SK174899A3 - Urokinase inhibitors - Google Patents

Abstract

Compounds having formula (I) are inhibitors of urokinase and are useful in the treatment of diseases in which urokinase plays a role. Also disclosed are urokinase-inhibiting compositions and a method of inhibiting urokinase in a mammal.

Description

Technical field

This application is another part of U.S.Application Ser. 08 / 901,040, filed June 25, 1997, pending

The invention provides naphthamidine compounds having urokinase enzyme inhibitory effects, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds.

BACKGROUND OF THE INVENTION

Urokinase (a urinary type of plasminogen activator or uPA (International Union of Biochemistry classification number: EC3.4.21.3 1)) is a proteolytic enzyme highly specific for a single peptide bond in plasminogen. Activation of plasminogen (enzymatic cleavage of said binding by urokinase) leads to the generation of plasmin, an effective general protease.

Many cell types utilize urokinase as a key initiator of plasmin-mediated degradation or modification of extracellular support structures such as extracellular matrix (ECM) and basement membrane (BM). The space defined by ECM and BM in tissues and organs allows the cells to exist, move and interact with each other. Local proteolytic degradation or modification of structures is required for movement of cells in or along the ECM, allowing cells to penetrate adjacent areas that are unavailable to these cells prior to cell degradation or modification

Urokinase-initiated cell invasiveness is critical to many normal and pathological physiological processes (Blasi F, Vassalli JD, and Dano K., J. Cell Biol. 104: 801-804, 1987; Dano K., Anderson PA, Grondahl Hansen J., Kristensen P., Nielsen LS, and Skriver L., Adv Cancer Res., 44.1392

266, 1985, Littlefield B. A, N. N Acad Sci, 622 167-175, 1991, Sakscla O, Biochim Biophys Acla 823, 35-65. 1985, Testa JE and Quigley J 1, Cancer Mctast Rew, 9 353-367, 1990) These processes include, but are not limited to, angiogenesis (neovascularization), bone structure changes, uterine egg nesting, immune cell infiltration into inflammatory sites, ovulation, spermatogenesis, tissue transformation in wound healing and organ differentiation, fibrosis, tumor invasion, spread of tumor cells from primary sites to secondary metastases, and tissue destruction in arthritis For example, amiloride, a known urokinase inhibitor with only moderate efficacy, is reported inhibits tumor metastasis in vivo (Kellen JA, Mirakian A., Kolin A, Anticancer Res., 81373-1376 1988) and vascular / capillary network formation in vitro (Alliegro MC, and Glaser BM, J.Celi Biol., 115 [ 3 Pt 2], 402a, 1991).

Therefore, urokinase inhibitors have antiangiogenic, anti-arthritic, anti-inflammatory, antiretinopathic (in angiogenic retinopathies), contraceptive and tumorostatic applications based on these effects.

SUMMARY OF THE INVENTION

In a basic embodiment, the invention provides compounds of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof:

B

A

(D where

Z represents a group selected from the group consisting of (2) methine, and (3) methine substituted with -NR 1 R 2,

A represents a group selected from the group consisting of (1) hydrogen and (2) -L _and Ra

B is selected from (1) hydrogen and (2) -L _b R _b

C represents a group selected from the group consisting of (1) hydrogen and (2) -L _c R c with the proviso, at least one of A, B or C is other than hydrogen; and provided that when A is other than hydrogen and at least one of B or C is other than hydrogen and wherein A, B, and C, and La, Lb and _Lc are each independently selected from:

1) covalent bond,

(2) - (CH ₂ ) _m -,

3) -NR, -,

4) -NR ₂ C (X) NR ₃ 5) -C (X) -,

6) -NR ₂ C (X) -,

7) -C (X) NR 4 ₂

8) -CH = CH 9 -CsC-,

10) -ΟΙ D -S (O) r,

12) -C = C (CH ₂ ) _n NR ₂ C (X) -,

13) -C (X) NR ₂ (CH ₂ ) 5 CsCl 4 - (CH ₂ ) _n NSO ₂ -,

15) -NR ₂ SO ₂ (CH ₂ ) _n OC-,

16) -C = C (CH ₂ ) _n NR ₂ SO ₂ NR ₃ 17) -NR ₂ SO ₂ NR ₃ (CH ₂ ) ₁₁ C = C 18) -SO ₂ NR ₂ -,

19) _2, -NR 20 SO ₂₎ -NR ₂ SO ₂ NR ₃ -,

21) -N = N-

22) -C (X) N (OR ₂ ) -,

23) -N (OR ₂ ) C (X) -,

24) -HC = CH (CH ₂ ) n NR ₂ C (X)

25) - (CH ₂ ) n NR ₂ C (X) CH = CH

26) -CH = CH (CH ₂ ) nSO ₂ -,

27) -NR ₂ SO ₂ (CH ₂ ) ₁₁ Cl 2 = CH-,

28) - (CH ₂ ) n NR ₂ SO ₂ NR, -, p

29) -NlbSO / NMCH.-OnCH CH-,

30) -NR ₂ ((()) O-,

1) -OC (()) NR ₂ -,

(32) -CH-NO-,

(33) -ΟΝ-CH- a

IN

34) w _j wherein W is a group selected from the group:

a) -0-

b) -S-,

c) -NR 1 and

d) - (CH ₂ ) _m wherein each of said functional groups is shown such that its right end is intended to attach a naphthyl or quinolyl ring and its left end is intended to attach R _A , R'r or R _c ;

R _a , R b and R c are independently selected from the group consisting of:

1) aryl;

2) arylalkoxy in which the alkylene group has 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.

7) halogen;

8) -NR 1 R ₂ ;

9) heterocycle;

(10) cycloalkenyl of four to twelve carbon atoms;

1) cycloalkyl of three to twelve carbon atoms;

12) -NR ₁ C (O) NR ₂ R ₃ ; and

13) -NRiC (0) r, wherein _R 'means alkyl group of one to six carbon atoms, and wherein

R 1 at each occurrence is selected from the group consisting of.

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;

6) aryl;

7) arylalkyl wherein the alkylene group contains one to six carbon atoms;

8) cycloalkyl of three to eight carbon atoms; and

9) cycloalkylalkyl, wherein the cycloalkyl group contains from three to eight carbon atoms and alkylene having one to ten carbon atoms, and wherein R ₂ and R at each occurrence are independently selected from the group: ·

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,

5) aryl;

6) arylalkyl, wherein the alkylene group contains one to six carbon atoms,

7) cycloalkyl of three to eight carbon atoms, and

8) cycloalkylalkyl, wherein the cycloalkyl group contains three to eight carbon atoms and the alkylene group contains one to ten carbon atoms; and wherein, at each occurrence, X is independently selected from the group consisting of:

1) O a

2) S, and wherein at each occurrence m is 1 to 5, n is 0 to 4, t is 0 to 2; and wherein alkyl, alkenyl, alkynyl, aryl, heterocycle, cycloalkyl and cycloalkenyl groups are optionally substituted at each occurrence.

The invention also relates to a method of inhibiting urokinase in a mammal, particularly a human, comprising administering an effective amount of a composition comprising a compound of formula (1)

The

The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION.

In this specification and the appended claims, the following terms have the meanings indicated:

The term alkyl as used herein means a monovalent group derived from a straight or branched chain saturated hydrocarbon by removal of one hydrogen atom such as methyl, ethyl, n- and iso -propyl, n-, sec-, iso- and tert-butyl, neopentyl and likewise, wherein the group may be optionally substituted with one, two, three or four groups 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 contains one to six carbon atoms; 7) aryloyl; 8) azido; 9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; 11) halogen; 12) heterocycle; 13) (heterocycle) oxy; 14) (heterocycle) alkyl, 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) -CO 2 R 2; 22) -C (O) NR ₂ R 3; 23) -SO 2 R ₄ wherein R ₄ is selected from the group consisting of a) alkyl, b) aryl and c) arylalkyl, wherein the alkylene group contains one to six carbon atoms; 24) -SOiNRsRc, wherein R and R are independently selected from the group consisting of a) hydrogen, b) alkyl, c) aryl, d) arylalkyl, wherein the alkylene group has from one to six carbon atoms, 25) -NR ₇ R _X, wherein R ₇ and R _x are independently selected from a) hydrogen, b) 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 atoms f) aryl, g) arylalkyl wherein the alkylene group contains one to six carbon atoms, h) cycloalkyl of three to eight carbon atoms, and i) cycloalkylalkyl wherein the cycloalkyl group contains three to eight carbon atoms and the alkylene group contains one to ten with the proviso that no two groups are attached to the nitrogen atom via a carbonyl group or via a sulfonyl group.

The term alkanoyl as used herein means an alkyl group, as defined above, attached to the parent molecule through a carbonyl group also defined herein, and wherein the term means, for example, a group such as formyl, acetyl, propionyl, butanoyl and the like.

The term alkenyl "as used herein means a straight or branched chain monovalent group containing a carbon-carbon double bond derived from an alkene by removal of one hydrogen atom and means, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like, wherein the group may be optionally substituted with one, two, three, or four groups 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 contains one to six carbon atoms; 7) aryloyl; 8) azido; 9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; 11) halogen; 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) -CO ₂ R ₂ , 22) -C (O) NR ₂ R ₃ ; 23) -SO ₂ R ₄ wherein R ₄ is selected from the group consisting of a) alkyl, b) aryl and c) arylalkyl, wherein the alkylene group contains one to six carbon atoms, 24) -SO ₂ NR 5 R 6, wherein R 5 and R 6 are independently selected from a) hydrogen, b) alkyl, c) aryl, and d) arylalkyl, wherein the alkylene group contains one to six carbon atoms; 25) -NR ₂ R 5, wherein 1 7 7 and R _K are independently selected from the group consisting of a) hydrogen, b) N-protecting group, c) alkyl of one to six carbon atoms, d) alkenyl of two to six carbon atoms e) C 2 -C 6 alkynyl, f) aryl, g) arylalkyl, wherein the alkylene group contains one to six carbon atoms, h) cycloalkyl of three to eight carbon atoms, and i) cycloalkylalkyl, wherein the cycloalkyl group contains three to eight carbon atoms and the alkylene group contains one

ΙΟ up to ten carbon atoms, with the proviso that the two groups are not attached to the nitrogen atom via a carbonyl group or via a sulfonyl group

The term alkoxy as used herein means an alkyl group attached to the parent molecular moiety through an oxygen atom

The term alkoxyalkyl as used herein refers to an alkyl group attached to an alkoxy group.

The term alkoxycarbonyl as used herein means an ester group; t j. an alkoxy group attached to the parent molecule via a carbonyl group and exemplified by methoxycarbonyl, ethoxycarbonyl and the like.

The term alkylene as used herein means a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by removal of two hydrogen atoms and exemplified by methylene, ethylene, isopropylene and the like.

The term alkylsulfinyl used herein means an alkyl group attached to the parent molecular moiety through a -S (O) - group.

The term alkylsulfinylalkyl as used herein means an alkyl group as defined above substituted with a sulfinyl group.

The term alkylsulfonyl as used herein means an alkyl group attached to the parent molecular moiety through a -SO 2 - group.

The term alkylsulfonylalkyl as used herein means an alkyl group as defined above for a sulfonyl group.

The term alkynyl as used herein means a straight or branched chain monovalent group containing a carbon-to-halo triple bond derived from an alkyne by removal of one hydrogen atom and means, for example, ethynyl, I-propynyl, and the like, where the group may optionally be substituted with one, two, three or four groups independently selected from 1) alkoxy of one to six carbon atoms; 2) alkylsulfinyl having one to six carbon atoms; 3) alkylsulfonyl of one to six carbon atoms; 4) amino; 5) aryl, 6) arylalkoxy, wherein the alkylene group contains one to six carbon atoms; 7) aryloyl; 8) azido; 9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; 11) halogen, 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) -CO ₂ R ₂ , 22) -C (O) NR ₂ R 3; 23) -SO ₂ R 1, wherein R ₄ is selected from the group consisting of a) alkyl, b) aryl and c) arylalkyl, wherein the alkylene group contains 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 contains one to six carbon atoms; 25) -NR ₇ R _g , wherein R ₇ and R 8 are independently selected from the group consisting of a) hydrogen, b) N-protecting group, c) alkyl of one to six carbon atoms, d) alkenyl of two to six carbon atoms, e (f) aryl; (g) arylalkyl wherein the alkylene group contains one to six carbon atoms; (h) three to eight carbon atoms cycloalkyl; and (i) cycloalkylalkyl wherein the cycloalkyl group contains three to eight carbon atoms and the alkylene group contains one to ten carbon atoms, with the proviso that the two groups are not attached to the nitrogen atom through a carbonyl group or through a sulfonyl group.

The term amino as used herein refers to the group -NH ₂ .

The term aminoalkyl as used herein refers to an alkyl group as defined above substituted with an amino group.

The term aryl as used herein means a mono- or bicyclic carbocyclic ring system containing one or two aromatic rings and examples of which include groups such as phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl. and the like, wherein said system may be optionally substituted with one, two, three, or four groups 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 groups independently of one another contain from one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfonyl and alkyls wherein the alkyl and alkylene groups independently contain one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; ; 8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups independently contain one to six carbon atoms, 9) aryl;

10) arylalkyl, wherein the alkyl group contains one to six carbon atoms; 11) amino; 12) aminoalkyl of one to six carbon atoms; 13) aryl; 14) arylalkyl, wherein the alkylene group contains 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 contains one to six carbon atoms; 20) cycloalkyl of three to eight carbon atoms; 21) cycloalkylalkyl, wherein the cycloalkyl group has three to eight carbon atoms and the alkylene group has one to ten carbon atoms; 22) halogen; 23) haloalkyl of one to six carbon atoms; 24) heterocycle; 25) (heterocycle) oxy; 26) (heterocycle) oyl; 27) hydroxy; 28) hydroxy of one to six carbon atoms, 29) nitro; 30) nitroalkyl of one to six carbon atoms, 3 1) N-protected amino; 32) N-protected aminoalkyl wherein the alkylene group contains one to six carbon atoms; 33) oxo; 34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkylene groups independently contain one to six carbon atoms; 36) - (CH 2) _q CO 2 R 2, wherein q is zero to four, 37) - (CH ₂ ) _q C (O) NR 2 R 3; 38) - (CH 2) _q SO ₂ R ₄ , wherein R ₄ is selected from the group consisting of a) alkyl, b) aryl and c) arylalkyl, wherein the alkylene group contains one to six carbon atoms; 39) - (CH ₂ ) _q 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 contains one to six carbon atoms; 40) - (CH 2) _q NR 7 R 8, wherein R 7 and R 8 are independently selected from the group consisting of a) hydrogen, b) N-protecting group, c) alkyl of one to six carbon atoms, d) alkenyl of two to six carbon atoms e) C 2 -C 6 alkynyl, f) aryl, g) arylalkyl wherein the alkylene group contains one to six carbon atoms, h) cycloalkyl of three to eight carbon atoms, and i) cycloalkylalkyl, wherein the cycloalkyl group contains three to eight atoms carbon and an alkylene group contains one to ten carbon atoms, with the proviso that no two groups are attached to the nitrogen atom via a carbonyl group or via a sulfonyl group, 41) oxo; 42) perfluoroalkyl; 43) perfluoroalkoxy; 44) aryloxy; 45) cycloalkoxy; 46) cycloalkylalkoxy; and 47) arylalkoxy.

The term arylalkyl as used herein means an aryl group attached to the parent molecular moiety through an alkyl group.

The term arylalkoxy as used herein means an arylalkyl group attached to the parent molecular moiety through an oxygen atom.

The term aryloxy as used herein means an aryl group attached to the parent molecular moiety through an oxygen atom.

The term aryloyl as used herein means an aryl group attached to the parent molecular moiety through a carbonyl group.

The term azido as used herein refers to the group -N3.

The term azidoalkyl as used herein means an alkyl group as defined above substituted with an azide group.

The term carbonyl as used herein means a C = O group.

The term carboxaldehyde as used herein refers to the group -CHO.

The term (carboxaldehyde) alkyl) as used herein means an alkyl group as defined above substituted with a carboxaldehyde group.

The term carboxy as used herein refers to the group -CO 2 H.

The term carboxyalkyl as used herein means an alkyl group as defined above substituted with a carboxy group

The term cycloalkyl as used herein means a monovalent saturated cyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl and the like. The cycloalkyl groups of the invention may be optionally substituted with groups selected from the group consisting of I) 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 groups independently of one another contain one to six carbon atoms; 5) alkylsulfinyl of one to six carbon atoms; 6) alkylsulfinylalkyl, wherein the alkyl and alkylene groups each independently contain one to six carbon atoms; 7) alkylsulfonyl of one to six carbon atoms; 8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups each independently contain one to six carbon atoms; 9) aryl; 10) arylalkyl, wherein the alkyl group contains one to six carbon atoms; 11) amino, 12) aminoalkyl of one to six carbon atoms; 13) aryl; 14) arylalkyl, wherein the alkylene group contains 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 contains one to six carbon atoms; 20) cycloalkyl of three to eight carbon atoms; 21) cycloalkylalkyl wherein the cycloalkyl group has three to eight carbon atoms and the alkylene group has one to ten carbon atoms, 22) halogen; 23) haloalkyl of one to six carbon atoms; 24) heterocycle; 25) (heterocycle) oxy; 26) (heterocycle) oyl; 27) hydroxy; 28) hydroxy of one to six carbon atoms; 29) nitro; 30) nitroalkyl of one to six carbon atoms; 31) Non-deprotected amino; 32) N-protected aminoalkyl- wherein the alkylene group contains 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 another. they contain one to six carbon atoms; 36) - (CH 2) _q CO 2 R 2, wherein q is zero to four; 37) - (CH ₂ ) q C (O) NR ₂ R 3; 38) - (CH ₂ ) qSO ₂ R 4 wherein R ₄ is selected from the group consisting of a) alkyl, b) aryl and c) arylalkyl, wherein the alkylene group contains one to six carbon atoms; 39) - (CH 2) _q 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 contains one to six carbon atoms; ) - (CH _{2) q} NR ₇ R _p, wherein R ₇ and R _s are independently selected from the group consisting of a) hydrogen, b) N-protecting group, c) alkyl of one to six carbon atoms, d) alkenyl of e) two to six carbon atoms, f) aryl, g) arylalkyl wherein the alkylene group contains one to six carbon atoms, h) cycloalkyl of three to eight carbon atoms, and i) cycloalkylalkyl, wherein the cycloalkyl group it contains three to eight carbon atoms and the alkylene group contains one to ten carbon atoms, with the proviso that no two groups are attached to the nitrogen atom through a carbonyl group or through a sulfonyl group; 41) oxo; 42) perfluoroalkyl; 43) perfluoroalkoxy; 44) aryloxy; 45) cycloalkoxy; 46) cycloalkylalkoxy; and 47) arylalkoxy.

The term cycloalkenyl as used herein means a monovalent saturated cyclic hydrocarbon group containing at least one carbon-carbon double bond. The cycloalkenyl groups of the invention may be optionally substituted with groups selected from 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 groups independently of one another contain one to six carbon atoms; 5) alkylsulfinyl of one to six carbon atoms; 6) alkylsulfinylalkyl, wherein the alkyl and alkylene groups each independently contain one to six carbon atoms; 7) alkylsulfonyl of one to six carbon atoms; 8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups each independently contain one to six carbon atoms; 9) aryl; 10) arylalkyl, wherein the alkyl group contains one to six carbon atoms; 11) amino; 12) aminoalkyl of one to six carbon atoms; 13.) aryl; 14) arylalkyl, wherein the alkylene group contains 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 contains one to six carbon atoms; 20) cycloalkyl of three to eight carbon atoms; 21) cycloalkylalkyl, wherein the cycloalkyl group has three to eight carbon atoms and the alkylene group has one to ten carbon atoms; 22) halogen; 23) haloalkyl of one to six carbon atoms; 24) heterocycle; 25) (heterocycle) oxy; (26) (heterocycle) oyl; (27) hydroxy; (28) hydroxy of one to six carbon atoms; 29) nitro; 30) nitroalkyl of one to six carbon atoms; 3) N-protected amino, 32) N-protected aminoalkyl, wherein the alkylene group contains one to six carbon atoms, 33) oxo; 34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkylene groups independently contain one to six carbon atoms; 36) - (CH ₂ ) _q CO ₂ R ₂ , wherein q is known to be zero to four; 37) - (CH 2) _q C (O) N f <2 R j; 38) - (CH ₂ ) _q SO ₂ R 1, wherein R 4 represents a group selected from the group consisting of a) alkyl, b) aryl and c) arylalkyl, wherein the alkylene group contains one to six carbon atoms, 39) - (CH 2) _q SO2NR5R _6, wherein R and R _ft are independently selected from the group consisting of a) hydrogen, b) alkyl, c) aryl, d) arylalkyl, wherein the alkylene group has from one to six carbon atoms; 40) - _{(CH2) q} NR7R8, wherein R7 and _Rg are independently selected from the group consisting of a) hydrogen, b) N-protecting group, c) alkyl of one to six carbon atoms, d) alkenyl of two to six f) aryl, g) arylalkyl wherein the alkylene group contains one to six carbon atoms, h) cycloalkyl of three to eight carbon atoms, and i) cycloalkylalkyl, wherein the cycloalkyl group contains three to six carbon atoms; eight carbon atoms and the alkylene group contains one to ten carbon atoms, with the proviso that no two groups are attached to the nitrogen atom through a carbonyl group or through a sulfonyl group; 41) oxo; 42) perfluoroalkyl; 43) perfluoroalkoxy; 44) aryloxy; 45) cycloalkoxy; 46) cycloalkylalkoxy; and 47) arylalkoxy.

The term cycloalkoxy as used herein means a cycloalkyl group, as defined above, attached to the parent molecule through an oxygen atom.

The term cycloalkylalkoxy as used herein means an alkoxy group, as defined above, to which a cycloalkyl group is attached.

The term cycloalkylalkyl as used herein means a cycloalkyl group as defined above, attached to the parent molecular moiety through an alkyl group.

The term haloalkyl as used herein means an alkyl group as defined above substituted with one, two, or three halogens and means, for example, a group such as chloromethyl, bromomethyl, trifluoromethyl and the like.

The term halogen as used herein means F, Cl, Br, and 1.

The term heterocycle used herein means a 5-, 6-, or 7-membered ring containing one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur said 5-membered ring has 0-2 double bonds and said 6-membered ring and 7-membered bonds of 0-3 double bonds The term heterocycle also includes hicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic bonds 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. Said heterocyclic groups include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, thiomorphol, thiol, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, isoindazolyl, triazolyl, tetrazolyl, oxadiazolyl, tetrahydrofuran, thiadiazol, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothienyl and the like Also included in the heterocyclic groups are compounds of formula

wherein F represents a group selected from the group consisting of -CH 2 -, -CH 2 O- and -O- and G represents a group selected from -C (O) - and - (C (R ') (R)) v -, wherein R' and R is independently selected from the group consisting of hydrogen and alkyl of one to four carbon atoms, and av is one to three, including groups such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Each of said heterocyclic groups may optionally be substituted with one, two, li, or four groups independently selected from 1) alkanoyl of one to six carbon atoms, 2) alkyl of one to six carbon atoms, 3) alkoxy of one to six atoms (4) alkoxyalkyl, wherein the alkyl and alkylene groups independently of one another contain from one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfonyl; wherein the alkyl n alkylene group independently contains one; up to six carbon atoms; 7) alkylsulfonyl having 1 to 6 carbon atoms; 8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups each independently contain one to six carbon atoms; 9) aryl; 10) arylalkyl wherein the alkyl group contains one to six carbon atoms, 11) amino, 12) aminoalkyl of one to six carbon atoms; 13) aryl; 14) arylalkyl, wherein the alkylene group contains 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 contains one to six carbon atoms; 20) cycloalkyl of three to eight carbon atoms; 21) cycloalkylalkyl, wherein the cycloalkyl group has three to eight carbon atoms and the alkylene group has one to ten carbon atoms; 22) halogen; 23) haloalkyl of one to six carbon atoms; 24) heterocycle; 25) (heterocycle) oxy; 26) (heterocycle) oyl; 27) hydroxy; 28) hydroxy 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 contains one to six carbon atoms; 33) oxo; 34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkylene groups independently contain one to six carbon atoms; 36) - (CH ₂ ) _q CO ₂ R _2> wherein q is zero to four; 37) - (CH ₂ ) _q C (O) NR ₂ R ₃ ; 38) - (CH ₂ ) qSO ₂ R ₄ , wherein R ₄ is selected from the group consisting of a) alkyl, b) aryl and c) arylalkyl, wherein the alkylene group contains one to six carbon atoms; 39) - (CH ₂ ) qSO 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 contains one to six carbon atoms; 40) - (CH _{2) q} NR ₇ R _p, wherein R ₇ and R _g is selected from the group consisting of a) hydrogen, b) N-protecting group, c) alkyl of one to six carbon atoms, d) alkenyl, (e) C 2-6 alkynyl; (f) aryl; (g) arylalkyl wherein the alkylene group contains one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms; and (i) cycloalkylalkyl wherein cycloalkyl; the group contains three to eight carbon atoms and the alkylene group contains one to ten carbon atoms, with the proviso that no two groups are attached to the nitrogen atom via a carbonyl group or via a sulfonyl group, (41), (42) perfluoroalkyl; 43) perfluoroalkoxy, 44) aryloxy, 45) cycloalkoxy; 46) cycloalkylalkoxy; and 47) arylalkoxy

The term (heterocycle) oxy as used herein means a heterocyclic group as defined above attached to the parent molecule through an oxygen atom.

The term "heterocycle" as used herein means a heterocyclic group, as defined above, attached to the parent molecule through a carbonyl group.

The term hydroxy as used herein means -OH.

The term hydroxyalkyl as used herein means an alkyl group as defined above substituted with one to three hydroxyl groups, with the proviso that only one hydroxyl group such as hydroxymethyl, dihydroxypropyl and the like may be attached to one carbon atom of the alkyl group.

The term meth as used herein means = C (H) -.

The term N-protected amine as used herein means an amine group as defined herein with an attached N-protecting or dustk-protecting group also defined herein.

The term N-protected aminoalkyl as used herein means an alkyl group as defined herein with an attached N-protecting or nitrogen-protecting group also defined herein.

The term nitro as used herein means a -NO 2 group.

The term nitroalkyl as used herein means an alkyl group substituted with a -NO 2 group.

The term N-protecting group or nitrogen protecting group as used herein means amino protecting groups and avoiding undesired reactions of this group in syntheses. The commonly used N-protecting group is disclosed in Greene, Piotective Groups in Organic Synthesis, (John Wiley (Sons, New York (1981)), which is incorporated herein by reference. Groups used as N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, achlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and chiral auxiliaries such as protected and unprotected D-, L- or D, L-amino acids such as alanine, leucine, phenylalanine and sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxyb enzyloxycarbonyl, pnitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,

3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p- biphenylyl) -1-methylethoxycarbonyl, α, α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, tert-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, methoxycarbonyl, alyloxycarbonyl, alyloxycarbonyl, alyloxycarbonyl fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; arylalkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, alanyl, phenylsulfonyl, benzyl, tert-butyloxycarbonyl (Boe) and benzyloxycarbonyl (Cbz).

The term eye used herein means = 0.

The term perfluoroalkyl as used herein means an alkyl group as defined above in which all of the radical hydrogen bonds to the alkyl chain are replaced by fluoride radicals. Examples of perfluoroalkyl groups include trifluoromethyl, pent and fluoroethyl and the like

The term perfluoroalkoxy as used herein means a perfluoroalkyl group as defined above attached to the parent molecule through an oxygen atom.

The term "pharmaceutically acceptable salt" as used herein means those salts which, according to medical judgment, are suitable for contact with the tissues of humans and lower animals and do not cause undesirable toxic, irritant, allergic and other other reactions in a reasoned benefit / risk assessment. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. disclose pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19 These salts can be prepared in situ during the final isolation of the purification of the compounds of the invention or alone, by reacting the free base group with a suitable organic acid. Typical examples of acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphor, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, haemepeptate, ethanesulfonate, ethanesulfonate, ethanesulfonate, ethanesulfonate, , hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmitate, palmitate 3 , phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate and the like. Typical examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, tetraethylammonium , dimethylamine, trimethylamine, triethylamine, ethylamine and the like.

The term pharmaceutically acceptable ester as used herein refers to esters that are hydrolyzed in vivo and include esters that readily degrade in the human body to provide the parent compound or a salt thereof. Suitable ester groups include, for example, esters derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic, alkene, cycloalkanoic and alkanedicarboxylic acids, in which each alkyl or alkenyl group preferably has less than 6 carbon atoms. Examples of individual esters include formates, acetates, propionates, butyrates, acrylates and ethyl succinates

The term "pharmaceutically acceptable prodrug" as used herein refers to prodrugs of those compounds of the invention which, according to medical judgment, in a reasoned benefit / risk and efficacy assessment for the intended target, are suitable for contacting the tissues of humans and lower animals without causing undesirable toxic, irritant, allergic and similar responses, and also includes zwitterionic forms of the compounds of the invention.

The term prodrug, as used herein, means compounds that are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. Details can be found in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. . 14 A.C.S. Syrios Syria, 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), incorporated herein by reference. text incorporated by reference.

The term spiroalkyl as used herein means an alkylene diradical, both ends of which are bonded to the same carbon atom of the parent compound to form a spirocyclic group.

The term sulfonyl as used herein refers to the group -SO 2 -.

The term thioalkoxy as used herein means an alkyl group attached to the parent molecular moiety through a sulfur atom.

The term thioalkoxyalkyl as used herein means an alkyl group substituted with a thioalkoxy group.

Asymmetric or chiral centers may be present in the compounds of the invention. It is believed that the present invention encompasses both different stereoisomers and mixtures thereof The individual stereoisomers of the compounds of the invention are prepared by synthesis from commercially available starting materials containing asymmetric or chiral centers, or by preparation of a mixture of enantiomeric compounds followed by resolution by methods known in the art. include, for example, (I) attaching a racemic mixture of enantiomers 23 labeled (±) to an optically active auxiliary, separating the resulting diastereomers by recrystallization or chromatography and releasing the optically pure product from the optically active auxiliary, or (2) directly separating the mixture of optical enantiomers on chiral chromatography columns. . Enantiomers are referred to herein as R or S depending on the configuration of the substituents around the chiral carbon atom.

The compounds of the invention may also exist in the form of geometric isomers. It is believed that the invention encompasses various geometric isomers and mixtures thereof resulting from the rearrangement of substituents around a carbon-carbon bond, the configuration of these isomers being referred to as Z or E, wherein Z denotes that the substituents are on the same side of the carbon-carbon double bond and the term E means that the substituents are on opposite sides of the carbon-carbon double bond.

Preferred embodiments

Preferred compounds of the invention have the formula (I) wherein

A and C are hydrogen and

B is -LbRb where

-L _r - represents -O-, a

Rh represents a C 2 -C 6 alkyl group, and wherein the alkyl group is substituted

More preferred embodiments of the invention include compounds of formula (I) wherein:

Λ denotes -L _and Ra and

B and C are hydrogen.

wherein -La- represents a group selected from the group consisting of

I) a covalent bond.

2) - (Cl 1 ·) ,,, -.

3) -NR ₂ C (X) -,

4) -C (X) NR 5 ₂₎ -NR ₂ C (X) NR ₃ 6) -C? C-,

7) -CH = CH 8) -C (X) NR ₂ (CH ₂ ) _n C = C 9) -C (X) -,

10) -ΟΙ 1) -OC (O) NR ₂ -, and

12) w; and where

R _a represents a group selected from the group consisting of:

1) amino;

2) aryl;

3) alkyl of one to ten carbon atoms,

4) arylalkyl, wherein the alkylene group contains one to ten carbon atoms

5) cycloalkyl of three to eight carbon atoms;

6) arylalkoxy, wherein the alkylene group contains one to ten carbon atoms; and

7) a heterocycle which is selected from the group consisting of.

1) furanyl,

2) thienyl;

3) imidazolyl; and

R2 represents a group selected at each occurrence from the group consisting of

(1) hydrogen; and

2) alkyl of one to six carbon atoms; and where at each occurrence m is two, n is one,

R 1 and R 3 are hydrogen,

W and X are O, aryl is phenyl, alkyl and aryl are optionally substituted and alkenyl is substituted

Even more preferred compounds of the invention are compounds of formula (I) wherein:

A and B are hydrogen.

-Lc represents a group selected from the group consisting of

1) a covalent bond.

2) -OC (O) NR 3 ₂₎ -SO ₂ NR ₂ -,

4) -C (X) NR ₂ -,

5) -NR, -a

6) -O-;

R c is a group selected from the group consisting of:

1) alkyl of one to six carbon atoms,

2) aryl;

3) arylalkyl, wherein the alkylene group contains one to six carbon atoms

4) a heterocycle, wherein said heterocycle is selected from the group consisting of

(I) furanyl,

2) pyrimidinyl, a is 1, wherein I · is -O-, G is - (C (R ') (R) _V - av

X is O, and

R 1 and R 2 are at each occurrence H, aryl is phenyl and the alkyl group is optionally substituted.

Even more preferred are compounds of the invention of formula (I) wherein:

A is -L _and Ra,

B is -LbRb,

C is hydrogen,

-La- and Lb- means -O- a

R _a and R r represent an alkyl group having one to carbon atoms.

Even more preferred are compounds of the invention of formula (I) wherein:

A is -L _and Ra,

B is -LrRh,

C is -LcRc,

_-L - L | J and L _c is a six-O-

R _a , R b and R c represent an alkyl group of one to six carbon atoms.

Even more preferred are compounds of the invention of formula (I) wherein:

A is hydrogen,

B is -LbRb,

C is -LrRc,

-Lk- represents -O-;

-Lc- represents a group selected from the group consisting of

1) covalent bond,

2) -0-,

3) -CH = CH-,

4) -NR, -a

5) -NR ₂ C (O) O-;

R b represents a group selected from the group consisting of

1) alkyl;

2) arylalkyl, wherein the alkylene group has one to six carbon atoms

R 1 represents a group 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

5) a heterocycle, wherein the heterocycle is selected from the group consisting of

1) benzofuranyl,

2) tetrahydrofuranyl,

3) pyrimidinyl,

4) pyrazolyl;

5) furanyl,

6) pyrimidinyl;

7) thiazolyl aq wherein F is -O-, G is (C (R ') (R)) _V;

R 1 and R 2 are hydrogen and v is 1; and wherein at each occurrence aryl is phenyl and alkyl, aryl and heterocycle are optionally substituted.

Preferred compounds of formula (I) and salts thereof include:

7.8-dimethoxy-2-naphthalenecarboximidamide mono (trifluoroacetate);

6.7.8-trimethoxy-2-naphthalenecarboximidamide mono (trifluoroacetate),

6,7-dimethoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate),

2 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] acetamidomono (trifluoroacetate),

7-benzyloxy-8-iodo-2-Naphthalenecarboximidamide mono (trifluoroacetate);

methyl [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] acetate mono (trifluoroacetate);

2 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] -yl 1-acetic acid mono (trifluoroacetate);

N- [4- (aminomethyl) phenyl] -6-aminoiminomethyl-2-naphthalenecarboxamide bis (trifluoroacetate);

N- [4- (amino) phenyl] -6-aminoimidomethyl-2-naphthalenecarboxamide bis (trifluoroacetate);

1 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] -3-hydroxypropanemone (trifluoroacetate);

phenyl methyl [7- (aminoimidomethyl) -1-naphthalenyl) carbamate mono (trifluoroacetate);

N- [7-aminoiminomethyl) -1-naphthalenyl) acetamide mono (trifluoroacetate);

methyl [7- (aminoiminomethyl) -1-naphthalenyl) carbamate mono (trifluoroacetate);

methyl 3 - [[7 R (aminoiminomethyl) -1-naphthalenyl] amino] -3-oxopropanoate mono (trifluoroacetate);

N- [7- (aminoiminomethyl) -1-naphthalenyl] -2- (phenylmethoxy) acetamide mono (trifluoroacetate);

N- [7- (aminoiminomethyl) -1-naphthalenyl] -1,3-benzodioxole-5-carboxamide mono (trifluoroacetate),

N- [7- (amino) -l-naphthalenyl] benzene metánsulfónamidinono (trifluoroacetate);

1 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] -3-bromopropanemone (hydrochloride);

3 - [(7-aminoiminomethyl-2-thioxy-1-naphthalenyl) oxy] propenone mono (trifluoroacetate);

1 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] -3-phenylpropanone (hydrochloride);

1 - [(7-aminoiminomethyl-2-meloxy-1-naphthalenyl) oxy] -3- [1- (3,4-dimethoxy) phenyl] propanone mono (hydrochloride);

7-methoxy-8- (2-furanyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate);

methyl 6- (aminoiminomethyl) -4 - [(methoxycarbonyl) amino] -2-2-naphthalenecarboxylate mono (trifluoroacetate);

(E) - (7-methoxy) -8- [2- (phenyl) ethenyl]) - 2-naftalénimidamid mono (trifluoroacetate);

6- (4-phenylbutinyl) -2-naphthalenecarboximidamide mono (trifluoroacetate);

7- (2-hydroxyethoxy) -8-iodo-2-naphthalenecarboximodamide mono (trifluoroacetate);

7- (2-hydroxyethoxy) -2-naftalénkarboximodamid mono (trifIuóracetát);

6- (4-methyl-1-pentinyl) -2-naphthalenecarboximidamide mono (trifluoroacetate);

6- (5-fenylpentinyl-2-Naphthalenecarboximidamide mono (trifluoroacetate);

6- (3-phenyl-1-propynyl) -2-naphthalenecarboximidamide mono (trifluoroacetate);

6- (phenylethynyl) -2-naftalénkaiboxinndamid mono (trifluoroacetate);

3-amino-N- [3- (6- (aminoiminomethyl) -2-naphthalenyl) -2-propynyl] benzamide mono (trifluoroacetate),

4-amino-N- [3- (6- (aminoaminomethyl) -2-naphthalenyl) -2-propynyl] benzamide mono (trifluoroacetate);

(S) -2-Amino-N- [1 - [(6- (aminoiminomethyl) -2-naphthalenyl) carbonyl] cycloliexyl] propionamide bis (tri fluoro acetate),

6-methoxy-8-benzyloxy-2-naphthalenecarboximidamide mono (trifluoroacetate),

2 - [(7-aminoiminomethyl-3-methoxy-1-naphthalenyl) oxy] acetamide mono (trifluoroacetate),

N- (6-aminoiminomethyl-2-naphthalenyl) -N'-phenylurea mono (tri fluoroacetate);

(E) -6- [2- (phenyl (ethenyl] -2-naftaIénkarboximidamid mono (trifluoroacetate);

6- [2- (phenyl) ethyl] -2-naphthalenecarboximidamide mono (trifluoroacetate);

7-propoxy-8-iodo-2-naphthalenecarboximidamide mono (trifluoroacetate), (±) -6- (3-phenyloxiranyl) -2-naphthalenecarboximidamide mono (trifluoroacetate);

(E) -6- [2- (2-thienyl) ethenyl] -2-Naphthalenecarboximidamide mono (tnfluóracetát);

6- (3-oxo-butyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate);

6- (3-methoxyphenyl) -2-naphthalenecarboximidamide mono (trifluoroacetate);

N- [3- (methyl) phenyl] -6-aminoiminomethyl-2-naphthalenecarboxamide mono (trifluoroacetate);

6- (2-formyl-phenoxy) -2-Naphthalenecarboximidamide mono (trifluoroacetate);

6- (2-formyIfenyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate),

6- (2- (liydroxymethyl) phenyl) -2-naphthalenecarboximidamide mono (trifluoroacetate);

6- (3-oxo-1-butenyl) -2-naphthalenecarboximidamide mono (trifluoroacetate),

7-methoxy-8- (1H-pyrazol-4-yl) -2-naphthalenecarboximidamide mono (trifluoroacetate);

J?

7-Methoxy-8-iodo-2-naphthalenecarboximidamide mono (trifluoroacetate);

N-phenyl-6-amino-imino-2-a naphthalene-mono (methanesulfonate);

4 - [(6-amino-imino-2-naphthalenyl) oxy] -N-metyIbenzénacetamidniono (trifluoroacetate);

6- [2- (methylthio) phenyl] -2-Naphthalenecarboximidamide mono (methanesulfonate);

6- [2- (2-thiomethoxyethyl) phenyl] naphthalene-2-carboximide mono (methanesulfonate);

7-Methoxy-8- (3-furanyl) -2-naphthalenecarboximidamide mono (methanesulfonate);

7-methoxy-8- (2-benzofuranyl) naphthalene-2-carboximidamide mono (methanesulfonate);

(E) -8- [2- (1,3-benzodioxo-5-yl) ethenyl] -2-naphthalenecarboximidamide mono (methanesulfonate);

(±) -7-methoxy-8- (tetrahydro-3-furanyl) -2-Naphthalenecarboximidamide mono (methanesulfonate);

6 - [[4- (2-aminoethyl) phenyl] ethynyl] -2-naphthalenecarboximidamide mono (trifluoroacetate);

7-Methoxy-8- [2-pyrimidinyl (oxy)] - 2-naphthalenecarboximidamide mono (trifluoroacetate),

7-methoxy-8- [2-thiazoyl (oxy)] - 2-naphthalene-2-carboximidamide mono (trifluoroacetate);

7-methoxy-8- (4-nitrophenoxy) -2-Naphthalenecarboximidamide mono (trifluoroacetate);

7-methoxy-8-pentafluorophenoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate);

7-methoxy-8- [N-2-pyrimidinyl (amino)] - 2-Naphthalenecarboximidamide mono (trifluoroacetate);

N- (6-Amino-methyl-2-naphthalenyl) -N'-benzyluronamide (tri fluoroacetate);

N- (6-amino-imino-2-naphthalenyl) -N'-methylurea mono (trifluoroacetate),

N- (6-aminoaminomethyl-2-naphthalenyl) -N'-isopropyl urea mono (trifluoroacetate);

N- (6-amino-imino-2-naphthalenyl) -N ' -phenyl-N ' -methyl-močovinamono (trifluoroacetate);

6-aminonaphthalene-2-carboximidamide mono (trifluoroacetate);

N- (6-Aminomethyl-2-naphthalenyl) -N'-cyclohexylurea-mono (trifluoroacetate);

N- (6-amino-imino-2-naphthalenyl) -N-benzyloxy urea-mono (trifluoroacetate);

1,1-dimethylethyl [4 - [[(6-cyano-2-naphthalenyl) amino] carbonyl] phenyl] carbamate mono (trifluoroacetate);

N- [6- (aminomethyl) -2-naphthalenyl] -4- (aminomethyl) benzamide mono (trifluoroacetate);

ethyl [6- (amino) -2-naphthalenyl] carbamate mono (trifluoroacetate);

1,1-dimethylethyl [4 - [[[6- (aminoiminomethyl) -2-naphthalenyl) amino] carbonyl] amino] phenyl] carbamate mono (trifluoroacetate);

(E) -6- [2- (phenylthio) ethenyl] -2-Naphthalenecarboximidamide mono (trifluoroacetate);

(E) -6- [2- (2-furanyl) ethenyl] -2-Naphthalenecarboximidamide mono (trifIuóracetát);

(E) -6- [2- (1H-imidazol-1-yl) ethenyl] -2-naphthalenecarboximidamino (trifluoroacetate);

(E) -4- [2- (6-aminoiminomethyl-2-naphthalenyl) ethenyl] -benzenesulfonamide mono (trifluoroacetate);

(E) -4- [2- (6-aminoiminomethyl-2-naphthalenyl) ethenyl] -benzoic acid mono (trifluoroacetate);

4- [7- (aminoiminomethyl) -2-methoxy-1-naphthalenyl] dihydro-2 (3H) -furanone mono (trifluoroacetate);

7-methoxy-8- (1-acetyl-ΙΗ-pyrazolyl) -2-naphthalene-carboximidamide mono (trifluoroacetate);

7-methoxy-8- [1-methylsulfonyl) -1H-4-pyrazolyl] -2-naphthalenecarboximidamide mono (trifluoroacetate);

(E) -4- [2- (6-amino-imino-2-naphthalenyl) ethenyl] benzamide mono (trifluoroacetate);

6- [2- (4-aminophenyl) ethoxy] -2-naphthalenecarboximidamide mono (trifluoroacetate);

methyl [3-methoxy-6- (amino) -4-naphthalenyl] carbamate mono (trifluoroacetate);

7-Methoxy-8- [2-pyrimidinyl (amino)] - 2-naphthalenecarboximidamide bis (trifluoroacetate);

phthalenecarboxamide mono (trifluoroacetate);

6- (4-aminophenyl) -2-naphthalenecarboximidamide bis (trifluoroacetate), methyl 2- [4 - [[[6- (aminoiminomethyl) -2-naphthalenyl] carbonyl] amino] phenoxy] acetate mono (trifluoroacetate, ( E) -6- [2 - [(3-hydroxymethyl) phenyl] ethenyl] -2-naphthalenecarboxamide mono (trifluoroacetate),

6- (2-phenyl-1-cyclopropyl) -2-naphthalenecarboximidamide mono (trifluoroacetate), (E) -6- [2- [4- (aminomethyl) phenyl] phenyl] -2-naphthalenecarboximidamide bis (trifluoroacetate);

(E) -6- [2- [4- (1,2-dihydroxyethyl) phenyl] ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate);

(E) -6- [2- [4- (1H-amino-2-liydroxyethyl) phenyl] ethenyl] -2-naphthalenecarboximidamide bis (trifluoroacetate);

7-Methoxy-8- (2-pyrimidinylamino) -2-naphthalenecarboximidamide bis (trifluoroacetate;

(E) -6- [2 - [[4- (dimethylamino) methyl] phenyl] ethenyl] -2-naphthalenecarboximidamide bis (trifluoroacetate);

(E) -6- [2- [4- (hydroxymethyl) phenyl] ethenyl] -2-naftalénkarboximidamidmono (trifluoroacetate);

4 - [[6- (amino) -2-naftaIenyl] ethynyl] -L-phenylalanine, mono (trifluoroacetate);

6- (3-formylphenyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate);

(E) -6- (l, 2,3,4-tetrahydro-6-isoquinolinyl) ethenyl] -2-Naphthalenecarboximidamide bis (trifluoroacetate);

(E) -6- [2- [3- (2-hydroxyethyl) phenyl] ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate);

6- (aminoiminomethyl) -N- (2,3-dihydro-1H-inden-5-yl) -2-naphthalenecarboxamido-mono (tri fluoroacetate),

6 - [(4-aminophenyl) ethynyl] -2-naftalénkaroximidamid bis (trifluoroacetate);

1,1-dimethylethyl [2- [3 - [[6- (aminoiminomethyl) -2-naphthalenyl] ethynyl] -6-methoxyphenyl] ethyl] carbamate mono (trifluoroacetate;

1,1-dimethylethyl [4 - [[6- (aminoiminomethyl) -2-naphthalenyl] -ethynyl] phenyl] methyl] carbamate mono (trifluoroacetate),

6 - [[4- (aminomethyl) phenyl] ethynyl] -2-naftaIénkarboximid-amide bis (trifluoroacetate);

6 - [[3- (2-aminoethyl) -4-methoxyphenyl] ethynyl] -2-naftalénkarboximidamidbis (trifluoroacetate),

6 - [[4- (hydroxymethyl) phenyl] ethynyl] -2-Naphthalenecarboximidamide mono (trifluoroacetate);

6 - [(1,2,3,4-tetrahydro-6-isoquinolinyl) ethynyl-2-naphthalenecarboximidamide bis (trifluoroacetate);

6- (aminoiminornetyl) -N- (4-methylphenyl) -2-a naphthalene-mono (trifluoroacetate),

1,1-dimethylethyl [[4 - [[[6-aminoiminomethyl) -2-naphthalenyl] amino] carbonyl] phenyl] methyl] carbamate mono (trifluoroacetate);

N- [6- (aminomethyl) -2-naphthalenyl) benzamide mono (trifluoroacetate);

1,1-dimethylethyl [[4 - [[[6-aminoiminomethyl) -2-naphthalenyl] amino] carbonyl] cyclohexyl] methyl] carbamate mono (trifluoroacetate);

N- [6- (aminoiminomethyl) -2-naphthalenyl) -N '- (4-aminophenyl) urea (tri fluoroacetate);

N- [6- (amino) -2-naphthalenyl) -4,4 (amino-methyl) cyklobexánkarboxamid-bis (tľifluóracetát).

N- [6- (aminoiminonethyl) -2-naphthalenyl] -N '- [(4-aminomethyl) phenyl] urea bis (trifluoro racetate),

6- (amino) -N- (4-ethyl-phenyl) -2-naphthalene-carboxamide (acetate);

6- (aminoiminomethyl) -N- (2-naphthalenyl) -2-naphthalenecarboxamido) trifluoroacetate;

6- (5-phenyl-2-oxazolyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate);

6- (5-phenyl-2-thiazolyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate);

6- (aminoiminomethyl) -N- (1,2,3,4-tetrahydro-6-quinolinyl) -2-naphthalenecarboxamide bis (trifluoroacetate);

6- [amino (hydroxyimino) methyl] -N-phenyl-2-naphthalenecarboxamide;

6- [4 - [(hydroxymethyl) phenyl] methoxy] -2-naftalénkarboximid amide (methanesulfonate);

6- (2-pyridinyletinyl) -2-Naphthalenecarboximidamide mono (trifIuóracetát);

N- [4- (aminocarbonyl) phenyl] -6- (amino) -2-a naphthalene-mono (trifluoroacetate);

6- (amino) -N- (2-thiazolyl) -2-a naphthalene monohydrochloride;

6- (aminoiminametyl) -N- (6-methoxy-3-pyridinyl) -2-naftalértkarboxamidmonohydrochlorid;

6- (amino) -N- (l, 3-benzodioxol-5-yl) -2-naftalénkarboxamidmono (trifluoroacetate);

6- (aminoiminomethyl) -N- (1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinyl) -2-naphthalene-carboxamide monohydrochloride);

6- (aminoiniinoinetyI) -N- (3,5-difluorophenyl) -2-naftalénkarboxamidmono (trifluoroacetate);

6- (aminoiminomethyl) -N- (1H-pyazol-3-yl) -2-naphthalenecarboxamide mono (trifluoroacetate);

6- (amino) -N- (5-methyl-3-isoxazolyl) -2-naftalénkarboxamidľnono (trifluoroacetate);

6- (aminoiminomethyl) -N- (pyrazinyl) -2-naphthalenecarboxamide mono (trifluoroacetate);

6- (aminoiminomethyl) -N- (6-methyl-2-pyridinyl) -2-naphthalenecarboxamide mono (trifluoroacetate);

6- (amino) -N- (3,4,5-trimethoxyphenyl) -2-naftalénkarboxamidmonohydrochlorid;

6- (amino) -N- (3-methyl-2-pyridinyl) -2-naftalénkarboxamidbis (trifluoroacetate);

6- (amino) -N- (5-bromo-2-thiazolyl) -2-naftalénkarboxamidmono (trifluoroacetate);

6- (amino) -N- (5-methyl-2-pyridinyl) -2-naftalénkarboxamidmono (trifluoroacetate);

6- (amino) -N- (4-methyl-2-thiazolyl) -2-naftalénkarboxamidmo.no (trifluoroacetate);

6- (amino) -N- (6-quinolinyl) -2-naftalénkarboxamidmono (trifluoroacetate);

6- (amino) -N- (lH-indazol-6-yl) -2-naftalénkarboxamidbis (trifluoroacetate);

6- (aminoiminomethyl) -N- (1H-indazol-5-yl) -2-naphthalenecarboxamide bis (trifluoroacetate);

6- (aminoiminomethyl) -N- (1H-indol-5-yl) -2-naphthalenecarboxamide mono (trifluoroacetate);

6- (aminoiminomethyl) -N- (5-pyrimidinyl) -2-naphthalenecarboxamide mono (trifluoroacetate).

6- (amino) -N- (3-pyridazinyl) -2-naftalénkarboxamidmono (trifluoroacetate);

6- (amino) -N- (5-bromo-2-pyridinyl) -2-naftalénkarboxamidmono (trifluoroacetate);

6- (aminoiminomethyl) -N- [3- (1-methylethoxy) phenyl] -2-naphthalenecarboxamide mono (trifluoroacetate);

6- (aminoiminomethyl) -N- (1H-imidazolyl) -2-naphthalenecarboxamide bis (trifluoroacetate);

6- [2- [4- (hydroxymethyl) phenyl] -1-cyclopropyl] -2-naphthalenecarboxamide mono (trifluoroacetate);

N- (ethoxycarbonyl) -6- (2-phenyl) -1-cyclopropyl) -2-naphthalenecarboxamide;

6- (amino) -N- (2-methyl-6-quinolinyl) -2-naftalénkarboxamidbis (trifluoroacetate);

6- (amino) -N- (3-propoxy-phenyl) -2-naftalénkarboxamidmono (trifluoroacetate);

6- (aminoiminomethyl) -N- [3- (1-ethylpropoxy) phenyl) -2-naphthalenecarboxamide mono (trifluoroacetate);

6- (aminoiminomethyl) -N- [3- (cyclopentyloxy) phenyl) -2-naphthalenecarboxamide mono (trifluoroacetate);

6- (amino) -N- (3-phenoxyphenyl) -2-naftalénkarboxarnidmono (trifluoroacetate);

6- (aminoiminomethyl) -N- [3- (phenylmethoxy) phenyl) -2-naphthalene carboxamide mono (trifluoroacetate),

6- (amino) -N- (3-ethoxyphenyl) -2-naftalénkarboxamidmono (trifluoroacetate);

6- (aminoiminomethyl) -N- (4-nitrophenyl) -2-naphthalene carboxamide mono (trifluoroacetate),

6- (aminoaminomethyl) -N- [3- (cyclobutylmethoxy) phenyl) -2-naphthalenecarboxamide mono (trifluoroacetate);

6- [amino (ethoxycarbonyl) imino] -N- [3- (1-methylethoxy) phenyl] -2-naphthalenecarboxamide;

6- (aminoiminomethyl) -4- [5- (ethylsulfonyl) -3-furanyl] -N-phenyl-2-naphthalenecarboxamide monohydrochloride;

methyl [7- (aminoiminomethyl) -2-methoxy-1-naphthalenyl) carbamate mono (trifluoroacetate);

7-Methoxy-8- (2-pyrimidinylamino) -2-naphthalenecarboximidamide bis (trifluoroacetate)

7-methoxy-8 - [(fenyImetyl) amino] -2-naftalénkarboximidamidmono (trifluoroacetate);

7-methoxy-8- (phenylamino) -2-naftaIénkarboximidamid mono (trifluoroacetate);

7-methoxy-8 - [(4-methoxyphenyl) amino] -2-Naphthalenecarboximidamide mono (trifluoroacetate);

(E) -3- [7- (aminoiminomethyl) -2-methoxy-1-naphthalenyl) -2-propenamide mono (trifluoroacetate);

7-methoxy-8- (3-oxo-1-cyclopenten-1-yl) -2-naphthalenecarboximidamide mono (trifluoroacetate);

ethyl 4 - [[[7- (aminoiminomethyl) -1- (2-pyrimidinylamino) -2-naphthalenyl] oxy] methyl] benzoate mono (trifluoroacetate;

4 - [[[7- (aminoiminomethyl) -1- (2-pyrimidinylamino) -2-naphthalinyl] oxy] methyl] benzo mono (trifluoroacetate),

7-methoxy-8- (pyrazinyloxy) -2-Naphthalenecarboximidamide dimethanesulfonate);

7-methoxy-8- (phenylthio) -2-nafialénkarboximidamid-metánsiilfonát).

7-methoxy-8- (pyrazinylamino) -2-Naphthalenecarboximidamide bis (trifluoroacetate);

methyl 5- [7 - [(aminoiminomethyl) -2-naphthalenyl] oxy] pentanoate mono (trifluoroacetate) acid 5 - [[6- (aminomethyl) -2-naphthalenyl] oxy] -pentánovámono (trifluoroacetate);

methyl 4 - [[[7-amino (hydroxyimino) methyl] -2-naphthalenyl] oxy] metyljbenzoát;

methyl 1-2 - [[6- (aminoiminomethyl) -2-naphthalenyl] oxy] acetate mono (trifluoroacetate);

7- [2- (4-morpholinyl) ethoxy] -2-Naphthalenecarboximidamide bis (trifluoroacetate);

2 - [[6- (aminoiminomethyl) -2-naphthalenyl] oxy] acetic mono (trifluoroacetate), methyl 4- [6 - [(aminoiminomethyl) -2-naphthalenyl] oxy] methylbenzoate mono (trifluoroacetate) ;

methyl [7- (aminoaminomethyl) -1-naphthalenyl] methylcarbamate mono (trifluoroacetate);

propyl [7- (aminoiminomethyl) -1-naphthalenyl] carbamate mono (trifluoroacetate);

N- [7- (aminoiminomethyl) -1-naphthalenyl] -N'-methylurea mono (trifluoroacetate);

ethyl [7- (aminoiminomethyl) -1-naphthalenyl) carbamate monotrifluoroacetate;

N- [7- (aminomethyl) -1-naphthalenyl) propanamide mono (trifluoroacetate),

N- [7- (aminoiminomethyl) -1-naphthalenyl) -2-methoxyacetamide mono (trifluoroacetate);

N- [7- (aminoiminomethyl) -1-naphthalenyl) urea mono (trifluoroacetate),

N- [7- (aminomethyl) -1-naphthalenyl) -2-hydroxyacetamide mono (trifluoroacetate);

8- (2-pyrimidinyl) -2-Naphthalenecarboximidamide bis (trifluoroacetate);

8-amino-2-Naphthalenecarboximidamide bis (trifluoroacetate);

8- (2-pyridinyIamino) -2-Naphthalenecarboximidamide bis (trifluoroacetate);

N-hydroxy-8- (2-pyrimidinyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate);

6- (amino) -4- (3-furanyl) -N- [4- (trifluoromethyl) phenyl] -2-a naphthalene-mono (trifluoroacetate);

6- (aminoiminomethyl) -4- (3-furanyl) -N- (4-pyridinyl) -2-naphthalenecarboxamide dihydrochloride;

6- (aminoiminomethyl) -4- (3-furanyl) -N- (1H-pyrazol-3-yl) -2-naphthalenecarboxamide dihydrochloride;

6- (aminoiminomethyl) -4- (3-furanyl) -N- (3-pyridinyl) -2-naphthalenecarboxamide dihydrochloride;

methyl [7- (aminoiminomethyl) -3 - [[[4- (aminomethyl) phenyl] amino] carbonyl] -1-naphthalenyl] carbamate bis (trifluoroacetate);

6- (aminoiminomethyl) -4- (3-furanyl) -N- (2-pyridinyl) -2-naphthalenecarboxamide dihydrochloride;

6- (amino-methyl) -4- (3-furanyl) -N-phenyl-2-naphthalenecarboxamide monohydrocliloride;

6- (amino) -4- [l- (inetylsulfonyl) -lH-pyrazol-4-yl] -N-phenyl-2naftalénkarboxamid monohydrochloride,

6- (aminoiminomethyl) -4- (5- (methylthio) -3-furanyl)] - N-phenyl-2-naphthalenecarboxamide monohydrochloride;

6- (amino) -N- [4- (aminomethyl) phenyl] -4- (2-pyrimidinyl) -2naftalénkarboxamid tris (trifluoroacetate);

6- (amino) -N-phenyl-4- (2-pyrimidinyl) -2-a naphthalene-mono (trifluoroacetate);

N - [(4- (aminomethyl) phenyl] -6- [amino (hydroxyimino) methyl] -4- (2-pyrimidinyl amino) -2-naphthalenecarboxamide bis (trifluoroacetate);

6- (aminoaminomethyl) -N- [4- (hydroxymethyl) phenyl] -4- (2-pyrimidinylamino) 2-naphthalenecarboxamide mono (trifluoroacetate);

methyl [3 - [[[4- (aminomethyl) phenyl] amino] carbonyl] -7- [4-amino (hydroxyimino) methyl] -1-naphthalenyl] carbamate-bis (trifluoroacetate);

6- (amino) -N-phenyl-4- (tetrahydro-3-furanyl) -2-a naphthalene monohydrochloride;

6- [amino (hydroxyimino) methyl] -N-phenyl-4- (2-pyrimidinyl-amino) -2naftalénkarboxamid;

6- (aminoiminomethyl) -4- [5- (ethylthio) -3-furanyl] -N-phenyl-2-naphthalene carboxamide monohydrochloride;

6- (aminoiminomethyl) -4- [5- (propylthio) -3-furanyl] -N-phenyl-2-naphthalenecarboxamide d-monohydrochloride;

6- (amino) -N-phenyl-4- (2-pyrrolidinyl) -2-naftalénkarboxamidmono (trifluoroacetate);

6- (aminoiminomethyl) -4- [5- (propylsulfonyl) -3-furanyl] -N-phenyl-2naftalénkarboxamid monohydrochloride,

6- (aminoiminomethyl) -4- [5 - [(methylthio) methyl] -3-furanyl) -N-phenyl-2-naphthalene and carboxamide monohydrochloride,

6- (amino) -4- [5- (methoxymethyl) -3-furanyl] -N-phenyl-2naftalénkarboxamid monohydrochloride;

6- (aminoiminomethyl) -4- [5- (methylsulfonyl) -3-furanyl] -N-phenyl-2-naphthalenecarboxamide mono (trifluoroacetate) and

6- (amino) -4- [5- (ethylthio) tetrahydro-3-furanyl] -N-phenyl-2naftalénkarboxamid monohydrochloride.

Determination of urokinase inhibition

The ability of the compounds of the invention to act as urokinase inhibitors is determined by measuring inhibition of the urokinase enzyme Abbokinase (Abbott Laboratories, Abbott Park, IL) on substrate S-24444 of the pyroGlu-Arg-pNA-HCl substrate (DiaPharma Group, Inc. Distributor of Chromgenix) at 200. μΜ.

The assay is performed in a 96 well flat bottom polystyrene plate in 50 mM Tris / 0.15 M NaCl + 0.5% Pluronic F-68 (Sigma P-5556), pH 7.4 buffer (with HCl). Compounds of the invention, 10 mM in DMSO, are diluted with DMSO to eight concentrations differing by half log units, for example 1200 μΜ, 400 μΜ, 120 μΜ, 40 μΜ, 12 μΜ, 4 μΜ, 1 μΜ and 0.4 μΜ U the four concentrations chosen are then diluted 5 μΙ in each case to a total volume of 200 μΐ for the determination. The respective final concentrations for the determination on the basis of the above example are then 30 μΜ, 10 μΜ, 3 μΜ, 1 μΜ, 0,3 μΜ, 0,1 μΜ, 0,03 μΜ, and 0,01 μΜ Substrate S-2444 is used for the determination at a concentration of 200 μΜ. Enzyme vials are diluted as described, aliquots are removed and stored frozen. The enzyme is then further diluted with assay buffer and 10 μΙ is used for the assay. The enzyme concentration in the assay is 2-3 nM. The assay is performed as follows: 175 μΙ of buffer is pipetted onto a polystyrene plate, 5 μΙ of the compound of the invention is added and the mixture is vortexed, then 10 μΐ of enzyme is added in the buffer. , add 10 μΐ of substrate in water, vortex again, and place the plate on a Spectromax® evaluation device (MolecularDevices Corporation, Sunnyvale, Ca) to monitor the reaction at 405 nm for 15 minutes. The Spectromax® device allows the evaluation of the reaction rates that are used to calculate the percent inhibition of the compounds of the invention by comparison with the reaction enzymatic rate in the absence of inhibitor. Ki values of inhibitors are calculated from percent inhibition and predetermined Km value. The compounds of the invention inhibit urokinase as shown in the following data presented in Table 1, which are referred to representative examples.

Table 1. Inhibitory activity of representative compounds on urokinase

Example lC ₅ o (μΜ) 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 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 60 0.72 61 0.73 62 0.64 63 0.37 64 0.56 65 0.54 66 3.13 67th 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 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 1 1 1 4.17 1 12 0.45 1 13 0,403 1 14 0,344

1 15 0,063 1 16 0,045 117 0,278 118 0,121 1 19 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 0,001 17 142 0.54 143 0.36 144 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 > 30 174 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 0.56 195 1.3 196 0.62 197 2.03 198 0,504 199 2.3 200 0,037 201 0,077 202 0,792 203 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 U 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 0,025 229 0,117 230 0,103 231 0,015 232 0,123

Pharmaceutical compositions

The present invention also provides pharmaceutical compositions comprising compounds of the invention in association with one or more pharmaceutically acceptable carriers. In particular, the compositions may have a composition suitable for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.

The pharmaceutical compositions of the invention may be in forms suitable for administration to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally or topically (in the form of powders, ointments or drops), buccally or in the form of oral or nasal spray. The term parenteral administration as used herein includes routes of administration such as intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intra-articular injection and infusion administration.

Pharmaceutical compositions of the invention for parenteral injectable form include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions at the time of application Examples of suitable aqueous and non-aqueous 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 oil), and injectable organic esters such as ethyl oleate. lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

Said compositions may also contain additives such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the effects of microorganisms can be ensured by incorporating various antimicrobial or fungicidal agents such as 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 forms may be ensured by the incorporation of absorption-enhancing agents (such as aluminum monostearate and gelatin).

In some cases, in order to prolong the effect of the drug by subcutaneous or intramuscular injection, it is desirable to slow the absorption of the drug. This can be achieved by using a liquid suspension of a crystalline or amorphous form of a low water solubility substance. The rate of absorption of the drug then depends on its rate of solubility, which in turn depends on the crystal size and crystalline form. Alternatively, prolonged absorption of the drug may be accomplished by dissolving or suspending the drug in an oily vehicle.

Injectable depot forms are prepared in the form of microencapsulated drug matrices in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, it is possible to control the degree of drug release. Examples of other suitable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

Injectable preparations can be sterilized, for example, by filtering with a bacteria-retaining filter or by incorporating sterilizing agents into sterile solid compositions which are dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active ingredient is admixed with at least one pharmaceutically acceptable excipient or carrier selected from the group consisting of sodium citrate or dibasic calcium phosphate and / or a) fillers or diluents such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia; c) humectants such as glycerol; (d) disintegrating agents such as 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) glidants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of dosage forms such as capsules, tablets and pills, buffers may also be included in the formulation. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols. Similarly.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as an enteric coating and other coatings known from pharmaceutical technology. Optionally, light-impermeable compositions may also be included in the compositions and may contain compositions of such a kind that the release of the active ingredient (s) occurs only or particularly in certain parts of the gastrointestinal tract, or optionally in a delayed manner. Polymeric substances and waxes may be used as components suitable for the incorporation of the active ingredients

The active compounds may also be, if appropriate in microencapsulated form, with one or more of the ingredients listed above.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs In addition to the active compounds, these liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate , ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cotton, peanut, corn, germ, olive, castor and sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, sorbitan esters and sorbitan esters thereof.

In addition to inert diluents, these oral compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, and flavoring and flavoring agents.

Suspensions may contain, in addition to the active compounds, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, and mixtures thereof. Compositions for rectal or vaginal administration are preferably in the form of suppositories, which may be prepared by mixing the compounds of the invention with suitable non-irritating ingredients or carriers such as cocoa butter, polyethylene glycol or suppository wax that are solid at room temperature but at body temperature. in the liquid state and therefore in the rectal or vaginal cavity, the active compound melts and releases.

The compounds of the invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid moieties. Liposomes are formed from monolayer or multilayer hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The liposome form of the invention may additionally contain stabilizers, preservatives, additives and the like. Preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for preparing liposomes are known in the art, and are disclosed, for example, in Prescott Ed., Methods in Cell Biology, Vol. XIV, Academic Press, New York, N.Y (1976) p.33 and following.

Dosage forms for topical administration of the compounds of the invention include powders, sprays, ointments and inhalants. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and each of the optional preservatives, buffer or propellant. The invention also includes ophthalmic formulations, eye ointments, powders and solutions.

The actual dosage range of the active ingredients of the invention may be variable so that the amount of active compound (s) is sufficient to achieve a therapeutic response in a particular patient, composition and route of administration. The selected dosage range will also depend on the efficacy of the individual compound, the route of administration, the severity of the condition being treated and the condition and history of the patient being treated. However, according to the prior art, dosages of the compound are lower than necessary to achieve the desired therapeutic effect, and then the doses are gradually increased until the desired effect is achieved. In general, the dosage range is from about 1 to about 50, more preferably from 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 example two or four separate doses per day, for administration purposes.

Preparation of Compounds of the Invention

Compounds of the invention may be prepared by a variety of synthetic methods. Typical methods are shown in the following Schemes I to 6.

abbreviations:

In the following descriptions of the schemes and examples, the following abbreviations are used: THF means tetrahydrofuran, DMF means N, N-dimethylformamide,

OEt ₂ is diethyl ether, 1-DC is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; NMY1 means N-methylmorpholine; LDA means lithium duzopropylamide; TFA means trifluoroacetic acid; DMSO means dimethylsulfoxide, DMAP means 4- (N, N-dimethylamino) pyridine; HATU means O- (azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate; Boe means tert-butylcarbonyloxy, DDQ means 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; Bn represents benzyl, DPPA diphenylphosphoryl azide; DCC means dicyclohexylcarbodiimide, EDC means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; SEM means 2- (trimethylsilyl) ethoxymethyl; dppf means 1,1'-bis (diphenylphosphino) ferrocene; and dba means dibenzylideneacetone. Starting materials, reagents and solvents were from Aldrich Chemical Company (Milwaukee, Wi).

Scheme 1 depicts the preparation of naphthalenecarbonitriles 4, 5 and 6 by treating 3-cyanopropionaldehyde 2 diethyl acetal with a strong base such as lithium diisopropylamide, followed by treatment of the resulting anion with suitably substituted benzaldehyde 1, followed by cyclization and aromatization as the corresponding cyanohydrin 3. sulfuric acid.

Scheme 1

wherein A, B and C are hydrogen and -L _A R _A. mu »R h, -L, and -Lh- -Lc- represent - () R, R" and R _{in the} meaning of alkyl, ·

-LcRc

C

B

, CN where

4: A is hydrogen; B and C are OCH?

S-A, Ba and C are OCH 3

6: A and B are OCH ₃ and C is hydrogen.

Scheme 2 depicts selective demethylation of 4 with a Lewis acid such as AlCl 3 or BBr ₃ , preferably AlCl 3, to form Compound 7. Compound 7 is treated with a base such as potassium carbonate, sodium hydride or cesium fluoride followed by R c-X, where X is a leaving group to form compound 8 (-L _c - represents -O-). Alternatively, treatment of 7 with trifluoromethanesulfonic anhydride or 1,1,1-trifluoro-N-phenyl-N - [(trifluoromethyl) sulfonyl] methanesulfonamide gives 9, which can be treated with Rc-B (OH) 2,

wherein R c is an unsubstituted or substituted aryl or heterocyclic group, in the presence of a palladium catalyst, preferably Pd (11) Cb (dba) or Pd (Ph ₃ P) ₄ and a base, preferably cesium fluoride or potassium carbonate, to give compound 10 .

Alternatively, compound 9 can be treated with R _L-R | R _2, wherein R _c is an unsubstituted or substituted aryl or heterocyclic group, and at least one of R | or 1 <2 represents hydrogen, in the presence of a strong base such as potassium tert-butoxide and a catalyst such as Pd (II) Cl ₂ (dba)

2

R c represents an unsubstituted or substituted aryl or heterocyclic group,

10: -Lc- means a covalent bond,

1 · -Lc- means -NR 1 -.

As shown in Scheme 3, by selective O-triflation of compound 12 followed by introduction of the amino protecting group of the resulting compound 13. wherein the protecting group is an acid-labile carbobenzyloxy group, compound 14 is obtained. Conversion of compound 14 to compound 15 is accomplished by KCN in tris (dibenzylideneaceto) dipalladium (O) -chloroform adduct, and deprotecting compound 15 with an acid, preferably 30% HBr in acetic acid, affords compound I6. Treatment of compound 15 with acylating agents RcC (O) VI and a base, preferably triethylamine, diisopropylamine or potassium carbonate yielded intermediate I7

Scheme 3

iú J7

-L _c - represents -C (O) NR 1 - or -OC (O) NR 1 a

R c is unsubstituted or substituted alkyl.

alkenyl, heterocyclic or aryl.

Scheme 4 illustrates the selective demethylation of the 8-methoxy group of compound 18 with a Lewis acid such as AlCl 3 or BBr ₃ , preferably with AlCl 3, and subsequent introduction of the phenol 19 protecting group by alkylation with Bn-X where X is Cl, Br or I in the presence of a base such as is potassium carbonate, sodium hydride or cesium fluoride. Compound 20 is prepared by depretonizing this intermediate with a strong non-nucleophilic base such as lithium, sodium or potassium diisopropylamide or alkoxide, followed by treatment with an alkyl formate, preferably ethyl formate, to afford enol 20. Treatment of 20 with hydroxylamine yields isoxazole 21 which can be opened with lithium alkoxide. , sodium or potassium, preferably sodium methoxide, to give compound 22 Reduction of the carbonyl group with concomitant formation of alkene with sodium borohydride affords compound 23., aromatization with DDQ and catalytic debenzylation with hydrogen in the presence of a palladium catalyst, preferably palladium on carbon to give compound 24. Compound 24 is alkylated by treatment with a base such as potassium carbonate, sodium hydride or cesium fluoride followed by treatment with R ₍ -X).

Scheme 4

A is -L _and R _a , and C is -LcRc. wherein -L _and - and -Lc- are -O- and R _A is an alkyl group,

C is -L _c R c, where

Lc is -O- and Rc is aralkyl

A is -L _A R _A , wherein -L _and - is

-O- and R _a represents an alkyl group

According to Scheme 5, monoliydiolysis of compound 25 with one equivalent of base such as lithium, sodium or potassium hydroxide affords the acid ester 26 Treatment of 26 with thionyl chloride or oxalyl chloride / DMP followed by treatment with ammonia gives amide 27 Treatment of 27 with dehydrating agent Chloride or phosphorus oxychloride gives the nitrile 28

By positional selective grinding of compound 28 with nitric acid / potassium nitrate and subsequent reduction of the nitro group with a palladium catalyst, preferably palladium on carbon, intermediate 3 is obtained which is treated with R ₁ C (O) Cl or R, OC (O) Cl and a base. , preferably with diisopropyl ethylamine or potassium carbonate, provides compound 37

Hydrolysis of compound 28 with one equivalent of lithium, sodium or potassium hydroxide affords the carboxylic acid 29. which then treatment with DPPa or thionyl chloride and then sodium azide followed by hydrolysis of the intermediate isocyanate 32 with an acid, preferably sulfuric acid, provides the amine 33 32 with a primary or secondary amine gives urea 34 (-L _A - = -NR ₁ C (X) R ₂ -, where X is O).

Compound 29 can be coupled with primary or secondary amines, and compound 33 can be coupled with carboxylic acids to form the respective amides 35 and 36, respectively. In each case, coupling of both amines and carboxylic acids is accomplished using a dehydrating agent such as DCC, EDC or HATU.

Scheme 5

-1. _Λ denotes a covalent bond and R _A denotes an alkoxycarbonyl group

J

LCRC

-L _c - represents -C (X) NR 1 or -OC (O) NR 1 and R c represents an unsubstituted or substituted alkyl, alkenyl, heterocycle or aryl group;

X is O

-L, - - represents -NR 1 C (X) wherein X represents O

-L _and - is -C (X) NR 1 where X is O

Scheme 6 illustrates the preparation of intermediates in which-1. _A- represents OC- or -C = C- by treating compound 38 with a triflating agent, preferably trifluoromethanesulfonylanhydride, to form compound 39. followed by coupling with suitably substituted alkenes or unsubstituted alkynes, using a palladium catalyst, preferably palladium (II) acetate, to form the compound 40

Scheme 6

.CN

Scheme 7 shows the conversion of nitrile intermediates to carboximidamide urokinase 41 inhibitors, which can be accomplished in three ways (1) treating the intermediate carbonitriles with a non-nucleophilic base such as sodium or potassium bis (trimethylsilylamide), preferably lithium bis (trimethylsilylamide), followed by acid hydrolysis, preferably HCl; (2) treating said nitrile with an acid, preferably HCl, and then treating with ammonium acetate; and (3) treating said nitrile with H 2 S and subsequent treating with ammonia gas in methanol Of the three methods, a preferred method is₂S / NH 3 / methanol. The compounds of the invention precipitate as the hydrochloride or methanesulfonate salts or are purified by reverse phase medium pressure chromatography to form the mono- or trifluoroacetate salts.

Scheme 7

B

C NH

Synthesis methods

The foregoing description will be more apparent from the following examples, illustrating possible processes for the preparation of the compounds of the invention, but not in any way limiting the scope of the invention as defined in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

7,8-dimethoxy-2-naftaIénkarboximidamid mono (trifluoroacetate)

Example IA

7,8-dimethoxy-2-naphthalenecarbonitrile

A solution of freshly prepared LDA in THF was treated dropwise with 3-cyanopropionaldehyde diethyl acetal (3.0 g) in THF (5 mL) at -78 ° C, stirred for 1 hour and then treated with 2,3-dimethoxybenzaldehyde (3). 2 g) in THF (5 ml), warmed to room temperature over 90 minutes, treated with water (40 ml), concentrated and extracted with chloroform. The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated to give 1.5 g of a yellow oil.

MS (DCI / _NH3) m / e 341 (M + H ₂ 0 ^+).

A solution of the above oil in methanol (5 mL) was then added dropwise to 20% aqueous sulfuric acid (100 mL) at 90 ° C. This solution was then heated for 90 minutes, then cooled to room temperature and extracted with chloroform. The combined organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated to give 1.0 g of a brown solid, which was purified by flash chromatography on silica gel with 3: 1 hexane / ethyl acetate to give 800 mg of the title compound.

MS (DCI / NH 3) m / e 23 1 (M + H ₂ O) *

Example 1B

7,8-dimethoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate)

A solution of Example 1 (200 mg) in THF (5 mL) was treated at 0 ° C with lithium bis (trimethylsilylamide) (1.0 M in hexane, 1.1 mL), stirred at rt for 18 h, with a put work up with 10% HCl (10 mL), stir at room temperature for 24 hours, concentrate and purify by medium pressure liquid chromatography using a 30 cm x 2 cm C-18 (40 micron, J T. Baker) column with UV detection at 250 nm and a solvent mixture for gradient elution ranging from 90% A (0.1% aqueous TFA) / 10% B (methanol) to 10% A / 90% B at a flow rate of 5 ml / min (fractions collected each time) 2 min for 100 min (product detection by TLC (acetonitrile / water / acetic acid)) to give 100 mg of the title compound.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 4.41 (s, 3H), 4.62 (s, 3H), 7.41 (d, 1H), 7.43 (dd, 1H), 7 60 (d, 1H); 7.89 (d, 1H); 8.49 (d, 1H); 9.31 (bs, 2H); 9.48 (bs, 2H);

MS (DCI / _NH3) m / e 231 (M + H)

Calcd for C13H14N2O2.TFA: C, 52.33; H, 4.39; N, 8.14. Found: C, 51.91; H, 4.35; N, 8.05.

Example 2

6,7,8-trimethoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 2A

6,7,8-trimethoxy-2-naphthalenecarbonitrile

The title compound was prepared as described in Example 1A except that 2,3,4-trimethoxybenzaldehyde was used in place of 2,3-dimethoxybenzaldehyde.

MS (DCI / NH) m / e 261 (Μ · ₂ 0 + Ι1) \

Example 2B

6,7,8-trimethoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared and purified as described in Example IB to give 100 mg of the title compound.

1 H NMR (DMSO-d 6, 300 MHz) δ 3.91 (s, 3H), 3.98 (s, 3H), 4.06 (s, 3H), 7.36 (s, 1H), 7, 75 (dd, 1 H), 7.99 (d, 1 H), 8.49 (d, 1 H), 9.18 (bs, 2 H), 9.38 (bs, 2 H);

MS (DCI / NH ₃ ) m / e 261 (M + H) &lt; ^{+ &gt};.

Anal. Calcd for C 14 H 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.

Example 3

6,7-dimethoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 3A

6,7-dimethoxy-2-naphthalenecarbonitrile

The title compound was prepared as described in Example IA except that 3,4-dimethoxybenzaldehyde was used in place of 2,3-dimethoxybenzaldehyde to give 1.3 g of the title compound.

MS (DCI / NH 3) m / e 23 1 (M + H ₂ O) +

Example 3 B

6,7-dimethoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared and purified as described in Example 1B to give 100 mg of the title compound.

1 H NMR (DMSO-d ₆ , 300 MHz) δ 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 (DCI / NH ₃ ) m / e 231 (M + H) &lt; ^{+ &gt};.

Calcd for C13H14N2O2.TFA: C, 52.33; H, 4.39; N, 8.14. Found ´C 52.15; H, 4.20; N, 8.10.

Example 4

2 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] acetamide mono (trifluoroacetate)

Example 4A

7-methoxy-8-hydroxynaphthalene-2-carbonitrile

A solution of Example ΙΑ (1 g) in methylene chloride (100 mL) at 0 ° C was treated with AlCl ₃ , stirred for 4 hours at 0 ° C and 18 hours at room temperature, poured into water (200 mL) containing 6 N HCl (20 mL), stirred again for 1 hour and diluted with methylene chloride (100 mL). The layers were separated and the organic layer was washed with brine and dried (MgSO ₄ ) to give 810 mg of the title compound as an off-white solid.

MS (DCI / NH 3) m / e 217 (M + H ₂ O) ⁴ .

Example 4B

1,1-Dimethyl-2 - [(7-cyano-2-methoxy-1-naphthalenyl) oxy] acetate

The slurry containing Example 4A (100 mg), K ₂ CO ₃ (70 mg), tert-butyl bromoacetate (120 mg) and tetrabutylammonium iodide (25 mg) in DMF (3 mL) was stirred at room temperature for 18 hours, 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 give 200 mg of the title compound as a clear oil.

MS (DCI / _NH3) m / e 331 (M + H ₂ 0 ^+).

Example 4C

2 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] acetamide mono (trifluoroacetate)

Example 4B (100 mg) in methanol (5 mL) was treated at 0 ° C with HCl (g), then stirred at room temperature for 18 hours and concentrated to give an off-white solid. This was treated with 2 N NH ₃ in methanol (10 mL), heated at 50 ° C for 3.5 hours, then cooled and concentrated to give a yellow solid which was purified by the procedure of Example 1B to give 10 mg. of the title compound.

H NMR (300 MHz, _DMSO-f)) δ 3.93 (s, 3H), 4.79 (s, 2H), 7.55 (d, 2H), 7.65 (dd, 1H), 7.72 (d, 1H), 7.85 (d, 1H), 8.09 (d, 1H), 8.7 (d, 1H), 9.03 (bs, 2H), 9.45 (bs) (2H);

MS (DCI / _NH3) m / e 274 (M + H) \

Analysis calculated for C ₁₄ H ₁₅ N ₃ O ₃ .TFA. C, 49.62; H, 4.16; N, 10.85. Found: C, 49.33; H, 4.03; N, 10.50

Example 5

7-benzyloxy-8-iodo-2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 5A

7-benzyloxy-8-iodo-2-naftalénkarbonitriI

The title compound was prepared as described in Example 43A except that benzyl bromide was used instead of propyl iodide.

MS (DCI / _NH3) m / e 403 (M + NH ₄₎ ^+.

Example 5B

7-benzyloxy-8-iodo-2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 5A as described in Example IB.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 9.30 (br, 4H), 8.44 (s, 1H), 8.12 (d, 1H), 7.71 (d, 2H), 7 67 (dd, 1H); 7.57 (d, 2H); 7.45-7.34 (m, 3H); 5.45 (s, 2H).

MS (DCI / _NH3) m / e 403 (M + H)

Anal. Calcd _S H | ₅ OI.TFA _N2: C, 46.53; H, 3.12; N, 5.43. Found: C, 46.55; H, 3.10; N, 5.19.

Example 6

Methyl - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] acetate mono (trifluoroacetate)

Example 6A

Methyl - [(7-cyano-2-methoxy-1-naphthalenyl) oxy] acetate

A solution of Example 4A (600 mg) Cs ₂ CO ₃ (500 mg), tert-butyl bromoacetate (120 mg) and tetrabutylammonium iodide (25 mg) in DMF (15 mL) was stirred at room temperature for 18 h, diluted with water (20 mL). 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 give 800 mg of the title compound as a clear oil.

MS (DCI / _NH3) m / e 331 (M + H ₂ 0 ^+).

Example 6B

Methyl - [(7-aminoiminomethyl-2-methoxy-1-naphthalenes) oxyacetate mono-trifluoroacetate)

Example 6A (100 mg) in methanol (30 mL) was treated at 0 ° C with HCl (g), stirred at room temperature for 18 hours, and concentrated to give an off-white solid. This was treated with ammonium acetate (100 mg) in methanol (10 mL), heated at 40 ° C for 15 h, cooled and concentrated to give a yellow solid which was purified by the procedure of Example 1B to give 10 mg of the title compound. compound.

Ή NMR (300 MHz, DMSO- d _d) δ 3.65 (s, 3H), 3.93 (s, 3H), 4.79 (s, 2H), 7.65 (dd, 1H), 7, 72 (d, 1 H), 7.85 (d, 1 H), 8.09 (d, 1 H), 8.7 (d, 1 H), 9.03 (bs, 2 H), 9.45 (bs, 2 H) );

MS (DCI / NH ₃ ) m / e 289 (M + H) +.

Analysis calculated for C | ₅ hi _fi N ₂ O ₄ .TFA: C 50.75; H, 4.26; N, 6.96. Found. C 50.42, H 4.03; N, 6.77.

Example 7 [(7-aminoiminomethyl-2-methoxy-1-11a phthalenyl) oxy] acetic acid mono (trifluoroacetate)

A solution of Example 6B (100 mg) and LiOH.H ₂ O (150 mg) in THF / H ₂ O 1: 1 (10 mL) was stirred for 45 min at 5 ° C and concentrated to give an off-white solid. This was dissolved in 1 N HCl (20 mL), stirred at room temperature for 48 hours, and filtered. The white solid obtained was purified as described in Example 1B to give 20 mg of the title compound.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 3.93 (s, 3H), 4.79 (s, 2H), 7.65 (dd, 1H), 7.72 (d, 1H), 7 85 (d, 1H); 8.09 (d, 1H); 8.7 (d, 1H); 9.23 (bs, 2H); 9.45 (bs, 2H);

MS (DC1 / _NH3) m / e 275 (M + H)

Calcd for C14H14N2O4.TFA: C, 49.49; H, 3.89; N, 7.21. found; C, 47.53; H, 3.71; N, 6.83.

Example-8

N- [4- (aminomethyl) phenyl] -6-aminoiľninometyl-naphthalen-2-carboxamide bis (trifluoroacetate)

Example 8A

2,6-Naphthalenedicarboxylic acid monomethyl ester

A suspension of dimethyl-2,6-naphthalenedicarboxylic acid (39.6 g, 162 mmol) in dioxane (1.20 L) was heated at 70-80 ° C until dissolution, slowly treated with 1 equivalent of KOH in methanol, stirred for additional 30 min at 70 ° C, cooled to room temperature, then filtered and washed with dioxane and diethyl ether, dissolved in water, treated with 1 N HCl so that the aqueous layer reacted acidic to pH paper, filtered again , washed with water and dried in vacuo to give 33 g of a white powder.

MS (DCI / NH 3) m / e 23 1 (M + H) ⁴ .

Example 8B

6- (Chlorocarbonyl) -2-naphthalenecarboxylic acid methyl ester

A suspension of Example 8A (15 g, 65 mmol) in toluene (190 mL) was treated with thionyl chloride (20 mL, 276 mmol) followed by DMAP (15 mg), heated at reflux for 1 h and then further 35 minutes at 85 ° C. The condenser is then replaced with a distillation head and 60 ml of solvent is removed. The resulting thick precipitate, which formed with cooling, was triturated with hexane and filtered to give 14.8 g of a white solid.

MS (DCI / NH 3) m / e 249 (M + H) ⁺ .

Example 8C

6- (Aminocarbonyl) -2-naphthalenecarboxylic acid methyl ester

A solution of Example 8B (15 g, 60.3 mmol) in methylene chloride (400 mL) was treated at room temperature with dry ammonia gas to precipitate the product. The resulting mixture was stirred for an additional 15 minutes and then filtered. The solid product was washed with water and dried in vacuo to give 13.3 g of a white powder

MS (DCI / NH 3) m / e 230 (M + H) +

Example 8D

6-Cyano-2-naphthalenecarboxylic acid methyl ester

A suspension of Example 8C (31 g, 135 mmol) in trimethyl phosphate (450 mL) was treated with triphosgene (27 g, 136 mmol), stirred for 20 minutes at room temperature and then heated in an oil bath at 80 ° C for 1 hour. C. Upon cooling to room temperature, the product precipitated out of solution. The resulting thick slurry was treated with water and filtered, the white solid was washed extensively with water and dried in vacuo to give 26.3 g of the title compound.

MS (DCI / NH,) m / e 212 (M + H) ¹

Example 8E

6-Cyano-2-naphthalenecarboxylic acid

Example 8D (1.9 g, 9 mmol) in THF / H ₂ O (40 mL) 1: 1 was treated with LiOH.H ₂ O (1.9 g, 45 mmol), stirred for 90 min at at room temperature and then concentrated to a thick slurry. This slurry was dissolved in water (20 mL), acidified to pH 2 with solid citric acid, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na ₂ SO 4) and concentrated to give 1.6 g of the title compound as a white solid.

MS (DCI / NH ₃ ) m / e 197 (M + H) &lt; ^{+ &gt};.

Example 8F t-butoxycarbonylamino-4-aminomethylaniline

4-Aminomethylaniline (2 g) in THF / H 2 O 2: 1 (30 mL) was treated with Boe anhydride (3.93 g), stirred at room temperature for 18 hours, diluted with water, and concentrated to a white solid. slurry This slurry was dissolved in ethyl acetate, washed with water and brine, dried (Na ₂ SO 4) and concentrated to give 2.4 g of a yellow solid.

MS (DC1 / _NH3) m / e 223 (M + H) ^+.

Example 8G

N- [4- (aminomethyl) phenyl] -6-cyano-2-naphthalenecarboxamide

A solution of Example 8E (200 mg) and Hunnigs base (180 μΐ) in DMF (5 mL) at 5 ° C was treated with HATU (193 mg), stirred at 5 ° C for 1 hour, treated with Example Compound. 8F (120 mg) and with diisopropylethylamine (100 μΐ) in DMF (5 mL), then stirred at room temperature for 8 hours, diluted with ethyl acetate (100 mL) and then washed sequentially with 1 N H 3 PO 4, saturated sodium bicarbonate and brine , dried (Na ₂ SO ₄ ) and concentrated to give a yellow oil, which was purified on silica gel with 1% methanol / methylene chloride to give 200 mg of the title compound.

MS (DCI / NH 3) m / e 419 (M + H ₂ 0 ^+).

Example 8H

N- [4- (aminomethyl) phenyl] -6-aminoiminomethyl-2-naphthalene-carboxamide bis (trifluoroacetate)

The title compound was prepared from Example 8G (200 mg) by the method and purification according to Example 5B to yield 37 mg of the title compound.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 4.08 (m, 2H), 7.45 (d, 2H), 7.88 (d, 2H), 7.95 (dd, 1H), 8 18 (dd, 1H), 8.20 (bs, 3H), 8.23 (d, 1H), 8.35 (d, 1H), 8.58 (s, 1H), 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) +

Calcd for C18H17N4O.TFA: C, 50.56; H, 3.69; N, 10.25. Found: C, 50.18; H, 3.59; N, 10.11

Example 9

N- [4- (amino) phenyl] -6-amino-imino-2-naphthalene-carboxamide bis (trifluoroacetate)

Example 9A

N- [4- (amino) phenyl] -6-cyano-2-a naphthalene

The title compound was prepared as described in Example 8G except that 1,4-diaminobenzene was used in place of Example 8F.

MS (DCI / NH 3) m / e 288 (M + H) +

Example 9B

N- [4- (amino) phenyl] -6-amino-imino-2-naphthalene-carboxamide bis (trifluoroacetate)

The title compound was prepared from Example 9A (100 mg) by the method and purification according to Example 6B.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 7.15 (d, 2H), 7.75 (d, 2H), 7.95 (dd, 1H), 8.18 (dd, 1H), 8 23 (bs, 3H), 8.35 (d, 1H), 8.58 (s, 1H), 8.70 (s, 1H), 9.25 (s, 2H), 9.48 (s, 1H) 2H), 10.58 (s, 1 H);

MS (DCI / NH 3) m / e 305 (M + H) ’

Analysis: Calculated for C _S Hi O.2TFA _{least 4} N · C 49.63; H, 3.41; N, 10.52. Found: C, 46.57; H, 3.62; N, 10.66

Example ΙΟ

1 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] -3-hydroxypropanone (trifluoroacetate)

Example 10A ¹ - [(7-Cyano-2-methoxy-1-naphthalenyl) oxy] -3 - [(2-tetrahydro-2H-pyranyl) oxy] propane mono (trifluoroacetate)

A suspension of Example 4A (200 mg) and CS 2 CO 3 (0.32 g) in DMF (15 mL) was treated with 2- (3-bromopropyl) -tetrahydro-2H-pyran (0.25 g) by stirring at temperature The mixture was 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 give 320 mg of an oil.

MS (DCI / NH 3) m / e 323 (M + H) ⁺ .

Example 10B

1 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] -3-hydroxypropanone (trifluoroacetate)

Example 10A (0.3 g) was worked up and purified as in Example IB to give 110 mg of off-white solid.

H NMR (300 MHz, DMSO-d _f,) δ 1.97 (q, 2H), 3.67 (t, 2H), 4.20 (t, 2H), 7.61-7.70 (m 3H) 7.84 (d, 1H), 8.08 (d, 1H), 8.50 (d, 1H);

MS (DCI / NH 3) m / e 275 (M + H) +.

Calc'd for C15Hi ', Nto .TFA.0,75H ₂ O _2: C, 50.81; H, 5.14; N, 6.97. Found - C, 51.23; H, 5.28; N, 6.97.

Example I

8-amino-2-naphthalenecarbonitrile hydrobromide

Example 1 1A

2-trifluórmetánsuIfonyloxy-8-aminonaphthalene

A solution of 8-amino-2-naphthol (10 g) and triethylamine (12 mL) in dioxane (200 mL) was treated with N-phenyltrifluoromethanesulfonimide (25 g) in dioxane (80 mL), stirred for 4 hours and then concentrated . The dark brown product obtained was triturated with hexane and filtered to give 12 g of the title compound as a brown solid.

MS (DCI / NH ₃ ) m / e 292 (M + H) &lt; ^{+ &gt};.

Example 1 1B

2-trifluórmetánsulfonyIoxy-8-karbonylbenzyloxyaminonaftaIén

A solution of Example 11A (2 g) in 10% aqueous Na ₂ CO ₃ (20 mL) and dioxane (250 mL) was treated with benzyl chloroformate (2 mL) in dioxane, stirred at room temperature for 5 hours and then extracted with ethyl acetate. The organic layer was dried _(MgSO4) and concentrated and the crude product chromatographed on silica gel using hexane / ethyl acetate 7: 1 to give 2.5 g (86%) of the title compound.

MS (DCI / NH ₃ ) m / e 443 (M + NH ₄ ) ⁺ .

Example 1 IC

8- (N-carbonylbenzyloxy) -2-naphthalenecarbonitrile

The adduct consisting of tris (dibenzylideneacetone) -dipalladium (O) chloroform (120 mg), 1,1'-bis (diphenylphosphino) -ferocene (260 mg), potassium cyanide (766 mg), the compound of Example I IB (2, 5 g) and N-methyl-2-pyrrolidinone (5 ml), the mixture is stirred until a yellow reaction product is formed and then heated at 80 ° C for 40 minutes. The dark brown reaction mixture was cooled to room temperature and chromatographed on silica gel with hexane / ethyl acetate 9: 1 to give 1.5 g of the title compound as a colorless solid.

MS (DC1 / _NH3) m / e 292 (M + NH ₄₎ ^+.

Example 1 I D

8-amino-2-naphthalenecarbonitrile hydrobromide

Example 11C (1.4 g) was treated with a solution of 30% HBr in acetic acid (5 mL) and the mixture was stirred at room temperature for 6 hours. The reaction mixture was then treated with diethyl ether and filtered to give 1.1 g of the title compound as a yellow solid.

MS (DCI / _NH3) m / e 186 (M + NH ₄₎ ^+.

Example 12

General Acylation Method

A suspension of Example 10D (1 equivalent), triethylamine (1 equivalent) and DMAP (0.25 equivalents) in methylene chloride (0.3 M) was treated dropwise with the appropriate acid chloride (1.1 equivalents) in methylene chloride (0.1 M). The mixture was stirred at room temperature for 30 minutes and then treated with water (50 mL). The organic layer was dried (MgSO ₄ ), concentrated and used in subsequent reactions without further purification.

Example 13

General method for amidine synthesis

A solution containing the crude acylation products of Example 12 (about 100 mg) in pyridine: triethylamine 10. 1 (10 mL) at room temperature was treated with hydrogen sulfide for 5 minutes, then stirred at room temperature for 18 hours, diluted with water (50 mL) and extracted with ethyl acetate. The ethyl acetate was dried (MgSO 4) and concentrated. The residue was dissolved in acetone (30 mL), treated with methyl iodide (2 mL), heated at reflux for 1 hour, then evaporated to dryness, redissolved in methanol (25 mL), treated with ammonium acetate. (100 mg), then stirred at room temperature for 18 hours, concentrated and purified as described in Example 1B to give Examples 14-20 as white solids.

Example 14

8- (carbonylbenzyloxy) amino-2-naphthalenecarboximidamide mono (trifluoroacetate) 1 H NMR (DMSO-d 6, 300 MHz) δ 5.14 (s, 2H), 7.36-7.50 (m, 5H), 7.677 90 (m, 4H), 8.24 (d, 1H), 8.67 (s, 1H), 9.08 (s, 2H), 9.37 (s, 2H), 9.78 (s, 1H);

MS (DCI / _NH3) m / e 320 (M + H) \

Analysis: Calculated for C 9 H _{1 2 3} N3O .5TFA.0,5H ₂ O: C, 52.91; H, 3.94; N, 8.41. Found: C, 52.86; H, 4.07; N 8.18.

Example 15

N- [7- (aminoiminomethyl) -1-naphthalenyl) acetamide mono (trifluoroacetate) 1 H NMR (DMSO-d 6, 300 MHz) δ 4.19 (s, 3H), 7.66-7.88 (m, 3H), 8.128.16 (m, 2H), 8.69 (s, 1H), 8.98 (d, 1H), 9.16 (s, 2H), 9.47 (s, 2H), 10, 14 (s, 1 H),

MS (DC1 / _NH3) m / e 228 (M + H).

Anal. Calcd for C 11 H 11 N 3 O 1.2 TFA 0.25H 2 O: C 50.18; H, 4.02; N, 11.40. Found: C, 50.62; H, 4.47; N, 10.90.

Example 16

Methyl [7- (aminoiminomethyl) -1-naphthalenyl) carbamate mono (trifluoroacetate) 1 H NMR (DMSO-d 6, 300 MHz) δ 3.88 (s, 3H), 7.67-7.85 (m, 4H), 8.14 (d, 1H), 8.6 (s, 1H), 8.28 (s, 3H), 9.67 (s, 1H);

MS (DCI / _NH3) m / e 244 (M + H)

Analysis: Calculated for C ₃ H | % N ₃ O _2. TFA: C 50.43; H, 3.95; N, 11.76. Found: C, 50.12; H, 4.05; N, 11.61

Example 17

Methyl 3 - [[7- (aminoiminomethyl) -1-naphthalenyl] amino] -3-oxopropionate mono (trifluoroacetate) 1 H NMR (DMSO-d 6, 300 MHz) δ 3.69 (s, 2H ), 3.71 (s, 3H), 7.69 (m, 4H), 8.18 (d, 1H), 8.58 (s, 1H), 9.11 (s, 2H), 9.48 (s, 2H);

MS (DCI / _NH3) m / e 286 (M + H)

Analysis calculated for ₅ íîñòü ₃ O ₃ TFA.H ₂ O: C 48.18, H 4.26; N, 9.80. Found: C, 48.30; H, 4.09; N, 9.58.

Example 18

N- [7- (aminoiminomethyl) -1-naphthalenyl] -2- (phenylmethoxy) acetamide mono (trifluoroacetate) 1 H NMR (DMSO-d 6, 300 MHz) δ 4.29 (s, 2H), 4.73 ( s, 2H), 7.73-7.48 (m, 5H), 7.69 (m, 4H), 8.17 (d, 1H), 8.47 (s, 1H), 9.21 (br) 4H), 10.0 (s, 1H);

MS (DCI / _NH3) m / e 334 (M + H)

Calcd for C20H18N3O2.ITFA.H2O: C 56.67; H, 4.76; N, 9.03. Found: C, 56.84; H, 4.49; N, 8.93.

Example 19

N- [7- (aminoiminomethyl) -1-naphthalenyl] -1,3-benzodioxole-5-carboxamide mono (trifluoroacetate) 1 H NMR (DMSO-d 6, 300 MHz) δ 6.19 (1H, 2H), 7.12 (d, 1H), 7.657.79 (m, 5H), 7.97 (d, 1H), 8.20 (s, 1H), 8.53 (s, 1H), 9.2 (br s, 3H) 11.35 (s, 2H);

MS (DCI / NH ₃ ) m / e 334 (M + H +)

Anal. Calcd for C ₁₈ H ₁₄ N ₃ O ₂ .TFA · C 55.82; H, 3.68; N, 9.30. Found: C, 55.69; H, 33.61; N, 9.23.

Example 20

N- [7- (aminoiminomethyl) -1-naphthalenyl] benzenemethanesulfonamide mono (trifluoroacetate) 1 H NMR (DMSO-d 6, 300 MHz) δ 4.60 (s, 2H), 7.32-7.33 (m, 5H), 7.677.70 (m, 2H), 7.82 (d, 1H), 7.92 (d, 1H), 8.17 (s, 1H), 8.70 (s, 1H), 9.14 (s, 2H); 9.35 (s, 2H); 9.19 (s, 1H);

MS (DCI / NH 3) m / e 340 (M + H) +

Anal. Calcd. For C 18 H 17 N 3 O 2 S.TFA.H 2 O. C, 50.95; H, 4.28; N, 8.91. Found: C, 50.76; H, 3.70; N, 8.65.

Example 21

- [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy-3-bromopropane mono (hydrochloride)

Example 21A 1 - [(7-Cyano-2-methoxy-1-naphthalenyl) oxy] -3-bromopropane mono (hydrochloride)

The title compound was prepared from Example 4A and 1,3-dibromopropane by the method of Example 10A.

MS (DCI / NH 3) m / e 337 (M + NH ₄ ) ⁺ .

Example 21B

- [(7-Aminomethyl-2-methoxy-1-naphthalenyl) oxy] -3-bromo-propane-mono (hydrochloride)

The title compound was prepared from Example 21A by the method of Example IB After hydrolysis with HCl, the solution was cooled to 0 ° C, and the white solid product thus precipitated was filtered off and dried to give the title compound. 1 H NMR (300 MHz, DMSO-) d _fi ) δ 2.35 (m, 2H), 3.86 (t, 2H), 4.00 (s, 3H), 4.25 (t, 2H), 7.65 (dd, 1H), 7 70 (d, 1H), 7.90 (d, 1H), 8.10 (d, 1H), 8.55 (s, 1H), 9.15 (br s, 2H), 9.42 (br) s, 211);

MS (DCI / _NH3) m / e 337 (M + H) \

Calcd for C 15 H 17 BrN ₂ O ₂ .HCl 0.75H ₂ O: C 46.53; H, 5.05; N, 7.23. Found: C, 46.55; H 5.1 1; N, 7.16.

Example 22

3 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] propenone mono (trifluoroacetate)

Example 22A

3 - [(7-Cyano-2-methoxy-1-naphthalenyl) oxy] propene

The title compound is obtained as a second product of the procedure of Example 21A.

MS (DCI / _NH3) m / e 257 (M + NH ₄₎ ^+.

Example 22B

3 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] propenone mono (trifluoroacetate)

The title compound was prepared from Example 22A by the purification procedure of Example 1B.

H NMR (300 MHz, _DMSO- d) δ 4.00 (s, 3H), 4.70 (d, 2H), 5.22 (d, 1H), 5.42 (d, IH), 6 18 (m, 1H), 7.62 (dd, 1H), 7.85 (d, 1H), 8.10 (d, 1H), 8.50 (s, 1H), 9.12 (br s) (2H), 9.45 (brs, 2H),

MS (DCI / NH ;,) m / e 257 (M + H) ^r.

Anal. Calcd for C 18 H 16 N ₂ O ₂ .TFA 0.25H ₂ O: C 54.47; H, 4.71; N, 7.47. Found: C, 54.61; H, 4.38; N, 7.40.

Example 23

1 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] -3-phenylpropanone (hydrochloride)

Example 23A

- [(7-cyano-2-methoxy-1-naphthalenyl) oxy] -3-phenyl propane

The title compound was prepared from Example 4A and 1-bromo-3-phenylpropane by the method of Example 10A.

MS (DCI / NH ₃ ) m / e 335 (M + NH 4) ⁺ .

Example 23B 1 - [(7-Aminoiminomethyl, -2-methoxy-1-naphthalenyl) oxy] -3-phenylpropanone (hydrochloride)

The title compound was prepared from Example 23A by the method and purification procedure of Example 21B.

H NMR (300 MHz, _CD? OD) δ 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, 1H), 8.02 (d, 1H), 8.62 (s, 1H) );

MS (DCI / NH 3) m / e 335 (M + H) +.

HRMS (FAB) m / e calcd for C 21 H 23 N 2 O 2 .HCl. 335.1760 (M + H) ⁺ Found m / e 335 1762

Example 24

1 - [(7-aminoaminomethyl-2-methoxy-1-naphthalenyl) oxy] -3- [1- (3,4-dimethoxy) phenyl] propanone mono (hydrochloride)

Example 24A

bromo-3- (3,4-dimethoxyphenyl) -propane

The title compound was prepared from 3- (3,4-dimethoxyphenyl) -1-propanol by the method described in Journal of the American Chemical Society, 95, 8749 (1973), which is incorporated herein by reference.

MS (DCI / NH 3) m / e 276 (M + NH ₄ ) ⁺ .

Example 24B

- [(7-Cyano-2-methoxy-1-naphthalenyl) oxy] -3- [1- (3,4-dimethoxy) phenyl] -propane

The title compound was prepared from the compounds of Examples 4a and 24A by the method of Example 10A.

MS (DCI / NH 3) m / e 395 (M + NH ₄ ) ⁺ .

Example 24C

- [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] -3- [1- (3,4-dimethoxy) phenyl] propanone mono (hydrochloride)

The title compound was prepared from Example 24B from Example 21 B H NMR (300 MHz, _DMSO-ft) δ 2.11 (m, 2H), 2.80 (t, 2H), 3.74 (s 6H), 3.98 (s, 3H), 4.15 (t, 2H), 6.75-6.92 (m, 3H), 7.65 (dd, 1H), 7.70 (d, 1H), 7.86 (d, 1H), 8.10 (d, 1H), 8.55 (s, 2H), 9.15 (br s, 2H), 9.53 (br s, 2H);

MS (DCI / NH 3) m / e 395 (M + H) ’

Anal. Calcd for Cr, H _{2 F} , N ₂ O ₄ .HCl 0.5H ₂ O: C 62.79; H, 6.42; N, 6.37. Found: C, 63.08; H, 6.38; N, 6.17.

Example 25

7-methoxy-8- (2-furanyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 25A

7-methoxy-8-trifluórmetánsulfbnyloxy-2-naphthalenecarbonitrile

A solution of Example 4A (310 mg) in 0 ° C methylene chloride (5 mL) was treated with 1,1,1-trifluoro-N-phenyl-N - [(trifluoromethyl) sulfonyl] methanesulfonamide (614 mg) and triethylamine (240). mL), the mixture was stirred at room temperature for 18 h, diluted with methylene chloride (100 mL), washed with water and 20% aqueous NaOH, dried (MgSO ₄ ) and concentrated to give the title compound as a white solid.

MS (DCI) m / e 349 (M + H ₂ 0) \

Example 25B

Furan-2-boric acid

A solution of furan (5.3 mL, 73 mmol) in diethyl ether (67 mL) was treated at -20 ° C with butyllithium (2.5 M in hexanes, 26 mL, 65 mmol), stirred for 2 hours at

-20 ° C and then cannulated to a solution of triisopropylborate (33 mL, 147 mmol) in -20 ° C diethyl ether (17 mL) This warm mixture was warmed to room temperature, treated with 3 N HCl (200 mL) and extracted with diethyl ether. The extracts were washed with 1 N KOH, the KOH layer was cooled to 0 ° C and acidified with 6 N Hcl. The acidic solution was extracted with diethyl ether, the acidic ether extracts were washed with brine, dried _(MgSO4) and concentrated to give the title compound.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 6.45 (dd, 1H), 7.05 (t, 1H), 7.80 (dd, 1H), 8.19 (s, 2H)

Example 25C

7-methoxy-8- (2-furanyl) -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 10 minutes, treated with the compound of Example 25B (1.32 mmol) and Cs ₂ CO ₃ (3.3 mmol), heated at 85 ° C for 6 hours, cooled to room temperature and chromatographed on silica gel using 10 % ethyl acetate / hexane gave the title compound.

MS (DCI / NH ₃ ) m / e 250 (M + H) &lt; ^{+ &gt};.

Example 25D

S- (2-Fluoro) -7-methoxy-2-naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 25C by the method and purification according to Example IB.

H NMR (300 MHz, _DMSO- d) δ 3.97 (s, 3H), 6.73 (m, IH), 6.80 (m, IH), 7.64 (dd, 1 H), 7 78 (d, 1H), 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 (DCI / NH, m / e 267 / M + H) '

Analysis calculated for C ₁₁ H ₁₄ N ₂ O ₂ TFA. C 56.85; H, 3.98; N, 7.37. Found: C, 56.68; H, 3.67; N, 7.35.

Example 26

Methyl-6- (amino) -4 - [(methoxycarbonyl) amino] -2-naftalénkarboxylátmono (trifluoroacetate)

Example 26A

2-Cyano-1-nitro-6-carboxy-naphthalene methyl ester

A solution of 2-cyano-6-methylnaphthoate (5.2 g) in concentrated sulfuric acid (75 mL) at 0 ° C was treated with potassium nitrate (1.03 equivalents) added in one portion, stirred for 10 minutes, poured on ice (500 g) and extracted with ethyl acetate. The ethyl acetate layer was washed with water, 1N NaOH and brine, dried (MgSO ₄ ), treated with silica gel and filtered with suction. The product is precipitated by concentrating ethyl acetate to about 200 ml. This mixture was heated to dissolve the solid, treated with MeOH (20 mL) and ether (20 mL) and stirred overnight. The resulting solid was filtered and washed with methanol to give 2.31 g of the title compound as a cream colored solid. The mother liquor was evaporated, treated with methylene chloride (250 mL), then solid silica gel, filtered and evaporated. Crystallization from ethyl acetate / methanol gave an additional 1.6 g of the product in a total yield of 3.91 g (62%).

MS (DCI / NH 4 +) m / e 257 (M + H) ⁺ .

Example 26B

2-Cyano-1-amino-6-carboxy-naphthalene methyl ester

A solution of Example 26A (1 g, 3.9 mmol) and 10% Pd on carbon (112 mg) in ethyl acetate (80 mL) was stirred under a hydrogen atmosphere at 1 atm for 9 h, then purged with nitrogen for 1 h. then the mixture was filtered and evaporated to give 810 mg (92%) of the title compound as a yellow solid.

MS (DC1 / _NH3) m / e 227 / M + NH ₄₎ ^+.

Example 26C

6-Cyano [(methoxycarbonyl) amino] -2-naphthalenecarboxylic acid methyl ester

A solution of Example 26B (2.50 mmol) in methylene chloride (40 mL) was treated sequentially with diisopropylethylamine (2 mL), methyl chloroformate (195 µL, 2.52 mmol), stirred for 2 hours, treated with methanol (10 mL). ml), stirred for an additional 10 minutes, then diluted with methylene chloride (60 ml), washed with water and brine, dried (MgSO ₄ ) and evaporated. Purification of the residue on silica gel using 10% ethyl acetate / hexane gave 280 mg (59%) of a pale yellow solid.

MS (DC1 / _NH3) m / e 285 / M + H) ^4th

Example 26D

Methyl-6- (amino) -4 - [(methoxycarbonyl) amino] -2-naftalénkarboxylátmono (trifluoroacetate)

The title compound was prepared from Example 26C (125 mg, 0.44 mmol) according to Example 40D to give 35 mg of a white solid. 1 H NMR (DMSO-d 6) δ 3.78 (s, 3H), 3 95 (s, 3H), 7.89 (dd, 1H), 8.378.40 (m, 3H), 8.53 (s, 1H), 8.740 (s, 1H), 9.18 (br s, 2H) ), 9.45 (br s, 2H), 9.90 (s, 1H), 8.42 (s, 1H), 8.63 (d, 1H), 9.18 (br s, 4H), 10 58 (s, 1H);

MS (DCI / NH 3) m / e 302 (M + H)

Analysis ^- Calculated for C15H15N1O4 TFA. 1.5H2O: C, 46.16; H, 4.33; N, 9.50. Found: C, 45.96; H, 4.06; N, 9.12.

Example 27 (E) - ^ 7-methoxy-8- [2- (phenyl) ethenyl] ^e, 2-naftalénimidamid mono (trifluoroacetate)

Example 27A (E) - {7-Methoxy-8- [2- (phenyl) ethenyl] / 2-naphthalenecarbonitrile

Example 25A and boric acid styrene ester prepared according to the method of Journal of the American Chemical Society, 97, 5249 (1975), the disclosure of which is incorporated herein by reference, are treated as in Example 26B to give the title compound.

MS (DCI / NH ₃ ) m / e 303 (M + NH ₄ ) ⁺ .

Example 27B (E) -? 7-Methoxy-8- [2- (phenyl) ethenyl] -2-naphthalenimidamide mono (trifluoroacetate)

The title compound was prepared from Example 27A by the method of Example 1B.

Ή NMR (300 MHz, _DMSO- d) δ 3.98 (s, 3H), 7.28 (t, 2H), 7.39 (t, 2H), 7.64 (m, 5H), 8, 00 (d, 1H), 8.10 (d, 1H), 8.62 (s, 1H), 9.22 (br s, 2H), 9.42 (br s, 2H),

MS (DCI / NH 3) m / e 303 (M + H) +

Anal. Calcd for C 21 H 15 S 1 N 2 O TFA: C 63.46; H, 4.60; N, 6.73. Found: C, 63.10; H, 4.73; N, 6.43

Example 28

6- (4-fenylbutinyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

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. Dilute with ethyl acetate (50 mL), triturate with 10% aqueous sodium hydroxide, and filter through Celite®. The filtrate was 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 (DC1 / _NH3) m / e 170 / M + H)

Example 28B

6- (trifluoromethanesulphonyloxy) -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 trilluoromethylsuironic anhydride (28 mL). g, 99.4 mmol) then warmed to 25 ° C for 48 hours, concentrated, redissolved in ethanol (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-fenylbutinyl) -2-naphthalenecarbonitrile

The title compound was prepared from Example 28B and 4-phenyl-1-butyne by the method of Example 57B.

MS (DCI / NH 3) m / e 299 (M + NH ₄ ) ⁺ .

Example 28D

6- (4-fenylbutinyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate).

The title compound was prepared from Example 28C by the method of Example 1B.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 2.80 (t, 2H), 2.95 (t, 2H), 7.22 (m, 1H), 7.36 (m, 4H), 7 58 (d, 1H), 7.82 (d, 1H), 8.05 (d, 1H), 8.10 (d, 2H), 8.45 (s, 1H), 9.10 (br s) (2H), 9.42 (brs, 2H);

MS (DCI / NH 3) m / e 299 (M + H) ⁺ .

Anal. Calcd for C ₂₁ H ₁₈ N ₂ .TFA.0.75H ₂ O: C 64.86; H, 4.85; N, 6.58. Found: C, 64.78; H, 4.64; N, 6.03

Example 29

7- (2-hydroxyethoxy) -8-iodo-2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 29A

3 - [[(1-Dimethylethyl) dimethylsilyl] oxy] -1-propanol-4-nitrobenzenesulfonate

A solution of 3-tert-butyldimethylsiloxy-1-propanol (7.6 g, 40 mmol), prepared according to the method of McDougal et al., JOC, 1986, 51, 3388, incorporated herein by reference, and diisopropylethylamine (10). (4 mL, 60 mmol) in methylene chloride (200 mL) at 0 ° C was treated with p-nitrophenylsulfonyl chloride (9.7 g, 44 mmol), stirred for 3 hours, then poured into saturated NaHCO ₃ and extracted with diethyl ether. . The extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated. Chromatography of the residue on silica gel with 5% ethyl acetate / hexanes gave 6.00 g of the title compound.

MS (DCI / _NH3) m / e 395 / M + NH ₄₎ ^+.

Example 29B

7 - [- 2 [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethoxy] -8-iodo-2-naphthalenecarbonitrile

The title compound was prepared in an analogous manner to that described in Example 43A but substituting Example 29A instead of propyl iodide.

MS (DC1 / _NH3) m / e 468 / M + H) \

Example 29C

7- (2-hydroxyethoxy) -8-iodo-2-naphthalenecarbonitrile

The title compound was prepared in an analogous manner to that described in Example 53F, but using the compound of Example 29B instead of Example 53E.

MS (DCI / NH ₃ ) m / e 357 (M + H) +.

Example 29D

7- (2-hydroxyethoxy) -8-iodo-2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 29B by the method of Example 1B 1 H NMR (300 MHz, DMSO-d 6) δ 1.96 (m, 2H), 3.69 (t, 2H), 4.33 ( t, 2H), 4.58 (br, 1H), 7.63 (d, 1H), 7.66 (dd, 1H), 8.12 (dd, 1H), 8.42 (s, 1H), 9.20 (s, 2H); 9.53 (s, 2H);

MS (DCI / NH 3) m / e 245 (M + H) +

Analysis: Calculated for C ₃ H | ₂ N ₂ O ₂ I.TFA.0.21H ₂ O: C 53.07; H, 4.85; N, 7.74. Found: C, 53.07; H, 4.75; N, 7.65.

Example 30

7- (2-hydroxyethoxy) -2-Naphthalenecarboximidamide mono (trifIuóracetát)

Example 30A

7- (2-hydroxyethoxy) -2-naphthalenecarbonitrile

Example 29B (120 mg, 0.26 mmol), palladium (II) Cl ₂ dppf (46 mg, 0.03 mmol) and diisopropylamine (263 mg, 2.6 mmol) were heated in a sealed tube for 2 hours at 100 ° C. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, dried (Na ₂ SO 4) and concentrated. Purification of the residue on silica gel with 15% ethyl acetate / hexanes gave 85 mg of the title compound

MS (DCI / NH 3) m / e 342 (M + H) ’

Example 30B

7- (2-hydroxyethoxy) -2-naftalénkarboxiľnidamid mono (trifluoroacetate)

The title compound was prepared from Example 29B by the method of Example IB.

H NMR (300 MHz, _DMSO-ft) δ 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, 1H), 8.42 (s, 1H), 9.20 (s, 2H), 9.53 (s, 2H);

MS (DCI / NH ₃ ) m / e 228 (M + H) &lt; ^{+ &gt};.

Calcd for C14H15N2O2.TFA: C, 53.78; H, 4.51; N, 7.84. Found: C, 53.60; H, 4.30; N, 7.81.

Example 3 1

6- (4-Methyl-1-pentinyl) -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 3 1A

6- (4-Methyl-1-pentyl) -2-naphthalene and carbonyl

The title compound was prepared from Example 28B and 4-methyl-1-pentine according to the method of Example 57B.

MS (DCI / _NH3) m / e 251 / M + NH ₄₎ ^+.

Example 3 IB

6- (4-Methyl-1-pentinyl) -2-naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 3 1A by the method of Example 1B.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 1.05 (d, 6H), 1.90 (m, 1H), 2.20 (d, 2H), 7.62 (dd, 1H), 7 82 (dd, 1H), 8.09 (d, 1H), 8.12 (d, 1H), 8.18 (s, 1H), 8.48 (s, 1H), 9.12 (br s) (2H), 9.42 (brs, 2H,

MS (DCI / NH 3) m / e 251 (M + H) ⁺ .

Anal. Calcd ₈ 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-fenylpentinyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 32A

6- (5-Phenylpentinyl) -2-naphthalenecarbonitrile

The title compound was prepared from Example 28B and 4-phenyl-1-pentine by the method of Example 57B.

MS (DCI / NH 3) m / e 313 (M + NH ₄ ) ⁺ .

Example 32B

6- (5-ľenylpentinyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 32A by the method of Example 1B.

H NMR (300 MHz, _DMSO- d) δ 1.90 (m, 2H), 2.80 (t, 2H), 3.39 (t, 2H), 7.19-7.37 (m, 5H), 7.62 (dd, 1H), 7.82 (dd, 1H), 8.08 (d, 1H), 8.15 (d, 1H), 8.18 (s, 1H), 8, 48 (s, 1H), 9.15-9.45 (br d, 4H;

MS (DCI / NH 3) m / e 313 (M + H) ⁺ .

Calcd for C 22 H 20 N 2 .TFA · C 67.60; H, 4.96; N, 6.57. Found: C, 67.32; H, 5.21; N, 6.27.

Example 33

6- (3-phenyl-l-propynyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 33A

6- (3-phenyl-1-propynyl) -2-naphthalenecarbonitrile

The title compound was prepared from Example 28B and 3-phenyl-1-propyne by the method of Example 57B.

MS (DCI / NH 3) m / e 285 (M + NH ₄ ) ⁺ .

Example 33B

6- (3-Phenyl-1-propyl) -2-naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 33A by the method of Example 5B.

1 H NMR (300 MHz, DMSO-d 6) δ 4.00 (s, 2H), 7.28-7.50 (m, 5H), 7.70 (dd, 1H), 7.85 (dd, 1H), 8.09 (d, 1H), 8.15 (d, 1H), 8.21 (s, 1H), 8.49 (s, 1H), 9.21 (br s, 2H), 9 .45 (br s, 2H);

100

MS (DCI / _NH3) m / e 285 / M + H) +.

Analysis ^- calculated for C20H16N2.TFA 0.25H ₂ O: C 65.59, H 4.38; N 6.95 Found ^- C 65.43, H 3.95; N, 6.70

Example 34

6- (phenylethynyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 34A

6- (phenylethynyl) -2-naphthalenecarbonitrile

The title compound was prepared from Example 28B and phenylacetylene by the method of Example 57B.

MS (DCI / NH 3) m / e 271 (M + NH ₄ ) ⁺ .

Example 34B

6- (phenylethynyl) -2-naftaIénkarboximidamid mono (trifluoroacetate)

The title compound was prepared from Example 34A by the method of Example 1B.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 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, 2H);

MS (DCI / NH 3) m / e 271 (M + H) ⁺

Anal ^. Calcd ₄ N ₂ .TFA: C 65.62; H, 3.93; N, 7.29. Found: C, 65.64; H, 4.1; N, 7.21.

101

Example 35

3-Amino-N- [3- [6- (aminoimidomethyl) -2-naphthalenyl-2-propyl] -benzamide mono (trifluoroacetate)

Example 35A

6- (3-amino-1-propenyl) -2-naphthalenecarbonitrile

The title compound was prepared from Example 28B and propargylamine according to the method of Example 41A.

MS (DCI / NH 3) m / e 207 (M + NH ₄ ) ⁺ .

Example 35B

3-amino-N- [3- (6-cyano-2-naphthalenyl) -2-propynyl] benzamide

A solution of Example 35A (100 mg, 0.49 mmol), 3-aminobenzoic acid (73 mg, 0.53 mmol), EDC (141 mg, 0.74 mmol) and DMAP (89 mg, 0.74 mmol) in THF (5.5 ml) was stirred at room temperature for 2.5 hours and then concentrated. The residue was dissolved in methylene chloride, washed with 1N HCl, saturated NaHCO ₃ , brine, dried (MgSO ₄ ), and concentrated and flash chromatography on silica gel with 2% ethanol / methylene chloride to give the title compound.

MS (DCI / NH 3) m / e 326 (M + H) ⁺ .

Example 35C

-amino-N- [3- [6- (aminomethyl) -2-naphthalenyl-2-propyl] -benzamide mono (trifluoroacetate)

102

The title compound was prepared from Example 35B by the method of Example IB.

Ή NMR (300 MHz, _DMSO- d) δ 4.32 (d, 2H), 5.69 (br s, 2H), 6.58 (d, 2H), 7.62 (m, 3H), 7 82 (d, 1H), 8.08 (d, 1H), 8.14 (d, 1H), 8.20 (s, 1H), 8.43 (s, 1H), 8.60 (t, 1H), 9.19 (br s, 2H), 9.42 (br s, 2H);

MS (DCI / NH 3) m / e 343 (M + H) ⁺ .

Analysis: Calculated for C ₂ | Hi O.TFA.0,25H2O _S S _4: C, 59.93; H, 4.26; N, 12.16. Found: C, 59.86; H, 3.97; N, 11.93.

Example 36

4-amino-N- [3- [6- (amino) -2-naphthalenyl-2-propynyl] -benzamidmono (trifluoroacetate)

Example 36A

4-amino-N- [3- (6-cyano-2-naphthalenyl) -2-propynyl] benzamide

Example 35A and 4-aminobenzoic acid were treated as in Example 35B to give the title compound.

MS (DCI / NH ₃ ) m / e 326 (M + H) &lt; ⁺ &gt; ^.

Example 36B

4-amino-N- [3- [6- (aminoiminomethyl) -2-naphthalenyl-2-propynyl] -benzamide mono (trinuoroacetate)

The title compound was prepared from Example 36A by the method of Example 5B.

103 1 H NMR (300 MHz, DMSO-d ₆ ) δ 4.38 (d, 2H), 6.89 (m, 1H), 7.20 (m, 2H), 7.22 (s, 1H), 7.63 (dd, 1 H), 7.82 (dd, 1 H), 8.09 (d, 1 H), 8.12 (d, 1 H), 8.20 (s, 1 H), 8.46 (s) 1 H, 8.95 (t, 1 H), 9.19 (br s, 2 H), 9.42 (br s, 2 H);

MS (DCI / NH 3 · m) 343 (M + H) +

Calcd for C ₂₁ H 11 N ₄ O _{2 •} 2.5 TFA: 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- [6- (aminoiminomethyl) -2-naphthalenyl) carbonyl] cyclohexyl] propionamide bis (trifluoroacetate)

Example 37A

6 - [(1-Aminocyclohexyl) ethynyl] -2-naphthalenecarbonitrile

The title compound was prepared from Example 28B and 1-ethynylcyclohexylamine according to the method of Example 41A.

MS (DCI / NH ₃ ) m / e 275 (M + NH ₄ ) ⁺ .

Example 37B (S) -2-Amino-N- [1 - [(6-cyano-2-naphthalenyl) carbonyl] cyclohexyl] -2-propionamide

Example 37A and N- (tert-butoxycarbonyl) -L-alanine were treated as described in Example 35B to give the title compound.

MS (DCI / _NH3) m / e 446 / M + H)

104

Example 37C (S) -2-amino-N- [1 - [(6-aminoaminomethyl-2-naphthalenyl) carbonyl] cyclohexyl] propionamide bis (trifluoroacetate)

The title compound was prepared from the compound of Example 37B by rearrangement according to the method of Example 5B.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 1.24 (d, 3H), 1.40-1.62 (m, 8H), 2.152.26 (s, 1H), 2.29-2, 38 (s, 1H), 3.51 (d, 1H), 3.78 (d, 1H), 3.82 (s, 1H), 7.90 (dd, 2H), 8.09 (dd, 1H) ), 8.18 (d, 1H), 8.37 (d, 1H), 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) ⁺ .

Calcd for C23H28N4O2.2TFA.2H2O: C 49.39; H, 5.22; N, 8.53. Found: C, 49.15; H, 4.79; N, 8.70.

Example 38

6-methoxy-8-benzyloxy-2-Naphthalenecarboximidamide mono (trifluoroacetate)

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 mmol), prepared as described by J. Chem.Soc., London 2782 (1955), where this work is incorporated herein by reference, treated in methylene chloride (150 mL) at 0 ° C with AlCl 3 added portionwise (14.3 g, 107 mmol), stirred at room temperature for 20 hours, poured under stirring with ice and extracted with ice-cold methylene chloride The extracts were washed with water and brine, dried (MgSO ₄ ) and concentrated to give 13.8 g of the title compound.

105

MS (DCI / NH ⁴ +) m / e 193 (M + H) +

Example 38B

8-Benzyl oxy-6-methoxy-3,4-dihydro-2H-naphthalen-1-one

A mixture of Example 38A (2.5 g, 13 mmol), benzyl bromide (2.1 mL, 17.8 mmol), powdered K ₂ CO ₃ (14.3 g, 100 mmol), and 2-butanone (88 mL). After stirring for 4 hours at reflux, the mixture was treated with additional benzyl bromide (1.0 mL, 8.5 mmol), stirred at reflux for an additional 3 hours, cooled to room temperature, filtered and concentrated. The residue was dissolved in methylene chloride, washed with 1 N HCl, water and brine, dried (MgSO ₄ ) and concentrated. The crude product was purified by silica gel chromatography using 30% ethyl acetate / hexanes to afford the title compound.

MS (DCI / NH 3) m / e 283 (M + H) ⁺ .

Example 38C

3,4-Dihydro-2- (hydroxymethylene) -6-methoxy-8- (phenylmethoxy) -1 (2H) -naphthalenone

To a mixture of ethanol (4.2 mL) and benzene (15 mL) was added portionwise sodium metal (1.29 g, 55.9 mmol). The mixture was stirred at reflux for 1.5 hours, then cooled to 0 ° C and treated dropwise with ethyl formate (5.6 mL, 70 mmol) and then dropwise with a solution of the compound of Example 38B (6.7). g, 23.8 mmol) in benzene (20 mL), stirred for 2 h, then cooled to 0 ° C and treated sequentially with ice / water and 6 N HCl (75 mL) and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO ₄ ) and concentrated to give the title compound.

MS (DCI / NH) m / e 3 1 1 / M + H) ⁴

106

Example 38D

4,5-Dihydro-7-methoxy-9- (phenylmethoxy) naphth [2,1-d] isoxazole- [2,1-d] isoxazole

A suspension of Example 38C (7.5 g, 24.3 mmol), hydroxylamine hydrochloride (4.0 g, 57.6 mmol), and acetic acid (63 mL) was stirred at 110 ° C for 7 min. The mixture was cooled to room temperature, diluted with water and brine, dried (MgSO ₄ ) and concentrated. The crude product was purified by flash chromatography on silica gel using 30% ethyl acetate / hexanes to afford the title compound.

MS (DCI / NH 3) m / e 308 (M + H) ⁺

Example 38E

8-Benzyloxy-6-cyano-6-methoxy-3,4-dihydronaphthalen-1-one

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 mmol) in methanol. benzene (50 ml), the mixture was stirred at room temperature for 4.5 hours and then treated sequentially with water and 1 N HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO ₄ ) and concentrated to give the title compound.

MS (DCI / NH 3) m / e 308 (M + H) +

Example 38F

2-cyano-6-methoxy-8-benzyloxy-3,4-dihydronaphthalene

A suspension of Example 38E (2.6 g, 8.6 mmol) in absolute ethanol (25 mL) was treated portionwise with NaBH ₄ (1.6 g), stirred for 20 minutes at room temperature and 20 minutes at room temperature. at room temperature, treated with water (20 mL) and concentrated. The residue was dissolved

107 in methylene chloride, washed with water and brine, dried (MgSO 4, filtered and concentrated to give 2.6 g of an orange foam. The foam was stirred at reflux for 20 minutes with p-toluenesulfonic acid monohydrate (0.52 g). , 2.7 mmol) in benzene (52 mL), then cooled to room temperature, diluted with ethyl acetate, washed with water and brine and dried (MgSO 4) and concentrated to give the title compound.

MS (DCI / NH 3) m / e 309 (M + NH ₄ ) ⁺

Example 38G

2-cyano-6-methoxy-8-benzyloxynaphthalene

A solution of Example 38F (0.4 g, 1.4 mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.79 g, 3.5 mmol) in benzene (40 mL) was added. After stirring for 4 hours at reflux temperature, it was treated with additional 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.4 g, 1.8 mmol) and the reaction mixture was stirred an additional 5 hours at reflux temperature. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated NaHCO 3, brine and dried (MgSO ₄ ) and concentrated to give the title compound.

MS (DCI / NH 3) m / e 290 (M + H) ⁺ .

Example 38H

8-benzyloxy-6-methoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared! from the compound of Example 38G according to the method of Example IB.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 8.46 (s, 1H), 8.95 (t, 1H), 9.19 (br s, 2H), 9.42 (br s, 2H);

108

MS (DCI / NH 4 +) m / e 307 (M + H) ⁺

For C19H18N2O2.TFA: C, 60.00; H, 4.56; N, 6.66. Found C, 59.93; H, 4.46; N, 6.51.

Example 39

2 - [(7-aminoiminomethyl-3-methoxy-1-naphthalenyl) oxy] acetamide mono (trifluoroacetate)

Example 39A

6-methoxy-8-hydroxy-2-naphthalenecarbonitrile

A mixture of Example 38G (1.62 g, 5.6 mmol) and 10% dry Pd / C (0.50 g) in methanol (150 mL) was hydrogenated in a Parr shaker at room temperature and 4 atm for 30 h. . The mixture was then filtered and concentrated to give the title compound.

MS (DCI / NH 3) m / e 217 (M + NH ₄ ) ⁺ .

Example 39B

2 - [(7-Cyano-3-methoxy-1-naphthalenyl) oxy] acetamide

Example 39A and 2-bromoacetamide were subjected to the conditions described in Example 5A to give the title compound.

MS (DCI / NH 3) m / e 274 (M + NH ₄ ) ⁺ .

109

Example 39C

2 - [(7-aminoiminomethyl-3-methoxy-1-naphthalenyl) oxy] acetamide mono (trifluoroacetate)

The title compound was prepared from Example 39B by the method of Example 1B.

1 H NMR (300 MHz, DMSO-d 6) δ 3.93 (s, 3H), 4.70 (s, 2H), 6.70 (d, 1H), 7.09 (d, 1H), 7, 65 (s, 2H), 7.82 (dd, 1H), 7.99 (d, 1H), 8.70 (s, 1H), 9.05 (s, 2H), 9.38 (s, 2H) );

MS (DCI / NH ₃ ) m / e 274 (M + H) ^&lt; ^{+ &gt};;

Anal. Calcd for C 14 H 15 N 3 O 3. TFA: C 49.62; H, 4.16; N, 10.85. Found: C, 49.68; H, 4.24; N, 10.61.

Example 40

N- (6-amino-imino-2-naphthalenyl) -N'-phenylurea mono (trifluoroacetate)

Example 40A

6-cyano-2-naftalénkarbonylchlorid

A suspension of Example 8E (4.4 g, 22.3 mmol) in toluene (100 mL) was treated with thionyl chloride (6.0 mL and DMAP (5 mg)) then heated at 55 ° C for 1 h. with further thionyl chloride (3 ml), heated at 95 ° C for 1 hour, cooled to room temperature, stirred in hexane (75 ml) for 2.5 hours, and 3.62 g of the title compound was obtained as a white powder by filtration. The filtrate was concentrated and triturated with ether to give an additional 1.02 g of the title compound.

MS (DCI / NH 3) m / e 215 (M + H) ⁺

110

Example 40B

2-cyano-6-naphthoyl azide

A solution of Example 40A (1.65 g, 7.65 mmol) in acetone (600 mL) was treated at room temperature with a solution of sodium azide (3 g, 46 mmol) in water (10 mL), the reaction mixture was stirred for 1 h. The resulting solid product was filtered off, washed with water and dried to give 4.24 g of the title compound as a white powder.

MS (DCI / NH 3) m / e 240 (M + NH ₄ ) ⁺ .

Example 40C

N- (6-cyano-2-naphthalenyl) -N'-phenylurea

A solution of Example 40B (221.2 mg, 1 mmol) in toluene (18 mL) was heated for 1 hour at 85 ° C then 1.5 hours at 95 ⁰ C, cooled to room temperature, treated with aniline (240 μ sa, 2.63 mmol), the reaction mixture was stirred for 25 minutes and then treated with ether (10 mL). The solid obtained is collected, washed with ether and dried in vacuo to give 230 mg of a white powder.

MS (DCI / NH 3) m / e 305 (M + NH ₄ ) ^f

Example 40D

N- (6-amino-imino-2-naphthalenyl) -N'-phenylurea mono (trifluoroacetate)

A solution of Example 40C (148 mg, 0.5 mmol) in pyridine: triethylamine 10 · 1 (10 mL) was treated with H ₂ S for 5 min, then the reaction mixture was stirred at room temperature for 18 h and concentrated. the product was dissolved in acetone (15 mL), treated with iodomethane (0.8 mL, 12.8 mmol), then stirred for 2 hours, diluted with ether (10 mL), filtered, washed with ether and dried in a vacuum. The solid obtained is dissolved in methanol and treated with 2 N NH 3. in methanol (2 mL), heated at 50 ° C for 4 hours, and then concentrated. The product was purified as described in Example IB to give 62 mg of the title compound.

Δ NMR (300 MHz, DMSO-d ₆ ) δ 7.00 (t, 1H), 7.31 (dd, 2H), 7.52 (d, 1H), 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, 1H), 9.33 (br s, 2H), 9.42 (s, 1H);

MS (DC1 / _NH3) m / e 305 / M + H) ^+.

Anal. Calcd ₆ N ₄ O.TFA: C 57.42; H, 4.10; N, 13.39. Found: C, 57.50; H, 4.05; N, 13.08.

Example 41 (E) -6- [2- (phenyl) ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 41A (E) -6- [2- (phenyl) ethenyl] -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) were heated at 100 ° C in a sealed tube with minimal free space for 19 hours, then the mixture was diluted with ethyl acetate (20 ml), washed with water, dried (MgSO ₄ ) and concentrate with silica gel (4 g). This mixture was chromatographed on silica gel using 10% ethyl acetate / hexane to give 160 mg of the title compound.

MS (DCI / NH ₃ ) m / e 273 (M + NH ₄ ) +.

112

Example 4 1 B (E) -6- [2- (phenyl) ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate) 1 H NMR (300 MHz, DMSO-d ₆ ) δ 7.33 (t, 1H), 7 4 (t, 2H), 7.5 (d, 2H), 7.69 (d, 1H), 7.70 (d, 1H), 7.81 (dd, 1H), 8.03 (dd, 1H), 1H), 8.10 (d, 1H), 8.13 (d, 1H), 8.17 (s, 1H), 8.44 (s, 1H), 8.97 (s, 2H), 9, 41 (s. 2H);

MS (DCI / _NH3) m / e 273 / M + H) \

Anal. Calcd ₉ Hi ₆ N 2 TFA: C 65.28; H, 4.43; N, 7.25. Found: C, 64.95; H, 4.60; N, 6.42.

Example 42

6- [2- (phenyl) ethyl] -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 42A

6- [2- (phenyl) ethyl] -2-naftalénkarbonitriI

A mixture of Example 57B and palladium on carbon (20% water, 50 mg) in methanol (5 mL) was stirred for 0.5 hour under 1 atmosphere of hydrogen, then filtered and concentrated to give 72 mg of the title compound.

MS (DCI / NH 3) m / e 275 (M + NH ₄ ) ⁺ .

Example 42B

6- [2- (phenyl) ethyl] -2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 42A by the method of Example 1B.

113 H NMR (300 MHz, _DMSO- d) δ 3.03 (m, 2H), 7.23 (m, 5 H), 7.60 (dd, IH), 7.76 (dd, 1H), 7.85 (s, 1H), 8.03 (t, 2H), 8.42 (s, 1H), 8.99 (s, 2H), 9.39 (s, 2H),

MS (DCI / NH 3) m / e 275 (M + H) +

Anal. Calcd for C 16 H 20 N 2 O 1 • 33 TFA: C, 61.29; H, 4.59; N, 6.61. Found: C, 61.56; H, 4.62; N, 5.21

Example 43

7-propoxy-8-iodo-2-naftaIénkarboximidamid mono (trifluoroacetate)

Example 43A

7-propoxy-8-iodo-2-naphthalenecarbonitrile

Example 53A (65 mg, 0.25 mmol) in DMF (2 mL), treated with propyl iodide (40 mL), stirred at 65 ° C for 1 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 give 160 mg of the title compound.

MS (DCI / _NH3) m / e 355 (M + H) ⁴

Example 43B

7-pľopoxy-8-iodo-2-naftalénkarboxiinidamid mono (trifluoroacetate)

The title compound was prepared from Example 43A by the method of Example 1B.

114 H NMR (300 MHz, _DMSO-fi) δ 1.09 (t, 3H), 1.82 (m, 2H), 4.23 (t, 2H), 7.62 (d, 1 H); 7.65 (dd, 1H), 8.12 (dd, 1H), 9.15 (s, 2H), 9.42 (s, 1H), 9.53 (s, 2H),

MS (DCI / NH 3) m / e 355 (M + H) ⁺ ;

Anal. Calcd for C 11 H 11 _{N 2} O ₁ · 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 (±) -6- (3-Phenyloxiranyl) -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 44A (±) -6- (3-Phenyloxiranyl) -2-naphthalenecarbonitrile

A solution of Example 41A (69 mg, 0.27 mmol) and chloroperbenzoic acid (70 mg, 0.41 mmol) in methylene chloride (3 mL) was stirred at 25 ° C for 3 days, then the reaction mixture was concentrated, brought to silica gel column (pretreated with 0.1% triethylamine in ethyl acetate) and eluting with 10% ethyl acetate / hexane gave 72 mg of the title compound.

MS (DCI / NH 3) m / e 289 (M + NH ₄ ) ⁺ .

Example 44B (±) -6- (3-Phenyloxiranyl) -2-naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 44A by the method of Example 1B

115 H NMR (300 MHz, _DMSO-ft) δ 4.26 (d, IH), 4.35 (d, IH), 7.43 (m, 5 H), 7.67 (dd, IH); 7.83 (dd, 1H), 8.12 (s, IH), 8.13 (d, IH), 8.16 (d, IH), 8.50 (s, IH), 9.03 (s 2 H, 9.44 (s, 2 H;

MS (DCI / NH 3) m / e 289 (M + H) +

Analysis: Calcd. 1,3TFA. C, 64.52; H, 4.55; N, 6.51. Found: C, 64.35; H, 4.60; N, 5.87.

Example 45 (E) -6- [2- (2-Thienyl) ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 45A

2-vinylthiophene

A suspension of methyltriphenylphosphonium bromide (19.13 g, 53.5 mmol) in THF (100 mL) was treated dropwise with 2 M butyllithium in THF (17.8 mL) and then dropwise with 2-carboxythiophene (5 g, 44.6). mmol), the reaction mixture is then stirred for 30 minutes and then distilled at 74-78 ° C to give the title compound.

MS (DCI / NH 3) m / e 111 (M + H) ⁺

Example 45B (E) -6- [2- (2-Thienyl) ethenyl] -2-naphthalenecarbonitrile

The title compound was prepared from Example 45A by the method of Example 4 IA

MS (DCI / NH 3) m / e 279 (M + NH ⁴ ) ⁴ .

116

Example 45C (E) -6- [2- (2-Thienyl) ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 45B by the method of Example 1B.

H NMR (300 MHz, _DMSO-C)? 7.12 (d, 2H), 7.15 (d, 1H), 7.32 (d, IH), 7.6 (d, 1H), 7 74 (d, 1H); 7.80 (dd, 1H); 7.9-8.1 (m, 3H); 8.14 (s, 1H); 8.43 (s, 1H); Δ (s, 2H), 9.42 (s, 2H,

MS (DCI / _NH3) m / e 279 (M + H) +;

Calcd for C17H14N2O2S.TFA: C, 53.77; H, 3.56; N, 6.60. Found: C, 54.88; H, 3.66; N, 6.45.

Example 46

6- (3-oxo-butyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 46A

6- (3-oxo-butyl) -2-naftalénkarbonitriI

The title compound was prepared from Example 28B and 1-buten-3-ol by the method of Example 41A.

MS (DCI / NH 3) m / e 241 (M + NH ₄ ) ⁺ .

Example 46B

6- (3-Oxobutyl) -2-naphthalenecarboxiidin-mono (tri fluoroacetate)

117

The title compound was prepared from Example 46A by the method of Example 1B.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 2.13 (s, 1H), 2.94 (m, 4H), 7.57 (dd, 1H), 7.78 (dd, 1H), 7 , 85 (s, 1H), 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) ^&lt; ^{+ &gt};;

Anal. Calcd for C ₁₁ H ₁₆ N ₂ O • 1.3 TFA: 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)

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 1,1'-bis (diphenylphosphino) ferrocene (111 mg, 0.2 mmol) was stirred 15 min in DMF (3 mL), then treated with Cs ₂ CO ₃ (813 mg, 2.5 mmol) and 3-methoxyphenylboronic acid (228 mg, 1.5 mmol), stirred at 80 ° C for 20 min, then 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 give 140 mg of the title compound as a white solid.

MS (DCI / NH 0 m / e 277 (M + NH ₄₎ ^+.

Example 47B

118

6- (3-Methoxyphenyl) -2-naphthalenecarboximidamido (trifluoroacetate)

The title compound was prepared from Example 47A by the method of Example 1B.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 3.88 (s, 3H), 7.03 (m, 1H), 7.44 (m, 3H), 7.84 (dd, 1H), 8 .05 (dd, 1H), 8.19 (d, IH), 8.21 (d, IH), .41 (s, IH), 8.51 (s, IH), 9.11 (s, 2H) 9.45 (s, 2H);

MS (DCI / NH 3) m / e 277 (M + H) ⁺ ;

Calcd for C18H18N2O.TFA.0.240: C, 61.03; H, 4.45; N, 7.12. Found: C, 61.03; H 4.1 1; N, 6.86.

Example 48

N- [3- (methyl) phenyl] -6-aminoiminomethyl-2-naphthalenecarboxamide mono (trifluoroacetate)

Example 48A

N- [3- (methyl) phenyl] -6-cyano-2-a naphthalene

The title compound was prepared from 3-methylphenyl-isocyanate and Example 55C by the method of Example 55C.

MS (DCI / NH 3) m / e 287 (M + H) ⁺ .

Example 48B

N - [3- (methyl) phenyl] -6-aminoiminomethyl-2-naphthalenecarboxamines d-mono (tri fluoroacetate)

119

The title compound was prepared from Example 48A by the method of Example 1B

Ή NMR (300 MHz, _DMSO-fi) δ 2.34 (s, 3H), 6.96 (d, 1H), 7.27 (t, 1H), 7.62 (d, IH), 7. 66 (s, 1H), 7.91 (dd, 1H), 8.15 (dd, 1H), 8.29 (d, 1H), 8.31 (d, 1H), 8.54 (s, IH) ), 8.68 (s, 1H), 9.15 (s, 2H), 9.49 (s, 2H), 10.46 (s, 1H);

MS (DCI / NH 3) m / e 304 (M + H) ⁺ .

Calcd for C19H17N3O.TFA.0.12C7H8: C, 61.23; H, 4.46; N, 9.81. Found: C, 61.12; H, 4.42; N, 9.43.

Example 49

6- (2-formyIfenoxy) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 49A

6- (2-formyl-phenoxy) -2-naphthalenecarbonitrile

A solution of 2-hydroxybenzaldehyde (72 mg, 0.59 mmol), 6-bromo-1-cyanaphthalene (150 mg, 0.65 mmol) and Cs ₂ CO ₃ (248 mg, 0.76 mmol) in DMF (10 mL) The mixture was heated at 90 ° C for 2 days, then treated with water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO ₄ ), concentrated and purified by column chromatography using 10% ethyl acetate / hexane to give 40 mg of the title compound.

MS (DCI / NH 3) m / e 291 (M + NH ₄ ) ⁺

Example 49B

6- (2-formyl-phenoxy) -2-naftalénkaľboximidamid mono (trifluoroacetate)

120

The title compound was prepared from Example 49A by the method of Example 1B.

H NMR (300 MHz, _DMSO- d) δ 7.19 (d, 1H), 7.44 (t, 1H), 7.56 (s, 1H), 7.60 (d, 1 H); 7.79 (m, 2H), 7.94 (dd, 1H), 8.01 (d, 1H), 8.2 (d, 1H), 8.51 (s, 1H), 9.03 (s) 2 H, 9.41 (s, 2 H), 10.35 (s, 2 H);

MS (DCI / NH ₃ ) m / e 291 (M + H) ^&lt; ^{+ &gt};;

Anal. Calcd _X Hi ₄ N ₂ O ₂ .TFA. 1.7H ₂ O: C, 55.16; H, 4.27; N, 6.43. Found: C, 55.17; H, 3.92; N, 5.94.

Example 50

6- (2-formylphenyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 50A

6- (2-formylphenyl) -2-naphthalenecarbonitrile

The title compound was prepared from the compound of Example 28B and the acid

2-formylphenylboronic acid according to the method of Example 47A.

MS (DCI / NH ₃ ) m / e 275 (M + NH ₄ ) ⁺ .

Example 50B

6- (2-formylphenyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 50A by the method of Example 1B.

121 1 H NMR (300 MHz, DMSO-d ₆ ) δ 7.71-7.64 (m, 2H), 7.79 (d, 1H), 7.81 (s, 1H), 7.88 (dd) 1 H, 7.9 (d, 1 H), 8.16 (d, 1 H), 8.23 (t, 2 H), 8.56 (s, 1 H), 9.05 (s, 2 H), 9 48 (s, 2H), 9.92 (s, 1H);

MS (DCI / _NH3) m / e 275 (M + H) ^+.

Analysis: Calculated for C H _S | ₄ O.TFA _N2: C, 61.86; H, 3.89; N, 7.21. Found: C 61.98, H 3.59; N, 6.88.

Example 5 1

6- [2- (hydroxymethyl) phenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 51A

6- [2- (hydroxymethyl) phenyl) -2-naftalénkarbonitriI

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 purification of the residue on silica gel with 30% ethyl acetate / hexane gave 90 mg of the title compound.

MS (DCI / NH 3) m / e 277 (M + NH ₄ ) ⁺ .

Example 5 1 B

6- [2- (hydroxymethyl) phenyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 51A by the method of Example 1B.

122 1 H NMR (300 MHz, DMSO-d 6) δ 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), 4 46 (s, 2H);

MS (DCI / NH 3) m / e 277 (M + H) ⁴ ,

Calc'd for C _{with 6} N Hi ₂ 0.1,44TFA: C, 56.93; H, 3.99; N, 6.36. found; C 56.94; H, 3.88; N, 6.46.

Example 52

6- (3-oxo-1-butenyl) -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 52A

6- (3-oxo-1-butenyl) -2-naphthalenecarbonitrile

The title compound was prepared from methyl acrylate and Example 28B by the method of Example 41A

MS (DCI / NH ₃ ) m / e 222 (M + H) &lt; ^{+ &gt};.

Example 52B

6- (3-oxo-1-butenyl) -2-naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 52A by the method of Example 1B.

H NMR (300 MHz, _DMSO- d) δ 9.46 (s, 2H), 9.13 (s, 2H), 8.48 (s, IH), 8.38 (s, 2H), 8 18 (d, 1H), 8.15 (d, 1H), 8.01 (dd, IH), 7.85 (dd, IH), 7.82 (d, 1H), 7.03 (d) 1 H, 2.40 (s, 1 H),

123

MS (DC1 / _NH3) m / e 239 (M + H) \

Calcd for C15H14N2O 1.58TFA: C, 52.13; H, 3.75; N, 6.69. Found: C, 52.09; H, 3.63; N, 6.64

Example 53

7-Methoxy-8- (1H-pyrazol-4-yl) -2-naphthalenecarboximidamide bis (trifluoroacetate)

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 mmol) and I2 (31.8 g, 125.2 mmol) in water (500 mL) and THF (80 mL) at 0 ° C was stirred for 3 hours at room temperature, then acidified with 1 M HCl and extracted with ethyl acetate. The extracts are then washed with saturated Na ₂ SO ₂ and brine, dried (Na 2 SO 4) and concentrated. Recrystallization of the product from ethyl acetate gave 33 g of the title compound.

MS (DCI / NH ₃ ) m / e 313 (M + NH ₄ ) ⁺

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 with 2M trimethylsilyldiazomethane in hexane (260 mL) for 3 hours, then stirred for 24 hours , and concentration and recrystallization from ethyl acetate gave 36.4 g of the title compound.

MS (DCI / NH ₅₎ m / e 327 / M + NH ₄₎ *

124

Example 53C

4-Iodo-1 - [[(2- (trimethylsilyl) ethoxy] methyl] -1H-pyrazole

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) for 1 hour. The mixture was stirred, treated with SEM chloride (9.00 mL, 50.8 mmol), stirred at room temperature for 1 hour, poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried _(MgSO4) and concentrated. Chromatography of the residue on silica gel with 10% ethyl acetate / hexanes afforded 14.4 g of the title compound.

MS (DCI / NH 3) m / e 325 (M + H) ⁺ .

Example 53D [1 - [[2- (Trimethylsilyl) ethoxy] methyl] -1H-pyrazol-4-yl] boronic acid

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 for 10 minutes at -78 ° C, treated with trimethyl borate (1 1.36 mL, 100 mmol), warmed to room temperature, treated with 3 M Hcl (400 mL), and extracted with ethyl acetate. The extracts were concentrated, and the residue was dissolved in 1 M NaOH (500 mL), extracted with diethyl ether, acidified with concentrated HCl, and extracted with ethyl acetate. Then, the extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. Chromatography of the residue on silica gel with ethyl acetate gave 2.20 g of the title compound.

MS (DC1 / _NH3) m / e 199 (MB (OH) ₂₎ ^+.

Example 53E

125

7-Methoxy-8- [1 - [[2- (trimethylsilyl) ethoxy] methyl] -1H-pyrazol-4-yl] -2-naphthalenecarbonitrile

Example 53B (1.55 g, 5 mmol) and 53D (1.45 g, 6 mmol) were treated as in Example 47A to give 1.64 g of the title compound.

MS (DCI / NH 3) m / e 380 (M + H) ⁺

Example 53F

7-Methoxy-8- (1H-pyrazol-4-yl) -2-naphthalenecarbonitrile

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), heated at reflux for 6 h, and concentrated. The residue was chromatographed on silica gel using ethyl acetate / hexanes 1: 1 to give 0.88 g of the title compound.

MS (DCI / NH 3) m / e 267 (M + NH ₄ ) ⁺ .

Example 53G

7-methoxy-8- (lH-pyrazol-4-yl) -2-naftaIénkarboximidamid bis (trifluoroacetate)

The title compound was prepared from Example 53F by the method of Example 1B.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 3.89 (s, 3H), 7.60 (dd, 1H), 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 C 21 H 21 N 4 O 2.8 TFA: C, 42.30; H, 2.90; N, 9.59. Found ^- C. 42.54, H 3.1 L; N, 9.03

126

Example 54

7-methoxy-8-iodo-2-naftalénkarboxirnidamid mono (trifluoroacetate)

The title compound was prepared from Example 53B by the method of Example IB.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 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 / _NH3) m / e 327 (M + H) ^+.

Analysis Calcd for C ₂ H | ₂ N ₂ OI. 1.2TFA: C 37.28; H, 2.87; N, 6.04. Found: C, 37.35; H, 2.47; N, 5.93.

Example 55

N-phenyl-6-amino-imino-2-a naphthalene-mono (methanesulfonate)

A solution of 6-bromo-2-naphthol (4.96 g, 22.25 mmol), N-phenyl trifluoromethanesulfonate (7.95 g, 22.25 mmol) and diisopropylethylamine (7.75 mL, 44.5 mmol) in methylene chloride (25 ml) was stirred for 3 hours at room temperature, then poured into water and extracted with diethyl ether extracts were washed with brine, dried _(MgSO4) and concentrated. The residue was chromatographed on silica gel using 3% ethyl acetate / hexane to give 7.89 g of the title compound.

MS (DCI / _NH3) m / e 354 and 356 (M + H) +.

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 90 ° C for 3 hours, then cooled to room temperature,

127 treated with saturated NaHCO 3; and extracted with diethyl ether extracts were then washed with brine, dried _(MgSO4) and concentrated. The residue was chromatographed on silica gel using 5% ethyl acetate / hexanes to give 2.67 g of the title compound.

MS (DCI / NH 3) m / e 23 L and 233 (M + H) ⁺ .

Example 55C

N-phenyl-6-cyano-2-a naphthalene

A solution of Example 55B (224 mg, 0.965 mmol) in THF (3 mL) and hexanes (1 mL) at -100 ° C is treated with 2.5 M butyllithium in hexanes (0.386 mL, 0.965 mmol), Stir 5 min at -100 ° C, treat with phenylisocyanate (0.115 mL, 1.06 mmol), warm to room temperature, treat with pH 7 buffer (0.5 mL) and concentrate. Chromatography of the residue on silica gel using 20% ethyl acetate / hexanes gave 54 mg of the title compound.

MS (DCI / NH 3) m / e 273 (M + H) ⁺

Example 55D

N-phenyl-6-amino-imino-2-a naphthalene-mono (methanesulfonate)

A solution of Example 55C (52 mg, 0.191 mmol) in THF (2 mL) was treated with 1 M lithium bis (trimethylsilyl) amide in THF (0.6 mL), stirred for 16 hours, treated with 2 M HCl (4 mL), stirred for an additional 24 hours, basified with saturated Na ₂ CO ₃ and extracted with ethyl acetate. The extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The crude product was dissolved in a minimum amount of methanol (about 1 mL), treated with methanesulfonic acid (1 drop), diluted with diethyl ether (400 mL) and filtered to give 15 mg of the title compound.

128 H NMR (300 MHz, _DMSO-d) δ 2.32 (s, 3H), 7.15 (dd, 1H), 7.40 (dd, 2H), 7.83 (d, 2H); 7.90 (dd, 1H), 8.17 (dd, 1H), 8.25 (d, 1H), 8.34 (d, 1H), 8.57 (s, 1H), 8.70 (d, 1H); s, 1H), 8.70 (s, 1H), 9.09 (br s, 2H), 9.51 (br s, 2H),

MS (DCI / NH ₃ ) m / e 290 (M + H) ^&lt; ^{+ &gt};;

Analysis calculated for C18H18N2O. 1.CH3SO3H: C, 57.96; H, 4.95; N, 10.61. Found: C, 58.03; H, 4.48; N, 10.36.

Example 56

4 - [(6-amino-imino-2-naphthalenyl) oxy] -N-methyl-benzeneacetamide-mono (trifluoroacetate)

Example 56A

N-methyl-3-hydroxyphenylacetamide

A solution of 3-hydroxyphenylacetic acid (1.00 g, 6.57 mmol) of oxalyl chloride (0.63 mL, 7.22 mmol) in methylene chloride (20 mL) was treated dropwise with pyridine (0.6 mL, 7.37 mmol). The mixture was stirred for 90 minutes, poured into 40% aqueous methylamine (30 mL), stirred for 15 minutes, concentrated, dissolved in 1 M HCl and extracted with ethyl acetate. The extracts were washed with brine, dried _(MgSO4) and concentrated. Chromatography of the residue on silica gel using ethyl acetate gave 260 mg of the title compound.

MS (DCI / NH 3) m / e 166 (M + H) +.

Example 56B

4 - [(6-cyano-2-naphthalenyl) oxy] -N-methyl-benzeneacetamide

129

A mixture of Example 56A (245 mg, 1.48 mmol), Example 55B (344 mg, 1.48 mmol) and Cs ₂ CO ₃ (530 mg, 1.63 mmol) in DMF (3 mL) was stirred 72 hours at 120 ° C and then chromatographed on silica gel using ethyl acetate / hexanes I. I to give 54 mg of the title compound.

MS (DCI / _NH3) m / e 317 (M + H) +.

Example 56C

4 - [(6-amino-imino-2-naphthalenyl) oxy] -N-methyl-benzeneacetamide-mono (trifluoroacetate)

The title compound was prepared from Example 56B by the method of Example 55D.

H NMR (300 MHz, DMSO- d _d) δ 2.33 (s, 3H), 2.58 (d, IH), 3.42 (s, 2H), 7.05 (m, 2H), 7 12 (d, 1H); 7.40 (d, 1H); 7.45 (m, 2H); 7.79 (dd, 1H); 7.98 (q, 1H); 8.02 (d, 1H); 1H), 8.15 (d, 1H), 8.49 (s, 2H), 8.99 (br s, 2H), 9.39 (br s, 2H);

MS (DCI / _NH3) m / e 334 (M + H) ^+.

Analysis calculated for C ₁₉ H ₁₇ N ₃ O 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) phenyl] -2-Naphthalenecarboximidamide mono (methanesulfonate)

Example 57A

2-Cyano-naphthalene-6-boric acid

130

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 mL, 27.5 mmol), the reaction mixture was then stirred for 10 min at -100 ° C, treated with trimethylborate (7.8 mL, 68.6 mmol), warmed to room temperature, treated with 3 M HCl (400 mL) and extracted with ethyl acetate. The extracts were concentrated and the residue was dissolved in 1 M NaOH (500 mL), extracted with diethyl ether, acidified with 12 M HCl and extracted with ethyl acetate. The extracts are then washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was dissolved in a minimum volume of methanol and ethyl acetate and triturated with hexanes to give 2.74 g of the title compound.

MS (DCI / NH ₃ ) m / e 215 (M + NH ₄ ) ⁺ .

Example 57B

6- [2- (methylthio) phenyl] -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 (diphenylphosphinoferocene) (120 mg, 0.22 mmol) in DMF (5 ml) was stirred for 10 minutes and then treated with Example 57A (260 mg, 1.32 mmol) and with CS 2 CO 3 (1.07 g, 3.3 mmol), then heated at 85 ° C for 6 h. cooled to room temperature and chromatography on silica gel using 10% ethyl acetate / hexanes afforded 155 mg of the title compound.

MS (DCI / NH 3) m / e 231 (M + NH ₄ ) ⁺ .

Example 57C

6- [2- (methylthio) phenyl] -2-naftalénkaiboximidamid mono (methanesulfonate)

The title compound was prepared from Example 57B by the method of Example 55D.

131 H NMR (300 MHz, _DMSO-d) δ 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, 1H), 8.55 (s 1 H, 9.03 (br s, 2H), 9.56 (br s, 2H);

MS (DCI / NH 3) m / e 293 (M + H) ⁺

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.

Example 58

6- [2- (2-methylthioethyl) phenyl] naphthalene-2-carboximidamide mono (methanesulfonate)

Example 58A

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 Ph3PBr ₂ (13.8 g, 32.65 mmol). The reaction mixture was stirred at 0 ° C for 2 hours, then diluted with hexanes and filtered through a pad of silica gel using 25% diethyl ether / hexanes to give 6.0 g of the title compound.

MS (DCI / NH 3) m / e 263 (M + H) ⁺ .

Example 58B

2- (2-methylthioethyl) bromobenzene

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 90 ° C for 5 h, then cooled and chromatographed on silica gel using 1% ethyl acetate / hexanes gave 646 mg of the title compound.

132

MS (DCI / NH 3) m / e 231, 233 (M + H) ⁺ .

Example 58C

6- [2- (2-methylthioethyl) phenyl] -2-naphthalenecarbonitrile

The title compound was prepared from the compound of Example 58B (300 mg, 1.30 mmol), the compound of Example 57A (260 mg, 1.32 mmol) and the method of Example 57B.

MS (DCI / NH ₃ ) m / e 321 (M + H) &lt; ^{+ &gt};.

Example 58D

6- [2- (2-methylthioethyl) phenyl] naphthalene-2-carboximidamide mono (methanesulfonate)

The title compound was prepared from Example 58C by the method of Example 55D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1 H), 7.85 (dd, 1 H), 8.04 (s, 1 H), 8.18 (d, 1 H), 8, 20 (d, 1H), 8.55 (s, 1H), 9.01 (br s, 2H), 9.43 (br s, 2H);

MS (DCI / NH 3) m / e 321 (M + H) ⁺

Analysis: Calculated for C20H20N2S2.1,35CH 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-Naphthalenecarboximidamide mono (methanesulfonate)

133

Example 59A

7-methoxy-8- (3-furanyl) -2-naphthalenecarbonitrile

The title compound was prepared from Example 53B and furan-3-boronic acid (873 mg, 7.80 mmol) according to the method of Example 57B.

MS (DCI / NH 3) m / e 267 (M + NH ₄ ) +

Example 59B

7-methoxy-8- (3-furanyl) -2-Naphthalenecarboximidamide mono (methanesulfonate)

The title compound was prepared from 58C according to the method for example

55D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 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, IH), 8.25 (s, 1H), 1H), 8.96 (br s, 2H), 9.35 (br s, 2H);

MS (DCI / NH 3) m / e 267 (M + H) ⁺ ;

Calcd for C16HMN2O2CH3SO3H: C, 55.77; H, 5.00; N, 7.63. Found: C, 55.73; H, 4.61; N, 7.48.

Example 60

7-methoxy-8- (2-benzofuranyl) naphthalene-2-carboximidamide mono (methanesulfonate)

Example 60A

7-methoxy-8- (3-furanyl) -2-naphthalenecarbonitrile

134

The title compound was prepared from Example 53B (166 mg, 0.50 mmol) and benzofuran-2-boronic acid (113 mg, 0.70 mmol) according to the method of Example 57B

MS (DCI / NH 3) m / e 317 (M + NH ₄ ) +

Example 60B

7-methoxy-8- (2-benzofuranyl) naphthalene-2-carboximidamide mono (methanesulfonate)

The title compound was prepared from 60A (72 mg, 0.240 mmol) according to the procedure of Example 55D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 2.30 (s, 3H), 3.98 (s, 3H), 7.24 (s, 2H), 7.36 (m, 2H), 7 67 (m, 2H); 7.75 (m, 1H); 7.84 (d, 1H); 8.21 (d, 1H); 8.30 (d, 1H); 8.32 (s, 1H); 1H), 8.88 (br s, 2H), 9.39 (br s, 2H);

MS (DCI / NH ₃ ) m / e 317 (M + H) ^&lt; ^{+ &gt};;

Anal. Calcd for C 20 H 11 N ₂ O ₂ .3.3CH 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 (E) -8- [2- (1,3-Benzodioxol-5-yl) ethenyl] -2-naphthalenecarboximide mono (methanesulfonate)

Example 6 IA (E) -8- [2- (1,3-benzodioxol-5-yl) etcnyl] -2-naphthalenecarbonitrile

Example 53B (75 mg, 0.243 mmol), PdCl ₂ (dppf) (20 mg, 0.024 mmol), 3,4-methylenedioxystyrene (43 mg, 0.291 mmol), and diisopropylethyla135 min (0.170 mL, 0.97 mmol) in N-methylpyrrolidinone (2 mL) was stirred at 90 ° C for 18 h, then the reaction mixture was cooled to room temperature and chromatography on silica gel with 20% ethyl acetate / hexanes afforded 46 mg of the title compound.

MS (DCI / NH 3) m / e 347 (M + NH ₄ ) +.

Example 6 1 B (E) -8- [2- (1,3-Benzodioxol-5-yl) ethenyl] -2-naphthalenecarboximidamide mono (methanesulfonate)

The title compound was prepared from 61A (43 mg, 0.131 mmol) according to the procedure of Example 55D.

Δ NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 7.56 (d, 1H), 7.66 (d, 2H), 7.72 (d, 1H) ), 8.06 (s, 1H), 8.03 (d, 1H), 8.12 (d, 1H), 8.66 (s, 1H), 8.96 (br s, 2H) 9.44 (br s, 2H);

MS (DCI / NH 3) m / e 347 (M + H) ⁺ .

Analysis: Calculated for Ο _{2 ιΗ} Ι8 Ν ₂ Ο ₃ .1, 1 CH ₃ SO ₃ H: C, 58.72; H, 4.99; N, 6.20. Found: C, 58.77; H, 5.07; N, 5.99.

Example 62 (±) -7-Methoxy-8- (tetrahydro-3-fluoro) -2-naphthalenecarboximidamide mono (methanesulfonate)

Example 62A

136 (±) -7-Methoxy-8- (3-hydroxy-1- (hydroxymethyl) -1-propenyl) -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 1 h, then cooled to room temperature and chromatographed on silica gel with 30% ethyl acetate / hexanes to provide diastereomeric mixture 2. 19 g of the title compound.

MS (DCI / NH 3) m / e 269 (M + H) ⁺ .

Example 62B (±) -7-Methoxy-8- (tetrahydro-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 .EEt ₂ (0.096 mL, 0.78). mmol), the reaction mixture was stirred at room temperature for 4 hours, concentrated and chromatographed on silica gel with 25% ethyl acetate / hexanes to give 100 mg of the title compound.

MS (DCI / _NH3) m / e 271 (M + NH ₄₎ ^+.

Example 62C (±) -7-Methoxy-8- (tetrahydro-3-furanyl) -2-naphthalenecarboximidamide mono (methanesulfonate)

The title compound was prepared from 62B (96 mg, 0.379 mmol) according to the procedure of Example 55D.

H NMR (300 MHz, _DMSO-d) δ 3H), 3.99 (s, 3H), 3.90-4.03 (m, 3H), 4.1 7.68 (d, IH); 8.01 (d, 1H), 8.10 (d, 1H), s, 2H),

2.20 (m, 1H), 2.33 (m, 1H), 2.39 (s, 1 (m, 1H), 4.42 (m, 1H), 7.64 (d, 1H), 8 70 (s, 1H); 9.01 (br s, 1H); 9.41 (br

137

MS (DCI / NH 3) m / e 271 (M + H) +

analysis; calculated for Cu, HihN ₂ O ₂ . 1,2CH ₃ SO 3 H: C, 53.57, H, 5.96; N, 7.26. Found ^- C 53.67, H 5.78, N 6.72.

Example 63

6 - [[4- (2-aminoethyl) phenyl] ethynyl] -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 63A

6- (trimetylsilyIetinyl) -2-naphthalenecarbonitrile

The title compound was prepared from Example 28B and trimethylsilylacetylene under the conditions described in Example 42C.

MS (DCI / NH 3) m / e 267 (M + NH 4) ⁺ .

Example 63B

6-ethynyl-2-naphthalenecarbonitrile

A mixture of Example 63A (0.4 g, 1.6 mmol) and K 2 CO 3 (0.4 g, 3.2 mmol) in methanol (16 mL) was stirred at room temperature for 18 h. water and extracted with methylene chloride. The organic layer was washed with 0.5 N HCl, brine, dried (MgSO ₄ ) and evaporated to give the title compound.

MS (DCI / NH 3) m / e 195 (M + NH ₄ ) +

Example 63C

138

4-Bromo- (N-tert-butoxycarbonyl) phenethylamine

The title compound is obtained from 4-bromophenethylamine and di-tert-butyl dicarbonate under the conditions described in Synthesis, 48, 1986.

MS (DCI / NH 3) m / e 319 (M + NH ₄ ) +

Example 63D

6 - [[4- (2-t-butoxycarbonylaminoethyl) phenyl] ethynyl] -2-naphthalenecarbonitrile

The title compound was obtained from Example 63B and Example 63B by the method of Example 57B.

MS (DCI / NH 3) m / e 414 (M + NH ₄ ) ⁺ .

Example 63E

6 - [[4- (2-aminoethyl) fenyljetinyl] -2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from 63D by the method of Example 5B.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 2.90 (t, 2H), 3.09 (m, 2H), 7.36 (d, 2H), 7.60 (d, 2H), 7 76 (d, 2H); 7.76 (dd, 1H); 7.85 (s, 2H); 7.87 (dd, 1H); 8.13 (d, 1H); 1H), 8.3 L (s, 1H), 8.50 (s, 1H), 9.18 (s, 2H), 9.45 (s, 2H);

MS (DCI / NH 3) m / e 31 (M + H) ⁺

Calcd for C 21 H 19 N 3 ₂ TFA · H ₂ O: C 53.67, H 4.14; N, 7.15. Found. C 53.37; H, 3.93; N, 7.17

Example 64

139

7-methoxy-8- [2-pyrimidinyl (oxy)] - 2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 64A

7-methoxy-8- [2-pyrimidinyl (oxy)] - 2-naphthalenecarbonitrile

The title compound was prepared in a yield of 101 mg from Example 4A (125 mg, 0.627 mmol) and 2-chloropyrimidine (143 mg, 1.25 mmol) by the method of Example 6A.

MS (DCI / NH ₃ ) m / e 278 (M + H) &lt; ^{+ &gt};.

Example 64B

7-methoxy-8- [2-pyrimidinyl (oxy)] - 2-naftaIénkarboximidamid mono (trifluoroacetate)

The title compound was prepared from 64A by the method of Example 1B.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 2.51 (s, 3H), 3.83 (s, 3H), 7.18 (t, 1H), 7.70 (dd, 1H), 7 80 (d, 1H), 8.05 (d, 1H), 8.19 (d, 1H), 8.34 (s, 1H), 8.62 (d, 2H), 9.07 (br s) (2H), 9.45 (brs, 2H);

MS (DCI / NH 3) m / e 295 (M + H) ⁺

Calcd for C 21 H 16 N 4 O 4 .1.33TFA C 40.48, H 2.60; N, 8.35. Found: C, 40.25; H, 2.94; N, 8.92.

Example 65

7-methoxy-8- [2-thiazolyl (oxy)] naphthalene-2-carboximidamide mono (trifluoroacetate)

140

Example 65A

7-nietoxy-8- [2-thiazolyl (oxy)] - 2-naphthalenecarbonitrile

A mixture of Example 4A (250 mg, 1.25 mmol), 2-bromothiazole (225 mL, 2.59 mmol) and CsF (208 mg, 1.38 mmol) in DMSO (4 mL) was stirred for 4 days at 120 ° C. C, then cooled and chromatographed on silica gel with 30% ethyl acetate / hexanes to give 162 mg of the title compound.

MS (DCI / _NH3) m / e 283 (M + H) ^+.

Example 65B

7-methoxy-8- [2-thiazolyl (oxy)] naphthalene-2-carboximidamide mono (trifluoroacetate)

The title compound was prepared from 65A by the method of Example IB.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 3.98 (s, 3H), 7.25 (m, 2H), 7.73 (dd, 1H), 7.86 (d, 1H), 8 12 (d, 1H), 8.22 (d, 1H), 8.35, 9.09 (bs, 2H), (s, 1H), 9.48 (bs, 2H);

MS (DC1 / _NH3) m / e 300 (M + H) ⁺

Analysis: Calculated for C ₅ H | ₃ N ₃ O2S.TFA: C 49.40, H 3.41; N, 10.70. Found: C, 49.10; H, 3.40; N, 10.69.

Example 66

7-methoxy-8- (4-nitrophenoxy) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 66A

141

7-methoxy-8- (4-nitrophenoxy) -2-naphthalenecarbonitrile

The title compound was prepared in a yield of 227 mg from Example 4A (125 mg, 0.627 mmol) and 1,4-dinitrobenzene (143 mg, 1.25 mmol) according to the method of Example 65A.

MS (DCI / NH 3) m / e 338 (M + NH ₄ ) ⁺

Example 66B

7-methoxy-8- (4-nitrophenoxy) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from compound 66A according to the method for example

55D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 9.43 (br s, 2H), 8.94 (br s, 2H), 8.25 (m, 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) ⁺ .

Analysis: Calculated for C ₃ H _S Hi5N ₄ .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-methoxy-8-pentafluorophenoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 67A

7-methoxy-8-pentafluorophenoxy-2-naphthalenecarbonitrile

142

The title compound was prepared in a yield of 150 mg from Example 4A (100 mg, 0.50 mmol) and hexafluorobenzene (115 mL, 1.00 mmol) according to the procedure of Example 65A.

MS (DCI / NH 3) m / e 383 (M + NH ₄ ) ⁺

Example 67B

7-methoxy-8-pentafluorophenoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Compound 67A according to the method of Example

55D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 2.31 (s, 3H), 3.82 (s, 3 s), 7.87 (dd, 1H), 7.88 (d, 1H), 8 0.02 (d, 1H), 8.20 (d, 1H), 8.65 (s, 1H), 9.04 (br s, 2H), 9.47 (br s, 2H);

MS (DCI / NH ₃ ) m / e 383 (M + H) &lt; ^{+ &gt};.

Analysis: Calculated for C, H, _S, F i N ₂ O _{5 second} 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

7-Methoxy-8- [N-2-phenyl (amino)] naphthalene-2-carboximidamide mono (trifluoroacetate)

Example 68A

7-methoxy-8- [N-phenyl-2 (amino)] - 2-naphthalenecarbonitrile

A solution of Example 25A (309 mg, 1.00 mmol), aniline (0.109 mL, 1.2 mmol), NaO-tert-butyl (115 mg, 1.2 mmol), Pd ₂ (dba) ₃ (10 mg , 0.01 mmol) and dppI (17 mg, 0.03 mmol) in toluene (5 mL) were stirred at 100 ° C for 3 h,

143 was then cooled and chromatographed on silica gel with 10% ethyl acetate / hexanes to give 175 mg of the title compound

MS (DCI / _NH3) m / e 275 (M + H)

Example 68B

7-methoxy-8- [N-phenyl-2 (amino)] - 2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from 68A according to the method for example

55D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 3.95 (s, 3H), 5.92 (bs, 1H), 6.61 (d, 2H), 6.94 (t, 1H), 7 16 (dd, 2H), 7.45 (dd, 1H), 7.48 (d, 1H), 7.76 (d, IH), 7.88 (d, IH), 8.13 (d, 1H), 1H), 9.08 (bs, 2H), 9.3 L (bs, 2H).

MS (DCI / _NH3) m / e 292 (M + H /.

Anal. Calcd for C ₁₈ H ₁₇ N ₃ O.TFA: C 59.26, H 4.48; N, 10.37. Found: C, 59.20; H, 4.32; N, 10.15.

Example 69

N- (6-amino-imino-2-naphthalenyl) -N-benzyl-urea-mono (trifIuóracetát)

Example 69A

N- (6-cyano-2-naphthalenyl) -N'-benzylurea

The title compound was prepared from Example 40A by the method of Example 40B.

MS (DCI / _NH3) m / e 302 (M + H) ^4th

144

Example 69B

N- (6-aminoiminomethyl-2-naphthalenyl) -N'-benzyl urea-mono (trifluoroacetate)

The title compound was prepared from 69A according to the method for example

40D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 4.35 (d, 2H), 6.91 (t, 1H), 7.35-7.24 (m, 5H), 7.59 (dd, 1H), 7.72 (dd, 1H), 7.95 (d, 1H), 7.96 (d, 1H), 8.22 (d, 1H), 8.35 (d, 1H), 8, 92 (br s, 2H), 9.13 (s, 1H), 9.32 (br s, 2H).

MS (DCI / _NH3) m / e 319 (M + H) \

For C19H18N4O.TFA: C, 50.57; H, 4.24; N, 15.72. Found: C, 50.34; H, 4.15; N, 15.54.

Example 70

N- (6-amino-imino-2-naphthalenyl) -N'-methylurea mono (trifluoroacetate)

Example 70A

N- (6-cyano-2-naphthalenyl) -N'-methyl urea

The title compound was prepared from Example 40A (221.2 mg, 1.00 mmol) and methylamine (2.3 mL, 2.34 mmol) in THF (10 mL) by the method of Example 40B.

MS (DCI / NH 3) m / e 226 (M + H) ⁺ .

Example 70B

N- (6-amino-imino-2-naphthalenyl) -N'-methylurea mono (trifluoroacetate)

145

The title compound was prepared from compound 70A according to the method for example

1 H NMR (300 MHz, DMSO-d ₆ ) δ 2.69 (d, 3H), 6.32 (q, 1H), 7.60 (dd, IH), 7.33 (dd, IH), 7.93 (d, 1H), 7.95 (d, IH), 8.19 (d, IH), 8.49 (d, IH), 9.09 (s, IH), 9.15 (br) s, 2H);

MS (DCI / NH 3) m / e 243 (M + H) ⁺ .

Anal. Calcd H 14 N ₄ O.TFA: C 50.57, H 4.24; N, 15.72. Found. C, 50.34; H, 4.15; N, 15.54.

Example 71

N- (6-amino-imino-2-naphthalenyl) -N-isopropyl-urea-mono (trifluoroacetate)

Example 71A

N- (6-cyano-2-naphthalenyl) -N-isopropyl-urea

The title compound was prepared from Example 40A and isopropylamine by the method of Example 40B.

MS (DCI / NH 3) m / e 254 (M + H) ⁺ .

Example 71 B

N- (6-aiiiinoiminometyl-2-naphthalenyl) -N-isopropyl-urea-mono (trifluoroacetate)

The title compound was prepared from 71A by the method of Example 5B

146 H NMR (300 MHz, _DMSO- d) δ 1.13 (d, 6H), 3.76-3.84 (m, 1H), 6.28 (d, 1H), 7.55 (dd 1 H, 7.72 (dd, 1H), 7.94 (d, 1H), 7.95 (d, 1H), 8.19 (d, 1H), 8.34 (d, 1H), 8 85 (s, 1H); 9.3 (br s, 2H); 9.0 (br s, 2H);

MS (DCI / NH 3) m / e 271 (M + H) ⁺

Calcd for C15H18N4O.TFA: C 53.12, H 4.98; N, 14.58. Found: C, 15.13; H, 4.84; N, 14.50.

Example 72

N- (6-amino-imino-2-naphthalenyl) -N ' -phenyl-N ' metyImočovina mono (trifluoroacetate)

Example 72A

N- (6-cyano-2-naphthyl) -N-phenyl-N-methylurea

The title compound was prepared from Example 40A and N-methyl-N-phenylamine by the method of Example 40B.

MS (DCI / NH 3) m / e 302 (M + H) ⁺ .

Example 72B

N- (6-arninoiminometyl-2-naphthyl) -N-phenyl-N-methylurea mono (trifluoroacetate)

The title compound was prepared from 72A according to the method for example

40D

147 H NMR (300 MHz, _DMSO- d) δ 3.33 (s, 3H), 7.25-7.47 (m, 5H), 7.95 (two overlapping d, 2H), 8, 16 (d, 1H), 8.35 (d, 1H), 8.64 (s, 1H), 8.96 (br s, 1H), 9.34 (br s, 2H);

MS (DCI / NH 3) m / e 319 (M + H) ⁺ .

Calcd for C ₂₀ H ₁₇ N 10 O. TFA: C 58.33, H 4.43; N, 11.96. Found: C, 58.38; H, 4.69; N, 1.82.

Example 73

N-aminonaphthalene-2-carboximidamide mono (trifluoroacetate)

Example 73A

N-phenylcarbamoyl-2-naphthalenecarbonitrile

The title compound was prepared from Example 40A and phenol by the method of Example 40B.

MS (DCI / NH 3) m / e 289 (M + H) ⁺ .

Example 73B

6-aminonaphthalene-2-carboximidamide mono (trifluoroacetate)

The title compound was prepared from compound 73A by the method of example

40D.

1 H NMR (300 MHz, DMSO-d 6) δ 6.01 (br s, 2H), 6.86 (d, 1H), 7.58-7.67 (m, 2H), 7.74 (d 1 H, 8.21 (d, 1H), 8.74 (br s, 2H), 9.16 (br s, 2H);

MS (DCI / NH 3) m / e 196 (M + H) +

148

H, 4.04; N, 14.04. Found: C, 52.18; Found. C, 51.92; H, 3.87; N, 13.80

Example 74

N- (6-Aminoiminomethyl-2-naphthalenyl) -N'-cyclohexyl urea-mono (trifluoroacetate)

Example 74A

N- (6-cyano-2-naphthalenyl) -N'-cyclohexylurea

The title compound was prepared from Example 40A and cyclohexylamine by the method of Example 40B.

MS (DCI / NH 3) m / e 294 (M + H) ⁺ .

Example 74B

N- (6-aminoiminomethyl-2-naphthalenyl) -N'-cyclohexyl urea-mono (trifluoroacetate)

The title compound was prepared from 74A according to the method for example

40D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 7.93 (d, 1H), 7.95 (d, 1H), 8.18 (d, 1H), 8.35 (d, 1H), 8.87 (s, 1H), 9.00 (br s, 2H), 9.28 (br s, 2H);

MS (DCI / NH ₃ ) m / e 3 1 (M + 1) ¹

149

Calcd for C19H21N4O 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-naphthalenyl) -N'-benzyloxymethyl-mono (trifluoroacetate)

Example 75A

N- (6-cyano-2-naphthalenyl) -N-benzyloxy urea

The title compound was prepared from the compound of Example 40A and 0-benzylhydroxylamine according to the method of Example 40B.

MS (DCI / NH 3) m / e 318 (M + H) ⁺ .

Example 75B

N- (6-amino-imino-2-naphthalenyl) -N-benzyloxy urea-mono (trifluoroacetate)

The title compound was prepared from compound 75A by the method of example

40D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 4.87 (s, 2H), 7.25-7.42 (m, 3H), 7.487.51 (m, 2H), 7.75 (dd, 1H), 7.75 (dd, IH), 7.97 (d, 2H), 8.30 (d, IH), 8.38 (d, IH), 8.97 (br s, IH), 9 21 (s, 1H), 9.35 (br s, 2H), 9.77 (s, 1H);

MS (DCI / NH 3) m / e 335 (M + H) ⁺ .

Calcd for C 19 H 16 N 3 Cl 2 TFA ^- C 56.25, H 4.27; N, 12.49. Found: C, 56.26; H, 4.39; N, 12.30

150

Example 76

1,1'-Dimethylethyl [4 - [[(6-aminoiminomethyl-2-naphthalenyl) amino] carbonyl] phenyl] carbamate mono (trifluoroacetate)

Example 76A

6-amino-2-naphthalenecarbonitrile

Example 40B (6.5 g) was treated with sulfuric acid (45 mL), stirred for 30 minutes, then warmed to room temperature for 20 minutes, poured into ice, diluted to about 500 mL with water, Cool to 0 ° C and treat with 50% aqueous NaOH such that the temperature does not exceed 35 ° C. The light solid which precipitated was filtered off, washed with water to pH 7, dried and purified on silica gel with 20% ethyl acetate / hexanes to give 3.3 g of the title compound.

MS (DCI / NH 3) m / e 169 (M + H) ⁺

Example 76B

1,1-Dimethylethyl [4 - [[(6-cyano-2-naphthalenyl) amino] carbonyl] phenyl] carbamate monotrifluoroacetate

The title compound was prepared from Example 76A, 4-N-Bocaminomethylbenzoic acid by the method of Example 35B using methylene chloride instead of THF.

MS (DCI / NH 3) m / e 417 (M + H) +

Example 76C

151

1,1-dimethylethyl [4 - [[(6-aminoiminomethyl-2-naphthalenyl) amino] carbonyl] phenyl] carbamate mono trifluoroacetate

The title compound was prepared from Example 76B by the method of Example 40D.

H NMR (300 MHz, _DMSO-fi) δ 3.30 (s, 9 H), 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, 1H), 8.63 (d, 1H), 9, 18 (br s, 4H), 10.58 (s, 1H);

MS (DC1 / _NH3) m / e 434 (M + H)

Analysis calc'd for C ₂ 4 H _{2 3} .TFA 7N5O: C, 59.56; H, 5.00; N, 10.29. Found: C, 58.55; H, 4.85; N, 10.41.

Example 77

N- [6- (amino) -2-naphthalenyl] -4- (aminomethyl) benzamide mono (trifluoroacetate)

Example 77A

N- [6- (amino) -2-naphthalenyl] -4- (aminomethyl) benzamide mono (trifluoroacetate)

A solution of Example 76B (35 mg, 0.07 mmol) in 1: 1 TFA / methylene chloride was stirred at room temperature for 1 h and then concentrated. The residue was dissolved in water (12 mL), filtered and concentrated. The solid residue was suspended in diethyl ether and filtered to give 27 mg of the title compound as a white solid.

152 H NMR (300 MHz, DMSO-d _f>) δ 4.17 (q, 2H), 7.65 (d, 2H), 7.80 (dd, 2H), 7.99 (dd, 1H) 8.06-8.12 (m, 4H), 8.30 (br s, 2H), 8.44 (d, 1H), 8.64 (d, 1H), 9.13 (br s, 2H) ), 9.40 (br s, 2H), 10.70 (s, 1H);

MS (DCI / NH ₃ ) m / e 3 19 (M + H) +

Analysis: Calculated for Ci9HigN O.2,25TFA.0,5H ₄ O _2: C, 48.34; H, 3.67; N, 9.59. Found: C, 48.45; H, 3.74; N, 9.45.

Example 78

Ethyl 1- [6- (aminoiminomethyl) -2-naphthalenyl] carbamate mono (trifluoroacetate)

Example 78A

Ethyl (6-cyano-2-naftaIenyl) carbamate mono (trifluoroacetate)

The title compound was prepared from Example 40A and ethanol by the method of Example 40B

MS (DCI / NH 3) m / e 241 (M + H) ⁺ .

Example 78B

Ethyl [6- (amino) -2-naphthalenyl] carbamate mono (trifluoroacetate)

The title compound was prepared from Example 78A by the method of Example 40D.

H NMR (300 MHz, _DMSO-f)) δ 1.29 (t, 3H), 4.19 (q, 2H), 7.69 (dd, 2H), 7.76 (dd, IH); 8.1 (d, 2H), 8.23 (d, 1H), 8.38 (d, 1H), 9.03 (br s, 2H), 9.33 (br s, 2H), 10, 11 (s, 1H);

153

MS (DCI / NH3) m / e 258 (M + H) ’

Anal. Calcd for C 14 H 11 N 3 O 2. TFA: C 51.76, H 4.34, N 11.32. Found C, 5.32; H 4.1 5; N, 10.93

Example 79

1,1-Dimethylethyl [4 - [[[6-aminoiminomethyl) -2-naphthalenyl] amino] carbonyl] amino] phenyl] carbamate mono (trifluoroacetate)

Example 79A

1,1-Dimethyl [4 - [[[(6-cyano-2-naphthalenyl) amino] carbonyl] amino] phenyl] carbamate

The title compound was prepared from Example 40B and 4- (N-tert-butoxycarbonylamino) aminobenzene by the method of Example 40C.

MS (DCI / NH ₃ ) m / e 403 (M + H) &lt; ⁺ &gt; ^.

Example 79B

1,1-dimethylethyl [4 - [[[6-aminoiminomethyl) -2-naphthalenyl) amino] carbonyl] amino] phenyl] carbamate mono (trifluoroacetate)

The title compound was prepared from Example 79A by the method of Example 40D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 1.22 (s, 9H), 7.38 (s, 4H), 7.62 (dd, 1H), 7.75 (dd, IH), 8 0.10 (d, 2H), 8.27 (d, 1H), 8.38 (d, 1H), 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) ’

154

Analysis calculated for C 25 H 25 N ₅ O ₃ .2TFA. C 56.28, H 4.91; N, 13.13. Found: C, 56.18; H, 5.07; N, 12.44.

Example 80 (E) -6- [2- (Phenylthio) ethenyl] -2-naphthalenecarboimidamide mono (trifluoroacetate)

Example 80A (E) -6- [2- (phenylthio) ethenyl] -2-naphthalenecarbonitrile

The title compound was prepared from Example 55B and phenylvinyl sulfide by the method of Example 57B.

MS (DCI / _NH3) m / e 305 (M + NH ₄₎ ^+.

Example 80B (E) -6- [2- (Phenylthio) ethenyl] -2-naphthalenecarboimidamide mono (trifluoroacetate)

The title compound was prepared from Example 80A by the method of Example 1B.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 9.03 (s, 2H) 9.40 (s, 2H);

MS (DC1 / _NH3) m / e 305 (M + H) ¹

Calcd. 1.1 TFA C 59.55, H 4.03, N 6.57. Found: C, 59.53; H, 4.12; N, 6.60

155

Example 8 1 (E) -6- [2- (2-Furanyl) ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 8 1A

2-vinyl furan

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) followed by furfural (6 g, 62.5 mmol). The reaction mixture was stirred for 0.5 h and distilled at 6972 ° C to give the title compound as less of an impurity as a clear, colorless liquid.

MS (DCI / NH 3) m / e 83 (M + H) ⁺ .

Example 81B (E) -6- [2- (2-furanyl) ethenyl] -2-naphthalenecarbonitrile

The title compound was prepared from the compound of Example 55B and the compound of Example 81A by the method of Example 57B.

MS (DCI / _NH3) m / e 263 (M + NH ₄₎ ⁺

Example 8 I C (E) -6- [2- (2-furanyl) ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 81B by the method of Example 1B.

156

Ή NMR (300 MHz, _DMSO- d) δ 6.61 (dd, 1H), 6.66 (d, IH), 7.19 (d, IH), 7.38 (d, IH), 7 77 (d, 1H); 7.80 (dd, 3H); 8.14-7.97 (m, 3H); 8.44 (s, 1H); 9.05 (s, 2H); 42 (s. 2H);

MS (DCI / NH 3) m / e 263 (M + H) ⁴

analysis; calculated for CnHi _? 0.1,2TFA N _2: C, 58.49, H, 3.85, N, 7.04. Found: C, 58.45; H 3.78, N 7.36.

Example 82 (E) -6- [2- (1H-imidazol-1-yl) ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 82A (E) -6- [2- (1H-imidazol-1-yl) ethenyl] -2-naphthalenecarbonitrile

The title compound was prepared from Example 55B and 1-vinyl imidazole according to the method of Example 42C.

MS (DCI / _NH3) m / e 263 (M + NH ₄₎ ^+.

Example 82B (E) -6- [2- (1H-imidazol-1-yl) ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 82B from Example 40D H NMR (300 MHz, _DMSO-ft) δ 9.44 (s, 2H), 9.14 (s, 2H), 8.15 (d, 1H), 8.17-8.05 (m, 4H), 7.93 (d, 1H), 7.14 (dd, 3H), 7.59 (s, 1H), 7.49 (d, IH) );

157

MS (DCI / NH 3) m / e 263 (M + H) +

Anal. Calcd HijN4.2,7TFA _least: 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) ethenyl] benzenesulfonamide mono (trifluoroacetate)

Example 83A

4-vinyl sulfonamide

A solution of thionyl chloride (7.5 mL) and 4-tert-butylcatachol (45 mg, 0.3 mmol) in DMF (9 mL) was treated at 0 ° C with 4-vinylbenzenesulfonic acid sodium salt (3 g, 14.6 mmol), the reaction mixture was stirred for 6 hours then allowed to stand at -10 ° C for 3 days, poured into ice water and extracted with benzene. The organic layer was washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated to give 4-vinylsulfonyl chloride as a clear, colorless oil. A portion of this chloride (1 g, 4.95 mmol) was dissolved in THF (10 mL), cooled to 0 ° C, treated dropwise with concentrated ammonium hydroxide until gas no longer escaped and then extracted with ethyl acetate. The combined extracts were dried (Na 2 SO 4) and concentrated to give 707 mg of the title compound as a pale yellow solid.

MS (DCI / NH 3) m / e 201 (Μ + ΝΗ ₄ ) ⁺ .

Example 83B (E) -4- [2- (6-Cyano-2-naphthalenyl) ethenyl] benzenesulfonamide

158

The title compound was prepared from the compound of Example 55B and the compound of Example 83A by the method of Example 57B.

MS (DCI / NH 3) m / e 352 (M + NH ₄ ) +

Example 83C (E) -4- [2- (6-Aminoiminomethyl-2-naphthalenyl) ethenyl] benzenesulfonamide mono (trifluoroacetate)

The title compound was prepared from Example 83B by the method of Example 40D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 9.43 (s, 2H), 9.05 (s, 2H), 8.46 (s, 1H), 8.21 (s, 1H), 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, 2 H);

MS (DCI / NH 3) m / e 352 (M + H) ⁺ .

Anal. Calcd for C 19 H ₁₇ N ₃ O ₂ S. 1.5C ₂ F ₃ O 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) ethenyl] benzoic acid mono (trifluoroacetate)

Example 84A (E) -4- [2- (6-Cyano-2-naphthalenyl) ethenyl] benzoic acid

The title compound was prepared from Example 55B and the acid

4-vinyl benzo by the method of Example 57B

159

MS (DCI / NH ₃ ) m / e 300 (M + H) &lt; ⁺ &gt; ^.

Example 84B (E) -4- [2- (6-Aminoiminomethyl-2-naphthalenyl) ethenyl] benzoic acid mono (trifluoroacetate)

The title compound was prepared from Example 84A by the method of Example 40D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 9.35 (bs, 2H);

MS (DCI / _NH3) m / e 317 (M + H) ^+.

Anal. Calcd for C ₂₀ H 16 N ₂ O ₂ .TFA · C 61.40, H 3.98; N, 6.51. Found: C, 61.10; H, 3.63; N, 6.45.

Example 85

4- [7- (aminoiminomethyl) -2-methoxy-1-naphthalenyl] dihydro-2 (3H) -furanone mono (trifluoroacetate)

Example 85A

4- (7-Cyano-2-methoxy-1-naphthalenyl) dihydro-2 (3H) -furanone

Example 62A (269 mg, 1.00 mmol) and pyridinium chlorochromate (360 mg, 1.67 mmol) in methylene chloride (15 mL) were stirred at room temperature for 24 h, then filtered through Celite ^R and concentrated. processing

The residue was chromatographed on silica gel with 20% ethyl acetate / hexanes to give 170 mg of the title compound.

MS (DC1 / _NH3) m / e 285 (M + NH ₄₎ ^+.

Example 85B

4- [7- (aminoiminomethyl) -2-methoxy-1-naphthalenyl] dihydro-2 (3H) -furanone mono (trifluoroacetate)

The title compound was prepared from Example 85A by the method of Example 40D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 2.96-2.75 (m, 2H), 3.96 (s, 3H), 4.33 (m, 1H), 4.66 (t, 1H), 8.85 (m, 1H), 7.68 (dd, 1H), 7.73 (d, 1H), 8.08 (d, 1H), 8.12 (d, 1H), 8, 67 (s, 1H); 9.14 (s, 2H); 9.43 (s, 2H);

MS (DCI / NH ₃ ) m / e 285 (M + H) &lt; ^{+ &gt};.

Anal. Calcd for C ₁₆ H ₁₆ N ₂ O ₃ .1.1TFA: C 53.72, H 4.24; N, 6.91. Found: C, 53.75; H, 4.26; N, 6.94.

Example 86

7-Methoxy-8- (1-acetyl-β-pyrazolyl) -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 86A

7-Methoxy-8- (1-acetyl-1H-pyrazolyl) -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.

161 (0.866 mL, 0.433 mmol), the reaction mixture was stirred for 5 min and then treated with acetyl chloride (38 mL, 0.542 mmol), stirred for 10 min and concentrated. Chromatography of the crude product on silica gel using 25% ethyl acetate / hexanes afforded 67 mg of the title compound.

MS (DCI / NH 3) m / e 309 (M + NH 4) ⁺ .

Example 86B

7-Methoxy-8- (1-acetyl-1H-pyrazolyl) -2-naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from 86A according to the method for example

40D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 3.89 (s, 3H), 7.59 (d, 1H), 7.92 (s, 1H), 8.06 (d, IH), 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) ⁺ .

For C17H16N4O3.1.9TFA: C, 47.59; H, 3.44; N, 10.67. Found: C, 54.03; H, 4.06; N, 13.26.

Example 87

7-Methoxy-8- [1- (methylsulfonyl) -1H-4-pyrazolyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 87A

7-Methoxy-8- [1- (methylsulfonyl) -1H-4-pyrazolyl] -2-naphthalene carbonitrile

162

The title compound was prepared from Example 53F (190 mg, 0.762 mmol) and methanesulfonyl chloride (0.088 mL, 1.14 mmol) by the method of Example 86A to yield 122 mg of the title compound.

MS (DCI / _NH3) m / e 345 (M + NH ₄₎ ^+.

Example 87B

7-Methoxy-8- [1- (methylsulfonyl) -1H-4-pyrazolyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 87A by the method of Example 40D.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 2.75 (s, 3H), 3.98 (s, 3H), 7.64 (dd, 1H), 7.78 (d, IH), 8 , 15 (s, 1H), 8.18 (s, 1H), 8.21 (s, 1H), 8.24 (s, 1H), 8.62 (s, 1H), 8.97 (s, 1H), 2H), 9.40 (s, 2H);

MS (DCI / _NH3) m / e 345 (M + H) ^+.

Analysis: Calculated for Ci6H _ID N ₄ O ₃ S. 1,4TFA: 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-Aminoiminomethyl-2-naphthalenyl) ethenyl] benzamide mono (trifluoroacetate)

Example 88A (E) -4- [2- (6-Cyano-2-naphthalenyl) ethenyl] benzamide

Example 85A (160 mg, 0.54 mmol) in thionyl chloride (4 mL) was heated at reflux for 0.5 h then cooled to room temperature.

163

OC, treated with concentrated aqueous ammonia until gas evolution ceased, diluted with ethyl acetate, warmed to dissolve the remaining solids, washed with water, dried (MgSO ₄ ) and concentrated to give 100 mg of the title compound as an orange solid. .

MS (DCI / NH 3) m / e 316 (M + NH ₄ ) +.

Example 88B (E) -4- [2- (6-Aminoiminomethyl-2-naphthalenyl) ethenyl] benzamide mono (trifluoroacetate)

The title compound was prepared from Example 88A by the method of Example 1B.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 7.34 (br, 1H), 7.51 (d, 1H), 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);

MS (DCI / NH ₃ ) m / e 316 (M + H) &lt; ^{+ &gt};.

For C20H17N3O.1.1TFA: C, 60.09; H, 4.11; N, 9.44. Found: C, 60.22; H, 4.13; N, 8.79.

Example 89

6- [2- (4-aminophenyl) ethoxy] -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 89A

6- [2- (4-aminophenyl) ethoxy] -2-naphthalenecarbonitrile

A solution of Example 4A (300 mg), Cs ₂ CO ₃ (1.2 g), 4-aminophenethyl bromide (470 mg) and tetrabutylammonium iodide (10 mg) in DMF (5

The organic extract was washed with saturated aqueous NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and concentrated to give 200 mg of the title compound as a dark brown oil. compound.

MS (DCI / _NH3) m / e 306 (M + NH ₄₎ +.

Example 89B

6- [2- (4-aminophenyl) ethoxy] -2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 89A by the method of Example 5B.

H NMR (300 MHz, _DMSO- d) δ 3.15 (t, 2H), 3.6 (bs, 3H), 4.35 (t, 2H), 6.93 (d, 2H), 7 24 (d, 2H), 7.38 (dd, 2H), 7.55 (d, 1H), 7.78 (dd, IH), 7.98 (dd, IH), 8.21 (d, 1H) 1H), 8.4 (d, 1H), 9.21 (bs, 2H), 9.39 (bs, 2H);

MS m / e 306 (M + H) &lt; ^{+ &gt};.

Analysis: Calculated for Ci9Hi ₉ N ₃ O.2TFA: C 51.79, H 3.97; N, 7.78. Found: C, 50.99; H, 4.68; N, 7.59.

Example 90

Methyl [3-methoxy-6- (aminoiminomethyl) -4-naphthalenyl] carbamate mono (tri fluoroacetate)

Example 90A

7-methoxy-2-trifluórmetánsuIfonyloxynaftalén

165

A solution of 7-methoxy-2-naphthol (3.24 g, 18 mmol) in DMF (20 mL) and methylene chloride (20 mL) was treated with N-phenyl-trifluoromethanesulfonimide (6.6 g, 18 mmol) and triethylamine (5 mL). , 2 mL, 37 mmol), stirred at room temperature for 20 h, then diluted with CH 2 Cl 2 (100 mL), washed sequentially with distilled water, 20% KOH and brine, and dried (MgSO ₄ ) and concentrated to give as a clear oil the title compound.

MS (DC1 / _NH?,): M / e 272 (M + NH ₄₎ ⁺

Example 90B

7-methoxy-2-naphthalenecarbonitrile

Example 90A (12 mmol), zinc cyanide (12 mmol), Pd (OAc) 2 (0.3 mmol) and triphenylphosphine (1.2 mmol) in DMF (40 mL) were heated at 85 ° C for 6 h, then the reaction mixture is diluted with ethyl acetate (200 mL), washed with saturated NaHCO 3, brine, dried (MgSO ₄ ), and concentrated to a dark oily residue. Purification of this residue on silica gel with hexane: methylene chloride 1: 1 then CH 2 Cl 2 gave 1.8 g of the title compound as a white solid.

MS (DCI / NH 3) m / e 201 (M + NH ₄ ) ⁺ .

Example 90C

7-methoxy-8-nitro-2-naphthalenecarbonitrile

Example 90B (3 g, 16.4 mmol) in acetic anhydride (30 mL) was treated with fuming FINO? (1.2 mL) and the resulting thick slurry was diluted with water (20 mL) then stirred for 20 minutes, filtered and dried in vacuo to give 3.69 g of the title compound as a yellow solid.

MS (DCI / NH 3) m / e 246 (M + NH ₄ ) +.

166

Example 90D

7-methoxy-8-amino-2-naphthonitrile

Example 90C (3.69 g, 16.1 mmol) and 10% Pd / C (0.4 g) in ethyl acetate (100 mL) was stirred under hydrogen atmosphere at room temperature for 2 hours, then the reaction mixture was filtered and concentration gave 3 g of the title compound as a yellow solid

MS (DCI / NH 3) m / e 217 (M + NH ₄ ) +

Example 90E

Methyl [3-methoxy-6-cyano-4-naphthalenyl] carbamate

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) and the reaction was stirred for 2 hours then diluted with ethyl acetate, washed with water, dried (MgSO 4) and concentrated to give 105 mg of the title compound.

MS (DCI / _NH3) m / e 274 (M + NH ₄₎ \

Example 90F

Methyl [3-methoxy-6- (amino) -4-naphthalenyl] carbamate mono (trifluoroacetate)

The title compound was prepared from Example 90E by the method of Example 40D.

1 H NMR (300 MHz, DMSO-d _c ) δ 9.48 (s, 2H), 8.99 (s, 2H), 8.93 (br, 2H), 8.34 (s, 1H), 8 12 (d, 1H), 8.04 (d, 1H), 7.72 (d, 1H), 7.65 (dd, 1H), 3.95 (s, 3H);

167

MS (DCI / NH 2) m / e 274 (MH +) -,

Analysis calculated for C 11 H 15 N 3 O 3. 1,8TFA; C 44.07, H 3.53; N, 8.74 Found. C, 44.14; H, 3.20; N, 8.53

Example 91

7-methoxy-8- [2-pyrimidinyl (amino)] - 2-Naphthalenecarboximidamide bis (trifluoroacetate)

Example 91A

7-methoxy-8- [2-pyrimidinyl (amino)] - 2-naphthalenecarbonitrile

A solution of Example 90D (230 mg, 1.2 mmol), 2-chloropyrimidine (280 mg, 2 mmol), sodium tert-butoxide (120 mg, 1.2 mmol), Pd (dba) 3.CHCl 3 and dppf in toluene (5 mL) was heated in a sealed tube at 100 ° C for 18 hours, then the contents of the tube were diluted with ethyl acetate (100 mL), washed with brine, dried (MgSO ₄ ) and concentrated to give 100 mg of a brown oil.

MS (DCI / NH 3) m / e 294 (M + NH ₄ ) ⁺ .

Example 91B

7-methoxy-8- [2-pyrimidinyl (amino)] - 2-Naphthalenecarboximidamide bis (trifluoroacetate)

The title compound was prepared in a manner similar to that described in the Example

40D H NMR (300 MHz, _DMSO-fi) δ 9.43 (s, 2H), 9.1 1 (s, 2H), 8.46 (s, IH), 8.16 (br, 3H) , 8.15 (d, 1H), 8.04 (d, 1H), 7.82 (dd, 1H), 7.75 (d, 1H), 7.54 (s, 1H), 7.50 (d, 1H); 4.08 (d, 2H);

168

MS (DCI / _NH3) m / e 294 (M + H) +.

Analysis calculated for C |,> S | O.3,8TFA 5 N _5. C 39.01, H 2.61; N, 9.64. Found C, 39.01; H, 3.06; N, 9.63.

Example 92

6- (amino) -N- [4- (hydroxymethyl) phenyl] -2-a naphthalene-mono (trifluoroacetate)

Example 92A

4-amino-benzyloxy-terc.butyIdimetylsilyléter

A solution of 4-aminobenzyl alcohol (1 g, 8.1 mmol) in DMF (20 mL) was treated with imidazole (0.54 g, 8.1 mmol) and tert-butyl dimethylsilyl chloride (1.22 g, 8.12 mmol). The reaction mixture was 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 from which Purification on silica gel with hexanes: ethyl acetate 3: 1 gave 0.5 g of a clear oil.

MS m / z 238 (M + H) ^&lt; ^{+ &gt};;

Example 92B

Example 92A (0.3, 1.1 mmol) and 6-carboxy-2-naphthonitrile, Example 8E (0.2 g, 1 mmol) were treated as in Example 95C to give 100 mg of the title compound. .

MS m / z 434 (M + NH ₄₎ +,

169

Example 92C

A solution of Example 92B in 1 M tetrabutylammonium fluoride in THF (2 mL) was stirred at room temperature for 1 h, then 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 (MgSO ₄ ) and concentrated to give a light brown oil which was triturated with methylene chloride and filtered to give 0.1 g of the title compound as a white solid.

MS m / z 320 (M + NH ₄ F;

Example 92D

6- (amino) -N- [4- (hydroxymethyl) phenyl] -2-a naphthalene-mono (trifluoroacetate)

Example 92C (0.1 g, 0.33 mmol) was treated and purified as in Example 95D to give 15 mg of the title compound.

MS m / z 320 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 10.45 (s, 1H), 9.45 (bs, 4H), 8.75 (s, 1H), 8.59 (s, 1H), 8 32 (d, 1H), 8.22 (d, 1H), 8.18 (dd, 1H), 7.92 (dd, 1H), 7.85 (d, 2H), 7.45 (d, 1H), 2H), 4.20 (s, 2H);

Anal. Calcd for C 19 H 17 N 3 O 2 TFA: C 58.20, H 4.19; N, 9.70. Found: C, 57.80; H, 3.91; N, 9.35.

Example 93

6- (4-aminophenyl) -2-Naphthalenecarboximidamide bis (trifluoroacetate)

170

Example 93A

6-Cyano-2-naphthaleneboronic acid (0.3 g, 1.64 mmol), 4-iodoaniline (0.36 g, 1.64 mmol), palladium [1,1'-bis (diphenylphosphino) ferrocene] dichloride (0.13 g, 0.164 mmol) and CsF (0.75 g, 4.92 mmol) were mixed together in DMF (8 mL) and the mixture was heated at 80 ° C for 20 h. The mixture was diluted with ethyl acetate (100 mL). , washed with 1 N H 3 PO 4, saturated NaHCl, 10% NaCl, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed in vacuo to give a brown solid residue. This solid residue was purified on silica gel using 3: 1 hexanes: ethyl acetate as eluent. The fractions corresponding to the desired compound were concentrated in vacuo to give a yellow solid residue. 0.2 g, 75%.

MS (M + _NH4) ^+; 262

Example 93B

6- (4-aminophenyl) -2-Naphthalenecarboximidamide bis (trifluoroacetate)

The title compound was obtained from the product prepared according to Example 93A (0.1 g, 0.41 mmol) using the method of Example 94D. yield; 35 mg, 53%.

MS (M + H) &lt; ^{+ &gt};262;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 9.45 (bs, 2H), 9.35 (bs, 2H), 8.45 (d, 1H), 8.22 (s, 1H), 8 15 (d, 1H); 8.10 (d, 1H); 7.99 (dd, 1H); 7.79 (dd, 1H); 7.65 (d, 2H); 6.95 (d, 1H); 2H), 4.80 (bs, 3H),

· Analysis calculated for C ₂ H ₇ N and _L, F ₆ O _6: C 51.54, H 3.50; N, 8.59. Found: C, 51.95; H, 3.84.

Example 95

171

Methyl 2- [4 - [[[6- (aminoimino-methyl) -2-naphthalenyl] carbonyl] amino] phenoxy] acetate mono (trifluoroacetate)

Example 95A

4-Acetamidophenol (5 g, 33 mmol) was dissolved in THF (100 mL) and treated with cesium carbonate (10.25 g, 33 mmol) and methyl bromoacetate (3.4 mL, 36 mmol) and the reaction mixture was stirred at room temperature. is stirred at room temperature for 24 hours. The reaction mixture was then diluted with water (100 mL) and concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with INH ₃ PO ₄ (20 mL), saturated NaHCO ₃ (20 mL), 10% NaCl (20 mL) and dried over Na ₂ SO ₄ . The desiccant is filtered off and the solvent is removed in vacuo to give the title compound as a white solid; 6.8 g (92%).

MS (M + NH ₄₎ ^+: 241

Example 95B

The product of Example 95A was treated with 2N HCl (75 mL) and heated at reflux for 3 hours. The clear mixture is then cooled to room temperature and concentrated in vacuo to give the title compound as an off-white solid; 6 g, 92%.

MS (M + _NH4) ^+: 198th

Example 95C

Dissolve 6-carboxy-2-naphthonitrile (0.1 g, 0.51 mmol) in DMF (5 mL) and cool to 5 ° C in an ice bath. Add diisopropylethylamine (0.18 mL, 1 mL) to the homogeneous mixture. 05 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexa-hexafluorophosphate (HATU). The resulting slurry was stirred for 45 mL at 5 ° C. To this slurry was added the product of Example 95B (0.12 g, 0.56 mmol) and the mixture was stirred overnight at room temperature. The next day, the reaction mixture was diluted with ethyl acetate (100 mL), washed with 1 NH ₃ PO ₄ (20 mL), saturated NaHCO ₃ (20 mL), 10% NaCl, dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated 0.28 g, 65% of the title compound are obtained as a brown solid.

MS (M + _NH4) ^+: 378th

Example 95D

Methyl 2- [4 - [[[6- (aminomethyl) -2-naphthalenyl] carbonyl] amino] phenoxy] acetate mono (trifluoroacetate)

The product prepared according to Example 95C (0.28 g, 0.78 mmol) was dissolved in methanol saturated with HCl (g) (30 mL) and the solution was stirred at room temperature for 18 hours. The solvent was then removed in vacuo and the resulting yellow solid was treated with 2 M NH ₃ / in methanol (20 mL). The solution was heated at reflux for 6 hours, then cooled, the solvent was removed in vacuo and the brown solid obtained was purified by reverse phase HPLC. The title compound is obtained after lyophilization; 19.3 mg, 20%.

MS (M + H) &lt; ^{+ &gt};378;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 10.45 (s, 1H), 9.45 (bs, 4Η), 8.65 (d, 1H), 8.59 (s, 1H), 8 15 (d, 1H); 8.10 (d, 1H); 8.08 (d, 1H); 7.92 (d, 1H); 7.75 (d, 2H); 6.98 (d, 1H); d, 2H), 4.80 (s, 2H), 3.75 (s, 3H);

Anal. Calcd for C ₂₃ H ₂₁ N ₃ O ₆ F ₃ · C 56.10; H 4.3; N, 8.53. Found: C, 55.80; H, 3.93; N, 8.33.

Example 96

173 (E) -6- [2 - [(3-hydroxymethyl) phenyl] ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 96A

The compound of Example 96A was prepared from 3-iodobenzyl alcohol by the method of Example 41A.

MS (DCI / NH 3) m / z (M + NH ₃ ) - 303

Example 96B (E) -6- [2 - [(3-hydroxymethyl) phenyl] ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

The above compound was prepared from Example 96A by the method of Example 40D.

MS (DCI / NH ₃ ) m / z (M + H) ⁺ 303 1 H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 7.57 (d, 2H), 7.51 (d 1 H, 7.39 (t, 1H), 7.28 (d, 1H), 5.27 (t, 1H), 4.55 (d, 2H);

Analysis: Calculated for C ₂₂ H | ₉ N ₂ O ₃ F ₃ .3 / 10TFA: C 60.64; H, 4.35; N, 6.28. Found: C, 60.53; H, 4.87; N, 6.57

Example 97

6- (2-Phenyl-1-cyclopropyl) -2-naphthalenecarboximidamide mono (trifluoroacetate)

174

Example 97A

Copper (I) chloride (43 mg, 0.4 mmol), zinc powder (26 mg, 0.4 mmol) were suspended in 1 mL dioxane for 18 h. The product of Example 41B (60 mg, 0.2 mmol) was then added and the reaction mixture was stirred at 95 ° C for 20 h. The reaction mixture was then concentrated on silica gel and purified on silica gel to give the title compound

MS (DCI / NH 3) m / z (M + NH 3/287).

Example 97B

6- (2-phenyl-1-cyclopropyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 1 by the method of Example 1B.

MS (DCI / NH 3) m / z (M + _NH?) ⁺ 287th

1 H NMR (300 MHz, DMSO-d ₆ ) δ 9.41 (s, 2H), 9.16 (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) 1.38-2.28 (m, 2H), 1.61 (t, 2H);

Calcd for C22H19N2O2F3.1 / 10TFA: C, 65.00; H, 4.70; N, 6.84. Found: C, 65.22; H, 5.23; N, 5.10.

Example 98 (E) -6- [2- [4- (Aminomethyl) phenyl] ethenyl] -2-naphthalenecarboximidamide bis (trifluoroacetate)

Example 98A

175

The title compound was prepared using 500 atm of ethene in a manner similar to that of Example 41A.

MS (DCI / NH ₃ ) m / z (M + NH 3) + 197.

Example 98B

4- (Aminomethyl) iodobenzene hydrochloride (1 g, 3.7 mmol) and Boe anhydride (1.22 g, 5.6 mmol) were mixed with 10% NaOH (15 mL) and ethyl acetate, and the reaction mixture was stirred for 2 hours. hours. The organic layer was washed with 5% sodium bicarbonate (2 x 10 mL), dried (magnesium sulfate) and concentrated to give 1.22 g of the title compound.

MS (DCI / NH 3) m / z (M + NH ₃ ) ⁺ 351

Example 98C

The title compound was prepared from the products of Examples 98a and 98B in a manner similar to that of Example 41A.

MS (DCI / NH 3) m / z (M + NH 3) ⁺ 402.

Example 98D (E) -6- [2- [4- (Aminomethyl) phenyl] ethenyl] -2-naphthalenecarboximidamide bis (trifluoroacetate)

The above compound was prepared in a manner similar to that in Example 40D using trifluoroacetic acid in methylene chloride to remove the Boe group.

MS (DCI / NH 3) m / z (M + H) ⁺ 302,

176 @ 1 H NMR (300 MHz, DMSO-d6) .delta. 9.43 (s, 2H), 9.11 (s, 2H), 8.46 (s, 1H), 16.16 (br, 3H) 8.15 (d, 1H), 8.04 (d, IH), 7.82 (dd, IH), 7.75 (d, IH), 7.54 (s, IH), 7.50 (d) 1 H, 4.08 (d, 2H);

Anal. Calcd for C ₂₁ H 21 N ₃ O ₄ F ₆ 2 / 5TFA: C 50.46; H, 3.63; N, 6.99. Found: C, 50.37; H, 3.86; N, 7.05

Example 99

Methyl [7- (aminoiminomethyl) -2-methoxy-1-naphthalenyl) carbamate mono (trifluoroacetate)

The title compound was prepared from the product of Example 90D by the methods described in Examples 91A and 40D.

MS (DCI / _NH3) m / z (M + H) ⁺ 306 H NMR (300 MHz, _DMSO- d) δ 9.33 (s, 2H), 8.98 (s, 2H), 8 63 (s, 1H), 7.99 (d, IH), 7.60 (dd, IH), 7.58 (s, IH), 7.54 (d, IH), 7.35-7, 20 (m, 5H); 4.52 (s, 2H);

Calcd for C21H20N3O3F3.13 / 5TFA: 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-pyrimidinyl) -2-Naphthalenecarboximidamide bis (trifluoroacetate)

The title compound was prepared from the product of Example 90D by the methods described in Examples 91A and 40D.

MS (DCI / NH 3) m / z (M + H) + 322,

177 1 H NMR (300 MHz, DMSO-d 6) δ 9.35 (s, 2H), 8.90 (s, 2H), 8.34 (s, 1H), 8.11 (d, 1H) , 7.90 (d, 1H), 7.72 (d, 1H), 7.60 (dd, 1H), 7.47 (s, 2H), 6.70 (d, 2H), 6.49 (s) d, 2H), 3.88 (s, 3H), 3.64 (s, 3H),

Analysis: Calculated for C ₂ | H ₂ "N ₃ O4F3.1 / 10TF: C 56.90; H, 4.53; N, 9.38. Found: C, 56.88; H, 4.41; N, 9.43

Example 101

7-methoxy-8 - [(phenylmethyl) amino] -2-naftaIénkarboximidamid mono (trifluoroacetate)

Example 101A

4-Bromo-styrene (4.8 g, 26.2 mmol) was dissolved in 100 mL THF and cooled to -78 ° C. Butyllithium (2.5 M in hexanes, 28.8 mmol) was added dropwise and the reaction stirred for 5 minutes. Then iodine in THF is added dropwise until the orange / red color persists. Concentrated aqueous ammonium chloride (20 mL), the mixture was warmed to room temperature, diluted with ether, washed with 10% aqueous Na ₂ S ₂ 0j (1 x 50 mL), brine (1 x 50 mL), dried (magnesium sulfate) and concentration to give the title compound.

MS (DCI / NH ₃ ) m / z 122;

Example 101 B

The product prepared according to Example 104A (2.35 g, 10.2 mmol), a solution of N-methylmorpholinine N-oxide / water (1.6 mL, 60%), acetone (3.75 mL) and 0.1 mL of water were stirred 1 hour. A solution of osmium tetroxide in tert-butanol (0.02 mmol / ml) was then added and the reaction mixture was stirred at 0 ° C for 20 hours. The reaction mixture is concentrated on silica gel and purified on silica gel to give the title compound.

178

MS (DCI / NH 3) m / z (M + NH 2) + 282.

Example 101C

The title compound was prepared from Example 104B by coupling in the manner of Example 41A

MS (DCI / NH 3) m / z (M + NH ₃ ) + 333.

Example 101D

7-Methoxy-8- [(phenylmethyl) amino] -2-naphthalenecarboximidamide mono (trifluoroacetate)

The above compound was prepared from Example 104C by the method of Example 40D.

MS (DCI / NH 3) m / z (M + H) ⁺ 333;

1 H NMR (300 MHz, DMSO-d 6) δ 9.42 (s, 2H), 9.12 (s, 2H), 8.45 (s, 1H), 8.15-8.05 (m, 4H) ), 7.81 (dd, 1H), 7.63 (d, 2H), 7.48 (d, 1H), 7.39 (d, 2H), 4.56 (t, 1H), 3.45 (d, 2H);

Calcd for C23H21N2O4F3.2 / 5TFA: C, 58.19; H, 4.39; N, 5.71. Found: C, 58.17; H, 4.41; N, 5.87.

Example 102

7-methoxy-8- (fenylainino) -2-naftalénkai'boximidamid mono (trifluoroacetate)

Example 102A

179

Tert-butyl carbamate (3.62 g, 15.7 mmol) was dissolved in 63 mL of propanol, and 118 mL of a NaOH / water solution (0.4 N), tert-butylcloronate (5.5 mL, 47.8 mmol) was added. ) and (DHQD) ₂ PHAL (612 mg, 0.61 mmol) in 50 mL of propanol and stirred for 10 minutes. The product prepared according to Example 2 (3.62 g, 15.7 mmol) and K ₂ OsO ₄ dihydrate (21 L mg, 0.63 mmol) were then added and the reaction mixture was stirred for 24 hours. The reaction mixture is concentrated and recrystallized from ethanol / hexanes to give the title compound.

MS (DC1 / _NH3) m / z (M + NH ₃₎ ⁴ 38 1st

Example 102B

This compound was prepared from Example 102 following the procedure of Example 41A

MS (DCI / NH ₃ ) m / z (M + H) &lt; ^{+ &gt;} 415

Example 102C

7-methoxy-8- (phenylamino) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

The above compound was prepared from Example 102B by the method of Example 94D.

MS (DCI / NH ₃ ) m / z (M + H) &lt; ^{+ &gt;} 264.

H NMR (300 MHz, _DMSO-fi) 5 9.42 (s, 2H), 9.07 (s, 2H), 8.45 (s, IH), 8.33 (br, 3H), 8 6-8.03 (m, 4H), 7.75 (d, 2H), 7.56 (s, 2H), 7.49 (d, 1H), 5.49 (br, 1H), 4, 28 (br, 1H); 3.62 (m, 2H);

· Analysis calculated for C ₂₃ Jl ₂ N ₃ O ₅ Fň.5TFA C 37.30; H, 2.51; N, 3.74. Found: C 37.06, H 3.12; N, 4.42.

180

Example 103

7-methoxy-8 - [(4-methoxyphenyl) amino] -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 103A

4-Bromobenzaldehyde (600 mg, 3.24 mmol), 16.2 mL of 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 and acidified to pH = 2 and extracted with ether (3 x 20 mL). The aqueous solution was basified with NaOH / water to pH = 12 and extracted with methylene chloride (3 x 30 mL), acidified with HCl / methanol and concentrated to give the title compound.

MS (DCI / NH 3) m / z (M + H) ⁺ 214.

Example 103B

The compound of the above example was prepared from the compound of Example 107A by the method of Example 41A.

MS (DCI / _NH3) m / z (M + H) ⁺ 313

Example 103C

7-methoxy-8 - [(4-methoxyphenyl) amino] -2-Naphthalenecarboximidamide mono (trifluoroacetate)

The above compound was prepared from the compound of Example 103 by the method of Example 40D.

MS (DCI / NH ₃ ) m / z (M + H) + 294;

181 1 H-NMR (300 MHz, DMSO-d 6) δ 9.43 (s, 2H), 9.1 L (s, 2H), 8.46 (s, 1H), 8.18-8.06 ( m, 4H), 7.84 (d, 4H), 7.60 (s, 2H), 7.56 (s, 1H), 4.53 (s, 2H), 3.05 (s, 6H),

analysis; calcd for C26H25N3O4F6.7 / 5TFA. C, 48.46; H, 3.73; N, 5.91. Found: C, 48.36; H, 4.25; N, 6.19

Example 104 (E) -6- [2- [4- (1,2-dihydroxyethyl) phenyl] ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 104A

The compound of this example was prepared from 4-bromobenzyl alcohol and the compound of Example 98A by the method of Example 41A.

MS (DCI / NH ₃ ) m / z (M + NH ₃ ) ⁺ 303;

Example 104B (E) -6- [2- [4- (1,2-dihydroxyethyl) phenyl] ethenyl] -2-naphthalenecarboximido-mono (trifluoroacetate)

The above compound was prepared from Example 104A by the method of Example 40D

MS (DCI / NH ₃ ) m / z (M + H) + 303;

1 H-NMR (300 MHz, DMSO-d 6) δ 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, 1H), 7.36 (d, 2H), 5.21 (br, 1H), 4.53 (s, 2H);

182

Calcd for C22H19N2O3F3.4 / 5TFA: C, 55.84; H, 3.93; N, 5.52. Found - C 55.60, H 3.93; N, 6.41

Example 105 (E) -6- [2- [4- (1 R-Amino-2-hydroxyethyl) phenyl] ethenyl] -2-naphthalenecarboximidamide bis (trifluoroacetate)

Example 105A

Said compound was prepared according to the method of Example 121A, wherein

4-Iodoaniline is replaced with N-BOC-β-iodophenylalanine (BACHEM Bioscience Inc.)

MS (DCI / _NH3) m / z 458 (M + _NH4) ^+;

1 H-NMR (300 MHz, DMSO-d 6) δ 1.35 (s, 9H), 2.90 (t, 1H), 3.09 (dd, 1H), 4.15 (m, 1H), 7 20 (d, 1H); 7.36 (d, 2H); 7.56 (d, 2H); 7.78 (d, 1H); 7.85 (d, 1H); 8.12 (d, 1H); 1H), 8.17 (d, 1H), 8.32 (s, 1H), 8.62 (s, 1H).

Example 105B

The title compound was prepared from the product prepared according to Example 105A by the method of Example 40D

MS (ESI) mlz 458 (M + H) +;

1 H-NMR (300 MHz, DMSO-d ₆ ) δ 1.35 (s, 9H), 2.90 (dd, 1H), 3.10 (dd, 1H), 4.13 (m, 1H), 7.10 (d, 1H), 7.36 (d, 2H), 7.55 (d, 2H), 7.78 (dd, 1H), 7.85 (dd, 1H), 8.13 (d) 1 H, 8.19 (d, 1 H), 8.30 (s, 1 H), 8.50 (s, 1 H), 9.22 (s, 2 H), 9.42 (s, 2 H).

183

Example 105C (E) -6- [2- [4 '(1R-Amino-2-hydroxyethyl) phenyl] ethenyl] -2-naphthalenecarboximidamide bis (trifluoroacetate)

The title compound was prepared from the product of Example 105B by the method of Example 124D.

MS (ESI) m / z 358 (M + H) ⁺ , 1 H-NMR (300 MHz, DMSO-d 6) δ 3.02 (m, 1H), 3.19 (dd, 1H), 3.63 ( t, 1H), 7.39 (d, 2H), 7.58 (d, 2H), 7.76 (d, 1H), 7.88 (d, 1H), 8.15 (d, 1H), 8.19 (d, 1H); 8.30 (s, 1H); 8.51 (s, 1H); 9.41 (s, 2H); 9.80 (s, 2H);

Calcd for C24H20F3N3O4.H2O: C 58.90; H, 4.53; N, 8.59. Found: C, 58.75; H, 4.22; N, 8.28.

Example 106

7-methoxy-8- (2-pyrimidinyl) -2-Naphthalenecarboximidamide bis (trifluoroacetate)

Example 106A

To a suspension of (4-bromobenzoyl) methanol (2.5 g, 11.6 mmol), Maybridge Chem.Co) in 25 mL absolute ethanol was added sodium borohydride (0.22 g, 5.8 mmol). The reaction mixture was stirred at reflux for 1 hour. After cooling to room temperature, the ethanol was evaporated in vacuo and water was added to the residue. This mixture is extracted with CH ₂ Cl ₂ The extracts are washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and evaporated in vacuo to give the title compound.

MS (DC 1 / NH ₃ ) m / z 234/236 (Μ + ΝΗ ₄ ) ',

184 1 H NMR (300 MHz, CDCl 3) δ 2.10 (t, 1H), 2.62 (dm IH), 3.63 (m, 1H), 3.78 (m, IH), 4, 81 (m, 1H); 7.25 (d, 2H); 7.50 (d, 2H)

Example 106B

The title compound was prepared from the product of Example 106A and by the method of Example 226218-A.

MS (DCI / _NH3) m / z 331 (M + _NH4) +;

1 H-NMR (300 MHz, CDCl 3)? Δ 3.45 (t, 1H), 4.59 (q, 1H), 4.76 (t, 1H), 5.36 (d, 1H), 7 42 (d, 2H), 7.59 (d, 2H), 7.78 (dd, 1H), 7.85 (dd, 1H), 8.10 (d, 1H), 8.15 (d, 1H), 1H), 8.30 (s, 1H), 8.61 (s, 1H).

Example 106C

7-methoxy-8- (2-pyrimidinyl) -2-Naphthalenecarboximidamide bis (trifluoroacetate)

The title compound was prepared from Example 106B by the method of Example 40D.

MS (ESI) mlz 331 (M + H) ⁺ ;

1 H-NMR (300 MHz, DMSO) δ 3.45 (t, 1H), 4.59 (q, 1H), 4.78 (t, 1H), 5.38 (d, 1H), 7.42 (d, 2H), 7.59 (d, 2H), 7.78 (dd, 1H), 7.84 (dd, 1H), 8.12 (d, 1H), 8.18 (d, IH) 8.31 (s, 1H), 8.50 (s, 1H), 9.20 (s, 2H), 9.43 (s, 2H);

Calcd for C 21 H 19 F 3 N 2 O 4 .H 2 O C 59.74; H, 4.58; N, 6.06. Found: C, 59.95; H, 4.17; N, 6.13

Example 107

185 (E) -6- [2 - [[4- (dimethylamino) methyl] phenyl] ethenyl] -2-naphthalenecarboximidamide bis (trifluoroacetate)

Example 107A

The title compound was prepared according to the method of Example 121A using 3-benzyloxybromobenzene (Chem. Ber. 124 (1), 163, 1991) instead of 4-iodoaniline.

MS (DCI / _NH3) m / z 337 (M + _NH4) ^+;

1 H-NMR (300 MHz, CDCl ₃ ) δ 5.11 (s, 2H), 7.02 (d, 1H), 7.20 (m, 2H),

7.29 (d, 1H); 7.31 (d, 1H); 7.42 (m, 3H); 7.60-7.75 (m, 1H); 7.89 (t, 2H); , 08 (s, 1H), 8.21 (s, 1H).

Example 107B (E) -6- [2 - [[4- (dimethylamino) methyl] phenyl] ethenyl] -2-naphthalenecarboximidamide bis (trifluoroacetate)

The title compound was prepared from Example 108B by the method of Example 40D.

MS (ESI) m / z 377 (M + H) &lt; + &gt;;

1 H-NMR (300 MHz, DMSO) δ 5.18 (s, 2H), 7.12 (dd, 1H), 7.22 (d, 1H), 7.28 (m, 1H), 7.40 (t, 3H), 7.45 (t, 3H), 7.79 (dd, 1H), 7.85 (dd, 1H), 8.16 (d, 1H), 8.20 (d, 1H) 8.35 (s, 1H); 8.50 (s, 1H); 9.30 (s, 1H);

Analysis: Calculated for C k H _{2 2} | F ₃ N ₂ O ₃ .0,25H ₂ O: C, 67.94; H, 4.38; N, 5.66. Found: C 67.80, H 4.48; N, 5.43.

186

Example 108 (E) -6- [2- [4- (hydroxymethyl) phenyl] ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from Example 108A by the method of Example 94D

MS (ESI) mlz 287 (M + H) ⁺ ;

H H-NMR (300 MHz, DMSO) δ 6.89 (m, 1H), 6.98 (t, 1H), 7.03 (d, 1H),

7.29 (t, 1H), 7.78 (dd, IH), 8.13 (d, IH), 8.17 (d, IH), 8.32 (s, 1H), 8.50 (s) 1 H, 9.40 (s, 5H);

Analysis: Calculated for C ₂ iHi5F3N O3.0,5H ₂ O _2: C, 61.62; H, 3.94; N, 6.84. Found: C, 61.29; H, 3.81; N, 6.59.

Example 109

4 - [[6- (amino) -2-naphthalenyl] ethynyl] -L-phenylalanine, mono (trifluoroacetate)

Example 109A

To a solution of the product prepared according to 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 THF was distilled off in a short path distillation. The mixture was heated at 70 ° C for 2 hours, cooled, quenched with 1 M HCl and extracted twice with ethyl acetate. The extracts were washed with water and brine, dried with Na ₂ SO ₄ and concentrated. The crude product was chromatographed on SiO ₂ using 50% ethyl acetate / hexanes as eluent to yield 1.12 g (61%) of the title compound.

MS (DCI / NH 3) m / z 201 (M + NH ₄ ) +,

187 1 H-NMR (300 MHz, CDCl 3) δ 8.22 (s, 1H), 7.90 (m, 3H), 7.61 (m, 2H), 4.92 (d, 2H), 1, 84 (t, 1H).

Example I09B

To a solution of the product of Example 109A (2.12 g, 11.57 mmol) and LiBr (1.11 g, 12.73 mmol) in DMF (100 mL) at 0 ^° C was added PBr ₃ (1.21 mL, 12.73 mmol) and the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was then quenched with pH 7 buffer and extracted 3 times with diethyl ether / hexanes. The extracts were washed twice with water, twice with brine, dried over Na ₂ SO ₄ and concentrated to give 2.72 g (96%) of the title compound.

MS (DCI / NH ₃ ) m / z 185 (M + NH _{4. Br} ) ⁺ ;

1 H-NMR (300 MHz, CDCl ₃ ) δ 8.22 (s, 1H), 7.92 (s, 1H), 7.90 (s, 2H), 7.62 (dd, 2H), 4, 64 (s, 2 H).

Example 109C

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 mixture was stirred at room temperature for 20 minutes. Example 109B (270 mg, 1.1 mmol) was then added and the reaction stirred for 10 minutes. Chromatography of the crude reaction mixture on SiO ₂ using hexanes as eluent gave 220 mg (77%) of the title compound.

MS (DCI / NH ₃ ) m / z 305 (M + NH ₄ ) ⁺ , 1 H-NMR (300 MHz, CDCl 3) δ 8.22 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.91 (s, 1H), 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).

188

Example I09D

4 - [[6- (amino) -2-naphthalenyl] ethynyl] -L-phenylalanine, mono (trifluoroacetate)

The title compound was prepared from Example IO9C by the method of Example 55D.

MS (DCI / NH ₃ ) m / z 305 (M + H) +, 1 H-NMR (300 MHz, DMSO-d ₆ ) δ 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);

Anal. Calcd for C 21 H ₂₀ N ₂ O. 1.4CH ₄ SO 3: C 58.56; H, 5.88; N, 6.38. Found: C, 58.55; H, 5.56; N, 6.39

Example 111

6- (3-formylphenyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 111A

The product prepared according to Example 28B (334, 1.1 1 mmol), palladium acetate (25 mg, 0.11 mmol) and dppf (123 mg, 0.22 mmol) was dissolved in degassed DMF (5 mL) and stirred 1 / 2 hours at room temperature. Cesium carbonate (902 mg, 2.8 mmol) and 2-formylphenylboronic acid (251 mg, 1.27 mmol) were then added, and the reaction mixture was stirred under nitrogen at 80 ° C for 1 hour, then poured into pH 7 buffer. , extracted with diethyl ether (3 x 20 mL) and dried. The desired compound was purified by chromatography using 10% ethyl acetate / hexanes

MS (DCI / NH 3) m / z 275 (M + NH ₃ ) ⁺ ,

189

Example 1 1 I B

6- (3-formylphenyl) -2-naftalénkarboxiniidamid mono (trifluoroacetate)

The above compound was prepared in a manner similar to that described in Example IB.

MS (DCI / NH ₃ ) m / z (M + H) + 274, 1 H-NMR (300 MHz, DMSO-d 6) δ 10.16 (s, 1H), 9.47 (s, 2H), 9.10 (s, 2H); 8.54 (s, 1H); 8.52 (s, 1H); 8.41 (s, 1H); 8.28-8.23 (m, 3H); 12 (dd, 1H), 8.00 (dd, 1H), 7.87 (dd, 1H), 7.80 (t, 1H);

Analysis: calculated for C ₂₀ H ₅ N ₂ O ₃ F ₃ • ₂ / 5TFA: C 59.28; H, 3.70; N, 6.34. Found: C, 59.36; H, 3.89; N, 7.21.

Example 112 (E) -6- [2- (1,2,3,4-tetrahydro-6-isoquinolinyl) ethenyl] -2-naphthalenecarboximidamide bis (trifluoroacetate)

Example 112A

The title compound was prepared from Example 127 following the procedure of Example 41 A.

MS (DC1 / _NH3) m / z (M + H) * 4 11;

Example 1 12B (E) -6- [2- (1,2,3,4-tetrahydro-6-isoquinolinyl) ethenyl] -2-naphthalenecarboximidamide bis (trifluoroacetate)

190

The title compound was prepared as described in Example 40D.

MS (DC1 / _NH3) m / z (M + H / 328, H-NMR (300 MHz, _DMSO-d) δ 9.36 (s, 2H), 9.25 (s, 2H), 9 10 (d, 2H); 8.41 (s, 1H); 7.99 (t, 2H); 7.89 (d, 1H); 7.78 (d, 1H); 7.71 (dd, 1H); 1H), 7.56 (m, 4H), 7.43 (s, 1H), 3.11 (br, 2H), 2.16 (br, 2H), 1.78 (br, 2H);

Analysis: calculated for C26H23N3O4F6.3 / 5TFA. C, 52.31; H, 3.81; N, 6.72. Found. C, 52.13; H, 4.42; N, 7.23.

Example 113 (E) -6- [2- [3- (2-hydroxyethyl) phenyl] ethenyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 113A

The title compound was prepared from 2-bromo-3- (hydroxyethyl) -alcohol and the compound prepared according to Example 98A by the method of Example 41A.

MS (DCI / NH ₃ ) m / z (M + NH ₃ ) ⁺ 317;

Example 113 (E) -6- [2- [3- (2-Hydroxyethyl) phenyl] ethyl] -2-naphthalecarboximidamide mono (trifluoroacetate)

The above compound was prepared from Example 11A by the method of Example 40D.

MS (DC1 / _NH) m / z (M + H) * 17 3;

191 H-NMR (300 MHz, _DMSO-fi) δ 8.9 (br, 4H), 8.46 (s, IH), 8.17 (s, IH), 8.13-8.03 ( m, 3H), 7.82 (dd, 1H), 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);

Calcd for C23H21N2O3F3.3 / 10 OTFA: C, 61.41; H, 4.66; N, 6.09. Found: C, 64.18; H, 4.92; N 6.5 1

Example 1 I 4

6- (amino) -4- (3-furanyl) -N- [4- (trifluoromethyl) phenyl] -2-a naphthalene-mono (trifluoroacetate)

Example I

The product prepared according to 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 the reaction mixture is stirred for 24 hours. The reaction mixture was concentrated on silica gel and purified by chromatography (Biotage Flash 40) using ethyl acetate / hexanes.

MS (ESI) mlz (M + H) ⁺ 406;

Example 114B

6- (aminoiminomethyl) -4- (3-furanyl) -N- [4- (trifluoromethyl) phenyl] -2-a naphthalene-mono (trifluoroacetate)

The above compound was prepared from Example 11A by the method of Example IB.

MS (Cl) m / z (M + H) &lt; ^{+ &gt};424;

192 1 H-NMR (300 MHz, DMSO-d 6) δ 10.91 (s, 1H), 9.51 (s, 2H), 9.1 L (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, 1H);

Calcd for C25H17N3O4F6.1 / 10TFA: C 55.37, H 3.15; N, 7.70. Found: C, 55.44; H, 3.15; N, 7.31

Example 1 1 5

6- (aminoiminomethyl) -4- (3-furanyl) -N- (4-pyridinyl) -2-naphthalenecarboxamide dihydrochloride

Example 115A

The above compound was prepared by the method of Example 114A.

MS (ESI) mlz (M + H) ⁺ 340.

Example 115B

6- (aminoiminomethyl) -4- (3-furanyl) -N- (4-pyridinyl) -2-naphthalenecarboxamide hydrochloride

The above compound was prepared from Example 115A by the method of Example IB.

MS (AP / CI) m / z (M + H) ⁺ 357 H-NMR (300 MHz, _DMSO-fi) δ 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, 1H), 7.97-7.95 (m, 2H), 7.27 (s, 1H);

193

Calcd for C21H18N4O2Cl2.37 / IOHCl: C, 44.65; H, 3.88; N 9.92 Found: C 44.72, H 3.70, N 9.5 1.

Example 1 16

6- (aminoiminomethyl) -4- (3-furanyl) -N- (1H-pyrazol-3-yl) -2-naphthalenecarboxamide dihydrochloride

Example 116A

The compound of the above example was prepared by the method of Example 114A.

MS (ESI) mlz (M + H) ⁺ 329

Example 1 16B

6- (amino) -4- (3-furanyl) -N- (lH-pyrazol-3-yl) -2-naftalénkarboxamiddihydrochlorid

The above compound was prepared from Example 116A by the method of Example IB.

MS (CI) m / z (M + H) &lt; ^{+ &gt};344;

1 H-NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 7.96-7.88 (m, 3H), 7.69 (m, 1H), 7 15 (s, 1H); 6.69 (m, 1H);

Calcd. For C21H17N5O2Cl2.9 / 1 OHCl: C, 50.63; H, 4.00; N, 15.54. Found: C, 5.05; H, 4.62; N, 14.26.

194

Example 1 1 Ί

6- (amino) -4- (3-furanyl) -N- (3-pyridinyl) -2-naftalénkarboxamiddihydrochlorid

Example 1 17A

The above product was prepared by the method of Example 114A.

MS (ESI) mlz (M + H) ⁺ 340;

Example 117B

6- (amino) -4- (3-furanyl) -N- (3-pyridinyl) -2-naftalénkarboxamiddihydrochlorid

The above compound was prepared from Example 117B by the method of Example IB.

MS (CI) m / z (M + H) &lt; ^{+ &gt};357;

1 H-NMR (300 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.59 (s, 2H), 9.26 (s, 2H), 9.03 (s, 2H), 8.74 (s, 1H), 8.63 (s, 1H), 8.42-8.26 (m, 3H), 8.22 (s, 1H), 7.97-7.91 (m, 2H), 7.47-7.43 (m, 2H), 7.17 (m, 1H);

Calcd for C21HlN4O2Cl2 55 / 10HCl; C 40.00; H, 3.76; N, 89. C, 40.09; H, 3.78; N, 8.44.

Example 118

6- (Aminomethyl) -N- (2,3-dihydro-1H-inden-5-yl) -2-naphthalenecarboxamide mono (trifluoroacetate)

195

Example I 18A

To a solution of 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 5-aminoindene (300 mg, 2.2 mmol). The reaction mixture was stirred overnight at room temperature. Then the solvent was evaporated and the product was purified by crystallization from ether to yield 226 mg (56%) of the purified product as a white solid.

Mass spectrum (CI +), 3113 (M + 1) +.

Example 1 1 8B

6- (aminoiminomethyl) -N- (2,3-dihydro-1H-inden-5-yl) -2-naphthalenecarboxamide mono (trifluoroacetate)

To the compound prepared according to Example 118A (205 mg, 0.66 mmol) in THF (20 mL) at room temperature was added butyllithium (1 mL, 1 mmol) followed by chlorotrimethylsilane (180 μΐ, 1.5 mmol). After 10 minutes, additional butyllithium (3 mL, 3 mmol) was added to the mixture. The reaction mixture was then stirred overnight at room temperature. Then a solution of 4 N HCl in dioxane was added to the reaction mixture, the mixture was stirred for one hour, and then water was added and the mixture was evaporated. The product was purified by MPLC RPC, eluting with methanol-water and 0.1% TFA. Obtained as a white solid as a TFA salt with 0.25% water in a yield of 51 mg (17%).

MS (ESI +), 330 (M + 1) ^&lt; ^{+ &gt};;

1 H-NMR (300 MHz, DMSO-d ₆ ) δ 10.45 (s, 1H), 9.51 (s, 2H), 9.21 (s, 2H), 8.66 (s, 1H), 8.55 (s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.20 (Abq, J = 9.0 Hz, 2H), 7.90 (dd, J, = 9.0 Hz, J ₂ = 1.5 Hz, 1H), 7.73 (s, IH), 7.53 (dd, J = 8.0 Hz, J ₂ = 1.5 Hz, IH), 7.22 (d, J = 8.1 Hz, 1H), 2.91-2.82 (m, 4H), 2.04 (quintet, J = 7.3)

Hz, 2H);

196

9.38

Anal. Calcd for C 21 H 16 N ₃ O • TFA 0.25H ₂ O: C 61.67, H 4.61; N Found: C 61.63; H, 4.43; N, 9.25.

Example 119

Methyl-5- [7 - [(amino) -2-naphthalenyl] oxy] pentanoate mono (trifluoroacetate)

Example 119A

7-hydroxy-2-cyano-naphthalene

7-Methoxy-2-cyano-naphthalene (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 stirred, cooled (ice / water) suspension of aluminum iodide (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 reflux for 2.5 hours. The heating was then removed and after cooling to near room temperature, the reaction mixture was cooled in an ice bath and quenched with water (100 mL). The resulting mixture was further diluted with 2M aqueous sodium thiosulfate solution (50 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were dried and evaporated. The solid obtained was dissolved in a minimum amount of hot ethyl acetate, diluted with hot hexanes until turbid, and placed in a refrigerator for 2 hours. The desired compound was then collected by filtration, (1.99 g, 77%).

MS (DCI _(NH3)) m / z 187 (M + NH ₄₎ \

Example I 19B

The product prepared according to Example 11A was treated with methyl 5-bromovalerate in a manner similar to that described in Example 11A.

197

MS (DC1 (NH ₃₎₎ m / z 301 (M + _NH4) '

Example 1 19C

Methyl-5- [7 - [(amino) -2-naphthalenyl] oxy] pentanoate mono (trifluoroacetate)

The product of Example 119B (380 mg, 1.3412 mmol) was treated in a manner similar to that described in Example 94D to give the title compound (369 mg, 73%).

MS (DCI (NH ₃ )) m / z 301 (M + H) ^&lt; ^{+ &gt};;

1 H-NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 7.980 (d, 1H), 8.070 (d, 1H), 8.322 (d, 1H), 9.230 (in br s, 3H);

Calcd for C17H20N2O3.C2HO2F3: C, 55.07; H, 5.11; N, 6.76. Found: C, 54.96; H, 5.22; N, 6.66.

Example 120 (E) -3- [7- (Aminoiminomethyl) -2-methoxy-1-naphthalenyl) -2-propenamide mono (trifluoroacetate)

Example 120A

The product obtained according to Example 53B and the acrylamide were subjected to the conditions described in Example 41A to give the title compound.

MS (DCI (NH ₃ )) m / z 253 (M + H) +;

198

Example I20B (E) -3- [7- (aminoiminomethyl) -2-methoxy-1-naphthalenyl) -2-propenamide mono (trifluoroacetate)

The product prepared in Example 120A was treated under the conditions described in Example 94D to give the title compound.

MS (DCI / NH ₃ ) m / z 270 (M + H) &lt; + &gt;;

1 H-NMR (300 MHz, DMSO) δ 4.02 (s, 3H), 6.90 (d, 1H), 7.22 (s, 1H), 7.62-7.70 (m, 2H) 7.74 (d, 1H), 8.02 (d, IH), 8.11 (d, IH), 8.15 (d, IH), 8.58 (s, IH), 9.18 (d, 1H), s, 2H), 9.50 (s, 2H);

Calcd for C ₁₇ H ₁₆ F ₃ N ₃ O ₄ .H ₂ O: C 50.88; H, 4.52; N, 10.47. Found. C, 50.89; H, 4.32; N, 10.43.

Example 121

6 - [(4-aminophenyl) ethynyl] -2-Naphthalenecarboximidamide bis (trifluoroacetate)

Example 121

A mixture of the product prepared according to Example 63B (130 mg, 0.73 mmol), 4-iodoaniline (173 mg, 0.79 mmol), dichloro-bis (triphenylphosphine) palladium (II) (25 mg, 0.0325 mmol), copper iodide. (1) (2.7 mg, 0.0186 mmol), DMF (0.65 mL), and triethylamine (1.95 mL) were degassed with N ₂ and stirred at 75-80 ° C for 1.5 h. The mixture was then cooled to room temperature, diluted with CH ₂ Cl ₂ , washed with water, filtered and evaporated in vacuo to give an oil which was purified by flash chromatography using a mixture of hexanes. ethyl acetate 3. 1, the title compound is obtained

MS (DC1 / _NH3) m / z 269 (M-II) "

199

Example 12 I B

6 - [(4-aminophenyl) ethynyl] -2-Naphthalenecarboximidamide bis (trifluoroacetate)

The title compound was prepared from the product prepared according to Example 121A by the method of Example 40D

MS (DCI / NH ₃ ) m / z 286 (M + H) &lt; + &gt;;

1 H-NMR (300 MHz, DMSO) δ 6.80 (d, 2H), 7.29 (d, 2H), 7.77 (dd, 1H), 7.85 (dd, 1H), 8.09 (d, 1H), 8.14 (d, 1H), 8.20 (s, 1H), 8.45 (s, 1H), 9.09 (s, 2H), 9.42 (s, 2H) ;

Analysis: Calculated for C 23 H ₇ F6N O4.0,25H2O _3: C, 53.34; H, 3.41; N, 8.11. Found: C, 53.45; H, 4.70; N, 7.76.

Example 122

1,1-Dimethylethyl- [2- [3 - [[6-amino-aminomethyl) -2-naphthalenyl] -ethynyl] -6-methoxyphenyl] ethyl] carbamate mono (trifluoroacetate)

Example 122A

The title compound was prepared using 5-bromo-2-methoxyphenethylamine hydrobromide (Transworld) as described in Example 63C.

MS (DCI / _NH3) m / z 330 (M + H) +;

Example 122B

The title compound was prepared according to the procedure described for Example 121A, substituting Example 4 for the preparation of Example 4A.

I22A

200

MS (ESI) mlz 427 (M + H) +;

Example 122C

1,1-Dimethylethyl [2- [3 - [[6-aminoiminomethyl) -2-naphthalenyl] -ethynyl] -6-methoxyphenyl] ethyl] carbamate mono (trifluoroacetate)

The title compound was prepared from the product prepared as in Example A-226638-B by the method of Example 40D.

MS (DCI / NH ₃ ) m / z 444 (M + H) ^&lt; ^{+ &gt};;

1 H-NMR (300 MHz, DMSO) δ 1.38 (d, 9H), 2.70 (t, 2H), 3.15 (q, 2H), 3.85 (s, 3H), 6.89 (t, 1H), 7.04 (d, IH), 7.37 (d, IH), 7.49 (dd, IH), 7.75 (dd, IH), 7.85 (dd, IH) 8.11 (d, 1H); 8.16 (d, IH); 8.30 (s, 1H); 8.48 (s, 1H); 9.07 (s, 2H); 9.42 (s, 2H);

Analysis: Calculated for C 29 H ₃ F ₃ N ₃ 0 ₂ 0 ₅ .0,25H: 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 - [[6- (aminoiminomethyl) -2-naphthalenyl] ethynyl] phenyl] methyl] carbamate mono (trifluoroacetate)

Example 123A

The title compound was prepared using 4-bromobenzylamine according to the method of Example 63C

MS (DC1 / _NH3) m / z 303 (M + NH ₄₎ ^4,

201

Example 123B

The title compound was prepared according to the procedure in Example 121A, substituting 4-iodoaniline for the compound prepared according to Example 123

MS (DC 1 / NH ₃ ) m / z 400 (M + NH ₄ ) ⁺ ,

Example 123C

1,1-Dimethylethyl [[4 - [[6- (aminoiminomethyl) -2-naphthalenyl] ethynyl] phenyl] methyl] carbamate mono (trifluoroacetate)

The title compound was prepared from the product prepared as in Example 123B by the method of Example 40D.

MS (DCI / NH ₃ ) m / z 400 (M + H) ^&lt; ^{+ &gt};;

1 H-NMR (300 MHz, DMSO) δ 1.40 (s, 9H), 4.18 (d, 2H), 7.34 (d, 2H), 7.45 (t, 1H), 7.58 (d, 2H), 7.78 (dd, 1H), 7.86 (dd, 1H), 8.15 (d, 1H), 8.19 (d, 1H), 8.31 (s, 1H) ), 8.50 (s, 1H), 9.10-9.42 (s, 4H);

Anal. Calcd for C 27 H 26 F ₃ N ₃ O ₄ : C 63.15; H, 5.10; N, 8.18. Found: C, 62.95; H, 4.97; N, 8.09.

Example 124

6 - [[4- (aminomethyl) phenyl] ethynyl] -2-Naphthalenecarboximidamide bis (trifluoroacetate)

To a suspension of Example 123C (80 mg, 0.2 mmol) with 1.5 mL of CH ₂ Cl ₂ was added trifluoroacetic acid (0.73 mL). The reaction mixture was stirred at room temperature for 0.25 h and evaporated. to dryness under vacuum. Toluene is then added and evaporated several times in vacuo to give a tan-like product which is purified by reverse phase chromatography using methanol / 0.1% aqueous TFA to give the title compound.

202

MS (APCI) m / z 300 (M + H) +, 1 H-NMR (300 MHz, DMSO) δ 4.10 (s, 2H), 7.55 (d, 2H), 7.70 (d, 2H), 7.79 (dd, 1H), 7.89 (dd, 1H), 8.16 (d, 1H), 8.19 (dd, 1H), 8.20 (s, 2H), 8, 36 (s, 1H), 8.53 (s, 1H), 9.20 (s, 2H), 9.44 (s, 2H);

Calcd for C24H19FGN3O4: C, 54.66; H, 3.63; N, 7.97. Found: C, 54.42; H, 3.57; N, 7.76.

Example 125

6 - [[3- (2-aminoethyl) -4-methoxyphenyl] ethynyl] -2-naftalénkarboximidamidbis (trifluoroacetate)

The title compound was prepared from the product prepared according to Example 122C and by the method of Example 124.

MS (ESI) mlz 344 (M + H) ⁺ ;

1 H-NMR (300 MHz, DMSO) δ 2.90 (t, 2H), 3.06 (t, 2H), 3.88 (s, 3H),

7.11 (d, 1H), 7.44 (d, IH), 7.57 (dd, IH), 7.75 (dd, IH), 7.82 (s, 2H), 7.88 ( dd, 1H), 8.12 (d, IH), 8.17 (d, IH), 8.28 (s, IH), 8.50 (s, IH), 9.20 (s, 2H), 9.45 (s, 2 H);

Anal. Calcd for C ₂₁ H 23 F ₆ N ₃ O ₅ 0.5H ₂ O: C 53.80; H, 4.17; N, 7.24. Found: C, 53.89; H, 4.31; N, 6.83

Example 126

6 - [[4- (hydroxymethyl) phenyl] ethynyl-2-Naphthalenecarboximidamide mono (trifluoroacetate)

203

Example 126A

The title compound was prepared according to the procedure for EXAMPLE 121A, substituting 4-bromo-benzyl alcohol for 4-iodoaniline.

MS (DCI / _NH3) m / z 301 (M + NH ₄₎ ⁺

Example 126B

6 - [[4- (hydroxymethyl) phenyl] ethynyl] -2-Naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared from the product prepared according to Example 126A by the method of Example 94B

MS (ESI) m / z 301 (M + H) +, 1 H-NMR (300 MHz, DMSO) δ 4.58 (d, 2H), 5.32 (t, 1H), 7.41 (d, 2H), 7.59 (d, 1H), 7.79 (dd, IH), 7.86 (dd, IH), 8.12 (d, IH), 8.18 (d, IH), 8, 32 (s, 1H), 8.50 (s, 1H), 9.14 (s, 2H), 9.46 (s, 2H);

Analysis: Calculated for C ₂₂ Hi ₇ F ₃ N ₂ O ₃ .0,5H ₂ O: C, 62.41; H, 4.29; N, 6.62. Found: C, 62.56; H, 4.13; N, 6.65

Example 127

6 - [(1,2,3,4-tetrahydro-6-isoquinolinyl) ethynyl] -2-naphthalenecarboximidamide bis (trifluoroacetate)

Example 127A

A solution of boron tribromide (1.2 mL, 12.5 mmol) in 12.5 mL of CH ₂ C1 ₂ was added dropwise at -78 to a solution ^of 6-metoxytetrahydroizochinolínu (1.0 g, 5.0

204 mol, Org Synth, 67, 60, 1998) in 38 mL of CH ₂ Cl ₂ The reaction mixture was stirred for 1 hour at -78 ° C, 1 hour at 0 ° C and 0.25 hours at room temperature. The reaction mixture was then cooled to -78 ° C and 20 mL of methanol was added dropwise. The solution was stirred at room temperature for 1 hour. The solvent is evaporated in vacuo and the residue is dried to give the title compound

MS (DCI) m / z 150 (M + H) ^1.

Example 127B

The product prepared as in Example 127A (1.15 g, 5.0 mmol) was treated as described in Example 63C. A portion (2.1 g) of the above product is stirred at reflux for 1.5 hours with 60 ml of methanol and 9 ml of 10% aqueous NaOH. After cooling to room temperature, the methanol was evaporated in vacuo. Water was added and the solution was acidified with 6 N HCl. The mixture was extracted with CH ₂ C1 _2nd The organic layer was washed with water, saturated aqueous sodium chloride, dried (MgSO ₄ ), filtered and the solvent evaporated in vacuo to give the title compound.

MS (DCI / _NH3) m / z 267 (M + NH ₄₎ ^+.

Example 127C

The title compound was prepared from the product prepared as in Example 127B and by the method of Example 28B.

MS (DCI / _NH3) m / z 399 (M + NH ₄₎ ⁺

Example 127D

The title compound was prepared according to the procedure for EXAMPLE 121A, substituting EXAMPLE 127C for 4-iodoaniline.

205

MS (DCI / _NH3) m / z 426 (M + NH ₄₎ +,

Example 127E

The title compound was prepared from the compound of Example 127D and the method of Example 40D.

MS (ESI) m / z 426 (M + H) &lt; + &gt;;

1 H-NMR (300 MHz, DMSO) δ 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, 1H) 8.35 (s, 1H); 8.51 (s, 1H); 9.20 (s, 2H); 9.45 (s, 2H).

Example 127F

6 - [(1,2,3,4-tetrahydro-6-isoquinolinyl) ethynyl] -2-naphthalenecarboximidamide bis (trifluoroacetate)

The desired product was prepared from Example 127E according to the method of Example 124D.

MS (ESI) m / z 326 (M + H) ⁺ , 1 H-NMR (300 MHz, DMSO) δ 3.03 (t, 2H), 3.42 (t, 2H), 4.35 (s, 2H), 7.35 (d, 1H), 7.46 (d, 2H), 7.88 (dd, 1H), 7.89 (dd, 1H), 8.15 (d, 1H), 8, 19 (d, 1H), 8.35 (s, 1H), 8.52 (s, 1H), 9.17 (s, 2H), 9.31 (s, 2H), 9.48 (s, 2H) );

Calcd for C ₂₁ H ₂₁ F ₆ N ₃ O ₄ C 56.42; H, 3.82; N, 7.59. Found C, 56.3; H, 3.81; N, 7.42.

Example 129

206

5-f [6- (Aminoiminomethyl) -2-naphthalenyl] oxy] pentanoic acid mono-tri fluoroacetate

Example 129A

The product prepared according to Example 119A (250 mg, 1.477 mmol) was treated with methyl 5-bromo-valerate in a manner similar to that described in Example 11B, to yield the title compound (394 mg, 94%).

MS (DCI (NH ₃ )) m / z 301 (M + NH ₄ ) ⁺ ;

Example 129B

5 - [[6- (Aminoiminomethyl) -2-naphthalenyl] oxy] pentanoic acid mono-trifluoroacetate

The product prepared in Example 129A (262 mg, 0.8723 mmol) was treated in a similar manner to Example 94D to give the amidine ester product. This product (140 mg, 0.542 mmol) was dissolved in methanol (11 mL). A solution of lithium hydroxide (68.2 mmol, 1.626 mmol) in water (3 mL) was then added and the resulting mixture was stirred under an inert atmosphere for 18 hours at room temperature. The reaction mixture was evaporated and the residue was purified by reverse phase chromatography to yield the title compound (184 mg, 74%).

MS (DCI (NH ₃ )) m / z 287 (M + H) ⁴ ;

H-NMR (300 MHz, _DMSO- d) δ 1.71 1 (m, 2H), 1.817 (m, 2H), 2.320 (t, 2H), 4.144 (t, 2H), 7.377 (d, H ), 7.472 (d, 1H), 7.632 (dd, 1H), 7.980 (d, 1H), 8.081 (d, 1H), 8.329 (s, 1H), 9,100 (br s, 2H), 9.390 (d, 1H); br s, 2H), 12.100 (br s, 1H);

Analysis: calculated for C ₁₆ H ₈ N ₂ O ₃ , (C ₂ H ₂ F ₃ ). 1.1 5 H ₂ O 0.65 ° C 51.22; H, 4.80; N, 6.53. Found: C, 51.30, H, 5.07; N, 6.12

207

Example 13 1

7-Methoxy-8- (3-oxo-1-cyclopenten-1-yl) -2-naphthalenecarboximidamide mono (tri fluoroacetate)

Example 131A

The product prepared according to the method of Example 25A (0.5 g, 1.5 mmol) and 3-tributylstannyl-2-cyclopentenone prepared according to the work of Labourd et al., Tet. catalyst as described in Stille et al., JACS 109, 5478-5486 (1987), and work-up by flash chromatography with hexanes: ethyl acetate 3: 1 to give a white solid; 300 mg, 72%.

MS (DCI / NH ₃ ): 281 (M + NH ₃ +);

Example 131B

7-Methoxy-8- (3-oxo-1-cyclopenten-1-yl) -2-naphthalenecarboximidamide mono (trifluoroacetate)

The product prepared above (130 mg, 0.4 mmol) was treated with H ₂ S / pyridine by the method of Example 40D. The title compound was obtained after reverse phase chromatography as an off-white solid, 52 mg, 45%.

MS (DCI / NH ₃ ). M + H + 281, 1 H-NMR (300 MHz, DMSO-d ₆ ) 9.45 (bs, 2H), 9.12 (bs, 2H), 8.25-8, 32 (m, 2H), 8.20 (dd, 1H), 7.86 (d, 1H), 7.75 (dd, 1H), 6.42 (m, 1H), 4.05 (s, 3H) ), 3.15 (m, 2H), 2.75 (m, 2H)

Analysis: Calculated for C | 9 H ₇ N ₂ O ₄ F ₃ .I, 75TFA- C 57.87; H, 4.35; N, 7.10. Found C 51.37, H 4.21, N 7.14

208

Example 132

6- (Aminomethyl) -N- (4-methylphenyl) -2-naphthalenecarboxamide mono (trifluoroacetate)

Example 132A

The title compound was obtained as an off-white solid (0.16 g, 56%) by coupling p-toluidine (0.11 g, 1 mmol) and the cyano ester prepared according to Example 8E by the method of Example 8G.

MS (ESI +, -): 287 (M &lt; + &gt;); 285 (M &lt; - &gt;).

Example 132B

6- (amino) -N- (4-methylphenyl) -2-a naphthalene-mono (trifluoroacetate)

The title compound was prepared according to the procedure for EXAMPLE 6B and purified by the procedure for EXAMPLE IB to give a white solid (35 mg, 35%).

MS (ES1 +). 304 (M &lt; + &gt;);

H-NMR (300 MHz, _DMSO-ft) 10.55 (s, IH), 9.45 (bs, 2H), 9.15 (bs, 2H), 8.65 (s, IH), 8 , 58 (s, 1H), 8.32 (d, IH), 8.20 (d, IH), 8.19 (dd, IH), 7.96 (dd, IH), 7.75 (d, 1H), 2H), 7.12 (d, 2H), 2.35 (s, 3H);

Analysis: Calculated for C ₂ | H | ₈ N ₃ O. · F ₃ . C 60.43, H 4.35; N, 10.07. Found: C 59.94, H 4.06; N, 9.80.

Example 133

209

Methyl 4 - [[[7- (aminoiminomethyl) -1- (2-pyrimidinyl amino) -2-naphthalenyl] oxy] methyl] benzoate mono (trifluoroacetate)

Example 133A

The product described in Example 91A was treated with AlII3 by the method of Example 119A and alkylated with 4-carbomethoxybenzyl bromide by the method of Example 109B to give 100 mg, 83% of the title compound as a white solid.

MS (ESI +, -): 411 (M &lt; + &gt;): 409 (M &lt; - &gt;).

Example I33B

Methyl 4 - [[[7- (aminoiminomethyl) -1- (2-pyrimidinyl) -2-naphthalenyl] oxy] methyl] benzoate mono (trifluoroacetate)

The title compound was prepared according to the procedure for EXAMPLE 40D and purified according to the procedure for EXAMPLE 119B to give a pale yellow solid (49 mg, 50%).

MS (ESI +, -): 428 (M +); 426 (M -);

H-NMR (300 MHz, _DMSO-fi) 9.45 (bs, 2H), 9.15 (s, IH), 8.97 (bs, 2H), 8.45 (dd, IH), 8 38 (d, 1H); 8.15 (d, 1H); 8.09 (d, 1H); 7.95 (d, 2H); 7.76 (d, 1H); 7.68 (dd, 1H); 1H), 7.35 (d, 2H), 6.85 (d, 2H), 5.39 (s, 2H), 3.85 (s, 3H);

Anal. Calcd for C ₂₁ H 22 N ₅ O ₅ F 3 C 57.67; H, 4.10; N, 12.93. Found C, 55.34; H, 3.88; N, 12.05

Example 134

210

4 - [[[7- (aminoiminomethyl) -1- (2-pyrimidinylamino) -2-naphthalenyl] oxy] methyl] benzoic acid mono (trifluoroacetate)

The product prepared according to Example 134 (40 mg) was dissolved in THF / water at a ratio of 1.1. To the clear solution was added LiOH / water (9 mg) and the resulting clear solution was stirred at room temperature for 18 hours. The reaction mixture was then concentrated to a yellow solid. This solid was dissolved in distilled water, acidified to pH 2 with 3 N HCl and stirred at room temperature for 2 hours. The title compound was collected by filtration, and dried in vacuo to give a yellow solid. Yield ^- 39 mg (46%)

MS (APCI): M + H ^{+ =} 414 1 H-NMR (300 MHz, DMSO-d ₆ ) 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);

Anal Calcd for C 25 F 19 N 5 O 5 F 5 Cl 2 H 2 O: C 48.67; H, 4.25; N, 11.35. Found: C, 49.64; H, 4.44; N, 1.69.

Example 135

1,1-Dimethyl - [[4 - [[[6- (aminoiminomethyl) -2-naphthalenyl] amino] carbonyl] phenyl] methyl] carbamate mono (trifluoroacetate)

Example 135A

To cold sulfuric acid (0 C, 45 mL) was added the product of Example 8B. Bubbles begin to form at 0 ° C for 1 minute. Bubble evolution was allowed to proceed for 30 minutes at 0 ° C and then warmed to room temperature. The mixture is left at room temperature for 20 minutes and then poured into ice and diluted with water (to about 500 ml). The resulting suspension is placed in an ice bath and then 50% aqueous sodium hydroxide is carefully added so that the temperature does not exceed 35 ° C. The yellow solid is filtered, then washed with water until the wash liquid is neutral to pH paper (7.0). The product is dried under vacuum. The product was purified on a silica gel column using 20% ethyl acetate / 80% hexanes as eluent to give 3.3 g (67%) of a pale yellow solid.

MS m / z 169 (M + 1) &lt; - &gt;

Example 135B

To a solution of Example 135A (135 mg, 0.8 mmol), 4N-Boc-aminomethylbenzoic acid (404 mg, 1.6 mmol) and EDCI (307 mg, 1.6 mmol) in methylene chloride (25 mL) was added at room temperature. DMAP (3 mg) was added at room temperature and the reaction was stirred overnight. The reaction mixture was then diluted with methylene chloride (60 mL), washed with 2% aqueous hydrochloric acid (2 x 30 mL), water (20 mL), 0.5 M aqueous sodium hydroxide (2 x 50 mL), and brine. The organic phase is dried over magnesium sulphate and evaporated. The product was purified on a silica gel column using a gradient elution of 25% to 60% ethyl acetate in hexanes. Yield as a white powder: 175 mg (54%).

Example 135C

1,1-dimethyl - [[4 - [[[6- (aminoiminomethyl) -2-naphthalenyl] amino] carbonyl] phenyl] methyl] carbamate mono (trifluoroacetate)

The reaction was carried out as described in Example 40D. The yield was 10 mg (64%).

MS m / z 408 (M + 1) + 425 (M + 18/1 H-NMR: 3.30 (s, 9H), 4.22 (d, 2H, J = 7.1 Hz), 7.42 (d, 2H, J = 8.5 Hz), 7.49 (t, 1H, J = 7.1 Hz), 7.79 (dd, 1H, J1 = 8.2 Hz, J2 = 2.0) Hz), 7.95-8.00 (m, 3H),

212

8.09 (d, 2H, J = 8.4 Hz), 8.42 (s, 1H), 8.63 (d, 1H, J = 2.0 Hz), 9.18 (br s, 4H) , 10.58 (s, 1H);

Calcd for C 26 H 27 F 3 N 4 O 5 · C 58.55; H, 4.85; N, 10.41. Found. C, 58.64; H, 5.11; N, 10.52.

Example 136

N- [6- (amino) -2-naftaIenyl] benzamide mono (trifluoroacetate)

The title compound was prepared according to the method for EXAMPLE 135.

1 H-NMR (300 MHz, DMSO-d ₆ ) 10.67 (s, 1H), 9.25 (br s, 4H), 8.65 (d, J = 1.5 Hz, 1H), 8, 43 (d, J = 1.4 Hz, 1H), 8.10 (d, J = 9.2 Hz, 2H), 8.03-7.97 (m, 3H), 7.81-7.78 (m, 1H), 7.65-7.55 (m, 3H);

MS (ESI / NH ₃ ) m / z 290 (M + H) ^&lt; ^{+ &gt};;

Analysis: Calculated for N _{3 5} CigHi O.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.

Example 137

1,1-Dimethylethyl [[4 - [[[6- (aminoiminomethyl) -2-naphthalenyl] amino] carbonyl] cyclohexyl] methyl] carbamate mono (trifluoroacetate)

Example 137A

To a solution of 6-amino-2-naphthalenecarbonitrile prepared according to Example 73 (100 mg, 0.6 mmol) in methylene chloride (35 mL) at room temperature was added 1-carboxy-4- (Boc-aminomethyl) cyclohexane (280 mg, 1.1). mmol) and then 1-ethyl-3- (3-diethylaminopropyl) -carbodiinide hydrochloride (EDAC, 225 mg, 1.2 mmol).

213

After 5 minutes, DMAP (20 mg, catalysis) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was then diluted with ethyl acetate: hexanes 7 3 and filtered through silica gel washing with the same solvent mixture.

The organic solvent was washed with aqueous acid (2% HCl, 2 x 50 mL), water and aqueous base (10% NaOH, 50 mL). The solvent was dried over magnesium sulfate, filtered and evaporated. Crystallization from ether / hexanes gave the desired product as a white solid. Yield: 166 mg (68%).

MS (DCI / NH 3) m / z 408 (M + H) ⁺ .

Example 137B

1,1-Dimethylethyl [[4 - [[[6- (aminoiminomethyl) -2-naphthalenyl] amino] carbonyl] cyclohexyl] methyl] carbamate mono (trifluoroacetate)

A solution of the substrate (compound of Example 137A) in Pyr: Et 3 N (10: 1.2 mL) was bubbled with H ₂ S for 5 minutes. The reaction mixture was then stirred overnight at room temperature. Ethyl acetate (100 mL) was added followed by 1% aqueous KHSO ₄ (60 mL) and the layers were separated; the organic layer was washed with water (2 x 50 mL), sodium bicarbonate and brine, dried (MgSO 4) and evaporated. To a suspension of the solid residue in acetone (25 mL) was added Mel (1.0 mL). The mixture was stirred at 50 ° C for 2 hours until all was dissolved. The solvent was evaporated completely to dryness and methanol (30 ml) and ammonium acetate (150 mg) were added. The mixture was stirred overnight at room temperature. Purify by reverse phase MPLC C, g. After evaporation, toluene is added and evaporated again (2x). The resulting oil was treated with methanol and ether to precipitate the product as a white solid (72 mg, 43%).

MS (ESI / NH 3) m / z 425 (M + H) \ 'H NMR (300 MHz, _DMSO-fi) 10.24 (s, IH), 9.05 (br s, 4H), 8, 49 (s, 1H), 8.38 (d, J = 1.7 Hz, 1H), 8.03-8.00 (m, 2H), 7.77-7.74 (m, 2H), 6 , 93-6.91

214 (m, 1H), 2.83-2.79 (, 2H), 2.40-2.30 (M1), 1.92-1.75 (m, 4H), 1.50-1.45 (m, 1H), 1.39 (s, 9H), 0.96-0.91 (m, 4H);

Calcd for C24H32N4O3.CF3COOH: C, 57.98, H, 6.18; N, 10.40. Found: C, 57.63; H, 6.24; N, 10.21.

Example 138

N- [6- (amino) -2-naphthalenyl] -N '- (4-aminophenyl) urea bis (trifluoroacetate)

Example 138A

To a solution of Example 40B (194.2 mg, 1 mmol) in dioxane (10 mL) at room temperature was added 4-phenylenediamine mono-Boc (416.5 mg, 2 mmol). Within a few minutes the product began to precipitate. After one hour, ether (5 mL) was added to the reaction mixture and the white solid product was filtered off and washed with ether to yield 350 mg (87%).

MS (DCI / NH 3) m / z 403 (M + H) ⁺ .

Example 138B

A solution of the corresponding nitrile prepared according to Example 138A (105 mg, 0.36 mmol) in Pyr Et 3 N (10: 1.20 mL) was bubbled with H ₂ S for 5 min and stirred overnight at room temperature. The reaction mixture was then diluted with ethyl acetate (100 mL), washed with aqueous 0.25 N HCl (25 mL) and then with water (2 x 50 mL), saturated sodium bicarbonate, and brine, dried over magnesium sulfate and evaporated to a residue. To a solution of the obtained solid residue in acetone (25 mL) was added Mel (1.0 mL) and the mixture was stirred at 50 ° C for 30 min with vigorous precipitation of precipitate. Ether was added and the yellow precipitate was filtered off.

Methanol (10 mL) and ammonium acetate (150 mg) were added to the 215 yellow solid and stirred overnight at room temperature. Purification was carried out as described in Example IB. The yield of a white solid was 69 mg

MS (DCI / NH ₃ ) m / z 420 (M + H) &lt; ⁺ &gt; ^.

Example 138C

N- [6- (amino) -2-naphthalenyl] -N '- (4-aminophenyl) urea bis (trifluoroacetate)

The Boe-protected substrate (Example 138B) was dissolved in methylene chloride: TFA 1: 1 (25 mL) and stirred at room temperature for 1 hour. Then the solvent was evaporated in vacuo, toluene was added and the solvent was evaporated again. Water, a small amount of acetonitrile was added, the mixture was filtered, lyophilized to give 36 mg of a white solid.

MS (ESI / NH 3) m / z 320 (M + H) ⁺ ;

1 H-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) = 1.7 Hz, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.95-7.91 (m, 2H), 7.68 (dd, J1 = 6.6) Hz, J2 = 2.0 Hz, 1H), 7.57 (dd, J1 = 9.2 Hz, J2 = 1.4 Hz, IH), 7.34 (d, J = 8.8 Hz, 2H) 6.91 (d, J = 8.4Hz, 2H);

Anal Calcd for C 14 H 11 N 3 O 4 CF 3 COOH · H 2 O: C 46.73; H, 3.74; N, 12.39. Found: C, 47.03; H, 3.55; N, 12.36.

Example 139

N - [6- (aminomethyl) -2-naphthalenyl] -4-4- (aminomethyl) cyclohexanecarboxamide bis (trifluoroacetate)

A solution of the substrate prepared according to Example 137 as the TFA salt (45 mg) in methylene chloride: TFA 1: 1 (20 mL) was stirred at room temperature for 1 hour.

216

Then the solvent was evaporated in vacuo and toluene was added and evaporated (2 x 20 ml). Dissolve the residue in water, filter through a sinter frit 0,45 μπι and lyophilize. 35 mg of a white solid are obtained in the form of the bis (TFA) salt.

MS (ESI / _NH3) m / z 325 (M + H) ^+, H-NMR (300 MHz, _DMSO- d) 10.31 (s, IH), 9.31 (br s, 2H); 9.10 (br s, 2H), 8.49 (s, 1H), 8.39 (s, 1H), 8.04-8.00 (m, 2H), 7.78-7.71 (m (2H), 2.71 (d, J = 7.0 Hz, 2H), 2.44-2.36 (m, 1H), 1.96-1.85 (m, 4H), 1.61- 1.42 (m, 3H); 1.091.02 (m, 2H);

Analysis: Calculated for Ci9H ₂₄ N ₄ O.2CF ₃ COOH: C, 50.00; H, 4.74; N, 10.14. Found: C, 49.95; H, 4.70; N, 9.96.

Example 140

N- [6-Aminomethyl) -2-naphthalenyl] -N'- [(4-aminomethyl) phenyl urea -abis (trifluoroacetate)]

Example 140A

To a solution of the isocyanate prepared according to Example 40B (140 mg, 0.72 mmol) in dioxane (8.0 mL) was added 4-N-Bocaminomethylbenzoic acid (320 mg, 1.44 mmol) at room temperature and the reaction mixture was stirred for 1 h. hour. The product precipitates during the reaction. The mixture was then diluted with ether (15 mL), filtered and washed with ether to give 215 mg (72%) of a white solid.

MS (DCI / NH 3) m / z 417 (M + 1) +.

Example I40B

217

A solution of the nitrile (Example 140A) (198 mg, 0.47 mmol) in pyridine: triethylamine 10 L (10 mL) was treated with H ₂ S for 5 minutes, then stirred at room temperature for 18 hours 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 solid obtained was dissolved in methanol (4 ml) and purified according to Example 1B to give 112 mg (54%) of the corresponding amidine.

MS (DCI / NH 3) m / z 434 (M + H) ⁺ .

Example 1400

N- [6-amino-imino) -2-naphthalenyl] -N '- [(4-aminomethyl) phenyl-močovinabis (trifluoroacetate)

A solution of the substrate prepared according to Example 140B in methylene chloride: TFA 1: 1 (20 mL) was stirred at room temperature for 1 hour. Then the solvent was evaporated in vacuo and toluene was added and evaporated (2 x 20 ml). Dissolve the residue in water, filter through a frit of 0,45 μηι and lyophilize. 38.1 mg of a white solid are obtained.

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 = 7.1 Hz, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.10 (br s, 3H), 8.04-7.99 (m, 2H), 7.76 (dd, J1 = 8.8 Hz, J2 = 1.8 Hz, 1H), 7.67 (dd, J1 = 8.8 Hz, J2 = 1.7 Hz, 1H), 7.58 (d,> 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 3.98 (br s, 2H);

Calcd for C19H19N5O.2CF3COOH.H2O: C 47.67; H 4.00, F 19.67, N 12.09. Found. C 47.33, H 3.70; F, 19.59; N, 1.71

218

Example 141

Methyl [7- (aminoiminomethyl) -3 - [[[4- (aminomethyl) phenyl] amino] carbonyl] -1-naphthalenyl] carbamate bis (trifluoroacetate)

Example 141A

To a solution of the ester prepared according to Example 26 (747 mg, 2.63 mmol) in dioxane (10 mL) was added acetone and excess sodium hydroxide (1 N in water, 10 mL). After 1 hour, water (40 mL) and ethyl acetate (85 mL) were added to the mixture, and then the mixture was acidified with aqueous 10% HCl. The ethyl acetate layer was separated, washed with water (2 x 20 mL) and then brine, dried over magnesium sulfate, filtered and evaporated. The product was isolated as a light yellow solid.

MS m / z 271 (M + 1) &lt; ^{+ &gt};.

Example 14 I B

To a suspension of the naphthoic acid derivative prepared according to Example 141A (270 mg, 1.1 mmol) in methylene chloride (8.0 mL) was added diisopropylethylamine (DIEA, 485 μΐ, 2.8 mmol) followed by O- (azabenzotriazole-1-). yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU, 527 mg, 1.39 mmol). After 10 minutes, 4-N-Boc-aminomethylaniline (370 mg, 1.7 mmol) was added. After one hour, ethyl acetate (120 mL) was added and the organic layer was washed with 5% aqueous citric acid (50 mL), water (2 x 40 mL), and brine (50 mL). The layer was dried over magnesium sulfate, filtered through a small pad of silica and the solvent was evaporated. The residue was purified on silica using ethyl acetate in hexanes. After concentration, ethyl acetate and ether were added to the product and filtered to give 3 50.0 mg (70%) of a yellow solid.

MS m / z 447 (M + 1) &lt; ^{+ &gt;}

219

Example 14 IC

A suspension of the naphtho derivative (Example 141 B) (300 mg, 0.67 mmol) in ethyl acetate (20 mL) was combined with 120 mg of Pd catalyst, and the reaction mixture was then stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 1 h. hours. The crude product was used in the next step without further purification or analysis.

To a solution of the crude amine in dioxane (25 mL) with 10% aqueous sodium carbonate (2.5 mL) was added methyl chloroformate (1.0 mL, large excess). After 2 hours, quench the reaction with methanol and then dilute 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 a silica gel column using a gradient elution with 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) ^&lt; ^{+ &gt};.

Example 141D

The title compound was prepared according to the method for EXAMPLE 26.

MS m / z 492 (M + 1) &lt; ^{+ &gt};.

Example 141 E

Methyl [7- (aminoiminomethyl) -3 - [[[4- (aminomethyl) phenyl] amino] carbonyl] -1-naphthenyl] carbamate bis (trifluoroacetate)

A solution of the substrate (Example 141 D compound) in methylene chloride: TFA 4: 1 (20 mL) was stirred at room temperature for 15 minutes. The solvent was then concentrated in vacuo and separation was performed on RP C18 MPLC. Yield 21 mg of off-white solid

220

MS m / z 392 (M + 18) 1 H-NMR (DMSO): 3.783 (s, 3H), 4.03 (q, 2H, J = 5.5 Hz), 7.47 (d, 2H) J = 8.4 Hz), 7.85 (d, 2H, j = 8.4 Hz), 7.94 (d, 1H, j = 8.8 Hz), 8.15 (broad s, 2H) 8.31 (d, 1H, J = 8.8 Hz), 8.33 (s, 1H), 8.47 (s, 18), 8.74 (s, 1H), 9.29 (s, 2H), 9.47 (s, 2H), 9.90 (s, 1H), 10.68 (s, 1H),

Anal. Calcd for C 25 H 25 F 6 N 5 OS (base molecule + 2TFA + 1 H ₂ O): C 47.04; H, 3.70; N, 10.52. Found. C 47.10; H, 3.95; N, 10.99.

Example 142

6- (amino) -N- (4-ethyl-phenyl) -2-a naphthalene acetate

Example 142A

The reaction was carried out as described in Example 141B. 374 mg (61%) of a white powder are obtained.

MS (DCI / NH 3): m / z 301 (M + NH ₄ +).

Example 142B

6- (Aminomethyl) -N- (4-ethylphenyl) -2-naphthalenecarboxamide acetate

The reaction was carried out in the same manner as described for the naphthyl analogue prepared in Example 141 D, 13 mg. The solid which precipitated during the last step was filtered off and washed with ether to give 71 mg (18%) of a white solid as the acetate salt.

MS (ECI) m / z 301 (M + H) +,

221 1 H NMR (300 MHz, DMSO-d ₆ ) δ 1.19 (t, J = 7.4 Hz, 3H), 2.60 (q, J = 7.4 Hz, 2H), 7.22 ( d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.94 (dd, J = 8.8 Hz, J ₂ = 1.7 Hz, 1H), 8.08-8.23 (m, 3H), 8.47 (d, J = 1.7 Hz, 1H), 8.63 (s, 1H), 10.43 (br s, 1H) .

Calcd for C 21 H 19 N 3 O.AcOH 0.5H ₂ O: C 68.38, H 6.26; N, 10.87. Found: C, 68.56; H, 6.21; N, 10.67.

Example 143

6- (amino) -N- (2-naphthalenyl) -2-a naphthalene-mono (trifluoroacetate)

Example 143A

To a solution of the acid chloride in methylene chloride (20 mL) prepared as described in Example 8B (341 mg, 1.6 mmol) was added a solution of 2 aminonaphthalene (249 mg, 1.74 mmol) in methylene chloride (10 mL) and propylene oxide (12 mL). The reaction mixture was stirred overnight at room temperature. Ether was added, the product was filtered off, washed with ether and hexanes and dried in vacuo. Yield: 440 mg (86%).

MS (DCI / NH ₃ ) mlz 340 (M + NH ₄ ) ⁺ .

Example 143B

6- (aminoiminoinetyl) -N- (2.naftalenyl) a naphthalene-2-on mono (trifluoroacetate)

The title compound was prepared according to the procedure for EXAMPLE 141B. The yield as a white solid was 40 mg (10%).

222

MS (ESI) m / z 340 (M + H) +;

1 H 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 = 8.8 Hz, 1H), 8.50 (d, J = 1.7 Hz, 1H), 8.57 (d J = 1.3 Hz, 1H), 8.75 (s, 1H), 9.33 (br s, 4H), 10.75 (s, 1H);

Analysis calculated for C 22 H | 7N3O.TFA.0,25H ₂ O: C, 62.95; H, 4.07; N, 9.18. Found: C, 63.09; H 3.72, N 8.99.

Example 144

6- (5-phenyl-2-oxazolyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 144A

To a suspension of phenacylamine hydrochloride (Aldrich) (415 mg, 2.42 mmol) in a mixture of methylene chloride (50 mL) and propylene oxide (15 mL) was added a solution of 2-nitrile 6-chloride (560 mg, 2.6 mmol) in methylene chloride ( 30 mL) followed by DMF (3.0 mL). The reaction mixture was stirred at room temperature overnight. Ether (15 ml) was then added, the product was filtered off and washed with hexanes to give 555 mg (73%) of a white solid.

MS (DCI / NH ₃ ) m / z 315 (M + H) +.

Example 144B

A suspension of the substrate (compound of Example 144A) (354 mg, 1.12 mmol) in phosphorus oxychloride (3.5 mL) was boiled for 1.5 hours. The reaction mixture was poured onto ice and ethyl acetate (80 mL) and aqueous 10% potassium carbonate solution (100 mL) were added. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. Ether was added and filtered to give 249 mg (75%).

223

MS (DCI / _NH3) m / z 297 (M + H) +.

Example 144C

6- (5-phenyl-2-oxazolyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

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 the reaction mixture was stirred Stir overnight. The reaction was then quenched by the addition of 4 N HCl in dioxane (1 mL). After 10 minutes, a few drops of water are added and stirring is continued for another 30 minutes. The solvent is then removed in vacuo and the residue is purified by reverse phase chromatography. The yield was 58 mg of a white solid (41%).

MS (ESI / NH ₃ ) m / z 3 14 (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, 1H), 8.38-8.26 (m, 3H), 7.98 (s, 1H), 7.96-7.89 (m, 3H) 7.58-7.54 (m, 2H); 7.47-7.42 (m, 1H);

Calcd for C 20 H 15 N ₃ O. 1.15 CF ₃ COOH: C, 60.26; H, 3.66; N, 9.45; F, 14.75. Found: C, 60.1; H, 3.81; N, 9.20; F, 14.81.

Example 145

6- (5-phenyl-2-thiazolyl) -2-naftalénkaľboximidamid mono (trifluoroacetate)

Example 145A

A suspension of the substrate prepared according to Example 144A (340 mg, 1.1 mmol) and Lawesson's reagent (600 mg, 1.48 mmol) was heated at 85 ° C for 48 hours. The solvent was evaporated to dryness and the product was isolated on an oxide column.

224 silica, eluting with 10% ethyl acetate in hexanes. Yield 200.0 mg (59%) of a yellow solid.

MS (DC1 / _NH3) m / z 13 3 (M + H) +.

Example 145B

6- (5-phenyl-2-thiazolyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

To a solution of the substrate of 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 the reaction was stirred during the night. The reaction was then quenched by the addition of 4 N HCl in dioxane (1 mL). After 10 minutes, a few drops of water are added and the mixture is stirred for an additional 30 minutes. The solvent was evaporated in vacuo and the residue was purified by MPLC on RPC18. Yield: 36 mg (19%) of a white solid.

MS (ESI / NH ₃ ) m / z 330 (M + H) &lt; ^{+ &gt};.

1 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, 1H); 8.35-8.22 (m, 3H); 7.90-7.78 (m, 3H); 7.55-7.50 (m, 2H); 7.43 (m, 1H);

For C20H15N3S.CF3COOH.H2O: C 57.26, H 3.93 9.1 1. Found - C 56.83; H, 3.55; N, 8.79

Example 146

6- (aminoiniinometyl) -4- (3-furanyl) -N- (2-pyridinyl) -2-naftalénkarboxamiddihydrochlorid

Example 146A

225

The above product was prepared according to the method of Example 114A.

MS (ESI) mlz (M + H) + 340

Example 146B

6- (aminoiminomethyl) -4- (3-furanyl) -N- (2-pyridinyl) -2-naphthalenecarboxamide dihydrochloride

The above compound was prepared from Example 146A by the method of Example MSB.

MS (CI) m / z (M + H) ⁺ 357 1 H NMR (300 MHz, DMSO-d ₆ ) δ 11.27 (s, 1H), 9.56 (s, 2H), 9.17 (s , 2H), 8.76 (s, 1H), 8.63 (s, 1H), 8.45-8.24 (m, 5H), 7.96-7.89 (m, 3H), 7, 25 (m, 2H), 7.18 (s, 1H);

Anal. Calcd for C ₂₁ H ₁₈ N ₄ O ₂ Cl ₂ .19 / 10HCl: C 54.33; H, 4.75; N, 12.07. Found: C, 54.89; H, 5.28; N, 9.81.

Example 147

6- (amino) -N - (+, 2,3,4-tetrahydro-6-quinolinyl) -2-a naphthalene bis (trifluoroacetate)

Example I47A

The reaction was carried out in exactly the same manner as described in Example 11A using 6-aminocbinoline in 72% yield. Mass spectrum (C1 +) 324 (M + 1) ⁺ .

226

Example I47B

The reaction was carried out in exactly the same manner as described in Example 18B in 45% yield of product (off-white powder). Mass Spectrum (ES +) 341 (M + 1) ⁺ .

Example 147C

6- (amino) -N - (+, 2,3,4-tetrahydro-6-quinolinyl) -2-naphthalenecarboxamide bis (trifluoroacetate)

To a suspension of the substrate of Example 147B (261 mg, 0.6 mmol) in degassed methanol (15 mL) was added platinum oxide (10 mg, catalysis). The reaction mixture was then placed under atmospheric pressure and vigorous stirring under a hydrogen atmosphere. The next day, the solution is filtered through celite to remove the catalyst, and the product is purified by MPLC on RPC18 silica using methanol (+ 0.1% TFA) and water (+ 0.1% TFA) as eluent. 122 mg of a white solid are obtained in the form of the TFA salt.

MS (ESI +) 345 (M + 1) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d ₆ ) 10.51 (s, 1H), 9.56 (s, 2H), 9.50 (s, 2H), 8.64 (s, 1H), 8, 52 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.12 (Abq, J = 9.0 Hz, 2H), 7.86 (d, J = 9, 0 Hz, 1H), 7.61 (s, IH), 7.61 (s, IH), 7.56 (d, J = 8.0 Hz, IH), 6.98 (d, J = 8, 5 Hz, 1H), 3.28 (t, J = 5.5 Hz, 2H), 2.75 (t, J = 6.3 Hz, 2H), 1.92-1.86 (m, 2H) ;

Analysis Calcd for C ₂ H ₂ () ₄ N O.2,25 TFA.0,25H ₂ O: C 50.59 (50.46); H, 3.79 (3.79); N, 9.25 (0.25); F, 21.18 (20.83).

Example 148

7-methoxy-8- (pyrazinyloxy) -2-Naphthalenecarboximidamide-dimetyIsulfonát

227

Example 148A

The product prepared according to 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 mixture was stirred for 1 hour at 130 [deg.] C. Then, the reaction mixture was cooled and the crude mixture was chromatographed on SiO 2 using 40% ethyl acetate / hexanes as eluent to give 75 mg (43%) of the title compound.

MS (DCI / NH ₃ ) m / z 278 (M + H) &lt; + &gt;.

Example 148B

7-methoxy-8- (pyrazinyloxy) -2-dimethylsulfone-Naphthalenecarboximidamide

Example 148A (70 mg, 0.252 mmol) was treated as in Example 1B to afford the title compound (106 mg, 71%); 1.1. 155 ° C.

MS (DCI / _NH3) m / z 295 (M + H) +.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 9.42 (br s, 2H), 9.04 (br s, 2H), 8.72 (s, 2H), 8.38 (d, J = 3.0 H, 1H), 8.36 (m, 1H), 8.21 (d, J = 9.0 Hz, 1H), 8.09 (m, IH), 8.06 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 9 Hz, 1H), 7.73 (dd, J = 9.2 Hz, IH), 3.83 (s, 3H), 2.38 (s, 3H);

Anal. Calcd. For C 18 H ₂ N ₄ S ₂ O ₅ . 1.1CH4SO3: C 38.74, H 4.49; N, 9.46. Found: C, 38.68; H, 4.53; N, 9.34.

Example 149

7-methoxy-8- (phenylthio) -2-methanesulfonate Naphthalenecarboximidamide

228

Example 149A

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 mixture was stirred for 5 minutes. The product of Example 53B (309 mg) was then added. , 1 mmol) and the reaction mixture was heated at 100 ° C for 3 h. The crude reaction mixture was chromatographed on SiO ₂ using 20% ethyl acetate / hexanes as eluent. The product was taken up in ethyl acetate (10 mL) and methanol (10 mL) and treated with 2 M TMSCHN ₂ solution (10 mL). The reaction mixture was then stirred for 60 minutes and then concentrated. The crude product was chromatographed on SiO ₂ using 15% ethyl acetate / hexanes as eluent to give 115 mg (39%) of the title compound.

MS (DCI / _NH3) m / z 309 (M + NH ₄₎ ^+.

Example 149B

7-methoxy-8- (phenylthio) -2-methanesulfonate Naphthalenecarboximidamide

The title compound was prepared from Example 149A by the method of Example 55D.

MS (DCI / NH ₃ ) m / z 309 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 2.33 (s, 3H), 3.96 (s, 3H), 6.96 (d, 2H), 7.11 (dd, 1H), 7 , 20 (d, 1H), 7.22 (d, IH), 7.69 (dd, IH), 7.82 (d, IH), 8.22 (d, IH), 8.33 (d, 1H), 1H), 8.81 (s, 1H), 9.01 (br s, 2H), 9.46 (br s, 2H);

Anal. Calcd _X Hi _{n 2} OS. 1.15CH ₄ SO ₃ C 54.91; H, 4.96; N, 6.69. Found - C, 54.70; H, 5.15; N, 6.58.

Example 150

229

7-methoxy-8- (pyrazinylamino) -2-naľtalénkarboximidamid bis (trifluoroacetate)

The title compound was prepared from the product prepared as in Example 90D by the method of Example 91A followed by conversion to the amidine of Example 40D.

MS (DCI / _NH3) m / z (M + H) 294 H NMR (300 MHz, _DMSO- d) δ 9.39 (s, 2H), 9.02 (s, 2H), 8 , 95 (s, 1H), 8.40 (d, 1H), 8.14 (d, 1H), 8.03 (s, 2H), 7.92 (dd, 1H), 7.84 (d, 1H), 1H), 7.76 (d, 1H), 7.66 (dd, 1H), 3.90 (s, 3H);

Calcd for C20H17N5O5F6.1 / 2TFA: C, 43.79; H, 3.07; N, 12.20. Found: C, 43.81; H, 3.22; N, 12.24

Example 152

6- (amino) -4- (3-furanyl) -N-phenyl-2-naftalénkarboxamidmonohydrochlorid

Example 152A

To a solution of the product of Example 8D (5.50 g, 26.04 mmol) in CH ₂ C1 ₂ (125 ml) was added dibromodimethylhydantoin (4.47 g, 15.62 mmol) and trifluoromethanesulfonic acid (2.51 mL, 28 The reaction mixture was poured into aqueous NaHSO ₃ , basified with Na ₂ CO ₃ and extracted 3x with ethyl acetate, the extracts washed with brine, dried Na ₂ SO ₄ and concentrated by recrystallization of the product from ethanol / ethyl acetate to give the title compound in a yield of 5.80 g (77%).

MS (DC1 (NH ₃₎₎ m / z 307 (M + NH ₄₎ \

230

Example 152B

To a solution of the product prepared according to 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 reaction the mixture was stirred for 18 hours. This mixture is poured into 1M HCl and extracted 3 times with ethyl acetate, the extracts are washed with brine, dried over Na ₂ SO ₄ and concentrated to give 1.23 g (92%) of the title compound.

MS (DCI (NH ₃ )) m / z 295 (M + NH ₄ ) ⁺ .

Example 152C

To a solution of the product prepared according to Example 152B (440 mg, 1.60 mmol) in toluene (25 mL) was added oxalyl chloride (0.140 mL, 1.6 mmol) and the reaction mixture was stirred at 80 ° C for 18 h. The toluene is then removed by boiling until the HCl escapes, and then the mixture is cooled. Aniline (1 mL, 11 mmol) was added and the reaction was stirred for 10 min and poured into 1 M HCl. This solution is extracted 3 times with ethyl acetate, the extracts are washed with brine, dried over Na ₂ SO ₄ and concentrated to give 560 mg (99%) of the title compound.

MS (DCI (NH ₃ )) m / z 370 (M + NH ₄ ) +.

Example 152D

The title compound was prepared from Example 152C (408 mg, 1.16 mmol), furan-3-boronic acid (182 mg, 1.62 mmol) and according to the method of Example 57B to yield 220 mg (56%) of the title compound.

MS (DCI (NH 3)) m / z 356 (M + NH ₄ ) +.

Example 152E

231

6- (Aminomethyl) -4- (3-furanyl) -N-phenyl-2-naphthalenecarboxamide monohydrochloride

The title compound was prepared from Example 152D using the procedure of Example 40D.

MS (DCI / _NH3) m / z 356 (M + H) ^4th

1 H NMR (300 MHz, DMSO-d ₆ ) δ 7.15 (m, 2H), 7.41 (dd, 2H), 7.83 (d, 2H), 7.91 (d, 1H), 7 , 99 (dd, 1H), 8.19 (d, IH), 8.38 (s, IH), 8.41 (d, IH), 8.62 (s, IH), 8.69 (s, 1H), 1H), 9.15 (br s, 2H), 9.55 (br s, 2H);

Analysis: Calculated for C 22 H ₇ N ₃ O ₂ .2,75HCl: C 57.99; H, 4.37; N, 9.22. Found: C, 57.85; H, 4.84; N, 9.44.

Example 1 53

6- (Aminomethyl) -4- (1- (methylsulfonyl) -1H-pyrazol-4-yl) -N-phenyl-2-naphthalenecarboxamide monohydrochloride

Example 153A

The title compound was prepared from the product prepared according to Example 53D and the product prepared according to Example 152A by the method of Example 47A.

MS (DC1 / _NH3) m / z 408 (M + H) ⁴

Example 153B

The title compound was prepared from the product prepared according to Example 153A by the method of Example 53F.

232

MS (DCI / NH 3) m / z 278 (M + H) +.

Example 153C

The title compound was prepared from the product prepared as in Example 153B by the method of Example 87A (86A).

MS (DCI / NH ₃ ) m / z 373 (M + H) &lt; ^{+ &gt};.

Example 153D

The title compound was prepared from the product prepared as in Example 153C by the method of Examples 152B and 152C.

MS (DCI / NH ₃ ) m / z 356 (M-SO ₂ Me + NH ₄ ) ⁺ .

Example 153E

6- (aminoiminomethyl) -4- [1- (methylsulfonyl) -1H-pyrazol-4-yl] -N-phenyl-2-naphthalenecarboxamide monohydrochloride

The title compound was prepared from Example 153D following the procedure of Example 40D.

MS (DCI / NH ₃ ) is not;

H NMR (300 MHz, _DMSO-fi) δ 3.99 (s, 3H), 7.14 (t, IH), 7.40 (t, 2H), 7.84 (d, 2H), 7 91 (d, 1H), 8.08 (s, 1H), 8.15 (d, 1H), 8.35 (m, 2H), 8.65 (br s, 2H), 9.33 (br. s, 2H), 9.61 (br s, 2H), 10.58 (s, 1H),

Calc'd for C ₂₂ H _{1 <)} N ₅ SO ₃ · .2,75HC1 C 49.51; H, 4.11; N, 13.12. Found: C, 49.44; H, 3.83; N, 12.09

233

Example 154

6- (amino) -4- [5- (methylthio) -3-furanyl)] - N-phenyl-2-naftalénkarboxamidmonohydrochlorid

Example 154A

To a solution of 2-trimethylsilyl-3-bromofuran (4.17 g, 19.03 mmol) in THF (40 mL) at -78 ° C was added 1.5 M LDA solution (12.7 mL, 19.03 mmol). The reaction mixture 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 mixture was poured into a saturated aqueous NH ₄ Cl solution and extracted 3 times with diethyl ether. The combined extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude mixture is chromatographed on SiO ₂ using hexanes as eluent to give 3.02 g (60%) of the title compound.

MS (DCI / NH ₃ ) m / z 265, 267 (M + H) &lt; ^{+ &gt};.

Example 154B

A solution of the product prepared according to Example 154A (2.68 g, 10.1 mmol) and a 1M solution of TBAF (20.2 mL) in THF (20 mL) was stirred for 30 minutes. The reaction mixture was concentrated and the desired product was chromatographed on SiO ₂ using hexanes as eluent to give 1.39 g (71%) of 2-methylthio-4-bromofuran. This product was used directly in the next step. To a solution of this product (7 mmol) in THF (25 mL) at -78 ° C was added a 2.5 M BuLi solution (2.8 mL, 7 mmol) and the reaction mixture was stirred for 5 minutes. BujSnCl (1.90 mL, 7 mmol) was then added and the reaction stirred for 30 min and then allowed to warm to room temperature. The reaction mixture was poured into saturated aqueous NH ₄ Cl solution and extracted 3 times with diethyl ether. The combined extracts were washed brine, dried over Na ₂ SO ₄ and concentrated

234 was chromatographed on SiO ₂ using hexanes as eluent to give 1.24 g (30%) of the title compound.

MS (DCI / _NH3) m / z 404 (M + H)

Example 154C

A solution of the product prepared according to Example 154B (920 mg, 2.28 mmol), the product prepared according to Example 152A (662 mg, 2.28 mmol) and

PdCl ₂ (PPh ₃ ) ₂ (161 mg, 0.23 mmol) in CH ₃ CN (15 mL) was stirred at 80 ° C for 18 h. Then, the reaction mixture is concentrated and the crude product is chromatographed on SiO ₂ using 20% ethyl acetate / hexanes as eluent to give 671 mg (91%) of the title compound.

MS (DCI / NH ₃ ) m / z 324 (M + H) &lt; ^{+ &gt};.

Example 154D

The title compound was prepared from the product of Example 154C by the method of Example 152B.

MS (DCI / NH ₃ ) m / z 310 (M + H) &lt; + &gt;.

Example I54E

The title compound was prepared from the product of Example 154D by the method of Example 152C

MS (DC1 / _NH3) m / z 402 (M + _NH4) '

Example 154F

235

6- (aminoiminomethyl) -4- [5- (methylthio) -3-furanyl)] - N-phenyl-2-naphthalenecarboxamide monohydro chloride

The title compound was prepared from the product of Example 154E by the method of Example 144C.

MS (DC1 / _NH3) m / z 402 (M + H) +.

H NMR (300 MHz, _DMSO-d) δ 2.54 (s, 3H), 7.15 (t, IH), 7.24 (s, IH), 7.40 (t, 2H), 7 84 (d, 2H), 7.92 (dd, 1H), 8.19 (d, 1H), 8.39 (d, 1H), 8.44 (s, 1H), 8.61 (s, 1H); 1H), 8.69 (s, 1H), 9.35 (br s, 4H), 10.61 (s, 1H);

Analysis ^- calculated for C23Hi9N3SO2.2,25HCl: C, 57.14; H, 4.43; N, 8.69. Found. C, 57.13; H, 4.21; N, 8.56.

Example 155

Methyl- [7- (amino) -l-naphthalenyl] methyl carbamate mono (trifluoroacetate)

The title compound was prepared according to the methods described in Examples 12 and 13. Yield; 40 mg (42%) of a white solid.

MS m / z; 258 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (DMSO, 300 MHz): 3.28 (s, 3H), 3.82 (br, 3H), 7.66 (dd, 1H, J 1 = 7.5 Hz, J 2 = 1.4 Hz) ), 7.78 (m, 1H), 8.89 (Dd, 1H, J1 = 8.8 Hz, J2 = 2.0 Hz), 8.05 (d, 1H, 8.1 Hz), 8, 24 (d, 1H, 8.8 Hz), 8.30 (s, 1H), 9.09 (s, 2H, 9.52 (s, 2H),

Analysis calculated for C14H15N3O2.1,25C2F3O ₂ .O, 25H2O. C, 49.02; H, 4.18; N, 10.39. Found: C, 48.81; H, 3.91; N, 10.15.

Example 156

236

Propyl [7- (aminoiminomethyl) -1-naphthalenyl] carbamate mono (trifluoroacetate)

The title compound was prepared according to the procedures described in Examples 12 and 13. Yield: 52 mg (46%) of a white solid.

MS m / z: 272 (M + H / 1 H NMR (DMSO, 300 MHz)): 0.97 (t, 3H, J 1 = J 2 = 7.1 Hz), 1.67 (sextet, 2H, J = 7.1 Hz), 4.19 (t, 3H, J 1 = J 2 = 6.8 Hz), 7.71 (d, 1H, 8.5 Hz), 7.83 (m, 3H), 14 (d, J = 8.5 Hz), 8.67 (s, 1H), 9.22 (br, 3H), 9.63 (s, 1H);

Anal. Calcd ₅ Hi7N3O .0,25C ₂ F ₃ O ₂ .O _2, 75H ₂ O: C, 49.18; H, 4.66; N, 9.83. Found: C, 49.27; H, 4.87; N, 10.02.

Example 157

N- [7- (amino) -l-naphthalenyl] -N-methylurea mono (trifluoroacetate)

The title compound was prepared according to the methods of Examples 12 and 13. Yield: 36 mg (54%) of a white solid.

MS m / z: 243 (M + H) ⁺ 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, 1H), 9.07 (s, 2H), 9.47 (s, 2H), (s, 2H);

Calcd for C ₁₃ H ₁₄ N ₄ O • 1.5C ₂ F ₃ O ₂ HO, 5H ₂ O: C 45.50; H, 3.94; N, 13.27. Found: C, 45.22; H 3.86; N, 13.12.

Example 158

Ethyl [7- (aminoiminomethyl) -1-naphthalenyl] carbainate mono (tri fluoroacetate)

237

The title compound was prepared according to the methods of Examples 12 and 13. Yield ^- 70 mg (76%) of a white solid.

MS m / z: 258 (M + H) ⁺ 1 H NMR (DMSO, 300 MHz) 1.30 (t, 3H, J 1 = J 2 = 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);

Analysis: Calculated for C14H15N3O2.1,5C ₂ F ₃ O ₂ H: C, 47.67; H, 3.88; N, 9.81. Found: C, 47.97; H, 3.85; N, 9.78.

Example 159

N- [7- (aminoiminomethyl) -1-naphthalenyl] propanamide mono (trifluoroacetate)

The title compound was prepared according to the methods of Examples 12 and 13. Yield: 20 mg (23%) of a white solid.

MS m / z: 242 (M + H) &lt; ⁺ &gt; ^.

1 H NMR (DMSO, 300 MHz): 1.18 (t, 3H, 7.4 Hz), 3.38 (m, 2H), 7.89 (m, 3H), 7.81 (dd, 1H, J1) = 8.4 Hz, J 2 = 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);

Analysis: Calculated for C14H1JN30.1,15C F3O2H.O _2, 25H ₂ O: C, 51.94; H, 4.45; N, 11.15. Found: C, 52.02; H, 4.24; N, 10.76.

Example 160

N- [7- (aminoiminomethyl) -1-naphthalenyl] -2-methoxyacetamide mono (trifluoroacetate)

The title compound was prepared according to the methods of Examples 12 and 13. Yield 30 mg (30%) of a white solid

238

MS m / z 258 (M + H) ^{@ +} @ 1 H NMR (DMSO, 300 MHz) .delta. 3.49 (s, 3H), 4.18 (s, 2H), 7.80 (m, 3H), 7 93 (d, 1H, 7.7 Hz), 8.47 (d, 1H, 8.5 Hz), 8.47 (s, 1H), 9.10 (s, 2H), 9.46 (s (2H), 9.99 (s, 2H);

Anal. Calcd for C 14 H 15 N 3 O 2 .C 2 F 3 O 2 H. 1.25H ₂ O: 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 = 8.1) 8 Hz), 8.55 (s, 1H), 9.10 (s, 2H), 9.44 (s, 2H), 10.24 (s, 1H);

Calcd for C15H15N3O3.C2F3O2H.H2O: C 48.93; H, 4.35; N, 10.07. Found: C, 48.82; H, 4.27; N, 10.00.

Example 161

N- [7- (amino) -l-naphthalenyl] urea mono (trifluoroacetate)

The title compound was prepared according to the methods of Examples 12 and 13. Yield: 35 mg (54%) of a yellowish solid.

MS m / z: 229 (M + H) ⁺ 1 H NMR (DMSO, 300 MHz): 6.22 (s, 2H), 7.65 (m, 2H), 7.77 (dd, J 1 = 8) 8 Hz, J 2 = 1.5 Hz), 8.57 (s, 1H), 8.79 (s, 1H), 9.07 (s, 2H), 9.49 (br, 2H);

Analysis ^- Calculated for C12H12N40.1 F3O C ₂ HO _2, 75H2O: C, 40.90; H, 3.33; N, 1.95. Found: C, 40.95; H, 3.64; N, 12.31.

Example 162

N- [7- (aminoiminomethyl) -1-naphthalenyl] -2-hydroxyacetamide mono (trifluoroacetate)

239

The title compound was prepared according to the methods of Examples 12 and 13. Yield 24 mg (37%) of a white solid

MS m / z: 244 (M + H) @ 1 H NMR (DMSO, 300 MHz) 4.18 (s, 2H), 5.82 (br, 1H), 7.67 (m, 1H), 7, 85 (m, 3H), 8.20 (d, 1H), 9.18 (s, 2H), 9.42 (s, 2H), 9.89 (s, 1H);

Analysis: Calculated for C ₃ H ₃ N ₃ O ₂ .1 C ₂ F ₃ O ₂ HO 75H2O: C, 48.59; H, 4.21; N, 1.33. Found: C 48.64, H 3.89; N, 11.25.

Example 163

8- (2-pyrimidinyl) -2-Naphthalenecarboximidamide bis (trifluoroacetate)

The title compound was prepared according to the methods of Examples 91A and 13. Yield: 28 mg (28%) of a pale yellow solid.

MS m / z: 264 (M + H) &lt; ⁺ &gt; ^.

1 H NMR (DMSO, 300 MHz): 6.90 (t, 1H, J 1 = J 2 = 4.7 Hz), 7.69 (d, J = 7.8 Hz) m 7.80 (1H, J = 8) 1 Hz), 7.81 (1H, dd, J1 = 8.4 Hz, J2 = 2.1 Hz), 8.08 (1H, dd, J1 = 7.4 Hz, J2 = 0.6 Hz) 8.14 (1H, d, J = 8.5Hz), 8.49 (d, 2H), 8.75 (1H, d, J = 1.7Hz), 9.06 (s, 2H) 9.37 (s, 2H); 9.60 (s, 1H);

Anal. Calcd ₅ H | ₃ N ₅ .2,25C2F O2H.O _3, 25H2O: C, 44.67; H, 4.283.03; N, 13.36. Found: C, 44.49; H, 2.80; N, 13.40.

Example 164

8-amino-2-Naphthalenecarboximidamide bis (trifluoroacetate)

A solution of crude 8-amino-2-nitrile-naphthalene prepared as described in Example 10 in 10: 1 pyridine triethylamine (10 mL) at room temperature was bubbled with hydrogen sulfide for 5 minutes and then stirred overnight at room temperature.

240 room temperature To the reaction mixture, water (50 ml) was added and the product was extracted into ethyl acetate (3 x 30 ml). The combined organic extracts were dried over magnesium sulphate, filtered and evaporated. The resulting solid was taken up in acetone (30 ml) and then methyl iodide (2 ml) was added. The reaction mixture was boiled for 1 hour and then evaporated to dryness. To the obtained yellow product in methanol (25 mL) was added ammonium acetate (100 mg) and the reaction mixture was stirred overnight. Then, the solvent was removed in vacuo and the product was purified by reverse phase chromatography using 0.1% TFA / water and 0.1% TFA / methanol as eluents.

MS m / z: 186 (M + H) &lt; ⁺ &gt; ^.

1 H NMR (DMSO, 300 MHz): 5.14 (br, 3H), 6.80 (dd, J 1 = 7.8 Hz, J 2 = 1 Hz), 7.17 (d, 1H, J = 7, 8 Hz), 7.40 (dd, 1H, J1 = J2 = 7.8 Hz), 7.70 (dd, IH, J1 = 8.9 Hz, J2 = 2.1 Hz), 7.91 (d 1 H, J = 8.5 Hz), 8.65 (s, 1H), 8.95 (s, 2H), 9.23 (s, 2H);

Analysis: Calculated for C] H _(i N ₃ O ₃ .2,5C2F HO _2, 75H2O: C 39.72, H 3.13, N 8.69. Found: C, 40.01; H, 3.19; N 8 , 88th

Example 165

6- (amino) -N- [4- (aminomethyl) phenyl] -4- (2-pyrimidinyl-amino) -2naftalénkarboxamid tris (trifluoroacetate)

Example 165A

To a suspension of 2-nitrile-6-methyl-naphthalene ester according to Example 8D (5.0 g, 23 mmol) in concentrated sulfuric acid (50 mL) at -5 ° C was added solid potassium nitrate. The reaction mixture gradually turned dark brown. The reaction mixture was stirred for 15 minutes and then poured into ice-water. The precipitate was collected and washed with water. The crude product was recrystallized from ethyl acetate and ethanol to yield 4.3 g (68%) of a pale yellow powder.

241

Example 165B

To a solution of Example 165A 2-nitrile-6-methyl-8-nitro-naphthalene (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 an atmosphere of hydrogen at atmospheric pressure (balloon) and stirred at room temperature for 3.5 hours. The mixture was then filtered through celite and silica gel, washed with ethyl acetate and evaporated. The resulting solid was washed with ether (20 mL). Yield: 2.20 g (71%) of a yellow powder.

Example 165C

Mixture of 8-amino-naphthalene 2-nitrile-6-methyl ester according to 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 (1.677 g, 17.6 mmol), 2-bromopyrimidine (2.363 g, 14.9 mmol), and toluene (80 mL) in an oven-dried flask under nitrogen are stirred for 10 min. minutes at room temperature. The reaction mixture was then heated at 80 ° C for 1 hour. After completion of the reaction (TLC, hexanes + ethyl acetate 4: 1), a brine solution of 9200 mL was added. The reaction mixture was then extracted with CH ₂ Cl ₂ (4 x 250 mL). The solvent was evaporated. The yield was 3.5 g (93%) of a light yellow powder.

Example 165D

To a suspension of 8-N- (2-pyrimidine) -naphthalene 2-nitrile-6-methyl ester according to 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 h, turning the suspension to a clear solution. The reaction mixture was then allowed to cool and acidified with 2N HCl. The resulting precipitate was collected by filtration to give 4.5 g (90%) of a pale yellow powder. This product does not need to be further purified before use.

242

Example 165E

To a cold solution of (0 ° C) 2-nitrile-8-N- (2-pyrimidine) -6-carboxylic acid-naphthalene according to Example 165D (5.0 g, 17.2 mmol) in DMF (150 mL) was added D1EA (7.6 mL, 42.6 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (9.8 g, 25.7 mmol) and then tert. butoxycarbonylamino-4-aminomethylaniline (5.74 g, 20 mmol). The resulting 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 give 3.26 g (38%) of a pale yellow powder.

Example 165F

To a solution of the substrate of Example 165E (3.0 g, 6.07 mmol) in pyridine (150 mL) was added triethylamine (9 mL). The reaction mixture was passed through H ₂ S for 10 minutes and the resulting mixture was stirred at room temperature for 48 hours. 100 ml of water are then added to the reaction mixture and the precipitate is collected by filtration. Yield (3.0 g, 93%) as a yellow solid.

Example 165G

To a solution of the thioamide of Example 165 F in acetone (200 mL) was added MeI (6 mL) and the reaction mixture was stirred at room temperature overnight. This mixture was then evaporated to dryness to give 1.2 g (78%) of a yellow solid.

Example I65H

6- (aminoiininometyl) -N- [4- (aminoinetyl) phenyl] -4- (2-pyrimidinyl-amino) -2naftalénkarboxamid tris (trifluoroacetate)

To a solution of the imidate ester of Example I65G (1.5 g, 2.2 mmol) in methanol (50 mL) was added ammonium acetate (0.5 g, 6.4 mmol) and the reaction mixture was stirred for 15 min.

243 was stirred overnight at room temperature. After evaporation of the solvent, the residue was treated with ether (3 x 25 ml) and the ether was decanted. The residue was then dissolved in acetonitrile: acetic acid (50 ml) in a ratio of 101: 1. acetate salt and collected by filtration. To the solid was added 1: 1 TFA: methylene chloride (50 mL) containing thioanisole (0.5 mL) and then stirred at room temperature overnight. The product was purified by RPCig chromatography eluting with water: methanol with 0.1% TFA. After freeze-drying, 0.5 g (54%) of a light yellow solid is obtained.

MS m / z: 412 (M + H) ⁺ 1 H NMR (DMSO, 300 MHz) · 4.02 (q, 2H, J = 5.8), 6.94 (dd, 1H, J 12 = J 2 = 4) 8 Hz), 7.45 (d, 2H, J = 8.5 Hz), 7.84 (d, 2H, J = 8.4 Hz), 7.92 (dd, 1H, J 1 = 8, 5 Hz, J 2 = 1.7 Hz), 8.13 (br, 3H), 8.30 (d, 1H, J = 8.9 Hz), 8.41 (s, 1H), 8.52 (d , 2H), 8.55 (s, 1H), 8.81 (s, 1H), 9.19 (s, 2H), 9.43 (s, 2H), 9.75 (s, 1H), 10 62 (s, 1H);

Anal. Calcd for C ₂₃ H ₂₁ N ₇ O ₂ .5C ₂ F ₃ O ₂ H. 1H ₂ O: C 43.49; H, 3.22; N, 11.83. Found: C, 43.54; H, 3.34; N, 11.69.

Example 166

6- (aminoiminomethyl) -N-phenyl-4- (2-pyrimidinylamino) -2-naphthalenecarboxamide mono (trifluoroacetate)

The procedure of Example 165 was followed except that 4-aminobenzylamine was used instead of aniline.

MS m / z: 383 (M + H) ⁺ 1 H NMR (DMSO, 300 MHz) 6.93-6.96 (m, 1H), 7.14 (dd, 1H, J 1 = 7.3 Hz J 2 = 7.4 Hz), 7.40 (dd, 2H, J 1 = J 2 = 7.3 Hz), 7.80 (d, 2H, J = 8.1 Hz), 7.91 (d, 1H,

244

J = 8.9 Hz), 8.30 (d, 1H, J = 0.0 Hz), 8.41 (s, 1H), 8.52-8.54 (m, 3H), 8.80 (s, 1H), 9.16 (s, 2H), 9.45 (s, 2H), 9.45 (s, 2H), 9.78 (s, 1H), 10.55 (s, 1H) )

Analysis: Calculated for C ₂₂ HigN6O.2C2F O2H.0,25H2O _3: C, 50.78; H, 3.28; N, 13.31. Found: C, 50.85; H, 3.28; N, 13.31

Example 167

N - [(4- (aminomethyl) phenyl] -6- [amino (hydroxyimino) methyl] -4- (2-pyrimidinylamino) -2-naphthalenecarboxamide bis (trifluoroacetate)

To a suspension of Example 165E (0.20 g, 0.40 mmol) in methanol (40 mL) and water (20 mL) was added hydroxylamine hydrochloride (112 mg, 1.75 mmol) and sodium carbonate (85 mg, The reaction mixture was then heated at reflux for 10 hours, more solvents were removed, and 1.2 g of a pale yellow solid was collected by filtration. This solid was dissolved in 1: 1 TFA + CH ₂ Cl ₂ (30 mL) and stirred at room temperature for 24 hours. Then the solvents are removed in vacuo and the residue is applied to a reverse phase R18 column. Lyophilization of the appropriate fraction gave a light 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, 1H, J 1 = J 2 = 5.1 Hz), 7.46 (d, 2H, 8.4 Hz), 7.85 (d, 2H, J = 8.5 Hz), 7.88 (d, 1H, 9 Hz), 12 (d, 3H), 8.22 (d, 1H, J = 8.9 Hz), 8.40 (s, 1H), 8.48 (s, 1H), 8.51 (d, 2H, J) = 4.8 Hz), 8.64 (s, 1H), 9.74 (s, 2H), 10.61 (s, 2H),

Analysis calculated for C ₂₃ H 2 | ₃ N7O2.2,9C2F O2H. 1.25H ₂ O C 44.3 L; H, 3.41; N, 12.56; F, 21.17 Found: C, 44.08; H 3.30, N 12.50, F 21.25.

245

Example 168

6- (amino) -N- [4- (hydroxymethyl) phenyl] -4- (2-pyrimidinyl) -2naftalénkarboxamid mono (trifluoroacetate)

The title compound was prepared according to the method for EXAMPLE 165 using

4-aminobenzyl alcohol instead of 4-aminobenzylamine.

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), J 1 = J2 = 4.8 Hz), 7.32 (d, 2H, J = 8.8 Hz), 7.90 (d, 1H, J1 = 8.5 Hz, J2 = 1.7 Hz), 8.28 (d, 2H, J = 8.8 Hz), 8.41 (s, 1H), 8.54 (d, 2H, J = 4.8 Hz), 8.55 (dd, 1H, J = 1, 3 Hz), 8.80 (s, 1H), 9.08 (s, 2H), 9.43 (s, 2H), 9.73 (s, 1H), 10.48 (s, 1H);

Anal. Calcd for C 23 H ₂₀ N ₆ O 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 - [[[4- (aminomethyl) phenyl] amino] carbonyl] -7- [4-amino (hydroxyimino) methyl] -1-naphthalenyl] carbamate bis (trifluoroacetate)

Example 170A

To a suspension of the nitrile prepared according to Example 141D (213 mg, 0.45 mmol) in methanol (40 mL) and water (5 mL) was added potassium carbonate (538 mg, 3.9 mmol) and the reaction mixture was stirred overnight. the solvent was evaporated and the resulting solid was washed with ether and hexanes to give 153 mg (62%) of a white solid.

MS (EC1) m / z 508 (M + H) &lt; ^{+ &gt};.

246

Example 170B

Methyl [3-1 [[4- (aminomethyl) phenyl] amino] carbonyl] -7- [4-amino (hydroxyimino) methyl] -1-naphthalenyl] carbamate bis (trifluoroacetate)

The substrate, compound 170e protected by Example 170A, was combined with 3 mL of 4 N HCl in dioxane and stirred at room temperature for 20 minutes. Then, the solvent was evaporated in vacuo and the product was separated by MPLC on a PRCu column using methanol-water + 0.1% TFA as eluent. Yield: 117 mg (79%) of a white solid.

MS (ECI) m / z: 408 (M + H) ⁺ H NMR (300 MHz, _DMSO-d6): 3.77 (s, 3H), 4.03 (s, 2H), 4.01 ( q, J = 5.9 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.5 Hz, 2H), 7.90 (dd, J 1 = 8.5 Hz), J ₂ = 1.4 Hz (1H), 8.09-8.15 (m, 4H), 8.17 (d, J = 8.4 Hz, 1H), 8 29 (s, 1H), 8.42 (s, 1H), 8.56 (s, 1H), 9.80 (s, 1H), 10.62 (s, 1H);

Analysis Calcd for C ₂ H ₂ INJOY .2,5TFA.0,5H ₂ O _4: 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.

Example 1 71

6- [amino (hydroxyimino) methyl] -N-phenyl-2-a naphthalene

The title compound was prepared as described by Judkins et al., Synthetic Communications 26 (23), 4351-4367 (1996). Example 55C (0.1 g, 0.36 mmol) was dissolved in toluene: methanol 10: 1 to which was added hydroxylamine hydrochloride (3.6 mmol) and potassium tert-butoxide (3.6 mmol). The resulting slurry was heated at reflux for 17 hours, then the mixture was cooled and the solvents were removed in vacuo. The residue was taken up in distilled water (30 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were washed with 10% NaCl (50 mL) and dried over anhydrous Na ₂ SO ₄ . The desiccant was filtered off from the sample and evaporated in vacuo to give a white solid product (65 mg). This was purified by reverse phase medium pressure chromatography as described in Example 1. The title compound was obtained as a white solid (45 mg).

MS (m / z) M + H &lt; ^{+ &gt};.306;

1 H NMR (DMSO-d 6): 10.51 (s, 1H), 9.32 (s, OH), 8.70 (s, 1H), 8.57 (s, 1H), 8.34 (d) 1 H, 8.25 (d, 1 H), 8.17 (dd, 1 H), 7.90 (dd, 1 H), 7.83 (d, 2 H), 7.40 (dd, 2 H), 7 15 (dd, 1H); 6.25 (bs, 2H);

Calcd for C 20 H 16 N 3 O 4 F 3: C 57.28, H 3.85; N, 10.02. Found: C, 56.89; H, 3.65; N, 9.90.

Example 174

8- (2-pyridylamino) -2-Naphthalenecarboximidamide bis (trifIuóracetát)

Example 174A

To a solution of Example 11D (168 mg, 1.00 mmol) in 5 mL of toluene was added 2-bromopyridine (0.105 mL, 1.1 mmol), NaOtBu (135 mg, 1.4 mmol), Pd ₂ dba ₃ ( 92 mg, 0.1 mmol) and P (o-tolyl) ₃ (122 mg, 0.4 mmol) and the reaction mixture was stirred at 100 ° C for 24 h. Then the reaction mixture was cooled and the crude mixture was chromatographed on SiO ₂ using 50% ethyl acetate / hexanes as eluent to give 80 mg (33%) of the title compound.

MS (DCI (NH ₃ )) m / z 246 (M + H) &lt; ⁺ &gt; ^.

Example 174B

8- (2-pyridinylainino) -2-naftalénkarboximidainid bis (trifluoroacetate)

248

The product of Example 174A (121 mg, 0.493 mmol) was dissolved in THF (2 mL) and a 1 M solution of LiN (TMS) ₂ in THF was added. The reaction mixture was stirred for 5 minutes and then TMSCl (0.069 mL, 0.543 mmol) was added. After stirring for 30 minutes, an additional 1.09 mL of 1M LiN (TMS) ₂ solution was added. The reaction mixture was stirred for 18 hours and then 10 mL of 2 M aqueous HCl was added. The reaction mixture was then stirred for an additional 24 hours and then basified with saturated aqueous Na ₂ CO ₃ . This mixture is extracted 3 times with ethyl acetate, the extracts are washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by reverse phase HPLC to yield the title compound (21 mg, 7%); 1.1. 137-147 ° C.

MS (DCI (NH ₃ )) m / z 263 (M + H) &lt; ^{+ &gt};.

1 H NMR (300 MHz, DMSO) (9.98 (br s, 2H), 9.46 (br s, 2H), 9.27 (br s, 2H), 8.74 (s, 1H), 8 21 (d, J = 9Hz, 1H), 8.11 (d, J = 6Hz, IH), 8.02 (d, J = 9Hz, IH), 7.81-7.95 (m) 3H), 7.75 (dd, J = 9.9 Hz, 1H), 7.16 (m, 1H), 6.95 (m, 1H), 2.55 (s, 3H);

Calcd for C ₁₆ H ₄ N ₄ .3.1C ₂ HF ₃ O ₂ : C, 43.30; H, 2.80; N, 9.10. Found: C, 43.14; H, 3.04; N, 9.90

Example 176

6- [4 - [(hydroxymethyl) phenyl] methoxy] -2-methanesulfonyl-naftaIénkarboximidamid

Example 176A

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 the mixture was stirred at room temperature for 20 minutes. Methoxybenzyl chloride (4.07 mL, 30 mmol) was then added and the reaction mixture was stirred at 50 ° C for 2 h. The mixture was poured into water and extracted 3 times with diethyl ether, the combined extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated Crude

The 249 reaction mixture was chromatographed on SiO ₂ using hexanes as eluent to give 7.39 g (86%) of the title compound.

MS (DCI (NH ₃ )) m / z 326 (M + NH ₄ ) +.

1 H NMR (300 MHz, CDCl ₃ ) δ 7.47 (d, 2H), 7.28 (d, 2H), 7.23 (d, 2H), 6.90 (d, 2H), 4.48 (s, 3H), 4.47 (s, 2H), 3.91 (s, 3H).

Example 176B

To a solution of Example 176A (6.80 g, 22.13 mmol) in THF (100 mL) and hexanes (20 mL) at -100 ° C was added a 2.5 M BuLi solution (8.85 mL, 22 mL). 13 mmol) and the reaction mixture was stirred for 2 minutes. DMF (3.43 mL, 44.3 mmol) was then added and the reaction warmed to room temperature. The mixture was poured into water and 3 times with diethyl ether, the extracts are washed with brine, dried with Na ₂ SO ₄ and concentrated. The crude reaction mixture was taken up in methanol (100 mL) and NaBH ₄ (1.0 g, 26.2 mmol) was added portionwise. A few drops of water are then added and the mixture is concentrated. The residue was chromatographed on SiO ₂ eluting with 20% ethyl acetate / hexanes to give 3.32 g (58%) of the title compound.

MS (DCI (NH ₃ )) m / z 276 (M + NH ₄ ) ⁺ 1 H NMR (300 MHz, CDCl ₃ ) δ 7.38 (d, 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, 1H) ).

Example 176C

To a solution of Example 176B (193 mg, 0.747 mmol), Example 28A (130 mg, 0.822 mmol) and Ph ₃ P (216 mg, 0.822 mmol) in THF (10 mL) at 0 ° C was added diethyl azodicarboxylate (0.129 mL, 0.822 mmol) and the reaction was stirred at room temperature for 90 minutes. The crude reaction mixture was concentrated and chromatographed on SiO ₂ using

250% 10% ethyl acetate / hexanes gave 225 mg (74%) of the title compound.

MS (DCI (NH ₃ )) m / z 427 (M + NH ₄ ) +.

1 H NMR (300 MHz, CDCl 3) δ 8.15 (s, 1H), 7.81 (d, IH), 7.77 (d, IH), 7.58 (d, IH), 7.48 ( 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

To a solution of the product prepared according to Example 176C (220 mg, 0.537 mmol) in CH ₂ Cl ₂ (40 mL) and water (7 mL) was added DDQ (244 mg, 1.07 mmol) and the reaction mixture was stirred for 90 minutes. The crude reaction mixture was taken up in CH 2 Cl 2, washed twice with aqueous NaHCO 3 and brine, dried over Na ₂ SO ₄ and concentrated. Chromatography of the residue on SiO ₂ using 50% ethyl acetate / hexanes as eluent gave 89 mg (57%) of the title compound.

MS (DCI (NH ₃ )) m / z 307 (M + NH ₄ ) ⁺ .

1 H NMR (300 MHz, CDCl 3) δ 8.15 (s, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.49 (d, 2H), 7.41 ( d, 2H), 7.33 (d, 1H), 7.21 (d, 1H), 5.21 (s, 2H), 4.74 (s, 2H), 1.63 (br s, 1H) .

Example 176E

6- [4 - [(hydroxymethyl) phenyl] methoxy] -2-methanesulfonate Naphthalenecarboximidamide

The title compound was prepared from Example 176D following the procedure of Example 55D.

MS (DCI (NH ₃ )) m / z 307 (M + H) +.

251 1 H NMR (300 MHz, DMSO-d 6) δ 2.31 (s, 3H), 4.52 (s, 2H), 5.25 (s, 2H), 7.37 (d, 2H), 7.39 (dd, 1H), 7.47 (d, 2H), 7.59 (d, IH), 7.79 (dd, IH), 8.00 (d, IH), 8.03 (d) 1 H, 8.41 (s, 1H), 8.89 (br s, 2H), 9.34 (br s, 2H);

Analysis: Calculated for C, _with N ₂ H ₄ SO ₂ .1,15CH 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-pyrimidinyl) -2-naftaIénkarboximidamid mono (trifIuóracetát)

The title compound was prepared from the nitrile described in Example 163 as described in Example 167. Yield as a white powder: 60 mg.

MS m / z: 280 (M + H) &lt; ^{+ &gt};.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 6.90 (dd, 1H, J 1 = J 2 = 5.2 Hz), 7.45 (m, 3H), 8.0 (d, 1H, J = 8.5 Hz), 8.14 (d, 1H, J = 8.4 Hz), 8.49 (d, J = 5.3 Hz), 8.61 (s, 1H), 9.58 ( s, 1H);

Analysis: Calculated for Ci5Hi ₃ N ₅ O.2,0C2F O2H.0,5H2O _3: C, 44.20; H, 3.12; N, 13.56. Found: C, 44.24; H, 2.94; N, 13.49.

Example 179

6- (2-pyridinyletinyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate)

Example 179A

The title compound was prepared from the product prepared according to Example 28B and 2-ethynylpyridine (Lancaster Chemical Corp) by the method of Example

121 A

252

MS (DCI / _NH3) m / z 255 (M + H) ⁴

Example 179B

The title compound was prepared from the product prepared as in Example 179A by the method of Example 94D.

MS (DCI / _NH3) m / z 272 (M + H) ^+.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 7.45-7.50 (m, 1H), 7.72 (d, 1H), 7.82 (dd, 1H), 7.86-7, 92 (m, 2H), 8.18 (d, 1H), 8.22 (d, 1H), 8.42 (s, 1H), 8.54 (s, 1H), 8.68 (m, IH) 1.25 (s, 2H); 9.49 (s, 2H);

Anal ^. Calcd for C ₂₀ H ₁₄ F ₃ N ₃ O ₂ 0.25H ₂ O: C 61.62; H, 3.75; N, 10.78. Found: C, 61.72; H, 3.64; N, 10.66.

Example 180

6- (amino) -N-phenyl-4- (tetrahydro-3-furanyl) -2-naftalénkarboxamidmonohydrochlorid

Example 180A

The title compound was prepared from the product of Example 152 by the methods of Example 62A

MS (DCI / NH ₃ ) m / z 340 (MH ₂ O) ⁺ .

Example 180B

The title compound was prepared from the product of Example 180A by the method of Example 62B.

253

MS (DCI / _NH3) m / z 343 (M + H)

Example 180C

The title compound was prepared from Example 180B following the procedure of Example 55D

MS (DCI / _NH3) m / z 360 (M + H) +.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 2.20 (m, 1H), 2.52 (m, IH), 3.85 (dd, IH), 3.94 (ddd, IH), 4 Δ (ddd, 1H), 4.26 (dddd, 1H), 7.14 (t, 1H), 7.40 (t, 2H), 7.81 (d, 2H), 7.95 (d, 1H), 8.08 (s, IH), 8.32 (d, IH), 8.59 (s, IH), 8.79 (s, IH), 8.79 (s, IH), 9, 25 (br s, 2H); 9.61 (br s, 2H);

Anal. Calcd for C ₂ H 21 N ₃ O ₂ .2.6HCl: C 58.18; H, 5.24; N, 9.25. Found: C, 58.21; H, 4.91; N, 9.13

Example 181

6- [amino (hydroxyimino) methyl] -N-phenyl-4- (2-pyrimidinylamino) -2-naphthalenecarboxamide

Prepared in an analogous manner to that described in Example 177 using the product of Example 166.

MS m / z: 399 (M + H) \ 'H NMR (300 MHz, _DMSO-d) 6.88 (dd, IH, 4.7 Hz), 7.11 (dd, IH, J 1 = J 2 = 7.5 Hz), 7.37 (dd, 2H, J 1 = J 2 = 7.5 Hz), 7.82 (d, 2H, J = 8.8 Hz), 7.94 (dd, 1H, J 1 = 8.5 Hz, J 2 = 1.4 Hz), 8.04 (d, 1H, J = 8.8 Hz), 8.3 L (s, IH), 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);

254

Analysis calculated for C 22 H | g N _n is ₂ .0,4H2O: C 65.14; H, 4.67; N, 20.72. Found: C, 65.57; H, 4.45; N, 20.18

Example 182

Methyl 4 - [[[7-amino (hydroxyimino) methyl] -2-naftaIenyl] oxy] methyl] benzoate

The product prepared according to Example 213A (110 mg, 0.347 mmol), hydroxylamine hydrochloride (26.5 mg, 0.381 mmol), triethylamine (53 μΐ, 0.381 mmol) and N, N-dimethylformamide (12 mL) were combined in a 4-inch pressure glass tube. . The tube is sealed and heated at 80 ° C for 24 hours. The tube was then cooled to room temperature and additional hydroxylamine hydrochloride (48.1 mg, 0.693 mmol) and triethylamine (96.6 μΐ, 0.693 mmol) in N, N-dimethylformamide (2 mL) were added. The tube is then resealed and heated at 80 ° C for 24 hours. The above procedure is repeated once more, then the tube is resealed and heated at 80 ° C for 72 hours. The reaction mixture was then concentrated to a solid residue, which was purified by silica gel column chromatography (60 g) using 15% acetone in methylene chloride to yield the title compound as a white solid (43 mg, 50% based on starting material).

MS (DCI (NH ₃ )) m / z 351 (M + H) &lt; ^{+ &gt};.

H NMR (300 MHz, _DMSO- d) δ 3.860 (s, 3 H), 5.439 (s, 2H), 5.860 (s, 2H), 7.280 (br s, IH), 7.381 (d, H), 7.660 ( d, 2H), 7.688 (dd, IH), 7.805 (d, IH), 7.850 (d, IH), 8.010 (d, 2H), 8.070 (s, IH), 9.724 (s, IH),

Analyzers calculated for C ₂ nH | _S N ₂ O ₄ .0.15H ₂ O: C 68.04; H, 5.22; N 7.93 Found C 68.06, H 5.05; N, 7.87

Example 1 84

255

N- [4- (aminocarbonyl) phenyl] -6- (aminoiminomethyl) -2-naphthalenecarboxamide mono (trifluoroacetate)

Example 184A

A suspension of the product prepared according to Example 8A (300 mg, 1.39 mmol) and 5 mL of dichloromethane was added dropwise at 0 ° C to a solution of 4-aminobenzamide (207 mg, 1.52 mmol) and trimethylamine (0.44 mL, 3 mL). , 2 mmol) with 10 mL of dichloromethane. The reaction mixture was stirred at 0 ° C for 0.5 h and at room temperature for 18 h. Ether is added with stirring in excess, and the resulting solid product is filtered off, washed with 1N HCl, water, and dried in vacuo to give the title compound.

MS (DCI) m / z 333 (M + NH ₃₎ ^+.

Example 184B

N- [4- (aminocarbonyl) phenyl] -6- (amino) -2-naftalénkarboxamidmono (trifluoroacetate)

The title compound was prepared using the product of Example I84A and the method of Example 4C

MS (DCI) m / z 333 (M + H) &lt; ^{+ &gt};.

H NMR (300 MHz, _DMSO-d) δ 10.76 (s, 1H), 9.51 (s, 2H), 9.14 (s, 2H), 8.74 (s, 1H), 8 56 (s, 1H); 8.33 (d, 1H, J = 8.8 Hz); 8.26 (d, 1H, J = 8.8 Hz); 8.46, 1.11 Hz), 7.91 (m, 6H), 7.31 (s, 1H),

Anal. Calcd for C ₂₁ H ₁₇ F ₃ N ₄ O ₄ .1.5H ₂ O 53.28; H, 4.26; N, 11.83. Found: C, 53.47; H, 3.86; NI 1.96

256

Example 185

Methyl 2 - [[6- (amino) -2-naphthalenyl] oxy] acetate mono (trifluoroacetate)

Example 185A

7-Methoxy-2-cyano-naphthalene (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 stirred, cooled (ice / water) suspension of aluminum iodide (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 suspension formed is heated at reflux for 2.5 hours. The heating was then removed and after cooling to near room temperature, the reaction mixture was cooled in an ice bath and quenched with water (100 mL). The resulting mixture was further diluted with 2M aqueous sodium thiosulfate solution (50 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were dried and evaporated. Dissolve the remaining solid in a minimum amount of hot ethyl acetate, dilute with hexanes until turbid, and place in a refrigerator for 2 hours. The desired compound (1.99 g, 77%) was then filtered off.

MS (DCI (NH ₃ )) m / z 187 (M + NH ₄ ) ⁺

Example 185B

The product prepared according to Example 185A (217 mg, 1.283 mmol) was combined with cesium carbonate (460 mg, 1.41 mmol) and tetrabutylammonium iodide (cat.) In DMF (7 mL). Then tert-butyl bromoacetate (193 μΐ, 1.283 mmol) was added and the resulting reaction mixture was stirred under an inert atmosphere for 2 hours. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried and evaporated. The residue was purified by column chromatography to give the title compound (332 mg, 91%) as an oil;

257

MS (DC1 (NH ₃₎₎ m / z 284 30] (M + NH ₄ f.

Example 185C

Methyl 2 - [[6- (amino) -2-naphthalenyl] oxy] acetate mono (trifluoroacetate)

The product prepared according to Example 185B (323 mg, 1.140 mmol) was dissolved in anhydrous methanol (35 mL) under an inert atmosphere and cooled to 0 ° C. Anhydrous hydrogen chloride is bubbled through this solution until a saturated solution is formed. The reaction mixture was then stirred at 0 ° C for 15 minutes and then re-saturated with anhydrous hydrogen chloride. The solution was then stirred again for another 20 minutes at 0 ° C, and the solution was finally saturated once more with anhydrous hydrogen chloride and stirred for 18 hours while allowing to warm to room temperature. Then the reaction mixture was evaporated to a solid residue, which was dried under high vacuum for 2 hours. The solid residue was slurried with methanol (64 mL), ammonium acetate (220 mg, 2.850 mmol) was added and the mixture was heated at reflux for 2 h. The reaction mixture was evaporated and purified by reverse phase chromatography to give the title compound (265 mg, 90%).

MS (DCI (NH ₃ )) m / z 259 (M + H) &lt; ^{+ &gt};.

H NMR (300 MHz, DMSO- d _d) δ 3.735 (s, 3 H), 4.995 (s, 2H), 7.430 (d, H), 7.458 (s, IH), 7.669 (d, H), 8.025 ( d, 1H), 8.095 (d, 1H), 8.325 (d, 1H), 9.090 (br s, 1H), 9.410 (br s, 1H);

Anal. Calcd ₄ H ₄ N ₂ O _3. (C ₂ H 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

6- (amino) -N- (2-thiazolyl) -2-a naphthalene monohydrochloride

258

Example 186A

The above product was prepared as in Example 8A using 2-aminothiazole.

MS (APCI) m / z (M + H) &lt; ^{+ &gt};280;

Example 186B

6- (Aminomethyl) -N- (2-thiazolyl) -2-naphthalenecarboxamide monohydrochloride

The above compound was prepared by the method of Example 1B.

MS (APCI) m / z (M + H) &lt; ^{+ &gt};297;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 12.88 (s, 3H), 9.59 (s, 2H), 9.30 (s, 2H), 8.87 (s, 1H), 8 59 (s, 1H), 8.32-8.22 (m, 4H), 7.93 (dd, J = 1.8, 8.4 Hz, 1H), 7.61 (d, J = 3) 3 Hz, 1H), 7.33 (d, J = 3.3 Hz, 1H),

Analysis: Calculated for C ₅ H ₃ N ₄ OC1S.2 / 5HC1: C 52.03; H, 3.89; N, 16.18. Found: C, 52.01; H, 3.88; N, 16.12

Example 187

6- (Aminomethyl) -N- (6-methoxy-3-pyridinyl) -2-naphthalene-carboxamide monohydrochloride

Example 187A

The above product was prepared by the method of Example 8A using 5-amino-2-methoxy-pyridine

MS (APCI) m / z (M + H) ^4304,

259

Example 187B

6- (Aminomethyl) -N- (6-methoxy-3-pyridinyl) -2-naphthalene-carboxamide monohydrochloride

The above compound was prepared according to the method of Example 1B (144D).

MS (CI) m / z (M + H) &lt; + &gt;321;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H) m 3.87 (s, 3H);

Calcd for C20H17N4O4F3.1 / 2 TFA: C, 51.47; H, 3.60; N, 11.45. Found: C, 51.39; H, 3.88; N, 11.65.

Example 188

6- (aminoiminomethyl) -N- (1,3-benzodioxol-5-yl) -2-naphthalenecarboxamide mono (trifluoroacetate)

Example 188A

The above product was prepared according to the method of Example 8A using 3,4-methylenedioxy aniline.

MS (APCI) m / z (M + H) &lt; + &gt;

Example 188B

The product was prepared as described in Example 1B.

MS (Cl) m / z (M + H) &lt; + &gt;334;

260 1 H NMR (300 MHz, DMSO-d 6) δ 9.70 (s, 1H), 8.20 (s, 2H), 9.96 (s, 1H), 7.81-87.63 (m 3H), 7.31 (dd, J = 1.8 8.4 Hz, 1H), 7.11 (d, J = 4.2 Hz, IH), 6.91 (dd, J = 4.5) 10.8 Hz), 6.4 (d, J = 8.4 Hz, 1H), 5.59 (s, 2H);

Analysis Calcd for C ₂ H 16N3O3F3.3 / 5 TFA: C, 55.44; H, 3.48; N, 8.77. Found: C, 55.44; H, 3.52; N, 8.85.

Example 189

6- (aminoiminomethyl) -N- (1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinyl) -2-naphthalenecarboxamide monohydrochloride

Example 189A

The above product was prepared according to the method of Example 8A using 5-aminouracil.

MS (APCI) m / z (MH) &lt; ^{+ &gt;} 305,

Example 189B

6- (aminoiminomethyl) -N- (1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinyl) -2-naphthalenecarboxamide monohydrochloride

The above compound was prepared by the method of Example 1B.

MS (CI) m / z (M + H) &lt; + &gt;324;

H NMR (300 MHz, DMSO-d _f>) δ 11.50 (s, IH), 10.90 (m, IH), 9.53 (s, 3H), 9.21 (s, 2H); 8.70 (s, 1H), 8.55 (s, IH), 8.33 (d, J = 8.4 Hz, IH), 8.20 (d, J = 8.7 Hz, IH), 8.13-8.09 (m, 2H), S.00 (s, 1H), 7.88 (dd, J = 1.8 8.4 Hz, 1H),

261

Calcd for C16H14N5O3Cl.2 / 5 HCl C 51.49; H, 3.88; N, 18.76. Found: C, 51.87; H, 4.01; N, 17.68.

Example 190

6- (amino) -N- (3,5-difluorophenyl) -2-a naphthalene-mono- (trifIuóracetát)

Example 190A

The above product was prepared as in Example 8A using 3,5-difluoroaniline.

MS (APCI) m / z (M + H) &lt; ^{+ &gt};307;

Example 190B

6- (aminoiminomethyl) -N- (3,5-difluorophenyl) -2-naphthalenecarboxamide mono (trifluoroacetate)

The above compound was prepared as described in Example 1B.

MS (CI) m / z (M + H) &lt; ^{+ &gt};326;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 10.93 (s, 1H), 9.53 (s, 2H), 9.34 (s, 2H), 8.71 (s, 1H), 8 , 58 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.26 (d, &gt; 8.7 Hz, IH), 8.14 (m, 1H), 7, 92 (dd, > 0.9 8.1 Hz, 1H), 7.61 (d, > 7.8 Hz, 2H), 7.04-6.97 (m, 1H),

Analyzers calculated for C _{2 ohnny?} 0 ₂ F ₅ .2 / 5 TFA: C, 54.92; H, 3.21; N, 9.42. Found: C, 54.96; H, 3.36; N, 9.37

262

Example 191

6- (aminoiminomethyl) -N- (1H-pyrazol-3-yl) -2-naphthalenecarboxamide mono (trifluoroacetate)

Example 191 A

The above product was prepared according to the method of Example 8A using 3-aminopyrazole.

MS (APCI) m / z (M + H) &lt; ^{+ &gt;} 263.

Example 191B

6- (Aminomethyl) -N- (1H-pyrazol-3-yl) -2-naphthalenecarboxamide mono (trifluoroacetate)

The above compound was prepared by the method of Example IB.

MS (CI) m / z (M + H) &lt; ^{+ &gt};280;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 9.55 (s, 2H), 9.37 (s, 2H), 8.75 (s, 1H), 8 55 (s, 1H), 8.23 (d, J = 8.4Hz, IH), 8.12 (s, IH), 7.90 (d, J = 8.4Hz, IH), 7 70 (s, 1H); 6.69 (s, 1H);

Calcd for C17H14N5O3F3.7 / 10 TFA: C, 46.53; H, 3.12; N, 14.70. Found: C, 46.47; H, 3.16; N, 14.85.

Example 192

6- (amino) -N- (5-methyl-3-isoxazolyl) -2-naftalénkarboxamidmono (trifluoroacetate)

263

Example 192 A

The above product was prepared by the method of Example 8A using 3-amino-5-methylisoxazole.

MS (APCI) m / z (M + H) &lt; ^{+ &gt;} 278

Example 192B

6- (amino) -N- (5-methyl-3-isoxazolyl) -2-naftalénkarboxamidmono (trifluoroacetate)

The above compound was prepared as described in Example IB.

MS (CI) m / z (M + H) &lt; ^{+ &gt};295;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 6.81 (s, 1H), 2.44 (s, 3H);

Calcd for C18H15N4O4F3: C, 52.95; H, 3.70; N, 13.72. Found: C, 52.73; H, 3.64; N, 13.24.

Example 193

6- (amino) -N- (pyrazinyl) -2-a naphthalene-mono (trifluoroacetate)

Example 193 A

The above product was prepared by the method of Example 8A using 2-aminopyrazine.

MS (APCI) m / z (MH) &lt; ^{+ &gt;} 275.

264

Example 193B

6- (amino) -N- (pyrazinyl) -2-a naphthalene-mono (trifluoroacetate)

The above compound was prepared by the method of Example IB.

MS (CI) m / z (M + H) ⁺ 292, 1 H NMR (300 MHz, DMSO-d ₆ ) δ 11.41 (s, 1H), 9.52 (s, 2H), 9.49 ( s, 1H), 9.27 (s, 2H), 8.83 (s, 1H), 8.56 (s, 1H), 8.53-8.46 (m, 2H), 8.30 (d) 1 H, 8.23 (s, 2H), 7.90 (dd, 1H);

Calcd for C18H14N5O3F3: C, 49.36; H, 3.16; N, 15.15 1/2 TFA. Found: C, 49.53; H, 3.22; N, 14.87.

Example 194

6- (amino) -N- (6-methyl-2-pyridinyl) -2-naftalénkarboxamidmono (trifluoroacetate)

Example 194A

The above product was prepared as in Example 8A using 2-amino-6-methylpyridine.

MS (APCI) mlz (M + H) ⁺ 288.

Example 194B

6- (Aminomethyl) -N- (6-methyl-2-pyridinyl) -2-naphthalenecarboxamide mono (trifluoroacetate)

The above compound was prepared by the method of Example IB.

265

MS (CI) m / z (M + H) ^4305;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 11.02 (s, 1H), 9.53 (s, 2H), 9.37 (s, 1H), 8.80 (s, IH), 8 55 (s, 1H), 8.29 (d, 1H), 8.20 (s, 2H), 8.07 (d, 1H), 7.89 (d, 1H), 7.78 (t, 1H), 7.08 (d, 1H), 2.48 (s, 3H),

Anal. Calcd for C 21 H 17 N 4 O 3 F 3: C 48.74, H 3.33; N, 10.20 7/5 TFA. Found: C, 48.74; H, 3.59; N 10.1 l.

Example 195

6- (Aminomethyl) -N- (3,4,5-trimethoxyphenyl) -2-naphthalenecarboxamide monohydrochloride

Example 195A

The above product was prepared by the method of Example 8A using 3,4,5-trimethoxyaniline.

MS (APCI) m / z (M + H) &lt; ^{+ &gt;} 363.

Example 195B

6- (amino) -N- (3,4,5-trimethoxyphenyl) -2-naftalénkarboxamidmonohydrochlorid

The above compound was prepared by the method of Example IB.

MS (C1) m / z (M + H) ^4380;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H), 9.61 (s, 2H), 9.34 (s, 2H), 8.72 (s, 1H), 8 59 (s, 1H), 8.33-8.15 (m, 3H), 7.91 (dd, 1H), 7.30 (s, 2H), 3.80 (s, 9H);

266

Calcd. For C21H22N3O4Cl.63 / 1OHCl C 39.09; H, 4.42; N, 6.5. Found. C 38.94; H, 4.60; N, 7.61.

Example 196

6- (Aminomethyl) -N- (3-methyl-2-pyridinyl) -2-naphthalenecarboxamide bis (trifluoroacetate)

Example 196A

The title compound was prepared according to the procedure for EXAMPLE 184A using 2-amino-3-picolene in place of 4-aminobenzamide.

MS (DCI) mlz 288 (M + H) ⁺ .

Example 196B

6- (amino) -N- (3-methyl-2-pyridinyl) -2-naftalénkarboxamidbis (trifluoroacetate)

The above compound was prepared by the method of Example 1B using the product of Example 196A.

MS (DCI) m / z 305 (M + H) ^&lt; ^{+ &gt};;

H NMR (300 MHz, DMSO-d _rt) δ 10.85 (s, IH), 9.52 (s, 2H), 9.22 (s, 2H), 8.76 (s, IH), 8 , 56 (s, 1H), 8.35 (dd, J = 4.41 1.10), 8.32 (d, 1H,> 8.80), 8.22 (m, 2H), 7.90 (dd, IH, > 8.83 1.84), 7.80 (dd, 1H, J = 7.73, 1.11), 7.31 (dd, IH, J = 7.72 4, 78), 2.26 (s, 1H);

Analysis calculated for C ₂₂ H _{ι 8} Ρ ₆ Ν ₄ Ο ₃ .0,75 Η ₂ Ο. C 48.80; H 3.60, N 10.26 Found - C 48.81, H 3.66; N, 10.43.

267

Example 197

6- (amino) -N- (5-bromo-2-thiazolyl) -2-naftalénkarboxamidmono (trifluoroacetate)

Example 197A

The title compound was prepared according to the procedure for EXAMPLE 184A using 2-amino-5-bromothiazole in place of 4-aminobenzamide.

MS (DCI) m / z 358 (M + H) &lt; ^{+ &gt};.

Example 197B

6- (aminoiminomethyl) -N- (5-bromo-2-thiazolyl) -2-naphthalenecarboxamide mono (trifluoroacetate)

The above compound was prepared by the method of Example IB using the product of Example 197A

MS (ESI &^lt; ^{+ &gt};) m / z 375 (M + H) ^&lt; ^{+ &gt};;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.85 (s, 1H), 9.55 (s, 2H), 9.24 (s, 2H), 8.87 (s, 1H), 8 57 (d, 1H, 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. Calcd ₇ H | ₂ BrF ₃ SN ₄ O ₃ .1.25H ₂ O 0.25TFA: C 38.90; H, 2.75; N, 10.37. Found: C 38.97, H 3.24, N 10.66

Example 198

6- (aminoiminomethyl) -N- (5-methyl-2-pyridinyl) -2-naphthalenecarboxamide mono (trifluoroacetate)

268

Example 198A

The title compound was prepared according to the procedure for EXAMPLE 184A using 2-amino-5-picolene in place of 4-aminobenzamide.

MS (ESI) m / z 288 (M + H) '

Example 198B

6- (amino) -N- (5-methyl-2-pyridinyl) -2-naftalénkarboxamidmono (trifluoroacetate)

The above compound was prepared by the method of Example IB using the product of Example 198A

MS (ESI +) m / z 305 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 11.01 (s, 1H), 9.50 (s, 2H), 9.16 (s, 2H), 8.79 (s, 1H), 8 54 (s, 1H), 8.30 (d, 1H, J = 9.19), 8.27 (d, 1H, J = 1.47), 8.20 (s, 2H), 8.15 (d, 1H, J = 8.33), 7.89 (dd, IH, J = 8.46 1.48), 7.72 (dd, IH, J = 8.46, 1.84), 2 31 (s, 3H);

Calcd for C ₂₀ H ₁₇ F ₃ N ₄ O ₃ 0.25H ₂ 0.0.2TFA: C 54.98; H, 4.00; N, 12.57. Found: C, 54.99; H, 3.59; N, 12.43.

Example 199

6- (amino) -N- (4-methyl-2-tiazoIyl) -2-naftalénkarboxamidmono (trifluoroacetate)

Example 199A

The title compound was prepared according to the procedure for EXAMPLE 184A using 2-amino-5-methyl-benzothiazole in place of 4-aminobenzamide.

269

MS (ESI -) m / z 293 (M + H) &lt; + &gt;.

Example 199B

6- (amino) -N- (4-methyl-2-thiazolyl) -2-naftalénkarboxamidmono (trifluoroacetate)

The above compound was prepared by the method of Example IB using the product of Example 199A.

MS (ESI &^lt; ^{+ &gt};) m / z 311 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 9.51 (s, 2H), 9.25 (s, 2H), 8.86 (s, 1H), 8.55 (s, 1H,), 8.30 (d, 1H, J = 8.48), 8.25 (d, IH, J = 2.03), 7.91 (dd, IH, J = 8.48)

1.70), 6.87 (s, 1H), 2.34 (s, 3H);

Anal. Calcd for C 18 H 18 F 3 N 4 O • S · STFA: C, 47.40; H, 3.25; N

II, 64. Found: C, 47.90; H, 3.36; N, 11.71.

Example 200

6- (Aminomethyl) -4- (5- (ethylthio) -3-furanyl) -N-phenyl-2-2-naphthalenecarboxamide monohydrochloride

Example 200A

The title compound was prepared from 2-trimethylsilyl-3-bromofuran and diethylsulfide according to the method of Example I54A

MS (DC1 / _NH3) m / z 279, 281 (M + H) ⁺

270

Example 200B

A solution of the product prepared according to Example 200A (8.60 g, 30.8 mmol) in THF (20 mL) was stirred for 24 h with a 1 M solution of TBAF (61.6 mL). Thereafter, the reaction mixture was concentrated and chromatography on SiO ₂ eluting with hexanes gave 3.32 g (52%) of 2-ethylthio-4-bromofuran. From this product, the title compound was prepared as in Example 57A.

MS (DC1 / _NH3) m / z 127 (MB (OH) ₂₎ ⁺

Example 200C

The title compound was prepared from the products prepared according to Examples 200B and 152C by the method of Example 57B.

MS (DCI / _NH3) m / z 416 (M + NH ₄₎ ^+.

Example 200D

6- (amino) -4- [5- (ethylthio) -3-furanyl] -N-phenyl-2-naftalénkarboxamidmonohydrochlorid

The title compound was prepared from Example 200C by the method of Example 144C.

MS (DCI / _NH3) m / z 416 (M + H) ^4;

H NMR (300 MHz, _DMSO-fi) δ 1.30 (t, 3H), 2.92 (q, 2H), 7.15 (t, IH), 7.34 (s, IH), 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, 1H), 8.69 (s, 1H), 9.21 (br s, 2H), 9.58 (br s, 2H), 10.61 (s, 1H);

Anal. Calcd for C ₂₄ H ₂₁ N ₃ SO ₂ .1.5HCl C 61.3 L; H, 4.82; N, 8.94 Found C, 61.39; H, 4.89; N, 9.03

271

Example 201

6- (Aminomethyl) -4- [5- (propylthio) -3-furanyl] -N-phenyl-2-naphthalene to arboxamide monohydrochloride

Example 201A

The title compound was prepared from 2-trimethylsilyl-3-bromofuran and di-propylsulfide according to the method of Example I54A.

MS (DCI / _NH3) m / z 293, 295 (M + H) ^+.

Example 201B

The title compound was prepared from the product of Example 201A following the procedure of Example 154B.

MS (DCI / NH ₃ ) m / z 432 (M + H) &lt; ^{+ &gt};.

Example 201C

The title compound was prepared from the products prepared according to Examples 201B and 152C by the method of Example 154C.

MS (DCI / NH ₃ ) m / z 430 (M + NH 3) +.

Example 201 D

6- (amino) -4- [5- (propylthio) -3-furanyl] -N-phenyl-2-naftalénkarboxamidmonohydrochlorid

272

The title compound was prepared from Example 201 C by the method of Example I 44C.

MS (DCI / NH ₃ ) m / z 430 (M + H) +;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 1.01 (t, 3H), 1.66 (qt, 2H), 2.89 (t, 2H), 7.15 (t, 1H), 7 34 (s, 1H); 7.40 (t, 2H); 7.84 (d, 2H); 7.92 (dd, 1H); 8.20 (d, 1H); 8.40 (d, 1H); 1H), 8.47 (s, 1H), 8.60 (s, 1H), 8.69 (s, 1H), 9.22 (br s, 2H), 9.58 (br s, 2H), 10.61 (s, 1H);

Calcd for C25H23N3SO2.1.25HCl: C, 63.20; H, 5.14; N, 8.84. Found: C, 63.24; H 5.16; N, 8.93

Example 202

6- (amino) -N- (6-quinolinyl) -2-a naphthalene bis (trifluoroacetate)

Example 202A

To a solution of the acid chloride of the compound of Example 8B (331 mg, 1.5 mmol) in THF (15 mL) at room temperature was added propylene oxide (10 mL), DMAP (5 mg) and a drop of triethylamine and finally 6-aminoquinoline (288 mg). , 2.0 mmol). After 4 hours at room temperature, ethyl acetate (10 mL) and ether (20 mL) were added and the off-white solid was filtered off. Yield: 357 mg (72%).

MS (DCI / NH ₃ ) m / z 324 (M + H) ^&lt; ^{+ &gt};;

Example 202B

6- (amino) -N- (6-quinolinyl) -2-a naphthalene bis (trifluoroacetate)

The title compound was prepared by the method of Example 1B.

273

MS (ESI) m / z 341 (M + H) +, (ESI) 339 (M) 'H NMR (300 MHz, DMSO-d _f,) δ 10.98 (s, IH), 9, 53 (s, 2H), 9.25 (s, 2H), 8.93-8.91 (m, 1H), 8.77 (s, 1H), 8.67 (d, J = 1.8 Hz) 1 H, 8.58 (s, 1 H), 8.53 (d, J = 8.5 Hz, 1 H), 8.37-8.09 (m, 5H), 7.93 (dd, J 1 = 8.5 Hz, J 2 = 1.8 Hz, 1H), 7.65-7.62 (m, 1H);

Calcd for C21H16N4O.2TFA · C, 52.83; H, 3.19; N, 9.86. Found: C, 52.62; H, 2.94; N, 9.74.

Example 203

6- (amino) -N- (lH-indazol-6-yl) -2-a naphthalene bis (trifluoroacetate)

Example 203A

The title compound was prepared according to the procedure in Example 202A, substituting 6-amino-indazole for 6-aminoquinoline to give 285 mg of the title compound.

MS: ESI +: 313 (M + 1); ESI-3111 (M-1).

Example 203B

6- (aminoiminomethyl) -N- (1H-indazol-6-yl) -2-naphthalenecarboxamide bis (trifluoroacetate)

To a suspension of ammonium chloride (140 mg, 2.6 mmol) in toluene (2 mL) at 0 ° C was slowly added a 2 N solution of trimethylaluminium in toluene (871 μΙ, 1.74 mmol). After 5 minutes, the reaction mixture was allowed to warm 30 minutes at room temperature Nitrile is added to the aluminum reagent solution at room temperature,

274 of Example 203A of Section a) and the reaction mixture was heated at 100 ° C for 48 hours. After cooling, the reaction mixture was poured into a slurry of silica in chloroform and stirred for one hour. The silica is then filtered off and washed with methanol. The solvent is concentrated and purified by medium pressure liquid chromatography on a 30 cm x 2 cm C-18 column (40 microns, JTBaker) at UV detection of 250 nm, using a gradient elution of 90% A (0.1% aqueous 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 minutes to give 42 mg of the title compound.

MS (ESI ⁺ ) m / z 330 (M + H) &lt; + &gt;, (ESI &lt; - &gt;) 328 (M-1) &lt; - &gt;;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H), 9.47 (s, 4H), 8.65 (s, 2H), 8.50 (s, 2H), 8 25-8.23 (m, 2H), 8.17-8.10 (m, 2H), 7.94 (s, 1H), 7.867.84 (dd, J1 = 8.8 Hz, J2 = 1) 1.6 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H);

Calcd for C19H15N5O.2TFA: C, 49.56; H, 3.07; N, 12.56. Found: C, 49.68; H, 3.10; N, 12.47

Example 204

6- (aminoiminomethyl) -N- (lH-indazol-5-yl) -2-a naphthalene bis (trifluoroacetate)

Example 204A

The title compound was prepared according to the procedure in Example 202A, substituting 5-aminoindazole for 6-aminoquinoline to provide 362 mg of the title compound.

MS: ESI +: 3113 (M + 1), ES1-311 (M-1).

275

Example 204B

6- (amino) -N- (lH-indazol-5-yl) -2-a naphthalene bis (trifluoroacetate)

The title compound was prepared as described in Example 203B to give 55 mg of the product.

MS (ESI &lt; ^{+ &gt;} ) m / z 330 (M + H) &lt; + &gt;, (ESI &lt; - &gt;) 328 (M-1) &lt; - &gt;;

H NMR (300 MHz, DMSO- d _d) δ 13.06 (s, IH), 10.58 (s, IH), 9.51 (s, 2H), 9.15 (s, 2H), 8 71 (d, J = 1.9 Hz, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.34-8.17 (m, 4H), 8.10 (s, 1H), 7.90 (dd, J1 = 8.5 Hz, J2 = 1.7 Hz, IH), 7.63 (dd, J1 = 8.9 Hz, J2 = 1.7 Hz, IH), 7 56 (d, J = 8.8 Hz, 1H);

Analysis: calculated for C 19 H 15 N 5 O.TFA. 1.75H ₂ O: C, 53.11; H, 4.14; N, 14.75. Found: C, 53.20; H, 3.99; N, 14.42.

Example 205

6- (amino) -N- (lH-indol-5-yl) -2-naphthalenecarboxamide mono (trifluoroacetate)

Example 205A

The title compound was prepared according to the procedure in Example 202A, substituting 6-aminoindole for 6-aminoquinoline to give 744 mg of the title compound.

MS: ES + +: 329 (M + 1); ESI-327 (M-1).

Example 205B

6- (aminoiminomethyl) -N- (1H-indol-5-yl) -2-naphthalenecarboxamide mono (trifluoroacetate)

276

The title compound was prepared as described in Example 203B to give 90 mg of the product.

MS (ESI &lt; ^{+ &gt;} ) m / z 329 (M + H) &lt; + &gt;, (ESI &lt; + &gt;) 327 (M-1) &lt; - &gt;;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 10.40 (s, 1H), 9.51 (s, 2H), 9.15 (s, 2H), 8 71 (s, 1H), 8.55 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.26-8.17 (m, 2H), 8.05 ( d, J = 2.6 Hz, 1H), 7.90 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1H), 7.467.35 (m, 3H), 6.45-6 43 (m, 1H);

Analysis: Calculated for C _{2 4} oHi6N O.TFA: C 59.73; H, 3.87; N, 12.66. Found. C, 59.27; H, 4.17; N, 12.74.

Example 206

7- (2- (4-morpholinyl) ethoxy] -2-naphthalenecarboximidamide bis (trifluoroacetate)

Example 206A

The nitrile was prepared as described in Example 119A using 2-chloroethyl morpholine.

MS (DCI (NH ₃ )) m / z 283 (M + H) &lt; ^{+ &gt};.

Example 206B

7- [2- (4-morpholinyl) ethoxy] -2-naftaIénkarboximidamid bis (trifIuóracetát)

The title compound was prepared as in Example 11B as an off-white solid (yield 50%).

MS (DC1 (NH ₃₎₎ m / z 300 (M + H)

277 H NMR (300 MHz, _DMSO- d) δ 3.500 (br m, 4H), 3.700 (br m, 4H), 3.990 (br m, 4H), 4.490 (br m, 2H), 7.435 (d, 1H), 7.530 (d, IH), 7.680 (dd, IH), 8.035 (d, IH), 8,100 (d, IH), 8.345 (d, IH), 9.165 (br s, 2H), 9.420 (br s) (2H);

Analysis calculated for C 17 H 21 N ₃ O 2 (C 2 H 2 F ₃ ) 2, is: C 46.98; H, 4.29; N, 7.72. Found: C, 47.00; H, 4.32; N, 7.77.

Example 207

6- (amino) -N-phenyl-4- (2-pyrrolidinyl) -2-naftalénkarboxamidmono (trifluoroacetate)

Example 207A

The title compound was prepared from the product of Example 152A by the method of Example 68A.

MS (DCI (NH ₃ )) m / z 281 (M + H) &lt; ⁺ &gt; ^.

Example 207B

The title compound was prepared from the product of Example 207A by the method of Example 152B.

MS (DCI (NH ₃ )) m / z 267 (M + H) &lt; ⁺ &gt; ^.

Example 207C

A solution of the product prepared according to Example 207B (220 mg, 0.826 mmol), diisopropylamine (0.288 mL, 1.65 mmol) and O- (7-aza-benzotriazol-1-yl) 278

Ν, Ν, Ν ', Ν'-tetramethyluronium hexafluorophosphate (3 14 mg, 0.826 mmol) in DMF (10 mL) was stirred at 0 ° C for 30 min. Aniline (0.083 mL, 0.90 mmol) was then added and the reaction was Stir 4 hours at room temperature. The reaction mixture was poured into a saturated aqueous Na ₂ CO ₃ solution and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was recrystallized from ethanol / hexanes to give 212 mg (75%) of the title compound.

MS (DCI (NH ₃ )) m / z 342 (M + H) &lt; ^{+ &gt};.

Example 207D

6- (amino) -N-phenyl-4- (2-pyroIidinyI) -2-naftalénkarboxamidmono (trifluoroacetate)

The title compound was prepared from the product prepared as in Example 207C by the method of Example 1B.

MS (DCI (NH ₃ )) m / z 359 (M + H) &lt; ^{+ &gt};.

H NMR (300 MHz, DMSO- d _d) δ 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, 1H), 8.18 (d, 1H), 8.67 (s, 1H), 9.10 (br s) 2 H, 9.43 (br s, 2H), 10.41 (br d, 1H);

Analysis Calcd for C ₂₂ H22N ₄ OC ₂ HF ₃ O 2: C, 61.01; H, 4.91; N, 11.86. Found: C, 60.47; H, 5.36; N, 7.39.

Example 208

6- (amino) -N- (5-pyrimidinyl) -2-a naphthalene-Niono (trifIuóracetát)

279

Example 208A

6- (amino) -N- (5-pyrimidinyl) -2-a naphthalene-mono (trifluoroacetate)

Example 208A

The above product was prepared by the method of Example 8A using 5-aminopyrimidine.

MS (APCI) mlz (M + H) ⁺ 275

Example 208B

6- (amino) -N- (5-pyrimidinyl) -2-a naphthalene-mono (trifluoroacetate)

The above compound was prepared by the method of Example IB.

MS (CI) m / z (M + H) &lt; ^{+ &gt};292;

Δ NMR (300 MHz, DMSO-d _c ) δ 10.99 (s, 1H), 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) 4 Hz, 1H);

Anal Calcd for C 18 H 18 N 5 O 3 F 3 / 1OTFA: 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-pyridazinyl) -2-a naphthalene-mono (trifluoroacetate)

280

Example 209A

3-Amino-6-chloropyridazine (1.05 g, 8.2 mmol) was dissolved in 10 mL of methanol with 2 mL of ammonia / methanol. Palladium / carbon (200 mg, 10%) was added and the mixture was stirred for 4 hours under 1 atm of hydrogen. The reaction mixture was then filtered, concentrated and used without further purification.

MS (CI) m / z (M + H) &lt; ^{+ &gt;} 96.

Example 209B

The above product was prepared by the method of Example 12 using the product of Example 209A.

MS (APCI) m / z (M + H) &lt; ^{+ &gt;} 275.

Example 209C

6- (amino) -N- (3-pyridazinyl) -2-a naphthalene-mono (trifluoroacetate)

The above compound was prepared from Example 209B by the method of Example IB.

MS (CI) m / z (M + H) ⁺ 292, 1 H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H);

Analysis calculated for C 18 H 18 N 5 O 3 F 1/2 TFA. C, 49.29; H, 3.16; N, 14.73. Found: C, 49.56; H, 3.23; N, 14.73.

281

Example 210

6- (Aminomethyl) -N- (5-bromo-2-pyridinyl) -2-naphthalenecarboxamide mono (trifluoroacetate)

Example 210A

The title compound was prepared from the product prepared as in Example 8E, 2-amino-5-bromopyridine, and by the method of Example 8G.

MS (APCI) mlz 352 (M + H) ⁺ .

Example 210B

6- (aminoiminomethyl) -N- (5-bromo-2-pyridinyl) -2-naphthalenecarboxamide mono (trifluoroacetate)

The title compound was prepared from the product prepared according to Example 210A by the method of Example 1B.

MS (DCI) m / z 369 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 11.30 (s, 1H), 9.51 (s, 2H), 9.17 (s, 2H), 8.80 (s, 1H), 8 57 (d, 1H, J = 2.57), 8.55 (s, 1H), 8.31 (d, 1H, J = 8.45), 8.26 (d, 1H, J = 8, 82), 8.19-8.24 (m, 2H), 8.14 (dd, 1H, J = 2.57 9.19), 7.90 (dd, 1H, J = 1.83 8.82) )

Anal Calcd for C 18 H 18 BrF 3 N 2 O: C 47.22; H, 2.92; N, 11.59. Found: C, 47.60; H, 3.01; N, 1.30.

Example 21 1

282

6- (Aminomethyl) -N- [3- (1-methylethoxy) phenyl] -2-naphthalene carboxamide mono (trifluoroacetate)

Example 21 1A

The above product was prepared by the method of Example 12 using 3-isopropoxyaniline.

MS (APCI) m / z (M + H) + 331.

Example 211B

6- (aminoiminomethyl) -N- [3- (1-methylethoxy) phenyl] -2-naphthalenecarboxamide mono (trifluoroacetate)

MS (CI) m / z (M + H) &lt; ^{+ &gt};348;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 10.50 (s, 1H), 9.50 (s, 2H), 9.22 (s, 2H), 8.67 (s, 1H), 8 , 56 (s, 1H), 8.31 (d, 1H), 8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.51 (m, 1H), 7, 36 (m, 1H), 7.26 (t, 1H), 6.68 (dd, 1H), 4.59 (m, 1H), 1.30 (d, 6H);

Analysis: Calculated for C ₂₃ H ₂₂ N ₃ O4F ₃ .1 / 5TFA: C, 57.96; H, 4.61; N, 8.66. Found: C, 57.99, H, 4.90; N, 8.68.

Example 212

2 - [[6-aminoiminomethyl) -2-naphthalenyl] oxy] acetic acid mono (trifluoroacetate)

The product prepared according to Example 185C (140 mg, 0.542 mmol) was dissolved in methanol (11 mL). To this solution 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.

283 rooms and in an inert atmosphere for 18 hours. Thereafter, the reaction mixture was evaporated and purification of the residue by reverse phase chromatography gave the title compound (102 mg, 52%).

MS (DCI (NH ₃ )) m / z 245 (M + H) +;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 4.875 (s, 2H), 7.420 (s, 1H), 7.435 (dd, IH), 7.660 (dd, IH), 8.015 (d, IH), 8,100 ( d, 1H), 8.340 (d, 1H), 9.125 (br s, 1H), 9.420 (br s, 1H);

Analysis: Calculated for C] ₂ N 20 ₃ Hi _third (C2H0 ₂ F ₃₎ and _{t 3} of: 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-naphthalenyl] oxy] metylJbenzoátmono (trifluoroacetate)

Example 213A

The product of Example 185 was treated with methyl 4- (bromomethyl) benzoate as described in Example 119B.

MS (DCI (NH ₃ )) m / z 335 (M + NH ₄ ) ⁺ ;

Example 21B

Methyl 4- [6-aminoiminomethyl) -2-naphthalenyl] oxy] methyl] benzoatenione (tri fluoroacetate)

The product prepared in Example 213A (250 mg, 0.788 mmol) was treated in a manner similar to that described in Example 119C to give the title compound (130 mg, 79%).

284

MS (DCI (NH ₃ )) m / z 335 (M + H) +, 1 H NMR (300 MHz, DMSO-d ₆ ) δ 3.870 (s, 3H), 5.400 (s, 2H), 7.500 (dd, 1H), 7.540 (d, IH), 7.619 (dd, IH), 7.620 (d, 2H), 8.025 (d, 2H), 8.026 (d, IH), 8.090 (d, IH), 8.410 (d, IH) ), 9.260 (v br s, 3H);

Analysis: Calculated for C14H14N2O-1 C2HO2F ₃₎ .H2O 0.70: C, 57.32; H, 4.46; N, 6.08. Found: C, 57.33; H, 4.70; N, 5.95

Example 214

6- (aminoiminomethyl) -N- (1H-imidazolyl) -2-naphthalenecarboxamide bis (trifluoroacetate)

Example 214A

The title compound was prepared from Example 8E, 2-aminoimidazole, and by the method of Example 8G.

MS (ESI -) m / z 261 (M + H) &lt; + &gt;.

Example 214B

The title compound was prepared from the product of Example 214A by the method of Example 1B.

MS (ES +) m / z 280 (M + H) ⁺ ;

H NMR (300 MHz, _DMSO- d) δ 9.50 (s, 2H), 9.16 (s, 2H), 8.78 (s, IH), 8.53 (s, IH), 8 26-8.3 1 (m, 2H), 8.20 (d, 1H, J = 8.46), 7.88 (dd, 1H, J = 1.84 8.83), 6.95 ( s, 2H),

285

Anal. Calcd ₄ F ₃ N ₃ O ₃ 0.2TFA.H ₂ O C 48.14; H, 3.76; N, 16.13 Found ^- C, 48.54; H, 3.40; N, 16.02.

Example 21 5

6- [2- [4- (hydroxymethyl) phenyl] -1-cyclopropyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

Example 215A

The product prepared according to the method of Example 104 (210 mg, 0.52 mmol) was dissolved in THF (6 mL) and added dropwise to 10 mL of diazomethane cooled to 0 ° C and then Pd (OAc) ₂ (9 mL) was added to the reaction mixture. , 8 mg). The reaction mixture was bubbled vigorously for 5 minutes and the resulting black slurry was stirred for 20 minutes, then filtered and the solvent evaporated in vacuo to give 0.1 g of a clear oil.

MS (DCI (NH ₃ )): m / z (M + H / 316).

Example 215B

6- [2- [4- (hydroxymethyl) phenyl] -1-cyclopropyl] -2-naphthalenecarboximidamide mono (trifluoroacetate)

The title compound was prepared according to the procedure for EXAMPLE 1, and purified by reverse phase chromatography to give 19.9 mg of a white solid.

MS (DCI (NH ₃ )) m / z (M + H) ⁺ 3 16;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 9.41 (s, 2 s), 9.16 (s, 2Η), 8.46 (s, 1Η), 8.08 (d, 2H), 8 Δ (d, 1H), 7.85 (s, 1H), 7.75 (dd, 1H), 6.58 (dd, 1H), 7.3-7.1 (m, 4H), 4, 49 (s, 2H), 2.38-2.48 (m, 2H), 1.61-1.70 (m, 2H),

286

Analysis calculated for C23H21N2O2F3.1H ₂ O C, 62.10; H, 4.80; N, 6.29. Found. C 62.00; H, 4.75; N, 6.25

Example 216

N- (ethoxycarbonyl) -6- (2-phenyl-1-cyclopropyl) -2-naphthalenecarboximidamide

The product described in Example 97 (130 mg, 0.45 mmol) was dissolved in DMF (3 mL), cooled to 0 ° C and treated with triethylamine (0.01 mL) and ethyl chloroformate (0.05 mL). The resulting solution was stirred at room temperature for 3 days, then diluted with 100 mL of ethyl acetate, washed with distilled water (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give a clear oil. The oil was purified by silica gel chromatography eluting with hexanes / ethyl acetate (2: 1) to lyophilize the product to afford the title compound as a white powder (55 mg).

MS (DCI (NH ₃ )) m / z (M + H / 359;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 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) 1.38-2.28 (m, 2H), 1.61 (t, 2H), 1.25 (t, 3H);

Analysis Calcd for _C2 3 H ₂₂ N ₂ O _2: C, 77.07; H, 6.19; N, 7.82. Found: C, 76.63; H, 6.05; N, 7.45.

Example 217

6- (aminoiniinometyl) -N- (2-methyl-6-quinolinyl) -2-naftalénkarboxamidbis (trifluoroacetate)

The title compound was prepared in a manner similar to that described in Examples 8E and 144C.

287

MS m / z 355 (M + H) ⁺ , 1 H NMR (DMSO, 300 MHz) δ 10.95 (s, 1H), 9.51 (s, 2H), 9.14 (s, 2H), 8 , 75 (s, 1H), 8.65 (s, IH), 8.57 (s, IH), 8.35 (dd, IH, J 1 = J 2 = 8.5 Hz), 8.28 (dd) , IH, J1 = J2 = 8.5 Hz), 8.19 (dd, 1H, J1 = J2 = 8.8 Hz), 8.15 (dd, IH, J1 = J2 = 8.3 8.04 (dd, 1H, J1 = J2 = 8.8 Hz), 7.91 (dd, 1H, J1 = 8.4 Hz, J2 = 8.8 Hz), 7.60 (dd, 1H, J1 = J2 = 8.1 Hz), 5.99 (s, 3H),

Analysis calculated for C 22 H | GN ₄ O.2,25C2F3O2H.2H2O. C 49.20; H, 3.78; N, 8.66; F, 19.82. Found: C, 49.02; H, 3.36; N, 8.66.

Example 218

6- (aminoimidomethyl) -N- (3-propoxyphenyl) -2-naphthalenecarboxamide mono (trifluoroacetate)

Example 218A

3-Aminophenyl (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 of anhydrous THF. Diethyl azodicarboxylate (1.5 g, 8.6 mmol) was then added dropwise over 1 min. The solution was stirred for 15 minutes and then poured slowly into hexanes with stirring. The product as a viscous yellow oil is obtained after filtration through silica gel / celite.

MS (APCI) m / z (M + H) &lt; ^{+ &gt;} 152.

Example 218B

The above product was prepared by the method of Example 12 using the product of Example 218A.

288

MS (APCI) m / z (M + H) &lt; + &gt;

Example 21 8C

6- (Aminoiminomethyl) -N- (3-proxyphenyl) -2-naphthalenecarboxamide mono (trifluoroacetate)

The above compound was prepared from the compound of Example 218 as described in Example 1B

MS (CI) m / z (M + H) &lt; ^{+ &gt};348;

1 H NMR (300 MHz, d ₆ -DMSO) δ 10.51 (s, 1H), 9.50 (s, 2H), 9.18 (s, 2H), 8.68 (s, 1H), 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, 1H), 6.73 (dd, 1H), 3.94 (t, 2H), 1.75 (m, 2H), 1.00 (t, 3H);

Calcd for C23H22N3O4F3.1 / 20TFA: C, 59.49; H, 4.77; N, 9.02. Found: C, 59.43; H, 4.94; N, 9.10.

Example 219

6- (aminoiminomethyl) -N- [3- (1-ethylpropoxy) phenyl] -2-naphthalenecarboxamide mono (trifluoroacetate)

Example 219A

The above product was prepared as in Example 218A using 3-pentanol

MS (APCI) m / z (M + H) &lt; + &gt;

289

Example 2 19B

The above product was prepared by the method of Example 12 using the product of Example 219A

MS (APCI) mlz (M + H) ⁺ 359

Example 219C

6- (amino) -N- [3- (l-ethyl-propoxy) -phenyl] -2-naftalénkarboxamidmono (trifluoroacetate)

The above compound was prepared from the compound prepared according to Example 219B by the method of Example IB.

MS (CI) m / z (M + H) &lt; ^{+ &gt};376;

1 H NMR (300 MHz, d ₆ -DMSO) δ 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);

Analysis: calculated for C 25 H 26 N 3 O 4 F 3. C 61.34; H, 5.35; N, 8.58. Found: C, 61.05; H, 5.42; N, 8.22.

Example 220

6- (amino) -N- [3- (cyclopentyloxy) -phenyl] -2-naftalénkarboxamidmono (trifluoroacetate)

Example 220A

290

The above product was prepared by the method of Example 218A using cyclopentanol.

MS (APCI) mlz (M + H) + 86

Example 220B

The above product was prepared by the method of Example 12 using the product of Example 220A.

MS (APCI) mlz (M + H) ⁺ 357.

Example 220C

6- (amino) -N- [3- (cyclopentyloxy) phenyl] -2-naftalénkarboxamidmono (trifluoroacetate)

The above compound was prepared from the compound prepared according to Example 220B by the method of Example IB.

MS (Cl) m / z (M + H) &lt; ^{+ &gt};374;

1 H NMR (300 MHz, d ₆ -DMSO) δ 10.50 (s, 1H), 9.51 (s, 2H), 9.30 (s, 2H), 8.68 (s, 1H), 8 56 (s, 1H); 8.32 (d, 1H); 8.25-8.13 (m, 2H); 7.90 (dd, 1H); 7.49 (m, 1H); 38 (m, 1H), 7.26 (t, 1H), 6.72 (dd, 1H), 4.79 (m, 1H), 1,961.08 (m, 8H);

Calcd for C2SH24N3O4F3 2 / 5TFA: C, 60.68; H, 5.06; N, 8.49. Found: C, 60.68; H, 5.33; N, 8.65

Example 221

291

6- (aminoiminomethyl) -N- (3-phenoxyphenyl) -2-naphthalenecarboxamide mono (trifluoroacetate)

Example 221A

The above product was prepared by the method of Example 218A using 3-phenoxyaniline.

MS (APCI) mlz (M + H) ⁺ 365.

Example 221B

6- (amino) -N- (3-phenoxyphenyl) -2-naftalénkarboxamidmono (trifluoroacetate)

The above compound was prepared from Example 221A as described in Example IB.

1 H NMR (300 MHz, d ₆ -DMSO) δ 10.61 (s, 1H), 9.50 (s, 2H), 9.20 (s, 2H), 8.66 (s, 1H), 8 54 (s, 1H), 8.30 (d, 1H), 8.22 (d, IH), 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, 1H);

MS (CI) m / z (M + H) &lt; ^{+ &gt};382;

Calcd for C26H20N3O4F3: C, 63.03; H, 4.07; N, 8.47. Found: C, 62.87; H, 4.24; N, 8.08.

Example 222

6- (aminoiminonictyl) -N- [3- (phenylniethoxy) phenyl] -2-naphthalenecarboxamide mono (trifluoroacetate)

292

Example 222A

The above product was prepared by the method of Example 218A using 3-benzyloxyaniline.

MS (APCI) m / z (M + H) + 379

Example 222B

6- (Aminomethyl) -N- [3- (phenylmethoxy) phenyl] -2-naphthalenecarboxamide mono (trifluoroacetate)

The above compound was prepared from Example 222A as described in Example IB.

MS (CI) m / z (M + H) &lt; ^{+ &gt};396;

1 H NMR (300 MHz, d ₆ -DMSO) δ 10.53 (s, 1H), 9.50 (s, 2H), 9.22 (s, 2H), 8.68 (s, 1H), 8 55 (s, 1H), 8.3 (d, 1H), 8.23 (d, IH), 8.14 (dd, IH), 7.90 (dd, IH), 7.61-7 27 (m, 8H), 6.80 (dd, 1H), 5.13 (s, 2H);

Calcd for C27H22N3O4F3: C, 63.65; H, 4.35; N, 8.25. Found: C, 63.48; H, 4.27; N, 8.07.

Example 223

6- (aminoiminomethyl) -N- (3-ethoxyphenyl) -2-naftalénkarboxamidmono (trifluoroacetate)

Example 223A

The above product was prepared according to the method of Example 218A using 3-ethoxyaniline.

293

MS (APCl) m / z (M + H) &lt; ⁺ &gt;

Example 222B

6- (amino) -N- (3-ethoxyphenyl] -2-naftalénkarboxamidmono (trifluoroacetate)

The above compound was prepared from Example 223A as described in Example 1B

MS (CI) m / z (M + H) ⁺ 334, 1 H NMR (300 MHz, d ₆ -DMSO) δ 10.52 (s, 1H), 9.50 (s, 2H), 9.24 ( s, 2H), 8.68 (s, 1H), 8.55 (s, 1H), 8.32 (d, 1H), 8.25-8.13 (m, 2H), 7.90 (dd) , IH)

7.51 (m, 1H), 7.38 (m, 1H), 7.26 (t, 1H), 6.72 (dd, 1H), 4.04 (q, 2H), 1.34 (t 3H);

Calcd for C22H20N3O4F3: C, 59.06; H, 4.51; N, 9.39. Found: C, 58.69; H, 4.54; N, 9.82.

Example 224

6- (aminoiminofenyl) -N- (4-nitrophenyl) -2-a naphthalene-mono- (trifIuóracetát)

Example 224A

The above product was prepared by the method of Example 218A using 4-nitroaniline.

MS (APCI) m / z (M + H) &lt; ⁺ &gt;

294

Example 224B

6- (aminoiminomethyl) -N- (4-nitrophenyl) -2-naphthalenecarboxamide mono (trifluoroacetate)

The above compound was prepared from Example 224A as described in Example IB.

MS (CI) m / z (M + H) &lt; ^{+ &gt};335;

1 H NMR (300 MHz, d ₆ -DMSO) δ 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);

Calcd for C20H15N4O5F3.1 / 1 OTFA: C, 52.54; H, 3.29; N, 12.10. Found: C, 53.58; H, 3.37; N, 12.50.

Example 225

6- (amino) -N- [3- (cyclobutylmethoxy) phenyl] -2-naftalénkarboxamidmono (trifluoroacetate)

Example 225A

The above product was prepared by the method of Example 218A using cyclobutylmethanol.

MS (APCI) m / z (M + H) &lt; ^{+ &gt;} 177

Example 225B

The above product was prepared by the method of Example 225A using the product of Example 1 I.

295

MS (APCI) m / z (M + H) + 357.

Example 225C

6- (amino) -N- [3- (cyclobutylmethoxy) phenyl] -2-naftalénkarboxamidmono (trifluoroacetate)

The above compound was prepared from Example 225B by the method of Example 1B.

MS (CI) m / z (M + H) &lt; ^{+ &gt};374;

1 H NMR (300 MHz, d ₆ -DMSO) δ 10.50 (s, 1H), 9.50 (s, 2H), 9.20 (s, 2H), 8.68 (s, 1H), 8 55 (s, 1H), 8.32 (d, 1H), 8.25-8.13 (m, 2H), 7.90 (dd, 1H),

7.51 (m, 1H), 7.38 (m, 1H), 7.26 (t, 1H), 6.72 (dd, 1H), 3.95 (d, 2H), 2.11-1 81 (m. 7H),

Calcd for C25H24N3O4F3.7 / 5TFA: C 59.09, H 5.22; N, 8.27. Found: C, 59.02; H, 5.20; N, 8.55.

Example 226

6- [amino (ethoxycarbonyl) imino] -N- [3- (1-methylethoxy) phenyl] -2-naphthalenecarboxamide

The above compound was prepared from Example 211A by the method of Example 216.

MS (CI) m / z (M + H) &lt; ^{+ &gt};420;

H NMR (300 MHz, d _e DMSO) δ 10.41 (s, IH), 9.24 (br s, 2H), 8.67 (s, IH), 8.59 (s, IH); 8.12-7.96 (m, 4H), 7.47 (s, 1H), 7.36 (m, 1H), 7.25 (t, 1H), 6.67 (dd, 1H) 4.58 (m, 1H), 4.11 (q, 2H), 1.30 (m, 9H);

296

Anal Calcd for C24H25N3O4 1 / 4H ₂ O: C 67.99, H, 6.06; N, 9.91. Found: C 67.99, H 6.07, N 9.64

Example 227

6- (Aminomethyl) -4- [5- (ethylsulfonyl) -3-furanyl] -N-phenyl-2-naphthalenecarboxamide 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) for 1 h. The reaction mixture was then concentrated and chromatographed on SiO 2 using 50% ethyl acetate / hexanes as eluent to give 585 mg (81%) of the title compound.

MS (DCI / _NH3) m / z 448 (M + NH ₄₎ ^+.

Example 227B

6- (aminoiminomethyl) -4- [5- (ethylsulfonyl) -3-furanyl] -N-phenyl-2-naphthalenecarboxamide d-monohydrochloride

The title compound was prepared from Example 227A by the method of Example 13.

MS (DCI / NH 3) m / z 448 (M + H) +.

1 H NMR (300 MHz, DMSO-d 6) δ 1.29 (t, 3H), 3.50 (q, 2H), 7.16 (t, 1H), 7.42 (t, 2H), 7 83 (d, 2H), 7.95 (dd, 1H), 8.05 (s, 1H), 8.28 (s, 1H), 8.43 (d, 1H), 8.57 (s) 1 H), 8.74 (s, 1H), 8.79 (s, 1H), 9.19 (br s, 2H), 9.59 (br s, 2H), 10.61 (s, 1H) );

297

Analysis: Calculated for C24H22N3SO4.1, OHC1.1,0H ₂ O: C, 57.43; H, 4.82; N, 8.37. Found: C, 57.21; H, 5.04; N, 8.34

Example 228

6- (aminoiminomethyl) -4- [5- (propylsulfonyl) -3-furanyl] -N-phenyl-2-naphthalenecarboxamide monohydrochloride

Example 228A

The title compound was prepared from the product of Example 201C by the method of Example 227A.

MS (DCI / _NH3) m / z 462 (M + NH ₄₎ ^+.

Example 228B

6- (aminoiminomethyl) -4- [5- (propylsulfonyl) -3-furanyl] -N-phenyl-2-naphthalenecarboxamide monohydrochloride

The title compound was prepared from Example 228A by the method of Example 13.

MS (DCI / _NH3) m / z 462 (M + H) +.

Δ NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 8.05 (s, 1H), 8.28 (s, 1H), 8.42 (d, 1H) ), 8.58 (s, 1H), 8.77 (s, 1H), 8.82 (s, 1H), 9.28 (br s, 2H), 9.63 (br s, 2H), 10 66 (s, 1H);

Anal. Calcd. 1,0HCI. 1.5 H ₂ O: C 57.20, H 5.18; N, 8.00. Found: C, 56.86; H, 5.08; N, 8.28

298

Example 229

6- (aminoiminomethyl) -4- [5 - [(methylthio) methyl] -3-furanyl] -N-phenyl-2-naphthalenecarboxamide monohydrochloride

Example 229A

To a solution of 2-trimethylsilyl-3-bromofuran (10.41 g, 47.5 mmol) in THF (100 mL) at -75 ° C was added 1.5 M LDA solution (34.8 mL, 52.25 mmol). and the reaction mixture was stirred at -78 ° C for one hour. DMF (4.41 mL, 57.0 mmol) was then added, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was poured into a saturated aqueous NH ₄ Cl solution and extracted 3 times with diethyl ether. The combined extracts were washed with brine, dried with Na 2 SO 4 and concentrated. The residue was taken up in methanol (200 mL) and NaBH ₄ (1.15 g, 24.0 mmol) was added portionwise to the stirred solution. After 30 minutes, the solution was concentrated, taken up in pH 7 buffer and extracted 3 times with ethyl acetate. The combined extracts were washed with brine, dried with Na ₂ SO ₄ and concentrated. The crude product was chromatographed on SiO ₂ using 30% ethyl acetate / hexanes as eluent to give 5.52 g (47%) of the title compound.

MS (DCI / _NH3) m / z 250 (M + H) ^4th

Example 229B

To a solution of the product prepared as in 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 PCl-s (2). (12 mL, 24.36 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into saturated aqueous NH ₄ Cl solution and extracted 3 times with diethyl ether / hexanes. The combined extracts were washed twice with water, twice with brine, dried with Na ₂ SO ₄ and concentrated to give 4.70 g (79%) of the title compound.

299

Example 229C

A solution of the product prepared according to 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 mixture was then poured into saturated aqueous NaHCO ₃ and extracted 3 times with diethyl ether. The combined extracts were washed with brine, dried with Na ₂ SO ₄ and concentrated. The crude product was chromatographed on SiO 2 using 30% ethyl acetate / hexanes as eluent to give 4.00 g (82%) of the title compound.

Example 229D

The title compound was prepared from the product prepared according to Example 229C by the method of Example 154B.

MS (DCI / NH ₃ ) m / z 308 (Bu ₃ Sn + NH ₄ ) ⁺ .

Example 229E

The title compound was prepared from the product of Example D and from the product of Example 152C, following the procedure of Example 154C.

MS (DCI / _NH3) m / z 416 (M + NH ₄₎ ^+.

Example 229F

6- (amino) -4- [5 - [(methylthio) methyl] -3-furanyl] -N-phenyl-2naftalénkarboxamid monohydrochloride

The title compound was prepared from Example 229E by the method of Example 144C

300

MS (DC1 / _NH3) m / z 416 (M + H) ^+.

H NMR (300 MHz, DMSO-d _f>) delta 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) 1 H, 8.69 (s, 1H), 9.31 (br s, 2H), 9.61 (br s, 2H), 10.62 (s, 1H);

Calcd for C24H21N3SO2.1.4HCl: C, 61.79; H, 4.84; N, 9.01. Found - C, 61.38; H, 4.82; N, 9.13.

Example 230

6- (aminoiminomethyl) -4- [5- (methoxymethyl) -3-furanyl] -N-phenyl-2naftalénkarboxamid monohydrochloride

Example 230A

The title compound was prepared from 2-trimethylsilyl-3-bromofuran and chloromethyl methyl ether according to the procedure of Example 154A.

Example 230B

The title compound was prepared from the product of Example 230A by the method of Example 154B.

MS (DCI / NH ₃ ) m / z 308 (Bu ₃ Sn + NH ₄ ) ⁺ .

Example 230C

The title compound was prepared from the product prepared according to Example 230B and the product prepared according to Example 152C by the method of Example 154C

301

MS (DCI / NH ₃ ) m / z 400 (M + NH 4) ⁺ .

Example 230D

6- (aminoiminomethyl) -4- [5- (methoxymethyl) -3-furanyl] -N-phenyl-2-naphthalenecarboxamide monohydrochloride

The title compound was prepared from Example 230C by the method of Example 144C.

MS (DCI / NH ₃ ) m / z 400 (M + H) &lt; ^{+ &gt};.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 3.38 (s, 3H), 4.49 (s, 2H), 7.14 (t, 1H), 7.18 (t, 2H), 7 40 (t, 2H), 7.84 (d, 2H), 7.92 (dd, 1H), 8.19 (d, 1H), 8.38 (s, 1H), 8.42 (s, 1H), 8.64 (s, 1H), 8.70 (s, 1H), 9.32 (br s, 2H), 9.62 (br s, 2H), 10.68 (s, 1H);

Analysis: Calculated for C ₂₄ H ₂ O and ₃ .2,8HCl _3: C, 57.48; H, 4.78; N, 8.38. Found: C, 57.40; H, 4.44; N, 8.38.

Example 23 1

6-cyanobenzyl) -4- [5- (methylsulfonyl) -3-furanyl] -N-phenyl-2naftalénkarboxamid mono (trifluoroacetate)

Example 23 1 A

The title compound was prepared from the product prepared according to Example 152C by the method of Example 227A.

MS (DC1 / _NH3) m / z 434 (M + _NH4) '

302

Example 231B

6-Aminomethyl-4- [5- (methylsulfonyl) -3-fluoro] -N-phenyl-2-naphthalenecarboxamide mono (trifluoroacetate)

The title compound was prepared from the compound prepared according to Example 231A by the method of Example 13

MS (DCI / NH ₃ ) m / z 434 (M + H) &lt; ^{+ &gt};.

1 H NMR (300 MHz, DMSO-d 6) δ 3.44 (s, 3H), 7.16 (t, 1H), 7.40 (t, 2H), 7.82 (d, 2H), 7, 91 (s, 1H), 7.95 (dd, IH), 8.00 (s, IH), 8.36 (s, IH), 8.43 (d, IH), 8.57 (s, IH) ), 8.75 (s, 2H), 9.18 (br s, 2H), 9.53 (br s, 2H);

Analysis: Calculated for C23H19N3SO4.l, 0C2HF3O _2: C, 54.84; H, 3.68; N, 7.67. Found: C, 55.05; H, 3.74; N, 7.75.

Example 232

6- (aminoiminomethyl) -4- [5- (ethylthio) tetrahydro-3-furanyl] -N-phenyl-2-naphthalenecarboxamide monohydrochloride

Example 232A

The title compound was prepared from the product of Example 152 by the procedure of Example 62A.

MS (DC1 / _NH3) m / z 315 (M + NH 4) *

Example 232B

A solution of the product prepared according to Example 232A (1.62 g, 5.45 mmol), ethanethiol (2.2 mL), and concentrated HCl (0.80 mL) in CHCl 3 (22 mL) was stirred for 3 hours.

303 hours at room temperature and then concentrated. The crude product was chromatographed on SiO ₂ using 15% ethyl acetate / hexanes as eluent to give 1.20 g (65%) of the title compound.

MS (DC1 / _NH3) m / z 359 (M + NH ₄₎ ^+.

Example 232C

The desired product was prepared from the product prepared according to Example 232B by the method of Example 152B.

MS (DCI / _NH3) m / z 345 (M + NH ₄₎ \

Example 232D

The title compound was prepared from the product prepared as in Example 232C by the method of Example 207C

MS (DCI / _NH3) m / z 420 (M + NH ₄₎ ^+.

Example 232E

6- (amino) -4- [5- (ethylthio) tetrahydro-3-furanyl] -N-phenyl-2-a naphthalene monohydrochloride

The title compound was prepared from Example 232D by the method of Example 144C.

MS (DCI / NH ₃ ) m / z 420 (M + H) +.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 1.18 (dt, 3H), 2.42 (m, 1H), 3.50 (dq, 2H), 3.74 (m, 1H), 3 93 (m, 1H), 4.39 (m, 1H), 4.54 (m, 1H), 5.38 (dd, 0.5H), 5.42 (dd, 0.5H), 7, 14 (t, 1H), 7.40 (t, 2H), 7.82 (d, 2H), 7.95 (d, 1H), 8.06 (s,

304

0.5 Η), 8.20 (s, 0.5 Η), 8.32 (d, I Η), 8.60 (s, 1H), 8.71 (s, 0.5H), 8.80 (s 0.5H), 9.32 (br s, 2H), 9.62 (br s, 2H), 10.59 (br s, 1H);

Analysis calculated for C 24 H 25 N 3 O 2 S. 1, OHCl: C 63.22; H, 5.75; N, 9.21 Found: C, 62.93; H, 5.58; N, 9.01

Claims (16)

PATENT CLAIMS 1 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] -3- [1- (3,4-dimethoxy) phenyl] propanone mono (hydrochloride); 1 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] -3-bromopropanone (hydrochloride); 1) O a 1) hydrogen; 1) hydrogen; 11) cycloalkyl of three to twelve carbon atoms; 1) aryl; 1) covalent bond, A compound of the formula wherein Z is selected from the group consisting of (1) nitrogen; 2 - [(7-aminoimidomethyl-3-methoxy-1-naphthalenyl) oxy] acetamide mono (trifluoroacetate), 2 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] -yl-acetic acid mono (trifluoroacetate); l - [(7-amino-imino-2-methoxy-l-naphthalenyl) oxy] -3-hydroxypropánmono (trifluoroacetate); Phenyls Imethyl 1- [7- (aminoiminomethyl) -1-naphthalenyl) carbamate mono (trifluoroacetate); N- [7- (aminoiminomethyl) -1-naphthalenyl) acetamide mono (trifluoroacetate), methyl 1- [7- (aminomethyl) -1-naphthalenyl) carbamate mono (trifluoroacetate); methyl 3 - [[7- (aminoimidomethyl) -1-naphthalenyl] amino] -3-oxopropanoate mono (trifluoroacetate); 320 N- [7- (aminomethyl) -1-naphthalenyl] -2- (phenylmethoxy) acetamide mono (trifluoroacetate), N- [7- (amino) -l-naphthyl] -l, 3-benzodioxol-5-karboxamidmono (trifluoroacetate); N- [7- (amino) -l-naphthalenyl] benzenemethanesulfonamide mono (trifluoroacetate); l - [(7-amino-imino-2-methoxy-l-naphthalenyl) oxy] -3-brómpropánmono (hydrochloride); 2 - [(7-amino-imino-2-methoxy-l-naphthalenyl) oxy] acetamidmono (trifluoroacetate); 2 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] -yl acetic acid mono (trifluoroacetate); 1 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] -3-hydroxypropanemone (trifluoroacetate); 2 - [(7-aminoiminomethyl) -2-methoxy-1-naphthalenyl) oxy] acetamide mono (trifluoroacetate); 2 - [(7-amino-imino-3-methoxy-l-naphthalenyl) oxy] acetamidmono (trifluoroacetate); 2 - [[6- (aminoiminomethyl) -2-naphthalenyl] oxy] acetic acid-mono (trifluoroacetate), and methyl 4- [6- (aminoiminomethyl) -2-naphthalenyl] oxy] methyl] benzoate mono (trifluoroacetate) . A compound according to claim 1, wherein A and C are hydrogen and B is -LbRb 3 A compound according to claim 2 selected from the group consisting of: 2) S; and wherein at each occurrence m is 1 to 5, n is 0 to 4, t is 0 to 2; and wherein alkyl, alkenyl, alkynyl, aryl, heterocycle, cycloalkyl and cycloalkenyl groups are optionally substituted at each occurrence. 2) alkyl of one to six carbon atoms; 2) an N-protecting group; 2) arylalkoxy wherein the alkylene group has one to six carbon atoms; (2) - (CH ₂ ) _m -, (2) methine; and (3) meth substituted with -NR 1 R ₂ ; A represents a group selected from the group consisting of (1) hydrogen and (2) -L _and R _a . B represents a group selected from the group consisting of (1) hydrogen and (2) -L "R" 306 C represents a group selected from the group consisting of (1) hydrogen and (2) -LrR-c, provided that at least one of A, B or C is other than hydrogen; and provided that when A is other than hydrogen, at least one of B or C is other than hydrogen, and wherein A, B and C and L _A , Lb and Lc are independently selected from the group consisting of: 3 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] propenone mono (trifluoroacetate); l - [(7-amino-imino-2-methoxy-l-naphthalenyl) oxy] -3-fenylpropánmono (hydrochloride); 3 - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] propenone mono (trifluoroacetate); l - [(7-amino-imino-2-methoxy-l-naphthalenyl) oxy] -3-fenylpropánmono (hydrochloride); l - [(7-amino-imino-2-methoxy-l-naphthalenyl) oxy] -3- [l- (3,4-dimethoxy) -phenyl] propane mono (hydrochloride); 3) alkenyl of two to six carbon atoms; 3) alkyl of one to six carbon atoms; 3) alkyl of one to ten carbon atoms; 1 3) -OC (O) NR ₂ -, (32) -CH = NO-, 33) -ON = CH- a 34), wherein the W group is selected from the group consisting of 308 a) -Ο-, b) -S-, c) -NR, -a d) - (CH ₂ ) _m wherein each of said functional groups is shown such that its right end is intended to attach a naphthyl or quinolyl ring and its left end is intended to attach R _A , R b or R _c ; R _A , R b and R c are independently selected from the group consisting of ^- 3) -NR, -, 4- [7- (amino) -2-methoxy-l-naphthalenyl] dihydro-2 (3H) furanónmono (trifluoroacetate); ^{4 -} [[[7- (aminoiminomethyl) ^-1- (4-pyrimidinylamino) -4-naphthalenyl] oxylmethyl] benzoic acid-mono (trifluoroacetate), 4- [7- (amino) -2-methoxy-l-naphthalenyl] dihydro-2 (3H) -furanone mono (tnfluóracetát); The compound of claim 1, wherein A and B are hydrogen; and C stands for -LcRc · 4) alkynyl of two to six carbon atoms, 4) alkenyl of two to six carbon atoms; 4) alkenyl of two to ten carbon atoms; 4) -NR ₂ C (X) NR ₃ 6) -NR ₂ C (X) -, A compound according to claim 4 selected from the group consisting of: 5 - [[6- (aminoiminomethyl) -2-naphthalenyl] oxy] pentanoic acid mono (trifluoroacetate); methyl-4 - [[[7-amino (hydroxyimino) methyl] -2-naphthalenyl] oxy] methyl] benzoate, 311 methyl 2 - [[6- (aminoiminomethyl) -2-naphthalenyl] oxy] acetate mono (trifluoroacetate); 5) aryl; 5) alkynyl of two to six carbon atoms; 5) alkoxycarbonyl of one to six carbon atoms; 6-aminonaphthalene-2-carboximidamine and d-mono (trifluoroacetate), N- (6-amino-imino-2-naphthalenyl) -N-cyklohexylmočovinamono (trifluoroacetate); N- (6-amino-imino-2-naphthalenyl) -N-benzyloxymočovinamono (trifluoroacetate); 1,1-dimethylethyl [4 - [[(6-cyano-2-naphthalenyl) amino] carbonyl] phenyl] carbamate mono (trifluoroacetate); N- [6- (amino) -2-naphthalenyl] -4- (aminomethyl) benzamide mono (trifluoroacetate); 6-methoxy-8-benzyloxy-2-naphthalenecarboximidamino-mono (trifluoroacetate), 6,7-dimethoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate); 6.7.8-trimethoxy-2-naphthalenecarboximidamide mono (trifluoroacetate), 6- [2- (4-aminophenyl) ethoxy] -2-naphthalenecarboximidamide mono (trifluoroacetate), methyl [3-methoxy-6- (aminoiminomethyl) -4-naphthalenyl] carbamate mono (trifluoroacetate); 6- (amino) -4- [5- (ethylthio) tetrahydro-3-furanyl] -N-phenyl-2-a naphthalene monohydrochloride. 6- (amino) -4- [5- (methylsulfonyl) -3-furanyl] -N-phenyl-2-a naphthalene-mono (trifluoroacetate); and 6- (amino) -4- [5- (methoxymethyl) -3-furanyl] -N-phenyl-2-a naphthalene monohydrochloride; 6- (amino) -4- [5 - [(methylthio) methyl] -3-furanyl] -N-phenyl-2naftalénkarboxamid monohydrochloride, 6- (aminoiminomethyl) -4- [5- (propylsulfonyl) -3-furanyl] -N-phenyl-2-a naphthalene monohydrochloride; 6- (amino) -N-phenyl-4- (2-pyrrolidinyl) -2-a naphthalene-mono (trifluoroacetate), 6- (aminoiminomethyl) -4- [5- (propylthio) -3-furanyl] -N-phenyl-2-naphthalenecarboxamide mono hydrochloride; 315 6- (amino) -4- [5- (ethylthio) -3-furanyl] -N-phenyl-2-a naphthalene monohydrochloride; 6- [amino (hydroxyimino) methyl] -N-phenyl-4- (2-pyrimidinyl) -2-naphthalenecarboxamide; 6- (amino) -N-phenyl-4- (tetrahydro-3-furanyl) -2-a naphthalene monohydrochloride; 6- (amino) -N- [4- (hydroxymethyl) phenyl] -4- (2-pyrimidinyl) -2-a naphthalene-mono (trifluoroacetate); methyl [3 - [[[4- (aminomethyl) phenyl] amino] carbonyl] -7- [4-amino (hydroxyimino) methyl] -1-naphthalenyl] carbamate bis (trifluoroacetate); 6- (amino) -N-phenyl-4- (2-pyrimidinyl) -2-a naphthalene-mono (trifluoroacetate); N - [(4- (aminomethyl) phenyl] -6- [amino (hydroxyimino) methyl] -4- (2-pyrimidinyl) -2-a naphthalene bis (trifluoroacetate); 6- (amino) -N- [4- (aminomethyl) phenyl] -4- (2-pyrimidinyl) -2-a naphthalene-tris (trifluoroacetate); 6- (Aminomethyl) -4- (5- (methylthio) -3-furanyl)] - N-phenyl-2-naphthalenecarboxamide monohydrochloride; 6- (Aminomethyl) -4- (1- (methylsulfonyl) -1H-pyrazol-4-yl) -N-phenyl-2-naphthalenecarboxamide monohydrochloride; 6- (aminoiminomethyl) -4- (3-furanyl) -N-phenyl-2-naphthalenecarboxamide monohydrochloride; 6- (amino) -4- (3-furanyl) -N- (2-pyridinyl) -2naftalénkarboxamid dihydrochloride; 314 6- (aminoiminomethyl) -4- (3-furanyl) -N- (3-pyridinyl) -2-naphthalenecarboxamide dihydrochloride; methyl [7- (aminoiminomethyl) -3 - [[[4- (aminomethyl) phenyl] amino] carbonyl] -1-naphthalenyl] carbamate bis (trifluoroacetate), 6- (amino) -4- (3-furanyl) -N- (lH-pyrazol-3-yl) -2-a naphthalene dihydrochloride; 6- (amino) -4- (3-furanyl) -N- (4-pyridinyl) -2-a naphthalene dihydrochloride; 6- (amino) "4- (3-furanyl) -N- [4-trifluoromethyl) phenyl] -2-a naphthalene-mono (trifluoroacetate); 6-methoxy-8-benzyloxy-2-Naphthalenecarboximidamide mono (trifluoroacetate); A compound according to claim 1, wherein A is -L _A R 1 '. B is -L. Rh C is hydrogen. 313 6) arylalkyl, wherein the alkylene group contains one to six carbon atoms; 6) aryl; 6) alkynyl of two to ten carbon atoms; 7-methoxy-8- [2-pyrimidinyl (amino)] - 2-naphthalenecarboximidamide, and bis (trifluoroacetate) salt. 323 7-methoxy-8- [1- (methylsulfonyl) -1H-4-pyrazolyl] -2-naphthalenecarboximidamide mono (trifluoroacetate); methyl [3-methoxy-6- (aminoiminomethyl) -4-naphthalenyl] carbamate mono (trifluoroacetate); 7-Methoxy-8- (1-acetyl-1H-pyrazolyl) -2-naphthalenecarboximidamide mono (trifluoroacetate); 7-methoxy-8- [N-2-pyrimidinyl (amino)] - 2-naftaIénkarboximidamid mono (trifluoroacetate); N- (6-amino-imino-2-naphthalenyl) -N-benzylmočovinamono (trifluoroacetate); N- (6-amino-imino-2-naphthalenyl) -N-rnetylmočovinamono (trifluoroacetate); 322 N- (6-amino-imino-2-naphthalenyl) -N-izopropylmočovinamono (trifluoroacetate), N- (6-aminomethyl-2-naphthalenyl) -N'-phenyl-N'-methyl urea namono (trifluoroacetate), 7-methoxy-8-pentafluorophenoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate); 7-methoxy-8- (4-nitrophenoxy) -2-Naphthalenecarboximidamide mono (trifluoroacetate); 7-methoxy-8- [2-thiazolyl (oxy) naphthalen-2-carboximidamide mono (trifluoroacetate); 7-methoxy-8- [2-pyrimidinyl (oxy)] - 2-Naphthalenecarboximidamide mono (trifluoroacetate); (±) -7-methoxy-8- (tetrahydro-3-furanyl) -2-naftalénkarboximidamidmono (methanesulfonate); 7-methoxy-8- (2-benzofuranyl) naphthalene-2-karboximidamidmono (methanesulfonate); (E) -8- [2- (1,3-benzodioxol-5-yl) ethenyl] -2-naphthalenecarboximidamide mono (methanesulfonate); 7-methoxy-8- (3-furanyl) -2-Naphthalenecarboximidamide mono (methanesulfonate); 7-methoxy-8-iodo-2-Naphthalenecarboximidamide mono (trifluoroacetate), 7-methoxy-8- (1H-pyrazol-4-yl) -2-naphthalenecarboximidamide mono (trifluoroacetate); 7-Propoxy-8-iodo-2-naphthalenecarboximidammonium (trifluoroacetate), 321 7- (2-hydroxyethoxy) -2-Naphthalenecarboximidamide mono (trifluoroacetate); 7- (2-hydroxyethoxy) -8-iodo-2-Naphthalenecarboximidamide mono (trifluoroacetate); 7-methoxy-8- (2-furanyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate); methyl-6- (amino) -4 - [(methoxycarbonyl) amino] -2-naphthoate mono (trifluoroacetate); (E) -6- [2- (phenyl) ethenyl] -2-naftalénimidamid mono (trifluoroacetate); 7-benzyloxy-8-iodo-2-Naphthalenecarboximidamide mono (trifluoroacetate); methyl [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] acetate mono (trifluoroacetate); 7.8-dimethoxy-2-naphthalenecarboximidamide mono (trifluoroacetate), 7-methoxy-8- (pyrazinylamino) -2-Naphthalenecarboximidamide bis (trifluoroacetate). 7-methoxy-8- (phenylthio) -2-naphthalenecarboximidamide methanesulfonate, and 7-methoxy-8- (pyrazinyloxy) -2-Naphthalenecarboximidamide-dimethanesulfonate; 319 7-methoxy-8- (3-Oxo-l-cyclopenten-l-yl) -2-naftaIénkarboximidamid mono (trifluoroacetate); methyl 4 - [[[7- (amino) -l- (2-pyrimidinyl) -2-naphthalenyl] oxy] methyl] benzoate, mono (tnfluóracetát); 7-methoxy-8 - [(4-methoxyphenyl) amino] -2-Naphthalenecarboximidamide mono (trifluoroacetate); (E) -3- [7- (amino) -2-methoxy-l-naphthalenyl) -2-propenamide-mono (trifluoroacetate); 7-methoxy-8- (phenylamino) -2-Naphthalenecarboximidamide mono (trifluoroacetate); 7-methoxy-8 - [(phenylmethyl) amino] -2-Naphthalenecarboximidamide mono (trifluoroacetate); 7-methoxy-8- (2-pyrimidinylamino) -2-naphthalenecarboximidamide bis (trifluoroacetate); 7-Methoxy-8- [2-pyrimidinyl (amino)] - 2-naphthalenecarboximidamide bis (trifluoroacetate); methyl [7- (amino) -2-methoxy-1-naphthyl enyl] carbamate mono (trifluoroacetate); 7-Methoxy-8- [1- (methylsulfonyl) -1H-4-pyrazolyl] -2-naphthalenecarboximidamide mono (trifluoroacetate). 318 7-methoxy-8- (1-acetyl-1H-pyrazolyl) -2-naphthalenecarboximidamide mono (trifluoroacetate); 7-methoxy-8- [N-2-pyrimidinyl (amino)] - 2-naftalénkarboximidamidmono (trifluoroacetate); 7-methoxy-8-pentafluorophenoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate), 7-methoxy-8- (4-nitrophenoxy) -2-Naphthalenecarboximidamide mono (trifluoroacetate); 7-methoxy-8- [2-thiazoyl (oxy) naphthalen-2-carboximidamide mono (trifluoroacetate); 7-methoxy-8- [2-pyrimidinyl (oxy)] - 2-Naphthalenecarboximidamide mono (trifluoroacetate); (±) -7-methoxy-8- (tetrahydro-3-furanyl) -2-naftalénkarboximidamidmono (methanesulfonate); 7-methoxy-8- (2-benzofuranyl) naphthalene-2-karboximidaniid mono (methanesulfonate) (E) -8- [2- (1,3-benzodioxol-5-yl) ethenyl] -2-naftalénkarboximidamidmono (methanesulfonate); 7-methoxy-8- (3-furanyl) -2-Naphthalenecarboximidamide mono (methanesulfonate), 7-methoxy-8-iodo-2-Naphthalenecarboximidamide mono (trifluoroacetate), 7-methoxy-8- (lH-pyrazol-4-yl) -2-Naphthalenecarboximidamide bis (trifluoroacetate); 317 7-propoxy-8-iodo-2-Naphthalenecarboximidamide mono (trifluoroacetate); 7- (2-hydroxyethoxy) -8-iodo-2-Naphthalenecarboximidamide mono (trifluoroacetate); 7-methoxy-8- (2-furanyl) -2-Naphthalenecarboximidamide mono (trifluoroacetate); (E) -? 7-Methoxy-8- [2- (phenyl) ethenyl] / 2-naphthalenimidamide mono (trifluoroacetate); 7-benzyloxy-8-iodo-2-naphthalenecarboximidamide mono (trifluoroacetate), methyl - [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl) oxy] acetate mono (trifluoroacetate); 7,8-dimethoxy-2-Naphthalenecarboximidamide mono (trifluoroacetate); 316 The compound of Claim 6 which is 6,7-dimethoxy-2-naphthalenecarboximidamide mono (trifluoroacetate). 7- [2- (4-morpholinyl) ethoxy] -2-Naphthalenecarboximidamide bis (trifluoroacetate); 7- (2-hydroxyethoxy) -2-naphthalenecarboximidamide mono (trifluoroacetate), methyl 1-5- [7 - [(aminoiminomethyl) -2-naphthalenyl] oxy] pentanoate; mono (tri fluoroacetate); 7) cycloalkyl of three to eight carbon atoms, and 310 7) arylalkyl wherein the alkylene group contains one to six carbon atoms; 7) halogen, 7) -C (X) NR 8 ₂₎ CH = CH9) -C? C-, A compound according to claim 1, wherein A is -L _and Ra, B is hydrogen C is -LcRc 8- (2-pyridylamino) -2-Naphthalenecarboximidamide bis (trifluoroacetate); and N-hydroxy-8- (2-pyrimidinyl) -2-naftalénkarboximidamidmono (trifluoroacetate). 8-amino-2-Naphthalenecarboximidamide bis (trifluoroacetate), 8- (2-pyrimidinyl) -2-Naphthalenecarboximidamide bis (trifluoroacetate), 8 (carbonylbenzyloxy) amino-2-naftalénkarboximidamidmono (trifluoroacetate); N- [7- (aminoiminomethyl) -1-naphthalenyl) acetamide mono (trifluoroacetate), methyl [7- (aminoiminomethyl) -1-naphthalenyl) carbamate mono (trifluoroacetate); methyl-3 - [[7- (amino) -l-naphthalenyl] amino] -3-oxo-propionate monotrifluóracetát; N- [7- (aminoiminomethyl) -1-naphthalenyl] -2- (phenylmethoxy) acetamide mono (trifluoroacetate), N- [7- (aminoiminomethyl) -1-naphthalenyl] -1,3-benzodioxole-5-carboxamide mono (trifluoroacetate); 312 N- [7- (aminoiminomethyl) -1-naphthalenyl] benzenemethanesulfonamide mono (trifluoroacetate), methyl [7- (aminoiminomethyl) -1-naphthalenyl] methylcarbamate mono (trifluoroacetate); propyl [7- (aminoiminomethyl) -1-naphthalenyl] carbamate mono (trifluoroacetate); N- [7- (amino) -l-naphthalenyl] -N-methylurea mono (trifluoroacetate); ethyl [7- (amino) -l-naphthalenyl] carbamate mono (trifluoroacetate); N- [7- (aminoiminomethyl) -1-naphthalenyl] propanamide mono (trifluoroacetate); N- [7- (amino) -l-naphthalenyl) -2-methoxy-acetamide mono (trifluoroacetate); N- [7- (amino) -l-naphthalenyl] urea mono (trifluoroacetate); N- [7- (amino) -l-naphthalenyl] -2-hydroxy-mono (trifluoroacetate); 8) cycloalkylalkyl, wherein the cycloalkyl group contains three to eight carbon atoms and the alkylene group contains one to ten carbon atoms; and wherein each X occurrence is independently selected from the group consisting of ' 8) cycloalkyl of three to eight carbon atoms; and 8) -NR ₂ R; A compound according to claim 8 selected from the group consisting of: methyl-6- (amino) -4- [methoxycarbonyl) amino] -2-naphthoate mono (trifluoroacetate); (9) cycloalkylalalkyl, wherein the cycloalkyl group contains three to eight carbon atoms and the alkylene group contains one to ten carbon atoms, and wherein R 2 and R 3 at each occurrence independently represent a group selected from the group consisting of: 9) heterocycle; A compound according to claim 1, wherein A is -L _and Ra, B is -LbRb, and C is -LcRc (10) cycloalkenyl of four to twelve carbon atoms; 10) -011) -S (O) - The compound of Claim 10 which is 6,7,8-trimethoxy-2-naphthalenecarboximidamide mono (trifluoroacetate). The compound of claim 1, wherein A is hydrogen, B is -LbRb, and C is -LcRc 12) -NR C (O) NR ₂ R _3; and 12) -OC (CH ₂ ) _n NR ₂ C (X) -, A compound according to claim 12, selected from the group consisting of: 13) -NR C (0) r, wherein R _S is alkyl of one to six carbon atoms, and wherein 309 Ri at each occurrence is selected from the group consisting of: 13) -C (X) NR ₂ (CH ₂ ) 5 CsCl 4 - (CH ₂ ) 4 NSO ₂ -, »07 14 A compound selected from the group consisting of 15. A method of inhibiting urokinase comprising administering to a mammal in need of treatment a therapeutically effective amount of a compound of claim 1. 15) -NR ₂ S () ₂ (CH ₂ ) _n CsC-, 16) -CsC (CH ₂ ) n NR ₂ SO ₂ NR 11) -NR ₂ SO ₂ NR ₃ (CH ₂ ) n C = C-, 18) -SO ₂ NR ₂ -, 19) _2, -NR 20 SO ₂₎ -NR ₂ SO ₂ NR ₃ -, 21) -N = N- 22) -C (X) N (OR ₂ ) -, 23) -N (OR ₂ ) C (X) -, 24) -HC = CH (CH ₂ ) n NR ₂ C (X) 25) - (CH ₂ ) n NR ₂ C (X) CH = CH-, 26) -CH = CH (CH ₂ ) _n NSO ₂ -, 27) -NR ₂ SO ₂ (CH ₂ ) _n CH = CH-, 28) - (CH ₂ ) "NR ₂ SO ₂ NR ₃ -," 29) -NR ₂ SO ₂ NR ₃ (CH ₂ ) _n CH = CH-, 30) -NR ₂ C (O) O-, A composition for inhibiting urokinase comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.