JP2003292485A - Sulfonamide derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound effective as a therapeutic agent for human immunodeficiency virus (HIV) infectious diseases. <P>SOLUTION: The compound has two cyclic groups bound through sulfonamide as a linker, namely, a specific sulfonamide derivative has the cyclic groups on an S atom and an N atom of the sulfonamide, respectively. The compound is found to have a good reverse transcriptase inhibitory activity as a result of intensive studies made on a compound inhibiting the reverse transcriptase for developing a nonnucleic acid reverse transcriptase inhibitor. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a medicine, particularly anti-HIV.
It relates to a sulfonamide derivative useful as a medicine.

[0002]

2. Description of the Related Art Human Immunodeficiency Virus
ficiency Virus: HIV) is an acquired immunodeficiency syndrome (AID)
S) is the causative virus and CD4 such as helper T lymphocytes.
Infects positive cells and destroys and reduces them. As a result, the immune function is reduced, and opportunistic infections such as carini pneumonia and malignant tumors occur. Currently, clinically used anti-HIV drugs are nucleic acid reverse transcriptase inhibitors (NRT
I), a non-nucleic acid reverse transcriptase inhibitor (NNRTI) and a protease inhibitor (PI), which are roughly classified into 6 types as NRTIs (zidovudine (AZT), didanosine (ddI), salcitabine (ddC), Lamivudine (3TC), Sanilvudine (d4
T), abacavir (ABC)), 3 types as NNRTI (nevirapine (NVP), efavirenz (EFV), delavirdine (DLV)), 6 types as PI (indinavir (ID
V), saquinavir (SQV), ritonavir (RTV), nelfinavir (NFV), amprenavir (APV), lopinavir / ritonavir combination (LPV / RTV)) are used.
Recently, in order to reduce the mortality rate due to AIDS and the frequency of AIDS-related opportunistic infections, highly active antiretroviral therapies using three or more of these anti-HIV drugs have been developed.
y: HAART) is the standard treatment. HAART is NRTI 2
Agent and PI 1 agent, or NRTI 2 agent and NNRTI 1 agent are used in combination to reduce the HIV viral load in patients to below the detection limit, reconstitute the immune system, and increase the decreased CD4 again. be able to. However, the early introduction of HAART poses problems with long-term side effects and the emergence of resistant viruses. In particular, since PI requires a high dose and has serious side effects (such as elevated blood glucose levels and lipodystrophy), recently, the combination of NRTI 2 agent and NNRTI (among others, EFV) is the first therapy. Has been recommended. EFV 1 per day
A single dose (600 mg) is sufficient, and it is a drug superior to PI in terms of adherence. However, EFV has side effects such as the emergence of drug-resistant virus, rash, concentration disorder, and insomnia.
It cannot be said that the drug is sufficiently satisfactory for long-term administration. Therefore,
The development of NNRTI, which is resistant to drug-resistant virus, has few side effects, and can maintain adherence, is desired.
Several NNRTIs showing antiviral effects on existing NNRTI resistant strains have been reported. For example, WO96 / 10019 includes S, S
Imidazole derivatives that bind to phenyl via O, SO ₂ or methylene, WO00 / 27825 include pyrimidine derivatives having an arylamino group at the 2-position, and WO01 / 17982 includes 2
A phenyl ketone derivative having a carbamoylmethoxy group at the position has been reported.

Many compounds have been reported as sulfonamide derivatives. For example, in the following general formula (II),

[Chemical 4] 1) R ¹ is absent, that is, a is a double bond and b is a single bond, and R ³ is methyl as a sulfonamide derivative shown in Table 1 below, 2) R ² is absent, , A is a single bond and b is a double bond, R ³ is methyl, R ⁴ is lower alkyl, and A is phenyl which may be substituted only at the 3 or 4 position. The compounds shown in Table 2 have been reported.

[0004]

[Table 1]

[0005]

[Table 2]

(The abbreviations in the table have the following meanings: Cmp
d: compound number, Lit: source (see below for a to n), Me: methyl, Et: ethyl, iPr: 2-propyl, tBu: tert-butyl, Ac: acetyl, Ph: phenyl. Further, the number before the substituent indicates the substitution position, and for example, 4-Cl-Ph indicates 4-chlorophenyl. The same applies below. ) Sources a to n mean the following documents, etc. a: Khim. Geterotsikl. Soedin. (1967), (1), 153-4; b: Khim. Geterotsikl. Soedin. (1967), (1), 154-7; c: Khim. Geterotsikl. Soedin. (1969 ), (1), 56-8; d: J. Am. Chem. Soc. (1974), 96 (12), 3973-8; e: J. Chem. Soc., Perkin Trans. 1 (1980), (8), 177
3-8; f: US Patent No. US3097201; g: ChemDiv, Inc (USA) Reagent Catalog No. 1613-0032; h: Oak Samples Ltd (Ukraine) Reagent Catalog: (1) N
o.CD134441, (2) No.CD134440, (3) No.CD050023, (4) No.
CD050044, (5) No.CD050039, (6) No.CD123533, (7) No.CD
050006; j: Florida Center for Heterocyclic Compounds, Uni
v. of Florida (USA) Reagent Catalog: (1) No.23765, (2) N
o.23769, (3) No.23764, (4) No.20478, (5) No.20479,
(6) No.15722, (7) No.20480; k: The Ukrainian State Chemical-Technology Univers
ity (Ukraine) Reagent Catalog (1) No.USCTU G004846,
(2) No.USCTU GRB07005; m: AsInEx Ltd (Russia) Catalog (1) No.BAS0458427,
(2) No.BAS0458426, (3) No.BAS0458431; n: Chem. Abstr. 57, 3567g Among the above, n (Chem. Abstr. 57, 3567g) has a report on the use of the compound as a therapeutic agent for diabetes. However, in a to m, there is no disclosure concerning the use of the compound as an anti-HIV agent and of course its pharmaceutical use.

[0007]

DISCLOSURE OF THE INVENTION As described above, there is a strong demand for the development of an NNRTI in which drug-resistant viruses are less likely to appear, have fewer side effects, and can maintain adherence.

[0008]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies on compounds that inhibit reverse transcriptase, and as a result, compounds in which two ring groups are bound with sulfonamide as a linker,
That is, the inventors have found that a specific sulfonamide derivative having a ring group on each of the S atom and the N atom of sulfonamide has a good reverse transcriptase inhibitory activity, and completed the present invention. That is, according to the present invention, a sulfonamide derivative represented by the following general formula (I) (hereinafter referred to as “the present compound (I)”) or a pharmaceutically acceptable salt thereof, and one of these There is provided a medicine, particularly an anti-HIV agent, containing one or more kinds as an active ingredient.

[0009]

[Chemical 5] [The symbols in the formula have the following meanings. a and b: each represents a single bond or a double bond, at least one is a single bond and the other is a double bond, R ¹ : absent when a is a double bond and b is a single bond ; A
Is a single bond and b is a double bond, -H, -lower alkyl, -lower alkyl substituted with halogen, -lower alkylene-OH, -lower alkylene-heterocycle, -lower alkylene
-Optionally substituted aryl, -lower alkylene-O-
Lower alkyl, -lower alkylene-CHO, -lower alkylene
-CO ₂ H, - lower alkylene -CO ₂ - lower alkyl, - lower alkylene -CONH ₂ or - lower alkylene -OCONH ^_2, R _2: a double bond, and, when b is a single bond, -H, -Lower alkyl, -lower alkyl substituted with halogen, -lower alkylene-OH, -lower alkylene-heterocycle, -lower alkylene-optionally substituted aryl, -lower alkylene-O-lower alkyl, -lower alkylene -CHO, - lower alkylene -CO ₂ H, - lower alkylene -CO ₂ - lower alkyl, - lower alkylene -CONH ₂ or - lower alkylene -OCONH _2; a is a single bond, and, when b is a double bond, Absent, X: O or S, A: optionally substituted aryl or optionally substituted heteroaryl, B: optionally substituted nitrogen-containing heterocycle. However, when R ¹ is H and B is 4-methyl-5- (2-propyl) thiazol-2-yl, compounds in which A is phenyl or 4-methylphenyl are excluded. The same applies below. ]

The present invention also relates to a novel sulfonamide derivative represented by the following formula (I ') included in the formula (I) or a salt thereof.

[Chemical 6] [The symbols in the formula have the following meanings. a and b: each represents a single bond or a double bond, at least one is a single bond and the other is a double bond, R ¹ : absent when a is a double bond and b is a single bond ; A
Is a single bond and b is a double bond, -H, -lower alkyl, -lower alkyl substituted with halogen, -lower alkylene-OH, -lower alkylene-heterocycle, -lower alkylene
-Optionally substituted aryl, -lower alkylene-O-
Lower alkyl, -lower alkylene-CHO, -lower alkylene
-CO ₂ H, - lower alkylene -CO ₂ - lower alkyl, - lower alkylene -CONH ₂ or - lower alkylene -OCONH ^_2, R _2: a double bond, and, when b is a single bond, -H, -Lower alkyl, -lower alkyl substituted with halogen, -lower alkylene-OH, -lower alkylene-heterocycle, -lower alkylene-optionally substituted aryl, -lower alkylene-O-lower alkyl, -lower alkylene -CHO, - lower alkylene -CO ₂ H, - lower alkylene -CO ₂ - lower alkyl, - lower alkylene -CONH ₂ or - lower alkylene -OCONH _2; a is a single bond, and, when b is a double bond, Absent, X: O or S, A: optionally substituted aryl or optionally substituted heteroaryl, B: optionally substituted nitrogen-containing heterocycle. However, in the formula (I ′),

[Chemical 7] (In the formula, R ³ and R ⁴ represent the substituents of the above-mentioned “B optionally substituted nitrogen-containing heterocycle”.),
The following compounds are meant: 1) When R ² is absent, R ³ is methyl, and A is a phenyl group which may be substituted only at the 4-position, R ⁴ is C _2-6 alkyl. A compound, 2) R ² and R ³ are methyl, and R ⁴ is H, 2-propyl or t
When ert-butyl, A is chloro, methyl, N only at position 4
A compound other than phenyl optionally substituted with a group selected from H ₂ and NHCOCH ₃ , 3) when R ² and R ³ are methyl, and R ⁴ is C ₅ alkyl,
A is a compound other than phenyl optionally substituted with a group selected from methyl and NO ₂ only at the 4-position, 4) when R ² is ethyl, R ³ is methyl, and R ⁴ is H, A
Is a compound other than phenyl optionally substituted with a group selected from methyl and NHCOCH ₃ only at the 4-position, 5) when R ² is ethyl, R ³ is methyl, and R ⁴ is 2-propyl, A is a compound other than 4-methylphenyl, 6) a group in which when R ² is ethyl, R ³ is methyl, and R ⁴ is tert-butyl, A is selected from methyl, chloro and bromine only at the 4-position. Compounds other than phenyl substituted with 7), when R ² and R ³ are methyl, and R ⁴ is tert-butyl, A is a compound other than 3-nitrophenyl, 8) R ² is CH ₂ CH ₂ Cl Or CH ₂ CH ₂ OH, R ³ is methyl, and R ⁴
When H is H, A is a compound other than 4-chlorophenyl, 9) R ² is benzyl, R ³ is methyl, and when R ⁴ is H, methyl or diethylamino, A is a compound other than 4-methylphenyl, 10 ) R ² is methyl, R ³ is tert-butyl, and R ⁴ is chloro, A is a compound other than 4-methylphenyl, 11) R ¹ is H, R ³ is methyl, and R ⁴ is tert. -When it is butyl, A is a compound other than phenyl, 4-methylphenyl, 4-chlorophenyl, 3-nitrophenyl or 4-bromophenyl, 12) R ¹ is H, R ³ is methyl, and R ⁴ is 2- When propyl, A is a compound other than phenyl, 4-chlorophenyl or 4-methylphenyl, 13) when R ¹ is ethyl, R ³ is methyl, and R ⁴ is tert-butyl or 2-propyl, A is 4 -Compounds other than -chlorophenyl, and 14) when R ¹ is H, R ³ is methyl, and R ⁴ is CO ₂ Et, A
Is a compound other than 3-nitrophenyl. The same applies below. ]

The dotted lines in the formulas (I), (I ') and (II) and the formula (III) described later indicate that "a is a double bond, and
“B is a single bond” or “a is a single bond and b is a double bond” means that the compound has a partial structure shown below.

[Chemical 8] That is, when R ¹ is absent, a is a double bond and b is a single bond, and when R ² is absent, a is a single bond and b is a double bond.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. In the present specification, "alkyl", "alkylene",
“Alkenyl”, “alkenylene”, “alkynyl” and “alkynylene” mean a straight or branched hydrocarbon chain. “Lower alkyl” is, for example, C _1-8 alkyl, preferably C _1-6 alkyl, more preferably C _1-5 alkyl, further preferably methyl, ethyl, isopropyl, 2-methyl-2- Butyl and tert-butyl groups. "Lower alkylene" is, for example, C _1-8 alkylene, preferably C _1-6 alkylene, and more preferably C 1.
_1-4 alkylene, more preferably ethylene, butylene and 1,1-dimethylethylene. "Lower alkenyl"
Is, for example, one or more 2 at any position on the C _2-8 alkyl.
"Lower alkenylene" means having a heavy bond
Means, for example, having one or more double bonds at any position of C _2-8 alkylene. "Lower alkynyl"
Means, for example, having one or more triple bonds at any position of C _2-8 alkyl, and is “lower alkynylene”.
Means having one or more triple bonds at any position of, for example, C _2-8 alkylene. "Halogen" is
F, Cl, Br and I are shown, preferably F, Cl and Br. “Halogen-substituted lower alkyl” is lower alkyl substituted with one or more halogen, preferably C _1-2 alkyl having 1 to 5 F,
Examples include fluoromethyl, difluoromethyl, trifluoromethyl and trifluoroethyl. The “cycloalkyl group” is preferably a cycloalkyl group having 3 to 14 carbon atoms, and may be crosslinked. More preferred are cyclopentyl, cyclohexyl, cycloheptyl and adamantyl groups. "Aryl" is preferably a monocyclic to tricyclic aryl group having 6 to 14 carbon atoms. More preferred are phenyl and naphthyl groups, and even more preferred are phenyl groups. Further, a 5- to 8-membered cycloalkyl ring may be condensed with the phenyl group to form, for example, an indanyl or tetrahydronaphthyl group.

"Heteroaryl" means as a ring atom
A 5- to 8-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from O, S, and N is shown, which is a bicyclic to tricyclic heteroaryl which is condensed with heterocycles or with a benzene ring. Aryl may be formed. S or N may be oxidized to form an oxide. For example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl. Examples include quinoxalinyl and cinnolinyl. "Heterocycle" is a saturated or unsaturated 3- to 8-membered, preferably 5- to 7-membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from O, S and N as ring atoms. A group is shown, and the heterocycles may be condensed with each other or with a cycloalkyl ring or a benzene ring to form a bi- to tricyclic heterocyclic group. Any carbon atom which is a ring atom may be substituted with an oxo group, S
Alternatively, N may be oxidized to form an oxide or a dioxide. The heterocyclic group may be bridged, or may form a spiro ring (1,3-derived from an oxo group).
Including acetal such as dioxolane ring). Preferably, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl,
Benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, heteroaryl such as pyrrolidinyl, dihydropyridyl, dihydropyrrolyl, dihydrooxazolyl, dihydrothiazolyl, dihydroimidazolyl, piperidyl, Morpholinyl, piperazinyl, pyrazolidinyl, imidazolidinyl, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, chromanyl, dioxolanyl, 8-azabicyclo [3.2.1] octane-3-yl, 9-azabicyclo [3.
3.1] Nonane-3-yl, 3-azabicyclo [3.2.1] octane-6
-Yl, 7-azabicyclo [2.2.1] heptan-2-yl, 2-azatricyclo [3.3.1.1 ^3,7 ] decane-4-yl, 1-azabicyclo [2.2.2] octane-2-yl, 1- Azabicyclo [2.2.2]
Octan-3-yl, 1-azabicyclo [2.2.2] octane-4-
Ill, 3-azaspiro [5.5] undecane-9-yl, 2-azaspiro [4.5] decane-8-yl, 2-azaspiro [4.4] nonane-7-
And saturated or partially unsaturated heterocycles such as yl and 8-azaspiro [4.5] decan-2-yl. More preferred are pyridyl, quinolyl, oxazolyl, thiazolyl, benzothiazolylpyridyl, dihydrooxazolyl, dihydrothiazolyl, dihydrobenzothiazolyl and tetrahydrobenzothiazolyl groups.

The "nitrogen-containing heterocycle" means a heterocycle having at least one N as a ring atom among the above "heterocycle". Preferred are oxazolyl, thiazolyl, benzothiazolylpyridyl, dihydrooxazolyl, dihydrothiazolyl, dihydrobenzothiazolyl and tetrahydrobenzothiazolyl groups, and more preferred are thiazolyl and dihydrothiazolyl groups. Is.

"Optionally substituted aryl" or
Substitution in "optionally substituted heteroaryl"
The basis is that of these rings in medicine, especially in anti-HIV agents.
A group that can be used as a substituent,
You may have ~ 5 pieces. When having two or more substituents
In that case, they may be the same or different from each other. Replacement
The group is preferably a group selected from the following G1 group.
It G1: lower alkyl, lower alkenyl, lower alkynyl,
Halogen, lower alkyl substituted with halogen, OH, O-
Lower alkyl, lower alkyl substituted with O-halogen,
O-lower alkylene-aryl, SH, S-lower alkyl, N
O₂, NH₂, NH-lower alkyl, N (lower alkyl)₂, NH-CO-
Lower alkyl, N (lower alkyl) -CO-lower alkyl, NH-
CO₂-Lower alkyl, N (lower alkyl) -CO₂-Lower Archi
Le, NHSO₂-Lower alkyl, N (lower alkyl) SO₂-Lower
Rutile, O-CO-lower alkyl, O-CONH₂, CO₂H, CO₂-Low
Alkyl, CN, CONH₂, CONH-lower alkyl, CON (lower alkyl
(Rukiru)₂, CHO, C = NOH, C = N-O-CO-lower alkyl, C = NNH
₂, NHCO-lower alkyl, NHCO-lower alkylene-aryl
Group, NHCO-lower alkylene-heterocycle, NHCO-aryl, N
HCO-heterocycle, lower alkylene-CO₂H, lower alkylene-
CO₂-Lower alkyl, lower alkylene-CONH₂, Lower archi
Len-CN, lower alkylene-OH, lower alkylene-N ₃, Low
Primary alkylene-aryl, lower alkylene-heterocycle, low
Grade alkenylene-CO ₂H, lower alkenylene-CO₂-Lower Al
Kill, Lower Alkenylene-CONH₂, Lower alkenylene-C
N, lower alkenylene-OH, lower alkenylene-ary
Ru, lower alkenylene-heterocycle, aryl, hetero
Ring, CO-aryl, CO-heterocycle, O-aryl, O-hetero
Ring, O-lower alkylene-CO₂H, O-lower alkylene-CO₂-Low
Primary alkyl, O-lower alkylene-CONH₂, O-lower Alkyre
-CONH-lower alkyl, O-lower alkylene-CON (lower alkyl
(Rukiru)₂, O-lower alkylene-CONH-lower alkylene-O
H, O-lower alkylene-CO-heterocycle, O-lower alkylene-
Heterocycle and O-lower alkylene-CN. Where aryl
And heterocycle are lower alkyl, halogen, OH and O-low.
Substituted with 1 to 5 groups selected from primary alkyl
Good. Of the G1 group, more preferably lower alkyl,
Lower alkenyl, lower alkynyl, halogen, halogen
Lower alkyl substituted with, OH, O-lower alkyl, O-low
Alkylene-aryl, NO₂, NH₂, NH-lower alkyl,
O-CONH₂, CN, CONH₂, CONH-lower alkyl, CON (lower alkyl
(Rukiru)₂, CHO, C = NOH, lower alkylene-CN, lower ar
Xylene-OH, lower alkylene-aryl, lower alkylene
-Heterocycle, lower alkenylene-CN, lower alkenylene-O
H, lower alkenylene-aryl, lower alkenylene-f
Telocycle, aryl and heterocycle, more preferably lower
Alkyl, lower alkenyl, halogen, OH, O-lower ar
Kill, no₂, NH₂, O-CONH₂, CN and CONH₂Selected from
It is a base.

“Nitrogen-containing heterocycle which may be substituted”
The substituent in is a group that can be used as a substituent of these rings in a drug, particularly an anti-HIV agent, and may have 1 to 5 of these substituents. When having two or more substituents, they may be the same or different from each other. The substituent is preferably a group selected from the following G2 group. G2: lower alkyl, lower alkylene-OH, halogen, O
H, O-lower alkyl, O-lower alkylene-aryl, CO
₂ H, CO ₂ -lower alkyl, CN, CONH ₂ , CONH-lower alkyl, CON (lower alkyl) ₂ , CONH-cycloalkyl, CONH-
Lower alkylene-aryl, lower alkylene-CO ₂ H, lower alkylene-CO ₂ -lower alkyl, lower alkenylene-CO
₂ H, lower alkenylene-CO ₂ -lower alkyl, lower alkenylene-OH, lower alkylene-O-lower alkyl, lower alkylene-O-lower alkenyl, lower alkylene-O-lower alkynyl, lower alkylene-O-lower alkylene-aryl ,
Lower alkylene-S-lower alkylene-aryl, lower alkylene-NHCO-lower alkyl, lower alkylene-O-lower alkylene-CO ₂ -lower alkyl, lower alkylene-NH-lower alkylene-CO ₂ -lower alkyl, lower alkylene-NH -Lower alkylene-CO ₂ H, lower alkylene-N (lower alkyl)-
Lower alkylene-CO ₂ -lower alkyl, lower alkylene-N
(Lower alkyl) -lower alkylene-CO ₂ H, lower alkylene
-O-lower alkylene-CO ₂ H, lower alkylene-O-lower alkylene-CO-heterocycle, lower alkylene-O-lower alkylene-CONH ₂ , lower alkylene-O-lower alkylene-CONH-lower alkyl, lower alkylene- O-lower alkylene-CON (lower alkyl) ₂ , lower alkylene-aryl, lower alkylene-heterocycle, aryl, heterocycle, cycloalkyl and CO-heterocycle. Where aryl and heterocycle are
It may be substituted with 1 to 5 groups selected from lower alkyl, halogen, OH and O-lower alkyl. Among the G2 group, more preferably lower alkyl, lower alkylene-O
H, halogen, OH, O-lower alkyl, O-lower alkylene-
Aryl, CO ₂ H, CO ₂ -lower alkyl, CN, CONH ₂ , aryl, heterocycle and cycloalkyl, more preferably,
Lower alkyl, lower alkylene-OH, halogen, OH, CN
And a group selected from cycloalkyl.

A preferred compound in the present invention is a compound represented by the following formula (III).

[Chemical 9] The symbols in the above formula have the following meanings: R ¹ , R ² , a and b
As above. R ³ and R ⁴ : a group selected from the G2 group; or, R ³ and R ⁴ together form C _3-6 alkylene which may be substituted with 1 to 5 lower alkyl, or C (R ¹⁰ ) = C (R ¹¹ ) -C (R ¹² ) =
A group represented by C (R ¹³ )-, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ : the same or different from each other, H,
Lower alkyl or ^{phenyl, R 5, R 6, R} 7, R 8 and R ^9: a group selected from the G1 group. More preferably, R ¹ is absent, R ² is lower alkyl, halogen substituted lower alkyl or lower alkylene-O.
A compound in which H and a are double bonds and b is a single bond. Further, R ² is preferably C _1-3 alkyl, C _1-2 alkyl substituted with halogen or C _1-3 alkylene-OH, more preferably C _1-3 alkyl, particularly Preferred is methyl. R ³ is preferably halogen, CN or lower alkyl, more preferably halogen, CN or C _1-3 alkyl, and particularly preferably chloro, CN or methyl. R ⁴ is preferably C
_2-6 alkyl, more preferably C _3-5 alkyl, particularly preferably 2-propyl, 2-methyl-2-butyl or tert-butyl. As R ^{5 to} R ⁹ , 1) preferably, R ⁷ is H, and R ⁶ is a group other than H, and more preferably R ⁵ , R ⁷ , and R.
⁸ and R ⁹ are both H, more preferably R ⁶ is halogen or NO ₂ , or 2) preferably R ⁷ is H, and
R ⁵ and R ⁸ are groups other than H, more preferably R ⁶ , R ⁷ and R ⁹
Are both H, and more preferably, R ⁵ is CN, OH or NH ₂ ,
And R ⁸ is halogen or CN.

The compound (I) of the present invention may have geometrical isomers or tautomers (for example, keto-enol-like tautomerism) depending on the kind of the substituent. It also includes separated isomers or mixtures thereof. Further, the compound of the present invention may have an asymmetric carbon atom, and isomers based on the asymmetric carbon atom may exist.
The present invention includes a mixture of these optical isomers and an isolated one. The present invention also includes a compound obtained by labeling the compound of the present invention with a radioisotope.

The compound (I) of the present invention may form an acid addition salt or a salt with a base, and it is included in the present invention as long as such salt is a pharmaceutically acceptable salt.
Specifically, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,
Nitric acid, inorganic acids such as phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, Acid addition salts with organic acids such as aspartic acid and glutamic acid, sodium, potassium,
Inorganic bases such as magnesium, calcium, aluminum, methylamine, ethylamine, ethanolamine,
Examples thereof include salts with organic bases such as lysine and ornithine, ammonium salts and the like. Furthermore, the present invention also includes various hydrates and solvates of the compound (I) of the present invention and pharmaceutically acceptable salts thereof, and crystalline polymorphic substances. Also,
The compound (I) of the present invention also includes a pharmacologically acceptable prodrug. Pharmacologically acceptable prodrug means a prodrug of the present invention by solvolysis or under physiological conditions.
It is a compound having a group that can be converted into NH ₂ , OH, CO ₂ H and the like. As a group forming a prodrug, Prog. Med.,
5, 2157-2161 (1985) and "Development of Pharmaceuticals" (Hirokawa Shoten, 1
990) Volume 7 Molecular design 163-198 and the like.

(Production Method) The compound (I) of the present invention and a pharmaceutically acceptable salt thereof are produced by utilizing various known synthetic methods by utilizing the characteristics based on the basic skeleton or the kind of the substituent. It can be manufactured. At that time, depending on the kind of the functional group, it is effective in terms of manufacturing technology to protect the functional group with an appropriate protecting group at the stage of the raw material or the intermediate, or to replace it with a group which can be easily converted into the functional group. There is a case.
Examples of such a functional group include an amino group, a hydroxyl group, and a carboxyl group, and examples of protective groups thereof include Green (TW Greene) and Utz (PGM Wut).
s), “Protective Groups in Organic Synthesis (No.
3rd edition, 1999) ”,
These may be appropriately selected and used according to the reaction conditions.
In such a method, the desired compound can be obtained by introducing the protective group and carrying out the reaction, and then removing the protective group or converting it into a desired group as necessary. Further, the prodrug of the compound (I) of the present invention, like the above-mentioned protecting group, has a specific group introduced at the stage of starting material or intermediate,
Alternatively, it can be produced by carrying out a reaction using the obtained compound (I) of the present invention. The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation and dehydration. Hereinafter, a typical method for producing the compound (I) of the present invention will be described.

First production method (sulfonylation)

[Chemical 10] This production method comprises reacting an amino compound (IV) with a sulfonyl chloride compound (V) to give the compound of the present invention (I
a) is a method of obtaining. The reaction is benzene, toluene,
Aromatic hydrocarbons such as xylene, dichloromethane, 1,2-
Halogenated hydrocarbons such as dichloroethane and chloroform, diethyl ether, tetrahydrofuran (THF), ethers such as dioxane, N, N-dimethylformamide (D
(MF) in an inert solvent or without solvent, under cooling to heating,
Preferably, it is carried out at -20 ° C to 80 ° C. A base (preferably,
Reaction in the presence of (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.) may be advantageous for the smooth progress of the reaction.

Second production method (alkylation)

[Chemical 11] (In the formula, R represents a group corresponding to R ¹ or R ² , and L ¹ represents a leaving group. The same applies hereinafter.) In the present production method, the compound (Ib) of the present invention in which R ¹ is H is alkylated And a method for producing the compound (I) of the present invention. Here, examples of the leaving group L ¹ include halogen, methanesulfonyloxy, p-toluenesulfonyloxy and the like. The reaction is based on aromatic hydrocarbons, ethers,
DMF, dimethylsulfoxide (DMSO), in a solvent inert to the reaction such as dimethylacetamide (DMA) and N-methylpyrrolidone, sodium hydride, potassium hydroxide, potassium t-butoxy, in the presence of a base such as lithium diisopropylamide, It is carried out under cooling to heating, preferably at -20 ° C to 120 ° C. Two or more kinds of solvents may be mixed and used. This reaction may be advantageous in that the reaction proceeds smoothly in the presence of a phase transfer catalyst such as tetramethylammonium bromide or benzyltriethylammonium chloride.

Other Production Methods The compound (I) of the present invention having various substituents on the A ring and the B ring can be subjected to various reactions obvious to those skilled in the art to give the substituents other functional groups. It can be converted into a group. Typical production methods include, for example, the following production methods: 1) As the compound having an OH group (including lower alkylene-OH and the like, the same applies hereinafter), a compound having a methyl ether or benzyl ether group is used. `` Protective Groups in
It can be produced by appropriately selecting and using the deprotection method (for example, BBr ₃ ) described in “Organic Synthesis (3rd edition)”, or by subjecting it to a hydrolysis reaction using a compound having an ester group; 2 The compound having amide, ester, carbamate or urea can be produced by using a compound having an OH, amino or hydroxy group and reacting with various acylating agents. Examples of the acylating agent include mixed acid anhydrides, symmetrical acid anhydrides, acid halides, isocyanate compounds, thioisocyanate compounds and sulfonyl chloride compounds. The reaction can be carried out under substantially the same conditions as in the sulfonylation reaction; 3) Alkylating agents such as alkyl halides and nucleophiles (eg alcohols, amines, amides, imides, sulfonamides, nitrogen-containing heterocycles, thiols, etc.) Compounds having various alkyl groups can be produced by a nucleophilic substitution reaction with) or a reductive alkylation reaction of a carbonyl compound such as an aldehyde with an amine; 4) A compound having an amino group by a catalytic reduction reaction of a nitro group. 5) A compound having an OH group can be produced by a reduction reaction of an aldehyde group or an ester group.

As the raw material compound, a commercially available compound or a compound known in the literature can be used. The novel raw material compound can be easily produced by a known method, for example, the following method.

[Chemical 12] (In the formula, R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ and R ⁴⁵ represent H or lower alkyl and the like, and a group which becomes R ⁴³ as (R ⁴⁴ ) (R ⁴⁵ ) CH-,
(R ⁴¹ ) (R ⁴² ) (R ⁴³ ) C-represents a group which becomes R ⁴ . ) Aminothiazole compounds, particularly compounds (X) in which R ⁴¹ , R ⁴² and R ⁴³ are lower alkyl groups are described in Khim. Geterotsi
kl. Soedin. (1967), (1), 153-4, Khim. Geterotsikl.
Soedin. (1967), (1), 154-7 or Khim. Geterotsikl.
It can be produced by the method described in Soedin. (1969), (1), 56-8. In addition, various sulfonyl chloride compounds (V)
Is Journal Heterocyclic Chem., (1986), 23, 1253-1.
255, U.S. Pat.No. 5,081,275, or JP-A-63-10135.
It can be produced according to the method described in Japanese Patent Publication No. 9 or the like.

The reaction products obtained by the above-mentioned production methods are
It can be isolated and purified as various solvates such as free compounds, salts or hydrates thereof. The salt can be produced by subjecting it to an ordinary salt-forming treatment. Isolation, purification, extraction,
It can be carried out by applying ordinary chemical operations such as concentration, evaporation, crystallization, filtration, recrystallization and various chromatographies.
Various isomers can be isolated by a conventional method by utilizing the physicochemical difference between the isomers. For example, optical isomers can be separated by a general optical resolution method such as fractional crystallization or chromatography. The optical isomer can also be produced from a suitable optically active starting material compound.

[0026]

The compound of the present invention is useful as an active ingredient of a pharmaceutical preparation. In particular, since it has reverse transcriptase inhibitory activity, it is useful as an anti-HIV agent.

The pharmaceutical composition containing, as an active ingredient, one or more of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is a carrier for pharmaceuticals which is usually used in the art. It can be prepared by a commonly used method using a shaping agent and the like. Administration is oral administration by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intravenous and intramuscular, suppositories, eye drops, eye ointments, transdermal solutions, ointments, Transdermal patch, transmucosal fluid,
It may be in any form of parenteral administration such as transmucosal patch and inhalant. As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used.
In such solid compositions, the one or more active substances comprise at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. Acid mixed with magnesium aluminate etc. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrating agent such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with sugar coating or gastric or enteric coating agent.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and generally used inert solvents such as purified water, Contains ethanol. This composition contains auxiliary agents such as solubilizers, wetting agents and suspending agents, in addition to inert solvents.
It may contain a sweetening agent, a flavoring agent, an aromatic agent, and a preservative. Injections for parenteral administration include sterile aqueous or non-aqueous liquids, suspensions and emulsions. Examples of the aqueous solvent include distilled water for injection and physiological saline.
As the non-aqueous solvent, for example, propylene glycol,
Polyethylene glycol, vegetable oils such as olive oil,
Alcohols such as ethanol, polysorbate 80
(Product name) etc. Such a composition may further contain an isotonicity agent, a preservative, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent, and a solubilizing agent. These are sterilized by, for example, filtration through a bacteria-retaining filter, addition of a bactericide, or irradiation. In addition, these can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.

As the transmucosal agent, solid, liquid or semi-solid transmucosal agents are used, and they can be produced by a conventionally known method. For example, known pH adjusters, preservatives, thickeners and excipients are added as appropriate and molded into a solid, liquid or semi-solid form. For example, transnasal products are usually spray equipment, nasal containers,
It is administered using a tube, an intranasal insert, or the like. Normally, for oral administration, the daily dose is about 0.001 to 7 per body weight.
A suitable dose is 0 mg / kg, preferably 0.1 to 50 mg / kg, which may be administered once or in 2 to 4 divided doses. When administered intravenously, the daily dose is approximately 0.001 per body weight
10 mg / kg is appropriate, and it is administered once or in multiple divided doses daily. As a transmucosal agent, about 0.001 to 7 per body weight
Administer 0 mg / kg once a day or in multiple divided doses. The dose is appropriately determined according to each case, taking into consideration symptoms, age, sex, etc.

[0030]

The present invention will be described in more detail based on the following examples. The compound of the present invention is not limited to the compounds described in the examples below. A method for producing the raw material compound is shown in Reference Example. In addition, a compound with a number shown together with "S-" in the compound number (for example, S-1, S-100, etc.) indicates a raw material compound. Example 1-1 (Compound 2) 2-amino-5-t-butyl-4-methylthiazole hydrochloride (5.88
3-Nitrobenzenesulfonyl chloride (9.46 g) was added to the pyridine solution of g), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and the precipitated solid was collected by filtration and the obtained solid was purified by silica gel column chromatography (chloroform).
Further, it was crystallized from methanol to obtain 8.49 g of N- (5-t-butyl-4-methylthiazol-2-yl) -3-nitrobenzenesulfonamide (Compound 2). ¹ H-NMR (DMSO-d ₆ ) δ: 12.58 (1H, br-s), 8.46 (1H,
t), 8.42 (1H, ddd), 8.21 (1H, dd), 7.86 (1H, t), 2.
16 (3H, s), 1.30 (9H, s); FAB-MS: 356 [(M + H) ⁺ ] Example 1-2 (Compounds 1 and 653) 60% in a THF solution of Compound 2 (8.49 g). Sodium hydride (1.44
g) and methyl iodide (2.98 ml) were added under ice cooling, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform), N- (5-t-butyl-3,4-dimethyl-2,3-dihydrothiazole-2-ylidene) -3-nitrobenzenesulfonamide (Compound 1) and N- (5-t-butyl-4-methylthiazol-2-yl)
-N-methyl-3-nitrobenzenesulfonamide (Compound 65
3) got. Compound 1 was further recrystallized from methanol,
Compound 1 (6.56 g) was obtained. Compound 1: ¹ H-NMR (DMSO-d ₆ ) δ: 8.49 (1H, t), 8.42
(1H, dd), 8.26 (1H, d), 7.85 (1H, t), 3.43 (3H, s),
2.28 (3H, s), 1.32 (9H, s); FAB-MS: 370 [(M + H) ⁺ ] Compound 653: MS (AP): 370 [(M + H) ⁺ ] Examples 1-1 and Compounds shown in Tables 3 to 10 below were produced from the corresponding raw materials in the same manner as / or 1-2.

Example 2 (Compound 134) To a THF / ethanol solution of Compound 1 (1.00 g) was added 10% palladium carbon (0.1 g), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtration through Celite, the mixture was concentrated under reduced pressure, and the precipitated solid was washed with hot ethyl acetate and recrystallized from acetonitrile to give 3-amino-N- (5-t-butyl-3,4-dimethyl-2,3- 387 mg of dihydrothiazole-2-ylidene) benzenesulfonamide (Compound 134) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 7.11 (1H, t), 7.03 (1H, t),
6.90 (1H, d), 6.68 (1H, dd), 5.48 (2H, bs), 3.38 (3
H, s), 2.26 (3H, s), 1.31 (9H, s); FAB-MS: 340 [(M +
H) ⁺ ] In the same manner as in Example 2, the compounds shown in Tables 11 and 12 below were produced. Example 3 (Compound 16) A mixture of compound 6 (0.60 g), ethanol and 1 M aqueous sodium hydroxide solution (1.56 ml) was stirred at 70 ° C for 1 hour. After cooling to room temperature, ethyl acetate was added, the precipitated solid was collected by filtration, and sodium 3,4-dimethyl-2-[(3-nitrobenzenesulfonyl) imino] -2,3-dihydrothiazole-5-carboxylate ( Compound 16) 380 mg was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 8.49 (1H, t), 8.41 (1H, dd),
8.25 (1H, d), 7.84 (1H, t), 3.39 (3H, s); FAB-MS: 3
56 [(MH) ⁻ ] In the same manner as in Example 3, the compounds shown in Table 13 below were produced.

Example 4 (Compound 232) To a DMSO solution of compound 230 (300 mg) was added a 1 M aqueous sodium hydroxide solution (2.0 ml), and the mixture was cooled with ice to give a 30% hydrogen peroxide solution (2.0 m).
l) was added. The mixture was stirred at 100 ° C for 5 hours, allowed to cool, and then poured into ice water. The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitated solid was washed with ethyl acetate to give 3-{[(5-t-
Butyl-3,4-dimethyl-2,3-dihydrothiazole-2-ylidene) amino] sulfonyl} -4-hydroxybenzamide
(Compound 232) 136 mg was obtained. FAB-MS: 384 [(M + H) ⁺ ] In the same manner as in Example 4, the compounds shown in Table 14 below were produced. Example 5 (Compound 17) Compound 16 (100 mg) in DMF was added with WSC hydrochloride (56 mg) and HO.
Bt (39 mg) and piperidine (28.8 μl) were added, and the mixture was stirred at room temperature for 24 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the precipitated solid was collected by filtration and washed with a mixed solvent of isopropanol / ethanol to give N- [3,4-dimethyl-5-
(Piperidine-1-carbonyl) -2,3-dihydrothiazole-2
-Ylidene] -3-nitrobenzenesulfonamide (Compound 1
7) 70 mg was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 8.50 (1H, br s), 8.45 (1H, br
d), 8.28 (1H, br d), 7.87 (1H, t), 3.49-3.40 (4H,
m), 3.43 (3H, s), 2.20 (3H, s), 1.65-1.45 (6H,
m); FAB-MS: 425 [(M + H) ⁺ ] In the same manner as in Example 5, compounds shown in Table 15 below were produced.

Example 6 (Compound 34) Sodium borohydride (0.19 g) was added to a methanol solution of compound 5 (1.78 g) under ice cooling. After stirring at room temperature for 2 hours, sodium borohydride (0.38 g) was added and added there.
THF was added to make a clear solution, and the mixture was stirred at room temperature for 2.5 hours. Sodium borohydride (0.38 g) was added and the mixture was stirred at room temperature for 1 hour, and sodium borohydride (0.19 g) was added,
Stir for 12 hours at room temperature. After adding water-containing acetone, the mixture was concentrated under reduced pressure. Ethyl acetate was added, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol), and the obtained solid was washed with hot isopropanol to give N- [5- (1-hydroxyethyl) -3,4-dimethyl-2, 3-dihydrothiazole-2-
Ylidene] -3-nitrobenzenesulfonamide (Compound 34)
743 mg was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 8.49 (1H, t), 8.42 (1H, m),
8.26 (1H, m), 7.85 (1H, t), 5.66 (1H, d), 4.95 (1H,
dq), 3.42 (3H, s), 2.16 (3H, s), 1.28 (3H, d); FAB
-MS: 358 [(M + H) ⁺ ] In the same manner as in Example 6, the compound shown in Table 16 and the compound 126 shown in Table 17 were produced. Example 7 (Compound 98) To a THF solution of compound 97 (200 mg), isobutyl chloroformate (0.075 ml) and triethylamine (0.10 ml) were added at -10 ° C, and the mixture was stirred for 10 minutes. Sodium borohydride there
(183 mg) and ethanol mixture were added all at once. The mixture was stirred as it was at room temperature, 5% aqueous potassium hydrogen sulfate solution, 1 M aqueous hydrochloric acid solution and ethyl acetate were added, and the mixture was stirred at room temperature for 30 minutes. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / chloroform), and N- [5-t-butyl-3-
40 mg of (2-hydroxyethyl) -4-methyl-2,3-dihydrothiazole-2-ylidene] -3-nitrobenzenesulfonamide (Compound 98) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 8.48 (1H, t), 8.41 (1H, dd),
8.24 (1H, d), 7.84 (1H, t), 4.96 (1H, bs), 3.96 (2H,
t), 3.56 (2H, t), 2.32 (3H, s), 1.32 (9H, s); FAB
-MS: 400 [(M + H) ⁺ ]

Example 8 (Compound 263) To a solution of Compound 256 (500 mg) in dichloromethane was added 1-78 ° C.
M diisobutylaluminum hydride-dichloromethane solution (DIBAL: 1.8 ml) was added dropwise, and the mixture was stirred for 1 hour. Further, 1 M DIBAL (1.2 ml) was added dropwise, and the mixture was stirred for 1 hour. A saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was stirred at room temperature. Extracted with chloroform, the organic layer was washed with 1M aqueous hydrochloric acid solution and saturated brine, dried over anhydrous sodium sulfate,
It was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol), and crystallized from isopropanol to give N- (5-t-butyl-3,
28 mg of 4-dimethylthiazole-2 (3H) -ylidene) -5-chloro-2-formylbenzenesulfonamide (Compound 263) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 10.78 (1H, S), 7.94 (1H, d),
7.92 (1H, d), 7.84 (1H, dd), 3.41 (3H, s), 2.74
(3H, s), 1.31 (9H, s); FAB-MS: 387 [(M + H) ⁺ ] Compound S-11 shown in Table 17 below was produced in the same manner as in Example 8. Example 9 (Compound 35) Using Compound 34 (351 mg) in the same manner as in Example 1-2,
124 mg of N- [3,4-dimethyl-5- (1-methoxyethyl) -2,3-dihydrothiazole-2-ylidene] -3-nitrobenzenesulfonamide (Compound 35) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 8.50 (1H, t), 8.42 (1H, dd),
8.27 (1H, d), 7.86 (1H, t), 4.65 (1H, t), 3.43 (3H,
S), 3.15 (3H, S) 2.22 (3H, s), 1.31 (6H, d); FAB-M
S: 372 [(M + H) ⁺ ] In the same manner as in Example 9, the compounds shown in Tables 18 to 21 below and the compounds 9 and 10 shown in Table 22 were produced.

Example 10 (Compound 53) One third of Compound S-4 prepared from Compound S-3 (1.04 g)
Volume, room temperature, THF, piperidine (0.18 ml), acetic acid
(0.52 ml), sodium triacetoxyborohydride (5
75 mg) was added and the mixture was stirred for 2 days. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform / methanol / ammonia water).
After purification with, add 4 M hydrogen chloride-ethyl acetate solution and concentrate under reduced pressure.The residue is solidified with acetonitrile and N- [3,4
-Dimethyl-5- (1-methyl-2-piperidin-1-ylethyl)-
34 mg of 2,3-dihydrothiazole-2-ylidene] -3-nitrobenzenesulfonamide hydrochloride (Compound 53) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 9.48 (1H, bs), 8.51 (1H, t),
8.43 (1H, dd), 8.27 (1H, d), 3.75 (1H, q), 3.16-
3.44 (3H, m), 3.43 (3H, S), 2.79-2.96 (2H, m) 2.23
(3H, s), 1.61-1.82 (5H, m), 1.32-1.43 (1H, m), 1.2
3 (3H, d); FAB-MS: 439 [(M + H) ⁺ ] In the same manner as in Example 10, Compound 54 shown in Table 22 and Compound S-61 shown in Table 23 were produced. Example 11 (Compound 147) Compound 129 (234 mg), pyridine (5 ml) and acetic anhydride (0.5
The mixture (3 ml) was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate was added, washed successively with saturated aqueous sodium hydrogen carbonate solution, 1 M aqueous hydrochloric acid solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.The obtained residue was solidified with ethyl acetate,
(2-{[(5-t-butyl-3,4-dimethyl-2,3-dihydrothiazol-2-ylidene) amino] sulfonyl} -4-chlorophenoxy) ethyl acetate (Compound 147) 170 mg was obtained. . ¹ H-NMR (DMSO-d ₆ ) δ: 7.77 (1H, d), 7.59 (1H, d
d), 7.23 (1H, d), 4.23 (2H, t), 4.11 (2H, t), 3.38
(3H, S), 2.29 (3H, s), 1.97 (3H, s), 1.33 (9H,
s); FAB-MS: 461 [(M + H) ⁺ ] In the same manner as in Example 11, the compounds shown in Tables 24 to 28 below were produced.

Example 12 (Compound 172) Boron tribromide (1.0 ml) was added to a dichloromethane solution of the compound 170 (200 mg) at -78 ° C, the temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for 4 hours. . After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (methanol / chloroform) and then solidified with ether-hexane to give N- (5-t-butyl-3,4-dimethyl-2,3-dihydrothiazole-2-ylidene. ) -2-Hydroxybenzenesulfonamide (Compound 172) was obtained (167 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 10.12 (1H, s), 7.70 (1H, dd),
7.36 (1H, dt), 6.85-6.92 (2H, m), 3.38 (3H, s),
3.15 (3H, s), 2.27 (3H, s), 1.32 (9H, s); FAB-MS:
341 [(M + H) ⁺ ] In the same manner as in Example 12, the compounds shown in Tables 29 to 31 below were produced. Example 13 (Compound 256) To a solution of the compound 132 (1.0 g) in dichloromethane was added trifluoromethanesulfonic anhydride (0.67 ml), and 2,6-lutidine (0.62 ml) was added dropwise under ice cooling. After gradually warming to room temperature, the mixture was stirred at room temperature for 3 hours. Water and 5 in the reaction mixture
% Potassium hydrogen sulfate aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give a trifluoromethanesulfonic acid ester compound (1.4
4 g) was obtained. A mixture of the obtained compound (1.1 g), DMF (10 ml), methanol (10 ml), palladium acetate (49 mg), 1,3-bis (diphenylphosphino) propane (89 mg) and triethylamine (0.61 ml). After bubbling carbon monoxide for 10 minutes at room temperature, the mixture was stirred at 70 ° C. for 2 hours in a carbon monoxide atmosphere. After allowing to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / toluene) to give 2-{[(5-t-
Butyl-3,4-dimethylthiazole-2 (3H) -ylidene) amino] sulfonyl} -4-methyl chlorobenzoate (Compound 256) 66
0 mg was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 7.91 (1H, d), 7.75 (1H, dd),
7.61 (1H, d), 3.78 (3H, s), 3.43 (3H, s), 2.30 (3
H, s), 1.32 (9H, s); FAB-MS: 417 [(M + H) ⁺ ] Compound 413 shown in Table 32 below in the same manner as in Example 13.
Was manufactured.

Example 14 (Compound 435) A DMA solution of the corresponding trifluoromethanesulfonate ester compound (130 mg) prepared in the same manner as in Example 13 was added,
Under argon atmosphere, tris (dibenzylideneacetone) dipalladium (0) (4.1 mg), 1,1'-bis (diphenylphosphino) ferrocene (27.3 mg), zinc (2.0 mg) and zinc cyanide (17.3 mg) Was added and the mixture was stirred at 110 ° C. for 1.5 hours. After allowing to cool to room temperature, the reaction solution was poured into a 2 M aqueous ammonia solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / toluene), and the obtained solid was washed with ether. Thus, 50 mg of N- (5-sec-butyl-4-chloro-3-methylthiazole-2 (3H) -ylidene) -5-chloro-2-cyanobenzenesulfonamide (Compound 435) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 8.12 (1H, d), 8.05 (1H, d),
7.92 (1H, dd), 3.53 (3H, s), 2.96 (1H, tq), 1.6
6-1.56 (1H, m), 1.52-1.42 (1H, m), 1.18 (3H, d),
0.83 (3H, t); FAB-MS: 404 [(M + H) ⁺ ] Compound 43 shown in Table 32 below in the same manner as in Example 14.
6-438, 440 and 442-445 were produced. Example 15 (Compound 322) A mixture of compound 132 (600 mg), THF, 2-hydroxymethylpyridine (0.23 ml) and triphenylphosphine (629 mg) was added to a mixture of diethylazodicarboxylate (0.3
8 ml) was added, and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol / chloroform) and crystallized from acetonitrile to give N- (5-t-butyl-3,4-dimethylthiazole-2 ( 3H) -Ylidene) -5-chloro-2- (pyridin-2-ylmethoxy) benzenesulfonamide (compound 32
2) Obtained 280 mg. ¹ H-NMR (DMSO-d ₆ ) δ: 8.53 (1H, d), 7.82 (1H, dt),
7.79 (1H, d), 7.59 (1H, dd), 7.54 (1H, d), 7.30-7.3
5 (1H, m), 7.29 (1H, d), 5.26 (2H, s), 3.32 (3H, s), 2.
21 (3H, s), 1.26 (9H, s); FAB-MS: 466 [(M + H) ⁺ ] In the same manner as in Example 15, the compounds shown in Tables 33 and 34 below were produced.

Example 16 (Compound 43) To a DMF solution of compound 5 (1.0 g), potassium carbonate (1.16 g) and trimethylphosphonoacetate (666 mg) were added,
The mixture was stirred at ° C for 12 hours. After allowing to cool to room temperature, concentrate under reduced pressure,
Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate, and then the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / toluene) to give methyl 3- {3,4-dimethyl-2-[(3-nitrobenzenesulfonyl) imino] -2,3-dihydrothiazole-5. -Il} -2-
101 mg of butenoate (Compound 43) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 8.50 (1H, t), 8.44 (1H, d),
8.29 (1H, d), 7.59 (1H, d), 7.86 (1H, t), 5.92 (1H,
d), 3.67 (3H, s), 3.48 (3H, s), 2.40 (3H, d), 2.31 (3
H, s); FAB-MS: 412 [(M + H) ⁺ ] In the same manner as in Example 16, Compound S-3 shown in Table 36 below.
Was manufactured. Example 17 (Compound 55) Using the compound S-5 (200 mg), an intermediate methanesulfonate ester compound produced in the same manner as in Example 11 was treated with acetonitrile and 1,8-diazabicyclo [5.4.0] undec-. 7-en
(0.16 ml) was added and the mixture was stirred for 2 hours. 1,8-diazabicyclo
[5.4.0] Undec-7-ene (3.0 ml) was further added, and the mixture was stirred for 12 hours. The reaction mixture was allowed to cool to room temperature, 5% aqueous potassium hydrogen sulfate solution was added, the mixture was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate / toluene).
The solid obtained by purification with N was washed with diethyl ether to give N- (3,4-dimethyl-5-isopropenyl-2,3-dihydrothiazol-2-ylidene) -3-nitrobenzenesulfonamide (Compound 55 ) 32 mg was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 8.49 (1H, t), 8.43 (1H, dd),
8.28 (1H, d), 7.85 (1H, t), 5.30 (1H, s), 5.12 (1H,
s), 3.46 (3H, s), 2.27 (3H, s), 2.02 (3H, s); FAB-
MS: 354 [(M + H) ⁺ ] In the same manner as in Example 17, Compound 38 shown in Table 35 below and Compound 477 shown in Table 36 were produced.

Example 18 (Compound 59) Compound 58 (172 mg) in 40% methylamine-methanol solution
(20 ml) was added, and the mixture was stirred at room temperature for 4 hours. Concentrated under reduced pressure,
Chloroform was added and washed with water. After drying over anhydrous magnesium sulfate, concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (ammonia water / methanol / chloroform), 4 M hydrogen chloride-dioxane solution in methanol was added, and the mixture was concentrated under reduced pressure. . The obtained solid was washed with ethanol, and N- (4-aminomethyl-5-
t-Butyl-3-methyl-2,3-dihydrothiazole-2-ylidene) -3-nitrobenzenesulfonamide monohydrochloride (compound
59) 42 mg was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 8.50 (3H, m), 8.44 (1H, dd),
8.29 (1H, d), 7.87 (1H, t), 4.17 (2H, s), 3.50 (3H,
s), 1.38 (9H, s); FAB-MS: 385 [(M + H) ⁺ ] In the same manner as in Example 18, Compound 269 shown in Table 35 below.
Was manufactured. Example 19 (Compound 191) Thionyl chloride (1 ml) and DMF (3 drops) were added to compound S-14, and the mixture was stirred at 70 ° C for 1 hr. Thionyl chloride was distilled off under reduced pressure, chloroform was added, and the mixture was added dropwise to a mixture of chloroform / saturated aqueous ammonia (1: 1, 20 ml) at 0 ° C. The solvent was evaporated under reduced pressure, extracted with ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, concentration under reduced pressure, the resulting solid was washed with ethyl acetate-hexane to give 5-isopropyl-3-methyl-2- (3-nitrobenzenesulfonylimino) -2,3-dihydrothiazole. 547 mg of 4-carboxamide (Compound 191) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 8.50 (1H, m), 8.44 (1H, d),
8.28 (1H, d), 8.19 (1H, s), 8.15 (1H, s), 7.87 (1H,
t), 3.41 (3H, s), 3.31 (1H, m), 1.20 (6H, d); FAB
-MS: 385 [(M + H) ⁺ ] Compound S-12 shown in Table 37 below was prepared in the same manner as in Example 19.
Was manufactured.

Example 20 (Compound 187) To a solution of compound S-13 (0.217 g) in trifluoroacetic acid (2 ml) was added trifluoromethanesulfonic acid (0.1 ml) under ice cooling, and the mixture was stirred for 4 hours. Chloroform was added, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (methanol / chloroform) and crystallized from methanol to give N- (5
50 mg of -t-butyl-3,4-dimethyl-2,3-dihydrothiazol-2-ylidene) -5-chloro-2-sulfanylbenzenesulfonamide (Compound 187) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 7.97 (1H, s), 7.45 (2H, d),
6.22 (1H, bs), 3.43 (3H, s), 2.29 (3H, s), 1.32 (9
FAB-MS: 390 [(M + H) ⁺ ] Example 21 (Compound 192) A solution of Compound 191 (268 mg) in 1,2-dichloroethane under ice cooling under phosphorus oxychloride (0.33 ml). And DMF (2 ml) were sequentially added dropwise, and the mixture was stirred at 70 ° C for 1 hr. The reaction solution was poured into ice water, extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, the obtained solid was washed with ethyl acetate-hexane, and N- (4-cyano-5-isopropyl-3-methyl-3H-thiazol-2-ylidene)- 180 mg of 3-nitrobenzenesulfonamide (Compound 192) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 8.76 (1H, t), 8.40 (1H, ddd),
8.27 (1H, d), 7.70 (1H, t), 3.59 (3H, s), 3.38 (1H,
heptet), 1.37 (6H, d); FAB-MS: 367 [(M + H) ⁺ ] Compound 28 shown in Table 35 below in the same manner as in Example 21.
5, 408 and 416, and compounds 422 and 424 shown in Table 36
Was manufactured.

Example 22 (Compound 202) Compound 194 (150 mg), acetic acid, water and potassium cyanide (6
The mixture of 5 mg) was stirred at 80 ° C. for 1 hour. Potassium cyanide (65 mg) was added, and the mixture was stirred at 80 ° C for 4 hr, potassium cyanide (260 mg) was further added, and the mixture was stirred at 80 ° C for 2 hr. Water was added to the reaction mixture and the precipitated solid was collected by filtration and recrystallized from acetonitrile to give N- (5-t-butyl-3,4-dimethyl-2,3
56 mg of -dihydrothiazole-2-ylidene) -5-chloro-2-ureidobenzenesulfonamide (Compound 202) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 8.15 (1H, s), 8.14 (1H, d), 7.7
2 (1H, d), 7.52 (1H, dd), 3.44 (3H, s), 2.27 (1H,
s), 1.31 (9H, s); FAB-MS: 417 [(M + H) ⁺ ] Example 23 (Compound 206) Compound 195 (0.20 g), methanol (2 ml) and concentrated hydrochloric acid (2 m
The mixture of l) was stirred under reflux for 11 hours. Then acetic acid (4
ml) was added and the mixture was stirred for 22 hours under reflux. After allowing to cool, a saturated aqueous sodium hydrogen carbonate solution was added to neutralize, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the obtained residue was crystallized from methanol, and N- (5
74 mg of -t-butyl-3,4-dimethyl-2,3-dihydrothiazol-2-ylidene) -2-hydroxy-5-nitrobenzenesulfonamide (Compound 206) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 12.09 (1H, bs), 8.54 (1H, d),
8.26 (1H, dd), 7.06 (1H, d), 3.40 (3H, s), 2.29
(1H, s), 1.33 (9H, s); FAB-MS: 386 [(M + H) ⁺ ].

Example 24 (Compound 207) To compound S-16 (300 mg) were added trifluoroacetic acid, methanesulfonic acid and pentamethylbenzene (445 mg) at room temperature.
It was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / toluene) to give N-
(5-t-butyl-3,4-dimethyl-2,3-dihydrothiazole-2-
Ylidene) -4,5-dichloro-2-hydroxybenzenesulfonamide (Compound 207) (164 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 11.55 (1H, s), 7.91 (1H, s),
7.09 (1H, s), 3.42 (3H, s), 2.28 (1H, s), 1.31 (9
H, s); FAB-MS: 409 [(M + H) ⁺ ] Example 25 (Compound 389) Trifluoroacetic acid was added to Compound 388 (307 mg) at room temperature 15
Stir for minutes. After concentration under reduced pressure, ether was added, and the precipitated solid was recrystallized from isopropanol to give 3-bromo-N-
(5-t-butyl-3,4-dimethylthiazole-2 (3H) -ylidene)
198 mg of -6-fluoro-2-hydroxybenzenesulfonamide (Compound 389) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 10.73 (1H, s), 7.82 (1H, dd),
6.86 (1H, t), 3.46 (3H, s), 2.32 (1H, s), 1.34 (9
H, s); FAB-MS: 437, 439 [(M + H) ⁺ ] In the same manner as in Example 25, compound 390 shown in Table 35 below.
Was manufactured.

Example 26 (Compound 277) To a chloroform solution of the compound 34 (3.62 g), triethylamine (1.94 ml) and methanesulfonyl chloride (1.08 ml) were sequentially added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Furthermore, triethylamine (1.94 ml) and methanesulfonyl chloride (1.08 ml) were added, and the mixture was stirred at room temperature for 30 minutes. After adding water to the reaction mixture and extracting with chloroform, the organic layer was diluted to 1 M.
The extract was washed successively with aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methanesulfonic acid ester S-37 (5.16 g). The obtained compound was added to DMF and sodium azide (3.03
g) was added and the mixture was stirred at room temperature for 1 hour. After filtering the reaction mixture, a toluene-ethyl acetate (1: 1) mixed solution was added, and the mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / toluene) and crystallized from isopropanol to give 2-azidomethyl-N- (5-t-butyl-3,4-dimethylthiazole-2 (3H). -Ylidene) -5-chlorobenzenesulfonamide (Compound 227) 2.7
I got 9 g. ¹ H-NMR (DMSO-d ₆ ) δ: 7.90 (1H, d), 7.73 (1H, dd),
7.65 (1H, d), 4.93 (2H, s), 3.45 (3H, s), 2.28 (1H,
s), 1.30 (9H, s); FAB-MS: 414 [(M + H) ⁺ ] Example 27 (Compound 271) Compound S-37 (1.08 g) was added to DMF and potassium cyanide (0.33).
g) was added, and the mixture was stirred at 70 ° C for 50 minutes. Toluene-ethyl acetate (1: 1) mixture was added to the reaction mixture, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / toluene) and crystallized from isopropanol to give N- (5-t-butyl-3,4-dimethylthiazole-2 (3H) -ylidene)-. 176 mg of 5-chloro-2-cyanomethylbenzenesulfonamide (Compound 227) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 7.92 (1H, d), 7.75 (1H, dd),
7.67 (1H, d), 4.41 (2H, s), 3.45 (3H, s), 2.27 (1H,
s), 1.31 (9H, s); FAB-MS: 398 [(M + H) ⁺ ].

Example 28 (Compound 283) A mixture of compound 263 (500 mg), ethanol, hydroxylamine hydrochloride (99 mg) and pyridine (0.11 ml) was heated under reflux for 30 minutes. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, washed successively with a 1 M aqueous hydrochloric acid solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was washed with hot toluene-ethyl acetate mixed solution, and N- (5-t-butyl-3,4-dimethylthiazole-2 (3H) -ylidene) -5-chloro-2- (hydroxyimino) 395 mg of methyl) benzenesulfonamide (Compound 283) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 11.72 (1H, s), 8.84 (1H, s),
7.93 (1H, d), 7.88 (1H, d), 7.66 (1H, dd), 3.40 (3
H, s), 2.27 (1H, s), 1.30 (9H, s); FAB-MS: 402 [(M
+ H) ⁺ ] In the same manner as in Example 28, compounds 310 shown in Table 35 below were used.
And 343 were produced. Example 29 (Compound 294) Acetic acid (1 ml) was added to a methanol solution of compound 293 (1.06 g), and the mixture was stirred under reflux with heating for 7 hours. After allowing to cool, chloroform and methanol were added, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methanol /
After purification with chloroform), crystallize from ethanol-diethyl ether to give N- (5-t-butyl-3,4-dimethylthiazole-2 (3H) -ylidene) -5-chloro-2- (1H-imidazole.
-4-ylmethoxy) benzenesulfonamide (Compound 294) 4
41 mg was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 7.73 (1H, d), 7.52-7.61 (2H,
m), 7.45 (1H, d), 7.03 (1H, bs), 7.66 (1H, dd), 5.0
0 (2H, s), 3.28 (3H, s), 2.26 (1H, s), 1.32 (9H,
s); FAB-MS: 455 [(M + H) ⁺ ] Compound 354 shown in Table 35 below was prepared in the same manner as in Example 29.
And 359 were produced.

Example 30 (Compound 308) Compound 307 (0.59 g), ethanol, 28% sodium methoxide-methanol solution (0.28 ml) and diethyl carbonate (0.18 g).
(7 ml) was added, and the mixture was stirred for 2.5 hours while heating under reflux. Diethyl carbonate
(0.68 ml) was added and after stirring under reflux for 2.5 hours, 28%
Add sodium methoxide-methanol solution (0.28 ml)
The mixture was stirred under reflux for 1 hour. After allowing to cool, 1 M hydrochloric acid aqueous solution was added, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was crystallized from acetonitrile, N- (5-t-butyl-3,4-dimethylthiazole-2 (3H)
-Ylidene-5-chloro-2- (2,4-dioxooxazolidine-
326 mg of 5-yl) benzenesulfonamide (Compound 308) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 12.22 (1H, bs), 7.96 (1H, d),
7.74 (1H, dd), 7.54 (1H, d), 6.93 (1H, s), 3.45 (3
H, s), 2.28 (1H, s), 1.31 (9H, s); FAB-MS: 458 [(M
+ H) ⁺ ] Example 31 (Compound 341) Diphenylphosphino azide was added to a toluene / t-butanol (1: 1) solution of compound 257 (3.46 g) under an argon atmosphere.
(2.76 ml) and triethylamine (1.78 ml) were added under ice cooling, and the mixture was stirred for 10 minutes. After that, the temperature was raised to 90-C and the mixture was stirred for 1 hour. The reaction mixture was poured into water and then extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous potassium hydrogen sulfate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / toluene) and crystallized from hexane-ethyl acetate to give t-butyl (2-{[(5-t-butyl-3,4-dimethylthiazole-2 (3H ) -Ylidene) Amino]
Sulfonyl} -4-chlorophenyl) carbamate (Compound 34
1) Obtained 2.37 g. ¹ H-NMR (DMSO-d ₆ ) δ: 8.65 (1H, s), 8.15 (1H, d),
7.76 (1H, d), 6.62 (1H, dd), 3.45 (3H, s), 2.29 (3
H, s), 1.48 (9H, s), 1.31 (9H, s); FAB-MS: 446 [(M +
H) ⁺ ] In the same manner as in Example 31, the compound 349 shown in Table 35 below.
And 350 were produced.

Example 32 (Compound 347) Toluene and tributyltin azide (1.32 ml) were added to compound 285 (370 mg), and the mixture was stirred under heating reflux for 6 hours. After cooling down,
Add 1 M hydrochloric acid aqueous solution (20 ml) and methanol, and then at room temperature 4
It was stirred for 8 hours. After concentrating under reduced pressure, add chloroform and
The extract was washed with an aqueous solution of M hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / toluene) and crystallized from diethyl ether to give N- (5-t-butyl-3,4-dimethylthiazole-2 (3H) -ylidene). -5-chloro
-2- (1H-tetrazol-5-yl) benzenesulfonamide
(Compound 347) 166 mg was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 16.50 (1H, bs), 8.09 (1H, d),
7.84 (1H, dd), 7.63 (1H, d), 3.22 (3H, s), 2.26
(3H, s), 1.30 (9H, s); FAB-MS: 427 [(M + H) ⁺ ] In the same manner as in Example 32, compound 342 shown in Table 35 below.
Was manufactured. Example 33 (Compound 306) Ethanol, benzene and bromoacetone (0.133 ml) and triethylamine (0.108 ml) were added to Compound S-56 (0.29 g), and the mixture was stirred under reflux with heating for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from diethyl ether to give N- (5-t-butyl-3,4-dimethylthiazole-2 (3H) -ylidene). There was obtained 144 mg of -5-chloro-2-[(4-methylthiazol-2-yl) methoxy] benzenesulfonamide (Compound 306). ¹ H-NMR (DMSO-d ₆ ) δ: 7.78 (1H, d), 7.61 (1H, dd),
7.33 (1H, d), 7.27 (1H, s), 5.43 (2H, s), 3.33 (3
H, s), 2.34 (3H, s), 2.25 (3H, s), 1.32 (9H, s); FA
B-MS: 486 [(M + H) ⁺ ] In the same manner as in Example 33, compounds 344 shown in Table 35 below were used.
Was manufactured.

Example 34 (Compound 345) Ethyl orthoformate (13 ml) and boron trifluoride-diethyl ether (5 drops) were added to compound 343 (1.24 g), and the mixture was stirred under reflux with heating for 2 hours. After concentration under reduced pressure, chloroform was added, and the mixture was washed successively with 1 M aqueous hydrochloric acid solution and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / toluene), and crystallized from isopropanol to give 5-bromo-N- (5-t-butyl-
800 mg of 3,4-dimethylthiazol-2 (3H) -ylidene) -2- (1,2,4-oxadiazol-3-ylmethoxy) benzenesulfonamide (Compound 345) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 9.63 (1H, s), 7.90 (1H, d),
7.74 (1H, dd), 7.32 (1H, d), 5.35 (2H, s), 3.30 (3
H, s), 2.24 (3H, s), 1.30 (9H, s); FAB-MS: 501, 50
3 [(M + H) ⁺ ] Example 35 (Compound 361) Acetonitrile and methyl iodide (0.15 ml) were added to Compound S-62 (600 mg), and the mixture was stirred under reflux with heating for 1.5 hours. Methyl iodide (1.5 ml) was further added, and the mixture was stirred under reflux with heating for 1 hour. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure, methanol was added to the obtained residue, and the mixture was stirred under reflux with heating for 5 hours. After allowing to cool, the mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / chloroform), 4 M hydrogen chloride-ethyl acetate solution was added to the obtained compound, and the mixture was concentrated under reduced pressure. The obtained solid was mixed with diethyl ether-ethanol. Crystallized with liquid, 5-bromo-N- (5-t-butyl-3,4-dimethylthiazol-2 (3H) -ylidene) -2-[(1-methyl-1H-imidazol-5-yl ) Methoxy] benzenesulfonamide monohydrochloride dihydrate (compound
361) 105 mg were obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 9.09 (1H, s), 7.90 (1H, d),
7.77-7.81 (2H, m), 7.38 (1H, d), 5.35 (2H, s), 3.92
(3H, s), 3.30 (3H, s), 2.24 (3H, s), 1.29 (9H,
s) ； FAB-MS: 513, 515 [(M + H) ⁺ ].

Example 36 (Compound 371) Compound 370 (8.13 g), ethanol, water, ammonium chloride
A mixture of aluminum (0.47 g) and iron (9.78 g) under reflux for 2 hours.
It was stirred under. After cooling to room temperature, filter through Celite to reduce the filtrate.
It was concentrated under pressure. Chloroform was added to the obtained residue and saturated.
After washing with brine, drying over anhydrous sodium sulfate, and reducing pressure
Concentrated. The solid obtained is washed with acetonitrile,
3-amino-5-bromo-N- (5-t-butyl-4-methylthiazole
-2-yl) -2-methoxybenzenesulfonamide (Compound 37
1) Obtained 5.45 g.¹ H-NMR (DMSO-d₆) δ: 12.24 (1H, bs), 7.02 (1H, d),
 6.99 (1H, d), 5.57 (2H, s), 3.68 (3H, s), 2.16 (3
H, s), 1.30 (9H, s); FAB-MS: 434, 436 [(M + H) ⁺] Compound S-39 shown in Table 37 below was prepared in the same manner as in Example 36.
Was manufactured. Example 37 (Compound 449) Compound 416 (755 mg) and acetonitrile-water (1: 1) mixture
, Ammonium persulfate (883 mg) and sodium chloride
(452 mg) was added, and iron (II) sulfate pentahydrate (2
68 mg) aqueous solution was added dropwise over 30 minutes. Stir for 5 hours
After that, let cool to room temperature, add ethyl acetate, and wash with water.
It was After drying over anhydrous magnesium sulfate, concentrate under reduced pressure to obtain
The resulting residue is subjected to silica gel column chromatography (vinegar
Ethylate / toluene) and the resulting solid
Washed with ether and washed with 5-chloro-N- [4-chloro-5- (1-hi
Droxy-1-methylethyl) -3-methylthiazole-2 (3H)-
Ylidene] -2-cyanobenzenesulfonamide (Compound 44
9) Obtained 295 mg.¹ H-NMR (CDCl₃) δ: 8.15 (1H, d, J = 1.5Hz), 7.76 (1H,
 d, J = 6.3), 7.60 (H, dd, J = 1.5,, 6.3), 3.60 (3H, s),
 3.53 (1H, s), 1.66 (6H, s); FAB-MS: 406 [(M + H)⁺]

Example 38 (Compound 491) Dichloromethane was added to a 2 M dimethylzinc-toluene solution (2.5 ml), titanium (IV) tetrachloride (0.55 ml) was added under ice-cooling, and the mixture was stirred for 10 minutes to give compound 449 ( A dichloromethane solution of 100 mg) was added, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / chloroform), and the solid was washed with diethyl ether to give N- (5-t-butyl-4-chloro).
-3-Methylthiazole-2 (3H) -ylidene) -5-chloro-2-cyanobenzenesulfonamide (Compound 491) 56 mg was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 8.12 (1H, d), 8.04 (1H, d),
7.91 (1H, dd), 3.53 (3H, s), 1.37 (9H, s); FAB-MS:
404 [(M + H) ⁺ ] Example 39 (Compound 492) 2-Amino-5-t-butyl-4-methylthiazole hydrochloride (21 m
3-Cyanobenzenesulfonyl chloride (40 mg) was added to the pyridine solution of g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with chloroform. 1 M organic layer
It was washed successively with aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the aqueous layer was separated using anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give N- (5-t-butyl-4-methyl). 33 mg of thiazol-2-yl) -3-cyanobenzenesulfonamide (Compound 492) was obtained.

Example 40 (Compound 653) A solution of compound 2 (100 mg) in methanol (5.6 ml) was added at 0 ° C.
M (trimethylsilyl) diazomethane-hexane solution (1.1
2 ml) was added, and the mixture was stirred overnight at room temperature. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give N- (5-t-butyl-4-methylthiazol-2-yl) -N-methyl. -3-Nitrobenzenesulfonamide (Compound 653) 30 mg and Compound 1 (3
1 mg) was obtained. Example 41 (Compound 612) Using compound 645 (33 mg) and in the same manner as in Example 11, N 2
-(5-t-Butyl-4-methylthiazol-2-yl) -3-methanesulfonylaminobenzenesulfonamide (Compound 612) 17.
9 mg was obtained. Example 42 (Compound 618) To a mixture of Compound 645 (33 mg), dichloroethane and DMF,
Tetrahydrophthalic anhydride (23 mg) was added, and the mixture was stirred at 80 ° C overnight. The reaction mixture was cooled to room temperature, PS-trisamine (30 mg) was added, and the mixture was stirred at room temperature for 3 hr. The resin was filtered through a 1PS filter, the solvent was distilled off under reduced pressure, and N- (5-t
-Butyl-4-methylthiazol-2-yl) -3- (1,3-dioxo
-1,3,3a, 4,7,7a-hexahydroisoindol-2-yl)
25.8 mg of benzenesulfonamide (Compound 618) was obtained. Similarly to the method described in Examples 39 to 42, Table 38 below.
The compounds shown in 48 were prepared.

Reference Example 1 (Compound S-70) Concentrated sulfuric acid was gradually added to 2-amino-4-methylthiazole under ice cooling. Add tBuOH to this solution while cooling below 30 ° C.
Was dropped, and the mixture was returned to room temperature and then stirred for 16 hours. The reaction solution was poured into ice water, neutralized with sodium hydrogen carbonate, and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate solution was added under ice cooling, and the mixture was stirred at room temperature for 15 min. The solvent was distilled off under reduced pressure, the residue was dissolved in acetonitrile, washed with hexane, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-acetonitrile to obtain the compound 2-amino-5-t-butyl-4-methylthiazole hydrochloride (Compound S-70). FA
B-MS: 171 [(M + H) ⁺ ] In the same manner as in Reference Example 1, Compound S-71 shown in Table 49 below,
S-78, S-81, S-86, S-88 to S-92 were manufactured. Reference Example 2 (Compound S-72) Thiourea and iodine were added to an iPrOH solution of ethyl trifluoroacetoacetate, and the mixture was stirred with heating under reflux for 3 hours. The reaction solution was concentrated under reduced pressure and recrystallized from methanol-water to give methyl 2-amino-4-trifluoromethylthiazole.
-5-carboxylic acid was obtained. Di-t in a THF solution of the obtained compound.
-Butyl-dicarbonate ((Boc) ₂ O) and 4-dimethylaminopyridine were added, and the mixture was stirred at 60 ° C for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / toluene), methyl 2- (N-Boc).
Amino-4-trifluoromethylthiazole-5-carboxylic acid was obtained. To a solution of the obtained compound in THF at -78 ° C, 1.14 M
A methyllithium-diethyl ether solution was added and stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give t-butyl [5- (1-hydroxy-1 -
Methylethyl) -4-trifluoromethylthiazol-2-yl] carboxylic acid was obtained. Triethylsilane was added to a solution of the obtained compound in trifluoroacetic acid, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 2-amino-5- (1-methylethyl) -4-trifluoromethylthiazole (Compound S-72). Got FAB-MS: 211 [(M + H)
⁺ ]

Reference Example 3 (Compound S-73) DMSO was added dropwise to an acetonitrile solution of 4-methyl-2-pentanone and trimethylsilane bromide under ice cooling, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
Ethanol and thiourea were added to the crude product, and the mixture was heated under reflux for 2 hours. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate / hexane) to give 2-amino-5- (1-methyl Ethyl) -4-methylthiazole (Compound S-73) was obtained. FAB-MS: 157 [(M + H) ⁺ ] In the same manner as in Reference Example 3, Compound S-79 shown in Table 49 below,
S-80 and S-82 to S-84 were manufactured. Reference Example 4 (Compound S-74) Benzoyl isothiocyanate was added dropwise to a THF solution of 2-methoxy-5-phenylaniline under ice cooling, and then the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, methanol, water and sodium hydroxide were added, and the mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration and washed successively with water, ethanol and hexane to give N- (2-methoxy-5-phenylphenyl) thiourea. A chloroform solution of bromine was added dropwise to the chloroform solution of the obtained compound under ice cooling. After heating to reflux for 1 hour,
The mixture was allowed to cool to room temperature and the precipitated solid was collected by filtration to give the compound 2-amino-4-methoxy-7-phenylbenzothiazole hydrobromide. The obtained compound was added to a 48% hydrobromic acid aqueous solution, and the mixture was heated under reflux for 3 days. After allowing to cool, it was concentrated under reduced pressure. Acetic anhydride and pyridine were added to the obtained compound, and 2 days and nights,
Stir at room temperature. Water was added to the reaction solution, and the precipitated solid was collected by filtration and washed successively with water, ethanol, diethyl ether and hexane to give 2-acetylamino-4-acetoxy-7-phenylbenzothiazole. 1M for the obtained compound
Aqueous sodium hydroxide solution and methanol were added, and the mixture was stirred at room temperature for 30 minutes. Water was added, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-acetylamino-4-hydroxy-7-phenylbenzothiazole. 2,6-lutidine was added to the obtained compound, trifluoromethanesulfonic anhydride was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature. Then, 0.5 M hydrochloric acid aqueous solution was added, and the mixture was extracted with diethyl ether. The organic layer was washed with 0.5 M aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. DMF, triethylamine, formic acid (0.
88 ml), 1,3-bis (diphenylphosphino) propane and palladium acetate were added, and the mixture was stirred at 40 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with a 1: 1 mixed solvent of ethyl acetate and toluene. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate to give 2-acetylamino-7-phenylbenzothiazole. Methanol and 1 M were added to the obtained compound.
An aqueous solution of sodium hydroxide was added, and the mixture was stirred at 50 ° C for 2 days and nights. After distilling off methanol under reduced pressure, extraction with ethyl acetate,
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The precipitated solid is washed with diethyl ether / hexane to give 2-
Amino-7-phenylbenzothiazole (Compound S-74) was obtained. FAB-MS: 227 [(M + H) ⁺ ] In the same manner as in Reference Example 4, Compound S-85 shown in Table 49 below was produced.

Reference Example 5 (Compound S-75) Sodium azide was added to a DMF solution of 2,4-dichloro-5-formylthiazole, and the mixture was heated with stirring at 50 ° C for 2 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, and
The extract was washed successively with% saline and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 2-azido-4-chloro-5-formylthiazole. Triphenylphosphine was added to a THF solution of the obtained compound, and the mixture was heated under reflux for 1 hour. After distilling off the solvent under reduced pressure,
Acetic acid and water were added to the residue, and the mixture was heated with stirring at 100 ° C. for 2 hours.
The solvent was concentrated to about 1/4, the precipitated solid was collected by filtration, and water,
It was washed successively with ethanol and diethyl ether to give 2-amino-4-chloro-5-formylthiazole. (Boc) ₂ O and dimethylaminopyridine were added to a THF solution of the obtained compound), and the mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure,
The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give t-butyl (4-chloro-5-formylthiazol-2-yl) carbamate. About 3 M of the obtained compound and thiophenol in ethanol
A NaOEt-ethanol solution was added, and the mixture was heated under reflux for 1 hr. Cold water was added to the reaction solution, which was then concentrated, chloroform was added, and the organic layer was separated. The aqueous layer was extracted with chloroform, and the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give t-
Butyl (5-formyl-4-phenylsulfanylthiazol-2-yl) carbamate was obtained. t-butyl (4-chloro-5
A 0.63 M isopropylmagnesium bromide-THF solution was slowly added to the THF solution of -formylthiazol-2-yl) carbamate at -78 ° C under an argon atmosphere, and the mixture was stirred for 1 hour and further stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated,
The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give t-butyl [4-chloro-5].
-(1-Hydroxy-2-methylpropyl) thiazol-2-yl]
Carbamate and t-butyl (4-chloro-5-hydroxymethylthiazol-2-yl) carbamate were obtained. t-butyl
Triethylsilane was added to a TFA solution of [4-chloro-5- (1-hydroxy-2-methylpropyl) thiazol-2-yl] carbamate, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, saturated sodium hydrogen carbonate and chloroform were added to the residue, the organic layer was separated, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 2-amino-4-chloro-5-isobutylthiazole (Compound S-75). FAB-MS: 191 [(M + H) ⁺ ] In the same manner as in Reference Example 5, Compound S-87 shown in Table 49 below was produced. Reference Example 6 (Compound S-76) t-Butyl (4-chloro-5-formylthiazol-2-yl) carbamate, tBuOH, water, 2-methyl-2-butene and potassium dihydrogen phosphate (8.87 g) Was added, and an aqueous solution of sodium chlorite was added dropwise under ice cooling. Then, the mixture was stirred at room temperature for 4 hours, sodium chlorite) was similarly added under ice cooling, and the mixture was further stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture,
The extract was washed with 5% aqueous potassium hydrogen sulfate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated solid is washed with diethyl ether and treated with 2-t-butoxycarbonylamino.
-4-Chlorothiazole-5-carboxylic acid was obtained. Methanol, WSC hydrochloride and 4-dimethylaminopyridine were added to the obtained DMF solution of the compound, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with a mixed solvent of ethyl acetate-toluene 1: 1. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated solid is washed with hexane to remove methyl
2-t-butoxycarbonylamino-4-chlorothiazole-5
-The carboxylic acid is obtained. Using the obtained compound, Reference Example 5
Similarly to, t-butyl [4-chloro-5- (1-hydroxy-1
-Methylethyl) thiazol-2-yl] carbamate and 2-
Amino-4-chloro-5- (1-methylethyl) thiazole (Compound S-76) was obtained.

Reference Example 7 (Compound S-77) 2-t-Butoxycarbonylamino-4-chlorothiazole-5-
HOBt, WSC hydrochloride, diisopropylethylamine and N, O-dimethylhydroxylamine hydrochloride were added to the DMF solution of carboxylic acid, and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, 5% aqueous sodium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. It was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give N, O-dimethyl 5- [4-chloro-2- (t-
Butoxycarbonylamino) thiazole] carbohydroxamate was obtained. Using the obtained compound, in the same manner as in Reference Example 5, 5-acetyl-2-t-butoxycarbonylamino-4-chlorothiazole and t-butyl [4-chloro-5- (1
-Hydroxy-1-methylpropyl) thiazol-2-yl] carbamate, and 2-amino-4-chloro-5- (1-methylpropyl) thiazole (Compound S-77) [2-amino-4-chloro-5 -(1
-Methyl-1-propenyl) thiazole about 4: 5 mixture] was obtained. Compounds shown in Table 49 below were prepared in the same manner as in Reference Example 7.
S-93 was manufactured. Reference Example 8 (Compound S-94) To a mixture of iodine, magnesium and THF, a THF solution of 3-bromoanisole was added little by little while stirring at room temperature while refluxing due to the heat of reaction. The mixture was refluxed by heating at 60 ° C for 1.5 hours, and then allowed to cool to room temperature. The reaction mixture was added dropwise to a hexane solution of sulfuryl chloride under ice cooling. After stirring for 30 minutes under ice cooling, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 3-methoxybenzenesulfonyl chloride (Compound S-94). In the same manner as in Reference Example 8, compounds S-100 to S-102, S-110 and S-111 shown in Table 50 below were produced.

Reference Example 9 (Compound S-95) A mixture of 1-chloro-3,4-dinitrobenzene, sodium sulfite and water was heated under reflux for 18.5 hours. Then, the mixture was allowed to cool to room temperature and the precipitated solid was collected by filtration to obtain crude sodium 5-chloro-2-nitrobenzenesulfonate. While the mixture of phosphorus pentachloride and phosphorus oxychloride was stirred at 80 ° C, the above sodium salt was gradually added, and the mixture was heated and stirred at 80 ° C for 3 hours. Concentrate under reduced pressure, further add toluene, concentrate under reduced pressure, dissolve the residue in toluene, wash with saturated aqueous sodium hydrogen carbonate solution and saturated brine successively, dry over anhydrous sodium sulfate and concentrate under reduced pressure to give crude 5- Chloro-2-
Nitrobenzenesulfonyl chloride (Compound S-95). Reference Example 10 (Compound S-96) 4-Bromoanisole was added dropwise to chlorosulfuric acid under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, and the precipitated solid was collected by filtration, dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 5-bromo-2- Methoxybenzenesulfonyl chloride (Compound S-96) was obtained. Compounds S-109 and S-1 shown in Table 50 below were prepared in the same manner as in Reference Example 10.
12, S-113 and S-115 were produced.

Reference Example 11 (Compound S-97) To a mixture of 3-bromoanisole, water, a 1 M hydrochloric acid aqueous solution and hydroxylamine hydrochloride was heated under reflux, a heated aqueous chloral solution was added all at once, and the mixture was heated under reflux for 30 minutes. .
After cooling to room temperature, the precipitated solid was collected by filtration, the filtered material was dissolved in ethyl acetate, washed with water, the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated solid was washed with chloroform to obtain crude 3-bromoisonitrosoacetanilide. Water and concentrated sulfuric acid were added to the obtained compound under ice cooling, and the mixture was stirred at 75 ° C. for 1 hour and allowed to cool to room temperature. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. A 1 M aqueous sodium hydroxide solution and acetic acid were added to the obtained residue, and the precipitated 4-bromoisatin was filtered off. Concentrated hydrochloric acid was added to the mother liquor to adjust the pH to 1, and the precipitated solid was collected by filtration to obtain 6-bromoisatin. A mixture of 6-bromoisatin and a 1 M aqueous sodium hydroxide solution was added dropwise with 30% hydrogen peroxide with stirring under ice cooling. After stirring at room temperature for 1 hour, the precipitated solid was collected by filtration and washed with water to obtain 4-bromoanthranilic acid. Dimethylsulfate and triethylamine were added to a DMF solution of 4-bromoanthranilic acid, and the mixture was stirred at room temperature for 6.5 hours. After concentration under reduced pressure, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate /
Hexane) to give methyl 2-amino-4-bromobenzoic acid. The resulting compound, a mixture of acetic acid and concentrated hydrochloric acid was stirred at -5 ° C, an aqueous solution of sodium nitrite was added dropwise,
Stir for 1 hour at that temperature. On the other hand, copper (I) chloride, copper chloride
The above reaction mixture was added at 0 ° C. or lower to a mixture of (II), acetic acid and water at −5 ° C. with bubbling SO ₂ for 1.5 hours. After stirring for 1 hour at room temperature, the mixture was poured into ice water and the precipitated solid was collected by filtration. The filtrate was added to concentrated aqueous ammonia under ice cooling, and the mixture was stirred at room temperature overnight. Concentrate under reduced pressure, add saturated aqueous sodium hydrogen carbonate solution, wash with diethyl ether,
The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid and extracted with chloroform.
The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-bromo-1,2-benzisothiazol-3 (2H) -one-
1,1-dioxide was obtained. The mixture of the obtained compound and phosphorus pentachloride was stirred at 120 ° C. for 1.5 hours, allowed to cool to room temperature, and then poured into ice water. The mixture was stirred for 30 minutes as it was, extracted with ethyl acetate, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5-bromo-2.
-Cyanobenzenesulfonyl chloride (Compound S-97) was obtained. Compounds shown in Table 50 below were prepared in the same manner as in Reference Example 11.
S-103 to S-106, S-108 and S-114 were produced. Reference Example 12 (Compound S-98) A mixture of 5-bromo-2-methoxybenzenesulfonyl chloride and sulfuric acid was ice-cooled, and potassium nitrate was added at 10 ° C or lower,
The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into ice water, adjusted to pH 1-2 with potassium carbonate, extracted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product.
5-Bromo-3-nitro-2-methoxybenzenesulfonyl chloride (Compound S-98) was obtained. In the same manner as in Reference Example 12, compounds S-107 and S-116 shown in Table 50 below were produced.

Reference Example 13 (Compound S-28) Zinc cyanide and tetrakis (triphenylphosphine) palladium were sequentially added to a DMF solution of Compound 179, and the mixture was heated at 80 ° C. for 2 minutes.
It was stirred for 4 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, and washed successively with saturated aqueous ammonia, water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate / toluene), and N- (5-t-butyl-3,4-dimethylthiazole-2 (3H)- Ylidene) -5-cyano-2-methoxybenzenesulfonamide (Compound S-28) was obtained. FAB-MS: 38
0 [(M + H) ⁺ ] Reference Example 14 (Compound S-17) To a 1,2-dimethoxyethane solution of Compound 179, 2 M aqueous sodium carbonate solution, phenylboric acid and tetrakis (triphenylphosphine) palladium were sequentially added, The mixture was stirred at ℃ for 48 hours. 30% hydrogen peroxide solution was added to the reaction solution under ice cooling, extracted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. After purification by silica gel column chromatography (ethyl acetate / toluene), crystallize from ethyl acetate-hexane to give N- (5-t-butyl-3,4-dimethyl-3H-thiazol-2-ylidene) -2-methoxy. -5-Phenylbenzenesulfonamide (Compound S-17) was obtained. FAB-MS: 431 [(M + H) ⁺ ] Compound S-18 shown in Table 51 below was prepared in the same manner as in Reference Example 14.
~ S-22 was manufactured.

Reference Example 15 (Compound S-23) To a DMF solution of Compound 179, triethylamine, 4-chlorostyrene and bis (triphenylphosphine) palladium dichloride were sequentially added and stirred at 110 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate / benzene), and crystallized from ethyl acetate-hexane to give N- (5-t-butyl-3,4-dimethyl-3H-).
Thiazol-2-ylidene) -2-methoxy-5- (4-chlorostyryl) benzenesulfonamide (Compound S-23) was obtained. FAB
-MS: 457 [(M + H) ⁺ ] Compound S-24 shown in Table 51 described below in the same manner as in Reference Example 15.
And S-25 were manufactured. Reference Example 16 (Compound S-2) Compound 1, carbon tetrachloride, N-bromosuccinimide and 2,
The mixture of 2'-azobisisobutyronitrile was stirred with heating under reflux for 1 hour. After cooling, ethyl acetate was added, the mixture was washed with 1M aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated solid was washed with ethyl acetate, and N- (4-bromomethyl-5-t-butyl-3-methyl-3H
-Thiazole-2-ylidene) -3-nitrobenzenesulfonamide (Compound S-2) was obtained. FAB-MS: 448, 450 [(M + H) ⁺ ]

Reference Example 17 (Compound S-4) To a solution of compound S-3 in acetonitrile was added trimethylsilane iodide under ice cooling and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added, washed with water, dried over anhydrous magnesium sulfate,
Concentration under reduced pressure gave N- [3,4-dimethyl-5- (1-methyl-2-oxoethyl) thiazole-2 (3H) -ylidene] -3-nitrobenzenesulfonamide (Compound S-4). Reference Example 18 (Compound S-8) Pyridinium was added to a mixture of Compound 114, acetone and water.
p-Toluenesulfonate was added, and the mixture was stirred at room temperature for 1 hour and then heated under reflux for 4 hours. After cooling, acetone was distilled off under reduced pressure, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give N- (5-t-butyl-4-methylthiazole).
-2-yl) -3-nitro-N- (4-oxobutyl) benzenesulfonamide (Compound S-8) was obtained. In the same manner as in Reference Example 18, compounds S-6 to S-7 shown in Table 51 below and compound S-9 shown in Table 17 were produced.

Reference Example 19 (Compound S-47) Zinc iodide and trimethylsilyl cyanide were added to a dichloromethane solution of compound 263 under ice-cooling, and the mixture was stirred, diethyl ether was added, trimethylsilyl cyanide was further added, and the mixture was stirred at room temperature for 14 hours. It was stirred. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with 1 M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and concentrated under reduced pressure to give N- [5-t-butyl-3,4-dimethylthiazole-2 ( 3H) -Ylidene] -5-chloro-2- [cyano (trimethylsiloxy) methyl] benzenesulfonamide (Compound S-47) was obtained. Reference Example 20 (Compound S-56) Compound 244 and a 4 M hydrogen chloride-ethyl acetate solution mixture were added,
Diethyldithiophosphoric acid was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water was added, the mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform).
Purified with 2-{[5-t-butyl-3,4-dimethylthiazole-
2 (3H) -ylidene] sulfamoyl} -4-chlorophenoxythioacetamide (Compound S-56) was obtained. FAB-MS: 448
[(M + H) ⁺ ] Compound S-57 shown in Table 51 below was prepared in the same manner as in Reference Example 20.
Was manufactured.

Reference Example 21 (Compound S-64) A 48% aqueous solution of hydrobromic acid was added to Compound S-39, copper (II) sulfate pentahydrate was added at -5 ° C, and a sodium nitrite aqueous solution was added. Was added dropwise and stirred for 30 minutes. Copper (I) bromide in the reaction mixture
Was added and stirred at room temperature for 20 minutes, water was added and the mixture was extracted with chloroform. The organic layer was saturated aqueous sodium hydrogen carbonate solution, 1M
The extract was washed successively with aqueous hydrochloric acid solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform), the obtained solid was washed with acetonitrile, and N- (5
-t-Butyl-4-methylthiazol-2-yl) -3-bromo-5-chloro-2-methoxybenzenesulfonamide (Compound S-64)
Got ¹ H-NMR (DMSO-d ₆ ) δ: 12.48 (1H, bs), 8.04 (1H, d),
7.77 (1H, d), 3.87 (3H, s), 2.18 (3H, s), 1.31 (9
H, s); FAB-MS: 453, 455 [(M + H) ⁺ ] The following abbreviations are used in the tables below. No: Compound number, St
r: structural formula, Syn: raw material compound number used for production of each title compound (unless otherwise noted, a commercially available or obvious compound is used as a production raw material), Pr: 1-propyl, Boc: tBu-OC
O-, Bn: benzyl, Hex: hexyl, cHex: cyclohexyl, Dat: physicochemical data (F: FAB-MS [(M + H) ⁺ ]; F
N: FAB-MS [(MH) ^- ]; EI: EI-MS (M ⁺ ); AP: APCI-MS [(M
+ H) ⁺ ]; blank: used in the next reaction without purification). Further, the number before the substituent indicates a substitution position, and the one having a plurality of numbers indicates a plurality of substitutions. For example 4-Cl
-Ph represents 4-chlorophenyl, 2,5- (OMe) ₂ -Ph represents 2,5-dimethoxyphenyl, and 2-OMe-5-Br-Ph represents 2-methoxy-5-bromophenyl.

[0062]

[Table 3]

[0063]

[Table 4]

[0064]

[Table 5]

[0065]

[Table 6]

[0066]

[Table 7]

[0067]

[Table 8]

[0068]

[Table 9]

[0069]

[Table 10]

[0070]

[Table 11]

[0071]

[Table 12]

[0072]

[Table 13]

[0073]

[Table 14]

[0074]

[Table 15]

[0075]

[Table 16]

[0076]

[Table 17]

[0077]

[Table 18]

[0078]

[Table 19]

[0079]

[Table 20]

[0080]

[Table 21]

[0081]

[Table 22]

[0082]

[Table 23]

[0083]

[Table 24]

[0084]

[Table 25]

[0085]

[Table 26]

[0086]

[Table 27]

[0087]

[Table 28]

[0088]

[Table 29]

[0089]

[Table 30]

[0090]

[Table 31]

[0091]

[Table 32]

[0092]

[Table 33]

[0093]

[Table 34]

[0094]

[Table 35]

[0095]

[Table 36]

[0096]

[Table 37]

[0097]

[Table 38]

[0098]

[Table 39]

[0099]

[Table 40]

[0100]

[Table 41]

[0101]

[Table 42]

[0102]

[Table 43]

[0103]

[Table 44]

[0104]

[Table 45]

[0105]

[Table 46]

[0106]

[Table 47]

[0107]

[Table 48]

[0108]

[Table 49]

[0109]

[Table 50]

[0110]

[Table 51]

The action of the compound of the present invention was confirmed by the following pharmacological tests. HIV-1 Reverse Transcriptase Inhibition Test A) Enzyme Preparation Method by Saitoh A et al. (Microbiol. Immunol., 1990, 34, 5
09-521) to prepare the enzyme. K103 in which the 103rd Lys amino acid residue of HIV-1 reverse transcriptase (RT) was replaced with Asn
The expression vector of the amino acid mutation recombinant HIV-1RT of Y181C in which Nyr and 181st Tyr were replaced with Cys, the base codon AAA corresponding to 103rd Lys of pPG280 was converted into AAT (pPG280-K103
N), the base codon TAT corresponding to the 181st Tyr is TGT (pPG
280-Y181C). Wild-type RT (WT-
RT) and two mutant RTs (K103N-RT and Y181C-RT)
Are the expression vectors pPG280, pPG280-K103N and pPG280-Y1.
It was prepared using E. coli strain UT481 transformed with 81C. B) Assay Baba M. et al. (Proc. Natl. Acad. Sci. USA, 1991,
88, 2356-2360). Specifically, 50 m
M Tris (hydroxymethyl) aminomethane hydrochloride (pH 8.4), 2 mM dithiothreitol, 100 mM
Potassium chloride, 10 mM magnesium chloride, 0.1% Triton X-100, 1 μCi [1 ', 2'- ³ H] dGTP, 0.01 U (OD 260 nm) poly (rC) oligo (dG) as template primer
_12-18 , test substance, reverse transcriptase (0.01U for WT-RT, K103N-R
T and Y181C-RT contained 0.02 U), and reacted with 50 μl of liquid at 37 ° C. for 1 hour. Stop the reaction with 5% trichloroacetic acid and leave it in ice for 10 minutes. After trapping the precipitate in a filter, its radioactivity was measured with a liquid scintillation counter. The concentration of the test substance that inhibits the incorporation of ³ H-labeled dGTP by 50% was calculated as an IC ₅₀ value (unit: μM).
The results are shown in Table 52 below.

[0112]

[Table 52] As a result of the above test, it was confirmed that the compound of the present invention is useful as a reverse transcriptase inhibitor.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Coat (Reference) A61K 31/437 A61K 31/437 31/4439 31/4439 31/454 31/454 31/496 31/496 31 / 519 31/519 31/5377 31/5377 A61P 31/18 A61P 31/18 C07D 277/54 C07D 277/54 277/60 277/60 277/82 277/82 285/135 417/06 417/06 417 / 12 417/12 417/14 417/14 471/04 108E 471/04 108 487/04 144 487/04 144 285/12 E (72) Inventor Masahiro Fujii 21 Miyukigaoka, Tsukuba, Ibaraki Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Tetsuro Ogami 3-17-1, Hasune, Itabashi-ku, Tokyo Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Naoyuki Masuda 21 Miyukigaoka, Tsukuba City, Ibaraki Prefecture Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Fujiyasu Jiro 21 Miyukigaoka, Tsukuba-shi, Ibaraki Yamanouchi Pharmaceutical Co., Ltd. (72) Toru Kontani Toru Kontani 21 Miyukigaoka, Tsukuba, Ibaraki Prefecture Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor, Moriko Morinomo Miyukigaoka 21, Tsukuba, Ibaraki Prefecture Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor, Shunji Kageyama 3 Hasune, Itabashi-ku, Tokyo -17-1 Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Hiroshi Inoue 3-17-1 Hasune, Itabashi-ku, Tokyo Yamanouchi Pharmaceutical Co., Ltd. (72) Toshifumi Hatta 3-17-1 Hasune, Itabashi-ku, Tokyo Yamanouchi Pharmaceutical (72) Inventor Eiichi Kodama No. 411 Imperial Palace Riverside, 14-1, Mukojima-cho, Fushimi-ku, Kyoto-shi, Kyoto Prefecture (72) Inventor Masao Matsuoka 4-chome, Ohgi-sato, Otsu, Shiga Prefecture No. 204 F-term (reference) 4C036 AD08 AD16 AD17 AD21 AD24 AD27 AD30 4C050 AA01 BB05 CC08 EE03 FF02 GG01 HH04 4C063 AA01 AA03 BB03 BB06 BB07 CC62 CC71 CC73 CC81 CC92 DD07 DD02 DD07 DD02 DD02 DD02 DD05 DD02 DD02 DD05 DD02 DD02 DD02 DD54 DD02 DD02 DD02 DD02 DD02 DD02 DD01 DD02 DD02 DD05 DD02 DD02 DD02 DD05 DD02 DD02 DD02 DD01 DD02 JJ01 KK04 LL01 PP17 4C086 A A01 AA02 AA03 BC82 BC84 BC85 CB05 GA02 GA04 GA07 GA08 GA09 GA10 MA01 MA04 NA14 ZC55

Claims (3)

[Claims] 1. A sulfonamide derivative represented by the general formula (I ′) or a salt thereof. [Chemical 1] [The symbols in the formula have the following meanings. a and b: each represents a single bond or a double bond, at least one is a single bond and the other is a double bond, R ¹ : absent when a is a double bond and b is a single bond ; A
Is a single bond and b is a double bond, -H, -lower alkyl, -lower alkyl substituted with halogen, -lower alkylene-OH, -lower alkylene-heterocycle, -lower alkylene
-Optionally substituted aryl, -lower alkylene-O-
Lower alkyl, -lower alkylene-CHO, -lower alkylene
-CO ₂ H, - lower alkylene -CO ₂ - lower alkyl, - lower alkylene -CONH ₂ or - lower alkylene -OCONH ^_2, R _2: a double bond, and, when b is a single bond, -H, -Lower alkyl, -lower alkyl substituted with halogen, -lower alkylene-OH, -lower alkylene-heterocycle, -lower alkylene-optionally substituted aryl, -lower alkylene-O-lower alkyl, -lower alkylene -CHO, - lower alkylene -CO ₂ H, - lower alkylene -CO ₂ - lower alkyl, - lower alkylene -CONH ₂ or - lower alkylene -OCONH _2; a is a single bond, and, when b is a double bond, Absent, X: O or S, A: optionally substituted aryl or optionally substituted heteroaryl, B: optionally substituted nitrogen-containing heterocycle. However, in the formula (I ′), (In the formula, R ³ and R ⁴ represent the substituents of the above-mentioned “B optionally substituted nitrogen-containing heterocycle”.),
The following compounds are meant: 1) When R ² is absent, R ³ is methyl, and A is a phenyl group which may be substituted only at the 4-position, R ⁴ is C _2-6 alkyl. A compound, 2) R ² and R ³ are methyl, and R ⁴ is H, 2-propyl or t
When ert-butyl, A is chloro, methyl, N only at position 4
A compound other than phenyl optionally substituted with a group selected from H ₂ and NHCOCH ₃ , 3) when R ² and R ³ are methyl, and R ⁴ is C ₅ alkyl,
A is a compound other than phenyl optionally substituted with a group selected from methyl and NO ₂ only at the 4-position, 4) when R ² is ethyl, R ³ is methyl, and R ⁴ is H, A
Is a compound other than phenyl optionally substituted with a group selected from methyl and NHCOCH ₃ only at the 4-position, 5) when R ² is ethyl, R ³ is methyl, and R ⁴ is 2-propyl, A is a compound other than 4-methylphenyl, 6) a group in which when R ² is ethyl, R ³ is methyl, and R ⁴ is tert-butyl, A is selected from methyl, chloro and bromine only at the 4-position. Compounds other than phenyl substituted with 7), when R ² and R ³ are methyl, and R ⁴ is tert-butyl, A is a compound other than 3-nitrophenyl, 8) R ² is CH ₂ CH ₂ Cl Or CH ₂ CH ₂ OH, R ³ is methyl, and R ⁴
When H is H, A is a compound other than 4-chlorophenyl, 9) R ² is benzyl, R ³ is methyl, and when R ⁴ is H, methyl or diethylamino, A is a compound other than 4-methylphenyl, 10 ) R ² is methyl, R ³ is tert-butyl, and R ⁴ is chloro, A is a compound other than 4-methylphenyl, 11) R ¹ is H, R ³ is methyl, and R ⁴ is tert. -When it is butyl, A is a compound other than phenyl, 4-methylphenyl, 4-chlorophenyl, 3-nitrophenyl or 4-bromophenyl, 12) R ¹ is H, R ³ is methyl, and R ⁴ is 2- When propyl, A is a compound other than phenyl, 4-chlorophenyl or 4-methylphenyl, 13) when R ¹ is ethyl, R ³ is methyl, and R ⁴ is tert-butyl or 2-propyl, A is 4 -Compounds other than -chlorophenyl, and 14) when R ¹ is H, R ³ is methyl, and R ⁴ is CO ₂ Et, A
Is a compound other than 3-nitrophenyl. ] 2. A pharmaceutical composition comprising, as an active ingredient, one or two or more of the sulfonamide derivative represented by the general formula (I) or a salt thereof. [Chemical 3] [The symbols in the formula have the following meanings. a and b: each represents a single bond or a double bond, at least one is a single bond and the other is a double bond, R ¹ : absent when a is a double bond and b is a single bond ; A
Is a single bond and b is a double bond, -H, -lower alkyl, -lower alkyl substituted with halogen, -lower alkylene-OH, -lower alkylene-heterocycle, -lower alkylene
-Optionally substituted aryl, -lower alkylene-O-
Lower alkyl, -lower alkylene-CHO, -lower alkylene
-CO ₂ H, - lower alkylene -CO ₂ - lower alkyl, - lower alkylene -CONH ₂ or - lower alkylene -OCONH ^_2, R _2: a double bond, and, when b is a single bond, -H, -Lower alkyl, -lower alkyl substituted with halogen, -lower alkylene-OH, -lower alkylene-heterocycle, -lower alkylene-optionally substituted aryl, -lower alkylene-O-lower alkyl, -lower alkylene -CHO, - lower alkylene -CO ₂ H, - lower alkylene -CO ₂ - lower alkyl, - lower alkylene -CONH ₂ or - lower alkylene -OCONH _2; a is a single bond, and, when b is a double bond, Absent, X: O or S, A: optionally substituted aryl or optionally substituted heteroaryl, B: optionally substituted nitrogen-containing heterocycle. However, when R ¹ is H and B is 4-methyl-5- (2-propyl) thiazol-2-yl, compounds in which A is phenyl or 4-methylphenyl are excluded. ] 3. The pharmaceutical composition according to claim 2, which is an anti-HIV agent.