WO2013031930A1 - Imine derivative - Google Patents

Abstract

Provided is a novel imine derivative having an inhibitory activity on activated blood coagulation factor X or a pharmaceutically acceptable salt thereof. The present invention relates to a compound represented by formula (I) [wherein each symbol is as defined in the description] or a pharmaceutically acceptable salt thereof.

Description

Imine derivatives

The present invention relates to a novel imine derivative having activated blood coagulation factor X (hereinafter sometimes abbreviated as FXa) inhibitory activity, and an anti-blood for blood extracorporeal circuit such as hemodialysis, which contains the imine derivative. The present invention relates to a pharmaceutical composition that can be used as a coagulant.

Blood extracorporeal circulation is a circulation circuit that retransmits blood into a living body through a device (for example, an artificial cardiopulmonary device, a blood purification device, etc.) that performs a certain treatment using an artificial blood flow path from the inside of the living body to the outside of the body. Is done by. Extracorporeal blood treatment may be required during blood purification therapy such as hemodialysis, hemofiltration, hemodiafiltration, and plasma exchange, and during cardiopulmonary bypass during open heart surgery. A typical example of the blood purification apparatus is a dialyzer.

When blood comes into contact with a foreign object, the intrinsic blood coagulation cascade is usually activated, eventually coagulating and losing fluidity. Blood extracorporeal circuit consisting of artificial blood flow path and various devices during extracorporeal blood circulation is a foreign substance, and blood coagulates when it comes in contact with it, so it is necessary to take measures to prevent blood coagulation in extracorporeal blood circulation circuit by some method is there.

Conventionally, anti-blood coagulants (anticoagulants) such as unfractionated heparin and low molecular weight heparin have been used for the purpose of preventing blood coagulation in this extracorporeal circuit.

However, since unfractionated heparin has thrombin inhibitory activity in addition to FXa inhibitory activity, there is a known risk of bleeding tendency and it cannot be used for patients with a high bleeding risk. In addition, low molecular weight heparin is a drug that chemically treats heparin to more selectively inhibit FXa against thrombin and has no thrombin inhibitory activity, thus reducing the risk of bleeding tendency, Used for patients with a tendency. However, since low molecular weight heparin has a long elimination half-life, it is difficult to stop bleeding when bleeding symptoms are observed.

Some serine protease inhibitors also have anticoagulant action, and for example, nafamostat mesylate is used during some extracorporeal circulation such as hemodialysis. Nafamostat mesylate is also used for patients who already have bleeding lesions because of its short elimination half-life in vivo. However, nafamostat mesylate does not have strong inhibitory activity against FXa or thrombin and has a weak anticoagulant effect.

As described above, all drugs still have problems, and more effective and safe drugs are required.

It should be noted that a patient having an extracorporeal circuit has a blood coagulation problem only when the circuit is used, and is often different from a patient who must always prevent blood coagulation. A selective small molecule FXa inhibitor with a short blood half-life can be safely and conveniently used as an anti- (blood) coagulation agent (agent) for preventing blood coagulation for the extracorporeal circuit, and hemostasis after the end of the extracorporeal circulation It is thought that there is clearly less treatment and attention. Furthermore, if it is a compound that undergoes metabolism by the liver in the body and the activity disappears quickly, even if it is exposed to the body through the extracorporeal circuit, the active body is inactivated in the body by liver metabolism, Side effects such as bleeding risk are expected to be reduced.
As described above, these points have never been expected in the past.

Further, as the imine compounds exhibiting anticoagulant activity based on the selective FXa inhibitory action, the compounds described in Patent Documents 1 to 5 are known, but are structurally clearly different from the compounds of the present invention.

International Publication WO98 / 31661 Pamphlet International publication WO99 / 47503 pamphlet International Publication WO2004 / 108892 Pamphlet International Publication WO2006 / 083003 Pamphlet International Publication WO2010 / 005087 Pamphlet

An object of the present invention is to provide a novel compound having anticoagulant activity based on selective FXa inhibitory action.

The present invention is also aimed at providing a selective FXa inhibitor.

The present invention also aims to provide an anti- (blood) coagulant (agent) (especially for an extracorporeal circuit such as hemodialysis).

The present invention also aims to provide a pharmaceutical composition containing the novel compound.

As a result of conducting various studies in view of the above circumstances, the present inventors have found that a specific novel imine derivative, A′-LB ′ [wherein one of A ′ and B ′, has an ester bond in the molecule. Is an organic group having an imino group structure, the other is isoquinoline having an amino group, or thiophene, and L is a linker having an ester bond], and has a superior selective FXa inhibitory activity, and blood In order to complete the present invention, it has been found that it has a short half-life and is metabolized in the liver, and is therefore useful as an anti- (blood) coagulant (agent) (especially for blood extracorporeal circuits such as hemodialysis). Arrived.

That is, the present invention is as follows.
[1] Formula (I):

[Where:
Ar ¹ represents an aromatic hydrocarbon ring or an aromatic heterocyclic ring;
Ar ² is

Or

Represents;
V is an alkyl group having 1 to 10 carbon atoms which may have a substituent, an amino group which may be mono- or disubstituted with an alkyl group having 1 to 10 carbon atoms which may have a substituent, Or a 3- to 10-membered cyclic amino group which may have a substituent;
1 X is the same or different and each has a halogen atom, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, an optionally substituted alkyl group having 1 to 10 carbon atoms, or a substituent. An optionally substituted alkoxy group having 1 to 10 carbon atoms, an optionally substituted alkylthio group having 1 to 10 carbon atoms, an optionally substituted amino group, or a substituent. Represents an optionally substituted carbamoyl group;
m Zs are the same or different and each have a halogen atom, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, an optionally substituted alkyl group having 1 to 10 carbon atoms, or a substituent. An optionally substituted alkoxy group having 1 to 10 carbon atoms, an optionally substituted alkylthio group having 1 to 10 carbon atoms, an optionally substituted amino group, or a substituent. Represents an optionally substituted carbamoyl group;
Y ¹ is —C (═O) O—, —OC (═O) —, —C (═O) S—, —C (═S) O—, —SC (═O) — or —OC ( = S)-;
Y ² represents —O—, —S—, —NHC (═O) — or —C (═O) NH—;
l represents an integer of 0 to 2;
m represents an integer of 0 to 2;
n represents an integer of 1 to 3. ]
Or a pharmaceutically acceptable salt thereof (hereinafter abbreviated as compound (I)).
[2] Ar ² is

And Y ² is —O— or —S—, or a salt thereof.
[3] Ar ² is

And Y ² is —NHC (═O) — or —C (═O) NH—, or a salt thereof.
[4] The compound or a salt thereof according to any one of [1] to [3] above, wherein Ar ¹ is benzene or a 5- or 6-membered aromatic heterocyclic ring.
[5] The compound or a salt thereof according to any one of the above [1] to [4], wherein n is 1.
[6] The compound or a salt thereof according to any one of [1] to [5] above, wherein V is a 5- or 6-membered cyclic amino group which may have a substituent.
[7] The compound according to any one of [1] to [6] above, wherein Y ¹ is —C (═O) O—, —OC (═O) — or —C (═O) S—. Or its salt.
[8] The compound or salt thereof according to any one of [1] to [7] above, wherein Y ² is —O—.
[9] The compound or salt thereof according to any one of [1] to [7] above, wherein Y ² is —NHC (═O) —.
[10] The above [1], wherein one X is the same or different and each is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6 carbon atoms. ] To [9] or a salt thereof.
[11] The compound or a salt thereof according to any one of [1] to [10] above, wherein m Zs are the same or different and each is a halogen atom.
[12] Ar ¹ is benzene;
Ar ² is

And Y ² is —O— or Ar ² is

And Y ² is —NHC (═O) —;
V is a 5-membered cyclic amino group;
X is an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms;
Z is a halogen atom;
Y ¹ is —C (═O) O—;
l is 0 or 1;
m is 0 or 1; and n is 1.
The compound or salt thereof according to the above [1].
[13] An activated blood coagulation factor X inhibitor comprising the compound according to any one of [1] to [12] above or a pharmaceutically acceptable salt thereof.
[14] The activated blood coagulation factor X inhibitor according to [13], which selectively inhibits activated blood coagulation factor X.
[15] A pharmaceutical composition comprising the compound according to any one of [1] to [12] above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[16] The pharmaceutical composition according to the above [15], which is an anticoagulant.
[17] The pharmaceutical composition according to the above [15], which is an anticoagulant for a blood extracorporeal circuit.
[18] The pharmaceutical composition according to the above [15], which is an anticoagulant for hemodialysis.

The terms used in this specification are defined below.
In the present specification, the “aryl group” refers to a monocyclic to tricyclic aromatic hydrocarbon ring group which may have a substituent. Specific examples include a phenyl group, a naphthyl group, an acenaphthylenyl group, an anthryl group, a phenanthryl group, and the like, preferably those having 6 to 14 carbon atoms, more preferably those having 6 to 10 carbon atoms, Preferred are a phenyl group and a naphthyl group, and particularly preferred is a phenyl group. The “aryl group” may be a phenyl group in which a 5- to 8-membered cycloalkane or cycloalkene (the cycloalkane or cycloalkene may be further condensed with a benzene ring) is condensed. . Examples of the “5- to 8-membered cycloalkane or cycloalkene” fused with the phenyl group include cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene And cyclooctadiene. Examples of such a condensed ring include an indanyl group, an indenyl group, a dihydronaphthyl group, a tetrahydronaphthyl group, and a fluorenyl group.
In the present specification, the “aryl group having 6 to 14 carbon atoms” refers to the above aryl group having 6 to 14 carbon atoms, and the “aryl group having 6 to 10 carbon atoms” refers to the aryl group described above. Among groups, those having 6 to 10 carbon atoms.

In the present specification, the “aromatic hydrocarbon ring” means a monocyclic to tricyclic aromatic hydrocarbon ring. Specific examples include benzene, naphthalene, acenaphthylene, anthracene, phenanthrene and the like, preferably those having 6 to 14 carbon atoms, more preferably those having 6 to 10 carbon atoms, and further preferably benzene and naphthalene. Particularly preferred is benzene. The “aromatic hydrocarbon ring” is a benzene ring condensed with a 5- to 8-membered cycloalkane or cycloalkene (the cycloalkane or cycloalkene may be further condensed with a benzene ring). May be. Examples of the “5- to 8-membered cycloalkane or cycloalkene” fused with the benzene ring include cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene And cyclooctadiene. Examples of such a condensed ring include indane, indene, dihydronaphthalene, tetrahydronaphthalene, fluorene and the like.

In the present specification, the term “heteroaryl group” means a 5- to 10-membered monocyclic to bicyclic ring containing 1 to 6 heteroatoms selected from oxygen, sulfur and nitrogen atoms as ring atoms. An aromatic heterocyclic group. Specifically, for example, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, furyl group, thiophenyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl Group, oxadiazolyl group, thiadiazolyl group, benzofuryl group, benzothiophenyl group, indolyl group, isoindolyl group, benzoxazolyl group, benzothiazolyl group, benzimidazolyl group, indazolyl group, etc. 5- or 6-membered monocyclic heteroaryl Group: benzisoxazolyl group, benzisothiazolyl group, benzofurazanyl group, benzothiadiazolyl group, purinyl group, quinolinyl group, isoquinolinyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quino Sariniru group, pteridinyl group, imidazo benzoxazolyl group, imidazothiazolyl group, and bicyclic heteroaryl groups such as imidazoimidazolyl group. Preferred are those having 1 to 10 carbon atoms, more preferably a 5- or 6-membered monocyclic heteroaryl group, and still more preferably a pyridyl group or a thiophenyl group.
The “heteroaryl group having 1 to 10 carbon atoms” refers to the above-mentioned “heteroaryl group” having 1 to 10 carbon atoms, and the “heteroaryl group having 1 to 9 carbon atoms” refers to the above Among teloaryl groups, those having 1 to 9 carbon atoms.

In the present specification, the “aromatic heterocycle” means a 5- to 10-membered monocyclic to bicyclic ring containing 1 to 6 heteroatoms selected from oxygen, sulfur and nitrogen atoms as ring atoms. An aromatic heterocycle. Specifically, for example, 5 or 6 members such as pyridine, pyridazine, pyrimidine, pyrazine, furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, etc. A monocyclic aromatic heterocycle of: benzofuran, benzothiophene, indole, isoindole, benzoxazole, benzothiazole, benzimidazole, indazole, benzisoxazole, benzisothiazole, benzofurazan, benzothiadiazole, purine, quinoline, isoquinoline, Bicyclic ring such as cinnoline, phthalazine, quinazoline, quinoxaline, pteridine, imidazooxazole, imidazothiazole, imidazoimidazole Family heterocycles. Preferred are those having 1 to 10 carbon atoms, more preferred are 5 or 6-membered monocyclic aromatic heterocycles, and more preferred are pyridine and thiophene.

In the present specification, a “nitrogen-containing aliphatic heterocyclic group” (that is, a nitrogen-containing non-aromatic heterocyclic group) has at least one nitrogen atom as a ring atom, and one oxygen atom or sulfur atom. The term refers to a 4- to 10-membered monocyclic to bicyclic saturated or partially unsaturated aliphatic heterocyclic group which may have the above. Specifically, for example, pyrrolidinyl group, pyrazolidinyl group, imidazolidinyl group, pyrrolinyl group, pyrazolinyl group, imidazolyl group, thiazolidinyl group, piperidyl group, piperidino group, piperazinyl group, quinuclidinyl group, morpholino group, morpholinyl group, thiomorpholino group, Examples include thiomorpholinyl group, homopiperidyl group, homopiperazinyl group, indolinyl group, isoindolinyl group, tetrahydroquinolinyl group, tetrahydroisoquinolinyl group, and the like, preferably pyrrolidinyl group, piperidyl group, piperazinyl group, tetrahydroquinolinyl group , A tetrahydroisoquinolinyl group. Those having 2 to 8 carbon atoms are preferred, and piperidyl group, piperazinyl group and pyrrolidinyl group are particularly preferred.
The “nitrogen-containing aliphatic heterocyclic group having 1 to 9 carbon atoms” refers to those having 1 to 9 carbon atoms among the above-mentioned “nitrogen-containing aliphatic heterocyclic groups”. The “nitrogen-containing aliphatic heterocyclic group having 2 to 8 carbon atoms” refers to those having 2 to 8 carbon atoms among the above “nitrogen-containing aliphatic heterocyclic groups”.

In the present specification, the “3- to 10-membered cyclic amino group” has at least one nitrogen atom as a ring atom, and may further have one or more oxygen atoms or sulfur atoms. A monocyclic to bicyclic saturated or unsaturated heterocyclic group bonded to each other by the nitrogen atom. Specifically, for example, pyrrolidinyl group, pyrazolidinyl group, imidazolidinyl group, pyrrolinyl group, pyrazolinyl group, imidazolyl group, thiazolidinyl group, piperidyl group, piperidino group, piperazinyl group, quinuclidinyl group, morpholino group, morpholinyl group, thiomorpholino group, A thiomorpholinyl group, a homopiperidyl group, a homopiperazinyl group, an indolinyl group, an isoindolinyl group, a tetrahydroquinolinyl group, a tetrahydroisoquinolinyl group, etc. are mentioned, preferably a 5- or 6-membered cyclic amino group, more preferably A pyrrolinyl group, a pyrrolidinyl group, a piperidyl group, and a piperazinyl group are preferable, and a pyrrolinyl group and a pyrrolidinyl group are particularly preferable.

In the present specification, the “cycloalkyl group” refers to an aliphatic hydrocarbon ring group, which may contain a double bond in the ring. The “cycloalkyl group” preferably has 3 to 10 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclohexenyl group, a cyclopentenyl group, and the like. Particularly preferred is a cyclohexyl group.
The “cycloalkyl group having 3 to 10 carbon atoms” refers to the above “cycloalkyl group” having 3 to 10 carbon atoms. The “cycloalkyl group having 3 to 8 carbon atoms” refers to the above “cycloalkyl group” having 3 to 8 carbon atoms.

In this specification, “alkyl group” or “alkyl group moiety” in “alkylthio group”, “alkylamino group”, “alkoxy group”, “alkoxycarbonyl group” and the like is linear, branched, cyclic Or a partially cyclic aliphatic hydrocarbon group. Specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclopropylmethyl group, cyclobutyl group, pentyl group, isopentyl group, neopentyl group Group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, 1,1-dimethyl-propyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, etc. One having 1 to 10 carbon atoms is preferable, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 3 carbon atoms. Particularly preferred are methyl group, ethyl group, isopropyl group, isobutyl group and cyclopropyl group, and more preferred are methyl group, ethyl group, isopropyl group and cyclopropyl group.

In the present specification, the “alkyl group having 1 to 10 carbon atoms” means that having 1 to 10 carbon atoms among the above “alkyl groups”, and the “alkyl group having 1 to 6 carbon atoms” Among the above “alkyl groups”, those having 1 to 6 carbon atoms are meant.

In the present specification, the term “alkylthio group having 1 to 10 carbon atoms” means that the alkyl group portion has 1 to 10 carbon atoms in the above “alkyl group portion”. Methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, cyclopropylmethylthio group, pentylthio group, isopentylthio group, neopentylthio group, hexylthio group , Heptylthio group, octylthio group, nonylthio group, decylthio group, 1,1-dimethyl-propylthio group, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, cyclohexylthio group, cycloheptylthio group, cyclooctylthio group, etc. Is mentioned. “Alkylthio group having 1 to 6 carbon atoms” refers to those having 1 to 6 carbon atoms among the above “alkylthio groups having 1 to 10 carbon atoms”.

In the present specification, “an alkylamino group having 1 to 10 carbon atoms” refers to an amino group that is mono- or di-substituted with the above-mentioned “alkyl group moiety” having 1 to 10 carbon atoms. Is, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, cyclopropylmethylamino group, pentylamino group, Isopentylamino group, neopentylamino group, hexylamino group, heptylamino group, octylamino group, nonylamino group, decylamino group, (1,1-dimethyl-propyl) amino group, cyclopropylamino group, cyclobutylamino group, Cyclopentylamino group, cyclohexylamino group, cycloheptylamino group, cyclooctylamino Mono (alkyl) amino groups such as dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di-sec-butylamino group, di-tert-butylamino group, Di (cyclopropylmethyl) amino group, dipentylamino group, diisopentylamino group, dineopentylamino group, dihexylamino group, N-methyl-N-ethylamino group, N-methyl-N-propylamino group, N -Methyl-N-isopropylamino group, N-methyl-N-butylamino group, N-methyl-N-isobutylamino group, N-methyl-N-sec-butylamino group, N-methyl-N-tert-butyl Amino group, N-ethyl-N-propylamino group, N-ethyl-N-isopropylamino group, N-ethyl-N-butylamino And di (alkyl) amino groups such as N-ethyl-N-isobutylamino group, N-ethyl-N-sec-butylamino group, and N-ethyl-N-tert-butylamino group. “Alkylamino group having 1 to 6 carbon atoms” refers to an alkylamino group having 1 to 6 carbon atoms in the above “alkylamino group having 1 to 10 carbon atoms”.

In the present specification, the “alkoxy group having 1 to 10 carbon atoms” means that the alkyl group portion has 1 to 10 carbon atoms in the above “alkyl group portion”. Methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, cyclopropylmethoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, hexyloxy Group, heptyloxy group, octyloxy group, nonyloxy group, decyloxy group, 1,1-dimethyl-propoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, cyclooctyloxy group Etc. “Alkoxy group having 1 to 6 carbon atoms” refers to an “alkoxy group having 1 to 10 carbon atoms” having 1 to 6 carbon atoms.

In the present specification, the “alkoxycarbonyl group having 2 to 10 carbon atoms” refers to an alkyl group portion having 1 to 9 carbon atoms in the above “alkyl group portion”. Methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, cyclopropylmethoxycarbonyl group, pentyloxycarbonyl group, Isopentyloxycarbonyl group, neopentyloxycarbonyl group, hexyloxycarbonyl group, heptyloxycarbonyl group, octyloxycarbonyl group, nonyloxycarbonyl group, (1,1-dimethyl-propoxy) carbonyl group, cyclopropoxycarbonyl group Cyclo-butoxycarbonyl group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, cyclooctyloxy carbonyl group and the like. “Alkoxycarbonyl group having 2 to 7 carbon atoms” refers to an “alkoxycarbonyl group having 2 to 10 carbon atoms” having 2 to 7 carbon atoms.

In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a fluorine atom and a chlorine atom are preferable.

In the present specification, “alkylamino group” or “amino group substituted with an alkyl group” (when the substituent in the “amino group optionally having substituents” is an alkyl group), “alkyl” The “alkylamino moiety” as a component such as “carbamoyl group substituted with a group” (when the substituent is an alkyl group in “optionally substituted carbamoyl group”) includes a monoalkylamino group A dialkylamino group is also included. In the dialkylamino group, the two alkyl groups may be the same as or different from each other, and are bonded to each other to form a ring (for example, a nitrogen-containing heterocyclic ring corresponding to the above “nitrogen-containing heterocyclic group”, etc. (eg, pyrrolidine ring, pyrroline ring). )) May be formed.

In the present specification, as the substituent in the case of “may have a substituent”, for example,
(1) a halogen atom,
(2) hydroxyl group,
(3) an amino group,
(4) an alkyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms,
(5) an alkenyl group having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms (for example, vinyl group, allyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, butadienyl group, 2-methylallyl group, hexatrienyl group, 3-octenyl group, etc.),
(6) Alkynyl groups having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms (for example, ethynyl group, 2-propynyl group, isopropynyl group, butynyl group, tert-butynyl group, 3-hexynyl group, etc.),
(7) an alkoxy group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, optionally substituted with phenyl,
(8) an alkylamino group having 1 to 6 carbon atoms,
(9) a cyano group,
(10) a guanidino group,
(11) a carboxyl group,
(12) a carbamoyl group,
(13) an aryl group having 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms,
(14) a heteroaryl group having 1 to 10 carbon atoms, preferably 1 to 9 carbon atoms,
(15) a cycloalkyl group having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms,
(16) a nitrogen-containing aliphatic heterocyclic group having 1 to 9, preferably 2 to 8 carbon atoms,
(17) an alkylthio group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms,
(18) an acyloxy group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms,
(19) an acylamino group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms,
(20) Alkylsulfonamide groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms (for example, methylsulfonamide group, ethylsulfonamide group, propylsulfonamide group, isopropylsulfonamide group, butylsulfonamide group, isobutyl Sulfonamide group, sec-butylsulfonamide group, tert-butylsulfonamide group, cyclopropylmethylsulfonamide group, pentylsulfonamide group, isopentylsulfonamide group, neopentylsulfonamide group, hexylsulfonamide group, heptylsulfonamide Group, octylsulfonamide group, nonylsulfonamide group, decylsulfonamide group, (1,1-dimethyl-propyl) sulfonamide group, cyclopropylsulfonamide group, cyclobutylsulfonamide group, cyclopentyl Ruhon'amido group, a cyclohexyl sulfonamide group, a cycloheptyl sulfonamido group, cyclooctyl sulfonamido group),
(21) An alkoxycarbonyl group having 2 to 10 carbon atoms, preferably 2 to 7 carbon atoms, and the like can be mentioned.

In the present specification, “acyl group moiety” as a component such as “acyloxy group” and “acylamino group” includes formyl group, alkylcarbonyl group having 2 to 10 carbon atoms (for example, acetyl group, ethylcarbonyl group, propyl group) Carbonyl group, isopropylcarbonyl group, butylcarbonyl group, isobutylcarbonyl group, sec-butylcarbonyl group, tert-butylcarbonyl group, cyclopropylmethylcarbonyl group, pentylcarbonyl group, isopentylcarbonyl group, neopentylcarbonyl group, hexylcarbonyl group , Heptylcarbonyl group, octylcarbonyl group, nonylcarbonyl group, (1,1-dimethyl-propyl) carbonyl group, cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group, cyclohexylcarbonyl , Cycloheptylcarbonyl group, cyclooctylcarbonyl group, etc.), C7-11 arylcarbonyl groups (eg, benzoyl group, 1-naphthylcarbonyl group, 2-naphthylcarbonyl group, etc.) Groups. Of these, an acyl group having 1 to 10 carbon atoms is preferable, and an acyl group having 1 to 7 carbon atoms is more preferable. An acyl group having 1 to 6 carbon atoms is particularly preferable.

As a substituent, preferably
(1) a halogen atom,
(2) hydroxyl group,
(3) an amino group,
(4) an alkyl group having 1 to 6 carbon atoms,
(5) an alkenyl group having 2 to 6 carbon atoms,
(6) an alkynyl group having 2 to 6 carbon atoms,
(7) an alkoxy group having 1 to 6 carbon atoms which may be substituted with phenyl,
(8) an alkylamino group having 1 to 6 carbon atoms,
(9) a cyano group,
(10) a guanidino group,
(11) a carboxyl group,
(12) a carbamoyl group,
(13) an acyloxy group having 1 to 6 carbon atoms,
(14) an acylamino group having 1 to 6 carbon atoms,
(15) a cycloalkyl group having 3 to 8 carbon atoms,
(16) an alkylthio group having 1 to 6 carbon atoms,
(17) an alkylsulfonamido group having 1 to 6 carbon atoms, and (18) an alkoxycarbonyl group having 2 to 10 carbon atoms.
There is no particular limitation on the number and position of the substituents.

In addition, compound (I) includes a mixture of various stereoisomers such as geometric isomers, tautomers, optical isomers, isolated isomers, stable isotopes, and radioisotopes.

In the formula (I), Ar ¹ represents an aromatic hydrocarbon ring or an aromatic heterocyclic ring. Ar ¹ is preferably an aromatic hydrocarbon ring having 6 to 10 carbon atoms or a 5- or 6-membered monocyclic aromatic heterocycle, more preferably benzene or a 5- or 6-membered monocyclic aromatic ring. It is a heterocyclic ring, more preferably benzene, pyridine or thiophene, and particularly preferably benzene.

In the formula (I), V is mono- or di-substituted by an optionally substituted alkyl group having 1 to 10 carbon atoms and an optionally substituted alkyl group having 1 to 10 carbon atoms. An amino group which may be substituted, or a 3- to 10-membered cyclic amino group which may have a substituent. V is preferably a 3- to 10-membered cyclic amino group which may have a substituent, more preferably a 5- or 6-membered cyclic amino group which may have a substituent, and more preferably Is an optionally substituted 5-membered cyclic amino group, still more preferably a 5-membered cyclic amino group, and particularly preferably pyrrolinyl or pyrrolidinyl.

In formula (I), one X is the same or different and each is a halogen atom, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, or an alkyl group having 1 to 10 carbon atoms which may have a substituent. An alkoxy group having 1 to 10 carbon atoms which may have a substituent, an alkylthio group having 1 to 10 carbon atoms which may have a substituent, an amino group which may have a substituent, or The carbamoyl group which may have a substituent is shown. 1 X is preferably the same or different and each is a halogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, or an optionally substituted carbon group having 1 to 10 carbon atoms. Or an optionally substituted alkylthio group having 1 to 10 carbon atoms, and more preferably the same or different, a halogen atom, an alkyl group having 1 to 6 carbon atoms, An alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms, more preferably an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms, and particularly preferably Are the same or different and are each an alkoxy group having 1 to 3 carbon atoms (particularly methoxy) or an alkylthio group having 1 to 3 carbon atoms (particularly methylthio).

In the formula (I), m Zs are the same or different and each is a halogen atom, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, or an alkyl group having 1 to 10 carbon atoms which may have a substituent. An alkoxy group having 1 to 10 carbon atoms which may have a substituent, an alkylthio group having 1 to 10 carbon atoms which may have a substituent, an amino group which may have a substituent, or The carbamoyl group which may have a substituent is shown. The m Zs are preferably the same or different and each is a halogen atom, and more preferably the same or different and each is a chlorine atom.

Ar ² is

In this case, the bonding position of Z may be a benzene ring or a pyridine ring.

In Formula (I), Y ¹ represents —C (═O) O—, —OC (═O) —, —C (═O) S—, —C (═S) O—, —SC (═O )-Or -OC (= S)-. Y ¹ is preferably —C (═O) O—, —OC (═O) — or —C (═O) S—, more preferably —C (═O) O— or —C (═ O) S—, particularly preferably —C (═O) O—.

In the formula (I), Y ² represents —O—, —S—, —NHC (═O) — or —C (═O) NH—. Y ² is preferably Ar ²

Y ² is —O— or —S—, and Ar ² is

In this case, Y ² is —NHC (═O) — or —C (═O) NH—, and more preferably Ar ² is

In which Y ² is —O— and Ar ² is

In this case, Y ² is —NHC (═O) —.
In the formula (I), l represents an integer of 0-2. l is preferably 0 or 1.
In the formula (I), m represents an integer of 0-2. m is preferably 0 or 1.
In the formula (I), n represents an integer of 1 to 3. n is preferably 1.

In the present invention, a compound comprising a combination of preferable groups of the above symbols is preferable.

More specifically, the following compounds are preferred.

[Compound A]
Ar ¹ is benzene or a 5- or 6-membered monocyclic aromatic heterocycle;
Ar ² is

And Y ² is —O— or —S—, or Ar ² is

And Y ² is —NHC (═O) — or —C (═O) NH—;
V is an optionally substituted 5- or 6-membered cyclic amino group (preferably a 5- or 6-membered cyclic amino group);
X is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms;
Z is a halogen atom (preferably a chlorine atom);
Y ¹ is —C (═O) O—, —OC (═O) — or —C (═O) S—;
l is 0 or 1;
m is 0 or 1; and n is 1.
Compound (I) or a salt thereof.

[Compound B]
Ar ¹ is benzene, pyridine or thiophene;
Ar ² is

And Y ² is —O— or Ar ² is

And Y ² is —NHC (═O) —;
V is a 5-membered cyclic amino group (preferably pyrrolinyl or pyrrolidinyl);
X is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms;
Z is a halogen atom (preferably a chlorine atom);
Y ¹ is —C (═O) O—, —OC (═O) — or —C (═O) S—;
l is 0 or 1;
m is 0 or 1; and n is 1.
Compound (I) or a salt thereof.

[Compound C]
Ar ¹ is benzene;
Ar ² is

And Y ² is —O— or Ar ² is

And Y ² is —NHC (═O) —;
V is a 5-membered cyclic amino group (preferably pyrrolinyl or pyrrolidinyl);
X is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms;
Z is a halogen atom (preferably a chlorine atom);
Y ¹ is —C (═O) O— or —C (═O) S—;
l is 0 or 1;
m is 0 or 1; and n is 1.
Compound (I) or a salt thereof.

[Compound D]
Ar ¹ is benzene;
Ar ² is

And Y ² is —O— or Ar ² is

And Y ² is —NHC (═O) —;
V is a 5-membered cyclic amino group (preferably pyrrolinyl or pyrrolidinyl);
X is an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms;
Z is a halogen atom (preferably a chlorine atom);
Y ¹ is —C (═O) O—;
l is 0 or 1;
m is 0 or 1; and n is 1.
Compound (I) or a salt thereof.

More specifically, although not limited thereto, the compounds described in the examples are preferred. Above all,
4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] benzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl (Example 2);
4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-fluorobenzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl (Example 3);
4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methoxybenzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl (Example 5);
4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methylbenzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl (Example 6);
4- [imino (pyrrolidin-1-yl) methyl] benzenecarbothioic acid S- (2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl) (Example 10);
4- [imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzoic acid 2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl (Example 23); and 4- [2 , 5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methoxybenzoic acid 2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl (Example 24)
And their salts are more preferred.

The anti- (blood) coagulant (agent) for an extracorporeal blood circuit containing an FXa inhibitor as an active ingredient according to the present invention is preferably one that disappears rapidly from the blood. Here, “the disappearance from the blood is rapid” means that the half-life in the stability test in whole blood shown in Test Example 4 described later is 10 minutes or less, preferably 5 minutes or less. More preferably, in the stability test (test example 5) in the liver S9 fraction showing disappearance in the body (liver), the residual rate after 30 minutes of the FXa inhibitor is preferably 80% or less. Further, the FXa inhibitor is preferably FXa selective, and more specifically, the difference between pIC ₅₀ (FXa) and pIC ₅₀ (FIIa) in the inhibitory activity evaluation system shown in Test Examples 1 and 2 described later. A large is preferable.

“Blood extracorporeal circulation” is an artificial blood circulation that passes through a blood circuit constructed outside the living body.
The “blood extracorporeal circuit” is a blood circuit in extracorporeal blood circulation, for example, a blood circuit formed by connecting a living body and an artificial organ when using the artificial organ. More specifically, for example, those used at the time of cardiopulmonary bypass and hemodialysis are mentioned, and in the present invention, a blood extracorporeal circuit is particularly preferred at the time of hemodialysis.

Hereinafter, representative production methods of the compound (I) of the present invention will be described.
In general formula (I), Ar ² is

When Y ¹ is —C (═O) O—, Y ² is —O— and n is 1, an alcohol derivative (1) as an intermediate is obtained by the method shown below. be able to. That is, by reacting 7-hydroxyisoquinoline with ethylene carbonate in a solvent such as N, N-dimethylformamide (hereinafter DMF) in the presence of a base such as potassium carbonate, the alcohol derivative (2) can be obtained. . A hydroxyl protecting group is introduced into this by using, for example, benzyl bromide or tert-butyldimethylchlorosilane in the presence of a suitable solvent and a base, and then, for example, oxidation of m-chloroperbenzoic acid or the like in a solvent such as dichloromethane. An oxidant (3) can be obtained using an agent. An aminoisoquinoline derivative (4) can be obtained by forming a leaving group using paratoluenesulfonyl chloride or the like in a pyridine solvent and treating with aminoethanol. By deprotecting this, in the general formula (I), Ar ² is

And Y ¹ is —C (═O) O—, Y ² is —O— and n is 1, an alcohol derivative (1) which is an intermediate can be obtained.

[Each symbol in the formula is as defined above. ]

In general formula (I), Ar ² is

And Y ¹ is —C (═O) O— or —C (═O) S—, Y ² is —NHC (═O) —, and n is 1, The thiophene derivative (5) as an intermediate can be obtained by the method. That is, a thiophenecarboxylic acid derivative is formed in an acid chloride using a solvent such as dichloromethane, for example, oxalyl chloride or thionyl chloride, and treated with an amino alcohol or aminothiol in the general formula (I). Ar ² is

An intermediate in which Y ¹ is —C (═O) O— or —C (═O) S—, Y ² is —NHC (═O) —, and n is 1. A certain thiophene derivative (5) can be obtained.

[Wherein Y ³ represents an oxygen atom or a sulfur atom, and other symbols are as defined above. ]

In the general formula (I), V is an amino group which may be mono- or di-substituted with an alkyl group having 1 to 10 carbon atoms which may have a substituent, or 3 to 3 which may have a substituent. When it is a 10-membered cyclic amino group and Y ¹ is —C (═O) O— or —C (═O) S—, the carboxylic acid derivative (6) as an intermediate is obtained by the following method. Obtainable. That is, for example, by dissolving a cyanoarylcarboxylic acid or cyanoheteroarylcarboxylic acid such as 4-cyanobenzoic acid in an alcohol such as methanol or ethanol: R ¹ OH as a solvent and blowing hydrogen chloride gas as an acid, for example. The imidate derivative (7) can be obtained. By reacting this with a primary or secondary amine: R ² R ³ NH in a solvent such as an alcohol such as methanol or ethanol, in the general formula (I), V may have a substituent. An amino group which may be mono- or di-substituted by a good alkyl group having 1 to 10 carbon atoms, or a 3- to 10-membered cyclic amino group which may have a substituent, and Y ¹ is —C (= The intermediate carboxylic acid derivative (6) in the case of O) O— or —C (═O) S— can be obtained. For example, when a cyanoaryl ester or cyanoheteroaryl ester such as ethyl 4-cyanobenzoate is used, the ester bond is hydrolyzed under acidic conditions after imidate formation and alkylamidation in the same manner. Thus, in general formula (I), V may have an amino group which may be mono- or di-substituted by an alkyl group having 1 to 10 carbon atoms which may have a substituent, or a substituent. It is possible to obtain a carboxylic acid derivative (6) which is an intermediate when it is a 3- to 10-membered cyclic amino group and Y ¹ is —C (═O) O— or —C (═O) S—. it can.

[Wherein, R ¹ represents an alkyl group having 1 to 6 carbon atoms, and R ² and R ³ are the same or different and each represents a hydrogen atom or an optionally substituted alkyl having 1 to 10 carbon atoms. R ² and R ³ together with the nitrogen atom to which they are attached may form a cyclic amino group having 3 to 10 carbon atoms which may have a substituent. , R ⁴ represents an alkyl group having 1 to 6 carbon atoms, and other symbols are as defined above. ]

In the general formula (I), V is an amino group which may be mono- or di-substituted by an alkyl group having 1 to 10 carbon atoms which may have a substituent, or 3 to 3 which may have a substituent. When it is a 10-membered cyclic amino group and Y ¹ is —C (═O) O— or —C (═O) S—, compound (Ia) can be obtained by the following method. That is, the carboxylic acid derivative (6) is dissolved in pyridine or N-methylpyrrolidinone (hereinafter referred to as NMP) or a mixed solvent of both solvents, and the corresponding alcohol or thiol derivative (7) and, for example, N, N′-dicyclohexylcarbodiimide In the general formula (I), V has a substituent by allowing a condensing agent such as DCC (hereinafter DCC) or a catalytic amount of 4-dimethylaminopyridine (hereinafter DMAP) to act as necessary. An amino group which may be mono- or di-substituted by an alkyl group having 1 to 10 carbon atoms, or a 3- to 10-membered cyclic amino group which may have a substituent, and Y ¹ is —C ( Compound (Ia) in the case of ═O) O— or —C (═O) S— can be obtained.

[Each symbol in the formula is as defined above. ]

When the compound (I) of the present invention can be in the form of a salt, the salt may be pharmaceutically acceptable, for example, an acidic group in the case where an acidic group such as a carboxyl group is present in the formula In contrast, ammonium salts; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; aluminum salts; zinc salts; triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine And salts with organic amines such as arginine and salts with basic amino acids such as lysine.

When a basic group is present in the formula, a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid; acetic acid, trifluoroacetic acid, citric acid, benzoic acid Organic carboxylic acids such as acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, hybenzic acid, pamoic acid, enanthic acid, decanoic acid, teocric acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, malic acid And salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
As a method for forming a salt, compound (I) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is carried out from other salt forms. It can also be obtained by doing.

The compound of the present invention also includes solvates of compound (I), such as hydrates and alcohol adducts.

The compound of the present invention can be converted into a prodrug. The prodrug in the present invention refers to a compound that is converted in the body to produce the compound of the present invention. For example, when the active main body contains a carboxyl group or a phosphate group, their esters and amides can be mentioned. Further, when the active main body contains an amino group, its amide, carbamate and the like can be mentioned. When the active main body contains a hydroxyl group, its ester, carbonate, carbamate and the like can be mentioned. When the compound of the present invention is converted into a prodrug, it may be bound to an amino acid or a saccharide.

The compound (I) which is the compound of the present invention or a pharmaceutically acceptable salt thereof can be produced and administered as it is, or as a pharmaceutical composition according to a conventional method using an ordinary formulation aid. Examples of the dosage form of such a pharmaceutical composition include tablets, powders, injections, lyophilized injections, or pills, granules, capsules, suppositories, solutions, dragees, devoted drugs, syrups, Suspensions, emulsions, lozenges, sublinguals, patches, buccal disintegrants (tablets), inhalants, enemas, ointments, patches, tapes, eye drops and the like.

The compound or pharmaceutical composition of the present invention is administered into a blood extracorporeal circuit or to a patient. Preferred administration methods include direct administration into the blood extracorporeal circuit, intravenous administration, intramuscular administration, subcutaneous administration, and in some cases oral administration, rectal administration, intranasal administration, sublingual administration Is also possible. In the case of direct administration into the blood extracorporeal circuit, it is preferable to administer the blood at a site as close to the body as possible of the circuit for circulating blood outside the body. Is available.

The administration target is not particularly limited, and examples thereof include mammals (eg, mouse, rat, hamster, rabbit, cat, dog, pig, cow, sheep, horse, monkey, human, etc.).

In addition, the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing them is provided as an anti- (blood) coagulant (agent) for hemodialysis, and dissolved or dispersed in a dialysate at the time of use. Thus, the FXa inhibitor composition used in the dialyzer can be provided not only as it is, but also in the form of a dialysate or dialysate concentrate containing the FXa inhibitor. Examples of the dialysate concentrate include a powder formulation for an artificial kidney, and can be prepared, for example, by concentrating a dialysate containing an FXa inhibitor by lyophilization or the like. The dialysate concentrate can be diluted with an appropriate method before use, for example, with purified water to obtain a dialysate.

The compound of the present invention or the pharmaceutical composition is administered once or continuously in one blood extracorporeal circulation once, or divided into several times as necessary. The dose of the compound of the present invention or the pharmaceutical composition is 0.01 mg to 10 g, preferably 1 mg to 1,000 mg as the amount of the compound that is an active ingredient per blood circulation or active ingredient per day. The dose can be increased or decreased as appropriate according to the age, weight, symptoms, etc. of the patient / subject. Also, the appropriate concentration of the active ingredient compound in the dialysate depends on the compound used, the severity of the disease being treated and the characteristics of the patient being treated, but usually at the appropriate equilibrium of the compounds that can be used. The average plasma concentration is in the range of 0.0001 to 1000 μmol / L, preferably 0.005 to 20 μmol / L.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 Intermediate 1: Synthesis of 2-[(1-aminoisoquinolin-7-yl) oxy] ethanol hydrochloride 1 of 7- (2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) isoquinoline Synthesis N-N-dimethylformamide (hereinafter DMF) (100 mL), ethylene carbonate (11.3 g, 129 mmol), potassium carbonate (17.8 g, 129 mmol) were added to 7-hydroxyisoquinoline (15.6 g, 107 mmol), Stir at 100 ° C. overnight. 4N Hydrochloric acid / 1,4-dioxane solution (50 mL) was added at room temperature, and the mixture was stirred for 15 minutes. The solvent was removed under reduced pressure, extracted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution and saturated brine, magnesium sulfate. And the solvent was distilled off under reduced pressure, and DMF (100 mL), tert-butyldimethylchlorosilane (19.3 g, 128.4 mmol), and imidazole (17.5 g, 257 mmol) were added to the resulting residue at room temperature. Stir for 1 hour. The mixture was extracted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound.
Yield: 18 g (59 mmol) Yield: 56%
MS (ESI, m / z) 304 [M + H] ⁺

Step 2 Synthesis of 2-[(1-Aminoisoquinolin-7-yl) oxy] ethanol trifluoroacetate salt To 7- (2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) isoquinoline (18 g, 59 mmol) Dichloromethane (100 mL) was added, m-chloroperbenzoic acid (12.9 g, 75 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Extracted with dichloromethane, washed with 1N sodium hydroxide and saturated brine, dried over magnesium sulfate, evaporated under reduced pressure, and the residue was purified by pyridine (50 mL), paratoluenesulfonyl chloride (8.9 g). 46 mmol) and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, aminoethanol (20 mL) was added to the resulting residue, and the mixture was stirred overnight at room temperature. Extracted with dichloromethane, washed with 1N sodium hydroxide and brine, dried over magnesium sulfate, evaporated under reduced pressure, and trifluoroacetic acid (hereinafter TFA) (50 mL) was added to the resulting residue. For 2 hours. After removing the solvent under reduced pressure, the obtained residue was subjected to reverse phase HPLC using ODS as a filler, and eluted with a mixed solution of water and acetonitrile containing 0.1% trifluoroacetic acid (v / v). The desired fraction was lyophilized to give the TFA salt of the title compound.
Yield: 4 g (12.5 mmol) Yield: 21%
MS (ESI, m / z) 205 [M + H] ⁺

Step 3 Synthesis of Intermediate 1 2-[(1-Aminoisoquinolin-7-yl) oxy] ethanol trifluoroacetate (4 g, 12.5 mmol) was dissolved in water (100 mL), and 1N hydrochloric acid (30 mL) was added. The solvent was distilled off under reduced pressure. After performing this operation three times, the title compound was obtained by washing with acetonitrile.
Yield: 2.86 g (12.0 mmol) Yield: 96%
MS (ESI, m / z) 205 [M + H] ^+
1 H NMR (DMSO-d ₆ , 400 MHz) δ 3.80 (t, J = 5.0 Hz, 2H), 4.19 (t, J = 5.0 Hz, 2H), 4.99 (br s, 1H), 7.20 (d, J = 6.9 Hz, 1H), 7.48-7.69 (m, 2H), 7.90 (d, J = 8.9 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 9.05 (br s, 2H), 13.42 (s , 1H).

Reference Example 2 Intermediate 2: Synthesis of 5-chloro-N- (2-hydroxyethyl) thiophene-2-carboxamide 5-Chlorothiophene-2-carboxylic acid (2.17 g, 13.3 mmol) was added dichloromethane (10 mL). In addition, oxalyl chloride (1.4 mL, 16.5 mmol) and a catalytic amount of DMF were added dropwise, and the mixture was stirred at room temperature for 2 hours. After removing the solvent under reduced pressure, dichloromethane (10 mL), aminoethanol (0.99 mL, 16.5 mmol), and triethylamine (2.3 mL, 16.5 mmol) were added to the resulting residue, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the mixture was extracted with ethyl acetate, washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, dried over magnesium sulfate, and the solid obtained by evaporating the solvent under reduced pressure was diluted with acetonitrile. Washing gave the title compound.
Yield: 1.78 g (8.64 mmol) Yield: 65%
MS (ESI, m / z) 206 [M + H] ^+
1 H NMR (CDCl ₃ , 400 MHz) δ 2.29 (br s, 1H), 3.55-3.64 (m, 2H), 3.78-3.86 (m, 2H), 6.37 (br s, 1H), 6.90 (d, J = 4.0 Hz, 1H), 7.28 (d, J = 4.0 Hz, 1H).

Reference Example 3 Intermediate 3: Synthesis of 5-chloro-N- (2-mercaptoethyl) thiophene-2-carboxamide Dichloromethane (10 mL) was added to 5-chlorothiophene-2-carboxylic acid (2.17 g, 13.3 mmol). , Oxalyl chloride (1.4 mL, 16.5 mmol) and a catalytic amount of DMF were added dropwise and stirred at room temperature for 2 hours. After removing the solvent under reduced pressure, dichloromethane (10 mL), aminoethanethiol (1.23 g, 16.5 mmol) and triethylamine (4.4 mL, 31.6 mmol) were added to the resulting residue, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, extracted with ethyl acetate, washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound.
Yield: 1.28 g (5.77 mmol) Yield: 43%
MS (ESI, m / z) 222 [M + H] ⁺

Example 1
4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid 2-[(1-Aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid Acid (52.9 mg, 0.21 mmol) and intermediate 1 (50.0 mg, 0.21 mmol) were dissolved in pyridine (1.0 mL) at room temperature. N, N′-dicyclohexylcarbodiimide (hereinafter DCC) (51.4 mg, 0.25 mmol) was added to the solution, and the mixture was stirred at 50 ° C. for 1.5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 18.6 mg (0.05 mmol) Yield: 22%
MS (ESI, m / z) 405 [M + H] ^+
1 H NMR (DMSO-d ₆ , 400 MHz) δ 1.86 (dt, J = 14.6, 6.9 Hz, 2H), 2.05 (dt, J = 13.9, 7.2 Hz, 3H), 3.49-3.60 (m, 2H) , 4.47-4.62 (m, 2H), 4.68-4.84 (m, 2H), 7.23 (d, J = 6.9 Hz, 1H), 7.59 (d, J = 6.8 Hz, 1H), 7.67 (dd, J = 8.8 , 2.4 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.9 Hz, 1H), 8.07 (s, 1H), 8.16 (d, J = 8.4 Hz, 2H), 8.89 (s, 3H), 9.36 (s, 1H), 12.97-13.21 (m, 1H).

Example 2
4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] benzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate step 1 4- [2 , 5-Dihydro-1H-pyrrol-1-yl (imino) methyl] benzoic acid hydrochloride Synthesis of 4-cyanobenzoic acid (1.50 g, 10.20 mmol) in ethanol (1.5 mL) with 4N hydrochloric acid / 1 , 4-Dioxane solution (50.0 mL) was added at room temperature and stirred overnight under sealing. The reaction mixture was concentrated, and the precipitate was collected by filtration and dried under reduced pressure at room temperature for about 2 hours to obtain ethyl 4- [ethoxy (imino) methyl] benzoate hydrochloride (2.50 g). A part (2.31 g) of this was suspended in toluene (15.0 mL) and ethanol (15.0 mL), and triethylamine (3.1 mL) was added dropwise under ice cooling. After confirming homogenization, 3-pyrroline (0.8 mL) was added at room temperature and stirred overnight. Toluene (100 mL) was added to the reaction solution and filtered, and 4N hydrochloric acid / 1,4-dioxane solution (20.0 mL) and water (20.0 mL) were added to the residue, followed by stirring at 60 ° C. for 1 hour. After concentration, crystallization was performed with water, methanol, and ethyl acetate, and the precipitate was collected by filtration and dried under reduced pressure to obtain the title compound.
Yield: 1.36 g (5.38 mmol) Total yield: 57%
MS (ESI, m / z) 217 [M + H] ^+
1 H NMR (DMSO-d ₆ , 400MHz) δ4.12-4.19 (m, 2H), 4.38-4.46 (m, 2H), 5.86-5.93 (m, 1H), 6.03-6.09 (m, 1H), 7.77 -7.85 (m, 2H), 8.09-8.16 (m, 2H), 9.26 (s, 1H), 9.67 (s, 1H), 13.44 (br s, 1H).

Step 2 Synthesis of Example 2 Compound 4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] benzoic acid hydrochloride (52.5 mg, 0.21 mmol) and intermediate 1 (50 mg, 0 .21 mmol) was dissolved in pyridine (1.0 mL) at room temperature. DCC (51.4 mg, 0.25 mmol) was added to the solution and stirred at 50 ° C. for 1.5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 19.2 mg (0.05 mmol) Yield: 23%
MS (ESI, m / z) 403 [M + H] ^+
1 H NMR (DMSO-d ₆ , 400 MHz) δ4.06-4.19 (m, 2H), 4.29-4.44 (m, 2H), 4.50-4.61 (m, 1H), 4.69-4.87 (m, 1H), 5.90 (d, J = 7.4 Hz, 1H), 6.07 (d, J = 5.3 Hz, 1H), 7.23 (d, J = 6.2 Hz, 1H), 7.59 (d, J = 6.8 Hz, 1H), 7.67 ( d, J = 10.9 Hz, 1H), 7.83 (dd, J = 8.2, 2.2 Hz, 2H), 7.93 (d, J = 10.5 Hz, 1H), 8.08 (s, 1H), 8.17 (dd, J = 8.1 , 2.2 Hz, 2H), 8.88 (s, 2H), 9.07 (s, 1H), 9.59 (s, 1H), 13.09 (s, 1H).

Example 3
4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2-fluorobenzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate step 1 Synthesis of 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-fluorobenzoic acid hydrochloride Dry ethanol of 2-fluoro-4-cyanobenzoic acid (720 mg, 4.35 mmol) A 4N hydrochloric acid / 1,4-dioxane solution (40 mL) was added to the solution (10 mL), and the mixture was stirred at room temperature for 2 days under sealed conditions. The solvent was distilled off under reduced pressure, dry ethanol (50 mL) was added to the resulting residue, 3-pyrroline (600 mg, 8.7 mmol) was added, and the mixture was stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, methanol was added to the resulting residue, acetone was added and stirred, and the precipitated solid was collected by filtration. 1,4-Dioxane (40 mL) and 4N hydrochloric acid / 1,4-dioxane solution (12 mL) were added to the solid and stirred, and the solid was collected by filtration and dried to give the title compound.
Yield: 360 mg (1.33 mmol) Yield: 31%
MS (ESI, m / z) 235 [M + H] ⁺

Step 2 Synthesis of Example 3 Compound 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-fluorobenzoic acid hydrochloride (113 mg, 0.323 mmol), intermediate 1 ( Pyridine (2.0 mL) was added to 66.0 mg, 0.323 mmol) and DCC (133 mg, 0.646 mmol), and the mixture was stirred at 40 ° C. for 1.5 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 35.1 mg (0.0541 mmol) Yield: 17%
MS (ESI, m / z) 421 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ4.12-4.22 (m, 2H), 4.31-4.41 (m, 2H), 4.47-4.56 (m, 2H), 4.72-4.81 (m, 2H), 5.87-5.95 (m, 1H), 6.01-6.10 (m, 1H), 7.23 (d, J = 6.9 Hz, 1H), 7.59 (d, J = 6.9 Hz, 1H), 7.61-7.69 (m, 2H) , 7.79 (dd, J = 10.8, 1.4 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 8.03-8.15 (m, 2H), 8.99 (br s, 2H), 9.17 (s, 1H) , 9.65 (s, 1H), 13.36 (br s, 1H).

Example 4
4- [imino (pyrrolidin-1-yl) methyl] -2-methylbenzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate step 1 4-cyano-2-methylbenzoic acid Synthesis of ethyl acid Ethanol (0.870 mL), diisopropylethylamine (1.74 mL, 10.0 mmol) and tetrakis (triphenyl) in a DMF solution (10 mL) of 4-bromo-2-methylbenzonitrile (980 mg, 5.00 mmol) Phosphine) palladium (289 mg, 0.250 mmol) was added, and the mixture was stirred overnight at 70 ° C. in a carbon monoxide atmosphere. Ethanol (0.870 mL) was added to the reaction mixture, and the mixture was stirred at 70 ° C. for 3 days under a carbon monoxide atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography (hexane: ethyl acetate 93: 7) to give the title compound.
Yield: 187 mg (0.988 mmol) Yield: 20%
¹ H-NMR (CDCl ₃ , 300MHz) δ1.41 (t, J = 7.2Hz, 3H), 2.62 (s, 3H), 4.39 (q, J = 7.2Hz, 2H), 7.53 -7.55 (m, 2H ), 7.95-7.98 (m, 1H).

Step 2 Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] -2-methylbenzoic acid hydrochloride 4-ethyl-2-cyano-2-methylbenzoate (1.98 g, 10.5 mmol) in ethanol (8.0 mL) 4N hydrochloric acid / 1,4-dioxane solution (39.0 mL) was added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated, diluted with ethanol (40.0 mL) and concentrated, pyrrolidine (1.7 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 4.5 hr. The reaction solution was concentrated, 1N aqueous hydrochloric acid solution (100 mL) was added, and the mixture was stirred at 70 ° C. overnight and concentrated three times. The obtained residue was crystallized from ethanol / ethyl acetate, and the precipitate was collected by filtration and dried in vacuo at 50 ° C. overnight to give the title compound.
Yield: 1.75 g (6.50 mmol) Yield: 62%
MS (ESI, m / z) 233 [M + H] ^+
1 H NMR (DMSO-d ₆ , 400MHz) δ1.86 (quint, 2H), 2.05 (quint, J = 6.7 Hz, 2H), 2.57 (s, 3H), 3.38 (t, J = 6.9 Hz, 2H) , 3.56 (t, J = 6.9 Hz, 2H), 7.51-7.60 (m, 2H), 7.96 (d, J = 8.0 Hz, 1H), 9.00 (s, 1H), 9.37 (s, 1H), 13.30 ( br s, 1H).

Step 3 Synthesis of Example 4 Compound 4- [Imino (pyrrolidin-1-yl) methyl] -2-methylbenzoic acid hydrochloride (28.0 mg, 0.104 mmol), Intermediate 1 (25.0 mg, 0.104 mmol) ) And DCC (22.0 mg, 0.104 mmol) were added with pyridine (3.0 mL), and the mixture was stirred at room temperature for 5 and a half hours. DCC (22.0 mg, 0.104 mmol) and NMP (1.0 mL) were added to the reaction solution, and the mixture was stirred at 30 ° C. overnight. The reaction solution was treated by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 12.0 mg (0.0186 mmol) Yield: 18%
MS (ESI, m / z) 419 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ 1.80-1.91 (m, 2H), 1.99-2.11 (m, 2H), 2.57 (s, 3H), 3.36 (t, J = 6.9 Hz, 2H) , 3.54 (t, J = 6.9 Hz, 2H), 4.48-4.56 (m, 2H), 4.70-4.76 (m, 2H), 7.23 (d, J = 6.9 Hz, 1H), 7.54-7.62 (m, 3H ), 7.66 (dd, J = 8.9, 2.4 Hz, 1H), 7.89-8.00 (m, 2H), 8.07 (d, J = 2.3 Hz, 1H), 8.88 (s, 1H), 8.99 (br s, 2H ), 9.32 (s, 1H), 13.35 (br s, 1H).

Example 5
4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methoxybenzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate step 1 Synthesis of ethyl 4-cyano-2-hydroxybenzoate 3-hydroxy-4-iodobenzonitrile (21.6 g, 88.1 mmol) was added to DMF (200 mL), ethanol (10.2 mL, 175 mmol), triethylamine (24.6 mL). , 175 mmol) and palladium acetate (catalytic amount) were added, and the mixture was stirred at 70 ° C. for 2 days in the presence of carbon monoxide. The mixture was extracted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, anhydrous magnesium sulfate and activated carbon were added to the organic phase, and the solid was filtered. The filtrate was evaporated under reduced pressure to remove the solvent, and the resulting residue was washed with hexane to obtain the title compound.
Yield: 13.6 g (71.2 mmol) Yield: 81%

Step 2 Synthesis of ethyl 4-cyano-2-methoxybenzoate Ethyl 4-cyano-2-hydroxybenzoate (13.6 g, 71.2 mmol) was added to DMF (100 mL), potassium carbonate (11.8 g, 85 mmol), iodine Methyl chloride (5.3 mL, 85 mmol) was added and stirred overnight. Extracted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, evaporated under reduced pressure to remove the residue, suspended in hexane: ethyl acetate (5: 1), solid The title compound was obtained by filtration.
Yield: 10.0 g (48.8 mmol) Yield: 69%
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.39 (t, J = 7.1 Hz, 1H), 3.93 (s, 1H), 4.38 (q, J = 7.1 Hz, 1H), 7.21 (d, J = 1.4 Hz , 1H), 7.28 (dd, J = 7.9, 1.4 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H).

Step 3 Synthesis of 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methoxybenzoic acid hydrochloride Ethyl 4-cyano-2-methoxybenzoate (2.05 g, 10. 0 mmol) was dissolved in 4N hydrochloric acid / 1,4-dioxane (27 mL), dry ethanol (3 mL) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, dried 1,4-dioxane (40 mL) was added to the resulting residue and concentrated under reduced pressure. Dry 1,4-dioxane (40 mL) and petroleum ether (20 mL) were added to the residue. After stirring, the solid was collected by filtration. The obtained solid was suspended in toluene (20 mL) and dry ethanol (20 mL), and triethylamine (1.18 mL, 8.44 mmol) and 3-pyrroline (0.587 mL, 7.73 mmol) were added under ice cooling at room temperature. Stir overnight. The reaction mixture was concentrated to about half volume under reduced pressure, toluene (15 mL) and diethyl ether (5 mL) were added and stirred, and the precipitated solid was collected by filtration. Water (10 mL) and 4N hydrochloric acid / 1,4-dioxane (20 mL) were added to the obtained solid under ice cooling, and the mixture was stirred at 60 ° C. for 1 hr and at 70 ° C. for 3 hr. 4N Hydrochloric acid / 1,4-dioxane (5 mL) was added to the reaction mixture, and the mixture was stirred at 70 ° C. for 2 hr, and the solvent was evaporated under reduced pressure. The operation of adding 1,4-dioxane (20 mL) to the residue and evaporating the solvent under reduced pressure was performed twice, and then the operation of adding methanol and ethyl acetate and evaporating the solvent under reduced pressure was performed twice. The obtained residue was dissolved in acetonitrile (2 mL), acetone was added, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in acetonitrile (2 mL). Acetone and a small amount of methanol were added and stirred. The title compound was obtained by filtering the solid.
Yield: 1.05 g (3.71 mmol) Yield: 37%
MS (ESI, m / z) 247 [M + H] ^+
1 H NMR (DMSO-d ₆ , 400MHz) δ3.88 (s, 3H), 4.18-4.24 (m, 2H), 4.37-4.42 (m, 2H), 5.89-5.95 (m, 1H), 6.03-6.09 (m, 1H), 7.26 (dd, J = 7.8, 1.4 Hz, 1H), 7.44 (d, J = 1.4 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 9.25 (s, 1H) , 9.64 (s, 1H), 13.10 (br s, 1H).

Step 4 Synthesis of Example 5 Compound 4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methoxybenzoic acid hydrochloride (70.0 mg, 0.248 mmol), Intermediate 1 Pyridine (2.0 mL) and NMP (0.5 mL) were added to (60.0 mg, 0.248 mmol) and DCC (51.0 mg, 0.248 mmol), and the mixture was stirred at 30 ° C. for 3.5 hours. DCC (26.0 mg, 0.126 mmol) was added to the reaction solution, and the mixture was stirred at 40 ° C. for 1 hour, and then the post-reaction treatment was performed by reversed-phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound. Obtained.
Yield: 14.0 mg (0.0212 mmol) Yield: 8.5%
MS (ESI, m / z) 433 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ 3.85 (s, 3H), 4.15-4.22 (m, 2H), 4.33-4.40 (m, 2H), 4.46-4.52 (m, 2H), 4.64- 4.72 (m, 2H), 5.87-5.94 (m, 1H), 6.02-6.09 (m, 1H), 7.22 (d, J = 6.9 Hz, 1H), 7.28 (dd, J = 7.9, 1.4 Hz, 1H) , 7.48 (d, J = 1.4 Hz, 1H), 7.59 (d, J = 6.9 Hz, 1H), 7.66 (dd, J = 8.9, 2.4 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H) , 7.93 (d, J = 8.9 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 9.01 (br s, 2H), 9.11 (s, 1H), 9.58 (s, 1H), 13.36 (br s, 1H).

Example 6
4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methylbenzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate step 1 Synthesis of 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methylbenzoic acid hydrochloride 4-cyano-2-methylbenzoate (0.990 g, 5.23 mmol) 4N hydrochloric acid / 1,4-dioxane solution (19.5 mL) was added to an ethanol (4.0 mL) solution, and the mixture was stirred at room temperature to 30 ° C. for 2 days. The reaction mixture was concentrated, diluted with ethanol and concentrated three times. Ethanol (10 mL) and 3-pyrroline (0.8 mL) were added to the resulting residue, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 1N aqueous hydrochloric acid (60 mL) was added, and the mixture was stirred at 60 ° C. to 80 ° C. for 5 hr. The residue obtained by concentration was crystallized from ethanol / ethyl acetate, and the precipitate was collected by filtration As a result, the title compound was obtained.
Yield: 0.11 g (0.43 mmol) Yield: 8.2%
MS (ESI, m / z) 231 [M + H] ⁺

Step 2 Synthesis of Example 6 Compound 4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methylbenzoic acid hydrochloride (30.1 mg, 0.113 mmol) and intermediate 1 Pyridine (1.0 mL) and NMP (0.5 mL) were added to (27.2 mg, 0.113 mmol) and DCC (23.3 mg, 0.113 mmol), and the mixture was stirred at 30 ° C. for 1.5 hours. DCC (23.3 mg, 0.113 mmol) was added to the reaction mixture, and the mixture was stirred overnight at 30 ° C., and the post-reaction treatment was performed by reversed-phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound. Obtained.
Yield: 15.9 mg (0.0247 mmol) Yield: 22%
MS (ESI, m / z) 417 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ2.58 (s, 3H), 4.13-4.19 (m, 2H), 4.34-4.40 (m, 2H), 4.50-4.56 (m, 2H), 4.71- 4.76 (m, 2H), 5.86-5.93 (m, 1H), 6.01-6.10 (m, 1H), 7.22 (d, J = 6.9 Hz, 1H), 7.61 (t, J = 7.2 Hz, 2H), 7.63 -7.68 (m, 2H), 7.90-8.01 (m, 2H), 8.10 (d, J = 2.3 Hz, 1H), 9.01 (br s, 2H), 9.08 (s, 1H), 9.56 (s, 1H) , 13.36 (br s, 1H).

Example 7
4- [imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate step 1 4-bromo-2- Synthesis of ethyl (methylthio) benzoate 4-Bromo-2-fluorobenzoic acid (2.50 g, 11.4 mmol) was dissolved in a mixed solvent of dichloromethane / ethanol (43 mL / 2.5 mL) at room temperature. 1-Ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (2.63 g, 13.7 mmol) and 4-dimethylaminopyridine (hereinafter referred to as DMAP) (167 mg, 1.37 mmol) were added to the solution. And stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain a crude ester product. The ester was dissolved in THF (45 mL), sodium thiomethoxide (1.0 g, 14.3 mmol) was added, and the mixture was stirred at 80 ° C. for 20 hr. Ethyl acetate was added to the solution, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the title compound was obtained without purification.
Yield: 2.85 g (10.4 mmol) Yield: 91%
MS (ESI, m / z) 276 [M + H] ^+
1 H-NMR (CDCl ₃ , 400 MHz) δ1.42 (t, J = 7.1 Hz, 3H), 2.49 (s, 3H), 4.42 (q, J = 7.1 Hz, 2H), 7.42 (dd, J = 8.1 , 1.5Hz, 1H), 7.49 (d, J = 1.5Hz, 1H), 8.08 (d, J = 8.1Hz, 1H).

Step 2 Synthesis of 4-cyano-2- (methylthio) benzoic acid Ethyl 4-bromo-2- (methylthio) benzoate (2.85 g, 10.4 mmol) was dissolved in DMF (25 mL) and copper cyanide (1 .39 g, 15.5 mmol) was added and the mixture was stirred at 150 ° C. for 15 hours. The solution was cooled to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added and stirred for a while, and the precipitated insoluble material was filtered through celite. The filtrate was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, a cyano compound as a crude product was obtained. The cyano compound was suspended in a mixed solution of THF / methanol (20 mL / 20 mL). 2N aqueous sodium hydroxide solution (25 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, neutralized with 1N hydrochloric acid, ethyl acetate was added, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained without purification by removing the solvent under reduced pressure.
Yield: 1.21 g (5.28 mmol) Yield: 61%
MS (ESI, m / z) 194 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ 2.48 (s, 3H), 7.65 (dd, J = 1.5Hz, 8.1Hz, 1H), 7.76 (d, J = 1.5Hz, 1H), 8.00 ( d, J = 8.1Hz, 1H).

Step 3 Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzoic acid 4-Cyano-2- (methylthio) benzoic acid (1.50 g, 7.76 mmol) was added to 4N hydrochloric acid / 1. , 4-Dioxane solution (14 mL) was suspended, dry ethanol (1.4 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the precipitate was filtered using 1,4-dioxane and petroleum ether. Toluene / ethanol (10 mL / 10 mL) was added and suspended in the obtained solid, pyrrolidine (1.41 mL, 17.1 mmol) was added, and the mixture was stirred for 5 hours. The precipitated solid was filtered and washed with a mixed solution of acetone / water (V / V = 10/1) to obtain the title compound.
Yield: 1.30 g (4.92 mmol) Yield: 63%
MS (ESI, m / z) 265 [M + H] ^+
1 H-NMR (D ₂ O, 400 MHz) δ1.82-1.91 (m, 2H), 2.03-2.12 (m, 2H), 2.39 (s, 3H), 3.41-3.47 (m, 2H), 3.51-3.58 (m, 2H), 7.28 (dd, J = 1.5, 7.8Hz, 1H), 7.37 (d, J = 1.5Hz, 1H), 7.52 (d, J = 7.8Hz, 1H).

Step 4 Synthesis of Example 7 Compound 4- [Imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzoic acid (52.9 mg, 0.200 mmol) was dissolved in NMP (0.5 mL). Thionyl chloride (0.016 mL, 0.220 mmol) was added at 0 ° C., and the mixture was stirred at 8 ° C. for 30 minutes. After thionyl chloride (0.0058 mL, 0.0800 mmol) was added and stirred at 8 ° C. for 2 hours, thionyl chloride (0.0058 mL, 0.0800 mmol) was further added and stirred at 8 ° C. for 3.5 hours and a half. Intermediate 1 (48.1 mg, 0.200 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. The post-reaction treatment was performed by reversed-phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound. It was.
Yield: 46.2 mg (0.0681 mmol) Yield: 34%
MS (ESI, m / z) 451 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ 1.79-1.94 (m, 2H), 1.99-2.12 (m, 2H), 2.49 (s, 3H), 3.37 (t, J = 6.9 Hz, 2H) , 3.55 (t, J = 6.9 Hz, 2H), 4.50-4.58 (m, 2H), 4.69-4.78 (m, 2H), 7.21 (d, J = 6.9 Hz, 1H), 7.45 (dd, J = 8.1 , 1.5 Hz, 1H), 7.55-7.62 (m, 2H), 7.65 (dd, J = 8.9, 2.4 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 8.06 (d, J = 8.1 Hz , 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.93-9.20 (m, 3H), 9.41 (s, 1H), 13.47 (br s, 1H).

Example 8
4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzoic acid 2-[(1-aminoisoquinolin-7-yl) oxy] ethyl ditrifluoroacetate Step 1 Synthesis of 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzoic acid 4-cyano-2- (methylthio) benzoic acid (800 mg, 4.14 mmol) ) Was suspended in 4N hydrochloric acid / 1,4-dioxane (14 mL), ethanol (1.4 mL, 25 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, ethanol / toluene (12 mL / 12 mL) was added to the resulting residue, and the mixture was ice-cooled. 3-pyrroline (0.38 mL, 4.97 mmol) and triethylamine (0.69 mL, 4.97 mmol) And stirred at room temperature for 5 hours. After removing the solvent under reduced pressure, the obtained residue was washed with acetone to obtain the title compound.
Yield: 311 mg (1.19 mmol) Yield: 29%
MS (ESI, m / z) 263 [M + H] ^+
1 H-NMR (D ₂ O, 400 MHz) δ2.41 (s, 3H), 4.20-4.24 (m, 2H), 4.35-4.40 (m, 2H), 5.79-5.84 (m, 1H), 5.88-5.94 (m, 1H), 7.31 (dd, J = 7.9, 1.5 Hz, 1H), 7.40 (d, J = 1.5 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H).

Step 2 Synthesis of Example 8 Compound 4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzoic acid (57.7 mg, 0.220 mmol) was treated with NMP (0 5 mL), thionyl chloride (0.0176 mL, 0.242 mmol) was added at 8 ° C., and the mixture was stirred at 8 ° C. for 40 minutes. Thionyl chloride (0.0080 mL, 0.110 mmol) was added and stirred at 8 ° C. for 40 minutes, and then thionyl chloride (0.010 mL, 0.138 mmol) was further added and stirred at 8 ° C. for 1.5 hours. Intermediate 1 (48.1 mg, 0.200 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. The post-reaction treatment was performed by reversed-phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound. It was.
Yield: 63.1 mg (0.0933 mmol) Yield: 47%
MS (ESI, m / z) 449 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ4.12-4.21 (m, 2H), 4.32-4.40 (m, 2H), 4.49-4.57 (m, 2H), 4.69-4.78 (m, 2H), 5.87-5.94 (m, 1H), 6.02-6.10 (m, 1H), 7.22 (d, J = 6.9 Hz, 1H), 7.50 (dd, J = 8.1, 1.5 Hz, 1H), 7.57-7.68 (m, 3H), 7.93 (d, J = 9.0 Hz, 1H), 8.04-8.11 (m, 2H), 9.03 (br s, 2H), 9.13 (s, 1H), 9.60 (s, 1H), 13.44 (br s , 1H).

Example 9
4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid 2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl trifluoroacetate Intermediate 2 (50 mg, 0.24 mmol) was converted to NMP ( 250 μL) and pyridine (250 μL) and cooled at 0 ° C. under argon. 4- [Imino (pyrrolidin-1-yl) methyl] benzoyl chloride (66.1 mg, 0.24 mmol) was added and stirred at 0 ° C. for 2 hours. Further, 4- [imino (pyrrolidin-1-yl) methyl] benzoyl chloride (33 mg) was added, and the mixture was stirred for 2 hours and then overnight at room temperature. Isopropanol (20 μL) was added to the reaction solution, and then purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 15.5 mg (0.04 mmol) Yield: 16%
MS (ESI, m / z) 406 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz) δ 1.79-1.95 (m, 2H), 1.98-2.10 (m, 2H), 3.20-3.48 (m, 2H), 3.48-3.68 (m, 4H), 4.39 (t, J = 3.6Hz, 2H), 7.16 (d, J = 3.9Hz, 1H), 7.60 (d, J = 4.2Hz, 1H), 7.76 (d, J = 8.4Hz, 2H), 8.13 ( d, J = 8.4Hz, 2H), 8.80-8.85 (m, 2H), 8.88 (s, 1H), 9.34 (s, 1H).

Example 10
4- [Imino (pyrrolidin-1-yl) methyl] benzenecarbothioic acid S- (2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl) trifluoroacetate salt 5-chlorothiophene-2- Carboxylic acid (3.25 g, 20 mmol) and thionyl chloride (20 mL) were stirred at 65 ° C. and concentrated under reduced pressure. The residue was diluted with dichloromethane, and a solution of 2-aminoethanethiol (40 mmol) in dichloromethane was added dropwise to the two portions and stirred at room temperature. The reaction solution was washed with water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride (255 mg, 1 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (hereinafter referred to as DMC) was added to a pyridine solution obtained by dividing the residue into 10 parts. And stirred at room temperature. This reaction mixture was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 191 mg (0.356 mmol) Yield: 36%
MS (ESI, m / z) 422 [M + H] ⁺

Example 11
4- [Imino (pyrrolidin-1-yl) methyl] phenyl N-[(5-chloro-2-thienyl) carbonyl] -β-alaninate Trifluoroacetate Step 1 N-[(5-Chloro-2-thienyl) Synthesis of Carbonyl] -β-Alanine 5-Chlorothiophene-2-carboxylic acid (2.17 g, 13.3 mmol) was mixed with dichloromethane (30 ml), oxalyl chloride (1.4 mL, 16.0 mmol), and DMF (catalytic amount). The mixture was further stirred at room temperature for 2 hours. To the residue obtained by evaporating the solvent under reduced pressure, THF (30 mL), β-alanine methyl ester hydrochloride (2.2 g, 16.0 mmol), triethylamine (4.4 mL, 32 mmol) were added, and then at room temperature. Stir overnight. Extracted with ethyl acetate, washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, dried over magnesium sulfate, and the resulting residue was added with 1N sodium hydroxide (30 mL), THF (60 mL), methanol (60 mL). ) And stirred overnight at room temperature. The residue obtained by evaporating the solvent under reduced pressure was extracted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over magnesium sulfate to give the title compound.
Yield: 1.20 g (5.10 mmol) Yield: 39%
MS (ESI, m / z) 234 [M + H] ^+
1 H NMR (DMSO-d ₆ , 400MHz) δ2.46-2.52 (m, 2H), 3.41 (dd, J = 12.6, 7.0 Hz, 2H), 7.17 (d, J = 4.0 Hz, 1H), 7.62 ( d, J = 4.0 Hz, 1H), 8.62-8.69 (m, 1H), 12.24 (br s, 1H).

Step 2 Synthesis of Example 11 Compound N-[(5-Chloro-2-thienyl) carbonyl] -β-alanine (1.3 mg, 0.44 mmol), 4- [imino (pyrrolidin-1-yl) methyl] phenol DMC (149 mg, 0.88 mmol) was added to a pyridine solution (1 mL) of hydrochloride (100.0 mg, 0.44 mmol) and DMAP (0.044 mmol), and the mixture was stirred at room temperature. This reaction mixture was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 56 mg (0.108 mmol) Yield: 24%
MS (ESI, m / z) 406 [M + H] ⁺

Example 12
2-Fluoro-4- [imino (pyrrolidin-1-yl) methyl] benzoic acid 2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl trifluoroacetate step 1 2-fluoro-4- [ Synthesis of imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride 4-Cyano-2-fluorobenzoic acid (1.00 g, 6.06 mmol) was dissolved in 4N hydrochloric acid / 1,4-dioxane solution and dried ethanol. (0.9 mL) was added, and the mixture was stirred overnight at room temperature. Dry ethanol (20 mL) and pyrrolidine (1.01 mL, 12.1 mmol) were added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated to about half volume under reduced pressure, ethyl acetate (6 mL) was added, and the precipitated solid was collected by filtration, suspended in 4N hydrochloric acid / ethyl acetate solution (6 mL) and stirred at room temperature for 30 minutes. The title compound was obtained by taking.
Yield: 947 mg (3.47 mmol) Yield: 57%
MS (ESI, m / z) 237 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.87 (quint, J = 6.9 Hz, 2H), 2.05 (quint, J = 6.9 Hz, 2H), 3.38 (t, J = 6.9 Hz, 2H), 3.57 (t, J = 6.9Hz, 2H), 7.55-7.58 (m, 1H), 7.68-7.72 (m, 1H), 8.05 (t, J = 7.5Hz, 1H), 9.16 (s, 1H), 9.51 (s, 1H).

Step 2 Synthesis of Example 12 Compound 5-Chlorothiophene-2-carboxylic acid (3.25 g, 20 mmol) and thionyl chloride (20 mL) were stirred at 65 ° C. and concentrated under reduced pressure. The residue was diluted with dichloromethane, and a solution of 2-aminoethanol (40 mmol) in dichloromethane was added dropwise to the two portions and stirred at room temperature. The reaction solution was washed with water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To this pyridine solution divided into 10 portions, 2-fluoro-4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride (273 mg, 1.00 mmol) and DMC were added and stirred at room temperature. This reaction mixture was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 232 mg (0.431 mmol) Yield: 43%
MS (ESI, m / z) 424 [M + H] ⁺

Example 13
4- [Imino (pyrrolidin-1-yl) methyl] -2-methoxyphenyl N-[(5-chloro-2-thienyl) carbonyl] -β-alaninate Trifluoroacetate step 1 4- [Imino (pyrrolidine-1 -Yl) methyl] -2-methoxyphenol Synthesis of hydrochloride To a dry ethanol solution (10 mL) of 4-hydroxy-3-methoxybenzonitrile (5.00 g, 33.2 mmol), 4N hydrochloric acid / 1,4-dioxane solution (40 mL) was added, and the mixture was stirred at room temperature for 2 days under sealed conditions. After the solvent was distilled off under reduced pressure, dry ethanol (50 mL) was added to the resulting residue, pyrrolidine (5.55 mL, 66.6 mmol) was added, and the mixture was stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, methanol was added to the resulting residue, acetone was added and stirred, and the precipitated solid was collected by filtration. 1,4-Dioxane (40 mL) and 4N hydrochloric acid / 1,4-dioxane solution (12 mL) were added to the solid and stirred, and the solid was collected by filtration and dried to give the title compound.
Yield: 3.1 g (12.1 mmol) Yield: 36%
MS (ESI, m / z) 221 [M + H] ⁺

Step 2 Synthesis of Example 13 Compound 4- [Imino (pyrrolidin-1-yl) methyl] -2-methoxyphenol hydrochloride (95.0 mg, 0.370 mmol) and 3-{[(5-chloro-2-thienyl) ) Carbonyl] amino} propionic acid (100.0 mg, 0.428 mmol) was dissolved in pyridine (2.5 mL) at room temperature. DCC (114.6 mg, 0.56 mmol) was added to the solution, and DCC (114.6 mg, 0.56 mmol) was added at 50 ° C. for 2 hours, followed by stirring at room temperature for 15.5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 44.16 mg (0.0803 mmol) Yield: 21.7%
MS (ESI, m / z) 436 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ 1.85-1.91 (m, 2H), 2.02-2.09 (m, 2H), 2.89 (t, J = 6.0Hz, 2H), 3.44 (t, J = 6.0Hz, 2H), 3.54 (t, J = 6.0Hz, 2H), 3.59 (dd, J = 8.0Hz, 12.0Hz, 2H), 3.79 (s, 3H), 7.21 (d, J = 4.0Hz, 1H ), 7.24 (dd, J = 1.9Hz, 8.2Hz, 1H), 7.35 (d, J = 8.2Hz, 1H), 7.41 (d, J = 1.9Hz, 1H), 7.65 (d, J = 4.0Hz, 1H), 8.82-8.85 (m, 2H), 9.3 (s, 1H).

Example 14
6- [imino (pyrrolidin-1-yl) methyl] nicotinic acid 2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl trifluoroacetate step 1 6- [imino (pyrrolidin-1-yl) Synthesis of methyl] nicotinic acid hydrochloride Methanol (20 mL) was added to 6-cyanonicotinic acid (1.59 g, 10.7 mmol), pyrrolidine (2.74 mL) and L-acetylcysteine (1.78 g) at 62 ° C. Stir for 2 hours. Concentrated hydrochloric acid (6 mL) and water (44 mL) were added to the residue obtained by concentration and drying under reduced pressure, and the mixture was stirred at 80 ° C. for 1 hour and concentrated. The residue was crystallized from methanol / ethyl acetate, and the precipitate was collected by filtration and dried under reduced pressure at 50 ° C. overnight to obtain the title compound.
Yield: 1.85 g (7.23 mmol) Yield: 67%
MS (ESI, m / z) 220 [M + H] ^+
1 H NMR (DMSO-d ₆ , 400MHz) δ1.84-1.94 (m, 2H), 2.01-2.10 (m, 2H), 3.47 (t, J = 7.0 Hz, 2H), 3.63 (t, J = 7.0 Hz, 2H), 7.97 (dd, J = 8.1, 0.8 Hz, 1H), 8.55 (dd, J = 8.1, 2.1 Hz, 1H), 9.20 (dd, J = 2.1, 0.8 Hz, 1H), 9.31 (s , 1H), 9.68 (s, 1H), 13.92 (br s, 1H).

Step 2 Synthesis of Example 14 Compound 6- [Imino (pyrrolidin-1-yl) methyl] nicotinic acid hydrochloride (108.0 mg, 0.422 mmol) and intermediate 2 (100.0 mg, 0.486 mmol) were converted to pyridine ( 2.5 mL) at room temperature. DCC (152.0 mg, 0.737 mmol) was added to the solution and stirred at 50 ° C. for 36.5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 32.3 mg (0.0619 mmol) Yield: 13%
MS (ESI, m / z) 407 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400MHz) δ1.85-1.92 (m, 2H), 2.03-2.09 (m, 2H), 3.46 (t, J = 6.0Hz, 2H), 3.61 (t, J = 6.0Hz, 2H), 3.66 (dd, J = 4.0Hz, 8.0Hz, 2H), 4.46 (t, J = 6.0Hz, 2H), 7.19 (d, J = 4.0Hz, 1H), 7.63 (d, J = 4.0Hz, 1H), 7.99 (dd, J = 0.8Hz, 8.2Hz, 1H), 8.58 (dd, J = 4.0Hz, 8.0Hz, 1H), 8.86-8.89 (m, 1H), 8.88 (t, J = 6.0Hz, 1H), 9.23-9.24 (m, 1H), 9.58 (s, 1H).

Example 15
4- [imino (pyrrolidin-1-yl) methyl] -2-methylbenzoic acid 2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl trifluoroacetate 4- [imino (pyrrolidin-1- Yl) methyl] -2-methylbenzoic acid hydrochloride (152 mg, 0.564 mmol) and intermediate 2 (100.0 mg, 0.486 mmol) were dissolved in pyridine (2.5 mL) at room temperature. DCC (151.6 mg, 0.735 mmol) was added to the solution and stirred at 50 ° C. for 3.5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 34.8 mg (0.0652 mmol) Yield: 12%
MS (ESI, m / z) 420 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400MHz) δ1.82-1.89 (m, 2H), 2.01-2.08 (m, 2H), 2.53 (s, 3H), 3.37 (t, J = 8.0Hz, 2H) , 3.54 (t, J = 6.0Hz, 2H), 3.61-3.65 (m, 2H), 4.41 (t, J = 4.0Hz), 2H, 7.20 (d, J = 4.0Hz, 1H), 7.55-7.57 ( m, 1H), 7.58 (s, 1H), 7.63 (d, J = 4.0Hz, 1H), 7.97 (d, J = 8.0Hz, 1H), 8.83 (t, J = 6.0Hz, 1H), 8.87 ( s, 1H), 9.31 (s, 1H).

Example 16
4- [Imino (pyrrolidin-1-yl) methyl] -2-methoxybenzoic acid 2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl trifluoroacetate step 1 4-cyano-2-methoxy Synthesis of Benzoic Acid Ethyl 4-cyano-2-methoxybenzoate (1.14 g, 5.51 mmol) was dissolved in a mixed solvent of ethanol (8 mL) and tetrahydrofuran (hereinafter THF) (8 mL), and 2N water was added under ice cooling. An aqueous sodium oxide solution (5.5 mL) was added dropwise. The mixture was stirred at room temperature for 1.5 hours, neutralized with 2N hydrochloric acid under ice-cooling, concentrated under reduced pressure, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The compound was obtained without purification.
Yield: 948 mg (5.35 mmol) Yield: 97%
¹ H-NMR (CDCl ₃ , 300 MHz) δ4.12 (s, 3H), 7.32-7.33 (m, 1H), 7.42-7.45 (m, 1H), 8.25 (d, J = 8.1 Hz, 1H).

Step 2 Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] -2-methoxybenzoic acid hydrochloride 4-Cyano-2-methoxybenzoic acid (945 mg, 5.33 mmol) was converted into 4N hydrochloric acid / 1,4-dioxane. It melt | dissolved in the solution (7 mL), dry ethanol (0.775 mL) was added, and it stirred for 2 night under room temperature sealing. A 4N hydrochloric acid / 1,4-dioxane solution (1 mL) was added to the reaction mixture, and the mixture was stirred for 6 hours under sealed room temperature. The residue obtained by evaporating the solvent under reduced pressure was dissolved in dry ethanol (18 mL), pyrrolidine (1.78 mL, 21.3 mmol) was added, and the mixture was stirred at room temperature for 3 days. The residue obtained by distilling off the solvent under reduced pressure was purified by reverse-phase HPLC in the same manner as in Step 2 of Reference Example 1, and the residue obtained by lyophilization was added with 4N hydrochloric acid / 1,4-dioxane solution (15 mL). ) Was added and concentrated under reduced pressure three times, and then the residue was dissolved in water and lyophilized to obtain the title compound.
Yield: 268 mg (0.941 mmol) Yield: 18%
MS (ESI, m / z) 249 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz) δ 1.83-1.92 (m, 2H), 2.02-2.11 (m, 2H), 3.39-3.60 (m, 4H), 3.88 (s, 3H), 7.21- 7.24 (m, 1H), 7.36-7.39 (m, 1H), 7.77 (d, J = 7.8Hz, 1H), 8.87 (s, 1H), 9.32 (s, 1H).

Step 3 Synthesis of Example 16 Compound 4- [Imino (pyrrolidin-1-yl) methyl] -2-methoxybenzoic acid hydrochloride (100.0 mg, 0.351 mmol) and intermediate 2 (72.0 mg, 0.350 mmol) ) Was dissolved in pyridine (2.5 mL) at room temperature. DCC (108.3 mg, 0.525 mmol) was added to the solution and added at 50 ° C. for 3.5 hours, followed by addition of DCC (108.3 mg, 0.525 mmol) at 50 ° C. for 5 hours and 12. Stir for 5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 18.0 mg (0.0327 mmol) Yield: 9.3%
MS (ESI, m / z) 436 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400MHz) δ1.83-1.90 (m, 2H), 2.02-2.09 (m, 2H), 3.53 (t, J = 8.0Hz, 2H), 3.59 (dd, J = 4.0Hz, 12.0Hz, 2H), 3.83 (s, 3H), 4.37 (t, J = 6.0Hz, 2H), 7.20 (d, J = 4.0Hz, 1H), 7.24 (dd, J = 1.4Hz, 7.9 Hz, 1H), 7.39 (d, J = 1.3Hz, 1H), 7.63 (d, J = 4.0Hz, 1H), 7.80 (d, J = 8.0Hz, 1H), 8.78 (t, J = 6.0Hz, 1H), 8.96 (s, 1H), 9.30 (s, 1H).

Example 17
4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-fluorobenzoic acid 2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl trifluoroacetate intermediate Form 2 (100 mg, 0.49 mmol), 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-fluorobenzoic acid hydrochloride (123 mg, 0.49 mmol), DMC (103 mg , 0.61 mmol) was added dehydrated pyridine (1 mL) and stirred overnight. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 28 mg (0.052 mmol) Yield: 11%
MS (ESI, m / z) 422 [M + H] ⁺

Example 18
2-Fluoro-4- [imino (pyrrolidin-1-yl) methyl] benzenecarbothioic acid S- (2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl) trifluoroacetate intermediate 3 (99 mg, 0.45 mmol), 2-fluoro-4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride (127 mg, 0.54 mmol), and DMC (91 mg, 0.55 mmol) in dehydrated pyridine ( 1 mL) was added and stirred overnight. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield 45 mg (0.10 mmol) Yield: 23%
MS (ESI, m / z) 440 [M + H] ⁺

Example 19
4- [Imino (pyrrolidin-1-yl) methyl] -2-methylbenzenecarbothioic acid S- (2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl) trifluoroacetate salt Example 18 In the same manner as in 2-fluoro-4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride, instead of 4- [imino (pyrrolidin-1-yl) methyl] -2-methylbenzoic acid hydrochloride Performed with salt to give the title compound.
Yield: 25 mg (0.045 mmol) Yield: 10%
MS (ESI, m / z) 436 [M + H] ⁺

Example 20
5- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] thiophene-2-carboxylic acid 2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl trifluoroacetate step 1 Synthesis of 5-[(2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] thiophene-2-carboxylic acid hydrochloride 5-formyl-2-thiophenecarboxylic acid (2.3 g, 16.9 mmol) ) Acetic acid (20 mL), sodium acetate (5.5 g, 67.6 mmol) and hydroxylamine hydrochloride (1.75 g, 25.4 mmol) were added, and the mixture was stirred at 60 ° C. for 1 hour, and then acetic anhydride (3.19 mL). , 34.0 mmol), and stirred for 1 hour at 100 ° C. The solvent was distilled off under reduced pressure, and the resulting residue was extracted with ethyl acetate and washed with 1N hydrochloric acid and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and half of the resulting residue was added to a 4N hydrochloric acid / 1,4-dioxane solution (16 mL) and a dry ethanol solution (4 mL) and sealed. After stirring for 2 days at room temperature, the solvent was evaporated under reduced pressure, dry ethanol (10 mL) was added to the residue, 3-pyrroline (1.11 g, 17 mmol) was added, and the mixture was stirred at room temperature for 1 day. To the residue obtained by distilling off the solvent under reduced pressure, 4N hydrochloric acid / 1,4-dioxane solution (12 mL) was added. After distilling off the solvent under reduced pressure, methanol was added, and then acetone was added and stirred to precipitate. The resulting solid was collected by filtration and dried to obtain the hydrochloride of the title compound.
Yield: 550 mg (2.10 mmol) Yield: 25%
MS (ESI, m / z) 223 [M + H] ⁺

Step 2 Synthesis of Example 20 Compound Intermediate 2 (100 mg, 0.49 mmol), 5- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] thiophene-2-carboxylic acid hydrochloride (126 mg 0.49 mmol), 1 ml of dehydrated pyridine was added to DMC (103 mg, 0.61 mmol), and the mixture was stirred overnight. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 22 mg (0.042 mmol) Yield: 9%
MS (ESI, m / z) 410 [M + H] ⁺

Example 21
5- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] thiophene-2-carbothioic acid S- (2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl) tri Fluoroacetate The same procedure as in Example 18 was performed except that 5-[(2,5-dihydro-1H-pyrrole-) was used instead of 2-fluoro-4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride. 1-yl (imino) methyl] thiophene-2-carboxylic acid hydrochloride was used to give the title compound.
Yield: 37 mg (0.069 mmol) Yield: 15%
MS (ESI, m / z) 426 [M + H] +

Example 22
5- [Imino (pyrrolidin-1-yl) methyl] thiophene-2-carbothioic acid S- (2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl) trifluoroacetate step 1 5- [ Synthesis of imino (pyrrolidin-1-yl) methyl] thiophene-2-carboxylic acid hydrochloride 5-formyl-2-thiophenecarboxylic acid (2.3 g, 16.9 mmol) in acetic acid (20 mL) was added to sodium acetate (5. 5 g, 67.6 mmol) and hydroxylamine hydrochloride (1.75 g, 25.4 mmol) were added. After stirring at 60 ° C. for 1 hour, acetic anhydride (3.19 mL, 34 mmol) was added and stirred at 100 ° C. for 1 hour. . The residue obtained by evaporating the solvent under reduced pressure was extracted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, and then the solvent obtained by evaporating the solvent under reduced pressure. Half of the solution was added to a 4N hydrochloric acid / 1,4-dioxane solution (16 mL) and a dry ethanol solution (4 mL), and the mixture was stirred at room temperature for 2 days under sealed conditions. After the solvent was distilled off under reduced pressure, dry ethanol (10 mL) was added to the resulting residue, pyrrolidine (1.41 mL, 17 mmol) was added, and the mixture was stirred at room temperature for 1 day. To the residue obtained by distilling off the solvent under reduced pressure, 4N hydrochloric acid / 1,4-dioxane solution (12 mL) was added. After distilling off the solvent under reduced pressure, methanol was added, and then acetone was added and stirred to precipitate. The resulting solid was collected by filtration and dried to obtain the hydrochloride of the title compound.
Yield: 725 mg (2.8 mmol) Yield: 33%
MS (ESI, m / z) 225 [M + H] ⁺

Step 2 Synthesis of Example 22 Compound 5- [imino (pyrrolidin-1-yl) methyl] thiophene-2-carboxylic acid hydrochloride (65.2 mg, 0.250 mmol) and intermediate 3 (55.4 mg, 0.250 mmol) ), Pyridine (2.0 mL) was added to DCC (51.5 mg, 0.250 mmol), and the mixture was stirred at room temperature for 1.5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 92.9 mg (0.171 mmol) Yield: 69%
MS (ESI, m / z) 428 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ 1.85-1.95 (m, 2H), 1.99-2.09 (m, 2H), 3.29 (t, J = 6.6 Hz, 2H), 3.47-3.65 (m, 6H), 7.19 (d, J = 4.1 Hz, 1H), 7.62 (d, J = 4.1 Hz, 1H), 7.77 (d, J = 4.1 Hz, 1H), 8.01 (d, J = 4.1 Hz, 1H) , 8.87 (t, J = 5.7 Hz, 1H), 8.95 (s, 1H), 9.46 (s, 1H).

Example 23
4- [imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzoic acid 2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl trifluoroacetate 4- [imino (pyrrolidine- 1-yl) methyl] -2- (methylthio) benzoic acid (500 mg, 1.67 mmol) was dissolved in NMP (4.0 mL), and thionyl chloride (0.159 mL, 2.18 mmol) was added at 5 ° C. After stirring at 90 ° C. for 90 minutes, Intermediate 2 (309 mg, 1.50 mmol) was added to the reaction solution, stirred overnight at room temperature, and purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound. Obtained.
Yield: 527 mg (0.905 mmol) Yield: 55.8%
MS (ESI, m / z) 453 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ 1.83-1.91 (m, 2H), 2.01-2.10 (m, 2H), 2.46 (s, 3H), 3.51-3.57 (m, 2H), 3.59- 3.66 (m, 2H), 4.40 (dd, J = 5.4Hz, 1H), 7.19 (d, J = 3.9Hz, 1H), 7.46 (dd, J = 1.5Hz, 8.1Hz, 1H), 7.55 (d, J = 1.5Hz, 1H), 7.62 (d, J = 3.9Hz, 1H), 8.08 (d, J = 8.1Hz, 1H), 8.78-8.85 (m, 1H), 8.90 (s, 1H), 9.35 ( s, 1H).

Example 24
4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methoxybenzoic acid 2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl trifluoroacetate intermediate Form 2 (47 mg, 0.23 mmol), 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methoxybenzoic acid hydrochloride (65 mg, 0.23 mmol), and DMC ( 42 mg, 0.23 mmol) was added dehydrated pyridine (1 mL), and the mixture was stirred overnight. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 8 mg (0.015 mmol) Yield: 6%
MS (ESI, m / z) 434 [M + H] ^+
1 H NMR (DMSO-d ₆ , 400MHz) δ 3.59 (dd, J = 11.1, 5.6 Hz, 2H), 3.83 (s, 3H), 4.18-4.22 (m, 2H), 4.33-4.40 (m, 4H) , 5.89-5.94 (m, 1H), 6.04-6.08 (m, 1H), 7.20 (d, J = 4.1 Hz, 1H), 7.28 (dd, J = 7.9, 1.4 Hz, 1H), 7.45 (d, J = 1.4 Hz, 1H), 7.63 (d, J = 4.1 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 8.78 (t, J = 5.6 Hz, 1H), 9.05 (s, 1H), 9.54 (s, 1H).

Example 25
4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methoxybenzenecarbothioic acid S- {2-[(5-chloro-thiophen-2-carbonyl) -amino]- Ethyl} ester trifluoroacetate salt The title compound was obtained in the same manner as the Example 24, using the intermediate 3 instead of the intermediate 2.
Yield: 12 mg (0.021 mmol) Yield: 9%
MS (ESI, m / z) 450 [M + H] ⁺

Example 26
4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methylbenzenecarbothioic acid S- (2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl ) Trifluoroacetic acid salt 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2-methylbenzoic acid hydrochloride (32.4 mg, 0.122 mmol) and intermediate 3 (27. 1 mg, 0.122 mmol) was dissolved in pyridine (1.5 mL) at room temperature. DCC (50.4 mg, 0.244 mmol) was added to the solution and stirred at room temperature for 17 hours. After removing the solvent under reduced pressure, purification was conducted by reversed-phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 39.7 mg (0.0438 mmol) Yield: 59%
MS (ESI, m / z) 435 [M + H] ⁺

Example 27
4- [Imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzenecarbothioic acid S- (2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl) trifluoroacetate step 1 4- [Imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzoic acid Synthesis of trifluoroacetate
4-Cyano-2- (methylthio) benzoic acid (100 mg, 0.518 mmol) was suspended in a 4N hydrochloric acid / 1,4-dioxane solution (1.5 mL), and dry ethanol (0.15 mL) was added at room temperature. Stir for 20 hours. The reaction mixture was concentrated under reduced pressure, dried ethanol (1.5 mL) was added and suspended, pyrrolidine (0.086 mL, 1.04 mmol) was added, and the mixture was stirred for 4 hr. After removing the solvent under reduced pressure, the obtained residue was subjected to reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 31.8 mg (0.0841 mmol) Yield: 16%
MS (ESI, m / z) 265 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ1.83-1.92 (m, 2H), 2.02-2.11 (m, 2H), 2.46 (s, 3H), 3.37-3.43 (m, 2H), 3.52- 3.57 (m, 2H), 7.43 (dd, J = 8.1, 1.5Hz, 1H), 7.52 (d, J = 1.5Hz, 1H), 8.04 (d, J = 8.1Hz, 1H), 8.87 (s, 1H ), 9.33 (s, 1H).

Step 2 Synthesis of Example 27 Compound 4- [Imino (pyrrolidin-1-yl) methyl] -2- (methylthio) benzoic acid trifluoroacetate (67.7 mg, 0.225 mmol) and Intermediate 3 (50.0 mg , 0.225 mmol) was dissolved in pyridine (2.0 mL) at room temperature. DCC (92.3 mg, 0.450 mmol) was added to the solution and stirred at room temperature for 24 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 9.3 mg (0.0438 mmol) Yield: 7.1%
MS (ESI, m / z) 469 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ1.83-1.92 (m, 2H), 2.02-2.10 (m, 2H), 3.22-3.28 (m, 2H), 3.37-3.45 (m, 2H), 3.47-3.57 (m, 4H), 7.19 (d.J = 4.2Hz, 1H), 7.50 (dd, J = 1.5, 8.1Hz, 1H), 7.60 (d, J = 1.5Hz, 1H), 7.62 (d , J = 4.2Hz, 1H), 8.82 (d, J = 8.1Hz, 1H), 8.84-8.88 (m, 1H), 8.90 (s, 1H), 9.33 (s, 1H).

Example 28
4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzoic acid 2-{[(5-chloro-2-thienyl) carbonyl] amino} ethyl trifluoroacetic acid Salt 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzoic acid (63.0 mg, 0.240 mmol) was dissolved in NMP (0.5 mL), Thionyl chloride (0.0192 mL, 0.264 mmol) was added at 8 ° C., and the mixture was stirred at 8 ° C. for 40 minutes. After thionyl chloride (0.0087 mL, 0.120 mmol) was added and stirred at 8 ° C. for 40 minutes, thionyl chloride (0.010 mL, 0.138 mmol) was further added and stirred at 8 ° C. for 1.5 hours. Intermediate 2 (41.1 mg, 0.200 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight and purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 61.0 mg (0.108 mmol) Yield: 54%
MS (ESI, m / z) 450 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ2.46 (s, 3H), 3.59-3.66 (m, 2H), 4.15-4.21 (m, 2H), 4.35-4.43 (m, 4H), 5.88- 5.93 (m, 1H), 6.04-6.09 (m, 1H), 7.19 (d, J = 4.0 Hz, 1H), 7.51 (dd, J = 8.0, 1.4 Hz, 1H), 7.61 (d, J = 1.4 Hz , 1H), 7.64 (d, J = 4.1 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.81-8.87 (m, 1H), 9.11 (s, 1H), 9.58 (s, 1H) .

Example 29
4- [2,5-Dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzenecarbothioic acid S- (2-{[(5-chloro-2-thienyl) carbonyl] amino } Ethyl) trifluoroacetate salt 4- [2,5-dihydro-1H-pyrrol-1-yl (imino) methyl] -2- (methylthio) benzoic acid (50.0 mg, 0.191 mmol) was added to NMP (1. 0 mL) and cooled to 5 ° C., thionyl chloride (0.0417 mL, 0.573 mmol) was added, and the mixture was stirred for 1 hour. Intermediate 3 (42.4 mg, 0.191 mmol) was added to the solution and stirred overnight at room temperature. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Reference Example 1 to obtain the title compound.
Yield: 16.5 mg (0.0284 mmol) Yield: 15%
MS (ESI, m / z) 467 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz) δ 2.49 (s, 3H), 3.23-3.28 (m, 2H), 3.47-3.54 (m, 2H), 4.18-4.22 (m, 2H), 4.35- 4.39 (m, 2H), 5.88-5.93 (m, 1H), 6.03-6.09 (m, 1H), 7.19 (d.J = 4.2Hz, 1H), 7,55 (dd, J = 1.5, 8.1Hz, 1H), 7.63 (d. J = 4.2Hz, 1H), 7.66 (d. J = 1.5Hz, 1H), 8.03 (d, J = 8.1Hz, 1H), 8.86-8.92 (m, 1H), 9.12 ( s, 1H), 9.57 (s, 1H).

Table 1 and Table 2 show the structural formulas of the compounds described in the examples. In the formula, TFA represents trifluoroacetic acid.

Test Example 1 Measurement of Activation Factor X Activity Inhibitory Activity Using a 96-well plate (# 3396, Costar), 100 mM Tris-HCl buffer containing 0.02% Tween20, 0.1% PEG6000, 0.2M NaCl After 130 μL of 10 μL of 0.015 U / mL FXa and 10 μL of the test compound were mixed for 10 minutes, 50 μL of chromogenic substrate 0.2 mM S-2222 was added. Using a microplate reader Benchmark Plus (BIO-RAD), the reaction rate was measured from the change over time in absorbance at 405 nm. The control reaction rate was 100%, and the negative logarithm of the concentration at which the control reaction rate was suppressed by 50% was defined as the pIC ₅₀ value. The results are shown in Table 3.

Test Example 2 Activation Factor II (FIIa, Thrombin) Inhibitory Activity Measurement Using a 96-well plate (# 3396, Costar), 100 mM Tris containing 0.02% Tween20, 0.1% PEG6000, 0.2M NaCl -10 μL of 0.125 U / mL activated factor IIA (thrombin) and 10 μL of the test compound were mixed in 130 μL of HCl buffer for 10 minutes, and then 50 μL of chromogenic substrate 0.1 mM S-2238 was added. Using a microplate reader Benchmark Plus (BIO-RAD), the reaction rate was measured from the change over time in absorbance at 405 nm. The control reaction rate was 100%, and the negative logarithm of the concentration at which the control reaction rate was suppressed by 50% was defined as the pIC ₅₀ value. The results are shown in Table 3.

Test Example 3 Measurement of anticoagulant activity The measurement was performed in accordance with the aPTT measurement method using a fully automatic blood coagulation time measurement device Sysmex Cs-2000i. 8 μL of 10 mg / mL DDVP solution (DDVP standard product, Wako) and 40 μL of test compound solution are placed in a sample tube (MS-18, Nippon Medical Science) and human plasma (standard human plasma for blood coagulation test, GCH-100A). , Sysmex) 360 μL was used as a test sample. 50 μL of the test sample was incubated at 37 ° C. for 1 minute, 50 μL of Dataphi APTT (rabbit brain-derived sephaline, DADE Beiling) was added, and further incubated at 37 ° C. for 2 minutes. To the sample solution, 50 μL of 0.02M calcium chloride was added, and the time until the plasma coagulated was automatically measured.
For anticoagulant activity, the negative logarithm of the concentration that doubles the control aPTT was shown as paPTT2. The results are shown in Table 3.

Test Example 4 Stability Evaluation in Whole Blood 6 μL each of a test compound DMSO solution prepared to 200 μM was added to 588 μL human blood (final compound concentration 2 μM), and incubated at 37 ° C. with stirring. 120 μL was sampled at 0 minutes, 1 minute, 2 minutes, 5 minutes and 10 minutes after addition of the chemical solution, and mixed with 12 μL of the DDVP solution prepared to 2 mg / mL to stop the reaction. After stopping the reaction, plasma was separated by centrifugation at 15,000 rpm for 5 minutes to obtain 50 μL of plasma. 100 μL of acetonitrile was added to and mixed with 50 μL of plasma, and protein removal treatment was performed by centrifugation at 15,000 rpm for 5 minutes to obtain 50 μL of centrifugal supernatant. 100 μL of 0.2% formic acid aqueous solution was added to 50 μL of the centrifugal supernatant, and the mixed solution was measured with LC / MS / MS (API 3200, AB SCIEX). Half-life (T1 / 2) was calculated using the initial 3-4 time points. The results are shown in Table 4.

Test Example 5 Stability evaluation in liver S9 fraction Metabolic reaction mixture (0.1 mM EDTA-100 mM potassium phosphate buffer (pH 7.4), 2 mg / mL human liver S9 fraction, 0.5 mM nicotinamide adenine dinucleotide phosphorus Acid-oxidized 5 mM glucose-6-phosphate, 1 unit / mL glucose-6-phosphate dehydrogenase) was prewarmed at 37 ° C. for 5 minutes. After pre-warming, a DMSO solution of the substrate was added so that the final drug solution concentration was 2 μM, and metabolic reaction was started at 37 ° C. A fixed amount was sampled at 0 minutes, 5 minutes, 10 minutes and 30 minutes after the start of the reaction, and acetonitrile containing 0.1 mg / mL DDVP was added and mixed to stop the reaction. After stopping the reaction, protein removal treatment was performed by centrifugation at 15,000 rpm for 5 minutes, and 0.3% formic acid aqueous solution was added to the centrifuged supernatant, mixed, and measured by LC / MS / MS. Next, the ratio with respect to the density | concentration at the time of 0 minute was computed as a residual rate (%) after 30 minutes. The results are shown in Table 4.

As shown in the above test examples, compound (I) and pharmaceutically acceptable salts thereof have high FXa inhibitory activity and anti- (blood) clotting action, and as anti- (blood) clotting agents (agents), Various diseases in which FXa-dependent coagulation processes are involved in the pathology, such as thrombus formation during extracorporeal circulation, cerebral infarction, cerebral thrombus, cerebral embolism, transient ischemic attack (TIA), acute and chronic myocardial infarction Stable angina, pulmonary embolism, peripheral arterial occlusion, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial vascular surgery and valve replacement, reocclusion and restenosis after coronary artery bypass surgery, percutaneous It can be used as a therapeutic or prophylactic agent for re-occlusion and restenosis after vascular reconstruction such as mechanical transluminal coronary angioplasty (PTCA) or percutaneous coronary artery recanalization therapy (PTCR).

In particular, Compound (I) and pharmaceutically acceptable salts thereof are useful as anti- (blood) coagulants (agents) in blood extracorporeal circuits (for example, hemodialyzers, heart-lung machines, etc.).

Compound (I) and pharmaceutically acceptable salts thereof are rapidly eliminated from the blood, that is, have a short half-life in blood, so that it is easy to stop bleeding when bleeding symptoms are observed during administration. It is useful as an anti- (blood) coagulant (agent) that can be used safely.

Furthermore, compound (I) and pharmaceutically acceptable salts thereof have low thrombin inhibitory activity, are selective FXa inhibitors, and can be used safely in terms of bleeding risk (agents) ).

Claims (18)

Formula (I):

[Where:
Ar ¹ represents an aromatic hydrocarbon ring or an aromatic heterocyclic ring;
Ar ² is

Or

Represents;
V is an alkyl group having 1 to 10 carbon atoms which may have a substituent, an amino group which may be mono- or disubstituted with an alkyl group having 1 to 10 carbon atoms which may have a substituent, Or a 3- to 10-membered cyclic amino group which may have a substituent;
1 X is the same or different and each has a halogen atom, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, an optionally substituted alkyl group having 1 to 10 carbon atoms, or a substituent. An optionally substituted alkoxy group having 1 to 10 carbon atoms, an optionally substituted alkylthio group having 1 to 10 carbon atoms, an optionally substituted amino group, or a substituent. Represents an optionally substituted carbamoyl group;
m Zs are the same or different and each have a halogen atom, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, an optionally substituted alkyl group having 1 to 10 carbon atoms, or a substituent. An optionally substituted alkoxy group having 1 to 10 carbon atoms, an optionally substituted alkylthio group having 1 to 10 carbon atoms, an optionally substituted amino group, or a substituent. Represents an optionally substituted carbamoyl group;
Y ¹ is —C (═O) O—, —OC (═O) —, —C (═O) S—, —C (═S) O—, —SC (═O) — or —OC ( = S)-;
Y ² represents —O—, —S—, —NHC (═O) — or —C (═O) NH—;
l represents an integer of 0 to 2;
m represents an integer of 0 to 2;
n represents an integer of 1 to 3. ]
Or a pharmaceutically acceptable salt thereof. Ar ² is

The compound or a salt thereof according to claim 1, wherein Y ² is -O- or -S-. Ar ² is

The compound or a salt thereof according to claim 1, wherein Y ² is -NHC (= O)-or -C (= O) NH-. The compound or a salt thereof according to claim 1, wherein Ar ¹ is benzene or a 5- or 6-membered aromatic heterocyclic ring. The compound or a salt thereof according to claim 1, wherein n is 1. The compound or a salt thereof according to claim 1, wherein V is a 5- or 6-membered cyclic amino group which may have a substituent. The compound or a salt thereof according to claim ¹ , wherein Y ¹ is -C (= O) O-, -OC (= O)-or -C (= O) S-. The compound or a salt thereof according to claim 2, wherein Y ² is -O-. The compound or a salt thereof according to claim 3, wherein Y ² is -NHC (= O)-. The compound according to claim 1, wherein 1 X is the same or different and each is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms. Or its salt. The compound or a salt thereof according to claim 1, wherein the m Zs are the same or different and each is a halogen atom. Ar ¹ is benzene;
Ar ² is

And Y ² is —O— or Ar ² is

And Y ² is —NHC (═O) —;
V is a 5-membered cyclic amino group;
X is an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms;
Z is a halogen atom;
Y ¹ is —C (═O) O—;
l is 0 or 1;
m is 0 or 1; and n is 1.
The compound according to claim 1 or a salt thereof. An activated blood coagulation factor X inhibitor comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof. The activated blood coagulation factor X inhibitor according to claim 13, which selectively inhibits activated blood coagulation factor X. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 15, which is an anticoagulant. 16. The pharmaceutical composition according to claim 15, which is an anticoagulant for blood extracorporeal circuit. The pharmaceutical composition according to claim 15, which is an anticoagulant for hemodialysis.