AU8587498A - Urokinase inhibitors - Google Patents

Urokinase inhibitors Download PDF

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Publication number
AU8587498A
AU8587498A AU85874/98A AU8587498A AU8587498A AU 8587498 A AU8587498 A AU 8587498A AU 85874/98 A AU85874/98 A AU 85874/98A AU 8587498 A AU8587498 A AU 8587498A AU 8587498 A AU8587498 A AU 8587498A
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AU
Australia
Prior art keywords
salt
trifluoroacetate
mono
aminoiminomethyl
methoxy
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Abandoned
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AU85874/98A
Inventor
Andrew G. Geyer
William J. Mcclellan
Todd W. Rockway
Kent D. Stewart
Moshe Weitzberg
Michael D Wendt
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Abbott Laboratories
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Abbott Laboratories
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Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of AU8587498A publication Critical patent/AU8587498A/en
Abandoned legal-status Critical Current

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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

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Description

WO 99/05096 PCTIUS98/15386 UROKINASE INHIBITORS Cross Reference to Related Applications 5 This application is a continuation-in-part of U.S. Application Ser. No. 08/901,040, filed July 25, 1997, pending. Background of the Invention The present invention provides naphthamidine compounds which inhibit the urokinase 10 enzyme, pharmaceutical compositions containing these compounds and medical methods of treatment using these compounds. Technical Field Urokinase (urinary-type plasminogen activator or uPA (International Union of 15 Biochemistry classification number: EC3.4.21.31)) is a proteolytic enzyme which is highly specific for a single peptide bond in plasminogen. Plasminogen activation (cleavage of this bond by the urokinase enzyme) results in formation of plasmin, a potent general protease. Many cell types use urokinase as a key initiator of plasmin-mediated proteolytic degradation or modification of extracellular support structures such as extracellular matrix 20 (ECM) and basement membrane (BM). Cells exist, move and interact with each other in tissues and organs within the physical framework provided by ECM and BM. Movement of cells within ECM or across BM requires local proteolytic degradation or modification of the structures and allows cells to invade adjacent areas previously unavailable prior to the degredation or modification. 25 Cellular invasiveness intiated by urokinase is central to a variety of normal and disease state physiological processes (Blasi, F., Vassalli, J. D., and Dano, K. J. Cell Biol. 104:801 804, 1987; Dano, K., Anderson, P. A., Grondahl-Hansen, J., Kristensen, P., Nielsen, L. S., and Skriver, L. Adv. Cancer Res. 44:139-266, 1985; Littlefield, B. A. Ann. N. Y. Acad. Sci. 622: 167-175, 1991; Saksela, 0., Biochim. Biophys. Acta 823: 35-65, 1985; Testa, J. E. and 30 Quigley, J. P. Cancer Metast. Rev. 9:353-367, 1990). Such processes include, but are not limited to, angiogenesis (neovascularization), bone restructuring, embryo implantation in the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue remodelling during wound repair and organ differentiation, fibrosis, tumor invasion, metastatic -1 SUBSTITUTE SHEET (RULE 26) WO 99/05096 PCT/US98/15386 spread of tumor cells from primary to secondary sites and tissue destruction in arthritis. Amiloride, for example, a known urokinase inhibitor of only moderate potency, has been reported to inhibit tumor metastasis in vivo (Kellen, J. A., Mirakian, A. Kolin, A. Anticancer Res. 8:1373-1376, 1988) and angiogenesis/capillary network formation in vitro (Alliegro, M. 5 C. and Glaser, B. M. J. Cell Biol. 115[3 Pt 2]: 402a, 1991). Inhibitors of urokinase, therefore, have mechanism-based anti-angiogenic, anti-arthritic, anti-inflammatory, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive and tumoristatic uses. 10 Summary of the Invention In its principle embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester or prodrug thereof, of formula (I) C NH BA
NH
2 AX Z- (I), wherein 15 Z is selected from the group consisting of (1) nitrogen; (2) methine; and (3) methine substituted with -NRiR 2 ; 20 A is selected from the group consisting of (1) hydrogen and (2) -LARA; B is selected from the group consisting of 25 (1) hydrogen and (2) -LBRB and C is selected from the group consisting of (1) hydrogen and 30 (2) -LCRC, with the proviso that at least one of A, B or C is other than hydrogen; and -2 Sunnrmrre IT ==-r ma1 1n e WO 99/05096 PCT/US98/15386 with the proviso that when A is other than hydrogen, at least one of B or C is other than hydrogen, wherein for A, B, and C, LA, LB and LC are independently selected from the group consisting of 5 (1) a covalent bond, (2) -(CH 2 )m-, (3) -NRi-, (4) -NR 2
C(X)NR
3 -, (5) -C(X)-, 10 (6) -NR 2 C(X)-, (7) -C(X)NR 2 -, (8) -CH=CH-, (9) -C=C-, (10) -0-, 1.5 (11) -S(O)t-, (12) -C=C(CH 2 )nNR2C(X)-, (13) -C(X)NR 2
(CH
2 )nC=C-, (14) -(CH 2 )nNS0 2 -, (15) -NR 2
SO
2
(CH
2 )nC=C-, 20 (16) -CEC(CH 2 )nNR 2
SO
2
NR
3 -, (17) -NR 2
SO
2
NR
3
(CH
2 )nC=C-, (18) -SO 2
NR
2 -, (19) -NR 2
SO
2 -, (20) -NR 2
SO
2
NR
3 -, 25 (21) -N=N-, (22) -C(X)N(OR 2 )-, (23) -N(OR 2 )C(X)-, (24) -HC=CH(CH 2 )nNR 2 C(X)-, (25) -(CH 2 )nNR 2 C(X)CH=CH-, 30 (26) -CH=CH(CH 2 )nNSO 2 -, (27) -NR 2
SO
2
(CH
2 )nCH=CH-, (28) -(CH2)nNR2SO 2
NR
3 -, (29) -NR 2
SO
2
NR
3
(CH
2 )nCH=CH-, (30) -NR 2 C(0)O-, -3 SURSTIrre cuc-r t n -.
WO 99/05096 PCT/US98/15386 (31) -OC(O)NR 2 -, (32) -CH=NO-, (33) -ON=CH- and (34) W ,wherein W is selected from the group consisting of 5 (a) -0-, (b) -S-, (c) -NRI- and (d) -(CH 2 )m-, wherein each functional group is depicted with its right-hand end being the end which is 10 attached to the naphthyl or quinolyl ring and its left-hand end being the end which is attached to RA, RB or RC; RA, RB and RC are independently selected from the group consisting of (1) aryl; 15 (2) arylalkoxy, wherein the alkylene group is of one to six carbon atoms; (3) alkyl of one to ten carbon atoms; (4) alkenyl of two to ten carbon atoms; (5) alkoxycarbonyl of one to six carbon atoms; (6) alkynyl of two to ten carbon atoms; 20 (7) halogen; (8) -NRIR 2 ; (9) heterocycle; (10) cycloalkenyl of four to twelve carbon atoms; (11) cycloalkyl of three to twelve carbon atoms; 25 (12) -NRIC(O)NR 2
R
3 ; and (13) -NRIC(O)R 50 , wherein R 50 is alkyl of one to six carbon atoms; wherein, at each occurence, R I is selected from the group consisting of (1) hydrogen; (2) an N-protecting group; 30 (3) alkyl of one to six carbon atoms; (4) alkenyl of two to six carbon atoms; (5) alkynyl of two to six carbon atoms; (6) aryl; -4 SURBTmrr Cu=-r f 1 11 c - WO 99/05096 PCT/US98/15386 (7) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (8) cycloalkyl of three to eight carbon atoms and (9) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms; and 5 wherein, at each occurence, R 2 and R 3 are independently selected from the group consisting of (1) hydrogen; (2) alkyl of one to six carbon atoms; (3) alkenyl of two to six carbon atoms; (4) alkynyl of two to six carbon atoms; 10 (5) aryl; (6) arylalkyl, wherein the alkylene group is of one to six carbon atoms (7) cycloalkyl of three to eight carbon atoms and (8) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms; and 15 wherein, at each occurence, X is selected from the group consisting of (1) O and (2) S; and wherein, at each occurence, m is one to five, 20 n is zero to four and t is zero to two; and wherein, at each occurence, the alkyl, alkenyl, alkynyl, aryl, heterocycle, cycloalkyl, and cycloalkenyl groups are optionally substituted. The present invention also relates to a method of inhibiting urokinase in a mammal, 25 particularly humans, by administering a therapeutically effective amount of a composition comprising a compound of formula (I). The present invention also relates to pharmaceutical compositions which comprise a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier. 30 Detailed Description of the Invention As used throughout this specification and the appended claims, the following terms have the meanings specified: -5 SuRTITI IT= CU -r 1m ir 0 m WO 99/05096 PCT/US98/15386 The term "alkyl," as used herein, represents a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom and is exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl and the like and may be optionally substituted with one, two, three or four substituents independently 5 selected from the group consisting of (1) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) amino; (5) aryl; (6) arylalkoxy, wherein the alkylene group is of one to six carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (11) halo; (12) heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxy; (16) N-protected amino; (17) nitro; (18) 10 oxo; (19) spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one to six carbon atoms; (21) -C0 2
R
2 ; (22) -C(O)NR 2
R
3 ; (23) -S0 2
R
4 , wherein R 4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (24) -SO 2
NR
5
R
6 , wherein R 5 and R 6 are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of 15 one to six carbon atoms; (25) -NR 7 Rg, wherein R 7 and R 8 are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight 20 carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group. The term "alkanoyl," as used herein, represents an alkyl group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl, acetyl, propionyl, butanoyl and the like. 25 The term "alkenyl," as used herein, represents monovalent straight or branched chain groups containing a carbon-carbon double bond derived from an alkene by the removal of one hydrogen atom and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2 -methyl-1-propenyl, 1 butenyl, 2-butenyl and the like and may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of (1) alkoxy of one to six carbon 30 atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) amino; (5) aryl; (6) arylalkoxy, wherein the alkylene group is of one to six carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (11) halo; (12) heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxy; (16) N protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20) -6 SUBSTITUT= C;14u T I It WO 99/05096 PCT/US98/15386 thioalkoxy of one to six carbon atoms; (21) -C0 2
R
2 ; (22) -C(O)NR 2
R
3 ; (23) -S0 2
R
4 , wherein
R
4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (24) -SO 2
NR
5
R
6 , wherein R 5 and R 6 are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) 5 arylalkyl, wherein the alkylene group is of one to six carbon atoms; (25) -NR 7
R
8 , wherein R 7 and R 8 are independently selected from the group consisting of (a) hydrogen; (b) an N protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, 10 wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group. The term "alkoxy," as used herein, represents an alkyl group attached to the parent molecular group through an oxygen atom. 15 The term "alkoxyalkyl" as used herein, represents an alkyl group to which is attached an alkoxy group. The term "alkoxycarbonyl," as used herein, represents an ester group; i.e. an alkoxy group, attached to the parent molecular group through a carbonyl group and is exemplified by methoxycarbonyl, ethoxycarbonyl and the like. 20 The term "alkylene," as used herein, represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene and the like. The term "alkylsulfinyl," as used herein, represents an alkyl group attached to the parent molecular group through an -S(O)- group. 25 The term "alkylsulfinylalkyl," as used herein, represents an alkyl group, as defined herein, substituted by a sulfinyl group. The term "alkylsulfonyl," as used herein, represents an alkyl group attached to the parent molecular group through an -SO 2 - group. The term "alkylsulfonylalkyl," as used herein, represents an alkyl group, as defined 30 herein, substituted by a sulfonyl group. The term "alkynyl," as used herein, represents monovalent straight or branched chain groups of two to six carbon atoms containing a carbon-carbon triple bond derived from an alkyne by the removal of one hydrogen atom and is exemplified by ethynyl, 1-propynyl, and the like and may be optionally substituted with one, two, three or four substituents -7 SUBSTmITF : -r 1011m C =I WO 99/05096 PCT/US98/15386 independently selected from the group consisting of (1) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) amino; (5) aryl; (6) arylalkoxy, wherein the alkylene group is of one to six carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (11) halo; 5 (12) heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxy; (16) N-protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one to six carbon atoms; (21) -C02R 2 ; (22) -C(O)NR 2
R
3 ; (23) -S0 2
R
4 , wherein R 4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (24) -SO 2
NR
5
R
6 , wherein R5 and R 6 are independently selected 10 from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (25) -NR 7
R
8 , wherein R 7 and R 8 are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon 15 atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group. The term "amino," as used herein, represents an -NH 2 group. 20 The term "aminoalkyl," as used herein, represents an alkyl group, as defined herein, substituted by an amino group. The term "aryl," as used herein, represents a mono- or bicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like and may be optionally 25 substituted with one, two, three, four or five substituents independently selected from the group consisting of (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkylene goups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of one to 30 six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) -8 SuSs-rrn IT= cZLue-r ICm it- WO 99/05096 PCT/US98/15386 carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylene group is of one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocycle; (25) 5 (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32) N protected aminoalkyl, wherein the alkylene group is of one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (36) -(CH2)qCO2R2, wherein q is zero to 10 four; (37) -(CH2)qC(O)NR2R 3 ; (38) -(CH2)qSO2R4, wherein R 4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (39) -(CH2)qSO2NR5R 6 , wherein R 5 and R 6 are independently selected from the group consisting of(a) hydrogen, (b) alkyl, (c) aryl and(d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (40) -(CH2)qNR 7 Rg, wherein R 7 and R 8 are independently 15 selected from the group consisting of (a) hydrogen, (b) an N-protecting group, (c) alkyl of one to six carbon atoms, (d) alkenyl of two to six carbon atoms, (e) alkynyl of two to six carbon atoms, (f) aryl, (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms, (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the 20 proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44) aryloxy; (45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy. The term "arylalkyl," as used herein, represents an aryl group attached to the parent molecular group through an alkyl group. 25 The term "arylalkoxy," as used herein, represents an arylalkyl group attached to the parent molecular group through an oxygen atom. The term "aryloxy," as used herein, represents an aryl group which is attached to the parent molecular group through an oxygen atom. The term "aryloyl," as used herein, represents an aryl group which is attached to the 30 parent molecular group through a carbonyl group. The term "azido," as used herein, represents an -N 3 group. The term "azidoalkyl," as used herein, represents an alkyl group, as defined herein, substituted by an azido group. The term "carbonyl," as used herein, represents a C=O group. -9 SUBST rrIT= c -r m0n11 WO 99/05096 PCT/US98/15386 The term "carboxaldehyde," as used herein, represents a -CHO group. The term "(carboxaldehyde)alkyl," as used herein, represents an alkyl group, as defined herein, substituted by a carboxaldehyde group. The term "carboxy," as used herein, represents a -CO 2 H group. 5 The term "carboxyalkyl," as used herein, represents an alkyl group, as defined herein, substituted by a carboxy group. The term "cycloalkyl," as used herein represents a monovalent saturated cyclic hydrocarbon group and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2. l]heptyl and the like. The cycloalkyl groups of this invention can be 10 optionally substituted with (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkylene goups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, 15 wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylene group is of one to six 20 carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocycle; (25) (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32) N 25 protected aminoalkyl, wherein the alkylene group is of one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (36) -(CH2)qCO2R2, wherein q is zero to four; (37) -(CH2)qC(O)NR 2
R
3 ; (38) -(CH2)qSO2R 4 , wherein R 4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six 30 carbon atoms; (39) -(CH2)qSO2NR5R6, wherein R 5 and R 6 are independently selected from the group consisting of(a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (40) -(CH2)qNR 7
R
8 , wherein R 7 and R 8 are independently selected from the group consisting of (a) hydrogen, (b) an N-protecting group, (c) alkyl of one to six carbon atoms, (d) alkenyl of two to six carbon atoms, (e) alkynyl of two to six carbon -10 SUBSTITTF: Cu-r m oii net WO 99/05096 PCTIUS98/15386 atoms, (f) aryl, (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms, (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a 5 sulfonyl group; (41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44) aryloxy; (45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy. The term "cycloalkenyl," as used herein represents a monovalent cyclic hydrocarbon having at least one carbon-carbon double bond. The cycloalkenyl groups of this invention can be optionally substituted with (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six 10 carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkylene goups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (9) aryl: 15 (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylene group is of one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, wherein the 20 cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocycle; (25) (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32) N protected aminoalkyl, wherein the alkylene group is of one to six carbon atoms; (33) oxo; (34) 25 thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (36) -(CH2)qCO2R2, wherein q is zero to four; (37) -(CH2)qC(O)NR 2
R
3 ; (38) -(CH2)qSO2R 4 , wherein R 4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (39) -(CH2)qSO2NR5R 6 , wherein R 5 and R 6 are independently selected from the 30 group consisting of(a) hydrogen, (b) alkyl, (c) aryl and(d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (40) -(CH2)qNR 7 Rg, wherein R 7 and Rg are independently selected from the group consisting of (a) hydrogen, (b) an N-protecting group, (c) alkyl of one to six carbon atoms, (d) alkenyl of two to six carbon atoms, (e) alkynyl of two to six carbon atoms, (f) aryl, (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms, (h) -11 SUBSTITUTE W=FT 1wr Cm = WO 99/05096 PCT/US98/15386 cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44) aryloxy; 5 (45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy. The term "cycloalkoxy," as used herein represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an oxygen atom. The term "cycloalkylalkoxy," as used herein, represents an alkoxy group, as defined herein, to which is attached a cycloalkyl group. 10 The term "cycloalkylalkyl," as used herein, represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an alkyl group. The term "haloalkyl," as used herein, represents an alkyl group, as defined herein, substituted by one, two, or three halogen atoms and is exemplified by chloromethyl, bromoethyl, trifluoromethyl and the like. 15 The term "halogen," as used herein, represents F, Cl, Br and I. The term "heterocycle," as used herein, represents a 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The 5-membered ring has zero to two double bonds and the 6 and 7-membered rings have zero to three double bonds. The term "heterocycle" also includes 20 bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring and another monocyclic heterocyclic ring such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, 25 pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, isoindazoyl, triazolyl, 30 tetrazolyl, oxadiazolyl, uricyl, thiadiazolyl, pyrimidyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothienyl and the like. Heterocyclic groups also include compounds of the formula -12 SUBSTITIITF CW=T lo 11 WO 99/05096 PCT/US98/15386 , wherein F is selected from the group consisting of -CH 2 -, -CH 2 0- and -0-, and G is selected from the group consisting of -C(O)- and -(C(R')(R"))v -, wherein R and R" are independently selected from the group consisting of hydrogen or alkyl of one to four carbon atoms, and v is one to three and includes groups such as 1,3-benzodioxolyl, 1,4-benzodioxanyl 5 and the like. Any of the heterocycle groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkylene goups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) 10 alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms: (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the alkylene group is of one to six carbon 15 atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylene group is of one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocycle; (25) 20 (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32) N protected aminoalkyl, wherein the alkylene group is of one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (36) -(CH2)qCO2R2, wherein q is zero to 25 four; (37) -(CH2)qC(O)NR2R 3 ; (38) -(CH2)qSO2R4, wherein R 4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms;(39) -(CH2)qSO2NR5R 6 , wherein R 5 and R 6 are independently selected from the group consisting of(a) hydrogen, (b) alkyl, (c) aryl and(d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (40) -(CH2)qNR 7
R
8 , wherein R 7 and R 8 are independently 30 selected from the group consisting of (a) hydrogen, (b) an N-protecting group, (c) alkyl of one to six carbon atoms, (d) alkenyl of two to six carbon atoms, (e) alkynyl of two to six carbon -13 SURTITI ITn Cu=-r I1 1n e WQ 99/05096 PCT/US98/15386 atoms, (f) aryl, (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms, (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a 5 sulfonyl group; (41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44) aryloxy; (45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy. The term "(heterocycle)oxy," as used herein, represents a heterocycle group, as defined herein, attached to the parent molecular group through oxygen. The term "(heterocycle)oyl," as used herein, represents a heterocycle group, as defined 10 herein, attached to the parent molecular group through a carbonyl group. The term "hydroxy" as used herein, represents an -OH group. The term "hydroxyalkyl," as used herein, represents an alkyl group, as defined herein, substituted by one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group and is exemplified by 15 hydroxymethyl, dihydroxypropyl and the like. The term "methine" as used herein, represents a =C(H)- group. The term "N-protected amino," as used herein, refers to an amino group, as defined herein, to which is attached an N-protecting or nitrogen-protecting group, as defined herein. The term "N-protected aminoalkyl," as used herein, refers to an alkyl group, as defined 20 herein, which is substituted by an N-protecting or nitrogen-protecting group, as defined herein. The term "nitro," as used herein, represents an -NO 2 group. The term "nitroalkyl," as used herein, represents an alkyl group substituted by an -N02 group. The terms "N-protecting group" or "nitrogen protecting group" as used herein, represent 25 those groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)), which is incorporated herein by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, 30 o-nitrophenoxyacetyl, o:-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4 nitrobenzoyl and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2 -14 SUBSTITI IT U=-r r0 it c WO 99/05096 PCT/US98/15386 nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5 dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4 methoxybenzyloxycarbonyl, 2 -nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5 trimethoxybenzyloxycarbonyl, I -(p-biphenylyl)- 1 -methylethoxycarbonyl, a,cc-dimethyl-3,5 5 dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; arylalkyl groups such as benzyl, 1o triphenylmethyl, benzyloxymethyl and the like and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The term "oxo," as used herein, represents =0. The term "perfluoroalkyl," as used herein, represents an alkyl group, as defined herein, 15 wherein each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical. Perfluoroalkyl groups are exemplified by trifluoromethyl, pentafluoroethyl, and the like. The term "perfluoroalkoxy," as used herein, refers to a perfluoroalkyl group, as defined herein, attached to the parent molecular group through an oxygen atom. The term "pharmaceutically acceptable salt," as use herein, represents those salts which 20 are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. The salts can be prepared in situ 25 during the final isolation and purification of the compounds of the invention or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, 30 heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2 naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like. -15 SUBSTIT IT <:M-r1 C 3r WO 99/05096 PCT/US98/15386 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. 5 The term "pharmaceutically acceptable ester," as used herein, represents esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl group preferably has not 10 more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyates, acrylates and ethylsuccinates. The term "pharmaceutically acceptable prodrugs" as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with with the tissues of humans and lower 15 animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug," as used herein, represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis 20 in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and Judkins, et al.Synthetic Communications, 26(23), 4351-4367 (1996), each of which is incorporated herein by reference. 25 The term "spiroalkyl," as used herein, represents an alkylene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group. The term "sulfonyl," as used herein, represents an -S02-group. The term "thioalkoxy," as used herein, represents represents an alkyl group attached to the parent molecular group through a sulfur atom. 30 The term "thioalkoxyalkyl," as used herein, represents an alkyl group substituted by a thioalkoxy group. Asymmetric or chiral centers may exist in the compounds of the present invention. The present invention contemplates the various stereoisomers and mixtures thereof. Individual stereoisomers of compounds of the present invention are prepared synthetically from -16 SUBSTITUTE SHF=T Rill =1 WO 99/05096 PCT/US98/15386 commercially available starting materials which contain asymmetric or chiral centers or by preparation of mixtures of enantiomeric compounds followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a racemic mixture of enantiomers, designated (± ), to a chiral auxiliary, separation of the 5 resulting diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Enantiomers are designated herein by the symbols "R" or "S," depending on the configuration of subsitiuents around the chiral carbon atom. Geometric isomers may also exist in the compounds of the present invention. The 10 present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond and designates such isomers as of the Z or E configuration, wherein the term "Z" represents substituents on the same side of the carbon-carbon double bond and the term "E" represents substituents on opposite sides of the carbon-carbon double bond. 15 Preferred Embodiments Preferred compounds of the present invention have formula (I), wherein A and C are hydrogen and 20 B is -LBRB, wherein -LB- is -0-, and RB is alkyl of two to six carbon atoms, and wherein the alkyl group is substituted. More preferred embodiments of the present invention have formula (1), wherein 25 A is -LARA and B and C are hydrogen, wherein -LA- is selected from the group consisting of (1) a covalent bond, (2) -(CH 2 )m-, 30 (3) -NR 2 C(X)-, (4) -C(X)NR 2 -, (5) -NR 2
C(X)NR
3 -, (6) -C=C-, (7) -CH=CH-, -17 SUBSTITUTF ;1w=r i1n IM WO 99/05096 PCTIUS98/15386 (8) -C(X)NR 2
(CH
2 )nC=C (9) -C(X)-, (10) -0-, (11) -OC(O)NR 2 - and 5 (12) W ; and wherein RA is selected from the group consisting of (1) amino; (2) aryl; 10 (3) alkyl of one to ten carbon atoms; (4) arylalkyl, wherein the alkylene group is of one to ten carbon atoms; (5) cycloalkyl of three to eight carbon atoms; (6) arylalkoxy, wherein the alkylene group is of one to ten carbon atoms and (7) heterocycle, wherein the heterocycle is selected from the group consisting of 15 (1) furanyl, (2) thienyl and (3) imidazolyl; and wherein, at each occurence, R 2 is selected from the group consisting of (1) hydrogen and 20 (2) alkyl of one to six carbon atoms; and wherein, at each occurence, m is two, n is one, R I and R 3 are hydrogen, 25 W and X are 0, aryl is phenyl, the alkyl group and the aryl group are optionally substituted and the alkenyl group is substituted. 30 Still more preferred compounds of the present invention have formula (I), wherein A and B are hydrogen; -18 SUBSTITUTE nWFFr rInt eI o WO 99/05096 PCT/US98/15386 C is -LCRC; -LC- is selected from the group consisting of 5 (1) a covalent bond, (2) -OC(O)NR 2 -, (3) -SO 2
NR
2 -, (4) -C(X)NR 2 -, (5) -NRI- and 10 (6) -0-; RC is selected from the group consisting of (1) alkyl of one to six carbon atoms; (2) aryl; 15 (3) arylalkyl, wherein the alkylene group is of one to six carbon atoms and (4) hererocycle, wherein the heterocycle is selected from the group consisting of (1) furanyl; (2) pyrimidinyl; and (3) , wherein F is -0-, G is -(C(R')(R"))y-, R' and R" are hydrogen and v is 20 one; X is 0; and wherein, at each occurence,
R
1 and R 2 are H, aryl is phenyl and 25 the alkyl is optionally substituted. Still more preferred compounds of the present invention have formula (I) wherein A is -LARA, B is -LBRB, C is hydrogen, 30 -LA- and -LB- are -0-, and RA and RB are alkyl of one to six carbon atoms. Still more preferred compounds of the present invention have formula (I) wherein -19 SUBSTITUTF qWFFT 1n = 1=1 WO 99/05096 PCT/US98/15386 A is -LARA, B is -LBRB, C is -LCRC, -LA-, -LB-, and -LC- are -0- and 5 RA, RB, and RC are alkyl of one to six carbon atoms. Still more preferred compounds of the present invention have formula (I) wherein A is hydrogen; B is -LBRB; C is -LCRC; 10 -LB- is -0-; -LC- is selected from the group consisting of (1) a covalent bond, (2) -0-, (3) -CH=CH-, 15 (4) -NRI- and (5) -NR 2 C(0)O-; RB is selected from the group consisting of (1) alkyl and (2) arylalkyl, wherein the alkylene group is of one to six carbon atoms; 20 RC is selected from the group consisting of (1) alkyl of one to six carbon atoms; (2) alkenyl of one to six carbon atoms; (3) halogen; (4) aryl and 25 (5) heterocycle, wherein the heterocycle is selected from the group consisting of (1) benzofuranyl; (2) tetrahydrofuranyl; (3) pyrimidinyl; 30 (4) pyrazolyl; (5) furanyl; (6) pyrimidinyl; (7) thiazolyl and -20 SUBSTITIm: CZW=T foD 11 C WO 99/05096 PCT/US98/15386 (8) ' , wherein F is -0-, G is -(C(R')(R"))v -, R and R" are hydrogen and v is one; and wherein, at each occurence, aryl is phenyl and 5 alkyl, aryl and heterocycle are optionally substituted. Preferred compounds falling within the scope of formula (I) include: 7, 8-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 6, 7, 8-trimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 6, 7-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 10 2-[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt; 7-benzyloxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; methyl [(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy] acetate mono(trifluoroacetate) salt; 2-[(7-aminoiminomethyl-2-methoxy-1- naphthalenyl)oxy] -yl-acetic acid mono(trifluoroacetate) 15 salt; N-[4-(aminomethyl)phenyl]- 6 -aminoiminomethyl-2-naphthalenecarboxamide bis(trifluoroacetate) salt; N- [4-(amino)phenyl] - 6 -aminoiminomethyl-2-naphthalenecarboxamide bis(trifluoroacetate) salt; 1-[(7-aminoiminomethyl-2-methoxy- 1-naphthalenyl)oxy]-3-hydroxypropane 20 mono(trifluoroacetate) salt; phenylmethyl [7-(aminoiminomethyl)- 1 -naphthalenyl)carbamate mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl )-1 -naphthalenyl)acetamide mono(trifluoroacetate) salt; methyl [7-(aminoiminomethyl)- 1 -naphthalenyl)carbamate mono (trifluoroacetate) salt; methyl 3-[[7-(aminoiminomethyl)- I -naphthalenyl]aminol-3-oxopropanoate 25 mono(trifluoroacetate) salt; N-[7-(an-inoiminomethyl)- I -naphthalenyl]-2-(phenylmethoxy)acetamide mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- 1 -naphthalenyl]-1,3-benzodioxole-5-carboxamide mono(trifluoroacetate) salt; 30 N-[7-(aminoiminomethyl)- 1 -naphthalenyl] benzenemethanesulfonamide mono(trifluoroacetate) salt: -21 SUBSTITUTF C;-WFPr rM1 C e WO 99/05096 PCT/US98/15386 1-[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]-3-bromopropane mono(hydrochloride) salt; 3-[(7-aminoiminomethyl-2-methoxy- I -naphthalenyl)oxy]propene mono(trifluoroacetate) salt; 1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-phenylpropane 5 mono(hydrochloride) salt: 1-[(7-aminoiminomethyl-2-methoxy- I -naphthalenyl)oxy]-3- [I-(3,4-dimethoxy)phenyl] propane mono(hydrochloride) salt; 7-methoxy-8-(2-furanyl)-2-naphthalenecarboxinidamide mono(trifluoroacetate) salt; methyl 6-(aminoiminomethyl)-4- [(methoxycarbonyl)amino] -2-naphthalenecarboxylate 10 mono(trifluoroacetate) salt; (E)-(7-methoxy-8-[2-(Phenyl)ethenyl])-2-naphthaleneimidamide mono(trifluoroacetate) salt 6-(4-phenylbutynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 7-(2-hydroxyethoxy)-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 7-(2-hydroxyethoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 15 6-(4-methyl- I -pentynyl)- 2 -naphthalenecarboximidamide mono(trifluoroacetate) salt; 6-(5-phenylpentynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 6-(3-phenyl- 1 -propynyl)- 2 -naphthalenecarboximidamide mono(trifluoroacetate) salt; 6-(phenylethynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 3-amino-N- [ 3
-[
6 -(aminoiminomethyl)-2-naphthalenyl] -2-propynyllbenzamide 20 mono(trifluoroacetate) salt; 4 -amino-N-[3-(6-aminoiminomethyl-2-naphthalenyl)-2-propynyl] benzamide mono(trifluoroacetate) salt; (S)-2-amino-N-[ I -[( 6 -aminoiminomethyl-2-naphthalenyl)carbonyl]cyclohexyl]propionamide bis(trifluoroacetate) salt: 25 6-methoxy-8-benzyloxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 2-[(7-aminoiminomethyl-3-methoxy-1-naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt;
N-(
6 -aminoiminomethyl-2-naphthalenyl)-N'-phenylurea mono(trifluoroacetate) salt; (E)-6-[2-(phenyl)ethenyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 6-[2-(phenyl)ethyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 30 7-propoxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; (+ )- 6-( 3 -phenyloxiranyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; (E)-6-[2-(2-thienyl)ethenyl]- 2 -naphthalenecarboximidamide mono(trifluoroacetate) salt; 6-(3-oxobutyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 6-(3-methoxyphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; -22 SUBSTITm: qW: -r rIM 1C 3= WO 99/05096 PCTIUS98/15386 N-f 3-(methyl)phenvl] -6-aminoim-inomethyl-2-naphthalenecarboxarnide mono(trifluoroacetate) salt; 6-(2-formylphenoxy)-2-naphthalenecarboximi dan-ide mono(trifluoroacetate) salt; 6-(2-formylphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; -5 6- [2-(hydroxymethyl)phenyl]-2-naphthalenecarboximidamide mon o(trifluoro acetate) salt, 6-(3-oxo- 1 -butenyl)-2-naphthalenecarboximi~dam-ide mono (trifluoroacetate) salt; 7-methoxy-8-( 1H-pyrazol-4-yl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 7-methoxy-8 -iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; N-phenyl-6-aminoiminomethyl-2-naphthalenecarboxamide mono(methanesulfonate) salt; 10 4- [(6-am-inoiminomethyl-2-naphthalenyl)oxy] -N-methylbenzeneacetamide mono(trifluoroacetate) salt; 6-[12-(methylthio)phenyl] -2-naphthalenecarboxiniidamide mono (methanesulfonate) salt; 6-f [2- (2-thiometh ox oxyethyl)phenyl] naphthalene- 2-c arboximidamnide mono (meth anesulfonate) salt; Is 7-methoxy-8-(3-furanyl)-2-naphthalenecarboximidamide mono (methanesulfonate) salt; 7 -meth oxy- 8- (2- ben zofuran yl)naphth alene-2 -carboxin-idamide mono(methanesulfonate) salt; (E)-8-[2-(1I,3-benzodioxol-5-yl)ethenyl]-2-naphthalenecarboximidamide mono (methanesulfonate) salt; (± )-7-methoxy-8-(tetrahydro-3-furanyl)-2-naphthalenecarboximidamide 20 mono (methanesulfonate) salt; 6-f 14-(2-am-inoethyl)phenyl]ethynyll -2-naphthalenecarboximi~dami de m-ono(trifluoroacetate) salt; 7-methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarboximidan-lde mono (trifluoroacetate) salt; 7 -metho xy- 8 -[2- thiazoyl (oxy) ] naphthalene- 2-carboximidamide mono (trifluoroacetate) salt; 25 7-methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidanmjde mono (trifluoroacetate) salt; 7-methoxy-8-pentafluorophenoxy-2-naphthalenecarboxin-jdamide mono (ri fl uoroacetate) salt; 7 -meth oxy-8-f[N- 2 -pyrimi din yl (amino)] -2- naphthalenecarboxinjdanm ide mono(trifluoroacetate) salt; N-(6-amainoin-inomethyl-2-naphthalenyl)-N'-benzylurea mono (trifluoroacetate) salt; 30 N-(6-am-inoimainomethyl-2-naphthalenyl)-N'-methylurea mono(trifluoroacetate) salt; N-(6-aminoimi nomethyl-2-naphthalenyl)-N'-i sopropylurea mono (trifluoro acetate) salt; N-(6-aminoiminomethyl-2-naphthalenyl)-N'-phenyl.N'-methylurea mono(trifluoroacetate) salt; 6-aminonaphthalene-2-carboxim-idami de mono(trifluoroacetate) salt; N-(6-am-inoim-inomethyl-2-naphthalenyl)-N'-cyclohexylurea mono(ftifluoroacetate) salt; -23 SURSTITI ITF: qI.4F-r 1011 Ci na WO 99/05096 PCT/US98/15386 N-(6-aminoiminomethyl-2-naphthalenyl)-N'-benzyloxyurea mono(trifluoroacetate) salt; 1,1-dimethylethyl [4-[[( 6 -cyano-2-naphthalenyl)amino]carbonyl]phenyl]carbamate mono(trifluoroacetate) salt N-[6-(aminoiminomethyl)-2-naphthalenyl]-4-(aminomethyl)benzamide mono(trifluoroacetate) 5 salt; ethyl [6-(aminoiminomethyl)-2-naphthalenyl]carbamate mono(trifluoroacetate) salt; 1,1-dimethylethyl [ 4 -[[[6-aminoiminomethyl)- 2 -naphthalenyl)amino]carbonyl]amino]phenyl] carbamate mono(trifluoroacetate) salt; (E)-6-[ 2 -(phenylthio)ethenyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; i0 (E)-6-[2-(2-furanyl)ethenyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; (E)-6-[2-( IH-imidazol-1-yl)ethenyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; (E)-4-[ 2
-(
6 -aminoiminomethyl-2-naphthalenyl)ethenyl]benzenesulfonamide mono(trifluoroacetate) salt;
(E)-
4
-[
2
-(
6 -aminoiminomethyl-2-naphthalenyl)ethenyl]benzoic acid mono(trifluoroacetate) salt; 15 4-[7-(aminoiminomethyl)-2-methoxy- I -naphthalenyl]dihydro-2(3H)-furanone mono(trifluoroacetate) salt; 7-methoxy-8-(1 -acetyl- 1 H-pyrazolyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 7-methoxy-8-[I1-(methylsulfonyl)-1H- 4 -pyrazolyl]-2-naphthalenecarboxnimidamide 20 mono(trifluoroacetate) salt; (E)-4-[ 2
-(
6 -aminoininomethyl-2-naphthalenyl)ethenyl]benzamide mono(trifluoroacetate) salt; 6-[2-(4-aminophenyl)ethoxy]- 2 -naphthalenecarboximidamide mono(trifluoroacetate) salt; methyl [ 3 -methoxy- 6 -(aminoiminomethyl)-4-naphthalenyl]carbamate mono(trifluoroacetate) salt; 25 7 -methoxy- 8
-[
2 -pyrimidinyl(amino)]-2-naphthalenecarboximidamide bis(trifluoroacetate) salt; fhthalenecarboxamide, mono(trifluoroacetate) salt; 6-(4-aminophenyl)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; methyl 2
-[
4
-[[[
6 -(aminoiminomethyl)-2-naphthalenyl]carbonyl]amino] phenoxylacetate,mono(trifluoroacetate) salt; 30 (E)- 6
-[
2
-[(
3 -hydroxymethyl)phenyl]ethenyl]-2-naphthalenecarboximijdamide, mono(trifluoroacetate) salt; 6-(2-phenyl- I -cyclopropyl)- 2 -naphthalenecarboximidamide, mono(trifluoroacetate) salt; (E)-6-[2-[4-(aminomethyl)phenyl]ethenyl]- 2 -naphthalenecarboximidamide, bis(trifluoroacetate) salt; -24 SUBSTITUTF cWFFT (r111 C WO 99/05096 PCTJUS98/15386 (E)-6- [2- [4-(1I, 2 -dihdyroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidaide, mono(trifluoro acetate) salt; (E)-6-!2-114-( 1R-amino- 2 -hydroxyethyl)phenyl~ethenyl]-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; 5 7 -methoxy- 8
-(
2 -pyrirnidinylamidno)-2-naphthalenecarboximidamjdde, bis(trifluoroacetate) salt-, (E)-6-[12-[14-(dimethylam-ino)methyl] phenyll ethenyl] -2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; (E)-6-[12-[14-(hydroxymethyl)phenyl] ethenyl]-2-naphthalenecarboximjldan-jde. mono(trifluoroacetate) salt; 10 4-[1[6-(am-inoiminomethyl)-2-naphthalenyl] ethynyl] -L-phenylalanine, mono(trifluoroacetate) salt; 6-(3-formylphenyl)-2-naphthalenecarboximi damde, mono(trifluoroacetate) salt; (E)-6-[2-( 1, 2 ,3,4-tetrahydro-6-isoquinolinyl)ethenyl]
-
2 -naphthalenecarboximidamide, b is (tifl uoro acetate) salt-, 15 (E )- 6-12-13-(2-hydroxyethyl)phenyllethenyl] -2-naphthalenecarboxiidamide. mono(trifluoroacetate) salt; 6-(ami noimidnomethyl)-N-(2,3-dihydro- 1 H-inden-5-yl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt; 6-1(4-aminophenyl)ethynyll -2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; 20 1, 1 -dimethylethyl [ 2
-[
3 -111 6 -(aminoiminomethyl)-2-naphathalenyllethynyl-6 methoxyphenyl] ethyl] carbamnate, mono (trifluoroacetate) salt; 1,1 -dimethylethyl [114- 111 6 -(ainoinnomethyl)-2-naphathalenyl]ethynyl] phenylimethylicarbamate, mono (trifl uoroacetate) salt; 6-[[14- (aminomethyl)phenyllethynyl]-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; 25 6-[[13-(2-ainoethyl)-4-methoxyphenyllethyny 1- 2 -naphthalenecarboximidamidde, bi s(trifl uoro acetate) salt; 6 -f1 4 -(hydroxymethyl)phenyliethyny1-2naphthalenecarboxpnijdamjde, mono (trifluoroacetate) salt; 6-t( l, 2
,
3
,
4 -tetrahydro- 6 -isoquinoliny1)ethynyl]-2-naphthalenecarboximidamide, 30 bis(trifluoroacetate) salt;, 6 -(anminoiminomethyl)-N-( 4 -methylphenyl)-2-naphthalenecarboxanmjde, mono(trifluoroacetate) salt; 1,1 -dimethylethyl [[14-[11 [ 6 -(anhnoiminomethyl)-2-naphathalenyl] amino] carbon yl]p henyl] methyl]jcarbamate, mono (trifluoroacetate) salt; -25 SUBSTMTITTF QW=' fDI 11 WO 99/05096 PCTJUS98/15386 N-L6- (aminoim-inomethyl)-2-naphthalenyl)benzamide, mono (trifl uoroacetate) salt; 1,1 -dimethylethyl [ [4-[ [[ 6 -(aminoim-inomethyl)-2-naphathalenyl] amino] carbonyl] cyclohexyll] methylicarbamate, mono(trifluoroacetate) salt; N-[6-(am-inoiminomethyl)-2-naphthalenyl]-N' -(4-am-inophenyl)urea, bis(trifluoroacetate) salt; 5 N- [6-(aminoiminomethy l)-2-naphthalenyl] - 4
-
4 -(aminomethyl)cyclohexanecarboxanmide, bis(trifluoroacetate) salt; N-16-(aminoiniinomethyl)-2-naphthalenyll-N '- [(4-aminomethyl)phenylj urea, bis(trifluoroacetate) salt; 6-(aminoiminomethyl)-N-(4-ethylphenyl)-2-naphthalenecarjoxarn-de, acetate salt; 10 6 -(ami~noimiinomethyl)-N-(2-naphthalenyl)-2-naphthalenecarboxan-ide, mono(trifluoroacetate) salt; 6-(5-phenyl- 2 -oxazolyl)-2-naphthalenecarboxirnidamide, mono(trifluoroacetate) salt; 6-(5-phenyl- 2 -thiazolyl)-2-naphthalenecarboxji-damjde, mono (trifluoroacetate) salt; 6- aminoi min ometh yl)- N- (1 , 2 3
,
4 -terahydro-6 -quin o 11nyl)- 2-naph thalen ecarboxamide, 15 bis(trifluoroacetate) salt; 6 -ranmino(hydroxyinmino)methyl]-N-phenyl-2-naphthalenecarboxamde; 6-[4-II(hydroxymethyl)phenyllImethoxy]-2-naphthalenecarboxin-jdan-Lde, methanesulfonate salt; 6-(2-pyridinylethynyl)-2-naphthalenecarboximidamde, mono (trifluoroacetate) salt;
N-[
4 -(arminocarbonyl)phenyl]-6-(arminoiminomethyl>2-naphthalenecarboxamide, 20 mono(trifluoroacetate) salt; 6 -(aminoiminomethyl)-N-(2-thiazolyl)-2-naphthalenecarboxamide, mono hydrochloride 6-(am-inoiminomethyl)-N- (6- mnethoxy- 3-pyridinyl)-2- naphthalenecarboxamide, mono hydrochloride 6-(aminoiminomethyl)-N-( 1, 3 -benzodioxol-5-yl)-2-naphthalenecarboxanmide, 25 r-nono(trifluoroacetate) salt; 6-(aminoiminomethyl)-N-( 1, 2 ,3, 4 -tetrahydro-2,4-dioxo5-pyrimidinyl) 2-naphthalenecarboxamide, monohydrochloride 6 -(aminoiminomethyl)-N-(3,5-difluoropiienyly2-naphthalenecarboxanmjde, mono(trifluoroacetate) salt; 30 6-(aminoimidnomethyl)-N-( 1 H-pyrazol-3-yl)-2-naphthalenecarboxamjde, mono(trifluoroacetate) salt; 6 -(aminoiminomethyl)-N-( 5 -methyl-3-isoxazolyll>2-naphthalenecarboxamide, mono(trifluoroacetate) salt; 6 -(anminoiminomethyl)-N-(pyrazinyl)-2-naphthalenecarboxarnde, mono(trifluoroacetate) salt; -26 SUBSTITI ITP -qHFT DIn C WO 99/05096 PCTIUS98/15386 6-(aminoiminomethyl)-N-(6-methyl-2-pyridinyl)-2-naphthalenecarboxanmide, mono(trifluoroacetate) salt; 6-(aminoiminomethyl)-N-(3,4,5-trimethoxyphenyl)-2-naphthalenecarboxamide, monohydrochioride 5 6-(aminoiminomethyl)-N-(3-methyl-2-pyridinyl)-2-naphthalenecarboxamide, bis(trifluoroacetate) salt; 6-(aminoiminomethyl)-N-(5-bromo-2-thiazolyll)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt; 6-(aminoiminomethyl)-N- (5 -methyl- 2-pyridinyl)-2- naphtha] enecarboxamide, 10 mono(trifluoroacetate) salt; 6-(amninoiminomethyl)-N-(4-methyl-2-thiazolyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt; 6-.(ami noiminomethyl)-N-(6-quinolinyl)-2.-naphthalenecarboxamide, bis (tifl uoro acetate) salt; 15 6-(ami noimninomethyl)-N-( 1 H-indazol-6-yl)-2-naphthalenecarboxamjide, bis(trifluoroacetate) salt; 6-(am-inoiminomethyl)-N-( IH-indazol-5-yl)-2-naphthalenecarboxamide, bis(trifluoroacetate) salt; 6-(aminoirninomethyl)-N-( I H-indol-5-yl)-2-naphthalenecarboxan-jde, 20 mono(trifluoroacetate) salt; 6-(ami noimi~nomethyl)-N-(5-pyrimidinyl)-2-naphthalenecarboxamj de, mono (trifluoroacetate) salt; 6-(aminoiirninoniethyl)-N-(3-pyridazinyl)-2-naphthalenecarboxamide, mono (trifluoroacetate) salt; 25 6 -(aminolininomethyl)-N-(5-bromo-2.-pyidinyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt; 6-(aminoiminomethyl)-N-[3-( 1 -methylethoxy)phenyl]-2-naphthalenecarboxami de, mono(trifluoroacetate) salt; 6-(aniinoiminomethyl)-N-( I H-imiddazolyl)-2-naphthalenecarboxamidde, 30 bis(trifluoroacetate) salt; 6-12-4-(hydroxymethyl)phenyl]-l1-cyclopropyl]-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt; N-(ethoxycarbonyl)-6-(2-phenyl- 1 -cyclopropyl)-2-naphthalenecarboximjidamide 6-a-ion oehl--2mty--unlnl--ahhlncroaie -27 SUBSTITI ITP Qw=- f m ii c r WO 99/05096 PCTJUS98/15386 bis(trifluoroacetate) salt:, 6-(aminoiminomethyl)-N- ( 3 -propoxyphenyl)-2-naphthalenecarboxami de, mono(trifluoroacetate) salt; 6-(aminoiminomethyl)-N- 13-( I-ethylpropoxy)phenyl]-2-naphthalenecarboxamide, -5 mono(trifluoroacetate) salt; 6-(am-inoiminomethyl)-N- [3-(cyclopentyloxy)phenyl] -2-naphthalenecarboxamide, mono(trifluoro acetate) salt; 6-(aminoiminomethyl)-N-(3-phenoxyphenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt; 10 6-(amiinoiminomethyl)-N- [3-(phenylmethoxy)phenyll -2-naphthalenecarboxami de, mono(trifluoro acetate) salt; 6-(aminoiminomethyl)-N-(3-ethoxyphenyl)-2-naphthalenecarboxamide, mono(trifluoro acetate) salt; 6- (amino imin omethyI)- N- (4-nitrop hen ylV2- naphthalenec arboxaniide, 15 mono (trifluoro acetate) salt; 6-(am-inoiminomethyl)-N-[3-(cyclobutylmethoxy)phenyl] -2 nap hthalenecarboxamide,mono (trifluoroacetate) salt; 6-[ami no(ethoxycarbonyl)imino]-N-[3-( 1-methylethoxy)phenyl]-2-naphthalenecarboxamidde; 6- (aminoimi nomethyl) -4- [5 -(ethyl sulfo nyl)-3 -furanyl] -N-phenyl- 2-n aphthalenecarbo xamidde, 20 monohydrochloride; methyl [7-(ami noiminomethyl)-2-methoxy-l1-naphthalenyl)carbamate, mono (trifluoroacetate) salt; 7-methoxy-8-(2-pyrnidinylamino)-2-naphthalenecarboximiddamide, bis (trifluoro acetate) salt; 7-methoxy-8-II(phenylmethyl)amino]-2-naphthalenecarboximidamide, 25 mono(tri fl uoro acetate) salt-, 7-methoxy-8-(phenylam-ino)-2-naphthalenecarboximi damide, mono (tifluoroacetate) salt; 7 -rnethoxy- 8- f 4 -meth ox yphenyl)amino] -2 -nap hthalenecarboximidan-ide, i-ono(trifluoro acetate) salt; (E)-3-[7 -(arninoiminomethyl)-2-methoxy- 1 -naphthalenyl)-2-propenamide, 30 mono (trifluoroacetate) salt; 7-methoxy-8-(3-oxo- 1-cyclopenten- 1 -yl)-2-naphthalenecarboximiddamidde, mono(trifluoroacetate) salt; methyl 4- [[[7-(aminoiminomethyl)- 1- (2-pyimidinylamino)-2 naphthalenyl] oxy] methyl] benzoate, mono (trifluoroacetate) salt; -28 SUBSTITI ITP QW==- 10111 0 = WO 99/05096 PCT/US98/15386 4-[[[7-(aminoiminomethyl1)- 1-( 2 -pyrimidinylamino)-2-naphthalenyl]oxy]methyl] benzoic acid, mono(trifluoroacetate) salt; 7-methoxy-8-(pyrazinyloxy)-2-naphthalenecarboximidamide, dimethanesulfonate salt; 7-methoxy-8-(phenylthio)-2-naphthalenecarboximidamide, methanesulfonate; 5 7-methoxy-8-(pyrazinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; methyl 5-[7-[(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoate, mono(trifluoroacetate) salt; 5-[[6-(aminoiminomethyl)-2-naphthalenylloxy]pentanoic acid, mono(trifluoroacetate) salt; methyl 4-[[[7-amino(hydroxyimino)methyl]-2-naphthalenyl]oxy]methyl]benzoate; methyl 2-[ [6-(aminoiminomethyl)-2-naphthalenyl] oxy] acetate, mono(trifluoroacetate) salt; 10 7-[2-(4-morpholinyl)ethoxy]-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; 2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetic acid, mono(trifluoroacetate) salt; methyl 4-[6-(aminoiminomethyl)-2-naphthalenyl]oxy]methyl]benzoate, mono(trifluoroacetate) salt; methyl [7-(aminoiminomethyl)- 1-naphthalenyl]methylcarbamate, mono(trifluoroacetate) salt; 15 propyl [7-(aminoiminomethyl)- 1 -naphthalenyl]carbamate, mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- I -naphthalenyl]-N'-methylurea, mono(trifluoroacetate) salt; ethyl [7-(aminoiminomethyl)- 1 -naphthalenyl)carbamate, mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)-l -naphthalenyl)propanamide, mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- I -naphthalenyl)-2-methoxyacetamide, mono(trifluoroacetate) salt; 20 N-[7-(aminoiminomethyl)- 1 -naphthalenyl]urea, mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)-1-naphthalenyll-2-hydroxyacetamide, mono(trifluoroacetate) salt; 8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; 8-amino-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; 8-(2-pyridinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; 25 N-hydroxy-8-(2-pyrimidinylamino)- 2-naphthalenecarboximidamide, mono(trifluoroacetate) salt; 6-(aminoiminomethyl)-4-(3-furanyl)-N-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxamide, mono(trifluoroacetate) salt; 6 -(aminoiminomethyl)- 4 -(3-furanyl)-N-(4-pyridinyl)-2-naphthalenecarboxamide, 30 dihydrochloride; 6-(aminoiminomethyl)-4-(3-furanyl)-N-(I H-pyrazol-3-yl)-2-naphthalenecarboxamide, dihydrochloride; 6 -(aminoiminomethyl)- 4 -(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride; -29 SUBSTm: I <: cw -r me it c WO 99/05096 PCTJUS98/15386. methyl [ 7 -(aminoiminomethyl)-3-[[[4-(amninomethyl)phenyllarrinolcarbonyl]-1 naphathalenylicarbamate, bis(trifluoroacetate) salt; 6-(aminoiminomethyl)-4- ( 3 -furanyl)-N-(2-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride; -5 6-(aminoim-inomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamide, monohydrochloride 6-(aminoiminomethyl-4-[l -(methylsulfonyl)- I H-pyrazol-4-yl]-N-phenyl-2 naphthalenecarboxamide, monohydrochioride:, 6- (antinoiminomethyl)-4- [15- (methylthio)- 3-furanyl)]-N-phenyl-2 -nap hthalenecarboxarride, monohydrochloride; 10 6-(aminoimidnomethyl)-N-[4-(aminomethyl)phenyl] -4-(2-pyrimnidinylamino)-2 naphthalenecarboxamide, tris(trifluoroacetate) salt; 6-(aminoiminomethyl)-N-phenyl-4-(2-pyfimi dinylamino)-2naphthalenecarboxan-ide, mono(trifluoroacetate) salt; N-[(4-(aminomethyl)phenyl]-6- [amino(hydroxyimi no)methy1-4(2pyrimidinylami no)-2 15 naphthalenecarboxamide, bis(trifluoroacetate) salt; 6- (amin oi min omethy1)- N- [4- (hydroxymeth yl)p henyl ] -4-(2-pyrimidinylamjno) 2-naphthalenecarboxan-ide, mono (tri fl uoroacetate) salt; methyl I 3
-[[
4 -(aminomethyl)phenyl]am-ino]carbonyl-7-[4-an-iino(hycfroxyin-lno)methyl]
-
nap hth alenyl] carbamnate, bis(tifluoroacetate) salt; 20 6-(aminoiminomethyl)-N-phenyl-4-(tet-ahydro-3-furanyl)-2 naphthalenecarboxam-ide,monohydrochloride; 6-Ilamino (hydroxyimino)methyl] -N-phenyl- 4 -(2-pyrimidinylamino)-2-naphthalenecarboxamide 6-(aminoiminomethyl)-4-[15-(ethylthio)-3-furanyl]-N-phenyl-2 naphthalenecarboxam-ide~monohydrochloride; 25 6-(aminoiminomethyl)-4-[5-(propylthio)-3-furanylj -N-phenyl-2 n aphthalenec arbo xami de, mono hydrochloride-, 6 -(arni no iminometh yl)- N-phenyl-4-(2-pyrrolidiny)2-nap hthalenecarboxamjude, mono(trifluoroacetate) salt; 6-(aminoiminomethyl)-4- [5- (propyisulfonyl)- 3-furanyl] -N-phenyl-2-naphthalenecarboxamide, 30 monohydrochloride; 6-(arninoiminomethyl)-4-[5-[methylthio)methyl]3-uranyl]N-phenyl12 naphthalenecarboxamide, monohydrochloride; 6-(amiinoiminomethyl)-4- [5- (methoxymethyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide, monohydrochioride; -30 SUBSTITI~r IT J =rt~i nc &- WO 99/05096 PCT/US98/15386 6-(aminoiminomethyl)- 4
-[
5 -(methylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide, mono(trifluoroacetate) salt; and 6-(aminoiminomethyl)-4-[5-(ethythio)tetrahydro-3-furanyl]-N-phenyl-2 naphthalenecarboxamide, monohydrochloride. 5 Determination of Urokinase inhibition The efficacy of the compounds of this invention as urokinase inhibitors was determined by measuring the inhibition of the urokinase enzyme Abbokinase (Abbott Laboratories, Abbott Park, IL) on substrate S-2444, of formula pyroGlu-Arg-pNA-HCl (DiaPharma Group, Inc. 10 Distributor of Chromogenix) at 200 iLM. The assay was performed in a 96 well polystyrene, flat bottom plate in a 50 mM Tris/0.15 M NaCl + 0.5 % Pluronic F-68 (Sigma P-5556), pH 7.4 (with HCl) buffer. The compounds of this invention, 10 mM in DMSO, were diluted with DMSO to eight half log concentrations, for example: 1200 tM, 400 .tM, 120 4M, 40 [tM, 12 tM, 4 4M, 1 tM 15 and 0.4 jiM. Four concentrations were chosen, then 5 [l of each were diluted to a total assay volume of 200 [1. The final compound concentrations in the assay, according to the above example, were 30 jiM, 10 [M, 3 [pM, I jiM, 0.3 [tM, 0.1 [LM, 0.03 jiM and 0.01 jiM, respectively. The substrate S-2444 was used at 200 jiM in the assay. Several vials were reconstituted as directed on the vial, aliquoted and stored frozen. The enzyme was 20 further diluted in assay buffer and 10 [l was used in the assay. Enzyme concentration in the assay was 2-3 nM. The assay was performed as follows: 175 [pL of buffer was pipetted into the polystyrene plate, 5 [tL solution of a compound of this invention in DMSO was added, the mixture was vortexed, 10 jiL of enzyme in buffer was added, the mixture was vortexed, 10 [LL of substrate in water was added, the mixture was vortexed, 25 and the plate was placed in a Spectromax ® (Molecular Devices Corporation, Sunnyvale, Ca) plate reader to follow the course of the reaction for 15 min at 405 nm. The Spectromax @ calculated the reaction rates which were used to calculate percent inhibition of the compounds of this invention versus the reaction rate of the enzyme in the absence of any inhibitor. The Ki 's of the inhibitors were calculated from the percent inhibition and 30 previously established Km. The compounds of this invention inhibit urokinase as shown by the data for representative examples in Table 1. Table I Inhibitory Potency of Representative Compounds Against Urokinase -31 SUBSTTI IT mWn1-r 1 n WO 99/05096 PCT/US98/15386 Example
IC
50 (4M) 1 6.6 2 9.8 3 36 4 0.5 5 2.5 6 2.3 7 3.5 8 0.1 9 1.1 10 3.2 14 0.33 15 2.5 16 0.03 17 4.26 18 0.42 19 2.21 20 0.803 21 1.7 22 1.7 23 4.0 24 4.9 25 2.1 26 0.04 27 0.93 28 2.1 29 2.5 30 3.6 -32 SUBSTITI IT= CZU-r rot it c nm WO 99/05096 PCT/US98/15386 31 2.93 32 4.6 33 2.4 34 3.5 35 3.97 36 1.75 37 2.34 38 6.35 39 12.2 40 0.31 41 2.38 42 2.08 43 2.2 44 0.35 45 2.94 46 2.4 47 4.8 48 1.3 49 3.3 50 6.13 51 4.7 52 4.7 53 2.96 54 2.7 55 0.9 56 2.9 57 3.4 58 2.53 59 0.41 -33 SUBSTIT IT= cucr rov it oi WO 99/05096 PCT/US98/15386 60 0.72 61 0.73 62 0.64 63 0.37 64 0.56 65 0.54 66 3.13 67 2.78 68 1.74 69 1.38 70 2.57 71 2.39 72 4.30 73 3.3 74 1.61 75 2.09 76 0.96 77 0.23 78 3.57 79 0.96 80 1.93 81 3.21 82 3.08 83 2.24 84 10.0 85 1.38 86 3.6 87 0.63 88 2.73 -34 SUBSTITIT: :W=-r fr it cm WO 99/05096 PCT/US98/15386, 89 6.5 90 0.07 91 0.05 92 0.04 93 2.36 95 1.73 96 0.86 97 1.31 98 0.24 99 3.02 100 3.16 101 0.8 102 0.34 103 0.57 104 1.2 105 0.84 106 0.76 107 2.34 108 0.996 109 2.85 1 10 111 4.17 112 0.45 113 0.403 114 0.344 115 0.063 -35 SUBSTITI m: r:r r r ii mn om WO 99/05096 PCT/US98/15386 116 0.045 117 0.278 118 0.121 119 4.41 120 0.93 121 0.89 122 0.33 123 1.24 124 0.12 125 0.23 126 0.87 127 0.085 129 4.84 131 4.18 132 0.96 133 0.044 134 0.064 135 1.91 136 1.67 137 0.82 138 0.46 139 2.64 140 0.46 141 0.00117 142 0.54 143 0.36 -36 SUBSTITUTF nun-r run miic o WO 99/05096 PCT/US98/15386 144 1.26 145 2.59 146 0.372 147 0.213 148 0.81 149 3.8 150 0.16 152 0.083 153 0.877 154 0.035 155 2.33 156 0.18 157 3.12 158 0.09 159 2.23 160 2.62 161 1.59 162 1.33 163 0.03 164 0.45 165 0.00068 166 0.002 167 0.052 168 0.003 170 0.695 171 >30 -37 SUBSTITUTE CWg:FT 1In1 M o WO 99/05096 PCT/US98/15386 174 0.17 176 5.011 177 14.9 179 1.61 180 0.097 181 8.92 182 >30 184 0.375 185 3.19 186 2.98 187 0.613 188 0.22 189 1.3 190 0.565 191 0.887 192 1.6 193 0.85 194 0.56 1 95 1.3 196 0.62 197 2.03 198 0.504 199 2.3 200 0.037 201 0.077 202 0.792 -38 SUBSTITT IT= Cu-r mit ii om WO 99/05096 PCT/US98/15386 203 0.624 204 0.331 205 0.337 206 5.73 207 4.12 208 0.96 209 0.82 210 0.78 211 0.072 212 5.09 213 4.58 214 2.559 215 1.1 216 >30 217 0.67 218 0.086 219 0.103 220 0.03 221 0.52 222 0.346 223 0.07 224 1.773 225 0.104 226 >30 227 0.015 228 0.025 -39 SUBSTITI ITF= -r Ini c mz% WO 99/05096 PCT/US98/15386 229 0.117 230 0.103 231 0.015 232 0.123 Pharmaceutical Compositions The present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic 5 pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally . intracisternally, intravaginally, intraperitoneally or 10 topically (such as powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenteral" administration, as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. Pharmaceutical compositions of this invention for parenteral injection comprise 15 pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils (such as olive 20 oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be 25 ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable -40 SUBSTITIIT cU=-r fr OR E WO 99/05096 PCT/US98/15386 pharmaceutical form may be brought about by the inclusion of agents (such as aluminum monostearate and gelatin) which delay absorption . In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be 5 accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. 10 Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in 15 liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. 20 Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, 25 sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, 30 magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. -41 SUBSTITUTE SIF=T IM n F = WO 99/05096 PCT/US98/15386 The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a 5 certain part of the intestinal tract, optionally or in delayed fashion. Examples of embedding compositions which can be used include polymeric substances and waxes. The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable 10 emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, 15 castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof. Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents such as 20 ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room 25 temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which 30 are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are -42 SUBSTITUTE SHFT MIt P 9Am WO 99/05096 PCT/US98/15386 known in the art, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq. Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile 5 conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to 10 achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired 15 therapeutic effect and to gradually increase the dosage until the desired effect is achieved. Generally dosage levels of about I to about 50, more preferably of about 5 to about 20 mg, of active compound per kilogram of body weight per day when administered orally to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day. 20 Preparation of Compounds of this Invention The compounds of this invention may be prepared by a variety of synthetic routes. Representative procedures are outlined in the following Schemes 1-6. 25 Abbreviations Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: THF for tetrahydrofuran; DMF for N,N-dimethylformamide; OEt 2 for diethyl ether; EDC for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; NMM for N-methylmorpholine; LDA for lithium diisopropylamide; TFA for trifluoroacetic acid; 30 DMSO for dimethylsulfoxide; DMAP for 4 -(N,N-dimethylamino)pyridine; HATU for O-(azabenzotriazole- I -yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphate; Boc for tert butylcarbonyloxy; DDQ for 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone; Bn for benzyl; DPPA for diphenylphosphoryl azide; DCC for dicyclohexylcarbodiimide; EDC for I-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; SEM for 2 -43 SUBSTITUTP qW;FwT 111 C 13 WO 99/05096 PCT/US98/15386 (trimethylsilyl)ethoxymethyl ; dppf for 1,1 '-bis(diphenylphosphino)ferrocene; and dba for dibenzylideneacetone. Starting materials, reagents and solvents were purchased from Aldrich Chemical Company (Milwaukee, Wi). 5 As shown in Scheme 1, naphthalenecarbonitriles 4, 5 and 6 were prepared by treating 3 cyanopropionaldehyde diethyl acetal 2 with a strong base such as lithium diisopropylamide then treating the resulting anion with the appropriately substituted benzaldehyde I followed by cyclization and aromatization of the corresponding cyanohydrins 3 with a Lewis acid such as sulfuric acid. 10 Scheme I C C OH B CHO CN B CN N ~ + H 3 CO A OCH 3 A OCH 3 2 3 OCH 3 A, B and C are hydrogen and -LARA, -LBRB, -LcRC -LA-, -LB- and -Lc- are -0 RA, RB and Rc are alkyl C BA CN 4: A is hydrogen; B and C are OCH 3 5: A, B and C are OCH 3 6: A and B are OCH 3 , and C is hydrogen 15 As shown in Scheme 2, selective demethylation of 4 with a Lewis acid such as AICl 3 or BBr 3 , preferably AlCl 3 , provided 7. 7 was treated with a base such as potassium carbonate, sodium hydride or cesium fluoride followed by RC-X, wherein X is a leaving group, to provide -44 SUBSTIT1Tr c:U=r 1011m M WO 99/05096 PCT/US98/15386 8 (-Lc- is -0-). Alternatively, treatment of 7 with trifluoromethanesulfonic anhydride or 1,1,1 trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide provided 9, which may 0P be treated with Rc-B(OH) 2 , O , RC-I, or Rc wherein RC is unsubstituted or substituted aryl or heterocycle, in the presence of a palladium catalyst, 5 preferably Pd(II)C1 2 (dba) or Pd(Ph 3
P)
4 , and base, preferably cesium fluoride or potassium carbonate, to provide 10. Alternatively, 2 may be treated with Rc-NRIR 2 , wherein Rc is unsubstituted or substituted aryl or heterocycle, and at least one of R 1 or R2 is hydrogen, in the presence of a strong base, such as potassium t-butoxide, and a catalyst, such as Pd(II)Cl 2 (dba), to provide 11. 10 Scheme 2 OH LCRC
H
3 CO CN H 3 C CN 4 WH H( 7 8 OTf LCRC
H
3 C CN H 3 C CN H ! H 9 - Rc is unsubstituted or substituted aryl or heterocycle 10: -Lc- is a covalent bond 11: -Lc- is -NR 1 15 As shown in Scheme 3, selective 0-triflation of 12 followed by protection of the amino group of the resulting 13 with acid-labile carbobenzlyoxy provided 14. Conversion of 14 to 15 was achieved with KCN in the presence of a palladium catalyst, preferably -45 SUBSTITUTF cF:Ir rIn C om WO 99/05096 PCT/US98/15386 tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, and deprotection of 15 to provide 16 was accomplished with acid, preferably 30% HBr in acetic acid. Treatment of 15 with acylating agents RCC(O)CI and base, preferably triethylamine, diisopropylethylamine or potassium carbonate provided intermediate 17. 5 Scheme 3
NH
2
NH
2 NHCbz NHCbz OH OTf OTf CN 12 13 14 15
NH
2 -HBr LcRc CN CN 16 17 -Lc- is -C(O)NR 1 - or -OC(O)NRI- and RC is unsubstituted or substituted alkyl, alkeneyl, hererocycle or aryl 10 As shown in Scheme 4, selective demethylation of the 8-methoxy group of 18 with a Lewis acid such as AIC1 3 or BBr 3 , preferably AiCl 3 , was followed by reprotection of phenol 19 by alkylation with Bn-X, wherein X is Cl, Br or I, in the presence of a base such as potassium carbonate, sodium hydride or cesium fluoride. 20 was prepared by deprotonation of this intermediate with a strong, non-nucleophilic base such as lithium, sodium or potassium 15 diisopropylamide or alkoxide followed by treatment with an alkyl formate, preferably ethyl formate to provide enol 20. Treatment of 20 with hydroxylamine provided isoxazole 21 which may be opened with lithium, sodium or potassium alkoxide, preferably sodium methoxide, to provide 22. Carbonyl reduction with concomitant alkene formation with achieved with sodium borohydride to provide 23; and aromatization with DDQ and catalytic debenzylation with 20 hydrogen and a palladium catalyst, preferably palladium on carbon, provided 24. 24 was -46 SUBSTITI ITP cw r 1n11 C i WO 99/05096 PCT/US98/15386 alkylated by treatment with a base such as potassium carbonate, sodium hydride or cesium fluoride followed by treatment RC-X. Scheme 4 5 LCRcO OH 0 C 0 OH C 0-N A A A A 18 19 20 21 A is -LARA, and C is -LcRc, wherein C is -LcRc, wherein Lc is -0- and -LA- and -Lc- are -0- and RA is alkyl Rc is arylalkyl C 0 C OH OCN A CN A CN Aj Aj ACO 22 23 24 A is -LARA, wherein -LA- is -0- and RA is alkyl As shown in Scheme 5, monohydrolysis of 25 with one equivalent of base such as lithium, sodium or potassium hydroxide provided the acid-ester 26. Treatment of 26 with 10 thionyl chloride or oxalyl chloride/DMF followed by treatment with ammonia provided amide 27. Treatment of 27 with a dehydrating agent such as thionyl chloride or phosphorus oxychloride provided nitrile 28. Regioselective nitration of 28 with nitric acid/potassium nitrate followed by reduction of the nitro group with a palladium catalyst, preferably palladium on carbon, provided intermediate 15 31, which was treated with RCC(O)Cl or RCOC(O)Cl and base, preferably diisopropylethylamine or potassium carbonate, to provide 37. Hydrolysis of 28 with one equivalent of lithium, sodium or potassium hydroxide to form carboxylic acid 29 followed by treatment with DPPA or thionyl chloride then sodium azide and hydrolysis of the intermediate isocyanate 32 with acid, preferably sulfuric acid, provided 20 amine 33. Alternatively, treatment of 32 with a primary or secondary amine provided urea 3 -47 SUBSTITUTE SHFFT (Pill : WO 99/05096 PCTIUS98/15386 (-LA- = -NRiC(X)R 2 -, wherein X is 0). 29 may be coupled to primary or secondary amines, and 33 may be coupled to carboxylic acids to form amides 35 and 3, respectively. In either case, the amines and carboxylic acids are coupled using a dehydrating agent such as DCC, EDC or HATU. 5 Scheme 5 CO2CH3 CO2H
CONH
2
H
3 CO2C
H
3
CO
2 C :) N r H 3 CO2 25 26 27 RALACN HOCCN RALACN RAL H2CJ RAL A 28 29 30 -LA-is a covalent bond and RA is alkoxycarbonyl CN 0=0= N 32RALA C 32 34
NH
2 CN RALA 31 H2N CN 33 -48 SUBSTITImF CW:PT rin 11 C WO 99/05096 PCT/US98/15386 LCRC ~ ON RALA CN 37 -Lc- is -C(X)NR 1 - or -OC(O)NR 1 - and Rc is unsubstituted or substituted alkyl, alkeneyl, hererocycle or aryl; XisO 29 RA LA 35 -LA- is -NR 1
C(X)
wherein X is 0 RALA 36 -LA- is -C(X)NR 1 wherein X is 0 5 As shown in Scheme 6, intermediates wherein -LA- is -C=C- or -C=C- were prepared by treatment of of 38 with a triflating agent, preferably trifluoromethanesulfonyl anhydride, to form 39 followed by coupling of the appropriate substituted alkenes or unsubstituted or substituted alkynes using a palladium catalyst, preferably palladium (II) acetate, to form 40. 10 -49 SUBSTITUTP n-qHFr n1n II M WO 99/05096 PCT/US98/15386 Scheme 6 HO CN TfO = CN RALA CN 38 39 40 As shown in Scheme 7, conversion of the nitrile intermediates to the carboximidamide urokinase inhibitors 41 was achieved by three methods: (1) treatment of the intermediate carbonitriles with a non-nucleophilic base such as lithium, sodium or potassium bis(trimethylsilylamide), preferably lithium bis(trimethylsilylamide) followed by hydrolysis 10 with acid, preferably HCl; (2) treatment of the nitrile with acid, preferably HCl, followed by treatment with ammonium acetate; and (3) treatment of the nitrile with H 2 S followed by treatment with ammonia gas in methanol. Of the three methods, the H2S/NH3/methanol method is preferred. The compounds of the invention were precipitated as hydrochloride or methane sulfonate salts or were purified by reversed phase medium pressure chromatography to form 15 mono- or bis- trifluoroacetate salts. Scheme 7 C C NH B N CN B 6
NH
2 A A 41 20 Synthetic Methods The foregoing may be better understood by reference to the following examples which illustrate the methods by which the compounds of the invention may be prepared and are not intended to limit the scope of the invention as defined in the appended claims. 25 Example 1 -50 SUBSTITrrF c-W r run: 1 Cm WO 99/05096 PCT/US98/15386 7, 8 -Dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 1 A 7. 8-Dimethoxy-2-naphthalenecarbonitrile 5 A solution of freshly prepared LDA in THF at -78 'C was treated dropwise with 3 cyanopropionaldehyde diethyl acetal (3.0 g) in THF (5 mL), stirred for I h, treated with 2,3 dimethoxybenzaldehyde (3.2 g) in THF (5 mL), warmed to room temperature over 90 min, treated with water (40 mL), concentrated and extracted with chloroform. The organic layer was washed with brine, dried (MgSO4) and concentrated to provide 1.5 g of a yellow oil. 10 MS (DCI/NH 3 ) m/e 341 (M+H 2 0)+. A solution of the oil in methanol (5 mL) was added dropwise to 20% aqueous sulfuric acid (100 mL) at 90 'C. The solution was heated for 90 min, cooled to room temperature and extracted with chloroform. The combined organic extracts are washed with brine, dried (MgS04) and concentrated to provide 1.0 g of a brown solid which was purified by flash 15 chromatography on silica gel with 3:1 hexane/ethyl acetate to provide 800 mg of the title compound. MS (DCI/NH 3 ) m/e 231 (M+H 2 0)+. Example I B 20 7, 8 -Dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt A solution of Example 1 (200 mg) in THF (5 mL) at 0 0 C was treated with lithium bis(trimethylsilylamide) (1.0 M in hexane, 1.1 mL), stirred for 18 h at room temperature, treated with 10% HCl (10 mL), stirred for 24 h at room temperature, concentrated and purified by medium pressure liquid chromatography on a 30 cm x 2 cm C- 18 column (40 micron, J.T 25 Baker) with UV detection at 250 nM with solvent mixtures in a gradient ranging from 90%A (0.1% aq TFA)/10%B (methanol) to 10%A/90%B over 160 min at a flow rate of 5 mL/min (fractions were collected every 2 min for 100 min and analyzed by TLC (10:1:1 acetonitrile/water/acetic acid) for product) to provide 100 mg of the title compound. 1 H NMR (300 MHz, DMSO-d 6 ) 6 4.41 (s, 3H), 4.62 (s, 3H), 7.41 (d, lH), 7.43 (dd, 1H), 30 7.60 (d, 1H), 7.80 (d, 1H), 8.49 (d, 1H), 9.31 (bs, 2H), 9.48 (bs, 2H); MS (DCI/NH 3 ) m/e 231 (M+H)+. Anal. calcd for C13H1 4
N
2 0 2 -TFA: C, 52.33; H, 4.39; N, 8.14. Found: C, 51.91; H, 4.35; N, 8.05. -51 SUBSTITUTE SHEET (RI1 F 9rm WO 99/05096 PCT/US98/15386 Example 2 6. 7. 8-trimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 2A 5 6. 7, 8 -trimethoxy-2-naphthalenecarbonitrile The title compound was prepared as described in Example IA but substituting 2, 3, 4 trimethoxybenzaldehyde for 2, 3-trimethoxybenzaldehyde. MS (DCI/NH 3 ) m/e 261 (M+H 2 0)+. 10 Example 2B 6, 7. 8 -trimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared and purified as described in Example lB to provide 100 mg of the title compound. 1 H NMR (DMSO-d 6 , 300 MHz) 6 3.91 (s, 3H), 3.98 (s, 3H), 4.06 (s, 3H), 7.36 (s, I H), 15 7.75 (dd, lH) 7.99 (d, lH), 8.49 (d, lH), 9.18 (bs, 2H), 9.38 (bs, 2H); MS (DCI/NH 3 ) m/e 261 (M+H)+. Anal. calcd for C 1 4H 16
N
2
O
3 -TFA: C, 51.34; H, 4.58; N, 7.48. Found: C, 50.91; H, 4.25; N, 7.35. 20 Example 3 6. 7-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 3A 6, 7 -dimethoxy-2-naphthalenecarbonitrile 25 The title compound was prepared as described in Example IA but substituting 3,4 dimethoxybenzaldehyde for 2, 3-dimethoxy-benzaldehyde to provide 1.3 g of the title compound. MS (DCI/NH 3 ) m/e 231 (M+H 2 0)+. 30 Example 3B 6. 7 -dimethoxv-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared and purified as described in Example I B to provide 100 mg of the title compound. -52 SUBSTITUTF qHF=T fRI 11 WO 99/05096 PCT/US98/15386 1 H NMR (DMSO-d 6 , 300 MHz) 6 3.92 (s, 3H), 3.94 (s, 3H), 7.41 (s, 1H), 7.44 (s, 1H), 7.69 (dd, 1H), 7.93 (d, 1H), 8.49 (d, 1H), 9.18 (bs, 2H), 9.38 (bs, 2H); MS (DCLNH 3 ) m/e 231 (M+H)+. Anal. calcd for C 13
H
1 4
N
2 02.TFA: C, 52.33; H, 4.39; N 8.14. Found: C, 52.15; H, 4.20; N 5 8.10. Example 4 2-[(7-Aminoiminomethyl-2-methoxv--l-naphthalenyl)oxy lacetamide mono(trifluoroacetate) salt 10 Example 4A 7-Methoxy-8-hydroxynaDhthalene-2-carbonitrile A solution of Example 1 A (1 g) in methylene chloride (100 mL) at 0 C was treated with AiCl 3 , stirred for 4 h at 0 C and at room temperature for 18 h, poured into water (200 mL) containing 6N HCl (20 mL), stirred for I h and diluted with methylene chloride (100 mL). The 15 layers were separated, and the organic layer was washed with brine and dried (MgSO 4 ) to provide 810 mg of the title compound as an off-white solid. MS (DCI/NH 3 ) m/e 217 (M+H 2 0)+. Example 4B 20 1,1 -Dimethylethyl 2-[(7-Cyano-2-methoxy- 1 -naphthalenvl) oxyl acetate A slurry Example 4A (100 mg), K 2
CO
3 (70 mg), t-butyl bromoacetate (120 mg) and tetrabutylammonium iodide (25 mg) in DMF (3 mL) was stirred for 18 h at room temperature, diluted with water (20 mL) and extracted with ethyl acetate. The organic extract was washed with saturated NaHCO 3 and brine, dried (Na 2
SO
4 ) and concentrated to provide 25 200 mg of the title compound as a clear oil. MS (DCI/NH 3 ) m/e 331 (M+H 2 0)+. Example 4C 2-f(7-Aminoiminomethyl-2-methoxy- I -naphthalenyl)oxylacetamide mono(trifluoroacetate) salt 30 Example 4B (100 mg) in methanol (5 mL) at 0 'C was treated with HCl(g), stirred for 18 h at room temperature and concentrated to provide an off-white solid. The solid was treated with 2N NH 3 in methanol (10 mL), heated at 50 C for 3.5 h, cooled and concentrated to a yellow solid which was purified as described in Example lB to provide 10 mg of the title compound. -53 SURBTITI IT= CU=-r 101 im WO 99/05096 PCT/US98/15386 1 H NMR (300 MHz, DMSO-d 6 ) 8 3.93 (s, 3H), 4.79 (s, 2H), 7.55 (d, 2H), 7.65 (dd, 1H), 7.72 (d, 1H), 7.85 (d, lH), 8.09 (d, IH), 8.7 (d, 1H), 9.03 (bs, 2H), 9.45 (bs, 2H); MS (DCI/NH 3 ) m/e 274 (M+H)+. Anal. calcd for C 14
H
15
N
3 03.TFA: C, 49.62; H, 4.16; N, 10.85. Found: C, 49.33; H, 4.03; 5 N, 10.50. Example 5 7-Benzvloxy-8-iodo-2-naphthalenecarboximidarnide mono (trifluoroacetate) salt 10 Example 5A 7 -Benzyloxy-8-iodo-2-naphthalenecarbonitrile The title compound was prepared as described in Example 43A but substituting benzyl bromide for propyl iodide. MS (DCI/NH 3 ) m/e 403 (M+NH 4 )+. 15 Example 5B 7 -Benzyloxv-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 5A according to the procedure of Example lB. IH NMR (300 MHz, DMSO-d 6 ) 6 9.30 (br, 4H), 8.44 (s, lH), 8.12 (d, lH), 7.71 (d, 2H), 20 7.67 (dd, lH), 7.57 (d, 2H), 7.45-7.34 (m, 3H), 5.45 (s, 2H); MS (DCI/NH 3 ) m/e 403 (M+H)+. Anal. calcd for C 18
H
15
N
2 01-TFA: C, 46.53; H, 3.12; N, 5.43. Found: C; 46.55; H, 3.10; N, 5.19. 25 Example 6 Methyl [(7-aminoiminomethyl-2-methoxy- I -naphthalenyl)oxylacetate mono(trifluoroacetate) salt Example 6A 30 Methyl F(7-cyano-2-methoxy- 1 -naphthalenyl)oxylacetate A solution of Example 4A (600 mg), Cs2CO 3 (500 mg), t-butyl bromoacetate (120 mg) and tetrabutylammonium iodide (25 mg) in DMF (15 mL) was stirred for 18 h at room temperature, diluted with water (20 mL) and extracted with ethyl acetate. The organic extract -54 SUBSTITIm: <:w r rin Ei c3 WO 99/05096 PCTIUS98/15386 was washed with saturated NaHCO 3 and brine, dried (Na2SO 4 ) and concentrated to provide 800 mg of the title compound as a clear oil. MS (DCI/NH 3 ) ne 331 (M+H 2 0)+. 5 Example 6B Methyl [(7-aminoiminomethyl-2-methoxy- I -naphthalenvl)oxyl acetate mono(trifluoroacetate) alt Example 6A (100 mg) in methanol (30 mL) at 0 C was treated with HCl(g), stirred for 18 h at room temperature and concentrated to provide an off-white solid. The solid was treated 10 with ammonium acetate (100 mg) in methanol (10 mL), heated at 40 C for 15 h, cooled and concentrated to a yellow solid which was purified as described in Example IB to provide 10 mg of the title compound. 1 H NMR (300 MHz, DMSO-d 6 ) 6 3.65 (s, 3H), 3.93 (s, 3H), 4.79 (s, 2H), 7.65 (dd, lH), 7.72 (d, lH), 7.85 (d, 1H), 8.09 (d, lH), 8.7 (d, 1H), 9.03 (bs, 2H), 15 9.45 (bs, 2H); MS (DCI/NH 3 ) nm/e 289 (M+H)+. Anal. calcd for C 15
H
16
N
2 04-TFA: C, 50.75; H, 4.26; N, 6.96. Found: C, 50.42; H, 4.03; N, 6.77. 20 Example 7 [(7-aminoiminomethyl-2-methoxy- I -naphthalenvlloxyl acetic acid mono(trifluoroacetate) salt A solution of Example 6B (100 mg) and LiOH-H 2 0 (150 mg) in 1:1 THF/H 2 0 (10 mL) at 5 'C was stirred 45 min and concentrated to provide an off-white solid. The solid was dissolved in IN HCI (20 mL), stirred 48 h at room temperature and filtered. The resulting 25 white solid was purified as described in Example 1B to provide 20 mg of the title compound. IH NMR (300 MHz, DMSO-d 6 ) 6 3.93 (s, 3H), 4.79 (s, 2H), 7.65 (dd, IH), 7.72 (d, IH), 7.85 (d, 1H), 8.09 (d, lH), 8.7 (d, lH), 9.23 (bs, 2H), 9.45 (bs, 2H); MS (DCI/NH 3 ) m/e 275 (M+H)+. Anal. calcd for C14H14N 2 04TFA: C, 49.49; H, 3.89; N, 7.21. Found: C, 47.53; H, 3.71; N, 30 6.83. Example 8 N-[4-(Aminomethyl'phenyll- 6 -aminoiminomethyl-2-naphthalenecarboxamide bis(trifluoroacetate) salt -55 SUBSTITIIT n n-r u it C WO 99/05096 PCT/US98/15386 Example 8A 2, 6-Naphthalenedicarboxylic acid, monomethyl ester A suspension of dimethyl 2, 6-naphthalenedicarboxylic acid 5 (39.6 g, 162 mmole) in dioxane (1.20 L) was heated at 70-80 'C until all solid dissolved, slowly treated with 1 equivalent of KOH in methanol, stirred for additional 30 minutes at 70 'C, cooled to room temperature, filtered and washed with dioxane and diethyl ether, dissolved in water, treated with 1N HCl until the aqueous layer was acidic to pH paper, filtered, washed with water and dried under vacuum to provide 33 g of a white powder. 10 MS (DCI/NH 3 ) m/e 231 (M+H)+. Example 8B 6 -(Chlorocarbonyl)-2-naphthalenecarboxylic acid, methyl ester A suspension of Example 8A (15 g, 65 mmole) in toluene (190 mL) was treated with 15 thionyl chloride (20 mL, 276 mmole) then DMAP (15 mg), heated at reflux for 1 h and heated at 85 'C for an additional 35 mn. The condenser was replaced with a distilling head and 60 mL of solvent was removed. The thick precipitate which formed while cooling to room temperature was triturated with hexane and filtered to provide 14.8 g of white solid. MS (DCI/NH 3 ) m/e 249 (M+H)+. 20 Example 8C 6 -(Aminocarbonyl)-2-naphthalenecarboxylic acid, methyl ester A solution of Example 8B (15 g, 60.3 mmole) in methylene chloride (400 mL) at room temperature was treated with dry ammonia gas to precipitate the product. The mixture was 25 stirred for an additional 15 min and filtered. The solid was washed with water and dried under vacuum to yield 13.3 g of a white powder. MS (DCI/NH 3 ) m/e 230 (M+H)+. Example 8D 30 6 -Cvano-2-naphthalenecarboxylic acid, methyl ester A suspension of Example 8C (31 g, 135 mmole) in trimethyl phosphate (450 mL) was treated with triphosgene (27 g, 136 mmole), stirred for 20 min at room temperature and heated in an oil bath at 80 'C for 1 h. The product precipated from the solution while cooling to room -56 SUBSTITUTF qwF:=r rui it c WO 99/05096 PCT/US98/15386 temperature. The thick slurry was treated with water and filtered, and the white solid was thoroughly washed with water and dried under vacuum to provide 26.3 g of the title compound. MS (DCI/NH 3 ) m/e 212 (M+H)+. Example 8E 6-Cvano-2-naphthalenecarboxylic acid Example 8D (1.9 g, 9 mmole) in 1:1 THF/H 2 0 (40 mL) was treated with LiOH-H 2 0 (1.9 g, 45 mmole), stirred 90 min at room temperature and concentrated to a thick slurry. The slurry was dissolved in water (20 mL), acidified to pH 2 with solid citric acid and extracted 10 with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO 4 ) and concentrated to provide 1.6 g of the title compound as a white solid. MS (DCIINH 3 ) m/e 197 (M+H)+. Example 8F 15 tert-Butoxycarbonylamino-4-aminomethylaniline 4-Aminomethylaniline (2 g) in 2:1 THF/H 2 0 (30 mL) was treated with Boc anhydride (3.93 g), stirred at room temperature for 18 h, diluted with water and concentrated to white slurry. The slurry was dissolved in ethyl acetate, washed with water and brine, dried (Na2SO 4 ) and concentrated to provide 2.4 g of a yellow solid. 20 MS (DCI/NH 3 ) m/e 223 (M+H)+. Example 8G N-[4-(aminomethyl)phenyl - 6 -cvano-2-naphthalenecarboxamide A solution of Example 8E (200 mg) and hunig's base (180 iL) in DMF (5 mL) at 5 'C 25 was treated with HATU (193 mg), stirred for I h at 5 'C, treated with Example 8F (120 mg) and diisopropylethylamine (100 tL) in DMF (5 mL), stirred for 8 h at room temperature, diluted with ethyl acetate (100 mL), washed sequentially with IN H 3
PO
4 , saturated sodium bicarbonate and brine, dried (Na 2 SO4) and concentrated to provide a yellow oil which was purified on silica gel with 1% methanol/methylene chloride to provide 200 mg of 30 the title compound. MS (DCI/NH 3 ) m/e 419 (M+H 2 O)+. Example 8H -57 SUBSTmIT FcZu=-r r011 C n WO 99/05096 PCT/US98/15386
N-[
4 -(aminomethyl)phenvll-6-aminoininomethyl-2-naphthalenecarboxamide bis(trifluoroacetate) salt The title compound was prepared from Example 8G (200 mg) by the procedure and purification from Example 5B to provide 37 mg of the title compound. 5 1H NMR (300 MHz, DMSO-d 6 ) 5 4.08 (m, 2H), 7.45 (d, 2H), 7.88 (d, 2H), 7.95 (dd, 1H), 8.18 (dd,lH), 8.20 (bs, 3H), 8.23 (d,1H), 8.35 (d,1H), 8.58 (s,lH), 8.70 (s, 1H), 9.39 (s, 2H), 9.55 (s, 2H), 10.68 (s, 1H); MS (DCI/NH 3 ) m/e 319 (M+H)+. Anal. calcd for C 19
H
17
N
4 0TFA: C, 50.56; H, 3.69; N, 10.25; Found: C, 50.18; H, 3.59; N, 10 10.11. Example 9 N-r4-(amino)phenyll-6-aminoiminomethyl-2-naphthalenecarboxamide bis(trifluoroacetate) salt 15 Example 9A N-r 4 -(amino)phenyll-6-cvano-2-naphthalenecarboxamide The title compound was prepared according to the procedure described for Example 8G but substituting 1,4-diaminobenzene for Example 8F. MS (DCI/NH 3 ) m/e 288 (M+H)+. 20 Example 9B N-r4-(amino)phenyll- 6 -aminoiminomethyl-2-naphthalenecarboxamide bis(trifluoroacetate) salt The title compound was prepared with Example 9A (100 mg) following the procedure and purification from Example 6B. 1 H NMR (300 MHz, DMSO-d 6 ) 8 7.15 (d, 2H), 7.75 (d, 2H), 7.95 (dd, lH), 8.18 (dd, lH), 25 8.23 (d, lH), 8.35 (d, lH), 8.58 (s, 1H), 8.70 (s, 1H), 9.25 (s, 2H), 9.48 (s, 2H), 10.58 (s, I H); MS (DCI/NH 3 ) m/e 305 (M+H)+. Anal. calcd for C 1 8H 16
N
4 0-2TFA: C, 49.63; H, 3.41; N, 10.52; Found: C, 46.57; H, 3.62; N, 10.66. 30 Example 10 1 -[(7-Aminoiminomethyl-2-methoxy- 1 -naphthalenvl)oxyl-3-hydroxypropane mono(trifluoroacetate) salt -58 SUR5RTIT m cucr iDE iio & WO 99/05096 PCT/US98/15386 Example IOA 1-F(7-Cyano-2-methoxy-1-naphthalenyl)oxyl-3-f(2-tetrahydro-2H-pyranvlloxv)propane mono(trifluoroacetate) salt A suspension of Example 4A (200 mg) and Cs 2
CO
3 (0.32 g) in DMF (15 mL) was 5 treated with 2-(3-bromopropyl)-tetrahydro-2H-pyran (0.25 g), stirred at room temperature for 18 h then diluted with water (100 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with 10% citric acid, water and brine, dried (MgSO 4 ) and concentrated to provide 320 mg of an oil. MS (DCI/NH 3 ) m/e 323 (M+H)+. 10 Example lOB 1-[(7-Aminoiminomethyl-2-methoxy- 1 -naphthalenylloxyl-3-hydroxvpropane mono(trifluoroacetate) salt Example 10A (0.3 g) was processed and purified according to the procedure of Example 15 1 B to provide 110 mg of an off-white solid. I H NMR (300 MHz, DMSO-d 6 ) 8 1.97 (q, 2H), 3.67 (t, 2H), 4.20 (t, 2H), 7.61-7.70 (m, 3H), 7.84 (d,lH), 8.08 (d, 1H), 8.50 (d, 1H); MS (DCI/NH 3 ) m/e 275 (M+H)+. Anal. calcd for C13H 13
N
3 02-TFA-0.75H 2 0: C, 50.81; H, 5.14; N, 6.97. Found: C, 51.23; 20 H, 5.28; N, 6.97. Example 11 8-amino-2-naphthalenecarbonitrile hydrobromide 25 Example 1IA 2 -Trifluoromethanesulfonyloxy-8-aminonaphthelene A solution of 8-amino-2-naphthol (10 g) and triethylamine (12 mL) in dioxane (200 mL) was treated with N-phenyltrifluoromethane sulfonimide (25 g) in dioxane (80 mL), stirred for 4 h and concentrated. The resulting dark brown solid was triturated with hexane and filtered to 30 provide 12 g of the title compound as a brown solid. MS (DCI/NH 3 ) m/e 292 (M+H)+. Example 11 B 2 -Trifluoromethanesulfonyloxy-8-carbonylbenzvloxvaminonaphthelene -59 SUBSTTI ITS ci-i=r in C na% WQ 99/05096 PCT/US98/15386 A solution of Example 11 A (2 g) in 10% aq Na2CO 3 (20 mL) and dioxane (250 mL) was treated with benzylchloroformate (2 mL) in dioxane (20 mL), stirred at room temperature for 5 h then extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated, and the crude product was chromatographed on silica gel with 7:1 hexane/ethyl 5 acetate to provide 2.5 g (86%) of the title compound. MS (DCI/NH 3 ) m/e 443 (M+NH 4 )+ Example 11 C 8 -(N-carbonylbenzyloxy)-2-naphthalenecarbonitrile 10 Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (120 mg), 1,1 '-bis(diphenylphosphino)-ferrocene (260 mg), potassium cyanide (766 mg), Example 1lB (2.5 g) and N-methyl-2-pyrrolidione (5 mL) were combined sequentially, stirred at room temperature until a yellow reaction complex formed then warmed to 80 'C for 40 min. The dark brown reaction mixture was cooled to room temperature and chromatographed on 15 silica gel with 9:1 hexane/ethyl acetate to provide 1.5 g of the title compound as a colorless solid. MS (DCI/NH 3 ) m/e 292 (M+NH 4 )+. Example 1 ID 20 8-Amino-2-naphthalenecarbonitrile hydrobromide Example I IC (1.4 g) was treated with a solution of 30% HBr in acetic acid (5 mL) and stirred at room temperature for 6 h. The reaction mixture was treated with diethyl ether and filtered to provide 1.1 g of the title compound as a yellow solid. MS (DCI/NH 3 ) m/e 186 (M+NH 4 )+ 25 Example 12 General Acylation Procedure A suspension of Example IOD (1 equivalent), triethylamine (1 equivalent) and DMAP (0.25 equivalents) in methylene chloride (0.3M) was treated dropwise with the appropriate acid 30 chloride (1.1 equivalents) in methylene chloride (0.3 M), stirred at room temperature for 30 min and treated with water (50 mL). The organic layer was dried (MgS04), concentrated and used in following reactions without further purification. Example 13 -60- WO 99/05096 PCT/US98/15386 General Amidine Synthesis Procedure A solution of crude acylation products from Example 12 (ca. 100 mg) at room temperature in 10:1 pyridine:triethylamine (10 mL) was treated with hydrogen sulfide for 5 min, stirred at room temperature for 18 h, diluted with water (50 mL) and extracted with ethyl 5 acetate. The ethyl acetate was dried (MgSO4) and concentrated. The residue was dissolved in acetone (30 mL), treated with methyl iodide (2 mL), refluxed for 1 hour, evaporated to dryness, redissolved in methanol (25 mL), treated with ammonium acetate (100 mg), stirred for 18 h at room temperature, concentrated and purified as described in Example IB to provide Examples 14-20 as white solids. 10 Example 14 8-(carbonylbenzyloxy)amino-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 1 H NMR (DMSO-d 6 , 300 MHz) 5 5.14 (s, 2H), 7.36-7.50 (m, 5H), 7.67-7.90 (m, 4H), 8.14 (d, lH), 8.67 (s, IH), 9.08 (s, 2H), 9.37 (s, 2H), 9.78 (s, 1H); 15 MS (DCI/NH 3 ) m/e 320 (M+H)+. Anal. calcd for Cj9H15N 3 02-1.5TFA-0.5H 2 0: C, 52.91; H, 3.94; N, 8.41. Found: C, 52.86; H, 4.07; N, 8.18. Example 15 20 N-[7-(aminoiiinomethyl)- I -naphthalenvl)acetamide mono(trifluoroacetate) salt 1 H NMR (DMSO-d 6 , 300 MHz) 6 4.19 (s, 3H), 7.66-7.88 (m, 3H), 8.12-8.16 (in, 2H), 8.69 (s, 1H), 8.98 (d, IH), 9.16 (s, 2H), 9.47 (s, 2H), 10.14 (s, IH); MS (DCI/NH 3 ) m/e 228 (M+H)+. Anal. calcd for C14H1 2
N
3 0-1.2TFA-0.25H 2 0: C, 50.18; H, 4.02; N, 11.40. Found: C, 25 50.62; H, 4.47; N, 10.90. Example 16 Methyl [7-(aminoiminomethyl)- 1-n aphthalenvl)carbamate mono(trifluoroacetate) salt IH NMR (DMSO-d 6 , 300 MHz) 6 3.88 (s, 3H), 7.67-7.85 (m, 4H), 8.14 (d, lH), 8.6 (s, 30 1H), 8.28 (s, 3H), 9.67 (s, IH); MS (DCIINH 3 ) m/e 244 (M+H)+. Anal. calcd for C1 3 H1 3
N
3 02-TFA: C,50.43; H, 3.95; N, 11.76. Found: C, 50.12; H, 4.05; N, 11.61. -61 SUBSTmrr czwt-r im ii or WO 99/05096 PCTIUS98/15386 Example 17 Methyl 3-[[7-(aminoiminomethyl)- I -naphthalenyllaminol-3-oxopropionate mono(trifluoroacetate) salt 1 H NMR (DMSO-d 6 , 300 MHz) 6 3.69 (s, 2H), 3.71 (s, 3H), 7.69 (m, 4H), 8.18 (d, IH), 5 8.58 (s, 1H), 9.11 (s, 2H), 9.48 (s, 2H); MS (DCI/NH 3 ) m/e 286 (M+H)+. Anal. calcd for C 15 H1 4
N
3 03i1.lTFA-H 2 0: C, 48.18; H, 4.26; N, 9.80. Found: C, 48.30; H, 4.09; N, 9.58. 10 Example 18 N-r7-(aminoiminomethyl)- I -naphthalenyll-2-(phenylmethoxy)acetamide mono(trifluoroacetate) salt 1 H NMR (DMSO-d 6 , 300 MHz) 6 4.29 (s, 2H), 4.73 (s, 2H), 7.33-7.48 (m, 5H), 7.69 (m, 4H), 8.17 (d, 1H), 8.47 (s, 1H), 9.21 (br, 4H), 15 10.0 (s, I H); MS (DCI/NH 3 ) n/e 334 (M+H)+. Anal. calcd for C 20
H
18
N
3 02-lTFA-H 2 0: C, 56.77; H, 4.76; N, 9.03. Found: C, 56.84; H, 4.49; N, 8.93. 20 Example 19 N-[7-(aminoiminomethyl)- 1 -naphthalenyll- 1,3-benzodioxole-5-carboxamide mono(trifluoroacetate) salt 1 H NMR (DMSO-d 6 , 300 MHz) 6 6.19 (1H, 2H), 7.12 (d, 1H), 7.65-7.79 (m, 5H), 7.97 (d, I H), 8.20 (s, IH), 8.53 (s, IH), 9.2 (br s, 3H), 25 10.35 (s, 2H); MS (DCI/NH 3 ) m/e 334 (M+H)+. Anal. calcd for C 18
H
1 4
N
3 02.TFA: C, 55.82; H, 3.68; N, 9.30. Found: C, 55.69; H, 33.61; N, 9.23. 30 Example 20 N-[7-(aminoininomethyl) -1 -naphthalenyllbenzenemethanesulfonamide mono(trifluoroacetate) salt 1 H NMR (DMSO-d 6 , 300 MHz) 6 4.60 (s, 2H), 7.32-7.33 (m, 5H), 7.67-7.70 (m, 2H), 7.82 (d,1H), 7.92 (d,1H), 8.17 (s, 1H), 8.70 (s, 1H), -62 SUmSTIT r= eu==r tom n e- WO 99/05096 PCT/US98/15386 9.14 (s, 2H), 9.35 (s, 2H), 9.19 (s, 1H); MS (DCI/NH 3 ) m/e 340 (M+H)+. Anal. calcd for C18H1 7
N
3 0 2
S-TFA-H
2 0: C, 50.95; H, 4.28; N, 8.91; Found: C, 50.76; H, 3.70; N, 8.65. 5 Example 21 1-[(7-aminoiminomethyl-2-methoxy- I -naphthalenvl)oxyl-3-bromopropane mono(hydrochloride) salt 10 Example 21A 1 -(7-Cvano-2-methoxy- I -naphthalenvl)oxyl-3-bromopropane mono(hydrochloride) salt The title compound was prepared from Example 4A, 1,3-dibromopropane and the procedure of Example 10A. MS (DCI/NH 3 ) m/e 337 (M+NH 4 )+. 15 Example 21B 1 -[(7-Aminoiminomethyl-2-methoxy- I -naphthalenvlloxyl-3-bromopropane mono(hydrochloride) salt The title compound was prepared from Example 21A and the procedure of Example 1B. 20 After HC hydrolysis, the solution was cooled to 0 'C, and the white solid which precipitated was filtered and dried to provide the title compound. I H NMR (300 MHz, DMSO-d 6 ) 6 2.35 (m, 2H), 3.86 (t, 2H), 4.00 (s, 3H), 4.25 (t, 2H), 7.65 (dd, lH), 7.70 (d, 1H), 7.90 (d, IH), 8.10 (d, 1H), 8.55 (s, IH), 9.15 (br s, 2H), 9.42 (br s, 2H); 25 MS (DCI/NH 3 ) m/e 337 (M+H)+. Anal. calcd for C1 5
HI
7 BrN 2 02-HCl-0.75H 2 0: C, 46.53; H, 5.08; N, 7.23. Found: C, 46.65; H, 5.11; N, 7.16. Example 22 30 3-f(7-Aminoiminomethyl-2-methoxy- I -naphthalenvlloxylpropene mono(trifluoroacetate) salt Example 22A 3-f(7-Cvano-2-methoxy- I -naphthalenvl)oxylpropene -63 SURRTIT T czrc=- in i. r n& WO 99/05096 PCTIUS98/15386 The title compound was obtained as a biproduct from the procedure of Example 21A. MS (DCI/NH 3 ) m/e 257 (M+N1 4 )+. Example 22B 5 3-[(7-Aminoiminomethyl-2-methoxy- I -naphthalenvlloxylpropene mono(trifluoroacetate) salt The title compound was prepared from Example 22A and the procedure and purification in Example IB. 1 H NMR (300 MHz, DMSO-d 6 ) 8 4.00 (s, 3H), 4.70 (d, 2H), 5.22 (d, lH), 5.42 (d, 1H), 6.18 (n, lH), 7.62 (dd, 1H), 7.85 (d, 1H), 8.10 (d, IH), 8.50 (s, IH), 9.12 (br s, 2H), 9.45 10 (br s, 2H); MS (DCI/NH 3 ) m/e 257 (M+H)+. Anal. calcd for C 15
H
16
N
2
O
2 TFA-0.25H 2 0: C, 54.47; H, 4.71; N, 7.47. Found: C, 54.61; H, 4.38; N, 7.40. 15 Example 23 1 -[(7-Aminoiminomethyl-2-methoxy- I -naphthalenylloxyl-3-phenylpropane mono(hydrochloride) salt Example 23A 20 1-[(7-Cvano-2-methoxy- I -naphthalenvl)oxyl-3-phenvlpropane The title compound was prepared from Example 4A, 1-bromo-3-phenylpropane, and the procedure of Example 1OA. MS (DCI/NH 3 ) m/e 335 (M+NH 4 )+. 25 Example 23B 1 -(7-Aminoiminomethyl-2-methoxy- I -naphthalenvl)oxyl-3-phenvlpropane mono(hydrochloride) salt The title compound was prepared from Example 23A and the procedure of Example 21B. 30 1 H NMR (300 MHz, CD 3 0D) 6 2.21 (m, 2H), 2.94 (t, 2H), 4.00 (s, 3H), 4.22 (t, 2H), 7.18 (m, 1H), 7.28 (m, 4H), 7.62 (m, 2H), 7.79 (d, lH), 8.02 (d, 1H), 8.62 (s, 1H); MS (DCI/NH 3 ) m/e 335 (M+H)+. HRMS (FAB) calcd m/e for C21H 2 3N 2
O
2 -HCl: 335.1760 (M+H)+. Found m/e 335.1762. -64 SUBSTITI ITP cW==-r rIn1 11 C WO 99/05096 PCTIUS98/15386 Example 24 1-F(7-Aninoiminomethyl-2-methoxv- 1-naphthalenyl)oxyl-3-[1-(3,4 dimethoxy)phenyllpropane mono(hydrochloride) salt 5 Example 24A 1 -Bromo-3-(3, 4 -dimethoxvphenvl)propane The title compound was prepared from 3-(3,4-dimethoxyphenyl)-1-propanol as described in Journal of the American Chemical Society, 95 , 8749 (1973), which is incorporated herein by reference, to provide the title compound. 10 MS (DCI/NH 3 ) m/e 276 (M+NH 4 )+. Example 24B 1-[(7-Cvano-2-methoxy- I -naphthalenylloxyl-3-[1-(3,4-dimethoxylohenvllpropane The title compound was prepared from Examples 4A and 24A and the procedure of 15 Example 10A. MS (DCI/NH3) m/e 395 (M+NH 4 )+. Example 24C 1-[(7-Aminoiminomethyl-2-methoxv- 1 -naphthalenvl)oxyl-3-[1-(3,4 20 dimethoxv)phenvllpropane mono(hydrochloride) salt The title compound was prepared from Example 24B and the procedure of Example 21B. I H NMR (300 MHz, DMSO-d 6 ) 6 2.11 (m, 2H), 2.80 (t, 2H), 3.74 (s, 6H), 3.98 (s, 3H), 4.15 (t, 2H), 6.75-6.92 (n, 3H), 7.65 (dd, 1H), 7.70 (d, IH), 7.86 (d, lH), 8.10 (d, IH), 25 8.55 (s, 1H), 9.15 (br s, 2H), 9.53 (br s, 2H) MS (DCI/NH 3 ) rn/e 395 (M+H)+. Anal. calcd for C23H 26 N204HCl-0.5H 2 0: C, 62.79; H, 6.42; N, 6.37. Found: C, 63.08; H, 6.38; N, 6.17. 30 Example 25 7-Methoxy- 8 -(2-furanyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 25A 7 -Methoxv-8-trifluoromethanesulfonyloxy-2-naphthalenecarbonitile -65 SU1BSTmm= cTP Qm=-r ro,,, C WO 99/05096 PCT/US98/15386 A solution of Example 4A (310 mg) in methylene chloride (5 mL) at 0 'C was treated with 1,1,1 -trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (614 mg) and triethylamine (240 mL), stirred for 18 h at room temperature, diluted with methylene chloride (100 mL), washed with water and 20% aq NaOH, dried (MgS04) and concentrated to provide 5 560 mg of the title compound as a white solid. MS (DCI) m/e 349 (M+H 2 0)+. Example 25B Furan-2-boronic acid 10 A solution of furan (5.3 mL, 73 mmole) in diethyl ether (67 mL) at -20 'C was treated with n-butyllithium (2.5 M in hexanes, 26 mL, 65 mmole), stirred for 2 hours at -20 'C and transferred by cannula to a -20 'C solution of triisopropyl borate (33 mL, 147 mmole) in diethyl ether (17 mL). The thick mixture was warmed to room temperature, treated with 3N HCl (200 mL) and extracted with diethyl ether. The extracts were washed with IN KOH, and the KOH 15 layer was cooled to 0 'C and acidified with 6N HCl. The acidic solution was extracted with diethyl ether, and the acidic ether extracts were washed with brine, dried (MgSO 4 ) and concentrated to provide the title compound. 1 H NMR (300 MHz, DMSO-d 6 ) 6 6.45 (dd, 1H), 7.05 (t, 1H), 7.80 (dd, 1H), 8.19 (s, 2H). 20 Example 25C 7 -Methoxy- 8 -(2-furanyll-2-naphthalenecarbonitrile Example 25A (1.10 mmol) was combined with Pd(OAc) 2 (0.11 mmol) and 1,1' bis(diphenylphosphino)ferrocene (0.22 mmol) in DMF (5 mL), stirred for 10 min, treated with 25 Example 25B (1.32 mmol) and Cs2CO 3 (3.3 mmol), heated at 85 'C for 6 h, cooled to room temperature and chromatographed on silica gel with 10% ethyl acetate/hexane to provide the title compound. MS (DCI/NH 3 ) m/e 250 (M+H)+. 30 Example 25D 8-(2-Furanyl)- 7 -methoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 25C and the procedure and purification in Example 1B. -66 SUBSTITUTF I-qwIFT mRI 11 m WO 99/05096 PCT/US98/15386 1 H NMR (300 MHz, DMSO-d 6 ) 5 3.97 (s, 3H), 6.73 (m, 1H), 6.80 (m, 1H), 7.64 (dd, 1H), 7.78 (d, lH), 7.91 (m, 1H), 8.16 (d, 1H), 8.20 (d, 1H), 8.30 (s, 1H), 9.08 (br s, 2H), 9.40 (br s, 2H); MS (DClI/NH 3 ) m/e 267 (M+H)+. 5 Anal. calcd for C 16
H
14
N
2 02-TFA: C, 56.85; H, 3.98; N, 7.37. Found: C, 56.68; H, 3.67; N, 7.35. Example 26 methyl 6 -(aminoiminomethyl)-4-[(methoxycarbonyl)aminol-2-naphthalenecarboxylate 10 mono(trifluoroacetate) salt Example 26A 2-Cyano- 1 -nitro-6-carboxvnaphthalene methyl ester A solution of 2-cyano-6-methylnaphthoate (5.2 g) in concentrated sufuric acid (75 mL) 15 at 0 'C was treated with potassium nitrate (1.03 eq) in one portion, stirred for 10 mn, poured onto ice (500 g) and extracted with ethyl acetate. The ethyl acetate layer was washed with water, IN NaOH and brine, dried (MgS04), treated with silica gel and filtered. Concentration of the ethyl acetate to ca. 200 mL precipitated the product. The mixture was heated until all solid dissolved, treated with MeOH (20 mL) and ether (20 mL) and stirred overnight. The resulting 20 solid was filtered and washed with methanol to provide 2.31 g of the title compound as a cream-colored solid. The mother liqueuor was evaporated, treated with methylene chloride (250 mL) then solid silica gel, filtered and concentrated. Crystalization from ethyl acetate/methanol provided an additional 1.6 g of product for a total yield: 3.91 g (62%). MS (DCI/NH 3 ) m/e 257 (M+H)+. 25 Example 26B 2-Cyano- I -amino-6-carboxynaphthalene methyl ester A solution of Example 26A (lg, 3.9mmole) and 10% Pd on carbon (112 mg) in ethyl acetate (80 mL) was stirred under I atm of hydrogen for 9 h, purged with nitrogen for 1 h, 30 filtered and evaporated to provide 810 mg (92%) of the title compound as a yellow solid. MS (DCI/NH 3 ) m/e 227 (M+NH 4 )+. Example 26C 6-Cyano-4-[(methoxvcarbonyl)aminol-2-naphthalenecarboxylic acid, methyl ester -67 SUBSTITI F cQWFT r0In1 C o WO 99/05096 PCT/US98/15386 A solution of Example 26B (2.50 mmol) in methylene chloride (40 mL) was treated sequentially with diisopropylethylamine (2 mL) and methylchloroformate (195 iL, 2.52 mmole), stirred for 2 h, treated with methanol (10 mL), stirred for an additional 10 minutes, diluted with methylene chloride (60 mL), washed with water and brine, dried (MgSO4) and 5 evaporated. The residue was purified on silica gel using 10% ethyl acetate/hexane to provide 280 mg (59%) of light yellow solid. MS (DCI/NH 3 ) m/e 285 (M+H)+. Example 26D 10 Methyl 6 -(aminoiminomethyl)-4-[(methoxvcarbonvllaminol-2-naphthalenecarboxylate mono(trifluoroacetate) salt The title compound was prepared using Example 26C (125 mg, 0.44 mmol) and the procedure in Example 40D to provide 35mg of a white solid. 1 H NMR (DMSO-d 6 ) 6 3.78 (s, 3H), 3.95 (s, 3H), 7.89 (dd, 1H), 8.37-8.40 (m, 3H), 8.53 15 (s, 1H), 8.740 (s, IH) 9.18 (br s, 2H), 9.45 (br s, 2H), 9.90 (s, 1H), 8.42 (s, lH), 8.63 (d, I H), 9.18 (br s, 4H), 10.58 (s, 1H); MS (DCI/NH 3 ) m/e 302 (M+H)+. Anal. calcd for C 15
H
15
N
3 04 TFA-l.5H 2 0: C, 46.16; H, 4.33; N, 9.50. Found: C, 45.96; 46.16; H, 4.06; N, 9.12. 20 Example 27 (E)- { 7-Methoxy-8-[2-(Phenvylethenyll }-2-naphthaleneimidamide mono(trifluoroacetate) salt Example 27A 25 (E)- 7-Methoxy-8-[2-(Phenvl)ethenyll }-2-naphthalenecarbonitrile Example 25A and styrene boronic ester, prepared according to the procedure of Journal of the American Chemical Society, 27 5249 (1975), which is incorporated herein by reference, was processed according to the procedure described in Example 26B to provide the title compound. 30 MS (DCI/NH 3 ) m/e 303 (M+NH 4 )+. Example 27B (E)- 7-Methoxy-8-[2-(Phenvl)ethenyll }-2-naphthaleneimidamide mono(trifluoroacetate) salt The title compound was prepared from Example 27A and the procedure of Example 1B. -68 SUBSTITI ITF c e-r /mil l e n WO 99/05096 PCT/US98/15386 IH NMR (300 MHz, DMSO-d 6 ) 6 3.98 (s, 3H), 7.28 (t, 2H), 7.39 (t, 2H), 7.64 (m, 5H), 8.00 (d, lH), 8.10 (d, IH), 8.62 (s, lH), 9.22 (br s, 2H), 9.42 (br s, 2H); MS (DCI/NH 3 ) m/e 303 (M+H)+. Anal. calcd for C 20
H
18
N
2 0-TFA: C, 63.46; H, 4.60; N, 6.73. Found: C, 63.10; H, 4.73; N, 5 6.43. Example 28 6-(4-Phenylbutynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 10 Example 28A 6-Hydroxy-2-naphthalenecarbonitrile A solution of 6-bromo-2-naphthol (25.0 g, 112 mmol) and copper(I) cyanide (11 g, 123 mmol) in DMF (30 mL) was heated at 135 'C for 18 h, cooled, diluted with ethyl acetate (50 rnL), triturated with 10% aq sodium hydroxide and filtered through Celite@. The filtrate was 15 acidified to pH 2 and extracted with ethyl acetate. The combined extracts were concentrated, dissolved in ethanol (150 mL) and triturated with water to precipitate 14.01 g of the title compound. MS (DCI/NH 3 ) m/e 170 (M+H)+. 20 Example 28B 6-(Trifluoromethanesulfonyloxy)-2-naphthalenecarbonitrile A solution of Example 28A (14.01 g, 82.8 mmol) and triethylamine (9.2 g, 91.1 mmol) in methylene chloride (40 mL) at 0 'C was treated dropwise with trifluoromethylsulfonic anhydride (28 g, 99.4 mmol), warmed to 25 'C for 48 h, concentrated, redissolved in ethanol 25 (50 mL) and triturated with water to precipitate 8.4 g of the title compound. MS (DCI/NH 3 ) m/e 319 (M+NH 4 )+. Example 28C 6
-(
4 -Phenvlbutynyl)-2-naphthalenecarbonitrile 30 The title compound was prepared from Example 28B, 4-phenyl- I -butyne and the procedure of Example 57B. MS (DCI/NH 3 ) m/e 299 (M+NH 4 )+. Example 28D -69 SUBSTITIT n -r r011 C: n a WO 99/05096 PCT/US98/15386 6-(4-Phenvlbutynvl)-2-naphthalenecarboximidanide mono(trifluoroacetate) salt The title compound was prepared from Example 28C and the procedure of Example lB. 1 H NMR (300 MHz, DMSO-d 6 ) 6 2.80 (t, 2H), 2.95 (t, 2H), 7.22 (m, lH), 7.36 (m, 4H), 7.58 (d, 1H), 7.82 (d, lH), 8.05 (d, lH), 8.10 (d, 2H), 8.45 (s, 1H), 9.10 (br s, 2H), 9.42 5 (br s, 2H); MS (DCI/NH 3 ) m/e 299 (M+H)+. Anal. called for C 21
H
18
N
2 -TFA 0.75H 2 0: C, 64.86; H, 4.85; N, 6.58. Found: C, 64.78; H, 4.64; N, 6.03. 10 Example 29 7-(2-Hydroxyethoxy)-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 29A 3-[[(11 -Dimethylethyl)dimethylsilylloxyl- I -propanol, 4-nitrobenzenesulfonate 15 A solution of 3 -t-butlydimethylsiloxy-1-propanol, prepared by the method of McDougal, et al. JOC, 1986, 51, 3388, which is incorporated herein by reference, (7.6 g, 40 mmol) and diisopropylethylamine (10.4 mL, 60 mmol) in methylene chloride (200 mL) at 0 OC was treated with p-nitrophenylsulfonyl chloride (9.7 g, 44 mmol), stirred for 3 h, poured into saturated NaHCO 3 and extracted with diethyl ether. The extracts were washed with brine, dried 20 (Na2SO4), and concentrated. The residue was chromatographed on silica gel with 5% ethyl acetate/hexanes to provide 6.00 g of the title compound. MS (DCI/NH 3 ) m/e 395 (M+NH 4 )+. Example 29B 25 7-[2-[ (1,1 -Dimethylethyl)dimethylsilvlloxylethoxyl-8-iodo-2-naphthalenecarbonitrile The title compound was prepared in a manner analogous to that of Example 43A but substituting Example 29A for propyl iodide. MS (DCI/NH 3 ) m/e 468 (M+H)+. 30 Example 29C 7
-(
2 -Hydroxvethoxy)-8-iodo-2-naphthalenecarbonitrile The title compound was prepared in a manner analogous to that of Example 53F but substituting Example 29B for Example 53E. MS (DCI/NH 3 ) m/e 357 (M+H)+. -70 SUBSTITUTP qwFnF-T r1 C om WO 99/05096 PCT/US98/15386 Example 29D 7-(2-Hydroxvethoxy)-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 29B according to the procedure of 5 Example lB. 1 H NMR (300 MHz, DMSO-d 6 ) 5 1.96 (m, 2H), 3.69 (t, 2H), 4.33 (t, 2H), 4.58 (br, IH), 7.63 (d, 1H), 7.66 (dd, 1H), 8.12 (dd, 2H), 8.42 (s, 1H), 9.20 (s, 2H), 9.53 (s, 2H); MS (DCI/NH 3 ) m/e 245 (M+H)+; Anal. calcd for C13H12N 2
O
2 I-TFA-0.2lH 2 0: C, 53.07; H, 4.85; N, 7.74. 10 Found: C, 53.07; H, 4.75; N, 7.65. Example 30 7-(2-Hydroxvethoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 15 Example 30A 7
-(
2 -Hydroxvethoxy)-2-naphthalenecarbonitrile Example 29B (120 mg, 0.26 mmol), palladium(II)Cl2dppf (46 mg, 0.03 mmol) and diisopropylamine (263 mg, 2.6 mmol) were heated in a sealed tube for 2 h at 100 C, cooled to room temperature, diluted with ethyl acetate, washed with water, dried (Na2SO4), and 20 concentrated. The residue was purified on silica gel with 15% ethyl acetate/hexanes to provide 85 mg of the title compound. MS (DCI/NH 3 ) m/e 342 (M+H)+. Example 30B 7-( 2 -Hydroxvethoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 25 The title compound was prepared from Example 29B according to the procedure of Example lB. I H NMR (300 MHz, DMSO-d 6 ) 6 1.96 (m, 2H), 3.69 (t, 2H), 4.33 (t, 2H), 4.58 (br, IH), 7.63 (d, lH), 7.66 (dd, IH), 8.12 (dd, 2H), 8.42 (s, 1H), 9.20 (s, 2H), 9.53 (s, 2H); MS (DCI/NH 3 ) m/e 228 (M+H)+; 30 Anal. called for C 1 4
H
15
N
2
O
2 -TFA: C, 53.78; H, 4.51; N, 7.84. Found: C, 53.60; H, 4.30; N, 7.81. Example 31 6-(4-Methyl- 1 -pentynvl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt -71 SUBSTITUTF 1FFT mn 1 Cm WO 99/05096 PCT/US98/15386 Example 31A 6-(4-Methyl-1I -pentynyl)-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, 4-methyl-i -pentyne and the 5 procedure of Example 57B. MS (DCI/NH 3 ) m/e 251 (M+NH4)+. Example 31B 6-(4-Methyl-1- pentynvl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 10 The title compound was prepared from Example 3 1A and the procedure of Example lB. 1 H NMR (300 MHz, DMSO-d 6 ) 6 1.05 (d, 6H), 1.90 (m, 1H), 2.20 (d, 2H), 7.62 (dd, 1H), 7.82 (dd, IH), 8.09 (d, IH), 8.12 (d, IH), 8.18 (s, iH), 8.48 (s, 1H), 9.12 (br s, 2H), 9.42 (br s, 2H); MS (DCI/NH 3 ) m/e 251 (M+H)+. 15 Anal. calcd for C 17
H
18
N
2 .TFA: C, 62.63; H, 5.26; N, 7.69. Found: C, 64.85; H, 5.32; N, 7.46. Example 32 6-(5-Phenvlpentynvl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 20 Example 32A 6 -(5-Phenvlpentynvl)-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, 5-phenyl-I-pentyne and the procedure of Example 57B. 25 MS (DCI/NH 3 ) m/e 313 (M+NH 4 )+. Example 32B 6-(5-Phenylpentynvl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 32A and the procedure of Example 1B. 30 1 H NMR (300 MHz, DMSO-d 6 ) 6 1.90 (m, 2H), 2.80 (t, 2H), 3.39 (t, 2H), 7.19-7.37 (m, 5H), 7.62 (dd, IH), 7.82 (dd, IH), 8.08 (d, 1H), 8.15 (d, IH), 8.18 (s, IH), 8.48 (s, IH), 9.15-9.45 (br d, 4H); MS (DCI/NH 3 ) n/e 313 (M+H)+. -72 SUBSTITUTF nw.IFFT M(I It WO 99/05096 PCT/US98/15386 Anal. calcd for C22H 2
ON
2 -TFA: C, 67.60; H, 4.96; N, 6.57. Found: C, 67.32; H, 5.21; N, 6.27. Example 33 5 6-(3-Phenyl- I -propynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 33A 6-(3-Phenyl- 1 -propynyl)-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, 3-phenyl- 1-propyne and the 10 procedure of Example 57B. MS (DCI/NH 3 ) m/e 285 (M+NH 4 )+. Example 33B 6-(3-Phenyl- I -propynyl)-2-naphthalenecarboximidamide mono (trifluoroacetate) salt 15 The title compound was prepared from Example 33A and the procedure of Example 5B. IH NMR (300 MHz, DMSO-d 6 ) 6 4.00 (s, 2H), 7.28-7.50 (m, 5H), 7.70 (dd, lH), 7.85 (dd, 1H), 8.09 (d, 1H), 8.15 (d, 1H), 8.21 (s, lH), 8.49 (s, 1H), 9.21 (br s, 2H), 9.45 (br s, 2H); MS (DCI/NH 3 ) m/e 285 (M+H)+. Anal. calcd for C20H1 6
N
2 -TFA-0.25H 2 0: C, 65.59; H, 4.38; N, 6.95. Found: C, 65.43; H, 20 3.95; N, 6.70. Example 34 6-(Phenylethynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 25 Example 34A 6 -(Phenylethynyl)-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, phenylacetylene and the procedure of Example 57B. MS (DCI/NH 3 ) m/e 271 (M+NH 4 )+. 30 Example 34B 6-(Phenylethynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 34A and the procedure of Example lB. IH NMR (300 MHz, DMSO-d 6 ) 6 7.49 (t, 3H), 7.62 (m, 2H), 7.80 (dd, 1H), 7.86 (dd, 1H), 8.15 (d, 1H), 8.19 (d, 1H), 8.38 (s, 1H), 8.52 (s, 1H), 9.38 (br s, 4H); -73 SUBSTITrrITF qWFw T 1n 11 WO 99/05096 PCT/US98/15386 MS (DCI/NH 3 ) m/e 271 (M+H)+. Anal. calcd for C 19
H
1 4
N
2 -TFA: C, 65.62; H, 3.93; N, 7.29. Found: C, 65.64; H, 4.11; N, 7.21. 5 Example 35 3-Amino-N-[3-[6-(aminoiminomethyl)-2-naphthalenyll-2-propvynyllbenzamide mono(trifluoroacetate) salt Example 35A 10 6-(3-Amino-I -propynyl)-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, propargyl amine and the procedure of Example 41A. MS (DCI/NH 3 ) m/e 207 (M+NH 4 )+. 15 Example 35B 3 -Amino-N-[3-(6-cyano-2-naphthalenyl)-2-propynyllbenzamide A solution of Example 35A (100 mg, 0.49 mmole), 3-aminobenzoic acid (73 mg, 0.53 mmole), EDC (141 mg, 0.74 mmole) and DMAP (89mg, 0.74 mmole), in THF (5.5 mL) was stirred at room temperature for 2.5 h and concentrated. The residue was dissolved in methylene 20 chloride, washed with IN HCl, water, saturated NaHCO 3 , and brine, dried (MgSO4), concentrated and purified by flash chromatography on silica gel with 2% ethanol/methylene chloride to provide the title compound. MS (DCI/NH 3 ) m/e 326 (M+H)+. 25 Example 35C 3 -Amino-N-[ 3
-[
6 -(aminoiminomethyl)-2-naphthalenyll-2-propynyllbenzamide mono(trifluoroacetate) salt The title compound was prepared from Example 35B and the procedure of Example 1B. I H NMR (300 MHz, DMSO-d 6 ) 5 4.32 (d, 2H), 5.69 (br s, 2H), 6.58 (d, 2H), 30 7.62 (m, 3H), 7.82 (d, 1H), 8.08 (d, 1H), 8.14 (d, 1H), 8.20 (s, 1H), 8.43 (s, lH), 8.60 (t, IH), 9.19 (br s, 2H), 9.42 (br s, 2H); MS (DCI/NH 3 ) m/e 343 (M+H)+. Anal. calcd for C 2 1H18N 4 0-TFA.0.25H 2 0: C, 59.93; H, 4.26; N, 12.16. Found: C, 59.86; H, 3.97; N, 11.93. -74 SUBSTITT= c:M -T I if C WO 99/05096 PCT/US98/15386 Example 36 4 -Amino-N-r3-(6-aminoiminomethyl-2-naphthalenvyl-2-propynvllbenzamide mono(trifluoroacetate) salt 5 Example 36A 4-Amino-N-[3-(6-cvano-2-naphthalenyl)-2-propynvllbenzamide Example 35A and 4-aminobenzoic acid were subjected to the conditions described in Example 35B to afford the title compound. 10 MS (DCI/NH 3 ) m/e 326 (M+H)+. Example 36B 4 -Amino-N-r3-(6-aminoiminomethyl-2-naphthalenvl)-2-propynyllbenzamide mono(trifluoroacetate) salt 15 The title compound was prepared from Example 36A and the procedure of Example 5B. IH NMR (300 MHz, DMSO-d 6 ) 6 4.38 (d, 2H), 6.89 (m, IH), 7.20 (m, 2H), 7.22 (s, lH), 7.63 (dd, lH), 7.82 (dd, 1H), 8.09 (d, lH), 8.12 (d, 1H), 8.20 (s, IH), 8.46 (s, lH), 8.95 (t, 1H), 9.19 (br s, 2H), 9.42 (br s, 2H); MS (DCI/NH 3 ) m/e 343 (M+H)+. 20 Anal. calcd for C21H1 6
N
4 0-2.5TFA: C, 49.27; H, 3.19; N, 8.54. Found: C, 49.27; H, 3.33; N, 8.89. Example 37 (S)-2-Amino-N-[ 1 -r( 6 -aminoiminomethyl-2-naphthalenvl)carbonvllcyclohexyllpropionamide 25 bis(trifluoroacetate) salt Example 37A 6-r( -Aminocyclohexvl)ethynvll-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, 1-ethynylcyclohexylamine and the 30 procedure of Example 41A. MS (DCI/NH 3 ) m/e 275 (M+NH 4 )+. Example 37B (S)-2-Amino-N-f l-r( 6 -cvano-2-naphthalenyl)carbonyllcyclohexyllpropionamide -75 SUBSTITuTP c:wHF-T rft 1 =M WO 99/05096 PCT/US98/15386 Example 37A and N-(t-butoxycarbonyl)-L-alanine were subjected to the conditions described in Example 35B to provide the title compound. MS (DCI/NH 3 ) m/e 446 (M+H)+. 5 Example 37C (Sl-2-Amino-N-[1 -[( 6 -aminoiminomethyl-2-naphthalenvl)carbonyllcyclohexvlpropionamide bis(trifluoroacetate) salt The title compound was a rearrangement product of Example 37B resulting from the procedure of Example 5B. 10 IH NMR (300 MHz, DMSO-d 6 ) 8 1.24 (d, 3H), 1.40-1.62 (m, 8H), 2.15-2.26 (s, 1H), 2.29 2.38 (s, 1H), 3.51 (d, lH), 3.78 (d, lH), 3.82 (s, 1H), 7.90 (dd, 2H), 8.09 (dd, 1H), 8.18 (d, 1H), 8.37 (d, lH), 8.55 (s, 1H), 8.78 (s, 1H), 9.31 (s, 2H), 9.50 (s, 2H); MS (DCI/NH 3 ) m/e 381 (M+H)+. 15 Anal. calcd for C23H 2 8N 4 02.2TFA-2H 2 0: C, 49.39: H, 5.22; N, 8.53. Found: C, 49.15; H, 4.79; N, 8.70. Example 38 6-methoxv-8-benzyloxy- 2 -naphthalenecarboximidamide mono(trifluoroacetate) salt 20 Example 38A 8-Hydroxy-6-methoxy-3. 4 -dihydro-2H-naphthalen- 1-one A solution of 6, 8-dimethoxy-3, 4 -dihydro-2H-naphthalen- 1-one (15 g, 72.8 mmole), prepared according to the procedure of J. Chem. Soc., London 2782 (1955), which is 25 incorporated herein by reference, in methylene chloride (150 mL) at 0 'C was treated portionwise with AIC1 3 (14.3 g, 107 mmole), stirred for 20 h at room temperature, poured onto ice with stirring and extracted with methylene chloride when the ice melted. The extracts were washed with water and brine, dried (MgS04) and concentrated to provide 13.8 g of the title compound. 30 MS (DCI/NH 3 ) m/e 193 (M+H)+. Example 38B 8 -Benzyloxv- 6 -methoxy-3.4-dihydro-2H-naphthalen- 1-one -76 SUBSTITUTF R4FFT 32 1= 11 WO 99/05096 PCT/US98/15386 A mixture of Example 38A (2.5 g, 13 mmole), benzyl bromide (2.1 mL, 17.8 mmole), K2CO 3 powder (14.3 g, 100 mmole), and 2-butanone (88 mL) was stirred at reflux for 4 h, treated with additional benzyl bromide (1.0 mL, 8.5 mmole), stirred at reflux for an additional 3 h, cooled to room temperature, filtered and concentrated. The residue was dissolved in 5 methylene chloride, washed with IN HCl, water and brine, dried (MgS04) and concentrated. The crude product was purified on silica gel with 30% ethyl acetate/hexanes to provide the title compound. MS (DCI/NI 3 ) m/e 283 (M+H)+. 10 Example 38C 3.
4 -Dihydro-2-(hydroxymethylene)-6-methoxy-8-(phenvlmethoxy)- l(2H)-naphthalenone Sodium metal (1.29 g, 55.9 mmole) was added portionwise to a mixture of ethanol (4.2 mL) and benzene (15 mL). The mixture was stirred at reflux for 1.5 h, cooled to 0 'C and treated dropwise with ethyl formate (5.6 mL, 70 mmole) then dropwise with of a solution of 15 Example 38B (6.7g, 23.8 mmole) in benzene (20 mL), stirred at room temperature for 2 h, cooled to 0 'C, treated sequentially with ice/water and 6N HCl (75 mL) and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated to provide the title compound. MS (DCI/NH 3 ) m/e 311 (M+H)+. 20 Example 38D 4 .5-Dihydro-7-methoxy-9-(phenvlmethoxynaphth[2, I-dlisoxazole [2,1-dlisoxazole A suspension of Example 38C (7.5 g, 24.3 mmole), hydroxylamine hydrochloride (4.0 25 g, 57.6 mmole) and acetic acid (63 mL) was stirred at 110 'C for 7 min, cooled to room temperature, diluted with water and extracted with methylene chloride. The extracts were washed with water and brine, dried (MgSO 4 ), and concentrated. The crude product was purified by flash chromatography on silica gel with 30% ethyl acetate/hexanes to provide the title compound. 30 MS (DCI/NH 3 ) m/e 308 (M+H)+. Example 38E 8 -Benzyloxy- 2 -cvano-6-methoxv-3,4-dihydronaphthalen- 1-one -77 SUBSTITUTE SHFFT Min 1: Pm WO 99/05096 PCT/US98/15386 Sodium methoxide, prepared from sodium metal (0.17 g, 7.35 mmol) in methanol (3.9 mL), was treated dropwise with a solution of Example 38D (1.5 g, 4.9 mole) in benzene (50 mL), stirred at room temperature for 4.5 h, treated sequentially with water and IN HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (MgS04) and 5 concentrated to provide the title compound. MS (DCI/NH 3 ) m/e 308 (M+H)+. Example 38F 2-Cyano-6-methoxy-8-Benzyloxy-3,4-dihydronaphthalene 10 A suspension of Example 38E (2.6 g, 8.6 mmole) in absolute ethanol (25 mL) at room temperature was treated portionwise with NaBH 4 (1.6 g), stirred for 20 min at room temperature and for 20 min at reflux, cooled to room temperature, treated with water (20 mL) and concentrated. The residue was dissolved in methylene chloride, washed with water and brine, dried (MgSO4), filtered and concentrated to provide 2.6 g of an orange foam. The foam 15 was stirred at reflux for 20 min with p-toluenesulfonic acid monohydrate (0.52 g, 2.7 mmole) in benzene (52 mL), cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated to provide the title compound. MS (DCI/NH 3 ) m/e 309 (M+NH4)+. 20 Example 38G 2 -Cvano- 6 -methoxy-8-benzyloxvnaphthalene A solution of Example 38F (0.4 g, 1.4 mmole), 2,3-dichloro-5,6-dicyano-1,4 benzoquinone (0.79 g, 3.5 mmole) in benzene (40 mL) was stirred at reflux for 4 hours, treated with additional 2 ,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.4 g, 1.8 mmole), stirred at 25 reflux for an additional 5 h, cooled to room temperature, diluted with ethyl acetate, washed with saturated NaHCO 3 and brine, dried (MgSO 4 ) and concentrated to provide the title compound. MS (DCI/NH 3 ) m/e 290 (M+H)+. Example 38H 30 8 -Benzyloxy-6-methoxy-2-naphthalenecarboximidanide mono(trifluoroacetate) salt The title compound was prepared from Example 38G and the procedure of Example lB. 1 H NMR (300 MHz, DMSO-d 6 ) 6 4.38 (d, 2H), 6.89 (m, 1H), 7.20 (m, 2H), 7.22 (s, 1H), 7.63 (dd, 1H), 7.82 (dd, 1H), 8.09 (d, 1H), 8.12 (d, 1H), 8.20 (s, lH), 8.46 (s, 1H), 8.95 (t, IH), 9.19 (br s, 2H), 9.42 (br s, 2H); -78 SUBSTITUTF coW= rn if C WO 99/05096 PCT/US98/15386 MS (DCI/NH3) m/e 307 (M+H)+. Anal. calcd for C 19
H
18
N
2
O
2 -TFA: C, 60.00; H, 4.56; N, 6.66. Found: C, 59.93; H, 4.46; N, 6.51. 5 Example 39 2-f(7-Aminoiminomethyl-3-methoxy- 1 -naphthalenvl)oxylacetamide mono(trifluoroacetate) salt Example 39A 6-Methoxy- 8 -hydroxy-2-naphthalenecarbonitrile 10 A mixture of Example 38G (1.62 g, 5.6 mmole) and 10% dry Pd/C (0.50 g) in methanol (150 mL) was hydrogenated in a Parr shaker at room temperature under 4 atm for 30 h. The mixture was filtered and concentrated to provide the title compound. MS (DCI/NH 3 ) m/e 217 (M+NH 4 )+. 15 Example 39B 2-[(7-Cyano-3-methoxy- I -naphthalenyoxylacetamide Example 39A and 2-bromoacetamide were subjected to the conditions described in Example 5A to provide the title compound. MS (DCI/NH 3 ) m/e 274 (M+NI- 4 )+. 20 Example 39C 2-r(7-Aminoiminomethyl-3-methoxy- I -naphthalenvl)oxylacetamide mono(trifluoroacetate) salt The title compound was prepared from Example 39B and the procedure of Example lB. 1 H NMR (300 MHz, DMSO-d 6 ) 6 3.93 (s, 3H), 4.70 (s, 2H), 6.70 (d, lH), 7.09 (d, lH), 25 7.65 (s, 2H), 7.82 (dd, 1H), 7.99 (d, lH), 8.70 (s, 1H), 9.05 (s, 2H), 9.38 (s, 2H); MS (DCI/NH 3 ) nVe 274 (M+H)+. Anal. calcd for C 14
H
15
N
3 0 3 -TFA: C, 49.62; H, 4.16; N, 10.85. Found: C, 49.68; H, 4.24; N, 10.61. 30 Example 40
N-(
6 -aminoiminomethyl-2-naphthalenvl)-N'-phenvlurea mono(trifluoroacetate) salt Example 40A 6 -Cyano-2-naphthalenecarbonvl chloride -79 SUBSTITimF qwFFT mail WO 99/05096 PCT/US98/15386 A suspension Example 8E (4.4 g, 22.3 mmol) in toluene (100 mL) was treated with thionyl chloride (6.0 mL) and DMAP (5 mg), heated at 55 'C for lh, treated with additional thionyl chloride (3 mL), warmed to 95 'C for lh, cooled to room temperature, stirred in hexane (75 mL) for 2.5 h and fitered to provide 3.62 of the title 5 compound as a white powder. The filtrate was concentrated and triturated with ether to provide an additional 1.02 g of the title compound. MS (DCI/NH 3 ) m/e 215 (M+H)+. Example 40B 10 2-Cvano-6-naphthovl azide A solution of Example 40A (1.65 g, 7.65 mmole) in acetone (600 mL) at room temperature was treated with a solution of sodium azide (3 g, 46 mmole) in water (10 mL), stirred for 1.5 h and diluted with water (60 mL). The resulting solid was filtered, washed with water and dried to provide 4.24 g of the title compound as a white powder. 15 MS (DCI/NH 3 ) m/e 240 (M+NH 4 )+. Example 40C
N-(
6 -cyano-2-naphthalenvl)-N'-phenvlurea A solution of Example 40B (221.2 mg, 1 mmole) in toluene (18 mL) was heated at 85 20 'C for I h then at 95 'C for 1.5 h, cooled to room temperature, treated with aniline (240 tL, 2.63 mmole), stirred for 25 mn and treated with ether (10 mL). The resulting solid was collected, washed with ether and dried under vacuum to yield 230 mg of white powder. MS (DCI/NH 3 ) m/e 305 (M+NH 4 )+. 25 Example 40D
N-(
6 -aminoiminomethyl-2-naphthalenvl)-N'-phenvlurea mono(trifluoroacetate) salt A solution of Example 40C (148 mg, 0.5 mmole) in 10:1 pyridine:triethylamine (10 mL) was treated with H 2 S for 5 min, stirred at room temperature for 18 h and concentrated. The resulting solid was dissolved in acetone (15 mL), treated with iodomethane (0.8 mL, 12.8 30 mmole), stirred for 2 h, diluted with ether (10 mL), filtered, washed with ether and dried under vacuum. The resulting solid was dissolved in methanol, treated with 2N NH 3 in methanol (2 mL), warmed to 50 'C for 4 h and concentrated. The product was purified according to the procedure described in Example IB to provide 62 mg of the title compound. 1 H NMR (300 MHz, DMSO-d 6 ) 6 7.00 (t, 1H), 7.31 (dd, 2H), 7.52 (d, 1H), -80 SUBSTITIIT :M -r r01 it C run WO 99/05096 PCT/US98/15386 7.65 (dd, 1H), 7.76 (dd, 1H, 8.02 (d, 2H), 8.30 (s, 1H), 8.39 (s, 1H), 9.05 (br s, 2H), 9.11 (s, IH), 9.33 (br s, 2H), 9.42 (s, 1H); MS (DCI/NH 3 ) n/e 305 (M+H)+; Anal. calcd for C18H1 6
N
4 0-TFA: C, 57.42; H, 4.10; N, 13.39. Found: C, 57.50; H, 4.05; 5 N, 13.08. Example 41
(E)-
6
-F
2 -(Phenvl)ethenyll-2-naphthalenecarboxinidamide mono(trifluoroacetate) salt 10 Example 41A (El- 6
-[
2 -(Phenyl)ethenyll-2-naphthalenecarbonitrile A solution of Example 28B (350 mg, 1.16 mmol), styrene (157 mg, 1.51 mmol), palladium (II) acetate (26 mg, 0.12 mmol), triphenylphosphine (61 mg, 0.23 mmol), triethylamine (2 mL) and acetonitrile (1 mL) in a sealed tube with minimal head volume was 15 heated at 100 0 C for 19 h, diluted with ethyl acetate (20 mL), washed with water, dried (MgSO4) and concentrated with silica gel (4 g). The mixture was chromatographed on silica gel with 10% ethyl acetate/hexane to provide 160 mg of the title compound. MS (DCI/NH 3 ) m/e 273 (M+NH 4 )+. 20 Example 41B (E)-6-[2-(Phenyl)ethenvll- 2 -naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 41 A from the procedure of Example l B. 1 H NMR (300 MHz, DMSO-d 6 ) 5 7.33 (t, 1H), 7.4 (t, 2H), 7.5 (d, 2H), 7.69 (d, lH), 7.70 25 (d, 1H), 7.81 (dd, IH), 8.03 (dd, 1H), 8.10 (d, 1H), 8.13 (d, 1H), 8.17 (s, lH), 8.44 (s, I H), 8.97 (s, 2H), 9.41 (s, 2H); MS (DCI/NH 3 ) m/e 273 (M+H)+; Anal. calcd for C 19
H
16
N
2 -TFA: C, 65.28; H, 4.43; N, 7.25. Found: C; 64.95; H, 4.60; N, 6.42. 30 Example 42 6-r 2 -(Phenvl)ethyll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 42A -81 SUBSTITUTF WwT (rm 1 cr WO 99/05096 PCT/US98/15386 6-r2-(Phenvylethyll-2-naphthalenecarbonitrile A mixture of Example 57B (80 mg, 0.31 mmol) and palladium on carbon (20% water, 50 mg) in methanol (5 mL) was stirred under 1 atm of hydrogen for 0.5 h, filtered and concentrated to provide 72 mg of the title compound. 5 MS (DCI/NH 3 ) m/e 275 (M+NH 4 )+. Example 42B 6-r2-(Phenvylethyll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 42A and the procedure of Example lB. 10 IH NMR (300 MHz, DMSO-d 6 ) 6 3.03 (m, 2H), 7.23 (m, 5H), 7.60 (dd, 1H), 7.76 (dd, lH), 7.85 (s, 1H), 8.03 (t, 2H), 8.42 (s, IH), 8.99 (s, 2H), 9.39 (s, 2H); MS (DCI/NH3) m/e 275 (M+H)+. Anal. calcd for C 1 9H 18
N
2 0-1.33TFA: C, 61.29; H, 4.59; N, 6.61. Found: C; 61.56; H, 4.62; N, 5.21. 15 Example 43 7-Propoxy-8-iodo-2-naphthalenecarboximidaniide mono(trifluoroacetate) salt Example 43A 20 7 -propoxy-8-iodo-2-naphthalenecarbonitrile Example 53A (65 mg, 0.25 mmol) in DMF (2 mL) was treated with propyl iodide (40 mL), stirred at 65 'C for I h, diluted with water and extracted with diethyl ether. The organic extracts were dried (MgSO 4 ) and concentrated, and the residue was purified on silica gel with 10% ethyl acetate/hexanes to provide 160 mg of the title compound. 25 MS (DCI/NH 3 ) m/e 355 (M+H)+. Example 43B 7-Propoxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from the product in Example 43A according to the 30 procedure of Example 1B. 1 H NMR (300 MHz, DMSO-d 6 ) 6 1.09 (t, 3H), 1.82 (m, 2H), 4.23 (t, 2H), 7.62 (d, 1H), 7.65 (dd, 1H), 8.12 (dd, 2H), 9.15 (s, 2H), 9.42 (s, lH), 9.53 (s, 2H); MS (DCI/NH 3 ) m/e 355 (M+H)+. -82 SUBSTITUTF SHEFT (Il om WO 99/05096 PCT/US98/15386 Anal. calcd. for C 1 4
H
1 5N 2 OI TFA-0.26C 7
H
8 : C, 43.49; H, 3.70; N, 5.69. Found: C; 43.50; H, 3.59; N, 5.75. Example 44 5 (i )- 6-(3-Phenyloxiranyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 44A (i )-6-(3-Phenvloxiranyl)-2-naphthalenecarbonitrile A solution of Example 41A (69 mg, 0.27 mmol) and m-chloroperbenzoic acid (70 mg, 10 0.41 mmol) in methylene chloride (3 mL) was stirred at 25 'C for 3 days, concentrated, loaded on a silica gel column (pretreated with 0.1% triethylamine in ethyl acetate) and eluted with 10% ethyl acetate/hexane) to provide 72 mg of the title compound. MS (DCI/NH 3 ) m/e 289 (M+NH 4 )+. 15 Example 44B (i )- 6-(3-Phenvloxiranyl)-2-naphthalenecarboxinidamide mono(trifluoroacetate) salt The title compound was prepared with Example 44A from the procedure of Example lB. 1 H NMR (300 MHz, DMSO-d 6 ) 5 4.24 (d, 1H), 4.35 (d, 1H), 7.43 (m, 5H), 7.67 (dd, IH), 20 7.83 (dd, lH), 8.12 (s, 1H), 8.13 (d, lH), 8.16 (d, 1H), 8.50 (s, IH), 9.03 (s, 2 H), 9.44 (s, 2H); MS (DCI/NH 3 ) m/e 289 (M+H)+. Anal. calcd for C19H 1 6
N
2 0-1.3 TFA: C, 64.52; H, 4.55; N, 6.51. Found: C; 64.35; H, 4.60; N, 5.87. 25 Example 45 (E)-6-[2-(2-Thienvylethenyll-2-naphthalenecarboxinidanide mono(trifluoroacetate) salt 30 Example 45A 2-Vinvlthiophene A suspension of methyltriphenylphosphonium bromide (19.13 g, 53.5 mmol) in THF (100 mL) was treated dropwise with 2M butyllithium in THF (17.8 mL) then dropwise with 2 -83 SUBSTITUTF q4FMT (RI 11 o WO 99/05096 PCT/US98/15386 carboxythiophene (5 g, 44.6 mmol), stirred for 30 min then distilled at 74-78 'C to provide the title compound. MS (DCI/NH 3 ) m/e 111 (M+H)+. 5 Example 45B (E)-6-[2-(2-Thienyl)ethenvll-2-naphthalenecarbonitrile The title compound was prepared from the product of Example 45A and the procedure of Example 41 A. MS (DCI/NH 3 ) m/e 279 (M+NH 3 )+. 10 Example 45C
(E)-
6
-[
2
-(
2 -Thienvl)ethenvll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 45B and the procedure of Example lB. 15 IH-NMR (300 MHz, DMSO-d 6 ) 6 7.12 (dd, 2H), 7.15 (d, 1H), 7.32 (d, 1H), 7.6 (d, 1H), 7.74 (d, lH), 7.80 (dd, lH), 7.9-8.1 (m, 3H), 8.14 (s, 1H), 8.43 (s, lH), 9.03 (s, 2H), 9.42 (s, 2H); MS (DCI/NH 3 ) m/e 279 (M+H)+; Anal. calcd. for C 17
H
14
N
2 0 2 S-TFA: C, 53.77; H, 3.56; N, 6.60. Found: C; 54.88; H, 3.66; 20 N, 6.45. Example 46 6-(3-Oxobutvl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 25 Example 46A 6
-(
3 -Oxobutvil)-2-naphthalenecarbonitrile The title compound was prepared from Example 28B, 1-buten-3-ol and the procedure of Example 41A. MS (DCI/NH 3 ) m/e 241 (M+NH 4 )+. 30 Example 46B 6-(3-Oxobutvl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 46A and the procedure of ExamplelB. -84 SUBSTITUT= CZw=Fr 1un 1 o WO 99/05096 PCT/US98/15386 1 H NMR (300 MHz, DMSO-d 6 ) 6 2.13 (s, 1H), 2.94 (m, 4H), 7.57 (dd, 1H) 7.78 (dd, 1H), 7.85 (s, lH), 8.01 (d, 1H), 8.05 (d, 1H), 8.43 (s, 1H), 8.48 (m, 2H), 9.06 (s, 2H), 9.40 (s, 2H); MS (DCI/NH 3 ) m/e 241 (M+H)+; 5 Anal. calcd. for C 15
H
16
N
2 0-l.3TFA: C, 54.31; H, 4.48; N, 7.19. Found: C; 54.33; H, 4.35; N, 7.27. Example 47 6 -(3-Methoxyphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 10 Example 47A 6
-(
3 -Methoxyphenyl)-2-naphthalenecarbonitrile A solution of Example 28B (300 mg, 1 mmol), palladium (II) acetate (22 mg, 0.1 mmol) and 1-1l'-bis(diphenyphosphino)ferrocene (111 mg, 0.2 mmol) was stirred in DMF (3 15 mL) for 15 min, treated with Cs 2
CO
3 (813 mg, 2.5 mmol) and 3-methoxyphenylboronic acid (228 mg, 1.5 mmol), stirred for 20 min at 80 'C, cooled, treated with pH 7 buffer (10 mL) and extracted with diethyl ether. The ether extracts were dried (MgSO 4 ), concentrated and purified on silica gel with 10% ethyl acetate/hexane to provide 140 mg of the title compound as a white solid. 20 MS (DCI/NH 3 ) m/e 277 (M+NH 4 )+. Example 47B 6-(3-Methoxyphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 47A and the procedure of Example 1B. 25 1 H NMR (300 MHz, DMSO-d 6 ) 6 3.88 (s, 3H), 7.03 (m, lH), 7.44 (m, 3H), 7.84 (dd, 1H), 8.05 (dd, lH), 8.19 (d, lH), 8.21 (d, IH), .41 (s, 1H), 8.51 (s, IH), 9.11 (s, 2H), 9.45 (s, 2H); MS (DCI/NH 3 ) m/e 277 (M+H)+; Anal. calcd for C1 8
H
16
N
2 0-TFA.0.2H 2 0: C, 61.03; H, 4.45; N, 7.12. Found: C; 61.03; H, 30 4.11; N, 6.86. Example 48 N-r 3 -(methyl)phenyll-6-aminoiminomethyl-2-naphthalenecarboxamide mono(trifluoroacetate) salt -85 SUBSTITUT= c:MFF-T 101n E 3R WO 99/05096 PCTIUS98/15386 Example 48A N-[3-(methyl)phenvll- 6 -cvano-2-naphthalenecarboxamide The title compound was prepared from 3-methyl phenylisocyanate, Example 55C and 5 the procedure from Example 55C. MS (DCI/NH 3 ) m/e 287 (M+H)+. Example 48B N-[3-(methyl)phenvll-6-aminoiminomethyl-2-naphthalenecarboxamide mono (trifluoroacetate) 10 salt The title compound was prepared from Example 48A and the procedure of Example IB. 1 H NMR (300 MHz, DMSO-d 6 ) 6 2.34 (s, 3H), 6.96 (d, 1H), 7.27 (t, 1H), 7.62 (d, lH), 7.66 (s, IH), 7.91 (dd, IH), 8.15 (dd, 1H), 8.29 (d, 1H), 8.31 (d, 1H), 8.54 (s, lH), 8.68 (s, lH), 9.15 (s, 2H), 9.49 (s, 2H), 10.46 (s, 1H); 15 MS (DCI/NH 3 ) m/e 304 (M+H)+; Anal. calcd for Cj9H1 7
N
3 0-TFA-0.l2C 7
H
8 : C, 61.23; H, 4.46; N, 9.81. Found: C; 61.12; H, 4.42; N, 9.43. Example 49 20 6
-(
2 -Formvlphenoxv)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 49A 6
-(
2 -Formylphenoxy)-2-naphthalenecarbonitrile A solution of 2-hydroxybenzaldehyde (72 mg, 0.59 mmol), 25 6-bromo-1-cyanonaphthalene (150 mg, 0.65 mmol), and Cs2CO 3 (248 mg, 0.76 mmol) in DMF (10 mL) was heated at 90 'C for 2 days, treated with water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO 4 ) and concentrated, and the crude product was purified by column chromatography with 10% ethyl acetate/hexane to provide 40 mg of the title compound. 30 MS (DCI/NH 3 ) m/e 291 (M+NH 4 )+. Example 49B 6
-(
2 -Formvlphenoxv)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared with Example 49A and the procedure of Example lB. -86 SUBSTITUTE SHEET Min I= PM WO 99/05096 PCT/US98/15386 IH-NMR (300 MHz, DMSO-d 6 ) 6 7.19 (d, 1H), 7.44 (t, 1H), 7.56 (s, 1H), 7.60 (d, IH), 7.79 (m, 2H), 7.94 (dd, 1H), 8.01 (d, 1H), 8.2 (d, 1H), 8.51 (s, 1H), 9.03 (s, 2H), 9.41 (s, 2H), 10.35 (s, 1H); MS (DCI/NH 3 ) m/e 291 (M+H)+. 5 Anal. calcd. for C 18
H
14
N
2 0 2 -TFA-1.7H 2 0: C, 55.16; H, 4.27; N, 6.43. Found: C; 55.17; H, 3.92; N, 5.94. Example 50 6-(2-Formvlphenyl)- 2 -naphthalenecarboximidanide mono(trifluoroacetate) salt 10 Example 50A 6
-(
2 -Formylphenyl)-2-naphthalenecarbonitrile The title compound was prepared from Example 28B, 2-formylphenylboronic acid and the procedure of Example 47A. 15 MS (DCI/NH 3 ) m/e 275 (M+NH 4 )+. Example 50B 6-( 2 -Formvlphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 50A and the procedure of Example 1B. 20 IH NMR (300 MHz, DMSO-d 6 ) 6 7.71-7.64 (m, 2H), 7.79 (d, 1H), 7.81 (s, IH), 7.88 (dd, lH),7.9 (d, lH), 8.16 (d, 1H), 8.23 (t, 2H), 8.56 (s, 1H), 9.05 (s, 2H), 9.48 (s, 2H), 9.92 (s, 1H); MS (DCI/NH 3 ) m/e 275 (M+H)+; Anal. calcd for CI 8
H
1 4
N
2 0-TFA: C, 61.86; H, 3.89; N, 7.21. Found: C; 61.98; H, 3.59; N, 25 6.88. Example 51 6-[ 2 -(Hydroxymethyl)phenyll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 30 Example 51A 6-[2-(Hydroxymethyl)1- 2 -naphthalenecarbonitrile Example 50A (98 mg, 0.38 mmol) and sodium borohydride (15 mg, 0.80 mmol) were dissolved in methanol (10 mL) and stirred for 0.5 h. The solution was concentrated, and the -87 SUBSTITUTE SHWFT min f I!) WO 99/05096 PCT/US98/15386 residue was purified on silica gel with 30% ethyl acetate/hexane to provide 90 mg of the title compound. MS (DCI/NH 3 ) m/e 277 (M+NH 4 )+. 5 Example 5 1B 6-r2-(HydroxymethyllphenvlH-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 51 A and the procedure of Example 1B. IH NMR (300 MHz, DMSO-d 6 ) 6 9.46 (s, 2H), 9.06 (s, 2H), 8.54 (s, 1H), 8.16 (t, 2H), 8.07 (s, 1H), 7.85 (dd, 1H), 7.74 (dd, 1H), 7.63 (d, 1H), 7.49-7.34 (m, 3H), 10 4.46 (s, 2H); MS (DCI/NH 3 ) m/e 277 (M+H)+; Anal. calcd. for C 1 8H1 6
N
2 0-1.44TFA: C, 56.93; H, 3.99; N, 6.36. Found: C; 56.94; H, 3.88; N, 6.46. 15 Example 52 6-(3-Oxo- I -butenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 52A 6-(3-Oxo- I -butenvll-2-naphthalenecarbonitrile 20 The title compound was prepared from methyl acrylate, Example 28B and the procedure of Example 41 A. MS (DCI/NH 3 ) m/e 222 (M+H)+. Example 52B 6-(3-Oxo- I -butenvl)-2-naphthalenecarboximidanide mono(trifluoroacetate) salt 25 The title compound was prepared from Example 52A and the procedure of Example 1B. 1 H NMR (300 MHz, DMSO-d 6 ) 6 9.46 (s, 2H), 9.13 (s, 2H), 8.48 (s, lH), 8.38 (s, 1H), 8.18 (d, 1H), 8.15 (d, 1H), 8.01 (dd, lH), 7.85 (dd, 1H), 7.82 (d, 1H), 7.03 (d, 1H), 2.40 (s, 1H); MS (DCI/NH 3 ) m/e 239 (M+H)+. 30 Anal. calcd for C 15
H
14
N
2 0-1.58TFA: C, 52.13; H, 3.75; N, 6.69. Found: C; 52.09; H, 3.63; N, 6.64. Example 53 7-Methoxv-8-( IH-pyrazol-4-vl)-2-naphthalenecarboximidamide bis(trifluoroacetate) salt -88 SUBSTITUTF qWFF=T (mI Pi l WO 99/05096 PCTIUS98/15386 Example 53A 7-hydroxy-8-iodo-2-naphthalenecarbonitrile A mixture of 7-cyano-2-naphthol (22.3 g, 131.8 mmol), sodium carbonate (29.3 g, 277 5 mmol) and 12 (31.8 g, 125.2 mmol) in water (500 mL) and THF (80 mL) at 0 'C was stirred at room temperature for 3 h, acidified with IM HCl and extracted with ethyl acetate. The extracts were washed with saturated Na2S2O 3 and brine, dried (Na2SO 4 ) and concentrated. The product was recrystallized from ethyl acetate to yield 33 g of the title compound. MS (DCI/NH 3 ) m/e 313 (M+NH 4 )+. 10 Example 53B 7-Methoxy-8-iodo-2-naphthalenecarbonitrile Example 53A (36.7 g, 124.2 mmol) in methanol (500 mL) and ethyl acetate (300 mL) was treated over 3 h with 2M trimethylsilyldiazomethane in hexane (260 mL), stirred for 24 h, 15 concentrated and recrystallized from ethyl acetate to provide 36.4 g of the title compound. MS (DCI/NH 3 ) m/e 327 (M+NH 4 )+. Example 53C 4-Iodo- I-rr2-(trimethylsilyl)ethoxylmethyll-I H-pyrazole 20 A slurry of NaH (1.94 g, 48.5 mmol) in THF (40 mL) at 0 'C was treated with a solution of 4-iodopyrazole (8.97 g, 46.2 mmol) in THF (20 mL), stirred for 1 h, treated with SEM chloride (9.00 mL, 50.8 mmol), stirred at room temperature for 1 h, poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried (MgS04) and concentrated. The residue was chromatographed on silica gel with 10% ethyl acetate/hexanes to 25 provide 14.4 g of the title compound. MS (DCI/NH 3 ) m/e 325 (M+H)+. Example 53D r1-rr2-(Trimethylsilvl)ethoxylmethyll- IH-pyrazol4-vllboronic acid 30 Example 53C (12.97 g, 40 mmol) in THF (250 mL) at -78 'C was treated with 2.5 M butyllithium in hexanes (17.6 mL, 44 mmol), stirred at -78 'C for 10 mn, treated with trimethyl borate (11.36 mL, 100 mmol), warmed to room temperature, treated with 3M HCl (400 mL) and extracted with ethyl acetate. The extracts were concentrated, and the residue was dissolved -89 SUBSTITUTF qWPTAt 1 1- WO 99/05096 PCT/US98/15386 in 1 M NaOH (500 mL), extracted with diethyl ether, acidified with concentrated HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel with ethyl acetate to provide 2.20 g of the title compound. 5 MS (DCI/NH 3 ) m/e 199 (M-B(OH) 2 )+. Example 53E 7-Methoxy-8-[I-[[2-(trimethylsilvl)ethoxylmethyll- IH-pyrazol-4-vl]-2-naphthalenecarbonitrile Examples 53B (1.55 g, 5 mmol) and 53D (1.45 g, 6 mmol) were subjected to the procedure 10 described in Example 47A to provide 1.64 g of the title compound. MS (DCI/NH 3 ) m/e 380 (M+H)+. Example 53F 7-Methoxy-8-(1 H-pyrazol-4-vi)-2-naphthalenecarbonitrile 15 A solution of Example 53E (1.84 g, 4.85 mmol) in THF (10 mL) was treated with 1 M tetrabutylammonium fluoride in THF (24 mL), refluxed for 6 h and concentrated. The residue was chromatographed on silica gel with 1:1 ethyl acetate/hexanes to provide 0.88 g of the title compound. MS (DCI/NH 3 ) m/e 267 (M+NH 4 )+. 20 Example 53G 7-Methoxy-8-(I H-pyrazol-4-vl)-2-naphthalenecarboximidamide bis(trifluoroacetate) salt The title compound was prepared from Example 53F and the procedure of Example 1B. 25 1 H NMR (300 MHz, DMSO-d 6 ) 6 3.89 (s, 3H), 7.60 (dd, lH), 7.71 (d, 1H), 7.92 (s, 2H), 8.05 (d, 1H), 8.12 (d, 1H), 8.29 (s, 1H), 9.33 (s, 2H), 9.34 (s, 2H); MS (DCI/NH 3 ) m/e 267 (M+H)+; Anal. calcd. for C1 5
H
14
N
4 0-2.8TFA: C, 42.30; H, 2.90; N, 9.59. Found: C; 42.54; H, 3.11; N, 9.03. 30 Example 54 7-Methoxy-8-iodo-2-naphthalenecarboximidanide mono(trifluoroacetate) salt The title compound was prepared from Example 53B and the procedure of Example 1B. -90 SUBSTITUTF CFT 1r1 It = 3M WO 99/05096 PCTIUS98/15386 1 H NMR (300 MHz, DMSO-d 6 ) 6 4.01 (s, 3H), 7.65 (m, 2H), 8.12 (d, 1H), 8.15 (d, 1H), 8.42 (s, 1H), 9.14 (s, 2H), 9.52 (s, 2H); MS (DCI/NH 3 ) m/e 327 (M+H)+. Anal. calcd for C 12
H
12
N
2 OI-1.2TFA: C, 37.28; H, 2.87; N, 6.04. Found: C; 37.35; H, 2.47; 5 N, 5.93. Example 55 N-phenvl-6-aminoiminomethyl-2-naphthalenecarboxanide mono(methanesulfonate) salt 10 Example 55A 2 -Trifluoromethanesulfonyloxy-6-bromonaphthalene A solution of 6-bromo-2-naphthol (4.96 g, 22.25 mmol), N-phenyltrifluoromethanesulfonate (7.95 g, 22.25 mmol), and diisopropylethylamine (7.75 mL, 44.5 mmol) in methylene chloride (25 mL) were stirred for 3 h at room temperature, 15 poured into water and extracted with diethyl ether. The extracts were washed with brine, dried (MgSO 4 ), and concentrated. The residue was chromatographed on silica gel with 3% ethyl acetate/hexane to provide 7.89 g of the title compound. MS (DCI/NH 3 ) m/e 354 and 356 (M+H)+. 20 Example 55B 6 -Bromo-2-naphthalenecarbonitrile Example 55A (7.89 g, 22.2 mmol) was combined with Zn(CN) 2 (1.33 g, 11.33 mmol) and Pd(PPh 3
)
4 (256 mg, 0.22 mmol) in DMF (50 mL), heated at 900 C for 3 h, cooled to room temperature, treated with saturated NaHCO 3 and extracted with diethyl ether. 25 The extracts were washed with brine, dried over (MgS04), and condensed. The residue was chromatographed on silica gel with 5% ethyl acetate/hexanes to provide 2.67 g of the title compound. MS (DCI/NH 3 ) m/e 231 and 233 (M+H)+. 30 Example 55C N-phenyl- 6 -cyano-2-naphthalenecarboxamide A solution of Example 55B (224 mg, 0.965 mmol) in THF (3 mL) and hexanes (1 mL) at -100' C was treated with 2.5 M butyllithium in hexanes (0.386 mL, 0.965 mmol), stirred at -100' C for 5 min, treated with phenyl isocyanate (0.115 mL, 1.06 mmol), warmed to room -91 SUBSTITUTF wm=-r mIn [mi WO 99/05096 PCTIUS98/15386 temperature, treated with pH 7 buffer (0.5 mL) and concentrated. The residue was chromatographed on silica gel with 20% ethyl acetate/hexanes as eluent, to provide 54 mg of the title compound: MS (DCI/NH 3 ) m/e 273 (M+H)+. 5 Example 55D N-phenvl-6-aminoiminomethyl-2-naphthalenecarboxamide mono(methanesulfonate) salt A solution of Example 55C (52 mg, 0.191 mmol) in THF (2 mL) was treated with IM lithium bis(trimethylsilyl)amide in THF (0.6 mL), stirred for 18 h, treated with 2M HCl (4 10 mL), stirred for another 24 h, made basic with saturated Na 2
CO
3 and extracted with ethyl acetate. The extracts were washed with brine, dried (Na2SO 4 ) and concentrated. The crude product was dissoved into a minimal amount of methanol (ca. 1 mL), treated with methanesulfonic acid (I drop), diluted with diethyl ether (400 mL) and filtered to provide 15 mg of the title compound. 15 1 H NMR (300 MHz, DMSO-d 6 ) 6 2.32 (s, 3H), 7.15 (dd, 1H), 7.40 (dd, 2H), 7.83 (d, 2H), 7.90 (dd, IH), 8.17 (dd, lH), 8.25 (d, IH), 8.34 (d, 1H), 8.57 (s, IH), 8.70 (s, lH), 9.09 (br s, 2H), 9.51 (br s, 2H); MS (DCI/NH 3 ) m/e 290 (M+H)+. Anal. calcd for C 1 gH 16
N
3 0-1.1 CH 3
SO
3 H: C, 57.96; H, 4.95; N, 10.61. Found: C, 58.03; 20 H, 4.48; N, 10.36. Example 56 4
-[(
6 -Aminoiminomethyl-2-naphthalenyloxyl-N-methylbenzeneacetamide 25 mono(trifluoroacetate) salt Example 56A N-methyl-3-hydroxyphenvlacetamide A solution of 3-hydroxyphenylacetic acid (1.00 g, 6.57 mmol) and oxalyl chloride 30 (0.63 mL, 7.22 mmol) in methylene chloride (20 mL) was treated dropwise with pyridine (0.6 mL, 7.37 mmol), stirred for 90 min, poured into 40% aqueous methylamine (30 mL), stirred for 15 min, concentrated, dissolved into 1 M HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with ethyl acetate to provide 260 mg of the title compound. -92 SUBSTITUTE SWFFT (mi 1= OM WO 99/05096 PCT/US98/15386 MS (DCI/NH 3 ) m/e 166 (M+H)+. Example 56B 4 -[(6-Cyano-2-naphthalenylloxyl-N-methylbenzeneacetamide 5 A mixture of Example 56A (245 mg, 1.48 mmol), Example 55B (344 mg, 1.48 mmol) and Cs 2 CO3 (530 mg, 1.63 mmol) in DMF (3 mL) was stirred for 72 h at 120 'C, cooled and chromatographed on silica gel with 1:1 ethyl acetate/hexanes to provide 54 mg of the title compound. MS (DCI/NH 3 ) m/e 317 (M+H)+. 10 Example 56C 4-[(6-Aminoiminomethyl-2-naphthalenyl)oxyl-N-methylbenzeneacetamide mono(trifluoroacetate) salt The title compound was prepared from Example 56B and the procedure of Example 15 55D. I H NMR (300 MHz, DMSO-d 6 ) 8 2.33 (s, 3H), 2.58 (d, 3H), 3.42 (s, 2H), 7.05 (m, 2H),7.12 (d, 1H), 7.40 (dd, 1H), 7.45 (m, 2H), 7.79 (dd, lH), 7.98 (q, IH), 8.02 (d, lH), 8.15 (d, lH), 8.49 (s, 1H), 8.99 (br s, 2H), 9.39 (br s, 2H); MS (DCI/NH 3 ) m/e 334 (M+H)+. 20 Anal. calcd for Ci9H 17
N
3 0 2 -1.5CH 3
SO
3 H: C, 54.08; H, 5.28; N, 8.80. Found: C, 53.80; H, 5.37; N, 8.52. Example 57 6-[2-(Methylthio)phenyll-2-naphthalenecarboximidamide mono(methanesulfonate) salt 25 Example 57A 2-Cyanonaphthalene-6-boronic acid A solution of Example 55B (6.37 g, 27.45 mmol) in THF (220 mL) and hexanes (50 mL) at -100 'C was treated with 2.5 M butyllithium in hexanes (11.0 mL, 27.5 mmol), stirred at -100 30 'C for 10 min, treated with trimethyl borate (7.8 mL, 68.6 mmol), warmed to room temperature, treated with 3M HCl (400 mL) and extracted with ethyl acetate. The extracts were concentrated and the residue was dissolved into IM NaOH (500 mL), extracted with diethyl ether, acidified with 12M HCI and extracted with ethyl acetate. The extracts were washed with -93- SUBSTITUTP qWFT mIn #3 r WO 99/05096 PCTIUS98/15386 brine, dried (Na2SO4), and concentrated. The residue was dissolved into minimal methanol and ethyl acetate and triturated with hexanes to yield 2.74 g of the title compound. MS (DCI/NH 3 ) m/e 215 (M+NH 4 )+. 5 Example 57B 6-[2-(Methylthiol)phenyll-2-naphthalenecarbonitrile A solution of 2-bromothioanisole (0.147 mL, 1.10 mmol), Pd(OAc) 2 (24 mg, 0.11 mmol) and 1,1'-bis(diphenylphosphinoferrocene) (120 mg, 0.22 mmol) in DMF (5 mL) was stirred for 10 min, treated with Example 57A (260 mg, 1.32 mmol) and Cs2CO3 (1.07 g, 3.3 mmol), heated 10 at 85 0 C for 6 h, cooled to room temperature and chromatographed on silica gel with 10% ethyl acetate/hexanes to provide 155 mg of the title compound. MS (DCI/NH 3 ) m/e 231 (M+NI 4 )+. Example 57C 15 6-[2-(Methylthio)phenvll-2-naphthalenecarboximidamide mono(methanesulfonate) salt The title compound was prepared from Example 57B and the procedure of Example 55D. 1 H NMR (300 MHz, DMSO-d 6 ) 6 2.32 (s, 3H), 2.40 (s, 3H), 7.34 (m, 2H), 7.45 (m, 2H), 7.82 (dd, 2H), 7.95 (dd, 1H), 8.06 (s, 1H), 8.15 (d, 1H), 8.20 (d, lH), 8.55 (s, lH), 9.03 20 (br s, 2H), 9.56 (br s, 2H); MS (DCI/NH 3 ) m/e 293 (M+H)+. Anal. calcd for C 18
H
17
N
2
S-CH
3
SO
3 H: C, 58.18; H, 5.18; N, 7.12. Found: C, 57.97; H, 5.31; N, 6.97. 25 Example 58 6-[2-(2-Thiomethoxoxvethyl)phenyllnaphthalene-2-carboxin-midamide mono(methanesulfonate) salt Example 58A 30 2-(2-Bromoethyl)bromobenzene A solution of 2-bromophenethyl alcohol (5.05 g, 25.1 mmol) and pyridine (3.65 mL, 45.2 mmol) in acetonitrile (60 mL) was treated with Ph 3 PBr 2 (13.8 g, 32.65 mmol), stirred at 00 C for 2 h, diluted with hexanes and filtered through a plug of silica gel with 25% diethyl ether/hexanes to provide 6.0 g of the title compound. -94 SUBSTITUTP qwnT rm1 = OM WO 99/05096 PCT/US98/15386 MS (DCI/NH 3 ) m/e 263 (M+H)+. Example 58B 2 -(2-Thiomethoxyethyl)bromobenzene 5 A solution of Example 58A (990 mg, 3.75 mmol) and sodium thiomethoxide (290 mg, 4.12 mmol) in DMF (5 mL) was heated at 900 C for 5 h, cooled and chromatographed on silica gel with 1% ethyl acetate/hexanes to provide 646 mg of the title compound. MS (DCI/NH 3 ) m/e 231, 233 (M+H)+. 10 Example 58C 6-r2-(2-Thiomethoxyethyl)phenvll-2-naphthalenecarbonitrile The title compound was prepared from Example 58B (300 mg, 1.30 mmol), Example 57A (260 mg, 1.32 mmol) and the procedure described in Example 57B. MS (DCI/NH 3 ) m/e 321 (M+NH 4 )+. 15 Example 58D 6-r 2
-(
2 -Thiomethoxoxvethyl)phenyllnaphthalene-2-carboximidamide mono(methanesulfonate) salt The title compound was prepared from Example 58C and the procedure from Example 20 55D. 1 H NMR (300 MHz, DMSO-d 6 ) 8 1.78 (s, 3H), 2.31 (s, 3H), 2.55 (m, 2H), 2.85 (m, 2H), 7.30-7.48 (m, 4H), 7.66 (dd, 1H), 7.85 (dd, 1H), 8.04 (s, lH), 8.18 (d, 1H), 8.20 (d, 1H), 8.55 (s, lH), 9.01 (br s, 2H), 9.43 (br s, 2H); MS (DCI/NH 3 ) m/e 321 (M+H)+. 25 Anal. calcd for C20H 2 0
N
2
S
2 1.35CH 3
SO
3 H: C, 56.96; H, 5.69; N, 6.22. Found: C, 57.08; H, 5.49; N, 6.14. Example 59 7-Methoxy-8-(3-furanyl)-2-naphthalenecarboximidamnide mono(methanesulfonate) salt 30 Example 59A 7 -Methoxy- 8
-(
3 -furanyl)-2-naphthalenecarbonitrile The title compound was prepared from Example 53B, furan-3-boronic acid (873 mg, 7.80 mmol) and the procedure of Example 57B. -95 SUBSTITUTE qWFFT mI II 1 WO 99/05096 PCT/US98/15386 MS (DCI/NH 3 ) m/e 267 (M+NH 4 )+. Example 59B 7-Methoxy-8-(3-furanyl)-2-naphthalenecarboximidamide mono(methanesulfonate) salt 5 The title compound was prepared from Example 58C and the procedure from Example 55D. I H NMR (300 MHz, DMSO-d 6 ) 6 2.34 (s, 3H), 3.91 (s, 3H), 6.76 (s, 2H), 7.62 (dd, 1H), 7.74 (d, 1H), 7.87 (dd, IH), 7.96 (s, IH), 8.12 (d, IH), 8.15 (d, 1H), 8.25 (s, 1H), 8.96 (br s, 2H), 9.35 (br s, 2H); 10 MS (DCI/NH 3 ) m/e 267 (M+H)+. Anal. calcd for C16H1 4
N
2 02 CH 3
SO
3 H: C, 55.77; H, 5.00; N, 7.63. Found: C, 55.73; H, 4.61; N, 7.48. Example 60 15 7-Methoxy-8-(2-benzofuranyl)naphthalene-2-carboximidamide mono(methanesulfonate) salt Example 60A 7 -Methoxy-8-(2-benzofuranyl)-2-naphthalenecarbonitrile The title compound was prepared from Example 53B (166 mg, 0.50 mmol), benzofuran-2 20 boronic acid (113 mg, 0.70 mmol) and the procedure of Example 57B. MS (DCI/NH 3 ) m/e 317 (M+NH 4 )+. Example 60B 7-Methoxv-8- ( 2 -benzofuranyl)naphthalene-2-carboximidamide mono(methanesulfonate) salt 25 The title compound was prepared from Example 60A (72 mg, 0.240 mmol) and the procedure from Example 55D. I H NMR (300 MHz, DMSO-d 6 ) 6 2.30 (s, 3H), 3.98 (s, 3H), 7.24 (s, I H), 7.36 (m, 2H), 7.67 (m, 2H), 7.75 (m, 1H), 7.84 (d, lH), 8.21 (d, lH), 8.30 (d, lH), 8.32 (s, 1H), 8.88 (br s, 2H), 9.39 (br s, 2H); 30 MS (DCI/NH 3 ) m/e 317 (M+H)+. Anal. calcd for C20H1 6
N
2
O
2 -1.3CH 3
SO
3 H: C, 57.98; H, 4.84; N, 6.35. Found: C, 57.79; H, 4.78; N, 6.22. Example 61 -96 SUBSTITUTE SHEET (RULI= 9M WO 99/05096 PCT/US98/15386 (E)-8-r2-(1,3-Benzodioxol-5-vl)ethenvI l-2-naphthalenecarboximidamide mono(methanesulfonate) salt Example 61A 5 (E)-8-r2-(1, 3 -Benzodioxol-5-yl)ethenyll-2-naphthalenecarbonitrile Example 53B (75 mg, 0.243 mmol), PdCl2(dppf) (20 mg, 0.024 mmol), 3,4 methylenedioxystyrene (43 mg, 0.291 mmol) and diisopropylethylamine (0.170 mL, 0.97 mmol) in N-methylpyrrolidinone (2 mL) were stirred at 900 C for 18 h, cooled to room temperature and chromatographed on silica gel with 20% ethyl acetate/hexanes to provide 46 mg 10 of the title compound. MS (DCI/NH 3 ) m/e 347 (M+NH 4 )-. Example 61 B (E)-8-[2-(1, 3 -Benzodioxol-5-vylethenyll-2-naphthalenecarboximidamide 15 mono(methanesulfonate) salt The title compound was prepared from Example 61A (43 mg, 0.131 mmol) and the procedure from Example 55D. I H NMR (300 MHz, DMSO-d 6 ) 6 2.32 (s, 3H), 4.01 (s, 3H), 6.07 (s, 2H), 6.96 (d, 2H), 7.10 (d, 2H), 7.32 (d, 2H), 7.45 (s, IH), 7.56 (d, IH), 7.66 (d, 2H), 7.72 (d, I H), 8.06 (s, 20 1 H), 8.03 (d, IH), 8.12 (d, IH), 8.66 (s, IH), 8.96 (br s, 2H), 9.44 (br s, 2H); MS (DCI/NH 3 ) m/e 347 (M+H)+. Anal. calcd for C2 1
H
1 8N203 1.1CH 3
SO
3 H: C, 58.72; H, 4.99; N, 6.20. Found: C, 58.77; H, 5.07; N, 5.99. 25 Example 62 (i )-7-Methoxy-X-(tetrahydro-3-furanyl)-2-naphthalenecarboximidamide mono(methanesulfonate) salt Example 62A 30 (i )-7-methoxy-8-[3-hydroxy- I -(hydroxymethyl)- I -propenvll-2-naphthalenecarbonitrile A solution of Example 53B (3.09 g, 10 mmol), PdCl 2 (120 mg, 1 mmol), cis-2-butene-1,4-diol (1.23 mL, 15 mmol) and NaHCO 3 (1.01 g, 12 mmol) in N-methylpyrrolidinone (10 mL) was stirred at 130 'C for I h, cooled to room temperature and chromatographed on silica gel with -97 SUBSTITUTE SHFFT (Mil P 9rM WO 99/05096 PCT/US98/15386 30% ethyl acetate/hexanes to provide 2.19 g of the title compound as a mixture of diastereomers. MS (DCI/NH 3 ) n/e 269 (M+H)+. 5 Example 62B (i )-7-Methoxy-8-(tetrahvdro-3-furanyl)-2-naphthalenecarbonitrile Example 62A (140 mg, 0.52 mmol) in methylene chloride (3 mL) at 0 'C was treated with triethylsilane (0.166 mL, 1.04 mmol) and BF 3 -OEt 2 (0.096 mL, 0.78 mmol), stirred at room temperature for 4 h, concentrated and chromatographed on silica gel with 25% ethyl 10 acetate/hexanes to provide 100 mg of the title compound. MS (DCI/NH 3 ) n/e 271 (M+NH 4 )+. Example 62C (i )-7-Methoxy-8-(tetrahvdro-3-furanyl)-2-naphthalenecarboximidamide 15 mono(methanesulfonate) salt The title compound was prepared from Example 62B (96 ig, 0.379 mmol) and the procedure from Example 55D. IH NMR (300 MHz, DMSO-d 6 ) 6 2.20 (m, lH), 2.33 (m, lH), 2.39 (s, 3H), 3.99 (s, 3H), 3.90-4.03 (m, 3H), 4.11 (in, lH), 4.42 (m, IH), 7.64 (d, IH), 7.68 (d, 1H), 8.01 (d, lH), 20 8.10 (d, IH), 8.70 (s, IH), 9.01 (br s, 2H), 9.41 (br s, 2H), MS (DCI/NH 3 ) m/e 271 (M+H)+. Anal. calcd for C1 6 HigN 2
O
2 -l.2CH 3
SO
3 H: C, 53.57; H, 5.96; N, 7.26. Found: C, 53.67; H, 5.78; N, 6.72. 25 Example 63 6-l[4-(2-Aminoethyl)phenvlethynvll-2-naphthalenecarboxi midamide mono(trifluoroacetate salt Example 63A 30 6-(Trimethylsilvlethynvl)-2-naphthalenecarbonitrile Example 28B and trimethylsilylacetylene were submitted to the conditions described in Example 42C to provide the title compound. MS (DCI/NH 3 ) m/e 267 (M+NH 4 )+. -98 SUBSTITUTP qWF=T rm2 1 =M WO 99/05096 PCTIUS98/15386 Example 63B 6-Ethynyl-2-naphthalenecarbonitrile A mixture of Example 63A (0.4 g, 1.6 mmole) and K 2
CO
3 (0.4 g, 3.2 mmole) in methanol (16 mL) was stirred at room temperature for 18 h. concentrated, treated with water 5 and extracted with methylene chloride. The organic layer was washed with 0.5 NHCl and brine, dried (MgSO4) and evaporated to provide the title compound. MS (DCI/NH 3 ) m/e 195 (M+NH 4 )+. Example 63C 10 4 -Bromo-(N-tert-butoxvcarbonyl)phenethylamine 4-Bromophenethylamine and di-t-butyldicarbonate were subjected to the conditions described in Synthesis, 48, 1986 to provide the title compound. MS (DCI/NH 3 ) m/e 319 (M+NH 4 )+. 15 Example 63D 6-4f4-( 2 -N-tert-butoxycarbonylaminoethyl)phenvllethvnyl-2-naphthalenecarbonitrile The title compound was obtained with Examples 63B and C from the procedure described in Example 57B to provide the title compound. MS (DCI/NH 3 ) m/e 414 (M+NH 4 )+. 20 Example 63E 6-[{4-(2-Aminoethyl)phenvllethynvll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared with Example 63D and the procedure of Example 5B. 25 1 H NMR (300 MHz, DMSO-d 6 ) 6 2.90 (t, 2H), 3.09 (m, 2H) 7.36 (d, 2H), 7.60 (d, 2H), 7.76 (d, 2H), 7.76 (dd, IH), 7.85 (s, 2H), 7.87 (dd, lH), 8.13 (d, lH), 8.18 (d, 1H), 8.31 (s, I H), 8.50 (s, 1H), 9.18 (s, 2H), 9.45 (s, 2H); MS (DCI/NH 3 ) m/e 314 (M+H)+. Anal. calcd for C 21
H
19
N
3 -2TFA-H 2 0: C, 53.67; H, 4.14; N, 7.15. Found: C, 53.37; H, 30 3.93: N, 7.17. Example 64 7-Methoxy-8-[2-pyrimidinvl (oxv)1-2-naphthalenecarboximidamide mono(trifluoroacetate) -99 SUBSTITUTE SHEET (R1L1 P1 WO 99/05096 PCT/US98/15386 Example 64A 7 -Methoxy- 8
-[
2 -pyrimidinyl(oxv)1-2-naphthalenecarbonitrile Example 4A (125 mg, 0.627 mmol) and 2-chloropyrimidine (143 mg, 1.25 mmol) were subjected to the procedure described in Example 6A to provide 101 mg of the title compound. 5 MS (DCI/NH 3 ) m/e 278 (M+H)+. Example 64B 7-Methoxy-8-[ 2 -pyrimidinvl(oxy)1-2-naphthalenecarboximidamide mono(trifluoroacetate) The title compound was prepared with Example 64A and the procedure of Example lB. 10 IH NMR (300 MHz, DMSO-d 6 ) 6 2.51 (s, 3H), 3.83 (s, 3H), 7.18 (t, lH), 7.70 (dd, IH), 7.80 (d, lH), 8.05 (d, lH), 8.19 (d, lH), 8.34 (s, 1H), 8.62 (d, 2H), 9.07 (br s, 2H), 9.45 (br s, 2H); MS (DCI/NH3) m/e 295 (M+H)+. Anal. calcd for C 20
H
1 6
N
4 04-l.33TFA: C, 40.48: H, 2.60; N, 8.35. Found: C, 40.25; H, 15 2.94; N, 8.92. Example 65 7-Methoxy-8-[2-thiazovl(oxy)naphthalene-2-carboximidamide mono(trifluoroacetate) salt 20 Example 65A 7 -Methoxy- 8 -[2-thiazovl(oxy)1-2-naphthalenecarbonitrile A mixture of Example 4A (250 mg, 1.25 mmol), 2-bromothiazole (225 mL, 2.50 mmol) and CsF (209 mg, 1.38 mmol) in DMSO (4 mL) was stirred at 120 'C for 4 days, cooled and chromatographed on silica gel with 30% ethyl acetate/hexanes to provide 162 mg of the title 25 compound. MS (DCI/NH 3 ) m/e 283 (M+H)+. Example 65B 7-Methoxv-8-[ 2 -thiazovl(oxy)lnaphthalene-2-carboximidanide mono(trifluoroacetate) salt 30 The title compound was prepared with Example 65A and the procedure of Example I B. IH NMR (300 MHz, DMSO-d 6 ) 6 3.98 (s, 3H) 7.25 (m, 2H), 7.73 (dd, 1H), 7.86 (d, IH), 8.12 (d, 1H), 8.22 (d, lH), 8.35 9.09 (bs, 2H), (s, 1H), 9.48 (bs, 2H). MS (DCI/NH 3 ) m/e 300 (M+H)+. Anal. calcd for C 1 5H 1 3
N
3 0 2 S-TFA: C, 49.40; H, 3.41; N, 10.70. Found: C, 49.10; -100 SUBSTITUTF SHFFT fmi 1 =m WO 99/05096 PCT/US98/15386 H, 3.40; N, 10.69. Example 66 7-Methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 5 Example 66A 7 -Methoxy- 8
-(
4 -nitrophenoxy)-2-naphthalenecarbonitrile The title compound was prepared from Example 4A (125 mg, 0.627 mmol), 1,4 dinitrobenzene (143 mg, 1.25 mmol) and the procedure described in Example 65A to provide i0 227 mg of the title compound. MS (DCI/NH 3 ) m/e 338 (M+NH 4 )+. Example 66B 7-Methoxy-8-(4-nitrophenoxv)- 2 -naphthalenecarboximidamide mono(trifluoroacetate) salt 15 The title compound was prepared with Example 66A and the procedure of Example 55D. I H NMR (300 MHz, DMSO-d 6 ) 6 9.43 (br s, 2H), 8.94 (br s, 2H), 8.25 (in, 4H), 8.15 (d, 1H), 7.88 (d, 1H), 7.72 (dd, 1H), 7.05 (d, 2H), 3.91 (s, 3H), 2.30 (s, 3H); MS (DCI/NH 3 ) m/e 338 (M+H)+. 20 Anal. calcd for CigH15N 3 04-1.75CH 3
SO
3 H: C, 46.93; H, 4.39; N, 8.31. Found: C, 47.17; H, 4.32; N, 8.12. Example 67 7 -Methoxv-8-pentafluorophenoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 25 Example 67A 7 -Methoxy-8-pentafluorophenoxy-2-naphthalenecarbonitrile Example 4A (100 mg, 0.50 mmol) and hexafluorobenzene (115 mL, 1.00 mmol) were subjected to the procedure described in Example 65A to provide 150 mg of the title compound. 30 MS (DCI/NH 3 ) m/e 383 (M+NH 4 )+. Example 67B 7-Methoxy-8-pentafluorophenoxy- 2 -naphthalenecarboximidamide mono(trifluoroacetate) salt -101 SUBSTITUTE qHFFT ml OM WO 99/05096 PCT/US98/15386 The title compound was prepared with Example 67A and the procedure of Example 55D. IH NMR (300 MHz, DMSO-d 6 ) 6 2.31 (s, 3H), 3.82 (s, 3H), 7.87 (dd, 1H), 7.88 (d, IH), 8.02 (d, 1H), 8.20 (d, 1H), 8.65 (s, IH), 9.04 (br s, 2H), 9.47 (br s, 2H); 5 MS (DCI/NH 3 ) m/e 383 (M+H)+. Anal. calcd for Ci 8 H1 IN 2
F
5 0 2 1.2CH 3
SO
3 H: C, 46.67; H, 3.19; N, 5.68. Found: C, 46.55; H, 3.00; N, 5.58. Example 68 10 7-Methoxv-8-FN-2-phenvlamino)]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 68A 7- Methoxy-8-[N-2-phenyl(amino')I-2-naphthalenecarbonitrile A solution of Example 25A (309 mg, 1.00 mmol), aniline (0.109 mL, 1.2 mmol), 15 NaOtBu (115 mg, 1.2 mmol), Pd 2 (dba) 3 (10 mg, 0.01 mmol) and dppf (17 mg, 0.03 mmol) in toluene (5 mL) was stirred for 3 h at 100 'C, cooled and chromatographed on silica gel with 10% ethyl acetate/hexanes to provide 175 mg of the title compound. MS (DCI/NH 3 ) m/e 275 (M+H)+. 20 Example 68B 7-Methoxv-8-(N-2-phenylamino)-2-naphthalenecarboximid amide mono(trifluoroacetate) salt The title compound was prepared with Example 68A and the procedure of Example 55D. IH NMR (300 MHz, DMSO-d 6 ) 6 3.95 (s, 3H), 5.92 (bs, 1H), 6.61 (d, 2H), 6.94 (t, lH), 25 7.16 (dd, 2H), 7.45 (dd, IH), 7.48 (d, IH), 7.76 (d, I H), 7.88 (d, IH), 8.13 (d, IH), 9.08 (bs, 2H), 9.31 (bs, 2H). MS (DCI/NH 3 ) m/e 292 (M+H)+. Anal. Calcd for CjgH 17
N
3 0-TFA: C, 59.26; H, 4.48; N, 10.37. Found: C, 59.20; H, 4.32; N, 10.15. 30 Example 69 N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-benzvlurea mono(trifluoroacetate) salt Example 69A -102 SUBSTITT= qW -r ri 1 C nal WO 99/05096 PCT/US98/15386 N-(6-Cyano-2-naphthalenvl)-N'-benzylurea The title compound was prepared with Example 40A, benzylamine and the procedure from Example 40B. MS (DCI/NH 3 ) m/e 302 (M+H)+. Example 69B N-(6-Aminoiminomethyl-2-naphthalenvl)-N'-benzvlurea mono(trifluoroacetate) salt The title compound was prepared with Example 69A and the procedure from Example 40D. 1 H NMR (300 MHz, DMSO-d 6 ) 6 4.35 (d, 2H), 6.91 (t, lH), 7.35-7.24 (m, 5H), 7.59 (dd, 10 1H), 7.72 (dd, 1 H), 7.95 (d, 1H), 7.96 (d, I H), 8.22 (d, IH), 8.35 (d, 1H), 8.92 (br s, 2H), 9.13 (s, IH), 9.32 (br s, 2H). MS (DCI/NH 3 ) m/e 319 (M+H)+. Anal. calcd for C 19 HIgN 4 0TFA: C, 50.57: H, 4.24; N, 15.72. Found: C, 50.34; H, 4.15; N, 15.54. 15 Example 70 N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-methylurea mono(trifluoroacetate) salt Example 70A 20 N-(6-Cvano-2-naphthalenvl)-N'-methylurea The title compound was prepared with Example 40A (221.2 mg, 1.00 mmole) and methylarnine (2.3 mL, 2.34 mmol) in THF (10 mL) according to the procedure from Example 40B. MS (DCI/NH 3 ) m/e 226 (M+H)+. 25 Example 70B N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-methylurea mono(trifluoroacetate) salt The title compound was prepared with Example 70A and the procedure of Example 40D. 30 1 H NMR (300 MHz, DMSO-d 6 ) 6 2.69 (d, 3H), 6.32 (q, lH), 7.60 (dd, 1H), 7.73 (dd, 1H), 7.93 (d, IH), 7.95 (d, lH, 8.19 (d, 1H), 8.49 (d, lH), 9.09 (s, 1H), 9.15 (br. s, 4H); MS (DCI/NH 3 ) m/e 243 (M+H)+. -103 SUBSTITIITT cW:-r rom 11 C WO 99/05096 PCT/US98/15386 Anal. calcd for C 13 H1 4
N
4 0-TFA: C, 50.57; H, 4.24; N, 15.72. Found: C. 50.34; H, 4.15; N, 15.54. Example 71 5 N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-isopropylurea mono(trifluoroacetate) salt Example 71 A
N-(
6 -Cyano-2-naphthalenyl)-N'-isopropylurea The title compound was prepared with Example 40A, isopropylamine and the procedure 10 from Example 40B. MS (DCI/NH 3 ) m/e 254 (M+H)+. Example 71B
N-(
6 -Aminoiminomethyl-2-naphthalenyl)-N'-isopropylurea mono(trifluoroacetate) salt 15 The title compound was prepared with Example 71A and the procedure of Example 5B. I H NMR (300 MHz, DMSO-d 6 ) 6 1.13 (d, 6H), 3.76-3.84 (m, I H), 6.28 (d, IH), 7.55 (dd, IH), 7.72 (dd, lH), 7.94 (d, lH), 7.95 (d, lH), 8.19 (d, 1H), 8.34 (d, 1H), 8.85 (s, lH), 9.3 (br s, 2H), 9.0 (br s, 2H); MS (DCI/NH 3 ) m/e 271 (M+H)+. 20 Anal. calcd for C1 5
H
18
N
4 0-TFA: C, 53.12; H, 4.98; N, 14.58. Found: C, 15.13; H, 4.84; N, 14.50. Example 72 N-(6-A minoiminomethyl-2-naphthalenyl)-N'-phenyl-N'-methylurea mono(trifluoroacetate) salt 25 Example 72A N-(6-Cyano-2-naphthalenyl)-N'-phenyl-N'-methylurea The title compound was prepared with Example 40A, N-methyl-N-phenylamine and the procedure from Example 40B. 30 MS (DCI/NH 3 ) m/e 302 (M+H)+. Example 72B
N-(
6 -Aminoiminomethyl-2-naphthalenyl-N'-phenyl-N'-methylurea mono(trifluoroacetate) salt The title compound was prepared with Example 72A and the procedure of Example 40D. -104 SUBSTITUTS qHF;=T [Pill = WO 99/05096 PCTIUS98/15386 1 H NMR (300 MHz, DMSO-d 6 ) 6 3.33 (s, 3H), 7.25-7.47 (m, 5H), 7.71-7.77 (m, 2H), 7.95 (two overlaping doublets, 2H), 8.16 (d, IH), 8.35 (d, 1H), 8.64 (s, 1H), 8.96 (br s, 2H), 9.34 (br s, 2H); MS (DCI/NH 3 ) n/e 319 (M+H)+. 5 Anal. calcd for C 20
H
17
N
4 0-TFA: C, 58.33; H, 4.43; N, 11.96. Found: C, 58.38; H, 4.69; N, 11.82. Example 73 6-Aminonaphthalene-2-carboximidamide mono(trifluoroacetate) salt 10 Example 73A 6-Phenylcarbamoyl-2-naphthalenecarbonitrile The title compound was prepared from Example 40A, phenol and the procedure from Example 40B. 15 MS (DCI/NH 3 ) m/e 289 (M+H)+. Example 73B 6-Aminonaphthalene-2-carboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 73A and the procedure of Example 20 40D. I H NMR (300 MHz, DMSO-d 6 ) 6 6.01 (br s, 2H), 6.86 (d, IH), 7.06 (dd, lH), 7.58-7.67 (n, 2H), 7.74 (d, I H), 8.21 (d, IH), 8.74 (br s, 2H), 9.16 (br s, 2H); MS (DCI/NH 3 ) m/e 196 (M+H)+. Anal. calcd for C 12
H
10
N
3 .TFA: C, 52.18; H, 4.04; N, 14.04. Found: C, 51.92: H, 3.87; N, 25 13.80. Example 74
N-(
6 -aminoiminomethyl-2-naphthalenyl)-N'-cyclohexvlurea mono(trifluoroacetate) salt 30 Example 74A
N-(
6 -Cyano-2-naphthalenl)-N'-cyclohexvlurea The title compound was preparedwith Example 40A, cyclohexylanine and the procedure from Example 40B. MS (DCINH 3 ) m/e 294 (M+H)+. -105 SUBSTITrT cW: -r 101i C =1 WO 99/05096 PCTIUS98/15386 Example 74B N-(6-aminoiminomethyl-2-naphthalenvl)-N'-cyclohexvlurea mono(trifluoroacetate) salt The title compound was prepared with Example 74A and the procedure of Example 40D. 5 IH NMR (300 MHz, DMSO-d 6 ) 6 1.14-1.39 (m, 5H), 1.54-1.58 (m, 1H), 1.65-1.72 (m, 2H), 1.81-1.86 (m, 2H), 3.46-3.52 (m, 1H), 6.36 (d, 1H), 7.55 (dd, 1H), 7.72 (dd, IH), 7.93 (d, lH), 7.95 (d, IH), 8.18 (d, 1H), 8.35 (d, 1H), 8.87 (s, lH), 9.00 (br s, 2H), 9.28 (br s, 2H); MS (DCI/NH 3 ) m/e 311 (M+H)+. 10 Anal. calcd for C 19
H
2 1N 4 0-TFA: C, 56.60; H, 5.46; N, 13.20. Found: C. 56.61; H, 5.72; N, 13.03. Example 75 N-(6-aminoiminomethyl-2-nachthalenvl)-N'-benzyloxyurea mono(trifluoroacetate) salt 15 Example 75A N-(6-cyano-2-naphthalenyl)-N'-benzyloxyurea The title compound was prepared with Example 40A, O-benzylhydroxylamine and the procedure from Example 40B. 20 MS (DCI/NH 3 ) m/e 318 (M+H)+. Example 75B
N-(
6 -aminoiminomethyl-2-naphthalenyl)-N'-benzyloxyurea mono(trifluoroacetate) salt The title compound was prepared with Example 75A and the procedure of Example 40D. 25 1 H NMR (300 MHz, DMSO-d 6 ) 6 4.87 (s, 2H), 7.25-7.42 (m, 3H), 7.48-7.51 (m, 2H), 7.75 (dd, lH), 7.75 (dd, IH), 7.97 (d, 2H), 8.30 (d, 1H), 8.38 (d, 1H), 8.97 (br s, 2H), 9.21 (s, I H), 9.35 (br s, 2H), 9.77 (s, IH); MS (DCI/NH 3 ) mn/e 335 (M+H)+. Anal. calcd for C 19
H
18
N
4 02-TFA: C, 56.25; H, 4.27; N, 12.49. Found: C, 56.26; H, 4.39; 3o N, 12.30. Example 76 l. -Dimethylethyl [ 4
-[[(
6 -aminoimin omethyl-2-naphthalenvl)aminolcarbonyllphenvllcarbanate mono(trifluoroacetate) salt -106 SUBSTITUTF SHFFT (RIn 1 M WO 99/05096 PCT/US98/15386 Example 76A 6-Amino-2-naphthalenecarbonitrile Sulfuric acid (45mL) was treated with Example 40B (6.5 g), stirred for 30 min, warmed 5 to room temperature for 20 min, poured onto ice, diluted with water to approximately 500 mL, cooled to 0 C and treated with 50% aq sodium hydroxide such that the temperature did not exceed 35 'C. The light solid which precipitated was filtered, washed with water to pH 7, dried under vacuum and purified on silica gel with 20% ethyl acetate/ hexanes to provide 3.3 g of the title compound. MS (DCI/NH 3 ) m/e 169 (M+H)+. 10 Example 76B .1 -Dimethylethyl [ 4 -[[(6-cyano-2-naphthalenvllaminolcarbonyllphenvllcarbamate mono(trifluoroacetate) salt The title compound was prepared from Example 76A, 4-N-Boc-aminomethylbenzoic 15 acid, the procedure from Example 35B with methylene chloride in place of THF. MS (DCI/NH 3 ) m/e 417 (M+H)+. Example 76C ,1 -Dimethylethyl [4-[[( 6 -aminoiminomethyl-2-naphthalenvllaminolcarbonyllphenyllcarbamate 20 mono(trifluoroacetate) salt The title compound was prepared with Example 76B and the procedure of Example 40D. I H NMR (300 MHz, DMSO-d 6 ) 5 3.30 (s, 9H), 4.22 (d, 2H), 7.42 (d, 2H), 7.49 (t, 1H), 7.79 (dd, 1H), 7.95-8.00 (m, 3H), 8.09 (d, 2H), 8.42 (s, IH), 8.63 (d, 1H), 9.18 (br s, 4H), 10.58 (s, 11H); 25 MS m/e 434 (M+H)+. Anal. calcd for C 24
H
27 N503-TFA: C, 59.56; H, 5.00; N, 10.29. Found: C, 58.55; H, 4.85: N, 10.41. Example 77 30 N-[6-(Aminoiminometh yl)-2-naphthalenvl1-4--(aminomethyl)benzamide mono(trifluoroacetate) salt Example 77A -107 SUBSTITUTE SHEFT IR11 P= 9R WO 99/05096 PCT/US98/15386 N-[6-(Aminoiminomethyl)-2-naphthalenvll-4-(aminomethyllbenzamide mono(trifluoroacetate) salt A solution of Example 76B (35 mg, 0.07 mmole) in 1:1 TFA/methylene chloride was stirred at room temperature for 1 h then concentrated. The residue was dissolved in water (12 5 mL), filtered through a 0.45 t filter and concentrated. The solid was suspended in diethyl ether and filtered to yield 27 mg of the title compound as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) 6 4.17 (q, 2H), 7.65 (d, 2H), 7.80 (dd, IH), 7.99 (dd, lH), 8.06-8.12 (m, 4H), 8.30 (br s, 2H), 8.44 (d, lH), 8.64 (d, lH), 9.13 (br s, 2H), 9.40 (br s, 2H), 10.70 (s, IH); i0 MS (DCI/NH 3 ) m/e 319 (M+H)+. Anal. calcd for Ci 9 H18N 4 02.25TFA-0.5H 2 0: C, 48.34; H, 3.67; N, 9.59. Found: C, 48.45; H, 3.74; N, 9.45. Example 78 15 Ethyl [6-(aminoiminomethyl)- 2 -naphthalenyllcarbamate mono(trifluoroacetate) salt Example 78A Ethyl ( 6 -cyano-2-naphthalenvllcarbamate mono(trifluoroacetate) salt The title compound was prepared with Example 40A, ethanol and the procedure from 20 Example 40B. MS (DCI/NH 3 ) m/e 241 (M+H)+. Example 78B Ethyl [6-(aminoiminomethyl)- 2 -naphthalenyllcarbamate mono(trifluoroacetate) salt 25 The title compound was prepared with Example 78A and the procedure of Example 40D. I H NMR (300 MHz, DMSO-d 6 ) 6 1.29 (t, 3H), 4.19 (q, 2H), 7.69 (dd, IH), 7.76 (dd, 1H), 8.1 (d, 2H), 8.23 (d, 1H), 8.38 (d, lH), 9.03 (br s, 2H), 9.33 (br s, 2H), 10.11 (s, lH); 30 MS (DCI/NH 3 ) m/e 258 (M+H)+. Anal. calcd for C 1 4
H
15
N
3 02-TFA: C, 51.76; H, 4.34; N, 11.32. Found: C, 51.32; H, 4.15; N, 10.93. Example 79 -108 SUBSTITUTP mWFF- rai n 11 WO 99/05096 PCT/US98/15386 1 -dimethylethyl [4-[[[6-aminoiminomethyl)- 2-naphthalenvllaminolcarbonyllaminolhenvl carbamate mono(trifluoroacetate) salt Example 79A 5 1,1-Dimethyl [ 4
-F[[(
6 -cyano- 2 -naphthalenvl)aminolcarbonyllaminolphenyllcarbamate The title compound was prepared with Example 40B, 4-(N-tert-butoxycarbonylamino) aminobenzene and the procedure from Example 40C. MS (DCI/NH 3 ) m/e 403 (M+H)+. 10 Example 79B 1,1-dimethylethyl [4-[[[6-aminoiminomethyl)- 2-naphthalenvl)amino lcarbonyllamino]phenvll carbamate mono(trifluoroacetate) salt The title compound was prepared with Example 79A and the procedure of Example 40D. 15 1 H NMR (300 MHz, DMSO-d 6 ) 6 1.22 (s, 9H), 7.38 (s, 4H), 7.62 (dd, I H), 7.75 (dd, 1H), 8.00 (d, 2H), 8.27 (d, lH), 8.38 (d, lH), 8.77 (s, 1H), 8.90 (br s, 2H), 9.16 (s, 1H), 9.20 (s, 1H), 9.33 (br s, 2H); MS (DCI/NH 3 ) m/e 420 (M+H)+. Anal. calcd for C 23
H
25
N
5 03-2TFA: C, 56.28; H, 4.91; N, 13.13. Found: C, 56.18; H, 5.07; 20 N, 12.44. Example 80 (E)-6-[2-(Phenvlthiolethenyll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 25 Example 80A (E)-6-[2-(Phenvlthio)ethenyll-2-naphthalenecarbonitrile The title compound was prepared from Example 55B, phenylvinyl sulfide and the procedure of Example 57B. MS (DCI/NH 3 ) m/e 305 (M+NH 4 )+. 30 Example 80B (E)-6-F2-(Phenvlthio)ethenyll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 80A and the procedure of Example 1B. -109 SUBSTITUTE SHFFT (RII F grn WO 99/05096 PCT/US98/15386 IH NMR (300 MHz, DMSO-d 6 ) 6 6.91 (d, 1H), 7.52-7.33 (m, 5H), 7.50 (d, 1H), 7.75- 7.83 (m, 1H), 7.98-8.89 (m, 1H), 8.08-8.80 (m, 3H), 8.44 (m, lH), 9.03 (s, 2H), 9.40 (s, 2H); MS (DCI/NH 3 ) m/e 305 (M+H)+. Anal. calcd for Ci 9
H
16
N
2 S1.lTFA: C, 59.55; H, 4.03; N, 6.57. Found: C, 59.53; H, 4.12; 5 N, 6.60. Example 81
(E)-
6
-[
2
-(
2 -Furanvllethenyll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 10 Example 81 A 2-Vinylfuran A solution of methyl(triphenylphosphonium)bromide (26.78 g, 75 mmol) in toluene (80 mL) was treated with butyllithium in hexanes (27.5 mL, 68.75 mmol) then furfural (6 g, 62.5 nmol), stirred for 0.5 h and distilled at 69-72 'C to provide the title compound as a clear, 15 colorless liquid with some toluene contaminant. MS (DCI/NH 3 ) m/e 83 (M+H)+. Example 81B
(E)-
6
-[
2
-(
2 -Furanl)ethenyll-2-naphthalenecarbonitrile 20 The title compound was prepared from Examples 55B and 81A and the procedure of Example 57B. MS (DCI/NH 3 ) n/e 263 (M+NH 4 )+. Example 81C 25 (E)-6-12-(2-Furanyl)ethenvl]- 2 -naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 81B and the procedure of Example lB. IH NMR (300 MHz, DMSO-d 6 ) 6 6.61 (dd, lH), 6.66 (d, IH), 7.19 (d, 1H), 7.38 (d, lH), 7.77 (d, 1H), 7.80 (dd, lH), 8.14-7.97 (m, 3H), 8.44 (s, IH), 9.05 (s, 2H), 9.42 (s, 2H); MS (DCI/NH 3 ) m/e 263 (M+H)+. 30 Anal. calcd for C 17
H
13
N
2 0-1.2TFA: C, 58.49; H, 3.85; N, 7.04. Found: C, 58.45; H, 3.78; N, 7.36. Example 82 (E)-6-[2-(IH-Lmidazol- 1 -vl)ethenyll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt -110 SUBSTITUTF quWP-T r9n111 WO 99/05096 PCT/US98/15386 Example 82A (E)-6-[2-(1 H-Imidazol-l -vl)ethenyll-2-naphthalenecarbonitrile The title compound was prepared from Example 55B, 1-vinylimidazole and the 5 procedure of Example 42C. MS (DCI/NH 3 ) m/e 263 (M+NH 4 )+. Example 82B (E)-6-[2-( 1H-Imidazol- I -vlethenyll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 10 The title compound was prepared from Example 82B and the procedure of Example 40D. 1 H NMR (300 MHz, DMSO-d 6 ) 6 9.44 (s, 2H), 9.14 (s, 2H), 8.15 (d, lH), 8.17-8.05 (m, 4H), 7.93 (d, IH), 7.84 (dd, I H), 7.59 (s, IH), 7.49 (d, IH); MS (DCI/NH 3 ) m/e 263 (M+H)+. 15 Anal. calcd for C 16
H
1 3
N
4 -2.7TFA: C, 45.28; H, 2.97; N, 9.91. Found: C, 45.33; H, 3.52; N, 9.79. Example 83
(E)-
4
-[
2
-(
6 -Aminoiminomethyl-2-naphthalenyl)ethenyllbenzenesulfonamide 20 mono(trifluoroacetate) salt Example 83A 4-vinylsulfonamide A solution of thionyl chloride (7.5 mL) and 4-t-butylcatachol (45 mg, 0.3 imol) in 25 DMF (9 mL) at 0 'C was treated with 4-vinylbenzene sulfonic acid sodium salt (3 g, 14.6 mmol), stirred for 6 h, stored at -10 'C for 3 days, poured into ice water and extracted with benzene. The organic layer was washed with water, dried (Na2SO 4 ), filtered and concentrated to provide 4-vilylsulfonyl chloride as a clear, colorless oil. A portion of the chloride (I g, 4.95 mmol) was disslolved in THF (10 mL), cooled to 0 C, treated dropwise with concentrated 30 ammonium hydroxide until gas evolution ceased and extracted with ethyl acetate. The combined extracts were dried (Na2SO 4 ), and concentrated to provide 707 mg of the title compound as a pale yellow solid. MS (DCI/NH 3 ) m/e 201(M+NH 4 )+. -111 SUBSTITUTE SHEET (RULF 9M WO 99/05096 PCT/US98/15386 Example 83B
(E)-
4 -[2-(6-Cyano-2-naphthalenyl)ethenyllbenzenesulfonamide The title compound was prepared from Example 55B, Example 83A and the procedure of Example 57B. 5 MS (DCI/NH 3 ) m/e 352 (M+NH 4 )+. Example 83C
(E)-
4
-[
2
-(
6 -Aminoiminomethyl-2-naphthalenyl)ethenvllbenzenesulfonamide mono(trifluoroacetate) salt 10 The title compound was prepared from Example 83B and the procedure of Example 40D. 1 H NMR (300 MHz, DMSO-d 6 ) 6 9.43 (s, 2H), 9.05 (s, 2H), 8.46 (s, 1H), 8.21 (s, 11H), 8.16-7.95 (m, 3H), 7.86 (s, 2H), 7.84-7.67 (m, 2H), 7.62 (d, 1H), 7.4-7.36 (m, 2H); MS (DCI/NH 3 ) m/e 352 (M+H)+. 15 Anal. calcd for CI9H 17 N30 2 S-1.5C 2
F
3 0 2 H: C, 50.84; H, 3.59; N, 8.11. Found: C, 50.83; H, 3.89; N, 7.88. Example 84 (E)-4-[ 2
-(
6 -Aminoiminomethyl-2-naphthalenyl)ethenyllbenzoic acid mono(trifluoroacetate) salt 20 Example 84A (El- 4 -[2-(6-Cyano-2-naphthalenyl)ethenyllbenzoic acid The title compound was prepared from Example 55B, 4-vinylbenzoic acid and the procedure of Example 57B. 25 MS (DCI/NH 3 ) m/e 300 (M+H)+. Example 84B
(E)-
4
-[
2
-(
6 -Aminoiminomethyl-2-naphthalenvl)ethenvllbenzoic acid mono(trifluoroacetate) salt The title compound was prepared with Example 84A and the procedure of Example 30 40D. 1 H NMR (300 MHz, DMSO-d 6 ) 6 7.62 - 7.58 (m, 2H), 7.90 (d, 2H), 7.98 (d, 1H), 8.12 8.04 (m, 3H), 8.20 (s, 1H), 8.56 (s, 1H), 9.07 (bs, 2H), 9.35 (bs, 2H). MS (DCI/NH 3 ) m/e 317 (M+H)+. Anal. calcd for C2 0
H
16
N
2 0 2 -TFA: C, 61.40; H, 3.98; N, 6.51. Found: C, 61.10; -112 SUBSTITUTE SHEET (RULF 9rn WO 99/05096 PCT/US98/15386 H, 3.63; N, 6.45. Example 85 4-[7-(Aminoiminomethyl)-2-methoxy- I -naphthalenvlldihydro-2(3H)-furanone mono(trifluoroacetate) salt Example 85A 4-(7-Cyano-2-methoxy- I -naphthalenvlldihydro-2(3H)-furanone Example 62A (269 mg, 1.00 mmol) and pyridinium chlorochromate (360 mg, 1.67 mmol) in 10 methylene chloride (15 mL) were stirred at room temperature for 24 h, filtered through Celite@ and concentrated. The residue was chromatographed on silica gel with 20% ethyl acetate/ hexanes to provide 170 mg of the title compound. MS (DCI/NH 3 ) m/e 285 (M+NH 4 )+. 15 Example 85B 4-{7-(Aminoiminomethyl)-2-methoxy-I -naphthalenvlldihydro-2(3H)-furanone mono(trifluoroacetate) salt The title compound was prepared from Example 85A and the procedure of Example 40D. 20 1 H NMR (300 MHz, DMSO-d 6 ) 6 2.96-2.75 (m, 2H), 3.96 (s, 3H), 4.33 (m, 1H), 4.66 (t, I H), 8.85 (m, I H), 7.68 (dd, IH), 7.73 (d, IH), 8.08 (d, IH), 8.12 (d, IH), 8.67 (s, IH), 9.14 (s, 2H), 9.43 (s, 2H); MS (DCI/NH 3 ) m/e 285 (M+H)+. Anal. calcd for C 16
H
16
N
2 0 3 1.lTFA: C, 53.72; H, 4.24; N, 6.91. Found: C, 53.75; H, 4.26; 25 N, 6.94. Example 86 7- Methoxy-8-(1 -acetyl- 1 H-pyrazolvl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 30 Example 86A 7-Methoxy-8-(I-acetyl- I H-pyrazolvll-2-naphthalenecarbonitrile A solution of Example 53F (90 mg, 0.361 mmol) in THF (2 mL) was treated with a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (0.866 mL, 0.433 mmol), stirred for 5 -113 SUBSTITUTF R PT (g l 1 C I WO 99/05096 PCTIUS98/15386 min, treated with acetyl chloride (38 mL, 0.542 mmol), stirred for 10 min and concentrated. The crude product was chromatographed on silica gel with 25% ethyl acetate/hexanes to yield 67 mg of the title compound. MS MS (DCI/NH 3 ) m/e 309 (M+NH 4 )+. Example 86B 7-Methoxy-8-(I-acetvl- 1 H-pvrazolvl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared with Example 86A and the procedure of Example it 40D. I H NMR (300 MHz, DMSO-d 6 ) 6 3.89 (s, 3H), 7.59 (d, lH), 7.92 (s, 2H), 8.06 (d, lH), 8.12 (d, 1H), 8.28 (s, 1H), 8.94 (s, 2H), 9.34 (s, 2H); MS (DCI/NH 3 ) m/e 309 (M+H)+. Anal. calcd for C 17
H
16
N
4 0-1.9TFA: C, 47.59; H, 3.44; N, 10.67. Found: C, 54.03: H, 15 4.06; N, 13.26. Example 87 7-Methoxy-8-1 I -(methylsulfonyl)- I H- 4 -pyrazolvl1-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 20 Example 87A 7-Methoxy-8-F 1 -(methylsulfonyl)- I H- 4 -pyrazolyll-2-naphthalenecarbonitrile The title compound was prepared from Example 53F (190 mg, 0.762 mmol), methanesulfonyl chloride (0.088 mL, 1.14 mmol) and the procedure of Example 86A to 25 provide 122 mg of the title compound. MS (DCI/NH 3 ) m/e 345 (M+NH 4 )+. Example 87B 7-Methoxy-8-F 1 -(methylsulfonyl)- I H- 4 -pyrazolyll-2-naphthalenecarboximidamide 30 mono(trifluoroacetate) salt The title compound was prepared from Example 87A and the procedure of Example 40D. -114 SUBSTITUTE SHEET (RULE 2RI WO 99/05096 PCTIUS98/15386 1 H NMR (300 MHz, DMSO-d 6 ) 6 2.75 (s, 3H), 3.98 (s, 3H) 7.64 (dd, 1H), 7.78 (d, 1H), 8.15 (s, 1H), 8.18 (s, 1H), 8.21 (s, IH), 8.24 (s, 1H), 8.62 (s, 1H), 8.97 (s, 2H), 9.40 (s, 2H); MS (DCI/NH 3 ) m/e 345 (M+H)+. 5 Anal. calcd for C 16
H
1 6
N
4 0 3 S4l.4TFA: C, 44.75; H, 3.47; N, 11.09. Found: C, 44.59; H, 3.86; N, 11.38. Example 88 (E)-4-[2-(6-Aminoininomethvl-2-naphthalenyllethenyl l benzamide mono(tifluoroacetate) salt 10 Example 88A
(E)-
4
-[
2 -(6-Cyano-2-naphthalenvl)ethenvllbenzamide Example 85A (160 mg, 0.54 mmol) in thionyl chloride (4 ml) was refluxed for 0.5 h, cooled to 0 'C, treated with concentrated aqueous ammonia until gas evolution ceased, diluted 15 with ethyl acetate, heated to dissolve residual solids, washed with water, dried (MgSO 4 ) and concentrated to provide 100 mg of the title compound as an orange solid. MS (DCI/NH 3 ) rn/e 316 (M+NH 4 )+. Example 88B 20 (E)-4-[2-(6-Aminoininomethyl-2-naphthalenvl)ethenyl lbenzamide mono(trifluoroacetate) salt The title compound was prepared with Example 88A and the procedure of Example I B. 1 H NMR (300 MHz, DMSO-d 6 ) 6 7.34 (br, IH), 7.51 (d, I H), 7.56 (d, 2H), 7.73 (d, 2H), 7.82 (m, 2H), 7.90 (d, 2H), 7.96 (br, 1H), 8.09 (q, 3H), 8.17 (s, 1H), 8.43 (s, 1H), 9.01 (s, 2H), 9.40 (s, 2H): 25 MS (DCI/NH 3 ) m/e 316 (M+H)+. Anal. calcd for C 20
H
17
N
3 0-1.l TFA: C, 60.09; H, 4.11; N, 9.44. Found: C, 60.22; H, 4.13; N, 8.79. 30 Example 89 6
-[
2
-(
4 -Aminophenvl)ethoxyl-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 89A 6- [ 2
-(
4 -Aminophenyl)ethoxyl-2-naphthalenecarbonitrile -115 SUBSTITUTE SHEET (RUJLF 29m WO 99/05096 PCT/US98/15386 A solution of Example 4A, (300 mg), Cs2CO 3 (1.2 g ), 4-aminophenethylbromide (470 mg) and tetrabutylammonium iodide (10 mg) in DMF (5 ml) was stirred for 18 h at room temperature, diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated aq NaHCO 3 and brine, dried (Na2SO4) and concentrated to provide 200 5 mg of the title compound as a dark brown oil. MS (DCI/NH 3 ) m/e 306 (M+N1 4 )+. Example 89B 6-[2-(4-Aminophenyl)ethoxyl-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compund was prepared with Example 89A according to the procedure of Example 5B. 1 H NMR (300 MHz, DMSO-d 6 ) 6 3.15 (t, 2H), 3.6 (bs, 3H), 4.35 (t, 2H), 6.93 (d, 2H), 7.24 (d, 2H) 7.38 (dd, IH), 7.55 (d, 1H), 7.78 (dd, IH), 7.98 (dd, lH), 8.21 (d, 11H), 8.4 (d, IH), 9.21 (bs, 2H), 9.39 (bs, 2H); 15 MS m/e 306 (M+H)+. Anal. calcd for Ci 9
H
19
N
3 0-2TFA: C, 51.79; H, 3.97; N, 7.88; Found: C, 50.99; H, 4.68; N, 7.59. Example 90 20 Methyl [ 3 -methoxy- 6 -(aminoiminomethyl)-4-naphthalenvllcarbamate mono(trifluoroacetate) salt Example 90A 7 -Methoxy-2-trifluoromethanesulfonyloxv naphthalene A solution of 7-methoxy-2-naphthol (3.24 g, 18 mmole) in DMF (20 mL) and 25 methylene chloride (20 mL) was treated with N-phenyl trifluoromethanesulfonimide (6.6 g, 18 mmole) and triethylamine (5.2 mL, 37 mmole), stirred 20 h at room temperature, diluted with
CH
2 Cl 2 (100 mL) , washed sequentially with distilled water, 20 % KOH and brine, dried (MgSO4) and concentrated to provide the title compound as a clear oil. MS (DCI/NH 3 ): m/e 272 (M + NH 4 )+. 30 Example 90B 7 -Methoxy-2-naphthalenecarbonitrile Example 90A (12 mmole), zinc cyanide (12 mmole), Pd(OAc) 2 (0.3 mmole) and triphenylphosphine (1.2 mmole) in DMF (40 mL) was heated for 6 h at 85 'C, diluted with -116 SUBSTITUTE SHEET (RULF 9Am WO 99/05096 PCT/US98/15386 ethyl acetate (200 mL), washed with saturated NaHCO 3 , brine, dried (MgSO4) and concentrated to a dark oily residue. Purification of the residue on silica gel with 1:1 hexane: methylene chloride then CH 2 Cl 2 provided 1.8 g of the title compound as a white solid. MS (DCI/NH 3 ) m/e 201 (M + NH4)+. 5 Example 90C 7 -Methoxv-8-nitro-2-naphthalenecarbonitrile Example 90B (3 g, 16.4 mmole) in acetic anhydride (30 mL) at 0 'C was treated with fuming HNO 3 (1.2 mL), and the resulting thick slurry was diluted with water (20 mL), stirred 10 20 min then filtered and dried in vacuo to provide 3.69 g of the title compound as a yellow solid. MS (DCI/NH 3 ) m/e 246 (M+NH 4 )+. Example 90D 15 7-Methoxy-8-amino-2-naphthonitrile Example 90 C (3.69 g, 16.1 mmole) and 10% Pd/C (0.4 g) in ethyl acetate (100 mL) was stirred under a hydrogen atmosphere for 2 h at room temperature, filtered and concentrated to provide 3 g of the title compound as a yellow solid. MS (DCI/NH 3 ) m/e 217 (M+NH 4 )+. 20 Example 90E Methyl [ 3 -methoxy-6-cvano-4-naphthalenvllcarbamate Example 90D (81 mg, 0.41 mmol) in dioxane (7 mL) and 10% NaOH (15 mL) was treated with methyl chloroformate (112 mg. 0.98 mmol), stirred for 2 h, diluted with ethyl 25 acetate, washed with water, dried (MgSO4) and concentrated to provide 105 mg of the title compound. MS (DCI/NH 3 ) m/e 274 (M+NH3)+. Example 90F Methyl [ 3 -methoxy- 6 -(aminoiminomethyl)-4-naphthalenvllcarbamate mono(trifluoroacetate) salt 30 The title compound was prepared from Example 90E according to the procedure of Example 40D. 1 H-NMR (300 MHz, DMSO-d 6 ) 6 9.48 (s, 2H), 8.99 (s, 2H), 8.93 (br, 1H), 8.34 (s, IH), 8.12 (d, IH), 8.04 (d, IH), 7.72 (d, IH), 7.65 (dd, IH), 3.95 (s, 3H); MS (DCI/NH 3 ) m/e 274 (M+H)+; -117 SUBSTITUTE SHEET (RULF 1 WO 99/05096 PCT/US98/15386 Anal. calcd for C 14
H
15
N
3 0 3 .l.8TFA: C. 44.07; H, 3.53; N, 8.74. Found: C, 44.14; H, 3.20; N, 8.53. Example 91 5 7-Methoxy-8-[2-pyrimidinvl(amino)1-2-naphthalenecarboximidamide bis(trifluoroacetate) salt Example 91A 7-Methoxy-8-[2-pyrimidinvl(amino)1-2-naphthalenecarbonitile A solution of Example 90D (230 mg, 1.2 mmole), 2-chloropyrimidine (280 mg, 2 10 mmole), sodium-tert-butoxide (120 mg, 1.2 mmole), Pd(dba) 3 -CHCl 3 and dppf in toluene (5 mL) was heated in a sealed tube for 18 h at 100 'C, diluted with ethyl acetate (100 mL), washed with brine, dried (MgSO4) and concentrated to provide 100 mg of a brown oil. MS (DCI/NH 3 ) m/e 294 (M+NH 4 )+. 15 Example 91 B 7- Methoxv-8-[ 2-vrimidinvl(amino)]-2-naphth alenecarboximidamide bis(trifluoroacetate) salt The title compound was prepared in a manner analogous to that of Example 40D. IH NMR (300 MHz, DMSO-d6) 8 9.43 (s, 2H), 9.11 (s, 2H), 8.46 (s, lH), 8.16 (br, 3H), 8.15 (d, lH), 8.04 (d, IH), 7.82 (dd, IH), 7.75 (d, lH), 7.54 (s, lH) 7.50 (d, lH), 4.08 (d, 2H); 20 MS (DCI/NH 3 ) m/e 294 (M+H)+. Anal. calcd for C 16
H
1 5N50-3.8TFA: C, 39.01; H, 2.61; N,9.64; Found: C, 39.01; H, 3.06; N, 9.63. Example 92 6-( aminoiminomethyl)-N-[ 4 -(hydroxymethyl)phenvll-2-naphthalenecarboxamide, 25 mono(trifluoroacetate)(salt) Example 92A 4-amino-ben zyloxy-rert-butvldimethylsilvl ether A solution of 4-aminobenzyl alcohol (1 g, 8.1 mmol) in DMF (20 mL) was treated with 30 imidazole (0.54 g, 8.1 mmol) and tert-butyl dimethylsilyl chloride (1.22 g, 8.12 mmol), stirred overnight at room temperature, diluted with ethyl acetate (100 mL), washed with 1 N H 3
PO
4 , saturated NaHCO 3 and 10% NaCl, dried (Na 2
SO
4 ) and concentrated to an oil which was purified on silica gel with 3: 1 hexanes: ethyl acetate to provide 0.5 g of a clear oil. MS m/z 238 (M+H)+. -118 SUBSTITUTE SHEFT 'RmaI F: WO 99/05096 PCT/US98/15386 Example 92B Example 92A (0.3, 1.1 mmol) and 6-carboxy-2-naphthonitrile, Example 8E (0.2 g, I mmol) were processed as described in Example 95C to provide 100 mg of the desired 5 compound. MS m/z 434 (M+NH 4 )+. Example 92C A solution of Example 92B in I M tetrabutyl ammonium fluoride THF solution (2 mL) 10 was stirred for Ihour at room temperature, quenched with 10% NH 4 Cl solution (50 mL) and diluted with ethyl acetate (100 mL). The layers were separated, and the organic layer was washed with 10% NaCl, dried (MgSO4) and concentrated to provide a light brown oil which was triturated with methylene chloride and filtered to provide 0.1 g of the desired compound as a white solid. 15 MS m/z 320 (M+NH 4 )+. Example 92D 6 -(aminoiminomethyl)-N-f 4 -(hydroxymethyl)phenvll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) 20 Example 92C (0. 1 g, 0.33 mmol) was processed and purified according to the procedure in Example 95D to provide 15 mg of the desired compound. MS m/z 320 (M+H)+; 1 H NMR 300 MHz, (DMSO-d 6 ): 6 10.45 (s, 1H), 9.45 (bs, 4H), 8.75 (s, lH), 8.59 (s, 1H), 8.32 (d, I H), 8.22 (d, I H), 8.18 (dd, I H), 7.92 (dd, I H), 7.85 (d, 2H), 7.45 (d, 2H), 4.20 25 (s, 2H); Anal. calc'd for Ci 9
H
17
N
3 02 TFA: C, 58.20; H, 4.19: N, 9.70. Found: C. 57.80; H, 3.91; N, 9.35. Example 93 30 6-(4-aminophenvl)- 2 -naphthalenecarboximidamide, bis(trifluoroacetate) salt Example 93A 6-cyano-2-naphthalene boronic acid (0.3 g, 1.64 mmol), 4-iodoaniline (0.36 g, 1.64 mmol), Palladium[1, '-Bis (diphenylphosphino)-ferrocene] dichloride (0.13 g, 0.164 mmol) -119 SUBSTITUTE SHEET (RULF 1m WO 99/05096 PCT/US98/15386 and CsF (0.75 g, 4.92 mmol) are mixed together in DMF (8 mL) heated 20 hours. at 80 'C. The mixture is diluted with ethyl acetate (100 mL) washed with I N H 3
PO
4 , saturated NaHCO3, 10% NaCl, dried over anhydrous sodium sulfate. The drying agent filtered, solvent removed under vacuum leaving a brown solid. The solid is purified on silica gel eluting with 3: 5 1 hexanes: ethyl acetate. The fractions corresponding to the desired compound are concentrated under vacuum leaving a yellow solid. 0.2 g, 75%. MS (M+NH 4 +): 262. Example 93B 10 6-( 4 -aminophenvl)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt The desired compound is obtained from the material prepared in Example 93A (0.1 g, 0.41 mmol) using the procedure described in Example 94D Yield: 35 mg, 53% MS (M+H)+ 262; 15 1 H NMR 300 MHz, (DMSO-d 6 ): 6 9.45 (bs, 2H), 9.35 (bs, 2H), 8.45 (d, IH), 8.22 (s, I H), 8.15 (d, l H), 8.10 (d, IH), 7.99 (dd, I H), 7.79 (dd, I H), 7.65 (d, 2H), 6.95 (d, 2H), 4.80 (bs, 3H); Anal. calc'd: C 2 1
H
17
N
3 0 6
F
6 : C, 51.54, H, 3.50, N, 8.59, Found: C, 51.95, H, 3.84. 20 Example 95 methyl 2-[4- [[ 6 -(aminoiminomethyl)-2-naphthalenyllcarbonyllaminolphenoxyl acetate, mono(trifluoroacetate) salt Example 95A 25 4-Acetamidophenol (5 g, 33 mmol) is dissolved in THF (100 mL) treated with Cesium carbonate (10.25 g, 33 mmol) and Methyl bromoacetate (3.4 mL, 36 mmol) and stirred 24 hours at room temperature. The reaction mixture is diluted with water (100 mL) and concentrated under vacuum. The residue is dissolved in ethyl acetate (100 mL) washed with I N H 3
PO
4 (20 mL), saturated NaHCO 3 (20 mL), 10% NaCl (20 mL) and dried over anhydrous 30 Na2SO4. The drying agent is filtered and the solvent removed under vacuum leaving the desired compound as a white solid, 6.8 g, (92%). MS (M+NH 4 +): 241. Example 95B -120 SUBSTITUTP cUFimT IRI It =m WO 99/05096 PCT/US98/15386 The material obtained in Example 95A is treated with 2 N HCl (75 mL) and refluxed for 3 hours. The clear mixture is cooled to room temperature then concentrated under vacuum to an off white solid as the desired compound. 6 g, 92%. MS (M+NH 4 +): 198. 5 Example 95C 6-carboxy-2-naphthonitrile (0.1 g, .51 mmol) is dissolved in DMF (5 mL) cooled in an ice bath to 5 'C. To the homogeneous mixture is added Diisopropylethylamine (0.18 mL, 1.05 mmol) and 0- (7-Azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate 10 (HATU). The resultant slurry is stirred at 5 'C 45 minutes. To this slurry is added the material obtained in Example 95B (0.12 g, .56 mmol) and the mixture is stirred at room temperature overnight. The next day, the reaction mixture is diluted with ethyl acetate (100 mL) washed with I N H 3
PO
4 (20 mL), saturated NaHCO 3 (20 mL). 10% NaCl, dried over anhydrous Na2SO4 filtered and solvent removed under vacuum yielding the desired compound as a brown 15 solid. 0.28 g, 65%. MS (M+NH 4 )+: 378. Example 95D methyl 2-[ 4
-[[[
6 -(aminoiminomethyl)-2-naphthalenvllcarbonyllaminolphenoxylacetate, 20 mono(trifluoroacetate) salt The material obtained in Example 95C (0.28 g, .78 mmol) is dissolved in methanol saturated with HCl (g) (30 mL) stirred 18 hours at room temperature. The solvent removed under vacuum and the resultant yellow solid is treated with 2 M NH3/methanol (20 mL). This solution is refluxed 6 hours, cooled, solvent removed under vacuum and the resulting brown 25 solid is purified by reverse phase HPLC. The desired compound is obtained from lyophilization. 19.3 mg, 20%7c. MS (M+H)+: 378 1 HNMR 300 MHz, (DMSO-d 6 ): 6 10.45 (s, l H), 9.45 (bs, 4H), 8.65 (d, IH), 8.59 (s, IH), 8.15 (d, IH), 8.10 (d, IH), 8.08 (d, IH), 7.92 (d, 1H), 7.75 (d, 2H), 6.98 (d, 2H), 4.80 (s, 30 2H), 3.75 (s, 3H), Anal. calc'd: C 23
H
2 1
N
3 0 6
F
3 : C, 56.10, H, 4.3, N, 8.53, Found: C, 55.80, H, 3.93, N, 8.33. Example 96
(E)-
6
-[
2
-[(
3 -hydroxymethyl)phenyllethenvil-2-naphthalenecarboximidamide, -121 SUBSTITUTF qWFFT IRI 1 = WO 99/05096 PCT/US98/15386 mono(trifluoroacetate)(salt) Example 96A The above was prepared from 3-iodobenzyl alcohol using the procedure in Example 5 41A. MS (DCI/NH 3 ) m/z (M+NH 3 )+ 303. Example 96B (E)-6-[ 2
-[(
3 -hydroxymethyl)phenvllethenvll-2-naphthalenecarboximidanide, 10 mono(trifluoroacetate)(salt) The above was prepared from Example 96A using method from Example 40D. MS (DCI/NH 3 ) m/z (M+H)+ 303; IH-NMR (300 MHz, DMSO-d 6 ) 6 9.18 (br, 4H), 8.45 (s, 1H), 8.17 (s, 1H), 8.13-8.04 (m, 3H), 7.81 (dd, 1H), 7.64 (s. lH), 7.57 (d, 2H), 7.51 (d, lH) 7.39 (t, lH), 7.28 (d, 1H), 15 5.27 (t, 1H), 4.55 (d, 2H); Anal. calc'd for C 22
H
19
N
2 0 3
F
3 3/10 TFA: C, 60.64; H, 4.35; N, 6.28. Found: C, 60.53; H, 4.87; N, 6.57. Example 97 20 6-(2-phenyl- I -cyclopropyl )-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) Example 97A Copper (1) chloride (43 mg, 0.4 mmol), powdered zinc (26 mg, 0.4 mmol) were suspended in 1 mL dioxane for 18 hours. The product from Example 41 B (60 mg, 0.2 mmol) 25 was added and stirred and heated at 95 'C for 20 hours. The reaction mixture was concentrated on silica gel and purified by silica gel chromatography to give the desired compound. MS (DCI/NH 3 ) m/z (M+NH 3 )+ 287. Example 97B 30 6-(2-phenvl- I -cyclopropyl)-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) The above was prepared from Example I using method from Example lB. MS (DCI/NH 3 ) m/z (M+H)+ 287; -122 SUBSTITUTF FPT MI It I IM WO 99/05096 PCT/US98/15386 IH-NMR (300 MHz, DMSO-d 6 ) 6 9.41 (s, 2H), 9.16 (s, 2H), 8.46 (s, 1H), 7.83 (d, 2H), 7.62 (s, IH), 7.58 (dd, IH), 7.34 (dd, IH), 7.35-7.29 (m, 3H), 7.25-7.17 (m, 2H) 2.38-2.28 (n, 2H), 1.61 (t, 2H); Anal. calc'd for C 22
H
19
N
2 0 2
F
3 1/10 TFA: C, 65.00; H, 4.70; N, 6.84. Found: C, 65.22; H, 5 5.23; N, 5.10. Example 98 (E)-6-[2-[4-(aminomethylphenvllethenyll-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) 10 Example 98A The desired compound was prepared using ethene under 500 atm pressure in a manner; Analagous to that of Example 41A. MS (DCI/NH 3 ) m/z (M+NH 3 )+ 197. 15 Example 98B 4- (Aminomethyl)-iodobenzene hydrochloride (1 g, 3.7 mmol) and Boc anhydride (1.22 g, 5.6 mmol) were mixed with 10% NaOH (15 mL), ethyl acetate (20 mL) and stirred 2 hours. The organic layer was washed with 5% sodium bicarbonate (2x, 10 mL), dried (magnesium 20 sulfate), and concentrated to give 1.22 g of desired compound. MS (DCI/NH 3 ) m/z (M+NH 3 )+ 351. Example 98C The desired compound was prepared using the product from Example s 98A and 98B in 25 a manner analagous to that of Example 41 A. MS (DCI/NH 3 ) m/z (M+NH 3 )+ 402. Example 98D (E)-6-[2-[4-(aminomethyl)phenyllethenyll-2-naphthalenecarboximidamide, 30 bis(trifluoroacetate)(salt) The above product was prepared in a manner analogous to that of Example 40D with the addition of trifluoroacetic acid in methylene chloride to remove the Boc group. MS (DCI/NH 3 ) m/z (M+H)+ 302; -123 SUBSTITUTF qWFF-T (mi ll WO 99/05096 PCT/US98/15386 1 H-NMR (300 MHz, DMSO-d 6 ) 6 9.43 (s, 2H), 9.11 (s, 2H), 8.46 (s, 1H), 8.16 (br, 3H), 8.15 (d, 1H), 8.04 (d, 1H), 7.82 (dd, 1H), 7.75 (d, IH), 7.54 (s, 1H) 7.50 (d, 1H), 4.08 (d, 2H); Anal. calc'd for C 24
H
2 1
N
3 0 4
F
6 2/5 TFA: C, 50.46; H, 3.63; N, 6.99. Found: C; 50.37; H, 5 3.86; N, 7.05. Example 99 methyl [7-(aminoiminomethyl)-2-methoxy- 1 -naphthalenyl)carbamate, mono (tifluoroacetate)(salt) 10 The desired compound was prepared using material prepared as described in Example 90D and utilizing the procedures described in Example 91A and Example 40D. MS (DCI/NH 3 ) m/z (M+H)+ 306; IH-NMR (300 MHz, DMSO-d 6 ) 6 9.33 (s, 2H), 8.98 (s, 2H), 8.63 (s, lH), 7.99 (d, IH), 7.60 (dd, lH), 7.58 (s, lH), 7.54 (d, lH), 7.35-7.20 (m, 5H), 4.52 (s, 2H); 15 Anal. calc'd for C 2 1
H
20
N
3 0 3
F
3 13/5 TFA: C, 44.03; H, 3.19: N, 5.89. Found: C; 43.97; H, 3.55; N, 6.10. Example 100 7-methoxy-8-( 2 -pvrimidinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) 20 The desired compound was prepared using material prepared as described in Example 90D and utilizing the procedures described in Example 91A and Example 40D. MS (DCI/NH 3 ) m/z (M+H)+ 322; IH-NMR (300 MHz, DMSO-d 6 ) 6 9.35 (s, 2H), 8.90 (s, 2H), 8.34 (s, lH), 8.11 (d, lH), 7.90 (d, IH), 7.72 (d, IH), 7.60 (dd, IH), 7.47 (s, 2H), 6.70 (d, 2H) 6.49 (d, 2H), 3.88 (s, 25 3H), 3.64 (s, 3H); Anal. calc'd for C2 1
H
20
N
3 0 4
F
3 1/10 TFA: C, 56.90; H, 4.53; N, 9.38. Found: C; 56.88: H, 4.41; N, 9.43. Example 101 30 7 -methoxy-8-[(phenylmethyl)aninol-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) Example 101A -124 SUBSTITUTE m;F-r mIn M 11 WO 99/05096 PCT/US98/15386 4-Bromostyrene (4.8 g, 26.2 mmol) was dissolved in 100 mL THF and cooled to -78 'C. Butyl lithium (2.5 M in hexanes, 28.8 mmol) was added dropwise and stirred 5 minutes. Iodine in THF was added dropwise until an orange/red color persisted. Concentrated aqueous ammonium chloride (20 mL) was added and the reaction was warmed to room temperature, 5 diluted with ether, washed with 10% Na2S 2 05 solution (1x, 50 mL), and brine (lx, 50 mL), dried (magnesium sulfate), and concentrated to give the desired compound. MS (DCI/NH 3 ) m/z 122. Example 101B 10 The product from 104A (2.35 g, 10.2 mmol), 1.6 mL 60%, N-methylmorphiline-N oxide/water solution, 3.75 mL acetone, 0.1 mL water were stirred I hour. 20 mL Osmium tetroxide/tert-butanol solution (0.02 mmol/mL) was added and stirred at 0 'C for 20 hours. The reaction was concentrated on silica gel and purified by silica gel chromatography to give the desired compound. 15 MS (DCI/NH 3 ) m/z (M+NH-l 3 )+ 282. Example 101C The desired compound from Example 104B is coupled using Method 41A. MS (DCI/NH 3 ) m/z (M+NH 3 )+ 333. 20 Example 101D 7-methoxy-8-[(phenvlmethyllamino] -2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) The above was prepared from Example 104C using method described in Example 40D. 25 MS (DCI/NH 3 ) m/z (M+H)+ 333; ' H-NMR (300 MHz, DMSO-d 6 ) 6 9.42 (s, 2H), 9.12 (s, 2H), 8.45 (s, I H), 8.15-8.05 (m, 4H), 7.81 (dd, 1H), 7.63 (d, 2H), 7.48 (d, 2H), 7.39 (d, 2H), 4.56 (t, 1H), 3.45 (d, 2H); Anal. calc'd for C 23
H
2 1
N
2 0 4
F
3 2/5 TFA: C, 58.19; H, 4.39; N, 5.71. Found: C, 58.17; H, 4.41; N, 5.87. 30 Example 102 7 -methoxy-8-(phenvlamino)-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) Example 102A -125 SUBSTmT T cunny- rot: it c c WO 99/05096 PCT/US98/15386 Tert-butylcarbamate (3.62 g, 15.7 mmol) was dissolved in 63 mL propanol. 118 mL NaOH/water solution (0.4 N), tert-butyl hypochlorite (5.5 mL, 47.8 mmol), and
(DHQD)
2 PHAL (612 mg, 0.61 mmol) in 50 mL propanol were added and stirred 10 minutes. The product from Example 2 (3.62 g, 15.7 mmol), and K20sO 4 -2 water (211 mg, 0.63 mmol) 5 were added and stirred 24 hours. The reaction was concentrated and recrystallized from ethanol/hexanes to give the desired compound. MS (DCI/NH 3 ) m/z (M+NH 3 )+ 381. Example 102B 10 The above was prepared from Example 102 using the method described in Example 41A. MS (DCI/NH 3 ) m/z (M+H)+ 415. Example 102C 15 7-methoxy-8-(phenylamino)-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) The above was prepared from Example 102B using the method described in Example 94D. MS (DCI/NH 3 ) m/z (M+H)+ 264; I H-NMR (300 MHz, DMSO-d 6 ) 6 9.42 (s, 2H), 9.07 (s, 2H), 8.45 (s, 1H), 8.33 (br, 3H), 20 8.16-8.03 (in, 4H) 7.75 (d, 2H), 7.56 (s, 2H), 7.49 (d, 2H), 5.49 (br 1 h), 4.28 (br 1H), 3.62 (m, 2H); Anal. calc'd for C 2 5
H
23
N
3 0 5
F
6 -5 TFA: C, 37.30; H, 2.51; N, 3.74. Found: C; 37.06; H, 3.12; N, 4.42. 25 Example 103 7-methoxy-8-[(4-nethoxyphenyllaminol-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) Example 103A 30 4-Bromobenzaldehyde (600 mg, 3.24 mmol), 16.2 mL dimethylamine in THF (32.4 mmol), and sodium triacetoxyborohydride (1.24 g, 5.8 mmol) were suspended in dichloroethane (10 mL). The reaction mixture was concentrated, diluted with water acidified to pH=2 and extracted with ether (3x, 20 mL). The aqueous solution was basified with -126 SUBSTITuTF qWF;-T mI DI m WO 99/05096 PCT/US98/15386 NaOH/water to pH=12 and extracted with methylene chloride (3x, 30 mL, acidified with HCI/methanol and concentrated to give the desired compund. MS (DCI/NH3) m/z (M)+ 214. 5 Example 103B The above was prepared from Example 107A using method from Example 41A. MS (DCI/NH 3 ) m/z (M+H)+ 313. Example 103C 10 7-methoxy-8-[( 4 -methoxyphenvblaminol-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) The above was prepared from Example 103 using method from Example 40D. MS (DCI/NH 3 ) m/z (M+H)+ 294; IH-NMR (300 MHz, DMSO-d 6 ) 6 9.43 (s, 2H), 9.11 (s, 2H), 8.46 (s, IH), 8.18-8.06 (m, 15 4H), 7.84 (d, 4H), 7.60 (s, 2H), 7.56 (s, 1H), 4.53 (s, 2H), 3.05 (s, 6H); Anal. calc'd for C 26
H
25
N
3 0 4
F
6 7/5 TFA: C, 48.46; H, 3.73; N, 5.91. Found: C, 48.36; H, 4.25; N, 6.19. Example 104 20 (E)-6-[2-[4-(1, 2-dihdyroxvethyl)phenvll ethenvll -2-naphth alenecarboximidamide, mono(trifluoroacetate)(salt) Example 104A The above was prepared from 4-bromobenzyl alcohol and the compound prepared in 25 Example 98A using the method from Example 41A. MS (DCI/NH 3 ) m/z (M+NH 3 )+ 303. Example 104B (E)-6-[2-[4-(1, 2-dihdyroxvethyl)phenvllethenvll-2-naphthalenecarboximidamide, 30 mono(trifluoroacetate)(salt) The above was prepared from Example 104A using method from Example 40D. MS (DCI/NH 3 ) m/z (M+H)+ 303; IH-NMR (300 MHz, DMSO-d 6 ) 6 9.00 (br, 4H), 8.44 (s, 1H), 8.15-8.01 (m, 4H), 7.81 (dd, 1H), 7.64 (d, 2H), 7.48 (d, lH), 7.36 (d, 2H), 5.21 (br, 1H) 4.53 (s, 2H); -127 SUBSTITTrrF CF:r rnI I 1M WO 99/05096 PCT/US98/15386 Anal. calc'd for C 22
H
19
N
2 0 3
F
3 4/5 TFA: C, 55.84; H, 3.93; N, 5.52. Found: C, 55.60; H, 3.93; N, 6.41. Example 105 5 (El-6-F2-[4-(] R-amino-2-hydroxvethyl)phenvllethenyll-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) Example 105A Using the procedure described for Example 121 A, and substituting N-BOC-p 10 iodophenylalanine (BACHEM Bioscience Inc.) for 4-iodoaniline, the desired compound was obtained. MS (DCI/NH 3 ) m/z 458 (M+NH 4 )+; IH NMR (300 MHz, CDCl 3 ) 6 1.35 (s, 9H), 2.90 (t, 1H), 3.09 (dd, 1H), 4.15 (m, lH), 7.20 (d, 1H), 7.36 (d, 2H), 7.56 (d, 2H), 7.78 (d, lH). 7.85 (d, IH), 8.12 (d, 1H), 8.17 (d, IH), 15 8.32 (s, 1 H), 8.62 (s, 1H). Example 105B Using the product obtained in Example 105A and the procedure described in Example 40D the desired compound was obtained. 20 MS (ESI) m/z 458 (M+H)+; I H NMR (300 MHz, DMSO) 6 1.35 (s, 9H), 2.90 (dd, IH), 3.10 (dd, 1H), 4.13 (m, 1H), 7.10 (d, I H), 7.36 (d, 2H), 7.55 (d, 2H), 7.78 (dd, 1H), 7.85 (dd, IH), 8.13 (d, I H), 8.19 (d, 1H), 8.30 (s, 1H), 8.50 (s, 1H), 9.22 (s, 2H), 9.42 (s, 2H). 25 Example 105C (E)-6-12-[4-(1 R-amino-2-hydroxvethyl)phenvl lethenvil-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) Using the product obtained in Example 105B and the procedure described for Example 124D, the desired compound was obtained. 30 MS (ESI) m/z 358 (M+H)+; 1 H NMR (300 MHz, DMSO) 6 3.02 (mi, 1H), 3.19 (dd, lH), 3.63 (t, lH), 7.39 (d, 2H), 7.58 (d, 2H), 7.76 (d, lH), 7.88 (d, 1H), 8.15 (d, 1H), 8.19 (d, IH), 8.30 (s, IH), 8.51 (s, IH), 9.41 (s, 2H), 9.80 (s, 2H); -128 SUBSTITI m: cW -r r01m C= WO 99/05096 PCT/US98/15386 Anal. calc'd for C 24
H
20
F
3
N
3
O
4
-H
2 0: C, 58.90; H, 4.53; N, 8.59. Found: C, 58.75; H, 4.22; N, 8.28. Example 106 5 7 -methoxy- 8
-(
2 -pyrimidinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) Example 106A Sodium borohydride (0.22 g, 5.8 mmol) was added to a suspension of (4 bromobenzoyl)methanol (2.5 g, 11.6 mmol, Maybridge Chem. Co.) and 25 mL abs. ethanol. 10 The reaction mixture was stirred at reflux for 1 hour. After cooling to room temperature, the ethanol was evaporated under vacuum, and water was added to the residue. The mixture was extracted with CH 2 C1 2 . The extracts were washed with saturated aqueous sodium chloride, dried over MgSO4, filtered, and evaporated under vacuum to afford the desired compound. MS (DCI/NH 3 ) m/z 234/236 (M+NH 4 )+; 15 1 H NMR (300 MHz, CDCl 3 ) 6 2.10 (t, I H), 2.62 (d, I H), 3.63 (m,I 1H), 3.78 (m, I H), 4.81 (in, lH), 7.25 (d, 2H), 7.50 (d, 2H). Example 106B Using the product obtained in Example 106A and the procdure described in Example A 20 226218-A, the desired compound was obtained. MS (DCI/NH 3 ) m/z 331 (M+NH 4 )+; I H NMR (300 MHz, CDCl3) d3.45 (t, I H), 4.59 (q, 1H), 4.76 (t, I H), 5.36 (d, I H), 7.42 (d, 2H), 7.59 (d, 2H), 7.78 (dd, lH), 7.85 (dd, IH), 8.10 (d, 1H), 8.15 (d, IH), 8.30 (s, IH), 8.61 (s, I H). 25 Example 106C 7 -inethoxy-8-( 2 -pyrimidinvlamino)-2-naphthalenecarboximidamide bis(trifluoroacetate)(salt) Using the product obtained in Example 106B, and the procedure described in Example 40D, the desired compound was obtained. 30 MS (ESI) m/z 331 (M+H)+; IH NMR (300 MHz, DMSO) 6 3.45 (t, 1H), 4.59 (q, 1H), 4.78 (t, lH), 5.38 (d, lH), 7.42 (d, 2H), 7.59 (d, 2H), 7.78 (dd, 1H), 7.84 (dd, 1H), 8.12 (d, lH), 8.18 (d, 1H), 8.31 (s, 1H), 8.50 (s, lH), 9.20 (s, 2H), 9.43 (s, 2H); -129 SUBSTITUTE SHFFT (Rill : 9Am WO 99/05096 PCT/US98/15386 Anal. calc'd for C 23
H
19
F
3
N
2 0 4
-H
2 0: C, 59.74; H, 4.58; N, 6.06. Found: C, 59.95; H, 4.17; N, 6.13. Example 107 5 (E)-6-[2-[[ 4 -(dimethylamino)methyllphenyllethenyll-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) Example 107A Using the procedure described for Example 121A, and substituting 3 10 benzyloxybromobenzene (Chem. Ber.124 (1), 163, 1991) for 4-iodoaniline, the desired compound was obtained. MS (DCI/NH 3 ) m/z 377 (M+NH4)+; IH NMR (300 MHz, CDCl 3 ) 6 5.11 (s, 2H), 7.02 (d, IH), 7.20 (m, 2H), 7.29 (d, I H), 7.31 (d, IH), 7.42 (m. 3H), 7.60-7.75 (m, 3H), 7.89 (t. 2H), 8.08 (s, IH), 8.21 (s, 1H). 15 Example 107B (E)-6-12-[[ 4 -(dimethvlamino)methyllphenyllethenyll-2-naphthalenecarboxiinidamide, bis(trifluoroacetate)(salt) Using the product obtained in Example 108B, and the procedure described in Example 20 40D, the desired compound was obtained. MS (ESI) m/z 377 (M+H)+; IH NMR (300 MHz, DMSO) 6 5.18 (S, 2H), 7.12 (dd, 1H), 7.22 (d, lH), 7.28 (m, IH), 7.40 (t, 3H), 7.45 (t, 3H), 7.79 (dd, 1H), 7.85 (dd, 1H), 8.16 (d, lH), 8.20 (d, 1H), 8.35 (s, 1 H), 8.50 (s, 1 H), 9. 30 (s, 1 H); 25 Anal. calc'd for C 2 8
H
2 1
F
3
N
2 0 3 0.25 H 2 0: C, 67.94; H, 4.38; N, 5.66. Found: C, 67.80; H, 4.48; N, 5.43. Example 108
(E)-
6
-[
2
-[
4 -(hydroxymethyl)phenvllethenyll-2-naphthalenecarboximidamide, 30 mono(trifl uoroacetate)(salt) Using the product obtained in Example 108A and the procedure described in Example 94D the desired compound was obtained. MS (ESI) m/z 287 (M+H)+; -130 SUBSTITUTF qw4FFT Rm : om WO 99/05096 PCT/US98/15386 1 H NMR (300 MHz, DMSO) 6 6.89 (m, 1 H), 6.98 (t, 1H), 7.03 (d, 1H), 7.29 (t, I H), 7.78 (dd, 1H), 7.88 (dd, 1H), 8.13 (d, 1H), 8.17 (d, IH), 8.32 (s, 1H), 8.50 (s, lH), 9.40 (s, 5H); Anal. calc'd for C 2 1
H
15
F
3
N
2 0 3 0.5 H 2 0: C, 61.62; H, 3.94; N, 6.84. Found: C, 61.29; H, 5 3.81; N, 6.59. Example 109 4-[r6-(aminoiminomethyl)-2-naphthalenyllethynyll-L-phenylalanine, mono(trifluoroacetate)(salt) 10 Example 109A To a solution of the product from Example 8D (2.13 g, 10.08 mmol) and LiBH 4 (121 mg, 5.55 mmol) in THF (5 mL) was added toluene (2 mL), and the THF was boiled off using a short-path distillation apparatus over several hours. The reaction was then heated at 70'C for 2 15 hours, cooled, quenched with I M HCl, and extracted with 2x ethyl acetate. The extracts were washed with water and brine, dried over Na 2
SO
4 , and condensed. The crude product was chromatographed on SiO 2 using 50% ethyl acetate/hexanes as eluent, to yield 1.12 g (61%) of the desired compound. MS (DCI (NH 3 )) m/z 201 (M+NH 4 )+; 20 1 H NMR (300 MHz, CDCl 3 ) 6 8.22 (s, 1H), 7.90 (m, 3H), 7.61 (m, 2H), 4.92 (d, 2H), 1.84 (t, 1H). Example 109B To a solution of the product from Example 109A (2.12 g, 11.57 mmol) and LiBr (1.11 25 g, 12.73 mmol) in DMF (100 mL) was added PBr 3 (1.21 mL, 12.73 mmol) at 0 0 C, and the reaction was warmed to room temperature, and stirred for I hours. The reaction was then quenched with pH 7 buffer, and extracted with 3x diethyl ether/hexanes. The extracts were washed with 2x water and 2x brine, dried over Na 2
SO
4 , and condensed, to yield 2.72 g (96%) of the desired compound. 30 MS (DCI (NH 3 )) m/z 185 (M+NH4-Br)+; I H NMR (300 MHz, CDCl 3 ) 6 8.22 (s, 1H), 7.92 (s, 1H), 7.90 (s, 2H), 7.62 (dd, 2H), 4.64 (s, 2H). Example 109C -131 SUBSTITUTE SHEFT (RUiE 9r1 WO 99/05096 PCTIUS98/15386 To a solution of NaH (60% in mineral oil, 44 mg, 1. 1 mmol) in DMF (5 mL) was added 4-ethylphenol (122 mg, 1.0 mmol), and the reaction was stirred at room temperature for 20 minutes. The product from Example 109B (270 mg, 1.1 mmol) was then added, and the reaction was stirred for 10 minutes. The crude reaction mixture was chromatographed on SiO 2 5 using hexanes as eluent, to yield 220 mg (77%) of the desired compound. MS (DCI (NH 3 )) m/z 305 (M+NH 4 )+; I H NMR (300 MHz, CDCl 3 ) 6 8.22 (s, I H), 7.95 (s, IH), 7.93 (s, 1H), 7.91 (s, IH), 7.66 (dd, 1H), 7.61 (dd, 1H), 7.15 (d, 2H), 6.94 (d, 2H), 5.22 (d, 2H), 2.60 (q, 2H), 1.21 (t, 3H). 10 Example 109D 4-[[ 6 -(aminoiminomethyl)-2-naphthalenyllethynvll-L-phenylalanine, mono(trifluoroacetate)(salt) The desired compound was prepared from Example 109C and the procedure of Example 15 55D. MS (DCI/NH 3 ) m/z 305 (M+H)+; I H NMR (300 MHz, DMSO-d 6 ) 6 1.15 (t, 3H), 2.14 (s, 3H), 2.56 (q, 2H), 5.30 (s, 2H), 6.98 (d, 2H), 7.14 (d, 2H), 7.74 (dd, 1H), 7.82 (dd, 1H), 8.15 (m, 3H), 8.48 (s, 1H), 9.01 (br s, 2H), 9.62 (br s, 2H); 20 Anal. calc'd for C 20
H
20
N
2 0-1.4 CH 4
SO
3 : C, 58.56; H, 5.88; N, 6.38. Found: C, 58.55; H, 5.56; N, 6.39. Example I11 6-(3-formvlphenyl)-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) 25 Example lI l A The product from Example 28B (334 mg, 1. 11 mmol), palladium acetate (25 mg, 0.11 mmol), dppf (123 mg, 0.22 mmol) were dissolved in degassed DMF (5 mL) and stirred at room temperature for 1/2 hour. Cesium carbonate (902 mg, 2.8 mmol) and 2 30 formylphenylboronic acid (251 mg, 1.27 mmol) were added and stirred under nitrogen at 80 C for I hour, poured into pH 7 buffer, extrated with diethyl ether (3x, 20 mL), and dried. The desired compound was purified by chromotography eluting with 10% ethyl acetate/ hexanes. MS (DCI/NH 3 ) m/z (M+NH 3 )+ 275. -132 SUBSTITUTE SHEET (RULF 9m WO 99/05096 PCTIUS98/15386 Example 11 B 6-(3-formvlphenyl)-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) The above product was prepared in a manner analogous to that of Example lB. MS (DCI/NH 3 ) m/z (M+H)+ 274; 5 IH-NMR (300 MHz, DMSO-d 6 ) 6 10.16 (s, IH), 9.47 (s, 2H), 9.10 (s, 2H), 8.54 (s, lH), 8.52 (s, 1H), 8.41 (s, 1H), 8.28-8.23 (m, 3H), 8.12 (dd, IH), 8.00 (dd, 1H), 7.87 (dd, IH), 7.80 (t, IH); Anal. calc'd for C 20
H
15
N
2
O
3
F
3 2/5 TFA: C, 59.28; H, 3.70; N, 6.34. Found: C; 59.36; H, 3.89; N, 7.21. 10 Example 112 (E)-6-[2-(1, 2, 3, 4-tetrahydro-6-isoquinolinvylethenvll-2-naphthalenecarboximidamide, bis(trifl uoroacetate)(salt) 15 Example I 12A The above was prepared from Example 127 using method described in Example 41 A. MS (DCI/NH 3 ) m/z (M+H)+411. Example 112B 20 (E)-6-[2-(1, 2, 3, 4 -tetrahydro- 6 -isoquinolinvl)ethenyll-2-naphthalenecarboximidamide, bis(trifl uoroacetate)(salt) The desired compound was prepared by the method described in Example 40D. MS (DCI/NH 3 ) m/z (M+H)+ 328; IH-NMR (300 MHz, DMSO-d 6 ) 6 9.36 (s, 2H), 9.25 (s, 2H), 9.10 (d, 2H), 8.41 (s, lH), 25 7.99 (t, 2H), 7.89 (d, lH), 7.78 (d, lH), 7.71 (dd, 1H), 7.56 (m, 4H). 7.43 (s, lH), 3.11 (br, 2H) 2.16 (br 2H), 1.78 (br, 2H); Anal. calc'd for C 26
H
23
N
3 0 4
F
6 3/5 TFA: C, 52.31; H, 3.81; N, 6.72. Found: C, 52.13; H, 4.42; N, 7.23. 30 Example 113 (E)- 6-[2-[3-(2-hydroxvethylnphenvllethenvyl-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) Example 11 3A -133 SUBSTITUTE qW;F-T 1r 9111 WO 99/05096 PCT/US98/15386 The above was prepared from 2-bromo-3 (hydroxyethyl)alcohol and the compound prepared in Example 98A using method described in Example 41A. MS (DCI/NH 3 ) m/z (M+NH 3 )+ 317. 5 Example I 13B (E)- 6-[2-[3-(2-hydroxvethyl)phenvllethenvll -2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) The above was prepared from Example 113A using method described in Example 40D. MS (DCIINH 3 ) m/z (M+H)+ 317; 10 IH-NMR (300 MHz, DMSO-d 6 ) 6 8.9 (br, 4H), 8.46 (s, lH), 8.17 (s, 1H), 8.13-8.03 (m, 3H), 7.82 (dd, lH), 7.54 (s, 2H), 7.49 (s, 2H), 7.33 (t, 1H) 7.18 (d, 1H), 4.71 (t, 1H), 3.66 (m, 2H), 2.78 (t, 2H); Anal. calc'd for C 23
H
2 1
N
2 0 3
F
3 3/10 TFA: C, 61.41; H, 4.66; N, 6.09. Found: C, 64.18; H, 4.92; N, 6.51. 15 Example 114 6-(aminoiminomethyl)- 4 -(3-furanyl)-N-[4-(trifluoromethvl)phenvll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) 20 Example 114A The product from Example 152B (100 mg, 0.36 mmol), 4- (trifluoromethyl)aniline (86 mg, 0.53 mmol), and DMAP (5 mg, 0.04 mmol) were dissolved in THF (5 mL) and stirred for 24 hours. The reaction mixture was concentrated on silica gel and purified by chromotography (Biotage Flash 40) using ethyl acetate/hexanes. 25 MS (ESI) m/z (M+H)+ 406. Example 114B 6-(aminoiminomethyl - 4
-(
3 -furanyl)-N-r4-(trifluoromethyl)phenvll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) 30 The above was prepared from Example 1 14A using method described in Example lB. MS (CI) m/z (M+H)+ 424; -134 SUBSTITUTE SHEET (RULE 2rn WO 99/05096 PCTIUS98/15386 1 H-NMR (300 MHz, DMSO-d 6 ) 6 10.91 (s, 1H), 9.51 (s, 2H), 9.11 (s, 2H), 8.69 (s, 1H), 8.62 (s, 1H), 8.43-8.35 (m, 2H), 8.18 (d, 1H), 8.06 (d, 2H), 7.98 (t, 1H), 7.92 (dd, 1H), 7.78 (dd, 2H) 7.14 (m, IH); Anal. calc'd for C 25
H
17
N
3 0 4
F
6 1/10 TFA: C, 55.37; H, 3.15; N, 7.70. Found: C, 55.44; H, 5 3.15; N, 7.31. Example 115 6-(aminoiminomethyl)-4-(3-furanyl)-N-( 4 -pyridinyl)-2-naphthalenecarboxamide, dihydrochloride 10 Example 115A The above product was prepared in the manner of Example I 14A. MS (ESI) m/z (M+H)+ 340. 15 Example 115B 6 -(aminoiminomethyl)-4-(3-furanyl)-N-(4-pvridinyl)-2-naphthalenecarboxamide, dihydrochloride The above was prepared from Example 1 I5A using method described in Example IB. MS (AP/CI) m/z (M+H)+ 357; 20 1 H-NMR (300 MHz, DMSO-d 6 ) 6 12.43 (s, 1H), 9.69 (s, 2H), 9.40 (s, 2H), 8.94 (s, 1H), 8.81 (d, 2H), 8.65 (s, 1H), 8.58-8.56 (m, 2H), 8.49 (s, 1H), 8.42 (d, 1H), 8.30 (m, IH) 7.97-7.95 (m, 2H), 7.27 (s, 1H); Anal. calc'd for C 2 1 HIgN 4 02Cl 2 37/10 HC: C, 44.65 H, 3.88 N, 9.92. Found: C, 44.72; H, 3.70; N, 9.5 1. Example 116 6-(aminoiminomethvl)-4-(3-furanyl)-N-(I H-pyrazol-3-yl)-2-naphthalenecarboxamide, dihydrochloride 30 Example 116A The above product was prepared in the manner of Example 11 4A. MS (ES I) m/z (M+H)+ 329. Example 1 16B -135 SUBSTITUTE SHEET (RULE 261 WO 99/05096 PCT/US98/15386 6-(aminoiminomethyl)-4-(3-furanyl)-N-(I H-pyrazol-3-vl)-2-naphthalenecarboxamide, dihydrochloride The above was prepared from Example 116A using method described in Example lB. MS (CI) m/z (M-H)+ 344; 5 1 H-NMR (300 MHz, DMSO-d 6 ) 6 11.16 (s, 1H), 9.52 (s, 2H), 9.10 (s, 2H), 8.69 (s, 1H), 8.61 (s, 1H), 8.35 (m, 2H), 8.24 (s, lH), 7.96-7.88 (m. 3H), 7.69 (m, 1H), 7.15 (s, lH) 6.69 (m, IH); Anal. calc'd for Cj 9
H
17
N
5 0 2 Cl 2 9/10 HCl: C, 50.63; H, 4.00; N, 15.54. Found: C, 51.05; H, 4.62; N, 14.26. 10 Example 117 6-(aminoiminomethyl)-4-(3-furanyll-N-(3-pyridinvl)-2-naphthalenecarboxamide, dihydrochloride 15 Example 1 17A The above product was prepared in the manner of Example 11 4A. MS (ES I) m/z (M+H)* 340. Example 117B 20 6-(aminoiminomethyl)-4-(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride The above was prepared from Example 1 17B using method described in Example lB. MS (CI) m/z (M+H)+ 357; I H-NMR (300 MHz, DMSO-d 6 ) 6 10.90 (s, 1H), 9.59 (s, 2H), 9.26 (s, 2H), 9.03 (s, 2H), 25 8.74 (s, 1H). 8.63 (s, 1H), 8.42-8.26 (in, 3H), 8.22 (s, 1H), 7.97-7.91 (m, 2H), 7.47-7.43 (n, 2H), 7.17 (s, IH); Anal. calc'd for C 2 1
H
18
N
4 0 2 C1 2 55/10 HCl: C, 40.00 H, 3.76 N, 8.89. Found: C, 40.09; H, 3.78; N, 8.44. 30 Example 118 6-(aminoiminomethyl)-N-(2, 3-dihydro- I H-inden-5-yl)-2-naphthalenecarboxamide, mono (trifluoroacetate)(salt) Example I 18A -136 SUBSTITUTE SHEET (RULE 261 WO 99/05096 PCT/US98/15386 To a solution of the compound prepared in Example 8E (303 mg, 1.4 mmol) in THF (30 mL) and propylene oxide (15 mL) was added two drops of Et 3 N followed by the 5 aminoindene (300 mg, 2.2 mmol). The reaction was stirred at room temperature overnight. The solvent was evaporated and the product was purified via crystallization from ether to yield 226 5 mg (56%) of the product as white solid. Mass spectrum (CI+), 313 (M+1)*. Example 118B 6-(aminoiminomethyl)-N-(2. 3-dihydro-1H-inden-5-vl)-2-naphthalenecarboxamide. mono(trifluoroacetate) (salt) 10 The compound prepared in Example 118A (205 mg, 0.66 mmol) in THF (20 mL) at room temperature, was added butyl lithium (1 mL, 1 mmol) followed by chlorotrimethyl silane (180 tL, 1.5 mmol). After 10 minutes the mixture was charged with additional butyl lithium (3 mL, 3 mmol). The reaction was stirred at room temperature, overnight. The reaction mixture was added a solution of 4 N HCl in dioxane stirred for an hour then added water and 15 evaporated. The product was purified by MPLC RP C 18 with methanol-water and 0.1% TFA as eluent chromatography. The yield of the product as TFA salt with 0.25% water as white solid 51 mg (17%). MS (ESI+) 330 (M+1)*; 1 H NMR (DMSO-d6) 10.45 (s, lH), 9.51 (s, 2H), 9.21 (s, 2H), 8.66 (s, lH), 8.55 (s, 1H), 20 8.32 (d, J=8.5Hz, IH), 8.20 (Abq, J=9.OHz, 2H), 7.90 (dd, JI=9.OHz, J2=1.5Hz, lH), 7.73 (s, 1H), 7.53 (dd, Ji=8.OHz, J 2 =1.5Hz, IH), 7.22 (d, J=8.lHz, 1H), 2.91-2.82 (m, 4H), 2.04 (quintet, J=7.3Hz, 2H): Anal. calc'd for C 21
H
19
N
3 0-TFA-0.25 H 2 0 C: 61.67; H, 4.61; N, 9.38. Found: C: 61.63; H, 4.43; N, 9.25. 25 Example 119 methyl 5-[7-[(aminoiminomethyl)-2-naphthalenvlloxy lpentanoate mono(trifluoroacetate) (salt) Example 119A 30 7 -hydroxy-2-cvanonaphthalene 7-methoxy-2-cyanonaphthalene (2.79 g, 5.23 mmol) and tetrabutylammonium iodide (17 mg, 0.157 mmol) were combined in a mixture of benzene (35 mL) and cyclohexanes (17.5 mL). The resulting solution was added to a rapidly stirring, cooled (ice/water) suspension of aluminum triiodide (6.21 g, 15.23 mmol) in a mixture of benzene (35 mL) and cyclohexanes -137 SUBSTITUTE SHEET (RULE 261 WO 99/05096 PCT/US98/15386 (17.5 mL) under an inert atmosphere. After the addition, the resulting suspension was heated at reflux for 2.5 hours. The heating was removed and after cooling to near room temperature, the reaction mixture was cooled in an ice bath and quenched by the addition of water (100 mL). The resulting mixture was further diluted with 2 M aqueous sodium thiosulfate solution (50 mL) and 5 extracted with ethyl acetate (3 X 80 mL). The combined organic layers were dried and evaporated. The resulting solid was dissolved in a minimum of hot ethyl acetate, diluted hot with hexanes to the cloud point and placed in a refrigerator for 2 hours. The desired compound was collected by filtration, (1.99 g, 77%). MS (DCI (NH 3 )) m/z 187 (M+NH 4 )+. 10 Example I 19B The resulting product from Example 1 19A was treated with methyl 5-bromovalerate in an analogous manner as described in Example 1 19A. MS (DCI (NH 3 )) m/z 301 (M+NH 4 )+. 15 Example I19C methyl 5-17-[(aminoiminomethyl)-2-naphthalenylloxylpentanoate, mono(trifluoroacetate) (salt) The resulting product from Example I 19B (380 mg, 1.3412 mmol) was treated in an analogous manner as described in Example 94D to yield the desired compound (369 mg, 73%). 20 MS (DCI (NH 3 )) m/z 301 (M+H)+; I H NMR (300 MHz, DMSO-d6) 6 1.785 (m, 4H), 2.425 (t, 2H), 3.600 (s, 3H), 4.150 (t, 2H), 7.380 (dd, 1H), 7.460 (d, 1H), 7.640 (dd, lH), 7.980 (d, lH), 8.070 (d, 1H), 8.322 (d, I H), 9.230 (v br s, 3H); Anal. calc'd for C1 7
H
20
N
2 03-C 2
HO
2
F
3 : C, 55.07; H, 5.11; N, 6.76. Found: C, 54.96; H, 25 5.22; N., 6.66. Example 120 (E)-3-[7-(aminoiminomethyl)-2-methoxy- I -naphthalenyl)-2-propenamide mono(trifluoroacetate)(salt) 30 Example 120A The product obtained from Example 53B and acrylaiide were subjected to the conditions described in Example 41A to provide the desired compound. MS (DCI/NH 3 ) m/z 253 (M+H)+. -138 SUBSTITUTE SHEET (Rul = 9m WO 99/05096 PCT/US98/15386 Example 120B (E)-3-[7-(aminoiminomethyl)-2-methoxy- I -naphthalenvl)-2-propenamide, mono(trifluoroacetate)(salt) 5 The product obtained from Example 120A was subjected to the conditions described in Example 94D to provide the desired compound. MS (DCI/NH 3 ) m/z 270 (M+H)+; 1 H NMR (300 MHz, DMSO) 8 4.02 (s, 3H), 6.90 (d, 1H), 7.22 (s, 1H), 7.62-7.70 (m, 2H), 7.74 (d, IH), 8.02 (d, IH), 8.11 (d, IH), 8.15 (d, 1H), 8.58 (s, IH), 9.18 (s, 2H), 9.50 (s, 10 2H); Anal. calc'd for C17H16F3N304-H 2 0: C, 50.88; H, 4.52; N, 10.47. Found: C, 50.89; H, 4.32; N, 10.43. Example 121 6 -f( 4 -aminophenyl)ethynyll-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) 15 Example 121A A mixture of the product obtained in Example 63B (130 mg, 0.73 mmol), 4-iodoaniline (173 mg, 0.79 mol), dichlorobis (triphenylphosphine)palladium (II) (25 mg, 0.0325 mmol), copper (I) iodide (2.7 mg, 0.0 186 mmol), DMF (0.65 mL), and triethylamine (1.95 mL) was 20 degassed with N 2 and was stirred at 750-80' for 1.5 hour. The mixture was cooled to room temperature, diluted with CH 2
CI
2 , washed with water, dried (MgSO4), filtered, and evaporated under vacuum to afford an oil which was purified by flash chromatography, eluting with 3: 1 hexanes: ethyl acetate to afford the desired compound. MS (DCI/NH 3 ) m/z 269 (M+H)+. 25 Example 121B 6
-(
4 -aminophenyl)ethynyll-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) Using the product obtained in Example 121A and the procedure described in Example 40D, the desired compound was obtained. 30 MS (DCI/NH 3 ) m/z 286 (M+H)+; 1 H NMR (300 MHz, DMSO) 6 6.80 (d, 2H), 7.29 (d, 2H), 7.70 (dd, 1H), 7.85 (dd, 1H), 8.09 (d, 1H), 8.14 (d, IH), 8.20 (s, IH), 8.45 (s, I H), 9.09 (s, 2H), 9.42 (s, 2H); Anal. calc'd for C 23
H
17
F
6
N
3 04-0.25 H 2 0: C, 53.34; H, 3.41; N, 8.11. Found: C, 53.45; H, 3.70; N, 7.76. -139 SUBSTITUTE SHEET (RULE 9m WO 99/05096 PCT/US98/15386 Example 122 1, 1-dimethylethyl [2-[ 3 -[[6-(aminoiminomethyl)-2-naphathalenvllethynyll-6 methoxvphenyll ethylIcarbamate, mono(trifluoroacetate)(salt) Example 122A Using 5-bromo-2-methoxyphenethylamine hydrobromide (Transworld), and the procedure described in Example 63C, the desired compound was obtained. MS (DCI/NH 3 ) m/z 330 (M+H)+. 10 Example 122B Using the procedure described for Example 121 A, and substituting the product obtained in Example 122A for 4-iodoaniline, the desired compound was obtained. MS (ESI) m/z 427 (M+H)+. 15 Example 122C 1, 1-dimethylethyl [ 2
-[
3
-[[
6 -(aminoiminomethyll-2-naphathalenvllethynyll-6 methoxyphenyllethyllcarbamate, mono(trifluoroacetate)(salt) Using the product obtained in Example A-226638-B and the procedure described in 20 Example 40-D, the desired compound was obtained. MS (DCI/NH 3 ) m/z 444 (M+H)+; I H NMR (300 MHz, DMSO) 6 1.38 (s, 9H), 2.70 (t, 2H), 3.15 (q, 2H), 3.85 (s, 3H), 6.89 (t, I H), 7.04 (d, IH), 7.37 (d, IH), 7.49 (dd, I H), 7.75 (dd, IH), 7.85 (dd, 1H), 8.11 (d, 1 H), 8.16 (d, l H), 8.30 (s, IH), 8.48 (s, 1H), 9.07 (s, 2H), 9.42 (s, 2H) ; 25 Anal. calc'd for C 29
H
30
F
3
N
3 0 5 -0.25 H 2 0: C, 61.97; H, 5.47; N, 7.48. Found: C, 61.81; H, 5.14; N, 7.21. Example 123 1. 1-dimethylethyl [[4-[r 6 -(aminoiminomethvl)-2-naphathalenvllethynvllphenvllmethyll 30 carbamate. mono(trifluoroacetate)(salt) Example 123A Using 4-bromobenzylamine, and the procedure described in Example 63C, the desired compound was obtained. -140 SUBSTITUTE SHEET (Ril P m WO 99/05096 PCT/US98/15386 MS (DCI/NH 3 ) m/z 303 (M+NH 4 )+. Example 123B Using the procedure described for Example 121A, and substituting the product obtained 5 in Example 123 for 4-iodoaniline, the desired compound was obtained. MS (DCI/NH 3 ) m/z 400 (M+NH 4 )+. Example 123C 1, 1-dimethylethyl 1[ 4
-[[
6 -(aminoiminomethyl)-2-naphathalenvllethynyllVhenvllmethyll 10 carbamate, mono(trifluoroacetate)(salt) Using the product obtained in Example 123B and the procedure described in Example 40D, the desired compound was obtained. MS (DCI/NH 3 ) m/z 400 (M+H)+; 1 H NMR (300 MHz, DMSO) 6 1.40 (s, 9H), 4.18 (d, 2H), 7.34 (d, 2H), 7.45 (t, 1H), 7.58 15 (d, 2H), 7.78 (dd, 1H), 7.86 (dd, IH), 8.15 (d, IH), 8.19 (d, 1H), 8.31 (s, IH), 8.50 (s, I H), 9.10-9.42 (s, 4H) Anal. calc'd for C 27
H
26
F
3
N
3 0 4 : C, 63.15; H, 5.10; N, 8.18. Found: C, 62.95; H, 4.97; N, 8.09. 20 Example 124 6
-[[
4 -(aminomethylphenyllethvn.ll-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) Trifluoroacetic acid (0.73 mL) was added dropwise to a suspension of the product obtained in Example 123C (80 mg, 0.2 mmol) and 1.5 rnL CH 2 Cl 2 . The reaction mixture was 25 stirred for 0.25 hour at room temperature, then was evaporated to dryness under vacuum. Toluene was added and evaporated under vacuum several times to afford a tan solid which was purified by reverse phase chromatography, eluting with methanol / 0.1% aqueous TFA to afford the desired compound. MS (APCI) m/z 300 (M+H)+; 30 1 H NMR (300 MHz, DMSO) 6 4.10 (s, 2H), 7.55 (d, 2H), 7.70 (d, 2H), 7.79 (dd, 1 H), 7.89 (dd, 11H), 8.16 (d, 1H), 8.19 (d, 11H), 8.20 (s, 2H), 8.36 (s, IH), 8.53 (S, 1H), 9.20 (s, 2H), 9.44 (s, 2H); Anal. calc'd for C 24
H
19
F
6
N
3 0 4 : C, 54.66; H, 3.63; N, 7.97. Found: C, 54.42; H, 3.57; N, 7.76. -141 SUBSTITUTE SHEET (RULE 9M WO 99/05096 PCTIUS98/15386 Example 125 6
-[[
3
-(
2 -aminoethyl)-4-methoxyphenvllethynvll-2-naphthalenecarboxidan-imide, bis(trifl uoroacetate)(salt) 5 Using the product obtained in Example 122C and the procedure described for Example 124, the desired compound was obtained. MS (ESI) m/z 344 (M+H)+; 1 H NMR (300 MHz, DMSO) 6 2.90 (t, 2H), 3.06 (t, 2H), 3.88 (s, 3H), 7.11 (d, 1H), 7.44 1( (d, 1H), 7.57 (dd, 1H), 7.75 (dd, 1H), 7.82 (s, 2H), 7.88 (dd, IH), 8.12 (d, 1H), 8.17 (d, 1H), 8.28 (s, 1H), 8.50 (s, 1H), 9.20 (s, 2H), 9.45 (s, 2H); Anal. calc'd for C 26
H
23
F
6
N
3 05-0.5 H 2 0: C, 53.80; H, 4.17; N, 7.24. Found: C, 53.89; H, 4.31; N, 6.83. 15 Example 126 6-[[4-(hydroxvmethyl)phenvllethynvll-2-naphthalenecarboximidamide, mono(trifl uoroacetate)(salt) Example 126A 20 Using the procedure described for Example 121A, and substituting 4-bromobenzyl alcohol for 4-iodoaniline, the desired compound was obtained. MS (DCI/NH 3 ) m/z 301 (M+NH 4 )+. Example 126B 25 6-[[4-(hydroxvmethyl )phenvllethvnylIl-2-naphthalenecarboximidamide, mono(trifl uoroacetate)(salt) Using the product obtained in Example 126A and the procedure described in Example 94B the desired compound was obtained. MS (ESI) m/z 301 (M+H)+; 30 1 H NMR (300 MHz, DMSO) 6 4.58 (d, 2H), 5.32 (t, 1H), 7.41 (d, 2H), 7.59 (d, 1H), 7.79 (dd, 1H), 7.86 (dd, 1H), 8.12 (d, 1H), 8.18 (d, 1H), 8.32 (s, 1H), 8.50 (s, 1H), 9.14 (s, 2H), 9.46 (s, 2H); Anal. calc'd for C 22
H
17
F
3
N
2 03-0.5 H 2 0: C, 62.41; H, 4.29; N, 6.62. Found: C, 62.56; H, 4.13; N, 6.65. -142 SUBSTITUTE SHEFT (R111= 9r WO 99/05096 PCT/US98/15386 Example 127 6-[(1, 2, 3, 4 -tetrahydro- 6 -isoquinolinvlethynvll-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) 5 Example 127A A solution of boron tribromide (1.2 mL, 12.5 mmol) and 12.5 mL CH 2 Cl 2 was added dropwise to a -78' solution of 6 -methoxytetrahydroisoquinoline (1.0 g, 5.0 mole, Org. Synth., 67, 60, 1988) and 38 mL CH 2 Cl 2 . The reaction mixture was stirred for 1 hour at -78', 1 hour at 10 00, and 0.25 hour at room temperature. The reaction mixture was cooled to -78', and 20 mL methanol was added dropwise. The solution was stirred for 1 hour at room temperature. Solvent was evaporated under vacuum and the residue was dried under vacuum to afford the desired compound. MS (DCI) n/z 150 (M+H)+. 15 Example 127B The product obtained in Example 127A (1.15 g, 5.0 mmol) was subjected to the conditions described in Example 63C. A 2.1 g portion of this material was stirred at reflux for 1.5 hour with 60 mL methanol and 9 mL 10% aqueous NaOH. After cooling to room 20 temperature, methanol was evaporated under vacuum. Water was added and the solution was acidified with 6 N HCl. The mixture was extracted with CH 2 Cl 2 . The organic layer was washed with water, saturated aqueous sodium chloride, dried (MgSO4), filtered, and solvent evaporated under vacuum to afford the desired compound. MS (DCI/NH 3 ) m/z 267 (M+NH 4 )+. 25 Example 127C Using the product from Example 127B and the procedure described in Example 28B, the desired compound was obtained. MS (DCI/NH 3 ) m/z 399 (M+NH 4 )+. 30 Example 127D Using the procedure described for Example 121A, and substituting the product obtained in Example 127C for 4-iodoaniline, the desired compound was obtained. MS (DCI/NH 3 ) m/z 426 (M+NH 4 )+. -143 SUBSTITUTF swEFT II 1 P m WO 99/05096 PCT/US98/15386 Example 127E Using the product obtained in Example 127D and the procedure described in Example 40D, the desired compound was obtained. 5 MS (ESI) m/z 426 (M+H)+; 1 H NMR (300 MHz, DMSO) 5 1.45 (s, 9H), 2.82 (t, 2H), 3.59 (t, 2H), 4.58 (s, 2H), 7.29 (d, 1H), 7.42 (d, 2H), 7.76 (dd, 1H), 7.83 (dd, 1H), 8.15 (d, 1H), 8.19 (d, IH), 8.35 (s, lH), 8.51 (s, (1H), 9.20 (s, 2H), 9.45 (s, 2H). 1t) Example 127F 6-[(1, 2, 3, 4-tetrahydro-6-isoquinolinyl)ethynyll-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) Using the product obtained in Example 127E and the procedure described in Example 124D, the desired compound was obtained. 15 MS (ESI) m/z 326 (M+H)+; I H NMR (300 MHz, DMSO) 6 3.03 (t, 2H), 3.42 (t, 2H), 4.35 (s, 2H), 7.35 (d, 1H), 7.46 (d, 2H), 7.78 (dd, lH), 7.89 (dd, lH), 8.15 (d, lH), 8.19 (d, 1H), 8.35 (s, 1H), 8.52 (s, IH), 9.17 (s, 2H), 9.31 (s, 2H), 9.48 (s, 2H); Anal. calc'd for C 2 6
H
2 1
F
6
N
3 0 4 : C, 56.42; H, 3.82; N, 7.59. Found: C, 56.31; H, 3.81; N, 20 7.42. Example 129 5-[[6-(aminoiminomethyl)-2-naphthalenvlloxylpentanoic acid, mono(trifluoroacetate)(salt) 25 Example 129A The resulting product from Example 1 19A (250 mg, 1.477 mmol) was treated with methyl 5-bromovalerate in an analogous manner as described in Example I 19B to yield the desired compound (394 mg, 94%). MS (DCI (NH 3 )) m/z 301 (M+NH 4 )+. 30 Example 129B 5-[[ 6 -(aminoiminomethyl)-2-naphthalenvlloxylpentanoic acid. mono(trifluoroacetate)(salt) The resulting product from Example 129A (262 mg, 0.8723 mmol) was treated in an analogous manner as described in Example 94D to yield the ester amidine product. The product -144 SUBSTITUTE RWFFT mI It = M WO 99/05096 PCT/US98/15386 (140 mg, 0.542 mmol) was dissolved in methanol (11 mL). To this was added a solution of lithium hydroxide (68.2 mg, 1.626 mmol) in water (3 mL) and the resulting mixture was stirred at room temperature under an inert atmosphere for 18 hours. The reaction was evaporated and the residue purified by reverse phase chromatography to yield the desired compound (184 mg, 5 74%). MS (DCI (NH 3 )) m/z 287 (M+H) +; IH NMR (300 MHz, DMSO-d6) 6 1.711 (m, 2H), 1.817 (m, 2H), 2.320 (t, 2H), 4.144 (t, 2H), 7.377 (dd, lH), 7.472 (d, lH), 7.632 (dd, 1H), 7.980 (d, 1H), 8.081 (d, lH), 8.329 (s lH), 9.100 (br s, 2H), 9.390 (br s, 2H), 12.100 (br s, 1H); 10 Anal. calc'd for C 16 HigN 2
O
3 - (C 2
HO
2
F
3 ) 1.15-H 2 0 0.65: C, 51.22; H, 4.80; N, 6.53. Found: C, 51.30; H, 5.07; N, 6.12. Example 131 7-methoxy-8-(3-oxo- I -cyclopenten- I -vil)-2-naphthalenecarboximidamide, 15 mono(trifluoroacetate)(salt) Example 131 A The material prepared as described in Example 25A (0.5 g, 1.5 mmol) and the 3 tributylstannyl-2-cyclopentenone prepared as described by Labourde et al. Tet Letters 31, (13), 20 1837-1840 (1990) are coupled via Pd catalyst as described by the method of Stille et al. lACS 109, 5478-5486 (1987) yielding after flash chromatography with 3: 1 hexanes/ethyl acetate a white solid. 300 mg, 72%. MS (DCI/NH 3 ): 281 (M+NH 4 ). 25 Example 131B 7-methoxy-8-(3-oxo- I -cyclopenten- I -vi)- 2 -naphthalenecarboximidamide mono(trifluoroacetate)(salt) The material prepared above (130 mg, .4 mmol) is prepared according to the H2S/pyridine method described in Example 40D. The desired compound was obtained as an 30 off-white solid after reverse phase chromatography. 52 mg, 45%. MS (DCI/NH3): M+H+ 281 IH NMR (DMSO-d6): 9.45 (bs, 2H); 9.12 (bs, 2H), 8.25 -8.32 (m, 2H), 8.20 (dd, lH), 7.86 (d, IH), 7.75 (dd, IH), 6.42 (m, 1H), 4.05 (s, 3H), 3.15 (m, 2H), 2.75 (m, 2H) -145 SUBSTITUTF RWF:Fr fr l 1 WO 99/05096 PCT/US98/15386 Anal. calc'd for C 19
H
17
N
2 0 4
F
3 -1.75 TFA: C, 57.87; H, 4.35; N, 7.10. Found: C, 51.37; H, 4.21; N, 7.14. Example 132 5 6 -(aminoiminomethyl)-N-(4-methylphenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) Example 132A p-Toluidine (0.11 g, 1 mmol), and the cyano ester prepared in Example 8E (0.2 g, I 10 mmol) are coupled according to the procedure described in Example 8G, providing an off-white solid as the desired compound (0.16 g, 56%). MS (ESI +, -): 287 (M+) ; 285 (M-). Example 132B 15 6-(aminoiminomethyl)-N-(4-methylphenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The desired compound is prepared according to the procedure described in Example 6B and purified as described in Example lB, yielding a white solid (35 mg, 35%). MS (ESI +): 304 (M+) 20 IHNMR (DMSO-d6): 10.55 (s, IH); 9.45 (bs, 2H); 9.15 (bs, 2H); 8.65 (s, 1H); 8.58 (s, 1H); 8.32 (d, 11H), 8.20 (d, 1H), 8.19 (dd, 1H); 7.96 (dd, IH), 7.75 (d, 2H), 7.12 (d, 2H), 2.35 (s, 3H); Anal. calc'd for C 2 1 Hl 8
N
3 0 3
F
3 : C, 60.43; H, 4.35; N, 10.07 Found: C, 59.94; H, 4.06; N, 9.80. 25 Example 133 methyl 4-[[17-(aminoiminomethyl)-1-( 2 -pyrimidinvlamino)-2-naphthalenylloxylmethyll benzoate, mono(trifluoroacetate)(salt) 30 Example 133A The material described in Example 91 A is treated with All 3 according to the procedure described in Example 11 9A and alkylated with 4 -CarbomethoxyBenzylbromide according to the procedure described in Example 109B, yielding the desired compound as a white solid, 100 mg, 83%. -146 SUBSTITUTE SHFFT (RI 1 = 9m WO 99/05096 PCT/US98/15386 MS (ESI +, -): 411 (M+) ; 409 (M-). Example 133B methyl 4-[f[7-(aminoiminomethyl)-1-(2-pyrimidinylamino)-2-naphthalenylloxylmethyl 5 benzoate, mono(trifluoroacetate)(salt) The desired compound is prepared according to the procedure described in Example 40D and purified according to the procedure described in Example 11 9B, yielding a light yellow solid, (49 mg, 50%). MS (ESI +, -): 428 (M+); 426 (M-) 10 1 H NMR (DMSO-d6): 9.45 (bs, 2H); 9.15 (s, 1H); 8.97 (bs, 2H); 8.45 (dd, 1H); 8.38 (d, 1H); 8.15 (d, 1H), 8.09 (d, 1H), 7.95 (d, 2H); 7.76 (d, 1H), 7.68 (dd, 1H), 7.35 (d, 2H), 6.85 (d, 2H), 5.39 (s, 2H); 3.85 (s, 3H); Anal. calc'd for C 26
H
22
N
5 0 5
F
3 : C, 57.67; H, 4.10; N, 12.93 Found: C, 55.34: H, 3.88; N, 12.05. 15 Example 134 4-[[[7-(aminoiminomethyl)- 1-( 2 -pyrimidinylamino)-2-naphthalenvlloxylmethyl] benzoic acid, mono(trifluoroacetate)(salt) 20 The material prepared in Example 134 (40 mg) is dissolved in 1: 1 THF/water. To the clear solution is added LiOH-water (9 mg), the resulting clear solution is stirred 18 hours at room temperature. The reaction mixture is concentrated to a yellow solid. The solid is dissolved in distilled water. acidified to pH 2 with 3 N HCl and stirred 2 hours at room temperature. The desired compound is isolated by filtration, dried under vacuum as a yellow solid. Yield: 39 mg 25 (46%) MS (APCI): M+H+: 414 1 H NMR (DMSO-d6): 9.45 (bs, 2H); 9.15 (s, 1H); 8.97 (bs, 2H); 8.45 (dd, 1H); 8.38 (d, I H); 8.15 (d, IH), 8.09 (d, IH), 7.95 (d, 2H); 7.76 (d, I H), 7.68 (dd, 1H), 7.35 (d, 2H), 6.85 (d, 2H), 5.39 (s, 2H); 30 Anal. calc'd for C 2 5H 20 N50 5
F
3 Cl-3 H 2 0: C, 48.67; H, 4.25; N, 11.35 Found: C, 49.64; H, 4.44; N, 11.69. Example 135 -147 SUBSTITUTE SwEFT Mn11 : 9m WO 99/05096 PCT/US98/15386 1. 1-dimethylethyl [[ 4 -[[[6-(aminoiminomethyl)-2-naphathalenyllaminolcarbonl l phenvllmethyllcarbamate, mono(trifluoroacetate)(salt) Example 135A 5 The material prepared in Example 8B was added to cold (0 0 C) sulfuric acid (45 mL). Within 1 minutes at 0 0 C bubling started to form. Allowed to bubble at 0 0 C for 30 minutes than slowly warmed to room temperature. Left at room temperature for 20 minutes. then poured into ice and diluted with water (to approx. 500 mL). The suspension was placed in an ice bath and carefully added a solution of 50% aqueuos sodium hydroxide so that the temperature would not 10 exceed 35'C. The light yellow solid was filtered than washed with water till the wash became neutral to pH paper (7.0). The product was dried under vacuum. The product was purified on silica gel column using 20% ethyl acetate 80% hexanes as eluent to yield 3.3 g (67%) of light yellow solid. MS m/z 169 (M+1)*. 15 Example 135B A solution of Example 135A (135 mg, 0.8 mmol), 4-N-Boc-aminomethylbenzoic acid (404 mg, 1.6 mmol) and EDCI (307 mg, 1.6 mmol) in methylene chloride (25 mL), at room temperature, was added DMAP (3 mg) and stirred overnight. The reaction mixture was diluted 20 with methylene chloride (60 mL) then washed 2% aqueous hydrochloric acid (2x30 mL), water (20 mL), 0.5 M aqeuos sodium hydroxide (2x50 mL) and brine. The organic phase was dried over magnesium sulfate and evapoorated. The product was purified via on silica column usinga gradient of 25% to 60% ethyl acetate in hexanes as eluent. Yield 175 mg (54%) of white powder. 25 Example 135C 1, 1-dimethylethyl [[ 4
-[[[
6 -(aminoiminomethyl)-2-naphathalenvllaminoIcarbonyll phenvllmethyllcarbamate, mono(trifluoroacetate)(salt) The reaction was carried out in the same manner as described in Example 40D. Yield 30 110 mg (64%). MS m/z 408 (M+ 1)' 425 (M+l 8)* 1 H NMR: 3.30 (s, 9H), 4.22 (d, 2H, J=7.1 Hz), 7.42 (d, 2H, J=8.5Hz), 7.49 (t, 1H, J=7.lHz), 7.79 (dd, 1H, Jl=8.2Hz, J2=2.OHz), 7.95-8.00 (m, 3H), 8.09 (d, 2H, J=8.4Hz), 8.42 (s, IH), 8.63 (d, 1H, J=2.OHz), 9.18 (br s, 4H), 10.58 (s, 1H); -148 SUBSTITUT: R1pT mi 1:: P 0 WO 99/05096 PCT/US98/15386 Anal. calc'd for C2 6
H
27
F
3
N
4 0 5 : C, 58.55; H, 4.85: N, 10.41. Found: C, 58.64; H, 5.11; N, 10.52. Example 136 5 N-[ 6 -(aninoiminomethyl)-2-naphthalenvl)benzamide, mono(trifluoroacetate)(salt) The desired compound is prepared as described in Example 135: 1 H NMR (300 MHz, DMSO-d 6 ) 10.67 (s, 1H), 9.25 (br.s, 4H), 8.65 (d, J=1.5Hz, 1H), 8.43 (d, J=1.4Hz, IH), 8.10 (d, J=9.2Hz, 2H), 8.03-7.97 (m, 3H), 7.81-7.78 (m, IH), 7.65-7.55 10 (in, 3H). MS (ESI/NH 3 ) m/z 290 (M+H)+; Anal. calc'd for C18H15N 3 0-CF 3 COOH: C, 59.55; H, 4.00; F, 14.13; N, 10.42. Found: C, 50.47; H, 3.88; F, 14.42: N, 10.39. 15 Example 137 1, 1-dimethylethyl 1[ 4 -[[1 6 -(aminoiminomethyl)-2-naphathalenvllamino]carbonyl
I
cyclohexylllmethyllcarbamate, mono(trifl uoroacetate)(salt) Example 137A 20 To a solution of the 6 -Amino-2-naphthalenecarbonitrile prepared in Example 73 (100 mg, 0.6 mmol) in methylene chloride (35 mL) at room temperature, was added I -carboxy-4 (Boc-aminomethyl)cyclohexanes (280 mg, 1.1 mmol) followed by 1-ethyl-3- (3 dimethylaminopropyl)carbodiimide hydrochloride (EDAC, 225 mg, 1.2 mmol). After 5 minutes to the reaction mixture was added DMAP (20 mg, catalytic). The reaction was stirred at room 25 temperature for 72 hours. The reaction mixture was diluted 7: 3 ethyl acetate: hexanes then filtered through silica gel and washed with the same solvent mixture. The organic solvent was washed by aq. Acid (2% Hcl, 2x50 mL), water and aq. Base (10% NaOH, 50 mL). The solvent was dried over magnesium sulfate filtered and evaporated. Crystalization from ether/ hexanes afforded the product as white solid. Yield 166 mg (68%). 30 MS (DCI/NH 3 ) m/z 408 (M+H)+. Example 137B 1, 1 -dimethylethyl [[4-[[[ 6 -(aminoiminomethyl)-2-naphathalenvllaminolcarbonyll cyclohexylllmethyllcarbamate, mono(trifluoroacetate)(salt) -149 SUBSTITUTE S;FFT (mil1 P 0 WO 99/05096 PCT/US98/15386 A solution of the substrate (Example 137A) in Pyr: Et 3 N (10: 1, 20 mL) was bubbled
H
2 S for 5 minutes. Stirred at room temperature overnight. The reaction mixture was added ethyl acetate (100 mL) followed by 1% aq. KHSO4 (60 mL) and separated: washed organic layer with water (2x50 mL), sodium bicarb. And brine, dried over magnesium sulfate & 5 evaporated. To a suspension of the resulting solid in acetone (25 mL) and added Mel (1.0 mL). Stirred at 50'C for 2 hours, all dissolved. Evaporated solvent to a complete dryness and added methanol (30 mL) and ammonium acetate (150 mg). The mixture was stirred at room temperature overnight. Purification by Reverse Phase C 18 MPLC. After evaporation added toluene & evaporated (2x40 mL). The resulting oil was treated with methanol and ether and the 10 product precipitated as white solid (72 mg, 43%). MS (ESI/NH 3 ) m/z 425 (M+H)+; IH NMR (300 MHz, DMSO-d 6 ) 10.24 (s, 1H), 9.05 (br.s, 4H), 8.49 (s, 1H), 8.38 (d, J=1.7Hz, IH), 8.03-8.00 (m, 2H), 7.77-7.74 (m, 2H), 6.93-6.91 (m, lH), 2.83-2.79 (m, 2H), 2.40-2.30 (ml), 1.92-1.75 (m, 4H), 1.50-1.45 (m, IH), 1.39 (s, 9H), 0.96-0.91 (m, 15 4H); Anal. calc'd for C2 4
H
32
N
4 03-CF 3 COOH: C, 57.98; H, 6.18; N, 10.40. Found: C, 57.63; H, 6.24; N, 10.21. Example 138 20 N-[6-(aminoiminomethvll-2-naphthalenyll-N'-(4-aminophenyl)urea, bis(trifluoroacetate)(salt) Example 138A To a solution of the compound prepared in Example 40B (194.2 mg, 1 mmol) in dioxane (10 mL) at room temperature, was added 4-phenylenediamine mono Boc (416, 5 mg, 2 25 nmol). The product started to precipitate within minutes. After an hour the reaction mixture was added ether (5 mL) and the white solid product was filtered and washed with ether to yield 350 mg (87%). MS (DCI/NH 3 ) m/z 403 (M+H)+. 30 Example 138B A solution of the corresponding nitrile prepared in Example 138A (105 mg, 0.36 nmol) in Pyr: Et 3 N (10: 1, 20 mL) was bubbled H 2 S for 5 minutes and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL) washed with aqueous 0.25 N HCl (25 mL) followed by water (2x50 mL), saturated solution of sodium bicarbonate, -150 SUBSTITUTF -imW-T fmI 1 : WO 99/05096 PCT/US98/15386 and brine, dried over magnesium sulfate & evaporated. To a solution of the resulting solid in acetone (25 mL) was added Mel (1.0 mL)and stirred at 50'C for 30 minutes- very strong precipitate was observed. Added ether and filtered the yellow precipitated. The yellow solid was added methanol (10 mL) and ammonium acetate (150 mg) and stirred at room temperature 5 overnight. Purified as described inExample IB. Yield of the white solid 69 mg. MS (DCI/NH 3 ) m/z 420 (M+H)+. Example 138C N-[6-(aminoiminomethvl)-2-naphthalenvll-N'-(4-aminophenvl)urea, bi s(trifluoroacetate)(salt) 10 The Boc protected substrate (Example 138B) was dissolved in methylene chloride: TFA 1: 1 (25 mL) and stirred at room temperature forl hour. Evaporated solvent under vacuum added toluene & evaporated again. Added water & little acetonitrile, filtered & lyophilized. 36 mg of white solid. MS (ESI/NH 3 ) m/z 320 (M+H)+; 15 IH NMR (300 MHz, DMSO-d 6 ) 9.26 (br.s, 2H), 9.21 (br.s, 1H), 8.85 (br.s, 2H), 8.31 (d, J=1.7Hz, 1H), 8.18 (d, J=1.7Hz, IH), 7.95-7.91 (m, 2H), 7.68 (dd, JI=6.6Hz, J2=2.OHz, IH), 7.57 (dd, JI=9.2Hz, J2=1.4Hz, IH), 7.34 (d, J=8.8Hz, 2H), 6.91 (d, J=8.4Hz, 2H); Anal. calc'd for C 18
HI
7 NsO-2-CF 3
COOH-H
2 0: C, 46.73; H, 3.74; N, 12.39. Found: C, C, 47.03; H, 3.55: N, 12.36. 20 Example 139
N-[
6 -(aminoiminomethvl- 2 -naphthalenvll-4-4-(aminomethyl)cyclohexanescarboxamide, bis(trifluoroacetate) (salt) 25 A solution of the substrate prepared in Example 137 as TFA salt (45 mg) in methylene chloride: TFA 1: 1 (20 mL) was stirred at room temperature for 1 hour. The solvent was evaporated under vacuum, added toluene & evaporated (20 mLx2). Dissolved in water, filtered 0.45 t frit and lyophilized. 35 mg, white solid as bis TFA salt. MS (ESI/NH3) m/z 325 (M+H)+; 30 IH NMR (300 MHz, DMSO-d 6 ) 10.31 (s, lH), 9.31 (br.s, 2H), 9.10 (br.s, 2H), 8.49 (s, lH), 8.39 (s, lH), 8.04-8.00 (m, 2H), 7.78-7.71 (m, 2H), 2.71 (d, J=7.OHz, 2H), 2.44-2.36 (m, lH)1.96-1.85 (m, 4H), 1.61-1.42 (m, 3H), 1.09-1.02 (m, 2H); Anal. calc'd for C19H24N40-2 CF 3 COOH: C, 50.00; H, 4.74; N, 10.14. Found: C, 49.95; H, 4.70; N, 09.96. -151 SUBSTITUTF qHFFT [Rill F 9R WO 99/05096 PCT/US98/15386 Example 140 N-[ 6 -(aminoimin omethyl)-2-naphthalenvll-N'-[(4-aminomethyllphenyllurea, bis(trifluoroacetate)(salt) Example 140A To a solution of the isocyanate prepared in Example 40B (140 mg, 0.72 mmol) in dioxane (8.0 mL) at room temperature, was added 4-N-Boc-aminomethylbenzoic acid (320 mg, 1.44 mmol) and stirred for 1 hour. The product was precipitating during the reaction. The 10 mixture diluted with ether (15 mL), filtered and washed with ether to yield 215 mg (72%) of white solid. MS (DCI/NH 3 ) m/z 417 (M+H)+. Example 140B 15 A solution of the nitrile (Example 140A) (198 mg, 0.47 mmol) in 10: 1 pyridine: triethylamine (10 rnL) was treated with H 2 S for 5 min, stirred at room temperature for 18 h and concentrated. The resulting solid was dissolved in acetone (15 mL), treated with iodomethane (0.8 mL, 12.8 mmol), stirred for 2 hours, diluted with ether (10 mL), filtered, washed with ether and dried under vacuum. The resulting solid was dissolved in methanol (4 mL) and was 20 added NH40Ac (200 mg. 2.6 mmol) at room temperature overnight. The product was purified according to the procedure described in Example IB to provide 112 mg (54%) of the corresponding amidine. MS (DCI/NH 3 ) m/z 434 (M+H)+. 25 Example 140C N-[6-(aminoiminomethyl)-2-naphthalenvll-N'-[(4-aminomethyllphenvllurea, bi s(trifluoroacetate)(salt) A solution of the substrate (Example 140B) in methylene chloride: TFA 1: 1 (20 mL) was stirred at room temperature for 1 hour. The solvent was evaporated under vacuum, added 30 toluene & evaporated (20 mLx2). Dissolved in water, filtered- 0.45.t frit and lyophilized. 38.1 mg, white solid. MS (ESI/NH 3 ) m/z 334 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ) 9.68 (s, 1H), 9.45 (s, 1H), 9.35 (br.s, 2H), 9.08 (br. s, 2H), 8.40 (d, J=1.7Hz, lH), 8.31 (d, J=1.8Hz, 1H), 8.10 (br.s, 3H), 8.04-7.99 (m, 2H), -152 SUBSTITUTF qWFFT rl 1 CO WO 99/05096 PCT/US98/15386 7.76 (dd, Jl=8.8Hz, J2=1.8Hz, 1H), 7.67 (dd, Jl=8.8Hz, J2=1.7Hz, lH), 7.58 (d, J=8.4Hz, 2H), 7.39 (d, J=8.4Hz, 2H), 3.98 (br. s, 2H); Anal. calc'd for C19HliN 5 01-2-CF 3
COOH.H
2 0: C, 47.67; H, 4.00; F, 19.67; N, 12.09. Found: C, 47.33; H, 3.70; F, 19.59; N, 11.71. 5 Example 141 methyl [7-(aminoiminomethyl)-3-[[r4-(aminomethvllphenyllaminolcarbonyll-1 naphathalenvllcarbamate, bis(trifluoroacetate)(salt) 10 Example 141A To a solution of the ester, prepared as described in Example 26, (747 mg, 2.63 mmol) in dioxane (10 mL) was added acetone (1 mL) and an excess of sodium hydroxide (1 N in water, 10 mL). After 1 hour the mixture was added water (40 mL) and ethyl acetate (85 mL) then was acidified with 10% aq. HCl. The ethyl acetate layer was separated washed with water 15 (2x20 mL) then brine, dried over magnesium sulfate filtered and evaporated. The product was isolated as a light yellow solid. MS m/z 271 (M+1)*. Example 141B 20 To a suspension of naphthoic acid derivative, prepared in Example 141A (270 mg, 1.1 mmol) in methylene chloride (8.0 mL) was added diisopropylethylamine (DIEA, 485 tL, 2.8 mmol) followed by 0- (azabenzotriazole-1-yl)-N, N, N', N' tetramethyluroniumhexafluorophosphate (HATU, 527 mg, 1.39 mmol). After 10 minutes added the 4-N-Boc-aminomethylaniline (370 mg, 1.7 mmol). After an hour, added ethyl acetate 25 (120 mL) and washed organic layer with 5% aq. citric acid (50 mL), water (2x40 mL) and brine (50 mL). The rxn was dried over magnesium sulfate filtered through small amount of silica and evaporated. Purification on silica eluting with ethyl acetate in hexanes. The product, after concentration, was added ethyl acetate and ether and filtered to yield 350.0 mg (70%) of yellow solid. 30 MS m/z 447 (M+1)+. Example 141C A suspension of the naph derivative (Example 141B) (300 mg, 0.67 mmol) in ethyl acetate (20 mL) was added 120 mg of the Pd catalysit then stirred at room temperature, under -153 SUBSTTUTF :w -r ro it=1 WO 99/05096 PCT/US98/15386 hydrogen, at atmospheric pressure and stirred for I hour.. The crude was carried on to the next step without any purifications or analysis. To a solution of the crude amine in dioxane (25 mL) and 10% aqeuos sodium carbonate (2.5 mL) was added the methyl chloroformate (1.0 mL, large excess). After 2 hours the rxn 5 was quenched with methanol then diluted with ethyl acetate (80 mL) and water (50 mL). The ethyl acetate layer was separated, dried over magnesium sulfate filtered and evaporated. The product was separated on silica column using a gradient of ethyl acetate in hexanes (from 5 to 30% ethyl acetate in hexanes). Yield 140 mg of off white solid. MS m/z 492 (M+18)*' 10 Example 141D The desired compound was prepared as described in Example 26. MS m/z 492 (M+1*. 15 Example 141E methyl [ 7 -(aminoiminomethyl)-3-[r[4-(aminomethyllphenyllaminolcarbonyl>-1 naphathalenvllcarbamate, bis(trifluoroacetate)(salt) A solution of the substrate (Example 141 D) in a mixture of methylene chloride: TFA 4: 1 (20 mL) was stirred at room temperature for 15 minutes. The solvent was concentrated under 20 vacuum, and separated on RP C18 MPLC. Yield, 21 mg off white solid. MS m/z 392 (M+18)* 1 H NMR (DMSO): 3.783 (s, 3H), 4.03 (q, 2H, J=5.5Hz), 7.47 (d, 2H, j=8.4Hz), 7.85 (d, 2H, j=8.4Hz), 7.94 (d, IH, j=8.8Hz), 8.15 (wide s, 2H), 8.31 (d, IH, j=8.8Hz), 8.33 (s, 11H), 8.47 (s, 11H), 8.74 (s, 1H), 9.29 (s, 2H), 9.47 (s, 2H), 9.90 (s, 1H), 10.68 (s, IH). 25 Anal. calc'd for C 25
H
25
F
6
N
5 0 8 (base molecule + 2 TFA+1 H 2 0): C, 47.04: H, 3.70; N, 10.52. Found: C, 47.10: H, 3.95; N, 10.99. Example 142 6 -(aminoiminomethvl)-N-( 4 -ethylphenyl)-2-naphthalenecarboxamide, acetate(salt) 30 Example 142A The reaction was carried out in the same manner as described in Example 141B. Yield 374 mg (61%) of white powder. MS DCI/NH3): m/z 301 (M+NH4+). -154 SUBSTITTF c:WI-T IMI 11 C WO 99/05096 PCT/US98/15386 Example 142B 6 -(aminoiminomethyl)-N-(4-ethylphenvl)-2-naphthalenecarboxamide, acetate(salt) The reaction was carried out in the same manner as described for the naphthyl analog prepared in Example 141D, 313 mg. The solid that precipitated during the last step was filtered 5 and washed in ether to yield 71 mg (18%) of white solid, as acetate salt. MS (ECI) m/z 301 (M+H)+; IH NMR (300 MHz, DMSO-d 6 ) 8 1.19 (t, J=7.4Hz, 3H), 2.60 (q, J=7.4Hz, 2H), 7.22 (d, J=8.5Hz, 2H), 7.72 (d, J=8.5Hz, 2H), 7.94 (dd, Ji=8.8Hz, J 2 =1.7Hz, lH), 8.08-8.23 (m, 3H), 8.47 (d, J=1.7Hz, 1H), 8.63 (s, 1H), 10.43 (br. s, 1H); 10 Anal. calc'd for C 20
H
19
N
3 0AcOH- 0.5 H 2 0: C, 68.38; H, 6.26; N, 10.87. Found: C, 68.56; H, 6.21; N, 10.67. Example 143 6-(aminoiminomethyl)-N-( 2 -nachthalenyl)-2-naphthalenecarboxamide, 15 mono (trifluoroacetate)(salt) Example 143A To a solution of the acid chloride prepared as described in Example 8B (341 mg, 1.6 mmol) in methylene chloride (20 m-L) was added a solution of the 2-Amino naphthalene (249 20 mg, 1.74 mmol) in methylene chloride (10 mL) and propylene oxide (12 mL). The rxn was stirred at room temperature overnight. The reaction mixture was added ether and the product was filtered, washed with ether and hexanes and dried under vacuum. Yield 440 mg (86%). MS (DCI/NH3) m/z 340 (M+NH4)+. 25 Example 143B 6 -(aminoiminomethyl)-N-(2-naphthalenyll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The desired compound is prepared as described in Example 141B. Yield of white solid 40 mg (10%). 30 MS (ESI) m/z 340 (M+H)+; IH NMR (300 MHz, DMSO-d 6 ) 7.43-7.55 (m, 2H), 7.86-7.96 (m, 5H), 8.20-8.28 (m, 2H), 8.08-8.23 (m, 3H), 8.34 (d, J=8.8Hz, IH), 8.50 (d, J=1.7Hz, 1H), 8.57 (d, J=1.3Hz, 1H), 8.75 (s, 1H), 9.33 (br. s, 4H) 10.75 (s, 1H); -155 SUBSTITUTE SHEFT Ri I I: m WO 99/05096 PCT/US98/15386 Anal. calc'd for C 22
H
1 7
N
3 0-TFA- 0.25 H 2 0: C, 62.95: H, 4.07; N, 9.18. Found: C, 63.09; H, 3.72; N, 8.99. Example 144 5 6-(5-phenyl-2-oxazolyl)-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) Example 144A To a suspension of the phenacyl amine hydrochloride (Aldrich) (415 mg, 2.42 mmol) in a mixrure of methylene chloride (50 mL) and propylene oxide (15 mL) at room temperature was 10 added a solution of the 2-nitrile-6-acidchloride (560 mg, 2.6 mmol) in methylene chloride (30 mL) followed by DMF (3.0 mL). Thje reaction was stirred at room temperature overnight. The reaction mixture was added ether (15 mL) and the product was filtered and washed with hexanes to yield 555 mg (73%) of white solid. MS (DCI/NH 3 ) m/z 315 (M+H)+. 15 Example 144B A suspension of the substrate (Example 144A) (354 mg, 1.12 mmol) in phosphorous oxychloride (3.5 mL) was boiled for 1.5 hours. The reaction mixture was poured into ice and the mixture was added ethyl acetate (80 mL) and aqeuous solution of 10% potassium carbonate 20 (100 mL). The organic layer was separated, washed with brine dried over magnesium sulfate and evaporated. Added ether and filtered 249 mg (75%). MS (DCI/NH 3 ) m/z 297 (M+H)+. Example 144C 25 6-(5-phenvl-2-oxazolyl)- 2 -naphthalenecarboximidamide, mono(trifluoroacetate)(salt) To a solution of the substrate Example 144B (132 mg, 0.44 mmol) in THF (20 mL) at room temperature was added a solution of 1 N LiHMDS in hexanes (1.5 mL, 1.5 mmol) and stirred overnight. Quenched with 4 N HCl in dioxane (1 mL). After 10 minutes added a few drops of water and stirred for additional 30 minutes. The solvent was evaporated under vacuum 30 and the residue was purified on reverse phase chromatography. Yield 58 mg of white solid 41%). MS (ESI/NH 3 ) m/z 314 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ) 9.50 (s, 2H), 9.19 (s, 2H), 8.86 (s, 1H), 8.55 (s, lH), 8.38 8.26 (m, 3H), 7.98 (s, lH), 7.96-7.89 (m, 3H), 7.58-7.54 (m, 2H), 7.47-7.42 (m, 1H); -156 SUBSTITUTE SHEET (Mill = 9m WO 99/05096 PCT/US98/15386 Anal. calc'd for C 2 0H 15
N
3 0- 1.15CF 3 COOH: C, 60.26; H, 3.66; N, 9.45; F, 14.75. Found: C, 60.11; H, 3.81: N, 9.20; F, 14.81. Example 145 5 6-(5-phenyl -2-thiazolyl)- 2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) Example 145A A suspension of the substrate, prepared in Example 144A, (340 mg, 1.1 mmol) and Lawesson's reagent (600 mg, 1.48 mmol) was heated to 85 0 C for 48hours. Solvent was 10 evaporated to dryness and the product was isolated via silica column using 10% ethyl acetate in hexanes as eluent. Yield: 200.0 mg (59%) of yellow solid. MS (DCI/NH 3 ) m/z 313 (M+H)+. Example 145B 15 6-(5-phenyl-2-thiazolyl)-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) To a solution of the substrate, Example 145A (180 mg, 0.58 mmol) in THF (20 mL) at room temperature was added a solution of 1 N LiHMDS in hexanes (2.0 mL, 2.0 mmol) and stirred overnight. Quenched with 4 N HCl in dioxane (1 mL). After 10 minutes added a few 20 drops of water and stirred for additional 30 minutes. The solvent was evaporated under vacuum and the residue was purified on MPLC RPC18. Yield 36 mg (19%) of white solid. MS (ESI/NH 3 ) m/z 330 (M+H)+; I H NMR (300 MHz, DMSO-d 6 ) 9.49 (s, 2H), 9.14 (s, 2H), 8.71 (s, 1H), 8.52 (s, 1H), 8.47 (s, I H), 8.35-8.22 (m, 3H), 7.90-7.78 (m, 3H), 7.55-7.50 (m, 2H), 7.46-7.43 (n, IH); 25 Anal. calc'd for C20H 1SN 3
S-CF
3
COOH-H
2 0: C, 57.26; H, 3.93; N, 9.11. Found: C, 56.83; H, 3.55; N, 8.79. Example 146 6-(aminoimino methyl)- 4
-(
3 -furanyl)-N-(2-pyridinyl)-2-naphthalenecarboxamide, 30 dihydrochloride Example 146A The above product was prepared in the manner of Example I 14A. MS (ESI) m/z (M+H)+ 340. -157 SUBSTITUTF ql4;==T RI 11 = WO 99/05096 PCT/US98/15386 Example 146B 6-(aminoiminomethyl)-4-(3-furanyl)-N-(2-pyridinvl)-2-naphthalenecarboxamide, dihydrochloride 5 The above was prepared from Example 146A using method described in 145B. MS (CI) m/z (M+H)+ 357; IH-NMR (300 MHz, DMSO-d 6 ) 6 11.27 (s, 1H), 9.56 (s, 2H), 9.17 (s, 2H), 8.76 (s, 1H), 8.63 (s, IH), 8.45-8.24 (m, 5H), 7.96-7.89 (m, 3H), 7.25 (m, 2H), 7.18 (s, IH): Anal. calc'd for C 2 1
H
18
N
4 0 2 Cl 2 19/10 HC: C, 54.33 H, 4.75 N, 12.07. Found: C, 54.89; 10 H, 5.28; N, 9.81. Example 147 6-(aminoiminomethyl)-N-(1, 2, 3, 4 -tetrahydro-6-quinolinvl)-2-naphthalenecarboxamide, bis(trifluoroacetate)(salt) 15 Example 147A The reaction was carried out in exactly the same manner as described for Example 1 18A using 6-aminoquinoline to yield the product in 72%. Mass spectrum (CI+) 324 (M+1)*. 20 Example 147B The reaction was carried out in exactly the same manner as described for Example 11 8B to yield the product in 45% (off white solid). Mass spectrum (ESI+) 341 (M+1)*. Example 147C 25 6-(aminoiminomethyl)-N-(1, 2, 3, 4 -tetrahydro-6-quinolinvl)-2-naphthalenecarboxamide, bis(trifluoroacetate)(salt) To a suspension of the substrate, Example 147B (261 mg, 0.6 mmol) in degassed methanol (15 mL) was added platinum oxide (10 mg, cat.). The reaction mixture was charged with hydrogen at atmospheric pressure and stirred vigorously overnight. The next day the 30 solution was filtered through celite to remove the catalyst, and the product was purified over mplc with RPC18 silica using methanol (+ 0.1% TFA) and water (+ 0.1% TFA) as eluent. Yield 122 mg of white solid and bis TFA salt. MS (ESI+) 345 (M+1)*; -158 SUBSTITUTE RHFFT RI 1 =m WO 99/05096 PCTIUS98/15386 1 H NMR (DMSO-d6) 10.51 (s, 1H), 9.65 (s, 2H), 9.50 (s, 2H), 8.64 (s, 1H), 8.52 (s, 1H), 8.22 (d, J=8.OHz, 1H), 8.12 (Abq, J=9.0Hz, 2H), 7.86 (d, J=9.OHz, 1H), 7.61 (s, 1H), 7.56 (d, J=8.OHz, 1H), 6.98 (d, J=8.5Hz, lH), 3.28 (t, J=5.5Hz, 2H), 2.75 (t, J=6.3Hz, 2H), 1.92-1.86 (m, 2H); 5 Anal. calc'd for C 2 1
H
2 0N 4 0+2.25 TFA+0.25 H 2 0: C, 50.59 (50.46); H, 3.79 (3.79); N, 9.25 (9.25); F, 21.18 (20.83). Example 148 7-methoxy- 8 -(pyrazinvloxy)-2-naphthalenecarboximidamide, dimethanesulfonate(salt) 10 Example 148A The product from Example 4A (125 mg, 0.627 mmol) was combined with chloropyrazine (112 mL, 1.25 mmol) and Cs 2
CO
3 (409 mg, 1.25 mmol) in N methylpyrrolidinone (4 mL), and the reaction was stirred at 130 'C for 1 hour. The reaction was 15 cooled, and the crude mixture was chromatographed on SiO 2 using 40% ethyl acetate/hexanes as eluent, to yield 75 mg (43%) of the desired compound. MS (DCI (NH 3 ) m/z 278 (M+H)+. Example 148B 20 7-methoxy-8-(pvyrazinvloxy)-2-naphthalenecarboximidamide, dimethanesulfonate(salt) The product from Example 148A (70 mg, 0.252 mmol) was subjected to the procedure described in Example 1B to yield the desired compound (106 mg, 71%). m.p. 155' C. MS (DCI (NH 3 ) m/z 295 (M+H)+; I H NMR (300 MHz, DMSO) 8 9.42 (br s, 2H), 9.04 (br s, 2H), 8.72 (s, 1H), 8.38 (d, J=3 25 Hz, I H), 8.36 (m, I H), 8.21 (d, J=9 Hz, I H), 8.09 (m, I H), 8.06 (d, J=9 Hz, I H), 7.82 (d, J=9 Hz, 1H), 7.73 (dd, J=9, 2 Hz, 1H), 3.83 (s, 3H), 2.38 (s, 3H); Anal. calc'd for C 1 gH 22
N
4
S
2 Og-1.1CH 4
SO
3 : C, 38.74; H, 4.49; N, 9.46. Found: C, 38.68; H, 4.53; N, 9.34. 30 Example 149 7-methoxy-8-(phenylthio)-2-naphthalenecarboximidamide, methanesulfonate Example 149A -159 SUBSTITUTE SHEFT IRI 1 F 9m WO 99/05096 PCT/US98/15386 To a solution of NaH (48 mg, 60%, 1.2 mmol) in HMPA (2 mL) was added PhSH (0.133 mL, 1.3 mmol), and the reaction was stirred for 5 minutes. To this was added the product from Example 53B (309 mg, 1 mmol), and the reaction was heated at 100'C for 3 hours. The crude reaction mixture was chromatographed on Si02 using 20% ethyl 5 acetate/hexanes as eluent. The product was taken up in ethyl acetate (10 mL) and methanol (10 mL), and treated with a 2 M solution of TMSCHN 2 (10 mL). The reaction was stirred for 60 minutes and condensed. The crude product was chromatographed on SiO 2 using 15% ethyl acetate/hexanes as eluent, to yield 115 mg (39%) of the desired compound: MS (DCI (NH3) m/z 309 (M+NH 4 )+. 10 Example 149B 7-methoxy-8-(phenvlthio)-2-naphthalenecarboximidamide, methanesulfonate The desired compound was prepared from Example 149A and the procedure of Example 55D. 15 MS (DCI/NH 3 ) m/z 309 (M+H)+; I H NMR (300 MHz, DMSO-d 6 ) 6 2.33 (s, 3H), 3.96 (s, 3H), 6.96 (d, 2H), 7.11 (dd, lH), 7.20 (d, lH), 7.22 (d, IH), 7.69 (dd, 1H), 7.82 (d, lH), 8.22 (d, IH), 8.33 (d, IH), 8.81 (s, I H), 9.01 (br s, 2H), 9.46 (br s, 2H); Anal. calc'd for C 18
H
16
N
2 0S-1.15 CH 4
SO
3 : C, 5 4 .91; H, 4.96; N, 6.69. Found: C, 54.70; 20 H, 5.15; N, 6.58. Example 150 7-methoxy-8-(pvrazinylamino)- 2 -naphthalenecarboximidamide, bis(trifluoroacetate)(salt) 25 The desired compound was prepared from the product prepared in Example 90D using the method described in Example 91A, then converted to the amidine as described in Example 40D. MS (DCI/NH 3 ) m/z (M+H)+ 294; IH-NMR (300 MHz, DMSO-d 6 ) 6 9.39 (s, 2H), 9.02 (s, 2H), 8.95 (s, IH), 8.40 (d, lH), 30 8.14 (d, IH), 8.03 (s, 2H), 7.92 (dd, 1H), 7.84 (d, 1 H), 7.76 (d, IH) 7.66 (dd IH), 3.90 (s, 3H); Anal. calc'd for C 20
H
17
N
5 0 5
F
6 1/2 TFA: C, 43.79; H, 3.07; N, 12.20. Found: C; 43.81; H, 3.22; N, 12.24. -160 SUBSTITUTE SHFFT IRil F= 9m WO 99/05096 PCT/US98/15386 Example 152 6 -(aminoiminomethyl)- 4 -(3-furanyl)-N-phenyl-2-naphthalenecarboxamide, monohydrochloride Example 152A 5 To a solution of the product from Example 8D (5.50 g, 26.04 mmol) in CH 2 Cl 2 (125 mL) was added dibromodimethylhydantoin (4.47 g, 15.62 mmol) and trifluoromethanesulfonic acid (2.51 mL, 28.41 mmol), and the reaction was stirred at 23'C in the dark for 18 hours. The mixture was poured into aqueous NaHSO 3 . the solution was made basic with Na2CO 3 , and extracted with 3x ethyl acetate, and the extracts were washed with brine, dried over Na 2
SO
4 , 10 and condensed. The product was recrystallized from ethanol/ethyl acetate, to yield 5.80 g (77%) of the desired compound. MS (DCI (NH 3 ) m/z 307 (M+NH 4 )+. Example 152B 15 To a solution of the product from Example 152A (1.40 g, 4.826 mmol) in THF (40 mL), water (10 mL), and methanol (10 mL) was added LiOH-water (405 mg, 9.65 mmol), and the reaction was stirred for 18 hours. The mixture was poured into 1 M HCl and extracted with 3x ethyl acetate, and the extracts were washed with brine, dried over Na2SO 4 , and condensed, to yield 1.23 g (92%) of the desired compound. 20 MS (DCI (NH 3 )) m/z 295 (M+NH 4 )+. Example 152C To a solution of the product from Example 152B (440 mg, 1.60 mmol), in toluene (25 mL) was added oxalyl chloride (0.140 mL, 1.6 mmol), and the reaction was stirred at 80 'C for 25 18 hours. The toluene was boiled off until HCl evolution ceased, and the reaction was then cooled. Aniline (1 mL, 11 mmol) was added, and the reaction was stirred for 10 min, nad poured into I M HCl. The solution was extracted with 3x ethyl acetate, and the extracts were washed with brine, dried over Na 2
SO
4 , and condensed, to yield 560 mg (99%) of the desired compound. 30 MS (DCI (NH 3 )) m/z 370 (M+NH 4 )+. Example 152D -161 SUBSTITUTE SHEET (RUL= 9M WO 99/05096 PCT/US98/15386 The desired compound was prepared from Example 152C (408 mg, 1.16 mmol), furan 3-boronic acid (182 mg, 1.62 mmol) and the procedure of Example 57B, to yield 220 mg (56%) of the desired compound. MS (DCI (NH 3 )) m/z 356 (M+NH 4 )+. 5 Example 152E 6 -(aminoiminomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamide, monohydrochloride The desired compound was prepared from Example 152D and the procedure of Example 40D. 10 MS (DCI/NH 3 ) m/z 356 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ) 8 7.15 (m, 2H), 7.41 (dd, 2H), 7.83 (d, 2H), 7.91 (d, 1H), 7.99 (dd, IH), 8.19 (d, lH), 8.38 (s, 1H). 8.41 (d, 1H), 8.62 (s, IH), 8.69 (s, 1H), 9.15 (br s, 2H), 9.55 (br s, 2H); Anal. calc'd for C 22
H
17
N
3 0 2 2.75 HCl: C, 57.99; H, 4.37: N, 9.22. Found: C, 57.85; H, 15 4.84; N. 9.44. Example 153 6-(aminoiminomethyl)-4-[ I-(methylsulfonyl)-1 H-pyrazol-4-vIl-N-phenyl-2 naphthalenecarboxamide, monohydrochloride 20 Example 153A The desired compound was prepared from the product from Example 53D and the product from Example 152A by the procedure of Example 47A. MS (DCI/NH 3 ) m/z 408 (M+H)+. 25 Example 153B The desired compound was prepared from the product from Example 153A, by the procedure of Example 53F. MS (DCI/NH 3 ) m/z 278 (M+H)+. 30 Example 153C The desired compound was prepared from the product from Example 153B, by the procedure of Example 87A (86A). MS (DCI/NH 3 ) m/z 373 (M+NH 4 )+. -162 SUBSTITUTE SHEFT fRi 11 = gm WO 99/05096 PCT/US98/15386 Example 153D The desired compound was prepared from the product from Example 153C, by the procedures of Example s 152B and 152C 5 MS (DCI/NH 3 ) m/z 356 (M-SO 2 Me+NH 4 )+. Example 153E 6-(aminoiminomethyl)-4-[ I -(methylsulfonyl)- I H-pyrazol-4-vll-N-phenvl-2 naphthalenecarboxamide, monohydrochloride 10 The desired compound was prepared from Example 153D and the procedure of Example 40D. MS (DCI/NH 3 ) NONE; 1 H NMR (300 MHz, DMSO-d 6 ) 6 3.99 (s, 3H), 7.14 (t, 1H), 7.40 (t, 2H), 7.84 (d, 2H), 7.91 (d, IH), 8.08 (s, 1H), 8.15 (d, 1H), 8.35 (m. 2H), 8.65 (br s, 2H), 9.33 (br s, 2H), 15 9.61 (br s, 2H), 10.58 (s, 1H); Anal. calc'd for C22HI 9 N5SO 3 -2.75 HCl: C, 49.51; H, 4.11; N, 13.12. Found: C, 49.44; H, 3.83; N, 12.09. Example 154 20 6-(aminoiminomethyl)-4-[5-(methylthio)-3-furanyll-N-phenvl-2-naphthalenecarboxamide, monohydrochloride Example 154A To a solution of 2-trimethylsilyl-3-bromofuran (4.17 g, 19.03 mmol) in THF (40 mL) 25 at -78'C was added a 1.5 M solution of LDA (12.7 mL, 19.03 mmol), and the reaction was stirred at -78'C for 1 hour. Methyl disulfide (1.89 mL, 20.93 mmol) was then added, and the reaction was allowed to warm to room temperature overnight. The reaction was poured into saturated aqueous NH 4 Cl solution, and extracted with 3x diethyl ether. The combined extracts were washed with brine, dried over Na 2
SO
4 , and condensed. The crude material was 30 chromatographed on SiO 2 using hexanes as eluent, to yield 3.02 g (60%) of the desired compound. MS (DCI/NH 3 ) m/z 265, 267 (M+H)+. Example 154B -163 SUBSTITUTE I-IwFFT RIJ1 F 9m WO 99/05096 PCTIUS98/15386 A solution of the product from Example 154A (2.68 g, 10.1 mmol) and a 1 M solution of TBAF (20.2 mL) in THF (20 mL) was stirred for 30 minutes. The reaction was condensed and The desired compound was chromatographed on SiO 2 using hexanes as eluent, to yield 1.39 g (71 %) of 2-methylthio-4-bromofuran. This material was taken on directly to the next 5 step. To a solution of this product (7 mmol) in THF (25 mL) at -78'C was added a 2.5 M solution of BuLi (2.8 mL, 7 mmol), and the reaction was stirred for 5 minutes. Bu3SnC (1.90 mL, 7 mmol) was then added, the reaction was stirred for 30 min, and then allowed to warm to room temperature. The reaction was poured into saturated aqueous NH 4 Cl solution, and extracted with 3x diethyl ether. The combined extracts were washed with brine, dried over 10 Na2SO4, and condensed. The crude material was chromatographed on SiO 2 using hexanes as eluent, to yield 1.24 g (30%) of the desired compound. MS (DCI/NH 3 ) m/z 404 (M+H)+. Example 154C 15 A solution of the product from Example 154B (920 mg, 2.28 mmol), the product from Example 152A (662 mg, 2.28 mmol), and PdC1 2 (PPh 3
)
2 (161 mg, 0.23 mmol) in CH 3 CN (15 mL) was stirred for 18 hours at 80'C. The reaction was condensed and the crude material was chromatographed on SiO 2 using 20% ethyl acetate/hexanes as eluent, to yield 671 mg (91%) of the desired compound. 20 MS (DCI/NH 3 ) m/z 324 (M+H)+. Example 154D The desired compound was prepared from the product from Example 154C, by the procedure of Example 152 B. 25 MS (DCI/NH 3 ) m/z 310 (M+H)+. Example 154E The desired compound was prepared from the product from Example 154D, by the procedure of Example 152C. 30 MS (DCI/NH 3 ) m/z 402 (M+NH 4 )+. Example 154F 6-(aminoiminomethvl)-4-F5-(methylthio)-3-furanyl)]-N-phenvl-2-naphthalenecarboxamide, monohydrochloride -164 SUBSTITUTE SHEET [Rill 1= 9m WO 99/05096 PCT/US98/15386 The desired compound was prepared from Example 154E and the procedure of Example 144C. MS (DCI/NH 3 ) m/z 402 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ) 6 2.54 (s, 3H), 7.15 (t, 1H), 7.24 (s, 1H), 7.40 (t, 2H), 7.84 5 (d, 2H), 7.92 (dd, 1H), 8.19 (d, 1H), 8.39 (d, 1H), 8.44 (s, 1H), 8.61 (s, IH), 8.69 (s, 1H), 9.35 (br s, 4H), 10.61 (s, 1H); Anal. calc'd for C 23
H
19
N
3 SO2'2.25 HCl: C, 57.14; H, 4.43; N, 8.69. Found: C, 57.13; H, 4.21; N, 8.56. 10 Example 155 methyl [7-(aminoiminomethyl)- I -naphthalenyllmethylcarbamate, mono(trifluoroacetate) (salt) The desired compound is prepared according to the procedures described in Example s 12 and 13. Yield: 40 mg (42%) of white solid 15 MS m/z: 258 (M+H)+ 1 H NMR (DMSO, 300 MHz): 3.28 (s, 3H), 3.82 (br, 3H), 7.66 (dd, I H, Jl=7.5 Hz, J2=1.4 Hz), 7.78 (m, IH), 8. 89 (Dd, lH, Jl=8.8 Hz, J2=2.0 Hz), 8.05 (d, I H, 8.1 Hz), 8.24 (d, 1 H, 8.8 Hz), 8.30 (s, I H), 9.09 (s, 2H), 9.52 (s, 2H); Anal. calc'd for C 14
H
15
N
3 0 2 . 1.25 C 2
F
3 0 2 H0.25 H 2 0: C, 49.02; H, 4.18; N, 10.39. 20 Found: C 48.81; H, 3.91; N, 10.15. Example 156 propyl [7-(aminoiminomethyl)-1-naphthalenvllcarbamate, mono(trifluoroacetate)(salt) 25 The desired compound is prepared according to the procedures described in Example s 12 and 13. Yield: 52 mg (46%) of white solid MS m/z: 272 (M+H)+ 1 H NMR (DMSO, 300 MHz): 0.97 (t, 3H, JI=J2=7.1 Hz), 1.67 (Sextet, 2H, J=7.1 Hz), 4.19 (t, 3H, JI=J2=6.8 Hz). 7.71 (d, 1 H, 8.5 Hz), 7.83 (m, 3H), 8.14 (d, 1H, J=8.5 Hz), 8.67 30 (s, 1H), 9.22 (Br, 3H), 9.63 (s, 1H); Anal. calc'd for C 1 5
H
17
N
3 0 2 . 0.25 C 2
F
3 0 2 H-0.75 H 2 0: C, 49.18; H, 4.66; N, 9.83. Found: C, 49.27; H, 4.87; N, 10.02. Example 157 -165 SUBSTITUTF qHFPT RI I om WO 99/05096 PCTIUS98/15386 N- [7-(aminoiminomethyl)- I -naphthalenvl -N'-methylurea. mono(trifluoroacetate)(salt) The desired compound is prepared according to the procedures described in Example s 12 and 13. Yield: 36 mg (54%) of white solid MS m/z: 243 (M+H)+ 5 1 H NMR (DMSO, 300 MHz): 2.80 (d, 1H), 6.45 (d, 1H), 7.70 (m, 2H), 7.82 (dd, J1=8.9 Hz, J2=2.1 Hz), 8.08 (dd, 7.4 Hz, J=1.3 Hz), 8.17 (d, 1H, J=8.5 Hz), 8.62 (s, 1H), 8.72 (s, lH), 9.07 (s, 2H), 9.47 (s, 2H), (s, 2H); Anal. calc'd for C 13
H
1 4
N
4 0. 1.5 C 2
F
3 0 2 H-0.5 H 2 0: C, 45.50; H, 3.94; N, 13.27. Found: C, 45.22; H, 3.86; N, 13.12. 10 Example 158 ethyl [7-(aminoiminomethyl)- 1 -naphthalenvllcarbamate, mono(trifluoroacetate)(salt) The desired compound is prepared according to the procedures described in Example s 12 and 13. Yield: 70 mg (76%) of white solid 15 MS m/z: 258 (M+H)+ 1 H NMR (DMSO, 300 MHz): 1.30 (t, 3H, Jl=J2=7.4 Hz), 4.20 (q, 2H, J=7.0 Hz), 7.80 (m, 4H), 8.15 (d, 8.5 Hz), 8.68 (s, 1H), 9.13 (s, 2H), 9.38 (s, 2H), 9.66 (s, 1H); Anal. calc'd for C 1 4
H
15
N
3 0 2 -1.5 C 2
F
3 0 2 H: C, 47.67; H, 3.88; N, 9.81. Found: C, 47.97; H, 3.85; N, 9.78. 20 Example 159 N-[7-(aminoiminomethyl)- I -naphthalenvl)propanamide, mono(trifluoroacetate)(salt) The desired compound is prepared according to the procedures described in examples 12 and 13. 25 Yield: 20 mg (23 %) of white solid MS m/z: 242 (M+H)+ I H NMR (DMSO, 300 MHz): 1.18 (t, 3H, 7.4Hz), 3.38 (m, 2H), 7.89 (m, 3H), 7.81 (dd, 1H, JI=8.4Hz, J2=1.9 Hz), 7.87 (d, 1H, 8.5 Hz), 8.58 (s, 1H), 9.02 (s, 2H), 9.47 (s, 2H), 9.97 (s, 1H). 30 Anal. calc'd for C 14
H
15
N
3 0. 1.15 C2F 3 0 2 H .0.25 H 2 0: C, 51.94; H, 4.45; N, 11.15; Found: C, 52.02; H, 4.24; N, 10.76. Example 160 -166 SUBSTITUTE SHEET (RULF 9M WO 99/05096 PCT/US98/15386 N-r7-(aminoiminomethyl)- 1 -naphthalenyll-2-methoxvacetamide, mono(trifluoroacetate)(salt) The desired compound is prepared according to the procedures described in Example s 12 and 13. Yield: 30 mg (30%) of white solid MS m/z: 258 (M+H)+ 5 1 H NMR (DMSO, 300 MHz): 3.49 (s, 3H), 4.18 (s, 2H), 7.80 (m, 3H), 7.93 (d, 1 H, 7.7 Hz), 8.47 (d, 1 H, 8.5 Hz), 8.47 (s, 1H), 9.10 (s, 2H), 9.46 (s, 2H), 9.99 (s, 2H); Anal. calc'd for C 1 4
H
15
N
3 02-1C 2
F
3 0 2 H-1.25 H 2 0: C, 48.80; H, 4.73; N, 10.67. Found: C, 48.53; H, 4.34; N, 10.54; 1 H NMR (DMSO, 300 MHz): 2.16 (s, 3H), 4.85 (s, 2H), 7.82 (m, 4H), 8.18 (d, 1H, J=8.18 10 Hz), 8.55 (s, 1H), 9.10 (s, 2H), 9.44 (s, 2H), 10.24 (s, 1H); Anal. calc'd for C 15
H
15
N
3 0 3 1C 2
F
3 0 2 H-1 H 2 0: C, 48.93; H, 4.35; N, 10.07. Found: C, 48.82; H, 4.27; N, 10.00. Example 161 15 N-[7-(aminoiminomethyl)- I -naphthalenyllurea, mono(trifluoroacetate)(salt) The desired compound is prepared according to the procedures described in Example s 12 and 13. Yield: 35 mg (54%) of yellownish solid MS m/z: 229 (M+H)+ 1 H NMR (DMSO, 300 MHz): 6.22 (s, 2H), 7.65 (m, 2H), 7.77 (dd, J1=8.8 Hz, J2=1.5Hz). 20 8.57 (s, IH), 8.79 (s, I H), 9.07 (s, 2H), 9.49 (br, 2H); Anal. calc'd for C 12
H
12
N
4 0. 1 C 2
F
3 0 2 H-0.75 H 2 0: C, 40.90; H, 3.33; N, 11.95. Found: C, 40.95; H, 3.64; N, 12.31. Example 162 25 N-[7-(aminoiminomethyl)- I -naphthalenvll-2-hydroxvacetamide, mono(trifluoroacetate)(salt) The desired compound is prepared according to the procedures described in Examples 12 and 13. Yield: 24 mg (37%) of white solid MS m/z: 244 (M+H)+ 1 H NMR (DMSO, 300 MHz): 4.18 (s, 2H), 5.82 (br, 11H). 7.67 (m, 1H), 7.85 (m, 3H), 8.20 30 (d, 1H), 9.18 (s, 2H), 9.42 (s, 2H), 9.89 (s, 1H); Anal. calc'd for C 13
H
13
N
3 0 2 -1 C 2
F
3 0 2 H-0.75 H 2 0: C, 48.59; H, 4.21; N, 11.33. Found: C, 48.64: H, 3.89; N, 11.25. Example 163 -167 SUBSTITUTE SHEET (RULF 9m WO 99/05096 PCT/US98/15386 8-(2-pyrimidinvlamino)-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt) The desired compound is prepared according to the procedures described in Examples 91A and 13.Yield: 28 mg (28%) of pale yellow solid MS m/z: 264 (M+H)+ 5 1H NMR (DMSO, 300 MHz): 6.90 (t, lH, J1=J2=4.7 Hz), 7.69 (d, J=7.8 Hz), 7.80 (1 H, J=8.1 Hz), 7.81 (1 H, dd, J1=8.4 Hz, J2=2.1 Hz), 8.08 (lH, dd, J1=7.4Hz, J2=0.6 Hz), 8.14 (lH, d, J=8.5 Hz), 8.49 (d, 2H), 8.75 (lH, d, J=1.7 Hz). 9.06 (s, 2H), 9.37 (s, 2H), 9.60 (s, I H); Anal. calc'd for C 15
H
13
N
5 . 2.25 C 2
F
3 0 2 H-0.25 H 2 0: C, 44.67; H, 4.283.03; N, 13.36. 10 Found: C, 44.49; H, 2.80; N, 13.40. Example 164 8-amino-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) To a solution of crude 8-amino-2-nitrile-naphthalene prepared as described in Example 15 10 at room temperature in 10:1 pyridine: triethylamine (10 mL) was bubbled hydrogen sulfide for 5 minutes and stirred at room temperature overnight. The reaction mixture was added water (50 mL) and the product was extracted into ethyl acetate (3x30 mL) . The combined organic solvent was dried over magnesium sulfate, filtered and evaporated. The resulting yellow substance was taken up in acetone (30 mL) then added methyl iodide (2 mL). The reaction 20 mixture was boiled for 1 hour, then evaporated to dryness. To the resulting yellow substance in methanol (25 mL) was added ammonium acetate (100 mg) and stirred at room temperature overnight. The solvent was removed under vacuum and the product was purified via reverse phase chromatography using 0.1% TFA/water and 0.1% TFA/methanol as eluent. MS m/z: 186 (M+H)+ 25 1 H NMR (DMSO, 300 MHz): 5.14 (br, 3H), 6.80 (dd, 1H, J1=7.8 Hz, J2=1 Hz), 7.17 (d, 1H, J=7.8 Hz), 7.40 (dd, 1H, JI=J2=7.8 Hz), 7.70 (dd, IH, J1=8.9 Hz, J2=2.1 Hz), 7.91 (d, IH, J=8.5 Hz), 8.65 (s, 1H), 8.95 (s, 2H), 9.23 (s, 2H); Anal. calc'd for CIIH11N3-2.5 C 2
F
3 0 2 H-0.75 H 2 0: C, 39.72; H, 3.13; N, 8.69. Found: C, 40.01; H, 3.19: N, 8.88. 30 Example 165 6-(aminoiminomethyl)-N-[4-(aminomethyll)phenvll-4-(2-pyrimidinvlamino)-2 naphthalenecarboxamide. tris(trifluoroacetate)(salt) -168 SUBSTITUTE S-WEFT (Rill F 99m WO 99/05096 PCTIUS98/15386 Example 165A A suspension of 2-nitrile-6-methyester naphthalene Example 8D (5.0 g, 23 mmol) in concentrated sulfuric acid (50 mL) at -5 0 C was added a solid potassium nitrate. The colour of reaction mixture was gradually changed into a dark brown. The reaction mixture was stirred for 5 15 minutes and was poured into ice-water. Collected the precipitate and washed with water. The crude product was recrystallized from ethyl acetate and ethanol. Yield 4.3 g (68%) of pale yellow powder. Example 165B 10 To a solution of 2 -nitrile-6-methylester-8-nitro-naphthalene, Example 165A (3.5 g, 13.6 mmol) in a mixture of THF (100 mL) and ethyl acetate (120 mL) was added 10% Pd-C (350 mg). The reaction mixture was placed under hydrogen at atmospheric pressure (balloon) and stirred at room temperature for 3 5 hour. The mixture was filtered through celite and silica gel, washed with ethyl acetate and evaporated. The resulting solid was washed with ether (20 mL). 15 Yield 2.20 g (7 1%) of yellow powder. Example 165C A mixture containing 2- Nitrile-6-methylester-8-amino-naphthalene, Example 165B (2.8 g, 12.3 mmol), BINAP (116 mg, 0.186 mmol), Pd 2
(DBA)
3 <64 mg, 0.061 mmol), NaO-t-Bu 20 (1.667 g, 17.6 mmol), 2-Bromopyrimidine (2.363 g, 14.9 mmol) and Toluene (80 mL) in an oven-dried flask under nitrogen, was stirred at room temperature for 10 minutes. The reaction mixture was heated to 80 *C for 1 hour. At the end of the reaction (TLC, hexanes+ethyl acetate=4: 1), brine 9200 mL) was added. Extracted the mixture with CH 2 Cl 2 . (4x250 mL). Evaporated the solvent. Yield 3.5 g (93%) of pale yellow powder. 25 Example 165D To a suspension of 2-nitrile-6-methylester-8-N- (2-pyrimidine)-naphthalene, Example 165C (5.2 g, 17.1 mmol ) in ethanol (150 mL) was added potassium carbonate (3.54 g, 33.3 mmol) in water (200 mL). The resulting suspension was heated at 120 'C for 2 hours, at that 30 time all the suspension turned into a clear solution. The mixture is cooled down, then acidified with 2 N HCl. The resulting precipitate was collected by filtration to yield 4.5 g (90%) of pale yellow powder. No further purification was required for the next step. Example 165E -169 SUBSTITUTF sWFFT In 11 = WO 99/05096 PCT/US98/15386 To a cold (0 0 C) solution of 2-nitrile-8-N- ( 2 -pyrimidine)-6-carboxylic acid naphthaleneExample 165D (5.0 g, 17.2 mmol) in DMF (150 mL) was added DIEA (7.6 mL, 42.6 mmol) and 0- (7-Azabenzotriazol-1-yl)-N, N, N', N' tetramethyluroniumhexafluorophosphate (9.8 g, 25.7 mmol) followed by tert 5 Butoxycarbonylamino-4-aminomethylaniline (5.74 g, 20 mmol). The resuting reaction mixture was stirred for about 1 hour. The reaction was quenched with water (200 mL) and the resulting precipitate was collected by filtration to yield 3.26 g (38%) of pale yellow powder. Example 165F 10 To a solution of the substrate, Example 165E (3.0 g, 6.07 mmol) in pyridine (150 mL) was added triethylamine (9 mL). H 2 S was passed for 10 minutes and the resultiing mixture was stirred at room temperature for 48 hour. 100 mL of water was added to the reaction mixture and the precipitate was Collected by filtration. Yield (3.0 g (93%) of yellow solid. 15 Example 165G To a solution of the thioamide, Example 165F in acetone (200 mL) was added Mel (6 mL) and the mixture was stirred at room temperature overnight. The mixture was evaporated to dryness to yield 1.2 g (78%) of yellow solid. 20 Example 165H 6 -(aminoiminomethyl)-N-[4-(aminomethyl)phenyll-4-(2-pyrimidinvlamino)-2 naphthalenecarboxamide, tris(trifluoroacetate)(salt) To a solution of the imidate ester, Example 165G, (1.5 g, 2.2 mmol) in methanol (50 mL) was added ammonium acetate (0.5 g, 6.4 mmol) and stirred at room temperature 25 overnight. After evaporation of the solvent the residue was treated with ether (3x25 mL) and the ether was decanterd out. The residue was dissolved in a mixture of 10: 1: 1 acetonitrile: water: acetic acid (50 mL). After addition of ether (100 mL), the Boc protected product precipitated as an acetate salt and was colleted by filtration. The solid was added 1: 1 TFA: methylene chloride (50 mL) containing thioanisole (0.5 mL). The reaction mixture was stirred at room temperature 30 overnight. The product was purified over RPC 18 chromatography using water: methanol with 0.1% TFA as eluent. Yield after lyophilization 0.5 g (54%) of pale yellow solid. MS m/z: 412 (M+H)+ 1 H NMR (DMSO, 300 MHz): 4.02 (q, 2H, J=5.8), 6.94 (dd, 1H, J12=J2=4.8 Hz), 7.45 (d, 2H, J=8.5 Hz), 7.84 (d, 2H, J=8.4 Hz), 7.92 (dd, 1H, Jl=8.5 Hz, J2=1.7 Hz), 8.13 (br, -170 SUBSTITUTF qWl4 r rn II T WO 99/05096 PCT/US98/15386 3H), 8.30 (d, 1H, J=8.9 Hz), 8.41 (s, 1H), 8.52 (d., 2H), 8.55 (s, lH), 8.81 (s, IH), 9.19 (s, 2H), 9.43 (s, 2H), 9.75 (s, 1H), 10.62 (s, 1H); Anal. calc'd for C2 3
H
2 1N 7 0-2.5 C 2
F
3 0 2 H-1 H 2 0: C, 43.49; H, 3.22: N, 11.83. Found: C, 43.54; H, 3.34; N, 11.69. Example 166 6-(aminoiminomethyl)-N-phenvl- 4
-(
2 -pyrimidinvlamino)-2-naphthalenecarboxamide, mono(trifluoroacetate) (salt) The same procedure as described in Examples 165 substituting aniline for 4-amino 10 benzyl amine. MS m/z: 383 (M+H)+ 1 H NMR (DMSO, 300 MHz): 6.93-6.96 (m, 1H), 7.14 (dd, 1H, J1=7.3 Hz, J2=7.4 Hz), 7.40 (dd, 2H, JI=J2=7.3 Hz), 7.80 (, d, 2H, J=8.1 Hz), 7.91 (d, 1H, J=8.9 Hz), 8.30 (d, I H, J=9.0 Hz), 8.41 (s, 1H), 8.52-8.54 (m, 3H), 8.80 (s, 1H), 9.16 (s, 2H), 9.45 (s, 2H), 15 9.78 (s, IH), 10.55 (s, IH); Anal. calc'd for C22H 18
N
6 0-2 C 2
F
3 0 2 H-0.25 H 2 0: C, 50.78; H, 3.28; N, 13.31. Found: C, 50.85; H, 3.28; N, 13.31. Example 167 20 N-[( 4 -(aminomethyl)phenyll-6-[amino(hydroxvimino)methyll-4-(2-pyrimidinvlamino) 2-naphthalenecarboxamide, bis(trifluoroacetate)(salt) To a suspension of compound, prepared in Example 165 E (0.20 g, 0.40 mmol ) in methanol (40 mL) and water (20 mL) was added hydroxylamine hydro-chloride (112 mg, 1.75 mmol) and sodium carbonate (85 mg, 0.80 mmol), the reaction mixture was stirred for 48 25 hours at room temperature, TLC showed no reaction. Th reaction mixture was heated at reflux for 10 hours and removed the most of the solvents, the precipitate was collected by filtration, gave 1.2 g of pale yellow solid. The solid was disoolved in 1: 1 TFA+CH 2 C1 2 (30 mL) and sitrred at room temperature for 24 hours. The solvents was removed under vaccuum and the residue was loaded to a R18 reverse phase column. The fraction was lyophilized and yielded a 30 pale yellow powder (80 mg, 66%). MS m/z: 428 (M+H)+ 1 H NMR (DMSO, 300 MHz): 4.02 (q, 2H, J=6.1 Hz), 6.92 (dd, I H, JI=J2=5.1 Hz), 7.46 (d, 2H, 8.4 Hz), 7.85 (d, 2H, J=8.5 Hz), 7.88 (d, 1H, 9Hz), 8.12 (br, 3H), 8.22 (d, 1H, J=8.9 Hz), 8.40 (s, -171 SUBSTITUTE SHEFT fRiln F 991 WO 99/05096 PCT/US98/15386 IH ), 8.48 (s, 1H), 8.51 (d, 2H, J=4.8 Hz), 8.64 (s, 1H), 9.74 (s, 2H), 10.61 (s, 2H); Anal. calc'd for C 2 3
H
2 1
N
7 02-2.9 C 2
F
3 0 2 H 1.25 H 2 0: C, 44.31; H, 3.41; N, 12.56; F, 21.17 Found: C, 44.08; H, 3.30: N, 12.50, F, 21.25. 5 Example 168 6-(aminoiminomethyl)-N-[4-(hydroxymethyllphenvll-4-(2-pyrimidinylamino) 2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The desired compound is prepared as described in Example 165 using 4-amino benzyl alcohol instead of 4-amino benzylamine. 10 MS m/z: 413 (M+H)+ 1 H NMR (DMSO, 300 MHz): 4.48 (s, 2H), 6.94 (dd, 1H, 2H, J=8.8 Hz), J1=J2=4.8 Hz), 7.32 (d, 2H, J=8.8 Hz), 7.90 (dd, 1H, JI=8.5 Hz, J2=1.7 Hz), 8.28 (d, 2H, J=8.8 Hz), 8.41 (s, lH), 8.54 (d, 2H, J=4.8 Hz), 8.55 (dd, IH, J=1.3 Hz), 8.80 (s, 1H), 9.08 (s, 2H), 9.43 (s, 2H), 9.73 (s, lH), 10.48 (s, lH); 15 Anal. calc'd for C 23
H
2
ON
6 0 2 : C, 49.06; H, 3.83; N, 12.81; F, 16.50. Found: C, 48.74; H, 3.86; N, 12.63, F, 16.54. Example 170 methyl [3-[rF4-(aminomethyl)phenvllaminolcarbonyll-7-[4-amino(hydroxvimino)methyll 20 1-naphthalenvllcarbamate, bis(trifluoroacetate)(salt) Example 170A To a suspension of the nitrile, Example 141D (213 mg, 0.45 mmol) and hydroxylamine hydrochloride (338 mg, 4.86 mmol) in methanol (40 mL) water (5 mL) was added potassium 25 carbonate (538 mg, 3.9 mmol) stirred at room temperature overnight. The solvent was evaporated and the resulting solid was washed with ether and hexanes to yield the product as white solid 153 mg (62%). MS (ECI) m/z 508 (M+H)+. 30 Example 170B methyl F3-[F[4-(aminomethyl)phenyllamino]carbonyll-7- 4-amino(hydroxvimino)methyll 1-naphthalenvllcarbamate, bis(trifluoroacetate)(salt) The Boc protected substrate, Example 170A was added 3 mL of 4 N HCI in dioxane and stirred at room temperature for 20 minutes. The solvent was evaporated under vacuum and -172 SUBSTITUTF s-IFFT In 11 WO 99/05096 PCT/US98/15386 the product was separated on MPLC with a column of RP C 18 using methanol-water +0. 1%TFA as eluent. Yield of white solid 117 mg (79%). MS (ECI) m/z 408 (M+H)+; IH NMR (300 MHz, DMSO-d 6 ) 6 3.77 (S, 3H), 4.03 (s, 2H), 4.01 (q, J=5.9 2H), 7.46 (d, 5 J=8.5Hz, 2H), 7.86 (d, J=8.5Hz, 2H), 7.90 (dd, Ji=8.5, Hz, J 2 =1.4Hz, 1H), 8.09-8.15 (m, 4H), 8.17 (d, J=8.4Hz, 1H), 8.29 (s, 1H), 8.42 (s, 1H), 8.56 (s, 1H), 9.80 (s, 1H), 10.62 (s, 1H); Anal. calc'd for C21H21N5042.5 TFA.0.5 H 2 0: C, 44.52; H, 3.52; F, 20.31; N, 9.98. Found: C, 44.78; H, 3.57; F, 19.82; N, 9.87. 10 Example 171 6-amino(hydroxvimino)methyl]-N-phenvl-2-naphthalenecarboxanide The title compound is prepared as described by Judkins et al., Synthetic Communications 26 (23), 4351-4367 (1996). The compound prepared in Example 55C (0.1 15 g, .36 mmole) is dissolved in a 10: 1 mixture of Toluene: methanol to which is added hydroxylamine hydrochloride (3.6 mmole) and potassium tert-butoxide (3.6 mmole). The resulting slurry is refluxed for 17 hr., cooled, solvents removed under vacuum. The residue is taken up in distilled water (30 nl) extracted with ethyl acetate (2 X 100 ml). The combined organic extracts are washed with 10% NaCl (50 ml), dried over anhydrous Na2SO4. The 20 sample is filtered of drying agent and the solvent removed under vacuum leaving a white solid (65 mg). The material is purified by medium pressure reverse phase chromatography as described in Example 1. The title compound is obtained as white solid (45 mg) MS (m/z) M + H+: 306 1H NMR (DMSO-d 6 ): 10.51 (s, lH), 9.32 (s, OH), 8.70 (s, IH), 8.57 (s, 1H), 8.34 (d, lH), 25 8.25 (d, IH), 8.17 (dd, lH), 7.90 (dd, lH), 7.83 (d, 2H), 7.40 (dd, 2H), 7.15 (dd, 1H), 6.25 (bs, 2H). Analysis: calc'd for C 20
H
16
N
3 0 4
F
3 : C, 57.28, H, 3.85, N, 10.02; Found C, 56.89, H, 3.65, N, 9.90. 30 Example 174 8-(2-pyridinvlamino)-2-naphthalenecarboximidamide. bis(trifluoroacetate) salt Example 174A -173 SUBSTITUTF quJ4rT rIn C 3 WO 99/05096 PCT/US98/15386 To a solution of the product from 1ID (168 mg, 1.00 mmol) in 5 mL toluene was added 2-bromopyridine (0.105 mL, 1.1 mmol), NaOtBu (135 mg, 1.4 mmol), Pd2dba 3 (92 mg, 0.1 mmol), and P (o-tolyl)3 (122 mg, 0.4 mmol), and the reaction was stirred for 24 hours at 100 'C. The reaction was cooled, and the crude reaction mixture was chromatographed on SiO 2 5 using 50% ethyl acetate/hexanes as fluent to yield 80 mg (33%) of the desired compound. MS (DCI (NH 3 )) m/z 246 (M+H)+. Example 174B 8
-(
2 -pyridinvlamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt 10 The product from Example 174A (121 mg, 0.493 mmol) was dissolved in THF (2 mL) and 0.543 mL of a 1 M solution of LiN (TMS) 2 in THF was added. The reaction was stirred for 5 min, and TMSCl (0.069 mL, 0.543 mmol) was added. After stirring for 30 mn, another 1.09 mL of the I M solution of LiN (TMS) 2 was added. The reaction was stirred for 18 hours, and 10 mL of a 2 M aq. HCI solution was added. The reaction was stirred for another 24 hours, 15 and was basicified with saturated aq. Na 2
CO
3 . The mixture was extracted with 3x ethyl acetate, and the extracts were washed with brine, dried over Na2SO 4 , and condensed. The crude product was purified by reverse-phase HPLC to yield the desired compound (21 mg, 7%): m.p. 137-147 0 C. MS (DC (NH 3 ) m/z 263 (M+H)+; 20 IH NMR (300 MHz, DMSO) 6 9.98 (br s, 1H), 9.46 (br s, 2H), 9.27 (br s, 2H), 8.74 (s, IH), 8.21 (d, J=9 Hz, 1H), 8.11 (d, J=6 Hz, 1H), 8.02 (d, J=9 Hz, lH), 7.81-7.95 (m, 3H), 7.75 (dd, J=9, 9 Hz, 1H), 7.16 (m, 1H), 6.95 (m, IH), 2.55 (s, 3H); Anal. calc'd for C 16
H
14
N
4 -3.1C 2
HF
3 0 2 : C, 43.30; H, 2.80; N, 9.10. Found: C, 43.14; H, 3.04; N, 9.90. 25 Example 176 6
-[
4 -[(hydroxvmethyl)phenyllmethoxyl-2-naphthalenecarboximidamide, methanesulfonate(salt) Example 176A 30 To a solution of NaH (60% in mineral oil, 1.17 g, 29.3 mmol) in THF (50 mL) was added 4-bromobenzyl alcohol (5.22 g, 27.9 mmol) in THF (50 mL), and the reaction was stirred at room temperature for 20 minutes. p-Methoxybenzyl chloride (4.07 mL, 30 mmol) was then added, and the reaction was stirred at 50'C for 2 hours. The mixture was poured into water and extracted with 3x diethyl ether, and the extracts were washed with brine, dried over -174 SUBSTITUTE nWu r fi 11 C WO 99/05096 PCT/US98/15386 Na2SO4, and condensed. The crude reaction mixture was chromatographed on SiO 2 using hexanes as eluent, to yield 7.39 g (86%) of the desired compound. MS (DCI (NH 3 )) m/z 326 (M+NH 4 )+; 1 H NMR (300 MHz, CDCl 3 ) 6 7.47 (d, 2H), 7.28 (d, 2H), 7.23 (d, 2H), 6.90 (d, 2H), 4.48 5 (s, 3H), 4.47 (s, 2H), 3.91 (s, 3H). Example 176B To a solution of the product from Example 176A (6.80 g, 22.13 mmol) in THF (100 mL) and hexanes (20 mL) at -I 00 0 C was added a 2.5 M solution of BuLi (8.85 mL, 22.13 10 mmol), and the reaction was stirred for 2 minutes. DMF (3.43 mL, 44.3 mmol) was then added, and the reaction was warmed to room temperature. The mixture was poured into water and extracted with 3x diethyl ether, and the extracts were washed with brine, dried over Na2SO4, and condensed. The crude reaction mixture was taken up in methanol (100 mL) and NaBH4 (1.0 g, 26.2 mmol) was added in portions. A few drops of water were added, and the 15 mixture condensed. The residue was chromatographed on SiO 2 using 20% ethyl acetate/hexanes as eluent, to yield 3.32 g (58%) of the desired compound. MS (DCI (NH 3 )) m/z 276 (M+NH 4 )+; 1 H NMR (300 MHz, CDCl 3 ) 8 7.38 (s, 4H), 7.29 (d, 2H), 6.90 (d, 2H), 4.70 (s, 2H), 4.54 (s, 2H), 4.49 (s, 2H), 3.81 (s, 3H), 1.62 (s, IH). 20 Example 176C To a solution of the product from Example 176B (193 mg, 0.747 mmol), the product from Example 28A (139 mg, 0.822 mmol), and Ph 3 P (216 mg, 0.822 mmol) in THF (10 mL) at 0 0 C was added diethylazodicarboxylate (0.129 mL, 0.822 mmol), and the reaction was 25 stirred for 90 minutes at room temperature. The crude reaction mixture was condensed, and the residue was chromatographed on SiO 2 using 10% ethyl acetate/hexanes as eluent, to yield 225 mg (74%) of the desired compound. MS (DCI (NH 3 )) m/z 427 (M+NH 4 )+; IH NMR (300 MHz, CDCl 3 ) 6 8.15 (s, 1H), 7.81 (d, lH), 7.77 (d, 1H), 7.58 (dd, 1H), 7.48 30 (d, 2H), 7.42 (d, 2H), 7.02-7.15 (m, 4H), 6.90 (d, 2H), 5.21 (s, 2H), 4.56 (s, 2H), 4.51 (s, 2H), 3.91 (s, 3H). Example 176D -175 SUBSTITUTE RHFF-r iRi i i WO 99/05096 PCT/US98/15386 To a solution of the product from Example 176C (220 mg, 0.537 mmol) in CH 2 C1 2 (40 mL) and water (7 mL) was added DDQ (244 mg, 1.07 mmol), and the reaction was stirred for 90 minutes. The crude reaction mixture was taken up in CH 2 Cl 2 , washed with 2x aqueous NaHCO 3 and brine, dried over Na2SO 4 , and condensed. The residue was chromatographed on 5 SiO 2 using 50% ethyl acetate/hexanes as eluent, to yield 89 mg (57%) of the desired compound. MS (DCI (NH 3 )) m/z 307 (M+NH 4 )+; IH NMR (300 MHz, CDCl 3 ) 6 8.15 (s, 1H), 7.81 (d, IH), 7.77 (d, 1H), 7.57 (dd, 1H), 7.49 (d, 2H), 7.41 (d, 2H), 7.33 (dd, 1H), 7.21 (d, IH), 5.21 (s, 2H), 4.74 (s, 2H), 1.63 (br s, 10 1H); Example 176E 6
-
4 -[(hydroxymethyl)phenyllmethoxyl-2-naphthalenecarboximidamide, methanesulfonate(salt) The desired compound was prepared from Example 176D and the procedure of Example 15 55D. MS (DCI/NH 3 ) m/z 307 (M+H)+; I H NMR (300 MHz, DMSO-d 6 ) 6 2.31 (s, 3H), 4.52 (s, 2H), 5.25 (s, 2H), 7.37 (d, 2H), 7.39 (dd, lH), 7.47 (d, 2H), 7.59 (d, lH), 7.79 (dd, 1H), 8.00 (d, 1H), 8.03 (d, IH), 8.41 (s, IH), 8.89 (br s, 2H), 9.34 (br s, 2H); 20 Anal. calc'd for C 19
H
18
N
2 02-1.15 CH 4
SO
3 : C, 58.06; H, 5.46; N, 6.72. Found: C, 58.24; H, 5.62; N, 6.59. Example 177 N-hydroxy-8-(2-pyrimidinvlamino)- 2 -naphthalenecarboximidamide, 25 mono(trifluoroacetate)(salt) The desired compound is prepared from the nitrile described in Example 163 and utilizing the procedure described in Example 167. Yield as a white powder: 50 mg MS m/z: 280 (M+H)+ 30 IH NMR (DMSO, 300 MHz): 6.90 (dd, 1H, J1=J2=5.2Hz), 7.45 (m, 3H), 8.0 (d, 1H, J=8.5 Hz), 8.14 (d, 1H, J=8.4Hz), 8.49 (d, J=5.3 Hz), 8.61 (s, 1H), 9.58 (s, 1H); Anal. calc'd for C 1 5
H
13
N
5 0-2.0 C 2
F
3 0 2 H-0.5 H 2 0: C, 44.20; H, 3.12; N, 13.56. Found: C, 44.24; H, 2.94; N, 13.49. -176 SUBSTITUTF qWFF-T 1n1 It C WO 99/05096 PCT/US98/15386 Example 179 6-(2-pyridinvlethynvl)-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) Example 179A .5 Using the product obtained in Example 28B, 2-ethynylpyridine (Lancaster Chemical Corp.) and the procedure described in Example 121 A, the desired compound was obtained. MS (DCI/NH 3 ) m/z 255 (M+H)+. Example 179B 10 Using the product obtained in Example 179A and the procedure described in Example 94D the desired compound was obtained. MS (DCI) m/z 272 (M+H)+; 1 H NMR (300 MHz, DMSO) 6 7.45-7.50 (m, lH), 7.72 (d, IH), 7.82 (dd, IH), 7.86-7.92 (m, 2H), 8.18 (d, lH), 8.22 (d, lH), 8.42 (s, lH), 8.54 (s, lH), 8.68 (m, lH), 9.25 (s, 2H), 15 9.49 (s, 2H); Anal. calc'd for C 20
H
1 4
F
3 N30 2 -0.25 H 2 0: C, 61.62; H, 3.75; N, 10.78. Found: C, 61.72; H, 3.64; N, 10.66. Example 180 20 6-(aminoiminomethyl)-N-phenvl-4-(tetrahydro-3-furanyl)-2-naphthalenecarboxainde, monohydrochloride Example 180A The desired compound was prepared from the product from Example 152 by the 25 procedure of Example 62A. MS (DCI/NH 3 ) n/z 340 (M-H 2 0)+. Example 180B The desired compound was prepared from the product from Example 180A by the 30 procedure of Example 62B. MS (DCI/NH 3 ) m/z 343 (M+H)+. Example 180C -177 SUBSTITUJTF qWFPT RIn 11 o WO 99/05096 PCT/US98/15386 The desired compound was prepared from Example 180B and the procedure of Example 55D. MS (DCI/NH 3 ) m/z 360 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ) 6 2.20 (m, 1H), 2.52 (m, 1H), 3.85 (dd, 1H), 3.94 (ddd, 5 lH), 4.08 (ddd, lh), 4.26 (dddd, 1H), 4.39 (dd, 1H), 7.14 (t, 1H), 7.40 (t, 2H), 7.81 (d, 2H), 7.95 (d, IH), 8.08 (s, 1H), 8.32 (d, lH), 8.59 (s, lH), 8.79 (s, 1H), 9.25 (br s, 2H), 9.61 (br s, 2H); Anal. calc'd for C 22
H
2 1
N
3 02 2.6 HCl: C, 58.18; H, 5.24; N, 9.25. Found: C, 58.21; H, 4.91; N, 9.13. 10 Example 181 6-[amino(hydroxvimino)methylI -N-phenvl-4-(2-pyrimidinvlamino)-2-naphthalenecarboxamide Prepared in a similar manner as described in Example 177 using the material prepared in Example 166. 15 MS m/z: 399 (M+H)+ 1 H NMR (DMSO, 300 MHz): 6.88 (dd, 1H, 4.7Hz), 7.11 (dd, lH, Jl=J2=7.5Hz), 7.37 (dd, 2H, Jl=J2=7.5 Hz), 7.82 (d, 2H, J=8.8 Hz), 7.94 (dd, lH, JI=8.5Hz, J2=1.4 Hz), 8.04 (d, 1H, J=8.8Hz), 8.31 (s, 1H), 8.43 (dd, IH, J=14 Hz), 8.74 (d, 2H, J=4.7 Hz), 8.52 (s, 1H), 9.55 (s, 1H), 9.85 (s, 2H), 10.41 (s, 1H); 20 Anal. calc'd for C 22
H
18
N
6 02-0.4 H 2 0: C, 65.14; H, 4.67; N, 20.72. Found: C, 65.57; H, 4.45; N, 20.18. Example 182 methyl 4 -f[F 7 -amino(hydroxvimino)methyll-2-naphthalenvlloxvlmethyllbenzoate 25 The resulting product from Example 213A (110 mg, 0.347 mmol), hydroxylamine hydrochloride (26.5 mg, 0.381 mmol), triethylamine (53 l, 0.381 mmol) and N, N dimethylformamide (12 mL) were combined in a four inch glass pressure tube. The tube was sealed and heated for 24 hours at 80 'C. The tube was cooled to room temperature and additional hydroxylamine hydrochloride (48.1 mg, 0.693 mmol) and triethylamine (96.6 1tl, 30 0.693 mmol) in N, N-dimethylformamide (2 mL) was added. The tube was resealed and heated for 24 hours at 80 C. The addition, as above, was repeated a second time, the tube was resealed and heated for 72 hours at 80 C. The reaction mixture was concentrated to a solide residue which was purified by column chromatography on silica gel (60 g) eluted with 15% -178 SUBSTITrT q:M-r lot E1 C WO 99/05096 PCT/US98/15386 acetone in methylene chloride to yield the target compound as a white solid (43 mg, 50% based on recovered starting material). MS (DCI (NH 3 )) m/z 351 (M+H)+; 1 H NMR NMR (300 MHz, DMSO-d6) 6 3.860 (s, 3H), 5.349 (s, 2H), 5.860 (s, 2H), 7.280 5 (dd, lH), 7.381 (d, 1H), 7.660 (d, 2H), 7.688 (dd, 1H), 7.805 (d, 1H), 7.850 (d, 1H), 8.010 (d, 2H), 8.070 (s, 1H), 9.724 (s, lH); Anal. calc'd for C20H18N204-0.15 H 2 0: C, 68.04; H, 5.22; N, 7.93. Found: C, 68.06; H, 5.05; N, 7.87. 10 Example 184
N-[
4 -(aminocarbonylphenyll-6-(aminoiminomethyll-2-naphthalenecarboxamide, mono(trifluoroacetate) salt Example 184A 15 A suspension of the product obtained in Example 8A (300 mg, 1.39 mmol) and 5 mL dichloromethane was added dropwise to a 00 solution of 4-aminobenzamide (207 mg, 1.52 mmol), triethylamine (0.44 mL, 3.2 mmol), and 10 mL dichloromethane. The reaction mixture was stirred for 0.5 hour at 00 and for 18 hours at room temperature. Excess ether was added with stirring and the resultant solid was filtered, washed with 1 N HCl, water, and was dried 20 under vacuum to afford the desired compound. MS (DCI) m/z 333 (M+NH 3 )+. Example 184B
N-[
4 -(aminocarbonyl)phenvl]-6-(aminoiminomethyl)-2-naphthalenecarboxamide, 25 mono(trifluoroacetate) salt Using the product obtained in Example 184A and the procedure described in Example 4C the desired compound was obtained. MS (DCI) m/z 333 (M+H)+; IH NMR (300 MHz, DMSO) 6 10.76 (S, 1H), 9.51 (S, 2H), 9.14 (S, 2H), 8.74 (S, 1H), 30 8.56 (S, IH), 8.33 (D, lH, J=8.8 Hz), 8.26 (D, 1H, J=8.8 HZ Hz), 8.16 (DD, 1H, J=8.46, 1.11 Hz), 7.91 (M, 6H), 7.31 (S, 1H); Anal. calc'd for C20H1 7 F3N 4 04-1.5 H 2 0: C, 53.28; H, 4.26; N, 11.83. Found: C, 53.47; H, 3.86; N, 11.96. -179 SUBSTITUTF WFT fmIn I= WO 99/05096 PCTIUS98/15386 Example 185 methyl 2- [ [6-(aminoiminomethyl)-2-naphthalenvll oxyl acetate, mono(trifluoroacetate)(salt) Example 185A 5 7-methoxy-2-cyanonaphthalene, (2.79 g, 5.23 mmol) and tetrabutylammonium iodide (17 mg, 0.157 mmol) were combined in a mixture of benzene (35 mL) and cyclohexanes (17.5 mL). The resulting solution was added to a rapidly stirring, cooled (ice/water) suspension of aluminum triiodide (6.21 g, 15.23 mmol) in a mixture of benzene (35 mL) and cyclohexanes (17.5 mL) under an inert atmosphere. After the addition, the resulting suspension was heated at 10 reflux for 2.5 hours. The heating was removed and after cooling to near room temperature, the reaction mixture was cooled in an ice bath and quenched by the addition of water (100 mL). The resulting mixture was further diluted with 2 M aqueous sodium thiosulfate solution (50 mL) and extracted with ethyl acetate (3 X 80 mL). The combined organic layers were dried and evaporated. The resulting solid was dissolved in a minimum of hot ethyl acetate, diluted hot 15 with hexanes to the cloud point and placed in a refrigerator for 2 hours. The desired compound was collected by filtration, (1.99 g, 77%). MS (DCI (NH 3 )) m/z 187 (M+NH 4 )+. Example 185B 20 The resulting product from Example 185A (217 mg, 1.283 mmol) was combined with cesium carbonate (460 mg, 1.411 mmol) and tetrabuthylammonium iodide (catalytic) in DMF (7 mL). To this was added t-butyl bromoacetate (193 tL, 1.283 mmol) and the resulting mixture was stirred 2 hours under an inert atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were dried 25 and evaporated. The residue was purified by column chromatography to yield the desired compound as an oil (332 mg, 9 1%): MS (DCI (NH 3 )) m/z 284 (M+H) +, 301 (M+NH 4 )+. Example 185C 30 methyl 2-[[6-(aminoiminomethyl)-2-naphthalenvlloxylacetate, mono(trifluoroacetate)(salt) The product from Example 185B (323 mg, 1.140 mmol) was dissolved in anhydrous methanol (32 mL) under an inert atmosphere and cooled to 0 'C. Anhydrous hydrogen chloride was bubbled into the solution until it became saturated. The reaction was stirred for 15 minutes at 0 'C and saturated again with anhydrous hydrogen chloride. After stirring for an additional 20 -180 SUBSTITUTE ql4F=T mi 1= I m WO 99/05096 PCT/US98/15386 minutes at 0 'C the solution was saturated one final time with anhydrous hydrogen chloride and stirred 18 hours while warming to room temperature. The reaction was evaporated to a solid and dried under high vacuum for 2 hours. The solid was slurried in methanol (64 mL), ammonium acetate (220 mg, 2.850 mmol) was added, and the mixture was heated at reflux 2 5 hours. The reaction was evaporated and purified by reverse phase chromatography to give the desired compound (265 mg, 90%). MS (DCI (NH 3 )) m/z 259 (M+H)+; IH NMR (300 MHz, DMSO-d6) 6 3.735 (s, 3H), 4.995 (s, 2H), 7.430 (dd, 1H), 7.458 (s, lH), 7.669 (dd, 1H), 8.025 (d, 1H), 8.095 (d, IH), 8.325 (d, 1H), 9.090 (br s, 1H), 9.410 10 (br s, IH; Anal. calc'd for C 1 4
H
14
N
2 0 3 - (C 2
HO
2
F
3 ) 1.05: C, 51.16; H, 4.01; N, 7.41. Found: C, 51.35; H, 3.98; N, 7.48. Example 186 15 6-(aminoiminomethyl)-N-(2-thiazolyl)-2-naphthalenecarboxamide, monohydrochloride Example 186A The above product was prepared in the manner of Example 8A using 2-aminothiazole. MS (APCI) m/z (M+H)+ 280. 20 Example 186B 6 -(aminoiminomethyl)-N-(2-thiazolvl)-2-naphthalenecarboxamide, monohydrochloride The above was prepared from Example lB. MS (APCI) m/z (M+H)+ 297; 25 1 H-NMR (300 MHz, DMSO-d 6 ) 6 12.88 (s, IH), 9.59 (s, 2H), 9.30 (s, 2H), 8.87 (s, IH), 8.59 (s, IH), 8.32-8.22 (m, 4H), 7.93 (dd, J=1.8, 8.4 Hz, 1H), 7.61 (d, J=3.3 Hz, lH), 7.33 (d, J=3.3 Hz, lH); Anal. calc'd for C 15
H
13
N
4 0CIS 2/5 HCl: C, 52.03; H, 3.89; N, 16.18. Found: C, 52.01; H, 3.88; N, 16.12. 30 Example 187 6-(aminoiminomethyl)-N-(6-methoxv-3-pyridinl)-2-naphthalenecarboxamide, monohydrochloride -181 SUBSTITUTF qwFI=T rn C om WO 99/05096 PCTIUS98/15386 Example 187A The above product was prepared in the manner of Example 8A using 5-amino-2 methoxypyridine. MS (APCI) m/z (M+H)+ 304. 5 Example 187B 6 -(aminoiminomethyl)-N-(6-methoxy-3-pyridinyl)-2-naphthalenecarboxamide, monohydrochloride The above was prepared as described Example lB (144D). 10 MS (CI) m/z (M+H)+ 321; lH-NMR (300 MHz, DMSO-d 6 ) 6 10.71 (s, 1H), 9/60 (s, 2H), 9.41 (s, 2H), 8.76 (s, 1H), 8.60 (s, 2H), 8.30 (d, J=9, 1H), 8.25-8.12 (m, 4H), 7.93 (dd, J=1.8, 8.7 Hz, 1H), 6.89 (d, J=9.0 Hz, IH), 3.87 (s, 3H); Anal. calc'd for C 20
H
17
N
4 0 4
F
3 1/2 TFA: C, 51.47; H, 3.60; N, 11.45. Found: C, 51.39; H, 15 3.88; N, 11.65. Example 188 6-(aminoiminomethyl)-N-(1. 3 -benzodioxol-5-vl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) 20 Example 188A The above product was prepared in the manner of Example 8A using 3, 4 methylenedioxyaniline. MS (APCI) m/z (M+H)+ 317. 25 Example 188B The above was prepared as described Example 1 B. MS (CI) m/z (M+H)+ 334; I H-NMR (300 MHz, DMSO-d 6 ) 6 9.70 (s, 1H), 8.20 (s, 2H), 9.96 (s, 1H), 7.81-87.63 (m, 30 3H), 7.31 (dd, J=1.8, 8.4 Hz, 1H), 7.11 (d, J=4.2 Hz, 1H), 6.91 (dd, J=4.5, 10.8 Hz), 6.4 (d, J=8.4 Hz, 1H), 5.59 (s, 2H); Anal. calc'd for C 2 1
H
16
N
3 0 3
F
3 3/5 TFA: C, 55.44; H, 3.48; N, 8.77. Found: C, 55.44; H, 3.52; N, 8.85. -182 SUBSTITUTF s-sFFT RIn 1= P WO 99/05096 PCTIUS98/15386 Example 189 6-(aminoiminomethyl)-N-(l, 2, 3, 4-tetrahydro-2, 4-dioxo5-pyrimidinvl) 2-naphthalenecarboxamide. monohydrochloride 5 Example 189A The above product was prepared in the manner of Example 8A using 5-aminouracil. MS (APCI) m/z (M-H)+ 305. Example 189B 10 6-(aminoiminomethyl)-N-(1, 2. 3, 4-tetrahydro-2, 4-dioxo5-pyrimidinvl) 2-naphthalenecarboxamide, monohydrochloride The above was prepared as described in Example lB. MS (CI) m/z (M+H)+ 324; IH-NMR (300 MHz, DMSO-d 6 ) 6 11.50 (s, 1H), 10.90 (m, lH), 9.53 (s, 3H), 9.21 (s, 2H), 15 8.70 (s, lH), 8.55 (s, 1H), 8.33 (d, J=8.4 Hz, lH), 8.20 (d, J=8.7 Hz, lH), 8.13-8.09 (m, 2H), 8.00 (s, lH), 7.88 (dd, J=1.8, 8.4 Hz, lH); Anal. calc'd for C 16
H
14
N
5 0 3 Cl 2/5 HCl: C, 51.49; H, 3.88; N, 18.76. Found: C, 51.87; H, 4.01; N, 17.68. 20 Example 190 6-(aminoiminomethyl)-N-(3, 5-difluorophenvl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) Example 190A 25 The above product was prepared in the manner of Example 8A using 3, 5 difluoroaniline. MS (APCI) m/z (M-H)+ 307. Example 190B 30 6-(aminoiminomethyl)-N-(3, 5-difluorophenvl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) The above was prepared as described in Example lB. MS (CI) m/z (M+H)+ 326; -183 SUBSTITUTE S4FFT Ri 11 = IM WO 99/05096 PCT/US98/15386 lH-NMR (300 MHz, DMSO-d 6 ) 6 10.93 (s, IH), 9.53 (s, 2H), 9.34 (s, 2H), 8.71 (s, 1H), 8.58 (s, IH), 8.33 (d, J=8.4 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 8.14 (m, 1H), 7.92 (dd, J=0.9, 8.1 Hz, 1H), 7.61 (d, J=7.8 Hz, 2H), 7.04-6.97 (m, 1H); Anal. calc'd for C 20
H
14
N
3 0 2
F
5 2/5 TFA: C, 54.92; H, 3.21; N, 9.42. Found: C, 54.96; H, 5 3.36; N, 9.37. Example 191 6-(aminoiminomethyl)-N-(1H-pyrazol-3-vl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) 10 Example 191 A The above product was prepared in the manner of Example 8A using 3-aminopyrazole. MS (APCI) m/z (M+H)+ 263. 15 Example 191B 6-(aminoiminomethyl)-N-(1 H-pyrazol-3-vl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The above was prepared as desribed in Example lB. MS (CI) m/z (M+H)+ 280; 20 IH-NMR (300 MHz, DMSO-d 6 ) 6 11.13 (s, 1H), 9.55 (s, 2H), 9.37 (s, 2H), 8.75 (s, 1H), 8.55 (s, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.12 (s, 2H), 7.90 (d, J=8.4 Hz, 1H), 7.70 (s, 1H), 6.69 (s, IH); Anal. calc'd for C 1 7
H
14
N
5 0 3
F
3 7/10 TFA: C, 46.53; H, 3.12; N, 14.70. Found: C, 46.47; H, 3.16; N, 14.85. 25 Example 192 6-(aminoiminomethyl)-N-(5-methyl-3-isoxazolvll)-2-naphthalenecarboxan-ide, mono(trifluoroacetate)(salt) 30 Example 192A The above product was prepared in the manner of Example 8A using 3-amino-5 methylisoxazole. MS (APCI) m/z (M+H)+ 278. -184 SUBSTITUTE SHEET (RUL= 9M WO 99/05096 PCT/US98/15386 Example 192B 6-(aminoiminomethyl)-N-(5-methyl-3-isoxazolvll)-2-naphthalenecarboxaniide, mono(trifluoroacetate)(salt) The above was prepared as described in Example lB. 5 MS (CI) m/z (M+H)+ 295; lH-NMR (300 MHz, d 6 -DMSO) 6 11.62 (s, 1H), 9.52 (s, 2H), 9.33 (s, 2H), 8.78 (s, 1H), 8.55 (dd, 1H), 8.31-8.16 (m, 3H), 7.90 (dd, IH), 6.81 (s, lH), 2.44 (s, 3H) Anal. calc'd for C 18
H
15
N
4 0 4
F
3 : C, 52.95; H, 3.70; N, 13.72. Found: C, 52.73; H, 3.64; N, 13.24. 10 Example 193 6-(aminoiminomethyl)-N-(pyrazinvl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) Example 193A 15 The above product was prepared in the manner of Example 8A using 2-aminopyrazine. MS (APCI) m/z (M-H)+ 275. Example 193B 6-(aminoiminomethyl)-N-(pyrazinvl)- 2 -naphthalenecarboxamide. mono(trifluoroacetate)(salt) 20 The above was prepared as described in Example lB. MS (CI) m/z (M+H)+ 292; 1 H-NMR (300 MHz, d 6 -DMSO) 5 11.41 (s, lH), 9.52 (s, 2H), 9.49 (s, 1H), 9.27 (s, 2H), 8.83 (s, lH), 8.56 (s, IH), 8.53-8.46 (m, 2H), 8.30 (d, 1H), 8.23 (s, 2H), 7.90 (dd, lH); Anal. calc'd for Cj 8
H
14
N
5 0 3
F
3 : C, 49.36; H, 3.16; N, 15.15 1/2 TFA. Found: C, 49.53; H, 25 3.22; N, 14.87. Example 194 6 -(aminoiminomethyll-N-(6-methyl-2-pvridinyl)-2-naphthalenecarboxamide, mono(trifl uoroacetate)(salt) 30 Example 194A The above product was prepared in the manner of Example 8A using 2-amino-6 methylpyridine. MS (APCI) m/z (M+H)+ 288. -185 SUBSTITUTE SHFRT Im n = -rm WO 99/05096 PCT/US98/15386 Example 194B 6 -(aminoiminomethyl)-N-(6-methyl-2-pyridinvll-2-naphthalenecarboxamijde, mono(trifluoroacetate)(salt) 5 The above was prepared as described in Example 1B. MS (CI) m/z (M+H)+ 305; IH-NMR (300 MHz, d 6 -DMSO) 8 11.02 (s, 1H), 9.53 (s, 2H), 9.37 (s, 2H), 8.80 (s, 1H), 8.55 (s, 1H), 8.29 (d, lH), 8.20 (s, 2H), 8.07 (d, 1H), 7.89 (d, 1H), 7.78 (t, 1H), 7.08 (d, I H), 2.48 (s, 3H); 10 Anal. calc'd for C 20
H
17
N
4 0 3
F
3 : C, 48.74; H, 3.33; N, 10.20 7/5 TFA. Found: C, 48.74; H, 3.59; N, 10.11. Example 195 6-(aminoiminomethyl)-N-(3, 4, 5-trimethoxvphenvl)-2-naphth alenecarboxamide, 15 monohydrochloride Example 195A The above product was prepared in the manner of Example 8A using 3, 4, 5 trimethoxyaniline. 20 MS (APCI) m/z (M+H)+ 363. Example 195B 6-(aminoiminomethyl)-N-(3, 4, 5-trimethoxyphenvl)-2-naphthalenecarboxamide, monohydrochloride 25 The above was prepared as described in Example lB. MS (CI) m/z (M+H)+ 380; IH-NMR (300 MHz, d 6 -DMSO) 6 10.54 (s, lH), 9.61 (s, 2H), 9.34 (s, 2H), 8.72 (s, 1H), 8.59 (s, lH), 8.33-8.15 (m, 3H), 7.91 (dd, 1H), 7.30 (s, 2H), 3.80 (s, 9H) Anal. calc'd for C 2 1
H
22
N
3 0 4 Cl 63/10 HCl: C, 39.09; H, 4.42; N, 6.51. Found: C, 38.94; H, 30 4.60; N, 7.61. Example 196 6 -(aminoiminomethyl)-N-(3-methyl-2-pyridinvl)-2-naphthalenecarboxamide, bis(trifluoroacetate)(salt) -186 SUBSTITUTF wnFrFT 1121 It m WO 99/05096 PCT/US98/15386 Example 196A Using the procedure described for Example 184A and substituting 2-amino-3-picolene for 4-aminobenzanide, the desired compound was obtained. 5 MS (DCI) m/z 288 (M+H)+. Example 196B 6 -(aminoiminomethyl)-N-(3-methyl-2-pyridinyll-2-naphthalenecarboxamide, bis(trifluoroacetate)(salt) 10 Using the procedure described in Example 1B and the product obtained in Example 196A, the desired compound was obtained. MS (DCI) m/z 305 (M+H)+; IH NMR (300 MHz, DMSO) 6 10.85 (s, IH), 9.52 (s, 2H), 9.22 (s, 2H), 8.76 (s, lH), 8.56 (s, lH), 8.35 (dd, lH, J=4.41, 1.10), 8.32 (d, 1H, J=8.80), 8.22 (m, 2H), 7.90 (dd, 1H, 15 J=8.83, 1.84), 7.80 (dd, IH, J=7.73, 1.11), 7.31 (dd, lH, J=7.72, 4.78), 2.26 (s, lH); Anal. calc'd for C 22 HigF 6
N
4 0 3 -0.75 H 2 0: C, 48.40; H, 3.60; N, 10.26. Found: C, 48.81; H, 3.66; N, 10.43. Example 197 20 6 -(aminoiminomethyl)-N-(5-bromo-2-thiazolll)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) Example 197A Using the procedure described for Example 184A and substituting 2-amino-5 25 bromothiazole for 4-aminobenzamide, the desired compound was obtained. MS (DCI) n/z 358 (M+H)+. Example 197B 6 -(aminoiminomethyl)-N-(5-bromo-2-thiazolvll)-2-naphthalenecarboxamide, 30 mono(trifluoroacetate)(salt) Using the procedure described in Example lB and the product obtained in Example 197A, the desired compound was obtained. MS (ESI+) m/z 375 (M+H)+; -187 SUBSTITUTF suFFT RInn M i WO 99/05096 PCT/US98/15386 IH NMR (300 MHz, DMSO) 6 10.85 (s, 1H), 9.55 (s, 2H), 9.24 (s, 2H), 8.87 (s, IH), 8.57 (d, IH, J=1.69), 8.31 (d, 1H, J=8.47), 8.25 (d, 2H, J=1.01), 7.92 (dd, 1H, J=8.48, 2.04), 7.71 (s, 1H); Anal. calc'd for C 17
H
12 BrF 3
SN
4 03-1.25 H 2 0-0.25 TFA: C, 38.90; H, 2.75; N, 10.37. 5 Found: C, 38.97; H, 3.24; N, 10.66. Example 198 6-(aminoiminomethyl)-N-(5-methyl-2-pyridinvl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) 10 Example 198A Using the procedure described for Example 184A and substituting 2-amino-5-picolene for 4-aminobenzamide, the desired compound was obtained. MS (ESI+) m/z 288 (M+H)+. 15 Example 198B 6-(aminoiminomethyl)-N-(5-methyl-2-pyridinvl)-2-nahthalenecarboxamide, mono(trifluoroacetate)(salt) Using the procedure described in Example lB and the product obtained in Example 20 198A, the desired compound was obtained. MS (DCI) m/z 305 (M+H)+; IH NMR (300 MHz, DMSO) 6 11.01 (s, IH), 9.50 (s, 2H), 9.16 (s, 2H), 8.79 (s, lH), 8.54 (s, lH), 8.30 (d, lH, J=9.19), 8.27 (d, 1H, J=1.47), 8.20 (s, 2H), 8.15 (d, lH, J=8.83), 7.89 (dd, IH, J=8.46, 1.48), 7.72 (dd, IH, J=8.46, 1.84), 2.31 (s, 3H); 25 Anal. calc'd for C 20
H
17
F
3
N
4 0 3 -0.25 H 2 0-0.2 TFA: C, 54.98; H, 4.00; N, 12.57. Found: C, 54.99; H, 3.59; N, 12.43. Example 199 6-(aminoiminomethyl)-N-(4-methyl-2-thiazolyl)-2-naphthalenecarboxamide, 30 mono(trifluoroacetate)(salt) Example 199A Using the procedure described for Example 184A and substituting 2-amino-5-methyl benzothiazole for 4-aminobenzamide, the desired compound was obtained. -188 SUBSTITUTF -q-T RI 1 =IM WO 99/05096 PCTIUS98/15386 MS (ESI-) m/z 293 (M+H)-. Example 199B 6-(aminoiminomethyl)-N-(4-methyl-2-thiazolyl)-2-naphthalenecarboxamide, S mono(trifluoroacetate)(salt) Using the procedure described in Example lB and the product obtained in Example 199A, the desired compound was obtained. MS (ESI+) m/z 311 (M+H)+; IH NMR (300 MHz, DMSO) 8 9.51 (s, 2H), 9.25 (s, 2H), 8.86 (s, 1H), 8.55 (s, lH), 8.30 10 (d, 1H, J=8.48), 8.25 (d, IH, J=2.03), 7.91 (dd, 1H, J=8.48, 1.70), 6.87 (s, 1H), 2.34 (s, 3H); Anal. calc'd for C 18
H
1 5
F
3
N
4
SO
3 -0.5 TFA: C, 47.40; H, 3.25; N, 11.64. Found: C, 47.90; H, 3.36; N, 11.71. 15 Example 200 6-(aminoiminomethyl)-4-45-(ethylthio)-3-furanyll-N-phenyl-2-naphthalenecarboxamide, monohydrochloride Example 200A 20 The desired compound was prepared from 2-trimethylsilyl-3-bromofuran and diethyldisulfide by the procedure of Example 154A. MS (DCI/NH 3 ) m/z 279, 281 (M+H)+. Example 200B 25 A solution of the product from Example 200A (8.60 g, 30.8 mmol) in THF (20 mL) and a I M solution of TBAF (61.6 mL) was stirred for 24 hours. The reaction was condensed and chromatographed on Si0 2 using hexanes as eluent, to yield 3.32 g (52%) of 2-ethylthio-4 bromofuran. The desired compound was prepared from this material by the procedure of Example 57A. 30 MS (DCI/NH 3 ) m/z 127 (M-B (OH) 2 )+. Example 200C The desired compound was prepared from the product from Example 200B and the product from Example 152C by the procedure of Example 57B. -189 SUBSTITUTE SHEFT Rin 1= POM WO 99/05096 PCTIUS98/15386 MS (DCI/NH 3 ) m/z 416 (M+NH 4 )+. Example 200D 6-(aminoiminomethyl)-4-[5-(ethvlthio)-3-furanyll-N-phenvl-2-naphthalenecarboxamide, monohydrochloride The desired compound was prepared from Example 200C and the procedure of Example 144C. MS (DCI/NH 3 ) m/z 416 (M+H)+; IH NMR (300 MHz, DMSO-d 6 ) 5 1.30 (t, 3H), 2.92 (q, 2H), 7.15 (t, IH), 7.34 (s, IH), 10 7.40 (t, 2H), 7.83 (d, 2H), 7.92 (dd, 1H), 8.20 (d, 1H), 8.40 (d, 1H), 8.47 (s, 1H), 8.60 (s, lH), 8.69 (s, IH), 9.21 (br s, 2H), 9.58 (br s, 2H), 10.61 (s, 1H); Anal. calc'd for C 24
H
2 1
N
3 SO2-1.5 HC1: C, 61.31; H, 4.82; N, 8.94. Found: C, 61.39; H, 4.89; N, 9.03. 15 Example 201 6-(aminoiminomethyl)-4-[5-(propylthio)-3-furanyll -N-phenyl-2-naphthalenecarboxamide, monohydrochloride Example 201 A 20 The desired compound was prepared from 2-trimethylsilyl-3-bromofuran and dipropyldisulfide by the procedure of Example 154A. MS (DCI/NH 3 ) m/z 293, 295 (M+H)+. Example 201B 25 The desired compound was prepared from the product from Example 201A by the procedure of 154B. MS (DCI/NH 3 ) m/z 432 (M+H)+. Example 201C 30 The desired compound was prepared from the product from Example 201 B and the product from Example 152C by the procedure of Example 154C. MS (DCI/NH 3 ) m/z 430 (M+NH 4 )+. Example 201D -190 SUBSTITUTE SH1FT [Pill : im WO 99/05096 PCT/US98/15386 6-(aminoiminomethvl)-4- r5-(propylthio)-3-furanyll -N-phenyl-2-naphthalenecarboxamide, monohydrochloride The desired compound was prepared from Example 201 C and the procedure of Example 144C. 5 MS (DCI/NH 3 ) m/z 430 (M+H)+; IH NMR (300 MHz, DMSO-d 6 ) 6 1.01 (t, 3H), 1.66 (qt, 2H), 2.89 (t, 2H), 7.15 (t, 1H), 7.34 (s, IH), 7.40 (t, 2H), 7.84 (d, 2H), 7.92 (dd, 1H), 8.20 (d, 1H), 8.40 (d, 1H), 8.47 (s, lH), 8.60 (s, 1H), 8.69 (s, IH), 9.22 (br s, 2H), 9.58 (br s, 2H), 10.61 (s, IH); Anal. calc'd for C 25
H
23
N
3
SO
2 -1.25 HCl: C, 63.20; H, 5.14; N, 8.84. Found: C, 63.24; H, 10 5.16; N, 8.93. Example 202 6 -(aminoiminomethyl)-N-(6-quinolinyl)-2-naphthalenecarboxamide, bis(trifl uoro acetate)(salt) 15 Example 202A To a solution of the acid chloride, Example 8B, (331 mg, 1.5 mmol) in THF (15 mL), at room temperature, was added propylene oxide (10 mL), DMAP (5 mg), a drop of triethylamine and finally 6-aminoquinoline (288 mg, 2.0 mmol). After 4 hours at room 20 temperature, added ethyl acetate (10 mL) and ether (20 mL) and filtered the off-white solid product. Yield 357 mg (72%). MS (DCI/NH 3 ) m/z 324 (M+H)+. Example 202B 25 6 -(aminoiminomethyl)-N-(6-quinolinvl)-2-naphthalenecarboxamide, bis(trifluoroacetate)(salt) The desired compound was prepared as described in Example 1 B. MS (ESI*) m/z 341 (M+H)+, (ESI) 339 (M-1)-; IH NMR (300 MHz, DMSO-d 6 ) 6 10.98 (s, lH), 9.53 (s, 2H), 9.25 (s, 2H), 8.93-8.91 (m, 30 IH), 8.77 (s, 1H), 8.67 (d, J=1.8Hz, 1H), 8.58 (s, 1H), 8.53 (d, J=8.5Hz, 1H), 8.37-8.09 (m, 5H), 7.93 (dd, Jl=8.5Hz, J2=1.8Hz, 1H), 7.65-7.62 (m, 1H); Anal. calc'd for C,,H 16
N
4 0-2TFA: C, 52.83; H, 3.19; N, 9.86. Found: C, 52.62; H, 2.94; N, 9.74. -191 SUBSTITUTE SHFFT (Rill : 9Am WO 99/05096 PCT/US98/15386 Example 203 6-(aminoiminomethyl)-N-(1 H-indazol-6-vl)-2-naphthalenecarboxamide, bis(trifluoroacetate)(salt) 5 Example 203A The desired compound was prepared as described for Example 202A but substituting 6 aminoquinoline for 6-aminoindazole to provide 285 mg of the desired compound. MS: ESI+: 313 (M+l); ESI-311 (M-1). 10 Example 203B 6-(aminoiminomethyl)-N-(I H-indazol-6-vl)-2-naphthalenecarboxamide. bis(trifluoroacetate)(salt) To a suspension of the ammonium chloride (140 mg, 2.6 mmol) in Toluene (2 mL) at 0 0 C was slowly added a solution of 2 N trimethylaluminium in toluene (87 1pL, 1.74 mmol). 15 After 5 minute the reaction mixture was allowed to warm to room temperature for 30 minutes. To the solution of the aluminium reagent at room temperature was added the nitrile, Example 203A from section (a) and the reaction mixture was heated to 100'C for 48 hours. The reaction mixture was cooled down then was poured into a suspension of silica in chloroform and stirred for an hour. The silica was filtered then washed with methanol. The solvent was concentrated 20 and purified by medium pressure liquid chromatography on a 30 cm x 2 cm C-18 column (40 micron, J.T Baker) with UV detection at 250 nM with solvent mixtures in a gradient ranging from 90%A (0.1% aq TFA)/10%B (methanol) to 10%A/90%B over 160 minutes at a flow rate of 5 mL/min (fractions were collected every 2 minutes for 100 min, to provide 42 mg of the desired compound. 25 MS (ESI+) m/z 330 (M+H)+, (ESI-) 328 (M-1)-; IH NMR (300 MHz, DMSO-d 6 ) 6 10.65 (s, 1H), 9.47 (m, 4H), 8.65 (s, 2H), 8.50 (s, 2H), 8.25-8.23 (m, 2H), 8.17-8.10 (m, 2H), 7.94 (s, lH), 7.86-7.84 (dd, JI=8.8Hz, J2=1.6Hz, IH), 7.66 (d, J=8.5Hz, IH), 7.37 (d, J=8.4Hz, lH); Anal. calc'd for C 19
H
15
N
5 O-2 TFA: C, 49.56; H, 3.07; N, 12.56. Found: C, 49.68; H, 30 3.10; N, 12.47. Example 204 6-(aminoiminomethyl)-N-(1 H-indazol-5-vl)-2-naphthalenecarboxamide, bis(trifluoroacetate)(salt) -192 SUBSTITUTE SHEET (Ri lI F 9m WO 99/05096 PCTIUS98/15386 Example 204A The desired compound was prepared as described for Example 202A but substituting 6 aminoquinoline for 5-aminoindazole to provide 362 mg of the desired compound. 5 MS: ESI+: 313 (M+1); ESI-311 (M-1). Example 204B 6-(aminoiminomethyl)-N-(1 H-indazol-5-vl)-2-naphthalenecarboxamide, bis(trifluoroacetate)(salt) 10 The desired compound was prepared as described for Example 203B to provide 55 mg of the desired compound. MS (ESI*) m/z 330 (M+H)+, (ESI~) 328 (M-1)-; 1 H NMR (300 MHz, DMSO-d 6 ) 6 13.06 (s, lH), 10.58 (s, iH), 9.51 (s, 2H), 9.15 (s, 2H), 8.71 (d, j=1.9Hz, lH), 8.56 (d, j=1.9Hz, lH), 8.34-8.17 (m, 4H), 8.10 (s, IH), 7.90 (dd, 15 Jl=8.5Hz, J2=1.7Hz, lH), 7.63 (dd, Jl=8.9Hz, J2=1.7Hz, lH), 7.56 (d, J=8.8Hz, lH); Anal. calc'd for C 19
H
15
N
5 O-TFA- 1.75 H 2 0: C, 53.11; H, 4.14; N, 14.75. Found: C, 53.20; H, 3.99; N, 14.42. Example 205 20 6-(aminoiminomethyl)-N-(1 H-indol-5-vl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) Example 205A The desired compound was prepared as described for Example 202A but substituting 6 25 aminoquinoline for 6-aminoindole to provide 744 mg of the desired compound. MS: (ESI)+: 329 (M+1)+ and (ESI)-: 327 (M-1)-. Example 205B 6-(aminoiminomethyl)-N-(1 H-indol-5-vl)-2-naphthalenecarboxamide. 30 mono(trifluoroacetate)(salt) The desired compound was prepared as described for Example 203B to provide 90 mg of the desired compound. MS (ESI*) m/z 329 (M+H)+, (ESI^) 327 (M-1)-; -193 SUBSTITUTE SHFFT [RIll F Dr WO 99/05096 PCTIUS98/15386 1 H NMR (300 MHz, DMSO-d 6 ) 5 11.09 (s, 1H), 10.40 (s, 1H), 9.51 (s, 2H), 9.15 (s, 2H), 8.71 (s, lH), 8.55 (s, 1H), 8.32 (d, J=8.4Hz, 1H), 8.26-8.17 (m, 2H), 8.05 (d, J=2.6Hz, lH), 7.90 (dd, Jl=8.4Hz, J2=1.8Hz, 1H), 7.46-7.35 (m, 3H), 6.45-6.43 (in, lH); Anal. calc'd for C 2 0
H
16
N
4 0.TFA: C, 59.73; H, 3.87; N, 12.66. Found: C, 59.27; H, 4.17; 5 N, 12.74. Example 206 7-r2-(4-morpholinyl)ethoxyl- 2 -naphthalenecarboximidamide, bis(trifluoroacetate)(salt) 10 Example 206A The nitrile was prepared as described in Example 119A using 2-chloroethylmorpholine. MS (DCI (NH 3 )) m/z 283 (M+H) +. Example 206B 15 7-[2-(4-morpholinyl)ethoxyl-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) The desired compound was prepared as described in Example I 19B, as an off-white solid (50% yield). MS (DCI (NH 3 )) m/z 300 (M+H)+; I H NMR (300 MHz, DMSO-d6) 6 3.500 (br m, 4H), 3.700 (br m, 2H), 3.990 (br m, 4H), 20 4.490 (br m, 2H), 7.435 (dd, 1H), 7.530 (d, 1H), 7.680 (dd, 1H), 8.035 (d, IH), 8.100 (d, I H), 8.345 (d 1H), 9.165 (br s, 2H), 9.420 (br s, 2H); Anal. calc'd for C 17
H
2 1
N
3 0 2
-(C
2
HO
2
F
3 ) 2.15: C, 46.98; H, 4.29; N, 7.72. Found: C, 47.00; H, 4.32; N, 7.77. 25 Example 207 6 -(aminoiminomethyl)-N-phenyl-4-(2-pyrrolidinyl)-2-nahthalenecarboxamide, mono(trifluoroacetate)(salt) Example 207A 30 The desired compound was prepared from the product from Example 152A, by the procedure of Example 68A. MS (DCI/NH 3 ) m/z 281 (M+H)+. Example 207B -194 SUBSTITUTE SWFFT [Rill r 9M WO 99/05096 PCT/US98/15386 The desired compound was prepared from the product from Example 207A by the procedure of Example 152B. MS (DCI/NH 3 ) m/z 267 (M+H)+. 5 Example 207C A solution of the product from Example 207B (220 mg, 0.826 mmol), diisopropylethyl amine (0.288 mL, 1.65 mmol), and 0- (7-azabenzotriazol-1-yl)-N, N, N', N' tetramethyluronium hexafluorophosphate (314 mg, 0.826 mmol) in DMF (10 mL) was stirred for 30 minutes at 0 0 C. Aniline (0.083 mL, 0.909 mmol) was added, and the reaction was 10 stirred at room temperature for 4 hours. The reaction was poured into saturated aqueous Na 2
CO
3 solution, and extracted with 3x ethyl acetate. The combined extracts were washed with water and brine, dried over Na2SO4, and condensed. The crude material was recrystallized from ethanol/hexanes to yield 212 mg (75%) of the desired compound. MS (DCI/NH 3 ) m/z 342 (M+H)+. 15 Example 207D 6-(aminoiminomethyl)-N-phenvl-4-(2-pyrrolidinvl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) The desired compound was prepared from Example 207C and the procedure of Example 20 1 B. MS (DCI/NH 3 ) m/z 359 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ) 8 2.02 (t, 4H), 3.55 (t, 4H), 7.13 (t, IH), 7.38 (t, 2H), 7.41 (s, 1H), 7.80 (m, 3H), 8.08 (s, lH), 8.18 (d, IH), 8.67 (s, lH), 9.10 (br s, 2H), 9.43 (br s, 2H), 10.41 (br s, 1H); 25 Anal. calc'd for C 2 2
H
22
N
4 0*1.0 C 2
HF
3 0 2 : C, 61.01; H, 4.91; N, 11.86. Found: C, 60.47; H, 5.36; N, 7.39. Example 208 6 -(aminoiminomethyl)-N-(5-pyrimidinyl)-2-naphthalenecarboxamide, 30 mono(trifluoroacetate)(salt) Example 208A The above product was prepared in the manner of Example 8A using 5 aminopyrimidne. -195 SUBSTITUTF -wq;;(T 1I If WO 99/05096 PCT/US98/15386 MS (APCI) m/z (M+H)+ 275. Example 208B 6 -(aminoiminomethyl)-N-(5-pyrimidinvl)-2-naphthalenecarboxamide, 5 mono(trifluoroacetate)(salt) The above was prepared as described in Example 1B. MS (CI) m/z (M+H)+ 292; 1 H-NMR (300 MHz, DMSO-d 6 ) 6 10.99 (s, IH), 9.52 (s, 2H), 9.27 (s, 2H), 9.24 (s, 2H), 8.98 (s, 1H), 8.76 (s, 1H), 8.58 (s, 1H), 8.36-8.18 (m, 3H), 7.92 (dd, J=1.5, 8.4 Hz, 1H); 10 Anal. calc'd for Ci 8
H
14
N
5 0 3
F
3 7/10 TFA: C, 47.97; H, 3.05; N, 14.40. Found: C, 47.78; H, 3.05; N, 14.67. Example 209 6 -(aminoiminomethyl)-N-(3-pyridazinvl)-2-naphthalenecarboxamide, 15 mono(trifluoroacetate)(salt) Example 209A 3-Amino-6-chloropyridazine (1.05 g, 8.2 mmol) was dissolved in 10 mL methanol with 2 mL ammonia/methanol. Palladium/carbon (200 mg, 10%) was added and stirred under 1 atm 20 hydrogen for 4 hours. The reaction was filtered, concentrated, and used without further purification. MS (CI) m/z (M+H)+ 96. Example 209B 25 The above product was prepared in the manner of Example 12 using the product from Example 209A. MS (APCI) m/z (M+H)+ 275. Example 209C 30 6 -(aminoiminomethyl)-N-(3-pyridazinvl)-2-naphthalenecarboxanide, mono(trifluoroacetate)(salt) The above was prepared from Example 209B as described in Example I B. MS (CI) m/z (M+H)+ 292; -196 SUBSTITUTE SHEET (RULF 91 WO 99/05096 PCT/US98/15386 IH-NMR (300 MHz, d 6 -DMSO) 6 11.72 (s, 1H), 9.51 (s, 2H), 9.22 (s, 2H), 9.06 (m, 1H), 8.86 (s, 1H), 8.56 (s, 1H), 8.45 (d, 1H), 8.31 (d, 1H), 8.23 (s, 2H), 7.90 (dd, 1H), 7.78 (dd, IH) Anal. calc'd for C 18
H
14
N
5 0 3
F
3 1/2 TFA: C, 49.29; H, 3.16; N, 14.73. Found: C, 49.56; H, 5 3.23; N, 14.73. Example 210 6-(aminoiminomethyl)-N-(5-bromo-2-pyridinvl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) 10 Example 210A Using the product obtained in Example 8E, 2-amino-5-bromopyridine, and the procedure described for Example 8G the desired compound was obtained. MS (APCI+) m/z 352 (M+H)+. 15 Example 210B 6 -(aminoiminomethyl)-N-(5-bromo-2-pyridinyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) Using the procedure described in Example 1B and the product obtained in Example 20 210A, the desired compound was obtained. MS (DCI) m/z 369 (M+H)+; 1 H NMR (300 MHz, DMSO) 6 11.30 (s, IH), 9.51 (s, 2H), 9.17 (s, 2H), 8.80 (s, 1H), 8.57 (d, 1H, J=2.57), 8.55 (s, lH), 8.31 (d, lH, J=8.45), 8.26 (d, 1H, J=8.82), 8.19-8.24 (m, 2H, ), 8.14 (dd, IH, J=2.57, 9.19), 7.90 (dd, 1H, J=1.83, 8.82; 25 Anal. calc'd for C 19
H
14 BrF 3
N
4 0 3 : C, 47.22; H, 2.92; N, 11.59. Found: C, 47.60; H, 3.01; N, 11.30. Example 211 6-(aminoiminomethyl)-N-[3-(I-methylethoxy)phenvll-2-naphthalenecarboxamide, 30 mono(trifluoroacetate)(salt) Example 211 A The above product was prepared in the manner of Example 12 using 3 isopropoxyaniline. -197 SUBSTITUTE SwE=T (RI 1: F 19m WO 99/05096 PCTIUS98/15386 MS (APCI) m/z (M+H)+ 331. Example 211 B 6-(aminoiminomethyl)-N-[3-(1 -methylethoxv)phenvll-2-naphthalenecarboxamide, 5 mono(trifluoroacetate)(salt) The above was prepared from Example 211 A using method 1B. MS (CI) m/z (M+H)+ 348; 1 H-NMR (300 MHz, d 6 -DMSO) 5 10.50 (s, 1H), 9.50 (s, 2H), 9.22 (s, 2H), 8.67 (s, 1H), 8.56 (s, 1H), 8.31 (d, IH), 8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.51 (m, 1H), 7.36 (m, 1H), 10 7.26 (t, lH), 6.68 (dd, IH), 4.59 (m, 1H), 1.30 (d, 6H) Anal. calc'd for C 23
H
22
N
3 0 4
F
3 1/5 TFA: C, 57.96; H, 4.61; N, 8.66. Found: C, 57.99; H, 4.90; N, 8.68. Example 212 15 2- [[6-(aminoiminomethyl)-2-naphthalenvlloxylacetic acid, mono(trifluoroacetate)(salt) The product from Example 185C (140 mg, 0.542 mmol) was dissolved in methanol (11 mL). To this was added a solution of lithium hydroxide (68.2 mg, 1.626 mmol) in water (3 mL) and the resulting mixture was stirred at room temperature under an inert atmosphere for 18 20 hours. The reaction was evaporated and the residue purified by reverse phase chromatography to yield the desired compound (102 mg, 52%). MS (DCI (NH 3 )) m/z 245 (M+H)+; IH NMR (300 MHz, DMSO-d6) 6 4.875 (s, 2H), 7.420 (s, 1H), 7.435 (dd, 1H), 7.660 (dd, 1H), 8.015 (d, IH), 8.100 (d, IH), 8.340 (d, 1H), 9.125 (br s, 1H), 9.420 (br s, IH; 25 Anal. calc'd for C 13
H
12
N
2 0 3 . (C 2
HO
2
F
3
)
1
.
30 : C, 47.74; H, 3.42; N, 7.14. Found: C, 47.93; H, 3.36; N, 7.17. Example 213 methyl 4
-[
6 -(aminoiminomethyl)-2-naphthalenvlloxylmethyllbenzoate, 30 mono(trifluoroacetate)(salt) Example 213A The resulting product from Example 185A was treated with methyl 4 (bromomethyl)benzoate in an analogous manner as described in Example 1 19B. -198 SUBSTITUTE SHEET (mI = M WO 99/05096 PCT/US98/15386 MS (DCI (NH 3 )) m/z 335 (M+NH 4 )+. Example 213B methyl 4-[6-(aminoiminomethyl)-2-naphthalenylloxylmethyllbenzoate, 5 mono(trifluoroacetate)(salt) The resulting product from Example 213A (250 mg, 0.788 mmol) was treated in an analogous manner as described in Example 11 9C to yield the desired compound (130 mg, 79%). MS (DCI (NH 3 )) m/z 335 (M+H) +; 10 I H NMR (300 MHz, DMSO-d6) 6 3.870 (s, 3H), 5.400 (s, 2H), 7.500 (dd, 1H), 7.540 (d, 1H), 7.619 (dd, 1H), 7.620 (d, 2H), 8.025 (d, 2H), 8.026 (d, 1H), 8.090 (d, IH), 8.410 (d, 1H), 9.260 (v br s, 3H); Anal. calc'd for C 14
H
1 4
N
2
O
3
C
2
HO
2
F
3
-H
2 0 0.70: C, 57.32; H, 4.46; N, 6.08. Found: C, 57.33; H, 4.70; N, 5.95. 15 Example 214 6-(aminoiminomethyl)-N-(1 H-imidazolyl)-2-naphthalenecarboxamide, bis(trifluoroacetate)(salt) 20 Example 214A Using the product obtained in Example 8E, 2-aminoimidazole, and the procedure described for Example 8G the desired compound was obtained. MS (ESI-) m/z 261 (M+H)-. 25 Example 214B Using the procedure described in Example lB and the product obtained in Example 214A, the desired compound was obtained. MS (ESI+) m/z 280 (M+H)+; I H NMR (300 MHz, DMSO) 6 9.50 (s, 2H), 9.16 (s, 2H), 8.78 (s, lH), 8.53 (s, I H), 8.26 30 8.31 (m, 2H), 8.20 (d, IH, J=8.46), 7.88 (dd, 1H, J=1.84, 8.83), 6.95 (s, 2H); Anal. calc'd for C 17
H
14
F
3 N503-0.2 TFA-H 2 0: C, 48.14; H, 3.76; N, 16.13. Found: C, 48.54; H, 3.40; N, 16.02. Example 215 -199 SUBSTITIIT Cwr rnan I I WO 99/05096 PCT/US98/15386 6-[2-[4-(hydroxvmethyl)phenyll- 1 -cyclopropvll-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) Example 215A 5 The material prepared as described in Example 104 (210 mg, .52 mmol) is dissolved in THF (6 mL) and added dropwise to 10 mL diazomethane cooled to 0 0 C then added Pd (OAc)2 (9.8 mg). Vigorous bubbling occurs for 5 minutes. the resulting black slurry is stirred 20 min, filtered and solvent removed under vacuum leaving 0.1 g clear oil. MS (DCI/NH 3 ): m/z (M+NH4): 316. 10 Example 215B 6-[2-[4-(hydroxymethyl Iphenvll-1-cyclopropyll-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) The desired compound is prepared as described in Example 1, purified by reverse phase 15 chromatography to give 19.9 mg of white solid. MS (DCI/NH 3 ) m/z (M+H)+ 316; IH-NMR (300 MHz, DMSO-d 6 ) 6 9.41 (s, 2H), 9.16 (s, 2H), 8.46 (s, 1H), 8.08 (d, 2H), 8.03 (d, IH), 7.85 (s, 1H), 7.75 (dd, 1H), 7.58 (dd, 1H), 7.3-7.1 (m, 4H), 4.49 (s, 2H), 2.38-2.48 (m, 2H), 1.61-1.70 (m, 2H); 20 Anal. calc'd for C 2 3
H
2 1
N
2 0 2
F
3 1 H 2 0: C, 62.10; H, 4.80; N, 6.29. Found: C, 62.00; H, 4, 75; N, 6.25. Example 216 N-(ethoxvcarbonyll-6-(2-phenyl- 1 -cyclopropyl)-2-naphthalenecarboximidamide 25 The sample described in Example 97 (130 mg, .45 mmol) is dissolved in DMF (3 mL) cooled to 0 0 C. and treated with triethylamine (0.01 mL) and ethyl chloroformate (0.05 mL). The resulting solution is stirred three days at room temperature then diluted with 100 mL ethyl acetate washed with distilled water (20 mL), dried over anhydrous sodium sulfate, filtered and 30 solvent removed under vacuum leaving a clear oil. The oil is purified by silica gel chromatography eluting with 2: 1 hexanes/ethyl acetate, lyophilized and the desired compound is isolated as a white powder (55 mg). MS (DCI/NH 3 ) m/z (M+H)+ 359; -200 SUBSTITUT= qH:FT fmI 1= Pom WO 99/05096 PCT/US98/15386 1 H-NMR (300 MHz, DMSO-d 6 ) 6 9.21 (s, 2H), 8.46 (s, 1H), 7.83 (d, 2H), 7.62 (s, 1H), 7.58 (dd, 1H), 7.34 (dd, 1H), 7.35-7.29 (m, 3H), 7.25-7.17 (m, 2H) 4.1 (q, 2H), 2.38-2.28 (m, 2H), 1.61 (t, 2H), 1.25 (t, 3H); Anal. calc'd for C 23
H
22
N
2 0 2 C, 77.07; H, 6.19; N, 7.82. Found: C, 76.63; H, 6.05; N, 5 7.45. Example 217 6 -(aminoiminomethyl)-N-(2-methyl-6-quinolinvl)-2-naphthalenecarboxamide, bis(trifluoroacetate)(salt) 10 The desired compound is prepared in a similar manner as described in Example 8E and 144C. MS m/z: 355 (M+H)+ 1 H NMR (DMSO, 300 MHz): 10.95 (s, lH), 9.51 (s, 2H), 9.14 (s, 2H), 8.75 (s, 1H), 8.65 15 (s, 1H), 8.57 (s, 1H), 8.35 (dd, 1H, JI=J2=8.5 Hz), 8.28 (dd, lH, JI=J2=8.5Hz), 8.19 (dd, lH, J1=J2=8.8 Hz), 8.15 (dd, 1H, JI=J2=8.3 Hz), 8.04 (dd, 1H, JI=J2=8.8Hz), 7.91 (dd, 1H, J1=8.4 Hz, J2=8.8 Hz), 7. 60 (dd, I H, JI=J2=8.1 Hz). 5.99 (S, 3H); Anal. calc'd for C 22
H
18
N
4 0-2.25 C 2
F
3 0 2 H-2 H 2 0: C, 49.20; H, 3.78; N, 8.66; F, 19.82. Found: C, 49.02; H, 3.36; N, 8.66. 20 Example 218 6 -(aminoininomethyl)-N-(3-propioxyphenvl-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) 25 Example 218A 3-Aminophenol (1 g, 7.2 mmol), triphenylphosphine (2.25 g, 8.6 mmol), and 1 propanol (0.517 g, 8.6 mmol) were dissolved in 25 mL anhydrous THF. Diethylazodicarboxylate (1.5 g, 8.6 mmol) was added dropwise over 1 minute. The solution was allowed to stir 15 minutes and poured slowly into hexanes while stirring. Filtration through 30 silica gel/celite afforded the product as a viscous yellow oil. MS (APCI) m/z (M+H)+ 152. Example 218B -201 SUBSTITUTE SHEET (RULF 9RM WO 99/05096 PCT/US98/15386 The above product was prepared in the manner of Example 12 using the product from Example 218A. MS (APCI) m/z (M+H)+ 331. 5 Example 218C 6 -(aminoiminomethyl)-N-(3-propoxyphenvl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The above was prepared from Example 218 as described in Example 1B. MS (CI) m/z (M+H)+ 348; 10 IH-NMR (300 MHz, d 6 -DMSO) 6 10.51 (s, 1H), 9.50 (s, 2H), 9.18 (s, 2H), 8.68 (s, lH), 8.55 (s, 1H), 8.32 (d, 1H), 8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.52-7.33 (m, 2H), 7.27 (t, lH), 6.73 (dd, IH), 3.94 (t, 2H), 1.75 m, 2H), 1.00 (t, 3H) Anal. calc'd for C 23
H
22
N
3 0 4
F
3 : 1/20 TFA: C, 59.49; H, 4.77; N, 9.02. Found: C, 59.43; H, 4.94; N, 9.10. 15 Example 219 6-(aminoiminomethyl)-N-[3-(] -ethylpropoxv)phenvll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) 20 Example 219A The above product was prepared in the manner of Example 218A using 3-pentanol. MS (APCI) m/z (M+H)+ 180. Example 219B 25 The above product was prepared in the manner of Example 12 using the product from Example 219A. MS (APCI) m/z (M+H)+ 359. Example 219C 30 6-(aminoiminomethyl)-N-[3-(l -ethylpropoxv)phenvll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The above was prepared from Example 219B as described in Example I B. MS (CI) m/z (M+H)+ 376; -202 SUBSTITUTE qW;:T (Ro I om WO 99/05096 PCTIUS98/15386 IH-NMR (300 MHz, d 6 -DMSO) 6 10.47 (s, 1H), 9.49 (s, 2H), 9.14 (s, 2H), 8.67 (s, 1H), 8.55 (s, 1H), 8.31 (d, 1H), 8.25-8.16 (m, 2H), 7.90 (dd, 1H), 7.51 (s, 1H), 7.38 (m, 1H), 7.26 (t, 1H), 6.72 (dd, 1H), 4.18 (m, 1H), 1.65 (m, 4H), 0.93 (t, 6H) Anal. calc'd for C 2 5
H
26
N
3 0 4
F
3 : C, 61.34; H, 5.35; N, 8.58. Found: C, 61.05; H, 5.42; N, 5 8.22. Example 220 6-(aminoiminomethyl)-N-[3-(cyclopentyloxy)phenyll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) 10 Example 220A The above product was prepared in the manner of Example 218A using cyclopentanol. MS (APCI) m/z (M+H)+ 86. 15 Example 220B The above product was prepared in the manner of Example 12 using the product from Example 220A. MS (APCI) m/z (M+H)+ 357. 20 Example 220C 6-(aminoiminomethyl)-N-r3-(cyclopentvloxy)phenyll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The above was prepared from Example 220B as described in Example I B. MS (CI) m/z (M+H)+ 374; 25 IH-NMR (300 MHz, d 6 -DMSO) 6 10.50 (s, lH), 9.51 (s, 2H), 9.30 (s, 2H), 8.68 (s, 1H), 8.56 (s, IH), 8.32 (d, 1H), 8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.49 (m, 1H), 7.38 (m, 1H), 7.26 (t, 1H), 6.72 (dd, 1H), 4.79 (m, 1H), 1.96-1.08 (m, 8H). Anal. calc'd for C 2 5
H
24
N
3 0 4
F
3 2/5 TFA: C, 60.68; H, 5.06; N, 8.49. Found: C, 60.68; H, 5.33; N, 8.65. 30 Example 221 6-(aminoiminomethyl)-N-( 3 -phenoxyphenvl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) -203 SUBSTITUTE S-FET RMI = 1M WO 99/05096 PCT/US98/15386 Example 221A The above product was prepared in the manner of Example 218A using 3 phenoxyanline. MS (APCI) m/z (M+H)+ 365. 5 Example 221B 6 -(aminoiminomethyl)-N-(3-phenoxyphenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The above was prepared from Example 221A as described in Example lB. 10 IH-NMR (300 MHz, d 6 -DMSO) 6 10.61 (s, lH), 9.50 (s, 2H), 9.20 (s, 2H), 8.66 (s, 1H), 8.54 (s, 1H), 8.30 (d, 1H), 8.22 (d, lH), 8.12 (dd, IH), 7.90 (dd, IH), 7.64-7.57 (m, 2H), 7.46-7.37 (m, 3H), 7.17 (m, 1H), 7.06 (m, 2H), 6.79 (dd, lH), MS (CI) m/z (M+H)+ 382; Anal. calc'd for C 26
H
20
N
3 0 4
F
3 : C, 63.03; H, 4.07; N, 8.48. Found: C, 62.87; H, 4.24; N, 15 8.08. Example 222 6-(aminoiminomethyl)-N-[3-(phenvlmethoxv)phenvll-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) 20 Example 222A The above product was prepared in the manner of Example 218A using 3 benzyloxyaniline. MS (APCI) m/z (M+H)+ 379. 25 Example 222B 6 -(aminoiminomethyl)-N-[3-(phenvlmethoxv)phenvll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The above was prepared from Example 222A as described in 1B. MS (CI) m/z (M+H)+ 396; 30 IH-NMR (300 MHz, d 6 -DMSO) 6 10.53 (s, 1H), 9.50 (s, 2H), 9.22 (s, 2H), 8.68 (s, 1H), 8.55 (s, lH), 8.31 (d, 1H), 8.23 (d, IH), 8.14 (dd, 1H), 7.90 (dd, 1H), 7.61-7.27 (m, 8H), 6.80 (dd, 1H), 5.13 (s, 2H) Anal. calc'd for C 27
H
22
N
3 0 4
F
3 : C, 63.65; H, 435; N, 8.25. Found: C, 63.48; H, 4.27; N, 8.07. -204 SUBSTITUTE SHFFT (MI : 9A WO 99/05096 PCT/US98/15386 Example 223 6 -(aminoiminomethyl)-N-(3-ethoxyphenvll-2-naphthalenecarboxanide, mono(trifluoroacetate)(salt) 5 Example 223A The above product was prepared in the manner of Example 218A using 3-ethoxyaniline. MS (APCI) m/z (M+H)+ 317. 10 Example 223B 6-(aminoiminomethyl)-N-(3-ethoxvphenyl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) The above was prepared from Example 223A as described in Example lB. MS (CI) rn/z (M+H)+ 334; 15 IH-NMR (300 MHz, d 6 -DMSO) 6 10.52 (s, IH), 9.50 (s, 2H), 9.24 (s, 2H), 8.68 (s, lH), 8.55 (s, 1H), 8.32 (d, lH), 8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.51 (m, lH), 7.38 (m, lH), 7.26 (t, IH), 6.72 (dd, 1H), 4.04 (q, 2H), 1.34 (t, 3H) Anal. calc'd for C 22
H
20
N
3 0 4
F
3 : C, 59.06; H, 4.51; N, 9.39. Found: C, 58.69; H, 4.54; N, 9.82. 20 Example 224 6-(aminoiminomethyl)-N-(4-nitrophenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) 25 Example 224A The above product was prepared in the manner of Example 218A using 4-nitroaniline. MS (APCI) m/z (M+H)+ 318. Example 224B 30 6 -(aminoiminomethyl)-N-(4-nitrophenvl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The above was prepared from Example 224A as described in Example lB. MS (CI) m/z (M+H)+ 335; -205 SUBSTITUTE SI4Fw T 11n = oa WO 99/05096 PCT/US98/15386 1 H-NMR (300 MHz, d 6 -DMSO) 5 11.15 (s, 1H), 9.55 (s, 2H), 9.22 (s, 2H), 8.77 (s, 1H), 8.58 (s, 1H), 8.36-8.12 (m, 7H) Anal. calc'd for C 20
H
15
N
4 0 5
F
3 1/10 TFA: C, 52.54; H, 3.29; N, 12.10. Found: C, 53.58; H, 3.37; N, 12.50. 5 Example 225 6-(aminoiminomethyl)-N-3-(cyclobutylmethoxy)Dhenvll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) 10 Example 225A The above product was prepared in the manner of Example 218A using cyclobutylmethanol. MS (APCI) m/z (M+H)+ 177. 15 Example 225B The above product was prepared in the manner of Example 225A using the product from Example 11 MS (APCI) m/z (M+H)+ 357. 20 Example 225C 6 -(aminoiminomethyl)-N-[3-(cyclobutvlmethoxy)phenvll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The above was prepared from Example 225B as described in Example 1 B. MS (CI) m/z (M+H)+ 374; 25 IH-NMR (300 MHz, d 6 -DMSO) 8 10.50 (s, 1H), 9.50 (s, 2H), 9.20 (s, 2H), 8.68 (s, 1H), 8.55 (s, 1H), 8.32 (d, lH), 8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.51 (m, 1H), 7.38 (m, 1H), 7.26 (t, lH), 6.72 (dd, IH), 3.95 (d, 2H), 2.11-1.81 (m, 7H); Anal. calc'd for C 25
H
24
N
3 0 4
F
3 7/5 TFA: C, 59.09; H, 5.22; N, 8.27. Found: C, 59.02; H, 5.20; N, 8.55. 30 Example 226 6-ramino(ethoxvcarbonyl)iminol-N-r3-(1-methylethoxy)phenyll-2-naphthalenecarboxamide The above was prepared from Example 211 A using method described in Example 216. -206 SUBSTITUTE SHEET (RULF 9m1 WO 99/05096 PCT/US98/15386 MS (CI) m/z (M+H)+ 420: IH-NMR (300 MHz, d 6 -DMSO) 6 10.41 (s, 1H), 9.24 (br, 2H), 8.67 (s, IH), 8.59 (s, lH), 8.12-7.96 (m, 4H), 7.47 (s, 1H), 7.36 (m, lH), 7.25 (t, 1H), 6.67 (dd, 1H), 4.58 (m, 1H), 4.11 (q, 2H), 1.30 (m, 9H) 5 Anal. calc'd for C24H 25
N
3 0 4 1/4 H 2 0: C, 67.99; H, 6.06 N, 9.91. Found: C, 67.99; H, 6.07; N, 9.64. Example 227 6-(aminoiminomethyl)-4-r5-(ethylsulfonyl)-3-furanvll-N-phenvl-2-naphthalenecarboxamide, 10 monohydrochloride Example 227A A solution of the product from Example 200C (670 mg, 1.68 mmol) and mCPBA (725 mg, 3.36 mmol) in CH 2 Cl 2 (25 mL) was stirred for 1 hour. The reaction was condensed and 15 chromatographed on SiO 2 using 50% ethyl acetate/hexanes as eluent, to yield 585 mg (8 1%) of the desired compound. MS (DCI/NH 3 ) m/z 448 (M+NH 4 )+. Example 227B 20 6 -(aminoimi nomethyl)- 4 -r5-(ethylsulfonyl)-3-furanyll-N-phenvl-2-naphthalenecarboxamide, monohydrochloride The desired compound was prepared from Example 227A and the procedure of Example 13. MS (DCI/NH 3 ) m/z 448 (M+H)+; 25 1 H NMR (300 MHz, DMSO-d 6 ) 6 1.29 (t, 3H), 3.50 (q, 2H), 7.16 (t, 1H), 7.42 (t, 2H), 7.83 (d, 2H), 7.95 (dd, IH), 8.05 (s, 1H), 8.28 (s, IH), 8.43 (d, 1H), 8.57 (s, 1H), 8.74 (s, 1H), 8.79 (s, 1H), 9.19 (br s, 2H), 9.59 (br s, 2H), 10.61 (s, 1H); Anal. calc'd for C24H22N3SO4- 1.0 HC1-1.0 H 2 0: C, 57.43; H, 4.82; N, 8.37. Found: C, 57.21; H, 5.04; N, 8.34. 30 Example 228 6-(aminoiminomethyl)-4-[5-(ropylsulfonyll-3-furanyll-N-phenvl-2-naphthalenecarboxamide, monohydrochloride -207 SUBSTITUTE SHFFT RIn : 9A1 WO 99/05096 PCTIUS98/15386 Example 228A The desired compound was prepared from the product from Example 201 C by the procedure of Example 227A. MS (DCI/NH 3 ) m/z 462 (M+NH 4 )+. 5 Example 228B 6-(aminoiminomethyl)-4-[5-(propylsulfonyl)-3-furanyll-N-phenvl-2-naphthalenecarboxamide. monohydrochloride The desired compound was prepared from Example 228A and the procedure of Example 10 13. MS (DCI/NH 3 ) m/z 462 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ) 8 1.03 (t, 3H), 1. 75 (qt, 2H), 3.48 (q, 2H), 7.16 (t, 1H), 7.41 (t, 2H), 7.84 (d, 2H), 7.95 (dd, IH), 8.05 (s, lH), 8.28 (d, 1H), 8.42 (d, 1H), 8.58 (s, 1H), 8.77 (s, 1H), 8.82 (s, lH), 9.28 (br s, 2H), 9.63 (br s, 2H), 10.66 (s, 1H); 15 Anal. calc'd for C 25
H
24
N
3
SO
4 -1.0 HClI-1.5 H 2 0: C, 57.20; H, 5.18; N, 8.00. Found: C, 56.86; H, 5.08; N, 8.28. Example 229 6-(aminoiminomethyl)-4-r5-[methylthio)methyll-3-furanyll-N-phenvl-2 20 naphthalenecarboxamide, monohydrochloride Example 229A To a solution of 2-trimethylsilyl-3-bromofuran (10.41 g, 47.5 mmol) in THF (100 mL) at -78'C was added a 1.5 M solution of LDA (34.8 mL, 52.25 mmol), and the reaction was 25 stirred at -78 0 C for 1 hour. DMF (4.41 mL, 57.0 mmol) was then added, and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was poured into saturated aqueous NH 4 Cl solution, and extracted with 3x diethyl ether. The combined extracts were washed with brine, dried over Na2SO 4 , and condensed. The crude material was taken up in methanol (200 mL) and NaBH 4 (1.15 g, 24.0 mmol) was added in portions to the stirred 30 solution. After 30 min, the solution was consensed, taken up in pH7 buffer, and extracted with 3x ethyl acetate. The combined extracts were washed with brine, dried over Na2SO 4 , and condensed. The crude product was chromatographed on SiO 2 using 30% ethyl acetate/hexanes as eluent, to yield 5.52 g (47%) of the desired compound. MS (DCI/NH 3 ) m/z 250 (M+H)+. -208 SUBSTITUTE SHEET (Rti [= 9m WO 99/05096 PCT/US98/15386 Example 229B To a solution of the product from Example 229A (5.52 g, 22.15 mmol) and LiCl (1.03 g, 24.36 mmol) in DMF (60 mL) at 0 'C was added PC1 3 (2.12 mL, 24.36 mmol), and the 5 reaction was stirred at room temperature for 1 hour. The reaction was poured into saturated aqueous NH 4 C1 solution, and extracted with 3x diethyl ether/hexanes. The combined extracts were washed with 2x water, 2x brine, dried over Na2SO 4 , and condensed to yield 4.70 g (79%) of the desired compound. 10 Example 229C A solution of the product from Example 229B (4.70 g, 17.56 mmol) and MeSNa (1.35 g, 19.3 mmol) in DMF (40 mL) was stirred at room temperature for 3 hours. The reaction was poured into saturated aqueous NaHCO 3 solution, and extracted with 3x Diethyl ether. The combined extracts were washed with brine, dried over Na2SO4, and condensed. The crude 15 product was chromatographed on SiO 2 using 30% ethyl acetate/hexanes as eluent, to yield 4.00 g (82%) of the desired compound. Example 229D The desired compound was prepared from the product from Example 229C by the 20 procedure of Example 154B. MS (DCI/NH 3 ) m/z 308 (Bu 3 Sn+NH 4 )+. Example 229E The desired compound was prepared from the product from Example D and the product 25 from Example 152C by the procedure of Example 154C. MS (DCI/NH 3 ) m/z 416 (M+NH 4 )+. Example 229F 6-(aminoiminomethyl)-4-[5-[methylthio)methyll-3-furanyll-N-phenvl-2 30 naphthalenecarboxamide. monohydrochloride The desired compound was prepared from Example 229E and the procedure of Example 144C. MS (DCI/NH 3 ) m/z 416 (M+H)+; -209 SUBSTITUTirF WF:T ri 1am WO 99/05096 PCT/US98/15386 IH NMR (300 MHz, DMSO-d 6 ) 5 2.15 (s, 3H), 3.87 (s, 2H), 7.14 (t, IH), 7.40 (t, 2H), 7.84 (d, 2H), 7.92 (dd, 1H), 8.19 (d, 1H), 8.32 (s, 1H), 8.39 (d, 1H), 8.64 (s, 1H), 8.69 (s, 1H), 9.31 (br s, 2H), 9.61 (br s, 2H), 10.62 (s, 1H); Anal. calc'd for C 24
H
2 1
N
3 SO2'1.4 HCI: C, 61.79: H, 4.84; N, 9.01. Found: C, 61.83; H, 5 4.82; N, 9.13. Example 230 6-(aminoiminomethyl)-4-[5-(methoxymethyl)-3-furanyll-N-phenvl-2-nahthalenecarboxamide, monohydrochloride 10 Example 230A The desired compound was prepared from 2-trimethylsilyl-3-bromofuran and chloromethyl methyl ether by the procedure of Example 154A. 15 Example 230B The desired compound was prepared from the product from Example 230A by the procedure of Example 154B. MS (DCI/NH 3 ) m/z 308 (Bu 3 Sn+NH 4 )+. 20 Example 230C The desired compound was prepared from the product from Example 230B and the product from Example 152C by the procedure of Example 154C. MS (DCI/NH 3 ) m/z 400 (M+NH 4 )+. 25 Example 230D 6 -(aminoiminomethyl)- 4 -[5-(methoxymethyl)-3-furanyll-N-phenvl-2-nachthalenecarboxamide, monohydrochloride The desired compound was prepared from Example 230C and the procedure of Example 144C. 30 MS (DCI/NH 3 ) m/z 400 (M+H)+; I H NMR (300 MHz, DMSO-d 6 ) 6 3.38 (s, 3H), 4.49 (s, 2H), 7.14 (t, 1H), 7.18 (t, 1H), 7.40 (t, 2H), 7.84 (d, 2H), 7.92 (dd, 1H), 8.19 (d, 1H), 8.38 (d, IH), 8.42 (s, 1H), 8.64 (s, IH), 8.70 (s, lH), 9.32 (br s, 2H), 9.62 (br s, 2H), 10.68 (s, 1H); -210 SUBSTITUTF qJ4FET fRm 1: Pm WO 99/05096 PCT/US98/15386 Anal. calc'd for C 24
H
21
N
3 03-2.8 HCl: C, 57.48; H, 4.78; N, 8.38. Found: C, 57.40; H, 4.44; N, 8.38. Example 231 5 6 -(aminoiminomethyl)- 4 -F5-(methylsulfonvl)-3-furanyll-N-phenyl-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) Example 231A The desired compound was prepared from the product from Example 152C by the 10 procedure of Example 227A. MS (DCI/NH 3 ) m/z 434 (M+NH 4 )+. Example 231B 6 -(aminoiminomethyl)- 4 -r5-(methylsulfonyl)-3-furanyll-N-phenvl-2-naphthalenecarboxamile, 15 mono(trifluoroacetate)(salt) The desired compound was prepared from Example 231 A and the procedure of Example 13. MS (DCI/NH 3 ) m/z 434 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ) 8 3.44 (s, 3H), 7.16 (t, 1H), 7.40 (t, 2H), 7.82 (d, 2H), 20 7.91 (s, lH), 7.95 (dd, IH), 8.00 (s, lH), 8.36 (s, lH), 8.43 (d, 11H), 8.57 (s, lH), 8.75 (s, 2H), 9.18 (br s, 2H), 9.53 (br s, 2H); Anal. calc'd for C 23
H
1 9
N
3
SO
4 -1.0 C 2
HF
3 0 2 : C, 54.84; H, 3.68; N, 7.67. Found: C, 55.05; H, 3.74; N, 7.75. 25 Example 232 6-(aminoiminomethyl)-4-[5-(ethvthio)tetrahydro-3-furanyll-N-phenyl-2 naphthalenecarboxamide, monohydrochloride Example 232A 30 The desired compound was prepared from the product from Example 152A by the procedure of Example 62A. MS (DCI/NH 3 ) m/z 315 (M+NH 4 )+. Example 232B -211 SUBSTITUTE SHEET (RillP 9Rm WO 99/05096 PCT/US98/15386 A solution of the product from Example 232A (1.62 g, 5.45 mmol), ethanethiol (2.2 mL), and conc. HC (0.80 mL) in CHC1 3 (22 mL) was stirred at room temperature for 3 hours and condensed. The crude product was chromatographed on SiO 2 using 15% ethyl acetate/hexanes as eluent, to yield 1.20 g (65%) of the desired compound. 5 MS (DCI/NH 3 ) m/z 359 (M+NH 4 )+. Example 232C The desired compound was prepared from the product from Example 232B by the procedure of Example 152B. 10 MS (DCI/NH 3 ) m/z 345 (M+NH 4 )+. Example 232D The desired compound was prepared from the product from Example 232C by the procedure of Example 207C. 15 MS (DCI/NH 3 ) m/z 420 (M+NH 4 )+. Example 232E 6-(aminoiminomethyl)-4-[5-(ethythio)tetrahydro-3-furanyll-N-phenvl-2 naphthalenecarboxamide. monohydrochloride 20 The desired compound was prepared from Example 232D and the procedure of Example 144C. MS (DCI/NH 3 ) m/z 420 (M+H)+; IH NMR (300 MHz, DMSO-d 6 ) 6 1.18 (dt, 3H), 2.42 (m, 1H), 3.50 (dq, 2H), 3.74 (m, lH), 3.93 (m, lh), 4.39 (m, 1H), 4.54 (m, lH), 5.38 (dd, 0.5H), 5.42 (dd, 0.5H), 7.14 (t, IH), 25 7.40 (t, 2H), 7.82 (d, 2H), 7.95 (d, IH), 8.06 (s, 0.5H), 8.20 (s, 0.5H), 8.32 (d, IH), 8.60 (s, lH), 8.71 (s, 0.5H), 8.80 (s, 0.5H), 9.32 (br s, 2H), 9.62 (br s, 2H), 10.59 (br s, lH); Anal. calc'd for C 24
H
25
N
3 0 2 S-1.0 HCl: C, 63.22; H, 5.75; N, 9.21. Found: C, 62.93; H, 5.58; N, 9.01. -212 SUBSTITUTE SHFET MIn I: F

Claims (11)

1. A compound having the formula C NH BA - NH 2 Ax Z" wherein Z is selected from the group consisting of (1) nitrogen: (2) methine: and 10 (3) methine substituted with -NR 1 R 2 ; A is selected from the group consisting of (1) hydrogen and (2) -LARA; 15 B is selected from the group consisting of (1) hydrogen and (2) -LBRB and 20 C is selected from the group consisting of (1) hydrogen and (2) -LcRc, with the proviso that at least one of A. B or C is other than hydrogen; and with the proviso that when A is other than hydrogen, at least one of B or C is other than 25 hydrogen, wherein for A. B, and C. LA, LB and LC are independently selected from the group consisting of (1) a covalent bond. (2) -(CH 2 )n-, 30 (3) -NR I-, (4) -NR 2 C(X)NR 3 -. -213- WO 99/05096 PCT/US98/15386 (5) -C(X)-, (6) -NR 2 C(X)-, (7) -C(X)NR 2 -. 35 (8) -CH=CH-, (9) -CaC-, (10) -0-, (11) -S(O)t-, (12) -C=C(CH 2 )nNR2C(X)-, 40 (13) -C(X)NR 2 (CH2)nC C-, (14) -(CH 2 )nNSO 2 -, (15) -NR2SO2(CH2)nC=C-. (16) -C=C(CH 2 )nNR2SO2NR 3 -, (17) -NR2SO2NR 3 (CH2)nC=C-, 45 (18) -SO2NR2-, (19) -NR2SO2-, (20) -NR 2 SO 2 NR 3 -, (21) -N=N-, (22) -C(X)N(OR 2 )-, 50 (23) -N(OR 2 )C(X)-, (24) -HC=CH(CH2)nNR 2 C(X)-, (25) -(CH2)nNR2C(X)CH=CH-, (26) -CH=CH(CH2)nNSO 2 -, (27) -NR2SO2(CH2,)nCH=CH-, 55 (28) -(CH2)nNR 2 SO2NR 3 -, (29) -NR2SO2NR 3 (CH2)nCH=CH-, (30) -NR 2 C(0)0-, (31) -OC(O)NR2-, (32) -CH=NO-, 60 (33) -ON=CH- and
7-/ (34) W wherein W is selected from the group consisting of (a) -0-, (b) -S-, (c) -NRI- and -214- WO 99/05096 PCTIUS98/15386 65 (d) -(CH 2 )m-, wherein each functional group is depicted with its right-hand end being the end which is attached to the naphthyl or quinolyl ring and its left-hand end being the end which is attached to RA, RB or Rc; 70 RA, RB and Rc are independently selected from the group consisting of (1) aryl; (2) arylalkoxv, wherein the alkylene group is of one to six carbon atoms: (3) alkyl of one to ten carbon atoms: (4) alkenyl of two to ten carbon atoms: 75 (5) alkoxvcarbonvl of one to six carbon atoms: (6) alkynyl of two to ten carbon atoms: (7) halogen: (8) -NR 1 Ri: (9) heterocycle: 80 (10) cycloalkenyl of four to twelve carbon atoms: (11) cycloalkyl of three to twelve carbon atoms: (12) -NRlC(O)NR2R 3 : and (13) -NRIC(O)Rs 0 . wherein R3 0 is alkyl of one to six carbon atoms; wherein, at each occurence, R I is selected from the group consisting of 85 (1) hydrogen: (2) an N-protecting group: (3) alkyl of one to six carbon atoms: (4) alkenyl of two to six carbon atoms: (5) alkynyl of two to six carbon atoms: 90 (6) aryl; (7) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (8) cycloalkyl of three to eight carbon atoms and (9) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms; and 95 wherein, at each occurence, R 2 and R 3 are independently selected from the group consisting of (1) hydrogen; (2) alkyl of one to six carbon atoms: -215- WO 99/05096 PCT/US98/15386 (3) alkenyl of two to six carbon atoms: 100 (4) alkynyl of two to six carbon atoms; (5) aryl; (6) arylalkyl, wherein the alkylene group is of one to six carbon atoms (7) cycloalkyl of three to eight carbon atoms and (8) cycloalkylalkyl. wherein the cycloalkyl group is of three to eight carbon 105 atoms, and the alkylene group is of one to ten carbon atoms: and wherein, at each occurence, X is selected from the group consisting of (1) O and (2) S; and wherein, at each occurence, 110 m is one to five, n is zero to four and t is zero to two: and wherein, at each occurence, the alkyl, alkenyl, alkynyl. aryl, heterocycle. cycloalkyl, and cycloalkenyl groups are optionally substituted. 115 2. A compound according to Claim I wherein A and C are hydrogen and B is -LBRB. 3. A compound according to Claim 2 selected from the group consisting of 7-(2-hydroxyethoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; methyl 5-[ 7 -[(aminoiminomethyl)-2-naphthalenyljoxy]pentanoate; mono(trifluoroacetate) salt: 5 5-[[ 6 -(aminoiminomethyl)-2-naphthalenyl]oxyjpentanoic acid, mono(trifluoroacetate) salt; methyl 4-[[[7-amino(hydroxyimino)methyl]-2-naphthalenyl]oxy]methyl]benzoate; methyl 2 -[[6-(aminoiminomethyl)-2-naphthalenyl] oxy]acetate, mono(trifluoroacetate) salt; 10 7-[2-(4-morpholinyl)ethoxy]- 2 -naphthalenecarboximidamide, bis(trifluoroacetate) salt; 2 -[[6-(aminoiminomethyl)-2-naphthalenyfloxy] acetic acid, mono(trifluoroacetate) salt; and methyl 4 -[6-(aminoiminomethyl)-2-naphthalenyl]oxy]methyl]benzoate, -216- WO 99/05096 PCT/US98/15386 mono(trifluoroacetate) salt. 15 4. A compound according to Claim 1 wherein A and B are hydrogen: and C is -LCRC. 5. A compound according to Claim 4 selected from the group consisting of
8-(carbonylbenzvloxy)amino- 2 -naphthalenecarboximidamide mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- 1 -naphthalenvl)acetamide mono(trifluoroacetate) salt; 5 methyl [7-(aminoiminomethyl)- I -naphthalenyl)carbamate mono(trifluoroacetate) salt; methyl 3-[[7-(aminoiminomethyl)- 1 -naphthalenyl]amino]-3-oxopropionate mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- I -naphthalenvl]-2-(phenvlmethoxy)acetarmide mono(trifluoroacetate) salt: 10 N-[7-(aminoiminomethyl)- 1-naphthalenyl]-1,3-benzodioxole-5-carboxamide mono(trifluoroacetate) salt, ^ N-[7-(aminoiminomethyl)- 1 -naphthalenyl]benzenemethanesulfonanide mono(trifluoroacetate) salt, methyl [7-(aminoiminomethyl)- 1 -naphthalenyllmethylcarbamate, mono(trifluoroacetate) 15 salt; propyl [7-(aminoiminomethyl)- 1 -naphthalenyl]carbamate, mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- -naphthalenyl]-N'-methylurea. mono(trifluoroacetate) salt; ethyl [7-(aminoiminomethyl)- 1 -naphthalenyl)carbamate, mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- 1-naphthalenyl)propanamide, mono(trifluoroacetate) salt: 20 N-[7-(aminoiminomethyl)- I -naphthalenyl)-2-methoxyacetanide, mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- 1 -naphthalenyl]urea, mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- 1 -naphthalenyl]-2-hydroxyacetamide, mono(trifluoroacetate) salt m 25 8-ami -2-napthalenecarboximidamide, bis(trifluoroacetate) salt; 8 -a idno- 2 -napthalenecarboximdamided bis(trifluoroacetate) salt; 8 -( 2 -pyidinylamino)-2-naphthalenecarboxijda , bis(trifluoroacetate) salt; and -217- WO 99/05096 PCT/US98/15386 N-hydroxy-8-(2-pyrimidinvlamino)- 2 -naphthalenecarboxin-idamide, mono(trifluoroacetate) salt. 30 6. A compound according to Claim I wherein A is -LARA, B is -LBRB, and C is hydrogen. 5 7. A compound according to Claim 6 which is 6, 7-Dimethoxy-2-naphthalenecarboximidaminde mono(trifluoroacetate) salt. 8. A compound according to Claim 1 wherein A is -LARA; B is hydrogen: and 5 C is -LcRC.
9. A compound according to Claim 8 selected from the group consisting of methyl 6-(aminoiminomethyl)-4-[(methoxycarbonyl)amino]-2-naphthalenecarboxylate mono(trifluoroacetate) salt; 6 -methoxy-8-benzyloxy-2-naphthalenecarboxin-idamide mono(trifluoroacetate) salt; 5 2-[(7-aminoinhdomethyl-3-methoxy- 1 -naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt; 6-(aminoiminomethyl)-4-(3-furanyl)-N-[ 4 -(trifluoromethyl)phenyl]-2 naphthalenecarboxamide. mono (trifluoroacetate) salt: 6-(aminoiminomethyl)- 4 -(' 3 -furanyl)-N-(4-pyridinyl)-2-naphthalenecarboxamide, 10 dihydrochloride; 6-(aminoiminomethyl)-4-(3-furanyl)-N-(1 H-pyrazol-3-yl)-2-naphthalenecarboxamide, dihydrochloride; 6-(aminoiminomethyl)-4-(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride; 15 methyl [7-(aminoiminomethyl)-3-[[[ 4 -(aminomethyl)phenyl]amino]carbonyl]-1 naphathalenyllcarbamate. bis(trifluoroacetate) salt; -218- WO 99/05096 PCTIUS98/15386 6-a-ni-nmty)4(-uay)N(2prdnl--ahhlncroaie dihydrochioride; 6-aiomnmty)4(-uay)Npey--ahhlncroaie 20 monohydrochioride; 6-(amidnoiminomethyl)-4- I1 -(methylsulfonyl)- 1 H-pyrazol-4-yl]-N-phenyl-2 naphthalenecarboxamide, monohydrochioride; 6 -(an-inoinminomethyl)-4-[5(methylthio)3fuanyl)-N-phenyl-2 naplithalenecarboxamide, monohydrochioride; 25 6-(amidnoiminomethyl )-N-[4- (aminomethyl)phenyl] -4-(2-pyrimidinylamino)-2. naphthalenecarboxa-ide. tris(trifluoroacetate) salt; 6-(am-inoiminomethyl)--hnl4(-yimdnlmn)2ahtaeeabxnde mono(trifluoroacetate) salt; N-(-a-nmty~hnl--aiohdoxiiomty]4(-yi-iiyain) 30 2-naphthalenecarboxarnide, bis(trifluoroacetate) salt; 6-(aminoiminomethyl )-N-[ 4 -(hydroxymethyl)phenyI]-4-(2-pyridinylamjino> 2-naphthalenecarboxan-Lide, mono(trifluoroacetate) salt; methyl [ 3 -[[[ 4 -(aminomethyl)plvenyllannocarbony-7-[4 am-ino(hydroxyimidno )methyl- -1 -naphthalenyljcarbamate, bis(trifluoroacetate) salt; 35 6 -(aminoin-inomethy)-Npheny-4(tetalydro3furanyl>2 naphthaleneboxa~ide~monohyrochloride; 6-[amino(hydroxyimino )methyl]-N-phenyl-4-(2-pyfirnjdinylamno-2 naphthalenecarboxam-ide; 6 -(an-inoiminomethyl)-4-[5-(ethylthio)3-firanyl].N-pheny-2 40 naphthalenecarboxamide,monohydrochlofide; 6 -(amidnoin-inomethy 1-4-[5 -(prop ylthio)3-fuanyll -N-phenyl-2 naphthalenecarboxamide~monohydrochJoride; 6-aiomnmty)Npey--2prrldnl--ahhlncroaie mono(trifluoroacetate) salt; 45 6-(aminoirninomethyl)-4- [ 5 -(propylsulfonyl)-3-furanyl] -N-phenyl-2 naphthalenecarboxami de, monohydrochlorjde; 6 -(aminoiminomethyl)-4-[5-[methylthio )methyl] -3-furanyl]-N-phenyl-2 naphthalenecarboxamide, monohydrochioride; 6 -(aminoiminomethyl)-4-[5-(metthoxymeffyl3furany]Nphenyl-2 50 naphthalenecarboxamide. monohydrochioride; -219- WO 99/05096 PCT/US98/15386 6 -(aminoiminomethyl)-4-[5-(methylsulfonyl)-3-furanyl]-N-phenyl-2 naphthalenecarboxamide, mono(trifluoroacetate) salt: and 6 -(aminoiminomethyl)-4-[5-(ethythio)tetrahydro-3-furanyl]-N-phenyl-2 naphthalenecarboxamide, monohydrochloride. 55
10. A compound according to Claim I wherein A is -LARA, B is -LBRB, and C is -LCRC. 5
11. A compound according to Claim 10 which is 6, 7, 8 -trimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt.
12. A compound according to Claim 1 wherein A is hydrogen: B is -LBRB; and C is -LCRC. 5
13. A compound according to Claim 12 selected from the group consisting of 7, 8 -Dimethoxy-2-naphthalenecarboxinidamide mono(trifluoroacetate) salt: 2 -[(7-aminoiminomethyl)-2-methoxy-1 -naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt; 5 7 -benzyloxy- 8 -iodo-2-naphthalenecarboximidanide mono(trifluoroacetate) salt; methyl [( 7 -aninoiminomethyl-2-methoxy- I -naphthalenyl)oxy]acetate mono(trifluoroacetate) salt: 2 -[(7-aminoiminomethyl-2-methoxy- -naphthalenyl)oxy]-yl-acetic acid mono(trifluoroacetate) salt; 10 1-[( 7 -aminoiminomethyl-2-methoxy- 1-naphthalenyl)oxy]-3-hydroxypropane mono(trifluoroacetate) salt; 1-[( 7 -aminoiminomethyl-2-methoxy- 1-naphthalenyl)oxy]-3-bromopropane mono(hydrochloride) salt; 3 -[( 7 -aminoiminomethyl-2-methoxy-1-naphthalenyl)oxyjpropene mono(trifluoroacetate) 15 salt; -220- WO 99/05096 PCTIUS98/15386 1-[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy] -3-phenylpropane mono(hydrochloride) salt; 1-[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]-3-[1-(3,4 dimethoxy)phenyljpropane mono(hydrochloride) salt; 20 7 -methoxy- 8 -( 2 -furanyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; (E)- { 7-methoxy-8-[2-(phenyl)ethenyl] }-2-naphthaleneimidamide mono(trifluoroacetate) salt 7 -( 2 -hydroxyethoxy)-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 7 -propoxy- 8 -iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 25 7-methoxy-8-(l H-pyrazol- 4 -yl)-2-naphtaenecarboximidanide bis(trifluoroacetate) salt; 7-methoxy- 8 -iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 7 -methoxy- 8 -(3-furanyl)-2-naphthalenecarboximidanmlide mono(methanesulfonate) salt; 7 -methoxy- 8 -(2-benzofuranyl)naphthalene-2-carboximiidamide mono(methanesulfonate) 30 salt; (E)-8-[2-(1,3-benzodioxol-5-yllethenyl]-2-naphthalenecarboximidamide mono(methanesulfonate) salt; (± )- 7 -methoxy- 8 -(tetrahydro-3-furanyl)-2-naphthalenecarboximidamide mono(methanesulfonate) salt; 35 7-methoxy-8-[2-pyrimidinyl(oxy)]- 2 -naphthalenecarboximidamide mono(trifluoroacetate) salt; 7-methoxy-8- [2-thiazoyl(oxy)] naphthalene-2-carboximidamide mono(trifluoroacetate) salt; 7-methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) 40 salt; 7-methoxy-8-pentafluorophenoxy-2-naphthalenecarboxiindamide mono(trifluoroacetate) salt; 7 -methoxy-8-[N-2-pyrimidinyl(aniino)]- 2 -naphthalenecarboximidamide mono(trifluoroacetate) salt; 45 4 -[ 7 -(aminoiminomethyl)-2-methoxy-1 -naphthalenyl]dihydro-2(3H)-furanone mono(trifluoroacetate) salt; 7-methoxy-8-(1-acetyl-1H-pyrazolyl)-2-naphthalenecarboxinidamlide mono(trifluoroacetate) salt; -221- WO 99/05096 PCT/US98/15386 7-methoxy-8-[ 1-(methylsulfonyl)- I H-4-pyrazolyl]-2-naphthalenecarboximidamide 50 mono(trifluoroacetate) salt; 6 -[ 2 -( 4 -aminophenyl)ethoxyl-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; methyl [ 3 -methoxy- 6 -(aminoiminomethvl)-4-naphthalenyl]carbamate mono(trifluoroacetate) salt; 55 7-methoxy-8-[2-pyrimidinyl(amino)]-2-naphthalenecarboximidamide bis(trifluoroacetate) salt; methyl [7-(amiunoiminomethyl)-2-methoxy-1-naphthalenyl)carbamate, mono(trifluoroacetate) salt; 7-methoxy-8-(2-pyrimidinylan-no)-2-naphthalenecarboximidamide, bis(trifluoroacetate) 60 salt; 7-methoxy-8-[(phenylmethyl)amino]-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt; 7 -methoxy- 8 -(phenylamino)-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt; 65 7-methoxy-8-[(4-methoxyphenyl)amino]-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt; (E)-3-[7-(aminoiminomethyl)-2-methoxy- 1-naphthalenyl)-2-propenamide, mono(trifluoroacetate) salt; 7-methoxy-8-(3-oxo- 1 -cyclopenten- 1 -yl)-2-naphthalenecarboximidamide, 70 mono(trifluoroacetate) salt; methyl 4-[[[7-(aminoiminomethyl)-1-(2-pyrimidinylamino)-2 naphthalenyl] oxy]methyl] benzoate, mono(trifluoroacetate) salt; 4 -[[[7-(aminoiminomethyl)- 1-( 2 -pyrimidinylamino)-2-naphthalenyl]oxy]methyl] benzoic acid, mono(trifluoroacetate) salt: 75 7 -methoxy- 8 -(pyrazinyloxy)-2-naphthalenecarboximidamide, dimethanesulfonate salt; 7 -methoxy- 8 -(phenylthio)-2-naphthalenecarboximidamide, methanesulfonate; and 7-methoxy-8-(pyrazinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt.
14. A compound selected from the group consisting of 7, 8 -dimethoxy- 2 -naphthalenecarboximidamide mono(trifluoroacetate) salt; 6, 7, 8 -trimethoxy-2-naphthalenecarboxinidamide mono(trifluoroacetate) salt; -222- WO 99/05096 PCT/US98/15386 6, 7-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 5 2-[(7-aminoiminomethyl-2-methoxy- I -naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt; 7-benzyloxy-8-iodo-2-naphthalenecarboximidanide mono(trifluoroacetate) salt; methyl [(7-aminroiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]acetate mono(trifluoroacetate) salt; 10 2-[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]-yl-acetic acid mono(trifluoroacetate) salt; 1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-hydroxypropane mono(trifluoroacetate) salt; phenylmethyl [7-(aminoiminomethyl)-1-naphthalenyl)carbamate 15 mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- I -naphthalenyl)acetamide mono(trifluoroacetate) salt; methyl [7-(aminoiminomethyl)- 1 -naphthalenyl)carbamate mono(trifluoroacetate) salt; methyl 3-[[7-(aminoiminomethyl)- 1 -naphthalenyl]amino]-3-oxopropanoate mono(trifluoroacetate) salt; 20 N-[7-(aminoiminomethyl)- 1 -naphthalenvl]-2-(phenylmethoxy)acetamide mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- 1 -naphthalenyl]- 1,3-benzodioxole-5-carboxamide mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- 1 -naphthalenyl]benzenemethanesulfonamide 25 mono(trifluoroacetate) salt; 1-[(7-aminoiminomethyl-2-methoxy- 1-naphthalenyl)oxy]-3-bromopropane mono(hydrochloride) salt; 3-[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]propene mono(trifluoroacetate) salt; 30 1-[(7-aminoiminomethyl-2-methoxy- 1-naphthalenyl)oxy]-3-phenylpropane mono(hydrochloride) salt; 1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-[1-(3,4 dimethoxy)phenyl]- propane mono(hydrochloride) salt; 7 -methoxy- 8 -(2-furanyl)-2-naphthalenecarboximidamjide mono(trifluoroacetate) salt; 35 methyl 6 -(aminoiminomethyl)-4-[(methoxycarbonyl)amino]-2 naphthalenecarboxylate mono(trifluoroacetate) salt; (E)-6-[ 2 -(phenyl)ethenyl]-2-naphthaleneimidamide mono(trifluoroacetate) salt; -223- WO 99/05096 PCT/US98/15386 7 -( 2 -hydroxyethoxy)-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 40 7-(2-hydroxyethoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 6-methoxy-8-benzyloxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 2 -[( 7 -aminoiminomethyl-3-methoxy-1 -naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt; 7-propoxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 45 7-methoxy-8-(1 H-pyrazol-4-y)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 7-methoxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 7-methoxy-8-(3-furanyl)-2-naphthalenecarboximidamide mono(methanesulfonate) salt; 7-methoxy-8-(2-benzofuranyl)naphthalene-2-carboximidamide 50 mono(methanesulfonate) salt; (E)-8-[2-(1,3-benzodioxol-5-yl)ethenyl]-2-naphthalenecarboximidamide mono(methanesulfonate) salt; (± )-7-methoxy-8-(tetrahydro-3-furanyl)-2-naphthalenecarboximidamide mono(methanesulfonate) salt; 55 7-methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 7-methoxy-8-[2-thiazoyl(oxy)]naphthalene-2-carboximidamide mono(trifluoroacetate) salt; 7-methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidamide 60 mono(trifluoroacetate) salt; 7-methoxy-8-pentafluorophenoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 7-methoxy-8-[N-2-pyriidinyl(amino)]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 65 N-( 6 -aminoiminomethyl-2-naphthalenyl)-N'-benzylurea mono(trifluoroacetate) salt; N-( 6 -aminoiminomethyl-2-naphthalenyl)-N'-methylurea mono(trifluoroacetate) salt; N-( 6 -aminoiminomethyl-2-naphthalenyl)-N'-isopropylurea mono(trifluoroacetate) salt; N-( 6 -aminoiminomethyl-2-naphthalenyl)-N'-phenyl-N'-metiylurea mono(trifluoroacetate) salt; 70 6-aminonaphthalene-2-carboximidamide mono(trifluoroacetate) salt; -224- WO 99/05096 PCT/US98/15386 N-(6-aminoiminomethyl-2-naphthalenyl)-N'-cyclohexylurea mono(trifluoroacetate) salt; N-(6-aminoiminomethyl-2-naphthalenyl)-N'-benzyloxyurea mono(trifluoroacetate) salt; 75 1,1-dimethylethyl [ 4 -[[( 6 -cyano- 2 -naphthalenyl)amino]carbonyl]phenyl]carbamate mono(trifluoroacetate) salt N-[6-(aminoiminomethyl)-2-naphthalenyl]-4-(aminomethyl)benzamide mono(trifluoroacetate) salt; 4-[7-(aminoiminomethyl)-2-methoxy- 1 -naphthalenyl]dihydro-2(3H)-furanone 80 mono(trifluoroacetate) salt; 7-methoxy-8-(1 -acetyl- 1 H-pyrazolyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 7-methoxy-8-[1-(methylsulfonyl)-IH- 4 -pyrazolyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt: 85 methyl [ 3 -methoxy-6-(aminoiminomethyl)-4-naphthalenyl]carbamate mono(trifluoroacetate) salt; 7-methoxy-8-[ 2 -pyrimidinyl(amino)]-2-naphthalenecarboximidamide; and bis(trifluoroacetate) salt.
15. A method for inhibiting urokinase in a mammal in need of such treatment, comprising adminstering to the mammal a therapeutically effective amount of a compound of Claim 1.
16. A composition for inhibiting urokinase comprising both a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1. -225-
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