CA2264037A1 - Thrombin inhibitors - Google Patents

Thrombin inhibitors Download PDF

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CA2264037A1
CA2264037A1 CA002264037A CA2264037A CA2264037A1 CA 2264037 A1 CA2264037 A1 CA 2264037A1 CA 002264037 A CA002264037 A CA 002264037A CA 2264037 A CA2264037 A CA 2264037A CA 2264037 A1 CA2264037 A1 CA 2264037A1
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mmol
alkyl
pct
solution
nmr
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CA002264037A
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French (fr)
Inventor
Adel M. Naylor-Olsen
Gerald S. Ponticello
Joseph P. Vacca
Randall W. Hungate
Craig Coburn
Brian T. Phillips
S. D. Lewis
Mark E. Fraley
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Merck and Co Inc
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Priority claimed from GBGB9624278.9A external-priority patent/GB9624278D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

A compound which inhibits human thrombin and which has general structure (I) such as formula (a).

Description

?CA 02264037 1999-02-26W0 98/ 10763 PCTlUS97/ 15989TITLE OF THE INVENTIONTHROMBIN INHIBITORSBACKGROUND OF THE INVENTIONThrombin is a serine protease present in blood plasma inthe form of a precursor, prothrombin. Thrombin plays a central rolein the mechanism of blood coagulation by converting the solutionplasma protein, fibrinogen, into insoluble fibrin.Edwards et al., J. Amer. Chem. Soc., (1992) vol. 114, pp.1854-63, describes peptidyl a-ketobenzoxazoles which are reversibleinhibitors of the serine proteases human leukocyte elastase and porcinepancreatic elastase.European Publication 363 284 describes analogs ofpeptidase substrates in which the nitrogen atom of the scissile amidegroup of the substrate peptide has been replaced by hydrogen or asubstituted carbonyl moiety.Australian Publication 86245677 also describes peptidaseinhibitors having an activated electrophilic ketone moiety such asfluoromethylene ketone or ot-keto carboxyl derivatives.Thrombin inhibitors described in prior publications containsidechains of arginine and lysine. These structures show low selectivityfor thrombin over other trypsin-like enzymes. Some of them showtoxicity of hypotension and liver toxicity.European Publication 601 459 describes sulfonamidoheterocyclic thrombin inhibitors, such as N-[4-[(aminoimino-methyl)amino]buty1]—1-[N-(2—naphthalenylsulfony1)—L—phenylalanyl]—L— -prolinamide.WO 94/29336 describes compounds which are useful asthrombin inhibitors.?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-2-SUMMARY OF THE INVENTIONA compound which inhibits human thrombin and which hasthe general structuresuch asCH3DEB»NH I \/NThe invention includes a composition for inhibiting loss ofblood platelets, inhibiting formation of blood platelet aggregates,inhibiting formation of fibrin, inhibiting thrombus fonnation, andinhibiting embolus formation in a mammal, comprising a compound ofthe invention in a pharmaceutically acceptable carrier. Thesecompositions may optionally include anticoagulants, antiplatelet agents,and thrombolytic agents. The compositions can be added to blood,blood products, or mammalian organs in order to effect the desiredinhibitions.The invention also includes a composition for preventing ortreating unstable angina, refractory angina, myocardial infarction,transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolicstroke, deep vein thrombosis, disseminated intravascular coagulation,ocular build up of fibrin, and reocclusion or restenosis of recanalizedvessels, in a mammal, comprising a compound of the invention in aphannaceutically acceptable carrier. These compositions may?CA 02264037 1999-02-26W0 98/ 10763 PCTlUS97/ 15989-3-optionally include anticoagulants, antiplatelet agents, and thrombolyticagents.The invention also includes the use of a compound of theinvention in the manufacture of a medicament for preventing or treatingunstable angina, refractory angina, myocardial infarction, transientischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke,deep vein thrombosis, disseminated intravascular coagulation, ocularbuild up of fibrin, and reocclusion or restenosis of recanalized vessels,in a mammal.The invention also includes a method for reducing thethrombogenicity of a surface in a mammal by attaching to the surface,either covalently or noncovalently, a compound of the invention.DETAILED DESCRIPTION OF THE INVENTIONCompounds of the invention have the following structure:-—-g J-AR2 R3Iand pharmaceutically acceptable salts thereof whereinX is-N(R4)-,-0-’-3-’-S02-,-SO-,—OCH2(CH2)n aryl—, or—OCH2(CH2)n C3-8cycloalkyl—,wherein n is l or 2;?W0 98/ 10763JisCA 02264037 1999-02-26PCT/US97/15989-(CH2)m-,-(CH2)mNH—,-SO2NH-,-S02(CH2)m-,-NHSO2-,-S02-, or-(CH2)mSO2-,wherein m is 1 or 2;R1, R2, and R4 are independently selected fromhydrogen,aryl,-CO2R5,aryl C1-4 alkyl,diaryl C 1-4 alkyl,dicyclo C3-8 alkyl C 1-4 alkyl,cyclo C3-8 alkyl C 1-4 alkyl,R5/-——CON\R6 , wherein R5 and R6 are independentlyhydrogen or C 1-4 alkyl, ‘substituted aryl with one or two substituents selected fromC1-4 alkyl,C1 -4 alkoxy,H5/CON\96 , wherein R5 and R5 are independentlyhydrogen or C 1-4 alkyl,aryloxy,cyclo C3-g alkoxy,methylenedioxy,halogen, orhydroxy,?CA 02264037 1999-02-26W0 98/10763 PCTIUS97/15989_5_heteroaryl with one or two heteroatoms selected from N,O, and S,cyclo C3-7 alkyl unsubstituted or substituted with one ormore of C1-4 alkyl, C 1-4 alkoxy, benzyl,cyclohexylmethyl or aryl,a C4-10 carbocyclic or bicyclic ring, orR1 and R2 along with the carbon to which they attach form a cyclo C3-7 alkyl ring;R3 ishydrogen,C1-4 alkyl,C1-4 alkenyl,C1-4 alkoxy,-NHR7 wherein R7 is hydrogen or C1-4 alkyl, or-NHSO2CH2aryl;A is selected from one of the following fragments__ /—\ NH _ Qg \ /N —N\-—/N‘/<NH2 H2N‘<\:\//NfgHN —— __H NHZN \B / 3 2 , wherein B is N or CH.One group of compounds of the invention have thefollowing structure:'--{J"AORK( \ ?CA 02264037 1999-02-26W0 98/10753 PCT/US97/15989-6-and pharmaceutically acceptable salts thereof whereinJ is (CH2)m, (CH2)mNH, or S02, where m is 1 or 2;R1 and R2 are independently selected fromhydrogen,aryl, orcyclo C3-7 alkyl unsubstituted or substituted with one or more ofC1-4 alkyl, C1-4 alkoxy, benzyl, cyclohexylmethyl or aryl;hydrogen,C1-4 alkyl, orC1 -4 alkenyl;A is selected from one of the following fragments__ /—\ NH __—N .N _3 \ /N \—/ _<NH2 »H2N_<\://\N , or7HN ._/\HZN B , wherein B is N or CH.One class of this group of compounds has the following—/ J-AR2 3IStl'llCt1lI'BI?CA 02264037 1999-02-26wo 98/10763 PCT/US97/15989- 7 -and pharmaceutically acceptable salts thereof whereinJ is CH2, CH2NH, or S02;R1 and R2 are independently selected fromhydrogen,aryl, orcyclohexyl;R3 ishydrogen,-CH=CH2, or—CH2CH3; andA is selected from one of the following fragments/“\ NH HNE \ /N —N\——/N—/< C E' NH2 1 or HZN .Specific exemplifications of this class areNH0 O ONH2 .CH30 __CV 2CVOQO-~”~*””' NH2“U3:0 \_._/?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989.3.©” 3 CH2//HCO --and pharrnaceutically acceptable salts thereof.ABBREVIATIONSDesigr_1ationBOC (Boc) t-butyloxycarbonylHBT(HOBT or HOBt) l-hydroxybenzotriazole hydrateBBC reagent benzotriazolyloxy—bis(pyrro1idino)-carbonium hexafluorophosphatePyClU 1,1,3,3-bis(tetramethylene)—chlorouronium hexafluorophosphateEDC 1-ethyl-3—(3—dimethylaminopropyl)carbodiimide hydrochloride(BOC)2O di—t-butyl dicarbonateDMF dimethylformamideEt3N or TEA triethylamine?W0 98/10763EtOAcTFADMAPDMEBH3-THFD-Phe(3 ,4-C12)D-3 ,3—dichaProArgGlyD—3,3,-diphe02264037 1999-02-26PCT /U S97/ 15989-9-ethyl acetatetrifluoroacetic aciddimethylaminopyridinedirnethoxyethaneBorane—tetrahydrofuran complexD—3,4-DichlorophenylalanineD—3,3-DicyclohexylalanineProlineArginineGlycineD-3,3—DiphenylalanineThe compounds of the present invention may have chiralcenters and occur as racemates, racemic mixtures and as individualdiastereomers, or enantiomers with all isomeric forms being included inthe present invention.When any variable occurs more than one time in anyconstituent or in formula 1, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.As used herein, except where noted, "alkyl" is intended toinclude both branched— and straight—chain saturated aliphatichydrocarbon groups having 1-8 carbon atoms (Me is methyl, Et is ethyl,Pr is propyl, Bu is butyl). "Alkenyl" is intended to include bothbranched— and straight—chain unsaturated aliphatic hydrocarbon groups.having 1-8 carbon atoms, e.g. ethenyl, propenyl, etc. "Cycloalkyl"includes cyclic saturated aliphatic hydrocarbon groups having 3-8carbon atoms. "Aryl" means a 6-membered organic radical derivedfrom an aromatic hydrocarbon by removal of one hydrogen atom."Heteroaryl" means a 5- or 6- membered organic radical having 1 or 2heteroatoms selected from N, O, and S. "Alkoxy" represents an alkylgroup having 1-8 carbon atoms attached through an oxygen bridge."Halo", as used herein, means fluoro, chloro, bromo and iodo.?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-10-"Counterion" is used to represent a small, single negatively-chargedspecies, such as chloride, bromide, hydroxide, acetate, trifluroacetate,perchlorate, nitrate, benzoate, maleate, tartrate, hemitartrate, benzenesulfonate, and the like.Under standard nonmenclature used throughout thisdisclosure unless specified otherwise, the terminal portion of thedesignated side chain is described first followed by the adjacentfunctionality toward the point of attachment. For example, an ethylsubstituent substituted with "methylcarbonylamino" is equivalent toH OI ll—CH2CH2—N-C-CH3The term heterocycle or heterocyclic, as used herein exceptwhere noted, represents a stable 5- to 7-membered mono- or bicyclic orstable 7- to 10-membered bicyclic heterocyclic ring system any ring ofwhich may be saturated or unsaturated, and which consists of carbonatoms and from one to three heteroatoms selected from the groupconsisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatommay optionally be quatemized, and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The heterocyclic ring may be attached at any heteroatom orcarbon atom which results in the creation of a stable structure.Examples of such heterocyclic elements include piperidinyl, piperazinyl-,2-oxopiperazinyl, 2—oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl,benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,?CA 02264037 1999-02-26W0 98/10763 PCTIUS97/15989-1]-thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same asmorpholinyl.The pharmaceutically-acceptable salts of the compounds ofFonnula I (in the form of water- or oil-soluble or dispersible products)include the conventional non-toxic salts or the quaternary ammoniumsalts which are formed, e.g., from inorganic or organic acids or bases.Examples of such acid addition salts include acetate, adipate, alginate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base saltsinclude ammonium salts, alkali metal salts such as sodium and potassiumsalts, alkaline earth metal salts such as calcium and magnesium salts,salts with organic bases such as dicyclohexylamine salts, N—methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and soforth. Also, the basic nitrogen-containing groups may be quatemizedwith such agents as lower alkyl halides, such as methyl, ethyl, propyl,and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl,diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides like benzyl and phenethyl bromides and others.Amide couplings used to form the compounds of thisinvention are typically performed by the carbodiirnide method withreagents such as dicyclohexylcarbodiimide, or l-ethyl-3-(3-dimethylaminopropyl) carbodiimide. Other methods of forming theamide or peptide bond include, but are not limited to the syntheticroutes via an acid chloride, azide, mixed anhydride or activated ester.Typically, solution phase amide coupling are performed, but solid-phasesynthesis by classical Merrifield techniques may be employed instead.?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989..12_The addition and removal of one or more protecting groups is alsotypical practice.Compounds of the invention can be prepared according tothe general procedures outlined in Schemes I—VI.Compounds found in table 1 were synthesized by thegeneral method outlined in Scheme I and are exempli?ed by, but notlimited to the examples 1-9. A phenolic ester such as ethyl 4-hydroxybenzoic acid (1) is alkylated with an alkyl bromide such asbenzyl bromide by using a base such as cesium carbonate to afford theproduct 1-3. The ester group is then reduced with a hydride reducingagent such as lithium aluminum hydride to afford the benzylic alcohol I-4. The benzylic alcohol is converted into a leaving group (such as abromide or tri?ate) and the benzylic leaving group is reacted with 4-aminopyridine to afford the final product.?CA 02264037 1999-02-26WO 98110763 PCT/US97ll5989-13-SCHEME I R1OH OCS2COa/DMFLAH ?H Br THFCO2CH2CH3 R1 CO2CH2CH3|-1 I-2 I-33 ,R1 R1Q THF/CBr4 O CH3CNi (C5H5)3P 4-aminopyridineCHZOHBrI-4 I-5NH2\?CA 02264037 1999-02-26W0 98/10763 PCT/US97/ 15989-14-A general method for synthesizing compounds found intables 2 and 3 is outlined Scheme II. A benzoic acid such as I1-1(obtained in standard fashion) is coupled to 4—amino-pyridine understandard amide bond coupling conditions. The resultant amide 11-2 isthen reduced with lithium aluminum anhydride to afford the desired‘product II-3.SCHEME HEDC/HOBTQ Et3N/DMF"'1 4-AP1) (COC|)2-CH2C|2EQN-DMFo2) 4-AP O NHn-2. / I\NLiAlH4fI’HF60°II-3?CA 02264037 1999-02-26W0 98/10763 PCT/US97l15989-15-A general method for synthesizing compounds found intable 2 is outlined Schemes II and III. A benzoate ester such as III-4(obtained in standard fashion) is reacted with an alkylating reagent (suchas bromomethyl cyclohexane) to afford O-alkylated product III-5. Theester is hydrolyzed with an aqueous base and is coupled to 4-aminopyridine under standard amide bond coupling conditions. Theresultant amide III-7 is then reduced with lithium aluminum hydride toafford the desired product III-8.?CA 02264037 1999-02-26 W0 98/ 10763 PCT/US97/15989- 16 _SCHEME H1H0 00 ;\,Br /V OCOOCH3 CSZCO3 / DMF CQOCH3I”-1 Ill-2HOEtOAc/ COOCH3m—3HO %\ BrCOQCH3 CSZCO3 / DMFIll-41:/\0J£:L NaOH / MeOHCOOCH3Ill-5,,.,.._....T__.__._,.__....,-0Ø 7. . 2, .2 .?CA 02264037 1999-02-26WO 98/10763 PCT/US97/15989-17-SCHEME III 1 CONTINUED 11/0 1. (ClCO)2/ DCE2. __COOHIll-6 wN .\ LIAIH /THFU “"‘—““’./Iw7 O?CA 02264037 1999-02-26 “'0 93/1076-"’ PCT/US97/15989_ 13 _SCHEME IVHO 0\®\ (?r W \|©\COOCH3 082003/DMF COOCH3‘V-1 IV-2Br COOCH3IV-3if .0Pd(PPh3)4 / dioxane/\snBu3 I COOCH3?CA 02264037 1999-02-26W0 93/10753 PCT/U S97/ 15989- 19 -SCHEME IV (CONTINUED)H2 / Pd (0) ZVOEtOAc COOCH3IV-5O DLiOH/THF EV r\®\ 1-(ClCO)2/ CMHO COOH 2. —2 H2N \ |V—60XV :1N I \ LiA|H4/THFO/N 5oc_IV-7 0mwgxN \[V-8 l ?CA 02264037 1999-02-26W0 93/10753 PCT/US97/15989-20-A method for preparing compounds found in table 4 isoutlined in Scheme V. Substituted benzene compound such as 4-benzy1oxy—benzene (V-1) is reacted with sulfuryl chloride at 80-120°Cto give a sulfonyl chloride. The sulfonyl chloride (V-2) is reacted withBoc-piperazine and the Boo protecting group is removed with a strongacid to afford the deprotected piperazine. The free nitrogen isconverted to the amidine with a guanylating reagent such asamidinosulfonic acid.?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-21-SCHEME VSO2CI2/ DMF100°C/2 h1Q0’/\ /—\CI HN NBOC\.__/ QC:Et3N / CH2C|2C???O’/\D HCI / EtOAcN -25°Cv-3 BOCSQ .<,/O M O.,O,/O\NHNR/I» H2N’"‘so3HK Et3N / DMFH - HCIQSOV-4,,0S\“WY;,/O0 N NH2~ CF3COOHV-5Q9NH?CA 02264037 1999-02-26W0 98/10763 PCTIUS97/15989-22..A general method for synthesizing compounds found intable 5 is outlined in Scheme VI. The ketone of a cyano-benzophenonesuch as 1 is reduced with a metal hydride reagent such as sodiumborohydride and the resultant alcohol is removed by treatment withdimethyldichlorosilane to afford the diphenylmethane VI-3. Themethoxy group is removed with borontribromide and the phenol isalkylated with an alkylating reagent such as benzyl bromide. The cyanogroup is then treated with sodium hexamethyldisilazane and thesilylirnidate is hydrolyzed with an acidic workup to afford the finalproduct.,., ,._-_-___-T_?CA 02264037 1999-02-26W0 98/ 10763 PCT/US97/15989 -23-SCHEMEVIo H OHH3CO CN H300 CNVI-1 V|-2 (Me)2SiCl2 BarsH3CO CNvn-3 +<j\/ Oa OHO CN 'Cs COvn-4 2 3VI-5 6CNOINaN(TMS)2 Q-HCIV|-6 HZN NH Unless otherwise shown, NMR data for the compoundsidentified below was obtained using a field strength of 400 MHz.?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-24-Preparation of compounds found in Table IEXAMPLE 1Preparation of 4—amino- I -(4-(1 ,1 -diphenylmethoxy)benzylpyridinium"bromide (1-6)F OLAHCSZCOE/DMOC02CH2CHs co2cH2cH31-2 1-3 O 4 CH3CN O .: (C6H5)3P : 4_Ap B; OCH CH E "‘2 Br @I\ / NH2"4 1-5 1-6Step A: Preparation of ethyl 4-(1,1-diphenylmethoxy)benzoate(1-3) 'Under N2, a mixture of ethyl 4-hydroxybenzoic acid (2.5g, 15 mmol) _1__—_L, and Cs2CO3 (5.0 g, 15 mmol) in DMF (50 ml) wasstirred at room temperature. After 15 min, diphenylmethyl bromide?CA 02264037 1999-02-26W0 98/10763 PCT/US97/ 15989-25-_1-_2 (4.0 g, 16 mmol) was added and then heated at 60°C. After 18h,saturated Na2CO3 was added and the mixture extracted with EtOAc(3x). The combined extracts were washed with H20, dried, filtered andconcentrated to dryness to yield _l;3.1H NMR (CDCl3) 5 1.3 (3H, t), 4.3 (2H, q), 6.95 (2H, s), 7.3 (IOH, m)and 7.95 (2H, d).Step B: Preparation of 4-(1,1-diphenylmethoxy)benzyl alcohol(1-4)To a suspension of LAH (3.2 g, 0.084 mmol) in THF (400ml) under N2 was added dropwise a solution of _l;3_ (21 g, 0.063 mol) inTHF (100 ml). After stirring overnight at room temperature, saturatedNa2SO4 was added to the reaction until a white suspension wasobserved. The mixture was filtered and the filtrate was combined withH20 and CHCI3, separated, and extracted further with CHCI3 (2x).The combined organic extracts were dried, ?ltered and concentrated todryness. The residue was triturated with hexane to yield _l_-_4.11-1 NMR 6 1.6 (1H, bs), 4.55 (2H, s), 6.2 (1H, s), 6.95 (2H, d), and 7.3(12H, In).Step C: Preparation of 4-(1,1-dipheny1methoxy)benzyl bromide'- (1-5) 1A solution of 1_-4_ (3.6 g, 12 mmol), triphenyl phosphine(3.1 g, 11.8 mmol) in THF (100 ml) was treated with carbontetrabromide (3.9 g, 11.8 mmol). After 12h additionaltriphenylphosphine (3.1 g, 11.8 mmol) was added and the mixtureallowed to stir at room temperature overnight. Some triphenylphosphine oxide was then filtered off and the filtrate concentrated todryness. The residue was chromatographed on a Still column (70 mm)and the product eluted with 5% EtOAc—hexane to yield _1_-_5_.1H NMR (CDCI3) 8 4.4 (2H, s), 6.2 (1H, s), 6.9 (2H, d) and 7.35 (l2H,rn).?CA 02264037 1999-02-26WO 98110763 PCT/US97/15989-25-Step D: Preparation of 4-amino-1-(4—(1,l-diphenyl—methox\L)benzvl)DVridium bromide (1-6)A solution of 1_—__5_ (0.58 g, 1.6 mmol) in CH3CN (25 ml)was treated under N2 with 4—aminopyridine (0.16 g, 1.7 mmol). Afterstirring overnight at room temperature, the solid was filtered off toyield 1_-_6. An analytical sample was crystallized from CH3CN.mp: 254-5°.Analysis calculated for C25H23BrN2OC, 67.12; H, 5.18; N, 6.26Found: C, 67.25; H, 5.07; N, 6.251H NMR (d5-DMSO) 8 5.2 (2H, s), 6.55 (1H, s), 6.8 (2H, d), 7.05 (2H,d), 7.3 (8H, m), 7.47 (4H, d), 8.13 (2H, bs exch) and 8.25 (2H, d).EXAMPLE 2Preparation of 4—amino—1-(4-(2-phenyl-1 —ethoxy)benzyl)pyridiniumbromide (2-2)E was prepared as described for the preparation of 1:6except 2-phenyl-1-bromoethane (_2_;_l_) was used in place of 1-2 in Step Aand synthesized. mp: l70—l°C (CH3CN);1H NMR (d6-DMSO) 5 3.0 (2H, t), 4.2 (2H, t), 5.3 (2H, s), 6.82 (2H,d), 6.96 (2H, d), 7.3 (7H, m), 8.15 (2H, exch bs) and 8.27 (2H; d).Analysis calculated for C20H21BrN2OC, 59.96; H, 5.71; N, 6.99Found: C, 59.62; H, 5.22; N, 7.14?CA 02264037 1999-02-26WO 98/10763 PCT/US97/ 15989-27-EXAMPLE 3Preparation of 4-amino-1-(4-(cyc1ohexylmethoxy)benzyl)pyridiniumbromide (3-3)3 was prepared as described for the synthesis of _l_;6except 4~hydroxy-benzyl alcohol (_3__-_l) and cyclohexylmethyl bromide(3—_2) were used in Step A to yield 4-(cyclohexylmethoxy)benzy1 alcoholdirectly. mp: 241-3°C;1H NMR .(d6—DMSO) 5 1.2 (5H, m), 1.75 (6H, m), 3.8 (2H, d), 5.28 (S,2H), 6.8 (2H, d), 6.95 (2H, d), 7.34 (2H, d), 8.1 (2H, exch bs), 8.25(2H, d).Analysis calculated for C19H25BrN2OC, 60.47; H, 6.68; N, 7.42Found: C, 60.57; H, 6.70; N, 7.15EXAMPLE 4Preparation of 4-amino-1—(4-(1-phenyl-l-carbomethoxy)methoxy—benzLl)nvridinium bromide (4-2)_4;_2_ was prepared as described for the synthesis of l_—§except methyl 1-bromo—l-phenylacetate (4_-_l_) was used in place of L-_2in Step A. The compound was crystallized from CH3CN; mp:- 188-90°C;1H NMR (d5-DMSO) 5 3.65 (3H, s), 5.27 (2H, s), 6.05 (1H, s), 6.83(2H, d), 7.2 (2H, d), 7.34 (2H, d), 7.42 (3H, m), 7.54 (2H, d), 8.14 (2H,exch bs) and 8.27 (2H, d). ‘Analysis calculated for C21H21BrN20-0.25 H20C, 58.14; H, 5.00; N, 6.46Found: C, 57.77; H, 4.94; N, 6.69?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-28-EXAMPLE 5Preparation of 4—amino—l-(4-(2,2-dicyclohexyl-1—etho)ty)benzyl)pyri-dinium bromide (5-5)THF5-1OHDEAD/T PPN2/THF5-2100% 5_352%5-4Step A: Preparation of 1.1-dicvclohexvl-2-hydroxLethane (5-2)A solution of 1,1-dicyclohexylacetic acid (§-_l_) (2.8 g, 12.5mmol) in THF (5 ml) under N2 was cooled in an ice bath and then 1.0M borane in THF (17 ml, 17 mmol) was added dropwise. Afteraddition, the solution was stirred at room temperature and then a 1:1mixture of TI-IF/I-I20 (10 ml) was added carefully. The mixture was?CA 02264037 1999-02-26WO 98/10763 PCT/US97/15989-29-added to saturated Na2CO3 and extracted with EtOAc (3x). Theorganic extracts were dried, filtered and concentrated to dryness toyield 5-2.1H NMR (CDCI3); 5 1.1 (11H, m), 1.6 (l2H, m), 3.65 (2H, (1)."Step B: Preparation of ethyl 4-(1,1-dicyclohexyl)ethoxybenzoate(5-4)Under N2, 5-_2 (1.1 g, 5.2 mmol), ethyl 4-hydroxybenzoate(5-3) (0.9 g, 5.2 mmol), triphenylphosphine (1.6 g, 5.2 mmol), diethylazodicarboxylate (1.1 g, 6.2 mmol) in THF (15 ml) were placed in a?ask and stirred at room temperature. After 2 days, water and Et2Owere added and separated. The aqueous layer was further extractedwith Et2O (2x) and the combined layers backwashed with saturatedNa2CO3, brine, dried, filtered and concentrated to dryness. Theresidue was chromatographed on a Still column (40 mm) and theproduct eluted with 20% EtOAc/hex to yield _5_-_4.§_-4 was converted to _5_-_5 as described in Example 1; mp:223-5°C;1H NMR (d6—DMSO) 5 1.4 (23 H, m), 3.93 (2H, s), 5.26 (2H, s), 6.85(2H, d), 6.95 (2H, d), 7.37 (2H, d), 8.15 (2H, exch bs) and 8.3 (2H, d).Analysis calculated for C25H37N2OBr-0.75 H20C, 64.12; H, 7.97; N 5.75Found: C, 64.25; H, 7.66; N 5.83?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-30-EXAMPLE 6Preparation of 4-amino-1-[4-(l ,3—diphenyl-1 -propoxy)benzyl]pyri-dinium bromide (6-8)Step A: Preparation of 1.3-diohenvlnronanol (6-2)N2 NBBH4ETOH [3-Phenylpropiophenone (_6_-_1) (7.5 g, 36.0 mmol) wassuspended in ethanol (100 ml) and sodium borohydride (0.68 g‘, 18.0mmol) was added under N2. The resulting solution was stirred atambient temperature overnight. The ethanol was removed in vacuoand the residual oil-solid was taken up in ethyl acetate (100 ml) andwater (30 ml). The ethyl acetate layer was removed, washed withwater, dried, filtered and concentrated in vacuo to give _6_-_2 as acolorless oil.1H NMR (d6—DMSO) 5 1.88 (2H, q), 2.6 (2H, m), 4.51 (1H, q), 5.28(1H, d), 7.1-7.37 (l0H, m).?CA 02264037 1999-02-26wo 98/10763 PCT/US97/15989_ 31 -Step B: Preparation of ethyl 4—(1,3-diphenyl-1-propoxy)benzoate(6-4)Ph3P N20 6_2 OH DEADOH6-3cooc2H5C6-4To 6_—2 (2.12 g, 10.0 mmol) in tetrahydrofuran (25 ml)under a nitrogen atmosphere was added ethyl 4-hydroxybenzoate (6-_3)(1.66 g, 10.0 mmol) followed by triphenyl phosphine (3.15 g, 12.0mmol). The mixture was cooled in an ice bath and diethylazodicarboxylate (2.09 g, 12 mmol) was added. This mixture wasstirred overnight at ambient temperature and the solvent was removedin vacuo. The residue was taken up in the water and the ether layer wasseparated, washed with sodium bicarbonate and water, dried, filteredand concentrated in vacuo to yield an oil. Chromatographic purificationon silica gel gave _6_;4_ as a colorless oil.1H NMR (d6-DMSO) 5 1.25 (3H, t), 2.1 (IH rn), 2.25 (lH, rn), 2.66(lH, rn), 2.75 (1H, m), 4.22 (2H, q), 5.4 (1H, t), 6.99 (2H, d), 7.12-7.44(IOH, rn), 7.8 (2H, d).~._._.,......_,._.._..._.......__._....._.._._,....._........... —. _-,_....T. .. ..?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-32-§tep_(_3: Preparation of 4-(1,3-diphenyl-1-propoxy)benzyl alcohol(6-5)OH6-5A solution of Q? (2.46 g, 6.8 mmol) in ether (30 ml) wasadded dropwise under nitrogen atmosphere to a stirred cold suspensionof lithium aluminum hydride (0.285 g, 7.5 mmol) in ether (5 ml). Themixture was stirred for 3 hrs at ambient temperature and wasdecomposed by carefully adding water and sodium hydroxide. Thismixture was extracted with ethyl acetate. The extract was washed withwater, dried, filtered and concentrated in vacuo to yield _6—_5 as acolorless viscious oil.1H NMR (d5-DMSO) 5 2.05 (1H, m), 2.2 (1H, m), 2.66 (1H, m), 2.75(1H, m), 4.34 (2H, d), 4.99 (1H, t), 5.26 (1H, t), 6.81 (2H, d), 7.04—7.4(l2H, m).?CA 02264037 1999-02-26W0 98/10763 PCT/US97/ 15989-33-Step D: Preparation of 4—(l,3-diphenyl—l-propoxy)benzylbromide (6-6)Ph3PBr2 N2CH3CN Py.96_5 OHEfoO 06-6 B’To an ice cold solution of _6_-Q (1.19 g, 6.0 mmol) inacetonitrile (15 ml) was added pyridine (0.76 g, 9.6 mmol) and thentriphenylphosphine dibromide (3.29 g, 7.8 mmol). The mixture wasstirred at ice bath temperature for 1/4 hr under N2 and at ambienttemperature for 1&3/4 hrs and then was filtered. Concentration of the Ifiltrate in vacuo gave a crude oil. The pure product _6_;§ was obtainedafter three silica gel chromatographic separations.1H NMR (d6-DMSO) 8 2.06 (1H, m), 2.2 (1H, m), 2.66 (1H, m), 2.75(1H, m), 4.62 (2H, s), 5.3 (1H, t), 6.82 (2H, d), 7.16-7.4 (12H, m).?CA 02264037 1999-02-26W0 98/10763 PCT/US97I15989-34-Step E: Preparation of 4-amino-1—[4-(1,3-diphenyl-l-propoxy)-benzvllovridinium bromide (6-8) 6-8 /To a solution of 4-(1,3-diphenyl-1—propoxy)benz};lbromide _6__-_6_ (0.381 g, 1.0 mmol) in acetonitrile (7 ml) was added 4-aminopyridine (6-1) (94 mg, 1.0 mmol) with stirring at roomtemperature. The mixture was stirred for 3 hrs and the resulting white_suspension was ?ltered. The white solid obtained 6_-8, melted at 215-216.5°C. Recrystallization from acetonitiile raised the melting point to218.5-220°C.1H NMR (d6-DMSO) 8 2.06 (1H, m), 2.2 (1H, m), 2.65 (1H, m), 2.75(1H, m), 5.2 (2H, s), 5.3 (1H, m), 6.8 (2H, d), 6.9 (2H, d), 7.16-7.41(12H, m), 8.12 (2H, s), 8.24 (2H, d).Analysis calculated for C271-l27N2OBrC, 68.21; H, 5.73; N, 5.89Found: C, 68.48; H, 5.68; N, 5.98?CA 02264037 1999-02-26W0 98/ 10763 PCTIUS97ll5989- 35 -EXAMPLE 7Preparation of 4-amino-1-[4-(2,2-diphenylethoxy)benzyl]pyridiniumbromide (7-7)Step A: Preparation of ethvl 4-(2.2-diohenvlethoxwbenzoate (7-3)9 Ph3P N2CH - CH2OH' OH DEAD7-17~2COOC2H59CH -CH2-O oooc2H5CV 2,2-Diphenylethanol (7_~l_) (5.95 g, 30 mmol) and ethyl 4-hydroxybenzoate (_7_-;) (5.48 g, 30 mmol) were reacted, as in Example ‘6. E was obtained after chromatography as a colorless oil.1H NMR (CDC13): 8 1.36 (3H, t), 4.33 (2H, q), 4.52 (3H, s), 6.9 (2H,d), 7.2-7.36 (10 H, m), 7.96 (2H, d).?CA 02264037 1999-02-26W0 93/10753 PCT/US97/15989-36-_S;e_p_?: Preparation of ethyl 4-(2,2-diphenylethoxy)benzyl alcohol(7-4)CH-CH2-O cooc2H5 —5iH—————N-2-»Etzo7-3999CH “ OH7-491-; (0.757 g, 2.2 mmol) was dissolved in ether (20 ml) andwas reduced with lithium aluminum hydride (92 mg, 2.4 mmol) undernitrogen as in Example 6, Step B. j? was obtained as a colorless oil.1H NMR (d5-DMSO) 5 1.55 (1H, t), 4.45-4.52 (3H, m), 4.61 (2H, d),6.88 (2H, d), 7.2-7.35 (12H, In). ~?CA 02264037 1999-02-26WO 98/10763 PCT/US97/15989-37-Step C: Preparation of 4—(2.2-diphenvlethoxv)benzvl bromide (7-5) \ PBr3'—— OH E1207-499:3CH-CH2*O B7-5I’QZ-_4 (0.572 g, 1.9 mmol) was dissolved in ether (10 ml).The solution was cooled in ice and phosphorus tribromide (0.204 g,0.75 mmol) was added. After 1/2 hr. the reaction was diluted withmethanol (2 ml) and water (5 ml). The ether layer was separated,washed with sodium bicarbonate and water, dried and filtered.‘Concentration of the filtrate in vacuo gave ]-_5 as a white solid.mp: 70—73°C.1H NMR (d6-DMSO): 5 4.43-4.62 (3H, m), 4.64 (2H, s), 6.9 (2H, d),7.15-7.4 (l2H, m).?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-38-Step D: Preparation of 4-amino-l—[4-(2,2-diphenyl-ethoxy)-benzvllnvridinium bromide (7-7) CH3CNCH-CH2—OCV Br NH2/7-5 \ I 7_6NCH-CH2—O QB,N_\ /7-7 NH21;_5_ (100 mg, 0.27 mmol) was reacted with 4-aminopyridine ];_6_ (28 mg, 0.30 mmol) in acetonitrile (3 ml) as inExample 6, Step E. The white solid product 1-1 was obtained.mp: l37—l39°C. .1H NMR (d6—DMSO) 5: 4.45-4.59 (3H, m), 5.27 (2H, s), 6.82 (2H, d),6.98 (2H, d), 7.l7—7.4 (l2H, m), 8.13 (2H, s), 8.27 (2H, d).Analysis calculated for (C26H25N2OBr-0.5 H20):C, 66.38; H, 5.57; N, 5.96Found: C, 66.57; H, 5.42; N, 5.98?CA 02264037 1999-02-26W0 93/10753 PCT/US97/15989-39-EXAMPLE 8Preparation of 4-a.mino-l-[4-(dicyclohexylmethoxy)benzy1]pyridiniumbromide (8-7)‘ Step A: Preparation of ethyl 4-(dicyclohexylmethoxy)benzoate(8-3)9 Ph3P N2CH--OHOH DEAD8-1© COOCQH59 QCH—O COOC2H58-3Dicyclohexylmethanol (§;l) (4.91 g, 25 mmol) and ethyl 4-hydroxybenzoate (&_2_) (4.15 g, 25 mmol) were reacted, as in Example6, Step B, to obtain a colorless oil §—_3 after chromatography. 1H NMR(CDCI3): 5 098-13 (1 1H, m), 1.36 (3H, t), 1.58-1.86 (IIH, m), 4.02(1H, t), 4.33 (2H, q), 6.92 (2H, d), 7.94 (2H, d).?CA 02264037 1999-02-26W0 98/ 10763 PCT/US97/15989-40-Step B: Preparation of 4-(dicyclohexylmethoxy)benzyl alcohol(8-4)CH—O cooc2H5 _______..LAH N2EtgoQ\.Q” -.H—o«:%OH8Reduction of 8_—3_ (2.8 g, 8.1 mmol) with lithium aluminumhydride (0.338 g, 8.9 mmol) in ether (30 ml) as in Example 6 gave ??as a colorless oil.1H NMR (CDC13): 51.01-1.31 (11H, m), 1.45-1.86 (1 1H, m), 3.91(1H, t), 4.6 (2H, d), 6.9 (2 H, d), 7.23 (2 H, d).?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-41-Step C: Preparation of 4-(dicyclohexylmethoxy)benzyl bromide (8-5)<:>\CH O C PBr3<:>/ OH Et208-40 ..<:>/ §_-3 (1.93 g, 6.4 mmol) was converted to the bromide usingphosphorus tribromide (1.69 g, 2.6 mmol) in ether (25 ml) as inExample 7. Recovered _8_-_5_ liquid.1H NMR (CDCI3) 5 1.0-1.32 (1 1H, m), 1.53-1.84 (11H, m), 3.91 (1H,t), 4.49 (2H, s), 6.85 (2H, d), 7.25 (2H, d).?CA 02264037 1999-02-26WO 98/10763 PCT/US97/15989-42-§gp_l_D_: Preparation of 4-amino—l-[4—(dicyclohexy1methoxy)-benzvllpvridinium bromide (8-7)CH3CNc»+—o«} WBr 2 NH28-_5 (183 mg, 0.5 mmol) and 4-aminopyridine 8-_6 (47 mg,0.5 mmol) were reacted in acetonitrile (4 ml) as in Example 1:Recovered white solid _8_-]_. mp: 248-249°C1H NMR (d6-DMSO) 5 0.94-1.28 (1 1H, m), 1.5-1.75 (1lH, m), 4.1(1H, t), 5.24 (2H, s), 6.83 (2H, d), 6.98 (H, d), 7.28 (2H, d), 8.14 (2H,s), 8.3 (2H, (1).Analysis calculated for C25H35N2OBrC, 65.35; H, 7.68; N, 6.10Found: C, 65.45; H, 7.62; N, 6.17?CA 02264037 1999-02-26W0 98/10763 PCT/US97l15989-43..EXAMPLE 9Preparation of 3,4—diamino—l-(4-benzyloxybenzyl)pyridinium bromide(9-7)Step A: Preparation of 4-benzyloxybenzyl bromide (9-2)PB<:>—\ '30—< >"? Et2OOH 9-1o-<:>—\Br9-2To a cold suspension of 4-benzyloxybenzyl alcohol 21(21.4 g, 0.10 mol) in ether (250 ml) was added phosphorus tribromide(10.8 g, 40 mmol) as in Example 7. Recovered 27.2 g of white solidwhich was recrystallized from hexane (200 ml). Obtained purebromide 9_-_2.1H NMR (CDCI3) 5 4.5 (2H, s), 5.05 (2H, s), 6.94 (2H, d), 7.26-7.45(71-I, In).?CA 02264037 1999-02-26“'0 93’10753 PCT/US97/15989-44-Step B: Preparation of 3,4-diamino—l-(4-benzyloxybenzyl);Dvridinium bromide 1 9-4) D—-\ CH3CNO‘<;>—\ NBr ’ | 9-39'2 \ NH2NH2©_\°_©‘\N@B/ f9-4 \ INH2NH22;; (1.38 g, 5.0 mmol) was reacted with 3,4-diaminopyridine (g) (0.573 g, 5.25 mmol) in acetonitrile (50 ml) as inExample 1. Recovered white solid Q?. Recrystallized fromacetonitrile, mp: 240-241 °C.1H NMR (d5-DMSO) 5 5.1 (2H, s), 5.25 (2H, s), 5.56 (2H, s),'6.74 (1H,d), 7.05 (2H, d), 7.24-7.46 (9H, m), 7.61 (1H, s), 7.96 (1H, d).Analysis calculated for (C19H2oN30+Br‘): (0.25 Et20)C, 59.09; H, 5.22; N, 10.88Found: C, 59.33; H, 5.60; N, 10.38The compounds shown in the table below are exemplarycompounds of the present invention. The range of Ki values associatedwith the specifically listed compounds is represented as follows:+ <O.l uM++ >O.l uM and <l.0 uM+++ >1.0 MM?WO 98/10763CA 02264037 1999-02-26PCT/U S97/ 15989-45-TABLEIR1_ x0R \ /2--Y / \ R2NH2R R1 2 Y R2 Ki mp(thr)LLMH CH CH H ++©_ H CH CH H +++H N CH H +++©-EH20-H CH CH H + 254-CH0-— 5°2H CH CH H ++ 170-CHZCHZO--‘ 1°H CH CH H ++ 218.5-CH2CH2-CHO 220° ‘H CH CH H + 241-@--— 3-?CAW0 98/1076302264037 1999-02-26PCT/US97/I 5989K1R R1 Z Y R2 mp(thr)H CH CH H ++ 188-CH(CH2CH3)--O-— 190°H CH CH H ++ 137-CHZCHZO-— 9°2 .H CH CH H ++ 223-CHCH2O—— 5°2H CH N H +++ 212-Q-»— 4-H CH CH H ++ 248-cHo— 9°2—OCH3 CH CH H +++ 183-C%c~2o—- 4»CH CH H -g-++ 125-<}-o— 7-H CH CH NH2 ++ 240-CH2O— 1° _?CA 02264037 1999-02-26W0 98/ 10763 I’CT/US97/ 15989-47-The general procedure outlined in Scheme 11 can be used tomake the following compounds.EXAMPLE 10Preparation of N-4—(4-benzvloxvbenzvllaminonvridine (10-3)Step A:OCroow/10-2 \ INMethod 1: Preparation of 4-(4-benzyloxyphenyl)carboxamido-Dvridine ( 10-2)A solution ofQAOQCOZH10-1(1.1 g, 4.8 mmol), 1-hydroxybenzotriazole (HOBT) (1.0 g, 7.4 mmol), A1—ethyl-3—(3—dimethylaminopropyl) carbodiimide-HCl (EDC) (1.4 g, 7.3mmol), Et3N (1 ml, 7.6 mmol) in DMF (40 ml) was treated under N2with 4—aminopyridine (4-AP) (0.54 g, 5.0 mmol). After stirringovernight at room temperature, the reaction was poured into saturatedNaHCO3 and extracted with EtOAc (310. The organic layers werewashed with H20 and brine, dried, ?ltered and concentrated to dryness.The residue was triturated with hexane to yield 1_0_-_2_. mp: 126-7°C;1H NMR (CDC13) 5 5.15 (2H, s), 7.04 (2H, d), 7.4 (5H, m), 7.6 (2H,d), 7.84 (2H, d), 8.12 (1H, exch bs), 8.42 (2H, d).?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-48-Method 2:Oxalyl chloride (3.3 g, 26 mmol) was added under N2dropwise to a suspension of 10-1 (5.0 g, 22 mmol) in CH2Cl2 (75 ml)with 4 drops of DMF. After 1 h the solution was concentrated todryness and flushed once with CHCI3. The residue was dissolved inCHCI3 (60 ml) and added dropwise to a suspension of 4-AP (6.2 g, 66mmol) in CHCI3 (100 ml). After 1 h at room temperature the solutionwas poured into saturated Na2CO3 and separated. The aqueous wasfurther extracted with EtOAc (3x). The combined extracts were dried,filtered and concentrated to dryness. The residue was chromatographedon a Still column (80 mm) and the product eluted with 10% CH3OH—CHCl3 to yield 1_0;2.10-3Preparation of 10-3: -A solution of 10-2 (3.5 g, 11.5 mmol) in THF (40 ml) wastreated dropwise under N2 with 1.0 M LAH in THF (17 ml, 17 mmol). AAfter addition, the solution was heated at 60°C. After 18 h, the solutionwas treated with saturated N a2SO4 to a white suspension. The mixture -was filtered and the pad washed with EtOAc (200 ml). The organicextracts were washed with saturated Na2CO3, dried, filtered andconcentrated to dryness to yield 1_O_-3, An analytical sample wascrystallized as the HCl salt from EtOH-Et20; mp: 224-6°C;1H NMR (d6—DMSO) 5 4.45 (2H, s), 5.1 (2H, s), 6.95 (4H, d and m),7.4 (7H, m), 8.2 (2H, d), 9.2 (1H, exch bs).Analysis calculated for C19H18N20-HCl-0.25 H20C, 68.87; H, 5.93; N, 8.46Found: C, 68.49; H, 5.80; N, 8.25?CA 02264037 1999-02-26W0 98l10763 PCT/U S97/ 15989-49..EXAMPLE 1 1Preparation of N-4-11,1-diphenylmethoxywenzylaminopyridine (11-1)The desired compound was prepared as described inExample 10 using Method 1 in Step A and then Step B; mp: 220-1°(EtOH-Et20);1H NMR (d6-DMSO) 5 3.4 (1H, exch bs), 4.4 (2H, s), 6.5 (1H, s), 6.9(2H, dd), 7.05 (2H, d), 7.6 (8H, m), 7.5 (4H, d), 8.15 (2H, dd), 9.1 (1H,exch t).Analysis calculated for C25H22N20-HCl-3/4 H20C, 72.10; H, 5.93; N, 6.75Found: C, 72.35; H, 5.71; N, 6.97EXAMPLE 12Preparation of N—4—(cvclohexvlmethoxv)benzvlaminopvridine (12-1)The desired compound was prepared as described for _1Q—_3_in Example 10 using Method 1 in Step A and then Step B; mp: 273—4°C(EtOH);1H NMR (d6-DMSO) 5 1.1 (5H, m), 1.7 (6H, m), 3.75 (2H, s), 4.45(2H, s), 6.9 (4H, bd), 7.28 (2H, bd), 8.15 (2H, bd), 9.25 (1H, exch bs).Analysis calculated for C19H24N20-HCIC 68.55, H 7.57, N 8.42Found: C 68.35, H 7.53, N 8.33?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-50-EXAMPLE 13Preparation of 4-[4-(2-methyl- l -phenylpropoxy)benzylamino] pyridine( 13-2).. Step A: Preparation of 1—Dhenvl-2-methvl-lgronanol (13-2)0 NaBH4 0“EtOH N213-1 13-2 Isobutyrophenone l3_—_l_ (29.6 g, 0.20 mmol) was dissolvedin ethanol (300 ml) and was reduced under N2 with sodiumborohydride (7.57 g, 0.20 mmol) for 4 hrs. at room temperature. Theethanol was removed in vacuo and the residue was taken up in ethylacetate (200 ml) and water (100 ml). The ethyl acetate extract waswashed with water, dried, ?ltered and concentrated in vacuo to obtainalcohol l_3;_2.1H NMR (CDCI3): 5 0.82 (3H, d), 1.0 (3H, d), 1.83 (1H, s), 2.0 (1H,m), 4.4 (1H, d), 7.26 (5H, m).?CA 02264037 1999-02-26WO 98110763 PCT/US97/15989-51-Step B: Preparation of ethyl 4-(2-methyl-l—pheny1-propoxv)benzoate (13-5)NH0}‘ CCI3OHNaHCl3CCN N213-313-2cyclohex. O COC2H5——————-———-—>CH2C|2 0“13-513_4 COOCZH5Sodium hydride (60% in mineral oil) (200 mg, 5 mmol)was washed with hexane under nitrogen and was suspended inanhydrous ether (30 ml). To the stirred suspension was added 13-2 (7.5g, 50 mmol) in ether (10 ml) and the mixture was stirred at RT for 1/2hr. After cooling to —5°C, trichloroacetonitrile (7.58 g, 52.5 mmol)was added. Stirring was continued for 1/2 hr. at 0°C and at ambienttemperature for 1 hr. The ether was removed in vacuo and the residualoil l?? was taken up in cyclohexane (20 ml) and methylene chloride(10 ml). To this solution was added ethyl 4-hydroxybenzoate (Lj?)(8.3 g, 50 mmol) followed by methylene chloride (25 ml) andtri?uoromethanesulfonic acid (0.2 ml). The mixture was stirred atambient temperature ovemight and was filtered and concentrated to anoil. Chromatography on silica gel gave L3_-_5.1H NMR (CDCI3) 5 0.91 (3H, d), 1.05 (3H, d), l.32 (3H, t), 2.15 (1H,m), 4.3 (2H, q), 4.88 (1H, d), 6.83 (2H, d), 7.2-7.4 (5 H, m), 8.7 (2H,d).?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-52-Step C: Preparation of 4—(2—methyl—l-phenylpropoxy)benzoic acid( 13-6) 'O—-©—COOC2H5 KOH13-5: O COOH1 3-6 To 13-5 (8.89 g, 29.8 mmol) was added 2N potassiumhydroxide (100 ml) and ethanol (50 ml). The mixture was stirred at100°C overnight. The ethanol was removed in vacuo and the aqueoussolution was cooled in ice and acidified with 6N HCl (35 ml, 0.21 mol).The acid was extracted into ethyl acetate (50 ml) and the extract waswashed with water, dried, filtered and concentrated in vacuo to obtainthe oil 13-6, which solidified. The white solid melted at 125-129°C.1H NMR (CDCI3) 5 0.91 (3H, d), 1.05 (3H, d), 2.15 (1H, m), 4.9 (1H, ‘d), 6.85 (2H, d), 7.2-7.35 (5H, m), 7.91 (2H, d).?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-53-Step D: Preparation of 4-(2-methyl-1-phenylpropoxy)benzoylchloride (13-7)COO“ oxalyl chlorideCHQCI2o—QOH: O—QC—CI1 3-713-6 (0.541 g, 2.0 mmol) was stirred in methylene chloride(3 ml) at room temperature and oxalyl chloride (0.381 g, 3.0 mmol)was added. After 3 hrs. at room temperature the solution wasconcentrated in vacuo to a pale yellow liquid 13-7. The acid chloridewas used without purification.?CA 02264037 1999-02-26W0 93/ 10763 PCT/US97/l5989-54-Step E: Preparation of 4—(2-methyl—1-phenylpropoxy)—N-(4-mridvhbenzamide (13-9)1?0 C-0’ Et3N THF©_‘§— 13-7 NH?\1 13-3/O No—©~<13-9 (EN/To an ice cold stirred solution of 13_-8 (0.188 g, 2.0 mmol)and triethylamine (0.233 g, 2.0 mmol) in tetrahydrofuran (10 ml) wasadded a solution 1_3? (0.54 g, 2.0 mmol) over a 5-10 min period. Thereaction was stirred at ambient temperature overnight. Then the THFwas removed in vacuo and the residue was taken up in ethyl acetate (50ml) and water (25 ml). The ethyl acetate extract was separated, washedwith water, dried and concentrated in vacuo to yield the oil L3‘-_9_.1H NMR (d6-DMSO) 5 0.84 (3H, d), 1.02 (3H, d), 2.12 (1H, m), 5.2(1H, d), 7.0 (2H, d), 7.2-7.4 (5H, m), 7.72 (2H, d), 7.82 (2H, d), 8.42(2H, d), 10.33 (1H, s).?WO 98/10763CA 02264037 1999-02-26PCT/US97l15989-55..Step F: Preparation of 4—[4-(2-methyl—1—phenylpropoxy)—benzvlaminolnvri dine ( 13-10)0o~©—< .N_H LIAIH4 N213_9 (5 Etgo\ IN°_©'\13-10 /I\NTo a stirred suspension of lithium aluminum hydride(0.152 g, 4.0 mmol) in ether (5 ml) under nitrogen was added a solutionof 13:-9 (0.71 g, 2.0 mmol) in tetrahydrofuran (5 ml) over a 5 minperiod. The mixture was stirred at ambient temperature overnight andthen was decomposed by adding water and sodium hydroxide. Ethylacetate (25 ml) was added and the mixture was filtered. The filtrate wasdried, filtered and concentrated in vacuo to 620 mg of colorless oilwhich was chromatographed on silica gel. l_3-_l_Q was obtained as an oil.The hydrochloride salt melted at 186-188°C.1H NMR (d6-DMSO) 8 0.5 (3H, d), 0.99 (3H, d), 1.16 (1H, t), 4.15(2H, d), 4.99 (1H, d), 6.47 (2H, d), 6.82 (2H, d), 7.05 (1H, t), 7.12 (2H, d), 7.2-7.25 (1H, m), 7.25-7.36 (4H, m), 7.96 (2H, d).Analysis calculated for (C22H24N20-HCl- 0.2 H20)C, 70.93; H, 6.87; N, 7.52Found: C, 70.99; H, 6.79; N, 7.62?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-55-EXAMPLE 14Preparation of 4-l 4-( 2.2—dinhenv1ethoxy)benzvlaminolDvridine (14-7)§t_ep_A_: Preparation of ethyl 4-(2.2-diphenvlethoxv)benzoate ( 14-3)9Ph3P N2 THFCH—CH H =20 OHDEAD14-114-2cooc2H5CH-CH2—O COOC2H5 / 14_3To 2,2-diphenylethanol (lgl;—_l) (5.95 g, 30 mmol) wasadded ethyl 4-hydroxybenzoate (_1_4_;2) (5.40 g, 30 mmol),triphenylphosphine (8.66 g, 33 mmol) and tetrahydrofuran (125 ml).The mixture was cooled in ice and diethyl azodicarboxylate (5.75 g, 33mmol) was added. The reaction mixture was stirred under nitrogen atambient temperature overnight and then the volatile components wereremoved in vacuo. The oil-solid residue was taken up in ethyl acetate(100 ml) and water (50 ml). Work up of the ethyl acetate portion givecrude solid. The product _l_4-__3 was purified by silica gelchromatography.1H NMR (CDCI3) 6 1.37 (3H, t), 4.33 (2H, q), 4.52 (3H, s), 6.9 (2H,d), 7.4-7.66 (IOH, m), 7.96 (2H, d).?CA 02264037 1999-02-26WO 98/10763 PCT/US97/15989-57-Step B: Preparation of 4-(2.2-diDhenv1ethoxv‘)benzoic acid) (14-4)CH - CH2-O cooc2H5 .___"_Ԥ9_':L..@/ EtOH/H2014-3CH- CH2-O COOH14-4A suspension of Vii (346 mg, 1.0 mmol) in 10% aqueoussodium hydroxide (15 ml) and ethanol (5 ml) was stirred at 100°Covernight. The resulting solution was cooled and acidified with excessHC1. A gum separated which was extracted into ethyl acetate (15 ml),washed with water, dried, filtered and concentrated in vacuo. The acid_1_£_l_-A was a pale yellow solid, mp: l40—146°C.1H NMR (CDCI3) 5 4.55 (3H, s), 6.94 (2H, d), 7.21-7.37 (10H, m),8.04 (2H, d).?CA 02264037 1999-02-26W0 98/10763 PCTIUS97/15989-58-§tep_C_: Preparation of 4-(2,2—diphenylethoxy)-N-(4-pyridyl)benz-amide (14-6)CH_CH2_O_©_COOH HOBT EDC TEA ;NH2DMF14‘4 / N2Q\ oCH-CH2— o ©/ To _1_§;? (125 mg, 0.393 mmol), 4-aminopyridine (_1A_-Q)(56 mg, 0.59 mmol), l-hydroxybenzotriazole hydrate (80 mg, 0.59mmol) and triethylamine (60 mg, 0.59 mmol) in DMF (5 ml) undernitrogen was added l-ethyl-3-(3-dimethylamino-propyl)carbodiimidehydrochloride (113 mg, 0.59 mmol). The mixture was stirred atambient temperature overnight and the DMF was removed under highvacuum. The residual oil was taken up in ethyl acetate (15 ml) andwashed with water and saturated sodium chloride, dried, filtered andconcentrated to an amber gum 1_4;_6_.?CA 02264037 1999-02-26W0 98/10763 PCT/US97l15989-59-Step D: Preparation of 4-[4-(2,2-diphenylethoxy)benzyl—aminolpvridine (14-7)0 LAH N2CH-CH2-O N/o9THF-Et2O14-e/\N9 QHHN/14-7Q/\ INTo a solution of _l_4;6 (0.144 g, 0.365 mmol) intetrahydrofuran (1 ml) and ether (3 ml) under nitrogen was addedlithium aluminum hydride (30 mg, 0.79 mmol). The mixture wasstirred at room temperature overnight and then was decomposed withwater and sodium hydroxide. The mixture was filtered andconcentrated in vacuo to a colorless oil _1_4_-1 which was purified bysilica gel chromatography and converted to the HCl salt, mp: 213-214.5°C.1H NMR (d6-DMSO) 8 3.36 (1H, s), 4.36-4.58 (6H, d, m), 6.84-7.0(3H, d, bm), 7.16-7.4 (1 1H, m), 8.06-8.25 (2H, d), 9.08-9.24 (1H, bs).Analysis calculated for (C22H24N20-HCl)C, 74.48; H, 6.10; N, 6.74Found: C, 74.89; H, 6.04; N, 6.72?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-50-EXAMPLE 15Preparation of 4—14—(2-cvclohexvlethoxv)benz\/laminolnvridine (15-8)Step A: Preparation of ethvl 4—(2-cvclohexvlethoxwbenzoate (15-3)Ox Ph3F’ THF N2OH15.1 0“ DEAD15-2cooo2H5: \—o——<—=—>— COOCZH515-32-Cyclohexylethanol 154 (3.2 g, 25 mmol) and ethyl 4-hydroxybenzoate 15;; (4.15 g, 25 mmol) were reacted as in Example14. The product _l_5;3_ was obtained as a waxy solid. _1H NMR (CDC13) 5 1.04 (2H, m), 1.08-1.3 (3H, m), 1.39 (3H, t), 1.42-158 (1H, m), 1.62-1.81 (7H, m), 4.04 (2H, t), 4.35 (2H, q), 6.9 (2H, d),7.98 (2H, d).?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-51-Step B: Preparation of 4—(2—cvc1ohexvlethoxvlbenzoic acid (15-4)o—©— cooc2H5H20/EtOH 15-3:3 \- o——©— COOH15-4Hydrolysis of1_5;3 (1.13 g, 3.1 mmol) as in Example 14gave the acid L?? as a white solid. mp, 129-132°C.1H NMR (CDCl3) 5 0.9-1.07 (2H, m), 1.08-1.36 (3H, m), 1.43-1.6 (1H,m), 1.6-1.82 (7H, m), 4.06 (2H, t), 6.92 (2H, d), 8.03 (2H, d).Step C: Preparation of 4-(2-cyclohexylethoxy)benzoyl chloride(15-5) x CHZCI2O < > COOH oxalyl chloride.15-4Ox ~0 C —— Cl15-5The acid chloride was prepared from 15-4 (0.497 g, 2mmol) as in Example 13. Crude product was obtained as an oil inquantitative yield and was used without further purification.?CA 02264037 1999-02-26W0 98/ 10763 PCT/US97/15989-62-Step D: Preparation of 4-(2-cyclohexylethoxy)-N-(4-pyridyl)-benzamide (15-7)NH215-5 N2/' 15-6\Ox 0 (O ”O/HN15-7/\ INThis amide was prepared from 1_5_-5 (0.53 g, 2 mmol) and4—aminopyridine (_1_§-_§_) (0.188 g, 2 mmol) as in Example 13. The solidobtained, _1_5_—Z, melted at 123-125°C.1H NMR (d6—DMSO) 5 0.88-1.03 (2H, m), 1.05—1.3 (3H, m), 1.4-1.56(1H, m), 1.56—l.8 (7H, m), 4.1 (2H, t), 7.08 (2H, d), 7.78 (2H, d), 7.95(2H, d), 8.45 (2H, d), 10.42 (1H, s).?CA 02264037 1999-02-26W0 98/ 10763 PCTIU S97! 15989-53-Step B: Preparation of 4-[4—(2-cyclohexylethoxy)-benzyl- Iaminolnvridine (15-8)Ox °O LAHH1 5_7 N/ THF/Et2O/ \Ch0‘<}—\ N/H/ 15-8\ lNReduction of Q1 (0.52 g, 1.6 mmol) as in Example 13gave the product 1533 as a white solid mp l15—120°C. Thehydrochloride melted at 227-228°C.1H NMR (d6-DMSO) 5 0.81-1.0 (3H, m), 1.02—1.3 (3H, m), 1.37-1.52(1H, m), 1.53-1.78 (7H, m), 3.95 (2H, t), 4.43 (2H, d), 6.91 (2H, d),6.82-7.04 (2H, m), 7.28 (2H, d), 8.15 (2H, d), 9.25 (1H, t);Analysis calculated for C20H25N20-HClC, 69.24; H, 7.58; N, 8,08Found: C, 69.16; H, 7.80; N, 8.08?CA 02264037 1999-02-26“'0 93/10763 PCT/US97/15989-64-EXAMPLE 16Preparation of 4-[4-(dicyclohexylmethoxy)—benzylamino]pyridine( 16-8)‘ Step A: Preparation of ethyl 4-(dicyclohexylmethoxy)benzoate(16-3)9CH_OH Ph3P THF N2OHDEAD<:>/ 16-2oooo2H5CH ——o—©— cooc2H5Q16-3Dicyclohexylmethanol (L6_-_l_) (6.97 g, 35.5 mmol) andethyl 4-hydroxybenzoate (l_6_-_2) (5.9 g, 35.5 mmol) were reacted as inExample 14 ‘and the product _l_6_-__3_ was isolated as a colorless oil.1H NMR (CDC13) 5 098-13 (1 1H, m), 1.35 (3H, t), 1.52-1.86 (1 1H,m), 4.02 (1H, t), 4.33 (2H, q), 6.91 (2H, d), 7.94 (2H, d).?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-55-Step B: Preparation of 4-(dicvclohexvlmethoxwbenzoic acid (16-4)CH —o—©—— cooc2H5 KO”EtOH/H2016-3CH—O COOH1 6-49 Q99Hydrolysis of 16-3 (7.9 g, 23 mmol) as in Example 14produced slightly crude acid 16-4.1H NMR (CDCI3) 5 0.98-1.32 (1 1H, m), 1.54-1.84 (l1H, m), 4.05 (1H,t), 6.92 (2H, d), 8.0 (2H, cl).?CA 02264037 1999-02-26W0 98/ 10763 PCT/US97/15989-66-§1§p__C: Preparation of 4-(dicyclohexylmethoxy)benzyl chloride(16-5)CH ClCH —o—@—— coo:-1 2 2 roxalyl chloride16-499?9CH—O C—Cl16-5QPreparation of the acid chloride of 16-4 (1.54 g, 5 mmol)as in Example 13 gave the product 16-5 as a pale yellow oil. It wasused without purification.?CA 02264037 1999-02-26WO 98110763 PCT/US97/15989-57-Step D: Preparation of 4-(4-dicyclohexy1methoxy)-N-(4-Dvridvhbenzamide (16-7)< >\ oCH O (I)! Cl Et3N THF N2NH2C>/ /<:>/ N”4—Aminopyridine _1_6_-_6_ (0.47 g, 5 mmol) was acylated with4-(dicyclohexylmethoxy)benzy1 chloride _l_6_-_§ (5 mmol) as in Example13 to give the amide 16;] as a white solid.1H NMR (d6—DMSO) 8 0.97-1.3 (11H, m), 1.53-1.76 (11H, m,), 4.25(1H, t), 7.1 (2H, d), 7.76 (2H, d), 7.88 (2H, d), 8.43 (2H, d), 10.38 (1H,s).?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-68..Step B: Preparation of 4-[4-(dicyclohexylmethoxy)-benzyl-aminolovridine (16-8) '<3\ 0LAH N2CH--O /H ————-—->N THF/E12016-7/\NN/16-8/\ INLithium aluminum hydride reduction of 16-7 (1.28 g, 3.3mmol) as in Example 14 gave product 16-8 as a colorless oil. .Thehydrochloride melted at 213-215°C.1H NMR (d5-DMSO) 8 0.93-1.28 (1 1H, m), 1.5-1.77 (11H, m), 4.04(1H, t), 4.41 (2H, d), 6.95 (4H, d), 7.22 (2H, d), 8.16 (2H, bd), 9.15(1H, t).Analysis calculated for C25H34N20-I-[ClC, 72.35; H, 8.50; N, 6.75Found: C, 72.63; H, 8.47; N, 6.76?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-69-EXAMPLE 17Preparation of 4-[4-(1,3—diphenyl-2-propoxy)benzylamino]pyridine( 17-9)Step A: Preparation of 1.3-divhenvl-2—proDanol 117-2)E NEBH4 Q0Q Em N2 017-1 OH17-2Reduction of 1,3-diphenylacetone 17-1 (21.0 g, 0.10 mole)was accomplished as in Example 13 in quantitative yield. The alcohol17-2 was a colorless oil.1H NMR (CDC13) 5 1.64 (1H, d), 2.71-2.91 (4H, dd), 4.07 (1H, In),7.18-7.37 (IOH, m).?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-70-Step B: Preparation of ethyl 4—(l,3-diphenyl-2-propoxy)ber1zoateQ7-4)O Ph3P THF N2OH 4G 0H DEAD17-2 El?’ 17_3c:ooo2H50.:D 17-: COOCZH5Reaction of 17-2 (5.3 g, 0.025 mol) and ethyl 4-hydroxybenzoate 17-2 (6.56 g, 0.025 mol) as in Example 14 gave theproduct l7-4 as a colorless oil.?CA 02264037 1999-02-26WO 98/10763 3 PCT/US97/ 15989-71-Ste}; C: Preparation of 4-(1,3-diphenyl-2-propoxy)benzoic acid(17-5)0 0 COOCZH5 ~Q EIOH/H2017-4: 17-5Hydrolysis of L7-_4 (7.47 g, 21 mmol) as in Example 14gave the acid _l_]_-_5_ as a viscious oil (4.28 g).1H NMR (CDCI3) 5 2.91-3.08 (4H, m), 4.77 (1H, m), 6.84 (2H, CI),7.16-7.33 (IOH, m), 7.96 (2H, d).?CA 02264037 1999-02-26W0 98/ 10763 PCT/US97/15989-72-§t_e;?)_: Preparation of 4-(1,3—diphenyl-2-propoxy)benzoylchloride (17-6)0 CH2Cl20 COOH© oxalyl chloride17-50 OHO C -CI17-6l7~5 (1.66 g, 5 mmol) was converted to the acid chloride17-6 as in Example 13. The viscous oil was used without furtherpurification. ?CA 02264037 1999-02-26WO 98/10763 ' PCT/US97/15989-73-§§p__E: Preparation of 4-(1,3-diphenyl-2-propoxy)-N-(4-pvridvhbemamide (17-8)O 0ll Et3N THF0 0 C—Cl NH217-6 /1 17_7017-8N0N/H/\ IN 4-Aminopyridine 17-7 (0.471 g, 5 mmol) was acylated with17-6 (1.75 g, 5 me!) using the conditions of Example 13. The amide17-8 was obtained as a solid foam.?CA 02264037 1999-02-26W0 93/10763 PCT/US97/15989-74-Step F: Preparation of 4-[4—(1,3—dipheny1-2-propoxy)-benzyl-aminolpvridine (17-9)6 O LAH N20 H9 N’ THF/Et2O17-e /Ki \NO—-< >-——. /H: N17-9 /\ INLithium aluminum hydride reduction of 1_'_/;8_ (1.36 g, 3.3mmol) as described in Example 14 gave a quant. yield of the product1_7_-9 as a viscous oil. The hydrochloride melted at 151-154°C.1H NMR (d6-DMSO) 5 2.88 (4H, d), 4.41 (2H, d), 4.73 (1H, m), 6.9(2H, d), 6.83—7.0 (2H, m), 7.16-7.82 (12H, m), 8.15 (2H, bd), 9.15 (1H,t).Analysis calculated for C27H26N20-HCl- 0.4 H20C, 74.00; H, 6.40; N, 6.39Found: C, 73.94; H, 6.28; N, 6.30?CA 02264037 1999-02-26W0 98/10763 PCTfUS97ll5989-75-EXAMPLE 18Preparation of 4-[4-(3,4-methylenedioxybenzyloxy)benzyl—aminolnvridine (18-7)Step A: Preparation of ethyl 4-(3,4-methylenedioxybenzyl-oxvlbenzoate (18-3)0or Ph3P THF N2 AVOHDEAD18-1 18-2cooc2H5o—@-— COOC2H518-33,4—Methylenedioxybenzyl alcohol 18-1 (6.2 g, 40.0 mmol)and ethyl 4-hydroxybenzoate 18-2 (6.65 g, 40.0 mmol) were reacted asin Example 14. The desired ester 18-3 was obtained as a white solid.?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-76-§t_ep_B_: Preparation of ethyl 4-(3,4-methy1enedioxybenzyl-oxv)benzoic acid (18-4)I, oO\@__\ LiOHDME/H20o——©— cooc2H5o——@-— COOH18-4 l3-_3 (2.5 g, 8.3 mmol) was hydrolyzed with lithiumhydroxide (0.8 g, 33.4 mmol) in dimethoxyethane (60 ml) and water(30 ml) at room temperature overnight. Then water (50 ml) was addedand the solution was acidified with 6N HCI. Filtered the white solidwhich had precipitated and obtained a quantitative yield of crude acidwhich was recrystallized from butyl chloride-ethyl acetate. The pureproducts _l_8_;3{ melted at l92—l94°C.1H NMR (d6-DMSO) 5 5.06 (2H, s), 6.02 (2H, s), 6.9-6.99 (2H, m),7.02-7.12 (3H, m), 7.9 (2H, d). .. , ?CA 02264037 1999-02-26W0 98/ 10763 PCT/US97/15989_ 77 -Step C: Preparation of 4-(3,4-methylenedioxybenzyloxy)-N-(4-Dvridvllbenzamide ( 18-6)oI’o\@_\ EDC HOBTNH2——< >-COOH0 E5 O ‘8'4 ’ 18-5NTo _1_§? (0.545 g, 2 mmol) was added 4-aminopyridine?? (0.235 g, 2.5 mmol), 1-hydroxy-benzotriazole hydrate (0.338 g,2.5 mmol), 1-ethyl-3—(3-dimethyl-aminopropyl)carbodiimide (0.479 g,2.5 mmol) and dry DMF (5 ml) followed by tiiethylamine (0.35 ml, 2.5mmol). The mixture was stirred at ambient temperature overnight.Then the DMF was removed under high vacuum. The residual oil waschromatographed on silica gel to obtain a white solid 1&6,?CA 02264037 1999-02-26W0 93/10753 PCTlUS97/ 15989-73-_S_te_:p_Q: Preparation of 4-[4~(3,4-methy1enedioxybenzyl-oxvlbenzvlaminolnvridine (18-7)18-6 /\ IN[,0O O-C}-« HN/\N18-6 (0.32 g, 0.9 mmol) was reduced with lithiumaluminum hydride (0.30 g, 8 mmol) as in Example 10. The product18-7 was obtained as an oil. The hydrochloride salt melted at 190-193°C. '1H NMR (d5-DMSO) 5 4.45 (2H, d), 4.99 (2H, s), 6.02 (2H, S), 6.83-7.06 (7H, m), 7.3 (2H, d), 8.16 (2H, bd), 9.2 (1H, t).Analysis calculated for C2()H1gN203-HCl- 0.2 H20C 64.15, H 5.22, N 7.48Found: C 63.82, H 5.16, N 7.51.?CA 02264037 1999-02-26W0 98ll0763 PCT/US97/15989-79-The compounds shown in the table below are exemplarycompounds of the present invention. The range of Ki values associatedwith the specifically listed compounds is represented as follows:+ <O.l LLM++ >0.l 11M and <l.O LLM+++ >1.0 uM?CA 02264037 1999-02-26 W0 98/10763 PCT/US97/15989_ 80 -H\ —N NR—C'H —x-—<:}——/ \ /R1TABLE 2R R1 X Ki (thr) mp (HCI)M+++H O 224-6°©_ ©__ 0 +++ 220-1°©__ H 0 +++ 273—4°C H2H O +++ 2I3—l4.5°(CH3)2CH- O +++ 186-8°O_ H O +++ 227 -8°CH2““?CA 02264037 1999-02-26WO 98/10763 PCT/US97/15989_ 31 -TABLE 2 §CONT'D)R R1 x Ki (thr) mp (HCI)M<:+ >~ 0 ++ ~<:>_ <:>___ O +++ 213—5°O +++ 151-4°C%c++2— C%<=H2—H O +++ 190-3°©_ H S +++ 21 1-3°<:>___ H NH +++ 202—5°H O +++ 171-3°@_ H NH +++ 200-2°?CA 02264037 1999-02-26W0 98/10763 ‘ PCT/US97/15989-32-R R1 X Ki (thr) mp (HCI)_—= = “M =@_ -CO2CH2 0 +++ 182-5°ll __©_ _ CNH2 O +++<:>_ ©__ 0 +++ 176-182°H 0 ++ 101-2°<3 CH7 CHZCHZ + (freebase)o H3CYCH300 CH 0 +++ 21o—11°IWCH2CH2- O +++ 163-4°<:>_ CH3- 0 +++ 12s-3o°?CA 02264037 1999-02-26W0 98/10763 PCT/US97ll5989-83-EXAMPLE 19Preparation of 4'-(4-cyclohexylmethyloxy—2-benzylphenylmethyl)—aminonvridine (19-3) Step A: Preparation of 4-cyclohexylmethyloxy—2-benzyl-benzoicacid (19-2) ©\/00 sec-BuLi, TMEDA;\®\ BnBrCOOH19-1 19-2 A solution of 4-cyclohexylmethyloxybenzoic acid (_1_9_-_1_)(1.00 g, 4.27 mol, 1 equiv) in tetrahydrofuran (10 mL) was added to ia solution of sec-butyllithium (1.3 M, 8.21 mL, 10.7 mol, 2. 50 equiv)and N, N, N’, N ’—tetramethy1ethylenediamine (1.61 mL, 10.7 mmol,2.50 equiv) in tetrahydrofuran (10 mL) at -100 °C (ethanol—N2(1)).The resultant orange suspension was stirred at -100 °C for 1 h, thenwarmed to -78 °C and held at that temperature for 15 min. Benzylbromide (2.00 mL, 16.8 mmol, 3.93 equiv) was added to the coldreaction mixture, causing the color to change to light yellow. Thesuspension was stirred at -78 °C for 35 min, then was poured into water(150 mL). The aqueous mixture was acidified to approximately pH 2?CA 02264037 1999-02-26W0 98/10763 ' PCT/US97/15989-84-with an aqueous 1 N hydrochloric acid solution and was extracted withethyl acetate (2 x 100 mL). The combined organic layers were driedover magnesium sulfate and were concentrated. The residue waspuri?ed by ?ash column chromatography (40% hexanes in ethyl acetateinitially, grading to 100% ethyl acetate) to afford the desired carboxylicacid _l_2-_2_ as a white solid.The coupling .L.9.i and 4-aminopyridine and subsequentreduction of the amide product were carried out as described inExample 14 to afford the final product ?gj.1H NMR (400 MHz, CDCI3), 5: 8.12 (br d, 2H, J=6.4 Hz, PyH), 7.26(m, 2H, PhH), 7.20 (in, 1H, PhH), 7.20 (d, 1H J=8.4 Hz, ArH), 7.09 (brd, 1H, J=7.1 Hz, PhH), 6.80 (d, 1H, J=2.8 Hz, ArH), 6.75 (dd, 1H,J=8.4, 2.6 Hz, ArH), 6.26 (br d, 2H, J=6.4 Hz, PyH), 4.12 (m, 3H,CHZNH and NH), 4.00 (s, 2H, ArCH2Ph), 3.73 (d, 2H, J=6.4 Hz,OCH2Cy), 1.86 (br d, 2H, J=12.8 Hz, CyH), 1.81-1.65 (m, 4H, CyH),1.37-1.13 (m, 3H, CyH), 1.05 (qd, 2H, J=12.1, 2.9 Hz, CyH); mp: 114-116°CEXAMPLE 20Preparation of 4-(4-cyclohexylmethyloxy—2-benzyloxybenzyl)amino-Dvridine (20-6) .20-6?CA 02264037 1999-02-26WO 98/10763 PCT/US97/ 15989-35-Step A: Preparation of Methyl-(4-cyclohexylrnethyloxy—2—hvdroxv)benzoate (20-2) co2cH3 B, co2cH360“ 0% CSZCO3 E:/EH+ DMFAOH 020-120-2Cyclohexylmethyl bromide (4.56 mL, 32.67 mmol, 1.1equiv) was added to a suspension of methyl 2,4-dihydroxy-benzoate (2(L_1_) (5.0 g, 29.7 mol, 1 equiv) and cesium carbonate (33.9 g, 104.1mmol, 3.5 equiv) in N, N-dirnethylformamide (100 mL) at 23°C. Thereaction mixture was heated to 70°C and was stirred at that temperaturefor 5 h. The solution was cooled to 23°C and was concentrated. Theresidue was diluted with ethyl acetate, and the resulting solution waswashed with an aqueous saturated ammonium chloride solution (2 x 25mL). The combined aqueous layers were further extracted with 50%ethyl acetate in hexane (2 x 100 mL). The combined organic layerswere dried over magnesium sulfate and were concentrated. The residuewas purified by ?ash column chromatography (3% ethyl acetate inhexanes) to afford ;Q_-_2_. TLC (30% EtOAc— hexane), Rf‘.=O.35(UV)TLC (5% EtOAc— hexane), Rf.= 0.51 (UV);1H NMR (400 MHz, CDCI3), 8: 10.94 (s, 1H, OH), 7.71 (d, 1H, J =9.52 Hz, ArI-I [ortho to CO2CH3]), 6.41 (m, 2H, ArH [meta toCO2CH3]), 3.90 (s, 3H, CO2CH3), 3.76 (d, 2H, J=6.04 Hz, OCH2Cy),1.77 (m, 6H, CyH), 1.26 (m, 3H, CyH), 1.05 (m, 2H, CyH).?CA 02264037 1999-02-26W0 98/ 10763 PCTIUS97/15989-35-Step B: Preparation of Methyl(4—cyclohexylmethyloxy-2- Ibenzvloxv)benzoate (20-3)CO2CH3 Br COZCHS0” CSZCO3 oA + DMF AO 020-2 20-3Benzyl bromide (0.216 mL, 1.81 mmol, 1.2 equiv) wasadded to a suspension of _2_()_-; (400 mg, 1.51 mol, 1 equiv) and cesiumcarbonate (1.72 g, 5.30 mmol, 3.5 equiv) in N, N-dimethylformamide(15 mL) at 23°C. The reaction mixture was heated to 70°C and wasstirred at that temperature for 2h. The solution was cooled to 23°C andwas concentrated. The residue was diluted with ethyl acetate (60 mL),and the resulting solution was washed with an aqueous saturatedammonium chloride solution (2 x 30 mL). The organic layer was driedover magnesium sulfate and was concentrated to afford the product _2_Q;_3_as a pale yellow oil which was used without further purification.1H NMR (400 MHz, CDCI3), 5: 7.87 (d, 1H, J = = 8.61 Hz, ArH[ortho to CO2CH3]), 7.53 (d, 2H, J=7.32 Hz, PhH), 7.39 (d, 2H, J: 6.95Hz, PhH), 7.32 (m, 1H, PhH), 6.53 (s, 1H, ArH [meta to CO2CH3]),6.51 (d, 1H, J=8.79 Hz, ArH [meta to CO2CH3]), 5.17 (s, 2H, CH2Ph),3.87 (s, 3H, COZCH3), 3.77 (d, 2H, J=6.22 Hz, CH2Cy), 1.85 (d, 2H,J=13.36 Hz, CyH), 1.76 (m, 4H, CyH), 1.27 (m, 2H, CyH), 1.05 (m, 2H,CyH); TLC (10% EtOAc-hexane), Rf; = 0.14 (UV)?CA 02264037 1999-02-26W0 98/ 10763 PCT /US97/15989-37-Step C: Preparation of (4-cyclohexylrnethyloxy-2-benzyl-oxvlbenzoic acid (20-4)co2cH3 co2Ho Q0NaOH1 ,4-dioxane O 020-3 20-4A solution of sodium hydroxide (302 mg, 7.55 mol, 5equiv) in water (3 mL) was added to a solution of 2Q_—_3_ (1.51 mol, 1equiv) in 1,4-dioxane (7 mL). The reaction mixture was heated atre?ux for 16 h. The solution was cooled to 23°C, and then was dilutedwith ethyl acetate (60 mL). The organic layer was washed with anaqueous 10% potassium hydrogen sulfate solution (2 x 30 mL) and wasdried over magnesium sulfate and was concentrated to afford 2Q;4_ as awhite solid, which was used without further purification.1H NMR (400 MHz, CD3OD), 5: 7.85 (d, 1H, J = = 8.79 Hz, ArH[ortho to CO2H]), 7.51 (d, 2H, J = = 7.51 Hz, PhH), 7.35 (m, 3H,PhH), 6.65 (d, 1H, J = = 2.01 Hz, ArH [meta to CO2H]), 6.57 (dd, 1H,J = = 8.79, 2.20 Hz, ArH [meta to CO2H], 5.25 (s, 2H, CH2Ph), 3.80(d, 2H, J = = 6.22 Hz, CH2Cy), 1.85 (d, 2H,J = = 14.10 Hz, CyH),1.76 (m, 4H, CyH), 1.29 (m, 3H, CyH), 1.10 (m, 2H, CyH).?CA 02264037 1999-02-26W0 98/10763 PCTIUS97/15989-88-Step D: Preparation of N-4-pyridyl-(4-cyclohexylmethylo)iy-2-benzvloxv)benzamide (20-5) J3 ° ~C|COCOCl; O4-aminopyridine020-520-4Oxalyl chloride (0.391 mL, 4.49 mol, 3 equiv) was addedto a solution of 2_0-_4_ (509 mg, 1.49 mol, 1 equiv) in dichloromethane(6 mL) at 23°C. Once gas evolution ceased (approximately 5 min afterthe addition of oxalyl chloride), the volatiles were removed in vacuo.The residue was dissolved in dichloromethane (11 mL), and theresulting solution was transferred via cannula to a suspension of 4-aminopyridine (704 mg, 7.47 mo], 5 equiv) and triethylamine (1.67mL, 11.96 mo], 8 equiv) in dichloromethane (10 mL) at 23°C. Thereaction mixture was stirred for 2 h at 23°C, then was concentrated invacuo. The residue was purified by ?ash column chromatography(15% hexanes in ethyl acetate) to afford the product 20-; as a whitesolid.1H NMR (400 MHz, CDCI3), 5: 9.99 (s, 1H, NH), 8.34 (d, 2H, J = =4.95 Hz, PyH), 8.24 (d, 1H, J = = 8.79 Hz, ArH [meta to 0CH2Cy]),7.55 (d, 2H, J = = 7.69 Hz, PhH), 7.52 (In, 3H, PhH), 7.06 (dd, 2H, J == 4.95, 1.28 Hz, PyH), 6.68 (d, 1H, J = = 8.79 Hz, ArH [ortho toOCH2Cy]), 6.65 (s, 1H, ArH [ortho to OCH2Cy]), 5.19 (s, 2H, CH2Ph),3.85 (d, 2H, J = = 6.23 Hz, CH2Cy), 1.89 (d, 2H, J = = 12.64 Hz,CyH), 1.77 (m, 4H, CyH), 1.29 (m, 2H, CyH), 1.09 (m, 2H, CyH); TLC(100% EtOAc), Rf: = 0.38 (UV)?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-39-Step E: Preparation of 4-(4-cyclohexylrnethyloxy—2-benzyl-ox benz lamino ridine 20-6oo _O4 ~49 O H / THF .20-5O40 Q, 20-6A solution of lithium aluminum hydride in tetrahydrofuran(1.0 M, 4.12 mL, 4.12 mol, 4 equiv) was added to a solution- of 20;;(430 mg, 1.03 mol, 1 equiv) in tetrahydrofuran (3 mL) at 0°C. Thereaction mixture was heated to 50°C and held at that temperature for 2h. The mixture was cooled to 0°C, and excess lithium aluminumhydride was quenched by the consecutive addition of water (0.155 mL), ‘aqueous 15% sodium hydroxide solution (0.155 mL), and water (0.467mL). The resulting aluminum salts were removed by ?ltration. Thefiltrate was concentrated, and the residue was purified by ?ash columnchromatography (0.5% methanol in chloroform saturated withammonia) to afford the product 2(_)_-6 as a white solid (mp = 131-132°C,330 mg, 80%).1H NMR (400 MHz, CDCI3), 5: 8.16 (dd, 2H, J = = 4.77, 1.46 Hz,PyH), 7.37 (m, 5H, PhH), 7.15 (d, 1H, J = = 8.24 Hz, ArH [meta toOCH2Cyl), 6.57 (d, 1H, J = = 2.02 Hz, ArH [ortho to OCH2C)']), 6.46?CA 02264037 1999-02-26WO 98/10763 PCT/US97/15989-90-(dd, 1H, J = = 3.24, 2.19 Hz, ArH [ortho to ocH2Cy]), 6.43 (dd, 2H, J= = 4.77, 1.46 Hz, PyH), 5.09 (s, 2H, CH2Ph), 4.50 (br s, 1H, NH),4.32 (d, 2H, J = = 5.86 Hz, CH2NH), 3.73 (d, 2H, J = = 6.41 Hz,CH2Cy), 1.86 (d, 2H, J = = 12.27 Hz, CyH), 1.75 (m, 4H, CyH), 1.27(m, 3H, CyH), 1.04 (m, 2H, CyH); TLC (0.5% CH3OH- CHC13 sat'dwith NH3), Rf‘. = 0.19 (UV)EXAMPLE 21Preparation of 4-{ [3-amino-4-(cyclohexylrnethyloxy)phenyl]methyl-amino lnvridine dihvdrochloride (21-6)Step A: Preparation of Ethyl 4-(cyclohexylmethyloxy)-3-nitrobenzoate (21-2)N02C61+ ——:-———-j:—>“Or:CO2Et21-1N02OK:21-2 To a mixture of ethyl 4-hydroxy-3-nitrobenzoate (QL)(2.1 lg, 10.0 mmol), cesium carbonate (6.52 g, 20.0 mmol), and sodiumiodide (O.l5g, l.0 mmol) in DMF (20 ml) under nitrogen was addedcyclohexylmethylbromide (1.67 ml, 12.0 mmol). The mixture wasstirred 48h at 60°C. The resulting mixture was evaporated underreduced pressure. To the residue was added water (100 ml), and theaqueous mixture was extracted with methylene chloride (2 x 200 ml).The organic fraction was washed with saturated sodium carbonatesolution (100 ml) and brine (100 ml), dried (sodium sulfate), and the?CA 02264037 1999-02-26W0 98ll0763 PCT/US97/15989-91-solvent was evaporated under reduced pressure. The residue wascrystallized from ether/hexane to give product _2l_-__2_ as yellow crystals,mp: 79—80°C.1H NMR (CDCI3) 5 8.49 (1H, d, J=2 Hz), 8.19 (1H, dd, J=9, 2 Hz),7.09 (1H, d, J=9 Hz), 4.39 (2H, q, J=7 Hz), 3.95 (2H, d, J=6 Hz), 1.69-1.89 (6H, m), 1.40 (3H, t, J=7 Hz), 1.06-1.38 (5H, In).Step B: Preparation of 4-(cyclohexylmethyloxy)-3—nitrobenzoicacid (21-3)To a solution of _2_g (1.38 g, 4.50 mmol) in THF (22.5ml) cooled in an ice-bath was added 1N lithium hydroxide solution(22.5 ml). The resulting solution was stirred 18h while warming toambient temperature. The solution was partially evaporated at reducedpressure, and the remaining aqueous solution was washed with ethylacetate (20 ml). The aqueous layer was cooled in an ice-bath, stirredrapidly, and concentrated hydrochloric acid (2 ml) was added dropwise,resulting in formation of a precipitate. The mixture was stirred 1h, theprecipitate was collected and dried in vacuo to give product 2_1-_3_ as awhite solid, mp: 200-202°C.1H NMR (CDCI3) 5 8.56 (1H, d, J=2 Hz), 8.24 (1H, dd, J=9, 2 Hz),7.13 (1H, d, J=9 Hz), 3.98 (2H, d, J=6 Hz), 1.70-1.90 (6H, m), 1.08-1.40 (5H, m). ‘_S_t_e_p_§_: Preparation of N-(4-pyridyl)-4-(cyclohexylmethyloxy)-3-nitrobenzamide (21 -4)N02HOb?rN \U21-4 0To a mixture of 21-3 (0.307 g, 1.1 mmol) and DMF (1drop) in methylene chloride (3 ml) under nitrogen cooled in an ice-bathwas added dropwise a solution of oxalyl chloride (0.113 ml, 1.3 mmol)?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-92-in methylene chloride (1 ml). The resulting solution was stirred 1hwith ice-bath cooling, lh at ambient temperature, then was evaporatedat reduced pressure to give crude 4-(cyclohexylrnethyloxy)-3-nitrobenzoyl chloride as an oil.To a mixture of the crude 4-(cyclohexylmethyloxy)—3-xnitrobenzoyl chloride in methylene chloride (2 ml) under nitrogencooled in an ice-bath was added dropwise a solution of 4-aminopyridine(0.282 g, 3.0 mmol) in methylene chloride (1 ml). The resultingsolution was stirred lh with ice-bath cooling, then 2h at ambienttemperature. The mixture was diluted with methylene chloride (10 ml)and washed with saturated sodium bicarbonate solution (5 ml). Theaqueous layer was extracted with methylene chloride (2 x 10 ml). Thecombined organic fractions were washed with water (10 ml), brine (10ml), dried (sodium sulfate), and the solvent was evaporated underreduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with methanolzethyl acetate(5:95), to give a solid. The solid was recrystallized from ethyl acetateto give the product 2_l_;4_ as white crystals, mp: 197-198°C.1H NMR (CDC13)8 8.57 (2H, d, J: 6 Hz), 8.37 (1H, d, J: 2 Hz), 8.14(2H, m), 7.62 (2H, d, J= 8 Hz), 7.13 (1H, d, J= 9 Hz), 3.98 (2H, d, J: 6Hz), 1.71-1.90 (6H, m), 1.08-1.38 (5H, in).Analysis calculated for C 19H21N 304C, 64.21; H, 5.96; N, 11.82Found: C, 64.18; H, 5.97; N, 11.70?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-93-§t_e;pQ: Preparation of N-(4—pyridyl)-3-amino—4-(cyclohexyl-methvloxv)benzamide (21 -5). NH2HN \O ) O U(21-5A mixture of _2L-A (0.171 g, 0.48 mmol) and 10% palladiumon carbon (0.040g) in ethanol (50 ml) was shaken on a Parrhydrogenation apparatus under hydrogen (50 psi) for 20h. The mixturewas filtered through ?lter aid and the ?ltrate was evaporated underreduced pressure to give a solid. The solid was dissolved in hot ethylacetate (50 ml), treated with charcoal, and the mixture was filteredthrough filter aid. The filtrate was evaporated to one—third volume andcooled. The resulting precipitate was collected and dried in vacuo togive product _2_l-_5 as a white crystalline solid, mp: 193-194°C.1H NMR (CDCI3) 5 8.52 (2H, d, J=6 Hz), 7.89 (1H, br s), 7.58 (2H, d,J=6 Hz), 7.25 (1H, d, J=2 Hz), 7.20 (1H, dd, J=8, 2 Hz), 6.80 (1H, d, J:8 Hz), 3.98 (2H, br s), 3.86 (2H, d, J=6 Hz), 1.66-1.91 (6H, m), 1.08-1.38 (5H, In); ‘Analysis calculated for C 19H23N302-0.10 ethyl acetateC, 69.71; H, 7.18; N, 12.57Found: C, 69.71; H, 7.17; N, 12.57?CA 02264037 1999-02-26WO 98/10763 PCT/US97/15989-94-Step B: Preparation of 4-{ [3-amino-4-(cyclohexy1methyl-ox hen lmeth lamino ridine dih drochloride 21-6 -2 HO!In a dry three-necked round bottom ?ask equipped with acondenser, nitrogen inlet, and septum, was placed a solution of 2_l;5_(0.059 g, 0.18 mmol) in anhydrous THF (2 ml). To the solution wasadded 2.0M borane-dimethylsulfide complex in THF (0.38 ml, 0.76mmol) dropwise via syringe. The resulting mixture was stirred 1h at60°C. The mixture was cooled to ambient temperature, and 6Nhydrochloric acid (1 ml) was added dropwise. The mixture was heatedin a 60°C oil-bath for ?ve minutes, cooled to ambient temperature, andpoured into saturated sodium carbonate solution ( 10 ml). The mixture 'was extracted with ethyl acetate (3 x 20 ml). The combined organicfractions were washed with brine (20 ml), dried (sodium sulfate), andthe solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting withmethanolzethyl acetate (10:90), to give a gummy solid. The solid(0.052g) was suspended in ethanol (1 ml) and ethanolic HCl (6 M, 0.065ml, 0.39 mmol) was added. The mixture was stirred, diluted with ether(10 ml), and the resulting precipitate was collected and dried in vacuoto give 2_1;6_, as a white solid, mp: 173-175°C.1H NMR (DMSO—d5) 5 9.26 (1H, t, J=6 Hz), 8.7-9.8 (2H, br s), 8.22(1H, d, J=7 Hz), 8.11 (1H, d, J=7 Hz), 7.25 (1H, s), 7.19 (1H, d, J=8Hz), 7.09 (1H, d, J=8 Hz), 7.00 (1H, dd, J=7, 2 Hz), 6.85 (1H, dd, J=7,2 Hz), 4.47 (2H, cl, J=6 Hz), 3.84 (2H, d, J=6 Hz), 3.3-4.1 (2H, br s),1.86 (2H, d, J=l2 Hz), 1.60-1.82 (4H, m), 1.11-1.32 (3H, m), 1.00-1.10(2H, m);Analysis calculated for C19H25N30-2 HCI-0.25 H20C, 58.68; H, 7.13; N, 10.81?CA 02264037 1999-02-26W0 98/10763 PCT/US97/ 15989-95..Found: C, 58.64; H, 6.99; N, 10.721.1HTlN \21-7c |-2 HCI , NStep F: Preparation of 4—{ [3-ethy1amino—4-(cyclohexylmethyl-ox hen 1 meth lamino ridine dih drochloride 21-7cStep 1: To a mixture of N-(4-pyridyl)-3-amino—4-(cyc1ohexyl—methy1oxy)benzamide (2_l_—]_a_) (0.065 g, 0.20 mmol) in methylenechloride (1 ml) under nitrogen cooled in ice-bath was added aceticanhydride (0.040 ml, 0.42 mmol). The resulting mixture was stirredwith ice-bath cooling for 2 h. The mixture was diluted with methylenechloride (4 ml), washed with 10% citric acid solution (2 ml), water (2 .ml), saturated sodium bicarbonate solution (2 ml), water (2 ml), andbrine (2 ml), dried over sodium sulfate, and concentrated in vacuo togive N-(4-pyridyl)-3-amino-4-(cyc1ohexy1methyloxy)benzamide (2E_b_)(0.060 g, 82%) as a foam. -dH(CDC13) 8.84 (1H, d, J 2 Hz), 8.52 (2H, d, J 6 Hz), 8.46 (1H, br s),7.81 (1H, br s), 7.76 (1H, dd, J9,2 Hz), 7.65 (2H, dd, J 5,1 Hz), 6.96(1H, d, J 8 Hz), 3.91 (2H, d, J 6 Hz), 2.24 (3H, s), 1.70-1.95 (6H, In),1.07-1.42 (5H, rn). _S;ep_2: Employing the procedure substantially as described for thepreparation of _2_1_-_6, but starting with ;1;_7_b (0.055g, 0.15 mmol), _2__l—_7§was obtained as a white solid, mp: 137-145°C.dH(DMSO-d6) 9.16 (1H, bs), 8.22 (1H, m), 8.13 (1H, m), 6.95-7.15(3H, m), 6.97 (1H, d, J 7 Hz), 6.87 (1H, d, J 7 Hz), 4.45 (2H, d, J 5 Hz),3.83 (2H, d, J 5 Hz), 3.4-3.8 (2H, br s), 3.18 (211, q, J7 Hz), 1.60-1.90(6H, In), 1.17 (3H, t, J7 Hz), 1.04-1.82 (5H, m).Analysis calculated for C21H29N30-2 HC1-0.50 H20?CA 02264037 1999-02-26wo 98/10763 PCT/US97/15989_ 95 -C, 59.85; H, 7.65; N, 9.97Found: C, 59.90; H, 7.49; N, 9.94°HC| I / NStep G: 4- { [3-(phenylrnethylsulfonamido)~4-(cyclohexylrnethyl-oxV)DhenVl]methvlamino lpxridine dihvdrochloride (21-7e)Step 1: To a mixture of _2_1_-La (0.065 g, 0.20 mmol) and pyridine(0.032 ml, 0.40 mmol) in methylene chloride (2 ml) under nitrogencooled in ice-bath was added alpha-toluenesulfonyl chloride (0.050 g,0.26 mmol). The resulting mixture was stirred with ice-bath coolingfor 3 h. The mixture was diluted with ethyl acetate (15 ml), washedwith saturated sodium bicarbonate solution (5 ml) and brine (5 ml),dried over sodium sulfate, and concentrated in vacuo to give a gum(0.106g). The gum was ?ash chromatographed on silica gel elutingwith ethyl acetate to give N-(4-pyridyl)-3—(phenylmethylsulfonamido)-4-(cyclohexylmethyl-oxy)benzarnide (21-7d) as a gum.dH(CDCl3) 8.55(lH, d, J 6 Hz), 8.06 (1H, bs), 8.46 (1H, br s), 7.80(1H, d, J 2 Hz), 7.71 (1H, dd, J9,2 Hz), 7.62 (2H, d, J 6 Hz),7.25-7.32(3H, In), 7.26 (2H, m), 6.94 (1H, d, J 9 Hz), 6.83 (1H, bs), 4.39 (2H, s), '3.81 (2H, d, J 6 Hz), 1.65-1.82 (6H, m), 1.13-1.33 (3H, m), 0.90-1.08(2H, In).Step 2: Employing the procedure substantially as described for thepreparation of 2_1_;§, but starting with _2__1_-_'_7g_ (0.077 g, 0.16 mmol), 21-__7_e, was obtained as a white solid, mp: 135-140°C.dH(DMSO-d6) 9.07 (1H, bs), 8.79 (1H, bs), 8.17 (2H, d, J 6 Hz), 7.26-7.35 (5H, m), 7.19 (1H, d,J 2 Hz),7.12 (1H, d, J 8 Hz), 7.03 (1H, d,J 8?CA 02264037 1999-02-26WO 98110763 PCT/US97/15989-97-Hz), 6.92 (2H, bs), 4.43 (4H, m), 3.80 (2H, d, J 6 Hz), 1.62-1.82 (6H,m), 1.12-1.30 (3H, m), 0.95-1.10 (2H, m).Analysis calculated for C26H31N303S-HCI:C, 62.20; H, 6.42; N, 8.37Found: C, 62.31; H, 6.44; N, 8.36?CA 02264037 1999-02-26W0 98ll0763 PCT/US97l15989-98-EXAMPLE 22Preparation of 4-{[3-propyl—4-(cyclohexy1methyl-ox v)DhenvHmethvlamino } nvridine (22-8)C5 C0 /DMFCOOCH3 2 3 COOCHa22-2 22-1HO/ COOCH3 EtOAc22-3HO B/ M r CSZCO3 / 22-4i\ NaOH / MeOHCOOCH322-5(,0 1. (ClCO)2/ DCE COOH 2' '-22-6 H2N‘<\:\,/NO .XV II-I LIAIHQ /THFN \Q22-7 0 ?CA 02264037 1999-02-26W0 93/10763 PCTIUS97/15989-99-Step A: Pre aration of Me h l4—all lox benzoate 22-2/\/O 22'2 COOCH3To a solution of methyl 4-hydroxybenzoate (L) (9.72 g,64.36 mmol) in 100 mL of DMF was added 24.8 g (76.0 mmol) ofCs2CO3 followed by 5.0 mL (58.5 mmol) of allyl bromide. Theresulting solution was then heated at 50°C for 5h. The solvent wasdistilled under reduced pressure and the residue was taken up in 200mL of EtOAc. The organic phasewas extracted with lL\l_ NaOH (2 x 50mL), water (5 x 50 mL) and brine (50 mL), dried (MgSO4) andconcentrated to afford product 2212 as a white solid.1H NMR (CDCI3) 5 8.00 (d, J=7.8 Hz, 2H), 6.95 (d, J=7.8 Hz, 2H),6.05 (m, 1H), 5.45 (d, 1H), 5.30 (d, 1H), 4.60 (d, J=6.4 Hz, 2H), 3.85(s, 3H). Step B: Preparation of Methyl 4-hudroxy-3-allvlbenzoate (22-3)XE)/ COOCH322-3The neat allyl ether 2;-__2_ from Step A (7.0 g, 38.6 mmol)was heated in an oil bath at 230°C for 1h. The reaction was followedby NMR and was found to be complete after 90 min. The resultingbrown oil was cooled and subjected to column chromatography (lzlEtOAc / Hexane) to afford Q; as a white solid.1H NMR (CDCI3) 5 7.80 (m, 2H), 6.90 (d, J=7.8 Hz, 1H), 6.00 (m,1H), 5.60 (s, 1H), 5.20 (s, 1H), 5.15 (d, J=6 Hz, 1H), 3.85 (s, 3H), 3.45(d, J=6.4 Hz, 2H),?CA 02264037 1999-02-26W0 93/10753 PCT/US97/15989-100-Step C: Preparation of Methvl 4-hvdroxv-3-nronvlbenzoate L22-4)fl:COOCH322-4To 1 (6.0 g, 33.2 mmol) in 50 mL of EtOAc was added60 mg of 5% Pd on carbon and the whole was hydrogenated atatmospheric pressure for 24h. Hydrogen was removed from thereaction mixture and the solution was filtered through Celite.Evaporation of the solvent afforded product L4 as a white solid.1H NMR (CDCI3) 5 7.84 (d, J=l.9 Hz, 1H), 7.79 (dd, J=2.0, 8.3 Hz,1H), 6.79 (cl, J=8.3 Hz, 1H), 5.49 (s, 1H), 3.88 (s, 3H), 2.60 (t, J=7.8Hz, 2H), 1.65 (m, 2H), 0.97 (t, J=7.3 Hz, 3H).Step D: Preparation of Methyl 4-(cyclohexylrnethyloxy)-3-provvlbenzoate (22-5)EmCOOCH322-5To a solution ofggé (915 mg, 5.0 mmol) in 10 mL ofDMF was added 1.78 g (5.50 mmol) of Cs2CO3 followed by 0.68 mL(4.9 mmol) of bromomethyl cyclohexane. The resulting solution wasthen heated at 50°C for 24h. The solvent was distilled under reducedpressure and the residue was taken up in 20 mL of EtOAc. The organicphase was extracted with lL\I_ NaOH (2 x 50 mL), water (5 x 5 mL) andbrine (5 mL), dried (MgSO4) and concentrated to afford 2&5 as anoil.1H NMR (CDCI3) 5 7.84 (dd, J=2.4, 8.8 Hz, 1H), 7.80 (d, J=2.4, Hz,1H), 6.80 (d, J=8.8 Hz, 1H), 3.87 (s, 3H), 3.80 (d, J=15.9 Hz, 2H), 2.60(t, J=7.8 Hz, 2H), 1.95-1.00 (m, 13H), 0.93 (t, J=7.3 Hz, 3H).?CA 02264037 1999-02-26wo 98/10763 PCT/US97/15989- 101 -Step B: Preparation of 4-(cyclohexylmethyloxy)-3-propylbenzoicacid (22-6)Z:/\")£>\COOH22-6To a solution of_22_-_5_ (1.0 g, 3.44 mmol) in 10 mL ofMeOH and 2 mL of THF was added 3.5 mL (14 mmol) of 4_N_ NaOH.The resulting solution was heated at 50°C for 24h, cooled and acidi?edby the addition of 15 mL of ll_\I_ HCl. The aqueous phase was extractedwith 2 x 40 mL of EtOAc. The organic extracts were washed with brine(5 mL) and dried over MgSO4. Evaporation of the solvent afforded2_2_-_6 which was used without purification.Step F: Preparation of N-(4-pyridyl)—3-propyl-4—(cyclohexyl-methvloxvlbenzamide (22-7) /O IT]N I \22-7 0 /NTo a solution of 22_-6_ (770 mg, 2.78 mmol) in 10 mL of(CH2Cl)2 and 0.05 mL of DMF was added 0.26 mL (3.05 mmol) ofoxalyl chloride. The resulting solution was heated at 50°C for 30 min,cooled to 0°C and treated with 1.20 g (13.8 mmol) of 4-aminopyridine.Stirring was continued for 2h before the heterogeneous mixture wasdiluted with 50 mL of EtOAc and quenched with 25 mL of 5%Na2CO3. The organic extract was washed with sat'd NH4Cl (3 x 50mL), water (2x 25 mL), brine (25 mL) and dried over MgSO4.Evaporation of the solvent and column chromatography (EtOAc)afforded product _2_2_?.1H NMR (CDCI3) 5 8.55 (d, J=8.0 Hz, 2H), 8.10 (bs, 1H), 7.75 (dd,J=2.4, 8.8 Hz, 1H), 7.70 (s, 1H), 7.60 (d, J=8.0 Hz, 2H), 6.85 (d, J=8.8?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-102-Hz, 1H), 3.80 (d, J=l5.9 Hz, 2H), 3.70 (s, 3H), 2.60 (t, J=7.8 Hz, 2H),1.95-1.00 (m, 13H), 0.90 (t, J=7.3 Hz, 3H),Step G: Preparation of 4-{ [3-propyl-4-(cyclohexylmethyl—oxvmhenvllmethvlamino l pvridine (22-8)22-8 I / NTo a solution of2_2_-1 (1.0 g, 2.8 mmol) in 30 mL of THFwas added 10.0 mL (10.0 mmol) of LiAlH4 ( 1M in THF) and theresulting solution was stirred at room temperature for 16 h, cooled to0°C and quenched with 1 mL of water, 1 mL of 15% NaOH then 3 mLof water. The heterogeneous mixture was diluted with 50 mL of EtOAcand washed with 3 x 5 mL of sodium potassium tartrate, water (2x 5mL), brine (5 mL) and dried over MgSO4. Evaporation of the solventand column chromatography (911 CHCI3 (sat'd NH3)/isopropyl alcohol)afforded L8.1H NMR (CDCI3) 5 8.18 (d, J=8.1 Hz, 2H), 7.10 (d, J=7.5 Hz, 1H),7.07 (s, 1H), 6.77 (d, J=7.5 Hz, 2H), 6.41 (d, J=8.1 Hz, 2H), 4.45 (bs,1H), 4.24 (d, J=15.9 Hz, 2H), 3.74 (d, J=5.1 Hz, 2H), 2.57 (t, J=7.8 Hz,2H), 2.00-1.00 (m, 13H), 0.94 (t, J=7.3 Hz, 3H);Analysis calculated for C22H3()N2OC, 78.06; H, 8.93, N, 8.28Found: C, 78.33; H, 8.99; N, 8.56?CA 02264037 1999-02-26W0 98/10763 PCT/US97ll5989- 103 —EXAMPLE 23Preparation of 4-{ [3—ethy1-4-(cyclohexylmethyloxy)phenyl]methyl-amino}Dvridine (23-8)“DOCOOCH3 23-1 CS2CO3 / DMF 23_20Br2 / Fe / HCOOH IV010° 0 Br COOCH323-3Pd(PPh3)4 / dioxane iv‘?/SnBu3 I COOCH323-40H2 / Pd (C) X\/BOA“ COOCH323-50LiOH /THF ivH20 COOH23-61. (ClCO)2 / DCM 0H2- _ W K]H2N \ ,N 23-7 I \O /NLiAlH4 / THF 2/0 H50°C [:123-3 /N© ?CA 02264037 1999-02-26W0 93/10753 PCTIUS97/15989- 104 -Step A: Preparation of Methyl 4-cyclohexylmethyloxy-benzoate(23-2)“VT:232 COOCH3To a solution of methyl 4—hydroxybenzoate Q; (24.3 g,160 mmol) in 250 mL of DMF was added 62 g (190 mmol) of Cs2CO3followed by 20.4 mL (146 mmol) of cyclohexylmethyl bromide. Theresulting slurry was then heated at 50°C for 20 h. The solvent wasdistilled under reduced pressure and the residue was taken up in 500 mLof EtOAc. The organic phase was extracted with lN_ NaOH (2 x 150mL), water (5 x 150 mL) and brine (150 mL), dried (MgSO4) andconcentrated to afford product 2_3;_2_ as a white solid.1H NMR (CDCI3) 5 7.98 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H),3.88 (s, 3H), 3.78 (d, J=6.l Hz, 2H), 2.00-1.00 (m, 11H).Step B: Preparation of Methyl 4—cyclohexylmethoxy-3—bromo—benzoate (23-3)WWI)233 Br COOCH3A solution of 232 (26.3 g, 106 mmol) was warmed on asteam bath in 110 mL of HCOOH with 592 mg (10.6 mmol) of Fepowder. Bromine (7.6 mL, 147.4 mmol) in 50 mL of HCOOH wasadded by dropping funnel over a period of 10 min. The reactionmixture was stirred an additional lh , cooled and poured onto ice. Theresulting gum was taken up in 500 mL of EtOAc and washed with sat'dNa2S203 (2 x 150 mL), water (5 x 100 mL), sat'd NaHCO3 (3 x 100mL) and brine (50 mL), dried (MgSO4) and concentrated to affordproduct 23_-3 as a white solid.1H NMR (CDCI3) 5 8.22 (s, 1H), 7.98 (d, J=8.5 Hz, 1H), 6.90 (d, J=8.5Hz, 1H), 3.88 (s, 3H), 3.78 (d, J=6.l Hz, 2H), 2.00-1.00 (m, 11 H).?CA 02264037 1999-02-26WO 98/10763 PCTIUS97/ 15989-105-Step C: Preparation of Methyl 4-cyclohexylmethyloxy—3—ethenyl-benzoate (23-4)EV“COOCH23-4 | 3To a solution of 23-3 (810 mg, 2.5 mmol) in 11.5 mL ofdioxane was added 820 mg (2.6 mmol) of vinyltributyl tin followed by58 mg (0.05 mmol) of Pd(PPh3)4. The resulting solution was thenheated at 100°C for 20 h. The solvent was distilled under reducedpressure and the residue was chromatographed to afford product 2&4,1H NMR (CDCI3) 8 8.19 (s, 1H), 7.85 (d, J=8.S Hz, 1H), 7.00 (dd, J=,1H), 6.92 (m, 1H), 5.85 (d, J=Hz, 1H), 5.35 (d, J=Hz, 1H), 3.88 (s, 3H),3.78 (d, J=6.1 Hz, 2H), 2.00-1.00 (m, 11H).Step D: Preparation of Methyl 4—cyclohexylmethy1oxy—3-ethyl-benzoate (23-5)iv‘?_,_3_5 coocnaTo 23-4 (560 mg, 2.0 mmol) in 15 mL of EtOAc wasadded 56 mg of 10% Pd on carbon and the whole was hydrogenated at 1atmospheric pressure for 24h. Hydrogen was removed from thereaction mixture and the solution was filtered through Celite.Evaporation of the solvent afforded 15 as a white solid.1H NMR (CDCI3) 5 7.84 (dd, J=2.4, 8.8 Hz, 1H), 7.80 (d, J=2.4 Hz,1H), 6.80 (d, J=8.8 Hz, 1H), 3.87 (s, 3H), 3.80 (d, J=l5.6 Hz, 2H), 2.60(q, J=7.5 Hz, 2H), 1.95-1.00 (m, 14H).?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989- 106 —Step E: Preparation of 4—cyclohexylmethyloxy—3-ethyl-benzoicacid (23-6)W023-6 COOHTo a solution of _2_§;_5_ (290 mg, 1.0 mmol) in 7.6 mL ofTHF and 10 mL of water was added 210 mg (5.0 mmol) of LiOH. Theresulting solution was stirred for 40h, then acidified by the addition of10 mL of IE HCl. The aqueous phase was extracted with 2 x 20 mL ofEtOAc. The organic extracts were washed with brine (5 ml.) and driedover MgSO4. Evaporation of the solvent afforded acid 2_3-_§ which wasused without purification.Step F: Preparation of N-(4—pyridyl)—3-ethyl-4-(cyclohexyl-methyloxyzbenzamide (23-7)0W ?gN \23-7 [O / NTo a solution of ;3_? (270 mg, 1.0 mmol) in 3.6 mL ofCH2Cl2 was added 0.13 mL (1.5 mmol) of oxalyl chloride. Theresulting solution was stirred for 1h, cooled to 0°C and treated with 380mg (4.0 mmol) of 4-aminopyridine. Stirring was continued for 1hbefore the heterogeneous mixture was diluted with CH2Cl2 andquenched with sat'd NaHCO3. The organic extract was washed withwater, brine and dried over Na2SO4. Evaporation of the solvent andcolumn chromatography (3:l EtOAc / Hexane) afforded product 2_3_—1.1H NMR (CDCI3) 5 8.55 (d, J=8.0 Hz, 2H), 8.10 (bs, 1H), 7.75 (dd,J=2.4, 8.8 Hz, 1H), 7.70 (s, 1H), 7.60 (d, J=8.0 Hz, 2H), 6.85 (d, J=8.8?CA 02264037 1999-02-26W0 98/ 10763 PCT/US97/ 15989-107-Hz, 1H), 3.80 (d, J=15.9 Hz, 2H), 2.60 (q, J=7.8 Hz, 2H), 1.95-1.00 (m,14H).§tgp_Q: Preparation of 4-{ [3—ethyl-4-(cyclohexyhnethyl-ox hen lmeth lamino ridine 23-8XV‘) 5423-8 “7©/ NTo a solution of ZZL7 (290 mg, 0.86 mmol) in 5 mL ofTHF was added 1.7 mL (1.7 mmol) of LiAlH4 (IM in THF) and theresulting solution was heated at 50°C for 2 h, cooled to 0°C andquenched with 0.07 mL of water, 0.07 mL of 15% NaOH and 0.2 ml.of water. The precipitate was filtered, concentrated and purified bycolumn chromatography (94:6:O.6 CHCI3 / IPA / NH4OH) to affordproduct _23_-8.1H NMR (CDCI3) 5 8.18 (d, J=8.l Hz, 2H), 7.10 (d, J=7.5 Hz, 1H),7.07 (s, 1H), 6.77 (d, J=7.5 Hz, 1H), 6.41 (d, J=8.1 Hz, 2H), 4.39 (bs,1H), 4.24 (d, J=l5.9 Hz, 2H), 3.74 (d, J=5.l Hz, 2H), 2.60 (q, J=7.8 Hz,2H), 2.00-1.00 (m, 14H);Analysis calculated for C21H28N2OC, 77.72; H, 8.71, N, 8.63Found: C, 77.53; H, 8.62; N, 8.56 The compounds shown in the table below are exemplarycompounds of the present invention. The range of Ki values associatedwith the specifically listed compounds is represented as follows:+ <O.l uM++ >O.1uM and <l.O uM+++ >l.O 11M and <l0.0 uM++++ >10.0 uM?CA 02264037 1999-02-26PCT/US97/15989WO 98110763-108-E we : m Eummuwmo W l®03: mm m : W : I02.. 3 m m mommummu- : I02.. one 2 : Eosb?u : 103.0: as m : EuN:u- : I0as z%sm E beam am E mmm VI —£\ ozolm2 / 2/II I mmm mqm??CA 02264037 1999-02-26PCT/US97/ 15989W0 98/10763-109-... 2 Namuiu : m : ION550-I mm : mmommummu m bmomma-0 is E m ©| : : IAU03: M: m m : IAUinfo .2.. 8... : m Nmuumu. : ION. 2 m : mmuamummu w Ifo l®no-2: 3 m m mmmuiummu m IAUas 21:5§ E L mm an E m?CA 02264037 1999-02-26PCT/U S97/ 15989W0 98/10763-110-03: mm m m $2. m 1052 S m mo m.. a lo022 Ex m mmummummo m I0.5 ufo032 3 m : m IOifoocoma: no : : mmommommu lfo I®Qmmuv no.032 mm m mmuo m : |AI|.vN. is m : mmummommo m IQ... N3 m m mmommoumo : Qas 22.52 E mm an E m?CA 02264037 1999-02-26PCT/U S97/ 15989W0 98/10763-111-$man_oo.€aim 3 m : Eommummu m {AUEmmnooro093 M: m m mmommummo m |®lom:o033 N3 m : mmummommu |© |®as 2.:.E§ em 2 an E m?WO 98/10763CA 02264037 1999-02-26PCT/US97/15989-112-, ..,,,T._.--_.-~-.. ..TABLE 4Xw N I \/ NR 1___ W X Y Z Ki (thr)C) i-amyl H H H +++1:) Ph H H H ++++O CH2OH H H H ++++/\ CH2NH2 H H H ++++/\ CHZNHCH3 H H H +++\//\ CONCH3 H H H ++++\//\ CH2CH20t H H H ++++\/ Bu/\. n-Pr piperidy H H +++\/ 1—methyl/\ n-Pr H Et H ++++\/?CAWO 98/1076302264037 1999-02-26- 113 -R W X Y(D n-Pr H HV n-Pr H H/i-butyl n-Pr H Hn-Pr H H8PCT/US97Il5989Z Ki (thr)CH3 +++H ++H +++H +++?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-114-EXAMPLE 24Preparation of N-((4-benzyloxy)phenylsulfonyl)-N’-aminomethyl-iminoninerazine (24-5)sozcuz / DMF100°C / 2 h O20» /,0s\ /—\/U C, HN NBOC\._JoEt3N / CH2Cl2 2\\ /,0S\Q E} HCI / EtOAcN -25°C4-14-\242 2-3 BOCO@/\O\\S:,O “VE3/\o K,4-4S\NNH/‘L 0 OH2N SO3H O N NH2.CF3CQQHEt3N/DMF 24-5 YNH ?CA 02264037 1999-02-26W0 98/10763 PCTIUS97/15989-115- Step A: Pre aration of 4-benz lox hen lsulfon lchloride 24-2O\\ 00To a 0°C solution of sulfonyl chloride (1.9 mL, 23.8mmol) in 2 mL of DMF was added 4.0 g (21.7 mmol) of benzyl phenylether (g1_-_l_). The resulting solution was then heated at 100°C for 2h.The reaction mixture was then cooled and poured onto crushed ice. Theaqueous layer was extracted with CH2Cl2 (x3). The combined organicextracts were dried (Na2SO4) and concentrated. Columnchromatography (95 : 5 Hexane / EtOAc) and trituration (hexane) of thepure fractions afforded 2i-2_ as a pink solid.1H NMR (CDCI3) 6 8.00 (d, J=7.8 Hz, 2H), 7.45 (m, 5H), 7.10 (d,J=7.8 Hz, 2H), 5.15 (s, 2H).Step B: Preparation of N-((4-benzyloxy)phenylsulfonyI)-N'—t—Butvloxvcarbonvlpinerazine (24-3) -O\\ /Os.’O “Wo K/N\24-3 500To a 0°C solution of _2$._2_ (250 mg, 1.0 mmol) in 3 mL ofCl-l2Cl2 was added 0.15 mL (1.1 mmol) of Et3N followed by 204 mg(1.1 mmol) of BOC piperazine. The resulting solution was allowed tostir to rt over 72h. The reaction mixture was diluted with CH2Cl2 andwashed with sat'd NaHCO3 (3 x 5 mL). The organic phase was dried(Na2SO4) and concentrated to afford product 24_-1 which was useddirectly without any purification.?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-116-1H NMR (CDCI3) 5 7.70 (d, J=7.8 Hz, 2H), 7.40 (m, 5H), 7.10 (d,J=7.8 Hz, 2H), 5.18 (s, 2H), 3.58 (t, J=7 Hz, 4H), 2.95 (t, J=7 Hz, 4H),1.40 (s, 9H).§;gp_Q: Preparation of N-((4-benzyloxy)pheny1su1fonyl)-Diperazine (24-4)O\\ ,0S.U “Wo LN24-4 H~HC|A -25°C solution of crude 24;; (390 mg, 0.94 mmol) in 10mL of EtOAc was treated with HCI gas for 5 min and then stirred for2h at this temperature. Excess HCl was displaced from the solution bybubbling N2 through the reaction mixture. The resulting solution wasconcentrated to give the amine hydrochloride as a white solid which wastriturated (EtOAc) to give product _2__4-_34_.1H NMR (CDC13) 5 7.80 (d, J=7.8 Hz, 2H), 7.40 (m, 5H), 7.20 (d,J=7.8 Hz, 2H), 5.10 (s, 21-I), 3,30 (m, 4H), 3.20 (m, 4H).Step D: Preparation of N-((4—benzy1oxy)phenylsulfonyl)-N'-aminomethvliminopinerazine (24-5)8.NCg C? NH2' CF3COOHCV ifNH_ To a -25°C solution of;4;4 (300 mg, 0.90 mmol) in 10 mLof DMF and 0.25 mL (1.79 mmol) of Et3N was added 111 mg (0.895mmol) of guanidine sulfonic acid. The resulting solution was allowed tostir to RT over 16h. The reaction mixture was concentrated and?CA 02264037 1999-02-26W0 98/ 10763 A PCT/U S97/ 15989-117-subjected to preparative HPLC to afford product 24-5 as its TFA salt.1H NMR (CD3OD) 5 7.80 (d, J=7.8 Hz, 2H), 7.40 (m, 5H), 7.20 (d,J=7.8 Hz, 2H), 5.20 (s, 2H), 3,60 (In, 4H), 3.05 (m, 4H); MS (FAB) =375;Analysis calculated for C1gH22N403S - 0.4 H20 - CF3COOHC, 48.46; H, 4.84, N, 11.30Found: C, 48.76; H, 4.69; N, 10.94EXAMPLE 25Preparation of N-((4-cyclohexylmethyloxy)-3—ethyl-phenylsulfonyl)-N‘-aminomethvliminopinerazine (25 - 1 )_2i_1_ was synthesized in the same manner as 24-5 bysubstituting 4-cyclohexylmethyloxy-3-ethylbenzene for 4-benzyloxybenzene in Step A, Example 24 .The compounds shown in the table below are exemplarycompounds of the present invention. The range of Ki values associatedwith the specifically listed compounds is represented as follows:+ <0.l ].LM++ >O.l uM and <1.0 uM+++ >1.0 uM and <10.0 uM++++ >10.0 uM?CA 02264037 1999-02-26WO 98/10763 PCT/US97/15989- 118 -R‘ NHR—CH2O SO2———N N/U\NH2L/TABLE 5R R1 Ki(thr) M mH +++ -@-—CH2CH3 ++ 237—9°?CA 02264037 1999-02-26WO 98/10763 PCT/US97/15989- 119 -EXAMPLE 26Preparation of 4-{ [4-(Pheny1methyloxy)pheny1]methyl }benzamidinehvdrochloride (26-6)Step A: Preparation of 4-[(4-Methoxyphenyl)hydroxy-methvllbenzonitrile (26-2)0” H OHH3CO | I CN H3CO CN26-126-2To a suspension of 4-(4—methoxybenzoyl)benzonitrile 261(J. Med. Chem.. 1991, 34, 2768-2778) (0.783 g, 3.3 mmol) in ethanol(35 ml) under nitrogen cooled in an ice-bath was added sodiumborohydride (0.250g, 6.6 mmol). The mixture was stirred 4h with ice-bath cooling. To the resulting solution was added saturated ammoniumchloride solution (35 ml). The mixture was partially evaporated underreduced pressure, and the resulting aqueous mixture was extracted withethyl acetate (2 x 100 ml). The combined organic fractions werewashed with brine (50 ml), dried (sodium sulfate), and the solvent wasevaporated under reduced pressure. The residue was purified by ?ashcolurrm chromatography on silica gel, eluting with ethyl acetate/hexane(1:6 increasing to 1:3), to give product 26;; as an oil.NMR 5 H(CDCl3) 7.61 (2H, d, J=8 Hz), 7.50 (2H, d, J=8 Hz), 7.23 (2H, 'd, J=9 Hz), 6.87 (2H, dd, J=9, 2 Hz), 5.82 (1H, d, 1:3 Hz), 3.79 (3H, s),2.37 (1H,bs); IR 2227 cm-1.?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-120-?§p_B: Preparation of 4-[(4-Methoxyphenyl)methy1]benzonitrile(26-3)H3CO CN26-3To a mixture of _2_6_-_2_ (0.622 g, 2.6 mmol) and sodiumiodide (1.56 g, 10.4 mmol) in acetonitrile (7 ml) at ambient temperaturein a 3—necked round bottom ?ask equipped with a nitrogen inlet andrubber septum was added dichlorodirnethylsilane (0.63 ml, 5.2 mmol)via syringe. The resulting mixture was stirred 60 min. Saturatedsodium bicarbonate solution (30 ml) was added and the mixture wasextracted with ethyl acetate (2 x 90 ml). The combined organicfractions were washed with 10% sodium thiosulfate solution (30 ml),brine (30 ml), dried (sodium sulfate), and the solvent was evaporatedunder reduced pressure. The residue was purified by ?ash columnchromatography on silica gel, eluting with ethyl acetate/hexane ( 1:6increasing to 1:5), to give product 26;; as a white solid, mp: 41.5-43.5°C.d1—1(CDCl3) 7.56 (2H, d, J: 8 Hz), 7.27 (2H, d, J: 8 Hz), 7.07 (2H, d, J:9 Hz), 6.85 (2H, d, J: 9 Hz), 3.97 (2H, s), 3.79 (3H, s).IR 2224 cm-1.Step C: Preparation of 4-[(4-Hydroxyphenyl)methyl]benzonitrile(26-4)26-4To a solution of 2_6_-3 (0.391 g, 1.75 mmol) in methylenechloride (6 ml) cooled in an ice-bath in a 3-necked round bottom ?askequipped with a nitrogen inlet and rubber septum was added 1.0Mboron tribromide in methylene chloride (3.9 ml, 3.9 mmol) via syringe.?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-121-The resulting mixture was stirred 18h while warming to ambienttemperature. Water (7 ml) was added and the mixture was extractedwith ether (35 ml). The organic fraction was washed with brine (10ml), dried (sodium sulfate), and the solvent was evaporated underreduced pressure. The residue was purified by ?ash columnchromatography on silica gel, eluting with ethyl acetate/hexane (l:5increasing to 1:3), to give product _2_6_-A as a white solid, mp: 163-164°C.6 H(CDCl3) 7.56 (2H, d, J: 8 Hz), 7.26 (2H, d, J: 8 Hz), 7.02 (2H, d,J: 8 Hz), 6.78 (2H, d, J: 8 Hz), 4.78 (1H, s), 3.96 (2H, s).IR 2230 cm-1. ’§_t§;g)_: Preparation of 4—{ [4-(Phenylmethyloxy)phenyl]-methvl lbenzonitrile (26-5)+Q.HO CN26-4 O 326-5 ICN To a mixture of _2§;? (0.105 g, 0.50 mmol) and cesiumcarbonate (0.326 g, 1.0 mmol) in dimethylformamide (1 ml) undernitrogen was added benzyl bromide (0.071 ml, 0.60 mmol). Themixture was stirred 18h at ambient temperature. The resulting mixturewas evaporated under reduced pressure. To the residue was addedsaturated sodium bicarbonate solution (15 ml), and the aqueous mixture?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-122-was extracted with methylene chloride (2 x 30 ml). The organicfraction was washed with brine (10 ml), dried (sodium sulfate), and thesolvent was evaporated under reduced pressure. The residue waspurified by ?ash column chromatography on silica gel, eluting withethyl acetate/hexane (l:6 increasing to 1:5), to give a white solid. The- solid was recrystallized from ethyl acetate/hexane to give product _2_6;5_as white crystals, mp: 110-l 11°C.5 H(CDCl3) 7.56 (2H, d, J=8 Hz), 7.32-7.44 (5H, m), 7.27 (2H, d, J=8Hz), 7.07 (2H, d, J=9 Hz), 6.92 (2H, d, J=9 Hz), 5.04 (2H, s), 3.97 (2H,S); IR 2223 cm'1;Analysis calculated for C21H17NOC, 84.25; H, 5.72; N, 4.68Found: C, 84.02; H, 5.66; N, 4.74Step B: Preparation of 4-{[4-(Phenylmethyloxy)phenyl]-methyl lbenzamidine hvdrochloride (26-6)Q“ 0 025-5 26-60 0ON HZN NHTo a solution of 26-5 (0.081 g, 0.27 mmol) in anhydrousether (4 ml) at ambient temperature in a 3-necked round bottom ?askequipped with a nitrogen inlet and rubber septum was added 1.0 _M_lithium bis(trimethysilyl)-amide in THF (0.30 ml, 0.30 mmol) viasyringe. The resulting solution was stirred 18h at ambient temperature.To the solution was added ethanolic HCl (6M, 0.18 ml, 1.1 mol, 4equivalents). The mixture was stirred 4h and the resulting precipitatewas filtered off to give a solid (0.094g). The solid was placed insaturated sodium bicarbonate solution (3 ml) and was extracted with?CA 02264037 1999-02-26W0 98/10763 PCTIUS97/ 15989-123-ethyl acetate (5 x 10 ml). The combined organic fractions were washedwith brine (10 ml), dried (sodium sulfate), and the solvent wasevaporated under reduced pressure. The residue (0.017g) wassuspended in ethanol (1 ml) and ethanolic HCl (6 M, 0.010 ml) wasadded. The mixture was stirred, diluted with ether (5 ml), and theresulting precipitate was collected. The precipitate was then stirredunder water (1 ml) for lh. The resulting solid was collected and driedin vacuo to give product 2§_-_6_, as an off—white solid, mp: 234-236°C.5 H(DMSO-d5) 9.30 (2H, br s), 9.09 (2H, br s), 7.74 (2H, d, J=8 Hz),7.32-7.47 (7H, m), 7.17 (2H, d, J=8 Hz), 6.95 (2H, d, J=8 Hz), 5.06(2H, s), 3.98 (2H, s).Analysis calculated for C21H2()N20-HCl-0.65 H20C, 69.18; H, 6.17; N, 7.68Found: C, 69.24; H, 5.93; N, 7.40EXAMPLE 27Preparation of 4- { [4-(Cyclohexylmethyloxy)phenyl]methyl }-benzamidine hvdrochloride (27-1) -+ ©\/ B’HO CN26-4Ck/O 627-1 0CN ?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-124-Step A: Preparation of 4-{[4-(Cyclohexylmethyloxy)phenyl]-methvlj benzonitrile (27-1)Employing the procedure substantially as described above,but substituting cyclohexylmethyl bromide for the benzyl bromide, thedesired compound 21;; was prepared: mp: 104-106°C;1H NMR (CDCI3) 5 7.56 (2H, d, J=8 Hz), 7.26 (2H, d, J=8 Hz), 7.05(2H, d, J=8 Hz), 6.83 (2H, d, J=8 Hz), 3.96 (2H, s), 3.72 (2H, d, J= 6Hz), 1.68-1.87 (6H, m), 1.17-1.38 (3H, m), 0.97-1.08 (2H, m); IR 2223cm-1.?tgp?z Preparation of 4-{ [4-(Cyclohexylmethyloxy)phenyl]—methvl lbenzamidine hvdrochloride (27-3)Q0 “Cg. ?g O O°HC|CN®\/O 027-3 0°HC|H2N NHEtO NH.1nto a suspension of ;7_-_1 (0.101 g, 0.33 mmol) in ethanol(3 ml) under nitrogen cooled in an ice—bath was bubbled hydrogenchloride until the mixture was saturated. The mixture was stirred 18hwhile warming to ambient temperature. To the resulting solution was?CA 02264037 1999-02-26WO 98/10763 PCT/US97/15989-125-added ether (12 ml) resulting in formation of a precipitate. Theprecipitate was collected and dried in vacuo to give ethyl 4-{ [4-(cyc1ohexylmethyloxy)pheny1]-methyl}benzimidate hydrochloride 2_7_;_2_as a white solid. NMR 5 H(DMSO-d6) 11.0-11.8 (2H, br s), 7.98 (2H, cl,J=8 Hz), 7.48 (2H, d, J=8 Hz), 7.13 (2H, d, J=8 Hz), 6.85 (2H, d, J=8- Hz), 4.57 (2H, q, J=7 Hz), 3.99 (2H, s), 3.72 (2H, d, J=6 Hz), 1.68-1.80(6H, m), 1.47 (3H, t, J=7 Hz), 1.19-1.26 (3H, m), 0.99-1.06 (2H, m).Into a suspension of 27;; (0.101 g, 0.26 mmol) in ethanol(5 ml) cooled in an ice-bath was bubbled ammonia until the mixture wassaturated. The mixture was stirred 18h while warming to ambienttemperature. The resulting solution was evaporated to one—half volumeunder reduced pressure. Addition of ether (2 ml) resulted in formationof a precipitate. The precipitate was ?ltered off. The filtrate wasevaporated under reduced pressure, and the residue was stirred underether (5 ml). The resulting precipitate was collected and dried to give asolid. The solid (0.042 g) was suspended in ethanol (1 ml) and ethanolicHCl (6 _M_, 0.025 ml) was added. The mixture was stirred, diluted withether (10 ml), and the resulting precipitate was collected and dried invacuo to give _2_7_-3, as a white solid, mp: 257-258°C.8 H(DMSO-d5) 9.1 (4H, br s), 7.73 (2H, d, J=8 Hz), 7.45 (2H, d, J=8Hz), 7.14 (2H, d, J=8 Hz), 6.84 (2H, d, J=8 Hz), 3.97 (2H, s), 3.72 (2H,d, J=6 Hz), 1.63-1.80 (6H, m), 1.15-1.30 (3H, m), 0.95-1.10 (2H, m);Analysis calculated for C21H25N20-HCl-0.40 H20C, 68.89; H, 7.65; N, 7.68Found: C, 68.84; H, 7.45; N, 7.75?CA 02264037 1999-02-26PCT/US97ll5989W0 98/10763-126-oN..~VNowuNWNOOEVMN£2 0m.o mmummommu- I 2N12:.o : :2525E:mmd . 3 I22: 2.33. ano mSm<.~E nfo u®.I >|x..mmm“(:66?CA 02264037 1999-02-26PCTIU S97! 15989W0 98/10763-127-032ooomsaomaNWNoomma?o$:-~:owed83.god‘ _,S3wasmmummu-Eu-mmummu-Eu-mmummummu-(566166?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989- 128 -EXAMPLE 28Preparation of N-(4-Dhenoxvmethvlbenzvl)amingpvridine (28-6)BrC COOH + 32 3284 DMF/r.t.COZCH3Q0 CO2CH328-3 5 E NaOH/EtOHCOZH1 )(COC|)2/cat.DM F 2) 4-APCH2C|2Q 0 2“HQ”28-5 HLAH/THF60°C)‘ $,<:N28-6 H?CA 02264037 1999-02-26W0 98/ 10763 PCT/US97/15989-129-Step A: Pre aration of meth 1 4- henox meth 1 benzoate 28-3In a round bottom ?ask under N2 was placed 28-1 (1.49 g,15.9 mmol), Cs2CO3 (5.2 g, 16 mmol), Q1-_2_ (3.6 g, 15.7 mmol) inDMF (250 ml) and the suspension stirred at room temperature. After18 h, the mixture was poured into saturated Na2CO3 and extracted withEtOAc (3x). The organic extracts were dried, filtered and conc'd todryness to yield 2_8_-_3_.1H NMR (CDCI3) 5 3.85 (3H, s), 5.05 (2H, s), 6.9 (3H, In), 7.2 (2H, d),7.45 (2H, d), 8.0 (2H, d).Step B: Preparation of 4-(ohenoxvmethvhbenzoic acid (28-4)Under N2, a mixture of 2g (4.1 g, 15.9 mmol) in EtOH(100 ml) and 5 _l\1 NaOH (100 ml) was stirred at room temperature.After 18 h, the reaction was heated at 80°C for 1/2 h, cooled to roomtemperature and then acidified with 6 _N_ HCl. The mixture wasextracted with EtOAc (3x) and the combined organic layer was washedwith brine, dried, ?ltered and concentrated to dryness. The residue wastriturated with Et2O to yield 2&4.1H NMR (d5-DMSO) 8 5.5 (2H, s), 7.35 (3H, m), 7.6 (H, m), 7.9 (2H,d), 8.35 (2H, d).Step C: Preparation of N-( 4-(phenoxymethyl)benzcarbox‘-amid0)D\'/ridine (28-51To a suspension of _2_8:{ (2.5 g, 11 mmol) in CH2Cl2 (40ml) with 4 drops of DMF was added with stirring under N2 at roomtemperature oxalyl chloride (1.7 g, 14 mmol). After 2h, the solutionwas concentrated to dryness, flushed with CHCI3 and then dissolved inCHCI3 (30 ml). This solution was then added dropwise to a suspensionof 4-aminopyridine (3.1 g, 33 mmol) in CHCI3 (50 ml). After stirringat room temperature overnight, a sat'd solution of Na2CO3 was addedand separated. The aqueous was further extracted with EtOAc (3x).The combined extracts were backwashed with H20, dried, filtered andconcentrated to dryness. The residue was chromatographed on a Still?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-130-colurrm (60 mm) and the product eluted with 10% CH3OH/CHCI3 toyield 28:5; mp: 195-197°C (EtOH-CH3OH);1H NMR (d6-DMSO) 5 5.2 (2H, s), 6.95 (1H, t), 7.03 (2H, cl), 7.3 (2H,t), 7.62 (2H, d), 7.79 (2H, d), 7.99 (2H, d), 8.48 (2H, d).Analysis calculated for C19H15N202. C 74.98, H 5.30, N 9.21Found: C 74.63, H 5.32, N 9.17Step D: Preparation of N-( 4-phenoxymethylbenzyl)amino—Qvridine (28-6)Under N2, a solution of LAH 1.0 __M in hexane (10 ml, 10mmol) was added dropwise to a suspension of 2&5 (1.75 g, 5.8 mmol)in THF (200 ml). After heating at 60° overnight with stirring, a sat'dsolution of Na2SO4 was added until a white suspension was formed.The mixture was poured through super cel and washed with EtOAc.The organic layer was washed with water and the aqueous layer furtherextracted with EtOAc (2x). The combined organic extracts were dried,filtered and concentrated to dryness. The residue was chromatographedon a Still column (40 mm) and the product eluted with 10% CH3OH-CHCI3. The hydrochloride salt was prepared from EtOH-HCI and theproduct crystallized from EtOH to yield _2_8_-6; mp: 213-215°C. Thecompound analyzed for C19H18N20-HCl; .1H NMR (d6-DMSO) 8 4.55 (2H, d), 5.05 (2H, s), 6.95 (5H, m), 7.25(2H, t), 7.4 (4H, q), 8.15 (2H, bd).Analysis calculated for C, 69.82; H, 5.86; N 8.57C, 69.82; H, 5.86; N, 8.57Found: C, 69.73; H, 5.88; N, 8.58The compounds shown in the table below are exemplarycompounds of the present invention. The range of Ki values associatedwith the specifically listed compounds is represented as follows:+ <O.l uM++ >O.1 uM and <l.0 uM+++ >1.0 uM and <l0.0 uM++++ >10.0 uM?CA 02264037 1999-02-26 wo 98/10763 PCT/US97/15989-’ 131 -TABLE 7R-X-Y CH2- R‘R X Y. R1 Ki(thr) mpM-CH2- -CH2- '— N +++ 117-9°O M-0- -CH2- -' N +++ 213-5°Q mEXAMPLE 29Preparation of 4-(2-(3-cyc1ohexylmethyloxy-pheny1)ethyl)amino-pvridine (29-6Cue29-6?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-132-Step A: Preparation of ethyl 3-hvdroxv-Dhenvlacetate (29-2)HO HOO EtOH OAOHOCHZCH329-1 29-2Sulfuric acid (0.018 mL, 0.329 mmol, 0.1 equiv) wasadded to a solution of 3-hydroxy-phenylacetic acid (E1) (500 mg, 3.29mo], 1 equiv) in ethanol (10 mL) at 23°C. The reaction mixture washeated at re?ux for 1.5 h. The solution was cooled to 23°C, then wasconcentrated. The residue was diluted with ethyl acetate, and theresulting solution was washed with water (2 x 20 mL). The organiclayer was dried over magnesium sulfate and was concentrated to affordthe product as a colorless oil _2_9;2 which was used without furtherpurification.1H NMR (400 MHz, CDCI3), 8: 7.17 (t, 1H, J = = 7.88 Hz, ArH [metato OH]), 6.83 (d, 1H, J = = 7.51 Hz, ArH [ortho to OH]), 6.78 (s, 1H,ArH [ortho to OH]), 6.74 (d, 1H, J = = 8.05 Hz, ArH [para to OH]),5.90 (br s, IH, ArOH), 4.17 (q, 2H, J = = 7.15 Hz, CO2CH2CH3), 3.57(s, 2H, CH2CO2CH2CH3), 1.26 (t, 3H, J = = 7.14 Hz, COQCHZCH3).Step B: Preparation of ethyl 3—cyclohexy1rnethy1oxy-phenylacetate(29-3LHO Bf /(S CSZCO3 O+ DMFO AOCHQCH3 OOCH2CH3 29-2 29-3?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-133-Cyclohexylmethyl bromide (0.459 mL, 3.29 mol, 1equiv) was added to a suspension of 22-_2 (592 mg, 3.29 mol, 1 equiv)and cesium carbonate (1.07 g, 3.29 mmol, 1 equiv) in N, N-dimethylformamide (6 mL) at 23°C. The reaction mixture was heatedto 70°C and was stirred at that temperature for 3h. The solution wascooled to 23°C and was concentrated. The residue was diluted withethyl acetate, and the resulting solution was washed with an aqueoussaturated ammonium chloride solution (2 x 20 mL). Organic layer wasdried over magnesium sulfate and was concentrated. The resulting oilwas purified by ?ash column chromatography (5% ethyl acetate inhexane) to afford the product as a colorless oil ;9_-3 as well asrecovered ethyl 3-hydroxy-phenylacetate.1H NMR (400 MHz, CDCI3), 5: 7.21 (t, 1H, J = 7.69 Hz, ArH [meta toOCHZCYD, 6.81 (m, 2H, ArH [ortho and para to OCH2Cy]), 6.83 (s,1H, ArH [ortho to the OCH2Cy]), 4.15 (q, 2H, J = 7.14 Hz,CO2CH2CH3), 3.74 (d, 2H, J =6.40 Hz, OCH2Cy), 3.57 (s, 2H,CH2CO2CH2CH3), 1.86 (d, 2H, .1: 12.6 Hz, CyH), 1.74 (m, 4H, CyH),1.24 (m, 3H, CyH), 1.25 (t, 3H, J=7.14 Hz, CO2CH2CH3), 1.05 (In, 2H,CyH); TLC (10% EtOAc-hexane), Rf; = 0.50 (UV)Step C: Preparation of _3-cyclohexylmethyloxy-phenylacetic acid(29-4)0% )O 1N NaOHt—BuOHAQ 029-3 OCHZCHS 29-4 OHA solution of aqueous sodium hydroxide (IN, 14 mL, 14.0mmol, 10 equiv) was added to a solution of ethyl 3-cyclohexyl-methyloxy-phenylacetate 22-3 (384 mg, 1.39 mol, 1 equiv) in amixture of t-butanol (8 mL) and water (4 mL) at 23°C. The reaction?CA 02264037 1999-02-26W0 98/10763 PCT/US97/15989-134-mixture was heated at re?ux for 2h. The solution was cooled to 23°Cand was diluted with ethyl acetate (50 mL). The organic layer waswashed with an aqueous 10% potassium hydrogen sulfate solution (2 x25 mL), then was dried over magnesium sulfate and was concentrated toafford the product _2_2;4_ as a white solid, which was used withoutfurther purification.1H NMR (400 MHz, CD3OD), 5: 7.19 (t, 1H, J= 7.88 Hz, ArH [meta toOCH2C)’]). 6.83 (s, 1H, ArH [ortho to OCH2Cy]), 6.79 (m, 2H, ArH[ortho and para to OCH2Cy]), 3.75 (d, 2H, J=6.04 Hz, OCH2Cy), 3.55(s, 2H, CH2CO2H), 1.87 (d, 2H, J: 12.5 Hz, CyH), 1.74 (m, 4H, CyH),1.29 (m, 3H, CyH), 1.10 (m, 2H, CyH).Step D: Preparation of N-4'—pyridyl-(3—cyclohexylmethyl-oxvlnhenvlacetamide (29-5)Q0 Cg. CICOCOCI;4-aminopyridineO Et3N 029-4OH H \29-5 I/ NOxalyl chloride (0.158 mL, 1.81 mol, 3 equiv) and acatalytic amount of N, N-dirnethylformamide (2 mL) were addedconsecutively to a solution of 29-4 (150 mg, 0.604 mol, 1 equiv) indichloromethane (2 mL) at 23°C. Once gas evolution ceased(approximately 2 min following the addition of the N, N-dimethylformarnide), the volatiles were removed in vacuo. The residuewas dissolved in dichloromethane (2 mL), and the resulting solution wastransferred via cannula to a suspension of 4-aminopyridine (284 mg,3.02 mo], 5 equiv) and triethylamine (0.673 mL, 4.83 mol, 8 equiv)in dichloromethane (2 mL) at 23°C. The reaction mixture was stirredfor 2.5 h at 23°C and then was concentrated in vacuo. The residue was?CA 02264037 1999-02-26WO 98/10763 PCT/US97/15989-135-diluted with ethyl acetate (50 mL), and the resulting solution waswashed with an aqueous saturated ammonium chloride solution (2 x 20mL). The organic layer was dried over magnesium sulfate and wasconcentrated. The residue was purified by ?ash columnchromatography (100% ethyl acetate) to afford 2945 as a yellow oil (36vmg, 18.4 %).1H NMR (400 MHz, CDC13 ), 5: 8.46 (dd, 2H, J =4.86, 1.56 Hz, PyH),7.36 (dd, 2H, J = 4.85, 1.56 Hz, PyH), 7.32 (t, 1H, J=7.88 Hz, ArH[meta to OCH2C)’]), 7.17 (s, 1H, Amide H), 6.88 (m, 2H, ArH [ortho toOCH2Cy]), 6.84 (d, 1H, J=1.83 Hz, ArH [para to OCH2Cy]), 3.76 (d,2H, J=6.23 Hz, OCH2Cy), 3.72 (s, 2H, CH2-amide), 1.86 (d, 2H,J=l3.l8 Hz, CyH), 1.76 (m, 4H, CyH), 1.29 (m, 3H, CyH), 1.04 (m, 2H,CyH). TLC (EtOAc), Rf‘. = 0.20 (UV).Step B: Preparation of 4-(2-(3-cyc1ohexylmethyloxy-menvl)ethvl)aminoovridine (29-6)Q. Q.H 1029-5HN HNI \ 29-6 I \A solution of lithium aluminum hydride in tetrahydrofuran(1.0 M, 0.308 ml, 0.308 mol, 4 equiv) was added to a solution of _2_9_-5(25 mg, 0.077 mo], 1 equiv) in tetrahydrofuran (2 mL) at 0°C. Thereaction mixture was heated to 50°C and was held at that temperaturefor 2 h. The mixture was cooled to 0°C, and excess lithium aluminumhydride was quenched by the consecutive addition of water (12 ul),aqueous 15% sodium hydroxide solution (12 1.11), and water (36 ul).The resulting aluminum salts were removed by filtration. The filtratewas concentrated, and the residue was purified by ?ash columnLATHFA?CA 02264037 1999-02-26W0 98/10763 PCT/US9‘7ll5989-136-chromatography (1% methanol in chloroform saturated with ammonia)to afford the product _2_9-_6_ as a pale yellow solid (mp: = 81-83°C).1H NMR (400 MHz, CDCI3 ), 6: 8.20 (dd, 2H, J =4.94, 1.47 Hz, PyH),7.23 (t, 1H, J=7.84 Hz, ArH [meta to OCH2Cy]), 6.78 (m, 3H, ArH[ortho and para to OCH2Cy]), 6.43 (dd, 2H, J=4.85, 1.56 Hz, PyH),4.15 (s, 1H, NH), 3.74 (d, 2H, J=6.22 Hz, OCH2Cy), 3.44 (q, 2H,J=6.87 Hz, CH2NH), 2.89 (t, 2H, J=6.87 Hz, CH2CH2NH), 1.87 (d, 2H,J=l3.37 Hz, CyH), 1.77 (m, 4H, CyH), 1.27 (m, 3H, CyH), 1.06 (m, 2H,CyH); TLC ( 1% MeOH-CHCI3 sat'd with NH3), Rf: = 0.27 (UV)In vitro assay for determining Droteinase inhibitionAssays of human a-thrombin and human trypsin wereperformed at 25°C in 0.05 M TRIS buffer pH 7.4, 0.15 M NaCl, 0.1%PEG. Trypsin assays also contained 1 mM CaCl2.In assays wherein rates of hydrolysis of a p-nitroanilide(pna) substrate were determined, a Thermomax 96-well plate readerwas used to measure (at 405 nm) the time dependent appearance of p-nitroaniline. sar-PR-pna (sarcosine-Pro-Arg-p-nitroanilide) was used toassay human a-thrombin (Km=125 11M) and human trypsin (Km=59nM). p-Nitroanilide substrate concentration was determined frommeasurements of absorbance at 342 nm using an extinction coefficientof 8270 cm-IM-1. 'In certain studies with potent inhibitors (Ki < 10 nM)where the degree of inhibition of thrombin was high, a more sensitiveactivity assay was employed. In this assay the rate of thrombincatalyzed hydrolysis of the fluorogenic substrate Z-GPR-afc (Cbz-Gly-Pro-Arg-7-amino-4-tri?uoromethyl coumarin) (Km=27 nM) wasdetermined from the increase in ?uorescence at 500 nm (excitation at400 nm) associated with production of 7-amino-4—trifluoromethylcoumarin. Concentrations of stock solutions of Z-GPR-afc weredetermined from measurements of absorbance at 380 nm of the 7-arnino-4-trifluoromethylcoumarin produced upon complete hydrolysisof an aliquot of the stock solution by thrombin.?CA 02264037 1999-02-26WO 98/10763 PCT/US97/15989-137-Activity assays were performed by diluting a stock solutionof substrate at least tenfold to a final concentration 0.5 Km into asolution containing enzyme or enzyme equilibrated with inhibitor.Times required to achieve equilibration between enzyme and inhibitorwere determined in control experiments. Initial velocities of product' formation in the absence (V0) or presence of inhibitor (Vi) weremeasured. Assuming competitive inhibition, and that unity is negligiblecompared Km/[S], [I]/e, and [I]/e (where [S], [I], and e respectivelyrepresent the total concentrations, of substrate, inhibitor and enzyme),the equilibrium constant (Ki) for dissociation of the inhibitor from theenzyme can be obtained from the dependence of V0/Vi on [1] shown inequation 1.Vo/Vi=1+[I]/Ki (1)The activities shown by this assay indicate that thecompounds of the invention are therapeutically useful for treatingvarious conditions in patients suffering from unstable angina, refractoryangina, myocardial infarction, transient ischemic attacks, atrialfibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis,disseminated intravascular coagulation, and reocclusion or restenosis ofrecanalized vessels.Thrombin Inhibitors - Therapeutic UsesAnticoagulant therapy is indicated for the treatment andprevention of a variety of thrombotic conditions, particularly coronaryartery and cerebrovascular disease. Those experienced in this field arereadily aware of the circumstances requiring anticoagulant therapy.The term "patient" used herein is taken to mean mammals such asprimates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats,and mice.Thrombin inhibition is useful not only in the anticoagulanttherapy of individuals having thrombotic conditions, but is usefulwhenever inhibition of blood coagulation is required such as to prevent?CA 02264037 1999-02-26WO 98/10763 PCT/US97/ 15989-138-coagulation of stored whole blood and to prevent coagulation in otherbiological samples for testing or storage. Thus, thrombin inhibitors canbe added to or contacted with any medium containing or suspected ofcontaining thrombin and in which it is desired that blood coagulation beinhibited, e.g., when contacting the mammal's blood with materialselected from the group consisting of vascular grafts, stents, orthopedicprothesis, cardiac prosthesis, and extracorporeal circulation systemsThe thrombin inhibitors of the invention can beadministered in such oral forms as tablets, capsules (each of whichincludes sustained release or timed release formulations), pills, powders,granules, elixers, tinctures, suspensions, syrups, and emulsions.Likewise, they may be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using formswell known to those of ordinary skill in the pharmaceutical arts. Aneffective but non—toxic amount of the compound desired can beemployed as an anti-aggregation agent. For treating ocular build up offibrin, the compounds may be administered intraocularly or topically aswell as orally or parenterally.The thrombin inhibitors can be administered in the form ofa depot injection or implant preparation which may be formulated insuch a manner as to permit a sustained release of the active ingredient.The active ingredient can be compressed into pellets or small cylindersand implanted subcutaneously or intramuscularly as depot injections orimplants. Implants may employ inert materials such as biodegradablepolymers or synthetic silicones, for example, Silastic, silicone rubber or _other polymers manufactured by the Dow—C0ming Corporation.The thrombin inhibitors can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.The thrombin inhibitors may also be delivered by the useof monoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The thrombin inhibitors may also be coupled?CA 02264037 1999-02-26W0 98/10763 PCTIUS97/15989-139-with soluble polymers as targetable drug carriers. Such polymers caninclude polyvinlypyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, orpolyethyleneoxide-polylysine substituted with palmitoyl residues.Furthermore, the thrombin inhibitors may be coupled to a class of‘ biodegradable polymers useful in achieving controlled release of a drug,for example, polylactic acid, polyglycolic acid, copolymers of polylacticand polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyricacid, polyorthoesters, polyacetals, polydihydropyrans,polycyanoacrylates and cross linked or amphipathic block copolymersof hydrogels.The dosage regimen utilizing the thrombin inhibitors isselected in accordance with a variety of factors including type, species,age, weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal andhepatic function of the patient; and the particular compound or saltthereof employed. An ordinarily skilled physician or veterinarian canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter, or arrest the progress of the condition.Oral dosages of the thrombin inhibitors, when used for theindicated effects, will range between about 0.1 mg per kg of bodyweight per day (mg/kg/day) to about 100 mg/kg/day and preferably 1.0-100 mg/kg/day and most preferably 1-20 mg/kg/day. Intravenously, themost preferred doses will range from about 0.01 to about 10mg/kg/minute during a constant rate infusion. Advantageously, thethrombin inhibitors may be administered in divided doses of two, three,or four times daily. Furthermore, they can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transderrnal skin patches wellknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration will,or course, be continuous rather than intermittent throughout the dosageregime.?CA 02264037 1999-02-26W0 98/ 10763 PCT/US97/ 15989-140-For example, oral tablets can be prepared which contain anamount of active compound of between 100 and 500 mg, typicallybetween 200 and 250 mg. Typically, a patient in need of thrombininhibitor compound, depending on weight and metabolism of thepatient, would be administered between about 100 and 1000 mg active' compound per day. For a patient requiring 1000 mg per day, twotablets containing 250 mg of active compound can be administered inthe morning and two tablets containing 250 mg of active compound canagain be administered in the evening. For a patient requiring 500 mgper day, one tablet containing 250 mg of active compound can beadministered in the morning and one tablet containing 250 mg of activecompound can again be administered in the evening.The thrombin inhibitors are typically administered as activeingredients in admixture with suitable pharmaceutical diluents,excipients or carriers (collectively referred to herein as "carrier"materials) suitably selected with respect to the intended form ofadministration, that is, oral tablets, capsules, elixers, syrups and the like,and consistent with convention pharmaceutical practices.For instance, for oral administration in the form of a tabletor capsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, marmitol, sorbitol and the like; fororal administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegrating agentsand coloring agents can also be incorporated into the mixture. Suitablebinders include starch, gelatin, natural sugars such as glucose or beta-lactose, com-sweeteners, natural and synthetic gums such as acacia,tragacanth or sodium alginate, carboxymethylcellulose, polyethyleneglycol, waxes and the like. Lubricants used in these dosage formsinclude sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegrators?CA 02264037 1999-02-26W0 93/10753 PCT/US97/15989-141-include, without limitation, starch methyl cellulose, agar, bentonite,xanthan gum and the like.The thrombin inhibitors can also be co-administered withsuitable anti-coagulation agents or thrombolytic agents such asplasminogen activators or streptokinase to achieve synergistic effects inthe treatment of various ascular pathologies. For example, thrombininhibitors enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion. Thrombin inhibitors may beadministered first following thrombus formation, and tissueplasminogen activator or other plasminogen activator is administeredthereafter. They may also be combined with heparin, aspirin, orwarfarin.EXAMPLE 10Tablet PreparationTablets containing 25.0, 50.0, and 100.0 mg., respectively,of the following active compound is prepared as illustrated below:4-amino-1 -(4-(1, l -diphenylmethoxy)benzylpyridinium bromideTABLE FOR DOSES CONTAINING FROM_ 25-IOOMG OF THE ACTIVE COMPOUNDAmount-mgActive Compound 25.0 50.0 100.0Microcrystalline cellulose 37.25 100.0 200.0Modified food corn starch 37.25 4.25 8.5Magnesium stearate 0.50 0.75 1.5?CA 02264037 1999-02-26W0 98/10763 PCTIUS97/15989-142-All of the active compound, cellulose, and a portion of thecorn starch are mixed and granulated to 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and the magnesium stearate. The resulting granulationis then compressed into tablets containing 25.0, 50.0, and 100.0 mg,'-respectively, of active ingredient per tablet.

Claims (14)

WHAT IS CLAIMED IS:
1. A compounds having the following structure:
and pharmaceutically acceptable salts thereof wherein X is -N(R4)-, -O-, -S-, -SO2, -SO-, -OCH2(CH2)n aryl-, or -OCH2(CH2)n C3-8cycloalkyl-, wherein n is 1 or 2;

J is -(CH2)m-, -(CH2)m NH-, -SO2NH-, -SO2(CH2)m-, -NHSO2-, -SO2-, or -(CH2)m SO2-, wherein m is 1 or 2;
R1, R2, and R4 are independently selected from hydrogen, aryl, -CO2R5, aryl C1-4 alkyl, diaryl C1-4 alkyl, dicyclo C3-8 aLkyl C1-4 alkyl, cyclo C3-8 alkyl C1-4 alkyl, , wherein R5 and R6 are independently hydrogen or C1-4 alkyl, substituted aryl with one or two substituents selected from C1-4 alkyl, C1-4 alkoxy, , wherein R5 and R6 are independently hydrogen or C1-4 alkyl, aryloxy, cyclo C3-8 alkoxy, methylenedioxy, halogen, or hydroxy, heteroaryl with one or two heteroatoms selected from N, O, and S, cyclo C3 7 alkyl unsubstituted or substituted with one or more of C1-4 alkyl, C1-4 alkoxy, benzyl, cyclohexylmethyl or aryl, a C4-10 carbocyclic or bicyclic ring, or R1 and R2 along with the carbon to which they attach form a cyclo C3-7 alkyl ring;
R3 is hydrogen, C1-4 alkyl, C1-4 alkenyl, C1-4 alkoxy, -NHR7 wherein R7 is hydrogen or C1-4 alkyl, or -NHSO2CH2aryl;

A is selected from one of the following fragments , , , , , wherein B is N or CH.
2. A compound of claim 1 having the following structure:
and pharmaceutically acceptable salts thereof wherein J is (CH2)m, (CH2)m NH, or SO2, where m is 1 or 2;

R1 and R2 are independently selected from hydrogen, aryl, or cyclo C3-7 alkyl unsubstituted or substituted with one or more of C1-4 alkyl, C1-4 alkoxy, benzyl, cyclohexylmethyl or aryl;

R3 is hydrogen, C1-4 alkyl, or C1-4 alkenyl;
A is selected from one of the following fragments , , , or , wherein B is N or CH.
3. A compound of claim 2 having the following structure:

and pharmaceutically acceptable salts thereof wherein J is CH2, CH2NH, or SO2;

R1 and R2 are independently selected from hydrogen, aryl, or cyclohexyl;
R3 is hydrogen, -CH=CH2, or -CH2CH3; and A is selected from one of the following fragments , , or .
4. A compound of Claim 3 which has the structure:

, , , , , and and pharmaceutically acceptable salts thereof.
5. A composition comprising a compound of Claim 1 and a pharmaceutically acceptable carrier.
6. A method for inhibiting thrombin in blood in a mammal comprising administering to the mammal a composition of Claim 5.
7. A method for inhibiting formation of blood platelet aggregates in blood in a mammal comprising administering to the mammal a composition of Claim 5.
8. A method for inhibiting formation of fibrin in blood in a mammal comprising administering to the mammal a composition of Claim 5.
9. A method for inhibiting thrombus formation in blood in a mammal comprising administering to the mammal a composition of Claim 5.
10. A method for inhibiting thrombin in stored blood comprising administering to the mammal a composition of Claim 5.
11. A method for inhibiting formation of blood platelet aggregates in stored blood comprising administering to the mammal a composition of Claim 5
12. A method for inhibiting formation of fibrin in stored blood comprising administering to the mammal a composition of Claim 5.
13. A method for inhibiting thrombus formation in stored blood comprising administering to the mammal a composition of Claim 5.
14. The use of a compound of Claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting thrombus formation, preventing thrombus formation, inhibiting thrombin, inhibiting formation of fibrin, and inhibiting formation of blood platelet aggregates, in a mammal.
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