Classifications

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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • 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
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  • C07D471/00—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
  • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
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  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
  • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D401/14—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • 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
  • C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • 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

• This invention is directed to oxoazaheterocycyl compounds which inhibit factor Xa, to pharmaceutical compositions comprising these compounds, to intermediates useful for preparing these compounds and to a method of inhibiting factor Xa.
• Factor Xa and Factor Xa assembled in the prothrombinase complex activates prothrombin to generate thrombin.
• Factor Xa is strategically located at the intersection of extrinsic and intrinsic pathways ofthe blood coagulation system.
• an inhibitor of Factor Xa inhibits the formation of thrombin and therefore is useful for preventing or treating disorders related to blood coagulation in mammals.
• 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 ofthe 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, intermittent claudication and bypass grafting ofthe coronary (CABG) or peripheral arteries.
• AMI acute myocardial infarction
• PTCA percutaneous transluminal coronary angioplasty
• CABG bypass grafting ofthe coronary
• 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 condition is characterized by a rapid consumption of coagulation factors and their plasma inhibitors resulting in the formation of life-threatening clots throughout the microvasculature of several organ systems.
• Factor Xa inhibitors are useful in the treatment or prevention of other diseases in which the generation of thrombin has been implicated as playing a physiologic role.
• thrombin has been proposed to contribute to the morbidity and mortality of such chronic and degenerative diseases as arthritis, cancer, atherosclerosis and Alzheimer's disease by virtue of its ability to regulate many different cell types through specific cleavage and activation of a cell surface thrombin receptor, mitogenic effects, diverse cellular functions such as cell proliferation, for example, abnormal proliferation of vascular cells resulting in restenosis or angiogenesis. release of PDGF and DNA syntheses. Inhibition of Factor Xa will effectively block thrombin generation and therefore neutralize any physiologic effects of thrombin on various cell types.
• Oxoazaheterocyclyl Factor Xa inhibitors are disclosed in International Patent Numbers PCT/US98/07158, published Oct. 22, 1998; PCT/US98/07159, published Oct. 22, 1998; PCT/US98/07160, published Oct. 22, 1998; PCT/US98/07161, published Oct. 22, 1998; and PCT/US96/09290, published Dec. 19, 1996.
• Oxoazaheterocyclyl fibrinogen antagonists are disclosed in International Patent Application Number PCT/US92/09467, published May 13, 1993.
• This invention is directed to a compound of formula I
• G* and G 2 are L,-Cy, or L 2 -Cy 2 , provided that when R, and R la or R 4 and R 4a taken together form O or S, then G, is L 2 -Cy 2 and G 2 is L,-Cy b or when R 2 and R 2a or R 3 and R 3a taken together form O or S, then G, is L r Cy, and G 2 is L 2 -Cy 2 ;
• Cy, and Cy 2 are independently selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted 3 heterocyclyl, optionally substituted heterocyclenyl, optionally substituted fused arylcycloalkyl, optionally substituted fused arylcycloalkenyl, optionally substituted fused arylheterocyclyl, optionally substituted fused arylheterocyclenyl, optionally substituted fused heteroarylcycloalkyl, optionally substituted fused heteroarylcycloalkenyl, optionally substituted fused heteroarylheterocyclyl and optionally substituted fused heteroarylheterocyclenyl;
• L is O, NR 5 , -S(0) p -, -S(0) P NR 5 -, -C(X)Y- or -L 3 -Q-L 4 -Q'-L 5 -,
• L 3 and L 5 are independently absent, optionally substituted alkylene, optionally substituted alkenylene or optionally substituted alkynylene;
• L 4 is optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene;
• Q and Q' are independently absent, O, S, NR 5 , -S(0) p -, -S(0) p NR 5 - or -C(X)Y-;
• A is CH orN
• Rstrich R, a , R 2 , R 2a , R 3 , R 3a , R,, and R 4a are independently selected from hydrogen, carboxy, alkoxycarbonyl, Y'Y ⁇ CO, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or R, and R, a , R 2 and R 2a , R 3 and R 3a , or R 4 and R 4a taken together form O or S;
• n and n are independently 0, 1 or 2, provided that m and n are not both 0 and further provided that when R, and R* a taken together form O or S, n is 1 and when R 4 and R 4a taken together form O or S, m is 1 ;
• L 2 is absent or a group of formula
• R ⁇ R*)o 4 R 5 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, R6 ⁇ (CH2) v -, R6 ⁇ 2C(CH2) ⁇ -,Y 1 Y 2 NC(0)(CH2) ⁇ - ) or Y 1 Y 2 N(CH2) V -;
• R6 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl or optionally substituted heteroaralkyl;
• Y and Y are independently hydrogen, optionally substituted alkyl, optionally substituted aryl,
• R 7 , R 8 , R, and R 10 are independently selected from hydrogen, hydroxy, alkoxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl and optionally substituted heteroaralkyl, provided that only one of R 7 and R 8 or one of Rg and R- 0 is hydroxy or alkoxy, and further provided when R 7 , R 8 , R 9 and R 10 is hydroxy or alkoxy, then the hydroxy or alkoxy is not ⁇ substituted to a N, O or S in Z;
• X is O or S
• Y is absent or is selected from O, S and NR,
• Z is absent or is selected from optionally substituted lower alkenylene, optionally substituted lower alkynylene, O, S(0) p , NR 5 , -NR 5 C(0)- and -C(0)NR 5 -;
• x is 1, 2, 3 or 4;
• v 2, 3 or 4;
• p 1 or 2;
• q and r are independently 0, 1, 2 or 3, provided that q and r are not both 0.
• this invention is directed to a pharmaceutical composition comprising a therapeutically effective amount ofthe compound of formula I and a pharmaceutically acceptable carrier.
• this invention is directed to a method of treating a physiological disorder capable of being modulated by inhibiting Factor Xa comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.
• this invention is directed to a compound of formula II
• P is H or a nitrogen protecting group
• R Volunteer R, a , R 2 , R 2a , R 3 , R 3a , R 4 and R 4a are independently selected from hydrogen, carboxy, alkoxycarbonyl, Y'Y ⁇ CO, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl;
• L 2 is a group of formula
• Cy 2 is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclenyl, optionally substituted fused arylcycloalkyl, optionally substituted fused arylcycloalkenyl, optionally substituted fused arylheterocyclyl, optionally substituted fused arylheterocyclenyl, optionally substituted fused heteroarylcycloalkyl, optionally substituted fused heteroarylcycloalkenyl, optionally substituted fused heteroarylheterocyclyl and optionally substituted fused heteroarylheterocyclenyl;
• R 5 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, R 6 0(CH 2 ) v -, R6 ⁇ 2C(CH 2 ) ⁇ -,Y l Y 2 NC(0)(CH2) ⁇ -, or Y 1 Y 2 N(CH 2 ) V -;
• R ⁇ * 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,
• R 7 , R 8 , R, and R 10 are independently selected from hydrogen, hydroxy, alkoxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl and optionally substituted heteroaralkyl, provided that only one of R 7 and R 8 or one of R, and R 10 is hydroxy or alkoxy, and further provided when R 7 , R 8 , R, and R 10 is hydroxy or alkoxy, then the hydroxy or alkoxy is not ⁇ substituted to a N, O or S in Z;
• Z is absent or is selected from optionally substituted lower alkenylene, optionally substituted lower alkynylene, O, S(0) p , NR 5 , -NR 5 C(0)- and -C(0)NR 5 -;
• x is 1, 2, 3 or 4;
• v 2, 3 or 4;
• q and r are independently 0, 1, 2 or 3, provided that q and r are not both 0, which is an intermediate useful in the preparation ofthe compound of formula I.
• Alkyl means an aliphatic hydrocarbon group which may be straight or branched 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 about 1 to about 4 carbon atoms in the chain which may be 7 straight or branched.
• the alkyl may be substituted with one or more "alkyl group substituents" which may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy, amino, carbamoyl, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkyloxycarbonyl and heteroaralkyloxycarbonyl.
• Representative alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, and pyridylmethyloxycarbonylmethyl.
• Alkenyl means a straight or branched aliphatic hydrocarbon group containing a carbon-carbon double bond and having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 6 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 alkyl group substituents as defined herein.
• alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, decenyl, and the like.
• Alkylene means a straight or branched bivalent hydrocarbon chain having from 1 to about 20 carbon atoms.
• the preferred alkylene groups are the lower alkylene groups having from 1 to about 6 carbon atoms.
• Alkylene may be substituted with 1 or more alkyl group substituents as defined herein.
• Representative alkylene groups include methylene, ethylene, and the like.
• Alkenylene means a bivalent group derived from a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond.
• the preferred alkenylene groups are the lower alkenylene groups having from 1 to about 6 carbon atoms.
• Alkenylene may be substituted by one or more alkyl group substituents as defined herein.
• Alkynylene means a bivalent group derived from a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond. Preferred alkynylene groups are the lower alkynylene groups having from 1 to about 6 carbon atoms. Alkynylene may be substituted by one or more alkyl group substituents as defined herein. Representative akynylene include _ CH. CH— , — CHE CH- CH 2 — , — CH “ : CH- CH(CH 3 )— , and the like
• Amidine means a group of formula wherein R, is selected from hydrogen, R ⁇ ,0 2 C-, R ⁇ O-, R ⁇ *C(0)-, cyano, optionally substituted lower alkyl, nitro or Y'Y ⁇ - and R, 2 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted aralkyl and optionally substituted heteroaralkyl.
• R ⁇ is hydrogen, R ⁇ *0, or optionally substituted lower alkyl and R l2 is as defined above. Most preferred amidino groups are those in which R n and R 12 are hydrogen.
• Base nitrogen atom means an sp 2 or sp 3 hybridized nitrogen atom having a non-bonded pair of electrons which is capable of being protonated.
• Examples of basic nitrogen atoms which may be optionally substituted where possible, include those in heteroaryl, heterocyclyl, heterocyclenyl, fused arylheterocyclyl, fused arylheterocyclenyl, fused heteroarylcycloalkyl, fused heteroarylcycloalkenyl, fused heteroarylheterocyclyl, fused heterocyclylheterocyclenyl, imino, amino and amidino groups.
• Cycloalkyl means a non-aromatic mono- or multicyclic hydrocarbon ring system of about 3 to about 10 carbon atoms.
• Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, cycloheptyl, and the like.
• Representative multicyclic cycloalkyl rings include decalinyl, norbornyl, adamantyl, and the like.
• cycloalkyl group is optionally substituted with one or more cycloalkyl group substituents which may be the same or different, where "cycloalkyl group substituent" includes oxo, 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, amid
• Cycloalkenyl means a non-aromatic monocyclic or multicyclic hydrocarbon ring system containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms.
• the cycloalkenyl group is optionally substituted by one or more cycloalkyl group substituents as defined herein.
• Representative monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl, and the like.
• a representative multicyclic cycloalkenyl ring is norbomylenyl.
• Preferred cycloalkenyl group substituents are amino and amidino.
• Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 ring atoms wherein the ring system contains one or more element(s) other than carbon.
• “Azaheterocyclyl” means heterocyclyl wherein one or more ofthe atoms in the ring system is/are nitrogen.
• Preferred heterocyclyl comprise about 5 to about 6 ring atoms wherein one or two ofthe ring atoms is/are independently selected from oxygen, nitrogen or sulfur.
• “Aza”, “oxo” or “thia”, when used as a prefix before heterocyclyl means that the ring system contains at lease one nitrogen, oxygen or sulfur atom.
• heterocyclyl is optionally substituted with one or more heterocyclyl group substituents which may be the same or different, where " heterocyclyl group substituent" includes oxo, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio
• Preferred heterocyclyl group substituents include amino, amidino, halogen, hydroxy, alkoxycarbonylalkyl and carboxyalkyl.
• Representative heterocyclyl include piperidyl, 9 pyrrolidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, tetrahydrofuryl, mo holinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-dithianyl, 1,3,5-triathianyl, tetrahydrothienyl, tetrahydrothiopyranyl, quinuclidinyl, and the like.
• heterocyclenyl means a heterocyclyl as defined herein which contains at least one carbon- carbon or carbon-nitrogen double bond.
• za oxo
• thia when used as a prefix before heterocyclenyl means that the ring system contains at lease one nitrogen, oxygen or sulfur atom.
• the heterocyclenyl is optionally substituted with one or more heterocyclyl group substituents as defined herein.
• heterocyclenyl include 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, 2H-pyranyl, 1 ,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,4- tetrahydropyridyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
• Preferred heterocyclyl group substituents include amino, amidino, halogen, hydroxy, alkoxycarbonylalkyl and carboxyalkyl.
• Aryl means a 6 to 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system.
• aryl is optionally substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent" includes hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aryldiazo, heteroaryldiazo, 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,
• Preferred aryl groups are optionally substituted phenyl or optionally substituted naphthyl.
• Preferred aryl group substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino.
• Heteroaryl means about a 5- to about a 10- membered aromatic monocyclic or multicyclic ring system wherein one or more ofthe atoms in the ring system is/are element(s) other than carbon.
• Preferred heteroaryl contain one to about 4 heteroatoms selected from oxygen, nitrogen and sulfur.
• “Aza”, “oxo” or “thia”, when used as a prefix before heteroaryl means that the ring system contains at lease one nitrogen, oxygen or sulfur atom.
• the heteroaryl is optionally substituted with one or more aryl group substituents as defined herein.
• heteroaryl groups include pyrrolyl, pyrazinyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thienopyridyl, pyrrolopyridyl, furanopyridyl, furazanyl, quinoxalinyl, quinazolinyl, quinolizinyl, imidazo[l,2-a]pyridyl, phthalazinyl, imidazo[2,l-b]thiazolyl, benzofuranyl, indolyl, isoindolyl, indolizinyl, indazolyl, azaindolyl, benzimidazolyl, benzothienyl, benz
• Preferred heteroaryl group substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino.
• heteroaryl contains a nitrogen atom, the nitrogen atom may be oxidized to the N-oxide.
• fused arylcycloalkyl means a fused aryl and cycloalkyl as defined herein.
• Preferred fused arylcycloalkyls are those wherein the aryl thereof is phenyl and the cycloalkyl consists of about 5 to about 6 carbon atoms.
• Representative fused phenylcycloalkyl groups include 1,2,3,4-tetrahydronaphthyl, indanyl, and the like.
• the fused arylcycloalkyl is optionally substituted with one or more fused arylcycloalkyl group substituents selected from, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aryldiazo, heteroaryldiazo, 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,
• the cycloalkyl moiety is further optionally substituted with oxo.
• Preferred fused phenylcycloalkyl group substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino.
• fused aryicycloalkenyl means a fused aryl and cycloalkenyl as defined herein.
• Preferred fused arylcycloalkyenl are those wherein the aryl thereof is phenyl and the cycloalkenyl consists of about 5 to about 6 carbon atoms.
• the fused aryicycloalkenyl is optionally substituted with one or more fused arylcycloalkyl group substituents as defined herein.
• Representative fused phenylcycloalkenyls include 1,2-dihydronaphthylenyl, indenyl, and the like.
• the cycloalkyl moiety is further optionally substituted with oxo.
• Preferred substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino.
• fused arylheterocyclyl means a fused aryl and heterocyclyl as defined herein.
• Preferred fused arylheterocyclyl are those wherein the aryl thereof is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms wherein one or two ofthe ring atoms is/are independently selected from oxygen, nitrogen and sulfur.
• "Aza", “oxo” or “thia”, when used as a prefix before the heterocyclyl portion ofthe fused arylheterocyclyl means that the heterocyclyl contains at lease one nitrogen, oxygen or sulfur atom.
• Representative preferred fused phenylheterocyclyl ring systems include indolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 1 ,2,3,4-tetrahydroquinolinyl, 1 H-2,3-dihydroisoindolyl, 2,3-dihydrobenz[f]isoindolyl, l,2,3,4-tetrahydrobenz[g]isoquinolinyl, and the like.
• the fused phenylheterocyclyl is optionally substituted with one or more fused phenylcycloalkyl group substituents 1 1 as defined herein.
• the heterocyclyl moiety is further optionally substituted with oxo.
• Preferred substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino.
• the nitrogen or sulphur atom ofthe heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
• Fused arylheterocyclenyl means a fused aryl and heterocyclenyl as defined herein. "Aza”,
• fused arylheterocyclyl when used as a prefix before the heterocyclenyl portion ofthe fused arylheterocyclenyl means that the heterocyclenyl contains at lease one nitrogen, oxygen or sulfur atom.
• Preferred fused arylheterocyclyl are those wherein the aryl thereof is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms wherein one or two ofthe ring atoms is/are independently selected from oxygen, nitrogen and sulfur.
• Representative preferred fused arylheterocycloalkenyl ring systems include 3H-indolinyl, lH-2-oxoquinolyl, 2H-l-oxoisoquinolyl, and the like.
• the fused arylheterocyclenyl is optionally substituted with one or more fused arylcycloalkyl group substituents as defined herein.
• the heterocyclyl moiety is further optionally substituted with oxo.
• Preferred substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino.
• the nitrogen or sulphur atom ofthe heterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
• fused heteroarylcycloalkyl means a fused heteroaryl and cycloalkyl as defined herein. "Aza”, “oxo” or “thia”, when used as a prefix before the heteroaryl portion ofthe fused heteroarylcycloalkyl means that the heteroaryl contains at lease one nitrogen, oxygen or sulfur atom.
• Preferred fused heteroarylcycloalkyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms in which one or two of the ring atoms are independently selected from oxygen, nitrogen and sulfur and the cycloalkyl consists of about 5 to about 6 ring atoms.
• Representative preferred fused heteroarylcycloalkyl include 5,6,7,8-tetrahydroisoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4,5,6,7-tetrahydro- 1 H-benzimidazolyl, 4,5,6,7-tetrahydrobenzoxazolyl, lH-4-oxa-l,5-diazanaphthalen-2-onyl, l,3-dihydroimidizole-[4,5]-pyridin-2-onyl, and the like.
• the fused heteroarylcycloalkyl is optionally substituted with one or more fused phenylcycloalkyl group substituents as defined herein.
• the cycloalkyl moiety is further optionally substituted with oxo.
• Preferred substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino.
• the nitrogen atom ofthe heteroaryl portion ofthe fused heteroarylcycloalkyl is optionally oxidized to the N- oxide.
• fused heteroarylcycloalkenyl means a 5- or 6-membered heteroaryl fused with a cycloalkenyl ring.
• “Aza”, “oxo” or “thia”, when used as a prefix before the heteroaryl portion ofthe fused heteroarylcycloalkenyl means that the cycloalkenyl contains at lease one nitrogen, oxygen or sulfur 12 atom.
• Preferred fused heteroarylcycloalkenyls are those wherein the heteroaryl thereof consists of about
• fused heteroarylcycloalkenyl include 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-lH-benzimidazolyl, 4,5-dihydrobenzoxazolyl, and the like.
• the fused heteroarylcycloalkenyl is optionally substituted with one or more fused phenylcycloalkyl group substituents as defined herein.
• the cycloalkenyl moiety is further optionally substituted with oxo.
• Preferred substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino.
• the nitrogen atom ofthe heteroaryl portion ofthe fused heteroarylcycloalkyl is optionally oxidized to the N-oxide.
• fused heteroarylheterocyclyl means a fused heteroaryl and heterocyclyl as defined herein.
• "Aza”, “oxo” or “thia”, when used as a prefix before the heteroaryl or heterocyclyl portion ofthe fused heteroarylheterocyclyl means that the heteroaryl or heterocyclyl contains at lease one nitrogen, oxygen or sulfur atom.
• Preferred fused heteroarylheterocyclyls are ring systems wherein one or two ofthe ring atoms ofthe heteroaryl are independently selected from oxygen, nitrogen and sulfur and the heterocyclyl portion consists of about 5 to about 6 ring atoms in which one or two ofthe ring atoms are independently selected from oxygen, nitrogen and sulfur.
• fused heteroarylheterocyclyl include 2,3-dihydro-lH pyrrol[3,4-b]quinolin-2-yl, 1,2,3,4-tetrahydrobenz [b][l,7]naphthyridin-2-yl, l,2,3,4-tetrahydrobenz [b][l,6]naphthyridin-2-yl, l,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2yl, 1 ,2,3 ,4-tetrahydro-9H-pyrido[4,3-b] indol-2yl, 2,3 ,-dihydro- 1 H-pyrrolo[3 ,4-b] indol-2-y 1, lH-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl, lH-2,3,4,5-tetrahydroazepino
• the fused heteroarylheterocyclyl is optionally substituted with one or more fused arylcycloalkyl group substituents as defined herein.
• the heterocyclyl moiety is further optionally substituted with oxo.
• Preferred substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino.
• the nitrogen atom ofthe heteroaryl portion is optionally oxidized to the N-oxide.
• the nitrogen or sulphur atom ofthe heterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
• fused heteroarylheterocyclenyl means a fused heteroaryl and heterocyclenyl as defined herein. "Aza”, “oxo” or “thia”, when used as a prefix before the heteroaryl or heterocyclenyl portion ofthe fused heteroarylheterocyclenyl means that the heteroaryl or heterocyclenyl contains at lease one nitrogen, 13 oxygen or sulfur atom.
• Preferred fused heteroarylcycloalkenyls are ring systems wherein the heteroaryl portion thereof consists of about 5 to about 6 ring atoms in which one or two ofthe ring atoms are independently selected from oxygen, nitrogen and sulfur and the heterocyclenyl portion consists of about
• fused heteroarylheterocyclenyl is optionally substituted with one or more fused arylcycloalkyl group substituents as defined herein.
• the heterocyclenyl moiety is further optionally substituted with oxo.
• Preferred substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino.
• the nitrogen atom ofthe heteroaryl portion is optionally oxidized to the
• the nitrogen or sulphur atom ofthe heterocyclenyl is optionally oxidized to the corresponding
• N-oxide, S-oxide or S,S-dioxide N-oxide, S-oxide or S,S-dioxide.
• Aralkyl means an aryl-alkyl- group in which the aryl and alkyl are as defined herein. Preferred aralkyls contain a lower alkyl moiety. Representative aralkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
• Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as defined herein. Preferred heteroaralkyls contain a lower alkyl moiety. Representative heteroaralkyl groups may contain thienylmethyl, pyridylmethyl, imidazolylmethyl and pyrazinylmethyl.
• Alkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein.
• Preferred aralkenyls contain a lower alkenyl moiety.
• An representative aralkenyl group is
• Heteroaralkenyl means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl are as defined herein. Preferred heteroaralkenyls contain a lower alkenyl moiety. Representative heteroaralkenyl groups may contain thienylethenyl, pyridylethenyl, imidazolylethenyl and pyrazinylethenyl.
• Hydroalkyl means a HO-alkyl- group in which alkyl is defined herein. Preferred hydroxyalkyls contain lower alkyl. Representative hydroxyalkyl groups include hydroxymethyl and
• acyl means an H-CO- or alkyl-CO- group in which alkyl is defined herein. Preferred acyls contain a lower alkyl. Representative acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
• Heteroaroyl means an means a heteroaryl-CO- group in which heteroaryl is defined herein.
• Representative heteroaryl groups include thiophenoyl and pyridinoyl.
• heteroaryldiazo groups include pyridyldiazo and thienyldiazo.
• Alkoxy means an alkyl-O- group in which alkyl is defined herein.
• Representative alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
• Aryloxy means an aryl-O- group in which aryl is defined herein.
• Representative aryloxy groups include phenoxy and naphthoxy.
• Alkyloxy means an aralkyl-O- group in aralkyl is defined herein.
• Representative aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
• Alkylthio means an alkyl-S- group in which alkyl is defined herein.
• Representative alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio.
• Arylthio means an aryl-S- group in which the aryl group is defined herein.
• Representative arylthio groups include phenylthio and naphthylthio.
• Alkylthio means an aralkyl-S- group in which aralkyl is defined herein.
• a representative aralkylthio group is benzylthio.
• Amino means a group of formula Y Y N- wherein Y and Y are defined herein. Preferred amino groups include amino (H2N-), methylamino, dimethylamino, diethylamino, benzylamino, or phenethylamino.
• Aminoalkyl means a Y Y N-alkylene- group wherein Y , Y and alkylene are defined herein.
• Alkoxycarbonyl means an alkyl-O-CO- group wherein alkyl is defined herein.
• Representative alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, or t-butyloxycarbonyl.
• Alkoxycarbonylalkyl means an alkyl-O-CO-alkylene- group wherein alkyl and alkylene are defined herein.
• Aryloxycarbonyl means an aryl-O-CO- group wherein aryl is defined herein.
• Representative aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
• Alkoxycarbonyl means an aralkyl-O-CO- group wherein aralkyl is defined herein.
• a representative aralkoxycarbonyl group is benzyloxycarbonyl.
• Carmyl means a group of formula Y Y r**JCO- wherein Y and Y are defined herein.
• carbamyl groups are carbamyl (H2NCO-) and dimethylaminocarbamyl (Me2NCO-). 15
• SulfamyP means a group of formula Y Y NSO2- wherein Y and Y are defined herein.
• Representative sulfamyl groups are aminosulfamoyl (H2NSO2-) and dimethylaminosulfamoyl
• Acylamino means an acyl-NH- group wherein acyl is defined herein.
• Aroylamino means an aroyl-NH- group wherein aroyl is defined herein.
• Alkylsulfonyl means an alkyl-S02- group wherein alkyl is defined herein. Preferred alkylsulfonyl groups are those in which the alkyl group is lower alkyl.
• Alkylsulfinyl means an alkyl-SO- group wherein alkyl is defined herein. Preferred alkylsulfinyl groups are those in which the alkyl group is lower alkyl.
• Arylsulfonyl means an aryl-S02- group wherein aryl is defined herein.
• Arylsulfinyl means an aryl-SO- group wherein aryl is defined herein.
• Halo or "halogen” means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo, and more preferred are fluoro or chloro.
• N-protecting group means an easily removable group which is known in the art to protect an amino group against undesirable reaction during synthetic procedures and to be selectively removable.
• the use of N-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, CF, for example, T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York ( 1991 ), inco ⁇ orated herein by reference.
• N-protecting groups are acyl, including formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl and the like, and acyloxy including methoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethxoycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl (BOC), 1 , 1 -dimethylpropynyloxycarbonyl, benzyloxycarbonyl (CBZ), p-nitrophenyl
• Compounds ofthe invention are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. It is understood that the activity of individual compounds of formula (I) will vary depending on the individual compound and assay employed. Compounds ofthe invention as used herein includes all compounds of formula (I) having an in-vitro activity of greater than 10% at 3.9 ⁇ M in the Factor Xa in vitro enzyme assay described herein. Similarly, reference to intermediates, whether or not they themselves are 16 claimed, is meant to embrace their salts, and solvates, where the context so permits.
• Prodrug means a form ofthe compound of formula I which may or may not itself be biologically active but which may be converted, for example by metabolic, solvolytic, or other physiological means, to a biologically active chemical entity, and is suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and effective for their intended use, including ketal, ester and zwitterionic forms.
• a prodrug is transformed in vivo to yield the parent compound ofthe above formula, for example by hydrolysis in blood.
• Solvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are inco ⁇ orated in the crystal lattice ofthe crystalline solid. "Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include ethanolates, methanolates, and the like. "Hydrate” is a solvate wherein the solvent molecule(s) is/are H 2 0. Where the compound of this invention is substituted with a basic moiety, acid addition salts may be formed.
• 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 ofthe salts, so that the beneficial effects inherent in the free base are not vitiated by side effects ascribable to the anions.
• pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources ofthe free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for pu ⁇ oses of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.
• salts within the scope ofthe 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 comprise the following: hydrohalides, e.g.
• hydrochloride and hydrobromide sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, 17 methylene-bis- ⁇ -hydroxynaphthoates, gentisates, mesylates, isethionates and di-p-toluoyltartratesmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
• Acid addition salts ofthe compounds of this invention are prepared by reaction ofthe free base with the appropriate acid by the application or adaptation of known methods.
• the acid addition salts ofthe 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 ofthe solution.
• the acid addition salts ofthe compounds of this invention can be regenerated from the salts by the application or adaptation of known methods.
• parent compounds ofthe 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.
• 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 ofthe salts, so that the beneficial effects 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 ofthe 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, trimethylammonia, triethylammonia, ethylenediamine, n-methylglucamine, 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 ofthe present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound ofthe chosen metal in an aqueous or organic solvent with the free acid form ofthe 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 ofthe present invention may be obtained by contacting an amine in an aqueous or organic solvent with the free acid form ofthe compound.
• Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as 18 tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone. Amino acid salts may be similarly prepared.
• the base addition salts ofthe compounds of this invention can be regenerated from the salts by the application or adaptation of known methods.
• parent compounds ofthe invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
• salts of compounds ofthe invention are useful for the pu ⁇ oses of purification ofthe compounds, for example by exploitation ofthe 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 this invention may exhibit stereoisomerism by virtue ofthe presence of one or more asymmetric or chiral centers in the compounds.
• the present invention contemplates the various stereoisomers and mixtures thereof. Desired enantiomers are obtained by chiral synthesis from commercially available chiral starting materials by methods well known in the art, or may be obtained from mixtures ofthe enantiomers by resolution using known techniques.
• Compounds of this invention may also exhibit geometrical isomerism. Geometrical isomers include the cis and trans forms of compounds ofthe invention having alkenyl or alkenylenyl moieties.
• the present invention comprises the individual geometrical isomers and stereoisomers and mixtures thereof.
• Preferred compounds have formula I wherein Cy 2 contains at least one nitrogen atom and when Cy 2 is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted fused phenylcycloalkyl or optionally substituted fused phenylcycloalkenyl, then said nitrogen atom is a basic nitrogen atom.
• Preferred compounds wherein Z is -NR 5 C(0)- or -C(0)NR 5 - are selected from 2-[4-(6-Chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazin-l-yl]-N-[2-(3H-imidazol-4-yl)- ethyl]acetamide, 53 2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]-N-pyridin-4-yl-acetamide,
• R 3 and R 3a taken together are O; and R,, R la , R 2 , R 2a , R 4 and R ⁇ are hydrogen.
• R 3 and R 3a taken together are O: R,, R, a , R 2 , R 2a and R ⁇ are hydrogen; and R 4a is optionally substituted alkyl.
• R 3 and R 3a taken together are O; R perpetrat R la , R 2 and R, are hydrogen; and R 2a and R ⁇ are optionally substituted alkyl.
• R 3 and R 3a taken together are O; R-, R 2 , R 2a and R, are hydrogen; and R la and R 4a are optionally substituted alkyl. 55
• R 3 and R 3a taken together are O; R perpetrat R 2 , R 2a ,
• R 4 and R 4a are hydrogen; and R la is carboxy, alkoxycarbonyl, Y'Y ⁇ CO or optionally substituted alkyl.
• R 3 and R 3a taken together are O; and R perpetrat R la , R 2 , R 4 and R 4a are hydrogen; and R 2a is carboxy, alkoxycarbonyl, Y'Y ⁇ CO or optionally substituted alkyl.
• More preferred compounds have formula I wherein L 2 is alkylene of one to three carbon atoms.
• Z is NR 5 ; q is 2; r is 0; R 5 is hydrogen or optionally substituted alkyl; and R 7 and R 8 are hydrogen.
• L 4 is optionally substituted alkenylene.
• L is -L3-Q-L4-Q'-L5-; L 3 is optionally substituted alkylene; and L 4 is optionally substituted alkenylene.
• Cy is optionally substituted phenyl, optionally substituted thienyl, optionally substituted benzothienyl, optionally substituted isoquinolinyl, optionally substituted indolyl, optionally substituted thienopyridyl, optionally substituted furanyl, optionally substituted pyridyl, or optionally substituted benzimidazolyl.
• Cy 2 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted imidazolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted cinnolinyl, optionally substituted azaindolyl, or optionally substituted thienopyridyl.
• Still more preferred compounds are selected from 4-[3-(6-Amino-pyridin-3-yl)-acryloyl]-l-(4-amino-quinazolin-7-ylmethyl)-3-(S)-methoxymethyl- piperazin-2-one, l-(l-Amino-isoquinolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-2-one, 4-(5'-Chloro-[2,2']bithiophenyl-5-ylmethyl)-3-(S)-methoxymethyl- 1 -( 1 H-pyrrolo[3,2-c]pyridin-2- ylmethyl)-piperazin-2-one, l-(4-Amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophen-2-ylmethyl)-piperazin-2-one, (S)-
• Still yet more preferred compounds are selected from l-(4-Amino-quinazolin-7-ylmethyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-3-(S)-methoxymethyl- piperazin-2-one, l-(4-Amino-quinazolin-7-ylmethyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-3-(S)-methoxymethyl-6- methyl-piperazin-2-one,
• Preferred intermediates according to this invention have formula II wherein Cy 2 contains at least one nitrogen atom and when Cy 2 is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted fused phenylcycloalkyl or optionally substituted fused phenylcycloalkenyl, then said nitrogen atom is a basic nitrogen atom.
• R 2a , R 4 and R 4a are hydrogen.
• More preferred intermediates according to this invention are selected from (2S, 6RS)-4-(4-chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine- 1 -carboxylic acid benzyl ester, 64 (3S,5RS)-l-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one,
• Sulfonamide formation is accomplished with a base such as a trialkylamine in an inert solvent such as dichloromethane, THF or acetonitrile at about 0 °C to about 100 °C in the presence or absence of an activating agent such as dimethvlaminopyridine (DMAP).
• a base such as a trialkylamine in an inert solvent such as dichloromethane, THF or acetonitrile at about 0 °C to about 100 °C in the presence or absence of an activating agent such as dimethvlaminopyridine (DMAP).
• Alkyl amine formation can be achieved with a suitable base such as K 2 C0 3 or trialkylamine in an appropriate solvent such as DMF or acetonitrile at about 0 °C to about 100 °C.
• Amide, urea, carbamate and sulfamyl urea formation can be conducted with acids and coupling reagents such as EDC or TBTU or with any variant of reactive acid derivatives and the use of an appropriate base additive such as triethylamine, N-methylmo ⁇ holine or diisopropylethylamine.
• the compound of formula II is prepared by removing a nitrogen protecting group P from the compound of formula 1.
• P is an alkyl, aralkyl or aryl carbamate moiety which is removed using strong acid, strong base or catalytic hydrogenation in an appropriate solvent such as methanol or ethanol.
• the compound of formula 1 is obtained by coupling a compound of formula 2 with an appropriate Cy 2 -L 2 -LG group wherein LG is a leaving group such as chloro, bromo, iodo, or optionally substituted lower alkylsulfonyloxy or arylsulfonyloxy in an inert organic solvent such as THF, Et 2 0 or DMF in the presence of a strong base such as NaH, lithium hexamethyldisilylazide or lithium diisopropylamine.
• P is an alkyl, aralkyl or aryl carbamate group.
• Ar monocyclic aryl or heteroaryl
• the corresponding acid is 68 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 5.
• 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 5.
• the acyl azide compound can be added directly to a high boiling inert solvent such as phenyl ether
• a compound of formula 8, prepared as described in Syn., 739 (1975), which is inco ⁇ orated herein by reference, or formula 5 above may be chlorinated using standard methods such as POCl 3 or
• Ar monocyclic aryl or heteroaryl
• an aminoheteroaryl carboxylic acid or an aminoarylcarboxylic acid 1 1 in which the amino and carboxylic acid are adjacent is treated with formamidine under heat to form the corresponding quinazolinone or thienopyrimidinone 12.
• the quinazolinone or thienopyrimidinone 12 is 69 then converted to the chloroquinazoline or chlorothienopyrimidine using a chlorinating reagent such as
• the chloroquinazoline or chlorothienopyrimidine is brominated at the benzylic carbon using radical bromination conditions.
• a chloroquinazoline or chlorothienopyrimidine, containing a hydroxy-methylene group is converted to the corresponding bromide using CBr 4 /PPh 3 ; or PBr 3 conditions.
• the bromide 13 is then reacted with the anion ofthe ring nitrogen of compounds of formula 2, formed using NaH, LiN(SiMe 3 ) 3 , NaN(SiMe 3 ) 3 , LDA, lithium alkoxides, sodium alkoxides or an appropriate base, in an inert solvent such as THF, DMF, ether, or DME.
• the chloro group is converted to an amino group using NH 3 in ethanol in the presence of a catalytic acid source.
• the chloro group is converted to a substituted amino using a primary or secondary amine in a solvent.
• the chloro group is converted to a hydroxy group using acetic acid in water with heating or using a hydroxide source.
• the chloro is converted to an alkoxy group using an alcoholic solvent with heated in the presence of a base.
• an amino-aryl nitrile or an amino heteroaryl nitrile 17 is treated with an aldehyde or ketone under imine forming conditions.
• the corresponding aryl or heteroaryl imine is brominated using radical bomination with NBS.
• the bromide is then reacted with the anion ofthe ring nitrogen of compounds of formula 2, formed using NaH, LiN(SiMe 3 ) 3 , NaN(SiMe 3 ) 3 , LDA, lithium alkoxides, sodium alkoxides or an appropriate base, in an inert solvent such as THF, DMF, ether, or DME.
• halogenated azaarenes exemplified by 4-chloro-7- trifluoromethylquinoline or cinnoline are treated with H 2 S0 4 (70 -95 %) at 180-220 °C for about 16 to 48 hours in a sealed reaction vessel.
• the solution is cooled, poured into water and neutralized with base to pH ⁇ 3-4.
• the product is dissolved in aqueous base and precipitated by acidification to yield 7-carboxy- 4-chloroquinoline or cinnoline.
• This material is converted to the alkyl ester (such as methyl or ethyl) by standard methods.
• 7-Alkyloxycarbonyl-4-chloroquinoline or cinnoline is dissolved in an anhydrous, aprotic solvent (THF or ether).
• THF or ether an anhydrous, aprotic solvent
• the solution is cooled (-60 to -95 °C) and treated with a reducing agent such as lithium aluminum hydride.
• the solution is warmed (approximately -40 to -50 °C) for about 15 to 30 minutes and quenched with a solvent such as ethyl acetate.
• Standard workup gives the product 7- hydroxymethyl-4-chloroquinoline or cinnoline.
• This material is treated with 45-50 % HBr and heated to about 100-140 °C for about 45 to 90 minutes. After cooling and standard workup 7-bromomethyl-4- chloroquinoline or cinnoline is obtained.
• pyrrolopyridine derivatives are prepared by alkylation of a suitably protected oxopiperazine with propargyl bromide in the presence of a base such as sodium hydride.
• the resulting alkyne is heated (100-120 °C) with a halopyridine optionally substituted with hydroxy, alkoxycarbonylamino, 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.
• a halopyridine optionally substituted with hydroxy, alkoxycarbonylamino, 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.
• pyrrolopyridines If the pyridine is substituted with an alkoxycarbonylamino moiety, additional treatment with DBU at about 60 °C in DMF yields pyrrolopyridines. Subsequent carbamate deprotection using transfer hydrogenation conditions such as Pd black in formic acid yields the desired oxopiperazine furopyridines or pyrrolopyridine- 1 -carboxylic acid alkyl ester derivatives. After further reaction with the L r Cy* group, an additional deprotection step such as Boc removal using, for example, TFA, HCl is required for generating the oxopiperazine pyrrolopyridines.
• transfer hydrogenation conditions such as Pd black in formic acid
• compounds of formula 40 are prepared from an appropriately protected mono- or di- substituted amino-acid.
• an amino-acetaldehyde protected as an acetal derivative, under standard peptide coupling procedures, employing activating reagents such as EDC, TBTU, or BOP.
• activating reagents such as EDC, TBTU, or BOP.
• the resulting dipeptidyl moiety is subjected to conditions which remove the acetal, such as acidic conditions (TsOH).
• TsOH acidic conditions
• the resulting cyclic material is reduced using hydrogenating conditions to yield compounds of formula 40. This reduction, alternatively can be carried out using a reagent which acts as a hydride source.
• a protected amino acid is coupled to a beta-aminoalcohol using standard peptide coupling procedures as describe above.
• the alcohol is then oxidized to a ketone using, for example, Swern oxidation conditions.
• the protecting group is removed and the resulting compound 73 is reduced under hydrogenation conditions to give the 2-piperidinone.
• the free amine can be reprotected and diastereomers are separated by chromatographic methods, or in some cases by recrystallization.
• an amino acid is protected as its trifluoroacetate derivative using trifluoroacetic anhydride and a base.
• An amino-alcohol is derivatized via reductive amination conditions using a benzaldehyde derivative, such as 2,4-dimethoxybenzaldehyde.
• the resulting secondary amine is then coupled to an amino-acid protected as a trifluoroacetate using standard peptide coupling procedures. Ring closure is then accomplished by utilizing Mitsinobu conditions.
• the trifluoroacetate group is removed under basic conditions, and the amide ofthe ring is deproteced using an aqueous solution of potassium persulfate and sodium phosphate and heat. All possible enantiomers of piperazin-2-one can be made from the corresponding amino-alcohol and amino acid as shown in scheme 2c.
• the compound of formula 61 is prepared by hydrolysis ofthe ester using a base such as NaOH or LiOH to yield the acid, coupling the corresponding acid with a primary or secondary amine or ammonia using standard coupling reagents such as TBTU or EDC and reduction of the ester using a reducing agent such as NaBH 4 to yield hydroxymethyl.
• an aldehyde containing the Cy 2 group is condensed with an amino acid ester under reductive amination conditions.
• the resulting secondary amine is then coupled to an N- protected amino acid.
• the resulting dipeptide is deprotected which in general results in cyclization to the Cy 2 diketopiperazine.
• diketopiperazine formation can be achieved using a peptide coupling reagent such as EDC, TBTU, or BOP.
• substituted sulfonyl chlorides are prepared by treatment ofthe appropriate aryl and heteroaryl compounds with a strong base such as n-BuLi at -78 °C followed by the addition of S0 2 gas and treatment ofthe lithium heteroaryl sulfonate with a chlorinating agent such as NCS or S0 2 C1 2 or, alternately, by homologation ofthe appropriate aryl and heteroaryl aldehydes using, for example, ethylmethanesulfonate and ethylchlorophosphonate.
• a strong base such as n-BuLi at -78 °C
• S0 2 gas the lithium heteroaryl sulfonate
• a chlorinating agent such as NCS or S0 2 C1 2
• homologation ofthe appropriate aryl and heteroaryl aldehydes using, for example, ethylmethanesulfonate and ethylchlorophosphonate.
• the requisite Cy- acids as defined above can be obtained by oxidation of the corresponding alcohols or the aldehydes using, for example, Mn0 2 , PDC or AgN0 3 in an appropriate solvent such as CH 2 C1 2 or H 2 0/EtOH.
• the Cy, substituted aryl and heteroaryl groups can be functional ized by deprotonation methods using an appropriate non-nucleophilic base such as n-BuLi in an appropriate solvent such as Et 2 0 or THF and quenching with an appropriate carbonyl electrophile such as DMF, C0 2 or alkyl chloroformate.
• the acids can also be generated by hydrolysis ofthe corresponding esters using, for example, NaOH or LiOH.
• the Cy--(alkenylene)- groups as defined above are generated by homologation ofthe Cy, aldehydes using the usual Wittig type or Horner-Emmons type reagents in an appropriate solvent such as CH 2 C1 2 or THF. 77
• alkyl and alkenyl halides as defined above can be prepared by halogenation ofthe corresponding alcohols using either NBS, CBr 4 or PBr 3 under standard solvent conditions.
• the alcohols are generated by reduction ofthe corresponding aldehydes or esters using NaBH 4 or DIBAL in an appropriate solvent.
• Cy isocyanates are obtained by chl ⁇ rocarbonylation methods using phosgene or triphosgene in an appropriate solvent such as CH 2 C1 2 with an appropriate base additive such as triethylamine or pyridine on the corresponding primary or secondary amines.
• the isocyanates can also be generated by Curtius rearrangement in an appropriate solvent such as toluene, p- dioxane or DMF ofthe corresponding Cy, carbonyl azides.
• the carbonyl azides are derived 78 from the corresponding carboxylic acids using either DPPA reagent or by proceeding through the mixed anhydride via an alkyl chloroformate reagent in an appropriate solvent such as DMF or acetone and using an appropriate base additive such as trithylamine.
• chloroformates are obtained by chlorocarbonylation methods using reagents such as phosgene, triphosgene or l,l '-carbonyldiimidazole in an appropriate solvent such as CH 2 C1 2 on the corresponding alcohols.
• reagents such as phosgene, triphosgene or l,l '-carbonyldiimidazole in an appropriate solvent such as CH 2 C1 2 on the corresponding alcohols.
• Activated sulfamyl esters are prepared from the corresponding amines using catechol sulfate in an appropriate solvent.
• alkylation of piperazin-2-one 96 is achieved with a strong base such as NaH and a t-butyl ester of haloacetic acid to give the acetate 97.
• Pd-catalyzed hydrogenation effectes removal ofthe CBZ group from the acetate 97 to give amine 98 which is converted to the compound 99 as described in Scheme 1 above.
• Hydrolysis of t-butyl ester 99 is accomplished using, for example, TFA/CH 2 C1 2 .
• the resulting acid 100 is coupled with the optionally protected amine HNCy 2 under typical amide bond formation conditions to give the acetamide 101.
• Piperidin-2-one 102 is alkylated as described above to give the ester 103 which is hydrolyzed to give the acid 104 or reduced to give aldehyde 105. Coupling ofthe acid 104 and amines affords amide 106 which is cyclized with acetic anhydride to give the compound 108. Wittig-coupling of aldehyde 105 produces compound 107.
• the solution is added by cannula to a precooled (-78°C) solution of S0 2 (200 g) in 100 mL of THF. After addition, the solution is allowed to warm to ambient temperature. After 0.5 hour, the solution is concentrated. The residue is suspended in hexanes (400 mL) and is cooled to 0°C. To the solution is added S0 2 C1 2 (12.5 g, 92.5 mmol). After stirring for 15 minutes, the solution is concentrated.
• A. 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid ethyl ester n-Butyllithium (53.1 mL, 2.5M solution in hexanes) is added dropwise to a solution of ethylmethanesulfonate (12.9 mL, 0.12 mol) in THF (300 mL) at -78°C. The reaction mixture is stirred for 15 min then ethylchlorophosphonate (9.9 mL, 0.07 mol) is added dropwise. The solution is stirred at -78°C for 30 minutes and then heated to 50°C for 1 hour.
• Tetrabutylammonium iodide (16.3 g, (44.2 mmol) is added to a solution of 2-(5-chloro-thiophen- 2-yl)-ethenesulfonic acid ethyl ester ( 11.3 g, 40.2 mmol) in acetone ( 100 mL) at room temperature. The mixture is heated to reflux and stirred overnight then cooled to RT and conconcentrated in vacuo. The residue is taken up in CH 2 Cl 2 then washed with water and brine. The organic layer is dried over MgS0 4 , filtered and concentrated to dryness to give an oil (18.74 g, 40.2 mmol) which is taken on to the next step without further purification.
• 6-Methyl-lH-isoquinolin-2-one (14.6 g, 91.7 mmol) in phosphorus oxychloride (160 mL) is heated at 60°C for 17 hours. The mixture is cooled to room temperature, then concentrated to a beige residue. The residue is diluted with ice water and the pH is adjusted to about 8 by slow addition of 10 N NaOH. The crude product is precipitated out during neutralization ofthe aqueous solution and the solid is filtered, washed with water and dried. The solid is recrystallize from MeOH to afford the title compound (12.0 g, 67.5 mmol) as a beige solid.
• N-Bromosuccinimide (12.9 g, 72.5 mmol) and benzoyl peroxide (0.33 g, 1.30 mmol) are added to a solution of 2-chloro-6-methyl-quinoline (12.0 g, 67.5 mmol) in carbon tetrachloride (300 mL).
• the mixture is heated at reflux for 6 hours.
• the resulting mixture is cooled to room temperature, filtered, washed with CH,C1 2 and concentrated in vacuo.
• the crude residue is recrystallized from 50% EtOAc/hexanes to yield the title compound (8.80 g, 34.3 mmol) as a beige crystalline solid.
• 3-(4-Chlorophenyl)-2-methyl-acryloyl azide (11.0 g, 50 mmol) is dissolved in 80 mL of diphenyl ether. The solution is added dropwise to a solution of tributyl amine (1 1.8 mL, 50mmol) in 170 mL of diphenyl ether at 210°C. After 4 hours., the solution is cooled 50°C and diluted with 1.5 L of hexanes. The resulting solid is collected by filtration giving the title compound as a white solid (7.2 g, 37 mmol).
• Example 10 To a solution of l,7-dichloro-3-methyl-isoquinoline (0.50 g, 2.36 mmol), Example 10, part C, in 5.5 mL of 9:1 acetic acid:H 2 0 at 75°C is added zinc (0.23 g, 3.54 mmol) After 75 minutes, the solution is cooled to ambient temperatures. The solution is diluted with a 4: 1 EtOAc:CH 2 Cl 2 solution. To the solution is added lOOmL of a IN NaOH solution. The aqueous solution is extracted with 4: 1 EtOAc:CH 2 Cl 2 . The combined organic layers are washed with a saturated NaCI solution. The organic layer is dried over MgS0 4 , filtered and concentrated.
• A. 6-Chloro-3,4-dihydro- 1 H-naphthalene-2-one To a solution of (4-chlorophenyl)-acetyl chloride (17.3 g, 92 mmol) in 50 mL of CH,C1 2 at -20°C is added a solution of A1C1 3 (24.4 g, 184 mmol) in 200 mL CH 2 C1 2 dropwise. After 20 minutes, ethylene (g) is bubbled through the solution for 30 minutes. The solution is stirred at -10°C for 15 minutes. The reaction mixture is poured into 300 g of ice. The layers are separated. The organic layer is washed with H 2 0, saturated NaHC0 3 and saturated NaCI.
• the mixture is allowed to warm to room temperature, diluted with water/ice and stirred for 15 minutes.
• the mixture is filtered through a pad of Celite and washed with CH,C1 2 .
• the layers are separated and the aqueous layer is extracted with CH 2 C1 2 .
• the combined organics are washed with saturated NaCI solution, dried over anhydrous Na 2 S0 4 , filtered and concentrated.
• the residue is purified via flash column chromatography eluting with a gradient of 15% EtOAc/hexanes to 25% EtOAc/hexanes to afford the title compound (4.18 g, 23.9 mmol) as an oil.
• Et 2 0 at 0°C is added phosphorous tribromide (1.34 mL, 14.3 mmol) in 10 mL of Et 2 0.
• the mixture is stirred at 0°C for 45 min, then at room temperature for 1.5 hours.
• the mixture is quenched by the addition of water/ice and diluted with Et 2 0.
• the layers are separated and the organic phase is washed with water until neutral (3x) and once with saturated NaCI solution.
• the organic layer is dried over anhydrous MgS0 4 , filtered and concentrated to provide the title compound (5.46 g, 23.0 mmol) as an oil.
• Nitrogen (g) is bubbled through a solution of 5-bromo-2-chloro-thiophene (1.00 g, 5.06 mmol) in 8 mL of piperidine. After 5 min, propargyl alcohol (0.32 mL, 5.56 mmol), tetrakis(triphenylphosphine) palladium(O) (0.06 g) and Cul (catalytic amount) are added to the solution. The mixture is heated at 80°C for 1 h in a sealed glass vessel. At this time, the mixture is cooled and diluted with EtOAc/Et 2 0. The organic layer is washed 3N HCl, water, saturated NaHC0 3 solution and saturated NaCI solution. The organic layer is dried, filtered and concentrated.
• A. 5-Chloro-2-methyl-indole-l -carboxylic acid tert-butyl ester A solution containing 5-chloro-2-methylindole (4.0 g, 24.1 mmol) and PMAP (295 mg, 2.42 mmol) in anhydrous THF (100 mL) is cooled to 0°C. A solution containing (Boc) 2 0 (5.27 g, 24.1 mmol) in anhydrous THF (100 mL) is then added over a 20 min period. The reaction mixture is stirred for 2 h at 0°C and then at ambient temperature for 16 hours.

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