to inhibit the HIV integrase activity and is used as an anti-HIV agent for treating or preventing AIDS. Further, this anti-HIV agent is combined with other anti-HIV agent, for example, a protease inhibitor or a reverse transcriptase inhibitor to give more effective anti-HIV agents. The fact that this inhibitor has specifically high inhibitory action to integrase means that this substance can become a medicine that is safe to human bodies with reduced side effects. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to novel 4-oxoquinoline compounds useful as anti-HIV agents or pharmaceutically acceptable salts thereof. The present invention also relates to a novel use of certain 4-oxoquinoline compounds or pharmaceutically acceptable salts thereof as anti-HIV agents. More particularly, the present invention relates to an anti-HIV agent comprising a 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof that exhibits an anti-HIV action, particularly by an integrase inhibitory activity.

HIV (Human Immunodeficiency Virus (type 1): human immunodeficiency virus) belonging to 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., and translated reverse transcriptase and integrase are present in the shell, and protease is present inside and outside the shell.
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 integrated 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 and nelfinavir are already commercially available as protease inhibitors.
In addition, multi-drug combination therapy using these drugs in combination 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 combination therapy has become the mainstream of AIDS treatment (see, for example, Non-Patent Document 1).
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 02/0704865 describes the following compounds [A], [B] and the like as anti-HIV agents having integrase inhibitory activity (see Patent Document 1).

  WO 02/36734 describes the following compound [C] and the like as an anti-HIV agent having integrase inhibitory activity (see Patent Document 2).

  WO 02/55079 describes the following compound [D] and the like as an anti-HIV agent having integrase inhibitory activity (see Patent Document 3).

  However, these publications do not include the 4-oxoquinoline compound disclosed in the present specification, and there is no description suggesting it.

Next, compounds that are relatively similar to the compounds of the present invention will be described.
US Pat. No. 3,472,859 describes the following compound [E] as an antibacterial agent or antibacterial agent (see Patent Document 4).

  JP-A-48-26772 describes the following compound [F] and the like as compounds having antibacterial activity (see, for example, Patent Document 5, Non-Patent Document 2, and Non-Patent Document 3). .

  Moreover, the following compound [G] etc. are pharmacologically evaluated as a dehydrogenase inhibitor (refer nonpatent literature 4).

  In addition, JP-T-2002-534416 (patent families: WO00 / 40561, US Pat. No. 6,248,739, EP1140850) includes the following compound [H] as a synthetic intermediate of a compound having antiviral activity. (See Patent Document 6).

  JP-T-2002-534417 (patent family: WO00 / 40563, US Pat. No. 6,248,736, EP1140851) also describes the following compound [J] as a synthetic intermediate of a compound having antiviral activity. (See Patent Document 7).

  In addition, WO01 / 98275 (patent family: US2001 / 103220) also describes the following compound [K] and the like as a synthetic intermediate of a compound having antiviral activity (see Patent Document 8). .

  JP-A-4-360872 (patent family: US 5,985,894, EP 498721 B1) describes the following compound [L] and the like as a compound having an antagonistic action against an anti-angiotensin II receptor. (See Patent Document 9).

WO02 / 0704865 (page 118, Example I-62, page 203, Example I-152) WO02 / 36734 (page 106, example 3) WO02 / 055079 (79 pages, Example 1) US Pat. No. 3,472,859 (column 11, line 10) JP 48-26772 A (6 pages, Example 9) Japanese translation of PCT publication No. 2002-534416 (page 141, chemical formula 60) Japanese translation of PCT publication No. 2002-534417 (page 34, chemical formula 18) WO01 / 98275 (39 pages, 29 lines) JP-A-4-360872 (page 64, Table 1) Guidelines for the Use of Antiviral Agents in HIV-Infected Adults and Adolescents. August 13, 2001 Kyushu Kyoritsu University Research Report, Faculty of Engineering, No. 14, March 1990, p21-32 Memoirs Kyushu Inst. Tech. (Eng.) No. 14, 1984, pp. 13-16 Journal of Medicinal Chemistry, vol. 15, no. 3, p. 235-237, 1972. table 1

From the findings obtained so far from pharmacological studies and clinical results, anti-HIV agents are effective in preventing and treating AIDS development, 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 (28).
(1) An anti-HIV agent comprising a 4-oxoquinoline compound represented by the following general formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient.

[Where:
Ring Cy is
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from the following group A, or
A heterocyclic group which may be substituted by 1 to 5 substituents selected from the following group A;
(Here, the heterocyclic group is a saturated or unsaturated ring including at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.)
Group A
Cyano group, phenyl group, nitro group, halogen atom, C _1-4 alkyl group,
Halo C _1-4 alkyl group, halo C _1-4 alkyloxy group,
-OR ^a1 , -SR ^a1 , -NR ^a1 R ^a2 ,
-CONR ^a1 R ^a2 , -SO ₂ NR ^a1 R ^a2 ,
-COR ^a3 , -NR ^a1 COR ^a3 , -SO ₂ R ^a3 , -NR ^a1 SO ₂ R ^a3 ,
-COOR ^a1 and -NR ^a2 COOR ^a3
A group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, or a benzyl group, and R ^a3 represents a C _1-4 alkyl group.)
R ¹ is
A substituent selected from the following group B, or
A C _1-10 alkyl group which may be substituted with a halogen atom and 1 to 3 substituents selected from the following group B;
Group B
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group optionally substituted with 1 to 5 substituents selected from Group A (as defined above);
-OR ^a4 , -SR ^a4 , -NR ^a4 R ^a5 ,
-CONR ^a4 R ^a5 , -SO ₂ NR ^a4 R ^a5 ,
-COR ^a6 , -NR ^a4 COR ^a6 , -SO ₂ R ^a6 , -NR ^a4 SO ₂ R ^a6 ,
-COOR ^a4 and -NR ^a5 COOR ^a6
{Wherein, R ^a4 and R ^a5 are the same or different and each is hydrogen atom, C _1-4 alkyl groups, 1 to 5 substituents which may be substituted with a substituent C _3-10 selected from the above-mentioned group A A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from Group A, wherein R ^a6 is a C _1-4 alkyl group, C _3-10 carbocyclic group which may be substituted with 1 to 5 substituents selected from group A, or heterocyclic group which may be substituted with 1 to 5 substituents selected from group A (As defined above). }
R ² is a hydrogen atom or a C _1-4 alkyl group,
R ³¹ represents a hydrogen atom, a cyano group, a hydroxy group, an amino group, a nitro group,
Halogen atom, C _1-4 alkyl group, C _1-4 alkoxy group, C _1-4 alkylsulfanyl group,
A halo C _1-4 alkyl group or a halo C _1-4 alkyloxy group,
X is C—R ³² or a nitrogen atom;
Y is C—R ³³ or a nitrogen atom;
Here, R ³² and R ³³ are the same or different and each represents a hydrogen atom, a cyano group, a nitro group, a halogen atom,
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group optionally substituted with 1 to 5 substituents selected from Group A (as defined above);
A C _1-10 alkyl group which may be substituted with a halogen atom and 1 to 3 substituents selected from the group B;
-OR ^a7 , -SR ^a7 , -NR ^a7 R ^a8 ,
-NR ^a7 COR ^a9 , -COOR ^a10 , or
-N = CH-NR ^a10 R ^a11
(Wherein, R ^a7 and R ^a8 are the same or different and each is hydrogen atom, group B, or may be substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B C _{1- 10 is} an alkyl group, R ^a9 is a C _1-4 alkyl group, and R ^a10 and R ^a11 are the same or different and each is a hydrogen atom or a C _1-4 alkyl group. ]
(2) X is C-R ^32, Y is an anti-HIV agent of the above (1), wherein the C-R ^33.
(3) Ring Cy is

[Wherein R ⁴ and R ⁶ are the same or different and each is a substituent selected from the following group A;
Here, group A is
Cyano group, phenyl group, nitro group, halogen atom, C _1-4 alkyl group,
Halo C _1-4 alkyl group, halo C _1-4 alkyloxy group,
-OR ^a1 , -SR ^a1 , -NR ^a1 R ^a2 ,
-CONR ^a1 R ^a2 , -SO ₂ NR ^a1 R ^a2 ,
-COR ^a3 , -NR ^a1 COR ^a3 , -SO ₂ R ^a3 , -NR ^a1 SO ₂ R ^a3 ,
-COOR ^a1 and -NR ^a2 COOR ^a3
A group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, or a benzyl group, and R ^a3 represents a C _1-4 alkyl group.)
R ⁵ is a hydrogen atom and a substituent selected from group A, wherein R ⁴ and R ⁵ may form a condensed ring together with the benzene ring they substitute, and m is 0 Or it is an integer of 1 to 3, and when m is 2 or 3, the R ^{6 s} may be the same or different from each other. ] The anti-HIV agent according to (1) above.
(4) The anti-HIV agent according to the above (1), wherein R ² is a hydrogen atom.
(5) A 4-oxoquinoline compound represented by the following general formula [II] or a pharmaceutically acceptable salt thereof.

[Where:
  R^FourAnd R⁶Are the same or different and each is a substituent selected from the following group A;
  Group A is here
Cyano group, phenyl group, nitro group, halogen atom, C_1-4An alkyl group,
Halo C_1-4Alkyl group, halo C_1-4An alkyloxy group,
-OR^a1, -SR^a1,
-NR^a1R^a2, -CONR^a1R^a2, -SO₂NR^a1R^a2,
-COR^a3, -NR^a1COR^a3, -SO₂R^a3, -NR^a1SO₂R^a3,
-COOR^a1And -NR^a2COOR^a3
A group consisting of
  (Where R^a1And R^a2Are the same or different and each represents a hydrogen atom, C_1-4R represents an alkyl group or a benzyl group, R^a3C_1-4An alkyl group is shown. )
  R^FiveIs a hydrogen atom and a substituent selected from Group A above, where R^FourAnd R^FiveMay form a condensed ring together with the benzene ring they substitute,
  m is 0 or an integer from 1 to 3, and when m is 2 or 3,⁶Each may be the same or different,
  R¹Is
A substituent selected from the following group B, or
C which may be substituted by a halogen atom and 1 to 3 substituents selected from group B below_1-10An alkyl group,
  Group B
C which may be substituted with 1 to 5 substituents selected from Group A above_3-10Carbocyclic groups,
A heterocyclic group optionally substituted by 1 to 5 substituents selected from Group A above;
  (Here, the heterocyclic group is a saturated or unsaturated ring including at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.)
-OR^a4, -SR^a4,
-NR^a4R^a5, -CONR^a4R^a5, -SO₂NR^a4R^a5,
-COR^a6, -NR^a4COR^a6, -SO₂R^a6, -NR^a4SO₂R^a6,
-COOR^a4And -NR^a5COOR^a6A group consisting of
  {Where R^a4And R^a5Are the same or different and each represents a hydrogen atom, C_1-4An alkyl group, which may be substituted with 1 to 5 substituents selected from group A above;_3-10A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from group A above;^a6C_1-4An alkyl group, which may be substituted with 1 to 5 substituents selected from group A above;_3-10A carbocyclic group or a heterocyclic group (as defined above) which may be substituted with 1 to 5 substituents selected from Group A above. }
  R³¹Is a hydrogen atom, a cyano group, a hydroxy group, an amino group, a nitro group,
Halogen atom, C_1-4Alkyl group, C_1-4Alkoxy group, C_1-4An alkylsulfanyl group,
Halo C_1-4Alkyl group or halo C_1-4An alkyloxy group,
  R³²And R³³Are the same or different and each represents a hydrogen atom, a cyano group, a nitro group, a halogen atom,
C which may be substituted with 1 to 5 substituents selected from Group A above_3-10Carbocyclic groups,
A heterocyclic group optionally substituted with 1 to 5 substituents selected from Group A (as defined above);
C which may be substituted with a halogen atom and 1 to 3 substituents selected from the above group B_1-10An alkyl group,
-OR^a7, -SR^a7, -NR^a7R^a8,
-NR^a7COR^a9, -COOR^a10Or
-N = CH-NR^a10R^a11
(Where R^a7And R^a8Are the same or different and each may be substituted with a hydrogen atom, a group B, or a halogen atom and 1 to 3 substituents selected from the group B._1-10An alkyl group, R^a9Is C_1-4An alkyl group, R^a10And R^a11Are the same or different and each represents a hydrogen atom or C_1-4It is an alkyl group. ). ]
  (6) R³¹Is a hydrogen atom, a cyano group, a hydroxy group, or C_1-4The 4-oxoquinoline compound according to the above (5) which is an alkoxy group or a pharmaceutically acceptable salt thereof.
  (7) R³¹Or a pharmaceutically acceptable salt thereof according to (6), wherein is a hydrogen atom.
  (8) R³²And R³³Are the same or different,
Hydrogen atom, cyano group, halogen atom,
A heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A;
  (Here, the heterocyclic group is a saturated or unsaturated ring including at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.)
  Group A is here
Cyano group, phenyl group, nitro group, halogen atom, C_1-4An alkyl group,
Halo C_1-4Alkyl group, halo C_1-4An alkyloxy group,
-OR^a1, -SR^a1,
-NR^a1R^a2, -CONR^a1R^a2, -SO₂NR^a1R^a2,
-COR^a3, -NR^a1COR^a3, -SO₂R^a3, -NR^a1SO₂R^a3,
-COOR^a1And -NR^a2COOR^a3
A group consisting of
  (Where R^a1And R^a2Are the same or different and each represents a hydrogen atom, C_1-4R represents an alkyl group or a benzyl group, R^a3C_1-4An alkyl group is shown. )
C which may be substituted by a halogen atom and 1 to 3 substituents selected from group B below_1-10An alkyl group,
  Group B is here
C which may be substituted with 1 to 5 substituents selected from Group A above_3-10Carbocyclic groups,
A heterocyclic group optionally substituted with 1 to 5 substituents selected from Group A (as defined above);
-OR^a4, -SR^a4,
-NR^a4R^a5, -CONR^a4R^a5, -SO₂NR^a4R^a5,
-COR^a6, -NR^a4COR^a6, -SO₂R^a6, -NR^a4SO₂R^a6,
-COOR^a4And -NR^a5COOR^a6A group consisting of
  {Where R^a4And R^a5Are the same or different and each represents a hydrogen atom, C_1-4An alkyl group, which may be substituted with 1 to 5 substituents selected from group A above;_3-10A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from group A above;^a6C_1-4An alkyl group, which may be substituted with 1 to 5 substituents selected from group A above;_3-10A carbocyclic group or a heterocyclic group (as defined above) which may be substituted with 1 to 5 substituents selected from Group A above. }
-OR^a7, -SR^a7, -NR^a7R^a8, -NR^a7COR^a9, -COOR^a10Or -N = CH-NR^a10R^a11
(Where R^a7And R^a8Are the same or different and each may be substituted with a hydrogen atom, a group B, or a halogen atom and 1 to 3 substituents selected from the group B._1-10An alkyl group, R^a9Is C_1-4An alkyl group, R^a10And R^a11Are the same or different and each represents a hydrogen atom or C_1-4It is an alkyl group. Or the pharmaceutically acceptable salt thereof.
  (9) R³²But,
Hydrogen atom, cyano group, halogen atom,
C which may be substituted by a halogen atom and 1 to 3 substituents selected from group B below_1-10An alkyl group,
  Group B is here
C which may be substituted with 1 to 5 substituents selected from Group A above_3-10Carbocyclic groups,
A heterocyclic group which may be substituted by 1 to 5 substituents selected from Group A (wherein the heterocyclic group is at least selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom) A saturated or unsaturated ring containing one heteroatom).
-OR^a4, -SR^a4,
-NR^a4R^a5, -CONR^a4R^a5, -SO₂NR^a4R^a5,
-COR^a6, -NR^a4COR^a6, -SO₂R^a6, -NR^a4SO₂R^a6,
-COOR^a4And -NR^a5COOR^a6A group consisting of
  {Where R^a4And R^a5Are the same or different and each represents a hydrogen atom, C_1-4An alkyl group, which may be substituted with 1 to 5 substituents selected from group A above;_3-10A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from group A above;^a6C_1-4An alkyl group, selected from group A above
C optionally substituted by 1 to 5 substituents_3-10A carbocyclic group or a heterocyclic group (as defined above) which may be substituted with 1 to 5 substituents selected from Group A above. }
-OR^a7, -SR^a7, -NR^a7R^a8, -NR^a7COR^a9And -COOR^a10(Where R^a7And R^a8Are the same or different and each may be substituted with a hydrogen atom, a group B, or a halogen atom and 1 to 3 substituents selected from the group B._1-10An alkyl group, R^a9Is C_1-4An alkyl group, R^a10Is a hydrogen atom or C_1-4It is an alkyl group. Or the pharmaceutically acceptable salt thereof.

(10) R ³² is a hydrogen atom, —OR ^a7 or —NR ^a7 R ^a8 (wherein R ^a7 and R ^a8 are the same or different and each represents a hydrogen atom, a group B, a halogen atom or the above group B) A 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to (9) above, which is a C _1-10 alkyl group _optionally substituted by 1 to 3 substituents selected from:
(11) R ³³ is
Hydrogen atom,
A C _1-10 alkyl group which may be substituted with a halogen atom and 1 to 3 substituents selected from the following group B;
Group B is here
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group which may be substituted by 1 to 5 substituents selected from Group A (wherein the heterocyclic group is at least selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom) A saturated or unsaturated ring containing one heteroatom).
-OR ^a4 , -SR ^a4 ,
-NR ^a4 R ^a5 , -CONR ^a4 R ^a5 , -SO ₂ NR ^a4 R ^a5 ,
-COR ^a6 , -NR ^a4 COR ^a6 , -SO ₂ R ^a6 , -NR ^a4 SO ₂ R ^a6 ,
-COOR ^a4 and -NR ^a5 COOR ^a6
{Wherein, R ^a4 and R ^a5 are the same or different and each is hydrogen atom, C _1-4 alkyl groups, 1 to 5 substituents which may be substituted with a substituent C _3-10 selected from the above-mentioned group A A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from Group A, wherein R ^a6 is a C _1-4 alkyl group, C _3-10 carbocyclic group which may be substituted with 1 to 5 substituents selected from group A, or heterocyclic group which may be substituted with 1 to 5 substituents selected from group A (As defined above). }
—OR ^a7 , or —NR ^a7 R ^a8 (wherein R ^a7 and R ^a8 are the same or different and each represents one to three selected from a hydrogen atom, a group B, a halogen atom and the group B) A 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to (8) above, which is a C _1-10 alkyl group which may be substituted by a substituent.
(12) R ³³ is a hydrogen atom, —OR ^a7 or —NR ^a7 R ^a8 (wherein R ^a7 and R ^a8 are the same or different and each represents a hydrogen atom, a group B, a halogen atom or the above group B) A 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to (11) above, which is a C _1-10 alkyl group _optionally substituted by 1 to 3 substituents selected from:
(13) R ^a7 and R ^a8 are the same or different and each is a halogen atom and a C _1-10 alkyl group which may be substituted with 1 to 3 substituents selected from the following group B [wherein group B is ,
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group which may be substituted by 1 to 5 substituents selected from Group A (wherein the heterocyclic group is at least selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom) A saturated or unsaturated ring containing one heteroatom).
-OR ^a4 , -SR ^a4 ,
-NR ^a4 R ^a5 , -CONR ^a4 R ^a5 , -SO ₂ NR ^a4 R ^a5 ,
-COR ^a6 , -NR ^a4 COR ^a6 , -SO ₂ R ^a6 , -NR ^a4 SO ₂ R ^a6 ,
-COOR ^a4 and -NR ^a5 COOR ^a6
{Wherein, R ^a4 and R ^a5 are the same or different and each is hydrogen atom, C _1-4 alkyl groups, 1 to 5 substituents which may be substituted with a substituent C _3-10 selected from the above-mentioned group A A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from Group A, wherein R ^a6 is a C _1-4 alkyl group, C _3-10 carbocyclic group which may be substituted with 1 to 5 substituents selected from group A, or heterocyclic group which may be substituted with 1 to 5 substituents selected from group A (As defined above). }] The 4-oxoquinoline compound of the above (8) to (12), or a pharmaceutically acceptable salt thereof.
(14) R ⁴ and R ⁵ are
Cyano group, phenyl group, nitro group, halogen atom, C _1-4 alkyl group, halo C _1-4 alkyl group, halo C _1-4 alkyloxy group, —OR ^a1 , —SR ^a1 , -NR ^a1 R ^a2 , -CONR ^a1 R ^a2 , -SO ₂ NR ^a1 R ^a2 , -NR ^a1 COR ^a3 , -SO ₂ R ^a3 , -NR ^a2 COOR ^a3 , and -COOR ^a1 (where R ^a1 and R ^a2 is the same or different and represents a hydrogen atom, a C _1-4 alkyl group or a benzyl group, and R ^a3 represents a substituent selected from the group consisting of C _1-4 alkyl groups. A 4-oxoquinoline compound according to the above (5) or a pharmaceutically acceptable salt thereof.
(15) R ⁴ is
Phenyl group, halogen atom, C _1-4 alkyl group, halo C _1-4 alkyloxy group, —OR ^a1 , —NR ^a1 R ^a2 , —CONR ^a1 R ^a2 , —SO ₂ NR ^a1 R ^a2 , —NR ^a1 COR ^a3 , —SO ₂ R ^a3 , —NR ^a1 SO ₂ R ^a3 , or —COOR ^a1 (wherein R ^a1 and R ^a2 are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, or 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to (14), wherein R ₄ represents a benzyl group, and R ^a3 represents a C _1-4 alkyl group.
(16) The 4-oxoquinoline compound according to the above (15), wherein R ⁴ is a halogen atom, or a pharmaceutically acceptable salt thereof.
(17) R ⁵ is
Hydrogen atom, cyano group, phenyl group, nitro group, halogen atom, C _1-4 alkyl group, halo C _1-4 alkyl group, —OR ^a1 , —SR ^a1 , —NR ^a1 R ^a2 , —CONR ^a1 R ^a2 , —SO ₂ NR ^a1 R ^a2 and —NR ^a1 COR ^a3 (wherein R ^a1 and R ^a2 are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, or a benzyl group; ^a3 represents a C _1-4 alkyl group.) The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to the above (5), which is a substituent selected from the group consisting of:
(18) The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to (5), wherein R ⁶ is a halogen atom.
(19) The 4-oxoquinoline compound according to the above (5), wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof.

  (20) R¹But,
C which may be substituted by 1 to 5 substituents selected from group A below_3-10Carbocyclic groups,
Group A is here
Cyano group, phenyl group, nitro group, halogen atom, C_1-4An alkyl group,
Halo C_1-4Alkyl group, halo C_1-4An alkyloxy group,
-OR^a1, -SR^a1,
-NR^a1R^a2, -CONR^a1R^a2, -SO₂NR^a1R^a2,
-COR^a3, -NR^a1COR^a3, -SO₂R^a3, -NR^a1SO₂R^a3,
-COOR^a1And -NR^a2COOR^a3
A group consisting of
  (Where R^a1And R^a2Are the same or different and each represents a hydrogen atom, C_1-4R represents an alkyl group or a benzyl group, R^a3C_1-4An alkyl group is shown. )
-NR^a4R^a5, -NR^a4COR^a6, -NR^a4SO₂R^a6And -NR^a5COOR^a6{Where R^a4And R^a5Are the same or different and each represents a hydrogen atom, C_1-4An alkyl group, which may be substituted with 1 to 5 substituents selected from group A above;_3-10A carbocyclic group, or a heterocyclic group which may be substituted with 1 to 5 substituents selected from the above group A (wherein the heterocyclic group includes a nitrogen atom, an oxygen atom and A saturated or unsaturated ring containing at least one heteroatom selected from sulfur atoms), and R^a6C_1-4An alkyl group, which may be substituted with 1 to 5 substituents selected from group A above;_3-10A carbocyclic group or a heterocyclic group (as defined above) which may be substituted with 1 to 5 substituents selected from Group A above. }, Or a substituent selected from
C optionally substituted by halogen atoms and 1 to 3 substituents selected from group B_1-10An alkyl group [where group B is
C which may be substituted with 1 to 5 substituents selected from Group A above_3-10Carbocyclic groups,
A heterocyclic group optionally substituted with 1 to 5 substituents selected from Group A (as defined above);
-OR^a4, -SR^a4, -NR^a4R^a5, -CONR^a4R^a5, -SO₂NR^a4R^a5, -COR^a6, -NR^a4COR^a6, -SO₂R^a6, -NR^a4SO₂R^a6, -COOR^a4And -NR^a5COOR^a6(Where R^a4, R^a5And R^a6And Group A is as defined above. Is a substituent selected from the group consisting of: ] The 4-oxoquinoline compound according to the above (5) or a pharmaceutically acceptable salt thereof.
  (21) R¹May be substituted with a halogen atom and 1 to 3 substituents selected from group B_1-10An alkyl group [wherein group B is
C which may be substituted with 1 to 5 substituents selected from Group A above_3-10Carbocyclic groups,
A heterocyclic group optionally substituted by 1 to 5 substituents selected from Group A above;
  (Here, the heterocyclic group is a saturated or unsaturated ring including at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.)
-OR^a4, -SR^a4,
-NR^a4R^a5, -CONR^a4R^a5, -SO₂NR^a4R^a5,
-COR^a6, -NR^a4COR^a6, -SO₂R^a6, -NR^a4SO₂R^a6,
-COOR^a4And -NR^a5COOR^a6A group consisting of
  {Where R^a4And R^a5Are the same or different and each represents a hydrogen atom, C_1-4An alkyl group, which may be substituted with 1 to 5 substituents selected from group A above;_3-10A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from group A above;^a6C_1-4An alkyl group, which may be substituted with 1 to 5 substituents selected from group A above;_3-10A carbocyclic group or a heterocyclic group (as defined above) which may be substituted with 1 to 5 substituents selected from Group A above. }] The 4-oxoquinoline compound of the above (20), or a pharmaceutically acceptable salt thereof.
  (22) 6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-1),
6- (2,3-dichlorobenzyl) -8-fluoro-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-2),
6- (2,3-dichlorobenzyl) -1- (2-methanesulfonylaminoethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-3),
6- (2,3-dichlorobenzyl) -1- (2-imidazol-1-ylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-4),
6- (2,3-dichlorobenzyl) -1-dimethylcarbamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-5),
6- (2,3-dichlorobenzyl) -1-methylcarbamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-6),
1-carbamoylmethyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-7),
6- (2,3-dichlorobenzyl) -1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-8),
6- (2,3-dichlorobenzyl) -4-oxo-1-sulfamoylmethyl-1,4-dihydroquinoline-3-carboxylic acid (Example 1-9),
1- (2-carboxyethyl) -4-oxo-6- (2,3-dichlorobenzyl) -1,4-dihydroquinoline-3-carboxylic acid (Example 1-10),
1- (2-hydroxyethyl) -6-naphthalen-1-ylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-11),
6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid methyl ester (Example 1-12),
1- (2-carbamoylethyl) -6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-13),
6- (2,3-dichlorobenzyl) -4-oxo-1- (2-oxopropyl) -1,4-dihydroquinoline-3-carboxylic acid (Example 1-14),
1-benzyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-15),
6- (2,3-dichlorobenzyl) -4-oxo-1-phenethyl-1,4-dihydroquinoline-3-carboxylic acid (Example 1-16),
6- (2,3-dichlorobenzyl) -1- (3-phenylpropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-17),
6- (2,3-dichlorobenzyl) -1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-18),
6- (2,3-dichlorobenzyl) -1- (4-phenylbutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-19),
1-biphenyl-2-ylmethyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-20),
6- (2,3-dichlorobenzyl) -1- (4-hydroxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-21),
1-benzo [b] thiophen-2-ylmethyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-22),
6- (2,3-dichlorobenzyl) -1- (3,4-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-23),
6- (2,3-dichlorobenzyl) -1- (2-dimethylaminoethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-24),
6- (2,3-dichlorobenzyl) -1- (3-hydroxypropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-25),
6- (2,3-dichlorobenzyl) -1- (2-methoxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-26),
6- (2,3-dichlorobenzyl) -1- (2,2,2-trifluoroethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-27),
1-carboxymethyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-28),
6- (2,3-Dichlorobenzyl) -1- [2- (4-methylthiazol-5-yl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-29) ), 6- (2,3-dichlorobenzyl) -1- (2-hydroxypropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-30),
6- (2,3-dichlorobenzyl) -1- (2-methylsulfanylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-32),
6- (2-chloro-6-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-33),
6- (2,3-dichlorobenzyl) -1- (5-hydroxypentyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-34),
6- (2,3-dichlorobenzyl) -1- (2-morpholin-4-ylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-35),
6- (2,3-dichlorobenzyl) -1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-36),
6- (2,3-dichlorobenzyl) -1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-37),
6- (2,3-dichlorobenzyl) -4-oxo-1-propyl-1,4-dihydroquinoline-3-carboxylic acid (Example 1-38),
1-butyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-39),
1-cyclopentylmethyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-40),
6- (2,3-dichlorobenzyl) -1- (2-methanesulfonylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-41),
1-cyclohexylmethyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-42),
6- (2,3-dichlorobenzyl) -1- (2-hydroxy-2-phenylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-43),
6- (2,3-dichlorobenzyl) -1- (2-fluoroethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-44),
6- (2,3-dichlorobenzyl) -4-oxo-1- (2-pyridin-2-ylethyl) -1,4-dihydroquinoline-3-carboxylic acid (Example 1-45),
1- (2-aminoethyl) -6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-46),
6- (2,3-dichlorobenzyl) -1- (2-hydroxy-2-methylpropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-47),
1- (2-acetylaminoethyl) -6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-48),
6- (2,3-dichlorobenzyl) -1- (2-ethoxycarbonylaminoethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-49),
6- (2,3-difluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-50),
6- (2-chloro-4-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-51),
6- (2-chlorobenzyl) -4-oxo-1-phenethyl-1,4-dihydroquinoline-3-carboxylic acid (Example 1-65),
6- (2-chloro-3-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-66),
6- (2,3-dichlorobenzyl) -1-methylsulfanylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-68),
6- (2,3-dichlorobenzyl) -1-methanesulfonylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-69),
1-tert-butylsulfamoylmethyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-70),
6- (2,3-dichlorobenzyl) -1-methylsulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-71),
6- (2,3-dichlorobenzyl) -1-dimethylsulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-72),
6- (2-chloro-3,6-difluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-73),
6- (2,3-dichlorobenzyl) -1- (2,3-dihydroxypropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-74),
6- (2-chloro-6-fluorobenzyl) -1-sulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-75),
6- (2-chloro-6-fluorobenzyl) -1-methylsulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-76),
6- (2-chloro-6-fluorobenzyl) -1-dimethylsulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-77),
6- (2-chloro-3-methylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-79),
6- (2-bromobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-80),
6- (2-chloro-3-methoxybenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-82),
1- (2-hydroxyethyl) -6- (2-methanesulfonylbenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-85),
6-biphenyl-2-ylmethyl-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-86),
6- (2-chlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-87),
6- (2-chloro-5-methylsulfanylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-92),
1- (2-hydroxyethyl) -4-oxo-6- (2-trifluoromethyloxybenzyl) -1,4-dihydroquinoline-3-carboxylic acid (Example 1-93),
6- (2-chloro-5-methylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-97),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-99),
6- (3-chloro-2,6-difluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-100),
6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-101),
1-cyclopropyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-102),
1-amino-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-1),
6- (2,3-dichlorobenzyl) -1-methoxycarbonylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-2),
1-acetylamino-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-3),
6- (2,3-dichlorobenzyl) -1-methanesulfonylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-4),
6- (2,3-dichlorobenzyl) -1- (N-methanesulfonyl-N-methylamino) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-5),
6- (2,3-dichlorobenzyl) -1-dimethylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-6),
6- (2,3-dichlorobenzyl) -1-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-7),
6- (2,3-dichlorobenzyl) -1-ethylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-8),
6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-1),
6- (3-chloro-2-methylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-2),
6- (3-chloro-2-methoxybenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-3),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-4),
6- (2,3-dichlorobenzyl) -5-hydroxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-5),
6- (2,3-dichlorobenzyl) -7-hydroxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-6),
1- (2-hydroxyethyl) -6- (2-methylaminobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-7),
6- (2-dimethylaminobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-8),
6- (2,3-dichlorobenzyl) -4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid (Example 3-9),
6- (2,3-dichlorobenzyl) -1- [2-hydroxy-1- (hydroxymethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-10),
1-cyclobutyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-12),
1-cyclopentyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-13),
6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-14),
6- (2-dimethylsulfamoylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-16),
6- (3-chloro-2,4-difluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-17),
6- (2-carboxybenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-18),
1- (2-hydroxyethyl) -6- (2-methylsulfamoylbenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-19),
6- (2,3-dichlorobenzyl) -7-ethoxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-20),
7-chloro-6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-21),
6- (2,3-Dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-7-
Trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid (Example 3-22), (S) -6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxy-1-methyl) Ethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-23),
(R) -6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxy-1-methylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3- 24),
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-8-trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid (Example 3-25) ,
6- (3-Chloro-2-fluorobenzyl) -1- [2-hydroxy-1- (hydroxymethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-26) ),
7-cyano-6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-27),
6- (2-ethylmethylaminobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-28),
6- [2- (N-methyl-N-propylamino) benzyl] -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-29),
6- [2- (N-benzyl-N-methylamino) benzyl] -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-30),
6- [2- (N-methanesulfonyl-N-methylamino) benzyl] -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-31) ,
6- [2- (N-isopropyl-N-methylamino) benzyl] -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-32),
1-tert-butyl-6- (3-chloro-2-fluorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-33),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-34),
8-amino-6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-35),
7-carboxy-6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-36),
6- (3-Chloro-2,6-difluorobenzyl) -1- (2-hydroxyethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-37) ,
6- (3-chloro-2-fluorobenzyl) -8-dimethylamino-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-38),
8-acetylamino-6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-39),
5-cyano-6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-40),
6- [2- (N-acetyl-N-methylamino) benzyl] -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-41),
6- (2-diethylaminobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-42),
6- (3-Chloro-2-fluorobenzyl) -1- (1,1-dimethyl-2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-43) ,
6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-44),
6- (3-Chloro-2-fluorobenzyl) -7,8-dimethoxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-45) ,
6- (3-chloro-2-fluorobenzyl) -8-ethoxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-47),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -8-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-48),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-7-propyloxy-1,4-dihydroquinoline-3-carboxylic acid (Example 3-49),
6- (3-Chloro-2-fluorobenzyl) -7- (dimethylaminomethyleneamino) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3) -50),
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid methyl ester (Example 3-51) ,
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-8-phenoxy-1,4-dihydroquinoline-3-carboxylic acid (Example 3-52), 6 -(3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-53),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-8-propylamino-1,4-dihydroquinoline-3-carboxylic acid (Example 3-54),
6- (3-chloro-2-fluorobenzyl) -8-ethylamino-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-55),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxy-1-methylethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 3-56),
(S) -6- (3-Chloro-2,6-difluorobenzyl) -1- (2-hydroxy-1-methylethyl) -8methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-57),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-8-propyloxy-1,4-dihydroquinoline-3-carboxylic acid (Example 3-58),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-59),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) propyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-60) ),
(S) -6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1- (2-hydroxy-1-methylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (
Example 3-61),
6- (3-chloro-2-fluorobenzyl) -7-dimethylamino-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-62),
6- (3-chloro-2-fluorobenzyl) -7-cyclohexylmethoxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-63),
6- (3-chloro-2-fluorobenzyl) -8-diethylamino-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-64),
6- (3-chloro-2-fluorobenzyl) -7-methylamino-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-65),
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-7-pyrrolidin-1-yl-1,4-dihydroquinoline-3-carboxylic acid (Example 3- 66),
(S) -6- (3-Chloro-2-fluorobenzyl) -8-ethoxy-1- (2-hydroxy-1-methylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 3-67),
(S) -6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1- [1- (hydroxymethyl) propyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 3-68),
6- (3-chloro-2-fluorobenzyl) -8-cyclohexylmethoxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-69),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-2-methylpropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3) -70),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-3-methylbutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3- 71),
(S) -6- (3-Chloro-2,6-difluorobenzyl) -1- [1- (hydroxymethyl) propyl] -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carvone Acid (Example 3-72),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) propyl] -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 3-73),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxy-1-methylethyl) -7-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 3-74),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-75),
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -7- (2-hydroxyethyloxy) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Examples) 3-76),
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -7- (3-hydroxypropyloxy) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Examples) 3-77),
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -8- (2
-Hydroxyethylamino) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-78),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) propyl] -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 3-79),
(S) -6- (3-Chloro-2-fluorobenzyl) -8-dimethylamino-1- (2-hydroxy-1-methylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-80),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxy-1-phenylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3- 81),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) butyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-82) ),
6- (3-Chloro-2-fluorobenzyl) -1-((1S, 2S) -1-hydroxymethyl-2-methylbutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Examples) 3-83),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxy-1-methylethyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 3-84),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-benzyl-2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3- 85),
6- (2-chloro-5-methanesulfonylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-1),
6- (2-ethylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-4),
6- (2-chloro-5-methylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-5),
6- (2-chloro-5-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-6),
6- (5-bromo-2-chlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-7),
6- (2,3-dichlorobenzyl) -7-fluoro-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-9),
6- (2-chloro-5-hydroxybenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-11),
6- (2,3-dichlorobenzyl) -5-fluoro-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-12),
6- (2-ethoxybenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-13),
6- (2-hydroxybenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-14),
6- (2,3-dichlorobenzyl) -7-methyl-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-15),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxy-1-methylethyl) -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-16),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) propyl] -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-ca
Rubonic acid (Examples 4-17),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4- 18),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-2-methylpropyl) -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carvone Acid (Examples 4-19),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -7-isopropyloxy-4-oxo-1,4-dihydroquinoline -3-carboxylic acid (Example 4-20),
(S) -6- (3-Chloro-2-fluorobenzyl) -8-ethoxy-1- [1- (hydroxymethyl) propyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 4-21),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2-cyclohexyl-1- (hydroxymethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 4-22),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-3-methylbutyl) -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-23),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-2-methylpropyl) -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carvone Acid (Examples 4-24),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-3-methylbutyl) -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-25),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -8-isopropyloxy-4-oxo-1,4-dihydroquinoline -3-carboxylic acid (Example 4-26),
6- (3-Chloro-2-fluorobenzyl) -1-((1S, 2S) -1-hydroxymethyl-2-methylbutyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carvone Acid (Example 4-27),
6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1-((1S, 2S) -1-hydroxymethyl-2-methylbutyl) -4-oxo-1,4-dihydroquinoline-3-carvone Acid (Example 4-28),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) propyl] -7-methylsulfanyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-29),
(S) -6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1- (1-hydroxymethyl-2-methylpropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-30),
(S) -6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -4-oxo-1,4-dihydroquinoline- 3-carboxylic acid (Example 4-31),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-2-methylpropyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-32),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -7-methoxy-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid (Example 4-33),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2,2-dimethyl-1- (
Hydroxymethyl) propyl] -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-34),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) butyl] -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-35),
(S) -6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1- [1- (hydroxymethyl) butyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 4-36),
(S) -6- (3-Chloro-2-fluorobenzyl) -8-ethoxy-1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -4-oxo-1,4-dihydroquinoline- 3-carboxylic acid (Example 4-37),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) butyl] -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 4-38),
6- (3-Chloro-2-fluorobenzyl) -1-((1S, 2S) -1-hydroxymethyl-2-methylbutyl) -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3- Carboxylic acid (Example 4-39),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-40),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -8-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-41),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-42),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -7-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-43),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-44),
(S) -6- (3-Chloro-2-fluorobenzyl) -8-ethoxy-1- (1-hydroxymethyl-2-methylpropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-45),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-2-methylpropyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-46),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) butyl] -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-47),
(S) -6- (3-Chloro-2-fluorobenzyl) -8-ethoxy-1- [1- (hydroxymethyl) butyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 4-48),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) butyl] -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 4-49),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-50), and
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid The 4-oxoquinoline compound according to the above (5) or a pharmaceutically acceptable salt thereof selected from the group consisting of (Example 4-52).
  (23) A pharmaceutical composition comprising the 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to any one of (5) to (22) above and a pharmaceutically acceptable carrier.
  (24) An integrase inhibitor comprising, as an active ingredient, the 4-oxoquinoline compound according to any one of (1) to (22) or a pharmaceutically acceptable salt thereof.
  (25) An antiviral agent comprising the 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to any one of (5) to (22) as an active ingredient.
  (26) An anti-HIV agent comprising the 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to any one of (5) to (22) as an active ingredient.
  (27) The 4-oxoquinoline compound according to any one of (1) to (22) or a pharmaceutically acceptable salt thereof, and one or more other anti-HIV active substances as active ingredients. An anti-HIV composition.
  (28) The 4-oxoquinoline compound according to any one of (1) to (22) above or a pharmaceutically acceptable salt thereof as an active ingredient for multi-drug combination therapy with other anti-HIV agents An anti-HIV agent.

The compounds of the present invention exhibit 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.

The definition of each substituent and each site used in the present specification is as follows.
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.
R ³² , R ³³ , R ⁴ , R ⁵ , R ⁶ , R ^{6 ′} , R ^{6 ″} , R ^{6 ′ ″} and group A are particularly preferably a fluorine atom and a chlorine atom, and R ³² and R ⁵ More preferably, it is a chlorine atom, which may be substituted as R ³¹ , R ³³ , R ⁴ , R ^{6 ′} and R ^{6 ′} ″ or “substituted by 1 to 3 substituents selected from a halogen atom and group B”. As the halogen atom of the “good C _1-10 alkyl group”, a fluorine atom is more preferable.

The “C _1-4 alkyl group” represents 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 -A butyl group and a tert- butyl group are mentioned.
R ² , R ³¹ and R ^a6 are preferably a methyl group and an ethyl group, and R ⁴ , R ⁵ , R ⁶ , R ^{6 ′} , R ^{6 ″} , R ^{6 ′ ″} and group A are preferably A methyl group, an ethyl group and an isopropyl group, more preferably a methyl group, and R ^a1 and R ^a2 are preferably a methyl group, an ethyl group, a propyl group and an isopropyl group, more preferably a methyl group, R ^a3 , R ^a9 , R ^a10 , R ^a11 and group A are preferably methyl groups, and R ^a4 and R ^a5 are preferably methyl groups, ethyl groups and tert-butyl groups.

The “halo C _1-4 alkyl group” is a “C _1-4 alkyl group” as defined above substituted with 1 to 9, preferably 1 to 3, “halogen atoms” as defined above.
Specifically, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 3-
Fluoropropyl group, 3-chloropropyl group, 4-fluorobutyl group, 4-chlorobutyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, 3,3,3-trifluoropropyl group, 4, Examples include 4,4-trifluorobutyl group, pentafluoroethyl group, 2,2,2-trifluoro-1-trifluoromethyl-ethyl group, and the like.
R ³¹ , R ⁴ , R ⁵ , R ⁶ , R ^{6 ′} , R ^{6 ″} , R ^{6 ′ ″} and Group A are preferably trifluoromethyl groups.

The “C _1-4 alkoxy group” is an alkyloxy group whose alkyl moiety is the “C _1-4 alkyl group” defined above, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropyloxy group. , Butoxy group, isobutyloxy group, and tert-butyloxy group.
R ³¹ is preferably a methoxy group.

The “C _1-4 alkylsulfanyl group” is an alkylsulfanyl group whose alkyl moiety is the above-defined “C _1-4 alkyl group”, specifically a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group. , Isopropylsulfanyl group, butylsulfanyl group, isobutylsulfanyl group, tert-butylsulfanyl group.
R ³¹ is preferably a methylsulfanyl group.

"Halo C _1-4 alkyl group", the haloalkyl portion is halo C _1-4 alkyloxy group is a "halo C _1-4 alkyl group" defined above.
Specifically, 2-fluoroethyloxy group, 2-chloroethyloxy group, 2-bromoethyloxy group, 3-fluoropropyloxy group, 3-chloropropyloxy group, 4-fluorobutyloxy group, 4-chloro Butyloxy group, trifluoromethyloxy group, 2,2,2-trifluoroethyloxy group, 3,3,3-trifluoropropyloxy group, 4,4,4-trifluorobutyloxy group, pentafluoroethyloxy Group, 2,2,2-trifluoro-1-trifluoromethyl-ethyloxy group and the like.
In R ³¹ , R ⁴ , R ⁵ , R ⁶ , R ^{6 ′} , R ^{6 ″} , R ^{6 ′ ″} and Group A, a trifluoromethyloxy group is preferable.

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 particularly 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, and a norbornanyl group, preferably a cyclopropyl group, a cyclobutyl group , Cyclopentyl group and cyclohexyl group.
The “cycloalkenyl group” includes at least one, preferably 1 or 2, double bonds, specifically, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexenyl group, A cyclohexadienyl group (2,4-cyclohexadien-1-yl group, 2,5-cyclohexadien-1-yl group, etc.), cycloheptenyl group, cyclooctenyl group and the like can be mentioned.
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 A naphthyl group (1,2,3,4-tetrahydro-2-naphthyl group, 5,6,7,8-tetrahydro-2-naphthyl group, etc.), a perhydronaphthyl group, etc. are mentioned. Preferably it is a condensed ring of a phenyl group and other ring, indenyl group, indanyl group,
A 1,4-dihydronaphthyl group, a 1,2,3,4-tetrahydronaphthyl group, and the like, particularly preferably an indanyl group.

“C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A” means 1 to 5, preferably 1 to 3 substituents selected from group A below. It is a “C _3-10 carbocyclic group” as defined above which may be substituted by, and includes an unsubstituted “C _3-10 carbocyclic group”.
“Group A” means cyano group, phenyl group, nitro group, “halogen atom” as defined above, “C _1-4 alkyl group” as defined above, “halo C _1-4 alkyl group” as defined above, Definition of “halo C _1-4 alkyloxy group”, —OR ^a1 , —SR ^a1 , —NR ^a1 R ^a2 , —CONR ^a1 R ^a2 , —SO ₂ NR ^a1 R ^a2 , —COR ^a3 , —NR ^a1 COR ^a3 , —SO ₂ R ^a3 , —NR ^a1 SO ₂ R ^a3 , —COOR ^a1, and —NR ^a2 COOR ^a3 , wherein R ^a1 and R ^a2 are the same or different and are each a hydrogen atom, “C _1-4 alkyl group” or benzyl group as defined, and R ^a3 represents “C _1-4 alkyl group” as defined above.
Specific examples of “—OR ^a1 ” include a hydroxy group, a methoxy group, an ethoxy group, a propoxy group, an isopropyloxy group, a tert-butoxy group, and the like.
Specific examples of “—SR ^a1 ” include a mercapto group, a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanyl group, a tert-butylsulfanyl group, and the like.
Specific examples of “—NR ^a1 R ^a2 ” include amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, tert-butylamino group, dimethylamino group, diethylamino group, and N-ethyl-N. -Methylamino group, N-methyl-N-propylamino group, N-isopropyl-N-methylamino group, N-benzyl-N-methylamino group, etc.
Specific examples of “—CONR ^a1 R ^a2 ” include carbamoyl group, methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, tert-butylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl Group, N-methyl-N-ethylaminocarbonyl group and the like,
Specific examples of “—SO ₂ NR ^a1 R ^a2 ” include sulfamoyl group, methylaminosulfonyl group, ethylaminosulfonyl group, propylaminosulfonyl group, isopropylaminosulfonyl group, tert-butylaminosulfonyl group, dimethylaminosulfonyl group, A diethylaminosulfonyl group, an N-methyl-N-ethylaminosulfonyl group, and the like.
Specific examples of “—COR ^a3 ” include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pivaloyl group, and the like.
Specific examples of “—NR ^a1 COR ^a3 ” include acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, pivaloylamino group, N-acetyl-N-methylamino group, and the like.
Specific examples of “—SO ₂ R ^a3 ” include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a tert-butylsulfonyl group, and the like.
Specific examples of “—NR ^a1 SO ₂ R ^a3 ” include methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylamino group, isopropylsulfonylamino group, tert-butylsulfonylamino group, N-methyl-N- (methyl Sulfonyl) amino group and the like,
Specific examples of “—COOR ^a1 ” include a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropyloxycarbonyl group, a tert-butoxycarbonyl group, and the like.
Specific examples of “—NR ^a2 COOR ^a3 ” include methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, isopropyloxycarbonylamino group, tert-butoxycarbonylamino group and the like.

Group A is preferably a cyano group, phenyl group, nitro group, fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, isopropyl group, trifluoromethyl group, trifluoromethyloxy group, hydroxy group, methoxy group, Ethoxy group, propoxy group, methylsulfanyl group, amino group, methylamino group, ethylamino group, isopropylamino group, dimethylamino group, diethylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino Group, N-isopropyl-N-methylamino group, N-benzyl-N-methylamino group, carbamoyl group, methylaminocarbonyl group, dimethylaminocarbonyl group, sulfamoyl group, methylaminosulfonyl group, dimethylaminosulfonyl group, acetyl group Acetylamino group, N- Cetyl -N- methylamino group, methylsulfonyl group, methylsulfonylamino group, N- methyl -N- (methylsulfonyl) amino group, a carboxyl group, methoxycarbonyl group, carboxyamino group and methoxycarbonylamino group.
Particularly preferably as group A, cyano group, phenyl group, nitro group, fluorine atom, chlorine atom, bromine atom, methyl group, trifluoromethyl group, trifluoromethyloxy group, hydroxy group, methoxy group, ethoxy group, methylsulfanyl Group, amino group, methylamino group, dimethylamino group, diethylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-isopropyl-N-methylamino group, N-benzyl- N-methylamino group, dimethylaminocarbonyl group, methylaminosulfonyl group, dimethylaminosulfonyl group, acetylamino group, N-acetyl-N-methylamino group, methylsulfonyl group, N-methyl-N- (methylsulfonyl) amino Group and carboxyl group, more preferably fluorine atom and Is a chlorine atom.
The number of substituents is preferably 1 to 3, and when the “C _3-10 carbocyclic group” is a phenyl group, the ring Cy is preferably 2-position mono-substituted, 3-position mono-substituted, 2, 3-position Di-substitution, 2,4-position di-substitution, 2,5-position di-substitution, 2,6-position di-substitution, 2,3,4-position tri-substitution, 2,3,5-position tri-substitution, 2,3,6-position tri-substitution Particularly preferred is 2,3-disubstituted.

Specific examples of the “C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A” include a phenyl group, a naphthyl group, a 2-fluorophenyl group, a 2-chlorophenyl group, 2-bromophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 3-bromophenyl group, 4-fluorophenyl group, 2-nitrophenyl group, 3-nitrophenyl group, 2-cyanophenyl group, 3-cyano Phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 2-isopropylphenyl group, 3-isopropylphenyl group, 2-trifluoromethyl Phenyl group, 3-trifluoromethylphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxy group Phenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 2-ethoxyphenyl group, 3-ethoxyphenyl group, 2-propoxyphenyl group, 3-propoxyphenyl group, 2- (trifluoromethyl) phenyl group, 3 -(Trifluoromethyl) phenyl group, 2- (trifluoromethyloxy) phenyl group, 3- (trifluoromethyloxy) phenyl group, 2-methylsulfamoylphenyl group, 3-methylsulfamoylphenyl group, 2 -Aminophenyl group, 3-aminophenyl group, 2- (methylamino) phenyl group, 3- (methylamino) phenyl group, 2- (dimethylamino) phenyl group, 3- (dimethylamino) phenyl group, 2- ( Acetylamino) phenyl group, 3- (acetylamino) phenyl group, 2-biphenyl group, 3-biphenyl Enyl group, 2- (methylsulfonyl) phenyl group, 3- (methylsulfonyl) phenyl group, 2-sulfamoylphenyl group, 3-sulfamoylphenyl group, 2- (methylaminosulfonyl) phenyl group, 3- ( Methylaminosulfonyl) phenyl group, 2- (dimethylaminosulfonyl) phenyl group, 3- (dimethylaminosulfonyl) phenyl group, 2- (dimethylsulfonyl) phenyl group, 2- (methylsulfonylamino) phenyl group, 3- (methyl Sulfonylamino) phenyl group, 2-carbamoylphenyl group, 3-carbamoylphenyl group, 2- (methylcarbamoyl) phenyl group, 3- (methylcarbamoyl) phenyl group, 2- (dimethylcarbamoyl) phenyl group, 3- (dimethylcarbamoyl) ) Phenyl group, 2,3-difluoro Phenyl group, 2,3-dichlorophenyl group, 2,3-dibromophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2,5-dichlorophenyl group, 2,6-dichlorophenyl group, 2-chloro -3-fluorophenyl group, 2-chloro-4-fluorophenyl group, 2-chloro-5-fluorophenyl group, 2-chloro-6-fluorophenyl group, 3-chloro-2-fluorophenyl group, 5-chloro 2-fluorophenyl group, 5-bromo-2-chlorophenyl group, 2-chloro-5-nitrophenyl group, 2-chloro-3-methylphenyl group, 2-chloro-5-methylphenyl group, 2-chloro- 3- (trifluoromethyl) phenyl group, 2-chloro-5- (trifluoromethyl) phenyl group, 2-chloro-3-hydroxypheny Group, 2-chloro-5-hydroxyphenyl group, 2-chloro-3-methoxyphenyl group, 2-chloro-5-methoxyphenyl group, 2-chloro-3-methylsulfamoylphenyl group, 2-chloro-5 -Methylsulfamoylphenyl group, 2-chloro-3-aminophenyl group, 2-chloro-5-aminophenyl group, 2-chloro-3- (methylamino) phenyl group, 2-chloro-5- (methylamino) ) Phenyl group, 2-chloro-3- (dimethylamino) phenyl group, 2-chloro-5- (dimethylamino) phenyl group, 2-chloro-3- (acetylamino) phenyl group, 2-chloro-5- ( Acetylamino) phenyl group, 2-chloro-3- (methylsulfonyl) phenyl group, 2-chloro-5- (methylsulfonyl) phenyl group, 2-chloro-3- ( Tylsulfonylamino) phenyl group, 2-chloro-5- (methylsulfonylamino) phenyl group, 2,3,4-trifluorophenyl group, 2-chloro-3,4-difluorophenyl group, 2-chloro-3, 5-difluorophenyl group, 2-chloro-3,6-difluorophenyl group, 2-chloro-4,5-difluorophenyl group, 2-chloro-4,6-difluorophenyl group, 3-chloro-2,4- Difluorophenyl group, 3-chloro-2,5-difluorophenyl group, 3-chloro-2,6-difluorophenyl group, 2,3-dichloro-4-fluorophenyl group, 3-chloro-2-fluoro-5- Trifluoromethylphenyl group, 2-chloro-3,5,6-trifluorophenyl group, 3-chloro-2,4,5-trifluorophenyl group, 3-chloro B-2,4,6-trifluorophenyl group, 2,3-dichloro-4,5,6-trifluorophenyl group, 3,5-dichloro-3,4,6-trifluorophenyl group, 2,6 -Dichloro-3,4,5-trifluorophenyl group, perfluorophenyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, 2-hydroxycyclopropyl group, 3-hydroxycyclobutyl group, 3-hydroxycyclopentyl group 2-hydroxycyclohexyl group, 3-hydroxycyclohexyl group, 4-hydroxycyclohexyl group, 4-indanyl group and 1H-inden-4-yl group.
The ring Cy is preferably a phenyl group, naphthyl group, 2-chlorophenyl group, 3-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 2-hydroxyphenyl. Group, 2-ethoxyphenyl group, 3- (trifluoromethyloxy) phenyl group, 3- (methylsulfonyl) phenyl group, 2,3-difluorophenyl group, 2,3-dichlorophenyl group, 2-chloro-3-fluoro Phenyl group, 2-chloro-4-fluorophenyl group, 2-chloro-5-fluorophenyl group, 2-chloro-6-fluorophenyl group, 3-chloro-2-fluorophenyl group, 5-bromo-2-chlorophenyl Group, 2-chloro-5-methylphenyl group, 2-chloro-5-hydroxyphenyl group, 2-chloro- -(Methylsulfonyl) phenyl group, 2-chloro-3,6-difluorophenyl group, 3-chloro-2,4-difluorophenyl group, 3-chloro-2,6-difluorophenyl group, 2-chloro-3- Methylphenyl group, 3-chloro-2-methylphenyl group, 2-chloro-3-methoxyphenyl group, 3-chloro-2-methoxyphenyl group, 3-nitrophenyl group, 3-cyanophenyl group, 4-methylphenyl Group, 3-trifluoromethylphenyl group, 2- (trifluoromethyloxy) phenyl group, 3-hydroxyphenyl group, 3-ethoxyphenyl group, 3-aminophenyl group, 2- (methylamino) phenyl group, 2- (Dimethylamino) phenyl group, 2- (diethylamino) phenyl group, 2- (N-ethyl-N-methylamino) phenyl group, -(N-isopropyl-N-methylamino) phenyl group, 2- (N-benzyl-N-methylamino) phenyl group, 2- (N-acetyl-N-methylamino) phenyl group, 2- (N-methyl) -N-methylsulfonylamino) phenyl group, 3- (methylamino) phenyl group, 2-carboxyphenyl group, 3- (dimethylaminocarbonyl) phenyl group, 3- (acetylamino) phenyl group, 2-biphenyl group, 2 -(Methylsulfonyl) phenyl group, 2-chloro-5-methylsulfanylphenyl group, 2-chloro-5-methylphenyl group, 2- (methylaminosulfonyl) phenyl group, 2- (dimethylaminosulfonyl) phenyl group and 3 -(Dimethylaminosulfonyl) phenyl group,
Particularly preferably, 2-chlorophenyl group, 2-bromophenyl group, 2-ethylphenyl group, 2-hydroxyphenyl group, 2-ethoxyphenyl group, 2,3-difluorophenyl group, 2,3-dichlorophenyl group, 2-chloro -3-fluorophenyl group, 3-chloro-2-fluorophenyl group, 2-chloro-4-fluorophenyl group, 2-chloro-5-fluorophenyl group, 2-chloro-6-fluorophenyl group, 5-bromo 2-chlorophenyl group, 2-chloro-5-hydroxyphenyl group, 2-chloro-5- (methylsulfonyl) phenyl group, 2-chloro-3,6-difluorophenyl group, 3-chloro-2,6-difluoro Phenyl group, 2-chloro-3-methylphenyl group, 2-chloro-3-methoxyphenyl group, 2-trifluoromethyl group Group, a 2- (methylsulfonyl) phenyl group, 2-chloro-5-methylsulfanylphenyl group, 2-chloro-5-methylphenyl group, and a 2- (dimethylamino) phenyl group,
More preferred are 2,3-dichlorophenyl group, 2,3-difluorophenyl group, 2-chloro-3-fluorophenyl group and 3-chloro-2-fluorophenyl group.
R ¹ and Group B are preferably phenyl group, 3,4-dichlorophenyl group, 2-biphenyl group, cyclopropyl group, 2-hydroxycyclopropyl group, cyclobutyl group, 2-hydroxycyclobutyl group, 3-hydroxycyclobutyl. Group, cyclopentyl group, 2-hydroxycyclopentyl group, 3-hydroxycyclopentyl group, cyclohexyl group, 2-hydroxycyclohexyl group, 3-hydroxycyclohexyl group and 4-hydroxycyclohexyl group, particularly preferably phenyl group, 3,4 -A dichlorophenyl group, a 2-biphenyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
R ³² , R ³³ , R ¹ and group B are preferably a phenyl group and a cyclohexyl group.

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 C _3-10 carbocyclic ring and a heterocyclic ring selected from benzene, cyclopentane, and cyclohexane, Of the condensed ring.
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, 2-oxopyrrolidinyl group, 2-oxopiperidinyl group, 4-oxopiperidinyl group 2,6-dioxopiperidinyl group and the like. Preferred 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, diazolyl 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-oxazolinyl group), isoxazolinyl group, thiazolinyl group, isothiazolinyl group, pyranyl group, 2-oxopyranyl group, 2-oxo-2,5-dihydrofuranyl Group, 1,1-dioxo-1H-isothiazolyl group. Preferably, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, 2-oxo-2,5-dihydrofuranyl and 1,1- Dioxo-1H-isothiazolyl group.
Examples of the “heterocyclic group that is a condensed ring” include an indolyl group (for example, 4-indolyl group, 7-indolyl group, etc.), isoindolyl group, 1,3-dihydro-1,3-dioxoisoindolyl group, Benzofuranyl group (for example, 4-benzofuranyl group, 7-benzofuranyl group, etc.), indazolyl group, isobenzofuranyl group, benzothiophenyl group (for example, 4-benzothiophenyl group, 7-benzothiophenyl group, etc.) Benzoxazolyl group (for example, 4-benzoxazolyl group, 7-benzoxazolyl group, etc.), benzimidazolyl group (for example, 4-benzimidazolyl group, 7-benzimidazolyl group, etc.), benzothiazolyl. Group (for example, 4-benzothiazolyl group, 7-benzothiazolyl group, etc.), indolizinyl group, quinolyl group, isoquino Group, 1,2-dihydro-2-oxoquinolyl group, quinazolinyl group, quinoxalinyl group, cinnolinyl group, phthalazinyl group, quinolidinyl group, prill group, pteridinyl group, indolinyl group, isoindolinyl group, 5,6,7,8-tetrahydro Quinolyl group, 1,2,3,4-tetrahydroquinolyl group, 2-oxo-1,2,3,4-tetrahydroquinolyl group, benzo [1,3] dioxolyl group, 3,4-methylenedioxy Examples include pyridyl group, 4,5-ethylenedioxypyrimidinyl group, chromenyl group, chromanyl group, and isochromanyl group.
Preferably, it is a condensed ring of a monocyclic 5-membered or 6-membered heterocyclic ring and a benzene ring, specifically, an indolyl group, a benzofuranyl group, a benzothiophenyl group, a benzimidazolyl group, a benzoxazolyl group, A benzothiazolyl group and a benzo [1,3] dioxolyl group;

The “heterocyclic group optionally substituted by 1 to 5 substituents selected from group A” means 1 to 5, preferably 1 to 3 substituents selected from “group A” defined above. It is a “heterocyclic group” as defined above which may be substituted by, and includes an unsubstituted “heterocyclic group”.
The “heterocyclic group” is preferably a monocyclic heterocycle containing 1 or 2 heteroatoms, or a heterocycle which is a condensed ring of these with a benzene ring.
Specific examples of the “heterocyclic group optionally substituted by 1 to 5 substituents selected from group A” include pyrrolidinyl group, piperidinyl group, morpholino group, pyrrolyl group, 2-pyrrolyl group, and 3-pyrrolyl group. 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 4,5-dichlorothiophen-3-yl group, 2-oxo-2,5-dihydrofuran-3-yl group, 1 , 1-Dioxo-1H-isothiazol-5-yl group, 4-methylthiazol-5-yl group, imidazolyl group, 2-imidazolyl group, 3-imidazolyl group, 4-imidazolyl group, pyrazolyl group, 2-oxazolyl group 3-isoxazolyl group, 2-thiazolyl group, 3-isothiazolyl group, 3-fluoropyridin-2-yl group, 3-chloropyridin-2-yl group, 3-chloro 4-fluoropyridin-2-yl group, 3,5-dichloropyridin-2-yl group, 3-pyridyl group, 2-fluoropyridin-3-yl group, 2-chloropyridin-3-yl group, 2-chloro -4-fluoropyridin-3-yl group, 2-chloro-5-fluoropyridin-3-yl group, 2,5-dichloropyridin-3-yl group, 2-chloro-6-fluoropyridin-3-yl group 2,6-dichloropyridin-3-yl group, 4-pyridyl group, 2-fluoropyridin-4-yl group, 2-chloropyridin-4-yl group, 2-chloro-3-fluoropyridin-4-yl Group, 2,3-difluoropyridin-4-yl group, 2,3-dichloropyridin-4-yl group, 2,5-dichloropyridin-4-yl group, 2-chloro-6-fluoropyridin-4-yl Group 2,6 Dichloropyridin-4-yl group, 2-chloro-3,6-difluoropyridin-4-yl group, 2-chloro-3,5-difluoropyridin-4-yl group, 2,3,6-trifluoropyridine- 4-yl group, 2,3,5,6-tetrafluoropyridin-4-yl group, 2-indolyl group, 3-indolyl group, 4-indolyl group, 7-indolyl group, 2-benzofuranyl group, 4-benzofuranyl group Group, 7-benzofuranyl group, 2-benzothiophenyl group, 4-benzothiophenyl group, 7-benzothiophenyl group, 2-benzimidazolyl group, 4-benzimidazolyl group, 2-benzooxazolyl group, 4- Benzoxazolyl group, 7-benzoxazolyl group, 2-benzothiazolyl group, 4-benzothiazolyl group, 7-benzothiazolyl group, 2-benzo [1, 3] Dioxolyl group, 4-benzo [1,3] dioxolyl group, 5-benzo [1,3] dioxolyl group and the like.
Ring Cy is preferably a 2-pyridyl group and a 4-pyridyl group,
R ¹ and group B are preferably imidazolyl group, 2-pyridyl group, 2-benzothiophenyl group, morpholino group and 4-methylthiazol-5-yl group,
R ³² and R ³³ are preferably pyrrolidinyl groups.

The “C _1-10 alkyl group _optionally substituted by 1 to 3 substituents selected from a halogen atom and group B” is selected from “halogen atom” defined above and “group B” defined below. It is a C _1-10 alkyl group which may be substituted by a substituent group, and may be an unsubstituted alkyl group. The alkyl moiety represents a linear or branched alkyl group having 1 to 10 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, 1-methylbutyl group, 1-ethylpropyl group, 2-ethylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, tert-pentyl group, hexyl group, Isohexyl group, 1-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 1-ethylbutyl group, 1-ethyl-1-methylpropyl group, 1- Ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methyl Lopyl group, heptyl group, isoheptyl group, 1-methylhexyl group, 1,1-dimethylpentyl group, 1,2-dimethylpentyl group, 1,3-dimethylpentyl group, 1,4-dimethylpentyl group, 1,1 , 2-trimethylbutyl group, 1,1,3-trimethylbutyl group, 1,2,2-trimethylbutyl group, 1,2,3-trimethylbutyl group, 1,3,3-trimethylbutyl group, 1-ethyl Pentyl group, 1-ethyl-2-methylbutyl group, 1-ethyl-3-methylbutyl group, 2-ethyl-1-methylbutyl group, 1-propylbutyl group, 1-ethyl-2,2-dimethylpropyl group, 1- Isopropyl-2-methylpropyl group, 1-isopropyl-1-methylpropyl group, 1,1-diethylpropyl group, 1,1,2,2-tetramethylpropyl group, 1- Examples include a sopropylbutyl group, a 1-ethyl-1-methylbutyl group, an octyl group, a nonyl group, a decanyl group, and the like, preferably a linear or branched alkyl group having 1 to 6 carbon atoms, particularly preferably a carbon number. 1 to 6 branched alkyl groups.
“Group B” means “C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A” as defined above, or “1 to 5 selected from group A” as defined above. -OR ^a4 , —SR ^a4 , —NR ^a4 R ^a5 , —CONR ^a4 R ^a5 , —SO ₂ NR ^a4 R ^a5 , —COR ^a6 , —NR ^a4 It is a group consisting of COR ^a6 , —SO ₂ R ^a6 , —NR ^a4 SO ₂ R ^a6 , —COOR ^a4 and —NR ^a5 COOR ^a6 .
Here, R ^a4 and R ^a5 are the same or different and each is substituted with a hydrogen atom, “C _1-4 alkyl group” as defined above, or “1 to 5 substituents selected from group A as defined above”. An _optionally substituted C _3-10 carbocyclic group ”or“ a heterocyclic group _optionally substituted by 1 to 5 substituents selected from group A ”as defined above, and R ^a6 is as defined above. “C _1-4 alkyl group”, as defined above, “C _{3-10 optionally} substituted with 1 to 5 substituents selected from group A
“Carbocyclic group” or “heterocyclic group optionally substituted by 1 to 5 substituents selected from group A” as defined above.
-OR ^a4 , -SR ^a4 , -NR ^a4 R ^a5 , -CONR ^a4 R ^a5 , -SO ₂ NR ^a4 R ^a5 , -COR ^a6 , -NR ^a4 COR ^a6 , -SO ₂ R ^a6 , -NR ^a4 SO ₂ R Specific examples of ^a6 , —COOR ^a4 and —NR ^a5 COOR ^a6 include “—OR ^a1 ”, “—SR ^a1 ”, “—NR ^a1 R ^a2 ”, “—CONR ^a1 R ^a2 ” of “Group A”, respectively. , “—SO ₂ NR ^a1 R ^a2 ”, “—COR ^a3 ”, “—NR ^a1 COR ^a3 ”, “—SO ₂ R ^a3 ”, “—NR ^a1 SO ₂ R ^a3 ”, “—COOR ^a1 ” and “ And the substituents mentioned in the definition of “—NR ^a2 COOR ^a3 ”.

Specific examples of the “C _1-10 alkyl group _optionally substituted by 1 to 3 substituents selected from a halogen atom and group B” include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, Isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, 1-methylbutyl group, 1-ethylpropyl group, 2-ethylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl Group, tert-pentyl group, hexyl group, isohexyl group, 1-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 1-ethylbutyl group, 1- Ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethyl Propyl group, 1-ethyl-1-methylpropyl group, heptyl group, isoheptyl group, 1-methylhexyl group, 1,1-dimethylpentyl group, 1,2-dimethylpentyl group, 1,3-dimethylpentyl group, 1 , 4-dimethylpentyl group, 1,1,2-trimethylbutyl group, 1,1,3-trimethylbutyl group, 1,2,2-trimethylbutyl group, 1,2,3-trimethylbutyl group, 1,3 , 3-trimethylbutyl group, 1-ethylpentyl group, 1-ethyl-2-methylbutyl group, 1-ethyl-3-methylbutyl group, 2-ethyl-1-methylbutyl group, 1-propylbutyl group, 1-ethyl- 2,2-dimethylpropyl group, 1-isopropyl-2-methylpropyl group, 1-isopropyl-1-methylpropyl group, 1,1-diethylpropyl group, 1,1,2 2-tetramethylpropyl group, 1-isopropylbutyl group, 1-ethyl-1-methylbutyl group, fluoromethyl group, trifluoromethyl group, chloroethyl group, 2-fluoroethyl group, 2-chloroethyl group, 3-fluoropropyl group 2-chloropropyl group, 2,2,2-trifluoroethyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, 2-hydroxy-1-methylethyl group, 2-hydroxy-1,1-dimethylethyl Group, 1- (hydroxymethyl) propyl group, 3-hydroxypropyl group, 2-hydroxybutyl group, 4-hydroxybutyl group, 2-hydroxypentyl group, 5-hydroxypentyl group, 2,3-dihydroxypropyl group, 2 , 3-dihydroxybutyl group, 2-hydroxy-1- (hydroxymethyl) ethyl group, 2-hydroxy-2-methylpropyl group, 1- (hydroxymethyl) butyl group, 1- (hydroxymethyl) -2-methylpropyl group, 1- (hydroxymethyl) -2,2-dimethylpropyl group, 1- ( Hydroxymethyl) -2-methylbutyl group, 2-hydroxy-1-phenylethyl group, 2-hydroxy-2-phenylethyl group, 1- (hydroxymethyl) -2-phenylethyl group, 3-methyl-1- (hydroxy Methyl) butyl group, 2-ethyl-1- (hydroxymethyl) butyl group, 3-hydroxy-1-methylpropyl group, 1,1-dimethyl-3-hydroxypropyl group, 1,2-dimethyl-3-hydroxypropyl Group, 1-isopropyl-3-hydroxypropyl group, 2,2-dimethyl-1- (2-hydroxyethyl) propyl group, 1 Ethyl-3-hydroxypropyl group, 2-hydroxy-1-isopropylpropyl group, 1-ethyl-1- (hydroxymethyl) propyl group, 1,1-dimethyl-2-hydroxypropyl group, 1,2-dimethyl-2 -Hydroxypropyl group, 1-ethyl-2-hydroxypropyl group, 4-hydroxy-1-methylbutyl group, 2-ethyl-1- (hydroxymethyl) -2-methylbutyl group, 3,3-dimethyl-1- (hydroxy) Methyl) butyl group, 1- (hydroxymethyl) pentyl group, 4-methyl-1- (hydroxymethyl) pentyl group, methoxymethyl group, 2-methoxyethyl group, methylsulfanylmethyl group, 2- (methylsulfanyl) ethyl group , 2-aminoethyl group, 2
-(Dimethylamino) ethyl group, carboxymethyl group, 2-carboxyethyl group, 2-carboxypropyl group, 3-carboxypropyl group, carbamoylmethyl group, 2-carbamoylethyl group, methylaminocarbonylmethyl group, dimethylaminocarbonylmethyl Group, 2- (phenylaminocarbonyl) ethyl group, 2-oxopropyl group, methylsulfonylmethyl group, 2- (methylsulfonyl) ethyl group, sulfamoylmethyl group, methylaminosulfonylmethyl group, dimethylaminosulfonylmethyl group, tert-butylaminosulfonylmethyl group, 2- (acetylamino) ethyl group, 2- (methylsulfonylamino) ethyl group, 2- (ethoxycarbonylamino) ethyl group, benzyl group, phenethyl group, 3-phenylpropyl group, 4 -F Nylbutyl group, 2-biphenylmethyl group, 3,4-dichlorobenzyl group, 2-hydroxy-2-phenylethyl group, cyclopentylmethyl group, cyclohexylmethyl group, 2-cyclohexylethyl group, 1-cyclohexyl-2-hydroxyethyl group 1-cyclohexylmethyl-2-hydroxyethyl group, phenylaminocarbonylmethyl group, 2-pyridin-2-ylethyl group, 2-imidazol-1-ylethyl group, 2-benzothiophen-2-ylethyl group, 2-morpholinoethyl Group, 2- (4-methylthiazolin-5-yl) ethyl group, 1-carboxyethyl group, 1-carbamoylethyl group, 1-carboxy-2-methylpropyl group, 1-carbamoyl-2-methylpropyl group, 2 -Hydroxy-1- (hydroxymethyl) propyl 1- (hydroxymethyl) -2-mercaptoethyl group, 1- (hydroxymethyl) -3- (methylsulfanyl) propyl group, 2-carboxy-1- (hydroxymethyl) ethyl group, 2-carbamoyl-1- ( Hydroxymethyl) ethyl group, 2- (indol-3-yl) -1- (hydroxymethyl) ethyl group, 2- (imidazol-4-yl) -1- (hydroxymethyl) ethyl group, 2- (4-hydroxy) A phenyl) -1- (hydroxymethyl) ethyl group, a 3-carbamoyl-1- (hydroxymethyl) propyl group, and a 5-amino-1- (hydroxymethyl) pentyl group.
R ¹ is preferably methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-hydroxyethyl. Group, 2-hydroxypropyl group, 3-hydroxypropyl group, 4-hydroxybutyl group, 5-hydroxypentyl group, 2,3-dihydroxypropyl group, 2-hydroxy-1-methylethyl group, 2-hydroxy-1, 1-dimethylethyl group, 2-hydroxy-1- (hydroxymethyl) ethyl group, 1- (hydroxymethyl) propyl group, 2-hydroxy-2-methylpropyl group, 1- (hydroxymethyl) butyl group, 1- ( Hydroxymethyl) -2-methylpropyl group, 1- (hydroxymethyl) -2,2-dimethylpropyl group, -(Hydroxymethyl) -2-methylbutyl group, 1- (hydroxymethyl) -3-methylbutyl group, 2-hydroxy-1-phenylethyl group, 2-hydroxy-2-phenylethyl group, 1- (hydroxymethyl)- 2-phenylethyl group, 2-methoxyethyl group, methylsulfanylmethyl group, 2- (methylsulfanyl) ethyl group, 2-aminoethyl group, 2- (dimethylamino) ethyl group, carboxymethyl group, 2-carboxyethyl group 3-carboxypropyl group, carbamoylmethyl group, 2-carbamoylethyl group, methylaminocarbonylmethyl group, dimethylaminocarbonylmethyl group, 2- (phenylaminocarbonyl) ethyl group, 2-oxopropyl group, methylsulfonylmethyl group, 2- (methylsulfonyl) ethyl group, sulf Amoylmethyl group, methylaminosulfonylmethyl group, dimethylaminosulfonylmethyl group, tert-butylaminosulfonylmethyl group, 2- (acetylamino) ethyl group, 2- (methylsulfonylamino) ethyl group, 2- (ethoxycarbonylamino) ethyl Group, benzyl group, phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 2-biphenylmethyl group, 3,4-dichlorobenzyl group, cyclopentylmethyl group, cyclohexylmethyl group, 1-cyclohexyl-2-hydroxyethyl Group, 1-cyclohexylmethyl-2-hydroxyethyl group, 2-pyridin-2-ylethyl group, 2-imidazol-1-ylethyl group, 2-morpholinoethyl group, 2- (4-methylthiazolin-5-yl) ethyl Group, benzothiophene-2 It is an ylmethyl group, particularly preferably an alkyl group branched at the 1-position and / or an alkyl group substituted with a hydroxy group, specifically, a 2-hydroxy-1-methylethyl group, 1- (hydroxy Methyl) -2-methylpropyl group, 1- (hydroxymethyl) -2,2-dimethylpropyl group, 1- (hydroxymethyl) -2-methylbutyl group, 2-hydroxy-1- (hydroxymethyl) ethyl group and 2 -Phenyl-1- (hydroxymethyl) ethyl group is mentioned. When these particularly preferable substituents are optically active substances, S-isomers are more preferable.
R ³² and R ³³ are preferably a methyl group, an ethyl group and a trifluoromethyl group, and R ^a7 and R ^a8 are preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a 2-hydroxyethyl group, 3 -A hydroxypropyl group and a cyclohexylmethyl group, more preferably a methyl group, an ethyl group and an isopropyl group, and particularly preferably a methyl group.

In the general formula [I], the ring Cy is preferably a “C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from the group A” as defined above, and more preferably

(Wherein R ⁴ , R ⁵ , R ⁶ and m are as defined above), and a more preferred embodiment is the same as in the case of the 4-oxoquinoline compound represented by the general formula [II]. Thus, m is preferably 0 or 1, and more preferably 0.
The group A in the ring Cy is preferably a cyano group, phenyl group, nitro group, “halogen atom” as defined above, “C _1-4 alkyl group” as defined above, or “halo C _1-4 alkyl group” as defined above. , “Halo C _1-4 alkyloxy group” defined above, “—OR ^a1 ” defined above, “—SR ^a1 ” defined above, “—NR ^a1 R ^a2 ” defined above, “—CONR” defined above. ^a1 R ^a2 ”,“ —SO ₂ NR ^a1 R ^a2 ”defined above,“ —NR ^a1 COR ^a3 ”defined above,“ —SO ₂ R ^a3 ”defined above, and“ —NR ^a1 SO ₂ R defined above ”. ^a3 ",
More preferably, cyano group, phenyl group, nitro group, “halogen atom”, “C _1-4 alkyl group”, “halo C _1-4 alkyl group”, “halo C _1-4 alkyloxy group”, “—OR” ^a1 ”,“ —SR ^a1 ”,“ —NR ^a1 R ^a2 ”,“ —SO ₂ R ^a3 ”,“ —SO ₂ NR ^a1 R ^a2 ”and“ —NR ^a1 COR ^a3 ”, particularly preferably the above-mentioned definition. Is a “halogen atom”.
Here, the ring Cy is more preferably

(Wherein R ^{6 ′} , R ^{6 ″} and R ^{6 ′ ″} are a hydrogen atom and a substituent selected from “Group A” as defined above, and R ⁴ and R ⁵ are as defined above.) It is.
R ⁴ is preferably a phenyl group, “halogen atom” as defined above, “C _1-4 alkyl group” as defined above, “halo C _1-4 alkyloxy group” as defined above, “—OR ^a1 ” as defined above. , “—NR ^a1 R ^a2 ” defined above, “—SO ₂ NR ^a1 R ^a2 ” defined above, “—NR ^a1 COR ^a3 ” defined above, “—SO ₂ R ^a3 ” defined above, “—COOR ^a1 ” and “—NR ^a1 SO ₂ R ^a3 ” as defined above,
More preferred are “halogen atom”, “C _1-4 alkyl group”, “halo C _1-4 alkyloxy group”, “—OR ^a1 ” and “—NR ^a1 R ^a2 ”, particularly preferably as defined above. A “halogen atom”,
R ⁵ is preferably a hydrogen atom, cyano group, nitro group, “halogen atom” as defined above, “C _1-4 alkyl group” as defined above, “halo C _1-4 alkyl group” as defined above, or as defined above. “—OR ^a1 ”, the above definition “—SR ^a1 ”, the above definition “—NR ^a1 R ^a2 ”, the above definition “—CONR ^a1 R ^a2 ”, the above definition “—SO ₂ NR ^a1 R ^a2 ”. And “—NR ^a1 COR ^a3 ” as defined above,
More preferred are a hydrogen atom, “halogen atom” and “C _1-4 alkyl group”, and particularly preferred is a “halogen atom”.
R ⁶ is preferably “halogen atom”, “C _1-4 alkyl group” defined above, “—SO ₂ R ^a3 ” defined above, “—OR ^a1 ” defined above, and “—SR ^a1 ” defined above. And more preferably “halogen atom”.
R ^{6 ′} and R ^{6 ′ ″} are preferably the same or different and each represents a hydrogen atom or the above-defined “halogen atom”, and R ^{6 ″} is preferably a hydrogen atom or the above-defined “halogen atom”. , “C _1-4 alkyl group” as defined above, “—SO ₂ R ^a3 ” as defined above, “—OR ^a1 ” as defined above and “—SR ^a1 ” as defined above, more preferably a hydrogen atom , “Halogen atom”, “C _1-4 alkyl group” as defined above and “—SR ^a1 ” as defined above, more preferably a hydrogen atom.

R ¹ is preferably “C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A” as defined above, or “1 to 5 groups selected from group A” as defined above. A heterocyclic group which may be substituted by a substituent of the above, “—OR ^a4 ” as defined above (specifically, preferably a methoxy group), “—NR ^a4 R ^a5 ” as defined above ( Here, specifically preferred are an amino group, a methylamino group, an ethylamino group and a dimethylamino group.), “—NR ^a4 COR ^a6 ” (specifically preferred here is acetylamino). A group such as “—NR ^a4 SO ₂ R ^a6 ” (specifically, preferably a methylsulfonylamino group and an N-methyl-N- (methylsulfonyl) amino group), "-NR ^a5 COOR" defined above ^a6 "(here, specifically preferably a methoxycarbonylamino group.), and good C _1-10 optionally substituted by 1 to 3 substituents selected from" a halogen atom and group B defined above An “alkyl group”, and more preferably “C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A” and “halogen atom and group B” as defined above. A C _1-10 alkyl group which may be substituted by 1 to 3 substituents, more preferably “1 to 3 substituents selected from halogen atom and group B” as defined above. A good C _1-10 alkyl group.
R ² is preferably a hydrogen atom.
R ³¹ is preferably a hydrogen atom, a cyano group, a “halogen atom” as defined above, a hydroxy group, and a “C _1-4 alkoxy group” as defined above, more preferably a hydrogen atom, a cyano group, A “halogen atom” and the “C _1-4 alkoxy group” defined above, more preferably a hydrogen atom, a cyano group, and a “C _1-4 alkoxy group” defined above, particularly preferably a hydrogen atom. is there.
R ³² is preferably a hydrogen atom, a cyano group, a “halogen atom” as defined above, a “heterocyclic group optionally substituted by 1 to 5 substituents selected from group A” as defined above, “C _1-10 alkyl group _optionally substituted by 1 to 3 substituents selected from a halogen atom and group B”, “—OR ^a7 ” as defined above, “—SR ^a7 ” as defined above, and as defined above “—NR ^a7 R ^a8 ”, “—COOR ^a10 ” as defined above and “—N═CH—NR ^a10 R ^a11 ” as defined above, more preferably a hydrogen atom, “—OR ^a7 ” as defined above. , “—SR ^a7 ” as defined above or “—NR ^a7 R ^a8 ” as defined above, more preferably a hydrogen atom or “—OR ^a7 ” as defined above, particularly preferably “—OR ^a7 ”. It is.
R ³³ is preferably a hydrogen atom, the above-defined “C _1-10 alkyl group _optionally substituted by 1 to 3 substituents selected from a halogen atom and group B”, or “—OR ^a7 ” as defined above. And “—NR ^a7 R ^a8 ” as defined above, more preferably a hydrogen atom, “—OR ^a7 ” as defined above, or “—NR ^a7 R ^a8 ” as defined above, and more preferably a hydrogen atom or “—OR ^a7 ” as defined above, particularly preferably a hydrogen atom.
One of R ³² and R ³³ is preferably a hydrogen atom and the other is “-OR ^a7 ” as defined above.
It is preferable that R ³¹ is a hydrogen atom and R ³² or R ³³ is other than a hydrogen atom.

  The “pharmaceutically acceptable salt thereof” may be any salt that forms a non-toxic salt with the compounds represented by the above general formulas [I] and [II], such as hydrochloric acid, sulfuric acid, phosphorus Acids, inorganic acids such as hydrobromic acid; or oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, Organic acids such as benzyl sulfonic acid; or inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide; or methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris (hydroxy Methyl), organic bases such as methylamine, guanidine, choline, cinchonine; or lysine, arginine, It can be obtained by reacting with amino acids such alanine. In the present invention, a hydrate or hydrate or solvate of each compound is also included.

  In the compounds represented by the above general formulas [I] and [II], various isomers exist. For example, E isomer and Z isomer exist as geometric isomers, and when an asymmetric carbon atom exists, enantiomers and diastereomers as stereoisomers based on these exist, tautomers Can exist. Accordingly, the scope of the present invention includes all these isomers and mixtures thereof. In the compound of the present invention, those isolated and purified from various isomers, by-products, metabolites, and prodrugs are preferred, those having a purity of 90% or more are preferred, and those having a purity of 95% or more are more preferred.

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 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. 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-diokyl-4-yl) methyl group and the like.

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, 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. .
The dose 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 the form of injections.

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.
Therefore, in the 4-oxoquinoline compound of the present invention, one of preferred embodiments is one that has high absorbability by oral administration, and one that maintains the blood concentration of the administered compound for a long time. It is done.

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

"Other anti-HIV agents" and "other anti-HIV active substances" used in multi-drug combination therapy include anti-HIV antibodies, HIV vaccines, immune enhancers such as interferons, HIV ribozymes, HIV antisense drugs, reverse transcription Examples thereof include enzyme inhibitors, protease inhibitors, virus binding host cell recognition receptors (CD4, CXCR4, CCR5, etc.) and virus 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) (Delavirdine mesylate), Combivir (R) (Zidovudine + Lamivudine), Trizivir (R) (abacavir sulfate + lamivudine + zidovudine), Coactinon (R) (emivirin), Phosphovir (R), Coviracyl (R), alovudine (3'-fluoro-3'-deoxythymidine), Thiovir (Thiovir) Formic acid), couplerabilin (5-[(3,5-dichloro Enyl) thio] -4-isopropyl-1- (4-pyridylmethyl) imidazole-2-methanolcarbamic acid), Tenofovir disoproxil fumarate ((R)-[[2- (6-amino-9H-purine-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- (cyclopropylethynyl) -3,4-dihydro-4- (Trifluoromethyl) -2 (1H) -quinazolinone), DAPD ((−)-β-D-2,6-diaminopurinedioxolane), Immunocal, MSK-055, MSA- 54, MSH-143, NV-01, TMC-120, DPC-817, GS-7340, TMC-125, SPD-754, D-A4FC, capraviline, UC-781, emtricitabine, alovudine, Phosphazid, UC-781 BCH-10618, DPC-083, Etravirine, BCH-13520, MIV-210, Abavir sulfate / lamivudine, GS-7340, GW-5634, GW-695634 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 mozenavirdylylate ([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-oxo-6-phenylethyl-6-propyl-2H-pyran-3-yl] propi ] -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-methylthiopropanoyl] 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) -in Nyl) -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-dihydroxyperhydro-1,3-diazepin-2-one), DMP-851 , RO-0334649, Nar-DG-35, R-944, VX-385, TMC-114, Tipranavir, Fosamprenavir sodium, Fosamprenavir calcium, Darunavir, GW-0385, R-0349, RO-0359, RO-0318 Etc.

Further, as HIV integrase inhibitors, S-1360, L-870810 and the like, DNA polymerase inhibitors or DNA synthesis inhibitors 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 (viscum alumm extract), Rubiteca n, etc., as HIV antisense drugs, HGTV-43, GEM-92, etc., as anti-HIV antibodies or other antibodies, NM-01, PRO-367, KD-247, Cytolin®, TNX-355 (CD4 antibody ), AGT-1, PRO-140 (CCR5 antibody), Anti-CTLA-4MAb, and other HIV vaccines or other vaccines such as ALVAC (R), AIDSVAX (R), Remune (R), HIV gp41 vaccine, HIV gp120 Vaccine, HIV gp140 vaccine, HIV gp160 vaccine, HIV p17 vaccine, HIV p24 vaccine, HIV p55 vaccine, AlphaVaxVector System, canarypox gp160 vaccine, AntiTat, MVA-F6 Nef vaccine , HIV rev vaccine, C4-V3 peptide, p2249f, VIR-201, HGP-30W, TBC-3B, PARTILE-3B, etc., Antiferon (interferon-α vaccine) etc., interferon or interferon agonist as Sumiferon (R), MultiFeron (R), interferon-τ, reticulose, human leukocyte interferon α, etc., SCH-351125 as a CCR5 antagonist, as an agent acting on HIVp24, GPG-NH2 (glycyl-prolyl-glycinamide), etc. as an HIV fusion inhibitor, FP-21399 (1,4-bis [3-[(2,4-dichlorophenyl) carbonylamino] -2-oxo-5,8-disodiumsulfonyl] naphthyl-2,5-dimeth Xylphenyl-1,4-dihydrazone), T-1249, Synthetic Polymeric Construction No3, pentafuside, FP-21399, PRO-542, Enfuvirtide, etc., IL-2 agonist or antagonist, interleukin-2, Imnes (R), Proleukin R), Multikine (R), Ontak (R), etc., as TNF-α antagonists, Thalomid (R) (thalidomide), Remicade (R) (infliximab), sulfated curdlan, etc., Bucast as α-glucosidase inhibitors (R) et al., Purdecine (2-amino-4-oxo-3H, 5H-7-[(3-pyridyl) methyl] pyrrolo [3,2-d] pyrimidine) as a purine nucleoside phosphorylase inhibitor 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), etc. As a cholinesterase inhibitor, Cognex (R), etc. As immunomodulators, Immunox (R), Prokine (R), Met-enkephalin (6-de-L-arginine-7-de-L-arginine-8-de -L-valineamide-adrenorphine), WF-10 (10-fold diluted solution of tetrachlorodecaoxide), Perthon, PRO-542, SCH-D, UK-427857, AMD-070, AK-602 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, Motexafin gadoolinium, GEM-92, CNI-1493, (±) -FTC, Ushercell, D2S, BufferGel ( R), VivaGel (R), Glyminox Vaginal gel, sodium lauryl sulfate, 2F5, 2F5 / 2G12, VRX-496, Ad5gag2, BG-777, IGIV-C, BILR-255 and the like.

The “other anti-HIV agent” and “other anti-HIV active substance” used in the multi-drug combination therapy with the compound of the present invention are 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, tenofovir, emtricitabine, indinavir, nelfinavir, atazanavir, ritonavir + indinavir, ritonavir + lopinavir, ritonavir + saquinavir, didanosine + lamivudine, zidovudine + didanodudine, stavudududine, stavudududine + A combination of the group consisting of lamivudine and emtriva and the 4-oxoquinoline compound [I] of the present invention (Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. August 13,2001). Particularly preferably, efavirenz, indinavir, nelfinavir, tenofovir, emtricitabine, zidovudine, lamivudine in combination with two drugs, and zidovudine + lamivudine, tenofovir + lamivudine, tenofovir + zidovudine, tenofovir + fenofovirnovirvirofenvir , Tenofovir + Emtricitabine, Emtricitabine + Lamivudine, Emtricitabine + Zidovudine, Emtricitabine + Efavirenz, Emtricitabine + Nelfinavir, Emtricitabine + Indinavir, Nelfinavir + Lamivudine, Nelfinavir + Ziflendinavirinabine + Zidovudine, a triple combination in combination with efavirenz + indinavir.

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 a post-process. 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 as necessary by crystallization, recrystallization, distillation, liquid separation, silica gel chromatography, preparative HPLC, etc. These commonly used methods may be appropriately selected and combined.

Manufacturing method 1-1

(Wherein, Hal is a halogen atom such as chlorine atom and bromine atom, Hal ¹ is a halogen atom such as a bromine atom and an iodine atom, 1 to R ^1A is selected from the "halogen atom and group B defined above A C _1-10 alkyl group _optionally substituted by three substituents. ”R ^2A is a“ C _1-4 alkyl group ”as defined above, wherein a methyl group and an ethyl group are preferred, and the compound [ 6], each R ^2A may be different, but is preferably the same (R ³ ) _n is a substituent of any one of R ³¹ , R ³² , and R ^{33 and is} the same or And n is an integer from 1 to 3, wherein the substituent R ³ is not substituted at both of the * positions at the same time (other symbols are as described above).

First Step After reacting zinc dust with 1,2-dibromoethane in a solvent under heating in a stream of argon or nitrogen, trimethylsilyl chloride is added and reacted. Next, the compound [2] can be obtained by reacting the compound [1] solution added to the reaction solution.
Preferred examples of the solvent include ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran (THF); hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
Second Step Compound [2] is cooled or heated in a solvent in the presence of a catalyst, optionally in the presence of a ligand such as triphenylphosphine or tri (2-furyl) phosphine, in an argon or nitrogen stream. The compound [4] can be obtained by reacting with the compound [3].
Catalysts include bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (benzonitrile) palladium, dichloroethylenediaminepalladium, palladium acetate, tetrakis (triphenylphosphine) palladium And palladium catalyst, nickel catalyst and the like.
Preferred examples of the solvent include ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran (THF); hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
Step 3 Compound [4] is reduced neutral or alkaline with zinc or iron; iron and acid; tin or tin (II) chloride and concentrated hydrochloric acid; alkali sulfide; alkaline hydrosulfite, etc., contact in hydrogen atmosphere Compound [5] can be obtained by reduction by a conventional method such as reduction.
For example, compound [5] can be obtained by adding acetic acid and zinc powder to compound [4] under cooling and reacting at room temperature. Alternatively, compound [5] can be obtained by adding palladium-carbon to a solution of compound [4] in a mixed solvent of THF and methanol in a hydrogen atmosphere and reacting at room temperature.

Step 4 Compound [5] is reacted with compound [6] under heating in a solvent.
Solvents include alcohol solvents such as methanol, ethanol, n-propanol, and isopropanol; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane. Solvents: Ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, or a mixed solvent thereof.
Then, after distilling off the solvent, the residue can be reacted under heating in a solvent such as diphenyl ether, a mixture of diphenyl ether and diphenyl, such as Dowtherm A (trade name, Fluka), to obtain compound [7]. .
Step 5 Compound [I-1] can be obtained by reacting compound [7] with compound [8] in the presence of a base in a solvent.
Examples of the base include potassium carbonate, sodium carbonate, lithium hydride, sodium hydride, potassium hydride and the like, preferably potassium carbonate.
As the solvent, hydrocarbon solvents such as benzene, toluene, hexane, xylene; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran; dimethylformamide, dimethyl sulfoxide, acetonitrile, etc. A polar solvent or a mixed solvent thereof may be mentioned.
Step 6 Compound [I-1] is hydrolyzed in a solvent at room temperature or under heating under basic conditions such as sodium hydroxide, potassium hydroxide, lithium hydroxide, or acidic conditions such as hydrochloric acid or sulfuric acid. Thus, compound [I-2] can be obtained.
Examples of the solvent include alcohol solvents such as methanol, ethanol, n-propanol, and isopropanol; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; halogen solvents such as dichloromethane, carbon tetrachloride, and 1,2-dichloroethane; Examples include ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran; polar solvents such as dimethylformamide, dimethyl sulfoxide, and acetonitrile; water or a mixed solvent thereof.

  Instead of compound [3]

Compound [I] can be obtained by performing the same reaction as in Production Method 1-1 using compound [20] represented by formula (1).

Production Method 1-2 Production Example Using Compound [9] Introduced with Hydroxyl Protecting Group

(Wherein, r is an integer of 1 to 6, R ^P1 is a hydroxyl-protecting group, and other symbols are as described above.)

Step 1 Compound [10] can be obtained by reacting compound [7] obtained in the same manner as in Production Method 1-1 with compound [9] in the same manner as in Step 5 of Production Method 1-1.
Second Step Compound [I-3] can be obtained by deprotecting compound [10] by a conventional method.
Examples of the hydroxyl protecting group include an acetyl group, a methyloxycarbonyl group, a methoxymethyl group, a methoxyethoxymethyl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, and a tert-butyldiphenylsilyl group.
For example, when R ^P1 is an acetyl group or a methyloxycarbonyl group, it can be deprotected by reacting under heating in the presence of a base such as sodium hydroxide or potassium hydroxide. A treatment such as heating by adding concentrated hydrochloric acid or heating in concentrated ammonia may be performed.
For example, when R ^P1 is a tert-butyldimethylsilyl group, treatment with tetrabutylammonium fluoride in THF at room temperature, or heat treatment in the presence of sodium hydroxide in THF, or room temperature Deprotection may be performed using a method such as treatment with acetic acid-water-THF under heating. In this step, R ^P1 deprotection and R ^2A hydrolysis can be divided into two stages.

Manufacturing method 2-1

(Wherein, Hal ² is a halogen atom, preferably a fluorine atom or a chlorine atom, R ^C3 and R ^C4 are the same or different and each is a lower alkyl group such as a methyl group, an ethyl group, R ^1B Are defined above as “C _1-10 alkyl group _optionally substituted by 1 to 3 substituents selected from halogen atom and group B”, as defined above, “1 to 5 substituents selected from group A” A C _3-10 carbocyclic group which may be substituted with a group ", a" heterocyclic group which may be substituted with 1 to 5 substituents selected from group A "as defined above or" -OR ^{a4 as} defined above. " The other symbols are as described above, and the substituent R ³ is not substituted at the * position.)

First Step Here, Hal ¹ is preferably bromine or iodine, and compound [12] can be obtained by a conventional halogenation.
For example, the compound [11] is allowed to react with a halogenating agent such as N-bromosuccinimide and N-iodosuccinimide in a solvent such as trifluoromethanesulfonic acid, acetic acid, concentrated sulfuric acid, and DMF at room temperature to heating. 12] can be obtained.
Second Step Compound [12] is converted into hydrocarbon, such as toluene, xylene; halogen-based solvent, such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane; oxalyl chloride under heating in a solvent, such as ethyl acetate, An acid halide is obtained by a conventional method such as adding a halogenating agent such as thionyl chloride and reacting.
Here, for example, when thionyl chloride is used as the halogenating agent, a catalytic amount of DMF may be added.
Then, compound [13] is added and reacted in the presence of a base such as triethylamine, diisopropylethylamine, potassium carbonate, pyridine and the like in a solvent at room temperature to heating, and then reacted with compound [14] at room temperature to heating. To obtain compound [15].
Solvents include hydrocarbon solvents such as benzene, toluene, hexane, xylene; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane; 1,4-dioxane, diethyl ether, 1,2- Examples include ether solvents such as dimethoxyethane and tetrahydrofuran; polar solvents such as acetonitrile; ethyl acetate or a mixed solvent thereof.
Third Step Compound [15] is reacted in a solvent in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium hydride, potassium hydride and the like. To obtain compound [16].
Further, as one of preferred production methods, compound [15] is reacted in a solvent in the presence of 1,8-diazacyclo [5.4.0] -7-undecene at room temperature to warming to give compound [16 ] Can also be obtained.
Solvents include hydrocarbon solvents such as benzene, toluene, hexane, and xylene; halogen solvents such as dichloromethane, carbon tetrachloride, and 1,2-dichloroethane; 1,4-dioxane, diethyl ether, and 1,2-dimethoxyethane. And ether solvents such as tetrahydrofuran; polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, and mixed solvents thereof.
Step 4 Compound [I-4] can be obtained by reacting compound [16] with compound [2] in the same manner as in Production Method 1-1, Step 2.
Step 5 Compound [I-5] can be obtained by hydrolyzing compound [I-4] in the same manner as in Production Method 1-1, Step 6.

Production Method 2-2 A production example including a step of introducing / deprotecting a hydroxyl-protecting group.

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

First Step By reacting Compound [12] obtained in the same manner as in Step 1 of Production Method 2-1, with Compound [13] and Compound [17] in the same manner as in Step 2 of Production Method 2-1. Compound [18] can be obtained.
Step 2 Compound [19] can be obtained by introducing a protecting group into the hydroxyl group of compound [18] by a conventional method and then cyclizing in the same manner as in Step 3 of Production Method 2-1.
Alternatively, compound [18] can be obtained by cyclization of compound [18] in the same manner as in production method 2-1, followed by introducing a protecting group to the hydroxyl group by a conventional method.
For example, when R ^P1 is a tert-butyldimethylsilyl group, the compound [18] may be reacted with imidazole and tert-butyldimethylsilyl chloride in DMF or toluene solvent at room temperature.
Further, when R ^P1 is a methoxycarbonyl group, the compound [18] may be reacted with pyridine and methyl chlorocarbonate in a chloroform solvent at cooling to room temperature.
In place of the compound [17], a similar production method can be used for NH ₂ —R ^{1A ′} (wherein R ^{1A ′} is a C _1-10 alkyl group which may be substituted with at least one hydroxyl group). Can be used.
Third Step Compound [I-6] can be obtained by reacting compound [19] with compound [2] in the same manner as in production method 1-1, second step.
Fourth Step Compound [I-7] can be obtained by hydrolyzing Compound [I-6] in the same manner as in Step 2 of Production Method 1-2. In this step, R ^P1 deprotection and R ^2A hydrolysis can be divided into two stages.

Manufacturing method 3

(In the formula, R ^{a7 ′} is a C _1-10 alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom and group B, and the other symbols are as described above.)
The fluorine atom on 4-oxoquinoline can be converted to —OR ^a7 , —SR ^a7 , —NR ^a7 R ^a8 by reaction with conventional nucleophiles. They can also be further converted into —NR ^a7 COR ^a9 and ^—N═CH —NR ^a10 R ^a11 by a conventional method.
This production method is suitable for introducing a substituent at the 7-position on 4-oxoquinoline.

Production method 3-1
Compound [I-8] can be obtained by introducing an alkoxy group into compound [21] by a conventional method.
For example, the compound [I-8] can be obtained by reacting with a metal alkoxide under heating in an alcohol solvent such as methanol, ethanol, propanol, or butanol, followed by hydrolysis.
A solvent and a metal alkoxide corresponding to a desired alkoxy group may be selected. In the case of a methoxy group, sodium methoxide or potassium methoxide in a methanol solvent, and in the case of an ethoxy group, sodium ethoxide or potassium ethoxide in an ethanol solvent. Can be reacted.

Manufacturing method 3-2
Compound [I-9] can be obtained by amination of compound [21] by a conventional method.
For example, compound [I-9] can be obtained by reacting with an amine under heating in an inert organic solvent such as THF, dioxane, chloroform, dichloromethane, methanol, ethanol, pyridine and the like.
In addition, compound [I-9] can also be obtained by reacting with an amine in DMF by microwave irradiation.

Manufacturing method 4
The example of a manufacturing method of intermediate compound [12] is given.

(In the formula, each symbol is as described above.)
Step 1 Compound [23] can be obtained by introducing a protecting group into the carboxylic acid of Compound [22] by a conventional method.
For example, in the case of esterification, the compound is reacted with an alkylating agent such as methyl iodide in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydride or potassium hydride in a solvent such as DMF, THF or toluene. [23] can be obtained.
Second Step Compound [24] can be obtained by reducing compound [23] in the same manner as in Production Method 1-1, third step.
Third Step Compound [25] can be obtained by halogenating compound [24] in the same manner as in Production Method 2-1, Step 1.
Step 4 Compound [25] is cooled to room temperature in water or an inert organic solvent such as THF, dioxane, ethyl acetate, chloroform, dichloromethane, methanol, ethanol, pyridine, sodium nitrite and hydrochloric acid or sulfuric acid. The compound [26] can then be obtained by diazotization with, followed by halogenation with cuprous halide such as copper chloride and concentrated hydrochloric acid under cooling or heating. Here, Hal ² is preferably a chlorine atom.
Step 5 Compound [27] can be obtained by deprotecting the hydroxyl group of compound [26] by a conventional method.
For example, when R ^P1 is a methyl group, compound [27] can be obtained by reacting with boron tribromide in dichloromethane under cooling.
Step 6 Compound [28] can be obtained by reacting compound [27] with compound [8] in the presence of a base in a solvent.
Examples of compound [8] include alkylating agents such as ethyl iodide.
Examples of the base include potassium carbonate, sodium carbonate, lithium hydride, sodium hydride, potassium hydride and the like, preferably potassium carbonate.
Solvents include alcohol solvents such as methanol, ethanol, n-propanol, and isopropanol; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane. Solvents; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran; polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile; water or a mixed solvent thereof.
Seventh Step Compound [12 ′] can be obtained by hydrolyzing compound [28] in the same manner as in Production Method 1-1, Step 6.
Step 8 When ^RP1 is the desired substituent in compound [26], compound [12 ′] can be obtained in the same manner as in Step 7.

Manufacturing method 5

(In the formula, each symbol is as described above.)
First Step Compound [30] can be obtained by halogenating compound [29] in the same manner as in Production Method 2-1, Step 1.
Second Step Compound [31] can be obtained by reacting Compound [30] with Compound [13] and Compound [17] in the same manner as in Step 2 of Production Method 2-1.
Third Step Compound [32] can be obtained by reacting Compound [31] in the same manner as in Step 3 of Production Method 2-1.
Fourth Step Compound [33] can be obtained by reacting Compound [32] in the same manner as in Step 2 of Production Method 2-2.
Step 5 Compound [I-10] can be obtained by reacting compound [33] with compound [2] in the same manner as in Production Method 1-1, Step 2.
Sixth Step Compound [I-11] can be obtained by hydrolyzing compound [I-10] in the same manner as in the second step of production method 1-2.
Step 7 Compound [I-12] can be obtained by introducing an alkoxy group of compound [I-11] in the same manner as in Production Method 3-1.

  Next, the 4-oxoquinoline 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.

Reference Example 1 Preparation of THF solution of 2,3-dichlorobenzylzinc chloride

  Under a stream of argon, 1,2-dibromoethane (1,2-Dibromoethane; 2.9 ml, 33.8 mmol) was added to a suspension of zinc powder (55.1 g, 843 mmol) in tetrahydrofuran (THF; 56 ml) and heated to reflux for 5 minutes. . Subsequently, trimethylsilyl chloride (8.6 ml, 67.5 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 5 minutes. Then, 2,3-dichlorobenzyl chloride (82.4 g, 421.7 mmol) was added. A THF (330 ml) solution was added dropwise under ice cooling. After completion of the addition, the solution was raised to room temperature and stirred for 1 hour to obtain a THF solution of 2,3-dichlorobenzylzinc chloride (2,3-dichlorobenzylzincChloride).

Example 1-1 Synthesis of 6- (2,3-dichlorobenzyl) -1,4-dihydro-1- (2-hydroxyethyl) -4-oxo-3-quinolinecarboxylic acid First step 1,2-dichloro Synthesis of -3- (4-nitrobenzyl) benzene

Under an argon stream, bis (dibenzylideneacetone) palladium (0) (Bis (dibenzylideneacetone) Palladium (0), 3.2 g, 5.6 mmol), tri (2-furyl) phosphine, 2.6 g, 11.2 mmol) was dissolved in THF (310 ml), and the THF reaction solution of 2,3-dichlorobenzylzinc chloride (421.7 mmol) obtained in Reference Example 1 was added dropwise through a cannula under ice cooling, followed by 4-iodonitrobenzene. A solution of (4-Iodonitrobenzene; 70.0 g, 281 mmol) in THF (700 ml) was added dropwise. After stirring at room temperature for 2 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the solid precipitated in the middle was collected by filtration. The filtrate was concentrated again under reduced pressure, and the solid precipitated in the middle was collected by filtration. The collected solids were combined, washed with n-hexane and dried under reduced pressure to obtain the desired product (60.2 g, yield 76%) as a light brown solid.
¹ H NMR (CDCl ₃ 400MHz) (δ) ppm: 4.24 (2H, s), 7.09 (1H, d, J = 7.7Hz), 7.18 (1H, dd,
J = 7.8Hz, 7.9Hz), 7.32 (2H, d, J = 8.9Hz), 7.40 (1H, d, J = 8.0Hz), 8.15 (2H, d, J = 8.7Hz)
MS (ESI): M-280

Step 2 Synthesis of 4- (2,3-dichlorobenzyl) phenylamine

1,2-Dichloro-3- (4-nitrobenzyl) benzene obtained in the first step (25.0 g,
88.6 mmol) was dissolved in acetic acid (400 ml), zinc powder (70 g, 1.1 mol) was added in portions at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through celite and washed with ethanol. The filtrate was concentrated under reduced pressure, and the precipitated solid was collected by filtration. The solid collected by filtration was washed with diethyl ether, dissolved in ethyl acetate (500 ml) and water (500 ml), and 4N aqueous sodium hydroxide solution was added to neutralize the aqueous layer. The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the solid deposited in the middle was collected by filtration. The solid collected by filtration was washed with n-hexane and dried under reduced pressure to obtain the desired product (18.1 g, yield 81%) as a light brown solid.
¹ H NMR (CDCl ₃ 400MHz) (δ) ppm: 3.52 (2H, brs), 4.01 (2H, s), 6.63 (2H, d, J = 8.2Hz), 6.97 (2H, d, J = 8.1Hz) , 7.02 (1H, d, J = 7.6Hz), 7.09 (1H, dd, J = 7.8Hz, 7.8Hz), 7.31 (1H, d, J = 7.8Hz)
MS (ESI): M + 252

Step 3 Synthesis of 6- (2,3-dichlorobenzyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester

4- (2,3-Dichlorobenzyl) phenylamine (10.0 g, 39.7 mmol) obtained in the second step is dissolved in toluene (100 ml), and ethoxymethylene malonate diethyl ester (DiethylEthoxymethylenemalonate, 8.8 ml, 43.7 mmol). And heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and diphenyl ether (DiphenylEther, 100 ml) was added to the residue for dissolution, and the mixture was heated with stirring at 250 ° C. for 3 hours. After allowing to cool, n-hexane was added to the reaction solution, and the precipitated solid was collected by filtration, washed with chloroform and then dried under reduced pressure to obtain the desired product (10.1 g, yield 68%) as a pale yellow solid.
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.27 (3H, t, J = 7.1Hz), 4.20 (2H, q, J = 7.1Hz), 4.27 (2H, s), 7.34-7.41 ( 2H, m), 7.55-7.57 (3H, m), 7.90 (1H, s), 8.49 (1H, d, J = 6.
6Hz), 12.26 (1H, brs)
MS (ESI): M + 376

Step 4 Synthesis of 1- (2-acetoxyethyl) -6- (2,3-dichlorobenzyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester

6- (2,3-Dichlorobenzyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (400 mg, 1.1 mmol) obtained in the third step was added to dimethylformamide (DMF; 8 ml). The mixture was suspended, 2-bromoethyl acetate (2-BromoethylAcetate; 152 μl, 1.4 mmol) and potassium carbonate (440 mg, 3.2 mmol) were added, and the mixture was heated and stirred at 80 ° C. On the way, 2-bromoethyl acetate (152 μl, 1.4 mmol) was added twice, and the mixture was heated and stirred at 80 ° C. for a total of 1.5 hours. After allowing to cool, saturated aqueous ammonium chloride was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure to obtain the desired product (468 mg, yield 95%) as a white solid.
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.25 (3H, t, J = 9.3Hz), 1.88 (3H, s), 4.20 (2H, q, J = 9.3Hz), 4.27 (2H, s), 4.33-4.41 (2H, m), 4.59-4.62 (2H, m), 7.32-7.41 (3H, m), 7.54 (1H, dd, J = 2.9Hz, 10.2Hz), 7.64 (1H, dd , J = 2.4Hz, 11.2Hz), 7.81 (1H, d, J = 11.7Hz), 7.88 (1H, d, J = 2.4Hz), 8.57 (1H, s)

Step 5 Synthesis of 6- (2,3-dichlorobenzyl) -1,4-dihydro-1- (2-hydroxyethyl) -4-oxo-3-quinolinecarboxylic acid

1- (2-acetoxyethyl) -6- (2,3-dichlorobenzyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester obtained in the fourth step (6.0 g, 13.0 mmol) ) Was suspended in ethanol (480 ml), 4N aqueous sodium hydroxide solution (84 ml, 21 mmol) was added, and the mixture was heated to reflux for 30 minutes. After standing to cool, the reaction mixture was partially concentrated under reduced pressure, hydrochloric acid was added and the precipitated solid was collected by filtration, washed with water and ethanol, and dried under reduced pressure to give the desired product as a white solid (4.5 g, 85% yield). Obtained.
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.75 (2H, t, J = 4.7Hz), 4.36 (2H, s), 4.60 (2H,
t, J = 4.8Hz), 4.98 (1H, brs), 7.37-7.39 (1H, m), 7.45 (1H, dd, J = 1.4, 7.6Hz), 7.57 (1H, dd, J = 1.5,8.0Hz ), 7.81 (1H, dd, J = 2.1, 8.9Hz), 8.02 (1H, d, J = 8.8Hz), 8.15 (1H, d, J = 1.8Hz), 8.86 (1H, s), 15.18 (1H , brs)
MS (ESI): M + 392
mp: 247-249 ℃

Example 1-2 Synthesis of 6- (2,3-dichlorobenzyl) -1,4-dihydro-8-fluoro-1- (2-hydroxyethyl) -4-oxo-3-quinolinecarboxylic acid First step 2 Of 1,3-difluoro-5-iodobenzoic acid

2,3-Difluorobenzoic acid (5.0 g, 31.6 mmol) is dissolved in trifluoromethanesulfonic acid (25 ml), and N-iodosuccinimide (8.55) at 0 ° C. under an argon stream. g, 38.0 mmol) was added in portions. After stirring at room temperature for 3 hours, the reaction solution was poured into an ice water solution of sodium sulfite and stirred. The precipitated solid was collected by filtration, washed with water and then dried under reduced pressure to obtain the desired product (7.5 g, yield 84%) as a pale pink solid.
¹ H NMR (CDCl ₃ 300 MHz) (δ) ppm: 7.74 (1H, m), 8.11 (1H, m)
MS (ESI): M-283

Second Step Synthesis of 2- (2,3-difluoro-5-iodobenzoyl) -3- (2-hydroxyethylamino) acrylic acid ethyl ester

2,3-Difluoro-5-iodobenzoic acid (3.0 g, 10.6 mmol) obtained in the first step was dissolved in toluene, thionyl chloride (3.0 ml, 41.1 mmol) and DMF (catalytic amount) were added, and 3 Heated to reflux for hours. The reaction solution was concentrated under reduced pressure, THF (15 ml) was added to the residue and dissolved, and 3-dimethylaminoacrylic acid ethyl ester (Ethyl3-Dimethylaminoacrylate, 1.66 g, 11.6 mmol) and triethylamine (1.77 ml, 12.7 mmol) in THF ( 10 ml) was added dropwise to the solution and stirred with heating at 50 ° C. for 2.5 hours. After allowing to cool, the reaction mixture was filtered and washed with THF (10 ml). Aminoethanol (Aminoethanol; 0.77 ml, 12.7 mmol) was added to the filtrate, and the mixture was heated and stirred at 40 ° C. for 1 hour. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 2: 1) to give the desired product (3.8 g, yield 85%) as a yellow solid of E, Z mixture. Got.
¹ H NMR (CDCl ₃ 400 MHz) (δ) ppm: 0.91-1.09 (3H, m), 1.80-1.89 (1H, m), 3.52-3.63 (2H, m), 3.83-3.91 (2H, m), 3.98 -4.09 (2H, m), 7.36-7.52 (2H, m), 8.15 (1H, d, J = 14.4Hz), 9.6 (0.22H, brs), 11.0 (0.78H, brs)
MS (ESI): M + 426

Step 3 Synthesis of 2- (2,3-difluoro-5-iodobenzoyl) -3- “2- (tert-butyldimethylsilyloxy) ethylamino] acrylic acid ethyl ester

2- (2,3-Difluoro-5-iodobenzoyl) -3- (2-hydroxyethylamino) acrylic acid ethyl ester (2.0 g, 4.7 mmol) obtained in the second step was dissolved in DMF (10 ml). Imidazole (705 mg, 10.4 mmol) and tert-butyldimethylsilyl chloride (1.49 g, 9.9 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 4) to obtain the desired product (2.3 g, yield 91%) as a white solid.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: 0.07 (6H, s), 0.90 (9H, s), 1.07 (3H, t, J = 7.1Hz),
3.45-3.55 (2H, m), 3.70-3.80 (2H, m), 4.04 (2H, q, J = 7.1Hz), 7.30-7.50 (2H, m), 8.14 (1H, d, J = 14.1Hz) , 10.80-11.10 (1H, m)
MS (ESI): M + 540

Step 4 Synthesis of 1,4-dihydro-8-fluoro-6-iodo-1- [2- (tert-butyldimethylsilyloxy) ethyl] -4-oxo-3-quinolinecarboxylic acid ethyl ester

2- (2,3-Difluoro-5-iodobenzoyl) -3- [2- (tert-butyldimethylsilyloxy) ethylamino] acrylic acid ethyl ester (2.3 g, 4.3 mmol) obtained in the third step was used. It melt | dissolved in THF (25 ml), Sodium hydride (256 mg, 6.4 mmol) was added under ice-cooling, and it stirred at 0 degreeC for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid (6.4 ml, 6.4 mmol), water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 2 to ethyl acetate: hexane = 2: 1) to give the desired product (2.0 g, yield) as a white solid. 92%).
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: -0.12 (6H, s), 0.79 (9H, s), 1.38 (3H, t, J = 7.1Hz), 3.90-4.00 (2H, m), 4.37 (2H, q, J = 7.1Hz), 4.40-4.50 (2H, m), 7.69 (1H, dd, J = 2.0Hz, 13.7Hz), 8.40 (1H, s), 8.69 (1H, d, J = 2.0Hz)
MS (ESI): M + 520

Step 5 6- (2,3-Dichlorobenzyl) -1,4-dihydro-8-fluoro-1- [2- (tert-butyldimethylsilyloxy) ethyl] -4-oxo-3-quinolinecarboxylate Synthesis of esters

Under a stream of argon, a 1M THF solution (2.9 ml, 2.9 mmol) of 2,3-dichlorobenzylzinc chloride obtained in the same manner as in Reference Example 1 was added to THF (20 ml), followed by bis (dibenzylideneacetone) palladium ( 0) (22 mg, 0.039 mmol), tri (2-furyl) phosphine (18 mg, 0.077 mmol) and 1,4-dihydro-8-fluoro-6-iodo-1- [2- (2- () obtained in the fourth step) tert-Butyldimethylsilyloxy) ethyl] -4-oxo-3-quinolinecarboxylic acid ethyl ester (1.0 g, 1.9 mmol) was added, and the mixture was stirred at room temperature for 17 hours. Further, 2,3-dichlorobenzylzinc chloride in THF solution (1.0 ml, 1.0 mmol) was added, and the mixture was heated to reflux for 1 hour. After allowing to cool, a saturated aqueous ammonium chloride solution was added to the reaction solution, and insoluble materials were filtered through Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was roughly purified by silica gel chromatography (ethyl acetate: hexane = 1: 1), followed by purification by PTLC (ethyl acetate: chloroform = 1: 2). A yellow oily target product (562 mg, 53% yield) was obtained.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: -0.13 (6H, s), 0.79 (9H, s), 1.38 (3H, t, J = 7.1Hz), 3.90-4.00 (2H, m), 4.23 (2H, s), 4.37 (2H, q, J = 7.1Hz), 4.40-4.50 (2H, m), 7.10-7.50 (4H, m), 8.20-8.30 (1H, m), 8.39 (1H, s )
MS (ESI): M + 552

Step 6 Synthesis of 6- (2,3-dichlorobenzyl) -1,4-dihydro-8-fluoro-1- (2-hydroxyethyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester

6- (2,3-Dichlorobenzyl) -1,4-dihydro-8-fluoro-1- [2- (tert-butyldimethylsilyloxy) ethyl] -4-oxo-3 obtained in the fifth step
-Quinolinecarboxylic acid ethyl ester (350 mg, 0.63 mmol) dissolved in THF (25 ml), tetrabutylammonium fluoride (1M THF solution);
1.9 ml, 1.9 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the desired product (279 mg, quantitative yield) as a pale yellow solid.
¹ H NMR (DMSO-d ₆ 300MHz) (δ) ppm: 1.27 (3H, t, J = 7.1Hz), 3.65-3.80 (2H, m), 4.21 (2H, q, J = 7.1Hz), 4.40- 4.50 (2H, m), 4.99 (1H, m), 7.30-7.90 (5H, m), 8.47 (1H, s) MS (ESI): M + 438

Step 7 Synthesis of 6- (2,3-dichlorobenzyl) -1,4-dihydro-8-fluoro-1- (2-hydroxyethyl) -4-oxo-3-quinolinecarboxylic acid

6- (2,3-Dichlorobenzyl) -1,4-dihydro-8-fluoro-1- (2-hydroxyethyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester obtained in the sixth step (80 mg , 0.18 mmol) was dissolved in a mixed solvent of ethanol (2 ml) and THF (1 ml), 1N aqueous sodium hydroxide solution (1 ml, 1.0 mmol) was added, and the mixture was heated with stirring at 60 ° C. for 1 hour. After allowing to cool, 10% aqueous citric acid solution was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with 30% ethanol water, and dried under reduced pressure to give the desired product (70 mg, 93% yield) as a white solid. Got.
¹ H NMR (DMSO-d ₆ 300MHz) (δ) ppm: 3.78 (2H, m), 4.35 (2H, s), 4.64 (2H, m), 5.00
(1H, m), 7.39 (2H, m), 7.47 (1H, m), 7.58 (1H, m), 8.00 (1H, m), 8.81 (1H, s), 14.80 (1H, s)
MS (ESI): M + 409

Example 3-38
1st process

2-Chloro-3-nitrobenzoic acid (6.00 g, 29.77 mmol) was dissolved in trifluoromethanesulfonic acid (40 ml), and N-iodosuccinimide (7.37 g, 32.76 mmol) was added in portions at 0 ° C. After stirring at 40 ° C. for 4 hours, the reaction solution was added to ice water and stirred, and then the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure. The obtained solid was dissolved in methanol (50 ml), concentrated sulfuric acid (catalytic amount) was added, and the mixture was heated to reflux for 5.5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 4) to give the object product (5.35 g, yield 53%) as a pale yellow solid.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: 3.98 (3H, s), 8.11 (1H, d, J = 2.1Hz), 8.24 (1H, d, J = 2.1Hz)
Second step

The compound obtained in the first step (5.35 g, 15.67 mmol) was dissolved in methanol (25 ml), 4N aqueous potassium hydroxide solution (10.00 ml, 4.00 mmol) was added, and the mixture was heated to reflux for 30 minutes. After allowing to cool, 1N hydrochloric acid was added to the reaction mixture, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the desired product (4.99 g, yield 97%) as a white solid.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: 8.14 (1H, d, J = 2.0Hz), 8.39 (1H, d, J = 2.1Hz)
3rd process

The compound obtained in the second step (4.99 g, 15.24 mmol) was dissolved in toluene (50 ml), thionyl chloride (5.00 ml, 68.54 mmol) and dimethylformamide (catalytic amount) were added, and the mixture was heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and a solution obtained by adding tetrahydrofuran (80 ml) to the residue was dissolved in tetrahydrofuran (50 ml) of ethyl 3,3-dimethylaminoacrylate (2.29 g, 16.00 mmol) and triethylamine (2.55 ml, 18.30 mmol). The solution was added dropwise to the solution, and stirred at 50 ° C. for 10 hours. After allowing to cool, aminoethanol (1.10 ml, 18.23 mmol) was added to the reaction mixture, and the mixture was stirred with heating at 40 ° C. for 1.5 hr. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 2: 1) to give a yellow solid target product (5.35 g, yield) mixed with E form and Z form. Rate 75%).
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: 0.82-1.01 (3H, m), 3.63 (2H, br), 3.85-4.06 (4H, m), 7.65-7.68 (1H, m), 8.02-8.06 (1H, m), 8.21-8.36 (1H, m), 9.78 (0.16H, br), 11.15 (0.84H, br)
4th process

The compound obtained in the third step (5.35 g, 11.42 mmol) was dissolved in dimethylformamide (50 ml), imidazole (1.71 g, 25.12 mmol) and tert-butyldimethylsilyl chloride (3.62 g, 24.02 mmol) were added, and room temperature was added. For 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product (7.10 g) as a pale yellow solid.
5th process

The crude product (7.10 g) obtained in the fourth step was dissolved in tetrahydrofuran (70 ml), sodium hydride (731 mg, 18.27 mmol) was added under ice cooling, and the mixture was stirred at 0 ° C. for 45 min. 1N Hydrochloric acid (18.3 ml) and water were added to the reaction mixture, and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate: hexane = 1: 4 to 1: 2) to obtain the desired product (5.58 g, yield 84%) as a yellow solid.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: -0.14 (6H, s), 0.73 (9H, s), 1.39 (3H, t, J = 7.1Hz), 3.74 (2H, t, J = 4.6Hz ), 4.02 (2H, t, J = 4.6Hz), 4.39 (2H, q, J = 7.1Hz), 8.13 (1H, d, J = 2.2Hz), 8.50 (1H, s), 9.02 (1H, d , J = 2.2Hz)
Step 6

The compound obtained in the fifth step (5.00 g, 9.15 mmol) was dissolved in tetrahydrofuran (100 ml), and bis (dibenzylideneacetone) palladium (0) (105 mg, 0.18 mmol) and tri (2-furyl) were added under an argon stream. Phosphine (85 mg, 0.37 mmol) was added, and a solution of 3-chloro-2-fluorobenzylzinc bromide (11.90 mmol) in tetrahydrofuran prepared as in Step 4 of Example 4-32 was added dropwise at 60 ° C. Heated to reflux for 4 hours. After allowing to cool, a saturated aqueous ammonium chloride solution was added to the reaction solution, and insoluble materials were filtered through Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and then saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 2 to 1: 1) to give the desired product (2.67 g, yield 52%) as a brown oil. Obtained.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: -0.19 (6H, s), 0.70 (9H, s), 1.39 (3H, t, J = 7.1Hz),
3.73 (2H, t, J = 4.6Hz), 4.03 (2H, t, J = 4.6Hz), 4.14 (2H, s), 4.38 (2H, q, J = 7.1Hz), 7.02-7.14 (2H, m ), 7.29-7.35 (1H, m), 7.73 (1H, d, J = 2.2Hz), 8.50 (1H, s), 8.59 (1H, s)
7th step

The compound obtained in the sixth step (1.00 g, 1.79 mmol) was dissolved in acetic acid (20 ml), zinc dust (1.16 g, 17.76 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate), sonicated with diethyl ether, filtered, and dried under reduced pressure to obtain the desired product (730 mg) as a pale orange solid. Yield 77%).
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: -0.06 (6H, s), 0.77 (9H, s), 1.41 (3H, t, J = 7.1Hz), 4.01 (2H, s), 4.08 (2H , t, J = 4.7Hz), 4.39 (2H, q, J = 7.1Hz), 4.50 (2H, brs), 4.75 (2H, t, J = 4.7Hz), 6.81 (1H, s), 6.94-7.08 (2H, m), 7.20-7.26 (1H, m), 7.91 (1H, s), 8.34 (1H, s)
8th step

The compound obtained in the seventh step (100 mg, 0.19 mmol) was dissolved in dimethylformamide (2 ml), methyl iodide (0.029 ml, 0.47 mmol) and sodium hydride (23 mg, 0.56 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Stir. A 10% aqueous citric acid solution was added to the reaction mixture and stirred, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and subjected to silica gel chromatography (ethyl acetate: hexane = 2: 1) to obtain a crude purified product (45 mg) as a pale red solid.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: -0.33-0.29 (6H, m), 0.64-0.69 (9H, m), 1.23-1.41 (3H, m), 2.66-2.70 (6H, m) , 3.55-3.59 (2H, m), 4.36-4.4.2 (4H, m), 4.82-4.96 (2H,
m), 6.96-7.11 (2H, m), 7.23-7.30 (2H, m), 8.16-8.15 (1H, m), 8.40-8.66 (1H, m)
9th step

The crude product (45 mg) obtained in the eighth step was dissolved in tetrahydrofuran (1 ml), 1M THF solution (1.00 ml, 1.00 mmol) of tetrabutylammonium fluoride was added, and the mixture was stirred at room temperature for 5 minutes. Ethanol (1 ml) and 1N aqueous sodium hydroxide solution (1 ml, 1.00 mmol) were added to the reaction solution, and the mixture was heated to reflux for 2 hours. After allowing to cool, 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was stirred and extracted twice with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and subjected to silica gel chromatography (chloroform: methanol: acetic acid = 10: 1: 0.1) to obtain a crude product. Ethanol water was added to the crude product, and sonication was performed. After filtration and drying under reduced pressure, the desired product (22 mg, 27% yield) was obtained as a beige solid.
¹ H NMR (DMSO-d ₆ 300 MHz) (δ) ppm: 2.67 (6H, s), 3.39 (2H, m), 4.21 (2H, s), 4.72 (1H, t), 4.97 (2H, t), 7.20-7.22 (1H, m), 7.40-7.50 (2H, m), 7.65 (1H, s), 7.84 (1H, s), 15.10 (1H, s)
MS (ESI): M + 419

Example 3-62
1st process

2,4-Difluoro-5-iodobenzoic acid (3.00 g, 10.60 mmol) obtained in the first step of Example 4-33 described below was dissolved in toluene (10 ml), and thionyl chloride (3.00 ml, 41.10 mmol) was dissolved. And dimethylformamide (catalytic amount) were added, and the mixture was heated to reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and a solution obtained by adding tetrahydrofuran (15 ml) to the residue was dissolved in tetrahydrofuran (10 ml) of ethyl 3,3-dimethylaminoacrylate (1.66 g, 11.60 mmol) and triethylamine (1.77 ml, 12.70 mmol). The solution was added dropwise to the solution, and the mixture was heated and stirred at 50 ° C for 2.5 hours. After allowing to cool, the reaction mixture was filtered and washed with tetrahydrofuran (10 ml). Aminoethanol (0.77 ml, 12.76 mmol) was added to the filtrate, and the mixture was stirred with heating at 40 ° C. for 1 hr. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 2: 1) to give a yellow solid crude product (3.00 g, 3.00 g, Yield 67%) was obtained.
Second step

The compound obtained in the first step (3.00 g, 7.06 mmol) is dissolved in dimethylformamide (15 ml), imidazole (1.06 g, 15.52 mmol) and tert-butyldimethylsilyl chloride (2.23 g, 14.82 mmol) are added, and room temperature is added. For 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 4) to obtain the desired product (3.22 g, yield 85%) as a white solid.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: 0.06 (6H, s), 0.90 (9H, s), 1.08 (3H, t, J = 7.1Hz),
3.51 (2H, br), 3.79 (2H, t, J = 4.9Hz), 4.05 (2H, q, J = 7.1Hz), 6.78 (1H, dd, J = 7.9,
9.4Hz), 7.71 (1H, dd, J = 7.3, 7.3Hz), 8.11 (1H, d, J = 14.0Hz), 10.91 (1H, br)
3rd process

The compound obtained in the second step (3.22 g, 5.97 mmol) was dissolved in tetrahydrofuran (35 ml), sodium hydride (358 mg, 8.95 mmol) was added under ice cooling, and the mixture was stirred at 0 ° C. for 2.5 hours. 1N Hydrochloric acid (8.90 ml, 8.90 mmol) and water (35 ml) were added to the reaction mixture and stirred. The precipitated solid was collected by filtration and purified by silica gel chromatography (ethyl acetate: hexane = 1: 2 to 2: 1). As a result, a light yellow solid target product (2.52 g, yield 81%) was obtained.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: -0.11 (6H, s), 0.79 (9H, s), 1.39 (3H, t, J = 7.1Hz),
3.96 (2H, t, J = 4.8Hz), 4.23 (2H, t, J = 4.8Hz), 4.38 (2H, q, J = 7.1Hz), 7.14 (1H, d, J = 9.3Hz), 8.47 ( 1H, s), 8.93 (1H, d, J = 7.2Hz)
4th process

The compound obtained in the third step (1.00 g, 1.93 mmol) was dissolved in tetrahydrofuran (20 ml), and bis (dibenzylideneacetone) palladium (0) (22 mg, 0.039 mmol) and tri (2-furyl) were added under an argon stream. Phosphine (18 mg, 0.077 mmol) was added, and a solution of 3-chloro-2-fluorobenzylzinc bromide (2.89 mmol) in tetrahydrofuran prepared as described above was added dropwise at 60 ° C. After completion of the addition, the mixture was heated to reflux for 1 hour. After allowing to cool, a saturated aqueous ammonium chloride solution was added to the reaction solution, and insoluble materials were filtered through Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and then saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 2: 1) to obtain the desired product (573 mg, yield 55%) as a pale yellow solid.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: -0.12 (6H, s), 0.78 (9H, s), 1.38 (3H, t, J = 7.1Hz),
3.99 (2H, t), 4.13 (2H, s), 4.23 (2H, t), 4.37 (2H, q, J = 7.1Hz), 6.96-7.13 (3H, m), 7.25-7.31 (1H, m) , 8.39 (1H, d), 8.46 (1H, s)
5th process

The compound obtained in the fourth step (170 mg, 0.32 mmol) was dissolved in tetrahydrofuran (1 ml), 2N aqueous sodium hydroxide solution (4.00 ml, 2.00 mmol) was added, and the mixture was heated to reflux for 3.5 hours. After allowing to cool, 10% citric acid aqueous solution was added to the reaction solution, and the precipitated solid was collected by filtration, washed with 50% ethanol water, and then dried under reduced pressure to give the desired product as a white solid (117 mg, yield 94%) Got.
¹ H NMR (DMSO-d ₆ 300 MHz) (δ) ppm: 3.73 (2H, br), 4.25 (2H, s), 4.58 (2H, br), 4.96 (1H, br), 7.19-7.22 (1H, m ), 7.30-7.36 (1H, m), 7.49-7.54 (1H, m), 8.03 (1H, d), 8.30 (1H, d), 8.88 (1H, s), 15.42 (1H, brs)
Step 6

The compound obtained in the fifth step (65 mg, 0.17 mmol) was dissolved in dimethyl sulfoxide (2.5 ml), and microwave irradiation was performed at 50 W for 20 minutes at 120 ° C. or lower. After allowing to cool, a 10% aqueous citric acid solution was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the desired product (66 mg, yield 96%) as a pale yellow solid. It was.
¹ H NMR (DMSO-d ₆ 300 MHz) (δ) ppm: 2.88 (6H, s), 3.70-3.80 (2H, m), 4.22 (2H, s), 4.60-4.70 (2H, m), 5.05 (1H , t), 7.20-7.31 (3H, m), 7.50-7.60 (1H, m), 7.80 (1H, s), 8.78 (1H, s), 15.30-15.40 (1H, brs)
MS (ESI): M + 419

Example 3-73
1st process

2,4-Difluoro-5-iodobenzoic acid (5.00 g, 17.60 mol) is dissolved in toluene (25 ml), oxalyl chloride (2.00 ml, 22.93 mmol) and dimethylformamide (catalytic amount) are added, and 12 hours at room temperature. Stir. The reaction mixture was filtered, concentrated under reduced pressure, toluene (20 ml) was added, and the insoluble material was filtered through celite. The filtrate was concentrated under reduced pressure, and tetrahydrofuran (20 ml) was added to the resulting residue to dissolve the resulting solution. Ethyl 3,3-dimethylaminoacrylate (3.28 g, 22.91 mmol) and triethylamine (3.70 ml, 26.55 mmol) in tetrahydrofuran (20 ml) was added dropwise to the solution and heated to reflux for 1 hour. After allowing to cool, water and ethyl acetate (50 ml) were added to the reaction mixture, and the mixture was stirred and separated. The organic layer was washed with 1N hydrochloric acid (20 ml), water (200 ml) and saturated brine in this order, and washed with sodium sulfate. Dried. After filtration, the filtrate was concentrated under reduced pressure to give a brown oily crude product (7.24 g).
Second step

The crude product (7.24 g) obtained in the first step was dissolved in tetrahydrofuran (20 ml), (S) -2-amino-1-butanol (1.89 g, 21.24 mmol) was added, and the mixture was heated and stirred at 60 ° C. for 1.5 hours. did. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dimethylformamide (20 ml), potassium carbonate (7.33 g, 53.02 mmol) was added, and the mixture was stirred with heating at 70 ° C. for 1 hr. After allowing to cool, the reaction mixture was concentrated under reduced pressure, water (150 ml) was added to the residue, and the mixture was stirred at room temperature for 30 min. The precipitated solid was collected by filtration. The obtained solid was washed with water (50 ml), followed by a mixed solvent of hexane: diethyl ether = 7: 3 (50 ml) and dried under reduced pressure to give the desired product (4.69 g, yield 61%) as a white solid. Got.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: 0.97 (3H, t, J = 7.4Hz), 1.40 (3H, t, J = 7.1Hz), 1.95-2.05 (1H, m), 2.11-2.21 ( 1H, m), 4.05 (1H, br), 4.34-4.39 (5H, m), 5.59 (1H, br), 7.30 (1H, d, J = 10.0Hz), 8.04 (1H, d, J = 7.1Hz ), 8.58 (1H, s)
3rd process

The compound obtained in the second step (4.69 g, 10.82 mmol) is dissolved in dimethylformamide (20 ml), imidazole (950 mg, 13.95 mmol) and tert-butyldimethylsilyl chloride (1.95 g, 12.96 mmol) are added, and For 14.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed 3 times with water and then with saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 3: 7) to give the desired product (5.06 g, yield 86%) as a yellow oil.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: -0.08 (3H, s), -0.05 (3H, s), 0.77 (9H, s), 0.98 (3H, t, J = 7.5Hz), 1.40 ( 3H, t, J = 7.2Hz), 1.94-2.10 (2H, m), 3.90 (2H, br), 4.35-4.43 (3H, m), 7.26 (1H, d, J = 9.9Hz), 8.59 (1H , s), 8.95 (1H, d, J = 7.2Hz)
4th process

The compound obtained in the third step (5.06 g, 9.24 mmol) was dissolved in tetrahydrofuran (20 ml), and bis (dibenzylideneacetone) palladium (0) (266 mg, 0.46 mmol) and tri (2-furyl) were added under a stream of argon. Phosphine (215 mg, 0.92 mmol) was added, and a tetrahydrofuran solution of 3-chloro-2-fluorobenzylzinc bromide (18.50 mmol) prepared as described above was added dropwise. After completion of the dropwise addition, the mixture was stirred with heating at 60 ° C. for 1 hour. After allowing to cool, water and ethyl acetate were added to the reaction mixture and the mixture was stirred and separated. The organic layer was washed with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and dried over sodium sulfate. After filtration, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate: hexane = 1: 1 to 2: 1) to give the desired product as a brown oil (3.86 g, yield 74%). Obtained.
¹ H NMR (CDCl ₃ 300 MHz) (δ) ppm: -0.10 (3H, s), -0.06 (3H, s), 0.752 (9H, s), 0.98 (3H,
t, J = 7.4Hz), 1.403H, t, J = 7.1Hz), 1.90-2.12 (2H, m), 3.89 (2H, br), 4.12 (2H, s),
4.35-4.49 (3H, m), 6.97-7.08 (2H, m), 7.22-7.29 (2H, m), 8.40 (1H, d, J = 8.7Hz), 8.58 (1H, s)
5th process

To the compound obtained in the fourth step (3.86 g, 6.85 mmol) was added 28% sodium methoxide methanol solution (40.00 ml, 0.20 mol) and water (2.00 ml, 0.11 mol), and the mixture was heated to reflux for 5.5 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, 6N hydrochloric acid was added to the resulting residue, and the mixture was stirred and extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.The residue obtained was recrystallized from ethanol (200 ml) to give the desired product (2.03 g, yield 68%).
¹ H NMR (DMSO-d ₆ 300MHz) (δ) ppm: 0.87 (3H, t, J = 7.3Hz), 1.80-2.10 (2H, m), 3.70-3.90 (2H, m), 4.02 (3H, s ), 4.11 (2H, s), 5.00-5.19 (2H, m), 7.16-7.24 (2H, m), 7.44-7.48 (2H, m), 8.04 (1H, s), 8.78 (1H, s), 15.44 (1H, s)
MS (ESI): M + 434

Example 3-75
1st process

2-Fluoro-5-iodobenzoic acid (6.60 g, 24.81 mmol) was dissolved in chloroform (70 ml), oxalyl chloride (4.30 ml, 49.29 mmol) and dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 3 hours. . The reaction solution was concentrated under reduced pressure, and a solution obtained by adding chloroform (35 ml) to the residue was dissolved in chloroform (35 ml) of ethyl 3,3-dimethylaminoacrylate (4.26 g, 29.75 mmol) and triethylamine (5.19 ml, 37.24 mmol). The solution was added dropwise to the solution and stirred at room temperature for 15 hours. Water was added to the reaction solution for liquid separation, and the organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the residue obtained by concentration under reduced pressure is purified by silica gel chromatography (ethyl acetate: hexane = 1: 2 to 1: 1) to obtain an orange solid target product in which E form and Z form are mixed (6.40 g, 66% yield) was obtained.
¹ H NMR (CDCl ₃ 400MHz) (δ) ppm: 0.94 (3H, t, J = 7.2Hz), 2.88 (3H, brs), 3.31 (3H, brs), 3.97 (2H, q), 6.78 (1H, dd, J = 8.4, 10.0Hz), 7.65-7.67 (1H, m), 7.78 (1H, s),
7,85 (1H, brs)
MS (ESI): M + 392
Second step

The compound obtained in the first step (300 mg, 0.77 mmol) is dissolved in tetrahydrofuran (1.5 ml), (S)-(+)-tert-leucinol (0.12 ml, 0.92 mmol) is added and heated at 60 ° C. for 1 hour. Stir. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dimethylformamide (1.2 ml), potassium carbonate (318 mg, 2.30 mmol) was added, and the mixture was heated with stirring at 70 ° C. for 5.5 hours. After cooling, 1N hydrochloric acid (5 ml) was added to the reaction mixture, and the mixture was stirred for 30 minutes under ice cooling, and the precipitated solid was collected by filtration. The obtained solid was washed with 30% aqueous ethanol (6 ml), followed by a mixed solvent of hexane: diethyl ether = 2: 1 (5 ml), and then dried under reduced pressure to give the desired product (276 mg, yield) as a pale yellow solid. 81%).
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: 0.98 (9H, s), 1.41 (3H, t, J = 7.0Hz), 4.25-4.41 (4H, m), 4.64-4.70 (1H, m), 5.14 (1H, br), 7.46 (1H, d, J = 9.0Hz), 7.89 (1H, dd, J = 2.2,
9.1Hz), 8.06 (1H, d, J = 2.1Hz), 8.69 (1H, s)
3rd process

The compound obtained in the second step (276 mg, 0.62 mmol) was dissolved in dimethylformamide (1 ml), imidazole (51 mg, 0.75 mmol) and tert-butyldimethylsilyl chloride (122 mg, 0.81 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Stir for minutes. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with water and then saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 3: 5) to give the desired product (314 mg, yield 91%) as a white amorphous product.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: -0.09 (3H, s), -0.01 (3H, s), 0.66 (9H, s), 1.04 (9H, s), 1.41 (3H, t, J = 7.2Hz), 4.10-4.14 (2H, m), 4.40 (2H, q, J = 7.0Hz), 4.58-4.63 (1H, m), 7.39 (1H, d, J = 9.3Hz), 7.89 (1H , dd, J = 2.2, 8.8Hz), 8.67 (1H, s), 8.87 (1H, d, J = 2.1Hz)
4th process

The compound obtained in the third step (314 mg, 0.56 mmol) was dissolved in tetrahydrofuran (1.2 ml), and bis (dibenzylideneacetone) palladium (0) (16 mg, 0.028 mmol) and tri (2-furyl) were added under an argon stream. Phosphine (13 mg, 0.056 mmol) was added, and a solution of 3-chloro-2-fluorobenzylzinc bromide (1.13 mmol) in tetrahydrofuran prepared as described above was added dropwise. After completion of the addition, the mixture was stirred with heating at 50 ° C. for 1.5 hours. After allowing to cool, water and ethyl acetate were added to the reaction mixture and stirred, and the insoluble material was filtered through Celite. The filtrate was separated, and the organic layer was washed with water and then saturated brine and dried over sodium sulfate. After filtration, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate: hexane = 1: 1) to obtain a brown amorphous target product (283 mg, yield 87%).
¹ H NMR (CDCl ₃ 400MHz) (δ) ppm: -0.11 (3H, s), -0.01 (3H, s), 0.63 (9H, s), 1.06 (9H, s), 1.41 (3H, t, J = 7.0Hz), 4.08-4.16 (4H, m), 4.38 (2H, q, J = 7.0Hz), 4.61-4.67 (1H, m), 6.95-7.08 (2H, m), 7.23-7.27 (1H, m), 7.47-7.49 (1H, m), 7.53-7.55 (1H, m), 8.41 (1H, d, J = 2.0Hz), 8.68 (1H, s)
5th process

The compound obtained in the fourth step (283 mg, 0.49 mmol) was dissolved in ethanol (2 ml), 1N aqueous sodium hydroxide solution (1.00 ml, 1.00 mmol) was added, and the mixture was heated to reflux for 1 hour. After allowing to cool, acetic acid (0.35 ml) was added to the reaction mixture and stirred, and the precipitated solid was collected by filtration. The resulting solid was suspended in diethyl ether (10 ml). Filtration and drying under reduced pressure gave the desired product (157 mg, yield 74%) as a white solid.
¹ H NMR (DMSO-d ₆ 400 MHz) (δ) ppm: 1.00 (9H, s), 4.07-4.12 (2H, m), 4.30 (2H, s), 5.12-5.14 (2H, m), 7.20-7.25 (1H, m), 7.40-7.45 (1H, m), 7.51-7.53 (1H, m), 7.87 (1H, d), 8.25 (1H, s), 8.41 (1H, d, J = 9.2Hz), 8.85 (1H, s), 15.20-15.21 (1H, br)
MS (ESI): M + 432

Example 4-20
1st process

2-Chloro-4-hydroxybenzoic acid (5.18 g, 30.02 mmol) was dissolved in trifluoromethanesulfonic acid (25 g), and N-iodosuccinimide (6.75 g, 30.00 mmol) was added in portions at 0 ° C. After stirring at room temperature for 15 hours, trifluoromethanesulfonic acid (25 g) was further added, and N-iodosuccinimide (2.02 g, 8.98 mmol) was added in portions at 0 ° C. After stirring at room temperature for 13.5 hours, the reaction solution was added to ice water (300 ml) and stirred for 2 hours. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to obtain a mixture of 2-chloro-4-hydroxy-5-iodobenzoic acid and 2-chloro-3,5-diiodo-4-hydroxybenzoic acid (8: 2) (5.76 g) was obtained.
Second step

The mixture obtained in the first step (3.89 g) was dissolved in dimethylformamide (20 ml), potassium carbonate (8.97 g, 64.90 mmol) and isopropyl iodide (6.50 ml, 65.15 mmol) were added, and the mixture was heated at 80 ° C. for 2.5 hours. Stir. The reaction mixture was added to 1N hydrochloric acid (100 ml), further toluene (100 ml) was added and stirred, and the insoluble material was filtered through Celite. The filtrate was separated, and the organic layer was washed 3 times with water and dried over sodium sulfate. After filtration, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate: hexane = 1: 9) to obtain the desired product as a mixture (4.08 g).
3rd process

The mixture (4.08 g) obtained in the second step was dissolved in ethanol (20 ml), 1N aqueous sodium hydroxide solution (20.00 ml, 20.00 mmol) was added, and the mixture was heated to reflux for 24 hours. After allowing to cool, 1N hydrochloric acid (30 ml) was added to the reaction mixture and stirred, followed by extraction with ethyl acetate three times. The organic layer was washed with water and saturated brine in that order, and dried over sodium sulfate. After filtration, the desired product was obtained as a mixture (3.40 g) by concentration under reduced pressure.
4th process

The mixture (3.40 g) obtained in the third step was dissolved in toluene (35 ml), thionyl chloride (3.40 ml, 46.61 mmol) and dimethylformamide (catalytic amount) were added, and the mixture was heated to reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and tetrahydrofuran (25 ml) was added to the residue to dissolve the solution.The resulting solution of ethyl 3,3-dimethylaminoacrylate (4.29 g, 30.00 mmol) and triethylamine (4.17 ml, 30.00 mmol) in tetrahydrofuran (10 ml) The solution was added dropwise and heated to reflux for 14 hours. After allowing to cool, water and ethyl acetate were added to the reaction mixture, and the mixture was stirred and separated. The organic layer was washed with water and saturated brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 1.5 to 1.5: 1) to obtain the desired product as a mixture (2.71 g).
5th process

The mixture (300 mg) obtained in the fourth step was dissolved in tetrahydrofuran (2 ml), (S)-(+)-tert leucinol (0.10 ml, 0.77 mmol) was added, and the mixture was heated to reflux for 20 minutes. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dimethylformamide (4 ml), imidazole (110 mg, 1.61 mmol) and tert-butyldimethylsilyl chloride (214 mg, 1.42 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. Stir for minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 4) to obtain the desired product as a mixture (391 mg).
Step 6

The mixture (391 mg) obtained in the fifth step was dissolved in toluene (5 ml), sodium hydride (29 mg, 0.73 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Dimethylformamide (3 ml), potassium carbonate (100 mg, 0.72 mmol) and ethyl iodide (0.058 ml, 0.73 mmol) were added to the reaction mixture, and the mixture was stirred with heating at 60 ° C. for 30 min. After cooling, the reaction mixture was added to ice water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 4: 5 to 2: 1) to give the desired product (258 mg, yield 19%) as a pale yellowish white solid. Got.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: -0.09 (3H, s), 0.00 (3H, s), 0.67 (9H, s), 1.05 (9H, s), 1.40 (3H, t, J = 7.1Hz), 1.46 (6H, d, J = 6.0Hz), 4.09-4.20 (2H, m), 4.39 (2H, q, J = 7.1Hz), 4.43-4.49 (1H, m), 4.61-4.69 ( 1H, m), 6.87 (1H, s), 8.60 (1H, s), 8.94 (1H, s)
7th step

1,4-Dihydro-1- {2,2-dimethyl-1-[(tert-butyldimethylsilyloxy) methyl] propyl} -6-iodo-7-isopropyloxy-4-oxo- obtained in the sixth step 3-Quinolinecarboxylic acid ethyl ester (258 mg, 0.42 mol) was dissolved in tetrahydrofuran (5 ml), and bis (dibenzylideneacetone) palladium (0) (9.7 mg, 0.017 mmol) and tri (2-furyl) were added under a stream of argon. Phosphine (7.8 mg, 0.034 mmol) was added, and a solution of 3-chloro-2-fluorobenzylzinc bromide (0.63 mmol) in tetrahydrofuran prepared as described above was added dropwise at 60 ° C. After completion of the addition, the mixture was heated to reflux for 1 hour. After allowing to cool, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred and filtered through celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was roughly purified by silica gel chromatography (ethyl acetate: hexane = 1: 1 to 2: 1) to obtain a crude product (216 mg) as a pale yellow oil.
8th step

The crude product (216 mg) obtained in the seventh step was dissolved in a mixed solvent of ethanol (2 ml) and tetrahydrofuran (1 ml), 1N aqueous sodium hydroxide solution (2.00 ml, 2.00 mmol) was added, and the mixture was heated to reflux for 1 hour. After allowing to cool, 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was treated with a mixed solvent of diethyl ether and hexane. After filtration and drying under reduced pressure, the target product (140 mg, yield 68%) was obtained as a white solid.
¹ H NMR (DMSO-d ₆ 300MHz) (δ) ppm: 0.97 (9H, s), 1.18 (3H, d, J = 5.9Hz), 1.26 (3H, d, J = 6.0Hz), 4.04-4.09 ( 4H, m), 5.09-5.13 (3H, m), 7.12-7.21 (2H, m), 7.43-7.51 (2H, m), 8.19 (1H, s), 8.78 (1H, s), 15.46 (1H, s)
MS (ESI): M + 490

Example 4-32
1st process

Dissolve 2,4-difluoro-5-iodobenzoic acid (650.57 g, 2.29 mol) in toluene (1300 ml), add thionyl chloride (184 ml, 2.52 mol) and dimethylformamide (catalytic amount), and continue at 90 ° C for 2 hours. Stir. After cooling, the reaction solution was concentrated under reduced pressure. The residue dissolved in toluene (330 ml) was concentrated under reduced pressure, and this was repeated again. A solution of the residue in toluene (690 ml) was added dropwise to a toluene (690 ml) solution of ethyl 3,3-dimethylaminoacrylate (361.52 g, 2.525 mol) and diisopropylethylamine (480 ml, 2.75 mol) at 90 ° C. The mixture was heated and stirred for 3 hours. After allowing to cool, (S)-(+)-valinol (260.00 g, 2.52 mol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Water (2600 ml) was added to the reaction solution for liquid separation, and the aqueous layer was extracted with toluene (680 ml). The organic layers were combined, washed twice with water (2000 ml), and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a brown oily crude product (1180 g).
Second step

The crude product (1180 g) obtained in the first step was dissolved in dimethylformamide (2500 ml), pulverized potassium carbonate (292.00 g, 1.06 mol) was added, and the mixture was stirred at room temperature for 22 hours. The reaction solution was added to ice water (about 10 L) and stirred for 30 minutes. The precipitated solid was collected by filtration and washed with water (2000 ml). The obtained solid was dried under reduced pressure and then suspended in ethyl acetate (5000 ml). Filtration and drying under reduced pressure gave the desired product (774.63 g, yield 82%) as a pale yellow solid.
¹ H NMR (DMSO-d ₆ 300 MHz) (δ) ppm: 0.72 (3H, d, J = 6.6 Hz), 1.10 (3H, d, J = 6.6 Hz), 1.28 (3H, t, J = 7.0 Hz) , 2.27 (1H, br), 3.77 (1H, br), 3.86 (1H, br), 4.23 (2H, q, J = 7.0Hz), 4.56 (1H, br), 5.12 (1H, t, J = 4.9 Hz), 8.09 (1H, d, J = 11.1Hz), 8.62 (1H, d, J = 7.5Hz), 8.68 (1H, s)
MS (ESI): M + 448
3rd process

The compound obtained in the second step (626.15 g, 1.40 mol) was dissolved in chloroform (1250 ml), and pyridine (433 ml, 5.60 mol) and 4- (dimethylamino) pyridine (17.10 g, 0.14 mol) were added. A chloroform (1250 ml) solution of methyl chloroformate (529.30 g, 5.60 mol) was added dropwise at 10 ° C. or lower, and the mixture was stirred at the same temperature for 30 minutes after the completion of the dropwise addition. The reaction solution was washed with water (1250 ml), 2N hydrochloric acid (1250 ml), water (630 ml) and saturated aqueous sodium hydrogen carbonate (630 ml) in this order, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a brown oily crude product (834.02 g).
4th process

(Preparation of 3-chloro-2-fluorobenzylzinc bromide tetrahydrofuran solution)
Zinc dust (113.02 g, 1.73 mol) was suspended in tetrahydrofuran (350 ml) under an argon stream, and 1,2-dibromoethane (1.207 ml, 14.00 mmol) and trimethylsilyl chloride (8.88 ml, 70.00 mmol) were suspended at 60 ° C. In addition, the mixture was heated and stirred for 30 minutes. A solution of 3-chloro-2-fluorobenzyl bromide (406.73 g, 1.82 mol) in tetrahydrofuran (700 ml) was added dropwise at 60 ° C. The mixture was stirred with heating for 1 hour to obtain a solution of 3-chloro-2-fluorobenzylzinc bromide.
(This process)
The crude product (834.02 g) obtained in the third step was dissolved in tetrahydrofuran (1060 ml), dichlorobis (triphenylphosphine) palladium (II) (19.65 g, 28.00 mmol) was added under a stream of argon, and the odor at 60 ° C. A solution of 3-chloro-2-fluorobenzylzinc chloride (1.82 mol) was added dropwise, and after completion of the addition, the mixture was heated to reflux for 1.5 hours. After allowing to cool, toluene (2120 ml) and 20% aqueous ammonium chloride solution (1410 ml) were added to the reaction mixture, and the mixture was stirred and separated. The organic layer was washed twice with 20% aqueous ammonium chloride (710 ml) and twice with saturated aqueous sodium hydrogen carbonate (710 ml), and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a brown oily crude product (849.34 g).
5th process

The crude product (849.34 g) obtained in the fourth step was dissolved in isopropanol (1100 ml), 4N aqueous sodium hydroxide solution (1050 ml, 4.20 mmol) was added, and the mixture was stirred with heating at 50 ° C. for 1.5 hr. Activated carbon (37 g) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes and filtered through celite. To the filtrate were added 6N hydrochloric acid (740 ml) and ethyl acetate (3650 ml), and the mixture was stirred and separated, and the organic layer was concentrated under reduced pressure. The residue was suspended in isopropanol (1070 ml), stirred at 60 ° C. for 1 hour, allowed to cool, and the solid was collected by filtration. The obtained solid was washed with isopropanol (740 ml) and dried under reduced pressure to obtain the desired product (446.51 g, yield 73%) as a pale yellow solid.
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.71 (3H, d, J = 6.5Hz), 1.13 (3H, d, J = 6.5Hz), 2.36 (1H, br), 3.77 (1H, br), 3.94 (1H, br), 4.25 (2H, s), 4.77 (1H, br), 5.16 (1H, t, J = 2.4Hz), 7.19-7.23 (1H, m), 7.32-7.35 (1H , m), 7.48-7.52 (1H, m), 8.24-8.28 (2H,
m), 9.00 (1H, s), 15.00 (1H, s)
MS (ESI): M + 436
Step 6

The compound obtained in the fifth step (443.59 g, 1.02 mol) is dissolved in methanol (2400 ml), 28% sodium methoxide methanol solution (2077 ml, 10.17 mol) and water (44.30 ml, 2.46 mol) are added, and 17.5 hours. Heated to reflux. Activated carbon (22 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, filtered through celite, and the filtrate was concentrated under reduced pressure. Water (1770 ml) was added to the residue, and the mixture was stirred for 1 hour under ice-cooling, 6N hydrochloric acid (1790 ml) was further added, and the mixture was stirred at room temperature for 2 hours. Thereafter, ethyl acetate (1770 ml) was added and the mixture was separated after stirring. The organic layer was washed twice with 10% brine (890 ml) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and a part of the residue was recrystallized several times (the final recrystallization solvent was methanol-water) to obtain the desired product (28.60 g, yield 67%) as a white solid.
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.72 (3H, d, J = 6.5Hz), 1.16 (3H, d, J = 6.5Hz), 2.30-2.50 (1H, m), 3.70- 3.90 (1H, m), 3.90-4.00 (1H, m), 4.03 (3H, s), 4.12 (2H, s), 4.80-4.90 (1H, m), 5.19 (1H, t, J = 5.2Hz) , 7.19-7.25 (2H, m), 7.46-7.51 (2H, m), 8.04 (1H, s), 8.88 (1H, s), 15.44 (1H, s)
MS (ESI): M + 448

Example 4-33
1st process

2,4-Difluorobenzoic acid (600.00 g, 3.80 mol) was dissolved in concentrated sulfuric acid (2400 ml), and N-iodosuccinimide (854.40 g, 3.60 mol) was added in portions at 5 ° C. or lower. After completion of the addition, the mixture was stirred at the same temperature for 3 hours. The reaction mixture was poured into ice water (about 10 L), then 10% aqueous sodium sulfite solution (40 ml) was added, and the mixture was stirred for 30 min. The precipitate was collected by filtration, suspended in water (about 3 L), and repeatedly filtered until the pH reached 3 or higher. The obtained wet crystal (1677 g) was recrystallized from 50% aqueous ethanol (3000 ml) to obtain the desired product (824.70 g, yield 76%) as a white solid.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: 6.94 (1H, dd, J = 10.3, 10.3Hz), 8.46 (1H, d, J = 7.5Hz)
Second step

The compound obtained in the first step (150.00 g, 0.53 mol) was dissolved in ethyl acetate (750 ml), oxalyl chloride (51.0 ml, 0.581 mol) and dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene (150 ml), concentrated under reduced pressure, and repeated again. The solution obtained by adding tetrahydrofuran (300 ml) to the residue was added dropwise to a tetrahydrofuran (450 ml) solution of ethyl 3,3-dimethylaminoacrylate (83.2 g, 0.581 mol) and triethylamine (96 ml, 0.686 mol) for 15 hours. Heated to reflux. The reaction liquid was filtered after standing_to_cool and the filtrate was concentrate | evaporated under reduced pressure. Ethyl acetate (750 ml) was added to the residue for dissolution, washed with aqueous ammonium chloride (400 ml), saturated aqueous sodium hydrogen carbonate (200 ml) and saturated brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a brown oily crude product (206.50 g).
3rd process

The crude product (206.50 g) obtained in the second step was dissolved in tetrahydrofuran (800 ml), and (S)-(+)-tert-leucinol hydrochloride (81.10 g, 0.53 mol) and triethylamine (74 ml, 0.53 mol) were dissolved. And stirred at room temperature for 50 minutes. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in dimethylformamide (1000 ml), potassium carbonate (146.0 g, 1.06 mol) was added, and the mixture was heated and stirred at 90 ° C. for 3 hours. The reaction solution was added to water (700 ml) under ice cooling, and the precipitated solid was collected by filtration and washed with water. The collected solid was suspended in 30% ethanol water (1000 ml) and collected by filtration. This operation was repeated with a mixture of hexane: ether = 1: 1. After filtration and drying under reduced pressure, the desired product (184.74 g, yield 76%) was obtained as a white solid.
¹ H NMR (DMSO-d ₆ 400 MHz) (δ) ppm: 0.968 (9H, s), 1.27 (3H, t), 3.96-3.98 (2H, m), 4.18-4.27 (2H, m), 4.80 (1H , t, J = 7.0Hz), 5.05 (1H, br), 8.22 (1H, d, J = 11.2Hz), 8.60 (1H, s), 8.61 (1H, d, J = 7.2Hz)
4th process

The compound obtained in the third step (150.00 g, 0.33 mol) is dissolved in dimethylformamide (600 ml), imidazole (28.80 g, 0.42 mol) and tert-butyldimethylsilyl chloride (28.80 g, 0.42 mol) are added, Stir at room temperature for 6 hours. Water (1200 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (800 ml). The organic layer was washed 3 times with water and then with saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 3 to 1: 2) to give a white amorphous target product (164.30 g, yield 88%). Obtained.
¹ H NMR (CDCl ₃ 300 MHz) (δ) ppm: -0.08 (3H, s), 0.00 (3H, s), 0.67 (9H, s), 1.06 (9H, s), 1.41 (3H, t, J = 7.1Hz), 4.05-4.18 (2H, m), 4.36-4.43 (3H, m), 7.32 (1H, d, J = 10.3Hz), 8.65 (1H, s), 8.95 (1H, d, J = 7.4 Hz)
5th process

The compound obtained in the fourth step (75.0 g, 0.13 mol) was dissolved in tetrahydrofuran (580 ml), and bis (dibenzylideneacetone) palladium (0) (2.99 g, 5.20 mmol) and tri (2-furyl) were added under an argon stream. ) Phosphine (2.41 g, 10.38 mmol) was added, and a tetrahydrofuran solution of 3-chloro-2-fluorobenzylzinc bromide (0.17 mol) was added dropwise at 60 ° C., and the mixture was heated to reflux for 2 hours after completion of the addition. After allowing to cool, ethyl acetate (75 ml) and saturated aqueous ammonium chloride solution (38 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min and separated. The organic layer was washed twice with water (75 ml) and then with saturated brine (200 ml), and dried over sodium sulfate. After filtration, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate: hexane = 1: 2 to 1: 1) to obtain the brown amorphous target product (66.80 g, yield 73%). It was.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: -0.10 (3H, s), -0.01 (3H, s), 0.64 (9H, s), 1.06 (9
H, s), 1.40 (3H, t, J = 7.1Hz), 4.04-4.15 (4H, m), 4.35-4.46 (3H, m), 6.95-7.03 (2H, m), 7.24-7.31 (2H, m), 8.38 (1H, d, J = 8.8Hz), 8.66 (1H, s)
Step 6

The compound obtained in the fifth step (2.41 g, 4.07 mmol) was dissolved in methanol (20 ml), 28% sodium methoxide methanol solution (8.4 ml, 40.70 mmol) and water (0.15 ml, 8.14 mmol) were added, 18 Heated to reflux for hours. Water (1.4 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours, filtered through celite, and the filtrate was concentrated under reduced pressure. Water (25 ml) and 2N hydrochloric acid (20 ml) were added to the residue, and the mixture was stirred for 5 minutes and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was sonicated with hexane (20 ml), allowed to stand, and then decanted to remove hexane. This was repeated three times. Diethyl ether (30 ml) was added to the residue, and after sonication, the solid was collected by filtration. The obtained solid was dissolved in ethyl acetate (15 ml) with heating, and hexane (15 ml) was added and recrystallized to obtain the desired product (1.21 g, yield 64%) as a white solid.
¹ H NMR (DMSO-d ₆ 300 MHz) (δ) ppm: 0.99 (9H, s), 3.99-4.11 (7H, m), 5.11-5.20 (2H, m), 7.19-7.25 (2H, m), 7.49 -7.52 (2H, m),
8.03 (1H, s), 8.78 (1H, s), 15.39 (1H, s)
MS (ESI): M + 462

Example 4-37
1st process

3-Methoxy-2-nitrobenzoic acid (20.00 g, 0.10 mol) is dissolved in dimethylformamide (100 ml), potassium carbonate (28.10 g, 0.20 mol) and methyl iodide (7.60 ml, 0.12 mol) are added, and room temperature is added. For 1 hour. The reaction mixture was added to water (300 ml) and stirred. The precipitated solid was collected by filtration, washed with water (200 ml), and then dried under reduced pressure to obtain a white solid crude product (23.90 g).
Second step

The crude product (23.90 g) obtained in the first step was suspended in a mixed solvent of tetrahydrofuran (150 ml) and methanol (50 ml), and 5% palladium-carbon (containing water) (2.30 g) was added. The mixture was stirred for 19.5 hours at room temperature under hydrogen atmosphere. Ethyl acetate (200 ml) was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and water was removed azeotropically with toluene to give a crude product (18.80 g) as a brown oil.
3rd process

The crude product (18.80 g) obtained in the second step was dissolved in dimethylformamide (200 ml), and N-bromosuccinimide (17.98 g, 0.10 mol) was added in portions at 5 ° C. After completion of the addition, the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into water (500 ml) and extracted twice with ethyl acetate (300 ml). The organic layer was washed with water (300 ml), saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (chloroform) to obtain the desired product (25.11 g, yield 95%) as a yellow oil.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: 3.86 (6H, s), 6.02 (2H, brs), 6.90 (1H, s), 7.60 (1H, s)
4th process

The compound obtained in the third step (25.11 g, 96.54 mmol) was suspended in water (50 ml), concentrated hydrochloric acid (25 ml) was added, and an aqueous solution (100 ml) of sodium nitrite (7.33 g, 106.22 mmol) was added at 5 ° C. Was dripped. After completion of dropping, the mixture was stirred at the same temperature for 5 minutes. The reaction solution was added dropwise at room temperature to a solution of cuprous chloride (9.55 g, 96.47 mmol) in concentrated hydrochloric acid (75 ml). After completion of the dropwise addition, the mixture was stirred at room temperature for 13 hours, water (200 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (400 ml). The organic layer was washed with water (400 ml) and saturated brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product (15.18 g, yield 56%) as an orange solid.
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: 3.92 (3H, s), 3.93 (3H, s), 7.16 (1H, d, J = 2.1Hz),
7.49 (1H, d, J = 2.2Hz)
5th process

The compound obtained in the fourth step (74.80 g, 0.27 mol) is dissolved in dichloromethane (300 ml), and 1M boron tribromide / dichloromethane solution (700 ml, 0.70 mol) is added dropwise at 10 ° C. or lower. Stir for 1.5 hours. The reaction solution was added to ice water (1500 ml), and the precipitated solid was collected by filtration. The filtrate was separated, the aqueous layer was extracted with ethyl acetate (200 ml), and the organic layers were combined and concentrated under reduced pressure. The solid collected by filtration and the residue were dissolved in diethyl ether (1000 ml), and extracted with 1N aqueous sodium hydroxide solution (1000 ml). 2N Hydrochloric acid (500 ml) was added to the aqueous layer and the mixture was stirred and extracted with ethyl acetate (800 ml). The mixture was separated, and the organic layer was washed with water and then saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the desired product (63.83 g, yield 95%) as a beige solid. Obtained.
¹ H NMR (DMSO-d ₆ 300 MHz) (δ) ppm: 7.23 (1H, d, J = 2.4 Hz), 7.28 (1H, d, J = 2.4 Hz), 10.99 (1H, s), 13.55 (1H, brs)
Step 6

The compound obtained in the fifth step (63.83 g, 0.25 mol) was dissolved in dimethylformamide (400 ml), potassium carbonate (87.70 g, 0.64 mol) and ethyl iodide (81.20 ml, 1.02 mol) were added, and the mixture was stirred at 50 ° C. The mixture was heated and stirred for 3 hours. Saturated aqueous ammonium chloride (600 ml) and ethyl acetate (400 ml) were added to the reaction solution, and the mixture was separated. The aqueous layer was extracted with ethyl acetate (400 ml), and the organic layers were combined and washed with brine (3 times) and saturated brine. After washing with sodium sulfate, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain the desired product (76.38 g, yield 98%) as a brown solid.
¹ H NMR (CDCl ₃ 400MHz) (δ) ppm: 1.39 (3H, t, J = 7.2Hz), 1.48 (3H, t), 4.11 (2H, q), 4.38 (2H, q, J = 7.2Hz) , 7.12 (1H, d, J = 2.0Hz), 7.42 (1H, d, J = 2.0Hz)
7th step

The compound obtained in the sixth step (76.38 g, 0.25 mol) was dissolved in ethanol (250 ml), 8N aqueous sodium hydroxide solution (62.00 ml, 0.50 mol) was added, and the mixture was stirred with heating at 50 ° C. for 30 min. 2N Hydrochloric acid (250 ml) was added to the reaction mixture under ice-cooling, and the mixture was stirred and extracted twice with ethyl acetate (350 ml). The organic layer was washed with water and then saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product (68.79 g, yield 99%) as a light brown solid.
¹ H NMR (CDCl ₃ 400MHz) (δ) ppm: 1.50 (3H, t, J = 6.8Hz), 4.12 (2H, q, J = 6.8Hz), 7.19
(1H, d, J = 2.4Hz), 7.65 (1H, d, J = 2.4Hz)
8th step

The compound obtained in the seventh step (85.17 g, 0.31 mol) was dissolved in toluene (450 ml), thionyl chloride (44.40 ml, 0.61 mol) and dimethylformamide (catalytic amount) were added, and the mixture was stirred at 90 ° C. for 1 hour. After allowing to cool, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in toluene. Then, the mixture was concentrated under reduced pressure, and this was repeated several times. A solution of the residue in tetrahydrofuran (250 ml) was added dropwise to a tetrahydrofuran (200 ml) solution of ethyl 3,3-dimethylaminoacrylate (43.60 g, 0.31 mol) and triethylamine (50.90 ml, 0.37 mol) and heated for 15 hours. Refluxed. After allowing to cool, water (300 ml) and ethyl acetate (500 ml) were added to the reaction mixture and the mixture was stirred and separated. The organic layer was washed with water (300 ml) and saturated brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a brown oily crude product (124.80 g).
9th process

The crude product (124.80 g) obtained in the eighth step was dissolved in tetrahydrofuran (500 ml), and (S)-(+)-tert-leucinol hydrochloride (46.80 g, 0.31 mol) and triethylamine (42.50 ml, 0.31 mol) were dissolved. ) And stirred at room temperature for 40 minutes. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (800 ml), washed twice with water and then with saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a brown oily crude product (131.30 g).
10th process

The crude product (131.30 g) obtained in the ninth step was dissolved in dimethylformamide (400 ml), imidazole (27.00 g, 0.40 mol) and tert-butyldimethylsilyl chloride (41.30 g, 0.27 mol) were added, and at room temperature. Stir for 14 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (500 ml). The organic layer was washed three times with water and then with saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a brown oily crude product (159.80 g).
Step 11

The crude product (159.80 g) obtained in the 10th step was dissolved in toluene (1100 ml), sodium hydride (15.80 g, 0.40 mol) was added, and the mixture was heated with stirring at 100 ° C. for 14 hours. 1N Hydrochloric acid (400 ml) was added to the reaction mixture under ice-cooling and the mixture was stirred and separated. The organic layer was washed with water and then saturated brine and dried over sodium sulfate. After filtration, the residue obtained by concentration under reduced pressure was dissolved in dimethylformamide (500 ml), potassium carbonate (42.10 g, 0.31 mol) and ethyl iodide (24.40 ml, 0.31 mol) were added, and the mixture was heated at 50 ° C. for 1.5 hours. Stir. Saturated aqueous ammonium chloride solution (400 ml) was added to the reaction mixture under ice cooling, and the mixture was stirred and extracted twice with ethyl acetate. The organic layer was washed twice with water and brine and then with saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 3 to 2: 3) to give the desired product (76.50 g, yield 45%) as a brown oil. Obtained.
¹ H NMR (CDCl ₃ 400MHz) (δ) ppm: -0.05 (3H, s), 0.01 (3H, s), 0.73 (9H, s), 0.98 (9H, s), 1.40 (3H, t), 1.53 -1.59 (3H, m), 4.10-4.24 (4H, m), 4.34-4.44 (2H, m), 6.10-6.14 (1H, m), 7.22 (1H, s), 8.32 (1H, t, J = 2.4Hz), 8.70 (1H, s)
Step 12

The compound obtained in the 11th step (76.50 g, 0.14 mol) was dissolved in tetrahydrofuran (500 ml), and bis (dibenzylideneacetone) palladium (0) (3.17 g, 5.51 mmol) and tri (2-furyl) were added under a stream of argon. ) Phosphine (2.56 g, 11.03 mmol) was added, and a solution of 3-chloro-2-fluorobenzylzinc bromide (0.28 mol) in tetrahydrofuran prepared as described above was added dropwise at 60 ° C., and the mixture was heated to reflux for 2.5 hours after completion of the addition. After allowing to cool, saturated aqueous ammonium chloride solution (600 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr and filtered through celite. After separation, the aqueous layer was extracted twice with ethyl acetate. On the other hand, the organic layer was concentrated under reduced pressure, redissolved in ethyl acetate, and combined with the previous extract. The organic layer was washed with 1N hydrochloric acid and saturated brine in that order, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was dissolved in dimethylformamide (400 ml), potassium carbonate (19.00 g, 0.14 mol) and ethyl iodide (11.00 ml, 0.14 mol) were added, and the mixture was heated with stirring at 50 ° C. for 1.5 hours. A saturated aqueous ammonium chloride solution (400 ml) was added to the reaction mixture under ice cooling, and the mixture was stirred and extracted with ethyl acetate (500 ml). The organic layer was washed with water, brine (twice) and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 2 to 1: 1) to give the desired product (72.10 g, yield 85%) as a brown oil. Obtained.
¹ H NMR (CDCl ₃ 400MHz) (δ) ppm: -0.07 (3H, s), 0.00 (3H, s), 0.70 (9H, s), 1.24 (9H, s), 1.39 (3H, t, J = 7.2Hz), 1.51-1.54 (3H, m), 4.05 (2H, s), 4.07-4.19 (4H, m),
4.33-4.45 (2H, m), 6.12-6.15 (1H, m), 6.99-7.02 (2H, m), 7.04-7.09 (1H, m), 7.19-7.25 (1H, m), 8.06 (1H, d , J = 2.4Hz), 8.69 (1H, s)
13th step

The compound obtained in the 12th step (65.80 g, 0.11 mol) was dissolved in ethanol (200 ml), 1N aqueous sodium hydroxide solution (640 ml, 0.64 mol) was added, and the mixture was heated to reflux for 2 hours. 2N Hydrochloric acid (350 ml) was added to the reaction mixture under ice-cooling, and the mixture was stirred and extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, diethyl ether (500 ml) was added to the residue, sonication was performed, and the resulting solid was collected by filtration. The filtered solid was dissolved in ethyl acetate (250 ml) with heating, hexane (50 ml) was added, and the crystallized solid was collected by filtration and dried under reduced pressure to obtain the desired product (41.10 g, yield 81%) as a white solid. )
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.93 (9H, s), 1.49 (3H, t, J = 6.9Hz), 4.00 (2H,
t, J = 6.4Hz), 4.20 (2H, s), 4.22-4.33 (2H, m), 5.12 (1H, t), 6.36 (1H, t, J = 6.8Hz), 7.21 (1H, m), 7.39-7.48 (2H, m), 7.54 (1H, s), 7.79 (1H, s), 8.79 (1H, s), 15.04 (1H, s)
MS (ESI): M + 476

Examples 1-3 to 1-102, 2-1 to 2-8, 3-1 to 3-86, 4-1 to 4-54
In the same manner as in Examples 1-1 and 1-2 and the above examples, Examples 1-3 to 1-102, 2-1 to 2-8, 3-1 to 3-86, and 4-1 to 4 are used. A compound of -54 was obtained. These chemical structural formulas are shown in Tables 1-1 to 1-9, Table 2, Tables 3-1 to 3-8, and Tables 4-1 to 4-5, respectively.

Test Example 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) Of nuclease expression vector pET21a-IN-F185H.
(Ii) Production and purification of integrase protein The recombinant Escherichia coli BL21 (DE3) transformed with the plasmid pET21a-IN-F185H obtained in (i) was subjected to shaking culture at 30 ° C. in a liquid medium containing ampicillin. When the logarithmic growth phase was reached, 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 accumulation of integrase protein, and 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 not containing sodium chloride, then mixed with SP-Sepharose (Pharmacia) and stirred at 4 ° C. for 60 minutes to adsorb the integrase protein to the resin. The resin was washed with Lysis buffer containing 100 mM sodium chloride, and integrase protein was eluted with Lysis buffer containing 1M sodium chloride.
The eluted integrase protein solution was applied to a Superdex 75 (Pharmacia) column and subjected to gel filtration. Protein was eluted with Lysis buffer containing 1M sodium chloride.
The resulting integrase protein fractions 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 allowed to react at 37 ° C. for 60 minutes.
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 and 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. The results are shown in Tables 5-1 to 5-2, Tables 6-1 to 6-2, and Table 7.
Inhibition rate (%) = [1- (Object-Blank) / (Control-Blank)] × 100
Object; Absorbance Control of wells in the presence of test compound; Absorbance of wells in the absence of test compound Blank; Absorbance of wells in the absence of test compound and in the absence of integrase protein

Evaluation of antiviral activity The combined effect of the compound of the present invention and a known anti-HIV agent can be measured in the following manner.
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 combined effect, etc. Are evaluated by the XTT method using CEM-SS cells infected with HIV-1IIIB.
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. A 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

The NMR and MS data of the example compounds shown in Table 1-1 to Table 4-5 above are described below.
Example 1-1
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 3.75 (2H, t, J = 4.7Hz), 4.36 (2H, s), 4.60 (2H, t,
J = 4.8Hz), 4.98 (1H, brs), 7.37-7.39 (1H, m), 7.45 (1H, dd, J = 1.4, 7.6Hz), 7.57 (1H, dd, J = 1.5, 8.0Hz), 7.81 (1H, dd, J = 2.1, 8.9Hz), 8.02 (1H, d, J = 8.8Hz), 8.15 (1H, d, J = 1.8Hz), 8.86 (1H, s), 15.18 (1H, brs )
MS (ESI): M + 392
Example 1-2
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.78 (2H, m), 4.35 (2H, s), 4.64 (2H, m), 5.00
(1H, m), 7.39 (2H, m), 7.47 (1H, m), 7.58 (1H, m), 8.00 (1H, m), 8.81 (1H, s), 14.80 (1H, s)
MS (ESI): M + 409
Example 1-3
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 2.85 (3H, s), 3.41 (2H, m), 4.37 (2H, s), 4.63 (2H, t, J = 5.6Hz), 7.25-7.29 (1H, m), 7.39 (1H, dd, J = 7.8, 7.8Hz), 7.47 (1H, dd, J = 1.5, 7.7Hz), 7.58 (1H, dd, J = 1.5, 7.8Hz), 7.84 (1H, dd, J = 2.0 , 8.9Hz), 8.00 (1H, d, J = 8.9Hz), 8.15 (1H, d, J = 1.8Hz), 8.91 (1H, s)
MS (ESI): M + 469
Example 1-4
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.38 (2H, s), 4.46 (2H, t, J = 5.9 Hz), 4.90 (2H, t, J = 5.9 Hz), 6.84 (1H, s), 7.14 (1H, s ), 7.37-7.47 (3H, m), 7.59 (1H, m), 7.82 (1H, m), 8.01 (1H, m), 8.15 (1H, s), 8.66 (1H, s), 14.99 (1H, s)
MS (ESI): M + 441
Example 1-5
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.87 (3H, s), 3.12 (3H, s), 4.35 (2H, s), 5.59
(2H, s), 7.38-7.45 (2H, m), 7.57 (1H, m), 7.71-7.76 (2H, m), 8.12 (1H, s), 8.94 (1H, s)
MS (ESI): M + 432
Example 1-6
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.64 (3H, d, J = 4.4), 4.35 (2H, s), 5.24 (2H, s), 7.35-7.47 (2H, m), 7.56-7.65 (2H, m), 7.80 (1H, m), 8.13 (1H, s), 8.32 (1H, q, J = 4.4 Hz), 9.00 (1H, s)
MS (ESI): M + 418
Example 1-7
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.36 (2H, s), 5.23 (2H, s), 7.35-7.45 (2H, m),
7.54-7.65 (3H, m), 7.83-7.88 (2H, m), 8.13 (1H, s), 9.01 (1H, s)
MS (ESI): M + 404
Example 1-8
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.57 (6H, d, J = 6.5 Hz), 4.37 (2H, s), 5.24 (1H, m), 7.38 (1H, dd, J = 7.7,7.7 Hz) 7.46 (1H, dd, J = 1.6, 7.7 Hz), 7.58 (1H, dd,
J = 1.6, 7.7 Hz), 7.85 (1H, dd, J = 2.1, 8.9 Hz), 8.15-8.18 (2H, m), 8.86 (1H, s) MS (ESI): M + 389
Example 1-9
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.35 (2H, s), 5.98 (2H, s), 7.37-7.44 (4H, m),
7.57 (1H, m), 7.83 (1H, m), 8.10-8.12 (2H, m), 8.99 (1H, s)
MS (ESI): M + 440
Example 1-10
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.85 (2H, m), 4.36 (2H, s), 4.74 (2H, m), 7.38-7.46 (2H, m), 7.58 (1H, m), 7.85 (1H, m) , 8.00 (1H, m), 8.14 (1H, s), 9.00 (1H, s)
MS (ESI): M + 419
Example 1-11
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.74 (2H, dt, J = 4.8, 5.6 Hz), 4.59 (2H, t, J =
4.9 Hz), 4.66 (2H, s), 4.98 (1H, t, J = 5.6 Hz), 7.48-7.53 (4H, m), 7.85-8.08 (5H, m), 8.18 (1H, m), 8.83 ( 1H, s), 15.24 (1H, brs)
MS (ESI): M + 373
Example 1-12
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.70 (2H, m), 3.72 (3H, s), 4.27 (2H, s), 4.38
(2H, m), 4.96 (1H, br), 7.32-7.41 (2H, m), 7.54 (1H, dd, J = 1.8, 7.3 Hz), 7.61 (1H, dd, J = 2.2, 8.8Hz), 7.76 (1H, d, J = 8.8 Hz), 8.00 (1H, d, J = 2.2 Hz), 8.55 (1H, s)
MS (ESI): M + 405
Example 1-13
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.67 (2H, m), 4.37 (2H, s), 4.73 (2H, m), 6.97
(1H, br), 7.38-7.48 (3H, m), 7.58 (1H, m), 7.87 (1H, m), 8.01 (1H, m), 8.15 (1H,
s), 8.93 (1H, s)
MS (ESI): M + 418
Example 1-14
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 2.30 (3H, s), 4.34 (2H, s), 5.62 (2H, s), 7.37
(1H, m), 7.44 (1H, m), 7.55 (1H, m), 7.72-7.78 (2H, m), 8.10 (1H, s), 8.90 (1H, s)
MS (ESI): M + 403
Example 1-15
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.31 (2H, s), 5.84 (2H, s), 7.26-7.41 (7H, m), 7.55 (1H, m), 7.73 (1H, m), 7.83 (1H, m) , 8.13 (1H, m), 9.23 (1H, s), 15.18 (1H, brs)
MS (ESI): M + 437
Example 1-16
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.12 (2H, t, J = 7.3 Hz), 4.38 (2H, s), 4.78 (2H, t, J = 7.3 Hz), 7.20-7.28 (5H, m), 7.37-7.47 (3H, m), 7.58 (1H, m), 7.85 (1H, m), 8.09 (1H, m), 8.15 (1H, s), 8.79 (1H, s), 15.07 (1H, brs)
MS (ESI): M + 451
Example 1-17
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.13 (2H, tt, J = 7.3, 7.6 Hz), 2.70 (1H, t, J =
7.6 Hz), 4.36 (2H, s), 4.58 (2H, t, J = 7.3 Hz), 7.15-7.24 (5H, m), 7.38-7.44 (3H, m), 7.57 (1H, m), 7.82 ( 1H, m), 7.96 (1H, m), 8.13 (1H, s), 8.98 (1H, s), 15.14
(1H, brs)
MS (ESI): M + 465
Example 1-18
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.89 (6H, d, J = 6.7 Hz), 2.16 (1H, tq, J = 6.7,
7.6 Hz), 4.37 (2H, s), 4.39 (2H, d, J = 7.6 Hz), 7.38-7.47 (2H, m), 7.58 (1H, m),
7.83 (1H, dd, J = 2.0, 8.9Hz), 8.02 (1H, d, J = 8.9Hz), 8.14 (1H, d, J = 2.0 Hz), 8.97 (1H, s), 15.15 (1H, brs )
MS (ESI): M + 403
Example 1-19
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.61-1.64 (2H, m), 1.76-1.84 (2H, m), 2.60 (2H, t, J = 7.5Hz), 4.36 (2H, s), 4.56 (2H, t, J = 7.2Hz), 7.15-7.17 (3H, m), 7.22-7.24 (2H, m), 7.38-7.40 (1H, m), 7.44 (1H, m), 7.56-7.59 (1H, m), 7.82 (1H, d, J = 2Hz), 7.96 (1H, d, J = 8.9Hz), 8.14 (1H, d, J = 1.8Hz), 9.01 (1H, s), 15.15 (1H, brs)
MS (ESI): M + 514
Example 1-20
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 4.28 (2H, s), 5.73 (2H, s), 7.02 (1H, d, J = 7.6Hz), 7.27-7.43 (11H, m), 7.55 (1H, d, J = 7.6Hz), 7.60-7.62 (1H, m), 8.08 (1H, d, J = 1.6Hz), 8.92 (1H, s), 14.97 (1H, brs)
MS (ESI): M + 502
Example 1-21
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 1.45-1.49 (2H, m), 1.81-1.85 (2H, m), 3.42 (2H, t, J = 6.3Hz), 4.36 (2H, s), 4.56 (2H, t, J = 7.4Hz), 7.38 (1H, dd, J = 7.7, 7.8Hz), 7.44-7.46 (1H, m), 7.57 (1H, dd, J = 1.4, 7.8Hz), 7.83 (1H, dd, J = 2.0, 8.8Hz), 8.0 (1H, d, J = 8.9Hz), 8.14 (1H, d, J = 1.8Hz), 9.01 (1H, s), 15.18 (1H, brs)
MS (ESI): M + 420
Example 1-22
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.32 (2H, s), 6.16 (2H, s), 7.32-7.42 (4H, m), 7.51-7.55 (2H, m), 7.77-7.89 (3H, m), 8.06- 8.12 (2H, m), 9.31 (1H, s), 15.02 (1H, brs)
MS (ESI): M + 494
Example 1-23
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.31 (2H, s), 5.83 (2H, s), 7.19-7.21 (1H, m), 7.33-7.43 (2H, m), 7.54-7.59 (2H, m), 7.68- 7.79 (3H, m), 8.12 (1H, s), 9.25 (1H, s), 15.
05 (1H, brs)
MS (ESI): M + 508
Example 1-24
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 2.18 (6H, s), 2.64 (2H, br), 4.36 (2H, s), 4.63 (2H, br), 7.38-7.40 (1H, m), 7.45 (1H, d, J = 1.3Hz), 7.56-7.58 (1H, m), 7.84 (1H, m), 8.00 (1H, d, J = 8.9Hz), 8.14 (1H, d, J = 1.7Hz), 8.90 (1H, s), 15.15 (1H, brs)
MS (ESI): M + 419
Example 1-25
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 1.93-1.98 (2H, m), 3.45 (2H, t, J = 5.6Hz), 4.36 (2H, s), 4.59 (2H, t, J = 7.0Hz), 4.68 (1H , br), 7.37 (1H, dd, J = 7.7, 7.8Hz), 7.44-7.468 (1H, m), 7.57 (1H, d, J = 7.8Hz), 7.83-7.99 (1H, m), 8.00 ( 1H, d, J = 8.9Hz), 8.14 (1H, s), 8.96 (1H, s), 15.16 (1H, brs)
MS (ESI): M + 406
Example 1-26
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.21 (3H, s), 3.70 (2H, t, J = 4.8Hz), 4.36 (2H, s), 4.75 (2H, t, J = 4.8Hz), 7.38 (1H, dd , J = 7.7, 7.7Hz), 7.44-7.47 (1H, m), 7.58 (1H, dd, J = 1.6, 7.8Hz), 7.83 (1H, dd, J = 2.1, 8.9Hz), 8.04 (1H, d, J = 8.9Hz), 8.14 (1H, d, J = 2.0Hz), 8.89 (1H, s), 15.14 (1H, brs)
MS (ESI): M + 406
Example 1-27
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.36 (2H, s), 5.68 (2H, q, J = 8.7Hz), 7.38 (1H, dd, J = 7.7, 7.7Hz), 7.46 (1H, dd, J = 1.7, 7.7Hz), 7.89 (1H, dd, J = 2.1, 8.9Hz), 8.13-8.16 (2H, m), 9.11 (1H, s), 14.71 (1H, brs)
MS (ESI): M + 430
Example 1-28
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.34 (2H, s), 4.78 (2H, s), 7.34-7.44 (2H, m), 7.55-7.57 (1H, m), 7.69 (1H, d, J = 8.7Hz) , 7.76 (1H, d, J = 9.0Hz), 8.09 (1H, s), 8.85 (1H,
s), 15.37 (1H, brs)
MS (ESI): M + 406
Example 1-29
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 2.04 (3H, s), 3.27-3.38 (2H, m), 4.37 (2H, s), 4.78 (2H, t, J = 6.8Hz), 7.37-7.39 (1H, m) , 7.45-7.47 (1H, m), 7.58-7.61 (1H, m), 7.85-7.87 (1H, m), 8.03-8.05 (1H, m), 8.15 (1H, s), 8.73 (1H, s) , 8.81 (1H, s)
MS (ESI): M + 473
Example 1-30
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.20 (3H, d, J = 6.2Hz), 3.96 (1H, br), 4.15-4.23 (1H, m), 4.36 (2H, s), 4.65-4.69 (1H, m) , 5.02 (1H, br), 7.37 (1H, dd, J = 7.7, 8.0Hz), 7.45 (1H, d, J = 6.6Hz), 7.57 (1H, d, J = 8.1Hz), 7.81 (1H, d, J = 8.8Hz), 8.03 (1H, d, J = 9.1Hz), 8.13 (1H, s), 8.84 (1H, s)
MS (ESI): M + 406
Example 1-31
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.75 (2H, m), 4.19 (2H, s), 4.61 (2H, m), 5.00
(1H, br), 7.27-7.40 (4H, m), 7.86 (1H, m), 8.02 (1H, m), 8.26 (1H, m), 8.86 (1H,
s), 15.29 (1H, s)
MS (ESI): M + 357
Example 1-32
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 2.10 (3H, s), 2.95 (2H, t, J = 6.6Hz), 4.37 (2H, s), 4.76 (2H, t, J = 6.6Hz), 7.38 (1H, dd , J = 7.7, 7.8Hz), 7.45-7.47 (1H, m), 7.58 (1H, dd, J = 1.5, 7.9Hz), 7.90 (1H, dd, J = 2.0, 8.9Hz), 8.00 (1H, d, J = 8.9Hz), 8.15 (1H, d, J = 1.8Hz), 9.02 (1H, s), 15.12 (1H, brs)
MS (ESI): M + 422
Example 1-33
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.75 (2H, s), 4.33 (2H, s), 4.60 (2H, t, J = 4.8Hz), 4.98 (1H, br), 7.30-7.33 (1H, m), 7.39 -7.42 (2H, m), 7.80 (1H, dd, J = 1.7, 8.9Hz), 8.02 (1H, d, J = 8.9Hz), 8.09 (1H, s), 8.85 (1H, s), 15, 14 (1H, brs)
MS (ESI): M + 375
Example 1-34
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.33-1.44 (4H, m), 1.75-1.81 (2H, m), 3.36-3.38 (2H, m), 4.54 (2H, t, J = 7.2Hz), 7.38 (1H, dd, J = 7.7, 7.7Hz), 7.46 (1H, d, J = 6.1Hz), 7.57 (1H, d, J = 7.8Hz), 7.83 (1H, d, J = 8.7Hz), 8.00 (1H, d, J = 8.9Hz), 8.14 (1H, s), 9.01 (1H, s), 15.19 (1H, brs)
MS (ESI): M + 434
Example 1-35
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 2.33-2.45 (4H, br), 2.64 (2H, t, J = 6.2Hz), 3.52 (2H, t, J = 4.4Hz), 4.27 (2H, s), 4.40 (2H , br), 7.34-7.42 (2H, m), 7.55-7.60 (2H, m), 7.71 (1H, d, J = 8.6Hz), 8.04 (1H, s), 8.57 (1H, s)
MS (ESI): M + 461
Example 1-36
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.08 (3H, s), 4.37 (2H, s), 7.37 (1H, dd, J = 7.7, 7.7Hz), 7.44-7.46 (1H, m), 7.57 (1H, dd, J = 1.7, 7.8Hz), 7.84-7.87 (1H, m), 7.92 (1H, d, J = 8.8Hz), 8.12 (1H, s), 9.01 (1H, s), 15.20 (1H, brs)
MS (ESI): M + 362
Example 1-37
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.41 (3H, t, J = 7.1Hz), 4.36 (2H, s), 4.58 (2H, q,
J = 7.1Hz), 7.38 (1H, dd, J = 7.8, 7.7Hz), 7.44-7.46 (1H, m), 7.57 (1H, dd, J = 1.5, 7.9Hz), 7.83 (1H, dd, J = 2.1, 8.8Hz), 8.01 (1H, d, J = 8.8Hz), 8.14 (1H, s), 9.02 (1H, s), 15.18 (1H, brs)
MS (ESI): M + 376
Example 1-38
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.90 (3H, t, J = 7.3Hz), 1.77-1.85 (2H, m), 4.36 (2H, s), 4.51 (2H, t, J = 7.3Hz), 7.38 (1H , dd, J = 7.8, 7.6Hz), 7.44-7.46 (1H, m), 7.58 (1H, dd, J = 1.7, 7.8Hz), 7.83 (1H, dd, J = 2.1, 8.8Hz), 8.02 ( 1H, d, J = 8.9Hz), 8.14 (1H, d, J = 2.0Hz), 9.02 (1H, s), 15.18 (1H, brs)
MS (ESI): M + 390
Example 1-39
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.90 (3H, t, J = 7.3Hz), 1.30-1.37 (2H, m), 1.74-1.79 (2H, m), 4.36 (2H, s), 4.54 (2H, t, J = 7.3Hz), 7.38 (1H, dd, J = 7.6, 7.8Hz), 7.46 (1H, dd, J = 1.7, 7.6Hz), 7.58 (1H, dd, J = 1.7, 7.8Hz), 7.83 ( 1H, dd, J = 2.1, 8.9Hz), 8.00 (1H, d, J = 8.9Hz), 8.14 (1H, d, J = 2.0Hz), 9.01 (1H, s), 15.18 (1H, brs)
MS (ESI): M + 404
Example 1-40
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.27-1.29 (2H, m), 1.47-1.50 (2H, m), 1.59-1.66 (4H, m), 2.31-2.40 (1H, m), 4.36 (2H, s), 4.51 (2H, d, J = 7.6Hz), 7.38-7.47 (2H, m), 7.57 (1H, dd, J = 1.5, 7.8Hz), 7.82 (1H, dd, J = 2.0, 8.8Hz), 8.05 (1H, d, J = 8.9Hz), 8.14 (1H, d, J = 1.8Hz), 9.028 (1H, s), 15.16 (1H, brs)
MS (ESI): M + 430
Example 1-41
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.11 (3H, s), 3.77 (2H, t), 4,37 (2H, s), 4.99 (2H, t), 7.35-7.41 (1H, m), 7.47 (1H, d), 7.58 (1H, d, J = 7.8Hz), 7.83-7.92 (2H, m), 8.16 (1H, s), 9.05 (1H, s)
MS (ESI): M + 454
Example 1-42
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.10 (4H, br), 1.54-1.65 (4H, br), 1.83 (1H, br),
4.36 (2H, s), 4.40 (2H, d, J = 7.4Hz), 7.38 (1H, dd, J = 7.7, 7.8Hz), 7.45-7.48 (1H, m),
7.58 (1H, dd, J = 1.6, 7.8Hz), 7.81-7.84 (1H, m), 8.02 (1H, d, J = 8.9Hz), 8.13 (1H, s),
8.93 (1H, s), 15.17 (1H, brs)
MS (ESI): M + 444
Example 1-43
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.37 (2H, s), 4.49-4.56 (1H, m), 4.77-4.82 (1H, m), 4.91-4.97 (1H, m), 5.81 (1H, d, J = 4.7 Hz), 7.30-760 (8H, m), 7.81 (1H, d, J = 11.0Hz), 8.08 (1H, d, J = 8.9Hz), 8.17 (1H, d), 8.93 (1H, s), 15.19 (1H, brs)
MS (ESI): M + 468
Example 1-44
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.37 (2H, s), 4.72-4.76 (1H, m), 4.92 (2H, t, J = 4.6Hz), 4.98-5.01 (1H, m), 7.38 (1H, dd, J = 7.8, 8.1Hz), 7.44-7.46 (1H, m), 7.58 (1H, dd, J = 1.6, 7.9Hz), 7.84 (1H, dd, J = 2.1, 9.0Hz), 8.03 (1H, d , J = 9.3Hz), 8.15 (1H, d, J = 1.8Hz), 8.78 (1H, s), 8.98 (1H, s)
MS (ESI): M + 394
Example 1-45
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.21 (2H, br), 4.27 (2H, s), 4.65 (2H, br), 7.20-7.28 (2H, m), 7.33-7.41 (2H, m), 7.54-7.70 ( 5H, m), 7.77 (1H, d, J = 8.7Hz), 8.05 (1H, s), 8.50 (1H, s), 8.52 (1H, s)
MS (ESI): M + 453
Example 1-46
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.93 (2H, t), 4.35 (2H, s), 4.48 (2H, s), 7.38 (1H, dd, J = 7.7, 7.7Hz), 7.45 (1H, d, J = 6.2Hz), 7.57 (1H, d, J = 7.7Hz), 7.82 (1H, d), 8.02 (1H, d, J = 9.1Hz), 8.13 (1H, s), 8.92 (1H, s)
MS (ESI): M + 391
Example 1-47
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.13 (6H, s), 4.35 (2H, s), 4.50 (2H, s), 4.90 (1H, brs), 7.35-7.46 (2H, m), 7.57 (1H, d, J = 7.7Hz), 7.78 (1H, d, J = 7.1Hz), 8.10 (1H, s), 8.19 (1H, d, J = 9.0Hz), 8.88 (1H, s), 15.22 (1H, brs)
MS (ESI): M + 420
Example 1-48
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.68 (3H, s), 3.46 (2H, br), 4.36 (2H, s), 4.56 (2H, br), 7.38-7.60 (3H, m), 7.81-8.13 (4H, m), 8.80 (1H, s)
MS (ESI): M + 433
Example 1-49
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.00 (3H, t, J = 7.0Hz), 3.41 (2H, br), 3.82 (2H, q), 4.36 (2H, s), 4.57 (2H, br), 7.24 (1H , m), 7.38 (1H, m), 7.46 (1H, m), 7.58 (1H, m),
7.83 (1H, m), 8.03 (1H, m), 8.13 (1H, s), 8.82 (1H, s)
MS (ESI): M + 463
Example 1-50
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.75 (2H, m), 4.26 (2H, s), 4.61 (2H, t, J = 4.8Hz), 5.00 (1H, br), 7.17-7.36 (3H, m), 7.83 (1H, dd, J = 2.0, 8.8Hz), 8.03 (1H, d, J = 8.9Hz), 8.21 (1H, s), 8.87 (1H, s), 15.22 (1H, brs)
MS (ESI): M + 360
Example 1-51
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.75 (2H, m), 4.28 (2H, s), 4.61 (2H, t, J = 4.8Hz), 5.00 (1H, br), 7.24-7.28 (1H, m), 7.44 -7.55 (2H, m), 7.80 (1H, dd, J = 2.1, 8.8Hz), 8
.02 (1H, d, J = 8.9Hz), 8.13 (1H, d, J = 1.9Hz), 8.86 (1H, s), 15.22 (1H, s)
MS (ESI): M + 376
Example 1-52
¹ H NMR (CDCl _Three (300MHz) (δ) ppm: 1.42 (3H, t, J = 7.1Hz), 4.05 (2H, s), 4.40 (2H, q, J = 7.1Hz), 5.35 (2H, s), 7.13-7.28 (8H , m), 7.33-7.35 (2H, m), 8.41 (1H, d, J = 2.0Hz), 8.58 (1H, s)
MS (ESI): M + 398
Example 1-53
¹ H NMR (CDCl _Three (300MHz) (δ) ppm: 4.10 (2H, s), 5.48 (2H, s), 7.13-7.50 (12H, m), 8.41 (1H, d, J = 1.9Hz), 8.87 (1H, s), 14.96 (1H, brs)
MS (ESI): M + 370
Example 1-54
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.16 (2H, s), 5.44 (2H, s), 7.19-7.34 (5H, m), 7.74 (1H, d, J = 8.8Hz), 7.83 (1H, dd, J = 2.0, 8.9Hz), 8.22 (1H, d, J = 1.9Hz), 9.08 (1H, s), 13.58 (1H, brs), 15.13 (1H, brs)
MS (ESI): M + 338
Example 1-55
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.89 (3H, t, J = 7.3Hz), 1.25-1.35 (5H, m), 1.66-1.76 (2H, m), 4.09 (2H, s), 4.21 (2H, q, J = 7.1Hz), 4.34 (2H, t, J = 7.2Hz), 7.20-7.33 (5H, m), 7.66 (1H, dd, J = 2.1, 8.7Hz), 7.74 (1H, d, J = 8.7 Hz), 8.06 (1H, d, J = 1.9Hz), 8.64 (1H, s)
MS (ESI): M + 364
Example 1-56
¹ H NMR (CDCl _Three (300MHz) (δ) ppm: 0.99 (3H, t, J = 7.3Hz), 1.43 (2H, m), 1.84-1.94 (2H,
m), 4.15 (2H, s), 4.28 (2H, t, J = 7.4Hz), 7.20-7.34 (5H, m), 7.52 (1H, d, J = 8.8Hz), 7.65 (1H, dd, J = 2.1, 8.8Hz), 8.42 (1H, d, J = 1.9Hz), 8.72 (1H, s), 15.04 (1H, brs)
MS (ESI): M + 336
Example 1-57
¹ H NMR (CDCl _Three (300MHz) (δ) ppm: 1.41 (3H, t, J = 7.2Hz), 3.85 (3H, s), 4.11 (2H, s), 4.39 (2H, q, J = 7.2Hz), 7.17-7.35 (6H , m), 7.51 (1H, dd, J = 2.4, 8.4Hz), 8.42 (1H, d, J = 1.8Hz), 8.45 (1H, s)
MS (ESI): M + 322
Example 1-58
¹ H NMR (CDCl _Three (300MHz) (δ) ppm: 3.99 (3H, s), 4.16 (2H, s), 7.19-7.33 (5H, m), 7.52 (1H, d, J = 8.7Hz), 7.68 (1H, dd, J = 2.0, 8.7Hz), 8.41 (1H, s), 8.72 (1H, s)
MS (ESI): M + 294
Example 1-59
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 2.08-2.15 (2H, m), 2.69 (2H, t, J = 7.8Hz), 4.16 (2H, s), 4.57 (2H, t, J = 7.3Hz), 7.15-7.31 (10H, m), 7.81 (1H, dd, J = 2.0, 8.8Hz), 7.92 (1H, d, J = 8.8Hz), 8.20 (1H, d, J = 1.9Hz), 8.96 (1H, s) , 15.21 (1H, brs)
MS (ESI): M + 398
Example 1-60
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.11 (2H, t, J = 7.3Hz), 4.18 (2H, s), 4.77 (2H, t,
J = 7.4Hz), 7.19-7.35 (10H, m), 7.86 (1H, d, J = 8.7Hz), 8.06 (1H, d, J = 8.8Hz), 8.22 (1H, s), 8.76 (1H, s), 15.14 (1H, brs)
MS (ESI): M + 384
Example 1-61
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.99-2.03 (2H, m), 2.37 (2H, t, J = 7.1Hz), 4.17 (2H, s), 4.54 (2H, t, J = 7.3Hz), 7.21-7.34 (5H, m), 7.87 (1H, dd, J = 2.0, 8.8Hz), 8.05 (1H, d, J = 8.8Hz), 8.21 (1H, d, J = 1.9Hz), 8.98 (1H, s) , 12.01 (1H, brs), 15.28 (1H, brs)
MS (ESI): M + 366
Example 1-62
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.15 (2H, s), 5.48 (2H, s), 7.06-7.10 (1H, m), 7.20-7.22 (1H, m), 7.28-7.34 (6H, m), 7.56- 7.58 (2H, m), 7.74 (1H, d, J = 8.8Hz), 7.848.9Hz), 8.23 (1H, s), 9.10 (1H, s), 10.63 (1H, brs), 15.18 (1H, brs )
MS (ESI): M + 413
Example 1-63
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.72 (2H, m), 4.26 (2H, s), 4.35 (2H, m), 5.23
(1H, br), 7.32-7.41 (2H, m), 7.53-7.58 (2H, m), 7.72 (1H, m), 8.05 (1H, s), 8.63
(1H, s)
MS (ESI): M + 391
Example 1-64
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.72 (2H, m), 4.23 (2H, s), 4.35 (2H, m), 5.24
(1H, br), 7.25-7.40 (3H, m), 7.57 (1H, m), 7.72 (1H, m), 8.03 (1H, s), 8.63 (1H, s)
MS (ESI): M + 375
Example 1-65
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.12 (2H, t, J = 7.3 Hz), 4.31 (2H, s), 4.78 (2H, t, J = 7.3 Hz), 7.20-7.36 (7H, m), 7.46-7.48 (2H, m), 7.86 (1H, m), 8.09 (1H, m), 8.15 (1H, s), 8.78 (1H, s), 15.08 (1H, brs)
MS (ESI): M + 417
Example 1-66
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.79 (2H, m), 4.39 (2H, s), 4.65 (2H, m), 5.04
(1H, m), 7.31-7.47 (3H, m), 7.88 (1H, m), 8.07 (1H, m), 8.19 (1H, m), 8.90 (1H, s), 15.25 (1H, s)
MS (ESI): M + 375
Example 1-67
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.74 (2H, m), 4.35 (2H, s), 4.62 (2H, m), 5.00
(1H, br), 7.62 (1H, m), 7.81 (1H, m), 7.90 (1H, m), 8.02-8.13 (2H, m), 8.23 (1H,
m), 8.32 (1H, m), 8.87 (1H, s)
MS (ESI): M + 368
Example 1-68
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.09 (3H, s), 4.35 (2H, s), 5.75 (2H, s), 7.37
(1H, m), 7.44 (1H, m), 7.55 (1H, m), 7.83 (1H, m), 8.01 (1H, m), 8.12 (1H, m), 9.10 (1H, s)
MS (ESI): M + 407
Example 1-69
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.20 (3H, s), 4.36 (2H, s), 6.22 (2H, s), 7.36-7.47 (2H, m), 7.58 (1H, m), 7.86 (1H, m) , 8.12-8.15 (2H, m), 9.04 (1H, s)
MS (ESI): M + 439
Example 1-70
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.22 (9H, s), 4.36 (2H, s), 5.99 (2H, s), 7.35-7.46 (3H, m), 7.58 (1H, m), 7.84 (1H, m) , 8.08-8.11 (2H, m), 8.95 (1H, s), 14.75 (1H, br)
MS (ESI): M + 496
Example 1-71
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.62 (3H, d, J = 4.7 Hz), 4.36 (2H, s), 6.11 (2H, s), 7.36-7.47 (2H, m), 7.54-7.60 (2H, m) , 7.84 (1H, m), 8.10-8.13 (2H, m), 8.98 (1H, s), 14.79 (1H, br)
MS (ESI): M + 454
Example 1-72
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.77 (6H, s), 4.37 (2H, s), 6.20 (2H, s), 7.39
(1H, dd, J = 7.8, 7.8 Hz), 7.47 (1H, dd, J = 1.7, 7.8 Hz), 7.59 (1H, dd, J = 1.7, 7.8 Hz), 7.89 (1H, m), 8.11- 8.14 (2H, m), 9.04 (1H, s), 14.69 (1H, br)
MS (ESI): M + 468
Example 1-73
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.75 (2H, br), 4.36 (2H, s), 4.60 (2H, m), 5.00 (1H, br), 7.39-7.49 (2H, m), 7.82 (1H, m) , 8.04 (1H, m), 8.11 (1H, s), 8.87 (1H, s), 15.14 (1H, brs)
MS (ESI): M + 393
Example 1-74
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.41 (1H, m), 3.51 (1H, m), 3.82 (1H, m), 4.26
(1H, m), 4.36 (2H, s), 4.79 (1H, m), 4.93 (1H, m), 5.19 (1H, m), 7.38 (1H, m), 7.46 (1H, m), 7.58 ( 1H, m), 7.84 (1H, m), 7.97 (1H, m), 8.15 (1H, m), 8.84 (1H, s)
MS (ESI): M + 421
Example 1-75
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.32 (2H, s), 5.98 (2H, s), 7.31-7.43 (5H, m),
7.80 (1H, m), 8.06 (1H, m), 8.12 (1H, m), 8.99 (1H, m), 14.81 (1H, brs)
MS (ESI): M + 424
Example 1-76
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.62 (3H, d, J = 4.4 Hz), 4.32 (2H, s), 6.11 (2H, s), 7.30-7.43 (3H, m), 7.53 (1H, q, J = 4.4 Hz), 7.84 (1H, m), 8.06 (1H, s), 8.12 (1H, m), 8.98 (1H, m), 14.74 (1H, s)
MS (ESI): M + 438
Example 1-77
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.77 (6H, s), 4.33 (2H, s), 6.19 (2H, s), 7.27-7.44 (3H, m), 7.89 (1H, m), 8.06-8.14 (2H, m), 9.03 (1H, s), 14.64 (1H, s)
MS (ESI): M + 452
Example 1-78
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.74 (2H, dt, J = 4.8, 5.6 Hz), 4.17 (2H, s), 4.60 (2H, t, J = 4.8 Hz), 4.99 (1H, t, J = 5.6 Hz ), 7.20-7.32 (5H, m), 7.82 (1H, m),
7.99 (1H, m), 8.21 (1H, m), 8.84 (1H, s), 15.27 (1H, s)
MS (ESI): M + 323
Example 1-79
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.34 (3H, s), 3.75 (2H, br), 4.30 (2H, s), 4.61 (2H, t, J = 4.7 Hz), 5.00 (1H, br), 7.21-7.31 (3H, m), 7.81 (1H, dd, J = 2.0, 8.9
Hz), 8.01 (1H, d, J = 8.9Hz), 8.15 (1H, d, J = 2.0 Hz), 8.86 (1H, s), 15.23 (1H, s)
MS (ESI): M + 371
Example 1-80
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.76 (2H, m), 4.31 (2H, s), 4.61 (2H, m), 5.01
(1H, m), 7.23 (1H, m), 7.36-7.47 (2H, m), 7.65 (1H, m), 7.81 (1H, m), 8.02 (1H,
m), 8.14 (1H, m), 8.86 (1H, s)
MS (ESI): M + 401
Example 1-81
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.26 (3H, s), 3.75 (2H, m), 4.12 (2H, s), 4.60
(2H, m), 4.99 (1H, m), 7.10-7.18 (4H, m), 7.80 (1H, m), 7.99 (1H, m), 8.20 (1H,
m), 8.85 (1H, s), 15.29 (1H, s)
MS (ESI): M + 337
Example 1-82
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.73 (2H, dt, J = 4.8, 5.2 Hz), 3.84 (3H, s), 4.28 (2H, s), 4.60 (2H, t, J = 4.8 Hz), 5.00 (1H , t, J = 5.2 Hz), 7.04-7.07 (2H, m),
7.30 (1H, m), 7.79 (1H, m), 8.00 (1H, m), 8.11 (1H, m), 8.84 (1H, s), 15.22 (1H, s)
MS (ESI): M + 387
Example 1-83
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 3.75 (2H, m), 4.50 (2H, s), 4.62 (2H, m), 7.60-8.15 (5H, m), 8.35 (1H, s), 8.68 (1H, m) , 8.87 (1H, s), 15.25 (1H, br)
MS (ESI): M + 324
Example 1-84
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.75 (2H, m), 4.33 (2H, s), 4.62 (2H, m), 7.57
(2H, d, J = 6.3 Hz), 7.89 (1H, dd, J = 2.1, 8.7 Hz), 8.07 (1H, d, J = 8.7 Hz), 8.32
(1H, d, J = 2.1 Hz), 8.62 (1H, d, J = 6.3 Hz), 8.88 (2H, s)
MS (ESI): M + 324
Example 1-85
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.21 (3H, s), 3.77 (2H, m), 4.61 (2H, m), 4.66
(2H, s), 5.02 (1H, m), 7.38 (1H, m), 7.55 (1H, m), 7.68 (1H, m), 7.81 (1H, m), 8.00-8.05 (2H, m), 8.19 (1H, m), 8.87 (1H, s)
MS (ESI): M + 401
Example 1-86
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.73 (2H, m), 4.15 (2H, s), 4.58 (2H, m), 5.00
(1H, m), 7.23-7.50 (10H, m), 7.88-7.92 (2H, m), 8.83 (1H, s)
MS (ESI): M + 399
Example 1-87
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.75 (2H, m), 4.30 (2H, s), 4.61 (2H, m), 5.00
(1H, br), 7.26-7.38 (2H, m), 7.43-7.49 (2H, m), 7.82 (1H, m), 8.02 (1H, m), 8.14
(1H, m), 8.86 (1H, s), 15.32 (1H, s)
MS (ESI): M + 357
Example 1-88
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.74 (2H, m), 4.25 (2H, s), 4.60 (2H, m), 4.98
(1H, br), 7.25-7.53 (6H, m), 7.59-7.66 (3H, m), 7.87 (1H, m), 8.10 (1H, m), 8.29
(1H, m), 8.85 (1H, s), 15.30 (1H, s)
MS (ESI): M + 399
Example 1-89
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.79 (2H, m), 4.33 (2H, s), 4.64 (2H, m), 5.03
(1H, m), 7.57-7.65 (3H, m), 7.76 (1H, m), 7.91 (1H, m), 8.06 (1H, m), 8.32 (1H, m), 8.90 (1H, s), 15.31 (1H, s)
MS (ESI): M + 391
Example 1-90
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 1.30 (3H, t, J = 6.8 Hz), 3.74 (2H, m), 3.98 (2H, q, J = 6.8 Hz), 4.12 (2H, s), 4.60 (2H, m ), 5.01 (1H, m), 6.76 (1H, m), 6.82-6.84 (2H, m), 7.20 (1H, m), 7.82 (1H, m), 7.99 (1H, m), 8.22 (1H, m), 8.85 (1H, s) MS (ESI): M + 367
Example 1-91
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.75 (2H, m), 4.25 (2H, s), 4.61 (2H, m), 7.53
(1H, m), 7.66-7.71 (2H, m), 7.83-7.89 (2H, m), 8.02 (1H, m), 8.28 (1H, m), 8.87 (1H, s)
MS (ESI): M + 348
Example 1-92
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 2.48 (3H, m), 3.74 (2H, m), 4.26 (2H, s), 4.61
(2H, m), 5.09 (1H, br), 7.19 (1H, m), 7.39 (2H, m), 7.82 (1H, m), 8.04 (1H, m), 8.13 (1H, s), 8.85 ( 1H, s), 15.22 (1H, s)
MS (ESI): M + 403
Example 1-93
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.75 (2H, m), 4.24 (2H, s), 4.61 (2H, m), 5.02
(1H, br), 7.38-7.47 (4H, m), 7.80 (1H, m), 8.03 (1H, m), 8.16 (1H, m), 8.86 (1H,
s), 15.23 (1H, s)
MS (ESI): M + 407
Example 1-94
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.76 (2H, m), 3.99 (2H, s), 4.61 (2H, m), 5.01
(3H, m), 6.41 (3H, m), 6.93 (1H, m), 7.78 (1H, m), 8.00 (1H, m), 8.20 (1H, m), 8.86 (1H, s)
MS (ESI): M + 338
Example 1-95
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.00 (3H, s), 3.76 (2H, m), 4.13 (2H, s), 4.61
(2H, m), 5.01 (1H, m), 6.98 (1H, m), 7.23 (1H, m), 7.43 (2H, m), 7.81 (1H, m), 8.01 (1H, m), 8.21 ( 1H, m), 8.86 (1H, s), 9.87 (1H, s)
MS (ESI): M + 380
Example 1-96
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.73 (2H, m), 4.18 (2H, s), 4.59 (2H, m), 4.98
(1H, br), 7.26 (1H, s), 7.29 (1H, m), 7.39 (1H, m), 7.53 (1H, m), 7.99 (1H, s), 8.24 (1H, m), 8.85 ( 1H, s), 15.25 (1H, s)
MS (ESI): M + 401
Example 1-97
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.28 (3H, s), 3.75 (2H, m), 4.25 (2H, s), 4.61
(2H, m), 5.04 (1H, br), 7.13 (1H, s), 7.29-7.36 (2H, m), 7.81 (1H, m), 8.03 (1H,
m), 8.13 (1H, s), 8.86 (1H, s), 15.24 (1H, s)
MS (ESI): M + 371
Example 1-98
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 2.59 (6H, s), 3.75 (2H, m), 4.33 (2H, s), 4.61
(2H, m), 5.00 (1H, m), 7.59-7.64 (3H, m), 7.73 (1H, m), 7.87 (1H, m), 8.03 (1H, m), 8.27 (1H, s), 8.86 (1H, s), 15.27 (1H, s)
MS (ESI): M + 430
Example 1-99
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.75 (2H, m), 4.26 (2H, s), 4.61 (2H, m), 5.00
(1H, br), 7.21 (1H, m), 7.38-7.51 (2H, m), 7.83 (1H, m), 8.03 (1H, m), 8.22 (1H, s), 8.87 (1H, s)
MS (ESI): M + 375
Example 1-100
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.76 (2H, m), 4.26 (2H, s), 4.61 (2H, m), 4.99 (1H, m), 7.25 (1H, m), 7.61 (1H, m), 7.81 (1H, m), 8.04 (1H, m), 8.16 (1H, m), 8.87 (1H, s), 15.16 (1H, s)
MS (ESI): M + 393
Example 1-101
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 3.79 (2H, m), 4.01 (3H, s), 4.19 (2H, s), 4.64-4.65 (2H, m), 5.02 (1H, t, J = 5.5Hz), 7.25 (1H, d, J = 1.6Hz), 7.31-7.35 (2H, m), 7.56-7.58 (1H, m), 7.82 (1H, s), 8.78 (1H, s), 15.38 (1H, brs)
MS (ESI): M + 422
Example 1-102
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.19 (2H, m), 1.30 (2H, m), 3.83 (1H, m), 4.37
(2H, s), 7.38 (1H, m), 7.46 (1H, m), 7.57 (1H, m), 7.89 (1H, m), 8.12 (1H, m), 8.24 (1H, m), 8.73 ( 1H, s), 15.05 (1H, s)
MS (ESI): M + 387
Example 2-1
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.37 (2H, s), 6.88 (2H, brs), 7.35-7.47 (2H, m), 7.58 (1H, m), 7.87 (1H, dd, J = 2.1, 8.9 Hz) , 8.08 (1H, d, J = 2.1 Hz), 8.16 (1H, d, J = 8.9 Hz), 8.86 (1H, s), 15.24 (1H, brs)
MS (ESI): M + 362
Example 2-2
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.75 (3H, brs), 4.36 (2H, s), 7.35 (1H, m), 7.42 (1H, m), 7.54 (1H, m), 7.72 (1H, m), 7.85 (1H, m), 8.10 (1H, s), 9.03 (1H, s),
11.61 (1H, brs)
MS (ESI): M + 420
Example 2-3
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.16 (3H, s), 4.36 (2H, s), 7.35-7.45 (2H, m), 7.58 (1H, dd, J = 1.8, 7.8Hz), 7.76-7.85 (2H, m), 8.10 (1H, s), 8.96 (1H, s), 12.02 (1H, brs), 14.77 (1H, brs)
MS (ESI): M + 405
Example 2-4
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.32 (3H, s), 4.37 (2H, s), 7.38 (1H, m), 7.46
(1H, m), 7.58 (1H, m), 7.86 (1H, m), 8.06-8.10 (2H, m), 8.82 (1H, s), 14.60 (1H, br)
MS (ESI): M + 440
Example 2-5
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.46 (3H, s), 3.53 (3H, s), 4.37 (2H, s), 7.38
(1H, dd, J = 7.8, 7.8 Hz), 7.47 (1H, dd, J = 2.1, 7.8 Hz), 7.58 (1H, dd, J = 2.1, 7.8 Hz), 7.88 (1H, dd, J = 1.8 , 8.7 Hz), 7.97 (1H, d, J = 8.7 Hz), 8.12 (1H, d, J = 1.8 Hz), 9.11 (1H, s), 15.54 (1H, brs)
MS (ESI): M + 454
Example 2-6
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.96 (6H, s), 4.36 (2H, s), 7.38 (1H, dd, J = 7.8, 7.8 Hz), 7.46 (1H, dd, J = 2.0, 7.8 Hz), 7.57 (1H, dd, J = 2.0, 7.8 Hz), 7.86 (1H, dd, J = 2.2, 8.8 Hz), 8.12 (1H, d, J = 2.2 Hz), 8.25 (1H, d, J = 8.8 Hz) , 9.25 (1H, s), 15.14 (1H, brs)
MS (ESI): M + 390
Example 2-7
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 2.84 (3H, d), 4.35 (2H, s), 7.19 (1H, q), 7.38
(1H, m), 7.45 (1H, m), 7.55 (1H, m), 7.85 (1H, m), 8.09-8.11 (2H, m), 8.99 (1H, m)
MS (ESI): M + 376
Example 2-8
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.09 (3H, t, J = 7.1 Hz), 3.13 (2H, dq, J = 6.1,
7.1 Hz), 4.36 (2H, s), 7.19 (1H, t, J = 6.1 Hz), 7.38 (1H, dd, J = 7.7, 7.7 Hz), 7.46 (1H, dd, J = 1.7, 7.7 Hz) , 7.58 (1H, dd, J = 1.7, 7.8 Hz), 7.85 (1H, dd, J = 2.1, 8.8 Hz), 8.10 (1H, d, J = 2.1 Hz), 8.15 (1H, d, J = 8.8 Hz), 8.99 (1H, s), 15.14 (1H, brs)
MS (ESI): M + 390
Example 3-1.
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.75 (2H, m), 3.79 (3H, s), 4.28 (2H, s), 4.57 (2H, m), 5.02 (1H, m), 7.17 (1H, m), 7.32 (1H, m), 7.57 (2H, m), 7.76 (1H, m), 8.83 (1H, m), 15.75 (1H, s)
MS (ESI): M + 421
Example 3-2
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 2.24 (3H, s), 3.77 (2H, dd, J = 5.2, 5.6Hz), 4.27 (2H, s), 4.61 (2H, t, J = 5.2Hz), 5.05 (1H , t, J = 5.6Hz), 7.23 (2H, m), 7.34 (1H, m), 7.76 (1H, m), 8.03 (1H, m), 8.08 (1H, m), 8.86 (1H, s) , 15.23 (1H, s)
MS (ESI): M + 371
Example 3-3
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.73 (5H, s), 4.21 (2H, s), 4.61 (2H, t, J = 4.8Hz), 5.01 (1H, t, J = 5.2Hz), 5.02 (1H, m ), 7.12 (1H, m), 7.25 (1H, m), 7.37 (1H, m), 7.81 (1H, m), 8.01 (1H, m), 8.19 (1H, m), 8.86 (1H, s) , 15.26 (1H, s)
MS (ESI): M + 387
Example 3-4
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.80 (2H, m), 4.01 (3H, s), 4.12 (2H, s), 4.65 (2H, m), 5.02 (1H, m), 7.17-7.50 (4H, m) , 8.03 (1H, s), 8.81 (1H, s), 15.45 (1H, s)
MS (ESI): M + 405
Example 3-5
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.74 (2H, t), 4.17 (2H, s), 4.56 (2H, t), 5.02 (1H, br), 7.20 (1H, m), 7.31 (1H, m), 7.38 (1H, m), 7.52-7.56 (2H, m), 8.86 (1H,
s), 13.63 (1H, s)
MS (ESI): M + 407
Example 3-6
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.78 (2H, t), 4.18 (2H, s), 4.44-4.49 (2H, m),
5.08 (1H, t), 7.20-7.25 (2H, m), 7.34-7.40 (1H, m), 7.56 (1H, d), 7.82 (1H, s),
8.77 (1H, s), 11.10-11.30 (1H, br), 15.49 (1H, s)
MS (ESI): M + 408
Example 3-7
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 2.68 (3H, d, J = 4.4Hz), 3.74 (2H, t, J = 4.8Hz), 4.04 (2H, s), 4.60 (2H, t, J = 4.8Hz), 5.01 (1H, t), 5.27 (1H, q, J = 5.2Hz), 6.51-6.56 (2H, m), 6.95 (1H, d), 7.07-7.09 (1H, m), 7.78 (1H, d, J = 9.2Hz), 7.98 (1H, d,
J = 8.8Hz), 8.21 (1H, s), 8.84 (1H, s), 15.33 (1H, s)
MS (ESI): M + 353
Example 3-8
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 2.62 (6H, s), 3.74 (2H, t), 4.24 (2H, s), 4.60
(2H, t, J = 4.8Hz), 5.01 (1H, t), 6.97-7.05 (2H, m), 7.21 (2H, m), 7.77 (1H, d, J = 11.2Hz), 7.97 (1H, d), 8.16 (1H, s), 8.85 (1H, s), 15.29 (1H, s)
MS (ESI): M + 367
Example 3-9
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 4.35 (2H, s), 7.11 (1H, d, J = 8.8Hz), 7.37-7.40
(1H, m), 7.44 (1H, d), 7.56 (1H, d), 7.69-7.74 (6H, m), 8.19 (1H, s), 8.68 (1H, s), 14.99 (1H, s)
MS (ESI): M + 424
Example 3-10
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 3.84-3.95 (4H, m), 4.36 (2H, s), 5.11-5.19 (3H, m), 7.38 (1H, m), 7.45 (1H, d), 7.57 (1H, d), 7.82 (1H, d, J = 9.2Hz), 8.15 (1H, d, J = 8.8Hz), 8.90 (1H, s), 15.21 (1H, s)
MS (ESI): M + 422
Example 3-11
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.76 (2H, t), 4.05 (2H, s), 4.59 (2H, t), 5.00
(1H, t), 6.61 (1H, d), 6.64 (1H, s), 6.70 (1H, d, J = 8.0Hz), 7.09-7.11 (1H, m), 7.81 (1H, d, J = 8.8 Hz), 8.00 (1H, d, J = 8.8Hz), 8.21 (1H, s), 8.86 (1H, s), 9.30 (1H, s), 15.30 (1H, s)
MS (ESI): M + 340
Example 3-12
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 1.80-1.90 (2H, m), 2.45-2.50 (2H, m), 2.60-2.70 (2H, m), 4.36 (2H, s), 5.11-5.16 (1H, m), 7.38-7.40 (1H, m), 7.45 (1H, d), 7.57
(1H, d), 7.81 (1H, d, J = 8.8Hz), 7.93 (1H, d), 8.14 (1H, s), 8.68 (1H, s), 15.16 (1H, s)
MS (ESI): M + 402
Example 3-13
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.70-1.90 (4H, m), 1.91-2.00 (2H, m), 2.20-2.30 (2H, m), 4.37 (2H, s), 5.20-5.30 (1H, m), 7.38-7.40 (1H, m), 7.45 (1H, d), 7.57
(1H, d), 7.86 (1H, d), 8.16 (1H, d), 8.19 (1H, s), 8.75 (1H, s), 15.16 (1H, s)
MS (ESI): M + 416
Example 3-14
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.70-3.80 (2H, m), 3.96 (3H, s), 4.32 (2H, s),
4.81 (2H, t), 4.90 (1H, t), 7.35-7.43 (2H, m), 7.54-7.59 (2H, m), 7.69 (1H, s), 8.69 (1H, s), 15.16 (1H, s)
MS (ESI): M + 422
Example 3-15
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.88 (3H, s), 2.95 (3H, s), 3.70-3.80 (2H, m),
4.21 (2H, s), 4.61 (2H, t), 4.99 (1H, t), 7.20-7.23 (1H, m), 7.33 (1H, s), 7.37-7.38 (2H, dx2), 7.86 (1H, d), 8.02 (1H, d, J = 8.8Hz), 8.26 (1H, s), 8.86 (1H, s), 15.30 (1H, s)
MS (ESI): M + 395
Example 3-16
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 2.71 (6H, s), 3.70-3.76 (2H, m), 4.58 (2H, s),
4.60 (2H, t, J = 5.2Hz), 5.02 (1H, t), 7.42 (1H, d), 7.51 (1H, m), 7.64 (1H, m), 7.80 (1H, d), 7.84 (1H , d), 8.01 (1H, d, J = 8.8Hz), 8.11 (1H, s), 8.86 (1H, s), 15.25 (1H, s)
MS (ESI): M + 431
Example 3-17
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.73-3.75 (2H, m), 4.24 (2H, s), 4.61 (2H, t),
5.00 (1H, t, J = 5.6Hz), 7.31 (1H, m), 7.48-7.51 (1H, m), 7.84 (1H, d), 8.02 (1H, d), 8.21 (1H, s), 8.87 (1H, s), 15.22 (1H, s)
MS (ESI): M + 394
Example 3-18
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.70-3.80 (2H, m), 4.56 (2H, s), 4.60 (2H, t),
5.00 (1H, t), 7.38-7.43 (2H, m), 7.52-7.54 (1H, m), 7.78 (1H, d), 7.87 (1H, d, J = 7.8Hz), 7.98 (1H, d, J = 8.9Hz), 8.11 (1H, s), 8.84 (1H, s), 12.60-13.00 (1H, br),
15.29 (1H, s)
MS (ESI): M + 368
Example 3-19
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.74-3.77 (2H, m), 4.58 (2H, s), 4.61 (2H, t),
5.02 (1H, t, J = 5.6Hz), 7.29 (1H, d), 7.46 (1H, m), 7.56 (1H, m), 7.70 (1H, m), 7.81 (1H, d), 7.87 (1H , d), 8.01 (1H, s), 8.18 (1H, s), 8.86 (1H, s), 15.27 (1H, s)
MS (ESI): M + 417
Example 3-20
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.37 (3H, t, J = 6.9Hz), 3.70-3.80 (2H, m), 4.22
(2H, s), 4.28 (2H, q, J = 6.9Hz), 4.65 (2H, t), 5.00 (1H, t), 7.30-7.34 (3H, m), 7.60 (1H, d), 7.92 ( 1H, s), 8.80 (1H, s), 15.44 (1H, s)
MS (ESI): M + 436
Example 3-21
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.76 (2H, m), 4.40 (2H, s), 4.63 (2H, t, J = 5.1Hz), 5.02 (1H, t, J = 5.6Hz), 7.20 (1H, d , J = 6.3Hz), 7.35-7.39 (1H, m), 7.62 (1H, d, J = 6.3Hz), 8.00 (1H, s), 8.32 (1H, s), 8.89 (1H, s), 15.87 (1H, s)
MS (ESI): M + 426
Example 3-22
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.80 (2H, t, J = 5.3Hz), 4.48 (2H, s), 4.75 (2H,
t, J = 4.6Hz), 5.06 (1H, t, J = 5.6Hz), 7.24 (1H, d, J = 6.3Hz), 7.39-7.42 (1H, m), 7.65 (1H, d, J = 6.7 Hz), 7.95 (1H, s), 8.40 (1H, s), 9.00 (1H, s), 14.62 (1H, s)
MS (ESI): M + 460
Example 3-23
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.53 (3H, d, J = 6.4Hz), 3.76-3.83 (2H, m), 4.26
(2H, s), 5.19-5.23 (2H, m), 7.20-7.22 (1H, m), 7.41-7.49 (2H, m), 7.86 (1H, d), 8.17 (1H, d, J = 8.8Hz ), 8.24 (1H, s), 8.88 (1H, s)
MS (ESI): M + 390
Example 3-24
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.53 (3H, d, J = 6.8Hz), 3.76-3.82 (2H, m), 4.26
(2H, s), 5.19-5.23 (2H, m), 7.22-7.24 (1H, m), 7.41-7.49 (2H, m), 7.86 (1H, d), 8.17 (1H, d, J = 9.2Hz ), 8.24 (1H, s), 8.88 (1H, s)
MS (ESI): M + 390
Example 3-25
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.40-3.50 (2H, m), 4.34 (2H, s), 4.57 (2H, t),
4.89 (1H, t), 7.24-7.27 (1H, m), 7.45-7.51 (2H, m), 8.35 (1H, s), 8.45 (1H, s), 9.00 (1H, s), 14.30-14.40 ( 1H, br)
MS (ESI): M + 444
Example 3-26
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.84-3.96 (4H, m), 4.26 (2H, s), 5.13-5.18 (3H, m), 7.19-7.21 (1H, m), 7.40-7.48 (2H, m), 7.84 (1H, d, J = 9.2Hz), 8.15 (1H, d, J = 8.8Hz), 8.23 (1H, s), 8.90 (1H, s), 15.24 (1H, s)
MS (ESI): M + 406
Example 3-27
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.77 (2H, t, J = 5.2Hz), 4.53 (2H, s), 4.68 (2H,
t, J = 4.8Hz), 5.01 (1H, t, J = 5.6Hz), 7.32 (1H, d, J = 6.0Hz), 7.39-7.43 (1H, m), 7.64 (1H, d, J = 6.4 Hz), 8.07 (1H, s), 8.79 (1H, s), 8.96 (1H, s), 14.61 (1H, s)
MS (ESI): M + 417
Example 3-28
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.97 (3H, t, J = 7.2Hz), 2.58 (3H, s), 2.84 (2H,
q, J = 7.2Hz), 3.77 (2H, t), 4.21 (2H, s), 4.60 (2H, t), 5.00 (1H, t), 7.00-7.02 (1H, m), 7.12 (1H, d ), 7.20-7.24 (2H, m), 7.78 (1H, d, J = 8.8Hz), 7.98 (1H, d, J = 8.8Hz), 8.17 (1H, s), 8.84 (1H, s), 15.31 (1H, s)
MS (ESI): M + 381
Example 3-29
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.78 (3H, t, J = 7.2Hz), 1.42 (2H, m), 2.56 (3H,
s), 2.76 (2H, t, J = 6.8Hz), 3.74 (2H, t), 4.23 (2H, s), 4.60 (2H, t, J = 4.8Hz), 5.
02 (1H, t, J = 5.6Hz), 7.00-7.03 (1H, m), 7.09 (1H, d), 7.20-7.21 (2H, m), 7.77 (1H, d, J = 9.2Hz), 7.99 (1H, d, J = 8.8Hz), 8.15 (1H, s), 8.85 (1H, s), 15.30 (1H, s)
MS (ESI): M + 395
Example 3-30
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 2.52 (3H, s), 3.77 (2H, t, J = 4.8Hz), 4.01 (2H,
s), 4.30 (2H, s), 4.61 (2H, t), 4.90-5.10 (1H, br), 7.03-7.09 (2H, m), 7.20-7.26
(7H, m), 7.76 (1H, d), 7.98 (1H, d), 8.17 (1H, s), 8.85 (1H, s), 15.30 (1H, s)
MS (ESI): M + 443
Example 3-31
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 2.94 (3H, s), 3.09 (3H, s), 3.75 (2H, m), 4.13-4.18 (1H, m), 4.44-4.48 (1H, m), 4.61 (2H, t), 5.02 (1H, t, J = 5.6Hz), 7.33-7.37 (3H, m), 7.52 (1H, d, J = 9.2Hz), 7.81 (1H, d), 8.01 (1H, d, J = 8.8Hz), 8.15 (1H, s), 8.86 (1H, s), 15.27 (1H, s)
MS (ESI): M + 431
Example 3-32
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.01 (6H, d), 2.52 (3H, s), 3.12-3.19 (1H, m),
3.73-3.75 (2H, m), 4.20 (2H, s), 4.60 (2H, t), 5.02 (1H, t), 7.00-7.02 (1H, m), 7.11 (1H, d), 7.19-7.22 ( 2H, m), 7.77 (1H, d, J = 8.8Hz), 7.98 (1H, d, J = 9.2Hz), 8.18 (1H, s), 8.84 (1H, s), 15.31 (1H, s)
MS (ESI): M + 395
Example 3-33
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 1.86 (9H, s), 4.26 (2H, s), 7.22-7.24 (1H, m),
7.42-7.49 (2H, m), 7.79 (1H, d, J = 9.2Hz), 8.28 (1H, s), 8.39 (1H, d, J = 8.8Hz), 8.98 (1H, s), 15.16 (1H , s)
MS (ESI): M + 388
Example 3-34
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.71 (2H, m), 3.96 (3H, s), 4.21 (2H, s), 4.81
(2H, t), 4.89 (1H, t), 7.19-7.24 (1H, m), 7.40-7.52 (3H, m), 7.77 (1H, s), 8.68 (1H, s), 15.17 (1H, s )
MS (ESI): M + 406
Example 3-35
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.75 (2H, m), 4.09 (2H, s), 4.83 (2H, t), 5.33
(1H, t), 5.81 (2H, s), 7.15 (1H, s), 7.15-7.24 (1H, m), 7.36 (1H, m), 7.48 (1H, m), 7.57 (1H, s), 8.77 (1H, s), 15.37 (1H, s)
MS (ESI): M + 391
Example 3-36
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 3.79 (2H, t), 4.60 (2H, s), 4.68 (2H, t), 5.05
(1H, t), 7.11 (1H, d, J = 6.0Hz), 7.30-7.34 (1H, m), 7.57 (1H, d, J = 6.8Hz), 8.02 (1H, s), 8.38 (1H, s), 8.95 (1H, s), 13.60-14.00 (1H, br), 14.88 (1H, s)
MS (ESI): M + 436
Example 3-37
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.70-3.72 (2H, m), 4.98 (3H, s), 4.23 (2H, s),
4.81 (2H, t), 4.89 (1H, t), 7.20-7.26 (1H, m), 7.50 (1H, s), 7.62-7.67 (2H, m), 8.68 (1H, s), 15.10 (1H, s)
MS (ESI): M + 424
Example 3-38
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.67 (6H, s), 3.39 (2H, m), 4.21 (2H, s), 4.72
(1H, t), 4.97 (2H, t), 7.20-7.22 (1H, m), 7.40-7.50 (2H, m), 7.65 (1H, s), 7.84 (1H, s), 15.10 (1H, s )
MS (ESI): M + 419
Example 3-39
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.10 (3H, s), 4.50-4.60 (2H, m), 4.23 (2H, s),
4.65 (2H, t), 5.00 (1H, t), 7.20-7.30 (1H, m), 7.40-7.50 (2H, m), 7.65 (1H, s), 8.20 (1H, s), 8.83 (1H, s), 10.20 (1H, s), 15.00 (1H, s)
MS (ESI): M + 433
Example 3-40
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.74-3.75 (2H, m), 4.55 (2H, s), 4.65 (2H, t),
5.00 (1H, t), 7.17 (1H, d, J = 6.3Hz), 7.34-7.39 (1H, m), 7.62 (1H, d, J = 6.6Hz), 7.73 (1H, d, J = 9.3Hz ), 8.34 (1H, d, J = 9.3Hz), 8.97 (1H, s), 14.62 (1H, s)
MS (ESI): M + 417
Example 3-41
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.45 (3H, s), 2.97 (3H, s), 3.74-3.76 (2H, m),
4.12 (2H, s), 4.61 (2H, m), 5.03 (1H, t, J = 5.6Hz), 7.24-7.30 (1H, m), 7.30-7.39 (3H, m), 7.76 (1H, d) , 8.01 (1H, d, J = 8.8Hz), 8.13 (1H, s), 8.87 (1H, s), 15.23 (1H, s)
MS (ESI): M + 395
Example 3-42
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.88 (6H, t, J = 7.2Hz), 2.91 (4H, q, J = 6.8Hz), 3.75 (2H, m), 4.23 (2H, s), 4.60 (2H, t ), 5.02 (1H, t, J = 5.6Hz), 7.00-7.06 (1H, m), 7.14-7.25 (3H, m), 7.77 (1H, d), 7.98 (1H, d, J = 8.8Hz) , 8.16 (1H, s), 8.84 (1H, s), 15.32 (1H, s)
MS (ESI): M + 395
Example 3-43
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 1.78 (6H, s), 3.99 (2H, s), 4.25 (2H, s), 4.23
(2H, s), 5.52 (1H, br), 7.20-7.22 (1H, m), 7.42-7.49 (2H, m), 7.76 (1H, d, J = 9.2Hz), 8.27 (1H, s), 8.34 (1H, d, J = 9.2Hz), 9.05 (1H, s)
MS (ESI): M + 404
Example 3-44
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.36 (3H, t, J = 6.9Hz), 3.70-3.80 (2H, m), 4.12
(2H, s), 4.24 (2H, q, J = 7.0Hz), 4.62 (2H, t), 5.00 (1H, t), 7.16-7.27 (3H, m), 7.40-7.50 (1H, m), 8.12 (1H, s), 8.80 (1H, s), 15.50 (1H, s)
MS (ESI): M + 420
Example 3-45
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.70-3.80 (2H, m), 3.84 (3H, s), 3.85 (3H, s), 4.19 (2H, s), 4.75 (2H, t), 4.92 (1H, t, J = 5.6Hz), 7.21-7.28 (2H, m), 7.45-7.50 (1H, m), 7.95 (1H, s), 8.75 (1H, s), 15.09 (1H, s)
MS (ESI): M + 436
Example 3-46
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.62 (3H, s), 3.74 (2H, m), 4.02 (2H, s), 4.61
(2H, t), 5.01 (1H, t), 5.50-5.60 (1H, m), 6.30-6.43 (3H, m), 6.95-7.01 (1H, m), 7.82 (1H, d), 7.99 (1H , d, J = 8.8Hz), 8.21 (1H, s), 8.85 (1H, s), 15.33 (1H, s)
MS (ESI): M + 353
Example 3-47
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.42 (3H, t, J = 6.8Hz), 3.70-3.80 (2H, m), 4.20-4.23 (4H, m), 4.84-5.00 (3H, m), 7.20-7.30 ( 1H, m), 7.40-7.49 (3H, m), 7.77 (1H,
s), 8.67 (1H, s)
MS (ESI): M + 420
Example 3-48
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.78 (3H, s), 3.60-3.70 (2H, m), 4.16 (2H, s),
4.75-4.79 (2H, m), 5.38 (1H, t), 6.20-6.27 (1H, m), 7.07 (1H, s), 7.20-7.23 (1H,
m), 7.39-7.49 (3H, m), 8.80 (1H, s), 15.32 (1H, s)
MS (ESI): M + 405
Example 3-49
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.94 (3H, t, J = 7.2Hz), 1.72-1.78 (2H, m), 3.77
(2H, m), 4.13-4.14 (4H, m), 4.62 (2H, t), 5.00 (1H, br), 7.12-7.18 (2H, m), 7.26
(1H, s), 7.44-7.46 (1H, m), 8.13 (1H, s), 8.79 (1H, s), 15.49 (1H, s)
MS (ESI): M + 434
Example 3-50
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.00 (3H, s), 3.08 (3H, s), 3.75-3.77 (2H, m),
4.16 (2H, s), 4.57 (2H, t), 5.00 (1H, t, J = 5.6Hz), 7.09-7.18 (2H, m), 7.24 (1H, s), 7.40-7.41 (1H, m) , 7.85 (1H, s), 8.01 (1H, s), 8.72 (1H, s), 15.67 (1H, s)
MS (ESI): M + 446
Example 3-51
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.72 (3H, s), 3.72-3.80 (2H, m), 3.95 (3H, s),
4.06 (2H, s), 4.40-4.50 (2H, m), 5.00 (1H, t), 7.12 (1H, s), 7.15-7.19 (2H, m), 7.40-7.45 (1H, m), 7.88 ( 1H, s), 8.51 (1H, s)
MS (ESI): M + 420
Example 3-52
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.77 (2H, m), 4.17 (2H, s), 4.72 (2H, t, J = 4.8Hz), 4.97 (1H, t, J = 5.6Hz), 7.08 (2H, d , J = 7.6Hz), 7.09-7.25 (2H, m), 7.31-7.36 (2H, m), 7.43-7.49 (3H, m), 8.04 (1H, s), 7.76 (1H, s), 15.02 ( 1H, s)
MS (ESI): M + 468
Example 3-53
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.24 (6H, d, J = 7.2Hz), 3.75 (2H, t), 4.08 (2H,
s), 4.61 (2H, t), 4.99-5.04 (2H, m), 7.11-7.20 (2H, m), 7.28 (1H, s), 7.43-7.45 (1H, m), 8.17 (1H, s) , 8.79 (1H, s), 15.52 (1H, s)
MS (ESI): M + 434
Example 3-54
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.99 (3H, t, J = 7.3Hz), 1.60-1.70 (2H, m), 3.00-3.10 (2H, m), 3.70-3.80 (2H, m), 4.15 (2H, s), 4.82 (2H, t), 5.50 (1H, t), 6.20 (1H, t), 7.08 (1H, s), 7.10-7.20 (1H, m), 7.40-7.51 (3H, m), 8.78 (1H, s), 15.30-15.40 (1H, br)
MS (ESI): M + 433
Example 3-55
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.24 (3H, t, J = 6.9Hz), 3.08 (2H, m), 3.71-3.80
(2H, m), 4.15 (2H, s), 4.83 (2H, t), 5.43 (1H, t), 6.21 (1H, t), 7.10 (1H, s), 7.17-7.23 (1H, m), 7.36-7.52 (3H, m), 8.78 (1H, s)
MS (ESI): M + 419
Example 3-56
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.53 (3H, d, J = 6.8Hz), 3.72 (2H, m), 3.99 (3H,
s), 4.21 (2H, s), 5.12 (1H, t), 5.70-5.90 (1H, m), 7.20-7.21 (1H, m), 7.40-7.55 (3H, m), 7.76 (1H, s) , 8.85 (1H, s), 15.00-15.20 (1H, br)
MS (ESI): M + 420
Example 3-57
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.52 (3H, d, J = 6.8Hz), 3.71 (2H, t), 4.00 (3H,
s), 4.23 (2H, s), 5.10 (1H, t), 5.80-5.90 (1H, m), 7.20-7.30 (1H, m), 7.51 (1H, s), 7.60-7.67 (2H, m) , 8.85 (1H, s), 14.90-15.10 (1H, br)
MS (ESI): M + 438
Example 3-58
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.03 (3H, d, J = 8.4Hz), 1.78-1.87 (2H, m), 3.73
-3.75 (2H, m), 4.12 (2H, t), 4.20 (2H, s), 4.85 (2H, t), 4.92 (1H, t), 7.20 (1H,
m), 7.39-7.51 (3H, m), 7.76 (1H, s), 8.68 (1H, s), 15.17 (1H, s)
MS (ESI): M + 434
Example 3-59
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.35 (6H, s), 3.72-3.75 (2H, m), 4.20 (2H, s),
4.83-4.91 (4H, m), 7.20 (1H, m), 7.39-7.49 (3H, m), 7.74 (1H, s), 8.66 (1H, s), 15.18 (1H, s)
MS (ESI): M + 434
Example 3-60
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.86 (3H, t, J = 7.3Hz), 1.80-2.10 (2H, m), 3.70-3.90 (2H, m), 4.26 (2H, s), 5.00-5.10 (1H, m), 5.17 (1H, t, J = 5.4Hz), 7.19-7.24 (1H, m), 7.39-7.51 (2H, m), 7.84 (1H, d, J = 8.8Hz), 8.20 (1H, d , J = 8.8Hz), 8.23 (1H, s), 8.86 (1H, s), 15.24 (1H, s)
MS (ESI): M + 404
Example 3-61
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.36 (3H, t, J = 6.9Hz), 1.52 (3H, d, J = 6.6Hz), 3.78-3.80 (2H, m), 4.12 (2H, s), 4.26 (2H , q, J = 7.0Hz), 5.21-5.30 (2H, m), 7.16-7.24 (2H, m), 7.40-7.46 (2H, m), 8.14 (1H, s), 8.81 (1H, s), 15.40-15.60 (1H, br)
MS (ESI): M + 434
Example 3-62
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.88 (6H, s), 3.70-3.80 (2H, m), 4.22 (2H, s),
4.60-4.70 (2H, m), 5.05 (1H, t), 7.20-7.31 (3H, m), 7.50-7.60 (1H, m), 7.80 (1H,
s), 8.78 (1H, s), 15.30-15.40 (1H, br)
MS (ESI): M + 419
Example 3-63
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.90-1.29 (5H, m), 1.62-1.80 (6H, m), 3.75-3.78 (2H, m), 3.96 (2H, d, J = 10.8Hz), 4.13 (2H, s), 4.60-4.62 (2H, m), 5.02 (1H, t),
7.06-7.24 (2H, m), 7.14 (1H, s), 7.42-7.44 (1H, m), 8.16 (1H, s), 8.79 (1H, s)
MS (ESI): M + 488
Example 3-64
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.85-0.89 (6H, m), 2.96-3.00 (2H, m), 3.10-3.20 (2H, m), 3.33-3.40 (2H, m), 4.22 (2H, s), 4.74 (1H, t), 5.09-5.10 (2H, m), 7.20
(1H, m), 7.38-7.47 (2H, m), 7.59 (1H, s), 7.89 (1H, s), 8.72 (1H, s), 15.08 (1H,
s)
MS (ESI): M + 447
Example 3-65
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.91 (3H, d, J = 4.7Hz), 3.75-3.81 (2H, m), 4.01
(2H, s), 4.50-4.55 (2H, m), 5.04 (1H, t, J = 5.5Hz), 6.59 (1H, s), 6.60-6.68 (1H, m), 7.15-7.24 (2H, m ), 7.51-7.55 (1H, m), 7.63 (1H, s), 8.65 (1H, s), 15.90 (1H, s)
MS (ESI): M + 405
Example 3-66
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.91-2.00 (4H, m), 3.40-3.50 (4H, m), 3.70-3.81 (2H, m), 4.30 (2H, s), 4.50-4.55 (2H, m), 5.05 (1H, t), 6.87 (1H, s), 7.10-7.12 (1H, m), 7.18-7.21 (1H, m), 7.49-7.52 (1H, m), 7.72 (1H, s), 8.69 ( 1H, s), 15.65 (1H, s)
MS (ESI): M + 445
Example 3-67
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.44 (3H, t), 1.55 (3H, d), 3.70-3.77, (2H, m), 4.19 (2H, s), 4.28 (2H, q, J = 8.8Hz), 5.14 (1H, t), 5.83-5.90 (1H, m), 7.20 (1H,
m), 7.39-7.40 (1H, m), 7.48-7.50 (2H, m), 7.75 (1H, s), 8.86 (1H, s), 15.13 (1H, s)
MS (ESI): M + 434
Example 3-68
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.86 (3H, t, J = 7.3Hz), 1.37 (3H, t, J = 6.9Hz), 1.80-2.00 (2H, m), 3.70-3.90 (2H, m), 4.12 (2H, s), 4.20-4.28 (2H, m), 5.00-5.17 (2H, m), 7.14-7.30 (2H, m), 7.42-7.49 (2H, m), 8.14 (1H, s), 8.78 (1H, s), 15.50 (1H, s)
MS (ESI): M + 448
Example 3-69
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.09-1.27 (5H, m), 1.68-1.82 (6H, m), 3.71-3.73 (2H, m), 3.99 (2H, d, J = 5.6Hz), 4.20 (2H, s), 4.80-4.85 (2H, m), 4.92 (1H, t, J = 5.6Hz), 7.20 (1H, m), 7.38-7.40 (1H, m), 7.40-7.53 (2H, m), 7.75 (1H, s), 8.68 (1H, s), 15.16 (1H, s)
MS (ESI): M + 488
Example 3-70
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.70 (3H, d, J = 6.4Hz), 1.12 (3H, d, J = 6.4Hz), 2.30-2.40 (1H, m), 3.75-3.78 (1H, m), 3.95 -4.00 (1H, m), 4.25 (2H, s), 4.80-4.85 (1H, m), 5.18 (1H, t), 7.20-7.21 (1H, m), 7.41-7.48 (2H, m), 7.84 (1H, d), 8.21 (1H, s), 8.25 (1H, d, J = 9.2Hz), 8.92 (1H, s), 15.21 (1H, s)
MS (ESI): M + 418
Example 3-71
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.85 (3H, d), 0.90 (3H, d), 1.40-1.50 (1H, m),
1.80-1.91 (2H, m), 3.71-3.80 (2H, m), 4.25 (2H, s), 5.15-5.20 (2H, m), 7.20-7.21
(1H, m), 7.41-7.48 (2H, m), 7.84 (1H, d, J = 8.8Hz), 8.22 (1H, s), 8.24 (1H, d, J = 8.8Hz), 8.83 (1H, s), 15.20 (1H, s)
MS (ESI): M + 432
Example 3-72
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.86 (3H, t, J = 7.3Hz), 1.23 (6H, m), 1.80-2.00
(2H, m), 3.70-3.90 (2H, m), 4.09 (2H, s), 5.00-5.18 (3H, m), 7.12-7.21 (2H, m), 7.44-7.47 (2H, m), 8.20 (1H, s), 8.79 (1H, s), 15.54 (1H, s)
MS (ESI): M + 462
Example 3-73
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.87 (3H, t, J = 7.3Hz), 1.80-2.10 (2H, m), 3.70-3.90 (2H, m), 4.02 (3H, s), 4.11 (2H, s) , 5.00-5.19 (2H, m), 7.16-7.24 (2H, m), 7.44-7.48 (2H, m), 8.04 (1H, s), 8.78 (1H, s), 15.44 (1H, s)
MS (ESI): M + 434
Example 3-74
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.23 (6H, dx2), 1.51 (3H, d, J = 6.6Hz), 3.77 (2H, t), 4.09 (2H, s), 4.90-5.10 (1H, m), 5.19 -5.30 (2H, m), 7.12-7.21 (2H, m), 7.41-7.47 (2H, m), 8.20 (1H, s), 8.81 (1H, s), 15.55 (1H, s)
MS (ESI): M + 448
Example 3-75
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.00 (9H, s), 4.07-4.12 (2H, m), 4.30 (2H, s),
5.12-5.14 (2H, m), 7.20-7.25 (1H, m), 7.40-7.45 (1H, m), 7.51-7.53 (1H, m), 7.87
(1H, d), 8.25 (1H, s), 8.41 (1H, d, J = 9.2Hz), 8.85 (1H, s), 15.20-15.21 (1H, br)
MS (ESI): M + 432
Example 3-76
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.70-3.81 (4H, m), 4.15 (2H, s), 4.24 (2H, t,
J = 5.0Hz), 4.60-4.62 (2H, m), 5.00-5.02 (2H, m), 7.15-7.20 (1H, m), 7.32-7.34 (2H,
m), 7.44-7.49 (1H, m), 8.06 (1H, s), 8.79 (1H, s), 15.48 (1H, s)
MS (ESI): M + 436
Example 3-77
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.90-1.92 (2H, m), 3.53-3.54 (2H, m), 3.70-3.80 (2H, m), 4.12 (2H, s), 4.20-4.30 (2H, m), 4.60-4.70 (3H, m), 5.02 (1H, t), 7.16-7.22 (2H, m), 7.30 (1H, s), 7.40-7.50 (1H, m), 8.11 (1H, s), 8.80 ( 1H, s)
MS (ESI): M + 450
Example 3-78
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.10-3.20 (2H, m), 3.60-3.80 (4H, m), 4.15 (2H, s), 4.78-4.85 (3H, m), 5.30-5.40 (1H, m), 6.10-6.20 (1H, m), 7.15-7.20 (2H, m),
7.30-7.52 (3H, m), 8.77 (1H, s), 15.33 (1H, s)
MS (ESI): M + 435
Example 3-79
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.89 (3H, t, J = 7.4Hz), 1.90-2.00 (2H, m), 3.70-3.80 (2H, m), 3.99 (3H, s), 4.22 (2H, s) , 5.15 (1H, t, J = 5.4Hz), 5.70-5.80 (1H, m), 7.19-7.24 (1H, m), 7.38-7.52 (2H, m), 7.55 (1H, s), 7.77 (1H , s), 8.86 (1H, s), 15.12 (1H, s)
MS (ESI): M + 434
Example 3-80
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 1.59 (3H, d, J = 7.2Hz), 2.61 (3H, s), 2.80 (3H,
s), 4.20 (2H, s), 4.96 (1H, t, J = 5.6Hz), 6.50-6.60 (1H, m), 7.19-7.23 (1H, m), 7.40-7.49 (2H, m), 7.60 (1H, s), 7.80 (1H, s), 8.81 (1H, s), 15.06 (1H, s)
MS (ESI): M + 433
Example 3-81
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 4.10-4.40 (4H, m), 5.50-5.60 (1H, m), 6.20-6.30 (1H, m), 7.19-7.22 (1H, m), 7.30-7.40 (6H, m ), 7.40-7.50 (1H, m), 7.77 (1H, d), 8.00 (1H, d), 8.21 (1H, s), 9.03 (1H, s), 15.11 (1H, s)
MS (ESI): M + 452
Example 3-82
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.86 (3H, t), 1.18-1.34 (2H, m), 1.87-1.98 (2H, m), 3.73-3.84 (2H, m), 4.25 (2H, s), 5.13- 5.17 (2H, m), 7.21 (1H, m), 7.41-7.48
(2H, m), 7.83 (1H, d, J = 8.0Hz), 8.19 (1H, d), 8.22 (1H, s), 8.85 (1H, s), 15.22 (1H, s)
MS (ESI): M + 418
Example 3-83
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.72 (3H, t, J = 7.3Hz), 0.90-1.20 (5H, m), 2.10-2.30 (1H, m), 3.70-3.80 (1H, m), 3.90-4.10 ( 1H, m), 4.26 (2H, s), 4.90-5.00 (1H,
m), 5.10-5.20 (1H, m), 7.20-7.25 (1H, m), 7.40-7.52 (2H, m), 7.84 (1H, d, J = 7.8Hz), 8.23 (1H, s), 8.26 (1H, d), 8.92 (1H, s), 15.22 (1H, s)
MS (ESI): M + 432
Example 3-84
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.54 (3H, d, J = 6.6Hz), 3.81-3.82 (2H, m), 4.02
(3H, s), 4.12 (2H, s), 5.22 (1H, t, J = 5.4Hz), 5.23-5.40 (1H, m), 7.15-7.26 (2H, m), 7.44-7.50 (2H, m ), 8.05 (1H, s), 8.82 (1H, s), 15.46 (1H, s)
MS (ESI): M- 418
Example 3-85
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.25-3.38 (2H, m), 3.82-3.89 (2H, m), 4.21 (2H, s), 5.27 (1H, t), 5.40-5.50 (1H, m), 7.10- 7.21 (6H, m), 7.30-7.40 (1H, m), 7.40-7.50 (1H, m), 7.77 (1H, d), 8.14 (1H, d), 8.14 (1H, s), 8.96 (1H, s), 15.15 (1H,
s)
MS (ESI): M + 466
Example 3-86
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.70-3.80 (2H, m), 4.42 (2H, s), 4.69 (2H, t),
4.95 (1H, t), 7.37-7.42 (1H, m), 7.51 (1H, d, J = 6.2Hz), 7.59 (1H, d, J = 7.9Hz), 8.48 (1H, s), 8.99 (1H , s), 9.04 (1H, s), 14.68 (1H, s)
MS (ESI): M + 393
Example 4-1
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.26 (3H, s), 3.74 (2H, m), 4.42 (2H, s), 4.61
(2H, m), 5.09 (1H, br), 7.78 (1H, m), 7.84 (2H, m), 8.04-8.07 (2H, m), 8.18 (1H, m), 8.86 (1H, s), 15.19 (1H, s)
MS (ESI): M + 435
Example 4-2
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.73 (2H, m), 4.23 (2H, s), 4.59 (2H, m), 4.99
(1H, br), 7.20 (1H, m), 7.31-7.34 (2H, m), 7.44 (1H, m), 7.85 (1H, m), 8.01 (1H, s), 8.26 (1H, m), 8.85 (1H, s), 15.27 (1H, s)
MS (ESI): M + 407
Example 4-3
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.15 (3H, t, J = 7.6 Hz), 2.57 (2H, q, J = 7.6 Hz), 3.73 (2H, m), 4.13 (2H, s), 4.59 (2H, m ), 4.99 (1H, m), 7.05 (2H, m), 7.13 (1H, m), 7.20 (1H, m), 7.81 (1H, m), 7.98 (1H, m), 8.21 (1H, s) , 8.84 (1H, s), 15.28 (1H, s)
MS (ESI): M + 351
Example 4-4
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 1.07 (3H, t, J = 7.53 Hz), 2.58 (2H, q, J = 7.53
Hz), 3.76 (2H, m), 4.22 (2H, s), 4.61 (2H, m), 5.02 (1H, m), 7.19-7.23 (4H, m), 7.76 (1H, m), 8.01 (1H , m), 8.09 (1H, s), 8.86 (1H, s), 15.26 (1H, s)
MS (ESI): M + 351
Example 4-5
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 2.28 (3H, s), 3.75 (2H, m), 4.24 (2H, s), 4.61 (2H, m), 5.04 (1H, br), 7.13 (1H, d, J = 8.1Hz), 7.28-7.36 (2H, m), 7.81 (1H, d, J = 6.7Hz),
8.03 (1H, d, J = 8.9Hz), 8.13 (1H, s), 8.86 (1H, s), 15.24 (1H, brs)
MS (ESI): M + 372
Example 4-6
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.75 (2H, m), 4.29 (2H, s), 4.62 (2H, m), 5.07
(1H, m), 7.19 (1H, m), 7.40 (1H, m), 7.52 (1H, m), 7.84 (1H, m), 8.05 (1H, m), 8.19 (1H, s), 8.87 ( 1H, s), 15.20 (1H, s)
MS (ESI): M + 375
Example 4-7
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.75 (2H, m), 4.29 (2H, s), 4.61 (2H, t, J = 5.0Hz), 5.01 (2H, t, J = 5.4Hz), 7.45 (1H, d ), 7.51 (1H, d, J = 11.2Hz), 7.74 (1H, d), 7.84 (1H,
dd), 8.01 (1H, d), 8.15 (1H, s), 8.86 (1H, s), 15.21 (1H, brs)
MS (ESI): M + 436
Example 4-8
Example 4-9
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.76 (2H, m), 4.34 (2H, s), 4.59 (2H, m), 5.01
(1H, m), 7.37 (2H, m), 7.62 (1H, m), 8.07 (2H, m), 8.88 (1H, s), 14.99 (1H, s) MS (ESI): M + 409
Example 4-10
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.20 (3H, s), 3.74 (2H, m), 4.31 (2H, s), 4.61 (2H
, t), 5.00 (1H, t), 7.55-7.66 (2H, m), 7.78 (1H, d), 7.84-7.89 (2H, m), 8.03 (1H, d, J = 8.9Hz), 8.30 ( 1H, s), 8.86 (1H, s), 15.27 (1H, brs)
MS (ESI): M + 402
Example 4-11
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 3.75 (2H, m), 4.18 (2H, s), 4.61 (2H, m), 5.02
(1H, m), 6.69 (1H, m), 6.77 (1H, m), 7.23 (1H, m), 7.80 (1H, m), 8.02 (1H, m), 8.15 (1H, s), 8.86 ( 1H, s), 9.66 (1H, s), 15.24 (1H, s)
MS (ESI): M + 373
Example 4-12
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 3.75 (2H, m), 4.29 (2H, s), 4.58 (2H, m), 5.00
(1H, s), 7.31 (1H, m), 7.35 (1H, m), 7.58 (1H, m), 7.71 (1H, m), 7.82 (1H, m), 8.86 (1H, s)
MS (ESI): M + 409
Example 4-13
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 1.34 (3H, t, J = 6.8Hz), 3.73 (2H, m), 4.00 (2H, q, J = 6.8Hz), 4.09 (2H, s), 4.59 (2H, m ), 5.00 (1H, m), 6.89 (1H, m), 6.95 (1H,
m), 7.19 (1H, m), 7.27 (1H, m), 7.83 (1H, m), 7.97 (1H, m), 8.24 (1H, s), 8.84 (1H, s), 15.33 (1H, s )
MS (ESI): M + 367
Example 4-14
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 3.73 (2H, m), 4.06 (2H, s), 4.60 (2H, m), 5.05
(1H, m), 6.74 (1H, m), 6.85 (1H, m), 7.05 (1H, m), 7.14 (1H, m), 7.82 (1H, m), 7.99 (1H, m), 8.19 ( 1H, s), 8.84 (1H, s), 9.55 (1H, s), 15.34 (1H, s)
MS (ESI): M + 339
Example 4-15
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 2.49 (3H, s), 3.77 (2H, m), 4.27 (2H, s), 4.60
(2H, m), 5.01 (1H, s), 7.17 (1H, m), 7.35 (1H, m), 7.59 (1H, m), 7.78 (1H, s), 7.95 (1H, s), 8.81 ( 1H, s), 15.22 (1H, s)
MS (ESI): M + 406
Example 4-16
¹ H NMR (DMSO-d ₆ (400MHz) (δ) ppm: 1.35 (3H, d), 1.40 (3H, d), 1.54 (3H, d, J = 6.8Hz), 3.72 (2H, m), 4.20 (2H, s), 4.86-4.92 (1H, m), 5.12 (1H, t, J = 5.2Hz), 5.80-5.90 (1H, m), 7.20 (1H, m), 7.39-7.52 (3H, m), 7.74 (1H, s), 8.84 (1H, s), 15.13 (1H, s)
MS (ESI): M + 448
Example 4-17
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.89 (3H, t, J = 7.2Hz), 1.35-1.37 (6H, d), 1.88-2.06 (2H, m), 3.73-3.79 (2H, m), 4.20 (2H, s), 4.80-5.00 (1H, m), 5.16 (1H, t), 5.81-5.84 (1H, m), 7.20 (1H, m), 7.40-7.53 (3H, m), 7.75 (1H, s) , 8.83 (1H, s), 15.09 (1H, s)
MS (ESI): M + 462
Example 4-18
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.80-1.40 (6H, m), 1.40-1.60 (2H, m), 1.70-1.80 (1H, m), 1.80-2.10 (2H, m), 3.70-3.80 (1H, m ), 3.90-4.00 (1H, m), 4.26 (2H, s),
4.80-5.00 (1H, m), 5.19 (1H, t), 7.22-7.25 (1H, m), 7.42-7.49 (2H, m), 7.85 (1H,
d), 8.22 (1H, s), 8.26 (1H, d, J = 9.1Hz), 8.95 (1H, s)
MS (ESI): M + 458
Example 4-19
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.70 (3H, d, J = 6.6Hz), 1.14 (3H, d, J = 6.4Hz), 1.21-1.24 (6H, m), 2.20-2.40 (1H, m), 3.70 -3.80 (1H, m), 3.90-4.00 (1H, m), 4.09
(2H, s), 4.80-4.90 (1H, m), 5.00-5.20 (2H, m), 7.12-7.22 (2H, m), 7.43-7.47 (2H, m), 8.19 (1H, s), 8.87 (1H, s), 15.51 (1H, s)
MS (ESI): M + 476
Example 4-20
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.97 (9H, s), 1.18 (3H, d, J = 5.9Hz), 1.26 (3H,
d, J = 6.0Hz), 4.04-4.09 (4H, m), 5.09-5.13 (3H, m), 7.12-7.21 (2H, m), 7.43-7.51 (2H, m), 8.19 (1H, s) , 8.78 (1H, s), 15.46 (1H, s)
MS (ESI): M + 490
Example 4-21
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.89 (3H, t, J = 7.6Hz), 1.44 (3H, t), 1.92-2.06
(2H, m), 3.78 (2H, m), 4.19 (2H, s), 4.25 (2H, q), 5.17 (1H, t, 5.6Hz), 5.78-5.83 (1H, m), 7.20 (1H, m), 7.39-7.51 (3H, m), 7.76 (1H, s), 8.85 (1H, s), 15.11 (1H, s)
MS (ESI): M + 448
Example 4-22
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.80-1.30 (6H, m), 1.50-1.80 (5H, m), 1.80-1.90 (2H, m), 3.60-3.80 (2H, m), 4.26 (2H, s), 5.10-5.20 (2H, m), 7.22 (1H, m), 7.30-7.50 (2H, m), 7.85 (1H, d), 8.23 (1H, d), 8.23 (1H, s), 8.84 (1H, s), 15.20 (1H, s)
MS (ESI): M + 472
Example 4-23
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.85 (3H, d), 0.91 (3H, d), 1.24-1.27 (6H, m),
1.35-1.43 (1H, m), 1.70-1.80 (1H, m), 1.91-1.95 (1H, m), 3.75-3.80 (2H, m), 4.08
(2H, s), 5.00-5.10 (1H, m), 5.16-5.19 (2H, m), 7.14-7.21 (2H, m), 7.43-7.44 (2H,
m), 8.18 (1H, s), 8.79 (1H, s)
MS (ESI): M + 490
Example 4-24
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.72 (3H, d), 1.09 (3H, d), 1.37-1.40 (6H, m),
2.35-2.38 (1H, m), 3.77-3.79 (1H, m), 3.91-3.94 (1H, m), 4.20 (2H, s), 4.92-4.96
(1H, m), 5.23 (1H, t), 5.74-5.76 (1H, m), 7.21 (1H, m), 7.40-7.53 (3H, m), 7.75 (1H, s), 8.88 (1H, s ), 15.08 (1H, s)
MS (ESI): M + 476
Example 4-25
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.84 (3H, d, J = 6.8Hz), 0.87 (3H, d, J = 6.4Hz), 1.37 (3H, d, J = 11.2Hz), 1.42 (3H, d, J = 10.8Hz), 1.83-1.87 (2H, m), 3.79-3.80 (2H,
m), 4.20 (2H, s), 4.90-4.96 (1H, m), 5.20 (1H, t), 6.08-6.10 (1H, m), 7.21 (1H, m), 7.39-7.55 (3H, m) , 7.75 (1H, s), 8.78 (1H, s), 15.08 (1H, s)
MS (ESI): M + 490
Example 4-26
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.91 (9H, s), 1.35 (3H, d), 1.44 (3H, d), 4.02-4.03 (2H, m), 4.20 (2H, s), 4.92-4.95 (1H, m), 5.15 (1H, t), 6.43 (1H, t), 7.19-7.21 (1H, m), 7.39-7.48 (2H, m), 7.55 (1H, s), 7.79 (1H, s), 8.80 (1H, s), 15.05 (1H, s)
MS (ESI): M + 490
Example 4-27
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.76 (3H, t), 0.97-1.03 (2H, m), 1.12 (3H, d),
2.10-2.20 (1H, m), 3.75-3.80 (1H, m), 3.98-4.02 (1H, m), 4.02 (3H, s), 4.11 (2H,
s), 4.92-4.95 (1H, m), 5.19 (1H, t), 7.16-7.25 (2H, m), 7.44-7.50 (2H, m), 8.02 (1H, s), 8.87 (1H, s) , 15.40 (1H, s)
MS (ESI): M + 462
Example 4-28
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.74 (3H, t, J = 7.6Hz), 0.99-1.03 (2H, m), 1.11
(3H, d), 1.37 (3H, t, J = 6.8Hz), 2.10-2.20 (1H, m), 3.70-3.80 (1H, m), 3.96-4.00 (1H, m), 4.11 (2H, s ), 4.26 (2H, q, J = 7.2Hz), 4.92-5.00 (1H, m), 5.18 (1H, t), 7.14-7.18 (1H, m), 7.24-7.25 (1H, m), 7.40 ( 1H, s), 7.44-7.46 (1H, m), 8.12 (1H, s), 8.86 (1H, s), 15.46 (1H, s)
MS (ESI): M + 476
Example 4-29
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.89 (3H, t, J = 7.3Hz), 1.98-2.01 (2H, m), 2.70
(3H, s), 3.80-3.90 (2H, m), 4.21 (2H, s), 5.10-5.21 (2H, m), 7.15-7.22 (2H, m), 7.49-7.51 (1H, m), 7.65 (1H, s), 8.04 (1H, s), 8.84 (1H, s), 15.25 (1H, s)
MS (ESI): M + 450
Example 4-30
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.70 (3H, d, J = 6.5Hz), 1.15 (3H, d, J = 6.5Hz), 1.37 (3H, t, J = 6.9Hz), 2.30-2.40 (1H, m ), 3.70-3.80 (1H, m), 3.90-4.00 (1H, m), 4.11 (2H, s), 4.20-4.30 (2H, m), 4.80-4.90 (1H, m), 5.18 (1H, t ), 7.14-7.20 (1H, m), 7.24-7.26 (1H, m), 7.43-7.49 (2H, m), 8.13 (1H, s), 8.87 (1H, s), 15.49 (1H, s)
MS (ESI): M + 462
Example 4-31
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.97 (9H, s), 1.37 (3H, t, J = 6.9Hz), 4.02-4.11
(4H, m), 4.25-4.31 (2H, m), 5.10-5.20 (2H, m), 7.14-7.26 (2H, m), 7.44-7.49 (2H,
m), 8.12 (1H, s), 8.78 (1H, s), 15.43 (1H, s)
MS (ESI): M + 476
Example 4-32
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.72 (3H, d, J = 6.5Hz), 1.16 (3H, d, J = 6.5Hz), 2.30-2.50 (1H, m), 3.70-3.90 (1H, m), 3.90 -4.00 (1H, m), 4.03 (3H, s), 4.12 (2H, s), 4.80-4.90 (1H, m), 5.19 (1H, t), 7.19-7.25 (2H, m), 7.46-7.51 (2H, m), 8.04 (1H, s), 8.88 (1H, s), 15.44 (1H, s)
MS (ESI): M + 448
Example 4-33
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.99 (9H, s), 3.99-4.11 (7H, m), 5.11-5.20 (2H, m), 7.19-7.25 (2H, m), 7.49-7.52 (2H, m), 8.03 (1H, s), 8.78 (1H, s), 15.39 (1H, s)
MS (ESI): M + 462
Example 4-34
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.93 (9H, s), 3.90-4.03 (5H, m), 4.22 (2H, s), 5.10 (1H, t), 6.20 (1H, t), 7.20-7.30 (1H, m), 7.40-7.57 (2H, m), 7.60 (1H, s), 7.79 (1H, s), 8.78 (1H, s), 15.05 (1H, s)
MS (ESI): M + 462
Example 4-35
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.86 (3H, t, J = 7.2Hz), 1.19-1.29 (8H, m), 1.90-1.93 (2H, m), 3.72-3.80 (2H, m), 4.08 (2H, s), 5.02-5.04 (1H, m), 5.10-5.20 (2H,
m), 7.11-7.22 (2H, m), 7.43-7.46 (2H, m), 8.18 (1H, s), 8.78 (1H, s), 15.51 (1H,
s)
MS (ESI): M + 476
Example 4-36
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.88 (3H, t, J = 7.2Hz), 1.20-1.35 (2H, m), 1.36
(3H, t, J = 6.8Hz), 1.80-2.00 (2H, m), 3.70-3.80 (2H, m), 4.11 (2H, s), 4.25 (2H, q, J = 7.2Hz), 5.17 ( 1H, t, J = 5.6Hz), 7.14-7.18 (1H, m), 7.24-7.26 (1H, m), 7.41 (1
H, s), 7.41-7.45 (1H, m), 8.13 (1H, s), 8.78 (1H, s), 15.48 (1H, s)
MS (ESI): M + 462
Example 4-37
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.93 (9H, s), 1.49 (3H, t), 4.00 (2H, t, J = 6.4Hz), 4.20 (2H, s), 4.22-4.33 (2H, m), 5.12 (1H, t), 6.36 (1H, t, J = 6.8Hz), 7.21 (1H, m), 7.39-7.48 (2H, m), 7.54 (1H, s), 7.79 (1H, s), 8.79 ( 1H, s), 15.04 (1H, s)
MS (ESI): M + 476
Example 4-38
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.89 (3H, t, J = 8.0Hz), 1.23-1.40 (2H, m), 1.80-2.00 (2H, m), 3.75-3.90 (2H, m), 4.02 (3H, s), 4.11 (2H, s), 5.10-5.21 (2H, m), 7.16-7.24 (2H, m), 7.44-7.49 (2H, m), 8.03 (1H, s), 8.80 (1H, s) , 15.44 (1H, br) MS (ESI): M + 448
Example 4-39
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.74 (3H, t, J = 7.1Hz), 0.84-1.24 (11H, m), 2.10-2.30 (1H, m), 3.70-3.80 (1H, m), 3.90-4.00 ( 1H, m), 4.09 (2H, s), 4.80-5.17 (3H, m), 7.15-7.22 (2H, m), 7.40-7.50 (2H, m), 8.19 (1H, s), 8.87 (1H, s), 15.51 (1H, s)
MS (ESI): M + 490
Example 4-40
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.80-0.89 (1H, m), 1.04-1.30 (11H, m), 1.50-1.60 (2H, m), 1.70-1.80 (1H, m), 1.93-2.01 (2H, m ), 3.73-3.76 (1H, m), 3.96-4.00 (1H, m), 4.07 (2H, s), 4.80-4.89 (1H, m), 5.00-5.17 (2H, m), 7.12-7.21 (2H , m), 7.40-7.42 (2H, m), 8.17 (1H, s), 8.87 (1H, s)
MS (ESI): M + 516
Example 4-41
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.80-1.30 (6H, m), 1.46 (3H, t, J = 6.9Hz), 1.50-1.70 (2H, m), 1.70-1.80 (1H, m), 1.90-2.10 ( 2H, m), 3.70-3.81 (1H, m), 3.92-4.00
(1H, m), 4.20 (3H, s), 4.23 (2H, q, J = 6.6Hz), 5.20 (1H, t, J = 4.8Hz), 5.70-5.81 (1H, m), 7.19-7.24 ( 1H, m), 7.38-7.51 (3H, m), 7.77 (1H, s), 8.91 (1H, s), 15.11 (1H, s)
MS (ESI): M + 502
Example 4-42
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.84-1.30 (6H, m), 1.50-1.70 (2H, m), 1.70-1.90 (1H, m), 1.94-2.10 (2H, m), 3.70-3.79 (1H, m ), 3.90-4.00 (1H, m), 4.03 (3H, s),
4.10 (2H, s), 4.80-5.00 (1H, m), 5.19 (1H, m), 7.19-7.30 (2H, m), 7.43-7.48 (2H,
m), 8.02 (1H, s), 8.87 (1H, s), 15.45 (1H, s)
MS (ESI): M + 488
Example 4-43
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.80-1.00 (1H, m), 1.14-1.28 (5H, m), 1.37 (3H, t, J = 6.9Hz), 1.50-1.70 (2H, m), 1.70-1.80 ( 1H, m), 1.90-2.10 (2H, m), 3.70-3.80
(1H, m), 3.90-4.00 (1H, m), 4.11 (2H, s), 4.25 (2H, q), 4.80-5.00 (1H, m), 5.18 (1H, m), 7.17-7.26 (2H , m), 7.41-7.47 (2H, m), 8.13 (1H, s), 8.89 (1H, s)
MS (ESI): M + 502
Example 4-44
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.80-1.00 (1H, m), 1.00-1.40 (5H, m), 1.50-1.70 (2H, m), 1.70-1.80 (1H, m), 1.90-2.10 (2H, m ), 3.70-3.80 (1H, m), 3.90-4.00 (1H, m), 3.98 (3H, s), 4.21 (2H, s), 5.20 (1H, m), 5.60-5.70 (1H, m), 7.19-7.25 (1H, m), 7.39-7.54 (3H, m), 7.77 (1H, s), 8.92 (1H, s)
MS (ESI): M + 488
Example 4-45
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.74 (3H, d, J = 4.0Hz), 1.08 (3H, d, J = 8.0Hz), 1.45 (3H, t, J = 8.0Hz), 2.36-2.40 (2H, m ), 3.70-3.80 (1H, m), 3.89-3.93 (1H, m), 4.19 (2H, s), 4.26 (2H, q, J = 8.0Hz), 5.20 (1H, t, J = 8.0Hz) , 5.69-5.73 (1H, m), 7.17-7.20 (1H, m), 7.39 (1H, m), 7.48-7.51 (2H, m), 7.76 (1H, s), 8.89 (1H, s)
MS (ESI): M + 462
Example 4-46
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.73 (3H, d, J = 6.8Hz), 1.08 (3H, d, J = 6.8Hz), 2.20-2.40 (2H, m), 3.81-3.91 (1H, m), 3.91 -3.99 (1H, m), 3.99 (3H, s), 4.22 (2H, s), 5.20 (1H, m), 5.55-5.58 (1H, m), 7.10-7.22 (1H, m), 7.41-7.55 (3H, m), 7.77 (1H, s), 8.91 (1H, s), 15.09 (1H, s)
MS (ESI): M + 448
Example 4-47
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.85 (3H, d, J = 7.3Hz), 1.10-1.34 (2H, m), 1.33
(6H, d, J = 6.0Hz), 1.70-2.00 (2H, m), 3.75 (2H, m), 4.17 (2H, s), 4.80-4.90 (1H, m), 5.14 (1H, m), 5.80-6.00 (1H, m), 7.10-7.20 (1H, m), 7.30-7.50 (3H, m), 7.72 (1H, s), 8.80 (1H, s)
MS (ESI): M + 476
Example 4-48
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.89 (3H, t), 1.20-1.40 (2H, m), 1.44 (3H, t),
1.80-2.00 (2H, m), 3.78 (2H, m), 4.20 (2H, s), 4.23 (2H, q, J = 6.8Hz), 5.16 (1H,
t, J = 5.6Hz), 5.90-5.92 (1H, m), 7.15-7.21 (1H, m), 7.39-7.52 (3H, m), 7.76 (1H, s), 8.84 (1H, s), 15.10 (1H, s)
MS (ESI): M + 462
Example 4-49
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.89 (3H, t), 1.23-1.35 (2H, m), 1.87-1.96 (2H, m), 3.72-3.79 (2H, m), 3.98 (3H, s), 4.21 ( 2H, s), 5.15 (1H, t, J = 5.2Hz), 5.85-5.88 (1H, m), 7.15-7.21 (1H, m), 7.39-7.48 (2H, m), 7.54 (1H, s) , 7.76 (1H, s), 8.85 (1H, s), 15.10 (1H, s)
MS (ESI): M + 448
Example 4-50
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.80-1.00 (1H, m), 1.11-1.20 (4H, m), 1.20-1.30 (1H, m), 1.35 (3H, d), 1.40 (3H, d), 1.55- 1.70 (2H, m), 1.72-1.80 (1H, m), 1.95-2.10 (2H, m), 3.77-3.79 (1H, m), 3.95-3.98 (1H, m), 4.20 (2H, s), 4.91-4.94 (1H, m), 5.24 (1H, t), 5.81-5.83 (1H, m), 7.15-7.21 (1H, m), 7.39-7.50 (2H, m), 7.53 (1H, s), 7.74 (1H, s), 8.89 (1H, s), 15.09 (1H, s)
MS (ESI): M + 516
Example 4-51
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.91 (9H, s), 1.48 (3H, t, J = 6.9Hz), 3.90-4.00
(2H, m), 4.13 (2H, s), 4.22 (2H, q, J = 7.0Hz), 4.90-5.00 (1H, m), 6.10-6.20 (1H, m), 7.17-7.22 (1H, m ), 7.34-7.36 (2H, m), 7.45-7.50 (1H, m), 7.77 (1H, s), 8.75 (1H, s)
MS (ESI): M + 476
Example 4-52
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.93 (9H, s), 3.90-4.02 (2H, m), 4.15 (2H, s),
4.80-4.81 (1H, m), 5.05 (1H, m), 7.19-7.21 (1H, m), 7.35-7.40 (1H, m), 7.43-7.45
(1H, m), 7.57 (1H, d), 8.01-8.03 (1H, d, J = 8.8Hz), 8.12 (1H, s), 8.76 (1H, s)
MS (ESI): M + 432
Example 4-53
¹ H NMR (DMSO-d ₆ 400MHz) (δ) ppm: 0.81 (3H, d), 1.20 (3H, d), 2.28-2.41 (1H, m),
3.98 (3H, s), 4.00-4.05 (2H, m), 4.08 (2H, s), 4.51-4.60 (1H, m), 7.02-7.08 (2H,
m), 7.19 (1H, s), 7.28-7.30 (1H, m), 8.15 (1H, s), 8.60 (1H, s)
MS (ESI): M + 448
Example 4-54
¹ H NMR (DMSO-d ₆ (300MHz) (δ) ppm: 0.95 (9H, s), 3.96 (3H, s), 3.96-4.03 (4H, m), 4.83 (1H, m), 5.17 (1H, m), 7.13-7.23 (2H, m), 7.28 (1H, s), 7.42-7.47 (1H, m),
7.80 (1H, s), 8.73 (1H, s)
MS (ESI): M + 462

Sequence Listing Free Text SEQ ID NO: 1: Donor for determining activity of HIV integrase + strand SEQ ID NO: 2: Donor for determining activity of HIV integrase-Strand SEQ ID NO: 3: Target for determining HIV integrase activity + strand SEQ ID NO: 4: HIV Target-chain for determining integrase activity

Claims (28)

An anti-HIV agent comprising a 4-oxoquinoline compound represented by the following general formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient.

[Where:
Ring Cy is
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from the following group A, or
A heterocyclic group which may be substituted by 1 to 5 substituents selected from the following group A;
(Here, the heterocyclic group is a saturated or unsaturated ring including at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.)
Group A
Cyano group, phenyl group, nitro group, halogen atom, C _1-4 alkyl group,
Halo C _1-4 alkyl group, halo C _1-4 alkyloxy group,
-OR ^a1 , -SR ^a1 , -NR ^a1 R ^a2 ,
-CONR ^a1 R ^a2 , -SO ₂ NR ^a1 R ^a2 ,
-COR ^a3 , -NR ^a1 COR ^a3 , -SO ₂ R ^a3 , -NR ^a1 SO ₂ R ^a3 ,
-COOR ^a1 and -NR ^a2 COOR ^a3
A group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, or a benzyl group, and R ^a3 represents a C _1-4 alkyl group.)
R ¹ is
A substituent selected from the following group B, or
A C _1-10 alkyl group which may be substituted with a halogen atom and 1 to 3 substituents selected from the following group B;
Group B
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group optionally substituted with 1 to 5 substituents selected from Group A (as defined above);
-OR ^a4 , -SR ^a4 , -NR ^a4 R ^a5 ,
-CONR ^a4 R ^a5 , -SO ₂ NR ^a4 R ^a5 ,
-COR ^a6 , -NR ^a4 COR ^a6 , -SO ₂ R ^a6 , -NR ^a4 SO ₂ R ^a6 ,
-COOR ^a4 and -NR ^a5 COOR ^a6
{Wherein, R ^a4 and R ^a5 are the same or different and each is hydrogen atom, C _1-4 alkyl groups, 1 to 5 substituents which may be substituted with a substituent C _3-10 selected from the above-mentioned group A A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from Group A, wherein R ^a6 is a C _1-4 alkyl group, C _3-10 carbocyclic group which may be substituted with 1 to 5 substituents selected from group A, or heterocyclic group which may be substituted with 1 to 5 substituents selected from group A (As defined above). }
R ² is a hydrogen atom or a C _1-4 alkyl group,
R ³¹ represents a hydrogen atom, a cyano group, a hydroxy group, an amino group, a nitro group,
Halogen atom, C _1-4 alkyl group, C _1-4 alkoxy group, C _1-4 alkylsulfanyl group,
A halo C _1-4 alkyl group or a halo C _1-4 alkyloxy group,
X is C—R ³² or a nitrogen atom;
Y is C—R ³³ or a nitrogen atom;
Here, R ³² and R ³³ are the same or different and each represents a hydrogen atom, a cyano group, a nitro group, a halogen atom,
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group optionally substituted with 1 to 5 substituents selected from Group A (as defined above);
A C _1-10 alkyl group which may be substituted with a halogen atom and 1 to 3 substituents selected from the group B;
-OR ^a7 , -SR ^a7 , -NR ^a7 R ^a8 ,
-NR ^a7 COR ^a9 , -COOR ^a10 , or
-N = CH-NR ^a10 R ^a11
(Wherein, R ^a7 and R ^a8 are the same or different and each is hydrogen atom, group B, or may be substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B C _{1- 10 is} an alkyl group, R ^a9 is a C _1-4 alkyl group, and R ^a10 and R ^a11 are the same or different and each is a hydrogen atom or a C _1-4 alkyl group. ] The anti-HIV agent according to claim 1, wherein X is C-R ³² and Y is C-R ³³ . Ring Cy is

[Wherein R ⁴ and R ⁶ are the same or different and each is a substituent selected from the following group A;
Here, group A is
Cyano group, phenyl group, nitro group, halogen atom, C _1-4 alkyl group,
Halo C _1-4 alkyl group, halo C _1-4 alkyloxy group,
-OR ^a1 , -SR ^a1 , -NR ^a1 R ^a2 ,
-CONR ^a1 R ^a2 , -SO ₂ NR ^a1 R ^a2 ,
-COR ^a3 , -NR ^a1 COR ^a3 , -SO ₂ R ^a3 , -NR ^a1 SO ₂ R ^a3 ,
-COOR ^a1 and -NR ^a2 COOR ^a3
A group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, or a benzyl group, and R ^a3 represents a C _1-4 alkyl group.)
R ⁵ is a hydrogen atom and a substituent selected from group A, wherein R ⁴ and R ⁵ may form a condensed ring together with the benzene ring they substitute, and m is 0 Or it is an integer of 1 to 3, and when m is 2 or 3, the R ^{6 s} may be the same or different from each other. The anti-HIV agent according to claim 1. The anti-HIV agent according to claim 1, wherein R ² is a hydrogen atom. 4-oxoquinoline compound represented by the following general formula [II] or a pharmaceutically acceptable salt thereof.

[Where:
R ⁴ and R ⁶ are the same or different and each is a substituent selected from the following group A;
Group A is here
Cyano group, phenyl group, nitro group, halogen atom, C _1-4 alkyl group,
Halo C _1-4 alkyl group, halo C _1-4 alkyloxy group,
−OR ^a1 , −SR ^a1 ,
-NR ^a1 R ^a2 , -CONR ^a1 R ^a2 , -SO ₂ NR ^a1 R ^a2 ,
-COR ^a3 , -NR ^a1 COR ^a3 , -SO ₂ R ^a3 , -NR ^a1 SO ₂ R ^a3 ,
-COOR ^a1 and -NR ^a2 COOR ^a3
A group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, or a benzyl group, and R ^a3 represents a C _1-4 alkyl group.)
R ⁵ is a hydrogen atom and a substituent selected from the above group A, wherein R ⁴ and R ⁵ together with the benzene ring they substitute may form a condensed ring;
m is 0 or an integer of 1 to 3, and when m is 2 or 3, each R ⁶ may be the same or different,
R ¹ is
A substituent selected from the following group B, or
A C _1-10 alkyl group which may be substituted with a halogen atom and 1 to 3 substituents selected from the following group B;
Group B
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group optionally substituted by 1 to 5 substituents selected from Group A above;
(Here, the heterocyclic group is a saturated or unsaturated ring including at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.)
-OR ^a4 , -SR ^a4 ,
-NR ^a4 R ^a5 , -CONR ^a4 R ^a5 , -SO ₂ NR ^a4 R ^a5 ,
-COR ^a6 , -NR ^a4 COR ^a6 , -SO ₂ R ^a6 , -NR ^a4 SO ₂ R ^a6 ,
-COOR ^a4 and -NR ^a5 COOR ^a6
{Wherein, R ^a4 and R ^a5 are the same or different and each is hydrogen atom, C _1-4 alkyl groups, 1 to 5 substituents which may be substituted with a substituent C _3-10 selected from the above-mentioned group A A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from Group A, wherein R ^a6 is a C _1-4 alkyl group, C _3-10 carbocyclic group which may be substituted with 1 to 5 substituents selected from group A, or heterocyclic group which may be substituted with 1 to 5 substituents selected from group A (As defined above). }
R ³¹ represents a hydrogen atom, a cyano group, a hydroxy group, an amino group, a nitro group,
Halogen atom, C _1-4 alkyl group, C _1-4 alkoxy group, C _1-4 alkylsulfanyl group,
A halo C _1-4 alkyl group or a halo C _1-4 alkyloxy group,
R ³² and R ³³ are the same or different and each represents a hydrogen atom, a cyano group, a nitro group, a halogen atom,
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group optionally substituted with 1 to 5 substituents selected from Group A (as defined above);
A C _1-10 alkyl group which may be substituted with a halogen atom and 1 to 3 substituents selected from the group B;
-OR ^a7 , -SR ^a7 , -NR ^a7 R ^a8 ,
-NR ^a7 COR ^a9 , -COOR ^a10 , or
-N = CH-NR ^a10 R ^a11
(Wherein, R ^a7 and R ^a8 are the same or different and each is hydrogen atom, group B, or may be substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B C _{1- 10 is} an alkyl group, R ^a9 is a C _1-4 alkyl group, and R ^a10 and R ^a11 are the same or different and each is a hydrogen atom or a C _1-4 alkyl group. ] The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R ³¹ is a hydrogen atom, a cyano group, a hydroxy group, or a C _1-4 alkoxy group. The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 6, wherein R ³¹ is a hydrogen atom. R ³² and R ³³ are the same or different,
Hydrogen atom, cyano group, halogen atom,
A heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A;
(Here, the heterocyclic group is a saturated or unsaturated ring including at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.)
Group A is here
Cyano group, phenyl group, nitro group, halogen atom, C _1-4 alkyl group,
Halo C _1-4 alkyl group, halo C _1-4 alkyloxy group,
−OR ^a1 , −SR ^a1 ,
-NR ^a1 R ^a2 , -CONR ^a1 R ^a2 , -SO ₂ NR ^a1 R ^a2 ,
-COR ^a3 , -NR ^a1 COR ^a3 , -SO ₂ R ^a3 , -NR ^a1 SO ₂ R ^a3 ,
-COOR ^a1 and -NR ^a2 COOR ^a3
A group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, or a benzyl group, and R ^a3 represents a C _1-4 alkyl group.)
A C _1-10 alkyl group which may be substituted with a halogen atom and 1 to 3 substituents selected from the following group B;
Group B is here
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group optionally substituted with 1 to 5 substituents selected from Group A (as defined above);
-OR ^a4 , -SR ^a4 ,
-NR ^a4 R ^a5 , -CONR ^a4 R ^a5 , -SO ₂ NR ^a4 R ^a5 ,
-COR ^a6 , -NR ^a4 COR ^a6 , -SO ₂ R ^a6 , -NR ^a4 SO ₂ R ^a6 ,
-COOR ^a4 and -NR ^a5 COOR ^a6
{Wherein, R ^a4 and R ^a5 are the same or different and each is hydrogen atom, C _1-4 alkyl groups, 1 to 5 substituents which may be substituted with a substituent C _3-10 selected from the above-mentioned group A A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from Group A, wherein R ^a6 is a C _1-4 alkyl group, C _3-10 carbocyclic group which may be substituted with 1 to 5 substituents selected from group A, or heterocyclic group which may be substituted with 1 to 5 substituents selected from group A (As defined above). }
—OR ^a7 , —SR ^a7 , —NR ^a7 R ^a8 , —NR ^a7 COR ^a9 , —COOR ^a10 , or ^—N═CH —NR ^a10 R ^a11
(Wherein, R ^a7 and R ^a8 are the same or different and each is hydrogen atom, group B, or may be substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B C _{1- 6 is} an alkyl group, R ^a9 is a C _1-4 alkyl group, and R ^a10 and R ^a11 are the same or different and each is a hydrogen atom or a C _1-4 alkyl group. 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof. R ³² is
Hydrogen atom, cyano group, halogen atom,
A C _1-10 alkyl group which may be substituted with a halogen atom and 1 to 3 substituents selected from the following group B;
Group B is here
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group which may be substituted by 1 to 5 substituents selected from Group A (wherein the heterocyclic group is at least selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom) A saturated or unsaturated ring containing one heteroatom).
-OR ^a4 , -SR ^a4 ,
-NR ^a4 R ^a5 , -CONR ^a4 R ^a5 , -SO ₂ NR ^a4 R ^a5 ,
-COR ^a6 , -NR ^a4 COR ^a6 , -SO ₂ R ^a6 , -NR ^a4 SO ₂ R ^a6 ,
-COOR ^a4 and -NR ^a5 COOR ^a6
{Wherein, R ^a4 and R ^a5 are the same or different and each is hydrogen atom, C _1-4 alkyl groups, 1 to 5 substituents which may be substituted with a substituent C _3-10 selected from the above-mentioned group A A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from Group A, wherein R ^a6 is a C _1-4 alkyl group, C _3-10 carbocyclic group which may be substituted with 1 to 5 substituents selected from group A, or heterocyclic group which may be substituted with 1 to 5 substituents selected from group A (As defined above). }
^{-OR a7, -SR a7, -NR a7} R a8, -NR a7 COR a9 or -COOR ^a10 (wherein, R ^a7 and R ^a8 are the same or different and each is hydrogen atom, group B, or a halogen atom And a C _1-10 alkyl group which may be substituted by 1 to 3 substituents selected from Group B, R ^a9 is a C _1-4 alkyl group, and R ^a10 is a hydrogen atom or C _1- The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 5, which is a ₄ alkyl group. R ³² is a hydrogen atom, —OR ^a7 or —NR ^a7 R ^a8 (wherein R ^a7 and R ^a8 are the same or different and are selected from a hydrogen atom, a group B, a halogen atom and the group B) A 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 9, which is a C _1-10 alkyl group which may be substituted by 1 to 3 substituents. R ³³ is
Hydrogen atom,
A C _1-10 alkyl group which may be substituted with a halogen atom and 1 to 3 substituents selected from the following group B;
Group B is here
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group which may be substituted by 1 to 5 substituents selected from Group A (wherein the heterocyclic group is at least selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom) A saturated or unsaturated ring containing one heteroatom).
-OR ^a4 , -SR ^a4 ,
-NR ^a4 R ^a5 , -CONR ^a4 R ^a5 , -SO ₂ NR ^a4 R ^a5 ,
-COR ^a6 , -NR ^a4 COR ^a6 , -SO ₂ R ^a6 , -NR ^a4 SO ₂ R ^a6 ,
-COOR ^a4 and -NR ^a5 COOR ^a6
{Wherein, R ^a4 and R ^a5 are the same or different and each is hydrogen atom, C _1-4 alkyl groups, 1 to 5 substituents which may be substituted with a substituent C _3-10 selected from the above-mentioned group A A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from Group A, wherein R ^a6 is a C _1-4 alkyl group, C _3-10 carbocyclic group which may be substituted with 1 to 5 substituents selected from group A, or heterocyclic group which may be substituted with 1 to 5 substituents selected from group A (As defined above). }
—OR ^a7 , or —NR ^a7 R ^a8 (wherein R ^a7 and R ^a8 are the same or different and each represents one to three selected from a hydrogen atom, a group B, a halogen atom, and the group B) A 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 8, which is a C _1-10 alkyl group which may be substituted by a substituent. R ³³ is a hydrogen atom, —OR ^a7 or —NR ^a7 R ^a8 (wherein R ^a7 and R ^a8 are the same or different and are selected from a hydrogen atom, a group B, a halogen atom and the group B) The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 11, which is a C _1-10 alkyl group which may be substituted with 1 to 3 substituents. R ^a7 and R ^a8 are the same or different and each is a halogen atom and a C _1-10 alkyl group which may be substituted with 1 to 3 substituents selected from the following group B [wherein group B is
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group which may be substituted by 1 to 5 substituents selected from Group A (wherein the heterocyclic group is at least selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom) A saturated or unsaturated ring containing one heteroatom).
-OR ^a4 , -SR ^a4 ,
-NR ^a4 R ^a5 , -CONR ^a4 R ^a5 , -SO ₂ NR ^a4 R ^a5 ,
-COR ^a6 , -NR ^a4 COR ^a6 , -SO ₂ R ^a6 , -NR ^a4 SO ₂ R ^a6 ,
-COOR ^a4 and -NR ^a5 COOR ^a6
{Wherein, R ^a4 and R ^a5 are the same or different and each is hydrogen atom, C _1-4 alkyl groups, 1 to 5 substituents which may be substituted with a substituent C _3-10 selected from the above-mentioned group A A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from Group A, wherein R ^a6 is a C _1-4 alkyl group, C _3-10 carbocyclic group which may be substituted with 1 to 5 substituents selected from group A, or heterocyclic group which may be substituted with 1 to 5 substituents selected from group A (As defined above). The 4-oxoquinoline compound according to claim 8 or a pharmaceutically acceptable salt thereof. R ⁴ and R ⁵ are
Cyano group, phenyl group, nitro group, halogen atom, C _1-4 alkyl group, halo C _1-4 alkyl group, halo C _1-4 alkyloxy group, —OR ^a1 , —SR ^a1 , -NR ^a1 R ^a2 , -CONR ^a1 R ^a2 , -SO ₂ NR ^a1 R ^a2 , -NR ^a1 COR ^a3 , -SO ₂ R ^a3 , -NR ^a2 COOR ^a3 , and -COOR ^a1 (where R ^a1 and R ^a2 is the same or different and represents a hydrogen atom, a C _1-4 alkyl group, or a benzyl group, and R ^a3 represents a C _1-4 alkyl group. The 4-oxoquinoline compound according to claim 5, or a pharmaceutically acceptable salt thereof. R ⁴ is
Phenyl group, halogen atom, C _1-4 alkyl group, halo C _1-4 alkyloxy group, —OR ^a1 , —NR ^a1 R ^a2 , —CONR ^a1 R ^a2 , —SO ₂ NR ^a1 R ^a2 , —NR ^a1 COR ^a3 , —SO ₂ R ^a3 , —NR ^a1 SO ₂ R ^a3 , or —COOR ^a1 (wherein R ^a1 and R ^a2 are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, or The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 14, wherein R ₄ represents a benzyl group, and R ^a3 represents a C _1-4 alkyl group. The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 15, wherein R ⁴ is a halogen atom. R ⁵ is
Hydrogen atom, cyano group, phenyl group, nitro group, halogen atom, C _1-4 alkyl group, halo C _1-4 alkyl group, —OR ^a1 , —SR ^a1 , —NR ^a1 R ^a2 , —CONR ^a1 R ^a2 , —SO ₂ NR ^a1 R ^a2 and —NR ^a1 COR ^a3 (wherein R ^a1 and R ^a2 are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, or a benzyl group; ^6. The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein ^a3 is a substituent selected from the group consisting of _C1-4 alkyl group. ^6. The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R ⁶ is a halogen atom.   6. The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein m is 0 or 1. R ¹ is
A C _3-10 carbocyclic group which may be substituted with 1 to 5 substituents selected from the following group A;
Group A is here
Cyano group, phenyl group, nitro group, halogen atom, C _1-4 alkyl group,
Halo C _1-4 alkyl group, halo C _1-4 alkyloxy group,
−OR ^a1 , −SR ^a1 ,
-NR ^a1 R ^a2 , -CONR ^a1 R ^a2 , -SO ₂ NR ^a1 R ^a2 ,
-COR ^a3 , -NR ^a1 COR ^a3 , -SO ₂ R ^a3 , -NR ^a1 SO ₂ R ^a3 ,
-COOR ^a1 and -NR ^a2 COOR ^a3
A group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, or a benzyl group, and R ^a3 represents a C _1-4 alkyl group.)
—NR ^a4 R ^a5 , —NR ^a4 COR ^a6 , —NR ^a4 SO ₂ R ^a6 , and —NR ^a5 COOR ^a6 {wherein R ^a4 and R ^a5 are the same or different and each represents a hydrogen atom, C _{1- A 4} alkyl group, a C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above, or a 1 to 5 substituent selected from Group A above; A good heterocyclic group (wherein the heterocyclic group is a saturated or unsaturated ring including at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom). R ^a6 represents a C _1-4 alkyl group, a C _3-10 carbocyclic group which may be substituted with 1 to 5 substituents selected from the above group A, or 1 to 1 selected from the above group A. Heterocyclic group optionally substituted with 5 substituents (above As of righteousness.) Shows the. } Or a C _1-10 alkyl group which may be substituted with a halogen atom and 1 to 3 substituents selected from group B [wherein group B is
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group optionally substituted with 1 to 5 substituents selected from Group A (as defined above);
-OR ^a4 , -SR ^a4 , -NR ^a4 R ^a5 , -CONR ^a4 R ^a5 , -SO ₂ NR ^a4 R ^a5 , -COR ^a6 , -NR ^a4 COR ^a6 , -SO ₂ R ^a6 , -NR ^a4 SO ₂ R ^a6, -COOR ^a4 and,, -NR ^a5 COOR ^a6 (wherein, R ^a4, R ^a5 and R ^a6 and group a are as. defined above) is a substituent selected from the group consisting of. The 4-oxoquinoline compound according to claim 5 or a pharmaceutically acceptable salt thereof. R ¹ is a halogen atom and a C _1-10 alkyl group _optionally substituted by 1 to 3 substituents selected from group B [wherein group B is
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A above,
A heterocyclic group optionally substituted by 1 to 5 substituents selected from Group A above;
(Here, the heterocyclic group is a saturated or unsaturated ring including at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.)
-OR ^a4 , -SR ^a4 ,
-NR ^a4 R ^a5 , -CONR ^a4 R ^a5 , -SO ₂ NR ^a4 R ^a5 ,
-COR ^a6 , -NR ^a4 COR ^a6 , -SO ₂ R ^a6 , -NR ^a4 SO ₂ R ^a6 ,
-COOR ^a4 and -NR ^a5 COOR ^a6
{Wherein, R ^a4 and R ^a5 are the same or different and each is hydrogen atom, C _1-4 alkyl groups, 1 to 5 substituents which may be substituted with a substituent C _3-10 selected from the above-mentioned group A A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from Group A, wherein R ^a6 is a C _1-4 alkyl group, C _3-10 carbocyclic group which may be substituted with 1 to 5 substituents selected from group A, or heterocyclic group which may be substituted with 1 to 5 substituents selected from group A (As defined above). 21] The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 20. 6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-1),
6- (2,3-dichlorobenzyl) -8-fluoro-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-2),
6- (2,3-dichlorobenzyl) -1- (2-methanesulfonylaminoethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-3),
6- (2,3-dichlorobenzyl) -1- (2-imidazol-1-ylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-4),
6- (2,3-Dichlorobenzyl) -1-dimethylcarbamoylmethyl-4-oxo-1
, 4-Dihydroquinoline-3-carboxylic acid (Example 1-5),
6- (2,3-dichlorobenzyl) -1-methylcarbamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-6),
1-carbamoylmethyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-7),
6- (2,3-dichlorobenzyl) -1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-8),
6- (2,3-dichlorobenzyl) -4-oxo-1-sulfamoylmethyl-1,4-dihydroquinoline-3-carboxylic acid (Example 1-9),
1- (2-carboxyethyl) -4-oxo-6- (2,3-dichlorobenzyl) -1,4-dihydroquinoline-3-carboxylic acid (Example 1-10),
1- (2-hydroxyethyl) -6-naphthalen-1-ylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-11),
6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid methyl ester (Example 1-12),
1- (2-carbamoylethyl) -6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-13),
6- (2,3-dichlorobenzyl) -4-oxo-1- (2-oxopropyl) -1,4-dihydroquinoline-3-carboxylic acid (Example 1-14),
1-benzyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-15),
6- (2,3-dichlorobenzyl) -4-oxo-1-phenethyl-1,4-dihydroquinoline-3-carboxylic acid (Example 1-16),
6- (2,3-dichlorobenzyl) -1- (3-phenylpropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-17),
6- (2,3-dichlorobenzyl) -1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-18),
6- (2,3-dichlorobenzyl) -1- (4-phenylbutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-19),
1-biphenyl-2-ylmethyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-20),
6- (2,3-dichlorobenzyl) -1- (4-hydroxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-21),
1-benzo [b] thiophen-2-ylmethyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-22),
6- (2,3-dichlorobenzyl) -1- (3,4-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-23),
6- (2,3-dichlorobenzyl) -1- (2-dimethylaminoethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-24),
6- (2,3-dichlorobenzyl) -1- (3-hydroxypropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-25),
6- (2,3-dichlorobenzyl) -1- (2-methoxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-26),
6- (2,3-dichlorobenzyl) -1- (2,2,2-trifluoroethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-27),
1-carboxymethyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-28),
6- (2,3-Dichlorobenzyl) -1- [2- (4-methylthiazol-5-yl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-29) ), 6- (2,3-dichlorobenzyl) -1- (2-hydroxypropyl) -4-oxo-1
, 4-Dihydroquinoline-3-carboxylic acid (Example 1-30),
6- (2,3-dichlorobenzyl) -1- (2-methylsulfanylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-32),
6- (2-chloro-6-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-33),
6- (2,3-dichlorobenzyl) -1- (5-hydroxypentyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-34),
6- (2,3-dichlorobenzyl) -1- (2-morpholin-4-ylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-35),
6- (2,3-dichlorobenzyl) -1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-36),
6- (2,3-dichlorobenzyl) -1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-37),
6- (2,3-dichlorobenzyl) -4-oxo-1-propyl-1,4-dihydroquinoline-3-carboxylic acid (Example 1-38),
1-butyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-39),
1-cyclopentylmethyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-40),
6- (2,3-dichlorobenzyl) -1- (2-methanesulfonylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-41),
1-cyclohexylmethyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-42),
6- (2,3-dichlorobenzyl) -1- (2-hydroxy-2-phenylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-43),
6- (2,3-dichlorobenzyl) -1- (2-fluoroethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-44),
6- (2,3-dichlorobenzyl) -4-oxo-1- (2-pyridin-2-ylethyl) -1,4-dihydroquinoline-3-carboxylic acid (Example 1-45),
1- (2-aminoethyl) -6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-46),
6- (2,3-dichlorobenzyl) -1- (2-hydroxy-2-methylpropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-47),
1- (2-acetylaminoethyl) -6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-48),
6- (2,3-dichlorobenzyl) -1- (2-ethoxycarbonylaminoethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-49),
6- (2,3-difluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-50),
6- (2-chloro-4-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-51),
6- (2-chlorobenzyl) -4-oxo-1-phenethyl-1,4-dihydroquinoline-3-carboxylic acid (Example 1-65),
6- (2-chloro-3-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-66),
6- (2,3-dichlorobenzyl) -1-methylsulfanylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-68),
6- (2,3-dichlorobenzyl) -1-methanesulfonylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-69),
1-tert-butylsulfamoylmethyl-6- (2,3-dichlorobenzyl) -4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-70),
6- (2,3-dichlorobenzyl) -1-methylsulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-71),
6- (2,3-dichlorobenzyl) -1-dimethylsulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-72),
6- (2-chloro-3,6-difluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-73),
6- (2,3-dichlorobenzyl) -1- (2,3-dihydroxypropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-74),
6- (2-chloro-6-fluorobenzyl) -1-sulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-75),
6- (2-chloro-6-fluorobenzyl) -1-methylsulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-76),
6- (2-chloro-6-fluorobenzyl) -1-dimethylsulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-77),
6- (2-chloro-3-methylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-79),
6- (2-bromobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-80),
6- (2-chloro-3-methoxybenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-82),
1- (2-hydroxyethyl) -6- (2-methanesulfonylbenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-85),
6-biphenyl-2-ylmethyl-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-86),
6- (2-chlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-87),
6- (2-chloro-5-methylsulfanylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-92),
1- (2-hydroxyethyl) -4-oxo-6- (2-trifluoromethyloxybenzyl) -1,4-dihydroquinoline-3-carboxylic acid (Example 1-93),
6- (2-chloro-5-methylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-97),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-99),
6- (3-chloro-2,6-difluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-100),
6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-101),
1-cyclopropyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 1-102),
1-amino-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-1),
6- (2,3-dichlorobenzyl) -1-methoxycarbonylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-2),
1-acetylamino-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-3),
6- (2,3-dichlorobenzyl) -1-methanesulfonylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-4),
6- (2,3-dichlorobenzyl) -1- (N-methanesulfonyl-N-methylamino) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-5),
6- (2,3-dichlorobenzyl) -1-dimethylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-6),
6- (2,3-dichlorobenzyl) -1-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-7),
6- (2,3-dichlorobenzyl) -1-ethylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2-8),
6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-1),
6- (3-chloro-2-methylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-2),
6- (3-chloro-2-methoxybenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-3),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-4),
6- (2,3-dichlorobenzyl) -5-hydroxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-5),
6- (2,3-dichlorobenzyl) -7-hydroxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-6),
1- (2-hydroxyethyl) -6- (2-methylaminobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-7),
6- (2-dimethylaminobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-8),
6- (2,3-dichlorobenzyl) -4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid (Example 3-9),
6- (2,3-dichlorobenzyl) -1- [2-hydroxy-1- (hydroxymethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-10),
1-cyclobutyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-12),
1-cyclopentyl-6- (2,3-dichlorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-13),
6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-14),
6- (2-dimethylsulfamoylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-16),
6- (3-chloro-2,4-difluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-17),
6- (2-carboxybenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-18),
1- (2-hydroxyethyl) -6- (2-methylsulfamoylbenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-19),
6- (2,3-dichlorobenzyl) -7-ethoxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-20),
7-chloro-6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-21),
6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-7-trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid (Example 3-22), ( S) -6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxy-1-methylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-23)
),
(R) -6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxy-1-methylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3- 24),
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-8-trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid (Example 3-25) ,
6- (3-Chloro-2-fluorobenzyl) -1- [2-hydroxy-1- (hydroxymethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-26) ),
7-cyano-6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-27),
6- (2-ethylmethylaminobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-28),
6- [2- (N-methyl-N-propylamino) benzyl] -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-29),
6- [2- (N-benzyl-N-methylamino) benzyl] -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-30),
6- [2- (N-methanesulfonyl-N-methylamino) benzyl] -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-31) ,
6- [2- (N-isopropyl-N-methylamino) benzyl] -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-32),
1-tert-butyl-6- (3-chloro-2-fluorobenzyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-33),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-34),
8-amino-6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-35),
7-carboxy-6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-36),
6- (3-Chloro-2,6-difluorobenzyl) -1- (2-hydroxyethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-37) ,
6- (3-chloro-2-fluorobenzyl) -8-dimethylamino-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-38),
8-acetylamino-6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-39),
5-cyano-6- (2,3-dichlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-40),
6- [2- (N-acetyl-N-methylamino) benzyl] -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-41),
6- (2-diethylaminobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-42),
6- (3-Chloro-2-fluorobenzyl) -1- (1,1-dimethyl-2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-43) ,
6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-44),
6- (3-Chloro-2-fluorobenzyl) -7,8-dimethoxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-45) ,
6- (3-chloro-2-fluorobenzyl) -8-ethoxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-47),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -8-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-48),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-7-propyloxy-1,4-dihydroquinoline-3-carboxylic acid (Example 3-49),
6- (3-Chloro-2-fluorobenzyl) -7- (dimethylaminomethyleneamino) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3) -50),
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid methyl ester (Example 3-51) ,
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-8-phenoxy-1,4-dihydroquinoline-3-carboxylic acid (Example 3-52), 6 -(3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-53),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-8-propylamino-1,4-dihydroquinoline-3-carboxylic acid (Example 3-54),
6- (3-chloro-2-fluorobenzyl) -8-ethylamino-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-55),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxy-1-methylethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 3-56),
(S) -6- (3-Chloro-2,6-difluorobenzyl) -1- (2-hydroxy-1-methylethyl) -8methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-57),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-8-propyloxy-1,4-dihydroquinoline-3-carboxylic acid (Example 3-58),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-59),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) propyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-60) ),
(S) -6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1- (2-hydroxy-1-methylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 3-61),
6- (3-Chloro-2-fluorobenzyl) -7-dimethylamino-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-62)
),
6- (3-chloro-2-fluorobenzyl) -7-cyclohexylmethoxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-63),
6- (3-chloro-2-fluorobenzyl) -8-diethylamino-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-64),
6- (3-chloro-2-fluorobenzyl) -7-methylamino-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-65),
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-7-pyrrolidin-1-yl-1,4-dihydroquinoline-3-carboxylic acid (Example 3- 66),
(S) -6- (3-Chloro-2-fluorobenzyl) -8-ethoxy-1- (2-hydroxy-1-methylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 3-67),
(S) -6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1- [1- (hydroxymethyl) propyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 3-68),
6- (3-chloro-2-fluorobenzyl) -8-cyclohexylmethoxy-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-69),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-2-methylpropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3) -70),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-3-methylbutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3- 71),
(S) -6- (3-Chloro-2,6-difluorobenzyl) -1- [1- (hydroxymethyl) propyl] -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carvone Acid (Example 3-72),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) propyl] -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 3-73),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxy-1-methylethyl) -7-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 3-74),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-75),
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -7- (2-hydroxyethyloxy) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Examples) 3-76),
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -7- (3-hydroxypropyloxy) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Examples) 3-77),
6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -8- (2-hydroxyethylamino) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Examples) 3-78),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl)
Propyl] -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-79),
(S) -6- (3-Chloro-2-fluorobenzyl) -8-dimethylamino-1- (2-hydroxy-1-methylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-80),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxy-1-phenylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3- 81),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) butyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3-82) ),
6- (3-Chloro-2-fluorobenzyl) -1-((1S, 2S) -1-hydroxymethyl-2-methylbutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Examples) 3-83),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxy-1-methylethyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 3-84),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-benzyl-2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 3- 85),
6- (2-chloro-5-methanesulfonylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-1),
6- (2-ethylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-4),
6- (2-chloro-5-methylbenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-5),
6- (2-chloro-5-fluorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-6),
6- (5-bromo-2-chlorobenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-7),
6- (2,3-dichlorobenzyl) -7-fluoro-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-9),
6- (2-chloro-5-hydroxybenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-11),
6- (2,3-dichlorobenzyl) -5-fluoro-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-12),
6- (2-ethoxybenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-13),
6- (2-hydroxybenzyl) -1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-14),
6- (2,3-dichlorobenzyl) -7-methyl-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-15),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (2-hydroxy-1-methylethyl) -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-16),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) propyl] -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-17),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4- 18),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-2-methylpropyl) -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carvone Acid (Examples 4-19),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -7-isopropyloxy-4-oxo-1,4-dihydroquinoline -3-carboxylic acid (Example 4-20),
(S) -6- (3-Chloro-2-fluorobenzyl) -8-ethoxy-1- [1- (hydroxymethyl) propyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 4-21),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2-cyclohexyl-1- (hydroxymethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 4-22),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-3-methylbutyl) -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-23),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-2-methylpropyl) -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carvone Acid (Examples 4-24),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-3-methylbutyl) -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-25),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -8-isopropyloxy-4-oxo-1,4-dihydroquinoline -3-carboxylic acid (Example 4-26),
6- (3-Chloro-2-fluorobenzyl) -1-((1S, 2S) -1-hydroxymethyl-2-methylbutyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carvone Acid (Example 4-27),
6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1-((1S, 2S) -1-hydroxymethyl-2-methylbutyl) -4-oxo-1,4-dihydroquinoline-3-carvone Acid (Example 4-28),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) propyl] -7-methylsulfanyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-29),
(S) -6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1- (1-hydroxymethyl-2-methylpropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-30),
(S) -6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -4-oxo-1,4-dihydroquinoline- 3-carboxylic acid (Example 4-31),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-2-methylpropyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-32),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -7-methoxy-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid (Example 4-33),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -8-methoxy-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid (Example 4-34),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl)
Butyl] -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-35),
(S) -6- (3-Chloro-2-fluorobenzyl) -7-ethoxy-1- [1- (hydroxymethyl) butyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 4-36),
(S) -6- (3-Chloro-2-fluorobenzyl) -8-ethoxy-1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -4-oxo-1,4-dihydroquinoline- 3-carboxylic acid (Example 4-37),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) butyl] -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 4-38),
6- (3-Chloro-2-fluorobenzyl) -1-((1S, 2S) -1-hydroxymethyl-2-methylbutyl) -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3- Carboxylic acid (Example 4-39),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-40),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -8-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-41),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-42),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -7-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-43),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-44),
(S) -6- (3-Chloro-2-fluorobenzyl) -8-ethoxy-1- (1-hydroxymethyl-2-methylpropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-45),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-hydroxymethyl-2-methylpropyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4-46),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) butyl] -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( Example 4-47),
(S) -6- (3-Chloro-2-fluorobenzyl) -8-ethoxy-1- [1- (hydroxymethyl) butyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 4-48),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) butyl] -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 4-49),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- (1-cyclohexyl-2-hydroxyethyl) -8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 4-50, and (S) -6- (3-chloro-2-fluorobenzyl) -1- [2,2-dimethyl-1- (hydroxymethyl) propyl] -4-oxo-1, The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 5, selected from the group consisting of 4-dihydroquinoline-3-carboxylic acid (Example 4-52).   A pharmaceutical composition comprising the 4-oxoquinoline compound according to any one of claims 5 to 22 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.   An integrase inhibitor comprising the 4-oxoquinoline compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient.   An antiviral agent comprising the 4-oxoquinoline compound according to any one of claims 5 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient.   An anti-HIV agent comprising the 4-oxoquinoline compound according to any one of claims 5 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient.   An anti-HIV composition comprising the 4-oxoquinoline compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof and one or more other anti-HIV active substances as active ingredients. An anti-HIV agent comprising the 4-oxoquinoline compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient for a multi-drug combination therapy with another anti-HIV agent .