EP1000018A2 - Urokinase inhibitors - Google Patents

Urokinase inhibitors

Info

Publication number
EP1000018A2
EP1000018A2 EP98937082A EP98937082A EP1000018A2 EP 1000018 A2 EP1000018 A2 EP 1000018A2 EP 98937082 A EP98937082 A EP 98937082A EP 98937082 A EP98937082 A EP 98937082A EP 1000018 A2 EP1000018 A2 EP 1000018A2
Authority
EP
European Patent Office
Prior art keywords
salt
mono
trifluoroacetate
aminoiminomethyl
methoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98937082A
Other languages
German (de)
French (fr)
Inventor
Andrew G. Geyer
William J. Mcclellan
Todd W. Rockway
Kent D. Stewart
Moshe Weitzberg
Michael D. Wendt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP1000018A2 publication Critical patent/EP1000018A2/en
Withdrawn legal-status Critical Current

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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
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    • A61P35/00—Antineoplastic agents
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    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
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    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention provides naphthamidine compounds which inhibit the urokinase enzyme, pharmaceutical compositions containing these compounds and medical methods of treatment using these compounds.
  • Urokinase (urinary-type plasminogen activator or uPA (International Union of Biochemistry classification number: EC3.4.21.31)) is a proteolytic enzyme which is highly specific for a single peptide bond in plasminogen. Plasminogen activation (cleavage of this bond by the urokinase enzyme) results in formation of plasmin, a potent general protease.
  • urokinase as a key initiator of plasmin-mediated proteolytic degradation or modification of extracellular support structures such as extracellular matrix (ECM) and basement membrane (BM).
  • ECM extracellular matrix
  • BM basement membrane
  • Cells exist, move and interact with each other in tissues and organs within the physical framework provided by ECM and BM. Movement of cells within ECM or across BM requires local proteolytic degradation or modification of the structures and allows cells to invade adjacent areas previously unavailable prior to the degredation or modification.
  • Cellular invasiveness intiated by urokinase is central to a variety of normal and disease- state physiological processes (Blasi, F., Vassalli, J. D., and Dano, K. J. Cell Biol.
  • Such processes include, but are not limited to, angiogenesis (neovascularization), bone restructuring, embryo implantation in the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue remodelling during wound repair and organ differentiation, fibrosis, tumor invasion, metastatic
  • SUBSTtTUTE SHEET (RULE 26) spread of tumor cells from primary to secondary sites and tissue destruction in arthritis.
  • Amiloride for example, a known urokinase inhibitor of only moderate potency, has been reported to inhibit tumor metastasis in vivo (Kellen, J. A., Mirakian, A. Kolin, A. Anticancer Res. 8: 1373-1376, 1988) and angiogenesis/capillary network formation in vitro (Alliegro, M. C. and Glaser, B. M. J. Cell Biol. 115[3 Pt 2]: 402a, 1991).
  • Inhibitors of urokinase therefore, have mechanism-based anti-angiogenic, anti-arthritic, anti-inflammatory, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive and tumoristatic uses.
  • the present invention provides a compound or a pharmaceutically acceptable salt, ester or prodrug thereof, of formula (I)
  • Z is selected from the group consisting of
  • A is selected from the group consisting of
  • B is selected from the group consisting of ( 1 ) hydrogen and (2) -LBRB and
  • C is selected from the group consisting of (1) hydrogen and (2) -L C Rc, with the proviso that at least one of A, B or C is other than hydrogen; and with the proviso that when A is other than hydrogen, at least one of B or C is other than hydrogen, wherein for A, B, and C, LA, LB and Lc are independently selected from the group consisting of
  • RA, R ⁇ an d Re are independently selected from the group consisting of
  • aryl (7) arylalkyl, wherein the alkyiene group is of one to six carbon atoms;
  • cycloalkylalkyl wherein the cycloalkyl group is of three to eight carbon atoms, and the alkyiene group is of one to ten carbon atoms; and wherein, at each occurence, R2 and R3 are independently selected from the group consisting of
  • cycloalkylalkyl wherein the cycloalkyl group is of three to eight carbon atoms, and the alkyiene group is of one to ten carbon atoms; and wherein, at each occurence, X is selected from the group consisting of
  • the present invention also relates to a method of inhibiting urokinase in a mammal, particularly humans, by administering a therapeutically effective amount of a composition comprising a compound of formula (I).
  • the present invention also relates to pharmaceutical compositions which comprise a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.
  • alkyl represents a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom and is exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl and the like and may be optionally substituted with one, two.
  • substituents 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 alkyiene group is of one to six carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (1 1) halo; (12) heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxy; (16) N-protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one to six carbon atoms; (21) -CO2R2; (22) -C(O)NR
  • alkanoyl represents an alkyl group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl, acetyl, propionyl, butanoyl and the like.
  • alkenyl represents monovalent straight or branched chain groups containing a carbon-carbon double bond derived from an alkene by the removal of one hydrogen atom and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl- l-propenyl, 1- butenyl, 2-butenyl and the like and may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of (1) alkoxy of one to six carbon 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 alkyiene group is of one to six carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (1
  • alkoxy represents an alkyl group attached to the parent molecular group through an oxygen atom.
  • alkoxyalkyl represents an alkyl group to which is attached an alkoxy group.
  • alkoxycarbonyl represents an ester group; i.e. an alkoxy group, attached to the parent molecular group through a carbonyl group and is exemplified by methoxycarbonyl, ethoxycarbonyl and the like.
  • alkyiene represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene and the like.
  • alkylsulfinyl represents an alkyl group attached to the parent molecular group through an -S(O)- group.
  • alkylsulfinylalkyl represents an alkyl group, as defined herein, substituted by a sulfinyl group.
  • alkylsulfonyl represents an alkyl group attached to the parent molecular group through an -SO 2 - group.
  • alkylsulfonylalkyl represents an alkyl group, as defined herein, substituted by a sulfonyl group.
  • alkynyl represents monovalent straight or branched chain groups of two to six carbon atoms containing a carbon-carbon triple bond derived from an alkyne by the removal of one hydrogen atom and is exemplified by ethynyl, 1-propynyl, and the like and may be optionally substituted with one, two, three or four substituents 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 alkyiene group is of one to six carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (11) halo; (12) heterocycle; (13) (hetero
  • amino represents an -NH 2 group.
  • aminoalkyl represents an alkyl group, as defined herein, substituted by an amino group.
  • aryl represents a mono- or bicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like and may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkyiene goups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon
  • arylalkyl represents an aryl group attached to the parent molecular group through an alkyl group.
  • arylalkoxy represents an arylalkyl group attached to the parent molecular group through an oxygen atom.
  • aryloxy represents an aryl group which is attached to the parent molecular group through an oxygen atom.
  • aryloyl represents an aryl group which is attached to the parent molecular group through a carbonyl group.
  • azidoalkyl represents an alkyl group, as defined herein, substituted by an azido group.
  • carboxydehyde represents a -CHO group.
  • (carboxaldehyde)alkyl represents an alkyl group, as defined herein, substituted by a carboxaldehyde group.
  • Carboxy represents a -CO 2 H group.
  • Carboxyalkyl represents an alkyl group, as defined herein, substituted by a carboxy group.
  • cycloalkyl represents a monovalent saturated cyclic hydrocarbon group and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2. l]heptyl and the like.
  • the cycloalkyl groups of this invention can be optionally substituted with (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms: (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkyiene goups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon
  • cycloalkenyl represents a monovalent cyclic hydrocarbon having at least one carbon-carbon double bond.
  • the cycloalkenyl groups of this invention can be optionally substituted with (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkyiene goups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (9) aryl: (10) arylalkyl
  • cycloalkoxy represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • cycloalkylalkoxy represents an alkoxy group, as defined herein, to which is attached a cycloalkyl group.
  • cycloalkylalkyl represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an alkyl group.
  • haloalkyl represents an alkyl group, as defined herein, substituted by one, two, or three halogen atoms and is exemplified by chloromethyl, bromoethyl, trifluoromethyl and the like.
  • halogen represents F, Cl, Br and I.
  • heterocycle represents a 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • the 5-membered ring has zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds.
  • heterocycle also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring and another monocyclic heterocyclic ring such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like.
  • Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidiny
  • F is selected from the group consisting of -CH 2 -, -CH 2 O- and -O-
  • G is selected from the group consisting of -C(O)- and -(C(R')(R"))v ->
  • R' and R" are independently selected from the group consisting of hydrogen or alkyl of one to four carbon atoms
  • v is one to three and includes groups such as 1,3-benzodioxolyl, 1 ,4-benzodioxanyl and the like.
  • any of the heterocycle groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkyiene goups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atom
  • (heterocycle)oxy represents a heterocycle group, as defined herein, attached to the parent molecular group through oxygen.
  • (heterocycle)oyl represents a heterocycle group, as defined herein, attached to the parent molecular group through a carbonyl group.
  • hydroxy as used herein, represents an -OH group.
  • hydroxyalkyi represents an alkyl group, as defined herein, substituted by one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group and is exemplified by hydroxymethyl, dihydroxypropyl and the like.
  • N-protected amino refers to an amino group, as defined herein, to which is attached an N-protecting or nitrogen-protecting group, as defined herein.
  • N-protected aminoalkyl refers to an alkyl group, as defined herein, which is substituted by an N-protecting or nitrogen-protecting group, as defined herein.
  • nitro represents an -NO 2 group.
  • nitroalkyl represents an alkyl group substituted by an -NO2 group.
  • N-protecting group or “nitrogen protecting group” as used herein, represent those groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)), which is incorporated herein by reference.
  • N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4- nitrobenzoyl and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl,
  • Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • perfluoroalkyl represents an alkyl group, as defined herein, wherein each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical. Perfluoroalkyl groups are exemplified by trifluoromethyl, pentafluoroethyl, and the like.
  • perfluoroalkoxy refers to a perfluoroalkyl group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base group with a suitable organic acid.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate.
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.
  • pharmaceutically acceptable ester represents esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl group preferably has not more than 6 carbon atoms.
  • Examples of particular esters includes formates, acetates, propionates, butyates, acrylates and ethylsuccinates.
  • prodrugs as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and Judkins, et al.Synthetic Communications, 26(23), 4351-4367 (1996), each of which is incorporated herein by reference.
  • spiroalkyl represents an alkyiene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group.
  • sulfonyl represents an -SO2-group.
  • thioalkoxy represents represents an alkyl group attached to the parent molecular group through a sulfur atom.
  • thioalkoxyalkyl represents an alkyl group substituted by a thioalkoxy group.
  • Asymmetric or chiral centers may exist in the compounds of the present invention.
  • the present invention contemplates the various stereoisomers and mixtures thereof.
  • Individual stereoisomers of compounds of the present invention are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of mixtures of enantiomeric compounds followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a racemic mixture of enantiomers, designated ( ⁇ ), to a chiral auxiliary, separation of the resulting diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • Enantiomers are designated herein by the symbols "R” or "S,” depending on the configuration of subsitiuents around the chiral carbon atom.
  • Geometric isomers may also exist in the compounds of the present invention.
  • the present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond and designates such isomers as of the Z or E configuration, wherein the term "Z” represents substituents on the same side of the carbon-carbon double bond and the term “E” represents substituents on opposite sides of the carbon-carbon double bond.
  • Preferred Embodiments Preferred compounds of the present invention have formula (I), wherein
  • a and C are hydrogen and B is -LBRB, wherein
  • -LB- is -O-
  • RB is alkyl of two to six carbon atoms, and wherein the alkyl group is substituted.
  • More preferred embodiments of the present invention have formula (I), wherein A is -LARA an d
  • B and C are hydrogen, wherein -LA- is selected from the group consisting of
  • RA is selected from the group consisting of
  • heterocycle wherein the heterocycle is selected from the group consisting of ( l) furanyl,
  • R2 is selected from the group consisting of (1) hydrogen and (2) alkyl of one to six carbon atoms; and wherein, at each occurence, m is two, n is one,
  • R l and R3 are hydrogen, W and X are O, aryl is phenyl, the alkyl group and the aryl group are optionally substituted and the alkenyl group is substituted.
  • Still more preferred compounds of the present invention have formula (I), wherein
  • a and B are hydrogen; C is -L C Rc;
  • -Lc- is selected from the group consisting of ( 1) a covalent bond,
  • Rc is selected from the group consisting of
  • heterocycle wherein the heterocycle is selected from the group consisting of
  • X is O; and wherein, at each occurence,
  • R l and R2 are H, aryl is phenyl and the alkyl is optionally substituted.
  • Still more preferred compounds of the present invention have formula (I) wherein
  • A is -LARA
  • C is hydrogen, -LA- and -LB- are -O-, and
  • RA and R ⁇ are alkyl of one to six carbon atoms.
  • Still more preferred compounds of the present invention have formula (I) wherein A is -LARA, B is -LBRB, C is -LcRc
  • -LA-, -L ⁇ -, and -Lc- are -O- and RA, R ⁇ , and Re are alkyl of one to six carbon atoms.
  • Still more preferred compounds of the present invention have formula (I) wherein A is hydrogen
  • C is -LcRc; -LB- is -O-;
  • -Lc- is selected from the group consisting of
  • R ⁇ is selected from the group consisting of
  • G is -(C(R')(R")) V -, R' and R" are hydrogen and v is one; and wherein, at each occurence, aryl is phenyl and alkyl, aryl and heterocycle are optionally substituted.
  • N-f7-(aminoiminomethyl)-l-naphthalenyl)acetamide mono(trifluoroacetate) salt methyl [7-(aminoiminomethyl)-l-naphthalenyl)carbamate mono(trifluoroacetate) salt; methyl 3-[[7-(aminoiminomethyl)--l-naphthalenylJaminol-3-oxopropanoate mono(trifluoroacetate) salt;
  • N-phenyl-6-aminoiminomethyl-2-naphthalenecarboxamide mono(methanesulfonate) salt 4-[(6-aminoiminomethyl-2-naphthalenyl)oxy]-N-methylbenzeneacetamide mono(trifluoroacetate) salt;
  • 2-naphthalenecarboxamide mono(trifluoroacetate) salt
  • Urokinase inhibition The efficacy of the compounds of this invention as urokinase inhibitors was determined by measuring the inhibition of the urokinase enzyme Abbokinase (Abbott Laboratories, Abbott Park, IL) on substrate S-2444, of formula pyroGlu-Arg-pNA-HCl (DiaPharma Group, Inc. Distributor of Chromogenix) at 200 ⁇ M.
  • Abbokinase Abbott Laboratories, Abbott Park, IL
  • pyroGlu-Arg-pNA-HCl DiaPharma Group, Inc. Distributor of Chromogenix
  • the assay was performed in a 96 well polystyrene, flat bottom plate in a 50 mM Tris/0.15 M NaCl + 0.5 % Pluronic F-68 (Sigma P-5556), pH 7.4 (with HC1) buffer.
  • the compounds of this invention 10 mM in DMSO, were diluted with DMSO to eight half log concentrations, for example: 1200 ⁇ M, 400 ⁇ M, 120 ⁇ M, 40 ⁇ M, 12 ⁇ M, 4 ⁇ M, 1 ⁇ M and 0.4 ⁇ M. Four concentrations were chosen, then 5 ⁇ l of each were diluted to a total assay volume of 200 ⁇ l.
  • the final compound concentrations in the assay were 30 ⁇ M, 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M and 0.01 ⁇ M, respectively.
  • the substrate S-2444 was used at 200 ⁇ M in the assay.
  • Several vials were reconstituted as directed on the vial, aliquoted and stored frozen.
  • the enzyme was further diluted in assay buffer and 10 ⁇ l was used in the assay. Enzyme concentration in the assay was 2-3 nM.
  • the assay was performed as follows: 175 ⁇ L of buffer was pipetted into the polystyrene plate, 5 ⁇ L solution of a compound of this invention in DMSO was added, the mixture was vortexed, 10 ⁇ L of enzyme in buffer was added, the mixture was vortexed, 10 ⁇ L of substrate in water was added, the mixture was vortexed, and the plate was placed in a Spectromax ® (Molecular Devices Corporation, Sunnyvale, Ca) plate reader to follow the course of the reaction for 15 min at 405 nm.
  • the Spectromax ® calculated the reaction rates which were used to calculate percent inhibition of the compounds of this invention versus the reaction rate of the enzyme in the absence of any inhibitor.
  • the Ki 's of the inhibitors were calculated from the percent inhibition and previously established Km.
  • the compounds of this invention inhibit urokinase as shown by the data for representative examples in Table 1.
  • T e present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally , intracisternally, intravaginally. intraperitoneally or topically (such as powders, ointments or drops), bucally or as an oral or nasal spray.
  • parenteral administration refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents (such as aluminum monostearate and gelatin) which delay absorption .
  • adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally or in delayed fashion. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystaUine cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg, of active compound per kilogram of body weight per day when administered orally to a mammalian patient.
  • the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
  • THF for tetrahydrofuran
  • DMF for N,N-dimethylformamide
  • OEt2 for diethyl ether
  • EDC for l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • NMM for N-methylmorpholine
  • LDA lithium diisopropylamide
  • TFA for trifluoroacetic acid
  • DMSO for dimethylsulfoxide
  • DMAP for 4-(N,N-dimethylamino)pyridine
  • HATU for
  • Starting materials, reagents and solvents were purchased from Aldrich Chemical Company (Milwaukee, Wi).
  • naphthalenecarbonitriles 4, 5 and 6 were prepared by treating 3- cyanopropionaldehyde diethyl acetal 2 with a strong base such as lithium diisopropylamide then treating the resulting anion with the appropriately substituted benzaldehyde 1 followed by cyclization and aromatization of the corresponding cyanohydrins 3_ with a Lewis acid such as sulfuric acid.
  • a strong base such as lithium diisopropylamide
  • A, B and C are hydrogen and -L A R A , -L B R B , -L C R C
  • R A , R B and R c are alkyl
  • A is hydrogen; B and C are OCH 3
  • A, B and C are OCH 3
  • a and B are OCH 3 , and C is hydrogen
  • BBr3, preferably AICI3, provided 7.
  • 7 was treated with a base such as potassium carbonate, sodium hydride or cesium fluoride followed by Rc-X, wherein X is a leaving group, to provide 8 (-Lc- is -0-).
  • Rc-X a base
  • X is a leaving group
  • 8 (-Lc- is -0-)
  • treatment of 1 with trifluoromethanesulfonic anhydride or 1,1,1- trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide provided , which may
  • a palladium catalyst preferably Pd(IT)Cl 2 (dba) or Pd(Ph3P) 4
  • base preferably cesium fluoride or potassium carbonate
  • 9 may be treated with RC-NR 1 R 2 , wherein Re is unsubstituted or substituted aryl or heterocycle, and at least one of R ⁇ or R 2 is hydrogen, in the presence of a strong base, such as potassium t-butoxide, and a catalyst, such as Pd(II)Cl 2 (dba), to provide 1 1.
  • R c is unsubstituted or substituted aryl or heterocycle 10: -L c - is a covalent bond 11: -L c - is -NR r
  • -Lc- is -C(0)NR r or -OC(O)NR r and R is unsubstituted or substituted alkyl, alkeneyl, hererocycle or aryl
  • Lewis acid such as AICI3 or BBr3, preferably AICI3, was followed by reprotection of phenol 1 by alkylation with Bn-X, wherein X is Cl, Br or I, in the presence of a base such as potassium carbonate, sodium hydride or cesium fluoride.
  • 20 was prepared by deprotonation of this intermediate with a strong, non-nucleophilic base such as lithium, sodium or potassium diisopropylamide or alkoxide followed by treatment with an alkyl formate, preferably ethyl formate to provide enol 20.
  • Treatment of 20 with hydroxylamine provided isoxazole 21 which may be opened with lithium, sodium or potassium alkoxide, preferably sodium methoxide, to provide 22.
  • 24 was alkylated by treatment with a base such as potassium carbonate, sodium hydride or cesium fluoride followed by treatment Rc-X-
  • A is -L A R A
  • C is -L C R C , wherein C is -L c Rc, wherein L c is -O- and
  • -L A - and -L - are -O- and R A is alkyl
  • R c is arylalkyl
  • A is -L A R A , wherein
  • 29 may be coupled to primary or secondary amines, and 33 may be coupled to carboxylic acids to form amides 35 and 36, respectively.
  • the amines and carboxylic acids are coupled using a dehydrating agent such as DCC, EDC or HATU.
  • -L c - is -C(X)J R ⁇ or -OC(O)NR and R c is unsubstituted or substituted alkyl, alkeneyl, hererocycle or aryl; X is O
  • conversion of the nitrile intermediates to the carboximidamide urokinase inhibitors 4 was achieved by three methods: (1) treatment of the intermediate carbonitriles with a non-nucleophilic base such as lithium, sodium or potassium bis(trimethylsilylamide), preferably lithium bis(trimethylsilylamide) followed by hydrolysis with acid, preferably HCl; (2) treatment of the nitrile with acid, preferably HCl, followed by treatment with ammonium acetate; and (3) treatment of the nitrile with H 2 S followed by treatment with ammonia gas in methanol.
  • the H 2 S/NH /methanol method is preferred.
  • the compounds of the invention were precipitated as hydrochloride or methane sulfonate salts or were purified by reversed phase medium pressure chromatography to form mono- or bis- trifluoroacetate salts.
  • Example 1A 8-Dimethoxy-2-naphthalenecarbonitrile
  • a solution of freshly prepared LDA in THF at -78 °C was treated dropwise with 3- cyanopropionaldehyde diethyl acetal (3.0 g) in THF (5 mL), stirred for 1 h, treated with 2,3- dimethoxybenzaldehyde (3.2 g) in THF (5 mL), warmed to room temperature over 90 min, treated with water (40 mL), concentrated and extracted with chloroform. The organic layer was washed with brine, dried (MgSO 4 ) and concentrated to provide 1.5 g of a yellow oil. MS (DCI/NH3) m/e 341 (M+H 2 O) + .
  • Example 1 A solution of Example 1 (200 mg) in THF (5 mL) at 0 °C was treated with lithium bis(trimethylsilylamide) (1.0 M in hexane, 1.1 mL), stirred for 18 h at room temperature, treated with 10% HCl (10 mL), stirred for 24 h at room temperature, concentrated and purified by medium pressure liquid chromatography on a 30 cm x 2 cm C- 18 column (40 micron, J.T Baker) with UV detection at 250 nM with solvent mixtures in a gradient ranging from 90%A (0.1 % aq TFA)/10%B (methanol) to 10%A/90%B over 160 min at a flow rate of 5 mL/min (fractions were collected every 2 min for 100 min and analyzed by TLC ( 10: 1 : 1 acetonitrile/water/acetic acid) for product) to provide 100 mg of the title compound.
  • lithium bis(trimethylsilylamide) 1.0 M in hexane, 1.1 m
  • Example 3 A 7-dimethoxy-2-naphthalenecarbonitrile
  • the title compound was prepared as described in Example 1 A but substituting 3,4- dimethoxybenzaldehyde for 2, 3-dimethoxy-benzaldehyde to provide 1.3 g of the title compound.
  • MS (DCI/NH3) m/e 231 (M+H 2 O)+.
  • Example 1 A 7-Methoxy-8-hvdroxynaphthalene-2-carbonitrile
  • MS (DCI/NH3) m/e 217 (M+H 2 O)+.
  • Example 4C 2-IY7- Aminoiminomethyl-2-methoxy- 1 -naphthalenvDoxylacetamide mono(trifluoroacetate) salt
  • Example 4B 100 mg in methanol (5 mL) at 0 °C was treated with HCl(g), stirred for
  • Example 4A 600 mg, CS2CO3 (500 mg), t-butyl bromoacetate (120 mg) and tetrabutylammonium iodide (25 mg) in DMF (15 mL) was stirred for 18 h at room temperature, diluted with water (20 mL) and extracted with ethyl acetate. The organic extract was washed with saturated NaHC03 and brine, dried (Na2SO4) and concentrated to provide 800 mg of the title compound as a clear oil. MS (DCI/NH3) m e 331 (M+H2 ⁇ ) + .
  • Example 6A (100 mg) in methanol (30 mL) at 0 C was treated with HCl(g), stirred for 18 h at room temperature and concentrated to provide an off-white solid. The solid was treated with ammonium acetate (100 mg) in methanol (10 mL), heated at 40 °C for 15 h, cooled and concentrated to a yellow solid which was purified as described in Example IB to provide 10 mg of the title compound.
  • Example 7 r(7-aminoiminomethyl-2-methoxy-l -naphthalenvDoxylacetic acid mono(trifluoroacetate) salt
  • the solid was dissolved in IN HCl (20 mL), stirred 48 h at room temperature and filtered. The resulting white solid was purified as described in Example IB to provide 20 mg of the title compound.
  • Example 8 N-r4- ( Aminomethyl ) phenyll-6-aminoiminomethyl-2-naphthalenecarboxamide bis(trifluoroacetate) salt.
  • Example 8A 6-Naphthalenedicarboxylic acid, monomethyl ester
  • a suspension of dimethyl 2, 6-naphthalenedicarboxylic acid (39.6 g, 162 mmole) in dioxane (1.20 L) was heated at 70-80 °C until all solid dissolved, slowly treated with 1 equivalent of KOH in methanol, stirred for additional 30 minutes at 70 °C, cooled to room temperature, filtered and washed with dioxane and diethyl ether, dissolved in water, treated with 1 N HCl until the aqueous layer was acidic to pH paper, filtered, washed with water and dried under vacuum to provide 33 g of a white powder.
  • MS DCI/NH3 m/e 231 (M+H) + .
  • Example 8B 6-(Chlorocarbonyl)-2-naphthalenecarboxylic acid, methyl ester
  • a suspension of Example 8 A (15 g, 65 mmole) in toluene (190 mL) was treated with thionyl chloride (20 mL, 276 mmole) then DMAP (15 mg), heated at reflux for 1 h and heated at 85 °C for an additional 35 min.
  • the condenser was replaced with a distilling head and 60 mL of solvent was removed.
  • the thick precipitate which formed while cooling to room temperature was triturated with hexane and filtered to provide 14.8 g of white solid.
  • MS (DCI/NH3) m/e 249 (M+H) +
  • Example 8C 6-(Aminocarbonyl)-2-naphthalenecarboxylic acid, methyl ester
  • a solution of Example 8B (15 g, 60.3 mmole) in methylene chloride (400 mL) at room temperature was treated with dry ammonia gas to precipitate the product. The mixture was stirred for an additional 15 min and filtered. The solid was washed with water and dried under vacuum to yield 13.3 g of a white powder.
  • MS DCI/NH3) m/e 230 (M+H) + .
  • Example 8C A suspension of Example 8C (31 g, 135 mmole) in trimethyl phosphate (450 mL) was treated with triphosgene (27 g, 136 mmole), stirred for 20 min at room temperature and heated in an oil bath at 80 °C for 1 h. The product precipated from the solution while cooling to room temperature. The thick slurry was treated with water and filtered, and the white solid was thoroughly washed with water and dried under vacuum to provide 26.3 g of the title compound. MS (DCI NH3) m e 212 (M+H) +
  • Example 8G N-r4-(aminomethvDphenyll-6-cvano-2-naphthalenecarboxamide A solution of Example 8E (200 mg) and hunig's base (180 ⁇ L) in DMF (5 mL) at 5 °C was treated with HATU (193 mg), stirred for 1 h at 5 °C, treated with
  • Example 8F 120 mg and diisopropylethylamine (100 ⁇ L) in DMF (5 mL), stirred for 8 h at room temperature, diluted with ethyl acetate (100 mL), washed sequentially with IN H3PO4, saturated sodium bicarbonate and brine, dried (Na2SO 4 ) and concentrated to provide a yellow oil which was purified on silica gel with 1 methanol/methylene chloride to provide 200 mg of the title compound.
  • Example 8H N-r4-(aminomethyl)phenyll-6-aminoininomethyl-2-naphthalenecarboxamide bisftrifluoroacetate) salt
  • the title compound was prepared from Example 8G (200 mg) by the procedure and purification from Example 5B to provide 37 mg of the title compound.
  • Example 10 l-r(7-Aminoiminomethyl-2-methoxy-l-naphthalenyl)oxyl-3-hydroxypropane mono(trifluoroacetate) salt
  • Example 10A 1 -f(7-Cvano-2-methoxy- 1 -naphthalenvDoxy1-3-r(2-tetrahydro-2H-pyranyl1oxy)propane mono(trifluoroacetate) salt
  • a suspension of Example 4A (200 mg) and CS2CO3 (0.32 g) in DMF (15 mL) was treated with 2-(3-bromopropyl)-tetrahydro-2H-pyran (0.25 g), stirred at room temperature for 18 h then diluted with water (100 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with 10% citric acid, water and brine, dried (MgSO4) and concentrated to provide 320 mg of an oil.
  • Example 10B l-r(7-Aminoiminomethyl-2-methoxy-l-naphthalenyl)oxyl-3-hydroxypropane mono(trifluoroacetate) salt
  • Example 10A (0.3 g) was processed and purified according to the procedure of Example 1 B to provide 1 10 mg of an off-white solid.
  • l H NMR 300 MHz, DMSO-d 6 ) ⁇ 1.97 (q, 2H), 3.67 (t, 2H), 4.20 (t, 2H), 7.61-7.70 (m, 3H), 7.84 (d.lH), 8.08 (d, IH), 8.50 (d, IH); MS (DCI/NH3) m/e 275 (M+H) + .
  • Example 1 IB 2-Trifluoromethanesulfonyloxy-8-carbonylbenzyloxyaminonaphthelene
  • a solution of Example 11 A (2 g) in 10% aq Na2CO3 (20 mL) and dioxane (250 mL) was treated with benzylchloroformate (2 mL) in dioxane (20 mL), stirred at room temperature for 5 h then extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated, and the crude product was chromatographed on silica gel with 7: 1 hexane/ethyl acetate to provide 2.5 g (86%) of the title compound.
  • Example 11C 8-(N-carbonylbenzyloxy)-2-naphthalenecarbonitrile Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (120 mg), l,r-bis(diphenylphosphino)-ferrocene (260 mg), potassium cyanide (766 mg), Example 1 IB (2.5 g) and N-methyl-2-pyrrolidione (5 mL) were combined sequentially, stirred at room temperature until a yellow reaction complex formed then warmed to 80 °C for 40 min.
  • Example 1 1C (1.4 g) was treated with a solution of 30% HBr in acetic acid (5 mL) and stirred at room temperature for 6 h. The reaction mixture was treated with diethyl ether and filtered to provide 1.1 g of the title compound as a yellow solid. MS (DCI/NH3) m/e 186 (M+NH 4 )+.
  • Example 12 General Acylation Procedure A suspension of Example 10D (1 equivalent), triethylamine (1 equivalent) and DMAP (0.25 equivalents) in methylene chloride (0.3M) was treated dropwise with the appropriate acid chloride (1.1 equivalents) in methylene chloride (0.3 M), stirred at room temperature for 30 min and treated with water (50 mL). The organic layer was dried (MgSO4), concentrated and used in following reactions without further purification.
  • Example 13 General Amidine Synthesis Procedure A solution of crude acylation products from Example 12 (ca. 100 mg) at room temperature in 10: 1 pyridine:triethylamine (10 mL) was treated with hydrogen sulfide for 5 min, stirred at room temperature for 18 h, diluted with water (50 mL) and extracted with ethyl acetate. The ethyl acetate was dried (MgSO 4 ) and concentrated.
  • Example IB The residue was dissolved in acetone (30 mL), treated with methyl iodide (2 mL), refluxed for 1 hour, evaporated to dryness, redissolved in methanol (25 mL), treated with ammonium acetate (100 mg), stirred for 18 h at room temperature, concentrated and purified as described in Example IB to provide Examples 14-20 as white solids.
  • Example 2 IB 1 -r(7-Aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxyl-3-bromopropane mono(hvdrochloride) salt
  • the title compound was prepared from Example 21 A and the procedure of Example IB. After HCl hydrolysis, the solution was cooled to 0 °C, and the white solid which precipitated was filtered and dried to provide the title compound.
  • Example 22A 3-r(7-Cvano-2-methoxy- 1 -naphthalenvDoxylpropene The title compound was obtained as a biproduct from the procedure of Example 21 A. MS (DCI/NH3) m/e 257 (M+NH4) -.
  • Example 22B 3-r(7-Aminoiminomethyl-2-methoxy- 1 -naphthalenvDoxylpropene mono(trifiuoroacetate) salt The title compound was prepared from Example 22A and the procedure and purification in Example IB.
  • Example 4A The title compound was prepared from Example 4A, l-bromo-3-phenylpropane, and the procedure of Example 10A. MS (DCI/NH3) m/e 335 (M+NH4)+.
  • Example 24A l-Bromo-3-(3.4-dimethoxyphenyl)propane
  • the title compound was prepared from 3-(3,4-dimethoxyphenyl)-l-propanol as described in Journal of the American Chemical Society, 95 , 8749 (1973), which is incorporated herein by reference, to provide the title compound.
  • MS (DCI/NH3) m/e 276 (M+Nt D ⁇
  • Example 24B 1 -r(7-Cvano-2-methoxy- 1 -naphthalenyl)oxyl-3-r 1 -(3.4-dimethoxy)phenyl1propane
  • the title compound was prepared from Examples 4A and 24A and the procedure of Example 10 A.
  • Example 25A 7-Methoxy-8-trifluoromethanesulfonyloxy-2-naphthalenecarbonitrile
  • MS (DCI) m/e 349 (M+H 2 O) + .
  • Example 25C 7-Methoxy-8-(2-furanyl)-2-naphthalenecarbonitrile
  • Example 25 A (1.10 mmol) was combined with Pd(OAc)2 (0.1 1 mmol) and 1,1 '- bis(diphenylphosphino)ferrocene (0.22 mmol) in DMF (5 mL), stirred for 10 min, treated with Example 25B (1.32 mmol) and CS 2 CO3 (3.3 mmol), heated at 85 °C for 6 h, cooled to room temperature and chromatographed on silica gel with 10% ethyl acetate/hexane to provide the title compound. MS (DCI/NH3) m/e 250 (M+H) + .
  • Example 26A 2-Cvano-l-nitro-6-carboxynaphthalene methyl ester
  • a solution of 2-cyano-6-methylnaphthoate (5.2 g) in concentrated sufuric acid (75 mL) at 0 °C was treated with potassium nitrate (1.03 eq) in one portion, stirred for 10 min, poured onto ice (500 g) and extracted with ethyl acetate. The ethyl acetate layer was washed with water, IN NaOH and brine, dried (MgSO 4 ), treated with silica gel and filtered. Concentration of the ethyl acetate to ca. 200 mL precipitated the product.
  • Example 26B 2-Cvano-l-amino-6-carboxynaphthalene methyl ester A solution of Example 26A (lg, 3.9mmole) and 10% Pd on carbon (1 12 mg) in ethyl acetate (80 mL) was stirred under 1 atm of hydrogen for 9 h, purged with nitrogen for 1 h, filtered and evaporated to provide 810 mg (92%) of the title compound as a yellow solid. MS (DCI/NH3) m/e 227 (M+NH 4 ) + .
  • Example 26C 6-Cvano-4- (methoxycarbonyl)aminol-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) and methylchloroformate (195 ⁇ L, 2.52 mmole), stirred for 2 h, treated with methanol (10 mL), stirred for an additional 10 minutes, diluted with methylene chloride (60 mL), washed with water and brine, dried (MgSO4) and evaporated. The residue was purified on silica gel using 10% ethyl acetate/hexane to provide 280 mg (59%) of light yellow solid. MS (DCI NH3) m e 285 (M+H) + .
  • Example 26D Methyl 6-(aminoiminomethyl)-4-r(methoxycarbonyl)amino1-2-naphthalenecarboxylate mono(trifluoroacetate) salt The title compound was prepared using Example 26C (125 mg, 0.44 mmol) and the procedure in Example 40D to provide 35mg of a white solid.
  • Example 25A and styrene boronic ester prepared according to the procedure of Journal of the American Chemical Society, 97 5249 (1975), which is incorporated herein by reference, was processed according to the procedure described in Example 26B to provide the title compound.
  • Example 27B ( EV ⁇ 7-Methoxy-8-r2- ( Phenyl ) ethenv ⁇ l-2-naphthaleneimidamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 27 A and the procedure of Example IB.
  • IH NMR 300 MHz, DMSO-d 6 ) ⁇ 3.98 (s, 3H), 7.28 (t, 2H), 7.39 (t, 2H), 7.64 (m, 5H), 8.00 (d, IH), 8.10 (d, IH), 8.62 (s, IH), 9.22 (br s, 2H), 9.42 (br s, 2H); MS (DCI/NH3) m/e 303 (M+H)+.
  • 6-Hvdroxy-2-naphthalenecarbonitrile A solution of 6-bromo-2-naphthol (25.0 g, 112 mmol) and copper(I) cyanide (11 g, 123 mmol) in DMF (30 mL) was heated at 135 °C for 18 h, cooled, diluted with ethyl acetate (50 mL), triturated with 10% aq sodium hydroxide and filtered 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 (DCI/NH3) m/e 170 (M+H)+.
  • Example 28A 6-(Trifluoromethanesulfonyloxy)-2-naphthalenecarbonitrile
  • MS DCI/NH3) m/e 319 (M+NH 4 )+.
  • Example 28C 6-(4-Phenylbutvnyl)-2-naphthalenecarbo nitrile
  • the title compound was prepared from Example 28B, 4-phenyl- 1 -butyne and the procedure of Example 57B.
  • MS (DCI/NH3) m/e 299 (M+NH ) + .
  • Example 28D 6-(4-PhenvIbutvnyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 28C and the procedure of Example IB.
  • IH NMR 300 MHz, DMSO-d 6 ) ⁇ 2.80 (t, 2H), 2.95 (t, 2H), 7.22 (m, IH), 7.36 (m, 4H), 7.58 (d, IH), 7.82 (d, IH), 8.05 (d, IH), 8.10 (d, 2H), 8.45 (s, IH), 9.10 (br s, 2H), 9.42 (br s, 2H);
  • Example 29A 3-IT ⁇ .1 -DimethvIethyPdimethylsilylloxyl- 1 -propanol. 4-nitrobenzenesulfonate A solution of 3-t-butlydimethylsiloxy-l -propanol, prepared by the method of
  • Example 29D 7-(2-Hvdroxyethoxy)-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • Example 29B 7-(2-Hvdroxyethoxy)-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • Example 30B 7-(2-Hvdroxyethoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 29B according to the procedure of
  • Example 31 6-(4-Methyl- 1 -pentvnyP-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • Example 31 A 6-(4-Methyl- 1 -pentvnyl)-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, 4-methyl-l-pentyne and the procedure of Example 57B.
  • Example 3 6-(4-Methyl- 1 -pentynvD-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 31 A and the procedure of Example IB.
  • Example 32A 6-(5-Phenylpentynyl)-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, 5-phenyl-l-pentyne and the procedure of Example 57B. MS (DCI/NH 3 ) m/e 313 (M+NH4) + .
  • Example 32B 6-(5-PhenylpentvnvD-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 32A and the procedure of Example IB.
  • H NMR 300 MHz, DMSO-d 6 ) ⁇ 1.90 (m, 2H), 2.80 (t, 2H), 3.39 (t, 2H), 7.19-7.37 (m, 5H), 7.62 (dd, IH), 7.82 (dd, IH), 8.08 (d, IH), 8.15 (d, IH), 8.18 (s, IH), 8.48 (s, IH), 9.15-9.45 (br d, 4H); MS (DCI/NH3) m/e 313 (M+H) + Anal, calcd for C 2 2H2 ⁇ N2'TFA: C, 67.60; H, 4.96; N, 6.57. Found: C, 67.32; H, 5.21; N, 6.27.
  • Example 33A 6-(3-Phenyl- 1 -propynvD-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, 3-phenyl- l-propyne and the procedure of Example 57B.
  • Example 36A 4-Amino-N-r3-(6-cvano-2-naphthalenvI)-2-propynyllbenzamide
  • Example 35A and 4-aminobenzoic acid were subjected to the conditions described in Example 35B to afford the title compound.
  • MS (DCI/NH3) m/e 326 (M+H) + .
  • Example 36B 4-Amino-N-r3-(6-aminoiminomethyl-2-naphthalenyl)-2-propynyl1benzamide mono(trifluoroacetate) salt The title compound was prepared from Example 36A and the procedure of Example 5B.
  • Example 37A 6-r(l -Aminocvclohexyl)ethvnyll-2-naphthalenecarbonitrile
  • the title compound was obtained from Example 28B, 1-ethynylcyclohexylamine and the procedure of Example 41 A.
  • Example 37B (S ) -2-Amino-N-ri-r(6-cvano-2-naphthalenyDcarbonyllcvclohexyllpropionamide
  • Example 37A and N-(t-butoxycarbonyl)-L-alanine were subjected to the conditions described in Example 35B to provide the title compound.
  • MS (DCI/NH3) m/e 446 (M+H) + .
  • Example 37C rS)-2-Amino-N-ri-r(6-aminoiminomethyl-2-naphthalenyl)carbonyllcvclohexyllpropionamide bis(trifluoroacetate) salt The title compound was a rearrangement product of Example 37B resulting from the procedure of Example 5B.
  • l H NMR 300 MHz, DMSO-d 6 ) ⁇ 1.24 (d, 3H), 1.40-1.62 (m, 8H), 2.15-2.26 (s, IH), 2.29-
  • Example 38A 8-Hydroxy-6-methoxy-3. 4-dihvdro-2H-naphthalen- 1 -one A solution of 6, 8-dimethoxy-3, 4-dihydro-2H-naphthalen-l-one (15 g, 72.8 mmole), prepared according to the procedure of J. Chem. Soc, London 2782 (1955), which is incorporated herein by reference, in methylene chloride (150 mL) at 0 °C was treated portionwise with AICI3 (14.3 g, 107 mmole), stirred for 20 h at room temperature, poured onto ice with stirring and extracted with methylene chloride when the ice melted. The extracts were washed with water and brine, dried (MgSO 4 ) and concentrated to provide 13.8 g of the title compound. MS (DCI/NH3) m/e 193 (M+H) +
  • Example 38B 8-Benzyloxy-6-methoxy-3,4-dihydro-2H-naphthalen- 1 -one
  • a mixture of Example 38A (2.5 g, 13 mmole), benzyl bromide (2.1 mL, 17.8 mmole), K2CO3 powder (14.3 g, 100 mmole), and 2-butanone (88 mL) was stirred at reflux for 4 h, treated with additional benzyl bromide (1.0 mL, 8.5 mmole), stirred at reflux for an additional 3 h, cooled to room temperature, filtered and concentrated. The residue was dissolved in methylene chloride, washed with IN HCl, water and brine, dried (MgSO 4 ) and concentrated. The crude product was purified on silica gel with 30% ethyl acetate/hexanes to provide the title compound. MS (DCI/NH3) m/e 283 (M+H) + .
  • Example 38D 4.5-Dihydro-7-methoxy-9-(phenylmethoxy)naphthr2.1-dlisoxazole r2.1-d1isoxazole
  • a suspension of Example 38C (7.5 g, 24.3 mmole), hydroxylamine hydrochloride (4.0 g, 57.6 mmole) and acetic acid (63 mL) was stirred at 1 10 °C for 7 min, cooled to room temperature, diluted with water and extracted with methylene chloride. The extracts were washed with water and brine, dried (MgSO 4 ), and concentrated. The crude product was purified by flash chromatography on silica gel with 30% ethyl acetate/hexanes to provide the title compound. MS (DCI NH3) m/e 308 (M+H)+.
  • Example 38E 8-Benzyloxy-2-cyano-6-methoxy-3.4-dihydronaphthalen-l-one
  • sodium methoxide prepared from sodium metal (0.17 g, 7.35 mmol) in methanol (3.9 mL)
  • a solution of Example 38D 1.5 g, 4.9 mmole
  • benzene 50 mL
  • the extracts were washed with brine, dried (MgSO4) and concentrated to provide the title compound.
  • MS (DCI/NH3) m/e 308 (M+H) + .
  • Example 38F 2-Cyano-6-rnethoxy-8-Benzyloxy-3.4-dihvdronaphthalene
  • a suspension of Example 38E (2.6 g, 8.6 mmole) in absolute ethanol (25 mL) at room temperature was treated portionwise with NaBH (1.6 g), stirred for 20 min at room temperature and for 20 min at reflux, cooled to room temperature, treated with water (20 mL) and concentrated. The residue was dissolved in methylene chloride, washed with water and brine, dried (MgSO ), filtered and concentrated to provide 2.6 g of an orange foam.
  • Example 38G The title compound was prepared from Example 38G and the procedure of Example IB.
  • IH NMR 300 MHz, DMSO-d 6 ) ⁇ 4.38 (d, 2H), 6.89 (m, IH), 7.20 (m, 2H), 7.22 (s, IH), 7.63 (dd, IH), 7.82 (dd, IH), 8.09 (d, IH), 8.12 (d, IH), 8.20 (s, IH), 8.46 (s, IH), 8.95 (t, IH), 9.19 (br s, 2H), 9.42 (br s, 2H); MS (DCI/NH3) m e 307 (M+H)+.
  • Example 39A 6-Methoxy-8-hydroxy-2-naphthalenecarbonitrile
  • a mixture of Example 38G (1.62 g, 5.6 mmole) and 10% dry Pd/C (0.50 g) in methanol (150 mL) was hydrogenated in a Parr shaker at room temperature under 4 atm for 30 h. The mixture was filtered and concentrated to provide the title compound.
  • Example 39C 2-r(7-Aminoiminomethyl-3-methoxy- 1 -naphthalenvDoxylacetamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 39B and the procedure of Example IB.
  • H NMR 300 MHz, DMSO-d 6 ) ⁇ 3.93 (s, 3H), 4.70 (s, 2H), 6.70 (d, IH), 7.09 (d, IH), 7.65 (s, 2H), 7.82 (dd, I H), 7.99 (d, IH), 8.70 (s, IH), 9.05 (s, 2H), 9.38 (s, 2H); MS (DCI/NH3) m/e 274 (M+H)+.
  • Example 40A 6-Cvano-2-naphthalenecarbonyl chloride A suspension Example 8E (4.4 g, 22.3 mmol) in toluene (100 mL) was treated with thionyl chloride (6.0 mL) and DMAP (5 mg), heated at 55 °C for lh, treated with additional thionyl chloride (3 mL), warmed to 95 °C for lh, cooled to room temperature, stirred in hexane (75 mL) for 2.5 h and fltered to provide 3.62 of the title compound as a white powder. The filtrate was concentrated and triturated with ether to provide an additional 1.02 g of the title compound. MS (DCI/NH3) m/e 215 (M+H)+.
  • Example 40A A solution of Example 40A (1.65 g, 7.65 mmole) in acetone (600 mL) at room temperature was treated with a solution of sodium azide (3 g, 46 mmole) in water (10 mL), stirred for 1.5 h and diluted with water (60 mL). The resulting solid was filtered, washed with water and dried to provide 4.24 g of the title compound as a white powder. MS (DCI/NH3) m/e 240 (M+NH4) + .
  • Example 40C N-(6-cvano-2-naphthalenyl)-N'-phenylurea
  • a solution of Example 40B (221.2 mg, 1 mmole) in toluene (18 mL) was heated at 85 °C for 1 h then at 95 °C for 1.5 h, cooled to room temperature, treated with aniline (240 ⁇ L, 2.63 mmole), stirred for 25 min and treated with ether (10 mL). The resulting solid was collected, washed with ether and dried under vacuum to yield 230 mg of white powder.
  • MS DCI/NH3) m e 305 (M+NH ⁇ ) + .
  • Example 42A 6-r2-(Phenyl)ethyn-2-naphthalenecarbonitrile
  • a mixture of Example 57B (80 mg, 0.31 mmol) and palladium on carbon (20% water, 50 mg) in methanol (5 mL) was stirred under 1 atm of hydrogen for 0.5 h, filtered and concentrated to provide 72 mg of the title compound.
  • Example 42B 6-r2-(Phenyl)ethyl1-2-naphthalenecarboximidamide mono(trifluoroace ⁇ ate) salt
  • the title compound was prepared from Example 42 A and the procedure of Example IB.
  • !H NMR 300 MHz, DMSO-d 6 ) ⁇ 3.03 (m, 2H), 7.23 (m, 5H), 7.60 (dd, IH), 7.76 (dd, IH), 7.85 (s, IH), 8.03 (t, 2H), 8.42 (s, IH), 8.99 (s, 2H), 9.39 (s, 2H); MS (DCI/NH3) m/e 275 (M+H) + .
  • Example 53A (65 mg, 0.25 mmol) in DMF (2 mL) was 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 provide 160 mg of the title compound. MS (DCI/NH3) m/e 355 (M+H) + .
  • Example 43B 7-Propoxy-8-iodo-2-naphthalenecarboximidamide ono(trifluoroacetate) salt The title compound was prepared from the product in Example 43A according to the procedure of Example IB.
  • Example 44A ( ⁇ )-6-(3-Phenyloxiranyl)-2-naphthalenecarbonitrile
  • Example 45B (E)-6-r2-(2-Thienyl)ethenyl1-2-naphthalenecarbonitrile The title compound was prepared from the product of Example 45A and the procedure of Example 41 A. MS (DCI/NH3) m/e 279 (M+NH )+.
  • Example 45C (E)-6-r2-(2-ThienyDethenyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 45B and the procedure of Example IB.
  • ' H-NMR 300 MHz, DMSO-d 6 ) ⁇ 7.12 (dd, 2H), 7.15 (d, IH), 7.32 (d, IH), 7.6 (d, IH), 7.74 (d, IH), 7.80 (dd, I H), 7.9-8.1 (m, 3H), 8.14 (s, IH), 8.43 (s, IH), 9.03 (s, 2H), 9.42 (s, 2H);
  • Example 46B 6- ( 3-Oxobutyl ) -2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 46 A and the procedure of ExamplelB.
  • 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 l-l'-bis(diphenyphosphino)ferrocene (111 mg, 0.2 mmol) was stirred in DMF (3 mL) for 15 min, treated with CS2CO3 (813 mg, 2.5 mmol) and 3-methoxyphenylboronic acid (228 mg, 1.5 mmol), stirred for 20 min at 80 °C, cooled, treated with pH 7 buffer (10 mL) and extracted with diethyl ether.
  • Example 47B 6-(3-Methoxyphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 47 A and the procedure of Example IB.
  • H NMR 300 MHz, DMSO-d 6 ) ⁇ 3.88 (s, 3H), 7.03 (m, IH), 7.44 (m, 3H), 7.84 (dd, IH), 8.05 (dd, I H), 8.19 (d, IH), 8.21 (d, IH), .41 (s, IH), 8.51 (s, IH), 9.1 1 (s, 2H), 9.45 (s, 2H);
  • Example 48 N-r3-(methyl ) phenv ⁇ -6-aminoiminomethyl-2-naphthalenecarboxamide mono(trifluoroacetate) salt
  • Example 48 A N-r3-(methyl)phenyl1-6-cvano-2-naphthalenecarboxamide The title compound was prepared from 3-methyl phenylis.ocyanate, Example 55C and the procedure from Example 55C. MS (DCI/NH3) m/e 287 (M+H)+
  • Example 48A The title compound was prepared from Example 48A and the procedure of Example IB.
  • IH NMR 300 MHz, DMSO-d 6 ) ⁇ 2.34 (s, 3H), 6.96 (d, IH), 7.27 (t, IH), 7.62 (d, IH), 7.66 (s, I H), 7.91 (dd, IH), 8.15 (dd, IH), 8.29 (d, IH), 8.31 (d, IH), 8.54 (s, IH), 8.68 (s, I H), 9.15 (s, 2H), 9.49 (s, 2H), 10.46 (s, IH); MS (DCI/NH3) m/e 304 (M+H) + ;
  • Example 49B 6-(2-Formylphenoxy)-2-naphthalenecarboxirnidamide mono(trifluoroacetate) salt
  • the title compound was prepared with Example 49A and the procedure of Example IB.
  • 1H-NMR 300 MHz, DMSO-d 6 ) ⁇ 7.19 (d, IH), 7.44 (t, IH), 7.56 (s, IH), 7.60 (d, IH), 7.79 (m, 2H), 7.94 (dd, IH), 8.01 (d, IH), 8.2 (d, IH), 8.51 (s, IH), 9.03 (s, 2H), 9.41 (s, 2H), 10.35 (s, IH);
  • Example 50A 6-(2-FormylphenvD-2-naphthalenecarbonitrile The title compound was prepared from Example 28B, 2-formylphenylboronic acid and the procedure of Example 47A. MS (DCI/NH 3 ) m/e 275 (M+NH ⁇ .
  • Example 50B 6-(2-Formylphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 50A and the procedure of Example IB.
  • 'H NMR 300 MHz, DMSO-d 6 ) ⁇ 7.71-7.64 (m, 2H), 7.79 (d, IH), 7.81 (s, IH), 7.88 (dd, 1H),7.9 (d, IH), 8.16 (d, IH), 8.23 (t, 2H), 8.56 (s, IH), 9.05 (s, 2H), 9.48 (s, 2H), 9.92 (s, IH);
  • Example 52A 6-(3-Oxo- 1 -butenyl)-2-naphthalenecarbonitrile
  • the title compound was prepared from methyl acrylate, Example 28B and the procedure of Example 41 A.
  • Example 52B 6-(3-Oxo- 1 -butenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 52A and the procedure of Example IB.
  • Example 53 7-Methoxy-8-( 1 H-pyrazol-4-vD-2-naphthalenecarboximidamide bis(trifluoroacetate) salt
  • Example 53A 7-hvdroxy-8-iodo-2-naphthalenecarbonitrile
  • Example 53B 7-Methoxy-8-iodo-2-naphthalenecarbonitrile
  • Example 53 A (36.7 g, 124.2 mmol) in methanol (500 mL) and ethyl acetate (300 mL) was treated over 3 h with 2M trimethylsilyldiazomethane in hexane (260 mL), stirred for 24 h, concentrated and recrystallized from ethyl acetate to provide 36.4 g of the title compound.
  • MS DCI/NH3 m/e 327 (M+NFL + .
  • Example 53C 4-Iodo- 1 -rr2-(trimethylsilyDethoxylmethyll- 1 H-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), stirred for 1 h, treated with SEM chloride (9.00 mL, 50.8 mmol), stirred at room temperature for 1 h, poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 10% ethyl acetate/hexanes to provide 14.4 g of the title compound. MS (DCI/NH3) m/e 325 (M+H) + .
  • Example 53C (12.97 g, 40 mmol) in THF (250 mL) at -78 °C was treated with 2.5 M butyllithium in hexanes (17.6 mL, 44 mmol), stirred at -78 °C for 10 min, treated with trimethyl borate (11.36 mL, 100 mmol), warmed to room temperature, treated with 3M HCl (400 mL) and extracted with ethyl acetate. The extracts were concentrated, and the residue was dissolved in 1M NaOH (500 mL), extracted with diethyl ether, acidified with concentrated HCl and extracted with ethyl acetate.
  • Example 53E 7-Methoxy-8-ri-rr2-(trimethylsiIyl)ethoxylmethvn-lH-pyrazol-4-yll-2-naphthalenecarbonitrile
  • Examples 53B (1.55 g, 5 mmol) and 53D (1.45 g, 6 mmol) were subjected to the procedure described in Example 47 A to provide 1.64 g of the title compound.
  • MS (DCI/NH3) m/e 380 (M+H) + .
  • Example 53F 7-Methoxy-8-( 1 H-pyrazol-4-yl)-2-naphthalenecarbonitrile A solution of Example 53E (1.84 g, 4.85 mmol) in THF
  • Example 54 7-Methoxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 53B and the procedure of Example IB.
  • IH NMR 300 MHz, DMSO-d 6 ) ⁇ 4.01 (s, 3H), 7.65 (m, 2H), 8.12 (d, IH), 8.15 (d, IH), 8.42 (s, IH), 9.14 (s, 2H), 9.52 (s, 2H); MS (DCI/NH3) m/e 327 (M+H)+.
  • N-phenyltrifluoromethanesulfonate (7.95 g, 22.25 mmol), and diisopropylethylamine (7.75 mL, 44.5 mmol) in methylene chloride (25 mL) were stirred for 3 h at room temperature, poured into water and extracted with diethyl ether. The extracts were washed with brine, dried
  • Example 55A 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 ) 4 (256 mg, 0.22 mmol) in DMF (50 mL), heated at 90° C for 3 h, cooled to room temperature, treated with saturated NaHCO3 and extracted with diethyl ether. The extracts were washed with brine, dried over (MgSU4), and condensed. The residue was chromatographed on silica gel with 5% ethyl acetate/hexanes to provide 2.67 g of the title compound. MS (DCI/NH3) m/e 231 and 233 (M+H)+.
  • Example 55D N-phenyl-6-aminoiminomethyl-2-naphthalenecarboxamide mono(methanesulfonate ) salt
  • a solution of Example 55C (52 mg, 0.191 mmol) in THF (2 mL) was treated with 1M lithium bis(trimethylsilyl)amide in THF (0.6 mL), stirred for 18 h, treated with 2M HCl (4 mL), stirred for another 24 h, made basic with saturated Na2CO3 and extracted with ethyl acetate. The extracts were washed with brine, dried (Na2SO ) and concentrated.
  • Example 56A N-methyl-3-hvdroxyphenylacetamide
  • 3-hydroxyphenylacetic acid (1.00 g, 6.57 mmol) and oxalyl chloride (0.63 mL, 7.22 mmol) in methylene chloride (20 mL) was treated dropwise with pyridine (0.6 mL, 7.37 mmol), stirred for 90 min, poured into 40% aqueous methylamine (30 mL), stirred for 15 min, concentrated, dissolved into 1M HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with ethyl acetate to provide 260 mg of the title compound. MS (DCI/NH3) m/e 166 (M+H) + .
  • Example 56B 4-r(6-Cvano-2-naphthalenyDoxyl-N-methylbenzeneacetamide
  • a mixture of Example 56A (245 mg, 1.48 mmol), Example 55B (344 mg, 1.48 mmol) and CS2CO3 (530 mg, 1.63 mmol) in DMF (3 mL) was stirred for 72 h at 120 °C, cooled and chromatographed on silica gel with 1 : 1 ethyl acetate/hexanes to provide 54 mg of the title compound.
  • MS DCI/NH3) m/e 317 (M+H)+.
  • Example 56C 4-r(6-Aminoiminomethyl-2-naphthalenyl)oxyl-N-methylbenzeneacetamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 56B and the procedure of Example 55D.
  • l H NMR 300 MHz, DMSO-d 6 ) ⁇ 2.33 (s, 3H), 2.58 (d, 3H), 3.42 (s, 2H), 7.05 (m, 2H),7.12 (d, IH), 7.40 (dd, IH), 7.45 (m, 2H), 7.79 (dd, IH), 7.98 (q, IH), 8.02 (d, IH), 8.15 (d, IH), 8.49 (s, IH), 8.99 (br s, 2H), 9.39 (br s, 2H); MS (DCI/NH3) m/e 334 (M+H) + .
  • Example 57A 2-Cvanonaphthalene-6-boronic acid A solution of Example 55B (6.37 g, 27.45 mmol) in THF (220 mL) and hexanes (50 mL) at -100 °C was treated with 2.5 M butyllithium in hexanes (11.0 mL, 27.5 mmol), st red at -100 °C for 10 min, treated with trimethyl borate (7.8 mL, 68.6 mmol), warmed to room temperature, treated with 3M HCl (400 mL) and extracted with ethyl acetate.
  • Example 57B The title compound was prepared from Example 57B and the procedure of Example 55D.
  • IH NMR 300 MHz, DMSO-d 6 ) ⁇ 2.32 (s, 3H), 2.40 (s, 3H), 7.34 (m, 2H), 7.45 (m, 2H),
  • Example 58B 2-(2-Thiomethoxyethyl)bromobenzene A solution of Example 58A (990 mg, 3.75 mmol) and sodium thiomethoxide (290 mg,
  • Example 58D 6-r2-(2-Thiomethoxoxyethyl)phenyl1naphthalene-2-carboximidamide mono(methanesulfonate) salt
  • the title compound was prepared from Example 58C and the procedure from Example 55D.
  • Example 59A 7-Methoxy-8-(3-furanyl)-2-naphthalenecarbonitrile
  • the title compound was prepared from Example 53B, furan-3-boronic acid (873 mg, 7.80 mmol) and the procedure of Example 57B.
  • Example 59B 7-Methoxy-8-(3-furanyl)-2-naphthalenecarboxirnidamide mono(methanesulfonate) salt
  • the title compound was prepared from Example 58C and the procedure from Example
  • Example 60A 7-Methoxy-8-(2-benzofuranyl)-2-naphthalenecarbonitrile
  • the title compound was prepared from Example 53B (166 mg, 0.50 mmol), benzofuran-2- boronic acid (1 13 mg, 0.70 mmol) and the procedure of Example 57B.
  • MS (DCI/NH3) m/e 317 (M+NH 4 ) + .
  • Example 60B 7-Methoxy-8-(2-benzofuranyl)naphthalene-2-carboximidamide mono(methanesulfonate) salt
  • the title compound was prepared from Example 60 A (72 mg, 0.240 mmol) and the procedure from Example 55D.
  • Example 53B (75 mg, 0.243 mmol), PdCl 2 (dppf) (20 mg, 0.024 mmol), 3,4- methylenedioxystyrene (43 mg, 0.291 mmol) and diisopropylethylamine (0.170 mL, 0.97 mmol) in N-methylpyrrolidinone (2 mL) were stirred at 90° C for 18 h, cooled to room temperature and chromatographed on silica gel with 20% ethyl acetate/hexanes to provide 46 mg of the title compound.
  • Example 61 A 43 mg, 0.131 mmol
  • Example 55D The title compound was prepared from Example 61 A (43 mg, 0.131 mmol) and the procedure from Example 55D.
  • Example 53B A solution of Example 53B (3.09 g, 10 mmol), PdCl2 (120 mg, 1 mmol), cis-2-butene-l ,4-diol ( 1.23 mL, 15 mmol) and NaHC03 ( 1.01 g, 12 mmol) in N-methylpyrrolidinone ( 10 mL) was stirred at 130 °C for 1 h, cooled to room temperature and chromatographed on silica gel with 30% ethyl acetate/hexanes to provide 2.19 g of the title compound as a mixture of diastereomers. MS (DCI/NH3) m/e 269 (M+H) + .
  • Example 62 A (140 mg, 0.52 mmol) in methylene chloride (3 mL) at 0 °C was treated with triethylsilane (0.166 mL, 1.04 mmol) and BF3-OEt2 (0.096 mL, 0.78 mmol). stirred at room temperature for 4 h, concentrated and chromatographed on silica gel with 25% ethyl acetate/hexanes to provide 100 mg of the title compound. MS (DCI/NH3) m/e 271 (M+NH 4 ) + .
  • Example 62B The title compound was prepared from Example 62B (96 mg, 0.379 mmol) and the procedure from Example 55D.
  • IH NMR 300 MHz. DMSO-d 6 ) ⁇ 2.20 (m, I H), 2.33 (m, I H), 2.39 (s, 3H), 3.99 (s, 3H),
  • Example 28B and trimethylsilylacetylene were submitted to the conditions described in Example 42C to provide the title compound.
  • Example 63B 6-Ethvnyl-2-naphthaIenecarbonitrile
  • a mixture of Example 63A (0.4 g, 1.6 mmole) and K 2 CO3 (0.4 g, 3.2 mmole) in methanol ( 16 mL) was stirred at room temperature for 18 h. concentrated, treated with water and extracted with methylene chloride. The organic layer was washed with 0.5 NHCl and brine, dried (MgSO4) and evaporated to provide the title compound.
  • Example 63E 6-rf4-(2-Aminoethyl)phenyl1ethvnvn-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • the title compound was prepared with Example 63D and the procedure of Example 5B.
  • Example 64 7-Methoxy-8-[2-pyrimidinyl(oxy)l-2-naphthalenecarboximidamide mono(trifluoroacetate)
  • Example 64A 7-Methoxy-8-[2-pyrimidinyl(oxy)1-2-naphthalenecarbonitrile
  • Example 4A 125 mg, 0.627 mmol
  • 2-chloropyrimidine 143 mg, 1.25 mmol
  • MS DCI/NH3 m/e 278 (M+H)+.
  • Example 64B 7-Methoxy-8-r2-pyrimidinyl(oxy)l-2-naphthalenecarboximidamide mono(trifluoroacetate)
  • the title compound was prepared with Example 64A and the procedure of Example IB.
  • IH NMR 300 MHz, DMSO-d 6 ) ⁇ 2.51 (s, 3H), 3.83 (s, 3H), 7.18 (t, IH), 7.70 (dd, IH), 7.80 (d, I H), 8.05 (d, IH), 8.19 (d, IH), 8.34 (s, IH), 8.62 (d, 2H), 9.07 (br s, 2H), 9.45 (br s, 2H);
  • Example 4A 7-Methoxy-8-r2-thiazoyl(o ⁇ y)l-2-naphthalenecarbonitrile
  • 2-bromothiazole 225 mL, 2.50 mmol
  • CsF 209 mg, 1.38 mmol
  • Example 65B 7-Methoxy-8-r2-thiazoyl ( oxy ) 1naphthalene-2-carboximidamide mono(trifluoroacetate) salt
  • the title compound was prepared with Example 65 A and the procedure of Example 1 B.
  • Example 66A 7-Methoxy-8-(4-nitrophenoxy)-2-naphthalenecarbonitrile
  • the title compound was prepared from Example 4A (125 mg, 0.627 mmol), 1,4- dinittobenzene (143 mg, 1.25 mmol) and the procedure described in Example 65A to provide 227 mg of the title compound.
  • Example 66B 7-Methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared with Example 66A and the procedure of Example
  • Example 67A 7-Methoxy-8-pentafluorophenoxy-2-naphthalenecarbonitrile
  • Example 4A 100 mg, 0.50 mmol
  • hexafluorobenzene 1 15 mL, 1.00 mmol
  • MS DCI/NH3 m/e 383 (M+NH4) + .
  • Example 67B 7-Methoxy-8-pentafluorophenoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared with Example 67A and the procedure of Example 55D.
  • Example 68A 7-Methoxy-8-rN-2-phenyl(amino)1-2-naphthalenecarbonitrile
  • a solution of Example 25A (309 mg, 1.00 mmol), aniline (0.109 mL, 1.2 mmol), NaO l Bu ( 1 15 mg, 1.2 mmol), Pd2(dba) 3 ( 10 mg, 0.01 mmol) and dppf ( 17 mg, 0.03 mmol) in toluene (5 mL) was stirred for 3 h at 100 °C, cooled and chromatographed on silica gel with 10% ethyl acetate/hexanes to provide 175 mg of the title compound. MS (DCI/NH3) m/e 275 (M+H)+.
  • Example 69A N-(6-Cvano-2-naphthalenyl)-N'-benzylurea
  • the title compound was prepared with Example 40A, benzylamine and the procedure from Example 40B.
  • MS (DCI/NH3) m/e 302 (M+H)+.
  • Example 69B N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-benzylurea mono(trifluoroacetate) salt
  • the title compound was prepared with Example 69A and the procedure from Example 40D.
  • !H NMR 300 MHz, DMSO-d 6 ) ⁇ 4.35 (d, 2H), 6.91 (t, IH), 7.35-7.24 (m, 5H), 7.59 (dd, IH), 7.72 (dd, IH), 7.95 (d, IH), 7.96 (d, IH), 8.22 (d, IH), 8.35 (d, IH), 8.92 (br s, 2H), 9.13 (s, I H), 9.32 (br s, 2H).
  • MS DC1/NH3) m/e 319 (M+H)+.
  • Example 40A The title compound was prepared with Example 40A (221.2 mg, 1.00 mmole) and methylamine (2.3 mL, 2.34 mmol) in THF (10 mL) according to the procedure from Example 40B.
  • Example 70B N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-methylurea mono(trifluoroacetate) salt The title compound was prepared with Example 70A and the procedure of Example 40D. ! H NMR (300 MHz, DMSO-d 6 ) ⁇ 2.69 (d, 3H), 6.32 (q, IH), 7.60 (dd, IH),
  • Example 71 A N-(6-Cvano-2-naphthalenyl)-N'-isopropylurea
  • the title compound was prepared with Example 40A, isopropylamine and the procedure from Example 40B.
  • Example 7 IB N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-isopropylurea mono(trifluoroacetate) salt The title compound was prepared with Example 71 A and the procedure of Example 5B.
  • Example 72A N-(6-Cvano-2-naphthalenyl)-N'-phenyl-N'-methylurea
  • the title compound was prepared with Example 40 A, N-methyl-N-phenylamine and the procedure from Example 40B.
  • MS (DCI/NH3) m/e 302 (M+H)+.
  • Example 72B N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-phenyl-N'-methylurea mono(trifluoroacetate) salt The title compound was prepared with Example 72A and the procedure of Example 40D.
  • IH NMR 300 MHz, DMSO-d 6 ) ⁇ 3.33 (s, 3H), 7.25-7.47 (m, 5H), 7.71 -7.77 (m, 2H), 7.95
  • Example 73A 6-Phenylcarbamoyl-2-naphthalenecarbonitrile
  • the title compound was prepared from Example 40A, phenol and the procedure from Example 40B.
  • MS (DCI/NH3) m/e 289 (M+H)+.
  • Example 73B 6-Aminonaphthalene-2-carboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 73A and the procedure of Example 40D.
  • Example 74B N-(6-aminoiminomethyl-2-naphthalenyl)-N'-cvclohexylurea mono(trifluoroacetate) salt The title compound was prepared with Example 74A and the procedure of Example 40D.
  • Example 75A N-(6-cyano-2-naphthalenyl)-N'-benzyloxyurea
  • the title compound was prepared with Example 40A, O-benzylhydroxylamine and the procedure from Example 40B.
  • Example 75B N-(6-aminoiminomethyl-2-naphthalenvD-N'-benzyloxyurea mono(trifluoroacetate) salt The title compound was prepared with Example 75A and the procedure of Example 40D. ' H NMR (300 MHz, DMSO-d 6 ) ⁇ 4.87 (s, 2H), 7.25-7.42 ( , 3H), 7.48-7.51 (m, 2H), 7.75
  • Ci9Hi8N O2-TFA Anal, calcd for Ci9Hi8N O2-TFA: C, 56.25; H, 4.27; N, 12.49. Found: C, 56.26; H, 4.39; N, 12.30.
  • Example 76 1.1 -Dimethylethyl r4-rr(6-aminoiminomethyl-2-naphthalenvPaminolcarbonvnphenyl1carbamate mono ( trifluoroacetate) salt
  • Example 76A 6-Amino-2-naphthalenecarbonitrile Sulfuric acid (45mL) was treated with Example 40B (6.5 g), stirred for 30 min, warmed to room temperature for 20 min, poured onto ice, diluted with water to approximately 500 mL, cooled to 0 °C and treated with 50% aq sodium hydroxide such that the temperature did not exceed 35 °C.
  • Example 76B 1.1 -Dimethylethyl r4-rr(6-cvano-2-naphthalenyl)aminolcarbonyllphen yllcarbamate mono(trifluoroacetate) salt
  • the title compound was prepared from Example 76A, 4-N-Boc-aminomethylbenzoic acid, the procedure from Example 35B with methylene chloride in place of THF.
  • MS (DCI NH3) m/e 417 (M+H) + .
  • Example 76B The title compound was prepared with Example 76B and the procedure of Example 40D.
  • l H NMR 300 MHz, DMSO-d 6 ) ⁇ 3.30 (s, 9H), 4.22 (d, 2H), 7.42 (d, 2H), 7.49 (t, IH),
  • Example 77A N-f6-(AminoiminomethvP-2-naphthalenyl l-4-(aminomethyl)benzamide mono(trifluoroacetate) salt
  • Example 78A Ethyl (6-cyano-2-naphthalenyl)carbamate mono(trifluoroacetate) salt The title compound was prepared with Example 40 A, ethanol and the procedure from Example 40B.
  • Example 78B Ethyl [6- ( aminoiminomethyl ) -2-naphthalenyllcarbamate mono(trifluoroacetate) salt The title compound was prepared with Example 78 A and the procedure of Example 78
  • Example 79 1.1 -dimethylethyl f4-rr[6-aminoiminornethyl)- 2-naphthaIenyl)amino1carbonyllaminolphenyll carbamate mono(trifluoroacetate) salt
  • Example 40B 4-(N-tert-butoxycarbonylamino)- aminobenzene and the procedure from Example 40C.
  • MS (DCI/NH3) m/e 403 (M+H) + .
  • Example 80B ( E ) -6-r2-(Phenylthio ) ethenvn-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 80A and the procedure of Example IB.
  • I H NMR 300 MHz, DMSO-d 6 ) ⁇ 6.91 (d, IH), 7.52-7.33 (m, 5H), 7.50 (d, IH), 7.75- 7.83 (m, IH), 7.98-8.89 (m, IH), 8.08-8.80 (m, 3H), 8.44 (m, IH), 9.03 (s, 2H), 9.40 (s, 2H); MS (DCI NH3) m/e 305 (M+H)+.
  • Example 81 B (E)-6-r2-(2-Furanyl)ethenv ⁇ -2-naphthalenecarbonitrile The title compound was prepared from Examples 55B and 81 A and the procedure of
  • Example 82 ( E)-6-r2-(l H-Imidazol-l - y l)ethenyll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
  • Example 82A (E)-6-12-(lH-Imidazol-l -yl)ethenyll-2-naphthalenecarbonitrile The title compound was prepared from Example 55B, 1-vinylimidazole and the procedure of Example 42C.
  • Example 83A 4-vinylsulfonamide
  • a solution of thionyl chloride (7.5 mL) and 4-t-butylcatachol (45 mg, 0.3 mmol) in DMF (9 mL) at 0 °C was treated with 4-vinylbenzene sulfonic acid sodium salt (3 g, 14.6 mmol), stirred for 6 h, stored at -10 °C for 3 days, poured into ice water and extracted with benzene. The organic layer was washed with water, dried (Na 2 S0 4 ), filtered and concenttated to provide 4-vilylsulfonyl chloride as a clear, colorless oil.
  • Example 83B (E)-4-r2-(6-Cvano-2-naphthalenyl)ethenyl1benzenesulfonamide The title compound was prepared from Example 55B, Example 83A and the procedure of Example 57B. MS (DCI/NH3) m/e 352 (M+NH 4 ) + .
  • Example 83C (E)-4-r2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyllbenzenesulfonamide mono(trifluoroacetate) salt
  • the title compound was prepared from Example 83B and the procedure of Example
  • Example 84A (E)-4-12-(6-Cyano-2-naphthalenyl)etheny ⁇ benzoic acid
  • the title compound was prepared from Example 55B, 4-vinylbenzoic acid and the procedure of Example 57B.
  • MS (DCI/NH3) m/e 300 (M+H)+.

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

UROKINASE INHIBITORS
Cross Reference to Related Applications This application is a continuation-in-part of U.S. Application Ser. No.
08/901,040, filed July 25, 1997, pending.
Background of the Invention The present invention provides naphthamidine compounds which inhibit the urokinase enzyme, pharmaceutical compositions containing these compounds and medical methods of treatment using these compounds.
Technical Field Urokinase (urinary-type plasminogen activator or uPA (International Union of Biochemistry classification number: EC3.4.21.31)) is a proteolytic enzyme which is highly specific for a single peptide bond in plasminogen. Plasminogen activation (cleavage of this bond by the urokinase enzyme) results in formation of plasmin, a potent general protease.
Many cell types use urokinase as a key initiator of plasmin-mediated proteolytic degradation or modification of extracellular support structures such as extracellular matrix (ECM) and basement membrane (BM). Cells exist, move and interact with each other in tissues and organs within the physical framework provided by ECM and BM. Movement of cells within ECM or across BM requires local proteolytic degradation or modification of the structures and allows cells to invade adjacent areas previously unavailable prior to the degredation or modification. Cellular invasiveness intiated by urokinase is central to a variety of normal and disease- state physiological processes (Blasi, F., Vassalli, J. D., and Dano, K. J. Cell Biol. 104:801 - 804, 1987; Dano, K., Anderson, P. A., Grondahl-Hansen, J., Kristensen, P., Nielsen, L. S., and Skriver, L. Adv. Cancer Res. 44: 139-266, 1985; Littlefield, B. A. Ann. N. Y. Acad. Sci. 622: 167-175, 1991; Saksela, O., Biochim. Biophys. Acta 823: 35-65, 1985; Testa, J. E. and Quigley, J. P. Cancer Metast. Rev. 9:353-367, 1990). Such processes include, but are not limited to, angiogenesis (neovascularization), bone restructuring, embryo implantation in the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue remodelling during wound repair and organ differentiation, fibrosis, tumor invasion, metastatic
-1-
SUBSTtTUTE SHEET (RULE 26) spread of tumor cells from primary to secondary sites and tissue destruction in arthritis. Amiloride, for example, a known urokinase inhibitor of only moderate potency, has been reported to inhibit tumor metastasis in vivo (Kellen, J. A., Mirakian, A. Kolin, A. Anticancer Res. 8: 1373-1376, 1988) and angiogenesis/capillary network formation in vitro (Alliegro, M. C. and Glaser, B. M. J. Cell Biol. 115[3 Pt 2]: 402a, 1991).
Inhibitors of urokinase, therefore, have mechanism-based anti-angiogenic, anti-arthritic, anti-inflammatory, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive and tumoristatic uses.
Summary of the Invention
In its principle embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester or prodrug thereof, of formula (I)
Z is selected from the group consisting of
( 1 ) nitrogen;
(2) methine; and
(3) methine substituted with -NR1R2;
A is selected from the group consisting of
(1) hydrogen and
(2) -LARA;
B is selected from the group consisting of ( 1 ) hydrogen and (2) -LBRB and
C is selected from the group consisting of (1) hydrogen and (2) -LCRc, with the proviso that at least one of A, B or C is other than hydrogen; and with the proviso that when A is other than hydrogen, at least one of B or C is other than hydrogen, wherein for A, B, and C, LA, LB and Lc are independently selected from the group consisting of
( 1) a covalent bond,
(2) -(CH2)m-,
(3) -NRi-,
(4) -NR C(X)NR3-,
(5) -C(X)-,
(6) -NR2C(X)-,
(7) -C(X)NR2-,
(8) -CH=CH-,
(9) -C≡C-,
( 10) -0-,
( I D -S(O)r,
( 12) -C≡C(CH2)nNR2C(X)-,
(13) -C(X)NR2(CH2)nC≡C-,
( 14) -(CH2)nNSO2-,
( 15) -NR2SO2(CH2)nC≡C-,
( 16) -C≡C(CH2)nNR2S02NR3-,
(17) -NR2SO2NR3(CH2)nC≡C-,
(18) -SO2NR2-,
( 19) -NR2SO2-,
(20) -NR2SO2NR3-,
(21 ) -N=N-,
(22) -C(X)N(OR2)-,
(23) -N(OR2)C(X)-,
(24) -HC=CH(CH2)nNR2C(X)-,
(25) -(CH2)nNR2C(X)CH=CH-,
(26) -CH=CH(CH2)nNSO2-,
(27) -NR2SO2(CH2)nCH=CH-,
(28) -(CH2)nNR2S02NR3-,
(29) -NR2SO2NR3(CH2)nCH=CH-,
(30) -NR2C(O)O-, (31) -OC(O)NR2-,
(32) -CH=NO-,
(33) -ON=CH- and
\/
(34) w , wherein W is selected from the group consisting of (a) -O-,
(b) -S-,
(c) -NRi- and
(d) -(CH2)m-, wherein each functional group is depicted with its right-hand end being the end which is attached to the naphthyl or quinolyl ring and its left-hand end being the end which is attached to RA, RB °r R(T>
RA, Rβ and Re are independently selected from the group consisting of
(I ) aryl; (2) arylalkoxy, wherein the alkylene group is of one to six carbon atoms;
(3) alkyl of one to ten carbon atoms;
(4) alkenyl of two to ten carbon atoms;
(5) alkoxycarbonyl of one to six carbon atoms;
(6) alkynyl of two to ten carbon atoms; (7) halogen;
(8) -NRιR2;
(9) heterocycle;
( 10) cycloalkenyl of four to twelve carbon atoms;
( I I) cycloalkyl of three to twelve carbon atoms; ( 12) -NR!C(O)NR2R3; and
( 13) -NRιC(O)R5o, wherein R50 is alkyl of one to six carbon atoms; wherein, at each occurence, Ri 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 alkyiene group is of one to six carbon atoms;
(8) cycloalkyl of three to eight carbon atoms and
(9) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkyiene group is of one to ten carbon atoms; and wherein, at each occurence, R2 and R3 are independently selected from the group consisting of
(1) hydrogen;
(2) alkyl of one to six carbon atoms;
(3) alkenyl of two to six carbon atoms;
(4) alkynyl of two to six carbon atoms; (5) aryl;
(6) arylalkyl, wherein the alkyiene group is of one to six carbon atoms
(7) cycloalkyl of three to eight carbon atoms and
(8) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkyiene group is of one to ten carbon atoms; and wherein, at each occurence, X is selected from the group consisting of
( 1 ) O and
(2) S; and wherein, at each occurence, m is one to five, n is zero to four and t is zero to two; and wherein, at each occurence, the alkyl, alkenyl, alkynyl, aryl, heterocycle, cycloalkyl, and cycloalkenyl groups are optionally substituted.
The present invention also relates to a method of inhibiting urokinase in a mammal, particularly humans, by administering a therapeutically effective amount of a composition comprising a compound of formula (I).
The present invention also relates to pharmaceutical compositions which comprise a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.
Detailed Description of the Invention As used throughout this specification and the appended claims, the following terms have the meanings specified: The term "alkyl," as used herein, represents a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom and is exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl and the like and may be optionally substituted with one, two. three or four substituents independently 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 alkyiene group is of one to six carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (1 1) halo; (12) heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxy; (16) N-protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one to six carbon atoms; (21) -CO2R2; (22) -C(O)NR2R3; (23) -SO2R4, wherein R4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (24) -SO2NR5R6, wherein R5 and RQ are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (25) -NRγRs, wherein R7 and Rg are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkyiene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group. The term "alkanoyl," as used herein, represents an alkyl group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl, acetyl, propionyl, butanoyl and the like. The term "alkenyl," as used herein, represents monovalent straight or branched chain groups containing a carbon-carbon double bond derived from an alkene by the removal of one hydrogen atom and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl- l-propenyl, 1- butenyl, 2-butenyl and the like and may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of (1) alkoxy of one to six carbon 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 alkyiene group is of one to six carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (1 1 ) halo; (12) heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxy; (16) N- protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one to six carbon atoms; (21) -CO2R ; (22) -C(O)NR2R3; (23) -SO2R4, wherein R4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (24) -SO2NRsR6, wherein R5 and Rg are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (25) -NR7R8, wherein R7 and Rs are independently selected from the group consisting of (a) hydrogen; (b) an N- protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkyiene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group.
The term "alkoxy," as used herein, represents an alkyl group attached to the parent molecular group through an oxygen atom. The term "alkoxyalkyl" as used herein, represents an alkyl group to which is attached an alkoxy group.
The term "alkoxycarbonyl," as used herein, represents an ester group; i.e. an alkoxy group, attached to the parent molecular group through a carbonyl group and is exemplified by methoxycarbonyl, ethoxycarbonyl and the like. The term "alkyiene," as used herein, represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene and the like.
The term "alkylsulfinyl," as used herein, represents an alkyl group attached to the parent molecular group through an -S(O)- group. The term "alkylsulfinylalkyl," as used herein, represents an alkyl group, as defined herein, substituted by a sulfinyl group.
The term "alkylsulfonyl," as used herein, represents an alkyl group attached to the parent molecular group through an -SO2- group.
The term "alkylsulfonylalkyl," as used herein, represents an alkyl group, as defined herein, substituted by a sulfonyl group.
The term "alkynyl," as used herein, represents monovalent straight or branched chain groups of two to six carbon atoms containing a carbon-carbon triple bond derived from an alkyne by the removal of one hydrogen atom and is exemplified by ethynyl, 1-propynyl, and the like and may be optionally substituted with one, two, three or four substituents 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 alkyiene group is of one to six carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (11) halo; (12) heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxy; (16) N-protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one to six carbon atoms: (21) -C02R2; (22) -C(O)NR2R3; (23) -SO2R_ι, wherein R4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (24) -SO2NR5R6, wherein R5 and R6 are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (25) -NR7R8, wherein R7 and Rs are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkyiene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group.
The term "amino," as used herein, represents an -NH2 group. The term "aminoalkyl," as used herein, represents an alkyl group, as defined herein, substituted by an amino group.
The term "aryl," as used herein, represents a mono- or bicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like and may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkyiene goups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkyiene group is of one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21 ) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkyiene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocycle; (25) (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy; (28) hydroxyalkyi 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 alkyiene group is of one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxy alkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (36) -(CH2)qCO2R2, wherein q is zero to four; (37) -(CH2)qC(O)NR R3; (38) -(CH2)qSO2R4, wherein R4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (39) -(CH2)qSO2N 5R , wherein R5 and R6 are independently selected from the group consisting of(a) hydrogen, (b) alkyl, (c) aryl and(d) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (40) wherein R7 and Rs are independently selected from the group consisting of (a) hydrogen, (b) an N-protecting group, (c) alkyl of one to six carbon atoms, (d) alkenyl of two to six carbon atoms, (e) alkynyl of two to six carbon atoms, (f) aryl, (g) arylalkyl, wherein the alkyiene group is of one to six carbon atoms, (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkyiene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44) aryloxy; (45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy.
The term "arylalkyl," as used herein, represents an aryl group attached to the parent molecular group through an alkyl group. The term "arylalkoxy," as used herein, represents an arylalkyl group attached to the parent molecular group through an oxygen atom.
The term "aryloxy," as used herein, represents an aryl group which is attached to the parent molecular group through an oxygen atom.
The term "aryloyl," as used herein, represents an aryl group which is attached to the parent molecular group through a carbonyl group.
The term "azido," as used herein, represents an -N3 group.
The term "azidoalkyl," as used herein, represents an alkyl group, as defined herein, substituted by an azido group.
The term "carbonyl," as used herein, represents a C=O group. The term "carboxaldehyde," as used herein, represents a -CHO group. The term "(carboxaldehyde)alkyl," as used herein, represents an alkyl group, as defined herein, substituted by a carboxaldehyde group.
The term "carboxy," as used herein, represents a -CO2H group. The term "carboxyalkyl," as used herein, represents an alkyl group, as defined herein, substituted by a carboxy group.
The term "cycloalkyl," as used herein represents a monovalent saturated cyclic hydrocarbon group and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2. l]heptyl and the like. The cycloalkyl groups of this invention can be optionally substituted with (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms: (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkyiene goups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkyiene group is of one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkyiene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocycle; (25) (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy; (28) hydroxyalkyi 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 alkyiene group is of one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (36) -(CH2)qCO2R2, wherein q is zero to four; (37) -(CH2)qC(O)NR2R3; (38) -(CH2)qSO2R4, wherein R4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (39) -(CH2)qS02NR5R6, wherein R5 and R are independently selected from the group consisting of(a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (40) -(C ^qNRγRg, wherein R7 and R% are independently selected from the group consisting of (a) hydrogen, (b) an N-protecting group, (c) alkyl of one to six carbon atoms, (d) alkenyl of two to six carbon atoms, (e) alkynyl of two to six carbon atoms, (f) aryl, (g) arylalkyl, wherein the alkyiene group is of one to six carbon atoms, (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkyiene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44) aryloxy; (45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy.
The term "cycloalkenyl," as used herein represents a monovalent cyclic hydrocarbon having at least one carbon-carbon double bond. The cycloalkenyl groups of this invention can be optionally substituted with (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkyiene goups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (9) aryl: (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkyiene group is of one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkyiene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocycle; (25) (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy; (28) hydroxyalkyi 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 alkyiene group is of one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (36) -(CH2)qCO2R2, wherein q is zero to four; (37) -(CH2)qC(O)NR2R3; (38) -(CH )qSO2R4, wherein R4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (39) -(CH2)qS02NR5R6, wherein R5 and Rβ are independently selected from the group consisting of(a) hydrogen, (b) alkyl, (c) aryl and(d) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (40) -(C ^qNRyRs, wherein R7 and Rs are independently selected from the group consisting of (a) hydrogen, (b) an N-protecting group, (c) alkyl of one to six carbon atoms, (d) alkenyl of two to six carbon atoms, (e) alkynyl of two to six carbon atoms, (f) aryl, (g) arylalkyl, wherein the alkyiene group is of one to six carbon atoms, (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkyiene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44) aryloxy; (45) cycloalkoxy; (46) cycloalkylalkoxy and (47) arylalkoxy.
The term "cycloalkoxy," as used herein represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an oxygen atom.
The term "cycloalkylalkoxy," as used herein, represents an alkoxy group, as defined herein, to which is attached a cycloalkyl group. The term "cycloalkylalkyl," as used herein, represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an alkyl group.
The term "haloalkyl," as used herein, represents an alkyl group, as defined herein, substituted by one, two, or three halogen atoms and is exemplified by chloromethyl, bromoethyl, trifluoromethyl and the like. The term "halogen," as used herein, represents F, Cl, Br and I.
The term "heterocycle," as used herein, represents a 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The 5-membered ring has zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds. The term "heterocycle" also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring and another monocyclic heterocyclic ring such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, isoindazoyl, triazolyl, tetrazolyl, oxadiazolyl, uricyl, thiadiazolyi, pyrimidyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothienyl and the like. Heterocyclic groups also include compounds of the formula ft
^ , wherein F is selected from the group consisting of -CH2-, -CH2O- and -O-, and G is selected from the group consisting of -C(O)- and -(C(R')(R"))v -> wherein R' and R" are independently selected from the group consisting of hydrogen or alkyl of one to four carbon atoms, and v is one to three and includes groups such as 1,3-benzodioxolyl, 1 ,4-benzodioxanyl and the like. Any of the heterocycle groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkyiene goups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms: (1 1) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkyiene group is of one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkyiene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocycle; (25) (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy; (28) hydroxyalkyi 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 alkyiene group is of one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkyiene groups are independently of one to six carbon atoms; (36) -(CH2)qCO2R2, wherein q is zero to four; (37) -(CH2)qC(O)NR2R3; (38) -(CH2)qSO2R4, wherein R4 is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkyiene group is of one to six carbon atoms;(39) -(CH2)qSO2NR5R6, wherein R5 and R6 are independently selected from the group consisting of(a) hydrogen, (b) alkyl, (c) aryl and(d) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; (40) -(CH2)q R7Rg, wherein R7 and Rs are independently selected from the group consisting of (a) hydrogen, (b) an N-protecting group, (c) alkyl of one to six carbon atoms, (d) alkenyl of two to six carbon atoms, (e) alkynyl of two to six carbon atoms, (f) aryl, (g) arylalkyl, wherein the alkyiene group is of one to six carbon atoms, (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkyiene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44) aryloxy; (45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy.
The term "(heterocycle)oxy," as used herein, represents a heterocycle group, as defined herein, attached to the parent molecular group through oxygen.
The term "(heterocycle)oyl," as used herein, represents a heterocycle group, as defined herein, attached to the parent molecular group through a carbonyl group.
The term "hydroxy" as used herein, represents an -OH group.
The term "hydroxyalkyi," as used herein, represents an alkyl group, as defined herein, substituted by one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group and is exemplified by hydroxymethyl, dihydroxypropyl and the like.
The term "methine" as used herein, represents a =C(H)- group.
The term "N-protected amino," as used herein, refers to an amino group, as defined herein, to which is attached an N-protecting or nitrogen-protecting group, as defined herein.
The term "N-protected aminoalkyl," as used herein, refers to an alkyl group, as defined herein, which is substituted by an N-protecting or nitrogen-protecting group, as defined herein.
The term "nitro," as used herein, represents an -NO2 group.
The term "nitroalkyl," as used herein, represents an alkyl group substituted by an -NO2 group.
The terms "N-protecting group" or "nitrogen protecting group" as used herein, represent those groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)), which is incorporated herein by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4- nitrobenzoyl and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2- nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5- dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5- trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-l-methylethoxycarbonyl, α,α-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; arylalkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The term "oxo," as used herein, represents =O. The term "perfluoroalkyl," as used herein, represents an alkyl group, as defined herein, wherein each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical. Perfluoroalkyl groups are exemplified by trifluoromethyl, pentafluoroethyl, and the like.
The term "perfluoroalkoxy," as used herein, refers to a perfluoroalkyl group, as defined herein, attached to the parent molecular group through an oxygen atom.
The term "pharmaceutically acceptable salt," as use herein, represents those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate. fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. The term "pharmaceutically acceptable ester," as used herein, represents esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl group preferably has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyates, acrylates and ethylsuccinates.
The term "pharmaceutically acceptable prodrugs" as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
The term "prodrug," as used herein, represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and Judkins, et al.Synthetic Communications, 26(23), 4351-4367 (1996), each of which is incorporated herein by reference. The term "spiroalkyl," as used herein, represents an alkyiene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group. The term "sulfonyl," as used herein, represents an -SO2-group. The term "thioalkoxy," as used herein, represents represents an alkyl group attached to the parent molecular group through a sulfur atom. The term "thioalkoxyalkyl," as used herein, represents an alkyl group substituted by a thioalkoxy group.
Asymmetric or chiral centers may exist in the compounds of the present invention. The present invention contemplates the various stereoisomers and mixtures thereof. Individual stereoisomers of compounds of the present invention are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of mixtures of enantiomeric compounds followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a racemic mixture of enantiomers, designated (± ), to a chiral auxiliary, separation of the resulting diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Enantiomers are designated herein by the symbols "R" or "S," depending on the configuration of subsitiuents around the chiral carbon atom.
Geometric isomers may also exist in the compounds of the present invention. The present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond and designates such isomers as of the Z or E configuration, wherein the term "Z" represents substituents on the same side of the carbon-carbon double bond and the term "E" represents substituents on opposite sides of the carbon-carbon double bond.
Preferred Embodiments Preferred compounds of the present invention have formula (I), wherein
A and C are hydrogen and B is -LBRB, wherein
-LB- is -O-, and
RB is alkyl of two to six carbon atoms, and wherein the alkyl group is substituted.
More preferred embodiments of the present invention have formula (I), wherein A is -LARA and
B and C are hydrogen, wherein -LA- is selected from the group consisting of
( 1 ) a covalent bond,
(2) -(CH2)m-, (3) -NR2C(X)-,
(4) -C(X)NR2-,
(5) -NR2C(X)NR3-,
(6) -C≡C-,
(7) -CH=CH-, (8) -C(X)NR2(CH2)nC≡C-
(9) -C(X)-, ( ΙO) -O-, (l l) -OC(O)NR2- and
( 12) w ; and wherein
RA is selected from the group consisting of
(1) amino;
(2) aryl; (3) alkyl of one to ten carbon atoms;
(4) arylalkyl, wherein the alkyiene group is of one to ten carbon atoms;
(5) cycloalkyl of three to eight carbon atoms;
(6) arylalkoxy, wherein the alkyiene group is of one to ten carbon atoms and
(7) heterocycle, wherein the heterocycle is selected from the group consisting of ( l) furanyl,
(2) thienyl and
(3) imidazolyl; and wherein, at each occurence, R2 is selected from the group consisting of (1) hydrogen and (2) alkyl of one to six carbon atoms; and wherein, at each occurence, m is two, n is one,
R l and R3 are hydrogen, W and X are O, aryl is phenyl, the alkyl group and the aryl group are optionally substituted and the alkenyl group is substituted.
Still more preferred compounds of the present invention have formula (I), wherein
A and B are hydrogen; C is -LCRc;
-Lc- is selected from the group consisting of ( 1) a covalent bond,
(2) -OC(O)NR2-,
(3) -SO2NR2-,
(4) -C(X)NR2-,
(5) -NRi- and (6) -O-;
Rc is selected from the group consisting of
( 1 ) alkyl of one to six carbon atoms;
(2) aryl; (3) arylalkyl, wherein the alkyiene group is of one to six carbon atoms and
(4) hererocycle, wherein the heterocycle is selected from the group consisting of
(1) furanyl;
(2) pyrimidinyl; and
(3) , wherein F is -O-, G is -(C(R')(R"))V-, R' and R" are hydrogen and v is one;
X is O; and wherein, at each occurence,
R l and R2 are H, aryl is phenyl and the alkyl is optionally substituted.
Still more preferred compounds of the present invention have formula (I) wherein
A is -LARA,
B is -LBRB,
C is hydrogen, -LA- and -LB- are -O-, and
RA and Rβ are alkyl of one to six carbon atoms.
Still more preferred compounds of the present invention have formula (I) wherein A is -LARA, B is -LBRB, C is -LcRc
-LA-, -Lβ-, and -Lc- are -O- and RA, Rβ, and Re are alkyl of one to six carbon atoms.
Still more preferred compounds of the present invention have formula (I) wherein A is hydrogen;
C is -LcRc; -LB- is -O-;
-Lc- is selected from the group consisting of
1) a covalent bond,
2) -O-,
3) -CH=CH-, (4) -NRi- and
5) -NR2C(0)O-; Rβ is selected from the group consisting of
1 ) alkyl and
2) arylalkyl, wherein the alkyiene group is of one to six carbon atoms; Re is selected from the group consisting of
1) alkyl of one to six carbon atoms;
2) alkenyl of one to six carbon atoms;
3) halogen;
4) aryl and (5) 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 and (8) , wherein F is -O-. G is -(C(R')(R"))V -, R' and R" are hydrogen and v is one; and wherein, at each occurence, aryl is phenyl and alkyl, aryl and heterocycle are optionally substituted.
Preferred compounds falling within the scope of formula (I) include:
7, 8-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
6, 7, 8-trimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt ;
6, 7-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt ; 2-[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt;
7-benzyloxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; methyl f(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyOoxyj acetate mono(trifluoroacetate) salt;
2-[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]-yl-acetic acid mono(trifluoroacetate) salt;
N-[4-(aminomethyl)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamide bis(trifluoroacetate) salt;
N-[4-(amino)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamide bis(trifluoroacetate) salt; l-[(7-aminoiminomethyl-2-methoxy- l-naphthalenyl)oxy]-3-hydroxypropane mono(trifluoroacetate) salt; phenylmethyl [7-(aminoiminomethyl)-l-naphthalenyl)carbamate mono(trifluoroacetate) salt;
N-f7-(aminoiminomethyl)-l-naphthalenyl)acetamide mono(trifluoroacetate) salt; methyl [7-(aminoiminomethyl)-l-naphthalenyl)carbamate mono(trifluoroacetate) salt; methyl 3-[[7-(aminoiminomethyl)--l-naphthalenylJaminol-3-oxopropanoate mono(trifluoroacetate) salt;
N-f7-(aminoiminomethyl)- 1 -naphthalenyl]-2-(phenylmethoxy)acetamide mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)- 1 -naphthalenyl]- 1 ,3-benzodioxole-5-carboxamide mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- 1 -naphthalenyljbenzenemethanesulfonamide mono(trifluoroacetate) salt; 1 -[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]-3-bromopropane mono(hydrochloride) salt;
3-[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]propene mono(trifluoroacetate) salt; l-[(7-aminoiminomethyl-2-methoxy-l-naphthalenyl)oxy]-3-phenylpropane mono(hydrochloride) salt: l-[(7-aminoiminomethyl-2-methoxy-l-naphthalenyl)oxy]-3-[l-(3,4-dimethoxy)phenyl]- propane mono(hydrochloride) salt;
7-methoxy-8-(2-furanyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; methyl 6-(aminoiminomethyl)-4-[(methoxycarbonyl)amino]-2-naphthalenecarboxylate mono(trifluoroacetate) salt;
(E)-(7-methoxy-8-[2-(Phenyl)ethenyl])-2-naphthaleneimidamide mono(trifluoroacetate) salt
6-(4-phenylbutynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
7-(2-hydroxyethoxy)-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
7-(2-hydroxyethoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 6-(4-methyl- 1 -pentynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
6-(5-phenylpentynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
6-(3-phenyl- 1 -propynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
6-(phenylethynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
3-amino-N-[3-[6-(aminoiminomethyl)-2-naphthalenyl]-2-propynyl]benzamide mono(trifluoroacetate) salt;
4-amino-N-[3-(6-aminoiminomethyl-2-naphthalenyl)-2-propynyl]benzamide mono(trifluoroacetate) salt;
(S)-2-amino-N-[l-[(6-aminoiminomethyl-2-naphthalenyl)carbonyl]cyclohexyl]propionamide bis(trifluoroacetate) salt: 6-methoxy-8-benzyloxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt:
2-[(7-aminoiminomethyl-3-rnethoxy- l-naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt;
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-phenylurea mono(trifluoroacetate) salt;
(E)-6-[2-(phenyl)ethenyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
6-[2-(phenyl)ethyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 7-propoxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
(± )- 6-(3-phenyloxiranyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
(E)-6-[2-(2-thienyl)ethenyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
6-(3-oxobutyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
6-(3-methoxyphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; N-f3-(methyl)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamide mono(trifluoroacetate) salt;
6-(2-formylphenoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
6-(2-formylphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 6-[2-(hydroxymethyl)phenyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
6-(3-oxo- l-butenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
7-methoxy-8-(lH-pyrazol-4-yl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
7-methoxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
N-phenyl-6-aminoiminomethyl-2-naphthalenecarboxamide mono(methanesulfonate) salt; 4-[(6-aminoiminomethyl-2-naphthalenyl)oxy]-N-methylbenzeneacetamide mono(trifluoroacetate) salt;
6-[2-(methylthio)phenyl]-2-naphthalenecarboximidamide mono(methanesulfonate) salt;
6-f2-(2-thiomethoxoxyethyl)phenyl]naphthalene-2-carboximidamide mono(methanesulfonate) salt; 7-methoxy-8-(3-furanyl)-2-naphthalenecarboximidamide mono(methanesulfonate) salt;
7-methoxy-8-(2-benzofuranyl)naphthalene-2-carboximidamide mono(methanesulfonate) salt;
(E)-8-[2-(l ,3-benzodioxol-5-yl)ethenyl]-2-naphthalenecarboximidamide mono(methanesulfonate) salt;
(± )-7-methoxy-8-(tetrahydro-3-furanyl)-2-naphthalenecarboximidamide mono(methanesulfonate) salt;
6-[[4-(2-aminoethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
7-methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
7-methoxy-8-[2-thiazoyl(oxy)]naphthalene-2-carboximidamide mono(trifluoroacetate) salt; 7-methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
7-methoxy-8-pentafluorophenoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
7-methoxy-8-[N-2-pyrimidinyl(amino)]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-benzylurea mono(trifluoroacetate) salt; N-(6-aminoiminomethyl-2-naphthalenyl)-N'-methylurea mono(trifluoroacetate) salt;
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-isopropylurea mono(trifluoroacetate) salt;
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-phenyl-N'-methylurea mono(trifluoroacetate) salt;
6-aminonaphthalene-2-carboximidamide mono(trifluoroacetate) salt;
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-cyclohexylurea mono(trifluoroacetate) salt; N-(6-aminoiminomethyl-2-naphthalenyl)-N'-benzyloxyurea mono(trifluoroacetate) salt;
1,1-dimethylethyl [4-[[(6-cyano-2-naphthalenyl)amino]carbonyl]phenyl]carbamate mono(trifluoroacetate) salt
N-[6-(aminoiminomethyl)-2-naphthalenyl]-4-(aminomethyl)benzamide mono(trifluoroacetate) salt; ethyl [6-(aminoiminomethyl)-2-naphthalenyl]carbamate mono(trifluoroacetate) salt;
1,1-dimethylethyl [4-[[[6-aminoiminomethyl)- 2-naphthalenyl)amino]carbonyl]amino]phenyl] carbamate mono(trifluoroacetate) salt;
(E)-6-[2-(phenylthio)ethenyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; (E)-6-[2-(2-furanyl)ethenyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
(E)-6-[2-(lH-imidazol-l-yl)ethenyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
(E)-4-[2-(6-aminoiminomethyl-2-naphthalenyl)ethenyl]benzenesulfonamide mono(trifluoroacetate) salt;
(E)-4-f2-(6-aminoiminomethyl-2-naphthalenyl)ethenyl]benzoic acid mono(trifluoroacetate) salt; 4-[7-(aminoiminomethyl)-2-methoxy-l -naphthalenyl]dihydro-2(3H)-furanone mono(trifluoroacetate) salt;
7-methoxy-8-( 1 -acetyl- 1 H-pyrazolyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
7-methoxy-8-[l-(methylsulfonyl)-lH-4-pyrazolyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
(E)-4-[2-(6-aminoininomethyl-2-naphthalenyl)ethenyl]benzamide mono(trifluoroacetate) salt;
6-[2-(4-aminophenyl)ethoxy]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; methyl [3-methoxy-6-(aminoirrrinomethyl)-4-naphthalenyl]carbamate mono(trifluoroacetate) salt; 7-methoxy-8-l2-pyrirnidinyl(amino)]-2-naphthalenecarboximidamide bis(trifluoroacetate) salt; fhthalenecarboxamide, mono(trifluoroacetate) salt;
6-(4-aminophenyl)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt: methyl 2-[4-[[[6-(aminoiminomethyl)-2-naphthalenyl]carbonyl]amino]- phenoxy]acetate,mono(trifluoroacetate) salt; (E)-6-f2-[(3-hydroxymethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt;
6-(2-phenyl- l-cyclopropyl)-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt;
(E)-6-[2-[4-(aminomethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; (E)-6-[2-[4-(l,2-dihdyroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt;
(E)-6-[2-[4-(lR-amino-2-hydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; 7-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt;
(E)-6-[2-[[4-(dimethylan ino)methyl]phenyl]ethenyl]-2-naphthalenecarboximidarnide, bis(trifluoroacetate) salt;
(E)-6-[2-[4-(hydroxymethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide. mono(trifluoroacetate) salt; 4-[[6-(aminoiminomethyl)-2-naphthalenyl]ethynyl]-L-phenylalanine, mono(trifluoroacetate) salt;
6-(3-formylphenyl)-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt;
(E)-6-[2-(l, 2,3,4- tetrahydro-6-isoquinolinyl)ethenyπ-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; (E)- 6-[2- 3-(2-hydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(2,3-dihydro-lH-inden-5-yl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-[(4-aminophenyl)ethynyl]-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; 1 ,1 -dimethylethyl [2-[3-[[6-(aminoiminomethyl)-2-naphathalenyl]ethynyl]-6- methoxyphenyl]ethyl]carbamate, mono(trifluoroacetate) salt;
1 , 1 -dimethylethyl [[4-[[6-(aminoiminomethyl)-2-naphathalenyl]ethynyl]- phenyl]methyl]carbamate, mono(trifluoroacetate) salt;
6-[[4-(aminomethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide, bis(rrifluoroacetate) salt; 6-[[3-(2-aminoethyl)-4-methoxyphenyl]ethynyll-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt;
6-[[4-(hydroxymethyl)phenylJethynyl]-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt;
6-[(l,2,3,4-tetrahydro-6-isoquinolinyl)ethynyl]-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt:
6-(aminoiminomethyl)-N-(4-methylphenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
1,1-dimethylethyl [[4-[[[6-(aminoiminomethyl)-2-naphathalenyl]amino]- carbonyl]phenyl]methyl]carbamate, mono(trifluoroacetate) salt; N-[6-(aminoiminomethyl)-2-naphthalenyl)benzamide, mono(trifluoroacetate) salt;
1,1-dimethylethyl [[4-[[[6-(aminoiminomethyl)-2-naphathalenyl]amino]carbonyl]- cyclohexyll]methyl]carbamate, mono(trifluoroacetate) salt;
N-[6-(aminoiminomethyl)-2-naphthalenyl]-N'-(4-aminophenyl)urea, bis(trifluoroacetate) salt; N-[6-(aminoiminomethyl)-2-naphthalenyl]-4-4-(aminomethyl)cyclohexanecarboxamide, bis(trifluoroacetate) salt;
N-[6-(aminoiminomethyl)-2-naphthalenyl]-N'-[(4-aminomethyl)phenyl]urea, bis(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(4-ethylphenyl)-2-naphthalenecarboxamide, acetate salt; 6-(aminoiminomethyl)-N-(2-naphthalenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(5-phenyl-2-oxazolyl)-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt;
6-(5-phenyl-2-thiazolyl)-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(l ,2,3,4-tetrahydro-6-quinolinyl)-2-naphthalenecarboxamide, bis(trifluoroacetate) salt;
6-[amino(hydroxyimino)methyll-N-phenyl-2-naphthalenecarboxamide;
6-[4-[(hydroxymethyl)phenyl]methoxy]-2-naphthalenecarboximidamide, methanesulfonate salt;
6-(2-pyridinylethynyl)-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt;
N-[4-(aminocarbonyl)phenyl]-6-(aminoiminomethyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(2-thiazolyl)-2-naphthalenecarboxamide, monohydrochloride
6-(aminoiminomethyl)-N-(6-methoxy-3-pyridinyl)-2-naphthalenecarboxamide, monohydrochloride
6-(aminoiminomethyl)-N-(l,3-benzodioxol-5-yl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-( 1,2,3,4- tetrahydro-2,4-dioxo5-pyrimidinyl)-
2-naphthalenecarboxamide, monohydrochloride
6-(aminoiminomethyl)-N-(3,5-difluorophenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt; 6-(aminoiminomethyl)-N-( 1 H-pyrazol-3-yl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(5-methyl-3-isoxazolyll)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(pyrazinyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt; 6-(aminoiminomethyl)-N-(6-methyl-2-pyridinyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(3,4,5-trimethoxyphenyl)-2-naphthalenecarboxamide, monohydrochloride 6-(aminoiminomethyl)-N-(3-methyl-2-pyridinyl)-2-naphthalenecarboxamide, bis(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(5-bromo-2-thiazolyll)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(5-methyl-2-pyridinyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(4-methyl-2-thiazolyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(6-quinolinyl)-2-naphthalenecarboxamide, bis(trifluoroacetate) salt; 6-(aminoiminomethyl)-N-(lH-indazol-6-yl)-2-naphthalenecarboxamide, bis(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(lH-indazol-5-yl)-2-naphthalenecarboxamide, bis(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(lH-indol-5-yl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(5-pyrimidinyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(3-pyridazinyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt; 6-(aminoiminomethyl)-N-(5-bromo-2-pyridinyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-[3-(l-methylethoxy)phenyl]-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-( 1 H-imidazolyl)-2-naphthalenecarboxamide, bis(trifluoroacetate) salt;
6-[2-[4-(hydroxymethyl)phenyl]-l-cyclopropyl]-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt;
N-(ethoxycarbonyl)-6-(2-phenyl-l-cyclopropyl)-2-naphthalenecarboximidamide 6-(aminoiminomethyl)-N-(2-methyl-6-quinolinyl)-2-naphthalenecarboxamide, bis(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(3-propoxyphenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-[3-(l-ethylpropoxy)phenyl]-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-[3-(cyclopentyloxy)phenyl]-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(3-phenoxyphenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt; 6-(aminoiminomethyl)-N-[3-(phenylmethoxy)phenyl]-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(3-ethoxyphenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(4-nitrophenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-[3-(cyclobutylmethoxy)phenyl]-2- naphthalenecarboxamide,mono(trifluoroacetate) salt;
6-[amino(ethoxycarbonyl)imino]-N-[3-(l-methylethoxy)phenyl]-2-naphthalenecarboxamide;
6-(aminoiminomethyl)-4-[5-(ethylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide, monohydrochloride; methyl [7-(aminoiminomethyl)-2-methoxy- l-naphthalenyl)carbamate, mono(trifluoroacetate) salt:
7-memoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt;
7-memoxy-8-[(phenylmethyl)amino]-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt:
7-methoxy-8-(phenylamino)-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt;
7-methoxy-8-[(4-methoxyphenyl)aminol-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt;
(E)-3-[7-(aminoiminomethyl)-2-methoxy- l-naphthalenyl)-2-propenamide, mono(trifluoroacetate) salt;
7-methoxy-8-(3-oxo-l-cyclopenten-l-yl)-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt; methyl 4-[[[7-(aminoiminomethyl)-l-(2-pyrimidinylamino)-2- naphthalenyl]oxy]methyl]benzoate, mono(trifluoroacetate) salt; 4-[[[7-(aminoiminomethyl)- l-(2-pyrimidinylamino)-2-naphthalenyl]oxy]methyl] benzoic acid, mono(trifluoroacetate) salt;
7-methoxy-8-(pyrazinyloxy)-2-naphthalenecarboximidamide, dimethanesulfonate salt;
7-methoxy-8-(phenylthio)-2-naphthalenecarboximidamide, methanesulfonate; 7-methoxy-8-(pyrazinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; methyl 5-[7-[(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoate, mono(trifluoroacetate) salt;
5-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoic acid, mono(trifluoroacetate) salt; methyl 4-[[[7-arnino(hydroxyimino)methyl]-2-naphthalenyl]oxy]methyl]benzoate; methyl 2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetate, mono(trifluoroacetate) salt; 7-[2-(4-mo holinyl)ethoxy]-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt;
2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetic acid, mono(trifluoroacetate) salt; methyl 4-[6-(aminoiminomethyl)-2-naphthalenyl]oxy]methyl]benzoate, mono(trifluoroacetate) salt; methyl [7-(aminoiminomethyl)-l-naphthalenyl]methylcarbamate, mono(trifluoroacetate) salt; propyl [7-(aminoiminomethyl)-l-naphthalenyl]carbamate, mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)- 1 -naphthalenyl]-N'-methylurea, mono(trifluoroacetate) salt; ethyl [7-(aminoiminomethyl)-l-naphthalenyl)carbamate, mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)- 1 -naphthalenyl)propanamide, mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)-l-naphthalenyl)-2-methoxyacetamide, mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)-l-naphthalenyl]urea, mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)- 1 -naphthalenyl]-2-hydroxyacetamide, mono(trifluoroacetate) salt;
8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt;
8-amino-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt;
8-(2-pyridinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; N-hydroxy-8-(2-pyrimidinylamino)- 2-naphthalenecarboximidamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-4-(3-furanyl)-N-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-4-(3-furanyl)-N-(4-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride;
6-(aminoiminomethyl)-4-(3-furanyl)-N-(lH-pyrazol-3-yl)-2-naphthalenecarboxamide, dihydrochloride;
6-(aminoiminomethyl)-4-(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride; methyl [7-(aminoiminomethyl)-3-[[[4-(arninomethyl)phenyl]amino]carbonyl]- 1 - naphathalenyl]carbamate, bis(trifluoroacetate) salt;
6-(aminoiminomethyl)-4-(3-furanyl)-N-(2-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride; 6-(aminoiminomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamide, monohydrochloride
6-(aminoiminomethyl)-4-[l-(methylsulfonyl)-lH-pyrazol-4-yl]-N-phenyl-2- naphthalenecarboxamide. monohydrochloride;
6-(aminoiminomethyl)-4-[5-(methylthio)-3-furanyl)]-N-phenyl-2-naphthalenecarboxamide, monohydrochloride; 6-(aminoiminomethyl)-N-[4-(aminomethyl)phenyl]-4-(2-pyrimidinylamino)-2- naphthalenecarboxamide, tris(trifluoroacetate) salt;
6-(aminoinτinomethyl)-N-phenyl-4-(2-pyrimidinylamino)-2naphthalenecarboxamide, mono(trifluoroacetate) salt;
N-[(4-(aminomethyl)phenyl]-6-[amino(hydroxyimino)methyl]-4-(2-pyrimidinylamino)-2- naphthalenecarboxamide, bis(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-r4-(hydroxymethyl)phenyl]-4-(2-pyrimidinylamino)-
2-naphthalenecarboxamide, mono(trifluoroacetate) salt; methyl [3-[[[4-(aminomethyl)phenyl]aminolcarbonyl]-7-[4-amino(hydroxyimino)methyl]- 1 - naphthalenyl]carbamate, bis(trifluoroacetate) salt; 6-(aminoiminomethyl)-N-phenyl-4-(tetrahydro-3-furanyl)-2- naphthalenecarboxamide,monohydrochloride;
6-[amino(hydroxyimino)methyl]-N-phenyl-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide
6-(aminoiminomethyl)-4-[5-(ethylthio)-3-furanyl]-N-phenyl-2- naphthalenecarboxamide.monohydrochloride; 6-(aminoiminomethyl)-4-[5-(propylthio)-3-furanyl]-N-phenyl-2- naphthalenecarboxamide, monohydrochloride;
6-(aminoiminomethyl)-N-phenyl-4-(2-pyrrolidinyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-4-[5-(propylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide, monohydrochloride;
6-(aminoiminomethyl)-4-[5-[methylthio)methyl]-3-furanyl]-N-phenyl-2- naphthalenecarboxamide, monohydrochloride;
6-(aminoiminomethyl)-4-[5-(methoxymethyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide, monohydrochloride; 6-(aminoiminomethyl)-4-[5-(methylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide, mono(trifluoroacetate) salt; and
6-(aminoiminomethyl)-4-[5-(ethythio)tetrahydro-3-furanyl]-N-phenyl-2- naphthalenecarboxamide, monohydrochloride.
Determination of Urokinase inhibition The efficacy of the compounds of this invention as urokinase inhibitors was determined by measuring the inhibition of the urokinase enzyme Abbokinase (Abbott Laboratories, Abbott Park, IL) on substrate S-2444, of formula pyroGlu-Arg-pNA-HCl (DiaPharma Group, Inc. Distributor of Chromogenix) at 200 μM.
The assay was performed in a 96 well polystyrene, flat bottom plate in a 50 mM Tris/0.15 M NaCl + 0.5 % Pluronic F-68 (Sigma P-5556), pH 7.4 (with HC1) buffer. The compounds of this invention, 10 mM in DMSO, were diluted with DMSO to eight half log concentrations, for example: 1200 μM, 400 μM, 120 μM, 40 μM, 12 μM, 4 μM, 1 μM and 0.4 μM. Four concentrations were chosen, then 5 μl of each were diluted to a total assay volume of 200 μl. The final compound concentrations in the assay, according to the above example, were 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM and 0.01 μM, respectively. The substrate S-2444 was used at 200 μM in the assay. Several vials were reconstituted as directed on the vial, aliquoted and stored frozen. The enzyme was further diluted in assay buffer and 10 μl was used in the assay. Enzyme concentration in the assay was 2-3 nM. The assay was performed as follows: 175 μL of buffer was pipetted into the polystyrene plate, 5 μL solution of a compound of this invention in DMSO was added, the mixture was vortexed, 10 μL of enzyme in buffer was added, the mixture was vortexed, 10 μL of substrate in water was added, the mixture was vortexed, and the plate was placed in a Spectromax ® (Molecular Devices Corporation, Sunnyvale, Ca) plate reader to follow the course of the reaction for 15 min at 405 nm. The Spectromax ® calculated the reaction rates which were used to calculate percent inhibition of the compounds of this invention versus the reaction rate of the enzyme in the absence of any inhibitor. The Ki 's of the inhibitors were calculated from the percent inhibition and previously established Km. The compounds of this invention inhibit urokinase as shown by the data for representative examples in Table 1.
Table 1
Inhibitory Potency of Representative Compounds Against Urokinase
Pharmaceutical Compositions
T e present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally , intracisternally, intravaginally. intraperitoneally or topically (such as powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenteral" administration, as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents (such as aluminum monostearate and gelatin) which delay absorption .
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally or in delayed fashion. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystaUine cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Generally dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg, of active compound per kilogram of body weight per day when administered orally to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
Preparation of Compounds of this Invention The compounds of this invention may be prepared by a variety of synthetic routes. Representative procedures are outlined in the following Schemes 1-6.
Abbreviations
Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: THF for tetrahydrofuran; DMF for N,N-dimethylformamide; OEt2 for diethyl ether; EDC for l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; NMM for N-methylmorpholine; LDA for lithium diisopropylamide; TFA for trifluoroacetic acid; DMSO for dimethylsulfoxide; DMAP for 4-(N,N-dimethylamino)pyridine; HATU for
O-(azabenzotriazole- l-yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphate; Boc for tert- butylcarbonyloxy; DDQ for 2,3-dichloro-5,6-dicyano- l ,4-benzoquinone; Bn for benzyl; DPPA for diphenylphosphoryl azide; DCC for dicyclohexylcarbodiimide; EDC for l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; SEM for 2- (trimethylsilyl)ethoxymethyl ; dppf for l,r-bis(diphenylphosphino)ferrocene; and dba for dibenzylideneacetone. Starting materials, reagents and solvents were purchased from Aldrich Chemical Company (Milwaukee, Wi).
As shown in Scheme 1, naphthalenecarbonitriles 4, 5 and 6 were prepared by treating 3- cyanopropionaldehyde diethyl acetal 2 with a strong base such as lithium diisopropylamide then treating the resulting anion with the appropriately substituted benzaldehyde 1 followed by cyclization and aromatization of the corresponding cyanohydrins 3_ with a Lewis acid such as sulfuric acid.
Scheme 1
A, B and C are hydrogen and -LARA, -LBRB, -LCRC
-LA-, -LB- and -L - are -O-
RA, RB and Rc are alkyl
4: A is hydrogen; B and C are OCH3
5: A, B and C are OCH3
6: A and B are OCH3, and C is hydrogen
As shown in Scheme 2, selective demethylation of 4 with a Lewis acid such as AICI3 or
BBr3, preferably AICI3, provided 7. 7 was treated with a base such as potassium carbonate, sodium hydride or cesium fluoride followed by Rc-X, wherein X is a leaving group, to provide 8 (-Lc- is -0-). Alternatively, treatment of 1 with trifluoromethanesulfonic anhydride or 1,1,1- trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide provided , which may
be treated with Rc-B(OH)2, , Rc-L or wherein Re is unsubstituted or substituted aryl or heterocycle, in the presence of a palladium catalyst, preferably Pd(IT)Cl2(dba) or Pd(Ph3P)4, and base, preferably cesium fluoride or potassium carbonate, to provide 10. Alternatively, 9 may be treated with RC-NR1R2, wherein Re is unsubstituted or substituted aryl or heterocycle, and at least one of R\ or R2 is hydrogen, in the presence of a strong base, such as potassium t-butoxide, and a catalyst, such as Pd(II)Cl2(dba), to provide 1 1.
Scheme 2
~ Rc is unsubstituted or substituted aryl or heterocycle 10: -Lc- is a covalent bond 11: -Lc- is -NRr
As shown in Scheme 3, selective 0-triflation of J_2 followed by protection of the amino group of the resulting 13 with acid-labile carbobenzlyoxy provided 14. Conversion of 14 to 15 was achieved with KCN in the presence of a palladium catalyst, preferably tris(dibenzylideneacetone)dipalladium(0)-chlorofoιm adduct, and deprotection of 15. to provide 16 was accomplished with acid, preferably 30% HBr in acetic acid. Treatment of 15 with acylating agents RcC(O)Cl and base, preferably triethylamine, diisopropylethylamine or potassium carbonate provided intermediate ,1,7.
Scheme 3
16 11
-Lc- is -C(0)NRr or -OC(O)NRr and R is unsubstituted or substituted alkyl, alkeneyl, hererocycle or aryl
As shown in Scheme 4, selective demethylation of the 8-methoxy group of 18 with a
Lewis acid such as AICI3 or BBr3, preferably AICI3, was followed by reprotection of phenol 1 by alkylation with Bn-X, wherein X is Cl, Br or I, in the presence of a base such as potassium carbonate, sodium hydride or cesium fluoride. 20 was prepared by deprotonation of this intermediate with a strong, non-nucleophilic base such as lithium, sodium or potassium diisopropylamide or alkoxide followed by treatment with an alkyl formate, preferably ethyl formate to provide enol 20. Treatment of 20 with hydroxylamine provided isoxazole 21 which may be opened with lithium, sodium or potassium alkoxide, preferably sodium methoxide, to provide 22. Carbonyl reduction with concomitant alkene formation with achieved with sodium borohydride to provide 23; and aromatization with DDQ and catalytic debenzylation with hydrogen and a palladium catalyst, preferably palladium on carbon, provided 24. 24 was alkylated by treatment with a base such as potassium carbonate, sodium hydride or cesium fluoride followed by treatment Rc-X-
Scheme 4
IS 12 20 2J
A is -LARA, and C is -LCRC, wherein C is -LcRc, wherein Lc is -O- and
-LA- and -L - are -O- and RA is alkyl Rc is arylalkyl
22 23 24
A is -LARA, wherein
-LA- is -O- and RA is alkyl
As shown in Scheme 5, monohydrolysis of 25 with one equivalent of base such as lithium, sodium or potassium hydroxide provided the acid-ester 26. Treatment of 26 with l() thionyl chloride or oxalyl chloride/DMF followed by treatment with ammonia provided amide 27. Treatment of 27 with a dehydrating agent such as thionyl chloride or phosphorus oxychloride provided nitrile 28.
Regioselective nitration of 28 with nitric acid/potassium nitrate followed by reduction of the nitro group with a palladium catalyst, preferably palladium on carbon, provided intermediate 15 31, which was treated with R C(O)Cl or R OC(O)Cl and base, preferably diisopropylethylamine or potassium carbonate, to provide 37.
Hydrolysis of 28 with one equivalent of lithium, sodium or potassium hydroxide to form carboxylic acid 29 followed by treatment with DPPA or thionyl chloride then sodium azide and hydrolysis of the intermediate isocyanate 32 with acid, preferably sulfuric acid, provided 20 amine 33. Alternatively, treatment of 32 with a primary or secondary amine provided urea 34 (-LA- = -NRιC(X)R2-, wherein X is O).
29 may be coupled to primary or secondary amines, and 33 may be coupled to carboxylic acids to form amides 35 and 36, respectively. In either case, the amines and carboxylic acids are coupled using a dehydrating agent such as DCC, EDC or HATU.
Scheme 5
25 26 27
37
-Lc- is -C(X)J R Γ or -OC(O)NR and Rc is unsubstituted or substituted alkyl, alkeneyl, hererocycle or aryl; X is O
36 -LA- is -C(X)NRr wherein X is O
As shown in Scheme 6, intermediates wherein -LA- is -C≡C- or -C=C- were prepared by treatment of of 38 with a triflating agent, preferably trifluoromethanesulfonyl anhydride, to form 39. followed by coupling of the appropriate substituted alkenes or unsubstituted or substituted alkynes using a palladium catalyst, preferably palladium (II) acetate, to form 40. Scheme 6
38 39 40
As shown in Scheme 7, conversion of the nitrile intermediates to the carboximidamide urokinase inhibitors 4 . was achieved by three methods: (1) treatment of the intermediate carbonitriles with a non-nucleophilic base such as lithium, sodium or potassium bis(trimethylsilylamide), preferably lithium bis(trimethylsilylamide) followed by hydrolysis with acid, preferably HCl; (2) treatment of the nitrile with acid, preferably HCl, followed by treatment with ammonium acetate; and (3) treatment of the nitrile with H2S followed by treatment with ammonia gas in methanol. Of the three methods, the H2S/NH /methanol method is preferred. The compounds of the invention were precipitated as hydrochloride or methane sulfonate salts or were purified by reversed phase medium pressure chromatography to form mono- or bis- trifluoroacetate salts.
Scheme 7
41
Synthetic Methods The foregoing may be better understood by reference to the following examples which illustrate the methods by which the compounds of the invention may be prepared and are not intended to limit the scope of the invention as defined in the appended claims.
Example 7. 8-Dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 1A 7. 8-Dimethoxy-2-naphthalenecarbonitrile A solution of freshly prepared LDA in THF at -78 °C was treated dropwise with 3- cyanopropionaldehyde diethyl acetal (3.0 g) in THF (5 mL), stirred for 1 h, treated with 2,3- dimethoxybenzaldehyde (3.2 g) in THF (5 mL), warmed to room temperature over 90 min, treated with water (40 mL), concentrated and extracted with chloroform. The organic layer was washed with brine, dried (MgSO4) and concentrated to provide 1.5 g of a yellow oil. MS (DCI/NH3) m/e 341 (M+H2O)+.
A solution of the oil in methanol (5 mL) was added dropwise to 20% aqueous sulfuric acid (100 mL) at 90 °C. The solution was heated for 90 min, cooled to room temperature and extracted with chloroform. The combined organic extracts are washed with brine, dried (MgSθ4) and concentrated to provide 1.0 g of a brown solid which was purified by flash chromatography on silica gel with 3: 1 hexane/ethyl acetate to provide 800 mg of the title compound. MS (DCI/NH3) m/e 231 (M+H2O)+.
Example IB 7.8-Dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
A solution of Example 1 (200 mg) in THF (5 mL) at 0 °C was treated with lithium bis(trimethylsilylamide) (1.0 M in hexane, 1.1 mL), stirred for 18 h at room temperature, treated with 10% HCl (10 mL), stirred for 24 h at room temperature, concentrated and purified by medium pressure liquid chromatography on a 30 cm x 2 cm C- 18 column (40 micron, J.T Baker) with UV detection at 250 nM with solvent mixtures in a gradient ranging from 90%A (0.1 % aq TFA)/10%B (methanol) to 10%A/90%B over 160 min at a flow rate of 5 mL/min (fractions were collected every 2 min for 100 min and analyzed by TLC ( 10: 1 : 1 acetonitrile/water/acetic acid) for product) to provide 100 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 4.41 (s, 3H), 4.62 (s, 3H), 7.41 (d, 1H), 7.43 (dd, 1H), 7.60 (d, 1H), 7.80 (d, 1H), 8.49 (d, 1H), 9.31 (bs, 2H), 9.48 (bs, 2H); MS (DCI/NH3) m/e 231 (M+H)+
Anal, calcd for C13H14N2O2 FA: 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) salt
Example 2A 6. 7. 8-trimethoxy-2-naphthalenecarbonitrile
The title compound was prepared as described in Example 1A but substituting 2, 3, 4- trimethoxybenzaldehyde for 2, 3-trimethoxybenzaldehyde. MS (DCI/NH3) m/e 261 (M+H2O)+.
Example 2B
6. 7. 8-trimethoχy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared and purified as described in Example IB to provide 100 mg of the title compound.
IH NMR (DMSO-d6, 300 MHz) δ 3.91 (s, 3H), 3.98 (s, 3H), 4.06 (s, 3H), 7.36 (s, I H), 7.75 (dd, IH) 7.99 (d, IH), 8.49 (d, IH), 9.18 (bs, 2H), 9.38 (bs, 2H); MS (DCI/NH3) m/e 261 (M+H)+.
Anal, calcd for C14H16N2O3 FA: 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) salt
Example 3 A 6. 7-dimethoxy-2-naphthalenecarbonitrile The title compound was prepared as described in Example 1 A but substituting 3,4- dimethoxybenzaldehyde for 2, 3-dimethoxy-benzaldehyde to provide 1.3 g of the title compound. MS (DCI/NH3) m/e 231 (M+H2O)+.
Example 3B
6. 7-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared and purified as described in Example 1 B to provide 100 mg of the title compound. JH NMR (DMSO-d6, 300 MHz) δ 3.92 (s, 3H), 3.94 (s, 3H), 7.41 (s, IH), 7.44 (s, IH), 7.69 (dd, IH), 7.93 (d, IH), 8.49 (d, IH), 9.18 (bs, 2H), 9.38 (bs, 2H); MS (DCI/NH3) m/e 231 (M+H)+.
Anal, calcd for Ci3Hi4N2O2-TFA: C, 52.33; H, 4.39; N 8.14. Found: C, 52.15; H, 4.20; N 8.10.
Example 4 2-r(7-Aminoiminomethyl-2-methoxy-l-naphthalenyl)oxylacetamide mono(trifluoroacetate) salt
Example 4A
7-Methoxy-8-hvdroxynaphthalene-2-carbonitrile A solution of Example 1 A (1 g) in methylene chloride (100 mL) at 0 °C was treated with AICI3, stirred for 4 h at 0 °C and at room temperature for 18 h, poured into water (200 mL) containing 6N HCl (20 mL), stirred for 1 h and diluted with methylene chloride (100 mL). The layers were separated, and the organic layer was washed with brine and dried (MgSO4) to provide 810 mg of the title compound as an off-white solid. MS (DCI/NH3) m/e 217 (M+H2O)+.
Example 4B 1,1 -Dimethylethyl 2-r(7-Cvano-2-methoxy- l-naphthalenyl)oxylacetate
A slurry Example 4A (100 mg), K2CO3 (70 mg), t-butyl bromoacetate (120 mg) and tetrabutylammonium iodide (25 mg) in DMF (3 mL) was stirred for 18 h at room temperature, diluted with water (20 mL) and extracted with ethyl acetate. The organic extract was washed with saturated NaHCθ3 and brine, dried (Na2SO4) and concentrated to provide 200 mg of the title compound as a clear oil. MS (DCI/NH3) m/e 331 (M+H20)+.
Example 4C 2-IY7- Aminoiminomethyl-2-methoxy- 1 -naphthalenvDoxylacetamide mono(trifluoroacetate) salt Example 4B (100 mg) in methanol (5 mL) at 0 °C was treated with HCl(g), stirred for
18 h at room temperature and concentrated to provide an off-white solid. The solid was treated with 2N NH3 in methanol (10 mL), heated at 50 °C for 3.5 h, cooled and concentrated to a yellow solid which was purified as described in Example IB to provide 10 mg of the title compound. IH NMR (300 MHz, DMSO-d6) δ 3.93 (s, 3H), 4.79 (s, 2H), 7.55 (d, 2H), 7.65 (dd, IH), 7.72 (d, IH), 7.85 (d, IH), 8.09 (d, IH), 8.7 (d, IH), 9.03 (bs, 2H), 9.45 (bs, 2H); MS (DCI/NH3) m/e 274 (M+H)+.
Anal, calcd for Cι4Hι5N3θ3-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) salt
Example 5A
7-Benzyloxy-8-iodo-2-naphthalenecarbonitrile The title compound was prepared as described in Example 43A but substituting benzyl bromide for propyl iodide. MS (DCI/NH3) m/e 403 (M+NH4)+. Example 5B
7-Benzyloxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 5A according to the procedure of Example IB.
IH NMR (300 MHz, DMSO-d6) δ 9.30 (br, 4H), 8.44 (s, IH), 8.12 (d, IH), 7.71 (d, 2H), 7.67 (dd, IH), 7.57 (d, 2H), 7.45-7.34 (m, 3H), 5.45 (s, 2H); MS (DCI/NH3) m/e 403 (M+H)+.
Anal, calcd for Cl8Hι5N2OI-TFA: C, 46.53; H, 3.12; N, 5.43. Found: C; 46.55; H, 3.10; N, 5. 19.
Example 6
Methyl I (7-aminoiminomethyl-2-methoxy- 1 -naphthalenvDoxylacetate mono(trifluoroacetate) salt
Example 6A Methyl r(7-cyano-2-methoxy- 1 -naphthalenvDoxylacetate
A solution of Example 4A (600 mg), CS2CO3 (500 mg), t-butyl bromoacetate (120 mg) and tetrabutylammonium iodide (25 mg) in DMF (15 mL) was stirred for 18 h at room temperature, diluted with water (20 mL) and extracted with ethyl acetate. The organic extract was washed with saturated NaHC03 and brine, dried (Na2SO4) and concentrated to provide 800 mg of the title compound as a clear oil. MS (DCI/NH3) m e 331 (M+H2θ)+.
Example 6B
Methyl r(7-aminoiminomethyl-2-methoxy- 1 -naphthalenvDoxylacetate mono(trifluoroacetate) salt Example 6A (100 mg) in methanol (30 mL) at 0 C was treated with HCl(g), stirred for 18 h at room temperature and concentrated to provide an off-white solid. The solid was treated with ammonium acetate (100 mg) in methanol (10 mL), heated at 40 °C for 15 h, cooled and concentrated to a yellow solid which was purified as described in Example IB to provide 10 mg of the title compound.
IH NMR (300 MHz, DMSO-d6) δ 3.65 (s, 3H), 3.93 (s, 3H), 4.79 (s, 2H), 7.65 (dd, IH), 7.72 (d, IH), 7.85 (d, IH), 8.09 (d, IH), 8.7 (d, IH), 9.03 (bs, 2H), 9.45 (bs, 2H);
MS (DCI/NH3) m e 289 (M+H)+.
Anal, calcd for C15H16N2O4 FA: C, 50.75; H, 4.26; N, 6.96. Found: C, 50.42; H, 4.03; N,
6.77.
Example 7 r(7-aminoiminomethyl-2-methoxy-l -naphthalenvDoxylacetic acid mono(trifluoroacetate) salt A solution of Example 6B (100 mg) and LiOH-H2O (150 mg) in 1: 1 THF/H2O (10 mL) at 5 °C was stirred 45 min and concentrated to provide an off-white solid. The solid was dissolved in IN HCl (20 mL), stirred 48 h at room temperature and filtered. The resulting white solid was purified as described in Example IB to provide 20 mg of the title compound. •H NMR (300 MHz, DMSO-d6) δ 3.93 (s, 3H), 4.79 (s, 2H), 7.65 (dd, IH), 7.72 (d, IH), 7.85 (d, IH), 8.09 (d, IH), 8.7 (d, IH), 9.23 (bs, 2H), 9.45 (bs, 2H); MS (DCI/NH3) m/e 275 (M+H)+. Anal, calcd for C14H14N2O4 FA: C, 49.49; H, 3.89; N, 7.21. Found: C, 47.53; H, 3.71; N, 6.83.
Example 8 N-r4-(Aminomethyl)phenyll-6-aminoiminomethyl-2-naphthalenecarboxamide bis(trifluoroacetate) salt. Example 8A 2, 6-Naphthalenedicarboxylic acid, monomethyl ester A suspension of dimethyl 2, 6-naphthalenedicarboxylic acid (39.6 g, 162 mmole) in dioxane (1.20 L) was heated at 70-80 °C until all solid dissolved, slowly treated with 1 equivalent of KOH in methanol, stirred for additional 30 minutes at 70 °C, cooled to room temperature, filtered and washed with dioxane and diethyl ether, dissolved in water, treated with 1 N HCl until the aqueous layer was acidic to pH paper, filtered, washed with water and dried under vacuum to provide 33 g of a white powder. MS (DCI/NH3) m/e 231 (M+H)+.
Example 8B 6-(Chlorocarbonyl)-2-naphthalenecarboxylic acid, methyl ester A suspension of Example 8 A (15 g, 65 mmole) in toluene (190 mL) was treated with thionyl chloride (20 mL, 276 mmole) then DMAP (15 mg), heated at reflux for 1 h and heated at 85 °C for an additional 35 min. The condenser was replaced with a distilling head and 60 mL of solvent was removed. The thick precipitate which formed while cooling to room temperature was triturated with hexane and filtered to provide 14.8 g of white solid. MS (DCI/NH3) m/e 249 (M+H)+
Example 8C 6-(Aminocarbonyl)-2-naphthalenecarboxylic acid, methyl ester A solution of Example 8B (15 g, 60.3 mmole) in methylene chloride (400 mL) at room temperature was treated with dry ammonia gas to precipitate the product. The mixture was stirred for an additional 15 min and filtered. The solid was washed with water and dried under vacuum to yield 13.3 g of a white powder. MS (DCI/NH3) m/e 230 (M+H)+.
Example 8D 6-Cyano-2-naphthalenecarboxylic acid, methyl ester
A suspension of Example 8C (31 g, 135 mmole) in trimethyl phosphate (450 mL) was treated with triphosgene (27 g, 136 mmole), stirred for 20 min at room temperature and heated in an oil bath at 80 °C for 1 h. The product precipated from the solution while cooling to room temperature. The thick slurry was treated with water and filtered, and the white solid was thoroughly washed with water and dried under vacuum to provide 26.3 g of the title compound. MS (DCI NH3) m e 212 (M+H)+
Example 8E
6-Cvano-2-naphthalenecarboxylic acid Example 8D (1.9 g, 9 mmole) in 1:1 THF/H2O (40 mL) was treated with LiOH-H2O ( 1.9 g, 45 mmole), stirred 90 min at room temperature and concentrated to a thick slurry. The slurry was dissolved in water (20 mL), acidified to pH 2 with solid citric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to provide 1.6 g of the title compound as a white solid. MS (DCI/NH3) m/e 197 (M+H)+.
Example 8F tert-Butoxycarbonylarnino-4-aminomethylaniline
4-Aminomethylaniline (2 g) in 2: 1 TΗF/H2O (30 mL) was treated with Boc anhydride (3.93 g), stirred at room temperature for 18 h, diluted with water and concentrated to white slurry. The slurry was dissolved in ethyl acetate, washed with water and brine, dried (Na2SO4) and concentrated to provide 2.4 g of a yellow solid. MS (DCI/NH3) m/e 223 (M+H)+.
Example 8G N-r4-(aminomethvDphenyll-6-cvano-2-naphthalenecarboxamide A solution of Example 8E (200 mg) and hunig's base (180 μL) in DMF (5 mL) at 5 °C was treated with HATU (193 mg), stirred for 1 h at 5 °C, treated with
Example 8F (120 mg) and diisopropylethylamine (100 μL) in DMF (5 mL), stirred for 8 h at room temperature, diluted with ethyl acetate (100 mL), washed sequentially with IN H3PO4, saturated sodium bicarbonate and brine, dried (Na2SO4) and concentrated to provide a yellow oil which was purified on silica gel with 1 methanol/methylene chloride to provide 200 mg of the title compound.
MS (DCI/NH3) m/e 419 (M+H2O)+.
Example 8H N-r4-(aminomethyl)phenyll-6-aminoininomethyl-2-naphthalenecarboxamide bisftrifluoroacetate) salt The title compound was prepared from Example 8G (200 mg) by the procedure and purification from Example 5B to provide 37 mg of the title compound. IH NMR (300 MHz, DMSO-d6) δ 4.08 (m, 2H), 7.45 (d, 2H), 7.88 (d, 2H), 7.95 (dd, IH), 8.18 (dd,lH), 8.20 (bs, 3H), 8.23 (d,lH), 8.35 (d,lH), 8.58 (s,lH), 8.70 (s, IH), 9.39 (s, 2H), 9.55 (s, 2H), 10.68 (s, IH); MS (DCI/NH3) m/e 319 (M+H)+
Anal, calcd for C19H17N4O FA: C, 50.56; H, 3.69; N, 10.25; Found: C, 50.18; H, 3.59; N, 10.1 1.
Example 9 N-r4-(amino)phenyll-6-aminoiminomethyl-2-naphthalenecarboxamide bis(trifluoroacetate) salt
Example 9A
N-r4-(amino)phenyn-6-cvano-2-naphthalenecarboxamide The title compound was prepared according to the procedure described for Example 8G but substituting 1 ,4-diaminobenzene for Example 8F. MS (DCI/NH3) m/e 288 (M+H)+.
Example 9B
N-r4-(amino)phenyll-6-aminoiminomethyl-2-naphthalenecarboxamide bis(trifluoroacetate) salt The title compound was prepared with Example 9A (100 mg) following the procedure and purification from Example 6B.
IH NMR (300 MHz, DMSO-d6) δ 7.15 (d, 2H), 7.75 (d, 2H), 7.95 (dd, IH), 8.18 (dd, IH), 8.23 (d, IH), 8.35 (d, IH), 8.58 (s, IH), 8.70 (s, IH), 9.25 (s, 2H), 9.48 (s, 2H), 10.58 (s,
IH);
MS (DCI/NH3) m/e 305 (M+H)+.
Anal, calcd for Cι8Hι6N4O-2TFA: C, 49.63; H, 3.41; N, 10.52; Found: C, 46.57; H, 3.62;
N, 10.66.
Example 10 l-r(7-Aminoiminomethyl-2-methoxy-l-naphthalenyl)oxyl-3-hydroxypropane mono(trifluoroacetate) salt Example 10A 1 -f(7-Cvano-2-methoxy- 1 -naphthalenvDoxy1-3-r(2-tetrahydro-2H-pyranyl1oxy)propane mono(trifluoroacetate) salt A suspension of Example 4A (200 mg) and CS2CO3 (0.32 g) in DMF (15 mL) was treated with 2-(3-bromopropyl)-tetrahydro-2H-pyran (0.25 g), stirred at room temperature for 18 h then diluted with water (100 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with 10% citric acid, water and brine, dried (MgSO4) and concentrated to provide 320 mg of an oil. MS (DCI/NH3) m/e 323 (M+H)+.
Example 10B l-r(7-Aminoiminomethyl-2-methoxy-l-naphthalenyl)oxyl-3-hydroxypropane mono(trifluoroacetate) salt Example 10A (0.3 g) was processed and purified according to the procedure of Example 1 B to provide 1 10 mg of an off-white solid. l H NMR (300 MHz, DMSO-d6) δ 1.97 (q, 2H), 3.67 (t, 2H), 4.20 (t, 2H), 7.61-7.70 (m, 3H), 7.84 (d.lH), 8.08 (d, IH), 8.50 (d, IH); MS (DCI/NH3) m/e 275 (M+H)+.
Anal, calcd for Ci3Hi3N3O2-TFA-0.75H2O: C, 50.81; H, 5.14; N, 6.97. Found: C, 51.23; H, 5.28; N, 6.97.
Example 1 1 8-amino-2-naphthalenecarbonitrile hydrobromide
Example 1 1 A
2-Trifluoromethanesulfonyloxy-8-aminonaphthelene A solution of 8-amino-2-naphthol (10 g) and triethylamine (12 mL) in dioxane (200 mL) was treated with N-phenyltrifluoromethane sulfonimide (25 g) in dioxane (80 mL), stirred for 4 h and concentrated. The resulting dark brown solid was triturated with hexane and filtered to provide 12 g of the title compound as a brown solid. MS (DCI/NH3) m/e 292 (M+H)+.
Example 1 IB 2-Trifluoromethanesulfonyloxy-8-carbonylbenzyloxyaminonaphthelene A solution of Example 11 A (2 g) in 10% aq Na2CO3 (20 mL) and dioxane (250 mL) was treated with benzylchloroformate (2 mL) in dioxane (20 mL), stirred at room temperature for 5 h then extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated, and the crude product was chromatographed on silica gel with 7: 1 hexane/ethyl acetate to provide 2.5 g (86%) of the title compound. MS (DCI/NH3) m/e 44 (M+NH4)+
Example 11C 8-(N-carbonylbenzyloxy)-2-naphthalenecarbonitrile Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (120 mg), l,r-bis(diphenylphosphino)-ferrocene (260 mg), potassium cyanide (766 mg), Example 1 IB (2.5 g) and N-methyl-2-pyrrolidione (5 mL) were combined sequentially, stirred at room temperature until a yellow reaction complex formed then warmed to 80 °C for 40 min. The dark brown reaction mixture was cooled to room temperature and chromatographed on silica gel with 9: 1 hexane/ethyl acetate to provide 1.5 g of the title compound as a colorless solid. MS (DC1 NH3) m/e 292 (M+NH4)+
Example I IP 8-Amino-2-naphthalenecarbonitrile hydrobromide
Example 1 1C (1.4 g) was treated with a solution of 30% HBr in acetic acid (5 mL) and stirred at room temperature for 6 h. The reaction mixture was treated with diethyl ether and filtered to provide 1.1 g of the title compound as a yellow solid. MS (DCI/NH3) m/e 186 (M+NH4)+.
Example 12 General Acylation Procedure A suspension of Example 10D (1 equivalent), triethylamine (1 equivalent) and DMAP (0.25 equivalents) in methylene chloride (0.3M) was treated dropwise with the appropriate acid chloride (1.1 equivalents) in methylene chloride (0.3 M), stirred at room temperature for 30 min and treated with water (50 mL). The organic layer was dried (MgSO4), concentrated and used in following reactions without further purification.
Example 13 General Amidine Synthesis Procedure A solution of crude acylation products from Example 12 (ca. 100 mg) at room temperature in 10: 1 pyridine:triethylamine (10 mL) was treated with hydrogen sulfide for 5 min, stirred at room temperature for 18 h, diluted with water (50 mL) and extracted with ethyl acetate. The ethyl acetate was dried (MgSO4) and concentrated. The residue was dissolved in acetone (30 mL), treated with methyl iodide (2 mL), refluxed for 1 hour, evaporated to dryness, redissolved in methanol (25 mL), treated with ammonium acetate (100 mg), stirred for 18 h at room temperature, concentrated and purified as described in Example IB to provide Examples 14-20 as white solids.
Example 14
8-(carbonylbenzyloxy)amino-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
IH NMR (DMSO-d6, 300 MHz) δ 5.14 (s, 2H), 7.36-7.50 (m, 5H), 7.67-7.90 (m, 4H), 8.14
(d, IH), 8.67 (s, I H), 9.08 (s, 2H), 9.37 (s, 2H), 9.78 (s, IH); MS (DCI/NH3) m/e 320 (M+H)+.
Anal, calcd for C19H15N3O2T .5TFA-O.5H2O: 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 -naphthalenvPacetamide mono(trifluoroacetate) salt
IH NMR (DMSO-d6, 300 MHz) δ 4.19 (s, 3H), 7.66-7.88 (m, 3H), 8.12-8.16 (m, 2H), 8.69
(s, IH), 8.98 (d, IH), 9.16 (s, 2H), 9.47 (s, 2H), 10.14 (s, IH);
MS (DCI/NH3) m/e 228 (M+H)+.
Anal, calcd for Ci4Hι2N3θ- 1.2TFA-0.25H2O: C, 50.18; H, 4.02; N, 1 1.40. Found: C, 50.62; H, 4.47; N, 10.90.
Example 16 Methyl r7-(aminoiminomethvD-l-naphthalenyl)carbamate mono(trifluoroacetate) salt !H NMR (DMSO-d6, 300 MHz) δ 3.88 (s, 3H), 7.67-7.85 (m, 4H), 8.14 (d, IH), 8.6 (s, IH), 8.28 (s, 3H), 9.67 (s, IH); MS (DCI/NH3) m/e 244 (M+H)+.
Anal, calcd for C13H13N3O2 FA: C,50.43; H, 3.95; N, 11.76. Found: C, 50.12; H, 4.05; N, 1 1.61. Example 17 Methyl 3-rr7-(aminoiminomethyl)- 1 -naphthalenyllaminol-3-oxopropionate mono(trifluoroacetate) salt *H NMR (DMSO-d6, 300 MHz) δ 3.69 (s, 2H), 3.71 (s, 3H), 7.69 (m, 4H), 8.18 (d, IH), 8.58 (s, I H), 9.1 1 (s, 2H), 9.48 (s, 2H); MS (DCI/NH3) m/e 286 (M+H)+.
Anal, calcd for Cι5Hι4N3θ3- l . lTFA-H2θ: C, 48.18; H, 4.26; N, 9.80. Found: C, 48.30; H, 4.09; N, 9.58.
Example 18
N-r7-(aminoiminomethvD- 1 -naphthalenyll-2-(phenylmethoxy)acetamide mono(trifluoroacetate) salt
IH NMR (DMSO-d6, 300 MHz) δ 4.29 (s, 2H), 4.73 (s, 2H), 7.33-7.48 (m, 5H), 7.69 (m,
4H), 8.17 (d, IH), 8.47 (s, IH), 9.21 (br, 4H), 10.0 (s, I H);
MS (DCI/NH3) m/e 334 (M+H)+.
Anal, calcd for C2oHιgN3θ2- lTFA-H2O: C, 56.77; H, 4.76; N, 9.03. Found: C, 56.84; H,
4.49; N, 8.93.
Example 19
N-r7-(aminoiminomethvD- 1 -naphthalenyll- 1.3-benzodioxole-5-carboxamide mono(tτifluoroacetate) salt IH NMR (DMSO-d6, 300 MHz) δ 6.19 (IH, 2H), 7.12 (d, IH), 7.65-7.79 (m, 5H), 7.97 (d, I H), 8.20 (s, IH), 8.53 (s, IH), 9.2 (br s, 3H), 10.35 (s, 2H);
MS (DCI/NH3) m/e 334 (M+H)+.
Anal, calcd for C18H14N3O2 FA: C, 55.82; H, 3.68; N, 9.30. Found: C, 55.69; H, 33.61 ;
N, 9.23.
Example 20
N-r7-(aminoiminomethyl)- 1 -naphthalenyllbenzenemethanesulfonamide mono(trifluoroacetate) salt !H NMR (DMSO-d6, 300 MHz) δ 4.60 (s, 2H), 7.32-7.33 (m, 5H), 7.67-7.70 (m, 2H), 7.82 (d,lH), 7.92 (d, lH), 8.17 (s, IH), 8.70 (s, IH), 9.14 (s, 2H), 9.35 (s, 2H), 9.19 (s, IH);
MS (DCI/NH3) m/e 340 (M+H)+.
Anal, calcd for Ci8Hι7N3θ2S-TFA-H2O: C, 50.95; H, 4.28; N, 8.91; Found: C, 50.76; H,
3.70; N, 8.65.
Example 21 l-r(7-aminoiminomethyl-2-methoxy-l-naphthalenyl)oxy1-3-bromopropane mono(hvdrochloride) salt
Example 21 A
1 -r(7-Cvano-2-methoxy- 1 -naphthalenyl)oxy1-3-bromopropane mono(hvdrochloride) salt The title compound was prepared from Example 4A, 1 ,3-dibromopropane and the procedure of Example 10 A. MS (DCI/NH3) m/e 337 (M+NH )+.
Example 2 IB 1 -r(7-Aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxyl-3-bromopropane mono(hvdrochloride) salt The title compound was prepared from Example 21 A and the procedure of Example IB. After HCl hydrolysis, the solution was cooled to 0 °C, and the white solid which precipitated was filtered and dried to provide the title compound.
IH NMR (300 MHz, DMSO-d6) δ 2.35 (m, 2H), 3.86 (t, 2H), 4.00 (s, 3H), 4.25 (t, 2H), 7.65 (dd, IH), 7.70 (d, IH), 7.90 (d, IH), 8.10 (d, IH), 8.55 (s, IH), 9.15 (br s, 2H), 9.42 (br s, 2H); MS (DCI NH3) m/e 337 (M+H)+.
Anal, calcd for Cι5Hι7BrN2θ2ΗCl-0.75H2θ: C, 46.53; H, 5.08; N, 7.23. Found: C, 46.65; H, 5.1 1; N, 7.16.
Example 22 3-r(7-Aminoirninomethyl-2-methoxy- 1 -naphthalenv oxylpropene mono(trifluoroacetate) salt
Example 22A 3-r(7-Cvano-2-methoxy- 1 -naphthalenvDoxylpropene The title compound was obtained as a biproduct from the procedure of Example 21 A. MS (DCI/NH3) m/e 257 (M+NH4) -.
Example 22B 3-r(7-Aminoiminomethyl-2-methoxy- 1 -naphthalenvDoxylpropene mono(trifiuoroacetate) salt The title compound was prepared from Example 22A and the procedure and purification in Example IB.
!H NMR (300 MHz, DMSO-d6) δ 4.00 (s, 3H), 4.70 (d, 2H), 5.22 (d, IH), 5.42 (d, IH),
6.18 (m, IH), 7.62 (dd, IH), 7.85 (d, IH), 8.10 (d, IH), 8.50 (s, IH), 9.12 (br s. 2H), 9.45 (br s, 2H);
MS (DCI/NH3) m/e 257 (M+H)+.
Anal, calcd for Cι5H16N2θ2-TFA-0.25H2θ: C, 54.47; H, 4.71; N, 7.47. Found: C, 54.61;
H, 4.38; N, 7.40.
Example 23
1 -r(7-Aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxyl-3-phenylpropane mono(hvdrochloride) salt
Example 23A l-r(7-Cvano-2-methoxy- l-naphthalenyl)oxyl-3-phenylpropane
The title compound was prepared from Example 4A, l-bromo-3-phenylpropane, and the procedure of Example 10A. MS (DCI/NH3) m/e 335 (M+NH4)+.
Example 23B
1 -IY7- Aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy1-3-phenylpropane mono(hvdrochloride) salt The title compound was prepared from Example 23A and the procedure of Example 21 B. lH NMR (300 MHz, CD3OD) δ 2.21 (m, 2H), 2.94 (t, 2H), 4.00 (s, 3H), 4.22 (t, 2H), 7.18 (m, IH), 7.28 (m, 4H), 7.62 (m, 2H), 7.79 (d, IH), 8.02 (d, IH), 8.62 (s, IH); MS (DCI/NH3) m/e 335 (M+H)+. HRMS (FAB) calcd m/e for C21H23N2O2ΗCI: 335.1760 (M+H)+. Found m/e 335.1762. Example 24 l-r(7-Aminoiminomethyl-2-methoxy- l-naphthalenyl)oxyl-3-ri -(3.4- dimethoxy)phenvIlpropane mono(hvdrochloride) salt
Example 24A l-Bromo-3-(3.4-dimethoxyphenyl)propane The title compound was prepared from 3-(3,4-dimethoxyphenyl)-l-propanol as described in Journal of the American Chemical Society, 95 , 8749 (1973), which is incorporated herein by reference, to provide the title compound. MS (DCI/NH3) m/e 276 (M+Nt D÷
Example 24B 1 -r(7-Cvano-2-methoxy- 1 -naphthalenyl)oxyl-3-r 1 -(3.4-dimethoxy)phenyl1propane The title compound was prepared from Examples 4A and 24A and the procedure of Example 10 A.
MS (DCI/NH3) m/e 395 (M+NH4)+.
Example 24C l-r(7-Aminoiminomethyl-2-methoxy- l-naphthalenyl)oxyl-3-π -(3.4- dimethoxy)phenyl1propane mono(hvdrochloride) salt
The title compound was prepared from Example 24B and the procedure of Example 21 B. I H NMR (300 MHz, DMSO-d6) δ 2.1 1 (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, I H), 7.70 (d, IH), 7.86 (d, IH), 8.10 (d, IH), 8.55 (s, I H), 9.15 (br s, 2H), 9.53 (br s, 2H) ; MS (DCI/NH3) m/e 395 (M+H)+.
Anal, calcd for C23H26N2O4-HC1-0.5H2O: 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 monoftrifiuoroacetate) salt
Example 25A 7-Methoxy-8-trifluoromethanesulfonyloxy-2-naphthalenecarbonitrile A solution of Example 4A (310 mg) in methylene chloride (5 mL) at 0 °C was treated with l,l,l-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (614 mg) and triethylamine (240 mL), stirred for 18 h at room temperature, diluted with methylene chloride (100 mL), washed with water and 20% aq NaOH, dried (MgSO4) and concentrated to provide 560 mg of the title compound as a white solid. MS (DCI) m/e 349 (M+H2O)+.
Example 25B Furan-2-boronic acid A solution of furan (5.3 mL, 73 mmole) in diethyl ether (67 mL) at -20 °C was treated with n-butyllithium (2.5 M in hexanes, 26 mL, 65 mmole), stirred for 2 hours at -20 °C and transferred by cannula to a -20 °C solution of triisopropyl borate (33 mL, 147 mmole) in diethyl ether (17 mL). The thick mixture was warmed to room temperature, treated with 3N HCl (200 mL) and extracted with diethyl ether. The extracts were washed with IN KOH, and the KOH layer was cooled to 0 °C and acidified with 6N HCl. The acidic solution was extracted with diethyl ether, and the acidic ether extracts were washed with brine, dried (MgSU4) and concentrated to provide the title compound. [H NMR (300 MHz, DMSO-d6) δ 6.45 (dd, IH), 7.05 (t, IH), 7.80 (dd, IH),
8.19 (s, 2H).
Example 25C 7-Methoxy-8-(2-furanyl)-2-naphthalenecarbonitrile Example 25 A (1.10 mmol) was combined with Pd(OAc)2 (0.1 1 mmol) and 1,1 '- bis(diphenylphosphino)ferrocene (0.22 mmol) in DMF (5 mL), stirred for 10 min, treated with Example 25B (1.32 mmol) and CS2CO3 (3.3 mmol), heated at 85 °C for 6 h, cooled to room temperature and chromatographed on silica gel with 10% ethyl acetate/hexane to provide the title compound. MS (DCI/NH3) m/e 250 (M+H)+.
Example 25D
8-(2-Furanyl)-7-methoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 25C and the procedure and purification in Example IB. lU NMR (300 MHz, DMSO-d6) δ 3.97 (s, 3H), 6.73 (m, IH), 6.80 (m, IH), 7.64 (dd, IH), 7.78 (d, IH), 7.91 (m, IH), 8.16 (d, IH), 8.20 (d, IH), 8.30 (s, IH), 9.08 (br s, 2H), 9.40 (br s, 2H);
MS (DCI/NH3) m/e 267 (M+H)+. Anal, calcd for Ci6Hι4N2O2-TFA: C, 56.85; H, 3.98; N, 7.37. Found: C, 56.68; H, 3.67; N, 7.35.
Example 26 methyl 6-(aminoiminomethyl)-4-[(methoxycarbonvDamino1-2-naphthalenecarboxylate mono(trifluoroacetate) salt
Example 26A 2-Cvano-l-nitro-6-carboxynaphthalene methyl ester A solution of 2-cyano-6-methylnaphthoate (5.2 g) in concentrated sufuric acid (75 mL) at 0 °C was treated with potassium nitrate (1.03 eq) in one portion, stirred for 10 min, poured onto ice (500 g) and extracted with ethyl acetate. The ethyl acetate layer was washed with water, IN NaOH and brine, dried (MgSO4), treated with silica gel and filtered. Concentration of the ethyl acetate to ca. 200 mL precipitated the product. The mixture was heated until all solid dissolved, treated with MeOH (20 mL) and ether (20 mL) and stirred overnight. The resulting solid was filtered and washed with methanol to provide 2.31 g of the title compound as a cream-colored solid. The mother liqueuor was evaporated, treated with methylene chloride (250 mL) then solid silica gel, filtered and concentrated. Crystalization from ethyl acetate/methanol provided an additional 1.6 g of product for a total yield: 3.91 g (62%). MS (DCI/NH3) m/e 257 (M+H)+.
Example 26B 2-Cvano-l-amino-6-carboxynaphthalene methyl ester A solution of Example 26A (lg, 3.9mmole) and 10% Pd on carbon (1 12 mg) in ethyl acetate (80 mL) was stirred under 1 atm of hydrogen for 9 h, purged with nitrogen for 1 h, filtered and evaporated to provide 810 mg (92%) of the title compound as a yellow solid. MS (DCI/NH3) m/e 227 (M+NH4)+.
Example 26C 6-Cvano-4- (methoxycarbonyl)aminol-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) and methylchloroformate (195 μL, 2.52 mmole), stirred for 2 h, treated with methanol (10 mL), stirred for an additional 10 minutes, diluted with methylene chloride (60 mL), washed with water and brine, dried (MgSO4) and evaporated. The residue was purified on silica gel using 10% ethyl acetate/hexane to provide 280 mg (59%) of light yellow solid. MS (DCI NH3) m e 285 (M+H)+.
Example 26D Methyl 6-(aminoiminomethyl)-4-r(methoxycarbonyl)amino1-2-naphthalenecarboxylate mono(trifluoroacetate) salt The title compound was prepared using Example 26C (125 mg, 0.44 mmol) and the procedure in Example 40D to provide 35mg of a white solid.
IH NMR (DMSO-d6) δ 3.78 (s, 3H), 3.95 (s, 3H), 7.89 (dd, IH), 8.37-8.40 (m, 3H), 8.53 (s, IH), 8.740 (s, IH) 9.18 (br s, 2H), 9.45 (br s, 2H), 9.90 (s, IH), 8.42 (s, IH), 8.63 (d, I H), 9.18 (br s, 4H), 10.58 (s, IH); MS (DCI/NH3) m/e 302 (M+H)+.
Anal, calcd for Cι5Hι5N3θ4-TFA- 1.5H2O: C, 46.16; H, 4.33; N, 9.50. Found: C, 45.96; 46.16; H, 4.06; N, 9.12.
Example 27 (E)-(7-Methoxy-8-r2-(Phenyl)ethenyfl l-2-naphthaleneimidamide mono(trifluoroacetate) salt
Example 27A (E)-(7-Methoxy-8-r2-(PhenvDethenvn }-2-naphthalenecarbonitrile
Example 25A and styrene boronic ester, prepared according to the procedure of Journal of the American Chemical Society, 97 5249 (1975), which is incorporated herein by reference, was processed according to the procedure described in Example 26B to provide the title compound. MS (DCI/NH3) m/e 303 (M+NH4)+.
Example 27B (EV <7-Methoxy-8-r2-(Phenyl)ethenvπ l-2-naphthaleneimidamide mono(trifluoroacetate) salt The title compound was prepared from Example 27 A and the procedure of Example IB. IH NMR (300 MHz, DMSO-d6) δ 3.98 (s, 3H), 7.28 (t, 2H), 7.39 (t, 2H), 7.64 (m, 5H), 8.00 (d, IH), 8.10 (d, IH), 8.62 (s, IH), 9.22 (br s, 2H), 9.42 (br s, 2H); MS (DCI/NH3) m/e 303 (M+H)+.
Anal, calcd for C2oHι8N20-TFA: C, 63.46; H, 4.60; N, 6.73. Found: C, 63.10; H, 4.73; N, 6.43.
Example 28 6-(4-Phenylbutvnyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 28 A
6-Hvdroxy-2-naphthalenecarbonitrile A solution of 6-bromo-2-naphthol (25.0 g, 112 mmol) and copper(I) cyanide (11 g, 123 mmol) in DMF (30 mL) was heated at 135 °C for 18 h, cooled, diluted with ethyl acetate (50 mL), triturated with 10% aq sodium hydroxide and filtered 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 (DCI/NH3) m/e 170 (M+H)+.
Example 28B
6-(Trifluoromethanesulfonyloxy)-2-naphthalenecarbonitrile A solution of Example 28A (14.01 g, 82.8 mmol) and triethylamine (9.2 g, 91.1 mmol) in methylene chloride (40 mL) at 0 °C was treated dropwise with trifluoromethylsulfonic anhydride (28 g, 99.4 mmol), warmed to 25 °C for 48 h, concentrated, redissolved in ethanol (50 mL) and triturated with water to precipitate 8.4 g of the title compound. MS (DCI/NH3) m/e 319 (M+NH4)+.
Example 28C 6-(4-Phenylbutvnyl)-2-naphthalenecarbo nitrile The title compound was prepared from Example 28B, 4-phenyl- 1 -butyne and the procedure of Example 57B. MS (DCI/NH3) m/e 299 (M+NH )+.
Example 28D 6-(4-PhenvIbutvnyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 28C and the procedure of Example IB. IH NMR (300 MHz, DMSO-d6) δ 2.80 (t, 2H), 2.95 (t, 2H), 7.22 (m, IH), 7.36 (m, 4H), 7.58 (d, IH), 7.82 (d, IH), 8.05 (d, IH), 8.10 (d, 2H), 8.45 (s, IH), 9.10 (br s, 2H), 9.42 (br s, 2H);
MS (DCI/NH3) m/e 299 (M+H)+.
Anal, calcd for C2iHi8N2-TFA-0.75H2O: C, 64.86; H, 4.85; N, 6.58. Found: C, 64.78; H,
4.64; N, 6.03.
Example 29
7-(2-Hvdroxyethoxy)-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 29A 3-ITπ .1 -DimethvIethyPdimethylsilylloxyl- 1 -propanol. 4-nitrobenzenesulfonate A solution of 3-t-butlydimethylsiloxy-l -propanol, prepared by the method of
McDougal, et al. JOC, 1986, 51, 3388, which is incorporated herein by reference, (7.6 g, 40 mmol) and diisopropylethylamine (10.4 mL, 60 mmol) in methylene chloride (200 mL) at 0 °C was treated with p-nitrophenylsulfonyl chloride (9.7 g, 44 mmol), stirred for 3 h, poured into saturated NaHCO3 and extracted with diethyl ether. The extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel with 5% ethyl acetate/hexanes to provide 6.00 g of the title compound. MS (DCI/NH3) m/e 395 (M+NH4)+.
Example 29B 7-r2-π (l .l-Dimethylethyl)dimethylsilylloxylethoxy1-8-iodo-2-naphthalenecarbonitriIe
The title compound was prepared in a manner analogous to that of Example 43A but substituting Example 29A for propyl iodide. MS (DCI/NH3) m/e 468 (M+H)+.
Example 29C
7-(2-Hvdroxyethoxy)-8-iodo-2-naphthalenecarbonitrile The title compound was prepared in a manner analogous to that of Example 53F but substituting Example 29B for Example 53E. MS (DCI/NH3) m/e 357 (M+H)+. Example 29D 7-(2-Hvdroxyethoxy)-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 29B according to the procedure of Example IB.
IH NMR (300 MHz, DMSO-d6) δ 1.96 (m, 2H), 3.69 (t, 2H), 4.33 (t, 2H), 4.58 (br, I H), 7.63 (d, IH), 7.66 (dd, IH), 8.12 (dd, 2H), 8.42 (s, IH), 9.20 (s, 2H), 9.53 (s, 2H); MS (DCI/NH3) m/e 245 (M+H)+;
Anal, calcd for Ci3Hi2N2O2I-TFA-0.21H2O: 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(trifluoroacetate) salt
Example 30A
7-(2-Hvdroxyethoxy)-2-naphthalenecarbonitrile Example 29B (120 mg, 0.26 mmol), palladium(II)Cl2dppf (46 mg, 0.03 mmol) and diisopropylamine (263 mg, 2.6 mmol) were heated in a sealed tube for 2 h at 100 °C, cooled to room temperature, diluted with ethyl acetate, washed with water, dried (Na2Sθ4), and concentrated. The residue was purified on silica gel with 15% ethyl acetate/hexanes to provide 85 mg of the title compound. MS (DCI NH3) m/e 342 (M+H)+.
Example 30B 7-(2-Hvdroxyethoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 29B according to the procedure of
Example I B.
I H NMR (300 MHz, DMSO-d6) δ 1.96 (m, 2H), 3.69 (t, 2H), 4.33 (t, 2H), 4.58 (br, IH), 7.63 (d, IH), 7.66 (dd, IH), 8.12 (dd, 2H), 8.42 (s, IH), 9.20 (s, 2H), 9.53 (s, 2H); MS (DCI/NH3) m/e 228 (M+H)+; Anal, calcd for C14H15N2O2 FA: C, 53.78; H, 4.51; N, 7.84. Found: C, 53.60; H, 4.30; N, 7.81.
Example 31 6-(4-Methyl- 1 -pentvnyP-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 31 A 6-(4-Methyl- 1 -pentvnyl)-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, 4-methyl-l-pentyne and the procedure of Example 57B.
MS (DCI/NH3) m e 251 (M+NH4)+.
Example 3 IB 6-(4-Methyl- 1 -pentynvD-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 31 A and the procedure of Example IB.
IH NMR (300 MHz, DMSO-d6) δ 1.05 (d, 6H), 1.90 (m, IH), 2.20 (d, 2H), 7.62 (dd, IH), 7.82 (dd, IH), 8.09 (d, IH), 8.12 (d, IH), 8.18 (s, IH), 8.48 (s, IH), 9.12 (br s, 2H), 9.42 (br s, 2H);
MS (DCI/NH3) m/e 251 (M+H)+. Anal, calcd for Cι7Hi8N -TFA: C, 62.63; H, 5.26; N, 7.69. Found: C, 64.85; H, 5.32; N, 7.46.
Example 32 6-(5-Phenylpentynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 32A 6-(5-Phenylpentynyl)-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, 5-phenyl-l-pentyne and the procedure of Example 57B. MS (DCI/NH3) m/e 313 (M+NH4)+.
Example 32B 6-(5-PhenylpentvnvD-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 32A and the procedure of Example IB. !H NMR (300 MHz, DMSO-d6) δ 1.90 (m, 2H), 2.80 (t, 2H), 3.39 (t, 2H), 7.19-7.37 (m, 5H), 7.62 (dd, IH), 7.82 (dd, IH), 8.08 (d, IH), 8.15 (d, IH), 8.18 (s, IH), 8.48 (s, IH), 9.15-9.45 (br d, 4H); MS (DCI/NH3) m/e 313 (M+H)+ Anal, calcd for C22H2θN2'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- 1 -propynyD-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 33A 6-(3-Phenyl- 1 -propynvD-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, 3-phenyl- l-propyne and the procedure of Example 57B.
MS (DCI/NH3) m e 285 (M+NH4J+.
Example 33B
6-(3-Phenyl- 1 -propynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 33A and the procedure of Example 5B. lH NMR (300 MHz, DMSO-d6) δ 4.00 (s, 2H), 7.28-7.50 (m, 5H), 7.70 (dd, IH), 7.85 (dd,
IH), 8.09 (d, IH), 8.15 (d, IH), 8.21 (s, IH), 8.49 (s, IH), 9.21 (br s, 2H), 9.45 (br s, 2H);
MS (DCI/NH3) m/e 285 (M+H)+.
Anal, calcd for C2oHi6N -TFA-0.25H2O: C, 65.59; H, 4.38; N, 6.95. Found: C, 65.43; H, 3.95; N, 6.70.
Example 34 6-(PhenylethynyP-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 34A
6-(PhenylethynyP-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, phenylacetylene and the procedure of Example 57B. MS (DCI/NH3) m/e 271 (M+NH4)+.
Example 34B
6-(PhenylethvnvP-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 34A and the procedure of Example IB. *H NMR (300 MHz, DMSO-d6) δ 7.49 (t, 3H), 7.62 (m, 2H), 7.80 (dd, IH), 7.86 (dd, IH), 8.15 (d, IH), 8.19 (d, IH), 8.38 (s, IH), 8.52 (s, IH), 9.38 (br s, 4H); MS (DCI/NH3) m/e 271 (M+H)+.
Anal, calcd for C19H14N2 FA: C, 65.62; H, 3.93; N, 7.29. Found: C, 65.64; H, 4.1 1 ; N,
7.21.
Example 35
3-Amino-N-r3-r6-(aminoiminomethyl)-2-naphthalenyl1-2-propynyllbenzamide mono(trifluoroacetate) salt
Example 35A 6-(3-Amino- 1 -propynyl)-2-naphthalenecarbo nitrile
The title compound was obtained from Example 28B, propargyl amine and the procedure of Example 41 A. MS (DCI/NH3) m/e 207 (M+NH4)+.
Example 35B
3-Amino-N-[3-(6-cyano-2-naphthalenyl)-2-propynyllbenzamide A solution of Example 35A (100 mg, 0.49 mmole), 3-aminobenzoic acid (73 mg, 0.53 mmole), EDC (141 mg, 0.74 mmole) and DMAP (89mg, 0.74 mmole), in THF (5.5 mL) was stirred at room temperature for 2.5 h and concentrated. The residue was dissolved in methylene chloride, washed with IN HCl, water, saturated NaHCO3, and brine, dried (MgSO4), concentrated and purified by flash chromatography on silica gel with 2% ethanol/methylene chloride to provide the title compound. MS (DCI/NH3) m/e 326 (M+H)+.
Example 35C
3-Amino-N-r3-r6-(aminoiminomethyl)-2-naphthalenvn-2-propynynbenzamide mono(trifluoroacetate) salt The title compound was prepared from Example 35B and the procedure of Example IB. *H NMR (300 MHz, DMSO-d6) δ 4.32 (d, 2H), 5.69 (br s, 2H), 6.58 (d, 2H), 7.62 (m, 3H), 7.82 (d, IH), 8.08 (d, IH), 8.14 (d, IH), 8.20 (s, IH), 8.43 (s, IH), 8.60 (t, IH), 9.19 (br s, 2H), 9.42 (br s, 2H); MS (DCI/NH3) m/e 343 (M+H)+.
Anal, calcd for C2iHi8N4O-TFA-0.25H2O: C, 59.93; H, 4.26; N, 12.16. Found: C, 59.86; H, 3.97; N, 1 1.93. Example 36 4-Amino-N-r3-(6-aminoiminomethyl-2-naphthalenvD-2-propynyllbenzamide mono(trifluoroacetate) salt
Example 36A 4-Amino-N-r3-(6-cvano-2-naphthalenvI)-2-propynyllbenzamide Example 35A and 4-aminobenzoic acid were subjected to the conditions described in Example 35B to afford the title compound. MS (DCI/NH3) m/e 326 (M+H)+.
Example 36B 4-Amino-N-r3-(6-aminoiminomethyl-2-naphthalenyl)-2-propynyl1benzamide mono(trifluoroacetate) salt The title compound was prepared from Example 36A and the procedure of Example 5B. l NMR (300 MHz, DMSO-d6) δ 4.38 (d, 2H), 6.89 (m, IH), 7.20 (m, 2H), 7.22 (s, I H), 7.63 (dd, IH), 7.82 (dd, IH), 8.09 (d, IH), 8.12 (d, IH), 8.20 (s, I H), 8.46 (s, IH), 8.95 (t, IH), 9.19 (br s, 2H), 9.42 (br s, 2H); MS (DCI/NH3) m/e 343 (M+H)+. Anal, calcd for C2ιHι6N4O-2.5TFA: C, 49.27; H, 3.19; N, 8.54. Found: C, 49.27; H, 3.33; N, 8.89.
Example 37 (S)-2-Amino-N-π -f(6-aminoiminomethyl-2-naphthalenvDcarbonvncvclohexynpropionamide bis(trifluoroacetate) salt
Example 37A 6-r(l -Aminocvclohexyl)ethvnyll-2-naphthalenecarbonitrile The title compound was obtained from Example 28B, 1-ethynylcyclohexylamine and the procedure of Example 41 A.
MS (DCI/NH3) m/e 275 (M+NH4)+.
Example 37B (S)-2-Amino-N-ri-r(6-cvano-2-naphthalenyDcarbonyllcvclohexyllpropionamide Example 37A and N-(t-butoxycarbonyl)-L-alanine were subjected to the conditions described in Example 35B to provide the title compound. MS (DCI/NH3) m/e 446 (M+H)+.
Example 37C rS)-2-Amino-N-ri-r(6-aminoiminomethyl-2-naphthalenyl)carbonyllcvclohexyllpropionamide bis(trifluoroacetate) salt The title compound was a rearrangement product of Example 37B resulting from the procedure of Example 5B. lH NMR (300 MHz, DMSO-d6) δ 1.24 (d, 3H), 1.40-1.62 (m, 8H), 2.15-2.26 (s, IH), 2.29-
2.38 (s, IH), 3.51 (d, IH), 3.78 (d, IH), 3.82 (s, IH),
7.90 (dd, 2H), 8.09 (dd, IH), 8.18 (d, IH), 8.37 (d, IH), 8.55 (s, IH), 8.78 (s, IH), 9.31 (s, 2H), 9.50 (s, 2H); MS (DCI/NH3) m/e 381 (M+H)+. Anal, calcd for C23H28N402-2TFA-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) salt
Example 38A 8-Hydroxy-6-methoxy-3. 4-dihvdro-2H-naphthalen- 1 -one A solution of 6, 8-dimethoxy-3, 4-dihydro-2H-naphthalen-l-one (15 g, 72.8 mmole), prepared according to the procedure of J. Chem. Soc, London 2782 (1955), which is incorporated herein by reference, in methylene chloride (150 mL) at 0 °C was treated portionwise with AICI3 (14.3 g, 107 mmole), stirred for 20 h at room temperature, poured onto ice with stirring and extracted with methylene chloride when the ice melted. The extracts were washed with water and brine, dried (MgSO4) and concentrated to provide 13.8 g of the title compound. MS (DCI/NH3) m/e 193 (M+H)+
Example 38B 8-Benzyloxy-6-methoxy-3,4-dihydro-2H-naphthalen- 1 -one A mixture of Example 38A (2.5 g, 13 mmole), benzyl bromide (2.1 mL, 17.8 mmole), K2CO3 powder (14.3 g, 100 mmole), and 2-butanone (88 mL) was stirred at reflux for 4 h, treated with additional benzyl bromide (1.0 mL, 8.5 mmole), stirred at reflux for an additional 3 h, cooled to room temperature, filtered and concentrated. The residue was dissolved in methylene chloride, washed with IN HCl, water and brine, dried (MgSO4) and concentrated. The crude product was purified on silica gel with 30% ethyl acetate/hexanes to provide the title compound. MS (DCI/NH3) m/e 283 (M+H)+.
Example 38C
3.4-Dihvdro-2-(hvdroxymethylene)-6-methoxy-8-(phenylmethoxy)-l(2H)-naphthalenone Sodium metal (1.29 g, 55.9 mmole) was added portionwise to a mixture of ethanol (4.2 mL) and benzene (15 mL). The mixture was stirred at reflux for 1.5 h, cooled to 0 °C and treated dropwise with ethyl formate (5.6 mL, 70 mmole) then dropwise with of a solution of Example 38B (6.7g, 23.8 mmole) in benzene (20 mL), stirred at room temperature for 2 h, cooled to 0 °C, treated sequentially with ice/water and 6N HCl (75 mL) and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated to provide the title compound.
MS (DCI/NH3) m/e 311 (M+H)+.
Example 38D 4.5-Dihydro-7-methoxy-9-(phenylmethoxy)naphthr2.1-dlisoxazole r2.1-d1isoxazole A suspension of Example 38C (7.5 g, 24.3 mmole), hydroxylamine hydrochloride (4.0 g, 57.6 mmole) and acetic acid (63 mL) was stirred at 1 10 °C for 7 min, cooled to room temperature, diluted with water and extracted with methylene chloride. The extracts were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by flash chromatography on silica gel with 30% ethyl acetate/hexanes to provide the title compound. MS (DCI NH3) m/e 308 (M+H)+.
Example 38E 8-Benzyloxy-2-cyano-6-methoxy-3.4-dihydronaphthalen-l-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 mmole) in benzene (50 mL), stirred at room temperature for 4.5 h, treated sequentially with water and IN HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated to provide the title compound. MS (DCI/NH3) m/e 308 (M+H)+.
Example 38F 2-Cyano-6-rnethoxy-8-Benzyloxy-3.4-dihvdronaphthalene A suspension of Example 38E (2.6 g, 8.6 mmole) in absolute ethanol (25 mL) at room temperature was treated portionwise with NaBH (1.6 g), stirred for 20 min at room temperature and for 20 min at reflux, cooled to room temperature, treated with water (20 mL) and concentrated. The residue was dissolved in methylene chloride, washed with water and brine, dried (MgSO ), filtered and concentrated to provide 2.6 g of an orange foam. The foam was stirred at reflux for 20 min with p-toluenesulfonic acid monohydrate (0.52 g, 2.7 mmole) in benzene (52 mL), cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated to provide the title compound. MS (DCI/NH3) m/e 309 (M+NH4J+.
Example 38G
2-Cvano-6-methoxy-8-benzyloxynaphthalene A solution of Example 38F (0.4 g, 1.4 mmole), 2,3-dichloro-5,6-dicyano-l,4- benzoquinone (0.79 g, 3.5 mmole) in benzene (40 mL) was stirred at reflux for 4 hours, treated with additional 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (0.4 g, 1.8 mmole), stirred at reflux for an additional 5 h, cooled to room temperature, diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried (MgSO4) and concentrated to provide the title compound. MS (DCI/NH3) m/e 290 (M+H)+.
Example 38H 8-Benzyloxy-6-methoxy-2-naphthalenecarboximidamide ono(trifluoroacetate) salt
The title compound was prepared from Example 38G and the procedure of Example IB. IH NMR (300 MHz, DMSO-d6) δ 4.38 (d, 2H), 6.89 (m, IH), 7.20 (m, 2H), 7.22 (s, IH), 7.63 (dd, IH), 7.82 (dd, IH), 8.09 (d, IH), 8.12 (d, IH), 8.20 (s, IH), 8.46 (s, IH), 8.95 (t, IH), 9.19 (br s, 2H), 9.42 (br s, 2H); MS (DCI/NH3) m e 307 (M+H)+.
Anal, calcd for Ci9Hi8N2O2-TFA: C, 60.00; H, 4.56; N, 6.66. Found: C, 59.93; H, 4.46; N,
6.51.
Example 39
2-l(7-Aminoiminomethyl-3-methoxy- 1 -naphthalenvDoxylacetamide mono(trifluoroacetate) salt
Example 39A 6-Methoxy-8-hydroxy-2-naphthalenecarbonitrile A mixture of Example 38G (1.62 g, 5.6 mmole) and 10% dry Pd/C (0.50 g) in methanol (150 mL) was hydrogenated in a Parr shaker at room temperature under 4 atm for 30 h. The mixture was filtered and concentrated to provide the title compound. MS (DCI/NH3) m/e 217 (M+NH4)+.
Example 39B
2-F(7-Cvano-3-methoxy- 1 -naphthalenvDoxylacetamide Example 39A and 2-bromoacetamide were subjected to the conditions described in Example 5A to provide the title compound. MS (DCI/NH3) m/e 274 (M+NFL ÷.
Example 39C 2-r(7-Aminoiminomethyl-3-methoxy- 1 -naphthalenvDoxylacetamide mono(trifluoroacetate) salt The title compound was prepared from Example 39B and the procedure of Example IB. ] H NMR (300 MHz, DMSO-d6) δ 3.93 (s, 3H), 4.70 (s, 2H), 6.70 (d, IH), 7.09 (d, IH), 7.65 (s, 2H), 7.82 (dd, I H), 7.99 (d, IH), 8.70 (s, IH), 9.05 (s, 2H), 9.38 (s, 2H); MS (DCI/NH3) m/e 274 (M+H)+.
Anal, calcd for Cι4Hι5N3θ3-TFA: C, 49.62; H, 4.16; N, 10.85. Found: C, 49.68; H, 4.24; N, 10.61.
Example 40
N-(6-aminoiminomethyI-2-naphthalenyl)-N'-phenylurea mono(trifluoroacetate) salt
Example 40A 6-Cvano-2-naphthalenecarbonyl chloride A suspension Example 8E (4.4 g, 22.3 mmol) in toluene (100 mL) was treated with thionyl chloride (6.0 mL) and DMAP (5 mg), heated at 55 °C for lh, treated with additional thionyl chloride (3 mL), warmed to 95 °C for lh, cooled to room temperature, stirred in hexane (75 mL) for 2.5 h and fltered to provide 3.62 of the title compound as a white powder. The filtrate was concentrated and triturated with ether to provide an additional 1.02 g of the title compound. MS (DCI/NH3) m/e 215 (M+H)+.
Example 40B 2-Cvano-6-naphthoyl azide
A solution of Example 40A (1.65 g, 7.65 mmole) in acetone (600 mL) at room temperature was treated with a solution of sodium azide (3 g, 46 mmole) in water (10 mL), stirred for 1.5 h and diluted with water (60 mL). The resulting solid was filtered, washed with water and dried to provide 4.24 g of the title compound as a white powder. MS (DCI/NH3) m/e 240 (M+NH4)+.
Example 40C N-(6-cvano-2-naphthalenyl)-N'-phenylurea A solution of Example 40B (221.2 mg, 1 mmole) in toluene (18 mL) was heated at 85 °C for 1 h then at 95 °C for 1.5 h, cooled to room temperature, treated with aniline (240 μL, 2.63 mmole), stirred for 25 min and treated with ether (10 mL). The resulting solid was collected, washed with ether and dried under vacuum to yield 230 mg of white powder. MS (DCI/NH3) m e 305 (M+NHι)+.
Example 40D
N-(6-amJnoiminomethyl-2-naphthaIenyP-N'-phenylurea mono(trifluoroacetate) salt A solution of Example 40C (148 mg, 0.5 mmole) in 10: 1 pyridine:triethylamine (10 mL) was treated with H2S for 5 min, stirred at room temperature for 18 h and concentrated. The resulting solid was dissolved in acetone (15 mL), treated with iodomethane (0.8 mL, 12.8 mmole), stirred for 2 h, diluted with ether (10 mL), filtered, washed with ether and dried under vacuum. The resulting solid was dissolved in methanol, treated with 2N NH3 in methanol (2 mL), warmed to 50 °C for 4 h and concentrated. The product was purified according to the procedure described in Example IB to provide 62 mg of the title compound. !H NMR (300 MHz, DMSO-d6) δ 7.00 (t, IH), 7.31 (dd , 2H), 7.52 (d, IH), 7.65 (dd, IH), 7.76 (dd, IH, 8.02 (d, 2H), 8.30 (s, IH), 8.39 (s, IH), 9.05 (br s, 2H), 9.11 (s, IH), 9.33 (br s, 2H), 9.42 (s, IH); MS (DCI/NH3) m/e 305 (M+H)+;
Anal, calcd for Cι8Hι6N4O-TFA: C, 57.42; H, 4.10; N, 13.39. Found: C, 57.50; H, 4.05; N, 13.08.
Example 41 (E)-6-r2-(Phenyl)ethenyIl-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 41 A
(E)-6-r2-(PhenvPethenvn-2-naphthalenecarbonitrile A solution of Example 28B (350 mg, 1.16 mmol), styrene (157 mg, 1.51 mmol), palladium (II) acetate (26 mg, 0.12 mmol), triphenylphosphine (61 mg, 0.23 mmol), triethylamine (2 mL) and acetonitrile (1 mL) in a sealed tube with minimal head volume was heated at 100 °C for 19 h, diluted with ethyl acetate (20 mL), washed with water, dried
(MgSθ4) and concentrated with silica gel (4 g). The mixture was chromatographed on silica gel with 10% ethyl acetate/hexane to provide 160 mg of the title compound. MS (DCI/NH3) m/e 273 (M+NH4)+.
Example 41B
(E)-6-r2-(Phenyl)ethenyll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 41 A from the procedure of Example
I B.
IH NMR (300 MHz, DMSO-d6) δ 7.33 (t, IH), 7.4 (t, 2H), 7.5 (d, 2H), 7.69 (d, IH), 7.70 (d, IH), 7.81 (dd, IH), 8.03 (dd, IH), 8.10 (d, IH), 8.13 (d, IH), 8.17 (s, IH), 8.44 (s,
I H), 8.97 (s, 2H), 9.41 (s, 2H);
MS (DCI/NH3) m/e 273 (M+H)+ ;
Anal, calcd for Cι9Hi6N2-TFA: C, 65.28; H, 4.43; N, 7.25. Found: C; 64.95; H, 4.60; N,
6.42.
Example 42 6-r2-(Phenyl)ethvH-2-naphthalenecarboximidarrude mono(trifluoroacetate) salt
Example 42A 6-r2-(Phenyl)ethyn-2-naphthalenecarbonitrile A mixture of Example 57B (80 mg, 0.31 mmol) and palladium on carbon (20% water, 50 mg) in methanol (5 mL) was stirred under 1 atm of hydrogen for 0.5 h, filtered and concentrated to provide 72 mg of the title compound. MS (DCI/NH3) m/e 275 (M+NH4) -.
Example 42B 6-r2-(Phenyl)ethyl1-2-naphthalenecarboximidamide mono(trifluoroaceτate) salt The title compound was prepared from Example 42 A and the procedure of Example IB. !H NMR (300 MHz, DMSO-d6) δ 3.03 (m, 2H), 7.23 (m, 5H), 7.60 (dd, IH), 7.76 (dd, IH), 7.85 (s, IH), 8.03 (t, 2H), 8.42 (s, IH), 8.99 (s, 2H), 9.39 (s, 2H); MS (DCI/NH3) m/e 275 (M+H)+.
Anal, calcd for Ci9Hι8N2O- 1.33TFA: 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-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 43A 7-propoxy-8-iodo-2-naphthalenecarbonitrile
Example 53A (65 mg, 0.25 mmol) in DMF (2 mL) was treated with propyl iodide (40 mL), stirred at 65 °C for 1 h, diluted with water and extracted with diethyl ether. The organic extracts were dried (MgSO4) and concentrated, and the residue was purified on silica gel with 10% ethyl acetate/hexanes to provide 160 mg of the title compound. MS (DCI/NH3) m/e 355 (M+H)+.
Example 43B 7-Propoxy-8-iodo-2-naphthalenecarboximidamide ono(trifluoroacetate) salt The title compound was prepared from the product in Example 43A according to the procedure of Example IB.
IH NMR (300 MHz, DMSO-d6) δ 1.09 (t, 3H), 1.82 (m, 2H), 4.23 (t, 2H), 7.62 (d, IH), 7.65 (dd, IH), 8.12 (dd, 2H), 9.15 (s, 2H), 9.42 (s, IH), 9.53 (s, 2H); MS (DCI/NH3) m/e 355 (M+H)+. Anal, calcd. for Ci4Hi5N2OI-TFA-0.26C7Hg: 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) salt
Example 44A ( ± )-6-(3-Phenyloxiranyl)-2-naphthalenecarbonitrile A solution of Example 41 A (69 mg, 0.27 mmol) and m-chloroperbenzoic acid (70 mg, 0.41 mmol) in methylene chloride (3 mL) was stirred at 25 °C for 3 days, concentrated, loaded on a silica gel column (pretreated with 0.1% triethylamine in ethyl acetate) and eluted with 10% ethyl acetate/hexane) to provide 72 mg of the title compound. MS (DCI/NH3) m/e 289 (M+NH4)+
Example 44B
(± )- 6-(3-Phenyloxiranyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared with Example 44A from the procedure of Example IB. lH NMR (300 MHz, DMSO-dό) δ 4.24 (d, IH), 4.35 (d, IH), 7.43 (m, 5H), 7.67 (dd, IH), 7.83 (dd, IH), 8.12 (s, IH), 8.13 (d, IH), 8.16 (d, IH), 8.50 (s, IH), 9.03 (s, 2 H), 9.44 (s, 2H);
MS (DCI NH3) m/e 289 (M+H)+.
Anal, calcd for Ci9Hι6N2O- 1.3 TFA: 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)ethenyll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 45 A
2-Vinylthiophene A suspension of methyltriphenylphosphonium bromide (19.13 g, 53.5 mmol) in THF (100 mL) was treated dropwise with 2M butyllithium in THF (17.8 mL) then dropwise with 2- carboxythiophene (5 g, 44.6 mmol), stirred for 30 min then distilled at 74-78 °C to provide the title compound.
MS (DCI/NH3) m/e 1 1 1 (M+H)+.
Example 45B (E)-6-r2-(2-Thienyl)ethenyl1-2-naphthalenecarbonitrile The title compound was prepared from the product of Example 45A and the procedure of Example 41 A. MS (DCI/NH3) m/e 279 (M+NH )+.
Example 45C (E)-6-r2-(2-ThienyDethenyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 45B and the procedure of Example IB. ' H-NMR (300 MHz, DMSO-d6) δ 7.12 (dd, 2H), 7.15 (d, IH), 7.32 (d, IH), 7.6 (d, IH), 7.74 (d, IH), 7.80 (dd, I H), 7.9-8.1 (m, 3H), 8.14 (s, IH), 8.43 (s, IH), 9.03 (s, 2H), 9.42 (s, 2H);
MS (DCI/NH3) m/e 279 (M+H)+;
Anal, calcd. for Cι7Hi4N2θ2S-TFA: C, 53.77; H, 3.56; N, 6.60. Found: C; 54.88; H, 3.66; N, 6.45.
Example 46 6-(3-Oxobutyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 46A
6-(3-Oxobutyl)-2-naphthalenecarbonitrile The title compound was prepared from Example 28B, l-buten-3-ol and the procedure of Example 41 A. MS (DCI/NH3) m/e 241 (M+NH4)+
Example 46B 6-(3-Oxobutyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 46 A and the procedure of ExamplelB.
-84-
SUBST1TUTE SHEET (RULE 26) IH NMR (300 MHz, DMSO-d6) δ 2.13 (s, IH), 2.94 (m, 4H), 7.57 (dd, IH) 7.78 (dd, IH), 7.85 (s, IH), 8.01 (d, IH), 8.05 (d, IH), 8.43 (s, IH), 8.48 (m, 2H), 9.06 (s, 2H), 9.40 (s, 2H);
MS (DCI/NH3) m/e 241 (M+H)+; Anal, calcd. for Cι5Hι6N2O 1.3TFA: C, 54.31; H, 4.48; N, 7.19. Found: C; 54.33; H, 4.35; N, 7.27.
Example 47 6-(3-Methoxyphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
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 l-l'-bis(diphenyphosphino)ferrocene (111 mg, 0.2 mmol) was stirred in DMF (3 mL) for 15 min, treated with CS2CO3 (813 mg, 2.5 mmol) and 3-methoxyphenylboronic acid (228 mg, 1.5 mmol), stirred for 20 min at 80 °C, cooled, treated with pH 7 buffer (10 mL) and extracted with diethyl ether. The ether extracts were dried (MgSO4), concentrated and purified on silica gel with 10% ethyl acetate/hexane to provide 140 mg of the title compound as a white solid. MS (DCI/NH3) m/e 277 (M+NH4J+.
Example 47B 6-(3-Methoxyphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 47 A and the procedure of Example IB. H NMR (300 MHz, DMSO-d6) δ 3.88 (s, 3H), 7.03 (m, IH), 7.44 (m, 3H), 7.84 (dd, IH), 8.05 (dd, I H), 8.19 (d, IH), 8.21 (d, IH), .41 (s, IH), 8.51 (s, IH), 9.1 1 (s, 2H), 9.45 (s, 2H);
MS (DCI/NH3) m e 277 (M+H)+;
Anal, calcd for Cι8Hι6N2θ-TFA-0.2H2O: C, 61.03; H, 4.45; N, 7.12. Found: C; 61.03; H, 4.11; N, 6.86.
Example 48 N-r3-(methyl)phenvπ-6-aminoiminomethyl-2-naphthalenecarboxamide mono(trifluoroacetate) salt Example 48 A N-r3-(methyl)phenyl1-6-cvano-2-naphthalenecarboxamide The title compound was prepared from 3-methyl phenylis.ocyanate, Example 55C and the procedure from Example 55C. MS (DCI/NH3) m/e 287 (M+H)+
Example 48B N-r3-(methyl)phenyll-6-aminoiminomethyl-2-naphthalenecarboxarrιide mono(trifluoroacetate) jjalt
The title compound was prepared from Example 48A and the procedure of Example IB. IH NMR (300 MHz, DMSO-d6) δ 2.34 (s, 3H), 6.96 (d, IH), 7.27 (t, IH), 7.62 (d, IH), 7.66 (s, I H), 7.91 (dd, IH), 8.15 (dd, IH), 8.29 (d, IH), 8.31 (d, IH), 8.54 (s, IH), 8.68 (s, I H), 9.15 (s, 2H), 9.49 (s, 2H), 10.46 (s, IH); MS (DCI/NH3) m/e 304 (M+H)+;
Anal, calcd for Ci9Hi7N3O-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-Formylphenoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 49A 6-(2-Formylphenoxy)-2-naphthalenecarbonitrile A solution of 2-hydroxybenzaldehyde (72 mg, 0.59 mmol), 6-bromo- l -cyanonaphthalene ( 150 mg, 0.65 mmol), and CS2CO3 (248 mg,
0.76 mmol) in DMF (10 mL) was heated at 90 °C for 2 days, treated with water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated, and the crude product was purified by column chromatography with 10% ethyl acetate/hexane to provide 40 mg of the title compound. MS (DCI/NH3) m/e 291 (M+NH4)+.
Example 49B 6-(2-Formylphenoxy)-2-naphthalenecarboxirnidamide mono(trifluoroacetate) salt The title compound was prepared with Example 49A and the procedure of Example IB. 1H-NMR (300 MHz, DMSO-d6) δ 7.19 (d, IH), 7.44 (t, IH), 7.56 (s, IH), 7.60 (d, IH), 7.79 (m, 2H), 7.94 (dd, IH), 8.01 (d, IH), 8.2 (d, IH), 8.51 (s, IH), 9.03 (s, 2H), 9.41 (s, 2H), 10.35 (s, IH); MS (DCI/NH3) m/e 291 (M+H)+. Anal, calcd. for Cι8H14N2θ2-TFA- 1.7H2O: 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) salt
Example 50A 6-(2-FormylphenvD-2-naphthalenecarbonitrile The title compound was prepared from Example 28B, 2-formylphenylboronic acid and the procedure of Example 47A. MS (DCI/NH3) m/e 275 (M+NH ÷.
Example 50B 6-(2-Formylphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 50A and the procedure of Example IB. 'H NMR (300 MHz, DMSO-d6) δ 7.71-7.64 (m, 2H), 7.79 (d, IH), 7.81 (s, IH), 7.88 (dd, 1H),7.9 (d, IH), 8.16 (d, IH), 8.23 (t, 2H), 8.56 (s, IH), 9.05 (s, 2H), 9.48 (s, 2H), 9.92 (s, IH);
MS (DCI/NH3) m/e 275 (M+H)+;
Anal, calcd for Cι8Hi4N2O-TFA: C, 61.86; H, 3.89; N, 7.21. Found: C; 61.98; H, 3.59; N, 6.88.
Example 51 6-r2-(Hvdroxymethyl)phenvn-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 51 A
6-r2-(Hvdroxymethyl)l-2-naphthalenecarbonitrile Example 50A (98 mg, 0.38 mmol) and sodium borohydride (15 mg, 0.80 mmol) were dissolved in methanol (10 mL) and stirred for 0.5 h. The solution was concentrated, and the residue was purified on silica gel with 30% ethyl acetate/hexane to provide 90 mg of the title compound.
MS (DCI/NH3) m/e 277 (M+NH4)+.
Example 5 IB
6-r2-(HvdroxymethvDphenyl1-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 51 A and the procedure of Example IB. 'H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 2H), 9.06 (s, 2H), 8.54 (s, IH), 8.16 (t, 2H), 8.07 (s, IH), 7.85 (dd, IH), 7.74 (dd, IH), 7.63 (d, IH), 7.49-7.34 (m, 3H), 4.46 (s, 2H);
MS (DCI/NH3) m/e 277 (M+H)+;
Anal, calcd. for Ci8Hι6N2O- 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 -butenvD-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 52A 6-(3-Oxo- 1 -butenyl)-2-naphthalenecarbonitrile The title compound was prepared from methyl acrylate, Example 28B and the procedure of Example 41 A. MS (DCI/NH3) m/e 222 (M+H)+.
Example 52B 6-(3-Oxo- 1 -butenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 52A and the procedure of Example IB.
!H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 2H), 9.13 (s, 2H), 8.48 (s, IH), 8.38 (s, I H), 8.18 (d, IH), 8.15 (d, IH), 8.01 (dd, IH), 7.85 (dd, IH), 7.82 (d, IH), 7.03 (d, IH), 2.40 (s, IH);
MS (DCI/NH3) m/e 239 (M+H)+. Anal, calcd for Cι5Hι4N2O- 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-( 1 H-pyrazol-4-vD-2-naphthalenecarboximidamide bis(trifluoroacetate) salt Example 53A 7-hvdroxy-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 at room temperature for 3 h, acidified with 1M HCl and extracted with ethyl acetate. The extracts were washed with saturated Na2S2U3 and brine, dried (Na2SO4) and concentrated. The product was recrystallized from ethyl acetate to yield 33 g of the title compound. MS (DCI/NH3) m/e 313 (M+NH4)+.
Example 53B 7-Methoxy-8-iodo-2-naphthalenecarbonitrile Example 53 A (36.7 g, 124.2 mmol) in methanol (500 mL) and ethyl acetate (300 mL) was treated over 3 h with 2M trimethylsilyldiazomethane in hexane (260 mL), stirred for 24 h, concentrated and recrystallized from ethyl acetate to provide 36.4 g of the title compound. MS (DCI/NH3) m/e 327 (M+NFL +.
Example 53C 4-Iodo- 1 -rr2-(trimethylsilyDethoxylmethyll- 1 H-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), stirred for 1 h, treated with SEM chloride (9.00 mL, 50.8 mmol), stirred at room temperature for 1 h, poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 10% ethyl acetate/hexanes to provide 14.4 g of the title compound. MS (DCI/NH3) m/e 325 (M+H)+.
Example 53D ri-rr2-(TrimethylsilvDethoxylmethyll-lH-pyrazol4-vnboronic 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 at -78 °C for 10 min, treated with trimethyl borate (11.36 mL, 100 mmol), warmed to room temperature, treated with 3M HCl (400 mL) and extracted with ethyl acetate. The extracts were concentrated, and the residue was dissolved in 1M NaOH (500 mL), extracted with diethyl ether, acidified with concentrated HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel with ethyl acetate to provide 2.20 g of the title compound. MS (DCI/NH3) m/e 199 (M-B(OH)2)+.
Example 53E 7-Methoxy-8-ri-rr2-(trimethylsiIyl)ethoxylmethvn-lH-pyrazol-4-yll-2-naphthalenecarbonitrile Examples 53B (1.55 g, 5 mmol) and 53D (1.45 g, 6 mmol) were subjected to the procedure described in Example 47 A to provide 1.64 g of the title compound. MS (DCI/NH3) m/e 380 (M+H)+.
Example 53F 7-Methoxy-8-( 1 H-pyrazol-4-yl)-2-naphthalenecarbonitrile A solution of Example 53E (1.84 g, 4.85 mmol) in THF
(10 mL) was treated with 1M tetrabutylammonium fluoride in THF (24 mL), refluxed for 6 h and concentrated. The residue was chromatographed on silica gel with 1 : 1 ethyl acetate/hexanes to provide 0.88 g of the title compound. MS (DCI/NH3) m/e 267 (M+NH4)+.
Example 53G 7-Methoxy-8-(l H-pyrazol-4-yl)-2-naphthalenecarboximidamide bis(trifluoroacetate) salt
The title compound was prepared from Example 53F and the procedure of Example IB. JH NMR (300 MHz, DMSO-d6) δ 3.89 (s, 3H), 7.60 (dd, IH), 7.71 (d, IH), 7.92 (s, 2H), 8.05 (d, IH), 8.12 (d, IH), 8.29 (s, IH), 9.33 (s, 2H), 9.34 (s, 2H); MS (DCI/NH3) m/e 267 (M+H)+ ;
Anal, calcd. for Cι5Hι4N4O-2.8TFA: C, 42.30; H, 2.90; N, 9.59. Found: C; 42.54; H, 3.11; N, 9.03.
Example 54 7-Methoxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 53B and the procedure of Example IB. IH NMR (300 MHz, DMSO-d6) δ 4.01 (s, 3H), 7.65 (m, 2H), 8.12 (d, IH), 8.15 (d, IH), 8.42 (s, IH), 9.14 (s, 2H), 9.52 (s, 2H); MS (DCI/NH3) m/e 327 (M+H)+.
Anal, calcd for Cι2Hι2N2OI-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-arninoiminomethyl-2-naphthalenecarboxamide mono(methanesulfonate) salt
Example 55A
2-TrifluoromethanesulfonvIoxy-6-bromonaphthalene
A solution of 6-bromo-2-naphthol (4.96 g, 22.25 mmol),
N-phenyltrifluoromethanesulfonate (7.95 g, 22.25 mmol), and diisopropylethylamine (7.75 mL, 44.5 mmol) in methylene chloride (25 mL) were stirred for 3 h at room temperature, poured into water and extracted with diethyl ether. The extracts were washed with brine, dried
(MgSO4), and concentrated. The residue was chromatographed on silica gel with 3% ethyl acetate/hexane to provide 7.89 g of the title compound.
MS (DCI/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 )4 (256 mg, 0.22 mmol) in DMF (50 mL), heated at 90° C for 3 h, cooled to room temperature, treated with saturated NaHCO3 and extracted with diethyl ether. The extracts were washed with brine, dried over (MgSU4), and condensed. The residue was chromatographed on silica gel with 5% ethyl acetate/hexanes to provide 2.67 g of the title compound. MS (DCI/NH3) m/e 231 and 233 (M+H)+.
Example 55C
N-phenyl-6-cyano-2-naphthalenecarboxamide A solution of Example 55B (224 mg, 0.965 mmol) in THF (3 mL) and hexanes (1 mL) at -100° C was treated with 2.5 M butyllithium in hexanes (0.386 mL, 0.965 mmol), stirred at - 100° C for 5 min, treated with phenyl isocyanate (0.115 mL, 1.06 mmol), warmed to room temperature, treated with pH 7 buffer (0.5 mL) and concentrated. The residue was chromatographed on silica gel with 20% ethyl acetate/hexanes as eluent, to provide 54 mg of the title compound:
MS (DCI/NH3) m/e 273 (M+H)+.
Example 55D N-phenyl-6-aminoiminomethyl-2-naphthalenecarboxamide mono(methanesulfonate) salt A solution of Example 55C (52 mg, 0.191 mmol) in THF (2 mL) was treated with 1M lithium bis(trimethylsilyl)amide in THF (0.6 mL), stirred for 18 h, treated with 2M HCl (4 mL), stirred for another 24 h, made basic with saturated Na2CO3 and extracted with ethyl acetate. The extracts were washed with brine, dried (Na2SO ) and concentrated. The crude product was dissoved into a minimal amount of methanol (ca.1 mL), treated with methanesulfonic acid (1 drop), diluted with diethyl ether (400 mL) and filtered to provide 15 mg of the title compound. JH NMR (300 MHz, DMSO-d6) δ 2.32 (s, 3H), 7.15 (dd, IH), 7.40 (dd, 2H), 7.83 (d, 2H),
7.90 (dd, IH), 8.17 (dd, IH), 8.25 (d, IH), 8.34 (d, IH), 8.57 (s, IH), 8.70 (s, IH), 9.09
(br s, 2H), 9.51 (br s, 2H);
MS (DCI/NH3) m/e 290 (M+H)+.
Anal, calcd for Ci8Hι6N3O- l . l CH3SO3H: C, 57.96; H, 4.95; N, 10.61. Found: C, 58.03; H, 4.48; N, 10.36.
Example 56 4-r(6-Aminoiminomethyl-2-naphthalenvDoxy1-N-methylbenzeneacetamide mono(trifluoroacetate) salt
Example 56A N-methyl-3-hvdroxyphenylacetamide A solution of 3-hydroxyphenylacetic acid (1.00 g, 6.57 mmol) and oxalyl chloride (0.63 mL, 7.22 mmol) in methylene chloride (20 mL) was treated dropwise with pyridine (0.6 mL, 7.37 mmol), stirred for 90 min, poured into 40% aqueous methylamine (30 mL), stirred for 15 min, concentrated, dissolved into 1M HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with ethyl acetate to provide 260 mg of the title compound. MS (DCI/NH3) m/e 166 (M+H)+.
Example 56B 4-r(6-Cvano-2-naphthalenyDoxyl-N-methylbenzeneacetamide A mixture of Example 56A (245 mg, 1.48 mmol), Example 55B (344 mg, 1.48 mmol) and CS2CO3 (530 mg, 1.63 mmol) in DMF (3 mL) was stirred for 72 h at 120 °C, cooled and chromatographed on silica gel with 1 : 1 ethyl acetate/hexanes to provide 54 mg of the title compound. MS (DCI/NH3) m/e 317 (M+H)+.
Example 56C 4-r(6-Aminoiminomethyl-2-naphthalenyl)oxyl-N-methylbenzeneacetamide mono(trifluoroacetate) salt The title compound was prepared from Example 56B and the procedure of Example 55D. lH NMR (300 MHz, DMSO-d6) δ 2.33 (s, 3H), 2.58 (d, 3H), 3.42 (s, 2H), 7.05 (m, 2H),7.12 (d, IH), 7.40 (dd, IH), 7.45 (m, 2H), 7.79 (dd, IH), 7.98 (q, IH), 8.02 (d, IH), 8.15 (d, IH), 8.49 (s, IH), 8.99 (br s, 2H), 9.39 (br s, 2H); MS (DCI/NH3) m/e 334 (M+H)+. Anal, calcd for C19H17N3O2 I.5CH3SO3H: C, 54.08; H, 5.28; N, 8.80. Found: C, 53.80; H, 5.37; N, 8.52.
Example 57 6-r2-(Methylthio)phenyll-2-naphthalenecarboximidamide mono(methanesulfonate) salt
Example 57A 2-Cvanonaphthalene-6-boronic acid A solution of Example 55B (6.37 g, 27.45 mmol) in THF (220 mL) and hexanes (50 mL) at -100 °C was treated with 2.5 M butyllithium in hexanes (11.0 mL, 27.5 mmol), st red at -100 °C for 10 min, treated with trimethyl borate (7.8 mL, 68.6 mmol), warmed to room temperature, treated with 3M HCl (400 mL) and extracted with ethyl acetate. The extracts were concentrated and the residue was dissolved into 1M NaOH (500 mL), exttacted with diethyl ether, acidified with 12M HCl and exttacted with ethyl acetate. The extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was dissolved into minimal methanol and ethyl acetate and triturated with hexanes to yield 2.74 g of the title compound. MS (DCI/NH3) m/e 215 (M+NH4)+
Example 57B
6-r2-(Methylthio)phenvn-2-naphthalenecarbonitrile A solution of 2-bromothioanisole (0.147 mL, 1.10 mmol), Pd(OAc)2 (24 mg, 0.11 mmol) and 1 , l'-bis(diphenylphosphinofenocene) (120 mg, 0.22 mmol) in DMF (5 mL) was stirred for 10 min, treated with Example 57 A (260 mg, 1.32 mmol) and CS2CO3 (1.07 g, 3.3 mmol), heated at 85 °C for 6 h, cooled to room temperature and chromatographed on silica gel with 10% ethyl acetate/hexanes to provide 155 mg of the title compound. MS (DCI/NH3) m/e 231 (M+NF ÷.
Example 57C 6-r2-(Methylthio)phenyll-2-naphthalenecarboximidamide mono(methanesulfonate) salt
The title compound was prepared from Example 57B and the procedure of Example 55D. IH NMR (300 MHz, DMSO-d6) δ 2.32 (s, 3H), 2.40 (s, 3H), 7.34 (m, 2H), 7.45 (m, 2H),
7.82 (dd, 2H), 7.95 (dd, IH), 8.06 (s, IH), 8.15 (d, IH), 8.20 (d, IH), 8.55 (s, IH), 9.03 (br s, 2H), 9.56 (br s, 2H);
MS (DCI/NH3) m/e 293 (M+H)+.
Anal, calcd for Ci8Hi7N2S-CH3SO3H: C, 58.18; H, 5.18; N, 7.12. Found: C, 57.97; H,
5.31; N, 6.97.
Example 58
6-r2-(2-Thiomethoxoxyethyl)phenyllnaphthalene-2-carboximidamide mono(methanesulfonate) salt
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 Ph3PBr2 (13.8 g, 32.65 mmol), stirred at 0° C for 2 h, diluted with hexanes and filtered through a plug of silica gel with 25% diethyl ether/hexanes to provide 6.0 g of the title compound. MS (DCI/NH3) m/e 263 (M+H)+.
Example 58B 2-(2-Thiomethoxyethyl)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, cooled and chromatographed on silica gel with 1 % ethyl acetate/hexanes to provide 646 mg of the title compound. MS (DCI/NH3) m/e 231, 233 (M+H)+.
Example 58C
6-r2-(2-Thiomethoxyethyl)phenyll-2-naphthalenecarbonitrile The tide compound was prepared from Example 58B (300 mg, 1.30 mmol), Example 57A (260 mg, 1.32 mmol) and the procedure described in Example 57B. MS (DC1/NH3) m/e 321 (M+NH4)+.
Example 58D 6-r2-(2-Thiomethoxoxyethyl)phenyl1naphthalene-2-carboximidamide mono(methanesulfonate) salt The title compound was prepared from Example 58C and the procedure from Example 55D.
*H NMR (300 MHz, DMSO-d6) 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, IH), 7.85 (dd, IH), 8.04 (s, IH), 8.18 (d, IH), 8.20 (d, IH), 8.55 (s, IH), 9.01 (br s, 2H), 9.43 (br s, 2H); MS (DCI/NH3) m/e 321 (M+H)+. Anal, calcd for C2oH2θN2S2- 1.35CH3SO3H: 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-furanvD-2-naphthalenecarboximidamide mono(methanesulfonate) salt
Example 59A 7-Methoxy-8-(3-furanyl)-2-naphthalenecarbonitrile The title compound was prepared from Example 53B, furan-3-boronic acid (873 mg, 7.80 mmol) and the procedure of Example 57B. MS (DCI/NH3) m/e 267 (M+NH4)+.
Example 59B 7-Methoxy-8-(3-furanyl)-2-naphthalenecarboxirnidamide mono(methanesulfonate) salt The title compound was prepared from Example 58C and the procedure from Example
55D.
JH NMR (300 MHz, DMSO-d6) δ 2.34 (s, 3H), 3.91 (s, 3H), 6.76 (s, 2H), 7.62 (dd, IH), 7.74 (d, IH), 7.87 (dd, IH), 7.96 (s, IH), 8.12 (d, IH), 8.15 (d, IH), 8.25 (s, IH), 8.96 (br s, 2H), 9.35 (br s, 2H); MS (DCI/NH3) m/e 267 (M+H)+.
Anal, calcd for Cι6Hι4N2θ2-CH3Sθ3H: 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) salt
Example 60A 7-Methoxy-8-(2-benzofuranyl)-2-naphthalenecarbonitrile The title compound was prepared from Example 53B (166 mg, 0.50 mmol), benzofuran-2- boronic acid (1 13 mg, 0.70 mmol) and the procedure of Example 57B. MS (DCI/NH3) m/e 317 (M+NH4)+.
Example 60B 7-Methoxy-8-(2-benzofuranyl)naphthalene-2-carboximidamide mono(methanesulfonate) salt The title compound was prepared from Example 60 A (72 mg, 0.240 mmol) and the procedure from Example 55D.
*H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 3.98 (s, 3H), 7.24 (s, IH), 7.36 (m, 2H),
7.67 (m, 2H), 7.75 (m, IH), 7.84 (d, IH), 8.21 (d, IH), 8.30 (d, IH), 8.32 (s, IH), 8.88 (br s, 2H), 9.39 (br s, 2H); MS (DCI/NH3) m/e 317 (M+H)+.
Anal, calcd for C2υHi6N2O2- 1.3CH3Sθ3H: C, 57.98; H, 4.84; N, 6.35. Found: C, 57.79;
H, 4.78; N, 6.22.
Example 61 (E)-8-r2-(1.3-Benzodioxol-5-yl)ethenyll-2-naphthalenecarboximidamide mono(methanesulfonate) salt
Example 61 A (E)-8-r2-( 1.3-Benzodioxol-5-yl)ethenyll-2-naphthalenecarbonitrile
Example 53B (75 mg, 0.243 mmol), PdCl2(dppf) (20 mg, 0.024 mmol), 3,4- methylenedioxystyrene (43 mg, 0.291 mmol) and diisopropylethylamine (0.170 mL, 0.97 mmol) in N-methylpyrrolidinone (2 mL) were stirred at 90° C for 18 h, cooled to room temperature and chromatographed on silica gel with 20% ethyl acetate/hexanes to provide 46 mg of the title compound.
MS (DCI/NH3) m/e 347 (M+NH4)+.
Example 6 IB (E)-8-r2-(1.3-Benzodioxol-5-yl)ethenyP-2-naphthalenecarboximidamide mono(methanesulfonate) salt
The title compound was prepared from Example 61 A (43 mg, 0.131 mmol) and the procedure from Example 55D.
I H NMR (300 MHz, DMSO-d6) 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, IH), 7.56 (d, IH), 7.66 (d, 2H), 7.72 (d, I H), 8.06 (s, I H), 8.03 (d, IH), 8.12 (d, I H), 8.66 (s, I H), 8.96 (br s, 2H), 9.44 (br s, 2H); MS (DCI/NH3) m/e 347 (M+H)+.
Anal, calcd for C2ιHi8N2θ - l . lCH3Sθ3H: C, 58.72; H, 4.99; N, 6.20. Found: C, 58.77; H, 5.07; N, 5.99.
Example 62
( ± )-7-Methoxy-8-(tetrahvdro-3-furanyl)-2-naphthalenecarboximidamide mono(methanesulfonate) salt
Example 62A ( ± )-7-methoxy-8-r3-hvdroxy- 1 -(hvdrox vmethyl)- 1 -propenyn-2-naphthalenecarbonitrile
A solution of Example 53B (3.09 g, 10 mmol), PdCl2 (120 mg, 1 mmol), cis-2-butene-l ,4-diol ( 1.23 mL, 15 mmol) and NaHC03 ( 1.01 g, 12 mmol) in N-methylpyrrolidinone ( 10 mL) was stirred at 130 °C for 1 h, cooled to room temperature and chromatographed on silica gel with 30% ethyl acetate/hexanes to provide 2.19 g of the title compound as a mixture of diastereomers. MS (DCI/NH3) m/e 269 (M+H)+.
Example 62B
(± )-7-Methoxy-8-(tetrahvdro-3-furanyl)-2-naphthalenecarbonitrile
Example 62 A (140 mg, 0.52 mmol) in methylene chloride (3 mL) at 0 °C was treated with triethylsilane (0.166 mL, 1.04 mmol) and BF3-OEt2 (0.096 mL, 0.78 mmol). stirred at room temperature for 4 h, concentrated and chromatographed on silica gel with 25% ethyl acetate/hexanes to provide 100 mg of the title compound. MS (DCI/NH3) m/e 271 (M+NH4)+.
Example 62C ( ± )-7-Methoxy-8-(tetrahvdro-3-furanyl)-2-naphthalenecarboximidamide mono(methanesulfonate) salt
The title compound was prepared from Example 62B (96 mg, 0.379 mmol) and the procedure from Example 55D. IH NMR (300 MHz. DMSO-d6) δ 2.20 (m, I H), 2.33 (m, I H), 2.39 (s, 3H), 3.99 (s, 3H),
3.90-4.03 (m, 3H), 4.1 1 (m, I H), 442 (m, I H), 7.64 (d, IH), 7.68 (d, IH), 8.01 (d, I H), 8.10 (d, I H), 8.70 (s, IH), 9.01 (br s, 2H), 9.41 (br s, 2H), MS (DCI/NH3) m/e 271 (M+H)+.
Anal, calcd for C ι6Hi8N2θ2- 1.2CH3Sθ3H: C, 53.57; H, 5.96; N, 7.26. Found: C, 53.67; H, 5.78; N, 6.72.
Example 63
6-1 [4-(2-Aminoethyl)phenyl lethvnyll-2-naphthalenecarboximidarnide mono(trifluoroacetate) salt
Example 63A 6-(Trimethylsilylethvnyl)-2-naphthalenecarbonitrile
Example 28B and trimethylsilylacetylene were submitted to the conditions described in Example 42C to provide the title compound. MS (DCI/NH3) m/e 267 (M+NH4)+. Example 63B 6-Ethvnyl-2-naphthaIenecarbonitrile A mixture of Example 63A (0.4 g, 1.6 mmole) and K2CO3 (0.4 g, 3.2 mmole) in methanol ( 16 mL) was stirred at room temperature for 18 h. concentrated, treated with water and extracted with methylene chloride. The organic layer was washed with 0.5 NHCl and brine, dried (MgSO4) and evaporated to provide the title compound. MS (DCI/NH3) m/e 195 (M+NH4)+.
Example 63C 4-Bromo-(N-tert-butoxycarbonyl)phenethylamine
4-Bromophenethylamine and di-t-butyldicarbonate were subjected to the conditions described in Synthesis, 48, 1986 to provide the title compound. MS (DCI/NH3) m/e 319 (M+NH4)+.
Example 63D
6-ir4-(2-N-tert-butoxycarbonylaminoethyl)phenyllethvnyll-2-naphthalenecarbonitrile The title compound was obtained with Examples 63B and C from the procedure described in Example 57B to provide the title compound. MS (DCI/NH3) m/e 414 (M+NH4)+.
Example 63E 6-rf4-(2-Aminoethyl)phenyl1ethvnvn-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared with Example 63D and the procedure of Example 5B. » H NMR (300 MHz, DMSO-d6) δ 2.90 (t, 2H), 3.09 (m, 2H) 7.36 (d, 2H), 7.60 (d, 2H), 7.76 (d, 2H), 7.76 (dd, IH), 7.85 (s, 2H), 7.87 (dd, IH), 8.13 (d, IH), 8.18 (d, IH), 8.31 (s, I H), 8.50 (s, IH), 9.18 (s, 2H), 9.45 (s, 2H); MS (DCI/NH3) m/e 314 (M+H)+.
Anal, calcd for C2iHi9N3-2TFA-H20: C, 53.67; H, 4.14; N, 7.15. Found: C, 53.37; H, 3.93; N, 7.17.
Example 64 7-Methoxy-8-[2-pyrimidinyl(oxy)l-2-naphthalenecarboximidamide mono(trifluoroacetate) Example 64A 7-Methoxy-8-[2-pyrimidinyl(oxy)1-2-naphthalenecarbonitrile Example 4A (125 mg, 0.627 mmol) and 2-chloropyrimidine (143 mg, 1.25 mmol) were subjected to the procedure described in Example 6A to provide 101 mg of the title compound. MS (DCI/NH3) m/e 278 (M+H)+.
Example 64B 7-Methoxy-8-r2-pyrimidinyl(oxy)l-2-naphthalenecarboximidamide mono(trifluoroacetate) The title compound was prepared with Example 64A and the procedure of Example IB. IH NMR (300 MHz, DMSO-d6) δ 2.51 (s, 3H), 3.83 (s, 3H), 7.18 (t, IH), 7.70 (dd, IH), 7.80 (d, I H), 8.05 (d, IH), 8.19 (d, IH), 8.34 (s, IH), 8.62 (d, 2H), 9.07 (br s, 2H), 9.45 (br s, 2H);
MS (DCI/NH3) m/e 295 (M+H)+.
Anal, calcd for C2oH i6N O4T .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-r2-thiazoyl(oxy)lnaphthalene-2-carboximidamide mono(trifluoroacetate) salt
Example 65A
7-Methoxy-8-r2-thiazoyl(oχy)l-2-naphthalenecarbonitrile A mixture of Example 4A (250 mg, 1.25 mmol), 2-bromothiazole (225 mL, 2.50 mmol) and CsF (209 mg, 1.38 mmol) in DMSO (4 mL) was stirred at 120 °C for 4 days, cooled and chromatographed on silica gel with 30% ethyl acetate/hexanes to provide 162 mg of the title compound.
MS (DCI/NH3) m/e 283 (M+H)+
Example 65B 7-Methoxy-8-r2-thiazoyl(oxy)1naphthalene-2-carboximidamide mono(trifluoroacetate) salt The title compound was prepared with Example 65 A and the procedure of Example 1 B.
'H NMR (300 MHz, DMSO-d6) δ 3.98 (s, 3H) 7.25 (m, 2H), 7.73 (dd, IH), 7.86 (d, IH),
8.12 (d, IH), 8.22 (d, IH). 8.35 9.09 (bs, 2H), (s, IH), 9.48 (bs, 2H).
MS (DCI/NH3) m/e 300 (M+H)+.
Anal, calcd for Ci5Hi3N 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) salt
Example 66A 7-Methoxy-8-(4-nitrophenoxy)-2-naphthalenecarbonitrile The title compound was prepared from Example 4A (125 mg, 0.627 mmol), 1,4- dinittobenzene (143 mg, 1.25 mmol) and the procedure described in Example 65A to provide 227 mg of the title compound.
MS (DCI/NH3) m/e 338 (M+NH4)+.
Example 66B 7-Methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared with Example 66A and the procedure of Example
55D.
'H NMR (300 MHz, DMSO-d6) δ 9.43 (br s, 2H), 8.94 (br s, 2H), 8.25 (m, 4H), 8.15 (d, I H), 7.88 (d, IH), 7.72 (dd, IH), 7.05 (d, 2H), 3.91 (s, 3H), 2.30 (s, 3H); MS (DCI/NH3) m/e 338 (M+H)+. Anal, calcd for Cι8Hi5N3θ4- 1.75CH3Sθ3H: 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) salt
Example 67A 7-Methoxy-8-pentafluorophenoxy-2-naphthalenecarbonitrile Example 4A (100 mg, 0.50 mmol) and hexafluorobenzene (1 15 mL, 1.00 mmol) were subjected to the procedure described in Example 65 A to provide 150 mg of the title compound. MS (DCI/NH3) m/e 383 (M+NH4)+.
Example 67B 7-Methoxy-8-pentafluorophenoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared with Example 67A and the procedure of Example 55D.
!H NMR (300 MHz, DMSO-d6) δ 2.31 (s, 3H), 3.82 (s, 3H), 7.87 (dd, IH), 7.88 (d, IH), 8.02 (d, I H), 8.20 (d, IH), 8.65 (s, I H), 9.04 (br s, 2H), 9.47 (br s, 2H); MS (DC1/NH3) m/e 383 (M+H)+.
Anal, calcd for Ci8HnN2F5θ2- 1.2CH3Sθ3H: C, 46.67; H, 3.19; N, 5.68. Found: C, 46.55; H, 3.00; N, 5.58.
Example 68 7-Methoxy-8-rN-2-phenylamino)l-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 68A 7-Methoxy-8-rN-2-phenyl(amino)1-2-naphthalenecarbonitrile A solution of Example 25A (309 mg, 1.00 mmol), aniline (0.109 mL, 1.2 mmol), NaOlBu ( 1 15 mg, 1.2 mmol), Pd2(dba)3 ( 10 mg, 0.01 mmol) and dppf ( 17 mg, 0.03 mmol) in toluene (5 mL) was stirred for 3 h at 100 °C, cooled and chromatographed on silica gel with 10% ethyl acetate/hexanes to provide 175 mg of the title compound. MS (DCI/NH3) m/e 275 (M+H)+.
Example 68B
7-Methoxy-8-(N-2-phenylamino)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared with Example 68A and the procedure of Example 55D. ' H NMR (300 MHz, DMSO-d6) δ 3.95 (s, 3H), 5.92 (bs, I H), 6.61 (d, 2H), 6.94 (t, IH), 7.16 (dd, 2H), 7.45 (dd, IH), 7.48 (d, I H), 7.76 (d, I H), 7.88 (d, I H), 8.13 (d, I H), 9.08 (bs, 2H), 9.31 (bs, 2H). MS (DCI/NH3) m/e 292 (M+H)+.
Anal. Calcd for C18H17N3O FA: C, 59.26; H, 4.48; N, 10.37. Found: C, 59.20; H, 4.32; N, 10.15.
Example 69 N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-benzylurea mono(trifluoroacetate) salt
Example 69A N-(6-Cvano-2-naphthalenyl)-N'-benzylurea The title compound was prepared with Example 40A, benzylamine and the procedure from Example 40B. MS (DCI/NH3) m/e 302 (M+H)+.
Example 69B N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-benzylurea mono(trifluoroacetate) salt The title compound was prepared with Example 69A and the procedure from Example 40D. !H NMR (300 MHz, DMSO-d6) δ 4.35 (d, 2H), 6.91 (t, IH), 7.35-7.24 (m, 5H), 7.59 (dd, IH), 7.72 (dd, IH), 7.95 (d, IH), 7.96 (d, IH), 8.22 (d, IH), 8.35 (d, IH), 8.92 (br s, 2H), 9.13 (s, I H), 9.32 (br s, 2H). MS (DC1/NH3) m/e 319 (M+H)+.
Anal, calcd for Ci9Hι8N40-TFA: C, 50.57: H, 4.24; N, 15.72. Found: C, 50.34; H, 4.15; N, 15.54.
Example 70 N-(6-Aminoiminomethyl-2-naphthalenvD-N'-methylurea mono(trifluoroacetate) salt
Example 70A N-(6-Cyano-2-naphthalenvI)-N'-methylurea
The title compound was prepared with Example 40A (221.2 mg, 1.00 mmole) and methylamine (2.3 mL, 2.34 mmol) in THF (10 mL) according to the procedure from Example 40B.
MS (DCI/NH3) m/e 226 (M+H)+.
Example 70B N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-methylurea mono(trifluoroacetate) salt The title compound was prepared with Example 70A and the procedure of Example 40D. !H NMR (300 MHz, DMSO-d6) δ 2.69 (d, 3H), 6.32 (q, IH), 7.60 (dd, IH),
7.73 (dd, IH), 7.93 (d, IH), 7.95 (d, IH, 8.19 (d, IH), 8.49 (d, IH), 9.09 (s, IH), 9.15 (br. s, 4H);
MS (DCI/NH3) m/e 243 (M+H)+. Anal, calcd for C13H14N4O FA: C, 50.57; H, 4.24; N, 15.72. Found: C 50.34; H, 4.15; N, 15.54.
Example 71 N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-isopropylurea mono(trifluoroacetate) salt
Example 71 A N-(6-Cvano-2-naphthalenyl)-N'-isopropylurea The title compound was prepared with Example 40A, isopropylamine and the procedure from Example 40B.
MS (DCI/NH3) m/e 254 (M+H)+.
Example 7 IB N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-isopropylurea mono(trifluoroacetate) salt The title compound was prepared with Example 71 A and the procedure of Example 5B.
[H NMR (300 MHz, DMSO-d6) δ 1.13 (d, 6H), 3.76-3.84 (m, I H), 6.28 (d, IH), 7.55 (dd, I H), 7.72 (dd, IH), 7.94 (d, I H), 7.95 (d, I H), 8.19 (d, IH), 8.34 (d, IH), 8.85 (s, IH), 9.3 (br s, 2H), 9.0 (br s, 2H); MS (DCI/NH3) m/e 271 (M+H)+. Anal, calcd for C15H18N4O FA: C, 53.12; H, 4.98; N, 14.58. Found: C, 15.13; H, 4.84; N, 14.50.
Example 72 N-(6-Aminoiminomethyl-2-naphthalenyl )-N'-phenyl-N'-methylurea mono(trifluoroacetate) salt
Example 72A N-(6-Cvano-2-naphthalenyl)-N'-phenyl-N'-methylurea The title compound was prepared with Example 40 A, N-methyl-N-phenylamine and the procedure from Example 40B. MS (DCI/NH3) m/e 302 (M+H)+.
Example 72B N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-phenyl-N'-methylurea mono(trifluoroacetate) salt The title compound was prepared with Example 72A and the procedure of Example 40D. IH NMR (300 MHz, DMSO-d6) δ 3.33 (s, 3H), 7.25-7.47 (m, 5H), 7.71 -7.77 (m, 2H), 7.95
(two overlaping doublets, 2H), 8.16 (d, IH), 8.35 (d, I H), 8.64 (s, I H), 8.96 (br s, 2H),
9.34 (br s. 2H);
MS (DCI/NH3) m/e 319 (M+H)+.
Anal, calcd for C2oHi7N4O-TFA: C, 58.33; H, 4.43; N, 1 1.96. Found: C, 58.38; H, 4.69;
N, 1 1.82.
Example 73 6-Aminonaphthalene-2-carboximidamide mono(trifluoroacetate) salt
Example 73A 6-Phenylcarbamoyl-2-naphthalenecarbonitrile The title compound was prepared from Example 40A, phenol and the procedure from Example 40B. MS (DCI/NH3) m/e 289 (M+H)+.
Example 73B 6-Aminonaphthalene-2-carboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 73A and the procedure of Example 40D.
I H NMR (300 MHz, DMSO-d6) δ 6.01 (br s, 2H), 6.86 (d, IH), 7.06 (dd, I H), 7.58-7.67
(m, 2H), 7.74 (d, I H), 8.21 (d, I H), 8.74 (br s, 2H), 9. 16 (br s, 2H); MS (DCI/NH3) m/e 196 (M+H)+.
Anal, calcd for Cι2H ιoN3-TFA: C, 52.18; H, 4.04; N, 14.04. Found: C, 51.92: H, 3.87; N, 13.80.
Example 74 N-(6-aminoiminomethyl-2-naphthalenyl)-N'-cvclohexylurea mono(trifluoroacetate) salt
Example 74A
N-(6-Cvano-2-naphthalenyl)-N'-cvcIohexylurea The title compound was preparedwith Example 40A, cyclohexylamine and the procedure from Example 40B. MS (DCI/NH3) m/e 294 (M+H)+.
- 105-
SUBST1TUTE SHEET (RULE 26) Example 74B N-(6-aminoiminomethyl-2-naphthalenyl)-N'-cvclohexylurea mono(trifluoroacetate) salt The title compound was prepared with Example 74A and the procedure of Example 40D. I H NMR (300 MHz, DMSO-d6) δ 1.14- 1.39 (m, 5H), 1.54- 1.58 (m, IH), 1.65- 1.72 (m, 2H), 1.81 - 1.86 (m, 2H), 3.46-3.52 (m, IH), 6.36 (d, IH), 7.55 (dd, IH), 7.72 (dd, IH), 7.93 (d, I H), 7.95 (d, IH), 8.18 (d, IH), 8.35 (d, I H), 8.87 (s, I H), 9.00 (br s, 2H), 9.28 (br s, 2H);
MS (DCI/NH3) m/e 31 1 (M+H)+.
Anal, calcd for Cι9H2iN40-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-naphthalenyD-N'-benzyloxyurea mono(trifluoroacetate) salt
Example 75A N-(6-cyano-2-naphthalenyl)-N'-benzyloxyurea The title compound was prepared with Example 40A, O-benzylhydroxylamine and the procedure from Example 40B. MS (DCI/NH3) m e 318 (M+H)+.
Example 75B N-(6-aminoiminomethyl-2-naphthalenvD-N'-benzyloxyurea mono(trifluoroacetate) salt The title compound was prepared with Example 75A and the procedure of Example 40D. ' H NMR (300 MHz, DMSO-d6) δ 4.87 (s, 2H), 7.25-7.42 ( , 3H), 7.48-7.51 (m, 2H), 7.75
(dd, I H), 7.75 (dd, I H), 7.97 (d, 2H), 8.30 (d, IH), 8.38 (d, I H), 8.97 (br s, 2H), 9.21 (s, I H), 9.35 (br s, 2H), 9.77 (s, I H); MS (DCI NH3) m/e 335 (M+H)+.
Anal, calcd for Ci9Hi8N O2-TFA: C, 56.25; H, 4.27; N, 12.49. Found: C, 56.26; H, 4.39; N, 12.30.
Example 76 1.1 -Dimethylethyl r4-rr(6-aminoiminomethyl-2-naphthalenvPaminolcarbonvnphenyl1carbamate mono(trifluoroacetate) salt Example 76A 6-Amino-2-naphthalenecarbonitrile Sulfuric acid (45mL) was treated with Example 40B (6.5 g), stirred for 30 min, warmed to room temperature for 20 min, poured onto ice, diluted with water to approximately 500 mL, cooled to 0 °C and treated with 50% aq sodium hydroxide such that the temperature did not exceed 35 °C. The light solid which precipitated was filtered, washed with water to pH 7, dried under vacuum and purified on silica gel with 20% ethyl acetate/ hexanes to provide 3.3 g of the title compound. MS (DCI/NH3) m/e 169 (M+H)+.
Example 76B 1.1 -Dimethylethyl r4-rr(6-cvano-2-naphthalenyl)aminolcarbonyllphen yllcarbamate mono(trifluoroacetate) salt The title compound was prepared from Example 76A, 4-N-Boc-aminomethylbenzoic acid, the procedure from Example 35B with methylene chloride in place of THF. MS (DCI NH3) m/e 417 (M+H)+.
Example 76C
1.1-Dimethylethyl [4-fr(6-aminoiminomethyl-2-naphthalenyl)aminolcarbonyllphenyllcarbamate mono(trifluoroacetate) salt
The title compound was prepared with Example 76B and the procedure of Example 40D. lH NMR (300 MHz, DMSO-d6) δ 3.30 (s, 9H), 4.22 (d, 2H), 7.42 (d, 2H), 7.49 (t, IH),
7.79 (dd, IH), 7.95-8.00 (m, 3H), 8.09 (d, 2H), 8.42 (s, IH), 8.63 (d, IH), 9.18 (br s, 4H),
10.58 (s, I H); MS m/e 434 (M+H)+
Anal, calcd for C24H27N5O3 FA: C, 59.56; H, 5.00: N, 10.29. Found: C, 58.55; H, 4.85;
N, 10.41.
Example 77 N-r6-(AminoiminomethyP-2-naphthalenyll-4-(aminomethvPbenzamide mono(trifluoroacetate) salt
Example 77A N-f6-(AminoiminomethvP-2-naphthalenyl l-4-(aminomethyl)benzamide mono(trifluoroacetate) salt A solution of Example 76B (35 mg, 0.07 mmole) in 1 : 1 TFA/methylene chloride was stirred at room temperature for 1 h then concentrated. The residue was dissolved in water (12 mL), filtered through a 045μ filter and concentrated. The solid was suspended in diethyl ether and filtered to yield 27 mg of the title compound as a white solid. I H NMR (300 MHz, DMSO-d6) δ 4.17 (q, 2H), 7.65 (d, 2H), 7.80 (dd, I H), 7.99 (dd, IH), 8.06-8.12 (m, 4H), 8.30 (br s, 2H), 8.44 (d, I H), 8.64 (d, IH), 9.13 (br s, 2H), 9.40 (br s, 2H), 10.70 (s, I H); MS (DCI NH3) m e 319 (M+H)+.
Anal, calcd for Ci 9HιgN4O-2.25TFA-0.5H2O: C, 48.34; H, 3.67; N, 9.59. Found: C, 48.45; H, 3.74; N, 9.45.
Example 78 Ethyl [6-(aminoiminomethyl)-2-naphthalenyl1carbamate mono(trifluoroacetate) salt
Example 78A Ethyl (6-cyano-2-naphthalenyl)carbamate mono(trifluoroacetate) salt The title compound was prepared with Example 40 A, ethanol and the procedure from Example 40B.
MS (DCI/NH3) m/e 241 (M+H)+.
Example 78B Ethyl [6-(aminoiminomethyl)-2-naphthalenyllcarbamate mono(trifluoroacetate) salt The title compound was prepared with Example 78 A and the procedure of Example
40D.
I H NMR (300 MHz, DMSO-d6) δ 1.29 (t, 3H), 4.19 (q, 2H), 7.69 (dd, I H),
7.76 (dd, I H), 8.1 (d, 2H), 8.23 (d, IH), 8.38 (d, IH), 9.03 (br s, 2H), 9.33 (br s, 2H),
10.1 1 (s, I H); MS (DCI/NH3) m/e 258 (M+H)+.
Anal, calcd for Ci4Hi5N3O2-TFA: C, 51.76; H, 4.34; N, 1 1.32. Found: C, 51.32; H, 4.15;
N, 10.93.
Example 79 1.1 -dimethylethyl f4-rr[6-aminoiminornethyl)- 2-naphthaIenyl)amino1carbonyllaminolphenyll carbamate mono(trifluoroacetate) salt
Example 79A 1.1-Dimethyl r4-rrF(6-cyano-2-naphthalenyl)aminolearbonyllaminolphenyllcarbamate
The title compound was prepared with Example 40B, 4-(N-tert-butoxycarbonylamino)- aminobenzene and the procedure from Example 40C. MS (DCI/NH3) m/e 403 (M+H)+.
Example 79B
1.1-dimethylethyl [4-riT6-aminoiminomethyl)- 2-naphthalenvDamino lcarbonyllaminolphenyll carbamate mono(trifluoroacetate) salt The title compound was prepared with Example 79A and the procedure of Example 40D. ' H NMR (300 MHz, DMSO-d6) δ 1.22 (s, 9H), 7.38 (s, 4H), 7.62 (dd, I H),
7.75 (dd, IH), 8.00 (d, 2H), 8.27 (d, IH), 8.38 (d, I H), 8.77 (s, I H), 8.90 (br s, 2H), 9.16 (s, I H), 9.20 (s, I H), 9.33 (br s, 2H); MS (DCI/NH3) m/e 420 (M+H)+.
Anal, calcd for C23H25N5θ3-2TFA: C, 56.28; H, 4.91 ; N, 13.13. Found: C, 56.18; H, 5.07; N, 12.44.
Example 80 (E)-6-r2-(Phenylthio)ethenvn-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 80A
(E)-6-12-(Phenylthio)ethenyll-2-naphthalenecarbonitrile The title compound was prepared from Example 55B, phenylvinyl sulfide and the procedure of Example 57B. MS (DCI/NH ) m/e 305 (M+NH4)+.
Example 80B (E)-6-r2-(Phenylthio)ethenvn-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 80A and the procedure of Example IB. I H NMR (300 MHz, DMSO-d6) δ 6.91 (d, IH), 7.52-7.33 (m, 5H), 7.50 (d, IH), 7.75- 7.83 (m, IH), 7.98-8.89 (m, IH), 8.08-8.80 (m, 3H), 8.44 (m, IH), 9.03 (s, 2H), 9.40 (s, 2H); MS (DCI NH3) m/e 305 (M+H)+.
Anal, calcd for Ci9Hι6N2S- l.lTFA: C, 59.55; H, 4.03; N, 6.57. Found: C, 59.53; H, 4.12; N, 6.60.
Example 81 (E)-6-r2-(2-Furanyl)ethenyl1-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 81 A
2-Vinylfuran A solution of methyl(triphenylphosphonium)bromide (26.78 g, 75 mmol) in toluene (80 mL) was treated with butyllithium in hexanes (27.5 mL, 68.75 mmol) then furfural (6 g, 62.5 mmol), stirred for 0.5 h and distilled at 69-72 °C to provide the title compound as a clear, colorless liquid with some toluene contaminant. MS (DCI/NH3) m/e 83 (M+H)+.
Example 81 B (E)-6-r2-(2-Furanyl)ethenvπ-2-naphthalenecarbonitrile The title compound was prepared from Examples 55B and 81 A and the procedure of
Example 57B. MS (DCI/NH3) m/e 263 (M+NH4)+.
Example 1 C (E)-6-12-(2-Furanyl)ethenyll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
The title compound was prepared from Example 81 B and the procedure of Example IB. ' H NMR (300 MHz, DMSO-d6) δ 6.61 (dd, IH), 6.66 (d, IH), 7.19 (d, IH), 7.38 (d, IH), 7.77 (d, I H), 7.80 (dd, IH), 8.14-7.97 (m, 3H), 8.44 (s, I H), 9.05 (s, 2H), 9.42 (s, 2H); MS (DCI/NH3) m/e 263 (M+H)+. Anal, calcd for Cι7Hi3N2O- 1.2TFA: C, 58.49; H, 3.85; N, 7.04. Found: C, 58.45; H, 3.78; N, 7.36.
Example 82 (E)-6-r2-(l H-Imidazol-l -yl)ethenyll-2-naphthalenecarboximidamide mono(trifluoroacetate) salt Example 82A (E)-6-12-(lH-Imidazol-l -yl)ethenyll-2-naphthalenecarbonitrile The title compound was prepared from Example 55B, 1-vinylimidazole and the procedure of Example 42C.
MS (DCI/NH3) m/e 263 (M+NH4)+.
Example 82B
(F)-6-12-( 1 H-Imidazol- 1 -vPethenvn-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared from Example 82B and the procedure of Example
40D.
IH NMR (300 MHz, DMSO-d6) δ 9.44 (s, 2H), 9.14 (s, 2H), 8.15 (d, IH), 8.17-8.05 (m,
4H), 7.93 (d, IH), 7.84 (dd, I H), 7.59 (s, IH), 7.49 (d, IH);
MS (DCI/NH3) m/e 263 (M+H)+. Anal, calcd for Ci6Hι3N4-2.7TFA: C, 45.28; H, 2.97; N, 9.91. Found: C, 45.33; H, 3.52;
N, 9.79.
Example 83 (E)-4-r2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyllbenzenesulfonamide mono(trifluoroacetate) salt
Example 83A 4-vinylsulfonamide A solution of thionyl chloride (7.5 mL) and 4-t-butylcatachol (45 mg, 0.3 mmol) in DMF (9 mL) at 0 °C was treated with 4-vinylbenzene sulfonic acid sodium salt (3 g, 14.6 mmol), stirred for 6 h, stored at -10 °C for 3 days, poured into ice water and extracted with benzene. The organic layer was washed with water, dried (Na2S04), filtered and concenttated to provide 4-vilylsulfonyl chloride as a clear, colorless oil. A portion of the chloride (1 g, 4.95 mmol) was disslolved in THF (10 mL), cooled to 0 °C, treated dropwise with concenttated ammonium hydroxide until gas evolution ceased and exttacted with ethyl acetate. The combined extracts were dried (Na2SO4), and concenttated to provide 707 mg of the title compound as a pale yellow solid. MS (DCI/NH3) m/e 201(M+NH4)+. Example 83B (E)-4-r2-(6-Cvano-2-naphthalenyl)ethenyl1benzenesulfonamide The title compound was prepared from Example 55B, Example 83A and the procedure of Example 57B. MS (DCI/NH3) m/e 352 (M+NH4)+.
Example 83C (E)-4-r2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyllbenzenesulfonamide mono(trifluoroacetate) salt The title compound was prepared from Example 83B and the procedure of Example
40D. 'H NMR (300 MHz, DMSO-d6) δ 9.43 (s, 2H), 9.05 (s, 2H), 8.46 (s, IH), 8.21 (s, IH),
8.16-7.95 (m, 3H), 7.86 (s, 2H), 7.84-7.67 ( , 2H), 7.62 (d, IH), 74-7.36 (m, 2H); MS (DCI/NH3) m/e 352 (M+H)+. Anal, calcd for Cι9Hi7N3θ2S- 1.5C2F3θ2H: C, 50.84; H, 3.59; N, 8.1 1. Found: C, 50.83; H, 3.89; N, 7.88.
Example 84 (E)-4-l2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyl1benzoic acid mono(trifluoroacetate) salt
Example 84A (E)-4-12-(6-Cyano-2-naphthalenyl)ethenyπbenzoic acid The title compound was prepared from Example 55B, 4-vinylbenzoic acid and the procedure of Example 57B. MS (DCI/NH3) m/e 300 (M+H)+.
Example 84B (E)-4-r2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyllbenzoic acid mono(trifluoroacetate) salt The title compound was prepared with Example 84A and the procedure of Example 40D.
IH NMR (300 MHz, DMSO-d6) δ 7.62 - 7.58 (m, 2H), 7.90 (d, 2H), 7.98 (d, IH), 8.12 -
8.04 (m, 3H), 8.20 (s, IH), 8.56 (s, IH), 9.07 (bs, 2H), 9.35 (bs, 2H).
MS (DCI/NH3) m e 317 (M+H)+.
Anal, calcd for C20H16N2O2 FA: C, 61.40; H, 3.98; N, 6.51. Found: C, 61.10; H, 3.63; N, 6.45.
Example 85 4-r7-(Aminoiminomethyl)-2-methoxy-l-naphthalenyl1dihvdro-2(3H)-furanone mono(trifluoroacetate) salt
Example 85A 4-(7-Cvano-2-methoxy- 1 -naphthalenvI)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, filtered through Ceiite® and concenttated. The residue was chromatographed on silica gel with 20% ethyl acetate/ hexanes to provide 170 mg of the title compound. MS (DCI/NH3) m/e 285 (M+NH4)+.
Example 85B
4-l7-(Aminoiminomethyl)-2-methoxy-l -naphthalenylldihvdro-2(3H)-furanone mono(ttifluoroacetate) salt The title compound was prepared from Example 85A and the procedure of Example 40D. I H NMR (300 MHz, DMSO-d6) δ 2.96-2.75 (m, 2H), 3.96 (s, 3H), 4.33 (m, IH), 4.66 (t,
I H), 8.85 (m, I H), 7.68 (dd, IH), 7.73 (d, IH), 8.08 (d, IH), 8.12 (d, IH), 8.67 (s, IH), 9.14 (s, 2H), 9.43 (s, 2H); MS (DCI/NH3) m/e 285 (M+H)+.
Anal, calcd for Cι6Hι6N2θ3- l . lTFA: C, 53.72; H, 4.24; N, 6.91. Found: C, 53.75; H, 4.26; N, 6.94.
Example 86 7-Methoxy-8-(l-acetyl-1 H-pyrazolyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 86A 7-Methoxy-8-( l-acetyl-l H-pyrazolyP-2-naphthalenecarbonitrile A solution of Example 53F (90 mg, 0.361 mmol) in THF (2 mL) was treated with a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (0.866 mL, 0.433 mmol), stirred for 5 min, tteated with acetyl chloride (38 mL, 0.542 mmol), stirred for 10 min and concentrated. The crude product was chromatographed on silica gel with 25% ethyl acetate/hexanes to yield 67 mg of the title compound. MS MS (DCI/NH3) m/e 309 (M+NH )+.
Example 86B 7-Methoxy-8-(l-acetyl-l H-pyrazolvD-2-naphthalenecarboximidamide mono(trifluoroacetate) salt The title compound was prepared with Example 86A and the procedure of Example 40D.
I H NMR (300 MHz, DMSO-d6) δ 3.89 (s, 3H), 7.59 (d, IH), 7.92 (s, 2H), 8.06 (d, I H), 8.12 (d, I H), 8.28 (s, I H), 8.94 (s, 2H), 9.34 (s, 2H); MS (DCI/NH3) m/e 309 (M+H)+.
Anal, calcd for Cι7H i6N4O2T .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 -(methylsulfonvD- 1 H-4-p yrazolvn-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 87A 7-Methoxy-8-f 1 -(methylsulfonvD- 1 H-4-pyrazol vIl-2-naphthalenecarbonitrile The title compound was prepared from Example 53F (190 mg, 0.762 mmol), methanesulfonyl chloride (0.088 mL, 1.14 mmol) and the procedure of Example 86A to provide 122 mg of the title compound. MS (DCI/NH3) m/e 345 (M+NH4)+.
Example 87B 7-Methoxy-8-IT -(methylsulfonvD- 1 H-4-pyrazol vn-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
The title compound was prepared from Example 87A and the procedure of Example 40D. lH NMR (300 MHz, DMSO-d6) δ 2.75 (s, 3H), 3.98 (s, 3H) 7.64 (dd, IH), 7.78 (d, IH), 8.15 (s, IH), 8.18 (s, IH), 8.21 (s, I H), 8.24 (s, IH), 8.62 (s, IH), 8.97 (s, 2H), 9.40 (s, 2H);
MS (DCI/NH3) m/e 345 (M+H)+. Anal, calcd for Cι6Hι6N4θ3S- 1.4TFA: C, 44.75; H, 3.47; N, 1 1.09. Found: C, 44.59; H, 3.86; N, 1 1.38.
Example 88 (E)-4-r2-(6-Aminoininomethyl-2-naphthalenyl)ethenvHbenzamide mono(trifluoroacetate) salt
Example 88A (E)-4-r2-(6-Cvano-2-naphthaIenyl)ethenyllbenzamide Example 85 A (160 mg, 0.54 mmol) in thionyl chloride (4 ml) was refluxed for 0.5 h, cooled to 0 °C, treated with concenttated aqueous ammonia until gas evolution ceased, diluted with ethyl acetate, heated to dissolve residual solids, washed with water, dried (MgS04) and concentrated to provide 100 mg of the title compound as an orange solid. MS (DCI/NH3) m/e 316 (M+NH4)+.
Example 88B (E)-4-r2-(6-Aminoininomethyl-2-naphthalenyl)ethenyl]benzamide mono(trifluoroacetate) salt The title compound was prepared with Example 88A and the procedure of Example I B. IH NMR (300 MHz, DMSO-d6) δ 7.34 (br, IH), 7.51 (d, I H), 7.56 (d, 2H), 7.73 (d, 2H), 7.82 (m, 2H), 7.90 (d, 2H), 7.96 (br, I H), 8.09 (q, 3H), 8.17 (s, IH), 8.43 (s, I H), 9.01 (s, 2H), 9.40 (s, 2H): MS (DCI/NH ) m/e 316 (M+H)+.
Anal, calcd for C^H p^O- l . l TFA: C, 60.09; H, 4. 1 1 ; N, 9.44. Found: C, 60.22; H, 4.13; N, 8.79.
Example 89
6-r2-(4-Aminophenyl)ethoxy1-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
Example 89A 6-F2-(4-Aminophenyl)ethoxy1-2-naphthalenecarbonitrile A solution of Example 4A, (300 mg), CS2CO3 (1.2 g ), 4-aminophenethylbromide (470 mg) and tetrabutylammonium iodide (10 mg) in DMF (5 ml) was stirred for 18 h at room temperature, diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated aq NaHCθ3 and brine, dried (Na2SO4) and concentrated to provide 200 mg of the title compound as a dark brown oil. MS (DCI/NH3) m/e 306 (M+NH4)+.
Example 89B 6-[2-(4-Aminophenyl)ethoxyl-2-naphthaIenecarboximidamide mono(trifluoroacetate) salt The title compund was prepared with Example 89A according to the procedure of
Example 5B.
IH NMR (300 MHz, DMSO-d6) δ 3.15 (t, 2H), 3.6 (bs, 3H), 4.35 (t, 2H), 6.93 (d, 2H),
7.24 (d, 2H) 7.38 (dd, I H), 7.55 (d, IH), 7.78 (dd, IH), 7.98 (dd, IH), 8.21 (d, I H), 8.4
(d, I H), 9.21 (bs, 2H), 9.39 (bs, 2H); MS m/e 306 (M+H)+.
Anal, calcd for Ci9Hi9N 0-2TFA: C, 51.79; H, 3.97; N, 7.88; Found: C, 50.99; H, 4.68; N,
7.59.
Example 90 Methyl B-methoxy-6-(aminoiminomethyl)-4-naphthalenyllcarbamate mono(ttifluoroacetate) salt
Example 90A 7-Methoxy-2-trifluoromethanesulfonyloxy naphthalene A solution of 7-methoxy-2-naphthol (3.24 g, 18 mmole) in DMF (20 mL) and methylene chloride (20 mL) was treated with N-phenyl trifluoromethanesulfonimide (6.6 g, 18 mmole) and triethylamine (5.2 mL, 37 mmole), stirred 20 h at room temperature, diluted with CH2CI2 (100 mL) , washed sequentially with distilled water, 20 % KOH and brine, dried (MgSO4) and concenttated to provide the title compound as a clear oil. MS (DCI/NH3): m/e 272 (M + NH4)+.
Example 90B 7-Methoxy-2-naphthalenecarbonitrile Example 90A (12 mmole), zinc cyanide (12 mmole), Pd(OAc)2 (0.3 mmole) and triphenylphosphine (1.2 mmole) in DMF (40 mL) was heated for 6 h at 85 °C, diluted with ethyl acetate (200 mL), washed with saturated NaHCOi, brine, dried (MgSO4) and concentrated to a dark oily residue. Purification of the residue on silica gel with 1 : 1 hexane: methylene chloride then CH2CI2 provided 1.8 g of the title compound as a white solid. MS (DCI/NH3) m/e 201 (M + NH4)+.
Example 90C 7-Methoxy-8-nitto-2-naphthalenecarbonitrile Example 90B (3 g, 16.4 mmole) in acetic anhydride (30 mL) at 0 °C was treated with fuming HNO3 (1.2 mL), and the resulting thick slurry was diluted with water (20 mL), stirred 20 min then filtered and dried in vacuo to provide 3.69 g of the title compound as a yellow solid. MS (DCI/NH3) m/e 246 (M+NH4)+.
Example 90D 7-Methoxy-8-amino-2-naphthonitrile
Example 90 C (3.69 g, 16.1 mmole) and 10% Pd/C (0.4 g) in ethyl acetate (100 mL) was stirred under a hydrogen atmosphere for 2 h at room temperature, filtered and concenttated to provide 3 g of the title compound as a yellow solid. MS (DCI/NH3) m/e 217 (M+NH4)+.
Example 90E Methyl r3-methoxy-6-cvano-4-naphthalenvπcarbamate Example 90D ( 1 mg, 0.41 mmol) in dioxane (7 mL) and 10% NaOH ( 15 mL) was treated with methyl chloroformate (1 12 mg. 0.98 mmol), stirred for 2 h, diluted with ethyl acetate, washed with water, dried (MgSU4) and concenttated to provide 105 mg of the title compound. MS (DCI/NH3) m/e 274 (M+NH3)+.
Example 90F Methyl r3-methoxy-6-(aminoiminomethyl)-4-naphthalenyllcarbamate mono(trifluoroacetate) salt The title compound was prepared from Example 90E according to the procedure of
Example 40D. 'H-NMR (300 MHz, DMSO-d ) δ 9.48 (s, 2H), 8.99 (s, 2H), 8.93 (br, I H), 8.34 (s, I H), 8.12 (d, I H), 8.04 (d, I H), 7.72 (d, I H), 7.65 (dd, IH), 3.95 (s, 3H); MS (DCI/NH ) m/e 274 (M+H)+; Anal, calcd for Cι4Hι5N3θ3- 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-r2-pyrimidinyl(amino)l-2-naphthalenecarboximidamide bis(trifluoroacetate) salt
Example 91 A 7-Methoxy-8-f2-pyrimidinyl(amino)1-2-naphthalenecarbonitrile A solution of Example 90D (230 mg, 1.2 mmole), 2-chloropyrimidine (280 mg, 2 mmole), sodium-tert-butoxide (120 mg, 1.2 mmole), Pd(dba)3-CHCl3 and dppf in toluene (5 mL) was heated in a sealed tube for 18 h at 100 °C, diluted with ethyl acetate (100 mL), washed with brine, dried (MgSO4) and concentrated to provide 100 mg of a brown oil. MS (DCI/NH3) m/e 294 (M+NH )+.
Example 9 IB
7-Methoxy-8-r2-pyrimidinyl(amino)1-2-naphthalenecarboximidamide bis(trifluoroacetate) salt The title compound was prepared in a manner analogous to that of Example 40D. 1H- NMR (300 MHz, DMSO-d6) δ 9.43 (s, 2H), 9.1 1 (s, 2H), 8.46 (s, IH), 8.16 (br, 3H), 8.15 (d, I H), 8.04 (d, I H), 7.82 (dd, I H), 7.75 (d, IH), 7.54 (s, I H) 7.50 (d, IH), 4.08 (d, 2H); MS (DCI/NH3) m/e 294 (M+H)+.
Anal, calcd for Ci6H i5N<;O-3.8TFA: C, 39.01 ; H, 2.61 ; N,9.64; Found: C, 39.01 ; H, 3.06; N, 9.63.
Example 92 6-(aminoiminomethyl)-N-[4-(hvdroxymethyl)phenyn-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
Example 92A 4-amino-benzyloxy-rert-butyldimethylsilyl ether 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 te/ -butyl dimethylsilyl chloride (1.22 g, 8.12 mmol), stirred overnight at room temperature, diluted with ethyl acetate ( 100 mL), washed with 1 N H3PO4, saturated NaHCO3 and 10% NaCl, dried (Na2SO4) and concenttated to an oil which was purified on silica gel with 3: 1 hexanes: ethyl acetate to provide 0.5 g of a clear oil. MS m/z 238 (M+H)+. Example 92B Example 92A (0.3, 1.1 mmol) and 6-carboxy-2-naphthonittile, Example 8E (0.2 g, 1 mmol) were processed as described in Example 95C to provide 100 mg of the desired compound.
MS m/z 434 (M+NH4)+.
Example 92C A solution of Example 92B in 1 M tetrabutyl ammonium fluoride THF solution (2 mL) was stirred for lhour at room temperature, quenched with 10% NH4CI solution (50 mL) and diluted with ethyl acetate (100 mL). The layers were separated, and the organic layer was washed with 10% NaCl, dried (MgSθ4) and concenttated to provide a light brown oil which was ttiturated with methylene chloride and filtered to provide 0.1 g of the desired compound as a white solid. MS m/z 320 (M+NH4)+.
Example 92D 6-(aminoiminomethyl)-N-f4-(hydroxymethyl)phenyn-2-naphthalenecarboxamide. mono(frifluoroacetate)(salt) Example 92C (0.1 g, 0.33 mmol) was processed and purified according to the procedure in Example 95D to provide 15 mg of the desired compound. MS m/z 320 (M+H)+;
Η NMR 300 MHz, (DMSO-d6): δ 10.45 (s, I H), 9.45 (bs, 4H), 8.75 (s, IH), 8.59 (s, I H), 8.32 (d, I H), 8.22 (d, I H), 8.18 (dd, I H), 7.92 (dd, I H), 7.85 (d, 2H), 7.45 (d, 2H), 4.20 (s, 2H);
Anal, calc'd for C19H17N3O2 FA: 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) salt
Example 93A 6-cyano-2-naphthalene boronic acid (0.3 g, 1.64 mmol), 4-iodoaniline (0.36 g, 1.64 mmol), Palladium[ l, 1 '-Bis (diphenylphosphino)-feπocene] dichloride (0.13 g, 0.164 mmol) and CsF (0.75 g, 4.92 mmol) are mixed together in DMF (8 mL) heated 20 hours, at 80 °C. The mixture is diluted with ethyl acetate ( 100 mL) washed with 1 N H3PO4, saturated NaHCO3, 10% NaCl, dried over anhydrous sodium sulfate. The drying agent filtered, solvent removed under vacuum leaving a brown solid. The solid is purified on silica gel eluting with 3: 1 hexanes: ethyl acetate. The fractions corresponding to the desired compound are concenttated under vacuum leaving a yellow solid. 0.2 g, 75%. MS (M+NH4 -): 262.
Example 93B 6-(4-aminophenyl)-2-naphthalenecarboximidamide. bis(trifluoroacetate) salt
The desired compound is obtained from the material prepared in Example 93 A (0.1 g, 0.41 mmol) using the procedure described in Example 94D Yield: 35 mg, 53% MS (M+H)+ 262; Η NMR 300 MHz, (DMSO-d6): δ 9.45 (bs, 2H), 9.35 (bs, 2H), 8.45 (d. I H), 8.22 (s, I H), 8.15 (d, I H), 8.10 (d, IH), 7.99 (dd, I H), 7.79 (dd, I H), 7.65 (d, 2H), 6.95 (d, 2H), 4.80 (bs, 3H); Anal, calc'd: C2iHι7N3O6F6: C, 51.54, H, 3.50, N, 8.59, Found: C, 51.95, H, 3.84.
Example 95 methyl 2-[4-[[ r6-(aminoiminomethyl)-2-naphthalenyllcarbonyllaminolphenoxylacetate, mono(trifluoroacetate) salt
Example 95A 4-Acetamidophenol (5 g, 33 mmol) is dissolved in THF ( 100 mL) treated with Cesium carbonate (10.25 g, 33 mmol) and Methyl bromoacetate (3.4 mL, 36 mmol) and stirred 24 hours at room temperature. The reaction mixture is diluted with water ( 100 mL) and concentrated under vacuum. The residue is dissolved in ethyl acetate (100 mL) washed with 1 N H3PO4 (20 mL), saturated NaHCU3 (20 mL), 10% NaCl (20 mL) and dried over anhydrous Na2SO4. The drying agent is filtered and the solvent removed under vacuum leaving the desired compound as a white solid, 6.8 g, (92%). MS (M+NH4+): 241.
Example 95B The material obtained in Example 95A is treated with 2 N HCl (75 mL) and refluxed for 3 hours. The clear mixture is cooled to room temperature then concentrated under vacuum to an off white solid as the desired compound. 6 g, 92%. MS (M+NH4+): 198.
Example 95C 6-carboxy-2-naphthonitrile (0.1 g, .51 mmol) is dissolved in DMF (5 mL) cooled in an ice bath to 5 °C. To the homogeneous mixture is added Diisopropylethylamine (0.18 mL, 1.05 mmol) and O- (7-Azabenzotriazol-l-yl)-N, N, N', N'-tettamethyluronium hexafluorophosphate (HATU). The resultant slurry is stirred at 5 °C 45 minutes. To this slurry is added the material obtained in Example 95B (0.12 g, .56 mmol) and the mixture is stirred at room temperature overnight. The next day, the reaction mixture is diluted with ethyl acetate (100 mL) washed with 1 N H3PO4 (20 mL). saturated NaHC03 (20 mL). 10% NaCl, dried over anhydrous Na2S04 filtered and solvent removed under vacuum yielding the desired compound as a brown solid. 0.28 g, 65%. MS (M+NH4)+: 378.
Example 95D methyl 2-l4-r[r6-(aminoiminomethyl)-2-naphthalenyllcarbonyllaminolphenoxylacetate. mono(trifluoroacetate) salt
The material obtained in Example 95C (0.28 g, .78 mmol) is dissolved in methanol saturated with HCl (g) (30 mL) stirred 18 hours at room temperature. The solvent removed under vacuum and the resultant yellow solid is treated with 2 M NH3/methanol (20 mL). This solution is refluxed 6 hours, cooled, solvent removed under vacuum and the resulting brown solid is purified by reverse phase HPLC. The desired compound is obtained from lyophilization. 19.3 mg, 20% . MS (M+H)+: 378
' HNMR 300 MHz, (DMSO-d6): δ 10.45 (s, I H), 9.45 (bs, 4H), 8.65 (d, IH), 8.59 (s, I H), 8.15 (d, I H), 8.10 (d, IH), 8.08 (d, IH), 7.92 (d, IH), 7.75 (d, 2H), 6.98 (d, 2H), 4.80 (s, 2H), 3.75 (s, 3H),
Anal, calc'd: C23H21 N3O6F3: C, 56.10, H, 4.3, N, 8.53, Found: C, 55.80, H, 3.93, N, 8.33.
Example 96 (E)-6-r2-[(3-hvdroxymethvDphenyllethenvn-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
Example 96A The above was prepared from 3-iodobenzyl alcohol using the procedure in Example 41 A. MS (DCI/NH3) m/z (M+NH3)+ 303.
Example 96B (E)-6-r2-r(3-hvdroxymethyl)phenyllethenyll-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
The above was prepared from Example 96A using method from Example 40D. MS (DCI/NH3) m/z (M+H)+ 303;
'H-NMR (300 MHz, DMSO-d6) δ 9.18 (br, 4H), 8.45 (s, IH), 8.17 (s, IH), 8.13-8.04 (m, 3H), 7.81 (dd, I H), 7.64 (s. IH), 7.57 (d. 2H), 7.51 (d, IH) 7.39 (t, IH), 7.28 (d, IH), 5.27 (t, I H), 4.55 (d, 2H);
Anal, calc'd for C22H19N2O3F3 3/10 TFA: 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 -cvclopropyP-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
Example 97A Copper (I) chloride (43 mg, 0.4 mmol), powdered zinc (26 mg, 0.4 mmol) were suspended in 1 L dioxane for 18 hours. The product from Example 41 B (60 mg, 0.2 mmol) was added and stirred and heated at 95 °C for 20 hours. The reaction mixture was concentrated on silica gel and purified by silica gel chromatography to give the desired compound. MS (DCI/NH3) m/z (M+NH3)+ 287.
Example 97B 6-(2-phenyl- 1 -cvclopropyl)-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
The above was prepared from Example 1 using method from Example IB. MS (DCI/NH3) m/z (M+H)+ 287; 'H-NMR (300 MHz. DMSO-d6) δ 9.41 (s, 2H), 9.16 (s, 2H), 8.46 (s, IH), 7.83 (d, 2H), 7.62 (s, I H), 7.58 (dd, IH), 7.34 (dd, I H), 7.35-7.29 (m, 3H), 7.25-7.17 (m, 2H) 2.38-2.28 (m, 2H), 1.61 (t, 2H);
Anal, calc'd for C22H19N2O2F3 1/10 TFA: C, 65.00; H, 4.70; N, 6.84. Found: C, 65.22; H, 5.23; N, 5.10.
Example 98 (E)-6-r2-r4-(aminomethyl)phenyl1ethenvn-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt)
Example 98A The desired compound was prepared using ethene under 500 atm pressure in a manner; Analagous to that of Example 41 A. MS (DCI/NH3) m/z (M+NH3)+ 197.
Example 98B 4- (Aminomethyl)-iodobenzene hydrochloride (1 g, 3.7 mmol) and Boc anhydride (1.22 g, 5.6 mmol) were mixed with 10% NaOH (15 mL), ethyl acetate (20 mL) and stirred 2 hours. The organic layer was washed with 5% sodium bicarbonate (2x, 10 mL), dried (magnesium sulfate), and concenttated to give 1.22 g of desired compound. MS (DCI/NH3) m/z (M+NH3)+ 351.
Example 98C The desired compound was prepared using the product from Example s 98A and 98B in a manner analagous to that of Example 41 A. MS (DCI/NH3) m/z (M+NH3)+ 402.
Example 98D (E)-6-[2-r4-(aminomethvDphenyllethenyll-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt)
The above product was prepared in a manner analogous to that of Example 40D with the addition of trifluoroacetic acid in methylene chloride to remove the Boc group. MS (DC1/NH3) m/z (M+H)+ 302; 'H-NMR (300 MHz, DMSO-d6) δ 9.43 (s, 2H), 9.1 1 (s, 2H), 8.46 (s, IH), 8.16 (br, 3H), 8.15 (d, IH), 8.04 (d, IH), 7.82 (dd, I H). 7.75 (d, IH), 7.54 (s, IH) 7.50 (d, IH), 4.08 (d, 2H);
Anal, calc'd for C24H2ιN3O4F62/5 TFA: 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)(salt) The desired compound was prepared using material prepared as described in Example
90D and utilizing the procedures described in Example 91 A and Example 40D. MS (DCI/NH3) m/z (M+H)+ 306;
'H-NMR (300 MHz, DMSO-d6) δ 9.33 (s, 2H), 8.98 (s, 2H), 8.63 (s, IH), 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); Anal, calc'd for C2iH2oN3O3F 13/5 TFA: C, 44.03; H, 3.19: N, 5.89. Found: C; 43.97; H, 3.55; N, 6.10.
Example 100 7-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide, bis(ttifluoroacetate)(salt) The desired compound was prepared using material prepared as described in Example
90D and utilizing the procedures described in Example 91 A and Example 40D.
MS (DCI/NH3) m/z (M+H)+ 322;
'H-NMR (300 MHz, DMSO-d6) δ 9.35 (s, 2H), 8.90 (s, 2H), 8.34 (s, IH), 8.1 1 (d, IH),
7.90 (d. I H), 7.72 (d, I H), 7.60 (dd, IH), 7.47 (s. 2H), 6.70 (d, 2H) 6.49 (d, 2H), 3.88 (s, 3H), 3.64 (s, 3H);
Anal, calc'd for C21H20N3O4F3 1/10 TFA: C, 56.90; H, 4.53; N, 9.38. Found: C; 56.88; H,
4.41 ; N, 9.43.
Example 101 7-methoxy-8-r(phenylmethyl)amino1-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
Example 1 1 A 4-Bromostyrene (4.8 g, 26.2 mmol) was dissolved in 100 mL THF and cooled to -78 °C. Butyl lithium (2.5 M in hexanes, 28.8 mmol) was added dropwise and stirred 5 minutes. Iodine in THF was added dropwise until an orange/red color persisted. Concentrated aqueous ammonium chloride (20 mL) was added and the reaction was warmed to room temperature, diluted with ether, washed with 10% Na2S2O5 solution (lx. 50 mL), and brine (l , 50 mL), dried (magnesium sulfate), and concentrated to give the desired compound. MS (DCI/NH3) m/z 122.
Example 101B The product from 104A (2.35 g, 10.2 mmol), 1.6 mL 60%, N-methylmorphiline-N- oxide/water solution, 3.75 mL acetone, 0.1 mL water were stirred 1 hour. 20 mL Osmium tetroxide/te/t-butanol solution (0.02 mmol/mL) was added and stirred at 0 °C for 20 hours. The reaction was concentrated on silica gel and purified by silica gel chromatography to give the desired compound. MS (DCI/NH3) m/z (M+NH )+ 282.
Example 101C The desired compound from Example 104B is coupled using Method 41 A. MS (DCI/NH3) m/z (M+NH3)+ 333.
Example 101D 7-methoxy-8-r(phenylmethyl)amino1-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) The above was prepared from Example 104C using method described in Example 40D. MS (DCI/NH3) m/z (M+H)+ 333;
' H-NMR (300 MHz, DMSO-d6) δ 9.42 (s, 2H), 9.12 (s, 2H), 8.45 (s, I H), 8.15-8.05 (m, 4H), 7.81 (dd, IH), 7.63 (d, 2H), 7.48 (d, 2H), 7.39 (d, 2H), 4.56 (t, IH), 3.45 (d, 2H); Anal, calc'd for C23H2ιN204F3 2/5 TFA: C, 58.19; H, 4.39; N, 5.71. Found: C, 58.17; H, 4.41 ; N, 5.87.
Example 102 7-methoxy-8-(phenylamino)-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
Example 102A Tert-butylcarbamate (3.62 g, 15.7 mmol) was dissolved in 63 mL propanol. 1 18 mL NaOH/water solution (0.4 N), tert-butyl hypochlorite (5.5 mL, 47.8 mmol), and (DHQD)2PHAL (612 mg, 0.61 mmol) in 50 mL propanol were added and stirred 10 minutes. The product from Example 2 (3.62 g, 15.7 mmol), and K2OsO4-2 water (21 1 mg, 0.63 mmol) were added and stirred 24 hours. The reaction was concentrated and recrystallized from ethanol/hexanes to give the desired compound. MS (DCI/NH3) m/z (M+NH )+ 381.
Example 102B The above was prepared from Example 102 using the method described in Example
41A. MS (DCI/NH3) m/z (M+H)+ 415.
Example 102C 7-methoxy-8-(phenylamino)-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt)
The above was prepared from Example 102B using the method described in Example
94D.
MS (DCI/NH3) m/z (M+H)+ 264;
' H-NMR (300 MHz, DMSO-d6) δ 9.42 (s, 2H), 9.07 (s, 2H), 8.45 (s, IH), 8.33 (br, 3H), 8.16-8.03 (m, 4H) 7.75 (d, 2H), 7.56 (s, 2H), 7.49 (d, 2H), 5.49 (br 1 h), 4.28 (br IH),
3.62 (m, 2H);
Anal, calc'd for C 5H23N3θ F6-5 TFA: C, 37.30; H, 2.51 ; N, 3.74. Found: C; 37.06; H,
3.12; N, 4.42.
Example 103
7-methoxy-8-[ (4-methoxyphenvPaminol-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt)
Example 103 A 4-Bromobenzaldehyde (600 mg, 3.24 mmol), 16.2 mL dimethylamine in THF (32.4 mmol), and sodium triacetoxyborohydride (1.24 g, 5.8 mmol) were suspended in dichloroethane ( 10 mL). The reaction mixture was concentiated, diluted with water acidified to pH=2 and extracted with ether (3x, 20 mL). The aqueous solution was basified with NaOH/water to pH=12 and exttacted with methylene chloride (3x, 30 mL, acidified with HCl/methanol and concentrated to give the desired compund. MS (DCI/NH3) m/z (M)+ 214.
Example 103B
The above was prepared from Example 107 A using method from Example 41 A. MS (DCI/NH3) m/z (M+H)+ 313.
Example 103C 7-methoxy-8-r(4-methoxyphenyl)amino1-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt) The above was prepared from Example 103 using method from Example 40D. MS (DCI/NH3) m/z (M+H)+ 294;
'H-NMR (300 MHz, DMSO-d6) δ 9.43 (s, 2H), 9.1 1 (s, 2H), 8.46 (s, IH), 8.18-8.06 (m, 4H), 7.84 (d, 4H), 7.60 (s, 2H), 7.56 (s, I H), 4.53 (s, 2H), 3.05 (s, 6H);
Anal, calc'd for C26H25N3θ4F6 7/5 TFA: C, 48.46; H, 3.73; N, 5.91. Found: C, 48.36; H, 4.25; N, 6.19.
Example 104 (E)-6-[2-r4-(l . 2-dihdyroxyethyl)phenyllethenyll-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
Example 104A The above was prepared from 4-bromobenzyl alcohol and the compound prepared in Example 98 A using the method from Example 41 A. MS (DCI/NH3) m/z (M+NH )+ 303.
Example 104B (E)-6-T2-14-( 1 , 2-dihdyroxyethyl)phenyl1ethenyl1-2-naphthalenecarboximidamide. mono(ttifluoroacetate)(salt)
The above was prepared from Example 104A using method from Example 40D. MS (DCI/NH3) m/z (M+H)+ 303;
'H-NMR (300 MHz, DMSO-d6) δ 9.00 (br, 4H), 8.44 (s, IH), 8.15-8.01 (m, 4H), 7.81 (dd, I H), 7.64 (d, 2H), 7.48 (d, IH), 7.36 (d, 2H), 5.21 (br, IH) 4.53 (s, 2H); Anal, calc'd for C Hi9N203F34/5 TFA: C, 55.84; H, 3.93; N, 5.52. Found: C, 55.60; H, 3.93; N, 6.41.
Example 105 (E)-6-[2-r4-(lR-amino-2-hvdroxyethyl)phenvnethenyll-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt)
Example 105 A Using the procedure described for Example 121 A, and substituting N-BOC-p- iodophenylalanine (BACHEM Bioscience Inc.) for 4-iodoaniline, the desired compound was obtained.
MS (DCI/NH3) m/z 458 (M+NH )+;
'H NMR (300 MHz, CDCI3) δ 1.35 (s, 9H), 2.90 (t, IH), 3.09 (dd, IH), 4.15 (m, IH), 7.20 (d, IH), 7.36 (d, 2H), 7.56 (d, 2H), 7.78 (d, IH).7.85 (d, IH), 8.12 (d, IH), 8.17 (d, IH), 8.32 (s, IH), 8.62 (s, IH).
Example 105B Using the product obtained in Example 105 A and the procedure described in Example 40D the desired compound was obtained. MS (ESI) m/z 458 (M+H)+;
'H NMR (300 MHz, DMSO) δ 1.35 (s, 9H), 2.90 (dd, IH), 3.10 (dd, IH), 4.13 (m, IH), 7.10 (d, IH), 7.36 (d, 2H), 7.55 (d, 2H), 7.78 (dd, IH), 7.85 (dd, IH), 8.13 (d, IH), 8.19 (d, IH), 8.30 (s, IH), 8.50 (s, IH), 9.22 (s, 2H), 9.42 (s, 2H).
Example 105C
(E)-6-l2-r4-(lR-amino-2-hvdroxyethyl)phenyllethenyll-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt) Using the product obtained in Example 105B and the procedure described for Example 124D, the desired compound was obtained. MS (ESI) mz 358 (M+H)+;
'H NMR (300 MHz, DMSO) δ 3.02 (m, IH), 3.19 (dd, IH), 3.63 (t, IH), 7.39 (d, 2H), 7.58 (d, 2H), 7.76 (d, IH), 7.88 (d, IH), 8.15 (d, IH), 8.19 (d, IH), 8.30 (s, IH), 8.51 (s, IH), 9.41 (s, 2H), 9.80 (s, 2H); Anal, calc'd for C2 H2θF3N304-H20: 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-pyrimidinylamino)-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt)
Example 106 A Sodium borohydride (0.22 g, 5.8 mmol) was added to a suspension of (4- bromobenzoyl)methanol (2.5 g, 1 1.6 mmol, Maybridge Chem. Co.) and 25 mL abs. ethanol. The reaction mixture was stirred at reflux for 1 hour. After cooling to room temperature, the ethanol was evaporated under vacuum, and water was added to the residue. The mixture was extracted with CH2CI2. The extracts were washed with saturated aqueous sodium chloride, dried over MgSO4, filtered, and evaporated under vacuum to afford the desired compound. MS (DCI/NH3) m/z 234/236 (M+NH4)+; ' H NMR (300 MHz, CDCI3) δ 2.10 (t, I H), 2.62 (d, I H), 3.63 (m, IH), 3.78 (m, I H), 4.81 (m, IH), 7.25 (d, 2H), 7.50 (d, 2H).
Example 106B Using the product obtained in Example 106A and the procdure described in Example A- 22621 -A, the desired compound was obtained. MS (DCI/NH3) m/z 331 (M+NFLι)+;
Η NMR (300 MHz, CDCI3) d3.45 (t, IH), 4.59 (q, IH), 4.76 (t, I H), 5.36 (d, I H), 7.42 (d, 2H), 7.59 (d, 2H), 7.78 (dd, IH), 7.85 (dd, I H), 8.10 (d, IH), 8.15 (d, I H), 8.30 (s, IH), 8.61 (s, I H).
Example 106C 7-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt) Using the product obtained in Example 106B, and the procedure described in Example 40D, the desired compound was obtained. MS (ESI) m/z 331 (M+H)+;
Η NMR (300 MHz, DMSO) δ 3.45 (t, IH), 4.59 (q, IH), 4.78 (t, IH), 5.38 (d, IH), 742 (d, 2H), 7.59 (d, 2H), 7.78 (dd, IH), 7.84 (dd, IH), 8.12 (d, IH), 8.18 (d, IH), 8.31 (s, IH), 8.50 (s, IH), 9.20 (s, 2H), 9.43 (s, 2H); Anal, calc'd for C2 Hi9F3N2θ -H20: C. 59.74; H, 4.58; N, 6.06. Found: C, 59.95; H, 4.17; N, 6.13.
Example 107 5 (E)-6-r2-rr4-(dimethylamino)methyllphenyllethenyn-2-naphthalenecarboximidamide, bis(ttifluoroacetate)(salt)
Example 107 A Using the procedure described for Example 121 A, and substituting 3- l() benzyloxybromobenzene (Chem. Ber.124 (1), 163, 1991) for 4-iodoaniline, the desired compound was obtained. MS (DCI/NH3) m/z 377 (M+NH4)+;
Η NMR (300 MHz, CDCl3) δ 5.1 1 (s, 2H), 7.02 (d, IH), 7.20 (m, 2H), 7.29 (d, I H), 7.31 (d, I H), 7.42 (m. 3H), 7.60-7.75 ( , 3H), 7.89 (t, 2H), 8.08 (s, I H), 8.21 (s, IH). is
Example 107B (E)-6-|2-[[4-(dimethylamino)methynphenyllethenyl1-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt) Using the product obtained in Example 108B, and the procedure described in Example 20 40D, the desired compound was obtained. MS (ESI) m/z 377 (M+H)+;
Η NMR (300 MHz, DMSO) δ 5.18 (S, 2H), 7.12 (dd, IH), 7.22 (d, IH), 7.28 (m, IH), 7.40 (t, 3H), 7.45 (t, 3H), 7.79 (dd, I H), 7.85 (dd, IH), 8.16 (d, IH), 8.20 (d, IH), 8.35 (s, I H), 8.50 (s, I H), 9. 30 (s, I H); 25 Anal, calc'd for C28H21F3N2O3O.25 H20: C, 67.94; H, 4.38; N, 5.66. Found: C, 67.80; H, 4.48; N, 5.43.
Example 108 (E)-6-[2-r4-(hydroxymethyl)phenyllethenyl1-2-naphthalenecarboximidamide. 30 mono(trifluoroacetate)(salt)
Using the product obtained in Example 108A and the procedure described in Example 94D the desired compound was obtained.
MS (ESI) m/z 287 (M+H)+; Η NMR (300 MHz, DMSO) δ 6.89 (m, IH), 6.98 (t, IH), 7.03 (d, IH), 7.29 (t, IH), 7.78 (dd, IH), 7.88 (dd, IH), 8.13 (d, IH), 8.17 (d, IH), 8.32 (s, IH), 8.50 (s, IH), 9.40 (s, 5H);
Anal, calc'd for C21H15F3N2O3O.5 H2O: C, 61.62; H, 3.94; N, 6.84. Found: C, 61.29; H, 3.81 ; N, 6.59.
Example 109 4-rr6-(aminoiminomethvD-2-naphthalenvnethvnvn-L-phenylalanine, mono(trifluoroacetate)(salt)
Example 109A To a solution of the product from Example 8D (2.13 g, 10.08 mmol) and LiBH4 (121 mg, 5.55 mmol) in THF (5 mL) was added toluene (2 mL), and the THF was boiled off using a short-path distillation apparatus over several hours. The reaction was then heated at 70°C for 2 hours, cooled, quenched with 1 M HCl, and extracted with 2x ethyl acetate. The exttacts were washed with water and brine, dried over Na2Sθ4, and condensed. The crude product was chromatographed on Siθ2 using 50% ethyl acetate/hexanes as eluent, to yield 1.12 g (61%) of the desired compound. MS (DCI (NH3)) m/z 201 (M+NH4)+; Η NMR (300 MHz, CDCI3) δ 8.22 (s, I H), 7.90 (m, 3H), 7.61 (m, 2H), 4.92 (d, 2H), 1.84 (t, IH).
Example 109B To a solution of the product from Example 109A (2.12 g, 1 1.57 mmol) and LiBr (1.1 1 g, 12.73 mmol) in DMF ( 100 mL) was added PBr3 ( 1.21 mL, 12.73 mmol) at 0°C, and the reaction was warmed to room temperature, and stiπed for 1 hours. The reaction was then quenched with pH 7 buffer, and extracted with 3x diethyl ether/hexanes. The exttacts were washed with 2x water and 2x brine, dried over Na2SU4, and condensed, to yield 2.72 g (96%) of the desired compound. MS (DCI (NH3)) m z 185 (M+NH4-Br)+,
'H NMR (300 MHz, CDCI3) δ 8.22 (s, IH), 7.92 (s, IH), 7.90 (s, 2H), 7.62 (dd, 2H), 4.64 (s, 2H).
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 was stirred at room temperature for 20 minutes. The product from Example 109B (270 mg, 1.1 mmol) was then added, and the reaction was stirred for 10 minutes. The crude reaction mixture was chromatographed on Siθ2 using hexanes as eluent, to yield 220 mg (77%) of the desired compound. MS (DCI (NH )) m/z 305 (M+NH4)+;
'H NMR (300 MHz, CDC13) δ 8.22 (s, IH), 7.95 (s, IH), 7.93 (s, IH), 7.91 (s, IH), 7.66 (dd, IH), 7.61 (dd, IH), 7.15 (d, 2H), 6.94 (d, 2H), 5.22 (d, 2H), 2.60 (q, 2H), 1.21 (t, 3H).
Example 109D 4-r[6-(aminoiminomethyl)-2-naphthalenyllethvnvn-L-phenylalanine. mono(trifluoroacetate)(salt) The desired compound was prepared from Example 109C and the procedure of Example 55D.
MS (DCI/NH3) m/z 305 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 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, IH), 7.82 (dd, IH), 8.15 (m, 3H), 8.48 (s, IH), 9.01 (br s, 2H), 9.62 (br s, 2H); Anal, calc'd for C2oH2oN2O- 1.4 CH4SO3: C, 58.56; H, 5.88; N, 6.38. Found: C, 58.55; H, 5.56; N, 6.39.
Example 1 1 1
6-(3-formylphenyl)-2-naphthalenecarboximidamide. mono(tτifluoroacetate)(salt)
Example 1 1 1A The product from Example 28B (334 mg, 1.1 1 mmol), palladium acetate (25 mg, 0.1 1 mmol), dppf (123 mg, 0.22 mmol) were dissolved in degassed DMF (5 mL) and stirred at room temperature for 1/2 hour. Cesium carbonate (902 mg, 2.8 mmol) and 2- formylphenylboronic acid (251 mg, 1.27 mmol) were added and stirred under nitrogen at 80 °C for 1 hour, poured into pH 7 buffer, extrated with diethyl ether (3x, 20 mL), and dried. The desired compound was purified by chromotography eluting with 10% ethyl acetate/ hexanes. MS (DCI/NH3) m/z (M+NH3)+ 275. Example 1 1 1 B 6-(3-formylphenyl)-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt) The above product was prepared in a manner analogous to that of Example IB. MS (DCI/NH3) m/z (M+H)+ 274; ' H-NMR (300 MHz, DMSO-d6) δ 10.16 (s, IH), 9.47 (s, 2H), 9.10 (s, 2H), 8.54 (s, I H), 8.52 (s, I H), 8.41 (s, IH), 8.28-8.23 (m, 3H), 8.12 (dd, I H), 8.00 (dd, IH), 7.87 (dd, IH), 7.80 (t, IH);
Anal, calc'd for C20H15N2O3F3 2/5 TFA: C, 59.28; H, 3.70; N, 6.34. Found: C; 59.36; H, 3.89; N, 7.21.
Example 1 12 (E)-6-12-( l . 2. 3. 4-tetrahvdro-6-isoquinolinyl)ethenvn-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt)
Example 1 12A
The above was prepared from Example 127 using method described in Example 41 A. MS (DCI/NH3) m/z (M+H)+ 41 1.
Example 1 12B (E)-6-l"2-( l . 2. 3. 4-tetrahydro-6-isoquinolinyl)ethenyn-2-naphthalenecarboximidamide, bis(trifluoroacetate)(saIt) The desired compound was prepared by the method described in Example 40D. MS (DCI/NH3) m/z (M+H)+ 328;
' H-NMR (300 MHz, DMSO-d6) δ 9.36 (s, 2H), 9.25 (s, 2H), 9.10 (d, 2H), 8.41 (s, IH), 7.99 (t, 2H). 7.89 (d, IH), 7.78 (d, IH), 7.71 (dd, I H), 7.56 (m, 4H). 7.43 (s, I H), 3.1 1 (br, 2H ) 2.16 (br 2H), 1.78 (br, 2H);
Anal, calc'd for C26H23N3O4F6 3/5 TFA: C, 52.31 ; H, 3.81 ; N, 6.72. Found: C, 52.13; H, 4.42; N, 7.23.
Example 1 13
(E)- 6-r2-r3-(2-hydroxyethyl)phenyllethenyl1-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
Example 1 13A The above was prepared from 2-bromo-3 (hydroxyethyl)alcohol and the compound prepared in Example 98A using method described in Example 41 A
MS (DCI/NH3) m/z (M+NH )+ 317.
Example 1 13B
(E)- 6-r2-r3-(2-hydroxyethyl)phenyllethenyll-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt) The above was prepared from Example 1 13A using method described in Example 40D. MS (DCI/NH3) m/z (M+H)+ 317; 'H-NMR (300 MHz, DMSO-d6) δ 8.9 (br, 4H), 8.46 (s, IH), 8. 17 (s, IH), 8.13-8.03 (m, 3H), 7.82 (dd, IH), 7.54 (s, 2H), 7.49 (s, 2H), 7.33 (t, IH) 7.18 (d, IH), 4.71 (t, I H), 3.66 (m, 2H), 2.78 (t, 2H):
Anal, calc'd for C23H21 N2O3F3 3/10 TFA: C, 61.41 ; H, 4.66; N, 6.09. Found: C, 64.18; H, 4.92; N, 6.51.
Example 1 14 6-(aminoiminomethvD-4-(3-furanvD-N-r4-(trifluoromethyl)phenyn-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
Example 1 14A
The product from Example 152B (100 mg, 0.36 mmol), 4- (trifluoromethyl)aniline (86 mg, 0.53 mmol), and DMAP (5 mg, 0.04 mmol) were dissolved in THF (5 mL) and stirred for 24 hours. The reaction mixture was concentrated on silica gel and purified by chromotography (Biotage Flash 40) using ethyl acetate/hexanes. MS (ESI) m/z (M+H)+ 406.
Example 1 14B 6-(aminoiminomethyl)-4-(3-furanvD-N-r4-(trifluoromethyl)phenyn-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
The above was prepared from Example 1 14A using method described in Example I B. MS (CD m/z (M+H)+ 424; 'H-NMR (300 MHz, DMSO-d6) δ 10.91 (s, I H), 9.51 (s, 2H), 9.1 1 (s. 2H), 8.69 (s, I H), 8.62 (s, IH), 8.43-8.35 (m, 2H), 8.18 (d, IH), 8.06 (d, 2H), 7.98 (t. IH), 7.92 (dd, IH), 7.78 (dd, 2H) 7.14 (m, IH);
Anal, calc'd for C25Hi7N O F6 1/10 TFA: C, 55.37; H, 3.15: N, 7.70. Found: C, 55.44; H, 3.15; N, 7.31.
Example 1 15 6-(aminoiminomethyl)-4-(3-furanyl)-N-(4-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride
Example 1 15A The above product was prepared in the manner of Example 1 14A. MS (ESI) m/z (M+H)+ 340.
Example 1 15B
6-(aminoiminomethyl)-4-(3-furanyl)-N-(4-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride The above was prepared from Example 1 15A using method described in Example IB. MS (AP/CI) m/z (M+H)+ 357; ' H-NMR (300 MHz, DMSO-d6) δ 12.43 (s, IH), 9.69 (s, 2H), 9.40 (s, 2H), 8.94 (s, I H), 8.81 (d, 2H), 8.65 (s, IH), 8.58-8.56 (m, 2H), 8.49 (s, I H), 8.42 (d, IH), 8.30 (m, IH) 7.97-7.95 (m, 2H), 7.27 (s, I H);
Anal, calc'd for C21H 18N4O2CI2 37/10 HCl: C, 44.65 H, 3.88 N, 9.92. Found: C, 44.72; H, 3.70; N, 9.51 .
Example 1 16 6-(aminoiminomethvD-4-(3-furanyl)-N-(l H-pyrazol-3-yl)-2-naphthalenecarboxamide, dihydrochloride
Example 1 16A
The above product was prepared in the manner of Example 1 14A. MS (ESI) m/z (M+H)+ 329.
Example 1 16B 6-(aminoiminomethyl)-4-(3-furanyl)-N-(l H-pyrazol-3-yl)-2-naphthalenecarboxamide. dihydrochloride The above was prepared from Example 1 16A using method described in Example IB. MS (CI) m/z (M-H)+ 344; 'H-NMR (300 MHz, DMSO-d6) δ 1 1.16 (s, IH), 9.52 (s, 2H), 9.10 (s, 2H), 8.69 (s, IH),
8.61 (s, IH), 8.35 (m, 2H), 8.24 (s, IH), 7.96-7.88 (m. 3H), 7.69 (m, IH), 7.15 (s, IH) 6.69 (m, I H);
Anal, calc'd for C1 H17N5O2CI2 9/10 HCl: C, 50.63; H, 4.00; N, 15.54. Found: C, 51.05; H, 4.62; N, 14.26.
Example 1 17 6-(aminoiminomethyl)-4-(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecarboxamide. dihydrochloride
Example 1 17A
The above product was prepared in the manner of Example 1 14A. MS (ESI) m/z (M+H)+ 340.
Example 1 17B 6-(aminoiminomethyl)-4-(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecarboxamide. dihydrochloride The above was prepared from Example 1 17B using method described in Example I B. MS (CI) m/z (M+H)+ 357; ' H-NMR (300 MHz, DMSO-d6) δ 10.90 (s, I H), 9.59 (s, 2H), 9.26 (s, 2H), 9.03 (s, 2H), 8.74 (s, I H). 8.63 (s, I H), 8.42-8.26 (m, 3H), 8.22 (s, I H), 7.97-7.91 ( , 2H), 7.47-7.43 ( m, 2H), 7.17 (s, I H);
Anal, calc'd for C21H 18N4O2CI2 55/10 HCl: C, 40.00 H, 3.76 N, 8.89. Found: C, 40.09; H, 3.78; N, 8.44.
Example 1 18
6-(aminoiminomethyl)-N-(2. 3-dihvdro- 1 H-inden-5-yl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
Example 1 18A To a solution of the compound prepared in Example 8E (303 mg, 1.4 mmol) in THF (30 mL) and propylene oxide (15 mL) was added two drops of Et3N followed by the 5- aminoindene (300 mg, 2.2 mmol). The reaction was stined at room temperature overnight. The solvent was evaporated and the product was purified via crystallization from ether to yield 226 5 mg (56%) of the product as white solid. Mass spectrum (CI+), 313 (M+l)+.
Example 1 18B 6-(aminoirninomethyl)-N-(2. 3-dihvdro- 1 H-inden-5-yl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) 10 The compound prepared in Example 1 18A (205 mg, 0.66 mmol) in THF (20 mL) at room temperature, was added butyl lithium ( 1 mL, 1 mmol) followed by chlorotrimethyl silane
( 180μL, 1.5 mmol). After 10 minutes the mixture was charged with additional butyl lithium (3 mL, 3 mmol). The reaction was stirred at room temperature, overnight. The reaction mixture was added a solution of 4 N HCl in dioxane stined for an hour then added water and i s evaporated. The product was purified by MPLC RP Cis with methanol-water and 0.1 % TFA as eluent chromatography. The yield of the product as TFA salt with 0.257c water as white solid
51 mg (17%).
MS (ESI+) 330 (M+l)+;
Η NMR (DMSO-d6) 10.45 (s, I H), 9.51 (s, 2H), 9.21 (s, 2H), 8.66 (s, IH), 8.55 (s, I H), 0 8.32 (d, J=8.5Hz, I H), 8.20 (Abq, J=9.0Hz, 2H), 7.90 (dd, Jι=9.0Hz, J2=1.5Hz, I H), 7.73
(s, IH), 7.53 (dd, Jι=8.0Hz, J =1.5Hz, I H), 7.22 (d, J=8.1Hz, IH), 2.91-2.82 (m, 4H),
2.04 (quintet, J=7.3Hz, 2H);
Anal, calc'd for C2ιH ι9N θ FA-0.25 H2O C: 61.67; H, 4.61 ; N, 9.38. Found: C: 61.63; H,
4.43; N, 9.25. 25
Example 1 19 methyl 5-l7-[(aminoiminomethyl)-2-naphthalenylloxylpentanoate, mono(ttifluoroacetate) (salt)
Example 1 19 A 30 7-hvdroxy-2-cvanonaphthaIene
7-methoxy-2-cyanonaphthalene (2.79 g, 5.23 mmol) and tetrabutylammonium iodide (17 mg, 0.157 mmol) were combined in a mixture of benzene (35 mL) and cyclohexanes (17.5 mL). The resulting solution was added to a rapidly stirring, cooled (ice/water) suspension of aluminum triiodide (6.21 g, 15.23 mmol) in a mixture of benzene (35 mL) and cyclohexanes ( 17.5 mL) under an inert atmosphere. After the addition, the resulting suspension was heated at reflux for 2.5 hours. The heating was removed and after cooling to near room temperature, the reaction mixture was cooled in an ice bath and quenched by the addition of water (100 mL). The resulting mixture was further diluted with 2 M aqueous sodium thiosulfate solution (50 mL) and exttacted with ethyl acetate (3 X 80 mL). The combined organic layers were dried and evaporated. The resulting solid was dissolved in a minimum of hot ethyl acetate, diluted hot with hexanes to the cloud point and placed in a refrigerator for 2 hours. The desired compound was collected by filtration, ( 1.99 g, 77%). MS (DCI (NH )) m/z 187 (M+NH4)+.
Example 1 19B The resulting product from Example 1 19A was treated with methyl 5-bromovalerate in an analogous manner as described in Example 1 19A. MS (DCI (NH )) m/z 301 (M+NH )+.
Example 1 19C methyl 5-l7-r(aminoiminomethyl)-2-naphthalenylloxylpentanoate. mono(trifluoroacetate) (salt) The resulting product from Example 1 19B (380 mg, 1.3412 mmol) was tteated in an analogous manner as described in Example 94D to yield the desired compound (369 mg, 73%). MS (DCI (NH )) m/z 301 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 1.785 (m, 4H), 2.425 (t, 2H), 3.600 (s, 3H), 4.150 (t,
2H), 7.380 (dd, IH), 7.460 (d, I H), 7.640 (dd, IH), 7.980 (d, IH), 8.070 (d, I H), 8.322 (d,
I H), 9.230 (v br s, 3H);
Anal, calc'd for Ci 7H2θN2θ3-C2H02F3: C, 55.07; H, 5.1 1 ; N, 6.76. Found: C, 54.96; H, 5.22; N. 6.66.
Example 120 (E)-3-l7-(aminoiminomethyl)-2-methoxy-l -naphthalenyl)-2-propenamide. mono(triflυoroacetate)(salt)
Example 120A The product obtained from Example 53B and acrylamide were subjected to the conditions described in Example 41 A to provide the desired compound. MS (DCI/NH3) m/z 253 (M+H)+. Example 120B (E)-3-r7-(aminoiminomethyl)-2-methoxy-l-naphthalenyl)-2-propenamide. mono(trifluoroacetate)(salt) The product obtained from Example 120 A was subjected to the conditions described in
Example 94D to provide the desired compound. MS (DCI/NH3) m/z 270 (M+H)+;
'H NMR (300 MHz, DMSO) δ 4.02 (s, 3H), 6.90 (d, IH), 7.22 (s, IH), 7.62-7.70 (m, 2H), 7.74 (d, IH), 8.02 (d, IH), 8.1 1 (d, IH), 8.15 (d, IH), 8.58 (s, IH), 9.18 (s, 2H), 9.50 (s, 2H);
Anal, calc'd for Ci7Hi6F3N3θ4-H2θ: C, 50.88; H, 4.52; N, 10.47. Found: C, 50.89; H, 4.32; N, 10.43.
Example 121 6-r(4-aminophenyl)ethynyll-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt)
Example 121 A A mixture of the product obtained in Example 63B (130 mg, 0.73 mmol), 4-iodoaniline (173 mg, 0.79 mmol), dichlorobis (triphenylphosphine)palladium (II) (25 mg, 0.0325 mmol), copper (I) iodide (2.7 mg, 0.0186 mmol), DMF (0.65 mL), and triethylamine (1.95 mL) was degassed with N2 and was stined at 75°-80° for 1.5 hour. The mixture was cooled to room temperature, diluted with CH2CI2, washed with water, dried (MgSO4), filtered, and evaporated under vacuum to afford an oil which was purified by flash chromatography, eluting with 3: 1 hexanes: ethyl acetate to afford the desired compound. MS (DCI/NH3) m/z 269 (M+H)+
Example 121 B 6-f(4-aminophenyl)ethynyl1-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt) Using the product obtained in Example 121 A and the procedure described in Example 40D, the desired compound was obtained. MS (DCI/NH3) m/z 286 (M+H)+;
'H NMR (300 MHz, DMSO) δ 6.80 (d, 2H), 7.29 (d, 2H), 7.70 (dd, IH), 7.85 (dd, IH), 8.09 (d, IH), 8.14 (d, IH), 8.20 (s, IH), 8.45 (s, I H), 9.09 (s, 2H), 9.42 (s, 2H); Anal, calc'd for C23H17F6N3O4O.25 H2O: C, 53.34; H, 3.41; N, 8.1 1. Found: C. 53.45; H, 3.70; N, 7.76. Example 122
1. 1 -dimethylethyl r2-r3-rr6-(aminoirrrinomethyl)-2-naphathalenyl1ethvnyπ-6- methoxyphenyllethyllcarbamate, mono(trifluoroacetate)(salt)
Example 122A Using 5-bromo-2-methoxyphenethylamine hydrobromide (Transworld), and the procedure described in Example 63C, the desired compound was obtained. MS (DCI/NH3) m/z 330 (M+H)+.
Example 122B Using the procedure described for Example 121 A, and substituting the product obtained in Example 122A for 4-iodoaniline, the desired compound was obtained.
MS (ESI) m/z 427 (M+H)+.
Example 122C 1. 1 -dimethylethyl r2-[3-rr6-(aminoiminomethvP-2-naphathalenyl1ethynyll-6- methoxyphenyl lethyllcarbamate. mono(trifluoroacetate)(salt) Using the product obtained in Example A-226638-B and the procedure described in Example 40-D, the desired compound was obtained. MS (DCI/NH3) m/z 444 (M+H)+;
Η NMR (300 MHz, DMSO) δ 1.38 (s, 9H), 2.70 (t, 2H), 3.15 (q, 2H), 3.85 (s, 3H), 6.89 (t, I H), 7.04 (d, I H), 7.37 (d, I H), 7.49 (dd, I H), 7.75 (dd, I H), 7.85 (dd, I H), 8.1 1 (d, I H), 8.16 (d, I H), 8.30 (s, IH), 8.48 (s, IH), 9.07 (s, 2H), 9.42 (s, 2H) ; Anal, calc'd for C29H30F3N3O5O.25 H20: C, 61.97; H, 5.47; N, 7.48. Found: C, 61.81 ; H, 5.14; N, 7.21 .
Example 123 1. 1 -dimethylethyl rr4-rr6-(aminoiminomethyl)-2-naphathalenvnethvnyllphenynmethyl1 carbamate. mono(trifluoroacetate)(salt)
Example 123 A Using 4-bromobenzylamine, and the procedure described in Example 63C, the desired compound was obtained. MS (DCI/NH3) m/z 303 (M+NH4) -.
Example 123B Using the procedure described for Example 121 A, and substituting the product obtained 5 in Example 123 for 4-iodoaniline, the desired compound was obtained. MS (DCI/NH3) m/z 400 (M+NH )+.
Example 123C 1. 1 -dimethylethyl I r4-r[6-(aminoiminomethyl)-2-naphathalenyllethvnyllphenyl1methyll 10 carbamate, mono(trifluoroaeetate)(salt)
Using the product obtained in Example 123B and the procedure described in Example 40D. the desired compound was obtained. MS (DCI NH3) m/z 400 (M+H)+;
Η NMR (300 MHz, DMSO) δ 1.40 (s, 9H), 4.1 (d, 2H), 7.34 (d, 2H), 745 (t, IH), 7.58 15 (d, 2H), 7.78 (dd, IH), 7.86 (dd, IH), 8.15 (d, IH). 8.19 (d, IH), 8.31 (s, IH), 8.50 (s, I H), 9.10-9.42 (s, 4H) ;
Anal, calc'd for C27H26F3N3O4: C, 63.15; H, 5.10; N, 8.18. Found: C, 62.95; H, 4.97; N, 8.09.
">ι 0 Example 124
6-rr4-(aminomethyl)phenyllethynyll-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt)
Trifluoroacetic acid (0.73 mL) was added dropwise to a suspension of the product obtained in Example 123C (80 mg, 0.2 mmol) and 1.5 mL CH2CI2. The reaction mixture was 25 stined for 0.25 hour at room temperature, then was evaporated to dryness under vacuum.
Toluene was added and evaporated under vacuum several times to afford a tan solid which was purified by reverse phase chromatography, eluting with methanol / 0.1 % aqueous TFA to afford the desired compound.
MS (APCI) m z 300 (M+H)+; 30 'H NMR (300 MHz, DMSO) δ 4.10 (s, 2H), 7.55 (d, 2H), 7.70 (d, 2H), 7.79 (dd, IH), 7.89
(dd, I H), 8.16 (d, IH), 8.19 (d, I H), 8.20 (s, 2H), 8.36 (s, I H), 8.53 (S, IH), 9.20 (s, 2H),
9.44 (s, 2H);
Anal, calc'd for C24Hi9F6N3O4: C, 54.66; H, 3.63; N, 7.97. Found: C, 54.42; H, 3.57; N,
7.76. Example 125 6-rr3-(2-aminoethyl)-4-methoxyphenyIlethynyll-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt)
Using the product obtained in Example 122C and the procedure described for Example 124, the desired compound was obtained. MS (ESI) m/z 344 (M+H)+; 'H NMR (300 MHz, DMSO) δ 2.90 (t, 2H), 3.06 (t, 2H), 3.88 (s, 3H), 7.1 1 (d, IH), 7.44 (d, IH). 7.57 (dd, IH), 7.75 (dd, I H), 7.82 (s, 2H). 7.88 (dd, IH), 8.12 (d, IH), 8.17 (d, I H), 8.28 (s, I H), 8.50 (s, I H), 9.20 (s, 2H), 9.45 (s, 2H); Anal, calc'd for C26H2 F6N3O5O.5 H20: C, 53.80; H, 4.17; N, 7.24. Found: C, 53.89; H,
4.31 ; N, 6.83.
Example 126
6-r[4-(hvdroxymethyl)phenyl1ethvnvn-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
Example 126A Using the procedure described for Example 121 A, and substituting 4-bromobenzyl alcohol for 4-iodoaniline, the desired compound was obtained. MS (DCI/NH3) m/z 301 (M+NH4)+.
Example 126B 6-rr4-(hvdroxymethyl)phenyllethvnyl l-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt) Using the product obtained in Example 126A and the procedure described in Example 94B the desired compound was obtained. MS (ESI) m/z 301 (M+H)+; ' H NMR (300 MHz, DMSO) δ 4.58 (d, 2H), 5.32 (t, IH), 7.41 (d, 2H), 7.59 (d, IH), 7.79 (dd, IH), 7.86 (dd, IH), 8.12 (d, I H), 8.18 (d, IH), 8.32 (s, IH), 8.50 (s, IH), 9.14 (s, 2H), 9.46 (s, 2H);
Anal, calc'd for C22H17F3N2O3O.5 H2O: C, 62.41; H, 4.29; N, 6.62. Found: C, 62.56; H, 4.13; N, 6.65. Example 127 6-1(1. 2. 3. 4-tetrahydro-6-isoquinolinyl)ethvnyll-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt)
Example 127A A solution of boron tribromide (1.2 mL, 12.5 mmol) and 12.5 mL CH2CI2 was added dropwise to a -78° solution of 6-methoxytetrahydroisoquinoline (1.0 g, 5.0 mole, Ore. Synth., 67, 60, 1988) and 38 mL CH2CI2. The reaction mixture was stined for 1 hour at -78°, 1 hour at 0°, and 0.25 hour at room temperature. The reaction mixture was cooled to -78°, and 20 mL methanol was added dropwise. The solution was stined for 1 hour at room temperature. Solvent was evaporated under vacuum and the residue was dried under vacuum to afford the desired compound. MS (DCI) m/z 150 (M+H)+.
Example 127B The product obtained in Example 127 A (1.15 g, 5.0 mmol) was subjected to the conditions described in Example 63C. A 2.1 g portion of this material was stirred at reflux for 1.5 hour with 60 mL methanol and 9 mL 10% aqueous NaOH. After cooling to room temperature, methanol was evaporated under vacuum. Water was added and the solution was acidified with 6 N HCl. The mixture was extracted with CH2CI2. The organic layer was washed with water, saturated aqueous sodium chloride, dried (MgSU4), filtered, and solvent evaporated under vacuum to afford the desired compound. MS (DCI/NH3) m/z 267 (M+NH4)+.
Example 127C Using the product from Example 127B and the procedure described in Example 28B, the desired compound was obtained. MS (DCI/NH3) m/z 399 (M+NH4) ".
Example 127D Using the procedure described for Example 121 A, and substituting the product obtained in Example 127C for 4-iodoaniline, the desired compound was obtained. MS (DCI/NH3) m/z 426 (M+NH4)+. Example 127E Using the product obtained in Example 127D and the procedure described in Example 40D, the desired compound was obtained. MS (ESI) m/z 426 (M+H)+;
'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, IH), 7.42 (d, 2H), 7.76 (dd, IH), 7.83 (dd, I H), 8.15 (d, I H), 8.19 (d, I H), 8.35 (s, I H), 8.51 (s, (IH), 9.20 (s, 2H), 9.45 (s, 2H).
Example 127F
64(1. 2. 3. 4-tetrahvdro-6-isoquinolinyl)ethynyll-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt) Using the product obtained in Example 127E and the procedure described in Example 124D, the desired compound was obtained. MS (ESI) m/z 326 (M+H)+;
Η NMR (300 MHz, DMSO) δ 3.03 (t, 2H), 3.42 (t, 2H), 4.35 (s, 2H), 7.35 (d, I H), 746 (d, 2H), 7.78 (dd, I H), 7.89 (dd, I H), 8.15 (d, I H), 8.19 (d, I H), 8.35 (s, IH), 8.52 (s, I H), 9.17 (s, 2H), 9.31 (s, 2H), 9.48 (s, 2H);
Anal, calc'd for C26H2iF6N3θ4: C, 56.42; H, 3.82; N, 7.59. Found: C, 56.31 ; H, 3.81 ; N, 7.42.
Example 129 5-rr6-(aminoiminomethyl)-2-naphthalenylloxy1pentanoic acid. mono(trifluoroacetate)(salt)
Example 129 A
The resulting product from Example 1 19A (250 mg, 1.477 mmol) was treated with methyl 5-bromovalerate in an analogous manner as described in Example 1 19B to yield the desired compound (394 mg, 94%). MS (DCI (NH3)) m/z 301 (M+NH4)+.
Example 129B 5-rr6-(aminoiminomethyl)-2-naphthalenylloxylpentanoic acid. mono(trifluoroacetate)(salt) The resulting product from Example 129A (262 mg, 0.8723 mmol) was tteated in an analogous manner as described in Example 94D to yield the ester amidine product. The product (140 mg, 0.542 mmol) was dissolved in methanol (1 1 mL). To this was added a solution of lithium hydroxide (68.2 mg, 1.626 mmol) in water (3 mL) and the resulting mixture was stirred at room temperature under an inert atmosphere for 18 hours. The reaction was evaporated and the residue purified by reverse phase chromatography to yield the desired compound (184 mg, 74%).
MS (DCI (NH3)) m/z 287 (M+H) +;
Η NMR (300 MHz, DMSO-d6) δ 1.71 1 (m, 2H), 1.817 (m, 2H), 2.320 (t, 2H), 4.144 (t, 2H), 7.377 (dd, IH), 7.472 (d, I H), 7.632 (dd, IH), 7.980 (d, IH), 8.081 (d, I H), 8.329 (s I H), 9.100 (br s, 2H), 9.390 (br s, 2H), 12.100 (br s, IH); Anal, calc'd for Ci6Hι8N2θ3- (C2HO2F3) 1.15-H20 0.65: C, 51.22; H, 4.80; N, 6.53. Found: C, 51.30; H, 5.07; N, 6.12.
Example 131 7-methoxy-8-(3-oxo- l -cyclopenten- l -yl)-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
Example 131 A The material prepared as described in Example 25 A (0.5 g, 1.5 mmol) and the 3- tributylstannyl-2-cyclopentenone prepared as described by Labourde et al. Tet Letters 31 , (13), 1837- 1 40 ( 1990) are coupled via Pd catalyst as described by the method of Stille et al. JACS 109, 5478-5486 (1987) yielding after flash chromatography with 3: 1 hexanes/ethyl acetate a white solid. 300 mg, 72%. MS (DCI/NH3): 281 (M+NH4).
Example 131 B
7-methoxy-8-(3-oxo- 1 -cvclopenten- 1 -yl )-2-naphthalenecarboximidamide, mono(ttifluoroacetate)(salt) The material prepared above (130 mg, .4 mmol) is prepared according to the H2S/pyridine method described in Example 40D. The desired compound was obtained as an off-white solid after reverse phase chromatography. 52 mg, 45%. MS (DCI/NH3): M+H+ 281
Η NMR (DMSO-d6): 9.45 (bs, 2H); 9.12 (bs, 2H), 8.25 -8.32 (m, 2H), 8.20 (dd, I H), 7.86 (d, IH), 7.75 (dd, I H), 6.42 (m, IH), 4.05 (s, 3H), 3.15 (m, 2H), 2.75 (m, 2H) Anal, calc'd for Ci9Hi7N2O4F3- 1.75 TFA: C. 57.87; H, 4.35; N. 7.10. Found: C, 51.37; H, 4.21 ; N, 7.14.
Example 132 6-(aminoiminomethyl)-N-(4-methylphenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt)
Example 132A p-Toluidine (0.1 1 g, 1 mmol), and the cyano ester prepared in Example 8E (0.2 g, 1 mmol) are coupled according to the procedure described in Example 8G, providing an off-white solid as the desired compound (0.16 g, 56%). MS (ESI +, -): 287 (M+) ; 285 (M-).
Example 132B 6-(aminoiminomethvP-N-(4-methylphenyP-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The desired compound is prepared according to the procedure described in Example 6B and purified as described in Example IB, yielding a white solid (35 mg, 35%). MS (ESI +): 304 (M+) IHNMR (DMSO-d6): 10.55 (s, IH); 9.45 (bs, 2H); 9.15 (bs, 2H); 8.65 (s, IH); 8.58 (s, IH); 8.32 (d, I H), 8.20 (d, IH), 8.19 (dd, IH); 7.96 (dd, I H), 7.75 (d, 2H), 7.12 (d, 2H), 2.35 (s, 3H);
Anal, calc'd for C21H 18N3O3F3: C, 60.43; H, 4.35; N, 10.07 Found: C, 59.94; H, 4.06; N, 9.80.
Example 133 methyl 4-[[|7-(aminoiminomethyl)-l-(2-pyrimidinylamino)-2-naphthalenynoxylmethyll benzoate, mono(trifluoroacetate)(salt)
Example 133A
The material described in Example 91 A is tteated with AII3 according to the procedure described in Example 1 19A and alkylated with 4-CarbomethoxyBenzylbromide according to the procedure described in Example 109B, yielding the desired compound as a white solid, 100 mg, 83%. MS (ESI +, -): 41 1 (M+) ; 409 (M-).
Example 133B methyl 4-rrr7-(aminoiminomethyl)-l-(2-pyrimidinyIamino)-2-naphthalenylloxy1methyll benzoate. mono(trifluoroacetate)(sait)
The desired compound is prepared according to the procedure described in Example 40D and purified according to the procedure described in Example 119B, yielding a light yellow solid, (49 mg, 50%). MS (ESI +, -): 428 (M+); 426 (M-) Η NMR (DMSO-d6): 9.45 (bs, 2H); 9.15 (s, IH); 8.97 (bs, 2H); 8.45 (dd, IH); 8.38 (d, IH); 8.15 (d, IH), 8.09 (d, IH), 7.95 (d, 2H); 7.76 (d, IH), 7.68 (dd, IH), 7.35 (d, 2H), 6.85 (d, 2H), 5.39 (s, 2H); 3.85 (s, 3H);
Anal, calc'd for C26H22N5O5F3: C, 57.67; H, 4.10; N, 12.93 Found: C, 55.34; H, 3.88; N, 12.05.
Example 134 4-rrr7-(aminoiminomethyl)-l-(2-pyrimidinylamino)-2-naphthalenvnoxy1methvn benzoic acid, mono(frifluoroacetate)(salt)
The material prepared in Example 134 (40 mg) is dissolved in 1 : 1 THF/water. To the clear solution is added LiOH-water (9 mg), the resulting clear solution is stined 18 hours at room temperature. The reaction mixture is concentrated to a yellow solid. The solid is dissolved in distilled water, acidified to pH 2 with 3 N HCl and stined 2 hours at room temperature. The desired compound is isolated by filtration, dried under vacuum as a yellow solid. Yield: 39 mg (46%)
MS (APCI): M+H+: 414
Η NMR (DMSO-d6): 945 (bs, 2H); 9.15 (s, IH); 8.97 (bs, 2H); 8.45 (dd, IH); 8.38 (d, I H); 8.15 (d, IH), 8.09 (d, IH), 7.95 (d, 2H); 7.76 (d, IH), 7.68 (dd, IH), 7.35 (d, 2H), 6.85 (d, 2H), 5.39 (s, 2H); Anal, calc'd for C25H2oN5O5F3Cl-3 H2O: C, 48.67; H, 4.25; N, 1 1.35 Found: C, 49.64; H, 4.44; N, 1 1.69.
Example 135 1. 1 -dimethylethyl rr4-rfr6-(aminoiminomethyl)-2-naphathalenvnaminolcarbonyl1- phenyllmethyllcarbamate. mono(trifluoroacetate)(salt)
Example 135 A The material prepared in Example 8B was added to cold (0°C) sulfuric acid (45 mL).
Within 1 minutes at 0°C bubling started to form. Allowed to bubble at 0°C for 30 minutes than slowly warmed to room temperature. Left at room temperature for 20 minutes, then poured into ice and diluted with water (to approx. 500 mL). The suspension was placed in an ice bath and carefully added a solution of 50% aqueuos sodium hydroxide so that the temperature would not exceed 35°C. The light yellow solid was filtered than washed with water till the wash became neutral to pH paper (7.0). The product was dried under vacuum. The product was purified on silica gel column using 20% ethyl acetate 80% hexanes as eluent to yield 3.3 g (67%) of light yellow solid. MS m/z 169 (M+1 )+.
Example 135B A solution of Example 135 A (135 mg, 0.8 mmol), 4-N-Boc-aminomethylbenzoic acid (404 mg, 1.6 mmol) and EDCI (307 mg, 1.6 mmol) in methylene chloride (25 mL), at room temperature, was added DMAP (3 mg) and stirred overnight. The reaction mixture was diluted with methylene chloride (60 mL) then washed 2% aqueous hydrochloric acid (2x30 mL), water (20 mL), 0.5 M aqeuos sodium hydroxide (2x50 mL) and brine. The organic phase was dried over magnesium sulfate and evapoorated. The product was purified via on silica column usinga gradient of 25% to 60% ethyl acetate in hexanes as eluent. Yield 175 mg (54%) of white powder.
Example 135C 1. 1 -dimethylethyl rr4-rrr6-(aminoiminomethyl)-2-naphathalenyl1aminolcarbonyl1- phenyllmethyllcarbamate. mono(trifluoroacetate)(salt) The reaction was canied out in the same manner as described in Example 40D. Yield 1 10 mg (64%).
MS m/z 408 (M+ 1 )+' 425 (M+ 1 )+
'H NMR: 3.30 (s, 9H), 4.22 (d, 2H, J=7.1 Hz), 7.42 (d, 2H, J=8.5Hz), 7.49 (t, IH, J=7.1Hz), 7.79 (dd, IH, J l=8.2Hz, J2=2.0Hz), 7.95-8.00 (m, 3H), 8.09 (d, 2H, J=8.4Hz), 8.42 (s, IH), 8.63 (d, IH, J=2.0Hz), 9.18 (br s, 4H), 10.58 (s, IH); Anal, calc'd for C26H27F3N O5: C, 58.55; H, 4.85; N, 10.41. Found: C, 58.64; H, 5.1 1 ; N, 10.52.
Example 136 N-f6-(aminoiminomethyl)-2-naphthalenyl)benzamide. mono(ttifluoroacetate)(salt)
The desired compound is prepared as described in Example 135; ' H NMR (300 MHz, DMSO-d6) 10.67 (s, IH), 9.25 (br.s, 4H), 8.65 (d, J= 1.5Hz, IH), 8.43 (d, J=1.4Hz, I H), 8.10 (d, J=9.2Hz, 2H), 8.03-7.97 (m, 3H), 7.81 -7.78 (m, IH), 7.65-7.55 (m, 3H).
MS (ESI/NH3) m/z 290 (M+H)+;
Anal, calc'd for Ci8H ι5N3θ-CF3COOH: 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 H4-ri[6-(aminoiminomethyl)-2-naphathalenyl1amino1carbonyl l- cyclohexyll]methyllcarbamate. mono(trifluoroacetate)(salt)
Example 137 A To a solution of the 6-Amino-2-naphthalenecarbonitrile prepared in Example 73 (100 mg, 0.6 mmol) in methylene chloride (35 mL) at room temperature, was added 1 -carboxy-4- (Boc-aminomethyl)cyclohexanes (280 mg, 1.1 mmol) followed by l -ethyl-3- (3- dimethylaminopropyPcarbodiimide hydrochloride (ED AC, 225 mg, 1.2 mmol). After 5 minutes to the reaction mixture was added DMAP (20 mg, catalytic). The reaction was stined at room temperature for 72 hours. The reaction mixture was diluted 7: 3 ethyl acetate: hexanes then filtered through silica gel and washed with the same solvent mixture.
The organic solvent was washed by aq. Acid (2% Hcl, 2x50 mL), water and aq. Base (10% NaOH, 50 mL). The solvent was dried over magnesium sulfate filtered and evaporated. Crystalization from ether/ hexanes afforded the product as white solid. Yield 166 mg (68%). MS (DCI/NH3) m/z 408 (M+H)+.
Example 137B
1. 1 -dimethylethyl rr4-rrr6-(aminoiminomethyl)-2-naphathalenyllamino1carbonyll- cyclohexylllmethyllcarbamate. mono(trifluoroacetate)(salt) A solution of the substrate (Example 137 A) in Pyr: Et3N ( 10: 1 , 20 mL) was bubbled H2S for 5 minutes. Stined at room temperature overnight. The reaction mixture was added ethyl acetate (100 mL) followed by 1 % aq. KHSO4 (60 mL) and separated: washed organic layer with water (2x50 mL), sodium bicarb. And brine, dried over magnesium sulfate & evaporated. To a suspension of the resulting solid in acetone (25 mL) and added Mel (1.0 mL). Stined at 50°C for 2 hours, all dissolved. Evaporated solvent to a complete dryness and added methanol (30 mL) and ammonium acetate (150 mg). The mixture was stined at room temperature overnight. Purification by Reverse Phase Cis MPLC. After evaporation added toluene & evaporated (2x40 mL). The resulting oil was treated with methanol and ether and the product precipitated as white solid (72 mg, 43%). MS (ESI/NH3) m/z 425 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 10.24 (s, IH), 9.05 (br.s, 4H), 8.49 (s, IH), 8.38 (d, J=1.7Hz, I H), 8.03-8.00 (m, 2H), 7.77-7.74 (m, 2H), 6.93-6.91 (m, I H), 2.83-2.79 (m, 2H), 2.40-2.30 (m l ), 1.92- 1.75 (m, 4H), 1.50- 1.45 (m, I H), 1.39 (s, 9H), 0.96-0.91 (m, 4H);
Anal, calc'd for C2 H 2N4O3-CF3COOH: C, 57.98; H, 6.18; N, 10.40. Found: C, 57.63; H, 6.24; N, 10.21.
Example 138 N-r6-(aminoiminomethyl)-2-naphthalenyll-N,-(4-aminophenyl)urea. bis(ttifluoroacetate)(salt)
Example 138A To a solution of the compound prepared in Example 40B (194.2 mg, 1 mmol) in dioxane (10 mL) at room temperature, was added 4-phenylenediamine mono Boc (416, 5 mg, 2 mmol). The product started to precipitate within minutes. After an hour the reaction mixture was added ether (5 mL) and the white solid product was filtered and washed with ether to yield 350 mg (87%). MS (DCI/NH3) m/z 403 (M+H)+.
Example 138B
A solution of the conesponding nitrile prepared in Example 138 A (105 mg, 0.36 mmol) in Pyr: Et3N (10: 1 , 20 mL) was bubbled H2S for 5 minutes and stined at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL) washed with aqueous 0.25 N HCl (25 mL) followed by water (2x50 mL), saturated solution of sodium bicarbonate, and brine, dried over magnesium sulfate & evaporated. To a solution of the resulting solid in acetone (25 mL) was added Mel (1.0 mL)and stined at 50°C for 30 minutes- very strong precipitate was observed. Added ether and filtered the yellow precipitated. The yellow solid was added methanol (10 mL) and ammonium acetate (150 mg) and stined at room temperature overnight. Purified as described inExample IB. Yield of the white solid 69 mg. MS (DCI/NH3) m/z 420 (M+H)+.
Example 138C N-r6-(aminoiminomethyl)-2-naphthalenyll-N'-(4-aminophenyl)urea. bis(trifluoroacetate)(salt) The Boc protected substrate (Example 138B) was dissolved in methylene chloride: TFA
1 : 1 (25 mL) and stined at room temperature forl hour. Evaporated solvent under vacuum added toluene & evaporated again. Added water & little acetonitrile, filtered & lyophilized. 36 mg of white solid. MS (ESI/NH3) m/z 320 (M+H)+; Η NMR (300 MHz, DMSO-d6) 9.26 (br.s, 2H), 9.21 (br.s, I H), 8.85 (br.s, 2H), 8.31 (d, J-1.7Hz. I H), 8.18 (d, J=1.7Hz, I H), 7.95-7.91 (m, 2H), 7.68 (dd, J l=6.6Hz, J2=2.0Hz, I H), 7.57 (dd, J l =9.2Hz, J2= 1.4Hz, I H), 7.34 (d, J=8.8Hz, 2H), 6.91 (d, J=8.4Hz, 2H); Anal, calc'd for Ci8Hι7N5O-2-CF3COOH-H2θ: C, 46.73; H, 3.74; N, 12.39. Found: C, C, 47.03; H, 3.55; N, 12.36.
Example 139 N-f6-(aminoiminomethyl)-2-naphthalenyll-4-4-(aminomethyl)cvclohexanescarboxamide. bis(ttifluoroacetate)(saIt)
A solution of the substrate prepared in Example 137 as TFA salt (45 mg) in methylene chloride: TFA 1 : 1 (20 mL) was stined at room temperature for 1 hour. The solvent was evaporated under vacuum, added toluene & evaporated (20 mLx2). Dissolved in water, filtered-
0.45μ frit and lyophilized. 35 mg, white solid as bis TFA salt.
MS (ESI/NH3) m/z 325 (M+H)+; Η NMR (300 MHz, DMSO-d6) 10.31 (s, IH), 9.31 (br.s, 2H), 9.10 (br.s, 2H), 8.49 (s,
I H), 8.39 (s, IH), 8.04-8.00 (m, 2H), 7.78-7.71 (m, 2H), 2.71 (d, J=7.0Hz, 2H), 2.44-2.36
(m, 1 H) 1.96- 1.85 (m, 4H), 1.61 -1.42 (m, 3H), 1 .09- 1.02 (m, 2H);
Anal, calc'd for Ci9H24N4O-2-CF3COOH: C, 50.00; H, 4.74; N, 10.14. Found: C, 49.95;
H, 4.70; N, 09.96. Example 140 N-r6-(aminoiminomethyl)-2-naphthalenvn-N,-r(4-aminomethvDphenyllurea. bis(ttifluoroacetate)(salt)
Example 140A To a solution of the isocyanate prepared in Example 40B (140 mg, 0.72 mmol) in dioxane (8.0 mL) at room temperature, was added 4-N-Boc-aminomethylbenzoic acid (320 mg, 144 mmol) and stined for 1 hour. The product was precipitating during the reaction. The mixture diluted with ether (15 mL), filtered and washed with ether to yield 215 mg (72%) of white solid. MS (DCI/NH3) m/z 417 (M+H)+.
Example 140B A solution of the nitrile (Example 140A) ( 198 mg, 0.47 mmol) in 10: 1 pyridine: triethylamine (10 mL) was treated with H2S for 5 min, stined at room temperature for 18 h and concentrated. The resulting solid was dissolved in acetone (15 mL), treated with iodomethane (0.8 mL, 12.8 mmol), stined for 2 hours, diluted with ether (10 mL), filtered, washed with ether and dried under vacuum. The resulting solid was dissolved in methanol (4 mL) and was added NH4OAC (200 mg, 2.6 mmol) at room temperature overnight. The product was purified according to the procedure described in Example IB to provide 1 12 mg (54%) of the conesponding amidine. MS (DCI/NH3) m/z 434 (M+H)+.
Example HOC
N-r6-(aminoiminomethyl)-2-naphthalenyn-N'-f(4-aminomethyl)phenyllurea. bis(frifluoroacetate)(salt) A solution of the substrate (Example 140B) in methylene chloride: TFA 1 : 1 (20 mL) was stined at room temperature for 1 hour. The solvent was evaporated under vacuum, added toluene & evaporated (20 mLx2). Dissolved in water, filtered- 0.45μ frit and lyophilized. 38.1 mg, white solid.
MS (ESI/NH3) m/z 334 (M+H)+;
'H NMR (300 MHz, DMSO-d6) 9.68 (s, IH), 9.45 (s, IH), 9.35 (br.s, 2H), 9.08 (br. s, 2H), 8.40 (d, J= 1.7Hz, IH), 8.31 (d, J=1.8Hz, IH), 8.10 (br.s, 3H), 8.04-7.99 (m, 2H), 7.76 (dd, J l=8.8Hz, J2=1.8Hz, IH), 7.67 (dd, J l=8.8Hz, J2=1.7Hz, IH), 7.58 (d, J=8.4Hz, 2H), 7.39 (d, J=8.4Hz, 2H), 3.98 (br. s, 2H);
Anal, calc'd for Ci9Hi9N5θι-2-CF COOH-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 1.71.
Example 141 methyl [7-(aminoiminomethyl)-3-rrr4-(aminomethyI)phenvnaminolcarbonvn- 1 - naphathalenyllcarbamate. bis(trifluoroacetate)(salt)
Example 141 A
To a solution of the ester, prepared as described in Example 26, (747 mg, 2.63 mmol) in dioxane (10 mL) was added acetone (1 mL) and an excess of sodium hydroxide (1 N in water, 10 mL). After 1 hour the mixture was added water (40 mL) and ethyl acetate (85 mL) then was acidified with 10% aq. HCl. The ethyl acetate layer was separated washed with water (2x20 mL) then brine, dried over magnesium sulfate filtered and evaporated. The product was isolated as a light yellow solid. MS m/z 271 (M+l)+.
Example 141 B To a suspension of naphthoic acid derivative, prepared in Example 141 A (270 mg, 1.1 mmol) in methylene chloride (8.0 mL) was added diisopropylethylamine (DIEA, 485μL, 2.8 mmol) followed by O- (azabenzotriazoIe- l -yl)-N, N, N', N'- tetramethyluroniumhexafluorophosphate (HATU, 527 mg, 1.39 mmol). After 10 minutes added the 4-N-Boc-aminomethylaniline (370 mg, 1.7 mmol). After an hour, added ethyl acetate ( 120 mL) and washed organic layer with 57c aq. citric acid (50 mL), water (2x40 mL) and brine (50 mL). The rxn was dried over magnesium sulfate filtered through small amount of silica and evaporated. Purification on silica eluting with ethyl acetate in hexanes. The product, after concentration, was added ethyl acetate and ether and filtered to yield 350.0 mg (70%) of yellow solid. MS m/z 447 (M+l )+.
Example 141 C A suspension of the naph derivative (Example 141B) (300 mg, 0.67 mmol) in ethyl acetate (20 mL) was added 120 mg of the Pd catalysit then stined at room temperature, under hydrogen, at atmospheric pressure and stined for 1 hour.. The crude was canied on to the next step without any purifications or analysis.
To a solution of the crude amine in dioxane (25 mL) and 10% aqeuos sodium carbonate (2.5 mL) was added the methyl chloroformate (1.0 mL, large excess). After 2 hours the rxn was quenched with methanol then diluted with ethyl acetate (80 mL) and water (50 mL). The ethyl acetate layer was separated, dried over magnesium sulfate filtered and evaporated. The product was separated on silica column using a gradient of ethyl acetate in hexanes (from 5 to 30% ethyl acetate in hexanes). Yield 140 mg of off white solid. MS m/z 492 (M+18)+'
Example 141D The desired compound was prepared as described in Example 26.
MS m/z 492 (M+l+.
Example 141 E methyl [7-(aminoiminomethvP-3-rrr4-(aminomethyl)phenyl1aminolcarbonyl1-l - naphathalenyllcarbamate. bis(trifluoroacetate)(salt) A solution of the substrate (Example 141 D) in a mixture of methylene chloride: TFA 4: 1 (20 mL) was stined at room temperature for 15 minutes. The solvent was concentrated under vacuum, and separated on RP C18 MPLC. Yield, 21 mg off white solid. MS m/z 392 (M+18)+
Η NMR (DMSO): 3.783 (s, 3H), 4.03 (q, 2H, J=5.5Hz), 7.47 (d, 2H, j=8.4Hz), 7.85 (d, 2H, j=8.4Hz), 7.94 (d, I H, j=8.8Hz), 8.15 (wide s, 2H), 8.31 (d, I H, j=8.8Hz), 8.33 (s, I H), 8.47 (s, I H), 8.74 (s, I H), 9.29 (s, 2H), 9.47 (s, 2H), 9.90 (s, I H), 10.68 (s, I H). Anal, calc'd for C25H25F6N5O8 (base molecule + 2 TFA+1 H 0): C. 47.04: H, 3.70; N, 10.52. Found: C, 47.10; H, 3.95; N, 10.99.
Example 142 6-(aminoiminomethyl)-N-(4-ethylphenyl)-2-naphthalenecarboxamide. acetate(salt)
Example 142A
The reaction was canied out in the same manner as described in Example 14 IB. Yield 374 mg (617c) of white powder. MS DCI/NH3): m/z 301 (M+NH4+). Example 142B 6-(aminoiminomethyl)-N-(4-ethylphenyl)-2-naphthalenecarboxamide. acetate(salt) The reaction was carried out in the same manner as described for the naphthyl analog prepared in Example 141D, 313 mg. The solid that precipitated during the last step was filtered and washed in ether to yield 71 mg (187c) of white solid, as acetate salt. MS (ECI) m/z 301 (M+H)+; Η NMR (300 MHz, DMSO-d6) δ 1.19 (t, J=7.4Hz, 3H), 2.60 (q, J=7.4Hz, 2H), 7.22 (d,
J=8.5Hz, 2H), 7.72 (d, J=8.5Hz, 2H), 7.94 (dd, Jι=8.8Hz, J2=1.7Hz, I H), 8.08-8.23 (m, 3H), 8.47 (d, J= 1.7Hz, I H), 8.63 (s, IH), 10.43 (br. s, IH); Anal, calc'd for C2oHi9N3θ-AcOH- 0.5 H20: C, 68.38; H, 6.26; N, 10.87. Found: C, 68.56; H, 6.21 ; N, 10.67.
Example 143 6-(aminoiminomethyl)-N-(2-naphthalenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt)
Example 143 A To a solution of the acid chloride prepared as described in Example 8B (341 mg, 1.6 mmol) in methylene chloride (20 mL) was added a solution of the 2-Amino naphthalene (249 mg, 1.74 mmol) in methylene chloride ( 10 mL) and propylene oxide ( 12 mL). The rxn was stined at room temperature overnight. The reaction mixture was added ether and the product was filtered, washed with ether and hexanes and dried under vacuum. Yield 440 mg (86%>). MS (DCI/NH3) m/z 340 (M+NH4)+.
Example 143B
6-(aminoiminomethyl)-N-(2-naphthalenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The desired compound is prepared as described in Example 141 B. Yield of white solid 40 mg (10%). MS (ESI) m z 340 (M+H)+;
Η NMR (300 MHz, DMSO-d6) 7.43-7.55 (m, 2H), 7.86-7.96 (m, 5H), 8.20-8.28 (m, 2H), 8.08-8.23 (m, 3H), 8.34 (d, J=8.8Hz, I H), 8.50 (d, J=1.7Hz, I H), 8.57 (d, J=1.3Hz, IH), 8.75 (s, IH), 9.33 (br. s, 4H) 10.75 (s, IH); Anal, calc'd for C22Hι7N30-TFA- 0.25 H20: 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)(salt)
Example 144A To a suspension of the phenacyl amine hydrochloride (Aldrich) (415 mg, 2.42 mmol) in a mixrure of methylene chloride (50 mL) and propylene oxide (15 mL) at room temperature was added a solution of the 2-nitrile-6-acidchloride (560 mg, 2.6 mmol) in methylene chloride (30 mL) followed by DMF (3.0 mL). Thje reaction was stirred at room temperature overnight. The reaction mixture was added ether (15 mL) and the product was filtered and washed with hexanes to yield 555 mg (73%) of white solid. MS (DCI/NH3) m/z 315 (M+H)+.
Example 144B A suspension of the substrate (Example 144A) (354 mg, 1.12 mmol) in phosphorous oxychloride (3.5 mL) was boiled for 1.5 hours. The reaction mixture was poured into ice and the mixture was added ethyl acetate (80 mL) and aqeuous solution of 107o potassium carbonate ( 100 mL). The organic layer was separated, washed with brine dried over magnesium sulfate and evaporated. Added ether and filtered 249 mg (75%>). MS (DCI NH3) m z 297 (M+H)+.
Example 144C 6-(5-phenyl-2-oxazolyl)-2-naphthalenecarboximidamide, mono(trifluoroacetate)(salt)
To a solution of the substrate Example 144B ( 132 mg, 0.44 mmol) in THF (20 mL) at room temperature was added a solution of 1 N LiHMDS in hexanes (1.5 mL, 1.5 mmol) and stined overnight. Quenched with 4 N HCl in dioxane ( 1 mL). After 10 minutes added a few drops of water and stirred for additional 30 minutes. The solvent was evaporated under vacuum and the residue was purified on reverse phase chromatography. Yield 58 mg of white solid 417c).
MS (ESI/NH3) m/z 314 (M+H)+;
'H NMR (300 MHz, DMSO-d6) 9.50 (s, 2H), 9.19 (s, 2H), 8.86 (s, IH), 8.55 (s, IH), 8.38- 8.26 (m, 3H), 7.98 (s, I H), 7.96-7.89 (m, 3H), 7.58-7.54 (m, 2H), 7.47-7.42 (m, IH); Anal, calc'd for C2θHι5N 0- 1.15CF3COOH: C, 60.26; H, 3.66; N, 9.45; F, 14.75. Found: C, 60.1 1 ; H, 3.81 ; N, 9.20; F, 14.81.
Example 145 6-(5-phenyl-2-thiazolyl)-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
Example 145 A A suspension of the substrate, prepared in Example 144A, (340 mg, 1.1 mmol) and Lawesson's reagent (600 mg, 1.48 mmol) was heated to 85°C for 48hours. Solvent was evaporated to dryness and the product was isolated via silica column using 10% ethyl acetate in hexanes as eluent. Yield: 200.0 mg (597c) of yellow solid. MS (DCI/NH3) m/z 313 (M+H)+.
Example 145B 6-(5-phenyl-2-thiazolyl)-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
To a solution of the substrate, Example 145A ( 1 0 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 stined overnight. Quenched with 4 N HCl in dioxane (1 mL). After 10 minutes added a few drops of water and stined for additional 30 minutes. The solvent was evaporated under vacuum and the residue was purified on MPLC RPC18. Yield 36 mg (19%) of white solid. MS (ESI/NH3) m/z 330 (M+H)+;
' H NMR (300 MHz, DMSO-d6) 9.49 (s, 2H), 9.14 (s, 2H), 8.71 (s, IH), 8.52 (s, I H), 8.47 (s, I H), 8.35-8.22 (m, 3H), 7.90-7.78 (m, 3H), 7.55-7.50 ( , 2H), 7.46-7.43 ( , I H); Anal, calc'd for C2oH ι5N3S-CF3COOH-H2θ: C, 57.26; H, 3.93; N, 9.1 1. Found: C, 56.83; H, 3.55; N, 8.79.
Example 146 6-(aminoiminomethvD-4-(3-furanyl)-N-(2-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride
Example 146A The above product was prepared in the manner of Example 1 14A. MS (ESI) m/z (M+H)+ 340. Example 146B 6-(aminoiminomethyl)-4-(3-furanyl)-N-(2-pyridinyl)-2-naphthalenecarboxamide. dihydrochloride The above was prepared from Example 146 A using method described in 145B.
MS (CI) m/z (M- H)+ 357; ' H-NMR (300 MHz, DMSO-d6) δ 1 1.27 (s, IH), 9.56 (s, 2H), 9.17 (s, 2H), 8.76 (s, I H),
8.63 (s, I H), 8.45-8.24 (m, 5H), 7.96-7.89 (m. 3H), 7.25 (m, 2H), 7.18 (s, IH): Anal, calc'd for C21H1 N4O2CI2 19/10 HCl: C, 54.33 H, 4.75 N, 12.07. Found: C, 54.89; H, 5.28; N, 9.81.
Example 147 6-(aminoiminomethyl)-N-( l . 2. 3. 4-tetrahvdro-6-quinolinyl)-2-naphthalenecarboxamide. bis(ttifluoroacetate)(salt)
Example 147 A The reaction was canied out in exactly the same manner as described for Example 1 18A using 6-aminoquinoline to yield the product in 72%. Mass spectrum (CI+) 324 (M+l )+.
Example 147B
The reaction was carried out in exactly the same manner as described for Example 1 18B to yield the product in 457o (off white solid). Mass spectrum (ESI+) 341 (M+l)+.
Example 147C 6-(aminoiminomethyl)-N-( l , 2. 3, 4-tetrahydro-6-quinolinyl)-2-naphthalenecarboxamide, bis(trifluoroacetate)(salt) To a suspension of the substrate, Example 147B (261 mg, 0.6 mmol) in degassed methanol ( 15 mL) was added platinum oxide (10 mg, cat). The reaction mixture was charged with hydrogen at atmospheric pressure and stined vigorously overnight. The next day the solution was filtered through ceiite to remove the catalyst, and the product was purified over mplc with RPC18 silica using methanol (+ 0.17o TFA) and water (+ 0.1 % TFA) as eluent Yield 122 mg of white solid and bis TFA salt. MS (ESI+) 345 (M+l)+; 'H NMR (DMSO-d6) 10.51 (s, I H), 9.65 (s, 2H), 9.50 (s, 2H), 8.64 (s, IH), 8.52 (s, IH), 8.22 (d, J=8.0Hz, IH), 8.12 (Abq, J=9.0Hz, 2H), 7.86 (d, J=9.0Hz, IH), 7.61 (s, IH), 7.56 (d, J=8.0Hz, IH), 6.98 (d, J=8.5Hz, IH), 3.28 (t. J=5.5Hz, 2H), 2.75 (t, J=6.3Hz, 2H), 1.92- 1.86 (m, 2H);
Anal, calc'd for C2iH20N4O+2.25 TFA+0.25 H20: C, 50.59 (50.46); H, 3.79 (3.79); N, 9.25 (9.25); F, 21.18 (20.83).
Example 148 7-methoxy-8-(pyrazinyloxy)-2-naphthalenecarboximidamide, dimethanesulfonate(salt)
Example 148 A The product from Example 4A (125 mg, 0.627 mmol) was combined with chloropyrazine (1 12 mL, 1.25 mmol) and CS2CO3 (409 mg, 1.25 mmol) in N- methylpyπolidinone (4 mL), and the reaction was stined at 130 °C for 1 hour. The reaction was cooled, and the crude mixture was chromatographed on Siθ2 using 407c ethyl acetate/hexanes as eluent, to yield 75 mg (437c) of the desired compound. MS (DCI (NH3) m/z 278 (M+H)+.
Example 148B 7-methoxy-8-(pyrazinyloxy)-2-naphthalenecarboximidamide, dimethanesulfonate(salt)
The product from Example 148 A (70 mg, 0.252 mmol) was subjected to the procedure described in Example IB to yield the desired compound (106 mg, 717c). m.p. 155° C.
MS (DCI (NH3) m/z 295 (M+H)+;
Η NMR (300 MHz, DMSO) δ 9.42 (br s, 2H), 9.04 (br s, 2H), 8.72 (s, IH), 8.38 (d, J=3 Hz, IH), 8.36 (m, I H), 8.21 (d, J=9 Hz, IH), 8.09 (m, IH), 8.06 (d. J=9 Hz, IH), 7.82 (d,
J=9 Hz, I H), 7.73 (dd, J=9, 2 Hz, I H), 3.83 (s, 3H), 2.38 (s, 3H);
Anal, calc'd for Ci8H22N4S2θ8- l . lCH4Sθ3: 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-naphthalenecarboximidamide, methanesulfonate
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 was stined for 5 minutes. To this was added the product from Example 53B (309 mg, 1 mmol), and the reaction was heated at 100°C for 3 hours. The crude reaction mixture was chromatographed on Siθ2 using 20% ethyl acetate/hexanes as eluent. The product was taken up in ethyl acetate (10 mL) and methanol (10 mL), and treated with a 2 M solution of TMSCHN2 (10 mL). The reaction was stined for 60 minutes and condensed. The crude product was chromatographed on Siθ2 using 15% ethyl acetate/hexanes as eluent, to yield 1 15 mg (397c) of the desired compound: MS (DCI (NH3) m/z 309 (M+NH4)+.
Example 149B 7-methoxy-8-(phenylthio)-2-naphthalenecarboximidamide. methanesulfonate The desired compound was prepared from Example 149A and the procedure of Example 55D. MS (DCI/NH3) m/z 309 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 2.33 (s, 3H), 3.96 (s, 3H), 6.96 (d, 2H), 7.1 1 (dd, IH), 7.20 (d, IH), 7.22 (d, I H), 7.69 (dd, IH), 7.82 (d, IH), 8.22 (d, IH), 8.33 (d, IH), 8.81 (s, I H), 9.01 (br s, 2H), 9.46 (br s, 2H);
Anal, calc'd for Ci8Hι6N2OS- 1.15 CH4SO3: C, 54.91 ; H, 4.96; N, 6.69. Found: C, 54.70; H, 5.15; N, 6.58.
Example 150
7-methoxy-8-(pyrazinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate)(salt)
The desired compound was prepared from the product prepared in Example 90D using the method described in Example 91 A, then converted to the amidine as described in Example
40D.
MS (DCI/NH3) m/z (M+H)+ 294;
' H-NMR (300 MHz, DMSO-d6) δ 9.39 (s, 2H), 9.02 (s, 2H), 8.95 (s, IH), 8.40 (d, IH), 8.14 (d, IH), 8.03 (s, 2H), 7.92 (dd, I H), 7.84 (d, I H), 7.76 (d, I H) 7.66 (dd I H), 3.90 (s,
3H);
Anal, calc'd for C20H17N5O F6 1/2 TFA: C, 43.79; H, 3.07; N, 12.20. Found: C; 43.81; H,
3.22; N, 12.24. Example 152 6-(aminoiminomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamide. monohydrochloride
Example 152A To a solution of the product from Example 8D (5.50 g, 26.04 mmol) in CH2CI2 (125 mL) was added dibromodimethylhydantoin (4.47 g, 15.62 mmol) and trifluoromethanesulfonic acid (2.51 mL, 28.41 mmol), and the reaction was stined at 23°C in the dark for 18 hours. The mixture was poured into aqueous NaHSO3. the solution was made basic with Na2CO3, and extracted with 3x ethyl acetate, and the extracts were washed with brine, dried over Na2SO4, and condensed. The product was recrystallized from ethanol/ethyl acetate, to yield 5.80 g (777c) of the desired compound. MS (DCI (NH3) m/z 307 (M+NH4)+.
Example 152B To a solution of the product from Example 152A (1.40 g, 4.826 mmol) in THF (40 mL), water (10 mL), and methanol (10 mL) was added LiOH-water (405 mg, 9.65 mmol), and the reaction was stirred for 18 hours. The mixture was poured into 1 M HCl and extracted with 3x ethyl acetate, and the extracts were washed with brine, dried over Na2S04, and condensed, to yield 1.23 g (92%) of the desired compound. MS (DCI (NH3)) m/z 295 (M+NH4)+.
Example 152C To a solution of the product from Example 152B (440 mg, 1.60 mmol), in toluene (25 L) was added oxalyl chloride (0.140 mL, 1.6 mmol), and the reaction was stined at 80 °C for 1 hours. The toluene was boiled off until HCl evolution ceased, and the reaction was then cooled. Aniline (1 mL, 1 1 mmol) was added, and the reaction was stined for 10 min, nad poured into 1 M HCl. The solution was exttacted with 3x ethyl acetate, and the extracts were washed with brine, dried over Na2SO4, and condensed, to yield 560 mg (997c) of the desired compound. MS (DCI (NH3)) m z 370 (M+NH4)+.
Example 152D The desired compound was prepared from Example 152C (408 mg, 1.16 mmol), furan-
3-boronic acid (182 mg, 1.62 mmol) and the procedure of Example 57B, to yield 220 mg
(56%) of the desired compound.
MS (DCI (NH3)) m/z 356 (M+NH4)+.
Example 152E
6-(aminoiminomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamide. monohydrochloride The desired compound was prepared from Example 152D and the procedure of Example
40D. MS (DCI/NH3) m/z 356 (M+H)+;
'H NMR (300 MHz, DMSO-d6) δ 7.15 (m, 2H), 7.41 (dd, 2H), 7.83 (d, 2H), 7.91 (d, IH),
7.99 (dd, IH), 8.19 (d, IH), 8.38 (s, IH). 8.41 (d, IH), 8.62 (s, IH), 8.69 (s, IH), 9.15 (br s, 2H), 9.55 (br s, 2H);
Anal, calc'd for C22Hι7N θ2-2.75 HCl: C, 57.99; H, 4.37; N, 9.22. Found: C, 57.85; H, 4.84; N. 9.44.
Example 153 6-(aminoiminomethyl)-4-[ l -(methylsulfonvD- 1 H-pyrazol-4-yn-N-phenyl-2- naphthalenecarboxamide. monohydrochloride
Example 153A The desired compound was prepared from the product from Example 53D and the product from Example 152 A by the procedure of Example 47A. MS (DCI/NH3) m/z 408 (M+H)+.
Example 153B The desired compound was prepared from the product from Example 153 A, by the procedure of Example 53F. MS (DCI/NH3) m/z 278 (M+H)+.
Example 153C The desired compound was prepared from the product from Example 153B, by the procedure of Example 87A (86A). MS (DCI/NH3) m/z 373 (M+NH4)+. Example 153D The desired compound was prepared from the product from Example 153C, by the procedures of Example s 152B and 152C MS (DCI/NH3) m/z 356 (M-SO Me+NH4)+.
Example 153E 6-(aminoiminomethyl)-4-r 1 -(methylsulfonvD- 1 H-pyrazol-4-vn-N-phenyl-2- naphthalenecarboxamide. monohydrochloride The desired compound was prepared from Example 153D and the procedure of Example
40D.
MS (DCI/NH3) NONE ;
Η NMR (300 MHz, DMSO-d6) δ 3.99 (s, 3H), 7.14 (t, IH), 7.40 (t, 2H), 7.84 (d, 2H), 7.91 (d, I H), 8.08 (s, IH), 8.15 (d, IH), 8.35 (m. 2H), 8.65 (br s, 2H), 9.33 (br s, 2H), 9.61 (br s, 2H), 10.58 (s, IH);
Anal, calc'd for C22Hi9N5SO3-2.75 HCl: C, 49.51; H, 4.1 1 ; N, 13.12. Found: C, 49.44; H, 3.83; N, 12.09.
Example 154 6-(aminoiminomethyl)-4-r5-(methylthio)-3-furanyl)l-N-phenyl-2-naphthalenecarboxamide. monohydrochloride
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 a 1.5 M solution of LDA (12.7 mL, 19.03 mmol), and the reaction was stined at -78°C for 1 hour. Methyl disulfide (1.89 mL, 20.93 mmol) was then added, and the reaction was allowed to warm to room temperature overnight. The reaction was poured into saturated aqueous NH4CI solution, and extracted with 3x diethyl ether. The combined extracts were washed with brine, dried over Na2SO4, and condensed. The crude material was chromatographed on Siθ2 using hexanes as eluent, to yield 3.02 g (607o) of the desired compound. MS (DCI/NH3) m/z 265, 267 (M+H)+.
Example 154B A solution of the product from Example 154A (2.68 g, 10.1 mmol) and a 1 M solution of TBAF (20.2 mL) in THF (20 mL) was stirred for 30 minutes. The reaction was condensed and The desired compound was chromatographed on Siθ2 using hexanes as eluent, to yield 1.39 g (717c) of 2-methylthio-4-bromofuran. This material was taken on directly to the next step. To a solution of this product (7 mmol) in THF (25 mL) at -78 °C was added a 2.5 M solution of BuLi (2.8 mL, 7 mmol), and the reaction was stined for 5 minutes. Bu3SnCl (1.90 mL, 7 mmol) was then added, the reaction was stined for 30 min, and then allowed to warm to room temperature. The reaction was poured into saturated aqueous NH4CI solution, and exttacted with 3x diethyl ether. The combined exttacts were washed with brine, dried over Na2SO4, and condensed. The crude material was chromatographed on Siθ2 using hexanes as eluent, to yield 1.24 g (30%>) of the desired compound. MS (DCI/NH3) m/z 404 (M+H)+.
Example 154C A solution of the product from Example 154B (920 mg, 2.28 mmol), the product from
Example 152A (662 mg, 2.28 mmol), and PdCl (PPh3)2 (161 mg, 0.23 mmol) in CH3CN (15 mL) was stined for 18 hours at 80°C. The reaction was condensed and the crude material was chromatographed on Siθ2 using 207c ethyl acetate/hexanes as eluent, to yield 671 mg (917c) of the desired compound. MS (DCI/NH3) m/z 324 (M+H)+.
Example 154D The desired compound was prepared from the product from Example 154C, by the procedure of Example 152 B. MS (DCI/NH3) m/z 310 (M+H)+.
Example 154E The desired compound was prepared from the product from Example 154D, by the procedure of Example 152C. MS (DCI/NH3) m/z 402 (M+NH4)+.
Example 154F 6-(aminoiminomethvD-4-r5-(methylthio)-3-furanyl)1-N-phenyl-2-naphthalenecarboxamide. monohydrochloride The desired compound was prepared from Example 154E and the procedure of Example 144C.
MS (DCI/NH3) m/z 402 (M+H)+;
'H NMR (300 MHz, DMSO-d6) δ 2.54 (s, 3H), 7.15 (t, IH), 7.24 (s, IH), 7.40 (t, 2H), 7.84 (d, 2H), 7.92 (dd, IH), 8.19 (d, IH), 8.39 (d, IH), 8.44 (s, IH), 8.61 (s, IH), 8.69 (s, IH), 9.35 (br s, 4H), 10.61 (s, IH);
Anal, calc'd for C23Hi N3SO -2.25 HCl: C, 57.14; H, 4.43; N, 8.69. Found: C, 57.13; H, 4.21 ; N, 8.56.
Example 155 methyl r7-(aminoiminomethvD-l -naphthalenyllmethylcarbamate. mono(trifluoroacetate) (salt)
The desired compound is prepared according to the procedures described in Example s
12 and 13. Yield: 40 mg (42%) of white solid MS m/z: 258 (M+H)+
Η NMR (DMSO, 300 MHz): 3.28 (s, 3H), 3.82 (br, 3H), 7.66 (dd, 1 H, Jl=7.5 Hz, J2=1.4
Hz), 7.78 (m, IH), 8. 89 (Dd, IH, J l=8.8 Hz, J2=2.0 Hz), 8.05 (d, 1 H, 8.1 Hz), 8.24 (d, 1
H, 8.8 Hz), 8.30 (s, I H), 9.09 (s, 2H), 9.52 (s, 2H);
Anal, calc'd for C14H15N3O2. 1.25 C2F O2H-0.25 H2O: C, 49.02; H, 4.18; N, 10.39. Found: C, 48.81; H, 3.91; N, 10.15.
Example 156 propyl [7-(arninoiminomethvP- 1 -naphthalenyllcarbamate. mono(rrifluoroacetate)(salt)
The desired compound is prepared according to the procedures described in Example s 12 and
13. Yield: 52 mg (46%) of white solid
MS m/z: 272 (M+H)+
Η NMR (DMSO, 300 MHz): 0.97 (t, 3H, J1=J2=7.1 Hz), 1.67 (Sextet, 2H, J=7.1 Hz), 4.19
(t, 3H, J1=J2=6.8 Hz). 7.71 (d, 1 H, 8.5 Hz), 7.83 (m, 3H), 8.14 (d, IH, J=8.5 Hz), 8.67 (s, IH), 9.22 (Br, 3H), 9.63 (s, IH);
Anal, calc'd for C15H17N3O2. 0.25 C F3O2H-0.75 H2O: C, 49.18; H, 4.66; N, 9.83. Found:
C, 49.27; H, 4.87; N, 10.02.
Example 157 N-r7-(aminoiminomethyl)-l-naphthalenyll-N'-methylurea. mono(trifluoroacetate)(salt) The desired compound is prepared according to the procedures described in Example s 12 and 13. Yield: 36 mg (547c) of white solid MS m z: 243 (M+H)+
'H NMR (DMSO, 300 MHz): 2.80 (d, IH), 6.45 (d, IH), 7.70 (m, 2H), 7.82 (dd. Jl=8.9 Hz, J2=2.1 Hz), 8.08 (dd, 7.4 Hz, J=1.3 Hz), 8.17 (d, IH, J=8.5 Hz), 8.62 (s, IH), 8.72 (s, I H), 9.07 (s, 2H), 9.47 (s, 2H), (s, 2H);
Anal, calc'd for C13H14N4O. 1.5 C2F3O2H O.5 H2O: C, 45.50; H, 3.94; N, 13.27. Found: C, 45.22; H, 3.86; N, 13.12.
Example 158 ethyl r7-(aminoiminomethvP- 1 -naphthalenyPcarbamate. mono(trifluoroacetate)(salt) The desired compound is prepared according to the procedures described in Example s 12 and 13. Yield: 70 mg (76%) of white solid MS m/z: 258 (M+H)+
Η NMR (DMSO, 300 MHz): 1.30 (t, 3H, J1=J2=7.4 Hz), 4.20 (q, 2H, J=7.0 Hz), 7.80 (m, 4H), 8.15 (d, 8.5 Hz), 8.68 (s, IH), 9.13 (s, 2H), 9.38 (s, 2H), 9.66 (s, IH); Anal, calc'd for Ci4Hi5N O2-1.5 C2F3O2H: C, 47.67; H, 3.88; N, 9.81. Found: C, 47.97; H, 3.85; N, 9.78.
Example 159 N-r7-(aminoiminomethyl)-l-naphthalenyl)propanamide. mono(ttifluoroacetate)(salt) The desired compound is prepared according to the procedures described in examples 12 and 13. Yield: 20 mg (23 7c) of white solid MS m/z: 242 (M+H)+
Η NMR (DMSO, 300 MHz): 1.18 (t, 3H, 7.4Hz), 3.38 (m, 2H), 7.89 (m, 3H), 7.81 (dd, IH, Jl=8.4Hz, J2=1.9 Hz), 7.87 (d, IH, 8.5 Hz), 8.58 (s, IH), 9.02 (s, 2H), 9.47 (s, 2H), 9.97 (s, IH). Anal, calc'd for Cι4Hι5N30. 1.15 C2F3O2H . 0.25 H2O: C, 51.94; H, 4.45; N, 11.15; Found: C, 52.02: H, 4.24; N, 10.76.
Example 160 N-r7-(aminoiminomethyP- 1 -naphthalenyl)-2-methoxyacetamide. mono(trifluoroacetate)(salt) The desired compound is prepared according to the procedures described in Example s 12 and 13. Yield: 30 mg (307c) of white solid MS m/z: 258 (M+H)+ 'H NMR (DMSO, 300 MHz): 3.49 (s, 3H), 4.18 (s, 2H), 7.80 (m, 3H), 7.93 (d, 1 H, 7.7 Hz), 8.47 (d, 1 H, 8.5 Hz), 8.47 (s, I H), 9.10 (s, 2H), 9.46 (s, 2H), 9.99 (s, 2H); Anal, calc'd for Cι4Hi5N3θ2-lC2F θ2H-1.25 H O: C, 48.80; H, 4.73; N, 10.67. Found: C, 48.53; H, 4.34; N, 10.54;
Η NMR (DMSO, 300 MHz): 2.16 (s, 3H), 4.85 (s, 2H), 7.82 (m, 4H), 8.18 (d, IH, J=8.18 Hz), 8.55 (s, IH), 9.10 (s, 2H), 9.44 (s, 2H), 10.24 (s, I H);
Anal, calc'd for Ci5Hi5N3θ3-l C2F3θ2H-l H2O: C, 48.93; H, 4.35; N, 10.07. Found: C, 48.82; H, 4.27; N, 10.00.
Example 161 N-r7-(aminoiminomethyl)- l-naphthalenyllurea. mono(trifluoroacetate)(salt)
The desired compound is prepared according to the procedures described in Example s 12 and 13. Yield: 35 mg (547c) of yellownish solid MS m/z: 229 (M+H)+
'H NMR (DMSO, 300 MHz): 6.22 (s, 2H), 7.65 (m, 2H), 7.77 (dd, J l=8.8 Hz, J2=1.5Hz). 8.57 (s, IH), 8.79 (s, I H), 9.07 (s, 2H), 9.49 (br, 2H);
Anal, calc'd for C12H12N4O. 1 C2F3O2HO.75 H2O: C, 40.90; H, 3.33; N, 1 1.95. Found: C, 40.95; H, 3.64; N, 12.31.
Example 162 N-r7-(aminoiminomethyl)-l -naphthalenyll-2-hvdroxyacetamide. mono(trifluoroacetate)(salt)
The desired compound is prepared according to the procedures described in Examples 12 and 13. Yield: 24 mg (37 %) of white solid MS m/z: 244 (M+H)+
Η NMR (DMSO, 300 MHz): 4.18 (s, 2H), 5.82 (br, IH). 7.67 (m, IH), 7.85 (m, 3H), 8.20 (d, IH), 9.18 (s, 2H), 9.42 (s, 2H), 9.89 (s, I H);
Anal, calc'd for C13H13N3O2T C2F3O2HO.75 H2O: C, 48.59; H, 4.21 ; N, 1 1.33. Found: C, 48.64; H, 3.89; N, 1 1.25.
Example 163 8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt) The desired compound is prepared according to the procedures described in Examples
91 A and 13. Yield: 28 mg (287c) of pale yellow solid
MS m/z: 264 (M+H)+ 'H NMR (DMSO, 300 MHz): 6.90 (t, IH, J1=J2=4.7 Hz), 7.69 (d, J=7.8 Hz), 7.80 (1 H,
J=8.1 Hz), 7.81 (1 H, dd, Jl=8.4 Hz, J2=2.1 Hz). 8.08 (IH, dd, Jl=7.4Hz, J2=0.6 Hz),
8.14 (IH, d, J=8.5 Hz), 8.49 (d, 2H), 8.75 (IH, d, J=1.7 Hz). 9.06 (s, 2H), 9.37 (s, 2H),
9.60 (s, IH);
Anal, calc'd for C15H13N5. 2.25 C2F3O2H O.25 H2O: 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)(salt) To a solution of crude 8-amino-2-nittile-naphthalene prepared as described in Example 10 at room temperature in 10: 1 pyridine: triethylamine ( 10 mL) was bubbled hydrogen sulfide for 5 minutes and stined at room temperature overnight. The reaction mixture was added water (50 mL) and the product was extracted into ethyl acetate (3x30 mL) . The combined organic solvent was dried over magnesium sulfate, filtered and evaporated. The resulting yellow substance was taken up in acetone (30 mL) then added methyl iodide (2 mL). The reaction mixture was boiled for 1 hour, then evaporated to dryness. To the resulting yellow substance in methanol (25 mL) was added ammonium acetate (100 mg) and stined at room temperature overnight. The solvent was removed under vacuum and the product was purified via reverse phase chromatography using 0.1 c TF A/water and 0.1 o TFA/methanol as eluent. MS m/z: 186 (M+H)+ ' H NMR (DMSO, 300 MHz): 5.14 (br, 3H), 6.80 (dd, IH, J l=7.8 Hz, J2=l Hz), 7.17 (d, I H, J=7.8 Hz), 7.40 (dd, I H, J1=J2=7.8 Hz), 7.70 (dd, I H, J l=8.9 Hz, J2=2.1 Hz), 7.91 (d, IH, J=8.5 Hz), 8.65 (s, IH), 8.95 (s, 2H), 9.23 (s, 2H);
Anal, calc'd for CnHnN3-2.5 C2F3O2H-0.75 H2O: C, 39.72; H, 3.13; N, 8.69. Found: C, 40.01 ; H, 3.19: N, 8.88.
Example 165 6-(aminoiminomethyl)-N-r4-(aminomethyl)phenyll-4-(2-pyrimidinylamino)-2- naphthalenecarboxamide. tris(trifluoroacetate)(salt) Example 165 A A suspension of 2-nitrile-6-methyester naphthalene Example 8D (5.0 g, 23 mmol) in concenttated sulfuric acid (50 mL) at -5 °C was added a solid potassium nitrate. The colour of reaction mixture was gradually changed into a dark brown. The reaction mixture was stined for 15 minutes and was poured into ice-water. Collected the precipitate and washed with water. The crude product was recrystallized from ethyl acetate and ethanol. Yield 4.3 g (68%) of pale yellow powder.
Example 165B To a solution of 2-nitrile-6-methylester-8-nitro-naphthalene, Example 165 A (3.5 g, 13.6 mmol) in a mixture of THF (100 mL) and ethyl acetate (120 mL) was added 107c Pd-C (350 mg). The reaction mixture was placed under hydrogen at atmospheric pressure (balloon) and stirred at room temperature for 3 5 hour. The mixture was filtered through ceiite and silica gel, washed with ethyl acetate and evaporated. The resulting solid was washed with ether (20 mL). Yield 2.20 g (717c) of yellow powder.
Example 165C A mixture containing 2- Nitrile-6-methylester-8-amino-naphthalene, Example 165B (2.8 g, 12.3 mmol), BINAP (116 mg, 0.186 mmol), Pd2 (DBA)3 (64 mg, 0.061 mmol), NaO-t-Bu (1.667 g, 17.6 mmol), 2-Bromopyrimidine (2.363 g, 14.9 mmol) and Toluene (80 mL) in an oven-dried flask under nitrogen, was stined at room temperature for 10 minutes. The reaction mixture was heated to 80 *C for 1 hour. At the end of the reaction (TLC, hexanes+ethyl acetate=4: 1 ), brine 9200 mL) was added. Exttacted the mixture with CH2CI2. (4x250 mL). Evaporated the solvent. Yield 3.5 g (937o) of pale yellow powder.
Example 165D TO a suspension of 2-nitrile-6-methylester-8-N- (2-pyrimidine)-naphthalene, Example 165C (5.2 g, 17.1 mmol ) in ethanol (150 mL) was added potassium carbonate (3.54 g, 33.3 mmol) in water (200 mL). The resulting suspension was heated at 120 °C for 2 hours, at that time all the suspension turned into a clear solution. The mixture is cooled down, then acidified with 2 N HCl. The resulting precipitate was collected by filtration to yield 4.5 g (90%>) of pale yellow powder. No further purification was required for the next step.
Example 165E To a cold (0°C) solution of 2-nitrile-8-N- (2-pyrimidine)-6-carboxylic acid- naphthaleneExample 165D (5.0 g, 17.2 mmol) in DMF (150 mL) was added DIEA (7.6 mL, 42.6 mmol) and O- (7-Azabenzottiazol-l-yl)-N, N, N\ N'- tetramethyluroniumhexafluorophosphate (9.8 g, 25.7 mmol) followed by tert- Butoxycarbonylamino-4-aminomethylaniline (5.74 g, 20 mmol). The resuting reaction mixture was stined for about 1 hour. The reaction was quenched with water (200 mL) and the resulting precipitate was collected by filtration to yield 3.26 g (38%) of pale yellow powder.
Example 165F To a solution of the substrate, Example 165E (3.0 g, 6.07 mmol) in pyridine (150 mL) was added triethylamine (9 mL). H2S was passed for 10 minutes and the resultiing mixture was stirred at room temperature for 48 hour. 100 mL of water was added to the reaction mixture and the precipitate was Collected by filtration. Yield (3.0 g (937c) of yellow solid.
Example 165G
To a solution of the thioamide, Example 165F in acetone (200 mL) was added Mel (6 mL) and the mixture was stined at room temperature overnight. The mixture was evaporated to dryness to yield 1.2 g (78%) of yellow solid.
Example 165H
6-(aminoiminomethyl)-N-r4-(aminomethyl)phenyll-4-(2-pyrimidinylamino)-2- naphthalenecarboxamide. tris(trifluoroacetate)(salt) To a solution of the imidate ester, Example 165G, (1.5 g, 2.2 mmol) in methanol (50 mL ) was added ammonium acetate (0.5 g, 6.4 mmol) and stined at room temperature overnight After evaporation of the solvent the residue was treated with ether (3x25 mL) and the ether was decanterd out. The residue was dissolved in a mixture of 10: 1: 1 acetonitrile: water: acetic acid (50 mL). After addition of ether (100 mL), the Boc protected product precipitated as an acetate salt and was colleted by filtration. The solid was added 1 : 1 TFA: methylene chloride (50 mL) containing thioanisole (0.5 mL). The reaction mixture was stined at room temperature overnight. The product was purified over RPC18 chromatography using water: methanol with 0.1 % TFA as eluent. Yield after lyophilization 0.5 g (547c) of pale yellow solid. MS m/z: 412 (M+H)+
Η NMR (DMSO, 300 MHz): 4.02 (q, 2H, J=5.8), 6.94 (dd, IH, J12=J2=4.8 Hz), 7.45 (d, 2H, J=8.5 Hz), 7.84 (d, 2H, J=8.4 Hz), 7.92 (dd, IH, Jl=8.5 Hz, J2=1.7 Hz), 8.13 (br, 3H), 8.30 (d, IH, J=8.9 Hz), 8.41 (s, IH), 8.52 (d., 2H), 8.55 (s, IH), 8.81 (s, IH), 9.19 (s, 2H), 9.43 (s, 2H), 9.75 (s, IH), 10.62 (s, IH);
Anal, calc'd for C23H2ιN7O-2.5 C2F3O2H I H2O: C, 43.49; H, 3.22: N, 1 1.83. Found: C, 43.54; H, 3.34; N, 1 1.69.
Example 166 6-(aminoiminomethyl)-N-phenyl-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide. mono(trifluoroacetate) (salt) The same procedure as described in Examples 165 substituting aniline for 4-amino benzyl amine.
MS m/z: 383 (M+H)+
'H NMR (DMSO, 300 MHz): 6.93-6.96 (m, IH), 7.14 (dd, IH, Jl=7.3 Hz, J2=7.4 Hz), 7.40 (dd, 2H, J 1=J2=7.3 Hz), 7.80 (, d, 2H, J=8.1 Hz), 7.91 (d, IH, J=8.9 Hz), 8.30 (d, I H, J=9.0 Hz), 8.41 (s, I H), 8.52-8.54 (m, 3H), 8.80 (s, I H), 9.16 (s, 2H), 9.45 (s, 2H), 9.78 (s, I H), 10.55 (s, I H);
Anal, calc'd for C22Hι8N6O-2 C2F3O2H-0.25 H2O: C, 50.78; H, 3.28; N, 13.31. Found: C, 50.85; H, 3.28; N, 13.31.
Example 167 N-r(4-(aminomethyl)phenyll-6-ramino(hydroxyimino)methyll-4-(2-pyrimidinylamino)-
2-naphthalenecarboxamide. bis(trifluoroacetate)(salt) To a suspension of compound, prepared in Example 165 E (0.20 g, 0.40 mmol ) in methanol (40 mL) and water (20 mL) was added hydroxylamine hydro-chloride (1 12 mg, 1.75 mmol) and sodium carbonate (85 mg, 0.80 mmol), the reaction mixture was stined for 48 hours at room temperature, TLC showed no reaction. Th reaction mixture was heated at reflux for 10 hours and removed the most of the solvents, the precipitate was collected by filtration, gave 1.2 g of pale yellow solid. The solid was disoolved in 1 : 1 TFA+CH2CI2 (30 mL) and sitned at room temperature for 24 hours. The solvents was removed under vaccuum and the residue was loaded to a R18 reverse phase column. The fraction was lyophilized and yielded a pale yellow powder (80 mg, 66%>). MS m/z: 428 (M+H)+
'H NMR (DMSO, 300 MHz): 4.02 (q, 2H, J=6.1 Hz), 6.92 (dd, I H, J1=J2=5.1 Hz), 7.46 (d, 2H, 8.4 Hz), 7.85 (d, 2H, J=8.5 Hz), 7.88 (d, IH, 9Hz), 8.12 (br, 3H), 8.22 (d, IH, J=8.9 Hz), 8.40 (s, 'H ), 8.48 (s, IH), 8.51 (d, 2H, J=4.8 Hz), 8.64 (s, IH), 9.74 (s, 2H), 10.61 (s, 2H); Anal, calc'd for C23H2iN7O2-2.9 C2F3O2H-1.25 H O: C, 44.31 : H, 3.41; N, 12.56; F, 21.17 Found: C, 44.08; H, 3.30: N, 12.50, F, 21.25.
Example 168
6-(aminoiminomethvD-N-l"4-(hvdroxymethyl)phenyl1-4-(2-pyrimidinylamino)-
2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) The desired compound is prepared as described in Example 165 using 4-amino benzyl alcohol instead of 4-amino benzylamine. MS m z: 413 (M+H)+
Η NMR (DMSO, 300 MHz): 4.48 (s, 2H), 6.94 (dd, IH, 2H, J=8.8 Hz), J1=J2=4.8 Hz), 7.32 (d, 2H, J=8.8 Hz), 7.90 (dd, IH, Jl=8.5 Hz, J2=1.7 Hz), 8.28 (d, 2H, J=8.8 Hz), 8.41 (s, IH), 8.54 (d, 2H, J=4.8 Hz), 8.55 (dd, I H, J=1.3 Hz), 8.80 (s, IH), 9.08 (s, 2H), 9.43 (s, 2H), 9.73 (s, IH), 10.48 (s, IH); Anal, calc'd for C23H2ON6θ2: 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 r3-rrf4-(aminomethvDphenyl1aminolcarbonvn-7-[4-amino(hydroxyimino)methvn- 1 -naphthalen yllcarbamate, bis(trifluoroacetate)(salt)
Example 170A To a suspension of the nitrile, Example 14 ID (213 mg, 0.45 mmol) and hydroxylamine hydrochloride (338 mg, 4.86 mmol) in methanol (40 mL) water (5 mL) was added potassium carbonate (538 mg, 3.9 mmol) stined at room temperature overnight. The solvent was evaporated and the resulting solid was washed with ether and hexanes to yield the product as white solid 153 mg (62%). MS (ECI) m/z 508 (M+H)+.
Example 170B methyl r3-rrr4-(aminomethyl)phenvnaminolcarbonyll-7-r4-amino(hydroxyimino)methyll- 1 -naphthalenyllcarbamate, bis(trifluoroacetate)(salt) The Boc protected substrate, Example 170A was added 3 mL of 4 N HCl in dioxane and stined at room temperature for 20 minutes. The solvent was evaporated under vacuum and the product was separated on MPLC with a column of RP CJ S using methanol-water
+0.17cTFA as eluent. Yield of white solid 117 mg (797c).
MS (ECI) m/z 408 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 3.77 (S, 3H), 4.03 (s, 2H), 4.01 (q, J=5.9 2H), 7.46 (d,
J=8.5Hz, 2H), 7.86 (d, J=8.5Hz, 2H), 7.90 (dd, Jι=8.5, Hz, J2= 1.4Hz, IH), 8.09-8.15 (m, 4H), 8.17 (d, J=8.4Hz, IH), 8.29 (s, IH), 8.42 (s, IH), 8.56 (s, IH), 9.80 (s, IH), 10.62 (s, IH);
Anal, calc'd for C2ιH2ιN5O4-2.5 TFA-0.5 H2O: 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 171 6-ramino(hvdroxyimino)methyll-N-phenyl-2-naphthalenecarboxamide The title compound is prepared as described by Judkins et al., Synthetic Communications 26 (23), 4351-4367 (1996). The compound prepared in Example 55C (0.1 g, .36 mmole) is dissolved in a 10: 1 mixture of Toluene: methanol to which is added hydroxylamine hydrochloride (3.6 mmole) and potassium tert-butoxide (3.6 mmole). The resulting sluny is refluxed for 17 hr., cooled, solvents removed under vacuum. The residue is taken up in distilled water (30 ml) exttacted with ethyl acetate (2 X 100 ml). The combined organic extracts are washed with 10% NaCl (50 ml), dried over anhydrous Na2S04. The sample is filtered of drying agent and the solvent removed under vacuum leaving a white solid (65 mg). The material is purified by medium pressure reverse phase chromatography as described in Example 1. The title compound is obtained as white solid (45 mg) MS (m/z) M + H+: 306 Η NMR (DMSO-d6): 10.51 (s, IH), 9.32 (s, OH), 8.70 (s, I H), 8.57 (s, IH), 8.34 (d, IH), 8.25 (d, IH), 8.17 (dd, IH), 7.90 (dd, IH), 7.83 (d, 2H), 7.40 (dd, 2H), 7.15 (dd, IH), 6.25 (bs, 2H).
Analysis: calc'd for C2oH i6N3O4 F : C, 57.28, H, 3.85, N, 10.02; Found C, 56.89, H, 3.65, N, 9.90.
Example 174
8-(2-pyridinylamino)-2-naphthalenecarboximidamide. bis(trifluoroacetate) salt
Example 174A To a solution of the product from 1 ID (168 mg, 1.00 mmol) in 5 mL toluene was added 2-bromopyridine (0.105 mL, 1.1 mmol), NaOtBu (135 mg, 1.4 mmol), Pd2dba3 (92 mg, 0.1 mmol), and P (o-tolyl)3 (122 mg, 0.4 mmol), and the reaction was stirred for 24 hours at 100 °C. The reaction was cooled, and the crude reaction mixture was chromatographed on Siθ2 using 507c ethyl acetate/hexanes as eluent to yield 80 mg (33 %>) of the desired compound. MS (DCI (NH )) m/z 246 (M+H)+.
Example 174B 8-(2-pyridinylamino)-2-naphthalenecarboximidamide. bis(trifluoroacetate) salt The product from Example 174A (121 mg, 0.493 mmol) was dissolved in THF (2 mL) and 0.543 mL of a 1 M solution of LiN (TMS)2 in THF was added. The reaction was stirred for 5 min, and TMSCl (0.069 mL, 0.543 mmol) was added. After stining for 30 min, another 1.09 mL of the 1 M solution of LiN (TMS)2 was added. The reaction was stined for 18 hours, and 10 mL of a 2 M aq. HCl solution was added. The reaction was stined for another 24 hours, and was basicified with saturated aq. Na2CO3. The mixture was extracted with 3x ethyl acetate, and the extracts were washed with brine, dried over Na2SO4, and condensed. The crude product was purified by reverse-phase HPLC to yield the desired compound (21 mg, 7%>): m.p. 137-147 °C. MS (DCI (NH3) m/z 263 (M+H)+; Η NMR (300 MHz, DMSO) δ 9.98 (br s, IH), 9.46 (br s, 2H), 9.27 (br s, 2H), 8.74 (s,
I H), 8.21 (d, J=9 Hz, IH), 8.1 1 (d, J=6 Hz, IH), 8.02 (d, J=9 Hz, I H), 7.81 -7.95 (m, 3H), 7.75 (dd, J=9, 9 Hz, IH), 7.16 (m, IH), 6.95 (m, IH), 2.55 (s, 3H); Anal, calc'd for Ci6H i4N4-3.1 C2HF3O2: C, 43.30; H, 2.80; N, 9.10. Found: C, 43.14; H, 3.04; N, 9.90.
Example 176 6-l4-f(hvdroxymethyl)phenyllmethoxyl-2-naphthalenecarboximidamide. methanesulfonate(salt)
Example 176 A To a solution of NaH (607c in mineral oil, 1.17 g, 29.3 mmol) in THF (50 mL) was added 4-bromobenzyl alcohol (5.22 g, 27.9 mmol) in THF (50 mL), and the reaction was stined at room temperature for 20 minutes. p-Methoxybenzyl chloride (4.07 mL, 30 mmol) was then added, and the reaction was stined at 50°C for 2 hours. The mixture was poured into water and extracted with 3x diethyl ether, and the exttacts were washed with brine, dried over Na2SO4, and condensed. The crude reaction mixture was chromatographed on Siθ2 using hexanes as eluent, to yield 7.39 g (86%>) of the desired compound. MS (DCI (NH3)) m/z 326 (M+NE )+;
'H NMR (300 MHz, CDC1 ) 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 the product from 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 solution of BuLi (8.85 mL, 22.13 mmol), and the reaction was stined for 2 minutes. DMF (3.43 mL, 44.3 mmol) was then added, and the reaction was warmed to room temperature. The mixture was poured into water and extracted with 3x diethyl ether, and the exttacts were washed with brine, dried over
Na2SO4, and condensed. The crude reaction mixture was taken up in methanol (100 mL) and
NaBH4 (1.0 g, 26.2 mmol) was added in portions. A few drops of water were added, and the mixture condensed. The residue was chromatographed on Siθ2 using 207c ethyl acetate/hexanes as eluent, to yield 3.32 g (587o) of the desired compound.
MS (DCI (NH3)) m z 276 (M+NH )+;
Η NMR (300 MHz, CDCI3) δ 7.38 (s, 4H), 7.29 (d, 2H), 6.90 (d, 2H), 4.70 (s, 2H), 4.54
(s, 2H), 4.49 (s, 2H), 3.81 (s, 3H), 1.62 (s, IH).
Example 176C To a solution of the product from Example 176B (193 mg, 0.747 mmol), the product from Example 28A (139 mg, 0.822 mmol), and Ph3P (216 mg, 0.822 mmol) in THF (10 mL) at 0°C was added diethylazodicarboxylate (0.129 mL, 0.822 mmol), and the reaction was stined for 90 minutes at room temperature. The crude reaction mixture was condensed, and the residue was chromatographed on Siθ2 using 107c ethyl acetate/hexanes as eluent, to yield 225 mg (747o) of the desired compound.
MS (DCI (NH3)) m/z 427 (M+NH4J+;
'H NMR (300 MHz, CDCI3) δ 8.15 (s, IH), 7.81 (d, IH), 7.77 (d, IH), 7.58 (dd, 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 from Example 176C (220 mg, 0.537 mmol) in CH2CI2 (40 mL) and water (7 mL) was added DDQ (244 mg, 1.07 mmol), and the reaction was stirred for 90 minutes. The crude reaction mixture was taken up in CH2CI2, washed with 2x aqueous NaHCO3 and brine, dried over Na2SO4, and condensed. The residue was chromatographed on Siθ2 using 507o ethyl acetate/hexanes as eluent, to yield 89 mg (577c) of the desired compound.
MS (DCI (NH3)) m/z 307 (M+NH4) -; 'H NMR (300 MHz, CDCI3) δ 8.15 (s, IH), 7.81 (d, I H), 7.77 (d, IH), 7.57 (dd, IH), 7.49
(d, 2H), 7.41 (d, 2H), 7.33 (dd, IH), 7.21 (d, IH), 5.21 (s, 2H), 4.74 (s, 2H), 1.63 (br s, I H);
Example 176E
6-r4-r(hvdroxymethyl)phenyl1methoxyl-2-naphthalenecarboximidamide. methanesulfonate(salt) The desired compound was prepared from Example 176D and the procedure of Example 55D.
MS (DCI/NH3) m/z 307 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 2.31 (s, 3H), 4.52 (s, 2H), 5.25 (s, 2H), 7.37 (d, 2H),
7.39 (dd, IH), 7.47 (d, 2H), 7.59 (d, I H), 7.79 (dd, IH), 8.00 (d, IH), 8.03 (d, IH), 8.41
(s, I H), 8.89 (br s, 2H), 9.34 (br s, 2H); Anal, calc'd for Ci9Hi8N2O2- 1.15 CH4SO3: C, 58.06; H, 5.46; N, 6.72. Found: C, 58.24;
H, 5.62; N, 6.59.
Example 177 N-hvdroxy-8-(2-pyrimidinylamino)- 2-naphthaienecarboximidamide, mono(trifluoroacetate)(salt)
The desired compound is prepared from the nitrile described in Example 163 and utilizing the procedure described in Example 167. Yield as a white powder: 50 mg MS m/z: 280 (M+H)+ 'H NMR (DMSO, 300 MHz): 6.90 (dd, IH, Jl=J2=5.2Hz), 7.45 (m. 3H), 8.0 (d, IH, J=8.5 Hz), 8.14 (d, IH, J=8.4Hz), 8.49 (d, J=5.3 Hz), 8.61 (s, IH), 9.58 (s, IH); Anal, calc'd for Ci5Hι3N5O-2.0 C2F3O2HO.5 H2O: C, 44.20; H, 3.12; N, 13.56. Found: C, 44.24; H, 2.94; N, 13.49. Example 179 6-(2-pyridinylethvnyl)-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
Example 179A Using the product obtained in Example 28B, 2-ethynylpyridine (Lancaster Chemical
Corp.) and the procedure described in Example 121 A, the desired compound was obtained. MS (DCI/NH3) m/z 255 (M+H)+
Example 179B Using the product obtained in Example 179A and the procedure described in Example
94D the desired compound was obtained.
MS (DCI) m/z 272 (M+H)+;
Η NMR (300 MHz, DMSO) δ 7.45-7.50 (m, IH), 7.72 (d, IH), 7.82 (dd, IH), 7.86-7.92
(m, 2H), 8.18 (d, IH), 8.22 (d, IH), 8.42 (s, IH), 8.54 (s, IH), 8.68 (m, IH), 9.25 (s, 2H), 9.49 (s, 2H);
Anal, calc'd for C20H14F3N3O2O.25 H2O: C, 61.62; H, 3.75; N, 10.78. Found: C, 61.72;
H, 3.64; N, 10.66.
Example 180 6-(aminoiminomethyl)-N-phenv]-4-(tettahvdro-3-furanyl)-2-naphthalenecarboxamide. monohydrochloride
Example 180A The desired compound was prepared from the product from Example 152 by the procedure of Example 62A.
MS (DCI/NH3) m/z 340 (M-H2O)+.
Example 180B The desired compound was prepared from the product from Example 180A by the procedure of Example 62B.
MS (DCI/NH3) m/z 343 (M+H)+.
Example 180C The desired compound was prepared from Example 180B and the procedure of Example 55D.
MS (DCI/NH3) m/z 360 (M+H)+;
'H NMR (300 MHz, DMSO-d6) δ 2.20 (m, IH), 2.52 (m, IH), 3.85 (dd, IH), 3.94 (ddd, I H), 4.08 (ddd, lh), 4.26 (dddd, IH), 4.39 (dd, IH), 7.14 (t, IH), 7.40 (t, 2H), 7.81 (d, 2H), 7.95 (d, IH), 8.08 (s, IH), 8.32 (d, IH), 8.59 (s, I H), 8.79 (s, IH), 9.25 (br s, 2H), 9.61 (br s, 2H);
Anal, calc'd for C22H2iN3O2-2.6 HCl: C, 58.18; H, 5.24; N, 9.25. Found: C, 58.21; H, 4.91 ; N, 9.13.
Example 181
6-ramino(hvdroxyimino)methyll-N-phenyl-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide Prepared in a similar manner as described in Example 177 using the material prepared in
Example 166. MS m/z: 399 (M+H)+
Η NMR (DMSO, 300 MHz): 6.88 (dd, IH, 4.7Hz), 7.1 1 (dd, I H, J l =J2=7.5Hz), 7.37 (dd,
2H, J1 =J2=7.5 Hz), 7.82 (d, 2H, J=8.8 Hz), 7.94 (dd, IH, Jl=8.5Hz, J2=1.4 Hz), 8.04 (d,
I H, J=8.8Hz), 8.31 (s, IH), 8.43 (dd, IH, J=14 Hz), 8.74 (d, 2H, J=4.7 Hz), 8.52 (s, IH),
9.55 (s, IH), 9.85 (s, 2H), 10.41 (s, IH); Anal, calc'd for C22Hi8N6O -0.4 H2O: C, 65.14; H, 4.67; N, 20.72. Found: C, 65.57; H,
4.45; N, 20.18.
Example 182 methyl 4-rrf7-amino(hvdroxyimino)methyl1-2-naphthalenyl1oxy1methvflbenzoate The resulting product from Example 213A (1 10 mg, 0.347 mmol), hydroxylamine hydrochloride (26.5 mg, 0.381 mmol), triethylamine (53 μl, 0.381 mmol) and N, N- dimethylformamide (12 mL) were combined in a four inch glass pressure tube. The tube was sealed and heated for 24 hours at 80 °C. The tube was cooled to room temperature and additional hydroxylamine hydrochloride (48.1 mg, 0.693 mmol) and triethylamine (96.6 μl, 0.693 mmol) in N, N-dimethylformamide (2 mL) was added. The tube was resealed and heated for 24 hours at 80 °C. The addition, as above, was repeated a second time, the tube was resealed and heated for 72 hours at 80 °C. The reaction mixture was concentrated to a solide residue which was purified by column chromatography on silica gel (60 g) eluted with 15% acetone in methylene chloride to yield the target compound as a white solid (43 mg, 50% based on recovered starting material). MS (DCI (NH3)) m/z 351 (M+H)+;
'H NMR NMR (300 MHz, DMSO-d6) δ 3.860 (s, 3H), 5.349 (s, 2H), 5.860 (s, 2H), 7.280 (dd, IH), 7.381 (d, IH), 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);
Anal, calc'd for C2θHi8N2O4-0.15 H2O: C, 68.04; H, 5.22; N, 7.93. Found: C, 68.06; H, 5.05; N, 7.87.
Example 184
N-r4-(aminocarbonyl)phenyl1-6-(aminoiminomethyl)-2-naphthalenecarboxamide. mono(trifluoroacetate) salt
Example 184A A suspension of the product obtained in Example 8A (300 mg, 1.39 mmol) and 5 mL dichloromethane was added dropwise to a 0° solution of 4-aminobenzamide (207 mg, 1.52 mmol), triethylamine (0.44 mL, 3.2 mmol), and 10 mL dichloromethane. The reaction mixture was stined for 0.5 hour at 0° and for 18 hours at room temperature. Excess ether was added with stining and the resultant solid was filtered, washed with 1 N HCl, water, and was dried under vacuum to afford the desired compound. MS (DCI) m/z 333 (M+NH3)+.
Example 184B N-f4-(aminocarbonyl)phenyl1-6-(aminoiminomethyD-2-naphthalenecarboxamide. mono(ttifluoroacetate) salt
Using the product obtained in Example 184A and the procedure described in Example 4C the desired compound was obtained. MS (DCI) m/z 333 (M+H)+;
'H NMR (300 MHz, DMSO) δ 10.76 (S, IH), 9.51 (S, 2H), 9.14 (S, 2H), 8.74 (S, IH), 8.56 (S, IH), 8.33 (D, IH, J=8.8 Hz), 8.26 (D, IH, J=8.8 HZ Hz), 8.16 (DD, IH, J=8.46, 1.1 1 Hz), 7.91 (M, 6H), 7.31 (S, IH);
Anal, calc'd for C20H17F3N4O4T .5 H20: C, 53.28; H, 4.26; N, 1 1.83. Found: C, 53.47; H, 3.86; N, 11.96. Example 185 methyl 2-rr6-(aminoiminomethyl)-2-naphthalenyl1oxylacetate, mono(trifluoroacetate)(salt)
Example 185A 7-methoxy-2-cyanonaphthalene, (2.79 g, 5.23 mmol) and tetrabutylammonium iodide
(17 mg, 0.157 mmol) were combined in a mixture of benzene (35 mL) and cyclohexanes (17.5 mL). The resulting solution was added to a rapidly stirring, cooled (ice/water) suspension of aluminum triiodide (6.21 g, 15.23 mmol) in a mixture of benzene (35 mL) and cyclohexanes (17.5 mL) under an inert atmosphere. After the addition, the resulting suspension was heated at reflux for 2.5 hours. The heating was removed and after cooling to near room temperature, the reaction mixture was cooled in an ice bath and quenched by the addition of water (100 mL). The resulting mixture was further diluted with 2 M aqueous sodium thiosulfate solution (50 mL) and exttacted with ethyl acetate (3 X 80 mL). The combined organic layers were dried and evaporated. The resulting solid was dissolved in a minimum of hot ethyl acetate, diluted hot with hexanes to the cloud point and placed in a refrigerator for 2 hours. The desired compound was collected by filtration, (1.99 g, 77%). MS (DCI (NH )) m/z 187 (M+NH4)+.
Example 185B The resulting product from Example 185A (217 mg, 1.283 mmol) was combined with cesium carbonate (460 mg, 1.411 mmol) and tettabuthylammonium iodide (catalytic) in DMF (7 mL). To this was added t-butyl bromoacetate (193 μL, 1.283 mmol) and the resulting mixture was stined 2 hours under an inert atmosphere. The reaction mixture was diluted with water (100 mL) and exttacted with ethyl acetate (2 X 50 mL). The combined organic layers were dried and evaporated. The residue was purified by column chromatography to yield the desired compound as an oil (332 mg, 91%>): MS (DCI (NH3)) m/z 284 (M+H) +, 301 (M+NH4)+.
Example 185C methyl 2-rr6-(aminoiminomethyl)-2-naphthalenylloxylacetate. mono(ttifluoroacetate)(salt)
The product from Example 185B (323 mg, 1.140 mmol) was dissolved in anhydrous methanol (32 mL) under an inert atmosphere and cooled to 0 °C. Anhydrous hydrogen chloride was bubbled into the solution until it became saturated. The reaction was stined for 15 minutes at 0 °C and saturated again with anhydrous hydrogen chloride. After stirring for an additional 20 minutes at 0 °C the solution was saturated one final time with anhydrous hydrogen chloride and stined 18 hours while warming to room temperature. The reaction was evaporated to a solid and dried under high vacuum for 2 hours. The solid was slurried in methanol (64 mL), ammonium acetate (220 mg, 2.850 mmol) was added, and the mixture was heated at reflux 2 hours. The reaction was evaporated and purified by reverse phase chromatography to give the desired compound (265 mg, 907c). MS (DCI (NH3)) m/z 259 (M+H)+; Η NMR (300 MHz, DMSO-d6) δ 3.735 (s, 3H), 4.995 (s, 2H), 7.430 (dd, IH), 7.458 (s,
IH), 7.669 (dd, IH), 8.025 (d, IH), 8.095 (d, IH), 8.325 (d, IH), 9.090 (br s, IH), 9.410 (br s, IH;
Anal, calc'd for C14H14N2O3- (C2H02F3) 1.05: C, 51.16; H, 4.01; N, 7.41. Found: C, 51.35; H, 3.98; N, 7.48.
Example 186 6-(aminoiminomethyl)-N-(2-thiazolyl)-2-naphthalenecarboxamide. monohydrochloride
Example 186A The above product was prepared in the manner of Example 8A using 2-aminothiazole. MS (APCI) m/z (M+H)+ 280.
Example 186B 6-(aminoiminomethyl)-N-(2-thiazolvP-2-naphthalenecarboxamide. monohydrochloride The above was prepared from Example IB. MS (APCI) m/z (M+H)+ 297; 1 H-NMR (300 MHz, DMSO-d6) δ 12.88 (s, IH), 9.59 (s, 2H), 9.30 (s, 2H), 8.87 (s, IH), 8.59 (s, IH), 8.32-8.22 (m, 4H), 7.93 (dd, J=1.8, 8.4 Hz, IH), 7.61 (d, J=3.3 Hz, IH), 7.33 (d, J=3.3 Hz, IH);
Anal, calc'd for C15H13N4OCIS 2/5 HCl: C, 52.03; H, 3.89; N, 16.18. Found: C, 52.01; H, 3.88; N, 16.12.
Example 187 6-(aminoiminomethyl)-N-(6-methoxy-3-pyridinyP-2-naphthalenecarboxamide. monohydrochloride Example 187A The above product was prepared in the manner of Example 8A using 5-amino-2- methoxypyridine. MS (APCI) m/z (M+H)+ 304.
Example 187B 6-(aminoiminomethyP-N-(6-methoxy-3-pyridinyP-2-naphthalenecarboxamide. monohydrochloride The above was prepared as described Example IB (144D). MS (CI) m/z (M+H)+ 321;
1H-NMR (300 MHz, DMSO-d6) δ 10.71 (s, IH), 9/60 (s, 2H), 9.41 (s, 2H), 8.76 (s, IH), 8.60 (s, 2H), 8.30 (d, J=9, IH), 8.25-8.12 (m, 4H), 7.93 (dd, J=1.8, 8.7 Hz, IH), 6.89 (d, J=9.0 Hz, I H), 3.87 (s, 3H);
Anal, calc'd for C20H17N4O4F3 1/2 TFA: C, 51.47; H, 3.60; N, 11.45. Found: C, 51.39; H, 3.88; N, 1 1.65.
Example 188 6-(aminoiminomethyl)-N-( 1. 3-benzodioxol-5-yl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
Example 188A The above product was prepared in the manner of Example 8A using 3, 4- methylenedioxyaniline. MS (APCI) m/z (M+H)+ 317.
Example 188B The above was prepared as described Example IB. MS (CI) m/z (M+H)+ 334;
1 H-NMR (300 MHz, DMSO-d6) δ 9.70 (s, IH), 8.20 (s, 2H), 9.96 (s, IH), 7.81-87.63 (m, 3H), 7.31 (dd, J=1.8, 8.4 Hz, IH), 7.1 1 (d, J=4.2 Hz, IH), 6.91 (dd, J=4.5, 10.8 Hz), 6.4 (d, J=8.4 Hz, IH), 5.59 (s, 2H);
Anal, calc'd for C21H16N3O3F3 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-(l . 2. 3. 4-tetrahydro-2. 4-dioxo5-pyrimidinyl)- 2-naphthalenecarboxamide. monohydrochloride
Example 189A
The above product was prepared in the manner of Example 8A using 5-aminouracil. MS (APCI) m/z (M-H)+ 305.
Example 189B 6-(aminoiminomethyl)-N-(l . 2. 3. 4-tetrahvdro-2. 4-dioxo5-pyrimidinyD-
2-naphthalenecarboxamide. monohydrochloride The above was prepared as described in Example IB. MS (CI) m/z (M+H)+ 324;
' H-NMR (300 MHz, DMSO-d6) δ 1 1.50 (s, I H), 10.90 (m, IH), 9.53 (s, 3H), 9.21 (s, 2H), 8.70 (s, IH), 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), 8.00 (s, IH), 7.88 (dd, J=1.8, 8.4 Hz, I H);
Anal, calc'd for C16H14N5O3CI 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-(aminoirninomethyl)-N-(3. 5-difluorophenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt)
Example 190A The above product was prepared in the manner of Example 8A using 3, 5- difluoroaniline. MS (APCI) m/z (M-H)+ 307.
Example 190B 6-(aminoiminomethyl)-N-(3. 5-difluorophenyl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) The above was prepared as described in Example IB. MS (CI) m/z (M+H)+ 326; IH-NMR (300 MHz, DMSO-d6) δ 10.93 (s, IH), 9.53 (s, 2H), 9.34 (s, 2H), 8.71 (s, IH), 8.58 (s, IH), 8.33 (d, J=8.4 Hz, IH), 8.26 (d, J=8.7 Hz, IH), 8.14 (m, IH), 7.92 (dd, J=0.9, 8.1 Hz, IH), 7.61 (d, J=7.8 Hz, 2H), 7.04-6.97 (m, IH);
Anal, calc'd for C20H14N3O2F5 2/5 TFA: C, 54.92; H, 3.21; N, 9.42. Found: C, 54.96; H, 3.36; N, 9.37.
Example 191 6-(aminoiminomethyl)-N-(lH-pyrazol-3-yl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt)
Example 191 A The above product was prepared in the manner of Example 8A using 3-aminopyrazole. MS (APCI) m/z (M+H)+ 263.
Example 191B
6-(aminoiminomethyl)-N-(lH-pyrazol-3-yD-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The above was prepared as desribed in Example IB. MS (CI) m/z (M+H)+ 280; IH-NMR (300 MHz, DMSO-d6) δ 1 1.13 (s, IH), 9.55 (s, 2H), 9.37 (s, 2H), 8.75 (s, IH), 8.55 (s, IH), 8.23 (d, J=8.4 Hz, IH), 8.12 (s, 2H), 7.90 (d, J=8.4 Hz, IH), 7.70 (s, IH), 6.69 (s, I H);
Anal, calc'd 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-(aminoiminomethvD-N-(5-methyl-3-isoxazolvID-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt)
Example 192A
The above product was prepared in the manner of Example 8A using 3-amino-5- methylisoxazole. MS (APCI) m/z (M+H)+ 278. Example 192B 6-(aminoiminomethvP-N-(5-methvI-3-isoxazolylP-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) The above was prepared as described in Example IB. MS (CI) m/z (M+H)+ 295;
IH-NMR (300 MHz, d6-DMSO) δ 11.62 (s, IH), 9.52 (s, 2H), 9.33 (s, 2H), 8.78 (s, IH), 8.55 (dd, IH), 8.31-8.16 (m, 3H), 7.90 (dd, IH), 6.81 (s, IH), 2.44 (s, 3H) Anal, calc'd for C18H15N4O4F3: C, 52.95; H, 3.70; N, 13.72. Found: C, 52.73; H, 3.64; N, 13.24.
Example 193 6-(aminoiminomethyl)-N-(pyrazinyl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
Example 193A The above product was prepared in the manner of Example 8 A using 2-aminopyrazine.
MS (APCI) m/z (M-H)+ 275.
Example 193B 6-(aminoiminomethyl)-N-(pyrazinyl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) The above was prepared as described in Example IB.
MS (CI) m/z (M+H)+ 292;
'H-NMR (300 MHz, d6-DMSO) δ 1 1.41 (s, IH), 9.52 (s, 2H), 9.49 (s, IH), 9.27 (s, 2H), 8.83 (s, IH), 8.56 (s, IH), 8.53-8.46 (m, 2H), 8.30 (d, IH), 8.23 (s, 2H), 7.90 (dd, IH); Anal, calc'd 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-(aminoiminomethyl)-N-(6-methyl-2-pyridinvP-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
Example 194A The above product was prepared in the manner of Example 8A using 2-amino-6- methylpyridine. MS (APCI) m/z (M+H)+ 288. Example 194B 6-(aminoiminomethyP-N-(6-methyl-2-pyridinyl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) The above was prepared as described in Example IB.
MS (CI) m/z (M+H)+ 305; 'H-NMR (300 MHz, d6-DMSO) δ 1 1.02 (s, IH), 9.53 (s, 2H), 9.37 (s, 2H), 8.80 (s, IH),
8.55 (s, IH), 8.29 (d, IH), 8.20 (s, 2H), 8.07 (d, IH), 7.89 (d, IH), 7.78 (t, IH), 7.08 (d, IH), 2.48 (s, 3H); Anal, calc'd for C20H17N4O3F3: C, 48.74; H, 3.33: N, 10.20 7/5 TFA. Found: C, 48.74; H, 3.59; N, 10.1 1.
Example 195 6-(aminoiminomethyl)-N-(3. 4, 5-trimethoxyphenvI)-2-naphthalenecarboxamide. monohydrochloride
Example 195A The above product was prepared in the manner of Example 8A using 3, 4, 5- trimethoxyaniline. MS (APCI) m/z (M+H)+ 363.
Example 195B 6-(aminoiminomethyl)-N-(3. 4. 5-trimethoxyphenyl)-2-naphthalenecarboxamide. monohydrochloride The above was prepared as described in Example I B.
MS (CI) m/z (M+H)+ 380;
'H-NMR (300 MHz, d6-DMSO) δ 10.54 (s, IH), 9.61 (s, 2H), 9.34 (s, 2H), 8.72 (s, IH), 8.59 (s, I H), 8.33-8.15 (m, 3H), 7.91 (dd, IH), 7.30 (s, 2H), 3.80 (s, 9H) Anal, calc'd for C21H22N3O4CI 63/10 HCl: C, 39.09; H, 4.42; N, 6.51. Found: C, 38.94; H, 4.60; N, 7.61.
Example 196 6-(aminoiminomethvP-N-(3-methyl-2-pyridinyl)-2-naphthalenecarboxamide. bis(trifluoroacetate)(salt) Example 196A Using the procedure described for Example 184A and substituting 2-amino-3-picolene for 4-aminobenzamide, the desired compound was obtained. MS (DCI) m/z 288 (M+H)+.
Example 196B 6-(aminoiminomethyl)-N-(3-methyl-2-pyridinvP-2-naphthalenecarboxamide. bis(trifluoroacetate)(salt) Using the procedure described in Example IB and the product obtained in Example
196A, the desired compound was obtained. MS (DCI) m/z 305 (M+H)+;
Η NMR (300 MHz, DMSO) δ 10.85 (s, IH), 9.52 (s, 2H), 9.22 (s, 2H), 8.76 (s, IH), 8.56 (s, I H). 8.35 (dd, I H, J=4.41 , 1.10), 8.32 (d, IH, J=8.80), 8.22 (m, 2H), 7.90 (dd, IH, J=8.83, 1.84), 7.80 (dd, IH, J=7.73, 1.1 1 ), 7.31 (dd, IH, J=7.72, 4.78), 2.26 (s, IH); Anal, calc'd for C22Hi8F6N4O3-0.75 H20: C, 48.40; H, 3.60; N, 10.26. Found: C, 48.81 ; H, 3.66; N, 10.43.
Example 197 6-(aminoiminomethyl)-N-(5-bromo-2-thiazolylP-2-naphthalenecarboxamide. mono(ttifluoroacetate)(salt)
Example 197 A Using the procedure described for Example 184A and substituting 2-amino-5- bromothiazole for 4-aminobenzamide, the desired compound was obtained. MS (DCI) m/z 358 (M+H)+.
Example 197B 6-(aminoiminomethvP-N-(5-bromo-2-thiazolyll)-2-naphthalenecarboxamide. mono(ttifluoroacetate)(salt)
Using the procedure described in Example IB and the product obtained in Example 197 A, the desired compound was obtained. MS (ESI+) m/z 375 (M+H)+; 'H NMR (300 MHz, DMSO) δ 10.85 (s, IH), 9.55 (s, 2H), 9.24 (s, 2H), 8.87 (s, IH), 8.57 (d, IH, J=1.69), 8.31 (d, IH, J=8.47), 8.25 (d, 2H, J=1.01), 7.92 (dd, IH, J=8.48, 2.04), 7.71 (s, IH);
Anal, calc'd for C17H.uBrF3SN4O3-l.25 H2O-0.25 TFA: C, 38.90; H, 2.75; N, 10.37. Found: C, 38.97; H, 3.24; N, 10.66.
Example 198 6-(aminoiminomethvP-N-(5-methyl-2-pyridinvD-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
Example 198A Using the procedure described for Example 184A and substituting 2-amino-5-picolene for 4-aminobenzamide, the desired compound was obtained.
MS (ESI+) m/z 288 (M+H)+.
Example 198B 6-(aminoiminomethyl)-N-(5-methyl-2-pyridinyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) Using the procedure described in Example IB and the product obtained in Example 198 A, the desired compound was obtained. MS (DCI) m/z 305 (M+H)+;
'H NMR (300 MHz, DMSO) δ 1 1.01 (s, IH), 9.50 (s, 2H), 9.16 (s, 2H), 8.79 (s, IH), 8.54 (s, IH), 8.30 (d, IH, J=9.19), 8.27 (d, IH, J=1.47), 8.20 (s, 2H), 8.15 (d, IH, J=8.83), 7.89 (dd, IH, J=8.46, 1.48), 7.72 (dd, I H, J=8.46, 1.84), 2.31 (s, 3H); Anal, calc'd for C20H17F3N4O3O.25 H2O-0.2 TFA: C, 54.98; H, 4.00; N, 12.57. Found: C, 54.99; H, 3.59; N, 12.43.
Example 199 6-(aminoiminomethvD-N-(4-methyl-2-thiazolyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt)
Example 199A Using the procedure described for Example 184A and substituting 2-amino-5-methyl benzothiazole for 4-aminobenzamide, the desired compound was obtained. MS (ESI-) m/z 293 (M+H)".
Example 199B 6-(aminoiminomethyl)-N-(4-methyl-2-thiazolvD-2-naphthalenecarboxamide. mono (trifluoroacetate) (salt)
Using the procedure described in Example IB and the product obtained in Example 199A, the desired compound was obtained. MS (ESI+) m/z 31 1 (M+H)+;
Η NMR (300 MHz, DMSO) δ 9.51 (s, 2H), 9.25 (s, 2H), 8.86 (s, IH), 8.55 (s, IH), 8.30 (d, IH, J=8.48), 8.25 (d, IH, J=2.03), 7.91 (dd, IH, J=8.48, 1.70), 6.87 (s, IH), 2.34 (s, 3H);
Anal, calc'd for C18H15F3N4SO3 .5 TFA: C, 47.40; H, 3.25; N, 1 1.64. Found: C, 47.90; H, 3.36; N, 1 1.71.
Example 200
6-(aminoiminomethyl)-4-[5-(ethylthio)-3-furanyll-N-phenyl-2-naphthalenecarboxamide, monohydrochloride
Example 200A The desired compound was prepared from 2-trimethylsilyl-3-bromofuran and diethyldisulfide by the procedure of Example 154A. MS (DCI/NH3) m/z 279, 281 (M+H)+.
Example 200B A solution of the product from Example 200A (8.60 g, 30.8 mmol) in THF (20 mL) and a 1 M solution of TBAF (61.6 mL) was stined for 24 hours. The reaction was condensed and chromatographed on Siθ2 using hexanes as eluent, to yield 3.32 g (527o) of 2-ethylthio-4- bromofuran. The desired compound was prepared from this material by the procedure of Example 57 A. MS (DCI/NH ) m/z l27 (M-B (OH)2)+.
Example 200C The desired compound was prepared from the product from Example 200B and the product from Example 152C by the procedure of Example 57B. MS (DCI/NH3) m/z 416 (M+NH4)+.
Example 200D 6-(aminoiminomethyl)-4-r5-(ethylthio)-3-furanyn-N-phenyl-2-naphthalenecarboxamide, monohydrochloride
The desired compound was prepared from Example 200C and the procedure of Example 144C.
MS (DCI/NH3) m/z 416 (M+H)+;
'H NMR (300 MHz, DMSO-d6) 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, IH), 8.20 (d, IH), 8.40 (d, IH), 8.47 (s, IH), 8.60 (s, IH), 8.69 (s, IH), 9.21 (br s, 2H), 9.58 (br s, 2H), 10.61 (s, IH); Anal, calc'd for C24H2iN3Sθ2- 1.5 HCl: C, 61.31 ; H, 4.82; N, 8.94. Found: C, 61.39; H, 4.89; N, 9.03.
Example 201
6-(aminoiminomethyl)-4-r5-(propylthio)-3-furanyll-N-phenyl-2-naphthalenecarboxamide. monohydrochloride
Example 201 A The desired compound was prepared from 2-trimethylsilyl-3-bromofuran and dipropyldisulfide by the procedure of Example 154A. MS (DCI/NH3) m/z 293, 295 (M+H)+.
Example 20 IB The desired compound was prepared from the product from Example 201 A by the procedure of 154B. MS (DCI/NH3) m/z 432 (M+H)+.
Example 201 C The desired compound was prepared from the product from Example 20 IB and the product from Example 152C by the procedure of Example 154C. MS (DCI/NH3) m/z 430 (M+NH4)+.
Example 20 ID 6-(aminoiminomethyl)-4-r5-(propylthio)-3-furanyll-N-phenyl-2-naphthalenecarboxamide. monohydrochloride The desired compound was prepared from Example 201C and the procedure of Example 144C. MS (DCI/NH3) m/z 430 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 1.01 (t, 3H), 1.66 (qt, 2H), 2.89 (t, 2H), 7.15 (t, IH), 7.34 (s, IH), 7.40 (t, 2H), 7.84 (d, 2H), 7.92 (dd, IH), 8.20 (d, IH), 8.40 (d, IH), 8.47 (s, I H), 8.60 (s, IH), 8.69 (s, I H), 9.22 (br s, 2H), 9.58 (br s, 2H), 10.61 (s, IH); Anal, calc'd for C25H23N3Sθ2- 1.25 HCl: C, 63.20; H, 5.14; N, 8.84. Found: C, 63.24; H, 5.16; N, 8.93.
Example 202 6-(aminoiminomethyl)-N-(6-quinolinyl)-2-naphthalenecarboxamide. bis(ttifluoroacetate)(salt)
Example 202A To a solution of the acid chloride, Example 8B, (331 mg, 1.5 mmol) in THF (15 mL), at room temperature, was added propylene oxide (10 mL), DMAP (5 mg), a drop of triethylamine and finally 6-aminoquinoline (288 mg, 2.0 mmol). After 4 hours at room temperature, added ethyl acetate (10 mL) and ether (20 mL) and filtered the off-white solid product. Yield 357 mg (727c). MS (DCI/NH3) m/z 324 (M+H)+.
Example 202B 6-(aminoiminomethvD-N-(6-quinolinyl)-2-naphthalenecarboxamide. bis(trifluoroacetate)(salt) The desired compound was prepared as described in Example IB. MS (ESI+) m/z 341 (M+H)+, (ESI ) 339 (M-l)~;
Η NMR (300 MHz, DMSO-d6) δ 10.98 (s, IH), 9.53 (s, 2H), 9.25 (s, 2H), 8.93-8.91 (m, I H), 8.77 (s, IH), 8.67 (d, J=1.8Hz, I H), 8.58 (s, IH), 8.53 (d, J=8.5Hz, IH), 8.37-8.09 (m, 5H), 7.93 (dd, J l=8.5Hz, J2=1.8Hz, I H), 7.65-7.62 (m, IH);
Anal, calc'd for C2,H16N40-2TFA: C, 52.83; H, 3.19; N, 9.86. Found: C, 52.62; H, 2.94; N, 9.74. Example 203 6-(aminoiminomethyl)-N-(lH-indazol-6-vD-2-naphthalenecarboxamide. bis(trifluoroacetate)(salf)
Example 203A
The desired compound was prepared as described for Example 202A but substituting 6- aminoquinoline for 6-aminoindazole to provide 285 mg of the desired compound. MS: ESI+: 313 (M+l); ESI-311 (M-l).
Example 203B
6-(aminoiminomethyl)-N-(l H-indazol-6-vD-2-naphthalenecarboxamide. bis(ttifluoroacetate)(salt) To a suspension of the ammonium chloride (140 mg, 2.6 mmol) in Toluene (2 mL) at 0°C was slowly added a solution of 2 N trimethylaluminium in toluene (871μL, 1.74 mmol). After 5 minute the reaction mixture was allowed to warm to room temperature for 30 minutes. To the solution of the aluminium reagent at room temperature was added the nitrile, Example 203 A from section (a) and the reaction mixture was heated to 100°C for 48 hours. The reaction mixture was cooled down then was poured into a suspension of silica in chloroform and stined for an hour. The silica was filtered then washed with methanol. The solvent was concenttated and purified by medium pressure liquid chromatography on a 30 cm x 2 cm C- 18 column (40 micron, J.T Baker) with UV detection at 250 nM with solvent mixtures in a gradient ranging from 907cA (0.17c aq TFA)/107cB (methanol) to 107cA/907oB over 160 minutes at a flow rate of 5 mL/min (fractions were collected every 2 minutes for 100 min, to provide 42 mg of the desired compound. MS (ESI+) m/z 330 (M+H)+, (ESI-) 328 (M- l)-;
'H NMR (300 MHz, DMSO-d6) δ 10.65 (s, IH), 9.47 (m, 4H), 8.65 (s, 2H), 8.50 (s, 2H),
8.25-8.23 (m, 2H), 8.17-8.10 (m, 2H), 7.94 (s, IH), 7.86-7.84 (dd, Jl=8.8Hz, J2=1.6Hz, IH), 7.66 (d, J=8.5Hz, IH), 7.37 (d, J=8.4Hz, IH);
Anal, calc'd for 9H15N5 0-2 TFA: 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-vD-2-naphthalenecarboxamide. bis(trifluoroacetate)(salt) Example 204A The desired compound was prepared as described for Example 202A but substituting 6- aminoquinoline for 5-aminoindazole to provide 362 mg of the desired compound. MS: ESI+: 313 (M+1); ESI-31 1 (M- 1).
Example 204B 6-(aminoiminomethyl)-N-(lH-indazol-5-yl)-2-naphthalenecarboxamide. bis(trifluoroacetate)(salt) The desired compound was prepared as described for Example 203B to provide 55 mg of the desired compound. MS (ESI+) m/z 330 (M+H)+, (ESI") 328 (M-l)";
Η NMR (300 MHz, DMSO-d6) δ 13.06 (s, IH), 10.58 (s, IH), 9.51 (s, 2H), 9.15 (s, 2H), 8.71 (d, j=1.9Hz, IH), 8.56 (d, j=1.9Hz, IH), 8.34-8.17 (m, 4H), 8.10 (s, IH), 7.90 (dd, J l =8.5Hz, J2=1.7Hz, I H), 7.63 (dd, J l=8.9Hz, J2=1.7Hz, IH), 7.56 (d, J=8.8Hz, IH); Anal, calc'd for C19H15N5 O-TFA- 1.75 H20: C, 53.1 1 ; H, 4.14; N, 14.75. Found: C, 53.20; H, 3.99; N, 14.42.
Example 205 6-(aminoiminomethyl)-N-(lH-indol-5-yl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salf)
Example 205A The desired compound was prepared as described for Example 202A but substituting 6- aminoquinoline for 6-aminoindole to provide 744 mg of the desired compound. MS: (ESI)+: 329 (M+l)+ and (ESI)-: 327 (M- l )-.
Example 205B 6-(aminoiminomethvD-N-(lH-indol-5-yl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
The desired compound was prepared as described for Example 203B to provide 90 mg of the desired compound. MS (ESO m/z 329 (M+H)+, (ESP) 327 (M-l)"; Η NMR (300 MHz, DMSO-d6) δ 1 1.09 (s, IH), 10.40 (s, IH), 9.51 (s, 2H), 9.15 (s, 2H), 8.71 (s, IH), 8.55 (s, IH), 8.32 (d, J=8.4Hz, IH), 8.26-8.17 (m, 2H), 8.05 (d, J=2.6Hz, IH), 7.90 (dd, J l=8.4Hz, J2=1.8Hz, IH), 7.46-7.35 (m, 3H), 6.45-6.43 (m, IH); Anal, calc'd for C2oHι6N4 O-TFA: C, 59.73; H, 3.87; N, 12.66. Found: C, 59.27; H, 4.17; N, 12.74.
Example 206 7-r2-(4-morpholinyl)ethoxyl-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt)
Example 206A
The nitrile was prepared as described in Example 1 19A using 2-chloroethylmorpholine. MS (DCI (NH3)) m/z 283 (M+H) +.
Example 206B 7-f2-(4-mo holinyl)ethoxyl-2-naphthalenecarboximidamide. bis(trifluoroacetate)(salt)
The desired compound was prepared as described in Example 1 19B, as an off-white solid (50% yield).
MS (DCI (NH3)) m/z 300 (M+H)+;
'H NMR (300 MHz, DMSO-d6) δ 3.500 (br m, 4H), 3.700 (br m, 2H), 3.990 (br m, 4H), 4.490 (br m, 2H), 7.435 (dd, IH), 7.530 (d, IH), 7.680 (dd, IH), 8.035 (d, IH), 8.100 (d,
I H), 8.345 (d IH), 9.165 (br s, 2H), 9.420 (br s, 2H);
Anal, calc'd for Cι7H2iN302- (C2H02F3) 2.i5: C, 46.98; H, 4.29; N, 7.72. Found: C, 47.00;
H, 4.32; N, 7.77.
Example 207
6-(aminoiminomethvP-N-phenyl-4-(2-pynolidinvP-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt)
Example 207A The desired compound was prepared from the product from Example 152 A, by the procedure of Example 68A. MS (DCI/NH3) m/z 281 (M+H)+.
Example 207B The desired compound was prepared from the product from Example 207A by the procedure of Example 152B. MS (DCI/NH3) m/z 267 (M+H)+.
Example 207 C
A solution of the product from Example 207B (220 mg, 0.826 mmol), diisopropylethyl amine (0.288 mL, 1.65 mmol), and O- (7-azabenzotriazol-l-yl)-N, N, N', N'- tettamethyluronium hexafluorophosphate (314 mg, 0.826 mmol) in DMF (10 mL) was stined for 30 minutes at 0°C. Aniline (0.083 mL, 0.909 mmol) was added, and the reaction was stined at room temperature for 4 hours. The reaction was poured into saturated aqueous
Na2Cθ3 solution, and exttacted with 3x ethyl acetate. The combined extracts were washed with water and brine, dried over Na2Sθ4, and condensed. The crude material was recrystallized from ethanol/hexanes to yield 212 mg (75%) of the desired compound. MS (DCI/NH3) m/z 342 (M+H)+.
Example 207D 6-(aminoiminomethyl)-N-phenyl-4-(2-pynolidinyl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) The desired compound was prepared from Example 207C and the procedure of Example IB.
MS (DCI/NH3) m/z 359 (M+H)+;
'H NMR (300 MHz, DMSO-d6) δ 2.02 (t, 4H), 3.55 (t, 4H), 7.13 (t, IH), 7.38 (t, 2H), 7.41 (s, IH), 7.80 (m, 3H), 8.08 (s, IH), 8.18 (d, IH), 8.67 (s, IH), 9.10 (br s, 2H), 9.43 (br s, 2H), 10.41 (br s, IH); Anal, calc'd for C22H22N4θ- 1.0 C2HF302: C, 61.01; H, 4.91; N, 1 1.86. Found: C, 60.47; H, 5.36; N, 7.39.
Example 208 6-(aminoiminomethyl)-N-(5-pyrimidinvD-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
Example 208A The above product was prepared in the manner of Example 8A using 5- aminopyrimidne. MS (APCI) m z (M+H)+ 275.
Example 208B 6-(aminoiminomethvD-N-(5-pyrimidinyl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
The above was prepared as described in Example IB. MS (CI) m/z (M+H)+ 292;
'H-NMR (300 MHz, DMSO-d6) δ 10.99 (s, IH), 9.52 (s, 2H), 9.27 (s, 2H), 9.24 (s, 2H), 8.98 (s, IH), 8.76 (s, IH), 8.58 (s, IH), 8.36-8.18 (m, 3H), 7.92 (dd, J=1.5, 8.4 Hz, IH); Anal, calc'd for C18H14N5O3F3 7/10 TFA: C, 47.97; H, 3.05; N, 14.40. Found: C, 47.78; H, 3.05; N, 14.67.
Example 209 6-(aminoiminomethyl)-N-(3-pyridazinvD-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
Example 209A 3-Amino-6-chloropyridazine (1.05 g, 8.2 mmol) was dissolved in 10 mL methanol with 2 mL ammonia/methanol. Palladium/carbon (200 mg, 10%) was added and stirred under 1 atm hydrogen for 4 hours. The reaction was filtered, concentrated, and used without further purification. MS (CI) m/z (M+H)+ 96.
Example 209B The above product was prepared in the manner of Example 12 using the product from
Example 209A. MS (APCI) m/z (M+H)+ 275.
Example 209C 6-(aminoiminomethyl)-N-(3-pyridazinvD-2-naphthalenecarboxamide. mono(ttifluoroacetate)(salt) The above was prepared from Example 209B as described in Example IB. MS (CI) m/z (M+H)+ 292; 'H-NMR (300 MHz, d6-DMSO) δ 1 1.72 (s, IH), 9.51 (s, 2H), 9.22 (s, 2H), 9.06 (m, IH), 8.86 (s, IH), 8.56 (s, IH), 8.45 (d, IH), 8.31 (d, IH), 8.23 (s, 2H), 7.90 (dd, IH), 7.78 (dd, IH) Anal, calc'd for Cι8Hι4N5θ3F3 1/2 TFA: C, 49.29; H, 3.16; N, 14.73. Found: C, 49.56; H, 3.23; N, 14.73.
Example 210 6-(aminoiminomethvD-N-(5-bromo-2-pyridinyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt)
Example 210A Using the product obtained in Example 8E, 2-amino-5-bromopyridine, and the procedure described for Example 8G the desired compound was obtained. MS (APCI+) m/z 352 (M+H)+.
Example 210B 6-(aminoiminomethvD-N-(5-bromo-2-pyridinyl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) Using the procedure described in Example IB and the product obtained in Example 210A, the desired compound was obtained. MS (DCI) m/z 369 (M+H)+;
'H NMR (300 MHz, DMSO) δ 1 1.30 (s, IH), 9.51 (s, 2H), 9.17 (s, 2H), 8.80 (s, IH), 8.57 (d, IH, J=2.57), 8.55 (s, IH), 8.31 (d, IH, J=8.45), 8.26 (d, IH, J=8.82), 8.19-8.24 (m, 2H, ), 8.14 (dd, IH, J=2.57, 9.19), 7.90 (dd, IH, J=1.83, 8.82; Anal, calc'd for C19Hi4BrF3N40 : C, 47.22; H, 2.92; N, 1 1.59. Found: C, 47.60; H, 3.01 ; N, 1 1.30.
Example 211 6-(aminoiminomethyl)-N-r3-(l-methylethoxy)phenyll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt)
Example 211 A The above product was prepared in the manner of Example 12 using 3- isopropoxyaniline. MS (APCI) m/z (M+H)+ 331.
Example 21 IB 6-(aminoiminomethyl)-N-r3-(l-methylethoxy)phenyl1-2-naphthalenecarboxamide. mono(ttifluoroacetate)(salt)
The above was prepared from Example 21 1 A using method IB. MS (CI) m/z (M+H)+ 348;
'H-NMR (300 MHz, d6-DMSO) δ 10.50 (s, IH), 9.50 (s, 2H), 9.22 (s, 2H), 8.67 (s, IH), 8.56 (s, IH), 8.31 (d, IH), 8.25-8.13 (m, 2H), 7.90 (dd, IH), 7.51 (m, IH), 7.36 (m, I H), 7.26 (t, IH), 6.68 (dd, IH), 4.59 (m, IH), 1.30 (d, 6H)
Anal, calc'd for C23H22N 04F3 1/5 TFA: C, 57.96; H, 4.61; N, 8.66. Found: C, 57.99; H, 4.90; N, 8.68.
Example 212 2-ri6-(aminoiminomethyl)-2-naphthalenylloxylacetic acid. mono(trifluoroacetate)(salt)
The product from Example 185C (140 mg, 0.542 mmol) was dissolved in methanol (1 1 mL). To this was added a solution of lithium hydroxide (68.2 mg, 1.626 mmol) in water (3 mL) and the resulting mixture was stined at room temperature under an inert atmosphere for 18 hours. The reaction was evaporated and the residue purified by reverse phase chromatography to yield the desired compound (102 mg, 52%>). MS (DCI (NH3)) m/z 245 (M+H)+;
'H NMR (300 MHz, DMSO-d6) δ 4.875 (s, 2H), 7.420 (s, IH), 7.435 (dd, IH), 7.660 (dd, IH), 8.015 (d, IH), 8.100 (d, IH), 8.340 (d, IH), 9.125 (br s, IH), 9.420 (br s, IH; Anal, calc'd for Ci3Hi2N2θ3' (C2HO2F3)ι.30: C, 47.74; H, 3.42; N, 7.14. Found: C, 47.93; H, 3.36; N, 7.17.
Example 213 methyl 4-r6-(aminoiminomethyl)-2-naphthalenynoxylmethyllbenzoate. mono (trifluoroacetate) (salt)
Example 213A The resulting product from Example 185A was tteated with methyl 4- (bromomethyl)benzoate in an analogous manner as described in Example 119B. MS (DCI (NH )) m/z 335 (M+NH )+.
Example 213B methyl 4-r6-(aminoiminomethyl)-2-naphthalenylloxylmethyllbenzoate. mono(trifluoroacetate)(salt)
The resulting product from Example 213A (250 mg, 0.788 mmol) was treated in an analogous manner as described in Example 1 19C to yield the desired compound (130 mg, 79%).
MS (DCI (NH3)) m/z 335 (M+H) +; 'H NMR (300 MHz, DMSO-d6) δ 3.870 (s, 3H), 5.400 (s, 2H), 7.500 (dd, IH), 7.540 (d, I H), 7.619 (dd, IH), 7.620 (d, 2H), 8.025 (d, 2H), 8.026 (d, IH), 8.090 (d, IH), 8.410 (d, I H), 9.260 (v br s, 3H);
Anal, calc'd for Ci4Hι4N2θ3-C2Hθ2F3-H20 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-( 1 H-imidazolyl)-2-naphthalenecarboxamide, bis(trifl uoro acetate) (salt)
Example 214A
Using the product obtained in Example 8E, 2-aminoimidazole, and the procedure described for Example 8G the desired compound was obtained. MS (ESI-) m z 261 (M+H)".
Example 214B
Using the procedure described in Example IB and the product obtained in Example
214A, the desired compound was obtained.
MS (ESI+) m/z 280 (M+H)+;
' H NMR (300 MHz, DMSO) δ 9.50 (s, 2H), 9.16 (s, 2H), 8.78 (s, IH), 8.53 (s, I H), 8.26- 8.31 (m, 2H), 8.20 (d, I H, J=8.46), 7.88 (dd, IH, J=1.84, 8.83), 6.95 (s, 2H);
Anal, calc'd for C17H14F3N5O3O.2 TFA-H20: C, 48.14; H, 3.76; N, 16.13. Found: C,
48.54; H, 3.40; N, 16.02.
Example 215 6-r2-r4-(hvdroxymethyl)phenvπ-l-cvclopropyll-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt)
Example 215A The material prepared as described in Example 104 (210 mg, .52 mmol) is dissolved in THF (6 mL) and added dropwise to 10 mL diazomethane cooled to 0 °C then added Pd (OAc)2 (9.8 mg). Vigorous bubbling occurs for 5 minutes, the resulting black slurry is stined 20 min, filtered and solvent removed under vacuum leaving 0.1 g clear oil. MS (DCI/NH3): m/z (M+NH4 +): 316.
Example 215B 6-r2-r4-(hvdroxymethyl)phenyll-l-cvclopropyll-2-naphthalenecarboximidamide. mono(trifluoroacetate)(salt) The desired compound is prepared as described in Example 1 , purified by reverse phase chromatography to give 19.9 mg of white solid. MS (DCI/NH3) m/z (M+H)+ 316;
'H-NMR (300 MHz, DMSO-d6) δ 9.41 (s, 2H), 9.16 (s, 2H), 8.46 (s, IH), 8.08 (d, 2H), 8.03 (d, IH), 7.85 (s, IH), 7.75 (dd, IH), 7.58 (dd, IH), 7.3-7.1 (m, 4H), 4.49 (s, 2H), 2.38-2.48 (m, 2H), 1.61-1.70 (m, 2H); Anal, calc'd for C23H21N2O2F3 1 H20: 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-l-cvclopropyl)-2-naphthalenecarboximidamide
The sample described in Example 97 (130 mg, .45 mmol) is 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 is stirred three days at room temperature then diluted with 100 mL ethyl acetate washed with distilled water (20 mL), dried over anhydrous sodium sulfate, filtered and solvent removed under vacuum leaving a clear oil. The oil is purified by silica gel chromatography eluting with 2: 1 hexanes/ethyl acetate, lyophilized and the desired compound is isolated as a white powder (55 mg). MS (DCI/NH3) m/z (M+H)+ 359; 'H-NMR (300 MHz, DMSO-d6) δ 9.21 (s, 2H), 8.46 (s, IH), 7.83 (d, 2H), 7.62 (s, IH), 7.58 (dd, IH), 7.34 (dd, IH), 7.35-7.29 (m, 3H), 7.25-7.17 (m, 2H) 4.1 (q, 2H), 2.38-2.28 (m, 2H), 1.61 (t, 2H), 1.25 (t, 3H);
Anal, calc'd for C23H22N2O2 C, 77.07; H, 6.19; N, 7.82. Found: C, 76.63; H, 6.05; N, 7.45.
Example 217 6-(aminoiminomethyl)-N-(2-methyl-6-quinolinyl)-2-naphthalenecarboxamide, bis(trifluoroacetate)(salt)
The desired compound is prepared in a similar manner as described in Example 8E and 144C.
MS m z: 355 (M+H)+
'H NMR (DMSO, 300 MHz): 10.95 (s, IH), 9.51 (s, 2H), 9.14 (s, 2H), 8.75 (s, IH), 8.65 (s, IH), 8.57 (s, IH), 8.35 (dd, IH, J1 =J2=8.5 Hz), 8.28 (dd, IH, J l=J2=8.5Hz), 8.19 (dd, I H, J 1=J2=8.8 Hz), 8.15 (dd, IH, J1=J2=8.3 Hz), 8.04 (dd, IH, J l=J2=8.8Hz), 7.91 (dd, IH, Jl=8.4 Hz, J2=8.8 Hz), 7. 60 (dd, IH, J1 =J2=8.1 Hz). 5.99 (S, 3H); Anal, calc'd for C22Hi8N40'2.25 C2F302H-2 H20: 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-(aminoiminomethyl)-N-(3-propoxyphenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt)
Example 218A
3-Aminophenol (1 g, 7.2 mmol), triphenylphosphine (2.25 g, 8.6 mmol), and 1- propanol (0.517 g, 8.6 mmol) were dissolved in 25 mL anhydrous THF.
Diethylazodicarboxylate (1.5 g, 8.6 mmol) was added dropwise over 1 minute. The solution was allowed to stir 15 minutes and poured slowly into hexanes while stirring. Filtration through silica gel/celite afforded the product as a viscous yellow oil.
MS (APCI) m/z (M+H)+ 152.
Example 218B The above product was prepared in the manner of Example 12 using the product from Example 218 A. MS (APCI) m/z (M+H)+ 331.
Example 218C
6-(aminoiminomethyl)-N-(3-propoxyphenyl)-2-naphthalenecarboxamide, mono(ttifluoroacetate)(salt) The above was prepared from Example 218 as described in Example IB. MS (CI) m/z (M+H)+ 348; 'H-NMR (300 MHz, d6-DMSO) δ 10.51 (s, IH), 9.50 (s, 2H), 9.18 (s, 2H), 8.68 (s, IH), 8.55 (s, IH), 8.32 (d, IH), 8.25-8.13 (m, 2H), 7.90 (dd, IH), 7.52-7.33 (m, 2H), 7.27 (t, I H), 6.73 (dd, IH), 3.94 (t, 2H), 1.75 m, 2H), 1.00 (t, 3H)
Anal, calc'd for C23H22N3O4F3: 1/20 TFA: C, 59.49; H, 4.77; N, 9.02. Found: C, 59.43; H, 4.94; N, 9.10.
Example 219 6-(aminoiminomethyl)-N-r3-(l -ethylpropoxy)phenyll-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
Example 219A
The above product was prepared in the manner of Example 218 A using 3-pentanol. MS (APCI) m/z (M+H)+ 180.
Example 219B The above product was prepared in the manner of Example 12 using the product from
Example 219A. MS (APCI) m/z (M+H)+ 359.
Example 219C 6-(aminoiminomethyl)-N-r3-(l -ethylpropoxy)phenyll-2-naphthalenecarboxamide. mono(trifluoroacetate)(saIt) The above was prepared from Example 219B as described in Example IB. MS (CI) m/z (M+H)+ 376; 'H-NMR (300 MHz, d6-DMSO) δ 10.47 (s, IH), 9.49 (s, 2H), 9.14 (s, 2H), 8.67 (s, IH),
8.55 (s, IH), 8.31 (d, IH), 8.25-8.16 (m, 2H), 7.90 (dd, IH), 7.51 (s, IH), 7.38 (m, IH), 7.26 (t, IH), 6.72 (dd, IH), 4.18 (m, IH), 1.65 (m, 4H), 0.93 (t, 6H)
Anal, calc'd for C25H26N3O4F3: C, 61.34; H, 5.35; N, 8.58. Found: C, 61.05; H, 5.42; N, 8.22.
Example 220 6-(aminoiminomethyl)-N-r3-(cvclopentyloxy)phenvn-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
Example 220A The above product was prepared in the manner of Example 218A using cyclopentanol. MS (APCI) m/z (M+H)+ 86.
Example 220B
The above product was prepared in the manner of Example 12 using the product from Example 220A. MS (APCI) m/z (M+H)+ 357.
Example 220C
6-(aminoiminomethyl)-N-r3-(cvclopentyloxy)phenvn-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The above was prepared from Example 220B as described in Example IB. MS (CI) m/z (M+H)+ 374; 'H-NMR (300 MHz, d6-DMSO) δ 10.50 (s, IH), 9.51 (s, 2H), 9.30 (s, 2H), 8.68 (s, IH),
8.56 (s, I H), 8.32 (d, IH), 8.25-8.13 (m, 2H), 7.90 (dd, IH), 7.49 (m, IH), 7.38 (m, IH), 7.26 (t, IH), 6.72 (dd, IH), 4.79 (m, IH), 1.96-1.08 (m, 8H).
Anal, calc'd for C25H24N3O4F3 2/5 TFA: C, 60.68; H, 5.06; N, 8.49. Found: C, 60.68; H, 5.33; N, 8.65.
Example 221
6-(aminoiminomethyl)-N-(3-phenoxyphenvD-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) Example 221 A The above product was prepared in the manner of Example 218 A using 3- phenoxyanline. MS (APCI) m/z (M+H)+ 365.
Example 221 B 6-(aminoiminomethyl)-N-(3-phenoxyphenvD-2-naphthalenecarboxamide. mono (tri fluoroacetate) (salt) The above was prepared from Example 221 A as described in Example IB. 'H-NMR (300 MHz, d6-DMSO) δ 10.61 (s, IH), 9.50 (s, 2H), 9.20 (s, 2H), 8.66 (s, IH),
8.54 (s, I H), 8.30 (d, IH), 8.22 (d, IH), 8.12 (dd, I H), 7.90 (dd, IH), 7.64-7.57 (m, 2H), 746-7.37 (m, 3H), 7.17 (m, IH), 7.06 (m, 2H), 6.79 (dd, IH),
MS (CI) m/z (M+H)+ 382;
Anal, calc'd for C26H20N3O4F3: C, 63.03; H, 4.07; N, 8.48. Found: C, 62.87; H, 4.24; N, 8.08.
Example 222 6-(aminoiminomethyl)-N-r3-(phenylmethoxy)phenyll-2-naphthalenecarboxamide, mono(ttifluoroacetate)(salt)
Example 222A
The above product was prepared in the manner of Example 218 A using 3- benzyloxyaniline. MS (APCI) m/z (M+H)+ 379.
Example 222B
6-(aminoiminomethyl)-N-r3-(phenylmethoxy)phenyll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt) The above was prepared from Example 222A as described in IB. MS (CI) m/z (M+H)+ 396; ' H-NMR (300 MHz, d6-DMSO) δ 10.53 (s, IH), 9.50 (s, 2H), 9.22 (s, 2H), 8.68 (s, IH),
8.55 (s, I H), 8.31 (d, IH), 8.23 (d, IH), 8.14 (dd, IH), 7.90 (dd, IH), 7.61-7.27 (m, 8H), 6.80 (dd, IH), 5.13 (s, 2H)
Anal, calc'd for C27H22N3O4F3: C, 63.65; H, 435; N, 8.25. Found: C, 63.48; H, 4.27; N, 8.07. Example 223
6-(aminoiminomethvP-N-(3-ethoxyphenyl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt)
Example 223A The above product was prepared in the manner of Example 218 A using 3-ethoxyaniline. MS (APCI) m/z (M+H)+ 317.
Example 223B
6-(aminoiminomethyl)-N-(3-ethoxyphenyl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) The above was prepared from Example 223A as described in Example IB. MS (CI) m/z (M+H)+ 334; 'H-NMR (300 MHz, d6-DMSO) δ 10.52 (s, IH), 9.50 (s, 2H), 9.24 (s, 2H), 8.68 (s, IH), 8.55 (s, IH), 8.32 (d, IH), 8.25-8.13 (m, 2H), 7.90 (dd, IH), 7.51 (m, IH), 7.38 (m, IH), 7.26 (t, IH), 6.72 (dd, IH), 4.04 (q, 2H), 1.34 (t, 3H)
Anal, calc'd for C22H20N3O4F3: C, 59.06; H, 4.51; N, 9.39. Found: C, 58.69; H, 4.54; N, 9.82.
Example 224
6-(aminoiminomethyl)-N-(4-nitrophenyl)-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt)
Example 224A
The above product was prepared in the manner of Example 218A using 4-nitroaniline. MS (APCI) m z (M+H)+ 318.
Example 224B 6-(aminoiminomethyl)-N-(4-nitrophenyl)-2-naphthalenecarboxamide. mono(trifluoroacetate)(salt) The above was prepared from Example 224A as described in Example IB. MS (CI) m/z (M+H)+ 335; 'H-NMR (300 MHz, d6-DMSO) δ 1 1.15 (s, IH), 9.55 (s, 2H), 9.22 (s, 2H), 8.77 (s, IH), 8.58 (s, IH), 8.36-8.12 (m, 7H)
Anal, calc'd for C20H15N4O5F3 1/10 TFA: C, 52.54; H, 3.29; N, 12.10. Found: C, 53.58; H, 3.37; N, 12.50.
Example 225 6-(aιrύnoirr nomethyl)-N-[3-(cvclobutylmethoxy)phenyll-2-naphthalenecarboxamide, mono(trifluoroacetate)(salt)
Example 225A
The above product was prepared in the manner of Example 218 A using cyclobutylmethanol. MS (APCI) m/z (M+H)+ 177.
Example 225B
The above product was prepared in the manner of Example 225 A using the product from Example 11 MS (APCI) m/z (M+H)+ 357.
Example 225C
6-(aminoiminomethyl)-N-r3-(cvclobutylmethoxy)phenvn-2-naphthalenecarboxamide, mono(trifluoroacetate)(saIt) The above was prepared from Example 225B as described in Example IB. MS (CI) m/z (M+H)+ 374; 'H-NMR (300 MHz, d6-DMSO) δ 10.50 (s, IH), 9.50 (s, 2H), 9.20 (s, 2H), 8.68 (s, IH), 8.55 (s, IH), 8.32 (d, IH), 8.25-8.13 (m, 2H), 7.90 (dd, IH), 7.51 (m, IH), 7.38 (m, I H), 7.26 (t, IH), 6.72 (dd, IH), 3.95 (d, 2H), 2.1 1-1.81 (m, 7H);
Anal, calc'd for C25H24N3O4F3 7/5 TFA: C, 59.09; H, 5.22; N, 8.27. Found: C, 59.02; H, 5.20; N, 8.55.
Example 226 6-ramino(ethoxycarbonyl)iminol-N-r3-(l-methylethoxy)phenyll-2-naphthaIenecarboxamide
The above was prepared from Example 21 1 A using method described in Example 216. MS (CI) m/z (M+H)+ 420:
'H-NMR (300 MHz, d6-DMSO) δ 10.41 (s, IH), 9.24 (br, 2H), 8.67 (s, IH), 8.59 (s, IH), 8.12-7.96 (m, 4H), 7.47 (s, IH), 7.36 (m, IH), 7.25 (t, IH), 6.67 (dd, IH), 4.58 (m, IH), 4.1 1 (q, 2H), 1.30 (m, 9H) Anal, calc'd for C24H25N3O4 1/4 H20: C, 67.99; H, 6.06 N, 9.91. Found: C, 67.99; H, 6.07; N, 9.64.
Example 227 6-(aminoiminomethyl)-4-r5-(ethylsulfonyl)-3-furanyll-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 CH2CI2 (25 mL) was stined for 1 hour. The reaction was condensed and chromatographed on Siθ2 using 507o ethyl acetate/hexanes as eluent, to yield 585 mg (817c) of the desired compound. MS (DCI/NH3) m z 448 (M+NH4) -.
Example 227B 6-(aminoiminomethyD-4-f5-(ethylsulfonyl)-3-furanvn-N-phenyl-2-naphthalenecarboxamide, monohydrochloride The desired compound was prepared from Example 227A and the procedure of Example 13.
MS (DCI/NH3) m/z 448 (M+H)+; ' H NMR (300 MHz, DMSO-d6) δ 1.29 (t, 3H), 3.50 (q, 2H), 7.16 (t, IH), 7.42 (t, 2H), 7.83 (d, 2H), 7.95 (dd, IH), 8.05 (s, IH), 8.28 (s, IH), 8.43 (d, IH), 8.57 (s, IH), 8.74 (s, IH), 8.79 (s, IH), 9.19 (br s, 2H), 9.59 (br s, 2H), 10.61 (s, IH);
Anal, calc'd for C24H22N3SO4T .O HCM.O H20: C, 57.43; H, 4.82; N, 8.37. Found: C, 57.21; H, 5.04; N, 8.34.
Example 228 6-(aminoiminomethyl)-4-r5-(propylsulfonyl)-3-furanyn-N-phenyl-2-naphthalenecarboxamide. monohydrochloride Example 228A The desired compound was prepared from the product from Example 201C by the procedure of Example 227A. MS (DCI/NH3) m/z 462 (M+NH4)+.
Example 228B 6-(aminoiminomethvD-4-r5-(propylsulfonyl)-3-furanvn-N-phenyl-2-naphthalenecarboxamide, monohydrochloride The desired compound was prepared from Example 228A and the procedure of Example 13.
MS (DCI/NH3) m/z 462 (M+H)+;
'H NMR (300 MHz, DMSO-d6) δ 1.03 (t, 3H), 1. 75 (qt, 2H), 3.48 (q, 2H), 7.16 (t, IH), 7.41 (t, 2H), 7.84 (d, 2H), 7.95 (dd, IH), 8.05 (s, IH), 8.28 (d, IH), 8.42 (d, IH), 8.58 (s, IH), 8.77 (s, IH), 8.82 (s, IH), 9.28 (br s, 2H), 9.63 (br s, 2H), 10.66 (s, IH); Anal, calc'd for 025^4^04- 1.0 HCM.5 H20: C, 57.20; H, 5.18; N, 8.00. Found: C, 56.86; H, 5.08; N, 8.28.
Example 229 6-(aminoiminomethyl)-4-r5-rmethylthio)methvn-3-furanvI1-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 -78°C was added a 1.5 M solution of LDA (34.8 mL, 52.25 mmol), and the reaction was stined at -78°C for 1 hour. DMF (4.41 mL, 57.0 mmol) was then added, and the reaction was allowed to warm to room temperature and stined for 1 hour. The reaction was poured into saturated aqueous NH4CI solution, and extracted with 3x diethyl ether. The combined extracts were washed with brine, dried over Na2Sθ4, and condensed. The crude material was taken up in methanol (200 mL) and NaBH4 (1.15 g, 24.0 mmol) was added in portions to the stined solution. After 30 min, the solution was consensed, taken up in pH7 buffer, and extracted with 3x ethyl acetate. The combined extracts were washed with brine, dried over Na2S04, and condensed. The crude product was chromatographed on Siθ2 using 30% ethyl acetate/hexanes as eluent, to yield 5.52 g (47%>) of the desired compound. MS (DCI/NH3) m/z 250 (M+H)+. Example 229B To a solution of the product from Example 229A (5.52 g, 22.15 mmol) and LiCl (1.03 g, 24.36 mmol) in DMF (60 mL) at 0 °C was added PCI3 (2.12 mL, 24.36 mmol), and the reaction was stined at room temperature for 1 hour. The reaction was poured into saturated aqueous NH4CI solution, and exttacted with 3x diethyl ether/hexanes. The combined exttacts were washed with 2x water, 2x brine, dried over Na2Sθ4, and condensed to yield 4.70 g (797c) of the desired compound.
Example 229C
A solution of the product from Example 229B (4.70 g, 17.56 mmol) and MeSNa (1.35 g, 19.3 mmol) in DMF (40 mL) was stined at room temperature for 3 hours. The reaction was poured into saturated aqueous NaHC03 solution, and exttacted with 3x Diethyl ether. The combined extracts were washed with brine, dried over Na2Sθ4, and condensed. The crude product was chromatographed on Siθ2 using 30% ethyl acetate/hexanes as eluent, to yield 4.00 g (827o) of the desired compound.
Example 229D The desired compound was prepared from the product from Example 229C by the procedure of Example 154B.
MS (DCI/NH3) m/z 308 (Bu3Sn+NH4)+.
Example 229E The desired compound was prepared from the product from Example D and the product from Example 152C by the procedure of Example 154C. MS (DCI/NH3) m/z 416 (M+NH4)+.
Example 229F 6-(aminoiminomethyl)-4-r5-[methylthio)methyl1-3-furanvn-N-phenyl-2- naphthalenecarboxamide. monohydrochloride
The desired compound was prepared from Example 229E and the procedure of Example 144C. MS (DCI/NH3) m/z 416 (M+H)+; Η NMR (300 MHz, DMSO-d6) δ 2.15 (s, 3H), 3.87 (s, 2H), 7.14 (t, IH), 7.40 (t, 2H), 7.84 (d, 2H), 7.92 (dd, IH), 8.19 (d, IH), 8.32 (s, IH), 8.39 (d, IH), 8.64 (s, IH), 8.69 (s, IH), 9.31 (br s, 2H), 9.61 (br s, 2H), 10.62 (s, IH);
Anal, calc'd for C24H2iN3Sθ2- 1.4 HCl: C, 61.79: H, 4.84; N, 9.01. Found: C, 61.83; H, 4.82; N, 9.13.
Example 230 6-(aminoiminomethyl)-4-r5-(methoxymethyl)-3-furanyll-N-phenyl-2-naphthalenecarboxamide, monohydrochloride
Example 230A The desired compound was prepared from 2-trimethylsilyl-3-bromofuran and chloromethyl methyl ether by the procedure of Example 154A.
Example 230B
The desired compound was prepared from the product from Example 230A by the procedure of Example 154B. MS (DCI/NH3) m/z 308 (Bu3Sn+NH4)+.
Example 230C
The desired compound was prepared from the product from Example 230B and the product from Example 152C by the procedure of Example 154C. MS (DCI/NH3) m/z 400 (M+NH4)+.
Example 230D
6-(aminoiminomethyl)-4-r5-(methoxymethyl)-3-furanyll-N-phenyl-2-naphthalenecarboxamide, monohydrochloride The desired compound was prepared from Example 230C and the procedure of Example 144C. MS (DCI/NH3) m/z 400 (M+H)+;
' H NMR (300 MHz, DMSO-d6) δ 3.38 (s, 3H), 4.49 (s, 2H), 7.14 (t, IH), 7.18 (t, IH), 7.40 (t, 2H), 7.84 (d, 2H), 7.92 (dd, IH), 8.19 (d, IH), 8.38 (d, IH), 8.42 (s, IH), 8.64 (s, IH), 8.70 (s, IH), 9.32 (br s, 2H), 9.62 (br s, 2H), 10.68 (s, IH); Anal, calc'd for C24H2iN3θ3-2.8 HCl: C, 57.48; H, 4.78; N, 8.38. Found: C, 57.40; H, 4.44; N, 8.38.
Example 231 6-(aminoiminomethyl)-4-r5-(methylsulfonvI)-3-furanvn-N-phenyl-2-naphthalenecarboxamide. mono (trifluoroacetate)( salt)
Example 231 A The desired compound was prepared from the product from Example 152C by the procedure of Example 227 A.
MS (DCI/NH3) m/z 434 (M+NH4)+.
Example 23 IB
6-(aminoiminomethyl)-4-r5-(methylsulfonyl)-3-furanvn-N-phenyl-2-naphthaienecarboxamide, mono(trifluoroacetate)(salt)
The desired compound was prepared from Example 231 A and the procedure of Example
13.
MS (DCI/NH3) m/z 434 (M+H)+;
Η NMR (300 MHz, DMSO-dό) δ 3.44 (s, 3H), 7.16 (t, IH), 7.40 (t, 2H), 7.82 (d, 2H), 7.91 (s, IH), 7.95 (dd, IH), 8.00 (s, IH), 8.36 (s, I H), 8.43 (d, IH), 8.57 (s, IH), 8.75 (s,
2H), 9.18 (br s, 2H), 9.53 (br s, 2H);
Anal, calc'd for C23Hι9N3SO4-1.0 C2HF3O2: C, 54.84; H, 3.68; N, 7.67. Found: C, 55.05;
H, 3.74; N, 7.75.
Example 232
6-(aminoiminomethyl)-4-r5-(ethvthio)tettahvdro-3-furanyll-N-phenyl-2- naphthalenecarboxamide. monohydrochloride
Example 232A The desired compound was prepared from the product from Example 152A by the procedure of Example 62A. MS (DCI/NH3) m/z 315 (M+NH4)+.
Example 232B A solution of the product from Example 232A (1.62 g, 5.45 mmol), ethanethiol (2.2 mL), and cone. HCl (0.80 mL) in CHCI3 (22 mL) was stirred at room temperature for 3 hours and condensed. The crude product was chromatographed on Siθ2 using 157o ethyl acetate/hexanes as eluent, to yield 1.20 g (657o) of the desired compound. MS (DCI/NH3) m z 359 (M+NH4)+.
Example 232C The desired compound was prepared from the product from Example 232B by the procedure of Example 152B. MS (DCI/NH3) m/z 345 (M+NH4)+.
Example 232D The desired compound was prepared from the product from Example 232C by the procedure of Example 207C. MS (DCI NH3) m/z 420 (M+NH )+.
Example 232E 6-(aminoiminomethyP-4-r5-(ethvthio)tettahvdro-3-furanyll-N-phenyl-2- naphthalenecarboxamide. monohydrochloride The desired compound was prepared from Example 232D and the procedure of Example
144C.
MS (DCI/NH3) m/z 420 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 1.18 (dt, 3H), 2.42 (m, IH), 3.50 (dq, 2H), 3.74 (m, IH), 3.93 (m, lh), 4.39 (m, IH), 4.54 (m, IH), 5.38 (dd, 0.5H), 5.42 (dd, 0.5H), 7.14 (t, IH), 7.40 (t, 2H), 7.82 (d, 2H), 7.95 (d, IH), 8.06 (s, 0.5H), 8.20 (s, 0.5H), 8.32 (d, IH), 8.60 (s, IH), 8.71 (s, 0.5H), 8.80 (s, 0.5H), 9.32 (br s, 2H), 9.62 (br s, 2H), 10.59 (br s, IH); Anal, calc'd for C24H25N3O2S- 1.0 HCl: C, 63.22; H, 5.75; N, 9.21. Found: C, 62.93; H, 5.58; N, 9.01.

Claims

WHAT IS CLAIMED IS.
1 . A compound having the formula
Z is selected from the group consisting ot
( 1 ) nitrogen:
(2) methine: and (3) methine substituted with -NR1R2,
A is selected from the group consisting of
( 1 ) hydrogen and
(2) -LARA,
B is selected from the group consisting of
( 1 ) hydrogen and
C is selected from the group consisting of
( 1 ) hydrogen and
(2) -LcRc, with the proviso that at least one of A. B or C is other than hydrogen; and with the proviso that when A is other than hydrogen, at least one of B or C is other than hydrogen, wherein for A. B, and C. LA, LB and Lc are independently selected from the group consisting of
(1 ) a covalent bond.
(2) -(CH2)m-, (3) -NRi-,
(4) -NR2C(X)NR -, (5) -C(X)-,
(6) -NR2C(X)-,
(7) -C(X)NR -.
(8) -CH=CH-.
(9) -CΓëíC-.
( 10) -0-,
( 11 ) -S(0)r,
(12) -CΓëíC(CH2)nNR2C(X)-.
( 13) -C(X)NR2(CH2)nCΓëíC-.
( 14) -(CH2)nNS02-,
( 15) -NR2S02(CH2)nCΓëíC-.
(16) -CΓëíC(CH2)n R2S02NR3-,
( 17) -NR2S02NR3(CH2)nCΓëíC-,
( 18) -SO2NR2-,
( 19) -NR2SO2-,
(20) -NR2SO2NR3-.
(21) -N=N-.
(22) -C(X)N(OR2)-,
(23) -N(OR )C(X)-,
(24) -HC=CH(CH2)nNR2C(X)-,
(25) -(CH2)nNR2C(X)CH=CH-,
(26) -CH=CH(CH2)nNSO2-,
(27) -NR2S02(CH2)nCH=CH-,
(28) -(CH2)nNR2S02NR -,
(29) -NR2S02NR3(CH2)nCH=CH-.
(30) -NR2C(0)0-,
(31) -OC(0)NR -,
(32) -CH=NO-,
(33) -ON=CH- and \ 7
(34) , wherein W is selected from the group consisting of
(a) -0-,
(b) -S-,
(c) -NRi- and (d) -(CH2)m-, wherein each functional group is depicted with its right-hand end being the end which is attached to the naphthyl or quinolyl ring and its left-hand end being the end which is attached to RA, R╬▓ or Re;
RA, R╬▓ and Re are independently selected from the group consisting of
(1) aryl;
(2) arylalkoxy, wherein the alkyiene group is of one to six carbon atoms:
(3) alkyl of one to ten carbon atoms:
(4) alkenyl of two to ten carbon atoms: (5) alkoxycarbonyl of one to six carbon atoms;
(6) alkynyl of two to ten carbon atoms:
(7) halogen:
(8) -NR╬╣R2:
(9) heterocycle: ( 10) cycloalkenyl of four to .twelve carbon atoms:
( 1 1 ) cycloalkyl of three to twelve carbon atoms:
(12) -NR╬╣C(0)NR2R3; and
(13) -NR╬╣C(0)R o. wherein R50 is alkyl of one to six carbon atoms; wherein, at each occurence, R 1 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 alkyiene group is of one to six carbon atoms;
(8) cycloalkyl of three to eight carbon atoms and
(9) cycloalkylalkyl. wherein the cycloalkyl group is of three to eight carbon atoms, and the alkyiene group is of one to ten carbon atoms; and wherein, at each occurence, R2 and R3 are independently selected from the group consisting of
(1) hydrogen;
(2) alkyl of one to six carbon atoms: (3) alkenyl of two to six carbon atoms:
100 (4) alkynyl of two to six carbon atoms;
(5) aryl;
(6) arylalkyl, wherein the alkyiene group is of one to six carbon atoms
(7) cycloalkyl of three to eight carbon atoms and
(8) cycloalkylalkyl. wherein the cycloalkyl group is of three to eight carbon 105 atoms, and the alkyiene group is of one to ten carbon atoms: and wherein, at each occurence, X is selected from the group consisting of
( 1 ) O and
(2) S; and wherein, at each occurence. 110 m is one to five, n is zero to four and t is zero to two: and wherein, at each occurence, the alkyl, alkenyl, alkynyl. aryl, heterocycle. cycloalkyl, and cycloalkenyl groups are optionally substituted. 115
2. A compound according to Claim 1 wherein A and C are hydrogen and
3. A compound according to Claim 2 selected from die group consisting of 7-(2-hydroxyethoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; methyl 5-[7-[(aπιinoiminomethyl)-2-naphthalenyl]oxy]pentanoate; mono(trifluoroacetate) salt:
5 5-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoic acid, mono(trifluoroacetate) salt; methyl 4-[[[7-amino(hydroxyimino)methyl]-2-naphthalenyl]oxy]methyl]benzoate; methyl 2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetate, mono(trifluoroacetate) salt 10 7-[2-(4-morphohnyl)ethoxy]-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt;
2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetic acid, mono(trifluoroacetate) salt; and methyl 4-[6-(aminoiminomethyl)-2-naphthalenyl]oxy]methyl]benzoate, mono(trifluoroacetate) salt
4. A compound according to Claim 1 wherein A and B are hydrogen: and
C is -LcRc-
5. A compound according to Claim 4 selected from the group consisting of 8-(carbonylbenzyloxy)amino-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)- l-naphthalenyl)acetamide mono(trifluoroacetate) salt; methyl [7-(aminoiminomethyl)- 1 -naphthalenyljcarbamate mono(trifluoroacetate) salt; methyl 3-[[7-(arrunoiminomethyl)- l-naphthalenyl]amino]-3-oxopropionate mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyD- 1 -naphthalenyl]-2-(phenylmethoxy)acetamide mono(trifluoro acetate) salt; N-[7-(aminoiminomethyl)- l -naphthalenyl]-l ,3-benzodioxole-5-carboxamide mono(trifluoroacetate) salt,
N-[7-(arrύnoiminomethyl)- l-naphthalenyl]benzenemethanesulfonamide mono(trifluoroacetate) salt, methyl [7-(aminoiminomethyl)- 1 -naphthalenyl]methylcarbamate, mono(trifluoroacetate) salt propyl [7-(aminoirninomethyl)- l -naphthalenylJcarbamate, mono(ttifluoroacetate) salt
N-[7-(aminoiminomethyl)- l-naphthaienyl]-N'-methylurea. mono(trifluoroacetate) salt; ethyl [7-(aminoiminomethyl)- l-naphthalenyl)carbamate, mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)- l-naphthalenyl)propanamide, mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)- 1 -naphthalenyl)-2-methoxyacetamide, mono(trifluoroacetate) salt
N-[7-(arr╬╣inoiminomethyD-l-naphthalenyl]urea, mono(trifluoroacetate) salt;
N-[7-(arrunoiminomethyl)- 1 -naphthalenyl]-2-hydroxyacetamide, mono(trifluoroacetate) salt 8-(2-pyrirnidinylanύι no)-2-naphthalenecarboxhτιidarnide, bis(trifluoroacetate) salt;
8-amino-2-napthalenecarboximidamide. bis(trifluoroacetate) salt;
8-(2-pyridinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt; and N-hydroxy-8-(2-pyrimidinylamino)- 2-naphthalenecarboximidamide, mono(trifluoroacetate) salt.
6. A compound according to Claim 1 wherein A is -LARA,
B is -LBRB, and C is hydrogen.
7. A compound according to Claim 6 which is
6, 7-Dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt.
8. A compound according to Claim 1 wherein
A is -L RA, B is hydrogen: and C is -LcRc-
9. A compound according to Claim 8 selected from die group consisting of methyl 6-(aminoiminomethyl)-4-[(methoxycarbonyl)amino]-2-naphthalenecarboxylate mono(trifluoroacetate) salt;
6-methoxy-8-benzyloxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 2-[(7-amhιoiιτιinomethyl-3-methoxy- 1 -naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt;
6-(aminoiminomethyD-4-(3-furanyl)-N-[4-(trifluoromethyl)phenyl]-2- naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(arr╬╣inoiminomethyD-4-(3-furanyl)-N-(4-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride:
6-(amdnoiminomethyI)-4-(3-furanyl)-N-(lH-pyrazol-3-yl)-2-naphthalenecarboxamide, dihydrochloride;
6-(arr noiminomethyl)-4-(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride; methyl [7-(arrύnoiιτtinomethyl)-3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-l- naphathalenyljcarbamate. bis(trifluoroacetate) salt; 6-(arnmoiminomethyl)-4-(3-furanyl)-N-(2-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride;
6-(arninoiminomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamide, monohydrochloride;
6-(aminoirninomethyl)-4-[l-(methylsulfonyl)-lH-pyrazol-4-yl]-N-phenyl-2- naphthalenecarboxamide, monohydrochloride;
6-(aminoiminomethyl)-4-[5-(methylthio)-3-furanyl)]-N-phenyl-2- naphthalenecarboxamide, monohydrochloride; 6-(aminoirninome yl)-N-[4-(aminomethyl)phenyl]-4-(2-pyrirradinylamino)-2- naphthalenecarboxamide, tris(trifluoroacetate) salt
6-(arninoirninomemyl)-N-phenyl-4-(2-pyrirnidinylamino)-2naphthalenecarboxarnide, mono(trifluoroacetate) salt;
N-[(4-(aminomethyl)phenyl]-6-[amino(hydroxyimino)methyl]-4-(2-pyrimidinylamino)- 2-naphthalenecarboxamide, bis(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-[4-(hydroxymethyl)phenyl]-4-(2-pyrimidinylamino)-
2-naphthalenecarboxamide, mono(trifluoroacetate) salt methyl [3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-7-[4- arrdno(hydroxyimino)methyl]- l-naphthalenyl]carbamate, bis(trifluoroacetate) salt 6-(aminoiminomethyl)-N-phenyl-4-(tetrahydro-3-furanyl)-2- naphthalenecarboxamide.monohydrochloride;
6-[amώo(hyα^oxyirnino)methyl]-N-phenyl-4-(2-pyrirnio nylamino)-2- naphthalenecarboxamide;
6-(aminoiminomethyl)-4-[5-(ethylthio)-3-furanyl]-N-phenyl-2- naphthalenecarboxamide.monohydrochloride;
6-(aminoirninomethyl)-4-[5-(propylthio)-3-furanyl]-N-phenyl-2- naphthalenecarboxamide,monohydrochloride;
6-(aminoiminomethyl)-N-phenyl-4-(2-pynolidinyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt 6-(aminoiminomethyl)-4-[5-(propylsulfonyl)-3-furanyl]-N-phenyl-2- naphthalenecarboxamide, monohydrochloride;
6-(aminoύninomethyl)-4-[5-[methylthio)methyl]-3-furanyl]-N-phenyl-2- naphthalenecarboxamide, monohydrochloride;
6-(arninoiminomethyl)-4-[5-(methoxymethyl)-3-furanyl]-N-phenyl-2- naphthalenecarboxamide. monohydrochloride; 6-(am oiminomethyl)-4-[5-(methylsulfonyl)-3-furanyl]-N-phenyl-2- naphthalenecarboxamide, mono(trifluoroacetate) salt and 6-(aminoiminomethyl)-4-[5-(ethythio)tetrahydro-3-furanyl]-N-phenyl-2- naphthalenecarboxamide, monohydrochloride.
10. A compound according to Claim 1 wherein A is -LARA, C is -LcRc-
1 1. A compound according to Claim 10 which is
6, 7, 8-tiimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt.
12. A compound according to Claim 1 wherein A is hydrogen; C is -LcRc-
13. A compound according to Claim 12 selected from the group consisting of
7, 8-Dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 2-[(7-aminoiminomethyl)-2-methoxy- 1 -naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt; 7-benzyloxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt methyl [(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]acetate mono(trifluoroacetate) salt:
2-[(7-aminoiminomethyl-2-methoxy- l-naphthalenyl)oxy]-yl-acetic acid mono(trifluoroacetate) salt l-[(7-aminoiminomethyl-2-methoxy-l-naphthalenyl)oxy]-3-hydroxypropane mono(trifluoroacetate) salt
1 -[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]-3-bromopropane mono(hydrochloride) salt
3-[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]propene mono(trifluoroacetate) salt l-[(7-arrύnoiminomethyl-2-methoxy-l-naphthalenyl)oxy]-3-phenylpropane mono(hydrochloride) salt l-[(7-aminoiminomethyl-2-methoxy-l-naphthalenyl)oxy]-3-[l-(3,4- dimethoxy)phenyl]propane mono(hydrochloride) salt; 7-methoxy-8-(2-furanyl)-2-naphthalenecarboximidamide mono(ttifluoroacetate) salt
(E)-{7-methoxy-8-[2-(phenyl)ethenyl] }-2-naphthaleneimidarnide mono(trifluoroacetate) salt
7-(2-hyo^oxyethoxy)-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
7-propoxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 7-memoxy-8-(lH-pyrazol-4-yl)-2-naphthalenecarboxirnidamide bis(trifluoroacetate) salt
7-methoxy-8-iodo-2-naphd╬╣alenecarboximidamide mono(trifluoroacetate) salt
7-methoxy-8-(3-furanyl)-2-naphth enecarboxirrddamide mono(methanesulfonate) salt
7-memoxy-8-(2-benzofuranyl)naphthalene-2-carboximidamide mono(methanesulfonate) salt
(E)-8-[2-(l ,3-benzodioxol-5-yl)ethenyl]-2-naphthalenecarboximidarnide mono(methanesulfonate) salt;
( ± )-7-memoxy-8-(tettahydro-3-furanyl)-2-naphthalenecarboximidamide mono(methanesulfonate) salt; 7-methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarboxiιτudamide mono(trifluoroacetate) salt
7-me oxy-8-[2-thiazoyl(oxy)]naphthalene-2-carboxirr╬╣idarmde mono(trifluoroacetate) salt
7-methoxy-8-(4-nittophenoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
7-memoxy-8-pentafluorophenoxy-2-naphthalenecarboxirnidarnide mono(trifluoroacetate) salt
7-methoxy-8-[N-2-pyrimidmyl(arnino)]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 4-[7-(aminoiminomethyl)-2-methoxy- 1 -naphthalenyl]dihydro-2(3H)-furanone mono(trifluoroacetate) salt
7-methoxy-8-( 1 -acetyl- 1 H-pyrazolyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 7-methoxy-8-[l-(methylsulfonyl)-lH-4-pyrazolyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
6-[2-(4-am ophenyl)ethoxy]-2-naphthalenecarboxir darmde mono(trifluoroacetate) salt methyl [3-methoxy-6-(aminoiminomethyl)-4-naphthalenyl]carbamate mono(trifluoroacetate) salt 7-methoxy-8-[2-pyrirmdinyl(arnino)]-2-naphmalenecarboxi╬╣nidamide bis(trifluoroacetate) salt; methyl [7-(aminoiminomethyl)-2-methoxy- 1 -naphthalenyl)carbamate, mono(trifluoroacetate) salt
7-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidarnide, bis(trifluoroacetate) salt
7-methoxy-8-[(phenylmethyl)amino]-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt
7-methoxy-8-(phenylamino)-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt 7-methoxy-8-[(4-me oxyphenyl)amino]-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt
(E)-3-[7-(aminoiminomethyl)-2-methoxy-l-naphthalenyl)-2-propenamide, mono(trifluoroacetate) salt
7-methoxy-8-(3-oxo- 1 -cyclopenten- 1 -yl)-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt methyl 4-[[[7-(arr╬╣inoiminomethyl)- l-(2-pyrimidinylamino)-2- naphthalenyl]oxy]methyl]benzoate, mono(trifluoroacetate) salt;
4-[[[7-(aminoirrύnomethyD- l-(2-pyrimidinylamino)-2-naphthalenyl]oxy]methyl] benzoic acid, mono(trifluoroacetate) salt: 7-methoxy-8-(pyrazinyloxy)-2-naphthalenecarboximidamide, dimethanesulfonate salt
7-methoxy-8-(phenylthio)-2-naphthalenecarboximidamide, methanesulfonate; and
7-methoxy-8-(pyrazinylarnmo)-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt.
14. A compound selected from the group consisting of
7, 8-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 6, 7, 8-trimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 6, 7-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt; 2-[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt
7-benzyloxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate) salt methyl [(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]acetate mono(trifluoroacetate) salt 2-[(7-aminoiminomethyl-2-methoxy-l-naphthalenyl)oxy]-yl-acetic acid mono(tτifluoroacetate) salt l-[(7-aminoiminomethyl-2-methoxy-l-naphthalenyl)oxy]-3-hydroxypropane mono(trifluoroacetate) salt phenylmethyl [7-(aminoiminomethyl)- l-naphthalenyl)carbamate mono(trifluoroacetate) salt
N-[7-(ammoiminomethyI)-l-naphthalenyl)acetamide mono(trifluoroacetate) salt; methyl [7-(arninoiminomethyl)- l-naphthalenyl)carbamate mono(trifluoroacetate) salt methyl 3-[[7-(aιτιinoiminomethyl)-l-naphthalenyl]amino]-3-oxopropanoate mono(trifluoroacetate) salt N-[7-(aminoiminomethyl)- 1 -naphthalenyl]-2-(phenylmethoxy)acetamide mono(trifluoroacetate) salt
N-[7-(aminoiminomethyl)- 1 -naphthalenyl]- 1 ,3-benzodioxole-5-carboxamide mono(trifluoroacetate) salt
N-[7-(aminoiminomethyl)- 1 -naphthalenyljbenzenemethanesulf onamide mono(trifluoroacetate) salt
1 -[(7-aminoiminomethyl-2-methoxy- l-naphthalenyl)oxy]-3-bromopropane mono(hydrochloride) salt
3-[(7-aminoiminomethyl-2-methoxy- 1 -naphthalenyl)oxy]propene mono(trifluoroacetate) salt l-[(7-aminoiminomethyl-2-methoxy-l-naphthalenyl)oxy]-3-phenylpropane mono(hydrochloride) salt l-[(7-aminoiminomethyl-2-methoxy-l-naphthalenyl)oxy]-3-[l-(3,4- dimethoxy)phenyl]- propane mono(hydrochloride) salt
7-methoxy-8-(2-furanyl)-2-naphthalenecarboxirnidamide mono(trifluoroacetate) salt methyl 6-(aminoinτinomethyl)-4-[(methoxycarbonyl)amino]-2- naphthalenecarboxylate mono(trifluoroacetate) salt;
(E)-6-[2-(phenyl)ethenyl]-2-naphthaleneimidarnide mono(trifluoroacetate) salt 7-(2-hydroxyethoxy)-8-iodo-2-naphthalenecarboxirnidamide mono(trifluoroacetate) salt 7-(2-hydroxyethoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
6-methoxy-8-benzyloxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
2-[(7-aminoiminomethyl-3-methoxy- 1 -naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt
7-propoxy-8-iodo-2-naphthalenecarboxirnidamide mono(trifluoroacetate) salt; 7-methoxy-8-( 1 H-pyrazol-4-yl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
7-methoxy-8-iodo-2-naphthalenecarboxirnidamide mono(trifluoroacetate) salt
7-methoxy-8-(3-fi)τanyl)-2-naphthalenecarboximidamide mono(methanesulfonate) salt
7-methoxy-8-(2-benzofuranyl)naphthalene-2-carboximidamide mono(methanesulfonate) salt;
(E)-8-[2-(l,3-benzodioxol-5-yl)ethenyl]-2-naphthalenecarboximidamide mono(methanesulfonate) salt;
( ┬▒ )-7-memoxy-8-(tettahydro-3-furanyl)-2-naphthalenecarboximidamide mono(methanesulfonate) salt; 7-methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
7-methoxy-8-[2-thiazoyl(oxy)]naphthalene-2-carboximidamide mono(trifluoroacetate) salt
7-methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
7-methoxy-8-pentafluorophenoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt
7-methoxy-8-[N-2-pyrirrτidinyl(arnino)]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt N-(6-aminoiminomethyl-2-naphthalenyl)-N'-benzylurea mono(trifluoroacetate) salt;
N-(6-ammoiminomethyl-2-naphthalenyl)-N'-methylurea mono(trifluoroacetate) salt;
N-(6-aminoirninomethyl-2-naphthalenyl)-N'-isopropylurea mono(trifluoroacetate) salt;
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-phenyl-N'-methylurea mono(trifluoroacetate) salt 6-aminonaphthalene-2-carboximidamide mono(ttifluoroacetate) salt N-(6-arninoiminomethyl-2-naphthalenyl)-N'-cyclohexylurea mono(trifluoroacetate) salt
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-benzyloxyurea mono(trifluoroacetate) salt 75 1 , 1 -dimethylethyl [4-[[(6-cyano-2-naphthalenyl)amino]carbonyl]phenyl]carbamate mono(trifluoroacetate) salt
N-[6-(aminoiminome yl)-2-naphthalenyl]-4-(aminomethyl)benzamide mono(trifluoroacetate) salt
4-[7-(aminoiminomethyl)-2-methoxy- 1 -naphthalenyl]dihydro-2(3H)-furanone 80 mono(trifluoroacetate) salt
7-methoxy-8-( 1 -acetyl- 1 H-pyrazolyl)-2-naphthalenecarboximidamide mono(tiifluoroacetate) salt
7-methoxy-8-[l-(me ylsulfonyD-lH-4-pyrazolyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt 85 methyl [3-methoxy-6-(aminoiminomethyl)-4-naphthalenyl]carbamate mono(trifluoroacetate) salt
7-memoxy-8-[2-pyrjTOidinyl(arruno)]-2-naphthalenecarboximidamide; and bis(trifluoroacetate) salt
15. A method for inhibiting urokinase in a mammal in need of such treatment comprising adminstering to the mammal a therapeutically effective amount of a compound of Claim 1.
16. A composition for inhibiting urokinase comprising both a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
EP98937082A 1997-07-25 1998-07-24 Urokinase inhibitors Withdrawn EP1000018A2 (en)

Applications Claiming Priority (3)

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US90104097A 1997-07-25 1997-07-25
US901040 1997-07-25
PCT/US1998/015386 WO1999005096A2 (en) 1997-07-25 1998-07-24 Urokinase inhibitors

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AR (1) AR013372A1 (en)
AU (1) AU8587498A (en)
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CA (1) CA2294300A1 (en)
HU (1) HUP0100353A3 (en)
IL (1) IL133368A0 (en)
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WO1999005096A2 (en) 1999-02-04
HUP0100353A3 (en) 2001-11-28
WO1999005096A3 (en) 1999-06-03
JP2002512636A (en) 2002-04-23
CA2294300A1 (en) 1999-02-04
IL133368A0 (en) 2001-04-30
KR20010014369A (en) 2001-02-26
HUP0100353A2 (en) 2001-05-28
SK174899A3 (en) 2000-06-12
BG103981A (en) 2000-11-30
PL339429A1 (en) 2000-12-18
NO996578L (en) 2000-01-25
NO996578D0 (en) 1999-12-30
CN1265645A (en) 2000-09-06
BR9811099A (en) 2002-05-14
ZA986594B (en) 1999-01-27
AU8587498A (en) 1999-02-16

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