JP2003119137A - Hiv inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound and its pharmaceutically permissible salt effective for suppressing the HIV proliferation of affected cell of latency phase and enabling the suppression of the proliferation of virus in the latency phase from the infection with HIV to the development of AIDS. SOLUTION: The HIV inhibitor contains a compound of general formula (1) (the definition of the signs in the formula are described in the specification) or its pharmacologically permissible salt as an active component.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to HIV inhibitors.

[0002]

Acquired immunodeficiency syndrome (acquired immunodeficiency syndrome) was first recognized as an immunodeficiency syndrome among homosexuals in the 1980s.
ncysynthrome (AIDS; AIDS) is known as a highly fatal disease in which infection is spread worldwide in an instant. In 1983, the causative virus, human immunodeficiency virus (human immunodeficiency virus)
Deficiency virus, HIV) was discovered. The number of HIV-infected persons was approximately 5000 as of 2000.
It has been reported that it has reached tens of millions, and as many as two million deaths each year.

HIV is an RNA virus having an envelope, and its genome is a single-stranded plus-strand RNA and is classified into the lentivirus subfamily of the retroviridae. HIV
Has a reverse transcriptase in a virus particle and is characterized in that viral genetic information is transmitted from RNA through DNA. HIV uses T cells or macrophages as host cells, and when HIV infects these cells, reverse transcriptase synthesizes viral DNA, and this is integrated into the chromosome of the cell to establish infection. In addition, HIV makes viral RNA by transcription of the integrated viral genome and subsequent translation of viral proteins aligns the viral material and ultimately forms particles. As the fate of cells infected with HIV,
There are 1) cases in which cells die due to explosive growth of viruses, 2) cases in which a small amount of virus particles are continuously produced or survive in a non-production state. H
When an individual is infected with IV, cases such as 2) are taken, and the viral genome is lurking in the body for a long time.
When symptoms as AIDS appear, explosive virus proliferation occurs, and a marked decrease in the number of CD4-positive T cells is characteristic.

By the way, as the current state of AIDS therapeutic agents,
Many reverse transcriptase inhibitors and protease inhibitors are used. On the other hand, the development of compounds having new pharmacological actions is also underway. For example, as reverse transcriptase inhibitors, the following compounds are disclosed in Japanese Patent No. 2926257.

[0005]

[Chemical 14]

Further, the following compounds are disclosed in Japanese Patent No. 2951724 as protease inhibitors.

[0007]

[Chemical 15]

In addition, HIV-TAT (transactivating transcription)
as a suppressive agent of JP-A-4-23028.
The following compounds are disclosed in Japanese Unexamined Patent Publication No.

[0009]

[Chemical 16]

However, these compounds have completely different structures from the compounds of the present invention.

On the other hand, WO 95/24408 and WO 96/29077 disclose compounds represented by the following general formula as structurally similar compounds having HIV inhibitory activity.

[0012]

[Chemical 17]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, hydroxy, halogen, lower alkyl,
Lower alkoxy, benzyloxy, trifluoromethyl, nitro or —NR ₈ R ₉ (wherein R ₈ and R ₉ are each independently hydrogen or lower alkyl);
R ₅ and R ₆ are each independently hydrogen, lower alkyl or phenyl; X is O, S (O) n or NR ₇ ; Y is O, S (O) n or NR ₈ ; R ₇ is hydrogen,
Lower alkyl, phenyl, benzyl, CH ₂ OR ₈ or halogen-substituted lower alkyl, phenyl, benzyl; R ₈ is hydrogen, lower alkyl or phenyl; n is an integer of 0, 1 or 2; However, X is NH
, Y is NH, R ₁ is H, R ₃ is H, and R ₄ is Br, then R ₂ is not methyl. )

However, these documents (WO95 /
24408 and WO96 / 29077) are not structurally identical to the compounds of the present invention. Differences of the present compound from the literature compounds are listed below. First, while the literature compounds are tricyclic, the compounds of the present invention also include tetracyclic compounds. Secondly, the tricyclic compounds in the literature require a seven-membered ring, whereas the tricyclic compounds of the present application include those without a seven-membered ring. Thirdly, in the literature, in the compound in which X is O or S, X is O,
It is considered to be S and similar to the compound of the present invention in which ring A is a 7-membered ring, but R ¹ is different and not the same compound. Furthermore, in this document, regarding the mechanism of action of anti-HIV, the DNA LTR of HIV as in the present application is described.
There is no description that it has a transcription inhibitory effect from
There is no disclosure of data suggesting this.

[0015]

Currently, as therapeutic agents for AIDS, there are reverse transcriptase inhibitors and protease inhibitors (inhibitors of enzymes involved in processing of viral precursor protein into functional protein and structural protein). It is used. In addition, recently, HAART (highly active a) has been obtained by combining two or three of these drugs.
Antiretroviral therapy has been performed and its effect has been confirmed. However, there is a problem that a resistant virus against these drugs easily appears and side effects due to the drugs appear because the drug must be taken for a long period of time. Furthermore, HAART therapy cannot completely eliminate the virus that is lurking in the body, so that interruption of administration causes explosive virus multiplication. Therefore, development of an HIV inhibitor having a new mechanism of action is strongly desired.

[0016]

[Means for Solving the Problems] A reverse transcriptase inhibitor is an early process in the life cycle of a virus (virus DN
Protease inhibitors act on HIV in the process before A is integrated into the host chromosome), and in the late process (involved in processing of the viral precursor protein and particle formation). In contrast, the compound of the present invention having the structure of the following formula (1) suppresses HIV proliferation from infected cells in a latent state, unlike the conventional inhibitors. This allows HIV
The inventors of the present application have found that it is possible to suppress the growth of the virus seen in the latent period from infection of E. coli to the onset of AIDS, and completed the present invention. Further, it is considered that the compound of the present invention suppresses HIV proliferation in vivo by taking it during HAART treatment and after the treatment is interrupted.

More specifically, it is as shown in the following [1] to [38]. [1] As the active ingredient, the general formula (1)

[0018]

[Chemical 18]

[In the formula, ring A is

[0020]

[Chemical 19]

(In the formula, A ¹ is an alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, and 2 to 2 carbon atoms.
6 alkenyl group, phenylalkenyl group, haloalkenyl group, alkynyl group, acyl group having 2 to 11 carbon atoms, alkoxycarbonylalkyl group having 3 to 13 carbon atoms, carboxyalkyl group or-(CH ₂ ) _n -r ¹⁰ { here,
r ^{10 is, -CO-N (r 11)} (r 12) ( where, r ¹¹ and r ¹² are the same or different, is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or r ¹¹ And r ¹² together with the adjacent nitrogen atom,

[0022]

[Chemical 20]

(In the formula, r ¹³ is a hydrogen atom or a carbon number 1
~ 6 alkyl groups) may be formed),

[0024]

[Chemical 21]

(In the formula, r ¹⁴ and r ¹⁵ are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group or 5 Is a tetrazolyl group), and n is 1
Is an integer of 4 to 4, and A ² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a benzyl group, an acyl group having 2 to 11 carbon atoms, an acyloxyalkyl group. a dialkylcarbamoyl group alkoxycarbonylalkyl group of 3 to 13 carbon atoms, carbon atoms in the cyanoalkyl group or each alkyl group is 1 to 6, a ³
Is, -O -, - S- or -N (r ³⁰⁾ - {wherein, r
³⁰ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a benzyl group (wherein the benzyl group is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom or a nitro group). a substituted also be)}, a ⁴ and a ⁵ are the same or different, and represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or a ⁴
And A ⁵ may be combined with the carbon atom to which A ⁵ is bonded to form a cyclohexane ring, and A ⁶ is —S—, —SO—
Or -N (r ⁶⁰⁾ - (wherein, r ⁶⁰ is an alkyl group or an alkenyl group having 2 to 6 carbon atoms having 1 to 6 carbon atoms)
In and, A ⁷ is, -N = N -, - NH -CO -, - CH 2
_{-CH 2 -, - O-CO} -, - O-CS -, - N = C
(R ⁷⁰ ) − or —CH═C (r ⁷⁰ ) — (where r ⁷⁰
Is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms) (however, these groups are represented by the atom bonded to the nitrogen atom of the> C = N- group), and A ⁸ is = N. -O-r
⁸⁰ (wherein r ⁸⁰ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 11 carbon atoms, an alkoxycarbonylalkyl group having 3 to 13 carbon atoms, or a carbamoylalkyl group having 2 to 7 carbon atoms) , ═N—NH—r ⁸¹ (where r ⁸¹ is an acyl group having 2 to 11 carbon atoms or a carbamoyl group) or ═C—C (═O) —r ⁸² (where r is ⁸² is an alkoxy group having 1 to 6 carbon atoms or an amino group), and A ⁹ and A ¹⁰ are the same or different and each is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms).
R ¹ and R ² are the same or different and are a hydrogen atom, a halogen atom, an acyl group having 2 to 11 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a cyano group, a nitro group, 5 -Tetrazolyl group, -OR
¹⁰ [wherein R ¹⁰ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, —SO ₂ —R
¹¹ (wherein R ¹¹ is an alkyl group having 1 to 6 carbon atoms,

[0026]

[Chemical formula 22]

(Wherein R ¹² and R ¹³ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a halogen atom), — (CH ₂ ) _m —R ¹⁴ ( Here, R ¹⁴ is a dialkylamino group in which each alkyl group has 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, a cyano group or a nitrogen atom. It is a 5- or 6-membered heterocyclic residue contained in 4 rings, m is an integer of 1 to 4), and has 2 to 7 carbon atoms.
Alkyl carbamoyl group, each alkyl group has 1 carbon atom
Is a dialkylcarbamoyl group having 2 to 6 carbon atoms, an alkylaminothiocarbonyl group having 2 to 7 carbon atoms, or a dialkylaminothiocarbonyl group having 1 to 6 carbon atoms in each alkyl group], —SO ₂ —N (R ¹⁵ ). (R ¹⁶ ) [where R
¹⁵ and R ^{1 6} are the same or different and each is an alkyl group having 1 to 6 hydrogen atoms or carbon atoms which may be substituted with a hydroxyl group, or R ¹⁵ together with the nitrogen atom to which the R ¹⁶ is adjacent Become,

[0028]

[Chemical formula 23]

(In the formula, R ¹⁷ is a hydrogen atom or a carbon number 1
~ 6 alkyl groups), -CO
^{-N (R 18) (R 19} ) ( wherein, R ¹⁸ and R ^19, same or different, a hydrogen atom, an alkyl group or a phenyl group having 1 to 6 carbon atoms), - N (R ²⁰⁾ (R ²¹ )
(Here, R ²⁰ and R ²¹ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 11 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, or 2 carbon atoms. ~ 7 alkoxycarbonyl group or alkenylcarbamoyl group, or R ²⁰ and R ²¹ together with the adjacent nitrogen atom,

[0030]

[Chemical formula 24]

May be formed), --SR^{twenty two}[here
And R^{twenty two}Is an alkyl group having 1 to 6 carbon atoms or -CO-
N (R^{twenty three}) (R^{twenty four}) (Where R^{twenty three}And R^{twenty four}Are the same
Or, differently, a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
Group), or --SO₂-R^{twenty five}(here,
R^{twenty five}Is an alkoxy group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms
Alkyl group, alkenyl group having 2 to 6 carbon atoms or benzyl
X is a sulfur atom, an oxygen atom, or -C.
H₂-CH₂-, -CH = CH- or -C (X ²⁰) (X
^{twenty one})-(Where X²⁰And X^{twenty one}Are the same or different
Is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms)
Provided that when ring A is a ring represented by formula (Aa)
If A¹Is an alkyl group having 1 to 6 carbon atoms, A²Is hydrogen
When it is an atom, R¹Is a hydrogen atom, nitro group, halogen
Atom, -OR^Ten(Where R^TenIs hydrogen atom or charcoal
Is an alkyl group having a prime number of 1 to 6) and -N (R²⁰)
(R^{twenty one}) (Where R²⁰And R^{twenty one}Are the same or different
A hydrogen atom or an alkyl group having 1 to 6 carbon atoms
A) or a compound represented by
An HIV inhibitor comprising a pharmaceutically acceptable salt. [2] The ring A is a ring represented by the formula (Aa),
The HIV inhibitor according to [1]. [3] R¹Is a hydrogen atom, a halogen atom, or a carbon number of 2 to 1.
1 acyl group, carboxyl group, C2-C7 alcohol
Xycarbonyl group, cyano group, nitro group, 5-tetrazo
Ryl group, -OR^Ten(In the formula, R^TenIs synonymous with [1] above
Yes, -SO₂-N (R¹⁵) (R¹⁶) (Where R is¹⁵Oh
And R¹⁶Is synonymous with the above [1]), -CO-N (R
¹⁸) (R¹⁹) (Where R is¹⁸And R¹⁹Is the same as [1] above
Meaning), -N (R²⁰) (R^{twenty one}) (Where R is²⁰and
R^{twenty one}Is synonymous with the above [1]), -SR^{twenty two}(here
And R^{twenty two}Is synonymous with the above [1]) or -SO₂−
R^{twenty five}(In the formula, R^{twenty five}Is synonymous with [1] above, and
R²Is a hydrogen atom, and X is a sulfur atom or an acid.
The HIV inhibitor according to [2] above, which is an elementary atom. [4] HIV inhibition according to the above [3], wherein X is a sulfur atom
Agent. [5] R¹Is a halogen atom, nitro group, -OR
^Ten(In the formula, R^TenIs the same as the above [1]) or -S
-R^{twenty two}(In the formula, R^{twenty two}Is the same as the above [1])
The HIV inhibitor according to [4] above. [6] A¹Is an alkyl group having 1 to 6 carbon atoms and 2 to 2 carbon atoms
6 alkenyl group, alkynyl group, 3 to 13 carbon atoms
Lucoxycarbonylalkyl group or-(CH₂)_n-R
^Ten(Where n and r^TenIs synonymous with [1] above)
An HIV inhibitor according to [5] above. [7] HIV inhibition according to the above [2], wherein X is an oxygen atom.
Agent. [8] R¹Is a halogen atom, nitro group, -OR
^Ten(In the formula, R^TenIs the same as the above [1]) or -S
-R^{twenty two}(In the formula, R^{twenty two}Is the same as the above [1])
The HIV inhibitor according to [7] above. [9] A¹Is an alkyl group having 1 to 6 carbon atoms and 2 to 2 carbon atoms
6 alkenyl group, alkynyl group, 3 to 13 carbon atoms
Lucoxycarbonylalkyl group or-(CH₂)_n-R
^Ten(Where n and r^TenIs synonymous with [1] above)
An HIV inhibitor according to [8] above. [10] The ring A is a ring represented by the formula (Ab),
The HIV inhibitor according to [1]. [11] R¹And R²But the same or different
A child, a hydroxyl group or an alkoxy group having 1 to 6 carbon atoms,
And X is -CH₂-CH₂-, -CH = CH- or-
C (X²⁰) (X^{twenty one})-(Wherein X²⁰And X^{twenty one}Is above
(Synonymous with [1])
Harmful agent. [12] A³Is -O-, the HIV blocker of [11] above.
Harmful agent. [13] A³Is -S-, the HIV blocker of [11] above.
Harmful agent. [14] A³Is -N (r³⁰)-(Where r³⁰Is above
(Synonymous with [1])
Harmful agent. [15] X is -C (X²⁰) (X^{twenty one})-(Wherein X²⁰And
And X^{twenty one}Is the same as [1] above, and the above [1
The HIV inhibitor according to any one of 0] to [14]. [16] R¹Is a hydrogen atom, and R²Is a carbon number of 1 to 6
Is a lucoxy group, A^FourIs a hydrogen atom, and A^FiveBut water
The HIV inhibitor according to [15] above, which is an elementary atom. [17] X is -CH₂-CH₂-The above [10]-
The HIV inhibitor according to any one of [14]. [18] R¹Is a hydrogen atom, and R²Is a carbon number of 1 to 6
Is a lucoxy group, A^FourIs a hydrogen atom, and A^FiveBut water
The HIV inhibitor according to [17] above, which is an elementary atom. [19] X is -CH = CH-, and the above [10]-
The HIV inhibitor according to any one of [14]. [20] R¹Is a hydrogen atom, and R²Is a carbon number of 1 to 6
Is a lucoxy group, A^FourIs a hydrogen atom, and A^FiveBut water
The HIV inhibitor according to [19] above, which is an elementary atom. [21] The ring A is the ring represented by formula (Ac),
The HIV inhibitor according to [1]. [22] R¹Is a hydrogen atom, a nitro group or a carbon number of 1 to
An alkoxy group of 6, R²Is a hydrogen atom
Where X is a sulfur atom, HIV inhibition according to [21] above
Agent. [23] R¹Is an alkoxy group having 1 to 6 carbon atoms
The HIV inhibitor according to [22] above. [24] A⁷Is -N = C (r⁷⁰)-Or -CH = C
(R⁷⁰)-(Where r⁷⁰Is the same as [1] above.
HIV inhibition according to any of [21] to [23] above
Agent. [25] A⁶Is -S-, [21] to [24] above.
HIV inhibitor of any of. [26] A⁶Is -N (r⁶⁰)-(Where r⁶⁰Is above
The above [21] to [24], which are synonymous with [1].
HIV inhibitor of any of. [27] The ring A is a ring represented by the formula (Ad),
The HIV inhibitor according to [1]. [28] R¹Is an alkoxy group having 1 to 6 carbon atoms,
R²Is a hydrogen atom, and X is a sulfur atom,
The HIV inhibitor according to [27] above. [29] R¹Is a methoxy group, H of [28] above
IV inhibitors. [30] A⁸Is = N-O-r⁸⁰(In the formula, r⁸⁰Is above
[27] to [29], which are synonymous with [1].
HIV inhibitor of any of. [31] r⁸⁰Is a hydrogen atom or an acyl group having 2 to 11 carbon atoms.
A HI group according to any one of the above [27] to [30]
V inhibitor. [32] As the active ingredient, the compound represented by the general formula (1 ′)

[0032]

[Chemical 25]

(In the formula, R ¹ is a hydrogen atom, a halogen atom, an acyl group having 2 to 11 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a cyano group, a nitro group, a 5-tetrazolyl group, -OR ¹⁰ [where R
¹⁰ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, and 2 carbon atoms
6 alkenyl group, -SO ₂ -R ¹¹ (wherein, R
¹¹ is an alkyl group having 1 to 6 carbon atoms,

[0034]

[Chemical formula 26]

(In the formula, R ¹² and R ¹³ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a halogen atom),-(CH ₂ ) _m -R ¹⁴ ( Here, R ¹⁴ is a dialkylamino group in which each alkyl group has 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, a cyano group or a nitrogen atom. It is a 5- or 6-membered heterocyclic residue contained in 4 rings, m is an integer of 1 to 4), and has 2 to 7 carbon atoms.
Alkyl carbamoyl group, each alkyl group has 1 carbon atom
Is a dialkylcarbamoyl group having 2 to 6 carbon atoms, an alkylaminothiocarbonyl group having 2 to 7 carbon atoms, or a dialkylaminothiocarbonyl group having 1 to 6 carbon atoms in each alkyl group], —SO ₂ —N (R ¹⁵ ). (R ¹⁶ ) [where R
¹⁵ and R ^{1 6} are the same or different and each is an alkyl group having 1 to 6 hydrogen atoms or carbon atoms which may be substituted with a hydroxyl group, or R ¹⁵ together with the nitrogen atom to which the R ¹⁶ is adjacent Become,

[0036]

[Chemical 27]

(In the formula, R ¹⁷ is a hydrogen atom or a carbon number 1
~ 6 alkyl groups), -CO
^{-N (R 18) (R 19} ) ( wherein, R ¹⁸ and R ^19, same or different, a hydrogen atom, an alkyl group or a phenyl group having 1 to 6 carbon atoms), - N (R ²⁰⁾ (R ²¹ )
(Here, R ²⁰ and R ²¹ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 11 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, or 2 carbon atoms. ~ 7 alkoxycarbonyl group or alkenylcarbamoyl group, or R ²⁰ and R ²¹ together with the adjacent nitrogen atom,

[0038]

[Chemical 28]

May be formed), --S--R ²² [wherein R ²² is an alkyl group having 1 to 6 carbon atoms or --CO--
N (R ²³ ) (R ²⁴ ) (wherein R ²³ and R ²⁴ are the same or different and each is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms)], or —SO ₂ —R ²⁵ (here,
R ²⁵ is an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or a benzyl group), and A ^{1 ′} has 1 to 6 carbon atoms. Hydroxyalkyl group, alkenyl group having 2 to 6 carbon atoms, phenylalkenyl group, haloalkenyl group, alkynyl group, acyl group having 2 to 11 carbon atoms, alkoxycarbonylalkyl group having 3 to 13 carbon atoms, carboxyalkyl group or-
(CH _{2) n} -r ¹⁰ (wherein, r ¹⁰ are, -CO-N
(R ¹¹ ) (r ¹² ) (where r ¹¹ and r ¹² are the same or different and each is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or a nitrogen atom in which r ¹¹ and r ¹² are adjacent to each other. Together with the atom,

[0040]

[Chemical 29]

(In the formula, r ¹³ is a hydrogen atom or a carbon number 1
~ 6 alkyl groups) may be formed),

[0042]

[Chemical 30]

(In the formula, r ¹⁴ and r ¹⁵ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group or 5 Is a tetrazolyl group), and n is 1
Is an integer of 4 to 4), and A ² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a benzyl group, an acyl group having 2 to 11 carbon atoms, an acyloxyalkyl group. A C3 to C13 alkoxycarbonylalkyl group, a cyanoalkyl group or a dialkylcarbamoyl group in which each alkyl group has 1 to 6 carbon atoms, and X ^'
Is a sulfur atom or an oxygen atom. ), Which comprises a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
V inhibitor. [33] X ^'is a sulfur atom, HIV above [32]
Inhibitor. [34] R ¹ is a halogen atom, a nitro group, —O—R ¹⁰
(In the formula, R ¹⁰ has the same meaning as [32] above) or -S
The HIV inhibitor according to [33] above, which is -R ²² (wherein R ²² has the same meaning as the above [32]). [35] A ^{1 'is} an alkenyl group having 2 to 6 carbon atoms, an alkynyl group, or an alkoxycarbonylalkyl group having 3 to 13 carbon atoms ^{_{- (CH 2) n -r 10}} ( wherein, n and r ¹⁰ is the (Synonymous with [32]), H in [34] above
IV inhibitors. [36] X ^'is an oxygen atom, HIV above [32]
Inhibitor. [37] R ¹ is a halogen atom, a nitro group, —O—R ¹⁰
(In the formula, R ¹⁰ has the same meaning as [32] above) or -S
The HIV inhibitor according to [36] above, which is -R ²² (wherein R ²² has the same meaning as in [32] above). [38] A ^{1 ′} represents an alkenyl group having 2 to 6 carbon atoms, an alkynyl group, an alkoxycarbonylalkyl group having 3 to 13 carbon atoms or — (CH ₂ ) _n —r ¹⁰ (wherein n and r ¹⁰ are the above. (Synonymous with [32]), H in [37] above
IV inhibitors.

[0044]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
The “halogen atom” in the present invention is a bromine atom, a fluorine atom, a chlorine atom, or an iodine atom. A bromine atom, a fluorine atom, a chlorine atom in R ¹ , a chlorine atom in R ¹² and R ¹³ , a chlorine atom in r ¹⁴ and r ¹⁵ ,
A fluorine atom is preferred. The halogen atom which is a substituent of the benzyl group for r ³⁰ is preferably a chlorine atom.

The "alkyl group having 1 to 6 carbon atoms" means carbon
A linear or branched alkyl group having a number of 1 to 6,
For example, methyl group, ethyl group, n-propyl group, isoprene
Ropyl group, n-butyl group, isobutyl group, sec-butyl
Group, tert-butyl group, pentyl group, isopentyl group
Group, hexyl group, isohexyl group and the like. A ⁹
And A^TenIn the above, an alkyl group having 1 to 4 carbon atoms (for example,
For example, methyl group, ethyl group, n-propyl group, n-butyl
Group) is preferable, and a methyl group is particularly preferable. r⁸⁰
In, the alkyl group having 1 to 4 carbon atoms (for example, methyl group
Group, ethyl group, n-propyl group, n-butyl group) is preferred.
The methyl group is particularly preferable. R^TenAt carbon
Number 1 to 3 alkyl (especially methyl, ethyl, n-propy
R, isopropyl); R¹¹In methyl; R¹²And
And R¹³In methyl; R¹⁷In methyl; R¹⁸
And R¹⁹In methyl; R²⁰And R^{twenty one}At
Is methyl; R^{twenty two}In, methyl, ethyl; R^{twenty three}and
R^{twenty four}In methyl; R ^{twenty five}In, methyl, ethi
Le; A¹In the above, alkyl having 2 to 5 carbon atoms (especially ethyl
Ru, n-propyl, n-butyl, isobutyl, isopene
Chill); r¹¹And r ¹²Where is methyl; r¹³smell
Is methyl; r¹⁴And r¹⁵In methyl; A²To
Where methyl, ethyl; A^FourAnd A^FiveIn meth
Le; r³⁰In, ethyl, n-propyl, n-butyl
, Isobutyl, pentyl, isopentyl, hexyl,
Isohexyl, etc .; X²⁰And X^{twenty one}Has 1 to 1 carbon atoms
4 alkyls (eg methyl, ethyl, n-propyi)
, N-butyl, etc.) are preferred. r⁶⁰Is the carbon number
1 to 4 alkyl groups (eg, methyl group, ethyl group, n
-Propyl group, isopropyl group, n-butyl group, isobutane
(A chill group) is preferable, and an isobutyl group is particularly preferable. r
⁷⁰In the above, an alkyl group having 1 to 4 carbon atoms (for example, methyl group
Group, ethyl group, n-propyl group, n-butyl group) is preferred.
Methyl group is particularly preferable. R¹And R²
Is an alkyl group having 1 to 4 carbon atoms (for example, methyl
Group, ethyl group, n-propyl group, n-butyl group) is preferred.
However, a methyl group is particularly preferable. r³⁰In
And an alkyl group having 1 to 6 carbon atoms which is a substituent of the benzyl group
Of these, methyl is preferred.

"Hydroxyalkyl group having 1 to 6 carbon atoms"
The "alkyl group" has the same meaning as the above-mentioned "alkyl group having 1 to 6 carbon atoms", and the alkyl group is a group substituted with a hydroxyl group, and the substitution position of the hydroxyl group is not particularly limited.
For example, hydroxymethyl; 1- or 2-hydroxyethyl; 1-, 2- or 3-hydroxypropyl; 1
-, 2-, 3- or 4-hydroxybutyl; 1-2
-, 3-, 4- or 5-hydroxypentyl; 1-,
2-, 3-, 4-, 5- or 6-hydroxyhexyl; 2-hydroxy-2-methylethyl and the like can be mentioned, and 2-hydroxyethyl is particularly preferable for A ¹ and A ^{1 ′} .

"1 carbon atom which may be substituted with a hydroxyl group
The "alkyl group having 6 to 6" is a group in which the "alkyl group having 1 to 6 carbon atoms" has the same meaning as the above "alkyl group having 1 to 6 carbon atoms", and the alkyl group may be substituted with a hydroxyl group. The substitution position of the hydroxyl group is not particularly limited. Examples of the case of being substituted with a hydroxyl group include those similar to the above-mentioned “hydroxyalkyl group having 1 to 6 carbon atoms”. In R ¹⁵ and R ¹⁶ , methyl and 2-hydroxyethyl are preferable.

The "alkoxy group having 1 to 6 carbon atoms" is charcoal.
Linear or branched alkoxy group having a prime number of 1 to 6
And, for example, methoxy group, ethoxy group, propoxy group
Group, isopropoxy group, butoxy group, isobutoxy group,
sec-butoxy group, tert-butoxy group, pentoxy group
And a hexyloxy group and the like. r⁸²At
Is preferably an alkoxy group having 1 to 4 carbon atoms (for example,
Toxy group, ethoxy group, n-propoxy group, n-butoxy group
Si group), particularly preferably a methoxy group. R ¹⁴smell
Is methoxy, ethoxy; R^{twenty five}Where ethoxy; r
¹⁴And r¹⁵In the above, methoxy is preferable. r³⁰To
Alkoxy having 1 to 6 carbon atoms which is a substituent of a benzyl group
As the si group, methoxy is preferable.

The "acyl group having 2 to 11 carbon atoms" includes, for example, alkylcarbonyl (eg, acetyl, propionyl, butyryl, valeryl, pivaloyl, etc., preferably alkylcarbonyl having 2 to 5 carbon atoms), arylcarbonyl group ( Examples thereof include benzoyl and naphthoyl. In R ¹ and R ² , alkylcarbonyl having 2 to 3 carbon atoms (especially acetyl); R ²⁰ and R ²¹
Alkylcarbonyl (especially acetyl, propionyl) of 2 to 3 carbon atoms in; A ¹ and in A ^{1 'alkylcarbonyl} having 2 to 3 carbon atoms (especially acetyl); A
Alkylcarbonyl having 2 to 3 carbon atoms in the ² (especially acetyl), an arylcarbonyl group (especially benzoyl) of 7-8 carbon atoms; 2 carbon atoms in the r ⁸⁰ and r ⁸¹
Alkylcarbonyl of 4 (eg, acetyl group, propionyl group, butyryl group, especially acetyl group) is preferable.

The "alkoxycarbonyl group having 2 to 7 carbon atoms" is a group in which the "alkoxy moiety" has the same meaning as the above "alkoxy group having 1 to 6 carbon atoms", and is an alkoxycarbonyl group having 1 to 4 carbon atoms. preferable. For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t
ert-butoxycarbonyl, pentoxycarbonyl,
Hexyloxycarbonyl and the like are mentioned, and in R ¹ and R ² , methoxycarbonyl; in R ¹⁴ , methoxycarbonyl; and in R ²⁰ and R ²¹ , ethoxycarbonyl is particularly preferable.

The "alkoxycarbonylalkyl group having 3 to 13 carbon atoms" means that the "alkoxy moiety" has 1 to 6 carbon atoms.
(Synonymous with the above “C1-6 alkoxy group”), preferably a linear or branched alkoxy group having 1 to 4 and an “alkyl portion” having 1 to 6 carbon atoms (the above “carbon”). Synonymous with "alkyl group of 1 to 6"), preferably a linear or branched alkyl group of 1 to 4. For example, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl, isobutoxycarbonylmethyl group, sec-butoxycarbonylmethyl, tert-butoxycarbonylmethyl, pentyloxycarbonylmethyl, neopentyloxycarbonyl. Methyl, hexyloxycarbonylmethyl, etc .;
Those in which these methyls are replaced with ethyl, propyl, butyl, pentyl, hexyl and the like can be mentioned. In r ⁸⁰ , an alkoxycarbonylalkyl group having 3 to 6 carbon atoms (eg, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, n-propoxycarbonylmethyl group, n-butoxycarbonylmethyl group, etc.)
Is preferred, and a methoxycarbonylmethyl group is particularly preferred. Ethoxycarbonylmethyl for A ¹ and A ^{1 ′} ; methoxycarbonylmethyl for A ² is particularly preferred.

The "alkenyl group having 2 to 6 carbon atoms" is a linear or branched alkenyl group having 2 to 6 carbon atoms, for example, vinyl group; allyl group; isopropenyl group;
Butenyl group (1-, 2- or 3-butenyl group); 2-
Methyl-2-propenyl group; pentenyl group (1-, 2
-, 3- or 4-pentenyl group); 3-methyl-2-
Butenyl; hexenyl (1-, 2-, 3-, 4- or 5-hexenyl), and the like, in r ⁶⁰ 2-methyl-2-propenyl group; in R ^25; allyl in R ¹⁰ Is allyl; in A ¹ and A ^{1 ′} , alkenyl having 3 to 5 carbon atoms (especially allyl, 2-methyl-
2-propenyl, 3-methyl-2-butenyl); in A ² , alkenyl having 3 to 4 carbon atoms (especially allyl, 2-
Methyl-2-propenyl) is preferred.

The "phenylalkenyl group" is a group in which the "alkenyl group" has the same meaning as the above "alkenyl group having 2 to 6 carbon atoms", and the alkenyl group is substituted with a phenyl group. The position is not particularly limited. For example, styryl; 1- (2- or 3-) phenyl-1-
(Or -2-) propenyl; 1- (2-, 3- or 4-) phenyl-1-(-2- or -3-) butenyl; 1- (2-, 3-, 4- or 5-) Phenyl-1
-(-2-, -3- or -4-) pentenyl, 1-
(2-, 3-, 4-, 5- or 6-) phenyl-1-
(-2-, -3-, -4- or -5) -hexenyl;
And the like, and phenylpropenyl (particularly 3-phenyl-2-propenyl) is preferable for A ¹ and A ^{1 ′} .

The "haloalkenyl group" is a group in which the "alkenyl group" has the same meaning as the above "alkenyl group having 2 to 6 carbon atoms" and the "halogen atom" has the same meaning as the above "halogen atom". The substitution position of the halogen atom is not particularly limited. Examples of the haloalkenyl group include 1- (or 2-) chlorovinyl; 1- (2- or 3-) chloro-1- (or-2-) propenyl; 1- (2-, 3
-Or 4-) chloro-1-(-2- or -3-) butenyl; 1- (2-, 3-, 4- or 5-) chloro-
1-(-2-, -3- or -4-) pentenyl, 1-
(2-, 3-, 4-, 5- or 6-) chloro-1-
(-2-, -3-, -4- or -5) -hexenyl;
Examples thereof include those in which chloro is substituted with bromo, iodo or fluoro, and chloropropenyl (particularly 2-chloro-2-propenyl) is preferable for A ¹ and A ^{1 ′} .

The "carbamoylalkyl group having 2 to 7 carbon atoms" is a group in which the "alkyl group" has the same meaning as the above "alkyl group having 1 to 6 carbon atoms", and the alkyl group is substituted with a carbamoyl group. The substitution position of the carbamoyl group is not particularly limited. Examples thereof include a carbamoylmethyl group, a carbamoylethyl group, a carbamoylpropyl group, a carbamoylbutyl group, a carbamoylpentyl group and a carbamoylhexyl group, and a carbamoylmethyl group is preferable. R ⁸⁰ is preferably a carbamoylalkyl group having 2 to 5 carbon atoms (eg, carbamoylmethyl group, carbamoylethyl group, carbamoylpropyl group, carbamoylbutyl group), and particularly preferably carbamoylmethyl group.

The "dialkylamino group in which each alkyl group has 1 to 6 carbon atoms" has the same meaning as that of each "alkyl moiety" and the above "alkyl group having 1 to 6 carbon atoms". The groups may be the same or different, and examples thereof include dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino and dihexylamino. R ¹⁴ is particularly preferably dimethylamino.

The "5- or 6-membered heterocyclic residue containing 1 to 4 nitrogen atoms in the ring" means, for example, pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl,
Pyridyl, pyrazinyl, tetrazolyl; pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, piperidinyl and the like, and in R ¹⁴ , pyridyl, 5-
Tetrazolyl is especially preferred.

In the "alkyl carbamoyl group having 2 to 7 carbon atoms", the "alkyl portion" is the same as the above "alkyl group having 1 to 6 carbon atoms", and examples thereof include methylcarbamoyl, ethylcarbamoyl and propylcarbamoyl. , Butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl and the like.

The “dialkylcarbamoyl group having 1 to 6 carbon atoms in each alkyl group” means that each “alkyl part” has the same meaning as the above “alkyl group having 1 to 6 carbon atoms”, and
Each "alkyl group" is the same or different, and examples thereof include dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, dibutylcarbamoyl, dipentylcarbamoyl, dihexylcarbamoyl, etc., and dimethylcarbamoyl is particularly preferable for R ¹⁰ and A ² . .

The “dialkylaminothiocarbonyl group having 1 to 6 carbon atoms in each alkyl group” means that each “alkyl part” has the same meaning as the above “alkyl group having 1 to 6 carbon atoms”, and each alkyl group Are the same or different groups, and examples thereof include dimethylaminothiocarbonyl, diethylaminothiocarbonyl, dipropylaminothiocarbonyl, dibutylaminothiocarbonyl, dipentylaminothiocarbonyl, dihexylaminothiocarbonyl, and the like. R ¹⁰ is dimethylamino. Thiocarbonyl is preferred.

The "alkylaminothiocarbonyl group having 2 to 7 carbon atoms" is an alkyl group having an alkyl portion having 1 to 6 carbon atoms, and the above "alkyl group having 1 to 6 carbon atoms".
And a group having the same meaning as, for example, methylaminothiocarbonyl, ethylaminothiocarbonyl, propylaminothiocarbonyl, butylaminothiocarbonyl, pentylaminothiocarbonyl, hexylaminothiocarbonyl and the like.

The term "carboxyalkyl group" means that the "alkyl group" has the same meaning as the above "alkyl group having 1 to 6 carbon atoms", and the alkyl group is substituted with a carboxyl group. The substitution position is not particularly limited.
It may be substituted at any position of the alkyl group, for example,
Carboxymethyl; 1- or 2-carboxyethyl;
1-, 2- or 3-carboxypropyl; 1-2
-, 3- or 4-carboxybutyl; 1-, 2-, 3
-, 4- or 5-carboxypentyl; 1-, 2-,
3-, 4-, 5- or 6-carboxyhexyl and the like can be mentioned, and carboxymethyl is particularly preferable for A ¹ and A ^{1 ′} .

"Alkylsulfonyl group having 1 to 6 carbon atoms"
Means that the alkyl part is the above "alkyl group having 1 to 6 carbon atoms".
A group having the same meaning as, for example, methylsulfonyl; ethylsulfonyl; 1- or 2-propylsulfonyl;
1- or 2-butylsulfonyl; 1-, 2- or 3
—Pentylsulfonyl; 1-, 2- or 3-hexylsulfonyl and the like can be mentioned, and in R ²⁰ and R ²¹ , methylsulfonyl is particularly preferable.

The "alkenylcarbamoyl group" is a group in which the alkenyl moiety is a linear or branched alkenyl group having preferably 2 to 5 carbon atoms, for example, vinylcarbamoyl; allylcarbamoyl; 1-, 2- or 3-butenylcarbamoyl; 1-, 2-, 3- or 4-pentenylcarbamoyl; 1-, 2-, 3-, 4-
Or 5-hexenylcarbamoyl and the like, R
^{For 20} and R ²¹ , allylcarbamoyl is particularly preferred.

The "alkynyl group" is a linear or branched alkynyl group having preferably 2 to 6 carbon atoms, more preferably 3 to 5 carbon atoms, for example, ethynyl;
Or 2-propynyl; 1-, 2- or 3-butynyl; 1-, 2-, 3- or 4-pentynyl; 1-2
-, 3-, 4- or 5-hexynyl and the like,
In A ¹ and A ^{1 ′} , 2-propynyl, 2-butynyl and 2-pentynyl are particularly preferable.

The "acyloxyalkyl group" includes the above-mentioned "acyl group having 2 to 11 carbon atoms" in the acyl portion, and the "alkyl portion" preferably has 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. A group which is a linear or branched alkyl group. For example, acetylmethyl, propionylmethyl, butyrylmethyl, pivaloylmethyl, benzoylmethyl, naphthoylmethyl, and the like; those in which these methyls are replaced with ethyl, propyl, butyl, etc., and tert-butanoyloxymethyl in A ² Is particularly preferable.

The "cyanoalkyl group" is preferably an "alkyl group" having 1 to 6 carbon atoms, more preferably 1 to 6 carbon atoms.
4 is a linear or branched alkyl group, wherein the cyano group may be substituted at any position of the alkyl group,
For example, cyanomethyl, cyanoethyl, cyanobutyl,
Examples thereof include cyanopropyl, cyanopentyl, cyanohexyl, and cyanomethyl is particularly preferable for A ² .

Specific examples of —SO ₂ —R ¹¹ in R ¹⁰ include p-tolylsulfonyl, methylsulfonyl, p-chlorophenylsulfonyl, 2-naphthylsulfonyl, 1-naphthylsulfonyl, 8-quinolinylsulfonyl and the like. Can be mentioned.

Preferable specific examples of-(CH ₂ ) _m -R ¹⁴ in R ¹⁰ include dimethylaminoethyl, 2-ethoxyethyl, (3-pyridyl) methyl and (2-pyridyl).
Methyl, methoxymethyl, methoxycarbonylmethyl,
Examples thereof include cyanomethyl, (5-tetrazolyl) methyl, (4-pyridyl) methyl and the like.

--SO ₂ --N at R ¹ and R ²
Specific examples of (R ¹⁵ ) and (R ¹⁶ ) include pyrrolidinylsulfonyl, (2-hydroxyethyl) aminosulfonyl,
4-Methyl-piperazinylsulfonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl and the like can be mentioned.

--CO--N (R ¹⁸ ) in R ¹ and R ²
Preferred specific examples of (R ¹⁹ ) include methylcarbamoyl, dimethylcarbamoyl and phenylcarbamoyl.

--N (R ²⁰ ) in R ¹ and R ²
Specific preferred examples of (R ²¹ ) include amino, ethoxycarbonylamino, allylcarbamoylamino, dimethylamino, methoxycarbonylamino, methylsulfonylamino, 1-piperidinyl, 2,5-dioxopyrrolidin-1-yl, 1- Pyrrolyl, 1-triazolyl,
2,4-dihydro-2-oxooxazol-3-yl may be mentioned.

Preferred examples of -S-R ²² in R ¹ and R ² include methylthio, ethylthio, dimethylcarbamoylthio and the like.

--CO--N (R ²³ ) (R ²⁴ ) at R ²²
As a preferred specific example of, dimethylcarbamoyl can be mentioned.

Preferable specific examples of --SO ₂ --R ²⁵ in R ¹ and R ² include methylsulfonyl, ethylsulfonyl, ethoxysulfonyl, allylsulfonyl, benzylsulfonyl and the like.

Preferred examples of -O-R ¹⁰ in R ¹ and R ² include methoxy, ethoxy, allyloxy, n-propyloxy, hydroxy, dimethylcarbamoyloxy, dimethylaminothiocarbonyloxy,
Isopropyloxy; dimethylaminoethoxy, 2-ethoxyethoxy, (3-pyridyl) methoxy, (2-pyridyl) methoxy, methoxymethoxy, methoxycarbonylmethoxy, cyanomethoxy, (5-tetrazolyl)
Methoxy, (4-pyridyl) methoxy; p-tolylsulfonyloxy, methylsulfonyloxy, p-chlorophenylsulfonyloxy, 2-naphthylsulfonyloxy, 1-naphthylsulfonyloxy, 8-quinolinylsulfonyloxy and the like can be mentioned.

--CO--N (r ¹¹ ) (r ¹² ) at r ¹⁰ .
Preferred specific examples of include dimethylcarbamoyl, carbamoyl and the like.

-(CH ₂ ) _n -r in A ¹ and A ^{1 '}
Preferred specific examples of ¹⁰ are dimethylcarbamoylmethyl; carbamoylmethyl; 4-methylpiperazinylcarbonylmethyl; pyrrolidinylcarbonylmethyl; m
-, P- and o-methoxybenzyl; m-, p- and o-methylbenzyl; m-, p- and o-chlorobenzyl; m- and p-nitrobenzyl; p-cyanobenzyl; 4- (2H- Tetrazol-5-yl) benzyl; benzyl; m- and o-fluorobenzyl; and the like.

In the optionally substituted naphthyl and the optionally substituted quinolyl represented by R ¹¹ , the substituent and the bonding position may be present in any of the rings constituting the condensed ring.

The 5-tetrazolyl group in the present invention is 1
H-tetrazol-5-yl, 2H-tetrazole-5
-Including yl.

In the present invention, the following formula (1)

[0082]

[Chemical 31]

The compound represented by the formula (wherein each symbol has the same meaning as defined above), or a pharmaceutically acceptable salt thereof, has a new mechanism of action different from that of the conventional inhibitors, that is,
It is a group of compounds useful as HIV inhibitors that suppress viral growth by inhibiting transcription from viral DNA (LTR) integrated into the host chromosome. In addition, since the compound of the present application has a different mechanism of action from the conventional inhibitors, it is considered that the compound of the present application is effective in suppressing a virus resistant to a reverse transcriptase inhibitor or a protease inhibitor. From the above, the compound of the present invention can control the growth of the virus observed in the latent period from HIV infection to the onset of AIDS.

The compounds of the formulas (1) and (1 ′) of the present invention may have an asymmetric carbon, in which case the optically pure enantiomer, its racemic form, or a combination and a ratio thereof are used. There is a mixture that is optional,
The present invention includes HIV inhibitors consisting of any of those isomers. In the case of a racemate, only one optically active substance can be obtained by an optical resolution method if necessary, and only one optically active substance can be directly obtained by using an asymmetric synthesis method. Further, the compounds of the formulas (1) and (1 ′) of the present invention may optionally be hydrates or solvates.

In the compound of formula (1) of the present invention, when ring A is a group represented by (Aa) above and R ² is a hydrogen atom (hereinafter, also referred to as compound (1a)), Suitable R ¹ is a halogen atom, a nitro group, —O—R ¹⁰ (R
¹⁰ has the same meaning as above) and -S-R ²² (R ²² has the same meaning as above), and suitable A ¹ is an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms. , an alkynyl group, an alkoxycarbonylalkyl group having 3 to 13 carbon atoms and - a ^{_{(CH 2) n -r 10 (}} n and r ¹⁰ are as defined above). More preferably, both R ¹ and A ¹ are the suitable substituents mentioned above.

Of the compounds (1a) of the present invention, those of the formula (1 ′)

[0087]

[Chemical 32]

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is preferable, and a suitable R in the compound is
¹ is a halogen atom, a nitro group, —O—R ¹⁰ (R ¹⁰ is as defined above) and —S—R ²² (R ²² is as defined above), and suitable A ^{1 ′} is alkenyl group, an alkynyl group having 2 to 6 carbon atoms, an alkoxycarbonylalkyl group of 3 to 13 carbon atoms and - a ^{_{(CH 2) n -r 10 (}} n and r ¹⁰ are as defined above). More preferably, both R ¹ and A ^{1 ′} are the suitable substituents mentioned above.

In the compound of formula (1) of the present invention, when ring A is a group represented by the above (Ab) (hereinafter, also referred to as compound (1b)), preferable R ¹ is hydrogen atom. There, R ² is an alkoxy group having 1 to 6 carbon atoms, preferred a ⁴ and a ⁵ are hydrogen atoms, preferred a ³ are -
O -, - S- or -N (r ³⁰⁾ - (wherein, r ³⁰ is
A hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a benzyl group (wherein the benzyl group may be substituted with a methyl group, a methoxy group, a chlorine atom or a nitro group), and X _{is, -CH 2 -CH 2 -, -} CH =
CH- or ^{-C (X 20) (X 21} ) - ( wherein, X ²⁰ and X ²¹ are the same or different, a hydrogen atom or an alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group,
n-propyl group, n-butyl group)).

In the compound of the formula (1) of the present invention, when ring A is a group represented by the above (Ac) and R ² is a hydrogen atom (hereinafter, also referred to as compound (1c)), Suitable R ¹ is an alkoxy group having 1 to 6 carbon atoms (specifically, a methoxy group), and suitable A ⁶ is —S— or —N.
(R ⁶⁰⁾ - (r ⁶⁰ is preferably an alkenyl group having 2 to 6 carbon isobutyl) or carbon in the alkyl group (specifically 1 to 4 carbon atoms (specifically 2-methyl-2-propenyl group) ) And preferable A ⁷ is —N═C (r ⁷⁰ ) — or —CH═C (r ⁷⁰ ) — (r ⁷⁰ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms (specifically, Is a methyl group) is preferred).

In the compound of formula (1) of the present invention, when ring A is a group represented by (Ad) and R ² is a hydrogen atom (hereinafter, also referred to as compound (1d)), Preferred R ¹ is methoxy group, preferred A ⁹ and A ¹⁰ are hydrogen atom or methyl group, and preferred A ⁸ is ═N—O—r ⁸⁰
(R ⁸⁰ is preferably a hydrogen atom or an acetyl group).

The production methods 1 and 2 which are the production methods of the compound (1a) are described below. Above formula (1 ') a compound represented by can be obtained even by the same method, the above formula (1' compound represented by), the following manufacturing method replacing the A ¹ in the following manufacturing method A ^{1 '} It can be obtained with 1 and 2. The methods for producing the compound (1a) and the compound of the formula (1 ′) are not limited to the following production methods, and the compounds can be synthesized by methods similar thereto. Each compound used in each production method may be protected or deprotected by a conventional method, if necessary.

Manufacturing Method 1

[0094]

[Chemical 33]

(In the formula, R ¹ , A ¹ , A ² , R ¹⁰ , R ¹⁵ and R ¹⁶ are the same as defined above, X ¹ is a halogen atom, and Y ¹ is an alkyl group having 1 to 6 carbon atoms. , An aryl group or an aralkyl group)

Step 1 The thiol compound (3a) can be obtained by reacting the aldehyde compound (2a) with ethylenediamine in a reaction solvent and further reacting the reaction product with sulfur. Specifically, for example, the aldehyde compound (2a)
Ethylenediamine is added to the solution of the reaction solvent of and heated. After completion of the reaction, thiol compound (3a) can be obtained by adding sulfur to this and stirring. Examples of the reaction solvent include alcohol solvents such as ethoxyethanol, methanol, ethanol, isopropyl alcohol, 2-propanol, tert-butanol, dichloromethane, tetrahydrofuran, benzene, and the like.
Examples thereof include aprotic solvents such as N, N-dimethylformamide, which can be used alone or in combination. The reaction temperature is 50 ° C to 150 ° C, preferably 1
The temperature is 00 ° C to 130 ° C.

Step 2 The benzothiophene compound (4a) can be obtained by reacting the thiol compound (3a) with a haloacetic acid ester in the presence of a base in a reaction solvent. Specifically, for example, the benzothiophene compound (4a) can be obtained by adding the thiol compound (3a) and the haloacetic acid ester to the reaction solvent, stirring the mixture, and then adding a base thereto. As the reaction solvent, for example, methanol,
Examples thereof include alcohol solvents such as ethanol, isopropyl alcohol, 2-propanol, and tert-butanol, and these can be used alone or in combination. Examples of the haloacetic acid ester to be reacted include methyl bromoacetate, methyl chloroacetate, ethyl bromoacetate, ethyl chloroacetate and the like. Examples of the base used in the reaction include hydroxides such as sodium hydroxide and potassium hydroxide; various carbonates such as potassium carbonate and sodium bicarbonate; pyrrolidine, piperidine, triethylamine, N-
An organic base such as methylmorpholine may be used. The reaction temperature is 0 ° C to 150 ° C, preferably room temperature to 10 ° C.
It is 0 ° C.

Step 3 The diazepine compound (5a) can be obtained by heating and stirring the benzothiophene compound (4a) in the presence of a base in a reaction solvent. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol, isopropyl alcohol, 2-propanol, and tert-butanol, and these can be used alone or in combination. Examples of the base used in the reaction include metal alkoxides such as potassium tert-butoxide, sodium methoxide and sodium ethoxide; and inorganic bases such as sodium hydroxide, potassium hydroxide and potassium carbonate. The reaction temperature is 0 ° C to 1
The temperature is 00 ° C, preferably room temperature to 90 ° C.

Step 4 In the reaction solvent, in the presence of a base and tert-butyldimethylchlorosilane, the diazepine compound (5a) and A ¹ -X ¹
The target compound (1a) can be obtained by reacting the compound (6a) represented by the formula (wherein A ¹ and X ¹ have the same meanings as described above). The reaction is preferably performed under an inert gas (for example, argon gas) atmosphere.
Specifically, for example, tert-butyldimethylchlorosilane is added to a solution of the diazepine compound (5a) in the reaction solvent under argon substitution, and the mixture is stirred. The target compound (1a) can be obtained by adding a base to this and stirring, and then adding the compound (6a) and further stirring. As a reaction solvent, tetrahydrofuran, benzene, N, N-
An aprotic solvent such as dimethylformamide; an ether solvent such as dimethoxyethane can be used, and these can be used alone or in combination. As the base used in the reaction, for example, an inorganic base such as sodium hydride, butyllithium, potassium tert-butoxide can be used. The reaction temperature is 0 ° C to 80 ° C, preferably 0 ° C to room temperature. In addition, the compound (1a) was added to the step 7 described later.
The compound (1-5a), which is one of the target compounds, can be obtained by subjecting it to a reaction similar to the above.

(When the object of R ¹ = -O-R ¹⁰ is obtained)
The compound of the present invention in which R ¹ = -O-R ¹⁰ has the same structure as the above-mentioned Step 1
4 and step 7 below, R ¹
It can also be obtained by subjecting steps (5) to (7) described below to the compound (1a) in which is —OMe.

Step 5 The hydroxy compound (1-3a), which is one of the target compounds, can be obtained by reacting the methoxy compound (1-2a) with boron tribromide (BBr ₃ ) in a reaction solvent. . The reaction is preferably carried out under an atmosphere of an inert gas (eg, argon gas). Specifically, for example, under argon substitution, a mixture of a methoxy compound (1-2a) and a reaction solvent is stirred, a solution of BBr ₃ dissolved in the reaction solvent is added thereto, and the mixture is further stirred,
A hydroxy compound (1-3a) can be obtained. Examples of the reaction solvent include methylene chloride, hexane, toluene, chloroform and the like, and these can be used alone or in combination. Reaction temperature is 0 ° C to 70 ° C
And preferably 0 ° C. to room temperature. The hydroxy compound (1-3a) can be isolated and purified by a conventional method, but the hydroxy compound (1-3a) can be used in the next step 6 without purification after isolation.

Step 6 In the reaction solvent, in the presence of a base, the hydroxy compound (1-3
a) and a compound (7a) represented by R ¹⁰ -X ¹ (wherein R ¹⁰ and X ¹ have the same meanings as described above) are reacted to obtain a compound (1-4a) which is one of the target compounds. ) Can be obtained. Specifically, for example, by adding a base and compound (7a) to a solution of a hydroxy compound (1-3a) in a reaction solvent and stirring the mixture, the compound (1-
4a) can be obtained. Examples of the reaction solvent include solvents such as acetone, acetonitrile, methanol, ethanol, N, N-dimethylformamide and the like, and these can be used alone or in combination. As the base used in the reaction, for example, an inorganic base such as sodium hydroxide, potassium hydroxide or potassium carbonate can be used. The reaction temperature is 0 ° C to 70 ° C, preferably 0 ° C.
C to room temperature. The compound (1-4a) can be isolated and purified by a conventional method.

Step 7 In a reaction solvent, in the presence of a base, compound (1-4a) and A ²
A compound (1-5a), which is one of the target compounds, can be obtained by reacting a compound (8a) represented by —X ¹ (wherein A ² and X ¹ are as defined above). it can. The reaction is preferably carried out under an inert gas (for example, argon gas) atmosphere. Specifically, for example, the compound (1-5a) can be obtained by adding a base and the compound (8a) to a solution prepared by dissolving the compound (1-4a) in a reaction solvent under argon substitution and stirring. it can. Examples of the reaction solvent include solvents such as acetone, acetonitrile, methanol, ethanol, N, N-dimethylformamide and the like, and these can be used alone or in combination. As the base used in the reaction, for example, an inorganic base such as sodium hydride, sodium hydroxide, potassium hydroxide or potassium carbonate can be used. The reaction temperature is -30 ° C to 100 ° C, preferably 0 ° C to 60 ° C.

[0104] (When obtaining the target compound of _{^{R 1 = -SO 2 -NR 15 R}} 16) a compound of the invention which is _{^{R 1 = -SO 2 -NR 15 R}} 16 may be obtained by the steps 1-4 and 7 However, the compound (1a) in which R ¹ is a hydrogen atom is added to Step 8 described below.
It can also be obtained by applying 9 and 9 and the above step 7.

Step 8 The halosulfone compound (9a) can be obtained by reacting the diazepine compound (1-6a) with halosulfonic acid in the presence of N, N-dimethylformamide and thionyl chloride in a reaction solvent. The reaction is preferably carried out under an atmosphere of an inert gas (eg, argon gas).
Specifically, for example, N, N-dimethylformamide and thionyl chloride are added to a reaction solvent solution of a diazepine compound (1-6a) under argon substitution and the mixture is stirred, and halosulfonic acid is added dropwise to the mixture and stirred. Thus, the halosulfone compound (9a) can be obtained. The N, N-dimethylformamide used here can also be used as a reaction solvent. As the reaction solvent, for example,
Chloroform, dichloromethane, tetrahydrofuran,
An aprotic solvent such as benzene can be used, and these can be used alone or in combination. The reaction temperature is 40 ° C to 100 ° C, preferably 50 ° C to 80 ° C.

Step 9 The halosulfone compound (9a) was treated with R ¹⁵ R ¹⁶ N in a reaction solvent.
A compound (1-7a), which is one of the target compounds, can be obtained by reacting with a compound (10a) represented by —H (wherein R ¹⁵ and R ¹⁶ are as defined above). . This reaction is preferably carried out in an inert gas (eg, argon gas) atmosphere. Specifically, for example, the compound (1-7a) can be obtained by adding the compound (10a) to a solution of the halosulfone compound (9a) in the reaction solvent under argon substitution and stirring. Examples of the reaction solvent include aprotic solvents such as dichloromethane, chloroform, tetrahydrofuran, benzene, N, N-dimethylformamide, etc. These can be used alone or in combination. Reaction temperature is 0 ℃
To 70 ° C, preferably 0 ° C to 50 ° C. still,
When the compound (1-5a) is desired, the compound (1-7
A) may be subjected to the same method as in step 7.

Manufacturing Method 2

[0108]

[Chemical 34]

(In the formula, R ¹ , A ¹ , A ² , R ¹⁰ , R ¹⁵ and R
¹⁶ , X ¹ and Y ¹ are as defined above, and Boc is ter
(It is an abbreviation for t-butoxycarbonyl group)

Step 1 In a reaction solvent, the aldehyde compound (11a) and N- (te
The imine compound (12a) can be obtained by reacting with rt-butoxycarbonyl) ethylenediamine. The reaction is preferably carried out under an inert gas (for example, argon gas) atmosphere. Specifically, the imine compound (12a) can be obtained by, for example, adding the aldehyde compound (11a) to a solution of a reaction solvent of N- (tert-butoxycarbonyl) ethylenediamine under argon substitution and stirring. The ethylenediamine in the formula is protected by the Boc group, but may be protected by an amino protecting group other than this. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol, isopropyl alcohol, 2-propanol, and tert-butanol, and these can be used alone or in combination. The reaction temperature is -30 ° C to 30 ° C.
And preferably -10 ° C to 10 ° C. The imine compound (12a) was subjected to the next step 2 without isolation and purification.
Can be used as is.

Step 2 The benzofuran compound (13a) can be obtained by reacting the imine compound (12a) with a dihaloacetic acid ester in the reaction solvent in the presence of a base. Specifically, for example, a benzofuran compound (13a) can be obtained by adding a base and a dihaloacetic acid ester to a solution of an imine compound (12a) in a reaction solvent and stirring the mixture. As the reaction solvent, for example, dichloromethane,
Examples of the aprotic solvent include tetrahydrofuran, benzene, N, N-dimethylformamide and the like, and these can be used alone or in combination. Examples of the base used in the reaction include hydroxides such as sodium hydroxide and potassium hydroxide; various carbonates such as potassium carbonate and sodium bicarbonate; pyrrolidine, piperidine, triethylamine and N.
-An organic base such as methylmorpholine may be used. As the dihaloacetic acid ester, methyl dichloroacetate is preferable. The reaction temperature is -10 ° C to 60 ° C, preferably 0 ° C to room temperature. The benzofuran compound (13a) can be isolated and purified by a conventional method, but the benzofuran compound (13a) can be isolated and purified without isolation.
It can be used in the next step 3.

Step 3 The deprotected amine hydrochloride compound (14a) can be obtained by reacting the benzofuran compound (13a) with hydrochloric acid in a reaction solvent. The reaction is preferably carried out under an inert gas (for example, argon gas) atmosphere. Specifically, for example, by adding hydrochloric acid to a solution of the reaction solvent of the benzofuran compound (13a) under argon substitution and stirring, the hydrochloride compound of the amine (14
a) can be obtained. The deprotection reaction can be performed by a conventionally known method, and the step may be appropriately changed depending on the kind of the amino protecting group of the benzofuran compound (13a). Examples of the reaction solvent include alcohol solvents such as methanol, ethanol, isopropyl alcohol, 2-propanol and tert-butanol;
Tetrahydrofuran, 1,4-dioxane, benzene,
Aprotic solvents such as toluene, acetonitrile and N, N-dimethylformamide are mentioned, and these can be used alone or in combination. Also, hydrochloric acid may be added as a solution of a reaction solvent or may be used as an aqueous solution. The reaction temperature is 0 ° C. to 60 ° C., preferably room temperature.

Step 4 Amine hydrochloride compound (1
The benzofurandiazepine compound (15a) can be obtained by cyclizing 4a). In particular,
For example, by adding a base such as sodium ethoxide to a solution of a reaction solvent of an amine hydrochloride compound (14a) and stirring the mixture, a benzofurandiazepine compound (15
a) can be obtained. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol, isopropyl alcohol, 2-propanol, and tert-butanol, and these can be used alone or in combination.
Examples of the base used in the reaction include potassium ter
t-butoxide, sodium methoxide, sodium
Metal alkoxides such as ethoxide; sodium hydroxide,
Inorganic bases such as potassium hydroxide and potassium carbonate can be used. The reaction temperature is 0 ° C. to 80 ° C., preferably room temperature.

Step 5 Step 5 can be performed in the same manner as Step 4 of the above-mentioned manufacturing method 1. Therefore, the target compound (1a) can be obtained by subjecting the benzofurandiazepine compound (15a) to the same reaction as in Step 4 of Production method 1.
By subjecting compound (1a) to the same reaction as in step 8 described below, compound (1-11) which is one of the target compounds is obtained.
a) can be obtained.

Step 6 to Step 8 The compound of the present invention in which R ¹ = -O-R ¹⁰ is prepared by the method described in Step 1 to
5 and step 8 below, but R ¹
It can also be obtained by subjecting steps (6-8) described below to the compound (1a) in which is -OMe. Steps 6 to 8 in manufacturing method 2 can be performed in the same manner as steps 5 to 7 in manufacturing method 1. That is, compound (1-9a), which is one of the target compounds, can be obtained by subjecting compound (1-8a) to the same reaction as in step 5 of production method 1,
Compound (1-10a), which is one of the target compounds, can be obtained by subjecting compound (1-9a) to the same reaction as in step 6 of production method 1. Furthermore, the compound (1-
By subjecting 9a) to the same reaction as in step 7 of production method 1, compound (1-11a), which is one of the target compounds, can be obtained.

Step 9 and Step 10 The compound of the present invention in which R ¹ = -SO ₂ -N (R ¹⁵ ) (R ¹⁶ ) can be obtained by the above-described Steps 1 to 5 and 8, but R ¹ is It can also be obtained by subjecting compound (1a) which is a hydrogen atom to steps 8 to 10 described later. Steps 9 and 10 in manufacturing method 2 can be performed in the same manner as steps 8 and 9 in manufacturing method 1. That is,
Compound (1-13a), which is one of the target compounds, can be obtained by subjecting compound (1-12a) to the same reaction as in Steps 8 and 9 of Production method 1. Furthermore, by subjecting compound (1-13a) to the same reaction as in step 7 of production method 1, compound (1
-11a) can be obtained.

The compound (1a) of the present invention and the compound of the formula (1 ′) obtained by the production methods 1 and 2 can be isolated by a conventional method and, if necessary, a conventional method such as recrystallization,
It can be purified by preparative thin layer chromatography, column chromatography and the like.

Hereinafter, Production Methods 1 to 4 which are the production methods of the compound (1b) will be described. The production method of compound (1b) is not limited to the following production methods, and the compound (1b) can also be synthesized by a method similar thereto. Each compound used in each production method may be protected or deprotected by a conventional method, if necessary.

Manufacturing Method 1

[0120]

[Chemical 35]

(In the formula, R ¹ , R ² , A ⁴ , A ⁵ and X ¹ are as defined above, and r ^{30 ′} is an alkyl group having 1 to 6 carbon atoms or a benzyl group (wherein the benzyl group is Has 1 carbon
6 alkyl group, an alkoxy group having 1 to 6 carbon atoms, substituted with a halogen atom or a nitro group is also be), R ⁹ is alkyl group having 1 to 6 carbon atoms)

Step 1-1 The ester compound (4b) can be obtained by reacting the indan-1-one compound (2b) with dimethyl carbonate (3b) in the presence of a base in a reaction solvent.
Specifically, for example, in the presence of a base, dimethyl carbonate (3
The indan-1-one compound (2b) is added to the solution of the reaction solvent of b) as it is or as a solution by dropwise addition, and the mixture is heated. The reaction can be terminated by adding an acid such as acetic acid, and the ester compound (4b) can be obtained by isolation and purification by a conventional method. Examples of the reaction solvent include benzene-based solvents (eg, xylene, toluene), ether-based solvents (eg, diethyl ether, tetrahydrofuran, dioxane), polar aprotic solvents (eg, N, N-dimethylformamide, dimethyl). Sulfoxide and the like), alcoholic solvents (eg, methanol and the like) and the like, and these can be used alone or in combination. Examples of the base used in the reaction include inorganic bases (eg sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride etc.), metal alkoxides (eg sodium methoxide, sodium ethoxide etc.) and the like. The reaction temperature is 0 ° C to 130 ° C, preferably 30 ° C to 80 ° C.
℃.

Step 1-2 The target compound (1-2b) can be obtained by reacting the ester compound (4b) with the diamine compound (5b) in the presence of an acid in a reaction solvent. In particular,
For example, in the presence of an acid, the ester compound (4b) is added to the solution of the diamine compound (5b) in the reaction solvent as it is or as a solution, and the mixture is heated and stirred while azeotropically dehydrating. Examples of the reaction solvent include benzene-based solvents (eg, xylene, toluene, etc.), ether-based solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), polar aprotic solvents (eg, N, N-dimethylformamide, etc.). Etc., and these can be used alone or in combination. Examples of the acid include inorganic acids (eg, hydrochloric acid, sulfuric acid, etc.), organic acids (eg, p-toluenesulfonic acid, acetic acid, etc.) and the like. The reaction temperature is 30 ° C to 200 ° C, preferably 100 ° C to 150 ° C.
℃.

Step 1-3 All steps can be carried out in the same manner as in Step 1-2 except that the diamine compound (5b) is replaced with the diamine compound (7b). In step 1-3, the target compound (1-3b) in which the nitrogen atom at the 1-position is substituted can be obtained.

Step 1-4 Compound represented by the target compound (1-2b) and R ⁹ -X ¹ (wherein R ⁹ and X ¹ have the same meanings as described above) in the reaction solvent in the presence of a base. By reacting (6b), the target compound (1-4b) in which the 6-position is 1-substituted can be obtained. Specifically, for example, a base is added to a solution of the target compound (1-2b) in a reaction solvent and the mixture is stirred to give the compound (6
Add b) and stir further. Examples of the reaction solvent include benzene-based solvents (eg, xylene, toluene, etc.), ether-based solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), polar aprotic solvents (eg, N, N-dimethylformamide, dimethyl). Sulfoxide etc.) and the like, and these can be used alone or in combination. Examples of the base used in the reaction include inorganic bases (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, etc.), metal alkoxides (eg, sodium methoxide, sodium ethoxide, n-butyllithium, etc.). Can be used. The reaction temperature is 0 ° C to 80 ° C, preferably 0 ° C to room temperature.

In step 1-4, when tert-butyldimethylsilyl chloride chlorosilane is further present, the target compound (1-5b) and the target compound (1-
6b) can be obtained. The tert-butyldimethylsilyl chloride is preferably added before adding the compound (6b). Target compounds (1-5b) and (1
The amount of the reagent and the reaction temperature may be appropriately changed depending on which of 6b) is obtained.

Manufacturing Method 2

[0128]

[Chemical 36]

(In the formula, R ¹ , R ² , A ⁴ , A ⁵ , X ¹ and r ^{30 ′} have the same meanings as described above.)

Step 2-1 In the step 2-1 except that the starting material is changed from the indan-1-one compound (2b) to the 1,2,3,4-tetrahydronaphthalen-1-one compound (8b). Process 1
It can be performed in the same manner as -1. The ester compound (9b) can be obtained by the step 2-1.

Step 2-2 Step 2-2 is the same as Step 1-2 except that the starting material is changed from the ester compound (4b) to the ester compound (9b).
It can be performed similarly to 2. The target compound (1-7b) can be obtained by the step 2-2.

Step 2-3 In the reaction solvent in the presence of a base, the target compound (1-7b)
r^{30 '}-X¹(In the formula, r ^{30 '}And X¹Is as defined above
By reacting a compound (7'b) represented by
To obtain the target compound (1-8b) substituted at the 1-position.
You can Specifically, for example, the target compound (1-7
To the reaction solvent solution of b), a base was added and stirred to give a compound.
By adding (7'b) and further stirring, the target compound
The product (1-8b) can be obtained. As a reaction solvent
Is, for example, a benzene-based solvent (for example, xylene or toluene).
Ether, etc., ether solvents (eg diethyl ether)
, Tetrahydrofuran, dioxane), polar non-pro
Solvent (eg, N, N-dimethylformamide,
Dimethyl sulfoxide etc.), etc.
Or they can be used together. As a base used in the reaction
Is, for example, an inorganic base (eg sodium hydroxide, water
Potassium oxide, lithium hydroxide, sodium hydride
Etc.), metal alkoxides (eg sodium methoxide)
Side, sodium ethoxide, etc.), n-butyllithium
Can be used. The reaction temperature is 0 ° C to 80 ° C.
And preferably 0 ° C to room temperature.

Step 2-4 The target compound (1-9b) can be obtained by subjecting the target compound (1-8b) to a dehydrogenation reaction. Specifically, for example, in a solution of the target compound (1-8b) in a reaction solvent, 2,3-dichloro-5,6-dicyano-1,4 is added.
-Add benzoquinone and stir. As the reaction solvent,
For example, toluene, acetic acid, dichloromethane, chloroform and the like can be mentioned. The reaction temperature is 0 ° C to 150 ° C, preferably 30 ° C to 80 ° C.

Step 2-5 In the presence of palladium carbon in a reaction solvent, the target compound (1
By subjecting -7b) to a dehydrogenation reaction, the target compound (1-10b) can be obtained. Specifically, for example, the target compound (1-7b), palladium carbon and the reaction solvent are heated and stirred. Examples of the reaction solvent include benzene-based solvents (eg, xylene, toluene, etc.), ether-based solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), polar aprotic solvents (eg, N, N-dimethylformamide, dimethyl). Sulfoxide, acetonitrile, acetone, etc.), acetic acid, etc., can be used alone or in combination. The reaction temperature is 0 ° C to 100 ° C, preferably room temperature to 80 ° C.

Manufacturing Method 3

[0136]

[Chemical 37]

(In the formula, R ¹ , R ² , A ⁴ and A ⁵ are the same as above, and Boc is an abbreviation for tert-butoxycarbonyl.)

Step 3-1 In the reaction solvent, in the presence of a catalyst, the ester compound (9b) is reacted with a brominating agent to give a bromine compound (10
b) can be obtained. Specifically, for example, a brominating agent is added to a solution of a reaction solvent of the ester compound (9b) and then stirred, and then a catalyst is further added and stirred. The ester compound (9b) can be isolated and purified by a conventional method. Examples of the reaction solvent include benzene-based solvents (eg, xylene, toluene, etc.), ether-based solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), halogen-based solvents (eg, dichloromethane, chloroform, etc.), These can be used alone or in combination. The brominating agent is not particularly limited as long as it is usually used for bromination, and for example,
Examples thereof include bromine and N-bromosuccinimide. Examples of the catalyst include α, α′-azobisisobutyronitrile. The reaction temperature is 0 ° C to 100 ° C,
It is preferably 0 ° C to 80 ° C.

Step 3-2 The naphthalene compound (11b) can be obtained by reacting the bromide (10b) with 1,8-diazabicyclo [5.4.0] -7-undecene in a reaction solvent. Specifically, for example, in a solution of 1,8-diazabicyclo [5.4.0] -7-undecene in a reaction solvent,
The bromide (10b) is added as is or as a solution dropwise and stirred. The bromide (10b) can be isolated and purified by a conventional method. Examples of the reaction solvent include benzene-based solvents (eg, xylene, toluene, etc.), ether-based solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), polar aprotic solvents (eg, N, N-dimethylformamide, etc.).
Dimethyl sulfoxide, etc.), alcoholic solvents (eg, methanol, ethanol, isopropyl alcohol, tert-butanol, etc.) and the like, and these can be used alone or in combination. The reaction temperature is 0 ° C to
It is 100 ° C., preferably 0 ° C. to 50 ° C.

Step 3-3 By subjecting the naphthalene compound (11b) and the protected amino compound (11b) to a dehydration reaction in a reaction solvent,
A naphthalene compound (13b) can be obtained. Specifically, for example, to a solution of a reaction solvent of a naphthalene compound (11b), a protected amino compound (11b) and triphenylphosphine, diethyl azodicarboxylate is added as it is or as a solution, and the mixture is stirred. . The naphthalene compound (13b) can be isolated and purified by a conventional method. Examples of the reaction solvent include benzene-based solvents (eg, xylene, toluene, etc.), ether-based solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), halogen-based solvents (eg, dichloromethane, chloroform, etc.), ester-based solvents ( For example, ethyl acetate, butyl acetate, etc.), a polar aprotic solvent (eg, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, etc.) and the like can be mentioned, and these can be used alone or in combination. The reaction temperature is -30 ° C to 100 ° C, preferably -30 ° C to room temperature.

Step 3-4 The amino-protecting group of the naphthalene compound (13b) may be deprotected according to a conventional method. Specifically, for example, a 4N-hydrochloric acid dioxane solution is added to the naphthalene compound (13b) and stirred. To do. As a result, the deprotected naphthalene compound (14b) is obtained as a hydrochloride, which can be converted into a free form according to a conventional method. When used in the next step, the hydrochloride may be used as it is.

Step 3-5 Deprotected naphthalene compound (14b) in a reaction solvent
Is subjected to an intramolecular cyclization reaction to give the target compound (1-
11b) can be obtained. Specifically, for example, 1,8-diazabicyclo [5.4.0] -7-undecene is added to a solution of the deprotected naphthalene compound (14b) in the reaction solvent, and the mixture is heated and stirred. Examples of the reaction solvent include benzene-based solvents (eg, xylene, toluene, etc.), ether-based solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), halogen-based solvents (eg, dichloromethane, chloroform, etc.), polar aprotic substances. Solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, etc.), alcohol solvents (eg, methanol, ethanol, isopropyl alcohol, tert-butanol, etc.) and the like can be mentioned, and these can be used alone or in combination. The reaction temperature is 0 ° C to
It is 150 ° C., preferably room temperature to 100 ° C.

Manufacturing Method 4

[0144]

[Chemical 38]

(In the formula, R ¹ , R ² , A ⁴ , A ⁵ and X ¹ are as defined above.)

Step 4-1 In the reaction solvent, in the presence of a base, the naphthalene compound (11
The dimethylaminothiocarbonyl compound (15b) can be obtained by reacting b) with dimethylaminothiocarbonyl chloride. Specifically, for example, a base is added to a solution of the reaction solvent of the naphthalene compound (11b) and the mixture is stirred, dimethylaminothiocarbonyl chloride is added, and the mixture is further stirred. As the reaction solvent,
For example, benzene-based solvents (eg, xylene, toluene, etc.), ether-based solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), polar aprotic solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone). Etc.) and the like, and these can be used alone or in combination. Examples of the base used in the reaction include inorganic bases (for example,
Sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Sodium hydrogen carbonate, etc.), organic bases (eg, pyrrolidine, piperidine, triethylamine, N-methylmorpholine, etc.), metal alkoxides (eg, sodium methoxide, sodium ethoxide, etc.) and the like. The reaction temperature is 0 ° C to 100 ° C, preferably room temperature to
It is 80 ° C.

Step 4-2 Dimethylaminothiocarbonyl compound (1
The dimethylcarbonylthio compound (16b) can be obtained by heating 5b). Specifically, for example, a dimethylaminothiocarbonyl compound (15b)
The solution of the reaction solvent of is heated. Examples of the reaction solvent include benzene-based solvents (eg, xylene, toluene, etc.), ether-based solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), halogen-based solvents (eg, dichloromethane, chloroform, etc.), ester-based solvents ( For example, ethyl acetate, butyl acetate, etc.), polar aprotic solvent (eg, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, etc.), alcohol solvent (eg, methanol, ethanol, isopropyl alcohol, tert-butanol). Etc.) and the like, and these can be used alone or in combination. The reaction temperature is 100 ° C to 300 ° C, preferably 200 ° C to 250 ° C.

Step 4-3 and Step 4-4 In Step 4-3, the compound (16b) is deprotected, and in Step 4-4, the deprotected compound (17b) obtained in Step 4-3 is used. The amine compound (18b) is subjected to an intermolecular cyclization reaction. Deprotected form (17b) obtained in step 4-3
Can be subjected to step 4-4 without isolation,
Furthermore, since step 4-4 easily proceeds in the presence of a base, it is preferable to perform step 4-3 and step 4-4 at the same time. Process 4
-3 and step 4-4 can be carried out by reacting the dimethylcarbamoylthio compound (16b) with the amine compound (18b) in the presence of a base in a reaction solvent, whereby the deprotected form (17b) can be obtained. The desired compound (1-12b) can be obtained via the route. Amine compound (1
8b) can also be used in the form of the hydrochloride.
As the reaction solvent, for example, a benzene-based solvent (for example,
Xylene, toluene etc.), ether solvents (eg diethyl ether, tetrahydrofuran, dioxane etc.), polar aprotic solvents (eg N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone etc.), alcohol solvents (eg , Methanol, ethanol, isopropyl alcohol, tert
-Butanol, etc.) and the like, and these can be used alone or in combination. Examples of the base used in the reaction include inorganic bases (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydride, etc.), organic bases (eg, pyrrolidine, piperidine). , Triethylamine, N-methylmorpholine, etc.), metal alkoxides (eg, sodium methoxide, sodium ethoxide, etc.) and the like. The reaction temperature is 0 ° C to 100
C, preferably 0 to 60 ° C.

Compound (1b) obtained by Production Method 1 to 4
Can be isolated by a conventional method and, if necessary, can be purified by a conventional method, for example, recrystallization, preparative thin layer chromatography, column chromatography and the like.

The production methods 1 to 3, which are the production methods of the compound (1c), are described below. The method for producing the compound of formula (1) is not limited to the following production methods, and can be synthesized by methods similar thereto. In addition, each compound used in each production method, if necessary, by a conventional method,
It may be protected or deprotected.

Production Method 1 (A ⁶ is -S- or SO-, and A ⁷ is -N = N-, -NH-CO-, -CH _{2
-CH 2 -, - N = C} (r 70) - or -CH = C (r
⁷⁰ )-if)

[0152]

[Chemical Formula 39]

(In the formula, R ¹ and r ⁷⁰ are as defined above.)

Step 1-1 Compound of formula (2c) obtained by the same method as in JP-A-9-509961 (hereinafter referred to as compound (2c))
By reacting with diphosphorus pentasulfide in a reaction solvent,
A compound of formula (3c) (hereinafter referred to as compound (3c)) can be obtained. Specifically, for example, the compound (2
Diphosphorus pentasulfide is added to the mixture of c) and the reaction solvent, and this is heated and stirred. Compound (3c) can be prepared by a conventional method.
It can be isolated and purified.

The reaction solvent used in Step 1-1 is, for example, a benzene-based solvent (eg, xylene, toluene,
Examples thereof include benzene), halogen-based solvents (such as chloroform), ether-based solvents (such as dioxane and tetrahydrofuran), and pyridine (aromatic basic). These may be used alone or in combination. Step 1-1 is usually performed at 20 ° C to 200 ° C, preferably 50 ° C to 150 ° C.

Step 1-2 The compound of the formula (4c) (hereinafter referred to as the compound (4c)) can be obtained by reacting the compound (3c) with methyl iodide in the reaction solvent in the presence of a base. . Specifically, for example, a compound (4c) can be obtained by adding a base to a mixture of the compound (3c) and a reaction solvent, then adding methyl iodide, preferably dropping and stirring. Compound (4c) was isolated by a conventional method.
It can be purified.

Examples of the base used in Step 1-2 include potassium carbonate, sodium hydroxide, sodium hydride, triethylamine and the like. Examples of the reaction solvent used in Step 1-2 include alcohol solvents (for example, methanol, ethanol, etc.), ether solvents (for example, dioxane, tetrahydrofuran (TH
F) and the like), acetone, N, N-dimethylformamide (DMF), water and the like. These may be used alone or in combination. Step 1-2 is usually -20
C. to 70.degree. C., preferably 0.degree. C. to 30.degree.

Step 1-3 In a reaction solvent in the presence of an acid, compound (4c) was converted to a compound of the formula: r ⁷⁰
-C (= O) -NHNH ₂ (wherein, r ⁷⁰ has the same meaning as defined above) by reaction with hydrazides represented by a compound of formula (1-1c) (hereinafter, compound (1-1
c)) can be obtained. Specifically, for example, a solution of compound (4c), a hydrazide and an acid in a reaction solvent is heated and stirred.

The solution of the reaction solvent used in step 1-3 includes, for example, n-butanol, DMF, dioxane, etc. These may be used alone or in combination. Examples of the hydrazides used in Steps 1-3 include acetohydrazide, formylhydrazide, butyric acid hydrazide, and the like. Examples of the acid used in Step 1-3 include p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, trifluoroacetic acid and the like, and hydrates thereof. Steps 1-3 are generally performed at 0 ° C to 170 ° C, preferably 80 ° C to 130 ° C.

Step 1-4 Compound (4c) was converted to the formula: NH _{2 in} the presence of an acid in a reaction solvent.
NHC (= O) -L ₁ (wherein L ₁ is a leaving group and may be a substituent capable of leaving under the conditions of Step 1-4, for example, methyl, ethyl, tert-butyl, Phenyl,
A compound of formula (1-2c) (hereinafter referred to as compound (1-2c)) can be obtained by reacting with a carbazate represented by benzyl and the like. Specifically, for example, a solution of compound (4c), a carbazate and an acid in a reaction solvent is heated and stirred.

Examples of the reaction solvent used in Steps 1-4 include n-butanol, DMF, dimethylsulfoxide (DMSO), THF, methanol and the like.
These may be used alone or in combination. Process 1
Examples of the carbazates used in -4 include methylcarbazate, ethylcarbazate, tert-butylcarbazate, phenylcarbazate, benzylcarbazate and the like, and hydrates thereof. Examples of the acid used in Steps 1-4 include p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like, and hydrates thereof. Steps 1-4 are usually 20 ° C to 150 ° C, preferably 90 ° C.
Perform at ~ 130 ° C.

Step 1-5 Compound (4c) is reacted with 2-chloroethylamine hydrochloride in the presence of a base in a reaction solvent to give a compound of formula (1
-3c) compound (hereinafter referred to as compound (1-3c))
Can be obtained. Specifically, for example, the compound (4
c), 2-chloroethylamine hydrochloride and the base are dissolved in the reaction solvent and the mixture is heated with stirring.

As the base used in Step 1-5, for example, triethylamine, diazabicycloundecene (D
BU), sodium hydrogen carbonate, sodium hydride, sodium hydroxide and the like. Examples of the reaction solvent used in Step 1-5 include ethanol (anhydrous), n-butanol, DMF, acetone, THF and the like,
These may be used alone or in combination. Process 1
-5 is usually 0 ° C to 150 ° C, preferably 50 ° C to 10 ° C.
Perform at 0 ° C.

Step 1-6 Compound (4c) was converted to a compound of the formula: NH _{2 in} the presence of an acid in a reaction solvent.
By reacting with an acetal compound represented by CH ₂ C (r ⁷⁰ ) (OMe) ₂ (in the formula, r ⁷⁰ has the same meaning as described above), a compound of the formula (1-4c) (hereinafter, compound (1 −
4c)) can be obtained. Specifically, for example, a solution of the compound (4c), the acetal compound, and the reaction solvent of the acid is heated and stirred.

Examples of the reaction solvent used in Step 1-6 include n-butanol, DMF, THF, ethyl acetate and the like, and these may be used alone or in combination. Examples of the acid used in Step 1-6 include p-
Toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid,
Examples include trifluoroacetic acid and hydrates thereof. Examples of the acetal compound used in Step 1-6 include aminoacetaldehyde dimethyl acetal and hydrates thereof. Step 1-6 is usually 0 ° C to 15 ° C.
It is carried out at 0 ° C, preferably 90 ° C to 120 ° C.

Step 1-6 can also be carried out by the following method when r ⁷⁰ is an alkyl group having 1 to 6 carbon atoms. In the presence of sodium acetate and acid in the reaction solvent,
The compound (4c) is represented by the formula: r ^{70 ′} ≡C—CH ₂ —NH ₂ (r ^{70 ′}
Is a straight-chain or branched-chain alkyl having 1 to 6 carbons), and thereby the compound (1-4c) can be obtained. Specifically, for example, the compound (4c) and the aminoalkyne are dissolved in a reaction solvent, and after heating, sodium acetate and an acid are added thereto and heated.

The reaction solvent in the method is, for example, an alcohol solvent (eg, methanol, ethanol, absolute ethanol, etc.), an ether solvent (eg,
Dioxane, THF and the like), DMF and the like.
Examples of the aminoalkyne used in the method include propargylamine and the like. Examples of the acid used in this method include p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid and sulfuric acid. The method is usually 0
C. to 200.degree. C., preferably 10 to 150.degree.

Step 1-7 A compound of formula (1-5c) (hereinafter referred to as compound (1-5c)) is obtained by reacting compound (1-4c) with m-chloroperbenzoic acid in a reaction solvent. Obtainable. Specifically, for example, m-chloroperbenzoic acid is added to a solution of the compound (1-4c) in a reaction solvent and stirred.
Examples of the reaction solvent used in Step 1-7 include methylene chloride, chloroform and the like, and these may be used alone or in combination. Step 1-7 is usually -2
It is carried out at 0 ° C to 50 ° C, preferably 0 ° C to 20 ° C.

Step 1-8 Compound (2c) is reacted with sodium azide in the presence of phosphorus oxychloride in a reaction solvent to give a compound of formula (1-6)
The compound (c) (hereinafter referred to as the compound (1-6c)) can be obtained. Specifically, for example, the compound (2
c), a solution of sodium azide and phosphorus oxychloride in the reaction solvent is heated and stirred.

Production Method 2 (A ⁶ is -N (r ⁶⁰ )-, and A ⁷ is -N = C (r ⁷⁰ )-or CH = C (r
⁷⁰ )-if)

[0171]

[Chemical 40]

(Wherein X ¹ is as defined above, Z ¹ is a linear or branched alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, etc.), aryl group (eg, ,
A phenyl group) and an aralkyl group (for example, a benzyl group), and R ¹ , r ⁶⁰ and r ⁷⁰ have the same meanings as described above.

Step 2-1 By reacting an aldehyde compound of formula (5c) (hereinafter referred to as compound (5c)) with ethylenediamine in a reaction solvent, and further reacting the reaction product with sulfur,
A thiol compound of formula (6c) (hereinafter referred to as compound (6c)) can be obtained. Specifically, for example, ethylenediamine is added to a reaction solvent solution of the compound (5c) and heated. After completion of the reaction, compound (6c) can be obtained by adding sulfur to this and stirring. Examples of the reaction solvent that can be used in Step 2-1 include alcohol solvents (eg, ethoxyethanol, methanol, ethanol, isopropyl alcohol, 2-propanol, tert-butanol, etc.), aprotic solvents (eg, dichloromethane, Tetrahydrofuran, benzene, N, N-dimethylformamide, etc.) and the like, and these may be used alone or in combination. Step 2-1 is 50 ° C to 150 ° C, preferably 100 ° C to
Perform at 130 ° C.

Step 2-2 A compound (6c) is reacted with a haloacetic acid ester in a reaction solvent in the presence of a base to obtain a benzothiophene compound of the formula (7c) (hereinafter referred to as compound (7c)). You can Specifically, for example, the compound (6c) and the haloacetic acid ester are added to the reaction solvent, the mixture is stirred,
Compound (7c) can be obtained by adding a base to this. The reaction solvent used in Step 2-2 is, for example, an alcohol solvent (eg, methanol,
Ethanol, isopropyl alcohol, 2-propanol, tert-butanol, etc.), and these may be used alone or in combination. Examples of the haloacetic acid ester used in Step 2-2 include methyl bromoacetate, methyl chloroacetate, ethyl bromoacetate, ethyl chloroacetate and the like. Examples of the base used in Step 2-2 include hydroxides such as sodium hydroxide and potassium hydroxide; various carbonates such as potassium carbonate and sodium bicarbonate; pyrrolidine, piperidine, triethylamine, N-
Examples include organic bases such as methylmorpholine. Process 2
-2 is 0 to 150 ° C, preferably room temperature to 100
Perform at ℃.

Step 2-3 By heating and stirring the compound (7c) in the reaction solvent in the presence of a base, the diazepine compound of the formula (8c) (hereinafter referred to as the compound (8c)) can be obtained. Examples of the reaction solvent used in Step 2-3 include alcohol solvents (eg, methanol, ethanol, isopropyl alcohol, 2-propanol, tert-butanol, etc.), which may be used alone or in combination. May be. Examples of the base used in Step 2-3 include, for example,
Metal alkoxides such as potassium tert-butoxide, sodium methoxide, sodium ethoxide;
Examples thereof include inorganic bases (eg sodium hydroxide, potassium hydroxide, potassium carbonate etc.), organic bases (eg DBU etc.) and the like. The reaction temperature is 0 ° C to 100 ° C
And preferably from room temperature to 90 ° C.

Step 2-4 By reacting compound (8c) with a compound of formula (9c) (hereinafter referred to as compound (9c)) in the presence of a base and tert-butyldimethylchlorosilane in a reaction solvent, a compound of formula (8 Compound of 10c) (hereinafter, compound (10c)
Can be obtained). The reaction is preferably performed under an inert gas (for example, argon gas) atmosphere.
Specifically, for example, the compound (8c) is replaced with argon.
Tert-Butylmethylchlorosilane is added to the solution of the reaction solvent of, and the mixture is stirred. A compound (10c) can be obtained by adding a base to this and stirring, and adding the compound (9c) and further stirring. As the reaction solvent used in Step 2-4, for example, an aprotic solvent (for example,
Tetrahydrofuran, benzene, N, N-dimethylformamide and the like); ether solvents (eg, dimethoxyethane and the like), and these may be used alone or in combination. Examples of the base used in Step 2-4 include sodium hydroxide, butyllithium, potassium t
Examples include inorganic bases such as ert-butoxide and sodium hydride. Steps 2-4 are performed at 0 ° C to 80 ° C, preferably 0 ° C to room temperature.

Step 2-5 Compound (10c) is reacted with phosphorus pentachloride in a reaction solvent to give a compound of formula (11c) (hereinafter referred to as compound (1
1c)) can be obtained. Specifically, for example, phosphorus pentachloride is added to the mixture of the compound (10c) and the reaction solvent, and the mixture is heated and stirred. Compound (11c) can be isolated and purified by a conventional method.

As the reaction solvent used in Step 2-5, for example, toluene, chloroform, dioxane and the like can be mentioned, and these may be used alone or in combination. Step 2-5 is usually 0 ° C to 150 ° C, preferably 80 ° C to
Perform at 120 ° C.

Step 2-6 Compound (11c) was converted to a compound of the formula: N in the presence of an acid in a reaction solvent.
H₂NH₂C (= O) r ⁷⁰(In the formula, r⁷⁰Is as defined above
By reacting with a hydrazine compound represented by
A compound of formula (1-7c) (hereinafter referred to as compound (1-7c
c)) can be obtained. Specifically,
For example, compound (11c), hydrazine compound and acid
The solution of the reaction solvent is heated and stirred.

Examples of the acid used in Step 2-6 include:
Methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, trifluoroacetic acid and the like can be mentioned. Examples of the reaction solvent used in Steps 2-6 include n-butanol, dioxane, chloroform and the like, and these may be used alone or in combination. Examples of the hydrazine compound used in Step 2-6 include formylhydrazine and acetohydrazine. Step 2-6 is usually 2
It is carried out at 0 ° C to 150 ° C, preferably 70 ° C to 120 ° C.

Step 2-7 Compound (11c) was converted to compound of the formula: N in the presence of an acid in a reaction solvent.
H ₂ CH ₂ C (r ⁷⁰ ) (OMe) ₂ (wherein, r ⁷⁰ is as defined above) is reacted with an acetal compound to give a compound of formula (1-8c) (1-8c)) can be obtained.

Examples of the solvent used in Step 2-7 include n-butanol, DMF, dioxane, chloroform and the like, and these may be used alone or in combination. Examples of the acid used in Step 2-7 include methanesulfonic acid, tosylic acid, hydrochloric acid, trifluoroacetic acid, sulfuric acid and the like. Examples of the acetal compound used in Step 2-7 include aminoacetaldodedimethylacetal. Step 2-7 is usually 0 ° C to 1
It is carried out at 50 ° C, preferably 50 ° C to 120 ° C.

Production Method 3 (A ⁶ is -S- and A ⁷
Is -O-CO- or -O-CS-)

[0184]

[Chemical 41]

(In the formula, R ¹ has the same meaning as above)

Step 3-1 Compound (4c) is reacted with hydroxylamine hydrochloride in the presence of a base in a reaction solvent to give a compound of formula (12)
A compound of c) (hereinafter referred to as compound (12c)) can be obtained. Specifically, for example, the compound (4c),
Hydroxylamine hydrochloride and base are added to the reaction solvent, which is heated and stirred.

Examples of the base used in Step 3-1 include sodium acetate, sodium hydrogen carbonate, triethylamine and the like. As the reaction solvent used in Step 3-1, for example, n-butanol, dioxane, DM
F and the like may be used, and these may be used alone or in combination. Step 3-1 is usually performed at 20 ° C to 150 ° C, preferably 90 ° C to 130 ° C.

Step 3-2 Compound (12c) is reacted with 1,1′-thiocarbonyldiimidazole in a reaction solvent to give a compound of formula (1-
The compound of 9c) (henceforth a compound (1-9c)) can be obtained. Specifically, for example, the compound (12
By stirring a solution of the reaction solvent of c) and 1,1′-thiocarbonyldiimidazole, the compound (1-9
c) can be obtained.

Examples of the reaction solvent used in Step 3-2 include DMF, THF, chloroform and the like.
These may be used alone or in combination. Process 3-2
Is usually 20 ° C. to 130 ° C., preferably 70 ° C. to 110
Perform at ℃.

Step 3-3 The compound of the formula (1-10c) (hereinafter referred to as the compound (1-10c)) can be obtained by reacting the compound (12c) with carbonyldiimidazole. Specifically, for example, a solution of the reaction solvent of the compound (12c) and carbonyldiimidazole is heated and stirred.

Examples of the reaction solvent used in Step 3-3 include THF, DMF, DMSO and the like, and these may be used alone or in combination. Step 3-3 is
It is usually performed at 0 ° C to 100 ° C, preferably 10 ° C to 30 ° C.

Compound (1c) obtained by Production Method 1 to 3
Can be isolated by a conventional method and, if necessary, can be purified by a conventional method, for example, recrystallization, preparative thin layer chromatography, column chromatography and the like.

The production method of compound (1d) is described below. The method for producing the compound (1d) is not limited to the following production methods, and the compound (1d) can also be synthesized by a method similar thereto. Each compound used in each production method may be protected or deprotected by a conventional method, if necessary.

[0194]

[Chemical 42]

(In the formula, R ¹ is an alkyl group having 1 to 6 carbon atoms, and A ⁹ is as defined above.)

Step 1 A compound of formula (2d) (hereinafter referred to as compound (2d)) is reacted with a compound of formula (3d) (hereinafter referred to as compound (3d)) in the presence of a base in a reaction solvent. ,
A compound of formula (4d) (hereinafter referred to as compound (4d)) can be obtained. Specifically, for example, the compound (2
d), a mixture of the base and the reaction solvent, the compound (3d)
Is added (preferably dropwise), and the mixture is heated and stirred.

Examples of the reaction solvent used in the step 1 include N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone and the like, preferably acetonitrile. Examples of the base used in step 1 include sodium hydride, lithium hydride, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. And potassium carbonate is preferable. Step 1 is generally performed at 50 ° C to 150 ° C, preferably 70 ° C to 100 ° C.

Step 2 By reacting compound (4d) with dimethylthiocarbamoyl chloride in the reaction solvent in the presence of a base,
A compound of formula (5d) (hereinafter referred to as compound (5d)) can be obtained. Specifically, for example, the compound (4
Dimethylthiocarbamoyl chloride and a base are added to the solution of the reaction solvent of d), and it heats and stirs.

Examples of the reaction solvent used in step 2 include N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone and the like, and N, N-dimethylformamide is preferable. Examples of the base used in step 2 include sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, 1,4-diazabicyclo [2.2.2] octane, 4,8-diazabicyclo [ 5.4.0] undec-7-ene and the like can be mentioned, and 1,4-diazabicyclo [2.2.2] octane is preferable. Step 2 is generally performed at -10 ° C to 70 ° C, preferably 0 ° C to room temperature.

Step 3 By reacting compound (5d) at a high temperature in a reaction solvent, a compound of formula (6d) (hereinafter referred to as compound (6d)) can be obtained. Specifically, for example, the compound (5d) is dissolved in a reaction solvent and heated and stirred at high temperature.
Step 3 can also be performed under an atmosphere of an inert gas (eg, argon gas, nitrogen gas, etc.).

The reaction solvent used in step 3 is preferably diphenyl ether, for example. Step 3 is usually 1
00 ° C to 300 ° C, preferably 200 ° C to 270 ° C
Done in.

Step 4 By reacting the compound (6d) in the presence of a base in a reaction solvent, the compound of the formula (7d) (hereinafter referred to as the compound (7
d)) can be obtained. Specifically, for example, by heating a mixture of the compound (6d), a base and a reaction solvent,
Stir. Step 4 can also be performed under an inert gas (for example, argon gas) atmosphere.

The reaction solvent used in Step 4 includes, for example, methanol, ethanol, isopropyl alcohol, tert-butanol, etc., preferably methanol. Examples of the base used in Step 4 include sodium methoxide, sodium ethoxide, t
ert-butoxy potassium and the like, and preferably sodium methoxide. Step 4 is usually 0 ° C to 100
C., preferably 50.degree. C. to 80.degree.

Step 5 Compound (7d) was prepared in the presence of sodium base in a reaction solvent.
The sodium salt can be obtained by reacting The resulting sodium salt is neutralized with an acid and then reduced with a reducing agent to obtain a 2-mercaptobenzoic acid derivative. The compound of formula (8d) (hereinafter referred to as compound (8d)) can be obtained by reacting the obtained 2-mercaptobenzoic acid derivative with chloroacetic acid in the presence of a base in a reaction solvent. After the neutralization and before the reduction, the reaction product can be brought into a solution state by adding a base (for example, sodium carbonate etc.).

The reaction solvent for obtaining the sodium salt used in step 5 includes, for example, methanol, ethanol and the like, preferably methanol. Examples of the base for obtaining the sodium salt used in Step 5 include:
Sodium hydroxide is preferred. The acid used in step 5 is preferably hydrochloric acid, for example. The reducing agent used in step 5 is preferably sodium hydrosulfite, for example. As the solvent used in the reaction with chloroacetic acid in Step 5, for example, water, methanol or a mixture thereof is preferable. Examples of the base used in the reaction with chloroacetic acid in step 5 include sodium carbonate, potassium carbonate and the like, and preferably sodium carbonate. Step 5 is
It is usually carried out at 0 ° C to 100 ° C, preferably room temperature to 70 ° C.

Step 6 Step 6 is, for example, Journal of Organic.
Chemistry (The Journal of Organic Chemistry) 1
0,381 (1945). That is, in the presence of a base in the reaction solvent, the compound (8d)
The compound of formula (9d) (hereinafter referred to as compound (9d)) can be obtained by intramolecular cyclization of

Examples of the reaction solvent used in Step 6 include ethyl acetate, butyl acetate, acetic anhydride and the like.
Acetic anhydride is preferred. Examples of the base used in step 6 include sodium acetate, lithium acetate and the like, and preferably sodium acetate.

Step 7 Heterocycles, Vol. 43, N
o. 1 (1996), the compound (9d) and the compound of the formula (10d) (hereinafter referred to as the compound (10d)).
The compound of formula (11d) (hereinafter referred to as compound (11d)) can be obtained by reacting

Step 8 By reacting compound (11d) with hydroxylamine or its hydrochloride in the presence of a base in a reaction solvent, a compound of formula (1-1d) (hereinafter referred to as compound (1-1
d)) can be obtained. Specifically, a base and hydroxylamine or its hydrochloride are added to a solution of the compound (11d) in a reaction solvent, and the mixture is heated and stirred.

The reaction solvent used in Step 8 includes, for example, methanol, ethanol, isopropyl alcohol, tert-butanol, pyridine, water, a mixture thereof and the like, and an aqueous ethanol solution and pyridine are preferable. Examples of the base used in step 8 include sodium acetate, lithium acetate and the like, and preferably sodium acetate. Step 8 is usually 50 ° C to 15 ° C
It is carried out at 0 ° C., preferably 80 ° C. to 120 ° C. Furthermore, two kinds of geometric isomers can be obtained by purifying the obtained compound by column chromatography.

[0211]

[Chemical 43]

(In the formula, R ¹ is an alkyl group having 1 to 6 carbon atoms, A ^{10 ′} is an alkyl group having 1 to 6 carbon atoms, and r 10
^{80 ′} is an acyl group having 2 to 11 carbon atoms, and A ⁹ , X ¹ and r ⁸¹ have the same meaning as described above. )

Step 9 In the same manner as in Step 8, the compound (11d) is reacted with the compound of the formula (12d) (hereinafter referred to as the compound (12d)) or its hydrochloride in the presence of a base in the reaction solvent. Thus, the compound of formula (1-2d) (hereinafter, compound (1-
2d)) can be obtained.

Examples of the reaction solvent used in Step 9 include methanol, ethanol, isopropyl alcohol, tert-butanol, pyridine, water and the like, preferably ethanol aqueous solution and pyridine. Examples of the base used in Step 9 include sodium acetate,
Examples thereof include lithium acetate, and sodium acetate is preferable. Step 9 is generally performed at 50 ° C to 150 ° C, preferably 80 ° C to 120 ° C.

Step 10 Compound (11d) was converted to compound of formula (1) in the presence of a base in a reaction solvent.
The compound of formula (14d) (hereinafter referred to as compound (14d)) can be obtained by reacting with the compound of 3d) (hereinafter referred to as compound (13d)). Specifically, for example, a base is added to a solution of the compound (11d) in the reaction solvent, and then the compound (13d) is added, and the temperature is returned to room temperature. Step 10 is preferably performed under an inert gas (for example, nitrogen gas) atmosphere.

Examples of the reaction solvent used in Step 10 include tetrahydrofuran, diethyl ether and the like, and preferably tetrahydrofuran. As the base used in Step 10, for example, lithium diisopropylamide is preferable. Step 10 is usually -100 ° C to 5
It is carried out at 0 ° C., preferably −80 ° C. to room temperature. Compound (1
4d) can be isolated and purified by a conventional method.

Step 11 Compound (14d) is reacted with hydroxylamine or a hydrochloride thereof in a reaction solvent to give a compound of formula (1-3)
The compound of d) (henceforth compound (1-3d)) can be obtained. Specifically, for example, the compound (14
Hydroxylamine or its hydrochloride is added to the solution of the reaction solvent in d), and the mixture is heated and stirred.

Examples of the reaction solvent used in Step 11 include methanol, ethanol, isopropyl alcohol, tert-butanol, pyridine and the like, with preference given to ethanol and pyridine. Step 11 is usually 50 ° C to 150 ° C, preferably 70 ° C to 120 ° C
Done in.

Step 12 In a reaction solvent, compound (11d) is reacted with a compound of formula (15d) (hereinafter referred to as compound (15d)) or its hydrochloride to give a compound of formula (1-4d) (hereinafter Compound (1-4d)) can be obtained.
Specifically, for example, the compound (15d) or its hydrochloride is added to a solution of the reaction solvent of the compound (11d), and the mixture is heated and stirred.

Examples of the reaction solvent used in Step 12 include methanol, ethanol, isopropyl alcohol, tert-butanol, pyridine, isopropyl alcohol and the like, with preference given to ethanol, pyridine and isopropyl alcohol. Examples of the compound (15d) used in step 12 include acetohydrazide and semicarbazide. Step 12 is usually performed at 50 ° C to 150 ° C, preferably 70 ° C to 120 ° C. In order to carry out this reaction more smoothly, p-
A catalyst such as toluene sulfonic acid may be used.

Step 13 A compound of formula (1-5d) (hereinafter referred to as compound (1-5d)) can be obtained by reacting compound (1-1d) with acetic anhydride in a reaction solvent. Specifically, for example, in a solution of the reaction solvent of the compound (1-1d),
Add acetic anhydride, heat and stir.

Examples of the reaction solvent used in Step 13 include methanol, ethanol, isopropyl alcohol, tert-butanol, pyridine and the like, and preferably pyridine. Step 13 is usually 0 ° C. to 7
It is carried out at 0 ° C., preferably room temperature.

Step 14 A compound of formula (1-6d) (hereinafter referred to as compound (1-6d)) is obtained by reacting compound (1-1d) with bromoacetic acid methyl ester in the presence of a base in a reaction solvent. Can be obtained. Specifically, for example, a base is added to the solution of the compound (1-1d) in the reaction solvent, and then bromoacetic acid methyl ester is added, and the mixture is heated and stirred. Step 14 is preferably performed under an atmosphere of an inert gas (for example, argon gas).

Examples of the reaction solvent used in Step 14 include N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone and the like, and preferably N, N-dimethylformamide. Examples of the base used in Step 14 include sodium hydride, sodium acetate, lithium acetate and the like, with preference given to sodium hydride and sodium acetate. Step 14 is generally performed at 0 ° C to 100 ° C, preferably room temperature to 50 ° C. When r ⁸⁰ is alkoxycarbonylalkyl having 3 to 9 carbon atoms, it can be produced according to the method of the above Step 14.

Step 15 An acetic acid salt compound is obtained by reacting compound (1-6d) in the presence of a base in a reaction solvent. The obtained acetate compound is converted into a carboxylic acid compound by a conventional method and then reacted with ammonium chloride in a reaction solvent in the presence of a condensing agent and an activator to give a compound of the formula (1-7d). (Hereinafter, referred to as compound (1-7d)) can be obtained. Specifically, for example, a condensing agent, an activator, and ammonium chloride are added to a solution of a carboxylic acid compound in a reaction solvent, and the mixture is heated and stirred.

The reaction solvent for obtaining the acetate compound used in step 15 includes, for example, methanol, ethanol, water and the like, preferably an aqueous methanol solution. Examples of the base for obtaining the acetate compound used in step 15 include sodium hydroxide, lithium hydroxide and the like, and preferably sodium hydroxide. The base is preferably added in the form of an aqueous solution. Examples of the reaction solvent used for the condensation reaction in Step 15 include N, N-dimethylformamide, dimethylsulfoxide, and the like, and N, N-dimethylformamide is preferable.
As the condensing agent used in Step 15, for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide is preferable. As the activator, for example, N-hydroxybenzotriazole monohydrate is preferable. Process 15
Is usually performed at 0 ° C. to 70 ° C., preferably room temperature. r ⁸⁰
When is a carbamoylalkyl having 2 to 7 carbon atoms, it can be produced according to the method of the above step 15.

Step 16 Lithium bis (trimethylsilyl) amide is reacted with phosphonoacetic acid trimethyl ester in a reaction solvent to obtain a carbanion compound. By reacting the obtained carbanion compound with the compound (11d) in the same reaction solvent, the compound of the formula (1-8d) (hereinafter, referred to as the compound (1-
8d)) can be obtained. Specifically, for example, in the reaction solvent, lithium bis (trimethylsilyl)
Amide and phosphonoacetic acid trimethyl ester are added, and after stirring, the compound (11d) or a solution thereof is added, and the mixture is heated and stirred. Step 16 is preferably performed under an inert gas (for example, nitrogen gas) atmosphere.

The reaction solvent used in Step 16 is, for example, tetrahydrofuran, diethyl ether or the like, preferably tetrahydrofuran. Process 16
Is usually 40 ° C to 100 ° C, preferably 60 ° C to 9
Perform at 0 ° C.

Step 17 The compound (1-8d) is reacted in the reaction solvent in the presence of a base to give a carboxylic acid compound. By reacting the obtained carboxylic acid compound with ammonium chloride in the presence of an activator and a condensing agent in a reaction solvent,
A compound of formula (1-9d) (hereinafter referred to as compound (1-9d)) can be obtained. Specifically, it may be performed in the same manner as in step 15.

Examples of the reaction solvent for obtaining the carboxylic acid compound in step 17 include methanol, ethanol,
Dioxane, water and the like, and preferably methanol,
It is a mixed solvent of dioxane and water. As the base for obtaining the carboxylic acid compound in Step 17, for example, sodium hydroxide is preferable. The base is preferably added in the form of an aqueous solution. As the reaction solvent used in the condensation reaction of Step 17, for example, N, N-dimethylformamide is preferable. As the activator used in Step 17, for example, N-hydroxybenzotriazool monohydrate is preferable. Examples of the condensing agent used in Step 17 include 1
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide is preferred. Step 17 is usually 0 ° C to 100 ° C.
C., preferably room temperature to 80.degree.

The compound (1d) of the present invention obtained by the above-mentioned production method can be isolated by a conventional method, and if necessary, a conventional method such as recrystallization, preparative thin layer chromatography, column chromatography. And the like.

Further, the compounds of the above formulas (1a) and (1 ′) can be converted into a pharmaceutically acceptable salt thereof, if necessary, by a conventional method and a known method. The compounds of the above formulas (1a) and (1 ′) can form an acid addition salt when they have a basic group, and as an acid for forming such an acid addition salt, a basic moiety and a salt are used. There is no particular limitation as long as it is an acid capable of forming a pharmaceutically acceptable acid. Examples of such acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid and p-toluenesulfonic acid.

When the compounds of the above formulas (1a) and (1 ') have an acidic group such as a carboxyl group,
For example, alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), organic base salts (eg, triethylamine salt, dicyclohexylamine salt, pyridine salt, etc.) Can be formed.

Pharmaceutical compositions containing the compound of formula (1a) or (1 ′) of the present invention or a pharmaceutically acceptable salt thereof are tablets, pills, powders, granules, suppositories, and injections. , Eye drops, liquids, capsules, troches, aerosols,
It can be orally or parenterally administered in the form of preparations such as elixirs, suspensions, emulsions and syrups. Each dosage form can be prepared by a method known per se. Conventionally known additives may be used as the additives to be used for the preparation of each dosage form. For example, an excipient (for example, starch,
Lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.), disintegrants ( For example, carboxymethyl cellulose calcium, talc, etc.) and the like.

The dose of the compound of the above formula (1a) or (1 ′) or a pharmaceutically acceptable salt thereof varies depending on the administration subject, symptoms and other factors. For example, when administered orally to an adult, 1 A dose of about 1 to 1000 mg / kg body weight is given once to several times a day.

The compounds of the above formulas (1a) and (1 ′) of the present invention and their pharmaceutically acceptable salts are useful as excellent HIV inhibitors for mammals.

[0237]

The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. Further, in the table, "〃" means the same as above. Example 1 9-methoxy-1- (2-methyl-2-propenyl) -1,2,3,4-tetrahydro-5H-
[1] Benzothieno [3,2-e] -1,4-diazepin-5-one a) 2- (4,5-dihydro-1H-imidazole-2
-Yl) -4-methoxybenzenethiol 2-bromo-5-methoxybenzaldehyde (180
g) ethylene glycol monomethyl ether (720
ml) solution was added ethylenediamine (115 ml) in one portion. The reaction solution was stirred at 120 ° C. for 2 hours, and then sulfur (26.6 g) was added. Red mixture at 110 ° C for 2
After stirring for 4 hours, the mixture was stirred under ice cooling for 2 hours. The obtained solid was collected by filtration, ethyl acetate (180 ml), water (18 ml)
It was washed with 0 ml) and the same operation was further repeated. After drying, the title compound (138 g) was obtained. The obtained crude solid was used for the next reaction without purification.

B) Methyl 3-((2-aminoethyl)
Amino) -5-methoxy-benzo [b] thiophene-2
-Carboxylate 2- (4,5-dihydro-1 obtained in a) of Example 1
H-imidazol-2-yl) -4-methoxybenzenethiol (137g) and 2-propanol (685m)
Methyl bromoacetate (63 ml) was added to the mixture of l), and the mixture was stirred at room temperature for 1 hr and then at 90 ° C. for 30 min. The reaction mixture was cooled to room temperature and potassium carbonate (45.
5 g) was added slowly. The mixture was stirred at 90 ° C. for 2 hours and then ice-cooled for 1 hour. The precipitated solid was collected by filtration, washed with 2-propanol (140 ml) and dried (55 ° C, 10 hr) to give a crude product of the title compound (24
8 g) was obtained. The obtained crude product was used for the next reaction without further purification.

C) 9-Methoxy-1,2,3,4-tetrahydro-5H- [1] benzothieno [3,2-e]-
1,4-diazepin-5-one Crude product of methyl 3-((2-aminoethyl) amino) -5-methoxy-benzo [b] thiophene-2-carboxylate obtained in b) of Example 1 Sodium methoxide (65 g) was added to a mixed liquid of (248 g) and methanol (1000 ml), and the mixture was stirred at 70 ° C. for 2 hours. The reaction solution was ice-cooled, concentrated hydrochloric acid water (60 ml) was added dropwise, and the pH was adjusted to 7 with a small amount of concentrated hydrochloric acid water. After stirring for 1 hour under ice cooling, the precipitated solid was collected by filtration. The obtained solid was washed with water, methanol, a 1: 1 mixture of ethyl acetate and hexane, and dried to give the title compound (95.3 g).

D) 9-methoxy-1- (2-methyl-2)
-Propenyl) -1,2,3,4-tetrahydro-5H
-[1] benzothieno [3,2-e] -1,4-diazepin-5-one 9-methoxy-1,2,3,4-tetrahydro-obtained in Example 1 c) under argon substitution. 5H- [1] benzothieno [3,2-e] -1,4-diazepin-5-one (650 mg) in dimethylformamide (10 ml)
The solution was ice-cooled, tert-butyldimethylchlorosilane (434 mg) was added, and the mixture was stirred for 5 minutes. Sodium hydride (230 mg) was added, and the mixture was stirred at room temperature for 10 minutes. 3-Bromo-2-methyl-propene (0.34m
1) was added, and the mixture was stirred for another 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography and then recrystallized from ethyl acetate to give the title compound (400 mg, 50%) (see Table 1).

Example 1-2 9-Ethoxy-4-methyl-1-propyl-1,2,3,4-tetrahydro-5H
-[1] Benzothieno [3,2-e] -1,4-diazepin-5-one a) 9-methoxy-1-propyl-1,2,3,4-tetrahydro-5H- [1] benzothieno [3 , 2-e]
-1,4-Diazepin-5-one 9-methoxy-1,2,3,4-tetrahydro-5H- [1] benzothieno [3,2-e obtained in Example 1 c) under argon substitution. ] -1,4-Diazepin-5-one (1.5 g) in tetrahydrofuran (15 ml) was ice-cooled, butyllithium (8.68 ml) was added, and 1
Stir for 5 minutes. After adding tert-butyldimethylchlorosilane (1.0 g) and stirring at room temperature for 15 minutes,
n-Propyl bromide (2.74 ml) was added, and the mixture was further stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine,
The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound (1.
0 g, 57%) was obtained.

B) 9-hydroxy-1-propyl-1,
2,3,4-Tetrahydro-5H- [1] benzothieno [3,2-e] -1,4-diazepin-5-one 9-methoxy obtained in a) of Example 1-2 under argon substitution. -1-Propyl-1,2,3,4-tetrahydro-5H- [1] benzothieno [3,2-e] -1,4-
A mixture of diazepin-5-one (5.164 g) and methylene chloride (26 ml) was stirred under ice cooling, and 1M-BBr was added.
_{A 3} / methylene chloride solution (34 ml) was added, and the mixture was stirred for 0.5 hr and then at room temperature for 1.5 hr. A saturated aqueous sodium hydrogen carbonate solution (34 ml) was added under cooling, and the mixture was stirred at room temperature for 2 hours. After adding hexane (30 ml), the precipitated yellow solid was collected by filtration and washed with water, a methylene chloride / hexane (1: 4) mixed solution, and hexane.
After drying, the title compound (4.716 g, 96%) was obtained as a yellow solid. This solid was used in the next reaction without purification.

C) 9-ethoxy-1-propyl-1,
2,3,4-Tetrahydro-5H- [1] benzothieno [3,2-e] -1,4-diazepin-5-one 9-hydroxy-1-propyl obtained in Example 1-2 b) -1,2,3,4-Tetrahydro-5H- [1]
Benzothieno [3,2-e] -1,4-diazepine-5
-One (100 mg) of dimethylformamide (1.5
(ml) solution, potassium carbonate (300 mg) and ethyl iodide (145 μl) were added, and the mixture was stirred at room temperature for 15 hours. Under cooling, add water and extract with a large amount of ethyl acetate,
The organic layer was washed with water and brine. After drying, the product was concentrated under reduced pressure to obtain a crude product. After purifying this by flash chromatography (tetrahydrofuran, chloroform),
By recrystallizing from ethyl acetate, the title compound (41
mg) was obtained.

D) 9-Ethoxy-4-methyl-1-propyl-1,2,3,4-tetrahydro-5H- [1] benzothieno [3,2-e] -1,4-diazepine-5-
9-Ethoxy-1-propyl-1,2,3,4-tetrahydro-5H- [1] benzothieno [3,2-e] -1 obtained in Example 1-2 c) under on-argon substitution. , 4-
A solution of diazepin-5-one (101 mg) in dimethylformamide (1.5 ml) was stirred under ice cooling to give 60%-
Sodium hydride (20 mg) and methyl iodide (3
1 μl) was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added under cooling, extraction was performed with a large amount of ethyl acetate, and the organic layer was washed with water and brine. After drying, concentration under reduced pressure gave a crude product of the title compound. The title compound (54 mg) was obtained by recrystallizing this with ethyl acetate (refer to Table 1).

The compounds of Examples 1-3 to 1-79 (R ² is a hydrogen atom) shown in Tables 1 to 3 below were produced according to the methods of Examples 1 and 1-2 above.

[0246]

[Table 1]

[0247]

[Table 2]

[0248]

[Table 3]

Example 2 1- (2-Methyl-2-propenyl) -9-nitro-1,2,3,4-tetrahydro-
5H- [1] benzothieno [3,2-e] -1,4-diazepin-5-one a) 2- (4,5-dihydro-1H-imidazole-2
-Yl) -4-nitrobenzenethiol 2-chloro-5-nitrobenzaldehyde (100.0
g) ethylene glycol monomethyl ether (1.0
L) Ethylenediamine (80 ml) was added to the solution at once. After the temperature of the reaction solution was raised to 60 ° C, sulfur (19.0
g) was added. The red mixture was stirred at 110 ° C. for 20 hours and then under ice cooling for 1.5 hours. The obtained solid was collected by filtration, and ethyl acetate (200 ml) and water (200 m)
It was washed with l). After drying, a crude solid (82.73 g) was obtained. Dimethyl sulfoxide (850 m
1) was added, the mixture was stirred at 130 ° C. for 1 hour, and then left at room temperature for 2 days. The insoluble matter was filtered off, and dimethyl sulfoxide (1
(00 ml). The filtrate was stirred under ice-cooling, and water (40
(0 ml), and the mixture was further stirred for 1 hour. The obtained crystals were collected by filtration and washed with water (200 ml). After drying, the title compound (69.20 g, 58%) was obtained.

B) Methyl 3-((2-aminoethyl)
Amino) -5-nitro-benzo [b] thiophene-2-
Carboxylate 2- (4,5-dihydro-1 obtained in a) of Example 2
To a mixture of H-imidazol-2-yl) -4-nitrobenzenethiol (24.3 g) and methanol (340 ml) was added methyl bromoacetate (10.5 ml), and 1
The mixture was stirred under reflux for hours. The reaction mixture was cooled to room temperature and potassium carbonate (7.60 g) and methanol (100 ml) were slowly added. The mixture was heated under reflux for 2 hours, and then stirred under ice cooling for 1 hour. The precipitated solid was collected by filtration, washed with methanol (70 ml) and dried (55 ° C, 10h).
r), a crude product of the title compound (32.5 g) was obtained. The obtained title compound was used in the next reaction without further purification.

C) 9-Nitro-1,2,3,4-tetrahydro-5H- [1] benzothieno [3,2-e]-
1,4-diazepin-5-one Crude product of methyl 3-((2-aminoethyl) amino) -5-nitro-benzo [b] thiophene-2-carboxylate obtained in b) of Example 2 Sodium methoxide (8.83 g) was added to a mixed solution of (32.5 g) and methanol (800 ml), and the mixture was stirred under reflux at 80 ° C. for 3 hours. The reaction solution was ice-cooled, and concentrated hydrochloric acid water (10 ml) was added dropwise. After stirring for 1 hour under ice cooling, the precipitated solid was collected by filtration. The obtained solid was washed with water and methanol and then dried to obtain the desired cyclized product 4 (24.3 g, 85
%) Was obtained.

D) 1- (2-methyl-2-propenyl)
-9-nitro-1,2,3,4-tetrahydro-5H-
[1] Benzothieno [3,2-e] -1,4-diazepin-5-one 9-Nitro-1,2,2, obtained in c) of Example 2 in the same manner as d) of Example 1. 3,4-tetrahydro-5H-
From [1] benzothieno [3,2-e] -1,4-diazepin-5-one (3.0 g), the title compound (2.14
g, 59%) was obtained (see Table 4).

In accordance with the method of Example 2 above, the following Table 4 to
The compounds of Examples 2-2 to 2-69 described in 6 (R ² is a hydrogen atom) were produced.

[0254]

[Table 4]

[0255]

[Table 5]

[0256]

[Table 6]

Example 3 9- (Methylaminosulfonyl) -1-isobutyl-1,2,3,4-tetrahydro-5H- [1] benzothieno [3,2-e] -1,4-
Diazepin-5-one a) 9- (chlorosulfonyl) -1-isobutyl-1,
2,3,4-Tetrahydro-5H- [1] benzothieno [3,2-e] -1,4-diazepin-5-one Obtained in the same manner as a) of Example 1-2 under argon substitution. 1-isobutyl-1,2,3,4-tetrahydro-
A solution of 5H- [1] benzothieno [3,2-e] -1,4-diazepin-5-one (7.134 g) in chloroform (107 ml) was ice-cooled, and 5 drops of dimethylformamide and thionyl chloride (5. 69 ml) was added and stirred for 5 minutes. Chlorosulfonic acid (8.64 ml) was added dropwise over 10 minutes, and the mixture was stirred at 60 ° C for 3 hours. Water was added to the reaction solution, extracted with a large amount of chloroform, and then washed with an aqueous sodium hydrogen carbonate solution and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (8.81 g, 91%) as a yellow crude product. The obtained crude product was used for the next reaction without purification.

B) 9- (methylaminosulfonyl) -1
-Isobutyl-1,2,3,4-tetrahydro-5H-
[1] Benzothieno [3,2-e] -1,4-diazepin-5-one 9- (chlorosulfonyl) -1-isobutyl-1,2 obtained in Example 3 a) under argon substitution. 3,4-Tetrahydro-5H- [1] benzothieno [3,2-e]
To a solution of -1,4-diazepin-5-one (224 mg) in tetrahydrofuran (3.4 ml) was added 40% aqueous methylamine solution (1.0 ml), and the mixture was stirred at room temperature for 1 hour. Water (10 ml), ethyl acetate and hexane (small amount) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitated crude crystals were collected by filtration and dried. Then, recrystallization was performed using ethyl acetate to give the title compound (103 mg, 47
%) Was obtained (see Table 7).

According to the method of Example 3 above, the compounds of Examples 3-2 to 3-13 (R ² is a hydrogen atom) shown in Table 7 below were produced.

[0260]

[Table 7]

Example 4 1- (2-Methyl-2-propenyl) -9-nitro-1,2,3,4-tetrahydro-
5H- [1] benzofurano [3,2-e] -1,4-diazepin-5-one a) methyl 3-((2- (tert-butoxycarbonylamino) ethyl) amino) -5-nitro-benzo [ b] Furan-2-carboxylate Under argon substitution, 2- (tert-butoxycarbonylamino) ethylamine (37.6 g) in methanol (3
74 ml) solution was cooled to 0 ° C. and 2-hydroxy-5-
After adding nitrobenzaldehyde (37.4 g), the solution was stirred at room temperature for 1 hour. Toluene (2
(00 ml) and concentrated under reduced pressure to quantitatively obtain an oily substance. The oil obtained was dissolved in N, N-dimethylformamide (370 ml), cooled to 0 ° C., potassium carbonate (92.5 g) and methyl chloroacetate (2
5.5 ml) was added, and the mixture was stirred at an internal temperature of 27 ° C to 37 ° C for 3 hours. Water (400 ml), hexane (10 ml) and ethyl acetate (1 ml) were added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 0.5 hr. The precipitated solid was collected by filtration, water,
Wash with hexane. The title compound (75.1 g) obtained as a solid after drying was used in the next reaction without purification.

B) 9-nitro-1,2,3,4-tetrahydro-5H-benzo [b] furano [3,2-e]-
1,4-diazepin-5-one methyl 3 obtained in a) of Example 4 under argon substitution
-((2- (tert-Butoxycarbonylamino) ethyl) amino) -5-nitro-benzo [b] furan-2
-Carboxylate (75.1 g) of dioxane (15
0 ml) solution to 4N-hydrochloric acid dioxane solution (300 m
After the addition of l), the solution was stirred at room temperature for 3 hours. The reaction solution was combined with toluene (200 ml) and concentrated under reduced pressure to give methyl 3-((2-aminoethyl) amino) -5-.
The hydrochloride of nitro-benzo [b] furan-2-carboxylate was obtained quantitatively. The obtained methyl 3-((2-
Aminoethyl) amino) -5-nitro-benzo [b] furan-2-carboxylate hydrochloride was added to methanol (5
00 ml), cooled to 0 ° C., added sodium methoxide (32 g), and heated at an internal temperature of 27 ° C. to 37 ° C. for 3
Stir for hours. Water (400 m) was added to the reaction solution under ice cooling.
l), hexane (10 ml) and ethyl acetate (1 m
1) was added, and the mixture was stirred under reflux for 12 hours. After cooling, the precipitated solid was filtered off and washed thoroughly with water and ethyl acetate. After drying, the title compound was obtained (31.5g).

C) 1- (2-methyl-2-propenyl)
-9-nitro-1,2,3,4-tetrahydro-5H-
[1] Benzofurano [3,2-e] -1,4-diazepin-5-one 9-nitro-1,2,3,4 obtained in b) of Example 4
-Tetrahydro-5H- [1] benzofurano [3,2-
e] -1,4-Diazepin-5-one (4 g) in the same manner as in d) of Example 1 to give the title compound (2.12 g)
Got

In accordance with the method of Example 4 above, the following Table 8 to
The compounds of Examples 4-2 to 4-40 described in Example 9 (R ² is a hydrogen atom) were produced.

[0265]

[Table 8]

[0266]

[Table 9]

Example 5 9-Methoxy-1,2,3,4
-Tetrahydro-5H-indeno [1,2-e] [1,
4] Diazepin-5-one a) 1-oxo-6-methoxyindane-2-carboxylate methyltetrahydrofuran (48 ml) was added with 60% sodium hydride (4.28 g) and dimethyl carbonate (9.64 g) to give a reaction solution. Was heated to 80 ° C., 6-methoxyindan-1-one (6.94 g) of N, N-dimethylformamide (48 ml) was added.
The solution was added dropwise over 0.5 hour. After completion of the dropwise addition, the mixture was refluxed for 1 hour, then the reaction solution was ice-cooled and acetic acid (6.43 ml) was added to terminate the reaction. Add water (200 ml) and add ethyl acetate:
It was extracted with a mixture of hexane (2: 1). The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give a crude product. This was purified by column chromatography to obtain the title compound a) (7.99 g). b) 9-methoxy-1,2,3,4-tetrahydro-5
H-indeno [1,2-e] [1,4] diazepine-5
P-Toluenesulfonic acid monohydrate (750 mg) was added to a solution of -one ethylenediamine (13.7 ml) in xylene (150 ml).
Methyl 1-oxo-6-methoxyindane-2-carboxylate (15.3 g) was added as a solid while heating to 0 ° C. Xylene (50 ml) was added, and the mixture was heated and stirred for 1.5 hours while azeotropically dehydrating. The reaction solution was cooled to room temperature, and the precipitated solid was collected by filtration. The extract was washed with ethyl acetate and hexane and dried to give the title compound (15.3 g). ¹ H-NMR (300 MHz, DMSO-d ₆ ): 3.30-3.35 (3H, m), 3.40-3.
46 (3H, m), 3.77 (3H, s), 6.89 (1H, dd, J = 8.3, 2.
3 Hz), 7.14 (1H, br), 7.30-7.35 (3H, m) .MS (FAB +)
m / z: 231.0 (M ++ H).

Example 5-2 1-Benzyl-9-methoxy-1,2,3,4-tetrahydro-5H-indeno [1,2-e] [1,4] diazepin-5-one N-benzylethylenediamine (8.34g) xylene (50
ml) solution, p-toluenesulfonic acid monohydrate (122 mg) was added, and methyl 1-oxo-6-methoxyindane-2-carboxylate (2.45 g) was added as a solid while heating to 100 ° C. . Add xylene (20 ml) and azeotropically dehydrate
The mixture was heated and stirred for 5 hours. The reaction solution was cooled to room temperature and the precipitated solid (4-benzyl-9-methoxy-1,2,3,3)
4-Tetrahydro-5H-indeno [1,2-e]
[1,4] diazepin-5-one) was filtered off. The filtrate washed with ethyl acetate was concentrated under reduced pressure and purified by column chromatography to obtain a crude product. The obtained oil was recrystallized from ether to give the title compound (11 mg). ¹ H-NMR (300 MHz, CHCl ₃ ): 3.38-3.49 (6H, m), 3.76 (3H,
s), 4.69 (2H, s), 6.18 (1H, br), 6.88 (1H, dd, J
= 8.1, 2.2 Hz), 6.94 (1H, d, J = 2.2 Hz), 7.29-7.5
0 (6H, m), MS (FAB) m / z 320.9 (M ++ H).

Example 5-3 9-Methoxy-6-n-propyl-1,2,3,4-tetrahydro-5H-indeno [1,2-e] [1,4] diazepin-5-one 9- Methoxy-1,2,3,4-tetrahydro-5H-
A solution of indeno [1,2-e] [1,4] diazepin-5-one (390 mg) in tetrahydrofuran (7.8 ml) was added at 0 ° C.
Cooled to n-butyllithium (1.6M hexane solution, 2.3
ml) and stirred for 15 minutes. 1-Bromopropane (0.7
7 ml) was added, and the mixture was stirred for 15 hours while gradually warming to room temperature. After adding saturated sodium hydrogen carbonate solution to the reaction solution,
It was extracted with ethyl acetate, and the organic layer was washed with saturated saline.
The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound (50 mg). ¹ H-NMR (300MHz, DMSO-d ₆ ): 0.60-1.15 (5H, m), 1.80-
2.00 (2H, m), 3.15-3.80 (5H, m), 3.77 (3H, s), 6.87
(1H, brd, J = 9.5 Hz), 7.00-7.25 (5H, m), 7.28 (1
H, brs), 7.29 (1H, d, J = 9.5 Hz). MS (FAB) m / z 273.0 (M ++ H).

Example 5-4 9-Methoxy-6,6-di-n-propyl-1,2,3,4-tetrahydro-5H
-Indeno [1,2-e] [1,4] diazepine-5-
On 9-methoxy-1,2,3,4-tetrahydro-5H-
A solution of indeno [1,2-e] [1,4] diazepin-5-one (1.00g) in tetrahydrofuran (12ml) was cooled to 0 ° C, and n-butyllithium (1.6M hexane solution, 8.4m) was added.
l) was added and stirred for 15 minutes. After adding t-butyldimethylsilyl chloride (720 mg) and stirring for 10 minutes, 1-bromopropane (0.83 ml) was added, and the mixture was stirred for 2 hours while gradually warming to room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to give a crude product. This was recrystallized from toluene to give the title compound (267 mg). ¹ H-NMR (300MHz, CDCl ₃ ): 0.30-0.60 (2H, m), 0.69 (6
H, t, J = 7.3 Hz), 0.80-1.10 (2H, m), 1.60-1.80
(2H, m), 2.44 (2H, td, J = 12.5, 4.8 Hz), 3.40-3.
75 (4H, m), 3.84 (3H, s), 4.90-5.10 (1H, brm), 5.5
5-5.75 (1H, brm), 6.74 (1H, d, J = 2.4 Hz), 6.93 (1
H, dd, J = 8.2, 2.4 Hz), 7.21 (1H, d, J = 8.2 Hz). MS (FAB) m / z 315.0 (M ++ H).

Example 5-5 9-Methoxy-1,6,6
-Tri-n-propyl-1,2,3,4-tetrahydro-5H-indeno [1,2-e] [1,4] diazepin-5-one 9-methoxy-1,2,3,4-tetrahydro -5H-
A solution of indeno [1,2-e] [1,4] diazepin-5-one (1.00g) in tetrahydrofuran (12ml) was cooled to 0 ° C, and n-butyllithium (1.6M hexane solution, 11.1m) was added.
l) was added and stirred for 15 minutes. t-Butyldimethylsilyl chloride (720 mg) was added and the mixture was stirred for 10 minutes, 1-bromopropane (1.22 ml) was added, and the mixture was stirred for 2 hours while gradually warming to room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to give a crude product. This was recrystallized from ether and hexane to give the title compound (149 mg). ¹ H-NMR (300MHz, CDCl ₃ ): 0.35-0.55 (2H, m), 0.68 (6
H, t, J = 7.2 Hz), 0.80-1.00 (2H, m), 0.99 (3H,
t, J = 7.4 Hz), 1.60-1.90 (4H, m), 2.44 (2H, td, J
= 12.5, 4.8 Hz), 3.25-3.55 (6H, m), 3.84 (3H,
s), 5.70-5.85 (1H, brm), 6.91 (1H, dd, J = 8.3, 2.3
Hz), 6.97 (1H, d, J = 2.3 Hz), 7.20 (1H, d, J =
8.3 Hz) .MS (FAB) m / z 357.2 (M ++ H).

The compounds of Examples 5-6 to 5-9 shown in Table 10 below were prepared in the same manner as any of Examples 5 to 5-5 above.

[0273]

[Table 10]

Example 6 10-Methoxy-1,2,3,3
4-tetrahydro-5H-naphtho [2,1-f] [1,
4] Oxazepin-5-one a) 7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid methyltetrahydrofuran (280 ml) in 60% sodium hydride (23.6 g) and carbonic acid. Dimethyl (55 ml) was added, the reaction solution was heated to 75 ° C., and a solution of 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-one (46.4 g) in tetrahydrofuran (190 ml) was added dropwise over 2 hours. did. After the dropwise addition was completed, the mixture was refluxed for 1 hour, and then the reaction solution was cooled with ice. The reaction was quenched with acetic acid to adjust the pH to 5.5, concentrated under reduced pressure, and ether and water were added to separate the layers. PH of organic layer
It was washed with water until it became 5.5, and washed with saturated saline.
The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain a crude product. After adding hexane to this and stirring well,
Only the supernatant layer was removed to give the title compound a) (49.8 g). The obtained product was used for the next reaction without further purification. b) 2-bromo-7-methoxy-1-oxo-1,2,
Methyl 3,4-tetrahydronaphthalene-2-carboxylate 7-Methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (49.8 g) in chloroform (500 ml) was dissolved in N-bromo. Succinimide (41.6 g) was added, and the mixture was stirred for 0.5 hr, 2,2′-azobisisobutyronitrile (210 mg) was added, and the temperature was raised to 50 ° C. After stirring for 1 hour, N-bromosuccinimide (4.2 g) was further added, and the mixture was stirred at 50 ° C for 1 hour. The reaction solution was cooled to room temperature, hexane (500 ml) was added to precipitate succinic acid, and the mixture was filtered off. The filtrate was concentrated under reduced pressure, the obtained solid was dissolved in chloroform (300 ml), and then hexane (350 ml) was added.
ml) was added and the residual succinic acid was filtered off as a solid. The filtrate was concentrated under reduced pressure and recrystallized from hexane and ethyl acetate to give the title compound b) (37.44 g). c) Methyl 1-hydroxy-7-methoxynaphthalene-2-carboxylate 1,8-diazabicyclo [5.4.0] -7-undecene (36 ml) in tetrahydrofuran (80 ml) was ice-cooled to give 2-bromo-. 7-methoxy-1-oxo-1,2,
2 parts of a solution of methyl 3,4-tetrahydronaphthalene-2-carboxylate (37.44 g) in tetrahydrofuran (360 ml) was added.
It dripped over time. The temperature was gradually raised to room temperature, and the mixture was stirred for 17 hours. After cooling the reaction solution with ice, a mixed solution of 6N-hydrochloric acid water (100 ml) and chloroform (300 ml) was added to terminate the reaction. After extraction with chloroform, the organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a solid. The obtained solid was recrystallized from ethanol and water to give the title compound c) (21.71 g). d) Methyl 1- (2- (t-butoxycarbonylamino) ethoxy) -7-methoxynaphthalene-2-carboxylate Methyl 1-hydroxy-7-methoxynaphthalene-2-carboxylate (1.16 g), Nt-butoxy A solution of carbonylethanolamine (0.93 ml) and triphenylphosphine (1.97 g) in tetrahydrofuran (50 ml) was ice-cooled, and diethylazodicarboxylate (40% toluene solution, 3.2 g) was added dropwise over about 15 minutes. The reaction solution was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound d) (1.80g). e) 10-methoxy-1,2,3,4-tetrahydro-
5H-naphtho [2,1-f] [1,4] oxazepine-
To 4-one 1- (2- (t-butoxycarbonylamino) ethoxy) -7-methoxynaphthalene-2-carboxylate (1.80 g) was added 4N-hydrochloric acid dioxane solution (24 ml),
Stirred at room temperature for 1 hour. The solid obtained by concentration under reduced pressure,
It was washed with a mixed solution of ether and hexane. After drying 1
-(2-aminoethoxy) -7-methoxynaphthalene-
Methyl 2-carboxylate hydrochloride (1.37 g) was obtained. The hydrochloride (830 mg) of N, N-dimethylformamide (20 m
l) In solution, 1,8-diazabicyclo [5.4.0]-
7-Undecene (0.6 ml) was added, and the mixture was heated with stirring at 70 ° C. for 0.5 hours and then with stirring at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure and then partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and the solvent was evaporated.
The residue was purified by column chromatography to give the title compound (491 mg). ¹ H-NMR (300 MHz, DMSO-d ₆ ): 3.39 (2H, q, J = 5.0 Hz),
3.90 (3H, s), 4.55 (2H, t, J = 4.6 Hz), 7.27 (1H,
dd, J = 8.7, 2.7 Hz), 7.55 (1H, d, J = 10.5Hz),
7.56 (1H, s), 7.63 (1H, d, J = 8.4 Hz), 7.84 (1H,
d, J = 8.7 Hz), 8.39 (H, br). MS (FAB +) m / z 244.0 (M ++ H).

The compounds of Examples 6-2 to 6-5 shown in Table 11 below were produced in the same manner as in the method of Example 6 above.

[0276]

[Table 11]

Example 7 10-Methoxy-1,2,3,3
4-tetrahydro-5H-naphtho [2,1-f] [1,
4] diazepin-5-one a) 1- (dimethylaminothiocarbonyloxy) -7
-Methyl methoxynaphthalene-2-carboxylate A solution of methyl 1-hydroxy-7-methoxynaphthalene-2-carboxylate (6.97 g) in N, N-dimethylformamide (150 ml) was ice-cooled to give 60% sodium hydride ( 1.44
g) was added little by little. After stirring under ice cooling for 0.5 hours, dimethylaminothiocarbonyl chloride (5.56 g) was added,
The mixture was stirred for 15 hours while gradually raising the temperature to room temperature. After the reaction was completed with acetic acid, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate,
After concentration under reduced pressure, purification by column chromatography gave the title compound a) (4.45 g). b) Methyl 1- (dimethylcarbamoylthio) -7-methoxynaphthalene-2-carboxylate Methyl 1- (dimethylaminothiocarbonyloxy) -7-methoxynaphthalene-2-carboxylate (4.43 g) in diphenyl ether (16 ml) Heat to 230 ° C and
Stir for hours. Cooled to room temperature and purified by column chromatography to give the title compound b) (4.46g). c) 10-methoxy-1,2,3,4-tetrahydro-
5H-naphtho [2,1-f] [1,4] diazepine-5
Sodium methoxide (492 mg) was added to a solution of methyl -one 1- (dimethylcarbamoylthio) -7-methoxynaphthalene-2-carboxylate (970 mg) in methanol (10 ml), and the mixture was heated with stirring at 75 ° C. After cooling the reaction solution to room temperature,
2-Chloroethylamine hydrochloride (458 mg) was added, and the mixture was heated with stirring at 75 ° C for 3 hours. After the reaction solution was concentrated under reduced pressure, the solution was separated with chloroform and water, and the organic layer was washed with water.
The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound (818m
g) was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ): 3.23 (2H, t, J = 6.0 Hz),
3.37 (2H, q, J = 6.3 Hz), 4.00 (3H, s), 7.15 (1H,
br), 7.24 (1H, dd, J = 8.0, 2.5 Hz), 7.56 (1H, d,
J = 8.3 Hz), 7.77 (1H, d, J = 8.9 Hz), 7.85 (1H,
d, J = 8.3 Hz), 8.09 (1H, d, J = 2.5 Hz). MS (FAB +) m / z 260.1 (M ++ H).

The compounds of Examples 7-2 to 7-4 shown in Table 12 below were produced in the same manner as in the method of Example 7 above.

[0279]

[Table 12]

Example 8 10-Methoxy-1,2,3
4-tetrahydro-5H-naphtho [2,1-f] [1,
4] diazepin-5-one a) 10-methoxy-1,2,3,4,5,6-hexahydro-7H-naphtho [2,1-f] [1,4] diazepin-5-one ethylenediamine (6.61 g) in xylene (32 ml) solution p
-Toluenesulfonic acid monohydrate (258 mg) was added, and the temperature was 110 ° C.
1-oxo-7-methoxy-1,2, while being heated to
A solution of methyl 3,4-tetrahydronaphthalene-2-carboxylate (5.15 g) in xylene (20 ml) was added dropwise over about 10 minutes. After completion of dropping, the mixture was heated and stirred for 4.5 hours while azeotropically dehydrating. Ethanol (5 ml) was added to the reaction solution, cooled to room temperature, and the precipitated solid was collected by filtration. The crystals were washed with ethyl acetate and hexane and dried to give the title compound a) (15.3 g). ¹ H-NMR (300MHz, CDCl ₃ ): 2.61-2.70 (4H, m), 3.46-3.5
0 (2H, m), 3.61-3.65 (2H, m), 3.82 (3H, s), 4.74
(1H, br), 6.16 (1H, br), 6.84 (1H, dd, J = 8.2, 2.
5 Hz), 6.97 (1H, d, J = 2.5 Hz), 7.15 (1H, d, J =
8.2 Hz), 7.26 (1H, s), MS (FAB +) m / z 245.1 (M ++ H).

B) 10-Methoxy-1,2,3,4-tetrahydro-5H-naphtho [2,1-f] [1,4] diazepin-5-one 10-methoxy-1,2,3,4 A mixture of 5,5,6-hexahydro-7H-naphtho [2,1-f] [1,4] diazepin-5-one (488 mg), 10% palladium on carbon (488 mg) and acetic acid (24 ml) was heated to 60 ° C. And stirred for 5 hours. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography. The obtained oily substance was crystallized from ether and chloroform to give the title compound (197 mg). ¹ H-NMR (300MHz, CDCl ₃ ): 3.56 (2H, dd, J = 8.8, 6.0
Hz), 3.80 (2H, dd, J = 5.5, 3.4 Hz), 3.94 (3H, s),
6.77 (1H, br), 7.18-7.26 (3H, m), 7.70 (1H, d, J =
8.8 Hz), 7.89 (1H, d, J = 8.8 Hz), MS (FAB +) m / z 243.0 (M ++ H).

Example 8-2 10-Methoxy-1-propyl-1,2,3,4-tetrahydro-5H-naphtho [2,1-f] [1,4] diazepin-5-one 10-methoxy- A solution of 1,2,3,4,5,6-hexahydro-7H-naphtho [2,1-f] [1,4] diazepin-5-one (2.0 g) in tetrahydrofuran (40 ml) was ice-cooled and n -Butyl lithium (1.6M hexane solution, 11.
3 ml) was added, and the mixture was stirred for 15 minutes, warmed to room temperature, and stirred for 15 minutes. 1-Bromopropane (2.2 ml) was added, the mixture was stirred at room temperature for 3 hr, and the reaction mixture was poured into aqueous sodium hydrogen carbonate and ethyl acetate. It was extracted with ethyl acetate and the organic layer was washed with brine. After drying with magnesium sulfate,
The solvent was distilled off and the residue was purified by column chromatography. The obtained crude product was recrystallized from toluene and hexane to give the title compound (1.22 g). ¹ H-NMR (300MHz, CDCl ₃ ): 0.81 (3H, t, J = 7.3 Hz),
1.52-1.63 (2H, m), 2.56-2.68 (4H, m), 2.92-2.97 (2
H, m), 3.43-3.52 (4H, m), 3.81 (3H, s), 6.20 (1H, b
r), 6.80 (1H, dd, J = 8.2, 2.8 Hz), 7.05 (1H, d, J
= 2.6 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.26 (1H, s), MS (FAB +) m / z 287.1 (M ++ H).

Example 8-3 1-Benzyl-10-methoxy-1,2,3,4,5,6-hexahydro-7H-
Naphtho [2,1-f] [1,4] diazepin-5-one The title compound was obtained in the same manner as in Example 8-2. However, benzyl bromide was used instead of 1-bromopropane. ¹ H-NMR (400MHz, CDCl ₃ ): 2.04-2.65 (2H, m), 2.69-2.7
3 (2H, m), 3.37-3.41 (2H, m), 3.46 (H, dd, J = 8.
4, 4.5 Hz), 3.61 (3H, s), 4.26 (2H, s), 6.12 (1H, b
r), 6.79 (1H, dd, J = 8.2, 2.6 Hz), 7.12 (1H, d, J
= 8.2 Hz), 7.17 (1H, d, J = 2.6 Hz), 7.24-7.36 (5
H, m) .MS (FAB +) m / z 335.1 (M ++ H).

Example 8-4 1-Benzyl-10-methoxy-1,2,3,4-tetrahydro-5H-naphtho [2,1-f] [1,4] diazepin-5-one 1-benzyl- 10-methoxy-1,2,3,4,5,5
6-hexahydro-7H-naphtho [2,1-f] [1,
4] Toluene (7 ml) of diazepin-5-one (336 mg)
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (342 mg) was added to the solution, and the mixture was stirred at room temperature for 40 minutes. Aqueous sodium hydrogen carbonate was added to the reaction solution, which was extracted with ethyl acetate,
The organic layer was washed with aqueous sodium hydrogen carbonate and brine. After drying over magnesium sulfate, the solvent was distilled off and the residue was purified by column chromatography. The obtained oil was recrystallized from methanol to give the title compound (40 mg). ¹ H-NMR (300MHz, CDCl ₃ ): 3.35 (2H, dd, J = 11.5, 5.9
Hz), 3.52 (2H, t, J = 5.7 Hz), 3.89 (3H, s), 4.44
(2H, s), 6.47 (1H, br), 7.19-7.41 (6H, m), 7.64-7.7
8 (4H, m) .MS (FAB +) m / z 333.1 (M ++ H).

In the same manner as in any of Examples 8 to 8-4 above, Examples 8-5 to 8-2 shown in Tables 13 to 15 below were carried out.
Two compounds were prepared.

[0286]

[Table 13]

[0287]

[Table 14]

[0288]

[Table 15]

Example 9 4,5-Dihydro-8-methoxy-3-methyl-benzo [b] thieno [2,3-f]
[1,2,4] Triazolo [4,3-d] [1,4] thiazepine a) 2,3-dihydro-9-methoxy-benzo [b] thieno [2,3-f] [1,4] Thiazepin-5-thione 2,3-dihydro-9-methoxy-benzo [b] thieno [2,3-f] -1,4-thiazepin-5-one (5.
To a suspension of 3 g) in xylene (140 ml) was added diphosphorus pentasulfide (6.6 g). The mixture was heated to reflux for 30 minutes. The red solution was cooled to room temperature and chloroform (3
00 ml) was added. After washing this solution with saturated saline,
It was dried over anhydrous magnesium sulfate. This was filtered, the filtrate was concentrated, and the obtained residue was purified by silica gel chromatography (chloroform: methanol = 20: 1).
Pure fractions were collected and concentrated to dryness to give a yellow solid (2.8g).
The title compound (1-a) of was obtained. ¹ H-NMR (300MHz, δ value,
ppm, CDCl ₃ ) 3.49-3.53 (2H, m), 3.85-3.93 (2H, m), 3.9
0 (3H, s), 7.11 (1H, dd, J = 2.4 and 9.0Hz), 7.29 (1H, d, J = 2.
4Hz), 7.65 (1H, d, J = 9.0Hz), 8.48 (1H, br.s).

B) 2,3-dihydro-9-methoxy-5
-Methylthio-benzo [b] thieno [2,3-f]
Potassium carbonate (0.276 g) was added to an acetone suspension (50 ml) of the [1,4] thiazepine compound (1-a) (0.281 g). Methyl iodide (155 mg) was added dropwise to this mixture, and the mixture was stirred at room temperature for 1 day. After removing the insoluble matter by filtration, the filtrate was concentrated to dryness. A solution of this residue in chloroform was washed with water. The solution was dried over anhydrous magnesium sulfate.
This was filtered, the filtrate was concentrated, and the obtained residue was chromatographed on silica gel (n-hexane: ethyl acetate = 3:
Purified in 1). The pure fractions were collected and concentrated to dryness to give the title compound (1-b) as a pale yellow solid (0.210g). ¹ H-NMR (400MHz, δ value, ppm, CDCl ₃ ) 2.48 (3H, s), 3.57-
3.6 (2H, m), 3.89 (3H, s), 4.08-4.13 (2H, m), 7.10 (1H, dd,
J = 8.7 and 2.7Hz), 7.26-7.28 (1H, m), 7.67 (1H, d, J = 9H
z).

C) 4,5-Dihydro-8-methoxy-3
-Methyl-benzo [b] thieno [2,3-f] [1,
N of 2,4] triazolo [4,3-d] [1,4] thiazepine compound (1-b) (150 mg), acetohydrazide (56 mg) and p-toluenesulfonic acid monohydrate (9.5 mg) 1 part of butanol solution (10 ml)
It was heated at 10 ° C. for 4 hours. The solution was concentrated to dryness and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. This was filtered, the filtrate was concentrated, and the obtained residue was chromatographed on silica gel (chloroform: methanol = 20: 1).
Purified in. Pure fractions were collected and concentrated to dryness, and the obtained solid was crystallized from a chloroform / ether mixed solvent,
The title compound (58 mg) was obtained. ¹ H-NMR (300MHz, δ value, ppm, DMSO-d ₆ ) 2.43 (3H, s), 3.5
2-3.55 (2H, m), 3.85 (3H, s), 4.56-4.59 (2H, m), 7.11-7.
14 (2H, m), 7.88 (1H, d, J = 9.2Hz).

Example 10 4,5-Dihydro-8-methoxy-benzo [b] thieno [2,3-f] [1,2,
4] The compound (1-b) was reacted in the same manner as in Example 9 except that formylhydrazide was used instead of triazolo [4,3-d] [1,4] thiazepine acetohydrazide. Extraction, purification and crystallization were carried out in the same manner as in Example 9 to obtain the title compound (2c). ¹ H-NMR (300MHz, δ value, ppm, DMSO-d ₆ ) 3.55-3.58 (2H,
m), 3.85 (3H, s), 4.74-4.77 (2H, m), 7.12-7.16 (2H, m),
7.9 (1H, d, J = 9Hz), 8.6 (1H, s).

Example 11 4,5-Dihydro-8-methoxy-3-methyl-benzo [b] thieno [2,3-f]
[1,3] Diazolo [1,2-d] [1,4] thiazepine compound (1-b) (200 mg), propargylamine (40.8 mg) and sodium acetate (60.7 m
g) was dissolved in absolute ethanol. 110 of this mixture
Heated to reflux overnight at 0 ° C. Sodium acetate (60.7m
g) and p-toluenesulfonic acid monohydrate (1.0 m
g) was added, and the mixture was further heated at 110 ° C. for 17 hours. The solution was concentrated to dryness and the residue was dissolved in chloroform. The target product was extracted from the chloroform solution with 1N hydrochloric acid water.
The resulting hydrochloric acid aqueous solution was made basic with 30% aqueous ammonia. The precipitated solid was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. This was filtered, the filtrate was concentrated, and the obtained residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 3: 1). Pure fractions were collected, concentrated to dryness, and the obtained solid was crystallized from a mixed solvent of chloroform / ether to give the title compound (3) (121 mg). ¹ H-NMR (300MHz, δ value, ppm, DMSO-d ₆ ) 2.24 (3H, s), 3.4
9-3.52 (2H, m), 3.83 (3H, s), 4.49-4.52 (2H, m), 6.82 (1
H, s), 7.02-7.07 (2H, m), 7.79 (1H, d, J = 9Hz).

Example 12 4,5-Dihydro-8-methoxy-benzo [b] thieno [2,3-f] [1,2,
2,3-Dihydro-9-methoxy-in 3,4] tetrazolo [1,5-d] [1,4] thiazepine acetonitrile
Benzo [b] thieno [2,3-f] [1,4] thiazepin-5-one (100 mg), sodium azide (4
8.7 mg) and phosphorus oxychloride (287 mg) to 18
Heated to reflux for hours. The solution was concentrated to dryness and the residue was dissolved in chloroform. The chloroform solution was washed with saturated saline and dried over anhydrous magnesium sulfate. This was filtered, and the residue obtained by concentrating the filtrate was purified by silica gel chromatography (n-hexane / ethyl acetate = 3: 1). Pure fractions were collected and concentrated to dryness, and the obtained solid was crystallized from a chloroform / ether mixed solvent to give the title compound (4) (57 mg). ¹ H-NMR (300MHz, δ value, ppm, DMSO-d ₆ ) 3.68-3.94 (2H,
m), 3.87 (3H, s), 5.17-5.2 (2H, m), 7.2-7.24 (2H, m), 7.
99 (1H, d, J = 9Hz).

Example 13 4,5-Dihydro-8-methoxy-benzo [b] thieno [2,3-f] [1,2,
4] Triazolo [4,3-d] [1,4] thiazepine-
A solution of 3-one compound (1-b) (200 mg), ethylcarbazate (90.6 mg) and p-toluenesulfonic acid monohydrate (6.5 mg) in n-butanol (5 ml) was added.
It was heated at 10 ° C. for 4 hours. The solution was concentrated to dryness and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. This was filtered, the filtrate was concentrated, and the resulting residue was treated with DMSO (5
0 ml). This solution was placed on an oil bath at 190 ° C for 4
Heated to reflux for hours. Chloroform and water were added to the cooled reaction solution to separate it. The organic layer was washed with water and dried over anhydrous magnesium sulfate. This was filtered, the filtrate was concentrated, and the obtained residue was purified by silica gel chromatography (chloroform: methanol = 20: 1). The pure fractions were collected and concentrated to dryness to give the title compound (5) as a pale yellow solid (10m
g) was obtained. ¹ H-NMR (300MHz, δ value, ppm, DMSO-d ₆ ) 3.5-3.53 (2H, m),
3.84 (3H, s), 4.23-4.25 (2H, m), 7.1-7.15 (2H, m), 7.87
(1H, d, J = 9Hz), 12.15 (1H, s).

Example 14 4,5-Dihydro-8-methoxy-benzo [b] thieno [2,3-f] [1,3] diazolo [1,2-d] [1,4] thiazepine compound (1 -B) (150 mg), aminoacetaldehyde dimethyl acetal (160 mg), and p-toluenesulfonic acid monohydrate (9.5 mg) in n-butanol solution (10 ml) were heated at 110 ° C for 3 hours. The solution was concentrated to dryness and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. This is filtered, the filtrate is concentrated, and the resulting residue is subjected to silica gel chromatography (chloroform:
Purified with methanol = 20: 1). Pure fractions were collected and concentrated to dryness, and the solid was crystallized from a chloroform / ether mixed solvent to obtain 120 mg of crystals. This solid was dissolved in a mixed solvent of methanol (1 ml) and concentrated hydrochloric acid (1 ml), and heated at 90 ° C. The reaction solution was concentrated to dryness, and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. This was filtered, the filtrate was concentrated, and the obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 3: 1). Pure fractions were collected and concentrated to dryness, and the obtained solid was crystallized from a mixed solvent of chloroform / ether to give the title compound (6) (53 mg). ¹ H-NMR (300MHz, δ value, ppm, DMSO-d ₆ ) 3.5-3.53 (2H, m),
3.84 (3H, s), 4.68-4.71 (2H, m), 7.01-7.08 (3H, m), 7.3
4 (1H, s), 7.82 (1H, d, J = 9Hz).

Example 15 2,3,4,5-Tetrahydro-8-methoxy-benzo [b] thieno [2,3-f]
[1,3] diazolo [1,2-d] [1,4] thiazepine compound (1-b) (150 mg), 2-chloroethylamine hydrochloride (115 mg) and triethylamine (1
01 mg) was dissolved in absolute ethanol (5 ml). The mixture was heated to reflux overnight. The reaction solution was concentrated to dryness, and the residue was dissolved in methylene chloride. This was washed with water and then dried over anhydrous magnesium sulfate. Filter this,
The filtrate was concentrated, and the obtained residue was purified by silica gel chromatography (chloroform: methanol: 2N ammonia methanol solution = 40: 1: 1). Pure fractions were collected and concentrated to dryness, and the obtained solid was crystallized from a chloroform / ether mixed solvent to give the title compound (7) (87 m
g) was obtained. ¹ H-NMR (300MHz, δ value, ppm, DMSO-d ₆ ) 3.5-3.53 (2H, m),
3.84-3.9 (9H, m), 7.2-7.24 (2H, m), 7.93 (1H, d, J = 9Hz).

Example 16 4,5-Dihydro-6-isobutyl-8-methoxy-benzo [b] thieno [2,3-
f] [1,3] diazolo [1,2-d] [1,4] diazepine a) 5-chloro-2,3-dihydro-1-isobutyl-9-methoxy-benzo [b] thieno [3,2] −
e] [1,4] diazepine 2,3-dihydro-1-isobutyl-9-methoxy-benzo [b] thieno [3,2-e] [1,4] diazepin-5-one (2.3 g) Toluene suspension (24 ml)
Phosphorus pentachloride (1.5 g) was added to. 110 of this mixture
The mixture was heated under reflux at 0 ° C for 2 hours. The reaction solution was concentrated to dryness, and the residue was dissolved in ethyl acetate. The solution was washed with water, saturated aqueous sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The solution was filtered, the filtrate was concentrated and left at room temperature. The precipitated yellow solid was collected by filtration and dried under reduced pressure to give the title compound (8-a)
(900 mg) was obtained. ¹ H-NMR (300MHz, δ value, ppm, CDCl ₃ ) 1.15 (6H, d, J = 6.6H
z), 2.18 (1H, m), 3.13 (2H, d, J = 7.8Hz), 3.19 (2H, m), 3.
87 (3H, s), 4.05 (2H, m), 7.09 (1H, dd, J = 8.9 and 2.5Hz),
7.34 (1H, d, J = 2.5Hz), 7.59 (1H, d, J = 9.0Hz).

B) 4,5-Dihydro-6-isobutyl-
8-Methoxy-benzo [b] thieno [2,3-f]
A solution of [1,3] diazolo [1,2-d] [1,4] diazepine compound (8) (587 mg), aminoacetaldehyde dimethyl acetal (0.238 ml) and methanesulfonic acid (24 μl) in n-butanol (6 ml). )
Was heated at 110 ° C. for 2 hours. Aminoacetaldehyde dimethyl acetal (0.060 ml) and methanesulfonic acid (0.153 ml) were added to the reaction solution, and further 1
Heated at 10 ° C. for 0.5 hours. Ethyl acetate and aqueous sodium hydrogen carbonate were added to the reaction solution. The separated organic layer was washed with water and then dried over anhydrous sodium sulfate. The solution was concentrated to dryness. The residue is chromatographed on silica gel (chloroform / THF).
= 10: 1). After collecting and concentrating the pure fractions,
The obtained solid was crystallized from ether to give the title compound (8
-B) (465 mg) was obtained. ¹ H-NMR (300MHz, δ value, ppm, CDCl ₃ ) 1.15 (6H, d, J = 6.6H
z), 2.09 (1H, m), 3.05 (2H, d, J = 7.7Hz), 3.55-3.57 (2H,
m), 3.87 (3H, s), 4.27-4.30 (1H, m), 6.96-7.00 (2H, m),
7.13 (1H, d, J = 1.2Hz), 7.25 (1H, s), 7.61 (1H, d, J = 8.7H
z).

Example 17 4,5-Dihydro-6-isobutyl-benzo [b] thieno [2,3-f] [1,3]
Diazolo [1,2-d] [1,4] diazepine a) 5-chloro-2,3-dihydro-1-isobutyl-
Benzo [b] thieno [3,2-e] [1,4] diazepine In the same manner as in Example 16 a), 2,3-dihydro-
1-isobutyl-benzo [b] thieno [3,2-e]
From [1,4] diazepin-5-one (2.38 g),
The title compound (9-a) (0.587 g) was obtained. ¹ H-NMR (300MHz, δ value, ppm, CDCl ₃ ) 1.12 (6H, d, J = 6.6H
z), 2.17 (1H, m), 3.17-3.21 (4H, m), 4.05 (2H, m), 7.33-
7.43 (2H, m), 7.72 (1H, d, J = 7.7Hz), 7.93 (1H, d, J = 8.1H
z).

B) 4,5-dihydro-6-isobutyl-
Benzo [b] thieno [2,3-f] [1,3] diazolo [1,2-d] [1,4] diazepine 2,3-dihydro-1-isobutyl-benzo was prepared in the same manner as in Example 16. [B] Thieno [3,2-e] [1,4]
Diazepin-5-one (153 mg), aminoacetaldehyde dimethyl acetal (0.12 ml) and p
A solution of toluenesulfonic acid (134 mg) in n-butanol was heated at 110 ° C. Extraction and crystallization were carried out in the same manner as in Example 16 to give the title compound (9-b) (117m
g) was obtained. ¹ H-NMR (300MHz, δ value, ppm, CDCl ₃ ) 1.13 (6H, d, J = 6.6H
z), 2.08 (1H, m), 3.09 (2H, d, J = 7.8Hz), 3.56 (2H, t, J = 4.
3Hz), 4.28 (2H, t, J = 4.3Hz), 6.98 (J = 1H, s), 7.13 (1H,
s), 7.31-7.34 (2H, m), 7.73-7.81 (2H, m).

Example 18 4,5-Dihydro-6-isobutyl-8-methoxy-benzo [b] thieno [2,3-
f] [1,2,4] triazolo [4,3-d] [1,
4] A solution of diazepine compound (8-a) (379 mg), formylhydrazine (141 mg) and methanesulfonic acid (15 μl) in n-butanol (2 ml) was heated at 95 ° C. for 1 hour. The reaction solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. This solution was washed with aqueous sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The solution was filtered, the filtrate was concentrated and left to stand to give yellow crystals. This was collected by filtration and dried under reduced pressure to give the title compound (10) (278 mg). ¹ H-NMR (300MHz, δ value, ppm, CDCl ₃ ) 1.17 (6H, d, J = 6.0H
z), 2.19 (1H, m), 3.12 (2H, d, J = 6.0Hz), 3.59-3.61 (2H,
m), 3.88 (3H, s), 4.34-4.37 (2H, m), 7.03 (2H, dd, J = 8.7H
z, 2.5Hz), 7.27 (1H, d, J = 2.5z), 7.64 (1H, d, J = 8.7Hz),
8.17 (1H, s).

Example 19 4,5-Dihydro-6-isobutyl-benzo [b] thieno [2,3-f] [1,2,
4] Triazolo [4,3-d] [1,4] diazepine In the same manner as in Example 18, 5-chloro-2,3-dihydro-1-isobutyl-benzo [b] thieno [3,2-
e] [1,4] diazepine (270 mg), formylhydrazine (111 mg) and methanesulfonic acid (12
μl) of n-butanol solution (2 ml) was warmed. Extraction and crystallization were performed in the same manner as in Example 18 to obtain the title compound (11) (205 mg). ¹ H-NMR (300MHz, δ value, ppm, CDCl ₃ ) 1.14 (6H, d, J = 6.6H
z), 2.09 (1H, m), 3.17 (2H, d, J = 7.8Hz), 3.59-3.61 (2H,
m), 4.34-4.39 (2H, m), 7.33-7.42 (2H, m), 7.76-7.86 (2
H, m), 8.19 (1H, s).

Example 20 4,5-Dihydro-6- (2
-Methyl-2-propenyl) -8-nitro-benzo [b] thieno [2,3-f] [1,2,4] triazolo [4,3-d] [1,4] diazepine Example 16a ) And 2,3-dihydro-1
-(2-Methyl-2-propenyl) -9-nitro-benzo [b] thieno [3,2-e] [1,4] diazepine-
Toluene suspension of 5-one (1.26 g) (13 ml)
, Phosphorus pentachloride (1.01 g) and DMF (0.093
ml) was added. The mixture was warmed at 90 ° C. for 1.5 hours. When the reaction solution was cooled to room temperature, a yellow solid was precipitated.
The supernatant was removed from this mixture and the solid was washed with toluene. This solid was suspended in ethyl acetate and cooled. The mixture was washed with saturated aqueous sodium hydrogen carbonate. The insoluble matter was filtered off. The ethyl acetate layer was treated as in Example 16 a). The insoluble material was dissolved in chloroform, treated in the same manner as in Example 16 a), and combined with the above ethyl acetate layer. The combined solution was dried over anhydrous sodium sulfate and then concentrated to dryness. 400 mg of the obtained solid (761 mg) (this intermediate was not soluble and unstable and therefore was not analyzed) was used for the next reaction.

A solid obtained in the same manner as in Example 19,
Formylhydrazine (143 mg) and methanesulfonic acid (15 μl) in n-butanol (4 ml) were added to 9 parts.
Warm at 0 ° C. for 2 hours. When the reaction solution was cooled to room temperature, yellow crystals were precipitated. This was collected by filtration and dried under reduced pressure to give the title compound (12) (373 mg). ¹ H-NMR (300MHz, δ value, ppm, DMSO-d ₆ ) 1.90 (3H, s), 3.4
3-3.45 (2H, m), 3.93 (2H, s), 4.42-4.45 (2H, m), 5.22 (1
H, s), 5.32 (1H, s), 8,21 (2H, m), 8.62 (1H, s), 8.67 (1H,
s).

Example 21 4,5-Dihydro-6- (2
-Methyl-2-propenyl) -8-nitro-benzo [b] thieno [2,3-f] [1,3] diazolo [1,
2-d] [1,4] diazepine p-toluenesulfonate 5-chloro-2,3-dihydro-1- (2-methyl-2)
-Propenyl) -9-nitro-benzo [b] thieno [3,2-e] [1,4] diazepine (361 mg),
Aminoacetaldehyde dimethyl acetal (0.22
ml) and p-methanesulfonic acid (15 μl) n-
The butanol solution (3.6 ml) was heated at 110 ° C. for 3 hours. The reaction solution was cooled to room temperature, and the obtained solid was collected by filtration. This was suspended again in n-butanol (3 ml), and p
-Toluenesulfonic acid monohydrate (135.4 mg) was added. The mixture was heated at 110 ° C. for 1.5 hours. After cooling the reaction solution, diethyl ether was added to precipitate yellow crystals. This was collected by filtration, and the filtrate was dried under reduced pressure to give the title compound (13) (317 mg). ¹ H-NMR (300MHz, δ value, ppm, CDCl ₃ ) 1.90 (3H, s), 2.29
(3H, s), 3.52 (2H, m), 4.01 (2H, br s), 4.98 (2H, m), 5.2
5 (1H, s), 5.31 (1H, s), 7.09 (1H, s), 7.10 (2H, d, J = 7.8H
z), 7.47 (2H, d, J = 7.8Hz), 7.60 (1H, s), 7.79 (1H, s), 8.
30 (2H, s), 8.68 (1H, s).

Example 22 4,5-Dihydro-8-methoxy-benzo [b] thieno [2,3-f] [1,3] diazolo [1,2-d] [1,4] thiazepine-6- On-compound (6) (49 mg) was dissolved in methylene chloride (2 ml) and cooled in an ice bath. M-Chloroperbenzoic acid (32 mg) was added to this solution, and the mixture was stirred for 45 minutes. Furthermore, m
-Chloroperbenzoic acid (19 mg) was added and stirred for 15 minutes. Water was added to this solution and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. When this solution was filtered and concentrated under reduced pressure, a pale yellow solid was precipitated. This was collected by filtration and dried under reduced pressure to give the title compound (14) (20 mg). ¹ H-NMR (300 MHz, δ value ppm, CDCl ₃ ) 3.21 (1H, m), 3.76 (1H,
m), 4.49 (1H, m), 5.25 (1H, m), 7.09 (1H, dd, J = 8.8 and
2.4Hz), 7.16 (1H, s), 7.20 (1H, s), 7.60 (1H, d, J = 2.4H
z), 7.71 (1H, d, J = 8.8Hz).

Example 23 4,5-Dihydro-8-methoxy-benzo [b] thieno [2,3-f] [1,2,
4] Oxadiazolo [4,3-d] [1,4] thiazepin-3-one a) 2,3-dihydro-5- (hydroxyimino) -9
-Methoxy-benzo [b] thieno [2,3-f] [1,
4] Thiazepine compound (1-b) (295 mg), hydroxylamine hydrochloride (139 mg) and sodium acetate (164 m)
g) was suspended in n-butanol (10 ml) and heated at 120 ° C.
And warmed for 3 hours. The precipitated yellow solid was collected by filtration and washed with water and chloroform. This is dried under reduced pressure,
The title compound (15-a) (228 mg) was obtained. ¹ H-NMR (300MHz, δ value, ppm, DMSO-d ₆ ) 3.22-3.26 (2H,
m), 3.50-3.55 (2H, m), 3.84 (3H, s), 6.77 (1H, m), 7.08
(1H, dd, J = 2.4 and 8.7Hz), 7.21 (1H, d, J = 2.4Hz), 7.82
(1H, d, J = 8.7z), 10.0 (1H, s).

B) 4,5-Dihydro-8-methoxy-benzo [b] thieno [2,3-f] [1,2,4] oxadiazolo [4,3-d] [1,4] thiazepine-3 A solution of the -one compound (15-a) (84 mg) and carbonyldiimidazole (53 mg) in THF (10 ml),
Heated at 90 ° C. for 2 hours. The reaction solution was cooled to room temperature and water (10 ml) was added. The obtained solid was collected by filtration and washed with diethyl ether. This was dried under reduced pressure to obtain 81 mg of the title compound (15-b). ¹ H-NMR (300MHz, δ value, ppm, CDCl ₃ ) 3.41-3.45 (2H, m),
3.91 (3H, s), 4.39-4.42 (2H, m), 7.15-7.18 (2H, m), 7.69
(1H, m).

Example 24 4,5-Dihydro-8-methoxy-benzo [b] thieno [2,3-f] [1,2,
4] Oxadiazolo [4,3-d] [1,4] thiazepine-3-thione compound (15-a) (84 mg) and thiocarbonyldiimidazole (80 mg) in DMF solution (2 ml)
Was stirred at room temperature for 4 hours. Water (2 ml) was added to this solution. The obtained solid was collected by filtration and washed with diethyl ether. This was dried under reduced pressure to give the title compound (16) (5
3 mg) was obtained. ¹ H-NMR (300MHz, δ value, ppm, DMSO-d ₆ ) 3.73-3.75 (2H,
m), 3.87 (3H, s), 4.64-4.67 (2H, m), 7.19 (1H, d, J = 2.7H
z), 7.27 (1H, dd, J = 2.7,9.3Hz), 7.99 (1H, d, J = 9.3Hz).

The compounds obtained in Examples 9 to 24 above are summarized in Table 16.

[0312]

[Table 16]

Example 25 6-Methoxy-2,3-dihydro-4,9-dithiafluoren-1-one oxime a) 2-hydroxy-5-methoxybenzoic acid methyl ester 2,5-dihydrobenzoic acid (50 g) ) And potassium carbonate (108 g) were suspended in acetonitrile (1000 ml), and dimethylsulfate (66 ml) was added dropwise with stirring at room temperature. The reaction mixture was reacted at 85 ° C for 2 hours. After returning to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was water (500 ml).
Was added. The pH was adjusted to 2 by adding 5N hydrochloric acid under stirring with ice cooling. Toluene was added for extraction, and the organic layer was washed successively with water and saturated brine. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (6
1.7 g) was obtained as an oil. ¹ H-NMR (300 MHz, δ ppm, CDCl ₃ ):
3.38 (3H, s), 3.95 (3H, s), 6.9
1 (1H, d, J = 9.1 Hz), 7.08 (1H, d
d, J = 3.1, 9.1 Hz), 7.28 (1H, d,
J = 3.1Hz), 10.37 (1H, s)

B) 2- (Dimethylthiocarbamoyloxy) -5-methoxybenzoic acid methyl ester The 2-hydroxy-5-methoxybenzoic acid methyl ester (53.1 g) obtained in Example 25 a) was used as N, N
-Dissolved in dimethylformamide (600 ml). Dimethylthiocarbamoyl chloride (5
5.9 g) and 1,4-diazabicyclo [2.2.2] octane (54.6 g) were sequentially added, and the mixture was reacted for 40 hours. The reaction solution was concentrated under reduced pressure, and the residue was treated with 1N hydrochloric acid (280 m
1) and ethyl acetate (280 ml) were added and the mixture was extracted. The organic layer was washed successively with water and saturated brine. The organic layer was dried using magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (6
3.4 g) was obtained. ¹ H-NMR (300 MHz, δ ppm, CDCl ₃ ):
3.39 (3H, s), 3.47 (3H, s), 3.8
4 (6H, s), 7.03 (1H, d, J = 8.7H
z), 7.09 (1H, dd, J = 3.0, 8.7H
z), 7.49 (1H, d, J = 3.3Hz)

C) 2- (Dimethylcarbamoylsulfanyl) -5-methoxybenzoic acid methyl ester 2- (Dimethylthiocarbamoyloxy) -5-methoxybenzoic acid methyl ester obtained in Example 25 b) (57.7 g). ) To diphenyl ether (180 ml)
And was allowed to react at 240 ° C. for 6 hours under an argon atmosphere. After returning to room temperature, diphenyl ether was distilled off. Ethyl acetate was added to the residue to dissolve it, and n-hexane was added dropwise with stirring at room temperature for crystallization. Precipitated crystals with ice cooling 9
After stirring for 0 minutes, the mixture was filtered and the title compound (45.67
g) was obtained. ¹ H-NMR (300 MHz, δ ppm, CDCl ₃ ):
2.9-3.2 (6H, m), 3.85 (3H, s),
3.88 (3H, s), 7.02 (1H, dd, J =
2.9, 8.6 Hz), 7.41 (1H, d, J = 2.
9Hz), 7.49 (1H, d, J = 8.6Hz)

D) 2-Mercapto-5-methoxybenzoic acid methyl ester 2- (Dimethylcarbamoylsulfanyl) -5-methoxybenzoic acid methyl ester (25.0 g) obtained in c) of Example 25 and sodium methoxide. (11.0
g) was suspended in methanol (250 ml) and reacted at 65 ° C. for 3 hours under an argon atmosphere. After returning to room temperature,
The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid (250 ml) was added to the residue, and the mixture was extracted with toluene. The organic layer was washed successively with water and saturated brine. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound (16.6 g) was obtained as an oil. ¹ H-NMR (300 MHz, δ ppm, CDCl ₃ ):
3.81 (3H, s), 3.93 (3H, s), 4.4
9 (1H, s), 6.93 (1H, dd, J = 3.0,
8.7 Hz), 7.21 (1H, d, J = 8.4H
z), 7.52 (1H, d, J = 3.0Hz)

E) 2- (Carboxymethylsulfanyl) -5-methoxybenzoic acid The 2-mercapto-5-methoxybenzoic acid methyl ester (16.6 g) obtained in Example 25 d) was added to methanol (250 ml). After dissolution, 2N aqueous sodium hydroxide solution (100 ml) was added with stirring at room temperature. The reaction mixture was reacted at 60 ° C. for 4 hours. After returning to room temperature, 2N hydrochloric acid (100 ml) was added dropwise to the reaction mixture while stirring with ice cooling, and sodium carbonate (55.1 g) was further added to dissolve the reaction mixture. Next, sodium hydrosulfite (42.0
g) was added and the mixture was heated under reflux for 30 minutes. Separately, chloroacetic acid (42.1 g) was dissolved in water (400 ml), and sodium carbonate (23.1 g) was added under ice-cooling stirring to prepare a solution. The solution was added dropwise to the above reaction mixture after reflux. After the dropwise addition, the mixture was heated under reflux for 1 hour, returned to room temperature, and concentrated hydrochloric acid (100 ml) was added dropwise. The precipitated crystals are filtered,
It was washed with water. By drying under reduced pressure at 50 ° C. for 18 hours, the title compound (21.7 g) was obtained as crystals. ¹ H-NMR (300 MHz, δ ppm, DMSO-
_{d 6): 3.73 (2H,} s), 3.77 (3H,
s), 7.14 (1H, dd, J = 3.0, 8.8H
z), 7.33 (1H, d, J = 8.8Hz), 7.3
6 (1H, d, J = 2.9Hz)

F) Acetic acid 5-methoxybenzo [b] thiophen-3-yl ester 2- (carboxymethylsulfanyl) -5-methoxybenzoic acid (7.2 g) obtained in e) of Example 25 and sodium acetate. (3.2 g) was suspended in acetic anhydride (65 ml). The reaction mixture was added to the Journal of Organic Chemistry (The Journal of Organic Chemistry).
organic Chemistry) 10,381 (1)
945) to give the title compound (7.85 g)
Was obtained as an oil. ¹ H-NMR (300 MHz, δ ppm, CDCl ₃ ):
2.99 (3H, s), 3.88 (3H, s), 7.0
1 (1H, dd, J = 2.4, 8.7 Hz), 7.09
(1H, d, J = 2.4 Hz), 7.39 (1H,
s), 7.64 (1H, d, J = 8.7Hz)

G) 6-Methoxy-2,3-dihydro-
80% of 4,9-dithiafluoren-1-one diphosphorus pentoxide (5.52 g) and methanesulfonic acid (30 ml) were added.
The mixture was stirred at 0 ° C for 30 minutes. To this was added the acetic acid 5-methoxybenzo [b] thiophene-3 obtained in Example 25 f).
-Yl ester (7.8 g) and 3-mercaptopropionic acid (3.4 ml) were added and reacted at 80 ° C for 40 seconds. Ice water was added to the reaction mixture and the mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine. The organic layer was treated with activated carbon and then dried using sodium sulfate.
After filtration, the filtrate was concentrated under reduced pressure, and the residue was treated by flash column chromatography (developing solvent; chloroform) to give the title compound (5.58 g) as a crystalline solid. ¹ H-NMR (300 MHz, δ ppm, CDCl ₃ ):
2.95-3.05 (2H, m), 3.4-3.5 (2
H, m), 3.90 (3H, s), 7.1-7.2 (2
H, m), 7.72 (1H, d, J = 8.4 Hz) FAB (+) MS (low resolution, m / z) 251

H) 6-methoxy-2,3-dihydro-
4,9-Dithiafluoren-1-one oxime The 6-methoxy-2,3-dihydro-4,9-dithiafluoren-1-one (310 obtained in g) of Example 25)
mg) was dissolved in 80% aqueous ethanol solution (10 ml), and hydroxylamine hydrochloride (142 mg) and sodium acetate (170 mg) were added. The mixture was heated under reflux for 3 hours. The precipitated crystals were filtered and treated with ethyl acetate at 100 ° C. for slurry to give the title compound (119 m
g) was obtained as a crystalline solid. ¹ H-NMR (300 MHz, δ ppm, DMSO-
_{d 6), E: Z =} 1: 1 mixture of: 2.9-3.
1 (total 2H, m), 3.2-3.4 (total
al 2H, m), 3.83, 3.85 (total)
3H, s), 7.05-7.15 (total 2H,
m), 7.81, 7.88 (total 1H, d, J
= 8.4 Hz), 11.53, 1180 (total)
1H, s) FAB (+) MS (low resolution, m / z) 266

Example 26 Using 6-methoxy-2,3-dihydro-4,9-dithiafluoren-1-one O-methyloxime hydroxylamine hydrochloride in place of O-methylhydroxylamine hydrochloride The title compound (53 mg) was obtained as a solid by a method similar to that in Example 25 h). ¹ H-NMR (300 MHz, δ ppm, DMSO-
_{d 6), E: Z =} 1: 1 mixture of: 2.95-
3.1 (total 2H, m), 3.2-3.35
(Total 2H, m), 3.83, 3.84 (to
tal 3H, s), 3.92, 3.97 (total)
3H, s), 7.05-7.2 (total 2H,
m), 7.82, 7.90 (total 1H, d, J
= 8.7 Hz) FAB (+) MS (low resolution, m / z) 279

Example 27 (27-1, 27-2) 6-
Methoxy-2,3-dihydro-4,9-dithiafluoren-1-one oxime The oxime derivative (mixture of E: Z = 1: 1: 800 mg) obtained by the same method as in Example 25 h) was used. Flash column chromatography (developing solvent; chloroform:
By treatment with acetone = 7: 1), the title compounds [(low polar compound (Example 27-1); 220 mg) and (high polar compound (Example 27-2); 225 mg)] were obtained as crystalline solids. Obtained.

[(Low polar compound)] ¹ H-NMR (300 MHz, δ ppm, DMSO-
_{d 6): 3.0-3.05 (2H,} m), 3.2-3.
3 (2H, m), 3.83 (3H, s), 7.04 (1
H, d, J = 2. Hz), 7.08 (1H, dd, J =
2.4, 8.4 Hz), 7.81 (1H, d, J = 8.
4Hz), 11.53 (1H, s) FAB (+) MS (low resolution, m / z) 266

[(Highly polar compound)] ¹ H-NMR (300 MHz, δ ppm, DMSO-
_{d 6): 2.95-3.0 (2H,} m), 3.25-
3.3 (2H, m), 3.85 (3H, s), 7.10
(1H, d, J = 3.0 Hz), 7.14 (1H, d
d, J = 2.4 Hz, 8.7 Hz), 7.88 (1H,
d, J = 8.7 Hz), 11.82 (1 H, s) FAB (+) MS (low resolution, m / z) 266

Example 28 (28-1, 28-2) 6-
Methoxy-2-methyl-2,3-dihydro-4,9-dithiafluoren-1-one Oxime 3-mercaptoisobutyric acid in place of 3-mercaptoisobutyric acid, similar to example 25 g). 6-methoxy-2-methyl-2,3-dihydro-obtained by the method
4,9-Dithiafluoren-1-one (750 mg) was dissolved in pyridine (15 ml) to give hydroxylamine.
The hydrochloride salt (392 mg) was added. The reaction mixture was reacted at 90 ° C. for 5 hours. After returning to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was treated by flash column chromatography (developing solvent; hexane: ethyl acetate = 3: 1) to give the title compound [(low polar compound (Example 28-
1); 195 mg) and (highly polar compound (Example 28-2);
215 mg)] was obtained as a crystalline solid.

[(Low polar substance)] ¹ H-NMR (300 MHz, δ ppm, DMSO-
_{d 6): 1.22 (3H,} d, J = 6.9Hz), 3.
11 (1H, dd, J = 2.9, 13.2Hz), 3.
41 (1H, d, J = 3.2, 13.2 Hz), 3.7
5-3.9 (4H, m), 7.05-7.1 (3H,
m), 7.80 (1H, d, J = 6.0 Hz), 11.
49 (1H, s) FAB (+) MS (low resolution, m / z) 297

[(Highly polar compound)] ¹ H-NMR (300 MHz, δ ppm, DMSO-
_{d 6): 1.26 (3H,} d, J = 6.0Hz), 3.
1-3.2 (2H, m), 3.35-3.4 (1H,
m), 3.85 (3H, s), 7.1-7.15 (2
H, m), 7.87 (2H, d, J = 9.0 Hz) FAB (+) MS (low resolution, m / z) 279

Example 29 6-Methoxy-2,2-dimethyl-2,3-dihydro-4,9-dithiafluorene-
1-one oxime 6-methoxy-2-methyl-2, obtained in Example 28,
3-Dihydro-4,9-dithiafluoren-1-one (1.05 g) was dissolved in tetrahydrofuran (10 ml). Cool to −78 ° C., and under a nitrogen atmosphere, lithium diisopropylamide (2.0 mol / L: 2.5 ml).
Was dropped and reacted for 30 minutes. Next, methyl iodide (0.37 ml) was added dropwise. The reaction mixture was returned to room temperature and reacted for 5 hours. The reaction mixture was extracted with saturated saline and ethyl acetate. The organic layer was washed with saturated saline and dried using sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was treated with flash column chromatography (developing solvent; hexane: ethyl acetate = 3: 1) to give the compound 6-methoxy-2,2-dimethyl-2,3-. Dihydro-4,9-dithiafluorene-1
-One (310 mg) was obtained as a solid.

6-methoxy-2,2-dimethyl-2,3
-Dihydro-4,9-dithiafluoren-1-one (3
(00 mg) was dissolved in pyridine (9 ml), and hydroxylamine hydrochloride (500 mg) was added. 1 at 90 ° C
The reaction was carried out for 8 hours. The reaction solution was concentrated under reduced pressure, and water and ethyl acetate were added to the residue for slurry treatment. Filter and wash the residue with water and ethyl acetate. By drying under reduced pressure at 50 ° C., the title compound (175 mg) was obtained as a solid. ¹ H-NMR (300 MHz, δ ppm, DMSO-
_{d 6): 1.43 (6H,} s), 3.07 (2H,
s), 3.90 (3H, s), 7.10 (1H, dd,
J = 2.1, 8.7 Hz), 7.15 (1H, d, J =
2.1 Hz), 7.70 (1 H, d, J = 8.1 Hz) FAB (+) MS (low resolution, m / z) 293

Example 30 6-Methoxy-2,3-dihydro-4,9-dithiafluoren-1-one Semicarbazone 6-Methoxy-2,3-dihydro-4, obtained in g) of Example 25. 9-dithiafluoren-1-one (100
mg) was dissolved in pyridine (2 ml), and semicarbazide hydrochloride (66 mg) was added. The reaction was carried out at 90 ° C for 18 hours. Saturated saline and chloroform were added to the reaction mixture for extraction. The organic layer was washed successively with saturated sodium hydrogen carbonate solution and saturated brine. The organic layer was dried with sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. By recrystallizing the residue from methanol and chloroform,
The title compound (53 mg) was obtained as a solid. ¹ H-NMR (300 MHz, δ ppm, DMSO-
_{d 6): 2.9-3.05 (2H,} m), 3.2-3.
3 (2H, m), 3.32 (1H, br s), 3.8
3 (3H, s), 6.2-6.45 (1H, br),
7.02 (1H, d, J = 2.3 Hz), 7.05-
7.1 (1H, m), 7.79 (1H, d, J = 8.7
Hz), 9.74 (1H, s) FAB (+) MS (low resolution, m / z) 307

Example 31 Acetic acid (6-methoxy-2,
3-Dihydro-4,9-dithiafluorene-1-ylidene) hydrazide 6-methoxy-2,3-dihydro-4,9-dithiafluoren-1-one (250 synthesized in Example 25 h)
mg), acetohydrazide (81 mg) and p-toluenesulfonic acid (catalytic amount) were added to isopropyl alcohol (5
ml) under heating and reacted at 95 ° C. for 2 hours.
After returning to room temperature, the precipitated crystals were filtered and recrystallized from chloroform to obtain the title compound (106 mg) as a solid. ¹ H-NMR (300 MHz, δ ppm, DMSO-
d ₆ ), as a mixture of E: Z = 1: 1: 2.01,
2.20 (total 3H, s), 3.0-3.05
(Total 2H, m), 3.25-3.3 (total
al 2H, m), 3.83 (3H, s), 7.0-
7.1 (total 2H, m), 7.81, 7.82
(Total 1H, d, J = 8.7 Hz), 10.5
6,10.73 (total 1H, s) FAB (+) MS (low resolution, m / z) 307

Example 32 1-[(Acetyloxy) imino] -6-methoxy-2,3-dihydro-4,9-dithiafluorene 6-methoxy-2,3 obtained in Example 25 h) -Dihydro-4,9-dithiafluoren-1-one oxime (71 mg) was dissolved in pyridine (0.5 ml), acetic anhydride (0.28 ml) was added with stirring at room temperature, and the mixture was reacted for 45 minutes. The precipitated crystal was filtered to obtain the title compound (63 mg) as a crystalline solid. ¹ H-NMR (300 MHz, δ ppm, DMSO-
d ₆ ), as a mixture of E: Z = 1: 3 (and vice versa): 2.21, 2.33 (total 3H,
s), 3.0-3.2 (total 2H, m), 3.
25-3.5 (total2H, m), 3.85, 3.
86 (total 3H, s), 7.1-7.25 (t
total 2H, m), 7.90, 7.97 (total)
l 1H, d, J = 8.7 Hz) FAB (+) MS (low resolution, m / z) 308

Example 33 (33-1, 33-2) 1-
[(Acetyloxy) imino] -6-methoxy-2-methyl-2,3-dihydro-4,9-dithiafluorene 6-methoxy-2-methyl-2, obtained in Example 28.
3-dihydro-4,9-dithiafluoren-1-one
Using an oxime (1.0 g), the title compound [(low polar compound (Example 33-1); 3
30 mg) and (highly polar compound (Example 33-2); 310 m)
g)] was obtained as a solid.

[(Low polar substance)] ¹ H-NMR (300 MHz, δ ppm, DMSO-
_{d 6): 1.39 (3H,} d, J = 6.0Hz), 2.
29 (3H, s), 2.96 (1H, dd, J = 3.0
Hz, 15.0 Hz), 3.54 (1H, dd, J =
3.0, 13.2 Hz), 3.9-3.95 (4H,
m), 7.05-7.1 (2H, m), 7.65 (1
H, d, J = 9.0 Hz) FAB (+) MS (low resolution, m / z) 321

[(Highly polar compound)] ¹ H-NMR (300 MHz, δppm, DMSO-
_{d 6): 1.43 (3H,} d, J = 6.9Hz), 2.
38 (3H, s), 3.09 (1H, dd, J = 4.
8, 13.2 Hz), 3.35-3.45 (1H,
m), 3.51 (1H, dd, J = 2.7, 12.6H)
z), 3.91 (3H, s), 7.1-7.2 (2H,
m), 7.72 (1H, d, J = 8.4 Hz) FAB (+) MS (low resolution, m / z) 321

Example 34 (6-methoxy-2,3-di
Hydro-4,9-dithiafluorene-1-ylideneami
Nooxy) acetic acid methyl ester 6-methoxy-2,3-di obtained in h) of Example 25
Hydro-4,9-dithiafluoren-1-one oxy
(200 mg) was stirred at room temperature with N, N-dimethylphosphine.
Dissolve it in Lumamide (4 ml) and water under an argon atmosphere.
Sodium hydride (60% oily; 42 mg) was added. Three
After stirring for 0 minutes, bromoacetic acid methyl ester (0.
1 ml) was added and stirred for 15 hours. The reaction solution was concentrated under reduced pressure.
Shrink, add ethyl acetate and saturated saline to the residue and extract,
The organic layer was washed with saturated saline. The organic layer is
Dried with um. After filtration, concentrate the filtrate under reduced pressure and leave
Flash column chromatography of the residue (developing solvent;
By treating with hexane: ethyl acetate = 3: 1)
The title compound (278 mg) was obtained as a solid. ¹ H-NMR (300 MHz, δppm, CDCl₃),
As a mixture of E: Z = 1: 1: 3.0-3.3 (to
tal 4H, m), 3.78, 3.80 (total)
  3H, s), 3.88, 3.90 (total 3
H, s), 4.75, 4.81 (total 2H,
s), 7.0-7.15 (total 2H, m),
7.61, 7.69 (total 1H, d, J = 8.
7Hz) FAB (+) MS (low resolution, m / z) 328

Example 35 2- (6-methoxy-2,3
-Dihydro-4,9-dithiafluorene-1-ylideneaminooxy) acetic acid amide a) (6-methoxy-2,3-dihydro-4,9-dithiafluorene-1-ylideneaminooxy) acetic acid sodium salt The (6-methoxy-2,3-dihydro-4,9-dithiafluorene-1-ylideneaminooxy) acetic acid methyl ester (243 mg) obtained in Example 34 was dissolved in methanol (15 ml) while heating. did. Return to room temperature, 1N
Aqueous sodium hydroxide solution (0.86 ml) was added, and 60
The reaction was carried out at 0 ° C for 3 hours. The reaction solution was concentrated under reduced pressure. The precipitate was filtered and then recrystallized from methanol-water to obtain the title compound (97 mg) as a solid. ¹ H-NMR (300 MHz, δ ppm, DMSO-
d ₆ ), as a mixture of E: Z = 1: 2 (and vice versa): 2.85-3.3 (total 4H, m),
3.83, 3.85 (total 3H, s), 4.2
3, 4.28 (total 2H, s), 7.1-7.
25 (total 2H, m), 7.80, 7.87
(Total 1H, d, J = 8.7 Hz) FAB (−) MS (low resolution, m / z) 322

B) 2- (6-Methoxy-2,3-dihydro-4,9-dithiafluorene-1-ylideneaminooxy) acetic acid amide The sodium salt obtained in a) of Example 35 was prepared by a conventional method. The carboxylic acid was converted to carboxylic acid, and 60 mg thereof was dissolved in N, N-dimethylformamide (4 ml). 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (78 mg), N-hydroxybenzotriazole monohydrate (63 mg), and ammonium chloride (50 mg) were sequentially added to this with stirring at room temperature. After stirring for 48 hours, saturated saline and ethyl acetate were added to the reaction mixture for extraction. The organic layer was washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried with sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the title compound (28
mg) was obtained as a solid. ¹ H-NMR (300 MHz, δ ppm, DMSO-
_{d 6), E: Z =} 1: 1 mixture of: 2.90-
3.4 (total 4H, m), 3.84, 3.85
(Total 3H, s), 4.48, 4.55 (to
tal 2H, s), 7.0-7.2 (total 3
H, m), 7.30, 7.35 (total 1H, b
r-s), 7.83, 7.93 (total 1H,
d, J = 8.8 Hz) FAB (+) MS (low resolution, m / z) 323

Example 36 (6-Methoxy-2,3-dihydro-4,9-dithiafluorene-1-ylidene) acetic acid methyl ester Under a nitrogen atmosphere, tetrahydrofuran (50 ml) was stirred under ice cooling with lithium bis (trimethylsilyl). ) Amide (4 ml) was added dropwise. Next, phosphonoacetic acid trimethyl ester (0.64 ml) was added dropwise, and the mixture was returned to room temperature and reacted for 1 hour. Next, a tetrahydrofuran solution (5 ml) of 6-methoxy-2,3-dihydro-4,9-dithiafluoren-1-one (500 mg) synthesized in Example 25 g) was added, and the mixture was reacted at 70 ° C. for 3 hours. Let After returning to room temperature, saturated saline and ethyl acetate were added to the reaction mixture for extraction. The organic layer was washed with saturated saline and dried using sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was treated by flash column chromatography (developing solvent; hexane: ethyl acetate = 5: 1) to obtain the title compound (25 mg) as a crystalline solid. ¹ H-NMR (300 MHz, δ ppm, CDCl ₃ ):
3.15-3.2 (2H, m), 3.45-3.5 (2
H, m), 3.75 (3H, s), 3.87 (3H,
s), 6.10 (1H, s), 7.0-7.1 (2H,
m), 7.60 (1 H, d, J = 6.0 Hz) FAB (+) MS (low resolution, m / z) 307

Example 37 2- (6-methoxy-3H-
4,9-Dithiafluoren-1-yl) acetic acid amide (6-methoxy-2,3-dihydro-4,9-dithiafluoren-1-ylidene) acetic acid synthesized in Example 36
Methyl ester (200mg) in methanol (5ml)
And dioxane (5 ml) and stir at room temperature for 2N
Aqueous sodium hydroxide solution (0.65 ml) was added dropwise.
After stirring at 70 ° C. for 1 hour, the reaction solution was concentrated under reduced pressure.
The residue was acidified with 2N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue is N,
It was dissolved in N-dimethylformamide (10 ml), and N-hydroxybenzotriazole monohydrate (104 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (195 mg) were added with stirring at room temperature. Then add ammonium chloride (41 mg) and add 18
Reacted for hours. The reaction mixture was extracted with saturated saline and chloroform. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water, 2N hydrochloric acid and saturated brine.
The organic layer was dried using magnesium sulfate. After filtration,
The filtrate was concentrated under reduced pressure, and the residue was subjected to flash column chromatography (developing solvent; hexane: ethyl acetate = 2: 1).
By treatment with, the title compound (11 mg) was obtained as a solid. ¹ H-NMR (300 MHz, δ ppm, DMSO-
d ₆ ), as a mixture of E: Z = 6: 1 (and vice versa): 3.15-3.2 (total 2H, m),
3.55-3.6 (total 2H, m), 3.8
3, 3.88 (total 3H, s), 5.77,
6.17 (total 1H, s), 7.0-7.05
(Total 2H, m), 7.10 (total 1
H, dd, J = 2.7, 8.7 Hz), 7.63 (1
H, br s), 7.84 (1H, d, J = 8.7H
z) FAB (+) MS (low resolution, m / z) 292

The compounds obtained in Examples 25 to 37 above are summarized in Table 17.

[0342]

[Table 17]

The present invention will be described in detail below with reference to formulation examples. Formulation Formulation Example Compound of Formula (1a) 3.0 mg Crystalline cellulose 67.0 mg Corn starch 25.0 mg Talc 4.0 mg Magnesium stearate 1.0 mg After thoroughly mixing the above components, granulating and drying, a tablet machine is used. One tablet was 100 mg.

Formulation Formulation Example Compound of Formula (1b) 3.0 mg Crystalline Cellulose 67.0 mg Corn Starch 25.0 mg Talc 4.0 mg Magnesium Stearate 1.0 mg The above composition was thoroughly mixed, granulated, dried and cast. Each tablet was made into 100 mg tablets using a tablet machine.

Formulation Formulation Example Compound of Formula (1c) 3.0 mg Crystalline cellulose 67.0 mg Corn starch 25.0 mg Talc 4.0 mg Magnesium stearate 1.0 mg The above composition was thoroughly mixed, granulated, dried and crushed. Each tablet was made into 100 mg tablets using a tablet machine.

Formulation Formulation Example Compound of formula (1d) 3.0 mg Crystalline cellulose 67.0 mg Corn starch 25.0 mg Talc 4.0 mg Magnesium stearate 1.0 mg The above composition was thoroughly mixed, granulated, dried and cast. Each tablet was made into 100 mg tablets using a tablet machine.

Test Example Pharmacological test 1. HIV DNA L under HIV-Tat stimulation
Transcriptional inhibition test 1A12 cells from TR (under the control of HIV-LTR promoter,
75 cm of recombinant HeLa cell clone that stably expresses the plasmid gene ligated with the luciferase gene
1.5 × 10 ⁵ cells / ml, 1 in ² culture flasks
6.7 ml of each was seeded, and DMEM (low glucose, 10
% Fetal bovine serum) at 37 ° C. for 1 day. The next day, after washing twice with serum-free medium DMEM (low glucose),
PCMV- which has been liposome-formed in advance with LipofectAmine (Lifetech Oriental Co., Ltd.)
16.7 μg of Tat plasmid was added and cultured. Three
After the lapse of time, DMEM (low glucose, 20% fetal bovine serum) was added in an equal amount, and the cells were further cultured for 3 hours. After that, adherent cells were recovered by trypsin digestion. These cell suspensions were added to 1.1 × 10 ⁵ cells / ml, 90 μl
Each was inoculated into a 96-well solid black plate (Corning International Co., Ltd.) and cultured at 37 ° C. The next day, 10 μl of DMEM (low glucose, 10% fetal bovine serum) medium containing the test compound was added,
It was further cultured for 24 hours. The test compound was dissolved in DMSO (dimethyl sulfoxide) and the final DM was added when cells were added.
The SO concentration was 0.1%. After completion of the culture, the expressed luciferase activity in the cultured cells was measured by the Micro-beta system using a luciferase activity measurement kit SteadyGlo (Promega). The concentration of the test compound at which the luciferase activity was 50% with respect to the test compound-non-added group was defined as an IC ₅₀ value and used as an index of the compound activity. The IC ₅₀ values for each Example compound are shown in the table below.

[0348]

[Table 18]

As is apparent from the above-mentioned test results, the compound of the present invention and pharmaceutically acceptable salts thereof were treated with HIV-Tat.
Under stimulation, it strongly inhibited transcription of HIV from the DNA LTR.

2. Anti-HIV test in latently infected cells OM10.1 cells (HL-60 cell clone incorporating one copy of HIV-1 gene) were used as RPMI1640.
Medium (RPMI1640, 10% fetal bovine serum, 100
U / ml penicillin G, 100 μg / ml streptomycin) and suspended in a 96-well microtiter plate at 1 × 10 ⁵ cells / ml, 100 μl / well.
Seed each. 100 μl of RPMI1640 medium containing a test compound was added, and the mixture was cultured at 37 ° C. for 2 hours, and 20 μl of human recombinant TNF-α (Roche; 1 ng / ml).
Was added and the cells were further cultured for 3 days. Test compound is DMS
It was lysed with O (dimethyl sulfoxide), and the final DMSO concentration at the time of adding cells was set to 0.2%.
After the completion of the culture, 120 μl of the culture supernatant was collected, and the HIV p24 antigen amount contained in the supernatant was adjusted to HIV-1 p24 A.
ntigen ELISA Kit (ZeptoMet
(Rix). The inhibition rate at each concentration of the test compound was calculated by the following formula, and the concentration that inhibits 50% with respect to the p24 amount in the test compound-free well was determined as IC _50.
The value was used as an index of the activity of the compound. Inhibition rate (%) = [1- (VPt-VPm) / (VPc-
VPm)] × 100 VPt: p24 antigen amount in the compound-added well VPc: p24 antigen amount in the compound-unadded well VPm: p2 in the TNF-α-unadded well without adding the compound
4 Antigen amount Table 19 shows the test results of the above test examples.

[0351]

[Table 19]

As is apparent from the above test, the novel compound of the present invention and its pharmaceutically acceptable salt strongly inhibited the virus growth in the test using HIV latently infected cells.

[0353]

From the above test results, the compound of the present invention is useful as an HIV inhibitor for suppressing virus growth, and is also effective for suppressing a virus that has acquired resistance to a reverse transcriptase inhibitor or a protease inhibitor. It is believed that there is. From these facts, it is useful as a new HIV inhibitor that suppresses the growth of virus that is observed in the latent period from HIV infection to the onset of AIDS.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 243/14 C07D 243/14 4C086 267/14 267/14 281/08 281/08 491/048 491/048 495/04 108 495/04 108 111 111 111 495/14 495/14 E 513/14 513/14 (72) Inventor Ryo Ikeda 1-1 Murasakicho, Takatsuki City, Osaka Prefecture Japan Tobacco Inc. Pharmaceutical Research Institute F-term (reference) 4C036 AB03 AB05 AB10 AB20 4C050 AA01 AA07 BB09 CC16 EE02 FF01 GG03 HH01 HH04 4C056 AA03 AB01 AC03 AD07 AE03 AF01 FA02 FA03 FB05 FC01 4C071 A01 AA07 BB01 BB05 A08A01 BB05 CC02FF01 BB05 CC02 CC07 CC07 CC07 CC21 CC21 CC02 CC07 CC07 CC07 CC07 CC07 CC02 CC01 CC02 CC07 CC07 CC01 BB03 BB06 CC03 CC04 CC17 EE19 FF19 GG01 GG07 JJ02 UU01 4C086 AA01 AA02 BB03 BC55 BC75 BC92 CB22 CB30 CB31 MA01 NA14 ZC55

Claims (38)

[Claims] 1. A compound represented by the general formula (1) as an active ingredient: [Chemical 1] [In the formula, ring A is [Chemical 2] (In the formula, A¹Is an alkyl group having 1 to 6 carbon atoms, 1 carbon atom
~ 6 hydroxyalkyl group, C2-6 alkeny
Group, phenylalkenyl group, haloalkenyl group, ar
Quinyl group, C2-C11 acyl group, C3-C13
The alkoxycarbonylalkyl group of carboxyalk
Group or-(CH₂)_n-R^Ten{Where r^TenIs -C
ON (r¹¹) (R¹²) (Where r¹¹And r¹²Is
The same or different, a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
Is a rukyll group or r¹¹And r¹²And adjacent to
Together with elementary atoms, [Chemical 3] (In the formula, r¹³Is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
May be a group)), [Chemical 4] (In the formula, r¹⁴And r¹⁵Are the same or different and are hydrogen
Atom, alkyl group having 1 to 6 carbon atoms, alkyl group having 1 to 6 carbon atoms
Coxy group, halogen atom, nitro group, cyano group or 5
Is a tetrazolyl group), and n is an integer of 1 to 4.
There is, and A²Is a hydrogen atom or an alkane having 1 to 6 carbon atoms.
Kill group, alkenyl group having 2 to 6 carbon atoms, benzyl group, charcoal
Acyl group, acyloxyalkyl group, charcoal having a prime number of 2 to 11
Alkoxycarbonylalkyl group having a prime number of 3 to 13, sia
No alkyl group or each alkyl group has 1 to 6 carbon atoms
A dialkylcarbamoyl group³Is -O-,
-S- or -N (r³⁰)-{Where r³⁰Is the hydrogen source
Child, alkyl group having 1 to 6 carbon atoms or benzyl group (here
And the benzyl group is an alkyl group having 1 to 6 carbon atoms, carbon
Number 1 to 6 alkoxy group, halogen atom or nitro group
May be substituted with)} and A^Fourand
A^FiveAre the same or different and each is a hydrogen atom or a carbon number 1.
~ 6 alkyl groups, or A^FourAnd A^FiveCombined
Forming a cyclohexane ring together with existing carbon atoms
May I⁶Is -S-, -SO- or -N (r
⁶⁰)-(Where r⁶⁰Is an alkyl group having 1 to 6 carbon atoms or
Is an alkenyl group having 2 to 6 carbon atoms), and A
⁷Is -N = N-, -NH-CO-, -CH₂-CH
₂-, -O-CO-, -O-CS-, -N = C (r⁷⁰)
-Or-CH = C (r⁷⁰)-(Where r⁷⁰Is hydrogen
Child or an alkyl group having 1 to 6 carbon atoms) (provided that
And these groups are bound to the nitrogen atom of the> C = N- group.
A), A⁸Is = N-O-r⁸⁰(here
And r⁸⁰Is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, charcoal
Acyl groups with 2 to 11 primes and alkoxy with 3 to 13 carbons
Carbonylalkyl group or carbamoy having 2 to 7 carbon atoms
Is an alkyl group), = N-NH-r⁸¹(Where r
⁸¹Is an acyl group having 2 to 11 carbon atoms or a carbamoyl group
Or = C-C (= O) -r⁸²(Where r⁸²
Is an alkoxy group having 1 to 6 carbon atoms or an amino group.
A)⁹And A^TenAre the same or different, water
A hydrogen atom or an alkyl group having 1 to 6 carbon atoms)
R; R¹And R²Are the same or different and are hydrogen atoms,
Halogen atom, C2-C11 acyl group, carboxy
Group, C2-7 alkoxycarbonyl group, cyano
Group, nitro group, 5-tetrazolyl group, -OR^Ten[here
And R^TenIs a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, charcoal
Alkenyl group having a prime number of 2 to 6, -SO₂-R¹¹(here,
R¹¹Is an alkyl group having 1 to 6 carbon atoms, [Chemical 5] (In the formula, R¹²And R¹³Are the same or different and are hydrogen
An atom, an alkyl group having 1 to 6 carbon atoms or a halogen atom
Yes),-(CH₂)_m-R¹⁴(Where R
¹⁴Is a dialkyl in which each alkyl group has 1 to 6 carbon atoms
Amino group, C1-C6 alkoxy group, C2-C7
Alkoxycarbonyl group, cyano group or nitrogen atom of
It is a 5- or 6-membered heterocyclic residue containing 1 to 4 rings.
, M is an integer of 1 to 4), and an alkyl having 2 to 7 carbon atoms.
The carbon number of the rucarbamoyl group and each alkyl group is 1 to 6
Dialkylcarbamoyl group, alkyl having 2 to 7 carbon atoms
The number of carbon atoms in the aminothiocarbonyl group or each alkyl group is
A dialkylaminothiocarbonyl group of 1 to 6
], -SO₂-N (R¹⁵) (R¹⁶) [Where R¹⁵And
And R^{1 6}Are the same or different and are a hydrogen atom or a hydroxyl group.
An alkyl group having 1 to 6 carbon atoms which may be substituted with
Or R¹⁵And R¹⁶Together with the adjacent nitrogen atom
become, [Chemical 6] (In the formula, R¹⁷Is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
May be a group)], —CO—N (R¹⁸)
(R¹⁹) (Where R¹⁸And R¹⁹Are the same or different
A hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or
Nyl group), -N (R²⁰) (R^{twenty one}) (Where R²⁰
And R^{twenty one}Are the same or different, hydrogen atom, carbon number
1 to 6 alkyl group, 2 to 11 carbon acyl group, carbon
Alkylsulfonyl group having 1 to 6 carbon atoms, 2 to 7 carbon atoms
With a coxycarbonyl group or an alkenylcarbamoyl group
Yes or R²⁰And R^{twenty one}And are adjacent to the nitrogen atom
In the beginning [Chemical 7] May be formed), -SR^{twenty two}[Where R^{twenty two}Is charcoal
Alkyl group having a prime number of 1 to 6 or -CO-N (R^{twenty three}) (R
^{twenty four}) (Where R^{twenty three}And R^{twenty four}Are the same or different
Is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms)
, Or -SO₂-R^{twenty five}(Where R^{twenty five}Is carbon
An alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms,
It is an alkenyl group having 2 to 6 carbon atoms or a benzyl group)
And X is a sulfur atom, an oxygen atom, -CH₂-CH
₂-, -CH = CH- or -C (X ²⁰) (X^{twenty one}) −
(Where X²⁰And X^{twenty one}Are the same or different, water
A hydrogen atom or an alkyl group having 1 to 6 carbon atoms)
Provided that when ring A is a ring represented by formula (Aa),
A¹Is an alkyl group having 1 to 6 carbon atoms, A²Is a hydrogen atom
Then R¹Is a hydrogen atom, nitro group, halogen source
Child, -OR^Ten(Where R^TenIs a hydrogen atom or carbon
Is an alkyl group of the numbers 1 to 6) and -N (R²⁰) (R
^{twenty one}) (Where R²⁰And R^{twenty one}Are the same or different
Is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms)
A compound represented by any of
An HIV inhibitor comprising the above acceptable salt. 2. A ring A is a ring represented by formula (Aa),
The HIV inhibitor according to claim 1. 3. R ¹ is a hydrogen atom, a halogen atom, an acyl group having 2 to 11 carbon atoms, a carboxyl group, or 2 to 7 carbon atoms.
Alkoxycarbonyl group, cyano group, nitro group, 5-
Tetrazolyl group, -O-R ¹⁰ (wherein, R ¹⁰ is as defined in claim _{1), - SO 2 -N (} R 15) (R 16) ( in the formula,
R ¹⁵ and R ¹⁶ are as defined in claim 1), —CO—N
^{(R 18) (R 19)} ( wherein, R ¹⁸ and R ¹⁹ are as defined in claim ^{1), - N (R 20} ) (R 21) ( wherein, R ²⁰ and R ²¹ are claim 1 synonymous), - S-R ²² (wherein, R ²² is as defined in claim 1) or -SO ₂ -R
²⁵ (wherein R ²⁵ has the same meaning as in claim 1) and R ²
Is a hydrogen atom, and X is a sulfur atom or an oxygen atom, The HIV inhibitor according to claim 2. 4. The H according to claim 3, wherein X is a sulfur atom.
IV inhibitors. 5. R ¹ is a halogen atom, a nitro group, or —O
-R ¹⁰ (wherein R ¹⁰ has the same meaning as in claim 1) or-
The HIV inhibitor according to claim 4, which is S-R ²² (wherein R ²² has the same meaning as in claim 1). 6. A ¹ is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group, or 3 to 3 carbon atoms.
13 alkoxycarbonylalkyl group or-(CH
_{2) n} -r ¹⁰ (wherein, n and r ¹⁰ are the same meaning as claim 1), HIV inhibitor according to claim 5, wherein. 7. The H according to claim 2, wherein X is an oxygen atom.
IV inhibitors. 8. R ¹ is a halogen atom, a nitro group, or —O
-R ¹⁰ (wherein R ¹⁰ has the same meaning as in claim 1) or-
The HIV inhibitor according to claim 7, which is S-R ²² (wherein R ²² has the same meaning as in claim 1). 9. A ¹ is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group, or 3 to 3 carbon atoms.
13 alkoxycarbonylalkyl group or-(CH
_{2) n} -r ¹⁰ (wherein, n and r ¹⁰ are the same meaning as claim 1), HIV inhibitor according to claim 8. 10. The HIV inhibitor according to claim 1, wherein ring A is a ring represented by formula (Ab). 11. R ¹ and R ² are the same or different and each is a hydrogen atom, a hydroxyl group or an alkoxy group having 1 to 6 carbon atoms, and X is —CH ₂ —CH ₂ —, —CH═CH.
- or ^{-C (X 20) (X 21} ) - ( wherein, X ²⁰ and X
²¹ has the same meaning as in claim 1), and the HIV inhibitor according to claim 10. 12. The HIV inhibitor according to claim 11, wherein A ³ is —O—. 13. The HIV inhibitor according to claim 11, wherein A ³ is —S—. 14. The HI of claim 11, wherein A ³ is —N (r ³⁰ ) —, where r ³⁰ has the same meaning as in claim 1.
V inhibitor. 15. X is --C (X ²⁰ ) (X ²¹ )-(wherein
X ²⁰ and X ²¹ are the same meaning as claim 1), HIV inhibitor according to any one of claims 10 to 14. 16. R ¹ is a hydrogen atom and R ² has 1 carbon atom.
16. The HIV inhibitor according to claim 15, which is an alkoxy group of 6 to 6, A ⁴ is a hydrogen atom, and A ⁵ is a hydrogen atom. 17. The HIV inhibitor according to claim 10, wherein X is —CH ₂ —CH ₂ —. 18. R ¹ is a hydrogen atom and R ² has 1 carbon atom.
The HIV inhibitor according to claim 17, which is an alkoxy group of 6 to 6, A ⁴ is a hydrogen atom, and A ⁵ is a hydrogen atom. 19. The method according to claim 1, wherein X is —CH═CH—.
The HIV inhibitor according to any one of 0 to 14. 20. R ¹ is a hydrogen atom and R ² has 1 carbon atom.
20. The HIV inhibitor according to claim 19, which is an alkoxy group of 6 to 6, A ⁴ is a hydrogen atom, and A ⁵ is a hydrogen atom. 21. The HIV inhibitor according to claim 1, wherein ring A is a ring represented by formula (Ac). 22. The H according to claim 21, wherein R ¹ is a hydrogen atom, a nitro group or an alkoxy group having 1 to 6 carbon atoms, R ² is a hydrogen atom, and X is a sulfur atom.
IV inhibitors. 23. The HIV inhibitor according to claim 22, wherein R ¹ is an alkoxy group having 1 to 6 carbon atoms. 24. A ⁷ is -N = C (r ⁷⁰ )-or -C.
H = C (r ⁷⁰⁾ - a (wherein, r ⁷⁰ is as defined in claim 1), HI according to any one of claims 21 to 23
V inhibitor. 25. The method according to claim 21, wherein A ⁶ is —S—.
The HIV inhibitor according to any one of 4 above. 26. The HIV inhibitor according to claim 21, wherein A ⁶ is —N (r ⁶⁰ ) — (wherein, r ⁶⁰ has the same meaning as in claim 1). 27. The HIV inhibitor according to claim 1, wherein ring A is a ring represented by formula (Ad). 28. The HIV inhibitor according to claim 27, wherein R ¹ is an alkoxy group having 1 to 6 carbon atoms, R ² is a hydrogen atom, and X is a sulfur atom. 29. The method according to claim 2, wherein R ¹ is a methoxy group.
The HIV inhibitor according to 8. 30. A ⁸ is ═N—O—r ⁸⁰ (wherein r ⁸⁰
Is synonymous with claim 1, and is 27 to 29.
The HIV inhibitor according to any one of 1. 31. r ⁸⁰ is a hydrogen atom or a carbon number of 2 to 1.
The HIV inhibitor according to any one of claims 27 to 30, which is 1 acyl group. 32. As an active ingredient, a compound represented by the general formula (1 ′): (In the formula, R ¹ is a hydrogen atom, a halogen atom, or a carbon number of 2 to 2.
11 acyl group, carboxyl group, alkoxycarbonyl group having 2 to 7 carbon atoms, cyano group, nitro group, 5-tetrazolyl group, -O-R ¹⁰ [wherein R ¹⁰ is a hydrogen atom, 1 to 6 carbon atoms] An alkyl group having 2 to 6 carbon atoms, -SO ₂ -R ¹¹ (wherein R ¹¹ is an alkyl group having 1 to 6 carbon atoms, (In the formula, R ¹² and R ¹³ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a halogen atom), — (CH ₂ ) _m —R ¹⁴ (wherein R
¹⁴ is a dialkylamino group in which each alkyl group has 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and 2 to 7 carbon atoms.
An alkoxycarbonyl group, a cyano group, or a 5- or 6-membered heterocyclic residue having 1 to 4 nitrogen atoms in the ring, m is an integer of 1 to 4), and an alkyl group having 2 to 7 carbon atoms. A carbamoyl group, a dialkylcarbamoyl group having 1 to 6 carbon atoms in each alkyl group, an alkylaminothiocarbonyl group having 2 to 7 carbon atoms, or a dialkylaminothiocarbonyl group having 1 to 6 carbon atoms in each alkyl group. ], - with ^{_{SO 2 -N (R 15) (}} R 16) [ wherein, R ¹⁵ and R ^{1 6} are the same or different, a hydrogen atom or a hydroxyl group with an alkyl having 1 to 6 carbon atoms which may be substituted A group, or R ¹⁵ and R ¹⁶ together with the adjacent nitrogen atom, (In the formula, R ¹⁷ may be a hydrogen atom or an alkyl group having 1 to 6 carbon atoms)], —CO—N (R ¹⁸ )
(R ¹⁹ ) (wherein R ¹⁸ and R ¹⁹ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group), —N (R ²⁰ ) (R ²¹ ) (here Then R ²⁰
And R ²¹ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 11 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms. Or an alkenylcarbamoyl group, or R ²⁰ and R ²¹ together with an adjacent nitrogen atom, May be formed), —S—R ²² [wherein R ²² is an alkyl group having 1 to 6 carbon atoms or —CO—N (R ²³ ) (R
²⁴ ) (wherein R ²³ and R ²⁴ are the same or different and each is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms)
In it, or -SO ₂ -R ²⁵ (wherein, R ²⁵ represents an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms,
It is an alkenyl group having 2 to 6 carbon atoms or a benzyl group)
And A ^{1 ′} is a hydroxyalkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a phenylalkenyl group, a haloalkenyl group, an alkynyl group, and a carbon number of 2 to 11
An acyl group, an alkoxycarbonyl alkyl group of 3 to 13 carbon atoms, a carboxyalkyl group or - (CH _{2) n} -
r ¹⁰ (where r ¹⁰ is —CO—N (r ¹¹ ) (r ¹² ).
(Here, r ¹¹ and r ¹² are the same or different and each is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or r ¹¹ and r ¹² together with an adjacent nitrogen atom, Chemical 12] (In the formula, r ¹³ may be a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), and (In the formula, r ¹⁴ and r ¹⁵ are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group or 5
Is a tetrazolyl group), n is an integer of 1 to 4), A ² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a benzyl group, An acyl group having 2 to 11 carbon atoms, an acyloxyalkyl group, an alkoxycarbonylalkyl group having 3 to 13 carbon atoms, a cyanoalkyl group, or a dialkylcarbamoyl group having 1 to 6 carbon atoms in each alkyl group, and X ^′ is It is a sulfur atom or an oxygen atom. ) An HIV inhibitor comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof. 33. The HIV inhibitor according to claim 32, wherein X ^′ is a sulfur atom. 34. R ¹ is a halogen atom, a nitro group, or
O-R ¹⁰ (wherein, R ^{1 0} is claim 32 as synonymous) or -S-R ²² (wherein, R ²² is as defined in claim 32)
34. The HIV inhibitor according to claim 33. 35. A ^{1 ′} represents an alkenyl group having 2 to 6 carbon atoms, an alkynyl group, an alkoxycarbonylalkyl group having 3 to 13 carbon atoms or — (CH ₂ ) _n —r ¹⁰ (wherein n and r ¹⁰ Is the same as claim 32),
The HIV inhibitor according to 4. 36. The HIV inhibitor according to claim 32, wherein X ^′ is an oxygen atom. 37. R ¹ is a halogen atom, a nitro group, or
O-R ¹⁰ (wherein, R ^{1 0} is claim 32 as synonymous) or -S-R ²² (wherein, R ²² is as defined in claim 32)
37. The HIV inhibitor according to claim 36. 38. A ^{1 ′} represents an alkenyl group having 2 to 6 carbon atoms, an alkynyl group, an alkoxycarbonylalkyl group having 3 to 13 carbon atoms or — (CH ₂ ) _n —r ¹⁰ (wherein n and r ^{10 are the same).} Is the same as claim 32),
HIV inhibitor according to 7.