JP3258531B2 - Benzimidazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound having a novel benzimidazole derivative structure which binds to DNA and suppresses cell proliferation, and a pharmaceutical composition containing the same, especially an anticancer agent,
It relates to the use for antiviral agents, antibacterial agents, etc.

[0002]

2. Description of the Related Art Some compounds acting on DNA are used as anticancer agents. For example, Adriamycin is useful as an anticancer agent that intercalates into DNA. Also, cisplatin, mitomycin (Mitom)
Compounds that react with DNA, such as ycin), are also commonly used. It is considered that the anticancer action by acting on DNA in this way has been established, if not fully explained. On the other hand, in recent years, distamycin or netropsin binds to DNA and is known as a substance having antitumor activity (Nature, 196).
203, 1064-65, 4 years). These are attracting attention as groove binders having a different DNA binding mode from conventional anticancer agents.

[0003] However, the knowledge of anticancer drugs to date suggests that with regard to the interaction with DNA, it is necessary to predict which partial structure in a compound is a necessary structure or what other structure can be substituted. Is completely impossible at the moment. However, it is meaningful to predict and search for the existence of a compound having a desirable structure, and it is considered that such a search for a new structure is particularly required for the creation of a novel anticancer agent. Further, a compound in which a structure of an alkylating agent is bound to a distamycin derivative is known. As a typical example, J.I. A
m. Chem. Soc. 1985 Volume 107 8266
P., EP246868, WO93-13739, J.P. M
ed. Chem. 1989, 32, 774 pages.
There is also known a compound in which an alkylating agent structure is bonded to a compound similar to distamicin in which N-methylimidazole is used as a partial structure and the partial structure is connected by an amide bond (US Pat. No. 5,237,991). Among these, there are those in which a bis (2-chloroethyl) amino residue is used as an alkylating agent, and this residue is already known to be part of the structure of an anticancer agent. For example, chlorambucil is known as an anticancer drug having a bis (2-chloroethyl) amino residue in the molecule. The anticancer activity of this compound is presumed to be the result of alkylation to DNA, enzymes and the like. However, the value of adding a structure of an alkylating agent such as a chloroethylamine structure as a part of a structure of an anticancer agent that binds to DNA has not yet been established.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a DN.
An object of the present invention is to provide a new compound acting on A or a new compound having a partial structure acting on DNA, which is useful as an anticancer agent, an antiviral agent, an antibacterial agent and the like.

[0005]

SUMMARY OF THE INVENTION Distamycin is a typical example of a compound that binds to DNA. Distamycin has the characteristic that the pyrrole rings are connected by amide bonds. However, since there are several types of compounds that bind to DNA, the present inventor has anticipated that there are other compounds having a structure different from that of known compounds and exhibiting an anticancer effect. And searched for a new structure. As a result, they have found that a novel compound having a structure in which a 5-membered aromatic ring and benzimidazole are directly bonded is useful as an anticancer agent. Preferred examples include 1H-2- [1-methyl- (substituted) pyrrole-2.
-Yl] benzimidazole-5-carboxamide derivative, 1H-2-[(substituted) pyrrol-2-yl] benzimidazole-5-carboxamide derivative, 1H-2-
[(Substituted) imidazol-2-yl] benzimidazole-5-carboxamide derivative, 1H-2- [1-methyl- (substituted) imidazol-2-yl] benzimidazole-5-carboxamide derivative, 1H-2-[( Substituted) furan-2-yl] benzimidazole-5-carboxamide derivative, 1H-2-[(substituted) thiophene-
2-yl] benzimidazole-5-carboxamide derivatives and 1H-2-[(substituted) thiophen-3-yl] benzimidazole-5-carboxamide derivatives.
These compounds have a novel structure and have never been known to be useful as anticancer agents.
These compounds, for example, 1H-2- (4-formyl-1)
-Methylpyrrol-2-yl) benzimidazole-5
-[N- (2-amidinoethyl)] carboxamide is
An increase in the measured Tm value (melting point of the duplex of DNA) was shown to bind to DNA, and the in vitro (in
In vitro), it showed the same growth inhibitory activity against tumor cells as distamycin.

[0006] Examples of compounds in which an alkylating agent is bound to a distamycin derivative are already known, and indicate that the activity as an anticancer agent may be enhanced by the addition of the alkylating agent. A novel compound having a structure in which a 5-membered aromatic ring and benzimidazole are directly bonded was also examined for its activity as an anticancer agent when an alkylating agent was bonded thereto. Compounds conjugated with an alkylating agent such as chlorambucil showed much higher anti-cancer activity than distamycin or chlorambucil. From this, a compound in which a 5-membered aromatic ring and benzimidazole are directly bonded,
It has been found that adding an alkylating agent in the same molecule results in a highly active anticancer agent. From the above, the present inventors have completed the invention of a new anticancer agent. That is, the present invention is a compound represented by the following formula (1) or a pharmacologically acceptable salt thereof.

[0007]

Embedded image [Wherein, X, Y and Z are each independently CH, N,
NH, N (CH ₂ ) _t CH ₃ , S, O (however, X, Y,
Z does not mean the same thing at the same time;
M and n each represent an integer of 0 to 5; R ₁ and R ₂ each independently represent a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, or a haloalkyl having 1 to 10 carbon atoms; Group, C1-C10 alkoxy group, oxoethylene group, ethyleneimino group, hydroxy group, C1-C10
Alkylthio group, amino group which may be substituted, ammonium group which may be substituted, sulfonium group which may be substituted, phenyl group which may be substituted, 5-membered hetero ring which may be substituted Group, optionally substituted hetero 6-membered ring group, optionally substituted hetero-fused ring group, optionally substituted amidino group, optionally substituted guanidino group, amino acid residue or formula (2 ) [Chemical formula 14]

[0008]

Embedded image In the formula, R ₃ represents (CH ₂ ) _r , (CH ₂ ) _r O (provided that r is an integer of 0 to 5 and O is present closer to the phenyl group), and R ₄ is hydrogen , An alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a halogen atom, a trifluoromethyl group, a cyano group, an amidino group, a guanidino group, a carboxyl group or -COR ₇ (where R ₇ is 1 to 5 alkyl groups, an alkylamino group optionally substituted with a substituted amino group or an amino group optionally substituted with a phenyl group which may be substituted,
R ₅ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a halogen atom,-(CH
_{2) p N (R 8)} 2 or - (CH ₂₎ shows the _p NR ₈ R ₉ (Here, p is an integer of 0-5), when R ₄ and R ₅ are occupying a position Tonaria' Can form a ring, and R ₆ is a hydrogen atom, — (CH ₂ ) _p N (R ₈ ) ₂ or — (CH ₂ ) _p N
R ₈ R ₉ (however, in R ₅ and R ₆ , R ₈ is —CH ₂
CH ₂ W, R ₉ represents an alkyl group having 1 to 5 carbon atoms or a mesyl group, and W represents a halogen atom, a hydroxy group, a mesyloxy group, a tosyloxy group or —OCOR ₇ (R ₇ and p
Represents the above-mentioned meaning). ｝] Hereinafter, the present invention will be described in more detail.

The 5-membered ring containing X, Y and Z in the compound of the formula (1) is pyrrole, 1-methylpyrrole, imidazole, 1-methylimidazole, furan, thiophene,
Oxazole, isoxazole, pyrazole and isothiazole are preferred. The alkyl group having 1 to 20 carbon atoms of R ₁ and R ₂ means a methyl group, an ethyl group, an n-propyl group, i
-Propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and stearyl are preferred. A haloalkyl group having 1 to 10 carbon atoms means a chloromethyl group, a chloroethyl group, a chloropropyl group, a chlorobutyl group, a chloropentyl group, a chlorohexyl group, a chloroheptyl group,
Bromomethyl group, bromoethyl group, bromopropyl group,
Bromobutyl, bromopentyl, bromohexyl, and bromoheptyl are preferred. The amino group which may be substituted is preferably an amino group or a monoalkylamino group or a dialkylamino group substituted with a linear or branched alkyl group having 1 to 10 carbon atoms. For example,
Methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, dimethylamino, diethylamino, dipropylamino, and diisopropylamino are preferred. 1 to 1 carbon atoms
The alkoxy group of 0 is methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy. , N-heptyloxy group and n-octyloxy group are preferred. Carbon number 1-10
The alkylthio group is a methylthio group, an ethylthio group,
Desirable are n-propylthio, i-propylthio, n-butylthio, i-butylthio, t-butylthio, n-pentylthio, n-hexylthio, n-heptylthio, and n-octylthio.

The optionally substituted ammonium group refers to a trialkylammonium group (eg, a trimethylammonium group, a triethylammonium group) substituted with a linear or branched alkyl group having 1 to 4 carbon atoms, or a compound represented by the formula ( 9) Ammonium group of [Formula 15]. Where equation (9)
In the formula, U ⁻ may be any pharmacologically recognized anion (eg, Cl ⁻ , I ⁻ , OSO ₃ ⁻ , NO ₃ ⁻ , HOOC)
CH = CHCOO- ^{and the} like). R ₁₁ and R ₁₂ have 1 to 1 carbon atoms
10 linear or branched alkyl groups, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group,
Desirable are n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl groups.

[0011]

Embedded image The optionally substituted sulfonium group is a group having 1 to 1 carbon atoms.
(E.g., dimethylsulfonium, diethylsulfonium, methylethylsulfonium, methylpropylsulfonium, diisopropylsulfonium, and methylisopropylsulfonium) substituted with a straight-chain or branched alkyl group 4
0) It is a sulfonium group of [Formula 16]. However, equation (1)
U 0) ^- anything may be used as long an anion which is recognized pharmacological (e.g. _{^{Cl -, I -, OSO 3}} -, NO 3
^-, HOOCCH = CHCOO ^-, etc.). R ₁₁ is a linear or branched alkyl group having 1 to 10 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t- Butyl group, n
-Pentyl group, n-hexyl group, n-heptyl group, n-
An octyl group is preferred.

[0012]

Embedded image The optionally substituted phenyl group includes a halogen atom (a fluorine atom, a chlorine atom, a bromine atom and an iodine atom), a linear or branched alkyl group having 1 to 5 carbon atoms, a linear chain having 1 to 5 carbon atoms or A phenyl group which may be substituted with a branched alkoxy group, an alkoxycarbonyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, a cyano group, an amidino group, and a dialkylamino group having 1 to 3 carbon atoms. Yes, for example, chlorophenyl, dichlorophenyl, trichlorophenyl, bromophenyl, dibromophenyl, tribromophenyl, fluorophenyl, difluorophenyl, trifluorophenyl, methylphenyl, ethylphenyl, n-propyl Phenyl group, i-
Propylphenyl group, n-butylphenyl group, i-butylphenyl group, t-butylphenyl group, methoxyphenyl group, ethoxyphenyl group, methoxycarbonylphenyl group, methylcarboxyphenyl group, trifluoromethylphenyl group, cyanophenyl group, An amidinophenyl group, a dimethylaminophenyl group, a dimethylaminophenyl group, and a 3,4,5-trimethoxyphenyl group are preferred. If there is no explicit description of the substitution position of the above substituents,
In the case of mono-substitution, the 2-, 3-, or 4-position is indicated; in the case of di-substitution, two of 2, 3, 4, 5, and 6; in the case of tri-substitution, 2, 3, 4, 5, 6 The three positions are shown.

The hetero 5-membered heterocyclic group which may be substituted includes a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a pyrazolyl group,
Thiazolyl group, isothiazolyl group, isoxazolyl group,
Pyrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, furazanyl, tetrahydrofuranyl, triazolyl, and tetrazoyl groups are preferred.
The hetero 6-membered ring group of the optionally substituted hetero 6-membered ring group may be pyridyl group, pyrimidinyl group, pyranyl group, pyrazinyl group, pyridazinyl group, piperidyl group, piperazinyl group, thiomorpholino group, 4-methyl-1 -A piperazino group, a 4-benzyl-1-piperazino group, a 1-morpholino group, a 1-piperidino group, a 4-piperidino group, and a 4-methyl-1-piperidino group are preferred. The hetero-fused ring group of the optionally substituted hetero-fused ring group includes a quinolyl group, an isoquinolyl group, an indolyl group, an isoindolyl group, a phthalazinyl group, a quinoxalyl group, a quinazolyl group, a cinnolyl group, an indolinyl group, an isoindolinyl group, and a carbazolyl group. , Acridinyl group, benzotriazolyl group, benzisoxazolyl group, azaindolyl group, azabenzion drill group, benzodioxanyl piperidinyl group,
Xanthenyl groups are preferred. However, the optionally substituted hetero 5-membered ring group, the optionally substituted hetero 6-membered ring group may be substituted in the optionally substituted hetero-fused ring group means that these substituents are A halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), a linear or branched alkyl group having 1 to 5 carbon atoms, 1 to 5 carbon atoms
5 substituted or unsubstituted with a linear or branched alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, a cyano group, an amidino group or a dialkylamino group having 1 to 3 carbon atoms. It is also good. The amidino group which may be substituted is preferably a group represented by the formula (11) [Formula 17]. R ₁₁ represents an alkyl group having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, and t.
-Butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl are preferred.

[0014]

Embedded image The optionally substituted guanidino group is represented by the formula (12)
The groups shown in [Formula 18] are desirable. R ₁₁ has 1 to 10 carbon atoms
And represents, for example, a methyl group, an ethyl group, n
-Propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl are preferred.

[0015]

Embedded image The amino acid residue referred to here is a portion obtained by removing a carboxyl group from an amino acid, and includes arginine,
Histidine and lysine are preferred. The halogen atom of R ₄ , R ₆ and R ₇ means F, Cl, Br and I. As the halogen atom of W, Cl and Br are desirable.

The alkyl group having 1 to 10 carbon atoms for R ₅ is
Methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, n-
Pentyl, n-hexyl, n-heptyl and n-octyl are preferred. The alkoxy group having 1 to 10 carbon atoms for R ₅ includes methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy Group, n-
Hexyloxy, n-heptyloxy and n-octyloxy are preferred. When R ₄ and R ₅ occupy adjacent positions to form a ring, the following formula (13)
Are preferred.

[0017]

Embedded image The alkylamino group optionally substituted with the substituted amino group for R ₇ includes a dimethylaminoethylamino group, a dimethylaminopropylamino group, a dimethylaminobutylamino group, a diethylaminoethylamino group, a diethylaminopropylamino group, and a diethylamino group. A butylamino group, a dipropylaminoethylamino group, a dipropylaminopropylamino group, a dipropylaminobutylamino group, a diisopropylaminoethylamino group, a diisopropylaminopropylamino group, and a diisopropylaminobutylamino group are preferable. As the amino group optionally substituted with an optionally substituted phenyl group for R ₇ , aniline, 4-dimethylaminoaniline and 4-chloroaniline are desirable. As the optionally substituted benzylamino group for R ₇ , benzylamine and 4-dimethylaminobenzylamine are preferable. Pharmaceutically acceptable salts include, for example, inorganic or organic acids such as hydrochloride, sulfate, nitrate, acetate, fumarate, maleate, citrate, oxalate, etc. Salt.

Hereinafter, the compounds of the formula (1) are represented by the following A:
The description will be made by dividing into three groups B and C. The compound numbers in this document indicate the numbers of the compounds shown in Tables 1 to 4 [Tables 1 to 236]. Group A: Of the compounds represented by Formula (1), compounds not included in Groups B and C, or pharmacologically acceptable salts thereof. Group B: Of the compounds represented by the formula (1), R ₂ is an oxoethylene group, an ethyleneimino group, an alkyl group having 1 to 10 carbon atoms substituted with a halogen atom, or a group represented by the formula (2) Certain compounds or pharmacologically acceptable salts thereof. Group C: Among the compounds represented by the formula (1), a compound wherein R ₁ and R ₂ are each a group represented by the formula (2), or a pharmacologically acceptable salt thereof.

The synthesis of these compounds will be described.
In the following description or examples, DCC is N, N'-
Dicyclohexylcarbodiimide, CDI is N, N'-
Carbonyl diimidazole, HOSu is N-hydroxysuccinimide, EDCI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, DEC
P is diethyl cyanophosphonate, HOBt is 1-hydroxybenzotriazole, DMAP is 4-dimethylaminopyridine, DMF is dimethylformamide, THF
Represents tetrahydrofuran. DMSO indicates dimethyl sulfoxide, and IPA indicates isopropanol. Pd /
C represents activated carbon with palladium, and the palladium is usually 5 to 10%.

A method for synthesizing a compound represented by the formula (3), which is a main intermediate, will be described. The following reaction formula (1)
0] and the aldehyde of the formula (5)
Diaminobenzoic acid or its ester in nitrobenzene at 100 ° C to reflux temperature, preferably 130 to 20
Heat at 0 ° C., return to room temperature and obtain the product 1H-2 of formula (3)
-Benzimidazole-5-carboxylic acid or its ester derivative can be collected by filtration. Here, when an ester is obtained, as shown in the reaction formula (2) [Chemical formula 21], the ester is hydrolyzed to obtain a 1H-2-benzimidazole-5-carboxylic acid derivative represented by the formula (14). be able to. The amounts of the aldehyde of the formula (5) and the 3,4-diaminobenzoic acid ester of the formula (6) are not particularly limited, but the amount of the latter is usually 80 to 120 mol parts per 100 mol parts of the former. The reaction in nitrobenzene may be monitored while the process is being carried out, and heating may be performed until the raw materials disappear, but the heating time gives a good result in any case for 5 to 100 hours. The heating time may be continuous or may be performed intermittently so that the total time becomes the above time. The ester may be hydrolyzed by using sodium hydroxide or potassium hydroxide and heated in a mixed solvent of water and ethanol or water and methanol. The ratio of water at this time is 5 to 90% by weight, but 40 to 60% by weight gives good results. The heating temperature can be from 50C to the reflux temperature.

[0021]

Embedded image

[0022]

Embedded image

Specific examples are as follows: 1-methyl-4-nitropyrrole-2-carboxaldehyde, 4-nitropyrrole-2-carboxaldehyde, 5-nitropyrrole-2-carboxaldehyde, 1-methyl-4 Starting from -nitroimidazole-2-carboxaldehyde, 4-nitroimidazole-2-carboxaldehyde, 5-nitrofuran-2-carboxaldehyde, 4-nitrothiophen-2-carboxyaldehyde, 2-nitrothiophen-4-carboxaldehyde If the raw material is selected, 1H-2- [1-methyl-4-
Nitropyrrol-2-yl] benzimidazole-5
Carboxylic acid, 1H-2- [4-nitropyrrol-2-yl] benzimidazole-5-carboxylic acid, 1H-2-
[5-Nitropyrrol-2-yl] benzimidazole-5-carboxylic acid, 1H-2- [1-methyl-4-nitroimidazol-2-yl] benzimidazole-5
Carboxylic acid, 1H-2- [4-nitroimidazole-2
-Yl] benzimidazole-5-carboxylic acid, 1H-
2- [5-nitrofuran-2-yl] benzimidazole-5-carboxylic acid, 1H-2- [4-nitrothiophen-2-yl] benzimidazole-5-carboxylic acid,
1H-2- [2-nitrothiophen-4-yl] benzimidazole-5-carboxylic acid can be synthesized.

The method for heating 1-H-2-phenylbenzimidazole by heating benzaldehyde having a substituent and 3,4-diaminobenzoic acid in nitrobenzene is as follows.
Already Syn. Commun. 1990, 955-
As shown on page 963, the example using the above-mentioned aromatic 5-membered aldehyde derivative having a nitro group is novel.
Alternatively, the compound of the formula (14) can be synthesized by the following method. For example, 1-methyl-4-nitro-2
The pyrrole carboxylic acid is converted to Tetrahedron 197
8 years, 34, 2389-2391, using 1-methyl-4-nitro-2-pyrrolecarboxylic acid chloride with thionyl chloride, and reacting it with 3,4-diaminobenzoic acid. In the compounds mentioned, 3-amino-4- (1-methyl-4-nitro-2-pyrrolecarboxamide) benzoic acid or 4-amino-3- (1-
Methyl-4-nitro-2-pyrrolecarboxamide) benzoic acid is obtained. At this time, you may obtain as a mixture of both.
As the solvent, methylene chloride, chloroform, DMF and the like can be used. Other solvents that do not participate in the reaction are also possible. By heating the obtained amide compound in trifluoroacetic acid, 1H-2- (1-methyl-
4-nitropyrrol-2-yl) benzimidazole-
5-carboxylic acid is obtained. Alternatively, Heterocyc
1-methyl-4-nitro-2-, which is a known compound shown in Les 1988, Vol. 27, pp. 1945-1952.
Trichloroacetylpyrrole is similarly reacted with 3,4-diaminobenzoic acid to give 3-amino-4- (1-methyl-4
-Nitro-2-pyrrolecarboxamide) benzoic acid or 4-amino-3- (1-methyl-4-nitro-2)
-Pyrrolecarboxamide) to obtain benzoic acid. At this time, you may obtain as a mixture of both. This is likewise 1H-2-
(1-Methyl-4-nitropyrrol-2-yl) benzimidazole-5-carboxylic acid. 1
The same reaction can be performed using the corresponding carboxylic acid as a raw material other than -methylpyrrole-2-carboxylic acid. The above reaction is summarized as follows (reaction formula (3))
[Formula 22]).

[0025]

Embedded image

Next, the synthesis of each group of compounds will be described. The synthesis of compounds of Group A is generally carried out by converting an amino compound represented by Formula (20) containing a moiety defined by R ₂ into a carboxylic acid of Formula (14) as shown in Reaction Formula (4) [Formula 23]. And suitable condensing agents such as DCC, CDI, EDCI, D
Synthesized by coupling using ECP or the like, further reducing the nitro group of the intermediate of formula (21) obtained here to an amino compound by catalytic hydrogenation, and reacting a carbonyl compound containing a moiety defined by R _1. it can.

[0027]

Embedded image

As the amino compound represented by the formula (20) containing the moiety defined as R ₂ , there are a compound available as a reagent and a compound which can be synthesized through several steps by combining known reactions. Those used include alkylamino compounds, such as methylamine,
Ethylamine, 1-aminopropane, 2-aminopropane, 1-aminobutane, 2-aminobutane and the like are used. Alternatively, it is an example of an amino compound substituted by using dimethylaminopropylamine, diethylaminopropylamine, dipropylaminopropylamine, or the like. Alternatively, examples of alkylthio groups can be obtained by using methylthiopropylamine, ethylthiopropylamine, propylthiopropylamine, butylthiopropylamine, and the like. Examples of ammonium groups can be obtained by using aminopropyltrimethylammonium, aminopropyltriethylammonium and the like. Reacting a derivative containing an amino group of each of a phenyl group which may be substituted, a 5-membered heterocyclic group which may be substituted, a 6-membered heterocyclic group which may be substituted or a condensed ring which may be substituted; by using the respective optionally substituted phenyl group, optionally substituted 5-membered heterocyclic group, optionally condensed ring be ring group or a substituted or good hetero 6-membered optionally be substituted R ₂ Can be synthesized. These amino compounds are represented by the formula (1)
4) a carboxylic acid and a suitable condensing agent such as DCC, CD
When combining using I, EDCI, DECP, etc.,
The solvent may be an ordinary solvent, but DMF or a mixed solvent containing DMF gives relatively good results. Reaction temperature is -5
It is better to carry out at 30 ° C. The reaction may be performed while checking the progress of the reaction, and the reaction time is generally 1 to 50 hours.

The compound having an amidino group in R ₂ can be synthesized as follows. First, as shown in reaction formula (5) [Formula 24], for example, a compound of formula (14) (for example, 1H-2-
(1-Methyl-4-nitropyrrol-2-yl) benzimidazole-5-carboxylic acid: the same applies to other intermediates) and 3-aminopropionitrile. At this time, general condensing agents such as DCC, CDI, EDCI and DECP can be used. HOBt or HOS in DCC
A method such as adding u can also be used. Reaction is 0 to 30
It is desirable to carry out at a temperature of ° C. This is suspended in ethanol,
The resulting crystals are filtered off while passing hydrogen chloride gas. This is dissolved or suspended in a solvent, and further passed with ammonia gas, whereby the target amidino compound (for example, 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- (2 -Amidinoethyl)] carboxamide: the same applies when other intermediates are used). The solvent at this time is desirably ethanol or a mixed solvent of ethanol and methanol. The ratio of ethanol can be freely selected from 10 to 100%.

[0030]

Embedded image Further, as shown in the reaction formula (6), the substituted amidino compound is obtained by reacting an amine such as methylamine or ethylamine instead of passing ammonia gas therethrough.

[0031]

Embedded image As a specific example of the compound of the formula (14), 1H-2-
[1-Methyl- (nitro-substituted) pyrrol-2-yl] benzimidazole-5-carboxylic acid, 1H-2-[(nitro-substituted) pyrrol-2-yl] benzimidazole-
5-carboxylic acid, 1H-2- [1-methyl- (nitro-substituted) imidazol-2-yl] benzimidazole-5
-Carboxylic acid, 1H-2-[(nitro-substituted) imidazol-2-yl] benzimidazole-5-carboxylic acid,
1H-2-[(nitro-substituted) furan-2-yl] benzimidazole-5-carboxylic acid, 1H-2-[(nitro-substituted) thiophen-2-yl] benzimidazole-5
-Carboxylic acid or 1H-2-[(nitro-substituted) thiophen-4-yl] benzimidazole-5-carboxylic acid can be used as a precursor to carry out the reactions of Reaction Formulas (4) to (6).

Next, a method for synthesizing a side chain corresponding to R ₁ will be described. First, a method for synthesizing a substituent represented by formula (2) as a side chain corresponding to R ₁ will be described. As the carboxylic acid derivative having a nitro group used here, a commercially available reagent or a compound that can be synthesized using a known reaction can be used. The nitroester-containing carboxylic ester derivative of the formula (25) shown in the reaction formula (7) [Formula 26] is reduced to the corresponding amino compound of the formula (26) by catalytic hydrogenation using Pd / C as a catalyst. As the solvent at this time, methanol, ethanol, DMF, or the like can be used alone or as a mixture of two or more. The reaction temperature is preferably from 0 to 30 ° C. The reaction time is 30 minutes to 2 hours. As shown in the following reaction formula, the amino compound of formula (26) produced here is reacted with ethylene oxide to obtain a compound of formula (27). The solvent at this time is 10-80% acetic acid,
Perform at 20-50 ° C. An appropriate reaction time is 1 to 50 hours. Further, the compound of the formula (27) is converted to a suitable compound such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride, mesyl chloride (in DMF) or mesyl chloride and sodium chloride, mesyl chloride and lithium chloride, dichlorotriphenylphosphorane and the like. The compound of formula (28) can be obtained by changing the OH group to a Cl group using a suitable reagent. The reaction is performed at 0-100 ° C. The reaction time is between 20 minutes and 5 hours. As the solvent, a general solvent such as chloroform, benzene, and toluene can be used. DMF can also be mixed with these solvents. The reaction can also be carried out without solvent in the case of thionyl chloride, oxalyl chloride or the like. The compound represented by the formula (28) can be hydrolyzed with an acid to obtain a carboxylic acid derivative represented by the formula (29). For example, using concentrated hydrochloric acid
It is advisable to heat at 0 to reflux temperature. Reaction time is 30 minutes ~
Five hours is desirable.

[0033]

Embedded image The side chains other than those shown here can be prepared by commercially available reagents or by performing several steps of a known reaction. For example, a compound represented by the formula (7) [Formula 10] and a compound represented by the formula (29)
Is converted to a suitable condensing agent such as DCC, CD
I, EDCI, DECP, etc., can be used for coupling. The solvent may be an ordinary solvent, but DMF or a mixed solvent containing DMF gives relatively good results. The reaction temperature is-
It is good to carry out at 5 to 30 ° C. The reaction may be performed while checking the progress of the reaction, and the reaction time is generally 1 to 50 hours. Alternatively, a compound of the formula (29) may be used in a common solvent (for example, methylene chloride, chloroform, toluene, DMF or the like can be used alone or as a mixture of two or more), for example, thionyl chloride, oxalyl chloride and the like. Is used to obtain an acid chloride, which can be combined with the compound represented by the formula (7). Here, the reaction temperature is preferably -5 to 30C. The reaction may be performed while checking the progress of the reaction, and the reaction time is generally 1 to 50 hours. As described above, the partial structures of R ₁ can be combined.

The synthesis of the compound of Group B will be described. First shown for the synthesis of side chain corresponding to the portion of the R _2. An aniline derivative having a nitro group or an aminoalkylbenzene derivative having a nitro group is selected as a starting material. At this time, a commercially available reagent can be used for the derivative containing a suitable substituent, or it can be obtained by a known reaction. Further, it can also be synthesized by the following method.

As shown in the reaction formula (8) [Formula 27],
J. Med. Chem. 1990 Volume 3314-3
According to the method shown on page 019, an amino compound of formula (31) is synthesized from a carboxylic acid of formula (30). By using this, a methylene chain derivative having two or more R ₃ moieties can be synthesized. (It is assumed that a substituent corresponding to R ₆ described below has already been introduced into the compound of the formula (30))

[0036]

Embedded image Next, introduction of a portion corresponding to R ₆ into a side chain corresponding to R ₂ will be described. The reaction can be generally performed by the following two methods. One is a halogenated benzene derivative containing a nitro group represented by the formula (32) and an appropriate substituent as shown in the reaction formula (9) [Formula 28] (In the formula (32), F is indicated as an example of a halogen atom.) ) Is reacted with N, N-bis (hydroxyethyl) amine to give a compound of formula (33). The solvent at this time was DMSO and the reaction temperature was 2
0-100 ° C. The reaction time is preferably from 10 minutes to 4 hours. Reaction of the intermediate of formula (33) with thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride, mesyl chloride or mesyl chloride (in DMF) with a suitable chlorinating agent such as sodium chloride Can be obtained. The reaction is performed at 0-100 ° C. The reaction time is between 20 minutes and 5 hours. The solvent is chloroform,
General solvents such as benzene and toluene can be used. DMF can also be mixed with these solvents. Further, the reaction can be performed without a solvent.

[0037]

Embedded image Alternatively, a nitro group-containing aniline derivative (when p = 0) or an aminoalkylbenzene derivative (when p is 1 or more) of the formula (35) in the reaction formula (10) [Formula 29]
To give a compound of formula (36). At this time, the solvent was 10-80% acetic acid (or p-
Methanol solution of toluenesulfonic acid) and -20
Perform at 50 ° C. An appropriate reaction time is 1 to 50 hours. The compound of formula (37) is chlorinated with a suitable chlorinating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride, mesyl chloride (in DMF) or mesyl chloride and sodium chloride. ) Can be obtained. Reaction is 0-10
The reaction is performed at 0 ° C., and the reaction time is 20 minutes to 5 hours. As the solvent, a general solvent such as chloroform, benzene, and toluene can be used. DMF can also be mixed with these solvents. The reaction can also be carried out without solvent in the case of thionyl chloride, oxalyl chloride or the like.

[0038]

Embedded image When synthesizing a corresponding amino compound from a nitrobenzene derivative, catalytic hydrogenation using Pd / C as a catalyst or a reaction using tin chloride and hydrochloric acid is a general method. However, a reduction method particularly in the case of the above-mentioned nitrobenzene derivative having an N, N-bis (chloroethyl) amino group bonded thereto is conventionally described in, for example, J. Am. Chem. Soc. 194
9 pp. 1972-83; Med. Che
m. As shown in 1990, Vol. 33, pp. 112-121, a method of reducing with tin chloride and hydrochloric acid has been generally known. However, this reduction reaction is performed by the following method.
The reaction can be performed efficiently, and the treatment after the reaction can be performed more easily. That is, first, the nitro compound as a raw material is dissolved in a suitable solvent, for example, ethanol, methanol, ethyl acetate, THF, DMF, alone or in a mixture of two or more, and Pd / C is dissolved in 0.5 to 50% of the nitro compound. An equivalent weight is added and hydrogenated at room temperature and normal pressure to obtain the corresponding amino compound. Also, at this time,
Hydrochloric acid can be added in an equimolar number or more, usually 1 to 1.2 times mol, of the nitro form. The catalyst is removed by filtration, the solvent is distilled off, and a suitable solvent such as ethanol,
The desired hydrochloride can be easily obtained by treating with IPA, ether or the like alone or in combination of two or more.

As shown in reaction formula (11) [Formula 30],
The nitro compound of formula (34) obtained by the previous reactions (reaction formulas (9) and (10)) is converted to an amino compound of formula (38) by catalytic hydrogenation. The nitro compound of the formula (37) can be similarly converted to an amino compound. At the time of catalytic hydrogenation, equimolar or more than the nitro form, generally 1 to
When 1.2 equimolar hydrochloric acid is added, an amino compound can be obtained stably. The catalytic hydrogenation is desirably performed at 5 to 30 ° C., and a general solvent is used as a solvent. For example, DMF or a mixed solvent of DMF and methanol is desirable. The DMF of this mixed solvent can be selected in the range of 5 to 100%, but is preferably 20 to 100%.

[0040]

Embedded image Next, as shown in the reaction formula (12) [Formula 31], the amino compound obtained here and the compound of the formula (14) are combined with a suitable condensing agent,
For example, the compound of formula (39) can be obtained by coupling using DCC, EDCI, DECP or the like. The solvent at this time may be a normal solvent, but DMF or a mixed solvent containing DMF gives relatively good results. Reaction temperature is -5 to 30 ° C
It is better to do it. The reaction may be performed while checking the progress of the reaction, and the reaction time is generally 1 to 50 hours.

[0041]

Embedded image Similarly, as shown in the reaction formula (13) [Formula 32], the formula (1)
The benzimidazole derivative of 4) and the amino compound of formula (31) obtained by the reduction reaction shown in reaction formula (8) are bonded using a general condensing agent (such as CDI, DECP, DCC or DCC and HOBt). Then, the compound of the formula (40) shown in the following reaction formula (13) can be synthesized. The solvent is preferably DMF, but other common solvents can be used. It may be confirmed that the reaction is completed while examining the state of the reaction by TLC or the like, but the reaction is desirably performed in 1 hour to 40 hours. The reaction temperature is preferably from -5C to 40C.

[0042]

Embedded image Here, the compound of the formula (39) is n of the compound of the formula (40)
= 0 may be treated as equivalent. Hereinafter, the reaction formula (19) will be described in the same manner. Reaction formula (1
4) As shown in [Formula 33], the nitro group of the compound of the formula (40) can be reduced to the corresponding amino group by catalytic hydrogenation using Pd / C as a catalyst. The reaction proceeds almost quantitatively. As the solvent at this time, ethanol, methanol or DMF can be used alone or in combination of two or more. At this time, hydrochloric acid can be added in an equimolar number or more, usually 1 to 1.2 times the molar number of the nitro form. The reaction is desirably performed for 10 minutes to 20 hours. The reaction is preferably carried out at a temperature of 0 ° C to 40 ° C.

[0043]

Embedded image The above-mentioned coupling of the aniline derivative in the reaction formula (13) and the subsequent reduction reaction in the reaction formula (14) are new synthesis routes not found in the literatures so far. For example, a binding reaction between a distamycin derivative and N, N-bis (2-chloroethyl) -1,4-phenylenediamine can be seen in JP-A-6-92933. A binding reaction of N, N-bis (2-chloroethyl) -1,4-phenylenediamine is performed. This is to terminate the bonding of the chemically reactive N, N-bis (2-chloroethyl) amino group last. However, the present inventors have shown that, contrary to this seemingly obvious reaction route, the desired compound can be obtained in a high yield even if the aniline derivative moiety is first introduced into the molecule.
As shown in the reaction formula (15) [Formula 34], the amino compound of the formula (41) obtained in the previous reduction reaction is combined with a carboxylic acid derivative of the formula (8) by a general condensing agent (for example, DCC, CDI,
EDCI, DECP, etc.) to link the R ₁ moiety. The solvent used for these reactions may be a general solvent, but DMF or a mixed solvent containing the same gives good results. Reaction time is 30 minutes to 40
Time is desirable. The reaction is preferably carried out at a temperature of 0 ° C to 40 ° C.

[0044]

Embedded image Examples of carboxylic acid derivatives, N, N- dimethyl amino propionic acids, N, the use of the N- dimethylamino butyric acid, can be introduced to an amino group substituted R ₁ moieties. If carboxypropyltrimethylammonium or the like is used, an ammonium group can be introduced into the R ₁ portion. If methylthiopropionic acid or the like is used, an alkylthio group can be introduced. 4-amidinobenzoic acid, 3-
When pyridinecarboxylic acid, 4-piperidinecarboxylic acid, pyrrole-2-carboxylic acid, indole-2-carboxylic acid, or the like is used, an optionally substituted phenyl group, an optionally substituted hetero 5-membered ring group, An optionally substituted hetero 6-membered ring group and an optionally substituted hetero-fused ring group can be introduced. Also, for example, the reaction formula (16)
As shown in [Formula 35], 1H-2- [4- (3-methylthiopropionylamino) -1-methylpyrrole-2
-Yl] benzimidazole-5- [N- [4- [N,
N-bis (2-chloroethyl) amino] phenylamino]] carboxamide hydrochloride was prepared according to J. Am. Org. Chem.
The sulfonium derivative represented by the formula (44) can be obtained according to 1960, Vol. 25, pp. 804-807, or by methylation with a general methylating agent (eg, methyl iodide, dimethyl sulfate, etc.). The solvent used here is formic acid, acetic acid, methanol or the like. The reaction time is desirably 1 to 60 hours. The reaction is preferably carried out at a temperature of 0 ° C to 60 ° C.

[0045]

Embedded image

The counter anion (I ⁻ ) of the sulfonium compound obtained here can be changed to another anion by a known method. For example, DOWEX 1 × 8, Cl
I ⁻ can be exchanged for Cl ⁻ using a ⁻ type ion exchange resin. Similarly, a compound having an amino group substituted by two alkyl groups at R ₁ can be further alkylated to obtain an ammonium compound. Also,
For example, a compound represented by the formula (46) can be obtained by reacting a pyridine derivative represented by the formula (45) represented by the reaction formula (17) with a compound represented by the formula (41). At this time, the pyridine derivative is converted to an acid chloride using a general reagent such as thionyl chloride, and bound using a general solvent such as methylene chloride or chloroform and further using a general base such as triethylamine. can do. The reaction is desirably performed at -5 ° C to 50 ° C. The reaction time is preferably 1 hour to 50 hours. Alternatively, the pyridine derivative can be condensed with the compound represented by the formula (41) using a suitable condensing agent such as DCC, CDI, EDCI, EDCP and the like. At this time, a common solvent such as DMF, chloroform, methylene chloride or the like is used. The reaction is desirably performed at -5 ° C to 50 ° C. The reaction time is preferably 1 hour to 50 hours.

[0047]

Embedded image Next, as shown in the reaction formula (18) [Formula 37], the formula (4)
The compound represented by formula (47) can be obtained by methylating the compound represented by 6) using methyl iodide. The solvent at this time is an ordinary solvent such as methanol, acetone,
Chloroform, methylene chloride and the like are used. The reaction is-
It is desirable to carry out at 5 ° C to 50 ° C. The reaction time is preferably 1 hour to 50 hours.

[0048]

Embedded image By reacting guanidine acetic acid with the amino compound of formula (41) shown in reaction formula (19) [formula 38], a compound of formula (48) in which guanidine is introduced into R ₁ can be synthesized.

[0049]

Embedded image This guanidino group undergoes acylation. A substituted guanidine derivative can be introduced into R ₁ by reacting an acid anhydride or an acid chloride. The reaction temperature is -5 to 30C,
As the solvent, a common solvent such as chloroform, benzene, toluene and DMF can be used alone or in combination of two or more. The reaction time is 1 to 50 hours. A carboxylic acid derivative containing a cyano group such as 3-cyanopropionic acid is converted into a general condensing agent (DCC, CDI, EDCI, DECP, etc.)
To join. The solvent used for this reaction may be a general solvent, but DMF or a mixed solvent containing the same gives good results. The reaction time is desirably 1 to 24 hours. The reaction temperature is desirably 0 to 40 ° C. Further, this was blown with hydrochloric acid gas using ethanol as a solvent (0 to 30).
C., 20 minutes to 2 hours), and an amino compound may be further reacted to synthesize an optionally substituted amidino compound. For example, an amidino compound can be synthesized by reacting ammonium acetate or blowing ammonia gas. For example, an amidino compound substituted with a methyl group can be synthesized by using methylamine. As a solvent used in this reaction, ethanol, methanol, a mixed solvent thereof or the like is used. The reaction time is preferably 30 minutes to 24 hours. Other compounds can be synthesized by changing the raw materials under the above conditions.

Next, the compounds of Group C will be described. As shown in the reaction formula (20) [Chemical formula 39], the compound represented by the formula (49) is subjected to catalytic hydrogenation at room temperature and pressure to obtain the corresponding compound (5).
Reduction to the amino compound of 0). The solvent used at this time was ethanol, methanol or DMF alone or
A mixture of more than one species can be used. At this time, hydrochloric acid can be added in an equimolar number or more, usually 1 to 1.2 times the molar number of the nitro form. Reaction is 10 minutes to 20 minutes
It is desirable to do it in time. The reaction temperature is desirably 0 to 40 ° C. Thereafter, the amino compound of the formula (50) shown in the reaction formula (21) [Formula 40] is reacted with the carboxylic acid derivative of the formula (51) to obtain the compound shown in the formula (52). At this time, a general condensing agent (for example, DCC, CD
I, EDCI, DECP, etc.). The solvent used for these reactions may be a general solvent, but DMF or a mixed solvent containing the same gives good results. The reaction time is preferably 30 minutes to 40 hours. The reaction temperature is desirably 0 to 40 ° C. The synthesis method is essentially the same as the above-mentioned compounds of Group A or Group B. In the compounds of Group C, a portion corresponding to Formula (2) is bonded to R ₁ and R ₂ .

[0051]

Embedded image

[0052]

Embedded image Examples of compounds included in the formula (1) of the present invention are shown in Tables 1 to 1.
4 [Tables 1-236]. In this table, the counter anions of the ammonium group and the sulfonium group are not shown. The counter anion may be any pharmacologically acceptable one. However, when it is necessary to specify the counter anion, it is specifically described.

[0053]

[Table 1]

[0054]

[Table 2] Table 1 (continued 1)

[0055]

[Table 3] Table-1 (continued 2)

[0056]

[Table 4] Table 1 (continued 3)

[0057]

[Table 5] Table-1 (continued 4)

[0058]

[Table 6] Table-1 (continued 5)

[0059]

[Table 7] Table 1 (continued 6)

[0060]

[Table 8] Table-1 (continued 7)

[0061]

[Table 9] Table-1 (continued 8)

[0062]

[Table 10] Table-1 (continued 9)

[0063]

[Table 11] Table-1 (continued 10)

[0064]

[Table 12] Table-1 (continued 11)

[0065]

[Table 13] Table-1 (continued 12)

[0066]

[Table 14] Table-1 (continued 13)

[0067]

[Table 15] Table-1 (continued 14)

[0068]

[Table 16] Table-1 (continued 15)

[0069]

[Table 17] Table-1 (continued 16)

[0070]

[Table 18] Table-1 (continued 17)

[0071]

[Table 19] Table-1 (continued 18)

[0072]

[Table 20] Table-1 (continued 19)

[0073]

[Table 21] Table-1 (continued 20)

[0074]

[Table 22] Table-1 (continuation 21)

[0075]

[Table 23] Table-1 (continued 22)

[0076]

[Table 24] Table-1 (continued 23)

[0077]

[Table 25] Table-1 (continued 24)

[0078]

[Table 26] Table-1 (continued 25)

[0079]

[Table 27] Table-1 (continued 26)

[0080]

[Table 28] Table-1 (continued 27)

[0081]

[Table 29] Table-1 (continued 28)

[0082]

[Table 30] Table-1 (continued 29)

[0083]

[Table 31] Table-1 (continuation 30)

[0084]

[Table 32] Table-1 (continuation 31)

[0085]

[Table 33] Table-1 (continued 32)

[0086]

Table 34 Table 1 (continued 33)

[0087]

[Table 35] Table-1 (continued 34)

[0088]

[Table 36] Table-1 (continued 35)

[0089]

[Table 37] Table-1 (continued 36)

[0090]

[Table 38] Table-1 (continued 37)

[0091]

[Table 39] Table-1 (Continued 38)

[0092]

Table 40 Table-1 (continued 39)

[0093]

[Table 41] Table-1 (continued 40)

[0094]

[Table 42] Table-1 (continued 41)

[0095]

[Table 43] Table-1 (continued 42)

[0096]

[Table 44] Table-1 (continued 43)

[0097]

[Table 45] Table-1 (continued 44)

[0098]

[Table 46] Table-1 (continued 45)

[0099]

[Table 47] Table-1 (Continued 46)

[0100]

[Table 48] Table-1 (continued 47)

[0101]

Table 49 Table 1 (continued 48)

[0102]

Table 50 Table-1 (Continued 49)

[0103]

Table 51 Table-1 (continued 50)

[0104]

[Table 52] Table-1 (continued 51)

[0105]

[Table 53] Table-1 (continued 52)

[0106]

Table 54 (Table 53)

[0107]

Table 55 Table 1 (Continued 54)

[0108]

[Table 56] Table-1 (continued 55)

[0109]

[Table 57] Table-1 (continued 56)

[0110]

[Table 58] Table-1 (Continued 57)

[0111]

[Table 59] Table-1 (Continued 58)

[0112]

[Table 60] Table-1 (Continued 59)

[0113]

Table 61 Table 1 (continued 60)

[0114]

[Table 62] Table-1 (continued 61)

[0115]

[Table 63] Table-1 (continued 62)

[0116]

[Table 64] Table-1 (continuation 63)

[0117]

[Table 65] Table-1 (continuation 64)

[0118]

[Table 66] Table-1 (continuation 65)

[0119]

[Table 67] Table-1 (continuation 66)

[0120]

[Table 68] Table-1 (continuation 67)

[0121]

[Table 69] Table-1 (Continued 68)

[0122]

[Table 70] Table-1 (continued 69)

[0123]

[Table 71] Table-1 (continuation 70)

[0124]

[Table 72] Table-1 (continued 71)

[0125]

[Table 73] Table-1 (continued 72)

[0126]

[Table 74] Table-1 (continued 73)

[0127]

[Table 75] Table-1 (continued 74)

[0128]

[Table 76] Table-1 (continued 75)

[0129]

[Table 77] Table-1 (continued 76)

[0130]

[Table 78] Table-1 (continuation 77)

[0131]

[Table 79] Table-1 (continued 78)

[0132]

[Table 80] Table-1 (continued 79)

[0133]

[Table 81] Table-1 (continued 80)

[0134]

[Table 82] Table-1 (continued 81)

[0135]

[Table 83] Table-1 (continued 82)

[0136]

[Table 84] Table-1 (continued 83)

[0137]

Table 85 Table 1 (continued 84)

[0138]

[Table 86] Table-2

[0139]

[Table 87] Table-2 (Continued 1)

[0140]

[Table 88] Table-2 (continued 2)

[0141]

[Table 89] Table-2 (continued 3)

[0142]

[Table 90] Table-2 (continued 4)

[0143]

[Table 91] Table-2 (continued 5)

[0144]

[Table 92] Table-2 (continued 6)

[0145]

[Table 93] Table-2 (continued 7)

[0146]

[Table 94] Table-2 (continued 8)

[0147]

[Table 95] Table-2 (continued 9)

[0148]

[Table 96] Table-2 (continued 10)

[0149]

[Table 97] Table-2 (continued 11)

[0150]

[Table 98] Table-2 (continued 12)

[0151]

[Table 99] Table-2 (Continued 13)

[0152]

[Table 100] Table-2 (continued 14)

[0153]

[Table 101] Table-2 (continued 15)

[0154]

[Table 102] Table-2 (continued 16)

[0155]

[Table 103] Table-2 (continuation 17)

[0156]

[Table 104] Table-2 (continued 18)

[0157]

[Table 105] Table-2 (continued 19)

[0158]

[Table 106] Table-2 (continued 20)

[0159]

[Table 107] Table-2 (continuation 21)

[0160]

[Table 108] Table-2 (continued 22)

[0161]

[Table 109] Table-2 (Continued 23)

[0162]

[Table 110] Table-2 (continued 24)

[0163]

[Table 111] Table-2 (continued 25)

[0164]

[Table 112] Table-2 (continued 26)

[0165]

[Table 113] Table-2 (continuation 27)

[0166]

[Table 114] Table-2 (continued 28)

[0167]

[Table 115] Table-2 (Continued 29)

[0168]

[Table 116] Table-2 (continuation 30)

[0169]

[Table 117] Table-2 (continuation 31)

[0170]

[Table 118] Table-2 (continuation 32)

[0171]

[Table 119] Table-2 (continued 33)

[0172]

[Table 120] Table-2 (continued 34)

[0173]

[Table 121] Table-2 (continued 35)

[0174]

[Table 122] Table-2 (continued 36)

[0175]

[Table 123] Table-2 (continued 37)

[0176]

[Table 124] Table-2 (continued 38)

[0177]

Table 125 Table 2 (continued 39)

[0178]

[Table 126] Table-2 (continuation 40)

[0179]

[Table 127] Table-2 (continuation 41)

[0180]

[Table 128] Table-2 (continued 42)

[0181]

[Table 129] Table-2 (continued 43)

[0182]

[Table 130] Table-2 (continued 44)

[0183]

[Table 131] Table-2 (continued 45)

[0184]

[Table 132] Table-2 (Continued 46)

[0185]

[Table 133] Table-2 (continued 47)

[0186]

[Table 134] Table-2 (Continued 48)

[0187]

[Table 135] Table-2 (continued 49)

[0188]

[Table 136] Table-2 (continued 50)

[0189]

[Table 137] Table-2 (Continued 51)

[0190]

[Table 138] Table-2 (continued 52)

[0191]

[Table 139] Table-2 (continued 53)

[0192]

[Table 140] Table-2 (Continued 54)

[0193]

[Table 141] Table-12 continued 55)

[0194]

[Table 142] Table-2 (Continued 56)

[0195]

[Table 143] Table-2 (continued 57)

[0196]

[Table 144] Table-2 (Continued 58)

[0197]

[Table 145] Table-2 (continued 59)

[0198]

[Table 146] Table-2 (continued 60)

[0199]

[Table 147] Table-2 (continued 61)

[0200]

[Table 148] Table-2 (continued 62)

[0201]

[Table 149] Table-2 (continuation 63)

[0202]

[Table 150] Table-2 (continuation 64)

[0203]

[Table 151] Table-12 continued 65)

[0204]

[Table 152] Table-2 (continued 66)

[0205]

[Table 153] Table-2 (Continued 67)

[0206]

[Table 154] Table-2 (Continued 68)

[0207]

[Table 155] Table-2 (Continued 69)

[0208]

[Table 156] Table-2 (continued 70)

[0209]

[Table 157] Table-2 (continued 71)

[0210]

[Table 158] Table-2 (continued 72)

[0211]

[Table 159] Table-2 (continued 73)

[0212]

[Table 160] Table-2 (continuation 74)

[0213]

[Table 161] Table-2 (continued 75)

[0214]

[Table 162] Table-2 (continued from 76)

[0215]

[Table 163] Table-2 (continuation 77)

[0216]

[Table 164] Table-2 (continued 78)

[0219]

[Table 165] Table-2 (continued 79)

[0218]

[Table 166] Table-2 (continued 80)

[0219]

Table 167 Table 2 (continued 81)

[0220]

[Table 168] Table-2 (Continued 82)

[0221]

[Table 169] Table 12 continued 83)

[0222]

[Table 170] Table-2 (continued 84)

[0223]

[Table 171] Table-2 (continued 85)

[0224]

[Table 172] Table-2 (continued 86)

[0225]

[Table 173] Table-2 (Continued 87)

[0226]

[Table 174] Table-2 (Continued 88)

[0227]

[Table 175] Table-2 (continued 89)

[0228]

[Table 176] Table-2 (continued 90)

[0229]

[Table 177] Table-2 (continued from 91)

[0230]

[Table 178] Table-2 (continued 92)

[0231]

[Table 179] Table-2 (Continued 93)

[0232]

[Table 180] Table-2 (Continued 94)

[0233]

[Table 181] Table-2 (continued 95)

[0234]

[Table 182] Table-2 (continued 96)

[0235]

[Table 183] Table-2 (continued 97)

[0236]

[Table 184] Table-2 (continued 98)

[0237]

[Table 185] Table-2 (continued 99)

[0238]

[Table 186] Table-2 (continued 100)

[0239]

[Table 187] Table-2 (continuation 101)

[0240]

[Table 188] Table-2 (continued 102)

[0241]

[Table 189] Table-2 (Continued 103)

[0242]

[Table 190] Table-2 (Continued 104)

[0243]

[Table 191] Table-2 (Continued 105)

[0244]

[Table 192] Table-2 (Continued 106)

[0245]

[Table 193] Table-2 (Continued 107)

[0246]

[Table 194] Table-2 (Continued 108)

[0247]

[Table 195] Table-2 (Continued 109)

[0248]

[Table 196] Table-2 (continuation 110)

[0249]

[Table 197] Table-2 (continued 111)

[0250]

[Table 198] Table-2 (Continued 112)

[0251]

[Table 199] Table-2 (continuation 113)

[0252]

[Table 200] Table-2 (continued 114)

[0253]

[Table 201] Table-2 (continued 115)

[0254]

[Table 202] Table-2 (Continued 116)

[0255]

[Table 203] Table-2 (Continued 117)

[0256]

[Table 204] Table-2 (Continued 118)

[0257]

Table 205 Table-2 (Continued 119)

[0258]

[Table 206] Table-2 (continuation 120)

[0259]

[Table 207] Table-2 (continuation 121)

[0260]

[Table 208] Table-2 (Continued 122)

[0261]

[Table 209] Table-3

[0262]

Table 210 (Continued 1)

[0263]

[Table 211] Table-3 (continuation 2)

[0264]

[Table 212] Table-3 (continuation 3)

[0265]

[Table 213] Table-3 (continuation 4)

[0266]

[Table 214] Table-3 (Continued 5)

[0267]

[Table 215] Table-3 (continuation 6)

[0268]

[Table 216] Table-3 (continued 7)

[0269]

[Table 217] Table-3 (continued 8)

[0270]

[Table 218] Table-3 (continued 9)

[0271]

[Table 219] Table-3 (continued 10)

[0272]

Table 220 (Continued 11)

[0273]

[Table 221] Table-3 (continued 12)

[0274]

[Table 222] Table-3 (Continued 13)

[0275]

[Table 223] Table-3 (continued 14)

[0276]

[Table 224] Table-3 (continuation 15)

[0277]

[Table 225] Table-3 (continuation 16)

[0278]

[Table 226] Table-3 (continued 17)

[0279]

[Table 227] Table-3 (continued 18)

[0280]

[Table 228] Table-3 (continued 19)

[0281]

[Table 229] Table-3 (continued 20)

[0282]

[Table 230] Table-3 (continuation 21)

[0283]

[Table 231] Table-4

[0284]

[Table 232] Table-4 (continued 1)

[0285]

[Table 233] Table-4 (continued 2)

[0286]

[Table 234] Table-4 (continued 3)

[0287]

[Table 235] Table-4 (continued 4)

[0288]

[Table 236] Table-4 (continued 5)

The compounds of the present invention can be used as anticancer agents having excellent activity. The carcinomas used are leukemia, osteosarcoma, breast cancer, ovarian cancer, stomach cancer, colon cancer, lung cancer, head and neck cancer and the like. Alternatively, these compounds can be used as antibacterial agents and antiviral agents. Formulation can be performed by a known method. As the dosage form, various forms can be selected according to the purpose of treatment, and representative examples thereof include solid preparations, liquid preparations, and other suppositories. More specifically,
Various preparations are as follows. As solid preparations, tablets,
Pills, powders, granules, capsules, etc., as liquids, besides injections as solutions, suspensions, syrups, emulsions, etc.
As other preparations, suppositories and the like can be considered.

In molding into tablets, various carriers well known in the art can be widely used. Examples include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin. Solution, shellac solution,
Binders such as methylcellulose solution, hydroxypropylcellulose solution, polyvinylpyrrolidone solution, carboxymethylcellulose solution, dried starch, sodium alginate, agar powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid Disintegrators such as monoglycerides, starch, lactose, sucrose, stearic acid, cocoa butter, disintegration inhibitors such as hydrogenated oils, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, Adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, crystalline cellulose, light anhydrous silicic acid, and lubricants such as talc, stearates, boric acid powder, and polyethylene glycol; Further, in the case of tablets, tablets which have been coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets or multi-layer tablets can be prepared.

In molding into the form of pills, those conventionally known in the art can be widely used as carriers. Examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, binders such as gum arabic, powder tragacanth, gelatin, disintegrants such as carmellose calcium, agar and the like. Can be mentioned. Capsules are prepared according to a conventional method, usually by mixing the active ingredient compound with the various carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like.

When the composition is prepared as an injection, when it is formed into a liquid, emulsion or suspension, it is generally used as a diluent in the art, for example, water, ethanol, macrogol, propylene glycol, ethoxylated. Isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, cottonseed oil, corn oil, peanut oil, olive oil and the like can be used. Further, water is added to the compound of the present invention, and the compound is used as a suspension aqueous solution in the presence of a suitable surfactant, or as an emulsion using a surfactant such as HCO-60. In addition, salt, glucose or glycerin may be contained in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent and the like may be added.

In the case of molding into a suppository form, conventionally known carriers can be widely used. Examples include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters,
Gelatin, semi-synthetic glyceride and the like can be mentioned. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals can be contained in the pharmaceutical preparation. The amount of the active ingredient compound to be contained in these pharmaceutical preparations of the present invention is not particularly limited and is appropriately selected from a wide range.
It is preferably 70% by weight, preferably about 5 to 50% by weight.

The administration method of these pharmaceutical preparations of the present invention is not particularly limited, and the pharmaceutical preparations are administered according to various preparation forms, age, sex and other conditions of patients, and degree of disease. For example,
In the case of tablets, pills, solutions, suspensions, emulsions, powders, granules, syrups and capsules, they are orally administered.
In the case of an injection, it is administered intravenously, alone or mixed with a normal replenisher such as glucose or amino acid, and if necessary, intramuscularly, subcutaneously or intraperitoneally.
Suppositories are administered rectally. Dosage of these pharmaceutical preparations of the present invention, dosage, age of patient, gender and other conditions,
Although it is appropriately selected depending on the degree of the disease, the amount of the active ingredient compound is usually preferably about 0.001 to 1000 mg per adult per day. It is desirable that the active ingredient compound is contained in the dosage unit form in the range of about 0.001 to 1000 mg. Generally speaking, even if a general drug such as adriamycin or cisplatin is used, it cannot be said that the side effect is small. From the state of the art, side effects should be considered in relation to potency and are somewhat unavoidable.
The side effect of the compound of the present invention is at a level that is not problematic to the extent that it is used as an anticancer agent.

[0295]

The present invention will be described below with reference to examples, but the present invention is not limited to these examples. In addition, the compound numbers shown in parentheses after the example numbers are shown in Table-1 to Table-
4 This corresponds to the compound number shown in [Tables 1 to 236]. Reference Production Example 1 Methyl 3,4-diaminobenzoate 3.0 g of 3,4-diaminobenzoic acid was suspended in methanol, and 1.86 mL of thionyl chloride was added dropwise. Thionyl chloride was added twice in 0.5 mL portions, and the mixture was heated under reflux for 10 hours and 40 minutes. Thionyl chloride and methanol are distilled off, dissolved in methylene chloride, washed with 0.5N aqueous sodium hydroxide solution and saturated saline, dried over sodium sulfate, and the solvent is distilled off.
-Sludge with hexane and dry to obtain the desired product 3.04
g (93%).

Reference Production Example 2 (Reaction 1) 3- [N, N-bis (2-hydroxyethyl
Le) amino] nitrobenzene 3-aminonitrobenzene 5.0 g (36.2 mmol)
1) was dissolved in 36 mL of 30% acetic acid, 22.9 mL of ethylene oxide was added under ice cooling, and the mixture was stirred overnight at room temperature. The mixture was extracted with ethyl acetate, concentrated after drying with sodium sulfate, and the residue was sludged with ether to obtain 5.21 g (23.0 mmol, 63.6%) of the title compound as yellow crystals. mp. 98.5-100 ° C (Reaction 2) 3- [N, N-bis (2-chloroethyl)
Amino] nitrobenzene 2.5 g (11.0 mmol) of 3- [N, N-bis (2-hydroxyethyl) amino] nitrobenzene is suspended in 25 mL of toluene, and 10.2 g (8.
5.7 mmol, 7.8 eq. ) And heated and stirred in an oil bath at 70 ° C. for 5 hours. The mixture was concentrated under reduced pressure, separated with ethyl acetate-water, extracted with ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure, and the residue was sludged with ether to give 2.67 g of the title compound (10.1 mmol, 9
2.2%) as yellow crystals. mp. 112-113 ° C (Reaction 3) N, N-bis (2-chloroethyl) -1,
3-phenylenediamine hydrochloride 3- [N, N-bis (2-chloroethyl) amino] nitrobenzene (2.0 g, 7.6 mmol) was added to concentrated hydrochloric acid (35 m).
L, and 6.9 g of tin (II) chloride dihydrate (3
0.6 mmol, 4.0 eq. ) And heated and stirred in an oil bath at 100 ° C. for 1 hour. The mixture was allowed to cool to room temperature, diluted with water, made basic with concentrated aqueous ammonia, extracted twice with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was concentrated by adding 4N hydrochloric acid / dioxane, and the residue was crystallized from a small amount of methanol / ether to obtain 1.97 g (7.3 mmol, 96.1%) of the title compound as yellow crystals. mp. 195-201 ° C

Example 1 (Compound 3017) 1H-2- (1-methyl-4-nitropyrrole-2-i
B) Benzimidazole-5-carboxylic acid (Reaction 1) 1-methyl-4-nitropyrrole-2-cal
Boxyaldehyde 1-methylpyrrole-2-carboxaldehyde 25 g
(0.23 mol) of acetic anhydride solution (200 mL)
Cooled to ° C. To this solution, 17.6 g of fuming nitric acid was added dropwise over 30 minutes, and the mixture was further stirred at -40 ° C for 1 hour and at -10 ° C for 2 hours. The reaction solution was poured on ice and left overnight. After extraction with ethyl acetate and neutralization with sodium hydrogen carbonate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-n-hexane, 1: 2).
Recrystallization from ethanol-water (5: 1) gave brown crystals.
67 g (16%) were obtained. (Reaction 2) 1H-2- (1-methyl-4-nitropyrro
Ru-2-yl) benzimidazole-5-carboxylic acid
Chill 1-methyl-4-nitro-pyrrole-2-carboxaldehyde 3.0 g (19.5 mmol), nitrobenzene solution 300mL of 3,4-diaminobenzoic acid methyl 3.4 g (20.5 mmol) at 150 to 160 ° C. 32
Heated to reflux for an hour. After completion of the reaction, the precipitated powder was separated by filtration, washed with 100 mL of IPA, and 4.79 g of a yellow powder was obtained.
(81.9%). IR (KBr) cm ^-1 : 3246, 1691, 162
8,1300,751 (Reaction 3) 1H-2- (1-methyl-4-nitropyrro
M-2- ( yl-2-ben) benzimidazole-5-carboxylic acid 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5-carboxylate 4.7
g (15.6 mmol) in ethanol solution (30 mL), potassium hydroxide (4.4 g) aqueous solution (30 mL) was added,
For 2.5 hours. After the completion of the reaction, the mixture was acidified with concentrated hydrochloric acid while it was warm, cooled to room temperature, and the precipitated powder was collected by filtration. After washing with water and ethanol, it was dried to obtain 4.1 g (92.4%) of pale yellow powder. IR (KBr) cm ^-1 : 3133, 1655, 162
5,1310,1120

Example 2 (Compound 318) 1H-2- (4-formylamino-1-methylpyrrole
-2-yl) benzimidazole-5- [N- (2-A
Midinoethyl)] carboxamide hydrochloride (Reaction 1) 1H-2- (1-methyl-4-nitropyrro
Ru-2-yl) benzimidazole-5- [N- (2-
Cyanoethyl)] carboxamide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5-carboxylic acid 608 mg
(2.13 mmol) in 18 mL of DMF
48 mg (2.76 mmol) were added and the mixture was added at room temperature for 30
Stirred for minutes. 446 mg of 2-aminopropionitrile
(6.38 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. After concentration, ethanol was added and the precipitated crystals were collected by filtration to obtain 360 mg (50%) of the desired product as pale yellow crystals. (Reaction 2) 1H-2- (1-methyl-4-nitropyrro
Ru-2-yl) benzimidazole-5- [N- (2-
Amidinoethyl)] carboxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- (2-cyanoethyl)] carboxamide (1.8 g, 5.32 mmol) in ethanol The suspension was suspended in 100 mL and stirred at 0 ° C. for 30 minutes while blowing hydrochloric acid gas. After stirring at room temperature for 1 hour while blowing in hydrochloric acid gas, nitrogen gas was blown in to remove excess hydrochloric acid gas. After concentration under reduced pressure, the residue was washed with ether. The suspension was suspended again in 60 mL of an ethanol-methanol (1: 1) mixed solvent, and stirred while blowing ammonia gas. After the completion of the reaction, nitrogen gas was blown in to remove excess ammonia gas, and the mixture was dried under reduced pressure. IPA was added to the residue, and the insolubles were collected by filtration to obtain 2.0 g (95.9%) of a yellow powder. (Reaction 3) 1H-2- (4-formylamino-1-methyl)
Rupyrol-2-yl) benzimidazole-5- [N
-(2-amidinoethyl)] carboxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- (2-amidinoethyl)] carboxamide hydrochloride 200 mg (0 mg .51m
mol) in a mixed solvent of DMF and methanol 1: 1 12 mL
And 1N hydrochloric acid 0.7 mL, 5% Pd / C180m
g was added and the inside of the reaction vessel was replaced with nitrogen. Under hydrogen atmosphere,
Stirred at room temperature for 2 hours. After completion of the reaction, the inside of the vessel was replaced with nitrogen again, and 5% Pd / C was filtered off, and methanol was distilled off under reduced pressure. The solution was cooled to 0 ° C., and 0.17 mL of triethylamine was added under a nitrogen atmosphere. To this solution, 5 mL of a tetrahydrofuran solution of N-formylimidazole (5 equivalents) prepared immediately before, 0.1 mL of formic acid (2.5 mL)
3 mmol) in 5 mL of tetrahydrofuran solution
Add 410 mg (2.53 mmol) of I
What was stirred for 1 minute was added. After stirring for 30 minutes, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / IPA / water = 5/2/1) to obtain 187 mg (94%) of a white powder. IR (KBr) cm ^-1 : 3276, 2938, 236
3,1636,1542,1519,1473,131
2 Elemental analysis: Calculated value (C ₃₀ H ₃₆ N ₈ O ₂ Cl ₂ .HCl.
_{0.5H 2 O): C: 54.84} , H: 5.83, N:
17.05, analysis value C: 55.07, H: 6.14,
N: 16.98

Example 3 (Compound 4)1H-2- [4- [4- [4- [N, N-bis (2-k
Loroethyl) amino] phenyl] butyrylamino] -1
-Methylpyrrol-2-yl] benzimidazole-5
-[N- (2-amidinoethyl)] carboxamide hydrochloride
salt 1H-2- (4-amino-1-methyl-2-pyrrole)
Benzimidazole-5- [N- (2-amidinoethyl
)] Carboxamide dihydrochloride 645 mg (1.62 m
mol), 739 mg of chlorambucil (2.43 mmol)
l), DCC 601 mg (2.91 mmol) and catalyst
Amount of DMAP in 19 mL of DMF
Add 164 mg (1.62 mmol) and add 3 hours at room temperature
Stirred. After completion of the reaction, the precipitated powder was filtered off, and the filtrate was filtered.
Concentrated. Flash column chromatography of the residue
(Ethyl acetate / IPA / water = 6/2/1)
170 mg of the product were obtained as pale red crystals. mp. ≧ 289 ° C (dec) IR (KBr) cm^-1: 3276, 2939, 236
3, 1637, 1542, 1519, 1474 Elemental analysis: Calculated value (C₃₀H₃₆N₈O_TwoCl_Two・ HCl  
 ) C: 55.60, H: 5.75, N: 17.29,
Analytical value C: 55.27, H: 6.14, N: 16.98

Example 4 (Compound 1) 1H-2- [4- [4- [N, N-bis (2-chloroe
Tyl) amino] benzoylamino] -1-methyl pillow
Ru-2-yl] benzimidazole-5- [N- (2-
Amidinoethyl)] carboxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- (2-amidinoethyl)] carboxamide hydrochloride (reaction 2 of Example 2) 500 mg (1.28 mmol) was dissolved in 30 mL of a 1: 1 mixed solvent of DMF-methanol, and 5% Pd / C
250 mg was added, and the inside of the reaction vessel was replaced with nitrogen. After stirring at room temperature for 2 hours in a hydrogen atmosphere, the mixture was further heated at 40 ° C. for 1 hour. After the completion of the reaction, the inside of the vessel was replaced with nitrogen again,
Pd / C was filtered off, and methanol was distilled off under reduced pressure. The solution was cooled to −40 ° C., and under a nitrogen atmosphere, 5 mL of a solution of 4- [N, N-bis (2-chloroethyl) amino] benzoic acid chloride (1.1 equivalent) in methylene chloride prepared immediately before.
Was added dropwise. After stirring for 30 minutes, it was left overnight. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / IPA / water = 6/2/1) to obtain 91 mg of a white powder. IR (KBr) cm ^-1 : 3329,2361,169
2,1607,1545,1281,759 Calcd _{(C 27 H 31 N 8 O} 2 Cl 3 + 2H 2 O)
C: 50.51, H: 5.50, N: 17.45, analysis value C: 50.37, H: 5.39, N: 17.20

Example 5 (Compound 326) 1H-2- (4-benzoylamino-1-methyl pillow
Ru-2-yl) benzimidazole-5- [N- (2-
Amidinoethyl)] carboxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- (2-amidinoethyl)] carboxamide hydrochloride 216 mg (5.51 m)
mol) in a 1: 1 mixed solvent of DMF-methanol 20m
Ld, and 200 mg of 5% Pd / C was added, followed by stirring at room temperature for 3 hours under a hydrogen atmosphere. After the reaction, the inside of the vessel was replaced with nitrogen again, Pd / C was separated by filtration, and methanol was distilled off under reduced pressure. The solution was cooled to 0 ° C., and under a nitrogen atmosphere, 5 mL of a solution of benzoic acid chloride (1.1 equivalent) in methylene chloride.
Was added dropwise. After stirring for 30 minutes, it was left overnight. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / IPA / water = 6/2/1) to obtain 50 mg (19.5%) of a white powder. IR (KBr) cm ^-1 : 3294, 1690, 163
8,1552,1309,708

Example 6 (Compound 341)1H-2- [4- (guanidinoacetylamino) -1-
Methylpyrrole-2-yl] benzimidazole-5
[N- (2-amidinoethyl)] carboxamide dihydrochloride
salt 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- (2-amidinoe)
Tyl)] carboxamide hydrochloride 33.1 mg (0.08
42 mmol) in a 1: 1 mixed solvent of methanol and DMF
Dissolve in 8.3 mL and use 16.0 mg of 10% Pd / C
After hydrogenation at room temperature to lead to the corresponding amino compound,
38.9 mg of anidine acetate hydrochloride (0.253 mmol
l), 53.9 mg (0.261 mmol) of DCC was added.
I got it. Stir at room temperature for 1 day, concentrate and flash residue
By ram chromatography (ODS, methanol-water)
Purification gave 19.5 mg (47%) of the desired product as colorless crystals.
Was. mp. 180-187 ° C (dec) IR (KBr) cm^-1: 3398, 1648, 156
1,1399,1320,1236 Elemental analysis: Calculated value (C₁₉H_{twenty four}N_TenO_Two・ 2HCl ) C:
45.88, H: 5.27, N: 28.16, analysis value
C: 45.83, H: 5.00, N: 28.02

Example 7 (Compound 340) 1H-2- (4-guanidinoacetylamino-1-methyl)
Rupyrol-2-yl) benzimidazole-5- [N
-(3-dimethylaminopropyl)] carboxamide salt
Acid salt (reaction 1) 1H-2- (1-methyl-4-nitropyrro
Ru-2-yl) benzimidazole-5- [N- (3-
Dimethylaminopropyl)] carboxamide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5-carboxylic acid 44.5 mg
(0.155 mmol) in DMF (1.3 mL) was added with 30.3 mg (0.187 mmol) of CDI,
Stirred at room temperature for 30 minutes. After concentrating, ethanol was added and the precipitated crystals were collected by filtration to obtain 43.8 m of the desired pale yellow crystals.
g (76%). mp. 244-246 ° C (Reaction 2) 1H-2- (4-guanidinoacetylamino
-1-methylpyrrole-2-yl) benzimidazole
-5- [N- (3-dimethylaminopropyl)] carbo
13.2 mg (0.0 mg of oxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- (3-dimethylaminopropyl)] carboxamide.
356 mmol) was dissolved in 1.4 mL of a 1: 1 mixed solvent of methanol-DMF, 6.8 mg of 10% Pd / C was added, and the mixture was hydrogenated at room temperature. Pd / C was filtered off and washed with DMF. Guanidine acetate hydrochloride 1 was added to the filtrate under a nitrogen atmosphere.
6.4 mg and DCC 22.8 mg (0.110 mmol
l) was added. After stirring at room temperature for 30 minutes under light shielding, the mixture was concentrated.
After concentration, the residue was subjected to flash column chromatography (ODS: methanol / water = 0/1 → 1/10), and the crystals obtained by concentration were dissolved in methanol. This gave 9.5 mg (56%) of the desired product as colorless crystals. mp. 190-195 ° C (dec)

Example 8 (Compound 321) 1H-2- (4-formylamino-1-methylpyrrole
-2-yl) benzimidazole-5- [N- (3-di
Methylaminopropyl)] 186 mg (4.03 mmol) of formic acid was added dropwise to a THF solution of 653 mg (4.03 mmol) of carboxamide hydrochloride CDI, and the mixture was stirred for 15 minutes. -2-yl) benzimidazole-5- [N-
(3-Dimethylaminopropyl)] carboxamide (0.805 mmol) dissolved in a mixed solvent of methanol and DMF was added dropwise at -40 ° C. 15 at room temperature
After stirring for minutes, the mixture was concentrated, separated by silica gel column chromatography (methanol / chloroform / aqueous ammonia), and the obtained oil was treated with IPA and ethyl acetate.
The mixture was treated with 4N hydrochloric acid to give 240 mg of the desired product as colorless crystals (7 mg).
4%). mp. 123-128 ° C (dec)

Example 9 (Compound 84) 1H-2- [4- [4- [N, N-bis (2-chloroe
Tyl) amino] phenylbutyrylamino] -1-methyl
Pyrrole-2-yl] benzimidazole-5- [N-
(3-dimethylaminopropyl)] carboxamide hydrochloride
In the same manner as in Example 3, 1H-2- (4-amino-1
-Methylpyrrol-2-yl) benzimidazole-5
-[N- (3-Dimethylaminopropyl)] carboxamide hydrochloride was combined with chlorambucil to give the title compound. mp. 134-140 ° C IR (KBr) cm ^-1 : 3424, 3282, 295
5,1655,1648,1579,1519,146
0

Example 10 (Compound 320)1H-2- (4-formylamino-1-methylpyrrole
-2-yl) benzimidazole-5- [N- (3,
4,5-trimethoxyphenyl)] carboxamide (Reaction 1)1H-2- (1-methyl-4-nitro pillow
Ru-2-yl) benzimidazole-5- [N- (3,
4,5-trimethoxyphenyl)] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) 233 mg of benzimidazole-5-carboxylic acid
(0.814 mmol), 218 mg of DCC (1.06
mmol), HOBt 132 mg (0.977 mmol
l) was stirred in 40 mL of DMF for 1 hour at room temperature. concentrated
Then, methanol was added and the precipitated crystals were collected by filtration to obtain the desired product.
360 mg (50%) of pale yellow crystals were obtained. (Reaction 2)1H-2- (4-formylamino-1-methyl)
Rupyrol-2-yl) benzimidazole-5- [N
-(3,4,5-trimethoxyphenyl)] carboxa
Mid 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- (3,4,5-to
Rimethoxyphenyl)] carboxamide with DMF-meta
10% Pd / C to a solution of ethanol (1: 1, 30 mL).
Then, the mixture was stirred at room temperature for 3 hours. Here the corresponding amino form
Then, formylation was performed in the same manner as in Example 8 to obtain
Thus, 100 mg (41%) of the target compound was obtained as colorless crystals. mp. 177-182 ° C IR (KBr) cm^-1: 3449, 3309, 165
5,1610,1509,1466,1409,131
5

Example 11 (Compound 339)1H-2- [4- [4- [N, N-bis (2-chloroe
Tyl) amino] benzoylamino] -1-methyl pillow
Ru-2-yl] benzimidazole-5- (N-stear
Lil) carboxamide (Reaction 1)1H-2- (1-methyl-4-nitro pillow
Ru-2-yl) benzimidazole-5- (N-steer
Lil) carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
F) 0.20 g of benzimidazole-5-carboxylic acid
(0.68 mmol) was dissolved in 5 mL of DMF.
0.12 g (0.74 mmol, 1.1 eq.) Was added.
Then, the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. Ice cold steer
0.20 g of lylamine (0.74 mmol, 1.1e
q. ), Return to room temperature, stir for 3.5 hours and release overnight
Was placed. After adding 5 mL of DMF and stirring for another 10 hours
The resulting solid is collected by filtration and washed with methanol.
0.23 g (0.45 mmol, 65.8) of the title compound
%) As yellow crystals. mp. 142-144 ° C (Reaction 2)1H-2- [4- [4- [N, N-bis (2
-Chloroethyl) amino] benzoylamino] -1-me
Cylpyrrol-2-yl] benzimidazole-5
(N-stearyl) carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) Benzimidazole-5- (N-stearyl) cal
0.25 g (0.43 mmol) of boxamide was added to DMF5
suspended in a mixed solvent of 5 mL of methanol and 5 mL of methanol.
Add 0.5 mL and hydrogenate at normal pressure using 10% Pd / C as catalyst
And led to the corresponding amino form. 1/2 of this amount
The DMF solution was stirred under ice-cooling under a nitrogen atmosphere.
68 μL (0.49 mmol, 2.0 eq.)
, 4- [N, N-bis (2-chloroethyl) amino]
Synthesized from 0.07 g (0.27 mmol) of benzoic acid
4- [N, N-bis (2-chloroethyl) amino] ben
A 2 mL solution of zoyl chloride in dichloromethane was added dropwise,
After returning to room temperature and stirring for 3.5 hours, it was left overnight. Reduced pressure
The residue is purified by silica gel column chromatography.
(Methylene chloride / methanol 2-4%), methyl chloride
36 mg of the title compound was obtained by crystallization from ren-water.
(0.048 mmol, 22.3%) as pale brown crystals
I got it. mp. 173-177 ° C IR (KBr) cm^-1: 3422, 2923, 163
6,1541,1473 Elemental analysis: Calculated value (C₄₂H₆₀N₆O_TwoCl_Two・ H_TwoO) C:
65.52, H: 8.12, N: 10.92, Cl:
9.21, analytical value C: 65.87, H: 8.24, N:
10.53, Cl: 9.21

Example 12 (Compound 337) 1H-2- (4-formylamino-1-methylpyrrole
-2-yl) benzimidazole-5- (N-stearyl)
B) Carboxamide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- (N-stearyl) carboxamide 0.22 g (0.43 mmol) in DMF5
The mixture was suspended in a mixed solvent of 5 mL of methanol and 5 mL of methanol, and 0.5 mL of 1N hydrochloric acid was added. The mixture was hydrogenated under normal pressure using 10% Pd / C as a catalyst to lead to a corresponding amino compound. This half amount of the DMF solution was stirred under ice-cooling under a nitrogen atmosphere, and 68 μL (0.49 mmol, 2.0 eq.) Of triethylamine was added. 0.17 g of CDI (1.05 mmol, 5.0e
q. ), Formic acid 40 μL (1.06 mmol, 5.0e)
q. 1) -Formylimidazole THF solution prepared in the above) was added dropwise, and the mixture was returned to room temperature, stirred for 5 hours, and left overnight.
After concentration under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride / methanol 4-8%).
The title compound 57 was obtained by crystallization from ether-water.
mg (0.11 mmol, 48.4%) were obtained as light brown crystals. mp. 160-163 ° C IR (KBr) cm ^-1 : 3368,2918,165
4,1541,1472 Calcd _{(C 32 H 49 N 5 O} 2 · 1.5H 2 O)
C: 68.29, H: 9.31, N: 12.44, analysis value C: 68.18, H: 9.03, N: 12.38.

Example 13 (Compound 14)1H-2- [4- [4- [N, N-bis (2-chloroe
Tyl) aminomethyl] benzoylamino] -1-methyl
Pyrrole-2-yl] benzimidazole-5- [N-
(2-amidinoethyl)] carboxamide hydrochloride (Reaction 1)4-chloromethyl methyl benzoate 2.0 g (12 mmol) of 4-chloromethylbenzoic acid
Five drops of concentrated sulfuric acid are added to 50 mL of the methanol solution, and the mixture is added for 4 days.
Hot reflux stirring was performed. Neutralized with 5% aqueous sodium carbonate solution
After that, extraction was performed with chloroform. With magnesium sulfate
After drying, the mixture was concentrated under reduced pressure to obtain 1.7 g of a colorless liquid. IR (KBr) cm^-1: 2953, 1720, 128
1,1106,713 (Reaction 2)4- [N, N-bis (2-hydroxyethyl
Le) aminomethyl] methyl benzoate 1.7 g of methyl 4-chloromethylbenzoate (9.2 mm
ol) in 25 mL of chloroform solution
10 g (95 mmol) are added and heated under reflux for 10 hours.
went. Wash the solution with water and dry over magnesium sulfate.
After drying, the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography.
Purified by chromatography (chloroform), colorless oil
1.5 g of the product were obtained. IR (KBr) cm^-1: 3384,2952,172
1,1283,754 (Reaction 3)4- [N, N-bis (2-chloroethyl) a
Minomethyl] methyl benzoate 4- [N, N-bis (2-hydroxyethyl) aminomethyl
[Chill] methyl benzoate 1.5 g (5.9 mmol) and salt
Add 5 mL of thionyl bromide, and stir at 50 ° C for 2 hours.
went. After distilling off excess thionyl chloride under reduced pressure,
Methylene chloride was added and distillation under reduced pressure was repeated twice to obtain a colorless oil.
9.5 g of the product were obtained. (Reaction 4)4- [N, N-bis (2-chloroethyl) a
Minomethyl] benzoic acid 4- [N, N-bis (2-chloroethyl) aminomethyl
]] To 9.5 g (32.7 mmol) of methyl benzoate
50 mL of hydrochloric acid was added, and the mixture was stirred under reflux with heating for 2 hours.
After evaporating the solvent under reduced pressure, sludge it with acetone to form a white
8.5 g of a colored powder were obtained. IR (KBr) cm^-1: 3409, 2917, 171
3,1220,1108,752 (Reaction 5)4- [N,
N-bis (2-chloroethyl) aminomethyl] benzoic acid
Chloride 4- [N, N-bis (2-chloroethyl) aminomethyl
Benzene] 320 mg (1.0 mmol) of benzoic acid
Add 1 mL of thionyl chloride to 2 mL of the solution, and add 2 hours at 80 ° C
During the heating, stirring was performed. After evaporating the solvent under reduced pressure, dry under reduced pressure
This gave a white solid. (Reaction 6)1H-2- [4- [4- [N, N-bis (2
-Chloroethyl) aminomethyl] benzoylamino]-
1-methylpyrrol-2-yl] benzimidazole-
5- [N- (2-amidinoethyl)] carboxamide salt
Acid salt 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- (2-amidinoe)
Tyl)] carboxamide hydrochloride was converted to DMF-methanol
Dissolve in 20 mL of 1: 1 mixed solvent, 1 mL of 1N hydrochloric acid, 5 mL
% Pd / C 250 mg was added and the inside of the reaction vessel was replaced with nitrogen.
Was. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After the reaction,
The inside of the container was replaced with nitrogen again, Pd / C was separated by filtration, and methanol was removed.
Under reduced pressure. The solution is cooled to 0 ° C. and
After adding 350 μL of triethylamine, 4-
[N, N-bis (2-chloroethyl) aminomethyl] amine
5 mL of a DMF solution of benzoic acid chloride (1.1 eq.)
It was dropped. After stirring for 3 hours, methanol was added.
And further stirred for 30 minutes. After distilling off the solvent under reduced pressure,
The residue is purified by silica gel column chromatography (ethyl acetate).
/ IPA / water / acetic acid = 5/2/1/1)
Thus, 110 mg of a white powder was obtained. IR (KBr) cm^-1: 3328, 1688, 156
0,1404,1027,674

Example 14 (Compound 334)1H-2- (4-formylamino-1-methylpyrrole
-2-yl) benzimidazole-5- (N-butyl)
Carboxamide (Reaction 1)1H-2- (1-methyl-4-nitro pillow
Ru-2-yl) benzimidazole-5- (N-butyi)
L) Carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
F) 0.30 g of benzimidazole-5-carboxylic acid
(1.05 mmol) in 10 mL of DMF
0.20 g (1.23 mmol, 1.2 eq.) Was added.
Then, the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. Ice-cooled butyl
0.11 mL of amine (1.11 mmol, 1.1e
q. ), Return to room temperature, stir for 3 hours and leave overnight
Was. Concentrate under reduced pressure and sludge with IPA
0.26 g (0.76 mmol, 72.8) of the title compound
%) As yellow crystals. mp. 229-230 ° C (Reaction 2)1H-2- (4-formylamino-1-methyl)
Rupyrol-2-yl) benzimidazole-5- (N
-Butyl) carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) Benzimidazole-5- (N-butyl) carboxy
0.24 g (0.71 mmol) of samide in 5 mL of DMF
And 5 mL of methanol and suspended in a mixed solvent of 1N hydrochloric acid.
7 mL was added. Atmospheric pressure hydrogenation using 10% Pd / C as catalyst
And led to the corresponding amino form. This 1/2 amount of D
The MF solution was stirred under ice-cooling under a nitrogen atmosphere, and triethylamine was added.
Add 49 μL (0.35 mmol, 1.0 eq.)
Was. 0.28 g of CDI (1.73 mmol, 5.0 e)
q. ), Formic acid 66 μL (1.75 mmol, 5.0e)
q. 1) -Formylimidazole in THF
The solution was added dropwise, returned to room temperature, stirred for 4 hours, and left overnight.
Concentrate under reduced pressure and concentrate the residue on silica gel column chromatography.
(Methylene chloride / methanol 5-8%)
By crystallizing from ether, the title compound 78m
g (0.23 mmol, 65.7%) as white purple crystals
I got it. mp. 228-230 ° C IR (KBr) cm^-1: 3277, 2960, 167
7, 1610, 1560, 1290, 1128 Elemental analysis: Calculated value (C₁₈H_{twenty one}N_FiveO_Two・ 0.2H_TwoO)
C: 63.03, H: 6.29, N: 20.42, analysis
Values C: 62.71, H: 6.07, N: 20.20

Example 15 (Compound 336)1H-2- [4- [4- [N, N-bis (2-chloroe
Tyl) amino] benzoylamino] -1-methyl pillow
Ru-2-yl] benzimidazole-5- (N-butyi)
L) Carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) Benzimidazole-5- (N-butyl) carboxy
0.24 g (0.71 mmol) of samide in 5 mL of DMF
And 5 mL of methanol suspended in a mixed solvent of 1N hydrochloric acid 0.7
mL, and hydrogenated at normal pressure using 10% Pd / C as a catalyst.
Led to the corresponding amino form. This half amount of DM
49 μL of triethylamine (0.35 mmol
1, 1.0 eq. ) And 4- [N, N-bis (2-
Chloroethyl) amino] benzoic acid 0.10 g (0.38
mmol, 1.1 eq. ), HOBt 52 mg (0.3
8 mmol, 1.1 eq. ) And ice-cooled in a nitrogen atmosphere
And 79 mg of DCC (0.38 mmol, 1.1e
q. ), Return to room temperature, stir for 4 hours and leave overnight
did. Concentrate under reduced pressure and concentrate the residue on silica gel column chromatography.
Purify by luffy (methylene chloride / methanol 4
%), Crystallized from ether to give the title compound 9
0 mg (0.16 mmol, 42.6%) of pale yellow crystals
As obtained. mp. 190-192 ° C IR (KBr) cm^-1: 3390, 2925, 165
5,1518,1458,1328,815 Elemental analysis: Calculated value (C₂₆H₂₉N₉O_TwoCl_Two・ HCl ・ 2
H_TwoO) C: 48.57, H: 5.33, N: 19.6
1, Cl: 16.54, Analytical value C: 48.38, H:
5.22, N: 19.26, Cl: 16.36

Example 16 (Compound 305)1H-2- [4- [2- [N, N-bis (2-chloroe
Tyl) amino] benzoylamino] -1-methyl pillow
Ru-2-yl] benzimidazole-5- [N- (2-
Amidinoethyl)] carboxamide hydrochloride (Reaction 1)2- [N, N-bis (2-hydroxyethyl
Le) Amino] ethyl benzoate 4.1 g (25 mmol) of ethyl 2-aminobenzoate
Ethylene oxide was added to 25 mL of a 30% acetic acid suspension under ice-cooling.
12 mL (242 mmol) was added dropwise and stirred for 1 hour.
Was. After further stirring at room temperature for 2 nights, nitrogen gas was blown in.
While stirring for 2 hours. Medium with sodium bicarbonate
After addition, add salt until saturated and extract with ethyl acetate
did. After drying over magnesium sulfate, the solvent is distilled off under reduced pressure
did. The residue was subjected to silica gel column chromatography (n
-Hexane: ethyl acetate = 1: 1 → 0: 1)
This gave 3.4 g (53%) of a pale yellow oil. IR (KBr) cm^-1: 3421, 957, 169
9,1252,1078,764 (Reaction 2)2- [N, N-bis (2-chloroethyl) a
Mino] ethyl benzoate 2- [N, N-bis (2-hydroxyethyl) amino]
1.0 g (4.0 mmol) of ethyl benzoate in methyl chloride
0.8 mL of thionyl chloride (11.0 m
mol), and the mixture was stirred at room temperature for 1 hour. Solvent distillation under reduced pressure
After addition, add a small amount of methylene chloride and distill under reduced pressure.
And then concentrated under reduced pressure to give 950 mg of a brown oil.
(83%). (Reaction 3)2- [N, N-bis (2-chloroethyl) a
Mino] benzoic acid 2- [N, N-bis (2-chloroethyl) amino] benzo
Ethyl perfume (950 mg, 3.3 mmol) was added to concentrated hydrochloric acid 15
Then, the mixture was heated and refluxed for 8 hours. Decompress the solvent
The residue is distilled off and the residue is purified by silica gel column chromatography.
(Methylene chloride → acetone) to give a white powder 52
0 mg (61%) was obtained. IR (KBr) cm^-1: 3433, 1695, 146
7,1131,776 (Reaction 4)1H-2- [4- [2- [N, N-bis (2
-Chloroethyl) amino] benzoylamino] -1-me
Cylpyrrol-2-yl] benzimidazole-5
[N- (2-amidinoethyl)] carboxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- (2-amidinoe)
Tyl)] carboxamide hydrochloride 300 mg (0.77 m
mol) in a 1: 1 mixed solvent of DMF-methanol 25m
L, 850 μL of 1N hydrochloric acid, 5% Pd / C250
mg was added and the inside of the reaction vessel was replaced with nitrogen. Hydrogen atmosphere
The mixture was stirred at room temperature for 2 hours. After the reaction is complete,
After purging with nitrogen, 5% Pd / C was removed by filtration, and methanol was removed.
The solvent was distilled off under reduced pressure. The solution is cooled to -40 ° C and nitrogen atmosphere
After adding 250 μL of triethylamine, immediately before
2- [N, N-bis (2-chloroethyl) amino] benzo
2- [N, N- prepared by using thionyl chloride from carboxylic acid
Bis (2-chloroethyl) amino] benzoic acid chloride
(1.1 eq.) In 5 mL of methylene chloride solution was added dropwise.
Was. After stirring for 30 minutes, add methanol
Stir for an additional 10 minutes. After distilling off the solvent under reduced pressure, the residue
To silica gel column chromatography (ethyl acetate /
IPA / water = 5/2/1) to give a white powder 29
1 mg (61%) was obtained. Elemental analysis: calculated value (C₂₇H₃₁N₈O_TwoCl_Three・ 2H_TwoO)
C: 50.51, H: 5.50, N: 17.45, analysis
Values C: 50.17, H: 5.36, N: 16.92

Example 17 (Compound 15)1H-2- [4- [3- [N, N-bis (2-chloroe
Tyl) amino] benzoylamino] -1-methyl pillow
Ru-2-yl] benzimidazole-5- [N- (2-
Amidinoethyl)] carboxamide hydrochloride (Reaction 1)3- [N, N-bis (2-hydroxyethyl
Le) Amino] methyl benzoate 3.8 g (25 mmol) of methyl 3-aminobenzoate
11 g of ethylene oxide in 25 mL of 30% acetic acid (25 g
0 mmol, 10 eq. ) And post-treatment. Profit
The crude product was purified by silica gel column chromatography.
(Methylene chloride / methanol 2-4%)
And 5.95 g (24.9 mmol, constant) of the title compound.
Quantitative) was obtained as a yellow oil. (Reaction 2)3- [N, N-bis (2-chloroethyl) a
Mino] methyl benzoate 3- [N, N-bis (2-hydroxyethyl) amino]
Methyl benzoate (3.0 g, 12.5 mmol)
Dissolve in 50 mL of zen and 7.5 mL of thionyl chloride under ice-cooling
(103 mmol, 8.3 eq.) At 80 ° C.
The mixture was heated and stirred in an ir bath for 1.5 hours. Concentrate under reduced pressure and leave
Ethyl acetate is added to the residue, and a saturated aqueous solution of sodium hydrogen carbonate is added.
(Twice), then separate with saturated saline and dry with sodium sulfate
After drying, concentrate under reduced pressure, silica gel column chromatography.
(N-hexane / ethyl acetate = 5/1)
And title by sludge with n-hexane
2.44 g (8.83 mmol, 70.7%) of the compound
Obtained as colored crystals. mp. 60.5-61.5 ° C (Reaction 3)3- [N, N-bis (2-chloroethyl) a
Mino] benzoic acid 3- [N, N-bis (2-chloroethyl) amino] benzo
To 2.0 g (7.44 mmol) of methyl fragrance was added concentrated hydrochloric acid 40.
Then, the mixture was heated and stirred in a 90 ° C. oil bath for 3 hours.
The crystals formed after dilution with water are collected by filtration and washed with 50% ethanol.
To give 1.95 g (7.44 mmol) of the title compound.
1, quantitative) as white crystals. mp. 179-180 ° C (Reaction 4)1H-2- [4- [3- [N, N-bis (2
-Chloroethyl) amino] benzoylamino] -1-me
Cylpyrrol-2-yl] benzimidazole-5
[N- (2-amidinoethyl)] carboxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- (2-amidinoe)
Chill)] carboxamide hydrochloride 0.80 g (2.0 mm
ol) was mixed with 15 mL of DMF and 10 mL of methanol.
Suspended in a solvent, concentrated hydrochloric acid 0.18 mL (2.16 mmol,
1.1 eq. ), And touch 0.38 g of 10% Pd / C.
The medium was hydrogenated under normal pressure to lead to the corresponding amino compound. This
Was dissolved in DMF and stirred under ice-cooling under a nitrogen atmosphere.
0.30 mL of triethylamine (2.15 mmol,
1.1 eq. ) And further add 3- [N, N-bis (2
-Chloroethyl) amino] thionyl chloride from benzoic acid
3- [N, N-bis (2-chloroethyl)
L) amino] benzoyl chloride (1.1 mmol)
A 5 mL solution of benzene was added dropwise over 7 minutes. At room temperature
After stirring for 3 hours, the resulting white crystals were filtered off and concentrated under reduced pressure.
did. The residue was subjected to silica gel column chromatography.
Purified (ethyl acetate / IPA / water = 6/2/1) ethanol
The title compound is obtained by crystallization from
0.39 g (0.64 mmol, 64.0%) of pale yellowish white
Obtained as colored crystals. mp> 275 ° C IR (KBr) cm^-1: 3257, 1637, 155
1,1350,1308,747 Elemental analysis: Calculated value (C₂₇H₃₀N₈O_TwoCl_Two・ HCl ・
1.8H_TwoO) C: 50.80, H: 5.46, N: 1
7.55, Cl: 16.66, analytical value C: 51.09,
H: 5.54, N: 17.15, Cl: 16.57

Example 18 (Compound 13)1H-2- [4- [4- [N, N-bis (2-chloroe
Tyl) amino] phenoxyacetylamino] -1-methyl
Rupyrol-2-yl] benzimidazole-5- [N
-(2-amidinoethyl)] carboxamide hydrochloride (Reaction 1)Methyl 4-nitrophenoxyacetate 5.0 g (25 mmol) of 4-nitrophenoxyacetic acid
1. Thionyl chloride in 250 mL of methanol solution under ice-cooling
3 mL was added dropwise, and the mixture was stirred at room temperature for 1 hour. Reduce solvent
After distillation under reduced pressure, the residue was dissolved in 50 mL of methylene chloride,
The mixture was neutralized with an aqueous solution of sodium hydrogen. Organic layer with saturated saline
After washing and drying over sodium sulfate, the solvent is distilled off under reduced pressure
Thus, 5.2 g (96%) of a pale yellow powder was obtained. IR (KBr) cm^-1: 2446, 1753, 159
4,1340,1221,856 (Reaction 2)Methyl 4-aminophenoxyacetate 5.0 g of methyl 4-nitrophenoxyacetate (24 mmol
l) was dissolved in 150 mL of methanol, and 5% Pd / C4
80 mg was added, and the inside of the container was replaced with nitrogen. Under hydrogen atmosphere
Stirred at room temperature for 2 hours. After the end of the reaction, the inside of the container is
After the substitution, Pd / C was separated by filtration, and then the solvent was distilled off under reduced pressure.
This gave 4.1 g (92%) of a brown oil. (Reaction 3)4- [N, N-bis (2-hydroxyethyl
Le) Amino] methyl phenoxyacetate 4.0 g of methyl 4-aminophenoxyacetate (22 mmol
l) in 22 mL of 30% acetic acid
10 g (227 mmol) of side were added. Shake overnight at room temperature
After stirring, nitrogen is blown in to remove excess ethylene oxide.
Removed. After neutralization with sodium bicarbonate, salt was added.
And extracted with n-butanol. Dry with magnesium sulfate
After drying, the solvent was distilled off. The residue is purified by silica gel column chromatography.
Tomography (chloroform / methanol = 20/1)
To give 5.29 g (89%) of the desired product as a colorless oil.
I got it. (Reaction 4)4- [N, N-bis (2-chloroethyl) a
Mino] methyl phenoxyacetate 4- [N, N-bis (2-hydroxyethyl) amino]
2.39 g (8.87 mmol) of methyl phenoxyacetate
In a 1,2-dichloroethane solution (72 mL) under ice-cooling.
3.17 g (26.6 mmol) of thionyl were added dropwise.
After stirring at room temperature for 4 hours, the residue obtained by concentration was flashed off.
Chromatography (chloroform / methanol =
200/3), and 2.0 g (74%) of the target product was browned.
Obtained as colored crystals. mp. 69-70 ° C IR (KBr) cm^-1: 3449, 2956, 175
9,1516,1440,1257,1220,109
2,829 (Reaction 5)4- [N, N-bis (2-chloroethyl) a
Mino] phenoxyacetic acid 4- [N, N-bis (2-chloroethyl) amino] fe
Concentration of 1.99 g (6.50 mmol) of methyl nonoxyacetate
The hydrochloric acid 60 mL suspension was heated at 50 ° C. for 30 minutes. chloride
After washing with methylene, neutralize with sodium bicarbonate and salt
Extracted with methylene chloride. After washing with saturated saline,
After drying with cesium and concentrating, 1.23 g (65
%) As colorless crystals. mp. 112-113 ° C IR (KBr) cm^-1: 3436, 2968, 174
3,1514,1433,1235,1201,109
9,817 (Reaction 6)1H-2- [4- [4- [N, N-bis (2
-Chloroethyl) amino] phenoxyacetylamino]
-1-methylpyrrole-2-yl] benzimidazole
-5- [N- (2-amidinoethyl)] carboxamide
Hydrochloride 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- (2-amidinoe)
Tyl)] 302 mg of carboxamide hydrochloride (0.77 m
mol) in 35 mL of methanol-DMF in 10% P
catalytic reduction of d / C with a catalyst at room temperature to give the corresponding amino form
Obtained. Then, triethylamine and 4- [N, N-bis
(2-chloroethyl) amino] phenoxyacetic acid and oxa
4- [N, N-bis (2-chloride) prepared from ril chloride
Loroethyl) amino] phenoxyacetic acid chloride,
Stir for 30 minutes. Concentrate and flash column residue
Chromatography (ethyl acetate / IPA / water = 6/2 /
Purification in 1) gave 218 mg (44%) of the desired product. mp. 270-290 ° C (dec) IR (KBr) cm^-1: 3271, 1687, 163
9,1561,1511,1238,1069,81
6,746

Example 19 (Compound 310) 1H-2- [4- [3,5-bis [N, N-bis (2-
Chloroethyl) amino] benzoylamino] -1-methyl
Rupyrol-2-yl] benzimidazole-5- [N
-(2-Amidinoethyl)] carboxamide hydrochloride (Reaction 1) Methyl 3,5-diaminobenzoate 3,5-Diaminobenzoic acid 5.0 g (33 mmol) in a methanol solution 250 mL under ice-cooling was added to thionyl chloride 3.
7 g was added dropwise, and the mixture was heated and refluxed at room temperature for 2 hours and further for 6 hours. After evaporating the solvent under reduced pressure, the residue was neutralized with aqueous ammonia and extracted with methylene chloride. After drying over sodium sulfate, the residue was dried under reduced pressure to obtain 3.3 g (60%) of a white powder. IR (KBr): 3389, 3314, 3219, 17
05,1602,771 (Reaction 2) 3,5-bis [N, N-bis (2- hydroxy
Methyl 3,5-diaminobenzoate 2.8 g (17 mmol)
15 g (341 mmol) of ethylene oxide was added to a solution of 1) in 17 mL of 30% acetic acid under ice-cooling. After stirring overnight at room temperature, nitrogen was blown in to remove excess ethylene oxide. After neutralization with sodium bicarbonate, n-
Extracted with butanol and dried over magnesium sulfate. After evaporating the solvent, the obtained residue was purified by column chromatography (methanol / chloroform = 1/10) to obtain 1.94 g of the desired product as colorless crystals. (Reaction 3) 3,5-bis [N, N-bis (2-chloroe
Methyl 3,5-bis [N, N-bis (2-hydroxyethyl) butyl ] amino] benzoate
Amino] methyl benzoate 1.94 g (5.67 mmol)
l) and phosphorus oxychloride (19 mL), and
Heated for a period of time (dissolves within minutes after heating). After the reaction,
The residue obtained by concentration was carefully added to ice-cooled aqueous sodium bicarbonate, and extracted with ethyl acetate. After washing with a saturated saline solution, the extract was dried over magnesium sulfate, concentrated, and purified by flash chromatography (methanol / chloroform = 3/200) to obtain 1.74 g of the desired product as brown crystals. (Reaction 4) 3,5-bis [N, N-bis (2-chloroe
A suspension of 1.59 g (3.82 mmol) of methyl 3,5-bis [N, N-bis (2-chloroethyl) amino] benzoate in 48 mL of concentrated hydrochloric acid was heated at 50 ° C. for 5 hours. did. After completion of the reaction, the mixture was extracted with methylene chloride, washed with aqueous sodium bicarbonate and saturated saline, dried over magnesium sulfate and concentrated.
The obtained residue was purified by flash chromatography (methanol / chloroform = 1/20) to obtain the desired compound 1.
01 g was obtained as colorless crystals. (Reaction 5) 1H-2- [4- [3,5-bis [N, N-
Bis (2-chloroethyl) amino] benzoylamino]
-1-methylpyrrole-2-yl] benzimidazole
-5- [N- (2-amidinoethyl)] carboxamide
Hydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- (2-amidinoethyl)] carboxamide hydrochloride 300 mg (0.766
mmol) and 0.84 mL of 1N hydrochloric acid in methanol
After replacing the DMF 30 mL solution with nitrogen, the mixture was cooled on ice and 10% Pd
/ C 145 mg was added. Subsequently, the mixture was stirred at room temperature for 45 minutes in a hydrogen gas atmosphere. After the completion of the reaction, Pd / C was filtered off under a nitrogen stream and washed with degassed DMF. The obtained filtrate is concentrated to obtain a DMF solution at −78 ° C. under a nitrogen atmosphere at 186 mg (1.84 mmol) of triethylamine and 3,5-bis [N, N-bis (2-chloroethyl) amino] benzoic acid chloride. 0 mL (0.193 M /
1,2-dichloroethane solution {3,5-bis [N, N-
Bis (2-chloroethyl) amino] benzoic acid 389 mg
(0.967 mmol) of 1,2-dichloroethane 12
368 mg of oxalyl chloride (2.9 mm
ol) at −20 ° C., stirred at room temperature overnight, and then concentrated to dryness. The resulting oil was dissolved in 1,2-dichloroethane (5.0 mL), and Preparation II was added dropwise, and the mixture was added for 30 minutes. Stirred. After completion of the reaction, the mixture was concentrated, and the residue was subjected to flash column chromatography (ethyl acetate / IPA / water = 6/2 /
16.5 mg (13%) of the desired product was obtained as an amorphous substance. IR (KBr) cm ^-1 : 3396, 1638, 159
1,1552,1476,1409,1358,130
6,746 Elemental analysis: Calculated value (C ₃₁ H ₃₇ N ₉ O ₂ Cl ₄ .HCl.
_{1.5H 2 O): C: 48.17} , H: 5.35, N:
16.31, analysis value C: 48.09, H: 5.60,
N: 16.02,

Example 20 (Compound 2)1H-2- [4- [2- [4- [N, N-bis (2-k
Loroethyl) amino] phenyl] acetylamino] -1
-Methylpyrrol-2-yl] benzimidazole-5
-[N- (2-amidinoethyl)] carboxamide hydrochloride
salt (Reaction 1)4- [N, N-bis (2-hydroxyethyl
Le) amino] methyl phenylacetate 5.5 g of methyl 4-aminophenylacetate (33 mmol
1) 45 g of ethylene oxide in 33 mL of 30% acetic acid
(341 mmol, 10 eq.) And post-treatment
Was. The obtained crude product is subjected to silica gel column chromatography.
Purified by filtration (n-hexane / ethyl acetate = 1/2 →
1/4) and sludge it with n-hexane.
From the title compound, 6.07 g (24.0 mmol, 7
2.6%) as white crystals. mp. 57-58 ° C (Reaction 2)4- [N, N-bis (2-chloroethyl) a
Mino] methyl phenylacetate 4- [N, N-bis (2-hydroxyethyl) amino]
3.0 g (11.8 mmol) of methyl phenylacetate
Dissolve in 8 mL of senzen and add 3 mL of ice-cooled phosphorus oxychloride (3
2.2 mmol, 2.7 eq. ) Is dropped at 80 ° C
The mixture was heated and stirred in a bath for 1.5 hours. Drop the reaction solution into water
After crushing unreacted phosphorus oxychloride, extract with ethyl acetate.
The resultant was washed with a saturated saline solution. Reduced after drying sodium sulfate
Concentration under pressure and purification by silica gel column chromatography
(N-hexane / ethyl acetate = 4/1)
2.97 g (10.2 mmol, 81.
0%) as a yellow oil (Reaction 3)4- [N, N-bis (2-chloroethyl) a
Mino] phenylacetic acid 4- [N, N-bis (2-chloroethyl) amino] fe
Concentrated hydrochloric acid was added to 2.0 g (6.9 mmol) of methyl nitryl acetate.
0 mL was added and the mixture was heated and stirred in a 90 ° C. oil bath for 1 hour.
Dilute with water and extract three times with methylene chloride. Raw material remains
Reverse extraction of the product with a 1N aqueous solution of sodium hydroxide
The aqueous layer was acidified with hydrochloric acid, extracted again with methylene chloride, and dried.
It was dried and concentrated under reduced pressure. The residue obtained is washed with n-hexane.
By lugging, 1.61 g of the title compound was obtained.
(5.83 mmol, 84.5%) as white crystals.
Was. mp. 102.5-104 ° C (Reaction 4)1H-2- [4- [2- [4- [N, N-bi
[(2-chloroethyl) amino] phenyl] acetyla
Mino] -1-methylpyrrol-2-yl] benzimida
Zol-5- [N- (2-amidinoethyl)] carboxy
Samide hydrochloride 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- (2-amidinoe)
Chill)] carboxamide hydrochloride 0.80 g (2.0 mm
ol) in 15 mL-10 mL of DMF-methanol
0.18 mL of concentrated hydrochloric acid (almost insoluble) (2.16 mm
ol, 1.1 eq. ) And 10% Pd / C 0.38 g
Is hydrogenated at normal pressure using the catalyst as a catalyst to lead to the corresponding amino compound.
Was. This half amount was dissolved in DMF and ice-cooled under a nitrogen atmosphere.
After stirring, triethylamine 0.30 mL (2.15 mmol
1, 1.1 eq. ) And 4- [N, N-bis (2-
Chloroethyl) amino] phenylacetyl chloride
(1.12 mmol) / methylene chloride 5 mL solution for 7 minutes
Dropped over time. After returning to room temperature and stirring for 1.5 hours,
The separated white crystals were separated by filtration and concentrated under reduced pressure. Silica gel residue
Purification by column chromatography (ethyl acetate /
IPA / water = 6/2/1), from ethanol-ether
By crystallization, 0.33 g (0.53 g) of the title compound was obtained.
mmol, 53.2%) as a pale yellow-white amorphous powder.
Was. IR (KBr) cm^-1: 3409, 1637, 151
9,1308

Example 21 (Compound 6)1H-2- [4- [3-methoxy-4- [N, N-bis
(2-chloroethyl) amino] benzoylamino] -1
-Methylpyrrol-2-yl] benzimidazole-5
-[N- (2-amidinoethyl)] carboxamide hydrochloride
salt (Reaction 1)Methyl 3-methoxy-4-nitrobenzoate 4.7 g of 3-methoxy-4-nitrobenzoic acid (24 mm
ol) in 250 mL of methanol solution under ice-cooling
3.7 g was added dropwise at room temperature for 2 hours and further 3 hours.
Hot reflux stirring was performed. After evaporating the solvent under reduced pressure, ammonia
Neutralized with water and extracted with methylene chloride. Sodium sulfate
And dried under reduced pressure to give 4.9 g (97%) of white powder.
Obtained. IR (KBr) cm^-11732, 1614, 152
9,1306,1249,745 (Reaction 2)Methyl 3-methoxy-4-aminobenzoate 4.8 g of methyl 3-methoxy-4-nitrobenzoate (2
3 mmol) in methanol-tetrahydrofuran 2: 1
Dissolve in 150 mL of a mixed solvent, and 480 mg of 5% Pd / C
Was added and stirred at room temperature under a hydrogen atmosphere for 2 hours. End of reaction
After completion, Pd / C was separated by filtration, and the solvent was distilled off under reduced pressure.
3.9 g (54%) were obtained. IR (KBr) cm^-1: 3482, 3362, 168
0,1311,1231,765 (Reaction 3)3-methoxy-4- [N, N-bis (2-h
Droxyethyl) amino] methyl benzoate 3.9 g of methyl 3-methoxy-4-aminobenzoate (2
2 mmol) in a 30% acetic acid suspension under ice cooling.
Drop 16.5 mL (333 mmol) of Tylene oxide
And stirred for 1 hour. After further stirring at room temperature for two nights,
The mixture was stirred for 2 hours while blowing nitrogen gas. Hydrogen carbonate
Neutralize with thorium and add salt until saturated.
And extracted with ethyl acetate. Dried over magnesium sulfate
After that, the solvent was distilled off under reduced pressure. Silica gel column residue
Chromatography (methylene chloride: ethyl acetate = 1: 1)
→ 0: 1) to give 3.1 g (54
%). IR (KBr) cm^-1: 3421, 2951, 171
6,1268,1033,766 (Reaction 4)3-methoxy-4- [N, N-bis (2-
Loloethyl) amino] methyl benzoate 3-methoxy-4- [bis (2-hydroxyethyl) a
Mino] Salt of methyl benzoate 1.0 g (3.7 mmol)
0.7 mL of thionyl chloride in 20 mL of methylene chloride solution
(9.6 mmol) and stirred at room temperature for 3 hours. Dissolution
After distilling off the solvent under reduced pressure, a small amount of methylene chloride was further added to reduce the
The operation of distilling off the pressure was performed twice, and the residue was evaporated to dryness under reduced pressure to obtain a brown oily substance.
1.0 g (88%) was obtained. (Reaction 5)3-methoxy-4- [N, N-bis (2-
Loloethyl) amino] benzoic acid 3-methoxy-4- [bis (2-chloroethyl) amido
[N] 1.0 g (3.3 mmol) of methyl benzoate in concentrated salt
The mixture was added to 20 mL of the acid, and heated under reflux for 30 minutes. Dissolution
The solvent was distilled off under reduced pressure to obtain 707 mg (74%) of a white powder.
Was. IR (KBr): 3435, 1674, 1600, 12
79,751 (Reaction 6)1H-2- [4- [3-methoxy-4-
[N, N-bis (2-chloroethyl) amino] benzoy
Ruamino] -1-methylpyrrol-2-yl] benzi
Midazole-5- [N- (2-amidinoethyl)] cal
Boxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- (2-amidinoe)
Tyl)] carboxamide hydrochloride 300 mg (0.77 m
mol) in a 1: 1 mixed solvent of DMF-methanol 25m
L, 850 μL of 1N hydrochloric acid, 5% Pd / C250
mg was added and the inside of the reaction vessel was replaced with nitrogen. Hydrogen atmosphere
The mixture was stirred at room temperature for 2 hours. After the reaction is complete,
After purging with nitrogen, Pd / C was filtered off and methanol was decompressed.
Distilled off. The solution is cooled to -40 ° C and a nitrogen atmosphere
After adding 250 μL of triethylamine, adjust immediately before
3-methoxy-4- [N, N-bis (2-chloro
Ethyl) amino] benzoic acid chloride (1.1 eq.)
5 mL of a methylene chloride solution was added dropwise. 30 minutes as it is
After stirring, add methanol and stir for another 10 minutes.
Was. After the solvent was distilled off under reduced pressure, the residue was
Chromatography (ethyl acetate / IPA / water = 5/2 /
Purification according to 1) to obtain 241 mg (49%) of white powder
Was. IR (KBr) cm^-1: 3422, 2312, 168
5,1541,1313,756

Example 22 (Compound 3)1H-2- [4- [3- [4- [N, N-bis (2-k
Loroethyl) amino] phenyl] propionylamino]
-1-methylpyrrole-2-yl] benzimidazole
-5- [N- (2-amidinoethyl)] carboxamide
Hydrochloride (Reaction 1)4- [N, N-bis (2-hydroxyethyl
Ru) Amino] methyl phenylpropionate Methyl 3- (4-aminophenyl) propionate 4.3
g (24 mmol) in 24 mL of 30% acetic acid
Conducted with 11 g (250 mmol, 10 eq.) Of oxide
The reaction was carried out in the same manner as in Reaction 3 of Example 21. After processing
Crude product to silica gel column chromatography
And purified (methylene chloride / methanol 2-4%), n-
The title compound was obtained by crystallization from hexane-ether.
5.04 g (18.9 mmol, 78.6%) of white
Obtained as crystals. (Reaction 2)3- [4- [N, N-bis (2-chloroethyl
L) Amino] phenyl] methyl propionate 3- [4- [N, N-bis (2-hydroxyethyl) a
2.0 g of methyl [mino] phenyl] propionate (7.4
8 mmol) in 5 mL of benzene
2 mL (21.5 mmol, 2.9 eq.) Of phosphorus chloride
Then, the mixture was heated and stirred in an oil bath at 80 ° C. for 1.5 hours. Anti
The reaction solution was dropped into water to crush unreacted phosphorus oxychloride.
Thereafter, the mixture was extracted with ethyl acetate and washed with saturated saline. Sodium sulfate
After thorium drying, concentration under reduced pressure, silica gel column chromatography
Purification by chromatography (n-hexane / ethyl acetate = 4 /
1) to give 1.87 g (6.15 g) of the title compound.
mmol, 82.2%) as a yellow oil. (Reaction 3)3- [4- [N, N-bis (2-chloroethyl
Ru) amino] phenyl] propionic acid 3- [4- [N, N-bis (2-chloroethyl) amido
1.5 g of methyl [no] phenyl] propionate (4.93)
mmol), add 10 mL of concentrated hydrochloric acid, and add
The mixture was heated and stirred for 2.5 hours. Diluted with water and 5N hydroxide
Adjust the pH to about 2 with an aqueous solution of lithium and filter the resulting crystals.
To give 1.21 g (4.17 mmol) of the title compound.
1, 84.6%) as white crystals. (Reaction 4)3- [4- [N, N-bis (2-chloroethyl
L) amino] phenyl] propionyl chloride 3- [4- [N, N-bis (2-chloroethyl) amido
[No]] phenyl] propionic acid 0.24 g (0.83 m
mol) was dissolved in 5 mL of 1,2-dichloroethane.
0.22 mL of oxalyl chloride (2.58 mmol,
3.1 eq. ) Was dropped.
More ice cold). After dropping, return to room temperature and stir for 3 hours.
Left overnight. Concentrate under reduced pressure to give the crude title compound.
The product was obtained. Use this in the next reaction without purification
Was. (Reaction 5)1H-2- [4- [3- [4- [N, N-bi
[(2-chloroethyl) amino] phenyl] propioni
Ruamino] -1-methylpyrrol-2-yl] benzi
Midazole-5- [N- (2-amidinoethyl)] cal
Boxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- (2-amidinoe)
Chill)] carboxamide hydrochloride 0.30 g (0.77 m
mol) was mixed with 10 mL of DMF and 6.5 mL of methanol.
Suspended in a mixed solvent, and concentrated hydrochloric acid 65 μL (0.78 mmol,
1.0 eq. ) And touch 0.12 g of 10% Pd / C.
The mixture was subjected to normal pressure hydrogenation as a medium to lead to the corresponding amino compound.
This amino compound is dissolved in DMF and stirred under ice-cooling under a nitrogen atmosphere.
And triethylamine 0.21 mL (1.5 mmol,
1.9 eq. ) And 3- [4- [N, N-bis (2
-Chloroethyl) amino] phenyl] propionylchloro
Lide (0.83mmol) / methylene chloride 2mL solution
It was added dropwise over 7 minutes. After returning to room temperature and stirring for 4.5 hours
The resulting white crystals were separated by filtration and concentrated under reduced pressure. Silica residue
Gel column chromatography (ethyl acetate / IPA /
Water = 6/2/1) and purified with ethanol-ether
And 0.25 g (0.37 mmol, 4
7.6%) as a pale yellow-white amorphous substance. No clear melting point IR (KBr) cm^-1: 3267, 1638, 154
6,1519, 1350, 1308, 812, 747 Elemental analysis: Calculated value (C₂₉H₃₄N₈O_TwoCl_Two・ HCl ・ 2
H_TwoO) C: 51.98, H: 5.87, N: 16.7
2, Cl: 15.87, Analytical value C: 51.68, H:
5.83, N: 16.45, Cl: 16.26

Example 23 (Compound 260)1H-2- [4- [4- [N, N-bis (2-bromoe
Tyl) amino] benzoylamino] -1-methyl pillow
Ru-2-yl] benzimidazole-5- [N- (2-
Amidinoethyl)] carboxamide hydrochloride (Reaction 1)4- [N, N-bis (2-bromoethyl) a
Mino] ethyl benzoate 4- [N, N-bis (2-hydroxyethyl) amino]
Ethyl benzoate 2.0 g (7.9 mmol) methyl chloride
1.1 mL of phosphorus tribromide (11.3 m
mol) under ice-cooling and, after stirring for 2 hours,
Stirred at room temperature for 12 hours. After concentrating the solvent under reduced pressure, the residue
Was dissolved in ethanol to remove insolubles. silica gel
Column chromatography (ethyl acetate / n-hexane
= 3/1) and 1.0 g (34%) of white powder
I got (Reaction 2)4- [N, N-bis (2-bromoethyl) a
Mino] benzoic acid 4- [N, N-bis (2-bromoethyl) amino] benzo
1.0 g (2.6 mmol) of ethyl perfate was added to 47%
The solution was added to 10 mL of aqueous solution of hydrochloric acid, and heated under reflux for 30 minutes.
Was. The solvent was distilled off under reduced pressure to obtain 650 mg of a white powder (70 mg).
%). (Reaction 3)1H-2- [4- [4- [N, N-bis (2
-Bromoethyl) amino] benzoylamino] -1-me
Cylpyrrol-2-yl] benzimidazole-5
[N- (2-amidinoethyl)] carboxamide hydrochloride 1H-2- [1-methyl-4-nitropyrrole-2-i
Ru] benzimidazole-5- [N- (2-amidinoe)
Chill)] carboxamide 200 mg (0.51 mmol
l) in 20 mL of a 1: 1 mixed solvent of DMF and methanol
Dissolved, 5% Pd / C 200mg, 1N hydrochloric acid 0.7m
L was added and the inside of the reaction vessel was replaced with nitrogen. Hydrogen atmosphere lower chamber
Stirred at warm for 2 hours. After the reaction is completed, put the inside of the container again with nitrogen.
And 5% Pd / C is filtered off and methanol is distilled off under reduced pressure.
Was. The solution was cooled to 0 ° C., and
0.17 mL of 4-amine [N, N-
Bis (2-bromoethyl) amino] benzoic acid chloride
5 mL of a DMF solution of (1.1 eq.) Was added dropwise. That
After stirring for 30 minutes as is, add methanol for another 5 minutes
While stirring. After evaporating the solvent under reduced pressure, the residue was silica gel
Column chromatography (ethyl acetate / IPA / water =
5/2/1) and 193 mg (55%) of white powder.
%). mp. > 270 ° C IR (KBr) cm^-1: 3292, 2367, 169
0, 1606, 1543, 1350, 1204 Elemental analysis: Calculated value (C₂₇H₃₁N₈O_TwoCl₁Br_Two・ 5H_Two
O) C: 41.17, H: 4.43, N: 14.00,
Analytical value C: 41.32, H: 4.43, N: 14.28

Example 24 (Compound 332)1H-2- (4-benzoylamino-1-methyl pillow
Ru-2-yl) benzimidazole-5- [N- (2-
Aminoethyl)] carboxamide hydrochloride (Reaction 1)1H-2- (4-benzoylamino-1-me
Tylpyrrol-2-yl) benzimidazole-5
[N- [2- (t-butoxycarbonylamino) ethyl]
Le]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [2- (t-butane)
Xycarbonylamino) ethyl]] carboxamide 0.
11 g (0.26 mmol) in 3 mL of DMF and methanol
10% Pd / C 0.10 g suspended in 2 mL of mixed solvent
Is hydrogenated at normal pressure using the catalyst as a catalyst to lead to the corresponding amino compound.
Was. This DMF solution was ice-cooled and stirred under a nitrogen atmosphere,
45 μL of tylamine (0.32 mmol, 1.2e
q. ) And 36 μL of benzoyl chloride
(0.31 mmol, 1.2 eq.) Was added dropwise.
After stirring for 4 hours, the mixture was left overnight. Concentrate under reduced pressure and concentrate the residue
Purify by Kagel column chromatography (chloropho
Rum / methanol 8%), and the title compound
103 mg (0.20 mmol, 82.0%) of the product is indefinite
Obtained as a mold powder. (Reaction 2)1H-2- (4-benzoylamino-1-me
Tylpyrrol-2-yl) benzimidazole-5
[N- (2-aminoethyl)] carboxamide hydrochloride 1H-2- (4-benzoylamino-1-methyl pillow
Ru-2-yl) benzimidazole-5- [N- [2-
(T-butoxycarbonylamino) ethyl]] carbox
0.10 g (0.20 mmol) of samide
Dissolved in 2 mL of acetic acid and stirred at room temperature for 1 hour. Concentration under reduced pressure
After azeotropic distillation with toluene, 2 mL of 4N hydrochloric acid / dioxane was added.
After stirring for 1 hour, the mixture was concentrated under reduced pressure.
By crystallization, 84 mg of the title compound (0.18 mm
ol, 88.8%) as pale yellow-white crystals. mp. 252-260 ° C IR (KBr) cm^-1: 3400, 3044, 164
7, 1560, 1395, 1321, 823, 705 Elemental analysis: Calculated value (C_{twenty two}H_{twenty two}N₆O_Two・ 2HCl ・ 1.5
H_TwoO): C: 52.60, H: 5.42, N: 16.
73, Cl: 14.11, analytical value C: 52.73, H:
5.47, N: 16.46, Cl: 13.95

Example 25 (Compound 129)1H-2- [4- [4- [N, N-bis (2-chloroe
Tyl) amino] benzoylamino] -1-methyl pillow
Ru-2-yl] benzimidazole-5- [N- (2-
Aminoethyl)] carboxamide hydrochloride (Reaction 1)1H-2- (1-methyl-4-nitro pillow
Ru-2-yl) benzimidazole-5- [N- [2-
(T-butoxycarbonylamino) ethyl]] carbox
Samid 1H-2- (1-methyl-4-nitropyrrole-2-i
B) 0.10 g of benzimidazole-5-carboxylic acid
(0.35 mmol) was dissolved in 5 mL of DMF, and CDI was dissolved.
0.07 g (0.43 mmol, 1.2 eq.)
Then, the mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. Ice-cooled N
-T-butoxycarbonyl-1,2-ethanediamine
0.07 g (0.44 mmol, 1.2 eq.) / DM
Add 2mL of F, return to room temperature, stir for 4 hours and leave overnight
did. Concentrate under reduced pressure and sludge with methanol
Gives 0.11 g (0.26 mmol, 7
(3.3%) as yellow crystals. (Reaction 2)1H-2- [4- [4- [N, N-bis (2
-Chloroethyl) amino] benzoylamino] -1-me
Cylpyrrol-2-yl] benzimidazole-5
[N- [2- (t-butoxycarbonylamino) ethyl]
Le]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [2- (t-butane)
Xycarbonylamino) ethyl]] carboxamide 0.
11 g (0.26 mmol) in 3 mL of DMF and methanol
Suspended in 2 mL of a mixed solvent, and 10% Pd / C 0.10
g under normal pressure hydrogenation as a catalyst to lead to the corresponding amino compound.
Was. This DMF solution was stirred under ice-cooling under a nitrogen atmosphere, and triturated.
45 μL of ethylamine (0.32 mmol, 1.2e
q. ) And add 4- [N, N-bis (2-chloroethyl
Ru) amino] benzoic acid 0.09 g (0.34 mmol)
4- [N, N-bis (2-chloroethyl) synthesized from
Droplet of 2mL solution of [amino] benzoyl chloride in benzene
I dropped it. The mixture was returned to room temperature, stirred for 4 hours, and left overnight. Decompression
After concentration, the residue was subjected to silica gel column chromatography.
To purify (chloroform / methanol 5%) and concentrate
This gave 133 mg (0.21 mmol,
81.0%) as an amorphous powder. (Reaction 3)1H-2- [4- [4- [N, N-bis (2
-Chloroethyl) amino] benzoylamino] -1-me
Cylpyrrol-2-yl] benzimidazole-5
[N- (2-aminoethyl)] carboxamide hydrochloride 1H-2- [4- [4- [N, N-bis (2-chloroe
Tyl) amino] benzoylamino] -1-methyl pillow
Ru-2-yl] benzimidazole-5- [N- [2-
(T-butoxycarbonylamino) ethyl]] carbox
0.13 g (0.20 mmol) of samide
Dissolved in 2 mL of acetic acid and stirred at room temperature for 30 minutes. Under reduced pressure
After concentration and azeotropic distillation with toluene, 4N hydrochloric acid / dioxane was added.
The operation of concentration was repeated three times, and the residue was ethanol
Crystallized from the title compound to give 98 mg of the title compound.
(0.16 mmol, 79.6%) as pale yellowish white crystals
I got it. mp. > 275 ° C IR (KBr) cm^-1: 3423, 2959, 160
5,1560,1389,1059,828 Elemental analysis: Calculated value (C₂₆H₂₉N₇O_TwoCl_Two・ 2HCl ・
2H_TwoO) C: 47.94, H: 5.42, N: 15.
05, Cl: 21.77, analytical value C: 48.16, H:
5.34, N: 14.75, Cl: 21.43

Example 26 (Compound 223)1H-2- [4- [4- [N, N-bis (2-chloroe
Tyl) amino] benzoylamino] -1-methyl pillow
Ru-2-yl] benzimidazole-5- [N- (3-
Picolyl)] carboxamide hydrochloride (Reaction 1)1H-2- (1-methyl-4-nitro pillow
Ru-2-yl) benzimidazole-5- [N- (3-
Picolyl)] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
F) 0.20 g of benzimidazole-5-carboxylic acid
(0.70 mmol) was dissolved in 5 mL of DMF, and CDI was dissolved.
0.17 g (1.05 mmol, 1.5 eq.) Was added.
Then, the mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. Ice cold 3
-Picolylamine 0.12 mL (1.18 mmol,
1.7 eq. ), Return to room temperature and stir for 4 hours.
Left overnight. Concentrate under reduced pressure and sludge with methanol
To give the title compound 0.25 g (0.66 mm
ol, 93.8%) as yellow crystals. (Reaction 2)1H-2- [4- [4- [N, N-bis (2
-Chloroethyl) amino] benzoylamino] -1-me
Cylpyrrol-2-yl] benzimidazole-5
[N- (3-picolyl)] carboxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- (3-picoline)
Le)] 0.24 g (0.64 mmol) of carboxamide
Is suspended in a mixed solvent of 8 mL of DMF and 5 mL of methanol.
Add 2 equivalents of concentrated hydrochloric acid and catalyze 0.09 g of 10% Pd / C
And hydrogenated at normal pressure to lead to the corresponding amino compound. This
The DMF solution was stirred under ice-cooling in a nitrogen atmosphere.
0.2 mL of min (1.43 mmol, 2.2 eq.)
In addition, 4- [N, N-bis (2-chloroethyl) amido
[No] Synthesized from 0.18 g (0.69 mmol) of benzoic acid
4- [N, N-bis (2-chloroethyl) amino]
A solution of benzoyl chloride in benzene (5 mL) was added dropwise.
The mixture was returned to room temperature, stirred for 4 hours, and left overnight. Concentrate under reduced pressure
And the residue is purified by silica gel column chromatography.
(Chloroform / methanol 10%), suspended in water
The title compound was collected by filtration to give 0.12 g (0.20 m
mol, 31.2%) as white crystals. this house
52 mg (0.078 mmol) in 2 mL of ethanol
It was suspended, 4N hydrochloric acid / dioxane was added, and the mixture was concentrated.
The crystals were converted to the hydrochloride by washing with ether. mp. > 275 ° C IR (KBr) cm^-1: 3369, 1655, 160
4,1546,1277 Elemental analysis: Calculated value (C₃₀H₂₉N₇O_TwoCl_Two・ 2HCl ・
2.5H_TwoO) C: 50.86, H: 5.12, N: 1
3.84, Cl: 20.02, analysis value C: 50.67,
H: 4.86, N: 13.68, Cl: 20.34

Example 27 (Compound 247) 3-[[1H-2- [4- [4- [N, N-bis (2-
Chloroethyl) amino] benzoylamino] -1-methyl
Rupyrol-2-yl] benzimidazole-5-cal
Boxamide] methyl] -1-methylpyridinium black
Lido 1H-2- [4- [4- [N, N-bis (2-chloroethyl) amino] benzoylamino] -1-methylpyrrol-2-yl] benzimidazole-5- [N- (3-
Picolyl)] carboxamide 84 mg (0.13 mmol
l) was dissolved in 2 mL of DMF, and 40 μL of methyl iodide was dissolved.
(0.642 mmol, 5.1 eq.), Stirred at room temperature for 6 hours, and left overnight. The residue obtained by evaporating the solvent under reduced pressure was dissolved in methanol, and the mixture was ion-exchanged (DOWE)
X 1 × 8, 200-400 mesh, Cl type) to exchange counter ions for chlorine. Crystallization from ether and washing with chloroform gave 46 mg (0.072 mmol, 56.5%) of the title compound as white crystals. mp. 189-193 ° C (dec.) IR (KBr) cm ^-1 : 3420, 1637, 160
5,1541 Calcd _{(C 31 H 32 N 7 O} 2 Cl 3 · 0.25C
_{HCl 3 · 2H 2 O) C} : 53.10, H: 5.17,
N: 13.87, Cl: 18.81, Analysis value C: 52.
96, H: 5.01, N: 13.50, Cl: 18.5
3

Example 28 (Compound 16) 1H-2- [4- (6-bromohexanoylamino)-
1-methylpyrrol-2-yl] benzimidazole-
5- [N- (2-amidinoethyl)] carboxamide salt
Salt 1H-2- [1- methyl-4-nitro-pyrrol-2-yl] benzimidazole -5- [N- (2- Amijinoechiru)] carboxamide hydrochloride 200 mg (0.51 m
mol) in a 1: 1 mixed solvent of DMF and methanol 12m
L, dissolved in 5% Pd / C 200 mg, 1N hydrochloric acid 0.7
The reaction vessel was purged with nitrogen by adding mL. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After completion of the reaction, the inside of the vessel was replaced with nitrogen again, 5% Pd / C was filtered off, and methanol was distilled off under reduced pressure. The solution was cooled to 0 ° C., and under a nitrogen atmosphere, 0.17 mL of triethylamine and 1.1 equivalents of 6-bromohexanoic acid chloride were added. After stirring for 30 minutes as it was, methanol was added and the mixture was further stirred for 5 minutes. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / IPA / water = 5/2/1) to obtain 200 mg (73%) of a white powder. IR (KBr) cm ^-1 : 3272, 2362, 169
0,1637,1542,1311,958

Example 29 (Compound 1001) 1H-2- [1-methyl-4- (2-guanidinoacetyl)
Ruamino) pyrrol-2-yl] benzimidazole-
5- [N- [4- [N, N-bis (2-chloroethyl)
Amino] phenyl]] carboxamide hydrochloride (Reaction 1) N, N-bis (2-chloroethyl) -1,
4-phenylenediamine hydrochloride 4-nitro- [N, N-bis (2-chloroethyl)] aniline (5.0 g, 19.0 mmol) was added to ethyl acetate 50.
It was dissolved in a mixed solvent of 25 mL of methanol and 25 mL of methanol, and 5.0 mL of 4N hydrochloric acid was added. This was hydrogenated using 10% Pd / C at normal pressure and room temperature. Pd / C was removed by filtration, and the solvent was distilled off. This is crystallized from ethanol-ether,
4.1 g (15.2 mmol, 80%) of the desired product was obtained. mp. 230-233 ° C (Reaction 2) 1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [4
-[N, N-bis (2-chloroethyl) amino] phenyl
]] 0.3 g of carboxamide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5-carboxylic acid
(1.05 mmol) was dissolved in 6 mL of DMF, into which 0.3 g of N, N-bis (2-chloroethyl) -1,4-phenylenediamine hydrochloride (1.1 mmol, 1.0 mmol) was added.
5 eq. ) And 0.15 mL of triethylamine (1.82)
mmol, 3.1 eq. ) Was dissolved in 8 mL of DMF and added dropwise. HOBt 0.16 g (1.18 mmol, 1.
1 eq. ) And ice-cooled under a nitrogen atmosphere.
4 g (1.16 mmol, 1.1 eq.) Was added, and the mixture was returned to room temperature, stirred for 3 hours, and left overnight. The resulting solid was separated by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / methanol 2%) and subjected to methanol sludge to afford the title compound 0.1.
38 g (0.76 mmol, 72.2%) were obtained as yellow crystals. mp. 144-148 ° C (Reaction 3) 1H-2- [1-methyl-4- (2- guar
Nidinoacetylamino) pyrrol-2-yl] benzi
Midazole-5- [N- [4- [N, N-bis (2-
Loroethyl) amino] phenyl]] carboxamide hydrochloride
Salt 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carboxamide 0.30 g (0.60 mmol) in DMF3
dissolved in a mixed solvent of 3 mL of methanol and 3 mL of methanol.
Using 0.12 g of catalyst as a catalyst, hydrogenation to the corresponding amino compound was carried out by hydrogenation under normal pressure. The DMF solution of this amino compound was stirred under ice-cooling under a stream of nitrogen, and triethylamine 0.17 mL (1.22 m
mol, 2.0 eq. ), 0.28 g (1.82 mmol, 3.0 eq.) Of 2-guanidineacetic acid hydrochloride, DC
0.37 g (1.79 mmol, 3.0 eq.) Of C was sequentially added, and the mixture was stirred for 1 hour and left overnight. After concentration under reduced pressure, the residue was purified by silica gel chromatography (eluted with methylene chloride-methanol 12%, and repeated twice).
78 mg of the title compound by slugging with
(0.13 mmol, 21.5%) as a light brown powder. IR (KBr) cm ^-1 : 3390, 2925, 165
5,1518,1458

Example 30 (Compound 1054)1H-2- [4- (2-guanidinoacetylamino)-
1-methylpyrrol-2-yl] benzimidazole-
5- [N- [4- [N, N-bis (2-acetoxyethyl)
L) amino] phenyl]] carboxamide hydrochloride (Reaction 1)4-nitro- [N, N-bis (2-acetoxy
Siethyl)] aniline 4-nitro- [N, N-bis (2-hydroxyethyl
L)] aniline (1.0 g, 4.42 mmol)
Acetyl chloride 0.80 under ice cooling.
mL (11.3 mmol, 2.5 eq.) and room temperature
Returned and stirred for 2 hours. Concentrate under reduced pressure and add 0.4N to the residue.
Add hydrochloric acid-ethyl acetate, extract twice, wash with hydrochloric acid aqueous solution
It was dried over sodium sulfate and concentrated. Residue in ether / meta
1.03 g of the title compound by washing with ethanol
(3.32 mmol, 75.1%) as yellowish white crystals
Obtained. (Reaction 2)4- [N, N-bis (2-acetoxyethyl
Ru) amino] aniline hydrochloride 4-nitro- [N, N-bis (2-acetoxyethyl
)] Aniline (0.30 g, 0.97 mmol)
Dissolved in a mixed solvent of 5 mL of ethanol and 3 mL of ethyl acetate
Then, normal pressure hydrogenation was performed using 10% Pd / C as a catalyst. catalyst
Is filtered off, concentrated under reduced pressure, dissolved in dioxane, and dissolved in 4N hydrochloric acid.
/ Dioxane, and concentrates to give ether / n-hexane /
The title compound 0.3 was obtained by crystallization from acetone.
6 g (1.12 mmol, quantitative) were obtained as white crystals.
Was. (Reaction 3)1H-2- (1-methyl-4-nitro pillow
Ru-2-yl) benzimidazole-5- [N- [4-
[N, N- [bis (2-acetoxyethyl)] amino]
Phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
F) 0.25 g of benzimidazole-5-carboxylic acid
(0.88 mmol) was dissolved in 4 mL of DMF and HOBt was dissolved.
0.13 g (0.96 mmol, 1.1 eq.)
And 4- [N, N-bis (2-acetoxyethyl) amido
[No] aniline hydrochloride 0.34 g (1.1 mmol, 1.
2eq. ) +0.15 mL of triethylamine (1.82)
mmol, 2 eq. ) / DMF 6 mL solution was added dropwise.
Under ice-cooling in a nitrogen atmosphere, DCC 0.20 g (0.97 mm
ol, 1.1 eq. ), Return to room temperature and stir for 6 hours
After that, it was left overnight. The resulting solid is filtered off and concentrated under reduced pressure to give a residue.
Is purified by silica gel column chromatography.
(Roloform / methanol 2-4%), methanol
By dipping, 0.28 g of the title compound (0.
51 mmol, 58.0%) as yellow crystals. (Reaction 4)1H-2- [4- (2-guanidinoacetyl
Amino) -1-methylpyrrol-2-yl] benziimi
Dazol-5- [N- [4- [N, N-bis (2-acetate)
Toxiethyl) amino] phenyl]] carboxamide salt
Acid salt 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [4- [N, N-
Bis (2-acetoxyethyl) amino] phenyl]]
0.27 g (0.49 mmol) of ruboxamide in DMF
Dissolve in a mixed solvent of 2 mL and methanol 2 mL, and add 4N salt
0.12 mL of acid is added, and 0.12 g of Pd / C is used as a catalyst.
Then, it was led to the corresponding amino compound by hydrogenation under normal pressure. this
The DMF solution of the amino compound was stirred under ice-cooling under a stream of nitrogen and triethyl was added.
Luamine 70 μL (0.50 mmol, 1.0e
q. ), 0.23 g (1.4 g) of 2-guanidineacetic acid hydrochloride
5 mmol, 3.0 eq. ), 0.23 g of DCC (1.
50 mmol, 3.0 eq. ) In order,
After stirring for an hour, the mixture was left overnight. After concentration under reduced pressure, the residue was silica gel
Purify by chromatography (1st time, chloroform / methano
16-20%, second time, ethyl acetate / IPA / water =
7/2/1 → 5/2/1), washing with ethyl acetate
To give the title compound 0.12 g (0.18 mmol, 3
(7.4%) as a white amorphous substance. mp. No clear melting point IR (KBr) cm^-1: 3385, 3178, 173
5,1655,1520,1231

Example 31 (Compound 1003) 1H-2- [4- (2-guanidinoacetylamino)-
1-methylpyrrol-2-yl] benzimidazole-
5- [N- [2- [4- [N, N-bis (2-chloroe
Tyl) amino] phenyl] ethyl]] carboxamide salt
Acid salt (reaction 1) 2- [4- [N, N-bis (2-chloroethyl
L ) amino] phenyl] ethylamine 3- [4- [N, N-bis (2-chloroethyl) amino] phenyl] propionic acid 0.20 g (0.69 mm
ol) was suspended in 1 mL of acetone and stirred under ice-cooling under a nitrogen atmosphere, and 115 μL of triethylamine (0.82 mmol,
1.2 eq. ), 79 μL of ethyl chloroformate (0.82
mmol, 1.2 eq. ) Were added sequentially. After 15 minutes 90 mg of sodium azide (1.38 mmol, 2.0e
q. ) / Water (1 mL) was added dropwise, and the mixture was stirred for 30 minutes and ice was added to stop the reaction. 15 mL of benzene was added and the mixture was extracted three times, combined, dried over sodium sulfate, and heated under reflux for 1 hour. The mixture was concentrated under reduced pressure.
After heating at 100 ° C. for 10 minutes and concentrating under reduced pressure, the residue was diluted with water, adjusted to pH 12 with concentrated aqueous ammonia, extracted with ethyl acetate, dried and concentrated to give 0.15 g of the crude title compound.
Was obtained as a brown oil. This was used for the next reaction without purification. (Reaction 2) 1H-2- (1-methyl-4-nitropyrro
Ru-2-yl) benzimidazole-5- [N- [2-
[4- [N, N-bis (2-chloroethyl) amino] f
[Enyl] ethyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5-carboxylic acid 0.1 g
(0.35 mmol) was dissolved in 3 mL of DMF, and CDI6
8 mg (0.42 mmol, 1.2 eq.) Was added, and the mixture was stirred at room temperature under a nitrogen stream for 1 hour. Ice-cooled 2- [4-
[N, N-bis (2-chloroethyl) amino] phenyl] ethylamine 0.15 g (1.1 mmol, 1.0
5 eq. , Crude) / DMF 2 mL solution was added dropwise,
The ice bath was removed, and the mixture was stirred for 7 hours and left overnight. The mixture was concentrated under reduced pressure, methanol was added to the residue, and the precipitated crystals were collected by filtration to give 0.14 g (0.26 mmol,
75.6%) as pale yellow crystals. (Reaction 3) 1H-2- [4- (2-guanidinoacetyl
Amino) -1-methylpyrrol-2-yl] benziimi
Dazol-5- [N- [2- [4- [N, N-bis (2
-Chloroethyl) amino] phenyl] ethyl]] carbo
Oxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [2- [4-
[N, N-bis (2-chloroethyl) amino] phenyl] ethyl]] carboxamide 0.30 g (0.57
mmol) in a mixed solvent of 5 mL of DMF and 5 mL of methanol, 0.6 mL of 1N hydrochloric acid was added, and 10% Pd /
Using 0.15 g of C as a catalyst, hydrogenation to the corresponding amino compound was carried out by hydrogenation under normal pressure. The DMF solution of the amino compound was stirred under ice-cooling under a nitrogen stream, and 108 μL of triethylamine (0.78 m
mol, 1.4 eq. ), 0.26 g (1.7 mmol, 3.0 eq.) Of 2-guanidine acetate hydrochloride, DCC
0.36 g (1.7 mmol, 3.0 eq.) Was added in order, and the mixture was stirred for 1 hour and left overnight. The resulting crystals were filtered off, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (first time, ethyl acetate / IPA / water = 7/2/1,
The second time, chloroform-methanol 12%, the third time, ethyl acetate / IPA / water = 7/2/1), and crystallization from ether gave 67 mg (0.11 mm) of the title compound.
ol, 18.5%) as white crystals. mp. 175-185 ° C (dec)

Example 32 (Compound 1004)1H-2- [4- (2-guanidinoacetylamino)-
1-methylpyrrol-2-yl] benzimidazole-
5- [N- [3- [4- [N, N-bis (2-chloroe
Tyl) amino] phenyl] propyl]] carboxamide
Hydrochloride (Reaction 1)3- [4- [N, N-bis (2-chloroethyl
L) amino] phenyl] propyllamine Chlorambucil 0.30 g (0.99 mmol)
Suspended in 2 mL of ice and stirred under ice-cooling in a nitrogen atmosphere.
0.17 mL (1.22 mmol, 1.2e
q. ), 0.11 mL of ethyl chloroformate (1.22 mm
ol, 1.2 eq. ). Azide after 20 minutes
0.13 g of sodium (2.0 mmol, 2.0e
q. ) / Water (2 mL) was added dropwise, and the mixture was stirred for 1 hour and ice was removed.
In addition, the reaction was stopped. Add 20 mL of benzene and extract three times
Take out, combine and dry with sodium sulfate and heat to reflux for 1 hour.
Was. The mixture was concentrated under reduced pressure.
Heated at 100 ° C. for minutes. The residue concentrated under reduced pressure is diluted with water.
After adjusting the pH to 12 with concentrated aqueous ammonia, ethyl acetate
Extract, dry and concentrate to give the crude title compound.
0.21 g was obtained as a highly viscous yellow oil. this
Was used for the next reaction without purification. (Reaction 2)1H-2- (1-methyl-4-nitro pillow
Ru-2-yl) benzimidazole-5- [N- [3-
[4- [N, N-bis (2-chloroethyl) amino] f
Enyl] propyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) 0.17 g of benzimidazole-5-carboxylic acid
(0.59 mmol) was dissolved in 5 mL of DMF.
0.12 g (0.74 mmol, 1.2 eq.) Was added.
Then, the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Ice-cooled, 3-
[4- [N, N-bis (2-chloroethyl) amino] f
[Enyl] propylamine 0.24 g (crude) / D
2 mL of MF solution was added dropwise, the ice bath was removed, and the mixture was stirred for 3 hours.
Left overnight. Concentrate under reduced pressure and add methanol to the residue.
The precipitated crystals were collected by filtration to give the title compound 0.1.
17 g (0.31 mmol, 53.0%) of pale yellow crystals
As obtained. mp. 164-168 ° C (Reaction 3)1H-2- [4- (2-guanidinoacetyl
Amino) -1-methylpyrrol-2-yl] benziimi
Dazol-5- [N- [3- [4- [N, N-bis (2
-Chloroethyl) amino] phenyl] propyl]] cal
Boxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [3- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
[Propyl]] carboxamide 0.26 g (0.48
mmol) in 3 mL of DMF-3 mL of methanol
Then, 0.12 mL of 4N hydrochloric acid was added, and 10% Pd / C0.
Using 11 g as a catalyst, hydrogenation to the corresponding amino compound by normal pressure hydrogenation
lead. The DMF solution of this amino compound was ice-cooled under a nitrogen stream.
Stir and add 67 μL of triethylamine (0.48 mmol,
1.0 eq. ), 0.22 g of 2-guanidinoacetic acid hydrochloride
(1.43 mmol, 3.0 eq.), DCC 0.30
g (1.45 mmol, 3.0 eq.) in that order.
The mixture was stirred for 6 hours and left overnight. After filtering off the resulting crystals
After concentration under reduced pressure, the residue was purified by silica gel chromatography.
(Ethyl acetate / IPA / water = 7/2/1, twice)
By crystallizing from the product, 91 mg of the title compound was obtained.
(0.14 mmol, 29.2%) as white crystals
Was. mp. 168-173 ° C Elemental analysis: Calculated value (C₂₉H₃₅N₉O_TwoCl_Two・ 2HCl )
C: 50.81, H: 5.44, N: 18.39, C
l: 20.69, analysis value C: 50.90, H: 5.8
0, N: 18.05, Cl: 21.06

Example 33 (Compound 2001)1H-2- [4- [4- [N, N-bis (2-chloroe
Tyl) amino] benzoylamino] -1-methyl pillow
Ru-2-yl] benzimidazole-5- [N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
Le]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
0.18 g (0.36 mmol) of oxamide was added to DMF1
Suspended in a mixed solvent of 0 mL and methanol 8 mL, concentrated hydrochloric acid
One equivalent was added, and 0.07 g of 10% Pd / C was used as a catalyst.
It was pressurized and hydrogenated to the corresponding amino compound. This DM
The solution F was stirred under ice-cooling under a nitrogen atmosphere, and triethylamine was added.
0.11 mL (0.79 mmol, 2.2 eq.) Was added.
And 4- [N, N-bis (2-chloroethyl)
Amino] benzoic acid from 0.11 g (0.42 mmol)
Synthesized 4- [N, N-bis (2-chloroethyl) amido
3] Benzoyl chloride benzene 3mL solution is added dropwise.
Was. The mixture was returned to room temperature, stirred for 5 hours, and left overnight. Reduced pressure
The residue is purified by silica gel column chromatography.
(Chloroform / methanol 2-4%), ethanol
The title compound 73 was obtained by crystallization from toluene / ether.
mg (0.10 mmol, 28.3%) as white crystals
I got it. mp. 168-174 ° C IR (KBr) cm^-1: 3414, 1655, 163
7, 1606, 1517, 1278 Elemental analysis: Calculated value (C₃₄H₃₅N₇O_TwoCl_Four・ 1.5H
_TwoO) C: 55.00, H: 5.16, N: 13.2
0, Cl: 19.10, analytical value C: 54.79, H:
4.89, N: 12.96, Cl: 18.73

Example 34 (Compound 342)1H-2- [1-methyl-4- [4- [N, N-bis
(2-Chloroethyl) amino] benzoylamino] imi
Dazol-2-yl] benzimidazole-5- [N-
(2-amidinoethyl)] carboxamide hydrochloride (Reaction 1)2-formyl-1-methylimidazole 0.5 g (6.1 mmol) of 1-methylimidazole
In a THF (dehydrated) 15 mL solution, cool with ice under a nitrogen atmosphere.
While stirring, 1.6 Mn-hexa of n-butyllithium was used.
4.6 mL (7.4 mmol, 1.2 eq.)
After the dropwise addition, the temperature was returned to room temperature. After 1.5 hours cool on ice again
1.4 mL of DMF (18.1 mmol, 3.0 eq.)
Was dropped and left as it was overnight. The resulting white solid is filtered.
The filtrate was concentrated under reduced pressure. Dissolve the residue in ethyl acetate
The extract was washed with water, dried over sodium sulfate and concentrated. This
Kagel column chromatography (n-hexane / acetic acid
(Ethyl = 3/1) to give 0.31 g of the title compound
(2.82 mmol, 46.2%) as a yellow oil
Obtained. (Reaction 2)2-formyl-1-methyl-4-nitroi
Midazole Cool 3mL of fuming nitric acid to -10 ° C and add 3mL of concentrated sulfuric acid dropwise.
I dropped it. This is treated with 2-formyl-1-methylimidazole
Drops at 0.5 g (4.54 mmol) at an internal temperature of -10 ° C or less
I dropped it. Allow it to warm to room temperature and let it sit overnight
Was. The reaction solution was poured into ice and neutralized with sodium carbonate. salt
Extract twice with methylene chloride, and wash the organic layer with saturated sodium bicarbonate
After washing with a solution, the extract was dried over sodium sulfate and concentrated.
By crystallizing the residue from ether / ethanol
The title compound 0.21 g (1.35 mmol, 29.
8%) as cream crystals. mp. 140-142 ° C (Reaction 3)1H-2- (1-methyl-4-nitroimi
Dazol-2-yl) benzimidazole-5-carbo
Acid 2-formyl-1-methyl-4-nitroimidazole
1.48 g (9.54 mmol), 3,4-diamino ammonium
1.45 g (9.53 mmol, 1.0 eq.) Of benzoic acid
Is suspended in 75 mL of nitrobenzene,
The mixture was heated and stirred for 27 hours. Crystals formed by cooling to room temperature
Was collected by filtration and washed with IPA to give the title compound 1.9.
2 g (6.68 mmol, 70.0%) as a brown solid
I got it. (Reaction 4)1H-2- (1-methyl-4-nitroimi
Dazol-2-yl) benzimidazole-5- [N-
(2-cyanoethyl)] carboxamide 1H-2- (1-methyl-4-nitroimidazole-2
-Yl) benzimidazole-5-carboxylic acid 1.44
g (5.01 mmol) was suspended in 50 mL of DMF, and C
0.89 g (5.49 mmol, 1.1 eq.) Of DI
In addition, the mixture was stirred at room temperature under a nitrogen atmosphere. 2.5 hours after ice cooling
0.37 mL of β-aminopropionitrile (5.01
mmol, 1.0 eq. ) Was added. Return to room temperature
After stirring for 5.5 hours, the mixture was left overnight. Concentrate under reduced pressure and remove the residue.
By sludge with IPA-methanol, the standard
1.36 g (4.0 mmol, 80.0%) of the title compound
Obtained as ocher crystals. mp. > 277 ° C (Reaction 5)1H-2- (1-methyl-4-nitroimi
Dazol-2-yl) benzimidazole-5- [N-
(2-amidinoethyl)] carboxamide hydrochloride 1H-2- (1-methyl-4-nitroimidazole-2
-Yl) benzimidazole-5- [N- (2-cyano
Ethyl)] 1.35 g of carboxamide (3.98 mmol)
l) is suspended in 45 mL of ethanol, and hydrogen chloride gas
(30 minutes). Return to room temperature after saturation
The mixture was stirred for 2 hours. Decompression after blowing nitrogen for 10 minutes
Concentrate under, add ether to the residue and decant twice
Was. The obtained solid is suspended in 40 mL of ethanol and cooled with ice.
Under ammonia gas was blown (1.5 hours). After saturation
The mixture was returned to room temperature, stirred for 3 hours and concentrated under reduced pressure. Eta the residue
And sludge it with ethanol.
Dissolve in methanol, treat with activated carbon, concentrate and concentrate with methanol
Sludge to give 1.20 g of the title compound (3.05 mmol)
1, 76.8%) as yellow crystals. mp. 198-210 ° C (Reaction 6)1H-2- [1-methyl-4- [4-
[N, N-bis (2-chloroethyl) amino] benzoy
Ruamino] imidazol-2-yl] benzimidazo
Ru-5- [N- (2-amidinoethyl)] carboxami
Do hydrochloride 1H-2- (1-methyl-4-nitroimidazole-2
-Yl) benzimidazole-5- [N- (2-amidi
Noethyl)] carboxamide hydrochloride 0.30 g (0.7
6 mmol) in 5 mL of DMF and 3.5 mL of methanol.
Suspended in mixed solution, using Pd / C 0.12g as catalyst, contact
Hydrogenation gave the corresponding amino form. This amino form
Was directly dissolved in 5 mL of DMF without purification. This solution
While stirring under ice-cooling under a nitrogen atmosphere, 4- [N, N-
Bis (2-chloroethyl) amino] benzoyl chloride
｛This is 4- [N, N-bis (2-chloroethyl) amido
[No] benzoic acid 0.26 g (0.99 mmol｝
2 mL of benzene dissolved in thionyl
The solution was added dropwise. The mixture was returned to room temperature and further stirred for 5 hours. Anti
The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography.
Purified by chromatography (ethyl acetate / IPA / water = 6 /
2/1), title by crystallization from ethanol
0.07 g (0.12 mmol, 15.2%) of the compound
Obtained as white crystals. mp. 218-228 ° C (dec.) IR (KBr) cm^-1: 3415, 1609, 154
2,1315,1186 Elemental analysis: Calculated value (C₂₆H₂₉N₉O_TwoCl_Two・ 1.8HC
l ・ 3H_TwoO) C: 45.25, H: 5.37, N: 1
8.27, Cl: 19.52, analytical value C: 45.35,
H: 5.35, N: 18.16, Cl: 19.52

Example 35 (Compound 345)1H-2- [1-methyl-4- [4- [N, N-bis
(2-chloroethyl) aminophenyl] butyrylamino
No] Imidazol-2-yl] benzimidazole-5
-[N- (2-amidinoethyl)] carboxamide hydrochloride
salt 1H-2- (1-methyl-4-nitroimidazole-2
-Yl) benzimidazole-5- [N- (2-amidi
Noethyl)] carboxamide hydrochloride 0.20 g (0.5
1 mmol) mixed with 5 mL of DMF and 4 mL of methanol
Suspended in a solvent and catalytically hydrogenated 0.08 g of Pd / C to the catalyst
Then, the corresponding amino compound was obtained. This amino form is
It was directly dissolved in 5 mL of DMF without production. In this solution,
Chlorambucil 0.16g while stirring under nitrogen atmosphere
(0.53 mmol, 1.03 eq.), HOBt76
mg (0.56 mmol, 1.1 eq.) in order.
Was. After cooling on ice, 0.12 g of DCC (0.58 mmol, 1.
1 eq. ), Return to room temperature, stir for 1.5 hours and overnight
I left it. After concentration under reduced pressure, the residue was purified by silica gel column chromatography.
Purified by chromatography (ethyl acetate / IPA / water = 6)
/ 1/2/1 → 4/2/1, twice) ethanol / ether
Crystallized from the title compound to give 40 mg of the title compound.
(0.061 mmol, 12.1%) with light pink crystals
I got it. mp. 163-168 ° C IR (KBr) cm^-1: 3409, 2924, 165
5,1560,1543,1388,1019 Elemental analysis: Calculated value (C₂₉H₃₅N₉O_TwoCl_Two・ HCl ・ 2
H_TwoO) C: 50.85, H: 5.89, N: 18.4
0, analytical value C: 50.94, H: 5.79, N: 18.
63

Example 36 (Compound 358) 1H-2- (1-methyl-4-formylaminoimidazo
2-yl) benzimidazole-5- [N- (2
-Amidinoethyl)] carboxamide hydrochloride 1H-2- (1-methyl-4-nitroimidazole-2
-Yl) benzimidazole-5- [N- (2-amidinoethyl)] carboxamide hydrochloride 0.20 g (0.5
1 mmol) was suspended in a mixed solvent of 5 mL of DMF and 5 mL of methanol, and catalytically hydrogenated using 0.8 g of Pd / C as a catalyst. After Pd / C filtration, methanol was distilled off under reduced pressure. 0.41 g (2.52 mmol) of 1-formylimidazole @ CDI was added to a DMF solution of the obtained amino compound as a crude product while stirring under ice-cooling under a nitrogen atmosphere.
Dissolve in 5 mL of HF and add 0.1 mL of formic acid (2.65 mmol
prepared by adding 1) and stirring for 1 hour.
Was added. The mixture was returned to room temperature, stirred for 6 hours, and left overnight. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / IPA / water = 6 /
2/1) and an ODS column (water / methanol 5% +
Acetic acid), gel filtration (Sephadex G-10, water)
26 mg (0.067) of the title compound
mmol, 13.0%) as an amorphous powder. IR (KBr) cm ^-1 : 3256, 1684, 155
9,1541,1398,1318 Calcd _{(C 16 H 18 N 8 O} 2 · HCl · 2H
₂ O) C: 45.02, H: 5.43, N: 22.3
0, analytical value C: 45.39, H: 5.28, N: 22.
30

Example 37 (Compound 1608) 1H-2- [4- (guanidinoacetyl) amino-1-
Methylimidazol-2-yl] benzimidazole-
5- [N- [4- [N, N-bis (2-chloroethyl)
Amino] phenyl]] carboxamide dihydrochloride (Reaction 1) 1H-2- (1-methyl-4-nitroimimi)
Dazol-2-yl) benzimidazole-5- [N-
[4- [N, N-bis (2-chloroethyl) amino] f
Enyl]] carboxamide 1H-2- (1-methyl-4-nitroimidazole-2
-Yl) benzimidazole-5-carboxylic acid 0.17
g (0.59 mmol), N, N-bis (2-chloroethyl) -1,4-phenylenediamine hydrochloride 0.16 g
(0.59 mmol, 1.0 eq.) Was dissolved in 5 mL of DMF. 0.25 mL of triethylamine (1.79 mmol) was added to this solution while stirring with ice cooling under a nitrogen stream.
1, 3.0 eq. ), DECP 0.13 mL (0.86
mmol, 1.5 eq. ) Was added in order. 1 as it is
After stirring for an hour, the mixture was left overnight. After concentration under reduced pressure, the residue was purified by gel filtration (Sephadex LH-20, methanol), and crystallized from ethanol to give 0.16 g (0.32 mmol, 54.0%) of the title compound as yellow crystals. . mp. 157-159 ° C (Reaction 2) 1H-2- [4- (guanidinoacetyl)
Amino-1-methylimidazol-2-yl] benzi
Midazole-5- [N- [4- [N, N-bis (2-
Loroethyl) amino] phenyl]] carboxamide disalt
Acid salt 1H-2- (1-methyl-4-nitroimidazole-2
-Yl) benzimidazole-5- [N- [4- [N,
N-bis (2-chloroethyl) amino] phenyl]] carboxamide 0.16 g (0.32 mmol) in DMF
Suspended in a mixed solution of methanol and methanol, 1N hydrochloric acid 0.35m
L was added thereto, and hydrogenation was performed under normal pressure using 10% Pd / C (wet) as a catalyst to lead to the corresponding amino compound. 55 μL of triethylamine (0.39 mmol, 1.2e) was added to the DMF solution of the amino compound under ice cooling and stirring under a nitrogen stream.
q. ), Guanidine acetate hydrochloride 0.14 g (0.91 m
mol, 3.0 eq. ), 0.19 g (0.92 g) of DCC
mmol, 3.0 eq. ) Were added in order. The mixture was returned to room temperature, stirred for 9 hours, and left overnight. The resulting solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to gel filtration (Sephad).
ex LH-20, methanol) and 4N hydrochloric acid / dioxane were added to the eluted fraction, concentrated, and crystallized from methanol to give 61 mg of the title compound (0.095m
mol, 29.6%) as a bright yellow crystal. mp. > 250 ° C IR (KBr) cm ^-1 : 3345, 1670, 154
2,1327 Elemental analysis: Calculated value (C ₂₅ H ₂₈ N ₁₀ O ₂ Cl ₂ .2.5HC
_{l · 1.5H 2 O) C:} 43.53, H: 4.90,
N: 20.31, Cl: 23.13, Analysis value C: 43.
43, H: 4.78, N: 20.21, Cl: 23.4
4

Example 38 (Compound 424)1H-2- [2- [4- [4- [N, N-bis (2-k
Loroethyl) amino] phenyl] butyrylamino] thio
Phen-4-yl] benzimidazole-5- [N-
(2-amidinoethyl)] carboxamide hydrochloride (Reaction 1)1H-2- (2-nitrothiophen-4-
Ill) benzimidazole-5-carboxylic acid 2-nitrothiophene-4-carboxaldehyde
0 g (12.7 mmol), 3,4-diaminobenzoic acid
2.0 g (12.8 mmol, 1.0 eq.) Of nitro
Dissolve in 100 mL of benzene and heat in an oil bath at 150 ° C
Stirred. After 32 hours, cool to room temperature and filter the resulting solid.
Take the title by washing with IPA and methylene chloride
2.02 g (7.78 mmol, 61.2%) of the compound
Obtained as earthy crystals. mp. > 270 ° C (Reaction 2)1H-2- (2-nitrothiophen-4-
Yl) benzimidazole-5- [N- (2-cyanoe)
Chill)] carboxamide 1H-2- (2-nitrothiophen-4-yl) benz
2.0 g of imidazole-5-carboxylic acid (7.8 mmol
l) is suspended in 40 mL of DMF, and 1.39 g of CDI is suspended.
(8.57 mmol, 1.1 eq.) In a nitrogen atmosphere
The mixture was stirred at room temperature. After 1.5 hours, cool on ice and
0.63 mL of ropionitrile (8.54 mmol, 1.
1 eq. ) Was added and the mixture was returned to room temperature and left overnight. End of reaction
After confirming the completion, concentrate under reduced pressure and sludge the residue with IPA.
To give 1.18 g (3.82 mm) of the title compound.
ol, 49.0%) as brown crystals. mp. > 270 ° C (Reaction 3)1H-2- (2-nitrothiophen-4-
Il) benzimidazole-5- [N- (2-amidino
Ethyl)] carboxamide hydrochloride 1H-2- (2-nitrothiophen-4-yl) benz
Imidazole-5- [N- (2-cyanoethyl)] cal
0.85 g (2.7 mmol) of boxamide in ethanol
Suspended in 25 mL, hydrogen chloride gas under ice cooling for 1 hour
Blow saturated. It returned to room temperature and stirred for 2 hours.
Thereafter, nitrogen was blown in for 10 minutes, and the mixture was concentrated under reduced pressure. A residue
We sludge at Tell. Suspended in 35 mL of ethanol
And blow ammonia gas under ice-cooling for 1 hour.
After the mixture was returned to room temperature, it was left as it was overnight. occured
The crystals were collected by filtration and 0.84 g (2.13 mm
ol, 78.8%) as brown crystals. mp. > 275 ° C (Reaction 4)1H-2- [2- [4- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl] butyryl
Amino] thiophen-4-yl] benzimidazole-
5- [N- (2-amidinoethyl)] carboxamide salt
Acid salt 1H-2- (2-nitrothiophen-4-yl) benz
Imidazole-5- [N- (2-amidinoethyl)] ca
0.15 g (0.38 mmol) of ruboxamide hydrochloride
Dissolve in 4 mL of DMF and touch 0.07 g of 10% Pd / C
Catalytic hydrogenation was performed as a medium. After filtration by Pd / C, nitrogen
Cool under ice with an atmosphere and add 4- [4- [N, N-bis (2-chloro
Ethyl) amino] phenyl] butyryl chloride (chlora
0.13 g of mbucil (0.43 mmol, 1.1e
q. ) To thionyl chloride 0.26 g (2.19 mmol,
5.1 eq. ), Leave at room temperature for 5 minutes, and then
1 mL of benzene (concentrated and prepared with benzene azeotrope twice)
The solution was added dropwise. Return to room temperature and stir for 5.3 hours, then release overnight
Was placed. Concentrate under reduced pressure to silica gel column chromatography.
Purify by luffy (ethyl acetate / IPA / water = 6/2)
/ 1), crystallized from ether to give the title compound
13 mg (0.02 mmol, 5.25%) of light brown crystals
As obtained. mp. > 275 ° C IR (KBr) cm^-1: 3160, 1637, 154
5,147,1289

Example 39 (Compound 438) 1H-2- (2-benzoylaminothiophen-4-i
B) benzimidazole-5- [N- (2-amidinoe)
Tyl)] carboxamide hydrochloride 1H-2- (2-nitrothiophen-4-yl) benzimidazole-5- [N- (2-amidinoethyl)] carboxamide hydrochloride 0.40 g (1.0 mmol) in D
The resultant was dissolved in MF (20 mL) and subjected to catalytic hydrogenation using 0.18 g of 10% Pd / C as a catalyst. After Pd / C filtration, the mixture was ice-cooled under a nitrogen atmosphere and triethylamine 0.16 mL (1.1
5 mmol, 1.1 eq. ), Benzoyl chloride 0.
13 mL (1.13 mmol, 1.1 eq.) Were added sequentially. After returning to room temperature for 4.5 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / IPA / water = 6/2/1), and crystallized from ether. Since impurities were confirmed by NMR, the product was further purified by gel filtration (Sephadex LH-2).
(0, methanol) and ether to give 24 mg (0.05 mmol, 5.0%) of the title compound as light brown crystals. mp. 220-223 ° C. Elemental analysis: Calculated _{(C 22 H 20 N 6 SO} 2 · 3H 2 O) C:
50.52, H: 5.20, N: 16.07, Analytical value C: 50.70, H: 5.02, N: 16.20

Example 40 (Compound 1617) 1H-2- [5- (guanidinoacetyl) aminothiol
Hen-3-yl] benzimidazole-5- [N- [4
-[N, N-bis (2-chloroethyl) amino] phenyl
]] Carboxamide dihydrochloride (Reaction 1) 1H-2- (5-nitrothiophen-3-
Yl) benzimidazole-5- [N- [4- [N, N
-Bis (2-chloroethyl) amino] phenyl]] cal
Boxamide 1H-2- (5- nitrothiophen -3-yl) benzimidazole-5-carboxylic acid 0.30 g (1.17 m
mol), N, N-bis (2-chloroethyl) -1,4
0.31 g of phenylenediamine hydrochloride (1.15 mm
ol, 1.0 eq. ) Was dissolved in 10 mL of DMF. Under ice-cooling and stirring under a nitrogen stream, triethylamine 0.49 was added.
mL (3.51 mmol, 3.0 eq.), DECP
0.27 mL (1.78 mmol, 1.5 eq.) Was added in order, stirred for 8 hours, and left overnight. After concentration under reduced pressure, methanol was added to the residue, and the insoluble solid was separated by filtration. The filtrate was purified by silica gel column chromatography (chloroform / methanol 2-4%) and sludged with methanol to give 0.11 g of the title compound.
(0.22 mmol, 19.0%) was obtained as brown crystals. (Reaction 2) 1H-2- [5- (guanidinoacetyl)
Aminothiophen-3-yl] benzimidazole-5
-[N- [4- [N, N-bis (2-chloroethyl) a
[Mino] phenyl]] carboxamide dihydrochloride 1H-2- (5-nitrothiophen-3-yl) benzimidazole-5- [N- [4- [N, N-bis (2-
Chloroethyl) amino] phenyl]] carboxamide (0.10 g, 0.20 mmol) was suspended in a mixed solution of DMF and methanol, and 0.22 mL of 1N hydrochloric acid was added.
Using 0.05 g of 0% Pd / C (wet) as a catalyst, the mixture was converted to the corresponding amino compound by hydrogenation under normal pressure. To a DMF solution of this amino compound was added 32 μl of triethylamine (0.23 mmol, 1.1e) while stirring with ice cooling under a nitrogen stream.
q. ), 93 mg of guanidine acetate hydrochloride (0.61 mm
ol, 3.0 eq. ), DCC 0.12 g (0.58 m
mol, 2.9 eq. ) Was added in order, returned to room temperature, stirred for 8 hours, and left overnight. The resulting solid was filtered off, the filtrate was concentrated under reduced pressure, DMF was added again to the residue, the resulting crystals were filtered off and concentrated, and the residue was subjected to gel filtration (Sephade).
x LH-20, methanol), 4
N hydrochloric acid / dioxane was added, and the mixture was concentrated and crystallized from ethanol to give 9 mg (0.014 mm) of the title compound.
ol, 7.0%) as brown crystals. mp. > 250 ° C IR (KBr) cm ^-1 : 3338, 1653, 151
7,1330,818

Example 41 (Compound 505)1H-2- [5- [4- [4- [N, N-bis (2-k
Loroethyl) amino] phenyl] butyrylamino] thio
Fen-2-yl] benzimidazole-5- [N-
(2-amidinoethyl)] carboxamide hydrochloride (Reaction 1)1H-2- (5-nitrothiophene-2-
Il) Methyl benzimidazole-5-carboxylate 5-nitro-2-thiophenecarboxaldehyde 0.
50 g (3.18 mmol) and 3,4-diaminobenzoate
0.53 g (3.19 mmol, 1.0e
q. ) Is suspended in 25 mL of nitrobenzene,
The mixture was heated and stirred in an ir bath for 28.5 hours. Solvent under reduced pressure
Distill off and sludge the residue with methanol
0.775 g (2.86 mmol, 8
9.9%) as ocher crystals. mp. > 280 ° C (Reaction 2)1H-2- (5-nitrothiophene-2-
Ill) benzimidazole-5-carboxylic acid 1H-2- (5-nitrothiophen-2-yl) benz
0.57 g of methyl imidazole-5-carboxylate (2.
22 mmol) in 15 mL of methanol, and
Add 15 mL of aqueous sodium chloride solution and add at 60 ° C for 1 hour.
Stirred hot. The methanol was distilled off under reduced pressure, and the remaining aqueous solution was removed.
Was acidified with 4N hydrochloric acid, and the resulting crystals were collected by filtration.
More title compound 0.55 g (2.14 mmol, 96.
3%) as dark brown crystals. mp. > 280 ° C (Reaction 3)1H-2- (5-nitrothiophene-2-
Yl) benzimidazole-5- [N- (2-cyanoe)
Chill)] carboxamide 1H-2- (5-nitrothiophen-2-yl) benz
1.5 g of imidazole-5-carboxylic acid (5.83 mm
ol) in 45 mL of DMF, and 1.04 g of CDI
(6.4 mmol, 1.1 eq.) And a nitrogen atmosphere
After stirring at room temperature for 1 hour, the mixture was ice-cooled for 1 hour, and
Tril 0.43 mL (5.8 mmol, 1.0 eq.)
Was added. The mixture was returned to room temperature, stirred for 30 minutes, and left overnight.
After confirming the completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified with a silica gel column.
Purify by chromatography (methylene chloride / methanoic
4-10%) to sludge with ether
More title compound 0.53 g (1.7 mmol, 29.3)
%) Were obtained as bright yellow crystals. mp. 219-222 ° C (Reaction 4)1H-2- (5-nitrothiophene-2-
Il) benzimidazole-5- [N- (2-amidino
Ethyl)] carboxamide hydrochloride 1H-2- (5-nitrothiophen-2-yl) benz
Imidazole-5- [N- (2-cyanoethyl)] cal
0.52 g (1.68 mmol) of boxamide in ethanol
Suspended in 15 mL of water and saturated with hydrogen chloride gas under ice-cooling.
(1 hour). After returning to room temperature and stirring for 3 hours,
The solvent was distilled off under reduced pressure. Ether was added to the residue and
After canting, dissolve in 15 mL of ethanol.
Monmonia gas was blown to saturation (2 hours). At room temperature
After stirring for 1 hour, the solvent was distilled off under reduced pressure.
The title compound 0.54 by ethanol sludge
g (1.49 mmol, 88.6%) as bright yellow crystals
I got it. mp. > 280 ° C (Reaction 5)1H-2- (5-aminothiophene-2-
Il) benzimidazole-5- [N- (2-amidino
Ethyl)] carboxamide hydrochloride 1H-2- (5-nitrothiophen-2-yl) benz
Imidazole-5- [N- (2-amidinoethyl)] ca
0.53 g (1.46 mmol) of ruboxamide hydrochloride
Suspended in a mixed solution of 5 mL of DMF and 5 mL of methanol,
Catalytic hydrogenation is performed using 0.22 g of Pd / C as a catalyst,
Led to the corresponding amino form. This amino compound was prepared in another example
It was used for the next reaction in the same manner as described above. (Reaction 6)1H-2- [5- [4- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl] butyryl
Amino] thiophen-2-yl] benzimidazole-
5- [N- (2-amidinoethyl)] carboxamide salt
Acid salt 1H-2- (5-aminothiophen-2-yl) benz
Imidazole-5- [N- (2-amidinoethyl)] ca
Obtained from 1.46 mmol of ruboxamide hydrochloride / nitro compound
Dissolved in approximately 3 mL of DMF
Is cooled under ice in a nitrogen atmosphere.
[N, N-bis (2-chloroethyl) amino] phenyl
Butyryl chloride @ chlorambucil 0.25 g (0.8
2 mmol, 1.1 eq. ) And 0.49 g of thionyl chloride
(4.1 mmol, 5.5 eq.)
Tylene 2mL solution, triethylamine 0.10mL
(0.72 mmol, 1.0 eq.) Were added in order. Room
The mixture was returned to warm temperature, stirred for 5 hours, and left overnight. Concentrate under reduced pressure
Purify by silica gel column chromatography (acetic acid
Ethyl / IPA / water = 7/2/1 → 9/2/1 → 12 /
2/1, a total of 3 times) by crystallization with ether
27 mg (0.044 mmol, 6.0 mg) of the title compound
%) Were obtained as brownish-white crystals. mp. > 275 ° C IR (KBr) cm^-1: 3220, 2930, 168
4,1541,1521,806 Elemental analysis: Calculated value (C₂₉H₃₃N₇SO_TwoCl_Two・ 2HCl
・ H_TwoO) C: 49.37, H: 5.29, N: 13.
90, analytical value C: 49.69, H: 5.29, N: 1
3.47

Example 42 (Compound 518)1H-2- (5-formylaminothiophen-2-i
B) benzimidazole-5- [N- (2-amidinoe)
Tyl)] carboxamide hydrochloride 1H-2- (5-aminothiophen-2-yl) benz
Imidazole-5- [N- (2-amidinoethyl)] ca
Combination of 1.46 mmol of ruboxamide hydrochloride ｛nitro compound
１ ／ volume, dissolved in approximately 3 mL of DMF
The product was cooled in a nitrogen atmosphere with ice, and formyl
Midazole in 8 mL of THF (0.59 g of CDI)
(3.63 mmol, 5 eq.) In 8 mL of THF
0.14 mL (3.71 mmol, 5 eq.)
Was added and the mixture was stirred for 2 hours.
The mixture was returned to room temperature, stirred for 8.5 hours, and left overnight. Reduced pressure
The residue is purified by silica gel column chromatography.
(Ethyl acetate / IPA / water = 7/2/1, 3 times
Line), crystallization from ethyl acetate / IPA
10 mg (0.025 mmol, 3.4%) of the title compound
Obtained as a brown powder (amorphous).

Example 43 (Compound 3024) 1H-2- (5-nitrofuran-2-yl) benziimi
0.50 g of dazole-5 -carboxylic acid 5-nitrofurfural (3.54 mmol
l) and 0.56 g of 3,4-diaminobenzoic acid (97%)
(3.57 mmol, 1.0 eq.) Was suspended in 25 mL of nitrobenzene, and heated and stirred in a 150 ° C. oil bath for 20 hours. The resulting crystals were collected by filtration under ice cooling to give 0.64 g (2.32 mmol) of the title compound as black-brown crystals. The filtrate was further concentrated and sludged with methylene chloride to give 0.89 g of the title compound (3.28 m
mol, 92.7%). mp. > 280 ° C

Example 44 (Compound 672)1H-2- (5-benzoylaminopyrrole-2-i
B) benzimidazole-5- [N- (2-amidinoe)
Tyl)] carboxamide hydrochloride (Reaction 1)1H-2- (5-nitropyrrole-2-i
B) Benzimidazole-5-carboxylic acid 1.03 g of 5-nitropyrrole-2-aldehyde (7.
35 mmol) and 3,4-diaminobenzoic acid 1.1
Dissolve 2 g (7.35 mmol) of nitrobenzene in 50 mL
The liquid was heated at 150 ° C. for 6 hours. After the reaction is completed,
The resulting crystals were collected by filtration and washed with IPA. Further DMF-water
To give 1.28 g (64%) of the desired product as green crystals
I got it. mp> 300 ° C IR (KBr) cm^-1: 3269, 2835, 166
5,1493,1458,1350,1306,125
4,1137 (Reaction 2)1H-2- (5-nitro-1-methyl pillow
Ru-2-yl) benzimidazole-5- [N- (2-
Cyanoethyl)] carboxamide 1H-2- (5-nitropyrrol-2-yl) benzi
633 mg of midazole-5-carboxylic acid (2.33 mm
ol) in 19 mL of DMF was added 566 mg of CDI (3.
49 mg) and stirred at room temperature for 30 minutes. Enough
After the crystals were precipitated and the raw materials disappeared by TLC, β-amino
489 mg (6.98 mmol) of propionitrile are added dropwise.
Then, the mixture was stirred at room temperature for 30 minutes until the crystals were dissolved. Anti
After completion of the reaction, the reaction mixture was concentrated, and IPA was added thereto. The precipitated crystals were collected by filtration.
And recrystallized with DMF-water to obtain 608 mg of the desired product
(80%) were obtained as ocher crystals. mp. 268-270 ° C IR (KBr) cm^-1: 3359, 2252, 163
0, 1545, 1351, 1305 (Reaction 3)1H-2- (5-nitropyrrole-2-i
B) benzimidazole-5- [N- (2-amidinoe)
Tyl)] carboxamide hydrochloride 1H-2- (5-nitro-1-methylpyrrole-2-i
B) benzimidazole-5- [N- (2-cyanoethyl
Le)] 771 mg (2.38 mmol) of carboxamide
54mL suspension of ethanol saturated with hydrochloric acid gas under ice-cooling
did. Stirred at room temperature for 1 hour. Excess hydrochloric acid gas
And then wash the concentrated residue with ether.
Was. Again, a 1: 1 mixed solution of methanol and ethanol 23
mL, and saturated with ammonia gas.
After dissolution, crystals precipitated. Inject nitrogen gas
After removing excess ammonia gas, the crystals are collected by filtration.
After washing with PA, 812 mg (90%) of the desired product
Obtained as crystals. mp. 299-300 ° C IR (KBr) cm^-1: 3363, 1702, 163
6,1545,1452,1405,1349,123
6,1193 (Reaction 4)1H-2- (5-benzoylaminopyrrole
-2-yl) benzimidazole-5- [N- (2-A
Midinoethyl)] carboxamide hydrochloride 1H-2- (5-nitropyrrol-2-yl) benzi
Midazole-5- [N- (2-amidinoethyl)] cal
153 mg (0.405 mmol) of boxamide hydrochloride
4.6 mL of DMF was added to 76.9 mg of 10% Pd / C.
Catalytic hydrogenation using the catalyst to form the corresponding amino compound
Reduced. The filtrate excluding Pd / C was added to the filtrate under nitrogen atmosphere.
At 8 ° C., 56.9 mg of benzoic acid chloride (0.405 m
mol) was added dropwise and stirred for 30 minutes. Concentrate the reaction solution
And the residue is purified by silica gel column chromatography (acetic acid).
Ethyl / IPA / water = 6/2/1)
6.4 mg (31%) were obtained. mp. 195-200 ° C IR (KBr) cm^-1: 3316, 1687, 163
8,1555,1432,1307

Example 45 (Compound 671)1H-2- (5-formylaminopyrrol-2-yl)
Benzimidazole-5- [N- (2-amidinoethyl
Le)] carboxamide hydrochloride 1H-2- (5-nitropyrrol-2-yl) benzi
Midazole-5- [N- (2-amidinoethyl)] cal
102 mg (0.270 mmol) of boxamide hydrochloride
DMF 3.1mL solution using 10% Pd / C as catalyst
Catalytic hydrogenation reduced the corresponding amino compound. P
The filtrate obtained excluding d / C was added to the N-form
Luimidazole THF solution @ CDI 87.6 mL
(0.54 mmol) in 2.6 mL of THF
24.9 mg (0.54 mmol) of 100% formic acid at room temperature
And stirred for 15 minutes to prepare｝ at -40 ° C.
I dropped it. After stirring at room temperature for 15 minutes, the reaction solution was concentrated,
Rush column chromatography (ethyl acetate / IP
A / water = 6/2/1) and 7.2 mg of the desired product (7.
1%). mp. 175-185 ° C (dec.) IR (KBr) cm^-1: 3406, 1671, 163
0,1561,1438,1319

Example 46 (Compound 665) 1H-2- [5- [4- [4- [N, N-bis (2-
Loroethyl) amino] phenyl] butyrylamino] pyro
2-yl] benzimidazole-5- [N- (2
-Amidinoethyl)] carboxamide hydrochloride 1H-2- (5-nitropyrrol-2-yl) benzimidazole-5- [N- (2-amidinoethyl)] carboxamide hydrochloride 111 mg (0.294 mmol) in DMF 3.3 mL The solution was catalytically hydrogenated with 55.8 mg of 10% Pd / C using a catalyst to reduce to the corresponding amino compound. A solution of 4- [4- [N, N-bis (2-chloroethyl) amino] phenyl] butyric acid chloride in 1,2-dichloroethane at ラ ム 78 ° C. in a nitrogen atmosphere was added to the filtrate from which Pd / C had been removed. .401mmo
153 mg (1.20 mmol) of oxalyl chloride was added to a solution of 1) in 6.1 mL of 1,2-dichloroethane for -20 minutes.
After dropwise stirring at room temperature and stirring overnight at room temperature, the oily substance obtained by concentration to dryness was dissolved in 1,2-dichloroethane (1.0 mL), and Preparation (2) was added dropwise, followed by stirring for 30 minutes. After the reaction,
After concentration, the residue was subjected to silica gel column chromatography (ethyl acetate / IPA / water = 6/2/1) to obtain 45.6 mg (24%) of the desired product. mp. 150-156 ° C (dec.) IR (KBr) cm ^-1 : 3269, 3133, 165
5,1557,1519,1438,1313,104
4

Example 47 (Compound 1592)1H-2- [4- (guanidinoacetyl) amino-1-
Methylpyrrole-2-yl] benzimidazole-5
[N- [3- [N- [4- [N, N-bis (2-chloro
Ethyl) amino] phenyl] carboxamide] prop
Le]] carboxamide hydrochloride (Reaction 1)4-[[1H-2- (1-methyl-4-nitto
Ropyrrol-2-yl) benzimidazole] -5-ca
Ruboxamide] butyric acid 1H-2- (1methyl-4-nitropyrrole-2-i
F) 0.30 g of benzimidazole-5-carboxylic acid
(1.05 mmol) was suspended in 10 mL of DMF,
0.25 g of CDI (1.54 mmol, 1.5e
q. ) Was added and the mixture was stirred at room temperature for 1.5 hours. ice
After cooling, 0.13 g of γ-aminobutyric acid (1.26 mmol,
1.2 eq. ), Return to room temperature and stir for 6.5 hours
Left overnight. Concentrate under reduced pressure, add methanol to the residue,
The resulting crystals were collected by filtration to give 0.29 g of the title compound.
(0.78 mmol, 74.4%) as yellow crystals.
Was. (Reaction 2)1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [3
-[N- [4- [N, N-bis (2-chloroethyl) a
Mino] phenyl] carboxamido] propyl]] carbo
Oxamide 4-[[1H-2- (1-methyl-4-nitropyrrole
-2-yl) benzimidazole] -5-carboxami
De] butyric acid 0.24 g (0.65 mmol), 4- [N,
N-bis (2-chloroethyl)] phenylenediamine salt
0.19 g (0.70 mmol, 1.08 eq.)
Was dissolved in 10 mL of DMF, and the mixture was stirred under ice-cooling under a stream of nitrogen. G
0.27 mL of liethylamine (1.94 mmol, 3.
0 eq. ), DECP 0.15mL (0.99mmo
1, 1.5 eq. ) In order and return to room temperature for 5 hours
After stirring, the mixture was left overnight. Concentrate under reduced pressure and concentrate the residue in methanol.
By crystallization, 0.26 g of the title compound (0.
45 mmol, 69.3%) as pale yellowish white crystals.
Was. (Reaction 3)1H-2- [4- (guanidinoacetyl)
Amino-1-methylpyrrol-2-yl] benzimidida
Zol-5- [N- [3- [N- [4- [N, N-bis
(2-Chloroethyl) amino] phenyl] carboxami
Do] propyl]] carboxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [3- [N- [4
-[N, N-bis (2-chloroethyl) amino] phenyl
[Carboxamide] propyl]] carboxamide
25 g (0.43 mmol) of 10% Pd / C (we
t) as catalyst to form the corresponding amino compound by hydrogenation under normal pressure
lead. The DMF solution of this amino compound was ice-cooled under a nitrogen stream.
After stirring, 68 μL of triethylamine (0.49 mmol,
1.1 eq. ), 0.20 g of guanidine acetate hydrochloride
(1.30 mmol, 3.0 eq.), DCC 0.27
g (1.31 mmol, 3.0 eq.) in this order.
The mixture was returned to warm temperature, stirred for 4 hours, and left overnight. Concentrate under reduced pressure and leave
The residue was subjected to gel filtration (Sephadex LH-20,
Methanol) and silica gel column chromatography
(Ethyl acetate / IPA / water = 6/2 /
1) By crystallizing with IPA, the title compound 88m
g (0.127 mmol, 29.6%) as white crystals
I got it. IR (KBr) cm^-1: 3317, 1655, 154
2,1518,1248 Elemental analysis: Calculated value (C₃₀H₃₆N_TenO_ThreeCl_Two・ HCl ・ 3
H_TwoO.0.5IPA) C: 48.75, H: 6.1
0, N: 18.05, Cl: 13.70, analytical value C: 4
8.79, H: 5.82, N: 17.67, Cl: 1
3.67

Example 48 (Compound 1017) 1H-2- [1-methyl-4- (guanidinoacetyla )
Mino) pyrrole-2-yl] benzimidazole-5
[N- [3-chloro-4- [N, N-bis (2-chloro
Ethyl) amino] phenyl]] carboxamide dihydrochloride (Reaction 1) 4- [N, N-bis (2-hydroxyethyl
L) amino] -3- chloro-nitrobenzene 10.0 g of 3-chloro-4-fluoronitrobenzene
(57.0 mmol) and 8.6 g of diethanolamine
(82 mmol) was dissolved in DMSO (8 mL). 1
After heating and stirring at 40 ° C. for 2 hours, extraction was performed with ethyl acetate. The solvent was distilled off under reduced pressure to give the title compound (9.5 g, 64 g).
%) As a yellow oil. (Reaction 2) 4- [N, N-bis (2-chloroethyl)
Amino] -3-chloro-nitrobenzene 4- [N, N-bis (2-hydroxyethyl) amino]
4.2 g (16.1 mm) of -3-chloro-nitrobenzene
ol) in 60 mL of a 1,2-dichloroethane solution was added with 6 mL (82 mmol) of thionyl chloride. After heating and stirring at 80 ° C. for 1 hour, the solvent was distilled off under reduced pressure to give the title compound.
0 g (83%) was obtained as a yellow oil. (Reaction 3) 1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [3
-Chloro-4- [N, N-bis (2-chloroethyl) a
Mino] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5-carboxylic acid 200 mg
(0.7 mmol) and 3-chloro-4- [N, N-bis (2-chloroethyl) amino] aniline hydrochloride {4-
[N, N-bis (2-chloroethyl) amino] -3-chloro-nitrobenzene 230 mg (0.49 mmol)
Is 100% 10% Pd / C in 20 mL methanol solution
Was obtained by catalytic hydrogenation of the catalyst. Was dissolved in 10 mL of DMF and cooled to 0 ° C. Triethylamine 1 under nitrogen atmosphere
17 μL (0.84 mmol) followed by DECP127
μL (0.84 mmol) was added, and the mixture was stirred for 40 minutes. After stirring at room temperature for 1 hour, the mixture was left overnight, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/1) to obtain 210 mg (51%) of the title compound as a yellow powder. (Reaction 4) 1H-2- [1-methyl-4- (guanidinium)
Noacetylamino) pyrrol-2-yl] benzimidida
Zol-5- [N- [3-chloro-4- [N, N-bis
(2-Chloroethyl) amino] phenyl]] carboxa
Mido dihydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [3-chloro-4
-[N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 200 mg (0.37 mmol)
Was dissolved in 10 mL of a 1: 1 mixed solvent of DMF and methanol, and 200 mg of 10% Pd / C was added under a nitrogen atmosphere, and 420 μL of 1N hydrochloric acid was added. The inside of the vessel was replaced with hydrogen and stirred at room temperature for 2 hours. After filtering off Pd / C, the filtrate was concentrated, and DMF was added.
The solution was used. The solution was added with triethylamine 62μ under ice cooling.
L (0.45 mmol), guanidine acetate hydrochloride 172
mg (1.12 mmol), DCC 231 mg (1.1
2 mmol) was added in order, and the mixture was stirred at room temperature for 1 hour and left overnight. After the resulting white precipitate was filtered off, the solvent was distilled off under reduced pressure. A 4N hydrochloric acid / dioxane solution was added to the residue, and the mixture was concentrated under reduced pressure. The residue was sludged with IPA, and the obtained yellow powder was further sludged with ethanol to give the title compound 10
0 mg (42%) was obtained as a yellow powder. IR (KBr) cm ^-1 : 3151, 1654, 150
0,1397,1061,824

Example 49 (Compound 1021) 1H-2- [1-methyl-4- (guanidinoacetyla )
Mino) pyrrole-2-yl] benzimidazole-5
[N- [3-fluoro-4- [N, N-bis (2-chloro
[Roethyl) amino] phenyl] carboxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [3-fluoro-
4- [N, N-bis (2-chloroethyl) amino] phenyl] carboxamide 150 mg (0.29 mmol)
Was dissolved in a mixed solvent of 10 mL of DMF and 10 mL of methanol, 200 mg of 10% Pd / C was added under a nitrogen atmosphere, 1N hydrochloric acid (300 μL) was added, and hydrogenation was performed at normal temperature and normal pressure. After filtering off Pd / C, the filtrate was concentrated and DM
F solution was obtained. Triethylamine 49 was added to this solution under ice cooling.
μL (0.29 mmol), guanidine acetate hydrochloride 13
3 mg (0.87 mmol), DCC 180 mg (0.
87 mmol) in that order and left overnight. After the reaction, the reaction solution was filtered and concentrated, and the brown oil residue was separated and concentrated with a fluorescent fraction by gel filtration column chromatography (Sephadex LH-20, methanol), and 4N hydrochloric acid / dioxane was added. To give 76.5 mg (yield: 40%) of the target yellow powder. Elemental analysis: Calculated value (C ₂₆ H ₂₈ Cl ₂ FN ₉ O ₂ .2HC
1) C: 47.22, H: 4.57, N: 19.06,
Analytical value C: 47.60, H: 4.53, N: 18.81

Example 50 (Compound 1013) 1H-2- [1-methyl-4- (guanidinoacetyla )
Mino) pyrrole-2-yl] benzimidazole-5
[N- [3-cyano-4- [N, N-bis (2-chloro
Ethyl) amino] phenyl]] carboxamide dihydrochloride (Reaction 1) 1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [3
-Cyano-4- [N, N-bis (2-chloroethyl) a
Mino] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5-carboxylic acid 105 mg
(0.37 mmol) and 3-cyano-4- [N, N-
Bis (2-chloroethyl) amino] aniline hydrochloride # 2
-[N, N-bis (2-chloroethyl) amino] -5-
Nitrobenzonitrile 104mg (0.36mmol)
(Methanol solution 10 mL) with 10% Pd / C 100m
and hydrogenated. ｝ Was dissolved in 5 mL of DMF and cooled to 0 ° C. Triethylamine 6 under nitrogen atmosphere
1 μL (0.44 mmol) followed by 67 μL DECP
(0.44 mmol), and the mixture was stirred for 30 minutes. After further stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to give the title compound (61 mg, 32%) as a yellow powder. (Reaction 2) 1H-2- [1-methyl-4- (guanidinium)
Noacetylamino) pyrrol-2-yl] benzimidida
Zol-5- [N- [3-cyano-4- [N, N-bis
(2-Chloroethyl) amino] phenyl]] carboxa
Mido dihydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [3-cyano-4
-[N, N-Bis (2-chloroethyl) amino] phenyl]] carboxamide (56 mg, 0.11 mmol) was dissolved in a mixed solvent of DMF and methanol (1: 1, 10 mL), and 10% Pd / C (50 mg) under a nitrogen atmosphere. 1
28 μL (1.2 eq.) Were added. The inside of the vessel was replaced with hydrogen and stirred at room temperature for 2 hours. After filtering off Pd / C, the filtrate was concentrated to obtain a DMF solution. 18 μL (0.13 mmol) of triethylamine, 50 mg (0.33 mmol) of guanidine acetate hydrochloride, 70 ml of DCC were added to this solution under ice cooling.
g (0.34 mmol) was added in order, and the mixture was stirred at room temperature for 1 hour and left overnight. After the resulting white precipitate was filtered off, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol and purified by gel filtration (Sephadex LH-20, methanol). After the solvent was distilled off under reduced pressure, a 4N hydrochloric acid / dioxane solution was added, and the mixture was concentrated again under reduced pressure. The residue was dissolved in methanol and reprecipitated by adding ethyl acetate to give the title compound 27
mg (38%) was obtained as a white powder. IR (KBr) cm ^-1 : 3146, 2216, 165
6,1506,1399,1059,823

Example 51 (Compound 1596)1H-2- [1-methyl-4- (guanidinoacetyla
Mino) pyrrole-2-yl] benzimidazole-5
[N- [4- [N, N-bis (2-chloroethyl) amido]
No-2-morpholinylcarboxamide] phenyl] car
Boxamide hydrochloride (Reaction 1)N- (2-nitro-5-chlorobenzoi
Le) morpholine 5.0 g of 2-nitro-5-chlorobenzoic acid (24.8 m
mol) was dissolved in thionyl chloride (20 mL).
The mixture was refluxed for 5 hours. The residue obtained by concentrating the reaction solution
Dissolve in 10 mL of acetone and add this solution to morpholine 4.
Drops in 7 mL (62 mmol) of acetone solution 20 mL
Then, the mixture was stirred at room temperature for 2 hours. After the reaction, concentrate and concentrate in ethyl acetate
Extraction was performed, and the ethyl acetate layer was dried and concentrated. Acetic acid residue
Recrystallized from ethyl / n-hexane to obtain white powder
5.64 g (84% yield) was obtained. (Reaction 2)N- [2-nitro-5- [N, N-bis
(2-hydroxyethyl) amino] chlorobenzoyl]
Morpholine N- (2-nitro-5-chlorobenzoyl) morpholine
1.0 g (3.69 mmol) and diethanolamine
Dissolve 1.16 g (11 mmol) in DMSO (4 mL)
Then, the mixture was heated and stirred at 140 ° C. for 3 hours. Concentrate the reaction solution
The residue obtained by the compaction is silica gel column chromatography.
(Chloroform / methanol = 10/1).
667 mg (yield: 53.5%) of a target yellow powder was obtained. (Reaction 3)N- [2-nitro-5- [N, N-bis
(2-Chloroethyl) amino] benzoyl] morpholine N- [2-nitro-5- [N, N-bis (2-hydroxy
Ciethyl) amino] benzoyl] morpholine 500mg
(1.5 mmol) was dissolved in DMF (5 mL).
Tansulfonyl chloride 414mg (3.6mmol)
Was added dropwise under ice cooling, and the mixture was heated and stirred at 70 ° C. for 1 hour. Reaction liquid
Of the residue obtained by silica gel column chromatography
Purified with chloroform (chloroform) to obtain the target yellow powder 53
9 mg (81% yield) was obtained. (Reaction 4)1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [4
-[N, N-bis (2-chloroethyl) amino] -2-
Morpholinylcarboxamide] phenyl] carboxami
Do N- [2-nitro-5- [N, N-bis (2-chloroe
Tyl) amino] benzoyl] morpholine 200mg
(0.56 mmol) dissolved in THF (10 mL)
And add 200 mg of 10% Pd / C under a nitrogen atmosphere.
N hydrochloric acid (140 μL) is added, and hydrogenation is performed at normal temperature and normal pressure.
went. After filtering off Pd / C, the filtrate was concentrated. There one
H-2- (1-methyl-4-nitropyrrole-2-i
L) 160 mg of benzimidazole-5-carboxylic acid
(0.56 mmol) and 120 μL of DECP
(0.84 mmol), 210 μL of triethylamine
(1.5 mmol) were added in order and left overnight. After the reaction,
The reaction mixture was concentrated, and the black-brown oil obtained was concentrated on a silica gel column.
Chromatography (chloroform → chloroform + 2
% Methanol) to obtain 100 mg of the target yellow powder
(Yield 31%) was obtained. (Reaction 5)1H-2- [1-methyl-4- (guanidinium
Noacetylamino) pyrrol-2-yl] benzimidida
Zol-5- [N- [4- [N, N-bis (2-chloro
Ethyl) amino] -2-morpholinylcarboxamide]
Phenyl] carboxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] -2-morpholinyl
Carboxamide] phenyl] carboxamide 100mg
(0.17 mmol) in DMF (10 mL) and methanol
(10 mL) and 10% Pd /
Add 100mg of C and add 1N hydrochloric acid (180μL)
Then, hydrogenation was performed at normal temperature and normal pressure. After filtering off Pd / C,
The filtrate was concentrated to a DMF solution. Add the solution under ice-cooling
Liethylamine 28 μL (0.17 mmol), Guani
Gin acetate hydrochloride 77 mg (0.50 mmol), DCC
Add 103mg (0.5mmol) in order and leave overnight
Was. After filtering off the insolubles precipitated after the reaction, the reaction solution was concentrated.
The obtained brown oil is subjected to gel filtration column chromatography.
(Sephadex LH-20, methanol)
Then, add 4N hydrochloric acid / dioxane and concentrate again.
And sludge it with a yellow powder (25 mg, yield 2).
0%).

Example 52 (Compound 1042)1H-2- [1-methyl-4- (guanidinoacetyla
Mino) pyrrole-2-yl] benzimidazole-5
[N- [2- [N-[(N, N-dimethylamino) ethyl]
L] carboxamide] -4- [N, N-bis (2-chloro
Roethyl) amino] phenyl]] carboxamide dihydrochloride
salt (Reaction 1)N-[(N, N-dimethylamino) ethyl
2-chloro-5-nitrobenzamide 10 g of 2-chloro-5-nitrobenzoic acid (0.050 m
mol) of a THF solution was cooled in an ice bath. CD
Ig (0.064 mol) was added and stirred at room temperature for 1 hour.
Stirred. Add N, N-dimethylethylenediamine to this solution
12 mL (0.11 mmol) is added dropwise, and it is 3 hours at room temperature.
Stirred. After evaporating the solvent, the residue is dissolved in ethyl acetate
did. After washing with 10% aqueous sodium hydrogen carbonate solution, sulfuric acid
Magnesium was added and dried. Ethyl acetate is distilled off under reduced pressure
And the residue is purified by silica gel column chromatography (acetic acid).
Ethyl) to give 10 g (74%) of the title compound.
Obtained as a colorless oil. (Reaction 2)N-[(N, N-dimethylamino) ethyl
] -2- [N, N-bis (2-hydroxyethyl) a
Mino] -5-nitrobenzamide N-[(N, N-dimethylamino) ethyl] -2-chloro
5 g (18.4 mmol) of b-5-nitrobenzamide
5 g of diethanolamine in 10 mL of a DMSO solution of
(48.6 mmol) and stirred at 150 ° C. for 3.5 hours.
Stirred. After cooling to room temperature, the mixture was extracted with ethyl acetate.
After adding magnesium sulfate and drying, the solvent was distilled off under reduced pressure.
Was. The residue was purified by silica gel column chromatography (acetic acid).
Ethyl / methanol = 1/0 → 1/1)
2.6 g (38%) of the compound were obtained as a colorless oil. (Reaction 3)N-[(N, N-dimethylamino) ethyl
] -2- [N, N-bis (2-chloroethyl) amido
No] -5-nitrobenzamide N-[(N, N-dimethylamino) ethyl] -2-
[N, N-bis (2-hydroxyethyl) amino] -5
2.6 g (0.76 mmol) of nitrobenzamide
To 20 mL of methylene chloride solution, add 4.5 mL of triethylamine.
mL (32 mmol) was added and cooled in an ice bath. This solution
1.8 mL (23 mmol) of mesyl chloride was added to the solution.
Then, the mixture was stirred at room temperature for 3 hours. Dilute the reaction solution with saturated
After washing with aqueous thorium, magnesium sulfate was added to the organic layer.
And dried. After the solvent was distilled off under reduced pressure, the residue was
Dissolve in 10 mL of MF, add 5 g of sodium chloride and add 1 g
Stirred at 50 ° C. for 30 minutes. After cooling to room temperature,
The sodium was filtered off and the solvent was distilled off under reduced pressure. Residue
Kagel column chromatography (chloroform / meta
(Nol = 10/1) to give the title compound (0.95 g).
(33%) as a yellow powder. (Reaction 4)1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [2
-[N-[(N, N-dimethylamino) ethyl] carbo
Oxamide] -4- [N, N-bis (2-chloroethyl)
Amino] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) 500 mg of benzimidazole-5-carboxylic acid
(1.8 mmol) and 2- [N-[(N, N-dimethyl)
Ruamino) ethyl] carboxamide] -4- [N, N-
Bis (2-chloroethyl) amino] aniline hydrochloride {N
-[(N, N-dimethylamino) ethyl] -5- [N,
N-bis (2-chloroethyl) amino] -2-nitrobe
200 mg (0.53 mmol)
Obtained by catalytic hydrogenation in 10 mL of toluene. ＤＭ to DMF10
Dissolved in mL and cooled to 0 ° C. Triet under nitrogen atmosphere
241 μL (1.8 mmol), followed by DEC
P265 μL (1.8 mmol) was added, and 30
Stirred for minutes. After further stirring at room temperature for 1 hour, leave overnight,
The solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography.
By chromatography (chloroform / methanol = 1/1)
And purified to give 96 mg (30%) of the title compound as yellow powder.
I got it. (Reaction 5)1H-2- (1-methyl-4-guanidino
Acetylaminopyrrole-2-yl) benzimidazo
5- [N- [2- [N-[(N, N-dimethylamido)
No) Ethyl] carboxamide] -4- [N, N-bis
(2-Chloroethyl) amino] phenyl]] carboxa
Mid dihydrochloride 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [2- [N-
[(N, N-dimethylamino) ethyl] carboxami
Do] -4- [N, N-bis (2-chloroethyl) amido
No] phenyl]] carboxamide 96 mg (0.16 m
mol) in a 1: 1 mixed solvent of DMF and methanol 10m
L, and 100% Pd / C 100 mg under a nitrogen atmosphere,
600 μL of 1N hydrochloric acid was added. Replace the inside of the container with hydrogen
Stirred at warm for 2 hours. After filtering off Pd / C, the filtrate is concentrated
Thus, a DMF solution was obtained. Triethyl alcohol was added to this solution under ice-cooling.
26 μL of min (0.19 mmol), guanidine acetate
Acid salt 72 mg (0.47 mmol), DCC 97 mg
(0.47 mmol), 36 mg of HOBt (0.24 m
mol) in order, and stirred at room temperature for 1 hour, then left overnight.
Was. After the resulting white precipitate was filtered off, the solvent was distilled off under reduced pressure.
Was. The residue was purified by silica gel column chromatography (acetic acid).
Ethyl / IPA / water = 4/2/1) to give the title compound.
50 mg (42%) of the product were obtained as a yellow powder. IR (KBr) cm^-1: 1654,1525,139
6,1063,821

Example 53 (Compound 1584)1H-2- [1-methyl-4- (arginylamino) pi
Roll-2-yl] benzimidazole-5- [N-
[4- [N, N-bis (2-chloroethyl) amino] f
Enyl]] carboxamide hydrochloride (Reaction 1)1H-2- [1-methyl-4-[[(N-
t-butoxycarbonyl) arginyl] amino] pillow
Ru-2-yl] benzimidazole-5- [N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
Le]] carboxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
0.41 g (0.82 mmol) of oxamide in 3 m of DMF
L and 3 mL of methanol
0.21 mL was added, and 0.18 g of 10% Pd / C was catalyzed.
It was led to the corresponding amino compound by hydrogenation under normal pressure. this
The DMF solution of the amino compound was stirred in a nitrogen stream under ice cooling, and
0.12 mL of ethylamine (0.86 mmol, 1.0
5 eq. ), N-Boc arginine 0.51 g (1.6
4 mmol, 2.0 eq. ), 0.34 g of DCC (1.
65 mmol, 2.0 eq. ) In order,
After stirring for an hour, the mixture was left overnight. The resulting crystals are filtered off and
After concentration, the residue was purified by silica gel chromatography (acetic acid
Chill / IPA / water = 7/2/1 then chloroform / me
15-20% of ethanol, 2 times in total) Crystallized from ether
80 mg (0.11 mmol) of the title compound
1, 12.8%) as light brown crystals. (Reaction 2)1H-2- [1-methyl-4- (arginine
Ruamino) pyrrol-2-yl] benzimidazole-
5- [N- [4- [N, N-bis (2-chloroethyl)
Amino] phenyl]] carboxamide hydrochloride 1H-2- [1-methyl-4-[[(Nt-butoxy
Carbonyl) arginyl] amino] pyrrole-2-i
Ru] benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
80 mg (0.105 mmol) of oxamide in ethanol
Dissolve in 4 mL, add 1 mL of 4N hydrochloric acid / dioxane and add room
After stirring at room temperature for 5 hours, the mixture was concentrated under reduced pressure. The residue is subjected to gel filtration (S
ephadex LH-20, methanol).
The title compound 50 was obtained by crystallization from setonitrile.
mg (0.071 mmol, 67.6%) as yellow crystals
I got it. mp. > 275 ° C IR (KBr) cm^-1: 3384, 1654, 154
1,1518 Elemental analysis (calculated value C₂₉H₃₆N_TenO_TwoCl_Two・ 2HCl ・
4.5H_TwoO) C: 42.58, H: 5.91, N: 1
7.12, analysis value C: 43.09, H: 5.76, N:
16.84

Example 54 (Compound 1585) 1H-2- [1-methyl-4-[(4-benzylpipera)
Dinyl) acetylamino] pyrrole-2-yl] benz
Imidazole-5- [N- [4- [N, N-bis (2-
Chloroethyl) amino] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carboxamide 0.31 g (0.62 mmol) in DMF 5m
Dissolved in a mixed solvent of L and methanol (5 mL), added with 1N hydrochloric acid (0.7 mL) and added 10% Pd / C (Wet)
Using g as a catalyst, hydrogenation to the corresponding amino compound was carried out by hydrogenation under normal pressure. The DMF solution of this amino compound was stirred under ice-cooling under a nitrogen atmosphere, and triethylamine 0.1 mL (0.72 mmol,
1.2 eq. ), 2- (4-benzylpiperazino) acetylimidazole {0.47 g of 2- (4-benzylpiperazino) acetic acid (including some impurities), 0.15 g of CDI
(0.93 mmol) / prepared from 5 mL of DMF was added, stirred for 4 hours, and left overnight. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol 4%) and crystallized from ether to give 0.25 g (0.36 mm) of the title compound.
ol, 58.6%) as pale red crystals. mp. 185-195 ° C (dec.) IR (KBr) cm ^-1 : 3284, 1654, 151
8,1327,815 Elemental analysis (calculated value C ₃₆ H ₄₀ N ₈ O ₂ Cl ₂ .H ₂ O) C: 6
1.27, H: 6.00, N: 15.88, analysis C:
61.14, H: 5.75, N: 15.95

Example 55 (Compound 1576)1H-2- [1-methyl-4-[(piperazinylacetyl
Ru) amino] pyrrol-2-yl] benzimidazole
-5- [N- [4- [N, N-bis (2-chloroethyl
Ru) amino] phenyl]] carboxamide 1H-2- [1-methyl-4-[(4-benzylpipera
Dinyl) acetylamino] pyrrole-2-yl] benz
Imidazole-5- [N- [4- [N, N-bis (2-
Chloroethyl) amino] phenyl]] carboxamide
0.24 g (0.35 mmol) was added to 3 mL of DMF and meta
And 3% Pd / C (w
et) Catalytic hydrogenation was performed using 0.12 g as a catalyst.
After 11 hours, some raw materials remained, but the reaction was stopped.
The Pd / C was filtered off and the filtrate was subjected to gel filtration (Sephad).
ex LH-20, methanol), eluted fraction
Add 4N hydrochloric acid / dioxane and crystallize from ethanol
Was. Additional silica gel column because of impurities
Purify by chromatography (DMF / toluene 1/1)
And crystallized from ether to give 103 mg of the title compound
(0.17 mmol, 49.1%) as yellowish white crystals
Obtained. mp. > 250 ° C IR (KBr) cm^-1: 3401, 1654, 151
8,815 Elemental analysis: Calculated value (C₂₉H₃₄N₈O_TwoCl_Two・ 2HCl ・
1.5H_TwoO.1.5EtOH) C: 50.01, H:
5.88, N: 15.55, analytical value C: 49.94,
H: 5.46, N: 15.62

Example 56 (Compound 1590)1H-2- [1-methyl-4- (2-imidazolylcar
Boxamido) pyrrol-2-yl] benzimidazole
-5- [N- [4- [N, N-bis (2-chloroethyl
Ru) amino] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
0.20 g (0.40 mmol) of oxamide in 3 m of DMF
Dissolved in a mixed solvent of L and methanol (3 mL).
Add 0.5 mL and 10% Pd / C (Wet) 0.10
Using g as a catalyst, hydrogenation at normal pressure leads to the corresponding amino compound
Was. The DMF solution of this amino compound was stirred under ice-cooling under a nitrogen atmosphere.
And triethylamine 68 μL (0.49 mmol,
1.2 eq. ), Imidazole-2-carboxylic acid 0.1
1 g (0.98 mmol, 2.5 eq.), HOBt5
9 mg (0.44 mmol, 1.1 eq.), DCC9
2 mg (0.45 mmol, 1.1 eq.) Were added,
The mixture was returned to room temperature, stirred for 4 hours, and left overnight. The resulting solid
After filtration, the filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel.
(Chloroform / methanol 4-8%).
4N hydrochloric acid / dioxane was added to the concentrated residue of the output fraction.
Enriched and crystallized from methanol for title
74 mg (0.13 mmol, 32.7%) of the compound
Obtained as brown crystals. mp. > 260 ° C IR (KBr) cm^-1: 3365, 1684, 159
2,1517,1398,1329,818 Elemental analysis: Calculated value (C₂₇H₂₆N₈O_TwoCl_Two・ 2HCl ・
2.5H_TwoO) C: 47.45, H: 4.87, N: 1
6.40, analysis C: 47.43, H: 4.98, N:
16.30

Example 57 (Compound 1589) 1H-2- [1-methyl-4-[[3- (imidazole)
-1-yl) propionyl] amino] pyrrole-2-i
Ru] benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
Oxamide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carboxamide 0.20 g (0.40 mmol) in DMF 3m
L and methanol 3mL, dissolved in 1N hydrochloric acid 0.50mL, 10% Pd / C (Wet) 0.1
Using 0 g as a catalyst, hydrogenation to the corresponding amino compound was carried out by hydrogenation at normal pressure. This DMF solution of the amino compound was stirred under ice-cooling under a stream of nitrogen, and then 75 μL of triethylamine (0.54 mmol, 1.
3eq. ), Separately prepared 3- (imidazole-
1-yl) propionyl imidazole in DMF solution # 3
-(4-benzylpiperazinyl) propionic acid 0.15
g (0.60 mmol), CDI 0.12 g (0.74
(mmol) of DMF was stirred at room temperature for 2.5 hours, Synthetic 順 に was added in order, and the mixture was returned to room temperature and stirred for 4.5 hours. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate / IPA / water = 6/2/1), and crystallized from ethyl acetate to give 103 mg of the title compound.
(0.17 mmol, 42.5%) as light brown crystals. mp. > 260 ° C IR (KBr) cm ^-1 : 3287,1636,151
8,1328,1239,815 Calcd _{(C 29 H 30 Cl 2 N} 8 O 2 · HCl)
C: 55.29, H: 4.96, N: 17.79, analysis value C: 54.94, H: 5.07, N: 17.81

Example 58 (Compound 1604)1H-2- [1-methyl-4-furoylaminopyrrole
-2-yl] benzimidazole-5- [N- [3-
[N-ethyl, N- (2-chloroethyl)] amino]
Enyl] carboxamide (Reaction 1)3-nitroacetanilide Acetic anhydride was added to 10 g (72 mmol) of 3-nitroaniline.
10 mL (106 mmol) was added and stirred. Fever and
In both cases, white crystals precipitated. After stirring for 10 minutes,
The solution was poured into ice water. Dissolve the crystals in chloroform and add 1N
Hydrochloric acid, saturated aqueous solution of sodium bicarbonate, saturated saline
Next, it was washed. After drying the organic layer with magnesium sulfate,
The solvent was distilled off under reduced pressure. Sludge with ether and white
11.6 g (yield 89%) of powder was obtained. (Reaction 2)3-nitro-N-ethylaniline Drying of 8 g (44 mmol) of 3-nitroacetanilide
4. Dimethyl sulfide borane in 200 mL of THF solution.
5 mL (58 mmol) of 5 mL of a THF solution was added.
After stirring at 80 ° C. for 4 hours, dimethyl sulfide borane
Additional 3mL (32mmol) at 80 ° C for 3 hours
While stirring. After adding 1N hydrochloric acid until the solution is homogeneous
The solvent was concentrated under reduced pressure. 10N aqueous sodium hydroxide in residue
The solution was added and extracted with chloroform. Wash with saturated saline
After purification, magnesium sulfate is added and dried, and the solvent is distilled off under reduced pressure.
I left. The residue was subjected to column chromatography (ethyl acetate
/ N-hexane = 4/1) to give the title compound 6.6.
g (89% yield) as a brown powder. (Reaction 3)3-[[N-ethyl, N- (2-hydroxy
Siethyl)] amino] nitrobenzene 6.0 g of 3- (N-ethyl) aminonitrobenzene (3
9.1 mmol) in 40 mL of 30% acetic acid aqueous solution
And 11.5 g (261 g) of ethylene oxide under a nitrogen atmosphere.
mmol) and stirred overnight at room temperature. After the reaction
Perform chill extraction, dry and concentrate the ethyl acetate layer.
This gave 5.27 g (yield 64.1%) of a brown oil. (Reaction 4)3-[[N-ethyl, N- (2-chloroe
Tyl)] amino] nitrobenzene 3- [N-ethyl, N- (2-hydroxyethyl)]
3.0 g (14.3 mmol) of minonitrobenzene
Dissolved in 50 mL of benzene, and 4.1 g of thionyl chloride (2
9.2 mmol) and stirred at 60 ° C. for 1 hour. Anti
After the reaction, the reaction solution was concentrated, and ethyl acetate / n-hexane was added.
Recrystallized, 3.18 g (97% yield) of the target yellow powder
I got (Reaction 5)3- [N-ethyl, N- (2-chloroethyl
Le)] aminoaniline 3-[[N-ethyl, N- (2-chloroethyl)] amido
[No] nitrobenzene (640 mg, 2.8 mmol)
1. Dissolve in hydrochloric acid (20 mL), tin chloride dihydrate thionyl
5 g (11 mmol) was added, and the mixture was stirred under reflux for 2 hours. Anti
After the reaction, add ammonia water to the reaction solution and extract with ethyl acetate.
The ethyl acetate layer was dried and concentrated to give a pale yellow oil. This
4N hydrochloric acid / dioxane is added to the oily substance of
624 mg (82% yield) of an oil were obtained. (Reaction 6)1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [3
-[[N-ethyl, N- (2-chloroethyl)] amido
No] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
F) 658 mg of benzimidazole-5-carboxylic acid
(2.3 mmol) and 3- [N-ethyl, N- (2-
Loroethyl)] aminoaniline 624 mg (2.3 mm
ol) was dissolved in 30 mL of DMF, and DECP5 under ice cooling.
30 μL (3.5 mmol) and triethylamine 960
Add μL (6.9 mmol) with a syringe and cool on ice for 2 hours
Then, it was left overnight at room temperature. After the reaction, the reaction solution was concentrated.
Silica gel column chromatography
-(Chloroform → 2% methanol / chloroform)
428 mg (yield 40%) of the target yellow powder
I got (Reaction 7)1H-2- (1-methyl-4-furoilua
Minopyrrol-2-yl) benzimidazole-5
[N- [3-[[N-ethyl, N- (2-chloroethyl
Le)] amino] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [3-[[N-E
Tyl, N- (2-chloroethyl) amino] phenyl]]
200 mg (0.43 mmol) of carboxamide in DM
F (10 mL) and methanol (10 mL)
250 mg of 10% Pd / C and 500 N of hydrochloric acid in a stream of air
μL was added and normal temperature and normal pressure hydrogenation was performed. Filter Pd / C
After the separation, the hydrogenated product was concentrated to obtain a DMF solution. This solution
Under ice-cooling, 120 µL of triethylamine, floyl chloride
56.2 mg (0.43 mmol) of methylene chloride
The liquid was added in order and left overnight. After the reaction, the reaction solution is concentrated
The obtained black-brown oil is subjected to silica gel column chromatography.
-(Chloroform / methanol = 30/1)
149 mg (66% yield) of the desired product was obtained as a white powder.
Was. Elemental analysis: calculated value (C₂₈H₂₇ClN₆O_Three・ 1.5H
_TwoO) C: 60.27, H: 5.42, N: 15.0
6, Analytical value C: 60.51, H: 5.12, N: 15.
41

Example 59 (Compound 1480) 1H-2- [1-methyl-4- (2-pyrrolecarboxy)
Samido) pyrrol-2-yl] benzimidazole-5
-[N- [4- [N, N-bis (2-chloroethyl) a
Mino] phenyl]] carboxamide hydrochloride 40 mg (0.36 mmol) 2-pyrrolecarboxylic acid
0.1 mL thionyl chloride in 10 mL benzene solution
(1.4 mmol), and the mixture was heated and stirred at 100 ° C. for 2 hours. After distilling off the solvent under reduced pressure, the operation of adding a small amount of benzene and distilling off under reduced pressure was repeated twice. The obtained acid chloride was used immediately in the next reaction. 1H-2- (1-methyl-
4-nitropyrrol-2-yl) benzimidazole-
5- [N- [4- [N, N-bis (2-chloroethyl)] amino] phenyl]] carboxamide 150 mg
(0.30 mmol) was dissolved in 10 mL of a 1: 1 mixed solvent of DMF and methanol, and 10% Pd / C
150 mg and 360 μL of 1N hydrochloric acid were added. The inside of the vessel was replaced with hydrogen and stirred at room temperature for 2 hours. After filtering off Pd / C,
The filtrate was concentrated to a DMF solution. To this solution, under ice cooling, 62 μL (0.45 mmol) of triethylamine and 2-pyrrolecarboxylic acid chloride previously synthesized were sequentially added. After stirring at room temperature for 1 hour, 5 mL of methanol was added and left overnight. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol = 95 /
Purification in 5) gave 50 mg (30%) of the title compound as a white powder. IR (KBr) cm ^-1 : 3148, 1636, 151
8,1419,812,756

Example 60 (Compound 1520) 1H-2- [1-methyl-4- [3- (methylthio) propyl
Ropionylamino] pyrrol-2-yl] benzimida
Zol-5- [N- [4- [N, N-bis (2-chloro
Ethyl) amino] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carboxamide 0.20 g (0.40 mmol) in DMF 3m
L and methanol 3mL, dissolved in 1N hydrochloric acid 0.45mL, 10% Pd / C (Wet) 0.1
Using 0 g as a catalyst, hydrogenation to the corresponding amino compound was carried out by hydrogenation at normal pressure. The DMF solution of this amino compound was stirred under ice-cooling under a stream of nitrogen and stirred with 67 μL of triethylamine (0.48 mmol, 1.
2eq. ), 3- (methylthio) propionylimidazole {3- (methylthio) propionic acid 0.06 g
(0.50 mmol, 1.2 eq.), 95 mg of CDI
(0.59 mmol, 1.4 eq.) / Prepared from 3 mL of DMF A DMF solution was added, the mixture was returned to room temperature, stirred for 4 hours, and left overnight. After concentration under reduced pressure, the residue was purified by silica gel chromatography (chloroform / methanol 4%), and crystallized from ethyl acetate-ether to obtain 164 mg (0.29 mmol, 71.6%) of the title compound as pale brown crystals. Was. IR (KBr) cm ^-1 : 3275, 1642, 151
8,1327,813 Calcd _{(C 27 H 30 Cl 2 N} 6 O 2 S) C: 5
6.54, H: 5.22, N: 14.30, Cl: 1
2.30, analysis value C: 56.12, H: 5.22, N:
14.30, Cl: 12.30

Example 61 (Compound 1527) 1H-2- [1-methyl-4- [3- (methylthio) propyl
Ropionylamino] pyrrol-2-yl] benzimida
Zol-5- [N- [3-chloro-4- [N, N-bis
(2-Chloroethyl) amino] phenyl]] carboxa
Mido 1H-2- [1-methyl-4-nitropyrrol-2-yl] benzimidazole-5- [N- [3-chloro-4
-[N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 201 mg (0.38 mmol)
Was dissolved in 10 mL of a 1: 1 mixed solvent of DMF and methanol, and 200 mg of 10% Pd / C and 1N hydrochloric acid (412 μL) were added under a nitrogen atmosphere. Replace the inside of the reaction vessel with hydrogen,
Stirred at room temperature for 2 hours. After filtering off Pd / C, the filtrate was concentrated to obtain a DMF solution. 78 μL (0.56 mmol) of triethylamine was added to this solution under ice cooling,
135 mg of (methylthio) propionic acid (1.12 mm
ol) and 182 mg (1.12 mmol) of CDI, 5 mL of a prepared DMF solution of the active intermediate was added, and the mixture was allowed to stand overnight. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform / chloroform).
(Methanol = 96/4). This was further purified by silica gel column chromatography (ethyl acetate / n-hexane = 3/1) to give the title compound (45 mg, 20%).
%) As a white powder.

Example 62 (Compound 1528)1H-2- [1-methyl-4- [3- (methylthio) p
Ropionylamino] pyrrol-2-yl] benzimida
Zol-5- [N- [3-fluoro-4- [N, N-bi
[(2-chloroethyl) amino] phenyl]] carbox
Samid (Reaction 1)3-fluoro-4- [N, N-bis (2-
Hydroxyethyl)] aminonitrobenzene 5.0 g of 3,4-difluoronitrobenzene (31.4)
mmol) and 8.3 g of diethanolamine (78.5 m
mol) in DMSO (4 mL)
The mixture was heated and stirred for 1 hour. After the reaction, extract with ethyl acetate
The ethyl acetate layer was dried and concentrated, and n-hexane was added to a reddish brown oil.
/ Ethyl acetate was added for crystallization. Object: yellow powder
6.93 g (90% yield) was obtained. (Reaction 2)3-fluoro-4- [N, N-bis (2-
Chloroethyl)] aminonitrobenzene 3-fluoro-4- [N, N-bis (2-hydroxy
1.3 g (5.32 mm) of tyl) amino] nitrobenzene
ol) in DMF (12 mL) and methanesulfo
1.47 g (12.8 mmol) of nyl chloride was cooled on ice
The mixture was dropped and heated and stirred at 70 ° C. for 1 hour. After the reaction, concentration
And the yellow oil is purified by silica gel column chromatography.
(Chloroform), n-hexane / ethyl acetate
And 1.2 g of a yellow powder (yield 81).
%). (Reaction 3)1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [3
-Fluoro-4- [N, N-bis (2-chloroethyl)
Amino] phenyl]] carboxamide 3-fluoro-4- [N, N-bis (2-chloroethyl
Le) amino] nitrobenzene 500 mg (1.78 mm
ol) in THF (10 mL) and dissolve in a nitrogen atmosphere
200 mg of 10% Pd / C was added, and 4N hydrochloric acid (450 μm) was added.
L) was added, and hydrogenation was performed at normal temperature and normal pressure. Pd / C
After filtration by filtration, the filtrate was concentrated. There 1H-2- (1-me
Tyl-4-nitropyrrol-2-yl) benzimidazo
510 mg (1.78 mmol) of toluene-5-carboxylic acid
And 468 μL (2.67 mmol) of DECP,
740 μL (5.34 mmol) of liethylamine was sequentially added.
In addition, it was left overnight. After the reaction, the reaction solution was concentrated to obtain a black-brown
Colored oils were separated by silica gel column chromatography
Purified with chloroform → chloroform + 2% methanol)
325.6 mg (yield 35%) of the desired product as a yellow powder
Obtained. (Reaction 4)1H-2- [1-methyl-4- [3- (me
Tylthio) propionylamino] pyrrol-2-yl]
Benzimidazole-5- [N- [3-fluoro-4-
[N, N-bis (2-chloroethyl) amino] phenyl
Le]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [3-fluoro-
4- [N, N-bis (2-chloroethyl) amino] fe
Nil]] carboxamide 150 mg (0.29 mmol
l) is a mixed solvent of 10 mL of DMF and 10 mL of methanol
And 10% Pd / C 200mg under nitrogen atmosphere
Add 1N hydrochloric acid (320 μL) and add water at room temperature and pressure.
Element addition. After filtering off Pd / C, the filtrate was concentrated, and D
An MF solution was obtained. Triethylamine 4 was added to this solution under ice cooling.
Reaction with 9 μL (0.29 mmol) in advance
105 mg of put 3- (methylthio) propionic acid
(0.87 mmol) and 141 mg of CDI (0.87 m
mol) in DMF (5 mL) and left overnight.
After the reaction, the brown oily substance obtained by concentrating the reaction solution was treated with silica gel.
Column chromatography (chloroform / methanol
= 95/5) and purified with n-hexane / chloroform.
And then sludge with 115 mg of the desired light yellow powder (yield
67%). Elemental analysis: calculated value (C₂₇H₂₉Cl_TwoFN₆O_TwoS ・ H_TwoO)
C: 53.20, H5.13, N: 13.79, analysis value
C: 53.62, H: 4.95, N: 13.79

Example 63 (Compound 1524) 1H-2- [1-methyl-4- [3- (methylthio) propyl
Ropionylamino] pyrrol-2-yl] benzimida
Zol-5- [N- [3-methyl-4- [N, N-bis
(2-Chloroethyl) amino] phenyl]] carboxa
Mido 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [3-methyl-4
-[N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 200 mg (0.39 mmol)
Was dissolved in 10 mL of a 1: 1 mixed solvent of DMF and methanol, and 150 mg of 10% Pd / C and 1N hydrochloric acid (427 μL) were added under a nitrogen atmosphere. Replace the inside of the reaction vessel with hydrogen,
Stirred at room temperature for 2 hours. After filtering off Pd / C, the filtrate was concentrated to obtain a DMF solution. To this solution was added 65 μL (0.46 mmol) of triethylamine under ice-cooling,
140 mg of (methylthio) propionic acid (1.17 mm
ol) was reacted with 200 mg (1.23 mmol) of CDI, 5 mL of a DMF solution of the active intermediate prepared was added, and the mixture was stirred at room temperature for 3 hours and left overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 95/5) to obtain 195 mg (86%) of the title compound as a white powder. IR (KBr) cm ^-1 : 3163, 1654, 150
9,1397,1063,805

Example 64 (Compound 1530) 1H-2- [1-methyl-4- [3- (methylthio) propyl
Ropionylamino] pyrrol-2-yl] benzimida
Zol-5- [N- [2-methyl-4- [N, N-bis
(2-Chloroethyl) amino] phenyl]] carboxa
Mido 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [2-methyl-4
-[N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 102 mg (0.20 mmol)
Was dissolved in 10 mL of a 1: 1 mixed solvent of DMF and methanol, and 100 mg of 10% Pd / C and 1N hydrochloric acid (218 μL) were added under a nitrogen atmosphere. Replace the inside of the reaction vessel with hydrogen,
Stirred at room temperature for 2 hours. After filtering off Pd / C, the filtrate was concentrated to obtain a DMF solution. 55 μL (0.39 mmol) of triethylamine was added to this solution under ice-cooling, and 3-
(Methylthio) propionic acid 71 mg (0.59 mmol
l) was reacted with 96 mg (0.59 mmol) of CDI, 5 mL of a prepared DMF solution of the active intermediate was added, and the mixture was allowed to stand overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 96/4) to give 100 mg of the title compound.
(86%) as a white powder.

Example 65 (Compound 1529)1H-2- [1-methyl-4- [3- (methylthio) p
Ropionylamino] pyrrol-2-yl] benzimida
Zol-5- [N- [3-trifluoromethyl-4-
[N, N-bis (2-chloroethyl) amino] phenyl
Le]] carboxamide (Reaction 1)3-trifluoromethyl-4- [N, N-
Bis (2-hydroxyethyl) aminonitro] benzene 2-fluoro-5-nitrobenzotrifluoride 5.0
g (23.9 mmol) and 6.0 g of diethanolamine
(57.1 mmol) dissolved in DMSO (30 mL)
Was. After heating and stirring at 140 ° C for 5 hours, extraction was performed with ethyl acetate.
The mixture was discharged and dried over magnesium sulfate. Brown color obtained
The oily substance was subjected to silica gel column chromatography (chloro
Purification with form / methanol = 10/1)
565 mg (8%) of the compound were obtained as a yellow powder. (Reaction 2)3-trifluoromethyl-4- [N, N-
Bis (2-chloroethyl)] amino] nitrobenzene 3-trifluoromethyl-4- [N, N-bis (2-h
0.556 g of droxyethyl) amino] nitrobenzene
(1.89 mmol) was dissolved in DMF (5 mL),
0.52 g of methanesulfonyl chloride (4.53 mmol)
l) was added, and the mixture was heated and stirred at 70 ° C. for 1 hour. Concentration after reaction
And the resulting brown oil is purified by silica gel column chromatography.
The residue was purified by luffy (chloroform) to give the title compound 434.
mg (70%) as a yellow powder. (Reaction 3)1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [3
-Trifluoromethyl-4- [N, N-bis (2-chloro
Roethyl) amino] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) 375 mg of benzimidazole-5-carboxylic acid
(1.33 mmol) and 3-trifluoromethyl-4
-[N, N-bis (2-chloroethyl) amino] anili
Hydrochloride3-trifluoromethyl-4- [N, N-bi
[(2-chloroethyl) amino] nitrobenzene434
mg (1.31 mmol) (10 mL of methanol solution)
Was obtained by catalytic hydrogenation of Pd / C with the catalyst. ｝ DMF 10m
And cooled to 0 ° C. Triethyl under nitrogen atmosphere
320 μL of amine (2.3 mmol) followed by DECP
220 μL (1.45 mmol) was added, and 30
Stirred for minutes. After stirring at room temperature for another 2 hours, the solvent was removed.
The solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography.
(Chloroform / methanol = 10/1)
To give 159 mg (32%) of the title compound as a yellow powder.
I got it. (Reaction 4)1H-2- [1-methyl-4- [3- (me
Tylthio) propionylamino] pyrrol-2-yl]
Benzimidazole-5- [N- [3-trifluoromethyl
Cyl-4- [N, N-bis (2-chloroethyl) amido
No] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [3-trifluoro
L-methyl-4- [N, N-bis (2-chloroethyl) a
Mino] phenyl]] carboxamide 116 mg (0.2
0 mmol) in a 1: 1 mixed solvent of DMF and methanol 8
dissolved in 10 mL of Pd / C under nitrogen atmosphere.
And 1N hydrochloric acid (224 μL). Hydrogen in the reaction vessel
And stirred at room temperature for 2 hours. After filtering off Pd / C,
The filtrate was concentrated to a DMF solution. Add the solution under ice-cooling
60 μL (0.43 mmol) of liethylamine
73 mg of 3- (methylthio) propionic acid (0.
61 mmol) and CDI 100 mg (0.62 mmol)
1) and reacting the prepared active intermediate in DMF
5 mL of the solution was added, and the mixture was stirred at room temperature for 6 hours and left overnight. Dissolution
The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography.
Matography (chloroform / methanol = 95 /
Purify in 5) to give 90 mg (69%) of the title compound as a white powder
I got it at the end.

Example 66 (Compound 1601)1H-2- [1-methyl-4- [3- (methylthio) p
Ropionylamino] pyrrol-2-yl] benzimida
Zol-5- [N- [4- [N, N-bis (2-chloro
Ethyl) amino] benzo-2-oxo-1,3-diazo
Ryl]] carboxamide (Reaction 1)4- [N, N-bis (2-hydroxyethyl
Ru) amino] -7-nitrobenzo-2-oxa-1,3
-Diazole 4-chloro-7-nitrobenzo-2-oxa-1,3-
5.0 g (25 mmol) of diazole and diethanol
Dissolve 6.6 g (63 mmol) of min in 4 mL of DMSO
did. After heating and stirring at 140 ° C for 2 hours,
An extraction was performed. The solvent was distilled off under reduced pressure, and the desired product was an orange powder.
5.8 g (87% yield) were obtained. (Reaction 2)4- [N, N-bis (2-chloroethyl)
Amino] -7-nitrobenzo-2-oxa-1,3-di
Azole 4- [N, N-bis (2-hydroxyethyl) amino]
-7-nitrobenzo-2-oxa-1,3-diazole
Dissolve 1.0 g (3.7 mmol) in DMF (10 mL)
Methanesulfonyl chloride 2 mL (9.0 mmol
l) was added, and the mixture was heated and stirred at 70 ° C. for 1 hour. Decompress the solvent
The brown oil obtained was distilled off using silica gel column chromatography.
Tomography (chloroform: methanol = 97: 3)
And 917 mg of the desired orange powder (81% yield)
I got (Reaction 3)1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [4
-[N, N-bis (2-chloroethyl) amino] benzo
-2-oxa-1,3-diazolyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) 243 mg of benzimidazole-5-carboxylic acid
(0.85 mmol) and 4- [N, N-bis (2-
Loroethyl) amino] -7-aminobenzo-2-oxa
-1,3-Diazole hydrochloride {4- [N, N-bis (2
-Chloroethyl) amino] -7-nitrobenzo-2-o
Kisa-1,3-diazole 300 mg (0.85 mmol
l) 10 ml of methanol solution is contacted with Pd / C catalyst
Obtained by hydrogenation. Dissolve｝ in 5 mL of DMF and cool to 0 ° C
did. 355 μL of triethylamine (2.
6 mmol), followed by 193 μL of DECP (1.3 mm
ol) and stirred for 30 minutes. 2 o'clock
After stirring at room temperature for a while, the solvent was distilled off under reduced pressure. Residue
Kagel column chromatography (chloroform / meta
(Nol = 10/1) to give the desired orange powder 1
75 mg (38% yield) were obtained. (Reaction 4)1H-2- [1-methyl-4- [3- (me
Tylthio) propionylamino] pyrrol-2-yl]
Benzimidazole-5- [N- [4- [N, N-bis
(2-Chloroethyl) amino] benzo-2-oxo-
1,3-diazolyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] benzo-2-oxo
-1,3-diazolyl]] carboxamide 169 mg
(0.31 mmol) in a 1: 1 mixture of DMF and methanol
Dissolve in 10 mL of the combined solvent and 10% Pd / C under nitrogen atmosphere
150 mg and 1N hydrochloric acid (342 μL) were added. Reaction volume
The atmosphere in the vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 2 hours. Pd / C
After filtration, the filtrate was concentrated to obtain a DMF solution. This solution
Under ice-cooling, 52 μL of triethylamine (0.37 mmol
l) and 3- (methylthio) propionic acid 1
12 mg (0.93 mmol) and 151 mg of CDI
(0.93 mmol) to react and prepare the activity
5 mL of a DMF solution of the intermediate was added and left overnight. Solvent
The residue obtained was distilled off under reduced pressure.
By chromatography (chloroform / methanol = 96/4)
Purified. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate, and
And reprecipitation was carried out.
g (46% yield). IR (KBr) cm^-1: 3134, 1654, 153
5,1289,811,743

Example 67 (I of compound 1056)^-salt)2- [N- [1-methyl-2- [5- [N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
]] Carbamoyl] -1H-benzimidazole-2
-Yl] pyrrol-4-yl] carbamoylethyl-di
Methylsulfonium iodide 1H-2- [1-methyl-4- [3- (methylthio) p
Ropionylamino] pyrrol-2-yl] benzimida
Zol-5- [N- [4- [N, N-bis (2-chloro
Ethyl) amino] phenyl]] carboxamide 76 mg
(0.13 mmol) in 0.5 mL of 80% formic acid, acetic acid
Dissolve in 0.25 mL, 0.2 mL of methyl iodide, and shield from light
After stirring at room temperature for 9 hours, the mixture was left overnight. Add methanol
And concentrated under reduced pressure. Ethanol azeotrope and IPA residue
Was added and the resulting solid was collected by filtration to give 54 mg of the title compound.
(0.075 mmol, 58.1%) in light brown hygroscopic solid
Obtained as body. Further concentrate the filtrate and treat with ethyl acetate
22 mg (0.031 mmol, 23.
7%). 76 mg in total (0.106 mmol, 8
1.8%) IR (KBr) cm^-1: 3397,1648,151
7,1327,814 Elemental analysis: Calculated value (C₂₈H₃₃Cl_TwoIN₆O_TwoS) C: 4
7.01, H: 4.84, N: 11.75, Analysis value C:
46.97, H: 4.84, N: 11.78

Example 68 (I of compound 1076)^-salt)2- [N- [1-methyl-2- [5- [N- [3-full
Oro-4- [N, N-bis (2-chloroethyl) amido
No] phenyl]] carbamoyl] -1H-benzimida
Zol-2-yl] pyrrol-4-yl] carbamoyl
Ethyl-dimethylsulfonium iodide 1H-2- [1-methyl-4- [3- (methylthio) p
Ropionylamino] pyrrol-2-yl] benzimida
Zol-5- [N- [3-fluoro-4- [N, N-bi
[(2-chloroethyl) amino]] phenyl] carboxy
100 mg (0.19 mmol) of samide was added to 80% formic acid
(1 mL), acetic acid (0.5 mL), methyl iodide (0.
4 mL), and the mixture was stirred at room temperature under light-shielded conditions for 2 nights.
After the reaction, methanol was added, and the mixture was azeotroped three times with ethanol.
Sludge with tanol, 100m light yellow powder
g (98% yield). Elemental analysis: calculated value (C₂₈H₃₂Cl_TwoFIN₆O_Two・ H
_TwoO), C: 44.75, H: 4.56, N: 11.1
8. Analytical value C: 44.60, H: 4.59, N: 10.
83

Example 69 (I ^- salt of compound 1060) 2- [N- [1-methyl-2- [5- [N- [3-methyl
Ru-4- [N, N-bis (2-chloroethyl) amino]
Phenyl]] carbamoyl] -1H-benzimidazo
Ru-2-yl] pyrrol-4-yl] carbamoylethyl
Ru-dimethylsulfonium iodide 1H-2- [1-methyl-4- [3- (methylthio) propionyl] aminopyrrol-2-yl] benzimidazole-5- [N- [3-methyl-4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide (40 mg, 0.068 mmol) was added to 80% formic acid 2
It was dissolved in a mixed solvent of 40 μL and 120 μL of acetic acid. 210 μL of methyl iodide was added to this solution,
After stirring at room temperature for 7 hours, the mixture was left overnight. The operation of adding methanol and distilling off the solvent under reduced pressure, adding toluene to the residue and distilling off under reduced pressure was repeated three times. Slugging with IPA gave 35 mg (70%) of the title compound as a pale yellow powder. IR (KBr) cm ^-1 : 3254, 1648, 151
0,1307,803,744

Example 70 (I ^- salt of compound 1079) 2- [N- [1-methyl-2- [5- [N- [2-methyl
Ru-4- [N, N-bis (2-chloroethyl) amino]
Phenyl]] carbamoyl] -1H-benzimidazo
Ru-2-yl] pyrrol-4-yl] carbamoylethyl
Ru-dimethylsulfonium iodide 1H-2- [1-methyl-4- [3- (methylthio) propionylamino] pyrrol-2-yl] benzimidazole-5- [N- [2-methyl-4- [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide (84 mg, 0.14 mmol) in 80% formic acid 500
It was dissolved in a mixed solvent of μL and 250 μL of acetic acid. 210 μL of methyl iodide was added to this solution, and the mixture was stirred at room temperature for 4 hours under light shielding conditions, and then left overnight. 210 μL of methyl iodide was added to the reaction solution, stirred for 10 hours, and left overnight. The operation of adding methanol and distilling off the solvent under reduced pressure, adding toluene to the residue and distilling off under reduced pressure was repeated three times. Sludge with ethyl acetate to give 99 mg of the title compound
(95%) as a white powder. IR (KBr) cm ^-1 : 3245, 1654, 151
2,1306,802,745

[0367] (Cl compounds 1077 ^- salt) Example 71 2- [N- [1- methyl--2- [5- [N- [3- tri
Fluoromethyl-4- [N, N-bis (2-chloroethyl
L) amino] phenyl]] carbamoyl] -1H-ben
Zimidazol-2-yl] pyrrol-4-yl] cal
Bamoylethyl-dimethylsulfonium chloride 1H-2- [1-methyl-4- [3- (methylthio) propionylamino] pyrrol-2-yl] benzimidazole-5- [N- [3-trifluoromethyl-4-
86 mg (0.13 mmol) of [N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide was dissolved in a mixed solvent of 500 μL of 80% formic acid and 250 μL of acetic acid. 210 μL of methyl iodide was added to this solution,
After stirring at room temperature for 1 hour under light shielding conditions, the mixture was left overnight.
The reaction solution was further added with 210 μL of methyl iodide, stirred at room temperature for 8 hours, and left overnight. The operation of adding methanol and evaporating the solvent under reduced pressure, adding toluene to the residue and evaporating under reduced pressure was repeated twice. Dissolve the residue in methanol,
The counter ion was exchanged from iodine to chlorine through an ion exchange resin (DOWEX 1 × 8, Cl type). The solvent was distilled off under reduced pressure, the residue was sludged with methanol,
75 mg (81%) of the title compound were obtained as a white powder. IR (KBr) cm ^-1 : 3240, 1356, 154
1,1418,1319,1048,747

Example 72 (Cl of compound 1602)^-salt)2- [N- [1-methyl-2- [5- [N- [4-
[N, N-bis (2-chloroethyl) amino] benzo-
2-oxa-1,3-diazolyl]] carbamoyl]-
1H-benzimidazol-2-yl] pyrrole-4-
Yl] carbamoylethyl-dimethylsulfonium chloride
Lido 1H-2- [1-methyl-4- [3- (methylthio) p
Ropionylamino] pyrrol-2-yl] benzimida
Zol-5- [N- [4- [N, N-bis (2-chloro
Ethyl) amino] benzo-2-oxa-1,3-diazo
Ril]] carboxamide 50 mg (0.081 mmol
l) is mixed with 300 μL of 80% formic acid and 150 μL of acetic acid
Dissolved in the solvent. 260 μL of methyl iodide is added to this solution.
(4.2 mmol) for 7 minutes at room temperature under shading conditions
After stirring, the mixture was left for 2 nights. Add methanol to remove solvent
An operation of distilling under reduced pressure, adding toluene to the residue and distilling under reduced pressure
Was repeated twice. The residue is dissolved in methanol and ion
Through exchange resin (DOWEX 1 × 8, Cl type)
The unter ion was changed from iodine to chlorine. Reduce solvent
The residue is sludged with methanol,
39 mg (yield 72%) of orange powder was obtained. IR (KBr) cm^-1: 3228, 1660, 153
4,1419,1290,813,740

Example 73 (Cl ^- salt of compound 1072) 2- [N- [1-methyl-2- [5- [N- [3-chloro
B-4- [N, N-bis (2-chloroethyl) amino]
Phenyl]] carbamoyl] -1H-benzimidazo
Ru-2-yl] pyrrol-4-yl] carbamoylethyl
2- dimethylsulfonium chloride 1H-2- [1-methyl-4- [3- (methylthio) propionylamino] pyrrol-2-yl] benzimidazole-5- [N- [3-chloro-4- [N, N -Bis (2-chloroethyl) amino] phenyl]] carboxamide (40 mg, 0.066 mmol) in 80% formic acid 24
It was dissolved in a mixed solvent of 0 μL and 120 μL of acetic acid. 210 μL of methyl iodide was added to this solution, and the mixture was stirred at room temperature for 8 hours under light-shielded conditions, and then left overnight. The operation of adding methanol and evaporating the solvent under reduced pressure, adding toluene to the residue and evaporating under reduced pressure was repeated twice. The residue was dissolved in methanol, and the counter ion was exchanged from iodine to chlorine through an ion exchange resin (DOWEX 1 × 8, Cl type). The solvent was distilled off under reduced pressure, and the residue was sludged with methanol / ethanol to obtain 38 mg (87%) of the title compound as a white powder. IR (KBr) cm ^-1 : 3248, 1656, 149
9,1394,1307,826,746

Example 74 (Cl of compound 1076)^-salt)2- [N- [1-methyl-2- [5- [N- [3-full
Oro-4- [N, N-bis (2-chloroethyl) amido
No] phenyl]] carbamoyl] -1H-benzimida
Zol-2-yl] pyrrol-4-yl] carbamoyl
Ethyl-dimethylsulfonium chloride 2- [N- [1-methyl-2- [5- [N- [3-fur
Oro-4- [N, N-bis (2-chloroethyl) amido
No] phenyl]] carbamoyl] -1H-benzimida
Zol-2-yl] pyrrol-4-yl] carbamoyl
Ethyl-dimethylsulfonium iodide 100mg
(0.17 mmol) in methanol
Cow through exchange resin (DOWEX 1 × 8, Cl type)
Intermediate ions were exchanged for chlorine. After elution,
Lugging and white powder 20mg (19% yield)
I got

Example 75 (Cl ^- salt of compound 1060) 2- [N- [1-methyl-2- [5- [N- [3-methyl
Ru-4- [N, N-bis (2-chloroethyl) amino]
Phenyl]] carbamoyl] -1H-benzimidazo
Ru-2-yl] pyrrol-4-yl] carbamoylethyl
Ru-dimethylsulfonium chloride 1H-2- [1-methyl-4- [3- (methylthio) propionylamino] pyrrol-2-yl] benzimidazole-5- [N- [3-methyl-4- [N, N -Bis (2-chloroethyl) amino] phenyl]] carboxamide (100 mg, 0.17 mmol) in 80% formic acid 6
It was dissolved in a mixed solvent of 00 μL and 300 μL of acetic acid. 250 μL of methyl iodide was added to this solution,
After stirring at room temperature for 6 hours, the mixture was left overnight. After further stirring at room temperature for 10 hours, the mixture was again left overnight. The operation of adding methanol and evaporating the solvent under reduced pressure, adding toluene to the residue and evaporating under reduced pressure was repeated twice. The residue is dissolved in methanol, and ion exchange resin (DOWEX 1 × 8, Cl type)
Through, the counter ion was exchanged from iodine to chlorine. The solvent was distilled off under reduced pressure, and the residue was sludged with methanol to obtain 60 mg (55%) of the title compound as a white powder. IR (KBr) cm ^-1 : 3248, 1648, 151
2,1307,803,742

[0372] (Cl compounds 1079 ^- salt) Example 76 2- [N- [1- methyl--2- [5- [N- [2- methylcarbamoyl
Ru-4- [N, N-bis (2-chloroethyl) amino]
Phenyl]] carbamoyl] -1H-benzimidazo
Ru-2-yl] pyrrol-4-yl] carbamoylethyl
Le-dimethylsulfonium chloride 2- [N- [1-methyl-2- [5- [N- [2-methyl-4- [N, N-bis (2-chloroethyl) amino]]]
[Phenyl]] carbamoyl] -1H-benzimidazol-2-yl] pyrrol-4-yl] carbamoylethyl-dimethylsulfonium iodide 50 mg (0.
068 mmol) in methanol and ion exchange column chromatography (DOWEX 1 × 8, Cl
And the counter ion was changed from iodine to chlorine to give 34 mg (78%) of the title compound as a white powder. IR (KBr) cm ^-1 : 3247, 1654, 150
9,1307,802,745

Example 77 (Compound 1904) 1H-2- [1-methyl-4- (methylthioacetyla
Mino) pyrrole-2-yl] benzimidazole-5
[N- [4- [N, N-bis (2-chloroethyl) amido]
No] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carboxamide (150 mg, 0.30 mmol) was added to DMF (1
0 mL) and methanol (10 mL)
200 mg of Pd / C and 1 N hydrochloric acid (320 μL) were added, and hydrogenation was performed at normal temperature and normal pressure. After filtering off Pd / C,
The filtrate was concentrated to a DMF solution. This solution was mixed with 50 μL (0.30 mmol) of triethylamine under ice-cooling, and 96 mg (0.1%) of methylthioacetic acid previously reacted.
90 mmol) and 146 mg of CDI (0.90 mmol)
1) DMF solution (5 mL) was added and left overnight. The brown oil obtained by concentrating the reaction solution was subjected to silica gel column chromatography (chloroform / methanol = 95/5).
And sludged with ether / chloroform to obtain 101 mg (yield: 59%) of the target substance as a pale yellow powder. IR (KBr) cm ^-1 : 3274, 2960, 291
8,1647,1558,1517,1326,814

Example 78 (I of compound 1336)^-salt)2- [N- [1-methyl-2- [5- [N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
]] Carbamoyl] -1H-benzimidazole-2
-Yl] pyrrol-4-yl] carbamoylmethyl-di
Methylsulfonium iodide 1H-2- [1-methyl-4- (methylthioacetyla
Mino) pyrrole-2-yl] benzimidazole-5
[N- [4- [N, N-bis (2-chloroethyl) amido]
[No] phenyl]] carboxamide 100 mg (0.19
mmol) in 80% formic acid (0.5 mL) and acetic acid (0.2
5 mL), and dissolved in methyl iodide (0.4 mL).
mL), and the mixture was stirred at room temperature for 4 days under light shielding. gel
Filtration chromatography (Sephadex LH-2
0, methanol), then sludge with methanol
Then, 68.5 mg (55% yield) of a white powder was obtained.
Was. IR (KBr) cm^-1: 3398, 1654, 15
78,1518,1325,816

Example 79 (Compound 1944)1H-2- [1-methyl-4- (2-pyridylacetyl)
Ru) aminopyrrole-2-yl] benzimidazole-
5- [N- [4- [N, N-bis (2-chloroethyl)
Amino] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
150 mg (0.30 mmol) of oxamide was added to DMF (1
0mL) and methanol (10mL)
And 10% Pd / C 200mg and 1N hydrochloric acid (320μ
L) was added, and hydrogenation was performed at normal temperature and normal pressure. Pd / C
After filtration, the filtrate was concentrated to obtain a DMF solution. This solution
Under ice-cooling, triethylamine 50μL (0.30mmo
l) and 2-pyridylacetic acid previously reacted
156 mg (0.90 mmol) of hydrochloride and CDI146
mg (0.90 mmol) in DMF (5 mL) was added.
Eh, let it sit overnight. The brown oil obtained by concentrating the reaction solution was
Ricagel column chromatography (chloroform / medium
(Ethanol = 10/1) and purified with ether / chloroform.
107 mg of the desired pale yellow powder
(61% yield). IR (KBr) cm^-1: 3270, 2958, 164
7, 1594, 1518, 1327, 815

Example 80 (Compound 1952)1H-2- [1-methyl-4- (4-pyridylacetyl)
Ru) aminopyrrole-2-yl] benzimidazole-
5- [N- [4- [N, N-bis (2-chloroethyl)
Amino] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
300 mg (0.60 mmol) of oxamide is added to DMF and
Dissolve in 10 mL of a 1: 1 mixed solvent of ethanol, and place in a nitrogen atmosphere
10% Pd / C 200mg and 1N hydrochloric acid (718μ
L) was added. Replace the inside of the reaction vessel with hydrogen,
While stirring. After filtering off Pd / C, the filtrate was concentrated, and DMF was added.
The solution was used. Triethylamine 100 was added to this solution under ice cooling.
μL (0.72 mmol) and 4-pyridine
Acetic acid 311mg (1.8mmol) and CDI 291mg
(1.8 mmol) to react and prepare
5 mL of a DMF solution of the intermediate was added and left overnight. Reduce solvent
The residue obtained is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography.
Rough fee (chloroform / methanol = 10/1 → 8
/ 2). After evaporating the solvent under reduced pressure, methanol and vinegar
The precipitate was reprecipitated with ethyl acetate, and 190 mg of the target white powder (yield
54%). IR (KBr) cm^-1: 3280, 1638, 151
8,1328, 815, 716 Elemental analysis: Calculated value (C₃₀H₂₉Cl_TwoN₇O_Two・ H_TwoO) C:
59.31, H: 4.98, N: 16.14, analysis value:
C: 59.31, H: 5.11, N: 16.04

Example 81 (Compound 1424) 1H-2- [1-Methyl-4- (3- pyridylacetyl)
Amino) pyrrol-2-yl] benzimidazole-5
-[N- [4- [N, N-bis (2-chloroethyl) a
[Mino] phenyl]] carboxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [4- [N, N-
Dissolve 400 mg (0.80 mmol) of bis (2-chloroethyl) amino] phenyl]] carboxamide in 10 mL of a 1: 1 mixed solvent of DMF and methanol, and under nitrogen atmosphere, 300 mg of 10% Pd / C and 1N hydrochloric acid (1.2 m 2).
L) was added. The inside of the reaction vessel was replaced with hydrogen and stirred at room temperature for 2 hours. After filtering off Pd / C, the filtrate was concentrated to obtain a DMF solution. 133 μL of triethylamine was added to this solution under ice cooling.
(0.95 mmol), 416 mg (2.4 mmol) of 3-pyridineacetic acid and 388 mg of CDI in advance.
(2.4 mmol) was reacted, 5 mL of a prepared DMF solution of the active intermediate was added, and the mixture was allowed to stand overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 95/5). After evaporating the solvent under reduced pressure, the residue was reprecipitated with methanol and ethyl acetate to give 270 mg of the objective white powder (yield 54
%). IR (KBr) cm ^-1 : 3096, 1648, 151
6,1327,814,711 Calcd _{(C 30 H 29 Cl 2 N} 7 O 2 · H 2 O) C:
59.31, H: 4.98, N: 16.14, analysis value:
C: 59.19, H: 4.88, N: 15.83

Example 82 (Cl of compound 1440)^-salt)3-[[N- [1-methyl-2- [5- [N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
]] Carbamoyl] -1H-benzimidazole-2
-Yl] pyrrol-4-yl] carbamoylmethyl] pi
Lizinium chloride 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
79 mg (0.13 mmol) of oxamide in acetone 50
Dissolve in 5 mL, add 5 mL of methyl iodide, and add
While stirring. After evaporating the solvent under reduced pressure, silica gel column chromatography
Tography (ethyl acetate / IPA / water / acetic acid = 3 /
(2/1/0 → 6/4/2/1). Obtained solid
The body is dissolved in methanol and ion-exchange resin (DOWEX)
 1 × 8, Cl type) to convert counter ion to chlorine
Replaced. This is further purified by gel filtration column chromatography.
-(Sephadex LH-20, methanol)
Purification, 47 mg (58% yield) of the target pale yellow powder
Obtained. IR (KBr) cm^-1: 3243, 1638, 151
8,1328,816,745

Example 83 (Cl of compound 1716)^-salt)2- [N- [1-methyl-2- [5- [N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
]] Carbamoyl] -1H-benzimidazole-2
-Yl] pyrrol-4-yl] carbamoylethyl-
Limethylammonium chloride 1H-2- [1-methyl-4- [3- (N, N-dimethyl
Ruamino) propionylamino] pyrrol-2-yl]
Benzimidazole-5- [N- [4- [N, N-bis
(2-Chloroethyl) amino] phenyl]] carboxa
150 mg (0.25 mmol) of amide in 5 m of methanol
L. 39 mg of sodium carbonate was added to this solution.
(0.37 mmol), dimethyl sulfate 70 mg (0.5
6 mmol) and stirred at room temperature for 2 nights. Reduce solvent
After pressure distillation, silica gel column chromatography (acetic acid)
Ethyl / IPA / water / acetic acid = 3/2/1/0 → 6/4 /
2/1). Dissolve the obtained solid in methanol
And ion exchange resin (DOWEX 1 × 8, Cl type)
To exchange the counter ion for chlorine. This further
Gel filtration column chromatography (Sephade)
x LH-20, methanol).
72 mg (46% yield) of a yellow powder were obtained. IR (KBr) cm^-1: 3261, 1648, 151
8,1328,817

Example 84 (Compound 1522) 1H-2- [1-methyl-4- [3- (methylthio) propyl
Lopionyl] aminopyrrol-2-yl] benzimida
Zol-5- [N- [2- [4- [N, N-bis (2-
Chloroethyl) amino] phenyl] ethyl]] carbox
Samide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [2- [4-
[N, N-bis (2-chloroethyl) amino] phenyl] ethyl]] carboxamide 0.25 g (0.47
mmol) was dissolved in a mixed solvent of 4 mL of DMF and 3 mL of methanol, and hydrogenated under normal pressure using 10% Pd / C (wet) as a catalyst to lead to the corresponding amino compound. The DMF solution obtained by concentrating the solvent was stirred under ice-cooling under a nitrogen stream, and triethylamine 75 μL (0.54 mmol, 1.1e
q. ), 3- (methylthio) propionylimidazole {3- (methylthio) propionic acid 0.07 g (0.5
8 mmol), 0.12 g of CDI (0.74 mmol,
1.3 eq. )), A DMF (4 mL) solution was added in order, and the mixture was returned to room temperature, stirred for 4 hours, and left overnight. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol 4%), and crystallized from ether to give 0.19 g of the title compound (0.1%).
32 mmol, 67.2%) as reddish white crystals. mp. 152-155 ° C IR (KBr) cm ^-1 : 3270, 2925, 161
8, 1542, 1519, 1349, 1303

Example 85 (I ^- salt of compound 1058) 2- [N- [1-methyl-2- [5- [N- [2- [4
-[N, N-bis (2-chloroethyl) amino] phenyl
[Ethyl] carbamoyl] -1H-benzimidazo
Ru-2-yl] pyrrol-4-yl] carbamoylethyl
Ru-dimethylsulfonium iodide 1H-2- [1-methyl-4- [3- (methylthio) propionyl] aminopyrrol-2-yl] benzimidazole-5- [N- [2- [4- [N, N -Screw (2-
Chloroethyl) amino] phenyl] ethyl]] carboxamide 0.10 g (0.17 mmol) in 80% formic acid 0.5 mL, acetic acid 0.25 mL, methyl iodide 0.2 m
L and left overnight at room temperature in the dark. After concentration under reduced pressure, the residue was subjected to gel filtration (Sephadex LH-
20, methanol) and 99 mg (0.13 mmol, 78.3) of the title compound by crystallization from ether.
%) As a reddish-white amorphous powder. IR (KBr) cm ^-1 : 3414, 1618, 154
3,1347,1308

Example 86 (Compound 1005) 1H-2- [1-methyl-4- (2-guanidinoacetyl)
Ruamino) pyrrol-2-yl] benzimidazole-
5- [N- [3-methyl-4- [N, N-bis (2-
Loroethyl) amino] phenyl]] carboxamide disalt
Acid salt (Reaction 1) 3-Methyl-4- [N, N-bis (2-H
[Droxyethyl) amino] nitrobenzene 2-fluoro-5-nitrotoluene 4.0 g (25.8
mmol) and 7.0 g (67 mmol) of diethanolamine.
l) was dissolved in DMSO (30 mL). After heating and stirring at 140 ° C. for 6.5 hours, extraction was performed with ethyl acetate. After evaporating the solvent under reduced pressure, sludge with ethyl acetate to obtain 5.2 g (84%) of a target yellow powder. (Reaction 2) 3-methyl-4- [N, N-bis (2-
Loroethyl) amino] nitrobenzene 3-methyl-4-
A solution of 2.0 g (8.3 mmol) of [N, N-bis (2-hydroxyethyl) amino] nitrobenzene in benzene 20
3 mL (40 mmol) of thionyl chloride was added to the mL.
After heating and stirring at 80 ° C. for 2 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/1) to obtain 2.0 g of the objective yellow powder (92%). %). (Reaction 3) 1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [3
-Methyl-4- [N, N-bis (2-chloroethyl) a
Mino] phenyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5-carboxylic acid 280 mg
(0.98 mmol) and 10 mL of a solution of 3-methyl-4- [N, N-bis (2-chloroethyl) amino] aniline hydrochloride derived from the corresponding nitro compound in DMF was cooled to 0 ° C. Triethylamine 320 under nitrogen atmosphere
μL (2.3 mmol) followed by 220 μL DECP
(1.45 mmol), and the mixture was stirred for 30 minutes. After further stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 159 mg (32%) of the target substance as a yellow powder. (Reaction 4) 1H-2- [1-methyl-4- (2-guar
Nidinoacetylamino) pyrrol-2-yl] benzi
Midazole-5- [N- [3-methyl-4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
Oxamide dihydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [3-methyl-4
-[N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 150 mg (0.29 mmol)
Was dissolved in 10 mL of a 1: 1 mixed solvent of DMF and methanol, and 120 mg of 10% Pd / C was added under a nitrogen atmosphere, and 350 μL of 1N hydrochloric acid was added. The inside of the vessel was replaced with hydrogen and stirred at room temperature for 2 hours. After filtering off Pd / C, the filtrate was concentrated, and DMF was added.
The solution was used. To this solution was added triethylamine (49μ) under ice-cooling.
L (0.35 mmol), guanidine acetate hydrochloride 134
mg (0.87 mmol), DCC 180 mg (0.8
7 mmol) in that order, stirred at room temperature for 1 hour, and left overnight. The white powder was filtered off and concentrated under reduced pressure to give a residue of 4%.
An N hydrochloric acid / dioxane solution was added, and the mixture was concentrated under reduced pressure. The residue is sludged with methanol, and the target yellow powder 70m
g (29%) was obtained. IR (KBr) cm ^-1 : 3378, 1655, 151
0,1310,1242,806

Example 87 (Compound 1260) 1H-2- [1-Methyl-4- [4- (N, N-dimethyl)
Ruamino) butyrylamino] pyrrol-2-yl] ben
Zimidazole-5- [N- [3-methyl-4- [N,
N-bis (2-chloroethyl) amino] phenyl]] f
Ruboxamide dihydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [3-methyl-4
237 mg (0.46 mmol) of-[N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide
Was dissolved in 10 mL of a 1: 1 mixed solvent of DMF and methanol, and 200 mg of 10% Pd / C and 1 mL of 1N hydrochloric acid were added under a nitrogen atmosphere. The inside of the vessel was replaced with hydrogen and stirred at room temperature for 2 hours. After filtering off Pd / C, the filtrate was concentrated to obtain a DMF solution. 77 μL of triethylamine was added to this solution under ice cooling.
(0.56 mmol), 230 mg (1.4 mmol) of N, N-dimethylaminobutyric acid hydrochloride, 285 mg of DCC
(1.4 mmol) was added in order, and the mixture was stirred at room temperature for 1 hour and left overnight. The white powder was removed by filtration, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate / IPA / water = 5/2/1) to obtain 60 mg (21%) of the target white powder. Obtained.

Example 88 (Compound 1464)1H-2- (1-methyl-4-furoylaminopyrrole
-2-yl) benzimidazole-5- [N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
Le]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
250 mg (0.50 mmol) of oxamide in DMF10
dissolved in a mixed solvent of 10 mL of methanol and 10 mL of methanol.
250 mg of 10% Pd / C flowing down and 500 μL of 1N hydrochloric acid
At room temperature and under normal pressure. Filter Pd / C
Thereafter, the filtrate was concentrated to obtain a DMF solution. Add this solution under ice cooling
140 μL of triethylamine, floyl chloride
2 mg (0.50 mmol) of methylene chloride solution
In addition, it was left overnight. The reaction mixture was concentrated to give a dark brown
Silica gel column chromatography of oily residue
(Chloroform / methanol = 20/1),
As a result, 191 mg (67%) of a light yellow powder of the intended product was obtained. IR (KBr) cm^-1: 3276, 2958, 164
3,1594,1518,1327,814,758

Example 89 (Compound 2089)1H-2- [1-methyl-4- [4- [N-ethyl, N
-(2-chloroethyl) amino] benzoylamino] pi
Roll-2-yl] benzimidazole-5- [N-
[4- [N-ethyl, N- (2-chloroethyl) amido
No] phenyl]] carboxamide hydrochloride (Reaction 1)4- [N-ethyl, N- (2-hydroxy
Ethyl) amino] nitrobenzene 5.0 g of 4-fluoronitrobenzene (35.4 mmol
l) and 6 g of 2- (ethylamino) ethanol (67.3)
mmol) was dissolved in 30 mL of DMSO. At 140 ° C
After heating and stirring for 4 hours, extraction was performed with ethyl acetate. Dissolution
After distilling off the medium under reduced pressure, sludge it with ethyl acetate,
6.3 g (85%) of a yellow powder were obtained. (Reaction 2)4- [N-ethyl, N- (2-chloroethyl
Le) amino] nitrobenzene 4- [N-ethyl, N- (2-hydroxyethyl) amido
[No] nitrobenzene 3.0 g (14.3 mmol)
Thionyl chloride 2.1 mL (2 mL
8.8 mmol) was added. Stir at 80 ° C for 2 hours
After that, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography.
Matography (ethyl acetate / n-hexane = 1/1)
Then, 3.0 g (92%) of a yellow powder was obtained. IR (KBr) cm^-1: 2975, 1598, 131
0,1277,1115,825,725 (Reaction 3)4- [N-ethyl, N- (2-chloroethyl
Ru) amino] aniline hydrochloride 4- [N-ethyl, N- (2-chloroethyl) amino]
3.0 g (13.1 mmol) of nitrobenzene in concentrated hydrochloric acid
10 g of tin chloride was added to 70 mL of the solution. 3 hours heating return
After flowing, treat with ammonia water and chloroform.
Extracted. After distilling off the solvent, a 4N hydrochloric acid / dioxane solution was added.
Then, sludge with IPA and 3.1g of white powder (1
00%). (Reaction 4)1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [4
-[N-ethyl, N- (2-chloroethyl) amino] f
Enyl]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) 400 mg of benzimidazole-5-carboxylic acid
(1.40 mmol) and 4- [N-ethyl, N- (2
-Chloroethyl) amino] aniline hydrochloride 329 mg
10 mL of a DMF solution (1.40 mmol) was cooled to 0 ° C.
Rejected. 400 μL of triethylamine under nitrogen atmosphere
(2.89 mmol) followed by 350 μL of DECP
(2.31 mmol) and stirred for 30 minutes as it is.
Was. After stirring at room temperature for another 2 hours, the solvent was distilled off under reduced pressure.
Was. The residue is purified by silica gel column chromatography (chromatography).
(Formaldehyde / methanol = 10/1)
240 mg (37%) of powder was obtained. (Reaction 5)4- [N-ethyl, N- (2-hydroxy
Ethyl) amino] benzonitrile 10 g of 4-fluorobenzonitrile (82.6 mmol
l) and 15 g of 2- (ethylamino) ethanol (0.1
7 mmol) in a DMSO solution (30 mL) at 140 ° C. for 3 hours
After stirring while heating, extraction was performed with ethyl acetate. Solvent
After distilling off under reduced pressure, sludge with ether to form white
6.9 g (44%) of crystals were obtained. IR (KBr) cm^-1: 3456, 2221, 160
9,1530,1407,1357,1177,104
3,822 (Reaction 6)4- [N-ethyl, N- (2-chloroethyl
Le) amino] benzonitrile 4- [N-ethyl, N- (2-hydroxyethyl) amido
[N] nitrobenzene 6.0 g (31.5 mmol)
Thionyl chloride 5 mL (68.
5 mmol) was added. Heated and stirred at 70 ° C for 3 hours
After that, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
Purified by chromatography (ethyl acetate) to give a white powder5.
0 g (76%) were obtained. (Reaction 7)4- [N-ethyl, N- (2-chloroethyl
Ru) amino] benzoic acid 4- [N-ethyl, N- (2-chloroethyl) amino]
2.5 g (12.0 mmol) of benzonitrile in ethanol
25 mL of concentrated hydrochloric acid is added to 25 mL of
Heat reflux was performed. After cooling, add sodium carbonate and add solution
Was made alkaline and washed with chloroform. Water layer
Was acidified with concentrated hydrochloric acid and extracted with chloroform. Solvent
After distilling off under reduced pressure, sludge with IPA to obtain white powder
1.1 g (40%) were obtained. (Reaction 8)1H-2- [1-methyl-4- [4- [N
-Ethyl, N- (2-chloroethyl) amino] benzoy
Ruamino] pyrrol-2-yl] benzimidazole-
5- [N- [4- [N-ethyl, N- (2-chloroethyl
L) amino] phenyl]] carboxamide hydrochloride 4- [N-ethyl, N- (2-chloroethyl) amino]
Dissolve 166mg (0.73mmol) of benzoic acid in benzene
0.6 mL of thionyl chloride (8.2 mmol
l) was added and the mixture was heated and stirred at 90 ° C. for 1.5 hours. Solvent
After distilling off under reduced pressure, adding a small amount of benzene and distilling off under reduced pressure
The crop was repeated twice. The resulting acid chloride is immediately
Used accordingly. 1H-2- (1-methyl-4-nitropi
(Rol-2-yl) benzimidazole-5- [N-
[4- [N-ethyl, N- (2-chloroethyl) amido
[No] phenyl]] carboxamide 200 mg (0.43
mmol) in a 1: 1 mixed solvent of DMF and methanol 10
dissolved in 10 mL of Pd / C under nitrogen atmosphere.
g, 1N hydrochloric acid (520 μL) was added. Hydrogen replacement in the container
Then, the mixture was stirred at room temperature for 2 hours. After filtering off Pd / C, the filtrate was
It was concentrated to obtain a DMF solution. To this solution was added triethyl
Luamine (120 μL, 0.87 mmol)
The acid chloride was added sequentially. After stirring for 1 hour at room temperature,
Was added and the mixture was left overnight. The solvent was distilled off under reduced pressure,
The residue is purified by silica gel column chromatography (chloropho
Lum / methanol = 98/2)
170 mg (61%) of a yellow powder were obtained. IR (KBr) cm^-1: 3422,1973,160
6,1519,1271,816 Elemental analysis: Calculated value (C₂₈H₂₇Cl_TwoN₇O_Two・ 1.5H
_TwoO) C: 56.86, H: 5.11, N: 16.5
7, Analytical value: C: 57.28, H: 4.91, N: 1
6.21

Example 90 (Compound 1048) 1H-2- [1-methyl-4- (2-guanidinoacetyl)
Ruamino) pyrrol-2-yl] benzimidazole-
5- [N- [4- [N-ethyl, N- (2-chloroethyl
L) amino] phenyl]] carboxamide dihydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [4- [N-ethyl, N- (2- Chloroethyl) amino] phenyl]] carboxamide (150 mg, 0.32 mmol)
F, dissolved in 10 mL of a 1: 1 mixed solvent of methanol, and 150 mg of 10% Pd / C in a nitrogen atmosphere, 353 of 1N hydrochloric acid.
μL was added. The inside of the vessel was replaced with hydrogen and stirred at room temperature for 2 hours. After filtering off Pd / C, the filtrate was concentrated to obtain a DMF solution. 54 μL of triethylamine was added to this solution under ice cooling.
(0.39 mmol), guanidine acetate hydrochloride 150 m
g (0.98 mmol), 199 mg of DCC (0.97
mmol) was added in order, and the mixture was stirred at room temperature for 1 hour and left overnight. The white powder was removed by filtration, the residue obtained by concentration under reduced pressure was dissolved in methanol, 4N hydrochloric acid / dioxane solution was added, and the mixture was concentrated again under reduced pressure. Sludge the residue with methanol,
115 mg (63%) of the desired yellow powder was obtained. IR (KBr) cm ^-1 : 3153, 1664, 154
9,1398,1324,826

Example 91 (Compound 1049) 1H-2- [1-methyl-4- (guanidinoacetyla )
Mino) pyrrole-2-yl] benzimidazole-5
[N- [3- [N-ethyl, N- (2-chloroethyl)
Amino] phenyl]] carboxamide hydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [3- [N-ethyl, N- (2-chloroethyl) amino] ] Phenyl]] carboxamide 200 mg (0.43 mmol) in DMF
(10 mL) and methanol (10 mL), 200 mg of 10% Pd / C and 500 μl of 1N hydrochloric acid under a nitrogen stream.
L was added and normal temperature and normal pressure hydrogenation was performed. Pd / C was filtered off, and the filtrate was concentrated to obtain a DMF solution. 75 μL of triethylamine and 197 m of guanidine hydrochloride were added to this solution under ice cooling.
g (1.3 mmol), DCC 265 mg (1.3 mm
ol) in that order and left overnight. After the reaction, a black-brown oil obtained by filtering and concentrating the reaction solution was purified by gel filtration column chromatography (Sephadex LH-20, methanol) to obtain 136 mg (56%) of the target product as a white powder.
%).

Example 92 (Compound 1009) 1H-2- [1-methyl-4- (guanidinoacetyla )
Mino) pyrrole-2-yl] benzimidazole-5
[N- [3-methoxy-4- [N, N-bis (2-chloro
Roethyl) amino] phenyl]] carboxamide dihydrochloride
Salt (Reaction 1) 3-methoxy-4- [N, N-bis (2-
[Hydroxyethyl) amino] nitrobenzene 2-methoxy-5-nitroaniline 5.0 g (29.7
20.0 g of ethylene oxide was added dropwise to 30 mL of a 30% acetic acid suspension (mmol) in an ice-cooled manner, followed by stirring for 1 hour.
After further stirring at room temperature overnight, the mixture was stirred at room temperature for 2 hours while blowing nitrogen gas. After neutralization by adding sodium hydrogen carbonate, sodium chloride was added until saturation, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / ethyl acetate = 1/1 → 0/1) to obtain 500 mg (6.6%) of a yellow powder. (Reaction 2) 3-methoxy-4- [N, N-bis (2-
Chloroethyl) amino] nitrobenzene 3-methoxy-4- [N, N-bis (2-hydroxyethyl) amino] nitrobenzene 0.48 g (1.9 mm
ol) in 20 mL of benzene solution and 1 mL of thionyl chloride
(14 mmol) was added. After heating and stirring at 90 ° C. for 3 hours, the solvent was distilled off under reduced pressure. The obtained yellow oil was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/1) to give 350 mg of yellow powder (6
4%). (Reaction 3) 1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [3
-Methoxy-4- [N, N-bis (2-chloroethyl)
Amino] phenyl]] carboxamide 3-methoxy-4- [N, N-bis (2-chloroethyl) amino] nitrobenzene 144 mg (0.49 mm
ol) in methanol 10 mL, tetrahydrofuran 2 m
L in a mixed solvent. Under a nitrogen atmosphere in this solution,
150 mg of 10% Pd / C was added. The inside of the reaction vessel was replaced with hydrogen and stirred at room temperature for 1 hour. After completion of the reaction, the inside of the vessel was replaced with nitrogen and stirred for 30 minutes. 10% Pd / C was separated by filtration, and 200 μL of a 4N hydrochloric acid / dioxane solution was added to the obtained methanol solution to obtain 3-methoxy-4- [N, N-bis (2-chloroethyl) amino] aniline hydrochloride. . This was used immediately in the next reaction. 1H-2-
200 mg of (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5-carboxylic acid (0.7 mm
ol) and the above 3-methoxy-4- [N, N-bis (2-chloroethyl) amino] aniline hydrochloride in DMF
Dissolved in 5 mL and cooled to 0 ° C. Under a nitrogen atmosphere, 102 μL (0.74 mmol) of triethylamine, followed by D
112 μL (0.74 mmol) of ECP was added, and the mixture was stirred as it was for 20 minutes. After stirring at room temperature for 1 hour, the mixture was left overnight, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / n-hexane = 1 /
Purification was performed in 1) to obtain 80 mg (31%) of a yellow powder. (Reaction 4) 1H-2- [1-methyl-4- (guanidinium)
Noacetylamino) pyrrol-2-yl] benzimidida
Zol-5- [N- [3-methoxy-4- [N, N-bi
[(2-chloroethyl) amino] phenyl]] carbox
Samide dihydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [3-methoxy-4- [N, N-bis (2-chloroethyl)] amino [Phenyl]] carboxamide (73 mg, 0.14 mmol) was dissolved in a mixed solvent of DMF and methanol (1: 1, 10 mL), and 10% Pd / C (70 mg) and 1N hydrochloric acid (151 μL) were added under a nitrogen atmosphere. The inside of the vessel was replaced with hydrogen and stirred at room temperature for 2 hours. Pd
After the / C was filtered off, the filtrate was concentrated to obtain a DMF solution. 23 μL of triethylamine (0.17 mm
ol), guanidine acetate hydrochloride 65 mg (0.42 mm
ol) and 85 mg (0.41 mmol) of DCC were sequentially added, and the mixture was stirred at room temperature for 1 hour and left overnight. The white powder was removed by filtration, and the filtrate was concentrated under reduced pressure. A 4N hydrochloric acid / dioxane solution was added to the residue, and the mixture was concentrated under reduced pressure. Residue is ethanol / I
After sludge with PA, 55 mg (5
9%).

Example 93 (Compound 1024) 1H-2- [1-methyl-4- (guanidinoacetyla )
Mino) pyrrole-2-yl] benzimidazole-5
[N- [2-methyl-4- [N, N-bis (2-chloro
Ethyl) amino] phenyl]] carboxamide dihydrochloride (Reaction 1) 2-Methyl-4- [N, N-bis (2-H
[Droxyethyl) amino] nitrobenzene 2-nitro-5-fluorotoluene 5.0 g (64.5
mmol) and 8.2 g (78 mmo) of diethanolamine.
l) was dissolved in DMSO (8 mL). After heating and stirring at 140 ° C. for 7 hours, extraction was performed with ethyl acetate. After evaporating the solvent under reduced pressure, sludge with ethyl acetate to obtain 10.1 g (65%) of yellow powder. (Reaction 2) 2-Methyl-4- [N, N-bis (2-
[Loroethyl) amino] nitrobenzene 2-methyl-4- [N, N-bis (2-hydroxyethyl) amino] nitrobenzene 1.0 g (4.2 mmol)
l) in 20 mL of benzene solution, 5 mL of thionyl chloride (6
9 mmol) was added. After heating and stirring at 80 ° C. for 6 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to give a yellow powder 7
35 mg (64%) were obtained. (Reaction 3) 1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [2
-Methyl-4- [N, N-bis (2-chloroethyl) a
Mino] phenyl]] carboxamide 2-methyl-4- [N, N-bis (2-chloroethyl)
Amino] nitrobenzene 300 mg (1.1 mmol)
Was dissolved in a mixed solvent of 5 mL of methanol and 2 mL of tetrahydrofuran. This solution was put in a nitrogen atmosphere and 10% P
200 mg of d / C were added. The inside of the reaction vessel was replaced with hydrogen and stirred at room temperature for 1 hour. After completion of the reaction, the inside of the vessel was replaced with nitrogen and stirred for 30 minutes. 10% Pd / C was filtered off, and the obtained methanol solution was added with a 4N hydrochloric acid / dioxane solution 40.
0 μL was added, and 2-methyl-4- [N, N-bis (2-
Chloroethyl) amino] aniline hydrochloride was obtained. 1H-
309 mg of 2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5-carboxylic acid (1.1
mmol) and the above 2-methyl-4- [N, N-bis (2-chloroethyl) amino] aniline hydrochloride in DMF
Dissolved in 10 mL and cooled to 0 ° C. 330 μL (2.4 mmol) of triethylamine under a nitrogen atmosphere, followed by D
197 μL (1.3 mmol) of ECP was added, and the mixture was stirred for 20 minutes. After stirring at room temperature for further 15 minutes, the mixture was left overnight, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (ethyl acetate / n-hexane = 1/1).
Then, 329 mg (59%) of a yellow powder was obtained. (Reaction 4) 1H-2- [1-methyl-4- (guanidinium)
Noacetylamino) pyrrol-2-yl] benzimidida
Zol-5- [N- [2-methyl-4- [N, N-bis
(2-Chloroethyl) amino] phenyl]] carboxa
Mido dihydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [2-methyl-4
-[N, N-bis (2-chloroethyl) amino] phenyl]] carboxamide 100 mg (0.19 mmol)
Was dissolved in 10 mL of a 1: 1 mixed solvent of DMF and methanol, and 90 mg of 10% Pd / C was added under a nitrogen atmosphere.
20 μL was added. The inside of the vessel was replaced with hydrogen and stirred at room temperature for 2 hours. After filtering off Pd / C, the filtrate was concentrated to obtain a DMF solution. To this solution, add 32 μL of triethylamine under ice-cooling.
(0.23 mmol), 89 mg of guanidine acetate hydrochloride
(0.58 mmol), 120 mg of DCC (0.58 m
mol) were added in order, and the mixture was stirred at room temperature for 1 hour and left overnight. The white powder was removed by filtration, and the filtrate was concentrated under reduced pressure. A 4N hydrochloric acid / dioxane solution was added to the residue, and the mixture was concentrated under reduced pressure. The residue was sludged with methanol to obtain the desired yellow powder 8
4 mg (66%) were obtained.

Example 94 (Compound 1256) 1H-2- [1-methyl-4- [4- (N, N-dimethyl)
Ruamino) butyrylamino] pyrrol-2-yl] ben
Zimidazole-5- [N- [4- [N, N-bis (2
-Chloroethyl) amino] phenyl]] carboxamide
Hydrochloride 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carboxamide 0.28 g (0.55 mmol) in DMF 3m
It was dissolved in a mixed solvent of L and methanol (3 mL), 4N hydrochloric acid (0.14 mL) was added, and the mixture was converted to the corresponding amino compound by hydrogenation at normal pressure using 0.13 g of 10% Pd / C as a catalyst. The DMF solution of this amino compound was stirred under ice-cooling under a nitrogen stream, and triethylamine was added in an amount of 0.16 mL (1.15 mmol, 2.0 e).
q. ), A solution of 4- (N, N-dimethylamino) butyryl chloride in methylene chloride {prepared from 0.14 g (0.84 mmol) of 4- (N, N-dimethylamino) butyric acid hydrochloride} was added in order, and 2 After stirring for an hour, the mixture was left overnight.
The resulting crystals were separated by filtration, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate / IPA / water = 6/2/1, twice) and crystallized from ether-IPA to give the title compound. 0.14g (0.23mmo
1, 41.3%) as pale brown crystals. IR (KBr) cm ^-1 : 3421, 1647, 163
6,1541,1521 ESI-mass spectrum; m / z (C ₂₉ H ₃₅ N ₇ O ₂ Cl
₂ ) 583.22, analysis value 583.85

Example 95 (Compound 1488)1H-2- [4- (4-aminobutyrylamino) -1-
Methylpyrrole-2-yl] benzimidazole-5
[N- [4- [N, N-bis (2-chloroethyl) amido]
No] phenyl]] carboxamide (Reaction 1)1H-2- [1-methyl-4- [4- (ben
Diloxycarbonylamino) butyrylamino] pillow
Ru-2-yl] benzimidazole-5- [N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
Le]] carboxamide 1H-2- (1-methyl-4-nitropyrrole-2-i
B) benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
0.20 g (0.40 mmol) of oxamide in 3 m of DMF
L and 3 mL of methanol
0.1 mL was added, and 0.14 g of 10% Pd / C was used as a catalyst.
Then, it was led to the corresponding amino compound by hydrogenation under normal pressure. This
The DMF solution of the amino compound was stirred under ice-cooling under a stream of nitrogen,
Luamine 60 μL (0.43 mmol, 1.08e
q. ), N- [4- (benzyloxycarbonylamido)
No) Butyryl] imidazole 4- (benzyloxyca)
0.14 g (0.59 mmol, rubonylamino) butyric acid
1.5 eq. ), CDI 0.10 g (0.62 mmo)
1, 1.5 eq. ) / Prepared from 3 mL of DMF
After stirring for 4 hours, the mixture was left overnight. Concentration under reduced pressure
And the residue is purified by silica gel chromatography.
(Chloroform / methanol = 96/4), ether
The title compound was crystallized from 0.18 g (0.2
(5 mmol, 63.7%) as pale ocher crystals. mp. 118-121 ° C (Reaction 2)1H-2- [4- (4-aminobutyryl lua
Mino) -1-methylpyrrol-2-yl] benzimida
Zol-5- [N- [4- [N, N-bis (2-chloro
Ethyl) amino] phenyl]] carboxamide 1H-2- [4- [4- (benzyloxycarbonyla
Mino) butyrylamino] -1-methylpyrrole-2-i
Ru] benzimidazole-5- [N- [4- [N, N-
Bis (2-chloroethyl) amino] phenyl]] carbo
0.15 g (0.2 mmol) of oxamide in methanol
Suspended, 60 μL of 4N hydrochloric acid / dioxane (0.24 mm
ol), and 0.07 g of 10% Pd / C was used as a catalyst.
Normal pressure hydrogenation was performed. After confirming the completion of the reaction, concentrate under reduced pressure.
Was. 4N hydrochloric acid / dioxane was added to the residue, and the mixture was concentrated.
Further crystallization gave 0.10 g of the title compound (0.
17 mmol, 76.7%) as yellow crystals. IR (KBr) cm^-1: 3364, 3067, 164
9, 1567, 1517, 1396, 1330, 106
0,818

Example 96 (Compound 1536)1H-2- [1-methyl-4- (4-morpholinecarbo
Nyl) aminopyrrol-2-yl] benzimidazole
-5- [N- [4- [N, N-bis (2-chloroethyl
Ru) amino] phenyl]] carboxamide 
 1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [4
-[N, N-bis (2-chloroethyl) amino] phenyl
]] Carboxamide 0.15 g (0.30 mmol)
Dissolved in a mixed solvent of 3 mL of DMF and 4 mL of methanol
Then, add 0.4 mL of 1N hydrochloric acid and add 10% Pd / C 0.08
g as a catalyst and lead to the corresponding amino compound by hydrogenation at normal pressure
Was. The DMF solution of this amino compound was ice-cooled under a nitrogen atmosphere.
After stirring, triethylamine 0.10 mL (0.72 mmol
1, 2.4 eq. ), 4-morpholinecarbonyl chloride
50 μL (0.43 mmol, 1.4 eq.)
Then, the mixture was returned to room temperature and stirred for 2.5 hours. Concentrate under reduced pressure and leave
The residue is purified by silica gel chromatography (chloro
(Form / methanol = 92/8), crystallized from ether
To give 0.1 g (0.17 mmol) of the title compound.
1, 57.0%) as red-brown white crystals. IR (KBr) cm^-1: 3421, 1636, 151
8,1256 Elemental analysis: Calculated value (C₂₈H₃₁N₇O_ThreeCl_Two H_TwoO) C:
55.82, H: 5.52, N: 16.27, analysis value:
C: 55.58, H: 5.39, N: 16.09

Example 97 (Compound 1047) 1H-2- [1-Methyl-4- (guanidinoacetyla )
Mino) pyrrole-2-yl] benzimidazole-5
[N- [3- [N, N-bis (2-chloroethyl) amido]
No] phenyl]] carboxamide dihydrochloride (reaction 1) 3- [N, N-bis (2-chloroethyl)
Amino] aniline hydrochloride 3- [N, N-bis (2-chloroethyl) amino] nitrobenzene 2.0 g (7.6 mmol) in concentrated hydrochloric acid 35 m
L, and 6.9 g of tin (II) chloride dihydrate (3
0.6 mmol, 4.0 eq. ) And heated and stirred in a 100 ° C. oil bath for 1 hour. The mixture was allowed to cool to room temperature, diluted with water, made basic with concentrated aqueous ammonia, extracted twice with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was concentrated by adding 4N hydrochloric acid / dioxane, and the residue was crystallized from a small amount of methanol / ether to give 1.97 g (7.3 mmol, 96.1%) of the title compound as yellow crystals. mp. 195-201 ° C (Reaction 2) 1H-2- (1-methyl-4-nitropyrro
2-yl) benzimidazole-5- [N- [3
-[N, N-bis (2-chloroethyl) amino] phenyl
]] Carboxamide 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5-carboxylic acid 0.40 g
(1.4 mmol), 0.38 g of 3- [N, N-bis (2-chloroethyl) amino] aniline hydrochloride (1.4 m
mol, 1.0 eq. ) Was suspended in 10 mL of DMF and stirred under ice-cooling under a stream of nitrogen. 0.60 mL of triethylamine
(4.3 mmol, 3.1 eq.), DECP 0.32
mL (2.1 mmol, 1.5 eq.) in order,
After stirring for 3.5 hours, the mixture was left overnight. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol = 98/2).
Crystallization from -n-hexane gave 0.41 g (0.82 mmol, 58.4%) of the title compound as a yellow powder. (Reaction 3) 1H-2- [4- (guanidinoacetyl)
Amino-1-methyl-pyrrol-2-yl] benziimi
Dazol-5- [N- [3- [N, N-bis (2-chloro
Roethyl) amino] phenyl]] carboxamide dihydrochloride
Salt 1H-2- (1-methyl-4-nitropyrrol-2-yl) benzimidazole-5- [N- [3- [N, N-
Dissolve 0.20 g (0.40 mmol) of bis (2-chloroethyl) amino] phenyl] carboxamide in a mixed solvent of DMF and methanol, add 0.46 mL of 1N hydrochloric acid, and use 0.11 g of 10% Pd / C as a catalyst. Atmospheric pressure hydrogenation led to the corresponding amino compound. DM of this thing
The F solution was stirred under ice-cooling under a nitrogen stream, and triethylamine 64
μL (0.46 mmol, 1.1 eq.), 0.18 g (1.17 mmol, 2.9 e) of guanidine acetate hydrochloride
q. ), DCC 0.25 g (1.21 mmol, 3.0
eq. ) Was added in order, the temperature was returned to room temperature, and the mixture was stirred for 5 hours and left overnight. After the resulting solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to gel filtration column chromatography (Sephadex).
(LH-20, methanol). The eluted fraction was concentrated by adding 4N hydrochloric acid / dioxane and sludged with ethanol to obtain 0.14 g of the title compound.
(0.21 mmol, 53.2%) as white crystals. mp. > 250 ° C IR (KBr) cm ^-1 : 3154,1657,160
8,1547,1497 Elemental analysis: Calculated value (C ₂₆ H ₂₉ N ₉ O ₂ Cl ₂ .2HCl.
_{2.5H 2 O) C: 45.36,} H: 5.27, N: 1
8.31, Cl: 20.60, Analysis value: C: 45.6
7, H: 5.21, N: 18.50, Cl: 20.73

Example 98 (Cl of compound 1056)^-salt)2- [N- [1-methyl-2- [5- [N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
]] Carbamoyl] -1H-benzimidazole-2
-Yl] pyrrol-4-yl] carbamoylethyl-di
Methylsulfonium chloride 2- [N- [1-methyl-2- [5- [N- [4-
[N, N-bis (2-chloroethyl) amino] phenyl
]] Carbamoyl] -1H-benzimidazole-2
-Yl] pyrrol-4-yl] carbamoylethyl-di
Methylsulfonium iodide (I of compound 1056
^-Dissolve 80 mg of salt in methanol and ion-exchange
Chromatography (DOWEX 1 × 8, Cl type)
Unterion I^-From Cl^-Was replaced. Gel filtration
(Sephadex LH-20, methanol)
To obtain 45 mg (64.5%) of the target substance as a pale yellow powder.
Was. IR (KBr) cm^-1: 3418, 1648, 151
7,1417,1328,1181,815

The NMR data of the compounds shown in the examples are shown below. Example 1 (Reaction 1) NMR (DMSO-d ₆ ) δ: 9.64 (s, 1H), 8.33 (s, 1H), 7.65 (s, 1H), 3.
95 (s, 1H) Example 1 (Reaction _{2) NMR (DMSO-d 6} ) δ: 8.28 (d, 1H), 8.17 (s, 1H), 7.86 (d, 1H), 7.
67 (d, 1H), 7.56 (d, 1H), 4.19 (s, 3H), 3.88 (s, 3H) Example 1 (Reaction _{3) NMR (DMSO-d 6} ) δ: 8.30 (d, 1H), 8.17 (s, 1H), 7.85 (d, 1H), 7.
65 (d, 1H), 7.59 (d, 1H), 4.20 (s, 3H) Example 2 (Reaction _{2) NMR (DMSO-d 6} ) δ: 9.09 (s, 2H), 8.85 (bs, 0.5H) , 8.74 (bs, 0.
5), 8.71 (s, 2H), 8.29 (s, 1H), 8.07 (s, 0.5H), 7.83-7.54 (m,
3.5H), 4.20 (s, 3H ), 3.63 (q, 2H), 2.71 (t, 2H) Example 2 (Reaction _{3) NMR (DMSO-d 6} ) δ: 9.91 (1H, s), 9.03 (2H , bs), 8.70 (1H, br),
8.62 (2H, bs), 8.20-7.90 (1H, m), 7.70 (1H, m), 7.65-7.4 (1
H, m), 7.09 (1H, s), 7.05 (2H, d), 6.91 (1H, br), 6.68 (2H, d),
4.06 (3H, s), 3.70 (8H, m), 3.62 (2H, m), 2.69 (2H, m), 2.49 (2
H, m), 2.26 (2H, m), 1.83 (2H, m) Example 3 NMR9.92 (1H, s), 9.06 (2H, bs), 8.73 (1H, br), 8.66 (2H, bs) ,
8.20-7.90 (1H, m), 7.71 (1H, m), 7.65-7.40 (1H, m), 7.27 (1
H, s), 7.05 (2H, d), 6.90 (1H, br), 6.67 (2H, d), 4.06 (3H, s),
3.70 (8H, m), 3.63 (2H, m), 2.70 (2H, m), 2.50 (2H, m), 2.27 (2
H, m), 1.83 (2H , m) Example _{4 NMR (DMSO-d 6)} δ: 9.90 (s, 1H), 8.94 (bs, 2H), 8.59 (bs, 2H),
8.49 (bs, 1H), 8.16 (bs, 1H, 7.88 (d, 1H)), 7.73 (d, 1H), 7.52
(bs, 1H), 7.36 (d, 1H), 7.13 (s, 1H), 6.85 (d, 2H), 4.11 (s, 3
H), 3.80 (m, 8H ), 3.67 (q, 2H), 2.76 (t, 2H) Example _{5 NMR (DMSO-d 6)} δ: 10.24 (s, 1H), 8.98 (bs, 2H), 8.66 (bs, 2
H), 8.52 (bs, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.74 (d, 1H), 7.
56-7.44 (m, 5H), 7.40 (d, 1H), 7.16 (bs, 1H), 4.12 (s, 3H), 3.
64 (bs, 2H), 2.70 (t, 2H)

Example 6 NMR (DMSO-d ₆ ) δ: 10.5 (1H, s), 9.20 (2H, bs), 8.85 (2H, s),
8.80 (1H, br), 8.14 (1H, br), 7.77 (1H, m), 7.63-7.35 (4H,
m), 7.33 (1H, s), 7.04 (1H, s), 4.08 (3H, s), 4.07 (2H, m), 2.7
4 (2H, m) Example 7 (Reaction _{1) NMR (DMSO-d 6} ) δ: 8.55 (1H, br), 8.26 (1H, s), 8.12 (1H, br),
7.75 (1H, d), 7.63 (1H, br), 7.55 (1H, s), 3.60-3.30 (2H, m),
2.37 (2H, t), 2.22 (6H, s), 1.71 (2H, q) Example 7 (Reaction _{2) NMR (DMSO-d 6} ) δ: 10.4 (1H, s), 8.65 (1H, br), 8.1 (1H, m), 7.
80-7.50 (2H, m), 7.31 (1H, s), 6.99 (1H, s), 4.08 (3H, s), 4.0
4 (2H, m), 3.4 (2H, m), 3.10 (2H, m), 2.77 (6H, s), 1.93 (2H, m) Example _{8 NMR (CDCl 3 + DMSO-} d 6) δ: 9.39 (1H, br), 8.40 (1H, br), 8.20
(1H, s), 8.09 (1H, s), 7.50 (2H, br), 7.20 (1H, br), 6.86 (1H,
s), 5.52 (2H, m), 3.99 (3H, s), 2.48 (2H, t), 2.28 (6H, s), 1.7
8 (2H, q) Example _{9 NMR (DMSO-d 6)} δ: 9.80 (1H, s), 8.06 (1H, s), 7.74 (2H, m), 7.
25 (2H, m), 7.02 (2H, d), 7.0 (1H, m), 6.66 (2H, d), 3.86 (3H,
s), 3.38 (8H, m), 2.77 (4H, m), 2.54 (2H, m), 2.48 (2H, m), 2.2
1 (2H, m), 1.80 (2H, m) Example 10 (Reaction _{2) NMR (DMSO-d 6} ) δ: 10.15 (1H, s), 8.15 (1H, s), 8.14 (1H, s),
7.83 (2H, m), 7.30 (1H, s), 7.25 (1H, s), 7.02 (1H, s), 3.89 (3
H, s), 3.78 (6H, s), 3.65 (3H, s)

Example 11 (Reaction 1) NMR (CDCl ₃ + DMSO-d ₆ ) δ: 8.10 (bs, 1H), 8.02 (s, 1H), 7.68
(m, 3H), 7.57 (s, 1H), 4.26 (s, 3H), 3.46 (q, 2H), 1.65 (m, 2
H), 1.25 (s, 30H ), 0.88 (t, 3H) Example 11 (Reaction _{2) NMR (DMSO-d 6} ) δ: 10.04 (s, 1H), 8.35-8.29 (m, 1H), 8.09 ( s,
0.5H), 7.86 (s, 0.5H), 7.80 (d, 2H, J = 8.8), 7.66-7.58 (d, 1
H), 7.53 (d, 0.5H), 7.37 (d, 0.5H), 7.34 (s, 1H), 7.05 (s, 0.5
H), 7.01 (s, 0.5H), 6.77 (d, 2H), 4.02 (s, 3H), 3.73 (m, 8H),
3.21 (m, 2H) Example _{12 NMR (DMSO-d 6)} δ: 10.08 (s, 1H), 8.32 (m, 1H), 8.09 (s, 1H + 0.
5H), 7.88 (s, 0.5H), 7.66-7.58 (d, 1H), 7.54 (d, 0.5H), 7.36
(d, 0.5H), 7.21 (s, 1H), 6.95 (s, 1H), 4.00 (s, 3H), 3.19 (m, 2
H), 1.46 (m, 2H ), 1.15 (s, 30H), 0.78 (t, 3H) Example 13 (Reaction _{1) NMR (CDCl 3) δ} : 8.04 (d, 2H), 7.46 (d, 2H) , 4.62 (s, 2H), 3.92
(s, 3H) Example 13 (Reaction _{2) NMR (CDCl 3) δ} : 8.00 (d, J = 7.8,2H), 7.41 (d, J = 8.6,2H), 3.9
2 (s, 3H), 3.77 (s, 2H), 3.64 (t, J = 5.1,4H), 2.73 (t, J = 5.1,4
H) Example 13 (Reaction _{4) NMR (DMSO-d 6} ) δ: 7.99 (d, 2H), 7.74 (d, 2H), 4.42 (bs, 2H),
3.99 (bs, 4H), 3.37 (bs, 4H) Example 13 (Reaction _{6) NMR (DMSO-d 6} ) δ: 10.44 (s, 1H), 9.05 (s, 2H), 8.64 (s, 2H),
8.18 (bs, 1H), 8.01 (bs, 1H), 7.75 (s, 1H), 7.49 (d, 2H), 7.46
(d, 1H), 7.17 (s, 1H), 4.21 (s, 3H), 3.83 (s, 2H), 3.66 (m, 6
H), 2.89 (t, 4H ), 2.71 (t, 2H) Example 14 (Reaction _{1) NMR (DMSO-d 6} ) δ: 8.50 (t, 0.5H), 8.42 (t, 0.5H), 8.29 ( d, 1
H), 8.24 (s, 0.5H), 8.00 (s, 0.5H), 7.81-7.57 (m, 2H), 7.57
(s, 1H), 4.19 (s, 3H), 3.28 (q, 2H), 1.54 (m, 2H), 1.35 (m, 2
H), 0.92 (t, 3H) Example 14 (Reaction 2) NMR (DMSO-d ₆ , 80 ° C) δ: 8.09 (bs, 1H), 7.66 (bd, 1H), 7.56-
7.43 (bm, 1H), 7.20 (s, 1H), 6.92 (s, 1H), 4.07 (s, 3H), 3.28
(m, 2H), 1.52 (m, 2H), 1.35 (m, 2H), 0.92 (t, 3H) Example 15 NMR (DMSO-d ₆ , 80 °) δ: 9.85 (s, 1H), 8.11 ( m, 1H), 7.86 (d, 2
H), 7.65 (d, 1H), 7.55-7.38 (m, 2H), 7.33 (s, 1H), 7.08 (s, 1
H), 6.84 (d, 2H), 4.09 (s, 3H), 3.78 (m, 8H), 3.29 (q, 2H), 1.5
6 (m, 2H), 1.38 (m, 2H), 0.93 (t, 3H)

Example 16 (Reaction 1) NMR (CDCl ₃ ) δ: 7.77 (dd, 1H), 7.52 (dt, 1H), 7.39 (d, 1H), 7.
21 (t, 1H), 4.39 (q, 2H), 3.54 (t, 4H), 3.22 (t, 4H), 1.40 (t, 3
H) Example 16 (Reaction _{2) NMR (CDCl 3) δ} : 8.17 (dd, 1H), 7.63 (t, 1H), 4.52 (q, 6H), 3.7
8 (t, 4H), 1.47 (t, 3H) Example 16 (Reaction _{3) NMR (CDCl 3) δ} : 7.85 (dd, 1H), 7.56 (m, 2H), 7.29 (dt, 1H), 3.
64 (t, 4H), 3.50 (t, 4H) Example 16 (Reaction _{4) NMR (DMSO-d 6} ) δ: 10.67 (s, 1H), 8.94 (bs, 2H), 8.58 (bs, 2
H), 8.48 (bt, 1H), 8.09 (bs, 1H), 7.52 (d, 1H), 7.47 (d, 1H),
7.39 (d, 1H), 7.37 (s, 1H), 7.23 (t, 1H), 7.07 (s, 1H), 3.69
(m, 6H), 3.54 ( t, 4H), 2.74 (s, 2H) Example 17 (Reaction _{1) NMR (CDCl 3) δ} : 7.37-7.22 (m, 3H), 6.86 (d, 1H), 3.87 (s, 3
H), 3.82 (t, 4H ), 3.58 (t, 4H) Example 17 (Reaction _{2) NMR (CDCl 3) δ} : 7.44 (d, 1H), 7.35 (s, 1H), 7.29 (t, 1H) , 6.88
(d, 1H), 3.91 ( s, 3H), 3.79 (t, 4H), 3.66 (t, 4H) Example 17 (Reaction _{3) NMR (CDCl 3 + DMSO} -d 6) δ: 7.48-7.29 (m , 3H), 6.90 (dd, 1H),
3.82-3.77 (m, 4H), 3.69-3.64 (m, 4H) Example 17 (Reaction _{4) NMR (DMSO-d 6} ) δ: 10.38 (s, 1H), 9.02 (bs, 2H), 8.73 (t , 0.5
H), 8.67 (t, 0.5H), 8.60 (bs, 2H), 8.20 (s, 0.5H), 7.96 (s, 0.
5H), 7.73 (d, 0.5H), 7.70 (d, 0.5H), 7.63 (d, 0.5H), 7.47 (d,
0.5H), 7.45 (s, 1H), 7.35 (d, 1H), 7.28 (t, 1H), 7.23 (s, 1H),
7.18 (s, 0.5H), 7.13 (s, 0.5H), 6.96 (d, 1H), 4.11 (s, 3H), 3.
80 (s, 8H), 3.63 (m, 2H), 2.68 (m, 2H) Example 18 (Reaction _{1) NMR (CDCl 3) δ} : 8.22 (d, 2H), 6.98 (d, 2H), 4.74 ( s, 2H), 3.83
(s, 3H) Example 18 (Reaction _{4) NMR (DMSO-d 6} ) δ: 6.83 (2H, d), 6.69 (2H, d), 4.67 (2H, s), 3.
75-3.60 (11H, m) Example 18 (Reaction 5) NMR (DMSO-d ₆ ) δ: 7.68 (1H, br, D2O exchangeable), 6.82 (2
H, d), 6.71 (2H , d), 4.55 (2H, s), 3.67 (8H, bs) Example 18 (Reaction _{6) NMR (DMSO-d 6} ) δ: 10.2 (1H, s), 9.03 ( 2H, br), 8.80-8.63 (1
H, m), 8.61 (2H, br), 8.19 (0.6H, m), 7.96 (0.4H, m), 7.28-7.
76 (3H, m), 7.06 (1H, m), 6.93 (2H, d), 6.73 (2H, d), 4.56 (2H,
s), 4.07 (3H, s ), 3.67 (8H, m), 3.63 (2H, m), 2.69 (2H, t) Example 19 (Reaction _{1) NMR (CDCl 3) δ} : 6.46 (d, 2H) , 6.05 (t, 1H), 5.15 (bs, 4H), 3.7
5 (s, 3H) Example 19 (Reaction _{5) NMR (DMSO-d 6} ) δ: 10.3 (1H, s), 9.00 (2H, bs), 8.72 (0.42H,
m), 8.64 (0.58H, m), 8.59 (2H, bs), 8.20 (0.58H, s), 7.95 (0.
42H, d, J = 2.2), 7.4-7.76 (3H, m), 7.15 (0.42H, d, J = 2.2), 7.
10 (0.58H, d, J = 2.2), 6.61 (2H, s), 6.15 (1H, s), 4.11 (3H,
s), 3.79 (16H, bs), 3.63 (2H, m), 2.68 (2H, m)

Example 20 (Reaction 1) NMR (CDCl ₃ ) δ: 7.13 (d, 2H), 6.65 (d, 2H), 3.84 (t, 2H), 3.68
(s, 3H), 3.56 ( t, 2H), 3.52 (s, 2H) Example 20 (Reaction _{2) NMR (CDCl 3) δ} : 7.17 (d, 2H), 6.65 (d, 2H), 3.75-3.69 (m, 4
H), 3.69 (s, 3H ), 3.65-3.59 (m, 4H), 3.54 (s, 2H) Example 20 (Reaction _{3) NMR (CDCl 3) δ} : 7.16 (d, 2H), 6.65 (d, 2H), 3.75-3.69 (d, 4
H), 3.65-3.59 (m, 4H ), 3.55 (s, 3H) Example 20 (Reaction _{4) NMR (DMSO-d 6} ) δ: 10.12 (s, 1H), 9.02 (bs, 2H), 8.72 ( t, 0.5
H), 8.64 (t, 0.5H), 8.61 (bs, 2H), 8.18 (s, 0.5H), 7.95 (s, 0.
5H), 7.72 (d, 0.5H), 7.70 (d, 0.5H), 7.61 (d, 0.5H), 7.46 (d,
0.5H), 7.24 (s, 1H), 7.17 (d, 2H), 6.96 (s, 0.5H), 6.91 (s, 0.
5H), 6.70 (d, 2H), 4.05 (s, 3H), 3.71 (s, 8H), 3.62 (m, 2H), 3.
44 (s, 2H), 2.68 (m, 2H) Example 21 (Reaction _{1) NMR (CDCl 3) δ} : 7.84 (d, 1H), 7.76 (d, 1H), 7.68 (dd, 1H), 4.0
2 (s, 3H), 3.97 (s, 3H) Example 21 (Reaction _{2) NMR (CDCl 3) δ} : 7.55 (dd, 1H), 7.45 (d, 1H), 6.66 (d, 1H), 4.2
2 (bs, 2H), 3.90 (s, 3H), 3.86 (s, 3H) Example 21 (Reaction _{3) NMR (CDCl 3) δ} : 7.64 (dd, 1H), 7.56 (d, 1H), 7.10 ( d, 1H), 3.9
2 (s, 3H), 3.90 (s, 3H), 3.66 (t, 4H), 3.37 (t, 4H), 2.95 (bs, 2
H) Example 21 (Reaction _{4) NMR (CDCl 3) δ} : 7.96 (d, 1H), 7.70 (d, 1H), 7.69 (s, 1H), 4.04
(s, 3H), 3.95 ( s, 3H), 3.87 (t, 4H), 3.72 (t, 4H) Example 21 (Reaction _{5) NMR (CDCl 3) δ} : 7.49 (dd, 1H), 7.44 (d , 1H), 7.01 (d, 1H), 3.8
4 (s, 3H), 3.65 (m, 8H) Example 21 (Reaction _{6) NMR (DMSO-d 6} ) δ: 10.02 (s, 1H), 8.92 (bs, 2H), 8.53 (bs, 2
H), 8.46 (bs, 1H), 8.17 (bs, 0.5H), 7.96 (bs, 0.5H), 7.72 (d,
1H), 7.56 (s, 1H), 7.55 (d, 1H), 7.36 (s, 1H), 7.13 (bs, 1H),
7.07 (d, 1H), 4.10 (s, 3H), 3.90 (s, 3H), 3.64 (m, 10H), 2.74
(t, 2H)

Example 22 (Reaction 5) NMR (DMSO-d ₆ ) δ: 9.92 (s, 1H), 9.02 (bs, 2H), 8.63 (bm, 1H),
8.57 (bs, 2H), 8.18 (bs, 0.5H), 7.96 (bs, 0.5H), 7.71 (bd, 1
H), 7.61 (bs, 0.5H), 7.47 (bs, 0.5H), 7.26 (s, 1H), 7.08 (d, 2
H), 6.91 (bs, 1H), 6.66 (d, 2H), 4.07 (s, 3H), 3.69 (s, 8H), 3.
65 (m, 2H), 2.83 (t, 2H), 2.69 (t, 2H), 2.52 (m, 2H) Example 23 (Reaction _{3) NMR (DMSO-d 6} ) δ: 9.78 (s, 1H), 8.85 (bs, 2H), 8.36 (1H + 2H),
8.07 (s, 1H + 1H), 7.86 (d, 2H), 7.70 (d, 1H), 7.53 (d, 1H), 7.3
2 (s, 1H), 7.11 (s, 1H), 6.83 (d, 2H), 4.09 (s, 3H), 3.82 (m, 1
H), 3.64 (m, 2H ), 2.74 (t, 2H) Example 24 (Reaction _{2) NMR (DMSO-d 6} ) δ: 10.67 (s, 1H), 8.97 (t, 1H), 8.28 (s, 1H),
8.14 (bs, 3H), 8.00 (d, 3H), 7.76 (d, 1H), 7.70 (s, 1H), 7.59-
7.50 (m, 3H), 7.37 (s, 1H), 4.12 (s, 3H), 3.58 (q, 2H), 3.03
(q, 2H) Example 25 (Reaction 3) NMR (DMSO-d ₆ ) δ: 10.34 (s, 1H), 8.97 (t, 1H), 8.27 (s, 1H),
8.15 (bs, 2H), 7.99 (d, 1H), 7.90 (d, 2H), 7.76 (d, 1H), 7.66
(s, 1H), 7.35 (s, 1H), 6.85 (d, 2H), 4.11 (s, 3H), 3.80 (m, 8
H), 3.58 (q, 2H), 3.02 (q, 2H) Example 26 (Reaction 2) NMR (DMSO-d ₆ ) δ: 10.33 (s, 1H), 9.58 (t, 1H), 8.94 (s, 1H),
8.84 (d, 1H), 8.55 (d, 1H), 8.27 (s, 1H), 8.04 (dd, 1H), 7.98
(d, 1H), 7.91 (d, 2H), 7.76 (d, 1H), 7.65 (s, 1H), 7.33 (s, 1
H), 6.86 (d, 2H ), 4.70 (d, 2H), 4.11 (s, 3H), 3.80 (bs, 8H) Example _{27 NMR (DMSO-d 6)} δ: 10.15 (s, 1H), 9.30 (bs, 1H), 9.03 (s, 1H),
8.89 (d, 1H), 8.54 (d, 1H), 8.33 (s, 0.5H), 8.25 (bs, 0.5H),
8.11 (dd, 1H), 7.87 (d, 2H), 7.77 (d, 1H), 7.57 (bm, 1H), 7.43
(s, 1H), 7.15 (s, 1H), 6.85 (d, 2H), 4.67 (d, 2H), 4.37 (s, 3
H), 4.10 (s, 3H), 3.79 (m, 8H)

Example 28 NMR (DMSO-d ₆ ) δ: 9.48 (s, 1H), 8.82 (bs, 2H), 8.38 (bs, 2H),
8.32 (t, 1H), 8.06 (s, 1H), 7.70 (d, 1H), 7.50 (d, 1H), 7.16
(s, 1H), 6.92 (s, 1H), 4.05 (s, 3H), 3.65 (q, 2H), 3.61 (t, 2
H), 2.75 (t, 2H), 2.28 (t, 2H), 1.76 (m, 2H), 1.63 (m, 2H), 1.4
7 (m, 2H) Example 29 (Reaction _{1) NMR (DMSO-d 6} ) δ: 10.1 (3H, br), 7.20 (2H, d), 6.82 (2H, d),
3.73 (8H, s) Example 29 (Reaction _{2) NMR (DMSO-d 6} ): 10.08 (s, 0.5H), 10.01 (s, 0.5H), 8.40 (s, 0.
5H), 8.10 (s, 0.5H), 8.31 (s, 1H), 7.91-7.83 (m, 1H), 7.75-
7.58 (m, 4H), 6.76 (d, 2H), 4.21 (s, 3H), 3.73 (s, 8H) Example 29 (Reaction _{3) NMR (DMSO-d 6} ) δ: 10.32 (s, 1H), 10.04 (s, 0.5H), 9.97 (s, 0.
5H), 8.32 (s, 0.5H), 8.03 (s, 0.5H), 7.81 (d, 1H), 7.67-7.50
(m, 3H), 7.60-7.20 (bs, 5H), 7.30 (s, 1H), 6.99 (s, 0.5H), 6.
97 (s, 0.5H), 6.75 (d, 2H), 4.09 (s, 3H), 4.03 (d, 2H), 3.73
(s, 8H) Example 30 (Reaction 4) NMR (DMSO-d ₆ ) δ: 10.32 (s, 1H), 10.00 (s, 0.5H), 9.94 (s, 0.
5H), 8.31 (s, 0.5H), 8.03 (s, 0.5H), 7.82 (d, 0.5H), 7.79 (d,
0.5H), 7.68-7.53 (m, 3H), 7.50-7.17 (bs, 4H), 7.30 (s, 1H),
6.99 (s, 0.5H), 6.97 (s, 0.5H), 6.78 (d, 2H), 4.16 (t, 4H), 4.
09 (s, 3H), 4.03 (d, 2H), 3.59 (t, 4H), 2.01 (s, 6H) Example 31 (Reaction _{3) NMR (DMSO-d 6} ) δ: 10.32 (s, 1H), 8.55 (t, 0.4H), 8.48 (t, 0.6
H), 8.15 (s, 0.6H), 7.93 (s, 0.4H), 7.74 (d, 0.4H), 7.70 (d,
0.6H), 7.62 (s, 1H), 7.60 (m, 0.6H), 7.46 (d, 0.4H), 7.43-7.
20 (bs, 4H), 7.10 (d, 2H), 6.98 (s, 0.4H), 6.95 (s, 0.6H), 6.7
9 (d, 2H), 4.08 (s, 3H), 4.03 (d, 2H), 3.70 (s, 8H), 3.43 (q, 2
H), 2.75 (t, 2H)

Example 32 (Reaction 1) NMR (DMSO-d ₆ ) δ; 7.07 (d, 2H), 6.62 (d, 2H), 3.73-3.56 (m, 8
H), 2.86 (bs, 2H), 2.76-2.72 (m, 2H), 2.59-2.51 (m, 2H), 1.8
2-1.74 (m, 2H) Example 32 (Reaction _{2) NMR (DMSO-d 6} ) δ: 8.52 (t, 0.5H), 8.44 (t, 0.5H), 8.30 (s, 1
H), 8.25 (s, 0.5H), 7.99 (s, 0.5H), 7.79 (d, 0.5H), 7.76-7.7
1 (m, 1H), 7.58-7.54 (m, 1.5H), 7.07 (d, 2H), 6.67 (d, 2H), 4.
19 (s, 3H), 3.70 (s, 8H), 3.32 (q, 2H), 2.53 (t, 2H), 1.80 (m, 2
H) Example 32 (Reaction 3) NMR (DMSO-d ₆ ) δ: 10.34 (s, 1H), 8.47 (t, 0.5H), 8.41 (t, 0.5
H), 8.17 (s, 0.5H), 7.94 (s, 0.5H), 7.74-7.62 (m, 2.5H), 7.4
8-7.29 (m, 5.5H), 7.08 (d, 2H), 6.98 (s, 0.5H), 6.95 (s, 0.5
H), 6.67 (d, 2H), 4.08 (s, 3H), 4.04 (q, 2H), 3.30 (m, 2H), 1.7
9 (m, 2H) Example _{33 NMR (DMSO-d 6)} δ: 10.13 (s, 1H), 9.98-10.02 (m, 1H), 8.33
(s, 0.5H), 8.03 (s, 0.5H), 7.88 (d, 2H), 7.81 (d, 1H), 7.65
(d, 2H), 7.52 (d, .1H), 7.43 (s, 1H), 7.13 (s, 1H), 6.85 (d, 2
H), 6.76 (d, 2H ), 4.11 (s, 3H), 3.80 (s, 8H), 3.73 (s, 8H) Example 34 (Reaction _{1) NMR (CDCl 3) δ} : 9.83 (s, 1H) , 7.28 (s, 1H), 7.12 (s, 1H), 4.03
(s, 3H) Example 34 (Reaction 2) NMR (CDCl ₃ ) δ: 9.85 (s, 1H), 7.91 (s, 1H), 4.13 (s, 3H) Example 34 (Reaction 3) NMR (DMSO- d ₆ ) δ: 8.71 (s, 1H), 8.31 (s, 0.5H), 8.15 (s, 0.5
H), 7.93 (d, 0.5H ), 7.60 (d, 0.5H), 4.28 (s, 3H) Example 34 (Reaction _{4) NMR (DMSO-d 6} ) δ: 8.88 (bs, 1H), 8.71 ( s, 1H), 8.32 (s, 0.5
H), 8.08 (s, 0.5H), 7.95-7.60 (m, 2H), 4.28 (s, 3H), 3.53 (q,
2H), 2.81 (t, 2H ) Example 34 (Reaction _{5) NMR (DMSO-d 6} ) δ: 9.04 (bs, 2H), 8.83 (t, 0.5H), 8.75 (t, 0.5
H), 8.73 (s, 1H), 8.63 (bs, 2H), 8.34 (s, 0.5H), 8.07 (s, 0.5
H), 7.87 (d, 0.5H), 7.80 (bs, 1H), 7.57 (d, 0.5H), 4.28 (s, 3
H), 3.63 (q, 2H ), 2.69 (t, 2H) Example 34 (Reaction _{6) NMR (DMSO-d 6} ) δ: 10.41 (s, 1H), 9.03 (bs, 2H), 8.74 (bs, 1
H), 8.60 (bs, 2H), 8.20 (s, 1H), 7.94 (d, 2H), 7.80 (d, 1H), 7.
68 (s, 1H), 7.65 (d, 1H), 6.82 (d, 2H), 4.20 (s, 3H), 3.79 (m, 8
H), 3.64 (m, 2H), 2.70 (m, 2H)

Example 35 NMR (DMSO-d ₆ ) δ: 10.22 (s, 1H), 9.01 (bs, 2H), 8.74 (m, 0.5
H), 8.68 (m, 0.5H), 8.59 (bs, 2H), 8.27 (s, 0.5H), 8.05 (s, 0.
5H), 7.81-7.73 (m, 2.5H), 7.57 (s, 0.5H), 7.54 (s, 1H), 7.05
(d, 2H, J = 8.1), 6.67 (d, 2H, J = 8.1), 4.15 (s, 3H), 3.70 (s, 8
H), 3.63 (m, 2H ), 2.68 (m, 2H), 2.37 (t, 2H), 1.84 (m, 2H) Example _{36 NMR (DMSO-d 6)} δ: 8.79 (bs, 1H), 8.24 (s, 1H), 8.16 (s, 1H),
7.74 (d, 1H), 7.62 (d, 1H), 7.56 (s, 1H), 4.16 (s, 3H), 3.59
(m, 2H), 2.62 ( t, 2H) Example 37 (Reaction _{1) NMR (DMSO-d 6} ) δ: 10.13 (s, 0.4H), 10.04 (s, 0.6H), 8.73 (s,
1H), 8.46 (s, 0.6H), 8.13 (s, 0.4H), 7.95 (d, 0.6H), 7.90-7.
82 (m, 1H), 7.67-7.60 (m, 2.6H), 6.77 (d, 2H), 4.29 (s, 3H),
3.73 (s, 8H) Example 37 (Reaction _{2) NMR (DMSO-d 6} ) δ: 10.62 (s, 1H), 10.10 (s, 1H), 8.30 (s, 1H),
7.91 (d, 1H, J = 8.8), 7.71 (d, 1H, J = 8.8), 7.65 (d, 3H), 7.59
(s, 1H), 7.70-7.20 (bs, 4H), 6.77 (d, 2H), 4.18 (s, 3H), 4.13
(d, 2H), 3.74 ( s, 3H) Example 38 (Reaction _{1) NMR (DMSO-d 6} ) δ: 8.68 (s, 2H), 8.26 (bs, 1H), 7.87 (d, 1H),
7.67 (bd, 1H) Example 38 (Reaction 2) NMR (DMSO-d ₆ ) δ: 8.85 (m, 1H), 8.68 (s, 2H), 8.23 (s, 0.5H),
8.05 (s, 0.5H), 7.82 (d, 0.5H), 7.62 (d, 0.5H), 7.74 (m, 1H),
3.55 (q, 2H), 2.81 (t, 2H) Example 38 (Reaction _{3) NMR (DMSO-d 6} ) δ: 9.12 (bs, 2H), 8.88 (m, 1H), 8.78 (bs, 2H),
8.72 (bs, 2H), 8.26 (s, 0.5H), 8.14 (s, 0.5H), 7.82 (d, 1H),
7.70 (d, 0.5H), 7.60 (d, 0.5H), 3.65 (q, 2H), 2.74 (t, 2H) Example 38 (Reaction _{4) NMR (DNSO-d 6} , 80 ° C) [delta]: 8.89 (bs, 2H), 8.48 (bs, 2H), 8.10
(s, 1H), 7.83 (s, 1H), 7.74 (d, 1H), 7.56 (d, 1H), 7.54 (s, 1H
H), 7.06 (d, 2H), 6.69 (d, 2H), 3.69 (s, 8H), 2.76-2.37 (m, 8
H), 1.90 (m, 2H) Example 39 NMR (DMSO-d ₆ ) δ: 8.11 (s, 1H), 8.00 (s, 1H), 7.80-7.45 (m, 8
H), 3.77 (t, 2H), 2.79 (t, 2H)

Example 40 (Reaction 1) NMR (DMSO-d ₆ ) δ: 10.08 (s, 0.5H), 10.03 (s, 0.5H), 8.69 (b
s, 2H), 8.35 (s, 0.5H), 8.13 (s, 0.5H), 7.87-7.70 (m, 2H), 7.
60 (d, 2H), 6.77 (d, 2H), 3.73 (s, 8H) Example 40 (Reaction _{2) NMR (DMSO-d 6} ) δ: 12.25 (s, 1H), 10.31 (s, 1H), 8.40 (s, 1H),
8.33 (s, 1H), 8.10 (d, 1H, J = 8.8), 7.85 (d, 1H, J = 8.8), 7.69
(m, 2H), 7.63 (d, 2H, J = 8.8), 7.60-7.25 (bs, 4H), 6.77 (d, 2
H), 4.22 (d, 2H ), 3.74 (s, 8H) Example 41 (Reaction _{1) NMR (DMSO-d 6} ) δ: 8.25 (m, 2H), 7.90 (m, 2H), 7.72 (d, 1H), 3.
89 (s, 3H) Example 41 (Reaction _{2) NMR (DMSO-d 6} ) δ: 8.24 (d, 1H), 8.21 (s, 1H), 7.95 (d, 1H), 7.
89 (d, 1H), 7.71 (d, 1H) Example 41 (Reaction _{3) NMR (DMSO-d 6} ) δ: 8.92 (t, 1H), 8.27 (d, 1H), 8.19 (s, 1H), 7.
90 (d, 1H), 7.81 (d, 1H), 7.70 (d, 1H), 3.53 (q, 2H), 2.78 (t, 2
H) Example 41 (Reaction 4) NMR (DMSO-d ₆ ) δ: 9.11 (bs, 2H), 8.88 (bs, 1H), 8.71 (bs, 2
H), 8.22 (m, 2H), 8.10 (s, 1H), 7.86 (d, 1H), 7.68 (bs, 1H), 3.
67 (q, 2H), 2.75 (t, 2H) Example 41 (Reaction 6) NMR (CD ₃ OD) δ: 8.04 (s, 1H), 7.73 (d, 1H), 7.59 (d, 1H), 7.55
(d, 1H), 7.08 (d, 2H), 6.72 (d, 1H), 6.65 (d, 2H), 3.77 (t, 2
H), 3.68 (t, 4H), 3.61 (t, 4H), 2.78 (t, 2H), 2.61 (t, 2H), 2.4
3 (t, 2H), 2.01 (m, 2H) Example _{42 NMR (DMSO-d 6)} δ: 9.08 (bs, 2H), 8.77 (m, 1H), 8.67 (bs, 2H),
8.40 (s, 1H), 8.07 (bs, 0.8H), 8.02 (s, 0.2H), 7.76 (bs, 1H),
7.70 (d, 1H), 7.53 (d, 1H), 6.82 (d, 1H), 3.63 (m, 2H), 2.72
(m, 2H) Example 43 NMR (DMSO-d ₆ ) δ: 8.3-8.15 (m, 1H), 7.91 (d, 1H), 7.90 (m, 1
H), 7.71-7.64 (m, 1H ), 7.57 (d, 1H) Example 44 (Reaction _{1) NMR (DMSO-d 6} ) δ: 14.2-11.3 (1H, br), 7.89 (1H, d, J = 8.2),
7.71 (1H, d, J = 8.2), 7.30 (1H, d, J = 4.4), 7.08 (1H, d, J = 4.
4), 5.8-2.5 (2H, br ) Example 44 (Reaction _{2) NMR (DMSO-d 6} ) δ: 8.90 (1H, t, J = 5.5), 8.16 (1H, s), 7.81 (1
(H, d, J = 8.1), 7.69 (1H, d, J = 8.1), 7.30 (1H, d, J = 3.7), 7.07
(1H, d, J = 3.7), 3.54 (2H, q, J = 5.9), 5.80-3.15 (2H, br), 2.8
2 (2H, t, J = 6.6) Example 44 (Reaction _{3) NMR (DMSO-d 6} ) δ: 9.06-8.80 (2H, br), 8.67-8.45 (2H, br),
8.56 (1H, m), 7.99 (1H, s), 7.64 (1H, d, J = 8.8), 7.48 (1H, d, J
= 8.8), 7.00 (1H, d, J = 3.7), 6.80 (1H, d, J = 3.7), 3.61 (2H,
m), 2.66 (2H, t , J = 6.6) Example 44 (Reaction _{4) NMR (DMSO-d 6} ) δ: 9.05 (2H, bs), 8.63 (2H, bs), 8.62-8.75 (1
H, m), 8.14-7.92 (3H, m), 7.4-7.74 (5H, m), 6.96-6.87 (1H,
m), 6.24 (1H, bs), 3.56-3.70 (2H, m), 2.70 (2H, t, J = 5.9)

Example 45 NMR (DMSO-d ₆ ) δ: 8.25 (1H, s), 7.98 (1H, bs), 7.69 (1H, dd),
7.51 (1H, d), 6.88 (1H, d), 5.93 (1H, d), 3.67 (2H, t), 2.57 (2H
(H, t) Example 46 NMR (DMSO-d ₆ ) δ: 7. (), 6.87 (1H, d), 6.66 (2H, d), 5.82 (1
H, d), 2.00 (2H, q), 3.77 (2H, t), 2.38 (2H, t), 2.61 (2H, t),
3.4-3.7 (8H, m), 2.78 (2H, t) Example 47 (Reaction _{1) (DMSO-d 6)} δ: 8.52 (m, 0.5H), 8.46 (m, 0.5H), 8.29 (s, 1H),
8.24 (s, 0.5H), 8.00 (s, 0.5H), 7.78-7.62 (m, 1.5H), 7.57 (b
s, 1.5H), 4.19 (s, 3H), 3.30 (m, 2H), 2.30 (t, 2H), 1.80 (m, 2
H) Example 47 (Reaction _{2) (DMSO-d 6)} δ: 9.66 (s, 1H), 8.56 (t, 0.5H), 8.48 (t, 0.5H),
8.29 (s, 1H), 8.26 (s, 0.5H), 8.00 (s, 0.5H), 7.82-7.71 (m,
1.5H), 7.58-7.54 (m, 1.5H), 7.41 (d, 2H), 6.68 (d, 2H), 4.19
(s, 3H), 3.68 ( s, 8H), 3.33 (m, 2H), 2.34 (t, 2H), 1.86 (m, 2H) Example 47 (Reaction _{3) (DMSO-d 6)} δ: 10.29 ( s, 1H), 9.69 (s, 1H), 8.5-8.4 (m, 1H),
8.19 (s, 0.5H), 7.95 (s, 0.5H), 7.73 (d, 0.5H), 7.69 (d, 0.5
H), 7.59 (d, 0.5H), 7.45 (d, 0.5H), 7.43 (d, 2H), 7.27 (s, 1
H), 7.60-7.20 (bs, 5H), 6.95 (d, 1H), 6.68 (d, 2H), 4.08 (s, 3
H), 4.02 (s, 2H), 3.68 (s, 8H), 3.35 (m, 2H), 2.34 (t, 2H), 1.8
6 (m, 2H) Example 48 (Reaction _{1) (CDCl 3) δ:} 8.26 (d, 1H), 8.07 (dd, 1H), 7.32 (d, 1H), 2.34 (b
Example 48 (Reaction 2) (CDCl ₃ ) δ: 8.28 (d, 1H), 8.10 (dd, 1H), 7.24 (d, 1H), 3.75
(t, 4H), 3.59 (t, 4H) Example 48 (Reaction 3) (DMSO-d ₆ ) δ: 10.34 (s, 1H), 8.41 (bs, 1H), 8.32 (d, 1H), 8.0
3 (d, 1H), 7.87 (d, 1H), 7.73 (dd, 1H), 7.71 (bs, 1H), 7.59 (d,
1H), 7.37 (d, 1H ), 4.21 (s, 3H), 3.61 (t, 4H), 3.50 (t, 4H) Example 48 (Reaction _{4) (DMSO-d 6)} δ: 10.53 (s, 2H ), 8.30 (s, 1H), 8.04 (d, 1H), 7.99
(d, 1H), 7.77 (d, 1H), 7.74 (dd, 1H), 7.66 (t, 1H), 7.48 (s, 1
H), 7.37 (4H + 1H), 7.18 (s, 1H), 4.11 (s, 3H), 4.06 (d, 2H), 3.
62 (t, 4H), 3.50 (t, 4H) Example _{49 (DMSO-d 6) δ} : 10.55 (s, 1H), 10.50 (s, 1H), 8.30-7.13 (m, 12
H), 4.11 (s, 3H), 4.07 (d, 2H), 3.67 (t, 4H), 3.56 (t, 4H)

Example 50 (Reaction 1) (DMSO-d ₆ ) δ: 10.45 (s, 0.5H), 10.38 (s, 0.5H), 8.62-7.10
(8H), 4.21 (s, 3H), 3.72 (s, 8H) Example 50 (Reaction 2) (DMSO-d ₆ ) δ: 10.58 (s, 1H), 10.50 (s, 1H), 8.30 (s, 1H), 8.1
9 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.64 (t, 1H), 7.45 (s, 1
H), 7.35 (4H + 1H), 7.15 (s, 1H), 4.10 (s, 3H), 4.07 (d, 2H), 3.
73 (s, 8H) Example 51 (Reaction 1) (CDCl ₃ ) δ: 8.17 (d, 1H), 7.54 (dd, 1H), 7.39 (d, 1H), 3.86-
3.23 (m, 8H) Example 51 (Reaction _{2) (DMSO-d 6)} δ: 8.02 (d, 1H), 6.84 (dd, 1H), 6.61 (d, 1H), 4.86
(bs, 2H), 3.67-3.01 (m, 14H) Example 51 (Reaction 3) (CDCl ₃ ) δ: 8.17 (d, 1H), 6.71 (dd, 1H), 6.50 (d, 1H), 4.11-
3.22 (m, 16H) Example 51 (Reaction _{4) (DMSO-d 6)} δ: 9.94 (d, 1H), 8.30-6.67 (m, 8H), 4.20 (s, 3H)
3.76 (s, 8H), 3.52 (s, 6H), 3.31 (s, 2H) Example 51 (Reaction _{5) (DMSO-d 6)} δ: 10.36 (s, 1H), 9.98 (s, 1H), 8.16 -6.66 (m, 13
H), 4.09 (s, 3H ), 4.03 (d, 2H), 3.77-3.35 (m, 16H) Example 52 (Reaction _{1) (CDCl 3) δ:} 8.05 (d, 1H), 7.68 (s, 1H ), 7.52 (m, 1H), 3.53 (q,
2H), 2.54 (t, 2H), 2.26 (s, 6H) Example 52 (Reaction 2) (DMSO-d ₆ ) δ: 8.27 (t, 1H), 7.94 (d, 1H), 6.80 (dd, 1H) ), 6.58
(d, 1H), 4.86 (bs, 2H), 3.55 (s, 8H), 3.27 (q, 2H), 2.38 (t, 2
H), 2.34 (s, 6H ) Example 52 (Reaction _{3) (DMSO-d 6)} δ: 8.42 (t, 1H), 7.98 (d, 1H), 6.95 (dd, 1H), 6.77
(d, 1H), 4.37 (t, 4H), 3.90 (t, H), 2.27 (s, 6H) (Comment:
Example 52 (Reaction 4) (DMSO-d ₆ ) δ: 10.25 (bs, 1H), 9.17 (bt, 1H), 8.36 ( d, 1H), 8.
32 (d, 1H), 8.21 (s, 0.5H), 8.09 (s, 0.5H), 7.88-7.62 (3H),
7.14 (d, 1H), 7.03 (dd, 1H), 4.22 (s, 3H), 3.82 (s, 8H), 3.69
(m, 2H), 3.30 ( m, 2H), 2.89 (s, 6H) Example 52 (Reaction _{5) (DMSO-d 6)} δ: 10.52 (s, 2H), 9.25 (bt, 1H), 8.64 ( bs, 1H), 8.
35 (d, 1H), 8.19 (S, 1H), 7.90 (d, 1H), 7.78 (d, 1H), 7.67 (t, 1
H), 7.46 (s, 1H), 7.39 (bs, 4H), 7.17 (s, 1H), 7.03 (d, 1H), 4.
11 (s, 3H), 4.06 (d, 2H), 4.00-3.40 (m, 10H), 3.32 (m, 2H), 2.
85 (d, 6H)

Example 53 (Reaction 1) (DMSO-d ₆ ) δ: 10.12 (s, 1H), 10.04 (s, 1H), 9.97 (s, 1H), 8.3
2 (s, 0.5H), 8.25 (m, 1H), 8.03 (s, 0.5H), 7.80-7.50 (m, 4H),
7.40-6.85 (bs, 4H), 7.29 (s, 1H), 6.96 (s, 1H), 6.75 (d, 2H),
4.08 (s, 3H), 3.73 (s, 8H), 3.34 (m, 2H) Example 53 (Reaction _{2) (DMSO-d 6)} δ: 11.10 (s, 1H), 10.20 (s, 1H), 8.28 (bs, 3H + 1
H), 7.98 (d, 1H), 7.89 (t, 1H), 7.76 (d, 1H), 7.63 (d, 2H), 7.5
4 (s, 1H), 7.23 (s, 1H), 7.65-6.90 (bs, 4H), 6.77 (d, 2H), 4.1
2 (s, 3H), 4.05 (m, 1H), 3.74 (s, 8H), 3.21 (m, 2H), 1.85 (m, 2
H), 1.57 (m, 2H ) Example _{54 (DMSO-d 6) δ} : 10.02 (s, 0.5H), 9.95 (s, 0.5H), 9.71 (s, 1H),
8.32 (s, 0.5H), 8.01 (s, 0.5H), 7.80 (dd, 1H), 7.66 (d, 2H),
7.62 (d, 0.5H), 7.49 (d, 0.5H), 7.33-7.30 (m, 6H), 7.03 (d, 1
H), 6.76 (d, 2H), 4.07 (s, 3H), 3.73 (s, 8H), 3.48 (s, 2H), 3.0
0 (s, 2H), 2.50-2.45 (bd, 8H) Example _{55 (DMSO-d 6) δ} : 10.05 (s, 0.5H), 9.97 (s, 0.5H), 9.93 (s, 1H),
8.31 (s, 0.5H), 8.03 (s, 0.5H), 7.82 (d, 0.5H), 7.79 (d, 0.5
H), 7.65 (m, 2.5H), 7.51 (d, 0.5H), 7.31 (s, 1H), 7.07 (s, 6.5
H), 7.03 (s, 6.5H), 6.75 (d, 2H), 4.08 (s, 3H), 3.73 (s, 8H),
3.38 (m, 2H), 3.10 (m, 4H), 2.73 (m, 4H) Example _{56 (DMSO-d 6) δ} : 11.71 (s, 1H), 10.20 (s, 1H), 8.29 (s, 1H ), 7.9
9 (d, 1H), 7.77 (d, 1H), 7.73 (s, 2H), 7.67 (s, 1H), 7.65 (d, 2
H), 7.36 (s, 1H ), 6.77 (d, 2H), 4.15 (s, 3H), 3.74 (s, 8H) Example _{57 (DMSO-d 6) δ} : 10.05 (s, 1H), 10.04 ( s, 0.6H), 9.96 (s, 0.4
H), 8.31 (s, 0.6H), 8.02 (s, 0.4H), 7.80 (m, 1H), 7.64 (bs, 3.
4H), 7.50 (d, 0.6H), 7.27 (s, 1H), 7.16 (s, 1H), 6.88 (m, 2H),
6.75 (d, 2H), 4.29 (t, 2H), 4.08 (s, 3H), 3.73 (s, 8H), 2.77
(t, 2H)

Example 58 (Reaction 1) (DMSO-d ₆ ) δ: 10.42 (bs, 1H), 8.62 (t, 1H), 7.89 (d, 1H), 7.8
8 (d, 1H), 7.59 (t, 1H), 2.10 (s, 3H) Example 58 (Reaction _{2) (DMSO-d 6)} δ: 7.30 (m, 3H), 6.97 (m, 1H), 6.33 (bt, 1H), 3.09
(m, 2H), 1.18 (t, 3H) Example 58 (Reaction 3) (CDCl ₃ ) δ: 7.53-7.46 (m, 2H), 7.30 (t, 1H), 7.00 (dd, 1H),
3.84 (t, 2H), 3.56-3.45 (m, 4H), 1.93 (bs, 1H), 1.20 (t, 3H) Example 58 (Reaction _{4) (CDCl 3) δ:} 8.21 (s, 1H), 8.15 -8.03 (m, 2H), 7.67 (t, 1H), 3.
82 (s, 4H), 3.63 (m, 2H), 1.30 (t, 3H) Example 58 (Reaction _{5) (CDCl 3) δ:} 10.32 (bs, 2H), 7.25 (t, 1H), 6.74-6.67 (m, 2H),
6.62 (d, 1H), 3.82-3.60 (m, 4H), 3.42 (q, 2H), 1.09 (t, 3H) Example 58 (Reaction _{6) (DMSO-d 6)} δ: 10.10 (s, 0.5H ), 10.01 (s, 0.5H), 8.41-6.44
(m, 9H), 4.21 (s, 3H), 3.74 (t, 2H), 3.61 (t, 2H), 3.46-3.38
(m, 2H), 1.12 (t, 3H) Example 58 (Reaction 7) (DMSO-d ₆ ) δ: 10.44 (s, 1H), 10.06 (s, 0.5H), 9.97 (s, 0.5
H), 8.35-6.33 (m, 12H), 4.12 (s, 3H), 3.75 (t, 2H), 3.61 (t, 2
H), 3.49-3.39 (m, 2H ), 1.13 (t, 3H) Example _{59 (DMSO-d 6) δ} : 10.02 (s, 0.5H), 9.96 (s, 0.5H), 9.92 (s, 1H ),
8.33 (s, 0.5H), 8.03 (s, 0.5H), 7.82 (t, 0.5H), 7.79 (d, 0.5
H), 7.66 (d, 2H), 7.63 (d, 0.5H), 7.52 (d, 0.5H), 7.36 (s, 1
H), 7.07 (dd, 0.5H), 6.97-6.93 (m, 2H), 6.76 (d, 2H), 6.15 (d
d, 1H), 4.11 (s, 3H), 3.73 (s, 8H)

Example 60 (DMSO-d ₆ ) δ: 9.97 (s, 2H), 8.19 (bs, 1H), 7.80 (d, 1H), 7.64
(d, 2H), 7.60 (m, 1H), 7.28 (s, 1H), 6.93 (s, 1H), 6.76 (d, 2
H), 4.08 (s, 3H), 3.73 (s, 8H), 2.75 (t, 2H), 2.56 (t, 2H), 2.0
9 (s, 3H) Example _{61 (DMSO-d 6) δ} : 10.33 (s, 0.5H), 10.27 (s, 0.5H), 9.99 (s, 1
H), 8.34 (bs, 1H), 8.04 (bs, 1H), 7.81 (d, 1H), 7.73 (d, 1H),
7.53 (bd, 1H), 7.36 (d, 1H), 7.28 (s, 1H + 1H), 6.93 (bs, 1H),
4.08 (s, 1H), 3.61 (t, 4H), 3.50 (t, 4H), 2.75 (t, 2H) 2.56 (t,
2H), 2.09 (s, 3H) Example 62 (Reaction 1) (CDCl ₃ ) δ: 7.95 to 7.86 (m, 2H), 6.95 to 6.88 (m, 1H), 3.91 (bs,
4H), 3.74-3.69 (m, 4H ), 2.87 (bs, 2H) Example 62 (Reaction _{2) (CDCl 3) δ:} 8.01-7.91 (m, 2H), 6.88 (t, 1H), 3.84 (t , 4H), 3.
68 (t, 4H) Example 62 (Reaction _{3) (DMSO-d 6)} δ: 10.29 (bs, 1H), 8.40-7.11 (m, 8H), 4.21 (s, 3
H), 3.66 (t, 4H), 3.55 (t, 4H) Example 62 (Reaction 4) (DMSO-d ₆ ) δ: 10.29 (s, 0.5 H), 10.22 (s, 0.5 H), 9.99 (s , 1
H), 8.33-6.92 (m, 12H), 4.08 (s, 3H), 3.66 (t, 4H), 3.55 (t, 4
H), 2.75 (t, 2H ), 2.56 (t, 2H), 2.09 (s, 3H) Example _{63 (DMSO-d 6) δ} : 9.98 (s, 1H), 9.64 (s, 0.5H), 9.58 (s, 0.5H),
8.30 (s, 0.5H), 8.03 (s, 0.5H), 7.83-7.78 (m, 1H), 7.65 (d,
0.5H), 7.50 (d, 0.5H), 7.27 (s, 1H), 7.15 (s, 0.5H), 7.12 (s,
0.5H), 6.93 (dd, 1H), 6.66 (s, 1H), 6.61 (d, 1H), 4.08 (s, 3
H), 3.75 (s, 8H), 2.75 (t, 2H), 2.56 (t, 2H), 2.21 (s, 3H), 2.0
9 (s, 3H) Example _{64 (DMSO-d 6) δ} : 9.98 (s, 1H), 9.64 (s, 0.5H), 9.58 (s, 0.5H),
8.61 (s, 0.5H), 8.30 (s, 0.5H), 8.03 (s, 0.5H), 7.96 (m1H),
7.65 (d, 1H), 7.50 (d, 1H), 7.35 (dd, 0.5H), 7.27 (s, 1H), 6.6
6 (s, 1H), 6.61 (d, 1H), 4.08 (s, 3H), 3.74 (s, 8H), 2.75 (t, 2
H), 2.56 (t, 2H), 2.21 (s, 3H), 2.09 (s, 3H)

Example 65 (Reaction 1) (CDCl ₃ ) δ: 8.34 (d, 1H), 8.29 (dd, 1H), 7.53 (d, 1H), 4.69
(t, 2H), 3.51 ( m, 4H), 3.41 (m, 4H) Example 65 (Reaction _{2) (CDCl 3) δ:} 8.55 (d, 1H), 8.36 (dd, 1H), 7.50 (d, 1H), 3.61
(m, 8H) Example 65 (Reaction 3) (DMSO-d ₆ ) δ: 10.58 (bs, 1H), 10.51 (bs, 1H), 8.45-7.57 (8
H), 4.21 (s, 3H ), 3.60 (t, 2H), 3.37 (t, 4H) Example 65 (Reaction _{4) (DMSO-d 6)} δ: 10.51 (s, 0.5H), 10.44 (s, 0.5H), 9.99 (s, 1
H), 8.37-6.93 (8H), 4.08 (s, 3H), 3.60 (t, 4H), 3.37 (t, 4H),
2.76 (t, 2H), 2.57 (t, 2H), 2.10 (s, 3H) Example 66 (Reaction _{1) (CDCl 3) δ:} 8.45 (d, 1H), 6.56 (d, 1H), 5.02 (t , 2H), 4.14 (b
s, 4H), 3.77 (m , 4H) Example 66 (Reaction _{2) (CDCl 3) δ:} 8.49 (d, 1H), 6.29 (d, 1H), 4.40 (t, 4H), 3.87 (t,
4H) Example 66 (Reaction 3) (DMSO-d ₆ ) δ: 10.46 (s, 0.5H), 10.40 (s, 0.5H), 8.45-7.51
(m, 6H), 6.52 ( d, 1H), 4.21 (s, 3H), 4.13 (t, 4H), 3.88 (t, 4H) Example 66 (Reaction _{4) (DMSO-d 6)} δ: 10.39 ( s, 0.5H), 10.35 (s, 0.5H), 9.99 (s, 1
H), 8.36 (s, 0.5H), 8.09 (s, 0.5H), 7.87-7.82 (m, 1H), 7.69
(d, 0.5H), 7.55-7.50 (m, 1.5H), 7.28 (s, 1H), 6.95 (dd, 1H),
6.52 (d, 1H), 4.13 (t, 4H), 4.09 (s, 3H), 3.88 (t, 4H), 2.76
(t, 2H), 2.57 ( t, 2H), 2.09 (s, 3H) Example _{67 (DMSO-d 6) δ} : 10.30 (s, 1H), 9.99 (s, 1H), 8.19 (bs, 1H) , 7.8
2 (d, 1H), 7.64 (d, 2H, 8.8), 7.58 (m, 1H), 7.29 (s, 1H), 6.96
(s, 1H), 6.76 (d, 2H), 4.09 (s, 3H), 3.73 (s, 8H), 3.54 (t, 2
H), 2.95 (s, 6H), 2.93 (m, 2H)

Example 68 (DMSO-d ₆ ) δ: 10.32 (s, 1H), 10.26 (bs, 1H), 8.33-6.97 (m, 8
H), 4.09 (s, 3H), 3.66 (t, 4H), 3.57-3.51 (m, 6H), 2.95-2.90
(m, 8H) Example _{69 (DMSO-d 6) δ} : 10.29 (s, 1H), 9.61 (bs, 1H), 8.23 (bs, 1H), 7.
58 (bs, 1H), 7.52 (d, 1H), 7.28 (s, 1H), 7.14 (d, 1H), 6.95 (s,
1H), 6.65 (s, 1H), 6.61 (d, 1H), 4.10 (s, 3H), 3.74 (s, 8H), 3.
54 (t, 2H), 2.95 (s, 6H), 2.93 (t, 2H), 2.21 (s, 3H) Example _{70 (DMSO-d 6) δ} : 10.29 (s, 1H), 9.64 (s, 0.5 H), 9.58 (s, 0.5H),
8.30-6.55 (8H), 4.09 (s, 3H), 3.74 (s, 8H), 3.54 (t, 2H), 2.9
5 (s, 6H), 2.93 (2H), 2.21 (s, 3H) Example _{71 (DMSO-d 6) δ} : 10.53 (s, 1H), 10.49 (s, 1H), 8.28 (1H + 1H), 8.
13 (dd, 1H), 7.87 (dd, 1H), 7.70 (d, 1H), 7.64 (d, 1H), 7.34
(d, 1H), 7.02 (d, 1H), 4.10 (s, 3H), 3.60 (t, 4H), 3.55 (t, 2
H), 3.37 (t, 4H ), 2.96 (s, 6H) Example _{72 (DMSO-d 6) δ} : 10.54 (s, 1H), 10.43 (bs, 1H), 8.26 (bs, 1H),
7.90 (d, 1H), 7.65 (d, 1H), 7.52 (d, 1H), 7.34 (s, 1H), 7.04
(s, 1H), 6.52 (d, 1H), 4.13 (t, 4H), 4.10 (s, 3H), 3.88 (t, 4
H), 3.56 (t, 2H ), 2.96 (6H + 2H) Example _{73 (DMSO-d 6) δ} : 10.37 (s, 1H), 10.33 (bs, 1H), 8.23 (bs, 1H),
8.04 (d, 1H), 7.85 (dd, 1H), 7.73 (dd, 1H), 7.63 (d, 1H), 7.37
(d, 1H), 7.33 (d, 1H), 7.00 (d, 1H), 4.09 (s, 3H), 3.61 (t, 4
H), 3.60 (m, 4H ), 3.51 (m, 6H), 2.95 (s, 6H), 2.94 (2H) Example _{74 (DMSO-d 6) δ} : 10.32 (s, 1H), 10.26 (bs, 1H), 7.83-6.97 (m, 8
H), 4.09 (s, 3H), 3.66 (t, 4H), 3.55-3.35 (m, 6H), 2.94-2.90
(m, 8H)

Example 75 (DMSO-d ₆ ) δ: 10.56 (s, 1H), 9.69 (s, 1H), 8.21 (s, 1H), 7.87
(d, 1H), 7.63 (d, 1H), 7.36 (s, 1H), 7.14 (d, 1H), 6.66 (s, 1
H), 6.62 (d, 1H), 4.09 (s, 3H), 3.75 (s, 8H), 3.56 (t, 2H), 2.9
6 (2H), 2.21 (s , 3H) Example _{76 (DMSO-d 6) δ} : 10.50 (s, 1H), 9.66 (s, 0.5H), 9.59 (s, 0.5H),
8.30 (s, 0.5H), 8.05 (s, 0.5H), 7.83-7.80 (m, 1H), 7.65 (d,
0.5H), 7.49 (d, 0.5H), 7.23 (s, 1H), 7.13 (d, 1H), 6.99 (d, 1
H), 6.66 (s, 1H), 6.61 (d, 1H), 4.09 (s, 3H), 3.74 (s, 8H), 3.5
5 (t, 2H), 2.96 (s, 6H), 2.96 (2H), 2.21 (s, 3H) Example _{77 NMR (DMSO-d 6)} δ: 10.07 (s, 1H), 9.98 (bs, 1H) , 8.32-7.63
(m, 5H), 7.29 (s, 1H), 6.95 (s, 1H), 6.72 (d, 2H), 4.08 (s, 3
H), 3.73 (s, 8H ), 3.10 (s, 2H), 2.17 (s, 3H) Example _{78 NMR (DMSO-d 6)} δ: 10.08 (s, 1H), 10.03 (s, 0.5H), 9.96 (s, 0.
5H), 8.33 (s, 0.5H), 8.03 (s, 0.5H), 7.85-7.79 (m, 1H), 7.72
-7.51 (m, 3H), 7.31 (s, 1H), 7.11 (d, 1H), 6.78-6.71 (m, 2H),
4.58 (s, 2H), 4.10 (s, 3H), 3.73 (s, 8H), 2.97 (s, 6H) Example _{79 NMR (DMSO-d 6)} δ: 10.26 (s, 1H), 10.02 (s, 0.5H), 9.96 (s, 0.
5H), 8.50 (d, 1H), 8.32 (s, 0.5H), 8.01 (s, 0.5H), 7.83-7.25
(m, 8H), 6.95 (d, 1H), 6.76 (d, 2H), 4.07 (s, 3H), 3.80 (s, 2
H), 3.73 (s, 8H ) Example _{80 NMR (DMSO-d 6)} δ: 10.27 (s, 1H), 10.01 (bs, 0.5H), 9.96 (bs,
0.5H), 8.52 (d, 2H), 8.32 (bs, 0.5H), 8.02 (bs, 0.5H), 7.81
(bd, 1H), 7.64 (bd, 2H + 0.5H), 7.51 (bd, 0.5H) .7.35 (d, 2H),
7.27 (s, 1H), 6.94 (bs, 1H), 6.76 (d, 2H), 4.07 (s, 3H), 3.73
(s, 8H), 3.66 ( s, 2H) Example _{81 NMR (DMSO-d 6)} δ: 10.25 (s, 1H), 10.02 (s, 0.5H), 9.96 (s, 0.
5H), 8.54 (dd, 1H), 8.47 (dd, 1H), 8.32 (s, 0.5H), 8.02 (s, 0.
5H), 7.83-7.72 (m, 2H), 7.66 (d, 2H), 7.63 (d, 0.5H), 7.51
(d, 0.5H), 7.36, (dd, 1H), 7.27 (s, 1H), 6.95 (dd, 1H), 6.76
(d, 2H), 4.07 (s, 3H), 3.73 (s, 8H), 3.65 (s, 2H)

Example 82 NMR (DMSO-d ₆ ) δ: 10.66 (s, 1H), 10.01 (s, 1H), 9.03 (s, 1H),
8.93 (d, 1H), 8.55 (d, 1H), 8.13 (s, 0.5H), 8.11 (d, 1H) .7.64
(d, 2H), 7.63 (bs, 1H), 7.30 (d, 1H), 7.00 (s, 1H), 6.76 (d, 2
H), 4.37 (s, 3H ), 4.08 (s, 3H), 3.99 (s, 2H), 3.73 (s, 8H) Example _{83 NMR (DMSO-d 6)} δ: 10.36 (s, 1H), 10.08 (s, 1H), 8.22 (bs, 1
H), 7.87 (d, 1H), 7.68 (d, 2H), 7.65 (d, 1H), 7.37 (s, 1H), 7.0
4 (s, 1H), 6.76 (d, 2H), 4.09 (s, 3H), 3.73 (s, 8H), 3.45-3.32
(m, 2H), 3.10 ( s, 9H), 2.40 (t, 2H), 2.05 (m, 2H) Example _{84 NMR (DMSO-d 6)} δ: 9.97 (s, 1H), 8.49 (bs, 1H ), 8.12-7.93 (m,
1H), 7.71-7.38 (m, 2H), 7.26 (s, 1H), 7.10 (d, 2H, J = 8.8), 6.
91 (s, 1H), 6.69 (d, 2H, J = 8.8), 4.06 (s, 3H), 3.70 (s, 8H), 3.
42-3.33 (m, 4H), 2.75 (t, 2H), 2.56 (t, 2H), 2.09 (s, 3H) Example _{85 NMR (DMSO-d 6)} δ: 10.31 (s, 0.7H), 9.98 (s, 0.3H), 8.47 (m, 1
H), 8.16 (s, 0.7H), 7.93 (s, 0.3H), 7.73-7.58 (m, 1.3H), 7.4
6 (d, 0.7H), 7.27 (s, 1H), 7.10 (d, 2H), 6.93 (d, 1H), 6.69 (d,
2H), 4.08 (s, 3H), 3.70 (s, 8H), 3.53 (t, 2H), 3.42 (m, 2H), 2.
94 (s, 8H), 2.75 (m, 2H) Example 86 (Reaction _{1) NMR (CDCl 3) δ} : 7.98 (d, 1H), 6.66 (m, 2H), 4.84 (d, 2H), 3.56
(s, 8H), 2.55 ( s, 3H) Example 86 (Reaction _{2) NMR (CDCl 3) δ} : 8.11 (d, 1H), 6.55 (dd, 1H), 6.47 (d, 1H), 3.8
4 (t, 4H), 3.68 (t, 4H), 2.66 (s, 3H) Example 86 (Reaction _{3) NMR (DMSO-d 6} ) δ: 9.92 (s, 1H), 8.30 (d, 1H), 8.29 (s, 1H), 7.
91 (d, 1H), 7.70 (d, 1H), 7.64 (d, 1H), 7.14 (d, 1H), 6.66 (s, 1
H), 6.61 (d, 1H ), 4.21 (s, 3H), 3.75 (s, 8H), 2.21 (s, 3H) Example 86 (Reaction _{4) NMR (DMSO-d 6} ) δ: 10.52 (s, 1H), 9.82 (s, 1H), 8.28 (s, 1H),
7.99 (d, 1H), 7.75 (d ,, 1H), 7.64 (t, 1H), 7.48 (s, 1H), 7.36
(bs, 4H), 7.18 (s, 1H), 7.14 (d, 1H), 6.66 (s, 1H), 6.62 (d, 1
H), 4.10 (s, 3H ), 4.06 (d, 2H), 3.75 (s, 8H), 2.21 (s, 3H) Example _{87 NMR (DMSO-d 6)} δ: 10.27 (s, 1H), 9.78 (s, 1H), 8.25 (s, 1H),
7.96 (d, 1H), 7.71 (d, 1H), 7.44 (d, 1H), 7.14 (d, 1H), 7.10
(s, 1H), 6.67 (s, 1H), 6.62 (d, 1H), 4.08 (s, 3H), 3.75 (s, 8
H), 3.06 (m, 2H), 2.75 (m, 6H), 2.40 (t, 2H), 2.21 (s, 3H), 1.9
7 (m, 2H)

Example 88 NMR (DMSO-d ₆ ) δ: 10.41 (s, 1H), 10.01 (s, 0.5H), 9.95 (s, 0.
5H), 8.33 (s, 1H), 8.03 (s, 1H), 7.90 (d, 1H), 7.80 (t, 1H), 7.
67-7.61 (m, 3H), 7.38 (s, 1H), 7.24 (d, 1H), 7.14-7.11 (m, 1
H), 6.76 (d, 2H ), 6.68 (dd, 1H), 3.4.11 (s, 3H), 3.73 (s, 8H) Example 89 (Reaction _{1) NMR (DMSO-d 6} ) δ: 8.02 ( d, 2H), 6.79 (d, 2H), 4.86 (t, 1H), 3.
58 (t, 2H), 3.51 (m, 4H), 1.13 (t, 3H) Example 89 (Reaction _{3) NMR (DMSO-d 6} ) δ: 7.24 (d, 2H), 6.89 (d, 2H), 3.79 (m, 4H), 3.
42 (q, 2H), 1.07 (t, 3H) Example 89 (Reaction _{4) NMR (DMSO-d 6} ) δ: 10.03 (s, 0.5H), 9.96 (s, 0.5H), 8.60-7.5
8 (7H), 6.71 (d, 2H), 4.21 (s, 3H), 3.72 (bm, 2H), 3.61 (bm, 2
H), 3.43 (q, 2H ), 1.10 (t, 3H) Example 89 (Reaction _{6) NMR (CDCl 3) δ} : 7.47 (d, 2H), 6.65 (d, 2H), 3.63 (m, 4H) , 3.48
(q, 2H), 1.21 ( t, 3H) Example 89 (Reaction _{7) NMR (CDCl 3) δ} : 7.97 (d, 2H), 6.67 (d, 2H), 3.63 (m, 4H), 3.51
(q, 2H), 1.22 ( t, 3H) Example 89 (Reaction _{8) NMR (DMSO-d 6} ) δ: 10.02 (s, 0.5H), 9.96 (s, 0.5H), 9.92 (s, 1
H), 8.33 (s, 0.5H), 8.03 (s, 0.5H), 7.81 (t, 1H), 7.64 (t, 2
H), 7.52 (d, 0.5H), 7.36 (s, 1H), 7.07 (d, 0.5H), 6.95 (d, 1
H), 6.76 (d, 1H), 6.15 (dd, 1H), 4.11 (s, 3H), 3.73 (s, 8H)

Example 90 NMR (DMSO-d ₆ ) δ: 10.56 (s, 1H), 10.39 (bs, 1H), 8.31 (s, 1H)
H), 8.03 (d, 1H), 7.79 (d, 3H), 7.67 (t, 1H), 7.52 (s, 1H), 7.
38 (bs, 4H), 7.22 (s, 1H), 7.10 (bd, 2H), 4.11 (s, 3H), 4.07
(d, 2H), 3.73 ( s, 4H), 3.49 (bm, 2H), 1.08 (t, 3H) Example _{91 NMR (DMSO-d 6)} δ: 10.37 (s, 1H), 10.02 (s, 1H ), 7.83-6.43
(m, 14H), 4.09 (s, 3H), 4.04 (d, 2H), 3.74 (t, 2H), 3.61 (t, 2
H), 1.12 (t, 3H) Example 92 (Reaction 1) NMR (CDCl ₃ ) δ: 7.86 (dd, 1H), 7.67 (d, 1H), 7.00 (d,
1H), 3.93 (s, 3H ), 3.80-3.54 (m, 8H) Example 92 (Reaction _{2) NMR (CDCl 3) δ} : 7.85 (dd, 1H), 7.74 (d, 1H), 6.90 (d, 1H), 4.0
3 (s, 3H), 3.73 (m, 4H), 3.62 (m, 4H) Example 92 (Reaction _{3) NMR (DMSO-d 6} ) δ: 10.19 (s, 1H), 8.31 (s, 2H), 7.88 (d, 1H),
7.69 (d, 1H), 7.59 (s, 2H), 7.38 (dd, 1H), 7.03 (d, 1H), 4.21
(s, 3H), 3.82 ( s, 3H), 3.58 (t, 4H), 3.45 (t, 4H) Example 92 (Reaction _{4) NMR (DMSO-d 6} ) δ: 10.54 (s, 1H), 10.38 (s, 1H), 8.31 (s, 1H),
8.03 (d, 1H), 7.79 (d, 1H), 7.64 (t, 1H), 7.60 (d, 1H), 7.51
(s, 1H), 7.39 (dd, 1H), 7.37 (bs, 4H), 7.21 (s, 1H), 7.05 (d, 1
H), 4.11 (s, 3H), 4.06 (d, 2H), 3.83 (s, 3H), 3.59 (t, 4H), 3.4
7 (t, 4H) Example 93 (Reaction _{1) NMR (DMSO-d 6} ) δ: 7.98 (d, 1H), 6.68 (m, 2H), 4.84 (t, 2H), 3.
56 (m, 8H), 2.55 (s, 3H) Example 93 (Reaction _{2) NMR (CDCl 3) δ} : 8.11 (d, 1H), 6.55 (dd, 1H), 6.47 (d, 1H), 3.8
4 (t, 4H), 3.68 (t, 4H), 1.58 (s, 3H) Example 93 (Reaction _{3) NMR (DMSO-d 6} ) δ: 9.71 (s, 0.5H), 9.64 (s, 0.5H ), 8.38 (s, 0.
5H), 8.31 (d, 1H), 8.11 (s, 0.5H), 7.91-7.57 (3H), 7.14 (d, 1
H), 6.67 (d, 1H), 6.61 (d, 1H), 4.21 (s, 3H), 3.75 (s, 8H), 2.2
1 (s, 3H) Example 93 (Reaction _{4) NMR (DMSO-d 6} ) δ: 10.58 (s, 1H), 9.89 (s, 1H), 8.31 (s, 1H),
8.05 (d, 1H), 7.79 (d ,, 1H), 7.67 (t, 1H), 7.54 (d, 1H), 7.38
(bs, 4H), 7.23 (d, 1H), 7.14 (d, 1H), 6.67 (s, 1H), 6.62 (d, 1
H), 4.11 (s, 3H ), 3.75 (s, 8H), 2.21 (s, 3H) Example _{94 NMR (DMSO-d 6)} δ: 10.23 (s, 1H), 10.06 (s, 0.4H), 9.98 (s, 0.
6H), 8.31 (s, 0.6H), 8.04 (s, 0.4H), 7.81 (m, 1H), 7.65 (m, 2.
4H), 7.51 (d, 0.6H), 7.30 (s, 1H), 6.99 (s, 0.4H), 6.96 (s, 0.
6H), 6.75 (d, 2H), 4.08 (s, 3H), 3.73 (s, 8H), 3.05 (m, 2H), 2.
74 (s, 6H), 2.40 (t, 2H), 1.99 (m, 2H)

Example 95 (Reaction 1) NMR (DMSO-d ₆ ) δ: 10.02 (s, 0.5 H), 9.95 (s, 0.5 H), 9.90 (s, 1
H), 8.31 (s, 0.5H), 8.01 (s, 0.5H), 7.80 (t, 1H), 7.65 (d, 2
H), 7.62 (d, 0.5H), 7.50 (d, 0.5H), 7.40-7.28 (m, 7H), 7.27
(s, 1H), 6.95 (s, 0.5H), 6.90 (s, 0.5H), 6.75 (d, 2H), 5.02
(s, 2H), 4.07 (s, 3H), 3.73 (s, 8H), 3.04 (q, 2H), 2.28 (t, 2
H), 1.72 (m, 2H ) Example 95 (Reaction _{2) NMR (DMSO-d 6} ) δ: 10.33 (s, 1H), 10.22 (s, 1H), 8.28 (s, 1H),
8.02-7.96 (m, 4H), 7.76 (d, 1H), 7.64 (d, 2H), 7.50 (s, 1H),
7.16 (s, 1H), 6.77 (d, 2H), 4.08 (s, 3H), 3.74 (s, 8H), 2.84
(q, 2H), 2.42 ( t, 2H), 1.88 (m, 2H) Example _{96 NMR (DMSO-d 6)} δ: 9.96 (bs, 1H), 8.56 (s, 1H), 8.30 (bs, 0.5
H), 7.98 (bs, 0.5H), 7.79 (d, 1H), 7.63 (d, 2H), 7.49 (m, 1H),
7.09 (s, 1H), 6.92 (s, 1H), 6.76 (d, 2H), 4.57 (s, 3H), 3.73
(s, 8H), 3.60 ( m, 4H), 3.40 (m, 4H) Example 97 (Reaction _{1) NMR (DMSO-d 6} ) δ: 10.30-9.80 (bs, 3H), 7.27 (t, 1H) , 6.76
(d, 1H), 6.73 ( s, 1H), 6.63 (d, 1H), 3.74 (s, 8H) Example 97 (Reaction _{2) NMR (DMSO-d 6} ) δ: 10.15 (s, 0.3H), 10.05 (s, 0.7H), 8.41 (s,
0.7H), 8.31 (s, 1H), 8.09 (s, 0.3H), 7.91-7.79 (m, 1H), 7.64
-7.59 (m, 2H), 7.35-7.14 (m, 3H), 6.49 (d, 1H), 4.21 (s, 3H),
3.75 (bs, 8H) Example 97 (Reaction 3) NMR (DMSO-d ₆ ) δ: 10.48 (s, 1H), 10.22 (s, 1H), 8.26 (s, 1H),
7.95 (d, 1H), 7.73 (d, 1H), 7.64 (t, 1H), 7.45 (s, 1H), 7.50-
7.14 (m, 4H), 7.30 (d, 1H), 7.23 (s, 1H), 7.17 (t, 1H), 7.14
(s, 1H), 6.51 ( d, 1H), 4.10 (s, 3H), 4.02 (d, 2H), 3.76 (m, 8H) Example _{98 NMR (DMSO-d 6)} δ: 10.60 (s, 1H ), 10.10 (s, 1H), 8.22 (s, 1H),
7.87 (d, 1H), 7.65 (d, 2H), 7.63 (s, 1H), 7.35 (s, 1H), 7.04
(s, 1H), 6.76 (d, 2H), 4.09 (s, 3H), 3.73 (s, 8H), 3.56 (t, 2
H), 2.96 (s + t, 8H)

Test Example 1 To examine the binding of these compounds to DNA, Tm
(Melting point) was measured. That is, the difference in Tm between when a compound was added to a citrate buffer of a mutual copolymer of A (adenine) and T (thymine) of DNA and when no compound was added (△
Tm) was measured. A Hitachi U-3200 type spectrophotometer was used for measurement, and a Hitachi SPR-10 type was used for temperature control. Table 5 [Table 237] shows the results of the representative examples. As a result, the pyrrolylbenzimidazole skeleton of the present invention or the compound having the same as a partial structure is represented by D
It was proved to have the property of binding to NA.

[0418]

[Table 237]

Test Example 2 The antitumor activity of these compounds will be described. Table-6
[Table 238] shows the antitumor activity of representative compounds. The method is the measurement of an in vitro tumor cell growth inhibitory effect. Mouse B16 melanoma cells were seeded on a 96-well culture plate, one day later, the drug was added, and the cells were further cultured at 37 ° C. in 5% CO _{2 for} 3 days. Cancer Res. 50% according to the method shown in 1988, 48, 589-601.
The concentration of the drug required to cause the growth inhibition of E. coli was determined. As a comparative example, the results of distamycin are also shown.

[0420]

[Table 238]

Test Example 3 The compound of the present invention was examined for its antitumor activity in vivo. P388 leukemia cells (10 ⁶ cells / individual) were implanted intraperitoneally into female CDF ₁ mice,
After 5 and 9 days, the compound (1, 3 or 10 mg / k
g) was administered intraperitoneally. As a blank test, 10 mL / kg of 5% glucose was intraperitoneally administered to mice. Using the blank test group as a control, the effect of the drug was indicated by ILS represented by the following formula [Equation 1].

[0422]

(Equation 1) When the test animals survived for 8 weeks, the number of survivors was shown without calculating ILS. The results are shown in Table 7 [Table 239].

[0423]

[Table 239] The numbers in parentheses in the table indicate the administered drug concentrations when the results are shown.

Test Example 4 Colon26 mouse colon cancer cells 1 × 10 ⁷ cells / mL HBS
A cell suspension having a concentration of S (Hanks' Balanced Salt Solution) was prepared. 0.1 mL of this cell suspension is added to a female CD
Were transplanted into F ₁ mice flank subcutaneously. After weighing the mice the day after tumor implantation, the compound solution (5% Twee
A 5% glucose solution containing n80) was administered into the tail vein of the mouse. Fifteen days after tumor implantation, tumors were excised and weighed. The ratio of the average tumor weight of the experimental group when the average tumor weight of the control group to which no drug was administered was taken as 100% was calculated as a T / C value. The results are shown in the following Table-8 [Table 240]. T / C is shown corresponding to the compound number.
The concentration of the drug when it was shown is shown.

[0425]

[Table 240]

[0426]

The compounds of the present invention act on DNA as is clear from the examples, and are useful as anticancer agents.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/496 A61K 31/496 31/541 31/541 A61P 35/00 A61P 35/00 C07D 401/14 C07D 401/14 403 / 14 403/14 405/04 405/04 405/14 405/14 409/04 409/04 413/14 413/14 (72) Inventor Kazue Etsuji 1900-1, Togo, Togo, Mobara-shi, Chiba In-house (72) Inventor Daiji Iwata 1900 Togo, Togo, Mobara City, Chiba Prefecture Inside (72) Inventor Kimiko Takezawa 1900-1, Togo, Togo, Mobara City, Chiba Prefecture Examination in Mitsui East Pressure Chemical Co., Ltd. Government Tamotsu Tominaga (56) References JP-B-49-14231 (JP, B1) UK Patent 1,094,903 (GB, B) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 403/04 C07D 401 / 14 C07D 403/14 C07D 405/04 C07D 405/14 C07D 409/04 C07D 413/14 CA (ST ) REGISTRY (STN)

Claims (13)

(57) [Claims] 1. A compound represented by the following formula (1) [Formula 1] or a pharmacologically acceptable salt thereof. Embedded image [Wherein, X, Y and Z are each independently CH, N,
NH, N (CH ₂ ) _t CH ₃ , S, O (however, X, Y,
Z does not mean the same thing at the same time;
M and n each represent an integer of 0 to 5; R ₁ and R ₂ each independently represent a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, or a haloalkyl having 1 to 10 carbon atoms; Group, C1-C10 alkoxy group, oxoethylene group, ethyleneimino group, hydroxy group, C1-C10
Alkylthio group, amino group which may be substituted, ammonium group which may be substituted, sulfonium group which may be substituted, phenyl group which may be substituted, 5-membered hetero ring which may be substituted Group, optionally substituted hetero 6-membered ring group, optionally substituted hetero-fused ring group, optionally substituted amidino group, optionally substituted guanidino group, amino acid residue or formula (2 ) [Chemical formula 2] Embedded image In the formula, R ₃ represents (CH ₂ ) _r , (CH ₂ ) _r O (provided that r is an integer of 0 to 5 and O is present closer to the phenyl group), and R ₄ is hydrogen , An alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a halogen atom, a trifluoromethyl group, a cyano group, an amidino group, a guanidino group, a carboxyl group or -COR ₇ (where R ₇ is 1 to 5 alkyl groups, an alkylamino group optionally substituted with a substituted amino group or an amino group optionally substituted with a phenyl group which may be substituted,
R ₅ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a halogen atom,-(CH
_{2) p N (R 8)} 2 or - (CH ₂₎ shows the _p NR ₈ R ₉ (Here, p is an integer of 0-5), when R ₄ and R ₅ are occupying a position Tonaria' Can form a ring, and R ₆ is a hydrogen atom, — (CH ₂ ) _p N (R ₈ ) ₂ or — (CH ₂ ) _p N
R ₈ R ₉ (however, in R ₅ and R ₆ , R ₈ is —CH ₂
CH ₂ W, R ₉ represents an alkyl group having 1 to 5 carbon atoms or a mesyl group, and W represents a halogen atom, a hydroxy group, a mesyloxy group, a tosyloxy group or —OCOR ₇ (R ₇ and p
Represents the above-mentioned meaning). ｝] 2. A 5-membered ring containing X, Y and Z is pyrrole,
The compound according to claim 1, wherein the compound is selected from any one of 1-methylpyrrole, imidazole, 1-methylimidazole, furan, and thiophene. 3. The compound according to claim 2, wherein R ₁ is a haloalkyl group having 1 to 10 carbon atoms or a group represented by the formula (2), or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 2, wherein R ₂ is a haloalkyl group having 1 to 10 carbon atoms or a group represented by the formula (2), or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 3, wherein R ₂ is a haloalkyl group having 1 to 10 carbon atoms or a group represented by the formula (2), or a pharmaceutically acceptable salt thereof. 6. An amino group wherein R ₂ may be substituted,
4. The compound according to claim 3, which is an optionally substituted guanidino group or an optionally substituted amidino group, or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 6, wherein R ₂ is an amino group, a guanidino group or an amidino group, or a pharmaceutically acceptable salt thereof. 8. An amino group wherein R ₁ is optionally substituted,
5. The compound according to claim 4, which is a guanidino group which may be substituted or an amidino group which may be substituted, or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 8, wherein R ₁ is an amino group, a guanidino group or an amidino group, or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 4, wherein R ₁ is an optionally substituted ammonium group or an optionally substituted sulfonium group, or a pharmaceutically acceptable salt thereof. 11. R ₁ is a trimethylammonium group, N
The compound according to claim 10, which is a -methylpicolyl group or a dimethylsulfonium group, or a pharmaceutically acceptable salt thereof. 12. The compound according to claim 4, wherein R ₁ is an alkylthio group having 1 to 10 carbon atoms, or a pharmacologically acceptable salt thereof. 13. The method as claimed in claim 1, wherein:
Or a pharmacologically acceptable salt thereof as an active ingredient
Anticancer agents contained as.