JP5745869B2 - Heterocyclic compounds having an aralkyl group - Google Patents

Description

  The present invention relates to a heterocyclic compound or a salt thereof useful as an anti-HIV agent.

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. The recent spread of infection, particularly 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およびＲ^２は、同一または異なって、Ｃ_１−２アルキル基を；Ｒ^３、Ｒ^４およびＲ^５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^１は、ＣＨまたはＮを；Ｚ^２は、ＣＲ^６「式中、Ｒ^６は、水素原子またはハロゲン原子を示す。」で表される基またはＮ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 and R ² are the same or different and each represents a C _1-2 alkyl group; R ³ , R ⁴ and R ⁵ are the same or different and may be a hydrogen atom, a halogen atom or a protected group. Z ¹ is CH or N; Z ² is CR ⁶ , wherein R ⁶ represents a hydrogen atom or a halogen atom, or represents N or a good amino group; The heterocyclic compound represented by the above or a salt thereof has an excellent anti-HIV activity and is useful as an anti-HIV agent, thereby completing the present invention.

  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.
A silyl group means a trimethylsilyl, triethylsilyl or tributylsilyl 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.

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.
Examples of the leaving group include a halogen atom, an alkylsulfonyloxy group, and an arylsulfonyloxy 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, propyl 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 generally known salts of basic groups such as amino groups.
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.

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 methyl group is preferable.
A compound in which R ² is a methyl group is preferable.
A compound in which R ³ is an amino group which may be protected is preferable, and a compound in which R ³ is an amino group is more preferable.
A compound in which R ⁴ is a hydrogen atom or a fluorine atom is preferable, and a compound in which R ⁴ is a hydrogen atom is more preferable.
A compound in which R ⁵ is a hydrogen atom or a fluorine atom is preferable, and a compound in which R ⁵ is a hydrogen atom is more preferable.
A compound in which Z ¹ is CH is preferred.
Z ² is preferably a compound represented by CR ⁶ "wherein R ⁶ has the same meaning as described above.", More preferably a compound that is CH or CF, and further a compound that is CF. preferable.

  In the compound of the general formula [1] or a salt thereof, when there are isomers (for example, optical isomers, geometric isomers, tautomers, etc.), the present invention includes those isomers, It includes solvates, 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、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^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｚ^１およびＺ^２は、前記と同様の意味を有する。」 [Production Method 1]

“Wherein L ¹ is a leaving group; R ^a and R ^b are the same or different and are substituted together with a hydroxyl group, an optionally substituted C _1-6 alkoxy group or a bonding boron atom. R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Z ¹ and Z ² 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 [1] 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.

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 [2], 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 [2], 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 [2].

Examples of the base that is optionally used in this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, 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 [2].

The amount of the compound of general formula [3] used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of general formula [2].
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.

  Next, a method for producing the compound of the general formula [2], which is a raw material for producing the compound of the present invention, will be described.

「式中、Ｌ^２は、脱離基を；Ｒ^３、Ｒ^４、Ｒ^５、Ｌ^１、Ｚ^１およびＺ^２は、前記と同様の意味を有する。」 [Production method A]

“Wherein L ² represents a leaving group; R ³ , R ⁴ , R ⁵ , L ¹ , Z ¹ and Z ² have the same meaning as described above.

The compound of the general formula [2] can be produced by reacting the compound of the general formula [4] with the compound of the general formula [5] 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 halogenated hydrocarbons, ethers, aromatic hydrocarbons, nitriles, amides and dimethyl sulfoxide. These solvents may be used as a mixture.
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 [4], More preferably, it is 5-100 times amount (v / w). is there.
Examples of the base optionally used in this reaction include sodium hydrogen carbonate, sodium 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 [4].
This reaction is usually carried out at 20 to 140 ° C., preferably 40 to 120 ° C. for 30 minutes to 24 hours.

「式中、Ｌ^３は、脱離基を；Ｒ^３、Ｒ^４、Ｒ^５、Ｌ^１、Ｚ^１およびＺ^２は、前記と同様の意味を有する。」 [Production method B]

“Wherein L ³ represents a leaving group; R ³ , R ⁴ , R ⁵ , L ¹ , Z ¹ and Z ² have the same meaning as described above.

(B-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.
N, N-dimethylformamide dimethyl acetal may be used as a solvent.
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.

(B-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 examples of the solvent include ethers and esters, and a mixed solvent of ethyl acetate and diisopropyl ether and ethyl acetate are 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.

(B-3)
The compound of the general formula [2] is, for example, in accordance with the method described in Collection of Czechoslovak Chemical Communications, Vol. 69, pages 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, sodium 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.

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 2, 3, 4 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. Four 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 concentrations of the compounds of Examples 2, 3, 4 and 5 in the serum were all 1.0 μg / mL or more, indicating good pharmacokinetics.

Next, the present invention will be described with reference to reference examples and examples, but the present invention is not limited thereto.
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,
DMSO: dimethyl sulfoxide,
Me: methyl,
S-Phos: 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl,
TBAB: Tetrothiammonium bromide,
TFA: trifluoroacetic acid,
THF: tetrahydrofuran,
DMSO-d ₆ : heavy dimethyl sulfoxide

４−フルオロ−２−ニトロベンジルブロミド1.96gおよび７−クロロキノリン−４−オール1.00gのＤＭＦ20mL溶液に炭酸カリウム1.54gを加え、70〜80℃で2時間攪拌した。反応混合物を冷却後、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；ヘキサン：酢酸エチル＝５：１→１：１］で精製し、得られた固形物に酢酸エチルおよびジイソプロピルエーテルを加えた。固形物を濾取し、褐色固体の７−クロロ−１−（４−フルオロ−２−ニトロベンジル）−１，４−ジヒドロ−４−オキソキノリン300mgを得た。
¹H-NMR(DMSO-d₆)δ値：
5.87(brs,2H),6.21(d,J=7.7Hz,1H),6.72(dd,J=8.8,5.4Hz,1H),7.41(dd,J=8.6,1.9Hz,1H),7.52(ddd,J=8.8,7.9,3.1Hz,1H),7.78(d,J=1.9Hz,1H),8.11(d,J=7.7Hz,1H),8.20(dd,J=8.7,3.1Hz,1H),8.21(d,J=8.6Hz,1H). Reference example 1

To a solution of 1.96 g of 4-fluoro-2-nitrobenzyl bromide and 1.00 g of 7-chloroquinolin-4-ol in 20 mL of DMF was added 1.54 g of potassium carbonate, and the mixture was stirred at 70 to 80 ° C. for 2 hours. After cooling the reaction mixture, ethyl acetate was added, washed successively with water and saturated aqueous sodium chloride solution, 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 = 5: 1 → 1: 1], and ethyl acetate and diisopropyl ether were added to the obtained solid. The solid was collected by filtration to obtain 300 mg of 7-chloro-1- (4-fluoro-2-nitrobenzyl) -1,4-dihydro-4-oxoquinoline as a brown solid.
¹ H-NMR (DMSO-d ₆ ) δ value:
5.87 (brs, 2H), 6.21 (d, J = 7.7Hz, 1H), 6.72 (dd, J = 8.8,5.4Hz, 1H), 7.41 (dd, J = 8.6,1.9Hz, 1H), 7.52 (ddd , J = 8.8,7.9,3.1Hz, 1H), 7.78 (d, J = 1.9Hz, 1H), 8.11 (d, J = 7.7Hz, 1H), 8.20 (dd, J = 8.7,3.1Hz, 1H) , 8.21 (d, J = 8.6Hz, 1H).

７−クロロ−１−（４−フルオロ−２−ニトロベンジル）−１，４−ジヒドロ−４−オキソキノリン300mg、鉄粉201mgおよび塩化アンモニウム20mgのエタノール3mLおよび水1.5mL懸濁液を58分間加熱還流した。不溶物を濾去後、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＝５：１→２：１］で精製し、黄色固体の１−（２−アミノ−４−フルオロベンジル）−７−クロロ−１，４−ジヒドロ−４−オキソキノリン126mgを得た。
¹H-NMR(DMSO-d₆)δ値：
5.21(s,2H),5.64(brs,2H),6.13(d,J=7.8Hz,1H),6.28(ddd,J=8.6,8.6,2.6Hz,1H),6.53(dd,J=11.5,2.6Hz,1H),6.59(dd,J=8.6,6.6Hz,1H),7.40(dd,J=8.6,1.9Hz,1H),7.57(d,J=1.9Hz,1H),7.96(d,J=7.8Hz,1H),8.18(d,J=8.6Hz,1H). Reference example 2

A suspension of 300 mL 7-chloro-1- (4-fluoro-2-nitrobenzyl) -1,4-dihydro-4-oxoquinoline, 201 mg iron powder and 20 mg ammonium chloride in 3 mL ethanol and 1.5 mL water is heated for 58 minutes. Refluxed. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: acetone = 5: 1 → 2: 1] to give 1- (2-amino-4-fluorobenzyl) -7-chloro- 126 mg of 1,4-dihydro-4-oxoquinoline was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value:
5.21 (s, 2H), 5.64 (brs, 2H), 6.13 (d, J = 7.8Hz, 1H), 6.28 (ddd, J = 8.6,8.6,2.6Hz, 1H), 6.53 (dd, J = 11.5, 2.6Hz, 1H), 6.59 (dd, J = 8.6,6.6Hz, 1H), 7.40 (dd, J = 8.6,1.9Hz, 1H), 7.57 (d, J = 1.9Hz, 1H), 7.96 (d, J = 7.8Hz, 1H), 8.18 (d, J = 8.6Hz, 1H).

２−ｔｅｒｔ−ブトキシカルボニルアミノ−３−フルオロベンジルアルコール0.31gのＴＨＦ6.4mL溶液にトリフェニルホスフィン0.40gおよび四臭化炭素0.48gを加え、室温で1時間攪拌した。不溶物を濾去後、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；ヘキサン：酢酸エチル＝６：１］で精製し、無色油状の２−ｔｅｒｔ−ブトキシカルボニルアミノ−３−フルオロベンジルブロミド0.28gを得た。
¹H-NMR(CDCl₃)δ値:
1.51(s,9H),4.54(s,2H),6.10(brs,1H),7.05-7.13(m,1H),7.17-7.22(m, 2H). Reference example 3

To a solution of 0.31 g of 2-tert-butoxycarbonylamino-3-fluorobenzyl alcohol in 6.4 mL of THF were added 0.40 g of triphenylphosphine and 0.48 g of carbon tetrabromide, and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 6: 1] to obtain 0.28 g of colorless oily 2-tert-butoxycarbonylamino-3-fluorobenzyl bromide.
¹ H-NMR (CDCl ₃ ) δ value:
1.51 (s, 9H), 4.54 (s, 2H), 6.10 (brs, 1H), 7.05-7.13 (m, 1H), 7.17-7.22 (m, 2H).

２−ｔｅｒｔ−ブトキシカルボニルアミノ−３−フルオロベンジルブロミド0.28g、７−クロロキノリン−４−オール0.15gおよび炭酸カリウム0.23gのＤＭＦ8.4mL懸濁液を80〜90℃で3時間攪拌した。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；クロロホルム：アセトン＝４：１］で精製し、得られた固形物に酢酸エチルおよびジイソプロピルエーテルを加えた。固形物を濾取し、白色固体の１−（２−ｔｅｒｔ−ブトキシカルボニルアミノ−３−フルオロベンジル）−７−クロロ−１，４−ジヒドロ−４−オキソキノリン0.18gを得た。
¹H-NMR(DMSO-d₆)δ値：1.46(s,9H),5.43(s,2H),6.16(d,J=7.8Hz,1H),6.50-6.58(m,1H),7.16-7.26(m,2H),7.38(dd,J=8.6,1.8Hz,1H),7.48(brs,1H),8.13(d,J=7.8Hz,1H),8.17(d,J=8.6Hz,1H),8.97(s,1H). Reference example 4

A suspension of 0.28 g of 2-tert-butoxycarbonylamino-3-fluorobenzyl bromide, 0.15 g of 7-chloroquinolin-4-ol and 0.23 g of potassium carbonate in 8.4 mL of DMF was stirred at 80 to 90 ° C. for 3 hours. 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: chloroform: acetone = 4: 1], and ethyl acetate and diisopropyl ether were added to the obtained solid. The solid was collected by filtration to obtain 0.18 g of 1- (2-tert-butoxycarbonylamino-3-fluorobenzyl) -7-chloro-1,4-dihydro-4-oxoquinoline as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.46 (s, 9H), 5.43 (s, 2H), 6.16 (d, J = 7.8Hz, 1H), 6.50-6.58 (m, 1H), 7.16- 7.26 (m, 2H), 7.38 (dd, J = 8.6,1.8Hz, 1H), 7.48 (brs, 1H), 8.13 (d, J = 7.8Hz, 1H), 8.17 (d, J = 8.6Hz, 1H ), 8.97 (s, 1H).

２−アミノ−３−（アミノメチル）ピリジン塩酸塩560mgの酢酸エチル3.5mL懸濁液にトリエチルアミン1.5mLおよび（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400mgを加え、50〜60℃で1時間50分間攪拌した。不溶物を濾去後、減圧下で溶媒を留去した。得られた残留物の酢酸エチル3.5mLおよびエタノール0.5mL溶液を50〜60℃で1時間30分間攪拌した。減圧下で溶媒を留去し、得られた残留物に酢酸エチルおよびジイソプロピルエーテルを加えた。固形物を濾取し、黄色固体の３−（（２−アミノピリジン−３−イル）メチルアミノ）−１−（４−ブロモ−２−フルオロフェニル）−２−プロペン−１−オン240mgを得た。
３−（（２−アミノピリジン−３−イル）メチルアミノ）−１−（４−ブロモ−２−フルオロフェニル）−２−プロペン−１−オン240mgのＤＭＦ4mL溶液に炭酸カリウム240mgを加え、60〜80℃で2時間攪拌した。反応混合物に酢酸エチルおよび水を加えた。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、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。得られた残留物に酢酸エチルおよびジイソプロピルエーテルを加えた。固形物を濾取し、淡黄色固体の１−（（２−アミノピリジン−３−イル）メチル）−７−ブロモ−１，４−ジヒドロ−４−オキソキノリン150mgを得た。
¹H-NMR(CDCl₆)δ値：
4.51(brs,2H),5.03(s,2H),6.32(d,J=7.8Hz,1H),6.70(dd,J=7.1,5.0Hz,1H),6.99(d,J=7.1Hz,1H),7.44(d,J=1.2Hz,1H),7.47(d,J=7.8Hz,1H),7.50(dd,J=8.5,1.2Hz,1H),8.14(dd,J=5.0,1.1Hz,1H),8.33(d,J=8.5Hz,1H). Reference Example 5

To a suspension of 2-amino-3- (aminomethyl) pyridine hydrochloride 560 mg in ethyl acetate 3.5 mL, triethylamine 1.5 mL and (E) -1- (4-bromo-2-fluorophenyl) -3-dimethylamino-2 -Propene-1-one 400mg was added and it stirred at 50-60 degreeC for 1 hour and 50 minutes. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. A solution of the obtained residue in ethyl acetate (3.5 mL) and ethanol (0.5 mL) was stirred at 50 to 60 ° C. for 1 hour and 30 minutes. The solvent was distilled off under reduced pressure, and ethyl acetate and diisopropyl ether were added to the obtained residue. The solid was collected by filtration to obtain 240 mg of yellow solid 3-((2-aminopyridin-3-yl) methylamino) -1- (4-bromo-2-fluorophenyl) -2-propen-1-one. It was.
3-((2-aminopyridin-3-yl) methylamino) -1- (4-bromo-2-fluorophenyl) -2-propen-1-one 240 mg of potassium carbonate 240 mg was added to a solution of 240 mg of DMF, and 60- Stir at 80 ° C. for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue. The solid was collected by filtration to obtain 150 mg of 1-((2-aminopyridin-3-yl) methyl) -7-bromo-1,4-dihydro-4-oxoquinoline as a pale yellow solid.
¹ H-NMR (CDCl ₆ ) δ value:
4.51 (brs, 2H), 5.03 (s, 2H), 6.32 (d, J = 7.8Hz, 1H), 6.70 (dd, J = 7.1,5.0Hz, 1H), 6.99 (d, J = 7.1Hz, 1H ), 7.44 (d, J = 1.2Hz, 1H), 7.47 (d, J = 7.8Hz, 1H), 7.50 (dd, J = 8.5,1.2Hz, 1H), 8.14 (dd, J = 5.0,1.1Hz , 1H), 8.33 (d, J = 8.5Hz, 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1.80gおよび２−アミノベンジルアミン1.05gの酢酸エチル3mLおよびジイソプロピルエーテル3mL溶液を50〜70℃で4時間攪拌した。減圧下で溶媒を留去し、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、得られた固形物に酢酸エチルおよびジイソプロピルエーテルを加えた。固形物を濾取し、淡黄色固体の３−（２−アミノベンジルアミノ）−１−（４−ブロモ−２−フルオロフェニル）−２−プロペン−１−オン760mgを得た。
３−（２−アミノベンジルアミノ）−１−（４−ブロモ−２−フルオロフェニル）−２−プロペン−１−オン760mgのＤＭＳＯ7.6mL溶液に炭酸カリウム760mgを加え、90℃で40分間攪拌した。反応混合物に酢酸エチルおよび水を加えた。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、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。得られた残留物に酢酸エチルおよびジイソプロピルエーテルを加えた。固形物を濾取し、褐色固体の１−（２−アミノベンジル）−７−ブロモ−１，４−ジヒドロ−４−オキソキノリン570mgを得た。
¹H-NMR(DMSO-d₆)δ値：
5.26(s,2H),5.29(brs,2H),6.14(d,J=7.8Hz,1H),6.45-6.51(m,1H),6.53(dd,J=7.7,1.6Hz,1H),6.76(d,J=8.1Hz,1H),6.98-7.06(m,1H),7.52(dd,J=8.7,1.7Hz,1H),7.71(d,J=1.7Hz,1H),8.00(d,J=7.8Hz,1H),8.10(d,J=8.7Hz,1H). Reference Example 6

(E) 1- (4-Bromo-2-fluorophenyl) -3-dimethylamino-2-propen-1-one 1.80 g and 2-aminobenzylamine 1.05 g in ethyl acetate 3 mL and diisopropyl ether 3 mL Stir at ~ 70 ° C for 4 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1], and ethyl acetate and diisopropyl ether were added to the obtained solid. . The solid was collected by filtration to obtain 760 mg of 3- (2-aminobenzylamino) -1- (4-bromo-2-fluorophenyl) -2-propen-1-one as a pale yellow solid.
760 mg of potassium carbonate was added to 7.6 mL of DMSO in 760 mg of 3- (2-aminobenzylamino) -1- (4-bromo-2-fluorophenyl) -2-propen-1-one and stirred at 90 ° C. for 40 minutes. . Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue. The solid was collected by filtration to obtain 570 mg of 1- (2-aminobenzyl) -7-bromo-1,4-dihydro-4-oxoquinoline as a brown solid.
¹ H-NMR (DMSO-d ₆ ) δ value:
5.26 (s, 2H), 5.29 (brs, 2H), 6.14 (d, J = 7.8Hz, 1H), 6.45-6.51 (m, 1H), 6.53 (dd, J = 7.7,1.6Hz, 1H), 6.76 (d, J = 8.1Hz, 1H), 6.98-7.06 (m, 1H), 7.52 (dd, J = 8.7,1.7Hz, 1H), 7.71 (d, J = 1.7Hz, 1H), 8.00 (d, J = 7.8Hz, 1H), 8.10 (d, J = 8.7Hz, 1H).

２−アミノ−３，５−ジフルオロベンゾニトリル1.0gのＴＨＦ10.0mL溶液に、窒素雰囲気下、1.06mol/LボランＴＨＦ錯体15.3mLを加え、1時間加熱還流した。固形物を濾取し、6mol/L塩酸2.7mLに懸濁させ、2時間30分間加熱還流し、さらに6mol/L塩酸2.7mLを加え、2時間45分間加熱還流した。反応混合物に20％水酸化ナトリウム水溶液、水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。得られた残留物にジイソプロピルエーテルを加えた。固形物を濾取し、淡褐色固体の２−アミノ−３，５−ジフルオロベンジルアミン505mgを得た。
¹H-NMR(DMSO-d₆)δ値：
2.10(brs,2H),3.64(s,2H),4.91(brs,2H),6.83-6.87(m,1H),6.91(ddd,J=11.3,8.7,2.6Hz,1H). Reference Example 7

To a 10.0 mL THF solution of 1.0 g of 2-amino-3,5-difluorobenzonitrile, 15.3 mL of 1.06 mol / L borane THF complex was added under a nitrogen atmosphere, and the mixture was heated to reflux for 1 hour. The solid was collected by filtration, suspended in 2.7 mL of 6 mol / L hydrochloric acid, heated to reflux for 2 hours and 30 minutes, further added with 2.7 mL of 6 mol / L hydrochloric acid, and heated to reflux for 2 hours and 45 minutes. To the reaction mixture was added 20% aqueous sodium hydroxide, water and ethyl acetate. 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. Diisopropyl ether was added to the obtained residue. The solid was collected by filtration to obtain 505 mg of 2-amino-3,5-difluorobenzylamine as a light brown solid.
¹ H-NMR (DMSO-d ₆ ) δ value:
2.10 (brs, 2H), 3.64 (s, 2H), 4.91 (brs, 2H), 6.83 to 6.87 (m, 1H), 6.91 (ddd, J = 11.3, 8.7, 2.6Hz, 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359mgおよび２−アミノ−３，５−ジフルオロベンジルアミン250mgの酢酸エチル3.5mL溶液を15時間45分間加熱還流した。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、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＝１０：１→３：１］で精製し、得られた固形物にジイソプロピルエーテルを加えた。固形物を濾取し、白色固体の３−（（２−アミノ−３，５−ジフルオロベンジルアミノ）−１−（４−ブロモ−２−フルオロフェニル）−２−プロペン−１−オン133mgを得た。
３−（２−アミノ−３，５−ジフルオロベンジルアミノ）−１−（４−ブロモ−２−フルオロフェニル）−２−プロペン−１−オン133mgのＤＭＳＯ1.5mL溶液に炭酸カリウム62mgを加え、80℃で1時間15分間攪拌した。反応混合物に水、飽和塩化ナトリウム水溶液、クロロホルム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：メタノール＝１５：１→１０：１］で精製し、得られた固形物にジイソプロピルエーテルおよびヘキサンを加えた。固形物を濾取し、白色固体の１−（２−アミノ−３，５−ジフルオロベンジル）−７−ブロモ−１，４−ジヒドロ−４−オキソキノリン96mgを得た。
¹H-NMR(CDCl₃)δ値：
3.61(brs,2H),5.10(s,2H),6.32(d,J=7.8Hz,1H),6.32(d,J=7.8Hz,1H),6.85(ddd,J=10.6,8.1,2.7Hz,1H),7.45(d,J=1.5Hz,1H),7.48(d,J=7.8Hz,1H),7.50(dd,J=8.4,1.5Hz,1H),8.33(d,J=8.4Hz,1H). Reference Example 8

A solution of 359 mg of (E) -1- (4-bromo-2-fluorophenyl) -3-dimethylamino-2-propen-1-one and 250 mg of 2-amino-3,5-difluorobenzylamine in 3.5 mL of ethyl acetate The mixture was heated to reflux for 15 hours and 45 minutes. 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 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 = 10: 1 → 3: 1], and diisopropyl ether was added to the obtained solid. The solid was collected by filtration to obtain 133 mg of 3-((2-amino-3,5-difluorobenzylamino) -1- (4-bromo-2-fluorophenyl) -2-propen-1-one as a white solid. It was.
To a solution of 133 mg of 3- (2-amino-3,5-difluorobenzylamino) -1- (4-bromo-2-fluorophenyl) -2-propen-1-one in 1.5 mL of DMSO was added 62 mg of potassium carbonate. The mixture was stirred at ° C for 1 hour and 15 minutes. Water, saturated aqueous sodium chloride solution, chloroform 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 purified by silica gel column chromatography [eluent: chloroform: methanol = 15: 1 → 10: 1], and diisopropyl ether and hexane were added to the obtained solid. The solid was collected by filtration to obtain 96 mg of 1- (2-amino-3,5-difluorobenzyl) -7-bromo-1,4-dihydro-4-oxoquinoline as a white solid.
¹ H-NMR (CDCl ₃ ) δ value:
3.61 (brs, 2H), 5.10 (s, 2H), 6.32 (d, J = 7.8Hz, 1H), 6.32 (d, J = 7.8Hz, 1H), 6.85 (ddd, J = 10.6,8.1,2.7Hz , 1H), 7.45 (d, J = 1.5Hz, 1H), 7.48 (d, J = 7.8Hz, 1H), 7.50 (dd, J = 8.4,1.5Hz, 1H), 8.33 (d, J = 8.4Hz , 1H).

１−（２−アミノ−４−フルオロベンジル）−７−クロロ−１，４−ジヒドロ−４−オキソキノリン120mg、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190mg、炭酸水素ナトリウム100mg、Ｓ−Ｐｈｏｓ33mgおよび酢酸パラジウム9mgのトルエン1.5mL、エタノール1.2mLおよび水0.8mLの懸濁液を、窒素雰囲気下、3時間加熱還流した。反応混合物に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190mg、炭酸水素ナトリウム100mg、Ｓ−Ｐｈｏｓ33mgおよび酢酸パラジウム9mgを加え、2時間30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；クロロホルム：アセトン＝３：１］で精製し、得られた固形物に酢酸エチルおよびジイソプロピルエーテルの混合溶媒を加えた。固形物を濾取し、淡褐色固体の１−（２−アミノ−４−フルオロベンジル）−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78mgを得た。
¹H-NMR(DMSO-d₆)δ値：
2.09(s,3H),2.26(s,3H),5.24(s,2H),5.66(brs,2H),6.15(d,J=7.7Hz,1H),6.27(ddd,J=8.6,8.5,2.6Hz,1H),6.53(dd,J=11.6,2.6Hz,1H),6.56(dd,J=8.6,6.8Hz,1H),7.25(d,J=1.2Hz,1H),7.39(dd,J=8.2,1.2Hz,1H),8.13(d,J=7.7Hz,1H),8.24(d,J=8.2Hz,1H). Example 1

1- (2-Amino-4-fluorobenzyl) -7-chloro-1,4-dihydro-4-oxoquinoline 120 mg, 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) isoxazole 190 mg, sodium bicarbonate 100 mg, S-Phos 33 mg and palladium acetate 9 mg in toluene 1.5 mL, ethanol 1.2 mL and water 0.8 mL under a nitrogen atmosphere, 3 Heated to reflux for hours. To the reaction mixture, 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoxazole 190 mg, sodium bicarbonate 100 mg, S-Phos 33 mg and palladium acetate 9 mg was added and heated to reflux for 2 hours 30 minutes. Ethyl acetate and water 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 purified by silica gel column chromatography [eluent: chloroform: acetone = 3: 1], and a mixed solvent of ethyl acetate and diisopropyl ether was added to the obtained solid. The solid was collected by filtration and 1- (2-amino-4-fluorobenzyl) -7- (3,5-dimethylisoxazol-4-yl) -1,4-dihydro-4-oxoquinoline as a light brown solid. 78 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value:
2.09 (s, 3H), 2.26 (s, 3H), 5.24 (s, 2H), 5.66 (brs, 2H), 6.15 (d, J = 7.7Hz, 1H), 6.27 (ddd, J = 8.6, 8.5, 2.6Hz, 1H), 6.53 (dd, J = 11.6, 2.6Hz, 1H), 6.56 (dd, J = 8.6, 6.8Hz, 1H), 7.25 (d, J = 1.2Hz, 1H), 7.39 (dd, J = 8.2,1.2Hz, 1H), 8.13 (d, J = 7.7Hz, 1H), 8.24 (d, J = 8.2Hz, 1H).

１−（２−ｔｅｒｔ−ブトキシカルボニルアミノ−３−フルオロベンジル）−７−クロロ−１，４−ジヒドロ−４−オキソキノリン0.73g、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0.81g、炭酸水素ナトリウム0.46g、ＴＢＡＢ2.90g、Ｓ−Ｐｈｏｓ223mgおよび酢酸パラジウム61mgのトルエン10mL、エタノール5mLおよび水1.5mLの懸濁液を、窒素雰囲気下、4時間20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；クロロホルム：アセトン＝６：１］で精製し、得られた固形物に酢酸エチルを加えた。固形物を濾取し、淡褐色固体の１−（２−ｔｅｒｔ−ブトキシカルボニルアミノ−３−フルオロベンジル）−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0.69gを得た。
１−（２−ｔｅｒｔ−ブトキシカルボニルアミノ−３−フルオロベンジル）−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0.69gのクロロホルム3mL溶液にＴＦＡ3mLを加え、室温で1時間攪拌した。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＝３：１］で精製し、得られた固形物に酢酸エチルを加えた。固形物を濾取し、白色固体の１−（２−アミノ−３−フルオロベンジル）−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274mgを得た。
¹H-NMR(DMSO-d₆)δ値：
2.05(s,3H),2.22(s,3H),5.36(s,2H),5.38(brs,2H),6.17(d,J=7.7Hz,1H),6.37(d,J=7.6Hz,1H),6.48(ddd,J=8.1,7.6,5.2Hz,1H),6.97(dd,J=10.9,8.1Hz,1H),7.21(s,1H),7.38(d,J=8.3Hz,1H),8.19(d,J=7.7Hz,1H),8.24(d,J=8.3Hz,1H) Example 2

1- (2-tert-butoxycarbonylamino-3-fluorobenzyl) -7-chloro-1,4-dihydro-4-oxoquinoline 0.73 g, 3,5-dimethyl-4- (4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl) isoxazole 0.81 g, sodium bicarbonate 0.46 g, TBAB 2.90 g, S-Phos 223 mg and palladium acetate 61 mg in toluene 10 mL, ethanol 5 mL and water 1.5 mL The suspension was heated to reflux for 4 hours and 20 minutes under a nitrogen atmosphere. Ethyl acetate and water 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 purified by silica gel column chromatography [eluent: chloroform: acetone = 6: 1], and ethyl acetate was added to the obtained solid. The solid was collected by filtration to give 1- (2-tert-butoxycarbonylamino-3-fluorobenzyl) -7- (3,5-dimethylisoxazol-4-yl) -1,4-dihydro- as a light brown solid. 0.69 g of 4-oxoquinoline was obtained.
1- (2-tert-Butoxycarbonylamino-3-fluorobenzyl) -7- (3,5-dimethylisoxazol-4-yl) -1,4-dihydro-4-oxoquinoline 0.69 g in chloroform 3 mL 3 mL of TFA was added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. 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: chloroform: acetone = 3: 1], and ethyl acetate was added to the obtained solid. The solid was collected by filtration to give 274 mg of 1- (2-amino-3-fluorobenzyl) -7- (3,5-dimethylisoxazol-4-yl) -1,4-dihydro-4-oxoquinoline as a white solid. Got.
¹ H-NMR (DMSO-d ₆ ) δ value:
2.05 (s, 3H), 2.22 (s, 3H), 5.36 (s, 2H), 5.38 (brs, 2H), 6.17 (d, J = 7.7Hz, 1H), 6.37 (d, J = 7.6Hz, 1H ), 6.48 (ddd, J = 8.1, 7.6, 5.2Hz, 1H), 6.97 (dd, J = 10.9, 8.1Hz, 1H), 7.21 (s, 1H), 7.38 (d, J = 8.3Hz, 1H) , 8.19 (d, J = 7.7Hz, 1H), 8.24 (d, J = 8.3Hz, 1H)

１−（２−アミノベンジル）−７−ブロモ−１，４−ジヒドロ−４−オキソキノリン560mg、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574mg、炭酸水素ナトリウム429mg、Ｓ−Ｐｈｏｓ70mgおよび酢酸パラジウム19mgのトルエン5.6mL、エタノール4.5mLおよび水2.8mL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；クロロホルム：アセトン＝２：１→１：１］で精製し、得られた固形物にエタノール、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を加えた。固形物を濾取し、白色固体の１−（２−アミノベンジル）−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339mgを得た。
¹H-NMR(DMSO-d₆)δ値：
2.05(s,3H),2.22(s,3H),5.29(s,2H),5.31(brs,2H),6.16(d,J=7.7Hz,1H),6.46-6.51(m,1H),6.53(dd,J=7.6Hz,1.5Hz,1H),6.75(d,J=7.8Hz,1H),6.95-7.04(m,1H),7.25(d,J=1.3Hz,1H),7.37(dd,J=8.3,1.3Hz,1H),8.17(d,J=7.7,1H),8.24(d,J=8.3Hz,1H). Example 3

1- (2-aminobenzyl) -7-bromo-1,4-dihydro-4-oxoquinoline 560 mg, 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) isoxazole 574 mg, sodium hydrogen carbonate 429 mg, S-Phos 70 mg and palladium acetate 19 mg in toluene 5.6 mL, ethanol 4.5 mL and water 2.8 mL were heated to reflux under a nitrogen atmosphere for 2 hours. . Ethyl acetate and water 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 purified by silica gel column chromatography [eluent: chloroform: acetone = 2: 1 → 1: 1], and ethanol, chloroform, ethyl acetate and diisopropyl ether were added to the obtained solid. The solid was collected by filtration to obtain 339 mg of 1- (2-aminobenzyl) -7- (3,5-dimethylisoxazol-4-yl) -1,4-dihydro-4-oxoquinoline as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value:
2.05 (s, 3H), 2.22 (s, 3H), 5.29 (s, 2H), 5.31 (brs, 2H), 6.16 (d, J = 7.7Hz, 1H), 6.46-6.51 (m, 1H), 6.53 (dd, J = 7.6Hz, 1.5Hz, 1H), 6.75 (d, J = 7.8Hz, 1H), 6.95-7.04 (m, 1H), 7.25 (d, J = 1.3Hz, 1H), 7.37 (dd , J = 8.3, 1.3Hz, 1H), 8.17 (d, J = 7.7, 1H), 8.24 (d, J = 8.3Hz, 1H).

１−（（２−アミノピリジン−３−イル）メチル）−７−ブロモ−１，４−ジヒドロ−４−オキソキノリン150mg、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163mg、炭酸水素ナトリウム110mg、Ｓ−Ｐｈｏｓ19mgおよび酢酸パラジウム5mgのトルエン1.5mL、エタノール1.2mLおよび水0.8mLの懸濁液を、窒素雰囲気下、1時間25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；クロロホルム：エタノール＝２０：１→１０：１］で精製し、得られた固形物に酢酸エチルを加えた。固形物を濾取し、淡黄色固体の１−（（２−アミノピリジン−３−イル）メチル）−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118mgを得た。
¹H-NMR(DMSO-d₆)δ値：
2.05(s,3H),2.23(s,3H),5.28(s,2H),6.13(brs,2H),6.17(d,J=7.8Hz,1H),6.48(dd,J=7.5,4.9Hz,1H),6.79(dd,J=7.5,1.5Hz,1H),7.18(d,J=1.2Hz,1H),7.39(dd,J=8.3,1.2Hz,1H),7.90(dd,J=4.9,1.5Hz,1H),8.17(d,J=7.8Hz,1H),8.25(d,J=8.3Hz,1H). Example 4

1-((2-Aminopyridin-3-yl) methyl) -7-bromo-1,4-dihydro-4-oxoquinoline 150 mg, 3,5-dimethyl-4- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) isoxazole 163 mg, sodium bicarbonate 110 mg, S-Phos 19 mg and palladium acetate 5 mg in toluene 1.5 mL, ethanol 1.2 mL and water 0.8 mL in a nitrogen atmosphere Under reflux for 1 hour and 25 minutes. Ethyl acetate and water 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 purified by silica gel column chromatography [eluent: chloroform: ethanol = 20: 1 → 10: 1], and ethyl acetate was added to the obtained solid. The solid was collected by filtration to give 1-((2-aminopyridin-3-yl) methyl) -7- (3,5-dimethylisoxazol-4-yl) -1,4-dihydro-4 as a pale yellow solid. -118 mg of oxoquinoline was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value:
2.05 (s, 3H), 2.23 (s, 3H), 5.28 (s, 2H), 6.13 (brs, 2H), 6.17 (d, J = 7.8Hz, 1H), 6.48 (dd, J = 7.5,4.9Hz , 1H), 6.79 (dd, J = 7.5,1.5Hz, 1H), 7.18 (d, J = 1.2Hz, 1H), 7.39 (dd, J = 8.3,1.2Hz, 1H), 7.90 (dd, J = 4.9, 1.5Hz, 1H), 8.17 (d, J = 7.8Hz, 1H), 8.25 (d, J = 8.3Hz, 1H).

１−（２−アミノ−３，５−ジフルオロベンジル）−７−ブロモ−１，４−ジヒドロ−４−オキソキノリン96mg、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70mg、炭酸水素ナトリウム66mg、トリフェニルホスフィン35mgおよび酢酸パラジウム3mgのトルエン1mL、エタノール0.8mLおよび水0.5mLの懸濁液を、窒素雰囲気下、3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；クロロホルム：メタノール＝１００：０→１０：１］で精製し、得られた固形物にジイソプロピルエーテルを加えた。固形物を濾取し、白色固体の１−（２−アミノ−３，５−ジフルオロベンジル）−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81mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.07(s,3H),2.25(s,3H),5.28(s,2H),5.37(s,2H),6.18(d,J=7.8Hz,1H),6.19-6.24(m,1H),7.07(ddd,J=11.3,8.5,2.7Hz,1H),7.21(brs,1H),7.40(dd,J=8.3,1.2Hz,1H),8.19(d,J=7.8Hz,1H),8.25(d,J=8.3Hz,1H). Example 5

1- (2-amino-3,5-difluorobenzyl) -7-bromo-1,4-dihydro-4-oxoquinoline 96 mg, 3,5-dimethyl-4- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) isoxazole 70 mg, sodium bicarbonate 66 mg, triphenylphosphine 35 mg and palladium acetate 3 mg in 1 mL toluene, ethanol 0.8 mL and water 0.5 mL under a nitrogen atmosphere The mixture was heated to reflux for 3 hours and 20 minutes. Chloroform and water 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 purified by silica gel column chromatography [eluent: chloroform: methanol = 100: 0 → 10: 1], and diisopropyl ether was added to the obtained solid. The solid was collected by filtration and white solid 1- (2-amino-3,5-difluorobenzyl) -7- (3,5-dimethylisoxazol-4-yl) -1,4-dihydro-4-oxo. 81 mg of quinoline was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.07 (s, 3H), 2.25 (s, 3H), 5.28 (s, 2H), 5.37 (s, 2H), 6.18 (d, J = 7.8Hz, 1H), 6.19-6.24 (m, 1H), 7.07 (ddd, J = 11.3, 8.5, 2.7Hz, 1H), 7.21 (brs, 1H), 7.40 (dd, J = 8.3, 1.2Hz, 1H), 8.19 (d, J = 7.8Hz, 1H), 8.25 (d, J = 8.3Hz, 1H).

  The heterocyclic compound having an aralkyl group or a 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 and R ² are the same or different and each represents a C _1-2 alkyl group; R ³ , R ⁴ and R ⁵ are the same or different and may be a hydrogen atom, a halogen atom or a protected group. A good amino group; Z ¹ represents CH or N; Z ² represents CR ⁶ , wherein R ⁶ represents a hydrogen atom or a halogen atom;
In the above, the protecting group for the amino group is a C _1-6 alkoxy C _1-6 alkyl group, an acyl group, a C _1-6 alkoxycarbonyl group , an aryloxycarbonyl group, a C _1-6 alkylsulfonyl group, an arylsulfonyl group or Represents a silyl group, and 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. Or a salt thereof. The heterocyclic compound or a salt thereof according to claim 1, wherein Z ¹ is CH. The heterocyclic compound or a salt thereof according to claim 1 or 2, wherein R ¹ is a methyl group; and R ² is a methyl group. The heterocyclic compound or a salt thereof according to any one of claims 1 to 3, wherein Z ² is a group represented by CR ⁶ "wherein R ⁶ represents a hydrogen atom or a halogen atom." R ³ is an amino group which may be protected; R ⁴ is a hydrogen atom: R ⁵ is a hydrogen atom or a fluorine atom; Z ² is CH or CF, wherein the protecting group for the amino group of R ³ Is the same as that of Claim 1, The heterocyclic compound or its salt as described in any one of Claims 1-3. R ³ is an optionally protected amino group; R ⁴ is a hydrogen atom: R ⁵ is a hydrogen atom; Z ² is CF, wherein the protecting group for the amino group of R ³ is The heterocyclic compound or its salt as described in any one of Claims 1-3 which is the same as that. The anti-HIV agent containing the heterocyclic compound or its salt as described in any one of Claims 1-6.