MXPA00004900A - Biphenylamidine derivatives - Google Patents

Abstract

Biphenylamidine derivatives represented by general formula (1) or pharmaceutically acceptable salts thereof, both being novel compounds functioning as clinically applicable Fxa inhibitors.

Description

BIFENYLAMIDINE DERIVATIVES TECHNICAL FIELD The present invention relates to activated selective and novel blood coagulation factor Xa inhibitors (hereinafter "FXa") of the general formula (I). BACKGROUND OF THE ART Anticoagulation therapy plays an important role in the medical treatment and in the prophylactic treatment of thromboembolisms, such as myocardial infarction, cerebral thrombosis, peripheral arterial thrombosis, and deep vein thrombosis. Particularly, for the prophylactic treatment of chronic thrombosis, it is desirable to have appropriate and non-harmful oral anticoagulants that can be administered for a long period of time. However, to date, potassium wuarfarin agents difficult to control in terms of the magnitude of anticoagulation are the only aforementioned anticoagulants, and therefore there is a need for easy-to-use anticoagulants. Although antithrombin agents have been developed as anticoagulants in the past, it is known that these agents, for example, hirudin, have a tendency to promote bleeding as a side effect. The fact that inhibition of FXa, located upstream of thrombin in the blood coagulation cascade, is consistently more effective than inhibition of thrombin and that FXa inhibitors do not cause the aforementioned significant side effect and are preferred from a clinical perspective, has begun to be understood. Biphenylamidine compounds that exhibit FXa inhibition activity were discovered in the 17th Symposium on Medicinal Chemistry, The 6th Annual Meeting of the Division of Medicinal Chemistry, (17th Symposium on Medical Chemistry, the 6th Annual Meeting of the Chemistry Division Medical), Abstracts, 184-185, 1997. However, compounds of the present invention are novel compounds that differ markedly in the use of a heteroatom in a bond between the biphenylamidine structure that can interact with a bag Si and the cyclic structure that can interact with an aryl linkage site, and in the presence of a substituent such as, for example, carboxyl groups in a benzene ring linker. In addition, Japanese Unexamined Patent Publication (Kokai) No. 4-264068 presents biphenylamidine derivatives as cyclic imino derivatives. However, compounds of the present invention differ in the presence of a bond, through a heteroatom, in a benzyl position. Accordingly, an object of the present invention is to provide a novel compound that can be an FXa inhibitor that has clinical application.

Presentation of the invention The inventors made efforts to achieve the aforementioned purpose and, as a result, created the following inventions 1-10. 1. A biphenylamidine derivative of the general formula (1): ( 1 ) where R is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a "hydroxyl group, an amino group, a nitro group, a C? -C8 alkyl group, or an alkoxy group C_ .- C8; L is a direct bond or an alkylene group C? -C; R2 is a fluorine atom; a chlorine atom; a bromine atom; a hydroxyl group; an amino group; a C? -C8 alkoxy group; a carboxyl group; an alkoxycarbonyl group C.-Cs; an aryloxycarbonyl group; an aralkoxycarbonyl group; a carbamoyl group wherein a nitrogen atom constituting the carbamoyl group can be substituted by a Ci-Cβ monoalkyl group or C? -C8 dialkyl or it can be a nitrogen atom in an amino acid; an alkylcarbonyl group C ".- C8; a C 1 -C 8 alkylsulfenyl group; a C 1 -C 8 alkylsulfinyl group; a C 1 -C 8 alkylsulfonyl group; a monoalkylamino group Ci-Cβ or dialkylamino C? ~ C8; a monoalkylaminosulfonyl group Ci-Cs or dialkylaminosulfonyl C? -C8; a sulfo group; a phosphono group; a bis (hydroxycarbonyl) methyl group; a bis (alkoxycarbonyl) methyl group; or a 5-tetrazolyl group; R3 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an amino group, a nitro group, a C?-C8 alkyl group, a C _.- C8 alkoxy group, a carboxyl group, or a C? -C8 alkoxycarbonyl group; X is any of the formulas: -O-, -S-, -SO-, -S02-, -NH-CO-NH-, -N (R4) -, -CO-N (R5) -, -N ( R5) -CO-, N (R5) -S02-, -S02-N (R5) -, where R4 is a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkylcarbonyl group, an alkylsulfonyl group C? -C? O, a C3-C6 cycloalkyl group, or an aryl group, R5 is a hydrogen atom, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, or an aryl group, wherein an alkyl group in R4 and R5 can be substituted by an aryl group, a hydroxyl group, an amino group, a fluorine atom, a chlorine atom, a bromine atom, a C? -C8 alkoxy group, a carboxyl group, a Ci-C8 alkoxycarbonyl group , an aryloxycarbonyl group, an aralkoxycarbonyl group, a carbamoyl group, or a 5-tetrazolyl group; Y is a C4-C8 cycloalkyl group where a methylene group in the C4-C8 cycloalkyl can be replaced with a carbonyl group, or it can be substituted by a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group , an amino group, a C? -C8 alkyl group, a C1-C alkoxy group, a carbamoyl group, a C1-Cs alkoxycarbonyl group or a carboxyl group, an aminoalkyl group, a monoalkylamino or dialkylamino group, or a monoalkylaminoalkyl or dialkylaminoalkyl group; or the next ring of 5 to 8 members of formulas 1-1 or 1-2: C I - i] [I 2] where, in formulas 1-1 and 1-2, in each cyclic system, the methylene group can be replaced by a carbonyl group, and the cycle can have unsaturated bonds, R6 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an amino group, a nitro group, a C? -C8 alkyl group, or a C_-C8 alkoxy group, W is CH, or a nitrogen atom, provided that W is not a nitrogen atom when the cycle is a 5-membered ring, Z is a hydrogen atom; a Ci-Cio alkyl group wherein the alkyl group may be substituted with a hydroxyl group except when Z is a C alquilo alkyl group, an amino group, a C?-C8 alkoxy group except when Z is an alkyl group Cl a group carboxyl, a C 1 -C 8 alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group; a C 1 -C 8 alkylcarbonyl group; an arylcarbonyl group; an aralkylcarbonyl group; an amidino group; or the next group of formula 1-3: where, in formula 1-3, R7 is a C? -C8 alkyl group, where the alkyl group may be substituted by a hydroxyl atom or an alkoxy group Ci-Ca, "an aralkyl group, or an aryl group, m is an integer from 1 to 3, n is an integer from 0 to 3, provided it is not a nitrogen atom when n is 0-1; or a pharmaceutically acceptable salt thereof 2. A derivative of b.yphenylamine where, in said formula (1), R1 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an amino group, a C? -C alkyl group or a C? -C alkoxy group; L is a direct bond or an alkylene group C_-C; R2 is a fluorine atom; a chlorine atom; a bromine atom; a hydroxyl group; an amino group; an alkoxy group C? -C8; a carboxyl group; a C 1 -C 8 alkoxycarbonyl group; an aryloxycarbonyl group; an aralkoxycarbonyl group; a carbamoyl group wherein a nitrogen atom in the carbamoyl group may be substituted by a C 1 -C 8 monoalkyl group or C 1 -C 8 dialkyl or it may be a nitrogen atom in an amino acid; a C 1 -C 8 alkylcarbonyl group; a C 1 -C 8 alkylsulfenyl group; a C 1 -C 8 alkylsulfinyl group; a C 1 -C 8 alkylsulfonyl group; a monoalkylamino group C _.- C8 or dialkylamino C _.- C8; a C? -C8 monoalkylaminosulfonyl or C? -C8 dialkylaminosulfonyl group; a sulfo group; a phosphono group; a bis (hydroxycarbonyl) methyl group; a bis (alkoxycarbonyl) methyl group; or a 5-tetrazolyl group; R3 is a hydrogen atom; X is any of the formulas: -O-, -S-, -N (R4) -, -C0-N (R5) -, -N (R5) -C0-, N (R5) -S02-, or -S02-N (R5) -; where R4 is a hydrogen atom, a Ci-Cio alkyl group, an Ci-Cio alkylcarbonyl group or an Ci-Cio alkylsulfonyl group, R5 is a hydrogen atom, or a Ci-Cio alkyl group, where an alkyl group in R4 and R5 may be substituted by an aryl group, a hydroxyl group, an amino group, a fluorine atom, a chlorine atom, a bromine atom, a Ci-Cβ alkoxy group, a carboxyl group, a Ci- C8 alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a carbamoyl group, or a 5-tetrazoyl group; Y is a C4-Cs cycloalkyl group where a methylene group constituting the C4-C8 cycloalkyl group can be replaced by a carbonyl group or it can be substituted by a fluorine atom, a chlorine atom, a bromine atom, a group hydroxyl, 1 an amino group, a C?-C8 alkyl group, a C?-C8 alkoxy group, a carbamoyl group, a C _-C8 alkoxycarbonyl group, a carboxyl group, an aminoalkyl group, a monoalkylamino or dialkylamino group, or a monoalkylaminoalkyl or dialkylaminoalkyl group; or the following ring of 5-8 members of the formulas II-1: [I I - 1] where, in formula II-1, in the cyclic system, the group * methylene can be replaced by a carbonyl group, R6 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a group hydroxyl, an amino group, a C1-C4 alkyl group, or a C-C4 alkoxy group, W is CH, or a nitrogen atom, provided that W is not a nitrogen group when the ring is a 5-membered ring , Z is a hydrogen atom; a C1-C10 alkyl group wherein the alkyl group may be substituted by a hydroxyl group except when Z is an alkyl group Ci, an amino group, a C6-C8 alkoxy group except when Z is an alkyl group d, a carboxyl group, a C 1 -C 8 alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group; a C 1 -C 8 alkylcarbonyl group; an arylcarbonyl group; an aralkylcarbonyl group; an amidino group; or the next group in formula II-2: ? (NH [i i - 2: wherein, in formula 11-2, R7 is a C? -C8 alkyl group, wherein the alkyl group may be substituted with a hydroxyl group or a C4-C4 alkoxy group; an aralkyl group; or an aryl group; m is an integer of 1 - 3; n is an integer from 0 - 3, provided that W does not. is a nitrogen atom when n is 0-1; or a pharmaceutically acceptable salt thereof. 3. A biphenylamidine derivative of the general formula (2) i (2) where L is a bond or a C? -C4 alkylene group; R2 is a carboxyl group; a C 1 -C 4 alkoxycarbonyl group; an aralkoxycarbonyl group; a carbamoyl group wherein a nitrogen atom replacing the carbamoyl group can be substituted by a group "C 1 -C 4 monoalkyl dialkyl C 4 -C 4 or can be a nitrogen atom in an amino acid, or a C 1 -C 4 alkylcarbonyl group X is -O-, -N (R4) -, or -NH-CO-, where R4 is a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkylcarbonyl group, or a C1-6 alkylsulfonyl group C10, the alkyl group is optionally substituted by a hydroxyl group, an amino group, a fluorine atom, a carboxyl group or a C? -C8 alkoxycarbonyl group and is a C5-C6 cycloalkyl group, wherein a methylene group constituting the C5-C6 cycloalkyl group may be substituted by a carbamoyl group, a C1-C4 alkoxy group, or a carboxyl group, or the following 5-6 membered ring of formula III-I: c m - i] where, in formulas III-1: is C-H, or a nitrogen atom, provided that it is not a nitrogen atom when the ring is a 5-membered ring, Z is a hydrogen atom; a C? -C alkyl group wherein the alkyl group may be substituted with a hydroxyl group except when Z is an alkyl group Ci, an amino group, a carboxyl group, or a C1-C4 alkoxycarbonyl group; a C1-C4 alkylcarbonyl group; an amidino group; or the next group of formula III-2: R7 NH [1- 2] where, in formula III-2, R7 is a C1-C4 alkyl group, wherein the alkyl group may be substituted by a hydroxyl group; n is an integer of 0-2; provided that W is not a nitrogen group when n is 0-1; or a pharmaceutically acceptable salt thereof. 4. A derivative of biphenylamine where, in said formula (2), X is -O-, or -N (R4) -, where R4 is a hydrogen atom, a Ci-Cio alkyl group, a C? -C10 alkylcarbonyl group, or a Ci-Cio alkylsulfonyl group, alkyl is optionally substituted by a hydroxyl group, an amino group, a fluorine atom, a carboxyl group or a C? -C8 alkoxycarbonyl group; or a pharmaceutically acceptable salt thereof. 5. A diphenylamidine derivative wherein in said formula (2), X is -NH-CO-, or a pharmaceutically acceptable salt thereof. 6. A biphenylamidine derivative where in the general formula (2), L is a link; R2 is a carboxyl group; or a methoxycarbonyl group; X is -O-, or -N (R4) -, where R4 is a hydrogen atom, a methyl group or a 2-hydroxyethyl group; And it is any of the formulas: n is 1; or a pharmaceutically acceptable salt thereof. 7. A prodrug that generates a biphenylamidine derivative or a pharmaceutically acceptable salt thereof according to any of said inventions 1-6, in vivo. 8. A blood coagulation inhibitor comprising at least one biphenylamidine derivative or a pharmaceutically acceptable salt thereof according to any one of said inventions 1-7, and a pharmaceutically acceptable carrier. 9. A prophylactic agent for thrombosis or embolism, comprising at least one biphenylamidine derivative or a pharmaceutically acceptable salt thereof according to any of the inventions 1-7, and a pharmaceutically acceptable carrier. 10. A therapeutic agent for thrombosis or embolism, comprising at least one biphenylamidine derivative or a pharmaceutically acceptable salt thereof, according to any of the inventions 1-7., and a pharmaceutically acceptable vehicle. PREFERRED MODE OF THE INVENTION The present invention is presented below with details. In the definition as to the substituents in a compound of the formula (1) of the present invention: the term "C? -8 alkyl" means a straight or branched carbon chain having from 1 to 8 carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neo-pentyl, isopentyl, 1, 2-dimethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2, 2-dimethylbutyl , 1-ethylbutyl, 2-ethylbutyl, isoheptyl, octyl, or isooctyl, etc. Among these, a carbon chain having 1 to 4 carbon atoms is preferred and methyl or ethyl is especially preferred. The term "alkoxy C? _8" means an alkoxy group having 1 to 8 carbon atoms and includes for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, neo-pentyloxy, tert-pentyloxy, 2-methylbutoxy, hexyloxy, isohexyloxy, heptyloxy, isoheptyloxy, octyloxy, or isooctyloxy, etc. Among them, a group having 1 to 4 carbon atoms, and especially methoxy or ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, neo-pentyloxy, tert-pentyloxy, 2 is preferred -methylbutoxy, hexyloxy, isohexyloxy, heptyloxy, isoheptyloxy, octyloxy, or isooctyloxy, etc. Among them, a group having 1 to 4 carbon atoms, and especially methoxy or ethoxy, is preferred. The term "C 1-4 alkylene" means a straight alkylene having from 1 to 4 carbon atoms, and includes methylene, ethylene, propylene, or butylene. The term "alkoxycarbonyl C? _8" means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, or octyloxycarbonyl, etc.; methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl; and especially, methoxycarbonyl. The term "aryloxycarbonyl" means phenoxycarbonyl, naphthyloxycarbonyl, 4-methylphenoxycarbonyl, 3-chlorophenoxycarbonyl, or 4-methoxyphenoxycarbonyl, etc .; with phenoxycarbonyl being preferred. The term "aralkoxycarbonyl" means benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, or 3-trifluoromethylbenzyloxycarbonyl, etc .; preferably benzyloxycarbonyl. The term "amino acid" means a commercially available natural or non-natural amino acid; preferably, it is glycine, alanine or β-alanine; and especially glycine. The term "C 8 -alkylcarbonyl" means a carbonyl group having a straight or branched carbon chain having from 1 to 8 carbon atoms, and includes, for example, hormone, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, or octanoyl, etc .; preferably it is a carbonyl group having from 1 to 4 carbon atoms; and especially it is acetyl or propionyl. The term "C 8 -alkylsulfenyl" means an alkylsulfenyl group having from 1 to 8 carbon atoms, and includes, for example, methylthio, ethylthio, butylthio, isobutylthio, pentthylthio, hexylthio, heptylthio, or octylthio, etc .; preferably methyl ethyl. The term "C 1 -C 8 alkylsulfinyl" means an alkylsulfinyl group having from 1 to 8 carbon atoms, and includes, for example, methylsulfinyl, ethylsulfinyl, butylsulfinyl, hexylsulfinyl, or octylsulfinyl, etc., and is preferably methylsulfinyl. The term "C 1 8 alkylsulfonyl" means an alkylsulfonyl group having from 1 to 8 carbon atoms, and includes, for example, methylsulfonyl, ethylsulfonyl, butylsulfonyl, hexylsulfonyl, or octylsulfonyl, etc., preferably it is methylsulfonyl. The term "monoalkylamino C? _8 or dialkylamino C? _8" means methylamino, dimethylamino, ethylamino, propylamino, diethylamino, isopropylamino, diisopropylamino, dibutylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino, heptylamino, or either octylamino, etc., is preferably methylamino, dimethylamino, ethylamino, diethylamino or propylamino; Methylamino or dimethylamino is especially preferred.

The term? Monoalkylaminosulfonyl dialkylaminosulfonyl C? -8 means for example methylaminosulfonyl, dimethylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, diethylaminosulfonyl, isopropylaminosulfonyl, diisopropilaminosulfonilo, dibutilaminosulfonilo, butylaminosulfonyl, isobutilaminosulfonilo, sec-butylaminosulfonyl, tert-butylaminosulfonyl, pentylaminosulphonyl, hexilaminosulfonilo, heptilaminosulfonilo or octylaminosulfonyl; etc.; preferably it is methylaminosulfonyl, dimethylaminosulfonyl, ethylaminosulfonyl, diethylaminosulfonyl or propylaminosulfonyl; and especially is methylaminosulfonyl or dimethylaminosulfonyl. The term "bis (alkoxycarbonyl) methyl" means, in particular, bis (methoxycarbonyl) ethyl or bis (ethoxycarbonyl) methyl, etc .; preferably it is bis (methoxycarbonyl) methyl. The term "C?-Βalkyl" means a straight or branched carbon chain having from 1 to 10 carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neo-pentyl, isopentyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, heptyl, isoheptyl, 1-methylhexyl, 2-methylhexyl, octyl, 2-ethylhexyl, nonyl, decyl, or 1-methylnonyl, etc. Among them, those having 1 to 4 carbon atoms, and especially methyl or ethyl, are preferred. The term "C 1 -C 8 alkylcarbonyl" means a carbonyl group having a straight or branched carbon chain having from 1 to 10 carbon atoms, and includes, for example, horyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, or decanoyl, etc .; preferably it is a carbon chain having 1 to 4 carbon atoms; and especially it is acetyl or propionyl. The term "C 1 - alkylsulfonyl" means an alkylsulfonyl group having 1 to 10 carbon atoms, and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl, nonnylsulfonyl, or decylsulfonyl, etc .; preferably it is a group having from 1 to 4 carbon atoms, and especially it is methylsulfonyl or ethylsulfonyl. The term "C3-8 cycloalkyl" means a cycloalkyl group having from 3 to 8 carbon atoms, and includes, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; cyclopropyl is preferred. The term "aryl" means in particular a carbocyclic aryl group such as phenyl or naphthyl, or heteroaryl, such as pyridyl or furyl, and is preferably phenyl. The term "C 4-8 cycloalkyl" means a cycloalkyl group having 4 to 8 carbon atoms, and includes particularly cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, etc .; and it is preferably cyclopentyl or cyclohexyl. The term "aminoalkyl" means a straight alkyl having an amino group and from 1 to 8 carbon atoms, and includes particularly 8-aminooctyl, 6-aminohexyl, 4-aminobutyl, 2-aminoethyl, or aminomethyl; preferably, it is 2-aminoethyl or aminomethyl. The term "monoalkylamino or dialkylamino" refers to methylamino, dimethylamino, ethylamino, propylamino, diethylamino, isopropylamino, diisopropylamino, dibutylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, etc .; preferably it is methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, or diisopropylamino; and especially it is ethylamino, diethylamino, or isopropylamino. The term "monoalkylaminoalkyl or dialkylaminoalkyl" refers particularly to methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, methylaminopropyl, dimethylaminopropyl, ethylaminopropyl, diethylaminopropyl, methylaminobutyl, or dimethylaminobutyl, etc.; it is preferably methylaminoethyl, dimethylaminoethyl or ethylaminoethyl. "Ci-io alkyl" which is bonded to a nitrogen atom as Z means a straight or branched carbon chain having from 1 to 10 carbon atoms, and is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neo-pentyl, isopentyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, heptyl, isoheptyl, 1- methylhexyl, 2-methylhexyl, octyl, 2-ethylhexyl, nonyl, decyl, or 1-methylnonyl, etc. Among them, a group having 1 to 4 carbon atoms is preferred, and isopropyl or propyl is especially preferred. The term "arylcarbonyl" means benzoyl, 4-methoxybenzoyl, or 3-trifluoromethylbenzoyl, etc., and is preferably benzoyl. The term "aralkylcarbonyl" includes in particular, benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl, 1-naphthylmethylcarbonyl or 2-naphthylmethylcarbonyl, etc .; benzylcarbonyl is preferred. The term "aralkyl" includes in particular benzyl, phenethyl, phenylpropyl, 1-naphthylmethyl, or 2-naphthylmethyl, etc .; and it is preferably benzyl.

Further, in the definition as to the substituent in a compound of the formula (2) of the present invention: the term "C 1 -4 alkoxycarbonyl" means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, or tert -butoxycarbonyl; methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl; preferably it is methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl; and especially it is methoxycarbonyl. The term "C 4 alkyl" refers to a straight or branched carbon chain having from 1 to 4 carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tertiary. butyl; preferably it is methyl or ethyl. The term "C 4 alkylcarbonyl" refers to a carbonyl group having a straight or branched carbon chain having from 1 to 4 carbon atoms, and includes, for example, hormone, acetyl, propionyl, butyryl, or isobutyryl , etc.; preferably it is acetyl or propionyl. The term "Cs-d cycloalkyl" refers to a cycloalkyl group having from 5 to 6 carbon atoms, and includes cyclopentyl or cyclohexyl; and is preferably cyclohexyl. The term "C 1 alkoxy" refers to an alkoxy group having 1 to 4 carbon atoms, and includes, in particular, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, or tert-butoxy , etc. Among them, methoxy or ethoxy is preferred. The compound (1) of the present invention can form salts by addition of acid. In addition, it can form salts with bases, depending on the species of the substituent. These salts are not restricted insofar as they are pharmaceutically acceptable, and they include, in particular, mineral salts such as, for example, hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate or sulfate, etc .; organic sulfonates such as methanesulfonate, 2-hydroxyethane sulfonate or p-toluenesulfonate, etc., and organic carbonates such as acetate, trifluoroacetate, propionate, oxalate, citrate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate, or mandelato, etc. As salts with bases, salts are included with inorganic bases such as sodium salts, potassium salts, magnesium salts, calcium salts, or aluminum salts, and salts with organic bases such as methylamine salts, ethylamine salts, salts of lysine or ornithine salts, etc. The preferred compounds of the present invention are found in test 1. The most preferred compounds of the invention are compounds specified by the following compound numbers, among the compounds listed in Table 1. Compounds No. 23, 29 , 30, 31, 53, 54, 57, 58, 59, 60, 91, 92, 93, 115, 119, 120, 121, 156, 166, 168, 201, 205, 206, 207, 244 245, and 246 The representative strategies for synthesizing compounds of formula (1) of the present invention are presented in detail in the following description. In accordance with the present invention, in the case where initial compounds or intermediates have substituents that influence the reaction such as hydroxyl, amino, or carboxyl, etc., it is preferred to adequately protect such functional groups to carry out the reaction of etherification and then separating the protecting group. The protective group is not limited insofar as it is a protective group usually employed in respective substituents and does not have a negative effect on the other elements during the protection and deprotection processes, and includes, for example, trialkylsilyl, alkoxymethyl C? _4, tetrahydropyranyl, acyl or C ?_4 alkoxycarbonyl as a protective group on hydroxyl; C 1-4 alkoxycarbonyl, benzyloxycarbonyl or acyl as the amino protecting group; and C 1-4 alkyl as a carboxyl protecting group. The deprotection reaction can be carried out in accordance with processes usually practiced in respective protecting groups. Among the nitriles which are precursors of the present compounds of the formula (1), compounds having an oxygen such as X can be synthesized, for example, in accordance with the following reaction: (a-1) where R1, R3, L, m and n are in accordance with that defined in formula (1); Y1 refers to a substituent Y defined in formula (1), except for the one having the structures defined in formula 1-3 as a substituent Z in Y; R8 refers to hydrogen, fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, or C? -8 alkoxy. That is, as can be seen in the above reaction (a-1), nitriles which are precursors of the compound of the present invention can be produced by the mixture of alcohol represented by the formula: Y1- (CH2) n-OH with a raw material, biphenylalkyl bromide in the presence of bases. In addition, among the precursor nitriles of the present compounds of the formula (1), compounds having an oxygen as X can be synthesized, for example, in accordance with the following reaction: (a-2) where R1, R3, L, m and n are in accordance with that defined in formula (1); Y1 refers to a substituent Y defined in formula (1) except for the one having the structures defined in formula 1-3 as a substituent Z in Y. That is, precursor nitriles of the present compound can be produced by mixing of an alcohol represented by the formula Y1- (CH2) n-0H with a raw material, 3-bromo-3-iodophenylalkyl bromide in the presence of bases to produce 3-bromo-3-iodophenylalkyl ether, then introducing a substituent - L-COOMe in the resulting ether by monocarbonylation or monoalkylation to produce 3-bromophenylalkyl ether, and then carry out the coupling reaction with a cyanophenylboronic acid derivative. The etherification of the first step in reactions (a-1) and (a-2) is carried out using an aliphatic ether solvent, such as for example tetrahydrofuran or diethyl ether, aprotic hydrocarbons such as for example benzene or toluene, polar aprotic solvents as per example DMF or HMPA, or a mixture thereof, etc., and as bases, a metal oxide such as for example barium oxide, zinc oxide, metal hydroxide such as for example sodium hydroxide or potassium hydroxide, or either a metal hydride such as sodium hydride, etc. The reaction is carried out at a temperature comprised between 0 and 100 ° C for 3 to 72 hours with stirring. Preferably, it is carried out at a temperature of 20 to 80 ° C for 8 to 36 hours, using sodium hydride, in absolute aliphatic ethers such as THF or ether. The reaction to introduce a substituent: -L-COOMe to ethers, which is the second step of the reaction (a-2), can be carried out in accordance with the following reactions (i) or (ii): (i) monocarbonylation by introduction of carbon monoxide (in the case where L is a bond): the iodine can be substituted with a methoxycarbonyl group by dissolving the ethers obtained from the first reaction step (a-1) in methanol, adding a bivalent palladium catalyst and bases such as for example tertiary amine such as for example triethylamine, and optionally a phosphine ligand such as for example triphenylphosphine, and with stirring for 3-48 hours at room temperature or with heating in a monoxide carbon. Preferably, it is carried out using, as a catalyst, palladium acetate or bistriphenylphosphine palladium and as a diisopropylethylamine or tributylaluminum base, at a temperature between 60 and 80 ° C for 12-36 hours. (ii) Monoalkylation using an organic zinc reagent (in the case where L is alkylene C? _8): the iodine can be substituted with alkyl by dissolving the ethers obtained from the first reaction step (a-1) and palladium catalyst of valence 0 as for example tetrakistriphenylphosphine palladium in the solvent as for example THF or DMF, benzene, or toluene, or a mixture thereof, by adding to this solution a solution of THF containing a zinc alkyl reagent of the formula: 1-Zn-L- COOMe, and with stirring for 3 to 48 hours at room temperature or with heating in an atmosphere of carbon monoxide. Preferably, it is carried out using, as catalyst, tetrakistriphenylphosphine palladium and as solvent, THF, at a temperature comprised between 20 and 80 ° C for 6-36 hours. The biphenylation which is the third step of the reaction (a-2) can be carried out by the reaction of monohalide with cyanophenylboronic acid in the presence of palladium catalyst. This reaction is usually carried out by heating, with stirring in DMF, the monohalide obtained from the second step of the reaction (a-2) and bivalent palladium catalyst such as for example palladium acetate, and further, bases such as triethylamine, and triarylphosphines to produce the cyanobiphenyl compound of interest. Preferably, it is carried out at a temperature of 60 to 100 ° C for 2-24 hours. In addition, among the nitriles which are precursors of the present compounds of formula (1), compounds having a nitrogen such as X can be synthesized, for example, in accordance with the following reactions (b-1), and (b-2): (b-l) where where R1, R3, L, m, and n are in accordance with that defined in formula (1); R9 means fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, C8-8 alkoxy or methoxycarbonyl between substituents R2 defined in formula (1); Y1 means a substituent Y defined in formula (1) except in the case of the one having the structures defined in formula 1-3 as a substituent Z in Y; R10 means a substituent R4 except in the case of hydrogen and aryl; E is a leaving group such as, for example, chlorine, bromine, iodine, acyloxy or sulfonyloxy. (b-2) where R1, R3, L, m, and n are in accordance with that defined in formula (1); R9 means fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, C? -8 alkoxy, or methoxycarbonyl between the substituents R2 defined in formula (1); Y1 means a substituent Y defined in formula (1) except in the case of the one having the structures defined in formula 1-3 as a substituent Z in Y; Ar means aril; E is a leaving group such as, for example, chlorine, bromine, iodine, acyloxy or sulfonyloxy. The N-alkylation of reactions (b-1) and (b-2) can be carried out using a condition for alkylation which is known. "That is to say, the starting material / biphenylalkyl bromide can react with amines of the formula: Y1- (CH2) n-NH2 in the presence of mineral salts such as potassium carbonate or amines such as tertiary amines which act as a base, producing a secondary amine which is a compound of the present invention.This compound can be reacted with an alkylating agent of the formula: R4-E to produce a tertiary amine which is a compound of the present invention. usually by mixing amines with alkylating agents in optional ratios in suitable solvents, and then stirring for 1-96 hours with cooling, at room temperature or with heating.The reactions are usually carried out using, as a base, mineral salts such as potassium carbonate or sodium carbonate or organic tertiary amines such as triethylamine or pyridine, and using, as a solvent, alcohols such as methanol or ethanol, hydrocarbons such as benzene or toluene, or solvents that do not influence the reaction such as, for example, THF, dioxane, acetonitrile, DMF or DMSO, or a mixture thereof, in a ratio of alkylation and amines from 1:10 - 10: 1. Preferably, this is carried out in a ratio between alkylating agents and amines of 1: 5-1: 1, at room temperature or with heating, for 2 to 24 hours.

Among the nitriles which are precursors of the present compounds of the formula (1), compounds having a sulfur atom such as X can be synthesized, for example, in accordance with the following reactions (c-1) and (c-2): (c-1) where R1, R3, L,, and n are in accordance with that defined in formula (1): R9 means fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, C-alkoxy? _8, or methoxycarbonyl between substituents R2 defined in formula (1); Y1 means a substituent Y defined in formula (1) except in the case of the one having the defined structures, in formula 1-3 as a substituent Z in Y; and E is a labile group such as for example chlorine, bromine, iodine, sulfonate. (c-2) where R1, R3, L, mynsn according to that defined in formula (1): R9 means fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, C18 alkoxy or methoxycarbonyl between substituents R 2 defined in formula (1); Y1 means a substituent Y defined in formula (1) except in the case of the one having the structures defined in formula 1-3 as a substituent Z in Y; and E is a labile group such as, for example, chlorine, bromine, iodine or sulfonate. The thioetherification of reactions (c-1) and (c-2) can be carried out using a condition for thioetherification which is known. Habitually, this is carried out by mixing alkyl halides with thiols in an optional ratio in suitable solvents in the presence of bases such as for example sodium hydroxide or ammonia, and with stirring under cooling condition, at room temperature or with heating for 30 minutes to 96 hours. As the solvent, compounds which do not act on the reaction are used, for example water, ethanol, DMF or toluene, and sodium hydroxide, ammonia or cesium carbonate, etc. are used as the base. The reactions are preferably carried out by mixing in a ratio between alkyl halides and thiols of 1: 5 to 5: 1, and with stirring at room temperature or with heating for 30 minutes to 24 hours. In addition, the resulting sulfide may be subjected to oxidation as for example in the following reaction (d) to produce a compound having sulfoxide or sulfone as X between the compound of the formula (1). (d) wherein R1, R3, L, m, and n are in accordance with that defined in formula (1): R9 means fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, C8-alkoxy or methoxycarbonyl between the substituents R 2 defined in the formula (1): and Y 1 signifies a substituent Y defined in the formula (1) except in the case of the one having the structures defined in formula 1-3 as a substituent Z in Y. Reaction oxidation (d) can be carried out in accordance with a procedure described in Jikken Kagaku Kohza (4th edition), 24, Organic Synthesis VI heteroelement metallic element compounds -, (Organic Synthesis VI - heteroelement-metallic element compounds ), pages 350 - 373, published by the Japan Chemical Association. Usually, the reaction is carried out using sulfides or sulfoxides using alcohols such as water or ethanol, etc., as a solvent and hydrogen peroxide, peracetic acid, metaperiodic acid or m-chloroperbenzoic acid, etc., as an oxidizing agent. under cooling, at room temperature or with heating with agitation for 30 minutes to 24 hours. Preferably, the sulfoxide is produced for 30 to 12 hours at 0-20 ° C, while the sulfone is produced for 1-12 hours at 0-80 ° C. In addition, among the nitriles which are precursors of the present compounds of the formula (1), compounds having an amido linkage such as X can be synthesized, for example, in accordance with the following reactions (e-1) and (e-2) : (e-1) wherein R1, R3, R5, L, m, and n are in accordance with that defined in formula (1); R9 means fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, C8-8 alkoxy, or methoxycarbonyl between substituents R2 defined in formula (1): Y1 means a substituent Y defined in formula (1) except which has the structures defined in formula 1-3 as a substituent Z in Y; and G is halogen, acyloxy, p-nitrophenoxy or hydroxyl, etc. (e-2) where R1, R3, R5, L, m, and n are in accordance with that defined in formula (1); R9 means fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, C? -8 alkoxy, or methoxycarbonyl between substituents R2 defined in formula (1): Y1 means a de-finite Y substituent in the formula ( 1) except that which has the structures defined in formula 1-3 as a substituent Z in Y; and G is halogen, acyloxy, p-nitrophenoxy or hydroxyl, etc. the reactions of (e-1) and (e-2) can be carried out employing a condition for amidation that is known. Usually, the amides can be obtained by mixing active derivatives of carboxylic acids with amine compounds in suitable solvents in the presence, of bases, for acylation. As active derivatives of carboxylic acids for use, active esters are used, for example, acid halides, mixed acid anhydrides or p-nitrophenol, -etc., Under cooling or at room temperature for 30 minutes to 24 hours. . Preferably, this is carried out in halogenated hydrocarbons such as for example dichloromethane, aliphatic ethers such as THF or diethyl ether, or solvents such as acetonitrile or DMF, or a mixture of solvents thereof, using tertiary amines such as triethylamine. as bases, at a temperature comprised within a range of 0 to 20 ° C for a period of 1 to 18 hours. Also, these amides can be obtained by condensation between amines and carboxylic acids in the presence of condensation agents such as carbodiimides. In this case, halogenated hydrocarbons such as DMF or chloroform as solvents are suitable, while N, N-dicyclohexylcarbodiimide, 1-ethyl- (3- (N, N-dimethylamino) propyl) carbodiimide, carbonyldiimidazole, diphenylphosphoryl, or diethylphosphoryl they are suitable as condensation agents. The reaction is usually carried out with cooling and at room temperature for 2-48 hours. In addition, between nitriles which are precursors of the present compounds of the formula (1), compounds having a sulfonamide structure such as X can be synthesized, for example, in accordance with the following reactions (f-1) or (f-) 2) : (fD where R1, R3, R5, L, m, and n are in accordance with that defined in formula (1): R9 means fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, C8-8 alkoxy, or methoxycarbonyl between substituents R 2 defined in formula (1): and Y 1 signifies a Y substituent defined in formula (1) except in the case of the one having the structures defined in formula 1-3 as a substituent Z in Y. (f-2) wherein R1, R3, R5, L, m, and n are in accordance with that defined in formula (1); R9 means fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, C8-8 alkoxy, or methoxycarbonyl between substituents 'R2 defined in formula (1): and Y1 means a substituent Y defined in the formula' ( 1) except for the one having the structures defined in formula 1-3 as a substituent Z in Y. The reactions of (f-1) and (f-2) can be carried out by reaction of an amine with derivatives sulfonic acid actives in suitable solvents in the presence of bases to produce sulfonamides of interest. As active derivatives of sulphonic acids, sulfonyl halide is preferred, and the reaction is carried out in halogenated hydrocarbons such as for example dichloromethane, aliphatic ethers such as THF or diethyl ether, a solvent such as acetonitrile or DMF, or a mixture of Solvents at a temperature of 0-20 ° C for 1-24 hours, using tertiary amines such as triethylamine as a base. Also, among the nitriles which are precursors of the present compounds of formula (1), compounds having a urea structure such as X can be synthesized, for example, in accordance with the following reaction (g): (g) where R1, R3, L, m, and n are in accordance with that defined in formula (1); R9 means fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, C? -8 alkoxy, or methoxycarbonyl between substituents R2 defined in formula (1): and Y1 signifies a Y substituent defined in formula (1) except that having the structures defined in formula 1-3 as a Z-substituent on Y. That is, compounds having a urea structure such as X can be produced by reaction, as a raw material, of an amine with isocyanate derivatives in a suitable solvent in cooling or heating condition. A solvent used in this reaction can be DMF, THF, dioxane, dichloroethane, chloroform, acetonitrile, DMSO, benzene or toluene, etc. The nitriles which are precursors of the compound of the present invention produced by the above reactions (a-1), (a-2), (bl), (b-2), (c-1), (c-2), (d), (e-1), (e-2), (f-1), (f-2), and (g) can be converted to the benzamidine derivatives which are a compound of the present invention by next amidination reaction: (h) where R1, R3, L, X, m, and n are in accordance with that defined in formula (1); Y1 means a substituent Y defined in formula (1) except that having the structures defined in formula 1-3 as a substituent Z in Y; R9 means fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, C? -8 alkoxy, or methoxycarbonyl between the substituents R2 defined in formula (1); and R11 means C alquilo- alkyl. This amidination is carried out in accordance with the reaction condition presented with details in the following points (iii) or (iv): (iii) amidination through imidation using hydrogen halide in an alcohol solution: the reaction by which imidates are obtained from nitriles and alcohols, is carried out, for example, by the dissolution of alkoxymethylphenylbenzonitriles in alcohols having from 1 to 4 carbon atoms (R1: LOH) containing hydrogen halides as per example hydrogen chloride or hydrogen bromide, etc., with stirring. The reaction is usually carried out at a temperature of -20 to 30 ° C, for 12 to 96 hours. Preferably, this is carried out in hydrogen chloride in a methanol or ethanol solution, at a temperature of -10 to +30 ° C, for 24-72 hours. The reaction between the imidate and the ammonia is carried out by stirring the imidate in an alcohol having from 1 to 4 carbon atoms such as for example methanol or ethanol containing ammonia or amines such as hydroxylamine, hydrazine or carbamate ester, or either in aliphatic ethers such as diethyl ether, or in halogenated hydrocarbons such as for example dichloromethane or chloroform, or a mixture thereof to produce the benzamidine derivative which is a compound of the present invention. The reaction is usually carried out at a temperature of -10 to +50 ° C, for 1 to 48 hours. Preferably, it is carried out at a temperature of 0 to 30 ° C for 2 to 12 hours. (iv) Amidination through an imidate prepared by direct bubbling of hydrogen halide: the reaction between nitriles and alcohols is carried out, for example by the dissolution of nitriles and aliphatic ethers such as diethyl ether, or halogenated hydrocarbons, for example chloroform or aprotic solvents such as benzene, adding the equivalent of an excess of an alcohol having 1 to 4 carbon atoms (R110H), bubbling hydrogen halides such as hydrogen chloride or hydrogen bromide at a temperature of -30 ° C at 0 ° C for 30 minutes at 6 hours with stirring, then suspending the bubbling, and stirring at a temperature of 0 to 50 ° C for 3 to 96 hours. Preferably, this is carried out by bubbling hydrogen chloride over a perof 1 to 3 hours at a temperature comprised within a range of -10 ° C to 0 ° C with stirring in halogenated hydrocarbons containing methane or ethanol equivalent or in excess, then suspending the bubbling, and stirring at a temperature comprised within a range of 10 to 40 ° C for 8 to 24 hours. The resulting imidates can be converted to benzamidine derivatives (1) which are compounds of the present invention by stirring them in alcohol solvents having from 1 to 4 carbon atoms such as for example methanol or ethanol containing ammonia or amines such as hydroxyamine , hydrazine or carbamate ester, or aliphatic ether solvents such as for example diethyl ether or halogenated hydrocarbon solvents such as chloroform, or a mixture thereof. The reaction is usually carried out at a temperature within a range of -20 ° C to + 50 ° C for 1-4 hours. Preferably, it is carried out in a saturated solution of ammonia ethanol at a temperature comprised within a range of 0 to 30 ° C for 2 to 12 hours. Among the compounds of the present invention of the formula (1), compounds having a Y substituent where a substituent Z has the structures defined in formula 1-3 can be produced by carrying out the imidolation of the following (j-1) and (j-2), after providing the benzamidine compounds having a secondary amino group in a Y substituent through the above reaction (h): J + .N (CH-k-X-CCH-Vw N-H (jD where R 1, R 3, R 6, L, X, Z, m and n are in accordance with that defined in formula (1): R 9 means fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, Cl-alkoxy 9, or methoxycarbonyl between the substituents R 2 defined in the formula (1). (j-2) where R 1, R 3, R 6, L, W, X, Z, m and n are in accordance with that defined in formula (1); R9 denotes fluorine, chlorine, bromine, hydroxyl or protected hydroxyl, amino or protected amino, Cl-9 alkoxy, or methoxycarbonyl between the substituents R2 defined in the formula (1). This imidolation is carried out by mixing the benzamidine compounds having a secondary amino group in a Y substituent with the equivalent or excess imidates in water, or alcohols having from 1 to 4 carbon atoms such as methanol or ethanol, or aliphatic ethers such as diethyl ether, or halogenated hydrocarbons such as for example chloroform, or polar solvents such as DMF or DMSO, or a mixture thereof in the presence of bases, with stirring. The reaction is usually carried out at room temperature for 1-24 hours. As a base, N-methylmorpholine, triethylamine, disopropylethylane, sodium hydroxide or potassium hydroxide, etc. may be used. Among the compounds of the present invention of the formula (1), compounds having a carboxyl as R2 are produced by ester hydrolysis of compounds having methoxycarbonyl, R9 among the benzamyl compounds produced by the above reaction (h), (j-1) and (j-2). This hydrolysis can be carried out under a basic condition, an acid condition, or a neutral condition if necessary. In the reaction in the basic condition, sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide, etc. may be used as the base, and in the acidic condition hydrochloric acid, sulfuric acid or Lewis such as for example boron trichloride, trifluoroacetic acid, or p-toluenesulfonic acid, etc., while in the neutral condition, a halogen ion such as for example lithium iodide or lithium bromide, alkali metal salts with thiol or selenol, iodotrimethylsilane, and enzymes such as esterase. The solvent for use includes polar solvents such as water, alcohols, acetone, dioxane, THF, DMF, DMSO, etc., or a mixture thereof. The reaction is usually carried out at room temperature or with the application of heat for 2-96 hours. The appropriate condition of the reaction temperature or reaction time, etc. It differs according to the reaction condition employed and can be appropriately selected through a conventional process. In compounds that have a carboxyl in a substituent R2, obtained through the above process, the carboxyl can be converted in the other esters through the following process (v), (vi), or (vii): (v) Conversion of carboxyl to alkoxycarbonyl: the carboxyl can be converted to alkoxycarbonyl by the reaction of carboxyl-containing compounds as a R 2 substituent between compounds of the formula (1) with the equivalent or excess of alkylating agents (e.g., methyl acyloxychlorides such as methyl acetochlorochloride or methyl pivaloyloxychloride, or allyl chlorides, or benzyl chlorides) in halogenated hydrocarbons such as dichloromethane, or aliphatic ethers such as THF or polar aprotic solvents such as DMF, or a mixture thereof, in the presence of tertiary amines such as triethylamine or disopropylethylamine , at a temperature comprised within a range of -10 to + 80 ° C for a period of 1 to 48 hours. Preferably, this is carried out using the equivalent or a slight excess of alkylating agent in the presence of disopropylethylamine at a temperature within a range of 20 to 60 ° C, for a period of 2 to 24 hours. (vi) Conversion of carboxyl to aralkoxycarbonyl: the carboxyl can be converted to aralkoxycarbonyl by the reaction of carboxyl-containing compounds as a substituent R 2 among compounds of the formula (1) with equivalent or excess of alcohols such as benzyl alcohol in a solvent of Halogenated hydrocarbons such as dichloromethane, in the presence of acid catalysts such as hydrogen chloride, sulfuric acid or sulfonic acid. The reaction is usually carried out at room temperature or with heating for 1-72 hours. Preferably, it is carried out using the equivalent up to a slight excess of alcohols in the presence of diisopropylethylamine, at a temperature comprised within a range of 20 to 60 ° C, for 2-24 hours. (vii) Conversion of carboxyl to aryloxycarbonyl: the carboxyl can be converted to the aryloxycarbonyl by the reaction of compounds having as a substituent R2 among the compounds of the formula (1) with the equivalent of an excess of aromatic compound having hydroxyl as phenol in a solvent of aliphatic ethers such as diethylether, in the presence of condensing agents such as dicyclohexylcarbodiimide. The reaction is usually carried out at a temperature comprised within a range of 0 to 50 ° C for a period of 1-48 hours. Preferably, it is carried out at room temperature for 3-24 hours. Also, compounds having a carboxyl such as R 2 can be converted to compounds having carbamoyl by known techniques such as, for example, by treating carboxyl with oxalyl chloride, etc., to produce acid halides, and by reaction with a solution of ammonia. Similarly, it can be converted to N-methyl-N-methoxycarbamoyl via acid halides with N-methyl-N-methoxyamine, and in addition this can be converted to alkylcarbonyl by reaction with various alkylmagnesium reagents. Among the present compounds synthesized by the aforementioned processes, compounds having an amidino group as a substituent can be introduced through one of the electrons into a nitrogen constituting the amidino group with various carbonyls through the following process (ix), ( x), or (xi). (viii) Aryloxycarbonylation of amidino: an aryloxycarbonyl can be introduced through one of the electrons into a nitrogen constituting an amidino by stirring compounds having an amidino as a substituent A between the compounds of the formula (1) with the equivalent to an excess of aryl chloroformates such as phenyl chloroformate in a mixed solvent of water and halogenated hydrocarbons such as dichloromethane in the presence of bases such as, for example, sodium hydroxide or potassium hydroxide. The reaction is usually carried out at a temperature of -10 to + 40 ° C for a period of 3 to 48 hours. Preferably, this is carried out using the equivalent or a slight excess of aryl chloroformate at a temperature comprised within a range of 0 to 30 ° C for 6-24 hours, (x) Alkoxycarbonylation of amidino: alkoxycarbonyl may be introduced through one of the electrons in a nitrogen constituting an amidino by reacting compounds having an amidino as a substituent A between the compounds of formula (1) with the equivalent to an excess of p-nitrophenyl ester of alkylcarbonic acid in a absolute solvent such as for example THF, or DMF in the presence of bases such as metal hydrides such as for example sodium hydride or tertiary amines, at a temperature comprised within a range of -10 to + 30 ° C for a period of 3 to 48 hours. Preferably, this is carried out with the equivalent to a slight excess of p-nitrophenyl ester of alkoxycarbonates in the presence of tertiary amines such as triethylamine or diisopropylethylamine, at a temperature comprised within a range of -10 to + 40 ° C during a period of 6 to 24 hours. (xi) Arylcarbonylation of amidino: arylcarbonyl can be introduced through one of the electrons into a nitrogen constituting an amidino by the reaction of compounds having an amidino as substituent A between the compounds of formula (1) with the equivalent up to a Excess of aromatic carboxylic acid chloride such as for example benzoyl chloride in halogenated hydrocarbons such as for example methylene chloride or solvents such as THF, DMF or pyridine, or a mixture thereof in the presence of bases such as for example amines, at a temperature comprised within a range of -10 to + 30 ° C for a period of 1 to 48 hours. Preferably, this is carried out with the equivalent up to a slight excess of aromatic carboxylic acid chloride in the presence of amines such as triethylamine, diisopropylethylamine or pyridine, at a temperature comprised within a range of -10 to + 40 ° C for a period of time. from 2 to 24 hours. In addition, the compounds of the formula (1) can be produced through an optional combination of other well-known processes of etherification, amidination, hydrolysis, alkylimidoylation, amidation or esterification, or through a process that is usually employed on the part of of the experts in the field. The alkoxymethylphenylbenzamidine derivatives (1) produced in accordance with that explained above can be isolated and purified by known techniques for example by extraction, precipitation, fractional chromatography, fractional crystallization, or recrystallization, etc. In addition, a pharmaceutically acceptable salt of the compound of the present invention can be produced by subjecting it to a usual salt formation reaction. The biphenylamidine derivatives and pharmaceutically acceptable salts thereof of the present invention have an effect of inhibiting FXa activity, and can be used as prophylactic and / or clinically applicable therapeutic agents against thromboembolisms such as myocardial infarction, cerebral thrombosis, artery thrombosis peripheral or deep vein thrombosis as Fxa inhibitor. In addition, the biphenylamidine derivatives of the present invention can constitute pharmaceutical compositions with pharmaceutically acceptable carriers, and can be administered orally or parenterally in various dosage forms. Parenteral administration includes, for example, intravenous, subcutaneous, intramuscular, transdermal, intrarectal, transnasal and instillation administration.

The dosage form of the pharmaceutical composition includes the following: for example, in the case of oral administration, tablets, pills; granules, powder, solution, suspension, syrup, or capsules, etc., can be used. As a method for the production of a tablet, said tablet can be formed by conventional techniques employing a pharmaceutically acceptable carrier with excipient, binder or disintegrant, etc. Likewise, the shape of the pills, granules or powder can be produced through conventional techniques using excipient, etc., in the same way as the tablet. The form of a solution, suspension or syrup can be produced by conventional techniques using esters of glycerol, alcohols, water or vegetable oils, etc. The capsule shape can be produced by filling a capsule made of gelatin, etc., with granules, powder or a solution, etc. Among agents for parenteral administration, in the case of intravenous administration as subcutaneous or intramuscular, it can be administered as an injection. An injection can be produced by dissolving the biphenylamidine derivatives in water-soluble solutions such as physiological saline, or water-insoluble solutions consisting of organic esters such as, for example, propylene glycol, polyethylene glycol or vegetable oils, etc. . In the case of transdermal administration, for example, an ointment or cream dosage form may be employed. The ointment can be produced by the use of the biphenylamidine derivative in the mixture of fats and oils or petrolatum, etc., and the cream can be produced by mixing biphenylamidine with emulsifiers. In the case of rectal administration, it can take the form of a suppository using a soft gelatin capsule.

In the case of transnasal administration, it may be employed in the form of a formulation consisting of a liquid or powder composition. As the base of a liquid formulation, water, saline, phosphate regulator, or acetate regulator, etc. are used, and may also contain surfactants, antioxidants, stabilizers, preservatives, or binders. A powder formulation base can include water absorbing materials such as polyacrylates highly water soluble, low alkyl ethers in cellulose, polyethylene glycol polyvinyl pyrrolidone, amylose or pullulan, etc., or materials that do not absorb water such as, for example, celluloses, starches, proteins, gums or cross-linked vinyl polymers. Materials that absorb water are preferred. These materials can be mixed for use. In addition, antioxidants, colorants, preservatives, or antiseptic agents, etc., can be added to the powder formulation. The liquid or powder formulation can be administered, for example, using a spray apparatus. In the case of the administration of eye drops, an aqueous or non-aqueous eye drop may be employed. In the case of an aqueous eye drop, as a solvent, sterilized and purified water or physiological saline, etc. can be used. When only sterilized and purified water is used as a solvent, an aqueous suspended eye drop can be formed by the addition of a suspension such as surfactants or high molecular weight binders, or a soluble eye drop can be formed by the addition of solubilizers such as nonionic surfactants. In the non-aqueous eye drop, a non-aqueous suspended eye drop can be formed by the use of non-aqueous injectable solvents as a solvent. In the case of administration through the eyes by means other than eye drops, dosage forms such as eye ointments, application solutions, diffusion agents or insertion agents may be employed. furtherIn the case of inhalation through the nose or through the mouth, a solution or suspension containing a biphenylamidine derivative and a pharmaceutical excipient which is generally used is inhaled, for example, by aerosol spray, etc. Likewise, a biphenylamidine derivative which is in the form of dry powder can be administered through an inhaler, etc., which comes into direct contact with the lungs. To these formulations, if necessary, pharmaceutically acceptable carriers such as isotonic agents, preservatives, wetting agents, regulators, emulsifiers, dispersions or stabilizers can be added. Also, if necessary, these formulations can be sterilized by the addition of a sterilant, filtration through a filter that retains the bacteria, or treatment with heat or irradiation, etc. Alternatively, it is possible to produce an aseptic solid formulation that can be used to be dissolved or suspended in a suitable aseptic solution immediately before use. The dose of the biphenylamidine of the present invention differs according to the types of disease, the route of administration, or condition, age, sex or weight of the patient, etc., but is generally about 1-500 mg / day / human body , preferably from 10 to 300 mg / day / human body in the case of oral administration, while it is approximately 0.1 - 100 g / day / human body, preferably from 0.3 - 30 mg / day / human body in the case of intravenous, subcutaneous, intramuscular, transdermal, intrarectal, transnasal administration, instillation or inhalation. When the biphenylamidine of the present invention is used as a prophylactic agent, it can be administered according to well-known procedures, according to the respective condition. MODALITIES The present invention will be illustrated using the following Productive Examples, Modalities, and Experiments. However, the scope of the present invention is not limited in any way to these examples. Production example 1: methyl 3-amino-5-hydroxymethylbenzoate: 85 g of 3-nitro-5-methoxycarbonylbenzoic acid were dissolved in 200 ml of THF under nitrogen flow, and 43.4 ml of a borane dimethylsulfide complex was added with stirring under ice cooling. After stirring for 18 hours, 200 ml of water was added, and then 96 g of potassium carbonate was added. It was extracted with ethyl acetate, and the organic layer was washed with a saline solution After drying with magnesium sulfate, the resulting solid was dissolved in 800 ml of ethyl acetate, 750 mg of Pd / C was added to the solution. 10%, and stirring continued under a flow of hydrogen.After the completion of the reaction, it was subjected to filtration, and then the filtrate was concentrated to yield 64 g of the title compound.1H-NMR (270MHz, CDC13): 2.30 (s, ÍH), 3.89 (s, 3H), 4.64 (s, 1H), 6.89 (s, ÍH), 7.26 (s, ÍH), 7.39 (s, 1H) Productive Example 2: 5-hydroxymethyl -3-methyl iodobenzoate: 34.3 g of the compound obtained from the production example 1 were dissolved in 200 ml of THF, and 75 g of hydroiodic acid were added with stirring under ice cooling.

A 100 ml solution containing 13.7 g of sodium nitrite was added. After stirring at 0 ° C for 40 minutes, a 150 ml solution containing 34.6 g of potassium iodide was added. After stirring at 40 ° C for two hours, 300 ml of water was added and concentrated. It was extracted with ethyl acetate, and the organic layer was washed with a saline solution. After drying with sodium sulfate, it was purified through silica gel column chromatography to yield 23.1 g (42%) of the title compound. 1H-NMR (270MHz, CDC13): s 1.81 (t, ÍH,, J = 5.6Hz), 3.92 (s, 3H), 4. 72 (d, 1H, J = 5.6Hz), 7.93 (s, ÍH), 7.98 (s, 1H), 8.29 (s, ÍH).

Production example 3: Dihydroxy- (3-cyanophenyl) borane: B (OH) 3 g of 3-bromobenzonitrile were dissolved in 100 ml of dry THF and, under a nitrogen atmosphere, 37.6 ml of triisopropoxyborane was added. That solution was cooled to a temperature of -78 ° C, and 98.3 ml of a 1.6M n-butyl-lithium hexane solution was added dropwise over 30 minutes with stirring. After stirring at room temperature for 30 minutes, it was cooled to a temperature of 0 ° C, and 220 ml of 4M sulfuric acid was added. That solution was refluxed with heating overnight, and then cooled again to 0 ° C. 340 ml of 5M sodium hydroxide was added, and extracted with 200 ml of diethyl ether. The aqueous layer was removed, and 6M hydrochloric acid was added until a pH of 2 was obtained. It was extracted twice with 300 ml of ethyl acetate, dried with magnesium sulfate and then the solvent was removed. The resulting crude product was recrystallized from DMFR-water to yield 11.6 g (72%) of the title compound as light yellow needle-like crystals. 1H-NMR (270MHz, DMSO-d6): s 7.6-8.3 (m, 4H), 8.5 (brs, 2H) Production example 4: methyl 3- (3-cyanophenyl) -5- (hydroxymethyl) benzoate: 3.08 g of the compound obtained from the previous production example 2 were dissolved in 500 ml of dry THF under nitrogen flow, and to this solution were added 2.32 g of the compound obtained from the productive example 3, 2.18 g of potassium carbonate and 456 tetrakis (triphenylphosphine) palladium mg and stirred with heating at 90 ° C overnight. The reaction was rapidly quenched by the addition of water, extracted with ethyl acetate, and dried over magnesium sulfate, and then the solvent was removed. It was purified by chromatography on silica gel columns to yield 2.05 g (73%) of the title compound as colorless crystals. 1H-NMR (270MHz, CD13): s 2.1 (brs, ÍH), 3.96 (s, 3H), 4.84 (d, 2H, J = 3.7Hz), 7.5-8.2 (, 7H). In accordance with the same procedure of the productive example 4, compounds of the productive examples 5-10 that appear in table two were synthesized.

Productive example 11: 3- (3-cyanofenyl) -5- (bromomethyl) benzoate methyl: to 1.0 g of the compound obtained from the above production example 4, 20 ml of diethyl ether was added to produce a suspension, and then 0.5 ml of phosphorus bromide was slowly added dropwise. The reaction solution was stirred at room temperature for 19 hours, and subjected to extraction. The organic layer was washed with a saturated saline solution, dried with sodium sulfate, and then the solvent was removed in vacuo to yield the title compound as a light yellow solid (1.2 g, 98%) 1H-NMR (270MHz, CDC13): s 3 ^ 97 (s, 3H), 4.58 (s, 2H) 7.5-7.9 (m, 5H), 8.1-8.2 (m, 2H). Production example 12: methyl 3- (3-cyanophenyl) -5- (aminomethyl) benzoate: 1.1 g of the compound obtained from the production example 11 were dissolved in 33 ml of DMF, and 325 mg of sodium azide was added. After stirring the reaction solution at room temperature for 2 hours, 80 ml of water and 120 ml of ethyl acetate were added to the organic substances, and the aqueous layer was extracted twice with 100 ml of ethyl acetate. The extraction was washed with a saturated saline solution, dried with an anhydrous solution of sodium sulfate, and the solvent was removed under vacuum to produce oily methyl 3- (3-cyanophenyl) -5-azidomethyl) benzoate, light yellow in color. , as a raw product. GC-MS (M-N2) = 264 The methyl 3- (3-cyanophenyl) -5- (azidomethyl) benzoate obtained in accordance with the above was placed in a flask, dissolved in 66 ml of ethanol and after the addition of 1.1. g of palladium-barium carbonate, air in the flask was removed with hydrogen. Stirring was continued at room temperature for 6 hours, the catalyst was subjected to filtration on Celite, and the filtrate was concentrated and purified with silica gel chromatography to yield 794 mg of the title compound (yield of two steps: 90%) . GC-MS (MH) = 265 Production example 13: 3- (-3-cyanophenyl) -5- [((Nt-butoxycarbonyl) piperidin-4-ylmethyl) aminomethyl) methyl benzoate: 5.5 g of the compound obtained from the Productive example 12 in 150 ml of dry THF. To this solution, 7.92 g of 4-aminomethyl- (N-t-butoxycarbonyl) piperidine was added and it was stirred at room temperature overnight. This reaction was quenched rapidly by pouring the solution into a 0.5M potassium bisulfate solution, and extracted with ethyl acetate. After drying with sodium sulfate, the solvent was removed to yield 10 g of the title compound (potassium bisulfate salt, quantitative). 1H-NMR (270MHz, CDC13): s 1.0-1.3 (m, 2H), 1.43 (s, 9H), 1.7 ~ 2.0 (m, -3H), 2.6-2.8 (m, 4H), 3.95 (s, 3H) ), 4.05-4.2 (brs, 4H), 7.5-7.7 (m, 2H), 7.9-8.0 (m, 2H), 8.20 (s, 2H). In accordance with the same procedure as in the productive example 13, productive example compounds 14 that appear in the list of table 2 were synthesized. Production example 15: 3- (3-cyanophenyl) -5- (Nt-butoxycarbonyl) piperidine -4-methyl carbonyl benzoate: 53 mg of the compound obtained from the previous production example 12 were dissolved in 2.0 ml of chloroform. To that solution, 57 mg of (N-t-butoxycarbonyl) isonipecotic acid, 27 mg of HOBt, and 48 mg of hydrochloride EDCI were added, and it was stirred at room temperature overnight. This reaction was subjected to the SCX cation exchange resin column for solid phase extraction and to the SAX anion exchange resin column for solid phase extraction, manufactured by Barian Company, and extracted with methanol with removal of impurities. The extract was concentrated to produce 100 mg of the title compound, quantitatively. -MS (M + l) = 478 In accordance with the same procedure as in the productive example 15, compounds of the productive examples 16-22 that appear in the list of table 2 were synthesized. Example, productive 23:; 3- (3-Cyanophenyl) -5- [N- [(N-t-buty-cyclo-phenyl-capperidin) -4-ylmethyl] -N-methylaminomethyl] -benzoate: 464 g of compound from the above production example 13 were dissolved in 13 ml of dimethylformamide, 276 mg of potassium carbonate and 94 μL of methyl iodide were added, and after stirring for 6 hours, extraction was carried out. The organic layer was washed with a saline solution and dried with sodium sulfate, the solvent was removed in vacuo, and purified by chromatography on silica gel to yield 289 mg of the title compound (yield: 61%). 1H-NMR (270MHz, CDC13): s 1.0-1.9 (m, 5H), 1.49 (s, 9H), 2.22 (s, 3H), 2.2-2.3 (m, 2H), 2.3-2.8 (, 2H) , 2.70 (t, 2H, J = 12.0Hz), 3.57 (s, 2H), 3.96 (s, 3H), 4.0 ~ 4.2 (m, 2H), 4.64 (s, ÍH), 4.72 (s, 1H), 7.5 ~ 7.7 (m, 2H), 7.72 (s, ÍH), 7.85 (d, ÍH, J = 7.6Hz), 8.01 (s, ÍH), 8.12 (s, ÍH). In accordance with the same procedure as that employed in the productive example 23, compounds of the productive examples 24-27 that appear in the list of table 2 were synthesized. C Production example 28: 3- (3-cyanophenyl) -5- [N- [(Nt-Butoxycarbonyl) piperidin-4-ylmethyl] -N-acetylaminomethyl] benzoate methyl: 464 g of the compound of the above production example 13 were dissolved in 10 ml of dimethylformamide and 277 μL of triethylamine were added. 92 ml of acetyl chloride were added and the stirring continued for 2 hours. 1 was poured into a sodium hydrogencarbonate solution and extracted with ethyl acetate. An organic layer was washed with a saline solution and dried with sodium sulfate, the solvent was removed in vacuo, and purified by chromatography on silica gel to yield 349 mg of the title compound (yield: 69%). 1H-NMR (270MHz, CDC13): s 1.0-2.0 (m, 5H), 1, 451.46 (s, 9H), 2.15 &2.21 (s, 3H), 2.5-2.8 (m, 2H), 3.2-3.3 (m, 2H), 3.96 &3.97 (s, 3H), 4.0 ~ 4.3 (m, 2H), 4.64 &4.72 (s, 2H), 7.4-8.0 (, 6H), 8.1-8.2 (m, 1H) ). In accordance with the same procedure as in the productive example 28, compounds of the productive examples 29-32 that appear in the list of table 2 were synthesized. Productive example 33: 3- (3-cyanophenyl) -5- [N- [(Nt-Butoxycarbonylpiperidin-4-yl) methyl] -N-trifluoroacetylaminomethyl] benzoate methyl: in a nitrogen atmosphere, 2.0 g of the compound of the above production example 13 were dissolved in 20 ml of dry DMF, and this solution was used at a temperature of 0 ° C. With stirring, 1.38 ml of triethylamine was added, and in addition, added 0.70 ml of trifluoroacetic anhydride. After stirring at room temperature for 5 hours, water and ethyl acetate were added. The ethyl acetate extraction was carried out, the organic layer was washed with dilute hydrochloric acid, and a sodium hydrogencarbonate solution, and dried with sulfate. of magnesium, and the solvent was removed. Purification through silica gel column chromatography resulted in obtaining 1.46 g (78%) of the title compound. MS (M + l) = 560 Production Example 34: methyl 3- (3-cyanophenyl) -5- [2- [(4-t-butoxycarbonyl) piperazinyl-l-ethoxy] methyl] benzoate: after suspending 24 g of sodium hydride (60% in oil) in 2.0 ml of dimethylformamide, 2.0 ml of a solution of dimethylformamide containing 150 mg of 1-t-butoxycarbonyl-4- (2- hydroxyethyl) piperazine, and - stirred for 10 minutes. After cooling to -30 ° C, 143 mg of the compound of the production example 11 dissolved in 2.0 ml of dimethylformamide was added, and it was stirred at -30 ° C to room temperature for 4 hours. It was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with a saturated saline solution and dried over magnesium sulfate. After removal of the solvent in vacuo, purification with silica gel chromatography resulted in 21 mg (yield: 10%) of the title compound. 1H-NMR (270 MHz, CDC13): dl.45 (s, 9H), 2.4 ~ 2.5 (m, 4H), 2.66 (t, 2H, j = 5.9 Hz), 3.4 ~ 3.5 (m, 4H), 3.66 (t, 2H, j = 5.8 Hz), 3.97 (s, 3H), 4.65 (s, 2H), 7.5 ~ 8.2 (m, 7H). Production Example 35: methyl 3- (3-cyanophenyl) -5- [(l-acetylpiperidin-4-yl) -methoxymethyl] benzoate: 400 mg of the compound of the production example 9 were dissolved in 20 ml of methanol and 20 ml of 2N hydrochloric acid were added with stirring under ice cooling. After stirring at a temperature of 0 ° C to room temperature for 7 hours, the concentration afforded the crude product of methyl 3- (3-cyanophenyl) -5- (piperidin-4-ylmethoxymethyl) benzoate. This product was dissolved in 20 mL of dichloromethane, and 3.0 L of triethylamine was added. 460 μL of acetyl chloride were added with stirring under ice cooling, the stirring was continued at 0 ° C to room temperature for 18 hours, it was emptied into a saturated potassium hydrogensulfate solution, and extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium hydrogencarbonate, and then saturated salt water, dried with magnesium sulfate. After removal of the solvent in vacuo, purification with silica gel column chromatography resulted in 260 mg (yield: 74%) - del. composed of the title. L 1 H-NMR (270 MHz, CDC13): dl.O 7 l-3 (m 2H), 1.7 ~ 2.0 (m, 3H), 2.09 (s, 3H), 2.56 (td, 1H, J = 12.8, 2.9 Hz), 3.06 (td, ÍH, J = 13.2, 2.0 Hz), 3.2 ~ 3.5 (m, 2H), - 3.83. { brd, ÍH, J * = 13.5 Hz), 3.97 (s, 3H), 4.65 (s, 2H), 4.5 ~ 4.8 (m, ÍH), 7.58 (t, ÍH, J = 7.8 Hz), 7.6 ~ 7.8 ( m, ÍH), 7.72 (s, ÍH), 7.85 (d, 1H, J = 7.9 Hz), 7.90 (s, ÍH), 8.03 ~ (s, 1H), 8.17 (s, ÍH) Example product 36: 3 Methyl (3-cyanophenyl) -5- ((1- (t-butyloxycarbonylmethyl) -4-piperidyl) -methoxymethyl) benzoate; ,, in the nitrogen atmosphere, 100 mg of methyl 3- (3-cyanophenyl) -5- (piperidin-4-ylmethoxymethyl) benzoate was dissolved which was obtained as in the production example 37 were dissolved in 5 ml of dry ethanol, and 56 mg of potassium carbonate and 69 μL of t-butyl bromoacetate were added and stirred at a temperature of 60 ° C overnight. The solvent was removed and the purification was carried out in silica gel croftography to yield 10 mg (7.6%) of the title compound. 1 H-NMR (270 MHz, CDC13): dl.2 ~ 1.4 (m, 2H), 1.46 (s, 9H), 1.6 ~ 1.8 (m, 3H), 2.17 (d, J = 11 Hz, 2H), 2.96 (d, J = 9 Hz, 2H), 3.11 (s, 2H), 3.38 (d, J = 6.3 Hz), 3.96 (s, 3H), 4.60 (s, 2H), 7.5 ~ 7.9 (m, 5H) , 8.03 ^ s ^ H), 7.5 ~ 7.9 (m, 5H), 8.03 (s, 1H), 8.15 (s, ÍH). Production Example 37: 3- (3-Cyanophenyl) -5- ((2,2,2-trifluoro-N- (methyl- (2- (2-hydroxyethyl) (4-piperidyl)) methyl) acetylamino) methyl) benzoate : To the compound obtained from the production example 35, 5 mL of trifluoroacetic acid was added at a temperature of 0 ° C, and it was stirred for 30 minutes. The solvent was removed. Under a nitrogen atmosphere, 20 mL of dry methanol was added to this solution, and then 300 mg of potassium carbonate and 250 μL of 2-bromoethanol were added and stirred at a temperature of 60 ° C overnight. The solvent was removed and purification with silica gel chromatography afforded 220 mg (71%) of the title compound. MS (M + H) = 504 Production example 38 3- (3-Cyanophenyl) -5- [2- (N-t-butoxycarbonylpiperidin-4-yl) -methoxymethyl] benzoic acid: 1.43 g of the compound of the production example 9 were dissolved in 20 mL of methanol, and 2 mL of water was added. 1.54 L of a 4N lithium hydroxide solution was added and stirred at room temperature for 3 hours.After acidification, by addition of a saturated aqueous solution of ammonium chloride, an extraction with ethyl acetate was carried out. The organic layer was washed with saturated water, and purification through silica gel column chromatography resulted "1.03 g (yield: 74%) of the title compound.1H-NMR (270 MHz, CDC13): dl .O ~ 1.3 '< m, 2H), 1.46 (s, 9H), 1. 7 ~ 2.0 (m, 3H), _2.56 (td, ÍH, J = 12.8, 2.9 Hz), 3.05 (td, ÍH, J = 13.2, 2.0 Hz), 3.2 ~ 3.5 (m, 2H), 3.83 ( brd, ÍH, J = 13.5 Hz), 4.65 (s, 2H), 4.6 ~ 4.8 (m, ÍH), 7.60 (t, ÍH, J = 7. 8 Hz), 7.6 ~ 7.8 (, ÍH), 7.74 (s, 1H), 7.85 (d, ÍH, J = 7.9 Hz), 7.90 (s, ÍH), 8.03 (s, 1H), 8.16 (s, ÍH) Productive example 39: 3- (3-cyanophenyl) -5- [2- (1-t-butoxycarbonylpiperidin-4-yl) methoxymethyl] benzoic acid dimethylamide: 300 mg of the compound of the working example 38 were dissolved in 10 mL of dichloromethane, 116 μL of oxalyl chloride and then 135 μL of pyridine were added at a temperature of 0 ° C and stirred at a temperature of 0 ° C for 1 hour. To this reaction solution, a 40% dimethylamine solution was added dropwise and stirred at room temperature for 1 hour. A saturated sodium hydrogencarbonate solution was added and extracted with ethyl acetate. The organic layer was washed with saturated salt water, and dried with magnesium sulfate, and the solvent was removed. The resulting crude product was purified by silica gel column chromatography to yield 268 mg (yield: 84%) of the title compound. 1H-NMR (270 MHz, CDC13): dl.Q ~ 1.3 (, 2H), 1.46 (m, 2H), 1.46 (s, 9H), 1.7-2.0 (m, 3H), 2.56 (td, 1H, J = 12.8, 2.9 Hz), 3.0 (brs, 4H), 3.14 (s, 3H), 3.2 ~ 3.5 (m, 2H), 3.83 (brd, 1H, J = 13.5 Hz), 4.65 (s, 2H), 4.6 - 4.9 (m, 1H), 7.60 (t, 1H, J = 7.8 Hz), 7.6 ~ 7.8 (m, ÍH), 7.74 (s, ÍH), 7.86 (d, ÍH, J = 7.8 Hz), 7.92 ( s, ÍH), 8.04 (s, ÍH), 8.17 (s, ÍH). Production Example 40: l-Acetyl-3- (3-cyanophenyl) -5- [2- (N-t-butoxycarbonylpiperidin-4-yl) methoxymethyl] benzene: 291 mg of the compound of the production example 38 were dissolved in 10 mL of dichloromethane, 116 μL of oxalyl chloride and then 135 μL of pyridine were added at a temperature of 0 ° C, and then it was stirred at 0 ° C for 1 hour. Then, 76 mg of N, O-dimethylhydroxylamine hydrochloride was added, and it was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added and extracted with ethyl acetate. The organic layer was washed in a saturated saline solution, dried with magnesium sulfate, and the solvent was removed. The resulting crude product was dissolved in 10 L of tetrahydrofuran, and under a nitrogen atmosphere, at a temperature of 0 ° C, 2.29 mL of methylmagnesium bromide was added. After stirring at a temperature of 0 ° C. For 40 minutes, a dilute solution of hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed with saturated salt water and dried with magnesium sulfate. The solvent was removed in vacuo and purification through silica gel column chromatography resulted in the production of 190 mg (yield: 65%) of the title compound. 1H-NMR (270 MHz, CDC13): dl.O ~ 1.3 (m, 2H), 1.46 (s, 9H), 1.7 ~ 2.0 (m, 3H), 2.09 (s, 3H), 2.56 (td, ÍH, J = 12.8, 2.9 Hz), 3.06 (td, ÍH, J = 13.2, 2.0 Hz), 3.2 ~ 3.5 (m, 2H), 3.83 (brd, ÍH, J = 13.5 Hz), 4.65 (s, 2H), 4.5 - 4.7 (m, ÍH), 7.60 (t, ÍH, J - 7.9 Hz), 7.6 ~ 7.8 (m, ÍH), 7.70 (s, - ÍH), 7.85 (d, ÍH, J = 7.9 Hz), 7.90 (s, ÍH), 8.02 (s, ÍH), 8.16 (s, ÍH). EXAMPLE 1 Methyl 3- (3-amidinophenyl) -5 - [(4-piperidinyl) methoxymethyl] -5-benzoate salt: 6.0 g of the compound were dissolved, from the productive example 9 in 60 mL of dichloromethane and 3.0 mL of methanol was added. The hydrochloric acid gas was bubbled into the solution with stirring under ice cooling. After application at a temperature of 0 ° C for 30 minutes and then at room temperature for 20 hours, it was concentrated to a dry solid. 30 mL of a saturated solution of ammonia-ethanol was added, stirred at room temperature for 5 hours, and concentrated. The resulting crude product was purified using HP-20 column chromatography (30 g, eluent: water-methanol) to yield the title compound (4.89 g, yield: 99%). 1 H-NMR (270 MHz, DMSO-d 6): dl.3 ~ 1.5 (m, 2H), 1.7 ~ 2.0 (m, 3H), 2.7 ~ 2.9 (m, 2H), 3.2 ~ 3.3 (m, 2H), 3.38 (d, 2H, J = 6.3 Hz), 3.91 (s, 3H), 4.64 (s, 2H), 7.69 (t, ÍH, J = 7.9 Hz), 7.86 (d, ÍH, J = 7.9 Hz), 7.99 (s, 1H), 8.02 (s, ÍH), 8.07 (d, ÍH, J = 7.6 Hz), 8.15 (s, .IH), 8.28 (s, ÍH), 8.55 & 8.85 (brs, ÍH), 9.19 & 9.52 (s, 2H). In accordance with the same reaction as in Example 1 above, except that HPLC (ODS, eluent: water-methanol) was used instead of HP-20 column chromatography for isolation and purification, the compounds of examples 2 were synthesized. -40 which appear in the list in Table 3. Example 41: 3- (3-Amidinophenyl) -5- [(l-acetoimidoyl-4-piperidinyl) methoxymethyl] benzoate salt: To 4.79 g of the compound of Example 1 and 3.10 g of ethylacetoimidate monohydrochloride, 50 ml of ethanol was added. 5.25 ml of triethylamine was added dropwise with stirring under ice cooling. After raising the temperature from 0 ° C to room temperature, the stirring was continued for 36 hours and the product was concentrated to form a dry solid. Purification with HPLC (ODS, eluent: "water-methanol) resulted in the title compound (4.37 g, yield: 82%). 1 H-NMR (270 MHz, DMSO ~ d6): dl.l ~ 1.4 (m, 2H),, 1.7 ~ 2.1 (m, 3H), 2.50 (s, 3H), 3.0 ~ 3.5 (m, 4H), 3.8 ~ 4.0 (m, ÍH), 3.91 (s, 3H), 4.04 ~ 4.2 (m , ÍH), 4.64 (s »2H), 7.74 (t, ÍH, J = 7.8 Hz), 7.87 (d, ÍH, J = 7.6 Hz), 8.00 (s, ÍH), 8.03 (s, 1H), 8.07 (d, ÍH, J = 7.6 Hz), 8.16 (s, ÍH), 8.28 (s, ÍH), 8.64 & 9.20 (brs, ÍH), 9.25 & 9.54 (brs, 2H) In accordance with the same reaction than in the previous example 41, the compounds of examples 42-57 appearing in the list in Table 3 were synthesized. In addition, using the same reaction as the previous reaction except for the use of ethyl propionimidate monohydrochloride instead of ethylacetoimidate monohydrochloride, they were synthesized the compounds of Examples 58-59 which appear in the list in Table 3. In addition, using the same reaction as above, except for the use of ethyl hydroxy acetoimidate monohydrochloride instead of ethylacetoimidate monohydrochloride, the compounds of the example were synthesized 60 which appear in the list in table 3. Example 61 3- (3-amidinophenyl) -5- acid hydrochloride. { l-acetoimidoyl-4-piperidinyl) methoxymethyl] benzoic acid: 2.71 g of the compound of Example 41 were dissolved in 27 ml of 2N hydrochloric acid, stirred at a temperature of 70 ° C for 24 hours, concentrated to form a dry solid, and isolated and purified using HPLC (ODS, eluent: water-methanol) to yield the title compound (2.00 g, yield: 76%). 1 H-NMR (270 MHz, DMSO-d 6): dl.2 ~ 1.6 (m, 2H), 1.9 ~ 2.2 (m, 3H), 2.31 (s, 3H), 3.0 ~ 3.4 (m, 2H), 3.47 (d, 2H, J = 5.9 Hz), 3.9 ~ 4.1 (m, 2H), 4.65 (s, 2H), 7.6 ~ 7.8 (m, 3H), 8.0 ~ 8.1 (, 2H), 8.10 (s, ÍH), 8.24 (s, 1H). In accordance with the same reaction as the previous reaction of Example 61, the compounds of Examples 62-68, 70 and 72-83 which appear in the list in Table 3 were synthesized. Example 69: 3- (3-) acid salt amidinophenyl) -5- [[(4-piperidyl) methyl [aminomethyl] phenylcarbonylaminoacetic: 73 mg of the compound of Example 68 were dissolved in 5 mL of DMF, and to this solution were added 38 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 20 mg of glycine, and 50 mg of triethylamine, and stirred at room temperature overnight. The solvent was removed and the isolation and purification using HPLC (ODS, eluent: water-methanol) resulted in the title compound (25 mg, yield: 30%). In accordance with the same reaction as in the previous example 69, the compounds of example 71 that appear in the list in table 3 were synthesized. Experiment 1 (1) Determination of the inhibition activity of activated blood coagulation factor X (FXa) ): The substance was dissolved for analysis in water or water in which a suitable concentration of organic solvents (DMSO, ethanol or methanol) was added as a sample. To 70 μL of the sample diluted in series with water, 90 μL of 100 mM Tris buffer (pH 8.4), 20 μL of 50 mM Tris buffer (pH 8.4) containing 50 mU / mL of human FXa, and 2 mM were added. of substrate (Daiichi Chemical S-2765), and incubated for 30 minutes. 50 mL of 50% acetic acid was added, and absorbance was determined (A405). As a target, Tris regulator was added instead of FXa while, as a control, water was added instead of the sample. The inhibition activity of 50% (IC50) was determined as the indication of FXa inhibition activity. The inhibition activity of human FXa by means of the present compound appears in the list of table 4. (2) Determination of thrombin inhibition activity: to 70 μL of the sample diluted in series with water, 90 μL of 100 mM Tris buffer (pH 8.4), 20 μL of 50 mM Tris buffer (pH 8.4) containing 1 U / mL of human thrombin, and 2 mM of substrate (Daiichi Chemical S-2238), and incubated for 30 minutes. 50 μL of 50% acetic acid was added, and the absorbance (A405) was determined. As a target, Tris buffer was added instead of thrombin, while water was added instead of the sample as a control. The 50% inhibition activity (ICso) was determined as the indication of thrombin inhibition activity. The activity of inhibiting human thrombin by the present compound is presented in the list in Table 4. (3) Determination of anticoagulation activity (APTT): A 100 μL of normal human plasma (Ci-Trol®) manufactured by DADE, 100 μL of the sample was added, and incubated at 37 ° C for 1 minute. To this solution, 100 μL of APTT reagent (manufactured by DADE) was added, which was maintained at a temperature of 37 ° C and after incubation at 37 ° C for 2 minutes, 100 μL of a calcium chloride solution was added. mM and the coagulation time was determined using a coagulation measuring device manufactured by AMELUNG. The clotting time when a physiological saline solution was added instead of the analyte is used as a control. The concentration of the sample corresponding to an elongation of 2 times this coagulation time (CT2) is calculated and this value is used as the indication of anticoagulation activity. The human APTT elongation activities of the present compounds appear in the list in Table 4. (4) Determination of acetylcholine esterase inhibition activity (AChE): The substance to be analyzed was dissolved in distilled water as a sample. To 50 μL of the sample diluted in series, 50 μL of an enzyme solution was added, where the human acetylcholine esterase (manufactured by Sigma, C-5400) had been dissolved in distilled water at 0.1 U / mL. To this solution was added 50 μL of the prepared solution by means of the solution of 5, 5'-dithiobis (manufactured by Nacarai Tesque, 141-01) in a phosphate buffer (0.1M, NaH2P04-Na2HP04, pH 7.0) a 0.5 mM, and mixed and then reacted with 50 μL of the solution in which acetyl thiocholine iodide (Wako Company, 017-09313) had been dissolved in 3 mM phosphate buffer, at room temperature. As a control, distilled water was added instead of the substance for analysis and the absorbance (A450) was determined over time. As a blank, a phosphate buffer was added in place of the enzyme solution, and the 50% inhibition activity (IC50) was determined. The activity of human AChE inhibition of the compound appears in table 4. (5) Determination of bioavailability (BA): The substance for analysis was dissolved in distilled water (for oral administration; 10 mg / kg) or in the form of a physiological saline solution (for intravenous administration, 3 mg / kg) to separate a solution for administration. This solution was administered to fasted ICR mice (males, 6 weeks of age), whole blood was extracted from the heart with ether anesthesia at 5 minutes, (only in the case of the intravenous administration group), 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours after administration, and the plasma was separated by centrifugation (3,500 revolutions per minute, 30 minutes, 4 ° C) to produce the sample (n = 4). Using the above method to determine the inhibition activity of FXa, the calibration curve for the substance for analysis was previously prepared and the concentration of the substance for analysis in the sample was determined. The lower area of the plasma concentration-time curve (AUC) was calculated and then the bioavailability in the mouse (BA) was calculated according to the following formula: BA (%) = (AUC po) / (AUC iv) x (dose iv) / (dose po) x 100 The bioavailability of the compound of the present invention in the mouse appears in the list of table 4. Industrial exploitation A biphenylamidine derivative, and a pharmaceutically acceptable salt thereof, of the present invention they have the effect of inhibiting FXa activity, and can be employed as a clinically applicable prophylactic and / or therapeutic agent against thromboembolisms such as myocardial infarction, cerebral thrombosis, peripheral artery thrombosis or deep vein thrombosis as an FXa inhibitor. Table 1 Compound L R X n No. 1 link -C02Me -NH- < J -C02Me link -NH- O link -C0 Me -NH- link -C02Me -NH- link -C02Me -NH- 1 ~~ (_ / - C02H 6 link -C02Me -NH- 1 -Q-Me 7 link -C02Me. -NH- 1 -0 ~, pf 8 link -C02Me -NH- 1 - (> - tBu - \ 9 link -C02Me -NH- 1 - oMe link -C02Me -NH- 1 11 link -C02Me -NH- 1 * ~ HN " 12 link -C02Me -NH- 1 GH 13 link -C02Me -NH- 1 NH 14 link -C02Me -NH- 1 1 link -C02Me -NH- 1 16 bond -C02Me -NH- 17 bond -C02Me -NH- 1 -o 18 bond -C02Me -NH- 1 -o > = NH 19 link -C02Me -NH- 1 -Ol = NH bond '-C02Me -NH- 1 - NH 21 bond -C02Me -NH- 1 - N- e 22 link -C02Me -NH- 1 - (N-ÍPr 23 link -C02Me -NH- 1 • 15 24 link -C02Me -NH- 1 - (N '^ COoM link -C02Me -NH- 1 - ~ N ^ COnH 26 link -C02Me -NH- 1 _ ~ "^ ^ H2 27 bond -C02Me -NH- 1 -CK 28 bond -C02Me -NH- 1 25 29 bond -C02Me -NH- '- \ NH link -C02Me -NH- 1 ~ X? 31 link -C02Me -NH- 1 32 link -C02Me -NH- 1 33 link -C02Me -NH- 1 10 34 link -C02H -NH- 1 link -C02H -NH- 1 15 36 link -C02H -NH- 1 - (V-C02H 37 link -C02H -NH- 1 - V-M. 39 link -C02H -NH- 1 - (~ - tBu 40 bond -C02H -NH- 1 - (j-OMe 5 41 link -C02H -NH- HN- ^ 42 bond -C02H -NH- 1 HN - * 43 link -C02H -NH- 1 V- NH 44 link -C02H -NH- 1"V-NH 45 link -C02H -NH- 1 \ -N ^ .NH 46 link -C02H -NH- 1 -f "^, NH 47 link -C02H -NH- 1 ^ -NH 48 link -C02H -NH- 1 • 15 49 link -C02H -NH- 1 50 link -C02H -NH- 1 and x 51 link -C02H -NH- 1 - NH 52 link -C02H -NH- 1 - (N-Mß 53 link -C02H -NH- 1? ? 54 link -C02H -NH-, OH 55 link -C02H -NH- 1 - (N ^ CO2H 56 link -C02H -NH- 1 / - NH 57 link -C02H -NH- 1 ^ NH, 58 link -C02H -NH- 1 / ~ NH 59 link -C02H -NH- 1 / - NH - N \ ~ - \ ~ H 60 link -C02H -NH- 1 - < N-X N - '^ - OH / - \ NH 61 link -C02H -NH- 1 '-' ^ "^ Oh 62 bond -C02Me -o- 1 XD 63 bond -C02Me -o- 1 XD 64 bond -C02Me -o- 1 - V-CONH2 65 link -C02Me -o- 1 - (V-C03 e 66 link -C02Me -0- COjH 67 link -C02Me -0- 1 - / Vfvle / 68 link -C02Me -o- 1 -o * 69 link -C02Me -0- 1 -0; 8? 70 link '-C02Me -o- 1 - (f -OMe 71 link -C02Me -0- 1 72 link -C02Me -0- 1 73 link -C02Me -0-. 1 - 74 link -C02Me -o- 1 \ -NH 75 link -C02Me -0- 1 .- and V - * ?. i, ^ r.NH 76 link -C02Me -0- 1 - -N ^ H 77 link -C02Me -0- 1 78 link -C02Me -0- 1 - ^ - H 79 link -C02Me 80 link -C02Me 81 link -C02Me 82 link -C02Me -0- 83 link -C02Me -0- -O Pr 84 link -C02Me -0- 85 link -C02Me -0- 86 link -C02Me -0- 1 - < ^ N "^ CO2H link -C02Me -0- 88 link -C02Me -0- N- ^ 89 link -C02Me -0- 90 link -C02Me -0- H. NH, NH 91. link -C02Me -0- U- \ - \ NH 92 link -C02Me -0- 1 / - N. NH 93 link -C02Me -0- 1 - (? < - / "A ^ OH / - \ NH 94 link -C02Me -o- 1 - X 95 link '-C02H -o- 1 yj 96 link -C02H -o- 1 97 link -C02H -o- 1 ~? ~ co2H 98 bond -C02H -o- 1 - / y-Me 99 link -C02H -0- 1) - Pr 100 link -C02H -o- 1 - ¿V-tBu 101 link -C02H -0- 1 (V-OMe 102 link -C02H -0- 1 103 link -C02H -0- 1 - 104 link -C02H -0- V-NH 105 link -C02H -0- 1 -NH 106 bond -C02H -0- 1 \ -N ^. H 107 link -C02H -0- 1 - N ^ NH 108 bond -C02H -0- 1 - -NH m 109 bond -C02H -o- 1 - x- H 110 link -C02H -0- 1 111 link -C02H -0- 1 112 link -C02H -o- 1 - ¿X 113 bond -C02H -0- 1 - / N-Me n - - - 114 bond -C02H - -o- 1 - N-iPr 115 link -C02H -o- 1 -Q, ~ OH 116 link • -C02H -0- N CO, H Nr 120 bond -C02H -0- N- 121 bond -C02H -0- 122 bond -C02H -0- 123 link -NH- N- ^ 124 link -NH- 125 link -NH- 126 link -NH- 127 link -NH- -O 128 link -NH- H 129 link -NH- ./ X 130 link - NH 131 link -NH-? .0" 132 link -0- NH 133 link -0- N-iPr 134 link 135 link -O- x 136 link -O- X. NH 137 link -0- NH 'Ni-Í- NH 138 link -0- 139 link NH 140 link -0- N- -OH 141 link -NH- H 142 link -NH- 143 link -NH- . or 144 link -NH- N- ^ 145 link -NH- NH 146 link -NH- N- (NH, NH 147 link -NH- N- ^ 148 link -NH- \ NH 149 link -NH- x OH 150 link -0- NH 151 link -0- N-iPr 152 link -0- 153 link -0- -XX 154 link -0- 155 link -0- NH 156 link -0- N- ^ 157 link -0- 158 link -0- 159 link -0- 160 link -NH-161 link -NH- 162 link -NH- 163 link -NH-, N ~ 164 link -NH- NH 165 link -NH- IM-? t H2 NH 166 link -NH- 167 link -NH- - NH 168 link -NH- 169 link -0- x NH 170 link -0- and ~ \ N-iPr 171 link -0- 172 link -0- or 173 link -0- N-4 NH 174 link -O- - ^ NH, NH 175 link -0- NX 176 link -0- 177 link -0- '~ ^ - ^ N ~ ^ -OH 178 link -C02H -0- 179 link -C02H -O- 0 - (-? Pr 180 link -C02H -o- 0 ^ ™ 181 link -C02H -0- 0 XX 182 -. 182 - link -C02H -0- 0" 183 link -C02H -o- 0 x? - 'x NHH2 184 link -C02H -o- 0 / * ÑH _ -XX? 185 link -C02H -or- 186 link -C02H -o- _N 187 link -C02H 1 1 Me ~ H - N-188 bond -C02H 1 1 - < ^ N-Me Me N 190 bond -C02H 1 1 / - ^ - ^ OH Me 191 bond -C02H N co2H Me N 192 bond -C02H I 1. ^ H. H. 193 link -C02H 194 link -C02H N-- / \ NH 195 link -C02H 1 1 Me -? ? _ N - NH 196 link -C02H • i 1 Me O ^ -OH / - \ NH 197 link -C02H 1 1 Me - '^^ OH V Y) ^ C02K 202 link -C02H 1 HO 203 link -C02H - N- NH 204 link -C02H N-S \ _ / NH, HO - N - -, NH 205 link -C02H 1 XX? HO N 206 link -C02H 1 -O ü. 207 link -C02H 5" - NH 208 bond -C02H 1 N- '^^ OH HO N 209 bond -C02H 1 ^ C02H ~ CNH N- - 210 bond -C02H 1 - N- e C02H 211 link -C02H 212 bond -C02H - - 213 bond -C02H 1 -. { ^ COjH O ^ CF3 214 bond -C02H 1 -Qr- "- O ^ CF3 N 215 bond -C02H 1 - < -f O ^ CF3 - 'NH, -N 1N- NH 216 bond -C02H O.X "". N- CF3 N - 217 bond -C02H I / - ^ N o = s = o I Me? _H - N - NH 218 bond -C02H I o = s = o M -OH I Me N 1 - v NH 219 bond -C02H o = s = o 1 - < NX 1 ^ ^ "CH Me 220 -CH2CH2- -C02H -NH- 1 X 221 -. 221 -CH2CH2- -C02H -NH- 1 222 -. 222-CH2CH2- -C02H -NH- 1"15 223 '-CH2CH2- -C02H -NH- 1 224 -. 224 -CH2CH2- -C02H -NH- 1 -0- 225 -CH2CH2- -C02H -NH- 1 - V- Bu 226 -. 226 -CH2CH2- -CO2H -NH- 1 - ¿V-OMe 227 -. 227 -CH2CH2- -C02H -NH- 1 • > ? 228 -CH2CH2- -C02H -NH- H ^ 229 -. 229 -CH2CH2- -C02H -NH- 1 ... \ - NH 230 -. 230 -CH2CH2- -CO2H -NH- 1 - Y ^ H 231 -. 231 -CH2CH2- -C02H -NH- 1 232 -. 232 -CH2CH2- -C02H -NH- 1 - - N ^ NH 233 -. 233 -CH2CH2- -C02H -NH- 1 V-NH 2. 3. 4 - . 234 -CH2CH2- -C02H -NH- 1 - ^ - NH 235 -. 235 -CH2CH2- -CO2H -NH- 1 O N- = H 236 -. 236 -CH2CH2- -C02H -NH- 1 237 -. 237 -CH2CH2- -C02H -NH- 1"O 238 -. 238 -CH2CH2- -C02H -NH- 1 - (N-Ms) 239 -. 239 -CH2CH2- -C02H -NH- 1 - < ^ N-? ° r 240 -. 240 -CH2CH2- -C02H -NH-, OH 241 -CH2CH2- -C02H -NH- 'C02H NH 243 -CH2CH2- -C02H -NH- NX: H, NH 244 -CH2CH2- -C02H -NH- NH 246 -CH2CH2- -C0 H -NH- X ^ .- OH NH 247 -CH2CH2- -CO2H -NH- N-i "OH 248 link -C02H -NH- - N NH 249 link - -NH- - N NH H, 250 link -C02H -NH- -N N OH .0 251 bond -NH- -N N-NH3 -OH 252 bond -C02H -NH- 2 -N N- co, H 253 bond - -NH- • N N- H, CO, H 254 link -CO? H -NH- 2 255 -. 255 -CH2CH2- -C02H -NH- 2 ~ N3 H "'- s NH 256 link -NH- 2 -N N- NH2 257 link -C02H -NH- 2 -0 ^ 258 bond -C02H -NH- 2 '- ^ NH -N N- \ / - NH 261 -. 261 -CH2- -C02H -NH- 1 X N- 262 link -C02H -NHCO- 0 -XJ 263 link -C02H -NHCO- 0 _ -0 264 link -C02H -NHCO- 0 265 link -C0 H -NHCO- Me 266 link -C02H -NHCO- 0 -? X-iPr 267 link -C02H -NHCO- 0 268 link -C02H -NHCO- 0 - (~ OMe 269 link -C02H -NHCO- 0 HN "^ 270 bond -C02H -NHCO- 0 1 - 271 bond -C02H -NHCO- 0"" 272 link -C02H -NHCO- 0 - ¿N-Me 273 link -C02H -NHCO- 0 - ^ ivi-iPr 274 link -C02H -NHCO- 0 275 link -C02H -NHCO- 0 - -. { N ^ "C02H 276 bond -C02H -NHCO- 0 77 bond -C02H -NHCO- 0 278 bond -C02H -NHCO- 279 link -C02H -NHCO- 0? X * ^ X 280 link -C02H -NHCO- 0 y-? H 281 link -C02H -NHCO- 0 or- 282 link -C02H -NHCO- 1 283 bond -C02H -NHCO- 1 - ~ V-C02H 284 link -C02H -NHCO- 1 -? ~ Me Table 2 Structure Example Structural data production 4 3. 7Hz), 7.5 ~ 8.2 (m, 7H).

XH-NMR (270MHz, CDCI3) d 0.9-1.2 (m 2H), 1.4 ~ 1.8 (m, 4H), 3.36 (d, 2H, J = 6.3 Hz), 3.97 (s, 3H), 7.5 ~ 8.2 (, 7H). (s, 9H) 1.7 ~ 1.9 (, 4H), 2.6 ~ 2.8 (m, 4H), 3.03 (t, 2H, J = 7.6 Hz), 3.36 (d, 2H, J = 6.3 Hz), 4.0 ~ 4.2 (m, 3H), 4.53 (s, 2H), 7.1 ~ "7.9 (, 7H). 7? H - NMR (270MHz, CDC13) d 2H), 3.5 ~ 3.7 (m, ÍH), 3.7 ~ 3.9 (m, 2H), 3.97 (s, 3H), 4.66 (s, 2H), 7.5 ~ 8.2 (m, 7H). 2H), 3.40 (d, 2H, J = 6.3 Hz), 3.8 ~ 4.1 (m, 2H), 3.97 (s, 3H), 4.60 (s, 2H), 7.5 ~ 8.2 (m, 7H). ÍH), 1.6 ~ 1.9 (, 2H), 2.71 (t, 2H, J = 12.2 Hz), 3.38 (d, 2H, J = 5.9 Hz) 3.97 (s, 3H) 4.0 ~ 4.2 (m, 2H), 4.60 (s, 2H), 7.5 ~ 7.9 ( m, 4H), 7.90 (s, 1H), 8.03 (s, ÍH), 8.16 (s, ÍH). (dt, 2H, J = 11.6 Hz), 3.38 (d, 2H, J = 6.6 Hz), 3.96 (s, 3H), 4.60 (s, 2H), 7.5 ~ 7.7 (, 2H), 7.74 (s, ÍH), 7.8 ~ 7.9 (, ÍH), 7.90 (s, ÍH), 8.03 (s, ÍH), 8.15 (s, 1H). eleven 8. 1 ~ 8.2 (m, 2H). 3H), 2.6 ~ 2.8 (m, 4H) 3.95 (s, 3H), 4.0 ~ 4.2 (br S, 4H), 7.5 ~ 7.7 (m, 2H), 7.9 ~ 8.0 (m, 2H), 8.09 (s, 2H), 8.20 (s, ÍH). 14 XE - NMR (270MHz, CDC13) d 0.8 ~ 1.0 (m, 2H), 1.0 ~ (s, 3H), 7.57 (dd, J = 7.8, 7.8 Hz, ÍH), 7.65 (d, J = 7.8 Hz, 1H), 7.7 (s, ÍH) , 7.85 (d, J = 7.8 Hz, ÍH), 7.91 (s, 1H), 8.03 (s, ÍH), 8.12 (s, ÍH). 10 XE - NMR • (270MHz, CDC13) d 2. 3 (m, 2H), 2.5 ~ 2.8 (m, 2H) 2.70 (t, 2H, J = 12.0 Hz), 3.57 (s, 2H), 3.96 (s, 3H), 4.0 ~ 4.2 (m, 2H), 4.64 & 4.72 (s, 2H), 7.5 ~ 7.7 (m, 2H), 7.72 (s, ÍH), 7.85 (d, ÍH, J = 7.6 Hz), 8.01 (s, 1H), 8.12 (s, ÍH). 24 J = 7.0 Hz), 2.42 (t, 2H, J = 7.0 Hz), 2.67 (brt, 2H, J = 11.3 Hz), 3.63 (s, 2H), 3.96 (s, 3H), 4.0 ~ 4.2 (m, ÍH), 7.5 ~ 8.2 (m, "7H).

? E - NMR (270MHz, CDC13) d 2. 2 ~ 2.3 (m, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.67 (t, J = 12 Hz, 2H) 3.62 (s, 2H), 3.96 (s, 3H), 3.9 ~ 4.1 (m, 2H), 7.57 (dd, J = 7.8, 7.8 Hz, ÍH), 7.67 (d, J = 7.8 Hz, ÍH), 7.72 (s, 1H), 7.84 (d, J = 7.9 Hz, ÍH), 7.89 (s, ÍH), 8.02 (s, ÍH), 8.11 (s, ÍH).

XH - NMR (270MHz, CDC13) d 9H), 1.5 ~ 2.0 (m, 4H), 2.32 (d, 2H, J = 7.0 Hz), 2.5 ~ 2.7 (m, 4H), 3.5 ~ 3.7 (m, 4H), 3.94 (s, 3H), 4.0 ~ 4.1 (brs, ÍH), 7.5 ~ 8.2 (m, 7H). 2H), 2.50 (d, 2H), 2.68 (m, 2H), 3.21 (s, 2H), 3.88 (s, 2H), 3.93 (s, 3H), 4.04 (m, 2H), 7.54 (m, 1H) ), 7.64 (d, 1H), 7.75 (s, 1H), 7.82 (d, 1H), 7.86 (s, ÍH), 8.00 (s, ÍH), 8.11 (s, ÍH).

? E - NMR (270MHz, CDC13) d 3.2 ~ 3.3 (, 2H), 3.96 & 3.97 (s, 3H), 4.0-4.3 (, 2H), 4.64 & 4.72 (s, 2H), 7.4 ~ 8.0 (s, 2H), 7.4 ~ 8.0 (, 6H), 8.1 ~ 8.2 (m, ÍH). 2. 32 & 2.37 (t, 2H, J = 7.6 Hz), 2.5-2.8 (m, 2H), 3.18 & 3.21 (s, 2H), 3.95 & 3.97 (s, 3H), 4.0 ~ 4.3 (brs, ÍH), 4.68 & 4.73 (s, 2H), 7.4 ~ 8.3 (m, 7H).

Hz, 9H), 2.35 (dt, J = 7.5, 20.5 Hz, 2H), 2.5 ~ 2.8 (m, 2H), 3.19 (d, J = 7.6 Hz, 1H), 3.96 (d, J = 3.7 Hz, 3H ), 4.0 ~ 4.3 (m, 2H), 4.7 (d, J = 12 Hz, 2H), 7.4 ~ 7.7 (m, 3H), 7.8 ~ 7.9 (m, 3H), 8.15 (d, J = 11 Hz, ÍH). 31? E - NMR (270MHz, CDC13) d Hz), 2.88 (s, 3H), 3.0 ~ 3.2 (m, 2H), 3.9 ~ 4.2 (, 2H), 3.98 (s, -3H), 4.50 (s, 2H), 7.60 (t, ÍH, J = 7.8 Hz), 7.69 (d, 1H, J = 7.6 Hz), 7.8 ~ 7.9 (m, ÍH), 7.89 (s, ÍH), 8.03 (s, 1H) 8.20 (s, 1H). 20 32 XH - NMR (270MHz, CDC13) d (t, J = 13 Hz, 2H), 2.9 ~ 3.0 (m, 2H), 3.1 ~ 3.2 (, 2H), 3.97 (s, 3H), 3.9 ~ 4.2 (m, 2H), 4.51 (s, 2H) ), 7.61 (dd, J = 7.7, 7.7 Hz, ÍH), 7.70 (d, J = 7.7 Hz, 1H), 7.8 ~ 7.9 (m, 3H), 8.03 (s, ÍH), 8.19 (s, ÍH) . 34 XH - NMR (270MHz, CDC13) d Hz), 3.4 ~ 3.5 (m, 4H), 3.66 (t, 2H, J = 5.8 Hz), 3.97 (s, 3H), 4.65 (s, 2H), 7.5 ~ 8.2 (m, 7H). 2.56 (td, ÍH, J = 12.8, 2.9 Hz), 3.06 (td, 1H, J = 13.2, 2.0 Hz), 3.2 ~ 3.5 (m, 2H), 3.83 (brd, ÍH, J = 13.5 Hz), 3.97 (s, 3H), 4.65 (s, 2H), 4.5 ~ 4.8 (m, ÍH), 7.58 (t, ÍH, J = 7.8 Hz), 7.6 ~ 7.8 (m, ÍH), 7.72 (s, 1H) , 7.85 (d, ÍH, J = 7.9 Hz), 7.90 (s, ÍH), 8.03 (s, ÍH), 8.17 (s, ÍH). 36 lH - NMR (270MHz, CDC13) d 2.17 (d, J = 11 Hz, 2H), 2.96 (d, J = 9 Hz, 2H), 3.11. (s, 2H), 3.38 (d, J = 6.3 Hz, 2H), 3.96 (s, 3H), 4.60 (s, 2H), 7.5 ~ 7.9 (m, 5H), 8.03 (s, ÍH), 8.15 (s, ÍH). 38 XH - NMR (270MHz, CDC13) d 2. 56 (td, ÍH, J = 12.8, 2.9 Hz), 3.05 (td, ÍH, J = 13.2, 2.0 Hz), 3.2 - 3.5 (m, 2H), 3.83 (brd, ÍH, J = 13.5 Hz), 4.65 (s, 2H), 4.6 - 4.8 (m, ÍH), 7.60 (t, ÍH, J = 7.8 Hz), 7.6 - 7.8 (, 1H), 7.74 (s, ÍH), 7.85 ( d, ÍH, J = 7.9 Hz), 7.90 (s, 1H), 8.03 (s, 1H), 8.16 (s, ÍH). 39 XH - NMR (270MHz, CDC13) d 2. 9 Hz), 3.0 (brs, 4H, 3.14 (s, 3H), 3.2 - 3.5 (m, 2H), 3.83 (brd, ÍH, J = 13.5 Hz), 4.65 (s, 2H), 4.6 - 4.9 (m, ÍH), 7.60 (t, ÍH, J = 7.8 Hz), 7.6 - 7.8 (, ÍH), 7.74 (s, ÍH), 7.86 ( d, ÍH, J = 7.8 Hz), 7.92 (s, ÍH), 8.04 (s, ÍH), 8.17 (s, ÍH). 40 * H - NMR (270MHz, CDC13) d 2. 09 (s, 3H), 2.56 (td, ÍH, J = 12.8, 2.9 Hz), 3.06 (td, 1H, J = 13.2, 2.0 Hz), 3.2 - 3.5 (m, 2H), 3.8s (brd, ÍH) , J = 13.5 Hz), 4.65 (s, 2H), 4.5 - 47 (m, ÍH), 7.60 (t, ÍH, J = 7.9 Hz), 7.6 - 7.8 (m, ÍH), 7.70 (s, ÍH) , 7.85 (d, 1H, J = 7.9 Hz), 7.90 (s, ÍH), 8.02 (s, ÍH), 8.16 (s, ÍH).

Table 3 Example Structure Structural data * HNMR (DMSO-de) d 1.3 - 1.5 (m, 2H), 1.7 - 2.0 (, 3H), 4. 64 (s, 2H), 7.69 (t, ÍH, J = 7.9Hz), 7.86 (d, ÍH, J = 7.9Hz), 7.99 (s, ÍH), 8.02 (s, ÍH), 8.07 (d, 1H , J = 7.6 Hz), 8.15 (s, ÍH), 8.28 (s, 1H), 8.55 & 8.85 (brs, Sal ÍH), 9.19 & 9.52 (s, 2H).

XH-NMR (DMSO-de) d 1.1 - 2.3 3. 92 (s, 3H), 4.63 (s, 2H), 7.6 - 8.3 (m, 7H), 9.1 - Salt 9.6 (m, 4H).

XH-NMR (DMSO-de) d0.8 ~ 2.2 (m, 10H), 3.2-3.4 (br s, 2H), 3.91 (s, 2H), 6.6-6.7 (brs, lH), 7.1- 7.2 (brs , lH), 7.7-8.3 (m, 7H), 9.0 - 9.2 (brs, ÍH), Sal 9.4 - 9.5 (brs, 2H) XH-NMR (DMSO-de) d 0.9 -2.3 3H), 4.61 (s, 2H), 7.6 - Sal 8.4 (m, 7H). 2 (m, 2H), Salt 2H), 7.6 - 8.3 (m, "7H).

XH-NMR (DMSO-de) d 1.26 (d, 6H, 3H), 4.65 (s, 2H), 7.74 (t, ÍH, J = 7.8Hz), 7.90 (d, ÍH, J = 7.9 Hz), 7.98 (s, 1H), 8.07 (s, ÍH), 8.08 ( d, ÍH, J = 8.3 Hz), 8.18 (s, ÍH), 8.27 (s, ÍH), 9.40 & Salt 9.62 (brs, 3H). 1 H-NMR (DMSO-de) d 1.25 (d, 3. 1 - 3.5 (m, 5H), 4.38 (q, 2H, J = 7.0 Hz), 4.65 (s, 2H), 7.74 (t, ÍH, J = 7.9 Hz), 7.87 (d, ÍH, J = 7.9 Hz ), 7.98 (s, ÍH), 8.05 (s, ÍH), 8.07 (d, ÍH, J = 12.2 Hz), 8.17 (s, 1H), 8.26 (s, 1H), 9.33 & 9.58 Salt (brs, 3H).

^ -NMR (DMSO-de) d 0.9 - 1.3 11. 7 Hz), 3.2 - 3.5 (m, 2H), 3.80 (brd, ÍH, J = 14.9 Hz), 3.91 (s; 3H), 4.37 (brd, ÍH, J = 4.37 Hz), 4.63 (s, 2H) , 7.71 (t, ÍH, J = 7.7 Hz) 7.83 (d, ÍH, J = 7.9 Hz), 7.98 (s, 2H), 8.02 (d, ÍH, J = 7.9 Hz), 8.11 (s, ÍH), 8.25 (s, ÍH), 8.17 (s, ÍH), 9.4 - Sal 10.0 (br, 3H).

XH-NMR (DMSO-de) d 1.5 - 2.0 (m, 5H), 2.9 - 3.7 (, 6H), 3. 74 (s, 3H), 3.92 (s, 3H), 4.64 (s, 2H), 7.7 - 8.3 (m, 7H), 9.14 (br s, 2H), 9.51 Salt (br s, 2H).

XH-NMR (DMSO-de) d 1.8 - 2.2 8. 3 (, 7H), 8.7 - 9.0 (brs, ÍH), 9.1 - 9.2 (brs, Sal 2H), 9.5 - 9.6 (brs, 2H).

XH-NMR (DMSO-de) d 2.6 - 2.8 (m, 6H), 3.0 - 3.2 (m, 4H), 3.5 - 3.8 (m, 2H), 3.92 (s, 3H), 4.66 (s, 2H), 7.6 - 8.3 (m, 7H), S.06 & 9.48 Salt (brs, 3H) H, N XH-NMR (270 MHz, DMSO-d6 + 4H), 3.97 (s, 3H), 4.32 (s, 2H), 7.76 (t / J = 7.8 Hz, HH), 7.89 (d, J = 7.8 Hz, Salt HH), 8.1-8.5 (m, 5H) .

^ -NMR (270 MHz, DMSO-d6 + 2. 3 (m, 1H), 2.8 - 3.2 (, 2H), 3.2 -4.0 (m, 8H), 3.88 (s, 3H), 4.82 (d, J = 21 Sal Hz, 2H), 7.6 - 8.3 (m, 7H). 1 H-NMR (270 MHz, DMSO-de + (t, J = 7.6 Hz, HH), 7.88 (d, J = 7.6 Hz, HH), 8.1-8.3 (m, 3H), 8.37 (s, Salt HH), 8.48 (s, 1H).

XH-NMR (DMSO-de) d 1.2 - 1.5 2H), 3.92 (s, - 3H), 4.85 (d, J = 20 Hz, 2H), 7.7 - 8.5 Salt (m, 7H).

XH-NMR (DMSO-de) d 1.1 - 1.6 (m, 2H), 1.8 - 2.3 (m, 3H), 2.4 - 3.2 (m, 9H), 3.93 (s, 3H), 4.3 - 4.7 (m, 3H) ), 7.8-8.0 (m, 2H), 8.1-8.6 (m, 4H), 9.1 & 9.55 (brs, Sal 3H).

XH-NMR (DMSO-de) d 0.83 (t, 3. 5 (m, 4H), 3.68 (s, 2H), 3.91 (s, 3H), 3.9-4.1 (brs, ÍH), 7.5-8.5 (m, Sal 7H).

XH-NMR (DMSO-de) d 0.7 - 0.8 (m, 4H), 3.97 (s, 3H), 4.5 (brs, 2H), 7.7 - 8.3 (m, 7H), 9.26 (brs, 2H), 9.57 Salt (brs, 2H). 2. 7-2.9 (m, 2H), 3.2-3.5 (m, 2H), 3.91 (s, 3H), 4.66 & 4.75 (s, 2H), 7.4 - Sal 8.3 (m, 7H), 9.13 (m, 3H).

^ -NMR (DMSO-de) d 0.84 & (t, 2H, J = 7.6 Hz), 2.4-2.6 (m, 2H), 2.9-3.1 (m, 2H), 3.20 & 3.25 (d, 2H, J = 7.6 Hz), 3.91 (s, 3H), 4.65 & 4.71 (s, 2H), 7.2 - Salt 8.2 (m, 7H).

^ - MR (DMSO-de) d 0.70 - - 3.4 (m, 3H), 3.89 (d, J = 2.7 Hz, 3H), 4.70 (d, J = 25.9 Hz, 2H), 7.7 - 8.3 (m, 7H), 9.26 (brs, 2H), 9.57 Salt (brs, 2H).

XH-NMR (DMSO-de) d 1.2-1.4 (m, 2H), 1.6-1.9 (m, 3H), 2.64 (t, 2H, J = 11.5 Hz), Hz), 7.90 (d, ÍH, J = 7.8 Hz), 8.05 (d, 1H, J = 10.5 Hz), 8.07 (s, ÍH), 8.13 (s, ÍH), 8.20 (s, ÍH), 8.31 ( s, Sal ÍH).

^ -NMR (DMSO-de) d 0.70-0.85 (m, 3H), 1.1-2.2 (m, 2. 7 Hz, 3H), 4.5-4.70 (m, 4H), 7.74 (dd, J = 7.7, 7.7 Hz, ÍH), 7.90 (d, J = 7.7 Hz, ÍH), 8.05 (d, J = 7.8 Hz, ÍH), 8.08 (s, ÍH), 8.13 (s, 1H), 8.20 (s, ÍH), 8.30 (s, ÍH), 9.26 (brs, 2H), Sal 9.57 (brs, 2H).

XH-NMR (DMSO-de) d 1.8 - 1.9 3H), 3.92 (s, 3H), 4.00 (brs, 2H), 7.75 (t, ÍH), 7.86 (d, ÍH), 8.0 - 8.1 (brs, 3H), 8.14 (s, ÍH), 8.27 (s) , ÍH), 9.22 (s, ÍH), Salt 9.52 (s, 2H).

Salt XH-NMR (DMSO-de) d 1.0 1.3 (m, 2H), 1.5-2.0 (m, Hz), 3.50 (t, 2H, J = 5.9 Hz), 3.73 (s, 2H), 3.89 (s, Salt 3H), 7.5-8.4 (m, 7H).

XH-NMR (DMSO-de) d 1.15 (t, J = 7.0 Hz, 3H), 1.33-1.52 (m, 2H), 1.73-1.95 (m, 3H), 2.63-2.75 (m, (s, 2H), 7.23 (s, 2H), 7.52 - 7.63 (, 2H) 7.64 - 7.72 (m, ÍH), 8.1 (s, ÍH), 9.2 Salt (brs, 3H).

Salt Salt XH-NMR (DMSO-de) d 1.3 - 1.5 (m, 2H), 1.7 - 2.0 (m, 3H), 2.7 - 2.9 (m, 2H), 2.97 (s, 3H), 3.15 - 3.3 (m, 2H) ) 3.38 (d, 2H, J = 6.3 Hz), 8. 01 (s, ÍH), 8.07 (d, ÍH, J = 7.6 Hz), 8.14 (s, ÍH), Salt 8.27 (s, ÍH).

XH-NMR (DMSO-de) d 1.3 - 1.4 (m, 2H), 1.7 - 2.0 (m, 3H), 2.7 - 2.9 (m, 2H), 2.97 (s, H, N ÍH, J = 7.98 Hz), 7.97 (s, ÍH), 8.00 (s, ÍH), 8.07 (d, ÍH, J = 7.6 Hz), 8.14 (s, Sal ÍH), 8.27 (s, ÍH).

Salt Salt Salt Salt H, N Salt XH-NMR (270 MHz, DMSO-de) d 1.1 - 1.4 (m, 2H), 1.7 - 2.1 (m, 3H), -2.50 (s, 3H), 3.0 ~ 3.5 (m, 4H), 3.8 - 4.0 (m, ÍH), 3.91 (s, 3H), Hz), 8.16 (s, ÍH), 8.28 (s, ÍH), 8.64 & 9.20 (brs, ÍH), Salt 9.25 & 9.54 (brs, 2H).

^ -NMR (270 MHz, DMSO-d6) d 1.3 - 2.1 (m, 5H), 2.27 (s, 3H), 2.9 - 3.2 (m, 2H), 8. 3 (m, 7H), 9.1-9.6 (m, Salt 4H). 6) d (m, (s, XH-NMR (270 MHz, DMSO-d6 + D20) d 1.2 - • 1.5 (m, 2H), 3. 9 - 4.1 (m, 2H), 4.35 (s, 2H), 7.8 - 8.2 (m, 6H), Salt 8.43 (s, ÍH).

XH-NMR (270 MHz, DMSO-de + D20) d 1.1-1.5 (m, 2H), 1.9-1.7 (m, 2H), 2.26 (s, 3H), 2.1-2.3 (m, 2H), 3.0 ( m, 5H), 8.13 (s, 1H), 8.3 Salt (m, 1H).

: H-NMR (270 MHz, DMSO-de) d 3H), 7.7-8.8 (m, 7H), Salt 9.47 & 9.70 (brs, 3H). 1 H-NMR (270 MHz, DMSO-d 6) d 0.83 (t, 3 H, J = 5.7 Hz), 1.0-1.6 (m, 6H), 1.8- 3. 5 (m, 4H), 3.68 (s, 2H), 3.91 (s, 3H), 3.9-4.1 (brs, ÍH), 7.5-8.5 (m, Sal 7H).

XH-NMR (270 MHz, DMSO-d6) d 0.7 - 0.8 (m, 3H), 1.1-2.2 (m, 15H), 2.24 (s, 3H), (brs, 2H), 7.8 - 8.3 (m, 7H), 9.3 (brs, 2H), 9.6 Salt (brs, 2H).

^ - MR (270 MHz, DMSO-d6) d 1.1 - 1.5 (m, 2H), 1.7 - 1.9 (m, 2H), 2.09 & 2.14 3. 0 - 4.3 (m, 6H), 3.91 (s, 3H), 4.67 & 4.77 (s, 2H), 7.7-8.4 (m, 7H), Sal 9.41 (brs, 3H).

XH-NMR (270 MHz, DMSO-d6) d 0.84 & 0.92 (t, 3H; J = 7.3 Hz), 1.0-1.3 (, 2H), 1.5-2.0 (m, 5H), 2.22 & 2.24 (s, 3H), 2.31 & 2.36 (t, 2H, J = 7.6 Hz), 2.4-2.6 (m, 2H), 2.9-3.1 (m, 2H), Sal 7H).

XH-NMR (270 MHz, DMSO-de) d 1.0 - 1.3 (, 2H), 1.6 - 2.0 (m, 3H), 2.24 (s, 3H), 2.8 - 3.5 (m, 6H), 3.02 (s, Hz), 8.03 (d, ÍH, J = 7.8 Hz), 8.08 (s, 1H), 8.18 (s, 1H), 8.23 (s, 1H), 8.29 (s, Sal HI), 9.4 (m, 3H).

^ -NMR (270MHz, DMSO-de) d 1.1 - 1.3 (m, 2H), 1.8 - 1.9 (, 3H), 2.22 (s, 3H), 3. 9 - 4.0 (brs, 2H), 3.91 (s, 3H), 7.76 (t, ÍH), 7.85 (d, 1H), 7.9 - 8.1 (m, 3H), 8.25 (s, ÍH), 8.44 (s, ÍH), 9.00 (S, 1H), 9.19 (s, 1H), Sal 9.44 (S, 2H).

^ -NMR (270MHz, DMSO-de) d 1.0 - 1.3 (, 2H), 1.5 - (brd, 2H, J = 12.4 Hz), 3.50 (t, 2H, J = 5.9 Hz), 3.73 (s, 2H), 3.89 (s, 3H), Salt 7.5 - 8.4 (m, 7H).

H-NMR (270MHz, DMSO-de) d 1.16 (t, J = 7.0Hz, 3H), 1.17 3H), 2.65 - 2.75 (m, 2H), 2.89 - 3.00 (m, 2H), 3.00 - 3.35 (m, 2H), 3.95 - 4.0 (m, ÍH), 4.1 (q, J = 7.0 Hz, 2H) , 4.55 (s, 2H), 7.22 (s, 1H), 7.55 - 7.59 (m, 2H), 7.65 - 7.73 (m, HH), 7.78 - 7.85 (m, HH), 7.98 - 8.02 (m, 1H) , 8.03 - 8.08 (m, ÍH), 8.14 (s, ÍH), 9.2 (br Sal s, ÍH), 9.55 (br s, ÍH).

XH-NMR (270MHz, DMSO-de + 3. 5 (m, 4H), 3.8-4.0 (m, HH), 4.0-4.2 (m, HH), 4.64 (s, 2H), 7.74 (t, HH, J = 7.8 Hz), 7.87 (d, 1H, J = 7.6 Hz), 8.00 (s, ÍH), 8.03 (s, ÍH), 8.07 (d, ÍH, J = 7.6Hz), 8.16 (s, ÍH), Salt 8.28 (s, 1H).

XH-MR (270MHz, DMSO-de + 3H), 3.0-3.5 (m, 4H), 3.8-4.0 (m, 1H), 4.0-4.2 (m, HH), 4.63 (s, 2H), 7.74 (t, HH, J = 7.8 Hz), 7.87 (d, ÍH, J = 7.6 Hz), 8.00 (s, 1H), 8.03 (s, 1H), 8.07 (d, 1H, J = 7.7Hz), 8.15 Salt (S, ÍH), 8.30 (s, ÍH) ).

Salt ^ -NMR (270MHz, DMS0-d6 + 2. 1 (brs, 2H), 2.61 (q, 2H, j = 7.6 Hz), 3.3 - 3.8 (m, 5H), 3.92 (s, 3H) 4.72 (s, 2H), 7.6 - 8.3 (m, Sal 7H) .

Salt Salt 3. 0 - 3.4 (m, 2H), 3.47 (d, 2H, J = 5.9 Hz), 3.9 - 4.1 (m, 2H), 4.65 (s, 2H) 7.6 - 7.8 (m, 3H), '8.0 - 8.1 ( m, 2H), 8.10 (s, ÍH), 8.24 (s, Hydrochloride (H).

^ -NMR (270MHz, DMSO-de) d 4H), 4.62 (s, 2H), 7.74 (t, ÍH, J = 7.8 Hz), 7.85 (d, ÍH, J = 7.9 Hz), 7.9 - 8.0 (m, 2H), 8.06 (d, ÍH, J = 7.9 Hz) 8.14 (s, 1H), 8.27 Hydrochloride (m, ÍH), 9.45 (brs, 3H). 2. 86 (t, J = 12 Hz, 2H), 3.3-3.5 (m, 6H), 4.59 (s, 2H), 7.6 - 8.1 (m, 6H), 8.21 (s, ÍH).

XHNMR (279MHz, DMSO-de) d 3.3 (m, (brs, 7H), 8.8 ~ 9.0 (brs, 1H), 9.1- 9.3 (brs, 2H), 9.6 ~ 9.7 (brs, Hydrochloride 2H). d 1. 75 ~ 1.95 (m, 3H), 2.6-2.9 (m, 2H), 3.1-3.5 (m, 5H), 4.33 (m, 2H), 4.62 (s 2H), 7.73 (t, ÍH, J = 7.9Hz ), 7.84 (d, ÍH, J = 7.6Hz), 7.94 (s, 1H), 8.06 (d, ÍH, J = 7.6Hz), 8.13 (s, 1H), 9.45 Hydrochloride (brs, 3H). 2H-NMR (270MHz, DMSO-de) d 1.6 -1.8 (m, brs, 2H), 1.9-2.1 (brs, 2H), 2.28 (s, 3H), 3.2 -3.5 (, 2H), 3.6-3.9 ( m, 3H), 4.70 (s, 2H), 7.6-8.4 Hydrochloride (m, 7H). .16 5H), 4.69 (s, 2H), 7.6-8.3 Hydrochloride (m, 7H).

XH-NMR (270MHz, DMSO-d5 + D20) d 1.3-1.5 (m, 2H), 1.96 (d, J = 14HZ, 2H), 2.11 (brs, ÍH), 2.7 ~ 3.00 (m, 4H), 4.30 (s, 2H), 7.74 (t J = 7.7Hz, ÍH), 7.87 (d, J = 7.7Hz, ÍH), 8.1- Hydrochloride 5 (m, 5H) Salt XH-NMR (270MHz, DMS0-d6 + D20) d 1.2 ~ 1.5 (m, 2H), 1.9-2.0 (m, 2H), 2.28 (s, 3H), 2.1-2.3 (, ÍH), 2.9-3.4 ( m, 4H), 4.02 (dd, J = 13.5, 53Hz, 2H), 4.34 (s, 2H), 7.7 ~ 8.0 (m, Hydrochloride 2H), 8.1-8.3 (m, 3H).

Salt ^ -NMR (270MHz, DMSO-d6 + D20) d 1.4-2.3 (, 5H), 2.9-3.9 (m, 10H), 4.33 (s, 2H), 7.80 (t, J = 7.6Hz? ÍH), 7.89 (d, J = 7.6Hz, ÍH), 8.1-8.3 (m, Hydrochloride 4H) 8.41 (s, ÍH) 73 7. 7 ~ 8.5 (m, 7H), 9.1 ~ 9.7 (m, Hydrochloride 3H). 74 XH-NMR (270MHz, DMSO-de) d 1.1-1.4 (m, 2H), 1.8-2.3 (m, 3H), 2.25 (s; 6H), 3.0- 4.3 (m, 8H), 7.7-8.6 ( m, 7H), Hydrochloride 9.16 &9.51 (brs, 3H).

, H), 2.24 (s, 3H), 2.3 ~ 2.5 (m, 4H), 3.0 ~ 3.5 (m, 4H), 3.68 (s, 2H), 3.9-4.1 (brs, ÍH), Hydrochloride 7.5-8.5 (m, 7H). .0, 2.3-2.6 (, 2H), 2.7-3.3 (m, 4H), 3.8 ~ 4.2 (m, 2H), 4.67 (brs, 2H), 7.74 (dd, 7.9.7.9 Hz, ÍH), 7.88 ( d, 7.8Hz, HH), 7.9 ~ 8.3 (m, 3H), 8.46 Hydrochloride (brs, HH), 8.56 (brs, HH). 77 XH-NMR (270MHz, DMSO-de) d 1.1-1.5 (m, 2H), 2.0-2.3 (m, ÍH), 2.08 &2.14 (s, 3H), 2.27 (s, 3H), 3.0 ~ 4.3 (m, 6H), 4.66 &4.73 (s, 2H), 7.7-8.5 (m, 7H), 9.28 (brs, Hydrochloride 3H). 78 4H), 2.0-2.2 (m, 2H), 2.30 (s, 3H), 2.4-2.5 (m, 2H), 3.0 ~ 3.5 (m, 4H). 4.00 (brs, ÍH), 4.67 (s, 2H), 7.0-8.3 Hydrochloride (m, 7H). 79 1H-MR (270MHz, DMSO-d6) d ll ~ 1.3 (m, 2H) 1.7-2.0 (m, 3H), 2.21 (s, 3H) 2.8-3.5 (m, 6H), 3.00 (s, 3H) , 4.49 (s, 2H), 7.7-7.9 (, 2H), 7.86 (s, ÍH). 8.04 (s, ÍH), 8.0 ~ 8.1 (m, 1H), 8.22 (s, ÍH) Hydrochloride, 8.46 (s, ÍH), 9.21 (m, 3H). 80 ^ -H-NMR (270MHz, DMSO-d6) d 1.1-1.3 (m, 2H), 1.8-1.9 (m, 3H), 2.25 (s, 3H), (m, 8. 08 (brs, 2H), 8.32 (brs, 2H), 8.67 (brs, 1H). 9.23 (s, 1H), 0.39 (s, ÍH). 9.58 Hydrochloride (s, 2H). 81 XH-NMR (270MHz, DMSO-de) d 1.0-1.3 (m, 2H), 1.5-2.0 H, N (m, 3H), 2.24 (s, 3H), 2.30 (d, 2H, J = 6.5Hz), 2.4-2.6 (m, 2H), 3.13.4 (brd, 2H, J = 12.4 Hz) , 3.50 (t, 2H, J = 5.9 Hz), 3.73 (s, 2H), 7.5- Hydrochloride 8. (m, 7H). 82 XH-NMR (270MHz, DMSO-de) d 1.21 ~ 1.43 (m, 2H), 1.78 -1.90 (m, 2H), 1.90-2.08 (m, 1H), 2.25 (s, 3H), 2.45-2.55 ( m, 5H), 2.88-2.98 (m, 2H), 3.5 (brs, 6H), 4.0 (m, ÍH), 4.55 (s, 2H), 7.25 (s, ÍH), 7.60-7.78 (m, 2H) 7.92 (m, Hydrochloride 2H), 8.3 (s, 1H).

Hydrochloride Table 4 Activity Activity APTT Activity Inhibitory mouse inhibiCT2 of inhibition of Fxa tion of (μM) thrombin tion AchE IC50 (μM) Compound 0.063 > 1000 0.76 49 10 Example 61 Compound 0.19 > 1000 2.0 140 11 of example 70 Compound 1.2 > 1000 11 > 250 13 of example 72 Compound 1.7 > 1000 13 > 250 ND of example 73 Compound 0.59 > 1000 5.4 150 13 Example 74 Compound 0.21 820 2.8 130 Example 81 Compound 0.13 > 1000 1.9 170 11 of Example 82 Compound 0.16 > 1000 1.9 760 12 of example 83

Claims (10)

CLAIMS A biphenylamidine derivative of the general formula (I) (cH2) n_?
1. (1) wherein R1 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an amino group, a nitro group, a C? -C8 alkyl group, or an alkoxy group C? -C8; L is a direct bond or a C? -C4 alkylene group; R2 is a fluorine atom; a chlorine atom; a bromine atom; a hydroxyl group; an amino group; a C? -C8 alkoxy group; a carboxyl group; a C 1 -C 8 alkoxycarbonyl group; an aryloxycarbonyl group; an aralkoxycarbonyl group; a carbamoyl group wherein a nitrogen atom constituting the carbamoyl group can be substituted with a C 1 -C 8 monoalkyl group or C 1 -C 8 dialkyl or it can be a nitrogen atom in an amino acid; a C 1 -C 8 alkylcarbonyl group; a C 1 -C 8 alkylsulfenyl group; a C 1 -C 8 alkylsulfinyl group; a C 1 -C 8 alkylsulfonyl group; a C 1 -C 8 monoalkylamino group or C 1 -C 8 dialkylamino group; a C? -C8 monoalkylaminosulfonyl or C? -C8 dialkylaminosulfonyl group; a sulfo group; a phosphono group; a bis (hydroxycarbonyl) methyl group; a bis (alkoxycarbonyl) methyl group; or a 5-tetrazolyl group; R3 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an amino group, a nitro group, a C? -C8 alkyl group, a C? -C8 alkoxy group, a carboxyl group, or a C? -C8 alkoxycarbonyl group; X is any of the formulas: -O-, -S-, -SO-, -S02-, -NH-CO-NH-, -N (R4) -, -CO-N (R5) -, -N ( R5) -CO-, N (R5) -S02-, -S02-N (R5) -, where R4 is a hydrogen atom, a Ci-Cio alkyl group, a Ci-Cio alkylcarbonyl group, an alkylsulfonyl group Ci- C? O, a C3-C8 cycloalkyl group, or an aryl group, R5 is a hydrogen atom, a Ci-Cio alkyl group, a C3-C8 cycloalkyl group, or an aryl group, where an alkyl group in R4 and R5 it can be substituted by an aryl group, a hydroxyl group, an amino group, a fluorine atom, a chlorine atom, a bromine atom, a C? -C8 alkoxy group, a carboxyl group, a C? -C8 alkoxycarbonyl group , an aryloxycarbonyl group, an aralkoxycarbonyl group, a carbamoyl group, or a 5-tetrazolyl group; Y is a C4-C8 cycloalkyl group where a methylene group in the C4-C8 cycloalkyl can be replaced with a carbonyl group, or it can be substituted by a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group , an amino group, a C? -C8 alkyl group, a C? -C8 alkoxy group, a carbamoyl group, a C1-Ce alkoxycarbonyl group, a carboxyl group, an aminoalkyl group, a monoalkylamino or dialkylamino group, or a monoalkylaminoalkyl group or dialkylaminoalkyl; or the next ring of 5 to 8 members of formulas 1-1 or 1-2: C i - i] 23 where, in formulas 1-1 and 1-2, in each cyclic system, the methylene group can be replaced by a carbonyl group, and the cycle can have unsaturated bonds, R6 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an amino group, a nitro group, a C? -C8 alkyl group, or a C? -C8 alkoxy group, W is CH, or a nitrogen atom, provided that W is not a nitrogen atom when the cycle is a 5-membered ring, Z is a hydrogen atom; a Ci-Cio alkyl group wherein the alkyl group may be substituted with a hydroxyl group except when Z is an alkyl group Ci, an amino group, a Ci-Cβ alkoxy group except when Z is an Ci alkyl group, a carboxyl group, a alkoxycarbonyl group Ci-Cs, an aryloxycarbonyl group or an aralkoxycarbonyl group; a C 1 -C 8 alkylcarbonyl group; an arylcarbonyl group; an aralkylcarbonyl group; an amidino group; or the next group of formula 1-3: wherein, in formula 1-3, R7 is a C? -C8 alkyl group, wherein the alkyl group may be substituted by a hydroxyl atom or a C? -C8 alkoxy group; an aralkyl group; or an aryl group; m is an integer from 1 to 3; n is an integer from 0 to 3, provided that W is not a nitrogen atom when n is 0-1; or a pharmaceutically acceptable salt thereof. A biphenylamidine derivative according to claim 1 wherein, in said formula (1), R1 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an amino group, a C1-C4 alkyl group, or a C1-C4 alkoxy group; L is a direct bond or a C? -C4 alkylene group; R2 is a fluorine atom; a chlorine atom; a bromine atom; a hydroxyl group; an amino group; an alkoxy group C? -C8; ' a carboxyl group; a C 1 -C 8 alkoxycarbonyl group; an aryloxycarbonyl group; an aralkoxycarbonyl group; a carbamoyl group wherein a nitrogen atom in the carbamoyl group can be substituted by a Ci-Cβ monoalkyl group or C? -C8 dialkyl or it can be a nitrogen atom in an amino acid; a C 1 -C 8 alkylcarbonyl group; a C 1 -C 8 alkylsulfenyl group; a C 1 -C 8 alkylsulfinyl group; a C 1 -C 8 alkylsulfonyl group; a C 1 -C 8 monoalkylamino group or C 1 -C 8 dialkylamino group; a C 1 -C 8 monoalkylaminosulfonyl or Ci-C 8 dialkylaminosulfonyl group; a sulfo group; a phosphono group; a bis (hydroxycarbonyl) methyl group; a bis (alkoxycarbonyl) methyl group; or a 5-tetrazolyl group; R3 is a hydrogen atom; X is any of the formulas: -O-, -S-, -N (R4) -, -C0-N (R5) -, -N (R5) -C0-, N (R5) -S02-, or -S02-N (R5) -; where R 4 is a hydrogen atom, a C 1 -C 10 alkyl group, a C 1 -C 10 alkylcarbonyl group, or a C 1 -C 0 alkylsulfonyl group, R 5 is a hydrogen atom, or a C 1 -C 10 alkyl group, wherein an alkyl group in R 4 and R 5 can be substituted by an aryl group, a hydroxyl group, an amino group, a fluorine atom, a chlorine atom, a bromine atom, a C 1 -C 8 alkoxy group, a carboxyl group, an alkoxycarbonyl group C ? -C8, an aryloxycarbonyl group, an aralkoxycarbonyl group, a carbamoyl group, or a 5-tetrazoyl group; Y is a C4-C8 cycloalkyl group where a methylene group constituting the C4-C8 cycloalkyl group can be replaced by a carbonyl group or it can be substituted by a fluorine atom, a chlorine atom, a bromine atom, a group hydroxyl, an amino group, a C? -C8 alkyl group, a C? -C8 alkoxy group, a carbamoyl group, a C? -C8 alkoxycarbonyl group, a carboxyl group, an aminoalkyl group, a monoalkylamino or dialkylamino group, or a monoalkylaminoalkyl or dialkylaminoalkyl group; or the following ring of 5-8 members of the formulas II-1: [I i - i] where, in formula II-1, in the cyclic system, the methylene group can be replaced by a carbonyl group, R6 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group , an amino group, a C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy group, W is C-H, or a nitrogen atom, provided that W is not a nitrogen group when the ring is a 5-membered ring, Z is a hydrogen atom; a Ci-Cio alkyl group wherein the alkyl group may be substituted by a hydroxyl group except when Z is an alkyl group Ci, an amino group, a C?-C8 alkoxy group except when Z is an alkyl group Ci, a carboxyl group, a Ci-Cβ alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group; a C 1 -C 8 alkylcarbonyl group; an arylcarbonyl group; an aralkylcarbonyl group; an amidino group; or the next group in formula II-2: R ' NH C I I ~ 2 where, in the formula I1-2, R7 is a C? -C8 alkyl group, where the alkyl group may be substituted with a hydroxyl group or a C? -C4 alkoxy group; an aralkyl group; or an aryl group; m is an integer of 1 - 3; n is an integer of 0-3, provided that W is not a nitrogen atom when n is 0-1; or a pharmaceutically acceptable salt thereof. A biphenylamidine derivative according to claim 1 or according to claim 2, of the general formula (2): C
2. 2) where L is a bond or a C? -C4 alkylene group; R2 is a carboxyl group; a C 1 -C 4 alkoxycarbonyl group; an aralkoxycarbonyl group; a carbamoyl group wherein a nitrogen atom which replaces the carbamoyl group may be substituted by a C 1 -C -alkyl group or C 1 -C 4 -alkyl group or it may be a nitrogen atom in an amino acid; or a C1-C4 alkylcarbonyl group; SX is -O-, -N (R4) -, or -NH-CO-, where R4 is a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkylcarbonyl group, or an alkylsulfonyl group. , the alkyl is optionally substituted by a hydroxyl group, an amino group, a fluorine atom, a carboxyl group or a C 1 -C 8 alkoxycarbonyl group; Y is a Cs-Ce cycloalkyl group, wherein a methylene group constituting the C5-C6 cycloalkyl group may be substituted by a carbamoyl group, a C1-C4 alkoxy group, or a carboxyl group; or the following ring of 5-6 members of formula III-1: [? I- IJ where, in formulas III-1: is C-H, or a nitrogen atom, provided that it is not a nitrogen atom when the ring is a 5-membered ring, Z is a hydrogen atom; a C1-C4 alkyl group wherein the alkyl group may be substituted with a hydroxyl group except when Z is an alkyl group Ci, an amino group, a carboxyl group, or a C: ~ C4 alkoxycarbonyl group; a C1-C4 alkylcarbonyl group; an amidino group; or the next group in formula III-2: [pr - 2 j where, in formula III-2, R7 is a C1-C4 alkyl group, where the alkyl group may be substituted by a hydroxyl group; n is an integer of 0-2; provided that W is not a nitrogen group when n is 0-1; or a pharmaceutically acceptable salt thereof. A biphenylamine derivative according to claim 3, wherein, in said formula (2), X is -0-, or -N (R4) -, where R4 is a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkylcarbonyl group, or an alkylsulfonyl group C? C10, the alkyl group is optionally substituted by a hydroxyl group, an amino group, a fluorine atom, a carboxyl group or a C? -C8 alkoxycarbonyl group; or a pharmaceutically acceptable salt thereof. A diphenylamidine derivative according to claim 3, wherein in said formula (2), X is -NH-C0-, or a pharmaceutically acceptable salt thereof. A biphenylamidine derivative according to claim 3 or according to claim 4, wherein in the general formula (2), L is a bond; R is a carboxyl group; or a methoxycarbonyl group; X is -O-, or -N (R4) -, where R4 is a hydrogen atom, a methyl group or a 2-hydroxyethyl group; And it is any of the formulas: n is 1; or a pharmaceutically acceptable salt thereof. 7. A prodrug that generates a biphenylamidine derivative or a pharmaceutically acceptable salt thereof according to any of claims 1-6, in vivo. 8. A blood coagulation inhibitor comprising at least one biphenylamidine derivative or a pharmaceutically acceptable salt thereof according to any of claims 1-7, and a pharmaceutically acceptable carrier. 9. A prophylactic agent for thrombosis or embolism, comprising at least one biphenylamidine derivative or a pharmaceutically acceptable salt thereof according to any of claims 1-7, and a pharmaceutically acceptable carrier. 10. A therapeutic agent for thrombosis or embolism, comprising at least one biphenylamidine derivative or a pharmaceutically acceptable salt thereof, according to any of claims 1-7, and a pharmaceutically acceptable carrier.