CA2239508A1 - Naphthyl-substituted benzimidazole derivatives as anticoagulants - Google Patents

Abstract

Novel naphthyl-substituted benzimidazole compounds and their pharmaceutically acceptable salts are described herein. This invention is also directed to an anticoagulant composition comprising a naphthyl-substituted benzimidazole compound described herein. The novel compound or its composition has inhibitory activity against human factor Xa or IIa, thereby useful in treating a disease state mediated by factor Xa or IIa.

Description

W O 97/21437 PCTnB96/01496 NAPHTh'iYL-S~JBST1TUTED BENZlMlDAZOi_E DERIVATIVES AS
ANTI-COAGUI~NTS
., held o~ the hl.'~ liU~
The prosent invent~on is directed to naphthyl-substituted ber~ derivatives and 5 their ph~.."acet~t!c~lly accc:~LaL~le ~alts, which inhibit certain enzymes in the coagulation ~c-~acle, such as factor Xa and factor lla ILl~ru~b;~ thereby being useful as anti-~oagu~ ts. It also ralates to ph~ Jtio~l ~ u".l-oa;Lions cu. ~;~ld the derivatives or their phallll~ceutically acc~Lal~le salts, and their ....:LIIo.l:, of use.

8ACKGROUND OF Th'iE INVENTION
Factor Xa is a member of the trypsin-like serine ptoLt:ase class of enzymes. A one-to-one binding of factors Xa and Va with calcium ions and phospho::r7id forms the pruLl..u,,,bi,,ase complex which converts ~-uLlllolllbin to factor lla (Ll,,u,,,i.:.,). Tl.lu...bill, in turn, converts fibrinogen to fibrin which poly",t~ es to form insoluble fibrin.
In the coa~ ation cascade, the is,uLl,ru",bi~ se complex is the convergent poi~of the 15 intrinsic (surface activated ) and ~)~L,in:.ic Ivessel injury-tissue factor) pathways (8;ochemistry (199i), Vol. 30, p. 10363; and Cell (1988), Vol. 53, pp. 505-518). The model of the roag~lation r~c~e has been refined further with the discovery of the mode of action of tissue factor pathway inhibitor (TFPI) (Seminars in ~Jemato/ogy (1992), Vol. 29, pp. 159-1 61 ). TFPI is a circulating multi-domain serine protease ir;hibitor with three Kunitz-like domains which competes 20 with factor Va for free factor Xa. Once formed, the binary cu..-l~le7c of factor Xa and TFPI
becomes a potent inhibitor of the factor Vlla and tissue factor complex.
Factor Xa can be activated by two distinct complexes, by tissue factor-factor Vlla co,..ple~c on the "Xa burst" paLll~a~r and by the factor IXa-Vll!a co~"pl~ ,c (TENase) of the "sustained Xa" pathway in the coagulation cascade. After vessel injury, the ~Xa burst" pathway 25 is activated via tissue factor (TF~. Up regulation of the coagutation r~ ade occurs via increased factor Xa production via the "sustained Xa" pathway. Down regulation of the coaguiation c~cr~d~3 occurs with the f~.,..dLon of the factor Xa-TFPI complex, which not oniy removes factor Xa but also inhibits further factor formation via the "Xa burst" pathway. Consequently, there is a ,~ natural regulation of the coagulation cascade by factor Xa.
Published data with the proteins a~ .La:,ii7 and tick anti-coagulant peptide (TAP) ~, demonstrate that factor Xa inhibitors are ~rtica- ;ous anti-roa~~ nts (Thrombosis and Haemostasis (1992), Voi. 67, pp. 371-376; and Science (1990), Vol. 248, pp. 593-~96). The active site of factor Xa can be blocked by either a meuban;a."-based or a tight bindir7g inhibitor la Sl,~ 1 l l IJTE SHEET (RULE 21;~

CA 02239~08 1998-06-04 WO 97/21437 PCT~B96tO1496 tight binding inhibitor differs from a mechanism-based inhibitor by the lack of a covalent link between the enzyme and the inhibitor). Two types of mechanism-based inhibitors are known, reversible and irreversible, which are distinguished by ease of hydrolysis of the enzyme-inhibitor .
link (Thrombosis Res (19~t2), Vol. 67, pp. 221-231; and Trends Pharmaco/. Sci. (1987), Vol. 8, pp. 303-307). A series of guanidino compounds are examples of tight-binding inhibitors "
(Thrombosis Res. (1980), Vol. 19, pp. 339-349). Arylsulfonyl-arginine-piperidinecarboxylic acid derivatives have also been shown to be tight-binding inh;L,iLors of thrombin (Biochem. ~1984), Vol. 23, pp. 85-90), as well as a series of arylamidine-containing compounds, including 3-amidinophenylsryl derivatives (Thrombosis Res. (1983), Vol. 29, pp. 635-642) and 10 bis(amidino)benzyl cycloketones (ThrombosisRes. (1980), Vol. 17, pp. 545-548). Therapeutic utility of these compounds, however, is limited by their poor selectivity for factor Xa.

Related Disclosures European Published Patent Application 0 540 051 (Nagahara et a/.) describes aromatic amidine derivatives which are stated to be capable of showing a strong anticoagulant effect 15 through reversible i,.hiLiLion of factor Xa.
The synthesis of a,o'-bis~amidinobenzylidene)cycloalkanones and o,o'-bis(amidino-benzyl)cycloalkanones is described in Pharmazie (1977), Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as being serine protease inhibitors.

SUMMARY OF THE INVENTION

This invention is directed to compounds or their pharmaceutically acceptable salts which are anti-coagulants by inhibiting enzymes in the coagulation cascade, such as human factor Xa and factor lla (Ll-ro~llbi--), and are therefore useful as pha.l..acolo~;cal agents for the treatment of disease-states .;I.~ ;L~ ed by thrombotic activity.
Accor~ -gly, in one aspect, this invention provides compounds of formula ( R ) n ~ ~ ( I ) R, A~ ~R 4 25 wherein:
n is 0 to 3;
A is a branched or straight chain alkylene, -C~O)- or -S(O)2-;

CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 R1 is hydrogen, -oR5 or-N(R5)R6;
earh R2 is independently nitro, alkyl (optionally substituted by halo, aryl, -C(O)OR8, -C(O)NIR8)R9,-N(R8)R9),-oR5,-NIR7)R7,-N(R7)R9,-NIR8)R9,-N(R8)C(o)R7,-C(O)OR8 -C(o)N(R7)R9, -C(O)N(R8)R9, or a heterocyclyl optionally substituted by one or more ~t 5 substituents selected from the group consisting of -C(NH)N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)R8, -C(NH)N(H)C(O)OR8, -C(O)ORa, -C(O)N(R8)R9, -R10-C(O)OR8, -R10-C(O)N~R8)R9 and -S03H;
R3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8,-C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O~OR8 or-C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)mOR8 (where m is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OP03H2 and -SR8;
R4 is -C(NH)-N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)R8 or -C(NH)N(H)C(O)OR8;
each R5 is independently:
hydrogen; or alkyl optionally substituted by one or more substituents selected from the groupconsiaLing of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)pOR8 (where p is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N~R8)R9, -OP03H2 and -SR8; or aryl optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, or -C(O)N(R8)R9; or heterocyclyl optionally substituted by one or more substituents selected from the group consisting of 1-iminoalkyl, -C(O)OR8, -C(O)N(R8)R9, -C(NH)N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)OR8, -R10-C(O)OR8, -R10-C(O)N(R8)R9 and -SO ~H;
R6 is hydrogen, alkyl, -R10-C(O)OR8, -R10-C~O)N(R8)R9, -C(o)R7, or aralkyl (optionally substituted by alkyl, halo, -N(R8)R9, -C(O)OR8, or -C(O)N(R8)R9);
35 R7 is a b.dl,ched or straight chain alkylene substituted by one or more substituents sele,_led from the group consisting of halo, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8), aryloxy, aralkoxy, alkenyl, haloalkenyl, cycloalkyl, CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/01496 imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, hydroxy, -C(O)OR8 or -N(R8)R9), -C(o)OP~8~ -N(R8~R9, -C(O)N(R8)R9, -C(O)(CH2)qOR8 (where q is 1 to 4), -N(R8)C(O)R8, -N(R8)C(o)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8;
each R8 and R9 is independently hydrogen, alkyl, aryl or aralkyl; and 5 each R10 is independently a branched or straight chain alkylene;
or a pharmaceutically accepLdble salt thereof.
In another aspect, this invention provides compositions useful in treating a human having a disease-state characterized by thrombotic activity, which co.l.posiLion comprises a therapeutically effective amount of a compound of the invention as described above, or a 10 pharmaceutically acceptsble salt thereof, and a pharmaceutically ac-~epL~l~,lc excipient.
In another aspect, this invention provides a method of treating a human having adisease-state characterized by thrombotic activity, which method comprises a.l,..i.,isL,~ring to a human in need thereof a therapeutically effective amount of a compound of the invention as described above.
In another aspect, this invention provides a method of treating a human having adisease-state alleviated by the inhibition of factor Xa, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention as described above.
In another aspect, this invention provides a method of treating a human having a20 disease-state alleviated by the inhibition of factor lla (thrombin~, which method comprises ad..-i.-;stering to a human in need thereof a therapeutically effective amount of a compound of the inv~ntion as described above.
In another aspect, this invention provides a method of inhibiting human factor Xa ;n vitro or in vivo by the aclr.,in,~L.~Lion of a compound of the invention.
In another aspect, this invention provides a method of inhibiting human factor lla (thrombin) in vitro or in vivo by the admini:,L~Lion of a compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION
D~ti..iliol~s As used in the specification and appended claims, unless specified to the contrary, the 30 following terms have the meaning indicated:
"Halo" refers to bromo, chloro, fluoro or iodo.
"Alkyl" refers to a straight or brd-,c.l-ed chain monovalent radical consisting solely of carbon and hydrogen, containing no unsaturation and having from one to six carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl (1-methylethyl), n-butyl, t-butyl (1,1-dimethylethyl), sec-butyl 35 (1-methylpropyl), n-pentyl, n-hexyl, and the iike.
"Alkenyl" refers to a straight or branched chain monovalent radical consisting solely of CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/01496 carbon and hydrogen, containing unsaturation and having from one to six carbon atoms, e g., ethenyl, n-prop-2-enyl, n-prop-1-enyl, n-but-2-enyl, n-but-3-enyl, 1-methylprop-1-enyl, and the like.
"Alkylene" refers to a straight or branched chain divalent radical consisting solely of carbon and hydrogen, containing no unsaturation and having from one to six carbon atoms, e.g., methylene, ethylene, n-propylene, isopropylene (1-methylethylene), n-butylene, t-butylene (1,1-dimethylethylene), sec-butylene (1-methylpropylene), n-pentylene, n-hexylene, and the like.
"Haloalkenyl" refers to an alkenyl radical, as defined above, substituted by one or more halo atoms, e.g., 1-bromoethenyl, n-1-chloroprop-2-enyl, n-3-chloroprop-1-enyl, n-3-chlorobut-2-10 enyl, n-4-bromobut-3-enyl, 1-(chloro)methylprop-1-enyl, and the like.
"Alkoxy" refers to a radical of the formula -~i~a where Ra is alkyl as defined above, e.g., methoxy, ethoxy, n-propoxy, t-butoxy, and the like.
"Alkanol" refers to an alkane of one to five carbons which is substituted by a hydroxy radical, e.g., methanol, ethanol, isopropanol, and the like.
"Aryl" refers to the phenyl or naphthyl radical.
"Aralkyl" refers to a radical of the formula -RaRb where Ra is alkyl as defined above and Rb is sryl as defined above, e.g., benzyl.
"Aralkoxy" refers to a radical of the formula -ORC where Rc iS aralkyl as defined above, e.g., benzyloxy, (phenyl)ethoxy, and the like.
"Amidino" refers to the radicsl -CtNH)NH2.
"Heterocyclyl" refers to a stabie 5- to 10-membered monocyclic or bicyclic ring radical which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group cons; .Ling of nitrogen, oxygen and sulfur, and wherein the nitrogen, carbon or sulfur atoms may be optionally oxidized, and the nitrogen atom may be 25 optionally qual~e~"i~ed, and including any bicyclic group in which any of the above-defined heterocyclic ring radicals is fused to a benzene molecule. The heterocyclic ring radical may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
Examples of such heterocyclic radicals include, but are not limited to, pi~ idinyi, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxo~ I, azepinyl, pyrrolyl, 30 4-piperidonyl, pyrrolidinyl, pyrazolyl, py,azolid;nyl, i",idazoiyl, imidazolinyl, imiclA~ yl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxa~Olidi.,yl, indanyl, isoxazolyl, isoxaLolldillyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoQuinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benL~lLllid~olyl~ benzoxazolyl, 35 furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, b~llLolll;~ ,rl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Preferred heterocyclic radicals for the purposes of this invention are imidazolyl, piperidinyl, pyrrolidinyl, and indolyl.

CA 02239~08 1998-06-04 W O 97/21437 PC~B96/0~496 "Cycloalkyl" refers to a 5- to 7-membered ring radical containing solely carbon and hydrogen atoms and no-unsaturation, i.e., cyclopentyl, cyclohexyl, and cycloheptyl.
"Factor lla" refers to thrombin.
"DEAD" refers to diethyl azodicarboxylate.
"THF" refers to tetrahydrofuran.
"HPLC" refers to high pressure liquid chromotagraphy.
"DMF" refers to dimethylformamide.
"Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or 10 circumstance occurs and instances in which it does not. For example, "heterocyclyl optionally substituted by one or more substituents selected from the group consisting of 1-iminoalkyl, -C~O)OR8, -C(O)N(RB)R9, -C(NH)N~R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)OR8, -R1 0-C(O)OR8, -Rl0-C(O)N(R8)R9 and -SO31t" means that the heterocyclic radical, as defined above, may or may not be substituted by the listed substituents and that this desc,iylion includes both substituted 15 heterocyclic radicals and heterocyclic radicals having no substitution. In addition, it is understood that the various substitutions must be feasibly possible, within the realm of knowledge of a chemist of ordinsry skill in the art and result in stable compounds.
"Pharmaceutically acceptable salt" includes both acid and base addition salts.
"Pharmaceutically accep~ acid addition salt" refers to those salts which retain the 20 biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic 25 acid, methanesulfonic acid, ~LIIanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
"Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an i"u,~anic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, 30 potassium, lithium, ammonium, calcium""a~l,esium, iron, zinc, copper, ma,.ganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from orgsnic bases include, but are not limited to, salts of ,, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, 35 trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, Iysine, arginine, histidine, caffeine, proc ,e, hydrabamine, choline, betaine, ethylenediamine, glutosd",:.,e, CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/01496 methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine.
"Therapeutically effective amount" refers to that amount of a compound of formula (I) 5 which, when administered to a human in need thereof, is sufficient to effect treatment, as defined below, for disease-states alleviated by inhibition of factor Xa or factor lla. The amount of a compound of formula (l) which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease-state and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his 10 own knowledge and to this disclosure.
"Treating" or "treatment" as used herein cover the treatment of a disease-state in a human, which disease-state is alleviated by inhibition of factor Xa or by factor lla; and include:
(i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet been diagnosed as having it;
~ii) inhibiting the disease-state, i.e. ~ sLi~g its development; or (iii) relieving the disease-state, i.e., causing r~y,e;,a;on of the disease-state.
The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield.
The compounds of the invention, or their pharmaceutically accepLable salts, may have 20 asymmetric carbon atoms in their structure. The compounds of the invention and their pharmaceutically scceptable salts may Lhe~fur~: exist as single aL~ oisomers~ racemates, and as mixtures of enantiomers and diasLel~o",ers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of this invention.
In addition, the compounds of the invention may exist as individual regioisomers or 25 mixtures thereof.
The nomenclature used herein for the compounds of the invention is basically a modified form of the l.U.P.A.C. system, wherein the compounds are named as derivatives of benzimidazole with the following numbering system:
( R ) n R 7 A_~ ~ R

A-,corclingly, a compound of the invention selected from formula (I) wherein A is 30 methylene, n is 1, R1 j5 piperidin-4-yloxy substituted on the nitrogen by 1-iminoethyl, R2 jS

W 097/21437 PCT~B96/01496 hydrogen, R3 is isopropyl and R4 is -C(NH)NH2, i.e,, ~ NX N H

[~ "~ ~ N H 2 J~
HtC NH

is named herein as 1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazoie; and wherein its regioisomer, i.e., ~ r N H 2 n> < N H
N

H3C ~NH

Is named herein as 1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-5-(N-11-iminoethyl)piperidin-4-5 yloxy)benzi.~ 7O'Q.

Utility and f~ lr '_n A. Utility The compounds of the invention are inhibitors of factor Xa and factor lla and therefore useful as anti-coagulsnts in treating disease-states characterized by thrombotic activity based on 10 factor Xa's or factor lla's role in the coagulation cascade ~see Background of the Invention above). A primary indication for the compounds is prophylaxis for long term risk following myocardial infarction. Additional indications are prophylaxis of deep vein thrombosis (DVT) CA 02239~08 1998-06-04 WO 97t21437 PCT~B96/01496 following orthopedic surgery or prophylaxis of selected patients following a transient ischemic attack. The compounds of the invention may also be useful for indications in which coumadin is currently used, such as for DVT or other types of surgical intervention such as coronary artery bypass graft and percutaneous transluminal coronary angioplasty. The compounds are also useful for the treatment of thrombotic complications associated with acute promyelocytic leukemia, .et~c~ multiple myelomas, disseminated intravascular coagulation associated with septic shock, purpura fulminanas associated infection, adult les,~ Lory distress syndrome, unstable angina, and thrombotic complications associated with aortic valve or vascular prosthesis. The compounds are also useful for prophylaxis for thrombotic rliseaces, in particular in patients who have a high risk 10 of developing such disease.
In addition, the compounds of the invention are useful as in vitro diagnostic reagents for inhibiting factor Xa or factor lla in the coagulation cascade.

B. Testing The primary bioassays used to demonstrate the inhibitory effect of the compounds of the 15 invention on factor Xa or factor lla are simple chromogenic assays involving only serine protease, the compound of the invention to be tested, substrate and buffer (see, e.g., Thromoosis Res.
(1979), Vol. 16, pp. 245-254). For example, four tissue human serine prc,L~ases can be used in the primary bioassay, free factor Xa, prothrombinase, thrombin (factor lla) and tissue plasminogen activator (tPA). The assay for tPA has been successfully used before to 20 demonstrate undesired side effects in the inhibition of the fibrinolytic process (see, e.g., J. Med.
Ch~m. (1993), Vol. 36, pp. 314-319).
Another bioassay useful in demonstrating the utility of the compounds of the invention in inhibiting factor Xa demonstrates the potency of the compounds against free factor Xa in citrated plasma. For example, the anticoagulant efficacy of the compounds of the invention will be tested 25 using either the prothrombin time (PT), or activated partial thromboplastin time (aPTT) while selectivity of the compounds is checked with the thrombin clotting time (TCT) asssy. Correlation of the K; in the primary enzyme assay with the Kj for free factor Xa in citrated plasma will screen against compounds which interact with or are inactivated by other plasma components.
Correlation of the Kj with the t:,~Lension of the PT is a necessary in vitro demonstration that 30 potency in the free factor Xa inhibition assay translates into potency in a clinical coagulation assay. In addition, extension of the PT in citrated plasma can be used to measure duration of action in subsequent pharmacodynamic studies.
For further information on assays to demonstrate the activity of the compounds of the invention, see R. Lottenberg et a/., Methods in ~nzymology (1981), Vol. 80, pp. 341-361, and 35 H. Ohno et al., Thrombosis Research (1980), Vol. 19, pp. 579-588.

CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 C. General A~ Iiun Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, adminisL,dlilJn 6 can be, for example, orally, nasally, parenterally, topically, transdermally, or rectally, in the form of solid, semi-solid, Iyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin ~:~psulec, powders, solutions, suspensions, or aerosols, or the like, pll rt,dbly in unit dosage forms suitable for simple administration of precise dosages. The compositions will include a conventional pharmaceutical carrier or excipient and a 10 compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adluvants, etc.
Generally, depending on the intended mode of ad.,.inial alion~ the pharmaceutically accepldble compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically a~ceplable salt thereof, and 99% to 1% by weight of a suitable 15 pharmaceutical excipient. Pre~erably, the co~,po~ilion will be about 5% to 75% by weight of a compoundls) of the invention, or a pharmaceutically acce~lal)le salt thereof, with the rest being suitable pharmaceutical e~ , lls.
The preferred route of ad.l.i..isl.dlion is oral, using a convenient daily dosage regimen which can be adjusted accor ling to the degree of severity of the disease-state to be treated. For 20 such oral ad.";l,i2,l,dlion, a pharmaceutically acceptable composition containing a compound(s) of the invention, or a pharmaceutically accepLdble salt thereof, is formed by the incorporation of any of -tb~e normally employed t:, cifJienl ;, such as, for exa."ple, phâllllaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccha-il~e, talcum, cell~ ose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Such 25 compositions take the form of solutions, suspensions, tablets, pills, c~rs~ les powders, sustained release formulations and the like.
Ple:relaLly such co-,-poaiLions will take the form of capsule, caplet or tablet and therefore will also contain a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a d;sinlt:~ldl.l such as ctuscallllellose sodium or derivatives thereof; a lubricant such as magnesium 30 stearate and the like; and a binder such as a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like.
The compounds of the invention, or their pharmaceutically accep~able salts, may also be formulated into a suppository using, for example, about 0.5% to about 50% active ingredient dicrosed in a carrier that slowly dissolves within the body, e.g., polyoxyethylene glycols and 35 polyethylene glycols (PEG~, e.g., PEG 1000 (96%) and PEG 4000 (4%J.
Liquid pharmacsutically admi"; .l, Is compositions can, for example, be prepared by dissolving, dispersing, etc., a compound(s) of the invention (about 0.5% to about 20%), or a CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/01496 pharmaceutically acceptable salt thereof, and optional pharmaceutical adiuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glyceroi, ethanoi and the like, to thereby form a solution or suspension.
If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remingron's Pharm~ceutical Sciences, 1 8th Ed., (Mack 10 Publishing Company, Easton, Pennsylvania, 1990). The composition to be adl"i";~ d will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically accepldble salt thereof, for treatment of a disease-state alleviated by the inhibition of factor Xa in accordance with the teachings of this invention.
The compounds of the invention, or their pharmaceutically acceplt,ble salts, are15 ad~"il,i5leled in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of &dlllin;~laliun, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. Generally, a therapeutically effective daily dose 20 is from about 0.14 mg to about 14.3 mg/kg of body weight per day of a compound of the invention, or a pharmaceutically acce~ e salt thereof; p~rt:.ably, from about 0.7 mg to about 1 0~~g/kg of body weight per day; and most preferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day. For example, for ad", ~ ,dlion to a 70 kg person, the dosage range would be from about 10 mg to about 1.0 gram per day of a compound of the invention, or a 25 pharmaceutically acceptable salt thereof, pl~7~elaiJiy from about 50 mg to about 700 mg per day, and most ~ rt:,ably from about 100 mg to about 500 mg per day.

r, .:f~ d Embod ru~
Of the compounds of the invention as set forth above in the Summary of the ~nvention, several groups of compounds are plt:re"ed.
One preferred group is that group of compounds of formula ~I) wherein n is 0 or 1; A is alkylene; Rl is -oR5 or-N(R5)R6; each R2 is independently nitro, alkyl (optionally substituted by -C(O)OR8), -oR5, -N(R7)R9, -C(o)oR3, -C(O)N(R8)R9 or piperidinyl optionally substituted by -C(O)OR8 or -Rl0-C(O)OR8: R3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, -C(O)OR8, or -C(O)N(R8)R9; R4 is 35 -C(NH)NH2; each R5 is independently hydrogen; or alkyl optionally substituted by one or more substituents selected from the group consisting of -C(O)OR8, -C(O)N(R8)R9 and phenyl (optionally CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 substituted by -C(O)OR8); or piperidinyl or pyrrolidinyl, each optionally substituted by 1-iminoalkyl, -C(NH)N(R8)R9, -R10-C(OJOR8 or -S03H; R6 is hydrogen, alkyl, benzyl (optionally substituted by -C(O)OR8), -R10-C(O)OR8, -R10-C(O)N(R8)R9 or -C(o)R7; R7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of -C(O~OR8 5 and aryl ~optionally substituted by -C~O~OR8); each R8 and R9 is independently hydrogen or alkyl;
and each R10 is independently a branched or straight chain alkylene.
Of this group of compounds, a preferred subgroup of compounds is that subgroup wherein n is 0 or 1; A is methylene: R1 is -oR5 or -N(R5)R6; R2 ;5 independently nitro, methyl (substituted iby -C(O)OR8), -oR5, -N(R7)R9, -C(O)OR8, -C(O)N(R8)R9 or piperidinyl optionally substituted by 10 -C(O)OR8 or -R10-C(O)OR8; R3 is hydrogen or alkyl optionally substituted by -C(O)OR8 or -C(O)N(R8)R9; R4 is -C(NH)NH2; each R5 is independently hydrogen; or alkyl optionally substituted by -C(O)OR8, -C(O)N(R8)R9 or phenyl (optionally substituted by -C(O)OR8); or piperidinyl optionally substituted by 1-iminoalkyl, -R10-C(O)OR8 or -S03H; R6 is hydrogen, alkyl, benzyl (optionally substituted by -C(O)OR8) or -R10-C(O)OR8; R7 is a branched or straight chain alkylene substituted 15 by one or more substituents selected from the grotip consisting of -C(O)OR8 and aryl (optionally substituted by -C(C~)OR8); each R8 and R9 is independently hydrogen, methyl or ethyl; and each Rl~ is independently a branched or straight chain alkylene.
Of this subgroup of compounds, a pr~r~ d class of compounds is that class wherein n is 0; A is methylene: R1 is -oR5; R3 is hydrogen or alikyl optionally substituted by -C(O)OR8 or 20 -C(O)N(R8)R9; R4 is -C(NH)NH2; R5 is piperidinyl optionaliy substituted by 1-iminoalkyl; and R8 and R9 are independently hydrogen, methyl or ethyl.
Of this class of compounds, the following compounds are more preire.,ùd:
1 -(4-amidinonaphth- 1 -yl)methyl-2-methyl-6-(N-( 1 -iminoethyl)piperidin-4-yloxybenzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(N-( 1 -iminoethyl)pi~.e~ i.li. ~-4-yloxybenzimidazole, 25 1-(4-amidinonaphth-1-yl)methyl-2-methyl-6-(N-~1-iminoethyl)p:, - id;.l-3-yloxybenzimidazole, 1-~4-amidinonaphth-1-yl)methyl-2-ethyl-6-(N-(l-iminoethyl)piperi, in-4-ylox~-,el. i...idazole, 1 -~4-amidinonaphth-1 -yl)methyl-2-ethyl-5-(N-~1 -iminoethyl)piperidin-4-yloxybenzimidazole, 1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-6-(N-(1-iminoethyl)pi~ lidi.,-4-yloxybenzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-5-~N-~1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 30 1 -~4-amidinonaphth- 1 -yl)methyl-2-t-butyl-6-(N-( 1 -iminoethyl)pi~.u, idin-4-yloxy) benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-t-butyl-5-(N-(1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-6-(N-( 1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 1-(4-amidinonaphth-1-yl)methyl-5-(N-(l-iminoethyl)piperidin-4-yloxy)b8llcill-;d~ ~18, 1 -(4-amidinonaphth-1 -yl)methyl-2-propyl-6-(N-(1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 35 1-(4-amidinonaphth-1-yl)methyl-2-propyl-5-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole, 1 -~4-amidinonaphth-1 -yl)methyl-2-propyl-6-(piperidin-4-yloxy)ber ci,--id~ Gle,1 -(4-amidinonaphth-1 -yl)methyl-2-propyl-5-(piperidin-4-yloxy)benzimidazole, CA 02239~08 1998-06-04 W O 97/21437 PCTn~96/01496 1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-6-(piperidin-4-yloxy)benzimidazole,1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-5-(piperidin-4-yloxy)benzimidazole,1 -(4-amidinonaphth-1 -yl)methyl-2-sec-butyl-6-(N-( 1 -iminoethyl)piperidin-4-yloxy)benZimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-sec-butyl-5-(N-(1 -iminoethyl)piperidin-4-yloxy~benzimidazole, 1-(4-amidinonaphth-1-yl)methyl-2-n-butyl-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-n-butyl-5-(N-(1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-(2-carboxyethyl)-6-(N-( 1 -iminoethyl)piperidin-4-yloxy) benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-(2-carboxyethyl)-5-(N-( 1 -iminoethyl)piperidin-4-yloxy)benzimidazole, and 1 -(4-amidinonaphth-1 -yl)methyl-2-(2-aminocsrbonylethyl)-6-(N-( 1 -iminoethyl)piperidin-4-yloxy)benzimidazole.
Of the subgroup of compounds, another preferred class of compounds is that classwherein n is O; A is methylene; R1 is -N(R5)R6; R3 is hydrogen or methyl; R4 is -C(NH)NH2; R5 is 15 piperidinyl optionally substituted by 1-iminoalkyl; R6 is hydrogen, -R10-C(O)OR8 or -C(O)N(R8)R9;
R8 and R9 are independently hydrogen or methyl; and Rl~ is a branched or strsight chain alkylene.
Of this class of compounds, the following compounds are more pr~:ter,ed:
1-(4-amidinonaphth-1-yl~methyl-6-(N-(1-iminoethyl)piperidin-4-yl)d,l ' ~obellzimidazole, 1 -14-amidinonaphth-1 -yl)methyl-2-methyl-6-(N-(N'-( 1 -iminoethyl)piperidin-4-yl)-N-((methoxycarbonyl)methyl)amino)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-6-(N-(N'-(1 -iminoethyl)piperidin-4-yi)-N-((aminocarbonyl)methyl)amino)benzimidazole, 1 -(4-smidinonaphth-1 -yl)methyl-2-methyl-6-(N-(N'-(1 -iminoethyl)piperidin-4-yl)-N-(3-carboxypropyl)amino)benzimidazole, 25 1-(4-amidinonsphth-1-yl)methyl-2-methyl-6-(N-(N'-(1-i",inoeLl,yl)piperidin-4-yl)-N-(2-(methoxycarbonyl)propyl)amino)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-6-(N-(N'-(1 -iminoethyl)piperidin-4-yl)-N-(2-(carboxy~propyl)amino)ben~;"~ ~a -le; and 1 -(4-amidinonaphth-1-yl)methyl-2-methyl-5-(N-(N'-(1 -il--illo~zLl,~l)p;,~e,idin-4-yl)-N-(2-(carboxy)propyl)amino)benzimidazole.
Of the subgroup of compounds, another preferred class of compounds is that classwherein n is 1; A is methylene; R1 is -oR5; R2 is nitro, -ORs, -N(R7)R9, -C(O)OR8, or piperidinyl (optionaliy substituted by -C(O)OR8); R3 is methyl or 1-isopropyl; R4 is -C(NH)NH2; each R5 is independently hydrogen or alkyl optionally substituted by -C(O)OR8, -C(O)N(R8)R9, aryl (optionally 35 substituted by -C(O)OR8), or piperidinyl ~optionally substituted by -R10-C(O)OR8 or 1-iminoethyl);
R7 is a branched or straight chain alkylene substituted by -C(O)OR8 or phenyl (optionally substituted by -C(O)OR8); and each R8 and R9 is independently hydrogen or methyl.

CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/01496 Of this class of compounds, the foliowing compounds are more preferred:
1 -t4-amidinonaphth-1 -yi)methyl-2-methyl-5-hydroxy-6-~N-( 1 -iminoethyl)piperidin-4-yloxy) benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-taminocarbonyl)methoxy-6-(N-t 1 -imino-ethyl)piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5~(carboxy)methoxy-6-(N-(1 -imino-ethyl)piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(4-(methoxycarbonyl~benzyloxy)-6-tN-( 1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 10 1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-t4-(carboxy)benzyloxy)-6-(N-( 1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-carboxy-6-(N-(1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(3-(methoxycarbonyl)benzyloxy)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(3-(carboxy)benzyloxy)-6-(N-tl-iminoethyl)~ ,e,i ii,--4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(methoxycarbonyl)methoxy-6-(N-( 1 -imino-ethyl)piperidin-4-yloxy)benzimidazole, 20 1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(1-(aminocarbonyl)ethoxy)-6-(N-tl-imino-ethyl)piperidin-4-yloxy)benzimidazole, ,amidinonaphth-1 -yl)methyl-2-methyl-5-( 1 -(methoxycarbonyl)ethoxy)-6-(N-( 1 -imino-ethyl)piye,i iill-4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(1 -(carboxy)ethoxy)-6-(N-(1 -imino- ethyl)pipe,idil~-4-yloxy)ben i,-lidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-4-methoxy-6-(pi~eridin-4-yloxy)benzimidazole, 1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-7-methoxy-5-(~, i ii-l-4-yloxy)ben ;-,-ida ole, 1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyi-4-methoxy-6-(N-(1 -iminoethyl)piperidin-4-yloxy)ben~i" ,idazole, 301-(4-amidinonaphth-1-yl)methyl-2-isopropyl-7-methoxy-5-(N-(1-iminoethyl)pi --i ~-4-yloxy)ben i...ids ~ la, 1 -(4-amidinonaphth- 1 -yl)methyl-2-methyl-5-(N-(4-carboxy~benzylamino~-6-(N-(1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth- 1 -yl~ methyl-2-isopropyl-4-(4-carboxy~ " i ii"-1-35yl)-6-(N-(1-iminoethyl~piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth- 1 -yl~methyl-2-isopropyl-4-(carboxy)methoxy-6-(N-( 1 -imino-ethyl)piperidin-4-yloxy)ben i.-,id~ole, CA 02239~08 1998-06-04 WO 97/21437 PCT~B96101496 1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-7-nitro-6-(N-(1 -imino-ethyl)piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth- 1 -yl)methyl-2-methyl-7-nitro-6-(N-( 1 -imino-ethyllpiperidin-4-yloxy~benzimidazole, 1-(~amidinonaphth-1-yl)methyl-2-isopropyl-5-(N-(2-carboxyprop-2-yl)amino)-6-(N-( 1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-5-(N-~4-carboxy)benzylamino)-6-(N-(1 -iminoethyllpiperidin-4-yloxy)benzimidazole, 1 -(~amidinonaphth-1 -yl)methyl-2-isopropyl-5-~N-(2-carboxyethyl)amino)-6-(N-(1-iminoethyl)pipeddin-4-yloxy)benzimidazole~ and 1 -(4-amidinonaphth- 1 -yl)methyl-2-methyl-5 -(N-(carboxymethyl)piperidin-4-yloxy) -6-(N-(1 -iminoethyl)piperidin-4-yloxy)benzimidazole.
Of the subgroup of compounds, a preferred class of compounds is that class wherein n is 1; A is methylene; R1 is -N(R5)R6; R2is-C(O)OR8 or -C(O)N(R8)R9; R3is 1-isopropyl; R4is 15 -C(NH)N~12; R5is piperidinyl optionally substituted by 1-iminoethyl; R6 j5 hydrogen; and each R8 and R9is independently hydrogen or methyl.
Of this class of compounds, the following compounds are more prere.,~:d:
1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-4-carboxy-6-(N-( 1 -iminoethyl)piperidin-4-ylamino)benzimidazole, and 20 1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-4-aminocarbonyl-6-(N-( 1 -iminoethyl)piperidin-4-ylamino)benzimidazole.

P~.,pa..~tiun of Compounds of The invention In the following Reaction Schemes, only one ~~:y;oison,er is shown as being prepared, although one of ordinary skill in the art, having the full di~clc!sure of this specification, including 25 the Preparations and Examples, would realize that certain steps in the Reaction Schemes result in mixtures of regioisomers, which can be separated and isolated by conventional techniques.

A. Prepnration of Compounds of Formulae (la) and ~Ib~.
Compounds of formulae (la) and (Ib) are compounds of the invention and are prepared as shown below in Reaction Scheme 1 wherein A is a branched or straight chain alkylene, -C(0)- or 30 -S(0)2-; R2 ;5 alkyl (optionally substituted by halo, aryl, -C(O)OR8, -C(O)N(R8)R9, -N(R8)R9), -oR5, -N(R7)R7,-N(R7)R9,-N(R8)R9,-N(R8)C(o)R7,-C(o)oR8~-C(o)N(R7)R9~-c(o)N(R8)R9; R3ishydrogen or alkyl optionally substituted by one or more substituents s~ected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, 3~ -N(R8)R9, -C~O)OR8, -C(O~N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, CA 02239~08 1998-06-04 W 097/21437 PCT~B96/01496 -N~R8)R9, -C(O)OR8, -C~o)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyi, indolyl, adamantyl ~optionally substituted by halo, alkyl, -N(R8)R9, -CIO)OR8 or -C(o)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)mOR8 (where m is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -NtR8~C(NH)N(R8)R9, -OP03H2 and -SR8; Rs j5 independently hydrogen; or alkyl optionally 5 substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(o)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(o)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by 10 halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)pOR8 (where p is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OP03H2 and -SR8; or aryl optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, or -C(O)N(R8)R9; R7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, aryl (optionally substituted by alkyl, 15 hydroxy, halo, -N(R8)R9, -C(O)OR8), aryloxy, aralkoxy, alkenyl, haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, hydroxy, -C(O)OR8 or -N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C~O)(CH2)qOR8 (where q is 1 to 4), -N(R8)C(O)R8, -N(R8)C(o)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OP03H2 and -SR8; each R8 and R9 is as described above in the Summary of the Invention; R11 is hydroxy or halo; and X is halo and W is a 20 protecting group for nitrogen such as tert-butoxycarbonyl:

W O 97/21437 PCT~B96/01496 Re&~ S~heme 1 N H ~

(2) R 3--C ( O ) R ~ ~ ~N\~--R 3 ' . Protec I N
HO W
( 3 ) R 3 ~ ~ N\? R 3 ( 4 ) ~ W ~~ H

W W
(s) (6) J fl ~CN

W (8) CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 R~ac~ion Scheme 1 continued S ( ~ ">~ ~ H

~ ~ , ~/ ( I b ) HN~NH2 Compounds of formulae (1), (4) and (7) are commercially available, for example, from Aldrich Co., or may be prepared acco.~ling to methods known to one skilled in the art.
Compounds of formula ~7) may also be prepared accordi,-g to the methods disclosed in European 5 Published Patent ~Fplic t;~n 0 540 051.
In general, compounds of formulae (la) and (Ib) are prepared by first treating a compound of formula (1) in a r~rotic solvent, preferably, methanol, with a hydrogenating agent, for example, with palladium on carbon in the presence of hydrogen, for 1 to 24 hours, pn~ rdbly, for 12 hours, with vigorous shaking. The compound of formula (2) is isolated from the reaction mixture by first treating the reaction mixture with a strong acid, pr~r~.dl~l~ 4N HCI, followed by filtration and concenL~dl;on.
The compound of formula (2) so formed is then dissolved in an aqueous acidic solvent, such as 4N aqueous HCI, and then an excess molar amount of the compound of formula R3-C(o)R1 1 where R1 t j5 hydroxy is added to the solution. The resulting reaction mixture is refluxed for 2 to 16 hours, preferably for 12 hours, and then basified, preferably with potassium bicarbonate, at ambient temperature. The product is isolated from the reaction mixture through extraction and evaporation to yield the unprotected analog of the compound of formula (3). The analog is dissolved in an aprotic solvent, p~er~.dbly tetrahydrofuran, and treated with di-tert-butyldicarbonate, at ambient temperature, for 2 to 12 hours, prerelably for 3 hours. The CA 02239~08 1998-06-04 WO 97/21437 PCTnB96/01496 compound of formula (3~ is isolated from the reaction mixture by aqueous extraction, followed by column chromatography.
Alternatively, the compound of formula (2) is dissolved in an aprotic solvent, preferably pyridine, and then treated with the compound of formula R3-C(o)R1 1 where R1 1 is chloro. The resulting reaction mixture is stirred for 4 to 16 hours, preferably for 16 hours, at ambient te",p~,aLure. The product is isolated from the reaction mixture by a~ueous exl,~.;lion and recrystallization to produce an intermediate amide, which is treated with a mineral acid, preferably 1N HCI. The resulting reaction mixture is refluxed for Z to 12 hours, pl~rerably for 3 hours, and then basified at ambient temperature. The resulting compound is dissolved in an aprotic solvent, 10 preferably tetrahydrofuran, and treated with di-tert-butyldicarbonate, at ambient temperature, for 2 to 12 hours, preferably for 3 hours. The compound of formula (33 is then isolated from the reaction mixture in a manner similar to that which is described above.
The compound of formula (3) is then dissolved in an aprotic solvent, preferably,tetrahydrofuran, to which is added the compound of formula (4) in the presence of 15 triphenylphosphine and diethylazodicarboxylate (DLAD) in excessive molar amount at ambient temperature. The resulting reaction mixture is stirred for 1 to 14 hours, pre~,al,ly for 12 hours.
Isolation by column chr~JlllaLography yielded the compound of formula (5), which is then dissolv.,d in a protic solvent, pr~rerably~ methanol. The resulting solution is then treated with a base, preferably ammonia, in a sealed flask and stirred for 2 to 16 hours, preferably, for 3 hours, at 20 45~C to 70~C, preferably, at 50~C. The compound of formula (6) is then isolated from the reaction mixture through conventional techniques, such as conce.-l-aLion and column chrclcnatography .
The compound of formula (6) is then dissolved in an aprotic solvent, prereraL,ly, DMF, and treated with a strong inorganic base, such as sodium hydride. The resulting reaction mixture is 25 stirred for 30 minutes to 3 hours, preferably for 1 hour, st ambient temperature. A compound of formula (7) is then added to the reaction mixture, and the resulting mixture is stirred for 1 to 24 hours, prt:reral,ly for 20 hours, at ambient temperature. Isolation through conventional techniques, such as aqueous extraction and column chromatography yielded the compound of formula (8).
The compound of formula (8) is then dissolved in an anhydrous alkanol, preferably ethanol and the resulting solution is then treated with an anhydrous mineral acid, pr~ft:lLbly HCI, while .,.ai~l..;ning the reaction temperatures between about -78~C and ambient temperature for between 2 hours and 24 hours, and allowing the telllperaLure to rise to ambient te""~eral~lre whiie monitoring for reaction completion, for example, through reverse phase HPLC. The solvent 35 is then removed and the resulting residue dissolved in fresh anhydrous alkanol, preferably ethanol.
The resulting solution is then treated with anhydrous ammonia at ambient pressure or in a sealed flask, at temperatures from between ambient temperature and 100~C for about 1 to about ~

CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 hours. The compound of formula ~la) are then isolated from the reaction mixture by standard techniques, such as concentration and reverse phase HPLC.
Alternatively, instead of treating the resulting soiution above with anhydrous ammonia, the resulting solution is treated with a compound of the formula -NH20R8 to prepare the corresponding compound of formula ~la) wherein R4 is -C(NH)N~H)OR8 substituent.
The compound of formula (la) may then be dissolved in a protic solvent, preferably methanol, and then, in the presence of a base, p,ete.~bly triethylamine, be treated with the appropriate imidate, preferably ethyl acetimidate, at ambient te",pe,tlLure, for 1 to 16 hours, preferably for 3 hours. The product, the compound of formula (Ib), is isolated from the reaction 10 mixture by standard techniques, such as concenL~aLion and reverse phase HPLC.Compounds of formulae ~la) and (Ib) wherein R2 contains -C~O)N(R8)R9 or -C(O)OR8 where each R8 and R9 are independently alkyl, aryl or aralkyl may be hydrolyzed under acidic conditions to prepare compounds of formula (la) and (Ib) where R2 contains -C(O)OR8 where R8 j5 hydrogen.
Compounds of formula (la) and (Ib) where R2 contains -C~O)OR8 where R8 j5 hydrogen 15 may be amidated or esterified under standard conditions to produce compounds of formulae (la) and (Ib) where R2 contains -C(O)OR8 where R8 j5 alkyl, aryl or aralkyl, or compounds of formulae (la) and (Ib) where R2 conl~ina -C(O)N(R8)R9 or -C(o)N(R7)R9 where R8 and R9 are independently hydrogen, alkyl, aryl or aralkyl and R7 is as defined above in the Summary of the Invention.
Compounds of formulae (ia) and (Ib) where R2 is nitro may be reduced under standard 20 conditions to produce compounds of formulae (la) and (Ib) where R2 is amino, which can further be treated with the appropriate alkylating agent to produce compounds of formulae (la) and ~Ib) wh~e R2 is -N(R7)R7, -N(R7)R9, -N(R8)R9 or -N(R8)C(o)R7 where each R8 snd R9 is hydrogen, alkyl, aryi or aralkyl and R7 is as defined above in the Summary of the Invention.
Compounds of formula (Ib) may further be treated with the approp,i~ acid halides, 25 prefe,dlJI~ acid chlorides, or with the appropriate acid anhydrides or equivalents, to yield compounds of the invention wherein R4 is -C(NH)NIH)C(O)R8. Alternatively, compounds of formula (Ib) may further be treated with calLallloyl chlorides, or their equivalents, to yield compounds of the invention where R4 is -C(NH)N(H)C(O)OR8.

B. F~e~ lion of Cornro~n~lc of Formula ~14a) Compounds of formula (14a) are i~ r",ediates in the preparation of the compounds of the invention and are prepared as shown below in Reaction Scheme 2 wherein R3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group conai,,Li~g of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, 35 -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by CA 02239~08 1998-06-04 halo, alkyl, -NtR8tR9, -C(O~OR8 or -C(O)N(R8)R9), -C(O)OR8, -NlRs)R9, -C(o)N(R8)R9, -C(O)(CH2)mOR8 (where m is 1 to 4), -N(R3)C(o)R8, -N(R8~C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3Hz and -SR8; R5 is hydrogen; or R5 is alkyl optionally substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally 5 substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(o)N(R8)R9), aryloxy (optionally substituted by aikyl, hydroxy, halo, -N~R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(o)N(R8)R9), haioalkenyl, cycloalkyl, imidazolyi, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O~(CH2)pOR8 (where p is 1 to 4), 1~ -N(R81C(O)R8, -N(R8)C(o)N(R8)R9, -N(R8)C(NH)N(R3)R9, -OPO3H2 and -SR8; R8, R9 and R10 are as defined above in the Summary of the Invention; R11 is hydroxy or halo; Y is a protecting group for oxygen, such as tetrabutyldimethylsilyl, and W is a protecting group for nitrogen, such as tert-butoxycarbonyl:

_ CA 02239~08 1998-06-04 WO97/21437 PCT~B96/01496 Reaction Scheme 2 F ~ ~ R 3 - C ( O ) R ~

( 9 ) ( ~ O ) ( I I ) OY ORS
P r o t e c t ~ >_ 3 X R S ~ >--R 3 H H
~12) (~3) ORs ORs 3 . (1 3 ) ~ R 3 ~ R 3 W W
( I 4 ) ( ~ 40 ) Compounds of formula (9) and the acid chloride used in Step 1 are commercially available, for example, from Lancaster Synthesis, Inc., or may be prepared accordi.lg to methods known to those skilled in the art.
In general, the compounds of formula (14a) are pr~pa,ed by first dissolving a compound of formula (9) in an aprotic solvent, prefersbly tetrahydrofuran, and saturating the solution with ammonia (gas) at 0~C. After the saturation, the reaction mixture is sealed and warmed to ambient temperature and stirred for 3 to 16 hours, preferably for 12 hours. The reaction mixture is filtered and the filtrate is concentrated and dissolved in a protic solvent, preferably methanol, 10 and treated with an excessive molar amount of an alkaline alkoxide, preferably sodium methoxide, and the reaction mixture is stirred at ambient temperature for 1 to 6 hours, p,~r~:rably 3 hours.
The compound of formula (10) was isolated from the reaction mixture through standard isolation techniques, such as exLla~ on and concentration.
The compound of formula (10) is then dissolved in an aprotic basic solvent, such as 15 pyridine, and treated with a slight molar excess of the compound of formula R3-C(O)CI. The reaction mixture is stirred for 1 to 16 hours, preferably for 1 hour, at room temperature. Isolation through conventional isolation techniques, such as evaporation, aqueous extraction and CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 recry~ ion, afforded the corresponding amide. The amide is dissolved in a protic solvent, preferably ethanol, in the presence of a strong acid, for example, 4N HCI, and then reduced under standard reducing conditions, such as palladium on carbon in the presence of hydrogen, to form the corresponding amine, which is isolated from the reaction mixture through standard techniques, such as filtration and concentration. The resulting product is then dissolved in a mineral acid, such as 2N HCI, and refluxed for 3 to 12 hours, preferably 4 hours. The product is isolated through concentration and dissolved in aqueous hydrogen bromide and refluxed for 1 to 16 hours, preferably 3 hours. The product is concentrated and redissolved in H20 and an inorganic base, such as potassium bicarbonate. The compound of formula 111) is isolated from 10 the reaction mixture by conventional methods, such as aqueous extraction and concentration.
The compound of formula (11) is then dissolved in an aprotic solvent, preferably, DMF, to which a weak base, such as imidazole, is added. To this reaction mixture is added an excessive molar amount of a bulky silyl halide, such as tert-butyldimethylsilyl chloride. The resulting reaction mixture is stirred for 1 to 12 hours, preferably for 1 hour, at ambient temperature. The 15 compound of formula (12) is then isolated from the reaction mixture through standard techniques, such as extraction and concenL-dLion.
The compound of formula (12~ is then dissolved in an sprotic solvent, such as DMF, and treated with a strong base, such as sodium hydride, at ambient temperature. The reaction is stirred for 1 to 6 hours, prere-t-bly for 4 hours, and the compound of formula XR5 is added to the 20 reaction mixture, while stirring, over a period of 1 to 3 hours. The compound of formula (13) is isolated from the reaction mixture by stsndard techniques, such as extraction and column chromatography .
The benzimidazole nitrogen of the compound of formula (13) is then protected in a manner similar to the process descrlbed above for a compound of formula ~2) to produce the 25 compound of formula (14). The compound of formula (14) is then dissolved in an aprotic solvent, such as DMF, and cooled to 0~C. Tetra-butyl ammonium fluoride, in an aprotic solvent, is then added to the solution, and the resulting mixture was stirred for 30 minutes to 3 hours, preferably for 1 hour at O~C. The compound of formula (14a) is then isolated from the reaction mixture through standard techniques, such as aqueous extraction and column chromatography.
The compound of formula (1 4a) may then be treated in a manner similar as described above for compound of formula ~3) to produce compounds of the invention.
In addition, the dimethoxybenzimidazole compound formed in the process of making the compound of formula (11) from the compound of formula (10) may be dissolved in aqueous hydrogen bromide and refluxed for a shorter time period, pr~rerably, for about 3 hours, to produce 35 the corresponding mono-hydroxymethoxy benzil--;dazole of compound (13), i.e., the compound wherein R5 is methyl and Y is hydrogen. This compound is then treated in the similar manner as described above for the compound of formula (13) to produce compounds of the invention.

CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/~1496 C. P~p~.~lion of Compounds of Formula (22) Compounds of formula (22) are intermediates in the preparation of the compounds of the invention and are prepared as shown below in Reaction Scheme 3 wherein R3 is hydrogen or alkyl optionaliy substituted by one or more substituents selected from the group consisting of halo, 5 alkenyl, hydroxy, alkoxy, aryl ~optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R3)R9, -C(O)OR8, -C(O)N(R8~R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C~O)OR8 or -c(o)N(R8)R9t~ -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, 10 -C(O)(CH2)mOR8 (where m is 1 to 4~, -N(R3)C(o)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OP03H2 and -SR8; R8 and R9 are each independently hydrogen, alkyl, aryl or aralkyl; R10 is a branched or straight chain alkylene; R12 is alkyl; X is halo; M is an alkaline metal anion and W is a protecting group for nitrogen, such as tert-butoxycarbonyl:

WO 97/21437 PCT~B96/01496 Reaction Scheme 3 R ~ ~-C ( O ) oR8 N O

(g) ( ~5) ( I 6~

~ -C( O )OR

2( I 6 ) + H 2 N ~ N N ~ 2 F N
H~3 ( 1 7 ) R - C ( O ) O R

3 . ( I 7 ) + R ~ 20 M+ ~ N
~,N ~2 R t 2 o~J~N
H
( ~ 8 ) ~ ~ ~ C ( O ) O R 8 ~ C ( O ) O R

4 . ( I ,3 ) + N R - C ( O ) X~ N

R 1 2 0 J~ N 11~R 1 2 ~ J~C NN\>_ R 3 ( I 9 ) ( 2 0 ) CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/01496 Re~-~lion Scheme 3 continued R~0_c(o)oR8 R~~-C(O)OR~

5 ~ ( 2 0 ) N P r o I e c I

H O /~ ~ R 3 H O /~ N~ R

H W
(21 ) (~2) Compounds of formulae (9) and (15), and the acid halide used in Step 4 are commercially avaiiable or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (22) are prepared by first dissoiving a compound of formula (9) in an aprotic solvent, preferably acetonitrile, and the resulting solution is chilled to sbout -1 0~C. An equivalent molar amount of a compound of formula (15) is then added to the solution in the presence of a base, ptt:r-:.ably diisopropylethylamine, and the resulting solution is allowed to warm to ambient temperature. The reaction mixture is stirred for 3 to 12 hours, preferably for 5 hours. Isolation through conventional techniques, such as evaporation of the 10 solvent, exl,d~Lion and concenL.t,lion, yields the corresponding compound of formula (16~.
The compound of formula (16) is then dissolved in an aprotic solvent, p,efelably~c~t~niL,ile and the resulting solution is chilled to about -10~C. E3enzylamine is added slowly to the solution in the p(esence of a base, preferably cliisopropylethylamine, and the resulting reaction mixture is allowed to warm to ambient temp,anilure. The reaction mixture is then refluxed for 24 15 to 48 hours, preferably for about Z4 hours. Conventional isolation techniques, such as removal of the solvent, aqueous organic extraction, and concsriLIaLion yields the compound of formula (1 7).
The compound of formula (17) is then dissolved in a protic solvent, preferably a alkanol such as methanol. An excessive molar amount of an alkaline alkoxide corresponding to the 20 alkanol used, such as sodium methoxide, is then added to the reaction mixture under nitrogen.
The resulting mixture is refluxed for 1 to 12 hours, preferably for 6 hours, and the reaction allowed to cool to ambient Le-,.pe.aL.Ire. The solvent is removed and the resulting residue is dissolved in an organic solvent. Conventional isolation techniques, such as aqueous extraction, concenL~dLion and chromatography yields the compound of formula (18).
The compound of formula (18) is then dissolved in a protic solvent and treated with a reducing agent, such as palladium on carbon, in the presence of an acid, such as HCI. The resulting mixture is then hydrogenated under pressure and the solids filtered out of the solution to CA 02239~08 1998-06-04 W O g7/21437 PCT~B96/01496 yield the HCI salt of the compound of formula (19).
The salt form of the compound of formula 119) is dissolved in an organic basic solvent, .
preferably, pyridine. An excessive molsr amount of a compound of formula R3-C(o)X is added to the solution at about 0~C. The mixture is allowed to warm to ambient temperature and then stirred for 12-16 hours, preferably for 12 hours. The solvent is removed and conventional isolation techniques, such as extraction an orç~anic solvent and conce"L~dLion, provides the product which is then dissolved in a strong mineral acid, prere,dbly 4N HCI and the resulting solution is refluxed for 8 to 16 hours, prt:rerably 16 hours. The acid ;s removed by evaporation and the resulting residue is then neutralized to pH 7 with a mild inorganic base, such as sodium 10 bicarbonate. Standard isolation techniques, such as removal of the resulting water by conce~L~ ion and trituration with tetrahydrofuran, provides the compound of formula (20).
The compound of formula (20) is then dealkylated in a manner similar to that described above for compounds of formula (11) to produce a compound of formula (21) and N-protected in a manner similar to that described above for compounds of formula (2) to produce the compound 15 of formula 122).
The resulting compound of formula (Z2) is then treated in a manner similar to that des~(iL,ed in Reaction Scheme 1 for compounds of formula (3) to produce compounds of the invention .

D. ~ .OI;OI~ of C~ ou., is of Formula 132~
Compounds of formula (32) are intermediates in the plepd~Lion of the compounds of the in~rention and are ptepa,~d as shown below for Reaction Scheme 4 wherein A is a branched or straight chain alkylene; R3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aryloxy (optionally substituted by 25 alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aralkoxy (opLion-~y substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), haioalkenyl, cycloalkyl, imidazolyl, indolyl, ad&lllallLyl (optionally substituted by halo, alkyl, -N(R8)R9, -ClO)OR8 or -C(o)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)mOR8 (where m is 1 to 4), -N(R8)C(O)R8, -NIR8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OP03H2 and -SR8; R5 is hydrogen; or R5 is alkyl optionally substituted by 30 one or more substituents selected from the group consiaLi,-g of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(o)oR5 or -C(o)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR
35 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)pOR8 (where p is 1 to 4), -N(R8)C(OlR8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8; or R5 is aryl optionally WO 97/21437 PCT~B96/01496 substituted by alkyl, hydroxy, halo, -N(R8)R9, -CtO)OR8, or -C(O~N(R8)R9; R8, R9 and R10 are as defined above in the Summary of the Invention; X is halo; each Y is an oxygen protecting group, such as tert-butyldimethylsilyl; and each W is a nitrogen protecting group such as tert-butoxycarbonyl:

CA 02239508 l998-06-04 W O 97/21437 PCT~B96/01496 Reaction Scheme 4 HO HO

H 2 ~ R 3 P r o i e c ~ ~C \~ R 3 ( 2 4 ) ( 2 5 ) r o N

[~ >--HO
W

(26) Y o H O ~ ~ ~ R 3 ~X~ W

( 4) ~ J
W ( 27 ) HO ro 3 . ( 2 7 ) ~ ~C ~ R 3 ~ ~ i e c ~ ~ N~ R 3 [~~ W [~0 H

W ( 28 ) W ( 29 ) 4 . ( 2 9 ~ + ~_~3C N ~ 5 W ( 30 ) CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 Reaction Scheme 4 continued HO
5 . ( 3 0 ) ~ ~ R 3 [~~ A ~ C N

W( 3 1 ~

RsO

. ( 3 ~ ) + X - R 5 ~ C N

W (32) Compounds of formulae (24), (4) and m sre commercially available or may be prepared by methods known to those skilled in the art or by the methods disclosed herein.In general, the compounds of formula (32) are prepared by first dissolvinçl a compound of 5 formula (24~ in an aprotic solvent, plerelaiJly~ tetrahydrofuran. The solution is basified to a pH of 7 to 10, pre:ierai ly, to pH 8, with a mild i"orçtanic base, p~ererably~ sodium bicarbonate, at ambient l~lllperaLure. An excessive molar amount of a nitrogen-prute-;Li"g reagent, such as di-tert-butyldicsrbonate, is sdded to the solution snd the resulting m;xture wss stirred at ambient temperature for 0.5 to 24 hours, preferably for 12 hours. The solvent is removed and the resulting residue is diluted and extracted with an organic solvent. Extraction and concentration provides the compound of formula 125).
The compound of formula (25~ is then clissolved in an aprotic solvent, preferabiy, DMF. A
mild base, preferably, imidazole, and an oxygen-pruLt5~;Li"~ reagent, such as tert-butyldimethylsilyl chloride, is added to the solution. The resulting mixture is stirred for 30 minutes to 5 hours, preferably for 1 hour, at ambient temperature. The compound of formula 126) is isolated from the reaction mixture by extraction and evaporation.
The compound of formula (26) is then dissolved in an aprotic solvent, preferably, tetrahydrofuran, and then reacted in a manner similar to thst described above for compounds of formula (3) to produce the compound of formuls ~27).
The compound of formula (27) is then dissolved in a protic solvent, prefersbly, methanol, and then deproLeuLtd by ammonolysis st 0~ to 50~C, preferably at 20~C, while stirring for 5 to 48 hours, preferably for 12 hours. Conventional isolation techniques, such as concenLIc:Lion and CA 02239~08 l998-06-04 W O 97/21437 PCTnB96/01496 drying provides the compound of formula (28).
The compound of formula ~28) is then dissolved in an aprotic solvent, preferably DMF, .
and 0-protected in a manner similar to that described above for the compound of formula (26) to produce the compound of formula (29).
The compound of formula (29) is then treated in a similar manner as that described above for the compounds of formula (6) to provide compounds of formula (30). The compound of formula ~30) is then dissoived in an aprotic solvent, preferably, tetrahydrofuran, and treated with a deprotecting agent, such as tetrabutyl ammonium fluoride, at ambient temperature. After stirring the reaction mixture for 30 minutes to an hour, prererably for 30 minutes, the compound 10 of formula (31~is isolated from the reaction mixture through conventional techniques, such as extraction and conce"L~nLion.
The compound of formula ~31)is then dissolved in an aprotic solvent, such as DMF. A
strong base, such as sodium hydride, is added to the solution, and the resulting mixture is allowed to stir for 30 minutes to 2 hours, prt7re~ably for 30 minutes, at ambient temperature. The 16 compound of formula XR5 is added to the reaction mixture, and the resulting mixture is stirred for 30 minutes to 3 hours, pr~re,~Lly, for 1 hour. The compound of formula (32) is then isolated from the reaction mixture through conventional isolation techniques, such as aqueous extraction, concentration and column chromatography.
The compound of formula (32) is then treated in a similar manner as that described above 20 for compounds of formula (8) to provide compounds of the invention.

E. F~.",....Jtiol) of Compounds of Formuia (36~
Compounds of formula (36) are intermediates in the preparation of the compounds of the invention and are prepared as shown below in Reaction Scheme 5 wherein A is a straight or branched chain alkylene; R3 is hydrogen or alkyl optionally substituted by one or more 25 substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)ORB, -C~O)N(R8)R9), aryloxy ~optionally substituted by alkyl, hydroxy, halo, -N(R3)R9, -C(O)OR8, -C(O)N(R8)R9~, aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or 30 -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(o)N(R8)R9, -C(O)(CH2)mOR8 (where m is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R3)R9, -OP03H2 and -SR8; R8, R9 and Rl~ are as defined above in the Summary of the Invention; X is hslo; Y is a prùLecLil,9 group for oxygen, such as tert-butyldimethylsilyl; and w1 is a ~ruL~-;Lillg group for nitrogen, such as tert-butoxycarbonyl and w2 is a di~rt:,el)L pruLe.;Ling group for nitrogen, such as benzyloxycarbonyl 35 (CBZ):

WO 97~1437 PCT~B96/01496 Re~lion Scheme 5 YO HO
[X~ \>--R 3 [~ \>--R

j ~ C N ~ j ~ C N

(30~ 1 (33 W W

~0 2 . ( 3 3 ) + ~N--W [j~ \>--R 3 ( 3 4 ) ~j ~ A ~ ~} C N

H W

~0 3 ' ( 3 4 ) ' [~ R 3 ( 3 5 ) [~0 A_~CN
W

IR -C(O)OR

~0 3 5 ~ X R ~ - C ( O ) O R 8 [~ R 3 ( 3 6 ) ~0 A_~CN

N

CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/01496 Compounds of formula (30) are prepared according to methods disclosed herein.
Compounds of formula (4) and XR10-C(O)OR8 are commercially available, or may be prepared accorcling to methods known to those skilled in the art.
In general, compounds of formula (36) are prepared by first dissolving a compound of formula (30) in an aprotic solvent, such as tetrahydrofuran, and then treating the resulting solution in a manner similar to that as described above for compounds of formula (30) to produce a compound of formula (33).
The compound of formula (33) is then treated with a compound of formula of formula (4) in a similar manner as described above for compounds of formula (26) to produce a compound of 10 formula (34).
The compound of formula (34) is then dissolved in a mixture of a protic and an aprotic solvent, such as a 9:1 mixture of methylene chloride and methanol. An organic acid, such as trifluoroacetic acid, is then added to the solution. The resulting reaction mixture is stirred for 3 to 24 hours, preferably for 6 hours, at ambient temperature. The compound of formula (35) is then 15 isolated from the reaction mixture by conventional techniques, such as concentration.
The compound of formula (35) is then dissolved in an aprotic solvent, such as tetrahydrofuran. A compound of formula XR10-C(O)OR9 in the presence of a mild base, pr~relably, potassium carbonate. The resulting reaction mixture is stirred at ambient temperature for 30 minutes to 6 hours, preferably for 1 hour. Conventional isolation techniques, such as 20 exL.a.;lion with an organic solvent, dryin~, concentration and chromatography provides a compound of formula (36).
The compound of formula (36) is then treated in a manner similar to that described above for the compound of formula (8) to provide compounds of the invention.

F. F~~p~.~lioll of Compounds of Formula (45) Compounds of formula (45) are i~ -edic~es in the p.~pa.~Lion of compounds of theinvention and are prepared as shown below in Reaction Scheme 6 wherein A is a branched or straight chain alkylene; R2 is alkyl (optionslly substituted by halo, aryl, -C(O)OR8, -ClO)NtR8)R9, -N~R8)R9), -oR5, -NtR7)R7, -N(R7)R9, -N(R8)R9, -N(R8)C(o)R7, -C(O~OR8, -C(o)N(R7)R9, -C(O)N(R8)R9, or a heterocyclyl optionally substituted by one or more substituents selected from 30 the group consisting of -C(NH)N(R8)R9, -C(NH)N~H)OR8, -C(NH)N(H)C~O)R8, -C(NH)N(H)C(O)OR8, -C(o)oR5, -CtO)N(R8)R9, -R10-C(O)OR8, -R10-CtO)N(R8)R9 and -S03H; R3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -NtR8)R9, -C(o)oR3, 35 -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by W O 97/21437 PCT~B96/01496 -~4-halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O~N(R8)R9, -C(O)(CH2)mOR8 (where m is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OP03H2 and -SR8; R7, R8, R9 and R10 are 85 defined above in the Summary of the Invention; X
is halo; and W is a protecting group for nitrogen, such as tert-butoxycarbonyl:

Re~,Lion Scheme 6 H O ( R - C ) 2 ~ ~"~ o J~ R 3 ( 37 ) ( 38 ) R ~<~ N o 2 2 . ( 3 8 ) ~ [~N,H
HO
o~R3 ( 3 9 ) 3 . ( 3 9 ) ,, ~ N N 2 R ~ NN~ R 3 HO o~R3 HO H

( 40 ) ( 4 1 ) 4 ~ ( 4 1 ) P r o t e c t ~ R 3 HO W
( 42 ) W O 97/21437 PCT~B96/01496 Reaction Scheme 6 continued H O ~ ~ \~ R ( 4 3 ) (4) [~~ \W

W

R 3 ( 4 4 ) ~1~

6 . ( 4 4 ) ~ ,~ C N ~ R 3 ( 7 ) C~ t ; C N

W ( 4 5 ) Compounds of formulae (373, (4) and (7) are co,.,r"c:~ ~"y available, for example, from Aldrich Co., or may be prepared according to methods known to those skilied in the art.
Compounds of formula (R3-C~o))2o are commercially available, for example, from Aldrich Co., or 5 may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (45) are prepared by first dissolving a compound of formula (37) in an aprotic basic solvent, such as pyridine. The appropriate anhydride is added to the solution at ambient le""~er~L-lre. The resulting reaction mixture is stirred for 1 to 48 hours, pr~telai,ly, for 12 hours, at ambient temperature. Removal of the solvent affords the compound 10 of formula ~38).

CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 The compound of formula (38) is then dissolved in protic acidic solvent, such astrifluoroacetic acid. Concentrated nitric acid is added to the solution at smbient temperature.
The resulting mixture is stirred at ambient temperature for 30 minutes to 12 hours, preferably for 2 hours. Isolation through recrystallization gives the compound of formula (39) and its nitro regioisomer.
The compound of formula (39) is then dissolved in a protic solvent, preferably, methanol, and treated with a reducing agent under standard conditions, such as palladium on carbon in the presence of hydrogen under pressure at ambient temperature. The resulting mixture is filtered and the filtrate is concentrated to give the compound of formula (40). The compound of (40) is 10 refluxed for 1 to 3 hours, preferably for 2 hours, in a mild organic acid, such as acetic acid, which corresponds to the anhydride used in Step 1. The acidic solvent is removed and the compound of formula (41 ) is isolated from the reaction mixture through extraction, drying and concentration.
The compound of formula (41~ is then protected in a manner similar to that described above for the compound of formula (2) to produce the compound of formula (42), which is further 15 treated in a manner similar to that described above for the compound of formula t3) to produce compounds of formula ~45) and compounds of the invention.

G. F~'~.p~.al;On of Compounds of Formulae (Ic) and (Id) Compounds of formulae (Ic) and (Id) are compounds of the invention and are prepared as shown below in Reaction Scheme .7 wherein A is a strai~ht or branched chain alkylene; R2 is 20 nitro, alkyl (optionally substituted by halo, aryl, -C(O)OR8, -C(o)N~R8)R9, -N(R8)R9), -oR5, -N~R,.7)R7, -N(R7)R9, -N(R8)R9, -N(R8)C(o)R7, -C(O)OR8, -C(o)N(R7)R9, -C(o)N(R3)R9, or a heterocyclyl optionally substituted by one or more substituents selected from the group consisting of -C(NH)N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)R8, -C(NH3N(H~C(O)OR8, -C(O)OR8, -C(O)N(R8)R9, -R10-C(O)OR8, -R10-C(O)N(R8)R9 and -S03H; R3 is hydrogen or alkyl optionally 25 substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by 30 halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)~CH2)mOR8 (where m is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OP03H2 and -SR8; R7, R8, R9 and R10 are as defined above in the Summary of the Invention; X
is halo; and W is a protecting group for nitrogen, such as tert-butoxycarbonyl:

CA 02239508 l998-06-04 W O 97/21437 PCT~B96/01496 Reaction Scheme 7 R~ R + ¦ ~ ~C N~H>--R

(46) ( 67 ) ~N
( 4 8 ) 2 ~ ~! R ~ + ~ ¦ J H>--( 4 9 ) H ~ H

< ~ H 2 N ( I d ) H j C

CA 02239~08 1998-06-04 7 PCT~B96/03496 Compounds of formula 146) are prepared according to methods described below in the Preparations. Compounds of formula (47) and (7) are commercially avaiiabie, for example, from Aidrich Co., or may be prepared according to methods known to those skilied in the art.
In general, the compounds of formuiae (Ic) and (Id) are prepared by first dissolving a compound of formuia (46) in a protic acidic solvent, such as a mixture of methanol and acetic acid. An excessive molar amount of a compound of formula (47)is then added to the solution at ambient temperature in the presence of a reducing agent, such as NaCNBH4. The reaction mixture is stirred at ambient temperature for 30 minutes to 3 hours, preferabiy, for 1 hour, and the solvent removed. Conventional isolation techniques, such as aqueous extraction, 10 concentration and column chromatography provides the compound of formuia (48).
The compound of formula (48)is then treated in a manner similar to that described above for the compound of formula (6? to produce the compound of formula (49), which is then treated in a manner similar to that described above for the compound of formula (8) to produce the compound of formula (Ic), which is then treated in a manner simiiar to that described above for 15 the compound of formula (la) to produce the compound of formula (Id).

H. i~el~a.c.~ ) of Comrou~ds of Formuls (55) Compounds of formula (5~) are intermediates in the preparation of compounds of the invention and are prepared as shown below in Reaction Scheme 8 wherein R3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, 20 alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C~ N(R8)R9), aryloxy (optionally substituted by aikyl, hydroxy, halo, -N(R8)R9, -C(O~OR8, -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, 25 -C(O)(CH2)mOR8 (where m is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OP03H2 and -SR8; R6 is hydrogen, alkyl, -R10-C(O)OR8, -R10-C(O)N(R8)R9, -C(o)R7, or aralkyl (optionally substituted by alkyl, halo, -N(R8)R9, -C(O)OR8, or -C(O)N(R8)R9); R7, R8, Rg and R10 are as defined above in the Summary of the Invention; X is halo; and W is a protecting group for nitrogen, such as tert-butoxycarbonyl and WZ is a iirrerer.l protecting group for nitrogen, such as 30 tosyl:

WO 97/21437 PCT~B96/01496 Re&cliollScheme 8 H ~ N N l1 R Z~L~ N

(50) (47) R 2 ~! ( s I ) 2 . ( 5 1 ) P r o I e c I ~ \~ R 3 H--N

( 5 2 ) 3 . ( 5 2 ) + R 6 _ X ~ \>--R 3 ( 5 3 ) R --N W

( 5 4 ) 4 . ( 5 4 ) --' ~ NN\>--R 3 R --N H

I (s5) CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 Compounds of formula (50) are prepared according to methods disclosed herein.
Compounds of formula (47) and R6X sre commercially available or may be prepared according to methods known to those of ordinary skill in the art.
In general, the compounds of formula (55) are produced by first treating a compound of 5 formula (50) with a compound of formula (47) in a manner similar to that described above for the compound of formula (46) to produce a compound of formula (51). The compound of formula (51 ) is then dissolved in an aprotic solvent, preferably, DMF, at about 0~C. A strong base, such as sodium hydride, is added to the solution in an excessive molar amount. The solution is stirred for about 30 minutes. A nitrogen-protecting producing group, such as tosyl chloride, is added to 10 the reaction mixture, and the resulting mixture is stirred for 30 minutes to 3 hours, preferably, for 1 hour, at about 0~C. Conventionai isolation techniques, such as extraction and concentration yields the compound of formula (52).
The compound of formula (5Z) is then dissolved in an aprotic solvent, such as DMF, in the presence of a mild base, such as potassium carbonate, and the compound of formula (53), such 15 as methyl iodide. The resulting reaction mixture is stirred for 10 to 24 hours, prere-ably, for 12 hours, at ambient temperature. Conventional isolation techniques, such as ex~ .Lion by organic solvent and concentrat;on, yields the compound of formula ~54~.
When the compound of formula ~53) is other than a methyl halide or ethyl bromo acetate and contains an alkylene group, an allyl halide is used to produce the compound of formula ~54) 20 and then the compound is reduced to produce the corresponding alkylene-containing R6 group.
The compound of formula (54) is then de-prc,~ d by dissolving it in a protic solvent, such as methanol, in the presence of a mild nucleophilic agent, such as an alkoxide or a mineral hydroxide, for example, sodium hydroxide. The reaction mixture is stirred for 1 to 3 hours, p.ererably for 1 hour, at ambient temperature. Conventional isolation techniques, such as 25 evaporation and column chromatography yields the compound of formula (55).
The compound of formula (55) is then further treated in a manner similar to that described above for compounds of formula (6) to produce compounds of the invention.

I. r-~pb.Jt;ol) of Compounds of Formulae (60) snd (62) Compounds of formulae (60) and (62) are in~t:.-l.ediates in the preparation of compounds 30 of the invention and are prepared as shown below in Reaction Scheme 9 wherein A is a straight or branched chain alkylene; R3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consislil1~ of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O~OR8, -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O~N(R8)R9), aralkoxy (optionally 35 substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O~OR8 or CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/~1496 -C(O~N(R8lR9), -C~O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2~mOR8 (where m is 1 to 4), -N(R8)C(o)R3, -N(R8)C(O)N~R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8; R6 is hydrogen, alkyl, -R10-C(O)OR8, -R10-C(O)N(R8)R9, -C(o)R7, or aralkyl (optionally substituted by alkyl, halo, -N(R8)R9, -C(O)OR8, or -C(o)N(R8)R9); R7 is a branched or straight chain alkylene substituted by 5 one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8), aryloxy, aralkoxy, alkenyl, haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, hydroxy, -C(O)OR8 or -N(R8~R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)~CH2)qOR8 (where q is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R3)R9, -OPO3H2 and -SR8; R8, R9 and Rl~
10 are as defined above in the Summary of the Invention; X is halo; and W is a protecting group for nitrogen, such as tert-butoxycarbonyl:

W 097/21437 PCT~B96/01496 Reaction Scheme 9 [~ \>--~ 3 [~C \>--R 3 ~C \>--R 3 H3C0 H H~CO H H0 H
( 56 ) ( 57 ) ( 58 ) H O ~ ~ ~ R 3 ( 4) \ H
~> (59) N~W
3 . ( 5 9 ) + ? ~ ~ 2 N \~ R 3 ~~ A ~L C N

W ( 6 0 ) 4 . ( 6 0 ) ~ R 3 ~~ A~CN

W ( 6 1 ) CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 Reaction Scheme 9 continued H--N
5. (61! + R 7 X ~ ~ R 3 A ~ C N

W (62) Compounds of formulae (56), (4), (7) and R7X are commercially available, for example, from Aldrich Co., or may be prepared according to methods known to those skilled in the art.
In general, the compounds of formula (62) are prepared by first dissolving a compound of 5 formula ~56) in a protic solvent, prt:re.àbly, trifluoroacetic acid, in the presence of nitric acid at ambient te",p~-~-Lure. The resulting reaction mixture is stirred for 6 to 16 hours, prefe-ably, for 12 hours. The solvents are removed by evaporation and the residue neutrali~ed to about pH 7 with a miid base, such as sodium bicarbonate. Conventional isolation techniques, such as ehL.~.;Lion, concentration and column chromatography yields the compound of formula (57).
The compound of formula (57) is then de-methylated in a manner similar to that des~i.il,ed above for compound of formula (11) to produce the compound of formula (58), which is then treated in a manner similar to that described above for the compound of formula (3) to produce the ~;ompound of formula (59).
The compound of formula (59) is then treated in a manner similar to that described above 15 for the compound of formula (7) to produce the compound of formula (60), which is then dissolved in a basic aprotic solvent, such ss pyridine. A mild reducing sgent, such ss tin (Ill) chloride dihydrate, is then added to the solution. The resulting slurry is then heated to 50~ to 60~C, preferably to 50~C, for 10 to 16 hours, preferably for 14 hours. The solvent is removed and the resulting residue dissolved in an organic solvent. Conventional isolation techniques, such 20 a filtrstion, conce~L~c~Lion snd chromstography, yields the compound of formula (61).
The compound of formula (61) is then dissolved in sn sprotic solvent, prefersbly, DMF.
An excessive molar smount of a compound of formuls R7X is then added to the solution in the presence of a mild bsse, such as potassium bicarbonate. The resction mixture is stirred for 24 to 48 hours, prefersbly for 48 hours, at 20~C to 55~C, preferably at 20~C. Conventional isolation 25 techniques, such as t~ ;Lion and chromatoqraphy, yields the compound of formula (62).
The compound of formula (62) is then treated in a manner similar to that described above for the compound of formula (8) to produce compounds of the invention.
In addition, the compound of formula ~60) may be treated in a manner similar to thst CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/01496 described above for the compound of formula (8~ to produce compounds of the invention.
In addition, all compounds of the invention that exist in free base form or free acid form may be converted to their pharmaceutically acceptable saits by treatment with the appropriate inorganic or organic acid, or by the appropriate inorganic or organic base. Salts of the 5 compounds of the invention can aiso be converted to the free base form or to the free acid form or to another salt.

* ~I * * ~

The foilowing specific preparations and examples are provided as a guide to assist in the practice of the invention, and are not intended as a limitation on the scope of the invention.

Compounds of formula (2) To a solution of 4-amino-3-nitrophenol (25.0 9, 162 mmol) and methanol (300 mL) was added 10% Pd/C (300 mg). The reaction was placed under hydrogen and shaken for 12 hours.
Afterward, 4 N HCI (50 mL) was added. The mixture was then filtered through celite. The 15 filtrate was concentrated to give 3,4-diaminophenol.

Compounds of formula (3) A. A solution of 3,4-diaminophenol (5.20 9, 42.0 mmol), isobutyric acid (5.80 mL, 63.0 mmol) and 4 N HCI (50 mL) was refluxed for 16 hours. After cooling to ambient 20 temperature, the reaction was neutralized (KHCO~). Filtration afforded a dark solid. The solid was dissolved in THF (100 mL) and H20 (20 mL). Di-tert-butyldicc,,LonaLe (4.09 9, 18.7 mmol) was added to the solution. After stirring for 12 hours, the reaction mixture was poured into H2O
(50 mL). The resulting mixture was extracted with ethyl acetate (2x150 mL). The organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated. The resulting oil was 25 chromatographed on SiO2 (50 9) with hexane/ethyl acetate (1:1) to afford 1-tert-butoxycarbonyl-6-hydroxy-2-isopropylbe~ ida~c~le.
B. In a similar manner, the following compounds of formula (3) were made:
1 -tert-butoxycarbonyl-6-hydroxybenzimidazole;
1 -tert-butoxycarbonyl-6-hydroxy-2-methylben~;" ,icla~ole;
30 1-tert-butoxycarbonyl-6-hydroxy-2-trifluoromethylbenzimidazole;
1 -tert-butoxycarbonyl-6-hydroxy-2-eth~lL~"~i,.,i~iR7ole;
1 -tert-butoxycarbonyl-6-hydroxy-2-propylbenzimidazole;
1 -tert-butoxycarbonyl-6-hydroxy-2-butylben~in ,idazole;

CA 02239~08 l998-06-04 W O 97t21437 PCT~B96/01496 1-tert-butoxycarbonyl-6-hYdroxy-2-isobutylben-imidazole; and 1 -tert-butoxycarbonyl-6-hydroxy-2-tert-butylben7imidazole .
C. Alternatively, succinic anhydride (11.2 9, 113 mmol, 2 eq) and 3,4-diaminophenol (7 g, 56 mmoL, 1 eq) were dissolved in 150 mL dry DMF and the mixture was heated to 100~C
for 3 hours. The DMF was removed in vacuo, and the residue was dissolved in 350 mL 4N HCI
and refluxed for 14 hours. The reaction was cooled, the water was removed in vacuo and the residue was dissolved in 200 mL methanol and to this was added 20 mL concenL~aLed sulfuric acid. This mixture was refluxed overnight. The methanol was stripped off and the residue neutralized to pH 7 with saturated aqueous sodium bicarbonate. The water was removed ;n 10 vacuo and the residue was triturated with THF (4x100 mL). The combined THF fractions were concentrated to about 100 mL volume and di-tert-butyldicarbonate (12 g, 56 mmol, 1 eq.) was added. The mixture was stirred overnight at ambient temperature and then concentrated. The crude oil was chromatographed (1:1 ethyl acetate/hexanes) to afford 1-tert-butoxycarbonyl-6-hydroxy-2-(methoxycarbonylethyl)benzimidazole as a colorless solid, 5 g ~42%, yield).

Compounds of formula (5) A. DEAD (0.60 mL, 3.80 mmol) was added to a solution of 1-tert-butoxycarbonyl-6-hydroxy-2-isopropylbenzimidazole (690 mg, 2.30 mmol), 1-tert-butoxycarbonyl-4-hydroxypiperidine (~25 mg, 4.60 mmol), triphenylphosphine (904 mg, 3.45 mmol) and THF
20 (5 mL~ at 25 ~C. After stirring for 12 hours, the solvent was removed in vacuo. Chromatography (SiO~2, 100 9) of the resulting oil with hexanelethyl acetate (1:1) afforded 1-tert-butoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-2-isopropylbeu~i"~id~ole.
B. In a similar manner, the following compounds of formula (5) were made:
1-tert-butoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxY)ben~ 7Ole;
25 1 -tert-butoxycarbonyl-6-(N -(tert-butoxycarbonyl)~;,,e, id;n-4-yloxy)-2-methylbenzimidazole;
1 -tert-butoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy) -2-trifluoromethyl-ben~i, . ,idaLole;
1 -tert-butoxycarbonyl-6-~N-(tert-butoxycarbonyl)p;,Jc:, idi..-4-yloxy)-2-ethylbel1~i--.ida~ole;
1 -tert-butoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-2-propylbenzimidazole;
30 1-tert-butoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-2-butylbenzimidazole;
1 -tert-butoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-2-isobutylbenzimidazole;
1 -tert-butoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-2-tert-butyl-beu~i",;dazole; and 1 -tert-butoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-2-isopropyl- 4-methoxybenzimidazole.

CA 02239~08 l998-06-04 W O 97/21437 PCT~B96/01496 Compounds of formuta (8) A. A solution of 1-tert-butoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-2-isopropylbenzimidazole (425 mg 0.92 mmol) and methanol ~10 mL) was cooled in a dry 5 ice/acetone bath and NH3 (9) was bubbled in. The reaction flask was sealed and heated to 50~C
for 12 hours. The solvent was removed in vacuo. The resulting oil was chromatooraphed on SiO2 (50 9) using ethyl acetate to afford a clear oil (a compound of formula (6)). To a solution of the oil and DMF (15 mL) was added NaH (28.0 mg 0.70 mmol). The solution was stirred for 1 hour before 7-bromomethyl-2-naphthonitrile (178 mg 0.72 mmol) was added. After stirring for 10 20 hours the reaction was poured into H20 (50 mL). The aclueous layer was extracted with ethyl acetate (2x60 mL). The organic layers were washed with brine (50 mL), dried (Na2S04) snd conce~LIt~Led. The resulting oil was chromatographed on SiO2 (20 9) with ethyl acetate to afford 6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-2-isopropyl-1-(4-cyanonaphth-1-yl)methyll)e~ "idazole and 5-~N-(tert-butoxycarbonyl)piperidin-4-yloxy)-2-isopropyl-1-(4-15 cyanonaphth-1-yl)methyll,e,.~ 7nle as a 1:1 mixture of compounds.
B. In a similar manner the following compounds of formula (8) were made:
6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphLI,-1-yl)be~ idszole and 5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1 -(4-cyanonaphth-1 -yl)ben~i, l ,idazole;
6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1 -(4-cyanonaphth-1 -yl)-2-methyl-benzimidazole and 5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)-2-methylbenzimidazole;
6-lN-(tert-butoxycarbonyl)piperidin-4-yloxy)-1 -(4-cyanonaphth-1 -yi)-2-trifluoromethyl-benzimidazole and 5-(N-(tert-butoxycarbonyl),~ eridi~1-4-yloxy)-1-(4-cyanonaphth-1-yl)-2-trifluoromethylbenzimidazole;
25 6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)-2-ethylb~ i.,.idazole and 5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)-2-ethylbenzimidazole;
6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanona~ l.-1-yl)-2-propyl-benzimidazole and 5-(N-(tert-butoxycarbonyl),ui~,e.. 'i ~-4-yloxy)-1-(4-cyanonaphth-1-yl)-2-propylbel-~i---idazole;
6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1 -(4-cyanonaphth-1 -yl)-2-but~Jlben~i".idazole and 5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)-2-butylbenzimidazole;
6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1 -(4-cyanonaphth-1 -yl)-2-isobutyi-benzimidazole and 5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)-2-isobutylbenzimidazole;

8-(N-~tert-butoxycarbonyl)piperidin-4-yloxy)-1 -(4-cyanonaphth-1 -yl)-2-tert-butyl-CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/01496 benzimidazole and 5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)-2-tert-but~11L en~il"ida~ole;
6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1 -(4-cyanonaphth-1 -yl)-2-isopropyl-4-methoxybenzimidazole and 5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)-2-isopropyl-4-methoxybenzimidazole;
6-(N-(terr-butoxycarbonyl)piperidin-4-yl)amino-1 -(4-cysnonaphth-1 -yl)benzimidazole;
6-(N-(tert-butoxycarbonyl)piperidin-4-yl)((methoxycarbonyl)methyl)amino-1 -(4-cyanonaphth-1 -yl)-2-methylbenzimidazole;
6-(N-(tert-butoxycarbonyl)piperidin-4-yl)(3-(methoxycarbonyl)prop-1 -yl)amino-1 -(4-cyanonaphth-1 -yl)-2-methylben~i,.,id~ole;
6-(N-(tert-butoxycarbonyl)piperidin-4-yl)~2-(methoxycarbonyl)prop-1 -yl)amino-1 -(4-cyanonaphth-1 -yl)-2-methylbenzimidazole;
5-(N-(tert-butoxycarbonyl)piperidin-4-yl) (2-(methoxycarbonyl)prop-1 -yl)amino-1 -(4-cyanonaphth-1 -yl)-2-methylbenzimidazole;
15 6-~N-(tert-butoxycarbonyl)piperidin-4-yl)amino-2-methyl-5-nitro-1 -(4-cyanonaphth-1-yl)be,.Li",id le; and 6-(N-ltert-butoxycarbonyl)piperidin-4-yl)amino-2-isopropyl-5-nitro-1 -(4-cyanonaphth-1 -yl)ben~i",idd~ole.

PREPARA~ION 5 Compounds of formula (10) To a solution of 1,3,5-trifluoro-2-nitrobenzene (25.0 p, 141 mmol) and THF (30 mL) cooled in a dry ice/acetone bsth was bubbled in NH3 (9). After saturation, the reaction tube was sealed and warmed to ambient temperature. After stirring for 12 h, the reaction mixture was filtered and the filtrate concentrated to afford a yellow oil. The yellow oil was dissolved in 25 methanol (150 mL). Over 1 hour, sodium methoxide (27.0 9, 500 mmol) was added. The reaction was stirred for 3 hours, then H2O (500 mL) was added. The mixture washed with ethyl acetate (3x700 mL). The organic layers were washed with brine (50 mL), dried (Na2SO2) and concenL~dled to afford 3,5-dimethoxy-2-nitroaniline as a red solid.

Compounds of formula (11) A. To a solution of 3,5-dimethoxy-2-nitroaniline (55.0 9, 321 mmol) and pyridine(400 mL) was added isobutyryl chloride (41.0 mL, 391 mmol). After stirring for 16 hours, the reaction mixture was conce"l,~lled in vacuo. The resulting oil was partitioned between H20 (200 mL) and ethyl acetate (200 mL~. The aqueous layer was ~xL,acLt:d with more ethyl acetate 35 (2x200 mL). The organic layers were washed with brine (50 mL), dried (MgSO4) and CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 concentrated. The solid was recrystaliized from hexane/ethyl acetate at 5~C to afford yellow crystais. To a slurry of the yellow crystals, 4N HCI ~200 mL) and ethanol (250 mL) was added 10% Pd/C (1.30 9). The slurry was placed under 50 psi of H2 (9) and shaken for 4 hours. The mixture was then filtered and conce~lL~dLion of the filtrate afforded a white solid. The white solid was dissolved in 2N HCI (200 mL) snd refiuxed for 4 hours. The reaction mixture was concentrated. The resulting solid was dissolved in 48% HBr (100 mL) and H20 (100 mL) and refluxed for 15 hours. The reaction was then cooied to ambient It:lllperaLLlre and concenL.~Led.
The solids were dissolved in H20 (200 mL) and neutralized ~KHC03). The aqueous layer was then extrscted with n-butanol ~3x500 mL). The organic layer was washed with brine (50 mL), treated 10 with activated charcoal and concentrated to afford 4,6-dihydroxy-2-isopropylbenzimidazole, a compound of formula (11) .
B. Alternatively, a solution of 4,6-dimethoxy-2-isopropylbenzimidazole (12.70 9,57.66 mmol) and 48% HBr ~100 mL) was refluxed for 3 hours, and then the solution was cooled to ambient temperature and concentrated. The resulting solids were dissolved in H20 ~100 mL) 15 and neutralized ~NaHC03). A brown precipitate formed which was isolated by filtration. The precipitate was dissolved in MeOH ~100 mL~, treated with charcoal and concellLlaL~d to afford 6-hydroxy-2-isopropyl-4-methoxybenzimidazole as a brown solid.

Compounds of formula (12) and (13) To a mixture of 4,6-dihydroxy-2-isopropylbenzimidazole t36.0 g, 113 mmol~, imidazole ~35_g 9, 514 mmol) and DMF (200 mL) was added tert-butyldi~ Ll-ylsilyl chloride (40.0 9, 265 mmol). The dark mixture was stirred for 10 hours, then it was partitioned between H20 ~500 mL) and ethyl acetate ~500 mL). The aqueous layer was exLld~Led with more ethyl acetate ~2x500 mO. The combined organic layers were washed with brine (100 mL), dried (Na2504), 25 treated with activated charcoal and con-;e~L~Lt:d to afford a dark oil, 4,6-di~tetrabutyldimethylsilyl30xy-2-isopropyibenz;".id~Lole. The oil ~12.2 9, 29 mmol) was dissolved in DMF ~150 mL) and treated with NaH (1.76 g, 44.0 mmol). After 4 hours, the solution was placed in an ice bath, then methyl bromoacatate ~1.50 mL, 15.8 mmol) was added dropwise.
The reaction was stirred for 40 minutes, then a second portion of methyl bromoacetate ~1.20 mL, 30 12.6 mmol) was added. After stirring for 20 more minutes, the reaction mixture was added to H20 ~300 mL). The aqueous layer was t~xLla~;Led with ethyl acetate ~3x300 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and conce--l-aLed to afford a oil.
Chromatography ~SiO2, 500 9) of the oil with hexane/ethyl acetate (1:1) afforded 2-isopropyl-4-(carboxy)methyl-6-(tetrabutyld;"~Lhyl-silyl)oxybenzimidazole.

CA 02239~08 l998-06-04 WO 97~1437 PCT~B96/01496 Compounds of formula (14a) A. To a mixture of 2-isopropyl-4-~carboxy)methoxy-6-(tetrabutyldimethyl-siiyl)oxybenzimidazole t9.00 9, 18.7 mmol) and THF (100 mL) was added di-tert-butyldicarbonate ~23.0 9, 105 mmol). The reaction mixture was refluxed for 7 hours. After cooling to ambient temperature, it was conce~LI ~led. The resulting oil was purified by chromatography (500 9 SiO2) with hexane/ethyl acetate (Z:1) to afford a clear oil. A solution (0.01 M) of the clear oil in THF
1300 mL) was placed in an ice bath. After a few minutes tetrabutyl ammonium fluoride (8.00 mL
of a 1.0 M solution, 8 mmol) was added. The reaction mixture was stirred for a few minutes, 10 then the reaction mixture was partitioned between H2O (300 mL~ and ether 1300 mL). The aqueous layer was extracted with more ether 12x300 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and concentrated to afford a yellow oil.
Chromatography (10 9 SiO2) using ether afforded 1-tert-butoxycarbonyl-2-isopropyl-4-(carboxy)methoxy-6-hydroxybenzimidazole.
B. Alternatively, to a mixture of 6-hydroxy-2-isopropyi-4-methoxyL,en i",idazole(3.44 9, 18 mmol), THF 150 mL) and H20 (50 mL) was added di-tert-butyl~ a-i onate (8.00 q, 37 mmol). The mixture was refluxed for 16 hours. ArLt: .r.c..ds, the reaction mixture was extracted with ethyl acetate I3x50 mL). The organic layers were washed with brine, dried tNa2SO4) and concentrated. Chromatogrsphy ~SiO2, 100 9) of the resulting oil with hexane/ethyl 20 acetate (1:1) afforded 1-tert-butoxycarbonyl-6-hydroxy-2-isopropyl-4-methoxybenzimidazole.

Compounds of formula (16) In a 1 L flask, 2,4,6-trifluoro-2-nitrobenzene (8.2 mL, 70 mmoL, 1.1 eq.) was added to 25 500 mL of dry aceLùniLlile and the solution chilled to -10~C. Diisoproi,ylethylamine (33 mL, 191 mmol, 3 eq) and ethyl isonipecotate (10 q, 64 mmoL, 1 eq.) were added slowly (approx.
20 min.) as a combined solution via addition funnel, under nitrogen. The reaction turned yellow almost immediately, and it was warmed to 20~C slowly. After 5 hours at 20~C, thin layer chromatography showed the reaction to be nearly complete (9515 hexanes/ethyl acetate). The 30 &ct5LuniL~ile was removed in vacuo and the resulting yeilow oil was Ji;.~olved in 1 L of ethyl acetate. This solution was washed with water (3x100 mL), brine (1x300 mL), dried over sodium sulfate, and concentrated to give 20 9 of a yellow oil. This material was identified as 6-(4-(ethoxycarbonyl)piperidin-1-yl)-2,4-difluoro-1-nitrobenzene by lH NMR.

Compounds of formula (17) 6-(4-(Ethoxycarbonyl)piperidin-1-yl)-2,4-difluoro-1-nitrobenzene (20 9, 64 mmoL, 1 eq) CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 was dissolved in 300 mL of dry acetonitrile and the solution chilled to -10~C.
Diisopropylethylamine (33 mL, 191 nmol, 3 eq~ and benzyl amine ~7 mL, 64 mmol, 1 eq) were added slowly (approx. 20 min.) as a combined solution via addition funnel, under nitrogen. The reaction turned yellow almost immediately, and it was warmed to 20~C slowly. After 48 hours at 20~C, thin layer chromatography showed the reaction was only about half con,Fl~te. The reaction was heated to 50~C for 24 hours, cooled, the acetonitrile was removed in vacuo and the resulting orange oil was dissolved in 1 L of ethyl acetate. This solution washed with water (3x100 mL), brine (1x300 mL), dried over sodium sulfate, and concellL. ,Led to give 20 9 of an orange oil. Chromatography (95/~ hexanes/ethyl acetate) gave 12 9 (48% yield) of 2-N-10 benzylamino-6-(4-(ethoxycarbonyl)piperidin-1 -yl)-4-fluoro-1 -nitrobenzene.

Compounds of formula (18) 2-/\/-Benzylamino-6-(4-(ethoxycarbonyl)piperidin-1-yl)-4-fluoro-1-nitrobenzene (11 9, 27 mmol, 1 eq) was added to 200 mL of dry methanol and to the mixture was added slowly 15 (approx. 20 min.) sodium methoxide (5.0 g) as a solution in 100 mL methanol, under nitrogen.
The reaction was heated to reflux for 6 hours, cooled, the methanol was removed jn vacuo and the resulting red solid was dissolved in 1 L of ethyl acetate. This solution washed with water ~3x100 mL), brine ~1x300 mL), dried over sodium sulfate, and concentrated to give a dark red oil.
Chromato~raphy (10-50% ethyl acetate in hexanes~ gave 4.3 9 (38% yield) of 2-N-benzylamino-20 6-(4-(methoxycarbonyl)piperidin-1-yl)-4-methoxy-1-nitrobenzene.

- Compounds of formula (19) 2-N-Benzylamino-6-~4-(methoxycarbonyl)piperidin-1-yl)-4-methoxy-1-nitrobenzene (4.3 9, 10 mmol, 1 eq) was dissolved in 100 mL ll.t:Lllanol and to the mixture was added a few srams of 25 10% Pd/C (wet Degussa type) followed by 50 mL of 4N HCL. The mixture was hydrogenated at 50 psi for 2 hours, the solids filtered out with Celite; and the filtrate concel.L,aLed to give a light tan solid. The HCI salt form of the diamine ~quant. yield) was identified as 1,2-diamino-6-(4-(methoxycarbonyl)piperidin-1-yl)-4-methoxybenzene by 1H NMR.

Compounds of formula (20) 1,2-Diamino-6-~4-(methoxycarbonyl~piperidin-1-yl)-4-methoxybenzene bis-hydrochloride (3.7 9, 10 mmol, 1 eq) was dissolved in 100 mL dry pyridine and to the mixture was added isobutyryl chloride (2.2 mL, 20 mmoL, 2 eq.) at 0~C. The mixture was allowed to slowly warm to 20~C and stirred overnisht. The pyridine was removed in vacuo and the residue was dissolved CA 02239~08 1998-06-04 W O 97~1437 PCT~B96/01496 in 500 mL of ethyl acetate. This solution was washed with water (3x100 mL), brine t1x300 mL~, dried over sodium sulfate, and concentrated to give 3.5 9 (87% yield) of a dark brown residue.
This material was identified as 1,2-di((1-methylethyl)carbonyl)amino-6-(4-~methoxycarbonyl)piperidin-1-yl)-~methoxybenzene by 1H NMR. The residue (3.5 9, 10 mmol, 1 eq) was dissolved in 100 mL 4N HCI and the mixture was refluxed overnight. The HCI was removed in vacuo and the residue was neutralized to pH 7 with saturated aqueous sodium bicarbonate. The water was removed in vacuo and the residue was triturated with THF
(4x100 mL). The combined THF fractions were dried over sodium sulfate and concentrated to give 2.5 9 t69% yield) of a dark solid. This material was identified as 2-isopropyl-4-~4-10 tcarboxy)piperidin-1-yl)-6-methoxybenzimidazole by ~H NMR.

Compounds of formula ~21) 4-(~(Carboxy)piperidin-1-yl)-6-methoxy-2-isopropylben i, lidazole ~2.5 9, 7.4 mmol, 1 eq) was dissolved in 60 mL 48% HBr and the mixture was refluxed for 3 hours. The HBr was 15 removed in vacuo and the residue was dissolved in 200 mL methanol and to this was added ZO
mL concerL,d~ed sulfuric acid. This mixture was rsfluxed overnight. The methanol was stripped off and the residue neutralized to pH 7 with saturated aqueous sodium bicarbonate. The water was removed in vacuo and the residue was triturated with THF (4x100 mL). The combined THF
fractions were dried over sodium sulfate and concen~ d to give 2 9 of a dark red solid. This 20 material was identified as 4-(4-(methoxycarbonyl)piperidin-1-yl)-6-hydroxy-2-isop~opylbenzimidazole by 1H NMR (with some methoxy product still remaining). Chromatography (2.5:1 ethyl acetate/hexanes) gave the desired product as a colorless soiid, 800 mg (32%, yield).

Compounds of formula (22) 4-(4-(Methoxycarbonyl)piperidin-1-yl)-6-hydroxy-2-isopropylbeu ;" ia7ole (800 mg, 2.4 mmol, 1 eq) was dissolved in 20 mL THF and to the solution was added di-tert-butyldicarbonate t520 mg, 2.4 mmoL, 1 eq.) and the resulting mixture was refluxed. Thin layer chromatography indicated that the reaction was sluggish, Ll-a~t:rore several 1 eq. aliquots of di-tert-butyldicarbonate were added over a period of 3 days of reflux. The reaction was cooled, 30 the THF removed ;n vacuo, and the residue chromatographed (4:1 hexanes/ethylacetate) to give 1-tert-butoxycarbonyl-4-~4-(methoxycsrbonyl~piperidin-1-yl)-6-hydroxy-2-isopropylbe" ;",idd~ole as a colorless solid, 590 mg (59%, yield).

_ CA 02239~08 1998-06-04 W O 97/21437 PCTnB96/01496 Compounds of formula (25) 2-Methyl-5,6-dihydroxybenzimidazole (100 9) in THF (1 L) was basified to pH 8 with aqueous NaHCO3, and to the resulting solution was then added di-tert-butyldicarbonate (104 ~).
After stirring for 3 hours, the THF was removed, and the aqueous residue was diluted and exL~c.uLed with ethyl acetate. The organic layer was dried and concentrated to afford 1-tert-butoxycarbonyl-2-methyl-5,6-dihydroxybenzimidszole as a white solid.

Compounds of formula (26) and (27) To 1-tert-butoxycarbonyl-2-methyl-5,6-dihydroxybenzimidazole (12 9) in DMF (100 mL) was added imidazoie (6.5 g) and tert-butyldimethylsilyl chloride (7.5 g) with vigorous stirring.
After stirring for 1 hour, the reaction was worked up between ethyl acetate/water. The organic layer was dried and concentrated to afford a mixture of 1-tert-butoxycarbonyl-2-methyl-5-(tert-butyld;~lleLll~lsiiyl)oxy-6-hydroxybenzimidazole~ 1-tert-butoxycarbonyl-2-methyl-6-~tert-15 butyldimethylsiiyl)oxy-5-hydroxybenzimidazole, and 1-tert-butoxycarbonyl-2-methyl-5,6-di~(tert-butyldimethylsilyl)oxy)ben~i...ida~ole. To the mixture in THF (150 mL) was first added N-tert-butoxycarbonyl-4-hydroxy-piperidine (12 9), PPh3115 g), and then DEAD (10 mL) in a dropwise fashion. After stirring at ambient te.~pe.aLLlre for 1 hour the solvent was removed and the residue was purified and the regioisomers sepa.dled by silica gel chromatography (hexane/ethyl 20 acetate, ylddienL) to afford 1-tert-butoxycarbonyl-2-methyl-5-(tert-butyld;.lle:Lll~lsilyl)oxy-6-(N
ltert-butoxYcarbonYl)piperidin-4-yloxy)benzimidazole, 1-tert-butoxycarbonyl-2-methyl-6-(tert-butyldimethylsilyl)oxy-5-(N-(tert-butoxycarbonyl)piperidin-4-yioxy)ben~;,.,idazole, and 1-tert-butoxycarbonyl-2-methyi-5,6-di((tert-butyld ,I~:Ll-ylsilyl)oxy)be~ Ic.

Compounds of formula (28) and (29) To 1-tert-butoxycarbonyl-2-methyl-5-(tert-butylJ;~ Ll-ylsilyl)oxy-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)be--~;.-.;da~ole (5 9) in Ill~LI~dnol (100 mL) was bubbled in ammonia at 0~C. After stirring for 12 hours at ambient Lelll~JeldLIJre in a sealed vessel the 30 reaction mixture was concenL,dLl:d and dried to afford 2-methyi-5-hydroxy-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)ben~;.,.;dazole (a compound of formula (28)). To the resulting product in DMF was added imidazole (0.66 g) and (tert-butyldimethylsilyl)chloride (1.5 g). After stirring at ambient temperature for 1 hour the reaction was worked up between ethyl acetate and H20. The organic layer was dried, conce~L~dLed and purified by silica gel chlullld~uylaphy 35 (hexane/ethyl acetate/CH2CI2/methanol, y- ~jLnL) to afford 2-methyl-5-(tert-butyldimethylsilyl)oxy-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole.

CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 Compounds of formula (30) To 2-methyl-5-(tert-butyldimethylsilyl3Oxy-6-~N-(tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole ~6.6 9) in DMF (50 mL) was added NaH (0.65 9~ at ambient temperature.
After stirring at ambient temperature for 30 minutes 7-bromomethyl-2-naphthonitrile (3.88 9) was added. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction was worked up between ethyl acetate and ~'2~ The organic layer was dried concentrated and purified by silica gel chromatography ~hexane/ethyt acetate/CH2CI2/methanol gradientl to afford 2-methyl-5-(tert-butyldimethylsilyl~oxy-6-(N-(tert-butoxycarbonyl~piperidin-4-yloxy)-1 -(4-10 cyanonaphth-1-yl)methylbenzimidazole and 2-methyl-6-(tert-butyldimethylsilyl)oxy-5-(N-(tert-butoxycarbonyl~piperidin-4-yloxy)-1 -(4-cyanonaphth-1 -yl~methylbenzimidazole.

Compounds of formula (31) To 2-methyl-5-(tert-butyldimethylsilyl)oxy-6-(N-(tert-butoxycarbonyl~piperidin-4-yloxy)-1-15 (4-cyanonaphth-1 -yl)methylbenzi". ~7nle (3 9) in THF (50 mL) was added tetrabutyl ammonium fluoride (3 mL 1 M)) at ambient temperature. After stirring at ambient temperature for 30 minutss the solvent was removed. The reaction was woriced up between ethyl acetate and H2O.
The organic layer was dried and conce~L~nl~:d to afford 2-methyl-5-hydroxy-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbe-, ;",idazole.

Compounds of formula (32) A. To 2-methyl-5-hydroxy-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole (1.11 9) in DMF (50 mb) was added NaH (0.15 9) at ambient temperature. After stirring at ambient for 30 minutes ethyl bromoacetate (0.4 m~) was 25 added. The reaction was stirred at ambient L.:",per ,L~3re for 1 hour and was worked up between ethyl acetate and H20. The organic layer was dried, concenll~Le:d and purified by silica gel chromatography (hexane/ethyl acetate/CH2CI2/methanol, ~ L) to afford 2-methyl-5-(ethoxycarbonylmethoxy)-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1 -(4-cyanonaphth-1 -yl)methylbenzimidazole.
B. In a similar manner, the following compounds of formula (32) were made:
2-methyl-5-(1 -(methoxycarbonyl)ethoxy)-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy) -1 -(4-cyanonaphth-1 -yl)methylbenzimidazole;
2-methyl-5-(4-(methoxycarbonyl)benzyloxy)-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazoie; and 35 2-methyl-5-(3-(methoxycarbonyl)benzyloxy)-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-.

CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/01496 1 -~4-cyanonaphth- 1 -yl)methylbenzimidazole.

Compounds of formula (33) To 2-methyl-6-(tert-butyldimethylsilyl)oxy-5-(N-(tert-butoxycarbonyl)piperidin~-yloxy)-1-(4-cyanonaphth-1-yl~methylbenzimidazole (3 9) in THF (50 mL) was added Bu4NF (4 mL, 1 M)~ at ambient temperature. After stirring at ambient temperature for 30 minutes the solvent was removed. The reaction was worked up between ethyl acetate and H20. The organic layer was dried, concentrsted and purified by silica gcl chromatography (hexane/ethyl acetate/CH2CI2/methanol, gradient) to afford 2-methyl-6-hydroxy-5-(N-(tert-10 butoxycarbonyl)piperidin-4-yloxy)-1 -~4-cyanonaphth-1 -yl)methylbenzimidazole.

PREPAP~ATION 23 Compounds of formula (34) To 2-methyl-6-hydroxy-5-~N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole (2.8 9) in THF (50 mL) was first added N-benzyloxycarbonyl-4-15 hydroxypiperidine (1.7 9), PPh3 (1.9 9~, and then DEAD ~1.2 mL~ in a dropwise fashion. After stirring at ambient temperature for 1 hour the solvent was removed and the residue was separated by silica gel chromatography ~hexane/ethyl acetate, gradient) to afford 2-methyl-6-~N-(benzyloxycarbonyl)piperidin-4-yloxy)-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1 -(4-cysnonaphth-1-yl)methylben i-~-;da ole.

PREPARAT~ON 24 Compounds of formula (35) and (36) To 2-methyl-6-(N-(benzyloxycarbonyl)piperidin-4-yloxy)-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole (4 9) in CH2CI2/methanol ~100 mL, 9:1, v/v) was added trifluoroacetic acid (20 mL). After stirring for 6 hours at ambient temperature the 25 reaction was concenLraLt:d to afford the trifluoroacetic acid salt of 2-methyl-6-(piperidin-4-yloxy)-~;-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(~cyanonaphth-1-yl)methylbenzimidazole (a compound of formula (35)). To the resulting product in THF (50 mL) was added ethyl bromoacetate (0.72 mL) and K2CO3 (5 g). After stirring at ambient temperature for 1 hour the reaction was worked up between ethyl acetate and H20. The organic layer was dried, 30 concenL-~Led and purified by silica gel chromatography (hexane/ethyl acetate/CH2CI2/methanol, ~J,adienL) to afford 2-methyl-6-(N-(ethoxycarbonyl-methyl)piperidin-4-yloxy)-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1 -(4-cyanonaphth-1 -yl)methylbenzimidazole.

CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 Compounds of formula (38) A.To 5-amino-2-methoxycarbonylphenoi ~60 9) in pyridine (200 mL) was added acetic anhydride (70 mL) at ambient temperature. After stirring at ambient temperature for 14 hours the solvent was removed to afford 5-acetylamino-2-methoxycarbonyl-1-acetoxybenzene.
B. In a similar manner, the following compound of formula (38) was prepared:
5-(2-methyl-1 -oxopropyl)amino-2-methoxycarbonyl-1 -(2-methyl-1 -oxopropoxy~benzene.

PREPARATlON 26 Compounds of formula (39) A. To 5-acetylamino-2-methoxycarbonyl-1-acetoxybenzene (20 g) in trifluoroaceticacid (150 mL) was added HNO3 (5 mL) at ambient temperature. After stirring at ambient temperature for 2 hours the solvent was removed. The resulting residue was recrystallized from ethyl acetate to afford a mixture of 5-acetylamino-4-nitro-2-methoxycarbonyl-1-hydroxybenzene and 5-acetylamino-6-nitro-2-methoxycarbonyl-1-hydroxybenzene.
B. In a similar manner, the following compounds of formula (39) were made:
5-(2-methyl-1-oxopropyl)amino-4-nitro-2-methoxycarbonyl-1-hydroxybenzene: and 5-(2-methyl-1 -oxopropyl)amino-6-nitro-2-methoxycarbonyl-1 -hydroxybenzene.

Compounds of formulae (41) A. To a mixture of 5-acetylamino-4-nitro-2-methoxycarbonyl-1-hydroxybenzene and 5-acetylamino-6-nitro-2-methoxycarbonyl-1-hydroxybenzene (15 9) in methanol (50 mL) was added Pd/C (10 9). The resulting mixture was hydrogenated at 50 psi for 3 hours until H2 intake d "inished. The catalyst was filtered off and the filtrate was concen~l~Led to afford a mixture of 5-acetylamino4-amino-2-methoxycarbonyl-1-hydroxybenzene and 5-acetylamino-6-amino-2-25 methoxycarbonyl-1-hydroxybenzene. This mixture was then refluxed in acetic acid (200 mL) for 2 hours. After removal of acetic acid the residue was worked up between ethyl acetate and aqueous NaHCO3. The organic layer was dried and concenLl~led to afford a mixture of 2-methyl-6-hydroxy-5-methoxy-carbonylbenzimidazole and 2-methyl-4-hydroxy-5-methoxycarbonyl-ben~ 701e.
B. In a similar manner, the following compound of formulae (41 ) was made:
2-isopropyl-6-hydroxy-5-methoxycarbonylbenzimidazole.

Compounds of formula (42) To a mixture of 2-methyl-6-hydroxy-5-methoxycarbon~lL,erl~illlidazole and 2-methyl-4-CA 02239~08 1998-06-04 W O 97~1437 PCT~B96/01496 hydroxy-5-methoxycarbonylbenzimidazole (7.2 9) in THF (50 mL) was added di-tert-butyldicarbonate (7.6 9) and triethylamine (5 mL). After stirring at 50~C for 6 hours the solvent was removed and the residue was triturated with ethyl acetate and filtered to afford 1-tert-butoxycarbonyl-2-methyl~6-hydroxy-5-methoxycarbonylbenzimidazole and 1-tert-butoxycarbonyl-5 2-methyl-4-hydroxy-5-methoxycarbonylbenzimidazole.

PREPARATlON 29 Compounds of formula (43) To a mixture of 1-tert-butoxycarbonyl-2-methyl-5-hydroxy-6-methoxycarbonyl-benzimidazole and 1-tert-butoxycarbonyl-2-methyl-6-hydroxy-5-methoxycarbonylbenzimidazole 10 (3.7 9) in THF (50 mL) was first added N-tert-butoxycarbonyl-4-hydroxypiperidine (3.2 9), PPh3 (4.2 9) and then DEAD (2.5 mL) in a dropwise fashion. After stirring at ambient temperature for 4 days the solvent was removed and the residue was separated by silica gel chromatography (hexane/ethyl acetate/CH2C12/methanol, glt~.l;enL) to afford a mixture of 1-tert-butoxycarbonyl-2-methyl-5-methoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)ben~i",ida~ole and 1-tert-15 butoxycarbonyl-2-methyl-6-methoxycarbonyl-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy) benzimidazole.

Compounds of formulae (44) and (45) To a mixture of 1-tert-butoxycarbonyl-2-methyl-5-methoxycarbonyl-6-(N-~tert-20 buto~cycarbonyl)piperidin-4-yloxy)benzimidazole and 1-tert-butoxycarbonyl-2-methyl-6-methoxycarbonyl-5-(N-(tert-butoxycarbonyl~piperidin-4-yloxy)ben~ 7Ole (2.5 9~ in methanol ~200 mL) was bubbled in ammonia at 0~C. After stirring for 2 hours at ambient temperature the reaction mixture was concentrated. The resulting residue was purified by silica geJ
chromatography (hexane/ethyl acetate/CH2C12/methanol, ~, ~ ,L) to afford 2-methyl-5-25 methoxycarbonyl-6-tN-(tert-butoxycarbonyl)F . i.li,l-4-yloxy)ben~i", '~701e. To this product (0.66 9) in l:)MF (20 mL) was added NaH (0.075 9) at ambient te"",e~Lure. After stirring at ambient temperature for 30 minutes 7-bromomethyl-2-naphthonitrile (0.5 9~ was added at 0~C.
The reaction mixture was stirred at ambient temperature for 0.5 hours. The reaction was worked up between ethyl acetate and H2O. The organic layer was dried and concentrated to afford a 30 mixture of 1-(4-cyanonaphth-1-yl)methyl-2-methyl-5-methoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy) benzimidazole and 1 -(4-cyanonaphth- 1 -yl)methyl-2-methyl-6-methoxycarbonyl-5-(N-(tert-butoxycarbonyl)pi~ue,idi-,-4-yloxy)be,)~ ida~ole in a ratio of 2 to 1, respectively.

CA 02239~08 1998-06-04 W O 97/21437 PCTnB96/01496 Compounds of formulfl (46) To 3,5-dinitro-1-carboxy-2-chlorobenzene (53 g) in acetonitrile I500 mL) and triethylamine (100 mL) was added benzylamine at 0~C in a dropwise fashion. The reaction was allowed to 5 warm to ambient temperature and stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure to afford the crude product, 3,5-dinitro-1-carboxy-2-(benzyl~aminobenzene. The product was dissolved in methanol/12N HCI (400 mL, 3:1, v/v), and was hydrogenated at 60 psi for 3 hours until H2 intake stopped. The solvent was removed under reduced pressure to afford the crude product, 2,3,5-triamino-1-carboxybenzene. To the product 10 in pyridine ~400 mL) was added isobutyric anhydride (200 mL), and the reaction mixture was stirred at ambient temperature for 14 hours. The sotvent was removed under reduced pressure to afford the crude product, 2,3,5-tri(isopropylcarbonylamino)-1-carboxybenzene. The product was refluxed in methanol/12N HCI (500 mL, 4:1, v/v) for 16 hours to afford the desired product, 2-isopropyl-4-methoxycarbonyl-6-aminobenzimidazole, after removal of the solvents under reduced 15 pressure.

Compounds of formula (48) To 2-isopropyl-4-methoxycarbonyl-6-aminoben~i-,-ida~ole in methanol/acetic acid (300 mL, 2:1, v/v) was added N-tert-butoxycarbonyl-4-piperidone (80 9), foilowed by NaCNBH4 (9 9) at 20 ambient temperature. After stirring st ambient l~:r,-pe-dL--re for 1 hour the solvents were removed and~the resulting residue was worked up between ethyl acetate and H20. The organic layer was dried, concentrated, and purified by silica gel chromatography (hexane/ethyl acetate/CH2CI2/methanol, gradient) to afford 2-isopropyl-4-methoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-ylamino)benzi,ll ~ ~le as a foam.

Compounds of formula (49) To 2-isopropyl-4-methoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-ylamino)ben~i...idazole (3.3 9) in DMF (200 mL) was added NaH (0.35 9) at ambient temperature.
After stirring at ambient temperature for 30 minutes, the reaction flask was cooled to -10~C and 30 7-bromomethyl-2-naphthonitrile (2.2 g) was added. The reaction was allowed to warm to ambient ltemperature and stirred at ambient temperature for 15 hours. The reaction was worked up between ethyl acetate and H20. The organic layer was dried, concenl~ d and purified by silica gel chromatography (hexane/ethyl acetate/CH2CI2/methanol, gradient) to afford 1-(4-cyanonaphth-1 -yl)methyl-2-isopropyl-4-methoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-35 ylamino)benzimidazole, and 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-7-methoxycarbonyl-5-(N-CA 02239~08 1998-06-04 WO 97~1437 PCT~B96/01496 (tert-butoxycarbonyl) -piperidin-4-ylamino) benzimidazole.

Compounds of formula (51) To a solution of 5-aminobenzimidazole (5.2 9, 40 mmol)"V-tert-butoxycarbonyl-4-h piperidone ~8.0 9, 40 mmol), and acetic acid ~3 mL) in methanol (250 mL) snd methyiene chloride (50 mL) at 0~C was added sodium cyanoborohydride (3.77 9, 60 mmol). The solution was stirred for 20 minutes at 0~C when it was allowed to warm to ambient temperature. After 12 hours, the reaction was worked up wlth ethyl acetate and water, dried ~MgSO4), and chrul,la~ugraphed on silica gel eluting with 7% methanol in methylene chloride to recover 9.47 9 10 (77%) of 5-((N-(tert-butoxycarbonyl)piperidin-4-yl)amino)ben~ da~ole.

Compounds of formula (52) and (54) A. To a solution of 5-~lN-(tert-butoxycarbonyl)piperidin-4-yl)amino)benzimidazole 11.50 9, 4.75 mmol) in DMF (30 mL) at 0~C was added NaH (210 mg, 5.2 mmol). The solution 15 was stirred for 0.5 hours when tosyl chloride (1.0 9, 5.2 mmol) was added. The reaction mixture was stirred for 1 hour at 0~C when it was worked up with ethyl acetate and water, dried (MgSO4), and concenLIaLt:d to an oil to afford 1-tosyl-5-((N-(tert-butoxycarbonyl)piperidin-4-yl)amino)benzimidazole and its re~ioisoll,er, 1-tosyl-6-((N-(tert-butoxycarbonyl)piperidin-4-yl)amino)ben~i"l;da~ . The resulting oil was taken up in DMF (30 mL) when it was charged with 20 K2CO3 (4 9) and methyl iodide (3 mL). After 12 hours at ambient temperature, the reaction mixture was worked up with ethyl acetate and water, dried (MgSO4), and concentrated to an oil.
The resulting tosylated product, 1-tosyl-5-((N-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)benzimidazole and the corresponding regioi:.o."er, was taken up in methanol (80 mL) and NaOH (0.3 9, 7.5 mmol) was added. After 1 hour at ambient temperature, the 25 methanol was removed in vacuo and the product recovered via chromatography on silica gel sluting with 5% to 10% methanol in methylene chloride to give 473 mg (30%) 5-((N-(tert-butoxycarbonyl) piperidin-4-yl) (methyl) amino) beu~i" ,;dazole .
B. In a similar manner, to a solution of 1-tosyl-2-methyl-5-((N-(tert-butoxycarbonyl)piperidin-4-yl)amino)ben~i,..idazcl~ (2.7 9, 5.58 mmol) in DMF (15 mL) was added 30 K2CO3 (3.85 g, 28 mmol) and methyl 3-bromo-2-methylene-propionate (1 9, 5.58 mmol). The solution was stirred at ambient temperature for 12 hours when it was worked up with ethyl acetate and water, dried (MgSO4), and conce"l-aLed to recover a foam (2.~ 9) containing 1-tosyl-2-methyl-~-(N-(tert-butoxycarbonyl)piperidin-4-yl)(~2-methoxycarbonyl)prop-2-en-1 -yl)aminobenzimidazole and trace starting mate~ial and DMF.
35 C. To a solution of the product of Pa"l~,(aph B above, 1-tosyl-2-methyl-5-(N-(tert-CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/01496 butoxycarbonyl)piperidin-4-yl)(2-~methoxycarbonyl)prop-2-en-1-yl)aminobenzimidazole, (2.5 9) in ethanol (100 mL) and ethyl acetate (30 mL3 was charged with Raney nickel (1 mL of a 50%
water siurry) and subjected to an atmosphere of hydrogen (20 psi). After 6 hours, the catalyst was filtered off, the solution dried (M~SO4) and concentrated to a solid to recover 1.5 g of 1-tosyl-2-methyl-5-(/\/-(tert-butoxycarbonyl)piperidin-4-yl)(2-(methoxycarbonyl)prop-1-yl)aminobenzimidazole.
D. To a solution of 1-tosyl-2-methyl-5-(N-(tert-butoxycarbonyl)piperidin-4-yl)aminoben~iml~ole (6.1 9, 12.1 mmol) and triethylamine (3.4 mL, 24 mmol) in methylene chloride (30 mL) at 0~C was added ethyl succinyl chloride (2.1 mL, 14.5 mmol). After 2.5 hours, 10 the solution was filtered and extracted with water and 1 M NaOH to recover 1-tosyl-2-methyl-5-(N-(tert-butoxycarbonyl)piperidin-4-yl)((2-(ethoxycarbonyl)ethyl)carbonyl)aminobenzimidazole.
E. In a manner similar to that described above in Paragraph A wherein the compound is treated with sodium hydroxide in methanol, the following compounds of formula (55) were made:
15 2-methyl-5-(N-(tert-butoxycarbonyl)piperidin-4-yl)(2-~methoxycarbonyl)prop-1 -yl)aminoben~;"-idazole;
2-methyl-5-(N-(tert-butoxycarbonyl)piperidin-4-yl)((methoxycarbonyl)-methyl)aminobenzimidazole:
2-methyl-5-(N-(tert-butoxycarbonyl)piperidin-4-yl)((2-(ethoxycarbonyl)ethyl)-carbonyl)a",i"oben~ -idazole; and 2-methyl-5-(N-(tert-butoxycarbonyl)p;,~,eridill-4-yl)(3-tmethoxycarbonyl~-prop-1 -yl)aminobenzimidazole.

Compounds of formula (56) To a solution of 1,2-diamino-4-methoxybenzene (50 9) in pyridine (400 mL) at 0~C was added isobutyryl chloride (100 mL). After 3 hours, the solvent was removed in vacuo and the solid partitioned between methylene chloride and wster. The orqanic layer was concentrated and taken up in 4 N HCI, and then heated to reflux overnight. The solution was concentrated to a solid, neutralized with sodium bicarbonate, then conce,.ll~L~d once again to a solid. The solid 30 was washed with THF to recover 2-isopropyl-5-methoxy-6-nitrobenzimidazole (29 S~)-Compounds of formula (57) A. 2-lsopropyl-5-methoxyben~illl;da~ole (50 9) was dissolved in 150 mL TFA and to the mixture was added 5 mL 90% nitric acid. The reaction was stirred overnight, and the 35 solvents removed in vacuo and the residue neutralized to pH 7 with saturated aqueous sodium CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/01496 bicarbonate. The residue was extract~d with ethyi acetate (4x100 mL). The combined ethyl acetate fractions were dried over sodium sulfate and concentrated to give a dark residue.
Chromatography (3% methanol/methylene chloride) gave 2-isopropyl-4-nitro-5-methoxybenzimidazole as a yellow solid, 24 9. Also obtained was 25 9 of 2-isopropyl-5-nitro-6-5 methoxybenzimidazole.
B. In a similar manner, the following compound of formula (57) was made:
2-methyl-4-nitro-5-methoxybenzimidazole and 2-methyi-5-nitro-6-methox~,L,e,.~i".idazole.
C. Alternatively, to a solution of 2-isopropyl-5-methoxybenzimidazole (50 9~ in trifluoroacetic acid (150 mL) at ambient temperature was added fuming HNO3 (15 mL). The 10 reaction was stirred overnight, the solvent removed in vacuo and the residue quenched with potassium carbonate. The aqueous layer was then extracted with ethyl acetate, the organic layer dried and concentrated to recover a mixture of the regioisomers, 2-isopropyl-6-methoxy-5-nitrobenzimidazole and 2-isopropyl-4-nitro-5-met~oxyl,el1~i".idazole (3:1 ratio) and. The regioisomers were separated by chromatography (3% methanol/methylene chloride) to recover 2-15 isopropyl-6-methoxy-5-nitrobenzimidazole (24 9) .

Compounds of formula (58) A. A solution of 2-isopropyl-6-methoxy-5-nitrobenzimidazole (t7 9) in concentrated HBr (300 mL) was refluxed for 7 hours when the solvent was removed in v~cuo. The residue 20 was quenched with potassium carbonate and extracted with ethyl acetate. The organic layer was dried and conce~ Led to recover 2-isopropyl-6-hydroxy-5-nitroben~;.,-id~,~ole as well as an HBr addition product (approx. 2:1 ratio).
B. In a similar manner, the following compound of formula ~58) was made:
2-methyl-6-hydroxy-5-nitrobenzimidazole;
25 2-methyl-5-hydroxy-4-nitroben~i",idazole; and 2-isopropyl-5-hydroxy-4-nitroben~il, ~idazole .

Compounds of formula (59) A. To a solution of Z-isopropyl-6-hydroxy-5-nitrobenzimidazole and the HBr addition 30 product (15 9), N-tert-butoxycarbonyl-4-hydroxypiperidine (17.7 9), PPh3 (23.1 9), and THF
(150 mL) at room temperature was added DEAD (14 mL). After 4 hours, the solvent was removed in vacuo and the product recovered from the crude using chromatography (3%
methanol/methylene chloride) to yield 2-isopropyl-5-(/~/-(tert-butoxycarbonyl)p;~,e.idin-4-yloxy)-6-ni~"~ben~i,--idaZole (16-5 Ç1)-35 B. In a similar manner, the following compound of formula (59) was made:

CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/Ot496 2-methyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy~-5-nitrobenzi" '~7c 1e;
2-methyl-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-4-nitrobenzimidazole; and 2-isopropyl-5-~N-(tert-butoxycarbonyl)piperidin-4-yloxy)-4-nitroben~ 701~.

Compounds of formula (60) A. To a solution of 2-isopropyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-5-nitrobenzimidazole (16.5 9) in DMF (50 mL) at 0~C was added NaH (2.45 9). After 40 minutes, 7-bromomethyl-2-naphthonitrile (11 9) was added and the reaction stored in the freezer (-35~C) overnight. The reaction was worked up with ethyl acetate and water and the organic layer dried 10 and concentrated to an oil. The product was isolated using 2% methanol/methylene chloride on silica gel to give a mixture of 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-5-nitrobenzimidazole and 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-5-(N-(tert-butoxycarbonyl~piperidin-4-yloxy)-6-nitroben~ idazole (2.5:1 ratio, 16.5 9).
B. In a s;milar manner, the following compound of formula (60) was made:
15 1-14-cyanonaphth-1-yl)methyl-Z-methyl-6-(N-(tert-butoxycarbonyl)p;~ edd ~-4-yloxy)-5-nitrobenzimidazole;
1 -(4-cyanonaphth-1 -yl)methyl-2-methyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-7-nitrobenzimidazole; and 1 -(4-cyanonaphth-1 -yl)methyl-2-isopropyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-7-nitroben~;~ "ida~ole.

Compounds of formula (61) A. 1-(4-Cyanonaphth-1-yl)methyl-2-isopropyl-7-nitro-8-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)ben~i,l-idazole (12 9, 21 mmoL, 1 eq.) was dissolved in 400 mL
25 dry pyridine and to this was added tin ~ chloride dihydrate (71 9, 315 mmoL, 15 eq.) which formed a finely divided suspension. The slurry was heated to 50~C for 14 hours. The pyridine was stripped off, and the salts triturated in 1 L ethyl acetate. The salts were removed by filtration through Celite and the filtrate was conct:~LlaLed to give a brown oil. Chromatography (3/2 ethyl acetate/hexanes) gave 7.6 9 (67% yield) of 1-~4-30 cyanonaphth-1-yl)methyl-2-isopropyl-7-amino-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole as a tan foam.
B. Alternatively, to a solution 1-(4-cyanonaphth-1yl)methyl-2-isopropyl-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-6-nitroben~ildida~Gle and 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-5-nitrObell~illlidd~ole (16.5 9) in CA 02239~08 1998-06-04 -~2-triethylamine (100 mL) and pyridine (50 mL) was added SnCi2 H2O ~32.7 9). The reaction was warmed to 60~C for 3 hours when the solvent was removed in vacLlo. The solid was taken up in ethyl acetate and filtered. The ethyl acetate was removed ;n vacuo and the product isolated using siiica gel eluting with 5% methanol/methylene chloride to recover 1-(4-cyanonaphth-1-5yl)methyl-2-isopropyl-6-(N-~tert-butoxycarbonyl)piperidin-4-yloxy)-5-aminobenzimidazote (5.7 9).
C. In a similar manner, the following compound of formula (61) was made:
1 -(4-cyanonaphth-1 -yl)methyl-2-methyi-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-5-aminobenzi."i '~7-~1e.

10Compounds of formula (62) A. 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-7-amino-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole (5.5 9, 10 mmol, 1 eq.) was dissolved in 50 mL
dry DMF and to this was added methyl bromoacetate (1.2 mL, 12 mmoL, 1.2 eq.) and then potassium carbonate (1.4 9, 1.2 eq.). The reaction was stirred at 20~C for 2 days. TLC
15 indicated the reaction to be nearly complete. The reaction mixturs was worked up between water and ethyl acetate. The ethyl acetate was removed in v,~cuo and the product was isolated by chromatography (3/2 hexanes/ethyl acetate) to afford 5 g of 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-7-((methoxycarbonyl)methyl)amino-6-(N-~tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole with a smali amount of the diaddition product.
B. Alternatively, to a suspension of 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-6-~N-(tert-butoxycarbonyi~piperidin-4-yloxy)-5-aminobenzimidazole (500 mg), potassium carbonate (642 mg), and DMF was added methyl 4-bromomethylbenzoate 1212 mg). After 2 days at ambient temperature, the reaction was worked up with ethyl acetate and water. The organic layer was dried and the product isolated on silics qel using 2% methanol/methylene chloride to 25 recover 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-5-(N-(4-me2hoxycarbonylbenzyl)-amino)benzimidazole (440 mg).
C. In a similar manner, the following compounds of formula (62) were made:
1 -(4-cyanonaphth- 1 -yl)methyl-2-isopropyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-5-(N-(2-methoxycarbonylethyl)amino)benzimidazole;
30 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-5-(N-(1-methoxycarbonyl-1-methylethyl)amino)be-, i,..idd ole;
1 -(4-cyanonaphth-1 -yl)methyl-2-methyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-5-(N-(4-methoxycarbonylbenzyl)amino)benzimidazole; and 1 -(4-cyanonaphth-1 -yl~methyl-2-isopropyl-6-(N-(tert-butoxycarbonyl)Piperidin-4-yloxy)-5-lN-(4-methoxycarbonylbenzyl)amino)benzimidazole.

CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 Compounds of formula (la) A. To a slurry of 1-(4-cyanonaphth-1-yl)methyl-2-isopropyi-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy~benzimidazole and 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-5-(N-ltert-butoxycarbonyl~Piperidin-4-yloxy)bell~inlidc- ole (320 mg, 62 mmoi) and ethanol (10 mL) cooled in a dry ice/acetone bath was bubbled HCI (9). After the solution was saturated, the reaction flask was sealed and the temperature maintained at 5~C for 16 hours. The solvent was removed in vacLto. The residue was dissolved in ethanol (20 mL~. The solution was cooled in a dry ice/acetone bath and ammonia (g) was bubbled in. The reaction flask was sealed then heated 10 at 80~C for 4 hours. The solvent was removed. The mixture was separated by HPLC on a C18 Dynamax column with a 5-20% ace~onil,ile in water gradient with 0.1 % trifluoroacetic acid to afford 1-(4-amidinonaphth-1-Yl~methyl-2-isopropyl-6-(piperidin-4-yloxy~benzimidazole ditrifluoroacetate salt, 1H NMR (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.20 (s, 2H), 8.60 (br s, 2H), 8.40 (s, 1H), 8.18 (d, 1H), 8.14 (d, 1H), 7.90-7.75 (m, 3H), 7.60 (m, 1H~, 7.40 (s, 1H), 7.25 15 (dd, 1H), 6.05 (s, 2H), 4.70 (m, 1H~, 3.65 (septuplet, 1H), 3.30-3.20 (m, 2H), 3.15-3.00 (m, 2H), 2.18-2.00 ~m, 2H~, 1.90-1.80 (m, 2H), 1.40 (d, 6H); and 1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-5-(piperidin-4-yloxy)benzimidazole ditrifluoroacetate salt,1H NMR (300 MHz, DMS0) ~

9.40 (s, 2H), 9.20 (s, 2H), 8.60 (br s, 2H), 8.40 (s, 1H), 8.18 (d, 1H), 8.14 (d, 1H), 7.90- 7.75 (m, 3H), 7.65-7.60 (m, 2H), 7.25 (dd, 1H), 6.05 (s, 2H), 4.70 (m, 1H), 3.65 (septuplet, 1H), 20 3.30-3.20 (m, 2H), 3.15-3.00 (m, 2H), 2.18-2.00 (m, 2H), 1.85-1.70 (m, 2H), 1.35 (d, 6H).
B. In a similar manner, the following compounds were made:
1-(4,amidinonaphth-1-yl)methyl-2-propyl-6-(piperidin-4-yloxy~ben i,lli ~ole, 'H
NMR (300 MHz, DMS0~ ~ 9.40 (s, 2H~, 9.20 (s, 2H), 8.60 (br s, 1H), 8.40 (s, 1 H), 8.18 (d, 1H), 8.10 (s, 1H), 7.95 (s, 1H~, 7.85 (d, 1H), 7.75 (d, 1H~, 7.65 (d, 1H~, 7.40 (s, 1H), 7.20 (dd, 1H), 5.95 (s, 2H), 4.70 (m, 1H), 3.30-3.00 (m, 6H), 2.18-2.00 (m, 2H), 1.85-1.70 (m, 4H), 0.90 (t, 3H);
1-(4-amidinonaphth-1-yl~methyl-2-propyl-5-(piperidin-4-yloxy)benzimidazole, 1H NMR (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.20 (s, 2H), 8.60 (br s, 2H), 8.40 (s, lH~, 8.18 (d, 1H), 8.14 (d, 1H~, 7.90- 7.80 (m, 3H), 7.65 (d, 1H), 7.60 (s, 1H), 7.25 (dd, 1H), 6.00 (s, 2H), 4.70 (m, 1H), 3.30-3.00 (m, 6H), 2.18-2.00 (m, 2H), 1.85-1.70 (m, 4H~, 0.90 (t, 3H~;
1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-4-methoxy-6-(piperidin-4-yloxy)benzimidazole, tH NMR (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.20 (s, 2H), 8.60 (br s, 2H), 8.40 (s, 1H~, 8.18 (d, 1H), 8.14 (d, 1H~, 7.80 (d, 1H~, 7.75 (s, 1H), 7.60 (d, 1H), 7.20 (s, 1H), 6.85 (s, 1H~, 6.00 (s, 2H), 4.70 (m, 1H), 4.05 (s, 3H), 3.60 (septuplet, 1H), 3.30-3.25 (m, 2H), 3.15-3.05 (m, 2H), 2.18-2.00 (m, 2H), 1.90-1.80 (m, ZH), 1.35 (d, 6H);
1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-7-methoxy-5-(piperidin-4-yloxy)benzimidazole, 1H NMR (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.20 (s, 2H), 8.60 (br s, 2H), 8.40 (s, 1H), CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 8.18 ~d, 1it), 8.14 (d, 1H), 7.80 (d, 1H~, 7.75 (s, 1H), 7.60 (d, 1H), 6.97 (s, lH), 6.80 (s, 1H), 6.05 (s, 2H~, 4.80 (m, lH), 3.85 (s, 3H3, 3.65 ~septuplet, lH), 3.30-3.25 (m, 2H), 3.20-3.05 (m, 2H), 2.18-2.00 (m, 2H~, 1.90-1.80 (m, 2H), 1.40 (d, 6H);
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-6-(piperidin-4-Y'oXY)benZimidazole~ ' H
NMR (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.20 (s, 2H), 8.60 (br s, 1H), 8.40 (s, lH), 8.18 (d, 1H), 8.10 (s, lH), 7.90-7.75 (m, 3H), 7.70 ~d, 1H), 7.58 (s, 1H), 7.20 (dd, lH), 5.95 (s, 2H), 4.70 (m, 1H), 3.30-3.20 lm, 2H), 3.10-3.00 (m, 2H), 2.80 (s, 3H), 2.10-2.00 (m, 2H), 1.85-1.75 (m, 2H);
1 -(4-amidinonaphth- 1 -yl)methyl-2-methyl-5-(piperidin-4-yloxy)benzimidazole, 1H NMR (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.20 (s, 2H), 8.60 (br s, lH), 8.40 (s, 1H), 8.18 (d, 1H), 8.10 (s, 1H), 7.99 (s, lH), 7.95 (d, lH), 7.75 (d, lH), 7.65 (d, lH), 7.40 (s, ltl), 7.20 (dd, lH), 5.95 (s, 2H), 4.80 (m, lH), 3.30-3.20 (m, 2H), 3.10-3.00 (m, 2H), 2.90 (s, 3H), 2.10-2.00 (m, 2H), 1.95-1.85 (m, 2H);
1-(4-amidinonaphth-1-yl)methyl-6-(piperidin-4-yloxy)benzimidazolP, lH NMR (300 MHz, DMS0) 9.80 (s, 1 H), 9.40 (s, 2H), 9.20 (s, 2H), 8.60 ( br s, 2H), 8.40 (s, 1 H), 8.20-8.00 (m, 3H), 7.90-7.75 (m, 3H), 7.60 (s, 1H), 7.25 (dd, 1H), 6.00 ~s, 2H), 4.70 (m, 1H), 3.30-3.20 (m, 2H), 3.20-3.00 (m, 2H), 2.20-2.00 (m, 2H), 1.85-1.75 (m, 2H);
1-(4-amidinonaphth-1-yl)methyl-5-(piperidin-4-yloxy)benzimidazole, 1H NMR (300 MHz, DMS0) o 9.80 (s, 1H), 9.40 (s, 2H), 9.20 (s, 2H), 8.60 (br s, 2H), 8.40 (s, 1H), 8.20-8.00 (m, 3H), 7.gO-7.75 (m, 3H), 7.45 (s, 1H), 7.20 (dd, 1H), 6.00 (s, 2H), 4.80 (m, 1H), 3.30-3.20 (m, 2H), 3.20-3.00 (m, 2H), 2.20-2.00 (m, 2H), 1.90-1.70 (m, 2H);
1 -~4~amidinonaphth-1 -yl)methyl-2-methyl-5-(aminocarbonyl)methoxy-6-(piperidin-4-yloxy)be,~il"idazel~, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-6-(aminocarbonyl)methoxy-5-(piperidin- 4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-6-(carboxy)methoxy-5-(piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-6-(piperkli"-3-yloxy~benzimidazole, 1 -(4-am;dinonaphth- 1 -yl)methyl-2-(2-amino ,a, Lonylethyi)-6-(piperidin-4-yloxy)ben i,llidacole, i-(4-amidinonaphth-1-yl)methyl-2-(2-carboxyethyl)-6-(pi~ eridin-4-yloxy)benzimidazole, 1-(4-amidinonaphth-1-yl)methyl-2-ethyl-6-(pi~,eridi"-4-yloxy)benzimidazole, lH
NMi~ (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.20 (s, 2H), 8.50 (br s, 1 H), 8.40 (s, 1 H), 8.20-8.05 (m, 2H), 7.90-7.80 (m, 3H), 7.65 (d, 1H), 7.60 (s, 1H) 7.25 (dd, 1H), 6.00 (s, 2H), 4.70 (m, lH), 3.30-3.00 (m, 6H), 2.10-2.00 (m, 2H), 1.90-1.70 (m, 2H), 1.35 (t, 3H);
1-(4-amidinonaphth-1-yl)methyl-2-ethyl-5-(piperidin-4-yloxY)ben~illlida~ole~ lH

W O 97/21437 PCT~B96101496 NMR (300 MHz, DMS0~ ~ 9.40 (s, 2H), 9.20 (s, 2H), 8.60 (br s, lH), 8.40 (s, 1H), 8.15 (d, 1H), 8.10 (d, 1H), 7.90 (s, lH), 7.85 (d, 1H), 7.75 (d, 1H), 7.60 (d, 1H), 7.40 (s, 1H), ~ 7.20 (dd, 1H), 6.00 (s, 2H), 4.70 (m, 1H), 3.30-3.00 (m, 6H), 2.10-2.00 ~m, 2H), 1.90-1.70 (m, 2H), 1.35 (t, 3H);
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(carboxy)methoxy-6-(piperidin-4-yloxy)benLi~ilid - ' ~, 1 -(4-amidinonaphth-1 -yl)methyl-6-(N-(piperidin-4-yl)-N-(4-methoxycarbonylbenzyl)-amino) benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-6-(N-(piperidin-4-yl)-N-(4-carboxybenzyl)-amino)benzimidazole, and 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-6-(N-(piperidin-4-yl)-N-(2-(methoxy-carbonyl)ethyi)amino)benzimidazole.

E~CAMPLE 2 Compounds of formula (Ib) 1 5 A. To a solution of 1-(4-smidinonaphth-1-yl)methyl-2-isopropyl-6-(piperidin-4-yloxy)benzimidazole and 1-(4-amidinonaphth-1-yl)msthyl-2-isopropyi-5-(piperidin-4-yloxy)benzimidazole as a 1 :1 mixture of compounds (288 mg, 0.65 mmol) and methanol ~5 mL) was added triethylamine (0.54 mL, 3.90 mmol) and ethylacetimidate (320 mg, 2.60 mmol). After stirring for 16 hours, the reaction was concentrated. The mixture was separated on HPLC on a C18 Dynamax column with a 1-20% acetonil,ilc in water gradient with 0.1 % trifluoroacetic acid to-~fford 1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-6-(N-(1-iminoethyl~piperidin-4-yloxy)benzimidazole ditrifluoroacetate salt; 1H NMR (300 MHz, DMS0~ ~ 9.40 (s, 2H), 9.20 (s, 2H), 9.15 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.20-8.10 (m, 2H), 7.90-7.70 (m, 3H), 7.60-7.50 (m, 2H), 7.24 (d, 1H), 6.00 (s, 2H), 4.80 (m, 1H), 3.80-3.40 (m, 5H), 2.28 (s, 3H), 2.05 (m, 2H), 1.80 (m, 2H), 1.30 (d, 6H); and 1-(4-t.,ll;d:.. onaphth-1-yl)methyl-2-isopropyl-5-(N-(1-iminoethyl)piperidin-4-yloxy)ben~il"idazole ditrifluoroacetate salt; 1H NMR (300 MHz, DMS0) 9.40 (s, 2H), 9.20 (s, 2H), 9.10 (s, lH), 8.60 (s, lH), 8.40 (s, lH), 8.20-8.00 (m, 2H), 7.90-7.75 (m, 3H), 7.60 (dd, lH), 7.40 (s, lH), 7.25 (dd, lH), 6.00 (s, 2H), 4.80 (m, 1 H), 3.80-3.65 (m, 3H), 3.55 (m, 2H), 2.30 (s, 3H), 2.10 (m, 2H), 1.80 (m, 2H), 1.40 (d, 6H).
B. In a similar manner, the following compounds were made:
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-6-(N-(1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 1H NMR (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.30 (s., 2H), 9.15 (s, 1 H), 8.60 (s, 1 H), 8.40 (s, lH), 8.20-8.05 (m, 2H), 7.90-7.75 (m, 3H), 7.65 (d, lH), 7.60 (s, lH), 7.25 (dd, lH), 6.00 (s, 2H), 4.80 (m, lH), 3.80-3.65 (m, 2H), 3.60-3.50 (m, 2H), 2.90 (s, 3H), 2.25 (s, 3H), 2.10-2.00 (m, 2H), 1.80-1.65 (m, 2H).
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(N-(1 -iminoethyl)piperidin-4-yloxy)benzimidazole, CA 02239~08 1998-06-04 WO 97/21437 PCTnB96/01496 1H NMR (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.20 (s, 2H), 9.10 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.20-8.00 (m, 2H), 7.95 (s, 1H), 7.80 (d, 1H~, 7.70 (d, 1H), 7.65 (d, 1H), 7.40 (s, 1H), 7.20 (dd, 1H), 5.95 (s, 2H), 4.80 (m, 1H), 3.85-3.65 (m, 2H), 3.60-3.50 (m, 2H), 2.90 (s, 3H~, 2.25 (s, 3H), 2.10-2.00 (m, 2H), 1.95-1.85 (m, 2H);
5 1-(4-amidinonaphth-1-yl)methyl-2-methyl-6-(N-(1-iminoethyl)piperidin-3-yloxy)benzimidazole, 1H-NMR (300 MHz, DMS0) ~ 9.50 (s, 2H~, 9.45 (s,2H), 9.30 (d, 1H~, 8.80 (s, 1H~, 8.40 (s, 1H~, 8.20 (dd, 2H~, 7.80 (dd, 2H~, 7.60 (dd, 2H), 7.20 (d, 1H), 5.90 (s, 2H), 4.80 (m, 1H), 3.90-3.40 (m, 4H), 2.80 (s, 3H), 1.95-1.50 (m, 6H);
t-(4-amidinonaphth-1-yl)methyl-2-ethyl-6-(N-(1-iminoethyl)piperi li-l-4-yloxy)benzimidazole, 1H NMR (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.30 (s, 2H), 9.15 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.20-8.05 (m, 2H), 7.90-7.75 (m, 3H), 7.65 ~d, 1H), 7.60 (s, 1H), 7.25 ~dd, 1H), 6.00 (s, 2H), 4.80 (m, 1H), 3.80-3.65 (m, 2H), 3.60-3.50 (m, 2H), 3.20 (q, 2H), 2.25 (s, 3H), 2.10-2.00 (m, 2H), 1.80-1.65 (m, 2H), 1.25 (t, 3H);
1 -(4-amidinonaphth-1 -yl)methyl-2-ethyl-5-(N-(1 -iminoethyi)piperidin-4-yloxY)benzimidazole, 1H NMR (300 MHz, DMS0) ~9.40 (s, 2H), 9.20 (s, 2H), 9.18 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.15 (d, 1H), 8.10 (d, 1H), 7.90 (s, lH), 7.85 (d, 2H), 7.65 (d, 1H), 7.40 (s, 1H), 7.20 (dd, 1H), 6.00 (s, 2H), 4.80 (m, 1H), 3.80-3.65 (m, 2H), 3.60-3.50 (m, 2H), 3.25 (q, 2H), 2.30 (s, 3H), 2.10-2.00 (m, 2H), 1.90-1.70 (m, 2H), 1.40 (t, 3H);
1 -(4-amidinonaphth-1 -yl)methyl-2-t-butyl-6-(N-(1 -iminoethyl)~ipel i.li, .-4-yloxy)ben ;.";da~Ole, 1H NMR (500 MHz, DMS0) ~ 9.40 (s, 2H), 9.20 (s, 2H), 9.18 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.18 (d, lH), 8.10 (d, 1H), 7.80- 7.77 (m, 2H), 7.70 (d, 1H), 7.59 (s, 1H), 7.25-7.20 (m, 2H), 6.00 (s, 2H), 4.60 (m, 1H), 3.70-3.60 (m, 2H), 3.50-3.40 (m, 2H), 2.30 (s, 3H), 2.00-1.90 (m, 2H), 1.75-1.60 (m, 2H), 1.48 (s, 9H);
1 -(4-amidinonaphth-1 -yl)methyl-2-t-butyl-5-(N-(1 -iminoethyl)piperidin-4-yloxy)ben i", ~701e, lH NMR (500 MHz, DMS0) ~ 9.40 (s, 2H), 9.10 (m, 3H), 8.60 (s, 1H3, 8.30 (s, lH), 8.18 (d, lH), 8.10 (d, 1H), 7.80 (d, 1H), 7.70- 7.60 (m, 2H), 7.45 (d, 1H), 7.40 (s, 1H), 7.20 (d, 1H), 6.00 (s, 2H), 4.60 (m, 1H), 3.80-3.70 (m, 2H), 3.60-3.50 (m, 2H), 2.30 (s, 3H), 2.20-2.00 (m, 2H), 1.90-1.60 (m, 2H), 1.60 (s, 9H);
1-(4-all nonapllLII-1-yl)methyl-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzi",: ~7nle, 1 H NMR (300 MHz, DMS0) ~ 9.70 (s, 1H), 9.45 (s, 2H), 9.30 (s, 2H), 9.20 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.25-8.18 (m, 2H), 8.10 (s, 1H), 7.90-7.80 (m, 3H), 7.60 (s, 1H), 7.30 (dd, 1H), 6.00 (s, 2H), 4.80 (m, 1H), 3.85-3.70 (m, 2H), 3.60-3.50 (m, 2H), 2.35 (s, 3H), 2.15-2.05 (m, 2H), 1.95-1.85 (m, 2H);
1 -(4-amidinonaphth-1 -yl)methyl-5-(N-(1 -iminoethyl)piperidin-4-yloxy)benzimidazole, lH NMR (300 MHz, DMS0) ~ 9.80 (s, 1H), 9.40 (s, 2H), 9.Z0 (s, 2H), 9.10 (s, 1H) 8.60 (s, 1H), 8.40 (s, 1H), 8.15-8.00 (m, 3H), 7.90-7.75 (m, 3H), 7.45 (s, 1H), 7.20 (dd, 1H), 6.00 (s, 2H), 4.80 (m, 1H), 3.80-3.70 (m, 2H), 3.60-3.45 (m, CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 2H), 2.30 (s, 3H), 2.20-2.00 (m, 2H), 1.90-1.70 (m, 2H);
1 -(4-amidinonaphth-1 -yl)methyl-2-propyl-6-~N-~1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 1H NMR (300 MHz, DMS0) ~9.40 (s, 2H), 9.20 (s, 2H), 9.18 (s, lH), 8.60 (s, 1H), 8.40 (s, lH), 8.18 (d, 1H), 8.14 (d, 1H), 7.90- 7.80 (m, 3H), 7.65 (d, 1H), 7.60 (s, 1H), 7.25 (dd, 1H), 6.00 ~s, 2H), 4.80 ~m, lH), 3.80-3.65 (m, 2H), 3.60-3.40 ~m, 2H), 3.20 ~t, 2H), 2.30 ~s, 3H), 2.18-2.00 ~m, 2H), 1.85-1.70 (m, 4H), 0.90 (t, 3H~;
1 -~4-amidinonaphth-1 -yl)methyl-2-propyl-5-~N-(1 -iminoethyl)piperidin-4-yloxy)benzi,I,iddzoIe, 1H NMR ~300 MHz, DMS0) ~ 9.40 Is, 2H), 9.20 (s, 2H), 9.18 ~s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.15 (d, 1H), 8.10 (d, lH), 7.90 (s, lH), 7.80 (d, lH), 7.70 (d, 1H), 7.63 (s, 1H), 7.40 (s, 1H), 7.20 (dd, 1H), 6.00 (s, 2H), 4.80 (m, lH), 3.80-3.65 ~m, 2H), 3.62-3.50 ~m, 2H), 3.23 ~t, 2H), 2.30 ~s, 3H), 2.20-2.00 ~m, 2H), 1.85-1.70 (m, 4H), 1.00 ~t, 3H);
1-~4-amidinonaphth-1-yI)methyI-2-sec-butyI-6-~N-~1-i".inoe~ 13piperidin-4-yIoxy)benzimidazoIe, 1H NMR (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.20 (s, 2H), 9.18 (s, 1H), 8.60 (s, 1 H), 8.40 (s, lH), 8.18 (d, lH), 8.10 (d, lH), 7.90- 7.77 (m, 3H), 7.65 (d, lH), 7.59 (s, 1H), 7.25 (dd, 1H~, 6.00 (s, 2H), 4.80 (m, lH), 3.80-3.70 (m, 2H), 3.60-3.50 (m, 2H), 3.10 (d, 2H), 2.30 (s, 3H), 2.18-2.00 (m, 3H), 1.85-1.70 (m, 2H), 0.90 (d, 6H);
1-(4-~ idil)ond,uhLII-1-yl)methyl-2-sec-butyl-5-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole, 1H NMR (300 MHz, DMS0) d9.40 (s, 2H), 9.20 (s, 2H), 9.18 (s, lH), 8.60 (s, lH), 8.40 (s, lH), 8.18 (d, lH), 8.10 (d, lH), 7.90 (s, lH), 7.85 (d, lH), 7.70 (d, lH), 7.60 (d, 1H), 7.45 (s, 1H), 7.20 (d, lH), 6.00 (s, 2H), 4.80 (m, lH), 3.80-3.70 (m, 2H), 3.60-3.50 (m, 2H), 3.10 (d, 2H), 2.30 (s, 3H), 2.18-2.00 (m, 3H), 1.85-1.70 (m, 2H), 0.95 (d, 6H);
1 -(4-amidinonaphth-1 -yl)methyl-2-n-butyl-6-(N-(1 -iminoethyl)piperidin-4-yioxy)benzimidazole, 1H NMR (300 MHz, DMSO) ~ 9.40 (s, 2H), 9.20 (s, 2H), 9.18 (s, 1H), 8.60 (s, 1H), 8.40 (s, lH), 8.18 (d, lH), 8.10 (d, lH), 7.90- 7.80 (m, 3H), 7.70-7.60 (m, 2H), 7.25 (dd, 1H), 6.00 (s, 2H), 4.80 (m, lH), 3.80-3.70 (m, 2H), 3.60-3.50 (m, 2HI, 3.20 (t, 2H), 2.30 (s, 3H), 2.18-2.00 (m, 2H), 1.85-1.60 (m, 4H~, 1.40 Im, 2H), 0.90 ~t, 3H);
1-(4-t,lll: iinonaphth-l-yl)methyl-2-n-butyl-5-(N-(1-i l i"o :LI,~I)p:"e(idil,-4-yloxy)benzimidazole, 1H NMR (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.20 (s, 2H), 9.1 8 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.18 (d, lH), 8.10 (d, lH), 7.90 (s, lH), 7.83 (d, lH), 7.75 (d, lH), 7.60 (d, 1H), 7.40 (s, 1H), 7.20 (d, 1H), 6.00 (s, 2H), 4.80 (m, 1H), 3.80-3.70 (m, 2H), 3.60-3.50 (m, 2H), 3.25 (t, 2H), 2.30 (s, 3H), 2.18-2.00 (m, 2H), 1.86-1.65 (m, 4H), 1.40 (m, 2H), 0.95 (t, 3H);
35 1-(4-amidinonaphth-1-yl)methyl-2-(2-carboxyethyl)-6-(N-(1-iminoethyl)piperidin-4-yIoxy)be" i"~ 7~ , 1H-NMR 9.45 (s, 2H), 9.39 (s, 2H), 9.20 (s, 1H), 8.60 (s, lH), 8.40 (s, 1H), 8.10 (dd, 2H), 7.80 ( d, 1H), 7.70 (dd, 3H), 7.45 (s, 1H), 7.10 ~d, 1H), CA 02239~08 1998-06-04 W O 97/21437 PCTnB96/01496 5.90 (s, 2H), 4.70 (m, 1H), 3.70 (m, 2H), 3.50 (m, 2H), 3.30 ~t, 2H), 3.10 tm, 1H~, 2.90 (t, 2H), 2.30 (s, 3H), 2.10 (m, 2H), 1.75 (m, 2H);
1 -(4-amidinonaphth-1 -yl)methyl-2-(2-carboxyethyl)-5-(N-(1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 1H-NMR 9.45 (s, 2H), 9.40 (s, 2H), 9.20 (s, 1H), 8.85 ( s, 1H), 8.40 (s, 1H), 8.10 (dd, 2H), 7.80 (m, 2H), 7.65 (dd, 2H), 7.40 (s, 1H), 7.10 (d, 1H), 5.95 (s, 2H), 4.85 (m, 1H), 3.80 (m, 2H), 3.50 (m, 2H), 3.25 (m, 2H), 3.10 (m, 1H), 2.95 (m, 2H), 2.30 (s, 3H), 2.10 ( m, 2H), 1.75 (m, 2H);
1 -(4-amidinonaphth-1 -yl)methyl-2-(2-aminocarbonylethyl)-6-(N-(1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 1H-NMR 9.42 (s, 2H), 9.35 (s, 2H), 9.20 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.10 (dd, 2H), 7.85 (d, 1H), 7.70 (m, 3H), 7.50 (s, 1H), 7.45 (s, 1H), 7.10 (d, 1H), 7.00 (s, 1H), 5.90 (s, 2H), 4.70 (m, 1H), 3.70 (m, 2H), 3.50 (m, 2H), 3.20 ~m, 3H), 2.80 (t, 2H), 2.00 (m, 2H), 1.70 (m, 2H);
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-6-(N-(N'-(1 -iminoethyl)piperidin-4-yl)-N-((methoxycarbonyl)methyl)amino)benzimidazole, lH NMR (300 MHz, DMS0) ~
1.70 (m, 4H), 2.25 (s, 3H), 2.80 (s, 3H), 3.20 (m, 2H), 3.50 (s, 3H), 3.90 (m, lH), 4.10 (m, 2H), 4.15 (s, 2H). 5.90 (s, 2H), 7.00 (s, 1H), 7.05 (d, lH), 7.B0 ~d, 1H), 7.70 ld, 1H), 7.80 (d, lH), 7.90 (s, 1H), 8.10 (d, 1H), 8.15 (d, 1H), 8.40 (s, 1H), 8.50 (s, 1H), 9.10 (s, 1H), 9.15 (s, 2H), 9.40 (s, 2H);
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-6-(N-(N'-(1 -iminoethyl)piperidin-4-yl)-N-((a,,,;~loca.L,onyl)methyl)amino)ben~i,.,idc.~ole, 1H NMR (300 MHz, DMS0) ~ 1.80 (m, 4H), 2.25 (s, 3H), 2.80 (s, 3H), 3.25 (m, 2H), 3.80 (s, 2H), 3.95 (m, 1H), 4.15 (m, 2H), 5.90 (s, 2H), 7.00 (d, 1H), 7.10 (s, 1H), 7.40 (br s, 1H), 7.60 (d, 1H), 7.70 (d, 1H), 7.83 (d, 1H), 7.95 (s, 1H), 8.10 (d, 1H), 8.15 (d, 1H), 8.40 (s, 1H), 8.55 (s, 1H), 9.10 (s, 1H), 9.15 (s, 2H), 9.40 (s, 2H);
25 1-(4-amidinonaphth-1-yl)methyl-2-methyl-6-(N-(N'-(1-iminoethyl)piperidin-4-yl)-N-(3-carboxypropyl)amino)benzimidazole, lH NMR (300 MHz, DMS0) ~ 1.60 (m, 2H), 1.80 (m, 4H), 2.20 (m, 2H), 2.25 (s, 3H), 2.80 (s, 3H), 3.20 (m, 4H), 3.95 (m, 1H), 4.10 (m, 2H), 5.90 (s, 2H), 7.15 (m, 2H), 7.65 (d, 1H), 7.70 (d, 1H), 7.80 (d, 1H), 7.95 (s, 1H), 8.10 (d, 1H), 8.15 (d, 1H), 8.40 (s, 1H), 8.58 ~s, 1H), 9.10 (m, 3H), 9.20 (s, 2H);
30 1 - (4-amidi no naphth- 1 -yl) methyl-2-methyl-6-(N-(N'-(1 -i mi noethyl ) 4-yl)-N-(2-(methoxycarbonyl)propyl)amino)benzimidazole, 1H NMR (300 MHz, DMS0) ~0.80 (d, 3H), 1.60 (m, 4H), 2.20 (s, 3H), 2.40 (m, 1H), 2.80 (s, 3H), 3.10 (m, 3H), 3.30 (m, 1H), 3.40 (s, 3H), 3.90 (m, 2H), 4.05 (m, 1H), 5.85 (d, 1H), 5.90 (d, 1H), 7.10 (d, 1H), 7.20 (d, 1H), 7.60 (d, 1H), 7.65 (d, 1H), 7.80 (d, 1H), 7.90 (s, 1H), 8.05 (d, 1H), 8.10 (d, 1H), 8.35 (s, 1H), 8.50 (m, 1H), 9.05 (br s, 1H), 9.10 (s, 2H), 9.40 (s, 2H);
1 -(4-amidinonaphth- 1 -yl)methyl-2-methyl-6-(N-(N'-(1 -iminoethyl)piperidin-4-yl)-N-(2-(carboxy)propyl)amino)benzimidazole, 1H NMR (300 MHz, DMS0) ~0.85 (d, CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 3H), 1.70 (m, 4H), 2.20 (s, 3H), 2.30 Im, 1H), 2.85 (s, 3H), 3.10 (m, 3H), 3.40 (m, 1H), 3.90 (m, 2H), 4.10 (m, 1H), 5.85 (d, 1H), 5.90 (d, 1H), 7.15 (d, 1H), 7.15 (d, 1H), 7.60 - (d, 1H), 7.65 (d, 1H), 7.80 (d, 1H), 7.95 (s, 1H), 8.05 (d, 1H), 8.10 (d, lH), 8.40 (s, 1H), 8.50 (s, 1H), 9.05 (br s, 1H), 9.10 (s, 2H), 9.40 (s, 2H);
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(N-(N-(1-iminoethyl)piperidin-4-yl)-N-(2-(carboxy)propyl)aminolbenzimidazole, lH NMR (300 MHz, DMS0) ~ 1.00 (d, 3H), 1.70 (m, 4H), 2.20 (s, 3H), 2.50 (m, 1H), 2.90 (s, 3H), 3.10 (m, 3H), 3.40 (m, 1H), 3.90 (m, 2H), 4.10 (m, 1H), 5.85 (s, 2H), 7.15 (d, lH), 7.20 (d, lH), 7.55 (d, 1H), 7.60 (d, 1H), 7.80 (d, 1H), 7.95 (s, 1H), 8.00 (d, 1H), 8.05 (d, lH), 8.40 (s, lH), 8.50 (s, lH), 9.05 (br s, lH), 9.10 (s, 2H), 9.40 (s, 2H);
1 -(4-amidinonaphth- 1 -yl)methyl-2-methyl-5-hydroxy-6-(N-(1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 1H NMR (DMS0, 300 MHz) ~ 9.50 (s, 4H), 9.20 (s, 1 H), 8.65 (s, 1H), 8.40-7.20 (m, 9H), 5.92 (s, lH), 5.88 (s, 1H), 4.80 (m, 0.5HI, 4.70 (m, 0.5H), 3.80-3.45 (m, 4H), 2.90 (s, 1.5H), 2.80 (s, 1.5H), 2.30 (s, 3H), 2.10-1.70 (m, 4H) (a mixture of two ,e~~ioiso,llers);
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(aminocarbonyl)methoxy-6-(N-(1 -imino-ethyl)piperidin-4-yloxy)benzimidazole, 1H NMR (DMS0, 300 MHz) o 9.46 ~s, 4H), 9.21 (s, 1~, ~.,~ (s, 1t~ 7,38 ~m, 1(~1~, 5.92 !s, lH!, 6.88 !s, lH!, 4 82 !m, Or5H!~ 4 76 (m, 0.5H), 4.62 (s, 1H), 4.52 (s, 1H), 3.80-3.40 (m, 4H), 2.80 (s, 1.5H), 2.78 (s, 1.5H), 2.25 (s, 1.5H), 2.23 (s, 1.5H), 2.16-1.75 (m, 4H) (a mixture of two regioisomers);
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(carboxy)methoxy-6-(N-(1 -imino-ethyl)piperidin-4-yloxy)benzimidazole, 1H NMR (DMS0, 300 MHz) ~ 9.60 (s, 2H), 9.50 (s, 2H), 9.20 (s, 1H), 8.70 (s, 1H), 8.40-7.40 (m, 9H), 5.96 (s, 2H), 4.90 (s, 1H), 4.80 (s, 1H), 4.70 (m, 1H), 3.80-3.50 (m, 4H), 2.80 (s, 3H), 2.30 (s, 3H), 2.15-1.70 (m, 4H) (a mixture of re~ioi~o" ,e, :,);
1 -(4-amidinonaphth- 1 -yl)methyl-2-methyl-5-(4-(methoxycarbonyl)benzyloxy)-6-(N-(1-iminoethyl)piperidin-4-yloxy)be" i",idazole, 1H NMR (DMS0, 300 MHz) ~ 9.42 (s, 2H), 9.30 (s, 2H), 9.18 (s, 1H), 8.60 (s, 1H), 8.40-7.40 (m, 12H), 5.90 (s, 2H), 5.35 (s, 2H), 4.70 (m, 1H), 3.90 (s, 3H), 3.80-3.40 (m 4H), 2.70 (s, 3H), 2.30 (s, 3H), 2.10-1.70 (m, 4H);
1 -(4-amidinonaphth-1 -yl~methyl-2-methyl-5-(4-(carboxy)benzyloxy)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole, 1H NMR (DMS0, 300 MHz) ~ 9.42 (s,2H), 9.30 (s,2H), 9.18 (s,1H), 8.60 (s, 1H), 8.18-7.40 (m, 12H), 5.90 (s, 2H~, 5.30 (s, 2H), 4.70 (m, 1H), 3.80-3.40 (m, 4H), 2.70 (s, 3H), 2.30 (s, 3H), 2.10-1.70 (m, 4H);
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-carboxy-6-(N-(1-iminoethyl)piperidin-4-yloxy)ben i"lidd ole, 1H NMR (DMS0, 300 MHz) ~ 9.40 (s, 4H), 9.20 (s, 1H), 8.63 ~s,1H), 8.40-7.60 (m, 9H), 6.00 (s, 2H), 4.90 (m, 1H), 3.70 (m, 4H), 2.70 ~s, 3H), 2.30 CA 02239~08 1998-06-04 W O 97~1437 PCT~B96/~t496 ~s, 3H), 2.05-1.80 (m, 4H);
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(carboxy)methoxy)-6-(N-(1 -iminoethyl)piperidin-4-yloxy)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-((aminocarbonyl)methoxy)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole, lH NMR ~DMS0, 300 MHz) ~ 9.60 (s, 2H), 9.30 (s, 2H), 9.12 (s, lH), 8.60 (s, 1H), 8.40-7.30 (m, 10H), 5.90 (s, 2H), 4.70 (m, lH), 4.60 (s, 2H), 3.80-3.40 (m, 4H), 2.70 (s, 3H), 2.30 (s, 3H), 2.12-1.80 (m, 4H);
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(3-(methoxycarbonyl)benzyloxy)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole, 1H NMR (DMS0, 300 MHz) ~ 9.65 (s, 2H), 9.30 (s, 2H), 9.16 (s, 1H), 8.60 (s, 1H), 8.40-7.40 (m, 12H), 5.90 (s, 2H), 5.30 ~s, 2H), 4.70 (m, 1H), 3.90 (s, 3H), 3.80-3.40 (m, 4H), 2.70 (s, 3H), 2.36 (s, 3H), 2.20-1.80 (m, 4H);
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-6-(3-(carboxy)benzyloxy)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole, 1H NMR (DMS0, 300 MHz) ~ 9.40 (s, 2H), 9.10 (s, 1H), 9.05 (s, 2H), 8.60 (s, lH), 8.40-7.40 (m, 12H), 5.90 (s, 2H), 5.35 (s, 2H), 4.70 (m, lH), 3.80-3.45 (m, 4H), 2.70 (s, 3H), 2.25 (s, 3H), 2.05-1.70 (m, 4H);
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(methoxycarbonyl)methoxy-6-(N-(1 -imino-ethyl)pipe,idin-4-yloxy)benzimidazole, 1H NMR (DMS0, 300 MHz) ~ 9.45 (s, 2H), 9.10 (s, 3H), 8.60 (s, 1H), 8.40-7.40 (m, 8H), 5.90 (s, 2H), 5.00 (s, 2H), 4.70 (m, 1H), 3.70 (s, 3H), 3.60 (m, 4H), 2.80 (s, 3H), 2.30 (s, 3H), 2.10-1.80 (m, 4H);
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(1 -(aminocarbonyl)ethoxy)-6-(N-(1 -imino-ethyl),~ .i.lin-4-yloxy)ben~ le, 1H NMR (DMS0, 300 MHz) ~ 9.40 (s, 2H), 9.20 (s,3H), 8.60 Is, 1H), 8.40-7.30 (m, 10H), 5.95 (s, 2H,), 4.70 (m, 2H), 3.80-3.50 (m, 4H), 2.80 (s, 3H), 2.30 (s, 3H), 2.10-1.80 (m, 4H), 1.50 (d, 3H);
25 1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(1-(methoxycarbonyl)ethoxy)-6-(N-(1-imino-ethyl)-piperidin-4-yloxy)benzimidazole, 1H NMR (DMS0, 300 MHz) ~S 9.45 (s, 2H), 9.30 (s, 2H), 9.20 (s, 1H), 8.60 (s, lH), 8.40-7.35 (m, 8H), 5.90 (s, 2H), 5.10 (m, 1H), 4.70 (m, lH), 3.90 (s, 3H), 3.70 (m, 4H), 2.76 (s, 3HI, 2.30 ~s, 3H), 2.10-1.80 (m, 4H), 1.60 (d, 3H);
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(1 -(carboxy)ethoxy)-6-(N-(1 -imino-ethyl)piperidin-4-yloxy)benzimidazole, 1H NMR (DMS0, 300 MHz) ~ 9.45 (s, 2H), 9.35 (s, 2H), 9.18 (s, 1H), 8.60 (s, 1H), 8.40-7.30 (m, 8H), 5.96 (s, 2H), 5.00 (m, 1H), 4.70 (m, 1H), 3.60 (m, 4H), 2.78 (s, 3H), 2.30 (s, 3H), 2.10-1.80 (m, 4H), 1.60 (d, 3H);
1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-4-methoxy-6-(N-(1 -iminoethyl)piperidin-4-yloxy)ben~i"-' '~701e, 1H NMR (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.20 (s, 2H~, 9.18 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.18 (d, 1H), 8.14 (d, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.60 (d, 1H), 7.25 (s, 1H), 6.80 (s, 1H), 6.00 (s, 2H), 4.80 (m, 1H), 4.10 (s, 3H), 3.80-3.65 (m, 2H), 3.60-3.45 (m, 3H), 2.30 (s, 3H) , 2.18-2.00 (m, 2H), 1.90-1.80 (m, 2H), CA 02239~08 1998-06-04 W O 97/21437 ~CT~B96/01496 1.35 (d, 6H);
1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-7-methoxy-5-(N-(1 -iminoethyl)p;~e~ idi"-- 4-yloxy)benzimidazole, 1 H NMR (300 MHz, DMS0) ~ 9.40 (s, 2H~, 9.20 (s, 3H), 8.60 (br s, 1H), 8.40 (s, 1H), 8.20-8.10 (m, 3H), 7.90-7.80 (m, 3H), 7.ô5 (d, 1H), 7.00 (5, 1H), 6.80 (s, 1H), 6.10 (s, 2H), 4.90 (m, 1H), 3.90-3.55 (m, 6H), 2.35 (s, 3H), 2.20-2.10 (m, 2H), 2.00-1.80 (m, 2H), 1.40 (d, 6H);
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(N-(4-carboxy)benzylamino)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole, (approx 1:1 mixture o~ rer~ioisomers) lH NMR (300 MHz, DMSO) ~ 1.85 (m, 2H), 2.00 (m, 2H), 2.25 (s, 3H), 2.60 (s, 1.5H), 2.75 (s, 1.5H), 3.60 (m, 2H), 3.80 (m, 2H), 4.40 (s, 1H), 4.50 (s, 1H), 4.80 (m, 0.5H), 4.90 (m, 0.5H), 5.65 (s, 1H), 5.85 (s, 1H), 6.50 (s, 0.5H), 6.60 (s, 0.5H), 7.25 (d, 1H), 7.30 (s, 1H), 7.40 ~m, 1H), 7.50 (s, 0.5H), 7.60 (d, 1H), 7.70 (d, 1H), 7.75 (d, 1H), 7.85 (d, 0.5H), 7.90 (d, 1H), 8.00 (d, lH), 8.05 (d, 1H), 8.10 (d, 1H), 8.35 (d, lH), 8.60 (s, 1H), 9.10 (s, 2H), 9.15 (s, 1H), 9.35 (s, 2H);
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-4-(4-carboxypiperidin-1-yi)-6-(N-(l-iminoethyl)piperidin-4-yloxy~benzimidazole, lH-NMR 9.38 (s, 2H), 9.05 (s, 3H), 8.50 (s, lH), 8.38 (s, lH), 8.05 (dd, 2H), 7.80 (d, lH), 7.70 (s, 1H), 7.58 (d, lH), 7.25 (s, lH), 6.70 (s, 1H), 5.95 (s, 2H), 4.70 (m, 1H), 3.65 (m, 2H), 3.50 (m, 4H), 2.85 (t, 2H), 2.40 (m, 2H), 2.20 (s, 3H), 1.95 (m, 5H), 1.70 (m, 2H), 1.30 (d, 6H);
1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-4-(carboxy)methoxy-6-(N-(1 -imino-ethyl)pi~,r,id ~-4-yloxy)benzi".ida,ole, lH-NMR 9.38 (s, 2H), 9.05 (s, 2H), 8.75 (s, 1H), 8,40 ( s, 1H), 8.05 (dd, 2H), 7,80 (d, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 7.25 (s, 1H), 6.75 (s, lH), 5.95 (s, 2H), 5.00 (s, 2H), 4.70 (m, lH), 3.80 - 3.40 (m, 5H), 2.20 (s, 3H), 2.00 (m, 2H), 1.85 (m, 2H), 1.30 (d, 6H);
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-7-nitro-6-(N-(1-imino-ethyl)piperidin-4-yloxy)ben~i,l,ir' He, lH-NMR 9.38 (s, 2H), 9.15 (s, 1H), 9.05 (s, 2H), 8.80 (s, 1H), 8.35 (s, 1H), 8.10 (d, lH), 8.05 (d, 1H), 7.95 (d, lH), 7.80 (d, 1H), 7.70 (s, lH), 7.60 (d, 1H), 7.50 (d, 1H), 5.95 (s, 2H), 5.00 ( m, 1H), 3.60-3.45 (m, 5H), 2.25 (s, 3H), 2.00 (m, 2H), 1.30 (d, 6H), 1.30 (d, 6H);
1-(4-amidinonaphth-1-yl)methyl-2-methyl-7-nitro-6-(N-(l-imino-ethyl)piperidin-4-yloxy)benzimidazole, lH NMR (DMS0, 300 MHz) ~ 9.45 (s, 2H), 9.38 (s, 2H), 9.20 (s, 1H), 8.65 (s, 1H), 8.42-7.30 (m, 8H), 5.81 (s, 2H), 4.90 (m, 1H), 3.60 (m, 4H), 2.60 (s, 3H), 2.23 (s, 3H), 2.10 (m, 2H), 1.80 (m, 2H);
1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-5-(N-(2-carboxyprop-2-yl)amino)-6-(N-(1-iminoethyl)piperidin-4-yloxy)ben~i-,-idA~ole, lH NMR (300 MHz, DMS0) ~ 1.25 (d, 6H), 1.55 (s, 6H), 1.80 (m, 2H), 2.00 (m, 2H), 2.25 (s, 3H), 3.50 (m, 3H), 3.70 (m, 2H), 4.80 (m, 1H), 5.95 (s, 2H), 6.70 (s, 1H), 7.60 (m, 2H), 7.70 (s, lH), 7.80 (d, 1H), 8.05 CA 02239~08 1998-06-04 W 097/21437 PCT~B96/01496 (d, lH), 8.10 (d, lH), 8.40 (s, 1H), 8.60 (s, 1H), 9.10 (s, 2H), 9.15 (s, 1H), 9.40 (s, 2H);
1 -~4-amidinonaphth-1 -yl)methyl-2-isopropyl-5-(N-(4-carboxy)benzyiamino)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole, lH NMR (300 MHz, DMS0) ~ 1.20 (d, 6H), 1.90 (m, 2H), 2.00 (m, 2H), 2.20 (s, 3H), 3.45 Isept, 1H), 3.60 (m, 2H), 3.80 (m, 2H), 4.55 (s, 2H), 4.93 (m, 1H), 5.95 (s, 2H), 6.45 (s, 1H), 7.45 ~d, 2H), 7.57 (s, 1H), 7.60 (d, 1H), 7.65 (s, 1H), 7.80 (d, 1H), 7.90 (d, 2H), 8.05 (d, 1H), 8.10 (d, 1H), 8.37 ~s, 1H), 8.60 (s, 1H), 9.10 (s, 2H), 9.15 (s, 1H), 9.18 (s, 2H);
1 -(4-amidinonaphth-1 -yl)methyl-2-isopropyl-5-(N-(2-carboxyethyl)amino)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole, lH NMR (300 MHz, DMS0) ~ 1.20 (d, 6H), 1.80 ~m, 2H), 1.95 (m, 2H), 2.20 (s, 3H), 2.55 (m, 2H), 3.40 (m, 2H), 3.50 (m, 3H), 3.70 (m, 2H), 4.80 (m, 1H), 5.95 (s, 2H), 6.85 (s, 1H), 7.50 (m, 2H), 7.65 (s, lH), 7.75 (d, 1H), 8.00 (d, 1H), 8.05 (d, 1H), 8.30 (s, 1H), 8.50 (s, 1H), 9.10 (s, 3H), 9.30 (s, 2H);
1 -(4-amidinonaphth-1 -yl)methyl-2-methyl-5-(N-(carboxymethyl)piperidin-4-yloxy)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole, lH NMR (DMS0, 300 I\AHz) ~ 10.40 (s, 1H), 9.70 (s, 2H), 9.45 (s, 3H), 8.98 (s, 1H), 8.70-7.80 (m, 8H), 6.24 (s, 2H), 5.00 (m, 2H), 4.48 (s, 2H), 4.0-3.40 (m, 8H), 3.20 (s, 3H), 2.60 (s, 3H), 2.40-2.00 (m, 8H);
1 -(4-amidinonaphth-1 -yl)methyl-6-~N-tN'-(1 -i."inoeLI-~yl)piperidin-4-yl)-N-((4-methoxycarbonyl)benzyl)amino)bèn~ J~
1 -(4-amidinonaphth-1 -yl)methyl-6-(N-(N'-(1 -iminoethyl)piperidin-4-yl)-N-((4-carboxy)benzyl)amino)benzimidazole, 1 -(4-amidinonaphth-1 -yl)methyl-2-trifluoromethyl-6-(N-(1 -iminoethyl)piperidin-4-yloxy)ben~in,ida~ole, 1H NMR (300 MHz, DMS0) ~ 9.40 (s, 2H), 9.20-9.t5 (m, 3H), 8.60 (s, 1H), 8.45 (s, 1H), 8.20-8.10 lm, 3H), 8.00 (d, lH), 7.80 (d, 2H), 7.43 (s, 1H), 7.20 (d, 1 H), 5.40 (s, 2H), 4.85-4.75 (m, 1 H), 4.20 (dd, 2H), 3.60-3.40 (dt, 2H), 2.80-2.60 (m, 2H, obscured by DMS0 signal), 2.40 (s, 3H), 2.15-2.00 (m, 2H);
1-(4-amidinonaphth-1-yl)methyl-6-(N-(N'-(1-iminoethyl)~,- i.lin-4-yl)-N-((2-(ethoxycarbonyl)ethyl)carbonyl)amino)be"zi",-'~701e, and 1 -(4-amidinonaphth-1 -yl)methyl-6-(N-(N'-(1 -i",:.,oe~l,yl)piperidin-4-yl)-N-((2-(carboxy)ethyl)carbonyl)amino)ben~i", Compounds of formula (Ic) To a mixture of 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-4-methoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperi.lil,-4-ylamino)benzimidazole, 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-7-methoxycarbonyl-5-(N-(tert-butoxycarbonyl)p;,.e.idin-4-ylaminobenzi",;dazole, and 2-isopropyl-4-35 methoxycarbonyl-6-(N-(tert-butoxycarbonyl)pipt(idin-4-yl)((4-cyanonaphth-1-yl)methyl)aminobenzimidazole [4 9, 50% 1-(4-cyanonaphth-1-yl~methyl-2-isopropyl-4-CA 02239~08 l998-06-04 WO 97/21437 PCT~B96/01496 methoxycarbonyl-6-(N-(t~t-butoxycarbonyl)piperidin-4-ylamino)ben~;"lid~ le~ in ethanol (150 mL) cooled in an ice water bath was bubbled HCI (g). After the solution was saturated, the reaction flask was sealed and the temperature maintained at ambient temperature for 16 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethanol ~50 mL).
The solution was cooled in a dry ice/acetone bath and ammonia (g) was bubbled in. The reaction flask was sealed and then heated at 70~C for 4 hours. The solvent was removed. The mixture was separated by HPLC on a Ct8 Dynamax column with a 3-25% ac~Lonil-ile in water gradient with 0.1 % trifluoroacetic acid to afford 1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-4-aminocarbonyl-6-(piperidin-4-ylamino)-benzimidazole as a white solid after concentration and 10 freeze-drying removal of the solvent.

Compounds of formulae (Id) A. To 1-(4-amidinonaphth-1-yl~methyl-2-isopropyl-4-aminocarbonyl-6-(piperidin-4-ylamino)benzimidazole ~1 9) in methanol (50 mL) was added triethylamine (3 mL) and 15 ethylaceLi,-, ~late (1 g). After stirring for 3 hours, the reaction was concentrated. The residue was purified by HPLC on a C18 Dynamax column with a 3-25% acetonitrile in water gradient with 0.1 % trifluoroacetic acid to afford 1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-4-aminocarbonyl-6-(N-(1-iminoethyl)piperidin-4-ylamino)benzimidazole, 1H NMR (DMS0, 300 MHz) 9.70 (s, 2H), 9.58 (5, 2H), 9.40 (s, 1H), 9.35 (s, lH), 8.82 (s, 1H), 8.62-7.20 (m, 9H), 6.10 (s, 20 2H), 4.10-3.50 (m, 6H), 2.50 (s, 3H), 2.26 (m, 2H), 1.70 (m, 2H), 1.60 (d, 6H), as white solid after freeze drying removal of the solvent.
B. In a similar manner, the following compound of formula (Id) was made:
1 -(4-amidinonaphth-1 -yl)methyl-6-(N-(1 -iminoethyl)piperidin-4-yl)aminobenzimidazole, 1H NMR (300 MHz, DMS0) ~ 1.40 (m, 2H), 2.00 ~m, 2H), 2.25 (s, 3H), 3.30 (m, 2H), 3.60 (m, 2H), 3.80 (m, 1H), 3.95 (m, 1H), 5.90 (s, 2H), 6.90 ~s, 1tl), 7.00 (d, 1H), 7.60 (d, 1H), 7.80 (d, lH), 7.85 (d, 1H), 8.00 (s, lH), 8.10 (d, lH), 8.15 (d, 1H), 8.40 (s, 1H), 8.55 (s, 1H), 9.15 (br s, 3H), 9.40 (s, 2H), 9.55 (s, 1H).

1 -(4-Amidinonaphth-1 -yl)methyl-2-isopropyl-4-aminocarbonyl-6-(N-(1 -iminoethyl)piperidin-30 4-ylamino)benzimidazole (2 9) was heated at 80~C in 12N HCI for 12 hours. The solvent was removed under reduced pressure. To the resulting residue in methanol (80 mL) was added triethylamine (10 mL) and ethylacetimidate (2 g). After stirring for 12 hours, the reaction mixture was concenL,~Led. The residue was purified by HPLC on a C18 Dynamax column with a 3-25%
acetonitrile in water ~,adie"L with 0.1 % trifluoroacetic acid to afford 1 -(4-amidinonaphth-1-35 yl)methyl-2-isopropyl-4-carboxy-6-(N-(l-iminoethyl)piperidin-4-ylamino)benzimidazole~ 1H NMR

CA 02239~08 1998-06-04 W 097/21437 PCT~B96/01496 (DMS0, 300 MHz) ~ 9.70 (s, 2H), 9.60 (s, 2H), 9.40 (s, 1H), 8.93 (s, 1H), 8.65-7.40 (m, 8H), 6.30 (s, 2H), 4.20-3.50 (m, 6H), 2.55 (s, 3H), 2.30 (m, 2H), 1.70 (m, 2H), 1.60 ~d, 6H), as a white solid after freeze-drying removal of the solvent.

This example illustrates the preparation of represerLaLive pharmaceutical compositions for oral ad~ ,aLion conLa;.l;l-g a compound of the invention, or a pharmaceutically acceptable salt thereof, e.g.,1-(4-amidinonaphth-1-yl)methyl-2-n-butyl-5-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole:
A. Inqredients % wt./wt.
Compound of the invention 20.0%
Lactose 79-5 %
Mâgnesium stearate 0.5Yo The above ingredients are mixed and dispensed into hard-shell gelatin capsuies containing 100 mg each, one capsule would approximate a total daily dosage.
15 B. InQredients % wt./wt.
Compound of the invention 20.0~h Magnesium stearate 0.9%
Starch 8.6%
Lactose 79.6%
PVP ~polyvinylpyrroiidine) 0.9%
The above ingredients with the exception of the magnesium stearate are combined and granulated using water as a granulating liquid. The formulation is then dried, mixed with the magnesium stearate and formed into tablets with an appropridle tableting machine.
C. I n4, ecl;e. I l~
Compound of the invention 0.1 9 Propylene glycol 20.0 9 Polyethylene glycol 400 20.0 9 Polysorbate 80 1.0 9 Water q.s. 100 mL
The compound of the invention is dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. A sufficient quantity of water is then added with stirring to provide 100 mL
of the solution which is filtered and bottled.
D. In4r~ enL:i % wt.lwt.
Compound of the invention 20.0%
Peanut Oil 78.0%
Span 60 2.0%

CA 02239~08 1998-06-04 W 0 97/21437 PCT~B96/01496 The above ingredients are melted, mixed and filled into soft elastic capsule E. Inqredients % wt./wt.
Compound of the invention 1.0%
Methyl or carboxymethyl cellulose 2.0%
0.9% saline q.s. 100 mL
The compound of the invention is dissolved in the cellulose/saline solution, filtered and bottled for use.

This example illustrates the preparation of a representative pharmaceutical formulation for parenteral admin;stration containing a compound of the invention, or a pharmaceutically accepLdble salt thereof, e.g., 1-(4-amidinonaphth-1-yl~methyl-2-t-butyl-5-~N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole:
Inqredients Compound of the invention 0.02 g Propylene glycol 20.0 9 Polyethylene glycol 40020.0 g Polysorbate 80 1.0 g 0.9% saline solution q.s. 100 mL
The compound of the invention is dissolved in propylene glycol, polyethylene glycol 400 and poiysorbate 80. A sufficient quantity of 0.9% saline soiution is then added with stirring to provide 100 mL of the l.V. solution which is filtered through a 0.2 ~ membrane filter and pacl~aged under sterile conditions.

This ~X&Ill, le illustrates the preparation of a representative pharmaceutical composition in 25 suppository form conlai~ 9 a compound of the invention, or a pharmaceutically ac~;dpLdi le salt thereof, e.g., 1-(4-amidinonaphth-1-yl)methyl-2-methyl-6-(N-~N-(1-iminoethyllpiperidin-4-yl~-N-((aminocarbonyllmethyllamino)ben~i"li~701e:
In~redients % wt./wt.
Compound of the invention 1.0%
Polyethylene glycol 1000 74 5%
Polyethylene glycol 4000 24.5%
The ingredients are melted together and mixed on a steam bath, and poured into moldscontaining 2.5 9 total weight.

CA 02239~08 1998-06-04 WO 97/21437 PCT~B96/01496 This example illustrates the preparation of a representative pharmaceutical formulation for insufflation containing a compound of the invention, or a pharmaceutically acceptable salt thereof, e.g., 1-(4-amidinonaphth-1-yl)methyl-2-propyl-5-(N-(1-iminoethyl)piperidin-4-5 yloxy)benzimidazole:
Inqredients % wt./wt.
Micronized compound of the invention 1.0%
Micronized lactose 99.0%
The ingredients are milled, mixed, and packaged in an insufflator equipped with a dosing 1 0 pump.

This example illustrates the preparation of a representative pharmaceutical formulation in nebulized form containing a compound of the invention, or a pharmaceutically acceptable salt thereof, e.g., 1 -(4-amidinonaphth- 1 -yl)methyl-2-methyl-5-( 1 -(methoxycarbonyl)ethoxy) -6-(N-~ 1 -1 5iminoethyl)piperidin-4-yloxy)benzimidazole:
Inu,eclienL~ % wt./wt.
Compound of the invention 0.005%
Water 89.995%
Ethanol 1 0.000%
The compound of the invention is dissolved in ethanol and blended with water. The formulation is then packaged in a nebulizer equirped with a dosing pump.

This example illustrates the prepaltlLion of a represe,-t~Live pharmaceutical formulation in aerosol form conLain;.~g a compound of the invention, or a pharmaceutically acc~:pLable salt 25 thereof, e.g., 1-(4-amidinonaphth-1-yi)methyl-2-isopropyl-4-carboxy-6-(N-(1-iminoethyl)piperidin-4-ylamino)benzimidazole:
Inaredients ~h wt.lwt.
Compound of the invention 0.10%
Propellant 11/12 98.90%
Oleic acid 1.00%
The compound of the invention is dispersed in oleic acid and the propellants. The resulting mixture is then poured into an aerosol container fitted with a metering valve.
-CA 02239~08 1998-06-04 EXAMPLE ~2 (/n vitro assay for Factor Xa and Thrombin) This assay demonstrates the activity of the compounds of the invention towards factor Xa, ~hrorllbill and tissue plasminogen activator. The activities were determined as an initiai rate 5 of cleavage of the peptide p-nitroaniiide by the enzyme. The cleavage product, p-niLIoa~ e~
absorbs at 405 nm with a molar extinction coefficient of 9920 M-~cm~1.
Rea~ents and Solutions:
Dimethyl sulfoxide (DMS0) (Baker analyzed grade~.
Assay buffer:
50 mM TrisHCI, 150 mM NaCI, 2.5 mM CaCI2, and 0.1% polyethylene glycol 6000, pH 7.5.
Enzymes (Enzyme Research Lab.):
1. Human factor Xa stock solution: 0.281 mg/mb in assay buffer, stored at -80~C (working solution (2X): 106 ng/mL or 2 nM in assay buffer, prepared prior to use).
15 2. Human thrombin stock solution: Stored at -80~C (working solution (2X): 1200 ng/mL or 40 nM in assay buffer, prepare prior to use~.
3. Human tissue pla:,n-inogen activator (tPA) (Two chains, Sigma~ stock solution: 1 mç~/mL, stored at -80~C (working solution (2X): 1361 ng/mL in assay buffer, prepare prior to use).
Chromogenic suL:,L,~Ies (Pharmacia Hepar Inc.):
20 1. S2222 (FXa assay~ stock solution: 6 mM in dH20, store at 4~C (working solution ~4X):
656,L~M in assay buffer).
2. S2302 (Thrombin assay) stock solution: 10 mM in dH20, stored at 4~C (working solution (4X): 1200 ~M in assay buffer).
3. S2288 (tPA assay) stock solution: 10 mM in dH20, stored at 4~C (working solution (4X):
1484,uM in assay buffer).
(All substrate working solutions were prepared on assay day 5.) Standard inhibitor compound stock solution:
5 mM in DMS0, stored at -20~C.
Test compounds (compounds of the invention) stock solutions:
10 mM in C)MS0, stored at -20~C.
Assav orocedure:
Assays were performed in 96-well ~ uLilt:r plates in a total volume of 200 ~I. Assay conducted in final concentration of 50 mM TrisHCI, 150 mM NaCI, 2.5 mM CaC12, 0.1 %
polyethylene glycol 6000, pH 7.5, in the absence or presence of the standard inhibitor or the test 35 compounds and enzyme and substrate at followin~ concellllaLions: (1) 1 nM factor Xa and 164 ,uM S2222; (2) 20 nM thrombin and 300,11M S2302; and (3) 10 nM tPA and 371 ~M S2288.
Concentrations of the standard inhibitor compound in the assay were from 5,uM to 0.021,uM in 1 CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 to 3 dilution. Concentration of the test compounds in the assay typically were from 10 ~M to 0.041 ~M in 1 to 3 dilution. For potent test compounds, the concentrations used in the factor Xa assay were further diluted 100 fold (100 nM to 0.41 nM) or 1000 fold (10 nM to 0.041 nM). All substrate concentrations used are equal to their Km values under the present assay conditions.
5 Assays were performed at ambient temperature.
The first step in the assay was the preparation of 10 mM test compound stock solutions in DMSO (for potent test compounds, 10 mM stock solutions were further diluted to 0.1 or 0.01 mM for the factor Xa assay), followed by the preparation of test compound working solutions (4X) by a serial dilutions of 10 mM stock solutions with Biomek 1000 (or Multiprobe 10 204) in 96 deep well plates as foliows:
la) Prepare a 40,uM working solution by diluting the 10 mM stock 1 to 250 in assay buffer in 2 steps: 1 to 100, and 1 to 2.5.
~b) Make another five serial dilutions ~1:3) of the 40,uM solution (600 ,uL for each concentration). A total of six diluted test compound solutions were used in the assay.
Standard inhibitor compound (5 mM stock) or DMSO ~control) went through the same dilution steps as those described above for test compounds.
The next step in the assay was to dispense 50,LIL of the test compound working solutions 14X) (from 40 uM to 0.164 uM), in duplicate, to microtiter plates with Biomek or MP204. To this was added 100 ~L of enzyme working solution (2X) with Biomek or MPZ04. The resulting 20 solutions were incubated at ambient temperature for 10 minutes.
To the solutions was added 50 ,LIL of substrate working solution (4X~ with Biomek or MP204.
The enzyme kinetics were measured at 405 nm, at 10 seconds interval, for five minutes in a THERMOmax piate reader at ambient temperature.
25 Calculation of K~ of the test comDounds:
Enzyme rates were calc~-lat.od as mOD/min based on the first two minutes readings. The IC50 values were dt:Ler,..il.ed by fitting the data to the log-logit eciuation ~linear) or the Morrison equation (non-linear) with an EXCEL spread-sheet. Ki values were then obtained by dividing the IC50 by 2. Routinely, Ki~factor Xa) values lower than 3 nM were cAlc~ t~d from the Morrison 30 equation.
Compounds of the invention, when tested in this assay, demonstrated the ability to inhibit human factor Xa and human thrombin.

(In vitro assay for Human Prothrombinase) This assay demon~ Les the ability of the compounds of the invention to inhibit prothrombinase. Prothrombinase (i'Tase) catalyzes the activation of prothrombin to yield CA 02239~08 1998-06-04 W O 97/21437 PCT~B96/01496 fragment 1.2 plus thrombin with meizothrombin as the intermediate. This assay is an end point assay. Activity of the prothrombinase is measured by activity of thrombin (one of the reaction products) or by the amount of thrombin formed/time based on a thrombin standard curve (nM vs mOD/min~. For determination of ICso (PTase) of the compounds of the invention, PTase activity 5 was expressed by thrombin activity (mOD/min).
Materials:
Enzymes:
1. Human factor Va (Haematologic Technologies Inc., Cat# HCVA-0110) working solution:
1.0 mg/mL in 50% glycerol, 2 mM CaC12, stored at -20~C.
10 2. Human factor Xa (Enzyme Res. Lab. cat# HFXalO11) workin~ solution: 0.281 mg/mL in assay buffer ~without BSA), stored at-80~C.
3. Human prothrombin ~FII) ~Enzyme Res. Lab., Cat# HP1002) working solution:
Diluted Fll to 4.85 mg/mL in assay buffer (without BSA), stored at -80~C.
Phospholipid ~PCPS) vesicles:
PCPS vesicles (80%PC, 20%PS) were prepared by modification of the method reported by Barenholz et a/., ~iochemistry (1977), Vol. 16, pp. 2806-2810.
Phosphatidyl serine (Avanti Polar Lipids, Inc., Cat#840032):
10 mg/mL in ;hlorofor.ll, purified from brain, stored -20~C under nitrooen or argon .
Phosphatidyl Choline ~Avanti Polar Lipids, Inc., Cat# 850457):
50 mg/mL in cl,lorotc.l.ll, synthetic 16:0-18:1 Palmitoyl-Oleoyl, stored at -20~C
under nitrogen or argon.
Spectrozyme-TH ~American Diagnostica Inc., Cat# 238L, 50 ~moles, stored at room temperature) working solution: Dissolved 50 ~moles in 10 mL dH2O.
25 BSA ~Sigma Chem Co., Cat# A-7888, FractionV, RIA grade).
Assay buffer: 50 mM TrisHCI, pH 7.5, 150 mM NaCI, 2.5 mM CaCI2, 0.1% PEG 6000 ~BDH), 0.05% BSA ~Sigma, Fr.V, RIA grade).
For one plate sssav. prepare the following working solutions:
1. Prothrombinase complex:
30 ~a) 100,uM PCPS (27.5 ~L of PCPS stock ~4.36 mM) diluted to final 1200,uL with assay buffer.
~b) 25 nM Human factor Va: 5.08 ,uL of Va stock (1 mg/mL) was diluted to final 1200 ~L with assay buffer.
(c) 5 pM Human factor Xa: Dilute Xa stock (0.281 mg/mL) 1 :1,220,000 with assay buffer. Prepare at least 1200 ~I.
Combine equal volumeç (1100,uL) of each component in the order of PCPS, factor Va and factor Xa. Let stand at ambient temperature for 5 to 10 minutes and use immediately, or - CA 02239~08 1998-06-04 W O 97~1437 PCTnB96/01496 store in ice ~bring to ambient temperature before use).
2. 6,uM Human prothrombin IFII): dilute 124~L of Fll stock (4.85 mg/mL) to final 1400~L
with assay buffer.
3. ZO mM EDTA/Assay buffer: 0.8 mL of 0.5 M EDTA (pH 8.5) plus 19.2 mL assay buffer.
4. 0.2 mM Spectrozyme-TH/EDTA buffer: 0.44 mL of SPTH stock (5 mM) pius 10.56 mL of 20 mM EDTA/assay buffer.
5. Test compounds (compounds of the invention):
Prepare a working solution ~5X) from 10 mM stock (DMSO) and make a series of 1:3dilution. Compounds were assayed at 6 concenL~Lions in duplicate.
10 Assav conditions and procedure:
Prothrombinase reaction was performed in final 50 ~L of mixture containing PTase ~20 uM
PCPS, 5 nM hFVa, and 1 pM hFXa), 1.2 uM human factor ll and varied concentration of the test compounds (5 ~M to 0.021 JIM or lower concentration range). Reaction was started by addition of PTase and incubated for 6 minutes at room temperature. Reaction was stopped by addition of 15 EDTA/buffer to final 10 mM. Activity of thrombin Iproduct) was then measured in the presence of 0.1 mM of Spectrozyme-TH as substrate at 405 nm for 5 minutes (10 second intervals), at ambient temperature, in a THEROmax microplate reader. Reactions were performed in 96-well micl oliLe~ plates.
In the first step of the assay, 10 ~L of diluted test compound t5X) or buffer was added to 20 the plates in dupliGate. Then 10 ,uL of pr.,lhor.lbin (hFII) (5X) was added to each well. Next 30 ,uL PTase was added to each well, mix for about 30 seconds. The plates were then incubated at ambient temperature for 6 minutes.
In the next step, 50 ~L of 20 mM EDTA (in assay buffer) was added to each well to stop the reaction. The resulting solutions were then mixed for about 10 seconds. Then 100 ,uL of 0.2 25 mM spectro~yme was added to each well. The thrombin reaction rate was then measured at 405 nm for 5 minutes (at 10 second intervals) in a Molecular Devices microplate reader.
Calculations:
Thrombin reaction rate was ~ .ressed as mOD/minute using OD readings from the five minute reaction. IC!;o values were c~lclll~t~d with the log-lo~it curve fit program.
The compounds of the invention demonstrated the ability to inhibit thrombinase when tested in this assay.

(In v;vo assayJ
The following assay demonsll~L~s the ability of the compounds to act as anti-coagulants.
Male rats (250-330 9) were ane~Lll~ ed with sodium pentobarbital (90 mg/kg, i.p.) and prepared for surgery. The left carotid artery was cannulated for the measurement of blood CA 02239~08 1998-06-04 pressure as well as for taking blood samples to monitor clotting variables (prothrombin time (PT) and activated partial thromboplastin time (aPTT~). The tail vein was cannulated for the purpose of administering the test compounds Ir.e., the compounds of the invention and standards~ and the thromboplastin infusion. The abdomen was opened via a mid-line incision and the abdom;nal vena 5 cava was isolated for 2-3 cm distal to the renal vein. All venous branches in this 2-3 cm segment of the abdominal vena cava were ligated. ~ollowing all surgery, the animals were allowed to stabilize prior to beginning the experiment. Test compounds were ad~ -i .Le.ed as an intravenous bolus (t=0). Three minutes later ~t=3), a 5-minute infusion of thromboplastin was begun. Two minutes into the infusion (t=~;), the abdominal vena cava was ligated at both the proximal and 10 distal ends. The vessel was left in place for 60 minutes, after which it was excised from the animal, slit open, the clot (if any) carefully removed, and weighed. SI~L;~LiCC,I analysis on the results was performed using a Wilcoxin-matched-pairs signed rank test.
The compounds of the invention, when tested in this assay, demonstrated the ability to clot the blood.

While the present invention has been described with r~:r~ nce to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made and equivalents may be 20 substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims (15)

WHAT IS CLAIMED IS:

1. A compound of formula (I):

wherein:
n is 0 to 3;
A is a branched or straight chain alkylene, -C(O)- or -S(O)2-;
R1 is hydrogen, -OR5 or -N(R5)R6;
each R2 is independently nitro, alkyl (optionally substituted by halo, aryl, -C(O)OR8, -C(O)N(R8)R9, -N(R8)R9), -OR5, -N(R7)R7, -N(R7)R9, -N(R8)R9, -N(R8)C(O)R7, -C(O)OR8, -C(O)N(R7)R9, -C(O)N(R8)R9, or a heterocyclyl optionally substituted by one or more substituents selected from the group consisting of -C(NH)N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)R8, -C(NH)N(H)C(O)OR8, -C(O)OR8, -C(O)N(R8)R9, -R10-C(O)OR8, R10-C(O)N(R8)R9 and -SO3H;
R3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or-C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)mOR8 (where m is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8;
R4 is -C(NH)-N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)R8 or -C(NH)N(H)C(O)OR8;
each R5 is independently:
hydrogen; or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)pOR8 (where p is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8; or aryl optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, or-C(O)N(R8)R9; or heterocyclyl optionally substituted by one or more substituents selected from the group consisting of 1-iminoalkyl, -C(O)OR8, -C(O)N(R8)R9, -C(NH)N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)OR8, -R10-C(O)OR8, -R10-C(O)N(R8)R9 and -SO3H;
R6 is hydrogen, alkyl, -R10-C(O)OR8, -R10-C(O)N(R8)R9, -C(O)R7, or aralkyl (optionaily substituted by alkyl, halo, -N(R8)R9, -C(O)OR8, or -C(O)N(R8)R9);
R7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8), aryloxy, aralkoxy, alkenyl, haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, hydroxy, -C(O)OR8 or -N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)qOR8 (where q is 1 to 4),-N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8;
each R8 and R9 is independently hydrogen, alkyl, aryl or aralkyl; and each R10 is independently a branched or straight chain alkylene;
or a pharmaceutically acceptable salt thereof.

2. The compound of Claim 1 wherein:
n is 0 or 1;
A is alkylene;
R1 is-OR5 or-N(R5)R6;
R2 is independently nitro, alkyl (optionally substituted by -C(O)OR8), -OR5, -N(R7)R9, -C(O)OR8, -C(O)N(R8)R9 or piperidinyl optionally substituted by -C(O)OR8 or -R10-C(O)OR8;
R3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, -C(O)OR8, or-C(O)N(R8)R9;
R4 is -C(NH)NH2;
each R5 is independently:
hydrogen; or alkyl optionally substituted by one or more substituents selected from the groupconsisting of -C(O)OR8, -C(O)N(R8)R9 and phenyl (optionally substituted by -C(O)OR3); or piperidinyl or pyrrolidinyl, each optionally substituted by 1-iminoalkyl, -C(NH)N(R8)R9, -R10-C(O)OR8 or -SO3H;
R6 is hydrogen, alkyl, benzyl (optionally substituted by -C(O)OR8), -R10-C(O)OR8, -R10-C(O)N(R8)R9 or -C(O)R7;
R7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of -C(O)OR8 and aryl (optionally substituted by -C(O)OR8);
each R8 and R9 is independently hydrogen or alkyl; and each R10 is independently a branched or straight chain alkylene.

3. The compound of Claim 2 wherein:
n is 0 or 1 ;
A is methylene;
R1 is-OR5 or-N(R5)R6;
R2 is independently nitro, methyl (substituted by -C(O)OR8), -OR5, -N(R7)R9, -C(O)OR8, -C(O)N(R8)R9 or piperidinyl optionally substituted by -C(O)OR8 or -R10-C(O)OR8;
R3 is hydrogen or alkyl optionally substituted by-C(O)OR8 or -C(O)N(R8)R9;
R4 is -C(NH)NH2;
each R5 is independently:
hydrogen; or alkyl optionally substituted by -C(O)OR8, -C(O)N(R8)R9 or phenyl (optionally substituted by-C(O)OR8); or piperidinyl optionally substituted by 1-iminoalkyl, -R10-C(O)OR8 or-SO3H;
R6 is hydrogen, alkyl, benzyl (optionally substituted by -C(O)OR8) or -R10-C(O)OR8:
R7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of -C(O)OR8 and aryl (optionally substituted by -C(O)OR8);
each R8 and R9 is independently hydrogen, methyl or ethyl; and each R10 is independently a branched or straight chain alkylene.

4. The compound of Claim 3 wherein:
n is 0;
A is methylene;
R1 is-OR5;
R3 is hydrogen or alkyl optionally substituted by -C(O)OR8 or -C(O)N(R8)R9;
R4 is -C(NH)NH2;
R5 is piperidinyl optionally substituted by 1-iminoalkyl; and R8 and R9 are independently hydrogen, methyl or ethyl.

5. The compound of Claim 4 selected from the group consisting of:
1-(4-amidinonaphth-1-yl)methyl-2-methyl-6-(N-(1-iminoethyl)piperidin-4-yloxybenzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(N-(1-iminoethyl)piperidin-4-yloxbenzimidazole;

1-(4-amidinonaphth-1-yl)methyl-2-methyl-6-(N-(1-iminoethyl)piperidin-3-yloxybenzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-ethyl-6-(N-(1-iminoethyl)piperidin-4-yloxybenzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-ethyl-5-(N-(1-iminoethyl)piperidin-4-yloxybenzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-6-(N-(1-iminoethyl)piperidin-4-yloxybenzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-5-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-t-butyl-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-t-butyl-5-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-5-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-propyl-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-propyl-5-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-propyl-6-(piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-propyl-5-(piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-6-(piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-5-(piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-sec-butyl-6-(N-1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-sec-butyl-5-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-n-butyl-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-n-butyl-5-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-(2-carboxyethyl)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-(2-carboxyethyl)-5-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole; and 1-(4-amidinonaphth-1-yl)methyl-2-(2-aminocarbonylethyl)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole.

6. The compound of Claim 3 wherein:
n is 0;
A is methylene;
R1 is-N(R5)R6;
R3 is hydrogen or methyl;
R4 is -C(NH)NH2;
R5 is piperidinyl optionally substituted by 1-iminoalkyl;
R6 is hydrogen, -R10-C(O)OR8 or -C(O)N(R8)R9;
R8 and R9 are independently hydrogen or methyl; and R10 is a branched or straight chain alkylene.

7. The compound of Claim 6 selected from the group consisting of:
1-(4-amidinonaphth-1-yl)methyl-6-(N-(1-iminoethyl)piperidin-4-yl)aminobenzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-6-(N-(N'-(1-iminoethyl)piperidin-4-yl)-N-((methoxycarbonyl)methyl)amino)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-6-(N-(N'-(1-iminoethyl)piperidin-4-yl)-N-((aminocarbonyl)methyl)amino)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-6-(N-(N'-(1-iminoethyl)piperidin-4-yl)-N-(3-carboxypropyl)amino) benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-6-(N-(N'-(1-iminoethyl)piperidin-4-yl)-N-(2-(methoxycarbonyl)propyl)amino)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-6-(N-(N'-(1-iminoethyl)piperidin-4-yl)-N-(2-(carboxy)propyl)amino)benzimidazole; and 1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(N-(N'-(1-iminoethyl)piperidin-4-yl)-N-(2-(carboxy)propyl)amino)benzimidazole.

8. The compound of Claim 3 wherein:
n is 1 ;
A is methylene;
R1 is -OR5;
R2 is nitro, -OR5, -N(R7)R9, -C(O)OR8, or piperidinyl (optionally substituted by -C(O)OR8);
R3 is methyl or 1-isopropyl;
R4 is -C(NH)NH2;
each R5 is independently hydrogen or alkyl optionally substituted by -C(O)OR5, -C(O)N(R8)R9, aryl (optionally substituted by -C(O)OR8), or piperidinyl (optionally substituted by -R10-C(O)OR5 or 1-iminoethyl);
R7 is a branched or straight chain alkylene substituted by -C(O)OR8 or phenyl (optionally substituted by-C(O)OR8); and each R8 and R9 is independently hydrogen or methyl.

9. The compound of Claim 8 selected from the group consisting of:
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-hydroxy-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(aminocarbonyl)methoxy-6-(N-(1-imino-ethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(carboxy)methoxy-6-(N-(1-imino-ethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(4-(methoxycarbonyl)benzyloxy)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(4-(carboxy)benzyloxy)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-carboxy-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-((aminocarbonyl)methoxy)-6-(N-(1-iminoethyl)piperidin-4-yloxy) benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(3-(methoxycarbonyl)benzyloxy)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(3-(carboxy)benzyloxy)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(methoxycarbonyl)methoxy-6-(N-(1-imino-ethyl) piperidin-4-yloxy) benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(1-(aminocarbonyl)ethoxy)-6-(N-(1-imino-ethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(1-(methoxycarbonyl)ethoxy)-6-(N-(1-imino-ethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(1-(carboxy)ethoxy)-6-(N-(1-imino-ethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-4-methoxy-6-(piperidin-4-yloxy) benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-7-methoxy-5-(piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-4-methoxy-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-7-methoxy-5-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(N-(4-carboxy)benzylamino)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-4-(4-carboxypiperidin-1-yl)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-4-(carboxy)methoxy-6-(N-(1-imino-ethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-7-nitro-6-(N-(1-imino-ethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-methyl-7-nitro-6-(N-(1-imino-ethyl)piperidin-4-yloxy)benzimidazole;

1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-5-(N-(2-carboxyprop-2-yl)amino)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-5-(N-(4-carboxy)benzylamino)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole;
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-5-(N-(2-carboxyethyl)amino)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole; and 1-(4-amidinonaphth-1-yl)methyl-2-methyl-5-(N-(carboxymethyl)piperidin-4-yloxy)-6-(N-(1-iminoethyl)piperidin-4-yloxy)benzimidazole.

10. The compound of Claim 3 wherein:
n is 1;
A is methylene;
R1 is -N(R5)R6;
R2 is -C(O)OR8 or -C(O)N(R8)R9;
R3 is 1-isopropyl;
R4 is -C(NH)NH2;
R5 is piperidinyl optionally substituted by 1-iminoethyl;
R6 is hydrogen; and each R8 and R9 is independently hydrogen or methyl.

11. The compound of Claim 10 selected from the group consisting of:
1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-4-carboxy-6-(N-(1-iminoethyl)piperidin-4-ylamino)benzimidazole; and 1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-4-aminocarbonyl-6-(N-(1-iminoethyl)piperidin-4-ylamino)benzimidazole.

12. A pharmaceutical composition useful in treating a human having a disease-state characterized by thrombotic activity which composition comprises a therapeutically effective amount of a compound of formula (I):

n is 0 to 3;
A is a branched or straight chain alkylene, -C(O)- or -S(O)2-;
R1 is hydrogen, -OR5 or-N(R5)R6;
each R2 is independently nitro, alkyl (optionally substituted by halo, aryl, -C(O)OR8, -C(O)N(R8)R9, -N(R8)R9), -OR5, -N(R7)R7, -N(R7)R9, -N(R8)R9, -N(R8)C(O)R7, -C(O)OR8, -C(O)N(R7)R9, -C(O)N(R8)R9, or a heterocyclyl optionally substituted by one or more substituents selected from the group consisting of -C(NH)N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)R3, -C(NH)N(H)C(O)OR8, -C(O)OR8, -C(O)N(R8)R9, -R10-C(O)OR8, -R10-C(O)N(R8)R9 and -SO3H;
R3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8,-C(O)N(R8)R9), haloalkenyl, cycloalkyl,imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)mOR8 (where m is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8;
R4 is -C(NH)-N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)R8 or -C(NH)N(H)C(O)OR8;
each R5 is independently:
hydrogen; or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)pOR8 (where p is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8; or aryl optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, or-C(O)N(R8)R9; or heterocyclyl optionally substituted by one or more substituents selected from the group consisting of 1-iminoalkyl, -C(O)OR8, -C(O)N(R8)R9, -C(NH)N(R8)R9,-C(NH)N(H)OR8, -C(NH)N(H)C(O)OR8, R10-C(O)OR8, -R10-C(O)N(R8)R9 and -SO3H;
R6 is hydrogen, alkyl, -R10-C(O)OR8, -R10-C(O)N(R8)R9, -C(O)R7, or aralkyl (optionally substituted by alkyl, halo, -N(R8)R9, -C(O)OR8, or-C(O)N(R8)R9);

R7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8), aryloxy, aralkoxy, alkenyl, haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, hydroxy, -C(O)OR8 or -N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)qOR8 (where q is 1 to 4),-N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8;
each R8 and R9 is independently hydrogen, alkyl, aryl or aralkyl; and each R10 is independently a branched or straight chain alkylene;
or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient thereof.

13. A method of treating a human having a disease-state characterized by thrombotic activity, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (I):
wherein:
n is 0 to 3;
A is a branched or straight chain alkylene, -C(O)- or -S(O)2-;
R1 is hydrogen, -OR5 or-N(R5)R6;
each R2 is independently nitro, alkyl (optionally substituted by halo, aryl, -C(O)OR8, -C(O)N(R8)R9, -N(R8)R9), -OR5, -N(R7)R7, -N(R7)R9, -N(R8)R9, -N(R8)C(O)R7, -C(O)OR8, -C(O)N(R7)R9, -C(O)N(R8)R9, or a heterocyclyl optionally substituted by one or more substituents selected from the group consisting of -C(NH)N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)R8, -C(NH)N(H)C(O)OR8, -C(O)OR8, -C(O)N(R8)R9, -R10-C(O)OR8, -R10-C(O)N(R8)R9 and -SO3H;
R3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8,-C(O)N(R8)R9), haloalkenyl, cycloalkyl,imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)mOR8 (where m is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8;
R4 is -C(NH)-N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)R8 or -C(NH)N(H)C(O)OR8;
each R5 is independently:
hydrogen; or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), arylkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)pOR8 (where p is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8; or aryl optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(C3)OR8, or-C(O)N(R8)R9; or heterocyclyl optionally substituted by one or more substituents selected from the group consisting of 1-iminoalkyl, -C(O)OR8, -C(O)N(R8)R9, -C(NH)N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)OR8, -R10-C(O)OR8, -R10-C(O)N(R8)R9 and -SO3H;
R6 is hydrogen, alkyl, -R10-C(O)OR8, -R10-C(O)N(R8)R9, -C(O)R7, or aralkyl (optionally substituted by alkyl, halo, -N(R8)R9, -C(O)OR8, or -C(O)N(R8)R9);
R7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8), aryloxy, aralkoxy, alkenyl, haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, hydroxy, -C(O)OR8 or -N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)qOR8 (where q is 1 to 4),-N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8;
each R8 and R9 is independently hydrogen, alkyl, aryl or aralkyl; snd each R10 is independently a branched or straight chain alkylene;
or a pharmaceutically acceptable salt thereof.

14. A method of treating a human having a disease-state alleviated by the inhibition of factor Xa, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (I):

wherein:
n is O to 3;
A is a branched or straight chain alkylene, -C(O)- or -S(O)2-;
R1 is hydrogen, -OR5 or-N(R5)R6;
each R2 is independently nitro, alkyl (optionally substituted by halo, aryl, -C(O)OR8, -C(O)N(R8)R9, -N(R8)R9), -OR5, -N(R7)R7, -N(R7)R9, -N(R8)R9, -N(R8)C(O)R7, -C(O)OR8, -C(O)N(R7)R9, -C(O)N(R8)R9, or a heterocyclyl optionally substituted by one or more substituents selected from the group consisting of -C(NH)N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)R8, -C(NH)N(H)C(O)OR8, -C(O)OR8, -C(O)N(R8)R9, -R10-C(O)OR8, -R10-C(O)N(R8)R9 and -SO3H;
R3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8,-C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or-C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)mOR8 (where m is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8;
R4 is -C(NH)-N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)R8 or -C(NH)N(H)C(O)OR8;
each R5 is independently:
hydrogen; or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R3)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)pOR8 (where p is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8; or aryl optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, or -C(O)N(R8)R9; or heterocyclyl optionally substituted by one or more substituents selected from the group consisting of 1-iminoalkyl, -C(O)OR8, -C(O)N(R8)R9, -C(NH)N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)OR8, -R10-C(O)OR8, -R10-C(O)N(R8)R9 and -SO3H;
R6 is hydrogen, alkyl, -R10-C(O)OR8, -R10-C(O)N(R8)R9, -C(O)R7, or aralkyl (optionally substituted by alkyl, halo, -N(R8)R9, -C(O)OR8, or -C(O)N(R8)R9);
R7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8), aryloxy, aralkoxy, alkenyl, haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, hydroxy, -C(O)OR8 or -N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)qOR8 (where q is 1 to 4),-N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8;
each R8 and R9 is independently hydrogen, alkyl, aryl or aralkyl; and each R10 is independently a branched or straight chain alkylene;
or a pharmaceutically acceptable salt thereof.

15. A method of inhibiting human factor Xa in vitro or in vivo by the administration of a compound of formula (I):

wherein:
n is 0 to 3;
A is a branched or straight chain alkylene, -C(O)- or -S(O)2-;
R1 is hydrogen, -OR5 or-N(R5)R6;
each R2 is independently nitro, alkyl (optionally substituted by halo, aryl, -C(O)OR8, -C(O)N(R8)R9, -N(R8)R9), -oR5, -N(R7)R7, -N(R7)R9, -N(R8)R9, -N(R8)C(o)R7, -C(O)OR8, -C(o)N(R7)R9, -C(O)N(R8)R9, or a heterocyclyl optionally substituted by one or more substituents selected from the group consisting of -C(NH)N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)R8, -C(NH)N(H)C(O)OR8, -C(O)OR8, -C(O)N(R8)R9, -R10-C(O)OR8 -R10-C(O)N(R8)R9 and -SO3H;
R3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)mOR8 (where m is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8;
R4 is -C(NH)-N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)R8 or -C(NH)N(H)C(O)OR8;
each R5 is independently:
hydrogen; or alkyl optionally substituted by one or more substituents selected from the groupconsisting of halo, alkenyl, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aryloxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), aralkoxy (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, -N(R8)R9, -C(O)OR8 or -C(O)N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)pOR8 (where p is 1 to 4), -N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8; or aryl optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8, or -C(O)N(R8)R9; or heterocyclyl optionally substituted by one or more substituents selected from the group consisting of 1-iminoalkyl, -C(O)OR8, -C(O)N(R8)R9, -C(NH)N(R8)R9, -C(NH)N(H)OR8, -C(NH)N(H)C(O)OR8, -R10-C(O)OR8, -R10-C(O)N(R8)R9 and -SO3H;
R6 is hydrogen, alkyl, -R10-C(O)OR8, -R10-C(O)N(R8)R9, -C(O)R7, or aralkyl (optionally substituted by alkyl, halo, -N(R8)R9, -C(O)OR8, or -C(O)N(R8)R9);
R7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, aryl (optionally substituted by alkyl, hydroxy, halo, -N(R8)R9, -C(O)OR8), aryloxy, aralkoxy, alkenyl, haloalkenyl, cycloalkyl, imidazolyl, indolyl, adamantyl (optionally substituted by halo, alkyl, hydroxy, -C(O)OR8 or -N(R8)R9), -C(O)OR8, -N(R8)R9, -C(O)N(R8)R9, -C(O)(CH2)qOR8 (where q is 1 to 4),-N(R8)C(O)R8, -N(R8)C(O)N(R8)R9, -N(R8)C(NH)N(R8)R9, -OPO3H2 and -SR8;
each R8 and R9 is independently hydrogen, alkyl, aryl or aralkyl; and each R10 is independently a branched or straight chain alkylene;
or a pharmaceutically acceptable salt thereof.