JP6175145B2 - Aryl amidine compounds and fungicides - Google Patents

Description

The present invention relates to arylamidine compounds and fungicides. More specifically, the present invention relates to a novel arylamidine compound that has excellent bactericidal activity, is excellent in safety, and can be advantageously synthesized industrially, and a bactericidal agent or plant containing the arylamidine compound as an active ingredient It relates to a disease control agent. The present invention also relates to an intermediate for producing the arylamidine compound.
This application includes Japanese Patent Application No. 2013-254973 filed in Japan on December 10, 2013, Japanese Patent Application No. 2014-084016 filed in Japan on April 15, 2014, and Japan on September 24, 2014. The priority is claimed based on Japanese Patent Application No. 2014-194454, and the contents thereof are incorporated herein.

  Patent documents 1, 2 or 3 state that certain arylamidine compounds have the effect of controlling fungi and plant diseases. And the antifungal agent and plant disease control agent etc. which contain this arylamidine compound as an active ingredient are proposed. Also disclosed are intermediates suitable for the synthesis of the arylamidine compounds.

WO2013 / 062024A1 WO2006 / 011499A1 WO2007 / 074868A1

  An object of the present invention is to provide a novel arylamidine compound that has excellent bactericidal activity, is excellent in safety, and can be advantageously synthesized industrially, and a bactericidal agent or plant disease control containing the arylamidine compound as an active ingredient Providing an agent, and providing an intermediate for producing the arylamidine compound.

The present invention includes the following aspects.
(1) A compound represented by the formula (I) or a salt thereof.

(In the formula (I),
Ar represents an unsubstituted or substituted divalent aromatic hydrocarbon residue, or an unsubstituted or substituted divalent heterocyclic compound residue,
Q is a single bond, unsubstituted or substituted phenylene, —CH═CH—, —C≡C—, —O—, —S—, —SO—, —SO ₂ —, or —N (R ⁹ )-is shown. R ⁹ is a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted group An alkoxycarbonyl group having an alkyl group, an unsubstituted or substituted aryloxy group, an unsubstituted or substituted amino group, an unsubstituted or substituted alkylsulfonyl group, an unsubstituted or substituted aryl A sulfonyl group, an unsubstituted or substituted heterocyclylsulfonyl group, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted heterocyclylcarbonyl Indicates a group.
X and Z are each independently an unsubstituted or substituted alkylene group, an unsubstituted or substituted alkenylene group, an unsubstituted or substituted alkynylene group, -T ^a -O-T ^b -, or ^{-T a -N (R 20) -T} b - indicate the. T ^a and T ^b each independently represent an unsubstituted or substituted alkylene group, and R ²⁰ represents a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted group. Having a heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted alkoxycarbonyl group, an unsubstituted or substituted aryloxy group, an unsubstituted or substituted group An amino group, an unsubstituted or substituted alkylsulfonyl group, an unsubstituted or substituted arylsulfonyl group, an unsubstituted or substituted heterocyclylsulfonyl group, an unsubstituted or substituted alkylcarbonyl group An unsubstituted or substituted arylcarbonyl group, Represents a heterocyclylcarbonyl group having unsubstituted or substituted.
Y is —C (═O) —NH—, —NH—C (═O) —, or Formula (Ia)

(In formula (Ia), A represents a single bond, —C (═O) —, or —SO ₂ —, and R ⁷ represents a hydrogen atom, an unsubstituted or substituted hydrocarbon group, or unsubstituted. Or a substituted or unsubstituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted aryloxy group, or an unsubstituted or substituted amino group. Indicate
W represents a single bond or —N (R ⁸ ) —. R ⁸ is a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted group An alkoxycarbonyl group having an alkyl group, an unsubstituted or substituted aryloxy group, an unsubstituted or substituted amino group, an unsubstituted or substituted alkylsulfonyl group, an unsubstituted or substituted aryl A sulfonyl group, an unsubstituted or substituted heterocyclylsulfonyl group, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted heterocyclylcarbonyl Indicates a group.
R ^{1 to} R ⁶ are each independently a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group. , Unsubstituted or substituted alkoxycarbonyl group, unsubstituted or substituted aryloxy group, unsubstituted or substituted amino group, unsubstituted or substituted alkylsulfonyl group, unsubstituted Or substituted arylsulfonyl group, unsubstituted or substituted heterocyclylsulfonyl group, unsubstituted or substituted alkylcarbonyl group, unsubstituted or substituted arylcarbonyl group, or unsubstituted Or a heterocyclylcarbonyl group having a substituent R ¹ and R ² , R ² and R ³ , R ⁴ and R ⁵ , or R ⁵ and R ⁶ may be bonded together to form a 4- to 8-membered ring. Any one of R ^{1 to} R ³ and Ar may be bonded together to form a 4- to 8-membered ring. )
(2) A compound represented by the formula (II) or a salt thereof.

(In the formula (II),
G represents a carbon atom or a nitrogen atom;
Q is a single bond, unsubstituted or substituted phenylene, —CH═CH—, —C≡C—, —O—, —S—, —SO—, —SO ₂ —, or —N (R ⁹ )-is shown. R ⁹ is a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted group An alkoxycarbonyl group having an alkyl group, an unsubstituted or substituted aryloxy group, an unsubstituted or substituted amino group, an unsubstituted or substituted alkylsulfonyl group, an unsubstituted or substituted aryl A sulfonyl group, an unsubstituted or substituted heterocyclylsulfonyl group, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted heterocyclylcarbonyl Indicates a group.
X and Z are each independently an unsubstituted or substituted alkylene group, an unsubstituted or substituted alkenylene group, an unsubstituted or substituted alkynylene group, -T ^a -O-T ^b -, or ^{-T a -N (R 20) -T} b - indicate the. T ^a and T ^b each independently represent an unsubstituted or substituted alkylene group, and R ²⁰ represents a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted group. Having a heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted alkoxycarbonyl group, an unsubstituted or substituted aryloxy group, an unsubstituted or substituted group An amino group, an unsubstituted or substituted alkylsulfonyl group, an unsubstituted or substituted arylsulfonyl group, an unsubstituted or substituted heterocyclylsulfonyl group, an unsubstituted or substituted alkylcarbonyl group An unsubstituted or substituted arylcarbonyl group, Represents a heterocyclylcarbonyl group having unsubstituted or substituted.
Y is —C (═O) —NH—, —NH—C (═O) —, or Formula (Ia)

(In formula (Ia), A represents a single bond, —C (═O) —, or —SO ₂ —, and R ⁷ represents a hydrogen atom, an unsubstituted or substituted hydrocarbon group, or unsubstituted. Or a substituted or unsubstituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted aryloxy group, or an unsubstituted or substituted amino group. The group shown by is shown.
W represents a single bond or —N (R ⁸ ) —. R ⁸ is a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted group An alkoxycarbonyl group having an alkyl group, an unsubstituted or substituted aryloxy group, an unsubstituted or substituted amino group, an unsubstituted or substituted alkylsulfonyl group, an unsubstituted or substituted aryl A sulfonyl group, an unsubstituted or substituted heterocyclylsulfonyl group, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted heterocyclylcarbonyl Indicates a group.
R ^{1 to} R ⁶ are each independently a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group. An unsubstituted or substituted alkoxycarbonyl group, an unsubstituted or substituted aryloxy group, an unsubstituted or substituted amino group, an unsubstituted or substituted alkylsulfonyl group, Substituted or substituted arylsulfonyl group, unsubstituted or substituted heterocyclylsulfonyl group, unsubstituted or substituted alkylcarbonyl group, unsubstituted or substituted arylcarbonyl group, or unsubstituted Or substituted heterocyclylcarbonyl group Show. R ¹ and R ² , R ² and R ³ , R ⁴ and R ⁵ , or R ⁵ and R ⁶ may be bonded together to form a 4- to 8-membered ring.
R ³⁰ is a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 6-10 aryl group, a 3-6 membered heterocyclyl group, a hydroxyl group, a C 1-6 alkoxy group, a C 6-10 aryloxy group, a carboxyl group, a halogeno group. group, Cl to 6 haloalkyl group, C6-10 haloaryl group, Cl to 6 haloalkoxy group, (the group represented by NH ₂₎ amino group, Cl to 6 alkyl substituted amino group, C6-10 arylamino group, C1 to 7 acylamino group, C1-6 alkoxycarbonylamino group, C1-6 alkylthio group, C6-10 arylthio group, heteroarylthio group, C7-11 aralkylthio group, C1-6 alkylsulfinyl group, C6-10 arylsulfinyl group, Heteroarylsulfinyl group, C7-11 aralkylsulfinyl group, C1-6 Alkylsulfonyl group, C6-10 arylsulfonyl group, heterocyclylsulfonyl group, a cyano group, a nitro group. R ^{1 to} R ³ and R ³⁰ may be bonded together to form a 4- to 8-membered ring.
p represents the number of R ³⁰ and is an integer of 0 to 4. )
(3) A bactericide containing as an active ingredient at least one selected from the compounds or salts thereof according to (1) or (2).
(4) A plant disease control agent comprising at least one selected from the compound according to (1) or (2) or a salt thereof.
(5) A compound represented by the formula (III-1).

(In the formula (III-1),
L represents a leaving group,
Q is a single bond, unsubstituted or substituted phenylene, —CH═CH—, —C≡C—, —O—, —S—, —SO—, —SO ₂ —, or —N (R ⁹ )-is shown.
R ⁹ is a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted group An alkoxycarbonyl group having an alkyl group, an unsubstituted or substituted aryloxy group, an unsubstituted or substituted amino group, an unsubstituted or substituted alkylsulfonyl group, an unsubstituted or substituted aryl A sulfonyl group, an unsubstituted or substituted heterocyclylsulfonyl group, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted heterocyclylcarbonyl Indicates a group.
Ar represents an unsubstituted or substituted divalent aromatic hydrocarbon residue, or an unsubstituted or substituted divalent heterocyclic compound residue,
X is an unsubstituted or substituted alkylene group, an unsubstituted or substituted alkenylene group, an unsubstituted or substituted alkynylene group, -T ^a -O-T ^b- , or -T ^a —N (R ²⁰ ) —T ^b —, wherein T ^a and T ^b each independently represents an unsubstituted or substituted alkylene group, and R ²⁰ represents a hydrogen atom, unsubstituted or substituted group. An unsubstituted or substituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted alkoxycarbonyl group, an unsubstituted or substituted group, Having an aryloxy group, unsubstituted or substituted amino group, unsubstituted or substituted alkylsulfonyl group, unsubstituted Or a substituted arylsulfonyl group, an unsubstituted or substituted heterocyclylsulfonyl group, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted Or the heterocyclyl carbonyl group which has a substituent is shown.
R ¹⁰ to R ¹² each independently represent a hydrogen atom or a t- butoxycarbonyl group. However, one or more of R ^{10 to} R ¹² are t-butoxycarbonyl groups. )
(6) A compound represented by the formula (III-2).

(In the formula (III-2),
Ar represents an unsubstituted or substituted divalent aromatic hydrocarbon residue, or an unsubstituted or substituted divalent heterocyclic compound residue,
Q is a single bond, unsubstituted or substituted phenylene, —CH═CH—, —C≡C—, —O—, —S—, —SO—, —SO ₂ —, or —N (R ⁹ )-is shown. R ⁹ is a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted group An alkoxycarbonyl group having an alkyl group, an unsubstituted or substituted aryloxy group, an unsubstituted or substituted amino group, an unsubstituted or substituted alkylsulfonyl group, an unsubstituted or substituted aryl A sulfonyl group, an unsubstituted or substituted heterocyclylsulfonyl group, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted heterocyclylcarbonyl Indicates a group.
X ¹ represents an unsubstituted or substituted alkylene group, an unsubstituted or substituted alkenylene group, an unsubstituted or substituted alkynylene group, -T ^a -O-T ^b- , or -T. ^a —N (R ²⁰ ) —T ^b —, each of T ^a and T ^b independently represents an unsubstituted or substituted alkylene group, and R ²⁰ represents a hydrogen atom, unsubstituted or substituted, A hydrocarbon group having a group, an unsubstituted or substituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted alkoxycarbonyl group, an unsubstituted or substituted group Aryloxy group having an unsubstituted, substituted or unsubstituted amino group, unsubstituted or substituted alkylsulfonyl group, unsubstituted Or a substituted arylsulfonyl group, an unsubstituted or substituted heterocyclylsulfonyl group, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or A heterocyclylcarbonyl group having a substituent is shown.
R ¹⁰ to R ¹² each independently represent a hydrogen atom or a t- butoxycarbonyl group. However, one or more of R ^{10 to} R ¹² are t-butoxycarbonyl groups. )
(7) A compound represented by formula (IV-1) or formula (IV-2).

(In the formula (IV-1),
L ⁴⁰ represents a leaving group or an aldehyde,
Boc represents a t-butoxycarbonyl group,
n1 represents an integer of 2, 3, or 6 to 10. )

(In the formula (IV-2),
L ⁴¹ represents a leaving group or an aldehyde,
Boc represents a t-butoxycarbonyl group,
n2 represents an integer of 2, 3, or 5-10. )

The arylamidine compound according to the first embodiment of the present invention (compound represented by formula (I) or formula (II) or a salt thereof) is excellent in bactericidal activity, excellent in safety, and industrially advantageous. Can be synthesized. The fungicide or plant disease control agent containing the arylamidine compound as an active ingredient is particularly excellent in the control value of plant diseases such as apple scab, cucumber gray mold, wheat powdery mildew, tomato blight, wheat rust. Yes.
An arylamidine compound (compound represented by formula (III-1) or formula (III-2)) and a guanidine compound (formula (IV-1) or formula (IV-2) according to the second embodiment of the present invention Is useful as an intermediate for producing the arylamidine compound of the first embodiment of the present invention (the compound represented by formula (I) or formula (II) or a salt thereof) at low cost. It is.

First, in the present invention, the term “unsubstituted” means only a group serving as a mother nucleus. When there is no description of “having a substituent” and only the name of the group serving as a mother nucleus is used, it means “unsubstituted” unless otherwise specified.
On the other hand, the term “having a substituent” means that any hydrogen atom of a group serving as a mother nucleus is substituted with a group having the same or different structure from the mother nucleus. Accordingly, the “substituent” is another group bonded to a group serving as a mother nucleus. The number of substituents may be one, or two or more. Two or more substituents may be the same or different.
Terms such as “C1-6” indicate that the number of carbon atoms of the group serving as the mother nucleus is 1-6. This number of carbon atoms does not include the number of carbon atoms in the substituent. For example, a butyl group having an ethoxy group as a substituent is classified as a C2 alkoxy C4 alkyl group.

The “substituent” is not particularly limited as long as it is chemically acceptable and has the effects of the present invention. Examples of groups that can be “substituents” are shown below.
C1-6 such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group and n-hexyl group An alkyl group;
Vinyl group, 1-propenyl group, 2-propenyl group (allyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, etc. A C2-6 alkenyl group of
C2-6 alkynyl groups such as ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group;
A C3-8 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group;
C4-8 cycloalkenyl groups such as 2-cyclopentenyl group, 3-cyclohexenyl group, 4-cyclooctenyl group;

A C6-10 aryl group such as a phenyl group or a naphthyl group;
A C7-11 aralkyl group such as a benzyl group or a phenethyl group;
A 3-6 membered heterocyclyl group;
C1-7 acyl groups such as formyl group, acetyl group, propionyl group, benzoyl group, cyclohexylcarbonyl group;

A hydroxyl group;
C1-6 alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy group, t-butoxy group;
C2-6 alkenyloxy groups such as vinyloxy group, allyloxy group, propenyloxy group, butenyloxy group;
A C2-6 alkynyloxy group such as an ethynyloxy group or a propargyloxy group;
C6-10 aryloxy groups such as phenoxy group and naphthoxy group;
A C7-11 aralkyloxy group such as a benzyloxy group or a phenethyloxy group;

C1-7 acyloxy groups such as formyloxy group, acetyloxy group, propionyloxy group, benzoyloxy group, cyclohexylcarbonyloxy group;
A C1-6 alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, a t-butoxycarbonyl group;
A C1-6 alkoxycarbonyloxy group such as a methoxycarbonyloxy group, ethoxycarbonyloxy group, n-propoxycarbonyloxy group, i-propoxycarbonyloxy group, n-butoxycarbonyloxy group, t-butoxycarbonyloxy group;
Carboxyl group;

Halogeno groups such as fluoro, chloro, bromo and iodo groups;
C1-6 haloalkyl groups such as chloromethyl group, chloroethyl group, trifluoromethyl group, 1,2-dichloro-n-propyl group, 1-fluoro-n-butyl group, perfluoro-n-pentyl group;
A C2-6 haloalkenyl group such as a 2-chloro-1-propenyl group and a 2-fluoro-1-butenyl group;
A C2-6 haloalkynyl group such as 4,4-dichloro-1-butynyl group, 4-fluoro-1-pentynyl group, 5-bromo-2-pentynyl group;
C6-10 haloaryl groups such as 4-chlorophenyl group, 4-fluorophenyl group, 2,4-dichlorophenyl group;
A C1-6 haloalkoxy group such as a trifluoromethoxy group, a 2-chloro-n-propoxy group, or a 2,3-dichlorobutoxy group;
A C2-6 haloalkenyloxy group such as a 2-chloropropenyloxy group and a 3-bromobutenyloxy group;
A C6-10 haloaryloxy group such as a 4-fluorophenyloxy group, a 4-chloro-1-naphthoxy group;
C1-7 haloacyl group such as chloroacetyl group, trifluoroacetyl group, trichloroacetyl group, 4-chlorobenzoyl group;

An amino group (a group represented by NH ₂ );
A C1-6 alkyl-substituted amino group such as a methylamino group, a dimethylamino group, or a diethylamino group;
A C6-10 arylamino group such as an anilino group or a naphthylamino group;
A C7-11 aralkylamino group such as a benzylamino group or a phenethylamino group;
C1-7 acylamino groups such as formylamino group, acetylamino group, propanoylamino group, butyrylamino group, i-propylcarbonylamino group, benzoylamino group;
A C1-6 alkoxycarbonylamino group such as a methoxycarbonylamino group, an ethoxycarbonylamino group, an n-propoxycarbonylamino group, an i-propoxycarbonylamino group;
An aminocarbonyl group having an unsubstituted or substituted group such as an aminocarbonyl group, a dimethylaminocarbonyl group, a phenylaminocarbonyl group, an N-phenyl-N-methylaminocarbonyl group;
Imino C1-6 alkyl groups such as an iminomethyl group, a (1-imino) ethyl group, a (1-imino) -n-propyl group;
N-hydroxy-iminomethyl group, (1- (N-hydroxy) -imino) ethyl group, (1- (N-hydroxy) -imino) propyl group, N-methoxy-iminomethyl group, (1- (N-methoxy) -Imino) N-hydroxyimino C1-6 alkyl group having an unsubstituted or substituted group such as an ethyl group;

A mercapto group;
A C1-6 alkylthio group such as methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, s-butylthio group, t-butylthio group;
A C6-10 arylthio group such as a phenylthio group or a naphthylthio group;
A heteroarylthio group such as a thiazolylthio group or a pyridylthio group;
A C7-11 aralkylthio group such as a benzylthio group or a phenethylthio group;
A C1-6 alkylsulfinyl group such as a methylsulfinyl group, an ethylsulfinyl group, or a t-butylsulfinyl group;
A C6-10 arylsulfinyl group such as a phenylsulfinyl group;
Heteroarylsulfinyl groups such as thiazolylsulfinyl group, pyridylsulfinyl group;
A C7-11 aralkylsulfinyl group such as a benzylsulfinyl group or a phenethylsulfinyl group;
A C1-6 alkylsulfonyl group such as a methylsulfonyl group, an ethylsulfonyl group, a t-butylsulfonyl group;
A C6-10 arylsulfonyl group such as a phenylsulfonyl group;
A heteroarylsulfonyl group such as a thiazolylsulfonyl group or a pyridylsulfonyl group;
A C7-11 aralkylsulfonyl group such as a benzylsulfonyl group or a phenethylsulfonyl group;
An aminocarbonyloxy group;
A C1-6 alkyl-substituted aminocarbonyloxy group such as an ethylaminocarbonyloxy group and a dimethylaminocarbonyloxy group;

A tri-C1-6 alkyl-substituted silyl group such as a trimethylsilyl group, a triethylsilyl group, or a t-butyldimethylsilyl group;
A triaryl-substituted silyl group such as a triphenylsilyl group;
Cyano group; Nitro group; Oxo group In these “substituents”, any hydrogen atom in the substituent may be substituted with a group having a different structure.

  Moreover, said "3-6 membered heterocyclyl group" contains 1-4 heteroatoms chosen from the group which consists of a nitrogen atom, an oxygen atom, and a sulfur atom as a ring structural atom. The heterocyclyl group may be monocyclic or polycyclic. In the polycyclic heterocyclyl group, if at least one ring is a hetero ring, the remaining ring may be a saturated alicyclic ring, an unsaturated alicyclic ring, or an aromatic ring. Examples of the “3-6 membered heterocyclyl group” include a 3-6 membered saturated heterocyclyl group, a 5-6 membered heteroaryl group, a 5-6 membered partially unsaturated heterocyclyl group, and the like.

  Examples of the 3-6 membered saturated heterocyclyl group include an aziridinyl group, an epoxy group, a pyrrolidinyl group, a tetrahydrofuranyl group, a thiazolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a dioxolanyl group, and a dioxanyl group.

Examples of 5-membered heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl Can do.
Examples of the 6-membered heteroaryl group include a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridanidyl group, and a triazinyl group.

Embodiment 1 << Aryl amidine compound that can be an active ingredient such as a bactericidal agent >>
The arylamidine compound according to Embodiment 1 of the present invention is represented by the compound represented by formula (I) (hereinafter sometimes referred to as compound (I)) or a salt thereof, preferably represented by formula (II). A compound (hereinafter sometimes referred to as compound (II)) or a salt thereof.

Ar in the formula (I) represents an unsubstituted or substituted divalent aromatic hydrocarbon residue, or an unsubstituted or substituted divalent heterocyclic compound residue.
The “divalent aromatic hydrocarbon residue” is a group formed by removing two hydrogen atoms from an aromatic hydrocarbon. The aromatic hydrocarbon may be either monocyclic or polycyclic. In the polycyclic aromatic hydrocarbon, as long as at least one ring is an aromatic ring, the remaining ring may be a saturated alicyclic ring, an unsaturated alicyclic ring, or an aromatic ring.
Examples of the “aromatic hydrocarbon” include benzene, naphthalene, azulene, indene, indane, tetralin and the like. Of these, benzene or naphthalene is preferred, and benzene is more preferred.

A “divalent heterocyclic compound residue” is a group formed by elimination of two hydrogen atoms from a heterocyclic compound. The heterocyclic compound may be either a monocyclic heterocyclic compound or a polycyclic heterocyclic compound. Examples of the monocyclic heterocyclic compound include a 5-membered heterocyclic compound and a 6-membered heterocyclic compound. In the polycyclic heterocyclic compound, as long as at least one ring is a heterocyclic ring, the remaining ring may be a saturated alicyclic ring, an unsaturated alicyclic ring, or an aromatic ring.
The “heterocyclic compound” is a cyclic compound containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom as ring constituent atoms.
“Monocyclic heterocyclic compounds” include five-membered aromatic heterocyclic compounds such as imidazole, pyrazole, oxazole, thiazole, triazole, tetrazole, pyrrole, furan, thiophene, pyridine, pyrazine, pyrimidine, pyridazine, triazine. 6-membered aromatic heterocyclic compounds such as, 5-membered saturated heterocyclic compounds such as pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazoline, 6-membered saturated heterocyclic compounds such as piperidine, tetrahydropyran, tetrahydrothiopyran, And 5-membered partially unsaturated heterocyclic compounds such as pyrroline, imidazoline, pyrazoline, oxazoline and isoxazoline.
Examples of the “polycyclic heterocyclic compound” include benzofuran, benzothiophene, indole, isoindole, benzimidazole, purine, quinoline, isoquinoline, quinoxaline, cinnoline, pteridine, chromene, and isochromene.
Among these, a 6-membered aromatic heterocyclic compound or a polycyclic heterocyclic compound is preferable, and pyridine or benzofuran is more preferable.

Examples of the substituent on the “divalent aromatic hydrocarbon residue” and “divalent heterocyclic compound residue” include C1-6 alkyl group, C3-8 cycloalkyl group, C6-10 aryl group, 3 -6 membered heterocyclyl group, hydroxyl group, C1-6 alkoxy group, C6-10 aryloxy group, carboxyl group, halogeno group, C1-6 haloalkyl group, C6-10 haloaryl group, C1-6 haloalkoxy group, amino group ( A group represented by NH ₂ ), a C1-6 alkyl-substituted amino group, a C6-10 arylamino group, a C1-7 acylamino group, a C1-6 alkoxycarbonylamino group, a C1-6 alkylthio group, a C6-10 arylthio group, Heteroarylthio group, C7-11 aralkylthio group, C1-6 alkylsulfinyl group, C6-10 arylsulfinyl group, Lower reel sulfinyl group, C7～11 aralkyl sulfinyl group, Cl to 6 alkylsulfonyl group, C6-10 arylsulfonyl group, heteroarylsulfonyl group, a cyano group, and nitro group are preferable. Among these, a C1-6 alkyl group, a C1-6 alkoxy group, a halogeno group, or a cyano group is more preferable.

Q in formula (I) or formula (II) is a single bond, unsubstituted or substituted phenylene, —CH═CH—, —C≡C—, —O—, —S—, —SO—. , -SO ₂ - or -N (R ^9), - indicating the. Among these, Q is preferably a single bond, unsubstituted or substituted phenylene, —CH═CH—, —C≡C—, —O—, or —S—.

As a substituent of “phenylene having a substituent”, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C6-10 aryl group, a 3-6 membered heterocyclyl group, a hydroxyl group, a C1-6 alkoxy group, a C6— 10 aryloxy group, carboxyl group, halogeno group, C1-6 haloalkyl group, C6-10 haloaryl group, C1-6 haloalkoxy group, amino group (group represented by NH ₂ ), C1-6 alkyl substituted amino group, C6-10 arylamino group, C1-7 acylamino group, C1-6 alkoxycarbonylamino group, C1-6 alkylthio group, C6-10 arylthio group, heteroarylthio group, C7-11 aralkylthio group, C1-6 alkylsulfinyl Group, C6-10 arylsulfinyl group, heteroarylsulfinyl group, C7-1 Aralkyl sulfinyl group, Cl to 6 alkylsulfonyl group, C6-10 arylsulfonyl group, heteroarylsulfonyl group, a cyano group, and nitro group are preferable.

R ⁹ is a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted group An alkoxycarbonyl group having an alkyl group, an unsubstituted or substituted aryloxy group, an unsubstituted or substituted amino group, an unsubstituted or substituted alkylsulfonyl group, an unsubstituted or substituted aryl A sulfonyl group, an unsubstituted or substituted heterocyclylsulfonyl group, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted heterocyclylcarbonyl Indicates a group.

  An unsubstituted or substituted hydrocarbon group is a group formed by elimination of one hydrogen atom in a hydrocarbon compound. Hydrocarbon compounds include saturated hydrocarbon compounds such as methane, ethane, propane, butane, pentane, hexane and heptane, unsaturated hydrocarbon compounds such as ethylene, acetylene and propylene, and alicyclic compounds such as cyclopentane, cyclohexane and cyclohexene. Examples thereof include hydrocarbon compounds, aromatic hydrocarbon compounds such as benzene and naphthalene.

  An unsubstituted or substituted heterocyclyl group is a group formed by elimination of one hydrogen atom in a heterocyclic compound. Heterocyclyl group includes aziridinyl group, epoxy group, pyrrolidinyl group, tetrahydrofuranyl group, thiazolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, dioxolanyl group, dioxanyl group; pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group Oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, triazolyl group, oxadiazolyl group, thiadiazolyl group, tetrazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridinyl group, triazinyl group and the like.

Examples of the unsubstituted or substituted alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an s-butoxy group, an i-butoxy group, and a t-butoxy group. Can be mentioned.
Examples of the unsubstituted or substituted alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, n-butoxycarbonyl group, s-butoxycarbonyl group, i-butoxycarbonyl. Group, t-butoxycarbonyl group and the like.

  Examples of the unsubstituted or substituted aryloxy group include a phenoxy group and a naphthoxy group.

Examples of unsubstituted or substituted amino groups include amino groups (groups represented by NH ₂ ), C 1-6 alkyl-substituted amino groups such as methylamino groups, dimethylamino groups, and diethylamino groups; anilino groups and naphthylamino groups. C6-10 arylamino group such as a group; C7-11 aralkylamino group such as benzylamino group, phenethylamino group; formylamino group, acetylamino group, propanoylamino group, butyrylamino group, i-propylcarbonylamino group, benzoyl C1-7 acylamino groups such as amino groups; C1-6 alkoxycarbonylamino groups such as methoxycarbonylamino group, ethoxycarbonylamino group, n-propoxycarbonylamino group, i-propoxycarbonylamino group and the like can be mentioned.

  Examples of the unsubstituted or substituted alkylsulfonyl group include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, i-propylsulfonyl group, n-butylsulfonyl group, s-butylsulfonyl group, i-butylsulfonyl. Group, t-butylsulfonyl group and the like.

  Examples of the unsubstituted or substituted arylsulfonyl group include a phenylsulfonyl group and a naphthylsulfonyl group.

  Examples of the unsubstituted or substituted heterocyclylsulfonyl group include aziridinylsulfonyl group, epoxysulfonyl group, pyrrolidinylsulfonyl group, tetrahydrofuranylsulfonyl group, thiazolidinylsulfonyl group, piperidylsulfonyl group, piperazinylsulfonyl Group, morpholinylsulfonyl group, dioxolanylsulfonyl group, dioxanylsulfonyl group; pyrrolylsulfonyl group, furylsulfonyl group, thienylsulfonyl group, imidazolylsulfonyl group, pyrazolylsulfonyl group, oxazolylsulfonyl group, isoxazolyl Rusulfonyl group, thiazolylsulfonyl group, isothiazolylsulfonyl group, triazolylsulfonyl group, oxadiazolylsulfonyl group, thiadiazolylsulfonyl group, tetrazolylsulfonyl group, Jirusuruhoniru group, pyrazinyl sulfonyl group, a pyrimidinyl sulfonyl group, pyridyl mite Jill sulfonyl group, and the like triazinyl sulfonyl group.

  Examples of the unsubstituted or substituted alkylcarbonyl group include methylcarbonyl group, ethylcarbonyl group, n-propylcarbonyl group, i-propylcarbonyl group, n-butylcarbonyl group, s-butylcarbonyl group, i-butylcarbonyl. Group, t-butylcarbonyl group and the like.

  Examples of the unsubstituted or substituted arylcarbonyl group include a phenylcarbonyl group and a naphthylcarbonyl group.

  Examples of the unsubstituted or substituted heterocyclylcarbonyl group include aziridinylcarbonyl group, epoxycarbonyl group, pyrrolidinylcarbonyl group, tetrahydrofuranylcarbonyl group, thiazolidinylcarbonyl group, piperidylcarbonyl group, piperazinylcarbonyl Group, morpholinylcarbonyl group, dioxolanylcarbonyl group, dioxanylcarbonyl group; pyrrolylcarbonyl group, furylcarbonyl group, thienylcarbonyl group, imidazolylcarbonyl group, pyrazolylcarbonyl group, oxazolylcarbonyl group, isoxazolyl Rucarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, triazolylcarbonyl, oxadiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, Jill carbonyl group, pyrazinylcarbonyl group, pyrimidinyl group, pyridyl mite Jill carbonyl group, and the like triazinyl group.

X and Z in formula (I) or formula (II) each independently have an unsubstituted or substituted alkylene group, an unsubstituted or substituted alkenylene group, an unsubstituted or substituted group alkynylene ^{group, -T a -O-T b -} , or ^{-T a -N (R 20) -T} b - indicate the. T ^a and T ^b each independently represent an unsubstituted or substituted alkylene group. R ²⁰ is a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted group An alkoxycarbonyl group having an alkyl group, an unsubstituted or substituted aryloxy group, an unsubstituted or substituted amino group, an unsubstituted or substituted alkylsulfonyl group, an unsubstituted or substituted aryl A sulfonyl group, an unsubstituted or substituted heterocyclylsulfonyl group, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted heterocyclylcarbonyl Group, more preferably hydrogen Indicates an atom.
X in the formula (I) or the formula (II) is preferably a C2-10 alkylene group, and more preferably a C2-6 alkylene group. Z in formula (I) or formula (II) is preferably a C2-12 alkylene group, and more preferably a C4-10 alkylene group.
Examples of the “alkylene group” include methylene group, ethylene group, propane-1,3-diyl group (also known as trimethylene group), propane-1,2-diyl group (also known as propylene group), butane-1,4-diyl. Group, butane-1,3-diyl group, butane-1,2-diyl group, pentane-1,5-diyl group, hexane-1,6-diyl group, heptane-1,7-diyl group, octane-1 , 8-diyl group.

Examples of the substituent on the “alkylene group” include C1-6 alkyl group, C6-10 aryl group, hydroxyl group, C1-6 alkoxy group, C6-10 aryloxy group, carboxyl group, halogeno group, C1-6 haloalkyl group. C6-10 haloaryl group, C1-6 haloalkoxy group, amino group (group represented by NH ₂ ), C1-6 alkyl-substituted amino group, C6-10 arylamino group, C1-7 acylamino group, C1-6 Alkylthio groups, C6-10 arylthio groups, heteroarylthio groups, C1-6 alkylsulfinyl groups, C1-6 alkylsulfonyl groups, C6-10 arylsulfonyl groups, heteroarylsulfonyl groups, cyano groups, oxo groups and the like are preferable.

  Y in formula (I) or formula (II) is —C (═O) —NH—, —NH—C (═O) —, or formula (Ia):

(In formula (Ia), A represents a single bond, —C (═O) —, or —SO ₂ —, and R ⁷ represents a hydrogen atom, an unsubstituted or substituted hydrocarbon group, or unsubstituted. Or a substituted or unsubstituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted aryloxy group, or an unsubstituted or substituted amino group. The group shown by is shown. Among these, Y is preferably —C (═O) —NH— or a group represented by the formula (Ia). A in formula (Ia) is preferably a single bond or —C (═O) —, and R ⁷ is a hydrogen atom or an unsubstituted or substituted hydrocarbon group (more preferably, C 1 It is more preferably a C1-6 alkyl group which may be substituted with a -6 alkyl-substituted amino group, or a phenyl group.

W in Formula (I) or Formula (II) represents a single bond or —N (R ⁸ ) —, and more preferably —N (R ⁸ ) —. R ⁸ is a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted heterocyclyl group, a hydroxyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted group An alkoxycarbonyl group having an alkyl group, an unsubstituted or substituted aryloxy group, an unsubstituted or substituted amino group, an unsubstituted or substituted alkylsulfonyl group, an unsubstituted or substituted aryl A sulfonyl group, an unsubstituted or substituted heterocyclylsulfonyl group, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted heterocyclylcarbonyl Group, more preferably hydrogen Indicates an atom.

R ^{1 to} R ^{6 in} formula (I) or formula (II) are each independently a hydrogen atom, an unsubstituted or substituted hydrocarbon group, an unsubstituted or substituted heterocyclyl group, or a hydroxyl group. An unsubstituted or substituted alkoxy group, an unsubstituted or substituted alkoxycarbonyl group, an unsubstituted or substituted aryloxy group, or an unsubstituted or substituted amino group, unsubstituted Or substituted or unsubstituted alkylsulfonyl group, unsubstituted or substituted arylsulfonyl group, unsubstituted or substituted heterocyclylsulfonyl group, unsubstituted or substituted alkylcarbonyl group, unsubstituted or An arylcarbonyl group having a substituent, or an unsubstituted or substituted It shows the Russian acrylic carbonyl group. Among these, R ^{1 to} R ⁶ are each independently a hydrogen atom, a C 1-6 alkyl group optionally substituted with a C 1-6 alkyl-substituted amino group, a C 2-6 alkenyl group, an unsubstituted or substituted group. It is more preferably a C1-6 alkylsulfonyl group having
R ¹ and R ² , R ² and R ³ , R ⁴ and R ⁵ , or R ⁵ and R ⁶ may be bonded together to form a 4- to 8-membered ring. Among these, it is preferable that R ¹ and R ² together form 1,4,5,6-tetrahydropyrimidine, 4,5-dihydro-1H-imidazole, or imidazole.

  G in the formula (II) represents a carbon atom or a nitrogen atom.

R ³⁰ in formula (II) is a C1-6 alkyl group, a C3-8 cycloalkyl group, a C6-10 aryl group, a 3-6 membered heterocyclyl group, a hydroxyl group, a C1-6 alkoxy group, a C6-10 aryloxy. group, a carboxyl group, a halogeno group, Cl to 6 haloalkyl group, C6-10 haloaryl group, Cl to 6 haloalkoxy group, (the group represented by NH ₂₎ amino group, Cl to 6 alkyl substituted amino group, C6-10 Arylamino group, C1-7 acylamino group, C1-6 alkoxycarbonylamino group, C1-6 alkylthio group, C6-10 arylthio group, heteroarylthio group, C7-11 aralkylthio group, C1-6 alkylsulfinyl group, C6 -10 arylsulfinyl group, heteroarylsulfinyl group, C7-11 aralkylsulfinyl group Shows C1~6 alkylsulfonyl group, C6-10 arylsulfonyl group, heterocyclylsulfonyl group, a cyano group, a nitro group. Among these, R ³⁰ preferably represents a C 1-6 alkyl group, a C 1-6 alkoxy group, a halogeno group, or a cyano group.
Any one of R ^{1 to} R ³ in formula (II) and R ³⁰ may be bonded together to form a 4- to 8-membered ring.
P in the formula (II) represents the number of R ³⁰ and is an integer of 0 to 4, preferably 0 or 1, more preferably 0.

  Specific examples of the compound represented by the formula (I) or the formula (II) include the following compounds.

  In the table, * means a bonding position with an amidino group, and ** means a bonding position with Q.

  In the table, * indicates a binding position.

  The compound (I) or compound (II) according to the present invention includes hydrates, various solvates and crystal polymorphs. Furthermore, the compound (I) or compound (II) according to the present invention includes stereoisomers, tautomers and mixtures thereof based on asymmetric carbon atoms, double bonds, and the like.

  The salt of compound (I) or (II) according to the present invention is not particularly limited as long as it is an agriculturally and horticulturally acceptable salt. For example, salts of inorganic acids such as hydrochloric acid and sulfuric acid; salts of organic acids such as acetic acid and lactic acid; salts of alkali metals such as lithium, sodium and potassium; salts of alkaline earth metals such as calcium and magnesium; iron and copper And salts of organic metals such as ammonia, triethylamine, tributylamine, pyridine, hydrazine, and the like. The salt of compound (I) or (II) can be obtained from compound (I) or (II) by a known method.

The arylamidine compound according to Embodiment 1 of the present invention is not particularly limited by its production method. The arylamidine compound according to Embodiment 1 of the present invention can be synthesized, for example, by combining known methods described in Patent Documents 1 to 3 and other known methods.
As a method suitable for producing the arylamidine compound according to Embodiment 1 of the present invention, a compound represented by the following formula (III-1) (hereinafter referred to as arylamidine compound (III-1)), a compound represented by the following formula (III- 2) (hereinafter referred to as arylamidine compound (III-2)), a compound represented by the following formula (IV-1) (hereinafter referred to as guanidine compound (IV-1)), or a compound represented by the following formula ( And IV-2) (hereinafter referred to as guanidine compound (IV-2)). Through the arylamidine compound (III-1), arylamidine compound (III-2), guanidine compound (IV-1) or guanidine compound (IV-2), the arylamidine compound according to Embodiment 1 of the present invention is obtained. It can be manufactured with high purity.

Embodiment 2 << Production Intermediate >>
The arylamidine compound (III-1) according to Embodiment 2 of the present invention is a compound represented by the formula (III-1). The arylamidine compound (III-2) according to Embodiment 2 of the present invention is a compound represented by the formula (III-2).

  Ar and Q in formula (III-1) and formula (III-2) are the same as Ar and Q in formula (I).

R ¹⁰ , R ¹¹ and R ¹² in formula (III-1) and formula (III-2) each independently represent a hydrogen atom or a t-butoxycarbonyl group. However, one or more of R ¹⁰ , R ¹¹ and R ¹² is a t-butoxycarbonyl group.

X in the formula (III-1) is the same as X in the formula (I).
X ^{1 in} formula (III-2) is the same as X in formula (I).

L in the formula (III-1) represents a leaving group. Examples of the leaving group include halogen atoms such as chlorine atom, bromine atom and iodine atom; alkylsulfonyloxy group such as methylsulfonyloxy group; arylsulfonyloxy group such as 4-methylphenylsulfonyloxy group; trifluoromethylsulfonyl A haloalkylsulfonyloxy group such as an oxy group; and the like. Of these, L is preferably a halogen atom.
The compound (III-1) or compound (III-2) according to the present invention includes stereoisomers based on asymmetric carbon atoms, double bonds, etc., tautomers and mixtures thereof.

<Synthesis method>
The method for synthesizing the arylamidine compound according to Embodiment 1 of the present invention and the method for synthesizing the compound according to Embodiment 2 of the present invention are specifically exemplified.

Synthesis method 1
The compound (1) and the dihalogen compound (2) are reacted to obtain the compound (3), and then the compound (3) and the azide compound are reacted to obtain the compound (4). The compound (5) having an amino group can be obtained by reducing the azide group of the compound (4). The compound (7) having a cyano group can be obtained by reacting the amino group of the compound (5) with the compound (6). The arylamidine compound (8) according to the present invention can be obtained by acid treatment of the compound (7) with hydrochloric acid or the like.

  In the formula, Ar, X and Z are the same as Ar, X and Z described in the formula (I), and Hal is a halogen atom.

Synthesis Method 2 (Synthesis Method via Compound (III-1))
Compound (1) can be treated with an acid such as hydrochloric acid to obtain amidine compound (9), and then amidino group can be protected with t-butoxycarbonyl group to obtain compound (10). The compound (13) can be obtained by reacting the compound (10) with the compound (2) to obtain the compound (III-1) and then reacting with the diamine compound (12). The compound (13) and compound (14) obtained are reacted to obtain the compound (15), and then the protective group P is deprotected to obtain the arylamidine compound (16) according to the present invention.

In the formula, Ar, X, Z, and Q are the same as Ar, X, Z, and Q described in the formula (I), and L, R ¹⁰ , R ¹¹ , and R ¹² are represented by the formula (III-1) Are the same as L, R ¹⁰ , R ¹¹ and R ¹² described in the above, and P represents a protecting group. Tf represents a trifluoromethanesulfonyl group.

Synthesis Method 3 (Synthesis Method via Compound (III-2))
Compound (19) can be obtained by reacting Compound (10) with Compound (17) to obtain Compound (18) and then deprotecting the protecting group for alcohol. Compound (III-2) can be obtained by oxidizing the alcohol of compound (19). Compound (13) can be obtained by subjecting the obtained compound (III-2) and compound (12) to a reductive amination reaction. The arylamidine compound (16) according to the present invention can be obtained from the compound (13) in the same manner as described above.

^{Wherein, Ar, L, R 10,} R 11, R 12 denotes defined in formula (III-1), Ar, L, the same as ^{R 10, R 11, R 12} , X 1 is defined in formula (III-1), the same meanings as X ^1. P and P ′ represent protecting groups. Tf represents a trifluoromethanesulfonyl group.

  The guanidine compound (IV-1) according to Embodiment 2 of the present invention is a compound represented by the formula (IV-1). The guanidine compound (IV-2) according to Embodiment 2 of the present invention is a compound represented by the formula (IV-2).

L ⁴⁰ and L ⁴¹ in formula (IV-1) and formula (IV-2) represent a leaving group or an aldehyde. Examples of the leaving group include halogen atoms such as chlorine atom, bromine atom and iodine atom; alkylsulfonyloxy group such as methylsulfonyloxy group; arylsulfonyloxy group such as 4-methylphenylsulfonyloxy group; trifluoromethylsulfonyl A haloalkylsulfonyloxy group such as an oxy group; and the like. Of these, L ⁴⁰ and L ⁴¹ are preferably halogen atoms.

  Boc in Formula (IV-1) and Formula (IV-2) represents a t-butoxycarbonyl group.

  N1 in Formula (IV-1) represents an integer of 2, 3, or 6-10.

  N2 in Formula (IV-2) represents an integer of 2, 3, or 5 to 10, preferably an integer of 5 to 10.

Synthesis Method 4 (Synthesis Method via Compound (IV-1) or Compound (IV-2))
The compound (30) can be obtained by reacting the compound (III-1) with an azide compound. A compound (31) having an amino group can be obtained by reducing the azide group of the compound (30).
Compound either by nucleophilic substitution reaction the amino group of (IV-1) L ⁴⁰ with a compound of (31) or to L ⁴⁰ with a compound of the compound (IV-1) the amino group of (31) to react reductive amination Thus, the compound (32) can be obtained. Finally, the arylamidine compound (16) according to the present invention can be obtained by deprotecting the protecting group of the compound (32) under acidic conditions such as hydrochloric acid.
Further, L ⁴¹ of compound (IV-2) and the amino group of compound (31) are subjected to nucleophilic substitution reaction, or L ⁴¹ of compound (IV-2) and the amino group of compound (31) are reductively aminated. Compound (33) can be obtained by reacting. Finally, the arylamidine compound (16) according to the present invention can be obtained by deprotecting the protecting group of the compound (33) under acidic conditions such as hydrochloric acid.

In the formula, Ar, X, Z and Q are the same as Ar, X, Z and Q described in the formula (I), and L, R ¹⁰ , R ¹¹ and R ¹² are represented by the formula (III-1) the same meanings as have been L, R ^10, R ¹¹ and R ¹² described, L ⁴⁰ and n1 have the same meanings as L ⁴⁰ and n1 described in the formula (IV-1), L ⁴¹ and n2 Represents the same as L ⁴¹ and n2 described in the formula (IV-2), and Boc represents a t-butoxycarbonyl group.

After completion of the synthesis reaction, the target product can be efficiently isolated by subjecting it to conventional post-treatment operations in organic synthetic chemistry and, if necessary, conventionally known separation and purification means.
The structure of the target product can be identified and confirmed by measuring ¹ H-NMR spectrum, IR spectrum, mass spectrum, elemental analysis, or the like.

Embodiment 3 << bactericidal agent, plant disease control agent >>
The fungicide or plant disease control agent according to the present invention contains at least one selected from the group consisting of compound (I) or (II) or a salt thereof.
The amount of the arylamidine compound contained in the fungicide or plant disease control agent of the present invention is preferably 0.01 to 90% by weight, more preferably 0.05 to 85% by weight, based on the entire preparation.

The fungicides or plant disease control agents of the present invention can be used in the form of agricultural chemicals, that is, in the form of agricultural chemical preparations such as wettable powders, granules, powders, emulsions, aqueous solvents, suspensions, and granular wettable powders. can do.
Additives and carriers used in solid formulations include vegetable powders such as soybean flour and wheat flour, mineral fine powders such as diatomaceous earth, apatite, gypsum, talc, bentonite, pyrophyllite, clay, sodium benzoate, urea And organic and inorganic compounds such as mirabilite.
Solvents used in liquid formulations include kerosene, xylene and petroleum aromatic hydrocarbons, cyclohexane, cyclohexanone, dimethylformamide, dimethyl sulfoxide, alcohol, acetone, trichloroethylene, methyl isobutyl ketone, mineral oil, vegetable oil, water, etc. Can be mentioned.

Furthermore, in order to take a uniform and stable form in these preparations, a surfactant can be added as necessary.
The surfactant that can be added is not particularly limited. For example, alkyl phenyl ether added with polyoxyethylene, alkyl ether added with polyoxyethylene, higher fatty acid ester added with polyoxyethylene, sorbitan higher fatty acid ester added with polyoxyethylene, tristyryl added with polyoxyethylene Nonionic surfactants such as phenyl ether, sulfates of alkylphenyl ethers added with polyoxyethylene, alkylbenzene sulfonates, sulfates of higher alcohols, alkylnaphthalene sulfonates, polycarboxylates, lignin sulfones Acid salt, formaldehyde condensate of alkyl naphthalene sulfonate, and isobutylene-maleic anhydride copolymer.

  The wettable powder, emulsion, flowable powder, aqueous solvent, or granular wettable powder thus obtained is diluted with water to a predetermined concentration and sprayed on plants as a solution, suspension or emulsion. Used in the method. Powders and granules are used as they are sprayed on plants.

  The bactericidal agent or plant disease control agent of the present invention is used by seed treatment, foliage application, soil application or water surface application for the control of various diseases that occur during cultivation of agricultural and horticultural crops including flower buds, turf, and grass. Can do.

The application amount of the fungicide or plant disease control agent of the present invention varies depending on weather conditions, formulation form, application time, application method, application location, disease to be controlled, target crop, etc., but usually the amount of active ingredient per hectare Preferably it is 1-1000g, More preferably, it is 10-100g.
When a wettable powder, emulsion, suspension, aqueous solvent, granular wettable powder or the like is diluted with water and applied, the applied concentration is preferably 1 to 1,000 ppm, more preferably 10 to 250 ppm.

The fungicides or plant disease control agents of the present invention can be applied to a wide variety of filamentous fungi, such as algae (Oomycetes), Ascomycetes, incomplete fungi (Deuteromycetes), and basidiomycetes. Has excellent bactericidal power against bacteria belonging to.
The diseases to which the fungicide or plant disease control agent of the present invention is preferably applied include apple black scab, cucumber gray mold, wheat powdery mildew, tomato plague, wheat rust, paddy rice blast, cucumber The vine split disease can be mentioned.
The fungicide or plant disease control agent of the present invention is a highly safe drug with little phytotoxicity, low toxicity to fish and warm-blooded animals.

  The fungicides or plant disease control agents of the present invention are mixed or used in combination with other fungicides, insecticides / miticides, nematicides, soil insecticides, insecticides, plant growth regulators, synergists, etc. You can also

  Hereinafter, the present invention will be described more specifically with reference to examples. It should be noted that the present invention is not limited by the following examples, and can of course be implemented with appropriate modifications within a range that can be adapted to the spirit of the present invention. To be included in the scope.

Example 1
(Step 1) Synthesis of 4- (4-bromobutoxy) benzonitrile

  4-Cyanophenol 5g was dissolved in acetonitrile 70mL, and potassium carbonate 6.39g and 1, 4- dibromobutane 45.3g were added to this at room temperature. The reaction mixture was heated to reflux and stirred at the same temperature for 5 hours. The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 9.53 g of 4- (4-bromobutoxy) benzonitrile in a yield of 89.3%.

(Step 2) Synthesis of 4- (4-azidobutoxy) benzonitrile

  8 g of 4- (4-bromobutoxy) benzonitrile was dissolved in 80 mL of N, N-dimethylformamide, and 8.19 g of sodium azide was added thereto at room temperature. The reaction mixture was heated to 70 ° C. and stirred at the same temperature for 4 hours. The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6.85 g of 4- (4-azidobutoxy) benzonitrile.

(Step 3) Synthesis of 4- (4-aminobutoxy) benzonitrile

  4- (4-Azidobutoxy) benzonitrile (3 g) was dissolved in methanol (30 mL), and palladium carbon (300 mg) was added thereto at room temperature. The reaction mixture was filtered through Celite (registered trademark: Celite Corporation), and the residue was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain 928.8 mg of 4- (4-aminobutoxy) benzonitrile in a yield of 35.2%.

(Step 4) Synthesis of 4- [4- (8-cyanooctylamino) butoxy] benzonitrile

  366 mg of 4- (4-aminobutoxy) benzonitrile was dissolved in 10 mL of N, N-dimethylformamide, and 420 mg of 9-bromononanenitrile, 796 mg of potassium carbonate, and 287 mg of sodium iodide were added thereto at room temperature. The reaction mixture was warmed to 50 ° C. and stirred at 50 ° C. for 4 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 295.7 mg of 4- [4- (8-cyanooctylamino) butoxy] benzonitrile in a yield of 47.0%.

(Step 5) Synthesis of 4- [4-[(9-amino-9-imino-nonyl) amino] butoxy] benzamidine trihydrochloride

  210 mg of ammonium chloride was suspended in 5 mL of toluene, and 1.85 mL of a 2M trimethylaluminum toluene solution was added thereto at room temperature, followed by stirring at room temperature for 30 minutes. Then, 451 mg of 4- [4- (8-cyanooctylamino) butoxy] benzonitrile dissolved in 6 mL of toluene and 6 mL of tetrahydrofuran was added to the reaction mixture at room temperature. The reaction mixture was warmed to 80 ° C. and stirred at 80 ° C. overnight. The reaction mixture was cooled to room temperature. Thereafter, 7 g of silica gel and 15 mL of tetrahydrofuran were added at room temperature and stirred for 1 hour. The reaction mixture was filtered through Celite (registered trademark: manufactured by Celite Corporation) and concentrated under reduced pressure. The free form of the target product was purified by GPC from the obtained residue. The free form was dissolved in 3 mL of methanol, and 0.5 mL of 4N hydrogen chloride dioxane solution was added thereto at room temperature, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 53.1 mg of 4- [4-[(9-amino-9-imino-nonyl) amino] butoxy] benzamidine trihydrochloride (Compound No. 1) in a yield of 10.4%. Obtained.

Example 2
(Step 1) Synthesis of 4-amidinophenol hydrochloride

  1 g of 4-cyanophenol was dissolved in 2 mL of ethanol, and 14 mL of 4M hydrogen chloride dioxane solution was added thereto at room temperature, followed by stirring at the same temperature for one week. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in 25 mL of ethanol, and 3.23 g of ammonium carbonate was added thereto at room temperature. The mixture was stirred overnight at the same temperature, and the reaction mixture was concentrated under reduced pressure to obtain 4-amidinophenol hydrochloride in a yield of about 100%.

(Step 2) Synthesis of t-butyl N- (4-hydroxybenzenecarboxyimidoyl) carbamate

  4-Amidinophenol hydrochloride 500 mg was dissolved in 7 mL of N, N-dimethylformamide, and 880 mL of triethylamine and 1.39 g of di-t-butyl dicarbonate were added thereto at room temperature. Stir at the same temperature overnight. Thereafter, water was added to the reaction mixture, followed by filtration. The obtained residue was dissolved in 12 mL of ethanol, 10 mL of 10% aqueous sodium hydroxide solution was added thereto at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 538 mg of t-butyl N- (4-hydroxybenzenecarboximidyl) carbamate in a yield of 78.7%.

(Step 3) Synthesis of t-butyl N- [4- (3-bromopropoxy) benzenecarboximidyl] carbamate

  300 mg of t-butyl N- (4-hydroxybenzenecarboxyimidoyl) carbamate was dissolved in 4 mL of acetonitrile, and 176 mg of potassium carbonate and 1.28 g of dibromopropane were added thereto at room temperature. The reaction mixture was heated to reflux and stirred at the same temperature for 4 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 287.7 mg of t-butyl N- [4- (3-bromopropoxy) benzenecarboximidyl] carbamate in a yield of 63.3%.

(Step 4) Synthesis of t-butyl N- [4- [3- (7-aminoheptylamino) propoxy] benzenecarboximidyl] carbamate

  700 mg of t-butyl N- [4- (3-bromopropoxy) benzenecarboxyimidoyl] carbamate was dissolved in 7 mL of N, N-dimethylformamide, and 541 mg of potassium carbonate and 510 mL of diaminoheptane were added thereto at room temperature. Stir for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 521 mg of t-butyl N- [4- [3- (7-aminoheptylamino) propoxy] benzenecarboximidyl] carbamate in a yield of 65.4%. It was.

(Step 5) of t-butyl N- [4- [3- [7-[[N, N′-bis (t-butoxycarbonyl) carbamimidoyl] amino] heptylamino] propoxy] benzenecarboxyimidoyl] carbamate Composition

  521 mg of t-butyl N- [4- [3- (7-aminoheptylamino) propoxy] benzenecarboximidyl] carbamate was dissolved in 8 mL of acetonitrile, and 248 mg of diisopropylethylamine and Goodman's reagent (1,3-bis) were dissolved at room temperature. 704 mg of (t-butoxycarbonyl) -2- (trifluoromethylsulfonyl) guanidine) was added and stirred at the same temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and t-butyl N- [4- [3- [7-[[N, N′-bis (t-butoxycarbonyl) carbamimidoyl] amino] heptylamino] Propoxy] benzenecarboximidoyl] carbamate (Compound No. 2) was obtained in 396.5 mg, yield 49.2%.

Example 3
Synthesis of 4- [3- (7-guanidinoheptylamino) propoxy] benzamidine trihydrochloride

  396 mg of t-butyl N- [4- [3- [7-[[N, N′-bis (t-butoxycarbonyl) carbamimidoyl] amino] heptylamino] propoxy] benzenecarboximidyl] carbamate in 4 mL of dichloromethane After dissolution, 0.4 mL of water and 4 mL of trifluoroacetic acid were added thereto at room temperature, and the mixture was stirred overnight at the same temperature. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in 3 mL of a mixed solvent of methanol and dichloromethane (1: 2), 4 mL of 10% aqueous sodium hydroxide solution was added thereto at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of methanol and dichloromethane (1: 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was dissolved in 3 mL of methanol. To this solution, 0.5 mL of 4N hydrogen chloride dioxane solution was added at room temperature and stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 216.4 mg of 4- [3- (7-guanidinoheptylamino) propoxy] benzamidine trihydrochloride (Compound No. 3) in a yield of 77.4%.

Examples 4-22
The compound according to the present invention was synthesized in the same manner as in Example 2 or 3. The structures of some of the synthesized compounds are shown in the following table.

  In the table, Boc means a t-butoxycarbonyl group.

Example 23
(Step 1) Synthesis of 6- (4-bromobutoxy) nicotinonitrile

  After dissolving 1.1 g of 6- (4-hydroxybutoxy) nicotinonitrile in 25 mL of dichloromethane, 2.9 g of carbon tetrabromide and 2.3 g of triphenylphosphine were added at room temperature. After stirring for 17 hours, the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography gave 1.0 g of 6- (4-bromobutoxy) nicotinonitrile. Mp 41-43 ° C.

(Step 2) Synthesis of t-butyl N- [Nt-butoxycarbonyl-N ′-[8- [4-[(5-cyano-2-pyridyl) oxy] butylamino] octyl] carbamidoyl] carbamate

0.26 g of 6- (4-bromobutoxy) nicotinonitrile and 0.42 g of t-butyl N-[(8-aminooctylamino)-(t-butoxycarbonylamino) methylene] carbamate were dissolved in 3 mL of dimethylformamide. . 0.21 g of potassium carbonate was added and stirred for 17 hours. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and t-butyl N- [Nt-butoxycarbonyl-N ′-[8- [4-[(5-cyano-2-pyridyl) oxy] butyl 0.18 g of amino] octyl] carbamidoyl] carbamate was obtained.
¹ HNMR (CDCl ₃ ): 8.45 (s, 1H), 7.76 (d, 1H), 6.77 (d, 1H), 4.36 (t, 2H), 3.37 (m, 2H) ), 2.65 (t, 2H), 2.56 (t, 2H), 1.80 (m, 2H), 1.44-1.62 (m, 24H), 1.28-1.32 ( m, 8H).

(Step 3) t-butyl N- [8-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] octyl] -N- [4-[[5- (Nt-butoxy Synthesis of Carbonylcarbamidoyl) -2-pyridyl] oxy] butyl] carbamate

t-butyl N- [N-t-butoxycarbonyl-N ′-[8- [4-[(5-cyano-2-pyridyl) oxy] butylamino] octyl] carbamidoyl] carbamate 0.18 g was added to 3 mL of tetrahydrofuran. Then, 2 mL of lithium bis (trimethylsilyl) amide (1.3 M tetrahydrofuran solution) was added under ice cooling. After stirring at room temperature for 24 hours, the reaction was stopped with a saturated aqueous ammonium chloride solution. After extraction with a mixed solvent of dichloromethane and methanol, the organic layer was concentrated. After the obtained mixture was dissolved in 3 mL of dimethylformamide, 0.32 g of triethylamine and 0.35 g of di-t-butyl dicarbonate were added. After stirring at room temperature for 28 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and t-butyl N- [8-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] octyl] -N- [4 0.06 g of-[[5- (Nt-butoxycarbonylcarbamidoyl) -2-pyridyl] oxy] butyl] carbamate (Compound No. 23) was obtained.
¹ HNMR (CDCl ₃ ): δ 11.48 (s, 1H), 8.60 (s, 1H), 8.28 (s, 1H), 8.12 (d, 1H), 6.72 (d, 1H) ), 4.33 (t, 2H), 3.35 (br, 2H), 3.10-3.17 (m, 4H), 1.62-1.75 (m, 8H), 1.42- 1.53 (m, 36H), 1.20-1.30 (m, 8H).

Example 24
Synthesis of 6- (4-((8-guanidinooctyl) amino) butoxy) nicotinimidoamide tetrahydrochloride

t-butyl N- [8-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] octyl] -N- [4-[[5- (Nt-butoxycarbonylcarbamidoyl) 0.06 g) -2-pyridyl] oxy] butyl] carbamate was dissolved in 5 mL dichloromethane and 1 mL trifluoroacetic acid was added. After stirring at room temperature for 16 hours, the solvent was distilled off and the residue was dissolved in 5 mL of methanol. After adding 3 mL of hydrogen chloride (4M dioxane solution) at room temperature, the mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure to obtain 25 mg of 6- (4-((8-guanidinooctyl) amino) butoxy) nicotinimidoamide hydrochloride (Compound No. 24).
¹ HNMR (MeOH-d ₄ ): δ 8.64 (s, 1H), 8.07 (d, 1H), 6.97 (d, 1H), 4.46 (br, 2H), 3.00-3 .17 (m, 6H), 1.85-1.95 (m, H), 1.59-1.70 (m, 4H), 1.35-1.40 (m, 8H).

Examples 25 and 26
The compound according to the present invention was synthesized in the same manner as in Example 23 or 24. The structures of some of the synthesized compounds are shown in the following table.

  In the table, Boc means a t-butoxycarbonyl group.

Example 27
(Step 1) Synthesis of t-butyl N [4- (4-aminobutoxy) benzenecarboximidyl] carbamate

4 g of t-butyl N- [4- (3-bromobutoxy) benzenecarboximidyl] carbamate was dissolved in 40 mL of dimethylformamide, and 2.8 g of sodium azide was added at room temperature. The reaction mixture was heated to 70 ° C. and stirred at the same temperature for 5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was dissolved in 30 mL of ethyl acetate, and 300 mg of 10% palladium carbon was added at room temperature. The reaction system was replaced with hydrogen gas and stirred at room temperature for 14 hours. Methanol 20mL was added to the reaction mixture at room temperature, and it stirred at the same temperature for 4 hours. The reaction mixture was filtered through Celite (registered trademark: Celite Corporation), concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain t-butyl N- [4- (4-aminobutoxy) benzenecarboximidyl. 1.099 g of carbamate was obtained in a yield of 33.2%.
¹ HNMR (CDCl ₃ ): δ = 1.55 (s, 8H), 1.90-1.76 (m, 4H), 2.98 (t, 2H), 4.02 (t, 2H), 6 .90 (d, 2H), 7.83 (d, 2H).

(Step 2) Synthesis of t-butyl N- [N '-(7-bromoheptyl) -Nt-butoxycarbonyl-carbamidoyl] carbamate

  1 g of 1,7-dibromoheptane was dissolved in 15 mL of dimethylformamide, and 640 mg of potassium carbonate and 2.98 g of t-butyl N- (Nt-butoxycarbonylcarbamidoyl) carbamate were added at room temperature. The reaction mixture was heated to 50 ° C. and stirred at the same temperature for 4 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain 1.344 g of t-butyl N- [N ′-(7-bromoheptyl) -Nt-butoxycarbonyl-carbamidoyl] carbamate (Compound No. 27). The yield was 80.0%.

(Step 3) Synthesis of t-butyl N- [4- [4- [7- [bis (t-butoxycarbonylamino) methyleneamino] heptylamino] butoxy] benzenecarboximidyl] carbamate

1.099 g of t-butyl N- [4- (4-aminobutoxy) benzenecarboxyimidoyl] carbamate is dissolved in 15 mL of dimethylformamide, and 510 mg of potassium carbonate and t-butyl N- [N ′-(7-bromo] are dissolved at room temperature. Heptyl) -Nt-butoxycarbonyl-carbamidoyl] carbamate 1.34 g was added and stirred at the same temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give t-butyl N- [4- [4- [7- [bis (t-butoxycarbonylamino) methyleneamino] heptylamino] butoxy] benzenecarboximidyl] carbamate ( 558 mg of Compound No. 4) was obtained with a yield of 27.3%.
¹ HNMR (CDCl ₃ ): δ = 1.4-2.20 (m, 6H), 1.49 (s, 9H), 1.51 (s, 9H), 1.72-1.60 (m, 6H), 1.90-1.80 (m, 2H), 2.59 (t, 2H), 2.67 (t, 2H), 3.88 (t, 2H), 4.02 (t, 2H) ), 6.90 (d, 2H), 7.84 (d, 2H).

(Step 4) Synthesis of 4- [4- (7-guanidinoheptylamino) butoxy] benzamidine trihydrochloride

  558 mg of t-butyl N- [4- [4- [4- [7- [bis (t-butoxycarbonylamino) methyleneamino] heptylamino] butoxy] benzenecarboximidyl] carbamate is dissolved in 5 mL of dichloromethane, and trifluoroacetic acid at room temperature. 5 mL was added and stirred overnight at the same temperature. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in 5 mL of methanol, and 5 mL of 4M hydrogen chloride dioxane solution was added at room temperature. The mixture was stirred at the same temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure to give 390 mg of 4- [4- (7-guanidinoheptylamino) butoxy] benzamidine trihydrochloride (Compound No. 5) in a yield of 98.2%. Obtained.

Synthesis example 1
Synthesis of t-butyl N- [2- [t-butoxycarbonyl- [Nt-butoxycarbonyl-C-methylsulfanyl-carboimidoyl] amino] ethyl] -N-methyl-carbamate

1,3-bis (t-butoxycarbonyl) -2-methyl-thio pseudourea (2.38 g), Nt-butoxycarbonyl-N-methyl-2-aminoethanol (2.02 g) and triphenylphosphine ( To a solution of 3.33 g) in tetrahydrofuran (30 mL) was added dropwise diisopropyl azodicarboxylate (1.9 M, 6.5 mL) at 0 ° C. Thereafter, the mixture was stirred overnight with heating under reflux. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 3.56 g (yield 97%) of the title compound.
¹ HNMR (CDCl ₃ ): 1.46 (s, 9H), 1.49 (s, 9H), 1.51 (s, 9H), 2.38 (s, 3H), 2.90 (s, 3H) ), 3.35-3.55 (m, 2H), 3.57-3.71 (m, 2H).

Synthesis example 2
Synthesis of t-butyl N- [N- (7-aminoheptyl) -N′-t-butoxycarbonyl-carbamidoyl] -N- [2- [t-butoxycarbonyl (methyl) amino] ethyl] carbamate

T-butyl N- [N- (7-aminoheptyl) -N′-t-butoxycarbonyl-carbamidoyl] -N- [2- [t-butoxycarbonyl (methyl) amino] obtained in Synthesis Example 1 To a solution of 1 g of ethyl] carbamate in tetrahydrofuran (10 mL) was added dropwise a solution of 1,7-diaminoheptane (1.05 g) in tetrahydrofuran (8 mL) at room temperature. After stirring at 50 ° C., the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography using amino silica to obtain 1.14 g (yield 97%) of the title compound.
¹ HNMR (CDCl ₃ ): 1.26—1.74 (m, 37H), 2.68 (t, 2H), 2.88 (s, 3H), 3.06-3.33 (m, 2H) 3.38 (t, 2H), 3.55-3.92 (m, 2H).

Synthesis example 3
The following compounds were synthesized in the same manner as in Synthesis Example 2.
t-butyl N- [N- (8-aminooctyl) -N'-t-butoxycarbonyl-carbamidoyl] -N- [2- [t-butoxycarbonyl (methyl) amino] ethyl] carbamate

¹ＨＮＭＲ（ＣＤＣｌ₃）：１．１２−１．７６（ｍ，３９Ｈ）、２．６７（ｔ，２Ｈ）、２．８８（ｓ，３Ｈ），３．０６−３．３３（ｍ，２Ｈ）、３．３８（ｔ，２Ｈ）、３．５５−３．８９（ｍ，２Ｈ）．

¹ HNMR (CDCl ₃ ): 1.12-1.76 (m, 39H), 2.67 (t, 2H), 2.88 (s, 3H), 3.06-3.33 (m, 2H) 3.38 (t, 2H), 3.55-3.89 (m, 2H).

Synthesis example 4
The following compounds were synthesized in the same manner as in Synthesis Example 2.
t-butyl N- [N- (7-aminoheptyl) -N′-t-butoxycarbonyl-carbamidoyl] -N-methyl-carbamate

¹ HNMR (CDCl ₃ ): 1.25-1.65 (m, 30H), 2.68 (t, 2H), 3.12 (s, 3H), 3.21 (dd, 2H).

Synthesis example 5
The following compounds were synthesized in the same manner as in Synthesis Example 2.
t-butyl N- [N- (7-aminoheptyl) -N′-t-butoxycarbonyl-carbamidoyl] -N- (2-butenyl) carbamate (E / Z = 5/1)

¹ HNMR (CDCl ₃ ): 1.19-1.74 (m, 33H), 2.68 (t, 2H), 3.21 (dd, 2H), 4.17 (d, 1.7H, E- isomer), 4.31 (d, 0.3H, Z-isomer), 5.38-5.76 (m, 2H).

Examples 28-39
Using the compounds obtained in Synthesis Examples 2 to 5, the compounds according to the present invention were synthesized in the same manner as in Example 23 or 24. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Example 40
(Step 1) Synthesis of t-butyl N-[(t-butoxycarbonylamino)-[7-[(2-nitrophenyl) sulfonylamino] heptylamino] methylene] carbamate

To a solution of 1,7-diaminoheptane (3.9 g) in ethanol (30 mL) was added dropwise a solution of 2-nitrobenzenesulfonyl chloride (2.2 g) in ethanol (30 mL) at 0 ° C. After stirring at 0 ° C. for 3 hours, the reaction solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, dissolved in tetrahydrofuran (30 mL), and 1,3-bis (t-butoxycarbonyl) -2-methylisothiourea (3.5 g) was added. After stirring at room temperature for 3.5 hours and distilling off the solvent, the residue was purified by silica gel column chromatography to obtain the title compound (3.3 g).
¹ HNMR (CDCl ₃ ): 1.26-1.32 (m, 6H), 1.46-1.65 (m, 22H), 3.10 (m, 2H), 3.37 (m, 2H) , 7.74-7.78 (m, 2H), 7.87 (m, 1H), 8.14 (m, 1H).

(Step 2) t-butyl N- [4- [4- [7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptyl- (2-nitrophenyl) sulfonyl-amino] Of [Butoxy] benzenecarboximidyl] carbamate

  T-Butyl N-[(t-butoxycarbonylamino)-[7-[(2-nitrophenyl) sulfonylamino] heptylamino] methylene] carbamate (0.15 g) obtained in Step 1 was added to tetrahydrofuran (3 mL). Dissolved. N-[(t-butoxycarbonylamino)-[7-[(2-nitrophenyl) sulfonylamino] heptylamino] methylene] carbamate (0.31 g) was added followed by triphenylphosphine (0.14 g ), Diethyl azodicarboxylate (2.2 M toluene solution, 0.25 mL) was added. After stirring at room temperature for 17 hours, the reaction solvent was distilled off. The residue was purified by silica gel column chromatography to obtain the title compound (Compound No .: 40, 0.17 g).

(Step 3) of t-butyl N- [4- [4- [7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptylamino] butoxy] benzenecarboximidyl] carbamate Composition

  T-Butyl N- [4- [4- [7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptyl- (2-nitrophenyl) sulfonyl- obtained in Step 2 Amino] butoxy] benzenecarboximidyl] carbamate (0.85 g) was dissolved in acetonitrile (5 mL), and potassium carbonate (0.41 g) and thiophenol (0.33 g) were added. After stirring for 18 hours at room temperature, the reaction solvent was distilled off. The residue was purified by silica gel column chromatography to obtain the title compound (Compound No: 4, 0.64 g).

Example 40-2
t-Butyl N- [4- [4- [7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptyl- (2-nitrophenyl) sulfonyl-amino] butoxy] benzenecarboxy Of Imidoyl] carbamate

t-Butyl ((4- (4-bromobutoxy) phenyl) (imino) methyl) carbamate (0.41 g) and t-butyl N-[(t-butoxycarbonylamino) obtained in Example 40 Step 1 -[7-[(2-Nitrophenyl) sulfonylamino] heptylamino] methylene] carbamate (0.56 g) was dissolved in dimethylformamide (3 mL). Potassium carbonate (0.17 g) was added and stirred at room temperature for 17 hours. The product was purified by silica gel column chromatography to obtain the title compound (Compound No .: 40, 0.68 g).
¹ HNMR (CDCl ₃ ): 1.22-1.25 (m, 6H), 1.47-1.55 (m, 31H), 1.68-1.75 (m, 4H), 3.24- 3.35 (m, 6H), 3.97 (m, 2H), 6.85 (d, 2H), 7.59-7.65 (m, 3H), 7.84 (d, 2H), 7 .99 (s, 1H).

Synthesis Example 6
(Step 1) Synthesis of 4- (4,5-dihydro-1H-imidazol-2-yl) phenol

4-Hydroxybenzonitrile (1.5 g) was dissolved in ethylenediamine (15 mL), and diphosphorus pentasulfide (1.68 g) was added at room temperature. The reaction mixture was heated to 120 ° C. and stirred at the same temperature overnight. The reaction mixture was cooled to room temperature, water was added, and the precipitated crystals were collected by filtration to obtain 2.02 g (quantitative) of the title compound.
¹ HNMR (CDCl ₃ ): 3.55-3.62 (m, 4H), 6.71 (d, 2H), 7.61 (d, 2H).

(Step 2) Synthesis of t-butyl 2- (4-t-butoxycarbonyloxyphenyl) -4,5-dihydroimidazole-1-carboxylate

4- (4,5-Dihydro-1H-imidazol-2-yl) phenol (1 g) obtained in step 1 was dissolved in dimethylformamide (10 mL), and triethylamine (1.87 g), di-t- was dissolved at room temperature. Butyl dicarbonate (3.36 g) was added and stirred at the same temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.00 g (yield: 89.7%) of the title compound.
¹ HNMR (CDCl ₃ ): 1.27 (s, 9H), 1.56 (s, 9H), 3.92-4.02 (m, 4H), 7.18 (d, 2H), 7.52 (D, 2H).

(Step 3) Synthesis of t-butyl 2- (4-hydroxyphenyl) -4,5-dihydroimidazole-1-carboxylate

T-Butyl 2- (4-t-butoxycarbonyloxyphenyl) -4,5-dihydroimidazole-1-carboxylate (2.00 g) obtained in step 2 was dissolved in methanol (15 mL) and 10% at room temperature. % Aqueous sodium hydroxide solution (7 mL) was added. The mixture was stirred at the same temperature for 4 hours, and the reaction mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 825 mg (yield 57.3%) of the title compound.
¹ HNMR (CDCl ₃ ): 1.31 (s, 9H), 3.91 (ddd, 2H), 3.98 (ddd, 2H), 6.65 (d, 2H), 7.32 (d, 2H) ).

(Step 4) Synthesis of t-butyl 2- [4- (4-bromobutoxy) phenyl] -4,5-dihydroimidazole-1-carboxylate

T-Butyl 2- (4-hydroxyphenyl) -4,5-dihydroimidazole-1-carboxylate (300 g) obtained in step 3 was dissolved in dimethylformamide (5 mL) and sodium hydride (52 mg) at 0 ° C. ) Was added. After stirring at the same temperature for 15 minutes, 1,6-dibromobutane (1.23 g) was added. The reaction mixture was warmed to room temperature and stirred at the same temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 493 mg (quantitative) of the title compound.
¹ HNMR (CDCl ₃ ): 1.32 (s, 9H), 1.90-1.98 (m, 2H), 2.12-2.04 (m, 2H), 3.49 (t, 2H) 3.91 (ddd, 2H), 4.00-3.95 (m, 2H), 4.02 (t, 2H), 6.86 (d, 2H), 7.47 (d, 2H).

Synthesis example 7
Synthesis of t-butyl 2- [4- (4-bromobutoxy) phenyl] -4,5-dihydroimidazole-1-carboxylate

The title compound was obtained in the same manner as in Synthesis Example 6 except that 4- (4,5-dihydro-1H-imidazol-2-yl) phenol was used.
¹ HNMR (CDCl ₃ ): 1.16 (s, 9H), 1.89-2.00 (m, 2H), 2.04-2.12 (m, 2H), 3.49 (t, 2H) 3.59 (t, 2H), 3.69 (t, 2H), 4.02 (t, 2H), 6.87 (d, 2H), 7.42 (d, 2H).

Examples 41-45
Using the compounds obtained in Synthesis Examples 6 and 7, the compounds according to the present invention were synthesized in the same manner as in Examples 2, 3, and 40. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Example 46
(Step 1) Synthesis of benzyl 4- (4- (N- (t-butoxycarbonyl) carbamidoyl) phenoxy) butanoate

After dissolving t-butyl ((4-hydroxyphenyl) (imino) methyl) carbamate (1.2 g) in acetonitrile (15 mL), benzyl 4-bromobutanoate (1.4 g) and potassium carbonate (0.83 g) ) Was added. After stirring at 60 ° C. for 9 hours, filtration was performed and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.7 g).
¹ HNMR (CDCl ₃ ): 1.54 (s, 9H), 2.13 (m, 2H), 2.57 (t, 2H), 4.03 (t, 2H), 5.12 (s, 2H) ), 6.86 (d, 2H), 7.34 (m, 5H), 7.81 (d, 2H).

(Step 2) 4- (4- (N- (t-butoxycarbonyl) carbamidoyl) phenoxy) butanoic acid

The benzyl 4- (4- (N- (t-butoxycarbonyl) carbamidoyl) phenoxy) butanoate (1.7 g) obtained in Step 1 was dissolved in ethyl acetate (20 mL), and then 10% palladium carbon (0 .2 g) was added. Under a hydrogen atmosphere, the mixture was stirred overnight at room temperature, and then filtered through Celite (registered trademark: manufactured by Celite Corporation). After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (1.4 g).
¹ HNMR (CDCl ₃ ): 1.44 (s, 9H), 1.94 (m, 2H), 2.39 (t, 2H), 4.05 (t, 2H), 6.99 (d, 2H) ), 7.93 (d, 2H).

(Step 3) t-butyl N- [4- [4- [7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptylamino] -4-oxo-butoxy] benzenecarboxy Of Imidoyl] carbamate

  4- (4- (N- (t-butoxycarbonyl) carbamidoyl) phenoxy) butanoic acid (0.32 g) obtained in Step 2 was dissolved in dimethylformamide (5 mL), and then diisopropylethylamine (0.15 g) was dissolved. ) And {{[(1-cyano-2-ethoxy-2-oxoethylidene) amino] oxy} -4-morpholinomethylene} dimethylammonium hexafluorophosphate (0.47 g) and t-butyl N-[(7 -Aminoheptylamino)-(t-butoxycarbonylamino) methylene] carbamate (0.41 g) was added. After stirring for one day at room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (Compound No. 47, 0.38 g).

Example 47
Synthesis of 4- (4-carbamidoylphenoxy) -N- (7-guanidinoheptyl) butanamide dihydrochloride

  T-Butyl N- [4- [4- [7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptylamino] -4-oxo-butoxy obtained in Example 46 [Benzenecarboximidoyl] carbamate (0.38 g) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1.5 mL) was added. After stirring overnight at room temperature, the solvent was distilled off under reduced pressure. Methanol (3 mL) and hydrogen chloride (4M dioxane solution, 3 mL) were added, and the mixture was stirred at room temperature for 2.5 hours. The solvent was evaporated under reduced pressure to give the title compound (Compound No. 46, 0.25 g). It was.

Examples 48 and 49
The compounds according to the present invention were synthesized in the same manner as in Examples 46 and 47. The structure of some of the synthesized compounds is shown in the table.

  Boc in the table means a t-butoxycarbonyl group.

Example 50
of t-butyl N- [4- [4- [acetyl- [7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptyl] amino] butoxy] benzenecarboximidyl] carbamate Composition

  Example 40 t-butyl N- [4- [4- [7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptylamino] butoxy] benzenecarboxy obtained in Step 3 Imidoyl] carbamate (100 mg) was dissolved in dichloromethane (3 mL), triethylamine (39 mg) and acetic anhydride (16 mg) were added at room temperature, and the mixture was stirred at the same temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 90 mg (yield: 85.7%) of the title compound (Compound No. 51). .

Examples 51-53
The compound according to the present invention was synthesized in the same manner as in Example 50 and Example 3. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Example 54
Synthesis of t-butyl N- [4- [4- [7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptyl-methyl-amino] butoxy] benzenecarboximidyl] carbamate

  Example 40 t-butyl N- [4- [4- [7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptylamino] butoxy] benzenecarboxy obtained in Step 3 Imidoyl] carbamate (224 mg) was dissolved in dichloromethane (5 mL) and formalin solution (10 mg) was added at 0 ° C. After heating up to room temperature, it stirred at the same temperature for 1 hour. After cooling to 0 ° C., sodium acetoxyborohydride (178 mg) was added at the same temperature. After heating up to room temperature, it stirred for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 119 mg (yield: 52.2%) of the title compound (Compound No. 55).

Examples 55-57
The compounds according to the present invention were synthesized in the same manner as in Example 54 and Example 3. The structure of some of the synthesized compounds is shown in the table.

  Boc in the table means a t-butoxycarbonyl group.

Synthesis Example 8
(Step 1) Synthesis of 4- (4-((t-butyldimethylsilyl) oxy) butoxy) -3-chlorobenzonitrile

4-((t-Butyldimethylsilyl) oxy) butan-1-ol (4.5 g) was dissolved in dimethylformamide (60 mL), and then sodium hydride (0.96 g) was added at 0 ° C. After stirring for 30 minutes, 3-chloro-4-fluorobenzonitrile (3.1 g) was added, and the mixture was stirred at room temperature for 18 hours. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and then purified by silica gel column chromatography to obtain the title compound (3.0 g).
¹ HNMR (CDCl ₃ ): 0.040 (s, 6H), 0.88 (s, 9H), 1.71 (m, 2H), 1.93 (m, 2H), 3.69 (t, 2H) ), 4.11 (t, 2H), 6.94 (d, 1H), 7.51 (d, 1H), 7.64 (s, 1H).

(Step 2) Synthesis of t-butyl ((3-chloro-4- (4-hydroxybutoxy) phenyl) (imino) methyl) carbamate

4- (4-((t-butyldimethylsilyl) oxy) butoxy) -3-chlorobenzonitrile (3.3 g) obtained in step 1 was dissolved in tetrahydrofuran (20 mL), and lithium diisopropylamide was obtained at room temperature. (1.3 M tetrahydrofuran solution, 10 mL) was added dropwise. After stirring for 19 hours, lithium diisopropylamide (1.3 M tetrahydrofuran solution, 5 mL) was added dropwise at room temperature, and the mixture was stirred for 21 hours. Hydrogen chloride (4M dioxane solution, 20 mL) and 20 mL of methanol were added to the reaction solution and stirred for 1.5 hours. The residue obtained by evaporating the solvent was dissolved in dimethylformamide (20 mL), and then triethylamine (5.0 g) and di-t-butyl dicarbonate (3.2 g) were added. After stirring at room temperature for 3.5 hours, water was added and the mixture was extracted with ethyl acetate. The solvent of the organic layer was distilled off under reduced pressure and then purified by silica gel column chromatography to obtain the title compound (1.1 g).
¹ HNMR (CDCl ₃ ): 1.52 (s, 9H), 1.78 (m, 2H), 1.95 (m, 2H), 4.73 (m, 2H), 4.09 (m, 2H) ), 6.88 (d, 1H), 7.73 (d, 1H), 7.92 (s, 1H).

Synthesis Example 9
(Step 1) Synthesis of t-butyl ((3-bromo-4-hydroxyphenyl) (imino) methyl) carbamate

3-Bromo-4-hydroxybenzonitrile (5.2 g) was dissolved in methanol (60 mL), and hydrochloric acid gas was blown at 0 ° C. After stirring for a whole day and night, the solvent was distilled off under reduced pressure, methanol (30 mL) and ammonia (7 M methanol solution, 15 mL) were added, and the mixture was stirred for 48 hours. After the solvent was distilled off under reduced pressure, dimethylformamide (60 mL) was added, and then triethylamine (7.9 g) and di-t-butyl dicarbonate (14.2 g) were added. After stirring overnight at room temperature, a 10% aqueous sodium hydroxide solution was added and stirred for 3 hours. After extraction with ethyl acetate, the organic layer was concentrated to obtain the title compound (4.4 g).
¹ HNMR (CDCl ₃ ): 1.50 (s, 9H), 7.10 (d, 1H), 7.62 (d, 1H), 7.98 (s, 1H).

(Step 2) t-Butyl ((3-bromo-4- (4-bromobutoxy) phenyl) (imino) methyl) carbamate

The t-butyl ((3-bromo-4-hydroxyphenyl) (imino) methyl) carbamate (4.4 g) obtained in Step 1 was dissolved in acetonitrile (50 mL), and then 1,4-dibromobutane (9. 1 g) and potassium carbonate (2.3 g) were added. After stirring at 60 ° C. for 8 hours, the mixture was filtered through Celite (registered trademark: manufactured by Celite Corporation), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.2 g).
¹ HNMR (CDCl ₃ ): 1.44 (s, 9H), 2.03 (m, 2H), 2.12 (m, 2H), 3.52 (t, 2H), 4.10 (m, 2H) ), 6.86 (d, 1H), 7.78 (d, 1H), 8.09 (s, 1H).

Synthesis Example 10
(Step 1) Synthesis of 3-bromo-4- (4-((t-butyldimethylsilyl) oxy) butoxy) benzonitrile

4-((t-Butyldimethylsilyl) oxy) butan-1-ol (2.0 g) was dissolved in tetrahydrofuran (30 mL), and then sodium hydride (0.48 g) was added at 0 ° C. After stirring for 30 minutes, 3-bromo-4-fluorobenzonitrile (2.2 g) was added, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After the organic layer was concentrated, the obtained residue was purified by silica gel column chromatography to obtain the title compound (3.4 g).
¹ HNMR (CDCl ₃ ): 0.040 (s, 6H), 0.88 (s, 9H), 1.72 (m, 2H), 1.93 (m, 2H), 3.69 (t, 2H) ), 4.11 (t, 2H), 6.89 (d, 1H), 7.55 (d, 1H), 7.81 (s, 1H).

(Step 2) Synthesis of 4- (4-((t-butyldimethylsilyl) oxy) butoxy) -3-methylbenzonitrile

3-Bromo-4- (4-((t-butyldimethylsilyl) oxy) butoxy) benzonitrile (3.3 g) obtained in Step 1 was dissolved in dioxane (25 mL) and water (5 mL), and then carbonated. Potassium (1.4 g), trimethylboroxine (1.6 g), tetrakis (triphenylphosphine) palladium (0) (0.50 g) were added. The mixture was heated under reflux for 24 hours and extracted with ethyl acetate. The organic layer was concentrated and purified by silica gel column chromatography to obtain the title compound (2.4 g).
¹ HNMR (CDCl ₃ ): 0.040 (s, 6H), 0.88 (s, 9H), 1.71 (m, 2H), 1.88 (m, 2H), 2.20 (s, 3H) ), 3.67 (t, 2H), 4.03 (t, 2H), 6.81 (d, 1H), 7.39 (s, 1H), 7.45 (d, 1H).

(Step 3) Synthesis of t-butyl ((4- (4-hydroxybutoxy) -3-methylphenyl) (imino) methyl) carbamate

Using 4- (4-((t-butyldimethylsilyl) oxy) butoxy) -3-methylbenzonitrile obtained in Step 2, the title compound was synthesized in the same manner as in Synthesis Example 8, Step 2. .
¹ HNMR (CDCl ₃ ): 1.54 (s, 9H), 1.77 (m, 2H), 1.91 (m, 2H), 2.22 (s, 3H), 3.72 (m, 2H) ), 4.03 (t, 2H), 6.79 (d, 1H), 7.66 (d, 1H), 7.69 (s, 1H).

Synthesis Example 11
(Step 1) Synthesis of 4- (4-((t-butyldimethylsilyl) oxy) butoxy) -3-fluorobenzonitrile

4-((t-Butyldimethylsilyl) oxy) butan-1-ol (4.5 g) was dissolved in dimethylformamide (60 mL), and then sodium hydride (0.96 g) was added at 0 ° C. After stirring for 30 minutes, 3,4-difluorobenzonitrile (2.8 g) was added and stirred at room temperature for 18 hours. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After the organic layer was concentrated, the residue was purified by silica gel column chromatography to obtain the title compound (3.6 g).
¹ HNMR (CDCl ₃ ): 0.040 (s, 6H), 0.88 (s, 9H), 1.69 (m, 2H), 1.91 (m, 2H), 3.68 (t, 2H) ), 4.11 (t, 2H), 6.99 (m, 1H), 7.33 (m, 1H), 7.38 (d, 1H).

(Step 2) t-butyl ((3-fluoro-4- (4-hydroxybutoxy) phenyl) (imino) methyl) carbamate

Using the 4- (4-((t-butyldimethylsilyl) oxy) butoxy) -3-fluorobenzonitrile obtained in Step 1, the title compound was synthesized in the same manner as in Synthesis Example 8, Step 2. .
¹ HNMR (CDCl ₃ ): 1.52 (s, 9H), 1.75 (m, 2H), 1.93 (m, 2H), 3.71 (t, 2H), 4.09 (t, 2H) ), 6.94 (m, 1H), 7.59 (m, 1H), 7.65 (d, 1H).

Synthesis Example 12
(Step 1) Synthesis of 4- (4-((t-butyldimethylsilyl) oxy) butoxy) -3-methoxybenzonitrile

4-Hydroxy-3-methoxybenzonitrile (1.49 g) and 4-((t-butyldimethylsilyl) oxy) butan-1-ol (2.2 g) were dissolved in tetrahydrofuran (30 mL), and then the mixture was heated to 0 ° C. Triphenylphosphine (3.9 g) and diethyl azodicarboxylate (2.2 M toluene solution, 7.5 mL) were added. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (3.3 g).
¹ HNMR (CDCl ₃ ): 0.033 (s, 6H), 0.87 (s, 9H), 1.67 (m, 2H), 1.92 (m, 2H), 3.67 (t, 2H) ), 3.86 (s, 3H), 4.08 (t, 2H), 6.87 (d, 1H), 7.05 (s, 1H), 7.23 (d, 1H).

(Step 2) t-butyl ((4- (4-hydroxybutoxy) -3-methoxyphenyl) (imino) methyl) carbamate

Using the 4- (4-((t-butyldimethylsilyl) oxy) butoxy) -3-methoxybenzonitrile obtained in Step 1, the title compound was synthesized in the same manner as in Synthesis Example 8, Step 2. .
¹ HNMR (CDCl ₃ ): 1.53 (s, 9H), 1.75 (m, 2H), 1.95 (m, 2H), 3.72 (m, 2H), 3.91 (s, 3H) ), 4.07 (m, 2H), 6.83 (d, 1H), 7.32 (d, 1H), 7.47 (s, 1H).

Examples 58-86
The compounds according to the present invention were synthesized in the same manner as in Example 40 or 40-2 using the compounds obtained in Synthesis Examples 8-12. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Synthesis Example 13
(Step 1) Synthesis of t-butyl N- [2-[(4-hydroxybenzenecarbomidoyl) amino] ethyl] -N-methyl-carbamate

Methyl 4-hydroxybenzenecarboimidate (1 g) was dissolved in methanol (20 mL) and triethylamine (4 mL), t-butyl N- (2-aminoethyl) -N-methyl-carbamate (1.11 g) at 0 ° C. Was added. The reaction mixture was warmed to room temperature and stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 1.01 g (yield 65.2%) of the title compound.
¹ HNMR (CDCl ₃ ): 1.42 (s, 9H), 2.79 (s, 3H), 3.30-3.50 (m, 4H), 6.50-6.64 (m, 2H) 7.30-7.39 (m, 2H).

(Step 2) Synthesis of t-butyl N- [2- [t-butoxycarbonyl- (4-hydroxybenzenecarbomidoyl) amino] ethyl] -N-methyl-carbamate

Using the t-butyl N- [2-[(4-hydroxybenzenecarbomidoyl) amino] ethyl] -N-methyl-carbamate obtained in Step 1, the title compound was prepared in the same manner as in Synthesis Example 6, Step 2. Obtained.
¹ HNMR (CDCl ₃ ): 1.40-1.50 (m, 18H), 2.92 (s, 3H), 3.46-3.60 (m, 4H), 6.50-6.62 ( m, 2H), 7.20 (d, 2H).

(Step 3) Synthesis of t-butyl N- [4- (4-bromobutoxy) benzenecarboximidyl] -N- [2- [t-butoxycarbonyl (methyl) amino] ethyl] carbamate

Using t-butyl N- [2- [t-butoxycarbonyl- (4-hydroxybenzenecarbomidoyl) amino] ethyl] -N-methyl-carbamate obtained in Step 2, the same as in Synthesis Example 9, Step 2. The title compound was obtained by the procedure.
¹ HNMR (CDCl ₃ ): 1.17 (s, 9H), 1.45 (s, 9H), 1.92-2.00 (m, 2H), 2.03-2.12 (m, 2H) 2.90 (s, 3H), 3.48 (t, 2H), 3.92-4.06 (m, 4H), 6.85 (d, 2H), 7.30-7.42 (m , 2H).

Synthesis Example 14
(Step 1) Synthesis of t-butyl ((4- (4-bromobutoxy) phenyl) ((methylsulfonyl) imino) methyl) carbamate

After dissolving t-butyl ((4- (4-bromobutoxy) phenyl) (imino) methyl) carbamate (0.45 g) in dichloromethane (5 mL), triethylamine (0.18 g), mesyl chloride (0.16 g) Was added. After stirring overnight at room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.32 g).
¹ HNMR (CDCl ₃ ): 1.42 (s, 9H), 1.97 (m, 2H), 2.03 (m, 2H), 3.12 (s, 3H), 3.48 (t, 2H) ), 4.04 (t, 2H), 6.89 (d, 2H), 7.56 (d, 2H).

(Step 2) Synthesis of 4- (4-bromobutoxy) -N- (methylsulfonyl) benzimidamide

T-Butyl ((4- (4-bromobutoxy) phenyl) ((methylsulfonyl) imino) methyl) carbamate (0.32 g) obtained in Step 1 was dissolved in dichloromethane (3 mL) and then trifluoroacetic acid (1 mL ) Was added. After stirring at room temperature for 17 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.22 g).
¹ HNMR (CDCl ₃ ): 1.97 (m, 2H), 2.06 (m, 2H), 3.09 (s, 3H), 3.48 (t, 2H), 4.05 (t, 2H) ), 6.92 (d, 2H), 7.76 (d, 2H).

Examples 87-90
Using the compounds obtained in Synthesis Examples 13 and 14, the compounds according to the present invention were synthesized in the same manner as in Example 40 or 40-2. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Synthesis Example 15
(Step 1) Synthesis of 5- (4-((t-butyldimethylsilyl) oxy) butoxy) picolinonitrile

4-((t-Butyldimethylsilyl) oxy) butan-1-ol (3.4 g) was dissolved in dimethylformamide (45 mL), and then sodium hydride (0.72 g) was added at 0 ° C. After stirring for 30 minutes, 5-fluoropicolinonitrile (1.8 g) was added and stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After the organic layer was concentrated, the residue was purified by silica gel column chromatography to obtain the title compound (1.1 g).
¹ HNMR (CDCl ₃ ): 0.040 (s, 6H), 0.88 (s, 9H), 1.67 (m, 2H), 1.90 (m, 2H), 3.67 (m, 2H) ), 4.09 (m, 2H), 7.20 (d, 1H), 7.62 (d, 1H), 8.34 (s, 1H).

(Step 2) t-butyl ((5- (4-hydroxybutoxy) pyridin-2-yl) (imino) methyl) carbamate

The title compound was obtained in the same manner as in Synthesis Example 8, Step 2, using 5- (4-((t-butyldimethylsilyl) oxy) butoxy) picolinonitrile obtained in Step 1.
¹ HNMR (CDCl ₃ ): 1.55 (s, 9H), 1.97-2.09 (m, 4H), 3.49 (t, 2H), 4.09 (t, 2H), 7.22 (D, 1H), 8.22 (s, 1H), 8.40 (d, 1H).

(Step 3) Synthesis of 4-((6- (N- (t-butoxycarbonyl) carbamidoyl) pyridin-3-yl) oxy) butyl methanesulfonate

t-Butyl ((5- (4-hydroxybutoxy) pyridin-2-yl) (imino) methyl) carbamate (0.8 g) was dissolved in dichloromethane (12 mL) and triethylamine (0.78 g) at 0 ° C. , Methanesulfonyl chloride (0.40 g) was added. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (0.85 g).
¹ HNMR (CDCl ₃ ): 1.55-1.60 (m, 11H), 1.97 (m, 2H), 3.01 (s, 3H), 4.09 (m, 2H), 4.30 (M, 2H), 7.21 (dd, 1H), 8.22 (d, 1H), 8.38 (d, 1H).

(Step 4) Synthesis of t-butyl ((5- (4-bromobutoxy) pyridin-2-yl) (imino) methyl) carbamate

4-((6- (N- (t-butoxycarbonyl) carbamidoyl) pyridin-3-yl) oxy) butyl methanesulfonate (0.85 g) obtained in step 3 was dissolved in acetonitrile (10 mL). Lithium bromide (0.38 g) was added at room temperature. After stirring at 40 ° C. for 4 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.49 g).
¹ HNMR (CDCl ₃ ): 1.55 (s, 9H), 1.97-2.09 (m, 4H), 3.49 (t, 2H), 4.09 (t, 2H), 7.22 (D, 1H), 8.22 (s, 1H), 8.40 (d, 1H).

Synthesis Example 16
(Step 1) Synthesis of 6- (3-((t-butyldimethylsilyl) oxy) propoxy) nicotinonitrile

After 3-((t-butyldimethylsilyl) oxy) propan-1-ol (1.9 g) was dissolved in tetrahydrofuran (30 mL), sodium hydride (0.48 g) was added at 0 ° C. After stirring for 30 minutes, 6-chloronicotinonitrile (1.5 g) was added, and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and then purified by silica gel column chromatography to obtain the title compound (2.7 g).
¹ HNMR (CDCl ₃ ): 0.022 (s, 6H), 0.87 (s, 9H), 1.98 (m, 2H), 3.75 (t, 2H), 4.45 (t, 2H) ), 6.77 (d, 1H), 7.75 (d, 1H), 8.46 (s, 1H).

(Step 2) t-Butyl ((6- (3-hydroxypropoxy) pyridin-3-yl) (imino) methyl) carbamate

The title compound was obtained in the same manner as in Synthesis Example 8, Step 2, using 6- (3-((t-butyldimethylsilyl) oxy) propoxy) nicotinonitrile obtained in Step 1.
¹ HNMR (CDCl ₃ ): 1.53 (s, 9H), 1.99 (m, 2H), 3.70 (t, 2H), 4.54 (t, 2H), 6.75 (d, 1H) ), 8.12 (d, 1H), 8.57 (s, 1H).

Examples 91-100
Using the compounds obtained in Synthesis Examples 15 and 16, the compounds according to the present invention were synthesized in the same manner as in Example 40 or 40-2. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Synthesis Example 17
(Step 1) Synthesis of 2- (3-((t-butyldimethylsilyl) oxy) propyl) benzofuran-5-carbonitrile

2- (3-hydroxypropyl) benzofuran-5-carbonitrile (8.3 g) was dissolved in dimethylformamide (20 mL), and then imidazole (6.8 g) and t-butyldimethylsilyl chloride (7.2 g) were added. It was. After stirring at room temperature for 1 hour, the residue was purified by silica gel column chromatography to obtain the title compound (11.5 g).
¹ HNMR (CDCl ₃ ): 0.043 (s, 6H), 0.89 (s, 9H), 1.95 (m, 2H), 2.87 (m, 2H), 3.68 (t, 2H) ), 6.44 (s, 1H), 7.44-7.48 (m, 2H), 7.80 (s, 1H).

(Step 2) Synthesis of t-butyl ((2- (3-hydroxypropyl) benzofuran-5-yl) (imino) methyl) carbamate

The title compound was obtained in the same manner as in Synthesis Example 8, Step 2, using 2- (3-((t-butyldimethylsilyl) oxy) propyl) benzofuran-5-carbonitrile obtained in Step 1.
¹ HNMR (CDCl ₃ ): 1.55 (s, 9H), 2.01 (m, 2H), 2.89 (m, 2H), 3.74 (m, 2H), 6.43 (s, 1H) ), 7.41 (d, 1H), 7.70 (d, 1H), 8.05 (s, 1H).

Synthesis Example 18
(Step 1) Synthesis of t-butyl N- (6-hydroxynaphthalene-2-carboimidoyl) carbamate

The title compound was synthesized in the same manner as in Synthesis Example 9 Step 1 using 6-hydroxy-2-naphthonitrile.
¹ HNMR (CDCl ₃ ): 1.54 (s, 9H), 7.11-7.16 (m, 2H), 7.70 (d, 1H), 7.79 (dd, 1H), 7.83 (D, 1H), 8.26-8.31 (m, 1H).

(Step 2) Synthesis of t-butyl N- [6- (2-bromoethoxy) naphthalene-2-carboximidyl] carbamate

The title compound was obtained in the same manner as in Synthesis Example 9, Step 2, using t-butyl N- (6-hydroxynaphthalene-2-carbomidoyl) carbamate obtained in Step 1.
¹ HNMR (CDCl ₃ ): 1.56 (s, 9H), 3.72 (t, 2H), 4.43 (t, 2H), 7.14 (d, 1H), 7.23 (dd, 1H) ), 7.75 (d, 2H), 7.82-7.90 (m, 2H), 8.38 (s, 1H).

Examples 101-110
Using the compounds obtained in Synthesis Examples 17 and 18, the compounds according to the present invention were synthesized in the same manner as in Example 40 or 40-2. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Example 111
(Step 1) Synthesis of t-butyl N- [4- (4-formylphenyl) benzenecarbomidoyl] carbamate

t-Butyl N- (4-bromobenzenecarbomidoyl) carbamate (500 mg) was dissolved in toluene (3 mL), and ethanol (2 mL) and water (1 mL) were added at room temperature. Further, (4-formylphenyl) boronic acid (250 mg), potassium carbonate (692 mg), and tetrakis (triphenylphosphine) palladium (0) (193 mg) were added at the same temperature. The reaction mixture was heated to 80 ° C. and stirred at the same temperature for 6 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 350 mg (yield 64.6%) of the title compound.
¹ HNMR (CDCl ₃ ): 7.70 (d, 2H), 7.78 (d, 2H), 8.02-7.96 (m, 4H).

(Step 2) t-Butyl N- [4- [4-[[7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptylamino] methyl] phenyl] benzenecarboximidyl Synthesis of carbamate

  T-Butyl N- [4- (4-formylphenyl) benzenecarbomidoyl] carbamate (115 mg) obtained in Step 1 was dissolved in methanol (3 mL) and t-butyl N-[(7-amino at room temperature). Heptylamino)-(t-butoxycarbonylamino) methylene] carbamate (100 mg) was added. After stirring at the same temperature for 1 hour, sodium borohydride (10.7 mg) was added, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 133 mg (yield 63.6%) of the title compound (Compound No. 112).

Synthesis Example 19
(Step 1) Synthesis of 4- (4-hydroxybutylsulfanyl) benzonitrile

4-Fluorobenzonitrile (950 mg) was dissolved in acetonitrile (10 mL), potassium carbonate (1.3 g) and 4-sulfanylbutan-1-ol (1 g) were added at room temperature, and the mixture was stirred at the same temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 660 mg (yield 40.5%) of the title compound.
¹ HNMR (CDCl ₃ ): 1.70-1.86 (m, 4H), 3.03 (dd, 2H), 3.70 (dd, 2H), 7.30 (d, 2H), 7.52 (D, 2H).

(Step 2) Synthesis of 4- [4- [t-butyl (dimethyl) silyl] oxybutylsulfanyl] benzonitrile

4- (4-hydroxybutylsulfanyl) benzonitrile (660 mg) was dissolved in dichloromethane (8 mL), and triethylamine (659 mg), t-butyldimethylsilyl chloride (590 mg) and 4-dimethylaminopyridine (40 mg) were dissolved at 0 ° C. added. The reaction mixture was warmed to room temperature and stirred at the same temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 978 mg (yield 93.4%) of the title compound.
¹ HNMR (CDCl ₃ ): 0.00 (s, 6H), 0.84 (s, 9H), 1.59-1.69 (m, 2H), 1.70-1.85 (m, 2H) 2.94-3.03 (m, 2H), 3.59-3.65 (m, 2H), 7.24 (d, 2H), 7.47 (d, 2H).

(Step 3) Synthesis of t-butyl N- [4- (4-hydroxybutylsulfanyl) benzenecarboximidyl] carbamate

The title compound was obtained in the same manner as in Synthesis Example 8, Step 2, using 4- [4- [t-butyl (dimethyl) silyl] oxybutylsulfanyl] benzonitrile obtained in Step 2.
¹ HNMR (CDCl ₃ ): 1.55 (s, 9H), 1.68-1.82 (m, 4H), 3.01 (dd, 2H), 3.67 (dd, 2H), 7.30 (D, 2H), 7.76 (d, 2H).

(Step 4) Synthesis of t-butyl N- [4- (4-bromobutylsulfanyl) benzenecarboximidyl] carbamate

Using the t-butyl N- [4- (4-hydroxybutylsulfanyl) benzenecarboxyimidoyl] carbamate obtained in Step 3, the title compound was obtained in the same manner as in Synthesis Example 15, Steps 3 and 4.
¹ HNMR (CDCl ₃ ): 1.54 (s, 9H), 1.80-1.92 (m, 2H), 1.98-2.08 (m, 2H), 3.01 (dd, 2H) 3.44 (dd, 2H), 7.26-7.36 (m, 2H), 7.71-7.80 (m, 2H).

Synthesis Example 20
(Step 1) Synthesis of 4-((3-((t-butyldimethylsilyl) oxy) propoxy) methyl) benzonitrile

After 3-((t-butyldimethylsilyl) oxy) propan-1-ol (1.1 g) was dissolved in tetrahydrofuran (18 mL), sodium hydride (0.26 g) was added at 0 ° C. After stirring for 15 minutes, 4- (bromomethyl) benzonitrile (0.98 g) was added, and the mixture was stirred at room temperature for 17 hours. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After the organic layer was concentrated, the residue was purified by silica gel column chromatography to obtain the title compound (1.2 g).
¹ HNMR (CDCl ₃ ): 0.030 (s, 6H), 0.87 (s, 9H), 1.82 (m, 2H), 3.58 (t, 2H), 3.71 (t, 2H) ), 4.54 (s, 2H), 7.42 (d, 2H), 7.61 (d, 2H).

(Step 2) Synthesis of t-butyl ((4-((3-hydroxypropoxy) methyl) phenyl) (imino) methyl) carbamate

The title compound was obtained in the same manner as in Synthesis Example 8, Step 2, using 4-((3-((t-butyldimethylsilyl) oxy) propoxy) methyl) benzonitrile obtained in Step 1.
¹ HNMR (CDCl ₃ ): 1.54 (s, 9H), 1.87 (m, 2H), 3.65 (t, 2H), 3.77 (m, 2H), 4.55 (s, 2H) ), 7.37 (d, 2H), 7.82 (d, 2H).

Examples 112-121
The compound according to the present invention was synthesized in the same manner as in Example 111. Moreover, the compound which concerns on this invention was synthesize | combined by the method similar to Example 40 or 40-2 using the compound obtained by the synthesis examples 19 and 20. FIG. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Example 122
(Step 1) Synthesis of t-butyl N- [N, N′-bis (t-butoxycarbonyl) carbamidoyl] -N- [6- [t-butyl (dimethyl) silyl] oxyhex-3-ynyl] carbamate

6- [t-Butyl (dimethyl) silyl] oxyhex-3-ynyl-1-ol (1.5 g) was dissolved in tetrahydrofuran (30 mL) and triphenylphosphine (1.73 g), t-butyl N was dissolved at 0 ° C. -[Bis (t-butoxycarbonylamino) methylene] carbamate (3.54 g), diethyl azodicarboxylate (2.2 M in toluene) (2.99 mL) were added. The reaction mixture was warmed to room temperature and stirred at the same temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 1.48 g (yield 39.6%) of the title compound.
¹ HNMR (CDCl ₃ ): 0.07 (s, 6H), 0.89 (s, 9H), 1.47-1.55 (m, 27H), 2.31-2.38 (m, 2H) 2.49-2.55 (m, 2H), 3.67 (t, 2H), 3.91 (t, 2H).

(Step 2) Synthesis of t-butyl N- [N, N'-bis (t-butoxycarbonyl) carbamidoyl] -N- (6-hydroxyhex-3-ynyl) carbamate

T-Butyl N- [N, N′-bis (t-butoxycarbonyl) carbamidoyl] -N- [6- [t-butyl (dimethyl) silyl] oxyhex-3-ynyl] carbamate obtained in Step 1 (1.48 g) was dissolved in tetrahydrofuran (15 mL), and tetrabutylammonium fluoride (1M tetrahydrofuran solution) (2.7 mL) was added at 0 ° C. The reaction mixture was warmed to room temperature and stirred at the same temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.02 g (yield 87.2%) of the title compound.
¹ HNMR (CDCl ₃ ): 1.48-1.54 (m, 27H), 2.36-2.42 (m, 2H), 2.50-2.56 (m, 2H), 3.66 ( dd, 2H), 3.96 (t, 2H).

(Step 3) t-butyl N- (N, N′-bis (t-butoxycarbonyl) carbamidoyl) -N- [6- [4- [4- (Nt-butoxycarbonylcarbamidoyl) phenoxy Synthesis of butyl- (2-nitrophenyl) sulfonyl-amino] hex-3-ynyl] carbamate

  T-Butyl N- [N, N′-bis (t-butoxycarbonyl) carbamidoyl] -N- (6-hydroxyhex-3-ynyl) carbamate (221 mg) obtained in Step 2 was added to tetrahydrofuran (4 mL). Triphenylphosphine (159 mg), t-butyl N- [4- [4-[(2-nitrophenyl) sulfonylamino] butoxy] benzenecarboximidyl] carbamate (200 mg), diethyl azodi at 0 ° C. Carboxylate (2.2 M in toluene) (277 μL) was added. The reaction mixture was warmed to room temperature and stirred at the same temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 115 mg (yield: 30.5%) of the title compound (Compound No. 124).

Synthesis Example 21
(Step 1) Synthesis of t-butyl N- [4- [4- [t-butyl (dimethyl) silyl] oxybut-2-ynoxy] benzenecarboximidyl] carbamate

4-Bromobut-2-ynoxy-t-butyl-dimethyl-silane (274 mg) was dissolved in acetonitrile (4 mL), and potassium carbonate (158 mg), t-butyl N- (4-hydroxybenzenecarboxyimidoyl) carbamate at room temperature. (246 mg) was added. The reaction mixture was heated to 60 ° C. and stirred at the same temperature for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 225 mg (yield 51.7%) of the title compound.
¹ HNMR (CDCl ₃ ): 0.09 (s, 6H), 0.89 (s, 9H), 1.55 (s, 9H), 4.34 (s, 2H), 4.77 (s, 2H) ), 6.99 (d, 2H), 7.83 (d, 2H).

(Step 2) Synthesis of t-butyl N- [4- (4-hydroxybut-2-ynoxy) benzenecarboximidyl] carbamate

T-butyl N- [4- [4- [t-butyl (dimethyl) silyl] oxybut-2-ynoxy] benzenecarboximidyl] carbamate (225 mg) obtained in step 1 was dissolved in tetrahydrofuran (3 mL), Tetrabutylammonium fluoride (1M tetrahydrofuran solution) (564 μL) was added at 0 ° C. The reaction mixture was warmed to room temperature and stirred at the same temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 131 mg (yield 80.4%) of the title compound.
¹ HNMR (CDCl ₃ ): 1.55 (s, 9H), 4.31 (s, 2H), 4.78 (s, 2H), 6.99 (d, 2H), 7.83 (d, 2H) ).

Examples 123-127
The compound according to the present invention was synthesized in the same manner as in Example 122. In addition, the compound according to the present invention was synthesized in the same manner as in Example 40 or 40-2 using the compound obtained in Synthesis Example 21. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Synthesis Example 22
(Step 1) Synthesis of 4- (5-hydroxypent-1-ynyl) benzonitrile

4-Bromobenzonitrile (2 g) was dissolved in diisopropylamine (20 mL), and 4-pentyn-1-ol (1.2 g), dichlorobis (triphenylphosphine) palladium (383 mg), copper iodide (62 mg) at room temperature. Was added. The reaction mixture was heated to 70 ° C. and stirred at the same temperature overnight. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.85 g (92.0%) of the title compound.
¹ HNMR (CDCl ₃ ): 1.88 (td, 2H), 2.57 (t, 2H), 3.82 (dd, 2H), 7.46 (d, 2H), 7.57 (d, 2H) ).

(Step 2) Synthesis of 4- [5- [t-butyl (dimethyl) silyl] oxypent-1-ynyl] benzonitrile

4- (5-Hydroxypent-1-ynyl) benzonitrile (1.85 g) obtained in Step 1 is dissolved in dichloromethane (20 mL), triethylamine (2.0 g), t-butyldimethylsilyl chloride at 0 ° C. (1.66 g) and 4-dimethylaminopyridine (122 mg) were added. The reaction mixture was warmed to room temperature and stirred at the same temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 2.84 g (yield 94.6%) of the title compound.
¹ HNMR (CDCl ₃ ): 0.07 (s, 6H), 0.91 (s, 9H), 1.82 (td, 2H), 2.51 (t, 2H), 3.75 (t, 2H) ), 7.45 (d, 2H), 7.56 (d, 2H).

(Step 3) Synthesis of t-butyl N- [4- (5-hydroxypent-1-ynyl) benzenecarboximidyl] carbamate

4- [5- [t-Butyl (dimethyl) silyl] oxypent-1-ynyl] benzonitrile (2 g) obtained in step 2 is dissolved in tetrahydrofuran (20 mL), and lithium bis (trimethylsilyl) amide (1 .3M tetrahydrofuran solution) (7.2 mL) was added. After stirring at the same temperature for 1 hour, hydrogen chloride (4M dioxane solution) (20 mL) and methanol (20 mL) were added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in dimethylformamide (20 mL), and triethylamine (2.7 g) and di-t-butyl dicarbonate (2.92 g) were added at 0 ° C. The reaction mixture was warmed to room temperature and stirred at the same temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.24 g (yield 61.3%) of the title compound.
¹ HNMR (CDCl ₃ ): 1.55 (s, 9H), 1.88 (td, 2H), 2.57 (t, 2H), 3.82 (dd, 2H), 7.44 (d, 2H) ), 7.79 (d, 2H).

(Step 4) Synthesis of 5- [4- (Nt-butoxycarbonylcarbamidoyl) phenyl] pent-4-ynyl methanesulfonate

T-Butyl N- [4- (5-hydroxypent-1-ynyl) benzenecarboximidyl] carbamate (500 mg) obtained in Step 3 was dissolved in dichloromethane (5 mL), triethylamine (400 mg) at 0 ° C., Methanesulfonyl chloride (227 mg) and 4-dimethylaminopyridine (20 mg) were added. The reaction mixture was warmed to room temperature and stirred at the same temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 640 mg (quantitative) of the title compound.
¹ HNMR (CDCl ₃ ): 1.55 (s, 9H), 2.06 (td, 2H), 2.61 (t, 2H), 3.04 (s, 3H), 4.41 (t, 2H) ), 7.44 (d, 2H), 7.79 (d, 2H).

(Step 5) Synthesis of t-butyl N- [4- (5-bromopent-1-ynyl) benzenecarboximidyl] carbamate

5- [4- (Nt-butoxycarbonylcarbamidoyl) phenyl] pent-4-ynyl methanesulfonate (646 mg) obtained in step 4 was dissolved in acetonitrile (7 mL), and lithium bromide (7 mL) was dissolved at room temperature. 295 mg) was added. The reaction mixture was heated to 50 ° C. and stirred at the same temperature for 5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 485 mg (yield 78.1%) of the title compound.
¹ HNMR (CDCl ₃ ): 1.55 (s, 9H), 2.20-2.12 (m, 2H), 2.63 (t, 2H), 3.62-3.54 (m, 3H) , 7.44 (d, 2H), 7.78 (d, 2H).

Examples 128-132
Using the compound obtained in Synthesis Example 22, the compound according to the present invention was synthesized in the same manner as in Example 40-2. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Example 133
t-butyl N- [4- [5- [7-[[(Z) -N, N'-bis (t-butoxycarbonyl) carbamidoyl] amino] heptylamino] pent-1-enyl] benzenecarboximide Of [Il] carbamate

  t-butyl N- [4- [5- [7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptylamino] pent-1-ynyl] benzenecarboxyimidoyl] carbamate ( Compound No .: 129, 100 mg) was dissolved in methanol (2 mL), and Lindlar catalyst (10 mg) was added at room temperature. The system was purged with hydrogen at the same temperature and stirred for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 55 mg (yield: 55.6%) of the title compound (Compound No. 134) (alkene / alkane = 4/1).

Example 134
Synthesis of t-butyl N- [4- [5- [7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptylamino] pentyl] benzenecarboximidyl] carbamate

  t-butyl N- [4- [5- [7-[[N, N′-bis (t-butoxycarbonyl) carbamidoyl] amino] heptylamino] pent-1-ynyl] benzenecarboxyimidoyl] carbamate ( Compound No. 129, 200 mg) was dissolved in methanol (5 mL), and 10% palladium carbon (20 mg) was added at room temperature. The system was purged with hydrogen at the same temperature and stirred overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 175 mg (yield: 87.1%) of the title compound (Compound No. 136).

Examples 135, 136
The compound according to the present invention was synthesized in the same manner as in Examples 133 and 134. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Synthesis Example 23
Synthesis of t-butyl-N-[[3- (3-aminopropoxy) propylamino]-(t-butoxycarbonylamino) methylene] carbamate

3- (3-Aminopropoxy) propan-1-amine (1.5 g) was dissolved in dichloromethane (30 mL), diisopropylethylamine (977 mg) and Goodman reagent (2.98 g) were added at room temperature, and 4 at the same temperature. Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.02 g (yield 71.4%) of the title compound.
¹ HNMR (CDCl ₃ ): 1.49 (s, 9H), 1.50 (s, 9H), 1.74 (tt, 2H), 1.83 (tt, 2H), 2.79 (t, 2H) ), 3.49-3.58 (m, 6H).

Examples 137, 138
Using the compound obtained in Synthesis Example 23, the compound according to the present invention was synthesized in the same manner as in Examples 23 and 24. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Example 139
(Step 1) t-butyl N-[(t-butoxycarbonylamino)-[5-[(2,2,2-trifluoroacetyl)-[2-[(2,2,2-trifluoroacetyl) amino ]] Ethyl] amino] pentylamino] methylene] carbamate

2,2,2-trifluoro-N- [2-[(2,2,2-trifluoroacetyl) amino] ethyl] acetamide (5.56 g) and t-butyl (N-[(5-bromopentylamino) )-(T-Butoxycarbonylamino) methylene] carbamate (3.00 g) in dimethylformamide (30 mL) was added potassium carbonate (3.05 g) and reacted at room temperature for 8 days, after which the reaction mixture was poured into water. The organic layers were combined, dried over anhydrous magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and 2.14 g (yield 50) of the title compound. %)Obtained.
¹ HNMR (CDCl ₃ ): 1.32 (dt, 2H), 1.48 (t, 9H), 1.52 (t, 9H), 1.57-1.76 (m, 4H), 3.42 (T, 2H), 3.53-3.69 (m, 4H), 3.90 (t, 2H), 7.48 (br.s, 1H), 9.25 (br.s, 2H).

(Step 2) Synthesis of 4- [3- [2- (5-guanidinopentylamino) ethylamino] propoxy] benzamidine tetrahydrochloride

  T-Butyl N-[(t-butoxycarbonylamino)-[5-[(2,2,2-trifluoroacetyl)-[2-[(2,2,2-trifluoroacetyl) obtained in Step 1 ) Amino] ethyl] amino] pentylamino] methylene] carbamate (1.21 g) and t-butyl N- [4- (4-bromobutoxy) benzenecarboximidyl] carbamate (1.20 g) in dimethylformamide (24 mL) Potassium carbonate (0.38 g) was added to the solution and reacted at 50 ° C. overnight. The reaction mixture was then cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.57 g (yield 32%) of Compound A.

  Next, the obtained compound A (0.57 g) was dissolved in methanol (57 mL), potassium carbonate (0.90 g) was added at room temperature, and the mixture was stirred at the same temperature for 3 days. Thereafter, the reaction mixture was concentrated under reduced pressure, and the resulting residue was poured into water and extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.28 g (yield 63%) of Compound B.

  Compound B (0.37 g) was then dissolved in dichloromethane (18 mL) and trifluoroacetic acid (9 mL) was added at room temperature. After stirring overnight at the same temperature, the mixture was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), hydrogen chloride dioxane solution (4 M, 15 mL) was added at room temperature, stirred at the same temperature for 1 hr, concentrated under reduced pressure, and the title compound (Compound No. 139) was reduced to 0. .49 g (quantitative) was obtained.

Example 140
The compound according to the present invention was synthesized in the same manner as in Example 139. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Examples 141-148
The compound according to the present invention was synthesized in the same manner as in Example 2 or 3. The structure of some of the synthesized compounds is shown in the table.

  Boc in the table means a t-butoxycarbonyl group. In the table, DBS means dodecylbenzenesulfonic acid.

Synthesis Example 24
(Step 1) Synthesis of t-butyl 2- [4- (5-hydroxypent-1-ynyl) phenyl] imidazole-1-carboxylate

The title compound was synthesized in the same manner as in Synthesis Example 22, Step 1 using t-butyl 2- (4-bromophenyl) -1H-imidazole-1-carboxylate.
¹ HNMR (CDCl ₃ ): 1.43 (s, 9H), 1.87 (tt, 2H), 2.56 (t, 2H), 3.84 (dd, 2H), 7.06 (d, 1H) ), 7.42 (d, 2H), 7.46-7.52 (m, 3H).

(Step 2) Synthesis of t-butyl 2- [4- (5-bromopent-1-ynyl) phenyl] imidazole-1-carboxylate

Using the t-butyl 2- [4- (5-hydroxypent-1-ynyl) phenyl] imidazole-1-carboxylate obtained in Step 1, the title compound was prepared in the same manner as in Synthesis Example 22, Steps 4 and 5. Was synthesized.
¹ HNMR (CDCl ₃ ): 1.44 (s, 9H), 2.15 (tt, 2H), 2.63 (t, 2H), 3.59 (t, 2H), 7.07 (d, 1H) ), 7.43 (d, 2H), 7.47-7.52 (m, 3H).

Synthesis Example 25
(Step 1) Synthesis of 4- (4-((t-butyldimethylsilyl) oxy) butoxy) -2-fluorobenzonitrile

The title compound was synthesized in the same manner as in Synthesis Example 12, Step 1 using 2-fluoro-4-hydroxybenzonitrile.
¹ HNMR (CDCl ₃ ): 0.06 (s, 6H), 0.90 (s, 9H), 1.61-1.72 (m, 2H), 1.81-1.92 (m, 2H) 3.68 (t, 2H), 4.03 (t, 2H), 6.69 (dd, 1H), 6.75 (dd, 1H), 7.50 (dd, 1H).

(Step 2) Synthesis of 6- [4- [t-butyl (dimethyl) silyl] oxybutoxy] -1,2-benzoxazol-3-amine

4- (4-((t-butyldimethylsilyl) oxy) butoxy) -2-fluorobenzonitrile (4 g) obtained in step 1 is dissolved in dimethylformamide (85 mL), and water (14 mL), carbonic acid is dissolved at room temperature. Potassium (10.28 g) and acetohydroxamic acid (2.78 g) were added. The reaction mixture was heated to 80 ° C. and stirred at the same temperature overnight. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.31 g (yield 55.5%) of the title compound.
¹ HNMR (CDCl ₃ ): 0.06 (s, 6H), 0.90 (s, 9H), 1.66-1.75 (m, 2H), 1.84-1.94 (m, 2H) 3.68 (t, 2H), 4.04 (t, 2H), 6.82-6.86 (m, 2H), 7.35 (d, 1H).

(Step 3) Synthesis of t-butyl Nt-butoxycarbonyl-N- [6- [4- [t-butyl (dimethyl) silyl] oxybutoxy] -1,2-benzoxazol-3-yl] carbamate

6- [4- [t-Butyl (dimethyl) silyl] oxybutoxy] -1,2-benzoxazol-3-amine (2.31 g) obtained in Step 2 was dissolved in dichloromethane, and triethylamine ( 1.39 g), di-t-butyl dicarbonate (1.94 g) and 4-dimethylaminopyridine (83 mg) were added. The reaction mixture was warmed to room temperature and stirred at the same temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.64 g (yield 44.6%) of the title compound.
¹ HNMR (CDCl ₃ ): 0.07 (s, 6H), 0.91 (s, 9H), 1.40 (s, 18H), 1.68-1.76 (m, 2H), 1.88 -1.94 (m, 2H), 3.71 (t, 2H), 4.07 (t, 2H), 6.95-6.99 (m, 2H), 7.36 (d, 1H).

(Step 4) Synthesis of t-butyl Nt-butoxycarbonyl-N- [6- (4-hydroxybutoxy) -1,2-benzoxazol-3-yl] carbamate

T-Butyl Nt-butoxycarbonyl-N- [6- [4- [t-butyl (dimethyl) silyl] oxybutoxy] -1,2-benzoxazol-3-yl] carbamate obtained in Step 3 ( 1.64 g) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (1M tetrahydrofuran solution) (3.4 mL) was added at 0 ° C. The reaction mixture was warmed to room temperature and stirred at the same temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 1.02 g (yield 79.2%) of the title compound.
¹ HNMR (CDCl ₃ ): 1.41 (s, 18H), 1.75-1.84 (m, 2H), 1.91-2.02 (m, 2H), 3.76 (dd, 2H) , 4.09 (t, 2H), 6.93-7.00 (m, 2H), 7.37 (d, 1H).

Synthesis Example 26
(Step 1) Synthesis of 4-hydroxy-N-methyl-benzamidine

Methyl 4-hydroxybenzenecarboxyimidate (2.5 g) was dissolved in methanol (40 mL), and triethylamine (13 mL) and methylamine (40% methanol solution) (2.07 g) were added at 0 ° C. The reaction mixture was warmed to room temperature and stirred at the same temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give the title compound.
¹ HNMR (CDCl ₃ ): 3.05 (s, 3H), 6.84 (d, 2H), 7.55 (d, 2H).

(Step 2) Synthesis of [4- (N′-t-butoxycarbonyl-N-methyl-carbamidoyl) phenyl) t-butyl carbamate

The title compound was obtained in the same manner as in Synthesis Example 6, Step 2, using 4-hydroxy-N-methyl-benzamidine obtained in Step 1.
¹ HNMR (CDCl ₃ ): 1.14 (s, 9H), 1.57 (s, 9H), 3.37 (brs, 3H), 7.19 (d, 2H), 7.36-7.48 (M, 2H).

(Step 3) Synthesis of t-butyl-N-[(4-hydroxyphenyl)-(methylamino) methylene] carbamate

Using [4- (N′-t-butoxycarbonyl-N-methyl-carbamidoyl) phenyl) t-butyl carbamate obtained in Step 2, the title compound was obtained in the same manner as in Synthesis Example 6, Step 3. It was.
¹ HNMR (CDCl ₃ ): 1.21 (s, 9H), 3.32 (s, 3H), 6.80 (d, 2H), 7.31 (d, 2H).

(Step 4) Synthesis of t-butyl-N-[[4- (4-bromobutoxy) phenyl]-(methylamino) methylene] carbamate

The title compound was obtained in the same manner as in Synthesis Example 6, Step 4, using t-butyl-N-[(4-hydroxyphenyl)-(methylamino) methylene] carbamate obtained in Step 3.
¹ HNMR (CDCl ₃ ): 1.18 (s, 9H), 1.92-2.01 (m, 2H), 2.02-2.13 (m, 2H), 3.34 (s, 3H) , 3.50 (t, 2H), 4.00-4.06 (m, 2H), 6.86-6.92 (m, 2H), 7.36 (d, 1H), 7.67 (d , 1H).

Examples 149-154
Using the compounds obtained in Synthesis Examples 24-26, the compounds according to the present invention were synthesized in the same manner as in Example 40 or 40-2. The structure of some of the synthesized compounds is shown in the table.

Boc in the table means a t-butoxycarbonyl group.

Formulation Example (Emulsion)
Compound of the present invention 5.62 parts by mass Surfactant 4.49 parts by mass Dimethylformamide 89.89 parts by mass The above components were mixed and dissolved to obtain an emulsion containing 5.62% by mass of the active ingredient.

(Apple black spot disease prevention test)
The emulsion prepared by the formulation of the preparation examples was diluted with water so that the active ingredient was 125 ppm. The diluted solution was sprayed on apple seedlings grown in an unglazed pot (variety “Wang Lin”, 3-4 leaf stage). Allow to dry naturally at room temperature. Then, conidia of apple scab (Venturia inaequalis) were inoculated, and the light and darkness was repeated every 12 hours and kept in a room at 20 ° C. and high humidity for 2 weeks. The control effect was examined by comparing the appearance of lesions on the leaves with no treatment.

  Compounds 7, 9, 19, 22, 28, 30, 32, 34, 36, 41, 43, 46, 58, 61, 64, 66, 68, 71, 74, 77, 80, 82, 84, 87, 89 , 91, 93, 95, 98, 101, 103, 105, 108, 115, 118, 120, 125, 128, 130, 133, 135, 137, 139, 141, 143, and 147 Went. All the compounds showed a control value of 75% or more.

(Cucumber gray mold control test)
The emulsion prepared by the formulation of the preparation examples was diluted with water so that the active ingredient was 125 ppm. The diluted solution was sprayed on cucumber seedlings grown in an unglazed pot (variety "Tokiwa Chiku", cotyledon stage). After natural drying at room temperature, a conidial spore suspension of cucumber gray mold fungus (Botrytis cinerea) was inoculated dropwise and kept in a dark place at 20 ° C. in a high humidity room for 4 days. The lesion appearance state on the leaf was compared with no treatment, and the control effect was obtained.

  Compound 7, 9, 13, 19, 22, 28, 30, 32, 34, 36, 38, 41, 43, 46, 48, 52, 54, 56, 58, 61, 64, 66, 68, 71, 74 77, 80, 82, 84, 87, 89, 91, 93, 95, 98, 101, 103, 105, 108, 111, 115, 118, 120, 122, 125, 128, 130, 133, 135, 137 139, 141, 142, 143, 144, and 147 were subjected to the cucumber gray mold control test. All the compounds showed a control value of 75% or more.

(Wheat powdery mildew control trial)
The emulsion prepared by the formulation of the preparation examples was diluted with water so that the active ingredient was 125 ppm. The diluted solution was sprayed on wheat seedlings grown in an unglazed pot (variety “Chihoku”, 1.0-1.2 leaf stage). After the leaves were air-dried, conidia spores of wheat powdery mildew (Erysiphe graminis f.sp.tritici) were shaken off and inoculated in a greenhouse at 22 to 25 ° C. for 7 days. The lesion appearance state on the leaf was compared with no treatment, and the control effect was obtained.

  Compounds 7, 9, 19, 28, 30, 32, 34, 36, 38, 41, 43, 46, 48, 54, 56, 58, 61, 64, 66, 68, 71, 74, 77, 80, 82 , 84, 87, 91, 93, 95, 98, 101, 103, 105, 111, 113, 115, 118, 120, 122, 125, 128, 130, 133, 135, 139, 141, 142, 143, 144 , And 147 were subjected to the wheat powdery mildew control test. All the compounds showed a control value of 75% or more.

(Tomato plague control trial)
The emulsion prepared by the formulation of the preparation examples was diluted with water so that the active ingredient was 125 ppm. The diluted solution was sprayed on tomato seedlings (variety “Regina”, 4-5 leaf stage) cultivated in an unglazed pot. After the leaves were air-dried, a zoospore suspension of Phytophthora infestans was spray-inoculated, and kept for 4 days in a high-humidity constant temperature room (20 ° C.) repeating light and dark every 12 hours. The lesion appearance on the leaves was compared with no treatment, and the control value was determined.

  For compounds 7, 9, 34, 41, 43, 58, 61, 64, 68, 71, 77, 82, 84, 87, 93, 98, 105, 108, 115, 120, 128, 130, 139, and 143 The tomato plague control test was conducted. All the compounds showed a control value of 75% or more.

(Wheat red rust prevention test)
The emulsion prepared by the formulation of the preparation examples was diluted with water so that the active ingredient was 125 ppm. The diluted solution was sprayed on wheat seedlings (variety “Noribayashi No. 61”, 1.0-1.2 leaf stage) cultivated in an unglazed pot. After the leaves were air-dried, summer spores of wheat rust (Puccinia recondita) were shaken off and inoculated in a greenhouse at 22 to 25 ° C. for 10 days. The lesion appearance state on the leaf was compared with no treatment, and the control effect was obtained.
Compounds 7, 9, 19, 22, 34, 41, 43, 54, 56, 61, 64, 66, 68, 71, 74, 77, 82, 84, 87, 91, 93, 98, 101, 103, 105 111, 113, 115, 120, 128, 130, 133, 135, 142, 143, 144, and 147 were subjected to the wheat rust control test. All the compounds showed a control value of 75% or more.

The arylamidine compound according to the first embodiment of the present invention (compound represented by formula (I) or formula (II) or a salt thereof) is excellent in bactericidal activity, excellent in safety, and industrially advantageous. Can be synthesized. The fungicide or plant disease control agent of the third embodiment containing the arylamidine compound as an active ingredient is used for plant diseases such as apple black scab, cucumber gray mold, wheat powdery mildew, tomato blight, wheat rust. Excellent control value.
An arylamidine compound (compound represented by formula (III-1) or formula (III-2)) and a guanidine compound (formula (IV-1) or formula (IV-2) according to the second embodiment of the present invention Is useful as an intermediate for producing the arylamidine compound of the first embodiment of the present invention (the compound represented by formula (I) or formula (II) or a salt thereof) at low cost. It is.

Claims (6)

A compound represented by formula (I) or a salt thereof.

(In the formula (I),
Ar represents a halogeno group, an alkyl group, an alkoxy group, or a cyano group may be substituted divalent aromatic hydrocarbons, or a divalent pyridine unsubstituted,
Q is a single bond, unsubstituted off Eniren, -CH = CH -, - C≡C -, - O -, - S -, - SO-, or, -SO ₂ - shows a.
X and Z are each independently an unsubstituted A alkylene group, an unsubstituted A Rukeniren group, an unsubstituted A Rukiniren group, -T ^a -O-T ^b - or ^-T a -N ^{(R 20),} -T ^b - shows the. T ^a and ^{T b} are each independently a non-substituted A alkylene ^{group, R 20} represents a hydrogen atom.
Y is —C (═O) —NH—, —NH—C (═O) —, or Formula (Ia)

In (Formula (Ia), A, a single bond, -C (= O) -, or -SO ₂ - indicates, ^{R 7} is a hydrogen atom, an unsubstituted alkyl group, an unsubstituted an alkoxy group or, shows the unsubstituted aryloxy group.) indicates,
W represents a single bond or —N (R ⁸ ) —. R ⁸ represents a hydrogen atom.
R ¹ to R ⁶ are each independently a hydrogen atom, an alkyl group which may be substituted with an alkylamino, an unsubstituted alkenyl group, a substituted or unsubstituted alkoxycarbonyl group, or an unsubstituted A alkylsulfonyl group Show. Bonded with R ¹ and R ² together, 1,4,5,6-tetrahydropyrimidine, 4,5-dihydro -1H- imidazole, or may form an imidazole. Any one of R ^{1 to} R ³ and Ar may be bonded together to form benzisoxazole . ) The compound or a salt thereof according to claim 1, wherein the formula (I) is represented by the formula (II).

(In the formula (II),
G represents a carbon atom or a nitrogen atom;
Q, X, Y, Z 2 , W, and R ^{1 to} R ⁶ are as defined in claim 1.
When G represents a carbon atom,
R ³⁰ represents C1~6 alkyl group, C 1 to 6 alkoxy groups, C Rogeno group, or a cyano group. Any one of R ^{1 to} R ³ and R ³⁰ may be bonded together to form a benzoisoxazole .
p represents the number of R ³⁰ and is an integer of 0 to 4.
When G represents a nitrogen atom, p is 0. )   A fungicide containing as an active ingredient at least one selected from the compound according to claim 1 or 2 or a salt thereof.   A plant disease control agent comprising at least one selected from the compound according to claim 1 or a salt thereof. A compound represented by the formula (III-2).

(In the formula (III-2),
Ar represents a halogeno group, an alkyl group, an alkoxy group, or a cyano group may be substituted divalent aromatic hydrocarbons, or a divalent pyridine unsubstituted,
Q is a single bond, unsubstituted off Eniren, -CH = CH -, - C≡C -, - O -, - S -, - SO-, or -SO ₂ - shows a.
X ¹ is an unsubstituted A alkylene group, an unsubstituted A Rukeniren group, an unsubstituted A Rukiniren ^{group, -T a -O-T b -} , or ^{-T a -N (R 20) -T} b - a shows, ^{T a} and ^{T b} are each independently a non-substituted a alkylene ^{group, R 20} represents a hydrogen atom.
R ¹⁰ to R ¹² each independently represent a hydrogen atom or a t- butoxycarbonyl group. However, one or more of R ^{10 to} R ¹² are t-butoxycarbonyl groups. ) A compound represented by formula (IV-1) or formula (IV-2).

(In the formula (IV-1),
L ⁴⁰ represents a halogeno group or a formyl group ,
Boc represents a t-butoxycarbonyl group,
n1 represents an integer of 2, 3, or 6 to 10. )

(In the formula (IV-2),
L ⁴¹ represents a halogeno group or a formyl group ,
Boc represents a t-butoxycarbonyl group,
n2 represents an integer of 2, 3, or 5-10. )