JP5616807B2 - Heterocyclic compounds having anti-HIV activity - Google Patents

Description

  The present invention relates to a heterocyclic compound having an anti-HIV activity or a salt thereof.

The retrovirus, human immunodeficiency virus (HIV), infects immune cells and causes acquired immune deficiency syndrome (AIDS). Currently, the number of HIV-infected people has reached tens of millions worldwide. In particular, the recent spread of infection in Asia and Africa is a serious problem.
HIV has an RNA gene encoded in a virus-specific enzyme (protease, reverse transcriptase, integrase, etc.) in its shell, and enters target cells via CD4 and chemokine receptors present on the surface of immune-responsive cells. . After uncoating, HIV releases complexes such as RNA and integrase into the cytoplasm, and reverse-transcribes its genetic information into double-stranded proviral DNA using its own reverse transcriptase. Furthermore, proviral DNA is integrated into the DNA of the target cell by HIV-specific integrase. In this way, the proviral DNA incorporated into the target cell is transcribed into an RNA strand and efficiently produces viral proteins by viral regulatory gene products such as Tat and Rev. Viral proteins bud from the host cell membrane surface in combination with separately formed viral RNA. Viruses that have migrated out of the cell repeatedly infect and proliferate immune-responsive cells (such as CD4-positive T cells and macrophages), resulting in immunodeficiency in the host.
Until now, anti-HIV agents targeting viral specific enzymes have been developed. For example, nucleic acid reverse transcriptase inhibitors zidovudine, didanosine, lamivudine, abacavir and tenofovir, etc .; non-nucleic acid reverse transcriptase inhibitors efavirenz and nevirapine, etc .; protease inhibitors lopinavir, phosphoamprenavir, atazanavir Raltegravir, an integrase inhibitor; and maraviroc, an entry inhibitor, are commercially available.
In the treatment of AIDS, multi-drug combination therapy using these drugs in combination is used. For example, a combination of one non-nucleic acid reverse transcriptase inhibitor and two nucleic acid reverse transcriptase inhibitors and a combination of one protease inhibitor and two nucleic acid reverse transcriptase inhibitors are recommended. (Non-Patent Document 1).
However, HIV is easily tolerated. Once the virus becomes resistant, the sensitivity of the virus to the same strain decreases (Non-patent Document 2). Furthermore, the number of drugs used in combination therapy is limited, and satisfactory effects are not always obtained.
Further, as side effects of currently used drugs, for example, complications such as lactic acidosis caused by nucleic acid reverse transcriptase inhibitors, lipid metabolism abnormalities caused by protease inhibitors, and diabetes have been reported (Non-Patent Documents 3 and 4). ).
On the other hand, naphthyridone or quinolone compounds having antiviral activity are known (Patent Documents 1 and 2).

Patent No. 3713291 Japanese Patent No. 3754467 Chemotherapy, 2009, 25, p26-33 Chemotherapy Areas, 2004, Volume 20, p58-68 Chemotherapy, 2009, 25, p40-53 Chemotherapy, 2009, 25, p54-61

  A compound having a novel action mechanism, excellent pharmacokinetics, few side effects, and excellent anti-HIV activity is strongly desired.

「式中、Ｒ^１は、ハロゲン原子、保護されていてもよいアミノ基または置換されていてもよいＣ_１−６アルキル基を；Ｒ^２およびＲ^３は、同一または異なって、Ｃ_１−２アルキル基を；Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、同一または異なって、水素原子、ハロゲン原子または保護されていてもよいアミノ基を；Ｚは、ＣＨまたはＮを；Ａは、メチレン基または結合手を示す。」で表される複素環化合物またはその塩が、優れた抗ＨＩＶ活性を有し、抗ＨＩＶ剤として有用であることを見出し、本発明を完成した。 As a result of intensive studies to solve the above problems, the present inventors have found that the general formula [1]

“Wherein R ¹ represents a halogen atom, an optionally protected amino group or an optionally substituted C _1-6 alkyl group; R ² and R ³ may be the same or different, and C _1-2 R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a halogen atom or an optionally protected amino group; Z represents CH or N; A represents methylene The present invention has been completed by discovering that the heterocyclic compound represented by “A group or a bond” or a salt thereof has excellent anti-HIV activity and is useful as an anti-HIV agent.

  The heterocyclic compound of the present invention or a salt thereof has excellent anti-HIV activity with excellent pharmacokinetics and few side effects, and is useful as an anti-HIV agent.

Hereinafter, the present invention will be described in detail.
In the present invention, unless otherwise specified, each term has the following meaning.
A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The C _1-2 alkyl group means a methyl group or an ethyl group.
The C _1-6 alkyl group is a linear or branched C _1-6 such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups. An alkyl group is meant.
An ar C _1-6 alkyl group means an ar C _1-6 alkyl group such as benzyl, diphenylmethyl, trityl, phenethyl and naphthylmethyl.
The C _1-6 alkoxy group is linear or branched C _1-6 such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. Means an alkyloxy group;
The C _1-6 alkoxy _{C 1-6} alkyl group means a _{C 1-6} alkyloxy _{C 1-6} alkyl group such as methoxymethyl and 1-ethoxyethyl.

The C _2-12 alkanoyl group means a linear or branched C _2-12 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl.
An aroyl group means a benzoyl or naphthoyl group.
The heterocyclic carbonyl group means nicotinoyl, thenoyl, pyrrolidinocarbonyl or furoyl group.
The (α-substituted) aminoacetyl group is an amino acid (glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine. , Tyrosine, tryptophan, proline and hydroxyproline, and the like.) N-terminal derived from (α-substituted) aminoacetyl group which may be protected.
An acyl group means a formyl group, a succinyl group, a glutaryl group, a maleoyl group, a phthaloyl group, a C _2-12 alkanoyl group, an aroyl group, a heterocyclic carbonyl group, or an (α-substituted) aminoacetyl group.

C _1-6 alkoxycarbonyl group means linear or branched C _1-6 alkyloxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1,1-dimethylpropoxycarbonyl. Means a group.
The al C _1-6 alkoxycarbonyl group means an al C _1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl.
An aryloxycarbonyl group means a phenyloxycarbonyl or naphthyloxycarbonyl group.

The C _1-6 alkylsulfonyl group means a C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl and propylsulfonyl.
An arylsulfonyl group means a benzenesulfonyl, p-toluenesulfonyl or naphthalenesulfonyl group.
The C _1-6 alkylsulfonyloxy group means a C _1-6 alkylsulfonyloxy group such as methylsulfonyloxy and ethylsulfonyloxy.
An arylsulfonyloxy group means a benzenesulfonyloxy group or a p-toluenesulfonyloxy group.

Boron-containing heterocyclic groups include 1,3,2-dioxaboltan-2-yl, 1,3,2-dioxaborolan-2-yl and 1,3,6,2-dioxaazaborocan-2-yl It means a monocyclic boron-containing heterocyclic group containing a boron atom as a hetero atom forming the ring.
A silyl group means a trimethylsilyl, triethylsilyl or tributylsilyl group.
Examples of the leaving group include a halogen atom, a C _1-6 alkylsulfonyloxy group, and an arylsulfonyloxy group.

Amino protecting groups include all groups that can be used as protecting groups for ordinary amino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, an al C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, an acyl group, a C _1-6 alkoxycarbonyl group, an al C _1-6 alkoxycarbonyl group, an aryloxycarbonyl group, Examples thereof include a C _1-6 alkylsulfonyl group, an arylsulfonyl group, and a silyl group. The above group may be substituted with one or more groups selected from a halogen atom, a nitro group, a cyano group, a C _1-6 alkyl group and a C _1-6 alkoxy group.

Halogenated hydrocarbons mean methylene chloride, chloroform or dichloroethane.
Ethers mean diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether.
Alcohol means methanol, ethanol, propanol, 2-propanol, butanol or 2-methyl-2-propanol.
Esters mean methyl acetate, ethyl acetate or butyl acetate.
Amides mean N, N-dimethylformamide, N, N-dimethylacetamide or 1-methyl-2-pyrrolidone.
Aromatic hydrocarbons mean benzene, toluene or xylene.

Examples of the salt of the compound represented by the general formula [1] include a commonly known basic group such as an amino group.
Examples of salts in basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid , Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid Is mentioned.
Furthermore, among the above salts, preferred salts of the compound of the general formula [1] include pharmacologically acceptable salts.

The C _1-6 alkyl group of R ¹ may be substituted with one or more groups selected from a halogen atom and a hydroxyl group.

In the compound of the general formula [1] of the present invention, preferred compounds include the following compounds.
A compound in which R ¹ is a halogen atom, an optionally protected amino group or a methyl group is preferred, a compound in which a halogen atom or a methyl group is preferred is more preferred, and a compound in which a methyl group is more preferred.
A compound in which R ² is a methyl group is preferable.
A compound in which R ³ is a methyl group is preferable.
A compound in which R ⁴ is a halogen atom is preferable, and a compound in which R ⁴ is a fluorine atom is more preferable.
A compound in which R ⁵ is a hydrogen atom or a halogen atom is preferable, and a compound in which R ⁵ is a hydrogen atom or a fluorine atom is more preferable.
A compound in which R ⁶ is a halogen atom is preferable, and a compound in which R ⁶ is a fluorine atom is more preferable.
A compound in which R ⁷ is an amino group which may be protected is preferable, and a compound in which R ⁷ is an amino group is more preferable.
A compound in which A is a bond is preferable.

  In the compound of the general formula [1] or a salt thereof, when there are isomers (for example, optical isomers, geometric isomers, tautomers and the like), the present invention includes those isomers and includes solvation. Products, hydrates and crystals of various shapes.

Next, the manufacturing method of this invention compound is demonstrated.
The compound of the present invention is produced by combining methods known per se, and can be produced, for example, according to the production method shown below.

「式中、Ｒ^１ａは、保護されていてもよいアミノ基または置換されていてもよいＣ_１−６アルキル基を；Ｌ^１は、脱離基を；Ｒ^ａおよびＲ^ｂは、同一または異なってヒドロキシル基、置換されていてもよいＣ_１−６アルコキシ基または結合するホウ素原子と一緒になって置換されていてもよい含ホウ素複素環式基を；Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、ＺおよびＡは、前記と同様の意味を有する。」 [Production Method 1]

“Wherein R ^1a represents an optionally protected amino group or an optionally substituted C _1-6 alkyl group; L ¹ represents a leaving group; R ^a and R ^b are the same or different. hydroxyl group Te, the optionally substituted C _1-6 alkoxy group or together with the binding boron atom may be substituted boron-containing heterocyclic ^{group; R 2, R 3, R} 4, R ⁵ , R ⁶ , R ⁷ , Z and A have the same meaning as described above.

Examples of the compound of the general formula [3] include 3,5-dimethylisoxazole-4-boronic acid and 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) isoxazole and the like are known.
Further, the compound of the general formula [3] can be produced from the corresponding halogeno compound according to the method described in, for example, Tetrahedron, Vol. 58, pages 3323-3328 (2002). .

  The compound of the general formula [1a] reacts with the compound of the general formula [3] in the presence or absence of a base, in the presence of a palladium catalyst, in the presence or absence of a ligand. Can be manufactured.

The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include halogenated hydrocarbons, ethers, alcohols, aromatic hydrocarbons, acetonitrile and water. These solvents may be used as a mixture.
Preferred solvents include alcohols, aromatic hydrocarbons and water mixed solvents and ethers, with ethanol, toluene and water mixed solvents and dioxane being preferred.
Although the usage-amount of a solvent is not specifically limited, Preferably, it is 1-100 times amount (v / w) with respect to the compound of general formula [2a], More preferably, 10-30 times amount (v / w) It is.

Examples of the palladium catalyst used in this reaction include metal palladium such as palladium-carbon and palladium black; inorganic palladium salt such as palladium chloride; organic palladium salt such as palladium acetate; tetrakis (triphenylphosphine) palladium (0). , Organopalladium complexes such as bis (triphenylphosphine) palladium (II) chloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride and tris (dibenzylideneacetone) dipalladium (0); and polymers Polymer-immobilized organopalladium complexes such as supported bis (acetate) triphenylphosphine palladium (II) and polymer-supported di (acetate) dicyclohexylphenylphosphine palladium (II). It may be used together.
The usage-amount of a palladium catalyst should just be 0.00001-1 times mole with respect to the compound of general formula [2a], Preferably it may be 0.01-0.2 times mole.

Examples of ligands that are optionally used in this reaction include trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; Reel phosphines; trialkyl phosphites such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; Imidazolium salts such as 3-bis (2,4,6-trimethylphenyl) imidazolium chloride; acetylacetone and octafluoroa Diketones such as tylacetone; amines such as trimethylamine, triethylamine, tripropylamine and tributylamine; 1,1′-bis (diphenylphosphino) ferrocene; 2,2′-bis (diphenylphosphino) -1,1 ′ -Binaphthyl; 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl;2-dicyclohexylphosphino-2', 4 ', 6'-triisopropylbiphenyl; 2- (di-tert-butylphosphino) -2 ', 4', 6'-triisopropylbiphenyl; as well as 2- (di-tert-butylphosphino) biphenyl, which may be used in combination.
The amount of the ligand used may be 0.00001 to 1 times mol, preferably 0.02 to 0.5 times mol, of the compound of the general formula [2a].

Examples of the base that is optionally used in this reaction include inorganic bases such as sodium bicarbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate, and organic bases such as triethylamine and diisopropylethylamine.
The amount of the base used may be 1 to 50 times mol, preferably 2 to 10 times mol, of the compound of the general formula [2a].

The amount of the compound of the general formula [3] used may be 1 to 50 times mol, preferably 1 to 2 times mol for the compound of the general formula [2a].
This reaction is usually carried out in an inert gas (for example, nitrogen and / or argon) atmosphere at 0 to 160 ° C., preferably 20 to 120 ° C., for 1 minute to 96 hours.

「式中、Ｌ^２は、脱離基を；Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、ＺおよびＡは、前記と同様の意味を有する。」 [Production Method 2]

“Wherein L ² represents a leaving group; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Z and A have the same meaning as described above.

(2-1)
The compound of the general formula [5] can be produced, for example, by subjecting the compound of the general formula [4] to a fluorination reaction according to the method described in International Publication No. 2006/95159 pamphlet or the like.

The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include halogenated hydrocarbons, ethers, amides, aromatic hydrocarbons, acetonitrile and water. These solvents may be used as a mixture.
Preferable solvents include halogenated hydrocarbons and acetonitrile, and a mixed solvent of methylene chloride and acetonitrile is preferable.
Although the usage-amount of a solvent is not specifically limited, Preferably, it is 1-200 times amount (v / w) with respect to the compound of General formula [4], More preferably, 10-50 times amount (v / w) It is.

Examples of the fluorinating agent used in this reaction include 2,6-dichloro-1-fluoropyridinium trifluoromethanesulfonate, N-fluorobenzenesulfonimide, N-chloromethyl-N′-fluorotriethylenediaminebis (tetrafluoro Borate), 1-fluoropyridinium trifluoromethanesulfonate and 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate, N-chloromethyl-N′-fluorotriethylenediaminebis (tetrafluoroborate) And N-fluorobenzenesulfonimide.
The amount of the fluorinating agent used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [4].
This reaction is usually performed at 0 to 150 ° C., preferably 20 to 60 ° C., for 10 minutes to 24 hours.

(2-2)
The compound of the general formula [1b] can be produced by subjecting the compound of the general formula [5] to a ring closure reaction in the presence or absence of a base.
The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include ethers, amides and dimethyl sulfoxide. These solvents may be used as a mixture. Good.
Preferred solvents include amides and dimethyl sulfoxide, with N, N-dimethylformamide and dimethyl sulfoxide being preferred.
Although the usage-amount of a solvent is not specifically limited, Preferably it is 1-1000 times amount (v / w) with respect to the compound of General formula [5], More preferably, it is 10-100 times amount (v / w). is there.

Examples of the base optionally used in this reaction include sodium hydrogen carbonate, potassium carbonate, potassium tert-butoxide and sodium hydride.
The usage-amount of a base should just be 1-5 times mole with respect to the compound of General formula [5].
This reaction is usually carried out at 0 to 140 ° C., preferably 40 to 120 ° C. for 30 minutes to 24 hours.

  Next, a method for producing the compound of general formula [2] and the compound of general formula [4], which are raw materials for producing the compound of the present invention, will be described.

「式中、Ｒ^１ｂは、保護されているアミノ基、ニトロ基または置換されていてもよいＣ_１−６アルキル基を；Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｚ、Ａ、Ｌ^１およびＬ^２は、前記と同様の意味を有する。」 [Production method A]

“Wherein R ^1b represents a protected amino group, a nitro group or an optionally substituted C _1-6 alkyl group; R ⁴ , R ⁵ , R ⁶ , R ⁷ , Z, A, L ¹ And L ² have the same meaning as above. "

(A-1)
The compound represented by the general formula [7] can be prepared by, for example, following the method described in Collection of Czechoslovak Chemical Communications, Vol. 69, pages 822-832 (2004). It can be produced by reacting the compound of the general formula [6] with N, N-dimethylformamide dimethyl acetal in the presence or absence of an anhydride.
The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include halogenated hydrocarbons, ethers, amides and aromatic hydrocarbons. These solvents may be used as a mixture.
Preferable solvents include amides, and N, N-dimethylformamide is preferable.
Although the usage-amount of a solvent is not specifically limited, Preferably it is 1-100 times amount (v / w) with respect to the compound of General formula [6], More preferably, it is 1-10 times amount (v / w). is there.
N, N-dimethylformamide dimethyl acetal may be used as a solvent.
The amount of N, N-dimethylformamide dimethyl acetal used is 1 to 100 times (v / w), more preferably 1 to 10 times (v / w) the amount of the compound of general formula [6]. .

Examples of the acid anhydride that is optionally used in this reaction include acetic anhydride.
The amount of the acid anhydride used is 1 to 100 times (v / w), more preferably 1 to 10 times (v / w) of the compound of the general formula [6].
When Z is a nitrogen atom, it is preferable to use an acid anhydride.
This reaction is usually carried out at 0 to 150 ° C., preferably 40 to 110 ° C., for 30 minutes to 24 hours.

(A-2)
The compound of the general formula [9] is, for example, in accordance with the method described in Collection of Czechoslovak Chemical Communications, Vol. 69, pages 822-832 (2004). It can be produced by reacting the compound of the formula [7] with the compound of the general formula [8].
The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. For example, halogenated hydrocarbons, ethers, alcohols, esters, aromatic hydrocarbons and formic acid. And organic acids such as acetic acid, and these solvents may be used in combination.
Preferred solvents include esters and organic acids, with ethyl acetate and acetic acid being preferred.
Although the usage-amount of a solvent is not specifically limited, Preferably it is 1-1000 times amount (v / w) with respect to the compound of General formula [7], More preferably, it is 1-50 times amount (v / w) is there.
This reaction is usually carried out at 0 to 110 ° C., preferably 20 to 80 ° C. for 30 minutes to 24 hours.

(A-3)
The compound of the general formula [2b] can be synthesized, for example, according to the method described in Collection of Czechoslovak Chemical Communications, Vol. 69, pp. 822-832 (2004). [9] The compound of [9] can be produced by subjecting it to a ring closure reaction in the presence or absence of a base.
The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include ethers, amides and dimethyl sulfoxide. These solvents may be used as a mixture. Good.
Preferred solvents include amides and dimethyl sulfoxide, with N, N-dimethylformamide and dimethyl sulfoxide being preferred.
Although the usage-amount of a solvent is not specifically limited, Preferably it is 1-1000 times amount (v / w) with respect to the compound of General formula [9], More preferably, it is 5-50 times amount (v / w). is there.
Examples of the base optionally used in this reaction include sodium hydrogen carbonate, potassium carbonate, potassium tert-butoxide and sodium hydride.
The usage-amount of a base should just be 1-5 times mole with respect to the compound of General formula [9].
This reaction is usually carried out at 0 to 140 ° C., preferably 40 to 120 ° C. for 30 minutes to 24 hours.

「式中、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^ａ、Ｒ^ｂ、Ｚ、Ａ、Ｌ^１およびＬ^２は、前記と同様の意味を有する。」 [Production method B]

“Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^a , R ^b , Z, A, L ¹ and L ² have the same meaning as described above.

(B-1)
The compound of the general formula [11] can be produced by reacting the compound of the general formula [10] with N, N-dimethylformamide dimethyl acetal in the presence or absence of an acid anhydride.
This reaction may be performed according to production method A-1.

(B-2)
The compound of the general formula [12] is reacted with the compound of the general formula [3] in the presence or absence of a base, in the presence of a palladium catalyst, in the presence or absence of a ligand. Can be manufactured.

  This reaction may be carried out according to production method 1.

(B-3)
The compound of the general formula [4] can be produced by reacting the compound of the general formula [12] with the compound of the general formula [8].
This reaction may be performed according to production method A-2.

In the compounds used in the above-described production methods, when there are isomers (for example, optical isomers, geometric isomers, tautomers, etc.), these isomers can also be used. In addition, when solvates, hydrates and crystals of various shapes are present, these solvates, hydrates and crystals of various shapes can also be used.
Among the compounds used in the above production method, compounds having an amino group may be protected in advance with a normal protecting group, and after the reaction, these protecting groups may be eliminated by a method known per se. it can.
Amino group protection and deprotection are described, for example, in W.W. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-926, John Wiley & Sons, INC .).

  The compound obtained by the above-described production method is subjected to a reaction known per se such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or the reaction is appropriately performed. In combination, it can be derived into other compounds.

  When the compound of the present invention is used as a pharmaceutical, formulation adjuvants such as excipients, carriers, and diluents that are usually used for formulation may be appropriately mixed. These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, patches in accordance with conventional methods. It can be administered orally or parenterally in the form of an agent, ointment or injection. In addition, the administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. In general, for adults, oral administration or parenteral administration (for example, injection, infusion, administration to the rectal site, etc.), 0.01 to 1000 mg / kg can be divided into 1 to several times a day. Good.

  Next, the usefulness of the representative compounds of the present invention will be described in the following test examples.

Test Example 1 Anti-HIV Activity The Journal of Clinical Microbiology, 2007, Vol. 45, pp. 477-487 was conducted as a reference.
Anti-HIV activity was evaluated using MaRBLE cells into which human T lymphocyte-derived HPB-M (a) was introduced with a luciferase gene whose expression was controlled by HIV-1 LTR, CCR5 gene and the like.
MaRBLE cells were suspended in RPMI1640 containing 10% FCS (fetal bovine serum) and penicillin / streptomycin, and infected with HIV-1 (JRCSF), and then seeded in a 96-well plate (1 × 10 ⁵ cells / well). As a control group, the same number of uninfected cells were seeded.
After incubating the plate at 37 ° C. and 5% CO ₂ for 2 hours, a fresh medium or a medium containing an appropriately diluted test compound was added to each well.
Furthermore, after culturing at 37 ° C. and 5% CO ₂ for 7 days, intracellular luciferase activity was measured using a Dual-Glo Luciferase assay system (Promega).
The virus growth rate was determined by the following formula.

Virus growth rate (%) = (A / B) × 100
A = (fire fly luciferase activity of compound-added well) − (non-infected cell fire fly luciferase activity)
B = (fire fly luciferase activity in wells without compound addition)-(uninfected cell fire fly luciferase activity)

The IC50 of the compound was calculated using the 4-parameter logistic model of curve fitting software XLfit 4 for the virus growth rate at each concentration.
The results are shown in Table 1.

本発明化合物は、優れた抗ＨＩＶ活性を示した。

The compound of the present invention showed excellent anti-HIV activity.

Test Example 2 Pharmacokinetic study in mice (oral administration)
The compounds of Examples 3 and 5 were used as test compounds.
A test compound (2.5 mg / mL) suspended in 0.5% methylcellulose was orally administered to male ICR mice (6 weeks old, 3 mice per group) at 10 mL / kg. Twelve hours after administration, the blood of the mouse was collected, and the concentration of the test compound in the serum was measured by HPLC.
As a result, the serum concentrations of the compounds of Examples 3 and 5 were both 1.0 μg / mL or more, indicating good pharmacokinetics.

Test Example 3 Oral Single-Dose Toxicity Test in Mice The compound of Example 3 was used as a test compound.
The test compound suspended in 0.5% methylcellulose was orally administered to male ICR mice (6 weeks old, one per group) at 10 mL / kg.
The state of the mouse was observed the day after the administration was completed.
As a result, the compound of Example 3 showed good safety at a dose of 500 mg / kg.

Test Example 4 Mouse In Vivo Micronucleus Test The compound of Example 3 was used as a test compound.
The test compound suspended in 0.5% methylcellulose was orally administered to male ICR mice (8 weeks old, 3 mice per group) twice at 24 hour intervals. In the control group, 0.5% methylcellulose was orally administered in the same manner.
In the highest dose group in which all mice survived, 24 hours after the final administration, the mice were exsanguinated under ether anesthesia, and one side of the femur was collected. After cutting the proximal end of the collected femur, bone marrow cells were washed into the centrifuge tube with fetal bovine serum using a disposable syringe, and the supernatant was removed after centrifugation (1000 rpm, 5 minutes, HITACHI 05PR-22). The portion was discarded to obtain a bone marrow cell suspension. This suspension was smeared on a slide glass, dried, and fixed with methanol to prepare a specimen.
Sample observation was performed by acridine orange staining.
Under a fluorescence microscope, observe the presence or absence of micronuclei in more than 1000 polychromatic erythrocytes (PCE) per individual, and the frequency of appearance of micronucleated polyerythrocytes (MNPCE) with micronuclei (micronuclei) Frequency of MNPCE) was calculated using the following formula. Samples with micronucleus appearance frequency exceeding 0.5% were judged positive.

      Micronucleus frequency (%) = (Number of MNPCE / Number of observed PCEs) x 100

  The compound of Example 3 was negative.

Next, the present invention will be described with reference examples and examples, but the present invention is not limited to these examples.
The mixing ratio in the eluent is a volume ratio. Unless otherwise specified, the carrier in silica gel column chromatography is Kanto Chemical Co., Inc., silica gel 60N (spherical, neutral, 63-210 μm).
In each example, each abbreviation has the following meaning.
Boc: tert-butoxycarbonyl,
DMF: N, N-dimethylformamide,
DMFDA: N, N-dimethylformamide dimethyl acetal,
DMSO: dimethyl sulfoxide,
Et: ethyl,
Me: methyl,
S-Phos: 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl,
DMSO-d ₆ : heavy dimethyl sulfoxide

１−（２，６−ジクロロピリジン−３−イル）プロパン−１−オン0.65gのＤＭＦＤＡ6mLおよび無水酢酸1mL溶液を、窒素雰囲気下、1時間20分間加熱還流した。反応混合物を冷却後、酢酸エチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をジイソプロピルエーテルに懸濁させ、固体を濾取し、褐色固体の（Ｅ）−１−（２，６−ジクロロピリジン−３−イル）−３−ジメチルアミノ−２−メチル−２−プロペン−１−オン0.33gを得た。
¹H-NMR(DMSO-d₆)値：
2.01(s,3H),3.06(s,6H),6.73(brs,1H),7.54(d,J=7.8Hz,1H),7.70(d, J=7.8Hz,1H). Reference example 1

A solution of 0.65 g of 1- (2,6-dichloropyridin-3-yl) propan-1-one in 6 mL of DMFDA and 1 mL of acetic anhydride was heated to reflux for 1 hour and 20 minutes under a nitrogen atmosphere. After cooling the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in diisopropyl ether, the solid was collected by filtration, and (E) -1- (2,6-dichloropyridin-3-yl) -3-dimethylamino-2-methyl- 0.33 g of 2-propen-1-one was obtained.
¹ H-NMR (DMSO-d ₆ ) value:
2.01 (s, 3H), 3.06 (s, 6H), 6.73 (brs, 1H), 7.54 (d, J = 7.8Hz, 1H), 7.70 (d, J = 7.8Hz, 1H).

（Ｅ）−１−（２，６−ジクロロピリジン−３−イル）−３−ジメチルアミノ−２−メチル−２−プロペン−１−オン500mgの酢酸2mL溶液にｔｅｒｔ−ブチル＝５−アミノ−２，４−ジフルオロフェニルカルバマート518mgを加え、60〜70℃で2時間加熱攪拌した。反応混合物を冷却後、酢酸エチルおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物のＤＭＦ10mL溶液に炭酸カリウム800mgを加え、90℃で40分間加熱攪拌した。反応混合物を冷却後、酢酸エチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、酢酸エチルおよびジイソプロピルエーテルの混合溶媒に懸濁させ、固体を濾取し、白色固体の１−（５−ｔｅｒｔ−ブトキシカルボニルアミノ−２，４−ジフルオロフェニル）−７−クロロ−３−メチル−１，４−ジヒドロ−４−オキソ−１，８−ナフチリジン620mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.46(s,9H),2.01(d,J=1.0Hz,3H),7.52(d,J=8.3Hz,1H),7.65(dd,J=10.2,10.2Hz,1H),7.92(dd,J=7.9,7.9Hz,1H),8.16(d,J=1.0Hz,1H),8.57(d,J=8.3Hz,1H),9.32(brs,1H). Reference example 2

(E) -1- (2,6-Dichloropyridin-3-yl) -3-dimethylamino-2-methyl-2-propen-1-one In a solution of 500 mg of acetic acid in 2 mL of acetic acid, tert-butyl = 5-amino-2 , 4-difluorophenylcarbamate 518 mg was added, and the mixture was heated with stirring at 60 to 70 ° C. for 2 hours. After cooling the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To a solution of the obtained residue in 10 mL of DMF was added 800 mg of potassium carbonate, and the mixture was stirred with heating at 90 ° C. for 40 minutes. After cooling the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1], suspended in a mixed solvent of ethyl acetate and diisopropyl ether, the solid was collected by filtration, and 1 of white solid was collected. -(5-tert-Butoxycarbonylamino-2,4-difluorophenyl) -7-chloro-3-methyl-1,4-dihydro-4-oxo-1,8-naphthyridine (620 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.46 (s, 9H), 2.01 (d, J = 1.0 Hz, 3H), 7.52 (d, J = 8.3 Hz, 1H), 7.65 (dd, J = 10.2,10.2Hz, 1H), 7.92 (dd, J = 7.9,7.9Hz, 1H), 8.16 (d, J = 1.0Hz, 1H), 8.57 (d, J = 8.3Hz, 1H), 9.32 (brs, 1H).

カリウムｔｅｒｔ−ブトキシド1.52gのＤＭＳＯ10mL懸濁液に、水冷下、ニトロメタン0.74mLおよび４−ブロモ−２−フルオロ安息香酸フェニル2.00gのＤＭＳＯ10mL溶液を滴下し、室温で40分間攪拌した。反応混合液を尿素0.41gの水50mL溶液に加えた後、6mol/L塩酸および酢酸エチルを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をジイソプロピルエーテルに懸濁させ、固体を濾取し、白色固体の１−（４−ブロモ−２−フルオロフェニル）−２−ニトロエタン−１−オン1.36gを得た。
¹H-NMR(DMSO-d₆)δ値：
6.28(d,J=2.9Hz,2H),7.65(dd,J=8.4,1.8Hz,1H),7.86(dd,J=10.9,1.8Hz,1H),7.87(dd,J=8.4,8.3Hz,1H). Reference example 3

To a suspension of 1.52 g of potassium tert-butoxide in 10 mL of DMSO, 0.74 mL of nitromethane and 10 mL of DMSO in 2.00 g of phenyl 4-bromo-2-fluorobenzoate were added dropwise with water cooling, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was added to a solution of 0.41 g of urea in 50 mL of water, and 6 mol / L hydrochloric acid and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in diisopropyl ether, and the solid was collected by filtration to obtain 1.36 g of 1- (4-bromo-2-fluorophenyl) -2-nitroethane-1-one as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value:
6.28 (d, J = 2.9Hz, 2H), 7.65 (dd, J = 8.4,1.8Hz, 1H), 7.86 (dd, J = 10.9,1.8Hz, 1H), 7.87 (dd, J = 8.4,8.3Hz , 1H).

１−（４−ブロモ−２−フルオロフェニル）−２−ニトロエタン−１−オン1.30gの酢酸エチル6.5mL懸濁液に、氷冷下、無水酢酸0.94mLおよびＤＭＦＤＡ1.32mLを加え、室温で1時間20分間攪拌した。減圧下で溶媒を留去し、得られた残留物の酢酸エチル6.5mL溶液にｔｅｒｔ−ブチル＝５−アミノ−２，４−ジフルオロフェニルカルバマート1.33gを加え、室温で3時間30分間攪拌後、さらに3時間加熱還流した。減圧下で溶媒を留去し、得られた残留物のＤＭＳＯ6.5mL溶液に炭酸カリウム1.37gを加え、80℃で2時間加熱攪拌した。反応混合物に水および酢酸エチルを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝３：１→２：１］で精製し、ジイソプロピルエーテルに懸濁させ、固体を濾取し、淡褐色固体の７−ブロモ−１−（５−ｔｅｒｔ−ブトキシカルボニルアミノ−２，４−ジフルオロフェニル）−３−ニトロ−１，４−ジヒドロ−４−オキソキノリン0.47gを得た。
¹H-NMR(DMSO-d₆)δ値：
1.46(s,9H),7.28(brs,1H),7.76(dd,J=9.8,9.8Hz,1H),7.79(dd,J=8.6,1.6Hz,1H),8.16-8.23(m,1H), 8.29(d,J=8.6Hz,1H),9.35(s,1H),9.45(brs,1H). Reference example 4

To a 6.5 mL suspension of 1.30 g of 1- (4-bromo-2-fluorophenyl) -2-nitroethan-1-one in ethyl acetate, 0.94 mL of acetic anhydride and 1.32 mL of DMFDA were added under ice-cooling. Stir for 20 minutes. The solvent was distilled off under reduced pressure, and 1.33 g of tert-butyl = 5-amino-2,4-difluorophenylcarbamate was added to a 6.5 mL solution of the resulting residue in ethyl acetate. The mixture was further heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, 1.37 g of potassium carbonate was added to a DMSO 6.5 mL solution of the obtained residue, and the mixture was stirred with heating at 80 ° C. for 2 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 3: 1 → 2: 1], suspended in diisopropyl ether, and the solid was collected by filtration to give a pale brown solid 7- 0.47 g of bromo-1- (5-tert-butoxycarbonylamino-2,4-difluorophenyl) -3-nitro-1,4-dihydro-4-oxoquinoline was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value:
1.46 (s, 9H), 7.28 (brs, 1H), 7.76 (dd, J = 9.8,9.8Hz, 1H), 7.79 (dd, J = 8.6,1.6Hz, 1H), 8.16-8.23 (m, 1H) , 8.29 (d, J = 8.6Hz, 1H), 9.35 (s, 1H), 9.45 (brs, 1H).

７−ブロモ−１−（５−ｔｅｒｔ−ブトキシカルボニルアミノ−２，４−ジフルオロフェニル）−３−ニトロ−１，４−ジヒドロ−４−オキソキノリン0.45g、鉄粉0.25gおよび塩化アンモニウム0.03gのエタノール9mL懸濁液に水4.5mLを加え、1時間20分間加熱還流した。反応混合物にクロロホルムおよび水を加え、不溶物を除去した。有機層を分取し、水で洗浄後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：アセトン＝１０：１→３：１］で精製し、ジイソプロピルエーテルに懸濁させ、固体を濾取し、淡褐色固体の３−アミノ−７−ブロモ−１−（５−ｔｅｒｔ−ブトキシカルボニルアミノ−２，４−ジフルオロフェニル）−１，４−ジヒドロ−４−オキソキノリン0.37gを得た。
¹H-NMR(DMSO-d₆)δ値：
1.45(s,9H),4.67(s,2H),7.05(s,1H),7.43(d,J=8.8Hz,1H),7.46(s,1H),7.72(dd,J=10.1,10.1Hz,1H),7.96(dd,J=8.1,8.1Hz,1H),8.16(d,J=8.8Hz,1H),9.39(brs,1H). Reference Example 5

7-bromo-1- (5-tert-butoxycarbonylamino-2,4-difluorophenyl) -3-nitro-1,4-dihydro-4-oxoquinoline 0.45 g, iron powder 0.25 g and ammonium chloride 0.03 g 4.5 mL of water was added to a 9 mL ethanol suspension, and the mixture was heated to reflux for 1 hour and 20 minutes. Chloroform and water were added to the reaction mixture to remove insoluble matters. The organic layer was separated and washed with water, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: acetone = 10: 1 → 3: 1], suspended in diisopropyl ether, and the solid was collected by filtration. 0.37 g of -7-bromo-1- (5-tert-butoxycarbonylamino-2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value:
1.45 (s, 9H), 4.67 (s, 2H), 7.05 (s, 1H), 7.43 (d, J = 8.8Hz, 1H), 7.46 (s, 1H), 7.72 (dd, J = 10.1,10.1Hz , 1H), 7.96 (dd, J = 8.1,8.1Hz, 1H), 8.16 (d, J = 8.8Hz, 1H), 9.39 (brs, 1H).

エチル＝３−（４−ブロモ−２−フルオロフェニル）−３−オキソプロピオナート20.0gの１，４−ジオキサン100mL溶液に6mol/L塩酸100mLを加え、3時間20分間加熱還流した。反応混合物に酢酸エチルを加え、有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にＤＭＦＤＡ40mLを加え、2時間30分間加熱還流した。反応混合物を減圧下で溶媒を留去後、酢酸エチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をジイソプロピルエーテルに懸濁させ、固体を濾取し、黄色固体の（Ｅ）−１−（４−ブロモ−２−フルオロフェニル）−３−ジメチルアミノ−２−プロペン−１−オン12.7gを得た。
¹H-NMR(CDCl₃)δ値：
2.91(s,3H),3.15(s,3H),5.59(dd,J=12.4,1.7Hz,1H),7.26(dd,J=10.0,1.7Hz,1H),7.33(dd,J=8.1,1.7Hz,1H),7.68(dd,J=8.1,7.9Hz,1H),7.76(brs,1H). Reference Example 6

To a solution of ethyl = 3- (4-bromo-2-fluorophenyl) -3-oxopropionate (20.0 g) in 1,4-dioxane (100 mL) was added 6 mol / L hydrochloric acid (100 mL), and the mixture was heated to reflux for 3 hours and 20 minutes. Ethyl acetate was added to the reaction mixture, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 40 mL of DMFDA was added to the obtained residue, and the mixture was heated to reflux for 2 hours and 30 minutes. The reaction mixture was evaporated under reduced pressure, and ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in diisopropyl ether, the solid was collected by filtration, and (E) -1- (4-bromo-2-fluorophenyl) -3-dimethylamino-2-propene-1- Obtained 12.7g on.
¹ H-NMR (CDCl ₃ ) δ value:
2.91 (s, 3H), 3.15 (s, 3H), 5.59 (dd, J = 12.4, 1.7Hz, 1H), 7.26 (dd, J = 10.0, 1.7Hz, 1H), 7.33 (dd, J = 8.1, 1.7Hz, 1H), 7.68 (dd, J = 8.1, 7.9Hz, 1H), 7.76 (brs, 1H).

（Ｅ）−１−（４−ブロモ−２−フルオロフェニル）−３−ジメチルアミノ−２−プロペン−１−オン10.0g、３，５−ジメチル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）イソオキサゾール9.84g、炭酸水素ナトリウム9.26g、トリフェニルホスフィン4.82gおよび酢酸パラジウム0.41gのトルエン100mL、エタノール80mLおよび水50mLの懸濁液を、窒素雰囲気下、2時間45分間加熱還流した。反応混合物に酢酸エチルおよび水を加え、有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：アセトン＝１：０→１０：１］で精製し、酢酸エチルおよびジイソプロピルエーテルの混合溶媒に懸濁させ、固体を濾取し、薄黄色固体の（Ｅ）−１−[４−（３，５−ジメチルイソオキサゾール−４−イル）−２−フルオロフェニル]−３−ジメチルアミノ−２−プロペン−１−オン9.03gを得た。
¹H-NMR(CDCl₃)δ値：
2.30(s,3H),2.44(s,3H),2.93(s,3H),3.17(s,3H),5.67(dd,J=12.4,2.0Hz,1H),6.98(dd,J=11.3,1.6Hz,1H),7.09(dd,J=7.8,1.6Hz,1H),7.80-7.88(m,1H),7.86(dd,J=7.8,7.6Hz,1H). Reference Example 7

(E) -1- (4-Bromo-2-fluorophenyl) -3-dimethylamino-2-propen-1-one 10.0 g, 3,5-dimethyl-4- (4,4,5,5-tetra A suspension of methyl-1,3,2-dioxaborolan-2-yl) isoxazole 9.84 g, sodium bicarbonate 9.26 g, triphenylphosphine 4.82 g and palladium acetate 0.41 g in toluene 100 mL, ethanol 80 mL and water 50 mL. The mixture was heated to reflux for 2 hours and 45 minutes under a nitrogen atmosphere. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: acetone = 1: 0 → 10: 1], suspended in a mixed solvent of ethyl acetate and diisopropyl ether, and the solid was collected by filtration. 9.03 g of yellow solid (E) -1- [4- (3,5-dimethylisoxazol-4-yl) -2-fluorophenyl] -3-dimethylamino-2-propen-1-one was obtained.
¹ H-NMR (CDCl ₃ ) δ value:
2.30 (s, 3H), 2.44 (s, 3H), 2.93 (s, 3H), 3.17 (s, 3H), 5.67 (dd, J = 12.4, 2.0Hz, 1H), 6.98 (dd, J = 11.3, 1.6Hz, 1H), 7.09 (dd, J = 7.8, 1.6Hz, 1H), 7.80-7.88 (m, 1H), 7.86 (dd, J = 7.8, 7.6Hz, 1H).

（Ｅ）−１−[４−（３，５−ジメチルイソオキサゾール−４−イル）−２−フルオロフェニル]−３−ジメチルアミノ−２−プロペン−１−オン2.00gおよびｔｅｒｔ−ブチル＝５−アミノ−２，４−ジフルオロフェニルカルバマート2.12gの酢酸20mL溶液を50〜70℃で4時間加熱攪拌した。反応混合物に酢酸エチル、水およびクロロホルムを加え、有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をクロロホルム、酢酸エチルおよびジイソプロピルエーテルの混合溶媒に懸濁させ、固体を濾取し、黄色固体のｔｅｒｔ−ブチル＝（２，４−ジフルオロ−５−（３−（４−（３，５−ジメチルイソオキサゾール−４−イル）−２−フルオロフェニル）−３−オキソ−１−プロペニル）アミノ）フェニルカルバマート2.66gを得た。
¹H-NMR(CDCl₃)δ値：
1.54(s,9H),2.32(s,3H),2.46(s,3H),6.11(dd,J=7.8,2.2Hz,1H),6.68(brs,1H),6.96(dd,J=10.2,10.2Hz,1H),7.02(dd,J=11.7,1.6Hz,1H),7.14(dd,J=8.0,1.6Hz,1H),7.51(dd,J=12.2,7.8Hz,1H),7.97(dd,J=8.0,7.9Hz,1H),8.12-8.22(m,1H),12.13(d,J=12.4Hz,1H). Reference Example 8

(E) -1- [4- (3,5-Dimethylisoxazol-4-yl) -2-fluorophenyl] -3-dimethylamino-2-propen-1-one 2.00 g and tert-butyl = 5- A solution of 2.12 g of amino-2,4-difluorophenylcarbamate in 20 mL of acetic acid was heated and stirred at 50 to 70 ° C. for 4 hours. Ethyl acetate, water and chloroform were added to the reaction mixture, and the organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in a mixed solvent of chloroform, ethyl acetate and diisopropyl ether, the solid was collected by filtration, and tert-butyl = (2,4-difluoro-5- (3- (4- ( 3,66 g of 3,5-dimethylisoxazol-4-yl) -2-fluorophenyl) -3-oxo-1-propenyl) amino) phenylcarbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value:
1.54 (s, 9H), 2.32 (s, 3H), 2.46 (s, 3H), 6.11 (dd, J = 7.8,2.2Hz, 1H), 6.68 (brs, 1H), 6.96 (dd, J = 10.2, 10.2Hz, 1H), 7.02 (dd, J = 11.7,1.6Hz, 1H), 7.14 (dd, J = 8.0,1.6Hz, 1H), 7.51 (dd, J = 12.2,7.8Hz, 1H), 7.97 ( dd, J = 8.0, 7.9Hz, 1H), 8.12-8.22 (m, 1H), 12.13 (d, J = 12.4Hz, 1H).

３−アミノ−７−ブロモ−１−（５−ｔｅｒｔ−ブトキシカルボニルアミノ−２，４−ジフルオロフェニル）−１，４−ジヒドロ−４−オキソキノリン0.35g、３，５−ジメチル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）イソオキサゾール0.20g、炭酸水素ナトリウム0.19g、Ｓ−Ｐｈｏｓ30mgおよび酢酸パラジウム8mgのトルエン3.5mL、エタノール2.8mLおよび水1.8mLの懸濁液を、窒素雰囲気下、2時間加熱還流した。反応混合物に酢酸エチルおよび水を加え、有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：アセトン＝１０：１→３：１］で精製し、ジイソプロピルエーテルに懸濁させ、固体を濾取し、淡黄色固体の３−アミノ−１−（５−ｔｅｒｔ−ブトキシカルボニルアミノ−２，４−ジフルオロフェニル）−７−（３，５−ジメチルイソオキサゾール−４−イル）−１，４−ジヒドロ−４−オキソキノリン0.34gを得た。
¹H-NMR(DMSO-d₆)δ値：
1.44(s,9H),2.15(s,3H),2.34(s,3H),4.63(s,2H),6.85(s,1H),7.33(d,J=8.4Hz,1H),7.53(s,1H),7.70(dd,J=10.1,10.1Hz,1H),8.00(dd,J=7.8,7.8Hz,1H),8.31(d,J=8.4Hz,1H),9.39(brs,1H). Example 1

3-Amino-7-bromo-1- (5-tert-butoxycarbonylamino-2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline 0.35 g, 3,5-dimethyl-4- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoxazole 0.20 g, sodium bicarbonate 0.19 g, S-Phos 30 mg and palladium acetate 8 mg in toluene 3.5 mL, ethanol 2.8 mL and water 1.8 mL of the suspension was heated to reflux for 2 hours under a nitrogen atmosphere. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated, washed successively with water and a saturated aqueous sodium chloride solution and then dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: acetone = 10: 1 → 3: 1], suspended in diisopropyl ether, and the solid was collected by filtration. -1- (5-tert-Butoxycarbonylamino-2,4-difluorophenyl) -7- (3,5-dimethylisoxazol-4-yl) -1,4-dihydro-4-oxoquinoline (0.34 g) was obtained. It was.
¹ H-NMR (DMSO-d ₆ ) δ value:
1.44 (s, 9H), 2.15 (s, 3H), 2.34 (s, 3H), 4.63 (s, 2H), 6.85 (s, 1H), 7.33 (d, J = 8.4Hz, 1H), 7.53 (s , 1H), 7.70 (dd, J = 10.1,10.1Hz, 1H), 8.00 (dd, J = 7.8,7.8Hz, 1H), 8.31 (d, J = 8.4Hz, 1H), 9.39 (brs, 1H) .

３−アミノ−１−（５−ｔｅｒｔ−ブトキシカルボニルアミノ−２，４−ジフルオロフェニル）−７−（３，５−ジメチルイソオキサゾール−４−イル）−１，４−ジヒドロ−４−オキソキノリン0.08gの１，４−ジオキサン0.80mL懸濁液に2mol/L塩酸0.80mLを加え、1時間加熱還流した。反応混合物に飽和炭酸水素ナトリウム水溶液および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：エタノール＝２０：１→１０：１］で精製し、酢酸エチルに懸濁させ、固体を濾取し、淡緑色固体の３−アミノ−１−（５−アミノ−２，４−ジフルオロフェニル）−７−（３，５−ジメチルイソオキサゾール−４−イル）−１，４−ジヒドロ−４−オキソキノリン0.04gを得た。
¹H-NMR(DMSO-d₆)δ値:
2.15(s,3H),2.34(s,3H),4.62(brs,2H),5.43(s,2H),6.83(s,1H),6.92(dd,J=8.4,8.3Hz,1H),7.30(d,J=8.4Hz,1H),7.42(dd,J=10.5,10.5Hz,1H),7.50(s,1H),8.28(d,J=8.4Hz,1H). Example 2

3-Amino-1- (5-tert-butoxycarbonylamino-2,4-difluorophenyl) -7- (3,5-dimethylisoxazol-4-yl) -1,4-dihydro-4-oxoquinoline 0.08 To a 0.80 mL suspension of g in 1,4-dioxane, 0.80 mL of 2 mol / L hydrochloric acid was added and heated to reflux for 1 hour. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: ethanol = 20: 1 → 10: 1], suspended in ethyl acetate, the solid was collected by filtration, and a light green solid 3-amino 0.04 g of -1- (5-amino-2,4-difluorophenyl) -7- (3,5-dimethylisoxazol-4-yl) -1,4-dihydro-4-oxoquinoline was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value:
2.15 (s, 3H), 2.34 (s, 3H), 4.62 (brs, 2H), 5.43 (s, 2H), 6.83 (s, 1H), 6.92 (dd, J = 8.4, 8.3Hz, 1H), 7.30 (d, J = 8.4Hz, 1H), 7.42 (dd, J = 10.5,10.5Hz, 1H), 7.50 (s, 1H), 8.28 (d, J = 8.4Hz, 1H).

１−（５−ｔｅｒｔ−ブトキシカルボニルアミノ−２，４−ジフルオロフェニル）−７−クロロ−３−メチル−１，４−ジヒドロ−４−オキソ−１，８−ナフチリジン0.68g、３，５−ジメチルイソオキサゾール−４−ボロン酸0.28g、トリエチルアミン1.1 mLおよびＳ−Ｐｈｏｓ0.13gの１，４−ジオキサン6.8mL溶液に、窒素雰囲気下、酢酸パラジウム36mgを加え、3時間30分間加熱還流した。反応混合物に酢酸エチルを加え、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：アセトン＝１０：１］で精製した。得られた黄白色固体0.62gに１，４−ジオキサン15mLおよび6mol/L塩酸5mLを加え、1時間10分間加熱還流した。反応混合物に飽和炭酸水素ナトリウム水溶液および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をジエチルエーテルおよび酢酸エチルの混合溶媒に懸濁させ、固体を濾取し、黄白色固体の１−（５−アミノ−２，４−ジフルオロフェニル）−７−（３，５−ジメチルイソオキサゾール−４−イル）−３−メチル−１，４−ジヒドロ−４−オキソ−１，８−ナフチリジン0.45gを得た。
¹H-NMR(DMSO-d₆)δ値：
2.02(s,3H),2.17(s,3H),2.46(s,3H),5.32(brs,2H),6.92(dd,J=8.4,8.3Hz,1H),7.36(dd,J=10.5,10.5Hz,1H),7.64(d,J=8.3Hz,1H),8.16(s,1H),8.60(d,J=8.3Hz,1H) Example 3

1- (5-tert-Butoxycarbonylamino-2,4-difluorophenyl) -7-chloro-3-methyl-1,4-dihydro-4-oxo-1,8-naphthyridine 0.68 g, 3,5-dimethyl Under a nitrogen atmosphere, 36 mg of palladium acetate was added to a solution of 0.28 g of isoxazole-4-boronic acid, 1.1 mL of triethylamine and 0.13 g of S-Phos in 6.8 mL of 1,4-dioxane, and the mixture was heated to reflux for 3 hours and 30 minutes. Ethyl acetate was added to the reaction mixture, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: acetone = 10: 1]. To 0.62 g of the obtained yellowish white solid, 15 mL of 1,4-dioxane and 5 mL of 6 mol / L hydrochloric acid were added, and the mixture was heated to reflux for 1 hour and 10 minutes. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in a mixed solvent of diethyl ether and ethyl acetate, the solid was collected by filtration, and 1- (5-amino-2,4-difluorophenyl) -7- (3,5 -Dimethylisoxazol-4-yl) -3-methyl-1,4-dihydro-4-oxo-1,8-naphthyridine (0.45 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value:
2.02 (s, 3H), 2.17 (s, 3H), 2.46 (s, 3H), 5.32 (brs, 2H), 6.92 (dd, J = 8.4, 8.3Hz, 1H), 7.36 (dd, J = 10.5, 10.5Hz, 1H), 7.64 (d, J = 8.3Hz, 1H), 8.16 (s, 1H), 8.60 (d, J = 8.3Hz, 1H)

ｔｅｒｔ−ブチル＝（２，４−ジフルオロ−５−（３−（４−（３，５−ジメチルイソオキサゾール−４−イル）−２−フルオロフェニル）−３−オキソ−１−プロペニル）アミノ）フェニルカルバマート3.00gの塩化メチレン62mL溶液に、Ｎ−クロロメチル−Ｎ’−フルオロトリエチレンジアミンビス（テトラフルオロボラート）2.83gおよびアセトニトリル62mLを加え、窒素雰囲気下、40℃で35分間攪拌した。反応混合物を減圧下で溶媒を留去し、酢酸エチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝９：１→２：１］で精製した。得られた化合物1.92gのＤＭＦ20mL溶液に炭酸カリウム0.68gを加え、60〜70℃で1時間07分間加熱攪拌した。反応混合物に水および酢酸エチルを加え、有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝４：１→１：１］で精製し、酢酸エチルおよびジイソプロピルエーテルの混合溶媒に懸濁させ、固体を濾取し、淡褐色粉末の１−（５−ｔｅｒｔ−ブトキシカルボニルアミノ−２，４−ジフルオロフェニル）−７−（３，５−ジメチルイソオキサゾール−４−イル）−３−フルオロ−１，４−ジヒドロ−４−オキソキノリン0.64gを得た。
¹H-NMR(DMSO-d₆)δ値：
1.44(s,9H),2.15(s,3H),2.35(s,3H),6.98(brs,1H),7.51(dd,J=8.4,1.5,1H),7.73(dd,J=10.1,10.1Hz,1H),8.04-8.15(m,1H),8.39(d,J=8.4Hz,1H),8.69(d,J=8.3Hz,1H),9.41(brs,1H) Example 4

tert-Butyl = (2,4-difluoro-5- (3- (4- (3,5-dimethylisoxazol-4-yl) -2-fluorophenyl) -3-oxo-1-propenyl) amino) phenyl 2.83 g of N-chloromethyl-N′-fluorotriethylenediaminebis (tetrafluoroborate) and 62 mL of acetonitrile were added to a solution of carbamate 3.00 g in methylene chloride, and the mixture was stirred at 40 ° C. for 35 minutes under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure, and ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 9: 1 → 2: 1]. 0.68 g of potassium carbonate was added to a solution of 1.92 g of the obtained compound in 20 mL of DMF, and the mixture was heated and stirred at 60 to 70 ° C. for 1 hour and 07 minutes. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 4: 1 → 1: 1], suspended in a mixed solvent of ethyl acetate and diisopropyl ether, and the solid was collected by filtration. 1- (5-tert-butoxycarbonylamino-2,4-difluorophenyl) -7- (3,5-dimethylisoxazol-4-yl) -3-fluoro-1,4-dihydro-4 as a light brown powder -0.64 g of oxoquinoline was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value:
1.44 (s, 9H), 2.15 (s, 3H), 2.35 (s, 3H), 6.98 (brs, 1H), 7.51 (dd, J = 8.4,1.5,1H), 7.73 (dd, J = 10.1,10.1 Hz, 1H), 8.04-8.15 (m, 1H), 8.39 (d, J = 8.4Hz, 1H), 8.69 (d, J = 8.3Hz, 1H), 9.41 (brs, 1H)

１−（５−ｔｅｒｔ−ブトキシカルボニルアミノ−２，４−ジフルオロフェニル）−７−（３，５−ジメチルイソオキサゾール−４−イル）−３−フルオロ−１，４−ジヒドロ−４−オキソキノリン0.62gの１，４−ジオキサン6.2mLおよび3mol/L塩酸6.2mL溶液を2時間加熱還流した。反応混合物に飽和炭酸水素ナトリウム水溶液および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を酢酸エチルおよびジイソプロピルエーテルの混合溶媒に懸濁させ、固体を濾取し、淡褐色固体の１−（５−アミノ−２，４−ジフルオロフェニル）−７−（３，５−ジメチルイソオキサゾール−４−イル）−３−フルオロ−１，４−ジヒドロ−４−オキソキノリン0.41gを得た。
¹H-NMR(DMSO-d₆)δ値：
2.16(s,3H),2.36(s,3H),5.48(s,2H),6.95-7.03(m,2H),7.47(dd,J=10.4,10.4Hz,1H),7.50(dd,J=8.3,1.5Hz,1H),8.37(d,J=8.3Hz,1H),8.67(d,J=8.3Hz,1H) Example 5

1- (5-tert-Butoxycarbonylamino-2,4-difluorophenyl) -7- (3,5-dimethylisoxazol-4-yl) -3-fluoro-1,4-dihydro-4-oxoquinoline 0.62 A solution of 6.2 g of 1,4-dioxane and 6.2 mL of 3 mol / L hydrochloric acid was heated to reflux for 2 hours. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in a mixed solvent of ethyl acetate and diisopropyl ether, the solid was collected by filtration, and 1- (5-amino-2,4-difluorophenyl) -7- (3,5 -Dimethylisoxazol-4-yl) -3-fluoro-1,4-dihydro-4-oxoquinoline 0.41 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value:
2.16 (s, 3H), 2.36 (s, 3H), 5.48 (s, 2H), 6.95-7.03 (m, 2H), 7.47 (dd, J = 10.4, 10.4Hz, 1H), 7.50 (dd, J = 8.3, 1.5Hz, 1H), 8.37 (d, J = 8.3Hz, 1H), 8.67 (d, J = 8.3Hz, 1H)

  The heterocyclic compound or salt thereof of the present invention has excellent anti-HIV activity and is useful as an anti-HIV agent.

Claims (7)

General formula

“Wherein R ¹ represents a halogen atom, an optionally protected amino group or an optionally substituted C _1-6 alkyl group; R ² and R ³ may be the same or different, and C _1-2 R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a halogen atom or an optionally protected amino group; Z represents CH or N; A represents methylene A heterocyclic compound or a salt thereof. The heterocyclic compound or a salt thereof according to claim 1, wherein A is a bond. The heterocyclic compound or a salt thereof according to claim 1 or 2, wherein R ² is a methyl group; and R ³ is a methyl group. R < ¹ > is a halogen atom, the amino group which may be protected, or a methyl group, The heterocyclic compound or its salt as described in any one of Claims 1-3. R ¹ is a heterocyclic compound or salt thereof according to any one of claims 1 to 3 is a methyl group. The R ⁴ is a halogen atom; R ⁵ is a hydrogen atom or a halogen atom; R ⁶ is a halogen atom; and R ⁷ is an amino group which may be protected. Or a salt thereof. The anti-HIV agent containing the heterocyclic compound or its salt of any one of Claims 1-6.