Classifications

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  • A61K31/47—Quinolines; Isoquinolines
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  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems

Definitions

• the compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are Factor Xa inhibitors.
• the present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of Factor Xa.
• Factor Xa is the penultimate enzyme in the coagulation cascade. Both free factor Xa and factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) are inhibited by compounds of formula I. Factor Xa inhibition is obtained by direct complex formation between the inhibitor and the enzyme, and is therefore independent of the plasma co-factor antithrombin III. Effective factor Xa inhibition is achieved by administering the compounds either by oral administration, continuous intravenous infusion, bolus intravenous administration or any other parenteral route such that it achieves the desired effect of preventing the factor Xa induced formation of thrombin from prothrombin.
• Anticoagulant therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature.
• abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature.
• the diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, and intermittent claudication and bypass grafting (CABG) of the coronary or peripheral arteries.
• AMI acute myocardial infarction
• PTCA percutaneous transluminal coronary angioplasty
• CABG intermittent claudication and bypass grafting
• Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long- term hemodialysis patients.
• restenosis vessel luminal narrowing
• CABG vessel luminal narrowing
• DVT deep vein thrombosis
• DVT further predisposes the patient to a higher risk of pulmonary thromboembolism.
• a systemic, disseminated intravascular coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections and cancer.
• This invention is directed to compounds of formula I below as well as to the pharmaceutical use for treating a patient suffering from a physiological disorder capable of being modulated by inhibiting the activity of Factor Xa:
• Z is alkylenyl, -(CH 2 ) r C(0)NR"(CH 2 ) s -, -(CH 2 ) s R"NC(0)(CH 2 ) r -, -(CH 2 ) r NR"(CH 2 ) s - or
• R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, R'0(CH 2 ) x -, R' ⁇ 2C(CH2) ⁇ -, R'C(0)(CH2) ⁇ -,Y 1 Y 2 NC(0)(CH2) ⁇ -
• R' and R" are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkenyl, optionally substituted heteroaralkenyl, optionally substituted aralkyl or optionally substituted heteroaralkyl;
• R 2 is hydrogen, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl, optionally substituted heteroaralkenyl, R 3 R 4 NC(0)(CH 2 )x-, R 3 S(0) p - or R 3 R 4 NS(0) p -;
• R 3 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl or optionally substituted heteroaralkenyl, or Rj and R 3 taken together with the -N-S(0) classroom- moiety or the -N-S(0) p -NR4- moiety through which R, and R 3 are linked form a 5 to 7 membered optionally substituted heterocyclyl; and R.
• X j and X la are independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or X j and X ja taken together form oxo;
• X 2 and X 2a are H, or taken together form oxo;
• X 3 is H, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted
• heteroaryl optionally substituted aralkyl or optionally substituted heteroaralkyl, or X, and one of X j and
• X. is H, optionally substituted alkyl, optionally substituted aralkyl, or hydroxyalkyl;
• X., X. and X are independently selected from H, R5R6N-, (hydroxy)HN-, (alkoxy)HN-, or
• X, X_ and X. is a substituent that is alpha to a nitrogen of said distal ring of and is selected from the group consisting of H, hydroxy and H 2 N-, (optionally substituted lower alkyl)HN (hydroxy)HN-, (alkoxy )HN-, or (amino)HN- that substitutes the
• Y and Y are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or
• R 5 and Rg are independently H or optionally substituted lower alkyl, or one of R 5 and R 6 is H and the
• R5 and R 6 is Rg(0)CCH 2 - or lower acyl
• R 7 is H, optionally substituted lower alkyl, lower acyl or R 8 (0)CCH - ;
• R is H, optionally substituted lower alkyl, alkoxy or hydroxy; m is 0, 1, 2 or 3; p and r 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 thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.
• Patient includes both humans and other mammals.
• Alkyl means an aliphatic hydrocarbon group which may be straight- or branched- chain having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. "Lower alkyl” means an alkyl group having about 1 to about 4 carbon atoms in the chain which may be straight or branched.
• the alkyl group may be substituted with one or more "alkyl group substituents" which may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl or R 9 R 10 NCO-, wherein R 9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or R, and R 10 taken together with the N through which R 9 and R 10 are linked form a 4 to 7 membered heterocyclyl.
• alkyl group substituents may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, acylamino, aroylamino
• Exemplary alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, «-propyl, /-propyl, tt-butyl, t-butyl, n- pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, pyridylmethyloxycarbonylmethy 1.
• Alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain, more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. "Lower alkenyl” means about 2 to about 4 carbon atoms in the chain, which may be straight or branched. The alkenyl group may be substituted by one or more halo or cycloalkyl groups.
• alkenyl groups include ethenyl, propenyl, n-butenyl, /-butenyl, 3-methylbut-2-enyl, ⁇ -pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
• Cycloalkyl means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms.
• Exemplary monocyclic cycloalkyl rings include cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl.
• Exemplary multicyclic cycloalkyl rings include 1-decalin, adamant-(l- or 2-)yl and norbornyl.
• Heterocyclyl means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 ring atoms. Preferred rings include about 5 to about 6 ring atoms wherein one of the ring atoms is oxygen, nitrogen or sulfur.
• the heterocyclyl is optionally partially unsaturated or optionally substituted by one or more alkyl, halo, aryl, heteroaryl, fused aryl or fused heteroaryl.
• Exemplary monocyclic heterocyclyl ring systems include pyrrolidyl, piperidyl, tetrahydrofuranyl, tetrahydrothienyl and tetrahydrothiopyranyl.
• heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
• exemplary multicyclic heterocyclyl ring systems include 1.4 diazabicyclo-[2.2.2]octane and 1.2-cyclohexanedicarboxylic acid anhydride.
• Aryl means a 6 to 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system.
• Exemplary aryl include phenyl or naphthyl, either of which may be substituted with one or more ring system substituents which may be the same or different, where "ring system substituents" are as defined herein.
• Ring system substituents means substituents attached to an aromatic or non-aromatic ring system, inclusive of hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, fused cycloalkyl, fused heterocyclyl, arylazo, heteroarylthi
• Preferred ring system substituents include hydrogen, alkyl, hydroxy, acyl, aryl aroyl, aryloxy, halo, nitro, alkoxy, cyano, alkoxycarbonyl, acylamino, alkylthio, R 9 R 10 N-, R 9 R 10 NCO- and R 9 R I0 NSO2-, where R 9 and R 10 are independently optionally substituted alkyl, aryl, aralkyl or heteroaralkyl.
• phenyl group substituents are hydroxy, halogen, alkyl and amino.
• Heteroaryl means about a 5- to about a 10- membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the carbon atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. A nitrogen atom in the ring system may be optionally oxidized to the N-oxide. Where the heteroaryl is a multicyclic hydrocarbon ring system then one of said ring systems is optionally partially or fully saturated. The "heteroaryl” may also be substituted by one or more of the above-mentioned "ring system substituents".
• heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, imidazo[2,l-b]thiazolyl, thiono[3,2-b]pyridyl, thieno[2,3- b]pyridyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl and 1,2,3,4- tetrahydroisoquinolinyl.
• heteroaryl is a multicyclic hydrocarbon ring system then it may be bonded to the rest of the molecule through any atom of the ring system thereof capable of such.
• Preferred heteroaryl groups in the R, substituent include benzothienyl, thienyl, thienopyridyl,
• bicyclic heteroaryl groups include isoquinolinyl, quinolinyl, benzothienyl, isoquinolinyl, isoquinazolinyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, (1,2- or 2,3-) benzodiazinyl and
• Preferred monocyclic heteroaryl groups include pyridyl.
• Preferred heteroaryl groups in the R 3 substituent include benzothienyl, thieno[3,2-b]pyridyl, naphthyl, or thieno[2,3-b]pyridyl.
• Alkyl means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthalenemethyl.
• Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl moiety. Exemplary heteroaralkyl groups include thienylalkyl, pyridylalkyl, imidazolylalkyl, pyrazinylalkyl, benzimidazolylmethyl, indolylmethyl, pyrazolylmethyl, and thiazolylmethyl.
• Alkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl moiety. An exemplary aralkenyl group is 2- phenethenyl.
• Heteroaralkenyl means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl moiety. Exemplary heteroaralkenyl groups include thienylallyl, thienyl-2-ethenyl, pyridyl-2-ethenyl, imidazolyl-2-ethenyl and pyrazinyl-2-ethenyl, thienylpropenyl, pyridylpropenyl, imidazolylpropenyl and pyrazinyl-propenyl.
• Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Exemplary hydroxyalkyl groups include hydroxymethyl and 1- hydroxyethyl.
• acyl means an H-CO- or alkyl-CO- group in which the alkyl group is as previously described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2- methylpropanoyl, butanoyl and palmitoyl.
• Aroyl means an aryl-CO- group in which the aryl group is as previously described.
• exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
• Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
• exemplary alkoxy groups include methoxy, ethoxy, «-propoxy, /-propoxy, M-butoxy, heptoxy and t- butoxy.
• Aryloxy means an aryl-O- group in which the aryl group is as previously described.
• exemplary aryloxy groups include phenoxy and naphthoxy.
• Heteroaryloxy means an heteroaryl-O- group in which the heteroaryl group is as previously described.
• exemplary heteroaryloxy groups include thienyloxy.
• Alkyloxy means an aralkyl-O- group in which the aralkyl groups is as previously described.
• exemplary aralkyloxy groups include benzyloxy and 1- or 2-naphthylmethoxy.
• Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
• alkylthio groups include methylthio, ethylthio, /-propylthio and heptylthio.
• Arylthio means an aryl-S- group in which the aryl group is as previously described.
• exemplary arylthio groups include phenylthio and naphthylthio.
• Alkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
• An exemplary aralkylthio group is benzylthio.
• amino groups include amino (H 9 N-), methylamino, ethylmethylamino, dimethylamino, diethylamino, pyrrolidino and piperidino.
• Alkoxycarbonyl means an alkyl-O-CO- group wherein alkyl is as defined herein.
• exemplary alkoxycarbonyl groups include (methoxy-, ethoxy- and t-butoxy)carbonyl.
• Aryloxycarbonyl means an aryl-O-CO- group wherein aryl is as defined herein.
• exemplary aryloxycarbonyl groups include phenoxy- and naphthoxycarbonyl.
• Alkoxycarbonyl means an aralkyl-O-CO- group wherein aralkyl is as defined herein.
• An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
• R, and R 10 are as previously described.
• Exemplary carbamoyl groups are carbamoyl (H.NCO-) and dimethylcarbamoyl (Me 2 NCO-).
• R 9 R, 0 NSO 2 - means a substituted or unsubstituted sulfamoyl group, wherein Kg and R 10 are as previously described.
• Exemplary sulfamoyl groups are sulfamoyl (H 2 NS0 2 -) and dimethylsulfamoyl (Me 2 NS0 2 -).
• acylamino is an acyl-NH- group wherein acyl is as defined herein.
• Aroylamino is an aroyl-NH- group wherein aroyl is as defined herein.
• Alkylsulfonyl means an alkyl-S0 2 - group wherein alkyl is as defined herein. Preferred groups are those in which the alkyl group is lower alkyl.
• Arylsulfonyl means an aryl-SO.- group wherein aryl is as defined herein.
• Alkylenyl means, for example a methylenyl, ethylenyl or propylenyl group.
• Halo means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo, and more preferred are fluoro or chloro. Preferred Embodiments
• a preferred embodiment of the invention is a method for treating a patient suffering from a physiological disorder capable of being modulated by inhibiting an activity of Factor Xa by administering a therapeutically effective amount of a compound of formula I.
• Preferred compound aspect of the invention is the compound of formula I wherein R, is H, optionally substituted heteroaralkyl, optionally substituted alkenyl, optionally substituted aralkyl or optionally substituted alkyl.
• R 2 is H, optionally substituted heteroaralkyl, optionally substituted alkenyl, optionally substituted aralkyl or optionally substituted alkyl.
• R 2 is H, optionally substituted heteroaralkyl, optionally substituted alkenyl, optionally substituted aralkyl or optionally substituted alkyl.
• R 3 S(0) P - and more preferable is R 3 S(0) p - wherein p is 2.
• R 9 is hydrogen, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl, optionally substituted heteroaralkenyl, or R 3 R 4 NC(0)(CH 2 )x-.
• R is hydrogen, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted thienyl, optionally substituted benzothienyl, optionally substituted thienopyridyl, optionally substituted quinolinyl, or optionally substituted isoquinolinyl; more preferred R, is optionally selected from substituted naphthyl, optionally substituted thienyl, optionally substituted benzothienyl and optionally substituted thienopyridyl.
• R. is selected from the group consisting of
• Another preferred compound aspect of the invention is the compound of formula I wherein R is
• R_ is hydrogen, alkyl, hydroxy, alkoxy, Y'Y 2 N-, halogen, -C0 2 Rj, -C(0)NY'Y 2 ,
• R b and R ⁇ are independently selected from hydrogen, hydroxy, alkoxy, Y'Y ⁇ N-, halogen, -COjRj, -
• Rj is hydrogen, optionally substituted alkyl, optionally substituted aralkyl or optionally substituted heteroaralkyl;
• Y 1 and Y 2 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y 1 and Y 2 taken together with the N through which Y 1 and Y 2 are linked form a 4 to 7 membered heterocyclyl;
• x is 1, 2, 3, 4, or 5.
• R 3 is optionally substituted aralkenyl or optionally substituted heteroaralkenyl, more preferably optionally substituted heteroaralkenyl.
• Another preferred compound aspect of the invention is the compound of formula I wherein when R 3 is optionally substituted aralkenyl or optionally substituted heteroaralkenyl, then the alkenyl moiety
• Another preferred compound aspect of the invention is the compound of formula I wherein when R. is optionally substituted aralkenyl or optionally substituted heteroaralkenyl, then the alkenyl moiety
• Q, and Q 2 is hydrogen, lower alkyl (more preferably methyl), or halo (more preferably fluoro or chloro) and the other of Q, and Q 2 is lower alkyl (more preferably methyl), or halo (more preferably fluoro or chloro).
• Another preferred compound aspect of the invention is the compound of formula I wherein when
• R 3 is optionally substituted aralkenyl then the aryl moiety thereof is halo substituted phenyl; more preferably chloro substituted phenyl.
• Another preferred compound aspect of the invention is the compound of formula I wherein when
• R 3 is optionally substituted heteroaralkenyl then the heteroaryl moiety thereof is halo substituted thienyl, more preferably 2-chlorothien-5-yl.
• Another preferred compound aspect of the invention is the compound of formula I wherein Z is methylenyl.
• Another preferred compound aspect of the invention is the compound of formula I wherein
• X • 5.a is selected from the group consisting of
• Another preferred compound aspect of the invention is the compound of formula I wherein
• heteroaryl ring is an optionally substituted heteroaryl ring, preferably 5 or 6 membered heteroaryl ring, more preferably containing at least one hetero atom which is preferably N or S, or an optionally substituted 6 membered aryl ring, and wherein said optional substituents are preferably chloro, hydroxy or amino.
• Another preferred compound aspect of the invention is the compound of formula I wherein Z, is S (sulfur).
• Another preferred compound aspect of the invention is the compound of formula I wherein Z, is S (sulfur); and R b and R ⁇ . taken together with the carbon atoms through which R b and R ⁇ . are linked form an optionally substituted 5 or 6 membered heteroaryl ring, preferably containing at least one hetero atom which is preferably N, or an optionally substituted 6 membered aryl ring, and wherein said optional substituents are preferably chloro, hydroxy or amino.
• Another preferred compound aspect of the invention is the compound of formula I wherein Z, is S (sulfur); R b is hydrogen; and R c is an optionally substituted heteroaryl ring, preferably a 5 or 6 membered heteroaryl ring, preferably containing at least one hetero atom which is preferably N or S, or an optionally substituted 6 membered aryl ring, and wherein said optional substituents are preferably chloro, hydroxy or amino.
• Another preferred compound aspect of the invention is the compound of formula I wherein Z is methylenyl, and m is 1.
• Another preferred compound aspect of the invention is the compound of formula I wherein X 2 and X tract 2a taken tog ⁇ ether are oxo.
• Another preferred compound aspect of the invention is the compound of formula I wherein each of X tract X la , X 3 and X 4 is H.
• Another preferred compound aspect of the invention is the compound of formula I wherein
• Another preferred compound aspect of the invention is the compound of formula I wherein
• Another preferred compound aspect of the invention is the compound of formula I wherein
• quinazolinyl is an optionally substituted quinazolinyl; more preferred the quinazolinyl is attached to Z at the 7-position thereof.
• Another preferred compound aspect of the invention is the compound of formula I wherein
• W is S, O or NR, meaning wherein R ⁇ is H, alkyl, aralkyl, heteroaralkyl, or R 8 (0)C(CH 2 ) q -, and A is independently CH or N; more preferably the moiety is bonded to Z through the ring containing W, and yet more preferably the moiety is bonded to Z through the ring containing W at the 2-position thereof.
• Another preferred compound aspect of the invention is the compound of formula I wherein one of X , X and X 5b is H, hydroxy or amino, more preferably hydroxy or amino substituted on the proximal
• Another preferred compound aspect of the invention is the compound of formula I wherein one
• X , X. a and X 5b is a substituent on the distal ring of at the position alpha to a nitrogen thereof selected from H , H 2 N-, (optionally substituted loweralkyl)HN-, (hydroxy )HN-, and (amino)HN-
• Preferred Species according to the invention are selected from the group consisting of: 3-[[l-(4-Aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-(5-chloro-lH-indol-2- ylmethyl)amino]propionic acid methyl ester; l-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-lH-indol-2-ylmethyl)-(3-ethylbutyl)amino]pyrrolidin-
• 6-Chloro-benzo[b]thiophene-2-sulfonic acid [l-(l-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)- yl] amide trifluoroacetate; 7-Methoxynaphthalene-2-sulfonic acid [l-(l-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-
• 6-Chloro-benzo[b]thiophene-2-sulfonic acid [l-(4-amino-thieno[2,3-d]pyrimidin-6-yl-methyl)-2- oxopyrrolidin-3-(S)-yl]amide trifluoroacetate
• 6-Chloro-benzo[b]thiophene-2-sulfonic acid [l-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl)-2- oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
• 6-Chloro-benzo[b]thiophene-2-sulfonic acid [(S)-l-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo- pyrrolidin-3-yl]-amide trifluoroacetate;
• 5'-Chloro-[2,2']bithiophenyl-5-sulfonic acid [l-(4-amino-thieno[3.2-d]pyrimidin-7-ylmethyl)-2-oxo- pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
• More preferred species according to the invention are selected from the group consisting of
• 6-Chloro-benzo[b]thiophene-2-sulfonic acid [2-oxo- l-(lH-pyrrolo[3 ,2-b]pyridin-2-ylmethyl)-pyrrolidin- 3-(S)-yl]-amide trifluoroacetate
• 6-Chloro-benzo[b]thiophene-2-sulfonic acid [2-oxo- 1 -( 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-pyrrolidin- 3-(S)-yl]-amide trifluoroacetate;
• 6-Chlorobenzo[b]thiophene-2-sulfonic acid ⁇ 2-oxo- l-[2-(pyridin-4-yl-amino)ethyl]-pyrrolidin-3-(S)-yl ⁇ - amide trifluoroacetate;
• 5'-Chloro-[2,2']bithiophenyl-5-sulfonic acid ⁇ 2-oxo- l-[2-(pyridin-4-y lamino)-ethyl]-pyrrolidin-3-yl ⁇ - amide;
• 6-Chlorobenzo[b]thiophene-2-sulfonic acid [l -(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)- yljamide trifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonic acid [l-(l-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)- yl]amide trifluoroacetate: l-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-l H-indol-2-ylmethyl)amino]pyrrolidin-2-one trifluoroacetate; l-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[3-(5-chlorothiophen-2-yl)allylamino]pyrrolidin-2-one trifluoroa
• 6-Chloro-benzo[b]thiophene-2-sulfonic acid [l-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)- yl]-amide trifluoroacetate
• Still more preferred species according to the invention are selected from the group consisting of:
• 6-Chlorobenzo[b]thiophene-2-sulfonic acid ⁇ 2-oxo- 1- [2-(pyridin-4-yl-amino)ethyl]-pyrrolidin-3-(S)-yl ⁇ - amide trifluoroacetate; ((6-Chloro-benzo[b]thiophene-2-sulfonyl)- ⁇ 2-oxo- l-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3(-yl ⁇ - amino)-acetic acid methyl ester;
• a compound of formula I may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature.
• a preparative embodiment according to the invention for preparing a compound of formula I wherein Ar R,, R 2 , X 3 , X 4 , X 5 , X 5a , X 5b , Z and m are as defined above, X, and X la are H and X 2 and X 2a , taken together, form oxo, may be prepared by coupling a compound of formula II
• X 3 , X 4 and are as defined above, X, and X la are H, X 2 and X 2a taken together form oxo, and P, is an (alkyl, aralkyl or aryl) carbamate with a compound of formula III wherein Ar, is bicyclic heteroaryl, X 5 , X 5a , X 5b and Z are as defined above, and one of X 5 , X 5a , X 5b is H, chloro, bromo or aryloxy at the position alpha to the nitrogen of the distal ring of Ar, and L is a leaving group such as chloro, bromo, iodo, or optionally substituted lower alkylsulfonyloxy or arylsulfonyloxy, to give a compound of formula IV
• a compound of formula IV is converted to a compound of formula I by the methods herein described.
• a compound of formula III may be prepared by reacting a compound of formula V,
• X 5c is H, R ⁇ N-, R 7 0-, R 5 R NCO-, R 5 R «NS0 2 -, R 7 CO-, halo, cyano, nitro or R 8 (0)C(CH 2 ) q -, and wherein an amino or hydroxy group thereof is suitably protected by an amino or hydroxy protecting group, n is 0 to 2, and Ar 2 is a monocyclic aryl or heteroaryl ring, with an appropriate malonic acid in a polar solvent such as pyridine or ethanol and a base such as piperidine or pyridine at reflux to give a compound of formula VI
• R 12 is H, X 5c attached to the carboxymethylidene moiety is H, X 5c attached to , n and
• R 12 is lower alkyl
• the ester is hydrolyzed to the corresponding carboxylic acid, wherein R 12 is H, by an appropriate strong acid or alkali base.
• the corresponding acid is converted to the acid chloride using standard methods such as thionyl chloride or is converted to the mixed anhydride in a polar solvent such as acetone or THF to form an activated acyl compound.
• the activated acyl compound is then treated with a solution of NaN 3 in water at about -10 °C to about 25 °C to yield the corresponding acyl azide.
• the acyl azide compound is then heated slowly in an inert solvent such as benzene or toluene at about 60 °C to about 110 °C then concentrated in vacuo and heated in a higher boiling inert solvent such as 1 ,2- dichlorobenzene or phenyl ether at about 180 °C to about 240 °C with a catalyst such as iodine or tributylamine to obtain a compound of formula VII,
• an inert solvent such as benzene or toluene
• a higher boiling inert solvent such as 1 ,2- dichlorobenzene or phenyl ether
• X 5c is H, R 5 R ⁇ ;N-, R 7 0-, R 7 CO-, halo, cyano, nitro or R 8 (0)C(CH 2 ) q -, and wherein an amino or hydroxy group thereof are suitably protected by an amino or hydroxy protecting group, n is 0, 1 or 2, and Ar 2 is a monocyclic aryl or heteroaryl ring.
• the acyl azide compound can be added directly to a high boiling inert solvent such as phenyl ether at about 190 °C to about 240 °C with a catalyst such as iodine or tributylamine to obtain the compound of formula VII.
• a compound of formula VIII is H, R 5 R ⁇ ;N-, R 7 0-, R 7 CO-, halo, cyano, nitro or R 8 (0)C(CH 2 ) q -, and wherein an amino or hydroxy group thereof are suitably protected by an amino or hydroxy protecting group, n is
• X 5c is H, RsR N-, R 7 0-, R 5 R 6 NC0-, R ⁇ NSO,-, R 7 CO-, halo, cyano, nitro or R 8 (0)C(CH 2 ) q -, and wherein an amino or hydroxy group thereof are suitably protected by an amino or hydroxy protecting group, n is 0, 1, or 2, and Ar 2 is a monocyclic aryl or heteroaryl ring, or formula VII above, or those compounds wherein the amino or hydroxy moieties thereof are suitably protected by an amino or hydroxy protecting group, may be chlorinated using standard methods such as POCl 3 or P0C1 3 /PC1 5 to obtain the following corresponding chlorinated intermediates such as compounds of formula (IX) and (X), wherein X 5c , n and Ar 2 are as defined above.
• a compound of formula IX and formula X wherein X 5c is a protected amino moiety wherein the protection is effected with an acid labile group such as acyl or dibenzylidene can be deprotected using standard methods such as a strong acid in an alcoholic solvent such as ethanol or a polar solvent such as ethyl acetate to yield the free amine which can then be chlorinated as above.
• an alcoholic solvent such as ethanol
• a polar solvent such as ethyl acetate
• the free amine may be liberated by the action of the POCl 3 , but in either case the free amine may be reprotected with a suitable protecting group such as dibenzylidene.
• X 5 , X 5a and X 5b is chloro at the position alpha to the nitrogen of the distal ring of Ar, when AR j is bicyclic, and the methyl moiety is attached to the proximal ring of Ar lake may be treated with NaBr or an arylhydroxy compound such as phenol and potassium hydroxide to afford a compound of formula XI wherein the chloro at the position alpha to the nitrogen of the distal ring of Ar, is replaced by bromo or aryloxy at that position.
• methyl moiety of a compound of formula XI wherein Ar,, X 5 , X 5a and X 5b are as defined above, provided that wherein X 5 , X 5a and X 5b is hydroxy or amino bearing a hydrogen then the hydroxy and amino are protected by appropriate hydroxy and/or amino protecting groups, may be halogenated using standard conditions such as N-halosuccinimide and benzoyl peroxide in an inert solvent such as carbon tetrachloride to give the corresponding halomethyl compound of formula III wherein L is bromo, chloro, or iodo, and one of X 5 , X 5a and X 5b is chloro, bromo or aryloxy at the position alpha to the nitrogen of the distal ring of Ar,.
• A is CH, W is NH and Z is 0 methylenyl, L is halo, o O ne of X 5 , X, 5a and X 5b is on the 5-me.mbered ring of
• X 5 , X 5a and X 5b is on the 6-membered ring of and is a substituent as defined above or one wherein amino or hydroxy moieties thereof are suitably protected, and the other of X 5 , X 5a and X 5b is hydrogen, chloro, bromo or aryloxy and is substituted alpha to the
• nitrogen in the 6-membered ring of may be prepared by reacting a compound of formula XII, formula XIII or formula XHIa
• a compound of formula XII or formula XIII wherein W is NH and X 7 is H can be protected using standard methods such as with benzenesulfonyl chloride using a strong base such as sodium hydroxide in an halogenated solvent such as dichloromethane in the presence of a phase transfer catalyst such as tetrabutylammonium chloride to yield a compound of formula XII or formula XIII wherein W is N-S0 2 Ph and X 7 is H.
• a compound of formula XII or formula XIII wherein W is N-S0 2 Ph and X 7 is -CH 2 OH may 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.
• a compound of formula III may be prepared by condensing an appropriate beta- aryl or beta-heteroaryl amino acid of formulae XIV or XV,
• W and X 7 are as defined herein, with Gold's reagent under basic conditions using sodium hydride or another equally strong base followed by an acidic work-up.
• the resulting compound is then processed as described above to yield a compound of formula III.
• a compound of formula II as defined above is treated with a strong base such as sodium hydride, lithium hexamethyldisilylazide, or lithium diisopropyl amine in an inert organic solvent such as tetrahydrofuran or dimethylformamide at about -78°C to about 25°C followed by the addition of a compound of formula III above wherein one X 5 , X 5a and X 5b is substituted alpha to a nitrogen of the distal ring of and is hydrogen, chloro, bromo or aryloxy, and L is a good leaving group such as chloro, bromo, or iodo, to give a compound of formula IV above.
• a strong base such as sodium hydride, lithium hex
• A is CH, W is NH and Z is methylenyl, L is halo, one of X 5 , X 5a and X 5b is on the 5-membered ring of
• X 5 , X 5a and X 5b is on the 6-membered ring of and is a substituent as defined above or one wherein amino or hydroxy moieties thereof are suitably protected, and the other of X 5 , X 5a and X 5b is hydrogen, chloro, bromo or aryloxy and is substituted alpha to the
• nitrogen in the 6-membered ring of may be prepared by alkylation of a (2-oxopyrrolidin-3-
• a base such as sodium hydride.
• the alkyne that is obtained is heated (100-120 °C) with a halopyridine optionally substituted with hydroxy, alkoxy carbony lam ino, or sulfhydryl, a catalyst such as Pd(PPh 3 ) 2 Cl 2 , copper iodide and triethylamine in a suitable solvent such as acetonitrile in a sealed vessel or in DMF, for 2-20 hours.
• furopyridines are isolated directly if the pyridine is substituted with an alkoxycarbonylamino moiety, additional treatment with DBU at about 60 °C in DMF yields pyrrolopyridines. Subsequent deprotection yields the desired 2-(3-(S)-amino-2- oxopyrrolidin-l-ylmethyl)-furopyridines or pyrrolopyridine- 1 -carboxylic acid alkyl esters.
• DMAP dimethyl aminopyridine
• nitrogen of the distal ring of is bromo or chloro may be converted to the corresponding aryloxide by reaction with an arylhydroxy compound such as phenol, and a strong alkali base such as potassium hydroxide at 70 °C to about 120 °C.
• nitrogen of the distal ri .ng of is bromo or chloro may be treated with an arylhydroxy such as phenol and an ammonium salt such as ammonium acetate at about 90 °C to 180 °C to give compounds represented by formula I wherein Ar,, R,, R 3 , R 4 , X,, X la , X 2 , X 2a , X 3 , X 4 , X 5 , X 5a , X 5b , Z and m are as defined above, and wherein one X 5 , X 5a and X 5b is substituted alpha to a nitrogen of the distal ring of
• a compound of formula I may be prepared starting with a compound of formula
• X 3 , X 4 , P, and m are as defined above, and P 2 is alkyl, aralkyl or aryl, by reductive amination using a (heteroaryl)alkylamine of formula XXI
• a compound of formula XXI used in the reductive amination described above may be prepared by treatment of a compound of formula III wherein one of X 5 , X 5a , X 5b is H or aryloxy at the position alpha to the nitrogen of the distal ring of Ar, and L is a leaving group such as chloro, bromo, iodo or the like, with sodium azide followed by reduction using standard reducing methods such as triphenylphosphine in solvents such as water/tetrahydrofuran or catalytic reduction.
• a compound of formula I in which R, is other than H may be prepared starting with a compound of formula I wherein R, is H by dissolving it in an inert organic solvent such as tetrahydrofuran, dioxane, or dimethyl formamide at about 0°C to about 100°C. To the resulting solution is added a base such as sodium hydride or potassium carbonate and a compound of formula XXII.
• an inert organic solvent such as tetrahydrofuran, dioxane, or dimethyl formamide
• R,-Halo XXII wherein R, is as defined above except that R j is not H, and Halo is a halogen such as bromo or chloro.
• a peracid for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane
• 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 within the scope of the invention.
• acid addition salts are formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form.
• the acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on the activity of Factor Xa inherent in the free base are not vitiated by side effects ascribable to the anions.
• salts within the scope of the 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, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like.
• the corresponding acid addition salts include the following: hydrohalides, e.g.
• hydrochloride and hydrobromide sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-B-hydroxynaphthoates, gentisates, mesylates, isothionates and di-p-toluoyltartrates, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
• acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods.
• the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
• the compounds of this invention may be regenerated from the acid addition salts by the application or adaptation of known methods.
• parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
• base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form.
• the bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on the activity of Factor Xa inherent in the free acid are not vitiated by side effects ascribable to the cations.
• salts including for example alkali and alkaline earth metal salts, within the scope of the invention are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
• Metal salts of compounds of the present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the chosen metal, in an aqueous or organic solvent, with the free acid form of the compound.
• the aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate.
• Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.
• Amine salts of compounds of the present invention may be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound.
• Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone.
• Amino acid salts may be similarly prepared.
• the base addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods.
• parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
• Salt forms according to invention also include compounds having a quarternarized nitrogen.
• the quarternarized salts are formed by methods such as by alkylation of a sp 3 or sp 2 hybridized nitrogen in the compounds.
• acid addition salts are most likely to be formed by compounds of this invention having a nitrogen-containing heteroaryl group and/or possessing an amino group as a substituent.
• Preferable acid addition salts of the compounds of the invention are those wherein there is not an acid labile group.
• salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
• Compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in either the (R) or (S) configuration. It will also be apparent to those skilled in the art that certain compounds of formula I may exhibit geometrical isomerism. Geometrical isomers include the cis and trans forms of compounds of the invention having an alkenyl moiety. The present invention comprises the individual geometrical isomers and stereoisomers and mixtures thereof.
• Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates, for example by the application or adaptation of methods described herein.
• 3-p-Tolyl-acryloyl chloride (22.3 g, 123.3 mmol) in dioxane (50 mL) is slowly added to an ice cooled solution of sodium azide (16 g, 246.6 mmol) in water/dioxane (50 mL, 1/1, v/v) so as to maintain the temperature between 5-10°C.
• the mixture was stirred for 1.5 hours then poured over 300 g of ice.
• the resulting white solid was filtered and washed with additional water.
• the solid (20.72 g, 1 10.7 mmol) was dried over P 2 0 5 under vacuum overnight and used in the next step without further purification.
• the residue is diluted with ice water and the pH is adjusted to ca. 8 by slow addition of 10 N NaOH.
• the aqueous solution is extracted with methylene chloride (4 x 20 mL) and the combined organic layers are washed with brine, dried over MgS0 4 , filtered and concentrated.
• the resulting dark oil is purified by column chromatography eluting with 25% EtOAc/hexanes to give the product (1.6 g, 9 mmol) as a light yellow solid.
• N-Bromosuccinimide (1.10 g, 6.19 mmol) and benzoyl peroxide ( 0.39 g, 1.13 mmol) are added to a solution of l-chloro-7-methylisoquinoline (1 g, 5.63 mmol) in carbon tetrachloride (70 mL).
• the resulting mixture is heated to reflux for 6 hours then cooled to room temperature and diluted with methylene chloride.
• the organic layer is washed with IN NaOH and brine, then dried over MgS0 4 , filtered and concentrated.
• the mixture is diluted with water and extracted with CHC1 3 (2 x 100 mL).
• the combined organic layers are washed successively with water, saturated NaHC0 3 solution and saturated NaCl.
• the organic phase is dried over anhydrous MgS0 4 , filtered and concentrated to give 10 g of a crude oil.
• the crude product is purified by column chromatography in a gradient of 5% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (3.8 g, 14.8 mmol) as a white crystalline solid.
• Phenol (6.81 g, 72.4 mmol) and potassium hydroxide ( 0.41 g, 7.31 mmol) are added to 7- methoxynaphthalene-2-sulfonic acid [l-(l-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]- amide (1.8 g, 3.6 mmol) and heated to 90°C until a homogeneous mixture is obtained. The mixture is stirred overnight at 90°C, then cooled to room temperature and diluted with methylene chloride (100 mL) and water.
• methylene chloride 100 mL
• the aqueous layer is neutralized to pH 7 using 1 N HC1, then the two layers are separated and the aqueous layer is extracted with additional methylene chloride. The combined organic layers are washed with brine, dried over MgS0 4 , filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 30% EtOAc/hexanes to 60% EtOAc/hexanes to give the product (1.66 g, 3 mmol) as a white solid.
• the title compound is prepared by resolution of the racemic compound described in EXAMPLE 1, Part M using a Chiralpak AD HPLC column (55% EtOH/Heptane(0.1% TFA)).
• the enantiomeric purity is 90.7% ee as determined by analytical Chiralpak AD reverse phase HPLC.
• the title compound is prepared as described in EXAMPLE 1 , Part L using 7-methoxynaphthalene-2- sulfonic acid [l-(l-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide in place of 7- methoxynaphthalene-2-sulfonic acid [l-(l-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]- amide.
• the title compound is prepared as described in EXAMPLE 1 , Part M using 7-methoxynaphthalene-2- sulfonic acid [l-(l-phenoxy-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]-methyl-amide in place of 7-methoxynaphthalene-2-sulfonic acid [l-(l-phenoxy-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3- (R,S)-yl]-amide.
• the title compound was prepared as described in EXAMPLE 2 using benzo[b]thiophene-2-sulfonic acid [l-(l-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide as the starting material. No extractive work up is performed.
• the crude product is purified by RP-HPLC eluting with a gradient of 10% CH 3 CN/H 2 0 (0.1% TFA) to 100% CH 3 CN. The appropriate fractions are lyophilized to provide the title compound as a white solid.
• a solution containing polyphosphoric acid (8 g) and chlorobenzene (50 mL) is heated to reflux.
• a solution containing l-chloro-3-(2,2-dimethoxy-ethyl-sulfanyl)-benzene (2.7 g, 1 1.6 mmol) in chlorobenzene (5 mL) is added dropwise to the refluxing polyphosphoric acid solution. After 6 hours, the solution is cooled to ambient temperatures.
• the solution is diluted with CH 2 C1 2 and washed with water and saturated NaCl (aq.).
• the organic layer is dried over MgS0 4 , filtered and concentrated.
• the crude product is purified by column chromatography eluting with hexanes to yield the title compounds (2.4 g, 9 mmol) as a 1 : 1 isomeric mixture.
• the title compound is prepared as described in EXAMPLE 8, Part A substituting the 4-chloro-benzo[b]- thiophene and 6-Chloro-benzo[b]-thiophene mixture for thianaphthalene.
• the crude product is purified by column chromatography eluting with hexanes to yield the title compound as well as 4- chlorobenzo[b]thiophene-2-sulfonyl chloride as white solids.
• the title compound is prepared as in EXAMPLE 1, Part K using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride in place of 7-methoxynaphthalene-2-sulfonyl chloride.
• the title compound is prepared as described in EXAMPLE 2 using 6-Chloro-benzo[b]thiophene-2- sulfonic acid [l-(l-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide as the starting material. No extractive work up is performed.
• the crude product is purified by RP-HPLC eluting with a gradient of 10% CH 3 CN/H 2 0 (0.1 % TFA) to 100% CH 3 CN. The appropriate fractions are lyophilized to provide the title compound as a solid.
• 3-(3-Methoxy-4-methylphenyl)propenoic acid (5.33 g, 27.7 mmol) (prepared according to the procedure described in J. Med. Chem. 1991, 34, 1662-1668) is suspended in benzene (30 mL) and treated dropwise with thionyl chloride (2.22 mL, 30.5 mmol) at 0°C. The reaction is heated to reflux and it is maintained for 1 hour. The volatiles are removed in vacuo and the resulting solid is dissolved in dioxane and added dropwise to a mixture of sodium azide (3.6 g, 55.4 mmol) in water/dioxane (30 mL, 1 :5) at 0°C.
• 6-Methoxy-7-methyl-2H-isoquinolin-l-one (2.6 g, 13.7 mmol) is converted to 6-methoxy-7-methyl-2- chloroisoquinoline (2.45 g, 1 1.8) by the method described in EXAMPLE 1, Part E.
• a portion of this material (1.20 g, 5.8 mmol) is converted to 7-bromomethyl-l-chloro-6-methoxy-isoquinoline (0.8 g, 2.8 mmol) by the method described in EXAMPLE 1, Part F.
• the reaction mixture is warmed to ambient temperature, stirred for 3 hours, quenched by the addition of saturated NH 4 C1 and diluted with EtOAc. The layers are separated. The organic layer is washed with saturated NaCl, dried over Na 2 S0 4 , filtered, and concentrated to give a white solid. The solid is collected, washed with a small amount of EtOAc and copious amounts of Et 2 0 to yield the title compound (0.18 g, 0.47 mmol).
• the reaction is cooled and partitioned between 0.5 N NaOH and CH 2 C1 2 .
• the organic layer is dried over Na 2 S0 4 and concentrated.
• the residue is purified by column chromatography eluting with 5% MeOH CH 2 Cl 2 .
• the product fractions are collected and concentrated to a small volume, then the residue is acidified with IN HCl/ether to give a beige solid (0.046 g, 0.095 mmol).
• the suspension is filtered, then the filtrate is concentrated and the residue is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 0 (0.1 % TFA) to 90% CH 3 CN/H 2 0 (0.1 % TFA).
• the title compound is prepared as described in EXAMPLE 1, Part E using 6-amino-7-methyl-2H- isoquinolin-1-one as the starting material.
• the crude product is purified by column chromatography eluting with a gradient of 5% MeOH/CH 2 Cl 2 to 10% MeOH/CH 2 Cl 2 to afford the title compound as a yellow solid.
• the crude material is diluted with CH 2 C1 2 and washed with saturated NaHC0 3 solution and brine. The organic layer is dried over MgS0 4 , filtered and concentrated. The crude product is purified by column chromatography using 10% EtOAc/hexanes as the eluent to afford the title compound (0.159 g, 0.45 mmol) as a yellow oil.
• the title compound is prepared as described in EXAMPLE 1, Part H using benzhydrylidene-(7- bromomethyl-l-chloro-isoquinolin-6-yl)-amine in place of 7-bromomethyl-l-chloroisoquinoline.
• the crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/hexanes to 30%) EtOAc/hexanes to give the product as a foamy yellow solid.
• the title compound is prepared as described in EXAMPLE 2 using 6-chloro-benzo[b]thiophene-2- sulfonic acid[l-(6-amino-l-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide as the starting material. No extractive work up is performed.
• the crude product is purified by RP-HPLC eluting with a gradient of 10% CH 3 CN/H 2 0 (0.1 % TFA) to 100% CH 3 CN/H 2 0. The appropriate fractions are lyophilized to provide the title compound as a tan solid.
• the title compound is prepared as described in EXAMPLE 1, Part I using [l-(2-chloro-quinolin-7- ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester as the starting material.
• the title compound is obtained as a white solid.
• the title compound is prepared in CH 2 C1 2 instead of CH 3 CN from 7-(3-(S)-amino-2-oxopyrrolidin-l- ylmethyl)-2-chloro-quinoline hydrochloride as described in EXAMPLE 1 , Part K using 6-chloro- benzo[b]thiophene-2-sulfonyl chloride as prepared in EXAMPLE 9, Parts A, B and C in place of 7- methoxynaphthalene-2-sulfonyl chloride.
• the crude product is triturated from EtOAc/hexanes to afford the title compound as a beige solid.
• the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 0 (0.1% TFA) to 80% CH 3 CN/H 2 0 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a tan solid.
• the title compound is prepared in CHC1 3 instead of CH 3 CN from 7-(3-(S)-amino-2-oxopyrrolidin-l- ylmethyl)-2-chloro-quinoline hydrochloride as described in EXAMPLE 1, Part K using benzo[b]thiophene-2-sulfonyl chloride as prepared in EXAMPLE 8, Part A in place of 7- methoxynaphthalene-2-sulfonyl chloride.
• the crude product is triturated from CH 2 C1 2 to afford the title compound as a beige solid.
• the crude product is partially purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 0 (0.1% TFA) to 80% CH 3 CN/H 2 0 (0.1% TFA) and the appropriate product fractions are concentrated in vacuo, filtered, triturated with MeOH and then purified further by column chromatography eluting with a gradient of 1 % MeOH CH 2 Cl 2 to 3% MeOH/CH 2 Cl 2 to yield the title compound as a pale yellow solid.
• the title compound is prepared as in EXAMPLES 18 AND 19, Part A using 7-methoxynaphthalene-2- sulfonic acid [l-(2-chloro-quinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide as the starting material.
• the crude product is purified by column chromatography eluting with 50% EtOAc/hexanes to afford the title compound as a white solid.
• the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 0 (0.1% TFA) to 80% CH 3 CN/H 2 0 (0.1% TFA) and the appropriate product fractions are lyophilized to provide 7- methoxynaphthalene-2-sulfonic acid [l-(2-aminoquinolin5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methyl amide trifluoroacetate as a white solid.
• the title compound is prepared as described in EXAMPLE 1, Part E using 6-methyl-lH-quinolin-2-one in place of 7-methyl-2H-isoquinolin-l-one.
• the crude product precipitated out during neutralization of the aqueous workup and the solid is filtered and dried.
• the crude product is recrystallized in MeOH to afford the title compound as a beige solid.
• the title compound is prepared as described in EXAMPLE 1, Part I using [l-(2-chloro-quinolin-6- ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester as the starting material.
• the title compound is obtained as a white solid.
• the title compound is prepared in CH 2 C1 2 instead of CH 3 CN as described in EXAMPLE 1, Part K using 6-(3-(S)-amino-2-oxopyrrolidin-l-ylmethyl)-2-chloro-quinoline hydrochloride as the starting material and 7-methoxynaphthalene-2-sulfonyl chloride.
• the crude product is triturated in CH 2 C1 2 and filtered to provide the title compound as a white solid.
• the crude mixture of products is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 0 (0.1 % TFA) to 60% CH 3 CN/H 2 0 (0.1% TFA) and the appropriate product fractions are concentrated in vacuo and then purified further by column chromatography eluting with 5% MeOH/CH 2 Cl 2 to yield 7- methoxynaphthalene-2-sulfonic acid [1 -(2-aminoquinolin6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide as a tan solid.
• the title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using 4-nitrobenzyl bromide in place of 7-bromomethyl-l-chloro- isoquinoline.
• the crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH,Cl 2 to 25% EtOAc/CH 2 Cl 2 to afford the title compound as a yellow solid.
• the resulting mixture is treated with a catalytic amount of NaN0 2 , followed by the dropwise addition of fuming HN0 3 (3.8 mL).
• the reaction mixture is stirred at 0°C for 1.5 hours, then at room temperature for 1.5 hours.
• a mixture of ice/ice water is added slowly with stirring.
• the mixture is diluted further with water and extracted with EtOAc (3 x 50 mL).
• EtOAc 3 x 50 mL
• the combined organic layers are washed twice with water.
• the organic phase is dried over anhydrous MgS0 4 , filtered and concentrated.
• the crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 0 (0.1% TFA) to 80% CH 3 CN/H 2 0 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound (0.17 g, 0.30 mmol) as a white solid.
• Boc-L-Asp-OBn (15 g, 46.4 mmol) is dissolved in THF (50 mL) and cooled to -10°C. The solution is treated with N-methylmorpholine (4.9 g, 48.7 mmol) and stirred for 5 minutes. To the solution is added dropwise isobutyl chloroformate (6.3 g, 46.4 mmol). After the addition is completed, the mixture is stirred for 1 minute and then filtered through a pad of Celite. The filtrate is cooled to -10°C. To the solution is added sodium borohydride (2.63 g, 70 mmol) which is predissolved in water (50 mL). The resulting solution is stirred for 2 minutes.
• the reaction mixture is stirred at -78°C for 1 hour and then is stirred at room temperature for 30 minutes.
• the solution is poured into a 20% citric acid/water (200 mL) solution.
• the resulting mixture is poured into a separatory funnel and the layers are separated.
• the organic layer is washed with water and saturated NaCl.
• the organic phase is dried over MgS0 4 , filtered and concentrated.
• the crude residue is purified by column chromatography eluting with a gradient of 10% EtOAc/hexanes to 30% EtOAc/hexanes to give the title compound (12.0 g, 39 mmol) as an oil.
• Boc-L-Asp(H)-OBn 3.3 g, 10.7 mmol
• methanol 50 mL
• 4A molecular sieves 4-nitrophenethylamine hydrochloride (4.35 g, 21.5 mmol) and triethylamine (2.25 g, 22.2 mmol).
• the solution is stirred at room temperature for 45 minutes and then the mixture is treated with sodium cyanoborohydride (0.72 g, 1 1.5 mmol).
• the reaction mixture is stirred at room temperature for 16 hours. After this time,l N NaOH (10 mL) followed by water (25 mL) is added.
• the resulting mixture is stirred for 30 minutes and then concentrated in vacuo to a smaller volume.
• the solution is diluted with EtOAc (250 mL), filtered through a pad of Celite and washed with water and EtOAc.
• the solution is poured into a separatory funnel and the layers are separated.
• the aqueous layer is extracted with EtOAc.
• the combined organic layers are washed with IN HC1, H 2 0, saturated NaHC0 3 solution and saturated NaCl.
• the organic phase is dried over MgS0 4 , filtered and concentrated.
• the crude residue is purified by column chromatography eluting with 50% EtOAc/CH 2 Cl 2 to afford the title compound (1.46 g, 4.18 mmol) as a pale yellow solid.
• the title compound is prepared as described in EXAMPLE 1, Part I using ⁇ l-[2-(4-nitrophenyl)-ethyl]-2- oxopyrrolidin-3-(S)-yl ⁇ -carbamic acid tert-butyl ester as the starting material.
• the title compound is obtained as a beige solid.
• the title compound is prepared in CH 2 C1 2 instead of CH 3 CN as described in EXAMPLE 1, Part K using 3-(S)-amino-l-[2-(4-nitrophenyl)-ethyl]-pyrrolidin-2-one hydrochloride as the starting material and trifluoroacetic anhydride in place of 7-methoxynaphthalene-2-sulfonyl chloride.
• the crude product is concentrated in vacuo and used as is in the subsequent step.
• the crude intermediate is concentrated in vacuo to yield N- ⁇ l-[2-(4-acetylamino-phenyl)-ethyl]-2-oxopyrrolidin-3-(S)-yl]-2,2,2- trifluoroacetamide as a residue (wet with HOAc) which is also used directly in the nitration step.
• the nitric acid reaction mixture is allowed to warm to room temperature and stirred for 18 hours.
• the crude product is purified by column chromatography eluting with a gradient of 25% EtOAc/CH 2 Cl 2 to 50% EtOAc/CH 2 Cl 2 to provide the title compound as a solid.
• the title compound is prepared as described in EXAMPLE 25, Part F using N- ⁇ l-[2-(4-acetylamino-3- nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide as the starting material.
• the reaction mixture is stirred at room temperature for 18 hours. After similar workup, the organic phase is concentrated in vacuo to give the title compound as a yellow solid which is used as is in the subsequent step.
• the title compound is prepared in CH 2 C1 2 instead of CH 3 CN as described in EXAMPLE 1 , Part K using 3-(S)-amino-l-[2-(4-amino-3-nitrophenyl)-ethyl]-pyrrolidin-2-one in place of 7-(3-(S)-amino-2- oxopyrrolidin- 1 -ylmethyl)- 1 -chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1, Part J. After similar workup, the organic phase is concentrated in vacuo to afford the title compound as a pale yellow solid which is used as is in the subsequent step.
• the title compound is prepared from 3-picoline-N-oxide according to the procedure described in Tetrahedron 1993, 2885.
• the crude product obtained is dissolved in EtOH and decolorizing carbon is added.
• the mixture is filtered through a large column of Si0 2 gel eluting with EtOH to provide the title compound as a beige solid.
• the title compound is prepared from lH-pyrrolo[3,2-c]pyridine as described in EXAMPLES 18 and 19, Part A using tert-butyl bromoacetate in place of methyl iodide.
• the crude product is purified by column chromatography eluting with a gradient of 3% MeOH/CH 2 Cl 2 to 6% MeOH CH 2 Cl 2 to give the title compound as an oil.
• the title compound is prepared in CH 2 C1 2 instead of CH 3 CN as described in EXAMPLE 1, Part K using the above 3-(S)-amino-l-(2-pyrrolo[3,2-c]pyridin-l-yl-ethyl)- pyrrolidin-2-one acetate in place of 7-(3-(S)-amino-2-oxopyrrolidin-l-ylmethyl)-l-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1, Part J.
• the crude product is partially purified by column chromatography eluting in a gradient of 3% MeOH/CH 2 Cl 2 to 5% MeOH/CH 2 Cl 2 .
• the residue obtained is further purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 0 (0.1% TFA) to 80% CH 3 CN/H 2 0 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
• the title compound is prepared as described in EXAMPLE 1, Part F substituting 4-chloro-6-methyl- quinazoline for l-chloro-7-methylisoquinoline.
• the crude product is purified by column chromatography eluting with a gradient of 5%> EtOAc/hexanes to 10% EtOAc/hexanes to give the title compound as a white solid.
• the title compound is prepared as described in EXAMPLE 6, Part A substituting 7-methoxynaphthalene- 2-sulfonic acid (2-oxopyrrolidin-3-(S)-yl)-amide for 7-methoxynaphthalene-2-sulfonic acid [l-(l-chloro- isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide.
• the crude product is purified by column chromatography eluting with a gradient of 40% EtOAc/CH 2 Cl 2 to 60% EtOAc/CH 2 Cl 2 to give the title compound as a white solid.
• the title compound is prepared as described in EXAMPLE 1, Part F substituting 4-chloro-6-methyl- thieno[2,3-d]pyrimidine for l-chloro-7-methylisoquinoline.
• the crude product is purified by column chromatography eluting with a gradient of 70%> CH 2 Cl 2 /hexanes to 100% CH 2 Cl 2 to give the title compound as a white solid.
• the title compound is prepared as described in EXAMPLE 1, Part H substituting 6-bromomethyl-4- chloro-thieno[2,3-d]pyrimidine for 7-bromomethyl-l-chloroisoquinoline.
• the crude product is purified by column chromatography eluting with a gradient of 20% EtOAc/CH 2 Cl 2 to 30% EtOAc/CH 2 Cl 2 to give the title compound as a white foam.
• the title compound is prepared as dscribed in EXAMPLE 28, Part G substituting 7-methoxynaphthalene- 2-sulfonic acid [l-(4-chloro-thieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide for 7- methoxynaphthalene-2-sulfonic acid [l-(4-chloro-quinazolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]- methyl amide.
• the residue is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 0 (0.1%
• the title compound is prepared as described in EXAMPLE 28, Part B substituting 7-methyl-thieno[2,3- d]pyrimidin-4-ol for 6-methyl-3H-quinazolin-4-one.
• the crude product is purified by column chromatography eluting with a gradient of CH 2 C1 2 to 10% EtOAc/CH 2 Cl 2 to give the title compound as a solid.
• the residue is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN/H 2 0 (0.1% TFA) to 80% CH 3 CN/H 2 0 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
• the title compound is prepared as described in EXAMPLE 1, Part H substituting 3-bromomethyl-7- chloro-thieno[2,3-c]pyridine for 7-bromomethyl-l-chloroisoquinoline.
• the crude product is purified by column chromatography eluting with a gradient of 20% EtOAc/CH 2 Cl 2 to 40% EtOAc/CH 2 Cl 2 to give the title compound as a white foam.
• the title compound is prepared as described in EXAMPLE 1, Part I substituting [l-(7-chloro-thieno[2,3- c]pyridin-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester for [l-(l-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester.
• the resulting product is then taken directly on as described in EXAMPLE 1, Part K.
• the crude product is purified by column chromatography eluting with a gradient of 30% EtOAc/CH 2 Cl 2 to 40% EtOAc/CH 2 Cl 2 to give the title compound as a white solid.
• EXAMPLE 32 7-Methoxynaphthalene-2-sulfonic acid [ 1 -(7-hvdroxy-thieno[2,3-c1pyridin-3-yl-methyl)-2- oxopyrrolidin-3-(S)-yllamide trifluoroacetate.
• the title compound is prepared as 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 treated as described in EXAMPLE 1, Part B, C, and D.
• the crude product is purified by column chromatography eluting with 1% MeOH/CH 2 Cl 2 to 5%> MeOH/CH 2 Cl, to give the title compound as a white solid.
• the title compound is prepared as described in EXAMPLE 1, Part K substituting 3-amino-l-(4-chloro- thieno[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-2-one for 3-(S)-amino-l-(l-chloro-isoquinolin-7-ylmethyl)- pyrrolidin-2-one hydrochloride.
• the title compound is obtained as a white solid.
• the title compound is prepared as described in EXAMPLE 1 , Part L substituting 7-methoxynaphthalene- 2-sulfonic acid [l-(4-chloro-thieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide for 7- methoxynaphthalene-2-sulfonic acid [l-(l-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]- amide.
• the resulting product is then treated as described in EXAMPLE 1, Part M.
• the residue is purified by RP-HPLC eluting with a gradient of 10% CH 3 CN/H 2 0 (0.1 % TFA) to 80% CH 3 CN/H 2 0 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
• the title compound is prepared as described in EXAMPLE 1 , Part L substituting 7-methoxynaphthalene- 2-sulfonic acid [l-(4-chloro-thieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide for 7- methoxynaphthalene-2-sulfonic acid [l-(l-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]- amide.
• the resulting product is then treated as described in EXAMPLE 1, Part M.
• the title compound is prepared as described in EXAMPLE 1, Part K substituting 3-amino-l-(4-chloro- thieno[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-2-one for 3-(S)-amino-l-(l-chloro-isoquinolin-7-ylmethyl)- pyrrolidin-2-one hydrochloride and benzo[b]thiophene-2-sulfonyl chloride for 7-methoxynaphthalene-2- sulfonyl chloride.
• the title compound is obtained as a white solid.
• the resulting colorless clear solution is diluted with THF (150 mL) under N 2 .
• the Grignard reagent is then cooled to room temperature and added via cannula to the solution of NiCl 2 dppp (0.54 g, 1 mmol) and 4- bromopyridine in THF.
• the resulting dark solution is refluxed overnight.
• the reaction mixture is then poured over saturated NH 4 C1 solution and extracted with diethyl ether (3 x 200 mL).
• the combined ethereal layers are acidified with 2 N HC1 (300 mL) and the aqueous layer is washed with diethyl ether.
• the aqueous layer is then cooled in an ice-bath and neutralized with sodium bicarbonate.
• the aqueous layer is extracted with ethyl acetate (3 x 200 mL) and the combined organic layers are dried over MgS0 4 , filtered and concentrated to give a brown solid.
• the crude solid is taken up in hot hexanes and the yellow solution is separated from the insoluble black solid.
• the hexane solution is concentrated and the above procedure is repeated. Upon cooling the hexane solution, yellow solid precipitates form. The yellow solid is collected to give the title compound (8.99 g, 55.8 mmol).
• n- BuLi 8.7 mL of a 2.5 M solution in hexanes, 21.7 mmol.
• S0 2 gas is bubbled through the solution for 30 minutes.
• the solution is then allowed to warm to room temperature and stirred overnight.
• the solution is concentrated to dryness and the resulting solid is suspended in hexane ( 100 mL).
• sulfuryl chloride 1.7 mL. 21.7 mmol. The ice bath is removed and the suspension is stirred for 2 hours.
• Ammonium acetate (0.12 g, 1.56 mmol), phenol (0.049 g, 0.52 mmol), and 5-pyridin-4-yl-thiophene-2- sulfonic acid-[l-(l-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.026 g, 0.052 mmol) is heated to 90°C for 6 hours then cooled to room temperature.
• the product is purified by RP- HPLC eluting with a gradient of 10% CH 3 CN/H 2 0 (0.1% TFA) to 80% CH 3 CN/H 2 0 (0.1% TFA) and the appropriate product fractions are lyophilized to give the title compound (0.005 g, 0.007 mmol) as a white solid.
• Triethylamine (0.35 mL, 2.5 mmol) is added dropwise to a solution of 5-pyridin-3-yl-thiophene-2- sulfonyl chloride (0.22 g, 0.85 mmol) and 3-(S)-amino-l-(l-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2- one hydrochloride (0.22 g, 0.71 mmol) in CH 3 CN (5 mL). The suspension is stirred at room temperature overnight then concentrated to dryness. The residue is diluted with methylene chloride and washed with saturated NaHC0 3 solution and brine.
• the title compound is prepared as described in EXAMPLE 36, Part P using 5-pyridin-3-yl-thiophene-2- sulfonic acid-[l-(l-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide in place of 5- pyridin-4-yl-thiophene-2-sulfonic acid-[l-(l-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]- amide and heating at 100°C overnight.
• the crude product is purified by RP-HPLC eluting with a gradient of 10% CH 3 CN/H 2 0 (0.1 % TFA) to 100% CH 3 CN.
• the appropriate product fractions are lyophilized to give the title compound as a white solid.
• 6-Methyl-(l /)-quinolin-4-one (1.57 g, 9.7 mmol) in 20 mL phosphorus oxychloride is heated to 1 10 °C for 4 hours. The mixture is cooled to room temperature then diluted with ice water (-200 mL) and the pH is adjusted to ca. 10 by the slow addition of 10 N NaOH. The aqueous solution is extracted with methylene chloride (4 x 250 mL) and the combined organic layers washed with brine, dried over Na 2 S0 4 , filtered and concentrated. The crude residue is filtered through silica gel with 33% EtOAc/hexanes to give the product (1.05 g, 5.9 mmol) as a yellow solid.
• N-Bromosuccinimide (1.1 g, 6.19 mmol) and 70% benzoyl peroxide (0.215 g, 0.62 mmol) are added to a solution of 4-chloro-6-methylquinoline (1.05 g, 5.93 mmol) in 35 mL carbon tetrachloride.
• the resulting mixture is heated to reflux overnight then cooled to room temperature and diluted with methylene chloride.
• the organic layer is washed with 1 N NaOH, dried over Na 2 S0 4 , filtered and concentrated. The residue is purified by column chromatography eluting with 33% EtOAc/hexanes to give the product (0.915 g, 3.57 mmol) as a white solid.
• Benzothiophene-2-sulfonic acid [l-(4-chloroquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.1 1 g, 0.23 mmol) is treated with phenol (1 g) and ammonium acetate (0.22 g, 2.8 mmol) at 110°C as previously described. After five hours the mixture is cooled to room temperature and diluted with 100 mL methylene chloride. The organic solution is washed with 1 N NaOH (2X) and saline, dried over Na 2 S0 4 , filtered and concentrated.
• EXAMPLE 39 6-Chloro-benzo[b1thiophene-2-sulfonic acid [l -(l-amino-isoquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)- yll-amide trifluoroacetate.
• the residue is purified by RP-HPLC eluting with a gradient of 10% CH 3 CN/H 2 0 (0.1% TFA) to 80%
• 6-Chloro-benzorb1thiophene-2-sulfonic acid [2-oxo- l-(l,2,3,4-tetrahvdro-isoquinolin-7-ylmethvD- pyrrolidin-3-(S)-yl]-amide trifluoroacetate.
• Benzenesulfonyl chloride (3 mL, 23.5 mmol) is added dropwise to a solution of tetrabutylammonium hydrogen sulfate (.0.53 g, 1.56 mmol), sodium hydroxide (1.56 g, 38.9 mmol) and 4-chloro-lH- pyrrolo[3,2-c]pyridine (2.38 g, 15.6 mmol) (prepared according to Rasmussen, M. J. Het. Chem, 1992, 29, 359) in CH 2 C1 2 . The mixture is stirred at room temperature for 4 hours the diluted with CH 2 C1 2 and washed with saturated NH 4 C1 solution and brine.
• Carbon tetrabromide (0.939 g, 2.83 mmol) is added to a solution of triphenylphosphine (1.485 g, 5.66 mmol) and l-benzenesulfonyl-4-chloro-lH-pyrrolo[3,2-c]pyridin-2-yl)-methanol (0.914 g, 2.83 mmol) in CH 2 C1 2 (12 mL) at 0°C.
• the resulting yellow solution is stirred for 1 hour at 0°C then warmed to room temperature over a 1 hour period.
• the reaction mixture is concentrated then purified by column chromatography eluting with 1% MeOH/CH 2 Cl 2 to afford the title product (0.760 g, 1.97 mmol) as a white solid.
• the title compound is prepared as described in EXAMPLE 1 , Part K using 6-chloro-benzo[b]thiophene- 2-sulfonyl chloride and 3-amino- 1 -( 1 -benzenesulfonyl-4-chloro- 1 H-pyrrolo[3 ,2-c]pyridin-2-ylmethyl)- pyrrolidin-2-one hydrochloride as the starting material.
• the crude product is purified by column chromatography eluting with a gradient of 1% MeOH/CH 2 Cl 2 to 3% MeOH/CH 2 Cl 2 to give the product as a white solid.
• the title compound is prepared from 5-chloro-lH-pyrrolo[3,2-b]pyridine as described in EXAMPLE 41, Part A.
• the crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to give the title compound as a solid.
• 'H NMR (CPC1 3 , 300 MHz) ⁇ 8.23 (d, IH), 7.87 (d, 2H), 7.81 (d, IH), 7.62 (m, IH), 7.49 (m, 2H), 7.26 (d, IH), 6.8 l (d, IH).
• the title compound is prepared from l-benzenesulfonyl-5-chloro-lH-pyrrolo[3,2-b]pyridine as described in EXAMPLE 41, Part B.
• the crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/hexanes to 33% EtOAc/hexanes to yield the title compound as a solid.
• the title compound is prepared from l-benzenesulfonyl-5-chloro-lH-pyrrolo[3,2-b]pyridine-2- carboxylic acid ethyl ester as described in EXAMPLE 41, Part C.
• the crude product is purified by column chromatography eluting with a gradient of 20% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound as a solid.
• the title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using l-benzenesulfonyl-2-bromomethyl-5-chloro-lH-pyrrolo[3,2- bjpyridine in place of 7-bromomethyl-l-chloro-isoquinoline.
• the crude product is purified by column chromatography eluting with a gradient of 15% EtOAc/hexanes to 50%> EtOAc/hexanes to give the title compound as a beige solid.
• the title compound is prepared as described in EXAMPLE 1, Part I using [l-(l-benzenesulfonyl-5- chloro-lH-pyrrolo[3,2-b]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester as the starting material.
• the title compound is obtained as a white solid.

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