HK1022685B - Substituted n-[ (aminoiminomethyly or aminomethyl) phenyl] propyl amides - Google Patents

Description

Substituted N- [ (aminoiminomethyl or aminomethyl) phenyl ] propyl amides

Technical Field

The compounds of formula I exhibit useful pharmacological activity and can therefore be incorporated into pharmaceutical compositions for the treatment of patients suffering from certain medical indications. More specifically, they are factor Xa inhibitors. The present invention relates to compounds of formula I, compositions containing compounds of formula I and their use for treating patients suffering from or susceptible to an indication that can be alleviated by administration of an inhibitor of coagulation factor Xa.

Factor Xa is the penultimate enzyme in the coagulation chain. The compounds of formula I inhibit both free factor Xa and factor Xa bound in the prothrombinase complex (factor Xa, factor Va, calcium and phospholipid). The inhibition of factor Xa is obtained by the direct formation of a complex between the inhibitor and the enzyme, which is therefore independent of the plasma cofactor antithrombin III. Effective factor Xa inhibition is achieved by administering the compound orally, by continuous intravenous infusion, by bolus intravenous administration, or by any other parenteral route, whereby the desired effect of preventing factor Xa from inducing prothrombin to form thrombin is achieved.

Anticoagulant therapy is suitable for the treatment and prevention of various thrombotic indications of arterial and venous vessels. In the arterial system, abnormal thrombosis is primarily associated with coronary arteries, cerebral vessels and peripheral vessels. Diseases associated with thrombotic closure of these vessels include primarily Acute Myocardial Infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and Percutaneous Transluminal Coronary Angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication and Coronary Artery Bypass Grafting (CABG) or peripheral artery bypass grafting. Long-term anticoagulant therapy is also beneficial in preventing vascular luminal stenosis (restenosis), which often follows PTCA and CABG; and is useful for maintaining vascular patency in long-term hemodialysis patients. In the case of venous vessels, pathological thrombosis often occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT also puts patients at high risk of being predisposed to pulmonary thromboembolism. Systemic Disseminated Intravascular Coagulation (DIC) often occurs in the vascular system during septic shock, certain viral infections and cancer. This indication is characterized by the rapid consumption of coagulation factors, their plasma inhibitors leading to life-threatening clot formation, spread over the tiny blood vessels of several organ systems. The indications discussed above include some, but not all, possible clinical situations suitable for anticoagulant therapy. Situations where short-term or long-term prophylactic anticoagulation therapy is required are well known to those skilled in the art.

Summary of The Invention

The present invention relates to compounds of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof:

is a single or double bond;

R_ais hydrogen, hydroxy or amino;

R₁and R₂Is hydrogen or together is ═ NR₉；

R₃Is hydrogen, -COR₂R₆、-C(O)R₆、-CONR₆R₆、-CH₂OR₇or-CH₂SR₇；

R₄Is hydrogen, alkyl, Q-alkyl or thiacyl, or is a group of the formula

Or

R₅Is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, aryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, heteroaryl, fused cycloalkylheteroaryl, fused heterocyclenylheteroaryl, fused heterocyclylheteroaryl, aralkyl, heteroaralkyl, aralkenyl, heteroaralkenyl, aralkynyl, or heteroaralkynyl;

R₆is hydrogen or lower alkyl;

R₇is hydrogen, lower alkyl, Ar (lower alkyl), lower acyl, aroyl or heteroaroyl;

R₈is hydrogen or lower alkyl;

R₉is hydrogen, R₁₀O₂C-、R₁₀O-, HO-, cyano, R₁₀CO-, HCO-, lower alkyl, nitro or Y^1aY^2aN-；

R₁₀Is alkyl, aralkyl or heteroaralkyl;

Y^1aand Y^2aIndependently hydrogen or alkyl;

a and B are hydrogen or together a bond;

q is R₇O-or R₇S-or Y¹Y²N-；

Y¹And Y²Independently hydrogen, alkyl, aryl and aralkyl, or Y¹And Y²One of which is acyl or aroyl, Y¹And Y²Is hydrogen, alkyl, aryl or aralkyl;

ar is aryl or heteroaryl; and is

n is 0, 1 or 2.

Detailed Description

Unless otherwise indicated, the following terms, as used above and throughout the specification of the present invention, shall be understood to have the following meanings:

definition of

"patient" includes humans or other mammals.

"alkyl" refers to a straight or branched chain aliphatic hydrocarbon group having from about 1 to about 15 chain carbon atoms. Preferred alkyl groups have from 1 to about 12 chain carbon atoms. Branched means that one or more lower alkyl groups, such as methyl, ethyl, propyl, are attached to a linear alkyl group. "lower alkyl" refers to straight or branched chain alkyl groups having from about 1 to about 6 chain carbon atoms. Alkyl groups may be substituted with one or more halo, cycloalkyl or cycloalkenyl groups. Representative alkyl groups include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl, and dodecyl.

"alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond, which may be straight or branched chain, and which contains from about 2 to about 15 chain carbon atoms. Preferred alkenyl groups contain 2 to about 12 chain carbon atoms; more preferably from about 2 to about 6 chain carbon atoms. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl group. "lower alkenyl" means a straight or branched chain alkenyl group of about 2 to about 4 chain carbon atoms. The alkenyl group may be substituted with one or more halogens. Representative alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl and dodecenyl.

"alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched chain and contains from about 2 to about 15 chain carbon atoms. Preferred alkynyl groups contain 2 to about 12 chain carbon atoms; more preferably from about 2 to about 4 chain carbon atoms. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a straight alkynyl group. "lower alkynyl" refers to straight or branched chain alkynyl groups of about 2 to about 4 carbon atoms in the chain. Representative alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl and dodecynyl.

"cycloalkyl" means a non-aromatic monocyclic or polycyclic ring system containing about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl groups have a ring containing about 5 to about 6 ring atoms. The cycloalkyl group may be optionally substituted by one or more "ring system substituents" (as defined herein), which may be the same or different. Representative monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Representative polycyclic cycloalkyl groups include 1-naphthylalkyl, norbornyl, adamantyl and the like.

"cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic ring system containing about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms, containing at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 6 ring atoms. The cycloalkenyl group can be optionally substituted with one or more "ring system substituents" (as defined herein), which may be the same or different. Representative monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Representative polycyclocycloalkenyls are norbornenyl.

"heterocycloalkenyl" means a non-aromatic mono-or polycyclic ring system containing about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is not a carbon atom, but an element such as a nitrogen, oxygen, or sulfur atom; and it contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Preferred heterocycloalkenyl groups contain from about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocycloalkenyl means that at least one nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The heterocycloalkenyl can be optionally substituted with one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen or sulfur atom of the heterocycloalkenyl group can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Representative monocyclic azacycloalkenyls include 1, 2, 3, 4-tetrahydropyridine, 1, 2-dihydropyridyl, 1, 4-dihydropyridyl, 1, 2, 3, 6-tetrahydropyridine, 1, 4, 5, 6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Representative oxacycloalkenyl groups include 3, 4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. A representative polycyclic oxacycloalkenyl group is 7-oxabicyclo [2.2.1] heptenyl. Representative monocyclic thiacycloalkenyl groups include dihydrothienyl, dihydrothiopyranyl, and the like.

"Heterocyclyl" means a non-aromatic saturated monocyclic or polycyclic ring system containing about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, wherein one or more of the ring atoms is not a carbon atom, but an element such as nitrogen, oxygen or sulfur. Preferred heterocyclic groups contain from about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that there is at least one nitrogen, oxygen or sulfur atom, respectively, as ring atom. The heterocyclyl group may be optionally substituted by one or more "ring system substituents" (as defined herein), which may be the same or different. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Representative monocyclic heterocyclic groups include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1, 3-dioxolanyl, 1, 4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, and the like.

An "aryl" group is an aromatic monocyclic or polycyclic ring system containing from 6 to about 14 carbon atoms, preferably from about 6 to about 10 carbon atoms. The aryl groups may be optionally substituted with one or more "ring system substituents" (as defined herein), which may be the same or different. Representative aryl groups include phenyl and naphthyl.

"heteroaryl" means an aromatic monocyclic or polycyclic ring system containing about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, wherein one or more of the ring atoms is not a carbon atom, but an element such as nitrogen, oxygen, or sulfur. Preferred heteroaryl groups contain from about 5 to about 6 ring atoms. The "heteroaryl" group may be optionally substituted by one or more "ring system substituents" (as defined herein), which may be the same or different. The prefix aza, oxa or thia before heteroaryl means that at least one nitrogen, oxygen or sulfur atom is present as a ring atom. The nitrogen atom of the heteroaryl group can optionally be oxidized to the N-oxide. Representative heteroaryl groups include pyrazinyl, furyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1, 2, 4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, 2, 3-naphthyridinyl, imidazo [1, 2-a ] pyridine, imidazo [2, 1-b ] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridinyl, isoquinolyl, benzazepindolyl, 1, 2, 4-triazinyl, benzothiazolyl, and the like.

"fused arylcycloalkenyl" refers to groups derived from fused aryl and cycloalkenyl groups as defined herein by removal of a hydrogen atom of the cycloalkenyl moiety. Preferred fused arylcycloalkenyls are those wherein aryl is phenyl and cycloalkenyl consists of about 5 to about 6 ring atoms. The fused arylcycloalkenyl can be optionally substituted with one or more ring system substituents, where "ring system substituent" is as defined herein. Representative fused arylcycloalkenyls include 1, 2-dihydronaphthalene, indene and the like, wherein the parent moiety is attached through a non-aromatic carbon atom.

"fused cycloalkenylaryl" refers to a group derived from a fused arylcycloalkenyl group, as defined herein, by removal of a hydrogen atom from the aryl moiety. Representative fused cycloalkenylaryl groups are as described herein for the fused arylcycloalkenyl group, except that the bond to the parent moiety is through an aromatic carbon atom.

"fused arylcycloalkyl" refers to groups derived from fused aryl and cycloalkyl groups as defined herein by removal of a hydrogen atom from the cycloalkyl moiety. Preferred fused arylcycloalkyls are those wherein aryl is phenyl and cycloalkyl consists of about 5 to about 6 ring atoms. Fused arylcycloalkyl groups may be optionally substituted with one or more ring system substituents, wherein "ring system substituent" is as defined herein. Representative fused arylcycloalkyls include 1, 2, 3, 4-tetrahydronaphthyl and the like, wherein the bond to the parent moiety is through a non-aromatic carbon atom.

"fused cycloalkylaryl" refers to a group derived from an arylcycloalkyl group, as defined herein, by removal of a hydrogen atom from the aryl moiety. Representative fused cycloalkylaryl groups are described herein for fused arylcycloalkyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"fused arylheterocycloalkenyl" refers to a group derived from fused aryl and heterocycloalkenyl groups as defined herein by removal of a hydrogen atom from the heterocycloalkenyl moiety. Preferred fused arylheterocycloalkenyls are those wherein the aryl group is phenyl and the heterocycloalkenyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl moiety of a fused aryl heterocyclenyl means that there is at least one nitrogen, oxygen or sulfur atom as a ring atom, respectively. The fused arylheterocycloalkenyl can be optionally substituted with one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen or sulfur atom of the heterocycloalkenyl portion of the fused arylheterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide, or S, S-dioxide. Representative fused aryl heterocyclenyl groups include 3H-indolinyl, 1H-2-oxoquinolinyl, 2H-1-oxoisoquinolinyl, 1, 2-dihydroquinolinyl, 3, 4-dihydroquinolinyl, 1, 2-dihydroisoquinolinyl, and 3, 4-dihydroisoquinolinyl, and the like, wherein the bond to the parent moiety is through a non-aromatic carbon atom.

"fused heterocycloalkenylaryl" refers to a group derived from a fused arylheterocycloalkenyl group as defined herein by the removal of a hydrogen atom from the aryl moiety. Representative fused heterocycloalkenylaryl groups are as described herein for fused arylheterocycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"fused arylheterocyclyl" refers to groups derived from fused aryl and heterocyclyl groups as defined herein by removal of a hydrogen atom from the heterocyclyl moiety. Preferred fused arylheterocyclyl groups are those wherein the aryl group is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that there is at least one nitrogen, oxygen or sulfur atom, respectively, as ring atom. The fused arylheterocyclyl group can be optionally substituted with one or more ring system substituents, wherein "ring system substituent" is defined herein. The nitrogen or sulfur atom of the heterocyclyl portion of the fused aryl heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide, or S, S-dioxide. Representative preferred fused aryl heterocyclyl ring systems include phthalimide, 1, 4-benzodioxane, indolinyl, 1, 2, 3, 4-tetrahydroisoquinoline, 1, 2, 3, 4-tetrahydroquinoline, 1H-2, 3-dihydroisoindolyl, 2, 3-dihydrobenzo [ f ] isoindolyl, 1, 2, 3, 4-tetrahydrobenzo [ g ] isoquinolyl, and the like, wherein the bond to the parent moiety is through a non-aromatic carbon atom.

"fused heterocyclylaryl" refers to a group derived from a fused arylheterocyclyl group as defined herein by removal of a hydrogen atom from the heterocyclyl moiety. Representative preferred fused heterocyclylaryl ring systems are as described for the fused arylheterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"fused heteroarylcycloalkenyl" refers to groups derived from fused heteroaryl and cycloalkenyl groups, as defined herein, by removal of a hydrogen atom from the cycloalkenyl moiety. Preferred fused heteroarylcycloalkenyls are those wherein the heteroaryl and cycloalkenyl each contain from about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that there is at least one nitrogen, oxygen or sulfur atom, respectively, as a ring atom. The fused heteroarylcycloalkenyl can be optionally substituted with one or more ring system substituents, where "ring system substituent" is defined herein. The nitrogen of the heteroaryl portion of the fused heteroarylcycloalkenyl can be optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkenyl groups include 5, 6-dihydroquinolinyl, 5, 6-dihydroisoquinolinyl, 5, 6-dihydroquinoxalinyl, 5, 6-dihydroquinazolinyl, 4, 5-dihydro-1H-benzimidazolyl, and 4, 5-dihydrobenzoxazolyl, and the like, wherein the bond to the parent moiety is through a non-aromatic carbon atom.

"fused heterocycloalkenylheteroaryl" refers to a group derived from a fused heterocycloalkenylas defined herein by removing a hydrogen atom from the heteroaryl moiety. Representative fused cycloalkenyl heteroaryls are as described for fused heteroarylcycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"fused heteroarylcycloalkyl" refers to a group derived from fused heteroaryl and cycloalkyl groups as defined herein by removal of a hydrogen atom from the cycloalkyl moiety. Preferred fused heteroarylcycloalkyl groups are those wherein the heteroaryl group contains from about 5 to about 6 ring atoms and the cycloalkyl group also contains from about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that there is at least one nitrogen, oxygen or sulfur atom, respectively, as a ring atom. The fused heteroarylcycloalkyl group may be optionally substituted with one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen of the heteroaryl portion of the fused heteroarylcycloalkyl group may be optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkyl groups include 5, 6, 7, 8-tetrahydroquinolinyl, 5, 6, 7, 8-tetrahydroisoquinolinyl, 5, 6, 7, 8-tetrahydroquinoxalinyl, 5, 6, 7, 8-tetrahydroquinazolinyl, 4, 5, 6, 7-tetrahydro-1H-benzimidazolyl, 4, 5, 6, 7-tetrahydrobenzoxazolyl, 1H-4-oxa-1, 5-naphthyridin-2-onyl (onyl), and 1, 3-dihydroimidazo- [4, 5] -pyridin-2-onyl (onyl), wherein the parent moiety is attached through a non-aromatic carbon atom.

"fused cycloalkylheteroaryl" refers to a group derived from a fused heteroarylcycloalkyl group as defined herein by removal of a hydrogen atom from the heteroaryl moiety. Representative fused cycloalkylheteroaryl groups are as described herein for the fused heteroarylcycloalkyl group, except that the bond to the parent moiety is through an aromatic carbon atom.

"fused heteroarylheterocycloalkenyl" refers to a group derived from fused heteroaryl and heterocycloalkenyl groups as defined herein by removal of a hydrogen atom from the heterocycloalkenyl moiety. Preferred fused heteroarylheterocycloalkenyls are those wherein the heteroaryl contains from about 5 to about 6 ring atoms and the heterocycloalkenyl also contains from about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl or heterocycloalkenyl, respectively, means that there is at least one nitrogen, oxygen or sulfur atom as a ring atom. The fused heteroarylheterocycloalkenyl can be optionally substituted with one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen of the heteroaryl portion of the fused heteroarylheterocycloalkenyl can be optionally oxidized to the corresponding N-oxide. The nitrogen or sulfur atom of the heterocycloalkenyl portion of the fused heteroarylheterocycloalkenyl can be optionally oxidized to an N-oxide, S-oxide, or S, S-dioxide. Representative fused heteroaryl heterocycloalkenyls include 7, 8-dihydro [1, 7] naphthyridinyl, 1, 2-dihydro [2, 7] naphthyridinyl 6, 7-dihydro-3H-imidazo [4, 5-c ] pyridinyl, 1, 2-dihydro-1, 5-naphthyridinyl, 1, 2-dihydro-1, 6-naphthyridinyl, 1, 2-dihydro-1, 7-naphthyridinyl, 1, 2-dihydro-1, 8-naphthyridinyl, 1, 2-dihydro-2, 6-naphthyridinyl, and the like, wherein the parent moiety is attached through a non-aromatic carbon atom.

"fused heterocycloalkenylheteroaryl" refers to a group derived from a fused heteroarylheterocycloalkenyl group as defined herein by the removal of a hydrogen atom from the heteroaryl moiety. Representative fused heterocycloalkenyl heteroaryl groups are as described herein for fused heteroarylheterocycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"fused heteroarylheterocyclyl" refers to groups derived from fused heteroaryl and heterocyclyl groups as defined herein by the removal of a hydrogen atom from the heterocyclyl moiety. Preferred fused heteroarylheterocyclyl groups are those wherein the heteroaryl group contains from about 5 to about 6 ring atoms and the heterocyclyl group also contains from about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl or heterocyclyl respectively means that there is at least one nitrogen, oxygen or sulfur atom as a ring atom. The fused heteroarylheterocyclyl may be optionally substituted with one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen of the heteroaryl portion of the fused heteroarylheterocyclyl may optionally be oxidized to the corresponding N-oxide. The nitrogen or sulfur atom of the heterocyclyl portion of the fused heteroarylheterocyclyl may be optionally oxidized to an N-oxide, S-oxide, or S, S-dioxide. Representative fused heteroaryl heterocyclic groups include 2, 3-dihydro-1H-pyrrolo [3, 4-b ] quinolin-2-yl, 1, 2, 3, 4-tetrahydrobenzo [ b ] [1, 7] naphthyridin-2-yl, 1, 2, 3, 4-tetrahydrobenzo [ b ] [1, 6] naphthyridin-2-yl, 1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4-b ] indol-2-yl, 1, 2, 3, 4-tetrahydro-9H-pyrido [4, 3-b ] indol-2-yl, 2, 3-dihydro-1H-pyrrolo [3, 4-b ] indol-2-yl, 1H-2, 3, 4, 5-tetrahydroazepino [3, 4-b ] indol-2-yl, 1H-2, 3, 4, 5-tetrahydroazepino [4, 3-b ] indol-3-yl, 1H-2, 3, 4, 5-tetrahydroazepino [4, 5-b ] indol-2-yl, 5, 6, 7, 8-tetrahydro [1, 7] naphthyridinyl, 1, 2, 3, 4-tetrahydro [2, 7] naphthyryl, 2, 3-dihydro [1, 4] dioxino [2, 3-b ] pyridyl, 3, 4-dihydro-2H-1-oxa [4, 6] naphthyryl, 4, 5, 6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridyl, 6, 7-dihydro [5, 8] naphthyridinyl, 1, 2, 3, 4-tetrahydro [1, 5] naphthyridinyl, 1, 2, 3, 4-tetrahydro [1, 6] naphthyridinyl, 1, 2, 3, 4-tetrahydro [1, 7] naphthyridinyl, 1, 2, 3, 4-tetrahydro [1, 8] naphthyridinyl, 1, 2, 3, 4-tetrahydro [2, 6] naphthyridinyl, and the like, wherein the bond to the parent moiety is through a non-aromatic carbon atom.

"fused heterocyclylheteroaryl" refers to a group derived from a fused heteroarylheterocyclyl group, as defined herein, by removal of the hydrogen atom of the heteroaryl moiety. Representative fused heterocyclylheteroaryl groups are as described herein for the fused heteroarylheterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"aralkyl" refers to an aryl-alkyl group in which the aryl and alkyl groups are as previously described. Preferred aralkyl groups contain a lower alkyl group. Representative aralkyl groups include benzyl, 2-phenylethyl and naphthylmethyl.

"arylalkenyl" refers to aryl-alkenyl groups in which the aryl and alkenyl groups are as previously described. Preferred aralkenyls contain a lower alkenyl group. Representative aralkenyls include 2-styryl and 2-naphthylvinyl.

"arylalkynyl" refers to an aryl-alkynyl group in which the aryl and alkynyl groups are as previously described. Preferred aralkynyl groups contain a lower alkynyl group. Representative aralkynyl groups include phenylethynyl and naphthylethynyl.

"heteroarylalkyl" refers to a heteroaryl-alkyl group wherein the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Representative heteroaralkyls include picolyl, 2- (furan-3-yl) ethyl, and quinolin-3-ylmethyl.

"Heteroarylalkenyl" refers to heteroaryl-alkenyl groups in which heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl group. Representative heteroaralkenyls include 2- (pyridin-3-yl) vinyl and 2- (quinolin-3-yl) vinyl.

"heteroarylalkynyl" refers to heteroaryl-alkynyl groups in which heteroaryl and alkynyl are as previously described. Preferred heteroarylalkynyls contain a lower alkynyl group. Representative heteroarylalkynyls include pyridin-3-ylethynyl and quinolin-3-ylethynyl.

"hydroxyalkyl" refers to a group wherein alkyl is HO-alkyl as previously defined. Preferred hydroxyalkyl groups contain lower alkyl groups. Representative hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"acyl" refers to a group wherein alkyl is H-CO-or alkyl-CO-as previously described. Preferred acyl groups contain lower alkyl groups. Representative acyl groups include formyl, acetyl, propionyl, 2-methylpropionyl, butyryl, and palmitoyl.

"aroyl" refers to an aryl-CO-group wherein aryl is as previously described. Representative groups include benzoyl and 1-and 2-naphthoyl.

"Heteroaroyl" refers to a heteroaryl-CO-group wherein the heteroaryl group is as previously described. Representative groups include nicotinoyl, pyrrol-2-ylcarbonyl, 1-naphthoyl and 2-naphthoyl.

"alkoxy" refers to an alkyl-O-group wherein alkyl is as previously described. Representative alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.

"aryloxy" refers to an aryl-O-group wherein the aryl group is as previously described. Representative aryloxy groups include phenoxy and naphthoxy.

"aralkoxy" means an aralkyl-O-group wherein the aralkyl group is as previously described. Representative aralkyloxy groups include benzyloxy and 1-or 2-naphthylmethoxy.

"alkylthio" refers to an alkyl-S-group wherein alkyl is as previously described. Representative alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.

"arylthio" means an aryl-S-group wherein aryl is as previously described. Representative arylthio groups include phenylthio and naphthylthio.

"aralkylthio" means an aralkyl-S-group wherein the aralkyl group is as previously described. A representative aralkylthio group is benzylthio.

“Y¹Y²N- "means a substituted or unsubstituted amino group, wherein Y is¹And Y²As previously described. Representative groups include amino (H)₂N-), methylamino, ethylmethylamino, dimethylamino, and diethylamino.

"alkoxycarbonyl" refers to an alkyl-O-CO-group. Representative alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.

"Aryloxycarbonyl" means an aryl-O-CO-group. Representative aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.

"aralkoxycarbonyl" refers to an aralkyl-O-CO-group. A representative aralkoxycarbonyl group is benzyloxycarbonyl.

“Y¹Y²NCO- "means a substituted or unsubstituted carbamoyl group, in which Y is¹And Y²As previously described. A representative group is carbamoyl (H)₂NCO-) and dimethylcarbamoyl (Me)₂NCO-)。

“Y¹Y²NSO₂- "denotes a substituted or unsubstituted aminosulfonyl group, wherein Y¹And Y²As previously described. A representative group is aminosulfonyl (H)₂NSO₂-) and dimethylaminosulfonyl (Me)₂NSO₂-)。

"alkylsulfonyl" means alkyl-SO₂-a group. Preferred groups are those wherein alkyl is lower alkyl.

"Alkylsulfinyl" refers to an alkyl-SO-group. Preferred groups are those wherein alkyl is lower alkyl.

"arylsulfonyl" means aryl-SO₂-a group.

"Arylsulfinyl" refers to an aryl-SO-group.

"halogen" means fluorine, chlorine, bromine or iodine. Preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

"Ring system substituent" means a substituent that can optionally replace a hydrogen atom on an aromatic or non-aromatic ring system. The ring system substituents are selected from aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryldiazo, heteroaryldiazo, amidino, Y¹Y²N-、Y¹Y²N-alkyl-, Y¹Y²NCO-or Y¹Y²NSO₂-, in which Y¹And Y²Independently hydrogen, alkyl, aryl and aralkyl; or in the substituent Y¹Y²N-or Y¹Y²N-alkyl-or Y¹And Y²An acyl group or an aroyl group in (1), Y¹And Y²Is hydrogen, alkyl, aryl or aralkyl. When the ring system is saturated or partially saturated, the "ring system substituent" also includes methylene (H)₂C ═ oxo (O ═) and thio (S ═).

Amido, aroylamino.

By "solvating" is meant the physical association of a compound of the invention with one or more solvent molecules. The physical association includes various degrees of separationAnd covalent bonding, including hydrogen bonding. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "solvates" includes both solution phase and isolatable solvates. Representative solvates include ethanolates, methanolates, and the like. A "hydrate" is one in which one or more solvent molecules is H₂A solvate of O.

"prodrug" means a form of the compound of formula I, including acetal, ester, and zwitterionic forms, suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and which is effective for the purposes of its use. The prodrug is converted in vivo (e.g., by hydrolysis in blood) to yield the parent compound of the above formula. Higuchi and V.stella in "prodrugs as New drug delivery Systems" (Pro-drugs as novel delivery Systems), A.C.S. proceedings volume 14 and Edward B.Roche, edited by "Bioreversible Cariers in drug design" (Bioreversible vehicles in drug design), American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.

Description of the preferred embodiments

A preferred embodiment of the invention is a method of treating a disease which is modulated by the inhibition of the production of factor Xa, comprising administering to a patient suffering from said disease an effective amount of a compound of formula I.

A preferred compound of the invention is a compound of formula I wherein (P12-1) is a single bond.

A preferred compound of the invention is a compound of formula I wherein (P12-2) is a double bond.

A preferred compound of the invention is that wherein R is_aA compound of formula I which is hydrogen.

A preferred compound of the invention is that wherein R is_aIs hydroxy or amino, more preferably R_aA compound of formula I which is hydroxy.

A preferred compound of the invention is that wherein R is₁And R₂Together is ═ NR₉A compound of formula I.

Another preferred compound of the invention is that wherein R is₁And R₂Together are ═ NH of the compounds of formula I.

A preferred compound of the invention is that wherein R is₃A compound of formula I which is hydrogen.

A preferred compound of the invention is that wherein R is₃is-CO₂R₆、-C(O)R₆、-CH₂OR₇or-CH₂SR₇(ii) a More preferably is-CO₂R₆、-CH₂OR₇or-CH₂SR₇(ii) a Most preferably is-CO₂R₆or-CH₂OR₇A compound of formula I.

Another preferred compound of the invention is that wherein R is₃is-CO₂R₆And R is₆A compound of formula I which is lower alkyl.

Another preferred compound of the invention is that wherein R is₃is-CH₂OR₇or-CH₂SR₇And R is₇A compound of formula I which is hydrogen or lower alkyl.

A preferred process of the invention is wherein R is₄A compound of formula I which is hydrogen, alkyl or Q-alkyl, or a group of the formula.

Another preferred compound of the invention is that wherein R is₄A compound of formula I which is lower alkyl or a group of the formula.

Wherein A and B are hydrogen and n is 1.

A preferred compound of the invention is that wherein R is₄A compound of formula I which is Q-alkyl.

Another preferred compound of the invention is that wherein R is₄Is R₇O (lower alkyl) -, compounds of formula I.

A preferred compound of the invention is that wherein R is₄And the thiacyclyl is the compound I.

A preferred compound of the invention is a compound of formula I, wherein R₅Is alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocycloalkenylaryl, fused cycloalkylheteroaryl, fused heterocycloalkenylheteroaryl, fused heterocyclylheteroaryl, aralkyl, heteroaralkyl, aralkenyl, heteroaralkenyl, aralkynyl, or heteroaralynyl; more preferred is fused cycloalkylaryl, fused heterocyclylaryl, fused heterocycloalkenylaryl, fused cycloalkylheteroaryl, fused heterocycloalkenylheteroaryl or fused heterocyclylheteroaryl.

Another preferred compound of the invention is that wherein R is₅Compounds of formula I are cycloalkyl, heterocyclyl, aralkyl or aralkynyl.

A preferred compound of the invention is that wherein R is₅A compound of formula I which is aryl or heteroaryl.

Another preferred compound of the invention is that wherein R is₅A compound of formula I which is phenyl, naphthyl or heteroaryl.

Another preferred compound of the invention is that wherein R is₅Is phenyl substituted by phenyl,Heteroaryl substituted phenyl, phenyl substituted heteroaryl or heteroaryl optionally substituted with heteroaryl.

Another preferred compound of the invention is that wherein R is₆A compound of formula I which is lower alkyl.

Another preferred compound of the invention is that wherein R is₇A compound of formula I which is hydrogen or lower alkyl.

A preferred compound of the invention is that wherein R is₇Compounds of formula I which are Ar (lower alkyl) or heteroaroyl.

Another preferred compound of the invention is that wherein R is₈A compound of formula I which is hydrogen.

Another preferred compound of the invention is that wherein R is₉A compound of formula I which is hydrogen.

A preferred compound of the invention is that of which A, B, R₈And R₉A compound of formula I which is hydrogen.

Another preferred compound of the invention is that wherein R is₁₀A compound of formula I which is lower alkyl.

A preferred compound of the invention is where Q is R₇O-compounds of formula I.

One preferred compound of the invention is a compound of formula I wherein n is 1.

Another preferred compound of the invention is a compound of formula I, wherein

The moiety is in phenyl orThe meta position of the connecting position of the moiety.

Another preferred compound of the invention is a compound of formula I, wherein R_aIs a hydroxyl group, an amino group, more preferably a hydroxyl groupIn thatPara to the moiety, the latter in turn being substituted with phenyl andthe consecutive positions of the moieties are meta.

Another preferred compound of the invention is a compound of formula I wherein Ar is aryl.

Another preferred compound of the invention is a compound of formula I wherein Ar is phenyl.

Also included within the scope of formula I is where R₁And R₂Together is ═ NR₉Wherein R is₉Is R₁₀O₂C-、R₁₀O-, cyano, R₁₀CO-, optionally substituted lower alkyl, nitro or Y¹Y²A compound of N-. Such derivatives per se include biologically active compounds useful in the treatment of diseases which can be modulated by the inhibition of the production of factor Xa in a patient, or as prodrugs which are converted under physiological conditions to such biologically active compounds.

Specific compounds of the invention are selected from:

(Z) -N- [3 (5-carbamimidoyl-2-hydroxyphenyl) allyl ] -4-pyridinyl-3-ylbenzamide;

4-pyridin-3-yl-3- (5-carbamimidoyl) -phenyl) -benzamide bistrifluoroacetate;

2-hydroxy-N- [3- (5-carbamimidoyl-2-phenyl) -propyl ] -4- (1-oxo-pyridin-4-yl) benzamide bistrifluoroacetate;

4- (6-oxo-1, 6-dihydropyridin-3-yl) benzamide trifluoroacetate salt, N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -4- (6-oxo-1, 6-dihydropyridin-3-yl);

n- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -4- (pyridazin-4-yl) benzamide bistrifluoroacetate;

2-chloro-N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -7-chlorobenzothiophene-carboxamide trifluoroacetate;

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4- (6-methoxy-pyridin-3-yl) benzamide trifluoroacetate salt;

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4- (6-oxo-1, 6-dihydropyridin-3-yl) benzamide trifluoroacetate salt;

(E) -biphenyl-4-carboxylic acid [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -amide trifluoroacetate salt;

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4-pyridin-3-yl-benzamide bistrifluoroacetate;

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4-pyridin-4-yl-benzamide bistrifluoroacetate;

(E) -biphenyl-3, 4 '-dicarboxylic acid 3-amide 4' - { [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -amide } trifluoroacetate;

(E) -4-tert-butyl-N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -benzamide trifluoroacetate salt;

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4- (3H-imidazol-4-yl) -benzamide bistrifluoroacetate;

(E) -biphenyl-4, 4 '-dicarboxylic acid 4' -amide 4- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -amide trifluoroacetate salt;

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4- (1H-imidazol-2-yl) -benzamide bistrifluoroacetate;

(E) -3-oxo-2, 3-dihydro-thieno [3, 2-c ] pyridazine-6-carboxylic acid [3- (5-amidino-2-hydroxyphenyl) -allyl ] -amide trifluoroacetate salt

(E) -5-pyridin-2-yl-thiophene-2-carboxylic acid [3- (5-amidino-2-hydroxyphenyl) -allyl ] -amide ditrifluoroacetate

Biphenyl-4-carboxylic acid [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -amide trifluoroacetate salt;

4- (6-methoxy-pyridin-3-yl) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -benzamide trifluoroacetate salt;

biphenyl-3, 4 '-dicarboxylic acid 3-amide 4' - { [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -amide } trifluoroacetate;

4-tert-butyl-N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -benzamide trifluoroacetate salt;

[3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -4- (3H-imidazol-4-yl) -benzamide bistrifluoroacetate;

4- (1H-imidazol-2-yl) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -benzamide ditrifluoroacetate;

5-pyridin-2-yl-thiophene-2-carboxylic acid [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -amide ditrifluoroacetate; and

n- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -4-piperidin-4-yl-benzamide bistrifluoroacetate.

More preferred compounds according to the present invention are 188, 209-211, 213, 217, 231, 276-277, 280-281, 297, 300-301, 306, 310, 321, 340 and 342.

It is to be understood that the invention covers all specific and preferred groups of suitable combinations.

The compounds of formula I may be prepared using or adapting known methods, used hereinbefore or described in the literature, or by using the methods of the invention.

Scheme a illustrates a general procedure for the preparation of intermediates useful in the preparation of the compounds of formula I of the present invention.

Reaction scheme A

Scheme B illustrates a general procedure for converting intermediates prepared according to scheme a into compounds of formula I of the present invention.

Reaction scheme B

Scheme C illustrates the general procedure for the internal conversion between compounds of formula I of the present invention.

Reaction scheme C

Further, wherein R₃Compounds of formula I which are hydroxymethyl can be converted to the corresponding mercaptomethyl compounds by treating the alcohol with an alkyl or aryl sulfonyl halide, replacing the alkyl or aryl sulfonate with NaSH, and then alkylating or acylating the compound to provide other compounds of the invention.

Scheme D illustrates a general method for converting nitrile intermediates to compounds of formula I, as well as another general method for internal conversion between compounds of formula I of the present invention.

Reaction scheme D

Scheme E illustrates yet another general method for the internal conversion between compounds of formula I of the present invention.

Reaction scheme E

Reaction scheme F illustrates the preparation of wherein R₄Is a general procedure for the preparation of the optionally substituted phenethyl compounds of the formula I according to the invention.

Reaction scheme F

Reaction scheme G illustrates the preparation of wherein R₄General procedure for the compounds of formula I according to the invention which are methyl.

Reaction scheme G

Scheme H illustrates a general method for preparing the compounds of the present invention.

Reaction scheme H

Scheme I illustrates a general method for preparing the compounds of the present invention.

Reaction scheme I

It will be clear to those skilled in the art that certain compounds of formula I may exist in isomeric, e.g., geometric, e.g., E or Z, isomeric forms, as well as optical isomers, e.g., R or S, configurations. Geometric isomers include cis and trans alkenyl bearing compounds of the present invention. The various geometric isomers and stereoisomers of the compounds of formula I and mixtures thereof are included within the scope of the present invention.

Such isomers may be isolated from their mixtures using or adapting known methods, such as chromatographic techniques and recrystallisation techniques, or they may be prepared separately from the appropriate intermediate isomers thereof, for example using or adapting the methods described herein.

The compounds of the invention may be used in the form of the free base or acid, or in the form of a pharmaceutically acceptable salt thereof. All of which are included within the scope of the present invention.

In the case where the compounds of the present invention are substituted with basic residues, more convenient acid addition salts may be formed; in practice, the use of the salt form is equivalent to the use of the free base form. Acids which may be used in the preparation of acid addition salts preferably include those which, when combined with the free base, produce a pharmaceutically acceptable salt, i.e., one whose anion is non-toxic to the patient at the salt concentration of the pharmaceutical dosage, so that the beneficial inhibitory effects inherent in the free base on factor Xa are not negated by the adverse effects of the anion. Although pharmaceutically acceptable salts of the basic compounds are preferred, all acid addition salts can be used as the source of the free base, even if the particular salt itself is used as an intermediate, e.g., in the formation of the salt for purification and identification purposes only, or it is used as an intermediate in the preparation of a pharmaceutically acceptable salt by ion exchange methods. The pharmaceutically acceptable salts of the present invention are those derived from the following acids: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts include the following, respectively: hydrohalic acid salts, such as hydrochloride and hydrobromide salts, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-B-hydroxynaphthoate, 2, 5-dihydroxybenzoate, methanesulfonate, isethionate and di-p-toluoyltartaric acid, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinic acid salts.

Alternatively, acid addition salts of the compounds of the invention may be prepared by reaction of the free base with a suitable acid using or adapting known procedures. For example, acid addition salts of the compounds of the invention may be prepared by dissolving the free base in an aqueous or aqueous-alcoholic solution containing the appropriate acid or other suitable solvent, and isolating the salt by evaporating the solution; or by reaction of the free base with an acid in an organic solvent, in which case the salt may be isolated directly or obtained by concentration of the solution.

The acid addition salts of the compounds of the present invention may be regenerated from the salts using or adapting known methods. For example, the parent compounds of the invention may be regenerated from their acid addition salts by treatment with a base, such as aqueous sodium bicarbonate or aqueous ammonia.

In the case where the compounds of the invention are substituted with acidic residues, more convenient base addition salts may be formed; in practice, the use of the salt form is equivalent to the use of the free acid form. Bases which can be used to prepare base addition salts preferably include those which, when combined with the free acid, yield a pharmaceutically acceptable salt (i.e., a salt whose cation is non-toxic to the patient at the pharmaceutical dosage salt concentration) such that the beneficial inhibitory effects inherent in the free acid on factor Xa are not negated by the adverse effects of the cation. Pharmaceutically acceptable salts within the scope of the present invention, including, for example, alkali metal and alkaline earth metal salts, are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N' -dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, tetramethylammonium hydroxide, and the like.

The metal salts of the compounds of the present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the selected metal with the compound in free acid form in an aqueous or organic solvent. The aqueous solvent used may be water or may be a mixture of water and an organic solvent; the organic solvent is preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran or an ester such as ethyl acetate. Such reactions are usually carried out at room temperature, if desired under heating.

Amine salts of the compounds of the present invention may be obtained by contacting an amine with the compound in free acid form in an aqueous or organic solvent. Suitable aqueous solvents include water and mixtures of water with alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, nitriles, such as acetonitrile, or ketones, such as acetone. Salts of amino acids can also be prepared similarly.

Base addition salts of the compounds of the present invention may be regenerated using or adapting known methods. For example, the parent compounds of the invention may be regenerated from their base addition salts by treatment with an acid, such as hydrochloric acid.

Pharmaceutically acceptable salts also include lower alkyl quaternary ammonium salts. According to the invention, quaternary ammonium salts are obtained by the exhaustive alkylation of basic nitrogen atoms, both non-aromatic and aromatic, in compounds, i.e. nitrogen with unbound electron pairs is alkylated with alkylating agents, such as methyl halides, in particular methyl iodide or dimethyl sulfate. Quaternization results in the nitrogen carrying a positive charge and binding to an anion.

It will be clear to those skilled in the art that certain compounds of the present invention are not capable of forming stable salts. However, acid addition salts are likely to be formed when the compounds of the present invention and/or compounds having nitrogen-containing heteroaryl groups contain amino groups as substituents. Preferred acid addition salts of the compounds of the present invention are those in which there are no acid labile groups.

In addition to their use as active compounds, salts of the compounds of the present invention may be employed for the purpose of purifying the compounds, e.g., by separation using techniques well known to those skilled in the art, which exploit differences in solubility of the salts with respect to the parent compound, byproducts, and/or starting materials.

The starting materials and intermediates may be prepared by applying or adapting known procedures, for example those described in the reference examples or their obvious chemical equivalents, or by carrying out the procedures of the invention.

The following illustrative examples illustrate the preparation of the compounds of the present invention, but do not limit the invention.

Chemical shifts in nuclear magnetic resonance (MNR) are expressed in parts per million (ppm) relative to tetramethylsilane. The abbreviations have the following meanings: s is singlet; d is bimodal; t is a triplet; m is multiplet; dd two doublets; ddd is two doublets; dt is double triplet; b is broad peak.

Example 1

Compound 1

To a stirred solution of 3-cyanobenzaldehyde (20g, 153mmol) in 100ml of anhydrous THF was added methyl (triphenylphosphoranylidene) acetate (61.2g, 183mmol) at room temperature under a nitrogen atmosphere. The mixture was allowed to stir at room temperature overnight and then concentrated in vacuo. Chromatography (40% ethyl acetate: hexane) of the crude residue gave 27.3g (96%) of acrylate 1.¹HNMR(CDCl₃，δ)：7.43-7.8(m，5H)，6.47(d，J＝12Hz，1H)，3.8(s，3H).

Example 2

Compound 2

To a stirred solution of compound 1(27.33g) in 150ml ethanol was added 2g of 10% palladium on calcium carbonate. The resulting mixture was hydrogenated under 45PSI of hydrogen pressure in a Parr shaker at room temperature for 8 hours. The mixture was then filtered through a pad of celite and the filtrate was concentrated in vacuo to give 26.93g (98%) of 2 as a clear oil.

¹H NMR(CDCl₃，d)：7.33-7.72(m，4H)，3.66(s，3H)，2.97(t，J＝7.8Hz，2H)，2.62(t，J＝7.8Hz，2H).

Example 3

Compound 3

To a stirred solution of compound 2(16.8g, 89mmol) in 200ml THF: MeOH (2: 1) was added dropwise 9ml 10N sodium hydroxide solution at room temperature. After 2 hours most of the solvent was removed in vacuo and 30ml of 5N hydrochloric acid was added. The resulting mixture was extracted several times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated to give 9.8g (63%) of pure white solid 3.¹H NMR(CDCl₃，δ)：7.35-7.55(m，4H)，2.98(t，J＝7.9Hz，2H)，2.7(t，J＝7.9Hz，2H).

Example 4

Compound 4

To a stirred solution of carboxylic acid 3(8.2g, 47mmol) and DMF (0.5ml) in dry dichloromethane was added oxalyl chloride (6.1ml, 70mmol) dropwise at room temperature under nitrogen. After 1 hour, bubbling was stopped and the solvent and excess oxalyl chloride were removed in vacuo. The residue was redissolved in 100ml of anhydrous dichloromethane and cooled to 0 ℃. Mercaptopyridine (5.6g, 50mmol) and triethylamine (7.9ml, 56mmol) were added. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was diluted with dichloromethane and washed with 1N sodium hydroxide. The organic layer was dried over magnesium sulfate, filtered and concentrated. Chromatography of the residue (50% ethyl acetate: hexane as eluent) gave 5.12g (84%) of thioester 4 as a yellow oil.

¹H NMR(CDCl₃，δ)：8.63(d，J＝9Hz，1H)，7.7-7.8(m，1H)，7.27-7.62(m，6H)，3.05(s，4H).

Example 5

Compound 5

Magnesium sulfate (19.55g, 162mmol) was added to a stirred solution of cinnamaldehyde (10.2ml, 81mmol) and p-anisidine (10g, 81mmol) in 200ml dichloromethane at 0 ℃ under a nitrogen atmosphere. After 4 hours, the mixture was filtered and the filtrate was concentrated to give 18.87g (98%) of imine compound 5 as a yellow-brown solid.¹H NMR(CDCl₃，δ)：8.28(m，1H)，7.52(m，2H)，7.38(m，3H)，7.2(m，2H)，7.12(m，2H)，6.93(m，2H)，3,82(s，3H).

Example 6

Compound 6

To a stirred solution of thioester 5(7g, 26mmol) in dry dichloromethane (120ml) was added titanium tetrachloride (26.1ml of a 1M solution in dichloromethane) at-78 deg.C under a nitrogen atmosphere. After 15 min triethylamine (3.6ml, 26mmol) was added dropwise. The resulting mixture was stirred at-78 ℃ for half an hour. A solution of imine 1 (4.42g, 19mmol in 20ml of dichloromethane) is then added dropwise. The mixture was allowed to warm to 0 ℃. After 1.5 hours at this temperature, the mixture was quenched with saturated sodium bicarbonate solution and partitioned in water. The organic layer was washed with 1N sodium hydroxide, dried over magnesium sulfate and concentrated in vacuo. Chromatography of the crude product (eluent: 40% ethyl acetate: hexane) gave 2.42g (32%) of a 5: 1 mixture of trans/cis b-lactams 6a and 6b as a gum. Major trans isomer 6 a:¹H NMR(CDCl，δ)：7.2-7.6(m，11H)，6.8(d，J＝11Hz，2H)，6.65(d，J＝15.8Hz，1H)，6.2(dd，J＝15.8，7.9Hz，1H)，4.32(m，1H)，3.72(s，3H)，3.42(m，3H).

example 7

Compound 7

To a stirred solution of 6a, 6b (1.5g, 3.8mmol) in 60ml THF/CH at-20 deg.C₃To the solution in CN (1/3) was added a solution of cerium ammonium nitrate (CAN, 3.13g, 5.7mmol in 10ml water). After 15 minutes, an additional 5ml of 1.5g CAN in water was added. After a further 30 minutes, the mixture was quenched with saturated sodium bicarbonate solution and allowed to warm to room temperature. The resulting suspension was filtered through a pad of celite, which was washed several times with dichloromethane (200 ml total). The filtrate layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the crude product (eluent 60% ethyl acetate: hexane) gave 476mg (43%) of the pure trans isomer 7a and 85mg of a mixture of cis-7 b and trans-7 a isomers.

Major trans isomer 7 a:¹H NMR(CDCl₃，d)：7.17-7.65(m，9H)，6.52(d，J＝15.8Hz，1H)，6.25(s，1H)，6.14(dd，J＝15.8，7.9Hz，1H)，3.97(m，1H)，3-3.33(m，3H).

minor cis isomer 7 b:¹H NMR(CDCl₃，d)：7.21-7.52(m，9H)，6.62(d，J＝15.8Hz，1H)，6.45(s，1H)，6.1(dd，J＝15.8，7.9Hz，1H)，4.46(m，1H).3.7(m，1H)，3.02-3.17(m，1H)，2.8-2.93(m，1H).

example 8

Compound 8

To a stirred solution of trans- β -lactam 7a in dry dichloromethane was added triethylamine (4.04ml, 29mmol) dropwise at room temperature under nitrogen. Bibenzoyl chloride (5.05g, 23.2mmol) was added followed by DMAP (50 mg). After 30 minutes, the mixture was diluted with dichloromethane and washed with 1N hydrochloric acid. The organic layer was dried over sodium sulfate, filtered and concentrated. Chromatography of the crude product (eluent 30% ethyl acetate: hexane) gave 2.19g (81%) of product 8 as a solid.¹HNMR(CDCl₃，δ)：8.06(m，2H)，7.2-7.75(m，16H)，6.67(d，J＝15.8.Hz，1H)，6.23(dd，J＝15.8，7.9Hz，1H)，4.63(m，1H)，3.46(m，1H)，3.1-3.3(m，2H).

Example 9

Compound 9

To a stirred solution of β -lactam 8(2.19g, 4.7mmol) in 50ml THF was added dropwise a 1N sodium hydroxide solution (13.6ml) at room temperature. After 2 hours most of the THF was removed in vacuo and 20ml of 1N hydrochloric acid were added. The resulting mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by RPHPLC (acetonitrile: water, 0.1% TFA, 40-100 gradient) and the product-containing fractions were lyophilized to give 1.1g (50%) of carboxylic acid 9 as a white solid.

¹H NMR(CDCl₃，δ)：7.18-7.97(m，18H)，6.61(d，J＝15.8Hz，1H)，6.2(dd，J＝15.8，7.9Hz，1H)，5.14(m，1H)，3-3.22(m，3H).

Example 10

Compound 10

To a solution of carboxylic acid 9(105mg, 0.22mmol) in 3ml of dry methanol at room temperature was added molecular sieves (ca. 50 mg). Hydrogen chloride gas was then introduced for about 2 minutes. The mixture was stirred at room temperature overnight and then concentrated under a stream of nitrogen. To the residue was then added a solution of ammonia in methanol (3ml of a 7N solution), the mixture was refluxed for 1.5 hours, then cooled and the solvent removed in vacuo. The residue was purified by RPHPLC (acetonitrile: water: 0.1% TFA, 40-100 gradient) and the product-containing fractions were lyophilized to yield 73mg (53%) of product 10 as a white solid.¹H NMR(DMSO-d₆，δ)：8.7(d，J＝8.6Hz，1H)，7.92(d，J＝9Hz，2H)，7.78(d，J＝9Hz，2H)，7.75-7.21(m，14H)，6.67(d，J＝16.1Hz，1H)，6.4(dd，J＝16.1，7.8Hz，1H)，4.98(dd，J＝16.1，7.8Hz，1H)，3.46(s，3H)，3.25-3.18(m，1H)，3.05-2.88(m，2H).

Example 11

Compound 11

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. Benzoyl chloride was used in place of 4-bibenzoyl chloride in the beta-lactam acylation step. The final product 11 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(MeOH-d₄，δ)：8.61(d，J＝11.3Hz，1H)，7.83(d，J＝7.5Hz，2H)，7.15-7.67(m，14H)，6.67(d，J＝15.8Hz，1H)，6.3(dd，J＝15.8，7.9Hz，1H)，4.98(m，1H)，3.55(s，3H)，3.27(m，1H)，3.1(m，2H).

Example 12

Compound 12

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. The 4-bibenzoyl chloride is replaced by o-toluoyl chloride in the beta-lactam acylation step. The final product 12 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，d)：9.3(s，1H)，9.15(s，1H)，8.7(d，J＝7.6Hz，1H)，7.7(d，J＝8Hz，2H)，7.6(d，J＝9Hz，2H)，7.2-7.6(m，12H)，6.9(d，J＝8Hz，1H)，6.6(d，J＝15Hz，1H)，6.35(dd，J＝15，6Hz，1H)，4.9(dd，J＝15，6Hz，1H)，3.55(s，3H)，3.2-3.3(m，1H)，2.8-3(m，1H)，2.3(s，3H).

Example 13

Compound 13

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. The 4-bibenzoyl chloride is replaced by m-toluoyl chloride in the beta-lactam acylation step. The final product 13 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，d)：9.3(s，1H)，9.2(s，1H)，8.7(d，J＝7.6Hz，1H)，7.7(d，J＝8Hz，2H)，7.6(d，J＝9Hz，2H)，7.2-7.6(m，12H)，6.9(d，J＝8Hz，1H)，6.6(d，J＝15Hz，1H)，6.35(dd，J＝15，6Hz，1H)，4.9(dd，J＝16，6Hz，1H)，3.6(s，3H)，3.2-3.3(m，1H)，2.8-3(m，1H)，2.35(s，3H).

Other compounds prepared using similar methods using appropriate starting materials include the following:

example 14

Compound 14

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. 4-bibenzoyl chloride is replaced by 4' -ethyl-4-bibenzoyl chloride in the step of acylation of the beta-lactam. The final product 14 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.3(s，1H)，9.15(s，1H)，8.9(d，J＝7.6Hz，1H)，8.2(d，J＝8Hz，2H)，8(d，J＝9Hz，2H)，7.4-7.9(m，12H)，7.2(d，J＝8Hz，1H)，6.9(d，J＝15Hz，1H)，6.6(dd，J＝15，6Hz，1H)，5.2(dd，J＝16，6Hz，1H)，3.7(s，3H)，3.4-3.5(m，1H)，3.1-3.2(m，1H)，2.85(q，2H)，1.4(t，3H).

Example 15

Compound 15

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. 3 ', 4' -dimethoxy-4-bibenzoyl chloride in place of 4-bibenzoyl chloride in the step of beta-lactam acylation. The final product 15 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，d)：9.5(s，1H)，9.3(s，1H)，8.9(d，J＝7.6Hz，1H)，8.1(d，J＝8Hz，2H)，7.9(d，J＝9Hz，2H)，7.8(s，2H)，7.4-7.7(m，11H)，7.25(d，J＝8Hz，1H)，6.6(d，J＝15Hz，1H)，6.4(dd，J＝15，6Hz，1H)，4(s，3H)，3.9(s，3H)，3.7(s，3H)，3.4-3.5(m，1H)，3.2-3.4(m，1H).

Example 16

Compound 16

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. 4-Bibenzoyl chloride was replaced by 4- (2' -pyridyl) benzoyl chloride in the step of beta-lactam acylation. The final product 16 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.5(s，1H)，9.3(s，1H)，8.9(d，J＝7.6Hz，1H)，8.8(s，1H)，8.4(d，J＝8Hz，2H)，8.3(d，J＝9Hz，1H)，8.1(d，J＝8Hz，2H)，7.9(s，2H)，7.4-7.8(m，10H)，7.4(d，J＝8Hz，1H)，6.9(d，J＝15Hz，1H)，6.6(dd，J＝15，6Hz，1H)，5.2(dd，J＝16，6Hz，1H)，3.7(s，3H)，3.4-3.5(m，1H)，3.2-3.4(m，1H).

Example 17

Compound 17

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. 4-Bibenzoyl chloride was replaced by 4- (3' -pyridyl) benzoyl chloride in the step of beta-lactam acylation. The final product 17 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.5(s，1H)，9.3(s，1H)，8.9(d，J＝7.6Hz，1H)，8.5(s，1H)，8.2(d，J＝8Hz，2H)，8.1(d，J＝9Hz，2H)，8(d，J＝8Hz，1H)，7.9(s，2H)，7.4-7.8(m，9H)，7.4(d，J＝8Hz，1H)，6.9(d，J＝15Hz，1H)，6.6(dd，J＝15，6Hz，1H)，5.2(dd，J＝16，6Hz，1H)，3.7(s，3H)，3.4-3.5(m，1H)，3.2-3.4(m，1H).

Example 18

Compound 18

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. 4-Bibenzoyl chloride is replaced by 4- (4' -pyridyl) benzoyl chloride in the step of acylation of the beta-lactam. The final product 18 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.5(s，1H)，9.3(s，1H)，9(d，J＝7.6Hz，1H)，8.2(s，4H)，7.8(s，2H)，7.5-7.8(m，11H)，7.4(d，J＝8Hz，1H)，6.9(d，J＝15Hz，1H)，6.6(dd，J＝15，6Hz，1H)，5.2(dd，J＝16，6Hz，1H)，3.7(s，3H)，3.4-3.5(m，1H)，3.2-3.4(m，1H).

Example 19

Compound 19

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. The 4-bibenzoyl chloride is replaced by 2' -methyl-4-bibenzoyl chloride in the step of acylation of the beta-lactam. The final product 19 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.25(s，1H)，9.03(s，1H)，8.71(d，J＝8.7Hz，1H)，7.86(d，J＝8Hz，2H)，7.61(d，J＝8Hz，2H)，7.6-7.12(m，13H)，6.67(d，J＝15.9Hz，1H)，6.42(dd，J＝15.9，7.8Hz，1H)，5.0(dd，J＝16，7.9Hz，1H)，3.32(s，3H)，3.3-3.15(m，1H)，3.11-2.9(m，2H)，2.21(s，3H).

Example 20

Compound 20

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. 3' -methyl-4-bibenzoyl chloride is used instead of 4-bibenzoyl chloride in the step of acylation of the beta-lactam. The final product 20 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.25(s，1H)，8.99(s，1H)，8.68(d，J＝8.7Hz，1H)，7.9(d，J＝9Hz，1H)，7.75(d，J＝9Hz，1H)，7.68-7.15(m，13H)，6.68(d，J＝15.9Hz，1H)，6.4(dd，J＝15.9，7.8Hz，1H)，5.0(dd，J＝16，7.9Hz，1H)，3.46(s，3H)，3.28-3.18(m，1H)，3.1-2.9(m，2H)，2.36(s，3H).

Example 21

Compound 21

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. The 4-bibenzoyl chloride is replaced by 2' -methoxy-4-bibenzoyl chloride in the step of acylation of the beta-lactam. The final product 21 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.25(s，1H)，9.03(s，1H)，8.76(δ，J＝8.7Hz，1H)，7.83(d，J＝9.5Hz，2H)，7.65-6.95(m，15H)，6.64(d，J＝15.9Hz，1H)，6.4(dd，J＝15.9，7.8Hz，1H)，4.99(dd，J＝16，7.9Hz，1H)，3.75(s，3H)，3.46(s，3H)，3.3-3.17(m，1H)，3.1-2.9(m，2H).

Example 22

Compound 22

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. The 4-bibenzoyl chloride is replaced by 3' -methoxy-4-bibenzoyl chloride in the step of acylation of the beta-lactam. The final product 22 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.23(s，1H)，8.96(s，1H)，8.69(d，J＝8.7Hz，1H)，7.9(d，J＝9.6Hz，2H)，7.68-7.18(m，12H)，6.96(dd，J＝9.6，2Hz，1H)，6.64(d，J＝15.9Hz，1H)，6.39(ddJ＝15.9，7.8Hz，1H)，4.98(dd，J＝16，7.9Hz，1H)，3.81(s，3H)，3.47(s，3H)，3.28-3.17(m，1H)，3.08-2.86(m，2H).

Example 23

Compound 23

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. The 4-bibenzoyl chloride is replaced by 2-naphthoyl chloride in the step of acylation of the beta-lactam. The final product 23 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.24(s，1H)，9.02(s，1H)，8.83(d，J＝8.6Hz，1H)，8.4(s，1H)，8.08-7.85(m，4H)，7.68-7.2(m，12H)，6.68(d，J＝15.8Hz，1H)，6.43(dd，J＝15.8，7.8Hz，1H)，5.03(dd，J＝15.8，7.8Hz，1H)，3.46(s，3H)，3.28-3.2(m，1H)，3.13-2.95(m，2H).

Example 24

Compound 24

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. The 4-bibenzoyl chloride is replaced by 1-naphthoyl chloride in the step of acylation of the beta-lactam. The final product 24 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.27(s，1H)，9.11(s，1H)，8.88(d，J＝8.67Hz，1H)，8.18-8.07(m，1H)，8.05-7.9(m，2H)，7.7-7.2(m，13H)，6.73(d，J＝15.9Hz，1H)，6.4(dd，J＝15.9，7.8Hz，1H)，5.07(dd，J＝16，7.9Hz，1H)，3.52(s，3H)，3.28-3.17(m，1H)，3.12-2.95(m，2H).

Example 25

Compound 25

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. 3' -ethyl-4-bibenzoyl chloride was used instead of 4-bibenzoyl chloride in the step of acylation of the beta-lactam. The final product 25 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.25(s，1H)，9.05(s，1H)，8.68(d，J＝8.6Hz，1H)，7.88(d，J＝9Hz，2H)，7.76(d，J＝9Hz，2H)，7.62(m，2H)，7.55-7.15(m，11H)，6.66(d，J＝16Hz，1H)，6.4(dd，J＝16，7.8Hz，1H)，4.96(dd，J＝16，7.8Hz，1H)，3.47(s，3H)，3.3-3.18(m，1H)，3.1-2.88(m，2H)，2.67(q，J＝8.5Hz，2H)，1.22(t，J＝8.5Hz，3H).

Example 26

Compound 26

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. 4-bibenzoyl chloride is replaced by 4' -methoxy-4-bibenzoyl chloride in the step of acylation of the beta-lactam. The final product 26 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.23(s，1H)，8.96(s，1H)，8.66(d，J＝8.7Hz，1H)，7.88(d，J＝9.1Hz，2H)，7.72-7.22(m，11H)，7.03(d，J＝8.7Hz，2H)，6.64(d，J＝16.1Hz，1H)，6.4(dd，J＝16.1，7.9Hz，1H)，4.97(dd，J＝16.1，7.9Hz，1H)，3.77(s，3H)，3.46(s，3H)，3.28-3.15(m，1H)，3.08-2.88(m，2H).

Example 27

Compound 27

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. The 4-bibenzoyl chloride is replaced by 2 ', 4' -dimethoxy-4-bibenzoyl chloride in the step of acylation of the beta-lactam. The final product 27 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.23(s，1H)，9.07(s，1H)，8.63(d，J＝9Hz，1H)，7.81(d，J＝8.9Hz，2H)，7.68-7.15(m，14H)，6.72-6.52(m，1H)，6.45-6.3(m，1H)，5.04-4.9(m，1H)3.78(s，3H)，3.75(s，3H)，3.51(s，3H)，3.21-3.15(m，1H)，3.08-2.85(m，2H).

Example 28

Compound 28

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. The 4-bibenzoyl chloride is replaced by 2' -ethyl-4-bibenzoyl chloride in the step of acylation of the beta-lactam. The final product 28 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.25(s，1H)，8.92(s，1H)，8.69(d，J＝8.7Hz，1H)，7.78(d，J＝9Hz，2H)，7.68-7.08(m，15H)，6.65(d，J＝15.9Hz，1H)，6.38(dd，J＝15.9，7.8Hz，1H)，5.0(dd，J＝16，7.9Hz，1H)，3.46(s，3H)，3.28-3.18(m，1H)，2.52(q，J＝9.6Hz，2H)，0.98(t，J＝9.6Hz，3H).

Example 29

Compound 29

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. 4-bibenzoyl chloride is replaced by 4' -methyl-4-bibenzoyl chloride in the step of acylation of the beta-lactam. The final product 29 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.22(s，1H)，8.91(s，1H)，8.68(d，J＝8.7Hz，1H)，7.85(d，J＝9Hz，2H)，7.75(d，J＝9Hz，2H)，7.65-7.2(m，13H)，6.65(d，J＝15.9Hz，1H)，6.39(dd，J＝15.9，7.8Hz，1H)，4.99(dd，J＝16，7.9Hz，1H)，3.46(s，3H)，3.28-3.18(m，1H)，3.08-2.88(m，2H)，2.35(s，3H).

Example 30

Compound 30

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. 3' -ethoxy-4-bibenzoyl chloride was used instead of 4-bibenzoyl chloride in the step of acylation of the beta-lactam. The final product 30 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.22(s，1H)，9.05(s，1H)，8.7(d，J＝8.7Hz，1H)，7.88(d，J＝9Hz，2H)，7.76(d，J＝9Hz，2H)，7.68-7.12(m，12H)，6.98-6.85(m，1H)，6.67(d，J＝16Hz，1H)，6.4(dd，J＝16，7.8Hz，1H)，5.01(dd，J＝16，7.8Hz，1H)，4.08(q，J＝7.5Hz，2H)，3.45(s，3H)，3.25-3.15(m，1H)，3.08-2.89(m，2H)，1.32(t，J＝7.5Hz，2H).

Example 31

Compound 31

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. 4-bibenzoyl chloride is replaced by 4' -ethoxy-4-bibenzoyl chloride in the step of acylation of the beta-lactam. The final product 31 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.26(s，1H)，9.02(s，1H)，8.64(d，J＝8.7Hz，1H)，7.86(d，J＝9Hz，2H)，7.72(d，J＝9Hz，2H)，7.7-7.22(m，11H)，7.01(d，J＝10.4Hz，2H)，6.64(d，J＝15.9Hz，1H)，6.38(dd，J＝15.9，7.8Hz，1H)，4.98(dd，J＝16，7.8Hz，1H)，4.06(q，J＝8.2Hz，2H)，3.45(s，3H)，3.3-3.18(m，1H)，3.08-2.85(m，2H)，1.32(t，J＝8.2Hz，3H).

Example 32

Compound 32

Starting from imine 5 and thioester 4, this compound was prepared in a manner analogous to compound 10 above. The 4-bibenzoyl chloride is replaced by 2' -ethoxy-4-bibenzoyl chloride in the step of acylation of the beta-lactam. The final product 32 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.24(s，1H)，9.11(s，1H)，8.68(d，J＝8.7Hz，1H)，7.85(d，J＝9Hz，2H)，7.6(d，J＝9Hz，2H)，7.59-6.95(m，13H)，6.65(d，J＝15.9Hz，1H)，6.39(dd，J＝15.9，7.8Hz，1H)，4.98(dd，J＝16，7.8Hz，1H)，4.03(q，J＝8.1Hz，2H)，3.47(s，3H)，3.28-3.18(m，1H)，3.1-2.88(m，2H)，1.24(t，J＝8.1Hz，3H).

Example 33

Compound 33

To a stirred solution of 2-naphthaldehyde (20g, 0.13mol) in 200ml of dichloromethane was added p-anisidine (15.8g, 0.13mol) followed by anhydrous magnesium sulfate (16.9g, 0.14mol) at room temperature. After 3.5 h, the mixture was filtered and the filtrate was concentrated in vacuo to give 31.5g (92%) of imine 33.

¹H NMR(CDCl₃，δ)：8.64(s，1H)，8.19(m，2H)，7.78-7.98(m，3H)，7.43-7.56(m，2H)，7.32(m，2H)，6.96(m，2H)，3.83(s，3H).

Example 34

Compound 34

Prepared as described for compound 33 using trans-3- (2' -naphthyl) acrolein, p-anisidine and anhydrous magnesium sulfate.

¹H NMR(CDCl₃，δ)：8.35(d，J＝9Hz，1H)，7.78-7.9(m，4H)，7.72(m，1H)，7.5(m，2H)，7.25(m，4H)，6.93(m，2H)，3.82(s，3H).

Example 35

Compound 35

Prepared as described for compound 33 using trans-3- (4' -biphenyl) acrolein, p-anisidine and anhydrous magnesium sulfate.

¹H NMR(CDCl₃，δ)：8.33(d，J＝9Hz，1H)，7.2-7.68(m，13H)，6.9(m，2H)，3.82(s，3H).

Example 36

Compound 36

Prepared as described for compound 33 using 4-biphenylcarboxaldehyde, p-anisidine and anhydrous magnesium sulfate.

¹H NMR(CDCl₃，δ)：8.52(s，1H)，7.97(m，2H)，7.62-7.73(m，4H)，7.35-7.52(m，3H)，7.27(m，2H)，6.95(m，2H)，3.85(s，3H).

Example 37

Compound 37

This compound was prepared in analogy to compound 10, using imine 33 and thioester 4. In the beta-lactam acylation step, 4-bibenzoyl chloride is replaced with benzoyl chloride. The final product 37 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(MeOH-d₄，δ)：9.01(d，J＝9.4Hz，1H)，7.77-7.98(m，6H)，7.43-7.67(m，9H)，5.53(m，1H)，3.56(m，1H)，3.54(s，3H)，3.1(m，1H)，2.81(m，1H).

Example 38

Compound 38

This compound was prepared in analogy to compound 10, using imine 34 and thioester 4. In the beta-lactam acylation step, 4-bibenzoyl chloride is replaced with benzoyl chloride. The final product 38 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.27(s，2H)，9.1(s，2H)，8.72(d，1H)，7.4-7.95(m，16H)，6.86(d，J＝18Hz，1H)，6.54(dd，J＝10，6Hz，1H)，5.03(m，1H)，3.48(s，3H)，3.32(m，1H)，3.04(m，2H).

Example 39

Compound 39

This compound was prepared in analogy to compound 10, using imine 35 and thioester 4. In the beta-lactam acylation step, 4-bibenzoyl chloride is replaced with benzoyl chloride. The final product 39 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.25(s，2H)，9.11(s，2H)，8,74(d，1H)，7.30-8(m，22H)，6.23(d，J＝18Hz，1H)，6.47(dd，J＝18，6Hz，1H)，5.04(m，1H)，3.49(s，3H)，3.3(m，1H)，3.03(m，2H).

Example 40

Compound 40

This compound was prepared in analogy to compound 10, using imine 36 and thioester 4. In the beta-lactam acylation step, 4-bibenzoyl chloride is replaced with benzoyl chloride. The final product 40 was purified by reverse phase HPLC (acetonitrile: water, 0.1% TFA) and lyophilized.

¹H NMR(DMSO-d₆，δ)：9.23(s，2H)，9.05(s，2H)，8.97(s，2H)，7.28-7.8(m，18H)，5.35(t，1H)，3.42(s，3H)，3.31(m，1H)，2.89(dd，1H)，2.6(dd，1H).

EXAMPLE 41

Compound 41

To a stirred solution of carboxylic acid 9(980mg, 2mmol) and triethylamine (0.44ml, 3.2mmol) in dry THF at 0 deg.C was added dropwise isobutyl chloroformate (0.39ml, 3 mmol). For 15 min, sodium borohydride solution (153mg, 4mmol of 5ml aqueous solution) was added dropwise. The mixture was allowed to warm to room temperature. After 1 hour, most of the THF was removed in vacuo. Then, water was added thereto, and extraction was performed with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography (eluent 35% ethyl acetate: hexane) to give 720mg (76%) of alcohol 41.¹H NMR(CDCl₃，δ)：7.92(d，J＝9Hz，2H)，7.2-7.72(m，16H)，6.67(d，J＝15.5Hz，1H)，6.27(dd，J＝15.5，7.8Hz，1H)，4.94(m，1H)，3.88(m，1H)，3.5(m，1H)，3.12(m，1H)，2.82-3.03(m，2H)，1.95(m，1H).

Example 42

Compound 42

To a stirred solution of alcohol 41(106mg, 0.22mmol) in 3ml of dry methanol at room temperature was added molecular sieves (ca. 50 mg). Hydrogen chloride gas was then introduced for 2 minutes. The mixture was stirred at room temperature overnight and then concentrated under a stream of nitrogen. To the residue was then added a solution of ammonia in methanol (3ml of a 7N solution) and the mixture was refluxed for 1.5 hours, allowed to cool and the solvent removed in vacuo. The residue was purified by RPHPLC (acetonitrile: water, 0.1% TFA, 40-100 gradient) and the product-containing fractions were lyophilized to give 29mg (22%) of the trifluoroacetate salt product 42.

Example 43

Compound 43

To a stirred solution of the alcohol compound (88mg, 0.2mmol) in 2ml 2: 1 THF: DMF at 0 deg.C under nitrogen was added sodium hydride (15mg of a 60% dispersion, 0.4 mmol). After 15 min, iodomethane (0.02ml, 0.3mmol) was added and the mixture was allowed to warm to room temperature. After 2 hours, the mixture was quenched with saturated sodium bicarbonate solution. Most of the THF was removed in vacuo and the residue was diluted with water and extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated. Chromatography of the crude product (35% ethyl acetate: hexane as eluent) gave 21mg (23%) of product 43 and 34mg of recovered alcohol 41.¹H NMR(CDCl₃，δ)：7.93(d，J＝9.3Hz，2H)，7.15-7.83(m，16H)，6.57(d，J＝15.8Hz，1H)，6.22(dd，J＝15.8，6.8Hz，1H)，5(m，1H)，3.75(m，1H)，3.42(s，3H)，3.27(m，1H)，2.87-3.03(m，2H)，2.12(m，1H).

Example 44

Compound 44

To a stirred solution of compound 43(20mg, 0.04mmol) in 1.5ml of 2: 1 pyridine triethylamine was passed hydrogen sulfide gas over for about 1 minute. The mixture was stirred at room temperature overnight, then concentrated under a stream of nitrogen and recovered into 2ml of dichloromethane. Methyl iodide (1ml) was added and the mixture was refluxed for 1 hour. The solvent was then removed in vacuo and the residue was taken up in 2ml of methanol and ammonium acetate (30mg) was added. The resulting mixture was refluxed for 1 hour and then allowed to cool. The solvent was removed in vacuo and the residue was purified by RPHPLC (acetonitrile: water, 0.1% TFA, 40-100 gradient) and the product-containing fractions were lyophilized to give 13mg (51%) of the trifluoroacetate salt product 44.¹H NMR(MeOH-d₄，δ)：8.47(d，J＝7.9Hz，1H)，7.95(d，J＝8Hz，2H)，7.78(d，J＝8Hz，2H)，7.17-7.73(m，14H)，6.55(d，J＝15.8Hz，1H)，6.31(dd，J＝15.8，7.9Hz，1H)，4.77(m，1H)，3.7(dd，J＝9.5，3.1Hz，1H)，3.47(dd，J＝9.5，3.1Hz，1H)，3(d，J＝7.9Hz，2H)，2.35(m，1H).

Example 45

Compound 45

A mixture of alcohol 41(480mg, 1mmol), pyridine (0.40ml, 4.9mmol) and acetic anhydride (0.12ml, 1.2mmol) was stirred at room temperature overnight. The next day, 3 drops of pyridine and acetic anhydride were added. The next day, the reaction was still incomplete, so 4mg DMAP was added. After 1 hour, the reaction was complete as monitored by thin layer chromatography. The mixture was diluted with dichloromethane and washed with 0.1N hydrochloric acid solution. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 520mg of compound 45.¹HNMR(CDCl₃，δ)：7.98(d，J＝8Hz，2H)，7.73(d，J＝8Hz，2H)，7.67(d，J＝8Hz，2H)，7.17-7.58(m，12H)，6.94(d，1H)，6.55(d，J＝18Hz，1H)，6.21(dd，J＝18，5Hz，1H)，5.1(m，1H)，4.38(m，1H)，4.08(m，1H)，2.68-2.97(m，2H)，2.51(m，1H).

Example 46

Compound 46

Compound 45 is converted to the corresponding amidine 46 by treatment with hydrogen sulfide, methyl iodide, ammonium acetate in sequence as described for the conversion of compound 43 to compound 44. Product 46 was purified by RPHPLC and isolated as its trifluoroacetate salt.¹H NMR(DMSO-d₆，δ)：9.31(s，2H)，8.97(s，2H)，8.7(d，1H)，7.18-8(m，18H)，6.6(d，J＝18Hz，1H)，6.40(dd，J＝18，6Hz，1H)，4.83(m，1H)，4.02(m，1H)，3.84(m，2H)，2.95(m，1H)，2.57(m，1H)，1.93(s，3H).

Example 47

Compound 47

Treatment with hydrogen sulfide, methyl iodide, ammonium acetate in sequence converts carboxylic acid 9 to the corresponding amidine 47 as described in the conversion of compound 43 to compound 44. Product 47 was purified by RPHPLC and isolated as its trifluoroacetate salt.¹H NMR(MeOH-d₄，δ)：8(d，J＝9Hz，2H)，7.82(d，J＝9Hz，2H)，7.22-7.77(m，14H)，6.73(d，J＝15.8Hz，1H)，6.4(dd，J＝15.8，7.9Hz，1H)，4.95(m，1H)，3.08-3.45(m，3H).

Example 49

Compound 49

To a stirred solution of carboxylic acid 48(120mg, 0.29mmol) in 5ml of anhydrous dichloromethane was added triethylamine (0.05ml, 0.38mmol) at room temperature under nitrogen, followed by dropwise addition of isopropyl chloride (0.38ml, 1M in toluene). After 30 min, DMAP (18mg, 0.15mmol) was added and the mixture was allowed to stir at room temperature for 1.5 h. The mixture was then diluted with dichloromethane and washed with 1N hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated. Chromatography of the crude product (eluent: 40% ethyl acetate: hexane) gave 44mg (33%) of the corresponding isopropyl ester. This compound was converted to the corresponding amidine 49 by treatment with hydrogen sulfide, methyl iodide, ammonium acetate in sequence as described for the conversion of compound 43 to compound 44. Product 49 was purified by RPHPLC and isolated to give its trifluoroacetate salt.¹H NMR(MeOH-d₄，δ)：8.6(d，J＝7.9Hz，1H)，7.85(d，J＝8Hz，2H)，7.16-7.7(m，12H)，6.69(d，J＝15.8Hz，1H)，6.32(dd，J＝15.8，7.9Hz，1H)，4.98(m，1H)，4.85(m，1H)，3.23(m，1H)，3.08(m，2H)，1.07(d，J＝6Hz，3H)，0.97(d，J＝6Hz，3H).

Example 50

Compound 50

This compound was prepared as described for the conversion of compound 43 to compound 44 by the sequential treatment of compound 48 with hydrogen sulfide, methyl iodide, ammonium acetate to the corresponding amidine. Product 50 was purified by RPHPLC to isolate its trifluoroacetate salt.¹H NMR (methanol-d)₄，δ)8.6(d，J＝7.9Hz，1H)，7.85(d，J＝8Hz，2H)，7.16-7.7(m，12H)，6.69(d，J＝15.8Hz，1H)，6.32(dd，J＝15.8，7.9Hz，1H)，4.98(m，1H)，4.85(m，1H)，3.23(m，1H)，3.08(m，2H)，1.07(d，J＝6Hz，3H)，0.97(d，J＝6Hz，3H).

Example 51

Compound 51

Hydrogen chloride gas was bubbled through a stirred solution of carboxylic acid 50(96mg, 0.18mmol) in 3ml of ethanol at room temperature for about 3 minutes. The mixture was stirred at room temperature for 7 hours and then stored in a refrigerator (0 ℃ C.) over the weekend. The solvent was removed in vacuo and the residue was purified by RPHPLC. The product 51 is isolated as the trifluoroacetate salt.

¹H NMR(MeOH-d₄，δ)：8.63(d，J＝7.9Hz，1H)，7.84(d，J＝8Hz，2H)，7.16-7.68(m，12H)，6.68(d，J＝15.8Hz，1H)，6.32(dd，J＝15.8，7.9Hz，1H)，5(m，1H)，4.02(q，2H)，3.25(m，1H)，3.07(d，J＝7.9Hz，2H)，1.05(t，3H).

Example 52

Compound 52

A mixture of compound 11 and 10% palladium on carbon (25mg) in ethyl acetate (2ml) to ethanol (5ml) was hydrogenated at 45PSI under hydrogen pressure for 19 hours at room temperature. The mixture was filtered through a pad of celite and the filtrate was concentrated. The crude product was purified by RPHPLC (acetonitrile: water: 0.1% TFA, 10-100% acetonitrile gradient) and the product-containing fractions were lyophilized to give 21mg of compound 52.

¹H NMR(MeOH-d₄，δ)：8.27(d，J＝9.3Hz，1H)，7.83(m，2H)，7.43-7.65(m，7H)，7.09-7.27(m，5H)，4.35(m，1H)，3.58(s，3H)，2.95-3.15(m，3H)，2.54-2.75(m，2H)，1.93(m，2H).

Resolution of Compound 10

Using preparative HPLC (Chiralpak AD column, 50mm ID × 500mm, 15 μm), racemic compound 10 (about 650mg, assuming a single diastereomer in cis-configuration) was resolved into its two enantiomers 53 (later eluting isomer) and 54 (first eluting isomer). The mobile phase was heptane with (a) 0.1% TFA and isopropanol (B) 0.1% TFA, no gradient 20% a, 80% B (flow rate 200 ml/min). The isomer eluted after separation was concentrated in vacuo. 180mg were obtained. The% ee of isomer 53 was found to be 100% by analytical HPLC (Chiralpak AD). Compounds 53 and 54 have the same¹H NMR spectrum.

¹H NMR(DMSO-d₆，δ)：8.7(d，J＝8.6Hz，1H)，7.92(d，J＝9Hz，2H)，7.78(d，J＝9Hz，2H)，7.75-7.21(m，14H)，6.67(d，J＝16.1Hz，1H)，6.4(dd，J＝16.1，7.8Hz，1H)，4.98(dd，J＝16.1，7.8Hz，1H)，3.46(s，3H)，3.25-3.18(m，1H)，3.05-2.88(m，2H).

Example 55

Compound 55

The hydrogenation of compound 53 (the late eluting enantiomer) was carried out as described for compound 52, but the ethyl acetate was omitted. The product was purified by RPHPLC (acetonitrile: water: 0.1% TFA, 40-100% acetonitrile) and isolated as the trifluoroacetate salt of product 55.¹HNMR (methanol-d)₄，δ)：8.3(d，J＝9.3Hz，1H)，7.84(m，2H)，7.07-7.8(m，16H)，4.37(m，1H)，3.6(s，3H)，2.97-3.17(m，3H)，2.57-2.77(m，2H)，1.95(m，2H).

Example 56

Compound 56

To a solution of N- α -Boc-D-phenylalanine (38mmol) in 80ml of dry tetrahydrofuran at-20 ℃ was added N-methylmorpholine (38mmol) in one portion followed by isobutyl chloroformate (38mmol) in a similar manner. The mixture was stirred at-20 ℃ for 10 minutes and filtered into a 0 ℃ solution of diazomethane (ca. 70mmol) in ether. The resulting solution was stirred at 0 ℃ for 20 minutes. Glacial acetic acid was added dropwise to decompose excess diazomethane and the solvent was removed in vacuo. The resulting oil was dissolved in 150ml of anhydrous methanol. A solution of silver benzoate (8mmol) in 17ml triethylamine was added slowly with stirring at room temperature. The resulting black reaction mixture was stirred at room temperature for 45 minutes. The methanol was removed in vacuo and the residue was taken up in 700ml of ethyl acetate. The mixture was filtered through celite, washing sequentially with saturated sodium bicarbonate solution (3X 150ml), water (1X 150ml), 1N potassium hydrogen sulfate (3X 150ml) and brine (1X 150 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo and purified by flash chromatography (3: 1 hexane: ethyl acetate).

Example 57

Compound 57

Compound 57 was prepared using the procedure described for compound 56, substituting the starting material with N- α -Boc-D-alanine.

Example 58

Compound 58

The starting material was replaced with N- α -Boc-D-homophenylalanine and compound 58 was prepared using the method described for compound 56.

Example 59

Compound 59

The starting material was replaced with N- α -Boc-D-3-pyridylalanine and compound 59 was prepared using the procedure described for the preparation of compound 56.

Example 60

Compound 60

The starting material was replaced with N- α -Boc-D-isoleucine and compound 60 was prepared using the procedure described for the preparation of compound 56.

Example 61

Compound 61

Compound 61 was prepared using the procedure described for compound 56, substituting the starting material with N- α -Boc-D-cyclohexylalanine.

Example 62

Compound 62

A solution of compound 56(11mmol) in 70ml of anhydrous tetrahydrofuran was cooled to-78 ℃ and a solution of lithium hexamethyldisilazane in tetrahydrofuran (33mmol) was added via syringe at such a rate that the temperature did not exceed-60 ℃. The reaction mixture was allowed to warm to-25 ℃ over 40 minutes and then cooled again to-78 ℃. A solution of 3-cyanobenzyl bromide (27mmol) in 20ml of tetrahydrofuran was added via syringe at a temperature such that the temperature did not exceed-60 ℃. The mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. 125ml of saturated sodium bicarbonate solution are added and the tetrahydrofuran is removed in vacuo. The residual material was partitioned between 500ml ethyl acetate and 150ml saturated sodium bicarbonate solution. The organic phase was further washed with saturated sodium bicarbonate (2X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with 40ml 4: 1 hexane: ethyl acetate. The filtered solid material was discarded. The filtrate containing the desired product was concentrated in vacuo.

Example 63

Compound 63

Compound 63 was prepared using the procedure described for the preparation of compound 62, substituting the starting material for the product obtained in example 57.

Example 64

Compound 64

Compound 64 was prepared using the procedure described for the preparation of compound 62, substituting the starting material for the product obtained in example 58.

Example 65

Compound 65

Compound 65 was prepared using the procedure described for the preparation of compound 62, substituting the starting material for the product obtained in example 59.

Example 66

Compound 66

Compound 66 was prepared using the procedure described for the preparation of compound 62, substituting the starting material for the product obtained in example 60.

Example 67

Compound 67

Compound 67 was prepared using the procedure described for the preparation of compound 62, substituting the starting material for the product obtained in example 61.

Example 68

Compound 68

To a solution of compound 62(5mmol) in 60ml of dichloromethane was added dropwise 20ml of trifluoroacetic acid at 0 ℃. The resulting solution was stirred at 0 ℃ for 2 hours. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC using a gradient of 30% to 70% acetonitrile in water containing 0.1% TFA. The acetonitrile was removed in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo.

Example 69

Compound 69

Compound 69 was prepared by the method described for the preparation of compound 68, substituting the starting material for the product obtained in example 63.

Example 70

Compound 70

The starting material was replaced with the product obtained in example 64 and compound 70 was prepared using the procedure described for the preparation of compound 68.

Example 71

Compound 71

Compound 71 was prepared using the procedure described for the preparation of compound 68, substituting the starting material for the product obtained in example 65.

Example 72

Compound 72

Compound 72 was prepared using the procedure described for the preparation of compound 68, substituting the starting material for the product obtained in example 66.

Example 73

Compound 73

Compound 73 was prepared by the method described for the preparation of compound 68, substituting the starting material for the product obtained in example 67.

Example 74

Compound 74

Solution (a): to a solution of 11.8ml of n-butyllithium (19mmol) in hexane in 13ml of tetrahydrofuran at-78 ℃ was added dropwise by syringe a solution of 1-bromo-2-fluorobenzene (19mmol) in 2ml of tetrahydrofuran. Stirring was continued for 1 hour at-78 ℃. A solution of zinc chloride (19mmol) in 38ml of tetrahydrofuran was added at-78 ℃ over 2 minutes. The temperature of the resulting solution was allowed to rise to room temperature over 40 minutes.

Solution (B): to a solution of bis (triphenylphosphine) palladium dichloride (1mmol) in 11ml tetrahydrofuran at room temperature was added a solution of diisobutylaluminum hydride (1mmol) in hexane, followed by the addition of methyl iodobenzoate (16mmol) at room temperature in one portion. Solution (a) was added to solution (B) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 300ml of diethyl ether and washed with 1N hydrochloric acid (3X 75ml) and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.

Example 75

Compound 75

Compound 75 was prepared by the procedure described for the preparation of compound 74, substituting the starting material for 1-bromo-3-fluorobenzene in the preparation of solution (a).

Example 76

Compound 76

In the preparation of solution (a), compound 76 was prepared using the procedure described for the preparation of compound 74, substituting the starting material with 1-bromo-4-fluorobenzene.

Example 77

Compound 77

In the preparation of solution (A), compound 77 was prepared by the method described for compound 74, substituting the starting material with 3, 4-ethylenedioxybromobenzene.

Example 78

Compound 78

In the preparation of solution (A), compound 78 was prepared as described for compound 74, substituting the starting material with 3, 4-methylenedioxybromobenzene.

Example 79

Compound 79

In the preparation of solution (A), compound 79 was prepared as described for compound 74, substituting starting material with 3, 4-dimethoxybromobenzene.

Example 80

Compound 80

In the preparation of solution (A), compound 80 was prepared as described for compound 74, substituting the starting material with 3-cyanobenzene.

Example 81

Compound 81

Ammonia gas was passed into a suspension of compound 80(24mmol) in 200ml of methanol for 5 minutes. Rhodium/alumina (5g) was added to the resulting solution and the suspension was shaken under positive hydrogen pressure for 36 hours. The catalyst was filtered off and methanol was removed in vacuo to give an oil which was further triturated with ether and filtered.

Example 82

Compound 82

A solution of compound 81(15.4mmol), triethylamine (17mmol), di-tert-butyl dicarbonate (15.4mmol) and 4-dimethylaminopyridine (1.5mmol) in 60ml of dimethylformamide was stirred at room temperature overnight. The solution was diluted with 800ml of ethyl acetate and washed with 1N hydrochloric acid (3X 150ml) and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo and purified by flash chromatography (3: 2 hexane: ethyl acetate).

Example 83

Compound 83

A solution of compound 81(2mmol), acetic anhydride (8mmol) and dimethylaminopyridine (0.2mmol) in 20ml pyridine was stirred at room temperature overnight. The reaction mixture was poured into 200ml of 5% hydrochloric acid and extracted with ethyl acetate (3X 200 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo and purified by flash chromatography (3: 1 hexane: ethyl acetate).

Example 84

Compound 84

In the preparation of solution (A), compound 84 was prepared as described for compound 74, substituting starting material with 4-cyanobenzene.

Example 85

Compound 85

Compound 85 was prepared by the procedure described for the preparation of compound 81, substituting the starting material for the product obtained in example 84.

Example 86

Compound 86

Compound 86 was prepared by the procedure described for the preparation of compound 82, substituting the starting material for the product obtained in example 85.

Example 87

Compound 87

Compound 87 was prepared by the method described for the preparation of compound 83, substituting the starting material for the product obtained in example 85.

Example 88

Compound 88

To a solution of methyl latissilate (6.5mmol) and 3-nitrostyrene (32.5mmol) in 30ml of meta-xylene, 10% palladium on carbon (2.5g) was added in one portion. The reaction mixture was heated at 140 ℃ overnight. After cooling, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The resulting slurry was triturated with 3: 1 hexane: ethyl acetate. The solid desired product is filtered off.

Example 89

Compound 89

The starting material was replaced with 4-nitrostyrene and compound 89 was prepared by the method described for compound 88.

Example 90

Compound 90

4-biphenylcarboxylic acid (20mmol) was added portionwise to a flask containing 100ml of atomized nitric acid at 0 ℃. Stirring was continued for 15 minutes at 0 ℃. Water (100ml) was added slowly and the filtrate was collected and recrystallized from ethanol.

Example 91

Compound 91

In the preparation of solution (A), the starting material was replaced with 3-benzyloxybromobenzene and compound 91 was prepared by the method described for the preparation of compound 74.

Example 92

Compound 92

In the preparation of solution (A), the starting material was replaced with 4-benzyloxybromobenzene and compound 92 was prepared by the method described for the preparation of compound 74.

Example 93

Compound 93

To a suspension of compound 74(1.6mmol) in 10ml of methanol and 20ml of tetrahydrofuran, 10ml of 2N sodium hydroxide solution are added dropwise at room temperature. The resulting solution was stirred at room temperature for 2 hours. The organic solvent is removed in vacuo and the residue is diluted with 20ml of water and brought to pH2 with 1N hydrochloric acid. The solid material was filtered off and dried in vacuo.

Example 94

Compound 94

Compound 94 was prepared according to the procedure described for the preparation of compound 93, substituting the starting material for the product obtained in example 75.

Example 95

Compound 95

Compound 95 was prepared according to the procedure described for the preparation of compound 93, substituting the starting material for the product obtained in example 76.

Example 96

Compound 96

Compound 96 was prepared according to the procedure described for the preparation of compound 93, substituting the starting material for the product obtained in example 77.

Example 97

Compound 97

Compound 97 was prepared according to the procedure described for the preparation of compound 93, substituting the starting material for the product obtained in example 78.

Example 98

Compound 98

Compound 98 was prepared according to the procedure described for the preparation of compound 93, substituting the starting material for the product obtained in example 79.

Example 99

Compound 99

Compound 99 was prepared according to the procedure described for the preparation of compound 93, substituting the starting material for the product obtained in example 82.

Example 100

Compound 100

Compound 100 was prepared according to the procedure described for the preparation of compound 93, substituting the starting material for the product obtained in example 83.

Example 101

Compound 101

Compound 101 was prepared as described for compound 93, substituting the starting material for the product from example 86.

Example 102

Compound 102

Compound 102 was prepared as described for compound 93, substituting the starting material for the product from example 87.

Example 103

Compound 103

Compound 103 was prepared according to the procedure described for the preparation of compound 93, substituting the starting material for the product from example 88.

Example 104

Compound 104

Compound 104 was prepared as described for compound 93, substituting the starting material for the product from example 89.

Example 105

Compound 105

Compound 105 was prepared according to the procedure described for the preparation of compound 93, substituting the starting material for the product of example 91.

Example 106

Compound 106

Compound 106 was prepared according to the procedure described for the preparation of compound 93, substituting the starting material for the product obtained in example 90.

Example 107

Compound 107

To a solution of compound 96(2mmol) in 10ml DMF at room temperature was added diisopropylethylamine (2mmol) in one portion, followed by the addition of 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate (2mmol) in a similar manner. The reaction mixture was stirred at room temperature for 2 minutes, then a solution of compound 70(2mmol) in 15ml of dimethylformamide was added in one portion. Stirring was continued at room temperature overnight. The reaction mixture was diluted with 300ml of ethyl acetate and washed successively with 1N hydrochloric acid (3X 75ml), saturated sodium bicarbonate (3X 75ml) and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo.

Example 108

Compound 108

Compound 108 was prepared as described for compound 107, substituting compound 93 for compound 96.

Example 109

Compound 109

Compound 109 was prepared as described for compound 107, substituting compound 94 for compound 96.

Example 110

Compound 110

Compound 110 was prepared as described for compound 107, substituting compound 95 for compound 96.

Example 111

Compound 111

Compound 111 was prepared as described for compound 107, substituting 4-biphenylcarboxylic acid for compound 96 and compound 68 for compound 70.

Example 112

Compound 112

Compound 112 was prepared as described for compound 107, substituting compound 97 for compound 96.

Example 113

Compound 113

Compound 113 was prepared as described for compound 107, substituting compound 98 for compound 96.

Example 114

Compound 114

Compound 114 was prepared as described for compound 107, substituting compound 99 for compound 96 and compound 68 for compound 70.

Example 115

Compound 115

Compound 115 was prepared as described for compound 107, substituting compound 100 for compound 96 and compound 68 for compound 70.

Example 116

Compound 116

Compound 116 was prepared as described for compound 107, substituting compound 101 for compound 96 and compound 68 for compound 70.

Example 117

Compound 117

Compound 117 was prepared as described for compound 107, substituting compound 102 for compound 96 and substituting compound 68 for compound 70.

Example 118

Compound 118

Compound 118 was prepared as described for compound 107, substituting compound 103 for compound 96 and substituting compound 68 for compound 70.

Example 119

Compound 119

Compound 119 was prepared as described for compound 107, substituting compound 104 for compound 96 and compound 68 for compound 70.

Example 120

Compound 120

Compound 120 was prepared as described for compound 107, substituting compound 90 for compound 96 and compound 68 for compound 70.

Example 121

Compound 121

Compound 121 was prepared as described for compound 107, substituting compound 105 for compound 96 and compound 68 for compound 70.

Example 122

Compound 122

Compound 121 was prepared as described for compound 107, substituting compound 105 for compound 96 and compound 68 for compound 70.

Example 123

Compound 123

Compound 123 was prepared as described for compound 107, substituting compound 99 for compound 96 and compound 69 for compound 70.

Example 124

Compound 124

Compound 124 was prepared as described for compound 107, substituting compound 99 for compound 96 and compound 73 for compound 70.

Example 125

Compound 125

Compound 125 was prepared as described for compound 107, substituting compound 99 for compound 96 and compound 71 for compound 70.

Example 126

Compound 126

Compound 126 was prepared as described for compound 107, substituting compound 99 for compound 96 and compound 72 for compound 70.

Example 127

Compound 127

Compound 127 was prepared according to the procedure described for the preparation of compound 107, substituting compound indole-6-carboxylic acid for compound 96 and substituting compound 69 for compound 70.

Example 128

Compound 128

Compound 128 was prepared according to the procedure described for the preparation of compound 107, substituting compound indole-5-carboxylic acid for compound 96 and substituting compound 69 for compound 70.

Example 129

Compound 129

To a solution of compound 107(1.2mmol) in 10ml of methanol and 10ml of tetrahydrofuran is added dropwise a solution of 10ml of 2N sodium hydroxide at 0 ℃. The solution was allowed to warm to room temperature and stirred at room temperature for 2.5 hours. The solution was cooled to 0 ℃ and 1N hydrochloric acid was added until pH7. The organic solvent was removed in vacuo and the residue diluted with 25ml of water. 1N hydrochloric acid was added to lower the pH to 2 and the mixture was extracted with ethyl acetate (3X 75 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The acid (1.1mmol) was dissolved in 15ml tetrahydrofuran and cooled to-20 ℃. N-methylmorpholine (1.45mmol) was added in one portion, followed by the dropwise addition of isobutyl chloroformate (1.45mmol) via syringe. The reaction mixture was stirred at-20 ℃ for 20 minutes. The mixture was filtered into a 20ml aqueous solution of sodium borohydride (11mmol) at 0 ℃. Stirring was continued for 1.5 hours at 0 ℃. The reaction mixture was diluted with 300ml of ethyl acetate, washed with water (3X 100ml) and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting alcohol was purified by flash chromatography (2: 3 ethyl acetate: hexane).

Example 130

Compound 130

Compound 130 was prepared as described for compound 129, substituting compound 108 for compound 107.

Example 131

Compound 131

Compound 131 was prepared as described for compound 129, substituting compound 109 for compound 107.

Example 132

Compound 132

Compound 132 was prepared as described for compound 129, substituting compound 110 for compound 107.

Example 133

Compound 133

Compound 133 was prepared as described for compound 129, substituting compound 112 for compound 107.

Example 134

Compound 134

Compound 134 was prepared as described for compound 129, substituting compound 113 for compound 107.

Example 135

Compound 135

Compound 135 was prepared as described for compound 129, substituting compound 114 for compound 107.

Example 136

Compound 136

Compound 136 was prepared as described for compound 129, substituting compound 115 for compound 107.

Example 137

Compound 137

Compound 137 was prepared by the procedure described for the preparation of compound 129, substituting compound 116 for compound 107.

Example 138

Compound 138

Compound 138 was prepared as described for compound 129, substituting compound 117 for compound 107.

Example 139

Compound 139

Compound 139 was prepared as described for compound 129, substituting compound 118 for compound 107.

Example 140

Compound 140

Compound 140 was prepared as described for compound 129, substituting compound 119 for compound 107.

Example 141

Compound 141

Compound 141 was prepared as described for compound 129, substituting compound 120 for compound 107.

Example 142

Compound 142

Compound 142 was prepared as described for compound 129, substituting compound 121 for compound 107.

Example 143

Compound 143

Compound 143 was prepared as described for compound 129, substituting compound 122 for compound 107.

Example 144

Compound 144

Compound 144 was prepared as described for compound 129, substituting compound 123 for compound 107.

Example 145

Compound 145

Compound 145 was prepared as described for compound 129, substituting compound 124 for compound 107.

Example 146

Compound 146

Compound 146 was prepared as described for compound 129, substituting compound 125 for compound 107.

Example 147

Compound 147

Compound 147 was prepared as described for compound 129, substituting compound 126 for compound 107.

Example 148

Compound 148

To a solution of compound 129(0.5mmol) in 8ml of dichloromethane was added pyridine (0.6mmol) in one portion at 0 ℃. Acetic anhydride (0.6mmol) was added in one portion, followed by a similar addition of dimethylaminopyridine. The temperature of the reaction mixture was allowed to rise to room temperature and then stirred overnight. The reaction mixture was partitioned between 10ml of 0.1N hydrochloric acid and 30ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.

Example 149

Compound 149

Compound 149 was prepared as described for compound 148, substituting compound 130 for compound 129.

Example 150

Compound 150

Compound 150 was prepared as described for compound 148, substituting compound 131 for compound 129.

Example 151

Compound 151

Compound 151 was prepared as described for compound 148, substituting compound 132 for compound 129.

Example 152

Compound 152

Compound 152 was prepared as described for compound 148, substituting compound 133 for compound 129.

Example 153

Compound 153

Compound 153 was prepared as described for compound 148, substituting compound 134 for compound 129.

Example 154

Compound 154

To a solution of compound 135(1.1mmol) in 30ml of dichloromethane at 0 ℃ was added 10ml of trifluoroacetic acid in one portion. The resulting solution was stirred at 0 ℃ for 3 hours. The solvent was removed in vacuo and the residue was partitioned between 10% aqueous sodium bicarbonate and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The free amine (1.1mmol) was dissolved in 10ml of glacial acetic acid and paraformaldehyde (11mmol) was added in one portion at room temperature. Stirring was continued overnight at room temperature. The reaction mixture was poured into 50ml of ice-cold 2N aqueous sodium hydroxide solution and extracted with ethyl acetate (3X 100 ml). The combined organic extracts were back-extracted with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The desired product was purified by reverse phase HPLC eluting with a gradient of 20% to 100% acetonitrile in water buffered with 0.1% trifluoroacetic acid.

Example 155

Compound 155

To a solution of compound 154(0.5mmol) in 10ml of acetone was added iodomethane (large excess, 2ml) in one portion. The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo to afford the desired tetramethylammonium salt.

Example 156

Compound 156

To a solution of compound 111(0.8mmol) in 2ml dimethylformamide and 8ml tetrahydrofuran at 0 ℃ was added sodium hydride (1mmol) in one portion. The solution was stirred at 0 ℃ for 1 hour, then methyl iodide (large excess) was added. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into 100ml of ice-water and extracted with ethyl acetate (3X 75 ml). The combined organic extracts were back-extracted with water, dried over magnesium sulfate, filtered and concentrated in vacuo and purified by flash chromatography (1: 2 ethyl acetate: hexane).

Example 157

Compound 157

Compound 157 was prepared as described for compound 154, substituting compound 123 for compound 135.

Example 158

Compound 158

Starting from compound 157, compound 158 was prepared according to the procedure described for the preparation of compound 155.

Example 159a

Compound 159

Add crushed 3 angstrom molecular sieve (ca. 1g) to 50mL of dry methanol solution of compound 129(1 mmol). The mixture was stirred at 0 ℃ for 10 minutes, and hydrogen chloride gas was introduced into the mixture at 0 ℃ for 10 minutes. The reaction mixture was then allowed to warm to room temperature and stirred overnight. Nitrogen was bubbled through the mixture for 5 minutes, then methanol was removed in vacuo. The residue was dried under vacuum to remove traces of hydrogen chloride and re-mixed with 75ml of anhydrous methanol. The mixture was cooled to 0 ℃ and ammonia gas was bubbled through the reaction mixture for 10 minutes. The reaction mixture was allowed to warm to room temperature and then heated at 60 ℃ for 3 hours. After cooling to room temperature, the reaction mixture was purged with nitrogen for 5 minutes and the mixture was filtered through celite, concentrated in vacuo and purified by reverse phase HPLC eluting with a gradient of 20% to 80% aqueous acetonitrile buffered with 0.1% trifluoroacetic acid. The acetonitrile was removed in vacuo and the aqueous phase was lyophilized to give the desired product as the trifluoroacetate salt.

Example 159b

Compound 159

¹H NMR (300MHz, d6 DMSO) δ 9.21(s, 2H), 9.01(s, 2H), 8.22(d, 1H, J ═ 9.6Hz), 7.85(d, 2H, J ═ 7.2Hz), 7.70(d, 2H, J ═ 7.2Hz), 7.62 to 7.38(M, 4H), 7.25 to 7.05(M, 7H), 6.93(d, 1H, J ═ 8.4Hz), 4.90 to 4.65(M, 1H), 4.24(s, 4H), 4.18 to 4.05(M, 2H), 2.78 to 2.63(M, 2H), 2.65 to 2.45(M, 2H), 2.08 to 1.75(M, 3H), MS, fab, calcualted, found (M + lrh) +.592..

To a solution of compound 129(1mmol) in 20ml of pyridine and 4ml of triethylamine was passed hydrogen sulfide at room temperature for 10 minutes. The solution was stirred at room temperature for 10 minutes. The reaction was purged with nitrogen for 5 minutes and the solvent removed in vacuo. The residue was dried in vacuo and then dissolved in 15ml of anhydrous acetone. To this solution was added 5ml of methyl iodide, heated at 50 ℃ for 1 hour, and then concentrated in vacuo. The residue was dissolved in 20ml of methanol, and ammonium acetate (2mmol) was added in one portion at room temperature. The reaction mixture was heated at 65 ℃ for 2 hours. After cooling, the methanol was removed in vacuo and the residue was purified by reverse phase HPLC using 20% -80% acetonitrile in water buffered with 0.1% trifluoroacetic acid. The acetonitrile was removed in vacuo and the aqueous phase was lyophilized to give the desired compound as the trifluoroacetate salt.

The following compounds were prepared from the appropriate starting materials using a procedure substantially similar to that described above.

Example 161

Compound 161

¹H NMR (300MHz, d6 DMSO) δ 9.23(s, 2H), 9.01(s, 2H), 8.27(d, 1H, J ═ 9.6Hz), 7.93(d, 2H, J ═ 7.2Hz), 7.72(d, 2H, J ═ 7.2Hz), 7.65-7.55(M, 2H), 7.54-7.42(M, 2H), 7.28-7.08(M, 7H), 6.94(d, 1H, J ═ 8.4Hz), 4.25(s, 4H), 4.24-4.11(M, 1H), 4.05-3.83(M, 2H), 2.86(dd, 1H, J ═ 6.0, 15.6Hz), 2.70-2.55(M, 2H), 2.53-2.43(M, 1H), 2.35H, 1H, 592 (1H), 1H, 592.90H, 1H + 20H), 1H + 20H, 1H, 592, 1H + 15.6Hz, 1H.

Example 162

Compound 162

¹H NMR(300MHz，d6 DMSO)δ9.21(s，2H)，9.01(s，2H)，8.22(d，1H，J＝9.6Hz)，7.85(d，2H，J＝7.2Hz)，7.70(d，2H，J＝7.2Hz), 7.62-7.38(M, 4H), 7.25-7.05(M, 7H), 6.93(d, 1H, J ═ 8.4Hz), 4.90-4.65(M, 1H), 4.24(s, 4H), 4.18-4.05(M, 2H), 2.78-2.63(M, 2H), 2.65-2.45(M, 2H), 2.08-1.75(M, 3H). MS, LRFAB, calc 591, found 592(M + H) +.

Example 163

Compound 163

¹H NMR 300MHz, d6 DMSO, δ 9.23(s, 2H), 9.09(s, 2H), 8.83(d, 1H, J ═ 9.6Hz), 7.97(d, 2H, J ═ 7.2Hz), 7.83(d, 1H, J ═ 7.2Hz), 7.65 to 7.35(m, 7H), 7.28 to 7.05(m, 6H), 4.26 to 4.10(m, 1H), 4.05 to 3.83(m, 2H), 2.87(dd, 1H, J ═ 6.0Hz, 15.6Hz), 2.70 to 2.55(m, 2H), 2.32 to 2.18(m, 1H), 2.03 to 1.90(m, 2H), 1.87(s, 3H), MS ion spray: calculation 551, found 552(M + H) +.

Example 164

Compound 164

¹H NMR 300MHz, d6 DMSO, δ 9.22(s, 2H), 9.02(s, 2H), 8.32(d, 1H, J ═ 9.6Hz), 7.96(d, 2H, J ═ 7.2Hz), 7.81-7.65(m, 4H), 7.65-7.40(m, 4H), 7.38-7.05(m, 7H), 4.25-4.10(m, 1H), 4.05-3.85(m, 2H), 2.87(dd, 1H, J ═ 6.0, 15.6Hz), 2.70-2.55(m, 2H), 2.54-2.43(m, 1H), 2.35-2.20(m, 1H), 1.98-1.90(m, 2H), 1.89(s, 3H), MS ion spray: calculation 551, found 552(M + H) +.

Example 165

Compound 165

¹H NMR, 300MHz, d6 DMSO, δ 9.25(s, 2H), 9.18(s, 2H), 8.35(d, 1H, J ═ 9.6Hz), 7.80(d, 2H, 7.2Hz), 7.73(d, 2H, J ═ 7.2Hz), 7.68(d, 2H, J ═ 6.0Hz), 7.62(br.s, 2H), 7.55-7.31(m, 5H), 7.25-7.03(m, 5H), 4.65-4.45(m, 1H), 3.53(s, 3H), 3.20-2.82(m, 5H). MS LRFAB: calculation 505, found 506(M + H) +.

Example 166

Compound 166

¹H NMR (300MHz, d6 DMSO) δ 9.23(s, 2H), 8.99(s, 2H), 8.26(d, 1H, J ═ 9.6Hz), 7.93(d, 2H, J ═ 7.2Hz), 7.72(d, 2H, J ═ 7.2Hz), 7.65 to 7.56(M, 2H), 7.54 to 7.42(M, 2H), 7.32(d, 1H, J ═ 2.4Hz), 7.28 to 7.08(M, 6H), 7.02(d, 1H, J ═ 8.4Hz), 6.07(s, 2H), 4.25 to 4.12(M, 1H), 4.06 to 3.85(M, 2H), 2.85(dd, 1H, J ═ 6.0, 15.6H), 2.68 to 2.68(M, 2H), 2.53 to 2H, 2H + 2H, 2H + 2H, 2.

Example 167

Compound 167

¹H NMR：9.5(s，1H)，9.4(s，1H)，8.4(d，¹H J Hz 9.0Hz, 8.1(d, 2H, J8.0 Hz), 7.9(d, 2H, J8.0 Hz), 7.5-7.8(m, 5H), 7.1-7.4(m, 7H), 5.0(m, 1H), 4.0-4.1(m, 1H), 4.0(s, 3H), 3.9(s, 3H), 3.6(m, 1H), 2.9-3.1(m, 4H), 2.1-2.3(m, 2H), 2.0(s, 3H) m.s. calculation 594.3, found 594.

Example 168

Compound 168

¹H NMR: 9.4(s, 1H), 9.0(s, 1H), 8.4(d, 1H, J ═ 9.0Hz), 8.1(d, 2H, J ═ 7.0Hz), 7.9(d, 2H, J ═ 7.0Hz), 7.5-7.8(m, 5H), 7.1-7.4(m, 7H), 5.0(m, 1H), 4.0-4.1(m, 1H), 4.0(s, 3H), 3.9(s, 3H), 3.6(m, H), 2.9-3.1(m, 4H), 2.1-2.3(m, 2H). m.s. calculation 552.1, 552 actual measurement

Example 169

Compound 169

¹H NMR, 300MHz, d6 DMSO, δ 9.22(s, 2H), 9.11(s, 2H), 7.92(d, 2H, J ═ 7.2Hz), 7.80-7.65(m, 4H), 7.62-7.40(m, 4H), 7.37-7.01(m, 7H), 4.85-4.65(m, 1H), 4.22-4.02(m, 1H), 3.55-3.36(m, 2H), 2.82-2.62(m, 2H), 2.60-2.45(m, 1H), 2.05-1.73(m, 3H). MS LRFAB: the calculation 509, 510(M + H) is measured.

Example 170

Compound 170

¹H NMR：8.5(d，1H，J＝9.0Hz)，7.8(d，2H，J＝9.0Hz)，7.7(d，2H，J＝9.0Hz)，7.1-7.6(m，11H)，4.5(m，1H)，4.4(s，2H)，4.0(dd，1H，J＝6.0Hz，10.0Hz)，3.7(dd，1H，(J＝6.0Hz，10.0Hz)，3.0(d，2H，J＝9.0Hz)，2.9(d，2H，J＝9.0Hz)，2.0(d，1H，J＝7.0Hz).MS M+HCalculation 549.2, actual measurement 549.

Example 171

Compound 171

¹H NMR: 8.5(d, 1H, J ═ 9.0Hz), 7.75-7.9(M, 6H), 7.4-7.7(M, 6H), 7.0-7.2(M, 5H), 4.4(M, 1H), 4.2(s, 2H), 4.0(dd, 1H), (J ═ 6.0Hz, 10.0Hz), 3.7(dd, 1H, J ═ 6.0Hz, 10.0Hz), 3.0(d, 2H, J ═ 9.0Hz), 2.9(d, 1H, (J ═ 9.0Hz), 2.0(M, 1H). MS M + H calculation 507.3, found 507.

Example 172

Compound 172

¹H NMR: 8.5(d, 1H, J ═ 9.0Hz), 7.8(d, 2H, J ═ 10.0Hz), 7.7(d, 2H, J ═ 10.0Hz), 7.6(d, 1H, J ═ 10.0Hz), 7.5(m, 3H), 7.0-7.3(m, 8H), 6.8(d, 1H, J ═ 9.0Hz), 4.5(m, 3H), 4.1(dd, 1H, J ═ 6.0Hz, 10.0Hz), 3.9(dd, H J ═ 6.0Hz, 10.0Hz), 3.1(d, 2H, J ═ 9.0Hz), 2.9(d, 2H, J ═ 9.0Hz), 2.0(m, 1H, 494H + 2.2, 494H, MSM, 494.

Example 173

Compound 173

¹H NMR：8.5(d，1H，J＝9.0Hz)，7.9(d，2H，J＝10.0Hz)，7.8(d，2H，J＝10.0Hz)，7.7(d，2H，J＝10.0Hz)，7.6(d，2H，J＝10.0Hz)，7.4(s，1H)，7.0-7.2(m，3H)，4.5(m，3H)，4.1(dd，H，J6.0 Hz, 10.0Hz), 3.9(dd, 1H J6.0 Hz, 10.0Hz), 3.1(d, 2H, J9.0 Hz), 2.9(d, 2H, J9.0 Hz), 2.1(d, 3H, J10.0 Hz), MS M + H calculation 549.3, found 549.

Example 174

Compound 174

¹H NMR: 8.5(d, 1H, J ═ 9.0Hz), 7.8(d, 2H, J ═ 8.0Hz), 7.6-7.8(M, 4H), 7.4-7.6(M, 4H), 7.1-7.3(M, 4H), 6.8(d, 2H, J ═ 9.0Hz), 4.3(M, 1H), 4.0(dd, 1H, J ═ 6.0Hz, 10.0Hz), 3.7(dd, 1H, J ═ 6.0Hz, 10.0Hz), 3.0(d, 2H, J ═ 4.0Hz), 2.9(d, 1H, J ═ 9.0Hz), 2.0(M, 1H). MS M + H calculation 507.3, actually measured 507, MS 507M + H calculation 507.3, measured

Example 175

Compound 175

M.S. calculation 494.2, actually measured 494

Example 176

Compound 176

¹H NMR 300MHz，d6 DMSO δ9.23(s，2H)，9.04(s，2H)，8.57(d，1H，9.6Hz)，8.42(s，1H)，8.32(d，2H，7.2Hz)，8.13(dd，1H，J＝1.2，7.2Hz)，7.75-7.40(m，7H)，7.25-7.13(m，4H)，7.12-7.05(m，2H)，4.48-4.35(m，1H)，3.58-3.42(m，2H)，3.10-2.62(m，4H)，2.15-1.95(m，1H).

Ms (lrfab): calculation 567, found 568(M + H) +.

Example 177

Compound 177

¹H NMR 300MHz, d6 DMSO δ 9.23(s, 2H), 8.98(s, 2H), 8.37-8.22(m, 3H), 7.97(d, 2H, J ═ 7.2Hz), 7.86(s, 4H), 7.65-7.40(m, 4H), 7.25-7.15(m, 3H), 7.13-7.05(m, 2H), 4.45-4.25(m, 1H), 3.62-3.48(m, 2H), 3.00-2.86(m, 2H), 2.85-2.65(m, 2H), 2.06-1.92(m, 1H). ms (lrfab): calculation 522, found 523(M + H) +.

Example 178

Compound 178

¹H NMR 300MHz, d6 DMSO, 9.23(d, 4H, J ═ 6Hz), 8.28(d, 1H, J ═ 10Hz), 7.77(d, 2H, J ═ 10Hz), 7.71-7.42(m, 8H), 7.22-7.12(m, 4H), 7.10-7.01(m, 3H), 4.45-4.25(m, 1H), 3.65-3.45(m, 2H), 3.05-2.87(m, 2H), 2.85-2.65(m, 2H), 2.05-1.95(m, 1H) ms (lrfab): calculated 492, found 493(M + H) +.

Example 179

Compound 179

¹H NMR 300MHz，d6 DMSO，9.38-9.21(m，4H)，8.28(d，1H，J＝10Hz)，8.16(d，1H，J＝10Hz)，7.70-7.45(m，5H)，7.42(d，2H，J＝7Hz)，7.23(s，1H)，7.21-7.03(m，8H)，4.48-4.23(m，1H)，3.64-3.40(m，2H)，3.10-2.85(m, 2H), 2.84-2.62(m, 2H), 2.03-1.87(m, 1H.) MS (LRFAB): calculation 507, found 508(M + H) +.

Example 180

Compound 180

¹H NMR 300MHz, d6 DMSO, 9.23(s, 2H), 8.95(s, 2H), 8.45(s, 1H), 8.32(d, 1H, J ═ 8.4Hz), 8.24(d, 1H, J ═ 8.4Hz), 8.18(d, 1H, J ═ 7.2Hz), 7.86(br.s, 4H), 7.83-7.73(m, 1H), 7.63-7.43(m, 4H), 7.25-7.16(m, 4H), 7.14-7.05(m, 1H), 4.45-4.30(m, 1H), 3.63-3.48(m, 2H), 3.02-2.88(m, 2H), 2.87-2.65(m, 2H), 2.08-1.93(m, 1H), lrh, b (fab): calculation 522, found 523(M + H) +.

Example 181

Compound 181

¹H NMR 300MHz, d6 DMSO, 9.25(s, 2H), 9.19(s, 2H), 8.30(d, 1H, J ═ 9.6Hz), 7.82(s, 1H), 7.82(d, 2H, J ═ 7.2Hz), 7.66(d, 2H, J ═ 7.2Hz), 7.63-7.45(m, 4H), 7.38-7.27(m, 1H), 7.25-7.13(m, 6H), 7.13-7.05(m, 1H), 6.93(d, 1H, J ═ 8.4Hz), 4.43-4.28(m, 1H), 3.65-3.45(m, 2H), 3.05-2.86(m, 2H), 2.83-2.68(m, 2H), 2.08-1.92 (lrm, 1H), 2 b (fam): calculated 492, found 493(M + H) +.

Example 182

Compound 182

¹H NMR 300MHz, d6 DMSO, 9.22(s, 2H), 9.07(s, 2H), 8.38(d, 1H, J ═ 10Hz), 7.93(s, 1H), 7.83(d, 2H, J ═ 7Hz), 7.65(d, 2H, J ═ 7Hz), 7.62 to 7.45(m, 5H), 7.42 to 7.28(m, 2H), 7.25 to 7.16(m, 4H), 7.13 to 7.07(m, 1H), 4.45 to 4.28(m, 1H), 3.63 to 3.53(m, 2H), 3.05 to 2.87(m, 2H), 2.85 to 2.68(m, 2H), 2.03(s, 3H), 2.02 to 1.93(m, 1H), ms (lrb): calculation 534, found 535(M + H) +.

Example 183

Compound 183

¹H NMR 300MHz, d6 DMSO, 10.05(s, 1H), 9.23(s, 2H), 9.10(s, 2H), 8.25(d, 1H, J ═ 10Hz), 7.78(d, 2H, J ═ 7Hz), 7.73-7.40(m, 10H), 7.21-7.13(m, 4H), 7.13-7.05(m, 1H), 4.43-4.25(m, 1H), 3.63-3.45(m, 2H), 3.03-2.85(m, 2H), 2.83-2.68(m, 2H), 2.04(s, 3H), 2.01-1.93(m, 1H). ms (fab): calculation 534, found 535(M + H) +.

Example 184

Compound 184

¹H NMR: 8.5(d, 1H, J ═ 7.0Hz), 7.8-8.0(M, 6H), 7.4-7.7(M, 6H), 7.1-7.3(M, 5H)4.6(M, 3H), 4.1(dd, 1H, J ═ 6.0Hz, 10.0Hz), 3.7(dd, 1H, J ═ 6.0Hz, 10.0Hz), 3.0(d, 2H, J ═ 9.0Hz), 2.9(s, 6H), 2.0(M, 1H). MS M + H calculates 535.3, 535.

Example 185

Compound 185

¹H NMR: 8.5(d, 1H, J ═ 7.0Hz), 7.8-8.0(M, 6H), 7.4-7.7(M, 6H), 7.1-7.3(M, 5H)4.6(M, 3H), 4.0(dd, 1H, J ═ 6.0Hz, 10.0Hz), 3.6(dd, 1H, J ═ 6.0Hz, 10.0Hz), 3.2(s, 9H), 3.0(d, 2H, J ═ 9.0Hz), 2.9(d, 2H, J ═ 9.0Hz), 2.0(M, 1H), MS M + H calculation 549.3, found.

Example 186

Compound 186

¹H NMR (300MHz, d6 DMSO), δ 9.30-9.11(M, 3H), 8.31(br.s, 2H), 8.15(d, 1H, J ═ 8.4Hz), 7.93(d, 2H, J ═ 7.2Hz), 7.86-7.68(M, 2H), 7.64-7.48(M, 6H), 4.30-4.15(M, 1H), 4.14-4.04(M, 2H), 2.75(d, 2H, J ═ 6.0Hz), 1.95-1.82(M, 1H), 1.80-1.68(M, 2H), 1.65-1.46(M, 5H), 1.42-1.32(M, 1H), 1.31-1.15(M, 1H), 1.13-0.93(M, 2H), 0.65-0.65 (M, 5H), 1.42-1H, 1H), 1.31-1.15(M, 1H), 1.13-0.93(M, 2H), 0.92 (M, 0.65, 0.512H) + (M, 512H, 512.

Example 187

Compound 187

¹H NMR: 9.0(s, 1H), 8.5(d, 1H, J ═ 9.0Hz), 7.9(d, 2H, J ═ 9.0Hz), 7.6 to 7.8(m, 4H), 7.3 to 7.5(m, 6H), 7.2 to 7.1(m, 6H), 3.5(s, 3H), 3.1(s, 3H), 3.0(d, 2H, J ═ 8.0Hz), 2.9(d, 2H, J ═ 8.0Hz) · m.s. calculation 520.1, found 520.

Example 188

Compound 188

¹H NMR: 9.4(d, 1H, J ═ 12.0Hz), 8.6(d, 1H, J ═ 10.0Hz), 8.1(d, 2H, J ═ 10.0Hz), 7.9-8.1(M, 4H), 7.6-7.8(M, 6H), 4.7(M, 1H)4,4(d, 2H, J ═ 9.0Hz), 3.7(s, 3H), 3.1-3.4(M, 4H), 1.6(d, 3H, J ═ 9.0H2). MS M + H calculation 459.2 found 459.

Example 189

Compound 189

¹H NMR: 9.4(d, 1H, J ═ 12.0Hz), 8.0(d, 1H, J ═ 10.0Hz), 8.1(d, 2H, J ═ 10.0Hz), 7.7-7.9(M, 4H), 7.4-7.6(M, 6H), 4.5(M, 1H), 4.2(d, 2H, J ═ 9.0Hz), 3.6(s, 3H), 3.0-3.2(M, 3H), 1.6(d, 3H, J ═ 9.0Hz). MS M + H calculates 475.1, found 475.

Example 190

Compound 190

¹H NMR: 8.4(d, 1H, J ═ 9.0Hz), 7.9(d, 2H, J ═ 10.0Hz), 7.7-7.9(M, 4H), 7.4-7.6(M, 6H), 4.6(M, H), 4.5(s, 2H), 3.6(s, 3H), 3.1-3.2(M, 3H), 2.9(s, 6H), 1.3(d, 3H, J ═ 9.0Hz), MS M + H calculation 459.2 found 459.

Example 191

Compound 191

¹H NMR: 9.3(d, 1H, J ═ 9.0Hz), 9.1(d, 1H, J ═ 9.0Hz), 8.4(d, 1H, J ═ 10.0Hz), 7.7-8.0(M, 4H), 7.3-7.6(M, 5H), 4.6(s, 2H), 4,4(M, 1H), 3.5(s, 3H), 3.1(s, 9H), 2.9-3.1(M, 3H), 1.6(d, 3H, J ═ 9.0Hz). MS M + H calculation 501.1 found 501.1.

Example 192

Compound 192

M.s., APCI calculated 392, found 393(M + H) +.

Example 193

Compound 193

M.s., APCI calculated 392, found 393(M + H) +.

Example 194

Compound 194

¹H NMR: 9.4(d, 1H, J ═ 12.0Hz), 8.6(d, 1H, J ═ 10.0Hz), 8.0(d, 2H, J ═ 9.0Hz), 7.7(d, 2H, J ═ 9.0Hz), 7.3-7.6(M, 6H), 7.0-7.2(M, 2H), 4.2(M, 3H), 4.0(dd, 1H, (J ═ 6.0Hz, 10.0Hz), 3.6(dd, 1H, (J ═ 6.0Hz, 10.0Hz), 3.0(d, 2H, J ═ 8.0Hz), 2.0(M, 1H), 1.6(M, H)1.1-1.3(M, 8H), MS M + H, 473.1, measured.

Example 195

Compound 195

Example 196

Compound 196

Example 197

Compound 197

To a stirred solution of the acetate salt of methyl (R) -3-aminobutyric acid (8.9g, 50mmol) and triethylamine (Et) under a nitrogen atmosphere at room temperature₃N) (21ml, 150mmol) in dry dichloromethane (CH)₂Cl₂) To the solution in (1) is added dropwise di-tert-butyl dicarbonate (BOC)₂O) (21.8g, 100 mmol). 4-Dimethylaminopyridine (DMAP) (about 50mg) was then added and the mixture was stirred at room temperature overnight. At this point, the mixture was taken up with saturated sodium bicarbonate (NaHCO)₃) And (4) washing the solution. The organic layer was washed with sodium sulfate (Na)₂SO₄) Dried, filtered and concentrated. Chromatography of the crude product (eluent ═ 20% to 40% ethyl acetate (EtOAc) in hexanes) afforded compound 197.

¹H NMR(CDCl₃，δ)：4.92(bs，1H)，3.96(bm，1H)，3.65(s，3H)，2.45-2.37(m，2H)，1.39(s，9H)，1.16(d，J＝7.9Hz，3H).

Example 198

Compound 198

To a stirred solution of compound 197(2.00g, 9.21mmol) in 50ml of anhydrous Tetrahydrofuran (THF) was added dropwise a solution of Lithium Hexamethyldisilazane (LHMDS) (25.8ml of 1.0M THF) at-78 deg.C under a nitrogen atmosphere. The mixture was then warmed to-20 to-25 ℃ for 30 minutes and cooled to-78 ℃. A solution of 3-cyanobenzylbromide (4.51g, 23.0mmol) in dry THF was then added dropwise and the resulting solution was allowed to warm to room temperature. After 1 hour at room temperature, the reaction of the mixture was stopped with saturated sodium bicarbonate solution and most of the THF was removed in vacuo. The residue was collected in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (eluent 25% ethyl acetate/hexanes). The semi-solid residue was then triturated with 20% ethyl acetate/hexanes and the white solid was filtered off. The filtrate was concentrated in vacuo to afford compound 198.¹HNMR(CDCl₃，δ)：7.25-7.50(m，4H)，5.21(bd，1H)，3.88(m，1H)，3.60(s，3H)，3.07-2.73(m，3H)，1.48(s，9H)，1.14(d，J＝7.9Hz，3H).

Example 199

Compound 199

To a stirred solution of compound 198(4.20g, 12.7mmol) in 10ml of dichloromethane was added 20ml of trifluoroacetic acid at room temperature under nitrogen. The mixture was stirred at room temperature overnight and then concentrated in vacuo to give 4.20g of compound 199 as a trifluoroacetic acid (TFA) salt.

¹H NMR(DMSO-d₆，δ)：8.07(bs，1H)，7.73-7.43(M，4H)，3.50(S，3H)，3.51(M，1H)，3.05-2.82(M，3H)，1.23(D，J＝7.9HZ，3H).

Alternatively, compound 4 can be prepared as follows:

example 200

Compound 200

To a stirred solution of methyl D-3-aminobutyrate (6.98g, 39.4mmol) acetate in 40ml dichloromethane was added a saturated solution of sodium bicarbonate (40 ml). Benzyl chloroformate (9.0ml, 63mmol) was then added dropwise and the mixture stirred vigorously at room temperature. After 3 hours, the organic layer was separated and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. Chromatography of the crude product (eluent 10% ethyl acetate/chloroform) afforded compound 200.

¹H NMR(CDCl₃，δ)：7.40-7.22(m，5H)，5.25(m，1H)，5.08(s，2H)，4.11(m，1H)，3.65(s，3H)，2.53(d，J＝7.0Hz，2H)，1.23(d，J＝7.9Hz，3H).

Example 201

Compound 201

To a stirred solution of compound 200(3.45g, 13.71mmol) in 20ml of anhydrous THF was added dropwise a solution of LHMDS (41.2ml, 1.0M solution) at-78 deg.C under a nitrogen atmosphere. The mixture was then warmed to-20 ℃ for 30 minutes and cooled to-78 ℃. A solution of 3-cyanobenzylbromide (4.51g, 23.0mmol) in dry THF was then added dropwise and the resulting solution was warmed to room temperature. After 1 hour at room temperature, the reaction of the mixture was stopped with saturated sodium bicarbonate and most of the THF was removed in vacuo. The residue was collected in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (eluent 30% ethyl acetate/hexanes). The semi-solid residue was then triturated with 20% ethyl acetate/hexane and the white solid was filtered off. The filtrate was concentrated in vacuo to afford compound 201.¹H NMR(CDCl₃，δ)7.20-7.65(m，9H)，5.57(bd，1H)，5.12(s，2H)，3.97(m，1H)，3.60(s，3H)，3.07-2.75(m，3H)，1.16(d，J＝7.9Hz，3H).

Example 202

Compound 199

To a stirred solution of compound 201(2.6g, 7.1mmol) in 25ml ethanol was added 520mg 10% Pd/C. The mixture was stirred at room temperature for 3 hours under one atmospheric pressure of hydrogen gas. Then, the catalyst was removed by filtration through celite to obtain 1.45g of compound 201.

Example 203

Compound 203

3' -pyridyl-4-benzoyl chloride (compound 228, prepared as in example 228) (384mg, 1.8mmol) was added once to a solution of the TFA salt of compound 199 (373mg, 1.6mmol) and triethylamine (0.67ml, 4.8mmol) in 5.0ml of absolute ethanol at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the crude product was purified by silica gel chromatography (eluent 70% ethyl acetate/hexanes) to afford compound 203.

¹H NMR(CDCl₃，δ)：8.88(m，1H)，8.63(m，1H)，7.85-8.00(m，7.70(m，2H)，7.57-7.33(m，6H)，4.51(m，1H)，3.65(s，3H)，3.10-2.82(m，3H)，1.28(d，J＝7.9Hz，3H).

Example 204

Compound 204

Compound 199 was acylated according to the procedure for example 203, using 4' -pyridyl-4-benzoyl chloride (compound 231, prepared as in example 231) instead of compound 228, to give compound 204 after work-up and chromatography.¹H NMR(CDCl₃，δ)：8.70(m，2H)，8.02-7.65(m，4H)，7.57-7.32(m，7H)，4.50(m，1H)，3.68(s，3H)，3.10-2.83(M，3H)，1.30(d，J＝7.9Hz，3H).

Example 205

Compound 205

Compound 199 was acylated with 4-bibenzoyl chloride instead of 3' -pyridyl-4-benzoyl chloride in dichloromethane instead of absolute ethanol according to the procedure for example 203 to give compound 205 after work-up and chromatography.¹H NMR(CDCl₃，δ)：7.93(m，2H)，7.73-7.30(m，12H)，4.50(m，1H)，3.66(s，3H)，3.10-2.83(m，3H)，1.26(d，J＝7.9Hz，3H).

Example 206

Compound 206

Compound 199 was acylated by 2-bibenzoyl chloride instead of 3' -pyridyl-4-benzoyl chloride according to the procedure for example 203 to give compound 206 after workup and chromatography.

¹H NMR(CDCl₃，δ)：7.55-7.27(m，5H)，7.07(m，2H)，6.85-6.66(m，5H)，4.44(m，1H)，3.65(s，3H)，3.05-2.80(m，3H)，1.23(d，J＝7.9Hz，3H).

Example 207

Compound 207

Meta-chloroperbenzoic acid (mCPBA) (381mg, 2.21mmol) was added to a solution of compound 204(608mg, 1.47mmol) in 10ml dichloromethane at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. At this point, the mixture was diluted with dichloromethane and washed with 5% sodium carbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated to give compound 207. MS: m⁺·+H⁺430; measured value (FAB) 430.

Example 208

Compound 208

Meta-chloroperbenzoic acid (mCPBA) (124mg, 0.72mmol) was added to a solution of compound 203(150mg, 0.36mmol) in 10ml dichloromethane at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. At this point, the mixture was diluted with dichloromethane and washed with 5% sodium carbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated to give compound 208.

¹H NMR(CDCl₃，δ)：8.57(m，1H)，8.30(m，1H)，7.95(m，2H)，7.73-7.35(m，9H)，4.50(m，1H)，3.68(s，3H)，3.07-2.85(m，3H)，1.20(d，J＝7.9Hz，3H).

Example 209

Compound 209

Hydrogen chloride gas was passed into a solution of compound 207(480mg) in 5.0ml of anhydrous methanol containing 3 angstrom molecular sieves (pellet, about 50mg) at room temperature for about 2 minutes. The mixture was stirred at room temperature overnight and then concentrated in vacuo. A methanol solution of ammonia (5.0ml of a 7N solution) was added and refluxed for 1 hour. The solvent was then removed in vacuo and the crude product was purified by RPHPLC (acetonitrile/water, 0.1% TFA, gradient: 10% -100% acetonitrile) and the product-containing fractions were lyophilized to afford compound 209.

¹H NMR(MeOH-d₄，δ)：8.42(m，2H)，8.00-7.85(m，6H)，7.68-7.47(m，4H)，4.47(m，1H)，3.60(s，3H)，3.18-3.00(m，3H)，1.33(d，J＝7.9Hz，3H).MS：M⁺·+H⁺447, (calculation); found (FAB) 447.

Example 210

Compound 210

Compound 203 was treated in a similar manner as example 209 to afford compound 210 after purification by RPHPLC.¹H NMR(DMSO-d6，δ)：9.36(m，3H)，8.50-8.27(m，2H)，8.00-7.80(m，3H)，7.80-7.40(m，4H)，4.40(m，1H)，3.49(s，3H)，3.13-2.81(m，3H)，1.25(d，J＝7.9Hz，3H).MS：M⁺·+H⁺431 (calculation); measured (FAB) ═ 431

Example 211

Compound 211

Compound 204 was treated in a similar manner to example 209 to afford compound 211 after purification by RPHPLC.

Example 212

Compound 212

Compound 205 was treated in a similar manner to example 209 to afford compound 212 after purification by RPHPLC.¹H NMR(DMSO-d₆，δ)：9.30(s，1H)，9.00(s，1H)，8.40(m，1H)，8.05-7.40(m，12H)，4.46(m，1H)，3.56(s，3H)，3.20-2.97(m，3H)，1.28(d，J＝7.9Hz，3H).MS：M⁺·+H⁺430; measured (FAB) 430.

Example 213

Compound 213

Compound 208 was treated in a similar manner to example 209 to afford compound 213 after purification by RPHPLC.¹H NMR(MeOH-d₄，δ)：8.67(m，1H)，8.50-8.35(m，2H)，8.00-7.78(m，5H)，7.72-7.48(m，5H)，4.47(m，1H)，3.60(s，3H)，3.16-3.05(m，3H)，1.32(d，J＝7.9Hz，3H).MS：M⁺·+H⁺447, (calculation); found (FAB) 447.

Example 214

Compound 214

Hydrogen sulfide was bubbled through a solution of compound 203(498mg, 1.21mmol) in 5.0ml pyridine and 1.0ml triethylamine for about 2 minutes. The resulting mixture was stirred at room temperature overnight and then concentrated to dryness under a stream of nitrogen. The residue was collected in 5ml of dichloromethane and 5ml of methyl iodide was added. The mixture was refluxed for 3 hours, allowed to cool to room temperature and concentrated in vacuo. The residue was collected in 5ml of anhydrous methanol, and ammonium acetate (300mg) was added. The resulting mixture was refluxed for 3 hours and then concentrated in vacuo. The crude product was purified by RPHPLC (acetonitrile/water, 0.1% TFA, gradient: 10% to 100% acetonitrile) and the product-containing fractions were lyophilized to afford compound 214.

¹H NMR(MeOH-d₄，δ)：9.35(s，1H)，8.92(m，2H)，8.50(d，1H)，8.17(m，1H)，8.08-7.92(m，4H)，7.66-7.50(m，4H)，4.50(s，3H)，4.50(m，1H)，3.58(s，3H)，3.15-3.02(m，3H)，1.34(d，J＝7.9Hz，3H).MS：M⁺445; found (FAB) 445.

Example 215

Compound 215

Compound 204 was treated in a similar manner as compound 203 in example 214 to afford compound 215 after purification by RPHPLC.¹H NMR(DMSO-d₆，δ)：9.05(m，1H)，8.55(m，3H)，8.20-7.97(m，5H)，7.65-7.47(m，4H)，4.33(s，3H)，4.10(m，1H)，3.13(s，3H)，3.13-2.90(m，3H)，1.27(d，J＝7.9Hz，3H).MS：M⁺445; found (FAB) 445.

Example 216

Compound 216

Compound 206 was treated in a similar manner to compound 203 in example 214 to afford compound 216 after purification by RPHPLC.

Example 217

Compound 217

To a stirred solution of sodium methoxide in methanol (12.4ml of a 0.5M solution) was added hydroxylamine hydrochloride. Once all the solids were dissolved, the solution was added to a solution of compound 207(530mg, 1.24mmol) in 5ml of methanol at room temperature. The resulting mixture was stirred at room temperature under nitrogen overnight. At this point, the solvent was removed in vacuo and the product was purified by flash chromatography (eluent 10% methanol/dichloromethane). The product-containing fractions were concentrated in vacuo and the residue was lyophilized in water to afford compound 217.

¹H NMR(CDCl₃，δ)：9.60(s，1H)，8.60-7.10(m，12H)，5.80(bs，1H)，4.40(m，1H)，4.45(s，3H)，3.15-2.80(m，3H)，1.15(d，J＝7.9Hz，3H).MS：M⁺·+H⁺463 (calculation); found (FAB) is 463.

Example 218

Compound 218

Compound 208 was treated in a similar manner to compound 207 in example 217 to afford compound 218 after purification by flash chromatography.¹H NMR (methanol-d)₄，δ)：8.69(m，1H)，8.35(m，1H)，8.00-7.75(m，5H)，7.72-7.25(m，5H)，4.47(m，1H)，3.57 9s，3H)，3.15-2.95(m，3H)，1.33(d，J＝-7.9Hz，3H).MS：M⁺·+H⁺463 (calculation); the measured value (ion spray) was 463.

Example 219

Compound 219

To a stirred solution of compound 204(319mg, 0.77mmol) in 4ml methanol/THF (1/1) was added 1N sodium hydroxide solution (10 ml). The resulting mixture was stirred at room temperature for 2 hours and then acidified with 12ml of 1N hydrochloric acid. The solid product compound 219 was filtered off and dried in vacuo.

¹H NMR(CDCl₃，δ)：9.30(bs，1H)，8.50(bs，1H)，8.30-7.80(m，6H)，7.65-7.28(m，5H)，4.40(m，1H)，3.20-2.85(m，3H)，a.33(d，J＝7.9Hz，3H).

Example 220

Compound 220

Triethylamine was added dropwise to a suspension of compound 219(0.11ml, 0.77mmol) in dry dichloromethane (10ml) at room temperature under nitrogen. After 10 min, isopropyl chloroformate (0.77ml, 0.77mmol) was added dropwise. After 30 min, DMAP (31mg) was added and the mixture was stirred at room temperature overnight. At this time, the mixture was diluted with dichloromethane and washed with 1N hydrochloric acid. The organic layer was dried over sodium sulfate, filtered and concentrated. Chromatography of the crude product with 40% ethyl acetate/hexane followed by 70% ethyl acetate/hexane afforded compound 224. MS: m⁺·+H⁺(calculated) 220; the measured value is 442.

Example 221

Compound 221

Compound 220 was treated in a similar manner as compound 203 in example 214 to afford compound 221 after purification by RPHPLC.¹H NMR(DMSO-d₆，δ)：9.28(m，1H)，9.00(m，3H)，8.53(m，1H)，8.23-7.92(m，4H)，7.32(s，1H)，7.15(s，1H)，7.00(s，1H)，4.38(m，1H)，4.32(s，3H)，3.14-2.93(m，3H)，1.25(m，3H)，0.99(m，3H)，0.87(m，3H).MS：M⁺473 (calculated); found (FAB) 473.

Example 222

Compound 222

Ethyl 4-bromobenzoate (7.0g, 31mmol) was dissolved in 100ml THF. To this solution was added Pd (Ph)₃P)₄(1.0g, 1.0mmol), tetrabutylammonium bromide (592mg, 1.8mmol), potassium hydroxide powder (3.4g, 61mmol), and diethyl- (3-pyridyl) borane (3.0 g). The resulting mixture was refluxed for 2.5 hours, allowed to cool to room temperature and concentrated in vacuo. The crude product was recovered in methanol and chromatographed (eluent gradient 50% ethyl acetate/hexane to 70% ethyl acetate/hexane) to give compound 222 after evaporation of the solvent.¹H NMR(CDCl₃，δ)：8.83(s，1H)，8.60(m，1H)，8.10(m，2H)，7.90-7.30(m，3H)，4.34(m，2H)，1.37(m，3H).

Example 223

Compound 223

Sodium hydroxide solution (25.5ml of a 1.0N solution) was added dropwise to a stirred solution of compound 222(2.7g, 12mmol) in 21ml 1/1 THF/MeOH at room temperature. After 3 hours, 25ml of 1N hydrochloric acid were added and the white precipitate was filtered off. The solid was dried in vacuo to afford compound 223.

¹H NMR(DMSO-d₆，δ)：8.90(s，1H)，8.60(s，1H)，8.13(m，1H)，8.05-7.80(m，4H)，7.50(m，1H).

Example 224

Compound 224

Sulfuryl chloride (5ml) was added to 1.3g of compound 223. The resulting mixture was refluxed for 2 hours, then concentrated in vacuo to afford compound 224. MS: m⁺217 (calculated); the measured value (EI) is 217.

Example 225

Compound 225

A mixture of methyl latissimaate (10g, 65mmol), 4-vinylpyridine (35ml, 325mmol) and 10% Pd/C (25g) in 1, 3, 5-trimethylbenzene (300ml) was heated at 200 ℃ for 30 hours. At this point, the mixture was cooled and filtered through celite, washing with chloroform. Most of the solvent was removed in vacuo and the residual liquid was chromatographed (eluent: gradient 50% ethyl acetate/hexane to 70% ethyl acetate/hexane) to afford compound 225. MS: m⁺213 (calculated value); the measured value (EI) is 213.

Example 226

Compound 226

Treatment of compound 225 with sodium hydroxide in THF/MeOH as in example 223 affords compound 226. MS: m⁺199 (calculated); the measured value (EI) is 199.

Example 227

Compound 227

Compound 226 is refluxed with sulfuryl chloride as in example 224 to provide compound 227. MS: m⁺217 (calculated); the measured value (EI) is 217.

Example 228

Compound 228

To a solution of N-BOC homophenylalanine methyl ester (5.57g, 18.1mmol) in 30ml THF was added dropwise a solution of LHMDS (54.3ml 1N THF) at-78 deg.C under nitrogen. The mixture was then warmed to 0 ℃ for 30 minutes and then cooled to-78 ℃. A solution of 3-cyanobenzylbromide (7.46g, 38.0mmol) in dry THF was then added dropwise and the resulting solution was allowed to warm to room temperature. After 1 hour at room temperature, the mixture was quenched with saturated sodium bicarbonate solution and most of the THF was removed in vacuo. The residue was taken up in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (eluent 25% ethyl acetate/hexane), the semi-solid residue was then triturated with 20% ethyl acetate/hexane and the white solid was filtered off. The filtrate was concentrated in vacuo to afford compound 228.

¹H NMR(CDCl₃，δ)：7.82-7.08((m，9H)，5.32(bd，1H)，3.84(m，1H)，3.60(s，3H)，3.06-2.57(m，5H)，1.70(m，2H)，1.47(s，9H).

Example 229

Compound 229

To a stirred solution of compound 228(1.42g, 3.35mmol) in 5.0ml of dichloromethane was added 3.5ml of trisAnd (3) fluoroacetic acid. The mixture was stirred at room temperature for 2 hours, then concentrated in vacuo to afford compound 229 as a TFA salt. MS: m⁺322 (calculated); the measured value (EI) is 322.

Example 230

Compound 230

After acylation 229 with compound 224 and work-up and chromatography according to example 203, compound 230 is obtained. MS: m⁺503 (calculated value); the measured value (EI) is 503.

Example 231

Compound 231

Compound 230 was treated with hydrochloric acid/methanol followed by ammonium acetate in a similar manner to compound 207 in example 209 to afford compound 231 after purification by RPHPLC. MS: m⁺521 (calculated value); measured value (FAB) 521.

Example 232

Compound 232

Compound 230 was treated in a similar manner as compound 203 in example 214 to afford compound 232 after purification by RPHPLC.¹H NMR(MeOH-d₄)：9.35(s，1H)，8.90(m，2H)，8.45(m，1H)，8.17(m，1H)，8.11-7.92(m，4H)，7.68-7.46(m，5H)，7.27-7.10(m，6H)，4.50(s，3H)，4.40(m，1H)，3.57(s，3H)，3.05(m，3H)，2.67(m，2H)，2.00(m，2H).

Example 233

Compound 233

Compound 230 was hydrolyzed with sodium hydroxide in THF/methanol using the method of example 223 and worked up to give compound 233. MS: m⁺·+H⁺(calculated) 490; measured value (FAB) 490.

Example 234

Compound 234

Compound 233 was treated in a similar manner as compound 203 in example 214 to afford compound 234 after purification by RPHPLC.¹H NMR(MeOH-d₄)：9.38(s，1H)，8.90(m，2H)，8.47(m，1H)，8.17(m，1H)，8.11-7.92(m，4H)，7.68-7.46(m，5H)，7.26-7.10(m，6H)，4.50(s，3H)，4.38(m，1H)，3.12-2.97(m，3H)，2.68(m，2H)，2.03(m，2H).

Example 235

Compound 235

This material was prepared according to the procedure described for the preparation of compound 123, substituting benzimidazole-5-carboxylic acid for compound 99.

Example 236

Compound 236

This material was prepared as described for the preparation of compound 123, substituting quinoline-7-carboxylic acid for compound 99.

Example 237

Compound 237

This material was prepared as described for the preparation of compound 123, substituting N- (4-pyridyl) -piperidine-4-carboxylic acid for compound 99.

Example 238

Compound 238

This material was prepared as described for the preparation of compound 123, substituting 2- (1-piperazinyl) -pyridine-5-carboxylic acid for compound 99.

Example 239

Compound 239

This material was prepared as described for the preparation of compound 123, substituting 2- (4-pyridyl) -1, 3-thiazole-4-carboxylic acid for compound 99.

Example 240

Compound 240

This material was prepared according to the procedure described for the preparation of compound 123, substituting 4- (5- (1, 2, 4-thiadiazole)) benzoic acid for compound 99.

Example 241

Compound 241

This material was prepared as described for the preparation of compound 123, substituting 2- (2-pyridyl) -thiophene-5-carboxylic acid for compound 99.

Example 242

Compound 242

This material was prepared as described for the preparation of compound 123, substituting 2- (3-pyridyl) thiophene-5-carboxylic acid for compound 99.

Example 243

Compound 243

This material was prepared as described for the preparation of compound 123, substituting 2- (4-pyridyl) thiophene-5-carboxylic acid for compound 99.

Example 244

Compound 244

This material was prepared as described for the preparation of compound 123, substituting 3- (2-pyridyl) thiophene-5-carboxylic acid for compound 99.

Example 245

Compound 245

This material was prepared as described for the preparation of compound 123, substituting 3- (3-pyridyl) thiophene-5-carboxylic acid for compound 99.

Example 246

Compound 246

This material was prepared as described for the preparation of compound 123, substituting 3- (4-pyridyl) thiophene-5-carboxylic acid for compound 99.

Example 247

Compound 247

This material was prepared as described for the preparation of compound 123, substituting 4- (1-imidazolyl) benzoic acid for compound 99.

Example 248

Compound 248

This material was prepared as described for the preparation of compound 123, substituting 4- (4-imidazolyl) benzoic acid for compound 99.

Example 249

Compound 249

This material was prepared as described for the preparation of compound 123, substituting 4- (2-imidazolyl) benzoic acid for compound 99.

Example 250

Compound 250

This material was prepared as described for the preparation of compound 123, substituting 3- (1-imidazolyl) benzoic acid for compound 99.

Example 251

Compound 251

This material was prepared as described for the preparation of compound 123, substituting 2- (1-imidazolyl) -pyridine-5-carboxylic acid for compound 99.

Example 252

Compound 252

This material was prepared as described for the preparation of compound 123, substituting 2- (1-pyrrolyl) -pyridine-5-carboxylic acid for compound 99.

Example 253

Compound 253

This material was prepared as described for the preparation of compound 123, substituting 4- (1-pyrrolyl) benzoic acid for compound 99.

Example 254

Compound 254

This material was prepared according to the procedure described for the preparation of compound 123, substituting 5- (3-pyridyl) -1, 3-thiazole-2-carboxylic acid for compound 99.

Example 255

Compound 255

This material was prepared according to the procedure described for the preparation of compound 123, substituting 2-phenyl-5-methyl-1, 2, 3-triazole-4-carboxylic acid for compound 99.

Example 256

Compound 256

This material was prepared as described for the preparation of compound 123, substituting 2- (2, 4-difluorophenyl) -1, 3-triazole-4-carboxylic acid for compound 99.

Example 257

Compound 257 (Novak)

This material was prepared as described for the preparation of compound 123, substituting 2- (2, 3-dichlorophenyl) -1, 3-thiazole-4-carboxylic acid for compound 99.

Example 258

Compound 258

This material was prepared according to the procedure described for the preparation of compound 123, substituting 3-phenyl-5-methyl-1, 2-oxadiazole-4-carboxylic acid for compound 99.

Example 259

Compound 259

This material was prepared according to the procedure described for the preparation of compound 123, substituting 1, 2-phthalimide-4-carboxylic acid for compound 99.

Example 260

Compound 260

This material was prepared according to the procedure described for the preparation of compound 123, substituting 3-aza-b-carboline-4-carboxylic acid for compound 99.

Example 261

Compound 261

This material was prepared as described for the preparation of compound 123, substituting 2-methyl-1-azaindolizine-3-carboxylic acid for compound 99.

Example 262

Compound 262

This material was prepared according to the procedure described for the preparation of compound 56, substituting N-a-BOC-O-benzyl-D-serine.

Example 263

Compound 263

This material was prepared according to the procedure described for the preparation of compound 62, substituting compound 262.

Example 264

Compound 264

This material was prepared according to the procedure described for the preparation of compound 68, substituting compound 263.

Example 265

Compound 265

This material was prepared according to the procedure described for the preparation of compound 114, substituting compound 264.

Example 266

Compound 266

This material was prepared according to the procedure described for the preparation of compound 129, substituting compound 265.

Example 267

Compound 267

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 235. MS: (M + H)⁺395.

Example 268

Compound 268

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 236. MS: (M + H)⁺406.

Example 269

Compound 269

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 237. MS: (M + H)⁺439.

Example 270

Compound 270

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 238. MS: (M + H)⁺440.

Example 271

Compound 271

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 239. MS: (M + H)⁺439.

Example 272

Compound 272

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 240. MS: (M + H)⁺439.

Example 273

Compound 273

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 241.

¹H NMR(DMSO-d₆)δ8.56-8.50(m，1H)，7.94-7.82(m，2H)，7.70(s，2H)，7.66-7.46(m，4H)，7.38-7.30(m，1H)，4.46-4.32(m，1H)，3.60(s，3H)，3.13-2.95(m，3H)，1.32(d，J＝7.2Hz，3H).MS：(M+H)⁺438.

Example 274

Compound 274

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 242.

¹H NMR(DMSO-d₆)δ9.06(s，1H)，8.68-8.62(m，1H)，8.53(d，J＝8.4Hz，1H)，7.85-7.78(m，1H)，7.75(d，J＝3.6Hz，1H)，7.68(d，J＝3.6Hz，1H)，7.65-7.45(m，4H)，4.48-4.33(m，1H)，3.57(s，3H)，3.13-3.00(m，3H)，1.32(d，J＝7.2Hz，3H).MS：(M+H)⁺438.

Example 275

Compound 275

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 243.

¹H NMR(DMSO-d₆)δ8.70(s，1H)，8.52(d，J＝9.6Hz，1H)，8.18-8.08(m，1H)，7.96(d，J＝3.6Hz，1H)，7.82(d，J＝3.6Hz，1H)，7.65-7.45(m，4H)，4.50-4.35(m，1H)，3.57(s，3H)，3.13-3.02(m，3H)，1.34(d，J＝7.2Hz，3H).MS：(M+H)⁺438.

Example 276

Compound 276

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 244.

¹H NMR(DMSO-d₆)δ8.66(d，J＝6.0Hz，1H)，8.37(s，1H)，8.32(s，1H)，8.20-8.11(m，1H)，8.04(d，J＝7.2Hz，1H)，7.65-7.44(m，5H)，4.50-4.35(m，1H)，3.60(s，3H)，3.17-3.02(m，3H)，1.33(d，J＝7.2Hz，3H).MS：(M+H)⁺438.

Example 277

Compound 277

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 245.

¹H NMR(DMSO-d₆)δ9.15-9.02(m，1H)，8.75-8.61(m，1H)，8.54(d，J＝8.4Hz，1H)，8.22(d，J＝8.4Hz，1H)，7.88-7.78(m，1H)，7.65-7.45(m，4H)，4.50-4.35(m，1H)，3.57(s，3H)，3.17-3.02(m，3H)，1.35(d，J＝7.2Hz，3H).MS：(M+H)⁺438.

Example 278

Compound 278

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 246.¹H NMR(DMSO-d₆)δ8.78(s，2H)，8.67(s，1H)，8.35(s，1H)，8.25(d，J＝8.4Hz，2H)，7.65-7.45(m，4H)，4.50-4.38(m，1H)，3.57(s，3H)，3.17-3.02(m，3H)，1.35(d，J＝7.2Hz，3H).MS：(M+H)⁺438.

Example 279

Compound 279

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 247.

¹H NMR(DMSO-d₆)δ9.5(s，1H)，8.2(s，1H)，8.1(d，J＝5.0Hz，2H)，7.9(d，J＝5.0Hz，2H)，，7.8(s，1H)，7.5-7.7(m，4H)，4.4-4.6(m，1H)，3.6(s，3H)，3.0-3.2(m，3H)，1.4(d，J＝5.0Hz，3H).MS：(M+H)⁺421.

Example 280

Compound 280

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 248.¹H NMR(DMSO-d₆)δ9.0(s，1H)，8.5(d，J＝5.0Hz，1H)，8.1(s，1H)，8.0(d，J＝5.0Hz，2H)，7.9(d，J＝5.0Hz，2H)，7.5-7.7(m，4H)，4.4-4.6(m，1H)，3.6(s，3H)，3.0-3.2(m，3H)，1.4(d，J＝5.0Hz，3H).MS：(M+H)⁺421.

Example 281

Compound 281

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 249.

¹H NMR(DMSO-d₆)δ8.5(d，J＝5.0Hz，1H)，7.80-8.10(m，4H)，7.8(d，J＝5.0Hz，2H)，7.5-7.7(m，4H)，4.4-4.6(m，1H)，3.6(s，3H)，3.0-3.1(m，3H)，1.4(d，J＝5.0Hz，3H).MS：(M+H)⁺421.

Example 282

Compound 282

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 250. MS: (M + H)⁺421.

Example 283

Compound 283

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 251. MS: (M + H)⁺422.

Example 284

Compound 284

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 252. MS: (M + H)⁺421.

Example 285

Compound 285

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 253. MS: (M + H)⁺420.

Example 286

Compound 286

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 254. MS: (M + H)⁺439.

Example 287

Compound 287

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 255. MS: (M + H)⁺436.

Example 288

Compound 288

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 256. MS: (M + H)⁺473.

Example 289

Compound 289

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 257. MS: (M + H)⁺507.

Example 290

Compound 290

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 258. MS: (M + H)⁺434.

Example 291

Compound 291

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 259. MS: (M + H)⁺421.

Example 292

Compound 292

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 260. MS: (M + H)⁺444.

Example 293

Compound 293

This material was prepared according to the procedure described for the preparation of compound 159a, substituting compound 261. MS: (M + H)⁺408.

Example 294

Compound 294

This material was prepared according to the procedure described for the preparation of compound 159b, substituting compound 265.

Example 295

Compound 295

This material was prepared according to the procedure described for the preparation of compound 159b, substituting compound 266.

Example 296

Compound 296

To a solution of compound 294(1mmol) in 20ml of dichloromethane was added 5ml of TFA with stirring at 0 ℃. Stirring was continued at 0 ℃ for 1 hour, then all solvent was removed in vacuo.

Example 297

Compound 297

Add about 50mg of 10% Pd/C to a solution of 296(1mmol) in 25mL of MeOH. The mixture was shaken under positive hydrogen pressure (55psi) for 24 hours and then filtered. The filtrate was concentrated in vacuo and purified by reverse phase HPLC.¹H NMR(DMSO-d₆)δ8.3(d，J＝6.0Hz，1H)，8.0(d，J＝5.0Hz，2H)，7.8(d，J＝5.0Hz，2H)，7.7(d，J＝6.0Hz，2H)，7.4-7.7(m，6H)，4.3-4.5(m，1H)，4.2(s，2H)，3.8(d，J＝4.0Hz，2H)，3.7(s，3H)，3.2-3.4(m，3H)，3.1-3.2(m，2H).MS：(M+H)⁺475.

Example 298

Compound 298

Compound 298 was prepared from compound 295 using the same procedure used to prepare compound 296.

Example 299

Compound 299

Compound 299 was prepared from compound 298 using the same procedure as for compound 297.

¹H NMR(DMSO-d₆)δ8.4(d，J＝5.0Hz，1H)，8.0(d，J＝5.0Hz，2H)，7.8(d，J＝5.0Hz，2H)，7.7(d，J＝4.0Hz，2H)，7.5-7.7(m，6H)，4.2(s，2H)，4.1-4.2(m，1H)，4.0(dd，J＝8.0，2.0Hz，1H)，3.8(s，2H)，3.7(dd，J＝8.0，2.0Hz，1H)，3.0(d，J＝5.0Hz，2H)，2.2-2.4(m，H).MS：(M+H)⁺448.

Example 300

Compound 300

Compound 300 was prepared from the appropriate starting materials using a procedure substantially similar to that used to prepare compound 297.¹H NMR(CD₃OD)δ7.94(d，J＝10.8Hz，2H)，7.85-7.72(m，4H)，7.70-7.45(m，6H)，4.32-4.23(m，1H)，4.22(s，2H)，3.62(s，3H)，3.83-3.55(m，2H)，3.18-3.02(m，3H)，0.94(t，J＝8.4Hz，3H).MS：(M+H)⁺474.

Example 301

Compound 301

Compound 301 was prepared from the appropriate starting materials using essentially the same procedure as that used to prepare compound 297.¹H NMR(CD₃OD)δ7.94(d，J＝10.8Hz，2H)，7.85-7.72(m，4H)，7.68-7.45(m，6H)，4.42-4.30(m，1H)，4.22(s，2H)，3.61(s，3H)，3.15-3.02(m，3H)，1.72-1.58(m，2H)，1.51-1.32(m，2H)，0.93(t，J＝8.4Hz，3H).MS：(M+H)⁺488.

Example 302

Compound 302

Compound 302 was prepared starting from the appropriate starting materials using a procedure substantially similar to that used to prepare compound 297.¹H NMR(CD₃OD)δ7.93(d，J＝10.8Hz，2H)，7.85-7.72(m，4H)，7.70-7.45(m，6H)，4.42-4.30(m，1H)，4.22(s，2H)，3.62(s，3H)，3.14-3.02(m，3H)，1.78-1.60(m，2H)，1.45-1.25(m，4H)，0.90(t，J＝8.4Hz，3H).MS：(M+H)⁺502.

Example 303

Compound 303

(Z) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) allyl ] -4-pyridin-3-ylbenzamide

A.5-iodo-2- (2-methoxy-ethoxymethoxy) benzaldehyde

A1M solution of iodine monochloride in dichloromethane (410ml, 0.41mol) was added to a solution of salicylaldehyde (50g, 0.41mol) in dichloromethane (150ml) at 0 ℃. The resulting solution was warmed to room temperature and stirred overnight. Placing the dark solution in saturated Na₂SO₃In aqueous solution (100 ml). The organic layer was separated, washed with water and MgSO₄Dried, filtered and concentrated. The crude product was recrystallized from cyclohexane to give 4-iodosalicylaldehyde as yellow crystals (61g, 0.25 mol). 4-Iodosalicylaldehyde (12.4g, 50mmol) and MEM chloride (M) were added at 0 deg.CA solution of EM chloride) (6ml, 53mmol) in THF (50ml) was added to a suspension of 60% NaH (2.2g, 55mmol) in THF (50 ml). The resulting mixture was stirred at room temperature for 2 hours. Water treatment and concentration gave the liquid product (15g, 45 mmol).

¹H NMR(CDCl₃，300MHz)δ10.36(s，1H)，8.11(d，1H)，7.73(dd，1H)，7.03(d，1H)，5.37(s，2H)，3.88(t，2H)，3.52(t，2H)，3.36(s，3H).EI MS[M]⁺＝436.

(Z, E) -3- [3- (1, 3-dioxo-1, 3-dihydroisoindol-2-yl) propenyl ] -4- (2-methoxyethoxymethoxy) benzonitrile

Potassium tert-butoxide (1.85g, 16.5mmol) was added to 5-iodo-2- (2-methoxyethoxymethoxy) benzaldehyde (5g, 15mmol) and [2- (1, 3-dioxo-1, 3-dihydroisoindol-2-yl) ethyl ] ethyl]-suspension of triphenylphosphonium bromide (7.7g, 15mmol) in THF (80 ml). The mixture was stirred at room temperature overnight. Removing the precipitated solid, concentrating the filtrate, diluting with water and adding CHCl₃The extraction was performed twice. The combined organic layers were washed with water, dried and over MgSO₄Dried, filtered and concentrated. The crude product was purified by chromatography (10% -30% EtOAc/hexanes) to give a yellow solid (3.1g, 6.3 mmol). This product (2.5g, 5.1mmol) was reacted with ZnCN₂(2.1g, 17.5mmol) and (Ph)₃P)₄Pd (0.3g, 0.26mmol) was mixed in DMF (15 ml). The mixture was heated at 75 ℃ for 4h, then cooled, diluted with EtOAc and washed with 5% NH₄OH, Water and brine (5X 25ml) over MgSO₄Dried, filtered and concentrated. The crude product was purified by flash chromatography (15% -30% EtOAc/hexanes) to give a mixture of the two isomers as a white solid (Z/E ═ 4/1) (1.0g, 26 mmol). Fab MS [ M + 1]]⁺＝393.

(Z) -2- (3-aminopropenyl) -4- (2-methoxy-ethoxymethoxy) benzonitrile

Mixing (Z, E) -3- [3- (1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) propenyl]-4- (2-methoxyethoxymethoxy) benzonitrile (0.2g, 0.51mmol) and NH₂NH₂Hydration ofThe material (0.15ml, 3mmol) was heated in 1-butanol (10ml) at 90 ℃ for 1 hour. The reaction was allowed to cool and the resulting suspension was filtered. The filtrate was concentrated to give a residue which was purified by chromatography (15% -20% ethanol/dichloromethane). The substance with the identified high Rf value was Z-isomer (30mg, 0.11 mmol).

¹H NMR(CDCl₃，300MHz)δ7.55(dd，1H)，7.45(d，1H)，7.20(d，1H)，6.50(d，1H)，5.9(m，1H)，5.37(s，2H)，3.80(t，2H)，3.50(m，4H)，3.30(s，3H).EI MS[M]⁺＝262.

(Z) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4-pyridin-3-ylbenzamide

A solution of (Z) -3- (3-aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile (30, g, 0.11mmol) in DMF (2ml) was added to a mixture of 4-pyridine-3-benzoic acid (24mg, 0.12mmol), TBTU (39mg, 0.12mmol) and triethylamine (12mg, 0.12mmol) in DMF (0.5ml) and stirred at room temperature overnight. The solution was diluted with water and extracted with dichloromethane (3 ×). The combined dichloromethane layers were washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography eluting with a 2% methanol/dichloromethane gradient to give a white solid (35mg, 0.079 mmol). The above product was treated with an ethanol solution (9ml) of hydrogen chloride for 20 minutes, then sealed and stirred overnight. After concentration to dryness, the product was treated with a saturated ammonia solution in methanol (10ml) at 50 ℃ for 2 hours. The reaction was sealed and stirred at room temperature overnight. The white solid was collected and washed with methanol. More product (26 mg total, 0.07mmol) was obtained after concentrating the filtrate to a smaller volume.

¹H NMR (DMSO, 300MHz) delta 9.05(bs, 1H), 8.95(s, 1H), 8.60(s, 1H), 8.15(d, 1H), 7.97(d, 2H), 7.84(d, 2H), 7.50(M, 2H), 7.40(d, 1H), 6.57(d, 1H), 6.20(d, 1H), 5.50(M, 1H), 4.17(bs, 2H). Ionic spray MS [ M + 1H ]]+＝373，[M+2]²⁺＝187.

Example 304

Compound 304

N- [3- (5-Amidino-2-hydroxyphenyl) -propyl ] -4-pyridin-3-ylbenzamide bistrifluoroacetate

Reacting N- [3- (5-amidino-2-hydroxyphenyl) -allyl]-4-pyridin-3-ylbenzamide (22mg, 0.059mmol) was dissolved in methanol (10ml) and hydrogenated in the presence of 5% Pd/C under 30psi of hydrogen pressure for 2 hours. The mixture was filtered, washed with methanol and concentrated. The product was purified by HPLC eluting with a gradient of 10% acetonitrile/water (0.1% THF) to 100% acetonitrile. The appropriate fractions were lyophilized to give the title compound as a white solid (35mg, 0.056 mmol).¹H NMR (DMSO, 300MHz) delta 10.6(bs, 1H), 8.97(bs, 2H), 8.70(M, 3H), 8.20(d, 1H), 7.90(d, 2H), 7.80(d, 2H), 7.55(M, 3H), 6.90(d, 1H), 3.25(t, 2H), 2.60(t, 2H), 1.78(M, 2H). ion spray MS [ M + 1H ]]+＝375，[M+2]²⁺＝188.

Example 305

Compound 305

N- [3- (5-Amidino-2-hydroxyphenyl) -propyl ] -4- (1-oxo-pyridin-4-yl) -benzamide bistrifluoroacetate

3- (3-aminopropyl) -4- (2-methoxy-ethoxymethoxy) benzonitrile

(Z, E) -3- [3- (1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) propenyl in the presence of 5% Pd/C]-4- (2-methoxy-ethoxymethoxy) benzonitrile (0.38g, 0.97mmol) was hydrogenated in 50% methanol in dichloromethane (10ml) (hydrogen filled balloon). The mixture was filtered, washed with dichloromethane, and concentrated. Mixing the residue with NH₂NH₂The hydrate (0.23ml, 4.6mmol) was heated in 1-butanol (15ml) at 90 ℃ for 1 hour. After cooling, the solid is filtered off and washed with 1-butanol. The filtrate was concentrated to give the title compound (0.23g, 0.87mmol) as a pale yellow solid.

¹H NMR(CDCl₃，300MHz)δ7.45(m，2H)，7.17(d，1H)，5.34(s，2H)，3.82(t，2H)，3.55(t，2H)，3.38(s，3H)，2.70(m，4H).1.70(m，2H).

N- [3- (5-Amidino-2-hydroxyphenyl) -propyl ] -4- (1-oxo-pyridin-3-yl) -benzamide bistrifluoroacetate

A solution of 3- (3-aminopropyl) -4- (2-methoxyethoxymethoxy) benzonitrile (88mg, 0.33mmol) in DMF (0.5m) was added to a mixture of 4-pyridine-4-benzoic acid (60mg, 0.3mmol), TBTU (106mg, 0.33mmol) and triethylamine (0.043ml, 0.033mmol) in DMF (1 ml). The mixture was stirred at 35 ℃ for 4 hours. The solution was diluted with ethyl acetate (20ml), washed with saturated sodium bicarbonate (3X 17ml) and brine (3X 17ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography (4% methanol in dichloromethane) to give 3- [4- (pyridin-4-yl) -benzoylamino ] propyl) -4- (2-methoxyethoxymethoxy) benzonitrile (0.09g, 0.20mmol) with unknown side products. The crude product (0.08g, 0.18mmol) was dissolved in dichloromethane (5ml), treated with MCPBA (57-86%, 92mg) at 0 ℃ and stirred at room temperature for 2 h. The residue obtained after workup with water and concentration is treated with anhydrous hydrogen chloride/ethanol and then subjected to ammonolysis as described in section D of example 303. HPLC purification (10% acetonitrile/0.1% aqueous TFA-100% acetonitrile) gave the title compound (0.007g, 0.01 mmol).

¹H NMR(CD₃OD, 300MHz) delta 8.94(bs, 1H), 8.65(bs, 1H), 8.40(M, 3H), 7.90(M, 6H), 7.64(d, 1H), 7.57(dd, 1H), 6.93(d, 1H), 3.43(t, 2H), 2.77(t, 2H), 1.97(M, 2H). Ionic spray MS [ M + 1H ]]+＝391，[M+2]²⁺＝196.

Example 306

Compound 306

N- [3- (5-amidino-2-hydroxyphenyl) -propyl ] -4- (6-oxo-1, 6-dihydropyridin-3-yl) benzamide trifluoroacetate salt

3- [4- (6-oxo-1, 6-dihydropyridin-3-yl) -benzoylamino ] propyl) -4-hydroxybenzonitrile

3- (3-aminopropyl) -4- (2-methoxyethoxymethyl) benzonitrile (0.048g, 0.18mmol) was treated with 4- (6-methoxypyridin-3-yl) benzoic acid (0.042g, 0.18mmol), TBTU (0.058g, 0.18mmol) and triethylamine (0.025ml) as described in example 305 part B to give, after purification by chromatography (dichloromethane-5% methanol/dichloromethane), 3- [4- (6-methoxypyridin-3-yl) -benzoylamino ] propyl) -4- (2-methoxyethoxymethoxy) -benzonitrile. The material was heated to melt with pyridinium hydrochloride for 15 minutes. The reaction mixture was cooled and diluted with water (20 ml); the precipitated product, 3- {3- [4- (6-methoxypyridin-3-yl) benzoylamino ] -propyl } -4-hydroxybenzonitrile (0.031g, 0.083mmol) was collected by filtration.

¹H NMR(CD₃OD, 300MHz) delta 8.1(M, 1H), 7.97(M, 1H), 7.90(AB, 2H), 7.76(bs, 1H), 7.60(AB, 2H), 7.95(s, 1H), 7.40(d, 1H), 6.93(d, 1H), 6.87(d, 1H), 6.67(d, 1H), 3.45(t, 2H), 2.73(t, 2H), 1.93(M, 2H). Ionic spray MS [ M + 1H ]]⁺＝374.

N- [3- (5-Amidino-2-hydroxyphenyl) -propyl ] -4- (6-oxo-1, 6-dihydropyridin-3-yl) -benzamide trifluoroacetate salt

3- {3- [4- (6-methoxypyridin-3-yl) benzoylamino ] -propyl } -4-hydroxybenzonitrile was converted to the title compound by treatment with anhydrous hydrogen chloride/ethanol and ammonolysis as described in section D of example 303. HPLC purification (10% acetonitrile/0.1% aqueous TFA-100% acetonitrile) gave the title compound (0.018g, 0.046 mmol).

¹H NMR(CD₃OD, 300MHz) delta 8.94(bs, 1H), 8.53(bs, 1H), 8.0(dd, 1H), 7.92(AB, 2H), 7.84(s, 1H), 7.65(M, 3H), 7.56(dd, 1H), 6.95(d, 1H), 6.67(d, 1H), 3.42(t, 2H), 2.77(t, 2H), 1.98(M, 2H). ion spray MS [ M + 1H ]]⁺＝391.

Example 307

Compound 307

N- [3- (5-Amidino-2-hydroxyphenyl) -propyl ] -4- (pyridazin-4-yl) -benzamide bistrifluoroacetate

3- {3- [ (pyridazin-4-yl) benzoylamino ] propyl } -4- (2-methoxyethoxymethoxy) -benzonitrile

3- (3-aminopropyl) -4- (2-methoxyethoxymethyl) benzonitrile (0.05g, 0.19mmol) was treated with 4- (pyridazin-4-yl) -benzoic acid (0.038g, 0.18mmol), TBTU (0.058g, 0.18mmol) and triethylamine (0.035ml) as described in example 305 for part B to give the title compound (0.045g, 0.10mmol) after chromatography (dichloromethane-5% methanol/dichloromethane).¹H NMR(CDCl₃300MHz) delta 9.47(d, 1H), 9.27(d, 1H), 7.97(AB, 2H), 7.63(AB, 2H), 7.69(dd, 1H), 7.46(s, 1H), 7.18(d, 1H), 6.69(d, 1H), 5.37(s, 2H), 3.82(M, 2H), 3.50(M, 4H), 3.35(s, 3H), 2.73(t, 2H), 1.97(M, 2H)]⁺＝447.

N- [3- (5-Amidino-2-hydroxyphenyl) -propyl ] -4- (pyridazin-4-yl) -benzamide bistrifluoroacetate

3- {3- [ (pyridazin-4-yl) benzoylamino ] propyl } -4- (2-methoxyethoxymethoxy) -benzonitrile was treated with anhydrous hydrogen chloride/ethanol and then aminolyzed as described in section D of example 303 to convert to the title compound. HPLC purification afforded the title compound (0.025g, 0.066 mmol).

¹H NMR (DMSO, 300MHz) delta 10.65(s, 1H), 9.70(s, 1H), 9.30(d, 1H), 9.0(bs, 2H), 8.71(M, 3H), 8.05(M, 5H), 7.63(s, 1H), 7.55(dd, 1H), 6.95(d, 1H), 3.3(M, 2H), 2.64(t, 2H), 1.85(M, 2H). Ionic spray MS [ M +1]⁺＝376.

Example 308

Compound 308

N- [3- (5-Amidino-2-hydroxyphenyl) -propyl ] -7-chlorobenzothiophene-2-carboxamide trifluoroacetate salt

3- (3-aminopropyl) -4- (2-methoxyethoxymethyl) benzonitrile (0.05g, 0.19mmol) was reacted with 7-chlorobenzothiophene-3-carboxylic acid (0.044g, 0.020mmol), TBTU (0.058g, 0.18mmol) andtriethylamine (0.025ml) was treated and chromatographed (dichloromethane-5% methanol/dichloromethane) to give 3- {3- [ 7-chlorobenzothiophene-2-carboxamido]Propyl } -4- (2-methoxyethoxymethoxy) -benzonitrile (0.020g, 0.048 mmol); ion spray MS, [ M + H ]]⁺447. This material was treated with anhydrous hydrogen chloride/ethanol and then aminolyzed as described in section D of example 303. HPLC purification (10% acetonitrile/0.1% aqueous TFA-100% acetonitrile) gave the title compound (0.005g, 0.012 mmol).

¹H NMR (DMSO, 300MHz) delta 10.66(s, 1H), 9.01(s, 2H), 8.78(M, 1H), 8.64(bs, 2H), 8.22(s, 1H), 8.08(s, 1H), 7.88(d, 1H), 7.66(d, 1H), 7.56(dd, 1H), 7.47(dd, 21H), 6.95(d, 1H), 3.32(M, 2H), 2.65(t, 2H), 1.86(M, 2H). ion spray MS [ M + 1H ]]⁺＝388,390.

Example 309

Compound 309

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4- (6-methoxypyridin-3-yl) -benzamide trifluoroacetate salt

(E) -3- [3- (1, 3-dioxo-1, 3-dihydroisoindol-2-yl) propenyl ] -4- (2-methoxyethoxymethoxy) benzonitrile

A solution of 2-bromo-4-cyanophenol (5g, 25mmol) and MEM chloride (3ml, 26mmol) in THF (25ml) was added to a suspension of NaH (60%, 1.1g, 28mmol) in THF (25ml) at 0 deg.C. The resulting mixture was stirred at room temperature for 2 hours, concentrated, diluted with ethyl acetate, washed with 1N sodium hydroxide and water. The organic layer was dried over magnesium sulfate and concentrated to obtain a clear liquid (6.6g, 23 mmol). This product (5.6g, 20mmol) was reacted with N-allylphthalimide (4g, 21mmol), Pd (OAc)₂(0.13g, 0.58mmol), P (o-toluene) 3(0.37g, 1.2mmol) and triethylamine (5.6ml, 40 mmol). The reaction mixture was heated in a sealed tube at 100 ℃ overnight, cooled, diluted with ethyl acetate and washed with water (3X 100 ml). The organic layer was dried over magnesium sulfate and concentrated. Chromatography of the residue (20% -50% ethyl acetate/hexane) gaveThe title compound (3.5g, 8.9mmol) was obtained as a white solid.¹H NMR(CDCl₃，δ)：300MHz)δ7.86(m，2H)，7.72(m，2H)，7.65(d，1H)，7.44(d，1H)，7.18(d，1H)，6.90(d，1H)，6.30(m，1H)，5.33(s，2H)，4.46(d，2H)，3.80(d，2H)，3.52(d，2H)，3.40(s，3H).

(E) -3- (3-Aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile

Mixing (E) -3- [3- (1, 3-dioxo-1, 3-dihydroisoindol-2-yl) propenyl]-4- (2-methoxyethoxymethoxy) benzonitrile (3.1g, 8.0mmol) and NH₂NH₂The hydrate (0.96ml, 20mmol) was heated under reflux in ethanol (100ml) for 1.5 hours. The mixture was concentrated, treated with aqueous sodium hydroxide and extracted with dichloromethane (3 ×). The dichloromethane layer was dried and concentrated to give the title compound as a clear oil (1.9g, 7.2 mmol).

¹H NMR(CDCl₃，300MHz)δ7.70(d，1H)，7.47(dd，1H)，7.22(d，1H)，6.75(d，1H)，6.34(m，1H)，5.35(s，2H)，3.80(t，2H)，3.50(m，4H)，3.27(s，3H).

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4- (6-methoxypyridin-3-yl) -benzamide trifluoroacetate salt

A solution of (E) -3- (3-aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile (0.12g, 0.46mmol) in DMF was treated with (6-methoxypyridin-3-yl) -benzoic acid, TBTU and triethylamine as described in example 305 part B. Conventional post-treatment and chromatography are carried out to obtain the required 3- {3- [6- (6-oxo-1, 6-dihydropyridin-3-yl) benzoylamino]Propyl } -4- (2-methoxyethoxymethoxy) benzonitrile (0.22g, 0.46 mmol). A portion of the benzonitrile (0.09g, 0.19mmol) was treated with anhydrous hydrogen chloride in ethanol and then converted to benzamidine by aminolysis as described in section D of example 303. The product was purified by HPLC eluting with 10% acetonitrile/water (0.1% TFA) -100% acetonitrile to give the title compound as a white solid (0.05g, 0.12 mmol).¹H NMR(CD₃OD，300MHz)δ8.43(d，1H)，7.95(m，4H)，7.70(d2H), 7.55(dd, 1H), 6.90(M, 3H), 6.53(M, 1H), 4.18(d, 2H), 3.95(s, 3H). ion spray MS [ M + H]⁺＝403.

Example 310

Compound 310

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4- (6-oxo-1, 6-dihydropyridin-3-yl) -benzamide trifluoroacetate salt

(E) -3- {3- [4- (6-methoxypyridin-3-yl) benzoylamino prepared as part C of example 309]Propenyl } -4- (2-methoxyethoxymethoxy) -benzonitrile (0.12g, 0.25mmol) was treated with pyridinium hydrochloride as described in part A of example 306 to give a white solid (0.087g, 0.24 mmol). This material was treated with anhydrous hydrogen chloride/ethanol and then aminolyzed as described in section D of example 303. The crude product was purified by HPLC eluting with a gradient of 10% acetonitrile/water (0.1% TFA) to 100% acetonitrile followed by recrystallization (acetonitrile/methanol) to give the title compound as a white solid (0.03g, 0.077 mmol).¹H NMR(DMSO，300MHz)δ11.92(bs，1H)，10.85(s，1H)，9.03(s，2H)，8.82(t，1H)，8.65(s，2H)，7.85(m，5H)，7,65(d，2H)，7.55(d，1H)，6.94(d，1H)，6,72(d，1H)，6.42(m，2H)，4.08(t，2H).

Ion spray MS [ M + 1]]⁺＝389.

Example 311

Compound 311

(E) -Biphenyl-4-carboxylic acid [3- (5-carbamimidoyl-2-hydroxyphenyl-allyl ] -amide trifluoroacetate salt

A solution of (E) -3- (3-aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile (0.04g, 0.2mmol) in DMF (0.5ml) was treated with biphenyl-4-carboxylic acid (0.042g, 0.21mmol), TBTU (0.07g, 0.22mmol) and triethylamine (60ml, 0.44mmol) at 35 ℃ for 4 hours, then at room temperature overnight. The reaction mixture was diluted with ethyl acetate (8ml), washed with water (3X 2ml) and concentrated under a stream of nitrogen to give a residue. The residue was treated with absolute ethanol (5ml), cooled and saturated with hydrogen chloride gas; the reaction vessel was sealed and the reaction was allowed to stir at room temperature overnight. Removing the solvent and excess hydrogen chloride with a nitrogen stream; the residue was dissolved in methanol (5ml), cooled and saturated with ammonia gas. The reaction vessel was sealed and the solution was allowed to stir at room temperature overnight. The solvent and excess ammonia were removed with a stream of nitrogen. The residue was purified by HPLC eluting with a gradient of 10% acetonitrile/water (0.1% TFA) to 100% acetonitrile. The appropriate fractions were lyophilized to give the title compound as a white solid (0.012g, 0.032 mmol).

¹H NMR(CD₃OD，300MHz)δ8.84(t，1H)，7.92(m，3H)，7.70(d，2H)，7.65(d，2H)，7.54(dd，1H)，7.42(m，3H)，6.92(m，2H)，6.50(m，1H)，4.20(t，2H).

Ion spray MS [ M + 1]]⁺＝372.

The compound of example 312-320 was prepared using a method analogous to that described in example 311:

example 312

Compound 312

(E) -N- [3- (5-carbamimidoyl) -2-hydroxyphenyl) -allyl ] -4-pyridin-3-yl-benzamide bistrifluoroacetate

The title compound was prepared from (E) -3- (3-aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile and 4-pyridine-3-benzoic acid.¹H NMR(DMSO，300MHz)δ10.87(s，1H)，9.05(s，2H)，9.00(s，1H)，8.90(t，1H)，8.73(s，2H)，8.61(d，1H)，8.25(d，1H)，8.00(d，2H)，7.85(m，3H)，7,57(m，2H)，6.95(d，1H)，6.70(d，1H)，6.45(m，1H)，4.08(t，2H).

Ion spray MS [ M +2 ]]⁺＝187.

Example 313

Compound 313

(E) -N- [3- (5-carbamimidoyl) -2-hydroxyphenyl) -allyl ] -4-pyridin-4-yl-benzamide bistrifluoroacetate

The title compound was prepared from (E) -3- (3-aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile and 4-pyridine-4-benzoic acid.¹H NMR(CD₃OD，300MHz)δ8.97(t，1H)，8.80(d，2H)，8.22(d，2H)，8.00(m，5H)，7.55(dd，1H)，6.90(m，2H)，6.55(m，1H)，4.22(t，2H).

Ion spray MS [ M +2 ]]⁺＝187.

Example 314

Compound 314

(E) -Biphenyl-3, 4 '-dicarboxylic acid 3-amide 4' - { [3- (5-carbamimidoyl) -2-hydroxyphenyl) -allyl ] -amide } trifluoroacetate salt

The title compound was prepared from (E) -3- (3-aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile and biphenyl-3, 4' -dicarboxylic acid 3-amide.

¹H NMR(CD₃OD，300MHz)δ8.87(t，1H)，8.18(s，1H)，7.96(d，2H)，7.85(m，5H)，7.55(m，2H)，6.95(m，2H)，6.53(m，1H)，4.21(t，2H).

Ion spray MS [ M + 1]]⁺＝415.

Example 315

Compound 315

(E) -4-tert-butyl-N- [3- (5-carbamimidoyl-2-hydroxyphenyl ] -allyl ] -benzamide trifluoroacetate salt

The title compound was prepared from (E) -3- (3-aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile and 4-tert-butylbenzoic acid.¹H NMR(CD₃OD，300MHz)δ8.72(t，1H)，7.90(d，1H)，7.78(d，2H)，7.50(m，3H)，6.90(m，2H)，6.50(m，1H)，4.17(t，2H)，1.34(s，9H).

Ion spray MS [ M + 1]]⁺＝352.

Example 316

Compound 316

(E) -N- [3- (5-carbamimidoyl) -2-hydroxyphenyl) -allyl ] -4- (3H-imidazol-4-yl) -benzamide bistrifluoroacetate

The title compound was prepared from (E) -3- (3-aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile and 4- (3H-imidazol-4-yl) benzoic acid.¹H NMR(CD₃OD，300MHz)δ8.90(m，2H)，8.00(m，3H)，7.90(d，1H)，7.85(d，2H)，7.57(dd，1H)，6.93(m，2H)，6.53(m，1H)，4.20(t，2H).

Ion spray MS [ M + 1]]⁺＝362；[M+2]²⁺＝181.4.

Example 317

Compound 317

(E) -Biphenyl-4, 4 '-dicarboxylic acid 4-amide 4' - { [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -amide } trifluoroacetate salt

The title compound was prepared from (E) -3- (3-aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile and biphenyl-4, 4' -dicarboxylic acid 4-amide.¹H NMR(CD₃OD，300MHz)δ8.87(t，1H)，7.96(m，5H)，7.79(m，4H)，7.55(d，1H)，6.90(m，2H)，6.50(m，1H)，4.22(t，2H).

Ion spray MS [ M + 1]]⁺＝415.

Example 318

Compound 318

(E) -N- [3- (5-carbamimidoyl) -2-hydroxyphenyl) -allyl ] -4- (1H-imidazol-2-yl) -benzamide bistrifluoroacetate

The title compound was prepared from (E) -3- (3-aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile and 4- (1H-imidazol-2-yl) benzoic acid.¹H NMR(CD₃OD，300MHz)δ9.02(t，1H)，8.08(d，2H)，8.00(d，2H)，7.90(d，1H)，7.67(s，2H)，7.53(dd，1H)，6.90(m，2H)，6.53(m，1H)，4.19(t，2H).

Ion spray MS [ M + 1]]⁺＝362；[M+2]⁺＝181.6.

Example 319

Compound 319

(E) -3-oxo-2, 3-dihydro-thieno [3, 2-c ] pyridazine-6-carboxylic acid [3- (5-amidino-2-hydroxyphenyl) -allyl ] -amide trifluoroacetate salt

From (E) -3- (3-aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile and 3-oxo-2, 3-dihydro-thieno [3, 2-c)]Pyridazine-6-carboxylic acid the title compound was prepared.¹H NMR(CD₃OD，300MHz)δ7.90(d，1H)，7.74(s，1H)，7.55(dd，1H)，7.40(s，1H)，6.90(m，2H)，6.49(m，1H)，4.13(d，2H).

Ion spray MS [ M + 1]]⁺＝370.

Example 320

Compound 320

(E) -5-pyridin-2-yl-thiophene-2-carboxylic acid [3- (5-amidino) -2-hydroxyphenyl) -allyl ] -amide ditrifluoroacetate

The title compound was prepared from (E) -3- (3-aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile and 5-pyridin-2-yl-thiophene-2-carboxylic acid.¹H NMR(CD₃OD，300MHz)δ8.97(bs，1H)，8.50(m，2H)，7.87(m，3H)，7.70(m，2H)，7.55(dd，1H)，7.30(m，1H)，6.89(m，2H)，6.47(m，1H)，4.15(d，2H).

Ion spray MS [ M + 1]]⁺＝379；[M+2]²⁺＝190.

Example 321

Compound 321

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4- (1-oxo-pyridin-4-yl) -benzamide bistrifluoroacetate

A.4- (1-oxy-pyridin-4-yl) -benzoic acid

A solution of methyl 4-pyridine-4-benzoate (0.32g, 1.6mmol) in dichloromethane (30ml) was treated with MCPBA (50-60%, 0.88g) at 0 ℃ and then stirred at room temperature for 3 hours. 1N sodium hydroxide was added to stop the reaction; the dichloromethane layer was washed with water, dried and concentrated to give methyl 4- (1-oxy-pyridin-4-yl) benzoate (0.23g, 1.0mmol) as a solid. The material was treated with 1N sodium hydroxide (1ml) in methanol/THF/water (1ml/lml/3ml) at room temperature for 3 hours and then neutralized to pH about 6 with 1N hydrochloric acid. The off-white solid was collected and washed with acetone to give 4- (1-oxy-pyridin-4-yl) benzoic acid (0.12g, 0.56 mmol).

¹H NMR(DMSO-d₆，300MHz)δ8.27(d，2H)，8.0(d，2H)，7.88(d，2H)，7.83(d，2H).

(E) -N- [3- (5-carbamimidoyl) -2-hydroxyphenyl) -allyl ] -4- (1-oxy-pyridin-4-yl) -benzamide bistrifluoroacetate

The title compound was prepared from (E) -3- (3-aminopropenyl) -4- (2-methoxyethoxymethoxy) benzonitrile and 4- (1-oxy-pyridin-4-yl) -benzoic acid essentially as described in part D of example 303.

¹H NMR(DMSO-d₆，300MHz)δ8.98(bs，1H)，8.50(bs，1H)，8.42(d，2H)，8.02(d，2H)，7.95-7.88(m，5H)，7.56(dd，1H)，6.94(d，1H)，6.88(d，1H)，6.50(m，1H)，4.18(d，2H).APCI MS，[M+H]⁺＝389.

Example 322

Compound 322

Biphenyl-4-carboxylic acid [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -amide trifluoroacetate salt

(E) -Biphenyl-4-carboxylic acid [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl, prepared as in example 311]-amide trifluoroacetate salt (0.006g, 0.0012mmol) was dissolved in methanol (5ml), treated with a catalytic amount of 10% palladium on carbon and stirred under hydrogen atmosphere overnight. Filtering to remove solids; the filtrate was concentrated under a stream of nitrogen.The residue was then purified by HPLC eluting with a gradient of 10% acetonitrile/water (0.1% TFA) to 100% acetonitrile. The appropriate fractions were lyophilized to give the title compound (0.006g, 0.012mmol) as a white solid.¹H NMR(CD₃OD，300MHz)δ7.90(d，2H)，7.70-7.60(m，5H)，7.54-7.35(m，4H)，6.90(d，1H)，3.43(t，2H)，2.75(t，2H)，1.97(m，2H).APCI MS[M+1]⁺＝374.

The compound of example 323-328 was prepared in a similar manner to that described in example 322.

Example 323

Compound 323

N- [3- (5-Amidino-2-hydroxyphenyl) -propyl ] -4- (6-methoxypyridin-3-yl) -benzamide trifluoroacetate salt

Reduction of (E) -N- [3- (5-amidino-2-hydroxyphenyl) -allyl]-4- (6-methoxypyridin-3-yl) -benzamide trifluoroacetate the title compound is prepared.¹H NMR(CD₃OD，300MHz)δ8.93(bs，1H)，8.50(m，2H)，8.00(d，1H)，7.90(d，2H)，7.68(d，2H)，7.64(d，1H)，7.55(dd，1H)，6.92(d，2H)，3.97(s，3H)，3.44(t，2H)，2.76(t，2H)，1.97(m，2H).APCI MS[M+1]⁺＝405.

Example 324

Compound 324

Biphenyl-3, 4 '-dicarboxylic acid 3-amide 4' - { [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -amide } trifluoroacetate salt

Reduction of (E) -Biphenyl-3, 4 '-dicarboxylic acid 3-amide 4' - ([3- (5-amidino-2-hydroxyphenyl) -allyl]-amide } trifluoroacetate the title compound was prepared.¹H NMR(CD₃OD，300MHz)δ8.17(s，1H)，7.94-7.76(m，6H)，7.65-7.52(m，3H)，6.92(d，1H)，3.44(t，2H)，2.75(t，2H)，1.97(m，2H).APCI MS[M+1]⁺＝417.

Example 325

Compound 325

4-tert-butyl-N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -benzamide trifluoroacetate salt

Reduction of (E) -4-tert-butyl-N- [3- (5-amidino-2-hydroxyphenyl) -allyl]-benzamide trifluoroacetate salt the title compound is prepared.¹H NMR(CD₃OD，300MHz)δ7.74(d，2H)，7.60(d，1H)，7.50(m，3H)，6.89(d，1H)，3.39(t，2H)，2.74(t，2H)，1.94(m，2H)，1.33(s，9H).APCI MS[M+1]⁺＝354.

Example 326

Compound 326

[3- (5-Amidino-2-hydroxyphenyl) -propyl ] -4- (3H-imidazol-4-yl) -benzamide bistrifluoroacetate

Reduction of (E) - [3- (5-amidino-2-hydroxyphenyl) -allyl]-4- (3H-imidazol-4-yl) -benzamide bistrifluoroacetate salt the title compound is prepared.¹H NMR(CD₃OD，300MHz)δ8.97(s，1H)，8,65(t，1H)，7.99(m，3H)，7.84(d，2H)，7.64(d，1H)，7.57(dd，1H)，6.93(d，1H)，3.44(m，2H)，2.76(t，2H)，1.98(m，2H).APCI MS[M+1]⁺＝364.

Example 327

Compound 327

N- [3- (5-Amidino-2-hydroxyphenyl) -propyl ] -4- (1H-imidazol-2-yl) -benzamide bistrifluoroacetate

Reduction of (E) -N- [3- (5-amidino-2-hydroxyphenyl) -allyl]-4- (1H-imidazol-2-yl) -benzamide bistrifluoroacetate salt the title compound is prepared.¹H NMR(CD₃OD，300MHz)δ8.77(t，1H)，8.06(m，4H)，7.69(s，2H)，7.65(d，1H)，7.57(dd，1H)，6.93(d，1H)，3.44(m，2H)，2.76(t，2H)，1.97(m，2H).APCI MS[M+1]⁺＝364.

Example 328

Compound 328

5-pyridin-2-yl-thiophene-2-carboxylic acid [3- (5-amidino-2-hydroxyphenyl) -allyl ] -amide ditrifluoroacetate

Reduction of (E) -5-pyridin-2-yl-thiophene-2-carboxylic acid [3- (5-amidino-2-hydroxyphenyl) -allyl]Amide ditrifluoroacetate salt to prepare the title compound.¹H NMR(CD₃OD，300MHz)δ8.92(bs，1H)，8.50(m，2H)，7.90(m，2H)，7.68(m，2H)，7.60(d，1H)，7.54(dd，1H)，7.34(m，1H)，6.89(d，1H)，3.38(t，2H)，2.76(t，2H)，1.97(m，2H).APCI MS[M+1]⁺＝381.

Example 329

Compound 329

N- [3- (5-Amidino-2-hydroxyphenyl) -propyl ] -4-piperidin-4-yl-benzamide bistrifluoroacetate

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] was treated as described in example 322]-4-piperidin-4-yl-benzamide ditrifluoroacetate followed by treatment in the presence of 10% Pd/C at 50psi hydrogen pressure for 5 hours. Filtration and concentration of the filtrate to dryness gave the title compound (0.005g, 0.008 mmol).¹H NMR(CD₃OD, 300MHz) delta 8.50(bs, 1H), 7.80(d, 2H), 7.59(d, 1H), 7.55(dd, 1H), 7.37(d, 2H), 6.93(d, 1H), 3.5-2.9(M, 7H), 2.75(t, 2H), 2.1-1.9(M, 6H). Ionic spray MS [ M +1]⁺＝381，[M+2]²⁺＝191.

Example 330

Compound 330

2- (3-Amidino-benzyl) -3- [4- (1-oxy-pyridin-4-yl) -benzoylamino ] -butyric acid trifluoroacetate salt

2- (3-Amidino-benzyl) -3- [4- (1-oxy-pyridin-4-yl) benzoylamino-butyric acid methyl ester hydrochloride (0.60g, 1.1mmol) was dissolved in 15% acetonitrile/waterTreated with 1.0N sodium hydroxide (6 ml). The mixture was stirred at room temperature for 2 hours, then acidified with TFA. The crude product was purified by HPLC eluting with a gradient of 10% acetonitrile/water (0.1% TFA) to 100% acetonitrile. The product fractions were lyophilized to give the title compound as a white solid (0.43g, 0.92 mmol).¹H NMR(DMSO-D₆，300MHz)δ9.25(s，2H)，9.0(s，2H)，8.38(d，1H)，8.28(d，2H)，7.92-7.80(m，5H)，7.60-7.46(m，4H)，4.40(m，1H)，2.94(m，3H)，1.23(d，3H).Fab MS，[M+H]^-＝433.

Example 331

Compound 331

2- (R) - (3-amidino-benzyl) -3- (R) - [ (3' -nitrobiphenyl-4-carbonyl) amino ] -butyric acid methyl ester trifluoroacetate salt

Methyl 2- (R) - (3-amidino-benzyl) -3- (R) - [ (3' -nitrobiphenyl-4-carbonyl) amino ] -butanoate trifluoroacetate is prepared in a substantially similar manner to that described above from the appropriate starting material.

¹H NMR(DMSO-d₆，300MHz)δ8.40-8.52(m，2H)，8.15-8.30(m，2H)，7.85-8.0(m，4H)，7.75-7.82(m，1H)，7.52(s，1H)，4.35-4.51(m，1H)，3.47(s，3H)，3.04-3.15(m，1H)，2.90-3.03(m，2H)，1.23(d，3H).

Ion spray MS, [ M + H ]]⁺＝490.

Example 332

Compound 332

2- (R) - (3-amidino-benzyl) -3(R) - (4-pyridin-2-yl-benzoylamino) -butyric acid methyl ester bistrifluoroacetate

2- (R) - (3-amidino-benzyl) -3(R) - (4-pyridin-2-yl-benzoylamino) -butyric acid methyl ester bistrifluoroacetate salt is prepared from the appropriate starting material by a method substantially similar to that described above.

¹H NMR(CD₃OD，300MHz)δ8.68(d，1H)，7.92-8.11(m，6H)，7.47-7.68(m，5H)，4.40-4.55(m，1H)，3.62(s，3H)，3.02-3.18(m，3H)，1.32(d，3H)

Ion spray MS, [ M + 1]]⁺＝431.

Example 333

Compound 333

2- (R) - (3-amidino-benzyl) -3(R) - [4- (1-oxo-pyridin-2-yl) -benzoylamino ] -butyric acid methyl ester trifluoroacetate salt

Preparation of 2- (R) - (3-amidino-benzyl) -3(R) - [4- (1-oxy-pyridin-2-yl) -benzoylamino from the appropriate starting Material by a method substantially analogous to that described above]-butyric acid methyl ester trifluoroacetate.¹H NMR(CD₃OD，300Mhz)δ8.46(d，1H)，7.92(m，4H)，7.67-7.77(m，2H)，7.45-7.66(m，5H)，4.40-4.55(m，1H)，3.60(s，3H)，3.02-3.18(m，3H)，1.34(d，3H)

Ion spray MS, [ M + 1]]⁺＝447.

Example 334

Compound 334

2- {4- [3- (3-carbamimidoyl-phenyl) -2(R) -methoxycarbonyl-1 (R) -methylpropylcarbamoyl ] -phenyl } -1-methyl-pyridinium-bistrifluoroacetate

Preparation of 2- {4- [3- (3-carbamimidoyl-phenyl) -2(R) -methoxycarbonyl-1 (R) -methylpropylcarbamoyl from the appropriate starting Material by a method substantially analogous to that described above]-phenyl } -1-methyl-pyridinium-bistrifluoroacetate.¹H NMR(CD₃OD，300Mhz)δ9.04(d，1H)，8.66(m，1H)，8.02-8.18(m，4H)，7.79(d，2H)，7.45-7.70(m，4H)，4.38-4.50(m，1H)，4.22(s，3H)，3.60(s，3H)，3.03-3.18(m，3H)，1.38(s，3H).Fab MS[M+]⁺＝445.

Example 335

Compound 335

2- (R) - (3-amidino-benzyl) -3- (R) - [ (3 ', 4' -dimethoxybiphenyl-4-carbonyl) amino ] -butyric acid methyl ester trifluoroacetate salt

Methyl 2- (R) - (3-amidino-benzyl) -3- (R) - [ (3 ', 4' -dimethoxybiphenyl-4-carbonyl) amino ] -butyrate trifluoroacetate is prepared in a substantially similar manner to that described above from the appropriate starting material.

¹H NMR(DMSO-d₆，300MHz)δ8.32(d，1H)，7.82-7.9(m，2H)，7.71-7.78(m，2H)，7.61(s，1H)，7.52(m，2H)7.22-7.30(m，2H)，7.06(d，1H)4.08-4.35(m，1H)，3.83(s，3H)，3.78(s，3H)，3.50(s，3H)，3.03-3.13(m，1H)，2.92-3.02(m，2H)，1.25(d，3H).

Ion spray MS, [ M + H ]]⁺＝490.

Example 336

Compound 336

2- (R) - (3-amidino-benzyl) -3- (R) - { [ (1-oxo-pyridin-2-yl) -thiophene-2-carbonyl ] -amino } -butyric acid methyl ester trifluoroacetate salt

Preparation of 2- (R) - (3-amidino-benzyl) -3- (R) - { [ (1-oxo-pyridin-2-yl) -thiophene-2-carbonyl from a suitable starting Material by a method substantially analogous to that described above]-amino } -butyric acid methyl ester trifluoroacetate salt.¹H NMR(CD₃OD，300Mhz)δ8.73(s，1H)，8.42(d，1H)，8.37(m，2H)，7.92-7.98(m，1H)，7.42-7.68(m，5H)，4.35-4.48(m，1H)，3.60(s，3H)，3.01-3.20(m，3H)，1.32(d，3H)

Ion spray MS, [ M + 1]]⁺＝453.

Example 337

Compound 337

2- {5- [3- (3-carbamimidoyl-phenyl) -2(R) -methoxycarbonyl-1 (R) -methylpropylcarbamoyl ] -thiophen-3-yl } -1-methyl-pyridinium-bistrifluoroacetate

Preparation of 2- {5- [3- (3-carbamimidoyl-phenyl) -2(R) -methoxycarbonyl-1 (R) -methylpropylcarbamoyl from the appropriate starting Material by a method substantially analogous to that described above]-thiophen-3-yl } -1-methyl-pyridinium-bistrifluoroacetate.¹H NMR(CD₃OD，300Mhz)δ8.99(d，1H)，8.60(m，1H)，8.28(s，1H)，8.02-8.17(m，3H)，7.45-7.68(m，4H)，4.38-4.50(m，1H)，4.32(s，3H)，3.55(s，3H)，3.02-3.15(m，3H)，1.34(d，3H).Fab MS[M+]⁺＝451.

Example 338

Compound 338

2- (R) - (3-Amidino-benzyl) -3(R) - { [ (1-oxo-pyridin-3-yl) -thiophene-2-carbonyl ] -amino } butanoic acid methyl ester trifluoroacetate salt

Preparation of 2- (R) - (3-amidino-benzyl) -3(R) - { [ (1-oxo-pyridin-3-yl) -thiophene-2-carbonyl from a suitable starting Material by a method substantially analogous to that described above]-amino } butanoic acid methyl ester trifluoroacetate salt.¹H NMR(CD₃OD，300MHz)δ8.67(s，1H)，8.36(d，1H)，8.30(dd，1H)，8.21(s，1H)，8.12(s，1H)，7.93(dd，1H)，7.45-7.68(m，4H)，4.37-51(m，1H)，3.61(s，3H)，3.02-3.18(m，3H)，1.32(d，3H).

Ion spray MS, [ M + H ]]⁺＝453.

Example 339

Compound 339

3- {5- [3- (3-carbamimidoyl-phenyl) -2(R) -methoxycarbonyl-1 (R) -methylpropylcarbamoyl ] -thiophen-3-yl } -1-methyl-pyridinium-bistrifluoroacetate

Preparation of 3- {5- [3- (3-carbamimidoyl-phenyl) -2(R) -methoxycarbonyl-1 (R) -methylpropylcarbamoyl from the appropriate starting Material by a method substantially analogous to that described above]-thiophen-3-yl } -1-methyl-pyridinium-bistrifluoroacetate.¹H NMR(CD₃OD，300MHz)δ9.34(s，1H)，8.80-8.88(m，2H)，8.36(s，1H)，8.25(s，1H)，8.09-8.17(m，1H)，7.48-7.68(m，4H)，4.46(s，3H)，4.37-4.45(m，1H)，3.58(s，3H)，3.02-3.18(m，3H)，1.33(d，3H).

Ion spray MS, N⁺＝451.

Example 340

Compound 340

2- (R) - (3-amidino-benzyl) -3(R) - [4- (6-oxo-1, 6-dihydro-pyridin-3-yl) -benzoylamino ] -butyric acid methyl ester trifluoroacetate salt

A.4- (6-methoxy-pyridin-3-yl) -benzoic acid ethyl ester

A1.6M solution of n-butyllithium in hexane (9.53ml, 15.24mmol) was added dropwise to a stirred solution of 5-bromo-2-methoxypyridine (2.72g, 14.52mmol) in THF (50ml) at-78 deg.C. The resulting mixture was stirred at-78 ℃ for 15 minutes. To this was added 0.5M zinc chloride in THF (29.04ml, 14.52mmol) and the resulting mixture was allowed to warm to room temperature. In another flask, tetrakis (triphenylphosphine) palladium (0) (0.58g, 0.50mmol) was stirred in THF (10 ml). To this was added 4-ethyl-iodobenzoate (3.61 g.13.07mmol). The contents of the two flasks were combined and stirred at room temperature for 1 hour. 5% aqueous ammonia (150ml) was added with stirring. The mixture was extracted with ethyl acetate (3 ×). The organic layers were combined and dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (2.5% ethyl acetate/hexane-5% ethyl acetate/hexane) to give the title compound as a white solid (2.43g, 9.44 mmol).

¹H NMR(CDCl₃，300MHz)d 8.41(d，1H)，8.08(d，2H)，7.82(dd，1H)，7.60(d，2H)，6.82(d，1H)，4.38(q，2H)，3.98(s，3H)，1.40(t，3H).

B.4- (6-methoxypyridin-3-yl) -benzoic acid

A1N sodium hydroxide solution (20ml) was added to a mixture of 4- (6-methoxypyridin-3-yl) -benzoic acid ethyl ester (2.43g, 9.44mmol) in methanol (20ml) and THF (20ml) and stirred at 35 ℃ for 1 h. The reaction was cooled and 1N hydrochloric acid was added until the pH was about 4. The precipitate was isolated by filtration and dried in a vacuum desiccator to give the product as a white solid (2.03g, 8.86 mmol).

¹H NMR(DMSO-d₆，300MHz)δ8.57(d，1H)，8.08(dd，1H)，7.99(d，2H)，7.82(d，2H)，6.95(d，1H)，3.89(s，3H).

C.2- (R) - (3-cyanobenzyl) -3(R) - [4- (6-methoxypyridin-3-yl) -benzoylamino ] -butyric acid methyl ester

Add DIPEA (0.44ml.2.54mmol), TBTU (0.91g, 2.54mmol) and methyl 2(R) - (3-cyanobenzyl) -3(R) -aminobutyric acid (0.59g, 2.54mmol) to a stirred solution of 4- (6-methoxypyridin-3-yl) -butyric acid (0.67g, 2.54mmol) in DMF (5 ml). The solution was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate (3 ×), brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (50% ethyl acetate/hexanes-60% ethyl acetate/hexanes) to give the title compound as a white solid (0.83g, 1.87 mmol).

¹H NMR(CDCl₃，300MHz)δ8.43(d，1H)，7.92(d，2H)，7.83(dd，1H)，7.63(d，1H)，7.30-7.55(m，4H)，6.87(d，1H)，4.42-4.53(m，1H)，3.98(s，3H)，3.66(s，3H)，2.85-3.08(m，3H)，1.28(d，3H).

2- (R) - (3-cyanobenzyl) -3(R) - [4- (6-oxo-1, 6-dihydropyridin-3-yl) -benzoylamino ] -butyric acid methyl ester

Reacting 2- (R) - (3-cyanobenzyl) -3(R) - [4- (6-methoxypyridin-3-yl) -benzoylamino]A mixture of methyl butyrate (0.80g, 1.805mmol) and pyridine hydrochloride (3.37g, 21.6mmol) was heated at 160 ℃ for 10 minutes. The reaction was cooled to room temperature and water (40ml) was added. The resulting mixture was partitioned between dichloromethane and saturated sodium bicarbonate. The organic layer was washed with saturated sodium bicarbonate (2 ×), brine, dried over magnesium sulfate, filtered and concentrated. The crude product was obtained as a brown foam (0.82 g).¹H NMR(CDCl₃，300Mhz)δ7.78-7.95(m，3H)，7.65-7.73(m，1H)，7.28-7.57(m，6H)，6.45(d，1H)，4.41-4.54(m，1H)，3.66(s，3H)，2.82-3.07(m，3H)，1.28(d，3H).

E.2- (R) - (3-amidino-benzyl) -3(R) - [4- (6-oxo-1, 6-dihydro-pyridin-3-yl) -benzoylamino ] -butyric acid methyl ester trifluoroacetate salt

The compound is prepared in a manner substantially similar to that described above using 2- (R) - (3-cyanobenzyl) -3(R) - [4- (6-oxo-1, 6-dihydropyridin-3-yl) -benzoylamino]-methyl butyrate is prepared as a raw material.¹H NMR(DMSO-d₆，300MHz)δ8.32(d，1H)，7.88(d，1H)，7.81-7.83(m，2H)，7.65-7.69(m，2H)，7.55-7.63(m，2H)，7.45-7.52(m，2H)，6.45(d，1H)，4.32-4.48(m，1H)，3.48(s，3H)，3.01-3.11(m，1H)，2.88-2.98(m，2H)，1.22(d，3H).

Ion spray MS, [ M + 1]]⁺＝447.

Example 341

Compound 341

2- (5-Amidino-2-hydroxybenzyl) -3- (4- (pyridin-3-yl)) -benzoylamino-propionic acid methyl ester

A.3- (4- (pyridin-3-yl) -benzoylamino) -propionic acid tert-butyl ester

Add DMF (8mL, 0.5mmol) to a suspension of 4- (pyridin-3-yl) -benzoic acid (1.32g, 6.6mmol) in dichloromethane (26mL) followed by oxalyl chloride (6.6mL, 2M in dichloromethane). The resulting suspension was stirred for 3 hours and then concentrated in vacuo. The residue was added to (3-amino) -propionic acid tert-butyl ester hydrochloride (1.089g, 6 mmol). The resulting mixture was diluted with dichloromethane (26ml) cooled to 0 ℃ and triethylamine (3.3ml, 24mmol) was added. The resulting mixture was stirred for 3 hours, then diluted with ethyl acetate: dichloromethane (ca. 2: 1), washed with water (3 ×), brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (60% ethyl acetate in dichloromethane) to give the title compound as a white solid, 1.22 g.

¹H NMR(CDCl₃)δ1.49(s，9H)，2.59(t，J＝7Hz，2H)，3.73(q，J＝7Hz，2H)，6.98(bt，J＝7Hz，1H)，7.40(m，1H)，7.67(d，J＝8Hz，2H)，7.89(m，3H)，8.63(bd，1H)，8.88(bs，1H).MS m/z 327(M+H).

B.2- (5-iodo-2- (2-methoxy-ethoxymethoxy) -benzyl) -3- (4- (pyridin-3-yl) -benzoylamino) -propionic acid tert-butyl ester

To a cooled (-15 ℃ C.) solution of diisopropylamine (1.6ml, 11.5mmol) in THE (20ml) was added dropwise n-butyllithium (4.6ml, 2.5M in hexane). The resulting solution was stirred for 10 minutes and then cooled to-78 ℃ over 10 minutes. To this solution was added a solution of 3- (4- (pyridin-3-yl) -benzoylamino) -propionic acid tert-butyl ester (1.65g, 5mmol) in THE/DMPU (6ml, 1/1). After the addition was complete, the reaction mixture was warmed to-40 ℃ over 15 minutes. To this solution was added a solution of bromine (2.13g, 5.3mmol) in THE (10 ml). The reaction mixture was stirred for 20 minutes, then hydrochloric acid (5ml, 1M) was added. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (80% ethyl acetate in hexane) to give 3.03g of the title compound as a foam.¹H NMR(CDCl₃)δ1.40(s，9H)，2.81(m，1H)，2.95(m，1H)，3.06(m，1H)，3.47(s，3H)，3.54(m，2H)，3.68(m，2H)，3.80(m，2H)，5.29(s，2H)，6.91(m，2H)，7.40(m，1H)，7.47(m，2H)，7.66(d，J＝8Hz，2H)，7.89(m，2H)，8.64(bd，1H)，8.88(bs，1H).MS m/z 647(M+H).

C.2- (5-iodo-2-hydroxybenzyl) -3- (4- (pyridin-3-yl)) -benzoylamino-propionic acid methyl ester

Add TFA (5ml) to a solution of 2- (5-iodo-2- (2-methoxy-ethoxymethoxy) -benzyl) -3- (4- (pyridin-3-yl) -benzoylamino) -propionic acid tert-butyl ester (3.03g, 4.69mmol) in dichloromethane (25 ml). The resulting solution was stirred for 19 hours and then concentrated to about half of the initial volume. To the solution was added toluene (20 ml). The solution was concentrated under reduced pressure. The residue was dissolved in THF (20ml) and cooled to-10 ℃. To this solution was added sodium methoxide (2.3ml, 25% wt solution in methanol). After stirring for 10 minutes, the pH of the reaction mixture was adjusted to 6 with hydrochloric acid (1M). The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (eluting with 80% ethyl acetate in hexane) to give 2.13g of the title compound.

¹H NMR(CDCl₃)δ3.01(m，3H)，3.68(m，2H)，3.70(s，3H)，6.67(d，J＝8Hz，1H)，7.39(m，3H)，7.48(d，J＝8Hz，2H)，7.85(m，3H)，8.6(dd，1H)，8.70(d，1H)，9.40(bs，1H).MS m/z 517(M+H).

2- (5-cyano-2-hydroxybenzyl) -3- (4- (pyridin-3-yl) -benzoylamino-propionic acid methyl ester

Add 2- (5-iodo-2-hydroxybenzyl) -3- (4- (pyridin-3-yl) -benzoylamino-propionic acid methyl ester (2.1g, 4.07mmol), (Ph)₃P)₄Pd (460mg, 0.4mmol) and ZnCN₂To the mixture (1.42g, 12.2mmol) was added DMF (20 ml). The resulting mixture was degassed and purged with nitrogen and then placed in an oil bath to maintain it at 73 ℃. The reaction mixture was stirred at this temperature for 90 minutes, cooled, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate dichloromethane (4: 1, 3X). The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (eluting with 90% ethyl acetate in dichloromethane) to yield 1.53g of the title compound.¹HNMR(CDCl₃)δ3.03(m，1H)，3.16(m，1H)，3.68(m，3H)，3.70(s，3H)，6.93(d，J＝8Hz，1H)，7.39(m，3H)，7.50(d，J＝8Hz，2H)，7.95(m，3H)，8.6(dd，1H)，8.71(d，1H).MS m/z 416(M+H).

E.2- (5-amidino-2-hydroxybenzyl) -3- (4- (pyridin-3-yl) -benzoylamino-propionic acid methyl ester

2- (5-cyano-2-hydroxybenzyl) -3- (4- (pyridin-3-yl) -benzoylamino-propionic acid methyl ester (623mg, 1.5mmol) was dissolved in a saturated methanol (15ml) solution of hydrogen chloride after stirring for 5 hours, concentrated under reduced pressure, the residue was taken up in a saturated methanol (10ml) solution of ammonia and stirred for 18 hours, then concentrated under reduced pressure, the residue was purified by flash chromatography (1% triethylamine/10% ethyl acetate in dichloromethane) to give 343mg of the title compound as a solid.

¹H NMR(CD₃OD)δ2.88(m，1H)，3.08(m，2H)，3.50(m，1H)，3.67(s，3H)，3.68(m，1H)，6.68(d，J＝8Hz，1H)，7.50(m，3H)，7.78(d，J＝8Hz，2H)，8.0(d，J＝8Hz，2H)，8.14(m，1H)，8.55(d，1H)，8.86(bs，1H).MS m/z 433(M+H).

Example 342

Compound 342

2(R) - (3-amidino-6-hydroxybenzyl) -3(R) - [4- (6-oxo-1, 6-dihydropyridin-3-yl) -benzoylamino ] -butyric acid methyl ester

2(R) - (3-amidino-6-hydroxybenzyl) -3(R) - [4- (6-oxo-1, 6-dihydropyridin-3-yl) -benzoylamino ] -butyric acid methyl ester was prepared using the above method.

The molecules described herein can inhibit blood coagulation due to their ability to inhibit the penultimate enzyme in the coagulation chain (i.e., factor Xa rather than thrombin). Both free factor Xa and factor Xa assembled in the prothrombinase complex (factor Xa, factor Va, calcium and phospholipid) can be inhibited. The inhibition of factor Xa is obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma cofactor antithrombin III. Effective factor Xa inhibition can be achieved by oral administration, continuous intravenous infusion, intravenous bolus injection or any other parenteral route of administration of the compound, which results in the desired prevention of factor Xa from inducing prothrombin to thrombin.

Anticoagulant therapy is useful for the treatment and prevention of various thrombotic indications of arterial and venous vessels. In the arterial system, abnormal thrombosis is primarily associated with coronary arteries, cerebral vessels and peripheral vessels. Diseases associated with thrombotic closure of these vessels include primarily Acute Myocardial Infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and Percutaneous Transluminal Coronary Angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication and Coronary Artery Bypass Grafting (CABG) or peripheral artery bypass grafting. Long-term anticoagulant therapy is also beneficial in preventing vascular luminal stenosis (restenosis), which often follows PTCA and CABG; and is useful for maintaining vascular patency in long-term hemodialysis patients. In the case of venous vessels, pathological thrombosis often occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT also puts patients at high risk of being predisposed to pulmonary thromboembolism. Systemic Disseminated Intravascular Coagulation (DIC) often occurs in the vascular system during septic shock, certain viral infections and cancer. This indication is characterized by the rapid consumption of coagulation factors, their plasma inhibitors leading to life-threatening clot formation, spread over the tiny blood vessels of several organ systems. The indications discussed above include some, but not all, possible clinical situations suitable for anticoagulant therapy. Situations where short-term or long-term prophylactic anticoagulation therapy is required are well known to those skilled in the art.

These compounds may be used alone or in combination with other diagnostic agents, anticoagulants, antiplatelet agents, or fibrinolytic agents. For example, administration of a factor Xa inhibitor in combination with standard heparin, low molecular weight heparin, a direct thrombin inhibitor (e.g., hirudin), aspirin, a fibrinogen receptor antagonist, streptokinase, urokinase, and/or a plasminogen activator can produce a more potent antithrombotic or thrombolytic effect. Administration of the compounds described herein can treat thrombotic complications in a variety of animals, such as primates (including humans), sheep, horses, cattle, pigs, dogs, rats and mice. The inhibition of factor Xa may be used not only in the anticoagulant treatment of patients with thrombotic indications, but also in any situation where inhibition of blood coagulation is desired, such as the prevention of coagulation of stored whole blood and the prevention of coagulation of other biological samples tested or stored. Thus, any factor Xa inhibitor can be added to or contacted with a medium containing or suspected of containing factor Xa and in which it is desired to inhibit blood coagulation.

In addition to their use in anticoagulant therapy, factor Xa inhibitors may also be useful in the treatment or prevention of other diseases in which thrombin generation is implicated in the pathology. Thrombin is thought to be associated with morbidity and mortality, for example, in the following chronic and degenerative diseases, for example, due to its ability to modulate a number of different types of cells by specifically cleaving and activating cell surface thrombin receptors: arthritis, cancer, atherosclerosis, and Alzheimer's disease. Inhibition of factor Xa will effectively block thrombin formation and thus neutralize the pathological effects of thrombin in various types of cells.

Thus, the present invention provides a method of inhibiting factor Xa comprising contacting a factor Xa inhibiting amount of a compound of formula I with a substance containing factor Xa. In another aspect, the invention provides a method of inhibiting thrombin formation comprising contacting a factor Xa inhibiting amount of a compound of formula I with a substance containing factor Xa.

In another aspect, the invention provides a method of treating a human or animal subject suffering from or susceptible to an indication that is alleviated by the administration of a factor Xa inhibitor, such as the indication described above, which method comprises administering an effective amount of a compound of formula I, or a composition comprising a compound of formula I. By "effective amount" is meant an amount of a compound of the invention effective to inhibit factor Xa and thereby produce the desired therapeutic effect.

Also included within the scope of the present invention are pharmaceutical formulations comprising at least one compound of formula I and a pharmaceutically acceptable carrier or coating.

In practice, the compounds of the invention will generally be administered parenterally, intravenously, subcutaneously, intramuscularly, intracolonically, intranasally, intraperitoneally, rectally or orally.

The products of the invention may be present in a form which allows administration by the most appropriate route, and the invention also relates to pharmaceutical compositions suitable for use in human and veterinary medicine containing at least one product of the invention. Such compositions may be prepared in conventional manner using one or more pharmaceutically acceptable adjuvants or excipients. Adjuvants include, inter alia, diluents, sterile aqueous vehicles, and various non-toxic organic solvents. The composition may be in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injections, elixirs or syrups, and may contain one or more substances selected from the group consisting of sweetening agents, flavoring agents, coloring agents and stabilizing agents, in order to obtain pharmaceutically acceptable preparations.

The choice of carrier and the amount of active substance will often depend on the solubility and chemical characteristics of the product, the particular mode of administration and the regulations to be observed in pharmaceutical practice. Excipients which can be used, for example, for the preparation of tablets are, for example, lactose, sodium citrate, calcium carbonate, dicalcium phosphate; disintegrants are, for example, starch, alginic acid and certain complex silicates; and lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc. For the preparation of capsules, it is advantageous to use lactose and polyethylene glycols of high molecular weight. When aqueous suspensions are employed, they may contain emulsifying or suspending agents. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.

For parenteral administration, the products of the invention may be used in the form of a mixture of vegetable oils, such as sesame, peanut or olive oil; or hydro-organic solutions such as water and propylene glycol; emulsions, suspensions or solutions in sterile aqueous solutions of injectable organic esters, such as ethyl oleate, and pharmaceutically acceptable salts thereof. Solutions of the salts of the products of the invention are particularly suitable for administration by intramuscular or subcutaneous injection. Aqueous solutions in purified distilled water, also including saline solutions, are useful for intravenous administration, provided that their pH is appropriately adjusted, they can be effectively buffered and made isotonic with sufficient glucose or sodium chloride, and they are sterilized by heat, radiation, or microfiltration.

Suitable compositions containing the compounds of the invention may be prepared by conventional methods. For example, the compounds of the invention may be dissolved or suspended in a carrier suitable for use in a nebulizer or suspension or solution aerosol, or adsorbed or absorbed in a solid carrier suitable for use in a dry powder inhaler.

The percentage of active ingredient in the compositions of the invention may vary, but will be in a proportion that provides a suitable dosage. Obviously, several unit doses may be administered at about the same time. The dosage employed will be determined by a physician and will depend upon the desired therapeutic effect, the route of administration and the duration of the treatment, as well as the condition of the patient. For adults, daily doses for inhalation will generally range from about 0.01 to about 100, preferably from about 0.01 to about 10mg/kg body weight, daily doses for oral administration will range from about 0.01 to 100, preferably from 0.1 to 70, more preferably from 0.5 to 10mg/kg body weight, and daily doses for intravenous administration will range from about 0.01 to 50, preferably from 0.01 to 10mg/kg body weight. In each particular case, the dosage will be determined by the condition of the subject to be treated, such as age, weight, health, and other characteristics affecting the efficacy of the drug.

The products of the invention may be administered at any frequency as required to achieve the desired therapeutic effect. Some patients respond rapidly to higher or lower doses, and maintenance doses can be found to be much lower. For other patients, prolonged treatment may be required at a frequency of 1-4 doses per day, according to the physiological requirements of the individual patient. In general, the active product can be administered orally 1 to 4 times daily. It goes without saying that for other patients, only a maximum of one or two daily doses may be required.

The compounds of the present invention may also be formulated, for use in combination with other therapeutic agents, such as drugs or therapeutic techniques associated with the treatment of pharmacological indications which may be alleviated by the use of the compounds of formula I as described herein above.

The compounds of the invention may be used in combination with anticoagulants, antiplatelet agents, antithrombotic agents or fibrinolytic agents. To be safe for surgery or to prevent the formation of harmful thrombi, patients are often treated with these types of drugs simultaneously before, during or after surgery. Examples of drugs in these classes are anticoagulants, antiplatelet agents, antithrombotic agents, or fibrinolytic agents, including any form of heparin, low molecular weight heparin, pentaglycan, fibrinogen receptor antagonist, thrombin inhibitor, factor Xa inhibitor, or factor VIIa inhibitor.

The compounds of the present invention may be used in combination with any antihypertensive agent or cholesterol or lipid modulating agent, or simultaneously in the treatment of restenosis, atherosclerosis or hypertension. Examples of drugs that may be used in combination with the compounds of the present invention in the treatment of hypertension include the following classes of compounds: beta-blockers, ACE inhibitors, calcium channel antagonists and alpha-receptor antagonists. Examples of drugs that may be used in combination with the compounds of the invention in the treatment of elevated cholesterol levels or disorders of lipid levels include compounds known as HMGCoA reductase inhibitors, fibric acid (fibrates).

It is to be understood that the present invention encompasses the combination of a compound of the present invention with one or more therapeutic agents of the above classes.

Compounds within the scope of the present invention exhibit significant pharmacological activity according to the literature and the assays described below, and it is believed that these assay results are consistent with pharmacological activity in humans or other mammals.

Enzyme analysis:

the ability of the compounds of the invention as inhibitors of coagulation factor Xa, thrombin, trypsin, tissue-plasmatase activator (t-PA), urokinase-plasmatase activator (u-PA), plasmin and activated protein C was evaluated by measuring the concentration of the inhibitor (IC50) which lost 50% of the enzymatic activity using pure enzyme.

All enzyme assays were performed in 96-well microtiter plates at room temperature using a final enzyme concentration of 1 nM. Concentrations of coagulation factor Xa and thrombin were determined by active site titration, all other enzyme concentrations being based on the concentrations provided by the manufacturer. Compounds of the invention were dissolved in DMSO, diluted with their respective buffers and analyzed at the maximum final concentration of 1.25% DMSO. Compound dilutions were added to the wells containing buffer and enzyme and pre-equilibrated for 5-30 min. The enzymatic reaction was initiated by the addition of substrate and the color generated by the hydrolysis of the peptide-p-nitroaniline substrate was monitored continuously at 405nm on a Vmax microplate reader (Molecular Devices) for 5 minutes. Under these conditions, only less than 10% of the substrate was utilized in all assays. The measured initial velocity was used to calculate the amount of inhibitor that caused a 50% reduction compared to the control velocity (IC 50). The apparent constant Ki value was then determined according to the Cheng-Prusoff equation (IC50 ═ Ki [1+ [ S ]/Km ]) assuming competitive inhibition kinetics.

Another in vitro assay can be used to evaluate the efficacy of the compounds of the invention in normal human plasma. Activated partial thromboplastin coagulation time is a plasma coagulation assay that relies on the in situ formation of factor Xa, which assembles into the prothrombinase complex and subsequently forms thrombus and fibrin, ultimately forming a clot as the end point of the assay. Clinically, this assay is often used in clinical evaluations to monitor the ex vivo utility of the commonly used anticoagulant heparin as well as the direct acting anticoagulant enzyme. Thus, activity in this in vitro assay is considered to be a representative indication of anticoagulant activity in vivo.

Human plasma coagulation assay：

Activated partial thromboplastin clotting times were determined repeatedly on an MLA electrora 800 instrument. Mu.l of citrated normal human plasma (Grorge King biological) was added to a cuvette containing 100. mu.l of a solution of the compound of the invention in Tris/NaCl buffer (pH7.5) and placed in the instrument. After 3 minutes of warming, the instrument automatically added 100. mu.l of activated cephaloplastin reagent (Actin, Dade) followed by 100. mu.l of 0.035M CaCl₂To initiate the setting reaction. Clot formation was determined spectrophotometrically and measured in seconds. The potency of a compound is defined as the concentration required to extend the clotting time of a control without the compound of the invention, measured with human plasma, to two-fold.

The in vivo antithrombotic efficacy of the compounds of the invention can also be evaluated in two well-established animal experimental models of acute vascular thrombosis. The antithrombotic activity of these compounds in different animal models typical of human venous thrombosis and arterial thrombosis was demonstrated using a rabbit jugular vein thrombosis model and a rat carotid artery thrombosis model, respectively.

Rabbit veinIn vivo experiments on thrombosis model:

this is a mature fibrin-rich venous thrombosis model that was well-established in the literature and that showed sensitivity to several anticoagulants including heparin (anti-thrombotic effects of recombinant truncated tissue factor pathway inhibitor (TFPI 1-161) in experimental venous thrombosis compared to low molecular weight heparin, j.holst, B, lindlab, d.bergqvist, o.nordfang, p.b.ostergaard, j.o.l.petersen, g.nielsen and u.hedner.,thrombosis and hemostasis (Thrombosis and Harmostasis),71, 214-219(1994)). The purpose of using this model was to evaluate the ability of the compounds of the invention to prevent venous thrombosis (clotting) and partial stasis formation in vivo at the site of injury in the jugular vein.

Male and female New Zealand white rabbits weighing 1.5-2kg were anesthetized (intramuscularly) with 35mg/kg ketamine and 5mg/kg xylazine in a volume of 1 ml/kg. A cannula was inserted in the right jugular vein for the infusion of anesthetic (ketamine/xylazine 17/2.5 mg/kg/hour was administered at a rate of about 0.5 ml/hour) and the test substance was administered. A cannula was inserted in the right carotid artery to record arterial blood pressure and to take blood samples. Body temperature was maintained at 39 ℃ with GAYMART-PUMP. The left lateral jugular vein was isolated and all branch vessels along the exposed 2-3 cm vessel were ligated. A cannula is inserted into the medial jugular vein, immediately superior to the branch of the common jugular vein, and the distal end of the cannula is advanced to the proximal end of the common jugular vein. A 1 cm section of the vein was isolated with a non-invasive vascular clamp and a relative stenosis was formed by ligating around the vein with an 18G needle at the lower portion immediately distal to the clamp. This creates a region of reduced flow velocity and partial pooling of blood at the site of injury. The separated vessel segments were gently rinsed 2-3 times with saline through the intravenous cannula. The isolated vessel segments were then perfused with 0.5ml of 0.5% polyethylene oxide (W-1) for 5 minutes. W-1 is a detergent that destroys the endothelial cells lining the vessel segment, thus providing a thrombogenic surface to initiate clot formation. After 5 minutes, W-1 was withdrawn from the vessel segment, and the vessel segment was again gently rinsed 2-3 times with saline. The vascular clamp is then removed and blood flow is restored through the portion of the vessel. The clot was allowed to form and grow for 30 minutes, after which the vein was cut at the lower end of the stenotic knot and blood flow was observed (recorded as complete closure when no blood flow was flowing). The entire isolated venous blood tube segment was then ligated, and the clot formed removed and weighed (wet weight). The effect of the test substance on the final clot weight was taken as the primary endpoint. Animals were maintained for an additional 30 minutes to measure the final pharmacokinetics of anticoagulation. Drug administration was started 15 minutes before the vessel was injured with W-1 and continued throughout clot formation and growth. Three blood samples (3ml each) were taken for evaluation of hemostatic parameters: the first time immediately prior to administration of W-1; second 30 minutes after removal of the vascular clamp; the third time at the end of the experiment. Antithrombotic efficacy is indicated by a reduction in the final clot weight in the preparations treated with the compounds of the invention relative to vehicle-treated control animals.

Rat arterial thrombosis model in vivo experiment:

using mature FeCl₂The induced rat carotid thrombosis model can evaluate the antithrombotic efficacy of coagulation factor Xa inhibitors on platelet-rich arterial thrombosis (superior activity of thromboxane receptor antagonists compared to aspirin in rat arterial and venous thrombosis models, w.a.schumacher, c.l.heran, t.e.stein bacher, s.youssef and m.l.oglette,journal of Cardiovascular pharmacology (Journal of Cardiovascular pharmacology) Pharmacology)22, 526-533 (1993); rat arterial thrombosis model induced by ferrous chloride, k.d.kurtz, b.w.main and g.e.sandusky,investigation of thrombosis (Thrombosis Research),60, 269-280(1990)). Thrombin inhibition in the rat arterial thrombosis model, r.j.broersma, l.w.kutcher and e.f.heninger,investigation of thrombosis,64, 405-412(1991)). This model is widely used to evaluate the antithrombotic efficacy of various substances including heparin and direct acting thrombin inhibitors.

Sprague Dawley rats weighing 375-450g were anesthetized with sodium pentobarbital (50mg/kg, i.p.). After the appropriate level of anesthesia has been reached,the surface of the neck and abdomen was shaved off for sterile surgery. Electrocardiographic electrodes were connected and the II lead was monitored throughout the experiment. PE-50 tubes were inserted into the right femoral vein and artery for administration of the compounds of the invention and blood sampling and monitoring of blood pressure, respectively. A midline incision was made on the surface of the neck and abdomen. The trachea is exposed and a PE-50 tube is inserted to ensure the airway is open. The right carotid artery was isolated and two 4-0 silk threads were placed around the vessels to assist instrument attachment. An electromagnetic flow probe (0.95-1.0mm lumens) was placed around the blood vessel to measure blood pressure. A 4 x 4mm parafilm was placed under the blood vessel at the distal end of the probe to separate the blood vessel from the surrounding muscles. After measuring the basal blood flow, 35% FeCl will be used in advance₂A medium saturated 2X 5mm strip of filter paper was placed on top of the vessel downstream of the probe for 10 minutes and then removed. FeCl₂Is thought to diffuse into the underlying arterial vessel, resulting in de-endothelialization and acute thrombosis. Use of FeCl₂After soaking the filter paper, blood pressure, carotid blood flow and heart rate were monitored for 60 minutes. After vessel closure (defined as zero measured blood flow), or if left open, 60 minutes after application of the filter paper, the proximal and distal arteries of the lesion were ligated and the vessels were excised. The thrombus was removed and weighed immediately and recorded as the primary endpoint of the study.

After the surgical instrument was installed, a control blood sample was taken (B1). All blood samples were taken from the arterial line and mixed with sodium citrate to prevent clotting. After each blood sample collection, the catheter was rinsed with 0.5ml 0.9% saline. The compounds of the invention are in FeCl₂Intravenous administration was started 5 minutes before application. Using FeCl₂And the time between when arterial blood flow reaches zero is recorded as the time to closure (TTO). The blood vessels that did not close within 60 minutes had a TTO recorded for 60 minutes. Using FeCl₂After 5 minutes, a second blood sample was taken (B2). With FeCl₂10 minutes after contact, the filter paper was removed from the vessel and the animal was monitored for the remainder of the experiment. After zero blood flow was reached, a third blood sample was taken (B3), and the clot removed and weighed. At the same time as the blood sample was taken, the typical bleeding time was measured on the plantar aspect of the forelimb. All blood samples were assayed for Activated Partial Thromboplastin Time (APTT) and prothrombin timeCoagulation of (PT). In some cases, the compounds of the invention may be administered orally. Rats were manually restrained using standard techniques and the compounds were administered via an intragastric feeding tube using an 18G curved dose needle (volume of 5 ml/kg). After 15 minutes intragastric administration, the animals were anesthetized and the instrument was installed as described previously. The experiment was then carried out according to the protocol described above.

For example, K of Compound 184 in factor Xa, Trypsin and Thrombin assays_iThe values were 27.0nM, 1.72. mu.M and 2.71. mu.M, respectively. K of Compound 45 in factor Xa, Trypsin and Thrombin assays_iValues were 94.0nM, 129nM and 477nM, respectively. K of Compound 167 in factor Xa, Trypsin and Thrombin assays_iValues were 19.0nM, 46nM and 1.228nM, respectively.

The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics.

Claims (5)

1. A compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is:

(Z) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) allyl ] -4-pyridin-3-ylbenzamide;

4-pyridin-3-yl-3- (5-carbamimidoyl) -propyl ] -benzamide bistrifluoroacetate;

2-hydroxy-N- [3- (5-carbamimidoyl-2-phenyl) -propyl ] -4- (1-oxo-pyridin-4-yl) benzamide bistrifluoroacetate;

4- (6-oxo-1, 6-dihydropyridin-3-yl) benzamide trifluoroacetate salt, N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -4- (6-oxo-1, 6-dihydropyridin-3-yl);

4- (pyridazin-4-yl) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -benzamide bistrifluoroacetate;

2-chloro-N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -7-chlorobenzothiophene-carboxamide trifluoroacetate;

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4- (6-methoxypyridin-3-yl) -benzamide trifluoroacetate salt;

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4- (6-oxo-1, 6-dihydropyridin-3-yl) -benzamide trifluoroacetate salt;

(E) -biphenyl-4-carboxylic acid [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -amide trifluoroacetate salt;

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4-pyridin-3-yl-benzamide bistrifluoroacetate;

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4-pyridin-4-yl-benzamide bistrifluoroacetate;

(E) -biphenyl-3, 4 '-dicarboxylic acid 3-amide 4' - { [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -amide } trifluoroacetate;

(E) -4-tert-butyl-N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -benzamide trifluoroacetate salt;

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4- (3H-imidazol-4-yl) -benzamide bistrifluoroacetate;

(E) -biphenyl-4, 4 '-dicarboxylic acid 4' -amide 4- { [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -amide } trifluoroacetate;

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4- (1H-imidazol-2-yl) -benzamide bistrifluoroacetate;

(E) -3-oxo-2, 3-dihydro-thieno [3, 2-c ] pyridazine-6-carboxylic acid [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -amide trifluoroacetate salt;

(E) -5-pyridin-2-yl-thiophene-2-carboxylic acid [3- (5-carbamimidoyl) -2-hydroxyphenyl ] -allyl ] -amide ditrifluoroacetate;

(E) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -4- (1-oxo-pyridin-4-yl) -benzamide bistrifluoroacetate;

biphenyl-4-carboxylic acid [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -amide trifluoroacetate salt;

4- (6-methoxypyridin-3-yl) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -benzamide trifluoroacetate salt;

biphenyl-3, 4 '-dicarboxylic acid 3-amide 4' - { [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -amide } trifluoroacetate;

4-tert-butyl-N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -benzamide trifluoroacetate salt;

[3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -4- (3H-imidazol-4-yl) -benzamide bistrifluoroacetate;

4- (1H-imidazol-2-yl) -N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -benzamide ditrifluoroacetate;

5-pyridin-2-yl-thiophene-2-carboxylic acid [3- (5-carbamimidoyl-2-hydroxyphenyl) -allyl ] -amide ditrifluoroacetate;

4-piperidin-4-yl-benzamide bis (trifluoroacetate) salt, N- [3- (5-carbamimidoyl-2-hydroxyphenyl) -propyl ] -benzamide;

2- (3-carbamimidoyl-benzyl) -3- [4- (1-oxy-pyridin-4-yl) -benzoylamino ] -butyric acid trifluoroacetate salt;

2- (R) - (3-amidino-benzyl) -3- (R) - [ (3' -nitrobiphenyl-4-carbonyl) amino ] -butyric acid methyl ester trifluoroacetate salt;

2- (R) - (3-amidino-benzyl) -3(R) - (4-pyridin-2-yl-benzoylamino) -butyric acid methyl ester bistrifluoroacetate;

2- (R) - (3-carbamimidoyl-benzyl) -3(R) - [4- (1-oxy-pyridin-2-yl) -benzoylamino ] -butyric acid methyl ester trifluoroacetate salt;

2- {4- [3- (3-carbamimidoyl-phenyl) -2(R) -methoxycarbonyl-1 (R) -methylpropylcarbamoyl ] -phenyl } -1-methyl-pyridinium-bistrifluoroacetate;

2- (R) - (3-amidino-benzyl) -3- (R) - [ (3 ', 4' -dimethoxybiphenyl-4-carbonyl) amino ] -butyric acid methyl ester trifluoroacetate salt;

2- (R) - (3-carbamimidoyl-benzyl) -3- (R) - { [ (1-oxo-pyridin-2-yl) -thiophene-2-carbonyl ] -amino } -butyric acid methyl ester trifluoroacetate salt;

2- {5- [3- (3-carbamimidoyl-phenyl) -2(R) -methoxycarbonyl-1 (R) -methylpropylcarbamoyl ] -thiophen-3-yl } -1-methyl-pyridinium-bistrifluoroacetate;

methyl 2- (R) - (3-amidino-benzyl) -3(R) - { [ (1-oxo-pyridin-3-yl) -thiophene-2-carbonyl ] -amino } butanoate trifluoroacetate salt.

2. A pharmaceutical composition comprising a pharmaceutically acceptable amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

3. The use of a compound according to claim 1 for the preparation of medicaments for the treatment of diseases which can be modulated by the inhibition of the production of factor Xa.

4. The use of a compound according to claim 1 for the preparation of a medicament for inhibiting factor Xa.

5. The use of a compound of claim 1 for the preparation of a medicament for inhibiting thrombin formation.