JPWO2016056606A1 - Benzisothiazolopyrimidine derivatives or salts thereof, viral infection inhibitors and pharmaceuticals - Google Patents

Abstract

Provided are novel compounds having antiviral activity. A compound represented by the following formula (I) or a salt thereof: R1 to R3 are independently H atom, halogen atom, C1-6 alkyl group, C1-6 alkoxy group, C2-6 alkenyl group, C2-6 alkynyl group, C2-6 alkylene group, aryl group. , Heteroaryl group, nitro group, alkylcarbonylamino group of C1-6 alkyl group, C1-6 fluoroalkyl group, amino group, C1-3 mono- or dialkylamino group, benzoylamino group, azide group, carboxyl group, C1-6 3 alkylcarbonyl group, C1-3 alkoxycarbonyl group, carbamoyl group, naphthyl group, heteroaryl group, styryl group, C1-3 alkylthio group, C1-6 hydroxyalkyl group, which may be substituted with a substituent, the same However, R1 and R2, R2 and R3 may be bridged, and bridges between adjacent substituents. May contain a heteroatom; R4 represents a C1-5 straight-chain alkylene group or a heteroatom, may be substituted with a substituent, and when R4 is the alkylene group, substitution on the alkylene group The groups may be bonded to each other to form a bridged structure or a ring structure; X1 and X2 independently represent a heteroatom, may be substituted with a substituent, and may be the same or different; May be.

Description

  The present invention relates to a benzisothiazolopyrimidine derivative or a salt thereof, and a virus infection inhibitor and a pharmaceutical product.

  In the treatment of HIV infection, certain effects have been recognized by HAART therapy in which a reverse transcriptase inhibitor and a protease inhibitor are combined. However, it is frequently observed that HIV tends to acquire drug resistance due to mutation and is difficult to treat with conventional drugs. For this reason, development of a new drug having a different mechanism of action from existing drugs is required.

Flexner, C. Nat. Rev. Drug Discov. 2007, 6, 959. De Clercq, E. Nat. Rev. Drug Discov. 2007, 6, 1001. Cohen, M. S .; Smith, M. K .; Muessig, K. E .; Hallett, T. B .; Powers, K. A .; Kashuba, A. D. Lancet, 2013, 382, 1515. Barre-Sinoussi, F .; Ross, A. L .; Delfraissy, J. F. Nat. Rev. Microbiol. 2013, 11, 877.

  Therefore, an object of the present invention is to provide a novel compound having antiviral activity.

The compound of the present invention or a salt thereof is represented by the following formula (I).
In the formula (I),
R ¹ , R ² , and R ³ each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a carbon number An alkynyl group having 2 to 6 carbon atoms, an alkylene group having 2 to 6 carbon atoms, an aryl group, a heteroaryl group, a nitro group, an alkylcarbonylamino group having an alkyl group of 1 to 6 carbon atoms, and a fluoroalkyl group having 1 to 6 carbon atoms , Amino group, mono- or dialkylamino group having 1 to 3 carbon atoms, benzoylamino group, azide group, carboxyl group, alkylcarbonyl group having 1 to 3 carbon atoms, alkoxycarbonyl group having 1 to 3 carbon atoms, carbamoyl group, naphthyl Group, heteroaryl group, styryl group, alkylthio group having 1 to 3 carbon atoms, hydroxyalkyl group having 1 to 6 carbon atoms,
R ¹ , R ² , and R ³ may be further substituted with a substituent,
R ¹ , R ² , and R ³ may be the same or different,
R ¹ and R ² , or R ² and R ³ may be bridged,
The bridge formed by the adjacent substituents may include one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom,
R ⁴ represents a linear alkylene group having 1 to 5 carbon atoms or a hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,
R ⁴ may be further substituted with a substituent,
When R ⁴ is the alkylene group, the substituents on the alkylene group may be bonded to each other to form a crosslinked structure or a ring structure;
X ¹ and X ² each independently represent a heteroatom selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom;
X ¹ and X ² may be further substituted with a substituent,
X ¹ and X ² may be the same or different,
X ¹ and X ² may be cross-linked.

  The viral infection inhibitor of the present invention comprises the compound of the present invention or a salt thereof.

  The pharmaceutical product of the present invention is characterized by comprising the compound of the present invention or a salt thereof.

The production method of the present invention uses at least one derivative of a pyrimidobenzothiazine-6-imine derivative (raw material A) and a pyrimidobenzothiazine-6-thione derivative (raw material B) as a synthetic raw material, Obtaining a thiophenol derivative from the raw material as an intermediate, and
The method for producing the compound of the present invention or a salt thereof, comprising a step of oxidizing the intermediate.

  Since the compound of the present invention has antiviral activity against HIV and the like, it can be used, for example, as a viral infection inhibitor and is extremely useful in the medical field.

FIG. 1 is a graph showing the relationship between the addition time of a drug sample after infection with HIV virus in Example 3 and the infection rate (%). FIG. 2 is a graph showing the results of herpesvirus infection inhibition rate in Example 3.

In the compound of the present invention or a salt thereof, for example, a compound in which X ¹ and X ² are crosslinked in the formula (I) is represented by the following formula (II).
In the formula (II),
R ¹ , R ² , and R ³ each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a carbon number An alkynyl group having 2 to 6 carbon atoms, an alkylene group having 2 to 6 carbon atoms, an aryl group, a heteroaryl group, a nitro group, an alkylcarbonylamino group having an alkyl group of 1 to 6 carbon atoms, and a fluoroalkyl group having 1 to 6 carbon atoms , Amino group, mono- or dialkylamino group having 1 to 3 carbon atoms, benzoylamino group, azide group, carboxyl group, alkylcarbonyl group having 1 to 3 carbon atoms, alkoxycarbonyl group having 1 to 3 carbon atoms, carbamoyl group, naphthyl A group, a styryl group, an alkylthio group having 1 to 3 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms,
R ¹ , R ² , and R ³ may be further substituted with a substituent,
R ¹ , R ² , and R ³ may be the same or different,
R ¹ and R ² , or R ² and R ³ may be bridged,
The bridge formed by the adjacent substituents may include one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom,
R ⁴ represents a linear alkylene group having 1 to 5 carbon atoms or a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom,
R ⁴ may be further substituted with a substituent,
When R ⁴ is the alkylene group, the substituents on the alkylene group may be bonded to each other to form a crosslinked structure or a ring structure;
The isothiazole ring may be opened by cleavage of the nitrogen-sulfur bond,
When the isothiazole ring is opened, the nitrogen atom derived from the nitrogen-sulfur bond may be substituted with an oxygen atom or a sulfur atom, and the sulfur atom derived from the nitrogen-sulfur bond is an oxygen atom or a nitrogen atom. May be substituted.

In the compound of the present invention or a salt thereof, for example, R ⁴ is a methylene group, an ethylene group or an ethylidene group.

In the compound of the present invention or a salt thereof, for example, R ⁴ is a group having a structure represented by the following formula (2) or (3).
In the formula (2),
R ⁶ represents an alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzoyl group,
R ⁶ may be further substituted with a substituent,
The substituent is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, or an alkyl having 1 to 3 carbon atoms. A sulfonyl group or halogen,
In the formula (3),
Y represents a methylene group or an oxygen atom,
Y may be further substituted with a substituent,
The substituent is an alkyl group having 1 to 6 carbon atoms or a halogen atom.

  In the compound of the present invention or a salt thereof, for example, the aryl group or the heteroaryl group is a 5-membered ring or a 6-membered ring.

In the compound of the present invention or a salt thereof, for example, the aryl group has a structure represented by the following formula (1).
In the formula (1),
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a 1 to 6 fluoroalkyl group, A fluoroalkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, an aminocarbonyl group, a halogen atom, a nitro group, a hydroxyl group, a cyano group, a methanesulfonylamino group, Represents a benzoyl group or an alkylcarbonylamino group having 1 to 3 carbon atoms which may be substituted with a phenyl group;
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ may be the same or different,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ may each form a ring with adjacent substituents,
The ring formed by the adjacent substituents may include one or more heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom.

In the compound of the present invention, or a salt thereof, for example, R ² is a hydrophobic functional group.

In the compound of the present invention or a salt thereof, for example, R ¹ , R ² , and R ³ are each independently a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms. An aryl group having 5 to 10 carbon atoms, an aryl group having 5 to 10 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, a nitro group, and an alkyl group having 1 carbon atom. Or an alkylcarbonylamino group having a carbon number of 6 or a fluoroalkyl group having 1 to 6 carbon atoms.

In the compound of the present invention, or a salt thereof, for example, the halogen atom is a bromine atom,
The alkyl group having 1 to 6 carbon atoms is a methyl group;
The alkoxy group having 1 to 6 carbon atoms is a methoxy group;
The aryl group having 5 to 10 carbon atoms is a phenyl group or a naphthyl group;
An aryl group having 5 to 10 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms is a methoxyphenyl group;
The heteroaryl group having 1 to 10 carbon atoms is a furanyl group or a thiophenyl group;
An alkylcarbonylamino group having an alkyl group of 1 to 6 carbon atoms is an acetylamino group,
A C1-C6 fluoroalkyl group is a trifluoromethyl group.

In the compound of the present invention, or a salt thereof, for example, R ¹ and R ³ are each independently a hydrogen atom,
R ² is a halogen atom, an alkoxy group having 1 to 6 carbon atoms, an aryl group having 5 to 10 carbon atoms, an aryl group having 5 to 10 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms, 10 heteroaryl groups, nitro groups, or fluoroalkyl groups having 1 to 6 carbon atoms.

In the compound of the present invention, or a salt thereof, for example, R ² and R ³ are each independently a hydrogen atom,
R ¹ is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group having 5 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Of the fluoroalkyl group.

In the compound of the present invention, or a salt thereof, for example, R ¹ and R ² are hydrogen,
R ³ is the aryl group, the substituted aryl group, the heteroaryl group, or the substituted heteroaryl group.

In the compound of the present invention, or a salt thereof, for example, any one of R ¹ , R ² and R ³ is the aryl group, the substituted aryl group, the heteroaryl group, or the substituted heteroaryl group. It is.

  In the compound of the present invention or a salt thereof, for example, in the substituted aryl group, the substituent is an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, a hydroxyl group, or a nitro group. is there.

  In the compound of the present invention or a salt thereof, for example, the substituent is a methoxy group, a methoxycarbonyl group, a hydroxyl group, or a nitro group.

  In the compound of the present invention or a salt thereof, for example, the substituted aryl group is a 3,4-methylenedioxyphenyl group or a naphthyl group.

  In the compound of the present invention or a salt thereof, for example, the heteroaryl group is a pyridinyl group.

  In the compound of the present invention or a salt thereof, for example, the heteroaryl group is a furanyl group, a thiophenyl group, an imidazolyl group, a pyrazolyl group, or a 1,2,3-triazolyl group.

The compound of the present invention, or a salt thereof, for example, in the formula (I),
X ¹ is a thiol group, a hydroxyl group, or an amino group (—NH ₂ ),
X ² is a nitrogen atom (—NH—).

  The pharmaceutical product of the present invention is for viral infections, for example.

  In the pharmaceutical of the present invention, for example, the virus is at least one virus selected from the group consisting of human immunodeficiency virus (HIV), human herpes virus, influenza virus and human hepatitis C virus (HCV).

In the production method of the present invention, for example, the synthetic raw material is the pyrimidobenzothiazine-6-imine derivative (raw material A),
The thiophenol derivative is obtained as an intermediate by acid decomposition of the synthetic raw material.

In the production method of the present invention, for example, the synthetic raw material is the pyrimidobenzothiazine-6-thione derivative (raw material B),
The synthetic raw material is alkali decomposed to obtain the thiophenol derivative as an intermediate.

  Unless otherwise specified, the compound of the present invention or a salt thereof is referred to as the compound of the present invention, and the compound of the present invention can be read as the salt of the compound of the present invention.

  The present invention is described in detail below. In this specification, unless otherwise specified, each term has the following meaning.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

  The alkyl group having 1 to 6 carbon atoms may be linear, branched, cyclic, or a combination thereof. Examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, Examples thereof include a cyclopropylmethyl group and a cyclobutylethyl group. In addition, an alkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 1 to 6 carbon atoms, an alkylcarbonylamino group having 1 to 6 carbon atoms, a fluoroalkyl group having 1 to 6 carbon atoms, and an alkylsulfonyl having 1 to 6 carbon atoms When the alkyl group having 1 to 6 carbon atoms is included in a part of the substituents such as a group, the alkyl group is the same, for example. As an example, when referring to “an alkylcarbonyl group having 1 to 6 carbon atoms” or the like, the indicated carbon number means the carbon number of the alkyl group and does not include the carbon of the carbonyl group.

  The aryl group is a monovalent aromatic hydrocarbon group. The aryl group may further have a substituent, for example. The aryl group may be, for example, monocyclic or polycyclic (fused ring) in which two or more monocycles are shared (fused). Each ring may be, for example, a 5-membered ring or a 6-membered ring. The number of carbon atoms of the aryl group is not particularly limited, and examples thereof include 5 to 60, 6 to 60; 5 to 20, 6 to 20; 5 to 10, 6 to 10 and the like. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, a pyrenyl group, a fluorenyl group, and a biphenyl group.

  The heteroaryl group is a group obtained by substituting any one or more carbons with another heteroatom in the monovalent aromatic hydrocarbon group. Examples of the hetero atom include an oxygen atom, a sulfur atom, and a nitrogen atom, and the number of the hetero atoms is not particularly limited. The heteroaryl group may further have a substituent, for example. The heteroaryl group may be, for example, monocyclic or polycyclic (fused ring) in which two or more monocycles are shared (fused). Each ring may be, for example, a 5-membered ring or a 6-membered ring. The number of carbon atoms of the heteroaryl group is not particularly limited, and is, for example, 2 to 60, 3 to 60, 5 to 60, 6 to 60; 2 to 20, 3 to 20, 5 to 20, 6 to 20; 10, 3 to 10, 5 to 10, 6 to 10 and the like. Examples of the heteroaryl group include a furanyl group, a thiophenyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a pyridazolyl group, a pyridyl group, a benzofuryl group, a benzothienyl group, and a thienothienyl group.

  The alkenyl group having 2 to 6 carbon atoms may be, for example, linear, branched, cyclic, or a combination thereof. Examples of the alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, and a cyclopropenylmethyl group.

  The alkynyl group having 2 to 6 carbon atoms may be, for example, linear or branched, and examples thereof include an ethynyl group and a propargyl group.

  An alkylene group is a divalent group having one free valence from the hydrocarbons at both ends of the alkane chain (chain saturated hydrocarbon). Examples of the linear alkylene group having 1 to 5 carbon atoms include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, and a pentamethylene group.

  In this specification, “a certain group may be substituted” means, for example, the number and position of substituents are not particularly limited. Moreover, there is no particular limitation on the type of substituent unless there is a specific definition for the type of substituent.

(1) Compound or salt thereof As described above, the compound of the present invention (including a salt thereof) is represented by the following formula (I).

In the above formula (I), R ¹ , R ² and R ³ may be the same or different, and may be further substituted with a substituent.

In the formula (I), for example, R ¹ and R ² may be bridged, and R ² and R ³ may be bridged. In this case, for example, a cyclic structure (for example, a five-membered ring or a six-membered ring) may be formed together with the carbon atom to which they (R ¹ and R ² , or R ² and R ³ ) are bonded by bridging. . Moreover, the bridge formed by the adjacent substituents may include at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom or a sulfur atom.

In the formula (I), R ⁴ represents a linear alkylene group having 1 to 5 carbon atoms or a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and R ⁴ represents Further, it may be substituted with a substituent. When R ⁴ is the alkylene group, the substituents on the alkylene group may be bonded to each other to form a crosslinked structure or a ring structure.

In the formula (I), for example, all of R ¹ , R ² and R ³ may be hydrogen atoms, any two may be hydrogen atoms, or any one may be a hydrogen atom. Specific examples of the compound of the present invention, for example, compounds in which all of R ^1, R ² and R ³ are hydrogen atoms, and is any one of hydrogen atoms of R ^1, R ² and R ³ and the remaining These are compounds in which the above two are substituents other than the hydrogen atom described above.

In said formula (I), R < ¹ >, R < ² > and R < ³ > are respectively independently a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, and C2-C6. An alkenyl group, an alkynyl group having 2 to 6 carbon atoms, an alkylene group having 2 to 6 carbon atoms, an aryl group, a heteroaryl group, a nitro group, an alkylcarbonylamino group having an alkyl group having 1 to 6 carbon atoms, 1 carbon atom Represents a fluoroalkyl group of ˜6. In the formula (I), R ¹ , R ² and R ³ are, for example, an amino group, a mono- or dialkylamino group having 1 to 3 carbon atoms, an alkylcarbonylamino group having 1 to 3 carbon atoms, or a benzoylamino group. , Azide group, carboxyl group, alkylcarbonyl group having 1 to 3 carbon atoms, alkoxycarbonyl group having 1 to 3 carbon atoms, carbamoyl group, naphthyl group, styryl group, alkylthio group having 1 to 3 carbon atoms, 1 to 6 carbon atoms It may be a hydroxyalkyl group.

In the formula (I), R ¹ , R ² and R ³ may be further substituted with a substituent as described above. The substituent is not particularly limited, and examples thereof include a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and an alkynyl group having 2 to 6 carbon atoms. , An alkylene group having 2 to 6 carbon atoms, an aryl group, a heteroaryl group, a nitro group, an alkylcarbonylamino group having an alkyl group having 1 to 6 carbon atoms, a fluoroalkyl group having 1 to 6 carbon atoms, an amino group, and a carbon number 1 to 3 mono or dialkylamino groups, 1 to 3 alkylcarbonylamino groups, benzoylamino groups, azide groups, carboxyl groups, 1 to 3 alkylcarbonyl groups, and 1 to 3 alkoxycarbonyl groups Carbamoyl group, naphthyl group, styryl group, alkylthio group having 1 to 3 carbon atoms, hydroxyalkyl group having 1 to 6 carbon atoms, and the like. As a specific example, the alkylcarbonyl group may be substituted with a phenyl group.

  When the aryl group or the heteroaryl group further has a substituent, the position of the substituent is not particularly limited. When the aryl group or the heteroaryl group is a six-membered ring, the substituent may be in the ortho position, the meta position, or the para position.

  In the formula (I), the aryl group or the heteroaryl group is preferably a 5-membered ring or a 6-membered ring.

Examples of the aryl group include a six-membered ring group having a structure represented by the following formula (1).
In the formula (1),
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a 1 to 6 fluoroalkyl group, A fluoroalkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, an aminocarbonyl group, a halogen atom, a nitro group, a hydroxyl group, a cyano group, a methanesulfonylamino group, A benzoyl group, an aryl group, a heteroaryl group, or an alkylcarbonylamino group having 1 to 3 carbon atoms which may be substituted with a phenyl group;
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ may be the same or different,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ may each form a ring with adjacent substituents,
The ring formed by the adjacent substituents may include one or more heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, or a sulfur atom.

  Examples of the heteroaryl group include a group having a structure in which at least one carbon atom constituting the six-membered ring in the formula (1) is substituted with a heteroatom. Examples of the hetero atom include a sulfur atom, a nitrogen atom, and an oxygen atom.

In the formula (I), R ² is preferably a hydrophobic functional group, for example. Examples of the hydrophobic functional group include a phenyl group, a naphthyl group, a methoxyphenyl group (also referred to as anisyl group), and the like.

In the formula (I), R ¹ , R ² and R ³ are each independently, for example, a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or 5 carbon atoms. C-10 aryl group, C1-C6 aryl group substituted by C1-C6 alkoxy group, C1-C10 heteroaryl group, nitro group, and alkyl group are C1-C6 An alkylcarbonylamino group or a fluoroalkyl group having 1 to 6 carbon atoms.

In the compound of the present invention, for example, the halogen atom is a bromine atom,
The alkyl group having 1 to 6 carbon atoms is a methyl group;
The alkoxy group having 1 to 6 carbon atoms is a methoxy group;
The aryl group having 5 to 10 carbon atoms is a phenyl group or a naphthyl group;
An aryl group having 5 to 10 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms is a methoxyphenyl group;
The heteroaryl group having 1 to 10 carbon atoms is a furanyl group or a thiophenyl group;
An alkylcarbonylamino group having an alkyl group of 1 to 6 carbon atoms is an acetylamino group,
A C1-C6 fluoroalkyl group is a trifluoromethyl group.

In the compound of the present invention, for example, R ¹ and R ³ are each independently a hydrogen atom,
R ² is a halogen atom, an alkoxy group having 1 to 6 carbon atoms, an aryl group having 5 to 10 carbon atoms, an aryl group having 5 to 10 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms, 10 heteroaryl groups, nitro groups, or fluoroalkyl groups having 1 to 6 carbon atoms.

In the compound of the present invention, for example, R ² and R ³ are each independently a hydrogen atom,
R ¹ is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group having 5 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Of the fluoroalkyl group.

In the compound of the present invention, for example, any one of R ¹ , R ² and R ³ is the aryl group, the substituted aryl group, the heteroaryl group, or the substituted heteroaryl group.

In the compound of the present invention, for example, R ¹ and R ³ are hydrogen, and R ² is the aryl group, the substituted aryl group, the heteroaryl group, or the substituted heteroaryl group. In the compound of the present invention, for example, R ¹ and R ² are hydrogen, and R ³ is the aryl group, the substituted aryl group, the heteroaryl group, or the substituted heteroaryl group. is there.

  In the compound of the present invention, for example, in the substituted aryl group, the substituent is an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, a hydroxyl group, or a nitro group.

  In the compound of the present invention, for example, the substituent is a methoxy group, a methoxycarbonyl group, a hydroxyl group, or a nitro group.

  In the compound of the present invention, for example, the substituted aryl group is a 3,4-methylenedioxyphenyl group or a naphthyl group.

  In the compound of the present invention, for example, the heteroaryl group is a pyridinyl group.

  In the compound of the present invention, for example, the heteroaryl group is a furanyl group, a thiophenyl group, an imidazolyl group, or a 1,2,3-triazolyl group.

In the compound of the present invention, for example, in the formula (I), X ¹ is a thiol group, a hydroxyl group, or an amino group (—NH ₂ ), and X ² is a nitrogen atom (—NH—). As a specific example, in the formula (I), for example, X ¹ is more preferably a thiol group, and X ² is more preferably a nitrogen atom (—NH—).

The compound of the present invention may not have R ⁴ in the formula (I). In this case, the ring having R ⁴ is, for example, a five-membered ring.

In the formula (I), R ⁴ is preferably, for example, an alkylene group having 1 to 6 carbon atoms. Examples of the alkylene include a methylene group (—CH ₂ —), an ethylene group (—CH ₂ —CH ₂ —), and an ethylidene group (CH—CH ₃ ). When R ⁴ is a methylene group, the ring having R ⁴ is, for example, a six-membered ring, and when R ⁴ is an ethylene group, the ring having R ⁴ is, for example, a seven-membered ring.

In the formula (I), R ⁴ may be further substituted with a substituent, for example, and examples of the substituent include the substituents as described above.

The substituent of R ⁴ may be crosslinked with an adjacent substituent. When the ring having R ⁴ in the formula (I) is a tetrahydropyrimidine ring, the substituent at R ^{4 at} the 5-position and the substituent at the 4-position or 6-position of the tetrahydropyrimidine ring may be bridged.

In the formula (I), R ⁴ may be a group having a structure represented by the following formula (2) or (3), for example.
In the formula (2),
R ⁶ represents an alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzoyl group,
R ⁶ may be further substituted with a substituent,
The substituent is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, or an alkyl having 1 to 3 carbon atoms. A sulfonyl group or halogen,
In the formula (3),
Y represents a methylene group or an oxygen atom,
Y may be further substituted with a substituent,
The substituent is an alkyl group having 1 to 6 carbon atoms or a halogen atom.

Specific examples of the ring having R ⁴ in the formula (I) are shown in Table 1 below, but the present invention is not limited to these examples.

  Specific examples of the compound represented by the formula (I) are shown in Table 2 below. Note that the present invention is not limited to these examples.

In the case of Table 2, R ⁴ is, for example, a methylene group (—CH ₂ —). The compounds in Table 2 are specific examples of the compound of the formula (I). In the formula (I), the groups of R ¹ , R ² and R ³ are not particularly limited, and for example, the following table The group shown to 3-6 may be sufficient.

In addition, as described above, the compound of the present invention may be a compound in which X ¹ and X ² are cross-linked in the formula (I), and the compound is represented by the following formula (II), for example.
In the formula (II),
R ¹ , R ² , and R ³ each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a carbon number An alkynyl group having 2 to 6 carbon atoms, an alkylene group having 2 to 6 carbon atoms, an aryl group, a heteroaryl group, a nitro group, an alkylcarbonylamino group having an alkyl group of 1 to 6 carbon atoms, and a fluoroalkyl group having 1 to 6 carbon atoms , Amino group, mono- or dialkylamino group having 1 to 3 carbon atoms, benzoylamino group, azide group, carboxyl group, alkylcarbonyl group having 1 to 3 carbon atoms, alkoxycarbonyl group having 1 to 3 carbon atoms, carbamoyl group, naphthyl A group, a styryl group, an alkylthio group having 1 to 3 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms,
R ¹ , R ² , and R ³ may be further substituted with a substituent,
R ¹ , R ² , and R ³ may be the same or different,
R ¹ and R ² , or R ² and R ³ may be bridged,
The bridge formed by the adjacent substituents may include one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom,
R ⁴ represents a linear alkylene group having 1 to 5 carbon atoms or a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom,
R ⁴ may be further substituted with a substituent,
When R ⁴ is the alkylene group, the substituents on the alkylene group may be bonded to each other to form a crosslinked structure or a ring structure;
The isothiazole ring may be opened by cleavage of the nitrogen-sulfur bond,
When the isothiazole ring is opened, the nitrogen atom derived from the nitrogen-sulfur bond may be substituted with an oxygen atom or a sulfur atom, and the sulfur atom derived from the nitrogen-sulfur bond is an oxygen atom or a nitrogen atom. May be substituted.

In the formula (II), R ¹ , R ² , R ³ and R ⁴ are the same as those in the formula (I), and the above description can be used. In the formula (II), the five-membered isothiazole ring containing a sulfur atom and a nitrogen atom may be opened by breaking a nitrogen-sulfur bond. When the isothiazole ring is opened, a nitrogen atom derived from the nitrogen-sulfur bond may be substituted with an oxygen atom or a sulfur atom, and a sulfur atom derived from the nitrogen-sulfur bond is an oxygen atom or nitrogen. An atom may be substituted.

  Specific examples of the compound represented by the formula (II) are shown in Tables 3 to 6 below. The compound (II) can be used, for example, as a precursor or prodrug for the compound (I). Note that the present invention is not limited to these examples.

In Table 3, the leftmost column is any one group of R ¹ , R ² and R ³ in the formula (II). In this case, the remaining two groups are, for example, a hydrogen atom, R ⁴ is, for example, a methylene group (—CH ₂ —). Then, in Table 3, also shown a specific example of a compound having a group described in column of the left end R ² or R ² and R ^3,. In Table 3, H is a hydrogen atom, OMe is a methoxy group, Ph is a phenyl group, m-anisyl is an m-methoxyphenyl group, Br is a bromine atom, CH ₃ is a methyl group, and NO ₂ is , Nitro group, NHAc represents an acetylamino group (—NH—CO—CH ₃ ), and — (CH═CH) ₂ — represents that R ¹ and R ² , or R ² and R ³ are bridged It shows that a benzene ring is formed (hereinafter the same).

In Table 4, the leftmost column is any one group of R ¹ , R ² and R ³ in the formula (II). In this case, the remaining two groups are, for example, a hydrogen atom, R ⁴ is, for example, a methylene group (—CH ₂ —). In Table 4, specific examples of compounds having the group described in the leftmost column in R ¹ or R ³ are also shown.

In Table 5, the leftmost column is ^one of R ¹ , R ² and R ³ in the formula (II). In this case, the remaining two groups are, for example, a hydrogen atom, R ⁴ is, for example, a methylene group (—CH ₂ —). Then, in Table 5, also shown a specific example of a compound having a group described in column of the left end R ^2.

In Table 6, the leftmost column is ^one of R ¹ , R ² and R ³ in the formula (II). In this case, the remaining two groups are, for example, a hydrogen atom, R ⁴ is, for example, a methylene group (—CH ₂ —). In Table 6, specific examples of compounds having the group described in the leftmost column in R ² are also shown.

  In the present invention, examples of the salt of the compound of the formula (I) include a salt in a basic group such as a commonly known amino group or a salt in an acidic group such as a phenolic hydroxyl group or a carboxyl group. it can. The same applies to the salt of the compound of the formula (II).

  Examples of the salt in the basic group 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 Etc.

  Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N- Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And salt. Among the salts described above, preferable salts include, for example, pharmacologically acceptable salts.

  The compound of the present invention includes, for example, an isomer (for example, an optical isomer, a geometric isomer, a tautomer, etc.), a hydrate, a solvation in the compound represented by the formula (I) or a salt thereof. And all crystalline forms. The same applies to the salt of the compound of the formula (II).

  The compounds of the present invention (including salts thereof) exhibit activity against, for example, RNA viruses, human immunodeficiency virus (HIV) and influenza virus, and DNA virus, human herpesvirus. For this reason, it is speculated that the compound of the present invention may inhibit a common site in the infection process of these viruses. In addition, it is speculated that the compound of the present invention may exhibit antiviral activity not only on these viruses but also on various viruses such as human hepatitis C virus (HCV). Many of the conventional antiviral agents target viral proteins, but the compounds of the present invention are effective against various viruses, and thus may act on host cells. It can also be expected to prevent infection.

  Viruses that can inhibit infection with the compounds of the present invention include, for example, human immunodeficiency virus (HIV) (for example, type 1 HIV and type 2 HIV), RNA viruses such as influenza virus, and DNA viruses such as herpes virus. Examples of the herpes virus include human herpes virus. Human herpesviruses include, for example, herpes simplex virus (HSV), and specific examples include herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). For this reason, the compound of this invention can be used as a viral infection inhibitor, for example.

  Moreover, since the compound of this invention can inhibit the infection of the above viruses, it can be used for the treatment of the said DNA virus infection and the said RNA virus infection, for example. In the present invention, treatment includes, for example, prevention.

  The compound of the present invention and a salt thereof can be synthesized, for example, by a known method or an appropriate combination thereof. As specific examples, the following documents can be referred to.

(1) Mizuhara, T .; Oishi, S .; Fujii, N .; Ohno, HJ Org. Chem. 2010, 75, 265-268.
(2) Mizuhara, T .; Oishi, S .; Ohno, H .; Shimura, K .; Matsuoka, M .; Fujii, N. Org. Biomol. Chem. 2012, 10, 6792-6802.
(3) Mizuhara, T .; Oishi, S .; Ohno, H .; Shimura, K .; Matsuoka, M .; Fujii, N. Bioorg. Med. Chem. 2012, 20, 6434-6441.
(4) Woods, PA; Morrill, LC; Lebl, T .; Slawin, AMZ; Bragg, RA; Smith, AD Org. Lett. 2010, 12, 2660-2663.
(5) Chen, D .; Wu, J .; Yang, J .; Huang, L .; Xiang, Y .; Bao, W. Tetrahedron Lett. 2012, 53, 7104-7107.

(2) Viral infection inhibitor As described above, the viral infection inhibitor of the present invention comprises the compound of the present invention or a salt thereof. The virus infection inhibitor of the present invention is characterized by containing the compound of the present invention (or a salt thereof), and other configurations are not limited at all. The description of the compound of the present invention or a salt thereof can be used for the virus infection inhibitor of the present invention, and in the above description, “compound or salt thereof” can be read as “virus infection inhibitor”.

  The viral infection inhibitor of the present invention may contain, for example, other components in addition to the compound of the present invention. The other components are not particularly limited. For example, excipients, binders, disintegrants, disintegration inhibitors, caking / adhesion preventing agents, lubricants, absorption / adsorption carriers, solvents, extenders, isotonic agents. Agent, solubilizer, emulsifier, suspending agent, thickener, coating agent, absorption accelerator, gelation / coagulation accelerator, light stabilizer, preservative, moisture-proofing agent, emulsification / suspension / dispersion stability Agents, coloring inhibitors, deoxygenation / antioxidants, flavoring / flavoring agents, coloring agents, foaming agents, antifoaming agents, soothing agents, antistatic agents, buffer / pH adjusting agents, and the like. The component is preferably, for example, a pharmaceutically acceptable component, and specifically, preferably a pharmaceutical additive. The virus infection inhibitor of the present invention is, for example, an oral preparation (tablet, capsule, powder, granule, fine granule, pill, suspension, and the like, in addition to the compound of the present invention. Preparations, emulsions, solutions, syrups, etc.), injections, eye drops and the like.

  The said formulation can be formulated by a normal method, for example.

  Oral solid preparations such as tablets, powders, granules and the like include, for example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, anhydrous dicalcium phosphate, partial alpha Excipients such as modified starch, corn starch and alginic acid; simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, sodium alginate, gum arabic, hydroxypropyl Binders such as methylcellulose, hydroxypropylcellulose, water and ethanol; dry starch, alginic acid, agar powder, starch, crosslinked polyvinylpyrrolidone, crosslinked carboxymethyl Disintegrants such as sodium cellulose, calcium carboxymethylcellulose and sodium starch glycolate; disintegrators such as stearyl alcohol, stearic acid, cocoa butter and hydrogenated oil; aluminum silicate, calcium hydrogen phosphate, magnesium oxide, talc, anhydrous silica Anti-caking and adhesion preventive agents such as acids; carnauba wax, light anhydrous silicic acid, aluminum silicate, magnesium silicate, hardened oil, hardened vegetable oil derivative, sesame oil, white beeswax, titanium oxide, dry aluminum hydroxide gel, stearic acid, Lubricants such as calcium stearate, magnesium stearate, talc, calcium hydrogen phosphate, sodium lauryl sulfate and polyethylene glycol; quaternary ammonium salts, sodium lauryl sulfate, urea and enzymes Absorption promoters; starches, lactose, kaolin, bentonite, silicic acid anhydride, hydrated silicon dioxide, absorption-adsorption carrier such as magnesium aluminometasilicate and colloidal silicic acid. The oral solid preparation can be prepared, for example, according to a conventional method using these pharmaceutical additives for solid preparation.

  The tablet can be, for example, a tablet with a normal coating, such as a sugar-coated tablet, a gelatin-encapsulated tablet, a gastric-coated tablet, an enteric-coated tablet, and a water-soluble film-coated tablet, if necessary.

  Capsules can be prepared, for example, by mixing the compound of the present invention with the other various components described above and filling hard gelatin capsules, soft capsules, and the like.

  Moreover, the said formulation can use the said components, such as a solvent, a filler, an isotonizing agent, a solubilizing agent, an emulsifier, a suspending agent, a thickener, for example. By using these additives for liquid formulation and preparing according to conventional methods, for example, liquid formulations such as aqueous or oily suspensions, solutions, syrups and elixirs can be obtained.

  Examples of the injection include diluents such as water, ethyl alcohol, macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide; sodium citrate, sodium acetate and phosphoric acid PH adjusters and buffers such as sodium; stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid and thiolactic acid; isotonic agents such as sodium chloride, glucose, mannitol or glycerin; sodium carboxymethylcellulose, propylene glycol Solubilizing agents such as sodium benzoate, benzyl benzoate, urethane, ethanolamine, glycerin; soothing agents such as calcium gluconate, chlorobutanol, glucose, benzyl alcohol; and ingredients such as local anesthetics That. The injection can be prepared according to a conventional method using these pharmaceutical additives for liquid preparation.

  Eye drops include, for example, preservatives such as chlorobutanol, sodium dehydroacetate, benzalkonium chloride, cetylpyridinium chloride, phenethyl alcohol, methyl paraoxybenzoate and benzethonium chloride; borax, boric acid, potassium dihydrogen phosphate, etc. Thickeners such as methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, sodium carboxymethylcellulose and chondroitin sulfate; solubilizers such as polysorbate 80 and polyoxyethylene hydrogenated castor oil 60; sodium edetate And stabilizers such as sodium bisulfite; and isotonic agents such as sodium chloride, potassium chloride and glycerin. The eye drop can be prepared according to a conventional method by appropriately blending these components.

  The administration method of the preparation is not particularly limited, and can be appropriately determined according to, for example, the form of the preparation, the patient's age, sex and other conditions, and the degree of symptoms of the patient.

  The dosage of the viral infection inhibitor of the present invention can be determined, for example, as the dosage of the compound of the present invention, which is an active ingredient. Specifically, the dosage, patient age, sex, disease form, other conditions, etc. It can be set appropriately according to. As a specific example, for example, usually 0.1 to 500 mg of the compound of the present invention per day may be divided and administered in one to several times, and preferably 40 to 40 mg per day. 500 mg may be divided into 1 to several doses.

(3) Pharmaceutical Product The pharmaceutical product of the present invention includes the compound of the present invention as described above. The pharmaceutical agent of the present invention is characterized by containing the compound of the present invention or a salt thereof, and other configurations are not limited at all. The description of the virus infection inhibitor of the present invention can be used for the drug of the present invention, and in the above description, “virus infection inhibitor” can be read as “medicament”.

  The pharmaceutical product of the present invention is for viral infections, for example. In the pharmaceutical product of the present invention, for example, the virus is at least one virus selected from the group consisting of human immunodeficiency virus (HIV), human herpes virus, and influenza virus.

(4) Production method As described above, the production method of the compound of the present invention or a salt thereof is pyrimidobenzothiazine-6-imine derivative (raw material A) and pyrimidobenzothiazine-6-thione derivative ( An intermediate production step of using at least one derivative of the raw material B) as a synthetic raw material and obtaining a thiophenol derivative from the synthetic raw material as an intermediate, and an oxidation step of oxidizing the intermediate are characterized.

  The said intermediate production | generation process can also be called the ring-opening process of the thiazine ring in the said raw material A and the raw material B, for example. Moreover, the oxidation step of the intermediate can also be referred to as, for example, a step of cyclizing a thiophenol derivative obtained by opening a thiazine ring as a five-membered ring by oxidation.

  In the intermediate production step, when a pyrimidobenzothiazine-6-imine derivative (raw material A) is used, it is preferably subjected to acid decomposition. By the acid decomposition, the thiophenol derivative of the raw material A is obtained as an intermediate.

  The acid decomposition conditions are not particularly limited. For example, it is preferable to use a solvent containing an acidic substance and treat the raw material A in the solvent. The acidic substance is not particularly limited, and examples thereof include trifluoroacetic acid. The solvent is, for example, an organic solvent, an aqueous solvent, or a mixed solvent thereof. As the solvent, for example, the organic solvent is preferable, and examples thereof include ethanol, a mixed solvent of ethanol and chloroform, and the like. Specific examples include use of ethanol or a mixed solvent of ethanol and chloroform containing the trifluoroacetic acid.

  In the intermediate production step, when a pyrimidobenzothiazine-6-thione derivative (raw material B) is used, it is preferably subjected to alkali decomposition. By the alkali decomposition, the thiophenol derivative of the raw material B is obtained as an intermediate.

  The conditions for the alkali decomposition are not particularly limited. For example, it is preferable to use a solvent containing an alkaline substance and treat the raw material B in the solvent. The alkaline substance is not particularly limited, and examples thereof include sodium hydroxide. The solvent is, for example, an organic solvent, an aqueous solvent, or a mixed solvent thereof. Examples of the solvent include an organic solvent or a mixed solvent of an organic solvent and an aqueous solvent. Examples of the organic solvent include methanol. Examples of the mixed solvent include a mixed solvent of methanol and water. . A specific example is the use of a mixed solvent of methanol and water containing sodium hydroxide.

The pyrimidobenzothiazine-6-imine derivative (raw material A) can be represented, for example, by the following formula (III). In Formula ^(III), R 1 ~R ⁴ is the same as ^R 1 to R ⁴ in the formula (I), the both can be incorporated according in the compound or a salt thereof of the present invention.

The pyrimidobenzothiazine-6-thione derivative (raw material B) can be represented, for example, by the following formula (IV). In Formula ^(IV), R 1 ~R ⁴ is the same as ^R 1 to R ⁴ in the formula (I), the both can be incorporated according in the compound or a salt thereof of the present invention.

(5) Treatment method The treatment method of the present invention comprises the step of administering the compound of the present invention to a subject. Since the compound of the present invention has antiviral activity against the RNA virus and DNA virus as described above, it can be used for the treatment of these infectious diseases. In the present invention, the treatment includes, for example, prevention.

  In the administration step, the administration method is not particularly limited, and examples thereof include oral administration and parenteral administration. The above-mentioned description can be used for the administration method, dosage conditions, and the like. The subject is not particularly limited, and examples thereof include humans and non-human animals. Examples of the non-human animals include mice, rats, guinea pigs, rabbits, sheep, pigs, cattle, cats, dogs, monkeys, baboons. And non-human mammals such as chimpanzees.

  EXAMPLES The present invention will be described more specifically with reference to the following examples, but these do not limit the scope of the present invention.

  In addition, in the following description, when “numeral” is described together with “compound” (for example, “compound 2” etc.), these indicate the compound numbers shown in Tables 2 to 6 above, and the compound names in the table above And corresponding.

[Example 1]
Various compounds were prepared according to the following synthesis examples.

¹ H NMR spectra were acquired on a JEOL AL-400 or JEOL ECA-500 spectrometer. The chemical shift is expressed as a relative value δ (ppm) relative to the internal standard tetramethylsilane (Me ₄ Si). ¹³ C NMR spectra were measured with residual solvent signal as internal standard. Accurate mass spectra (HRMS) were acquired with a JMS-HX / HX 110A mass spectrometer or a Shimadzu LC-ESI-IT-TOF-MS instrument. Wakogel C-300E (manufactured by Wako Pure Chemical Industries) was used for flash chromatography. For high performance liquid chromatography (HPLC) analysis, a Cosmosil 5C18-ARII column (4.6 × 250 mm, manufactured by Nacalai Tesque, Inc.) was used. Elution was performed with a linear gradient of acetonitrile containing 0.1% (v / v) trifluoroacetic acid (TFA) at a flow rate of 1 mL / min, and the eluate was detected by UV (254 nm). For preparative HPLC, a Cosmosil 5C18-ARII preparative column (20 × 250 mm, manufactured by Nacalai Tesque) was used. Elution was performed with a linear gradient of acetonitrile containing 0.1% (v / v) trifluoroacetic acid (TFA) at a flow rate of 8 mL / min. The purity of the compound was determined by elemental analysis or HPLC analysis (> 95%). In the following synthesis examples, the above conditions are applied unless otherwise specified.

Synthesis Example 1 Synthesis of 1036J-129 (Compound 2)

3,4-Dihydro-2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 2)
3,4-Dihydro-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (50.0 mg, 0.230 mmol) containing chloroform (2.30 mL) and ethanol (3.43 mL) ) Was added dropwise to a solution consisting of). After stirring at room temperature for 1 hour, the reaction was stopped by adding triethylamine (321 μL, 2.30 mmol). Subsequently, (diacetoxyiodo) benzene (72.6 mg, 0.226 mmol) was added and stirred at room temperature for 30 minutes, and then the mixture was concentrated. This was purified by HPLC to give compound 2 (trifluoroacetate salt) as colorless crystals (48.5 mg, 71%). Physical property values are shown below.
mp 200-202 ° C (from diethyl ether-methanol); IR (neat) cm ^-1 : 3117-3056 (OH), 1662 (C = O), 1630 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.30-2.35 (m, 2H, CH ₂ ), 3.67 (t, J = 5.4 Hz, 2H, CH ₂ ), 4.16 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.63-7.66 (m, 1H, Ar), 7.84-7.87 (m, 1H, Ar), 8.04 (d, J = 8.6 Hz, 1H, Ar), 8.17 (d, J = 8.0 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.7, 39.0, 46.3, 118.3 (q, J = 293.9 Hz), 122.5, 123.0, 125.1, 128.2, 134.7, 143.5, 156.0, 163.0 (q, J = 34.8 Hz); Anal. Calcd for C ₁₂ H ₁₁ F ₃ N ₂ O ₂ S: C, 47.37; H, 3.64; N, 9.21. Found: C, 47.32; H, 3.80; N, 9.29.

Synthesis Example 2 Synthesis of 1059B-184 (Compound 3)

3,4-Dihydro-8-methoxy-2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (compound 3)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9-methoxy-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 48) (supra (2 )) (52.0 mg, 0.182 mmol) gave compound 3 (trifluoroacetate) as a colorless solid (45.3 mg, 76%). Physical property values are shown below.
IR (neat) cm ^-1 : 3137-2942 (OH), 1666 (C = O), 1627 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.27-2.32 (m, 2H, CH ₂ ), 3.63 (t, J = 5.7 Hz, 2H, CH ₂ ), 3.94 (s, 3H, CH ₃ ), 4.09 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.20 (dd, J = 9.2, 2.3 Hz, 1H, Ar), 7.53 (d, J = 2.3 Hz, 1H, Ar), 8.02 (d, J = 9.2 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.8, 38.9, 46.1, 56.7, 104.4, 115.8, 117.7 (q, J = 290.3 Hz), 118.1, 126.3, 146.1, 155.4, 161.9 (q, J = 37.2 Hz), 165.5; HRMS (ESI): m / z calcd for C ₁₁ H ₁₃ N ₂ OS [M + H] ⁺ 221.0749; found: 221.0753.

Synthesis Example 3 Synthesis of 1059B-179 (Compound 4)

3,4-Dihydro-8-phenyl-2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (compound 4)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9-phenyl-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 49) (supra (2 )) (50.0 mg, 0.170 mmol) gave compound 4 (trifluoroacetate) as a pale yellow solid (46.1 mg, 73%). Physical property values are shown below.
IR (neat) cm ^-1 : 3125-3004 (OH), 1667 (C = O), 1625 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.32-2.36 (m, 2H, CH ₂ ), 3.69 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.17 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.47 (tt, J = 7.4, 1.6 Hz, 1H, Ar), 7.51-7.55 (m, 2H, Ar), 7.74-7.76 (m, 2H, Ar), 7.92 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 8.22 (d, J = 8.6 Hz, 1H, Ar ), 8.28 (d, J = 1.1 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.7, 39.0, 46.3, 118.1 (q, J = 289.1 Hz), 120.2, 121.8, 125.5 , 127.4, 128.5 (2C), 130.2, 130.3 (2C), 140.1, 144.3, 147.8, 155.7, 162.5 (q, J = 40.8 Hz); HRMS (FAB): m / z calcd for C ₁₆ H ₁₅ N ₂ S [M + H] ⁺ 267.0956; found: 267.0962.

Synthesis Example 4 Synthesis of 1036J-152 (Compound 5)

3,4-Dihydro-8- (3-methoxyphenyl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 5)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9- (3-methoxyphenyl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 50) (Refer to said literature (3)) (0.889 g, 2.75 mmol) gave compound 5 (trifluoroacetate) as colorless crystals (1.38 g, 73%). Physical property values are shown below.
mp 190-192 ° C (from diethyl ether-methanol); IR (neat) cm ^-1 : 3087-2884 (OH), 1687 (C = O), 1626 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.31-2.36 (m, 2H, CH ₂ ), 3.68 (t, J = 5.4 Hz, 2H, CH ₂ ), 3.88 (s, 3H, CH ₃ ), 4.16 (t, J = 5.7 Hz , 2H, CH ₂ ), 7.03-7.06 (m, 1H, Ar), 7.26 (dd, J = 2.0, 2.0 Hz, 1H, Ar), 7.30-7.32 (m, 1H, Ar), 7.44 (dd, J = 8.0, 8.0 Hz, 1H, Ar), 7.91 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 8.21 (d, J = 8.6 Hz, 1H, Ar), 8.27 (d, J = 1.1 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.7, 39.0, 46.3, 55.9, 114.2, 115.5, 118.3 (q, J = 293.9 Hz), 120.3, 120.9, 121.9, 125.4, 127.5, 131.4, 141.5, 144.2, 147.8, 155.8, 161.9, 163.0 (q, J = 34.8 Hz); Anal.calcd for C ₁₉ H ₁₇ F ₃ N ₂ O ₃ S: C, 55.60; H, 4.18; N, 6.83. Found: C, 55.46; H, 4.18; N, 6.80.

Synthesis Example 5 Synthesis of 1059B-4 (Compound 7)

2- (4-Bromo-2-mercaptophenyl) -1,4,5,6-tetrahydropyrimidine (Compound 6)
9-bromo-3,4-dihydro-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (compound 51) (see reference (2) above) (100 mg, 0.338 mmol ) -Containing chloroform (3.38 mL) and ethanol (5.04 mL) were reacted with trifluoroacetic acid (251 μL, 3.38 mmol) for 1 hour. After stirring at room temperature for 1 hour, the reaction was quenched with triethylamine (471 μL, 3.38 mmol). After concentration, purification by flash chromatography on aluminum oxide (chloroform-methanol (100: 0 to 95: 5)) gave compound 6 as colorless crystals (81.4 mg, 89%). Physical property values are shown below.
mp> 300 ° C (from chloroform-methanol); IR (neat) cm ^-1 : 2944-2847 (SH), 1633 (C = N); ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 1.88-1.92 (m, 2H, CH ₂ ), 3.46 (t, J = 5.7 Hz, 4H, CH ₂ ), 6.90 (dd, J = 8.9, 2.0 Hz, 1H, Ar), 7.39 (d, J = 8.6 Hz, 1H , Ar), 7.55 (d, J = 2.3 Hz, 1H, Ar), 11.32 (br s, 2H); ¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 17.9, 38.0 (2C), 120.8, 122.3 , 123.4, 128.6, 139.5, 159.0, 164.0; HRMS (FAB): m / z calcd for C ₁₀ H ₁₂ BrN ₂ S [M + H] ⁺ 270.9905; found: 270.9895.

8-Bromo-3,4-dihydro-2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 7)
A solution of compound 6 (40.0 mg, 0.184 mmol) in chloroform (3.69 mL) was reacted with (diacetoxyiodo) benzene (46.6 mg, 0.181 mmol). The mixture was stirred at room temperature for 30 minutes and then concentrated. Further purification by HPLC gave compound 7 (trifluoroacetate salt) as a white solid (32.7 mg, 47%). Physical property values are shown below.
IR (neat) cm ^-1 : 3093-2977 (OH), 1663 (C = O), 1630 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.28-2.33 (m, 2H, CH ₂ ), 3.65 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.13 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.80 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 8.04 (d, J = 8.6 Hz, 1H, Ar), 8.28 (d, J = 1.7 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.5, 39.0, 46.2, 117.4 (q , J = 271.1 Hz), 122.1, 125.5, 126.4, 129.3, 131.6, 145.1, 155.6, 163.0 (q, J = 30.0 Hz); HRMS (FAB): m / z calcd for C ₁₀ H ₁₀ BrN ₂ S (M + H] ⁺ 268.9748; found: 268.9747.

Synthesis Example 6 Synthesis of 1059B-186 (Compound 8)

3,4-Dihydro-8-trifluoromethyl-2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 8)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9-trifluoromethyl-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 52) (See (2)) (57.8 mg, 0.202 mmol) gave compound 8 (trifluoroacetate) as a white solid (54.9 mg, 75%). Physical property values are shown below.
IR (neat) cm ^-1 : 3273-3170 (OH), 1666 (C = O), 1635 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.31-2.36 (m, 2H, CH ₂ ), 3.69 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.19 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.92 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 8.35 (d, J = 8.6 Hz, 1H, Ar), 8.46 (d, J = 1.1 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.4, 39.1, 46.5, 117.5 (q , J = 289.1 Hz), 120.5 (d, J = 3.6 Hz), 124.6, 124.8 (q, J = 272.3 Hz), 125.9, 126.5, 135.7 (q, J = 33.6 Hz), 144.2, 155.5, 161.6 (q , J = 38.4 Hz); HRMS (FAB): m / z calcd for C ₁₁ H ₁₀ F ₃ N ₂ S [M + H] ⁺ 259.0517; found: 259.0515.

Synthesis Example 7 Synthesis of 1059B-173 (Compound 9)

3,4-Dihydro-8-nitro-2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 9)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9-nitro-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 53) )) (50.0 mg, 0.191 mmol) gave compound 9 (trifluoroacetate) as a yellow solid (64.0 mg, 98%). Physical property values are shown below.
IR (neat) cm ^-1 : 3137-3036 (OH), 1663 (C = O), 1638 (C = N), 1556 (NO ₂ ), 1525 (NO ₂ ); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.31-2.36 (m, 2H, CH ₂ ), 3.70 (t, J = 5.4 Hz, 2H, CH ₂ ), 4.21 (t, J = 5.7 Hz, 2H, CH ₂ ), 8.36 (d, J = 8.6 Hz, 1H, Ar), 8.43 (dd, J = 8.9, 2.0 Hz, 1H, Ar), 8.99 (d, J = 1.7 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD ): δ 20.3, 39.1, 46.7, 117.8 (q, J = 284.3 Hz), 118.9, 122.5, 126.8, 127.1, 144.5, 151.8, 155.2, 162.0 (q, J = 36.0 Hz); HRMS (FAB): m / z calcd for C ₁₀ H ₁₀ N ₃ O ₂ S [M + H] ⁺ 236.0494; found: 236.0494.

Synthesis Example 8 Synthesis of 1036J-154 (Compound 10)

8- (N-acetylamino) -3,4-dihydro-2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 10)
In the same manner as in Synthesis Example 1, 9- (N-acetylamino) -3,4-dihydro-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 54) (Refer to the above literature (2)) (21.3 mg, 0.0776 mmol) gave compound 10 (trifluoroacetate) as a pale yellow solid (19.4 mg, 69%). Physical property values are shown below.
IR (neat) cm ^-1 : 3173-2948 (OH), 1669 (C = O), 1621 (C = N); ¹ H NMR (400 MHz, CD ₃ OD): δ 2.19 (s, 3H, CH ₃ ), 2.27-2.33 (m, 2H, CH ₂ ), 3.64 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.10 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.60 (dd, J = 9.2, 1.4 Hz, 1H, Ar), 8.05 (d, J = 9.2 Hz, 1H, Ar), 8.53 (d, J = 1.4 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.8, 24.2, 38.9, 46.1, 111.0, 117.9, 118.3 (q, J = 296.3 Hz), 120.0, 125.6, 144.98, 145.01, 155.4, 163.0 (q, J = 32.4 Hz), 172.2; HRMS (FAB): m / z calcd for C ₁₂ H ₁₄ N ₃ OS [M + H] ⁺ 248.0858; found: 248.0862.

Synthesis Example 9 Synthesis of 1059B-189 (Compound 11)

3,4-Dihydro-9-methoxy-2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 11)
In the same manner as in Synthesis Example 1, 3,4-dihydro-10-methoxy-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 55) (supra (2 )) (57.4 mg, 0.232 mmol) gave compound 11 (trifluoroacetate) as a white solid (43.4 mg, 57%). Physical property values are shown below.
IR (neat) cm ^-1 : 3102-3018 (OH), 1688 (C = O), 1635 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.29-2.34 (m, 2H, CH ₂ ), 3.67 (t, J = 5.7 Hz, 2H, CH ₂ ), 3.92 (s, 3H, CH ₃ ), 4.14 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.48 (dd, J = 8.9, 2.6 Hz, 1H, Ar), 7.70 (d, J = 2.3 Hz, 1H, Ar), 7.90 (d, J = 8.6 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.8, 38.9, 46.4, 56.4, 106.2, 118.3 (q, J = 290.3 Hz), 123.5, 123.7, 125.0, 135.5, 155.6, 160.8, 163.0 (q, J = 37.2 Hz); HRMS (ESI): m / z calcd for C ₁₁ H ₁₃ N ₂ OS [M + H] ⁺ 221.0749; found: 221.0753.

Synthesis Example 10 Synthesis of 1059B-185 (Compound 12)

3,4-Dihydro-9-phenyl-2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 12)
In the same manner as in Synthesis Example 1, 3,4-dihydro-10-phenyl-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 56) (Reference (2) above) (18.5 mg, 0.0631 mmol) gave compound 12 (trifluoroacetate) as a white solid (16.0 mg, 68%). Physical property values are shown below.
IR (neat) cm ^-1 : 3147-3014 (OH), 1686 (C = O), 1638 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.32-2.37 (m, 2H, CH ₂ ), 3.70 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.18 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.44 (tt, J = 7.2, 1.6 Hz, 1H, Ar), 7.50-7.54 (m, 2H, Ar), 7.71-7.74 (m, 2H, Ar), 8.10 (d, J = 8.6 Hz, 1H, Ar), 8.15 (dd, J = 8.6, 1.7 Hz, 1H, Ar ), 8.45 (d, J = 1.7 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.5, 38.8, 46.1, 118.3 (q, J = 298.7 Hz), 122.6, 122.8, 123.4 , 127.8 (2C), 129.4, 130.2 (2C), 133.0, 139.4, 141.0, 141.9, 155.6, 162.8 (q, J = 35.6 Hz); HRMS (FAB): m / z calcd for C ₁₆ H ₁₅ N ₂ S [M + H] ⁺ 267.0956; found: 267.0956.

Synthesis Example 11 Synthesis of 1059B-163 (Compound 14)

3,4-Dihydro-10-methyl-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-thione (compound 13)
2- (2-fluoro-5-methylphenyl) -1,4,5,6-tetrahydropyrimidine (compound 57) (see reference (2) above) (578 mg, 3.00 mmol) and sodium hydride under argon atmosphere (240 mg, 6.00 mmol; 60% oil suspension) was mixed in N, N-dimethylformamide (10.0 mL) and carbon disulfide (361 μL, 6.00 mmol) was added. After stirring at 80 ° C. for 18 hours, the mixture was concentrated. This was purified by flash chromatography on silica gel (n-hexane-ethyl acetate (10: 0 to 10: 1)) to give compound 13 as yellow crystals (286 mg, 38%). Physical property values are shown below.
mp 131-132 ° C (from n-hexane-chloroform); IR (neat) cm ^-1 : 1592 (C = N); ¹ H NMR (500 MHz, CDCl ₃ ): δ 2.02-2.07 (m, 2H, CH ₂ ), 2.37 (s, 3H, CH ₃ ), 3.76 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.45 (t, J = 6.3 Hz, 2H, CH ₂ ), 6.94 (d, J = 8.0 Hz, 1H, Ar), 7.24 (dd, J = 8.0, 1.7 Hz, 1H, Ar), 8.02 (s, 1H, Ar); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 21.2, 21.6, 45.5, 48.7, 121.6, 126.1, 128.6, 128.9, 132.2, 137.7, 144.5, 190.0; Anal.calcd for C ₁₂ H ₁₂ N ₂ S ₂ : C, 58.03; H, 4.87; N, 11.28. Found: C, 58.16; H , 5.05; N, 11.17.

3,4-Dihydro-9-methyl-2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 14)
Compound 13 (60.0 mg, 0.242 mmol) was suspended in a methanol-H ₂ O (9: 1, 4.83 mL) solution containing 0.1 N sodium hydroxide. The mixture was stirred for 12 hours while refluxing, and then the reaction was stopped by adding 1N hydrochloric acid to pH 7. This was extracted with chloroform-methanol (95: 5) and dried over magnesium sulfate. After concentration, it was reacted with (diacetoxyiodo) benzene (76.3 mg, 0.237 mmol) in a chloroform (6.04 mL) solution. After stirring at room temperature for 30 minutes, the mixture was concentrated. Purification by HPLC gave Compound 14 (trifluoroacetate salt) as a white solid (4.5 mg, 6%). Physical property values are shown below.
IR (neat) cm ^-1 : 3265-3141 (OH), 1669 (C = O), 1630 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.29-2.34 (m, 2H, CH ₂ ), 2.53 (s, 3H, CH ₃ ), 3.66 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.14 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.71 (dd, J = 8.3, 1.4 Hz, 1H, Ar), 7.91 (d, J = 8.6 Hz, 1H, Ar), 7.96 (d, J = 1.7 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.7, 21.1, 38.9, 46.3, 118.6 (q, J = 255.5 Hz), 122.1, 123.0, 124.6, 136.2, 139.0, 140.6, 155.7, 162.7 (q, J = 33.6 Hz); HRMS (FAB): m / z calcd for C ₁₁ H ₁₃ N ₂ S [M + H] ⁺ 205.0799; found: 205.0795.

Synthesis Example 12 Synthesis of 1059B-195 (Compound 15)

9-Bromo-3,4-dihydro-2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 15)
10-Bromo-3,4-dihydro-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 58) by the same method as in Synthesis Example 1 (Reference (2)) (50.0 mg, 0.169 mmol) gave compound 15 (trifluoroacetate salt) as a white solid (45.9 mg, 72%). Physical property values are shown below.
IR (neat) cm ^-1 : 3137-3014 (OH), 1663 (C = O), 1631 (C = N); ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 2.15-2.20 (m, 2H , CH ₂ ), 3.56 (br s, 2H, CH ₂ ), 4.11 (br s, 2H, CH ₂ ), 8.02 (dd, J = 8.9, 2.0 Hz, 1H, Ar), 8.16 (d, J = 9.2 Hz, 1H, Ar), 8.58 (d, J = 1.7 Hz, 1H, Ar), 10.43 (s, 1H, NH); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.5, 39.0, 46.4, 118.3 (q, J = 297.5 Hz), 121.5, 124.4, 124.6, 127.9, 137.4, 142.5, 155.0, 163.0 (q, J = 31.2 Hz); HRMS (FAB): m / z calcd for C ₁₀ H ₁₀ BrN ₂ S [M + H] ⁺ 268.9748; found: 268.9755.

Synthesis Example 13 Synthesis of 1059B-164 (Compound 18)

2- (2-Fluoro-5-trifluoromethylphenyl) -1,4,5,6-tetrahydropyrimidine (Compound 16)
Propylenediamine (1.25 mL, 15.0 mmol) was added to a solution of 2-fluoro-5-trifluoromethylbenzaldehyde (1.36 mL, 10.0 mmol) in t-butyl alcohol (94.3 mL). After the mixture was stirred at 70 ° C. for 30 minutes, potassium carbonate (4.15 g, 30.0 mmol) and iodine (3.17 g, 12.5 mmol) were added. After stirring at 70 ° C. for 3 hours, the reaction was stopped by adding saturated sodium sulfite to the mixture until most of the iodine color disappeared. The reaction mixture was concentrated, and the resulting solid was dissolved in water, and the pH was adjusted to 12-14 with 2N sodium hydroxide. Extracted with chloroform and dried over magnesium sulfate. After concentration, this was purified by flash chromatography with aluminum oxide (chloroform-methanol (10: 0 to 10: 1)) to give compound 16 as light yellow crystals (1.56 g, 64%). Physical property values are shown below.
mp 109-111 ° C (from n-hexane-chloroform); IR (neat) cm ^-1 : 3154 (NH), 1631 (C = N); ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.86-1.92 ( m, 2H, CH ₂ ), 3.53 (t, J = 5.8 Hz, 4H, CH ₂ ), 7.17 (dd, J = 11.0, 8.7 Hz, 1H, Ar), 7.59-7.62 (m, 1H, Ar), 8.18 (dd, J = 7.0, 2.3 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 20.5, 42.3 (br, 2C), 116.7 (d, J = 25.2 Hz), 123.5 (q , J = 272.3 Hz), 125.2 (d, J = 13.2 Hz), 127.4-126.6 (m), 127.9-128.0 (m), 128.4-128.6 (m), 150.2, 161.7 (d, J = 253.1 Hz); HRMS (FAB): m / z calcd for C ₁₁ H ₁₁ F ₄ N ₂ [M + H] ⁺ 247.0858; found: 248.0857.

3,4-Dihydro-10-trifluoromethyl-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-thione (Compound 17)
Under an argon atmosphere, carbon disulfide (361 μL, 6.00 mmol) was added to N, N-dimethylformamide (10.0 mL) containing Compound 16 (739 mg, 3.00 mmol) and sodium hydride (240 mg, 6.00 mmol; 60% oil suspension). ) Was added. After stirring at 80 ° C. for 16 hours, the mixture was concentrated. This was purified by flash chromatography on silica gel (n-hexane-ethyl acetate (10: 0 to 4: 1)) to give Compound 17 as yellow crystals (251 mg, 28%). Physical property values are shown below.
mp 151-152 ° C (from n-hexane-chloroform); IR (neat) cm ^-1 : 1627 (C = N); ¹ H NMR (500 MHz, CDCl ₃ ): δ 2.04-2.08 (m, 2H, CH ₂ ), 3.78 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.44 (t, J = 6.3 Hz, 2H, CH ₂ ), 7.15 (d, J = 8.6 Hz, 1H, Ar), 7.63 (dd , J = 8.0, 1.7 Hz, 1H, Ar), 8.51 (d, J = 1.1 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 21.4, 45.5, 48.6, 122.3, 123.5 (q , J = 272.3 Hz), 126.3 (q, J = 4.0 Hz), 126.9, 127.4 (q, J = 3.6 Hz), 129.8 (q, J = 33.6 Hz), 135.9, 143.1, 188.5; Anal.calcd for C ₁₂ H ₉ F ₃ N ₂ S ₂ : C, 47.67; H, 3.00; N, 9.27.Found: C, 47.46; H, 3.06; N, 9.19.

3,4-Dihydro-9-trifluoromethyl-2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 18)
Compound 17 (60.0 mg, 0.198 mmol) was suspended in a methanol-water (9: 1, 3.97 mL) solution containing 0.1N sodium hydroxide. The mixture was stirred for 9.5 hours while refluxing, and then the reaction was stopped by adding 1N hydrochloric acid to pH 7. This was extracted with chloroform-methanol (95: 5) and dried over magnesium sulfate. After concentration, it was reacted with (diacetoxyiodo) benzene (62.6 mg, 0.194 mmol) in a chloroform (4.96 mL) solution. After stirring at room temperature for 30 minutes, the mixture was concentrated. Purification by HPLC gave Compound 18 (trifluoroacetate salt) as a white solid (23.0 mg, 32%). Physical property values are shown below.
IR (neat) cm ^-1 : 3125-3026 (OH), 1666 (C = O), 1624 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.31-2.36 (m, 2H, CH ₂ ), 3.68 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.18 (t, J = 5.7 Hz, 2H, CH ₂ ), 8.11 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 8.27 (d, J = 8.6 Hz, 1H, Ar), 8.59 (d, J = 1.1 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.4, 39.0, 46.4, 118.3 (q , J = 293.9 Hz), 122.9 (q, J = 4.4 Hz), 123.3, 124.1, 125.0 (q, J = 271.5 Hz), 129.9-130.7 (m, 2C), 147.3, 155.8, 162.9 (q, J = Anal.calcd for C ₁₃ H ₁₀ F ₆ N ₂ O ₂ S: C, 41.94; H, 2.71; N, 7.52. Found: C, 41.64; H, 2.80; N, 7.53.

Synthesis Example 14 Synthesis of 1059B-181 (Compound 19)

7-Bromo-3,4-dihydro-2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 19)
In the same manner as in Synthesis Example 1, 8-bromo-3,4-dihydro-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 59) (supra (2 )) (50.0 mg, 0.169 mmol) gave compound 19 (trifluoroacetate) as a white solid (50.9 mg, 80%). Physical property values are shown below.
IR (neat) cm ^-1 : 3096-3026 (OH), 1666 (C = O), 1640 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.32-2.37 (m, 2H, CH ₂ ), 3.68 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.19 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.63 (dd, J = 8.0, 8.0 Hz, 1H, Ar), 8.07 (d, J = 8.6 Hz, 1H, Ar), 8.21 (d, J = 7.4 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.4, 38.9, 46.9, 113.8, 118.3 (q, J = 302.3 Hz), 124.2, 124.7, 130.2, 137.1, 145.1, 157.0, 162.9 (q, J = 34.8 Hz); HRMS (FAB): m / z calcd for C ₁₀ H ₁₀ BrN ₂ S (M + H] ⁺ 268.9748; found: 268.9755.

Synthesis Example 15 Synthesis of 1036J-153 (Compound 20)

9,10-Dihydro-8H-naphtho [2 ', 1': 4,5] isothiazolo [2,3-a] pyrimidine (Compound 20)
In the same manner as in Synthesis Example 1, 3,4-dihydro-2H, 6H-pyrimido [1,2-c] naphtho [2,1-e] [1,3] thiazine-6-imine (Compound 60) ( Compound 20 (trifluoroacetate salt) was obtained as a white solid (66.8 mg, 86%) from (60.0 mg, 0.224 mmol). Physical property values are shown below.
IR (neat) cm ^-1 : 3088-3000 (OH), 1682 (C = O), 1627 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.36-2.40 (m, 2H, CH ₂ ), 3.72 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.28 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.78-7.81 (m, 1H, Ar), 7.85-7.88 (m , 1H, Ar), 8.00-8.04 (m, 2H, Ar), 8.09 (d, J = 8.6 Hz, 1H, Ar), 8.17 (d, J = 8.6 Hz, 1H, Ar); ¹³ C NMR (125 (MHz, CD ₃ OD): δ 20.5, 38.7, 46.5, 118.4 (q, J = 290.3 Hz), 118.8, 119.3, 124.7, 125.3, 129.0, 129.3, 130.0, 131.3, 135.0, 143.2, 155.8, 162.7 (q, J = 32.4 Hz); HRMS (FAB): m / z calcd for C ₁₄ H ₁₃ N ₂ S [M + H] ⁺ 241.0799; found: 241.0797.

Synthesis Example 16 Synthesis of 1059D-33 (Compound 21)

3,4-Dihydro-8- (4-methoxyphenyl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 21)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9- (4-methoxyphenyl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 61) (Refer to said literature (3)) (50.0 mg, 0.155 mmol) gave compound 21 (trifluoroacetate) as a white solid (48.4 mg, 78%). Physical property values are shown below.
IR (neat) cm ^-1 : 3111-2843 (OH), 1687 (C = O), 1625 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.31-2.36 (m, 2H, CH ₂ ), 3.68 (t, J = 5.7 Hz, 2H, CH ₂ ), 3.87 (s, 3H, CH ₃ ), 4.15 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.06-7.09 (m, 2H, Ar), 7.69-7.72 (m, 2H, Ar), 7.88 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 8.17 (d, J = 8.6 Hz, 1H, Ar), 8.22 (d, J = 1.1 Hz, 1H, Ar); ¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 19.1, 37.2, 44.7, 55.3, 114.7 (2C), 117.0 (q, J = 298.7 Hz), 118.6, 120.0 , 124.6, 125.0, 128.5 (2C), 130.4, 142.7, 144.2, 153.6, 158.4 (q, J = 33.6 Hz), 160.1; HRMS (FAB): m / z calcd for C ₁₇ H ₁₇ N ₂ OS [M + H] ⁺ 297.1062; found: 297.1052.

Synthesis Example 17 Synthesis of 1059D-38 (Compound 22)

3,4-Dihydro-8- (4-methoxycarbonylphenyl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 22)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9- (4-methoxycarbonylphenyl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 62 ) (See literature (3)) (50.0 mg, 0.142 mmol) gave compound 22 (trifluoroacetate) as a pale pink solid (35.3 mg, 58%). Physical property values are shown below.
IR (neat) cm ^-1 : 3219-3098 (OH), 1708 (C = O), 1636 (C = O), 1605 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.32 -2.36 (m, 2H, CH ₂ ), 3.69 (t, J = 5.7 Hz, 2H, CH ₂ ), 3.95 (s, 3H, CH ₃ ), 4.18 (t, J = 5.7 Hz, 2H, CH ₂ ) , 7.86-7.89 (m, 2H, Ar), 7.97 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 8.16-8.19 (m, 2H, Ar), 8.25 (d, J = 8.6 Hz, 1H, Ar), 8.34 (d, J = 1.1 Hz, 1H, Ar); ¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 19.1, 37.3, 44.8, 52.3, 116.7 (q, J = 292.7 Hz), 120.3 , 121.4, 124.8, 125.8, 127.6 (2C), 129.7, 130.0 (2C), 142.7, 142.8, 143.2, 153.6, 158.2 (q, J = 33.6 Hz), 165.8; HRMS (FAB): m / z calcd for C ₁₈ H ₁₇ N ₂ O ₂ S [M + H] ⁺ 325.1011; found: 325.1003.

Synthesis Example 18 Synthesis of 1059D-83 (Compound 25)

N- (tert-butyl) -3,4-dihydro-9- [4- (tert-butyldimethylsilyloxy) phenyl] -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6 -Imine (Compound 24)
Under an argon atmosphere, 9-bromo-N- (tert-butyl) -3,4-dihydro-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (compound 23) (above Reference (2)) (200mg, 0.568mmol) and 4- (tert-butyldimethylsilyloxy) phenylboronic acid (172mg, 0.681mmol), toluene (5.68mL), ethanol (3.40mL) and 1mol / To a mixture of L potassium carbonate aqueous solution (5.68 mL), tetrakis (triphenylphosphine) palladium (26.2 mg, 4 mol%) and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex ( 13.9 mg, 3 mol%) was added. This was stirred for 1.5 hours while refluxing, and then the mixture was extracted with chloroform. The extract was dried over magnesium sulfate and concentrated. This was purified by flash chromatography on aluminum oxide (n-hexane-ethyl acetate (10: 1)) to give compound 24 as colorless crystals (247 mg, 91%). Physical property values are shown below.
mp 105-107 ° C (from n-hexane); IR (neat) cm ^-1 : 1596 (C = N); ¹ H NMR (500 MHz, CDCl ₃ ): δ 0.22 (s, 6H, 2 × CH ₃ ) , 1.00 (s, 9H, 3 × CH ₃ ), 1.40 (s, 9H, 3 × CH ₃ ), 1.90-1.95 (m, 2H, CH ₂ ), 3.64 (t, J = 5.7 Hz, 2H, CH ₂ ), 3.89 (t, J = 6.0 Hz, 2H, CH ₂ ), 6.88-6.91 (m, 2H, Ar), 7.29 (d, J = 1.7 Hz, 1H, Ar), 7.39 (dd, J = 8.3, 2.0 Hz, 1H, Ar), 7.45-7.48 (m, 2H, Ar), 8.21 (d, J = 8.0 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CDCl ₃ ): δ -4.4 (2C) , 18.2, 21.9, 25.7 (3C), 30.0 (3C), 45.1, 45.5, 54.2, 120.5 (2C), 122.2, 124.4, 125.9, 128.1 (2C), 128.8, 129.4, 132.4, 138.4, 142.6, 147.9, 156.0 ; HRMS (FAB): m / z calcd for C ₂₇ H ₃₈ N ₃ OSSi [M + H] ⁺ 480.2505; found: 480.2510.

3,4-Dihydro-8- (4-hydroxyphenyl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 25)
To a mixture of a small amount of chloroform containing Compound 24 (112.6 mg, 0.235 mmol) and molecular sieve 4 Å (MS4 Å) (528 mg, powder, activated by heating with a Bunsen burner), trifluoroacetic acid (2.35 mL) was added. added. This was stirred for 4 hours while refluxing, and then triethylamine was added dropwise to the mixture at 0 ° C. to adjust the pH to 8-9. This was extracted with ethyl acetate, and the extract was washed with saturated sodium hydrogen carbonate and saturated brine, and then dried over magnesium sulfate. Concentration gave the crude imine as a pale yellow solid (73.9 mg). In the same manner as in Synthesis Example 1, compound 25 (trifluoroacetate) was obtained as a white solid (11.0 mg, 44% for 2 steps) from a part of the solid (20.0 mg). Physical property values are shown below.
IR (neat) cm ^-1 : 3237-3066 (OH), 1684 (C = O), 1632 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.31-2.35 (m, 2H, CH ₂ ), 3.67 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.15 (t, J = 6.0 Hz, 2H, CH ₂ ), 6.91-6.94 (m, 2H, Ar), 7.60-7.63 (m , 2H, Ar), 7.86 (dd, J = 8.6, 1.1 Hz, 1H, Ar), 8.15 (d, J = 8.6 Hz, 1H, Ar), 8.19 (d, J = 1.7 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.7, 39.0, 46.2, 117.1 (2C), 118.2 (q, J = 238.7 Hz), 119.0, 120.8, 125.3, 126.7, 129.8 (2C), 130.8, 144.3 , 147.7, 155.7, 160.0, 162.9 (q, J = 34.8 Hz); HRMS (ESI): m / z calcd for C ₁₆ H ₁₅ N ₂ OS [M + H] ⁺ 283.0905; found: 283.0908.

Synthesis Example 19 Synthesis of 1059D-35 (Compound 26)

3,4-Dihydro-8- (4-nitrophenyl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 26)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9- (4-nitrophenyl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 63) (Refer to the above literature (3)) (41.8 mg, 0.124 mmol) gave compound 26 (trifluoroacetate) as a pale yellow solid (28.7 mg, 56%). Physical property values are shown below.
IR (neat) cm ^-1 : 3129-3010 (OH), 1684 (C = O), 1632 (C = N), 1596 (NO ₂ ), 1516 (NO ₂ ); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.32-2.37 (m, 2H, CH ₂ ), 3.70 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.19 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.98-8.01 ( m, 3H, Ar), 8.28 (d, J = 8.6 Hz, 1H, Ar), 8.38 (d, J = 1.1 Hz, 1H, Ar), 8.39-8.42 (m, 2H, Ar); ¹³ C NMR ( 125 MHz, DMSO-d ₆ ): δ 19.0, 37.3, 44.9, 117.3 (q, J = 291.5 Hz), 120.7, 121.8, 124.3 (2C), 124.9, 126.0, 128.6 (2C), 142.1, 142.7, 144.7, 147.5, 153.6, 158.1 (q, J = 32.4 Hz); HRMS (FAB): m / z calcd for C ₁₆ H ₁₄ N ₃ O ₂ S [M + H] ⁺ 312.0807; found: 312.0808.

Synthesis Example 20 Synthesis of 1059D-39 (Compound 27)

3,4-Dihydro-8- (3-methoxycarbonylphenyl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 27)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9- (3-methoxycarbonylphenyl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 64 ) (See the literature (3)) (50.0 mg, 0.142 mmol) gave compound 27 (trifluoroacetate salt) as a pale pink solid (32.3 mg, 53%). Physical property values are shown below.
IR (neat) cm ^-1 : 3281-3163 (OH), 1713 (C = O), 1674 (C = O), 1629 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.32 -2.37 (m, 2H, CH ₂ ), 3.70 (t, J = 5.7 Hz, 2H, CH ₂ ), 3.96 (s, 3H, CH ₃ ), 4.18 (t, J = 5.7 Hz, 2H, CH ₂ ) , 7.67 (dd, J = 7.7, 7.7 Hz, 1H, Ar), 7.95 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 7.99-8.01 (m, 1H, Ar), 8.11-8.14 (m, 1H, Ar), 8.26 (d, J = 9.2 Hz, 1H, Ar), 8.33 (d, J = 1.1 Hz, 1H, Ar), 8.38 (dd, J = 1.7, 1.7 Hz, 1H, Ar); ¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 19.1, 37.2, 44.8, 52.4, 116.4 (q, J = 295.1 Hz), 120.1, 121.1, 125.0, 125.6, 127.5, 129.4, 129.9, 130.6, 131.9, 138.8 , 142.8, 143.2, 153.6, 158.4 (q, J = 33.6 Hz), 165.9; HRMS (FAB): m / z calcd for C ₁₈ H ₁₇ N ₂ O ₂ S [M + H] ⁺ 325.1011; found: 325.1009.

Synthesis Example 21 Synthesis of 1059D-109 (Compound 29)

N- (tert-butyl) -3,4-dihydro-9- [3- (tert-butyldimethylsilyloxy) phenyl] -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6 -Imine (Compound 28)
In the same manner as described for Compound 24, Compound 23 (200 mg, 0.568 mmol) and 3- (tert-butyldimethylsilyloxy) phenylboronic acid (172 mg, 0.681 mmol) were reacted for 2 hours. Purification by flash chromatography on aluminum oxide (n-hexane-ethyl acetate (10: 1)) gave compound 28 as colorless crystals (255 mg, 94%). Physical property values are shown below.
mp 97-99 ° C (from n-hexane); IR (neat) cm ^-1 : 1620 (C = N); ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 0.22 (s, 6H, 2 × CH ₃ ), 0.98 (s, 9H, 3 × CH ₃ ), 1.38 (s, 9H, 3 × CH ₃ ), 1.81-1.86 (m, 2H, CH ₂ ), 3.54 (t, J = 5.4 Hz, 2H, CH ₂ ), 3.81 (t, J = 6.0 Hz, 2H, CH ₂ ), 6.89 (ddd, J = 7.4, 2.3, 2.3 Hz, 1H, Ar), 7.16 (dd, J = 1.7, 1.7 Hz, 1H, Ar), 7.32-7.38 (m, 2H, Ar), 7.54 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 7.62 (d, J = 1.7 Hz, 1H, Ar), 8.21 (d, J = 8.6 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CDCl ₃ ): δ -4.4 (2C), 18.2, 21.9, 25.7 (3C), 30.0 (3C), 45.1, 45.4, 54.1, 118.8, 119.6, 120.1, 122.7, 124.8, 126.6, 128.9, 129.4, 129.8, 138.3, 140.9, 142.7, 147.7, 156.1; HRMS (FAB): m / z calcd for C ₂₇ H ₃₈ N ₃ OSSi [M + H] ⁺ 480.2505; found : 480.2513.

3,4-Dihydro-8- (3-hydroxyphenyl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 29)
To a mixture of a small amount of chloroform containing compound 28 (64.2 mg, 0.134 mmol) and MS4Å (402 mg, powder, activated by heating with a Bunsen burner) was added trifluoroacetic acid (2.68 mL). This was stirred for 7.5 hours while refluxing, and then triethylamine was added dropwise to the mixture at 0 ° C. to adjust the pH to 8-9. This was extracted with ethyl acetate, and the extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated. Compound 29 (trifluoroacetate salt) was obtained as a white solid (37.8 mg, 73%) from the residue by the same method as in Synthesis Example 1. Physical property values are shown below.
IR (neat) cm ^-1 : 3114-2996 (OH), 1672 (C = O), 1637 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.31-2.36 (m, 2H, CH ₂ ), 3.68 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.16 (t, J = 5.7 Hz, 2H, CH ₂ ), 6.88-6.90 (m, 1H, Ar), 7.13 (dd, J = 2.1, 2.1 Hz, 1H, Ar), 7.17-7.19 (m, 1H, Ar), 7.33 (dd, J = 8.0, 8.0 Hz, 1H, Ar), 7.86 (dd, J = 8.3, 1.4 Hz, 1H , Ar), 8.19 (d, J = 8.6 Hz, 1H, Ar), 8.23 (d, J = 1.1 Hz, 1H, Ar); ¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 19.1, 37.3, 44.7, 114.0, 116.0, 117.3 (q, J = 299.9 Hz), 117.9, 119.6, 120.6, 124.6, 125.5, 130.3, 139.7, 142.6, 144.8, 153.6, 158.2, 158.6 (q, J = 27.6 Hz); Anal. Calcd for C ₁₈ H ₁₅ F ₃ N ₂ O ₃ S: C, 54.54; H, 3.81; N, 7.07. Found: C, 54.35; H, 3.80; N, 7.14.

Synthesis Example 22 Synthesis of 1059D-36 (Compound 30)

3,4-Dihydro-8- (3-nitrophenyl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 30)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9- (3-nitrophenyl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 65) ( From the literature (3)) (50.0 mg, 0.148 mmol), compound 30 (trifluoroacetate salt) was obtained as a white solid (52.1 mg, 85%). Physical property values are shown below.
IR (neat) cm ^-1 : 3114-2996 (OH), 1685 (C = O), 1627 (C = N), 1603 (NO ₂ ), 1526 (NO ₂ ); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.32-2.37 (m, 2H, CH ₂ ), 3.70 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.19 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.80 (dd, J = 8.0, 8.0 Hz, 1H, Ar), 8.00 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 8.17 (ddd, J = 8.2, 1.4, 1.4 Hz, 1H, Ar), 8.29 (d, J = 8.6 Hz, 1H, Ar), 8.36 (ddd, J = 8.0, 2.3, 1.1 Hz, 1H, Ar), 8.38 (d, J = 1.1 Hz, 1H, Ar), 8.60 (dd, J = 2.0, 2.0 Hz, 1H, Ar); ¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 19.0, 37.3, 44.8, 117.1 (q, J = 293.9 Hz), 120.1, 121.36, 121.39, 123.3, 124.8, 125.5, 130.7, 133.5, 139.6, 141.6, 142.6, 148.2, 153.5, 158.5 (q, J = 27.6 Hz); HRMS (FAB): m / z calcd for C ₁₆ H ₁₄ N ₃ O ₂ S [M + H] ⁺ 312.0807 ; found: 312.0807.

Synthesis Example 23 Synthesis of 1059D-13 (Compound 31)

3,4-Dihydro-8- (3,4-methylenedioxyphenyl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 31)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9- (3,4-methylenedioxyphenyl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine ( Compound 31 (trifluoroacetate salt) was obtained as a pale yellow solid from Compound 66) (see the above literature (3)) (50.0 mg, 0.148 mmol). (48.2mg, 78%). Physical property values are shown below.
IR (neat) cm ^-1 : 3167-3044 (OH), 1687 (C = O), 1624 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.30-2.35 (m, 2H, CH ₂ ), 3.67 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.15 (t, J = 5.7 Hz, 2H, CH ₂ ), 6.04 (s, 2H, CH ₂ ), 6.97 (d, J = 8.6 Hz, 1H, Ar), 7.24-7.27 (m, 2H, Ar), 7.85 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 8.17 (d, J = 9.2 Hz, 1H, Ar), 8.19 (d, J = 1.1 Hz, 1H, Ar); ¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 19.1, 37.2, 44.7, 101.6, 107.3, 108.9, 117.3 (q, J = 299.9 Hz), 119.0 , 120.2, 121.3, 124.5, 125.4, 132.3, 142.6, 144.3, 148.1, 148.3, 153.6, 158.2 (q, J = 32.0 Hz); HRMS (FAB): m / z calcd for C ₁₇ H ₁₅ N ₂ O ₂ S [M + H] ⁺ 311.0854; found: 311.0860.

Synthesis Example 24 Synthesis of 1059D-23 (Compound 32)

3,4-Dihydro-8- (furan-2-yl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 32)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9- (furan-2-yl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 67) (Refer to the above literature (3)) (50.6 mg, 0.179 mmol) gave compound 32 (trifluoroacetate) as a white solid (50.0 mg, 77%).
IR (neat) cm ^-1 : 3219-3029 (OH), 1680 (C = O), 1632 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.30-2.35 (m, 2H, CH ₂ ), 3.67 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.14 (t, J = 5.7 Hz, 2H, CH ₂ ), 6.64 (dd, J = 3.4, 1.7 Hz, 1H, Ar), 7.12 (d, J = 4.0 Hz, 1H, Ar), 7.72 (d, J = 1.1 Hz, 1H, Ar), 7.95 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 8.14 (d, J = 8.6 Hz, 1H, Ar), 8.32 (d, J = 1.1 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.7, 38.9, 46.2, 110.6, 113.6, 116.1, 118.1 (q , J = 291.5 Hz), 121.1, 123.6, 125.5, 136.5, 144.4, 145.8, 152.9, 155.5, 162.6 (q, J = 34.8 Hz); HRMS (FAB): m / z calcd for C ₁₄ H ₁₃ N ₂ OS [M + H] ⁺ 257.0749; found: 257.0749.

Synthesis Example 25 Synthesis of 1059D-28 (Compound 33)

3,4-Dihydro-8- (thiophen-3-yl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 33)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9- (thiophen-3-yl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 68) (Refer to the above literature (3)) (40.1 mg, 0.134 mmol) gave compound 33 (trifluoroacetate) as a white solid (35.8 mg, 71%). Physical property values are shown below.
IR (neat) cm ^-1 : 3133-3029 (OH), 1672 (C = O), 1627 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.31-2.35 (m, 2H, CH ₂ ), 3.68 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.15 (t, J = 6.0 Hz, 2H, CH ₂ ), 7.58-7.61 (m, 2H, Ar), 7.95 (dd, J = 2.1, 2.1 Hz, 1H, Ar), 7.97 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 8.16 (d, J = 8.6 Hz, 1H, Ar), 8.29 (d, J = 1.1 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.6, 38.8, 46.1, 118.4 (q, J = 296.3 Hz), 118.7, 121.0, 124.9, 125.5, 126.2, 127.0, 128.5, 140.9, 141.6, 144.2, 155.4, 163.0 (q, J = 36.0 Hz); HRMS (FAB): m / z calcd for C ₁₄ H ₁₃ N ₂ S ₂ [M + H] ⁺ 273.0520; found: 273.0523.

Synthesis Example 26 Synthesis of 1059D-74 (Compound 34)

3,4-Dihydro-8- (naphthalen-2-yl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 34)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9- (naphthalen-2-yl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 69) (Refer to the above literature (3)) (40.8 mg, 0.119 mmol) gave compound 34 (trifluoroacetate) as a white solid (32.7 mg, 65%). Physical property values are shown below.
IR (neat) cm ^-1 : 3147-3018 (OH), 1675 (C = O), 1629 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.31-2.36 (m, 2H, CH ₂ ), 3.68 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.16 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.55-7.58 (m, 2H, Ar), 7.85 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 7.91-8.00 (m, 2H, Ar), 8.02 (d, J = 8.6 Hz, 1H, Ar), 8.05 (dd, J = 8.3, 1.4 Hz, 1H, Ar ), 8.22-8.24 (m, 2H, Ar), 8.38 (d, J = 1.1 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.3, 38.6, 45.8, 118.3 (q, J = 295.1 Hz), 119.7, 121.0, 125.1, 125.6, 126.8, 127.4, 127.6, 127.9, 128.5, 129.6, 129.7, 134.4, 134.5, 136.4, 143.6, 146.2, 154.9, 162.8 (q, J = 32.4 Hz); HRMS (FAB): m / z calcd for C ₂₀ H ₁₇ N ₂ S [M + H] ⁺ 317.1112; found: 317.1111.

Synthesis Example 27 Synthesis of 1059D-16 (Compound 37)

N- (tert-butyl) -3,4-dihydro-9- (pyridin-2-yl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 35)
Compound 23 (200 mg, 0.568 mmol), copper (I) iodide (21.6 mg, 20 mol%), palladium (II) acetate (6.4 mg, 5 mol%) and triphenylphosphine (14.9 mg, 10 mol%) under an argon atmosphere 2-pyridinyltriol borate lithium salt (145 mg, 0.681 mmol) was added to a solution of N, N-dimethylformamide (1.72 mL) containing. After stirring at 80 ° C. for 36 hours, the reaction was quenched with 5% aqueous ammonia and extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration, purification by flash chromatography with aluminum oxide (n-hexane-ethyl acetate (3: 1)) gave compound 35 as colorless crystals (118 mg, 59%). Physical property values are shown below.
mp 140-142 ° C (from n-hexane); IR (neat) cm ^-1 : 1582 (C = N); ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 1.39 (s, 9H, 3 × CH ₃ ), 1.82-1.87 (m, 2H, CH ₂ ), 3.56 (t, J = 5.4 Hz, 2H, CH ₂ ), 3.81 (t, J = 6.0 Hz, 2H, CH ₂ ), 7.41 (dd, J = 7.4, 4.6 Hz, 1H, Ar), 7.91 (ddd, J = 8.0, 8.0, 1.7 Hz, 1H, Ar), 8.00 (dd, J = 8.3, 2.0 Hz, 1H, Ar), 8.04-8.07 (m , 2H, Ar), 8.25 (d, J = 8.6 Hz, 1H, Ar), 8.69 (d, J = 4.6 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 21.8, 30.0 ( 3C), 45.1, 45.4, 54.2, 120.7, 122.8, 122.9, 124.2, 128.0, 128.8, 129.7, 136.9, 138.4, 140.8, 147.8, 149.8, 155.6; HRMS (FAB): m / z calcd for C ₂₀ H ₂₃ N ₄ S [M + H] ⁺ 351.1643; found: 351.1636.

3,4-Dihydro-9- (pyridin-2-yl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 36)
To a mixture of a small amount of chloroform containing Compound 35 (97.2 mg, 0.277 mmol) and MS4Å (624 mg, powder, activated by heating with a Bunsen burner) was added trifluoroacetic acid (2.77 mL). This was stirred for 4 hours while refluxing, and then triethylamine was added dropwise to the mixture at 0 ° C. to adjust the pH to 8-9. This was extracted with ethyl acetate, and the extract was washed with saturated sodium hydrogen carbonate and saturated brine, and then dried over magnesium sulfate. After concentration, purification by flash chromatography on aluminum oxide (n-hexane-ethyl acetate (1: 1)) gave compound 36 as pink crystals (73.6 mg, 90%). Physical property values are shown below.
mp 177-179 ° C (from n-hexane-chloroform); IR (neat) cm ^-1 : 1566 (C = N); ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.99-2.04 (m, 2H, CH ₂ ), 3.73 (t, J = 5.4 Hz, 2H, CH ₂ ), 4.06 (t, J = 6.3 Hz, 2H, CH ₂ ), 7.28-7.30 (m, 1H, Ar), 7.75-7.83 (m, 4H, Ar), 8.35 (d, J = 8.0 Hz, 1H, Ar), 8.71 (d, J = 4.6 Hz, 1H, Ar); ¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 20.7, 43.2 , 44.4, 120.8, 121.6, 123.5, 123.9, 126.2, 128.9, 129.6, 137.4, 140.6, 145.2, 149.5, 149.7, 154.0; HRMS (FAB): m / z calcd for C ₁₆ H ₁₅ N ₄ S (M + H ] ⁺ 295.1017; found: 295.1016.

3,4-Dihydro-8- (pyridin-2-yl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 37)
In the same manner as in Synthesis Example 1, compound 37 (trifluoroacetate) was obtained as a white solid (47.6 mg, 75%) from compound 36 (50.0 mg, 0.170 mmol). Physical property values are shown below.
IR (neat) cm ^-1 : 3129-2972 (OH), 1679 (C = O), 1630 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.32-2.37 (m, 2H, CH ₂ ), 3.70 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.18 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.48 (ddd, J = 7.3, 4.7, 1.3 Hz, 1H, Ar ), 7.97-8.04 (m, 2H, Ar), 8.26 (d, J = 1.1 Hz, 2H, Ar), 8.65 (dd, J = 1.1, 1.1 Hz, 1H, Ar), 8.72-8.74 (m, 1H , Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.5, 38.9, 46.2, 118.3 (q, J = 292.7 Hz), 120.3, 122.8, 122.9, 125.2, 125.4, 126.6, 139.1, 143.9, 144.9 , 150.9, 155.4, 155.7, 162.8 (q, J = 34.0 Hz); HRMS (FAB): m / z calcd for C ₁₅ H ₁₄ N ₃ S [M + H] ⁺ 268.0908; found: 268.0907.

Synthesis Example 28 Synthesis of 1059D-19 (Compound 38)

3,4-Dihydro-8- (pyridin-3-yl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 38)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9- (pyridin-3-yl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 70) (Refer to the above literature (3)) (50.0 mg, 0.170 mmol) gave compound 38 (trifluoroacetate) as a white solid (38.4 mg, 60%). Physical property values are shown below.
IR (neat) cm ^-1 : 3013-3004 (OH), 1664 (C = O), 1626 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.32-2.37 (m, 2H, CH ₂ ), 3.70 (t, J = 5.4 Hz, 2H, CH ₂ ), 4.19 (t, J = 5.7 Hz, 2H, CH ₂ ), 7.82 (dd, J = 7.4, 5.2 Hz, 1H, Ar), 8.00 (dd, J = 8.3, 1.4 Hz, 1H, Ar), 8.32 (d, J = 8.6 Hz, 1H, Ar), 8.38 (d, J = 1.1 Hz, 1H, Ar), 8.48 (ddd, J = 8.0, 1.7, 1.7 Hz, 1H, Ar), 8.76 (dd, J = 5.2, 1.7 Hz, 1H, Ar), 9.06 (d, J = 1.7 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.5, 39.0, 46.4, 117.9 (q, J = 291.5 Hz), 121.4, 123.5, 126.3, 127.3, 128.0, 138.9, 141.2, 143.5, 143.8, 144.5, 144.8, 155.6, 162.4 (q, J = 36.0 Hz); HRMS (FAB): m / z calcd for C ₁₅ H ₁₄ N ₃ S [M + H] ⁺ 268.0908; found: 268.0910.

Synthesis Example 29 Synthesis of 1059D-20 (Compound 39)

3,4-Dihydro-8- (pyridin-4-yl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 39)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9- (pyridin-4-yl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 71) (Refer to said literature (3)) (44.0 mg, 0.150 mmol) gave compound 39 (trifluoroacetate) as a white solid (48.6 mg, 87%). Physical property values are shown below.
IR (neat) cm ^-1 : 3100-2986 (OH), 1673 (C = O), 1623 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.33-2.37 (m, 2H, CH ₂ ), 3.70 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.20 (t, J = 5.7 Hz, 2H, CH ₂ ), 8.07-8.09 (m, 3H, Ar), 8.34 (d, J = 8.6 Hz, 1H, Ar), 8.49 (d, J = 1.7 Hz, 1H, Ar), 8.82 (dd, J = 5.2, 1.7 Hz, 2H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD) : δ 20.4, 39.0, 46.4, 118.0 (q, J = 292.7 Hz), 122.3 (2C), 124.7, 126.2 (2C), 126.5, 127.4, 141.2, 144.5 (2C), 155.5, 155.9, 162.6 (q, J = 35.6 Hz); HRMS (FAB): m / z calcd for C ₁₅ H ₁₄ N ₃ S [M + H] ⁺ 268.0908; found: 268.0915.

Synthesis Example 30 Synthesis of 1059D-25 (Compound 40)

3,4-Dihydro-8- (1H-pyrazol-1-yl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 40)
In the same manner as in Synthesis Example 1, 3,4-dihydro-9- (1H-pyrazol-1-yl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (compound 72) From compound (30.0) (50.0 mg, 0.176 mmol), compound 40 (trifluoroacetate) was obtained as a white solid (44.2 mg, 69%). Physical property values are shown below.
IR (neat) cm ^-1 : 3144-3048 (OH), 1671 (C = O), 1633 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.30-2.35 (m, 2H, CH ₂ ), 3.67 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.15 (t, J = 6.0 Hz, 2H, CH ₂ ), 6.63 (dd, J = 2.9, 1.7 Hz, 1H, Ar), 7.83 (d, J = 1.7 Hz, 1H, Ar), 8.10 (dd, J = 8.9, 2.0 Hz, 1H, Ar), 8.24 (d, J = 8.6 Hz, 1H, Ar), 8.42 (d, J = 2.3 Hz, 1H, Ar), 8.45 (d, J = 2.3 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.5, 38.7, 46.1, 110.3, 110.7, 118.2 (q, J = 285.5 Hz), 118.4, 120.0, 126.5, 129.3, 143.8, 144.3, 144.8, 155.0, 162.7 (br); HRMS (FAB): m / z calcd for C ₁₃ H ₁₃ N ₄ S [M + H] ⁺ 257.0861 ; found: 257.0864.

Synthesis Example 31 Synthesis of 1059D-49 (Compound 43)

N- (tert-butyl) -3,4-dihydro-9- (1H-1,2,3-triazol-1-yl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine -6-Imine (Compound 41)
Under an argon atmosphere, the compound 23 (200 mg, 0.568 mmol), 1H-1,2,3-triazole (39.5 μL, 0.681 mmol), copper (I) chloride (11.2 mg, 20 mol%) and potassium carbonate (86.3 mg, To a mixed solution of N-methylpyrrolidone (1.10 mL) containing 0.624 mmol), acetylacetone (17.4 μL, 30 mol%) was added. Stir at 130 ° C. for 4 days. To the mixture was added 5% NH ₃ aqueous solution to stop the reaction. This was extracted with ethyl acetate, and the extract was washed with saturated sodium hydrogen carbonate and saturated brine, and then dried over magnesium sulfate. After concentration, the residue was purified by flash chromatography with aluminum oxide (n-hexane-ethyl acetate (10: 1)) to obtain Compound 41 as colorless crystals (53.9 mg, 28%). Physical property values are shown below.
mp 110-112 ° C (from n-hexane-chloroform); IR (neat) cm ^-1 : 1601 (C = N); ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.40 (s, 9H, 3 × CH ₃ ), 1.92-1.96 (m, 2H, CH ₂ ), 3.65 (t, J = 5.7 Hz, 2H, CH ₂ ), 3.89 (t, J = 6.3 Hz, 2H, CH ₂ ), 7.84 (s, 2H , Ar), 7.89 (d, J = 2.3 Hz, 1H, Ar), 7.92 (dd, J = 8.9, 2.0 Hz, 1H, Ar), 8.33 (d, J = 9.2 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 21.8, 30.0 (3C), 45.1, 45.5, 54.3, 114.3, 116.3, 126.5, 129.9, 130.6, 136.1 (2C), 137.5, 140.5, 147.2; HRMS (FAB): m / z calcd for C ₁₇ H ₂₁ N ₆ S [M + H] ⁺ 341.1548; found: 341.1546.

3,4-Dihydro-9- (1H-1,2,3-triazol-1-yl) -2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (Compound 42)
By a method similar to the synthesis from Compound 35 to Compound 36, Compound 42 was obtained as colorless crystals (38.8 mg, 99%) from Compound 41 (47.0 mg, 0.138 mmol). Physical property values are shown below.
mp 205-207 ° C (from n-hexane-chloroform); IR (neat) cm ^-1 : 1619 (C = N); ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.98-2.02 (m, 2H, CH ₂ ), 3.72 (t, J = 5.4 Hz, 2H, CH ₂ ), 4.05 (t, J = 6.0 Hz, 2H, CH ₂ ), 7.82 (d, J = 2.3 Hz, 1H, Ar), 7.84 (s , 2H, Ar), 7.95 (dd, J = 9.2, 2.3 Hz, 1H, Ar), 8.37 (d, J = 8.6 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 20.9, 43.8, 45.0, 113.3, 116.5, 125.4, 130.3, 130.4, 136.2 (2C), 140.8, 145.9, 152.7; HRMS (FAB): m / z calcd for C ₁₃ H ₁₃ N ₆ S [M + H] ⁺ 285.0922; found: 285.0924.

3,4-Dihydro-8- (1H-1,2,3-triazol-1-yl) -2H-benzo [4,5] isothiazolo [2,3-a] pyrimidine (Compound 43)
Compound 43 (trifluoroacetate) was obtained as a white solid (19.8 mg, 47%) from compound 42 (32.6 mg, 0.115 mmol) by the same method as in Synthesis Example 1. Physical property values are shown below.
IR (neat) cm ^-1 : 3096-2888 (OH), 1685 (C = O), 1632 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.31-2.36 (m, 2H, CH ₂ ), 3.69 (t, J = 5.7 Hz, 2H, CH ₂ ), 4.17 (t, J = 6.0 Hz, 2H, CH ₂ ), 8.06 (s, 2H, Ar), 8.28 (d, J = 8.6 Hz, 1H, Ar), 8.40 (dd, J = 9.2, 1.7 Hz, 1H, Ar), 8.80 (d, J = 1.7 Hz, 1H, Ar); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.6, 39.0, 46.3, 111.8, 118.6 (q, J = 292.7 Hz), 118.9, 121.5, 126.6, 138.6 (2C), 144.1, 145.0, 155.4, 163.0 (br); HRMS (FAB): m / z calcd for C ₁₂ H ₁₂ N ₅ S [M + H] ⁺ 258.0813; found: 258.0818.

Synthesis Example 32 Synthesis of 1036J-167 (Compound 45)

2- (2-Mercaptophenyl) -1,4,5,6-tetrahydropyrimidine (Compound 45)
(Method A)
3,4-Dihydro-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-imine (1) (1.09 g, 5.00 mmol) in chloroform (50.0 mL) and ethanol (75.0 mL) ), Trifluoroacetic acid (3.70 mL, 50.0 mmol) was added dropwise. After stirring at room temperature for 1 hour, the reaction was stopped by adding triethylamine (7.20 mL, 50.0 mmol) at 0 ° C. and concentrated. This was purified by flash chromatography on amino silica gel (chloroform-methanol (10: 0 to 9: 1)) to give compound 45 as yellow crystals (999 mg, quant.). Physical property values are shown below.
mp 208-210 ° C (from n-hexane-chloroform-methanol); IR (neat) cm ^-1 : 3185-3092 (SH), 1590 (C = N); ¹ H NMR (500 MHz, CD ₃ OD): δ 2.05-2.09 (m, 2H, CH ₂ ), 3.55 (t, J = 5.7 Hz, 4H, CH ₂ ), 6.87-6.91 (m, 1H, Ar), 7.06 (ddd, J = 8.0, 8.0, 1.7 Hz, 1H, Ar), 7.28 (dd, J = 7.7, 1.4 Hz, 1H, Ar), 7.56 (dd, J = 8.0, 1.1 Hz, 1H, Ar); ¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 18.1, 38.1 (2C), 118.7, 122.8, 126.7, 128.8, 137.8, 158.9, 159.8; HRMS (FAB): m / z calcd for C ₁₀ H ₁₃ N ₂ S [M + H] ⁺ 193.0799; found : 193.0801.

(Method B)
3,4-dihydro-2H, 6H-pyrimido [1,2-c] [1,3] benzothiazine-6-thione (compound 44) (see reference (1) above) (1.15 g, 4.90 mmol) It was suspended in a methanol-water solution (9: 1, 98.0 mL) containing 0.1N sodium hydroxide. After stirring this for 12 hours while refluxing, the reaction was stopped by adding 1N hydrochloric acid to pH 7. This was extracted with chloroform-methanol (95: 5) and dried over magnesium sulfate. After concentration, the obtained solid was recrystallized from diethyl ether-chloroform-methanol to obtain Compound 45 as a yellow solid (655 mg, 70%). The spectral data was consistent with the spectral data of the compound synthesized by Method A.

Synthesis Example 33 Synthesis of 1059E-87 (Compound 46)

2- (2-hydroxyphenyl) -1,4,5,6-tetrahydropyrimidine (Compound 46)
A mixture of methyl salicylate (1.29 mL, 10.0 mmol) and propylenediamine (2.56 mL, 30.0 mmol) was refluxed for 16 hours. This was dissolved in methanol and crystallized with diethyl ether. Unreacted propylenediamine was removed by filtering the precipitate and washing with diethyl ether. The resulting solid was purified by flash chromatography on aluminum oxide (chloroform-methanol (10: 0 to 10: 1)) to give compound 46 as colorless crystals (497 mg, 28%). Physical property values are shown below.
mp 259-261 ° C (from diethyl ether-methanol); IR (neat) cm ^-1 : 3212-3050 (OH), 1620 (C = N); ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 1.83 -1.88 (m, 2H, CH ₂ ), 3.40 (t, J = 5.7 Hz, 4H, CH ₂ ), 6.27-6.30 (m, 1H, Ar), 6.46 (d, J = 8.6 Hz, 1H, Ar) , 7.04-7.08 (m, 1H, Ar), 7.45 (dd, J = 8.0, 1.7 Hz, 1H, Ar), 12.10 (br s, 1H, OH); ¹³ C NMR (125 MHz, CD ₃ OD): δ 20.0, 39.3 (2C), 111.2, 114.5, 124.4, 126.3, 135.1, 160.9, 172.5; Anal.calcd for C ₁₀ H ₁₂ N ₂ O: C, 68.16; H, 6.86; N, 15.90. Found: C, 68.13; H, 7.03; N, 16.09.

Synthesis Example 34 Synthesis of 1059E-41 (Compound 47)

2- (2-Aminophenyl) -1,4,5,6-tetrahydropyrimidine (Compound 47)
2- [2-N- (p-toluenesulfonylamino) phenyl] -1,4,5,6-tetrahydropyrimidine (compound 73) (see reference (2) above) (494 mg, 1.50 mmol) was added to concentrated sulfuric acid. After stirring in 100 mL for 30 minutes in (10.0 mL), the mixture was cooled to 0 ° C. The pH was adjusted to 12-14 with 2N sodium hydroxide. This was extracted with chloroform and dried over magnesium sulfate. After concentration, the obtained solid was recrystallized from n-hexane-chloroform to obtain Compound 47 as colorless crystals (137.4 mg, 52%). Physical property values are shown below.
mp 83-85 ° C; IR (neat) cm ^-1 : 2931 (NH ₂ ), 2851 (NH ₂ ), 1620 (C = N); ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.81-1.86 (m , 2H, CH ₂ ), 3.48 (t, J = 5.7 Hz, 4H, CH ₂ ), 4.71 (br s, 1H, NH), 5.72 (br s, 2H, NH ₂ ), 6.61-6.66 (m, 2H , Ar), 7.07-7.10 (m, 1H, Ar), 7.23-7.26 (m, 1H, Ar); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 20.7, 42.0 (2C), 116.56, 116.61, 119.3 , 126.3, 129.9, 147.1, 155.1; Anal.calcd for C ₁₀ H ₁₄ N ₃ : C, 68.54; H, 7.48; N, 23.98.Found: C, 68.28; H, 7.57; N, 23.75.

[Example 2]
The various compounds synthesized in Example 1 were evaluated for anti-HIV virus activity.

  The various compounds synthesized in Example 1 were evaluated for anti-HIV activity. The evaluation was performed by NCK assay based on the method described in the paper Journal of Clinical Microbiology, 2008, 46, 792-795 as shown below.

NCK45-β-Gal cells were seeded in a 96-well flat-bottom plate at 1 × 10 ⁴ cells / well, cultured for 24 hours, and then replaced with a medium containing an appropriate dilution of the previous compound. Subsequently, HIV-1 (IIIB strain) was infected with 60 NCK units. After 48 hours of culture, the cells were fixed and HIV-1-infected cells were stained with X-gal and counted. The anti-HIV-1 activity of various compounds was calculated as EC ₅₀ (50% effective concentration), the concentration that inhibits HIV-1 infection by 50%. Tables 7 to 9 show EC ₅₀ values obtained using the compounds described above as the compounds of the examples.

As shown in Table 7, each compound had an EC ₅₀ of less than 2.2 μM, and about half of them showed a sufficiently low value of 1 μM or less. From these results, it was found that the compounds of Examples have excellent anti-HIV activity. In particular, In the formula (II), the ^{R 2,} as the hydrophobic functional group, 1036J-152 which was introduced m- methoxyphenyl group (m- anisyl), in formula ^{(II), R 1, R} 2 and Compared with 1036J-129 in which all of R ³ are hydrogen atoms, the anti-HIV activity was improved by about 3 times, and it was found that the anti-HIV activity was particularly excellent. Moreover, even if it used these compounds at the density | concentration of 10 micromol / L, it turned out that cytotoxicity is not seen but shows high safety | security.

As shown in Table 8 above, all the compounds showed sufficiently low values with an EC ₅₀ of less than 1.5 μM, and most of the compounds showed very low values of less than 0.5 μM. From these results, it was found that the compounds of Examples have excellent anti-HIV activity. Particularly, in the formula (II), ^{R 2,} a is a hydrophobic modification aryl group 3,4-methylenedioxyphenyl group, furan-2-yl group or a 3-methoxycarbonyl 1059D-13 introduced with a phenyl group 1059D-23 and 1059D-39 showed superior anti-HIV activity over compounds incorporating hydrophilic modified aryl groups. Specifically, 1059D-13, 1059D-23 and 1059D-39 have about 6 times higher anti-HIV activity compared to 1036J-129 in which R ¹ , R ² and R ³ are all hydrogen atoms. And particularly excellent anti-HIV activity. From this, it was found that a more excellent anti-HIV activity can be realized by making R ² a hydrophobic aryl group. In addition, it was found that compounds other than 1059D-33 showed no safety even when used at a concentration of 10 μmol / L and showed high safety.

  As shown in Table 9, 1036J-167, which is a compound in which the isothiazole ring of 1036J-129 is opened, was also found to have equivalent excellent anti-HIV activity. From these results, it is suggested that the isothiazole derivative represented by the formula (II) may be ring-opened in a living body and exhibit antiviral activity as the thiophenol derivative represented by the formula (I). It was done. That is, the isothiazole derivative represented by the formula (II) can also be used as a prodrug of the thiophenol derivative represented by the formula (I).

[Example 3]
Of the various compounds synthesized in Example 1, 1036J-129 was evaluated for antiviral activity against various viruses.

(1) Time of drug addition test In the same manner as the NCK assay described above, NCK45-β-Gal cells were seeded and cultured, and virus (HIV-1 IIIB strain) was infected with 60 NCK units. The drug samples were added over time from 0 hours after virus inoculation (addition of drug immediately after virus inoculation) to 48 hours after (same as the end of culture). After culturing 48 hours after virus inoculation, the cultured cells were fixed, and HIV-1-infected cells were stained with X-gal and counted. The anti-HIV-1 activity of various compounds was calculated as EC ₅₀ (50% effective concentration), the concentration that inhibits HIV-1 infection by 50%. As the drug sample, 1036J-129 of Example 1 was used as an example, and DS5000 (dextran sulfate sodium salt, manufactured by Sigma), which is an existing antiviral agent, and AZT (3′-azido) were used as comparative examples. -3'-deoxythymidine (manufactured by Sigma) and RAL (raltegravir, manufactured by Selleck Chemicals) were used.

  FIG. 1 shows these results. FIG. 1 is a graph showing the relationship between the addition time of a drug sample after virus infection and the infection rate (%). As shown in FIG. 1, 1036J-129 of Example was compared with administration immediately after infection (0 h) and administration after 2 hours from infection. As a result, the latter (2 h) was more infected than the former (0 h). The rate (%) was high and the antiviral activity decreased. From these results, it was suggested that the compound of the present invention may act in the early stage of virus infection.

(2) Confirmation of anti-herpes simplex virus activity
Anti-HSV-1 activity and anti-HSV-2 activity by the following method according to Ann NY Acad Sci. 1994, 724, 472-488 (http://www.ncbi.nlm.nih.gov/pubmed/8030975) Was evaluated.

Using Vero cells derived from African green monkey kidney epithelial cells as target cells, the anti-HSV-1 activity and anti-HSV-2 activity of the drug samples were measured by plaque reduction assay (Plaque reduction assay). Specifically, the Vero cells were seeded in a 6-well plate at 5 × 10 ⁵ cells / well and cultured overnight. Then, the obtained culture solution was replaced with 5% bovine serum-added DMEM to which a drug sample was added so as to be 1 μmol / L or 10 μmol / L, and HSV-1 (VR-3 strain) or HSV-2 ( UW268 strain) was infected with 100 PFU. The cells were cultured at 37 ° C. for 48 hours, fixed with methanol, stained with 0.1% crystal violet solution, and the number of plaques was measured.

  As the drug sample, 1036J-129 of Example 1 was used as an example. As a control, dimethyl sulfoxide (DMSO) was added instead of the drug sample.

  Then, assuming that the number of plaques in the control was 100%, a relative value (%) of the number of plaques when each drug sample was used was determined, and this was used as a relative infection rate (%). These results are shown in FIG. FIG. 2 is a graph showing the infection rate (%), (A) shows the infection rate of HSV-1, and (B) shows the infection rate of HSV-2.

  As shown in FIG. 2, 1036J-129 of Example was shown to have infection inhibitory activity against DNA viruses HSV-1 and HSV-2.

(3) Confirmation of anti-influenza virus activity
According to J Virol Methods 1994 48: 257-265, anti-influenza virus activity was evaluated by the following MTT assay method using MDCK cells.

Specifically, the MDCK cells were seeded in a 96-well plate at 1 × 10 ⁴ cells / well and cultured overnight. The well plate was washed with 0.1% bovine serum albumin-added DMEM, then added with 1% bovine serum albumin-added DMEM containing a drug sample, and human influenza A virus (A / PR / 8/34 strain) was added. Infected. Then, after the cells were cultured at 37 ° C. for 72 to 96 hours, the number of viable cells was measured by the MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] method. As the drug sample, 1036J-129 of Example 1 was used as an example, and anti-influenza virus activity was evaluated. In addition, as a control, the 1% bovine serum albumin-added DMEM without the drug sample was used instead of the medium to which the drug sample was added.

The anti-influenza virus activity is calculated by calculating the EC ₅₀ (50% effective concentration) as the concentration that inhibits influenza virus infection by 50%, and the concentration at which 50% of the cells survive as CC ₅₀ (50% cytotoxicity concentration). Calculated.

  These results are shown in Table 10 below. As shown in Table 10 below, Example 1036J-129 also showed inhibitory activity against influenza virus.

  This application claims the priority on the basis of Japanese application Japanese Patent Application No. 2014-206613 for which it applied on October 7, 2014, and takes in those the indications of all here.

As described above, since the compound of the present invention has antiviral activity against HIV and the like, it can be used, for example, as a viral infection inhibitor and is extremely useful in the medical field.

Claims (26)

A compound represented by the following (I) or a salt thereof:
In the formula (I),
R ¹ , R ² , and R ³ each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a carbon number An alkynyl group having 2 to 6 carbon atoms, an alkylene group having 2 to 6 carbon atoms, an aryl group, a heteroaryl group, a nitro group, an alkylcarbonylamino group having an alkyl group of 1 to 6 carbon atoms, and a fluoroalkyl group having 1 to 6 carbon atoms , Amino group, mono- or dialkylamino group having 1 to 3 carbon atoms, benzoylamino group, azide group, carboxyl group, alkylcarbonyl group having 1 to 3 carbon atoms, alkoxycarbonyl group having 1 to 3 carbon atoms, carbamoyl group, naphthyl Group, heteroaryl group, styryl group, alkylthio group having 1 to 3 carbon atoms, hydroxyalkyl group having 1 to 6 carbon atoms,
R ¹ , R ² , and R ³ may be further substituted with a substituent,
R ¹ , R ² , and R ³ may be the same or different,
R ¹ and R ² , or R ² and R ³ may be bridged,
The bridge formed by the adjacent substituents may include one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom,
R ⁴ represents a linear alkylene group having 1 to 5 carbon atoms or a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom,
R ⁴ may be further substituted with a substituent,
When R ⁴ is the alkylene group, the substituents on the alkylene group may be bonded to each other to form a crosslinked structure or a ring structure;
X ¹ and X ² each independently represent a heteroatom selected from a sulfur atom, an oxygen atom and a nitrogen atom,
X ¹ and X ² may be further substituted with a substituent,
X ¹ and X ² may be the same or different,
X ¹ and X ² may be cross-linked. The compound according to claim 1, wherein the compound in which X ¹ and X ² are cross-linked in the formula (I) is represented by the following formula (II), or a salt thereof.
In the formula (II),
R ¹ , R ² , and R ³ each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a carbon number An alkynyl group having 2 to 6 carbon atoms, an alkylene group having 2 to 6 carbon atoms, an aryl group, a heteroaryl group, a nitro group, an alkylcarbonylamino group having an alkyl group of 1 to 6 carbon atoms, and a fluoroalkyl group having 1 to 6 carbon atoms , Amino group, mono- or dialkylamino group having 1 to 3 carbon atoms, benzoylamino group, azide group, carboxyl group, alkylcarbonyl group having 1 to 3 carbon atoms, alkoxycarbonyl group having 1 to 3 carbon atoms, carbamoyl group, naphthyl A group, a styryl group, an alkylthio group having 1 to 3 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms,
R ¹ , R ² , and R ³ may be further substituted with a substituent,
R ¹ , R ² , and R ³ may be the same or different,
R ¹ and R ² , or R ² and R ³ may be bridged,
The bridge formed by the adjacent substituents may include one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom,
R ⁴ represents a linear alkylene group having 1 to 5 carbon atoms or a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom,
R ⁴ may be further substituted with a substituent,
When R ⁴ is the alkylene group, the substituents on the alkylene group may be bonded to each other to form a crosslinked structure or a ring structure;
The isothiazole ring may be opened by cleavage of the nitrogen-sulfur bond,
When the isothiazole ring is opened, the nitrogen atom derived from the nitrogen-sulfur bond may be substituted with an oxygen atom or a sulfur atom, and the sulfur atom derived from the nitrogen-sulfur bond is an oxygen atom or a nitrogen atom. May be substituted. The compound according to claim 1 or 2, or a salt thereof, wherein R ⁴ is a methylene group, an ethylene group or an ethylidene group. The compound according to claim 1 or 2, or a salt thereof, wherein R ⁴ is a group having a structure represented by the following formula (2) or (3).
In the formula (2),
R ⁶ represents an alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzoyl group,
R ⁶ may be further substituted with a substituent,
The substituent is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, or an alkyl having 1 to 3 carbon atoms. A sulfonyl group or halogen,
In the formula (3),
Y represents a methylene group or an oxygen atom,
Y may be further substituted with a substituent,
The substituent is an alkyl group having 1 to 6 carbon atoms or a halogen atom. The compound according to any one of claims 1 to 4, or a salt thereof, wherein the aryl group or the heteroaryl group is a 5-membered ring or a 6-membered ring. The said aryl group is a compound as described in any one of Claim 1 to 5 which has a structure represented by following formula (1), or its salt.
In the formula (1),
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a 1 to 6 fluoroalkyl group, A fluoroalkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, an aminocarbonyl group, a halogen atom, a nitro group, a hydroxyl group, a cyano group, a methanesulfonylamino group, Represents a benzoyl group or an alkylcarbonylamino group having 1 to 3 carbon atoms which may be substituted with a phenyl group;
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ may be the same or different,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ may each form a ring with adjacent substituents,
The ring formed by the adjacent substituents may include one or more heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom. The compound according to any one of claims 1 to 6, wherein R ² is a hydrophobic functional group, or a salt thereof. R ¹ , R ² , and R ³ are each independently a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group having 5 to 10 carbon atoms, or a carbon number. An aryl group having 5 to 10 carbon atoms substituted by an alkoxy group having 1 to 6 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, a nitro group, an alkylcarbonylamino group having an alkyl group having 1 to 6 carbon atoms, or a carbon number The compound according to any one of claims 1 to 7, which is a 1-6 fluoroalkyl group, or a salt thereof. The halogen atom is a bromine atom;
The alkyl group having 1 to 6 carbon atoms is a methyl group;
The alkoxy group having 1 to 6 carbon atoms is a methoxy group;
The aryl group having 5 to 10 carbon atoms is a phenyl group or a naphthyl group;
An aryl group having 5 to 10 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms is a methoxyphenyl group;
The heteroaryl group having 1 to 10 carbon atoms is a furanyl group or a thiophenyl group;
An alkylcarbonylamino group having an alkyl group of 1 to 6 carbon atoms is an acetylamino group,
The compound or a salt thereof according to any one of claims 1 to 8, wherein the fluoroalkyl group having 1 to 6 carbon atoms is a trifluoromethyl group. R ¹ and R ³ are each independently a hydrogen atom,
R ² is a halogen atom, an alkoxy group having 1 to 6 carbon atoms, an aryl group having 5 to 10 carbon atoms, an aryl group having 5 to 10 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms, The compound as described in any one of Claims 1-9 which is a 10 heteroaryl group, a nitro group, or a C1-C6 fluoroalkyl group, or its salt. R ² and R ³ are each independently a hydrogen atom,
R ¹ is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group having 5 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, or 1 to 6 carbon atoms. The compound or its salt as described in any one of Claims 1-9 which is the fluoroalkyl group of these. R ¹ and R ² are hydrogen,
The compound according to any one of claims 1 to 9, or a salt thereof, wherein R ³ is the aryl group, the substituted aryl group, the heteroaryl group, or the substituted heteroaryl group. Any one of R ¹ , R ² and R ³ is the aryl group, the substituted aryl group, the heteroaryl group, or the substituted heteroaryl group. Or a salt thereof. 14. The substituted aryl group, wherein the substituent is an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, a hydroxyl group, or a nitro group. Or a salt thereof. The compound or its salt of Claim 14 whose said substituent is a methoxy group, a methoxycarbonyl group, a hydroxyl group, or a nitro group. The compound or a salt thereof according to any one of claims 1 to 15, wherein the substituted aryl group is a 3,4-methylenedioxyphenyl group or a naphthyl group. The compound according to any one of claims 1 to 16, wherein the heteroaryl group is a pyridinyl group, or a salt thereof. The compound or a salt thereof according to any one of claims 1 to 16, wherein the heteroaryl group is a furanyl group, a thiophenyl group, an imidazolyl group, a pyrazolyl group, or a 1,2,3-triazolyl group. In the formula (I),
X ¹ is a thiol group, a hydroxyl group, or an amino group (—NH ₂ ),
The compound or a salt thereof according to any one of claims 2 to 18, wherein X ² is a nitrogen atom (-NH-). A viral infection inhibitor comprising the compound according to any one of claims 1 to 19, or a salt thereof. A pharmaceutical comprising the compound according to any one of claims 1 to 19, or a salt thereof. The pharmaceutical product according to claim 21, which is for viral infection. 23. The pharmaceutical product according to claim 22, wherein the virus is at least one virus selected from the group consisting of human immunodeficiency virus (HIV), human herpes virus, influenza virus and human hepatitis C virus (HCV). At least one of a pyrimidobenzothiazine-6-imine derivative (raw material A) and a pyrimidobenzothiazine-6-thione derivative (raw material B) is used as a synthetic raw material, and a thiophenol derivative is intermediated from the synthetic raw material. Intermediate production step obtained as a body, and
The method for producing a compound or a salt thereof according to any one of claims 1 to 19, further comprising an oxidation step of oxidizing the intermediate. The synthetic raw material is the pyrimidobenzothiazine-6-imine derivative (raw material A),
The production method according to claim 24, wherein the thiophenol derivative is obtained as an intermediate by acid decomposition of the synthetic raw material. The synthetic raw material is the pyrimidobenzothiazine-6-thione derivative (raw material B),
The production method according to claim 24, wherein the thiophenol derivative is obtained as an intermediate by alkaline decomposition of the synthetic raw material.