CZ20004497A3 - Sulfonyl- or sulfonylamino-N-(heteroaralkyl)azaheterocyclylamide derivatives and pharmaceutical preparation containing thereof - Google Patents

Description

Qblást techniky

The compounds of formula I have advantageous pharmacological activity and are therefore useful as active ingredients in pharmaceutical compositions and are used for the treatment of patients suffering from certain diseases. More specifically, these agents are Factor Xa inhibitors. The present invention relates to compounds of formula I, compositions comprising compounds of formula I, and their use for treating patients suffering from diseases that can be alleviated by administration of a factor Xa inhibitor.

BACKGROUND OF THE INVENTION

Factor Xa is the penultimate enzyme in the collagen cascade. Free factor Xa and factor Xa contained in the prothrombinase complex (factor Xa, factor Va, calcium and phospholipid) are inhibited by the compounds of formula I. Inhibition of factor Xa is achieved by direct complex formation between inhibitor and enzyme and is therefore independent of the plasma cofactor antithrombin III. Effective inhibition of Factor Xa is achieved by administering the compounds either by the oral route, by continuous intravenous infusion, by intravenous bolus administration or by any other parenteral route, such that the desired factor Xa-induced thrombin formation from prothrombin is prevented.

Anticoagulant therapy is used for the treatment and prophylaxis of various thrombotic conditions of both the venous and arterial systems. In the arterial system, abnormal thrombus formation is primarily related to coronary arteries, the cerebral and peripheral vascular systems. Diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable • · • ·

angina, thromboembolism, acute vascular blockage associated with thrombolytic treatment and percutaneous transluminal angioplasty of the coronary arteries (PTCA), transient ischemic attack, stroke, intermittent limping and graft for coronary artery cardiovascular surgery (CAGB) or peripheral arteries. Chronic anti-coagulation therapy may also be beneficial in preventing luminal vasoconstriction (restenosis), which often occurs after PTCA and CAGB, and in maintaining access to the patient's blood vessels during long-term hemodialysis of the patient. As for the venous system, pathological thrombus formation often occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep venous thrombosis, DVT). DVT then causes the patient to be at greater risk of pulmonary thromboembolism. Systemic, multiple intracellular coagulopathy (DIC) generally occurs in the vascular system during septic shock, certain viral infections, and cancer. This condition is characterized by the rapid consumption of coagulation factors and their plasma inhibitors, resulting in occlusion in life-threatening micro-vascular systems of certain organs.

Representative indications discussed above include some (but not all) possible clinical situations that can be treated with anticoagulant therapy. Those of ordinary skill in the art will recognize circumstances that require either acute or prophylactic anticoagulant therapy.

SUMMARY OF THE INVENTION

The present invention relates to the compounds of formula I described below, as well as their pharmaceutical use for treating patients suffering from a physiological disorder that can be modulated by inhibiting factor Xa activity:

R

X

wherein the monocyclic heteroaryl group containing at least one nitrogen atom or the bicyclic heteroaryl group containing the first closest ring which is bonded to Z and the ring farther from the first ring, wherein the distal ring contains at least one nitrogen atom;

Z is an alkylenyl group, - (CH _{2) r} C (0) NR (CH _{2) s} - (CH ₂₎ RNC (0) _{(CH2) r} -, - (CH _{2) r} NR ( CH ₂ ) _s - or - (CH ₂ ) ₅ NR '' (CH ₂ ) _r -;

R. is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, R'O (CH ₂ ) _X -, R'O ₂ C (CH ₂ ) _X -, R 1 C (O) (CH ₂ ) _x -, Y 2 NCtO) (CH ₂ ) _x - or Y ^X Y ² N (CH _x -);

R 1 and R 2 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl;

R ₂ is hydrogen, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, R ₃ R ₄ NC (O) (CH ₂ ) _x -, R ₃ S (O) _p - or R ₃ R ₄ NS (O) _p -;

R ₃ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroaralkyl, optionally substituted arylalkenyl or optionally substituted heteroarylalkenyl a group, or R ₃ and R ₃ together with the group -NS (O) _p - or the group -NS (O) _p -NR 11 - through which R ₃ and R ₃ are joined to form a 5- to 7-membered optionally substituted heterocyclyl group; and

R ₄ . is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroaralkyl, or R ₃ and R ₃ together with the nitrogen atom R ₃ and R ₄ bonded to form an optionally substituted 4 to 7 membered heterocyclyl group; '

X ₃ and X _1a are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, or X ₃ and X _1a together form an oxo group;

X ₂ ^{and X} 2a are hydrogen or together form an oxo group;

X ₃ is a hydrogen atom, a hydroxyl group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted heteroarylalkyl group, or X ₃ and one of X ₁ and X _1a together form a four to a seven membered cycloalkyl pinpoint skin;

X 1 is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, or hydroxyalkyl;

X ₅ , X _5a and X _sb are independently selected from the group consisting of hydrogen, R ₅ R ₆ N-, (hydroxy) HN-, (alkoxy) HN-, or (amino) HN- , R ₇ O-, R ₅ R ₆ NCO-, R ₅ R _with NSO ₂ -, R ₇ CO-, halogen, cyano, nitro and R _with (O) C (CH ₂ ) _q - and where. / ^'X \ f Ar is a bicyclic heteroaryl group, one of X _5, X and _{-x 5b} is a substituent which is in alpha position to the nitrogen of the distal ring / X and is selected from ,, who -carbonyl ( _Α Γι) rou consisting of hydrogen, hydroxy and a group H ₂ N-, '(optionally substituted by lower alkyl) HN (hydroxy) HN-, (alkoxy) HN-, or (amino) HN-;

Y ‘and Y‘ are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl, or

Υ '* and Υ ² together with the nitrogen atom through which they are attached form a four to seven membered heterocyclyl group;

_R and _R are independently hydrogen or optionally substituted lower alkyl group, or one of R _s and _Rg is. hydrogen and the other of the groups _R and _R is R ₃ (O) CCH ₂ - 'or lower acyl;

R _? is hydrogen, optionally substituted lower alkyl, lower acyl or R ₈ (O) CCH ₂ -;

R _a is hydrogen, optionally substituted lower alkyl, alkoxy or hydroxyl; m is 0, 1, 2 or 3;

p and p are independently 1 or 2;

q is 0 or 1, s is 0, 1 or 2; and x is 1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the terms used in the description of the present invention have the following meanings:

Definition “Patient means human and other mammals.

"An alkyl group is an aliphatic hydrocarbon group which may contain a straight or branched chain of 1 to 20 carbon atoms. A preferred alkyl group contains 1 to 12 carbon atoms in the chain. Branched means that one or more ·· ···· '· · · · · _ .. _to ······· · ·· lower alkyl groups such as methyl group ·, ethyl or propyl is attached to a linear alkyl chain. "Lower alkyl" is an alkyl group having 1 to 4 carbon atoms, which may be straight or branched. The alkyl group may be substituted by one or more "alkyl group substituents, which may be the same or different, including halogen, cycloalkyl, hydroxyl, alkoxy, aryloxy, heteroaryloxy, amino, acylamino, aroylamino, carboxyl, alkoxycarbonyl , arylalkyloxycarbonyl, heteroarylalkyloxycarbonyl or R ₉ R ₁₀ NCO-, wherein R ₉ and R ₁₀ are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl, or R 9 ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl group. Examples include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl a carboxymethyl group, a methoxycarbonylethyl group, a benzyloxycarbonylmethyl group. a pyridylmethyloxycarbonylmethyl group.

An alkenyl group is a straight or branched aliphatic hydrocarbon group containing a carbon-carbon double bond and containing 2 to 15 carbon atoms in the chain. Preferred alkenyl groups contain 2 to 12 carbon atoms in the chain, more preferably 2 to 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as a methyl group, an ethyl group, or a lower alkyl group are attached to the linear alkenyl chain.

propyl group. "A lower alkenyl group is an alkenyl group having 2 to 4 carbon atoms in the chain, which may be straight or branched. The alkenyl group may be substituted by one or more halogen atoms or cycloalkyl groups. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.>

A cycloalkyl group is a non-aromatic mono- or multicyclic hydrocarbon ring system containing 3 to 10 carbon atoms. . Examples of the monocyclic cycloalkyl ring include cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl group is optionally partially unsaturated or optionally substituted with one or more halogen atoms, methylene groups (H ₂ C =), alkyl groups, fused aryl groups or fused heteroaryl groups. Examples of the multicyclic cycloalkyl ring include 1-decalin, adamant- (1- or 2-) yl and norbornyl.

"A heterocyclyl group is a non-automated saturated monocyclic or multicyclic ring system containing 3 to 10 ring atoms. A preferred heterocyclyl group contains 5 to 6 ring atoms, wherein one of the ring atoms is independently selected from the group consisting of oxygen, nitrogen or sulfur. The heterocyclyl group is optionally partially unsaturated or optionally substituted with one or more groups selected from the group consisting of alkyl, halogen, aryl, heteroaryl, fused aryl or fused heteroaryl. Examples of monocyclic heterocyclyl ring systems include pyrrolidyl, piperidyl, tetrahydrofuranyl, tetrahydrothienyl and tetrahydrothiopyranyl. The thio or nitrogen group of the heterocyclyl group may also optionally be oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Examples of multicyclic heterocyclyl systems include 1,4-diazabicyclo [2.2.2] octane and 1,2-cyclohexanedicarboxylic anhydride.

"Aryl is a 6 to 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system. Examples include phenyl or naphthyl, each of which may be substituted with one or more ring system substituents, which may be the same or different, wherein "ring system substituents" are defined below.

"Substituents of the ring system are substituents bonded to an aromatic or non-aromatic ring system including hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, arylalkoxy, acyl , aroyl, halogen, nitro, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, heteroarylthio, arylalkylthio, heteroarylalkylthio, fused cycloalkyl, fused heterocyclyl, arylazo, heteroarylazo, R ₉ R ₁₀ N-, R ₉ R ₁₀ NCO- or R ₉ R ₁₀ NSO ₂ -, wherein R ₉ and R ₁₀ are independently hydrogen, optionally substituted an alkyl group, an optionally substituted aryl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, or R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form a four to seven membered heterocyclyl ring. When the ring system is saturated or partially saturated, "ring system substituents further include methylene (CH ₂ =), oxo (O =) or thio (S =). Preferred substituents of the ring system include an atom. hydrogen, alkyl, hydroxyl, acyl, aryl, aroyl, aryloxy, halogen, nitro, alkoxy, cyano, alkoxycarbonyl, acylamino, alkylthio, R ₉ R ₁₀ N-,. R ₉ R ₁₀ NCO- and R ₉ R ₁₀ NSO ₂ -, wherein R ₉ and R ₁₀ are independently optionally substituted alkyl. aryl, arylalkyl or heteroarylalkyl. Particularly preferred phenyl substituents are hydroxyl, halogen, alkyl and amino.

"A heteroaryl group of 5- to 10-membered aromatic monocyclic or multicyclic hydrocarbon ring system wherein one or more carbon atoms in the ring system is / are elements other than a carbon atom, such as a nitrogen atom, an oxygen atom or a sulfur atom. be optionally oxidized to the N-oxide. If the heteroaryl group is a multicyclic hydrocarbon ring system, then one of said ring systems is optionally partially or fully saturated. The "heteroaryl group may also be substituted with one or more of the above-mentioned" ring system substituents. Examples of heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, iso11, thiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, imidazo [ 2,1-b] thiazolyl, thiono [3,2-b] pyridyl, thieno [2,3-b] pyridyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl a group, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl. If the heteroaryl group is a multicyclic hydrocarbon ring system, it may be attached to the remainder of the molecule through any atom of the ring system that allows binding. Preferred heteroaryl groups in R _x include benzothienyl, thienyl, thienopyridyl, isoquinolinyl and quinolinyl, all of which may be optionally substituted. Preferred X 1 bicyclic heteroaryl groups are, for example, ( ^Ar 1), isoquinolinyl, quinolinyl, benzothienyl, isoquinolinyl, isoquinazolinyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, (1,2- or 2,3-). · A benzodiazinyl group and an imidazopyridyl group. A preferred z ----- x monocyclic heteroaryl group ( ^Ar 1) is a pyridyl group. Preferred heteroaryl groups in R ₃ are benzothienyl, thieno [3,2-b] pyridyl, naphthyl or thieno [2,3-b] pyridyl.

"Arylalkyl is an aryl-alkyl group wherein both the aryl and alkyl moieties are as defined above. Preferred examples of arylalkyl groups include benzyl, 2-phenethyl and naphthalenomethyl.

"A heteroarylalkyl group is a heteroaryl-alkyl group wherein both the heteroaryl and the alkyl moieties are as defined above. Preferred heteroarylalkyl groups contain a lower alkyl group. Examples of heteroarylalkyl include thienylalkyl, pyridylalkyl, imidazolylalkyl, pyrazinylalkyl, benzimidazolylmethyl, indolylmethyl, pyrazolylmethyl and thiazolytmethyl.

"Arylalkenyl is an aryl-alkenyl group wherein the aryl and alkenyl groups are as defined above. Preferred arylalkenyl groups contain a lower alkenyl group. An example of arylalkenyl. group is 2-phenethenyl.

"Heteroarylalkenyl is a heteroaryl-alkenyl group, wherein the heteroaryl group and the alkenyl group are as defined above. Preferred heteroarylalkenyl groups contain a lower alkenyl group. Examples of heteroarylalkenyl groups include thienylallyl, thienyl-2-ethenyl, pyridyl-2-ethenyl, imidazolyl-2-ethenyl and pyrazinyl-2-ethenyl, thienylpropenyl, pyridylpropenyl, imidazolylpropenyl and pyrazinyl-propenyl.

"Hydroxyalkyl" is a ΗΟ-alkyl- group wherein the alkyl moiety is as defined above. Preferred hydroxyalkyl groups contain a lower alkyl group. Examples of hydroxyalkyl groups include hydroxymethyl and 1-hydroxyethyl.

• · ·

"Acyl is an H-CO- or alkyl-CO- group wherein the alkyl moiety is as defined above. Preferred alkyl groups contain a lower alkyl group. Examples of acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.

"Aroyl" is an aryl-CO- group. wherein the aryl group is as defined above. Examples of aroyl groups include benzoyl and 1- and 2-naphthoyl groups.

"Alkoxy" is an alkyl-O- group wherein the alkyl group is as defined above. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, heptoxy and t-butoxy.

"Aryloxy" is an aryl-O- _z group wherein the aryl group is as defined above. Examples of aryloxy include phenoxy and naphthoxy.

"Heteroaryloxy" is a heteroaryl-O- group wherein the heteroaryl moiety is as defined above. Examples of heteroaryloxy include thienyloxy.

"Arylalkyloxy is an arylalkyl-O- group wherein the arylalkyl group is as defined above. Examples of arylalkyloxy include bepzyloxy and 1- or 2-naphthylmethoxy.

"Alkylthio is an alkyl-S- group. wherein the alkyl group is as defined above. Examples of alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio.

9

9

9 9 9

9'9

9

9

9 • 9

"Arylthio" is an aryl-5- group wherein the aryl group is as defined above. Examples of arylthio include phenylthio and naphthylthio.

"Arylalkylthio is an arylalkyl-S- group wherein the arylalkyl group is as defined above. Examples of arylalkylthio include benzylthio.

R ₉ R ₁₀ N- is substituted or unsubstituted amino, wherein R ₉ and R ₁₀ are as defined above. Examples of amino groups include amino (H ₂ N-), methylamino, ethylmethylamino, dimethylamino, diethylamino, pyrrolidino and piperidino. _,,; An alkoxycarbonyl group is an alkyl-O-CO- group wherein the alkyl group is. as defined above. Examples of alkoxycarbonyl groups include (methoxy, ethoxy and t-butoxy) carbonyl.

Aryloxycarbonyl is an aryl-O-CO- group wherein the aryl group is as defined above. Examples of aryloxycarbonyl groups include phenoxy- and naphthoxycarbonyl groups.

Arylalkoxycarbonyl is an arylalkyl-O-CO- group wherein the arylalkyl group is as defined above. Examples of arylalkoxycarbonyl groups include benzyloxycarbonyl.

"R ₉ R ₁₀ NCO-" is a substituted or unsubstituted carbamoyl group wherein R ₉ and R ₁₀ are as defined above. Examples of carbamoyl groups include carbamoyl (H ₂ NCO-) and dimethylcarbamoyl (Me ₂ NCO-).

"R ₉ R ₁₀ NSO ₂ -" is a substituted or unsubstituted sulfamoyl group wherein R ₉ and R ₁₀ are as defined above. Examples of sul-

Famoyl groups include sulfamoyl (H ₂ NSO ₂ -) and dimethylsulfamoyl (Me ₂ NSO ₂ ).

"Acylamino is an acyl-ΝΗ- group wherein the acyl group is as defined above.

"Aroylamino is an aroyl-ΝΗ- group wherein the aroyl group is as defined above.

An "alkylsulfonyl group" is an alkyl-SO ₂ group wherein the alkyl group is as defined above. Preferred are those alkylsulfonyl groups which contain a lower alkyl group.

Arylsulfonyl is an aryl-SO ₂ - group, wherein the aryl group is as defined above.

"Alkylenyl" is. for example methylenyl, ethylenyl or propylenyl.

A "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferred are fluorine, chlorine or bromine, and more preferably fluorine or chlorine.

Preferred embodiments

A preferred embodiment of the present invention is a method of treating a patient suffering from a physiological disorder that can be adjusted by inhibiting factor Xa activity by administering a therapeutically effective amount of a compound of Formula I.

According to the present invention, a compound of formula I wherein R is hydrogen, optionally substituted heteroarylalkyl, optionally substituted alkenyl, optionally substituted arylalkyl or optionally substituted alkyl is preferred.

··· ···· ·

Another preferred compound of the present invention is a compound of formula I wherein R ₂ is R ₃ S (O) _p - and more preferably R ₃ S (O) _p - wherein p is 2.

Another preferred compound of the present invention is a compound of formula I wherein R ₂ is hydrogen, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, or R ₃ R ₄ NC (O) ( CH ₂ ) x -. Another preferred compound is a compound of formula I wherein -R ₃ is hydrogen, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted thienyl, optionally substituted benzothienyl, optionally substituted thienopyridyl, optionally substituted quinolinyl, or optionally substituted isochi nolinyl; more preferably, R _{3 is} optionally selected from substituted naphthyl, optionally substituted thienyl, optionally substituted benzothienyl, and optionally substituted thienopyridyl.

Other preferred compounds of the present invention are compounds of formula I wherein R ₂ is selected from the group consisting of

• · · ·

· · · · · · · · · · · · · · · · · · ·

• · ·······················

Cl 4 9 4 4

9 '4 ·' 4 · · · · · · · · · · · · · · ·

9 4 9 4 4 4 9

4 4 4 4 9 9 5

4994 44 94 44 449

The invention is which it forms

Another preferred compound of the present compound of formula I wherein R ₂ is selected from the group consisting of:

Another preferred compound of the present invention is a compound of formula I wherein R ₂ is

of;

-m

R _a is hydrogen, alkyl, hydroxyl, alkoxy, Y ^X Y ² N-, halogen, -CO ² R _d , -C (O) NY ^X Y ² , - (CH 2) _x OR _d , - (CH ₂ ) _X NY ^X Y ² , or -CN;

R _b and R _c . are independently selected from the group consisting of hydrogen, hydroxyl, alkoxy, Y ^X Y ² N-, halogen, -CO ² R d, C (O) NY ^X Y ² , - (CH 2) _x OR _d , - (CH ₂ ) _X NY ^X Y ² , -CN, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -arylalkyl, optionally substituted heteroarylalkyl, optionally substituted arylalkenyl or optionally-substituted heteroarylalkenyl, or R _b ai

R _c together with the carbon atom to which they are attached form an optionally substituted 5- to 7-membered fused cycloalkyl group, or an optionally substituted 5- to 7-membered heterocyclyl ring group or an optionally substituted 6-membered fused aryl group, or an optionally substituted 5- to 6-membered heteroaryl ring group;

R _d is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl;

Y ¹ and Y ² are independently hydrogen, optionally substituted. an alkyl group, an optionally substituted aryl group, an optionally substituted arylalkyl group, or an optionally substituted heteroarylalkyl group, or Y ¹ and Y ² together with the nitrogen atom to which Y ¹ and Y ² are attached form a four to seven membered heterocyclyl group;

Z _x is a sulfur atom or -CH = CH-; and x is 1, 2, 3, 4, or 5.

Further preferred compounds of the present invention are compounds of formula I wherein R ₃ is an optionally substituted arylalkenyl or an optionally substituted heteroarylalkenyl, more preferably an optionally substituted heteroarylalkenyl.

Another preferred compound of the present invention is a compound of formula I wherein if R ₃ is an optionally substituted arylalkenyl group or an optionally substituted heteroarylalkenyl group, then its alkenyl group has the formula

«· ····

Further preferred compounds of the invention are compounds of formula I wherein when R ₃ is an optionally substituted arylalkenyl or an optionally substituted heteroarylalkenyl, then its alkenyl group has the formula Q ₁ / Q ₂ wherein one of Q ₁ and Q ₂ is hydrogen, lower an alkyl group (more preferably a methyl group), or a halogen atom (more preferably a fluorine or chlorine atom), the second of Q ₃ and Q ₂ is a lower alkyl group (more preferably a methyl group), or a halogen atom (more preferably a fluorine or chlorine atom).

Another preferred object of the present invention is a compound of formula I wherein when R ₃ is an optionally substituted arylalkenyl group, then the aryl group thereof is a phenyl group substituted with a halogen atom; more preferably a phenyl group substituted with a chlorine atom.

Another preferred compound of the present invention is a compound of formula I wherein if R ₃ is an optionally substituted heteroarylalkenyl group, then its heteroaryl group is a thienyl group substituted with a halogen atom, more preferably a 2-chlorothien-5-yl group.

Another preferred compound of the present invention is a compound of formula I wherein Z is a methylenyl group.

Another preferred compound of the present invention is a compound of formula I wherein i

000 ·

Another preferred compound of the present invention is a compound of formula I wherein i

is selected from the group consisting of

·· ···· · ·

Another preferred compound of the present invention is a compound of formula I wherein Z _x is -CH = CH-; and R _a and. R _c together with the carbon atom to which R _b and R _c are bound to form an optionally substituted five to six membered heteroaryl ring group, preferably containing at least one heteroatom which is preferably a nitrogen atom or an optionally substituted six-membered aryl and wherein said optional substituents are selected from the group consisting of a chlorine atom, a hydroxyl group, and an amino group.

Another preferred compound of the present invention are compounds of formula I wherein Z _L is -CH = CH-; R _b is hydrogen; and R _c is an optionally substituted heteroaryl ring group, preferably a 5- to 6-membered heteroaryl ring, more preferably containing at least one heteroatom which is preferably a nitrogen or sulfur atom or an optionally substituted 6-membered aryl ring, and wherein the optional substituents are chlorine, hydroxyl or amino.

Another preferred compound of the present invention is a compound of formula I wherein Z _x is a sulfur atom.

• flfl fl fll fl fl fl fl fl

Another preferred compound of the present invention is a compound of formula I wherein Z _x is a sulfur atom and R _b and R _c together with the carbon atom to which R _b and R _e are attached form an optionally substituted 5- to 6-membered heteroaryl ring, preferably containing at least one heteroatom, which is preferably a nitrogen atom or an optionally substituted six-membered aryl ring and wherein the optional substituents are preferably a chlorine atom, a hydroxyl group or an amino group.

Further preferred compounds of the invention are compounds of formula I, wherein Z _x is sulfur; R _b is hydrogen; and R _c is an optionally substituted heteroaryl group, preferably a 5- or 6-membered heteroaryl ring, preferably containing at least one heteroatom which is preferably a nitrogen or sulfur atom or an optionally substituted 6-membered aryl ring, and wherein said optional substituents are preferably chlorine, hydroxyl or amino.

Another preferred compound of the present invention is a compound of formula I wherein Z is methylenyl and m is 1.

Another advantage of the compound of the present invention is a compound of formula I, wherein X ₂ and X _2a are together oxo.

Another advantage of the compounds of the present invention is a compound of formula I wherein each X _LZ X _a, X ₃ and X ₄ is hydrogen.

Another preferred compound of the present invention is _{with a} compound of Formula I wherein the optionally substituted isoquinolinyl group; more preferably, the isoquinolinyl group is bound to Z at its 7-position.

·················· •::: * · ··· · · · · · · ·

Another advantage of the compound of the present invention is a compound of formula I, wherein it is optionally substituted

b) a quinolinyl group; more preferably, the quinolinyl group is bound to Z at its 7-position.

Another preferred compound of the present invention is a compound of formula I wherein X is optionally substituted

a quinazolinyl group, more preferably the quinazolinyl group is bound to Z at its 7-position.

Another advantage of the compound of the present invention is an optionally substituted group of the formula

W / a a> \

or and W is sulfur, oxygen, or NR 1 _X , wherein R _1X is hydrogen, alkyl, arylalkyl, heteroarylalkyl, or R ₈ (O) C (CH ₂ ) _q -, and A is independently CH or a nitrogen atom, more preferably the group is bound to Z via a W-containing ring and even more preferably the group is bound to Z via a W-containing ring at its 2-position.

Another preferred compound of the present invention is a compound of formula I wherein one of X ₅ , X _5a and X _5b is hydrogen, hydroxyl or amino, more preferably a hydroxy or amino substituted on the nearest ring of the τ 'position, which is adjacent to the position (Α _Γ1 ) of the nearest circle to which it is attached.Z.

A further advantage of the compound of the present invention is a compound of formula I wherein one of the groups X _s , X _aa and X _sb is a substituent on the distal ring of the group at the alpha position (ArJ relative to its nitrogen atom selected from hydrogen ₂ N-, (optionally substituted lower alkyl) HN-, (hydroxy) HN-, and (amino) HN-.

Preferred compounds of the present invention are selected from the group consisting of:

3 - ((1- (4-Aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl) - (5-chloro-1H-indol-2-ylmethyl) -amino] -propionic acid methyl ester;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R - [(5-chloro-1H-indol-2-ylmethyl) - (3-ethylbutyl) amino] pyrrolidin-2-one;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [benzyl (5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) thiazol-5-ylmethylamino] pyrrolidin-2-one;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) - (2H-pyrazol-3-ylmethyl) amino] pyrrolidin-2-one;

1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(6-chlorobenzo [b] thiophen-2-ylmethyl) amino] pyrrolidin-2-one;

1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(6-chlorothieno [2,3-b] pyridin-2-ylmethyl) amino] pyrrolidin-2-one;

·· · ·

1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(1H-pyrrolo [2,3-c] pyridin-2-ylmethyl) amino] pyrrolidin-2-one;

- {[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) ylamino] methyl} -1H-quinolin-2-one;

1- (7-Aminothieno [3,2-b] pyridin-2-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one;

2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (R) -yl] -amide; {[2- (5-Chloro-thiophen-2-yl) -ethenesulfonyl] - [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 - (R) -yl] amino isopropyl ester [acetic acids;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro---indol-2-ylmethyl) amino] pyrrolidin-2-one;

5-chloro-1H-benzoimidazole-2-sulfonic acid [1- (4-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide;

7-methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R, S) -yl] -amide; . 7-methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 7-methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-yl-methyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; [1- (1-Aminoisoquinolin-7-ylmethyl) -2-oxopyrro- trifluoroacetate. 7-Methoxynaphthalene-2-sulfonic acid lidin-3- (R) -yl] amide;

7-Methoxy-naphthalene-2-sulfonic acid [1- (1-hydroxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R, S) -yl] -amide;

7-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R, S) -yl] -methylamide;

7-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide;

benzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 6-chloro-benzo [b] thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

7-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

7-methoxy-naphthalene-2-sulfonic acid [1- (6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 4- (2-chloro-6-nitrophenoxy) benzenesulfonic acid trifluoroacetate [1- (1-amino-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

7-methoxy-naphthalene-2-sulfonic acid [1- (1,6-diamino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate;

6-chlorobenzo [b] thiophene-2-sulfonic acid [1- (1,6-diamino-quinolin-7-yl-methyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

7-methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 6-chloro-benzo [b] thiophene-2-sulfonic acid [1- (2-amino-quinolin-7-ylmethyl-2-oxo-pyrrolidin-3- (S) -yl] -amide) trifluoroacetate; benzo [b] thiophene-2-sulfonic acid benzo [b] thiophene-2-sulfonic acid -2-oxopyrrolidin-3- (S) -yl] amide; 7-methoxy-naphthalene-2-sulfonic acid-methyl] -amide;

7-Methoxy-naphthalene-2-sulfonic acid [1- (2-hydroxy-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide;

7-methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate;

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · 99 ··· 7-Methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide;

7-Methoxy-naphthalene-2-sulfonic acid [1- (2-hydroxy-quinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide;

[1- (2-Aminoquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

7-methoxynaphthalene-2-sulfonic acid;

7-Methoxy-naphthalene-2-sulfonic acid [1- (2-hydroxy-quinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

7-Methoxy-naphthalene-2-sulfonic acid [1- (1H-benzimidazol-5-ylmethyl) -2-oxo-pyrrolo-, din-3- (S) -yl] -amide; 7-Methoxynaphthalene-2-sulfonic acid [2- (1H-benzimidazol-5-ylethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 7-Methoxy-naphthalene-2-sulfonic acid [1- (4-amino-quinazolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide;

7-methoxynaphthalene-2-sulfonic acid [1- (4-aminothieno [2,3-d] pyrimidin-6-ylmethyl) 2-oxo-pyrrolidin-3- (S) -yl] -amide;

7-methoxy-naphthalen-2-sulfonic acid [2- (S-aminothieno [2,3-d] pyrimidin-6-ylmethyl) -oxopyrrolidin-3- (S) -yl] -amide; 7-methoxy-naphthalene-2-sulfonic acid [1- (7-aminothieno [2,3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide trifluoroacetate;

7-methoxy-naphthalene-2-sulfonic acid [1- (7-hydroxy-thieno [2,3-e] pyridin-3-yl-methyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate;

7-methoxy-naphthalene-2-sulfonic acid [1- (4-aminothieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3 (R, S) -yl] -amide;

· · · · · · · * · * * * * * * * * * * * * * * * * * * * * * 7-methoxy-naphthalene-2-sulfonic acid [1- (4-hydroxy-thieno [3,2-c] pyridin-3-ylmethyl) 2-oxo-pyrrolidin-3- (R, S) -yl] -amide;

benzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (4-aminothieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3 (R, S) -yl] -amide;

Thieno [3,2-b] pyridine-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl), 2-oxo-pyrrolidin-3- (S) -yl] -amide;

Thieno [2,3-b] pyridine-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

4-Pyridin-3-yl-thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

5'-Chloro- [2,2 '] bithiophenyl-5-sulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide acids; 2- (5-Chloro-thiophen-2-yl) -ethenesulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide acids;

5'-chloro- [2,2 '] bithiophenyl-5-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide;

2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide; 6-chloro-benzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (4-amino-quinazolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

6-chloro-benzo [b] thiophene-2-sulfonic acid [1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide acids;

trifluoroacetate. [1- (4-amino-thieno [3,2-d] pyrimidin-7-yl-me- thyl) -2 ₇ pyrrolidin-3- (S) -yl) amide 6-chlorobenzo [b] thiophene-2-sulfonic. acids;

5'-chloro- [2,2 '] [1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate bithiophenyl-5-2-sulfonic acid;

Thieno [3,2-b] pyridine-2-sulfonic acid [1- (1,6-diamino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide;

2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide;

5'-chloro- [2,2 '] bithiophenyl-5-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide;

2- (5-Chloro-thiophen-2-yl) -ethenesulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide acids; 3- (R) -5-Chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide;

trifluoroacetate. 2- (S) - [[1- (4-Amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] - (6-chloro-benzo [b] thiophene-2-sulfonyl) -amino] methyl ester acetic acid;

2- (S) -6-Chloro-benzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide;

2- (S) - (5-Chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide;

Thieno [3,2-b] pyridine-2-sulfonic acid ditrifluoroacetate [1- (4-amino-quinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

N- (3-Amino-pyridin-4-yl) -2- [3- (7-methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -acetamide;

2- [3- (7-Methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -N-pyridin-4-yl-acetamide;

6-Chlorobenzo [b] thiophene-2-sulfonic acid trifluoroacetate {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3- (S) -yl} -amide;

5'-chloro- [2,2 '] bithiophenyl-5-sulfonic acid {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide;

6-Chloro-thieno [2,3-b] pyridine-2-sulfonic acid trifluoroacetate {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide ;

thieno [3,2-b] pyridine-2-sulfonic acid {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide ditrifluoroacetate; 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid {3-oxo-1- [2- (pyridio-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide;

(S) -5'-Chloro- [2,2- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} -amide ditrifluoroacetate bithiophenyl-5-sulfonic acid;

(S) -6-Chloro-benzo [b] thio- {1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} -amide ditrifluoroacetate -. fen-2-sulfonic acids;

((β-Chlorobenzo [b] thiophene-2-sulfonyl) - {2-oxo-1- [2- (pyridin-4-ylamino) ethyl] pyrrolidin-3-yl} amino) acetic acid methyl ester;

((6-chloro-benzo [b] thiophene-2-sulfonyl) - {2-oxo-1- [2- (pyridin-4-ylamino) ethyl] pyrrolidin-3-yl} amino) acetic acid trifluoroacetate;

Allyl- {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl}

6-chloro-benzo [b] thiophene-2-sulfonic acid amide;

6-chlorobenzo [b] thiophene-2-sulfonic acid methyl {2-oxo-1- [2- (pyridin-4-ylamino) ethyl] pyrrolidin-3-yl} amide;

(S) -2- (5-Chloro-thiophen-2-yl) -ethenesulfonic acid {1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} -amide trifluoroacetate;

(S) -thieno [3,2-b] pyridine {1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} -amide ditrifluoroacetate -2sulfonic acids;

([2- (5-chloro-thiophen-2-yl) -ethenesulfonyl] - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid methyl ester;

• φ • • • • • φ φ φ φ φ φ φ φ φ φ • • • • • φ φ φ φ φ φ φ isφ 2o-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid;

([2- (5-chloro-thiophen-2-yl) -ethenesulfonyl] - {2oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid trifluoroacetate;

2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate (2-methoxy-ethyl) - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide;

([2- (5-chloro-thiophen-2-yl) -ethenesulfonyl] - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid trifluoroacetate;

3- (5-chloro-thiophen-2-yl) -N- {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -alrylamide trifluoroacetate;

1- (1- (4-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl) -3- (4-chlorophenyl) urea trifluoroacetate;

N- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -2- (5-chloro-thiophen-2-yloxy) -acetamide trifluoroacetate; 1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(5-chloro-ΙΗ-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 1- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (5-chlorothiophen-2-yl) urea trifluoroacetate and trifluoroacetate [1- (4) 5-chlorothiophene-2-carboxylic acid-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

{[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] - [3- (5-chloro-thiophen-2-yl) -acryloyl] -aminoacetic acid trifluoroacetate;

6-chlorobenzo [b] thiophene-2-sulfonic acid [1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] amide trifluoroacetate; Thieno [3,2-b] pyridine-2-sulfonic acid trifluoroacetate [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide;

1- (4-Aminoquinolin-7-ylmethyl) -3- (S) - [(S-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate;

1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [3- (5-chlorothiophen-2-yl) allylamino] pyrrolidin-2-one trifluoroacetate;

N- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -3- (5-chloro-thiophen-2-yl) -acrylamide trifluoroacetate; 1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(5-chloro-1H-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; {[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] [2- (5-chloro-thiophen-2-yl) -ethenesulfonyl] -amino} -acetic acid trifluoroacetate;

{[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] (5-chloro-1H-indol-2-ylmethyl) amino] acetic acid trifluoroacetate;

{[1- (Amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] [3- (5-chloro-thiophen-2-yl) -allyl] -amino} -acetic acid trifluoroacetate;

{1- [1- (4-Amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -3- (5-chloro-thiophen-2-yl) -ureido} -acetic acid trifluoroacetate; >

N- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -3- (5-chloro-thiophen-2-yl) -acrylamide trifluoroacetate;

1- (4-Aminoquinazolin-7-ylmethyl) -3 - (R) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 1- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -3- (5-chlorothiophen-2-yl) urea trifluoroacetate and [1- (4-aminoquinazoline) trifluoroacetate 5-chlorothiophene-2-carboxylic acid-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide;

([1- (4-Amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 - (R) -yl] - (5-chloro-1H-indol-2-ylmethyl) -amino] -acetic acid trifluoroacetate;

0 0 « 0 0 0 00 0000 0 0 0 00 - 0 0 0 0 0 0 0 00 000 « 0 0 0 0 00 00 0 0 0 00 00

1- (4-Aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-1H-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 5-Chloro-benzo [b] thiophene-2-sulfonic acid [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate;

2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide;

7-methoxy-naphthalene-2-sulfonic acid [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide trifluoroacetate;

[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrole trifluoroacetate. 6-chloro-benzo [b] thiophene-2-sulfonic acid lidin-3- (S) -yl] -amide; _,.

5-chlorobenzo [b] thiophene-2-sulfonic acid (S) - [1- (4-amino-thieno [3,2-d] pyrimidin-S-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate;

Thieno [3,2-b] pyridine-2- (1-) - [1- (4-amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate sulfonic acids;

trifluoroacetate (S) - [1- (4-amino-thieno [3,2-d] ^pyrimidine; 6-ylmethyl} -2-oxopyrrolidin-3-yl] -amide 6-chlorobenzo [b] thiophene-2-sulphonic acids;

5'-chloro- [2,2 '] - bithiophenyl 5 (S) - [1- (4-amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate -sulfonic acids;

2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid (S) - [1- (4-amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide acids;

Triflu · φ triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu trifluoroacetate [(S) -1- (4-amino-thieno [3,2-d] 5-Chloro-benzo [b] thiophene-2-sulfonic acid pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl) -amide;

5-Chlorobenzo [b] thiophene-2-sulfonic acid trifluoroacetate [, (S) -1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl) -amide acids;

trifluoroacetate [(S) -1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxopyrrolidin-3-yl] -amide ^5-Chloro-1 [2,2 '] bithiofenyl- 5sulfonic acids;

Thieno [3,2-b] pyridine- [(S) -1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate 2-sulfonic acids;

6-chlorobenzo [b] thiophene-2-sulfonic acid [(S) -1- (4-amino-thieno [2,3-d] pyrimidin-5-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate;

5'-chloro- [2,2 '] bithiophenyl-5sulfonic acid [1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) 2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate acids;

Thieno [3,2-b] pyridine-2-sulfonic acid trifluoroacetate [1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) 2-oxo-pyrrolidin-3- (S) -yl] -amide ; 6-Chlorobenzo [b] thiophene-2-sulfonic acid [(S) -1- (4-amino-thieno [3,3-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide .

More preferred compounds of the present invention are selected from the group consisting of:

3 - [[1- (4-Aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 - (R) -yl] - (5-chloro-1H-indol-2-ylmethyl) -amino] -propionic acid methyl ester;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) - (3-ethylbutyl) amino] pyrrolidin-2-one;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [benzyl- (5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one;

• fl · • fl ···· • fl • · · • · • »· • • fl • fl • • · • · • · • · • · • fl ···· • fl • fl • fl •

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) thiazol-5-ylmethylamino] pyrrolidin-2-one;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) - (2H-pyrazol-3-ylmethyl) amino] pyrrolidin-2-one ;

1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(6-chlorobenzo [b] thiophen-2-ylmethyl) amino] pyrrolidin-2-one;

1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(6-chlorothieno [2,3-b] pyridin-2-ylmethyl) amino] pyrrolidin-2-one;

1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(1H-pyrrolo [2,3-c] pyridin-2-ylmethyl) amino] pyrrolidin-2-one;

3 - {[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) ylamino] methyl} -1H-quinolin-2-one;

1- (7-Aminothieno [3,2-b] pyridin-2-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one;

2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-C] pyridin-2-ylmethyl) -pyrrolidin-3 (R) -yl] -amide; {[2- (5-chlorothiophen-2-yl) ethenesulfonyl] - [2-oxo-1- (1H-pyrrolo [3,2-e] pyridin-2-ylmethyl) pyrrolidin-3- (R) -yl] amino isopropyl ester acetic acids;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one;

5-Chloro-1H-benzoimidazole-2-sulfonic acid [1- (4-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide;

7-methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1- (1-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide; 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide; benzo [b] thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate;

• · ···· φ «φφφφ * · · • φ φ φ t · <

6-chloro [1- (1-aminoisoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] amide trifluoroacetate ######## -benzo [b] thiophene-2-sulfonic acid;

7-methoxy-naphthalene-2-sulfonic acid [1- (1,5-diamino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate;

6-chloro-benzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (1,6-diaminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

7-methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 6-chloro-benzo [b] thiophene-2-sulfonic acid [1- (2-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate;

Benzo [b] thiophene-2-sulfonic acid trifluoroacetate [-1- (2-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 7-methoxy-naphthalene-2-sulfonic acid [1- (4-aminothieno [3,2-c] pyridin-2-ylmethyl) -2-oxo-3-yl] -amide trifluoroacetate; benzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (4-aminothieno [3,2-c] pyridin-2-ylmethyl) -2-oxo-3-yl] -amide; 5-Pyridin-4-yl-thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

5-Pyridin-3-yl-thiophene-2-sulfonic acid trifluoroacetate [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

benzothiophene-2-sulfonic acid [1- (4-aminoquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate;

6-chlorobenzo [b] thiophene-2-sulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide;

100 9 9 999999 9

9 9 9 9 9 9 999

9,999,999

9999 999 · 9

9 9 9 9 9

999 9999 99-9 99 999 7-Methoxy-naphthalene-2-sulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-b] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide trifluoroacetate acids;

6-chlorobenzo [b] thiophene-2-sulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-b] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide trifluoroacetate;

trifluoroacetate. 6-chlorobenzo [b] thiophene-2-sulfonic acid [2-oxo-1- (1H-pyrrolo [2,3-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide;

Thieno [3,2-b] pyridine-2-sulfonic acid ditrifluoroacetate [2-oxo-1- (1H-pyrrolo [2,3-c] pyridin-2-ylmethyl) -pyrrolidin-3 - (S) -yl] -amide ; .

Thieno [3,2-b] pyridine-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

5'-Chloro- [2,2 '] bithiophenyl-5-sulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide acids; 6-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate;

β-chloro-benzo [b] thiophene-2-sulfonic acid [1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate acids;

5'-chloro- [2,2 '] [1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate bithiophenyl-5-2-sulfonic acids;

Thieno [3,2-b] pyridine-2-sulfonic acid [1- (1,6-diaminoquinolin-7-ylmethyl) -2-oxo-p-pyrrolidin-3- (S) -yl] -amide;

2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

5'-chloro- [2,2 '] bithiophenyl-5-sulfonic acid (1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl) -amide;

2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [2-oxo-1- (N-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide; trifluoroacetate. 3- (R) -5-Chloro-thiophen-2-yl) -ethenesulfonic acid [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide;

2- (S) - [[1- (4-Aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] - (6-chloro-benzo [b] thiophene-2-sulfonyl) -amino] -acetic acid trifluoroacetate acids;

2- (S) -6-Chloro-benzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide; .

2- (S) - (5-Chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl) -amide;

Thieno [3,2-b] pyridine-2-sulfonic acid ditrifluoroacetate [1- (4-aminoquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

N- (3-Amino-pyridin-4-yl) -2- [3- (7-methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -acetamide;

2- [3- (7-Methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -N-pyridin-4-yl-acetamide;

6-chloro-benzo [b] thiophene-2-sulfonic acid trifluoroacetate {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3- (S) -yl} -amide;

{2-oxo-l- [2 - (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} amide ^5-chloro-1 [2,2 '] bithiophenyl-5-sulfonic acid;

6-chlorothieno [2,3-b] pyridine-2-sulfonic acid {2-oxo-1- [2- (pyridin-4-ylamino) ethyl] pyrrolidin-3-yl} amide trifluoroacetate;

Thieno [3,2-b] pyridine-2-sulfonic acid {2-oxo-1- [2- (pyridin-2-ylamino) ethyl] -pyrrolidin-3-yl} -amide ditrifluoroacetate;

·· ······ 9 9 9. 9 · 9 9 9 9 9 9

9,999 9 9 ©

9 9 9 9 9999 9 • 9 9 · 9 9 · 9

999 9999 99 99 99 991 2- (5-Chloro-thiophen-2-yl) -ethenesulfonic acid (2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide; ditrifluoroacetate {1- [ (S) -5'-Chloro- [2,2 '] bithiophenyl-5-sulfonic acid 2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} -amide;

(S) -6-Chloro-benzo [b] 1- (2- [2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} -ditrifluoroacetate thiophene-2-sulfonic acids;

((6-chloro-benzo [b] thiophene-2-sulfonyl) - (2-oxo-1- [2- (pyridin-4-ylamino) -ethyl) -pyrrolidin-3 (-yl) -amino) -acetic acid methyl ester;

((6-chlorobenzo [b] thiophene-2-sulfonyl) - (2-oxo-1- [2- (pyridin-4-ylamino) ethyl] pyrrolidin-3-yl} amino) acetic acid trifluoroacetate;

6-Chloro-benzo [b] thiophene-2-sulfonic acid allyl (2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide; 6-chlorobenzo [b] thiophene-2-sulfonic acid [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide; trifluoroacetate (1- [2- (2-amino-3-chloro-pyridin-4-) (S) -2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid ylamino) -ethyl] -2-oxo-pyrrolidiri-3-yl} -amide;

(1- [2- (2-Amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl (S) -thieno [3,2-b] pyridine-2-sulfonic acid amide trifluoroacetate;

methyl ester. ([2- (5-chloro-thiophen-2-yl) -ethenesulfonyl] - (2-oxo-1- [5- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid;

([2- (5-Chloro-thiophen-2-yl) -ethenesulfonyl] - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid isopropyl ester;

([2- (5-chloro-thiophen-2-yl) -ethenesulfonyl] - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid trifluoroacetate;

2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid (2-methoxy-ethyl) - (2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide) trifluoroacetate;

([2- (5-chloro-thiophen-2-yl) -ethenesulfonyl] - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid trifluoroacetate;

3- (5-chloro-thiophen-2-yl) -N- {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl-acrylamide trifluoroacetate;

1- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (4-chlorophenyl) urea trifluoroacetate;

N - '[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -2- (5-chloro-thiophen-2-yloxy) -acetamide trifluoroacetate;

1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(5-chloro-ΙΗ-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 1- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -3- (5-chloro-thiophen-2-yl) -urea trifluoroacetate and [1- (4-Aminoquinazoline) trifluoroacetate 5-chlorothiophene-2-carboxylic acid-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; {[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] - [3- (5-chloro-thiophen-2-yl) -acryloyl] -amino} -acetic acid trifluoroacetate;

6-chlorobenzo [b] thiophene-2-sulfonic acid [1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3 - (R) -yl] -amide;

Thieno [3,2-b] pyridine-2-sulfonic acid trifluoroacetate [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide;

1- (4-Aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate;

1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [3- (5-chlorothiophen-2-yl) allylamino] pyrrolidin-2- trifluoroacetate trifluoroacetate onu;

N- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -3- (5-chloro-thiophen-2-yl) -acrylamide trifluoroacetate; 1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(5-chloro-1H-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; {[1- (4-Amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] [2- (5-chloro-thiophen-2-yl) -ethanesulfonyl] -amino} -acetic acid trifluoroacetate;

{[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] (5-chloro-1H-indol-2-ylmethyl) amino] acetic acid trifluoroacetate;

{[1- (Aminoquinazolip-7-ylmethyl) 2-oxopyrrolidin-3- (S) -yl] [3- (5-chloro-thiophen-2-yl) allyl] amino} -acetic acid trifluoroacetate;

{1- [1- (4-Amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -3- (5-chloro-thiophen-2-yl) -ureido} -acetic acid trifluoroacetate;

N- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -3- (5-chloro-thiophen-2-yl) -acrylamide trifluoroacetate; 1- (4-Aminoquinazolin-7-ylmethyl) -3 - (R) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 1- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -3- (5-chlorothiophen-2-yl) urea trifluoroacetate and [1- (4-Aminoquinazoline) trifluoroacetate 5-chlorothiophene-2-carboxylic acid-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide; {[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] (5-chloro-1H-indol-2-ylmethyl) -amino] -acetic acid trifluoroacetate;

1- (4-Aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate;

·· ······ «9 • 9 * 9 99 9 9

9 ··· 999 * 9

9 99 999999 9

5-chlorobenzo [b] thiophen-2 trifluoroacetate [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide -sulfonic acids;

2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

7-methoxynaphthalene-2-sulfonic acid [1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate;

6-Chlorobenzo [b] thiophene-2-sulfonic acid trifluoroacetate [1-4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide;

5-chlorobenzo [b] thiophene-2-sulfonic acid (S) - [1- (4-aminothieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate;

thieno [3,2-b] pyridine-2-sulfonic acid trifluoroacetate (S) - [1- (4-aminothieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide;

6-chlorobenzo [b] thiophene-2-sulfonic acid (S) - [1- (4-aminothieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate;

5'-chloro- [2,2 '] bithiophenyl-5sulfonic acid (S) - [1- (4-aminothieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate ;

(S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolin-3-yl] -amide trifluoroacetate. 2- (5-chlorothiophen-2-yl) ethenesulfonic acid;

5-chlorobenzo [b] thiophene-2-sulfonic acid [(S) -1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate;

«« R · r r r r r r r

AQ tr tr tr tr tr tr tr tr 1 t t t 1t triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu 5-chlorobenzo [b] thiophene-2-sulfonic acid-aminothieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide;

5'-chloro- [2,2 '] - bithiophenyl-5-sulfonic acid [(S) -1- (4-aminothieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate acids;

Thieno [3,2-b] pyridine-2-sulfonic acid [(S) -1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate acids;

6-chlorobenzo [b] thiophene-2-sulfonic acid [(S) -1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate; 5'-Chloro- [2,2 '] bithiophenyl- [1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) 2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate 5 sulfonic acids;

Thieno [3,2-b] pyridine-2-sulfonic acid trifluoroacetate [1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) 2-oxo-pyrrolidin-3- (S) -yl] -amide and 6-chloro-benzo [b] thiophene-2-sulfonic acid [(S) -1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide acid.

Even more preferred compounds of the present invention are selected from the group consisting of:

7-Methoxy-naphthalene-2-sulfonic acid [1- (6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 1- (4-Aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-1H-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate;

2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide; 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide;

2- (5-chloro-thiophen-2-oxo-pyrrolidin-3-yl) -amide (S) - [1- (4-amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide -2-yl) ethenesulfonic acid;

Thieno [3,2-b] pyridine-2-sulfonic acid trifluoroacetate [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide; 6-Chlorobenzo [b] thiophene-2-sulfonic acid {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3- (S) -yl} -amide trifluoroacetate;

((6-Chloro-benzo [b] thiophene-2-sulfonyl) - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3 (-yl) -amino) -acetic acid methyl ester;

thieno [3,2-b] pyridine-2-sulfonic acid ditrifluoroacetate [2-oxo-1- (1H-pyrrolo [2,3-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide;

Thieno [3,2-b] pyridine-2-sulfonic acid trifluoroacetate [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 2 (S) - (5-Chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide; and β-chlorobenzo [b] thiophene-2-sulfonic acid bistrifluoroacetate [1- (1,6-diamino-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide.

The present invention also encompasses all preferred, combinations of preferred aspects of the present invention.

The compound of the present invention can be prepared using known or modified methods known in the art. refers to procedures previously used or described in the literature.

A compound of formula I according to the present invention wherein Ar _{1 is} R _1Z

R ₂ , X ₃ , X ₄ , X ₅ , X _5a , X _5b , Z and m are as defined above, X ₃ and X _1a are 9 9 9 9 9 · A hydrogen atom and X ₂ and X _2a together form an oxo group, can be prepared by condensation of a compound of formula II

(Π), where X ₃ , X "and m are as defined above, X! and X _1a are hydrogen, X ₂ ^and X _2a are together oxo, and P _x is (alkyl, arylalkyl or aryl) carbamate, with a compound of formula III

_where Ar is a bicyclic heteroaryl group, X _s, X _5a, X _5b and Z are as defined above and one of X _a, X _5a, X _5b is hydrogen, chloro, bromo or aryloxy at the position alpha to the carbon of the distal ring nitrogen Ar _L and L is a leaving group such as a chlorine, bromine, iodine atom, or an optionally substituted lower alkylsulfonyloxy or arylsulfonyloxy group to give a compound of formula IV

(IV).

• · · · · · · · · · · · ·

The compound of formula IV is converted to the compound of formula I by the methods described herein.

The compound of formula III can be prepared by reacting a compound of formula V

CHO (V) wherein X _5c is H, R _{S S} R N, R ₇ 0-, R @ ₅ R @ ₅ NCO, R ₅ R ₆ NSO ₂ -, R ₇ CO-, halo , cyano, nitro or R _e (O) C (CH ₂ ) _q , and wherein its amino or hydroxyl group is optionally protected with a suitable amino protecting group or a hydroxyl group, n is 0 to 2 and Ar ₂ is a monocyclic aryl group or a heteroaryl group, with a suitable malonic acid in a polar solvent such as pyridine or ethanol and a base such as piperidine or pyridine at boiling, to give a compound of formula VI

where R ₁₂ is a hydrogen atom, the group is a hydrogen atom,

5c attached to carboxymethylidene

X,

on

4 4 4

_ _ * 4 4 4 4 4 4 4

4444444 44 4 »44 44» are defined above. Alternatively, a compound of formula V can be reacted with a suitable Wittig reagent in an inert solvent such as tetrahydrofuran to give a compound of formula VI wherein R ₁₂ is lower alkyl,

as defined above. When R _{12 is a} lower alkyl group, the ester is hydrolyzed to the corresponding carboxylic acid, where R ₁₂ is a hydrogen atom, using a strong acid or an alkali base. The corresponding acid is converted to the acid chloride using standard methods, such as thionyl chloride, or converted to a mixed anhydride in a polar solvent such as acetone or tetrahydrofuran to give an activated acyl compound. The activated acyl compound is then reacted with a solution of NaN ₃ in water at about -10 ° C to 25 ° C to give the corresponding acylazide. The acyl azide compound is then slowly heated in an inert solvent such as benzene or toluene to about 60-110 ° C, then evaporated in vacuo and heated in a higher boiling inert solvent such as 1,2-dichlorobenzene or phenyl ether to about 180 ° C. to 240 ° C with a catalyst such as iodine or tributylamine to give a compound of formula VII

9 9999999 99 9

999 * · · ·

9 9 9 9 9

999 9999 99 · 9 99 999 where X _5c is hydrogen, R _S R _S N, R ₇₀ O-, R ₅ R ₆ NCO-, R ₅ R _with NSO ₂ -, R ₇ CO- , halogen, cyano, nitro or R ₃ (O) C (CH ₂ ) _q , and wherein its amino or hydroxyl group is optionally protected with a suitable amino protecting group or a hydroxyl group, n is 0, 1 or 2 and Ar ₂ is a monocyclic aryl group or a heteroaryl group. Alternatively, the acylazide compound can be added directly to a high boiling inert solvent such as phenyl ether at about 190 ° C to 240 ° C, with a catalyst such as iodine or tributylamine to give a compound of formula VII.

prepared according to the procedure described in Syn., 7.39 (1975), which is incorporated herein by reference, wherein X _5c is hydrogen, R ₅ R ₅ -N-, R ₇ O-, R ₅ R ₅ NCO-, _{R R} NSO ₂ -, R ₇ CO-, halo, cyano, nitro or _a group R (O) C (CH _{2) q,} and wherein the amino or hydroxy group is optionally protected by a suitable amino protecting group or a hydroxyl n is 0, 1 or 2 and Ar ₂ is a monocyclic aryl or heteroaryl group or a compound of formula VII above, or those compounds wherein their amino or hydroxyl groups are suitably protected with amino or hydroxyl protecting groups are. can be chlorinated using standard procedures such as POCl ₃ or POCl ₃ / PCl ₅ to give the following chlorinated intermediates, such as compounds of formula IX and X, as defined above.

«

• · · · · · · · · · ·

Where X _Sc on Ar ₂ are

(X).

Further, a compound of formula IX and formula X, wherein X _5c is a protected amino group wherein the protection is carried out by an acid-sensitive group such as an acyl group or a dibenzylidene group, can be deprotected using standard conditions such as ethyl acetate to give the free amine can be chlorinated using the procedure described above. alternatively, the free amine may be liberated by POCl ₃ , but in both cases the free amine may be re-protected with a suitable protecting group, such as. is a dibenzylidene group.

Compound of Formula XI

(X1) such as a compound of formula IX and X, wherein Ar _x , X ₅ , X _5a and X _5b are as defined above and one of X ₅ , X _5a and X _{5t 3} is a chlorine atom at the alpha position relative to the nitrogen atom further away of a ring of Ar _1z where Ar _x is bicyclic, and the methyl group is attached to a closer ring of Ar _x , can be reacted with a bromide, sodium or arylhydroxy compound such as phenol and potassium hydroxide to give a compound of formula XI wherein the chlorine atom in the alpha position relative to the nitrogen atom of the distal ring of the group Ar _x is replaced by a bromine atom or an aryloxy group at this position.

«1 1 1 • 1 1« «« «« «« «1 1 1 1 1

The methyl group of a compound of formula XI wherein Ar ₁ X ₅ , X _5a and. X

5b jso.u defined above, with the proviso that when X _s, X _5a and X _Sb is hydroxy or amino bearing a hydrogen then the hydroxy and amino are protected by appropriate hydroxy-protecting groups and / or amino groups, may be halogenated using standard conditions such as N-halosuccinimide and benzoyl peroxide in an inert solvent such as carbon tetrachloride, to yield the corresponding halomethyl compound of formula III wherein L is bromo, chloro or iodo, and one of X _a, X _5a and X _sb represents chlorine, bromine or aryloxy, in the alpha position relative to the nitrogen atom of the more distal ring of the group Ar _x .

A is CH, W is NH and Z is methylenyl, L is halogen, one of X ₅ , X _5a and X _sb is on the five-membered ring of group Y is a substituent defined

VY above or a compound whose amino or hydroxyl group is suitably protected, the other groups X ₅ , X _5a and X _5b are, on the six-membered ring of group f a is a substituent as is

as defined above, or a compound of which the amino or hydroxyl group is suitably protected, and the other X ₅ groups,

X _5a ^{and X} 5b are hydrogen, chlorine, bromine or aryloxy and is substituted in the alpha-to-nitrogen atom on the six-membered ring of group f A

VY * ·· ······ · · ··· ♦ 9 4 4 9 4 ·

4 4 9 4

494 4494 4 9 9 9 '44 9 94 prepared by reacting a compound of formula XII, a compound of formula XIII or a compound of formula XTIIa

(prepared according to the procedure described in J. Het. Chem., 29, 359 (1992); Bull. Soc. Chim. Belg. 301 (1970); and J. Med. Chem. 33,

2087 (1990), the contents of which are given herein as Qmark) wherein W is NH and X ₆ is hydrogen, with POCl ₃ or POCl ₃ / PCl ₅ as described above to yield the corresponding chlorinated compound. A compound of formula XII or formula XIII wherein W is NH and X ₇ is hydrogen may be protected using standard procedures such as benzenesulfonyl chloride in the presence of a strong base such as sodium hydroxide in a halogenated solvent such as dichloromethane in the presence of a phase transfer catalyst such as tetrabutylammonium chloride to give a compound of Formula XII or Formula XIII wherein W is N-SO ₂ Ph and X ₇ is hydrogen. These compounds are reacted with a strong base such as sodium hydride. lithium hexamethyldisilylazide, or lithium diisopropylamine, in an inert solvent such as tetrahydrofuran or dimethylformamide at a temperature of about -78 ° C to about 25 ° C, followed by addition of ethyl chloroformate to give a compound of Formula XII or Formula XIII wherein W is N-SO ₂ Ph and X ₇ is a C ₂ alkyl lower alkyl group which is then converted to a compound of Formula XII or Formula XIII, wherein W is N-SO ₂ Ph and X ₇ is -CH ₂ OH, using standard hydride reducing agents. agents such as lithium aluminum hydride in a suitable organic solvent such as diethyl ether at a temperature of about -10 ° C to about 25 ° C. Then, the compound of formula XII or formula XIII, wherein W is N57

99 99 9999 ·

999 9 9 9 9 9 99

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

999 9 9 9.9 99 99 99 999

SO ₂ Ph and X ₇ is a -CH ₂ OH group can be halogenated using standard conditions such as PBr ₃ in an organic solvent such as diethyl ether to give a compound of formula III as defined above.

Alternatively, a compound of formula III may be prepared by condensation of a suitable beta-aryl or beta-heteroarylamino acid of formula XIV or XV,

_ ^ NH ₂ CO ₂ H

X Λ X \ ^{C C} 2 ^H (XIV) or ^{W W NH} 2 (XV) wherein Wa X 1 are as defined above, with a Gold reagent under basic conditions using a hydride. sodium or other corresponding strong base followed by acid treatment. The obtained compound is then treated as described above to give a compound of formula III.

Compound. of Formula II, as above, is reacted with a strong base such as sodium hydride, lithium hexamethyldisilylazide, or lithium diisopropylamine in an inert organic solvent such as tetrahydrofuran or dimethylformamide at a temperature of about -78 ° C to about 25 ° C and then adding the compound of formula II, above, wherein one of the groups X _s , X _5a and X _sb is substituted in the semi-real with respect to the nitrogen atom of the farthest ring of the group - - α _γ j is a hydrogen atom, chlorine atom, bromine atom or aryloxy group; a leaving group such as. a chlorine atom, a bromine atom, or an iodine atom, to obtain a compound of formula IV as defined above.

Alternatively, a compound of formula IV wherein ##

A is CH, W is NH, L is halo, one of the five membered ring of / & ja Z methylenylová group, X _s, X _5a and X _5b is on, and it is a substituent as defined above or a compound having an amino group or hydroxyl group is suitably protected, another of X _with X _5a and X _5b is on the six membered ring groups XA and it is a substituent DEFI (M) ned above or a compound having an amino or hydroxyl group is suitably protected, another of X _s , _Xa and _X5b are hydrogen, chlorine, bromine or aryloxy and is substituted with alpha relative to the nitrogen atom of the six membered ring of group / λ can be prepared by alkylation of (2-oxopyrrolidin-3 (S) -yl) alkyl or arylalkyl ester carbamic acids with propargyl bromide in the presence of a base such as sodium hydride. The obtained alkyne is heated to 100 to 120 ° C with a halopyridine optionally substituted with a hydroxyl group, an alkoxycarbonylamino group, or a sulfhydryl group, with a catalyst such as Pd (PPh ₃ ) ₂ -Cl ₂ , copper iodide, triethylamine in a suitable solvent such as acetonitrile , in a closed vessel or in dimethylformamide, for 2 to 20 hours. When pyridine is substituted by a hydroxyl group, furopyridines are isolated directly when pyridine is substituted by alkoxycarbonylamino, further treated with DBU at about 60 ° C in dimethylformamide to give pyrrolopyridines. Removal of the protecting groups yields the desired 2- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) furopyridines or pyrrolopyridine-1-carboxylic acid alkyl esters.

4 4 4 4 4 4 .44 44 Selines. These compounds are conventionally sulfonylated (using arenesulfonyl chlorides and a base such as triethylamine) and, in the case of furopyridines, purified (HPLC) to give [2-oxo-1- (fluoropyridinyl-methyl) pyrrolidin-3- (S) -yl] - arenesulfonic acid amides usually in the form of salts with trifluoroacetic acid. In the case of pyrrolopyridines, a further deprotection step (such as acid for BOC protecting groups) affords the corresponding arenesulfonic acid [2-oxo-1- (pyrrolopyridinylmethyl) pyrrolidin-3- (S) -yl] amides.

Group P _x Compounds of formula IV are then removed by a suitable deprotection procedure known for carbamates such as strong acids, strong bases or catalytic hydrogenation to give a compound of formula XVI wherein Ar _{1 (} X ₅ , X _5a , X _5b , Z and m are defined above.

The amine of the compound of formula XVI released by the removal of P _{1 (} is then condensed to the compound of formula XVIII or XVIII

R ₃ S (O) _p halogen or R ₃ R ₄ NS (O) _p halogen;

(XVIII) '(XVIII) wherein R ₃ , R ₄ , and p are as defined above, and halogen is a halogen atom, such as a chlorine atom, using a base such as a trialkylamine in an inert solvent such as dichloromethane, tetrahydrofuran, ether or acetonitrile at a temperature of 0 to 100 ° C in the presence or absence of an activating agent such as dimethylaminopyridine (DMAP) to give a compound of formula XIX

wherein Ar _{Iz Iz} R R _3, R _4, X _l; X _a, X _2, X _2a, X _3, X _4, X _s, X _5a, X _Sb, Z and m are as defined above. '

Compounds of formula XIX wherein X ₅ , X _5a and X _5b is substituted alpha to the far ring nitrogen atom of the group _{R 5 and} i is bromo or chloro may be converted to the corresponding aryloxide by reaction with an arylhydroxy compound such as phenol, and a strong alkaline base such as potassium hydroxide at 70-120 ° C. The aryloxide intermediate (Y = ArO-) is then treated with an ammonium salt such as ammonium acetate, at 90 to 180 ° C, to give a compound of formula I, _where Ar, R _x, R _3, R _4, X _Ia Xiz X ₂ of X ₂ of X ₃ X ₄ out of ₅ X of X _from X _5b, Z and m are from as defined above, wherein one of X _with X _5a and. X _5b. substituted alpha to the far ring nitrogen of the group and is NH ₂ .

Alternatively, the compound of formula XIX, wherein X _a, X _5a and X _5b is substituted alpha to the ring, the nitrogen of the distal ring group.

and is a bromine atom or a chlorine atom, can be reacted with an arylhydroxyl compound such as phenol and an ammonium salt such as ammonium acetate at a temperature of about 90 to 180 ° C to give a compound of formula I wherein Ar _x , R _x , R ₃ , R ₄ , X 1 _Z X _1a , X ₂ , X _2a , X ₃ , X 1, X ₅ ', X _sa , X _5b , Z and m are as defined above and wherein one of the groups · · · · · · ·

wherein X ₃ , X ₄ , P _{3 and} m are as defined above, and P ₂ is an alkyl group, an arylalkyl group or an aryl group, by reductive amination using a (heteroaryl) alkylamine of formula XXI

wherein Ar _x , X ₅ , X _5a , X _5b and Z are as defined above, in an alcohol solvent such as methanol and an imine reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride at a temperature of about 0 to 100 ° C to give a cyclic structure of formula IV, which is then converted to a compound of formula I as defined above.

The compound of formula XXI used in the reductive amination described above may be prepared by reacting a compound of formula III wherein z'e one _X group, X _Sa, X _5b is H or aryloxy at the position alpha to the carbon 'nitrogen of the distal ring of Ar ₃ and L is a leaving group such as chlorine, bromine, iodine, or the like, with sodium azide, followed by reduction by standard reducing conditions such as triflate. Phenylphosphine in solvents such as water / tetrahydrofuran or catalytic reduction.

A compound of formula I wherein R ₁ is other than hydrogen may be prepared from a compound of formula I wherein R ₁ is hydrogen by dissolving it in an inert organic solvent such as tetrahydrofuran, dioxane, or dimethylformamide at 0 ° C to 100 ° C. Deň: 32 ° C. To the resulting solution is added a base such as sodium hydride or potassium carbonate and a compound of formula XXII.

wherein R ₃ is as defined above except that R _x is not a hydrogen atom, and halogen is a halogen atom such as a bromine or chlorine atom.

A compound of formula I containing a heteroaryl group containing one or more ring nitrogen atoms, preferably imine (= N-), can be converted to the corresponding compound wherein one or more ring nitrogen atoms of the heteroaryl group is oxidized to an N-oxide, preferably by reaction with a peracid, for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane at a temperature between room temperature and boiling point, preferably at elevated temperature.

The compounds of the present invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are part of the present invention.

When a compound of the present invention is substituted with a basic group, it forms acid addition salts which are a more convenient form for practical use; and in practice the use of the salt form corresponds to the use of the compound in the free base form. Acids which may be used for the preparation of acid addition salts «

• ····

- ·· ···

·.

preferably include those acids which, when coupled with a free base, provide pharmaceutically acceptable salts, i. salts whose anions are non-toxic to patients at pharmaceutical doses, so that the beneficial inhibitory effect on free base factor Xa activity is not impaired by the side effects of the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base forms, even if the corresponding salt itself is suitable only as an intermediate, for example when the salt is formed solely for purification and identification purposes or when used as an intermediate in the preparation of a pharmaceutically acceptable salt by ion exchange procedures. The pharmaceutically acceptable salts of the present invention are those derived from the following acids: mineral 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, ptoluenesulfonic acid, cyclohexylsulfamic acid; quinic acid, and the like. Appropriate acid addition salts include: hydrohalides such as hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-B- hydroxynaphthoate, gentisate, mesylate, isothionate and di-p-toluoyltartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.

In another embodiment, the acid addition salts of the compounds of the present invention are prepared by reacting the free base with the appropriate acid, by known or modified procedures. For example, acid addition salts of the compounds of the present invention are prepared either by dissolving the free base in aqueous or aqueous alcohol.

an aqueous solution or other suitable solvent containing the appropriate acid and isolating the salt by evaporating the solution or by reacting the free base and the acid in an organic solvent, wherein the salt separates directly or can be isolated by evaporating the solution.

The compounds of the present invention can be regenerated from the acid addition salts by methods known to those skilled in the art. For example, the parent compound of the present invention can be regenerated from its acid addition salt by treatment with a base, for example an aqueous sodium bicarbonate solution or an aqueous ammonia solution.

When a compound of the present invention is substituted with an acidic moiety, it may form base addition salts that are more suitable for use; and in practice the use of the salt form actually corresponds to the use of the free acid form. Bases which can be used for the preparation of base addition salts preferably include those bases which, when mixed with the free acid, form pharmaceutically acceptable base salts, i. salts whose cations are not toxic to animals in pharmaceutical doses, and thus the advantageous inhibitory effect of free acid on factor Xa activity is not abolished by the side effects of the cation present. Pharmaceutically acceptable salts, including, for example, the alkali metal and alkaline earth metal salts of the present invention, are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, hydroxide zinc, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N- ^1- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, tetramethylmethylamide, tetramethyl amine; alike.

• · · «· · • · • · ·· · · • • • · • • • · • • • · • · • · • • · · • • • · · · · · • · * · • · • ·

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

Salts of the compounds of the present invention and amines can be obtained by contacting the amine in an aqueous or organic solvent with the free acid form of the compound. 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. Amino acid salts can be prepared similarly.

The base addition salts of the compounds of the present invention can be regenerated from the salts using known procedures. For example, the parent compound of the present invention can be regenerated from its base addition salt by reaction with an acid, such as hydrochloric acid.

The salt forms of the present invention also include compounds having a quaternized nitrogen atom. Quaternized salts are obtained by methods such as alkylation of the sp ³ or sp ² hybridized nitrogen atom of the compounds.

It will be apparent to those skilled in the art that some of the compounds of the present invention do not form stable salts.

However, acid addition salts are best formed from compounds of the invention containing a heteroaryl group containing

a nitrogen atom and / or from compounds containing an amino group as a substituent. Preferred acid addition salts of the compounds of the present invention are those which do not contain acid-sensitive groups.

As well as the compounds themselves suitable as active compounds, the salts of the compounds of the present invention are useful for the purification of the compounds, for example using differences in solubility between the salt and the parent compound, by-products and / or starting materials using procedures well known to those skilled in the art. known.

The compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be either of the (R) or (S) configuration. It will also be apparent to those skilled in the art that certain compounds of Formula I may also exhibit geometric isomerism. Geometric isomers include cis and trans forms of a compound of the present invention containing alkenyl groups. The present invention includes the individual geometric isomers and austereoisomers and mixtures thereof.

These isomers may be separated from the mixtures by methods known to those skilled in the art, for example by chromatographic techniques and recrystallization techniques, or may be prepared separately from suitable isomeric intermediates, for example by methods known to those skilled in the art.

The starting materials and intermediates are prepared by known methods, for example by the methods described in the Reference Examples or by their apparent chemical equivalents.

• · • φ

..............

The present invention is further illustrated by the following non-limiting examples which illustrate the preparation of the compounds of the present invention.

In nuclear magnetic resonance (NMR) spectra Chemical shifts are expressed in ppm relative to tetramethylsilane. Abbreviations have the following meanings: s = singlet; d = doublet; t = triplet; m = multiplet; dd = · doublet doublet; ddd = doublet doublet; dt = triplet doublet; w = wide; ss = broad singlet; q = quadruplet; AB = AB system.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (R, S-yl) -amide trifluoroacetate

A. 3-p-Tolylacryloyl chloride.

9.44 ml (129.5 mmol) of Thionyl chloride was added dropwise at 0 ° C to a solution of 20 g (123.3 mmol) of 3-p-tolyl-acrylic acid in 50 ml of benzene. The resulting solution was allowed to stir at room temperature and then heated to reflux for two hours. The mixture was evaporated to. Drying on a rotary evaporator gave 22.3 g (123.3 mmol) of the crude product, which was used in the next step.

^{Χ Η} NMR (CDCl, 300 MHz) δ 7.80 (d, 1H), 7.50 (d,

2H), 7.26 (d, 2H), 6.58 (d, 1H), 2.40 (s, 3H).

B. 3-n-Tolylacryloylazide

22.3 g (123.3 mmol) of 3-p-Tolylacryloyl chloride in 50 ml of dioxane are slowly added to an ice-cold solution of 16 g (246.6 mmol) of sodium azide in 50 ml of a 1: 1 v / v mixture of water and dioxane. ,

to maintain the temperature between 5 and 10 ° C. The mixture was stirred for 1.5 hours, then poured onto 300 g of ice. The white solid obtained was filtered and washed with water. 2 0.72 g (110.7 mmol) of solid was dried over phosphorus pentoxide in vacuo overnight and used in the next step without purification.

¹ H NMR (CDCl 3, 300 MHz) δ 7.73 (d, 1H), 7.45 (d,

2H), 7.21 (d, 2H), 6.38 (d, 1H), 2.38 (s, 3H). EI.MS, [M] ⁺ = 187.

C. 1- (2-Isocyanatovinyl) -4-methylbenzene

20.72 g (110.7 mmol) of 3-p-Tolylacryloylazide in 100 ml of benzene was slowly heated at 75 ° C for 3.5 hours, then evaporated to give about 20 g of a brown oil. This material was used in the next step without purification.

^: Η NMR (CDCl, 300 MHz) δ 7.18 (d, 2H), 7.12 (d,

2H), 6.53 (d, 1H), 6.40 (d, 1H), 2.32 (s, 3H). EI MS, [M] ⁺ = 159.

D. 7-Methyl-2H-isoquinolin-1-one

0.63 g (2.51 mmol). of iodine is added to a solution of about 20 g (125.6 mmol) of 1- (2-isocyanatovinyl) -4-methylbenzene in 125 ml of o-dichlorobenzene, then heated to reflux at 180 ° C overnight. The mixture was cooled to room temperature, then evaporated to dryness. The residue was purified by column chromatography eluting with 40% ethyl acetate in hexane. 6.2 g (3-9.1 mmol) of product are obtained in the form of a solid.

¹ H NMR (CDCl 3, 300 MHz) δ 12.25 (bs, 1H), 8.21 (s,

1H), 7.42 (bs, 2H), 7.14 (d, 1H), 6.50 (d, 1H). 2.46 (s, 3H).

EI MS, [M] ^T = 159.

φ φφ ·· ···· © ® · · · φ φ φ φφφ ·· φ φ φ φ φ φφφ · · · _Λ φφ φ _φφφφ φφφφφφφ · * ·· ·· ·· ···

Ε. 1-Chloro-7-methylisoquinoline

7-Methyl-2H-isoquinolin-1-one (2.1 g, 13.2 mmol) in phosphorus oxychloride (30 ml) was heated under reflux for 13 hours. The mixture was cooled to room temperature, then evaporated to a smaller volume. The residue was diluted with ice water and then the pH was adjusted to approximately 8 by the addition of 10 N sodium hydroxide solution. The aqueous solution was extracted four times with 20 ml of dichloromethane and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The dark oil obtained was purified by column chromatography eluting with 25% ethyl acetate in hexane to give 1.6 g (9 mmol) of the product as a pale yellow solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.18 (d, 1H), 8.05 (d, ·

1H), 7.71 (d, 1H), 7.55 (m, 2H), 7.55 (s, 3H), EI MS ,. [M] ⁺ = 177, 179, Cl isotopes.

F. 7-Bromomethyl-1-chloroisoquinoline

1.10 g (6.19 mmol) of N-bromosuccinimide and 0.39 g (1.13 mmol) of benzoyl peroxide are added to a solution of 1 g (5.63 mmol) of 1-chloro-7-methylisoquinoline in 70 ml of carbon tetrachloride. The resulting mixture was heated at reflux for 6 hours, then cooled to room temperature and diluted with dichloromethane. The organic layer was washed with 1N sodium hydroxide solution and brine, then dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with a gradient of 10% ethyl acetate in hexane to 25% ethyl acetate in hexane to give 1.4 g (5.46 mmol) of the product as a white solid.

9 9 9 4

4 · 4

9. · «4 · · 4 · · 9 4 ·

1H), 8.28 (d,

4.69 (s, 2 H).

0 ······· ¹ H NMR (CDCl 3, 300 MHz) δ 8.31 (s,

1H), 7.86 (d, 1H), 7.77 (dd, 1H), 7.58 (d, 1H),

EI MS, [M] ⁺ = 255, 257. Cl, Br isotopes.

G. (2-Oxopyrrolidin-3- (S) -yl) carbamic acid tert -butyl ester, g (115 mmol) of (S) -Boc-Diaminobutanoic acid, 35 g (344 mmol) of triethylamine and 19.3 g (143 mmol) mmol) of hydroxybenzotriazole is dissolved in 300 ml of tetrahydrofuran. 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (27.4 g, 143 mmol) was added. The solution was heated to 60 ° C for 15 minutes. A white precipitate formed and the solution was kept at 60 ° C for 4 hours. Then the solution is filtered and the liquid obtained is evaporated. The crude product was purified by column chromatography eluting with a gradient of 1% methanol in dichloromethane to 3% methanol in dichloromethane to afford 19.6 g (98 mmol) of the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 6.17 (bs, 1H), 5.08 (bs,

1 H), 4.12 (m, 1 H), 3.33 (m, 2 H), 2.65 (m, 1 H), 2.00 (m, 1 H),

1.42 (s, 9H).

H. [1- (1-Chloroisoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -carbamic acid tert-butyl ester

0.24 g (6.05 mmol, 60% dispersion in mineral oil) of sodium hydride was added to a solution of 1.18 g of [2-oxopyrrolidin-3 (S) -yl] -carbamic acid tert-butyl ester in 0 ° C in 0 ° C. 62 ml of a 9: 1 mixture of tetrahydrofuran and dimethylformamide (v / v). After stirring for 2 minutes, a solution of 1.4 g (5.46 mmol) of 7-bromomethyl-1-chloroisoquinoline in 10 mL of tetrahydrofuran was added dropwise via cannula. The resulting yellow solution was stirred at 0 ° C for 1 hour and then at room temperature for 3 hours. The reaction was quenched by addition of saturated ammonium chloride solution, then diluted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with a gradient. 50% ethyl acetate in hexane to 70% ethyl acetate in hexane gave 1.67 g (4.44 mmol) of product as a white foamy solid.

NMR (CDCl 3, 300 MHz) δ 8.25 (d, 1H)., 8.12 (s,

1H), 7.83 (d, 1H), 7.68 (dd, 1H), 7.58 (d, 1H), 5.55 (bs, 1H), 4.71 (d, 2H), 4 30 (m, 1H); 3.26 (m, 2H); 2.60 (m, 1H); 1.98 (m, 1H); 1.46 (s, 9H). EI MS, [M + H] ⁺ = 376, 378, Cl isotopes.

I. 3- (S) -amino-1- (1-chloroisoquinolin-7-ylmethyl) pyrrolidin-2-one hydrochloride

To a solution of [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -carbamic acid tert-butyl ester (2.1 g, 5.6 mmol) in 170 ml of ethyl acetate at 0 ° Hydrogen chloride gas is bubbled through for 5 minutes. The solution was stirred at 0 ° C for 15 minutes, then the ice bath was removed and the solution was allowed to warm to room temperature. After 4 hours at. The solution was evaporated and the remaining solid was washed with ether to give 1.74 g (5.6 mmol) of the title compound as a pale yellow solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.64 (d, 3H) -,

8.31 (d, 1H), 8.18 (s, 1H), 8.10 (d, 1H), 7.90 (d, 1H), 7.80 (d, 1H), 4.71 (ΑΒ) (2H), 4.10 (m, 1 H), 3.30 (m, 2 H), 2.41 (m, 1 H), 1.98 (m, 1 H). FAB MS, [M + H] ⁺ = 276.

J. 7-Methoxynaphthalene-2-sulfonyl chloride

To the suspension. 15 g (60.9 mmol) of 7-hydroxynaphthalene-2-sulfonic acid sodium salt in 150 ml of a 2: 1 mixture of water and ethanol are added at

4.44 g (67 mmol) of solid sodium hydroxide was added at 4444 at room temperature. The mixture was stirred until a homogeneous solution was formed and then 6.34 ml (67 mmol) of dimethyl sulfate was added. A precipitate slowly formed and the mixture was stirred for 16 hours. The crude mixture was evaporated in vacuo and stirred in 100 ml of absolute ethanol as a suspension for 2 hours. The precipitate was filtered and dried. The solid was heated to reflux in 100 ml of 95% ethanol for 2 hours, allowed to cool to room temperature, filtered to give 12.6 g of crude 7-methoxynaphthalene-2-sulfonic acid sodium salt. A mixture of 12.6 g (48.6 mmol) of sodium sulfonic acid in 20 ml of phosphorus oxychloride and 13.2 g (63.2 mmol) of phosphorus pentachloride was slowly heated at 60 ° C until a homogeneous solution was formed and then heated for 4 hours. at 12 ° C. The resulting mixture was cooled in an ice bath and water / ice was added slowly with stirring. The mixture was diluted with water and extracted twice with 100 mL of dichloromethane. The combined organic layers were washed successively with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to give 10 g of a crude oil. The crude product was purified by column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 30% ethyl acetate in hexane to give 3.8 g (14.8 mmol) of the title compound as a white crystalline solid. (1 H NMR (CDCl 3, 300 MHz) δ 8.49 (d, 1H), 7.96 (d,

1H), 7.85 (d, 2H), 7.39 (dd, 1H), 7.29 (d, 1H), 3.99 (s, 3H).

EI MS, [M] + = 256.

TO'. 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide.

• 999 *

1.74 g (5.6 mmol) of 3- (S) -amino-1- (1-chloro-isoquinolin-7-ylmethyl) -pyrrolidin-2-one hydrochloride are suspended in 120 ml of acetonitrile. To this solution was added 2.35 mL (16.9 mmol) of triethylamine followed by 1.52 g (5.93 mmol) of 7-methoxynaphthalene-2-sulfonyl chloride. The mixture was stirred overnight, then evaporated to dryness. The crude product is purified by column chromatography. eluting with a gradient of 2% methanol in dichloromethane to 5% methanol in dichloromethane to give 2.7 g (5.4 mmol) of the title compound as a light yellow solid.

´ Ή NMR (deuterochloroform, 300 MHz) δ 8.35 (d, 1H), 8.27 (d,

1H), 8, 08 (S, 1H), 7.91 (d, 1H), 7.80 (d, 1H), 7.78 (S, 1 H), 7.74 (dd, 1H), 7.56 (s, 1H); 7.51 (d, 1H), 7.30 (dd, 1H), 7.24 (d, 1H), 5.42 (d, IH), 4.63 (AB, 2H), 3.95 (s, 3H); 3.78 (m, 1H), 3.25 (m, 2H), 2.60 (m, 1H), 2.08 (m, 1 H). FAB MS, [M + H] &lt; ⁺ &^gt; 496, 498, Cl isotopes.

7-Methoxy-naphthalene-2-sulfonic acid [1- (1-phenoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (R, S) -yl] -amide

6.81 g (72.4 mmol) of phenol and 0.41 g (7.31 mmol) of potassium hydroxide are added to [1- (1-chloroisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S). 7-Methoxynaphthalene-2-sulfonic acid 1-yl] amide and heated to 90 ° C until a homogeneous mixture is obtained. The mixture was stirred at 90 ° C overnight, then cooled to room temperature and diluted with 100 mL of dichloromethane and water. The aqueous layer was neutralized with 1N hydrochloric acid to pH 7, then the layers were separated and the aqueous layer was extracted with additional dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with a gradient of 30% ethyl acetate in hexane to 60% ethyl acetate in hexane to afford 1.66 g (3 mmol) of the product as a white solid.

4 9 9 9

9 4 9 9 4 • · · · · · · ·

• 74 ·· • 9 9 994 • · · ·· · • · • · • « • · · · “Η N MR (deuterochloroform, 3 00 MHZ) δ 8.40 (with, 1H) ', 8.20 (with, 1H), 7.94 (d, IH); 7.82 (d, 1H); 1H), 7.74 (d, 1H), 7.70 (d, 1H), 7.51 (dd, 1H); 7.40 (m, 2H); 7,15-7,30 (m, 7H), 5.80 (šs, 1H), 4.60 (AB, 2H), 3.98 (s, 3H), 3.82 (m, 1H), 3.20 (m, 2H), 2.52 (m, 1H), 2.04 (m, 1H). FAB MS , [M + H] ⁺ = 554.

M. 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (R, S) -yl] -amide trifluoroacetate,

In a round-bottom flask equipped with a water condenser, 0.318 g (0.574 mmol) of 7-methoxy-naphthalene-2-sulfonic acid [1- (1-phenoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide was heated and 5 g (65 mmol) of ammonium acetate at 160 ° C. After about 6 hours, the homogeneous mixture was cooled to room temperature and purified by reverse phase HPLC eluting. gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 100% acetonitrile. The appropriate fractions were lyophilized to give 0.157 g (0.266 mmol) of the racemic title compound as a white solid.

“H NI MR (perdeuterodimethylsulfoxide, 30 ' 0 MHz :) δ _: 8.95 (šs, 2H), 8.39 (WITH (1H), 8.23-8.29 (m, 2H), 8.02 (d, 1H), 7.95 (d, 1H), 7.93 (d (1H), 7.77 (d, 1H), 7.74 (dd, 1H), 7.65 (d, 1H), 7.58 (d, 1H) 7.35 (dd, 1H); 7.24 (d, 1 H), 4,56 (AB, 2H), 4.20 (m, 1H), 3, 89 (s, 3H) 3.15 (m, 2H), 2.05 (m, 1H), 1.60 (m, 1H).

FAB MS, [M + H] &lt; ⁺ &^gt; = 477.

Example 2 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide hydrochloride

In a round-bottomed flask equipped with a finger condenser, at 70 ° C, 0.569 g (6 mmol) of phenol and 0.2 g (0.4 mmol) are melted [9].

999 9919

. 9 11 9 9

9

1 9 9 9 ·

9 9 1 9 8

99 99 9 (1-Chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

Of 7-methoxynaphthalene-2-sulfonic acid. The mixture was stirred for 5 minutes, then 0.462 g (6 mmol) of ammonium acetate was added and the mixture was heated to 115 ° C for 2 hours. An additional 0.462 g (6 mmol) of ammonium acetate was then added. After 2 hours, the reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and 0.5N sodium hydroxide solution. The organic layer was separated and washed with water and brine, then dried over sodium sulfate, filtered and evaporated. The residue obtained is partially purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 100% acetonitrile. Appropriate fractions were evaporated in vacuo. The solid which precipitated out of solution was then filtered, dried and re-purified by column chromatography eluting with 5% methanol in dichloromethane. This product was then triturated with cold methanol and the filtered solid was suspended in methanol and cooled to 0 ° C. Hydrogen chloride gas was bubbled through the suspension for a few minutes, dissolving all solids in solution. The solvent was evaporated in vacuo and the title compound (0.11 g, 0.214 mmol) was washed with ether and dried.

¹ H NMR (CDCl 3, 300 MHz) δ 13.30 (bs, 1H),

9.18 (šs, 2H), 8.32 (with, 1H) , 8.25 (d, 1H), 7, 99 ( d, 1H, 7., 85- 7, '91 (m, 2H), 7,60- 7.80 (m, 3H), 7.50 (with, 1H ), 7 , 25 (dd, 1 H), 7.18 (d, 1H) ' 4.51 (AB, 2H) 4.23 (m, m). 1H), 3 , 85 (with, 3H), 3.1X (m, 2H), 1, 95 (m, 1H), 1, 65 (m, IH) . FAB MS, [M + H] ⁺ = 477.

mp 187-192 ° C. ·

The enantiomeric purity was 88% ee as determined by analytical reverse phase HPLC on a Chiralpak AD column.

• fl flflflfl · fl flfl flflfl fl fllfl flflflfl fl * flfl fl fllflfl fl fll fl flf fll flfl fll

Example 3

7-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 - (S) -yl] -amide trifluoroacetate

The title compound was prepared by resolution of the racemic compound described in Example 1, Part M, using a Chiralpak AD HPLC column (55% ethanol in heptane (0/1% trifluoroacetic acid)).

¹ H NMR (CDCl 3, 300 MHz) δ 8.95 (bs, 2H),

8.39 (d, 1H), 8.30 (with, 1H), 8.23 (d, 1 H), 8.04 (d, 1H), 7.95 (d, 1H), 7.93 (d, 1H), 7.77 (d, 1H), 7.74 (dd, 1H), 7,6.5 (d, 1H), 7.58 (d, 1H), 7.35 (dd, 1H), 7.24 (d, 1H), 4,56 (AB, 2H), 4.20 (m, 1H) 3.89 (with, 3H), 3.15 (m, 2H) 2.05 (m, 1Ή), 1.60

(m, 1 H). FAB MS, [M + H] &lt; ⁺ &^gt; = 477.

The enantiomeric purity was 96.3% ee and was determined by reverse phase analytical HPLC on a Chiralpak AD [α] _D + 3.16 ° (methanol) column. ,

Example 4 7-Methoxynaphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide trifluoroacetate

The title compound was prepared by resolution of the racemic compound described in Example 1, Part M, using a Chiralpak AD HPLC column (55% ethanol / heptane (0.1% trifluoroacetic acid)).

¹ H NMR (CDCl 3, 300 MHz) δ 8.95 (bs, 2H),

8.39 (d, 1H), 8.30 (with, 1H), 8.23 (d, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.93 (d, 1H), 7.77 (d, 1H), 7.74 (dd, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 7.35 (dd, 1H), 7.24 (d, 1H), 4,56 (AB, 2H),

9999

9 9 9

99

4.20 (m, .delta.), 3.89 (s, 3H), 3.15 (m, 2H), (m, 1H). FAB MS, [M + H] &lt; ⁺ &^gt; = 477.

2.05 (m.

1H), 1.60

The enantiomeric purity was 90.7% ee and was determined by reverse phase analytical HPLC on a Chiralpak AD [α] _D -3.89 ° (methanol) column.

Example 5 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-hydroxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (R, S) -yl] -amide

0.07 g (0.14 mmol) of 7-methoxy-naphthalene-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide, prepared according to the procedure as described in Example 1, part K, is treated with 1 ml dioxane and 3 ml 10% aqueous sodium hydroxide solution, and refluxed for 48 hours. Reaction. the mixture was cooled, acidified with 1N hydrochloric acid solution and extracted with dichloromethane. The organic layer was separated, dried and evaporated. The residue was purified by column chromatography eluting with 2.5% methanol in dichloromethane. Product containing fractions were combined, evaporated and the precipitate was diluted with hydrogen chloride in ether to give 0.041 g (0.086 mmol) of the title compound.

¹ H NMR (deuteromethanol, 300 MHz) δ 8.41 (s, 1H), 8.25 (d, 1H),. 8.06 (bs, 1H), 7.93 (d, 1H); 7.85 (d, 1 H), 7.76 (d, IH); 7.58 (AB, 2H), 7.39 (s, 1H). 7.24 (dd, 1H), 7.17 (d, 1H), 6.66 (šs, 1H), 4.55 (AB ,. 2H), 4.20 (m, IH), 3.92 (s, 3H), 19.19 (m, 2H), 2.20 (m, 1 H), 1.59 (m, IH), 1.70 (m, 1 H). FAB MS, [M + H] &lt; + &gt; ^. = 478.

Elemental analysis calculated with 1.6 mole of water: C = 58.42%, H = 4.71%, N = 8.18%; found C = 59.30%, H = 5.04%, N = 7.96%.

• · • 0

Example 6 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R, S) -yl] -methylamide

A. 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide

To a solution of 7-methoxy-naphthalene-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide (0.151 g, 0.304 mmol) in 20 mL of acetone was added 0.084 g. g (0.608 mmol) of potassium carbonate followed by 0.12 mL (1.93 mmol) of methyl iodide. The resulting mixture was heated at reflux overnight, then cooled to room temperature and diluted with dichloromethane. The solution was washed with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with 5% methanol in dichloromethane to give 0.093 g (0.18 mmol) of the product as an oil.

@ ¹ H NMR (CDCl3, 300 MHz) .delta 8.41 (with, ÍH), 8.04 (s, 1H), 8.23-8.26 (m, 2H), 8.07 (s, 1H), 7.90 (d, ÍH), 7.90 (d, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.58 (dd, ÍH), 7.28 (m, 1H), 5.02 (m, H), 4.63 (AB, 2H), 3.92 (s, ¹ 3H), 3.24 (m, 2H), 2.82 (s, 3H), 2.32 (m, 1H), 2.05 (m, 1H).

B. 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-phenoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (R, S) -yl] -amide

The title compound was prepared according to the procedure for EXAMPLE 1, Part L using 7-methoxy-naphthalene [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide 2-sulfonic acids instead of [1- (1-chloro-isoquinolin-7-yl) 79

7-Methoxynaphthalene-2-sulfonic acid amide-2-oxopyrrolidin-3- (S) -yl] -amide 7-methoxynaphthalene-2-sulfonate .

¹ H NMR (CDCl 3, 300 MHz) δ 8.45 (s, IH) 8,2 0 (with, 1H), 7.90 (d, 1H), 7.81 (d, 1H), 7.74 (d, 1H), 7.70 (d, IH), 7.54 (dd, 1H), 7.38-7.45 (m, 3H), 7.14 -7,30 (m, 6H) 5.00 (m, 1H), 4.62 (AB, 2H), 3.88 (s, 3H), 3.25 (m, 2Ή), 2.81 (with, 3H),

2.30 (m, 1 H), 2.01 (m, 1 H).

C. 7-Methoxynaphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 -, (R, S) -yl] -methylamide

The title compound was prepared according to the procedure for EXAMPLE 1, Part M using 7-methoxy-naphthalene- [1- (1-phenoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R, S) -yl] -methyl-amide. 2-sulfonic acids in place of 7-methoxy-naphthalene-2-sulfonic acid [1- (1-phenoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (R, S) -yl] -amide.

¹ H NMR (CDCl 3, 300 MHz) δ 9.00 (bs, 2H),

8.40 (with, IH), 8.26 (S, IH) 8,04 ' (d, IH), 7.90. -7 · 95 (m, 2H) 7.79 (d, IH), 7.71 (dd, IH) 7.65 (d, IH), 7.56 (d, 1H), 7.32 (d, IH), 7.21 (d, 1H), 4.95 (m, IH), 4.54 (AB, 2H), 3.86 (s, 3H), 3.20 (m, 2H), 2.65 (s, 3H), 2.00 (m, IH), 1.75 (m, 1H).

FAB MS, [M + H] ⁺ = 491. Elemental analysis calculated with 1.5 moles of water: C = 53/25%, H = 4.79%, N = 8.87%, found C = 53.43%, H = 4.50%,

N = 8.58%.

Example 7

7-Methoxy-naphthalene-2-sulfonic acid [1- (1,1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide trifluoroacetate. 1 iny · «····

The title compound was prepared by resolution of the racemic compound described in Example 6, Part C using a Chiralpak AD reverse phase HPLC column (55% ethanol / heptane (0.1% trifluoroacetic acid)). ^X H-NMR (perdeutero sulfoxide, 3 00 MHz) δ 13.5 (bs, 1H)

9,20 (šs, 2H), 8.40 (with, 1H), 8.26 (with, 1H), 8.04 (d, 1H), 7,90- 8.00 (m, 2H), 7.79 (d, 1H), 7.71 (dd, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 7.34 (dd, 1H), 7.23 . (d ,. 1H), 4.98 (m, 1H), 4.54 (AB, 2H), 3.86 (with, 3H), 3.20 (m, 2H), 2.68 (with, 3H), 2.05 (m, 1H),

1.80 (m, IH). FAB MS, [M + H] &lt; ⁺ &^gt; = 491. The enantiomeric purity was 92.6% ee as determined by reverse-phase HPLC. phase on a Chiralpak AD column.

Example 8 Benzo [b] thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

A. Benzo [b] thiophene-2-sulfonyl chloride

To a solution of 11.8 g (88.1 mmol) of thianaphthalene in 400 mL of tetrahydrofuran at -78 ° C was added 55 mL of a 1.6 M solution of n-butyllithium (88.1 mmol) in hexane. After 15 minutes, the solution is added via cannula to a cooled (-78 ° C) solution of 200 g of sulfur dioxide in 100 ml of tetrahydrofuran. After the addition, the solution was allowed to warm to room temperature. The residue was suspended in 400 mL hexane and cooled to 0 ° C. 12.5 g (92.5 mmol) of SO ₂ Cl ₂ are added to the solution. After 15 minutes, stirring, the solution was evaporated. The residue was dissolved in ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and evaporated. The crude product was dissolved in dichloromethane and filtered through a pad of silica gel.

· * * * * * * * ♦ ♦

The organic solution was then evaporated. The solid obtained was triturated with hexane to give 12.1 g (38 mmol) of the title compound.

¹ H NMR (CDCl 3, 300 MHz) δ 8.16 (s, 1H), 7.97 (m,

2H), 7.57 (m, 2H).

Β. Benzo [b] thiophene-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure for EXAMPLE 1, Part K, using benzo [b] thiophene-2-sulfonyl chloride in place of 7-methoxy-naphthalene-2-sulfonyl chloride.

¹ H NMR (CDCl 3, 300 MHz) δ 8.29 (d, 1H), 8.12 (s,

1H), 7.93 (s, 1H), 7.84-7.92 (m, 2H), 7.82 (d, 1H), 7.54-7.62 (m, 2H), 7.46 -7.52 (m, 2H), 5.50 (d, 1H), 4.66 (AB, 2H), 3.95 (m, 1H), 3.25 (m, 2H), 2.65 (m, 1 H), 2.15 (m, 1 H).

FAB MS, [Μ + ΗΓ-472, 474, Cl isotopes.

C. Benzo [b] thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

The title compound was prepared using the procedure described in Example 2 from benzo [b] thiophene-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as starting materials. No further processing is performed. The crude product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 100% acetonitrile. Appropriate fractions were lyophilized to give the title compound as a white solid. · ^X H NMR (perdeuterodimethylsulf oxide, 300 MHz) δ 9.00 (bs, 2H) "8.65 (d, 1H), 8.30 (s, 1H), 8.07 to 8.1 5 (m, 3H), 8.05 (d, 1H), 9949

9

9 • 9 • 99

7.94 (d, 1H), 7.80 '(d, 1H), 7.68 (d, 7.22 (d, 1H), 4.55 (AB, 2H), 4.31 (m)

1H), 7.45-7.58 (tn, 2H), 1H), 3.25 (tn, 2H), 2.20 (m, 1H), 1.73 - (in, 1H). FABMS, [M + H] + = 453.

Example 9

6-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

A. 1-Chloro-3- (2,2-dimethoxyethylsulfanyl) benzene

To a solution of 2.4 g (16.6 mmol) of 3-chlorothiophenol at 0 ° C was added 2.8 g (16.6 mmol) of bromoacetaldehyde dimethyl acetal. To the solution was added 0.70 g (17.4 mmol), 60% dispersion in mineral oil) of sodium hydride. The reaction mixture was stirred for 16 hours then quenched by addition of saturated aqueous ammonium chloride solution. The solution was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with hexane. This afforded 3.7 g (15.9 mmol) of the title compound as an oil.

^X H NMR (CDCl₃, 300 MHz) δ 7.32 (m, IH). 7.25 (m,

1H), 7.12. (m, 1H), 4.47 (m, 1H), 3.07 (s, 3H), 3.02 (s, 3H).

B. 4-Chlorobenzo [b] thiophene and 6-chloro-benzo [b] thiophene

A solution containing 8 g of polyphosphoric acid and 50 ml of chlorobenzene is heated to reflux. A solution containing 2.7 g (11.6 mmol) of 1-chloro-3- (2,2-dimethoxyethylsulfanyl) benzene in 5 ml of chlorobenzene was added dropwise to the boiling solution of polyphosphoric acid. After 6 hours, the solution was cooled to room temperature. The solution was diluted with dichloromethane and washed

0000 • ··

0. 0 * • 0 0 • 0 0 0 • · '0

000 0000 • 0 · 0 ·

0 0 0 0 0 0

00 .00 •

• 00 with water and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with hexane to give 2.4 g (9 mmol) of the title compound as a 1: 1 mixture of isomers.

¹ H NMR (CDCl 3, 300 MHz) δ 7.88 (m, 1H), 7.75 (m,

2H), 7.42 (m, 2H). EI MS, [M] ⁺ = 168, 170, Cl isotopes.

C. 6-Chlorobenzo [b] thiophene-2-sulfonyl chloride

The title compound was prepared according to the procedure described in Example 8, part A, by substitution. 4-chloro-benzo [b] thiophene and 6-chloro-benzo [b] thiophene with thianaphthalene. The crude product was purified by column chromatography eluting with hexane to give the title compound as well as 4-chlorobenzo [b] thiophene-2-sulfonyl chloride as a white solid.

6-Chloro-benzo [b] thiophene-2-sulfonyl chloride \

¹ H NMR (CDCl 3, 300 MHz) δ 8.11 (s, 1H), 7.88 (m,

2H), 7.50 (m, IH).

4-chloro-benzo [b] thiophene-2-sulfonyl chloride ^X H NMR (CDCl, 300 MHz) δ 8.32. (m, 1H); 7.81 (m,

1H), 7.53 (m, 2H).

D. 6-Chloro-benzo [b] thiophene-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide.

The title compound was prepared according to the procedure for EXAMPLE 1, Part K, using 6-chloro-benzo [b] thiophene-2-sulfonyl chloride in place of 7-methoxy-naphthalene-2-sulfonyl chloride.

^X H NMR (CDCl M, 300 MH z) δ 8.29 1H), 7.91 (s, 1H), 7.87 (m, 1 H), 7.83 (d, ¹ 7.60 7.58 (dd, 1H). 1H), 7.42 (dd, 1H), (AB, 2H), 3.95 (m, 1 H), 3.25 (m, 2H), 2.65 1H).

• · · · · · · · (d,. 1H), 1H), 7.80 5.50 (d, (m, 1H),

• · · · · · · · · · · ···

8.12 (s, (d, 1 H)),

1H), 4.65 2.15 (m,

FAB MS, [M + H] = 506, 508, Cl isotopes.

E. 6-Chloro-benzo [b] thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 '(S) -yl] -amide trifluoroacetate

The title compound was prepared according to the procedure for EXAMPLE 2 using 6-chloro-benzo [b] thiophene-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide acids like. starting materials. No extraction treatment is performed. The crude product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 100% acetonitrile. Appropriate fractions were lyophilized to give the title compound as a solid.

¹ H NMR (CDCl 3, 300 MHz) δ 9.00 (bs, 2H),

8.71 (d, 1H), 8.29 (bs, 2H), 8.05 (s, 1H), 8.01 (d, 1H), 7.94 (d, ÍH), 7.80 (d, 1H), 7.65 (d, 1H), 7.55 (dd, 1H), 7.21 (d, 1H), 4.58 (AB, 2H), 4.30 (m, 1H), 3.20 (m, 2H), 2.20 (m, 1 H), 1.75 (m, 1H).

FAB MS, [M + H] + = 487.489, Cl isotopes.

Example 10

7-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide •

A. 6-Methoxy-7-methyl-2H-isoquinolin-1-one. 5.33 g (27.7 mmol) of 3- (3-Methoxy-4-methylphenyl) propenoic acid (prepared according to the procedure described above) (J. Med Chem., 1991, 34, 1662-1668) is suspended in 30 ml of benzene and treated at 0 ° C with 2.22 ml (30.5 mmol) of thionyl chloride dropwise. The reaction mixture was heated under reflux for 1 hour. The volatiles were evaporated in vacuo and the solid obtained was dissolved in dioxane and added dropwise at 0 ° C to a mixture of 3.6 g (55.4 mmol) of sodium azide in 30 ml of a 1: 5 mixture of water and dioxane. After stirring for 1 hour, the solution was poured into ice water, the precipitate was collected and washed with water. The solid was dried under vacuum over phosphorus pentoxide for 24 hours, dissolved in 30 ml of benzene and heated slowly to reflux for 4 hours. The benzene was removed to give 2- (3-methoxy-4-methylphenyl) vinylisocyanate as a brown oil. The oil was taken up in o-dichlorobenzene, treated with iodine, and heated at reflux for 3.5 hours. The volatiles were evaporated and the residue was treated with 10 ml of 2.5% methanol in dichloromethane then allowed to stand overnight at room temperature. The resulting solid was collected, washed with hexane and ether, and dried to give 2.67 g (14.1 mmol) of the title compound. ¹ H NMR (CDCl 3, 300 MHz) δ 11.80 (bs, 1H), 7.16 (d, 1H),. 6.86 (s, 1H); 6.51 (d, 1H);

2.35 (s, 3H). EI MS, [M] &lt; ⁺ & gt ^; = 189.

1H), 8.18 (s,

3.94 (s, 3H);

B. 7-Bromomethyl-1-chloro-6-methoxyisoquinoline

2.6 g (13.7 mmol) of 6-methoxy-7-methyl-2H-isoquinolin-1-one was converted to 2.45 g (11.8 mmol) of 6-methoxy-7-methyl-2-chloroisoquinoline according to the procedure described in Example 1, part E. 1.20 g (5.8 mmol) of this material using the procedure described in Example 1.

1, Part F, was converted to 0.8 g (2.8 mmol) of methoxyisoquinoline (0.8 g, 2.8 mmol).

7-bromomethyl-1-chloro-6 Ή NMR (CDCl 3, 300 MHz) δ 8.30 (s, 1H), 8.22 (d,

1H), 7.49 (d, 1H), 7.10 (s, 1H), 4.70 (s, 2H), 4.06 (s, 3H).

EI MS, [M] ⁺ = 285, 287, Cl isotopes.

C. [1- (1-Chloro-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester

0.057 g (1.4 mmol, 60% dispersion in mineral oil) of sodium hydride was suspended in 5 mL of tetrahydrofuran and treated at 0 ° C with a solution of 0.223 g (1.1 mmol) of (2-oxopyrrolidin-3) tert -butyl ester. - (S) -yl) -carbamic acid and 0.32 g (1.1 mmol) of 7-bromomethyl-1-chloro-6-methoxyisoquinoline in 10 ml of a mixture of tetrahydrofuran and dimethylformamide (6: 1). The reaction mixture was warmed to room temperature, stirred for 3 hours, quenched by addition of saturated ammonium chloride solution and diluted with ethyl acetate. The layers were separated. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to give a white solid. The solid was collected, washed with a small amount of ethyl acetate and an equal amount of diethyl ether to give 0.18 g (0.47 mmol) of the title compound.

^X H NMR (CDCl₃, 300 MHz) δ 8.22 (d, 1H), 8.06 (s, 1H), 7.51 (d, 1H), 7.11 (s, 1H), 5.20 (šs, 1H), 4.68 (AB, 2H) 4.23 (m, 1H); 3.98 (s, 3H); 3.21 (m, 2H), 2.65 (m, 1H), 1.90

(m, 1H). 1.46 (s, 9H). FAB MS, [M + H] &lt; ⁺ &^gt; = 387.

D. 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-chloro-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

[1- (1-Chloro-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester 0.15 g (0.37 mmol) · * 9 «9999999 · 9 · _9" lazy using the procedure described in Example 1, part I, and K was converted to 0.08 g '(0.15 mmol). 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-chloro-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide.

¹ H NMR (CDCl 3 / CDCl 3, 300 MHz) δ 8.40 (s, 1H), 8.14 (d, 1H), 7.99 (s, 1H), 7.95 (d, 1Ή), 7 83 (d, 1H); 7.78 (d, 1H); 7.55 (d, 1H); 7.28 (s, 1H); 7.13 (s, 1H); 4.62 (s, 1H); 2H), 4.0 (s, 3H), 3.97 (s, 3H), 3.89 (dd, 1H), 3.2-3.4 (m, 2H), 2.52 (m, 1H) 2.07 (m, 1 H). FAB MS, [M + H] &lt; ⁺ &^gt; = 526.

E. hydrochloride. 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-6-methoxy-isoquinolin-7-ylmethyl) 2-oxo-pyrrolidin-3- (S) -yl] -amide

7-Methoxynaphthalene-2-sulfonic acid [1- (1-chloro-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide (0.080 g) and 0.430 g - (4.6 mmol) phenol is melted with stirring at 70 ° C for 5 minutes. 0.354 g (4.6 mmol) of ammonium acetate is added and the reaction mixture is heated at 115 ° C for 5 hours. An additional 0.177 g (2.3 mmol) of ammonium acetate was added and the reaction was heated for an additional 3 hours. The reaction mixture was cooled and extracted, between 0.5N sodium hydroxide solution and dichloromethane. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by column chromatography eluting with 5% methanol in dichloromethane. The product containing fractions were combined and evaporated to a small volume, then the residue was acidified with 1N HCl in ether to give 0.046 g (0.095 mmol) of the title compound as a beige solid.

¹ H NMR (deuteromethanol, 3 00 MHz) δ 8 .38 (s, 1H), 8.05 (s, IH), 7.88 (d, IH); 7.80 (d, 1H); 1H), 7.73 (dd, 1H). 7.44 (d, IH) 7.32 (d, 1H); 7.30 (s, 1H); 7.23 (dd, 1H), 7.07 (d, 1H), 4.53 (AB, 2H), 4.23 (t, 1H), 3.98 í (s,  3H), 3.89 '(s, 3H), 3.30. (m, 2H),

• ·

2.22 (m, 1H), 1.89 (m, 1H). FAB MS, [M + H] &lt; ⁺ &^gt; = 478. Elemental analysis calculated with 1.4 mol of water: C = 54.96%, H = 5.29%, N = 9.86%; found C = 54.81%, H = 5.12%, N = 9.71%.

Example 11

[1- (6-Methoxyisoquinolin-7-ylmethyl) -2-oxopyr- trifluoroacetate. 7-Methoxy-naphthalene-2-sulfonic acid rolidin-3- (S) -yl] -amide

A suspension of 7-methoxy-naphthalene-2-sulfonic acid [1- (1-chloro-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide in 35 mL of methanol / dichloromethane (6: 1) is treated with 5 ml of tetrahydrofuran, 5 ml of acetic acid and 0.04 g of 10% palladium on carbon. The suspension was stirred under a hydrogen atmosphere for 7 hours. The suspension was filtered, the filtrate was then evaporated and the residue purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 90% acetonitrile in water (0.1% trifluoroacetic acid). . The appropriate fractions were lyophilized to give 0.325 g (0.66 mmol) of the title compound as a white solid.

¹ H NMR (deuteromethanol, 300 MHz) δ 9.37 (s, 1H), 8.40 (d, 1H), 8,3 8 (d, ÍH), 8.23 (d, IH), 8.15 (s, IH) 7.93. (d, 1H) j 7.85 (d, ÍH), 7.77 (dd, 1H, 7.66 (with, 1H, 7.35 (s, 1H), 7.27 (dd, ÍH), 4.66 (AB, 2H), 4.28 (t, ÍH), 4.12 (s, 3H), 3.92 (s, 3H), 3.40 (m, 2H), 2.35 (m, 1H), 1,92 ' (m, 1H). FAB MS, [M + H] &lt; + &gt; ^. = 492.

Elemental analysis calculated for 1.2 mol of water: C = 53.66%, H = 4.57%, N = 6.70%; found C = 53.62%, H = 4.38%. N = 6.67%.

Example 12

4- (2-Chloro-6-nitro-phenoxy) -benzenesulfonic acid [1- (1-amino-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate •

9 9

[1- (1-Chloro-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester (0.845 g, 2 mmol) was converted according to the procedure described in Example 10, Part E, to [1- (1-amino-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester, 0.314 g (0.081 mmol). This was deprotected from 0.285 g (0.7 mmol) according to the procedure described in Example 1, Part I to give 0.28 g (0.78 mmol) of [T- (1-amino-6-methoxyisoquinoline-) - dihydrochloride. 7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amine and condensed according to the procedure described in Example 1, Part K with 0.35 g (1 mmol) of 4- (2-chloro-6-nitrophenoxy) benzenesulfonyl chloride. The obtained material was purified by reverse phase HPLC after extraction and purification by column chromatography to give 0.04 g (0.067 mmol) of the title compound.

¹ H NMR (deuteromethanol, 300 MHz) δ 8.14 (s, IH) 8.07 (d, IH), 7.92-7.98 (m, 3H), 7.53 -7.60 (m, 2H), 7 , 40 (s, IH), 7.18 (d, 1H), 7.05 (d, 2H), 4.63 (AB, 2H) , 4.18 ( : t, IH) 4.06 (with, 3H), 3.36 (m, 2H), 2.32 '(m, 1H) LH), 1.87 (m, lH) . FAB. MS, [M + H] &lt; ⁺ &^gt; 598,

600, Cl isotopes. Elemental analysis calculated with 1.5 mol of water: C = 47.13%, H = 3.82%, N = 9.48%; found C = 47.07%, H = 3.66%, N = 9.24%.

Example 13

7-Methoxy-naphthalene-2-sulfonic acid [1- (1,6-diamino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

A. 3- (3-Acetamido-4-methylphenyl) propenoic acid

To a solution of 14 g (79 mmol) of 3-acetamido-4-methylbenzaldehyde in 210 mL of pyridine was added 3.9 mL (39.4 mmol) of piperidine and 15.26 g (146.6 mmol) of malonic acid. The reaction mixture was heated at 100 ° C for 4 hours, then stirred overnight at room temperature. The solution was evaporated in vacuo, then diluted with water. A cold 1N hydrochloric acid solution is added to the suspension until a pH of about 4 is reached. 16.17 g (73.8 mmol) of solid product are obtained, which is collected and washed thoroughly with water. 16.178 g (73.8 mmol) of the title compound was then dried over phosphorus pentoxide in vacuo overnight to give a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 12.30 (bs, 1H), 9.30 (bs, 1H), 7.65 (s, 1H), 7.51 (d, 1H), 7.42 ( d, 1H), 7.25 (d, 1H), 6.42 (d, 1H), 2.25 (s, 3H), 2.09 (s, 3H). EIMS [M + H] &lt; + &^gt; = 220.

B. 3- (3-Acetylamino-4-methylphenyl) acrylazide

To a suspension of 3- (3-acetamido-4-methylphenyl) propenoic acid (20.11 g, 91.7 mmol) in acetone (450 mL) at 0 ° C was added triethylamine (12.8 mL, 91.8 mmol) and then stirred at room temperature overnight. Ethyl chloroformate (11.8 g, 123 mmol) was added dropwise over 10 minutes. The resulting yellow suspension was stirred with a mechanical stirrer for 1.5 hours, then a solution of 8.94 g (138 mmol) of sodium azide in 25 ml of water was added slowly to maintain the temperature below 5 ° C. The thick mixture was stirred at 0 ° C for 1 hour, then the ice bath was removed and the reaction mixture was allowed to warm to room temperature. The suspension is poured into 800 ml of water and then filtered. The remaining solid was washed with plenty of water and dried under vacuum over phosphorus pentoxide to give 21.40 g (87.6 mmol) of the product as a pale yellow solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.10 (s, 1H), 6.71 (d,

1H), 7.22 (m, 2H), 6.95 (bs, 1H), 6.38 (d, 1H), 2.29 (s, 3H),

2.21 (s, 3H). EI MS [M] ⁺ = 244.

• · ·· · ·

C. N- (7-Methyl-1-oxo-1,2-dihydro-isoquinolin-6-yl) -acetamide

To a solution of 250 mL of diphenyl ether and 11.9 mL (49.9 mmol) of tributylamine at 220-240 ° C was added a suspension of 12.2 g. (49.9 mmol) of 3- (3-acetylamino-4-methylphenyl) acryloylazide in diphenyl ether. After 2 hours, the yellow solution was cooled to room temperature and poured into 800 mL hexane. A brown solid precipitated and was recrystallized from dimethylformamide / methanol. to give 3.56 g (16.5 mmol) of the title compound as a light yellow solid.

1 H NMR (CDCl 3, 300 MHz) δ 11.0 (bs, 1H), 9.35 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.05 ( m, ΪΗ), 6.45 (d, 1H), 2.32 (s, 3H), 2.12 (s, 3H). EI MS [M] ⁺ = 216.

D. 6-Amino-7-methyl-2H-isoquinolin-1-one

0.366 g (1.69 mmol) of N- (7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yl) -acetamide and 0.5 ml of concentrated hydrochloric acid are heated to boiling under 0.84 ml of ethanol. reflux condenser. After 6 hours, the mixture was evaporated to dryness, then diluted with water and adjusted to pH 10 by addition of 1N sodium hydroxide solution. The aqueous solution was extracted four times with 50 ml of dichloromethane and the organic layers were combined and washed with brine, dried. over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with a gradient of 3% methanol in dichloromethane to 5% methanol in dichloromethane to afford 0.200 g (1.15 mmol) of the title compound as a white solid.

Ή NMR (CDCl 3, 300 MHz) δ 8.90 (bs, 1H), 8.06 (s, 1H), 6.90 (m, 1H), 6.65 (s, 1H), 6, 28 (d, 1H), 4.05 (bs, 2H), 2.20 (s, 3H, EIMS [M] ⁺ = 174).

♦ · · φ φ φ * φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Ε. 1-Chloro-7-methyl-isoquinolin-6-ylamine

The title compound was prepared according to the procedure for EXAMPLE 1, Part E using 6-amino-7-methyl-2H-isoquinolin-1-one as the starting material. The crude product was purified by column chromatography eluting with a gradient of 5% methanol in dichloromethane to 10% methanol in dichloromethane to give the title compound as a yellow solid.

^τ Η NMR (CDCl 3, 300 MHz) δ 8.05 (d, 1H), 8.00 (s, 1H), 7.30 (d, 1H), 6.90 (s, 1H), 4.25 ( bs, 2H), 2.40 (s, 3H). EI MS [M] ⁺ = 192.194, Cl isotopes. '

F. Benzhydrylidene- (1-chloro-7-methyl-isoquinolin-6-yl) amine

To a solution of 1-chloro-7-methyl-isoquinolin-6-ylamine (0.1 g, 0.52 mmol) in methanol (5 ml) was bubbled hydrogen chloride gas at 0 ° C for 1 minute, then the solvent was evaporated in vacuo. The remaining white solid was diluted with 1,2-dichloroethane and 0.15 mL (0.89 mmol) of imine benzophenone was added. The resulting suspension was heated at reflux for 48 hours, then cooled to room temperature and evaporated to dryness. The crude material was diluted with dichloromethane and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The crude product is purified by column chromatography using a white solid. elution with 10% ethyl acetate in hexane to give 0.159 g (0.45 mmol) of the title compound as a yellow oil.

^X H NMR (CDCl .300 MHz) δ 8,05 (m, 2H) , 7.80 (m, 2H), 7.45-7.55 (m, 4H), 7.20-7 , 30 (m. 3H) ', 7.10 (m, 2H), 6 , 75 (s, 1H). 2.50 (s, 3H). FAB MS, [M + H] ⁺ = 357. 359, Cl isotopes.

G. Benzhydrylidene- (7-bromomethyl-1-chloro-isoquinolin-6-yl) -amine ··········

The title compound was prepared according to the procedure for EXAMPLE 1, Part F, starting from benzhydrylidene- (1-chloro-7-methyl-isoquinolin-6-yl) -amine. The title compound is obtained as an oil.

¹ H NMR (CDCl 3, 300 MHz)? δ 8.33 (s, 1H), 8.06 (d,

1H), 7.84 (m, 2H), 7.41 (m, 4H), 7.32 (m, 4H), 7.20 (d, 1H), 6.66 (s, 1H), 4, 79 (s, 2 H). FAB MS, [M + H] + 435, 437, Cl, Br isotopes.

H. {1- [6- (Benzhydrylideneamino) -1-chloro-isoquinolin-7-ylmethyl] -2-oxo-pyrrolidin-3- (S) -yl} -carbamic acid tert-butyl ester

The title compound was prepared according to the procedure described in Example 1. Part H, using benzhydrylidene- (7-bromomethyl-1-chloro-isoquinolin-6-yl) -amine instead of 7-bromomethyl-1-chloro-isoquinoline. The crude product was purified by column chromatography eluting with a gradient of 10% ethyl acetate in hexane to 30% ethyl acetate in hexane to give the product as a foamy solid.

¹ H NMR (CDCl 3, 300 MHz): z) δ 8,09 (d, 1H), 8.01 . (with, 1H), 7.80 (m, 2H), 7.20-7.45 (m, 9H), 6.70 (with, 1H), 5.30 (d, 1H), 4.65 (s, 2H), 4.21 (m, 1H), 3.32 (m, 2H) 2.70 (m, 1H), 1.95 (m, 1H); 1.46 (s, 9H). FAB MS, [M + H] ⁺ = 555, 557, Cl

isotopes.

I. 7-Methoxy-naphthalene-2-sulfonic acid [1- (6-amino-1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

From {1- [6- (benzhydrylidene-amino) -1-chloroisoquinolin-7-ylmethyl] -2-oxo-pyrrolidin-3- (S) -yl} -carbamic acid tert-butyl ester, following the procedure described in Example 1, Part I , deprotecting to give 3 - (S) -amino-1- (6-amino-1-chloro-isoquinolin-7-ylmethyl) -pyrrolidin-2-one hydrochloride, which is • • ······ Condensed with 7-methoxynaphthalene-2-sulfonyl chloride according to the procedure described in Example 1, Part K. The material obtained after extraction is purified by column chromatography eluting with a gradient of 30% ethyl acetate in hexane to 60% ethyl acetate in hexane to give the title compound.

1 H), 3.20 (m, 2H), 2.52 spray MS, [M + H] ⁺ = 511, 513, Cl isotopes.

300 MHz) δ 8.34 (s, ÍH), 8.02 (d ,. (1H), 7.79 (d, 1H), 7.72 (dd, IH) , 7.25 (S, 1H, 6.77 (with, 1H, 5.61 50 (AB, 2H) , 3.92 (s, 3H), 3.85. (m, (m, 1H), 2.05 (m, 1H). Ionically

J. 7-Methoxy-naphthalene-2-sulfonic acid [1- (1,6-diamino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide

The title compound was prepared using the procedure described in Example 2, starting from 7-methoxy-naphthalene-2-sulfonic acid [1- (6-amino-1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide. substances. No extraction treatment is used. The crude product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 100% acetonitrile. Appropriate fractions were lyophilized to give the title compound as a white solid.

^X H NMR (perdeuterodimethylsulfoxi

8.34 -8.38 (d, 2H) 8.24 (d, 1H) 2H), 7., 68 (dd, IH) 7.53 (d, ÍH) 6.83 (d, 1H, 6.78 (s, IH ), 6 , 49 (m, ÍH), 3.90 (s, 3H), 3 , 06 (m, ÍH) .. FAB. MS, [M + H] &lt; + &gt; ^. = 492.

1.00 MHz) δ: 12.25 (šs, ÍH), 7.95 (d, 1H) 7.90 -7.93 (d, 7.38 (d, 1H), 7.30 (dd, ÍH), (bs, 2H), 4, 26 (AB, 2H), 4.20 2H), 2.00 (m, ÍH), 1.60 (m,

• «·· ···»

Example 14

6-Chloro-benzo [b] thiophene-2-sulfonic acid [1- (1,6-diaminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide trifluoroacetate

A. 6-Chloro-benzo [b] thiophene-2-sulfonic acid 1- (6-amino-1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The (1- [6- (benzhydrylideneamino) -1-chloro-isoquinolin-7-ylmethyl] -2-oxo-pyrrolidin-3- (S) -yl} -carbamic acid tert-butyl ester was deprotected as described in Example 1 Part I to give 3- (S) -amino-1- (6-amino-1-chloro-isoquinolin-7-ylmethyl) -pyrrolidin-2-one hydrochloride which was condensed according to the procedure described in Example 1 Extraction was purified by column chromatography eluting with a gradient of 20% ethyl acetate in hexane to 60% ethyl acetate in hexane to afford the title compound.

¹ H NMR (CDCl 3, 300 MHz) δ 8.05 (d, 1H), 8.02 (s,

1H),

7.44 (AB,

7.98 (s, 1 H), 7.89 (s, 1 H), 7.86 (d, 1 H), (dd, 1 H), 6.82 (s, 1 H), 5.40 (d, 1 H) 3.90 (m, 1H); 3.30 (m, 2H); 2.65 (m, 1H);

7.81 (d, 1H), (bs, 2H), 5.42

1H), 2.05 (m,

1H).

Ion spray MS, [M + H] ⁺ = 521, 523, Cl isotopes.

B. 6-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (1,6-diaminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure for EXAMPLE 2 using 6-chloro [1- (6-amino-1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide. -benzo [b] thio 99

······ Phen-2-sulfonic acid as starting material · No extraction treatment is used. The crude product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 100% acetonitrile. Appropriate fractions were lyophilized to give the title compound as a tan oil.

¹ H NMR (CDCl 3, 300 MHz) δ 12.05 (bs, IH),

8.70 (d, IH), 8.35 (SS, 2H), 8.20 (with, IH), 8.00-8.05 (m, 2H), 7.94 (with, IH),. 7.51 (d, IH), 7.38 (m, IH), 6.71-6.80 (m, 2H), 6.51 (šs, 2H), 4.30 (m, 3H), 3.20 (m, 2H), 2.15 (m, IH), 1.71

(tn, 1H).

Ion spray MS, [M + H] &lt; ⁺ &^gt; 502, 504, Cl isotopes.

Example 15

7-Methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

A. 7-Methyl-1H-quinolin-2-one and 5-methyl-1H-quinolin-2-one

The title compound was prepared from m-toluidine and cinnamoyl chloride according to the procedure described in Synthesis 1975, 739. The crude solid obtained was triturated with diethyl ether / hexane and filtered to give a 1.5: 1 mixture of 7-methyl-1H isomers. quinolin-2-one to 5-methyl-1H-quinolin-2-one as a beige solid. After several purifications by fractional crystallization in methanol, only an enriched 2: 1 mixture of isomers is obtained, which is used in the next step.

¹ H NMR (CDCl 3, 300 MHz) δ 7.85 (d, 1H), 7.53 (d, 1H), 7.09 (s, 1H), 7.01 (d, IH), 6.42 ( d, 1H), 2.38 (s, 3H) for the predominant isomer (7-methyl); and 8 8.03 (d, 1H). · · * * Ϊ! · ♦ · ·

..., .., 7.38 (dd, 1Η), 7.17 (s, 1Η), 7.01 (d, 1H), 6.51 (d, 1H) 2.50 (s, 3H) for the minor isomer (5-methyl).

B. 2-Chloro-7-methyquinoline and 2-chloro-5-methylquinoline

The title compound was prepared according to the procedure for EXAMPLE 1, Part E, using a 2: 1 mixture of 7-methyl-1H-quinolin-2-one and 5-methyl-1H-quinolin-2-one instead of 7. methyl-2H-isoquinolin-1-one. The crude product was purified by chromatography eluting with a gradient of 5% ethyl acetate in dichloromethane to 10% ethyl acetate in dichloromethane to give 2: 1 2-chloro-7-methylquinoline and 2-chloro-5-methylquinoline as a beige solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.02 (d, 1H), 7.78 (with, 1H), 7.68 (d, 1H), 7.39 (m, 1H), 7.30 (d, l.H), 2.56 (s, 3H) for the predominant isomer (7-methyl); and δ 8.25 (d, 1H), 7.86 (d, 1H), 7.60 (dd, 1H), 7.39 (m, 2H) 2.65 (with, 3H) for minority

isomer (5-methyl).

C. 7-Bromomethyl-2-chloroquinoline and 5-bromomethyl-2-chloroquinoline

The title compound was prepared according to the procedure described in Example 1, Part F, using 2: 1 2-chloro-7-methylquinoline and 2-chloro-5-methylquinoline instead of 1-chloro-7-methylisoquinoline. The obtained crude mixture of isomers was partially purified by trituration from ethyl acetate and hexane to give 7.4 g (38%) of 7-bromomethyl-2-chloroquinoline as a beige solid.

´ Ή NMR (deuterochloroform, 300 MHz) δ 8.10 (d, 1H), 8.00 (s,

1H), 7.82 (d, 1H), 7.60 (d, 1H), 4.67 (s, 2H).

The enriched 2: 1 mixture of 5-bromomethyl-2-chloroquinoline and 7-bromomethyl-2-chloroquinoline was isolated as 6.8 g of a beige solid. ··· ·· φ · '· ··· · ··· · · ·

From the concentrated filtrate by fractional recrystallization from a mixture of diethyl ether, hexane and ethyl acetate.

¹ H NMR (CDCl 3, 300 MHz) δ 8.43 (d, 1H), 8.09 (dd,

1H), 8.03 (m, 1H), 7.68 (m, 1H), 7.50 (d, 1H), 4.88 (s, 2H) for the predominant isomer (5-bromomethyl).

D. [1- (2-Chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester

The title compound was prepared from (2-oxopyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester according to the procedure described in Example 1, Part H, using 7-bromomethyl-2-chloroquinoline instead of 7-bromomethyl-1- chloroisoquinoline. The crude product was triturated with 20% ethyl acetate / hexane and filtered to give the title compound as a beige solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.10. (d, 1H). 7.83 (s,

1H), 7.80 (d, 1H), 7.46 (d, 1H), 7.40 (d, 1H), 5.17 (bs, 1H), 4.68 (AB, 2H), 4, 25 (m, 1H); 3.26 (m, 2H); 2.64 (m, 1H); 1.88 (m, 1H); 1.46 (s, 9H).

E. 7- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -2-chloroquinoline hydrochloride

The title compound was prepared according to the procedure for EXAMPLE 1, Part I, using [1- (2-chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester as starting materials. The title compound is isolated as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.75 (bs, 2H), 8.47 (d, 1H), 8.06 (d, 1H), 7.86 (s, 1H), .7 / 61 (d, 1H), 7.58. · · · · · · · · · · · · · · · · · · · · 4.69 (AB, 2H), 4.15 (m, 1H), 3.35 (m, 2H), 2.43 (tn,

1H), 2.04 (m, 1H). .

F. 7-Methoxy-naphthalene-2-sulfonic acid [1- (2-chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The compound was prepared according to the procedure in Example 1, Part K in dichloromethane instead of acetonitrile using 7- (3 - (S) -amino-2-oxopyrrolidin-1-ylmethyl) -2-chloroquinoline hydrochloride instead of 7- (3 - ( (S) -amino-2-oxopyrrolidin-1-ylmethyl) -1-chloro-isoquinoline and 7-methoxy-naphthalene-2-sulfonyl chloride as in Example 1, Part J. The crude product was triturated. in 20% ethyl acetate in hexane and filtered to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.38 (s, 1H), 8.08 (d,

1H), 7.92 (d, 1H), 7.81 (d, 1H), 7.76 (m, 3H), 7.38 (d, 1H), 7.36 (dd, 1H), 7.30 (dd, 1H), 7.25 (m, 1H), 5.44 (with, 1H), 4.61 (with, 2H), 3., 96 (with, 3H) ,, 3.78 (m, 1H), 3.23 (m, 2H), 2.60 (m,

1 H), 2.10 (m, 1 H). FAB MS, [M + H] &lt; ⁺ &^gt; = 496, 498. Cl isotopes.

Elemental analysis calculated: C = 60.54%, H = 4.47%, N = 8.47%,

Cl = 7.1.5%, found C = 60.44%, H = 4.18%, N = 8.45, Cl = 7.19%.

G. 7-Methoxynaphthalene-2-sulfonic acid [1- (2-chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 - (S) -yl] -amide [1- (2-chloroquinolin-7-ylmethyl) -] - 7-Methoxynaphthalene-2-sulfonic acid 2-oxopyrrolidin-3- (S) -yl] amide is converted to the title compound when heated to 125 ° C according to the procedure described in Example 2. The crude product is partially purified by HPLC reversed phase eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 60% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate fractions containing product were evaporated in vacuo, filtered and concentrated

······· ·· ·· ·· ··· tour. methanol as described above to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.62 (bs, 2H), 8.38 (s, 1H), 8.31 (d, 1H), 8.25 (d, IH), 8, 03 (d, 1H); 7.94 (d, 1H);

1H), 7.86 (d, IH), 7.72 (d, IH), 7.55 (s, IH), 7.43 (s, IH), 7.32 (dd, IH), 7 27 (d, 1H); 7.01 (d, 1H); 4.50. (AB, 2H), 4.1 1 (m, 1H), 3.88 (s, 3H), 3.09 (m, 2H), 2.00 (m, 1H), 1.58 (m,

IH). Ion spray MS, [M + H] ⁺ - 477. Elemental analysis calculated: C = 54.93%, H = 4.27%, N = 9.49%, found C = 54.69%, H = 4 , 24%,

N = 9.30%. The enantiomeric purity was 81.9% ee as determined on a Chiralpak AS RP-HPLC analytical column.

Example 16

6-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (2-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 - (S) -yl] -amide

A. 6-Chloro-benzo [b] thiophene-2-sulfonic acid [1- (2-chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide

The title compound was prepared according to the procedure described in Example 1, part K, in dichloromethane instead of acetonitrile from 7- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -2-chloroquinoline hydrochloride, using 6- of chiorobenzo [b] thiophene-2-sulfonyl chloride which was prepared according to Example 9, Parts A, B and C instead of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product was triturated from ethyl acetate / hexane to give the title compound as a beige solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.77 (d, 1H),

8.42 (d, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 8.04 (d, 1H), 8.02 (d, 1H), 7.75 (d, 1H); s, 1H), 7.58 (d, IH), 7.52 (dd, IH), 7.48 (d, 1H);

1H), 4.55 (AB, 2H), 4.28 (m, 1H), 3.18 (m, 2H), 2.18 (m, 1H),

1.71 (m, 1H). Ion spray MS, [M + H] ⁺ = 506, 508, Cl isotopes.

101 • ··· ·········

B. 6-Chloro-benzo [b] thiophene-2-sulfonic acid [1- (2-chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide [1- (2-chloro-quinoline-) - 6-Chloro-benzo [b] thiophene-2-sulfonic acid 7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide was converted into the title compound when heated to 120 ° C according to the procedure described in Example 2. The crude product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions. are lyophilized to give the title compound as a tan oil.

¹ H NMR (CDCl 3, 500 MHz) δ 8.73 (d, 1H),

8.34 (d, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 8.03 (d, 1H), 7.89 (d, 1H), 7.54 (dd) 1 H, 7.52 (d, 1 H), 7.47 (s, 1 H),. 7.31 (d, 1H), 7.04 (d, 1H), 6.94 (d, 1H), 6.42. (d, 1H), 4.53 (AB, 2H), 4.22 (m, 1H), 3.18 (m, 2H), 2.18 (m, 1H), 1.72 (m, 1H) . FAB MS, [M + H] &lt; ⁺ &^gt; = 487.

Example 17 Benzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (2-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

A. Benzo [b] thiophene-2-sulfonic acid [1- (2-chloro-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure described in Example 1, Part K, in chloroform instead of in acetonitrile from 7- (3- (S) amino-2-oxopyrrolidin-1-ylmethyl) -2-chloroquinoline hydrochloride, using benzo [ b] thiophene-2-sulfonyl chloride prepared in Example 8, Part A, instead of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product was triturated from dichloromethane 9

9 ···· ··

9 9 9

9 9 9 9 • 99 9 9 9.

9

99 99 9

102 to give the title compound as a beige solid.

^τ Η NMR (CDCl 3, 300 MHz) δ 8.08 (d, 1H), .7.95 (d,

1H), 7.88 (m, 2H), 7.99 (d, 1H), 7.76 (s, 1H), 7.49 (m, 2H), 7.39 (m, 2H), 5, 62 (s, 1H), 4.64 (s, 2H), 3.95 (m, 1H), 3.27 (m, 2H), 2.65 (m, 1H), 2.16 (m, 1H). IH). .

B. Benzo [b] thiophene-2-sulfonic acid [1- (2-chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide [1- (2-chloroquinolin-7-ylmethyl) -acetamide Benzo [b] thiophene-2-sulfonic acid -2-oxopyrrolidin-3- (S) -yl] amide was converted to the title compound when heated to 130 ° C according to the procedure described in Example 2. Crude product Purify by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 60% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions are lyophilized to give a tan solid substances.

¹ H NMR (CDCl 3, 500 MHz) δ 8.68 (d, 1H),

8.35 (d, 1H), 8.09 (dd, IH), 8.06 (s, IH), 8.02 (dd / IH), 7.90 (d, IH), 7.52 (m (2H), 7.45 (s, 1H), 7.32 (d, 1H), 7.04 (d, 1H), 4.53 (AB, 2H), 4.22 (m, 1H), 3 17 (m, 2H); 2.18 (m, 1H);

1.72 (m, 1H). Ion spray MS, [M + H] &lt; ⁺ &^gt; 453.

Examples 18 and 19

7-Methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide and methyl- [2-oxo-1- (2-oxo-) -acetamide 7-Methoxynaphthalene-2-sulfonic acid 1,2-dihydroquinolin-7-ylmethyl) pyrrolidin-3- (S) -yl] -amide • 0 0 ·· · · ·

4 9 4 45

103 • 4 · 0 · 00 0000 0 · 0 · 0

A. 7-Methoxy-naphthalene-2-sulfonic acid [1- (2-chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide

0.4 g (0.81 mmol) of 7-methoxy-naphthalene-2-sulfonic acid [1- (2-chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 - (S) -yl] -amide, prepared according to Example 15, part E, was dissolved in 20 ml of dimethylformamide and cooled to 0 ° C. To the solution was added 0.28 g (2.01 mmol) of methyl iodide and 34 mg (0.85 mmol, 60% dispersion in mineral oil) of sodium hydride. The ice bath was removed and the mixture was stirred at room temperature for 3 hours. The solution was poured into a separatory funnel and diluted with 100 mL of ethyl acetate. The organic layer was washed with 1N hydrochloric acid solution, water and saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and evaporated. The crude residue was purified by column chromatography eluting with 10% ethyl acetate in dichloromethane to give 0.36 g (0.71 mmol) of the title compound as a solid.

1 H NMR (CDCl 3, 300 MHz) δ 8.44 (s, 1H), 8.09 (d,

1H), 7.92 (d, 1 H), 7.82 (dd, 1H), 7.78 (m, 3H) 7.42 (dd. 1H), 7.40 (d, 1H), 7.28 (dd, 1H), 7.26 (with, 1H), 5.00 (m, 1H), 4.62 (AB, 2H), 3.94 (s, 3H), 3.23 (m, 2H), 2.84 (s, 3H), 2.33 (m, 1H), 2.03 (m, 1 H). B. trifluoroacetate [1- (2 -aminoquinoline -7-ylmethyl) -2- -oxopyrro-

7-Methoxynaphthalene-2-sulfonic acid lidin-3- (S) -yl] methylamide and methyl- [2-oxo-1- (2-oxo-1,2-dihydro-quinolin-7-ylmethyl) -pyrrolidin-3 - 7-Methoxy-naphthalene-2-sulfonic acid (1- (2-chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl) -methyl-amide 7-methoxy-naphthalene-2-sulfonic acid (S) -yl] -amide is converted to the title compound when heated to 125 ° C according to the procedure described in Example 2. The crude product mixture is purified

9 «· · · 9 9.'9 • ·» 9 9 999 9

-1 ζ. _Λ ·· · 9 9999

104 9999999 9999 99 by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized to afford 7-methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide trifluoroacetate ve. as a white solid ^X H NMR (DMSO-d₆, 300 MHz) δ 8.42 (s, IH)

8.33 (d, 1H), 8.04 (d, IH), 7.96 (d, 1H), 7.87 '(d, IH), 7.70 (dd, IH), 7.58 ( s, 1H), 7.42 (s, IH), 7.35 (dd, IH), 7.31 (d,

1H), 7.02 (d, 1H), 4.93 (m, 1H), 4.51 (AB, 2H), 3.89 (s, 3H),

3.18 (m, 2H), 2.70 (s, 3H), 2.02 (m, 1H), 1.78 (m, 1H). Ion spray MS, [M + H] &lt; ⁺ &^gt; = 491. Elemental analysis calculated with 1.8 mol of water C = 52.79%, H = 4.84%. N = 8.80%, found C = 52.80%, H = 4.35%,

N = 8.55%.

7-Methoxynaphthalene-2-sulfonic acid methyl [2-oxo-1- (2-oxo-1,2-dihydro-quinolin-7-ylmethyl) -pyrrolidin-3- (S) -yl] -amide is also isolated from reaction by-product.

Ή NMR (perdeuterodimethylsulfoxide, 300 MHz) δ 8.42 (s, 1H),

8, 04 (d, IH), 7.97 (d, IH), 7.85 (d, IH), 7.70 (d, IH), 7.60 (d, IH), 7.58 (with, IH), 7.35 (dd, IH), 7.04 (with, IH), 6.98 (d, IH), 6.4 5 (d, IH), 4.90 (m, IH), 4.40 (AB, 2H), 3.89 (WITH, 3H), 3.15 (m, 2H), 2.71 (with, 3H), 2.01 (m, IH), 1,7 6 (m, IH). Ion

MS, [M + H] &lt; ⁺ &^gt; = 492.

Example 20

7-Methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

A. [1- (2-Chloroquinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester

105 • · · · · ·

»»

The title compound was prepared from (2-oxopyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester as described in Example 1, Step H, using 2: 1 5-bromomethyl-2-chloroquinoline and 7-bromomethyl 2-chloroquinoline, which was prepared according to the procedure described in Example 15, part C, instead of 7-bromomethyl-1-chloroisoquinoline. The crude mixture was purified by column chromatography eluting with 1% methanol in 25% ethyl acetate in dichloromethane to give the title compound as a beige solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.53 (d, 1H), 7.98 (d,

1 H), 7.69 (dd, 1 H), 7.50 (d, 1 H), 7.41 (d, 1 H), 5.59 (d, 1 H), 4.89 (d, 1 H), 4, 22 (m, 1H), 3.19 (m, 1H), 3.12 (m, 1H), 2.51 (m, 1H), 1.86 (m, 1H), 1.45 (s, 9H) ).

B. 5- (3- (S) -Amino-2-oxo-pyrrolidin-1-ylmethyl) -2-chloroquinoline hydrochloride

The title compound was prepared according to the procedure for EXAMPLE 1, Part I, using [1- (2-chloroquinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester substances. The title compound is obtained as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.63 (d, 1H), 8.59 (bs, 3H), 7.94 (d, 1H), 7.81 (m, 1H), 7.65 ( m, 2H), 4.89 (s, 2H), 4.08 (m, 1H), 3.24 (m, 2H), 2.34 (m, 1H), 1.94 (m, 1H).

C. 7-Methoxy-naphthalene-2-sulfonic acid [1- (2-chloroquinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure described in Example 1, part K, in dichloromethane instead of acetonitrile using 5- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -hydrochloride.

9 9

9 9 9

9 9

9 9

106 • ethyl) -2-chloroquinoline instead of 7- (3- (S) amino-2-oxopyrrolidin-1-ylmethyl) -1-chloroisoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride, prepared as in Example 1, The crude product was purified by column chromatography eluting with 25% ethyl acetate in dichloromethane to give the title compound as a pale yellow solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.36 (d, 1H), 8.33 (s,

1H), 7.98 (d, 1H), 7.91 (d, 1H), 7.82 (d, 1H), 7.73 (d, 1H),

7.66 (m, 1H), 7.42 (d, 1H), 7.35 (d, 1H), 7.30 (dd, 1H), 7.25 (dd, 1H), 5.4O ( s, 1H), 4.82 (AB, 2H), 3.94 (s, 3H), 3.71 (m,

1H, 3.12 (m, 1H), 3.02 (m, 1H), 2.50 (m, 1H), 1.98 (m, 1H).

EI MS, [M] ⁺ = 495, 497, Cl isotopes. Elemental analysis calculated: C = 60.54%, H = 4.47%, N = 8.47%, Cl = 7.15%, found C = 59.7.9%, H = 4.70%, N = 8.88, Cl = 7.21%.

D. 7-Methoxynaphthalene-2-sulfonic acid [1- (2-chloroquinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide [1- (2-Chloroquinolin-5-ylmethyl) -] - 2-Oxopyrrolidin-3- (S) -yl] amide

The 7-methoxynaphthalene-2-sulfonic acid was converted to the title compound by heating to 125 ° C according to the procedure described in Example 2. The crude product was partially purified by reverse phase HPLC eluting with a gradient of the mixture) to 80% acetonitrile. in water (0.1% trifluoroacetic acid) and the appropriate fractions containing product were evaporated in vacuo, filtered, triturated with methanol and then further purified by column chromatography eluting with a gradient of 1% methanol in dichloromethane to 3% methanol in methanol. dichloromethane to give the title compound as a pale yellow solid.

^{Χ Η} NMR (DMSO-d₆, 300 MHz) δ 8.48 (d, H),

8.37 (s, 1H), 8.23 (d, 1H), 8.03 (d, 1H), 7.93 (d, 1H), 7.72 (m, 1H), 7.69 (d) (1H), 7.60 (d, 1H), 7.55 (s, 1H), 7.33 (m,

107, · 0 · · · · · ···

2Η), 7.07 (d, 1Η), 4., 71 (ΒΒ, 2Η), 4.11 (m, 1Η), 3.88 (s, 3Η), 3.00 (m, 2Η),. 1.94 (m, 1H), 1.48 (m, 1H). FAB MS, [Μ + Η] ⁺ = 477th Elemental analysis calculated with 2.5 mol of water C = 50.98%, H = 4.14%, N = 8.38%, found C = 50.96%, H = 4.14%, N = 8.38 %. The enantiomeric purity was 84.5% ee as determined by analytical reverse phase HPLC on a Chiralpak AS column. .

Examples 21 and 22

7-Methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide trifluoroacetate. and 7-methoxy-naphthalene-2-sulfonic acid methyl [2-oxo-1- (2-oxo-1,2-dihydro-quinolin-5-ylmethyl) -pyrrolidin-3- (S) -yl] -amide

A. 7-Methoxynaphthalene-2-sulfonic acid [1- (2-chloro-quinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide

The title compound was prepared as described in Examples 18 and 19, Part A, za. using 7-methoxy-naphthalene-2-sulfonic acid [1- (2-chloro-quinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as a starting material. The crude product was purified by column chromatography eluting with 50% ethyl acetate in hexane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.42 (s, 1H), 8.38 (s,

1H), 7.97 (d, 1 H), 7.91 (d, 1H), 7.78 (m, 2H) 7.66 (dd, 1 H), 7.43 (d, 1H), 7.30 (d, 1H), 7.25 (m, 2H, 4.92 (m, 1H), 4.80 (AB, 2H), 3.92 (s, 3H), 3.08 (m, 2H) 2.74 (s, 3H), 2.22 (m, 1H), 1, 80 (m, 1 H). B. Trifluoroacetate [i- ( 2-Aminoquinoline -5-ylmethyl) -2 -oxopyrro-

7-Methoxynaphthalene-2-sulfonic acid lidin-3- (S) -yl] methylamide and methyl- [2-oxo-1- (2-oxo-1,2-dihydroquinolin-5-ylmethyl)]

111 1

19 Dec

1 '· * · e

108 7-Methoxy-naphthalene 7-methoxy-naphthalene-2-sulfonic acid pyrrolidin-3- (S) -yl] -amide [1- (2-chloro-quinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide The -2-sulfonic acid is converted to the title compound when heated to 120 ° C according to the procedure described in Example 2. The crude product is purified by reverse phase HPLC. eluting with a mixture of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized to give trifluoroacetate [1- (2-aminoquinoline-5)]. 7-Methoxynaphthalene-2-sulfonic acid-2-oxopyrrolidin-3- (S) -yl] -methylamide as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.46 (d, 1H),

8.39 (s, 1H), 8.03 (d, 1H), 7.96 (d, 1H), 7.70 (m, 2H), 7.60 (d, 1H), 7.58 (s 1 H, 7.36 (dd, 1 H) ^; 7.34 (d, 1H); 7/06 (d, 1H);

1H), 4.90 (m, 1H), 4.71 (AB, 2H), 3.89 (s, 3H), 3.11 (m, 1H),

3.00 (m, 1H), 2.63 (s, 3H), 1.95 (m, 1H), 1.68 (m, 1H). FAB

MS, [M + H] ⁺ = 491.7.

Methoxynaphthalene-2-sulfonic acid methyl [2-oxo-1- (2-oxo-1,2-dihydroquinolin-5-ylmethyl) pyrrolidin-3 (S) -yl] amide is also isolated from the reaction mixture.

¹ H NMR (CDCl 3, 300 MHz) δ 8.39 (s, 1H),

8.04 (d, 1H), 7/98 (d, 1H), 7.94 (d, 1H), 7.68 (d, 1H) 7.57 (with, 1H), 7.42 (m, 1H) 7.34 (dd, 1H), 7.25 (d, 1H), 7.05 (d, 1H), 6.46 (d, 1H), 4.88 (m, 1H), 4.60 (AB, 2H), 3.89 (s, 3H); 3, 08 (m, 1H), 2.97 (m, 1H), 2.63 (with, 3H), 1.96 (m, 1H) 1.65

(m, 1 H). FAB-MS, [M + H]

492

109

9 4 · * * · · ·

Examples 23 and 24 7-Methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide and [2-oxo-1- (2-oxo) 7-Methoxynaphthalen-2-sulfonic acid-1,2-dihydro-quinolin-6-ylmethyl) -pyrrolidin-3- (S) -yl] -amide

A. 6-Methyl-1H-quinolin-2-one

The title compound was prepared from p-toluidine and cinnamoyl chloride according to the procedure described in Synthesis 1975, 739.

The crude product obtained. triturate from diethyl ether / hexane and filter to give the title compound as a beige solid, which is used in the next step.

1 H NMR (CDCl 3, 300 MHz) δ 11.60 (bs, 1H), 7.82 (d, 1H), 7.41 (s, 1H), 7.30 (d, 1H), 7.18 (d, 1H) d, 1H), 6.45 (d, 1H), 2.30 (s, 3H).

B., 2-Chloro-6-methyl-quinoline

The title compound was prepared according to the procedure for EXAMPLE 1, Part E, using 6-methyl-1H-quinolin-2-one instead of 7-methyl-2H-isoquinolin-1-one. The crude product precipitates upon neutralization during aqueous work-up and the solid is filtered off and dried. The crude product was recrystallized from methanol to give the title compound as a beige solid.

1 H NMR (CDCl 3, 300 MHz) δ 8.02 (d, 1H), 7.92 (d,

1H), 7.60 (s, 1H), 7.58 (d, 1H), 7.33 (d, 1H), 2.53 (s, 3H).

C. 6-Bromomethyl-2-chloroquinoline

The title compound was prepared according to the procedure for EXAMPLE 1, Part F, using 2-chloro-6-methylquinoline-2-chloro-6-methylquinoline. sur φ φ φ φ φ sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur sur crude residue with hexane and obtain as beige solid (d, 1H), 8.02 (d,

110 instead of 1-chloro-7-methylisoquinoline. The obtained recrystallized from a mixture of 50% ethyl acetate in 7.4 g (38%) of 6-bromomethyl-2-chloroquinoline.

¹ H NMR (CDCl 3, 300 MHz) δ 8.08

1H), 7.83 (s, 1H), 7.77 (dd, 1H), 7.40 (d, 1H), 4.65 (s, 2H).

EI MS, [M] ⁺ = 256, 258, Cl isotopes.

D. [1- (2-Chloroquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester

The title compound was prepared from (2-oxopyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester as described in Example 1, Part H, using 6-bromomethyl-2-chloro-quinoline instead of 7-bromomethyl -1-chloroisoquinoline. The crude product was purified by column chromatography eluting with a gradient of 2% methanol in dichloromethane to. 4. % methanol in dichloromethane to give the title compound as a beige solid. solids.

Δ NMR (CDCl 3, 300 MHz) δ 8.08 (d, 1H), 8.00 (d,

1H), 7.69 (s, 1H), 7.61 (dd, 1H), 7.40 (d, 1H), 5.23 (bs, 1H), 4.67 (AB, 2H), 4 25 (m, 1H); 3.26 (m, 2H); 2.63 (m, 1H); 1.90 (m, 1H); 1.46 (s, 9H).

E. 6- (3- (S) -Amino-2-oxopyrrolidin-1-ylmethyl) -2-chloroquinoline hydrochloride

The title compound was prepared according to the procedure described in Example 1, Part I, using [1- (2-chloroquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester. acids as starting materials. The title compound is obtained as a white solid.

^X H NMR (DMSO-d₆, 300 MHz) δ 8.74 (bs, 3H), ·· · ·· ·· ··· • »·· ·«>'<·· «« «• *« «· 4 · «· • * 9 4 4 4 4 9

8.48 (d, 1H), 8.00 (s, 1H) 7.95 (d, 1H) 7.71 (d, 1H), 7.60 (d, 1H), 4.64 (AB, 2H), 4.11 (m, 1H), 3.35 (m, 2H), 2.42 (m,%) 1H), 2.09 (m, 1H).

F. 7-Methoxy-naphthalene-2-sulfonic acid [1- (2-chloroquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure for EXAMPLE 1, step K using 6 - (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -2-chloro-quinoline hydrochloride as starting material and 7-methoxy-naphthalene- Of 2-sulfonyl chloride. The crude product was triturated from dichloromethane and filtered to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.36 (s, 1H), 8.03 (d, 1H), 7.97 (d, 1H), 7.91 (d, 1H), 7.80 ( d, 1H), 7.75 (dd, 1H), 7.60 (s, 1H), 7.51 (dd, 1H), 7.37 (d, 1H), 7.29 (dd, 1H), 7.25 (dd, 1H), 5.43 (s, 1H), 4.58 (AB, 2H), 3.94 (s, 3H), 3.76 (m, 1H), 3.22 (m 2H, 2.59 (m, 1 H), 2.09 (m, 1 H). FAB MS, [M + H] ⁺ = 496, 498, Cl isomers. Elemental analysis calculated: C = 60.54%, H = 4.47%, N = 8.47%, Cl = 7.15%, found C = 60.43%, H = 4.17%, N = 8.37, Cl = 7.06%.

G. 7-Methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide and [2-oxo-1- (2-oxo-1-ol)] 7-Methoxy-naphthalen-2-sulfonic acid [1- (2-chloroquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -pyrido-naphthalen-2-sulfonic acid 2-dihydro-quinolin-6-ylmethyl) -pyrrolidin-3- (S) -yl] -amide 7-Methoxy-naphthalene-2-sulfonic acid methylamide is converted to the title compound when heated to 130 ° C according to the procedure described in Example 2. The crude mixture is purified by reverse phase HPLC eluting with a gradient of 10 % acetonit112 • 9 9 9 9 9 9 * * 99 9 9 9 «9 · · 99999 99

999 9999 99 99 99 9 ril in water (0.1% trifluoroacetic acid) to 60% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions are evaporated in vacuo and then purified by column chromatography eluting mixture of 5% methanol in dichloromethane to give 7-methoxy-naphthalene-2-sulfonic acid (1- (2-amino-quinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl) -amide as a tan solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.38 (s, 1H),

8.23 (d, 1H), 8.03 (d, IH), 7.93 (d, IH), 7.80 (d, IH), 7.72 (d, IH), 7.55 (d, 1H); s, 1H), 7.41 (s, IH), 7.38 (d, IH), 7.32 (dd,

1H), 7.25 (d, 1H), 6.73 (d, 1H), 6.43 (bs, 2H), 4.37 (AB, 2H),

4.10 (m, 1H); 3.88 (s, 3H); 3.04 (m, 2H), 1.96 (m, 1H), 1.51 (m, 1H). FAB MS, [M + H] = 477. Elemental analysis calculated with 0.6 mol of water C = 61.58%, H = 5.22%, N = 1 1.49%, found C = 61.59%, H = 5.08%, N = 1 1.14%. The enantiomeric purity was 87.0% ee as determined by reverse phase HPLC on a Chiralpak-AS column.

7-Methoxynaphthalene-2-sulfonic acid [2-oxo-1- (2-oxo-1,2-dihydroquinolin-6-ylmethyl) -pyrrolidin-3 (S) -yl] -amide is also isolated from the reaction mixture.

¹ H NMR (CDCl 3, 300 MHz) δ 11.70 (bs, 1H), 8.37 (s, 1H), 8.21 (d, 1H), 8.01 (d, 1H), 7.93 ( d, 1H), 7.82 (d, IH), 7.69 (d, IH), 7.56 (s, IH), 7.45 (s, IH), 7.32 (m,

2H), 7.25 (m, 1H), 6.47 (d, 1H), 4.35 (s, 2H), 4.12 '(m, 1H),

3.89 (s, 3H), 3.06 (m, 2H), 1.97 (m, 1H), 1.53 (m, 1H). FAB

MS, [M + H] + = 478.

Example 25

7-Methoxynaphthalene-2-sulfonic acid [1- (1H-benzoimidazol-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -] amide trifluoroacetate

113 φ φ φ · φ φ φ φ φ φ · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

A. [1- (4-Nitrobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester

The title compound is prepared from (2-oxopyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester along. as described in Example 1, Step H, using 4-nitrobenzyl bromide instead of 7-bromomethyl-1-chloroisoquinoline. The crude product was purified by column chromatography eluting with a gradient of 10% ethyl acetate in dichloromethane to 25% ethyl acetate in hexane to give the title compound as a yellow solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.20 (d, 2H), 7.43 (d,

2H), 5.18 (bs, 1H), 4.58 (AB, 2H), 4.22 (m, 1H), 3.26 (m, 2H),

2.65 (m, 1 H), 1.93 (m, 1 H), 1.46 (s, 9H).

B. 3- (S) -Amino-1- (4-nitrobenzyl) pyrrolidin-2-one hydrochloride

The title compound was prepared according to the procedure for EXAMPLE 1, Part I, using [1- (4-nitrobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester as starting material. The title compound was obtained as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.65 (bs, 3H), 8.22 (d, 2H), 7.57 (d, 2H), 4.59 (AB, 2H), 4. -10 (m, 1H), 3.32 (m, 2H), 2.40 (m, 1H), 2.03 (m, 1H).

C. 2,2,2-Trifluoro-N- [1- (4-nitrobenzyl) -2-oxopyrrolidin-3- (S) yl] acetamide

The title compound was prepared according to the procedure described in Example 1, part K, in dichloromethane instead of acetonitrile using 3- (S) -amino-1- (4-nitrobenzyl) -pyrrolidin-2-one hydrochloride as starting material and anhydride trifluoroacetic acid • 0 ·· 00 * 0 * 0 ** 00 0 0 0 0 • 0 0 0 0

114 7-methoxynaphthalene-2-sulfonyl chloride. The crude product was evaporated in vacuo and used in the next step.

1 H NMR (CDCl 3, 300 MHz) δ 8.24 (d, 2H), 7.43 (d,

2H), 7.25 (bs, 1H), 4.60 (AB, 2H), 4.44 (m, 1H), 3.35 (m, 2H),

2.80 (m, 1 H), 2.01 (m, 1 H).

D. N- [1- (4-Acetylamino-3-nitrobenzyl) -2-oxopyrrolidin-3- (S) yl] -2,2,2-trifluoroacetamide

To 0.75 g (2.27 mmol) of a solution of 2,2,2-trifluoro-N- [1- (4-nitrobenzyl) -2-oxopyrrolidin-3- (S) -yl] -acetamide in 12 ml of acetic acid 1 ml of acetic anhydride and a catalytic amount of 10% palladium on charcoal are added. The heterogeneous mixture was hydrogenated at room temperature in a Parr apparatus at 50 psi hydrogen. After 4.5 hours, the reaction mixture was filtered through diatomaceous earth, washed with dichloromethane and then methanol. The crude product was evaporated in vacuo to give 1.2 g of N- [1- (4-acetylamino-benzyl) -2-oxopyrrolidin-3- (S) -yl] -2,2,2-trifluoroacetamide as a residue (moistened) acetic acid). A solution of 1.2 g of crude N [1- (4-acetylaminobenzyl) -2-oxopyrrolidin-3- (S) -yl] -2,2,2-trifluoroacetamide (moistened with acetic acid) in 12 ml of acetic acid was cooled to 0 ° C and 1 mL of acetic anhydride is added. The mixture is treated with a catalytic amount of sodium nitrite, then 2.8 ml of fuming nitric acid is added dropwise. The reaction mixture was stirred at 0 ° C for 1.5 hours, then at room temperature for 1.5 hours. After cooling to 0 ° C, a mixture of ice and water is added slowly with stirring. The mixture was diluted with additional water and extracted three times with 50 ml of ethyl acetate. The combined organic layers were washed twice with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with a gradient of 25% ethyl acetate in dichloromethane to 50% ethyl acetate in dichloromethane. ·

115 ··· ···· ·· ♦ · ·· · *

methane to give 0.65 g (1.67 mmol) of the title compound as a beige solid.

¹ H NMR (CDCl 3, 300 MHz) δ 10.27 (s, 1H), 8.77 (d;

1H), 8.08 (s, 1H), 7.54 (m, 1H), 7.40 (bs, 1H), 4.51 (AB, 2H), 4.46 (m, 1H), 3, 34 (m, 2H), 2.78 (m, 1H), 2.31 (s, 3H), 1.98 (m, 1H) for the major component of the rotamer mixture.

E. 3- (S) -Amino-1- (4-amino-3-nitrobenzyl) pyrrolidin-2-one

To a solution of 0.65 g (1.67 mmol) of N- (1- (4-acetylamino-3-nitrobenzyl) -2-oxopyrrolidin-3- (S) -yl) -2,2,2-trifluoroacetamide in 4 6 ml of 1N sodium hydroxide solution were added in 6 ml of ethanol, and the yellow mixture was heated at 50 [deg.] C. for 3 hours to give a brown solution, allowed to cool and then evaporated in vacuo. The organic layers were combined and dried over anhydrous sodium sulfate, filtered and evaporated to give 0.22 g (0.88 mmol) of the title compound as a yellow solid. that will be used in the next step.

¹ H NMR. (deuterochloroform, 300 MHz) δ 7.98 (s, 1H), 7.30 (dd,

1H), 6.79 (d, J), 6.12 (bs, 2H), 4.36 (AB, 2H), 3.67 (m, 1H),

3.19 (m, 2H); 2.43 (m, 1H); 1.71 (m, 1H).

F. 7-Methoxy-naphthalene-2-sulfonic acid [1- (4-amino-3-nitrobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure described in Example 1, Part K, in dichloromethane instead of acetonitrile using 3- (S) -amino-1- (4-amino-3-nitrobenzyl) -pyrrolidin-2-one instead of hydrochloride. 7- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -1-chloroisoquinoline and 7-methoxynaphthalene-2-sulfonyl chloride, prepared according to Example 1, Part J.

Purification by column chromatography eluting with a gradient of 20% ethyl acetate in dichloromethane to 50% ethyl acetate in dichloromethane gave the title compound as a pale yellow solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.37 (s, 1H), 7.94 (s,

1H), 7.92 (d, IH), 7.82 (d, IH), 7.75 (dd, IH), 7.30 (dd, IH), 7.25 (dd, IH), 7 19 (dd, 1H), 6.77 (d, 1H), 6.12 (bs, 2H), 5.38 (bs, IH), 4.30 (AB, 2H), 3.94 (s) 3H), 3.73 (m, 1H), 3.18 (m, 2H), 2.58 (m, 1H), 2.05 (m, 1H).

G. 7-Methoxy-naphthalene-2-sulfonic acid [1- (1H-benzoimidazol-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

To a solution of methoxynaphthalen-2-sulfonic acid [1- (4-amino-3-nitroberizyl) -2-oxopyrrolidin-3 (S) -yl] -amide (0.38 g, 0.82 mmol) in 15 mL of 88% formic acid is added a catalytic amount of 10% palladium on charcoal. The heterogeneous mixture was hydrogenated for 1 hour at room temperature in a Parr apparatus at 50 psi hydrogen. The reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate and methanol, and the filtrate was evaporated in vacuo. The crude product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized to give 0 17 g (0.30 mmol) of the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 9.38 (bs, IH),

8.38 (S; IH), 8.25 (d, 1H), 8.03 (d, 1H), 7.95 (d, 1H), 7.78 (d, IH), 7.72 (dd, IH), 7.66 (bs, IH), 7.56 (s, IH) 7.35 (d, IH), 7.32 (dd, IH), 4.48 (AB, 2H), 4.09 (m, 1H), 3.88 (s, 3H); 3.06 (m, 2H), 1.96 (m, 1H), 1.53 (m, 1H). FAB MS, [M + H] &lt; ⁺ &^gt; = 451.

0000

0 0 0 • · 0

117

Elemental analysis calculated with 1.2 mol of water: C = 51.19%, H = 4.37%, N = 9.55%, found 051.19%, H = 3.95%, N = 9.36% .

Example 26

7-Methoxy-naphthalene-2-sulfonic acid [2- (1H-benzoimidazol-5-ylethyl) -2-oxo-pyrrolidin-3 - (S) -yl] -amide

A. Boc-L-Asn (H) -OBn.

g (46-, 4 mmol) of Boc-L-Asp-OBn (15 g, 46.4 mmol) was dissolved in 50 mL of tetrahydrofuran and cooled to -10 ° C. The solution was treated with 4.9 g (48.7 mmol) of N-methylmorpholine and stirred for 5 minutes. 6.3 g (46.4 mmol) of isobutyl chloroformate are added dropwise to the solution. After the addition was complete, the mixture was stirred for 1 minute and filtered through celite. The filtrate was cooled to -10 ° C. To the solution was added 2.63 g (70 mmol) of sodium borohydride dissolved in 50 ml of water. The resulting solution was stirred for 2 minutes. The solution was poured into a separatory funnel and diluted with 800 mL of ethyl acetate. The organic layer was washed with water and. saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was added at -78 ° C to a solution of 30 ml (60 mmol, 2M solution in dichloromethane) of oxalyl chloride and 7.25 g (92.8 mmol) of methyl sulfoxide in 250 ml of dichloromethane. The mixture was stirred at -78 ° C for 40 min, then 14 g (140 mmol) of triethylamine was added. The reaction mixture was stirred for 1 hour at -78 ° C and then stirred for 30 minutes at room temperature. The solution is poured into 200 ml of 20% citric acid in water. The resulting mixture was poured into a separatory funnel and the layers were separated. The organic layer was washed with water and saturated brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The crude residue was purified by column chromatography eluting with a gradient of 10% ethyl acetate in hexane to 30% ethyl acetate in hexane and ^X 0 9 9 999 9 99

999 9999 99 99 99 to give 12.0 g (39 mmol) of the title compound as an oil.

¹ H NMR (CDCl 3, 300 MHz) δ 9.68 (s, 1H), 7.32 (m,

4H), 5.42 (bs, 1H), 5.16 (s, 2H), 4.62 (m, 2H), 3.05 (ddd,

2H), 1.40 (s, 9H).

B. (1- [2- (4-Nitrophenyl) ethyl] -2-oxopyrrolidin-3- (S) -yl (carbamic acid) tert-butyl ester

To a solution of 3.3 g (10.7 mmol) of Boc-L-Asp (H) -OBn dissolved in 50 mL of methanol was added 4A molecular sieves, 4.35 g (21.5 mmol) of 4-nitrophenethylamine hydrochloride and 2. 25 g (22.2 mmol) of triethylamine. The solution was stirred at room temperature for 45 minutes and then treated with 0.72 g (11.5 mmol) of sodium cyanoborohydride. The reaction mixture was stirred at room temperature for 16 hours. 10 ml of 1N sodium hydroxide solution and 25 ml of water are then added. The resulting mixture was stirred for 30 minutes and then evaporated in vacuo to a smaller volume. The solution was diluted with 250 mL of ethyl acetate, filtered through celite and washed with water and ethyl acetate. Pour the solution into a separatory funnel and separate the layers. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid solution, water, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and evaporated. The crude residue was purified by column chromatography eluting with 50% ethyl acetate *.

in dichloromethane to give 1.46 g (4.18 mmol) of the title compound as a light yellow solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.17 (d, 2H), 7.39 (d,

2H), 5.12 (bs, 1H), 4.09 (m, 1H), 3.63 (m, 2H), 3.25 (m, 2H), 2.99 (t, 2H), 2, 62 (m, 1H), 1.83 (m, 1H), 1.44 (s, 9H).

119

9 »9009 0 0 0 09 0000 00

C. 3- (S) -amino-1- [2- (4-nitrophenyl) ethyl] pyrrolidin-2-one hydrochloride

The title compound was prepared according to the procedure for EXAMPLE 1, Part I, using {1- [2- (4-nitrophenyl) -ethyl] -2-oxo-pyrrolidin-3- (S) -yl} -carbamic acid tert-butyl ester as the starting material substances. The title compound is isolated as a beige solid.

¹ H NMR (CDCl 3 / CDCl 3, 300 MHz) δ 8.77 (bs, 1H), 8.72 (bs, 1H), 8.16 (d, 2H), 7.45 (d, 2H), 4, 15 (m, 1H), 3.59 (t, 2H), 3.38 (m, 2H), 2.98 (t, 2H), 2.58 (m, 1H), 2.37 (m, 1H) ).

D. 2,2,2-Trifluoro-N- {1- [2- (4-nitrophenyl) ethyl] -2-oxopyrrolidin-3- (S) -yl} acetamide

The title compound was prepared according to the procedure for EXAMPLE 1, Part K in dichloromethane instead of acetonitrile, using 3- (S) -amino-1- [2- (4-nitrophenyl) ethyl] pyrrolidin-2-one hydrochloride as starting material and trifluoroacetic anhydride instead of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product was evaporated in vacuo and used in the next step without purification.

1 H NMR (CDCl 3, 300 MHz) δ 8.17 (d, 2H), 8.15 (bs, 1H), 7.39 (d, 2H), 4.40 (m, 1H), 3.70 (m, 1H), 3.55 (m, 1H), 3.34 (m, 2H), 2.99 (t, 2H), 2.68 (m, 1H), 1.96 (m, 1H) .

E. N- {1- [2- (4-Acetylamino-3-nitrophenyl) ethyl] -2-oxopyrrolidin-3- (S) -yl} -2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure for EXAMPLE 25, Part D, using 2,2,2-trifluoro-N- {1- [2- (4-nitrophenyl) -ethyl] -2-oxo-pyrrolidin-3- (S) - yl} -acetamide as above.

the substance of the substance. The crude intermediate was evaporated in vacuo to give N- {1- [2- (4-acetylaminophenyl) ethyl] -2-oxopyrrolidin-3- (S) -yl} 2,2,2-trifluoroacetamide (moistened with acetic acid) which se. used directly in nitration. The reaction mixture containing nitric acid was allowed to warm to room temperature and stirred for 18 hours. The crude product was purified by column chromatography eluting with a gradient of 25% ethyl acetate in dichloromethane to 50% ethyl acetate in dichloromethane to give the title compound as a solid.

¹ H NMR (CDCl 3, 300 MHz) δ 10.24 (s, 1H), 8.70 (d,

1 H), 7.98 (bs, 1H), 7.40 (d, 1H), 7.26 (bs, 1H), 4.43 (m, 1H), 3.58 (m, 2H), 3 38 (m, 2H), 2.94 (m, 2H), 2.66 (m, 1H), 2.0 (s, 3H), 1.98 (m, 1H) for the major component of the rotamer mixture.

F. 3- (S) -Amino-1- [2- (4-amino-3-nitrophenyl) ethyl] pyrrolidin-2-one

The title compound was prepared according to the procedure for EXAMPLE 25, Part F, using Ν- {1- [2- (4-acetylamino-3-nitrophenyl) -ethyl] -2-oxo-pyrrolidin-3- (S) -yl} - 2,2,2-Trifluoroacetamide as starting material. The reaction mixture was stirred at room temperature for 18 hours. After similar treatment, the organic phase was evaporated in vacuo to give the title compound as a yellow solid, which was used in the next step.

^X H NMR (CDCl₃, 300 MHz) δ. 7.90 (s, 1H), 7.25 (d,

1H), 6.80 (d, 1H), 6.24 (bs, 1H), 3.48 (m, 3H), 3.26 (m, 2H), 2.77 (t, 2H), 2, 40 (m, 1H), 2.25 (bs, 3H), 1.69 (m, 1H).

G. 7-Methoxy-naphthalene-2-sulfonic acid {1- [2- (4-amino-3-nitrophenyl) -ethyl] -2-oxo-pyrrolidin-3- (S) -yl} -amide

The title compound was prepared according to the procedure for EXAMPLE 1, Part K in Dichloromethane instead of in acetonitrile.

121 · '·· • 8 •

Λ

9999 · »

9 <»♦ • 9

9 9

9 ».

9

9 using 3- (S) -amino-1- [2- (4-amino-3-nitrophenyl) -ethyl] -pyrrolidin-2-one in place of Ί- (3- (S) -amino-2-oxopyrrolidine-) hydrochloride 1-ylmethyl) -1-chloroisoquinoline and 7-methoxynaphthalene-2-sulfonyl chloride, prepared as in Example 1, Part J. After similar treatment, the organic phase was evaporated in vacuo to give the title compound as a pale yellow solid which is used in the next step.

1 H NMR (CDCl 3, 300 MHz) δ 8.36 (s, 1H), 7.87 (d,

1H), 7.83 (s, 1H), 7.77 (d, 1H), 7.72 (dd, 1H), 7.27 (dd, 1H),

7.22 (s, 1H), 7.13 (dd, 1H), 6.68 (d, 1H), 6.04 (bs, 2H), 5.33 (bs, 1H), 3.93 (s) 3H), 3.68 (m, 1H). 3.44 (m, 2H); 3.20 (m,

2H), 2.68 (t, 2H), 2.49 (m, 1H), 1.98 (m, 1H).

H. 7-Methoxy-naphthalene-2-sulfonic acid {1- [2- (1H-benzoimidazol-5-yl) -ethyl] -2-oxo-pyrrolidin-3- (S) -yl} -amide trifluoroacetate {1- [2- 7-Methoxynaphthalene-2-sulfonic acid (4-amino-3-nitrophenyl) ethyl] -2-oxopyrrolidin-3- (S) -yl} amide was converted to the title compound according to the procedure described in Example 25, part H The crude product is purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 60% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions are lyophilized to afford the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 9.38 (bs, 1H),

8.35 . (WITH/ 1H), 8, 13 (d, 1 H), 8.02 (d, IH), 7.93 (d, 1H), 7.73 (d, 1H), 7.69 (with, 1H), 7.65 (d, 1H) 7.55 (with, 1H), 7.38 (d, 1H), 7.32 (dd, 1H), 3.90 (m, 1H), 3.88 (s, 3H), 3.39 (m, 2H) 3.11 (m, 2H), 2.88 (t, 2H) 1.94 (m, IH), 1.47 (m, 1H). FAB MS, [M + H] ⁺ = 465 . Elementary analysis calculated with 1.4 mol of water.

122 ♦ · · · · · · · 11 11

9 1 1 9 9 1 1 ··· ···· 99 99 19 9

C = 51.68%, H = 4.65%, N = 9.27%, found C = 51.68%, H-4.25%,

N = 8.93%.

Example 27 7-Methoxynaphthalene-2-sulfonic acid acetyl- [2-oxo-1- (2-pyrrolo [3,2-b] pyridin-1-ylethyl) -pyrrolidin-3 (S) -yl] -amide trifluoroacetate

A. 1H-Pyrrolo [3,2-c] pyridine

The title compound was prepared from 3-picoline-N-oxide according to the procedure described in Tetrahedron 1993, 2885. The obtained crude product was dissolved in ethanol and decolorizing charcoal was added. The mixture was filtered through a large silica gel column eluting with ethanol to give the title compound as a beige solid.

⁷ H NMR (CDCl 3, 300 MHz) δ 10.92 (bs, 1H), 8.98 (s,

1H), 8.31 (d, 1H), 7.36 (d, 1H), 7.32 (d, 1H), 6.66 (d, 1H).

B. Pyrrolo [3,2-c] pyridin-1-yl-acetic acid tert-butyl ester

The title compound was prepared from 1H-pyrrolo [3,2-c] pyridine according to the procedure described in Examples 18 and 19, Part A using tert-butyl bromoacetate instead of methyl iodide. The crude product was purified by column chromatography eluting with a gradient. of a mixture of 3% methanol in dichloromethane to 6% ethanol in dichloromethane to give the title compound as an oil.

¹ H NMR (CDCl 3, 300 MHz) δ 8.93 (s, 1H),

1H), 7.18 (d, 1H), 7.12 (d, 1H), 6.65 (d, 1H), 4.75

1.45. (s, 9H).

C. Pyrrolo [3,2-c] pyridin-1-ylacetic acid

8.34 (d, (s, 2H));

123 · ························································ · ·· «· ·· ···

Κ A solution of 0.44 g (1.89 mmol) of pyrrolo [3,2-c] pyridin-1-yl-acetic acid tert-butyl ester in 10 mL of dichloromethane was added at 0 ° C with 1 mL of trifluoroacetic acid. After 15 minutes, the solution was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was evaporated in vacuo and then azeotrolically distilled with toluene to give 0.5 g of the title compound (moistened with excess trifluoroacetic acid), which was used in the next step.

¹ H NMR (CDCl 3; + CDCl 3, 300 MHz) δ 9.09 (s, 1H), 8.34 (d, 1H), 7.91 (d, 1H),. 7.71 (d, 1H); 7.08 (d, 1H);

1H), 5.18 (s, 2H).

D. 2- (S) -Benzyloxycarbonylamino-4- (2-pyrrolo [3,2c] pyridin-1-yl-acetylamino) butanoic acid methyl ester

0.50 g of pyrrolo [3,2-c] pyridin-1-yl-acetic acid, 0.93 g (2.45 mmol) of 2- (S) -benzyloxycarbonylamino-4-aminobutyric acid methyl ester trifluoroacetate, 0.75 g (7.41 mmol) of 4-methylmorpholine and 0.36 g (2.65 mmol) of 1-hydroxybenzotriazole hydrate were dissolved in 11 ml of dimethylformamide and the resulting mixture was cooled to 0 ° C. 0.80 g (4.17 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added to the solution. The ice bath was removed and the reaction mixture was stirred at room temperature. After 18 hours, the solution was diluted with saturated ammonium chloride solution, and extracted twice with ethyl acetate. The combined organic layers were washed with water, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified by column chromatography eluting with a gradient of 3% MeOH / CH2Cl2 to 10% MeOH / CH2Cl2 to give the title compound as a white solid.

-ίο / l · · · * ···· • • 9 φ

0.33 g (0.78 mmol) of the title compound as a solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.95 (s, 1H), 8.35 (d,

1H), 7.34 (m, 3H), 7.27 (m, 1H) 3H), 7.17 (d, 1H), 6.73 (d, 1 H), 6.44 (šs, 1H), 5.45 (d, IH); 4.93 (with, 2H), 4.78 (with, 2H), 4.08 (m, 1H), 3.69 (s, 3H) 3.67 m, 1H), 2.90 (m, 1H), 2.03 (m, 1H), 1.58 (m, 1H).

E. trifluoroacetate. 7-Methoxy-naphthalene-2-sulfonic acid acetyl- [2-oxo-1- (2-pyrrolo [3,2-b] pyridin-1-yl-ethyl) -pyrrolidin-3- (S) -yl] -amide

To a solution of 0.51 g (1.20 mml) of 2- (S) -benzyloxycarbonylamino-4- (2-pyrrolo [3,2-c] pyridin-1-yl-acetylamino) -butanoic acid methyl ester in 5 mL of tetrahydrofuran 5 ml (0.500 mmol) of a 1M solution in tetrahydrofuran) diborane are added. The resulting mixture was stirred at room temperature for 4 hours and then evaporated in vacuo. The residue was suspended in 10 mL of ethyl acetate, treated with 10 drops of water, 5 drops of 1 N sodium hydroxide solution and then. is quenched with saturated ammonium chloride solution. The mixture was evaporated in vacuo to about 1/2 volume, partitioned between ethyl acetate and 10% sodium carbonate solution and the layers separated. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo. The crude product obtained is partially purified by column chromatography eluting with a gradient of 2% methanol in dichloromethane to 10% methanol in dichloromethane to give [2-oxo-1- (2-pyrrolo [3,2-c] pyridine-1) benzyl ester. -yl-ethyl) pyrrolidin-3- (S) -yl] carbamic acid. FAB MS, [M + H] ⁺ = 379.

To a solution of this crude [2-oxo-1- (2-pyrrolo [3,2-c] pyridin-1-yl-ethyl) -pyrrolidin-3 (S) -yl] -carbamic acid benzyl ester in 10 mL methanol and 3 mL of acetic acid. adds kataly44 · «·· •« • ·

125 »· • 4» 4444

4 4 4 4 4 4

4 44 · 44

4 Λ 4 4 4 10% palladium on activated carbon. The heterogeneous mixture was stirred at room temperature under a hydrogen balloon for 18 hours. The reaction mixture was filtered through a pad of diatomaceous earth and washed three times with methanol. The crude product was evaporated in vacuo and then azeotroped with toluene to give 3- (S) amino-1- (2-pyrrolo [3,2-c] pyridin-1-yl-ethyl) -pyrrolidin-2- acetate it (moistened with excess acetic acid). FAB MS, [M + H] &lt; ⁺ &^gt; = 245.

The title compound was prepared according to the procedure for EXAMPLE 1, Part K in dichloromethane instead of acetonitrile, using the above 3- (S) -amino-1- (2-pyrrolo [3,2c] pyridine-1-) acetate. yl-ethyl) pyrrolidin-2-one instead of 7 (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride, prepared according to Example 1, part J. Surový. the product was partially purified by column chromatography eluting with a gradient of 3% methanol in dichloromethane to 5% methanol in dichloromethane. The obtained residue was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized to afford the compound title compound as a white solid.

1 H NMR (DMSO, 300 MHz) δ

8.58 (s, 1 H), 8.48 (d, 1H), 8.20 . (d, 1H), 8.08 (d, 1H), 7.98 (with, 1H), 7.75 (dd, 1H), 7.61 (with, 1H), 7.03 (d, 1H), 4.87 (m, 1H), 4,56 (m, 2H), 3.63 (m, 2H) 3.30 (m, 2H), 2.27 (m, 1H), 2.15

(m, 1 H). FAB-MS, [M + H] ⁺ = 507.

9.24 (with, IHR, (d, 1H), 8, 00 1H), 7.42 (dd, 3.90 (with, 3H), (with, 3H) 2.04

• 00 00 0 0

0 0 0 0 0 0 0 000

- 0 0 * * 0 0 0

-, ~ - * 0-000 * β · · ·

125 · 0 «« φ * ·· #

0 · 0000 «0 00« 0 00

Example 28 7-Methoxy-naphthalene-2-sulfonic acid [1- (4-amino-quinazolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide

A. 6-Methyl-3H-quinazolin-4-one

2.6 g (65 mmol), 60% dispersion in mineral oil) of sodium hydride are added to 100 ml of dioxane at 0 ° C. To the solution was added

7.6 g (50 mmol) of 2-amino-5-methylbenzoic acid followed by 9.9 g (60 mmol) of [3- (dimethylamino) 2-azoprop-2-en-1-ylidene] dimethylammonium chloride. After the addition, the solution was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and 3 mL was added. methanol and 10 ml acetic acid. The solution was then heated at reflux for 3 hours. The solution was cooled to room temperature. The solution was evaporated. The solid obtained is diluted with 60 ml of water. The pH of the solution obtained is adjusted to 7. The solution is filtered. The resulting solid was dried in vacuo to give 6.0 g (38 mmol) of the title compound.

1 H NMR (CDCl 3, 300 MHz) δ 8.03 (s, 1H), 7.89 (s,

1H), 7.57 (m, 2H), 2.41 (s, 3H). EI MS, [M + H] &lt; ⁺ &^gt; = 507.

B. 4-Chloro-6-methylquinazoline

1.1 g (6.9 mmol) of 6-methyl-3H-quinazolin-4-one are dissolved in 70 ml of toluene. To the solution was added 1.82 g (18 mmol) of triethylamine and 1.06 g (6.9 mmol). P (O) C1 ₃ . The solution was heated to reflux. After 3 hours, the solution is poured into 100 ml of water. The solution was diluted with 200 mL of ethyl acetate. The layers are separated. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulphate and dried over magnesium sulphate.

7 ······· ♦ · 'φφφ ···· «φ« · «φ <

evaporate. 0.75 g (4.2 mmol) of the title compound is obtained as an oil.

¹ H NMR (CDCl 3, 300 MHz) δ 8.98 (s, 1H), 8.04 (s, 1H), 7.98 (d, 1H), 7.82 (d, 1H), 2.62 ( s, 3H).

C. 6-Bromomethyl-4-chloroquinazoline

The title compound was prepared according to the procedure described in Example 1, Part F, substituting 4-chloro-6-methylquinazoline for 1-chloro-7-methylisoquinoline. The crude product was purified by column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 10% ethyl acetate in hexane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 9.08 (s, 1H), 8.23 (s,

1H), 8.00 (dd, 2H), 4.68 (s, 2H).

D. 7-Methoxynaphthalene-2-sulfonic acid (2-oxopyrrolidin-3- (S) -yl) -amide

To a solution of 20 ml of trifluoroacetic acid in dichloromethane at 0 ° C was added 0.4 g (2 mmol) of (2-oxopyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester, prepared according to the procedure described in Example 1, part G. The resulting solution was allowed to warm to room temperature and stirred for 12 hours. The solution is then evaporated. The oil obtained is re-evaporated from toluene. The oil was then dissolved in 6 mL of acetonitrile. 6 ml of dichloromethane are added to the solution. The solution obtained is cooled to 0 DEG C. and 0.67 g (6.6 mmol) of triethylamine are added, followed by 0.64 g (2.5 mmol) of 7-methoxynaphthalenesulfonyl chloride. prepared according to Example 1 ', part J. The solution was stirred for 6 hours. The solution was then evaporated. The crude solid obtained was triturated from ethyl acetate. The crude solid was then purified by column chromatography eluting with a gradient of 2.5% methanol in dichloromethane to 5% methanol.

128 in dichloromethane to give 0.40 g of the title product as a white foam.

(1.25 mmol) of the compound

¹ H NMR. (deuterochloroform, 300 MHz) δ 8.35 (s, IH) 7.88 (d, 1H), 7.78 (d, 1H), 7.28 (m. 2H) , 5.65 (šs, 1H), 5.34 (šs, IH), 3.94 (s, 3H), 3.67 (m, 1H) , 3, 32 (m, 2H), 2.62 (m, IH), 2.21

(m, 1H).

E. 7-Methoxynaphthalene-2-sulfonic acid methyl- (2-oxopyrrolidin-3- (S) -yl) -amide

The title compound was prepared according to the procedure described in Example 6, Part A, substituting 7-methoxy-naphthalene-2-sulfonic acid (2-oxo-pyrrolidin-3- (S) -yl) -amide for [1- (1-chloro-isoquinoline-7). 7-Methoxy-naphthalene-2-sulfonic acid-2-oxo-pyrrolidin-3- (S) -yl] -amide. The crude product was purified by column chromatography eluting with a gradient of 40% ethyl acetate in dichloromethane to 60% ethyl acetate in dichloromethane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.39 (s, 1H), 7.90 (d, 1H), 7.76 (m, 2H), 7.28 (m, 2H), 6.42 (bs, 1H), 4.82 (m, 1H), 3.92 (s, 3H), 3.32 (m, 2H), 2.80 (s, 3H), 2.31 (m, 1H) , 2.05 (m, 1H).

F. 7-Methoxy-naphthalene-2-sulfonic acid [1- (4-chloroquinazolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide

To a solution of 7-methoxy-naphthalene-2-sulfonic acid methyl (2-oxo-pyrrolidin-3 - (S) -yl) -amide (0.3 g) (1.04 mmol) in tetrahydrofuran (7 mL) was added 1 mL (0 mL) at 0 ° C. 1 mmol, 1 M solution in tetrahydrofuran) LiN (SiMe ₃ ) ₂ . The solution was stirred at 0 ° C for 40 minutes. 0.24 g (0.94 mmol) of 6-bromomethyl-4-chloroquinazoline was then added. The reaction mixture was quenched by addition of saturated solution

4 »····

129

4 4 4 4 · 4 4 4 fl · ···· 4 9 4-9 ammonium chloride. The solution was diluted with ethyl acetate and water. The layers were separated. The organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with a gradient of 20% ethyl acetate in dichloromethane to 40% ethyl acetate in dichloromethane to afford 0.25 g (0.49 mmol) of compound. title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 9.03 (s, 1H), 8.40 (s,

1H), 8.03 (m, 2H), 7.89 (d, 1H), 7.81 (m, 3H), 7.28 (m, 2H), 5.00 (m, 1 H), 4.75 (AB, 1H), 4.50 (AB, 1H), 3.92 (with, 3H), 3.22 (m, 2H), 2.87 (with, 3H), 2.38 (m, 1H), 2.03 (m, 1H). . FAB MS,

[M + H] &lt; ⁺ &^gt; = 511.

G. 7-Methoxynaphthalene-2-sulfonic acid [1- (4-amino-quinazolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide

To 7-methoxy-naphthalene-2-sulfonic acid [1- (4-chloro-quinazolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide (0.05 g, 0.1 mmol) suspended in 10 ml of ethanol are added 0.02 g (0.2 mmol) of triethylamine and 0.8 g (1 mmol) of ammonium acetate. The reaction mixture was heated to 80 ° C. The solution was evaporated. The residue was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile. in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized to give 0.03 g (0.05 mmol) of the title compound as white solids.

¹ H NMR (CDCl 3, 3.00 MHz) δ 9.78 (bs, 2H), 8.78 (s, 1H), 8.36 (s, 1H), 8.11 (s, 1H), 8.02 ( d, 1H), 7.92 (d, 1H), 7.83 (d, 1H), 7.68 (m, 2H), 7.56 (s, 1H), δ 7.49 (s,

130 t 3 *

4 4 4 4 4 9 9 44

4 · 9

444 4444 4 4 4 4. 4 9

1H), 7.32 (dd, 1H), 4.93 (m, 1H), 4.50 (AB, 2H), 3.82 (s, 3H),

3.15 (m, 2 H) _; 2.62 (s, 3H), 2.02 (m, 1H), 1.78 (m, 1H). FAB

MS, [M + H] &lt; ⁺ &^gt; = 492.

Example 29 7-Methoxy-naphthalene-2-sulfonic acid [1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

A. 2-Amino-5-methylthiophene-3-carboxylic acid methyl ester

To a solution of methyl cyanoacetate (19.8 g, 200 mmol) in DMF (25 mL) was added triethylamine (10.9 g, 108 mmol). 6.4 g (200 mmol) of sulfur are added to the solution. The solution was heated to 60 ° C. After 20 minutes, propionaldehyde (11.6 g, 200 mmol) was added dropwise. After the addition, the solution was cooled to room temperature and stirred for 1 hour. The solution was stirred for 16 hours. The reaction mixture was poured into 300 ml of water. The solution obtained is extracted twice with 200 ml of ether. The combined ether extracts were washed with water and saturated brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The crude product obtained was recrystallized from methanol / dichloromethane to give 13.7 g (80 mmol) of the title compound as a yellow solid.

¹ H NMR (CDCl 3, 300 MHz) δ 6.58 (s, 1H), 5.78 (bs,

2H), 3.78 (s, 3H), 2.28 (s, 3H).

B. 2-Amino-5-methylthiophene-3-carboxylic acid

To a solution of 13.7 g (80 mmol) of 2-amino-5-methylthiophene-3-carboxylic acid methyl ester in 400 mL of 1: 1: 1 methanol / water / tetrahydrofuran was added 16 g (40 mmol) of lithium hydroxide hydrate. The solution is heated to 50 ° C. After 4 hours «

131

• 9 • 9

9,999 «9« 9 »

9 9 0 • 0

The solution is evaporated. The residue obtained is. Dissolve in water. The pH of the solution is adjusted to 5-6 with 1N hydrochloric acid. The precipitate is filtered off, washed with a small amount of water and dried in vacuo. This afforded 12 g (76 mmol) of the title compound as a yellow solid.

EI MS, [M] ⁺ = 157.

C. 6-Methylthieno [2,3-d] pyrimidin-4-ol

The title compound was prepared according to the procedure described in Example 28, part A by substituting 2-amino-5-methylthiophene-3-carboxylic acid for 2-amino-5-methylbenzoic acid. The crude product is purified by column chromatography eluting with a gradient of 2% methanol in dichloromethane to 6% methanol in dichloromethane to afford the title compound as a solid.

EI MS, [M] ⁺ = 165.

D. 4-Chloro-6-methyl-thieno [2,3-d] pyrimidine

The title compound was prepared according to the procedure for EXAMPLE 28, Part B by substituting 6-methyl-thieno [2,3d] pyrimidin-4-ol for 6-methyl-3H-quinazolin-4-one. The crude product is purified by column chromatography eluting with a gradient of dichloromethane to 5% ethyl acetate in dichloromethane to afford the title compound as a solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.84 (s, 1H), 7.42 (s,

1H), 2.68 (s, 3H).

E. 6-Bromomethyl-4-chloro-thieno [2,3-d] pyrimidine

The title compound was prepared according to the procedure for EXAMPLE 1, Part F by substituting 4-chloro-6-methyl-thieno [2,3-d] pyrazole.

9 • 9

132 9 9 9

9 9

9 9

999 9999 rimidine for 1-chloro-7-methylisoquinoline. The crude product was purified by column chromatography eluting with a gradient of 70% dichloromethane in hexane to 100 dichloromethane to afford the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.84 (s, 1H), 7.42 (s,

1H), 4.72 (s, 2H).

F. [1- (4-Chloro-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester

The title compound was prepared according to the procedure in Example 1, part H, substituting 6-bromomethyl-4-chloro-thieno [2,3-d] pyrimidine for 7-bromomethyl-1-chloroisoquinoline. The crude product is purified by column chromatography eluting with a gradient of 20% ethyl acetate in dichloromethane to 30% ethyl acetate in hexane to afford the title compound. form of white foam.

¹ H NMR (CDCl 3, 300 MHz) δ 8.8 0 (s, 1 H), 7.31 (s,

1H), 5.15 (bs, 1H), 4.75 (AB, 2H), 4.18 (m, 1H), 3.36 (m, 2H), 2.62 (m, 1H), 1, 96 (m, 1H), 1.42 (s, 9H).

G. 7-Methoxy-naphthalene-2-sulfonic acid [1- (4-chloro-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure in Example 1, Part I, substituting [1- (4-chloro-thieno [2,3d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -butyl ester. -yl] carbamic acid for [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester. The product is then directly reacted as described in Example 1, Part K. The crude product is then purified by column chromatography eluting with a gradient of 30% ethyl acetate in dichloromethane to 40% ethyl acetate in dichloromethane.

133 φ φ · φ φ φ φ za za za za za za φ φ φ φ φ φ za za za za za za za za za za za za za za za za za za za za za za za za za za za za za .

^X H NMR (CDCl₃, 300 MHz) δ

IH), 7.92 (d ,. IH), 7.76 , (m, 2H), 7.24 4.68 (s, 2H) 3.93 (s, 3H), 3.78 (m, (m, 1Ή), 2.12 (m, 1H).

8.80 (with, IH), 8.32 (with, (m, 3H), 5,51 (Šs, IH), IH), 3.32 (m, 2H), 2.62

H. 7-Methoxynaphthalene-2-sulfonic acid [1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

The title compound was prepared according to the procedure for EXAMPLE 28, part G, substituting [1- (4-chloro-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3 - ( S) -yl] amide. 7-Methoxy-naphthalene-2-sulfonic acid 7-methoxy-naphthalen-2-sulfonic acid for [1- (4-chloro-quinazolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide. The residue is purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions are lyophilized to give the title compound. in the title as a white solid.

^X · H NMR (DMSO-d₆, 300 MHz) δ 8.33 (m, 2H);

8.21 (d, IH), 8.02 (m , 2H), 7.91 (d, IH) 7.70 (dd ,. 1H), 7.52 (with, IH), 7.43 (with, IH) , 7.30 (dd, 1H), 4.58 (AB, 2H), 4.05 (m, 2H), 3.93 (with, 3H), 3, 17 (m, 2H), 1.98 (m, IH), 1.55 (m, 1H).

FAB MS, [M + H] &lt; ⁺ &^gt; = 484.

Example 30 7-Methoxy-naphthalene-2-sulfonic acid [2- (6-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate 134 • 1119 • 9 9 1

19 Dec

1112 11 i i 1

99

A. 4-Chloro-7-methyl-thieno [3,2-d] pyrimidine

The title compound was prepared according to the procedure described in Example 28, Part B, substituting 7-methyl-thieno [2,3d] pyrimidin-4-ol for 6-methyl-3H-quinazolin-4-one. The crude product was purified by column chromatography eluting with a gradient of dichloromethane to 10% ethyl acetate in dichloromethane to give the title compound as a solid.

⁴ H NMR (CDCl 3, 300 MHz) δ 9.02 (s, 1H), 7.68 (s,

1H), 2.51 (s, 3H).

B. 7-Bromomethyl-4-chloro-thieno [3,2-d] pyrimidine

The title compound was prepared according to the procedure described in Example 1, Part F, substituting 4-chloro-7-methylthieno [3,2-d] pyrimidine for 1-chloro-7-methylisoquinoline. The crude product was purified by column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 10%. ethyl acetate in hexane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 9.04 (s, 1H), · 8.08 (s,

1H), 4.77 (s, 2H).

C. [1- (4-Chloro-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester

The title compound was prepared according to the procedure described in Example 1, part H, substituting 7-bromomethyl-4-chloro-thieno [3,2-d] pyrimidine for 7-bromomethyl-1-chloroisoquinoline. The crude product was purified by column chromatography eluting with a gradient of 20% ethyl acetate in dichloromethane to 30% ethyl acetate in dichloromethane to give the title compound as a white foam.

136 * 0 0 · «0 0 ··

0 ^X H NMR (CDCl, 300 MHz) δ 8.95 (s, H), 8.06 (s,

1H), 5.18 (bs, 1H), 4.76 (AB, 2H), 4.13 (m, 1H), 3.44 (m, 1H),

3.37 (m, 1H), 2.64 (m, 1H), 1.92 (m, 1H), 1.42 (s, 9H).

D. 7-Methoxy-naphthalene-2-sulfonic acid [1- (4-chloro-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure in Example 1, Part I, substituting [1- (4-chloro-thieno [3,2d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) - - tert -butyl ester. yl] carbamic acid for [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester. The crude product was purified by column chromatography eluting with a gradient of 30% ethyl acetate in dichloromethane to 40% ethyl acetate in dichloromethane to afford the title compound as a white solid.

1 H NMR (CDCl 3, 300 MHz) δ 8.92 (with, ÍH), 8.32 (with, 1H), 7.96 (s, 1H), 7.86 (d, 1H), 7.74 (m, 2H), 7.28 (d, ÍH), 7.19 (d, 1H), 5.64 (bs, 1H), 4.71 (AB, 2H), 3.93 (WITH, 3H), 3.72 (m, 1H), 3.44 (m, 1H), 3.32 (m, 1H), 2.52 (m, ÍH), 2.05 (m,

ÍH).

E. 7-Methoxynaphthalene-2-sulfonic acid [2- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

The title compound was prepared according to the procedure for EXAMPLE 28, Part G, substituting [1- (4-chloro-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S). 7-Methoxy-naphthalene-2-sulfonic acid [1- (4-chloroquinazolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide 7-methoxy-naphthalene-2-sulfonic acid amide. The residue was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1

0 94 94 4 9 i -or 0 · 0 · 000 id 0 0 0 0 0 0 0 0 0 0 0 0 4 9 to 80% acetonitrile in water (0.1% of the appropriate fraction containing the product of the title compound in .form • 0 · * 4 4 4 9 4 4

% Of trifluoroacetic acid (trifluoroacetic acid) and lyophilized to give a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.55 (s, 1H),

8.35 (bs, 3H), 8.14 (d, 1H), 8.00 - (m, 2H), 7.93 (d, 1H), 7.68 (d, 1H), 7.52 ( s, 1H), 7.32 (dd, 1H), 4.49 (AB, 2H), 4.09 (m, 1H), 3.90 (s, 3H), 3.18 (m, 2H), 1.96 (m, 1 H), 1.54 (m, 1 H). FAB MS, [M + H] + = 483. Elemental analysis calculated with 1.5 mol of water and 1.5 mol of trifluoroacetate: C = 44.75%, H = 3.83%, N = 10.44%, found C = 44.75%, H = 3.77 %, N = 11.12%.

Example 31 7-Methoxynaphthalene-2-sulfonic acid [1- (7-amino-thieno [2,3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

A. 3-Bromomethyl-7-chloro-thieno [2,3-c] pyridine

The title compound was prepared according to the procedure described in Example 1, part Έ, substituting 7-chloro-3-methylthieno [2,3-c] pyrimidine for 1-chloro-7-methylisoquinoline. The crude product was purified by column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 10% ethyl acetate in hexane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.38 (d, 1H), 7.73 (s,

1H), 7.71 (d, 1H), 4.72 (s, 2H).

B. [1- (7-Chloro-thieno [2,3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester

The title compound was prepared according to the procedure described in Example 1, part H, substituting 3-bromomethyl-7-chloro-thieno [137]

94 94

944 »·

1, 4, 4, 4, 4 [2,3-c] pyridine with 7-bromomethyl-1-chloroisoquinoline. The crude product was purified by column chromatography eluting with a gradient of 20% ethyl acetate in dichloromethane to 40% ethyl acetate in hexane to give the title compound as a white foam.

¹ H NMR (CDCl 3, 300 MHz) δ 8.28 (d, 1H), 7.74 (d, 1H), 7.64 (s, 1H), 5.18 (bs, 1H), 4.68 (d, 1H); ΛΒ, 2H), 4.17 (m, 1H), 3.18 (m, 2H), 2.54 (m, 1H), 1.86 (m, 1H), 1.42 (s, 9H).

C. 7-Methoxy-naphthalene-2-sulfonic acid [1- (7-chloro-thieno [2,3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure in Example 1, Part I, substituting [1- (7-chloro-thieno [2,3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl tert-butyl ester. ] carbamic acid for [1- (1-chloro-isoquinolin-7ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester. The crude product is purified by column chromatography eluting with a gradient of 30% ethyl acetate in dichloromethane to 40% ethyl acetate in dichloromethane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.33 (s, 1H),

8.30 (d, 1H), 8.16 (d, 1H), 8.07 (s, 1H), 7.99 (d, 1H), 7.92 (d, 1H), 7.78 (d) (1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.28 (dd, 1H),

1H), 4.58 (λΒH, 2H), 4.08 (m, 1H), 3.88 (s, 2H), 1.89 (m, 1H),

1.48 (m, IH).

D. 7-Methoxynaphthalene-2-sulfonic acid [1- (7-amino-thieno [2,3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

9

138

9 · 999 · 9 9

9 9 9 9 9

The title compound was prepared according to the procedure for EXAMPLE 28, Part G by substituting [1- (7-chloro-thieno [2,3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3 (S) - yl] 7-methoxy-naphthalene-2-sulfonic acid amide of 7-methoxy-naphthalene-2-sulfonic acid [1- (4-chloro-quinazolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide. The residue was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized to afford the compound title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.90 (bs, 3H),

8.34 (with , IH), 8.16 (d, 1H); 7.90 (d, 1H); 7 '82 (d, IH), 7.68 (d, IH) , 7.62 (d, 1H), 7.34 (m, 3H), 7.23 (dd, IH), 4.64 (AB, 2H), 4, 0 8 (m, 1H), 3.88 (s, 3H), 3.09 (M, 2H), 2.11 (m, IH), 1.60 (m , IH). FAB MS, [M + H] &lt; ⁺ &^gt; = 483.

Example 32 7-Methoxynaphthalene-2-sulfonic acid [1- (7-hydroxy-thieno [2,3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

A. 7-Methoxynaphthalene-2-sulfonic acid [1- (7-hydroxy-thieno [2,3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

The title compound was prepared according to the procedure for EXAMPLE 28, Part G by substituting [1- (7-chloro-thieno [2,3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3 (S) - yl] 7-methoxy-naphthalene-2-sulfonic acid [1- (4-chloro-quinazolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide 7-methoxy-naphthalene-2-sulfonic acid amide. The residue is purified by reverse phase HPLC. 911 11 1 9 • ······

OQ * 0 · 0 0 19 9 1

J 7 07 111111

Elution with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized to afford the title compound. of the title in the form of a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.36 (s, 1H),

8.18 (d, 1H), 8.01 (d, IH), 7.92 (d, 1H), 7.86 (with, 1H), 7.68 (d, 1H), 7.52 (S, 1H), 7.28 (m, 3H), 6.62 (d, 1H), 4.42 (AB, 2H), 4.00 (m, 1H), 3.88 (s, 3H), 3.04 (m, 2H), 1.89 (m, 1H), 1.44 (m, 1H). FAB MS, [M + H] &lt; ⁺ &^gt; = 484

Example 33 7-Methoxy-naphthalene-2-sulfonic acid [1- (4-amino-thieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

A. 3- (5-Methylthiophen-2-yl) acrylic acid methyl ester

To 5 g (40 mmol) of 5-methylthiophene-2-carboxaldehyde in 10 ml of dichloromethane was added 13.3 g (40 mmol) of methyl (triphenylphosphoranylidene) acetate. The solution was stirred for 72 hours. The solution was then evaporated. The residue was suspended in diethyl ether. Filter the solution through a pad of diatomaceous earth. The filtrate was evaporated. The residue was purified by column chromatography eluting with a gradient of 50% ethyl acetate in hexane to 60% ethyl acetate in hexane to give 4.5 g (25 mmol) of the title compound as an oil.

¹ H NMR (CDCl 3, 300 MHz) δ 7.69 (d, 1H), 7.04 (d,

1H), 6.71 (d, 1H), 6.11 (d, 1H), 3.79 (s, 3H), 2.49 (s, 3H).

B. 3- (5-Methylthiophen-2-yl) acrylic acid © 99

9 99 99 • 9 9 9

140 ί «·· ::

999 9900 99

The title compound was prepared according to the procedure in Example 29, part B, substituting 3- (5-methyl-thiophen-2-yl) -acrylic acid methyl ester for 2-amino-5-methylthiophene-3-carboxylic acid methyl ester. The title compound is obtained by filtration as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 7.58 (d, 1H), 7.24 (d, 1H);

1H), 7.82 (d, 1H), 5.98 (d, 1H), 2.46 (s, 3H).

C. 2-Methyl-5H-thieno [3,2-c] pyridin-4-one

The title compound was prepared according to the procedure described in Example 1, Part A, substituting 3- (5-methyl-thiophen-2-yl) -acrylic acid for 3-p-tolyl-acrylic acid. The product is then reacted according to the procedure described in Example 1, part B, C and

D. The crude product was purified by column chromatography eluting with 1% methanol in dichloromethane to 5% methanol in dichloromethane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 11.72 (bs, 1H), 7.31 (s,

1H), 7.18 (d, 1H), 6.68 (d, 1H), 2.58 (s, 3H). EI MS, [M] &lt; ⁺ &^gt;

165

D. 4-Chloro-2-methyl-thieno [3,2-c] pyridine

The title compound was prepared according to the procedure described in Example 1, part E, substituting 2-methyl-5H-thieno [3,2-c] pyridin-4-one for 7-methyl-2H-isoquinolin-1-one. The crude product was purified by column chromatography eluting with a gradient of 70% dichloromethane in hexane to 100% dichloromethane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz), δ 8.13 (d, 1H), 7.58 (d,

1H), 7.16 (d, 1H), 2.61 (s, 3H).

141

ΦΦ φ »· ♦ · · · φ φ φ φ φ φ φ

Ε. 2-Bromomethyl-4-chloro-thieno [3,2-c] pyridine

The title compound was prepared according to the procedure described in Example 1, Part F, substituting 4-chloro-2-methylthieno [3,2-c] pyridine for 1-chloro-7-methylisoquinoline. The crude product was purified by column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 10% ethyl acetate in hexane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.21 (d, 1H), 7.63 (d,

1H), 7.49 (s, 1H), 4.80 (s, 2H).

F. [1- (4-Chloro-thieno [3,2-c] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester

The title compound was prepared according to the procedure described in Example 1, part H, substituting 2-bromomethyl-4-chloro-thieno [3,2-c] pyridine for 7-bromomethyl-1-chloroisoquinoline. The crude product was purified by column chromatography eluting with a gradient of 20% ethyl acetate in dichloromethane to 30% ethyl acetate in dichloromethane to give the title compound as a white foam.

¹ H NMR (CDCl 3, 300 MHz) δ 8.22 (d, 1H), 7.63 (d, 1H), 7.39 (s, 1H), 5.13 (bs, 1H), 4.78 (d, 1H); AB, 2H), 4.21 (m, 1H), 3.33 (m, 2H), 2.62 (m, 1H), 1.90 (m, 1H), 1.42 (s, 9H).

G. 3- (S) -Amino-1- (4-chloro-thieno [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-2-one hydrochloride

The title compound was prepared according to the procedure in Example 1, Part I, substituting 1- (4-chloro-thieno [3,2c] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] tert-butyl ester carbamic acids for tert-butyl ester [1- (1-chloroisoquinoline-7) • 99

9 9 9 9 9 9 • 9 9 9 9 9 9

1.42

9 9 9 9 9 9

9999999 99 99 9 (9-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] carbamic acid. The title compound is obtained as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.50 (bs, 3H), 8.22 (d, 1H), 8.06 (d, 1H), 7.51 (s, 1H), 4.81 (d, 1H) AB, 2H), 4.04 (m, 2H), 3.32 (m, 2H), 2.31 (m, 1H), 1.96 (m, 1H).

Η. 7-Methoxy-naphthalene-2-sulfonic acid [1- (4-chloro-thieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure in Example 1, Part K, substituting 3-amino-1- (4-chloro-thieno [3,2c] pyridin-2-ylmethyl) -pyrrolidin-2-one for 3- (S) hydrochloride. amino-1- (1-chloro-isoquinolin-7-ylmethyl) -pyrrolidin-2-one. The title compound is obtained as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.36 (s, 1H),

8.28 (d, 1H), 8.18 (d, 1H), 8.02 (m, 2H), 7.91 (d, 1H), 7.69 (d, 1H), 7.56 ( d, 1H), 7.42 (s, 1H), 7.29 (dd, 1H), 4.66 (AB,

2H), 4.10 (m, 1H), 3.88 (s, 3H), 3.14 (m, 2H), 1.97 (m, Ifi),

1.58 (m, IH).

I. 7-Methoxynaphthalene-2-sulfonic acid [1- (4-amino-thieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure for EXAMPLE 1, Part L, substituting [1- (4-chloro-thieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S). 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S-yl) -amide] 7-methoxy-naphthalene-2-sulfonic acid 1-yl-amide. The residue was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in 11 91 9911 91.

1111911111 • 9 9 1 1 «• 9 1 · · 111 ·

111191

110 1191 11 11 11 9

143 water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized to give the title compound as a white solid.

^X H NI MR (perdeuterodimethylsulfoxide, 30 0 MH: z) δ 8.58 (ŠS, 3H), 8.32 (s, 1 H), 8.26 (d, 1H); 8.02 (d, 1H); 1H), 7.92 (d, 1H), 7.78. (Sz 1H), 7.69 (m, 2H); 7.49 (dd, 1H); 7.28 (dd, 1H), 4.62 (AB, 2H), 4.02 (m, 1H), 3.88 (s, 3H), 3.13 (m, 2H), 1.96 (m, 1H), 1.58 (m, 1 H). FAB MS, [M + H] ⁺ = 483.

Example 34 7-Methoxynaphthalene-2-sulfonic acid [1- (4-hydroxy-thieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

A. 7-Methoxynaphthalene-2-sulfonic acid [1- (4-hydroxy-thieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

The title compound was prepared according to the procedure in Example 1, part L, substituting [1- (4-chloro-thieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S). 1-yl] amide. 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide 7-methoxy-naphthalene-2-sulfonic acid. The product was reacted as described in Example 1, Part M. The residue was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1). % and trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 11.32 (bs, 1H),

8.33 (s, 1H), 8.20 (d, 1H), 8.02 (d, 1H), 7.92 (d, 1H), 7.69 β 49 44 9444 49

4 4 9 9 4 · · · · ·

144 • · ·· · ·· 4 4 4 4 44 44 44 (d, 1H), 7.52 (d, 1H), 7.46 (s, 1H), 7.30 (m, 2H), 7.19 (m, 1H), 6.71 (d, 1H), 4.52 (AB, 2H) 4.06 (m, IH), 3.88 (s, 3H); 3.10 (m, 2H) 1.90 (m, 1H), 1.50 (m, 1 H). FAB MS, [M + H] &lt; ⁺ &^gt; = 484.

Example 35 [1- (4-Amino-thieno [3,2-c] pyridin-3-ylmethyl) - trifluoroacetate. Benzo [b] thiophene-2-sulfonic acid 2-oxopyrrolidin-3 (S) -yl] -amide

A. Benzo [b] thiophene-2-sulfonic acid [1- (4-chloro-thieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure in Example 1, Part K, substituting 3-amino-1- (4-chloro-thieno [3,2c] pyridin-2-ylmethyl) -pyrrolidin-2-one for 3- (S) hydrochloride. amino-1- (1-chloro-isoquinolin-7-ylmethyl) pyrrolidin-2-one and benzo [b] thiophene-2-sulfonyl chloride with 7-methoxynaphthalene-2-sulfonyl chloride. The title compound is obtained as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.21 (d, 1H), 7.96 (s, 1H), 7.90 (m, 2H), 7.64 (d, 1H), 7.49 ( m, 2H), 7.39 (s, 1H), 5.58 (bs, 1H), 4.76 (s, 2H), 3.97 (m, 1H), 3.38 (m, 2H), 2.68 (m, 1 H), 2.18 (m, 1 H).

C. Benzo [b] thiophene-2-sulfonic acid [1- (4-amino-thieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide trifluoroacetate acid

The title compound was prepared according to the procedure for EXAMPLE 1, Part L, substituting [1- (4-chloro-thieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S). Benzo [b] thiophene-2-sulfonic acid amide] 7-methoxy-naphthalene-2- [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide sulfo ·· • · ··

145

9

9

99 new acids. The product obtained is then reacted as described in Example 1, Part M. The residue is purified by reverse phase chromatography eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1). % of trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized to give the compound. title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.70 (d, 1H), 8.55 (bs, 2H), 8.07 (m, 3H), 7.78 (s, 1H), 7.70 (s, 1H) d, 1H), 7.49 (m, 3H), 4.66 (AB, 2H), 4.16 (m, 1H), 3.24 (m, 2H), 2.12 (m, 1H), 1.72 (m, 1H). FAB MS, [M + H] ⁺ = 45.9.

Example 36

5-Pyridin-4-yl-thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

A. 4-Thiophen-2-yl-pyridine

7.6 ml (78.5 mmol) of 2-bromothiophene was added dropwise to a calcined, vacuum-dried, round-bottomed, three-necked round bottom flask equipped with a reflux condenser, a stopper and containing 2 g (82.3 mmol) of magnesium in 70 ml of diethyl ether. The resulting gray solution was heated under reflux for 1.5 hours. Meanwhile, 4-bromopyridine hydrochloride is converted into the free base as follows: 15.3 g (78.7 mmol) of 4-bromopyridine hydrochloride are dissolved in 100 ml of water and cooled in an ice bath. About 100 ml of 1N sodium hydroxide solution are added dropwise to a pH of about 5.6. The ice-cold aqueous solution is extracted three times with 150 ml of hexane and the combined organic phases are dried over magnesium sulphate and filtered. The hexane is evaporated under vacuum (1.5 kPa) with cooling in an ice bath to a volume of about 30 ml. The resulting colorless clear solution was diluted with 150 ml under nitrogen

146 tetrahydrofuran. The Grignard reagent is then cooled to room temperature and cannulated to a solution of 0.54 g (1 mmol) of NiCl ₂ dppp and 4-bromopyridine in tetrahydrofuran. The dark solution obtained is heated to boiling overnight. The reaction mixture was then poured into a saturated ammonium chloride solution and extracted three times with 200 ml of diethyl ether. The combined ether layers were acidified with 300 mL of 2N hydrochloric acid solution and the aqueous layer was washed with diethyl ether. The aqueous layer was then cooled in an ice bath and neutralized with sodium bicarbonate. The aqueous layer was extracted three times with 200 mL of ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered, and evaporated to give a brown solution. The crude solid was taken up in hot hexane and the yellow solution separated from the insoluble black solid. The hexane solution was evaporated and the procedure described above was repeated. After cooling the hexane solution, a yellow solid precipitated. The yellow solid was filtered off to give 8.99 g (55.8 mmol) of the title compound.

¹ H NMR (CDCl 3, 300 MHz) δ 8.60 (d, 2H), 7.51 (m, 1H), 7.49 (d, 2H), 7.42 (dd, 1H), 7.14 (dd, 1 H). EI MS, [M] &lt; ⁺ & gt ^; = 161.

B. 5-Pyridin-4-yl-thiophene-2-sulfonyl chloride

To a solution of 3.33 g (20.7 mmol) of 4-thiophen-2-yl-pyridine in 137 mL of tetrahydrofuran at -78 ° C was added 8.7 mL (21.7 mmol, 2.5M solution in hexane). ) n-butyllithium. After stirring for 15 minutes, sulfur dioxide gas was bubbled through the solution for 30 minutes. The solution was then allowed to warm to room temperature and stirred overnight. The solution is evaporated to dryness and the solid obtained is suspended in 100 ml of hexane. To the ice-cold solution was added sulfuryl chloride (1.7 mL, 21.7 mmol). The ice bath was removed and the suspension was stirred for 2 hours. The mixture was then evaporated to a residue.

147 dry and dilute with ethyl acetate and wash with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 3.39 g (13.1 mmol) of the title compound as a yellow solid, which was used in the next step without purification.

¹ H NMR (CDCl 3, 300 MHz) δ 8.75 (d, 2H), 8.60 (d, 1H), 7.90 (d, 1H), 7.51 (d, 2H), EI, [M] ] ⁺ = 259, 261, Cl isotopes.

C. 5-Pyridin-4-yl-thiophene-2-sulfonic acid [1- (1-chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

5-Pyridin-4-yl, -thiophene-2-sulfonyl chloride is added to 0.12 g (0.38 mmol) of 3- (S) -amino-1- (1-chloroisoquinolin-7ylmethyl) -pyrrolidine-2- hydrochloride in 2 ml of pyridine. The resulting mixture was stirred overnight and then evaporated to dryness. The residue was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 105 mg of a crude solid. The crude product was purified by column chromatography eluting with 5% methanol in dichloromethane to give 0.026 g (0.052 mmol) of the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.67 (d, 2H), 8.30 (d,

1H), 8.14 (s, 1H), 7.83 (d, 1H), 7.70 (d, J), 7.57-7.61 (m, 2H), 7.48-7.46 (m, 3H), 5.60 (bs, 1H), 4.67 (AB, <2H), 3.98 (m, 1H), 3.29 (m, 2H), 2.68. (m, 1 H), 2.15 (m, 1 H). APCI MS, [M + H] + = 499, 501, Cl isotopes.

148 • · · · · · · ·

D. 5-Pyridin-4-yl-thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

0.12 g (1.56 mmol) of ammonium acetate, 0.049 g (0.52 mmol) of phenol;

1u, and 5-pyridin-4-yl-thiophene-2-sulfonic acid [1- (1-chloroisoquinolin-7-ylmethyl) 2-oxopyrrolidin-3- (S) -yl] amide was heated to 0.026 mmol (0.052 mmol). 6 hours at 90 ° C and then cooled to room temperature. The product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized. to afford 0.005 g (0.007 mmol) of the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 13.0 (bs, 1H), 9.0 (bs, 1H), 8.60-8.70 (m, 3H), 8.29 (s, 1H), 7.91 (d, 1H), 7.89 (d, 1H), 7.71-7.80 (m, 4H), 7.66 (d, 1H), 7.23 (d, 1H) . FD MS, [M + H] ⁺ = 48 °.

Example 37

5-Pyridin-3-yl-thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

A. 3-Thiophen-2-yl-pyridine

The title compound was prepared according to the procedure described in Example 36, Part A, using 3-bromopyridine instead of 4-bromopyridine hydrochloride.

¹ H NMR (CDCl 3, 300 MHz) δ 8.89 (dd, 1H), 8.52 (dd, 1H), 7.87 (ddd, 1H), 7.38 (s, 1H), 7.36 (d 1 H, 7.31 (m, 1 H), 7.12 (dd, 1 H), EI [M] ⁺ = 161.

9

• · • 9 · · • 9 9 9 9 • · • 9 . 9 • · • 9 9 9 9 • • ·· • 9. 9 9 9 9 9 99 9 9

Β. 5-Pyridin-3-yl-thiophene-2-sulfonyl chloride

The title compound was prepared according to the procedure for EXAMPLE 36, Part B, using 3-thiophen-2-yl-pyridine instead of 4-thiophen-2-yl-pyridine.

¹ H NMR (CDCl 3, 300 MHz) δ 8.95 (bs, 1H), 8.70 (bs, 1H), 7.95 (d, 1H), 7.90 (d, 1H), 7.45 (b) ss, 1H), 7.44 (d, 1H).

EI, [M] ⁺ = 259, 261, Cl isotopes.

C. 5-Pyridin-3-yl-thiophene-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

0.35 ml. (2.5 mmol) of Triethylamine is added dropwise to a solution of 0.22 g (0.85 mmol) of 5-pyridin-3-yl-thiophene-2-sulfonyl chloride and 0.22 g (0.71 mmol) of 3- (S) hydrochloride. 1-Amino-1- (1'-chloroisoquinolin-7-ylmethyl) -pyrrolidin-2-one in 5 mL of acetonitrile. The suspension was stirred at room temperature overnight and evaporated to dryness. The residue was diluted with dichloromethane and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, filtered, evaporated and then purified by column chromatography eluting with a gradient of 1% methanol in dichloromethane to 5% methanol in dichloromethane to give 0.23 g (0.45 mmol) of product. as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.89 (d, 1H), 8.63 (dd,

ÍH), 8.30 (d, ÍH), 8.13 (d, 1H), 7.82-7.89 (m, 2H), 7.70 (d, ÍH), 7.57 -7.68 (m, 2H), 7.33-7.40 (m, 2H), 5.45 (d, 1H, 4.67 (AB, 2H), 3.95 . (m ΊΗ), 3.28 (m, 2H); 2.75 (m, 1H), 2.10 (m, ÍH). Ion: spray MS, [M + H] ⁺ = 499, 501, Cl isotopes.

D. 5-Pyridin-3-yl-thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

9

9 · · 9 ·

150 «9 • · 9

9 • ·· 99

The title compound was prepared according to the procedure described in Example 36, part D. using 5-pyridin-3-yl-thiophene-2-sulfonic acid [1- (1-chloro-isoquinolin-7ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide instead of [1- (1- 5-Pyridin-4-yl-thiophene-2-sulfonic acid chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide and heated at 100 ° C overnight. The crude product was purified by reverse phase HPLC eluting with a mixture of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 100% acetonitrile. The appropriate product-containing fractions were lyophilized to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 12.95 (bs, IH),

8.90-9.05 (m, 2H), 8,55- 8.65 (m, 2H) 8.31 (with, IH), 8.17 (m, 1H), 8.96 (d, IH), 8.82 (d, 1H), 7.70 -7.72 (m, 2H), 7.65 (d, 1H), 7.53 (dd, IH), 7.21 (d, 1H), 4.60 (AB, 2H), 4.30 (m, IH),

3.25 (m, 2H), 2.29 (m, 1H), 1.78 (m, 1H). FAB MS, [M + H] &lt; ⁺ &^gt; = 480.

Example 38

Benzothiophene-2-sulfonic acid [1- (4-aminoquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3 - (S) -yl] -amide trifluoroacetate

A. 4-Chloro-6-methylquinoline

6-Methyl- (1 H) -quinolin-4-one (1.57 g, 9.7 mmol) in 20 ml of phosphorus oxychloride was heated at 110 ° C for 4 hours. The mixture was cooled to room temperature, then diluted with 200 ml of ice water and adjusted to pH 10 with 10N sodium hydroxide solution. The aqueous solution was extracted four times with 250 ml of dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporate. The crude residue was filtered through silica gel, eluting with 33% EtOAc (151)

4 4 · 4 4 4 4 4

44 4,444 4 4

4 4 4 4 4 5

44 44 4 444 m.p. in hexane to give 1.05 g (5.9 mmol) of the title compound as a yellow solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.69, (d, 1H), 8.0 (m,

2H), 7.58 (dd, 1H), 7.44 (d, 1H), 2.58 (s, 3H). EI MS, [M] &lt; ⁺ &^gt;

177, 179, Cl isotopes.

B. 6-Bromomethyl-4-chloroquinoline

1.1 g (6.19 mmol) of N-bromosuccinimide and 0.215 g (0.62 mmol) of 70% benzoyl chloride are added to a solution of 1.05 g (5.93 mmol) of 4-chloro-6-methylquinoline in 35 ml of carbon tetrachloride. The resulting mixture was heated at reflux overnight, then cooled to room temperature and diluted with dichloromethane. The organic layer was washed with 1N sodium hydroxide solution, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with 33% ethyl acetate in hexane to give 0.915 g (3.57 mmol) of the product as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.73 (d, 1H), 8.13 (d,

1H), 8.07 (d, 1H), 7.74 (dd, 1H), 7.42 (d, 1H), 4.67 (s, 2H). Ion Spray, [M + H] ⁺ = 2556, 25-8,260 Cl, Br isotopes.

C. 3- (S) -Amino-1- (4-chloroquinolin-6-ylmethyl) pyrrolidin-2-one hydrochloride. _with

0.096 g (2.4 mmol, 60% dispersion in mineral oil) of sodium hydride is added to a solution of 0.4 g (2 mmol) of [2-oxopyrrolidin-3- (S) -yl] carbamic acid tert-butyl ester at 0 ° C. of acid in 15 ml of tetrahydrofuran. The mixture was stirred for 30 minutes and then stirred. a solution of 0.513 g (2 mmol) of 6-bromomethyl-4-chloroquinoline in 15 ml of tetrahydrofuran was slowly added. The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, then ethyl acetate. Organic

The layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was dissolved in 50 ml of ethyl acetate and saturated with hydrogen chloride gas at 0 ° C. Solution, se. The mixture was stirred at 0 ° C for 15 minutes, then warmed to room temperature. After 4 hours at room temperature, the precipitated solid was filtered and washed with ether to give 0.445 g (1.43 mmol) of the title compound as a light yellow solid. - ...

@ ¹ H NMR (CDCl3, 300 MHz) .delta. 9.05 (d, 1H);

8.78 (bs, 3H), 8.27 (d, 1H), 8.23 (s, 1H), 8.02 (d, 1H), 7.96 (d, 1H), 4.67 (AB) 4.12 (m, 1H); 3.35 (m, 2H); 2.43 (m, 1H); (m, 1 H). Ion Spray MS, [M + H] &lt; ⁺ &^gt; = 276, 278.

D. Benzothiophene-2-sulfonic acid [1- (4-chloroquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

0.12 g (0.38 mmol) of 3- (S) -amino-1- (4-chloroquinolin-6-ylmethyl) -pyrrolidin-2-one hydrochloride is suspended in 15 ml of acetonitrile. To this solution was added 110 mL (0.79 mmol) of triethylamine followed by 0.094 g (0.40 mmol) of benzothiophene-2-sulfonyl chloride. The mixture was stirred overnight at room temperature, the aqueous was worked up and then evaporated to dryness. The crude product is purified by column chromatography eluting with mixtures. 2-10% methanol in dichloromethane to give 0.11 g (0.23 mmol) of the title compound as an off-white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.77 (d, 1H), 8.08 (d,

1H), 8.04 (with, 1H), 7.97 (with, 1H), 7.88 (m, 2H) 7.58 (dd, 1H), 7.49 (m, 3H), 6.01 (šs, 1H), 4.67 (AB, 2Ή), 4.03 (t, 1H), 3.27 (m, 2H) 2.65 (m, 1H), 2.16 (m, 1 H). FAB MS, [M + H] &lt; ⁺ &^gt; 4 7-2, 474,

Cl · isotopes.

• · · 0 · 9> 0 0 0 0 0 »0. · »· ·

153 • · · · ·

E. Benzothiophene-2-sulfonic acid [1- (4-aminoquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

0.11 g (0.23 mmol) of benzothiophene-2-sulfonic acid [1- (4-chloroquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3 - (S) -yl] -amide is treated with 1 g of phenol and 0.22 g (2.8 mmol) of ammonium acetate at 110 ° C as described above. After 5 hours, the reaction mixture was cooled to room temperature and diluted with 100 mL of dichloromethane. The organic solution was washed twice with 1N sodium hydroxide solution and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by HPLC eluting with a gradient of 10 to 100% acetonitrile / 0.1. % trifluoroacetic acid over 30 minutes. Product containing fractions were lyophilized to afford 0.02 g (0.044 mmol) of the title compound as a white solid.

¹ H NMR (deuteromethanol, 300 MHz) δ 8.25 (d, 1H), 8.13 (with, 1H), 7.97 (s, 1H); 7.85 (m, 2H), 7.80 (AB, 2H). 7.48 (m, 2H), 6.80 (d, 1H). 4.64 (s, 2H). 4.35 (t, 1H), 3.31 (m, 2H), 2.48 (m,

1H), 1.89 (m, 1H). Ion Spray MS, [M + H] &lt; ⁺ &^gt; = 453.

Example 39 6-Chloro-benzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (1-amino-isoquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

A. 1-Phenoxy-6-bromomethyl-isoquinoline

To 2.28 g (13.3 mmol) of 1-chloro-6-methyl-isoquinoline, prepared according to the procedure described in Example 1, part E, by replacing 6-methyl-2H-isoquinolin-1-one with 7- methyl-2H-isoquinolin-1-one, 20 g of phenol are added. The solution was heated to 80 ° C and potassium hydroxide (3.73 g, 66.4 mmol) was added. After the addition, the solution was stirred and heated to 140 ° C. After 24 hours, the solution was stirred

154 was cooled to room temperature and dissolved in dichloromethane. The organic solution was washed with water. The organic layer was washed with 1N sodium hydroxide solution and saturated sodium chloride solution, the organic layer was dried over magnesium sulfate, filtered and evaporated. The residue is dissolved in 50 ml of carbon tetrachloride. 2.01 g (11.27 mmol) of NBS and 0.6 g (1.73 mmol) of benzoyl peroxide are added to the obtained solution. The solution was heated to reflux. After 16 hours, dilute the solution with dichloromethane. The organic layer was washed with 10% sodium carbonate solution and saturated sodium chloride solution. The organic layer was dried with magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with 5% ethyl acetate in hexane and 10% ethyl acetate in hexane.

MS, [M]

313, 315, Br isotopes.

B. [1- (1-Chloro-isoquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -carbamic acid benzyl ester

To a solution of 0.15 g (0.64 mmol) of (2-oxopyrrolidin-3 (S) -yl) -carbamic acid benzyl ester in 6 ml of a 10: 1 mixture of tetrahydrofuran and dimethylformamide is added at 0 ° C 0.03 g (0, 71 mmol) of a 60% dispersion of sodium hydride in mineral oil and then 0.2 g (0.64 mmol) of 1-phenoxy-6-bromomethyl-isoquinoline. After 16 hours, the solution was treated with 10 mL of saturated ammonium chloride solution. The solution was diluted with dichloromethane. The organic layer was washed with water and saturated sodium chloride solution. The product obtained is suspended in 5 g of ammonium acetate and heated to 120 ° C. After 36 hours, the solution was cooled to room temperature. The solution was diluted with water and dichloromethane. the organic layer was washed with water and saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and evaporated

9 · ···· · · · · ······

GB GB · 9 9 9 9 ♦ - ····

133 · 9999999

9 9 999 9 9 9 9 99 99 The residue was purified by column chromatography eluting with 5% methanol in dichloromethane to 10% methanol in dichloromethane to give 0.043 g (0.11 mmol) of the product as a white solid.

¹ H, NMR (CDCl 3, 300 MHz) δ 8.41 (d, 1H), 7.98 (d, 1H), 7.63 (s, 1H), 7.42 (m, (3H), 7.32 (m, 4H), 7.22 (m, 5H), 5.40 (bs, 1H), 5.14 (s, 2H) , 4.64 (AB, 2H), 4.30 (τη, IH) 3.24

(m, 2H), 2.66 (m, 1H). 1.92 (m, 1H). FAB MS, [M + H] &lt; ⁺ &^gt; = 391.

C. 6-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide trifluoroacetate.

To a solution of 0.043 g (0.11 mmol) of [1- (1-chloro-isoquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -carbamic acid benzyl ester in 4 mL of methanol is added 0.02 g of 10 % palladium on coal. The atmosphere in the reaction mixture is exchanged for hydrogen. After 16 hours, the solution was filtered through Celite and the Celite was washed with methanol. The filtrate was evaporated. The residue was dissolved in 3 ml of a 2: 1 mixture of dichloromethane and ethanol. To the solution were added 0.01 g (0.11 mmol) of triethylamine and 0.03 g (0.11 mmol) of 6-chlorobenzo [b] thiophenesulfonyl chloride. After. The solution was evaporated for 4 hours. The residue was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1% trifluoroacetic acid). The appropriate product-containing fractions were lyophilized to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.95 (bs, 3H),

8.71 (d, IH), 8.46 (d, IH), 8.24 (with, IH), 8.04 (m, 2H), 7.71 (WITH, IH), 7.63 (d, IH), 7.52 (m, 2H), 7.12 (d, IH), 4.52 (AB, 2H), 4.28 (m, IH), 3.17 (m, 2H), 2.12 (m, IH), 1.67 (m, IH).

FAB MS, [M + H] ⁺ = 487, 489, Cl isotopes.

156

Example 40 6-Chloro-benzo [b] thiophene-2-sulfonic acid [2-oxo-1- (1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl) -pyrrolidin-3- (S) -yl] -amide trifluoroacetate acid

A. [1- (1,2,3,4-Tetrahydro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -carbamic acid tert-butyl ester

To a solution of [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -carbamic acid 0.48 g (1.28 mmol). of acid in 50 ml of a 1: 1 mixture of acetic acid and methanol is added 0.1 g of 5% palladium on carbon. The atmosphere above the reaction mixture was replaced with hydrogen. After 16 hours, the solution was filtered through Celite and the Celite was washed with methanol. The organic solution was evaporated to give the product as a white foam.

MS, [M + H] &lt; ⁺ &^gt; = 346.

B. 7- (3-tert-Butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester

To a solution of [1- (1- (1,2,3,4-Tetrahydro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -carbamic acid tert-butyl ester (0.54 g, 1.58 mmol) 0.66 ml (4.73 mmol) of triethylamine and 0.39 ml (1.89 mmol) of benzyl chloroformate were added in 50 ml of dichloromethane, the solution was stirred for 16 hours, then the solution was diluted with dichloromethane and the organic solution was washed with water and saturated aq. The residue was purified by column chromatography eluting with 20% ethyl acetate in dichloromethane.

^X H NMR (CDCl₃, 300 MHz) δ 7.35 (m, 5H), 7.08 (d, IH), 7.02 (d, 1H), 6.95 (s, 1H), 5.14 (with, 2H), 5.10 (m, IH), 4.58 (S, 2H) 4.38 (m, 2H); 4.16 (m, IH), 3.68 (m, 2H), 3.18

• flfl ···················································

- | r- · ················· (dd, 2H), 2.78 (m, 2H) 2.59 (tn, 1H), 1.81 (m, 1H), 1.42 (s,

9H).

FAB MS, [M + H] &lt; ⁺ &^gt;

C. 7- [3- (6-Chloro-benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester

To a solution of 0.347 g (0.72 mmol) of 7- (3-tert-butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester in 8 mL of dichloromethane was added 2 ml of trifluoroacetic acid. After 4 hours the solution was evaporated. The residue was dissolved in dichloromethane and 0.30 mL (2.17 mmol) of triethylamine and 0.23 g (0.87 mmol) of 6-chlorobenzo [b] thiophenesulfonyl chloride were added. After 16 hours, the solution was evaporated. The residue was purified by column chromatography eluting with 10% ethyl acetate in dichloromethane. 0.25 g (0.51 mmol) of product is obtained in the form of a white solid.

^X H NMR (CDCl₃, 300 MHz) δ 7.91 (with, 1H), 7.80 (m, 2H), 7.42 (d, 1H), 7.34 (m, 5H), 7.08 (d, ΙΗ), 6.96 (d, 1H), 6.88 (s, 1H); 5.10 (s, 2H); 4.58 (s, 1H); 2H), 4.34 (s, 2H) 3.88 (m, 1H), 3.68 (m, 2H), 3.18 (m, 2H), 2.77 (m, 2H), 2.59 (m,

1 H), 2.08 (m, 1 H).

D. 6-Chlorobenzo [b] thiophene-2-sulfonic acid [2-oxo-1- (1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl) -pyrrolidin-3- (S) -yl] -amide trifluoroacetate

0.25 g (0.51 mmol) of 7- [3- (6-chloro-benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester of the acid is added to 5 ml of 30% hydrogen bromide in acetic acid at 0 ° C. The solution was stirred for 30 minutes. 30 ml of diethyl ether are then added. The solid obtained is from »« ····

158 filters. The crude solid was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1% trifluoroacetic acid). The appropriate product-containing fractions were lyophilized to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.95 (bs, 2H), 868 (d, 1H), 8.24 (s, 1H), 8.00 (m, 2H), 7.51 (dd, 1H), 7.16 (d, 1H), 7.06 (m, 1H), 6.96 (s, 1H), 4.27 (s, 2H), 4.16 (m, 3H), 3 30 (m, 2H), 3.05 (m, 2H), 2.92 (m, 2H), 2.08 (m, 1H),

1.60 (m, 1H). FAB MS, [M + H] ⁺ = 476, 478, chlorine isotopes.

Example 41 6-Chloro-benzo [b] thiophene- [1- (4-chloro-1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide 2-sulfonic acids

A. 1-Benzenesulfonyl-4-chloro-1H-pyrrolo [3,2-c] pyridine ml (23.5 mmol) Benzenesulfonyl chloride was added dropwise to a solution of 0.53 g (1.56 mmol) of tetrabutylammonium hydrogen sulfate, 1.56 g ( 38.9 mmol) of sodium hydroxide and 2.38 g (15.6 mmol) of 4-chloro-1H-pyrrolo [3,2-c] pyridine (prepared according to the procedure described in Rasmussen, MJ Het. Chem, 1992, 29, 359) in dichloromethane.

The mixture was stirred at room temperature for 4 hours, diluted with dichloromethane and washed with saturated ammonium chloride solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with 1% methanol in dichloromethane to 2% methanol in dichloromethane to afford 3.21 g (11 mmol) of the product as a white solid.

·· ♦ * ···· · · ·

9 ·

9 ·

9 9 ·

99, ··

159:

··· ¹ H NMR (CDCl 3, 300 MHz) δ 8.25 ΙΗ), 7.90 (d, 1H), 7.83 (dd, 1H), 7.60-7.66

2H), 6.80 (dd, IH). EI MS, [M] ⁺ = 292, 294, Cl (d, 1H), 7.92 (m, (m, 2H), 7.51 (m, isotopes).

B. 1-Benzenesulfonyl-4-chloro-1H-pyrrolo [3,2-c] pyridine-2-carboxylic acid ethyl ester

Lithium diisopropylamide (3.2 mL, 4.80 mmol, 1.5 M in tetrahydrofuran) was added to a solution of 0.71 mL (4.75 mmol) of tetramethylethylenediamine and 1 g (3.42 mmol) of 1-benzenesulfonyl-4-chloro-1H- pyrrolo [3,2-c] pyridine in 13 mL of tetrahydrofuran. The resulting yellow solution was stirred at -78 ° C for 1 hour and then 0.78 ml (8.16 mmol) of ethyl chloroformate was added dropwise. The mixture was allowed to warm slowly to room temperature over 3.5 hours. The reaction was quenched with saturated ammonium chloride solution and then diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give 1.46 g of a light brown solid, which was used in the next step without purification.

^X H NMR (CDCl₃, 300 MHz) δ 8.30 (d, 1H), 8.12 ^(d!.

2H), 8.03 (d, 1H), 7.70 (m, 1H), 7.55 (m, 2H), 7.30 (s, 1H). 4.45 (qu, 2H), 1.46 (t, 3H). FAB MS, [M + H] ⁺ = 365, 367, Cl isotopes.

C. 1-Benzenesulfonyl-4-chloro-1H-pyrrolo [3,2-c] pyridin-2-yl) -methanol

3.4 ml (1M solution in tetrahydrofuran) of lithium aluminum hydride is added dropwise at 0 ° C to a solution of 1.46 g (3.42 mmol) of 1-benzenesulfonyl-4-chloro-1H-pyrrolo [3,2-o] pyridine- ethyl ester. Of 2-carboxylic acid in 27 ml of tetrahydrofuran. After stirring at 0 ° C for 1.5 h, the reaction was quenched with water, then diluted with ethyl acetate. The organic layer was washed with saturated sodium ·· ·· «* · ·· ·· ·« · • ···· ···· · · · _Λ ~ "9 9 · · · <···

ISO ammonium chloride and brine, then dried over magnesium sulphate, filtered and evaporated. The crude product was purified by column chromatography eluting with a gradient of 1% methanol in dichloromethane to 3% methanol in dichloromethane to give 0.78 g (2.42 mmol) of the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.25 (d, 1H),. 8.85-8.95 (m, 3H), 7.64 (m, 1H), 7.51 (m, 2H), 6.80 (s, 1H), 4.97 (d, 2H), 2 85 (t, 1 H). EI MS, [M] ⁺ = 322, 324, Cl isotopes.

D. 1-Benzenesulfonyl-2-bromomethyl-4-chloro-1H-pyrrolo [3,2-c] pyridine

0.939 g (2.83 mmol) of tetrabromomethane was added to a solution of 1.485 g (5.66 mmol) of triphenylphosphine and 0.914 g (2.83 mmol) of 1-benzenesulfonyl-4-chloro-1H-pyrrolo [3,2-a] at 0 ° C. -c] pyridin-2-yl-1-methanol in 12 mL of dichloromethane. The resulting yellow solution was stirred at 0 ° C for 1 hour, then warmed to room temperature over 1 hour. The reaction mixture was evaporated then purified by column chromatography eluting with 1% methanol in dichloromethane to give 0.760 g (1.97 mmol) of the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.27 (d, 1H), 7.91-8.00 (m, 3H), 7.67 (m, 1H), 7.51 (m, 2H) 6.95 (s, 1H); 4.94 (s,

2H). FAB MS, [M + H] ⁺ = 385, 387, 389, Br, Cl isotopes.

E. [1- (1-Benzenesulfonyl-4-chloro-1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] carbamic acid tert-butyl ester

0.081 g (2.02 mmol, 60% dispersion in mineral oil) of sodium hydride was added to a solution of 0.404 g (2.02 mmol) of [2-oxopyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester at 0 ° C. v 5 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · then then with mmol 1-Benzene161: · ml of dimethylformamide. The mixture was stirred for 10 minutes, cannula was added dropwise at 0 ° C to a solution of 0.74 g (1.92 sulfonyl-2-bromomethyl-4-chloro-1H-pyrrolo [3,2-c] pyridine in 10 mL of dimethylformamide). the solution was stirred for 1 hour at 0 ° C, then quenched with saturated ammonium chloride solution and diluted with ethyl acetate.The organic layer was washed with water and brine, then dried over magnesium sulfate, filtered and evaporated to give 0.94 g (1, 86 mmol) of solid product, which was used in the next step without purification.

¹ H NMR (CDCl 3, 300 MHz) δ 8.25 (d, 1H), 7.98 (m,

2H), 7.83 (d, 1H), 7.68 (m, 1H), 7.50 (m, 2H), 6.70 (s, 1H), 4.95 (AB, 2H) ·, 4 20 (m, 1H); 3.55 (m, 2H); 2.65 (m, 1H); 2.03 (m, 1H); 1.45 (s, 9H). FAB MS, [M + H] ⁺ = 505, 507, Cl isotopes.

F. 3- (S) -Amino-1- (1-benzenesulfonyl-4-chloro-1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-2-one hydrochloride

The title compound was prepared according to the procedure for EXAMPLE 1, Part I, using [1- (1-benzenesulfonyl-4-chloro-1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) - tert -butyl ester - 2oxopyrrolidin-3- (S) -yl] carbamic acid in place of [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3 (S) -yl] carbamic acid tert-butyl ester and after stirring for 2 hours at room temperature 0 ° C without warming to room temperature.

¹ H NMR (CDCl 3, 300 MHz) δ 8.50 (d, 1H), _s 8.2 8 (d, 1H), 8.04 (m, 2H), 7.82 (m, 1H), 7.65. (m, 2H), 6.83 (s, 1H), 4.93 (s, 2H), 4.20 (m, 1H), 3.51 (m, 2H), 2.41 (m, 1 H), 2.01

(m, 1 H). FAB MS, [M + H] ⁺ = 405, 407, Cl isotopes.

G. 6-Chloro-benzo [b- (1-benzenesulfonyl-4-chloro-1H-pyrrolo [3,2c] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide [b ] thiophene-2-sulfonic acids 0 · 0 · 0 · 0 · · · · · 00 0> 0 * 0 000 _Ί 0 000 · ···· ·

162 ··············································

The title compound was prepared according to the procedure for EXAMPLE 1, Part K, using 6-chloro-benzo [b] thiophene-2-sulfonyl chloride and 3-amino-1- (1-benzenesulfonyl-4-chloro-1H-pyrrolo [3, 4-chloro] hydrochloride). 2-c] pyridin-2-ylmethyl) pyrrolidin-2-one starting materials. The crude product was purified by column chromatography eluting with a gradient of 1% methanol in dichloromethane to 3% methanol in dichloromethane to give the product as a white solid.

¹ H NMR (CDCl 3, 300 MHz)? MHz) δ 8.23 (d, IH) 7.96 (d, ÍH), 7.90 (s, 1H), 7.70-7.7.88 (m, 3 H), 7,55-7,61 (m, 2H), 7,40- 7.50 (m, 3H), 6.51 (s, 1H) , 5, 45 (šs, 1H), 4.86 (with, 2H), 3.98 (m, 1H), 3.41 (m, 2H), 2.70 (m, IH), 2, 18 (m, lH)

FAB MS, [M + H] ⁺ = 635, 637, Cl isotopes.

Η. 6-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (4-chloro-1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide acid

Ammonia gas was bubbled through a solution of 0.14 g (0.22 mmol) of [1- (1-benzenesulfonyl-4-chloro-1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -2-oxopyrrolidin-3-one for 5 minutes. 6-Chlorobenzo [b] thiophene-2-sulfonic acid (S) -yl] amide in 10 mL of methanol. The solution was heated at reflux overnight and then evaporated to dryness. The crude product was purified by column chromatography eluting with 5% methanol in dichloromethane to give 0.065 g (0.13 mmol) of the title compound as a white solid. ¹ H NMR (CDCl 3, 300 MHz) δ 11.95 (bs, 1H), 8.71 (d, 1H) ', 8.30 (s, 1H), 8.05 (m, 1H), 7.91 (d, 1H), 7.50 (d, 1H), 7.35 (d, 1H), 6.40 (s, 1H), 4.50 (AB, 2H), 4.23 (m, • ·

163

ΦΦ • φ

(H), 3.23m, 2Η), 2.41 (Μ, 1Η), 1.78 (m, 1Η)

Φ Φ. · · Φ φ φ • • • • • • • φ φ · · ^{1 1}

Ion spray MS, [Μ + Η] ⁺ = 495, 497, Cl isotopes.

Example 42 6-Chlorobenzo [b] thiophene-2-sulfonic acid [2-oxo-1- (6-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide

0.1 g of palladium on carbon is added to a solution of [1- (4-chloro-1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide 6-chloro-benzo [b] thiophene-2-sulfonic acid in 5 mL of 95% ethanol and filled with hydrogen gas. The mixture was heated at 65 ° C overnight, then cooled to room temperature and filtered through diatomaceous earth. The solvent was evaporated in vacuo and the crude product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 100% acetonitrile. The appropriate product-containing fractions were lyophilized to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 14.60 (bs, IH), 12.70 (bs, IH), 9.15 (s, IH), 8.71 (d, IH), 8> 38 ( d, 1H), 8.29 (s, IH), 8.08 (s, IH), 8.00 (d, IH), 7.85 (d, IH), 7.52 (dd, 1H,

1H), 6.88 (s, 1H), 4.63 (AB, 2H), 4.21 (m, 1H), 3.25 (m, 2H),

2.10 (m, 1H), 1.75 (m, 1H). Ion spray MS, [M + H] ⁺ = 461, 463, Cl isotopes.

Example 43 7-Methoxy-naphthalene-2-sulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-b] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide trifluoroacetate

A. 5-Chloro-1H-pyrrolo [3,2-b] pyridine

A mixture of 1.33 g (9.91 mmol) of pyrrolo [3,2-b] pyrid-5-one (prepared according to the procedure described in J. Med Chem. 1990, 33, 2087) and 20. 1 Z “Λ ♦ * · · ·

Io4 4 9 ·· »· 4 4 4

4.4 99 4 9 4 4 4 4 4 9 444 ml of phosphorus oxychloride are heated in a sealed Parr stainless steel apparatus at 180 ° C for 2.5 hours. After cooling, the excess phosphorus oxychloride is removed in vacuo. The residue was cooled in an ice bath and quenched with water. The resulting mixture was neutralized by addition of saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. 1.07 g (7.01 mmol) of crude product was obtained, which was used in the next step without purification.

¹ H NMR (CDCl 3, CDCl 3, 300 MHz) δ 7.71 (d, 1H), 7.49 (d, 1H), 7.10 (d, 1H), 6.59 (d, 1H) ... EI MS, [M] &lt; ⁺ &^gt;

152, 154, Cl isotopes.

B. 1-Benzenesulfonyl-5-chloro-1H-pyrrolo [3,2-b] pyridine

The title compound was prepared from 5-chloro-1H-pyrrolo [3,2-b] pyridine according to the procedure described in Example 41, part A. The crude product was purified by column chromatography eluting with a gradient of 10% ethyl acetate in hexane to 20%. % ethyl acetate in hexane to give the title compound as a solid.

^X H NMR (CDCl₃, 300 MHz) δ 8.23 (d, 1Ή), 7.87 (d, 2Ή), 7.81 (d, H), 7.62 (m, H), 7.49 ( m, 2H), 7.26 (d, 1H), 6.81 (d, 1H).

C. 1-Benzenesulfonyl-5-chloro-1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid ethyl ester

The title compound was prepared from 1-benzenesulfonyl-5-chloro-1H-pyrrolo [3,2-b] pyridine according to the procedure described in Example 41, part B. The crude product was purified by column chromatography eluting with a gradient of 10% ethyl acetate. · · · · ·

165 «β β β β β β β β β β β β β β.

• ·

In hexane to 33% ethyl acetate in hexane to give the title compound as a solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.41 (d, 1H), 8.04 (d,

2H), 7.66 (m, 1H), 7.55 (m, 2H), 7.37 (d, 1H), 7.21 (s, 1H), 4/41 (kv, 2H), 1, 40 (t, 3 H). EI MS, [M] ⁺ = 364, 366, Cl isotopes.

D. (1-Benzenesulfonyl-5-chloro-1H-pyrrolo [3,2-b] pyridin-2-yl) methanol. .

The title compound was prepared from 1-benzenesulfonyl-5-chloro-1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid ethyl ester according to the procedure described in Example 1, Part C. The crude product was purified by column chromatography. eluting with a gradient of 20% ethyl acetate in hexane to 50% ethyl acetate in hexane to give the title compound as a solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.30 (d, 1H), 7.81 (d, 2H), 7.63 (m, 1H), 7.50 (m, 2H), 7.25 ( d, 1H), 6.80 (s, 1H), 4.97 (s, 2H), 2.99 (bs, 1H). EI MS, [M] ⁺ = 322, 324, Cl isotopes.

E. 1-Benzenesulfonyl-2-bromomethyl-5-chloro-1H-pyrrolo [3,2-b] pyridine

To a solution of 0.16 g (0.50 mmol) of (1-benzenesulfonyl-5-chloro-1H-pyrrolo [3,2-b] pyridin-2-yl) -methanol in a mixture of 4 mL of ethyl ether and dichloromethane (1: 1) 0.023 ml (0.25 mmol) of phosphorus tribromide was added dropwise at 0 ° C. The reaction vessel was kept in the dark and stirred at 0 ° C for 1 hour, then at room temperature for 2 hours. The mixture was diluted with water and ethyl acetate and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, saturated aqueous sodium bicarbonate solution and saturated ammonium chloride solution, then dried over magnesium sulfate, filtered and evaporated. 0.16 g is obtained

9-1999 (0.41 mmol) of crude product, which was used without purification in the next step.

¹ H NMR (CDCl 3, 300 MHz) δ 8.33 (d, 1H); 7.8.7 (d;

2H), 7.64 (m, 1H), 7.50 (m, 2H), 7.28 (d, 1H), 6.93 (s, 1H),

4.96 (s, 2 H).

F. [1- (1-Benzenesulfonyl-5-chloro-1H-pyrrolo [3,2b] pyridin-2-ylmethyl) -2-oxopyrrolidin-3- (S) -ylcarbamic acid t-butyl ester

The title compound is prepared from (2-oxopyrrolidin-3- (S) -yl) -carbamic acid t-butyl ester as described in Example 1, Part H, but 1- (7-bromomethyl-1-chloroisoquinoline) is substituted with 1- benzenesulfonyl-2-bromomethyl-5-chloro-1H-pyrrolo [3,2-b] pyridine. The crude product is purified by chromatography on silica gel with a gradient of 15% ethyl acetate in hexane to 50% ethyl acetate in hexane. This gives the title compound of m.p.

beige solid. ¹ H NMR (CDCl ₃ , , 300 MHz) δ 8.36 (d, IH) 7.80 (d, 2H); 7.64 (m, 1H), 7.50 (m, 2H), 7.25 (s, 1H), 6.58 (s, 1H), 5.13 (SS, IH), 4.93 (AB, 2H) 4.22 (m, 1H); 3.39 (m, 2H), 2.66 (m, 1H); 1.95

(m, 1H), 1.46 (s, 9H).

G. 3- (S) -Amino-1- (1-benzenesulfonyl-5-chloro-1H-pyrrolo [3,2-b] pyridin-2-ylmethyl) -pyrrolidin-2-one hydrochloride

The title compound was prepared as described in Example 1, part I. [1- (1-Benzenesulfonyl-5-chloro-1H-pyrrolo [3,2-b]] t-butyl ester was used as starting material. pyridin-2-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid. The title compound is obtained as a white solid.

• • 0 · · · · · 0 • 0 0 9 9 9 9 9 · β β 0 0 0 9 0 0 9 9 ^{Χ Η} NMR (DMSO-d₆, 300 MHz) δ 8.51 (bs, 2H);

8.42 (d, 1H), 8.00 (d, 2H), 7.78 (m, 1H), 7.64 (m, 2H) 7.41 (d, 1H), 6.96 (with, 1H), 4.90 (AB, 2H), 4.16 (m, 1H), 3.49 (m, 2H), 2.47 (m, 1H), 2.10 (m, 1H).

Η. 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-benzenesulfonyl-5-chloro-1H-pyrrolo [3,2-b] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure for EXAMPLE 1, Part K, using 7-methoxy-naphthalene-2-sulfonyl chloride and 3- (S) -amino-1- (1-benzenesulfonyl-5-chloro-1H-pyrrolo [3] -hydrochloride). (2-b] pyridin-2-ylmethyl) pyrrolidin-2-one starting materials. The crude product was used in the next step without purification:

^X H NMR (CDCl₃, 300 MHz) δ 8.3 7 (with, 1H), 8.34 (d, 1H), 7.92 (d, 1H), 7.79 (m, 2H), 7.72 (m, 2H), 7.58 (m, 1H), 7.45 (m, 2H) 7.31 (dd, 1 H), 7.24 (m, 2H), 6.48 (with, 1H), 5.42 (with, 1H), 4.85 (s, 2H), 3.96 (s, 3H), 3.76 (m, 1H), 3.34 (m,

2H), 2.63 (m, 1H), 2.10 (m, 1H).

I. 7-Methoxy-naphthalene-2-sulfonic acid [1- (5-chloro-1H-pyrrolo [3,2-b] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound is prepared from [1- (1-benzenesulfonyl-5-chloro-1H-pyrrolo [3,2-b] pyridin-2-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide 7-Methoxynaphthalene-2-sulfonic acid according to the procedure described in Example 41, part H. The crude product was purified by column chromatography eluting with a gradient of 1% methanol in dichloromethane to 6%. methanol in dichloromethane to give the title compound as a solid.

• »· · · · · ^X • H NMR (CDCl, 300 MHz) δ 9.73 (bs, 1H), 8.35 (s,

1H), 7.70 (m, 3H), 7.49 (d, 1H),. 7,3 0 (dd, 1H), 7.20 (m, IH), 6.99 (d, 1H), 6.75 (ŠS, 1H), 6.48 (with, 1H), 4.58 (m, 2H), 3.93 (m, 1H), 3, 90 (with, 3H), 3.35 (m, 2H), 2.48 (m, 1H), 2.08 (m,

1H).

J. 7-Methoxynaphthalene-2-sulfonic acid [1-oxo-1- (1H-pyrrolo [3,2-b] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide trifluoroacetate.

The title compound was prepared from 7-methoxy-naphthalene- [1- (5-chloro-1H-pyrrolo [3,2-b] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide. 2-sulfonic acids according to the procedure described in Example 42, at room temperature using a catalytic amount of potassium hydroxide in a mixture of methanol and benzene

(1: : 1) instead of ethanol as solvents. Crude product se cleans by HPLC on reverse phase eluting with a gradient of the mixture 10 % acetonitrile in water (0.1% acid trifluoroacetic) to 70 % acetonitrile in water (0.1% acid trifluoroacetic) and

respectively, the fractions containing the product are lyophilized to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 12.65 (bs, 1H), 8.60 (bs, 1H), 8. 43 (d, 1H), 8.39 (s, 1H), 8, 26 (d, 1H), 8.03 (d, 1H), 7.94 (d, 1H), 7.71 (dd, 1H), 7.56 (m, 2H), 7.32 (dd, 1H),

1H), 6.80 (s, 1H), 4.66 (AB, 2H), 4.17 (m, 1H), 3.88 (s, 3H),

3.20 (m, 2H), 2.00 (m, 1H), 1.60 (m, 1H). FAB MS, [M + H] &lt; ⁺ &^gt; = 451.

Example 44 6-Chloro-benzo [b] thiophene-2-sulfonic acid 1-fluoro [3,2-b] pyridin-2-ylmethyl-2-oxo-pyrrolidin-3- (S) -yl) -amide

A. [2-Oxo-1-prop-2-ynyl-pyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester

169

The title compound was prepared from (2-oxopyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester according to the procedure described in Example 1, Part H, using propargyl bromide instead of 7-bromomethyl-1-chloroisoquinoline. The crude product was triturated from diethyl ether / hexane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 5.09 (bs, 1H), 4.15 (m, 2H), 3.45 (m, 2H), 2.69 (m, 1H),

1.91 (m, 1H); 1.48 (s, 9H).

1H), 4.19 (m,

2.29 (t, 1 H),

B. (1-Furo [3,2-b] pyridin-2-ylmethyl-2-okopyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester

A mixture of 0.44 g (2 mmol) of 2-iodo-3-hydroxypyridine, 0.6 g (2.5 mmol) of (2-oxo-1-prop-2-ynylpyrrolidin-3- (S) -yl) tert -butyl ester ) carbamic acid, 50 mg. bis (triphenylphosphine) -palladium (II) chloride (Pd (PPh ₃ ) ₂ Cl ₂ ), 25 ml of copper (I) iodide and 3 ml of triethylamine in 3 ml of acetonitrile were heated in a sealed flask at 120 ° C for 2 hours. After cooling, the reaction mixture was diluted with water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated sodium chloride solution, then dried over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with a gradient of 25% ethyl acetate in dichloromethane to 90% ethyl acetate in dichloromethane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.53 (d, 1H), 7.72 (dd, 1H), 7.21 (dd, 1H), 6.86 (s, 1H), 5.15 ( bs, 1H), 4.69 (AB, 2H), 4.23 (m, 1H). 3.38 (m, 2H); 2.66 (m, 1H); 1.91 (m, 1H);

1.45 (s, 9H).

170

C. 3- (S) -amino-1- (furo [3,2-b] pyridin-2-ylmethyl) pyrrolidin-2-one hydrochloride

4 4 4 · · ♦ ·

444 4,444 4 4

4 4 · 4,444

444 4 ··· ·· ·· ·· 444

The title compound was prepared according to the procedure described in Example 1, Part I, using (1-furo [3,2b] pyridin-2-ylmethyl-2-oxopyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester as starting materials. The title compound is obtained as a tan solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.70 (bs, 2H), 8.65 (d, 1H), 8.35. (d, 1H), 7.58 (dd, 1H), 7.28 (s, 1H), 4.77 (s, 2H), 4.10 (m, 1H), 3.47 (m, 2H) 2.41 (m, 1H), 2.09 (m, 1H).

D. . 6-chlorobenzo, [b] thiophene-2-sulfonic acid (1-furo [3,2-b) pyridin-2-ylmethyl-2-oxopyrrolidin-3- (S) -yl) amide

The title compound was prepared according to the procedure for EXAMPLE 1, Part K, using 6-chloro-benzo [b] thiophene-2-sulfonyl chloride and 3- (S) -amino-1- (furo [3,2-b] hydrochloride). pyridin-2-ylmethyl) -pyrrolidin-2-one starting materials. The crude product was purified by column chromatography eluting with a gradient of 25% ethyl acetate in dichloromethane to 90% ethyl acetate in dichloromethane to give the title compound as a white solid.

¹ H NMR (CDCl 3, CDCl 3, 300 MHz) δ 8.49 (bs, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.81 (d, IH), 7, 77 (d, 1H), 7.41 (dd, 1H), 7.24 (m, 1H), 6.85 (s, 1H), 4.63 (AB, 2H), 4.03 (m, IH) 1.41 (m, 2H), 2.63 (m, 1H), 2.16 (m, 1H). FAB

MS, [M + H] ⁺ = 462, 464, Cl isotopes.

• 9 ·

9 9

9999 9 9 9 9 9 * 9 * 9 999 99 9

168 9 9999 9999 9

-L · -L 99 9,999 9,99

999 9999 99 99 9 · 999

Example 45 6-Chloro-benzo [b] thiophene-2-sulfonic acid 1-furo [3,2-b] pyridin-2-ylmethyl-2-oxo-pyrrolidin-3- (S) -yl) -amide

A. 1-Fluoro-3- (2,2-dimethoxyethylsulfanyl) benzene

The title compound was prepared according to the procedure described in Example 9, Part A, substituting 3-fluoro-thiophenol for 3-chlorothiophenol. The crude product was purified by column chromatography eluting with a gradient of hexane to 10% ethyl acetate in hexane to give the title compound as an oil.

¹ H NMR (CDCl 3, 300 MHz) δ 7.21 (m, 1H), 7.09 (m,

2H), 6.82 (m, 2H), 4.51 (m, 1H), 3.09. (s, 31H), 3.07 (s, 3H).

B. 6-Fluorobenzo [b] thiophene

The title compound was prepared according to the procedure described in Example 9, Part B, substituting 1-fluoro-3- (2,2-dimethoxyethylsulfanyl) benzene for 1-chloro-3- (2,2-dimethoxyethylsulfanyl) benzene. The crude product was purified by column chromatography eluting with hexane to give the title compound as a white solid.

EI MS, [M] ⁺ = 152.

C. 6-Fluorobenzo [b] thiophene-2-sulfonyl chloride

The title compound was prepared according to the procedure described in Example 8, Part A, substituting 6-fluoro-benzo [b] thiophene for thianaphthalene. The crude product was purified by column chromatography eluting with hexane to give the title compound as a white solid.

· '9999 • 9

172

9 9 99

9 9 · 9

9 · 9

99 999 ^X H NMR (CDCl, 300 MHz) δ 8.08 (s, H), 7.94

1H), 7.58 (dd, 1H), 7.23 (dt, 1H).

(dd,

D. 6-Fluoro-benzo [b] thiophene-2-sulfonic acid (1-furo [3,2-b] pyridin-2-ylmethyl-2-oxo-pyrrolidin-3- (S) -yl) -amide

The title compound was prepared according to the procedure described in Example -1, part K using 6-fluorobenzo [b] thiophene-2-sulfonyl chloride and 3- (S) -amino-1- (furo [3,2- b] pyridin-2-ylmethyl) -pyrrolidin-2-one as. starting materials. The crude product was purified by column chromatography eluting with 66% ethyl acetate in dichloromethane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.46 (m, 1H), 7.96 (s,

1H), 7.91 (m, 1H), 7.77 (d, 1H), 7.58 (d, 1H), 7.44 (s, 1H), 7.29 (m, 2H), 6 86 (s, 1H), 4.65 (s, 2H), 4.14 (m, 1H), 3.42 (m, 2H), 2.58 (m, 1H), 2.09 (m, ÍH). FAB MS, [M + H] &lt; ⁺ &^gt; = 446.

Example 46 [2-Oxo-1- (1H-pyrrolo [3,2-b] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide trifluoroacetate. 6-chlorobenzo [b] thiophene-2-sulfonic acid

A. 2-Iodo-3-nitropyridine

A solution of 6.3 g (92 mmol) of sodium nitrite in 40 ml of water was added dropwise to a solution of 8 g (57.5 mmol) of 2-amino-3-nitro-pyridine in 60 ml of 6N hydrochloric acid cooled to 0 DEG. The mixture was stirred at 0 ° C for 1.5 hours. 22.9 g (138 mmol) of a solution of potassium iodide in 40 ml of water are then added dropwise to the yellow solution. The resulting mixture was stirred at 0 ° C for 30 minutes and then heated to 60 ° C for 45 minutes. After cooling, 3N sodium hydroxide solution was carefully added to the mixture until basic pH was reached. The aqueous layer is • φ · ♦♦ ····. ·· φ φ φ φ · · · φ φ φ φ ««

Extract four times with dichloromethane and wash the combined organic layers with 1N hydrochloric acid solution, dilute sodium sulfite solution and water. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. 2.72 g (10.9 mmol) of crude product are obtained, which product is used as is in the following stage.

¹ H NMR (CDCl 3, 300 MHz) δ 8.65 (d, 1H), 8.25 (dd,

1H), 7.48 (m, IH). IS MS, [M + H] &lt; ⁺ &^gt; = 251.

B. 3-Amino-2-iodopyridine

To a solution of 2.72 g (10.9 mmol) of 2-iodo-3-nitropyridine in 10 mL of concentrated hydrochloric acid was added dropwise a solution of 10.3 g (45.7 mmol) of tin (II) chloride dihydrate in 12 mL of concentrated hydrochloric acid. The mixture was heated at 90 ° C for 15 minutes. The resulting red mixture was cooled to 0 ° C and stirred for 2 hours, whereupon a precipitate formed. The solid was filtered off and dissolved. The aqueous layer was extracted four times with dichloromethane and the combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. 1.5 g (6.82 mmol) of crude product are obtained, which product is used as is in the following stage.

¹ H NMR (CDCl 3, 300 MHz) δ 7.81 (m, 1H), 7.07 (m,

2H), 4.05 (bs, 2H). IS MS, [M + H] &lt; ⁺ &^gt; = 221.

C. (2-Iodo-pyridin-3-yl) -carbamic acid ethyl ester

0.91 ml (9.5 mmol) of ethyl chloroformate was added to a solution of 1.4 g (6.36 mmol) of 3-amino-2-iodo-pyridine in 15 ml of pyridine cooled to 0 ° C. The mixture was stirred at 0 ° C for 2 hours and allowed to warm slowly to room temperature. Then the excess pyridine is evaporated in vacuo. The residue is diluted with ethyl acetate and washed with water.

174 ♦ ♦ φ φ φ φ φ>> φ φ φ φ φ φ φ φ φ φ ou d d ou ou ou ou ou ou ou ou ou ou ou ou ou ou ou ou ou IN IN ou IN IN ou IN ou The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified by column chromatography eluting with 30% ethyl acetate in hexane to give 1.2 g (4.11 mmol) of the title compound as a beige solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.51 (d, 1H), 8.07 (dd, IH), 7.25 (dd, IH), 7.16 (bd, 1H), 4.28 ( kv, 2H), 1.38 (t, 3H).

D. 2- (3- (S) -tert-butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl) pyrrolo [3,2-b] pyridine-1-carboxylic acid ethyl ester

A mixture of 0.6 g (2.05 mmol) of (2-iodopyridin-3-yl) -carbamic acid ethyl ester, 0.49 g (2.05 mmol) of (2-oxo-1-prop-2-ynylpyrrolidin-3) tert -butyl ester (S) -yl) -carbamic acid, 72 mg of Pd (PPh ₃ ) ₂ Cl ₂ , 12 mg of copper (I) iodide and 1.1 ml of triethylamine in 4 ml of acetonitrile are heated in a sealed flask at 100 ° C for 18 hours. After cooling, the reaction mixture was diluted with methanol and filtered through a pad of diatomaceous earth. The filtrate was evaporated in vacuo. The residue was diluted with ethyl acetate and washed four times with water. The combined aqueous layers were extracted twice with ethyl acetate. The combined organic layers were washed with water, then dried over magnesium sulfate, filtered and evaporated to give the crude acetylene condensed intermediate. IS MS, [M + H] ⁺ = 403. The crude acetylene intermediate was dissolved in 16 mL of dimethylformamide and treated with 0.58 mL (4.1 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene. (DBU). The mixture was heated at 60 ° C for 2 hours. After cooling, the resulting mixture was diluted with water and ethyl acetate and the layers were separated. The organic layer was washed with water and then dried over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with 90% ethyl acetate in diflf

175 flfl flfl flfl

chloromethane to give 0.07 g (0.22 mmol) of the title compound as a beige solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.51 (d, d), 8.35 (d, 1H), 7.21 (dd, 1H), 6.60 (s, 1H), 5.34 ( S, 1H), 4.95 (AB, 2H), 4.55 (qu, 2H), 4.30 (m, 1H), 3.48 (m, 2H), 2.70 (m, 1H), 2.05 (m, 1H); 1.50 (t, 3H); 1.46 (s, 9H). . IS MS, [M + H] &lt; ⁺ &^gt; = 403.

E. 2- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -pyrrolo [3,2-b] pyridine-1-carboxylic acid ethyl ester hydrochloride

The title compound was prepared according to the procedure for EXAMPLE 1, Part I using 2- (3- (S) -tert-butoxycarbonylamino-2-oxo-pyrrolidin-1-ylmethyl) -pyrrolo [3,2-b] pyridin-1 ethyl ester -carboxylic acids as starting materials. The title compound is obtained as a beige solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.70 (m, 1H),

8.58. (m, 4H), 7.50 (m, J), 6.91 (s, 1H), 4.91 (m, 2H), 4.51 (kv, 2H), 4.01 ( m, 1H); 3.50 (m, 2H); 2.48 (m, 1H); 2.10 (m, 1H);

1H), 1.43 (t, 3H).

F. 2- [3- (S) - (6-Chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -pyrrolo [3,2-b] pyridine-1-carboxylic acid ethyl ester

The title compound was prepared according to the procedure for EXAMPLE 1, Part K using 6-chloro-benzo [b] thiophene-2-sulfonyl chloride and 2- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -ethyl ester hydrochloride -pyrrolo [3,2-b] pyridine-1-carboxylic acid starting material. The crude product was purified by column chromatography eluting with 60% ethyl acetate in dichloromethane to give the title compound as a solid.

176

¹ H NMR (CDCl 3, 300 MHz) δ 8.49 (d, 1H), 8.30 (d,

1H), 7.90 (S, 1H), 7.78 (s, 1H), 7.75 (d, 1H), 7.48 (dd, 1H), 7.20 (dd, 1H), 6, 88 (bs, 1H), 6.49 (s, 1H), 4.81 (AB, 2H),

4.49 (qu, 2H), 4.13 (m, 1H), 3.39 (m, 2H), 2.61 (m, 1H), 2.13 (m, 1H), 1.45 (t , 3H).

G. 6-Chloro-benzo [b] thiophene-2- [2-oxo-1- (1H-pyrrolo [3,2-b] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide trifluoroacetate sulfonic acids

To a solution of 0.03 g (0.06 mmol) of 2- [3- (S) - (6-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -pyrrolo [3,2- b] pyridine-1-carboxylic acid in 3 ml of methanol was added 4 drops of 10N sodium hydroxide solution. The mixture was stirred at room temperature for 1 hour. The crude mixture is purified by. Reversed phase HPLG eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized to give 0.015 g (0.026). mmol) of the title compound as a white solid.

NNMR (perdeuterodimethylsulfoxide, 300 MHz) δ 8.72 (d, 1H),

8.58 (bs, 1H), 8.41 (d, 1H), 8.27 (d, 1H), 8.05 (s, 1H), 8.02 (d, 1H), 7.55 (m) 2H, 6.69 (bs, 1H), 4.68 (AB, 2H), 4.25 (m, 1H), 3.30 (m, 2H), 2.20 (m, 1H), 1 73 (m, 1 H). IS MS, [M + H] ⁺ = 461, 463, Cl isotopes. Elemental analysis calculated with 1.6 mol of water: C = 43.76%, H = 3.54%, N = 9.28%, found C = 43.76%, H = 2.98%,

N = 8.95%.

«· · · ··· ·

177 • ····

Example 47 6-Chloro-benzo [b] thiophene-2- (2-oxo-1- (1H-pyrrolo [2,3-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide trifluoroacetate sulfonic acids.

A. 3- (S) -Amino-1-nrop-2-ynylpyrrolidin-2-one hydrochloride

The title compound was prepared according to the procedure described in Example 1, part I, using (2-oxo-1-prop-2-ynyl-pyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester as the starting material. The title compound is obtained as a beige solid.

¹ H NMR (CDCl 3, δ perdeuterodimethylsulfoxide, 300 MHz) δ 8.75 (bs, 3H), 4.15 (AB, 2H), 3.90 (m, 1H), 3.53 (m,

2H), 2.76 (t, 1H), 2.59 (m, 1H), 2.19 (m, 1H).

B. 6-Chloro-benzo [b] thiophene-2-sulfonic acid (2-oxo-1-prop-2-ynyl-pyrrolidin-3- (S) -yl) -amide

The title compound was prepared according to the procedure for EXAMPLE 1, Part K using 6-chloro-benzo [b] thiophene-2-sulfonyl chloride and 3- (S) -amino-1-prop-2-ynyl-pyrrolidine- 2-one as starting material. The crude product was isolated as a beige foam and used in the next step without purification.

¹ H NMR (CDCl 3, 300 MHz) δ 7.90 (s, 1H), 7.85 (s,

1H), 7.80 (d, 1H), 7.41 (dd, 1H), 5.53 (bs, 1H), 4.11 (AB, 2H), 3.91 (m, 1H), 3.42 (m, 2H), 2.70 (m, 1H), 2.27 (t, 1H), 2.15 (m, 1H).

C. (4-Iodopyridin-3-yl) carbamic acid tert-butyl ester

To a solution of 2.2 g (11.3 mmol) of (pyridin-3-yl) -carbamic acid tert-butyl ester (prepared according to the procedure described in »).

178

Tetrahedron Lett. 1994, 35, 9003) in 20 mL of tetrahydrofuran at -78 ° C was added dropwise 15.4 mL (26 mmol, 1.7 M solution in pentane) of tert-butyllithium. After 15 minutes, the solution was stirred at -10 ° C for 3 hours. The mixture was cooled to -78 ° C and a solution of 5.7 g (22.4 mmol) of iodine in 20 mL of tetrahydrofuran was added via syringe. The resulting mixture was stirred at -78 ° C for 1 hour, then allowed to warm to room temperature and quenched with saturated ammonium chloride solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid solution, water, dilute Na ₂ S ₂ O ₃ , saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with a gradient of 5% ethyl acetate in dichloromethane to 20% ethyl acetate-dichloromethane to give 1.3 g (4.06 mmol) of the title compound as a brown solid.

¹ H NMR (CDCl 3, 300 MHz) δ 9.17 (s, 1H), 7.92 (d,

1H), 7.70 (d, 1H), 6.69 (bs, 1H), 1.58 (s, 9H). EI MS, [M] &lt; ⁺ &^gt;

320.

D. 2- [3- (S) - (6-Chloro-benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -pyrrolo [2,3-c] pyridine-1-carboxylic acid tert-butyl ester acid

(4-Iodo-pyridin-3-yl) -carbamic acid tert-butyl ester, 0.85 g (2.65 mmol), 0.98 g (2.65 mmol) of (2-oxo-1-prop-2-ynylpyrrolidine) 6-chlorobenzo [b] thiophene-2-sulfonic acid -3- (S) -yl) -amide, 95 mg Pd (PPh ₃ ) ₂ Cl ₂ , 18 mg copper (I) iodide and 1.45 ml triethylamine · in 8 ml dimethylformamide was heated at 100 ° C for 1.5 hours. The reaction mixture was cooled to 50 ° C and DBU was added. The resulting mixture was heated at 50 ° C for 1.5 hours. After cooling • 4 000 9

179 • 9 • ··· »

0 ·

0 0 • 9 0

The crude mixture is diluted with ethyl acetate and washed with saturated ammonium chloride solution, water and saturated sodium chloride solution.

The organic layer was dried over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with a gradient of 1% methanol in dichloromethane to 4% methanol in dichloromethane to give 0.73 g (1.3 mmol) of the title compound as a tan oil.

¹ H NMR (CDCl 3, 300 MHz) δ 9.28 (s, 1H), 8.38 (d,

1H), 7.88 (m, 2H), 7.68 (d, 1H), 7.46 (m, 3H), 6.31 (s, 1H), 4.93 (AB, 2H), 4, Δ (m, 1H), 3.49 (m, 2H), 2.7.6 (m, 1H), 2.26 (m, 1H), 1.60 (s, 9H). IS MS, [M] ⁺ = 561, 563, Cl isotopes.

E. 6-Chloro-benzo [b] thiophene-2- [2-oxo-1- (1H-pyrrolo [2,3-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide trifluoroacetate sulfonic acids

The title compound is prepared from 2- [3- (S) - (6-chloro-benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -pyrrolo [2,3-c] pyridine tert-butyl ester The crude product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 80% acetonitrile in water (0). , 1% trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized to give the title compound as a white solid.

‘H NMR (300 MHz), δ 13.07 (bs, 1H),

9.07 (with, 1H), 8.74 (d, 1H) , 8.29 (s, 1H), 8.27 (d, IH) , 8.03 (m, 3H), 7.52 (dd, 1H), 6, 79 (s, 1 H), 4.71 - (AB, 2H), 4 27 (m, 1H), 3.29 (m, 2H), 2.20 (m, (1H), 1.77 (m, IH). : FAB MS, [M + H] &lt; ⁺ &^gt;

461, 463, Cl isotopes. Elemental analysis calculated with 0.7 mole 000 000

180

0 · ·· ···· 00 • · 0 0 · 0 · 0 · · · · · ·

0 0 0 0 0 0 0

0 0 0 0 0 water: C = 44.94%, H = 3.33%, N = 9.53% ,. found C = 44.92%, H = 2.91%, N = 8.91%.

Example 48 Thieno [3,2-b] pyridine-2-sulfonic acid [2-oxo-1- (1H-pyrrolo [2,3-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide ditrifluoroacetate acid

A. Thieno [3,2-b] pyridine-2-sulfonyl chloride

The title compound was prepared according to the procedure described in Example 8, Part A using thieno [3,2-b] pyridine (prepared according to the procedure described in J. Heterocyclic Chem. 1984, 21, 785) instead of thianaphthalene. The crude product was used in the next step without purification.

¹ H NMR (CDCl 3, 300 MHz) δ 8.93 (dd, 1H), 8.39 (s, 1H), 8.38 (d, 1H), 7.59 (m, 1H). EI MS, [M] ⁺ = 233, 235, Cl isotopes,

B. Thieno [3,2b] pyridine-2-sulfonic acid (2-oxo-1-prop-2-ynyl-pyrrolidin-3- (S) -yl) -amide

The title compound was prepared according to the procedure for EXAMPLE 1, Part K using thieno [3,2-b] pyridine-2-sulfonyl chloride and 3- (S) -amino-1-prop-2-ynyl-pyrrolidine hydrochloride -2-one as starting materials. The crude product was isolated as a white solid and used in the next step without purification.

³ H NMR (CDCl 3, 300 MHz) δ 8.81 (d, 1H), 8.22 (d, 1H), 8.13 (s, 1H), 7.41 (m, 1H), 6.05 ( Bs, 1H), 4.10 (m, 1H), 3.98 (m, 1H), 3.48 (m, 2H), 2.70 (m, 1H), 2.27 (t, 1H) , 2.17 (m, 1H). '

181

C. Thieno [3,2-b] pyridine-2-sulfonic acid [2-oxo-1- (1H-pyrrolo [2,3-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide ditrifluoroacetate acid

The title compound was prepared from thieno [3,2-b] pyridine-2-sulfonic acid (2-oxo-1-prop-2-ynyl-pyrrolidin-3- (S) -yl) -amide according to the procedure described in Example 47, Part D. The crude mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution, water and saturated sodium chloride solution. The aqueous layer was evaporated in vacuo. The salt mixture was triturated with methanol and dichloromethane, filtered, washed with a mixture of dichloromethane and methanol, and the yellow filtrate was evaporated. The crude product was purified by reverse phase HPLC, eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 50% acetonitrile in water (0.1% trifluoroacetic acid) and the appropriate product-containing fractions were lyophilized to yield The title compound is a beige solid.

^{Χ Η} NMR (DMSO-d₆, 300 MHz) δ 13.00 (bs, IH),

9.06 (with. IH), 8.88 (d, 1H); 8.77 (m, 1H), 8.60 (d, 1H), 8.26 (d, IH), 8.12 (s, 1H), 8.01 (d, 1H), 7.52 (m, IH), 6.80 (s, IH), 4.71 (AB, 2H), 4.35 (m, IH), 3.30 (m, 2H). 2.22 (m, 1H) 1.78 (m, IH). IS: MS, [M + H] ⁺ = 428. Elementary analysis calculated

with 1.9 mol of water : C = 40.05% H + 3.33%, N = 10.15% found C = 40.06%, H = 2.82%, N = 9.87%.

Example 49 Benzo [b] thiophene-2-sulfonic acid (2-oxo-1-thieno [3,2-c] pyridin-2-ylmethyl-pyrrolidin-3- (S) -yl) -amide trifluoroacetate

A. 1- (Thieno [3,2-c] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester

182

To a solution of 1- (4-chloro-thieno [3,2-c] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester (0.46 g, 1.2 mmol) of the acid prepared according to the procedure described in Example 33, Part F, in 20 ml of methanol is added 0.1 g of palladium on carbon and 0.13 g (2.4 mmol) of potassium hydroxide). The atmosphere of the reaction mixture was replaced with hydrogen and the solution was heated to 50 ° C. after 16 hours the solution was filtered through diatomaceous earth and the diatomaceous earth was washed with methanol. The crude material was purified by column chromatography eluting with a gradient of 30% ethyl acetate in dichloromethane to 40% ethyl acetate in dichloromethane to give 0.2 g (0.7 mmol) of the product as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 9.00 (s, 1H), 8.44 (d,

1H), 7.70 (s, 1H), 7.31. (s, 1H), - 5.12 (bs, 1H), 4.72 (AB, 2H), 4.18 (m, 1H), 3.32 (m, 2H), 2.62 (m, 1H) ), 1.88. (m, 1H). 1.42 (s, 9H). FAB MS, [M + H] &lt; ⁺ &^gt; = 348.

B. Benzo [b] thiophene-2-sulfonic acid (2-oxo-1-thieno [3,2-c] pyridin-2-ylmethyl-pyrrolidin-3- (S) -yl) -amide trifluoroacetate

To a solution of 1- (thieno [3,2-c] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester (0.1 g, 0.35 mmol) in 4 mL To the dichloromethane was added 0.08 g (0.78 mmol) of triethylamine and 0.08 g (0.35 mmol) of benzo [b] thiophenesulfonyl chloride. After 6 hours, the solution was diluted with dichloromethane and washed with 10% sodium carbonate solution and saturated sodium chloride solution. The residue was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1 trifluoroacetic acid) to 80% acetonitrile in water (0.1 trifluoroacetic acid). The appropriate product-containing fractions were lyophilized to give the title compound as a white solid.

• · · · · · · ^X • H NMR (DMSO-d₆, 300 MHz) δ 9.25 (bs, IH),

8.63 (d, IH), 8.50 (m, 1H), 8.39 (m, 1H), 7.99 (m, 4H) 7.61 (with, IH), 7.46 (m, 2H), 4.70 (s, 2H); 4.14 (m, 1H), 3.11 (m, 2H), 2.08 (m, IH), 1.62 (m, 1H). FAB MS, [M + H] &lt; ⁺ &^gt; 444.

Example 50

7-Methoxynaphthalene-2-sulfonic acid [1- (1H-imidazo [4,5-c] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

A. [3- (S) -Amino-2-oxocyclopentyl] -acetic acid benzyl ester hydrochloride

0.13 g (3.3 mmol, 60% dispersion) of sodium hydride is added to a solution of 0.6 g (3 mmol) of [2-oxopyrrolidin-3- (S) -yl] carbamic tert-butyl ester at 0 ° C. of acid in 30 ml of tetrahydrofuran. The mixture was stirred for 30 minutes and then 0.76 g (3.3 mmol) of benzyl 2-bromoacetate was added. The resulting solution was warmed to room temperature and stirred for 1.5 hours. Quench the reaction with saturated ammonium chloride solution then dilute with dichloromethane. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography (0-3% methanol in dichloromethane) and the isolated material was treated in ethyl acetate with hydrogen chloride gas (as described in Example 1, Part I) to give 0.55 g (1.9 mmol). the title compound as a yellow solid.

¹ H NMR (CDCl 3, 300 MHz) δ 7.32 (m, 5H), 5.17 (s, 2H), 4.15 (d, 2H), 4.08 (m, 1H), 3.54 ( m, 2H), 2.54 (m, 1H), 2.03 (m, 1H). EI MS, [M] ⁺ = 248.

B. 3- (S) - (7-Methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -acetic acid;

184 '»» »- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - · »» · · · · ·

0.34 g (1.2 mmol) of [3- (S) -amino-2-oxo-cyclopentyl] -acetic acid benzyl ester hydrochloride was suspended in 20 ml of acetonitrile. To this mixture was added 0.35 g (3.6 mmol) of triethylamine followed by 0.31 g (1.2 mmol) of 7-methoxynaphthalene-2-sulfonyl chloride. The mixture was stirred overnight at room temperature, then aqueous work-up was carried out and evaporated to dryness. Add the crude by flash chromatography (0-5% methanol in dichloromethane). Subsequent hydrogenolysis in a mixture of methanol and dichloromethane with 5% palladium on carbon at a pressure of 10 psig (172 kPa) gave 0.40 g (1 mmol) of the title compound as a white solid after 1.5 hours.

¹ H NMR (CDCl 3, 300 MHz) δ- 8.33 (s, 1H), 7.80 (m,

3H), 7.23 (m, 2H), 5.90 (b, 1H), 3.95 (m, 6H), 3.38 (m, 2H),

2.40 (m, 1H); 2.07 (m, 1H); Ion Spray MS, [M + H] ⁺ = 379.

C. N- (3-Aminopyridin-4-yl) -2- [3- (S) - (7-methoxy-naphthalene-2-sulfonylamino) -2-oxopyrrolidin-1-yl] acetamide

Triethylamine (0.13 g, 1.3 mmol) and isobutyl chloroformate (0.18 g, 1.3 mmol) were added to a solution of [3- (S) - (0.5 g, 1.3 mmol) at -10 ° C. Of 7-methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -acetic acid in 15 ml of tetrahydrofuran. The mixture was stirred for 20 minutes, then treated with a solution of 0.16 g (1.5 mmol) of 3,4-diaminopyridine in 5 mL of dimethylformamide. The resulting mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was evaporated in vacuo, then diluted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography (5-8% methanol in dichloromethane) to yield

0.27 g (0.58 mmol) of the title compound as a solid.

i • * · · · ·

185 • · φ φ

^{Χ Η} NMR (CDCl, 300 MHz) δ 8.88 (s,

1H), 8.30 (s,

1H), 8.00 (with, 1H), 7.85 (d, 1H), 7.70 (m, 3H), 7.40 (d, 1 H), 7.20 (d, 1H), 7 '12 (with, 1H), 5.28 (with, 2H), 4.07 (m, 4H), 3.88 (3, 3H), 3.34 ,. (m, 2H), 2.22 (m, 1H), 1.90 (m, 1H). Ion Spray

MS, [M + H] &lt; ⁺ &^gt; = 470.

D. 7-Methoxy-naphthalene-2-sulfonic acid [1- (1H-imidazo [4,5-c] pyridin-2-ylmethyl-2-oxo-pyrrolidin-3 (S) -yl] -amide trifluoroacetate

0.22 g (0.47 mmol). N- (3-Amino-pyridin-4-yl) -2- [3- (7-methoxy-naphthalen-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -acetamide in 15 mL of acetic acid was heated at 110 overnight. Deň: 32 ° C. The solution was evaporated to dryness. The residue was purified by HPLC eluting with a gradient of 10 to 100% acetonitrile / 0.1% trifluoroacetic acid in water over 30 minutes. Fractions containing pure product were lyophilized to give 0.24. g (0.42 mmol) of the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 9.30 (s, 1H), 8.40 (d,

1H), 8.28 (with, 1H), 7.95 (d, IH), 7.70 (m, 3H), 7.40 (m, 1 H), 7,2 0 (m, 2H),. 7.14 (with, 1H), 4.92 (m, 2H), 4.4 6 (m, 1H), 3.82 (with, 3H), 3.38 (m, 2H), 2.20 (m, 1H), 2.03 (m, lHj. Ion Spray

MS, [M + H] + = 452.

Example 51

7-Methoxy-naphthalene-2-sulfonic acid [1- (2-amino-3H-benzoimidazol-5-methyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

A. 7-Methoxy-naphthalen-2-sulfonic acid [1- (3,4-diaminobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

186 • ΦΦΦ φ · · • • • • • • φ

0.08 g of 10% Palladium on carbon was added to a solution of 0.22 g (0.5 mmol) of [1- (4-amino-3-nitro-benzyl) -2-oxopyrrolidin-3- (S) -yl] under a nitrogen atmosphere. 7-Methoxynaphthalene-2-sulfonic amide. acid (prepared according to the procedure described in Example 25, part F) in 40 mL of methanol and 3 mL of chloroform. The heterogeneous mixture is hydrogenated at room temperature in a Parr apparatus for 5 hours, at a hydrogen pressure of 324 kPa. The catalyst was filtered off and the starting material was found to be absent by TLC. The filtrate was evaporated in vacuo and used in the next step without purification.

¹ H NMR (deuteromethanol, 300 MHz) δ 8.41 (s, 1H), 7.93 (d, IH) ·, 7.85 (d, 1H); 7.73 (d, IH), 7.39 (d, 1H), 7.25 (dd, IH), 7.02 (d, 1H), 6.89 (S, IH) 6.79 (dd, IH), 4.3 0 (s, 2H), 4.13 (t, IH), 3.95 (s, 3H), 3.13 (m, 2H), 2.14 (m, 1H), 1.70 (m, IH).

Ion Spray MS, [M + H] &lt; ⁺ &^gt; = 441.

B. 7-Methoxynaphthalene-2-sulfonic acid [1- (2-amino-3H-benzoimidazol-5-methyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

0.063 ml (0.45 mmol) of Triethylamine was added to a solution of 0.205 g (0.47 mmol) of 7-methoxynaphthalene [1- (3,4-diaminobenzyl) -2-oxopyrrolidin-3- (S) -yl] amide under nitrogen. Of 2-sulfonic acid in 8 mL of methanol. At 0 ° C, 0.19 mL (0.56 mmol), a 3M solution of cyanogen bromide was added dropwise to the reaction mixture. After stirring at 0 ° C for 5 minutes, the reaction mixture was warmed to room temperature and stirred overnight. The clear solution was then evaporated in vacuo and the crude residue was purified by column chromatography eluting with a gradient of 9% methanol in dichloromethane to 50% methanol in dichloromethane to give 56% yield of the title compound. The product is lyophilized from a mixture of acetonitrile, 9

9

9 9

187

Trifluoroacetic acid and water to give the title compound as an off-white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.40 (d, 1H), 7.90 (d,

1H), 7.81 (d, IH), 7.75 (d, IH), 7.15 (d, IH), 7.11 (d, IH), 6.92 (t, IH), 3, 91 (s, 3 H), 3.10 (m,

7.36 (d, 1H), 7.25 (dd, 1H), (dd, 1H), 4.41 (AB, 2H), 4.15 2H), 2.10 (m, 1H), 1, 64 (m,

IH). Ion Spray MS, [M + H] &lt; ⁺ &^gt; = 466.

Example 52 3- (S) -Amino-1- (1-aminoisoquinolin-7-ylmethyl) pyrrolidin-2-one hydrochloride

A. 7-Methyl-1-phenoxyisoquinoline

The title compound was prepared according to the procedure for EXAMPLE 1, Part L using 1-chloro-7-methyl-isoquinoline as starting material. The crude material was purified by column chromatography eluting with 20% ethyl acetate in hexane to give the title compound as a pale yellow oil.

¹ H NMR (CDCl 3, 300 MHz) δ 8.22 (s, 1H), 7.90 (d,

1H), 7.68-7.60 (m, 1H), 7.60-7.52 (m, 1H), 7.50-7.40 (m, 2H),

7.30-7.20 (m, 4H); 2.57 (s, 3H).

B. 7-Bromomethyl-1-phenoxyisoquinoline

The title compound was prepared according to the procedure described in the example. 1, part F using 7-methyl-1-phenoxyisoquinoline as starting material. The crude product was purified by column chromatography eluting with 10% ethyl acetate in hexane to give the title compound as a clear oil.

188 ^X H NMR (CDCl, 300 MHz) δ H), 7.80-7.65. (m, 2H), 7.50-7.40 (m, 2H)

4.65 (s, 2 H).

· 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 ······· ··. ♦ · ·· · · «

8.40 (s, 1H); 7.95 (d,

2H), 7.30-7.20 (m, 4H),

C. 1- (1-Phenoxyisoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl], carbamic acid benzyl ester

The title compound was prepared according to the procedure for EXAMPLE I, Part H using 7-bromomethyl-1-phenoxy-isoquinoline and [2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid benzyl ester as starting materials. The crude product was purified by column chromatography eluting with 70% ethyl acetate in hexane to give the title compound as a clear oil.

^X H NMR (deuterochloroform, 300 MHz) δ 8.25 (with, IH), 7.97 (d, IH) 7.79 (d, 1H); 7.60 (d, 1H); ΓΗ), 7.48-7.40 ( m, 2H), 7.38-7.20 (m, 9H), 5.40 (bs, 1H), 5, 15 (s, 2H), 4.75 (AB, 2H), 4.30 (m,

1H), 3.30 (m, 2H), 2.67 (m, 1H), 1.90 (m, 1H).

D. [1- (1-Amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid benzyl ester

The title compound was prepared according to the procedure for EXAMPLE 1, Part M using [1- (1-phenoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid benzyl ester as starting material. The reaction mixture was diluted with dichloromethane and washed with 3N sodium hydroxide solution and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by column chromatography eluting with 10% methanol in dichloromethane to give the title compound as a yellow solid.

»9 · ^X · H NMR (CDCl

(d, 1H), 7.45 (d, 1H), 7 5.5.5 (m, 3H), 5.20-5.15 2H), 2.55 (m, (H), 2.27 (

• 9 • 9 • 9

189 ···.! ..

300 MHz) δ 7.95-7.87

0-7.30 (m, 5H), 7.00 m, 4H), 4.3-4.1 (m,

ÍH).

·

9 9

9

9 (m, 2H), 7.70 (d, 1H), 5.751H), 3.25 (m, 2H)

E. 3- (S) -Amino-1- (1-amino-isoquinolin-7-ylmethyl) -pyrrolidin-2-one hydrochloride

0.089 g of 10% Palladium on carbon is added to a solution of 0.33 g (0.84 mmol) of [1- (1-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] benzyl ester. The heterogeneous mixture is hydrogenated at room temperature in a Parr apparatus at a hydrogen pressure of 310 kPa for 3 hours. The reaction mixture was filtered through a pad of diatomaceous earth, washed with ethanol, and the filtrate was evaporated in vacuo to give 0.2 g (0.78 mmol) of the product as a foamy solid. The product was dissolved in diethyl ether and cooled to 0 ° C. Hydrogen chloride gas was bubbled through the solution to give the title hydrochloride.

¹ H NMR (CDCl 3, 300 MHz) δ 8.95-8.50 (b, 2H), 8.05 (s, 1H), 7.75-7.70 (m, 2H), 7.53 (d) 1H, 7.30-7.10 (b, 2H), 6.93 (d, 1H), 4.57 (AB, 2H), 3.40 (m, 1H), 3.15 (m, 1H, 2.37. (m, 1H), 2.02 (m, 1H). FAB MS: [M + H] &lt; ⁺ &^gt; = 257.

F. 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

The title compound was prepared in an alternative manner as described in Example 1, Part K, using 3- (S) -amino-1- (1-amino-isoquinolin-7-ylmethyl) -pyrrolidin-2-one hydrochloride -methoxynaphthalene-2-sulfonyl chloride starting materials.

190 · · * * * * · · · · · · · · · · · · · · ·· ·· · »

Example 53

6-Chlorothieno [2,3-b] pyridine-2-sulfonyl chloride

A. 2-Bromo-6-chlorothieno [2,3-b] pyridine

The title compound was prepared from 2-bromo-5-acetylthiophene according to the procedure described in J. Chem. Soc., Perkin Trans. I, 1981, 1531. The crude product was purified by column chromatography eluting with 2% ethyl acetate in hexane to give a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 7.89 (d, 1H), 7.28 (d,

1H), 7.27 (d, 1H). ·

B., 6-Chlorothieno [2,3-b] pyridine-2-sulfonyl chloride

The title compound was prepared according to the procedure described in Example 1, Part D after. using 2-bromo-6-chlorothieno [2,3b] pyridine in place of thianaphthalene. The product obtained as a white solid is sufficiently pure to be used in the next step.

¹ H NMR (CDCl 3, 300 MHz) δ 8.22 (d, 1H), 8.09 (s,

1H), 7.52 (d, 1H). EIMS, [M] ⁺ = 267, 269, Cl isotopes.

Example 54

6-Fluorobenzo [b] thiophene-2-sulfonyl chloride

The title compound was prepared according to the procedure described in Example 9, Part A-C, using 3-fluorothiophenol instead of 3-chlorothiophenol.

Example 55

6-Chlorothieno [3,2-b] pyridine-2-sulfonyl chloride

191 • · · · · · · · · · · · ·

9 9 9 · · · · · · · · · · · · · · 99 ·

The title compound was prepared according to the procedure described in Example 48, Part A using 6-chlorothieno [3,2-b] pyridine (prepared according to the procedure described in J. Heterocycin Chem. 1984, 21/785) instead of thianaphthalene. The crude product was used in the next step without purification.

The following compounds were also prepared according to the procedures described above:

where

X 5 is selected from the group they are formed from.

Xsa nh ₂

R _x , X ₅ , W and A are defined according to the invention and R ₂ is selected from the group consisting of:

-w o

O

193 • · flflfl fl fl fl fl • flflfl flflflfl ·· ····

O

• 4,444

197

4 4 4 4 4

Example 56 Thieno [3,2-b] pyridine-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

A. Thieno [3,2-b] pyridine-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

To a solution of 0.15 g (0.48 mmol) of 3- (S) -amino-1- (1-chloro-isoquinolin-7-ylmethyl) -pyrrolidin-2-one hydrochloride suspended in 2.5 mL of acetonitrile is added 0.23 ml (1.6 mmol) of triethylamine and then 0.14 g (0.55 mmol) of thieno [3,2-b] pyridine-2-sulfonyl chloride. The mixture was stirred overnight and then evaporated. The residue was diluted with dichloromethane and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by column chromatography eluting with 5% methanol in dichloromethane to give 0.076 g (0.16 mmol) of the title compound as a pale yellow solid.

^X H NMR (CDCl 3, 300 MHz) δ 8.85 (d, 1H, 8.32 (d, ÍH) , 8.27 (d, 1H), 8.15 (s, 2H), 7.85 (d, 1H); ÍH), 7,587,65 (m, 2H) ; 7.45 (dd, 1H, 5.60 (bs, 1H), 4.68 (AB, 2H), 4.00 (m, ÍH) , 3.3 1 (m, 2H), 2.72 (m, 1H), 2.20 (m, 1H); , ÍH) . El MS, [M] ⁺ =

472.

Β. Thieno [3,2-b] pyridine-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

1.36 g (2.88 mmol) thieno [3,2-b] pyridine-2-sulfonic acid [1- (1-chloroisoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide and 2.22 g (23.6 mmol) of phenol are melted together with stirring at 70 ° C over 5 minutes. 2.71 g (28.8 mmol) of ammonium acetate are added and the reaction mixture is heated to 90 ° C and stirred. flfl · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

198 ................

overnight. An additional 0.50 g (5.31 mmol) of ammonium acetate was added and the reaction mixture was heated for an additional 20 hours. The reaction mixture was cooled and the residue was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid to 100% acetonitrile). The appropriate product-containing fractions were lyophilized to give the title compound as Enantiomeric purity is 90.5% ee as determined by reverse phase analytical HPLC on a Chiralpak AS column.

¹ H NMR (CDCl 3, 300 MHz) δ 12.90. (bs, 1H), 9.00 (bs, 1H), 8.88 (d, 1H), 8.79 (dd, 1H), 8.60 (dd, 1H), 8.30 (s, 1H) 8.13 (s, 1H); 7.95 (d, 1H); 7.79 (dd, 1H); 7.65 (d, 1H); 7.53 (dd, 1H); 7.23 (dd, 1H); d, 1H), 4.50 (AB, 2H), 4.38 (m,

1H), 3.21 (m, 2H), 2.20 (m, 1H), 1.81 (m, 1H). Ion Spray, [M + H] &lt; ⁺ &^gt; = 454.

Example 57 Thieno [2,3-b] pyridine-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

A. Thieno [2,3-b] pyridine-2-sulfonyl chloride

6.0 ml (9.6 mmol, 1.6 M in hexane) of n-Butyllithium was added to a solution of 1.18 g (8.7 mmol) of thieno [2,3b] pyridine (J. Org. Chem., 1969, 34 (2), 347) in 30 ml of tetrahydrofurnau. After 40 minutes, the solution is added via cannula to a pre-cooled (-78 ° C) solution of sulfur dioxide (about 6 mL) in 30 mL of diethyl ether. After the addition, the solution was stirred for 30 minutes, then allowed to warm to room temperature. After 2 hours, the solution was evaporated to give a brown solid. The residue was suspended in 30 mL of hexane and 0.6 mL (7.5 mmol) of SO ₂ Cl ₂ was added dropwise at room temperature. After stirring for 1 hour, the solution was evaporated, then evaporated

199 ··· ················· · · · ·

Dilute with dichloromethane and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with 20% ethyl acetate in hexane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.81 (dd, 1H), 8.30 (dd,

1H), 8.12 (s, 1H), 7.50 (dd, 1H). EI MS, [M] ⁺ = 233, 235, Cl isotopes.

Β. Thieno [2,3-b] pyridine-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide. acid

The title compound was prepared according to the procedure for EXAMPLE 56, Part A using thieno [2,3-b] pyridine-2-sulfonyl chloride and 3- (S) -amino-1- (1-chloro-isoquinolin-7-ylmethyl) -hydrochloride 1-pyrrolidin-2-one starting materials. The crude product was purified by column chromatography eluting with 5% methanol in dichloromethane to give the title compound as white. solids.

¹ H NMR (CDCl 3, 300 MHz) δ 8.72 (dd, 1H), 8.31 (d, IH), 8.22 (dd, IH), 8.13 (d, IH), 7.92 ( s, 1H), 7.81 (d, IH), 7.60 (d, IH), 7.58 (d, IH), 7.43 (dd, IH), 5.89 (d, IH), 4.70 (AB, 2H), 4.05 (m, 1H), 3.31 (m, 2H), 2/68 (m, 1H), 2.13 (m, 1H). Ion Spray, [M + H] ⁺ = 473, 475, Cl isotopes.

C. Thieno [2,3-b] pyridine-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure for EXAMPLE 56, Part B using thieno [2,3- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide. -b] pyridine-2-sulfonic acid starting material. The crude product is

200 Purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile using reverse-phase HPLC. in water (0.1% trifluoroacetic acid) to 100% acetonitrile. The appropriate product-containing fractions were lyophilized to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 12.90 (bs, IH), 9.00 (bs, IH), 8.80 (d, IH), 8.72 (dd, IH), 8.42 ( dd, 1H), 8.27 (s, IH), 8.08 (s, IH), 7.95 (d, IH), 7.79 (d, IH), 7.65 (d, IH), 7.58 (dd, 1H), 7.21 (d, 1H), 4.50 (AB, 2H), 4.3.5 (m, 1H), 3.25 (m, 2H), 2.21. (m, 1H), 1.80 (m, 1H). Ion Spray, [M + H] &lt; ⁺ &^gt; = 454.

Example 58 4-Pyridin-3-yl-thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

A. 4-Pyridin-3-ylthiophene-2-sulfonyl chloride

The title compound was prepared according to the procedure for EXAMPLE 57, Part A using 2-bromo-4-pyridin-3-yl-thiophene (J. Het. Chem. 1995, 32, 435) instead of thieno [2,3-b] pyridine and the reaction is carried out at -100 ° C and not at -78 ° C. The crude product was purified by column chromatography eluting with a gradient of 10% ethyl acetate in hexane to 20% ethyl acetate in hexane to give a pale yellow solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.87 (dd, 1H), 8.65 (dd,

1H), 8.3 (d, 1H), 7.98 (d, 1H), 7.90 (m, 1H), 7.42 (m, 1H). El

MS, [M] ⁺ = 259, 261, Cl isotopes.

Β. 4-Pyridin-3-yl-thiophene-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) yl] -amide

201

The title compound was prepared according to the procedure for EXAMPLE 56, Part A using 4-pyridin-3-yl-thiophene-2-sulfonyl chloride and 3- (S) -amino-1- (1-chloro-isoquinolin-7-ylmethyl) - pyrrolidin-2-one starting materials. The crude product was purified by column chromatography eluting with a gradient of 2% methanol in dichloromethane to 4% methanol. in dichloromethane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.88 (d, 1H), 8.60 (dd,

1H), 8.31 (d, 1H), 8.14 (with, 1H), 7.95 (d, 1 H), 7.88 (m, 1H), 7.82 (d, 1H), 7.79 (d, 1H), 7,55-7,60 (m, 2H) 7.38 (m, 1H)., 5.45 (d, 1H), 4.63 (AB, 2H), 3.95 (m, 1H), 3.29 (m, 2H) 2.68 (m, 1H), 2.14 (m, 1H), 1.6 (s, 9H). : Ion Spray, [M + H] &lt; ⁺ &^gt; 499,

501,

C. 4-Pyridin-3-yl-thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure described in the example. 56, Part B using 4-pyridin-3-yl-thiophenesulfonic acid [1- (1-chloroisoquinolin-7ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as a starting material. The crude product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 100% acetonitrile. The appropriate product-containing fractions were lyophilized to give the title compound as a white solid.

´ Ή NMR (perdeuterodimethylsulfoxide, 300 MHz) δ 12.98 (bps, 1H),

9.00 (ŠS, 2H). , 8.48 -8.57 (m, 2H), 8.39 . (with, 1H), 8.27 (with, 1H), 8,15- 8.2.1 (m, 2H), 7.92 (d, 1H), 7.78 (d, 1H), 7.61 (d, ·. 1H), 7.48 (m, 1H), 7.21 (d, 1 H), 4.56 (AB, 2H), 4.3 9 (m, 1H), 3.20

(m, 2H), 2.20 (m, 1H), 1.73 (m, 1H). Ion Spray, [M + H] &lt; ⁺ &^gt; = 480.

202

Example 59 5'-Chloro [2,2 '] bithiophenyl-5 [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide -sulfonic acids

A. 4-Amino-3-iodopyridine

Potassium iodide (19.48 g, 117.4 mmol) and iodine (18.37 g, 72.3 mmol) in 77 ml of water were added dropwise to a boiling solution of 4-aminopyridine (9.21 g, 97.8 mmol) and 6.12 g (57.7 mmol) of sodium carbonate in 35 ml of water. When the addition was complete, the reaction mixture was stirred at reflux for 2 hours, then cooled to room temperature and extracted with ethyl acetate. The combined organic layers were washed three times with saturated sodium thiosulfate solution and brine, then dried over magnesium sulfate, filtered and evaporated to give 8.37 g (38.0 mmol) of the title compound and traces of the diiodo compound as a yellow-orange solid. This material was used in the next step without purification.

¹ H NMR (CDCl 3, 300 MHz) δ 8.70 (s, 1H), 8.10 (d,

1H), 6.55 (d, 1H), 4.60 (bs, 2H).

B. (3-Iodo-pyridin-4-yl) -carbamic acid tert-butyl ester

Di-tert-butyl dicarbonate (20.7 g, 94.8 mmol) was added to a solution of 4-amino-3-iodo-pyridine (19.0 g, 86.4 mmol) in tetrahydrofuran (86 mL). The resulting solution was stirred at room temperature for 2 hours, then evaporated to dryness. The residue was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography eluting with 1% ethyl acetate in dichloromethane to give the title compound and a small amount of BOC-protected diiodo compound. After trituration with ether mixtures

203 • 4 4 4 4 4 4 4 4 4 4 4

444 4444 44 44 4.4 444 and hexane removes the undesired compound from the title compound into solution. Filtration of the solid and evaporation of the filtrate gave 18.95 g (59.2 mmol) of the title compound.

¹ H NMR (CDCl 3, 300 MHz) δ 8.75 (s, 1H), 8.35 (d, IH), 8.1 (d, IH), 7.0 (bs, IH), 1.55 ( s, 9H).

C. (2-Oxo-1-prop-2-ynyl-pyrrolidin-3- (S) -yl) -carbamic acid benzyl ester

1.11 g (27.7 mmol, 60% dispersion in mineral oil) of sodium hydride is added to a solution of 6.20 g (26.4 mmol) of [2-oxopyrrolidin-3- (S) -yl] benzyl ester at 0 ° C. ] -carbamic acid in 88 ml of a mixture of tetrahydrofuran and dimethylformamide (3/1 by volume).

The mixture was stirred for 5 minutes, then 4.4 ml (49.4 mmol) of propargyl bromide was added dropwise. The resulting solution was stirred for 1 hour, then warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched. The reaction was quenched with saturated ammonium chloride solution, then diluted with ethyl acetate and washed four times with water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography eluting with 5% methanol in dichloromethane to give 7.20 g (26.4 mmol) of the product as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 7.35 (m, SH), 5.30 (bs,

1H), 5.12 (s, 2H), 4.21 (m, 1H), 4.13 (s, 2H), 3.43 (m, 2H),

2.73 (m, 1H), 2.25 (s, 1H), 1.95 (m, 1H).

D. 2- (3- (S) -Benzyloxycarbonylamino-2-oxopyrrolidin-1-ylmethyl) pyrrolo [3,2-c] pyridine-1-carboxylic acid tert-butyl ester

0.49 g (0.70 mmol) of Pd (PPh ₃ ) ₂ Cl ₂ , 0.08 g (0.42 mmol) of copper (I) iodide and then 7.8 ml (56.0 mmol) of triethylamine are added at room temperature to a solution of 3.8.1 g (13.9 mmol) of (2-oxo-1-prop-2-ynyl-pyrrolidin-3- (S) -yl) -carbamic acid benzyl ester and

204

0 '·· ·· ···· ·· ··· · · ·

0 0 0 .0 0 00 0000000 00 00 00 0

4.48 g (14.0 mmol) of (3-iodopyridin-4-yl) -carbamic acid tert-butyl ester in 50 ml of dimethylformamide. The reaction mixture was stirred at 100 ° C for 1.5 hours. The reaction mixture was then cooled to 50 ° C and DBU (4.2 mL, 28.1 mmol) was added. After 30 minutes, the solution was cooled to room temperature, diluted with ethyl acetate and washed with saturated ammonium chloride solution, water and brine. laňkou. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The obtained solid was purified by column chromatography eluting with a gradient of 2% methanol in dichloromethane to 5% methanol in dichloromethane to give 4.79 g (10.3 mmol) of the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.80 (s, 1H), 8.48 (d, 1H), 7.90 (d, 1H), 6.51 (s, 1H), 7.39 (m, 5H), 5.45 (d,. 1H), 5.19 (s, 2H); 4.90 (AB, 2H); 4.30 (m, 1H); 3.49 (m, 1H); 2H), 2.75

(m, 1H); 2.10 (m, 1H); 1.78 (s, 9H). Ion spray MS, [M + H] + = 465.

E. 2- [3- (S) -Amino-2-oxo-pyrrolidin-1-ylmethyl) -pyrrolo [3,2-c] pyridine-1-carboxylic acid tert-butyl ester

2.8 g (6.0 mmol) of 2- [3- (S) -benzyloxycarbonylamino-2-oxo-pyrrolidin-1-ylmethyl) -pyrrolo [3,2-c] pyridine-1-carboxylic acid tert-butyl ester in 30 ml of a 4.4% solution of formic acid in methanol is rapidly added via cannula to a solution of 2.0 g (18.8 mmol) of palladium black in 1 ml of water. After about 40 minutes, the catalyst was filtered through diatomaceous earth and the pH was adjusted to basic with saturated sodium bicarbonate solution. The filtrate was evaporated in vacuo to remove methanol, and the resulting solution was extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The white solid obtained can be used in the next step without further purification. Compound

205 The title product is purified as follows to prepare the sulfonamide library. The crude solid was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 100% acetonitrile. Appropriate fractions were combined and neutralized with saturated aqueous sodium bicarbonate solution, then evaporated. a. removing acetonitrile. The aqueous layer was extracted four times with dichloromethane and the organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to a residue.

to obtain the title compound in form white firmly substances. ¹ H NMR (CDCl 3, 300 MHz) δ 8.80 (with, IH), 8.43 (d, 1H), 7.90 (d, IH), 6.41 (s, IH), 4.88 (AB, 2H), 3.65 (m, 1H) 3.4S (m, 2H), 2.55 (m, 1H), 1.90 (m, 1H), 1.75 (with., 9H). Ion

spray MS, [M + H] &lt; ⁺ &^gt; = 331.

F. 5-Chloro- (2,2 ') -bithiophenyl

The title compound was prepared from 2-chloro-thiophene according to the procedure described in Bull. Chem. Soc. Japan, 1979, 1126. The crude product was purified by column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 10% ethyl acetate in hexane to give a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 7.24 (m, 1H), 7.11 (d,

1H), 7.03 (dd, 1H), 6.94 (d, 1H), 6.83 (d, 1H). EI MS, [M] &lt; ⁺ &^gt;

200, 202, Cl isotopes.

G. 5'-Chloro- [2,2 '] bithiophenyl-5-sulfonyl chloride)

The title compound was prepared according to the procedure for EXAMPLE 57, Part A using 5-chloro- [2,2 '] - bithiophenyl instead of thieno [2,3-b] pyridine. The crude product is purified by column chromatography, eluting with a gradient of 5% ethyl206, with a gradient of 5% ethyl206. Acetate in hexane to 10% ethyl acetate in hexane to give a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 7.76 (d, 1H), 7.14 (d,

1H), 7.09 (d, 1H), 6.92 (d, 1H). EI MS, [M] ⁺ = 298, 300, Cl isotopes.

H. 2- [3- (S) - (5'-Chloro - [2,2 '] bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -pyrrolo [3,2-c] tert-butyl ester pyridine-1-carboxylic acid

The title compound was prepared according to the procedure for EXAMPLE 56, Part A using 5'-chloro [2,2 '] bithiophenyl-5sulfonyl chloride and 2- [3- (S) -amino-2-oxopyrrolidine tert -butyl ester -1-ylmethyl] -pyrrolo [3,2c] pyridine-1-carboxylic acid starting material. The crude product can be purified by column chromatography eluting with 5% methanol in dichloromethane to give the title compound as a white solid or used in the next step after aqueous work-up without purification.

Ion spray MS, [M + H] ⁺ = 593, 595, Cl isotopes.

I. 5'-Chloro- [2,2 '] bithiophenyl-5 [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide sulfonic acids

1.0 ml (13.0 mmol) of trifluoroacetic acid was added dropwise at 0 ° C to a suspension of 0.13 g (0.22 mmol) of 2- [3- (S) - (5'-chloro [2.2] tert -butyl ester). bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] pyrrolo [3,2-c] pyridine-1-carboxylic acid in 2 mL of dichloromethane. After 30 minutes, the ice bath was removed and the solution was stirred at room temperature for 4 hours. The reaction mixture was evaporated to dryness and the crude product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 100% acetonitrile. pří207

good product-containing fractions were lyophilized to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz)

12.78 (s, 1H), 9.18 (s, 1H), 8.55 (d, IH); (d, 1 H), 7.61 (d, 1 H), 7.38 (d, 1H), 7.36 1H), 6.91 (with, 1H), 4.70 (AB, 2H) 4.21 (m, 2.25 (m, 1H), 1.75 (m, 1H). Ion spray MS,

isotopes.

δ 14.60 (bs, 1H), 8.40 (d, 1H), 7.88 (d, 1H), 7.2 t (d, 1H),

Δ), 3.30 (m, 2H), [M + H] ⁺ = 493, 495, Cl

Example 60 2- (5-Chloro-thiophen-2-yl) -ethenesulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide

A. 2- (5-Chloro-thiophen-2-yl) -ethenesulfonic acid ethyl ester

1.6 ml (4.0 mmol, 2.5M in hexane) n-Butyllithium is added dropwise at -78 ° C to a solution of 1.0 g (3.8 mmol) of ethyldiethylphosphoryl methanesulfonate prepared according to the procedure described in Tetrahedron, 1987, 43 (21), 5125, in 15 mL tetrahydrofuran. The mixture was stirred for 20 minutes, then 0.45 ml (4.2 mmol) of 5-chloro-2-thiophenecarboxaldehyde was slowly added. The yellow mixture was stirred at -78 ° C for 1 hour, then allowed to warm overnight. to room temperature. The solvent was evaporated and the residue was treated with 2 ml of water and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with dichloromethane to give the title compound as a yellow solid.

NMR (CDCl 3, 300 MHz) δ 7.55 (d, ΙΗ), 7.11 (d, ΙΗ), 6.90 (d, 1H), 6.41 (d, ΙΗ), 4.20 (kv, 2H), 1.39 (t, 3H). Ion spray MS, [M + H] &lt; ⁺ &^gt; = 253.

• «· · · ·

«. «

208 ·· • · 4 4 • 4 4 4 4

4 4 4 4 4 4

4 4 4 4 4 5

444 44 44

B. 2- (5-chloro-thiophen-2-yl) ethene tetra-n-bulylammonium sulfonate

0.92 g (3.2 mmol) of 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid ethyl ester in 16 ml of acetone was treated with 1.3 g (3.5 mmol) of tetrabutylammonium iodide. and reflux for 19 hours. The mixture was evaporated to dryness then. Dilute with dichloromethane and wash with water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to give an oily solid, which was used in the next step without purification.

¹ H NMR (CDCl 3, 300 MHz) δ 7.28 (d, 1H), 6.81 (d, IH), 6.77 (d, IH), 6.73 (d, IH), 3.29 ( t, 8H), 1.65 (m, 8), 1.45 (m, 8H), 1.00 (t, 12H).

C. 2- (5-chloro-thiophen-2-yl) -ethenesulfonyl chloride

Sulfuryl chloride (0.61 mL, 7.6 mmol) was added to a solution of triphenylphosphine (1.8 g, 6.9 mmol) in dichloromethane (8.6 mL) at 0 ° C. Remove the left bath and add 1.6 g (3.4 mmol) of 2- (5-chloro-thiophen-2-yl) -ethentetran-butylammoniumsulfonate in 17 mL of dichloromethane via cannula. The resulting yellow solution was stirred for 1.5 hours, then 200 mL of 1: 1 v / v hexane / ether was added until the solution became clear and the layers separated. The solution is decanted and the bottom oil layer is discarded. The solution was evaporated to dryness and the product was purified by column chromatography eluting with dichloromethane to give the title compound as a pale yellow solid.

^X H NMR (CDCl₃, 300 MHz) δ 7.71 (d, IH), 7.25 (d, IH), 7.00 (d, 1Ή), 6.91 (d IH _s). EI MS, [M] ⁺ = 242, 244, 246, Cl isotopes.

209

• «9 • · · • · '09 00 09 0 9 0 « 9 .0 9 '9 9 0 9. 9 • 9 9 · • • 9 '· 0 9 9 0 0 0 · 0 9 0 0 0 • 0 0 0

D. 2- {3- (S) - [2- (5-Chloro-thiophen-2-yl) -ethenesulfonylamino] -2-oxo-pyrrolidin-1-ylmethyl} -pyrrolo [3,2-p] pyridine-1-carboxylic acid tert-butyl ester

The title compound was prepared according to the procedure for EXAMPLE 56, Part A using 2- (5-chloro-thiophen-2-yl) -ethenesulfonyl chloride and 2- [3- (S) -amino-2-oxo-pyrrolidine-1- tert -butyl ester ylmethyl] -pyrrolo [3,2-c] pyridine-1-carboxylic acid starting material. The crude product can be purified by column chromatography eluting with 5% methanol in dichloromethane to give the title compound as a white solid or used in the next step after aqueous work-up without purification.

¹ H NMR (CDCl 3, 300 MHz) δ 8.75 (s, 1H)., 8.46 (d,

1H), 7.85 (d, IH), 7.48 (d, IH), 7.05 (d, IH), 6.85 (d, IH), 6.67 (d, IH), 6, 40 (s, 1H), 4.90 (AB, 2H), 4.15 (m, 1H), 3.49 (m, 2H), 2.71 (m, 1H), 2.21 (m 1 H, 1.7 (s, 9H). Ion spray

MS, [M + H] ⁺ = 537, 539, Cl isotopes.

E. 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid (2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl) -amide

The title compound was prepared according to the procedure for EXAMPLE 59, Part 1 using 2- {3- (S) - [2- (5-chloro-thiophen-2-yl) -ethenesulfonylamino] -2-oxo-pyrrolidine- lylmethyl} -pyrrolo [3,2-c] pyridine-1-carboxylic acid starting material. The crude product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 100% acetonitrile. The appropriate product-containing fractions were lyophilized to give the title compound as a white solid.

210 ^X1 H NMR (CDCl3, 300 MHz) δ 9.19 (s, 1H), δ 9.19 (s, 1H), δ 9.19 (s, 1H), · · ··· ····. ·· · «·· ·

8,4 8 (d, IH)., 7.91 (d, IH) 7.88 (d, IH), 7.50 (d, IH) 7.43 (d, IH), 7.20 (d, 1H), 7.02 (d, IH), 6.90 with, 1H), 4.71 (AB, 2H), 4.12 (m, . IH), 3.21 (m, 2H), .2,42 (m, IH), 1.85 (m, IH).

EI MS, [M] ⁺ = 436, 438, Cl isotopes.

Example 61 5'-Chloro- [2,2 '] bithiophenyl-5-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide

A. 5'-Chloro- [2,2 '] bithiophenyl-5-sulfonic acid [1- (1-chloroisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) yl] amide

The title compound was prepared according to the procedure for EXAMPLE 56, Part A using 5'-chloro [2,2 '] bithiophenyl-5sulfonyl chloride and 3- (S) -amino-1- (1-chloro-isoquinoline-7) hydrochloride. -ylmethyl) -pyrrolidin-2-one starting materials. The crude product was purified by column chromatography eluting with 5% methanol in dichloromethane to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 8.30 (d, 1H), 8.15 (s,

1H), 7.82 (d, IH), 7,52-7,60 (m, 3H), 7,01-7,09 (m, 2H) 6.88 (d, 1H), 5.41 (with, 1H), 4.68 (AB, 2H), 3.90 (m, 1H), 3.29 (m, 2H), 2.61 (m, IH), 2.11 (m, IH) '. Ion spray MS, [M + H] ⁺ = 538.

540, Cl isotopes.

5'-Chloro- [2,2 '] bithiophenyl-5-sulfonic acid B, [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) yl] -amide

The title compound was prepared according to the procedure for EXAMPLE 56, Part B using [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide 5 ¹ -chloro [2, 2 '] Bithiophenyl -5-sulfonic acid starting material. Surový profl

Flfl

4 4 1 flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl

The 44 product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid to 100% acetonitrile). The appropriate product-containing fractions were lyophilized to give the title compound as a white solid.

¹ H NMR (CDCl 3, 300 MHz) δ 9.03 (bs, 2H),

8.58 (d, 1H), 8.31 (s, 1H), 7.95 (d, 1H), 7.81. (d, 1H), 7.69 (d, 1H), 7.61 (d, IH); 7.30 -7.41 (m, 2H), 7,29- 7.25 (m, 2H),  4.60 (AB, 2H), 4.25 (m, 1H), 3.23 (m, 2H), 2.20 (m, 1H), 1, 75

(m, 1 H). Ion spray MS, [M + H] ⁺ = 519,521, Cl isotopes.

Example 62 2- (5-Chloro-thiophen-2-yl) -ethenesulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

The title compound was prepared according to the procedure for EXAMPLE 56, Part B using 2- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid starting material. The crude product was purified by reverse phase HPLC eluting with a gradient of 10% acetonitrile in water (0.1% trifluoroacetic acid) to 100% acetonitrile. The appropriate product-containing fractions were lyophilized to give the title compound of m.p. form of light pink solid.

¹ H NMR (CDCl 3, 300 MHz) δ 9.00 (bs,

8.32 (with, 1H), 7.90 -7.98 (m, 2H), 7.80 (d, 1H), 7.63 (d, 7.50 (d, 1H), ' 7.48 (d, 1H), 7.25 (d, 1H), 7.18 (d, 1 H), (d, 1H), 6.73 (d, 1H), 4.52 (AB, 2H) 4.20 . (m, 1H), 3.23 2H), 2.4 ₈ (m, 1H), 1.88 (m, 1H). Ion spray • MS, [M + H] &lt; + &gt; ^. 465, Cl isotope y-

2H), 1H), 7.0 (m,

463, •. 0 0 0 0 0 0 0 0 0 0

91? ·· ♦ ·····

0000000 · * · <· ·

Example 63 6-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (4-amino-quinazolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

The title compound was prepared according to the procedure for EXAMPLE 28, Parts E, F, G using 6-chloro-benzo [b] thiophene-2-sulfonyl chloride.

¹ H NMR (CDCl 3, 300 MHz) δ 9.83 (bs, 2H),

8.86 (m, 2H), 8.25 (s, IH), 8.11 (with, . IH) , 8.00 (m, 3H) 7.85 (m, 2H), 7.55 (m, 1H) 4.50 (AB, 2H) , 4, 15 (m, 1H), 3.14 (m, 2H), 2.17 (m, 1H), 1.72 (m, IH). FAB MS, [M + H] &lt; ⁺ &^gt; = 488,490 z · Cl

isotopes.

Example 64 6-Chloro-benzo [b] thiophene [1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate -sulfonic acids

The title compound was prepared according to the procedure for EXAMPLE 29, parts F, G and H, using 6-chlorobenzo [b] thiophene-2-sulfonyl chloride.

¹ H NMR (CDCl 3, 300 MHz) δ 8.78 (m, 2H),

8.28 (m, 2H), 8.04 (m, 2H), 7.82 (m, 2H), 7.51 (d, 1H), 7.40 (s, 1H), 4.58 (AB) 2H, 4.13 (m, 1H), 3.19 (m, 2H), 2.17 (m, 1H), 1.68 (m, 1H). FAB MS, [M + H] &lt; + &^gt; = 494, 496; Cl isotopes.

Example 65 6-Chloro-benzo [b] thiophene [1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate -sulfonic acids i

213 • ··· ·····································

The title compound was prepared according to the procedure for EXAMPLE 30, Part D, E using 6-chloro-benzo [b] thiophene-2-sulfonyl chloride.

^{Χ Η} NMR (DMSO-d₆, 300 MHz) δ 8.52 (m, 2H);

8.20 (m ,. IH), 8.11 (with, IH), 7.91 (m, 2H), 7.71 (s, 1H), 7.42 (m, IH), 7.30 (m,, 2H), 4.58 (AB, 2H) 4.15 (m, 1H), 3.21 (m, 2H), 2.20 (m, 1H), 1.72 (m, IH). FAB MS, [M + H] &lt; ⁺ &^gt; 494,496; Cl

isotopes.

Example 66 5'-Chloro- [2,2 '] bithiophenyl [1- (4-aminothieno [3,2-d] pyrimidin-7-ylmethyl) 2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate -5-2sulfonic acids

The title compound was prepared according to the procedure for EXAMPLE 30, Part D, E using 5'-chloro [2,2 '] bithiophenyl-5-sulfonyl chloride.

¹ H NMR (CDCl 3, 300 MHz) δ 9.30 (m, 2H),

8.70 (m, IH), 8.44 (m, IH), 8.20 (m, 1H), 7.55 (m, 1H), 7.21 (m, 2H), 7.00 (nt, IH), 4.57 (AB, 2H) 4.15 (m, 1H), 3.20 (m, 2H)., 2.19 (m, IH), 1.70 (m, IH). FAB MS, [M + H] &lt; + &gt; ^. = 526.528; Cl

isotopes.

Example 67 2- (3- (S) -Amino-2-oxo-pyrrolidin-1-ylmethyl) -pyrrolo [3,2-b] pyridine-1-carboxylic acid tert-butyl ester

A. (2-Bromo-pyridin-3-yl) -carbamic acid tert-butyl ester

To a solution of 1.5 g (8.7 mmol) of 3-amino-2-bromopyridine and 2.0 g (9.2 mmol) of di-tert-butyl dicarbonate in 15 mL of tetrahydrofuran at 0 ° C was added 18 mL mmol) of 1.0 M sodium bis (trimethylsilyl) amide214 hours at saturated solution temperature and washed with water.

in tetrahydrofuran. The mixture was stirred for 4 rooms and then evaporated, quenched with ammonium chloride, diluted with ethyl acetate

The organic layer was dried over magnesium sulfate, treated with charcoal, filtered and evaporated to dryness. 2.1 g (7.7 mmol) of the title compound are obtained as a light yellow solid.

^τ Η NMR (CDCl 3, 300 MHz) δ 8.44 (d, 1H), 8.03 (d,

1H), 7.20 (m, 1H), 7.12 (bs, 1H), 1.50 (s, 9H). EI MS [M + H] &lt; ⁺ &^gt;

273, 275.

B. 2- (3- (S) -Amino-2-oxo-pyrrolidin-1-ylmethyl) -pyrrolo [3,2-b] pyridine-1-carboxylic acid tert-butyl ester

The title compound was prepared from 1.6 g (5.9 mmol) of (2-bromo-pyridin-3-yl) -carbamic acid tert-butyl ester and

1.6 g (5.9 mmol) of (2-oxo-1-prop-2-ynyl-pyrrolidin-3- (S) -ylcarbamic acid benzyl ester) according to the procedure described in Example 59, Parts C, D and E. 29 g (0.88 mmol) of the title compound as a white solid.

¹ H NMR (CDCl 3, 3.00 MHz) δ, 8.45 (d, 1H),. 8.27 ¹ (d,

1H), 7.18 (dd, 1H), 6.50 (s, 1H), 4.90 (AB, 2H), 3.64 (m, 1H),

3.45 (m, 2H), 2.52 (m, 1H), 1.85 (m, 1H), 1.70 (s, 9H). EI MS [M + H] + = 331.

Example 68

6-Chloro-ΙΗ-benzimidazole-2-sulfonyl chloride

A mixture of 4.3 g (30 mmol) of 4-chloro-1,2-phenylenediamine (4/3 g, 30 mmol), 1.9 g (34 mmol) of potassium hydroxide, 2.1 ml (34 mmol) of carbon disulfide, ml of ethanol and 4.5 ml of water are heated at reflux for 3 hours. Add Dive, heat the mixture • 9 9 9 9 99 99 · ····

215 ············· 99 · 9 ·· reflux for 10 minutes, then filter. The hot filtrate is diluted with 30 ml of water at 50-75 ° C, then 7.5 ml of 33% aqueous acetic acid is added with stirring. A brown solid formed and the mixture was cooled in an ice bath. 4.2 g (2.3 mmol) of 6-chloro-1H-benzimidazole-2-thiol are separated, washed with water and dried in vacuo.

¹ H NMR (CDCl 3, 300 MHz) δ 7.75 (m, 2H), 7.50 (d,

ÍH).

Example S9

Thieno [2,3-b] pyridine-2-sulfonyl chloride

1.18 g (8.7 mmol) of Thieno [2,3-b] pyridine are reacted in. The crude product was purified by flash chromatography eluting with 20% ethyl acetate in hexane to give 0.59 g (2.5 mmol) of the title compound:

¹ H NMR (CDCl 3, 300 MHz) δ 8.78 (dd, 1H), 8.26 (dd,

1H), 8.10 (s, 1H), 7.47 (dd, 1H). EI MS [M] ⁺ = 233, 235.

Example 70

6-Chloro-thieno [2,3-b] pyridine-2-sulfonyl chloride

0.73 g (4.3 mmol) of 6-chloro-thieno [2,3-b] pyridine is reacted in three steps according to the procedure described in Example 8, Part A. After purification of the crude product by flash chromatography eluting with 15 % ethyl acetate in hexane gave 0.75 g (2.8 mmol) of the title compound:

¹ H NMR (CDCl 3, 300 MHz) δ 8.19 (d, 1H), 8.07 (s,

1H), 7.47 (d, 1H). EI MS [M] ⁺ = 267,269,271.

216

44 ····· 44 «4 · 4 444

444 4 44 4 4 5

4444 444

4444444 44 44 44 444

The compounds of Examples 71 to 74 were synthesized using methods and reagents analogous to those described above.

Example 71 Thieno [3,2-b] pyridine-2-sulfonic acid [1- (1,6-diaminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

EI MS, [M] ⁺ = 469.

Example 72 2- (5-Chloro-thiophen-2-yl) -ethenesulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

ESI MS, [M + H] ⁺ = 463, 465 (Cl isomers).

Example 73 [1- (l-amino-isoquinolin-7-ylmethyl) -2-o-o-pyrrolidin-3- (S) -yl] -amide ^5-Chloro-1 [2,2 '] bithiophenyl-5-sulfonic acid acid

EI MS, [M + H] ⁺ = 519, 521 (Cl isomers).

Example 74 2- (5-Chloro-thiophen-2-yl) -amide (2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl) -amide - ethenesulfonic acids

EI MS, [M + H] 436, 438. (Cl isotopes).

Example 75 3- (R) -5-Chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate [1- (4-Amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide · · · · · ·

217

Part A 7-Methyloxycarbonyl-4-chloroquinoline

5.0 g (21.6 mmol) of 4-Chloro-7-trifluoromethylquinoline in 100 ml of 80% sulfuric acid was heated in a sealed vessel at 200 ° C for 24 hours. The solution was cooled, poured into water and neutralized with sodium hydroxide to pH 3-4. The precipitated solid was collected, washed with water and dissolved in 2N sodium hydroxide. The aqueous solution was washed with ethyl acetate, then acidified to pH 3-4. The precipitate was collected, washed with water and dried in a vacuum oven overnight to give 5.1 g (24.6 mmol) of 7-carboxy-4-chloroquinoline. 2.0 g (9.6 mmol) of this material was treated with 200 ml of tetrahydrofuran and 2 ml of dimethylformamide and 14.5 ml (29 mmol) of 2M oxalyl chloride in dichloromethane, and the resulting suspension was stirred at room temperature for 2 hours. After stirring for 30 minutes, the solution was evaporated and the residue taken up in dichloromethane, washed with saturated sodium bicarbonate solution and dried over sodium sulfate and evaporated to give 2.1 g (9.5 mmol) of the title compound. title compound. MS m / z: m ⁺ = 221; ^X H NMR (CDCl 3Ό0 MHz) δ 8.6 (s, IH), 8.2 (s, IH), 7.9 (d, IH), ' 7.65 (d, 1H), 7.45 (s, 1H), 3.95 (s, 3H).

Part B 7-Hydroxymethyl-4-chloroquinoline

7-Methyloxycarbonyl-4-chloroquinoline (2.1 g, 9.5 mmol) was dissolved in tetrahydrofuran (25 mL) and anhydrous ether (200 mL). The solution was cooled in a dry ice / acetone bath and treated with 11.0 mL (11.0 mmol) of a 1M solution of lithium aluminum hydride in tetrahydrofuran. The solution was warmed to about -45 ° C for about 20 minutes and quenched with ethyl acetate. The solution is diluted with 100 ml of ether and treated with 36 ml of water, 36 ml of 15% sodium hydroxide solution and three times with 36 ml of water. The mixture was filtered and evaporated

218

0 0 0 0.0 0 0 00 0 0 00 0 0 0 0 0 000 0 000 0 0 0 0 0 0 0 0 0 0 0 0

2.0 g (9.7 mmol) of the title compound is obtained, which is dried under vacuum and used in the next reaction without purification.

MS m / z: M <^+> = 193; ¹ H NMR (CDCl 3, 300 MHz) δ 0.00, 8.65 (d, 1H), 8.15 (d, 1H), 8.0 (d, 1H), 7.6 (d, 1H), 7.45 (d, 1 H), 4.8 (s, 2 H).

Part C 7-Bromomethyl-4-chloroquinoline

0.2 g (0.97 mmol) of 7-hydroxymethyl-4-chloroquinoline was treated with 48% hydrobromic acid and heated at 120 ° C for 1 hour. The resulting solution was cooled with ice, diluted with water and treated with ethyl acetate and sodium bicarbonate until basic by pH paper. The layers were separated and the organic layer was washed with water, dried over sodium sulfate and evaporated to give 0.23 g (0.9 mmol) of 7-bromomethyl-4-chloroquinoline.

MS m / z: M &lt; ⁺ & gt ^; = 255; ¹ H NMR (CDCl 3, 300 MHz) δ 8.75 (d, 1H), 8.25 (d; 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.5 ( d, 1H),

4.7 (s, 2 H).

Part D 3-Amino-1- (4-chloroquinolin-7-ylmethyl) -2-oxopyrrolidinone hydrochloride

Dissolve 1.0 g (5.0 mmol) of 3- (R) - (t-butylcarbamyl) -2-oxopyrrolidinone in 70 ml of tetrahydrofuran, cool in an ice bath and react with 0,18 g of tretrabutylammonium iodide and 24 g (6.0 mmol) of 60% sodium hydride. The reaction mixture was stirred at 0 ° C for 30 min, then treated dropwise with a solution of 1.3 g (5.1 mmol) of 7-bromomethyl-4-chloroquinoline in 50 mL of tetrahydrofuran. The resulting solution was stirred at 0 ° C for 2 hours, then quenched with ammonium chloride and evaporated. The residue was diluted with ethyl acetate, washed with water, the organic layer was dried over sodium sulfate and evaporated. The residue was purified by chromatography, eluting with 3% methanol in dichloromethane, to give 1.3 g (3.3%).

219 3- (R) - (t-butylcarbamyl) -1- (4-chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidinone as a solid 219 . This was treated with a saturated solution of hydrogen chloride in ethyl acetate and stirred at room temperature for 2 hours. The solid was filtered off, washed with ethyl acetate and dried to give 0.95 g (3.0 mmol) of the title compound.

MS m / z: M &lt; ⁺ &^gt; ¹ H NMR (CDCl 3, 300 MHz) δ 9.0 (d, 1H), 8.5 (d, 1H), 8.15 (s, 1H), 8.0 (d, IH), 7.9 ( d, 1H), 4.9 (qu, 2H), 4.2 (t, 1H), 3.4 (m, 2H), 2.65 (m, 1H), 2.1 (m, 1H).

Part E 3- (R) -5-Chloro-thiophen-2-yl) -ethenesulfonic acid [1- (4-chloro-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide

40.0 mg (0.12 mmol) of 3-amino-1- (4-chloroquinolin-7-ylmethyl) -2-oxopyrrolidinone hydrochloride are treated at 0 ° C with 2 ml of dimethylformamide, 8 ml of acetonitrile, 1.2 ml of (8, 4 mmol) of triethylamine and a solution of 30.0 mg (0.12 mmol) of 5-chlorothiophen-2-yl) -ethenesulfonyl chloride in 2.0 ml of acetonitrile. After 2 hours, the solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and evaporated to give 28 mg (0.5 mmol) of the title compound.

MS m / z: 481 [M + 1] ^&lt; ⁺ &^gt;; ¹ H NMR (CDCl 3, 300 MHz) δ 8.8 (d, 1H), 8.15 (d, 1H), 7.9 (d, 2H), 7.85 (s, 1H), 7.4- 7.5- (m, 2H), 6.7 (d, 1H), 6.6 (d, 1H), 6.5 (d, 1H), 5-, 8-5.9 (m, 1H), 4.75 (qu, 2H), 4.2 (t, 1H), 3.3-3.4 (m, 2H), 2.6 (m, 1H), 2.0 (m, 1H).

Part F 3- (R) -5-Chloro-thiophen-2-yl) -ethenesulfonic acid [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide

9999

9 9 · 99 9 999

9 9 9 9 9

OOn * · 999 9999

220 99 9900 99

999 9999 99 99 99 9 mg of 3- (R) -5-chloro-thiophen-2-yl) -ethenesulfonic acid [1- (4-chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide, 0, 5 g of ammonium acetate and 1.0 g of phenol are heated in a sealed vessel at 120 ° C for 1.5 hours. The contents of the flask were diluted with ethyl acetate and washed four times with 100 ml of 1N sodium hydroxide solution, water, evaporated and purified by HPLC eluting with 20% acetonitrile in 0.1% aqueous trifluoroacetic acid to 100% acetonitrile) and lyophilized to give 2 0 mg of the title compound: MS m / z: 463 [M + H] ⁺ Η NMR (CDCl3, 3.0 MHz) δ 8.3 (m, 1Ή), 7.7 (s, 1H) , 7.6 (d, 1H), 7.5 (d, 1H), 7.2 (d, IH), 7.0 (s, IH), 6.9 (d, IH), 6.8 ( d, 1H). 4.9 (kv, 2H), 4.25 (t, 1H), 3.5 (m, 2H), 2.6 (m, 1H), 2.05 (m, 1H).

The compounds of Examples 76 to 81 were prepared using analogous methods and reagents as described above.

Example 76

2- (S) - [. [1- (4-Amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] - (6-chloro-benzo [b] thiophene-2-sulfonyl) -amino] -acetic acid trifluoroacetate- acid

ESI MS, [M + H] &lt; ⁺ &^gt; = 559, 561.

Example 77 2- (S) -6-Chloro-benzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (4-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide

ESI-MS, [M + H]; = 487.489.

0

221 · 00 · 00 0 · 0 0 0

0 · · ·

0 0 0 0 0

9 9 0 9 8

99 90

Example 78 2- (S) - (5-Chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide

ESI MS, [M + H] &lt; ⁺ &^gt; = 463, 465.

Example 79

Thieno [3,2-b] pyridine-2-sulfonic acid [1- (4-aminoquinolin-6-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] amide trifluoroacetate

ESI MS, [M + H] &lt; ⁺ &^gt; = 454.

Example 80

N- (3-Amino-pyridin-4-yl) -2- [3- (7-methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -acetamide

MS, [M + H] = 470.

Example 81

2- [3- (7-Methoxynaphthalene-2-sulfonylamino) -2-oxopyrrolidin-1-yl] -N-pyridin-4-ylacetamide

MS: [M + H] &lt; ⁺ &^gt; = 455.

Example 82 6-Chlorobenzo [b] thiophene-2-sulfonic acid trifluoroacetate {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3- (S) -yl} -amide

Part A [1- (2-Amino-ethyl) -2-oxo-pyrrolidin-3 (S) -yl] -carbamic acid tert-butyl ester

4.0 g (20 mmol) of [2-oxo-pyrrolidin-3 (S) -yl] -carbamic acid tert -butyl ester are dissolved in 150 ml of tetrahydrofuran. φφ φ φφφ ·

727 ° C is cooled in an ice bath and treated with 0.95 g (24 mmol) of 60% sodium hydride. The reaction mixture was stirred for 30 minutes, then treated with 0.16 g (0.044 mmol) of tetrabutylammonium iodide and 1.7 mL (24 mmol) of bromoacetonitrile. After 3 hours, quench the reaction with water, evaporate to a small volume and extract four times with dichloromethane. The combined organic extracts were evaporated and the residue purified by chromatography eluting with 2% methanol in dichloromethane to give [1-cyanomethyl-2-oxo-pyrrolidin-3 (S) -yl] -carbamic acid tert-butyl ester 3.4 g (14 mmol). EI MS: m / z: 240, [M + 1] ^&lt; ⁺ &^gt;; ¹ H NMR (CDCl 3, 300 MHz) δ 5.08 (b, 1H), 4.27. (m, 2H), 4.15 (m, 1H), 3.47 (m, 1H), 2.68 (m, 1H), 2.00 (m, 1H), 1.45 (s; 9H) ). This material (3.0 g, 12.6 mmol) was dissolved in ethanol (80 ml) and treated with platinum oxide (0.8 g) at 50 psi hydrogen pressure for 24 hours. The catalyst was filtered off and the solution was evaporated to give 2.9 g (12 mmol) of the title compound. EI MS m / z: 244, [M + 1] ^&lt; ⁺ &^gt;; ^X H NMR (CDCl₃, 300 MHz) δ .5,13 (br, 1H) ,. 4.13 (m, 1H); 3.34 (m,

5H), 2.85 (t, 1H), 2.60 (m, 1H), 1.90 (m, 1H), 1.40 (s, 9H).

Part B {2-Oxo-1- [2- (2,3,5,6-tetrachloro-pyridin-4-ylamino) -ethyl] -pyrrolidin-3 (S) -yl} -carbamic acid tert-butyl ester acid

[1- (2-Aminoethyl) -2-oxo-pyrrolidin-3-yl] -carbamic acid tert-butyl ester (2.7 g, 11 mmol) is dissolved in 100 ml of dichloromethane and treated with 3.2 g (12 mmol). 4-nitro-2,3,5,6-tetrachloropyridine and 2.6 mL (24 mmol) of N-methylmorpholine. The reaction mixture was stirred for 5 hours, evaporated and the residue purified by chromatography eluting with 50-60% ethyl acetate in hexane to give 3.2 g (7.0 mmol) of the title compound. EI MS

m / z: 456, 458, 460, 462 [M] ^&lt; ⁺ &^gt;; ¹ H NMR (deuterochloroform, 3 00 MHz) δ 5.6 (W, 1H), 5.07 (W, 1H), 4.15 (m, 1H); 3.94 (m, 2H), 3.60 (m, 2H); 3.36 (m, 2H); 2.65 (m, 1H), 1.98 (m, 1H), 1.44

(s, R H).

223 • ···································

Part C 3- (S) -Amino-1- [2- (pyridin-4-ylamino) ethyl] pyrrolidin-2-one

0.42 g (0.92 mmol) {2-oxo-1- [2- (2,3,5,6-tetrachloropyridin-4-ylamino) ethyl] pyrrolidin-3 (S) -yl] carbamate tert-butyl ester Dissolve in 16 ml of methanol and react with 18 ml. (8 mmol) of a 0.5 M sodium methoxide solution. The solution is treated with 10% palladium on carbon and shaken for 16 hours at 50 psi of hydrogen. The solvent was evaporated and the residue was treated with a saturated ammonium chloride solution and then a saturated sodium bicarbonate solution. The aqueous layer was extracted eight times with dichloromethane. The dichloromethane layer was dried over magnesium sulfate and evaporated to give 0.19 g (5.9 mmol) of a white foam.

EI MS m / z: 321, [M + 1] ^&lt; ⁺ &^gt;; @ ¹ H NMR (CDCl3, 300 MHz) .delta

8.20 (d, 2H), 6.45 (d, 2H), 5.1 (b, 1H), 4.9 (b, 1H), 4.1 (m, 1H), 3.7 (b, 1H); m, 1H), 3.4 (m, 5H), 2.57 (m, 1H), 1.96 (m, 1H), 1.46 (s, 9H). 0.14 g (0.44 mmol) of this material was treated with 10 ml of 15% trifluoroacetic acid in dichloromethane at room temperature for 2 hours. Evaporation of the solution gave the pure product as the trifluoroacetic acid salt. 0.072 g (0.33 mmol) of the free base is obtained after loading trifluoroacetate on a silica gel column and eluting with a mixture of ammonium hydroxide, methanol and dichloromethane (1:10:70). APCl MS m / z: 221, [M + 1] ^&lt; ⁺ &^gt;; ¹ H NMR (CDCl 3, 300 MHz) δ 8.17 (d, 2H), 6.40 (d, 2H), 4.90 (b, 1H), 3.55 (m, 3H), 3, 34 (m, 4H), 2.42 (m, 1H), 1.80 (m,

IH).

Part D 6-Chlorobenzo [b] thiophene-2-sulfonic acid trifluoroacetate {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3- (S) -yl} -amide

0.12 mmol of 3- (S) -Amino-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-2-one (0.12 mmol) was dissolved in 5 mL of acetonitrile and rea224

9999 • 9999 99 • 9 9 9 9 9

9

9 9 9 9 9

9

99 99 9 was treated with 0.035 ml (0.32 mmol) of 4-methylmorpholine, and 0.033 g (0.12 mmol) of 6-chlorobenzo [b] thiophene-2-sulfonyl chloride in 1 ml of acetonitrile was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, then purified by HPLC to give 0.060 g (0.11 mmol) of the title compound as a white solid. ^; MS m / z 451, 453 [M + 1] ^&lt; ⁺ &^gt;; ^X H NMR (deuteromethanol, 300 MHz) δ

8.15 (d, 1H), 8.05 (s, 1H), 8.0 (m, 2H), 7.03 (d, 1H), 6.96 (dd, 1H), 6.82 (dd, 1H), 4.05 (t, 1H), 3.60-3.35 (m, 6H), 2.37 (m, 1H), 1.83 (m, 1H).

The compounds of Examples 83-88 were prepared using analogous procedures and using analogous reagents as described above.

Example 83 5 'Chloro [2,2'] bithiophenyl-5-sulfonic acid {2-oxo-1- [2- (pyridin-4-ylamino) ethyl] pyrrolidin-3-yl] amide

MS, [M + H] ⁺ = 483,485-.

Example 84 6-Chloro-thieno [2,3-b] pyridine-2-sulfonic acid trifluoroacetate {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide

MS, [M + H] ⁺ = 452.445.

Example 85 Thieno [3,2-b] pyridine-2-sulfonic acid {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide ditrifluoroacetate

MS, [M + H] &lt; ⁺ &^gt; = 418.

225 • 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 99

999 99 99 99 99 99

Example 86

- (5-chloro-thiophen-2-yl) -ethenesulfonic acid (2-oxo-1- [2 (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl (amide)

MS, [M + H] ⁺ = 427.429.

Example 87 (S) -5'-Chloro- [2,2 '] amide (1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl ditrifluoroacetate bithiophenyl-5-sulfonic acid

MS, [M + H] &lt; ⁺ &^gt; = 532, 534, 536.

Example 88 (1- [2- (2-Amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl (S) -6-chloro-benzo [b] thiophene-2-sulfonic acid ditrifluoroacetate

MS, [M + H] &lt; ⁺ &^gt; = 500, 502, 504.

Example 89 ((6-Chlorobenzo [b] thiophene-2-sulfonyl)) - (2-oxo-1- [2 (pyridin-4-ylamino) ethyl] pyrrolidin-3-yl} amino) acetic acid methyl ester

To a solution of 6-chlorobenzo [b] thiophene-2-sulfonic acid in 2 mL of dimethylformamide was added 0.030 g (0.066 mmol) of (2-oxo-1- [2 (pyridin-4-ylamino) ethyl] pyrrolidine- (S) - After stirring at room temperature for 10 minutes, 0.01 ml (0.1 mmol) of bromoacetate was added and the mixture was stirred for 3 hours. The solvent was removed and the residue was purified by chromatography. eluting with ammonia, methanol and dichloromethane (1: 5: 95) to give 0.011 g (0.021 mmol) of the title compound as a white solid MS m / z 523,

226 • 4 4 44 4 4

44 44 4,444 · 4 4 · · 4 4 4 4

4 4 4 4 4 4

444 4444 44 44 44

525 [M + 1] ⁺ ; ¹ H NMR (deuterochloroform, 300 MHz) δ 8.15 (d, 2H), 7.98 . (s, 1H), 7.84 (s, 1H), 7.80 (d, 1H), 7.41 (d, ÍH), 6.35 (d, 2H), 4.72 (b, 1H), 4.55 (t, 1H), 4.18 (d, 1H), 3.85 (d, ÍH), 3.70 (s, 3H), 2.55 (m, 1H), 3.4 (m, SH), 2.60 (m, ÍH), 2.35 (m, 1H).

The compounds of Examples 90-100 were synthesized using methods and reagents analogous to those described above ...

Example 90 ((6-Chlorobenzo [b] thiophene-2-sulfonyl) {2-oxo-1- [2- (pyridin-4-ylamino) ethyl] pyrrolidin-3-yl} amino) acetic acid trifluoroacetate

MS, [M + H] ⁺ = 509,511.

Example 91 6-Chlorobenzo [b] thiophene-2-sulfonic acid allyl- {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -nyrrolidin-3-yl} -amide

MS. [M + H] ⁺ = 491.493.

Example 92 6-Chlorobenzo [b] thiophene-2-sulfonic acid methyl {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide

MS, [M + H] ⁺ = 465,467.

Example 93 (S) -2- (5-Chloro-thiophen-2-yl) -ethenesulfonic acid {1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} -amide trifluoroacetate φφ φ »··

227

Φ • • • φ φ

φ 'φ φ »φ φ» »»

MS, [+] ⁺ = 476, 478, 480.

Example 94 (S) -thieno [3,2-b] pyridine-2sulfonic acid (1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} -amide ditrifluoroacetate

MS, [M + H] &lt; ⁺ &^gt; = 467, 469.

Example 95 ([2- (5-Chloro-thiophen-2-yl) -ethenesulfonyl] - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid methyl ester

MS, [M + H] ⁺ = 499.501.

Example 96 ([2- (5-Chloro-thiophen-2-yl) -ethenesulfonyl] {2-oxo isopropyl ester

1- [2- (pyridin-4-ylamino) ethyl] pyrrolidin-3-yl} amino) acetic acids

MS, [M + H] ⁺ = 527.529.

Example 97 ([2- (5-Chloro-thiophen-2-yl) -ethenesulfonyl] {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid trifluoroacetate

MS, [M + H] &lt; ⁺ &^gt; = 485, 487.

··

228 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 98 2- (5-Chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate (2-methoxy-ethyl) - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide

MS, [M + H] ⁺ = 485. 487.

Example 99 ([2- (5-Chloro-thiophen-2-yl) -ethenesulfonyl] {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid trifluoroacetate

MS, [M + H] ⁺ = 513.515.

Example 100 3- (5-Chloro-thiophen-2-yl) -N- {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -acrylamide trifluoroacetate

MS, [M + H] ⁺ = 390.392.

Example 101 1- [1- (4'-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (4-chlorophenyl) urea trifluoroacetate

A. (2-Oxopyrrolidin-3- (S) -yl) carbamic acid tert -butyl ester g (92 mmol) of Na- (S) -tert-Butoxycarbonyl-α, γ-diaminobutanoic acid is suspended / dissolved in 360 ml of tetrahydrofuran, 15.5 g (100 mmol) of 1-hydroxybenzotriazole hydrate are added, followed by 28 g (280 mmol) of triethylamine. The suspension is stirred at room temperature for 15 minutes under a nitrogen atmosphere, then 22 g (115 mmol) of 1- [3- (dimethylamino) hydrochloride are added to the suspension.

polyl] -3-ethylcarbodiimide. The reaction mixture was heated at 60 ° C for 22 h, cooled, and the solid was filtered through a pad of silica gel. The solid and silica gel were washed with tetrahydrofuran until no more product appeared in the filtrate by TLC. The combined filtrates were evaporated and the remaining yellow, sticky substance was dried under high vacuum overnight. The remaining material was triturated with 100 mL of ethyl acetate, filtered and washed with ethyl acetate. and ethyl ether, then dried under high vacuum. 12.2 g (61 mmol) of product are isolated as colorless needles.

1 H-NMR (CDCl 3, 300MHz) δ 6.18 (m, 1H); 5.11 (m, IH); 4.15 (m, 1H); 3.35 (m, 2 H); 2.70 (m, 1H); 1.96 (m, 1H); 1.45 (s, 9H). ESI MS, [M + H] &lt; ⁺ &^gt; = 201.

B. 2-Benzylideneamino-4-methylbenzonitrile

Benzaldehyde (8.9 g, 84 mmol) was added to a suspension of 2-amino-4-methylbenzonitrile (10.0 g, 76 mmol) in heptane (250 mL) and the mixture was heated at reflux overnight. The hot solution was poured into a pre-heated flask to separate the brown insoluble matter and the solution was cooled to room temperature after addition of 2 mL of ethyl acetate. The solid obtained was filtered and washed twice with 25 ml of heptane / ethyl acetate and dried under high vacuum to give 12.54 g (57 mmol) of a beige powder.

1 H-NMR (CDCl 3, 300MHz) δ 8.46 (H, s), 7.95 (dd,

2H), 7.50 (m, 4H); 7.07 (dd, 1H); 6.97 (s, 1H); 2.43 (s, 3H).

C. 2-Amino-4- (bromomethyl) benzonitrile

1.31 g (8 mmol) of 2,2'-Azobisisobutyronitrile (AIBN) was added to a solution of 6.87 g (38 mmol) of N-bromosuccinimide and 7 g (31.8 mmol).

Of 2-benzylideneamino-4-methylbenzonitrile in 250 ml of carbon tetrachloride and the reaction mixture is heated to boiling under nitrogen overnight.

• · under reflux. The reaction mixture was cooled and filtered through a pad of diatomaceous earth and the diatomaceous earth was washed with 100 ml of carbon tetrachloride. The combined filtrates were washed with 1N hydrochloric acid solution, saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel. eluting with 10-20% ethyl acetate in hexane. The combined product fractions were evaporated and the sticky solid obtained was washed with ethyl acetate / hexane to give 3.26 g (15 mmol) of the product as a pale yellow solid.

^* H-NMR (CDCl, 300 MHz) δ .7,36 (d, 1H), 6.75 (m, 2H), 4.45 (bs, 2H), 4.35 (s, 2H). El MS. [M + H] &lt; ⁺ &^gt; = 212.

D. [1- (3-Amino-4-cyanobenzyl) -2-oxopyrrolidin-3- (S) -yl] carbamic acid tert -butyl ester g (5 mmol) of (2-oxopyrrolidin-3- (S) -yl) tert -butyl ester The carbamic acids were dissolved in 100 ml of tetrahydrofuran under nitrogen and cooled to 0 ° C. To the vigorously stirred solution was added 0.62 g (5.5 mmol) of potassium tert-butoxide in one portion, followed by 10 mg (0.038 mmol) of 18; -crown-6 and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The solution was cooled to 0 ° C and 1.16 g (5.5 mmol) of 2-amino-4- (bromomethyl) benzonitrile dissolved in 10 ml of tetrahydrofuran was added dropwise, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of 20 mL of 0.25 M hydrochloric acid solution, then neutralized with saturated aqueous sodium bicarbonate and brine was added. The solution is extracted with ethyl acetate and the organic phase is dried over magnesium sulphate, evaporated and purified by column chromatography on silica gel, eluting with a mixture of 0.5 to 5% methanol in dichloromethane. Product containing fractions were combined, evaporated and evaporated

• • · 0 • ·· ·· • 0 • 0 • 9 * 9 • 9 • 9 0 0 ’ «0 • 0 9 9 * 231 • * * 0 · 0 ······· ·· 0 9 9 • 0 • 9 • 9 the semi-solid oily residue was triturated with 25 ml mixtures Hexane and dichloromethane (100/1). Isolate 1.24 g (3.75 mmol). product in the form of a pale yellow powder. @ 1 H-NMR (CDCl3, 300 MHz) δ 7.35 (d, IH); 6.64 (d, IH); 6.58 (dd, 1H); 5.15 (bs, 1H); 4.40 (m. 4H) ; 4.19 (m, IH); 3.24 (m, 2 H); 2.60 (m, 1H); 1.90 (m, 1H); 1.45 (s, 9H). ESI

MS, [M + H] &lt; ⁺ &^gt; = 331.

E. [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester

[1- (3-Amino-4-cyanobenzyl) -2-oxopyrrolidin-3- (S) -yl] carbamic acid tert-butyl ester 890 mg (2.69 mmol) and 650 mg (8 mmol) 1,3,5 The triazine is mixed with 40 ml of ethanol and 480 mg (8 mmol) of acetic acid are added. The reaction mixture was heated to reflux overnight under nitrogen, cooled and adsorbed directly onto silica gel. The product was purified by column chromatography on silica gel eluting with 5-20% methanol in dichloromethane (containing 0.5-28% aqueous ammonium hydroxide). The fractions containing the product were evaporated and the residue was dried in vacuo overnight. (1.4 · mmol) of the product as a pale yellow powder.

‘H-NMR (CDCl 3, 300MHz) δ 9.90 (bs, 2Ή);

8.35 (with, IH) ; 8.16 (d, IH); 7.4 9 (d, IH); 7.31 (dd, 1H); 7.22 (šd, IH); 4, 57 (d, IH); 4.44 (d, IH) ; 4.20 (m, 1H); 3.18 (m, 2H); 2.23 (m , 1H); 1,8 0 (m, 1H); 1.39 (s, 9H). ESI MS, [M + H] &lt; ⁺ &^gt; 358.

F. 3- (S) -Amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one hydrochloride

[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester (1.70 g, 5.15 mmol) was dissolved.

in 100 ml of methanol and stirred at 0 ° C while bubbling hydrogen chloride gas through the solution until saturation (cloudy). The reaction mixture was left at room temperature for 10 minutes, then evaporated in vacuo. The residue was washed with ethyl acetate and ether and dried under high vacuum to give 1.33 g (4 mmol) of the product as a pale yellow powder.

@ 1 H-NMR (CDCl3, 300 MHz) .delta. 8.81 (s, 1H);

8.73 (bs, 2H); 8.57 (d, 1H); 7.87 (d, 1H); 7.65 (dd, 1H); 6.68 (bs, 2H); 4.73 (d, 1H); 4.60 (d, 1H); 4.13 (m, 1H); 3.35 (m, 2 H); 2.43 (m, 1H); 2.10 (m, 1H). ESI MS, [M + H] &lt; ⁺ &^gt; = 258.

G. 1- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (4-chlorophenyl) urea trifluoroacetate mg (0.15 mmol) of 3 - ( S) -amino-1- (1,4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one and 40 mg (0.40 mmol) of triethylamine in 3 mL of dimethylformamide were stirred at room temperature for 30 min and 25 mg (0 (16 mmol) of 4-chlorophenyl isocyanate in 2 ml of dimethylformamide. The reaction mixture is stirred for 1 hour at room temperature, then dimethylformamide is removed at 45 ° C and 172 kPa. The residue was dissolved in a mixture of 30% acetonitrile in water (2% trifluoroacetic acid) and purified by preparative reverse phase HPLC eluting with a gradient of 15 to 45% acetonitrile in water (0.1% trifluoroacetic acid).

The product containing fractions were combined, the acetonitrile was evaporated in vacuo and the aqueous solution was lyophilized to give the product as an off-white powder, which was washed with 2 mL of acetonitrile to give 45 mg (0.086 mmol) of the product as a white powder.

¹ H-NMR (CDCl 3, 300MHz) δ 9.60 (bs, 2H); 8.87 (s, 1H); 8.80 (s, 1H); 8.37 (d, 1H); 7.62 (dd, 1H); 7.58 (d, 1H); 7.43 (d, 2 H); 7.25 (d, 2 H); 6.65 (d, 1H); 4.64 (m, ·· ·· ····).

• · · · · · · · · ·

233 • ····

2H); 4.36 (m, 1H); 3.28 (m, 2 H); 2.40 (m, 1H); 1.91 (m, 1H).

ESI MS, [M + H] + = 411.

Example 102 N- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -2- (5-chloro-thiophen-2-yloxy) -acetamide trifluoroacetate mg (0.12 mmol) of 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one hydrochloride and 130 mg (1 mmol) of diisopropylethylamine in 1 ml of dimethylformamide was stirred at room temperature for 15 minutes. This solution was added to a solution of 23 mg (0.12 mmol) of 2- (5-chlorothiophen-2-yloxy) acetic acid, 20 mg (0.16 mmol) of diisopropylethylamine and 39 mg (0.12 mmol) of 2- (1H). (benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 1 mL dimethylformamide, which was stirred at room temperature for 5 minutes before addition. The reaction mixture was stirred at room temperature over the weekend. Dimethylformamide is evaporated at 45 ° C at 172 kPa and the residue is dissolved in a mixture of 20% acetonitrile in water (2% trifluoroacetic acid) and purified by reverse phase preparative HPLC eluting with 15-45% acetonitrile in water (0.1%). % trifluoroacetic acid). The product containing fractions were combined, the acetonitrile was evaporated in vacuo and the aqueous solution was lyophilized in vacuo to give 34 mg (0.062 mmol) of the product as an off-white powder.

^X H-NMR (DMSO-d₆, 300 MHz) δ 9.62 (bs, 2H); 8.80 (s, 1H); 8.64 (d, 1H); 8.34 (d, 1H); 7.62 (dd, 1H); 7.60 (d, 1H); 6.78 (d, 1H); 6.28 (d, 1H); 4.59 ' (m, 5H); 3.27 (m, 2 H); 2.32 (m, 1H); 1.97 (m, 1H). ESI MS, [M + H] + = 432.

Example 103 1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate

-i z · z 34 mg (0.12 mmol) of 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2 hydrochloride -one and 80 mg (0.58 mmol) of powdered potassium carbonate are dissolved / suspended in 1 ml of dimethylformamide and 41 mg (0.12 mmol) of 2-bromomethyl-1-tert-butoxycarbonyl-5-chloroindole dissolved in 1 ml are added. dimethylformamide. The reaction mixture was sonicated for 10 minutes. it was stirred overnight at room temperature. The dimethylformamide is evaporated at 45 ° C and 172 kPa and the residue is extracted into methanol (2 x 10 ml). The filtrate was diluted with 30 mL of methanol and cooled to 0 ° C, and dry was bubbled through the solution until saturated. hydrogen chloride gas. The reaction mixture was stirred at room temperature overnight. The resulting red solution was evaporated in vacuo and extracted with 2 mL of acetonitrile, diluted with water (1% trifluoroacetic acid) and the insoluble solid was filtered off and then the crude material was purified by preparative reverse phase HPLC eluting with a 20-60% gradient acetonitrile in water (0.1% trifluoroacetic acid). The product containing fractions were combined, the acetonitrile was evaporated in vacuo and the aqueous solution was lyophilized to give 12 mg (0.022 mmol) of the product as an off-white powder.

¹ H-NMR. (perdeutrodimethylsulfoxide, 300 MHz) δ 11.43 (s, 1H);

9.61 (ŠS, 3H) ; 8.78 (s, 1H); 8.36 (d, 1H); 7.67 (s, 1H); 7.63 (d, IH); 7.59 (dd, IH); 7.46 (d, 1H); 7.13 (dd, IH); 6.64 (d, IH); 4.70 (d, IH): ' 4.63 (d, 1H); 4.51 (m, 2H); 4.19 (m, 1H); 3.34 (m, 2H); 2.45 (m, 1H); 2.07 (m, 1H). ESI MS, [M + H] &lt; ⁺ &^gt; = 421.

Example 104 1- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -3- (5-chloro-thiophen-2-yl) -urea and trifluoroacetate [1- (4) 5-chlorothiophene-2-carboxylic acid-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

235 mg (0.12 mmol) of 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one hydrochloride and diisopropylethylamine are dissolved in 1 ml of dimethylformamide and added to 23 mg of (0, 12 mmol) of 5-chlorothiophene-2-carboxylic acid azide. The reaction mixture is heated at 100 ° C for 20 minutes, cooled to room temperature and the dimethylformamide is evaporated at 45 ° C and 172 kPa. The residue was dissolved in 30% acetonitrile in water (2% trifluoroacetic acid) and purified by preparative reverse phase HPLC eluting with a gradient of 15-30% acetonitrile in water (0.1% trifluoroacetic acid). Fractions containing two different products were combined separately, the acetonitrile was evaporated in vacuo and the aqueous solutions were lyophilized to give the products as white powders: 9 mg (0.017 mmol) urea; and 22 mg (0.043 mmol) of the amide.

Urea:

¹ H-NMR (perdeuterodimethylsulfoxide,

300 MHz) δ 9.98

(with,· IH); 9.59 (bs, 2H); 8.80 (with, IH); 8.38 (d, IH); 7.59 (m, 2H); 6.88 (d, 1 H); 6.75 (d ,. IH); 6.24 (d, IH); 4.67 (d, IH); 4.59 (d, IH); 4.39 (m, 1H); 3.27 (m, 2H); 2.40 (rft, IH); 1.94 (m, ih). : ESI MS, + H] = 421 .. Amid : ¹ H-NMR (CDCl 3):? hylsu lfoxid 3C 10 MHz ;) δ. 9.73 (šs, 2H); 9.02 (d, 1H); 8.82 (s, IH); 8.40 (d, IH); 7.65 (m, 3H); 7.21 (d, IH); 4.68 (m, 3H); 3.31 (m, 2H); 2.37 (m, IH); 2.06

(m, 1H). ESI MS, [M + H] &lt; ⁺ &^gt; = 421.

Example 105 {[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] - [3- (5-chloro-thiophen-2-yl) -acryloyl] -amino} -acetic acid trifluoroacetate acid

A. 3- (S) -Amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one.

236 ....... .....

600 mg (1.82 mmol) of 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one hydrochloride are chromatographed on silica gel eluting with 12% methanol / 2% aqueous ammonium hydroxide. (28% aqueous solution) / 86% dichloromethane and product containing fractions were combined and evaporated to give 360 mg (1.4 mmol) of the free base. in the form of a pale yellow powder.

¹ H NMR (CDCl 3, 300 MHz) δ 8.35 (s, 1H);

8.16 (d, IH); 7.74 (šs ,. 2H); 7.47 (d, 1H); 7.29 (dd, IH); 4.55 (d, IH); 4.49 (d, IH); 3.95 (bd, 2H); 3.55 (t, 1H); 3.18 (m, 2H); 2.27 (m, IH); 1.69 (m, 1H). ESI MS, [M + H] &lt; ⁺ &^gt; = 258.

B. {(1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amino) -acetic acid trifluoroacetate

Tert-Butyl bromoacetate (247 mg, 1.267 mmol) in DMF (5 mL) was added dropwise to a solution of 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one (326 mg, 1.267 mmol) and 100 mg. (1.267 mmol) of pyridine in dimethylformamide and the mixture was stirred at room temperature. After 90 minutes, an additional 100 mg (1.267 mmol) of pyridine in 2 mL of dimethylformamide was added, followed by an additional equivalent of 247 mg (1.267 mmol) of tert-butyl bromoacetate in 5 mL of dimethylformamide. The reaction mixture was allowed to stir for 180 minutes at room temperature, diluted with 150 mL of dichloromethane and chromatographed on silica gel eluting with pure dichloromethane then 20% methanol / 5% ammonium hydroxide (28% aqueous solution) / 75% dichloromethane. The crude product containing fractions were combined and evaporated to give a yellow solid containing impurities which was dissolved in a mixture of 15% acetonitrile in water (2% trifluoroacetic acid) and purified by preparative reverse phase HPLC eluting with a gradient of 10-50% acetonitrile. in water (0.1% trifluoroacetic acid). The product-containing fractions were combined and the solvent was evaporated in vacuo to a residue.

237

Φ ·· • Φ ···· • · • · · • · · t · 9 Φ · • · · 9 9 • · • · · · 9 9 «· 8 · · · ·· ·· 99 9

the residue was dried under high vacuum overnight. 300 mg (0.808 mmol) of product are isolated as a light pink solid.

^X H-NMR (perdeutrodimethylsulfoxid, 300 MHz) δ 9.76 (bs, 3H); 8.82 (s, 1 H); 839 (d, IH); 7.68 (d, IH); 7.61 (dd, IH); 4.64 (m, 2 H); 4.11 (m, 3H); 3.33 (m, 2 H); 2.40 (m, IH); 2.04 (m, IH); 1.47 (s, 9H). ESI MS, [M + H] &lt; ⁺ &^gt; = 372.

C. {[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] - [3- (5-chloro-thiophen-2-yl) -acryloyl] -amino} -acetate trifluoroacetate acid

Carry out the same condensation procedure as described above. is described in Example 102, except that {[1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3 - (S) -yl) amino} acetic acid tert-butyl ester and 3- (5- chlorothiophen-2-yl) acrylic acid. The evaporation residue was dissolved in a mixture of 40% acetonitrile in water (2% trifluoroacetic acid) and purified by preparative reverse phase HPLC eluting with a gradient of 30-100% acetonitrile in water (0.1% trifluoroacetic acid). The product containing fractions were combined, the solvent was evaporated in vacuo to give the tert-butyl ester intermediate as a white powder. This intermediate was dissolved in methanol and cooled to 0 ° C and hydrogen chloride gas was bubbled through the solution until saturated. The reaction mixture is left overnight at room temperature, then evaporated in vacuo and the residue is dissolved in a mixture of 20% acetonitrile in water (2% trifluoroacetic acid) and purified by preparative purification.

Reversed phase HPLC eluting with a gradient of 10 to 100% acetonitrile in water (0.1% trifluoroacetic acid). Fractions containing the product were combined, acetonitrile was evaporated in vacuo and the aqueous solution was lyophilized to give 9 mg (0.015 mmol). product in the form of a white powder.

φ φ φ · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

238 φ φ φ φ ^* H-NMR (DMSO-d₆, 300 MHz) mixture of rotamers: δ 9.78 (bs, 2H); 8.82, 8.83 (2s, 1H); 7.62 (m, 3H); 7.36 (m,

IH); 7.15 (m, 1H); 6.88-6.73 (2d, 1H); 5.28, 4.17 (2t, 1H); 4.40 (m, 3H); 3.64-3.59 (2s, 3H); 3.28 (m, 2 H); 2.37 (m, 1H); 2.10 (m, 1H). ESI MS, [M + H] &lt; ⁺ &^gt; = 500.

Example 106 6-Chlorobenzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3 - (R) -yl] -amide

A. (2-Oxopyrrolidin-3- (R) -yl) carbamic acid tert-butyl ester

The procedure of Example 101 A was repeated, but using the (R) enantiomer instead of the (S) enantiomer as the starting material.

¹ H-NMR- (CDCl 3, 300 MHz) δ 6.18 (m, 1H); 5.11 (m,

IH); 4.15. (m, 1H); 3.35 (m, 2 H); 2.70 · (m, 1H); 1.96 (m, 1H);

1.45 (s, 9H). ESI MS, [M + H] &lt; ⁺ &^gt; = 20.1.

[1- (3-Amino-4-cyanobenzyl) -2-oxo-pyrrolidin-3- (R) -yl] -carbamic acid tert-butyl ester

The procedure of Example 101 D was repeated, but using the (R) enantiomer instead of the (S) enantiomer as starting material.

¹ H-NMR (CDCl 3, 300 MHz) ) δ 7.35 (d, IH); 6.64 (d, IH); 6.58. (Dd, 1H); 5.15 (SS, 1H); 4.40 (m, 4H); 4.19 (m, IH); 3.24 (m, 2 H); 2.60 (m, 1H); 1.90 (m, 1H); 1.45 (with, 9H). ESI

MS, [M + H] &lt; ⁺ &^gt; = 331.

C. [1- (4-Amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -carbamic acid tert-butyl ester. acid

9 «· · 9 9

9 · · · ·

9 · ·· ·

239 «9 9999

The procedure of Example 101E was repeated, but using the (R) enantiomer instead of the (S) enantiomer as the starting material.

@ ¹ H-NMR (CDCl3, 300 MHz) .delta.9.90

8.35 (with, IH); 8.16 (d, IH); 7.49 (d, IH); 7, 31 (dd, (šd, IH); 4.57 (d, IH); 4.44 (d, 1H) ; 4.20 (m, 1H); 2H); 2.23 (m, IH); 1.80 (m, 1H); 1.39 (s, 9H) . ESI MS

358.

(bs, 2H); IH); 7.22 3.18 (m, [M + H] ⁺ =

D. 3- (R) -Amino-1- (4-Aminoquinazolin-7-ylmethyl) pyrrolidin-2-one

The procedure described in Example 101 F and then in Example 105A was repeated, but using the (R) enantiomer instead of the (S) enantiomer as starting material. .

^X H-NMR (perdeurodimethylsulfoxid, 300 MHz) δ .8,81 (s, IH); 8.73 (bs, 2H); 8.57 (d, 1H); 7.87 (d, 1H); 7.65 (dd, 1H); 6.68. (bs, 2H); 4.73 (d, 1H); 4.60 (d, 1H); 4.13 (m, 1H); 3.35 (m, 2 H); 2.43 (m, 1H); 2.10 (m, 1H). ESI MS, [M + H] &lt; ⁺ &^gt; = 258.

E. 6-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (R) -yl] -amide trifluoroacetate mg (0.14 mmol) of 3- (R) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one a _; 40 mg (0.15 mmol) of 6-chlorothiophene-2-sulfonyl chloride are dissolved in 2 ml of dichloromethane and 1 ml of dimethyl forms and triethylamine (36 mg, 0.35 mmol) is added. The reaction mixture was allowed to stir through the nov. at room temperature, then evaporated at 45 ° C and 172 kPa. The residue was dissolved in a mixture of 30% acetonitrile in water (2% trifluoroacetic acid) and purified by preparative. Reversed phase HPLC eluting with a gradient of 20-60% acetonitrile in water (0.1% trifluoroacetic acid). The product containing fractions were combined, acetonitrile was evaporated in vacuo and the aqueous solution was lyophilized to give 9 mg (0.15 mmol). product in the form of a white powder.

@ ¹ H-NMR (CDCl3, 300 MHz) .delta. 9.61 (bs, 2H);

8.75 (m, 2H); 8.34 (d, 1H); 8.27 (s, 1 H); 8.05 (s, 1H); 8.02 (d, 1H); 7.55 (m, 3H); 4.55 (m, 2 H); 4.25 (m, IH); 2.99 (m, 2H); 2.18 (m, 1H); 1.73 (t, 1H). ESI MS, [M + H] &lt; ⁺ &^gt; = 488.

Example 107 Thieno [3,2-b] pyridine-2-sulfonic acid trifluoroacetate [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide

A. [1- (1-Chloroisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3 - (R) -yl] carbamic acid tert-butyl ester

The procedure described in Example 101D is repeated, but using 312 mg (1.56 mmol) of (2-oxopyrrolidin-3- (R) -yl) carbamic acid tert -butyl ester and 440 mg (1.72 mmol) of 7-bromomethyl. -1-chloroisoquinoline as starting materials. The crude product was purified by column chromatography on silica gel eluting with 50-100% ethyl acetate in hexane. Product containing fractions were combined and evaporated to give 471 mg (1.25 mmol) of the product as a pale yellow powder.

¹ H-NMR (CDCl 3, 300MHz) δ 8.28 (d, 1H); 8.14 (s, 1H); 7.83 (d, 1H); 7.67 (dd, 1H): 7.55 ( d, 1H); 5.50 (bs, 1H); 4.77 (d, 1H); 4.65 (d, 1H); 4.31 (m, 1H); 3.27 (m, 2H) 2.60 (m, 1H); 1.96 (m, 1H); 1.47 (s, 9H). ESI MS, [M + H] ⁺ = 376.

B. 3- (R) -Amino-1- (1-amino-isoquinolin-7-ylmethyl) -pyrrolidin-2-one trifluoroacetate

384 mg (1- [1 (chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -carbamic acid tert-butyl ester, 962 mg (10.2 mmol) of phenol and 1.576 g ( 20.4 mmol) of anhydrous acetate ·· ··

I «

241 ·· ····

ammonium was mixed in a sealed flask and heated to 100 ° C overnight. After cooling, 20 ml of acetonitrile and 20 ml of water are added and the phases are separated. The aqueous phase was washed with ethyl acetate and evaporated to dryness. The evaporation residue is extracted with methanol, the solid is filtered off and the filtrate is evaporated. The residue was dissolved in a mixture of 10% acetonitrile in water (2% trifluoroacetic acid) and purified by preparative HPLC eluting with a gradient of 10-30% acetonitrile in water (0.1% trifluoroacetic acid). The product containing fractions were combined, the solvent was evaporated in vacuo and the product was dried under high vacuum. 88 mg (0.238 mmol) of product are isolated as a white powder.

¹ H-NMR (CDCl 3, 300MHz) δ 9.11 (bs, 2H);

8.43 (šs, 2H); 8.37 (s, IH); 7.98 (d, IH) ; 7.83 (dd, 1H); 7.69 (d, IH); 7.24 (d, lH): 4.66 (d, IH); 4, 59 (d, 1H); 4.09 (m, IH); 3.34 (m, 2H); 2.38 (m, 1H); 1.96 (m, IH). ESI MS, [M + H] &lt; ⁺ &^gt;

257

C. Thieno [3,2-b] pyridine-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide trifluoroacetate mg (0.216 mmol) of trifluoroacetate 3 - (R) -amino-1- (1-aminoisoquinolin-7-ylmethyl) pyrrolidin-2-one and 140 mg (1.08 mmol) of diisopropylethylamine are dissolved in 1.2 ml of acetonitrile and stirred for 15 minutes at room temperature, then thieno [3,2-b] pyridine-2-sulfonyl chloride was added dropwise as a solution in 8 mL of acetonitrile. The reaction mixture was stirred at room temperature overnight, 4 mL of water was added and the solution was evaporated in vacuo to remove acetonitrile (about 4 mL of solution). 4 ml of a mixture of 75% acetonitrile in water are added and the product is purified by preparative HPLC on. reverse phase eluting with a gradient of 10 to 40% acetonitrile in water (0.1% trifluoroacetic acid).

242 ·· ···· · · · · 4 · · · · · · ·

The product containing fractions were combined, the acetonitrile was evaporated in vacuo and the aqueous solution was lyophilized to give 52 mg (0.092 mmol) of the product as a white solid.

, 300 i. MHz) i δ 9.12 (šs, 2H); (d, 1H); 8.27 (s, 1H); 8.12 1H); 7.65 (d, 1H): 7.51 (dd, 4.47 (d, 1H); 4.36 (m, 1H);

3.19 (m, 2 H); 2.21 (m, IH); 1.74 (m, IH). ESI MS, [M + H] + = 454.

Example 108 1- (4-Aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate

A. 1- (4-Chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester

The procedure of Example 101D was repeated but using 7-bromomethyl-4-chloroquinoline as the electrophile. The crude product was purified by column chromatography on silica gel eluting with 1-20% methanol in ethyl acetate. Product containing fractions were combined and evaporated to give a semi-solid oily solid which was triturated with ether to give the product as a white powder.

1 H-NMR (CDCl 3, 300 MHz) δ 8.83 (d, 1H);

8, 17 (d, 1H); 7.95 (S,. 1H); 7.74 (d, 1H); 7.62 (dd, 1H); 7.22 (d, 1H); 4.66 (d, 1H); 4.57 (d, IH); 3.20 (m, 2 H); 2.23 (m, 1H); 1.83 (m, 1H); 1.39 (s, 9H). ESI, MS, [M + H] ⁺ = 376.

B. 3- (S) -amirto-1- (4-aminoquinolin-7-ylmethyl) pyrrolidin-2-one hydrochloride

250 mg (0.665 mmol) [1- (4-chloroquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester, 626 mg *

243 · * 9449 • ··

4 4

9 • · · · ··· ····

9 4

9 4 9

9 9 9

(6.65 mmol) of phenol and 513 mg (6.65 mmol) of anhydrous ammonium acetate were mixed and heated to 100 ° C under reflux overnight. The mixture was cooled to room temperature and. 20 ml of acetonitrile and 20 ml of water are added. The solution was separated into 2 phases (both containing the product) and evaporated to dryness and separately purified by preparative reverse phase HPLC eluting with a gradient of 20-40% acetonitrile in water (0.1% trifluoroacetic acid). The fractions containing the product of each step were combined, the solvents evaporated in vacuo and the residue dried under high vacuum overnight. Intermediate tert-butyl [1- (4-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] carbamic acid was dissolved in methanol and cooled to 0 ° C, then bubbled into the solution until saturated. The reaction mixture was left at room temperature for 2 hours and evaporated in vacuo and the residue washed with ether to give 170 mg (0.516 mmol) of pure product as a colorless powder.

¹ H-NMR (CDCl 3, 300 MHz), δ 9.15 (bs, 2H); 8.75 (bs, 2H); 8.50 (d, 1H); 8.35 (d, 1H); 7.96 (s, 1H); 7.53 (d, 1H); 6.79 (d, 1H); 4.71 (d, 1H); 4.58 (d, 1H); 4.11 (m, 1H); 3.11 (m, 2 H); 2.45 (m, 1H); 2.13 (m, 1H). ESI MS, [M + H] &lt; ⁺ &^gt;

257..

C. 1- (4-Aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate

The procedure described in Example 103 was repeated, but using 3- (S) -amino-1- (4-aminoquinolin-7-ylmethyl) pyrrolidin-2-one hydrochloride instead of 3- (S) -amino-1 (4) hydrochloride as starting material. (Aminoquinazolin-7-ylmethyl) pyrrolidin-2-one.

^X H-NMR (DMSO-d₆, 300 MHz) δ 11.39 (s, lH);

9.73 (bs, 1H); 8.97 (bs, 2H); 8.38 (m, 1H); 7.73 (s, 1H); 7.62 (d, 1H); 7.52 (d, 1H); 7.45 (d, 1H); 7.13 (dd, IH); 6.75 (d, · · ·· ·····)

244 • 9 9 9 9 9 9 9 9 9 9 9 9 9999999 9 9 9 9 ·· · 1H); 6.64 (s, 1H); 4.65 (m, 2H); 4.54 (d, IH); 4.46 (d, 1H); 4.15 (m, 1 H); 3,3 2 (m, 2H); 2.46 (m, IH); 2.05 (m, 1H). ESI

MS, [M + H] &lt; ⁺ &^gt; = 420.

Example Ϊ09

1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [3- (5-chloro-thiophen-2-yl) allylamino] -pyrrolidin-2-one mg (0.12 mmol) of 3- (S) - hydrochloride trifluoroacetate amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one and 80 mg (0.58 mmol) of powdered potassium carbonate were dissolved / suspended in 1 ml of dimethylformamide and 30 mg (0.126 mmol) was added to this solution. 3- (5-chlorothiophen-2-yl) allyl bromide dissolved in 1 mL dimethylformamide. The reaction mixture was sonicated for 10 minutes then stirred overnight at room temperature. The dimethylformamide is evaporated at 45 ° C and 172 kPa, the residue is extracted twice with 10 ml of methanol and the solid is filtered off. The filtrate was evaporated and the crude material was purified by preparative reverse phase HPLC eluting with a gradient of 20-60% acetonitrile in water (0.1% trifluoroacetic acid). The product containing fractions were combined, the acetonitrile was evaporated in vacuo and the aqueous solutions were lyophilized to give 15 mg (0.028 mmol) of the product as an off-white powder.

@ ¹ H-NMR (CDCl3, 300 MHz) .delta. 9.64 (bs, 3H); 8.79 (s, H); 7.68 (d, H); 7.59 (dd, H); 7.08 (d, H); 6.95 (d, H); 5.96 (m, H); 4.71 (d, J); 4.64 (d, H); 4.25 (t, H); 3.87 (d, H); 3.37 (m, 2 H); 2.47 (m, H); 2.05 (m, H). ESI MS, [M + H] &lt; ⁺ &^gt; = 414.

Example 110 N- [1,1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -3- (5-chloro-thiophen-2-yl) -acrylamide trifluoroacetate

245

The procedure described in Example 102 was repeated but using 3- (5-chlorothiophen-2-yl) acrylic acid instead of 2- (5-chlorothiophen-2-yloxy) acetic acid.

ESI MS, [M + H] ⁺ = 428.

Example 111 1- (4-Aminoquinazolin-7-ylmethyl) -3 - (S) - [(5-chloro-1H-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate

The procedure described in Example 103 was repeated, but using a mixture of 2-chloromethyl-1-tert-butoxycarbonyl-5-chlorobenzimidazole and 2-chloromethyl-1-tert-butoxycarbonyl-6-chlorobenzimidazole instead of 2-bromomethyl-1-tert-butoxycarbonyl- Of 5-chloroindole.

ESI MS, [M + H] + = 422.

Example 112 {[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] [2- (5-chloro-thiophen-2-yl) -ethenesulfonyl] -amino} -acetic acid trifluoroacetate

Repeat the same procedure as described in Example 106E, but using {[1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] amino} -acetic acid trifluoroacetate instead of 3 - (R) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one, and 2- (5-chlorothiophen-2-yl) ethenesulfonyl chloride instead of 6-chlorothiophene-2-sulfonyl chloride. The tert-butyl intermediate was isolated by preparative reverse phase HPLC eluting with a gradient of 10-100% acetonitrile in. water (0.1% trifluoroacetic acid). The product containing fractions were combined, the solvent was evaporated in vacuo and the intermediate dried overnight under high vacuum. The dried material was dissolved in methanol and cooled to 0 ° C and then bubbled through the solution

246 saturated hydrogen chloride gas. The mixture was allowed to stir at room temperature overnight. The reaction mixture is evaporated to dryness in vacuo and the residue is dissolved in a mixture of 20% acetonitrile in water (2% trifluoroacetic acid) and purified by reverse phase preparative HPLC eluting with a gradient of 20-100% acetonitrile in water (0, 1% trifluoroacetic acid). The product-containing fractions were combined, the acetonitrile was evaporated in vacuo and the aqueous solution was lyophilized to give the product as a white powder.

ESI MS, [M + H] &lt; ⁺ &^gt; = 536.

Example 113 {[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] (5-chloro-1H-indol-2-ylmethyl) amino} acetic acid trifluoroacetate

The procedure described in Example 103 is repeated, but using {[1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] amino} acetic acid trifluoroacetate instead of 3- hydrochloride (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one.

ESI MS, [M + H] &lt; ⁺ &^gt; = 493.

Example 114 {[1- (Aminoquinazolin-7-ylmethyl) 2-oxo-pyrrolidin-3- (S) -yl] [3- (5-chloro-thiophen-2-yl) allyl] amino} -acetic acid trifluoroacetate

The procedure described in Example 103 was repeated, but using ([1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3 (S) -yl] amino} acetic acid tert-butyl ester trifluoroacetate) instead of 3- (S) hydrochloride. 1-Amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrole

247 • · ··· ·

4 4 4 4 • 4 4 4 4 4

44-4 lidin-2-one, and 3- (5-chlorothiophen-2-yl) allyl bromides in place of 2-bromomethyl-1-tert-butoxycarbonyl-5-chloroindole.

ESI MS, [M + H] &lt; ⁺ &^gt; = 486.

Example 115 {1- [1- (4-Amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -3- (5-chloro-thiophen-2-yl) -ureido} -acetic acid trifluoroacetate

Repeat the same procedure as described in Example 104, but using {[1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] amino} -acetic acid trifluoroacetate instead of 3 - (R) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one. Only urea is present, not amide. The tert-butyl ester intermediate was isolated by preparative reverse phase HPLC eluting with a gradient of 10-100% acetonitrile in water (0.1% trifluoroacetic acid). Fractions containing product were combined, the solvents were evaporated in vacuo and the intermediate dried overnight The dried material was dissolved in methanol and cooled to 0 ° C and bubbled into saturated hydrogen chloride gas, stirred overnight at room temperature, evaporated to dryness in vacuo and the residue dissolved in 20% acetonitrile. in water (2% trifluoroacetic acid) and purified by preparative reverse phase HPLC eluting with a gradient of 20 to 60% acetonitrile in water (0.1% trifluoroacetic acid).

The product containing fractions were combined, the acetonitrile was evaporated in vacuo and the aqueous solution was lyophilized to give the product as a white powder.

ESI MS, [M + H] &lt; ⁺ &^gt; = 489.

248 • · φ φ φ φ · · • «« «· · · · · · · · · · · · · · · · · ·· ·· * · ···

Example 116 N- [1- (4-Aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -3- (5-chloro-thiophen-2-yl) -acrylamide trifluoroacetate

The procedure of Example 110 was repeated, but using the (R) enantiomer instead of the (S) enantiomer as starting material.

ESI MS, [M + H] &lt; ⁺ &^gt; = 428.

Example 117 1- (4-Aminoquinazolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate

The procedure of Example 103 was repeated, but using the (R) enantiomer instead of the (S) enantiomer as starting material.

ESI MS, [M + H] &lt; ⁺ &^gt; = 421.

Example 118 1- [1- (4-Amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -3- (5-chloro-thiophen-2-yl) -urea and trifluoroacetate [1- (4) 5-chlorothiophene-2-carboxylic acid-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide

The procedure described in Example 104 was repeated, but using the (R) enantiomer instead of the (S) enantiomer as starting material.

Urea: ESI MS, [M + H] &lt; ⁺ &^gt; = 417. Amide: ESI-MS. [M + H] ⁺ = 402.

Example 119 {[1- (4-Amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] [5-chloro-1H-indol-2-ylmethyl) -amino} -acetic acid trifluoroacetate

249 • 9 9 9 9 9 9.9 · 99 · 99

Φ Φ φ φ Φ · * · · φ

Φ φ Φ 4ΦΦ ΦΦ Φ

ΦΦ · Φ · · ΦΦΦ

A. {[1- (4-Amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amino} -acetic acid tert-butyl ester

The procedure of Example 105B was repeated, but using the (R) enantiomers instead of the (S) enantiomers as starting material. Since pure material is obtained after column chromatography, HPLC purification does not have to be performed. The free base product is isolated.

ESI MS, [M + H] &lt; ⁺ &^gt; = 372.

B. {[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] (5-chloro-1H-indol-2-ylmethyl) amino} acetic acid trifluoroacetate

The procedure described in Example 113 was repeated but followed. using {[1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3 (R) -yl] amino} acetic acid tert-butyl ester instead of {[1- (4-aminoquinazolin-7-ylmethyl) tert -butyl ester trifluoroacetate (2-oxopyrrolidin-3- (S) -yl] amino} acetic acid starting material.

ESI MS, [M + H] &lt; ⁺ &^gt; = 493.

Example 120 1- (4-Aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-1H-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate

The procedure described in Example 103 was repeated, but using 3- (S) -amino-1- (4-aminoquinolin-7-ylmethyl) pyrrolidin-2-one hydrochloride instead of 3- (S) -amino-1- (4) hydrochloride. -aminoquinazolin-7-ylmethyl) pyrrolidin-2-one starting material and a mixture of 2-chloromethyl-1-tert-butoxycarbonyl-5-chlorobenzimidazole and 2-chloromethyl-1-tert-butoxycarbonyl-6-chlorobenzimidazole instead of 2-bromomethyl-1-tert-butoxycarbonyl-5 -chlorindole.

• ····

250

ESI MS, [M + H] + = 421.

The compounds of Examples 121-138 were prepared using analogous methods and reagents as described above.

Example 121 5-Chlorobenzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

ESI MS, [M + H] = 487.489, Cl isotopes.

Example 122 2- (5-Chloro-thiopheh-2-yl) -ethenesulfonic acid [1- (4-aminothieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-: 3 (S) -yl] -amide

ESI MS, [M + H] = 470.472, Cl isotopes.

Example 123 7-Methoxynaphthalene-2-sulfonic acid [1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

ESI-MS, [M + H] = 477.

Example 124 2- (5-Chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide

ESI MS, [M + H] = 464.466, Cl isotopes.

9

9 9

9

9

9

251 • ·

9

9 9

9 9

9

Example 125 6-Chlorobenzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide

ESI MS, [M + H] ⁺ = 488, 490, Cl isotopes.

Example 126 5-Chlorobenzo [b] thiophene-2-sulfonic acid trifluoroacetate (S) - [1- (4-Aminothieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide

ESI MS, [M + H] ⁺ = 493, 395. Cl isotopes.

Example 127 Thieno [3,2-b] pyridine-2-sulfonic acid (S) - [1- (4-aminothieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate acid

ESI MS, [M + H] ⁺ = 466.

Example 128 6-Chloro-benzo [b] thiophene-2-sulfonic acid trifluoroacetate (S) - [1- (4-Aminothieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide

ESI MS, [M + H] &lt; ⁺ &^gt; = 493. 495, Cl isotopes.

Trifluoroacetate Example 129 (S) - [1- (4-amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxopyrrolidin-3-yl] amide, ^5-chloro-1 [2,2 ' ] Bithiophenyl-5sulfonic acid b · · · ♦ ith ith ith ith ith ith ith ith ith ith ith ith ith ith ith ith ·· ·· ·· ·

252

ESI MS, [M + H] ⁺ = 525, 527, Cl isotopes

Example 130 2- (5-chloro-thiophene-2- (1-) - [1- (4-amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate yl) ethenesulfonic acids

ESI MS, [M + H] ⁺ = 469, 471, Cl isotopes.

Example 131 5-Chlorobenzo [b] thiophene-2-sulfonic acid trifluoroacetate [(S) -1- (4-aminothieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide

ESI MS, [M + H] ⁺ = 493, 495, Cl isotopes.

Example 132 5-Chloro-benzo [b] thiophene-2-sulfonic acid [(S) -1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate acid

ESI. MS, [M + H] ⁺ = 493, 495, Cl isotopes.

Example 133 5'-Chloro- [2,2 '] bithiophenyl- [(S) -1- (4-aminothieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate 5sulfonic acids

ESI MS, [M + H] ⁺ = 525, 527, Cl isotopes.

Example 134

253 • 9 · 9 · 9

9 4 4 9 4 9 4 5

494 9494 94 44 44 444 Thieno [3,2-b] pyridine trifluoroacetate [(S) -1- (4-aminothieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide -2-sulfonic acids

ESI MS, [M + H] &lt; ⁺ &^gt; = 460.

and

Example 135 6-Chlorobenzo [b] thiophene-2-sulfonic acid trifluoroacetate [(S) -1- (4-aminothieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide

ESI MS, [M + H] ⁺ = 493, 495, Cl isotopes.

Example 136 5'-Chloro [2,2 '] bithiophenyl-5sulfonic acid [1- (4-aminothieno [3,2-d] pyrimidin-7-ylmethyl) 2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate

ESI MS, [M + H] ⁺ = 525, 527, Cl isotopes.

Example 137 Thieno [3,2-b] pyridine-2-sulfonic acid [1- (4-aminothieno [3,2-d] pyrimidin-7-ylmethyl) 2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate .

ESI MS, [M + H] &lt; ⁺ &^gt; = 460.

Example 138 6-Chlorobenzo [b] thiophene-2-sulfonic acid [(S) -1- (4-aminothieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide

ESI MS, [M + H] ⁺ = 493, 495, Cl isotopes.

t

253 · »·

In a similar manner, the following compounds were prepared using analogous procedures and reagents:

3 - [[1- (4-Amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 - (R) -yl] (5-chloro-1H-indol-2-ylmethyl) -amino] -propionic acid methyl ester;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) - (3-ethylbutyl) amino] pyrrolidin-2-one;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [benzyl (5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) thiazol-5-ylmethylamino] pyrrolidin-2-one;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) - (2H-pyrazol-3-ylmethyl) amino] pyrrolidin-2-one;

1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(6-chlorobenzo [b] thiophen-2-ylmethyl) amino] pyrrolidin-2-one;

1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(6-chlorothieno [2,3b] pyridin-2-ylmethyl) amino] pyrrolidin-2-one;

1- (4-Aminoquinazolin-7-ylmethyl) -3- (S) - [(1H-pyrrolo [2,3c] pyridin-2-ylmethyl) amino] pyrrolidin-2-one;

3 - {[1- (4-Aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) ylamino] methyl} -1H-quinolin-2-one;

1- (7-Aminothieno [3,2-b] pyridin-2-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one;

2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (R) -yl] -amide;

255 • 9

9 9 • 9 ····

• · 9 «99

9 9 9

9

9 9 9 »9 99 999 ([2- (5-Chloro-thiophen-2-yl) -ethenesulfonyl] - [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3-yl) -propyl ester (R) -yl] amino} acetic acid;

1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one; and

5.-Chloro-1H-benzoimidazole-2-sulfonic acid [1- (4-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide.

Preparation 1

The reaction flask was charged with 0.20 g (0.15 mmol) of 4-hydroxy-2,3,5,6-tetraflurobenzamide-methyl-copoly (styrene-1% -dinylbenzene) resin. Each flask was treated with dichloromethane (2 ml) for 10 minutes, then treated with aromatic sulfonyl chloride (0.45 mmol) and diisopropylethylamine (0.104 ml, 0.60 mmol). The containers were sealed and shaken for 16 hours. The reaction mixture was filtered separately and then washed 10 times with 20% aqueous dimethylformamide solution, 5 times with tetrahydrofuran and 5 times with dichloromethane, then dried in vacuo. vacuum at room temperature overnight. For example, 6-chlorobenzothiophene-2-sulfonyloxy-2,3,5,6-tetrafluorobenzamidomethyl-copoly- (styrene-1% -divinylbenzene) -resin shows: ¹⁹ F-NMR δ -144.572, -145.608; IR (cm ^-1 ) 1684 (C = 0 band), 1391, (asymmetric SO ₂ band) 1195, 1177 (symmetric)

SO ₂ strip).

The reaction flasks were charged with 0.024 g (0.012 mmol) of arylsulfonyloxy-2,3,5,6-tetrafluoro-benzamidomethyl-copoly (styrene-1% -dinylbenzene) -resins prepared according to the method described above. The resins were then swollen with dimethylformamide, then treated with a 0.01M solution of the amine (1 mL, 0.01 mmol) in dimethylformamide. The containers were covered with aluminum foil and shaken for 72 hours. The progress of the reaction was monitored by thin-layer chromatography on silica gel; 1,5,7-triazabicyclo [4.4.0] dec-5-ene resin is added to terminate the reactions. The reaction mixtures were individually filtered and the resins washed with methanol. The filtrates were evaporated under a stream of nitrogen. The residues were dissolved in methanol and evaporated again twice. The obtained residues were treated with 20% trifluoroacetic acid in 1 ml of dichloromethane and shaken overnight. The reaction mixture was evaporated under a stream of nitrogen. 1 ml of dichloromethane is added; evaporate with a stream of nitrogen. Add 1 ml of methanol; evaporate with a stream of nitrogen. The final residues are analyzed by LC mass spectroscopy; in any case, the presence of the desired product is detected. For example, the reaction product of 6-chlorobenzothiophene-2-sulfonyl) oxy-2,3,5, β-tetrafluorobenzamidomethyl-copoly- (styrene-1% -divinylbenzene) -resin with 2- (3- (S) -amino-tert-butyl ester -2-oxopyrrolidin-1-ylmethyl) pyrrolo [3,2-b] pyridine-1-carboxylic acid followed by deprotection with 20% trifluoroacetic acid in dichloromethane shows: M + H = 461. This compound has an IC ₅₀ against the factor of Xa less than 500 nM.

4 · 4 · 4 · 4 · 4 4 ·

4 4 4 445 4

257

444 4444

44 4

By the method described in this example, 2- (3 (S) -amino-2-oxopyrrolidin-1-ylmethyl) pyrrolo [3,2-b] pyridine-1-carboxylic acid tert-butyl ester 2- (3- (S) -butyl ester) (Amino-2-oxopyrrolidin-1-ylmethyl) pyrrolo [3,2-c] pyridine-1-carboxylic acid and 2- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -pyrrolo [tert-butyl ester] [ 2,3-c] pyridine-1-carboxylic acid is reacted with fourteen arylsulfonyloxy-2,3,5,6-tetrafluoro-benzamidomethyl-copoly- (styrene-1% -dinylbenzene) -resins to give (after deprotection) compounds of formula:

R _y is hydrogen;

and R ₂ is selected from the group consisting of:

LCMS: M + H = 463

LCMS: M + H = 429

H 'II O

LCMS: t + H = 454

LCMS: t + H = 462.

LCMS: t + H = 428

LCMS: M + H = 445

0 ⁵ N ^ ci

LCMS: t + H = 462

Cl

LCMS: t + H = 462

LCMS: t + H = 454

LCMS: t + H = 475

Cl

LCMS: M + H = 463

N

-S— <* W _M O 0 ^N

LCMS: Μ + H 44 445 ···· · · ·

258

or "©

A5a

Xib · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

R _x is hydrogen; and R ₂ is selected from the group consisting of:

LCMS: M + H = 463

LCMS: t + H = 454

LCMS: M + H = 429

LCMS: M + H = 445

O

N Cl

LCMS: t + H = 493

LCMS: t + H = 462

LCMS: t + H = 427

LCMS: t + H = 454

LCMS: M + H = 476 or

Cl

LCMS: t + H = 462

LCMS: t + H = 445

X ₅

^Ar i 7 “X5b X _5a is selected from:

R _x is hydrogen; and R ₂ is selected from the group consisting of:

259

•> * 09 0000 00 • 0 * 0 0 0 0

0 0 0 0 0 0 0 0 004 0000 00 00 ··

LCMS: M + H = 463

LCMS: M + H = 428h

ο

LCMS: + = 454

LCMS: Μ + Η = 463. LCMS: Μ + Η = 493

LCMS: M + H = 462 LCMS: M + H = 454 LCMS: M + H = 475

Cl

LCMS: M + H = 462; LCMS: M + H = 445

The compounds of formula:

·· ·· ····

R _x is hydrogen; and R ₂ is selected from the group consisting of: T

-Cl

V ⁵ //

In Q

Q, T = H, CH ₃ , F, Cl

Q, T = H, CH ₃ , F, Cl

The compounds of formula:

R _x is hydrogen; and R ₂ is selected from the group consisting of:

9 * 9

9 9 · · · · · ·

· ·

·

9999999 99

LCMS: M + H = 444, LCMS: M + H = 451

LCMS: M + H = 419

LCMS: <+> = 452

LCMS: M + H = 419

LCMS: t + H = 434 db

LCMS: M + H = 482

LCMS: t + H = 452

LCMS: M + H = 418

LCMS: t + H = 444

LCMS: M + H = 464

LCMS: M + H = 434

The molecules described according to the invention inhibit blood coagulation because they are capable of inhibiting the penultimate enzyme in the coagulation cascade, under the control of factor Xa activity. Both the free factor Xa activity and the factor Xa contained in the prothrombinase complex (factor Xa, factor Va, calcium and phospholipid) are inhibited by the compounds of formula I. Inhibition of factor Xa activity is achieved by direct complex formation between inhibitor and enzyme and therefore independent of plasma antithrombin III cofactor. Effective inhibition of factor Xa is achieved by administering the compounds either by the oral route, by continuous intravenous infusion, by the administration of nitro.

262 or any other parenteral route such that the factor Xa-induced thrombin generation from prothrombin is prevented in a desirable manner.

Anticoagulant therapy is used for the treatment and prophylaxis of various thrombotic conditions of both the venous and arterial systems. In the arterial system, abnormal thrombus formation is primarily related to coronary arteries, the cerebral and peripheral vascular systems. Diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vascular blockage associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic seizure, intermittent ischemic seizure coronary artery cardiovascular surgery (CAGB) or peripheral arteries. Chronic anti-coagulation therapy may also be beneficial in preventing luminal vasoconstriction (restenosis) often occurring after PTCA and CAGB and maintaining access to the patient's blood vessels during long-term hemodialysis of the patient. As for the venous system, pathological thrombus formation often occurs in the veins of the lower extremities after abdominal, knee, and hip surgery (deep venous thrombosis, DVT). DVT then causes the patient to be at greater risk of pulmonary thromboembolism. Systemic, multiple intracellular coagulopathy (DIC) generally occurs in the vascular system during septic shock, certain viral infections, and cancer. This condition is characterized by the rapid consumption of coagulation factors and their plasma inhibitors, resulting in occlusion in life-threatening micro-vascular systems of certain organs. Representative indications discussed above include some (but not all) possible clinical situations that can be treated with anticoagulant therapy. Those of ordinary skill in the art will recognize circumstances that require either acute or prophylactic anticoagulant therapy.

263 ·· 4 4 4 4 «4 • 4 4 · 4 β · · · 4, 4 4 44 4 4

4 4 4 4

44444 44 44 44

The compounds of the present invention may be used with other diagnostic agents, anticoagulants, anti-platelet agents or fibrinolytic agents. For example, the addition of factor Xa activity inhibitors with standard heparin, low molecular weight heparin, direct thrombin inhibitors (i.e., hirudin), aspirin, fibrinogen receptor antagonists, streptokinate, urokinase, and / or tissue plasminogen activator results in higher antithrombotic or thrombolytic activity. The compounds of the present invention can be administered to treat thrombotic complications in a variety of animals, such as primates, including humans. Inhibition of factor Xa is useful not only in anticoagulant therapy for patients suffering from thrombotic conditions, but is useful whenever inhibition of blood clotting is desired, for example, to prevent coagulation in whole blood storage and to prevent coagulation in other biological samples for testing or storage.

Thus, any inhibitor of factor Xa activity may be added or contacted with any medium containing (or expected to contain) factor Xa and which is required to inhibit blood coagulation.

In addition to their use in anticoagulant therapy, inhibitors of factor Xa activity may be used in the treatment or prevention of other physiological conditions in which thrombin formation is expected to play a pathological role. For example, thrombin is believed to contribute to the morbidity and mortality of chronic and degenerative diseases such as arthritis, cancer, atherosclerosis, coronary artery restenosis and Alzheimer's disease because of its ability to regulate many different cell types through specific cleavage and cell activation thrombin receptor surface. Inhibition of activity

264 • ········ · · · · · · · · · · · · · · · · · · · · · 0 0

0 · · 0 0 ·

Factor Xa will effectively block thrombin formation and will therefore neutralize any pathological effect of thrombin on various cell types.

According to another embodiment, the present invention provides a method of treating a human or animal suffering from a variety of physiological conditions which:. can be alleviated by administering an inhibitor of factor Xa activity, for example, the conditions described above, wherein the method comprises administering to said patient a therapeutically effective amount of a compound of Formula I or a composition comprising the compound. An "effective amount" means an amount of a compound of the present invention that is effective in inhibiting factor Xa activity and thus provides the desired therapeutic effect.

The present invention also encompasses pharmaceutical compositions comprising at least one compound of formula I together with a pharmaceutically acceptable carrier or coating.

In practice, the compounds of the present invention can be administered parenterally, intravenously, subcutaneously, intramuscularly, to the colon, nasally, intraperitoneally, rectally or orally.

The compounds of the present invention may be present in forms suitable for administration in the most suitable manner, and the invention also relates to pharmaceutical compositions comprising at least one compound of the present invention that are suitable for use in human or veterinary medicine. Such compositions may be prepared according to known procedures using one or more pharmaceutically acceptable adjuvants or excipients. Adjuvants include, but are not limited to, diluents, sterile aqueous media, and various non-toxic organic solvents. The compositions may be present in the form of tablets, pills, granules, chip.

265 Powders, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and may contain one or more agents selected from the group consisting of sweetening, flavoring, coloring or stabilizing agents. which are used in the preparation of pharmaceutically acceptable compositions.

The choice of carrier and active ingredient content of the carrier are generally determined by solubility and. the chemical properties of the product, the particular mode of administration and the conditions expected in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used to prepare the tablets. For the preparation of capsules, it is preferable to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used, they 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, emulsions, suspensions or solutions of the compounds of the present invention in vegetable oil, for example, sesame oil, peanut oil or olive oil or aqueous organic, solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous , pharmaceutically acceptable salt solutions. Salts of the compounds of the present invention are particularly suitable for administration by intramuscular or subcutaneous injection. For intravenous administration, aqueous solutions may also be used, including solutions of salts in pure distilled water, provided that their pH is appropriately adjusted so that they are appropriately buffered and maintained isotonic with sufficient ♦ φφφφ ·

266 φ φ · · stvím stvím stvím stvím stvím stvím stvím stvím φ φ φ φ φ φ φ φ φ φ φ φ stvím že že stvím že že že že že že že že že že že že že že že že že že že že že microfiltration.

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

Solid compositions for rectal administration include suppositories modified according to known methods and containing at least one compound of formula I.

The percentage of active ingredient in the composition of the present invention may be varied, it being necessary to form a proportion such that a suitable dosage is obtained. It will be appreciated that several unit dosage forms may be administered simultaneously. The dose employed will be determined by the physician and will depend upon the desired therapeutic effect, the mode of administration and the duration of treatment, and the condition of the patient. In adults, the dose will generally be from 0.01 to 100, preferably 0.01 to 10 mg / kg body weight per day by inhalation, from 0.01 to 100, preferably from 0.1 to 70 and more preferably 0 to 70 mg / kg body weight per day. 5 to 10 mg / kg body weight per day for oral administration and 0.01 to 50, preferably 0.01 to 10 mg / kg body weight per day for intravenous administration. In each particular case, the dosage is determined by factors that are characteristic of the patient being treated, such as age, weight, general health, and other characteristics that may affect the efficacy of the drug.

The compounds of the present invention may be administered as often as necessary to achieve the desired therapy.

effect. Some patients may respond more quickly to a higher or lower dose and may benefit from a much smaller adequate dose. For these patients, prolonged treatment at 1 to 4 doses per day may be required, depending on the physiological requirements of each particular patient. In general, the active ingredient may be administered 1 to 4 per day. However, for some patients it may be necessary not to prescribe more than one or two doses per day.

The compounds of the present invention are highly pharmacologically active according to the tests described in the literature and are believed to correspond to the pharmacological activity in humans and other mammals. The results of the following pharmacological tests are characteristic of the compounds of the present invention.

Enzyme tests:

The ability of the compounds of the present invention to act as inhibitors of factor Xa, thrombin, tripsin, tissue plasminogen activator (t-PA), urokinase plasminogen activator (µ-PA), plasmin and activated protein C is assessed by determining the concentration of inhibitor which results in 50% loss enzyme activity ( _IC5P ) using purified enzymes. All enzyme assays are performed at room temperature in 96-well microtiter plates using a final enzyme concentration of 1 nM. Factor Xa and thrombin concentrations are determined by active site titration, and all enzyme concentrations are based on the protein concentration supplied by the manufacturer. Compounds of the present invention are dissolved in dimethylsulfoxide, diluted with appropriate buffers, and tested at a maximum final dimethylsulfoxide concentration of 1.25%. Compound solutions are added to wells containing buffer and enzyme and pre-equilibrated for 5 to 30 minutes. Enzymatic reaction is induced by addition of substrate and 5 mi <φ

268

ΦΦΦΦ · «Φ

Φ Φ ΦΦΦΦ

Φ Φ Φ · Φ

Φ Φ Φ φ φ Φ

Φ Φ Φ Φ Φ Φ

405 φφ ΦΦ ΦΦΦ ΦΦΦ at 405 nm on a Vmax microplate reader (Molecular Devices) for color development due to hydrolysis of the peptide-p-nitroanilide substrate. Under these conditions, less than 10% of the substrate is used in each assay. Initial measured velocities are used to calculate the amount of inhibitor that results in a 50% reduction in control rate (IC ₅₀ ). The respective Ki values are then determined using the Cheng-Prusoff equation (IC 50 = Ki [1+ [S] / Km]) assuming kinetics of competitive inhibition.

For example, 7-methoxynaphthalene-2-sulfonic acid [1- (1,6-diaminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate has a Ki of 80 nM.

Další in. an in vitro assay can be used to determine the efficacy of the compounds of the present invention in normal human plasma. The partially activated thromboplastin time is a plasma-based clotting assay that relies on the in situ formation of factor Xa, its accumulation into the prothrombinase complex, and the subsequent formation of thrombin and fibrin, which eventually leads to clot formation as a result of the assay. This assay is currently used clinically to monitor the ex vivo effect of commonly used anticoagulant heparin drugs and also for clinical testing of the direct action of antithrombin agents. Therefore, activity in this in vitro assay is considered a surrogate marker for in vivo anticoagulant activity.

Human plasma-based clotting assay

The time of the partially activated thromboplastin is determined on double MLA. Electra 800 devices. 100 ml of citrated normal mixed human plasma (George King Biomedical) is added to a cuvette containing 100 ml of the compound of the present invention in Tris / NaCl buffer (pH 7.5) and placed in the apparatus. Mon 3,

· 1 ·

269

• 0 '

minutes of heating, the apparatus automatically adds 100 mL of activated cephaloplastin reagent (Actin, Dade) and then 100 mL of 0.035 M calcium chloride to initiate the precipitation reaction. The precipitate formation is recorded spectrophotometrically and measured in seconds. The potency of the compound is quantified as the concentration required to double the clotting control time measured with human plasma in the absence of the compound of the present invention.

The compounds of the present invention can also be evaluated for their in vivo antithrombotic activity using two well known experimental models of acute vascular thrombosis. To demonstrate the antithrombotic activity of these compounds in various animal models corresponding to human venous thrombosis and arterial thrombosis, a rabbit model of the cervical vein thrombosis and a rat model of the carotid thrombosis are used.

Experimental in vivo model of venous thrombosis in rabbit

It is a well characterized model of fibrin-rich venous thrombosis that has been proven in the literature and is sensitive to some anticoagulant drugs including heparin (Antithrombotic Effect of Recombinant Truncated Tissue Factor Patway Inhibitor (TFPI 1-161) in Experimental Venus Thrombosis-a Comparison with Low Molecular Weight Heparin, J. Holst, B. Lindblad, D. Bergqvist, O. Nordfang, PB Ostergaard, JGL Petersen, G. Nielsen, and U. Hedner, Thrombosis and Haematosis, 71, 214-219 (1994). This model is to determine the ability of compounds to prevent the formation of venous clots generated in vivo at the site of injury and against partial congestion of blood in the jugular vein.

Male and female New Zealand white rabbits weighing 1.5 to 2 kg are anesthetized with 35 mg / kg ketamine and 5 mg / kg xylazine.

0

0 0

0 0 0

270

0 0 0 ·

in a volume of 1 ml / kg (i.m.). The right jugular vein is cannulated for infusion of an anesthetic (ketamine / xylazine 17 / 2.5 mg / kg / hour at a rate of about 0.5 ml / hour) and administration of test substances. The right carotid artery is cannulated to record arterial blood pressure and collect blood samples. Body temperature is maintained at 39 ° C with a GAYMAR T-PUMP. The left outer cervical, vein is isolated and all lateral branches along the exposed 2-3 cm vessel are weighed. The inner jugular vein is cannulated just above the bifurcation of the main jugular vein and the end of the cannula is moved proximal to the main jugular vein. One-centimeter of the vein is isolated using non-traumatic vascular clamps, and relative blood congestion is achieved by ligating the ligature around the vessel with the 18G needle just below the distal clamp. This results in a reduced flow area and partial congestion at the point of damage. The isolated portion is gently rinsed two to three times with saline using a cannula in the internal jugular vein. Then the isolated part is filled with 0.5 ml of a 0.5% polyoxyethylene ether solution (W-1) for 5 minutes. W-1 is a detergent that ruptures endothelial cells along a segment to form a thrombogenic clot-initiating surface. After 5 minutes, W-1 is withdrawn from the segment and the segment is washed again two to three times with saline. The vascular clamps are then removed and blood flow through this portion of the vein is restored. A clot was allowed to form and grow for 30 minutes and then the vein was cut just below the stenotic ligation and blood flow was observed (absence of blood flow was recorded as complete blockage). The entire isolated vein segment is then weighed and the resulting precipitate is removed and weighed (wet weight). The effect of test agents on the final clot weight is used as the primary end result of the assay. The animals are kept for an additional thirty minutes to allow the final pharmacodynamic measurement of anticoagulation. Drug administration is initiated 15 minutes before venous injury by W-1 and is continued throughout the clot formation and

271 • 99 99 *

-9 9 9 * 9 9 · 9 9 • 9 9 9 9 99

9 999 9 99 999 9999 99 99 99 9 maturation. Three blood samples (3 ml ea) were taken to evaluate hemostatic parameters: the first one just prior to W-1 administration; the second 30 minutes after removal of the vascular clamps and the third at the end of the experiment. The antithrombotic activity is expressed as a reduction in the final weight of the precipitate in the preparations treated with the compound of the invention relative to the weight of the precipitate in the animals treated with the carrier.

Experimental model of in vivo arterial thrombosis in rats

The antithrombotic activity of Factor Xa inhibitors against platelet-rich arterial thrombosis can be evaluated using a well-characterized rat model of cervical artery thrombosis induced by ferrous chloride (Superior Activity of a Thromboxane Receptor Antagonist and Compared with Aspirin in Rat Models of Arterial and Venous Thrombosis, WA) CL Heran, TE Steinbacher, S. Youssef and MI Ogletree, Journal of Cardiovascular. Pharmacology, 22, 526-533 (1333); Rat Model of Arterial Thrombosis Induced by Ferric Chloride, KD Kurtz, BW Main, and GE Sausky; Thrombosis Research, 60 269-280 (1990), The Effect of Thrombin Inhibition in a Rat Arterial Thrombosis Model, RJ Broersma, LW Kutcher and EF Heminger, Thrombosis Research 64, 405-412 (1991). the potency of various agents including heparin and the direct action of thrombin inhibitors.

Sprague-Dawley rats weighing 375-450 g were anesthetized with sodium pentobarbital (50 mg / kg i.p.). After reaching an acceptable level of anesthesia, the abdominal side of the neck is shaved and prepared for aseptic surgery. Electrodes of the electrocardiogram are connected and lead II is monitored during the experiment. The right femoral vein and artery are cannulated with a PE-50 tube to administer the compound of the invention

272

9 99 9 9 9 9 9 9999 9 9 9 9 • 9 9 '9 9 9 9 9 · • 9 9 9 9 9 • 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 • 9 9

of the invention and for taking blood samples and monitoring blood pressure. A middle incision is made on the abdominal portion of the neck. The airway tube is exposed and intubated with a PR-240 trumpet to ensure airway freedom. The right carotid artery is revealed and two seams of 4-0 silk are placed around the vessel to facilitate instrumentation. To measure the blood flow, it is placed around a blood vessel. electromagnetic flow probe (0.95 to 1.0 lumen). A 4 x 4 cm parafilm strip is placed distally from the probe below the vessel to isolate the vessel from placement in the muscle. A baseline flow measurement is made, a strip of filter paper saturated with 35% ferric chloride is placed in the upstream portion of the probe for ten minutes and then removed. Ferrous chloride diffuses into the part of the artery below it and causes deendothelialization leading to acute thrombus formation. Blood pressure, carotid arterial blood flow, and cardiac rhythm are monitored for 60 minutes after application of ferric chloride-soaked filter paper. After closing the vessel (defined as achieving zero blood flow) or 60 minutes after applying the filter paper (if patency is maintained), the artery is ligated proximally and distally to the site of injury and the vessel is removed. The precipitate is removed and weighed immediately and the primary conclusion of the study is recorded.

A blood sample (B1) is taken after surgery. All blood samples are taken from the arterial catheter and mixed with sodium citrate to avoid clotting. After each blood sample, the catheter is washed with 0.5 ml 0.9% saline. The compound of the present invention is administered intravenously (i.v.) starting 5 minutes prior to ferrous chloride administration. The time between application of ferrous chloride and the time at which the blood flow in the carotid artery reaches zero is recorded as the blocking time (TTO). For blood vessels to be. do not close, this time is 60 minutes. The TTO is assigned a value of 60 minutes. Five minutes after application of ferrous chloride, a second blood sample (B2) is taken. After ten, ferrous iron is added to the iron oxide. the filter paper is removed from the vessel for the remainder after 273 minutes of exposure to chloride and the animals are lined. After the blood flow reaches zero, a third blood sample (B3) is taken and the clot is removed and weighed. Measurement of template bleeding time is performed on the forelimb foot toe at the same time as blood samples are taken. Coagulation profiles including partially activated thromboplastin time (APTT) and prothrombin time (PT) are performed on all blood samples. In some cases, the compound of the present invention may be administered orally. Rats are hand-held using conventional procedures and the compounds are administered by gastric tube using a curved needle # 18 dispensing needle (volume 5 ml / kg). Fifteen minutes after the stomach dosing, the animals are anesthetized and treated as described above. The experiments are then carried out according to the procedure described above.

The present invention may be practiced in other specific forms without affecting its nature.

274

• ·· • · ·· ···· • 9 9 • · · ·· · • 9 99 9 9 9 • · • · · · 9 9 9 ······· ·· ·· • 9

IM # -

Claims (27)

PA THESE CLAIMS A compound of formula I is the first closest ring that is bonded to Z and the ring farther from the first ring, wherein the farther ring contains at least one nitrogen atom; Z is alkylenyl; R _x is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, RO (CH ₂ ) _X -, R'O ₂ C (CH ₂ ) _x -, Y ^X Y ² NC (O (CH 2) X - or Y ^X Y ² N (CH 2) _x -; R 1: is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group; R ₂ is R ₃ S (O) _p - or R ₃ R ₄ NS (O) _p -; R ₃ is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, optionally 275 4 44 4 4 4 • 4 4444 4 44 4 4 • 4 • 4 • 4 4 4 4 4 4 4 4 • 4 44 44 4 4 4 • 4 4 4 4 · 4 '4 · 4 4 4 a substituted arylalkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted arylalkenyl group or an optionally substituted heteroarylalkenyl group, or R _x and R ₃ together with -NS (O) _p - or -NS (O) _p -NR ₄ -, via wherein R ₁ and R ₃ are joined to form a 5- to 7-membered optionally substituted heterocyclyl group; and R ₄ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group or an optionally substituted heteroaralkyl-alkyl group, or R ₃ and R ₄ together with the nitrogen atom R ₃ and R ₄ bonded to form an optionally substituted 4 to 7 membered heterocyclyl group; X _X X and _la are independently selected from the group consisting .atom hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or X, _X and X _Ia together form an oxo group; X ₂ and X _2a are hydrogen or together form an oxo group; X ₃ is a hydrogen atom, a hydroxyl group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted heteroarylalkyl group, or X ₃ and one of X _x and X _1a together form a four member a 7-membered cycloalkyl group; • · 111 1 · 11 • · ······· 276 X ₄ is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, or hydroxyalkyl; • X ₅ , X _5a ^and X _5b are independently selected from the group consisting of hydrogen, R ₅ R ₅ N-, (hydroxy) HN-, (alkoxy) HN-, or (amino) HN -, R ₇ 0-, R _to R ₆ NCO-, R ₅ R ₆ NSO ₂ -, R ₇ C0-, halogen, cyano, nitro, and R '(O) C (CH _{2) q} or one of X ₅ , X _5a and X _sb is a substituent that is in alpha position relative to the nitrogen atom of said distal ring s and is selected from the group consisting of hydrogen, hydroxyl, H ₂ N-, (optionally substituted lower alkyl) HN (hydroxy) HN-, (alkoxy) HN-, and (amino) HN-; Y ¹ and Y ² are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted, arylalkyl, or optionally substituted heteroarylalkyl, or Y ¹ and Y ² together with the nitrogen atom through which they are attached form a four to seven membered heterocyclyl group; . _R and _R are independently hydrogen or optionally substituted lower alkyl group, or one of _R and _R is hydrogen and the other of R _a and R _a is R ₈ (O) CCH ₂ or less an acyl group; R ₇ is hydrogen, optionally substituted lower alkyl, lower acyl or R ₈ (O) CCH ₂ -; 99 99 9999 99 99 9 9 9 9 9 9, 9 · 277 9 9999 9 9 9 99 999 99 999 99 99 994 R _e is hydrogen, optionally substituted lower alkyl, alkoxy or hydroxyl; m is 0, 1, 2 or 3; p is 1 or 2; q is 0 or 1, x is 1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof. 2.. A compound according to claim 1, wherein R ₂ is selected from the group consisting of The compound of claim 1, wherein \Α / is selected from the group consisting of The compound of claim 1, wherein R _x is hydrogen, optionally substituted heteroarylalkyl, optionally substituted arylalkyl, or optionally substituted alkyl. A compound according to claim 1, wherein R ₂ is a group, R ₃ S (O) _p -. '·· flfl ··· · fl The compound of claim 5, wherein p is 2. The compound of claim 5, wherein R ₃ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted thienyl, an optionally substituted benzothienyl, an optionally substituted thienylopyridyl, an optionally substituted quinolinyl or an optionally substituted isoquinolinyl. The compound of claim 1, wherein Z is a methylenyl group and rr. is 1. ‘ The compound of claim 1, wherein X ₂ and X _2a together form an oxo group. The compound of claim 1, wherein X ₂ , X _1a , X _3, and X ₄ is a hydrogen atom. 11. A compound according to claim 1, wherein Ar ^{1 ί>} ** - «* substituted isoquinolinyl. is optionally The compound of claim 11, wherein the nyl group is in the 7-position. group. where Z is Z is bound to an isoquinoline optionally The compound of claim 1, substituted quinolinyl A compound according to claim 13, wherein the group is at its 715 position. A compound according to claim 1, a substituted group of the formula wherein the bonded to the quinolines is optionally or 00 «» 280 • · 0 9 · * 0 0 0 9 9 9 · 90 > 90 and W is S, O or NR 1 _X where R _xx is hydrogen, alkyl, arylalkyl, heteroarylalkyl, R _and (O) C (CH ₂ ) _q - and A is CH or a nitrogen atom. The compound of claim 15, wherein Z is linked to said group via a five membered ring. The compound of claim 1, wherein one of X _s , X _aa and X _sb is a substituent that is on the proximal ring of the bicyclic group at an alpha position relative to the site to which Z is attached and is selected from the group of Ar ¹ f j consisting of hydrogen, hydroxy, and amino. The compound of claim 17, wherein one of X ₅ , X _5a, and X _{5b is a} hydroxyl or amino group. 19. The compound of claim 1 wherein one of X _a, X and X _{Sa Sb} that substitutes the distal ring of at a position alpha to the nitrogen atom it ,, is hydrogen or (H, optionally substituted lower alkyl, hydroxy or amino) HN-. A compound according to claim 1 which is selected from the group consisting of 3 - [[1- (4-Aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] - (5-chloro) methyl ester -1H-indol-2-ylmethyl) amino] propionic acid; 281 ·· 9 9 ' 9 · 9 9 9 • 99 9 • · · · ··· 1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) - (3-ethylbutyl) amino] pyrrolidin-2-one; . 1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [benzyl- (5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one; 1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) thiazol-5-ylmethylamino] pyrrolidin-2-one; 1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) - (2H-pyrazol-3-ylmethyl) amino] pyrrolidin-2-one; 1- (7-Aminothieno [3,2-b] pyridin-2-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one; 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (R) -yl] -amide; {[2- (5-chloro-thiophen-2-yl) -ethenesulfonyl] - [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3- (R) -yl] isopropyl ester Aminoacetic acid; 1- (4-Aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one; 5-Chloro-1H-benzoimidazole-2-sulfonic acid [1- (4-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide; 7-methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R, S) -yl] -amide; 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide hydrochloride; 7-methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-yl-methyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 7-methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide; 7-Methoxy-naphthalene-2-sulfonic acid [1- (1-hydroxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R, S) -yl] -amide; 7-methoxynaphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R, S) -yl] -methylamide; 4 · 4-Methoxy-naphthalene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide; benzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 6-chloro-benzo [b] thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 7-methoxy-naphthalene-2-sulfonic acid [1- (1-amino-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide hydrochloride; 7-methoxy-naphthalene-2-sulfonic acid [1- (6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 4- (2-Chloro-6-nitro-phenoxy) -benzenesulfonic acid [1- (1-amino-6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; trifluoroacetate. 7-Methoxy-naphthalene-2-sulfonic acid [1- (1,6-diamino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 6-chlorobenzo [b] thiophene-2-sulfonic acid [1- (1,6-diaminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 7-methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 6-chlorobenzo [b] thiophene-2-sulfonic acid [1- (2-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; benzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (2-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 7-methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide; 283 7-Methoxy-naphthalene-2-sulfonic acid [1- (2-hydroxy-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide; 7-methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 7-Methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide; 7-Methoxy-naphthalene-2-sulfonic acid [1- (2-hydroxy-quinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methyl-amide; 7-Methoxy-naphthalene-2-sulfonic acid [1- (2-amino-quinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 7-Methoxy-naphthalene-2-sulfonic acid [1- (2-hydroxy-quinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl-amide; 7-methoxynaphthalene-2-sulfonic acid [1- (1H-benzimidazol-5-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 7-methoxy-naphthalene-2-sulfonic acid [2- (1H-benzimidazol-5-ylethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 7-methoxy-naphthalene-2-sulfonic acid [1- (4-aminothieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 7-methoxy-naphthalene-2-sulfonic acid [2- (6-aminothieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 7-methoxy-naphthalene-2-sulfonic acid [1- (7-aminothieno [2,3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide trifluoroacetate; 7-methoxy-naphthalene-2-sulfonic acid [1- (7-hydroxy-thieno [2,3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 7-methoxy-naphthalene-2-sulfonic acid [1- (4-aminothieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3 (R, S) -yl] -amide; • · 284 »· ······· · · · · ·. Trifluoroacetate [1- (4-hydroxythieno [3,2-c] pyridin-3-ylmethyl) 2-oxopyrrolidin-3 trifluoroacetate 7-Methoxy-naphthalene-2-sulfonic acid (R, S) -yl] -amide; benzo [b] thiophene-2-sulfonic acid [1- (4-aminothieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3 (R, S) -yl] -amide trifluoroacetate; Thieno [3,2-b] pyridine-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; Thieno [2,3-b] pyridine-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 4-Pyridin-3-yl-thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 5'-Chloro- [2,2 '] - bithiophenyl-5 [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide -sulfonic acids; 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S-yl) -amide; [1- (l-amino-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3 (S) -yl] -amide 5'-chloro- [2.2 ^1] -bithiofenyl-5-sulfonic acid; 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 6-chloro-benzo [b] thiophene-2-sulfonic acid [1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate acids; 6-chlorobenzo [b] thiophene-2-sulfonic acid [1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; trifluoroacetate [1- (4-aminothieno (3,2-d] pyrimidin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide ^5-Chloro-1 [2,2 '] - bithiophenyl-52- sulfonic acids; Thieno [3,2-b] pyridine-2-sulfonic acid [1- (1,6-diamino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; • · 285 2- (5-Chloro-thiophen-2-yl) -ethenesulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide; 5'-chloro- [2,2 '] bithiophenyl-5-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide; 3- (R) -5-Chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide; 2- (S) - [[1- (4-Aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] - (6-chloro-benzo [b] thiophene-2-sulfonyl) -amino] trifluoroacetate acetic acid; 2- (S) -6-Chloro-benzo [b] thiophene-2-sulfonic acid trifluoroacetate [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide; 2- (S) - (5-Chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide; Thieno [3,2-b] pyridine-2-sulfonic acid ditrifluoroacetate [1- (4-aminoquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; N- (3-Amino-pyridin-4-yl) -2- [3- (7-methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -acetamide; 2- [3- (7-Methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -N-pyridin-4-ylacetamide; 6-chlorobenzo [b] thiophene-2-sulfonic acid trifluoroacetate {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3- (S) -yl} -amide; 5 'chloro- [2,2'] bithiophenyl-5-sulfonic acid {2-oxo-1- [2- (pyridin-4-ylamino) ethyl] pyrrolidin-3-yl} amide; • 10 «· · 286 6-Chloro-thieno [2,3-b] pyridine-2-sulfonic acid trifluoroacetate {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl (amide); {2-oxo-1- [2- (pyridin-4-ylamino) ethyl] pyrrolidin-3-yl (thieno [3,2-b] pyridine-2-sulfonic acid amide dithrifluoroacetate; {2-oxo-1- [ 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid 2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl (amide); {1- [2- (2-Amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl (S) -5'-chloro [2,2 '] bithiophenyl-5- ditrifluoroacetate sulfonic acids; {1- [2- (2-Amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl (S) -6-chloro-benzo [b] thiophene-2-sulfonic acid ditrifluoroacetate; ((6-Chlorobenzo [b] thiophene-2-sulfonyl)) - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3 (-yl (amino) -acetic acid) methyl ester; ((6-chlorobenzo [b] thiophene-2-sulfonyl) - {2-oxo-1- [2- (pyridin-4-ylamino) ethyl] pyrrolidin-3-yl (amino) acetic acid trifluoroacetate; 6-Chlorobenzo [b] thiophene-2-sulfonic acid allyl- {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl] -amide; 6-chlorobenzo [b] thiophene-2-sulfonic acid methyl {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide; {1- [2- (2-Amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl (S) -2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate; {1- [2- (2-Amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl (S) -thieno [3,2-b] pyridine-2-sulfonic acid amide trifluoroacetate; ([2- (5-chloro-thiophen-2-yl) -ethenesulfonyl] - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid methyl ester; ···· 28 * 7 ([2- (5-Chloro-thiophen-2-yl) -ethenesulfonyl] - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid isopropyl ester; ([2- (5-Chloro-thiophen-2-yl) -ethenesulfonyl] - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid trifluoroacetate acids; 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid (2-methoxy-ethyl) - (2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide) trifluoroacetate; ([2- (5-chloro-thiophen-2-yl) -ethenesulfonyl] - {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid trifluoroacetate; 3- (5-chloro-thiophen-2-yl) -N- {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -acrylamide trifluoroacetate; 6-chlorobenzo [b] thiophene-2-sulfonic acid [1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide; Thieno [3,2-b] pyridine-2-sulfonic acid trifluoroacetate [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide; 1- (4-aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-1H-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 1- (4-Aminoquinolin-7-ylmethyl) -3 - (S) - [(5-chloro-1H-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 5-chloro-benzo [b] thiophene-2-sulfonic acid [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 2- (5-Chloro-thiophen-2-yl) -ethenesulfonic acid [1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide ; • · · · · · 288 ···· '·'. * · · · · <<<<<<<· · · · · · · · · · . 5-chlorobenzo [b] thiophene- (S) - [1- (4-amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate 2-sulfonic acids; Thieno [3,2-b] pyridine-2-sulfonic acid (S) - [1- (4-amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate acids; 6-chlorobenzo [b] thiophene-2-sulfonic acid (S) - [1- (4-amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate; 5'-chloro [2,2 '] bithiophenyl-5-sulfonic acid (S) - [1- (4-amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate acids; 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid (S) - [1- (4-aminothieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate; 5-chlorobenzo [b] thiophene-2-sulfonic acid [(S) -1- (4-aminothieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate; 5-chlorobenzo [b] thiophene-2-sulfonic acid [(S) -1- (4-aminothieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate; [(S) -1- (4-Aminothieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate. 5'-chloro [2,2 '] bithiophenyl-5 sulfonic acid; thieno [3,2-b] pyridine-2-sulfonic acid trifluoroacetate [(S) -1- (4-aminothieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide; 6-chlorobenzo [b] thiophene-2-sulfonic acid [(S) -1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate; 9'-Chloro [2,2 '] bithiophenyl-5sulfonic acid [1- (4-aminothieno [3,2-d] pyrimidin-7-ylmethyl) 2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate acids; Thieno [3,2-b] pyridine-2-sulfonic acid trifluoroacetate [1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) 2-oxo-pyrrolidin-3- (S) -yl] -amide ; and 6-chlorobenzo [b] thiophene-2-sulfonic acid [(S) -1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide .. The compound of claim 1 selected from the group consisting of; 7-methoxy-naphthalene-2-sulfonic acid [1- (6-methoxy-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; 1- (4-Aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-1H-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid [2-oxo-1- (1H-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide; 2- (5-chloro-thiophen-2-yl) -ethenesulfonic acid (S) - [1- (4-aminothieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate ; Thieno [3,2-b] pyridine-2-sulfonic acid trifluoroacetate [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide; 6-Chlorobenzo [b] thiophene-2-sulfonic acid trifluoroacetate {2-oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3- (S) -yl] -amide; ((6-Chlorobenzo [b] thiophene-2-sulfonyl) - {2-oxo-1- [2- (pyridin-4-ylamino) ethyl] pyrrolidin-3 (yl) amino) acetic acid methyl ester; Thieno [3,2-b] pyridine-2-sulfonic acid ditrifluoroacetate [2-oxo-1- (1H-pyrrolo [2,3-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide; • 8 ·· * · · 290 • * • * · ·· ···· ^1-carboxylic acid [1- (l-amino-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] thieno [3,2- -b] pyridine-2-sulfonic acid; 2 (S) - (5-Chloro-thiophen-2-yl) -ethenesulfonic acid trifluoroacetate [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide; and 6-chloro-benzo [b] thiophene-2-sulfonic acid [1- (1,6-diaminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide bistrifluoroacetate. A compound according to claim 1 of formula ku, an alkyl group, an arylalkyl group, a heteroarylalkyl group, or an R group _with (O) C (CH ₂ ) _q -; A is CH or N; and R ₂ is a group selected from the group consisting of · v / Π «= I-R (-! W. ^From + K3 291 O \ • fl ···· 292 flfl • · · · ♦ • • • flflfl • fl · ♦ • · ·. Fl Fl J IT o o • 9111 293 44 4444 296 4 44 44 4 4 4. 4 4 * 4444 The compound of claim 1 of the formula? 'Is a group selected from the group consisting of R _x is hydrogen; and R ₂ Cl ·· ··· a 99999 99 99 99 9 or © X5b De 297 R 1 is hydrogen; and R ₂ is a group selected from the group consisting of N, Cl O O N-O Rj. is hydrogen; consists of: and R ₂ is a group selected from the group consisting of 298 '00 000000 00. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 · 0 0 0 · · 0000 00 ·· ·· Rj. is hydrogen; consists of: and R ₂ is a group selected from the group consisting of N ~ O O O 24. A pharmaceutical composition comprising a compound according to claim 1, wherein the pharmaceutically acceptable amount is a pharmaceutically acceptable carrier. with e merges 25. A method of treating a patient suffering from a physiological disorder which may be modulated by inhibiting factor Xa activity, comprising administering to the patient a therapeutically effective amount of a compound of claim 1. 26. The method of claim 25, wherein the physiological disorder is abnormal thrombus development, acute myocardial infarction, unstable angina, thromboembolism, acute vascular occlusion associated with thrombolytic therapy or percutaneous transluminal coronary angioplasty, transient ischemic attacks, stroke, pathological thrombus development • occurring in the veins of the lower extremities following abdominal, knee and hip surgery, the risk of pulmonary thromboembolism, or multiple systemic intravascular coagulopathy occurring in the vascular system during septic shock, certain viral infections, or cancer. , ···· 300 • ·· 41 · · fl, fl fl fl fl fl fl fl · fl 27. The method of claim 25, wherein the physiological disorder is abnormal thrombus development, acute myocardial infarction, unstable angina, thromboembolism, acute vascular occlusion associated with thrombolytic treatment, transient ischemic seizures, coronary or venous angioplasty restenosis, pathological thrombus formation occurring in the veins of the lower extremities following abdominal, knee and hip surgery or the risk of pulmonary thromboembolism. 28. The method of claim 25, wherein the physiological disorder is stroke, luminal vasoconstriction, or multiple systemic intravascular coagulopathy occurring in the vascular system during septic shock, certain viral infections, or cancer.