JP3567162B1 - 4-oxoquinoline compounds and their use as HIV integrase inhibitors - Google Patents

Abstract

（式中、各記号は明細書に記載の通りである。）で表される４−オキソキノリン化合物又は製薬上許容されるその塩、及びそれら化合物を含有してなる抗ＨＩＶ剤に関する。本発明の化合物は、ＨＩＶインテグラーゼ活性を阻害する作用を有し、抗ＨＩＶ剤としてエイズの治療剤若しくは予防剤として有用である。また、プロテアーゼ阻害剤、逆転写酵素阻害剤等の他の抗ＨＩＶ剤との併用により、更に有効な抗ＨＩＶ剤となり得る。また、インテグラーゼに特異的な高い阻害活性を有することは、人体に対し安全な副作用の少ない薬剤となり得る。
【選択図】 なし
PROBLEM TO BE SOLVED: To provide an anti-HIV agent having an HIV integrase inhibitory activity.
SOLUTION: The following general formula [I]
Embedded image

(Wherein each symbol is as described in the specification), or a pharmaceutically acceptable salt thereof, and an anti-HIV agent comprising the compound. The compound of the present invention has an activity of inhibiting HIV integrase activity and is useful as an anti-HIV agent as a therapeutic or prophylactic agent for AIDS. In addition, it can be a more effective anti-HIV agent when used in combination with other anti-HIV agents such as a protease inhibitor and a reverse transcriptase inhibitor. In addition, having a high inhibitory activity specific to integrase can be a drug that is safe for the human body and has few side effects.
[Selection diagram] None

Description

  The present invention relates to a novel 4-oxoquinoline compound useful as an anti-HIV agent or a pharmaceutically acceptable salt 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 specifically, the present invention relates to an anti-HIV agent containing a 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof, which exhibits an anti-HIV effect by an integrase inhibitory activity.

BACKGROUND ART HIV (Human Immunodeficiency Virus (type 1): a human immunodeficiency virus) belonging to a retrovirus is a causative virus of AIDS (Acquired Immunodeficiency Syndrome: 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, an agent that eradicates HIV or suppresses proliferation in vivo is effective.
HIV has two RNA genes in a shell, and the shell is covered with a coat protein. RNA encodes a plurality of enzymes (protease, reverse transcriptase, integrase) and the like specific to the virus. The translated reverse transcriptase and integrase are present in the shell, and the protease is present inside and outside the shell.
HIV contacts and invades a host cell, unshells, and releases a complex of RNA and integrase into the cytoplasm. DNA is transcribed from the RNA by reverse transcriptase to produce full-length double-stranded DNA. The DNA translocates into the host cell nucleus and is integrated into the host cell DNA by integrase. The integrated DNA is converted into mRNA by a polymerase of a host cell, and various proteins necessary for virus formation are synthesized from the mRNA by HIV protease or the like, and finally virus particles are formed, and budding and release.
These virus-specific enzymes are essential for the propagation of HIV, and are attracting attention as targets 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 marketed as reverse transcriptase inhibitors, and indinavir, nelfinavir and the like are already marketed as protease inhibitors.
In addition, a multidrug combination therapy using these drugs in combination is also used. For example, a dual drug combination of a reverse transcriptase inhibitor (zidovudine and didanosine), a reverse transcriptase inhibitor (zidovudine and lamivudine) and a protease inhibitor (nelfinavir) Are used clinically, and these multidrug combinations are becoming the mainstream of AIDS treatment (for example, see Non-Patent Document 1).
However, some of these drugs are known to have side effects such as hepatic dysfunction and central nervous system disorders such as dizziness, and obtaining resistance to the drugs is also a problem. Not only that, the emergence of HIV that exhibits multidrug resistance to multidrug therapy is also known.
Under such circumstances, further development of a new drug, particularly development of an anti-HIV agent by a new mechanism, is desired. Since an integrase characteristic of a retrovirus is an enzyme essential for HIV proliferation, The development of anti-HIV agents having integrase inhibitory activity is expected.
However, no effective integrase inhibitors have been found yet.

Next, known compounds relatively similar to the anti-HIV agent of the present invention will be described.
WO02 / 070486 describes the following compounds [A] and [B] as anti-HIV agents having integrase inhibitory activity (see Patent Document 1).

  In addition, WO02 / 36934 describes the following compound [C] and the like as anti-HIV agents having an integrase inhibitory activity (see Patent Document 2).

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

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

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

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

  In addition, the following compound [G] and the like have been pharmacologically evaluated as dehydrogenase inhibitors (see Non-Patent Document 4).

  JP-T-2002-534416 (patent family: WO 00/40561, US Pat. No. 6,248,739, EP 1140850) 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: WO 00/40563, 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).

  WO 01/98275 (patent family: US 2001/103220) also describes the following compound [K] as a synthetic intermediate of a compound having antiviral activity (see Patent Document 8). .

  Further, JP-A-4-360872 (patent family: US Pat. No. 5,985,894, EP 498721B1) describes the following compound [L] as a compound having an antagonistic action on anti-angiotensin II receptor. (See Patent Document 9).

WO 02/070486 (page 118, Example I-62, page 203, Example I-152) WO 02/36934 (p. 106, Example 3) WO 02/055079 (p. 79, Example 1) US Pat. No. 3,472,859 (column 11, line 10) JP-A-48-26772 (p. 6, Example 9) JP-T-2002-534416 (page 141, chemical formula 60) JP-T-2002-534417 (page 34, chemical formula 18) WO 01/98275 (p. 39, line 29) JP-A-4-360872 (64 pages, Table 1) Guidelines for the Use of Antiretroviral 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

Based on the findings obtained from pharmacological research and clinical results, anti-HIV agents are effective in preventing and treating the onset of AIDS. 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.

The present inventors have conducted intensive studies to find a compound having an anti-HIV action, particularly an integrase inhibitory action, and as a result, 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 Group A below, or
A heterocyclic group which may be substituted with 1 to 5 substituents selected from Group A below,
(Here, the heterocyclic group is a saturated or unsaturated ring containing at least one hetero atom 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
Group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represent 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 halogen atom and a C _1-10 alkyl group _optionally substituted by 1 to 3 substituents selected from the following group B,
Group B
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the above group A,
-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 ,
A group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6 ;
Wherein R ^a4 and R ^a5 are the same or different and are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _3-10 which may be substituted with 1 to 5 substituents selected from the above group A; A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A, and R ^a6 represents a C _1-4 alkyl group; A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A, or a heterocyclic group _optionally substituted by 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 alkyl sulfanyl group,
A halo C _1-4 alkyl group, or a halo C _1-4 alkyloxy group,
X is C- ^R32 or a nitrogen atom;
Y is C- ^R33 or a nitrogen atom,
Here, R ³² and R ³³ are the same or different and are each a hydrogen atom, a cyano group, a nitro group, a halogen atom,
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A,
A halogen atom and a C _1-10 alkyl group which may be substituted with 1 to 3 substituents selected from the above group B,
-OR ^a7 , -SR ^a7 , -NR ^a7 R ^a8 ,
-NR ^a7 COR ^a9 , -COOR ^a10 , or
-N = CH-NR ^a10 R ^a11
(Here, R ^a7 and R ^a8 are the same or different and are each independently a hydrogen atom, a group B, or a halogen atom and C _1- which may be substituted by 1 to 3 substituents selected from the above group B. an ₁₀ alkyl group, R ^a9 is C _1-4 alkyl group, 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) When the ring Cy is

[Where R ⁴ and R ⁶ are the same or different and are each a substituent selected from the following group A;
Here, 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
Group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represent 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 or a substituent selected from group A, wherein R ⁴ and R ⁵ may form a condensed ring together with the benzene ring which they substitute, and m is 0. Or, it is an integer of 1 to 3, and when m is 2 or 3, each R ⁶ may be the same or different. ] The anti-HIV agent according to the above (1), wherein
(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 ⁴ and R ⁶ are the same or different and are each a substituent selected from the following group A;
Here, 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
Group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represent 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 may form a condensed ring together with a benzene ring to be substituted therewith;
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 halogen atom and a C _1-10 alkyl group _optionally substituted by 1 to 3 substituents selected from the following group B,
Group B
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group which may be substituted with 1 to 5 substituents selected from the group A,
(Here, the heterocyclic group is a saturated or unsaturated ring containing at least one hetero atom 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 ,
A group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6 ;
Wherein R ^a4 and R ^a5 are the same or different and are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _3-10 which may be substituted with 1 to 5 substituents selected from the above group A; A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A, and R ^a6 represents a C _1-4 alkyl group; A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A, or a heterocyclic group _optionally substituted by 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 alkyl sulfanyl 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 are each a hydrogen atom, a cyano group, a nitro group, a halogen atom,
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A,
A halogen atom and a C _1-10 alkyl group which may be substituted with 1 to 3 substituents selected from the above group B,
-OR ^a7 , -SR ^a7 , -NR ^a7 R ^a8 ,
-NR ^a7 COR ^a9 , -COOR ^a10 , or
-N = CH-NR ^a10 R ^a11
(Here, R ^a7 and R ^a8 are the same or different and are each independently a hydrogen atom, a group B, or a halogen atom and C _1- which may be substituted by 1 to 3 substituents selected from the above group B. an ₁₀ alkyl group, R ^a9 is C _1-4 alkyl group, R ^a10 and R ^a11 are the same or different and each is a hydrogen atom or a C _1-4 alkyl group.). ]
(6) The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to the above (5), wherein R ³¹ is a hydrogen atom, a cyano group, a hydroxy group, or a C _1-4 alkoxy group.
(7) The 4-oxoquinoline compound according to the above (6), wherein R ³¹ is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
(8) R ³² and R ³³ are the same or different,
Hydrogen atom, cyano group, halogen atom,
A heterocyclic group which may be substituted with 1 to 5 substituents selected from Group A below,
(Here, the heterocyclic group is a saturated or unsaturated ring containing at least one hetero atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom in addition to a carbon atom.)
Here, 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 N R ^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
Group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represent a hydrogen atom, a C _1-4 alkyl group or a benzyl group, and R ^a3 represents a C _1-4 alkyl group.)
A halogen atom and a C _1-10 alkyl group _optionally substituted with 1 to 3 substituents selected from the following group B,
Here, group B
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A,
-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 ,
A group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6 ;
Wherein R ^a4 and R ^a5 are the same or different and are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _3-10 which may be substituted with 1 to 5 substituents selected from the above group A; A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A, and R ^a6 represents a C _1-4 alkyl group; A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A, or a heterocyclic group _optionally substituted by 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
(Where R ^a7 and R ^a8 are the same or different and are each independently a hydrogen atom, a group B, or a halogen atom and C _{1- optionally} substituted with 1 to 3 substituents selected from the above group B) R 5 is a ₁₀ alkyl group, R ^a9 is a C _1-4 alkyl group, and R ^a10 and R ^a11 are the same or different and are each a hydrogen atom or a C _1-4 alkyl group.) Or the pharmaceutically acceptable salt thereof.
(9) ^R32 is
Hydrogen atom, cyano group, halogen atom,
A halogen atom and a C _1-10 alkyl group _optionally substituted with 1 to 3 substituents selected from the following group B,
Here, group B
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group which may be substituted by 1 to 5 substituents selected from the group A (where the heterocyclic group is at least one 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 hetero 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 ,
A group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6 ;
Wherein R ^a4 and R ^a5 are the same or different and are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _3-10 which may be substituted with 1 to 5 substituents selected from the above group A; A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A, and R ^a6 represents a C _1-4 alkyl group; A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A, or a heterocyclic group _optionally substituted by 1 to 5 substituents selected from group A (As defined above). ｝
—OR ^a7 , —SR ^a7 , —NR ^a7 R ^a8 , —NR ^a7 COR ^a9 and —COOR ^a10 (where R ^a7 and R ^a8 are the same or different, and each represents a hydrogen atom, a group B, or a halogen atom. And a C _1-10 alkyl group which may be substituted by 1 to 3 substituents selected from the above 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 the above (5), which is a _4- alkyl group).

(10) R ³² is a hydrogen atom, —OR ^a7 or —NR ^a7 R ^a8 (where R ^a7 and R ^a8 are the same or different and are each a hydrogen atom, a group B, or a halogen atom and the above group B Or a pharmaceutically acceptable salt thereof according to the above (9), which is a C _1-10 alkyl group _optionally substituted with 1 to 3 substituents selected from the following.
(11) R ³³ is
Hydrogen atom,
A halogen atom and a C _1-10 alkyl group _optionally substituted with 1 to 3 substituents selected from the following group B,
Here, group B
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group which may be substituted by 1 to 5 substituents selected from the group A (where the heterocyclic group is at least one 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 hetero 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 ,
A group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6 ;
Wherein R ^a4 and R ^a5 are the same or different and are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _3-10 which may be substituted with 1 to 5 substituents selected from the above group A; A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A, and R ^a6 represents a C _1-4 alkyl group; A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A, or a heterocyclic group _optionally substituted by 1 to 5 substituents selected from group A (As defined above). ｝
—OR ^a7 or —NR ^a7 R ^a8 (where R ^a7 and R ^a8 are the same or different and are each a hydrogen atom, a group B, or a halogen atom and 1 to 3 groups selected from the group B) (8) a 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to the above (8), which is a C _1-10 alkyl group _optionally substituted with a substituent.
(12) R ³³ is a hydrogen atom, —OR ^a7 or —NR ^a7 R ^a8 (where R ^a7 and R ^a8 are the same or different and are each a hydrogen atom, a group B, or a halogen atom and the above group B Or a pharmaceutically acceptable salt thereof according to the above (11), which is a C _1-10 alkyl group _optionally substituted with 1 to 3 substituents selected from the following.
(13) R ^a7 and R ^a8 are the same or different and are each a halogen atom and a C _1-10 alkyl group which may be substituted by 1 to 3 substituents selected from the following group B [wherein group B is ,
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group which may be substituted by 1 to 5 substituents selected from the group A (where the heterocyclic group is at least one 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 hetero 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 ,
A group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6 ;
Wherein R ^a4 and R ^a5 are the same or different and are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _3-10 which may be substituted with 1 to 5 substituents selected from the above group A; A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A, and R ^a6 represents a C _1-4 alkyl group; A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A, or a heterocyclic group _optionally substituted by 1 to 5 substituents selected from group A (As defined above). And the 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to any one of the above (8) to (12).
(14) R ⁴ and R ⁵ are
The same or different, 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 (wherein, R ^a1 and R ^a2 is 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 certain 4-oxoquinoline compound according to the above (5) or a pharmaceutically acceptable salt thereof.
(15) R ⁴ is
A phenyl group, a halogen atom, C _1-4 alkyl, 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 (where R ^a1 and R ^a2 are respectively the same or different and are a hydrogen atom, a C _1-4 alkyl group, or Wherein R ₄ represents a benzyl group and R ^a3 represents a C _1-4 alkyl group.) Or a pharmaceutically acceptable salt thereof according to the above (14).
(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, a cyano group, a phenyl group, a nitro group, a halogen atom, C _1-4 alkyl, 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 (where R ^a1 and R ^a2 are the same or different and each represent 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 according to the above (5), wherein R ⁶ is a halogen atom, or a pharmaceutically acceptable salt thereof.
(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 with 1 to 5 substituents selected from the following group A_3-10Carbocyclic group,
Here, group A
Cyano group, phenyl group, nitro group, halogen atom, C_1-4Alkyl group,
Halo C_1-4Alkyl group, halo C_1-4Alkyloxy group,
-OR^a1, -SR^a1,
-NR^a1R^a2, -CONR^a1R^a2, -SO_TwoNR^a1R^a2,
-COR^a3, -NR^a1COR^a3, -SO_TwoR^a3, -NR^a1SO_TwoR^a3,
-COOR^a1, And -NR^a2COOR^a3
Group consisting of
  (Where R^a1And R^a2Are the same or different and are each a hydrogen atom, C_1-4Represents an alkyl group or a benzyl group;^a3Is C_1-4Shows an alkyl group. )
-NR^a4R^a5, -NR^a4COR^a6, -NR^a4SO_TwoR^a6, And -NR^a5COOR^a6Ｒ where R^a4And R^a5Are the same or different and are each a hydrogen atom, C_1-4An alkyl group, C which may be substituted by 1 to 5 substituents selected from the group A_3-10A carbocyclic group, or a heterocyclic group which may be substituted by 1 to 5 substituents selected from the group A (wherein the heterocyclic group is a nitrogen atom, an oxygen atom, A saturated or unsaturated ring containing at least one heteroatom selected from a sulfur atom).^a6Is C_1-4An alkyl group, C which may be substituted by 1 to 5 substituents selected from the group A_3-10A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A. Is a substituent selected from｝, or
C which may be substituted by a halogen atom and 1 to 3 substituents selected from group B_1-10Alkyl group [where group B is
C which may be substituted by 1 to 5 substituents selected from Group A_3-10Carbocyclic group,
A heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A,
-OR^a4, -SR^a4, -NR^a4R^a5, -CONR^a4R^a5, -SO_TwoNR^a4R^a5, -COR^a6, -NR^a4COR^a6, -SO_TwoR^a6, -NR^a4SO_TwoR^a6, -COOR^a4, And -NR^a5COOR^a6(Where R^a4, R^a5And R^a6And Group A are as defined above. ) Is a substituent selected from the group consisting of: Or the pharmaceutically acceptable salt thereof according to the above (5).
  (21) R¹May be substituted by a halogen atom and 1 to 3 substituents selected from group B_1-10Alkyl group [where group B is
C which may be substituted by 1 to 5 substituents selected from Group A_3-10Carbocyclic group,
A heterocyclic group which may be substituted with 1 to 5 substituents selected from the group A,
  (Here, the heterocyclic group is a saturated or unsaturated ring containing at least one hetero atom 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, -SO_TwoNR^a4R^a5,
-COR^a6, -NR^a4COR^a6, -SO_TwoR^a6, -NR^a4SO_TwoR^a6,
-COOR^a4, And -NR^a5COOR^a6Group consisting of
  Ｒ where R^a4And R^a5Are the same or different and are each a hydrogen atom, C_1-4An alkyl group, C which may be substituted by 1 to 5 substituents selected from the group A_3-10R represents a carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A;^a6Is C_1-4An alkyl group, C which may be substituted by 1 to 5 substituents selected from the group A_3-10A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A. ] The 4-oxoquinoline compound according to 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 (Examples 1-4),
6- (2,3-dichlorobenzyl) -1-dimethylcarbamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Examples 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 (Examples 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 (Examples 1-16),
6- (2,3-dichlorobenzyl) -1- (3-phenylpropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Examples 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 (Examples 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 (Examples 1-29 ), 6- (2,3-dichlorobenzyl) -1- (2-hydroxypropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Examples 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 (Examples 1-37),
6- (2,3-dichlorobenzyl) -4-oxo-1-propyl-1,4-dihydroquinoline-3-carboxylic acid (Examples 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 (Examples 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 (Examples 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 (Examples 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 (Examples 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 (Examples 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 (Examples 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 (Examples 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 (Examples 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 (Examples 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 (implemented 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-carboxylic acid Acid (Example 3-72),
(S) -6- (3-chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) propyl] -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (implemented 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 (Example 3-76),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -7- (3-hydroxypropyloxy) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 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 (implemented 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 (Example 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-carboxylic 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 (implemented Example 4-21),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2-cyclohexyl-1- (hydroxymethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (implemented 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-carboxylic 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-carboxylic acid Acid (Example 4-27),
6- (3-chloro-2-fluorobenzyl) -7-ethoxy-1-((1S, 2S) -1-hydroxymethyl-2-methylbutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic 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 (implemented 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 (implemented Example 4-38),
6- (3-chloro-2-fluorobenzyl) -1-((1S, 2S) -1-hydroxymethyl-2-methylbutyl) -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3- Carboxylic acids (Examples 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 (implemented Example 4-48),
(S) -6- (3-chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) butyl] -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (implemented 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 A 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to the above (5), which is selected from the group consisting of (Example 4-52).
  (23) A pharmaceutical composition comprising the 4-oxoquinoline compound according to any of (5) to (22) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  (24) An integrase inhibitor comprising, as an active ingredient, the 4-oxoquinoline compound or the pharmaceutically acceptable salt thereof according to any of (1) to (22).
  (25) An antiviral agent comprising, as an active ingredient, the 4-oxoquinoline compound or the pharmaceutically acceptable salt thereof according to any of (5) to (22).
  (26) An anti-HIV agent comprising the 4-oxoquinoline compound or the pharmaceutically acceptable salt thereof according to any 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 at least one other anti-HIV active substance as an active ingredient. An anti-HIV composition comprising:
  (28) Contains, as an active ingredient, the 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to any of the above (1) to (22) for a multidrug combination therapy with another anti-HIV agent. An anti-HIV agent.

The compounds of the present invention show 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. In addition, it can be a more effective anti-HIV agent when used in combination with other anti-HIV agents such as a protease inhibitor and a reverse transcriptase inhibitor. In addition, having a high inhibitory activity specific to integrase can be a drug that is safe for the human body and has few side effects.

The definition of each substituent and each part used in this specification is as follows.
“Halogen atom” is a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or 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 R ³¹ , R ³³ , R ⁴ , R ^{6 ′} and R ^{6 ′ ″} are more preferably chlorine atoms, and may be substituted with a halogen atom and 1 to 3 substituents selected from group B. The halogen atom of the “good C _1-10 alkyl group” is more preferably a fluorine atom.

The “C _1-4 alkyl group” refers to a linear or branched alkyl group having 1 to 4 carbon atoms, and specifically includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a sec group. -Butyl group and tert-butyl group.
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, preferably as R ^a1 and R ^a2 , a methyl group, an ethyl group, a propyl group and an isopropyl group, and more preferably a methyl group; Preferably, R ^a3 , R ^a9 , R ^a10 , R ^a11 and Group A are a methyl group, and R ^a4 and R ^a5 are preferably a methyl group, an ethyl group and a tert-butyl group.

The “halo C _1-4 alkyl group” is the above-defined “C _1-4 alkyl group” substituted with 1 to 9, preferably 1 to 3, “halogen atoms” as defined above.
Specifically, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 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 thereof include a 4,4-trifluorobutyl group, a pentafluoroethyl group, a 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.

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

“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 and 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, 2-chloroethyloxy, 2-bromoethyloxy, 3-fluoropropyloxy, 3-chloropropyloxy, 4-fluorobutyloxy, 4-chloro Butyloxy group, trifluoromethyloxy group, 2,2,2-trifluoroethyloxy group, 3,3,3-trifluoropropyloxy group, 4,4,4-trifluorobutyloxy group, pentafluoroethyloxy Group, a 2,2,2-trifluoro-1-trifluoromethyl-ethyloxy group and the like.
R ³¹ , R ⁴ , R ⁵ , R ⁶ , R ^{6 ′} , R ^{6 ″} , R ^{6 ′ ″} and Group A are preferably a trifluoromethyloxy group.

The “C _3-10 carbocyclic group” is a saturated or unsaturated cyclic hydrocarbon group having 3 to 10 carbon atoms, and means an aryl group, a cycloalkyl group, a cycloalkenyl group, or a condensed ring thereof.
Specific examples of the “aryl group” include a phenyl group, a naphthyl group, a pentalenyl group, an azulenyl group, and the like, preferably a phenyl group and a naphthyl group, 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, a norbornanyl group, and the like, preferably a cyclopropyl group, a cyclobutyl group , A cyclopentyl group and a cyclohexyl group.
The “cycloalkenyl group” includes at least one, preferably one or two double bonds, and specifically includes a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexenyl group, Examples include a cyclohexadienyl group (such as a 2,4-cyclohexadien-1-yl group and a 2,5-cyclohexadien-1-yl group), a cycloheptenyl group, and a cyclooctenyl group.
Specific examples of the condensed ring of these “aryl group”, “cycloalkyl group”, and “cycloalkenyl group” include an indenyl group, an indanyl group, a 1,4-dihydronaphthyl group, a 1,2,3,4-tetrahydro group. Examples include a naphthyl group (1,2,3,4-tetrahydro-2-naphthyl group, 5,6,7,8-tetrahydro-2-naphthyl group and the like), a perhydronaphthyl group and the like. Preferably a fused ring of a phenyl group and another ring, an indenyl group, an indanyl group,
Examples thereof include a 1,4-dihydronaphthyl group and a 1,2,3,4-tetrahydronaphthyl group, and an indanyl group is particularly preferred.

“C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from group A” refers to 1 to 5, preferably 1 to 3 substituents selected from group A below. _Is a “C _3-10 carbocyclic group” as defined above, which includes an unsubstituted “C _3-10 carbocyclic group”.
“Group A” includes 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, "halo C _1-4 alkyloxy group" ^{defined, -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, It represents a “C _1-4 alkyl group” or a benzyl group as defined, and R ^a3 represents a “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, methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino, dimethylamino, diethylamino, N-ethyl-N -Methylamino group, N-methyl-N-propylamino group, N-isopropyl-N-methylamino group, N-benzyl-N-methylamino group and the like,
Specific examples of “—CONR ^a1 R ^a2 ” include carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, dimethylaminocarbonyl, and diethylaminocarbonyl. Group, N-methyl-N-ethylaminocarbonyl group and the like,
Specific examples of “—SO ₂ NR ^a1 R ^a2 ” include a sulfamoyl group, a methylaminosulfonyl group, an ethylaminosulfonyl group, a propylaminosulfonyl group, an isopropylaminosulfonyl group, a tert-butylaminosulfonyl group, a 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 an acetylamino group, a propionylamino group, a butyrylamino group, an isobutyrylamino group, a pivaloylamino group, an 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, and a tert-butylsulfonyl group.
Specific examples of “—NR ^a1 SO ₂ R ^a3 ” include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, 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 a methoxycarbonylamino group, an ethoxycarbonylamino group, a propoxycarbonylamino group, an isopropyloxycarbonylamino group, and a tert-butoxycarbonylamino group.

Group A is preferably a cyano group, a phenyl group, a nitro group, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a trifluoromethyloxy group, a hydroxy group, a methoxy group, Ethoxy, propoxy, methylsulfanyl, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, 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 preferred as group A are 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 And a carboxyl group, more preferably a 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 mono-substituted at 2-position, mono-substituted at 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 And particularly preferably 2,3-disubstitution.

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, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-fluorophenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 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 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-bi Phenyl, 2- (methylsulfonyl) phenyl, 3- (methylsulfonyl) phenyl, 2-sulfamoylphenyl, 3-sulfamoylphenyl, 2- (methylaminosulfonyl) phenyl, 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-hydroxyphenyl 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, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 4-indanyl and 1H-inden-4-yl groups.
Ring Cy is preferably a phenyl group, a naphthyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 2-ethylphenyl group, a 3-ethylphenyl group, or a 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, -(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 preferred are 2-chlorophenyl, 2-bromophenyl, 2-ethylphenyl, 2-hydroxyphenyl, 2-ethoxyphenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, and 2-chlorophenyl. -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-trifluoromethylphenyl 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 a 2,3-dichlorophenyl group, a 2,3-difluorophenyl group, a 2-chloro-3-fluorophenyl group and a 3-chloro-2-fluorophenyl group.
R ¹ and group B are preferably phenyl, 3,4-dichlorophenyl, 2-biphenyl, cyclopropyl, 2-hydroxycyclopropyl, cyclobutyl, 2-hydroxycyclobutyl, and 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 -Dichlorophenyl group, 2-biphenyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group.
R ³² , R ³³ , R ¹ and group B are preferably a phenyl group and a cyclohexyl group.

The term "heterocyclic group" refers to a saturated or unsaturated (partially unsaturated) group containing at least one, preferably 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. And a fully unsaturated monocyclic 5- or 6-membered heterocyclic ring, a condensed ring of these heterocyclic rings, or a C _3-10 carbon ring and a heterocyclic ring selected from benzene, cyclopentane and cyclohexane. Means a condensed ring of
Examples of the “saturated monocyclic heterocyclic group” include a pyrrolidinyl group, a tetrahydrofuryl group, a tetrahydrothienyl group, an imidazolidinyl group, a pyrazolidinyl group, a 1,3-dioxolanyl group, a 1,3-oxathiolanyl group, an oxazolidinyl group, and a thiazolidinyl group. , Piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, morpholinyl, thiomorpholinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 4-oxopiperidinyl , 2,6-dioxopiperidinyl group and the like. Preferably, they are a pyrrolidinyl group, a piperidinyl group and a morpholinyl group.
As the "unsaturated monocyclic heterocyclic group", a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, a 1,2-dihydro-2-oxoimidazolyl group, a pyrazolyl group, a diazolyl group, an oxazolyl group, an 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 And a 1,1-dioxo-1H-isothiazolyl group. Preferably, a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a 2-oxo-2,5-dihydrofuranyl group and a 1,1- Dioxo-1H-isothiazolyl group.
Examples of the “condensed ring heterocyclic group” include an indolyl group (for example, a 4-indolyl group, a 7-indolyl group, etc.), an isoindolyl group, a 1,3-dihydro-1,3-dioxoisoindolyl group, Benzofuranyl group (eg, 4-benzofuranyl group, 7-benzofuranyl group, etc.), indazolyl group, isobenzofuranyl group, benzothiophenyl group (eg, 4-benzothiophenyl group, 7-benzothiophenyl group, etc.) Benzoxazolyl group (eg, 4-benzoxazolyl group, 7-benzoxazolyl group, etc.), benzimidazolyl group (eg, 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 a pyridyl group, a 4,5-ethylenedioxypyrimidinyl group, a chromenyl group, a chromanyl group, and an isochromanyl group.
Preferably, it is a condensed ring of a monocyclic 5- or 6-membered heterocyclic ring and a benzene ring, and specifically, an indolyl group, a benzofuranyl group, a benzothiophenyl group, a benzimidazolyl group, a benzoxazolyl group, And a benzothiazolyl group and a benzo [1,3] dioxolyl group.

"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" as defined above. Is a “heterocyclic group” as defined above, which includes an unsubstituted “heterocyclic group”.
The “heterocyclic group” is preferably a monocyclic heterocyclic ring containing one or two heteroatoms, or a heterocyclic ring which is a condensed ring thereof with a benzene ring.
Specific examples of the “heterocyclic group optionally substituted with 1 to 5 substituents selected from group A” include a pyrrolidinyl group, a piperidinyl group, a morpholino group, a pyrrolyl group, a 2-pyrrolyl group, and a 3-pyrrolyl group. , 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 4,5-dichlorothiophen-3-yl, 2-oxo-2,5-dihydrofuran-3-yl, 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-trifluoropyridin- 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, 7-benzofuranyl group, 2-benzothiophenyl group, 4-benzothiophenyl group, 7-benzothiophenyl group, 2-benzimidazolyl group, 4-benzimidazolyl group, 2-benzoxazolyl 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 and 5-benzo [1,3] dioxolyl group.
Ring Cy is preferably a 2-pyridyl group and a 4-pyridyl group,
R ¹ and group B are preferably an imidazolyl group, a 2-pyridyl group, a 2-benzothiophenyl group, a morpholino group and a 4-methylthiazol-5-yl group,
R ³² and R ³³ are preferably a pyrrolidinyl group.

The “halogen atom and a C _1-10 alkyl group _optionally substituted by 1 to 3 substituents selected from group B” are selected from the above-defined “halogen atom” and the following definition “group B” 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, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert- Butyl group, 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 Ropyl, heptyl, isoheptyl, 1-methylhexyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,1 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 thereof include a isopropylbutyl group, a 1-ethyl-1-methylbutyl group, an octyl group, a nonyl group, and a decanyl group, and are preferably a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and particularly preferably have a carbon number of 1 to 6. 1 to 6 branched alkyl groups.
“Group B” refers to “C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from Group A” as defined above, and “1 to 5 selected from Group A” as defined above. number of substituted heterocyclic group optionally substituted by group ^{", -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, a group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6.
Here, R ^a4 and R ^a5 are the same or different and are each substituted by a hydrogen atom, a “C _1-4 alkyl group” as defined above, or 1 to 5 substituents selected from “Group A” as defined above. Or a C _3-10 carbocyclic group which may be substituted, or a 'heterocyclic group which may be substituted with 1 to 5 substituents selected from group A' as defined above, wherein R ^a6 is as defined above. “C _1-4 alkyl group”, “C _3-10 which may be substituted by 1 to 5 substituents selected from group A as defined above.
A carbocyclic group "or a" 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 ^a6, examples of -COOR ^a4 and -NR ^a5 COOR ^a6, respectively "group a", "-OR ^a1" in "- SR ^a1", "- NR ^a1 R ^a2", "- CONR ^a1 R ^a2" , “—SO ₂ NR ^a1 Ra ^a2 ”, “—COR ^a3 ”, “—NR ^a1 COR ^a3 ”, “—SO ₂ R ^a3 ”, “—NR ^a1 SO ₂ R ^a3 ”, “—COOR ^a1 ” and “ —NR ^a2 COOR ^a3 ”.

Specific examples of the “C _1-10 alkyl group _optionally substituted with 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, 1-ethyl-1-methylpropyl, heptyl, isoheptyl, 1-methylhexyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1 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 N-butyl 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 a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a 2-fluoroethyl group, a 2,2,2-trifluoroethyl group, a 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 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. When these particularly preferred substituents are optically active isomers, it is more preferred that they are S-isomer.
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, and a -Hydroxypropyl group and cyclohexylmethyl group, more preferably methyl group, ethyl group and isopropyl group, particularly preferably methyl group.

In formula (I), ring Cy is preferably “C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A” as defined above, more preferably,

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

(In the formula, 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, a “halogen atom” as defined above, a “C _1-4 alkyl group” as defined above, a “halo C _1-4 alkyloxy group” as defined above, or “—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 "in the definition" -SO ₂ R ^a3 ", the definition "-COOR ^a1 " and "-NR ^a1 SO ₂ R ^a3 " as defined above,
More preferably, "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. "Halogen atom",
R ⁵ is preferably a hydrogen atom, a cyano group, a nitro group, a “halogen atom” as defined above, a “C _1-4 alkyl group” as defined above, a “halo C _1-4 alkyl group” as defined above, "-OR ^a1", "-SR ^a1" defined above, "-NR ^a1 R ^a2" defined above, "-CONR ^a1 R ^a2" defined above, the above-defined "-SO ₂ NR ^a1 R ^a2" of And “—NR ^a1 COR ^a3 ” as defined above,
More preferred are a hydrogen atom, a “halogen atom” and a “C _1-4 alkyl group”, and particularly preferred is a “halogen atom”.
R ⁶ is preferably “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. And more preferably a "halogen atom."
R ^{6 ′} and R ^{6 ′ ″} are preferably the same or different and are each a hydrogen atom and a “halogen atom” as defined above, and R ^{6 ″} is preferably a hydrogen atom and a “halogen atom” as defined above. A “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, and 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, and “1 to 5 carbon atoms selected from group A” as defined above. heterocyclic group "may be substituted by substituents, (where specifically preferably a methoxy group.)" -OR ^a4 "defined above, the above-defined" -NR ^a4 R ^a5 "( Here, specifically preferred are an amino group, a methylamino group, an ethylamino group and a dimethylamino group.), “-NR ^a4 COR ^a6 ” as defined above (here, specifically preferred is acetylamino is a group.), the above-defined "-NR ^a4 sO ₂ R ^a6" (here, specifically preferably, methylsulfonylamino group and N- methyl -N- (methylsulfonyl) amino group.) "-NR ^a5 COOR" as 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 Alkyl group ", and more preferably selected from" C _3-10 carbocyclic group which may be 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, and more preferably a C _1-10 alkyl group which is substituted by 1 to 3 substituents selected from a halogen atom and a group B 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, and more preferably a hydrogen atom, cyano group, or “ A `` halogen atom '' and a `` C _1-4 alkoxy group '' as defined above, more preferably a hydrogen atom, a cyano group, and a `` C _1-4 alkoxy group '' as 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 with 1 to 5 substituents selected from group A” as defined above, "A halogen atom and a C1-10 alkyl group _optionally substituted with 1 to 3 substituents selected from group B", "-OR ^a7 " as defined above, "-SR ^a7 " as defined above, 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. a "-NR ^a7 R ^a8" of "-SR ^a7" or the definition of the definition, more preferably, a "-OR ^a7" of the hydrogen atoms or the defined, particularly preferably, "- oR ^a7" It is.
Preferably, R ³³ is a hydrogen atom, a “C _1-10 alkyl group _optionally substituted with a halogen atom and 1 to 3 substituents selected from group B” as defined above, and “—OR ^a7 ” as defined above. and a "-NR ^a7 R ^a8" defined above, more preferably a hydrogen atom, a "-NR ^a7 R ^a8" defined above, "-OR ^a7" or above definitions, more preferably, a hydrogen atom or “—OR ^a7 ” as defined above, and particularly preferably a hydrogen atom.
Preferably, one of R ³² and R ³³ is a hydrogen atom, and the other is “—OR ^a7 ” as defined above.
It is preferred that R ³¹ is a hydrogen atom and R ³² or R ³³ is other than a hydrogen atom.

  The “pharmaceutically acceptable salt” may be any salt that forms a nontoxic salt with the compounds represented by the above general formulas [I] and [II], for example, 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 benzylsulfonic acid; or inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide; or methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris (hydroxy Organic bases such as methyl) methylamine, guanidine, choline, cinchonine, etc .; or lysine, arginine, It can be obtained by reacting with amino acids such alanine. In the present invention, hydrates, hydrates and solvates of the respective compounds are also included.

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

In the present invention, prodrugs and metabolites of each compound are also included.
A “prodrug” is a derivative of a compound of the present invention that has a chemically or metabolically degradable group, and that, after being administered to a living organism, reverts to the original compound and exhibits its original efficacy, Conjugates and salts.
Prodrugs are used, for example, for improving absorption in oral administration or for targeting to a target site.
Examples of the modification 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 modifying group for the hydroxyl 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. Carboxymethyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group, phenyl group, o-tolyl group and the like. Specific examples of the modifying group for the amino group include a hexylcarbamoyl group, a 3-methylthio-1- (acetylamino) propylcarbonyl group, a 1-sulfo-1- (3-ethoxy-4-hydroxyphenyl) methyl group, and (5 -Methyl-2-oxo-1,3-diokel-4-yl) methyl group and the like.

The compound of the present invention can be administered to mammals (humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.) as anti-HIV agents, integrase inhibitors, anti-viral agents and the like. .
When the compound of the present invention is used as a pharmaceutical preparation, it is usually known as a pharmaceutically acceptable carrier, excipient, diluent, extender, disintegrant, stabilizer, preservative, buffer, emulsifier, fragrance, coloring. Agents, sweeteners, thickeners, flavoring agents, solubilizing agents, and other additives, specifically, water, vegetable oils, alcohols such as ethanol or benzyl alcohol, carbohydrates such as polyethylene glycol, glycerol triacetate, gelatin, lactose, and starch. Tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches, aerosols, elixirs, etc. by mixing with, magnesium stearate, talc, lanolin, petrolatum, etc. , Suspensions, emulsions, syrups and the like can be administered systemically or locally, orally or parenterally. .
The dosage varies depending on the age, body weight, symptoms, therapeutic effect, administration method, etc., but is usually in the range of 0.01 mg to 1 g at a time, and once or several times a day, per oral or intravenous injection per adult. And the like.

In general, it is necessary for anti-HIV agents not only to temporarily suppress virus growth, but also to maintain its effect so that the virus does not grow again. Therefore, long-term administration is required, and it is often necessary to increase a single dose in order to maintain the effect over a long period of time, such as at night. These long-term and large doses increase the risk of side effects.
Therefore, among the 4-oxoquinoline compounds of the present invention, one of preferred embodiments includes those having high absorbability by oral administration, and those in which the blood concentration of the administered compound is maintained for a long time. Can be

  "Prevention of AIDS" means, for example, administering a drug to a person in whom HIV has been detected by a test or the like and having no symptoms of AIDS, or a person in whom the symptoms have been improved after AIDS treatment Therefore, administration of a drug to a person who is not eradicated for HIV and is likely to have a relapse of AIDS, and administers a drug before HIV infection due to fear of infection.

"Other anti-HIV agents" and "other anti-HIV active substances" used in the multidrug combination therapy include anti-HIV antibodies, HIV vaccines, immunopotentiators such as interferons, HIV ribozymes, HIV antisense drugs, reverse transcription. An enzyme inhibitor, a protease inhibitor, a binding inhibitor of a virus with a binding receptor (CD4, CXCR4, CCR5, etc.) of a host cell recognized by a virus, and the like can be mentioned.
Specific examples of HIV reverse transcriptase inhibitors include Retrovir (R) (Zidovudine), Epivir (R) (Lamivudine), Zerrit (R) (Sanirubudine), Videx (R) (Zidanocine), and Hybrid (R) ( Zalcitabine), ziagen (R) (abacavir sulfate), viramune (R) (nevirapine), stockrin (R) (efavirenz), rescriptor (R) (delavirdine mesylate), combivir (R) (zidovudine + lamivudine), Trizivir (R) (abacavir sulfate + lamivudine + zidovudine), Coactinon (R) (emivirin), Phosphovir (R), Coviracil (R), alovudine (3'-fluoro-3'-deoxythymidine), Thiovino Formic acid), caprabillin (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-diaminopurine dioxolane), Immunocal, MSK-055, MSA- 54, MSH-143, NV-01, TMC-120, DPC-817, GS-7340, TMC-125, SPD-754, D-A4FC, capravirine, UC-781, emtricitabine, alovudine, Phosphazid, UC-781, BCH-10618, DPC-083, Etravirine, BCH-13520, MIV-210, Abacavir sulfate / lamivudine, GS-7340, GW-5634, GW-69634 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 crixivan (R) (an indinavir sulfate adduct), saquinavir, invirase (R) (saquinavir mesylate), Novia (R) (ritonavir), and virasept (R) (mesyl). Nelfinavir acid), lopinavir, Prose (R) (amprenavir), Kaletra (R) (ritonavir + lopinavir), and mozenavirdimesylate ([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] propyl ] -5- (trifluoromethyl) -2-pyridinesulfonic acid amide), lasinavir (N- [5 (S)-(tert-butoxycarbonylamino) -4 (S) -hydroxy-6-phenyl-2 (R )-(2,3,4-trimethoxybenzyl) hexanoyl] -L-valine 2-methoxyethyleneamide), KNI-272 ((R) -N-tert-butyl-3-[(2S, 3S) -2 -Hydroxy-3-N-[(R) -2-N- (isoquinolin-5-yloxyacetyl) amino-3-methylthiopropanoyl] amino-4-phenylbutanoyl] -5,5-dimethyl-1, 3-thiazolidine-4-carboxamide), GW-433908, TMC-126, DPC-681, buckminsterfullerene, 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-0344, AG-0344R And the like.

Examples of HIV integrase inhibitors include S-1360 and L-870810, and DNA polymerase inhibitors or DNA synthesis inhibitors such as foscavir (R) and ACH-126443 (L-2 ′, 3′-didehydro-dideoxy-). 5-fluorocytidine), entecavir ((1S, 3S, 4S) -9- [4-hydroxy-3- (hydroxymethyl) -2-methylenecyclopentyl] guanine), calanolideA ([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-74447 (1,1′-azobisformamide), Iscador (viscum albm extract), Rubiteca n, HIV-sense agents such as HGTV-43, GEM-92 and the like; anti-HIV antibodies or other antibodies such as 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. Vaccines, 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, PARTICLE-3B, etc., Antiferon (interferon-α vaccine), etc., as interferons or interferon agonists, Sumiferon (R), MultiFeron (R), interferon-τ, Reticulose, human leukocyte interferon α, etc., SCH-351125, etc. as CCR5 antagonists, drugs acting on HIVp24, GPG-NH2 (glycyl-prolyl-glycinamide), etc., as HIV fusion inhibitors, FP-21399 (1,4-bis [3-[(2,4-dichlorophenyl) carbonylamino] -2-oxo-5,8-disodiumsulfonyl] naphthyl-2,5-dimet (Xyphenyl-1,4-dihydrazone), T-1249, Synthetic Polymeric Construction No. 3, pentafuside, FP-21399, PRO-542, Enfuvirtide, and the like. R), Multikine (R), Ontak (R), etc., as TNF-α antagonists, Thalomid (R) (thalidomide), Remicade (R) (infliximab), sulfated curdlan, etc., α-glucosidase inhibitors, Bucast (R) and the like, as purine nucleoside phosphorylase inhibitors, perdesine (2-amino-4-oxo-3H, 5H-7-[(3-pyridyl) methyl] pyrrolo [3,2-d] pyrimidine) , As apoptosis agonists or inhibitors, Arkin Z (R), Panavir (R), Coenzyme Q10 (2-deca (3-methyl-2-butenylene) -5,6-dimethoxy-3-methyl-p-benzoquinone), etc. , A cholinesterase inhibitor such as Cognex®, and immunomodulators Immunox®, Prokine®, Met-enkephalin (6-de-L-arginine-7-de-L-arginine-8-de). -L-valinamide-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), lidacol (R), answer 20 (R), Ampligen (R), Anticort (R), Inactivin (R), etc., PRO-2000, RevM10 gene, HIV-specific cytotoxic T cell (CTL immunotherapy, ACTG protocol 080 therapy, CD4-ζ gene therapy), SCA binding protein, RBC-CD4 complex, Motexafin gadolinium, GEM-92, CNI-1493, (±) -FTC, Ushercell, D2S, BufferGel ( R), VivaGel (R), Glyminox vital 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 the “other anti-HIV active substance” used in the multidrug combination therapy with the compound of the present invention are preferably reverse transcriptase inhibitors and protease inhibitors. Two or three or more drugs can be used in combination. At this time, a combination of drugs having different action mechanisms is one of preferred embodiments. In addition, it is preferable to select a drug that does not have side effects.
Specific combinations of the drugs include efavirenz, tenofovir, emtricitabine, indinavir, nelfinavir, atazanavir, ritonavir + indinavir, ritonavir + lopinavir, ritonavir + saquinavir, zidanocine + lamivudine, zidovudine + zidavudine, stavudinedine, stavudinedine + Lamivudine, Emtriever 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 preferred is a combination of two drugs in combination with efavirenz, indinavir, nelfinavir, tenofovir, emtricitabine, zidovudine, lamivudine, and zidovudine + lamivudine, tenofovir + lamivudine, tenofovir + zidovudine, tenofovir + efavirenovir, tenofoviril + tenofovirevir, tenofovirine, tenofovirine , Tenofovir + emtricitabine, emtricitabine + lamivudine, emtricitabine + zidovudine, emtricitabine + efavirenz, emtricitabine + nelfinavir, emtricitabine + indinavir, nelfinavir + lamivudine, nelfinavir + evidenavirine, finavirine finavirine, nelfinavir + efenvirine + Zidovudine, a triple combination in combination with efavirenz + indinavir.

Next, an example of a method for producing a compound used in the practice of the present invention will be described. However, the production method of the compound of the present invention is not limited to these.
Although not described in this production method, a protecting group is introduced into a functional group as necessary, and deprotection is performed in a subsequent step.The functional group is treated as a precursor in each step and converted into a desired functional group at an appropriate stage. In this case, efficient manufacturing may be performed by devising the manufacturing method and the order of the steps.
In each step, the treatment after the reaction may be performed by a method usually performed, and isolation and purification may be performed, if necessary, by crystallization, recrystallization, distillation, liquid separation, silica gel chromatography, preparative HPLC, etc. May be appropriately selected and combined.

Manufacturing method 1-1

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

First Step After reacting zinc powder with 1,2-dibromoethane in a solvent under heating under an argon or nitrogen stream, trimethylsilyl chloride is added and reacted. Next, the compound [2] can be obtained by adding a solution of the compound [1] to the reaction solution and causing the reaction to proceed.
Preferred examples of the solvent include ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran (THF); and hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
Step 2 Compound [2] is dissolved in a solvent in the presence of a catalyst, if necessary, in the presence of a ligand such as triphenylphosphine or tri (2-furyl) phosphine, under a stream of argon or nitrogen, or under cooling or heating. The compound [4] can be obtained by reacting with the compound [3].
As the catalyst, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (benzonitrile) palladium, dichloroethylenediaminepalladium, palladium acetate, tetrakis (triphenylphosphine) palladium And the like, a palladium catalyst, a 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); and hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
Third step Compound [4] is neutrally or alkalinely reduced with zinc or iron; iron and acid; tin or tin (II) chloride and concentrated hydrochloric acid; alkali sulfide; alkaline hydrosulfite or the like, contacted under 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 dust 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 under a hydrogen atmosphere and reacting at room temperature.

Fourth Step The compound [5] is reacted with the compound [6] in a solvent under heating.
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, chloroform, carbon tetrachloride and 1,2-dichloroethane. Solvents: Examples include ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran, and mixed solvents thereof.
Next, after distilling off the solvent, the compound [7] can be obtained by reacting the residue under heating in a solvent such as diphenyl ether, a mixture of diphenyl ether and diphenyl, for example, Dowtherm A (trade name, Fluka) or the like. .
Fifth Step The compound [I-1] can be obtained by reacting the compound [7] with the compound [8] in a solvent in the presence of a base.
Examples of the base include potassium carbonate, sodium carbonate, lithium hydride, sodium hydride, potassium hydride, and the like, with potassium carbonate being preferred.
Examples of the solvent include hydrocarbon solvents such as benzene, toluene, hexane, and xylene; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran; dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like. Examples thereof include a polar solvent and a mixed solvent thereof.
Sixth Step Compound [I-1] is hydrolyzed in a solvent at room temperature to under heating under basic conditions such as sodium hydroxide, potassium hydroxide and lithium hydroxide, or under acidic conditions such as hydrochloric acid and sulfuric acid. By doing so, 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; Ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran; polar solvents such as dimethylformamide, dimethylsulfoxide, and acetonitrile; and 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 the following formula:

Production method 1-2 Production example using compound [9] into which a hydroxyl-protecting group is introduced.

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

Step 1 By reacting compound [7] and compound [9] obtained in the same manner as in production method 1-1, in the same manner as in step 5 of production method 1-1, compound [10] can be obtained.
Step 2 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, it is treated with tetrabutylammonium fluoride in THF at room temperature, or heat-treated in THF in the presence of sodium hydroxide, or at room temperature. Deprotection may be performed using a method such as treatment with acetic acid-water-THF under heating. In this step, deprotection of R ^P1 and hydrolysis of R ^2A can be divided into two steps.

Manufacturing method 2-1

(In the formula, 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 are each a lower alkyl group such as a methyl group or an ethyl group, and R ^1B Is a “C _1-10 alkyl group _optionally substituted by a halogen atom and 1 to 3 substituents selected from group B” as defined above, and “1 to 5 substituents selected from group A” as defined above. A C _3-10 carbocyclic group _optionally substituted by a group ”, a“ heterocyclic group _optionally substituted by 1 to 5 substituents selected from group A ”as defined above, or“ —OR ^{a4 as} defined above. ] And the other symbols are as described above, wherein the substituent R ³ is not substituted at the * position.)

First Step Here, Hal ¹ is preferably bromine or iodine, and the compound [12] can be obtained by a conventional halogenation.
For example, the compound [11] is reacted with a halogenating agent such as N-bromosuccinimide or N-iodosuccinimide in a solvent such as trifluoromethanesulfonic acid, acetic acid, concentrated sulfuric acid, or DMF at room temperature or under heating to obtain a compound [11]. 12] can be obtained.
Step 2 Compound [12] is converted into a hydrocarbon-based solvent such as toluene and xylene; a halogen-based solvent such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; an oxalyl chloride in a solvent such as ethyl acetate under heating. 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.
Next, the compound [13] is added and reacted in a solvent at room temperature to under heating in the presence of a base such as triethylamine, diisopropylethylamine, potassium carbonate, and pyridine, and then reacted with compound [14] at room temperature to under heating. Can give compound [15].
Examples of the solvent include hydrocarbon solvents such as benzene, toluene, hexane, and xylene; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; and 1,4-dioxane, diethyl ether, and 1,2-dichloroethane. Ether solvents such as dimethoxyethane and tetrahydrofuran; polar solvents such as acetonitrile; ethyl acetate or a mixed solvent thereof.
Third Step The 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. By doing so, compound [16] can be obtained.
Further, as one of preferred production methods, compound [16] is obtained by reacting compound [15] in a solvent in the presence of 1,8-diazacyclo [5.4.0] -7-undecene from room temperature to heating. ] Can also be obtained.
Examples of the solvent 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, dimethylsulfoxide, and acetonitrile; and mixed solvents thereof.
Fourth Step Compound [I-4] can be obtained by reacting compound [16] with compound [2] in the same manner as in Production Method 1-1, second step.
Fifth Step The compound [I-5] can be obtained by hydrolyzing the compound [I-4] in the same manner as in the sixth step of Production Method 1-1.

Production Method 2-2 An example of a production method including a step of introducing and deprotecting a protecting group for a hydroxyl group.

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

Step 1 By reacting compound [12] obtained in the same manner as in the first step of production method 2-1 with compound [13] and compound [17] in the same manner as in the second step 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 the third step of Production method 2-1.
Compound [19] can also be obtained by cyclizing compound [18] in the same manner as in the third step of Production method 2-1 and then introducing a protecting group into a hydroxyl group by a conventional method.
For example, when R ^P1 is a tert-butyldimethylsilyl group, compound [18] may be reacted with imidazole and tert-butyldimethylsilyl chloride in DMF or toluene solvent at room temperature.
When R ^P1 is a methoxycarbonyl group, compound [18] may be reacted with pyridine and methyl chlorocarbonate in a chloroform solvent at cooling to room temperature.
In place of compound [17], the same production method is used for NH ₂ —R ^{1A ′} (where R ^{1A ′} is a C _1-10 alkyl group _optionally 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 A compound [I-7] can be obtained by hydrolyzing the compound [I-6] in the same manner as in the second step of Production Method 1-2. In this step, deprotection of R ^P1 and hydrolysis of R ^2A can be divided into two steps.

Manufacturing method 3

(In the formula, R ^{a7 ′} is a halogen atom and a C _1-10 alkyl group which may be substituted by 1 to 3 substituents selected from group B, and 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 a reaction with a conventional nucleophile. They can be further converted to -NR ^a7 COR ^a9 and -N = CH-NR ^a10 R ^a11 by a conventional method.
This process is suitable for introducing a substituent at the 7-position on 4-oxoquinoline.

Manufacturing method 3-1
Compound [I-8] can be obtained by introducing an alkoxy group into compound [21] in a conventional manner.
For example, the compound [I-8] can be obtained by reacting with a metal alkoxide in an alcohol solvent such as methanol, ethanol, propanol, or butanol under heating and then hydrolyzing.
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. May 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 in an inert organic solvent such as THF, dioxane, chloroform, dichloromethane, methanol, ethanol, pyridine and the like under heating.
Compound [I-9] can also be obtained by reacting with an amine by microwave irradiation in DMF.

Manufacturing method 4
A production example of the intermediate compound [12] will be described.

(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 a solvent such as DMF, THF or toluene in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydride or potassium hydride. [23] can be obtained.
Step 2 Compound [24] can be obtained by reducing compound [23] by a conventional method in the same manner as in Production Method 1-1, Step 3.
Third Step Compound [25] can be obtained by halogenating compound [24] by a conventional method in the same manner as in the first step of Production Method 2-1.
Fourth Step Compound [25] is dissolved in water or an inert organic solvent such as THF, dioxane, ethyl acetate, chloroform, dichloromethane, methanol, ethanol, pyridine or the like at a temperature of from cooling to room temperature under the condition of sodium nitrite and hydrochloric acid or sulfuric acid. The compound [26] can be obtained by diazotizing with a halogenated solution, followed by halogenation with a cuprous halide such as copper chloride or the like 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 ^RP1 is a methyl group, the compound [27] can be obtained by reacting with boron tribromide in dichloromethane under cooling.
Sixth Step Compound [28] can be obtained by reacting compound [27] with compound [8] in a solvent in the presence of a base.
Examples of the compound [8] include an alkylating agent such as ethyl iodide.
Examples of the base include potassium carbonate, sodium carbonate, lithium hydride, sodium hydride, potassium hydride, and the like, with potassium carbonate being preferred.
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, chloroform, carbon tetrachloride and 1,2-dichloroethane. Solvents; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran; polar solvents such as dimethylformamide, dimethylsulfoxide, and acetonitrile; water; and mixed solvents thereof.
Seventh Step Compound [12 '] can be obtained by hydrolyzing compound [28] by a conventional method in the same manner as in the sixth step of Production Method 1-1.
Eighth Step When R ^P1 is a desired substituent in compound [26], compound [12 ′] can be obtained in the same manner as in the seventh step.

Manufacturing method 5

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

  Next, the 4-oxoquinoline compound represented by the general formula [I] according to the present invention or a pharmaceutically acceptable salt thereof, and a method for producing the same will be specifically described with reference to Examples. However, the present invention is not limited by these examples.

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

  Under a stream of argon, 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 the mixture was heated under 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) of 2,3-dichlorobenzyl chloride (82.4 g, 421.7 mmol) was added. A THF (330 ml) solution was added dropwise under ice-cooling, and after completion of the addition, the temperature was raised to room temperature and stirred for 1 hour to obtain a THF solution of 2,3-dichlorobenzylzinc chloride (2,3-dichlorobenzylzinc Chloride).

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 a 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. (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 saline, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the solid precipitated during the filtration was collected by filtration. The filtrate was concentrated again under reduced pressure, and a solid precipitated during the filtration was collected by filtration. The collected solids were combined, washed with n-hexane, and dried under reduced pressure to obtain a light brown solid (60.2 g, yield 76%).
¹ H NMR (CDCl ₃ 400 MHz) (δ) ppm: 4.24 (2H, s), 7.09 (1H, d, J = 7.7 Hz), 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 dust (70 g, 1.1 mol) was added thereto at 0 ° C. in portions, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through celite and washed with ethanol, and the filtrate was concentrated under reduced pressure. The solid collected by filtration was washed with diethyl ether, dissolved in ethyl acetate (500 ml) and water (500 ml), and a 4N aqueous sodium hydroxide solution was added to neutralize the aqueous layer. The organic layer was separated, the aqueous layer was further extracted with ethyl acetate, and the organic layers were combined, washed with water and saturated saline, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the solid precipitated during the filtration was collected by filtration. The solid collected by filtration was washed with n-hexane and then 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 malonic acid diethyl ester (DiethylEthoxymethylenemalonate, 8.8 ml, 43.7 mmol) Was added and heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved by adding diphenyl ether (DiphenylEther, 100 ml), followed by heating and stirring at 250 ° C. for 3 hours. After cooling, n-hexane was added to the reaction solution, and the precipitated solid was collected by filtration, washed with chloroform, and dried under reduced pressure to obtain the target product as a pale yellow solid (10.1 g, yield 68%).
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

Fourth Step 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). After suspending, 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 solution, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the desired product as a white solid (468 mg, yield 95%).
¹ H NMR (DMSO-d ₆ 400 MHz) (δ) ppm: 1.25 (3H, t, J = 9.3 Hz), 1.88 (3H, s), 4.20 (2H, q, J = 9.3 Hz), 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)

Fifth Step 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 under reflux for 30 minutes. After allowing to cool, the reaction solution 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 obtain the target product as a white solid (4.5 g, yield 85%). 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 3,3-difluoro-5-iodobenzoic acid

2,3-Difluorobenzoic acid (2,3-Difluorobenzoic Acid; 5.0 g, 31.6 mmol) was dissolved in trifluoromethanesulfonic acid (25 ml) and N-iodosuccinimide (8.55) was added at 0 ° C. under an argon stream. g, 38.0 mmol). 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 dried under reduced pressure to obtain the desired product as a pale pink solid (7.5 g, yield 84%).
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 ethyl 2- (2,3-difluoro-5-iodobenzoyl) -3- (2-hydroxyethylamino) acrylate

The 2,3-difluoro-5-iodobenzoic acid (3.0 g, 10.6 mmol) obtained in the first step was dissolved in toluene, and thionyl chloride (3.0 ml, 41.1 mmol) and DMF (catalytic amount) were added. Heated to reflux for hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved by adding THF (15 ml). 10 ml), and the mixture was heated and stirred at 50 ° C. for 2.5 hours. After cooling, the reaction solution was filtered and washed with THF (10 ml). 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 solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, 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 target substance (3.8 g, yield 85%) as a yellow solid mixture of E and Z. Got.
¹ H NMR (CDCl ₃ 400MHz) (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

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

The 2- (2,3-difluoro-5-iodobenzoyl) -3- (2-hydroxyethylamino) acrylic acid ethyl ester (2.0 g, 4.7 mmol) obtained in the second step is dissolved in DMF (10 ml). And 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 solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, 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 give the desired product as a white solid (2.3 g, yield 91%).
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

Fourth step Synthesis of ethyl 1,4-dihydro-8-fluoro-6-iodo-1- [2- (tert-butyldimethylsilyloxy) ethyl] -4-oxo-3-quinolinecarboxylate

Ethyl 2- (2,3-difluoro-5-iodobenzoyl) -3- [2- (tert-butyldimethylsilyloxy) ethylamino] acrylate (2.3 g, 4.3 mmol) obtained in the third step The residue was dissolved in THF (25 ml), sodium hydride (256 mg, 6.4 mmol) was added under ice cooling, and the mixture was stirred at 0 ° C for 1 hour. The reaction solution was neutralized by adding 1N hydrochloric acid (6.4 ml, 6.4 mmol), further added water, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline 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 as a white solid (2.0 g, yield 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

Fifth step Ethyl 6- (2,3-dichlorobenzyl) -1,4-dihydro-8-fluoro-1- [2- (tert-butyldimethylsilyloxy) ethyl] -4-oxo-3-quinolinecarboxylate Ester synthesis

Under an argon stream, a 1MTHF 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- ( tert-butyldimethylsilyloxy) ethyl] -4-oxo-3-quinolinecarboxylic acid ethyl ester (1.0 g, 1.9 mmol), and the mixture was stirred at room temperature for 17 hours. Further, a THF solution of 2,3-dichlorobenzylzinc chloride in THF was added. (1.0 ml, 1.0 mmol) was added, and the mixture was heated under reflux for 1 hour. After cooling, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and insolubles were filtered through Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was crudely purified by silica gel chromatography (ethyl acetate: hexane = 1: 1), and then purified by PTLC (ethyl acetate: chloroform = 1: 2) to give a pale residue. The target product (562 mg, yield 53%) was obtained as a yellow oil.
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

Sixth step 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) was dissolved in THF (25 ml), and tetrabutylammonium fluoride (1M THF solution;
1.9 ml, 1.9 mmol) and 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 a light yellow solid target product (279 mg, quantitative yield).
¹ H NMR (DMSO-d ₆ 300 MHz) (δ) ppm: 1.27 (3H, t, J = 7.1 Hz), 3.65-3.80 (2H, m), 4.21 (2H, q, J = 7.1 Hz), 4.40- 4.50 (2H, m), 4.99 (1H, m), 7.30-7.90 (5H, m), 8.47 (1H, s) MS (ESI): M + 438

Seventh step 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), a 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 cooling, a 10% aqueous solution of citric acid was added to the reaction solution, and the precipitated solid was collected by filtration, washed with 30% aqueous ethanol, and dried under reduced pressure to obtain the target product as a white solid (70 mg, yield 93%). Got.
¹ H NMR (DMSO-d ₆ 300 MHz) (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 step

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 portionwise at 0 ° C. After stirring at 40 ° C. for 4 hours, the reaction solution was added to ice water and stirred. 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 under reflux for 5.5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 4) to give the desired product as a pale yellow solid (5.35 g, yield 53%).
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)
2nd step

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

The compound (4.99 g, 15.24 mmol) obtained in the second step 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 under 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 ethyl 3,3-dimethylaminoacrylate (2.29 g, 16.00 mmol) and triethylamine (2.55 ml, 18.30 mmol) in tetrahydrofuran (50 ml). ) The solution was added dropwise, and the mixture was heated and stirred at 50 ° C for 10 hours. After cooling, aminoethanol (1.10 ml, 18.23 mmol) was added to the reaction solution, and the mixture was heated and stirred at 40 ° C for 1.5 hours. After cooling, water was added to the reaction solution, and the mixture was 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 = 2: 1) to give the desired product (5.35 g, yield: yellow solid in which E-form and Z-form were mixed). 75%).
¹ H NMR (CDCl ₃ 300 MHz) (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 step

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 solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this order, 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.
Step 5

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 minutes. 1N Hydrochloric acid (18.3 ml) and water were added to the reaction solution, stirred, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this 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 as a yellow solid (5.58 g, yield 84%).
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)
6th step

The compound obtained in the fifth step (5.00 g, 9.15 mmol) was dissolved in tetrahydrofuran (100 ml), and under an argon stream, bis (dibenzylideneacetone) palladium (0) (105 mg, 0.18 mmol) and tri (2-furyl) 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 the fourth step of Example 4-32 was added dropwise at 60 ° C. The mixture was refluxed for 4 hours. After cooling, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and insolubles were filtered through Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline in this 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: 2 to 1: 1) to give the desired product as a brown oil (2.67 g, yield 52%). Obtained.
¹ H NMR (CDCl ₃ 300 MHz) (δ) ppm: -0.19 (6H, s), 0.70 (9H, s), 1.39 (3H, t, J = 7.1 Hz),
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 (1.00 g, 1.79 mmol) obtained in the sixth step 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 solution was filtered through celite, a saturated aqueous sodium hydrogen carbonate solution 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 saline in this order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel chromatography (ethyl acetate), sonication was performed by adding diethyl ether, and the filtrate was dried under reduced pressure to give the target compound as a pale orange solid (730 mg). , Yield 77%).
¹ H NMR (CDCl ₃ 300 MHz) (δ) ppm: -0.06 (6H, s), 0.77 (9H, s), 1.41 (3H, t, J = 7.1 Hz), 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 added at room temperature for 2 hours. Stirred. A 10% aqueous solution of citric acid was added to the reaction solution, and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this 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 crudely 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), a 1M THF solution of tetrabutylammonium fluoride (1.00 ml, 1.00 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Ethanol (1 ml) and a 1N aqueous sodium hydroxide solution (1 ml, 1.00 mmol) were added to the reaction solution, and the mixture was heated under reflux for 2 hours. After cooling, a 10% aqueous citric acid solution was added to the reaction solution, and the mixture was stirred and extracted twice with chloroform. The organic layer was washed with 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. The crude product was sonicated by adding ethanol water, filtered and dried under reduced pressure to obtain a target product (22 mg, yield 27%) as a beige solid.
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 3-62
1st step

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 under 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 ethyl 3,3-dimethylaminoacrylate (1.66 g, 11.60 mmol) and triethylamine (1.77 ml, 12.70 mmol) in tetrahydrofuran (10 ml). ) The solution was added dropwise, and the mixture was heated and stirred at 50 ° C for 2.5 hours. After cooling, the reaction solution was filtered and washed with tetrahydrofuran (10 ml). Aminoethanol (0.77 ml, 12.76 mmol) was added to the filtrate, and the mixture was heated with stirring at 40 ° C. for 1 hour. After cooling, water was added to the reaction solution, and the mixture was 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 = 2: 1) to give a crude purified yellow solid (3.00 g, Yield 67%).
2nd step

The compound obtained in the first step (3.00 g, 7.06 mmol) was dissolved in dimethylformamide (15 ml), imidazole (1.06 g, 15.52 mmol) and tert-butyldimethylsilyl chloride (2.23 g, 14.82 mmol) were added, and room temperature was added. For 14 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this 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: 4) to give the desired product as a white solid (3.22 g, yield 85%).
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 step

The compound (3.22 g, 5.97 mmol) obtained in the second step 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 solution, and the mixture was 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 target product (2.52 g, yield 81%) was obtained as a pale yellow solid.
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 step

The compound obtained in the third step (1.00 g, 1.93 mmol) was dissolved in tetrahydrofuran (20 ml), and under an argon stream, bis (dibenzylideneacetone) palladium (0) (22 mg, 0.039 mmol) and tri (2-furyl) 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 the completion of the addition, the mixture was heated under reflux for 1 hour. After cooling, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and insolubles were filtered through Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline in this 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 = 2: 1) to obtain the desired product as a pale yellow solid (573 mg, yield 55%).
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)
Step 5

The compound (170 mg, 0.32 mmol) obtained in the fourth step was dissolved in tetrahydrofuran (1 ml), a 2N aqueous sodium hydroxide solution (4.00 ml, 2.00 mmol) was added, and the mixture was heated under reflux for 3.5 hours. After cooling, a 10% aqueous citric acid solution was added to the reaction solution, and the precipitated solid was collected by filtration, washed with 50% aqueous ethanol, and dried under reduced pressure to give the target 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)
6th step

The compound (65 mg, 0.17 mmol) obtained in the fifth step 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 cooling, a 10% aqueous citric acid solution 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 target product as a yellow-white solid (66 mg, yield 96%). Was.
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, brs)
MS (ESI): M + 419

Example 3-73
1st step

2,4-Difluoro-5-iodobenzoic acid (5.00 g, 17.60 mol) was dissolved in toluene (25 ml), oxalyl chloride (2.00 ml, 22.93 mmol) and dimethylformamide (catalytic amount) were added, and the mixture was added at room temperature for 12 hours. Stirred. After filtration, the reaction solution was concentrated under reduced pressure, toluene (20 ml) was added, and insolubles were filtered through celite. A solution obtained by adding tetrahydrofuran (20 ml) to the residue obtained by concentrating the filtrate under reduced pressure was dissolved in ethyl 3,3-dimethylaminoacrylate (3.28 g, 22.91 mmol) and triethylamine (3.70 ml, 26.55 mmol) in tetrahydrofuran. (20 ml), and the mixture was heated under 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 saline in this order, and then washed with sodium sulfate. Dried. After filtration, the filtrate was concentrated under reduced pressure to obtain a brown oily crude product (7.24 g).
2nd step

The crude product obtained in the first step (7.24 g) 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 solution was concentrated under reduced pressure, the obtained residue was dissolved in dimethylformamide (20 ml), potassium carbonate (7.33 g, 53.02 mmol) was added, and the mixture was heated with stirring at 70 ° C. for 1 hour. After cooling, the reaction solution was concentrated under reduced pressure, water (150 ml) was added to the residue, and the mixture was stirred at room temperature for 30 minutes, and the precipitated solid was collected by filtration. The obtained solid was washed with water (50 ml), subsequently with a mixed solvent of hexane: diethyl ether = 7: 3 (50 ml), and dried under reduced pressure to obtain the target product as a white solid (4.69 g, yield 61%). 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 step

The compound obtained in the second step (4.69 g, 10.82 mmol) was dissolved in dimethylformamide (20 ml), imidazole (950 mg, 13.95 mmol) and tert-butyldimethylsilyl chloride (1.95 g, 12.96 mmol) were added, and room temperature was added. For 14.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed three times 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 = 3: 7) to give the desired product as a yellow oil (5.06 g, yield 86%).
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 under an argon stream, bis (dibenzylideneacetone) palladium (0) (266 mg, 0.46 mmol) and tri (2-furyl) Phosphine (215 mg, 0.92 mmol) was added, and a solution of 3-chloro-2-fluorobenzylzinc bromide (18.50 mmol) in tetrahydrofuran prepared as described above was added dropwise. After completion of the addition, the mixture was heated with stirring at 60 ° C. for 1 hour. After allowing to cool, water and ethyl acetate were added to the reaction solution, 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)
Step 5

A 28% sodium methoxide methanol solution (40.00 ml, 0.20 mol) and water (2.00 ml, 0.11 mol) were added to the compound (3.86 g, 6.85 mmol) obtained in the fourth step, and the mixture was heated under reflux for 5.5 hours. After cooling, the reaction solution was concentrated under reduced pressure, 6N hydrochloric acid was added to the obtained residue, and the mixture was stirred and extracted twice with ethyl acetate. The organic layer was washed with water and saturated saline in this order, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.The residue obtained was recrystallized from ethanol (200 ml) to give the desired product as a white solid (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 step

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 prepared by adding chloroform (35 ml) to the residue was dissolved in ethyl 3,3-dimethylaminoacrylate (4.26 g, 29.75 mmol) and triethylamine (5.19 ml, 37.24 mmol) in chloroform (35 ml). ) The solution was added dropwise and stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated saline 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 give the desired product as an orange solid in which the E-form and the Z-form are mixed. (6.40 g, yield 66%).
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
2nd step

The compound (300 mg, 0.77 mmol) obtained in the first step was dissolved in tetrahydrofuran (1.5 ml), (S)-(+)-tert-leucinol (0.12 ml, 0.92 mmol) was added, and the mixture was heated at 60 ° C. for 1 hour. Stirred. The reaction solution was concentrated under reduced pressure, the obtained 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 solution, 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), then with a mixed solvent of hexane: diethyl ether = 2: 1 (5 ml), and dried under reduced pressure to obtain a light yellow solid of the desired product (276 mg, yield Rate of 81%).
¹ H NMR (CDCl ₃ 300 MHz) (δ) ppm: 0.98 (9H, s), 1.41 (3H, t, J = 7.0 Hz), 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 step

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 added at room temperature for 30 minutes. Stirred for minutes. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice 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 = 3: 5) to obtain a white amorphous target product (314 mg, yield: 91%).
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 step

The compound obtained in the third step (314 mg, 0.56 mmol) was dissolved in tetrahydrofuran (1.2 ml), and under an argon stream, bis (dibenzylideneacetone) palladium (0) (16 mg, 0.028 mmol) and tri (2-furyl) 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 heated and stirred at 50 ° C. for 1.5 hours. After allowing to cool, water and ethyl acetate were added to the reaction solution, and the mixture was stirred, and the insoluble matter was filtered through celite. The filtrate was separated, and the organic layer was washed with water and saturated saline in this 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 give the desired product as a brown amorphous (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)
Step 5

The compound (283 mg, 0.49 mmol) obtained in the fourth step was dissolved in ethanol (2 ml), a 1 N aqueous sodium hydroxide solution (1.00 ml, 1.00 mmol) was added, and the mixture was heated under reflux for 1 hour. After cooling, acetic acid (0.35 ml) was added to the reaction solution, followed by stirring, and the precipitated solid was collected by filtration. The obtained solid was suspended in diethyl ether (10 ml). After filtration, the filtrate was dried under reduced pressure to obtain the target product as a white solid (157 mg, yield: 74%).
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 4-20
1st step

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 portionwise 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 portionwise 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 then 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.
2nd step

Dissolve the mixture obtained in the first step (3.89 g) in dimethylformamide (20 ml), add potassium carbonate (8.97 g, 64.90 mmol) and isopropyl iodide (6.50 ml, 65.15 mmol) and heat at 80 ° C. for 2.5 hours Stirred. The reaction solution was added to 1N hydrochloric acid (100 ml), toluene (100 ml) was further added, and the mixture was stirred. The filtrate was separated, and the organic layer was washed three times with water 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: 9) to give the desired product as a mixture (4.08 g).
3rd step

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

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 under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and a solution obtained by adding tetrahydrofuran (25 ml) to the residue was dissolved in ethyl 3,3-dimethylaminoacrylate (4.29 g, 30.00 mmol) and tetrahydrofuran (10 ml) of triethylamine (4.17 ml, 30.00 mmol). The solution was added dropwise, and the mixture was heated under reflux for 14 hours. After cooling, water and ethyl acetate were added to the reaction solution, and the mixture was stirred and separated. The organic layer was washed with water and saturated saline in this 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 give the desired product as a mixture (2.71 g).
Step 5

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 under reflux for 20 minutes. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained 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 added at room temperature for 20 minutes. Stirred for minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this 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: 4) to give the desired product as a mixture (391 mg).
6th step

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 solution, and the mixture was heated with stirring at 60 ° C. for 30 minutes. After cooling, the reaction solution was added to ice water, further neutralized by adding 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this 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 as a pale yellow-white solid (258 mg, yield 19%). Got.
¹ H NMR (CDCl ₃ 300 MHz) (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-quinoline carboxylic acid ethyl ester (258 mg, 0.42 mol) was dissolved in tetrahydrofuran (5 ml), and under an argon stream, bis (dibenzylideneacetone) palladium (0) (9.7 mg, 0.017 mmol) and tri (2-furyl) 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 the completion of the addition, the mixture was heated under reflux for 1 hour. After cooling, a saturated aqueous ammonium chloride solution was added to the reaction solution, 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 saturated brine in that order, 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 under reflux for 1 hour. After cooling, a 10% aqueous citric acid solution was added to the reaction solution, and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this 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, the filtrate was dried under reduced pressure to obtain the desired product as a white solid (140 mg, yield 68%).
¹ H NMR (DMSO-d ₆ 300 MHz) (δ) ppm: 0.97 (9H, s), 1.18 (3H, d, J = 5.9 Hz), 1.26 (3H, d, J = 6.0 Hz), 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 step

2,4-Difluoro-5-iodobenzoic acid (650.57 g, 2.29 mol) was dissolved in toluene (1300 ml), thionyl chloride (184 ml, 2.52 mol) and dimethylformamide (catalytic amount) were added, and the mixture was heated at 90 ° C for 2 hours. Stirred. 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 solution of ethyl 3,3-dimethylaminoacrylate (361.52 g, 2.525 mol) and diisopropylethylamine (480 ml, 2.75 mol) in toluene (690 ml). The mixture was heated and stirred for 3 hours. After cooling, (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, and the mixture was separated. The aqueous layer was extracted with toluene (680 ml), and the combined organic layers were washed twice with water (2000 ml) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a brown oily crude product (1180 g).
2nd step

The crude product (1180 g) obtained in the first step was dissolved in dimethylformamide (2500 ml), crushed 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), stirred for 30 minutes, and the precipitated solid was collected by filtration and washed with water (2000 ml). The obtained solid was dried under reduced pressure, and suspended in ethyl acetate (5000 ml). Filtration and drying under reduced pressure gave the target product (774.63 g, yield 82%) as a yellow-white 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 step

The compound (626.15 g, 1.40 mol) obtained in the second step 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. At 10 ° C. or lower, a chloroform (1250 ml) solution of methyl chloroformate (529.30 g, 5.60 mol) was added dropwise, and after completion of the addition, the mixture was stirred at the same temperature for 30 minutes. 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 that 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 step

(Preparation of 3-chloro-2-fluorobenzylzinc bromide tetrahydrofuran solution)
Under an argon stream, zinc dust (113.02 g, 1.73 mol) was suspended in tetrahydrofuran (350 ml), and 1,2-dibromoethane (1.207 ml, 14.00 mmol) and trimethylsilyl chloride (8.88 ml, 70.00 mmol) were suspended at 60 ° C. 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 under heating for 1 hour to obtain a solution of 3-chloro-2-fluorobenzylzinc bromide.
(This process)
The crude product obtained in the third step (834.02 g) was dissolved in tetrahydrofuran (1060 ml), and under an argon stream, dichlorobis (triphenylphosphine) palladium (II) (19.65 g, 28.00 mmol) was added, followed by odor at 60 ° C. A solution of 3-chloro-2-fluorobenzylzinc chloride (1.82 mol) was added dropwise, and the mixture was heated under reflux for 1.5 hours after completion of the addition. After cooling, toluene (2120 ml) and 20% aqueous ammonium chloride solution (1410 ml) were added to the reaction solution, and the mixture was stirred and separated. The organic layer was washed twice with a 20% aqueous ammonium chloride solution (710 ml) and twice with a saturated aqueous sodium bicarbonate solution (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).
Step 5

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 heated with stirring at 50 ° C. for 1.5 hours. Activated carbon (37 g) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes, and then filtered through celite. 6N Hydrochloric acid (740 ml) and ethyl acetate (3650 ml) were added to the filtrate, 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 as a pale yellow solid (446.51 g, yield 73%).
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
6th step

The compound obtained in the fifth step (443.59 g, 1.02 mol) was dissolved in methanol (2400 ml), 28% sodium methoxide methanol solution (2077 ml, 10.17 mol) and water (44.30 ml, 2.46 mol) were added, and 17.5 hours. Heated to reflux. Activated carbon (22 g) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, filtered through celite, and concentrated under reduced pressure. Water (1770 ml) was added to the residue, and the mixture was stirred under ice-cooling for 1 hour. Then, 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 stirred and separated. The organic layer was washed twice with 10% saline (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 as a white solid (28.60 g, yield 67%).
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 step

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 portionwise at 5 ° C. or lower. After completion of the addition, the mixture was stirred at the same temperature for 3 hours. The reaction solution was poured into ice water (about 10 L), then a 10% aqueous sodium sulfite solution (40 ml) was added, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration, suspended in water (about 3 L), and filtered repeatedly until the pH became 3 or more. The obtained wet crystals (1677 g) were recrystallized from 50% aqueous ethanol (3000 ml) to give the desired product as a white solid (824.70 g, yield 76%).
¹ H NMR (CDCl ₃ 300MHz) (δ) ppm: 6.94 (1H, dd, J = 10.3, 10.3Hz), 8.46 (1H, d, J = 7.5Hz)
2nd step

The compound (150.00 g, 0.53 mol) obtained in the first step 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. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene (150 ml), concentrated under reduced pressure, and the procedure was repeated again. A solution obtained by adding tetrahydrofuran (300 ml) to the residue and dissolving the solution was added dropwise to a solution of ethyl 3,3-dimethylaminoacrylate (83.2 g, 0.581 mol) and triethylamine (96 ml, 0.686 mol) in tetrahydrofuran (450 ml), and the mixture was added for 15 hours. Heated to reflux. After cooling, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (750 ml) was added to the residue to dissolve, washed with aqueous ammonium chloride (400 ml), saturated aqueous sodium bicarbonate (200 ml) and saturated saline in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a brown oily crude product (206.50 g).
3rd step

The crude product obtained in the second step (206.50 g) was dissolved in tetrahydrofuran (800 ml), and (S)-(+)-tert-leucinol hydrochloride (81.10 g, 0.53 mol) and triethylamine (74 ml, 0.53 mol) Was added and stirred at room temperature for 50 minutes. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dimethylformamide (1000 ml), potassium carbonate (146.0 g, 1.06 mol) was added, and the mixture was heated with stirring 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% aqueous ethanol (1000 ml) and collected by filtration. This operation was repeated with a mixed solution of hexane: ether = 1: 1. After filtration, the filtrate was dried under reduced pressure to obtain the target product as a white solid (184.74 g, yield: 76%).
¹ H NMR (DMSO-d ₆ 400MHz) (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 step

The compound obtained in the third step (150.00 g, 0.33 mol) was dissolved in dimethylformamide (600 ml), and imidazole (28.80 g, 0.42 mol) and tert-butyldimethylsilyl chloride (28.80 g, 0.42 mol) were added. Stirred at room temperature for 6 hours. Water (1200 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (800 ml). The organic layer was washed three times 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: 3 to 1: 2) to give the desired product as a white amorphous substance (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)
Step 5

The compound obtained in the fourth step (75.0 g, 0.13 mol) was dissolved in tetrahydrofuran (580 ml), and under a stream of argon, bis (dibenzylideneacetone) palladium (0) (2.99 g, 5.20 mmol) and tri (2-furyl) ) Phosphine (2.41 g, 10.38 mmol) was added, and a solution of 3-chloro-2-fluorobenzylzinc bromide (0.17 mol) in tetrahydrofuran was added dropwise at 60 ° C. After the addition was completed, the mixture was heated under reflux for 2 hours. After cooling, ethyl acetate (75 ml) and a saturated aqueous ammonium chloride solution (38 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes, and then separated. The organic layer was washed twice with water (75 ml) and saturated saline (200 ml) 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: 2 to 1: 1) to obtain a brown amorphous target product (66.80 g, yield 73%). Was.
¹ H NMR (CDCl ₃ 300 MHz) (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)
6th step

The compound obtained in the fifth step (2.41 g, 4.07 mmol) was dissolved in methanol (20 ml), and a 28% methanol solution of sodium methoxide (8.4 ml, 40.70 mmol) and water (0.15 ml, 8.14 mmol) were added. Heated to reflux for hours. Water (1.4 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours, filtered through celite, and concentrated under reduced pressure. Water (25 ml) and 2N hydrochloric acid (20 ml) were added to the residue, stirred for 5 minutes, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over sodium sulfate. After filtration, the mixture 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. After sonication with the addition of diethyl ether (30 ml) to the residue, the solid was collected by filtration. The obtained solid was dissolved by heating in ethyl acetate (15 ml), hexane (15 ml) was added, and the mixture was recrystallized to give the desired product as a white solid (1.21 g, yield 64%).
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 4-37
1st step

3-Methoxy-2-nitrobenzoic acid (20.00 g, 0.10 mol) was dissolved in dimethylformamide (100 ml), and potassium carbonate (28.10 g, 0.20 mol) and methyl iodide (7.60 ml, 0.12 mol) were added. For 1 hour. The reaction solution was added to water (300 ml) and stirred. The precipitated solid was collected by filtration, washed with water (200 ml), and dried under reduced pressure to obtain a white solid product (23.90 g).
2nd 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 (water-containing) (2.30 g) was added. The mixture was stirred under a hydrogen atmosphere at room temperature for 19.5 hours. Ethyl acetate (200 ml) was added to the reaction solution, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and water was removed azeotropically with toluene to obtain a brown oily crude product (18.80 g).
3rd step

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 portionwise at 5 ° C. After the addition, the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into water (500 ml), extracted twice with ethyl acetate (300 ml), and 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 obtained residue was purified by silica gel chromatography (chloroform) to give the desired product as a yellow oil (25.11 g, yield 95%).
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 step

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

The compound obtained in the fourth step (74.80 g, 0.27 mol) was dissolved in dichloromethane (300 ml), and a 1 M boron tribromide / dichloromethane solution (700 ml, 0.70 mol) was added dropwise at 10 ° C or lower, and at room temperature after completion of the addition. 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 collected solid and residue were dissolved in diethyl ether (1000 ml), and extracted with a 1N aqueous sodium hydroxide solution (1000 ml). To the aqueous layer was added 2N hydrochloric acid (500 ml), 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 saturated saline in this order, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the target product as a beige solid (63.83 g, yield 95%). Obtained.
_{^{1 H NMR (DMSO-d 6}} 300MHz) (δ) ppm: 7.23 (1H, d, J = 2.4Hz), 7.28 (1H, d, J = 2.4Hz), 10.99 (1H, s), 13.55 (1H, brs)
6th step

The compound obtained in the fifth step (63.83 g, 0.25 mol) was dissolved in dimethylformamide (400 ml), and potassium carbonate (87.70 g, 0.64 mol) and ethyl iodide (81.20 ml, 1.02 mol) were added. 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 combined organic layers were combined with brine (3 times) and saturated brine. , Dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the desired product as a brown solid (76.38 g, yield 98%).
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 (76.38 g, 0.25 mol) obtained in the sixth step was dissolved in ethanol (250 ml), 8N aqueous sodium hydroxide solution (62.00 ml, 0.50 mol) was added, and the mixture was heated with stirring at 50 ° C. for 30 minutes. After adding 2N hydrochloric acid (250 ml) to the reaction solution under ice cooling and stirring, the mixture was extracted twice with ethyl acetate (350 ml), and 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 to obtain the desired product as a light brown solid (68.79 g, yield 99%).
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 (85.17 g, 0.31 mol) obtained in the seventh step 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 cooling, the reaction solution was concentrated under reduced pressure, the residue was dissolved in toluene, and 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 solution of ethyl 3,3-dimethylaminoacrylate (43.60 g, 0.31 mol) and triethylamine (50.90 ml, 0.37 mol) in tetrahydrofuran (200 ml), and heated for 15 hours. Refluxed. After cooling, water (300 ml) and ethyl acetate (500 ml) were added to the reaction solution, 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 obtain a brown oily crude product (124.80 g).
9th step

The crude product obtained in the eighth step (124.80 g) 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) ) Was added and stirred at room temperature for 40 minutes. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate (800 ml), washed twice with water and saturated brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a brown oily crude product (131.30 g).
Step 10

The crude product obtained in the ninth step (131.30 g) 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 the mixture was added at room temperature. Stir for 14 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (500 ml). The organic layer was washed three times with water and saturated brine in that order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a brown oily crude product (159.80 g).
11th step

The crude product (159.80 g) obtained in the tenth 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. Under ice-cooling, 1N hydrochloric acid (400 ml) was added to the reaction solution, and the mixture was stirred and then separated. The organic layer was washed with water and saturated brine in that order, 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. Stirred. A 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 as a brown oil (76.50 g, yield 45%). 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)
12th step

The compound obtained in the eleventh 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 dissolved in an argon stream. ) 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. After the completion of the addition, the mixture was heated under reflux for 2.5 hours. After cooling, a saturated aqueous solution of ammonium chloride (600 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour and filtered through celite. After layer 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 above extract. The organic layer was washed with 1N hydrochloric acid and saturated saline in this 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 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 as a brown oil (72.10 g, yield 85%). 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 twelfth step (65.80 g, 0.11 mol) was dissolved in ethanol (200 ml), a 1N aqueous sodium hydroxide solution (640 ml, 0.64 mol) was added, and the mixture was heated under reflux for 2 hours. After adding 2N hydrochloric acid (350 ml) to the reaction mixture under ice cooling and stirring, the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated saline in this 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 obtained solid was collected by filtration. The solid collected by filtration was dissolved by heating in ethyl acetate (250 ml), hexane (50 ml) was added, and the crystallized solid was collected by filtration and dried under reduced pressure to give the target product as a white solid (41.10 g, yield 81%). ).
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
Examples 1-3 to 1-102, 2-1 to 2-8, 3-1 to 3-86 and 4-1 to 4 in the same manner as in Examples 1-1 and 1-2 and the above-described examples. The 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) was used. The restriction enzyme was inserted into the NdeI and XhoI sites to construct an integrase expression vector pET21a-IN-F185H.
(Ii) Production and purification of integrase protein The E. coli recombinant BL21 (DE3) transformed with the plasmid pET21a-IN-F185H obtained in (i) was cultured with shaking at 30 ° C in a liquid medium containing ampicillin. At the time of the logarithmic growth phase, the addition of isopropyl-β-D-thiogalactopyranoside (isopropyl-β-D-thiogalactopyranoside) promoted the expression of the integrase gene. Subsequently, the cells were cultured for 3 hours to promote accumulation of the integrase protein, and the recombinant E. coli was collected as a pellet by centrifugation and stored at -80 ° C.
This Escherichia coli was 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 the mixture was repeatedly crushed under pressure and reduced pressure. A water-soluble fraction (supernatant) was collected by centrifugation at 000 × g for 60 minutes. This was diluted 10-fold with a Lysis buffer solution containing no sodium chloride, mixed with SP-Sepharose (manufactured by Pharmacia), and stirred at 4 ° C for 60 minutes to adsorb the integrase protein to the resin. After washing the resin with a Lysis buffer containing 100 mM sodium chloride, the integrase protein was eluted with a Lysis buffer containing 1 M sodium chloride.
The eluted integrase protein solution was applied to a Superdex75 (Pharmacia) column, and gel filtration was performed. The protein was eluted with Lysis buffer containing 1 M sodium chloride.
The obtained integrase protein fractions were collected and stored at -80 ° C.
(Iii) Preparation of DNA solution The following DNA synthesized by Greiner was dissolved in TE buffer (10 mM Tris-hydrochloric acid (pH 8.0), 1 mM EDTA), donor DNA, target DNA, and their complementary strands (+ And-strand) were mixed at 1 µM, heated at 95 ° C for 5 minutes, at 80 ° C for 10 minutes, at 70 ° C for 10 minutes, at 60 ° C for 10 minutes, at 50 ° C for 10 minutes, and heated at 40 ° C for 10 minutes. The solution was kept at 25 ° C. to obtain a double-stranded DNA, which was used.
Donor DNA (-strand has biotin added to 5 'end)
Donor + chain: 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 (addition of digoxigenin to 3 'end of both + and-strands)
Target + chain: 5'-TGA CCA AGG GCT AAT TCACT-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 Donor DNA was diluted with TE buffer to 10 nM, and 50 μl was added to each well of a streptavidin-coated microtiter plate (Roche). Adsorbed at 60 ° C. for 60 minutes. Next, after washing with a phosphate buffer (Dulbecco PBS, manufactured by Sanko Junyaku) containing 0.1% Tween 20 and a phosphate buffer, a reaction solution having the following composition (70 μl) and a test substance diluted with the reaction solution ( 10 μl) and 100 μg / ml integrase protein (10 μl) were added to each well, and reacted at 37 ° C. for 60 minutes.
Then, 50 nM target DNA (10 μl) was added and reacted at 37 ° C. for 10 minutes, followed by washing with a phosphate buffer containing 0.1% Tween 20 to stop the reaction.
Next, a 100 mU / ml peroxidase-labeled anti-digoxigenin antibody solution (manufactured by Roche, 100 μl) was added, and the mixture was 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 the mixture was allowed to react 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 by 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 of well in the presence of test compound Control; absorbance of well in the absence of test compound Blank; absorbance of well in the absence of test compound and no 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, the effect of a two-drug combination of an existing nucleoside reverse transcriptase inhibitor (zidovudine, lamivun, tenofovir), a non-nucleoside reverse transcriptase inhibitor (efavirenz) or a protease inhibitor (indinavir, nelfinavir) and a test substance A, etc. Is evaluated by the XTT method using CEM-SS cells infected with HIV-1IIIB.
In addition, the three-drug combination with test substance A, zidovudine, and lamivun, or the effect of the three-drug combination with test substance A, tenofovir, and lamivun are evaluated.
Prior to the combination test, the IC ₅₀ and CC ₅₀ of each drug alone are measured. The five-concentration drug A and the nine-concentration drug B determined from these results are combined, and the two-drug combination effect is evaluated. In the case of the triple use, a high concentration of the drug B and the drug C are mixed, and the drug A and the concentration are evaluated in combination.
The experimental results of the test substance and the concomitant drug alone or in combination are analyzed by the programs of Prichard and Shipman MacSynergy II version 2.01 and Deltagraph version 1.5d. A three-dimensional plot was prepared with 95% (or 68%, 99%) confidence limits from the inhibition rate at the concentration of each drug combined obtained from three experiments, and the value of μM ² % calculated therefrom was used. Determine the combined effect. The criteria are shown below.
Definition of interaction μM ² %
Strong synergy> 100
Slight synergy +51 to +100
Additive effect + 50〜-50
Slight antagonism -51 to -100
Strong antagonism <-100

Hereinafter, NMR and MS data of the example compounds shown in Tables 1-1 to 4-5 are described.
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
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
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
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 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 = 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, m 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
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, m
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
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
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

Free text in the sequence listing SEQ ID NO: 1: Donor for determining the activity of HIV integrase + strand SEQ ID NO: 2: Donor for determining the activity of HIV integrase—strand SEQ ID NO: 3: Target for determining the activity of HIV integrase + 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 Group A below, or
A heterocyclic group which may be substituted with 1 to 5 substituents selected from Group A below,
(Here, the heterocyclic group is a saturated or unsaturated ring containing at least one hetero atom 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
Group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represent 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 substituted by a halogen atom and one to three substituents selected from the following group B;
Group B
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A,
-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 ,
A group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6 ;
Wherein R ^a4 and R ^a5 are the same or different and are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _3-10 which may be substituted with 1 to 5 substituents selected from the above group A; A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A, and R ^a6 represents a C _1-4 alkyl group; A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A, or a heterocyclic group _optionally substituted by 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 alkyl sulfanyl group,
A halo C _1-4 alkyl group, or a halo C _1-4 alkyloxy group,
X is C- ^R32 or a nitrogen atom;
Y is C- ^R33 or a nitrogen atom,
Here, R ³² and R ³³ are the same or different and are each a hydrogen atom, a cyano group, a nitro group, a halogen atom,
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A,
A halogen atom and a C _1-10 alkyl group which may be substituted with 1 to 3 substituents selected from the above group B,
-OR ^a7 , -SR ^a7 , -NR ^a7 R ^a8 ,
-NR ^a7 COR ^a9 , -COOR ^a10 , or
-N = CH-NR ^a10 R ^a11
(Here, R ^a7 and R ^a8 are the same or different and are each independently a hydrogen atom, a group B, or a halogen atom and C _1- which may be substituted by 1 to 3 substituents selected from the above group B. an ₁₀ alkyl group, R ^a9 is C _1-4 alkyl group, R ^a10 and R ^a11 are the same or different and each is a hydrogen atom or a C _1-4 alkyl group.). ] X is C-R ^32, an anti-HIV agent according to claim 1, wherein Y is C-R ^33. Ring Cy is

[Where R ⁴ and R ⁶ are the same or different and are each a substituent selected from the following group A;
Here, 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
Group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represent 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 or a substituent selected from group A, wherein R ⁴ and R ⁵ may form a condensed ring together with the benzene ring which they substitute, and m is 0. Or, it is an integer of 1 to 3, and when m is 2 or 3, each R ⁶ may be the same or different. The anti-HIV agent according to claim 1, wherein ^2. The anti-HIV agent according to claim 1, wherein R ² is a hydrogen atom. A 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 are each a substituent selected from the following group A;
Here, 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 N R ^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
Group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represent 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 may form a condensed ring together with a benzene ring to be substituted therewith;
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 substituted by a halogen atom and one to three substituents selected from the following group B;
Group B
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group which may be substituted with 1 to 5 substituents selected from the group A,
(Here, the heterocyclic group is a saturated or unsaturated ring containing at least one hetero atom 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 ,
A group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6 ;
Wherein R ^a4 and R ^a5 are the same or different and are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _3-10 which may be substituted with 1 to 5 substituents selected from the above group A; A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A, and R ^a6 represents a C _1-4 alkyl group; A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A, or a heterocyclic group _optionally substituted by 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 alkyl sulfanyl 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 are each a hydrogen atom, a cyano group, a nitro group, a halogen atom,
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A,
A halogen atom and a C _1-10 alkyl group which may be substituted with 1 to 3 substituents selected from the above group B,
-OR ^a7 , -SR ^a7 , -NR ^a7 R ^a8 ,
-NR ^a7 COR ^a9 , -COOR ^a10 , or
-N = CH-NR ^a10 R ^a11
(Here, R ^a7 and R ^a8 are the same or different and are each independently a hydrogen atom, a group B, or a halogen atom and C _1- which may be substituted by 1 to 3 substituents selected from the above group B. an ₁₀ alkyl group, R ^a9 is C _1-4 alkyl group, 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 according to claim 5, wherein R ³¹ is a hydrogen atom, a cyano group, a hydroxy group, or a C _1-4 alkoxy group, or a pharmaceutically acceptable salt thereof. 7. 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 which may be substituted with 1 to 5 substituents selected from Group A below,
(Here, the heterocyclic group is a saturated or unsaturated ring containing at least one hetero atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom in addition to a carbon atom.)
Here, 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 N R ^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
Group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represent a hydrogen atom, a C _1-4 alkyl group or a benzyl group, and R ^a3 represents a C _1-4 alkyl group.)
A halogen atom and a C _1-10 alkyl group _optionally substituted with 1 to 3 substituents selected from the following group B,
Here, group B
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A,
-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 ,
A group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6 ;
Wherein R ^a4 and R ^a5 are the same or different and are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _3-10 which may be substituted with 1 to 5 substituents selected from the above group A; A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A, and R ^a6 represents a C _1-4 alkyl group; A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A, or a heterocyclic group _optionally substituted by 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
(Where R ^a7 and R ^a8 are the same or different and are each independently a hydrogen atom, a group B, or a halogen atom and C _{1- optionally} substituted with 1 to 3 substituents selected from the above group B) _And R ^a9 is a C _1-4 alkyl group, and R ^a10 and R ^a11 are the same or different and are each a hydrogen atom or a C _1-4 alkyl group.). Or a pharmaceutically acceptable salt thereof. R ³² is
Hydrogen atom, cyano group, halogen atom,
A halogen atom and a C _1-10 alkyl group _optionally substituted with 1 to 3 substituents selected from the following group B,
Here, group B
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group which may be substituted by 1 to 5 substituents selected from the group A (where the heterocyclic group is at least one 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 hetero 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 ,
A group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6 ;
Wherein R ^a4 and R ^a5 are the same or different and are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _3-10 which may be substituted with 1 to 5 substituents selected from the above group A; A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A, and R ^a6 represents a C _1-4 alkyl group; A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A, or a heterocyclic group _optionally substituted by 1 to 5 substituents selected from group A (As defined above). ｝
—OR ^a7 , —SR ^a7 , —NR ^a7 R ^a8 , —NR ^a7 COR ^a9 and —COOR ^a10 (where R ^a7 and R ^a8 are the same or different, and each represents a hydrogen atom, a group B, or a halogen atom. And a C _1-10 alkyl group which may be substituted by 1 to 3 substituents selected from the group B, R ^a9 is a C _1-4 alkyl group, and R ^a10 is a hydrogen atom or a C _{1- 4.} 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 (where R ^a7 and R ^a8 are respectively the same or different and are selected from a hydrogen atom, group B, or a halogen atom and the above group B A 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 9, which is a C1-10 alkyl group _optionally substituted with 1 to 3 substituents. R ³³ is
Hydrogen atom,
A halogen atom and a C _1-10 alkyl group _optionally substituted with 1 to 3 substituents selected from the following group B,
Here, group B
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group which may be substituted by 1 to 5 substituents selected from the group A (where the heterocyclic group is at least one 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 hetero 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 ,
A group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6 ;
Wherein R ^a4 and R ^a5 are the same or different and are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _3-10 which may be substituted with 1 to 5 substituents selected from the above group A; A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A, and R ^a6 represents a C _1-4 alkyl group; A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A, or a heterocyclic group _optionally substituted by 1 to 5 substituents selected from group A (As defined above). ｝
—OR ^a7 or —NR ^a7 R ^a8 (where R ^a7 and R ^a8 are the same or different and are each a hydrogen atom, a group B, or a halogen atom and 1 to 3 groups selected from the above group B _9. A 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 8, which is a C _1-10 alkyl group _optionally substituted by a substituent. R ³³ is a hydrogen atom, —OR ^a7 or —NR ^a7 R ^a8 (where R ^a7 and R ^a8 are respectively the same or different and are selected from a hydrogen atom, a group B, or a halogen atom and the above group B The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 11, which is a C1-10 alkyl group _optionally substituted with 1 to 3 substituents. R ^a7 and R ^a8 are the same or different and are each a halogen atom and a C _1-10 alkyl group which may be substituted by 1 to 3 substituents selected from the following group B [wherein group B is
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group which may be substituted by 1 to 5 substituents selected from the group A (where the heterocyclic group is at least one 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 hetero 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 ,
A group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6 ;
Wherein R ^a4 and R ^a5 are the same or different and are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _3-10 which may be substituted with 1 to 5 substituents selected from the above group A; A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A, and R ^a6 represents a C _1-4 alkyl group; A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A, or a heterocyclic group _optionally substituted by 1 to 5 substituents selected from group A (As defined above). The 4-oxoquinoline compound according to claims 8 to 12, or a pharmaceutically acceptable salt thereof. R ⁴ and R ⁵ are
The same or different, a cyano group, a phenyl group, a nitro group, a halogen atom, C _1-4 alkyl, 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 (wherein, R ^a1 and R ^a2 is 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 4-oxoquinoline compound according to claim 5, or a pharmaceutically acceptable salt thereof. R ⁴ is
A phenyl group, a halogen atom, C _1-4 alkyl, 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 (where R ^a1 and R ^a2 are respectively the same or different and are a hydrogen atom, a C _1-4 alkyl group, or 15. 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 according to claim 15, wherein R ⁴ is a halogen atom, or a pharmaceutically acceptable salt thereof. R ⁵ is
Hydrogen atom, a cyano group, a phenyl group, a nitro group, a halogen atom, C _1-4 alkyl, 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 (where R ^a1 and R ^a2 are the same or different and each represent a hydrogen atom, a C _1-4 alkyl group, or a benzyl group; ^a3 is a C _1-4 alkyl group.) The 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof according to claim 5, which is a substituent selected from the group consisting of: The 4-oxoquinoline compound according to claim 5, wherein R ⁶ is a halogen atom, or a pharmaceutically acceptable salt thereof.   The 4-oxoquinoline compound according to claim 5, wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof. R ¹ is
A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from Group A below,
Here, 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 N R ^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
Group consisting of
(Here, R ^a1 and R ^a2 are the same or different and each represent 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 are each a hydrogen atom, C _{1- 4} alkyl groups, C _3-10 carbocyclic groups which may be substituted by 1 to 5 substituents selected from the group A, or 1 to 5 substituents selected from the group A (Where the heterocyclic group is a saturated or unsaturated ring containing at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom, in addition to a carbon atom). In the ^formula , 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 group A, or 1 to 4 selected from the group A. Heterocyclic group which may be substituted by five substituents (as described 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 which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A,
-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. And the pharmaceutically acceptable salt thereof. R ¹ is a C _1-10 alkyl group which may be substituted with a halogen atom and 1 to 3 substituents selected from group B [where group B is
A C _3-10 carbocyclic group which may be substituted by 1 to 5 substituents selected from the group A,
A heterocyclic group which may be substituted with 1 to 5 substituents selected from the group A,
(Here, the heterocyclic group is a saturated or unsaturated ring containing at least one hetero atom 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 ,
A group consisting of -COOR ^a4 and -NR ^a5 COOR ^a6 ;
Wherein R ^a4 and R ^a5 are the same or different and are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _3-10 which may be substituted with 1 to 5 substituents selected from the above group A; A carbocyclic group or a heterocyclic group (as defined above) which may be substituted by 1 to 5 substituents selected from the group A, and R ^a6 represents a C _1-4 alkyl group; A C _3-10 carbocyclic group _optionally substituted by 1 to 5 substituents selected from group A, or a heterocyclic group _optionally substituted by 1 to 5 substituents selected from group A (As defined above). 21. The 4-oxoquinoline compound according to claim 20, or a pharmaceutically acceptable salt thereof. 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 (Examples 1-4);
6- (2,3-dichlorobenzyl) -1-dimethylcarbamoylmethyl-4-oxo-1
, 4-Dihydroquinoline-3-carboxylic acid (Examples 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 (Examples 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 (Examples 1-16),
6- (2,3-dichlorobenzyl) -1- (3-phenylpropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Examples 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 (Examples 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 (Examples 1-29 ), 6- (2,3-dichlorobenzyl) -1- (2-hydroxypropyl) -4-oxo-1
, 4-Dihydroquinoline-3-carboxylic acid (Examples 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 (Examples 1-37),
6- (2,3-dichlorobenzyl) -4-oxo-1-propyl-1,4-dihydroquinoline-3-carboxylic acid (Examples 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 (Examples 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 (Examples 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 (Examples 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 (Examples 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 (Examples 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 (Examples 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 (Examples 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 (Examples 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 (Examples 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 (implemented 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-carboxylic acid Acid (Example 3-72),
(S) -6- (3-chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) propyl] -7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (implemented 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 (Example 3-76),
6- (3-chloro-2-fluorobenzyl) -1- (2-hydroxyethyl) -7- (3-hydroxypropyloxy) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 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 (Example 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 ( 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-carboxylic 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 (implemented Example 4-21),
(S) -6- (3-Chloro-2-fluorobenzyl) -1- [2-cyclohexyl-1- (hydroxymethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (implemented 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-carboxylic 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-carboxylic acid Acid (Example 4-27),
6- (3-chloro-2-fluorobenzyl) -7-ethoxy-1-((1S, 2S) -1-hydroxymethyl-2-methylbutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid 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 (implemented 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 (implemented Example 4-38),
6- (3-chloro-2-fluorobenzyl) -1-((1S, 2S) -1-hydroxymethyl-2-methylbutyl) -7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3- Carboxylic acids (Examples 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 (implemented Example 4-48),
(S) -6- (3-chloro-2-fluorobenzyl) -1- [1- (hydroxymethyl) butyl] -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (implemented 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 according to claim 5, which is selected from the group consisting of 4-dihydroquinoline-3-carboxylic acid (Example 4-52), or a pharmaceutically acceptable salt thereof.   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 at least one other anti-HIV active substance as an active ingredient. 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 multidrug combination therapy with another anti-HIV agent. .