EP1313696A2 - Amino(oxo)acetic acid protein tyrosine phosphatase inhibitors - Google Patents

Amino(oxo)acetic acid protein tyrosine phosphatase inhibitors

Info

Publication number
EP1313696A2
EP1313696A2 EP01964500A EP01964500A EP1313696A2 EP 1313696 A2 EP1313696 A2 EP 1313696A2 EP 01964500 A EP01964500 A EP 01964500A EP 01964500 A EP01964500 A EP 01964500A EP 1313696 A2 EP1313696 A2 EP 1313696A2
Authority
EP
European Patent Office
Prior art keywords
amino
carboxycarbonyl
benzoic acid
carboxyphenyl
mmol
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Withdrawn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
EP01964500A
Other languages
German (de)
French (fr)
Inventor
Gang Liu
Bruce G. Szczepankiewicz
Zhonghua Pei
Zhili Xin
Thorsten K. Oost
David A. Janowick
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
Priority claimed from US09/918,928 external-priority patent/US20020035137A1/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP1313696A2 publication Critical patent/EP1313696A2/en
Withdrawn legal-status Critical Current

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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
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    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
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    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
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    • C07C323/50—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
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    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Definitions

  • the instant invention is directed to compounds useful for inhibiting protein tyrosine phosphatase PTPIB, preparation of the compounds, compositions containing the compounds, and treatment of diseases using the compounds.
  • PTPIB belongs to a family of protein tyrosine phosphatases involved in the regulation of the cellular signaling mechanisms which are implicated in metabolism, growth, proliferation, and differentiation (Science 1991, 253, 401-406). Overexpression or altered activity of tyrosine phosphatase PTPIB can contribute to the progression of various diseases (Ann. Rev. Biochem. 1985, 54, 897-930). Two independent studies have indicated that PTP IB knock-out mice have increased glucose tolerance, increased insulin sensitivity and decreased weight gain on a high fat diet.
  • A is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl
  • R is selected from the group consisting of alkoxy, alkyl, amino, aminosulfonyl, aryl, arylalkyl, aryloxy, hydroxy, perfluoroalkoxy, and perfluoroalkyl;
  • R , R , and R are independently selected from the group consisting of hydrogen, alkoxy, alkyl, amido, amino, aminosulfonyl, arylcarbonylamino, cyano, halo, hydroxy, nitro, perfluoroalkoxy, and perfluoroalkyl;
  • R is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and (heterocycloalkyl)alkyl.
  • R is selected from the group consisting of hydrogen, amido alkoxy, arylcarbonylamino, cyano and hydroxy;
  • R is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and (heterocycloalkyl)alkyl; and ⁇ each R is independently selected from the group consisting of hydrogen and alkyl.
  • A is aryl
  • A is aryl; and R is hydroxy.
  • A is aryl; R 1 is hydroxy; and R is carboxy.
  • A is aryl; R 1 is hydroxy; R is carboxy; and R , R , and R 5 are independently selected from the group consisting of hydrogen and alkoxy.
  • A is aryl; R 1 is hydroxy; R " is carboxy; R , R , and R 5 are independently selected from the group consisting of hydrogen and alkoxy; and R is aryl, cycloalkyl, or heteroaryl.
  • a method for inhibiting protein tyrosine phosphatase at physiological pH comprising administering a therapeutically effective amount of a compound of formula (I).
  • a method for treating type II diabetes, obesity, impaired glucose tolerance and insulin resistance in a patient in recognized need thereof comprising administering to the patient a therapeutically effective amount of a compound of formula (I).
  • a composition comprising a compound of formula (I) in combination with a therapeutically acceptable excipient.
  • a method for inhibiting protein tyrosine phosphatase at physiological pH comprising administering a therapeutically effective amount of a compound of formula (II).
  • a method for treating type II diabetes, obesity, impaired glucose tolerance and insulin resistance in a patient in recognized need thereof comprising administering to the patient a therapeutically effective amount of a compound of formula (II).
  • composition comprising a compound of formula (II) in combination with a therapeutically acceptable excipient.
  • the instant invention provides a series of compounds which inhibit protein tyrosine phosphatase PTPIB. As used throughout the instant specification, the following terms have the meanings indicated:
  • alkanoyl represents an alkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkenyl represents a monovalent straight or branched chain hydrocarbon radical having from two to six carbons and at least one carbon-carbon double bond.
  • alkoxy represents an alkyl group attached to the parent molecular moiety through an oxygen atom.
  • alkoxycarbonyl represents an alkoxy group attached to the parent molecular moiety through a carbonyl group.
  • alkoxy carbonylalkenyl represents an alkoxycarbonyl group attached to the parent molecular moiety through an alkenyl group.
  • alkoxy carbonylalkyl represents an alkoxycarbonyl group attached to the parent molecular moiety through an alkyl group.
  • alkyl represents a saturated, monovalent straight or branched chain hydrocarbon having from one to six carbons.
  • alkylsufonyl represents an alkyl group attached to the parent molecular moiety through a sulfonyl group.
  • amino represents an amino group attached to the parent molecular moiety through a carbonyl group.
  • amidoalkenyl represents an amido group attached to the parent molecular moiety through an alkenyl group.
  • amidoalkyl represents an amido group attached to the parent molecular moiety through an alkyl group.
  • the alkyl part of the amidoalkyl can be optionally substituted with one or two substituents independently selected from hydroxy, thioalkoxy, RARB -, wherein RA and R B are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylsulfonyl, amido, aryl, arylalkyl, arylalkylcarbonyl, carboxyalkylcarbonyl, or a nitrogen protecting group.
  • amino represents -NR R , wherein R and R are independently selected from hydrogen, alkanoyl, alkenyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylsulfonyl, aryl, arylalkyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, hydroxy alkyl, a nitrogen protecting group, phenylsulfonyl, and
  • R A R ⁇ Ncarbonylalkyl, wherein RA and R B are previously defined or R and R , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of mo ⁇ holinyl, oxazinanyl, piperazinyl, piperidinyl, and pyrrolidinyl.
  • aminoalkenyl represents an amino group attached to the parent molecular moiety through an alkenyl group.
  • aminoalkyl represents an amino group attached to the parent molecular moiety through an alkyl group.
  • the alkyl part of the aminoalkyl can be optionally substituted with one or two substituents independently selected from halogen and hydroxy.
  • aminonosulfonyl represents an amino group attached to the parent molecular moiety through a sulfonyl group.
  • aryl represents dihydronaphthyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • Aryl groups having an unsaturated or partially saturated ring fused to an aromatic ring can be attached through the saturated or the unsaturated part of the group.
  • the aryl groups of the instant invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkoxy carbonylalkenyl, alkoxycarbonylalkyl, alkyl, alkylsufonyl, amido, amidoalkenyl, amidoalkyl, amino, aminoalkenyl, aminoalkyl, aminosulfonyl, carboxy, carboxyalkenyl, carboxyalkyl, cyano, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, hydroxy, hydroxyalkyl, nitro, perfluoroalkoxy, perfluoroalkyl, phenyl, phenylalkoxy, phenylalkyl, phenylcarbonyl and thioalkoxy.
  • arylalkyl represents an aryl group attached to the parent molecular moiety through an alkyl group, wherein the alkyl part of the arylalkyl can be optionally substituted with amido and NR A R B , wherein RA and R B are previously defined.
  • arylalkylcarbonyl represents an arylalkyl group attached to the parent molecular moiety through a carbonyl.
  • aryloxy represents an aryl group attached to the parent molecular moiety through an oxygen atom.
  • carbonyl represents -C(O)-.
  • carboxy represents -CO 2 H.
  • carboxyalkenyl represents a carboxy group attached to the parent molecular moiety through an alkenyl group.
  • carboxyalkyl represents a carboxy group attached to the parent molecular moiety through an alkyl group.
  • carboxy alky lcarbonyl represents a carboxyalkyl group attached to the parent molecular moiety through a carbonyl group.
  • cyano represents -CN
  • cycloalkenyl represents a monovalent cyclic or bicyclic hydrocarbon of four to twelve carbons having at least one carbon-carbon double bond.
  • cycloalkenylalkyl represents a cycloalkenyl group attached to the parent molecular moiety through an alkyl group.
  • cycloalkyl represents a monovalent saturated cyclic or bicyclic hydrocarbon group of three to twelve carbons.
  • the cycloalkyl groups of the invention can be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amido, carboxy, halo and hydroxy.
  • cycloalkylalkyl represents a cycloalkyl group attached to the parent molecular moiety through an alkyl group.
  • halo represents to F, Cl, Br, or I.
  • haloalkyl represents a halo group attached to the parent molecular moiety through an alkyl group.
  • heteroaryl represents cyclic, aromatic groups having five or six atoms, wherein at least one atom is selected from the group consisting of nitrogen, oxygen, and sulfur, and the remaining atoms are carbon.
  • the five-membered rings have two double bonds, and the six-membered rings have three double bonds.
  • Heteroaryls of the invention are exemplified by furanyl, thienyl, pynolyl, oxazolyl, thiazplyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazinyl, and the like.
  • the heteroaryl groups of the instant invention are connected to the parent moleculai' group through a carbon atom in the ring or, as exemplified by imidazole, indole, and pyrazole, through either a carbon atom or nitrogen atom in the ring.
  • the heteroaryl groups of the invention can also be fused to a second ring selected from the group consisting of heteroaryl, heterocycloalkyl, and phenyl, in which case the heteroaryl group can be connected to the parent molecular group through either the heteroaryl part, the heterocycloalkyl part, or the phenyl part of the fused ring system.
  • Heteroaryl groups of this type are exemplified by quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, benzoisoxazolyl, benzthiazolyl, benzooxazolyl, indolyl, thienopyrazinyl, thienylfuranyl, thienylpyridinyl, 2,3-dihydrothienofuranyl, and the like.
  • heteroaryl groups of this invention can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkyl, amido, amidoalkenyl, amidoalkyl, amino, aminoalkenyl, aminoalkyl, carboxy, carboxyalkenyl, carboxyalkyl, cyano, halo, haloalkyl, heterocycloalkyl, hydroxy, hydroxyalkyl, nitro, perfluoroalkoxy, perfluoroalkyl, phenyl, phenylalkoxy, phenylalkyl, and thioalkoxy.
  • heteroarylalkyl represents a heteroaryl group attached to the parent molecular moiety through an alkyl group.
  • heterocycloalkyl represents cyclic, non-aromatic, four-, five-, or six-membered groups containing at least one atom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • the four-membered rings have zero double bonds, the five-membered rings have zero or one double bonds, and the six-membered rings have zero, one, or two double bonds.
  • Heterocycloalkyl groups of the invention are exemplified by dihydropyridinyl, imidazolinyl, mo ⁇ holinyl, piperazinyl, pynolidinyl, pyrazolidinyl, tetrahydropyridinyl, piperidinyl, thiomo ⁇ holinyl, 1,3-dioxolanyl, 1,4- dioxanyl, 1,3-dioxanyl, and the like.
  • the heterocycloalkyls of the instant invention can be attached to the parent molecular group through a carbon atom or nitrogen atom in the ring.
  • heterocycloalkyl groups of the invention can also be fused to a phenyl ring, in which case the heterocycloalkyl group can be connected to the parent molecular group through either the heterocycloalkyl part or the phenyl part of the fused ring system.
  • Heterocycloalkyl groups of this type are exemplified by benzodioxolyl, indolinyl, tetrahydroquinolinyl, chromanyl, and the like.
  • the heterocycloalkyl groups of this invention can be optionally substituted one, two, three, four or five substituents independently selected from the group consisting of alkanoyl, alkyl, alkoxy, alkoxycarbonyl, amido, amidoalkenyl, amidoalkyl, amino, aminoalkenyl, aminoalkyl, aryl, arylalkyl, carboxy, cyano, halo, hydroxy, hydroxyalkyl, nitro, oxo and thioalkoxy.
  • heterocycloalkylalkyl represents a heterocycloalkyl group attached to the parent molecular moiety through an alkyl group.
  • hydroxy represents -OH.
  • hydroxyalkyl represents a hydroxy group attached the parent molecular moiety through an alkyl group.
  • nitro represents -NO 2 .
  • nitrogen protecting group represents selectively introducible and removable groups which protect amino groups against undesirable side reactions during synthetic procedures. Examples of amino protecting groups include methoxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl (Cbz), chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-butoxycarbonyl
  • perfluoralkyl represents an alkyl group in which all of the hydrogen atoms have been replaced with fluoride atoms.
  • phenyl represents a 6 membered aromatic ring that is unsubstituted.
  • phenylalkoxy represents a phenyl group attached to the parent molecular moiety through an alkoxy group.
  • phenylalkyl represents a phenyl group attached to the parent molecular moiety through an alkyl group.
  • phenylcarbonyl represents a phenyl group attached to the parent molecular moiety through a carbonyl group.
  • phenylsulfonyl represents a phenyl group attached to the parent molecular moiety through a sulfonyl group.
  • sulfonyl represents -SO 2 -.
  • thioalkoxy represents an alkyl group attached to the parent molecular moiety through a sulfur atom.
  • the instant compounds can exist as therapeutically acceptable salts.
  • therapeutically acceptable salt refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of diseases without undue toxicity, initation, and allergic response, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid.
  • Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fimiarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetic, trifluoroacetic, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like.
  • amino groups of the compounds can also be quatemized with alkyl chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.
  • Basic addition salts can be prepared during the final isolation and purification of the instant compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine.
  • the instant compounds can also exist as therapeutically acceptable prodrugs.
  • therapeutically acceptable prodrag refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, initation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • prodrag refers to compounds which are rapidly transformed in vivo to the parent compounds of formula (I) for example, by hydrolysis in blood.
  • Asymmetric centers can exist in the instant compounds. Individual stereoisomers of the compounds are prepared by synthesis from chiral starting materials or by preparation of racemic mixtures and separation by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns. Starting materials of particular stereochemistry are either commercially available or are made by the methods described hereinbelow and resolved by techniques well-known in the art. Geometric isomers can exist in the instant compounds The invention contemplates the various geometric isomers and mixtures thereof resulting from the disposal of substituents around a carbon-carbon double bond, a cycloalkyl group, or a heterocycloalkyl group. Substituents around a carbon-carbon double bond are designated as being of Z or E configuration and substituents around a cycloalkyl or heterocycloalkyl are designated as being of cis or trans configuration.
  • compositions of the instant compounds comprise an effective amount of the same formulated with one or more therapeutically acceptable excipients.
  • therapeutically acceptable excipient represents a non-toxic, solid, semi- solid or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type.
  • therapeutically acceptable excipients include sugars; cellulose and derivatives thereof; oils; glycols; solutions; buffering, coloring, releasing, coating, sweetening, flavoring, and perfuming agents; and the like.
  • These therapeutic compositions can be administered parenterally, intracisternally, orally, rectally, or intraperitoneally.
  • Liquid dosage forms for oral administration of the instant compounds comprise formulations of the same as emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms can contain diluents and/or solubilizing or emulsifying agents.
  • the oral compositions can include wetting, emulsifying, sweetening, flavoring, and perfuming agents.
  • injectable preparations of the instant compounds comprise sterile, injectable, aqueous and oleaginous solutions, suspensions or emulsions, any of which can be optionally formulated with parenterally acceptable diluents, dispersing, wetting, or suspending agents.
  • injectable preparations can be sterilized by filtration through a bacterial-retaining filter or formulated with sterilizing agents which dissolve or disperse in the injectable media.
  • PTP inhibition by the instant compounds can be delayed by using a liquid suspension of crystalline or amo ⁇ hous material with poor water solubility.
  • the rate of abso ⁇ tion of the compounds depends upon their rate of dissolution which, in turn, depends on their crystallinity. Delayed abso ⁇ tion of a parenterally administered compound can be accomplished by dissolving or suspending the compound in oil.
  • Injectable depot forms of the compounds can also be prepared by microencapsulating the same in biodegradable polymers. Depending upon the ratio of compound to polymer and the nature of the polymer employed, the rate of release can be controlled. Depot injectable formulations are also prepared by entrapping the compounds in liposomes or microemulsions which are compatible with body tissues.
  • Solid dosage forms for oral administration of the instant compounds include capsules, tablets, pills, powders, and granules.
  • the compound is mixed with at least one inert, therapeutically acceptable excipient such as a carrier, filler, extender, disintegrating agent, solution retarding agent, wetting agent, absorbent, or lubricant.
  • the excipient can also contain buffering agents.
  • Suppositories for rectal administration can be prepared by mixing the compounds with a suitable non- initating excipient which is solid at ordinary temperature but fluid in the rectum.
  • the instant compounds can be micro-encapsulated with one or more of the excipients discussed previously.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric and release- controlling.
  • the compounds can be mixed with at least one inert diluent and can optionally comprise tableting lubricants and aids.
  • Capsules can also optionally contain opacifying agents which delay release of the compounds in a desired part of the intestinal tract.
  • Transdermal patches have the added advantage of providing controlled delivery of the instant compounds to the body.
  • dosage forms are prepared by dissolving or dispensing the compounds in the proper medium. Abso ⁇ tion enhancers can also be used to increase the flux of the compounds across the skin, and the rate of abso ⁇ tion can be controlled by providing a rate controlling membrane or by dispersing the compounds in a polymer matrix or gel.
  • tyrosine phosphatase PTPIB activity Diseases caused or exacerbated by protein tyrosine phosphatase PTPIB activity are treated or prevented in a patient by administering to the same a therapeutically effective amount of the instant compounds in such an amount and for such time as is necessary to achieve the desired result.
  • therapeutically effective amount refers to a sufficient amount of the compound to treat protein tyrosine phosphatase PTPIB activity at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, rate of excretion; the duration of the treatment; and drags used in combination or coincidental therapy.
  • the total daily dose of the instant compounds in single or divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions can contain such amounts or submultiples thereof of the compounds to make up the daily dose.
  • treatment regimens comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compounds per day in single or multiple doses.
  • Specific compounds of formula (II) include, but are not limited to: 2-((carboxycarbonyl)(l-naphthyl)amino)benzoic acid;
  • Human protein tyrosine phosphatase IB from E. coli Human protein tyrosine phosphatase IB (PTPIB, amino acid residues 1-321) was expressed in E. coli BL21(D ⁇ 3).
  • the cell paste was resuspended in 4 cell paste volumes of lysis buffer containing 100 mM MES (pH 6.5), 100 mM NaCl, 1 mM EDTA, 1 mM DTT, 1 mM PMSF, 20 U/mL Benzonase, 0.5 mg/mL lysozyme, and 1 mM MgCl 2 and incubated for 35 minutes at room temperature.
  • the cells were lysed at 11,000 psi using a
  • test compounds in 5 ⁇ L of 10% DMSO were incubated for 5 minutes at room temperature in assay buffer (25 ⁇ l) containing 20 ⁇ M ⁇ IRK substrate in a round-bottom microtiter plate(Costar) pre-coated with 1% bovine serum albumin.
  • the assay was initiated by the addition of protein tyrosine phosphatase IB enzyme (20 ⁇ l )in assay buffer. After 10 minutes of incubation at room temperature, the reaction was terminated by the addition of 100 ⁇ L of malachite green (Upstate Biotechnology Inc.) containing 0.01% Tween-20. After a 5 minute incubation, quantitation of free phosphate released from the ⁇ IRK substrate was determined in a Victor II plate reader (Wallac; Turku, Finland) by measuring the absorbence of the malachite green at 620 nm.
  • the instant compounds were found to inhibit protein tyrosine phosphatase IB with inhibitory potencies in a range of about 0.05 ⁇ M to about 100 ⁇ M. In a preferred range, the compounds inhibited protein tyrosine phosphatase IB with inhibitory potencies in a range of about of about 0.05 ⁇ M to about 60 ⁇ M; and in a more prefened range, the compounds inhibited protein tyrosine phosphatase IB with inhibitory potencies in a range of about of about 0.05 ⁇ M to about 21 ⁇ M.
  • the instant compounds are useful for treating diseases caused by overexpressed or altered protein tyrosine phosphatase IB activity.
  • diseases include autoimmune diseases, acute and chronic inflammatory diseases, osteoporosis, obesity, cancer, malignant diseases, and type I and type II diabetes.
  • dba dibenzylideneacetone
  • DMSO dimethylsulfoxide
  • NMP N-methylpynolidinone
  • DMF N,N-dimethylformamide
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • ED AC l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate.
  • compounds of formula (2) (R is alkyl; X is Br or I) can be reacted with compounds of formula (3) (R is aryl or heteroaryl) in the presence of a palladium catalyst and base to form compounds of formula (4).
  • a palladium catalyst and base to form compounds of formula (4).
  • Representative palladium catalysts include Pd 2 ba 3 with 2-dicyclohexylphosphino-2'-(N,N- dimethyl)aminobiphenyl, Pd 2 dba 3 with tricyclohexylphosphine, and Pd 2 dba 3 with PPI1 3 .
  • Representative bases include sodium hydride, potassium hydride, and calcium hydride. Examples of solvents used in these reactions include benzene and toluene.
  • the reaction temperature is about 60 °C to about 110 °C and depends on the method chosen. Reaction times are typically about 2 to about 8 hours.
  • Compounds of formula (4) can be converted to compounds of formula (I) (R is hydroxy, R is carboxy) by treatment with an oxidizing agent.
  • Representative oxidizing agents include KM11O 4 , ozone and hydrogen peroxide, and Cr ⁇ 3 .
  • solvents used in these reactions include pyridine, water, and mixtures thereof.
  • the reaction temperature is about 0 °C to about 35 °C and depends on the method chosen. Reaction times are typically about 12 to about 24 hours.
  • Compounds of formula (6) can be reacted with ethyl chloro(oxo)acetate (7) in the presence of base to provide compounds of formula (8).
  • Representative bases include pyridine, friethylamine, and diisopropylethylamine.
  • solvents used in these reactions include diethyl ether, methyl tert-butyl ether, and dioxane.
  • the reaction temperature is about 20 °C to about 30 °C. Reaction times are typically about 8 to about 18 hours.
  • reaction temperature is about 70 °C to about 100 °C. Reaction times are typically about 4 to about 12 hours.
  • Example 1A methyl (2E)-3 -(2-bromophenyl)-2-propenoate
  • a solution of (2E)-3-(2-bromophenyl)-2-propenoic acid (1.53 g, 6.74 mmol) in N,N-dimethylformamide (10 mL) at room temperature was treated with K 2 CO 3 (900 mg, 6.51 mmol) and iodomethane (0.5 mL, 8.0 mmol), stined for 3 hours, poured into H 2 O (50 mL) and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (MgSO 4 ), filtered, and concentrated to provide the desired product.
  • K 2 CO 3 900 mg, 6.51 mmol
  • iodomethane 0.5 mL, 8.0 mmol
  • Example IB ethyl (2E)-3 -(2-bromophenyl)-2-propenoate
  • a mixture of Example 1A (135 mg, 0.56 mmol), 1-aminonaphthalene (80 mg, 0.56 mmol), tris(dibenzylideneacetone)-dipalladium(0) (3 mg, 0.003 mmol), 2- dicyclohexylphosphino-2'-(N,N-dimethyl)aminobiphenyl (4 mg, 0.01 mmol), and 60% NaH dispersion in mineral oil (50 mg, 1.2 mmol) in toluene (2 mL) was heated to reflux for 5.5 hours diluted with water (10 mL) and IN HC1 (5 mL), and extracted with ethyl acetate.
  • Example IC 2-((carboxycarbonyl)( 1 -naphthyl)amino)benzoic acid
  • pyridine 1.2 mL
  • KMnO 4 210 mg, 1.3 mmol
  • the mixture was treated with methanol (0.2 mL), stined for 5 minutes, treated with IN NaOH (4 mL), and filtered through diatomaceous earth (Celite ).
  • the filter cake was washed with water (15 mL) and the combined filtrates were washed with diethyl ether, cooled to 0 °C, adjusted to pH ⁇ 7 with 12N HO, and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by reverse-phase HPLC with 100 % acetonitrile to 70:30 (0.1% aqueous trifluoroacetic acid)/acetonitrile provide the desired product as a 3:2 mixture of rotamers.
  • Example 3 2-((carboxycarbonyl)-4-methoxyanilino)benzoic acid
  • 4-methoxyaniline (246 mg, 2 mmol)
  • diphenyliodonium-2- carboxylate monohydrate (821 mg, 2.4 mmol)
  • copper(II) acetate (18.2 mg, 0.1 mmol)
  • isopropanol (4 ml) in a sealed tube under nitrogen atmosphere was heated to 80 °C for 8 hours, cooled to room temperature, treated with IN NaOH (3 mL), and extracted with diethyl ether.
  • the aqueous phase was adjusted to pH 2 with IN HC1 and extracted with ethyl acetate.
  • the concentrate was purified by flash column chromatography on silica gel with 50:50:0.8 ethyl acetate/hexanes/acetic acid.
  • a solution of the purified concentrate (86 mg, 0.25 mmol) in ethanol (2 mL) at room temperature was treated with IN NaOH . (l mL), stined for 30 minutes, treated with IN HC1 (2 mL), and purified by reverse-phase HPLC with acetonitrile to 95:5 (0.1% aqueous trifluoroacetic acid)/ acetonitrile provide the desired product.
  • MS (ESI(-)) m/e 314 (M-H) " ; H NMR (300 MHz, DMSO-d 6 at 90
  • Example 5A 2-(2-chloro-5-methoxyanilino)benzoic acid A mixture of 2-chloro-5-methoxyaniline (260 mg, 1.65 mmol), diphenyliodonium-
  • Example 5B 2-((carboxycarbonyl)-2-chloro-5-methoxyanilino benzoic acid
  • a solution of Example 5A (354 mg, 1.27 mmol) and pyridine (0.5 mL) in ethyl acetate (5 mL) at 0 °C was treated with ethyl chloro(oxo)acetate (350 mL, 3.1 mmol), warmed to room temperature, stined for 2.5 hours, and poured into IN HCl (20 mL). The aqueous phase was extracted with diethyl ether and the combined extracts were washed with water and 2N NaOH.
  • Example 7A methyl 4-((((2S)-3-(4-aminophenyl)-2-((tert- butoxycarbonyl)amino)propanoyl)amino)methyl)cyclohexane-carboxylate
  • (2S)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid 350 mg, 1.25 mmol
  • Example 8 2-(4-((2S)-2-((tert-butoxycarbonyl)amino)-3-(((4-carboxycyclohexyl)methyl)amino)-3- oxopropyl)(carboxycarbonyl)anilino)benzoic acid
  • the desired product was isolated in the HPLC purification of Example 7B as a mixture of rotamers.
  • Example 9 2-((carboxycarbonyl)-2-iodoanilino)benzoic acid '
  • the desired product was prepared by substituting 2-iodoaniline for 4- methoxyaniline in Example 3.
  • MS (ESI(+)) m e 412 (M+H) + ; 1H NMR (300 MHz, DMSO-d 6 ) ⁇ 7.95 (dd, IH), 7.82 (dd, IH), 7.50-740 (m, 3H), 7.37 (dd, IH), 7.31 (d, IH), 7.04 (td, IH).
  • Example 11 2-((carboxycarbonyl)-3 -(trifluoromethyl)anilino)benzoic acid
  • the desired product was prepared by substituting 3-trifluoromethylaniline for 4- methoxyaniline in Example 3.
  • MS (ESI(-)) m/e 352 (M-H) " ; 1H NMR (300 MHz, DMSO-d 6 ) ⁇ 7.93 (m, IH), 7.83-7.65 (m, 3H), 7.64-7.55 (m, 2H), 7.54-7.38 (m, 2H).
  • Example 12 2-((carboxycarbonyl)(cyclobutyl)amino)benzoic acid The desired product was prepared by substituting cyclobutylamine for cyclohexylamine in Example 22. MS (APCI(+)) m/e 264 (M+H) + ; H NMR (500 MHz,
  • CD 3 CN CD 3 CN) ⁇ 8.00 (dd, IH), 7.66 (dt, IH), 7.53 (dt, IH), 7.32 (dd, IH), 4.86-4.79 (m, IH), 2.23-2.10 (m, IH), 1.95-1.90 (m, 2H), 1.70-1.64 (m, 2H), 1.64-1.60 (m, IH).
  • Example 13 A 7-(benzy loxy)- 1 -naphthalenamine
  • 8-amino-2-naphthol (1.59 g, 10.0 mmol) in IN KOH in methanol (10 mL) was concentrated, dissolved in N,N-dimethylformamide (10 mL), treated with benzyl bromide (1.2 mL, 10.1 mmol), stined for two hours, poured into H2O (50 mL), and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 70:30 hexanes/ethyl acetate to provide the desired product.
  • Example 13B 2-((7-(benzyloxy)- 1 -naphthyl)(carboxycarbonyl)amino)benzoic acid
  • the desired product was prepared as a mixture of rotamers by substituting Example 13A for 1-aminonaphthalene in Example 1.
  • Example 15 2-((carboxycarbonyl)-2-methylanilino)benzoic acid
  • the desired product was prepared by substituting ethyl (2E)-3-(2-bromophenyl)-2- propenoate and 2-methylaniline for Example 1 A and 2-aminonaphthalene, respectively, in
  • Example 16 2-((carboxycarbonyl)(2-methyl- 1 H-indol- 1 -yl)amino)benzoic acid
  • the desired product was prepared by substituting 2-methyl-l H-indol- 1 -amine for 4-methoxyaniline in Example 3.
  • MS (ESI(+)) m e 339 (M+H) + ; 1H NMR (300 MHz, DMSO-d 6 ) ⁇ 7.63-7.32 (m, 4H), 7.23-6.92 (m, 3H), 644-6.33 (m, IH), 6.26 (s, IH), 2.36
  • Example 17 2-((carboxycarbonyl)(7-hydroxy- 1 -naphthyl)amino)benzoic acid
  • the concentrate was purified by reverse-phase HPLC with acetonitrile to 70:30 (0.1% aqueous trifluoroacetic acid)/acetonitrile to provide the desired product as a 5:3 mixture of rotamers.
  • MS (ESI(+)) m/e 374 (M+Na) + ; 1H NMR (300 MHz, DMSO-d 6 ) ⁇ 10.04 (br s, IH), 9.91 (br s, IH), 7.87 (dd, 2H), 7.83 (d, 2H), 7.79 (d, IH), 7.61 (dd, IH), 7.55-7.21 (m, 5H), 7.16 (dd, IH), 7.12 (dd, IH), 6.92 (d, IH).
  • Example 18A 1 -(7-(benzyloxy)- 1 -naphthyl)-2( 1 H)-quinolinone
  • the desired product was prepared by substituting Example 13 A for 1- aminonaphthalene in Example IB.
  • Example 18B 1 -(7-hydroxy- 1 -naphthyl)-2( 1 H)-quinolinone
  • Example 18A (397 mg, 1.05 mmol) at room temperature was treated with 33% HBr in acetic acid (6 mL), stined for 1 hour, poured into water (30 mL), and extracted with ethyl acetate.
  • Example 18B l-(7-((6-phenylhexyl)oxy)-l-naphthyl)-2(lH)-quinolinone
  • 6-phenyl- 1 - hexanol 31 mg, 0.17 mmol
  • Example 18A 50 mg, 0.17 mmol
  • triphenylphosphine 46 mg, 0.17 mmol
  • THF 1 mL
  • diethylazodicarboxylate 30 mL, 0.19 mmol
  • the concentrate was dissolved in 1 :1 ethyl acetate/hexanes, decanted, concentrated, and purified by flash column chromatography on silica gel with 1 : 1 ethyl acetate/hexanes to provide the desired product.
  • Example 19 2-(( 1 , 1 '-biphenyl)-2-yl(carboxycarbonyl)amino)benzoic acid
  • the desired product was prepared as a mixture of rotamers by substituting (1,1'- biphenyl)-2-amine for 4-methoxyaniline in Example 3.
  • MS (ESI(-)) m/e 360 (M-H) " ; H
  • Example 21 2-((carboxycarbonyl)(5,6,7,8-tetrahydro-l-naphthalenyl)amino)benzoic acid
  • the desired product was prepared as a mixture of rotamers by substituting 5,6,7,8- tetrahydro-l-naphthalenarnine for 1-aminonaphfhalene in Example 1.
  • Example 22B methyl 2-(cyclohexyl(ethoxy(oxo)acetyl)amino)benzoate
  • a solution of Example 22A (23 mg, 0.1 mmol) in diethyl ether (1 mL) at room temperature was treated with pyridine (15 mL) and ethyl chloro(oxo)acetate (15 mL), stined for 15 hours, diluted with IN HCl (5 mL), and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 70:30 ethyl acetate/hexanes to provide the desired product.
  • Example 24 2-((carboxycarbonyl)(3-methylcyclohexyl)amino)benzoic acid
  • the desired product was prepared as mixtures of diastereomers and rotamers by substituting 3-methylcyclohexylamine for cyclohexylamine in Example 22.
  • Example 25-33 can be prepared:
  • Example 34A toluene-4-sulfonic acid l-amino-naphthalen-2-yl ester A mixture of 1 -amino-2-naphthol hydrochloride (3g, 15 mmol), ⁇ toluenesulfonyl chloride (2.9g, 15 mmol) and triethylamine (4.3mL, 31 mmol)in dichloromethane (150 mL) was stined at ambient temperature for 18hours, diluted with additional methylene chloride, washed with water, brine, dried (MgSO ), filtered, and concentrated under reduced pressure.
  • 1 -amino-2-naphthol hydrochloride 3g, 15 mmol
  • ⁇ toluenesulfonyl chloride 2.9g, 15 mmol
  • triethylamine 4.3mL, 31 mmol
  • dichloromethane 150 mL
  • Example 34B 2- 2-(toluene-4-sulfonyloxy)-naphthalen- 1 -ylamino] -benzoic acid
  • the desired product was prepared according to the method described in Example 48E using diphenyliodonium-2-carboxylate and toluene-4-sulfonic acid 1-amino- naphthalen-2-yl ester.
  • the combined ethyl acetate layers were dried (MgSO 4 ), filtered, concentrated under reduced pressure and purified via silica gel chromatography eluting with 1 :1 hexanes: ethyl acetate to provide the oxalamide ethyl ester 395mg (99%).
  • the ester was taken up in a mixture of 1.39 M NaOH (8 mL) in 20% aqueous ethanol (20 mL) and stined at ambient temperature for 16 hours. The solvents were removed under reduced pressure, the residue was taken up in water, acidified to a pH of 2 with IM HCl, and extracted with ethyl acetate.
  • Example 35A 2-acetylamino-3-(4-amino-naphthalen-l-yl)-acrylic acid methyl ester To a mixture of 4-bromo-l-naphthylamine (2.5 g, 11.3 mmol), Pd(OAc) 2 (140 mg,
  • aqueous layer was extracted once with ethyl acetate and the combined organic layers were washed with brine, dried (Na SO 4 ), filtered, concentrated under reduced pressure and purified on a silica gel to provide the titled compound (2.5 g, 76%).
  • Example 35D 2-acetylamino-3-(4-amino-naphfhalen- 1 -yl)-N-pentyl-propionamide
  • 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid 500 mg, 1.84 mmol
  • l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (493 mg, 2.57 mmol)
  • 1-hydroxybenzotriazole hydrate 360 mg, 2.21 mmol
  • amylamine 320 ⁇ L
  • Example 35F 2- ⁇ r4-(2-acetylamino-2-pentylcarbamoyl-ethyl)-naphthalen- 1 -yll-ethoxyoxalyl-amino ⁇ - benzoic acid
  • 2-[4-(2-acetylamino-2-pentylcarbamoyl-ethyl)-naphthalen- 1 - ylamino] -benzoic acid (790 mg, 1.71 mmol) and triethylamine (680 ⁇ L, 5.13 mmol) in dichloromethane (10 mL) was cooled to 0 °C, treated slowly with ethyl oxalyl chloride (452 ⁇ L, 4.04 mmol) over 30 min, warmed to room temperature, stined for 16 hours, treated with IN HCl (4 mL), and extracted with dichloromethane (2 x 20 mL).
  • Example 36A 2-(2-amino-5-bromo-phenyl)-ethanol To a solution of 2-aminophenethyl alcohol (10. Og, 72.9 mmol) in acetic acid (60 L) at 10 °C was added Br (3.8 mL, 72.9 mmol) in acetic acid (5 mL). Additional acetic acid (30 mL) was added and the reaction was stined for 1 hour. The mixture was filtered and the filter cake washed with diethyl ether. The solid was then partitioned between ethyl acetate and aqueous 3N NaOH. The organic layer was washed with brine, dried (Na SO 4 ), filtered and concentrated under reduced pressure to provide the titled compound (15.8 g).
  • Example 36B 4-bromo-2-( 1 -methyl- 1 -trimethylsilany l-ethoxymethyl)-phenylamine
  • 2-(2-amino-5-bromo-phenyl)-ethanol 15.8 g, 72.8 mmol
  • anhydrous N,N-dimethylformamide 50 mL
  • imidazole 6.0 g, 88.1 mmol
  • tert-butyl dimethylsilyl chloride (12.0 g, 79.6 mmol) sequentially.
  • the resulting mixture was stined at ambient temperature for 1.5 hour, partitioned between water and ethyl acetate.
  • Example 36C 2-acetylammo-3-r4-amino-3-(2-hydroxy-ethyl)-phenyll-propionic acid The titled compound was prepared according to the procedure described in
  • Example 79 B-C substituting 4-bromo-2-(l -methyl- 1-trimethylsilanyl-ethoxymetbyl)- phenylamine for the 4-bromo-2-ethylalanine.
  • the tert butyldimethyl silyl protecting group came off during the hydrogenation step as described in Example 79C.
  • MS (ESI+) m/e 381 (M+H) + .
  • Example 36D N-acetyl-4-r(carboxycarbonyl)(2-carboxyphenyl)aminol-N-pentyl-3-(2-hydroxyethane)- phenylalaninamide
  • the titled compound was prepared according to the procedure described in 35 C-G by substituting 2-acetylamino-3-[4-amino-3-(2-hydroxy-ethyl)-phenyl]-propionic acid for 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid.
  • MS (ESI+) m e 528 (M+H) , 545 (M+NH 4 ); 1H NMR (300 MHz,DMSO-d 6 ) (A mixture of rotamers) ⁇ 8.14-7.58 (m,
  • Example 37 4-r(carboxycarbonyl)(2-carboxyphenyl)amino1-6- ⁇ [N-acetyl-3-(l- naphthyl)alany!1 amino ⁇ hexanoic acid
  • the titled compound was prepared according to the procedure described in 35 D-G by substituting 6-amino-hexanoic acid methyl ester HCl salt for amylamine.
  • the titled compound was prepared according to the procedure described in Example 35 D substituting ⁇ -boc p-amino phenylalanine for 2-acetylamino-3-(4-amino- naphthalen- 1 -yl)-propionic acid.
  • Example 38B r2-(4-amino-3-iodo-phenyl)-l-pentylcarbamoyl-ethyll-carbamic acid tert-butyl ester
  • acetic acid 5 mL
  • Nal 0.59g, 3.9 mmol
  • chloramines-T trihydrate l.lg, 3.9 mmol
  • Example 38C 2-r4-(2-tert-butoxycarbonylamino-2-pentylcarbamoyl-ethyl)-2-iodo-phenylaminol- benzoic acid
  • a stined suspension of [2-(4-amino-3-iodo-phenyl)-l-pentylcarbamoyl-ethyl]- carbamic acid tert-butyl ester 222mg, 0.47 mmol
  • diphenyliodonium-2-carboxylate monohydrate 168mg, 0.49 mmol
  • N,N-dimethylformamide 5 mL
  • Example 38E 4-r(carboxycarbonyl)(2-carboxyphenyl)amino1-3-r(lE)-3-amino-3-oxo-l-propenyll-N- (tert-butoxycarbonyl)-N-pentyl-L-phenylalaninamide
  • Example 39B N-acetyl-4- [(carboxy carbonyl)(2-carboxyphenyl)amino1 -3 -isopropyl-N- pentylphenylalaninamide
  • the titled compound was prepared according to the procedure described in
  • Example 35 D-G substituting 2-acetylamino-3-(4-amino-3-isopropyl-phenyl)-propionic acid from Example 39A for 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid in Example 35 D.
  • MS (ESI(+)) m/e 526 (M+H) + , 543(M+NH 4 ) + ; 1H NMR (500 MHz, DMSO-d 6 ) A mixture of rotamers: ⁇ 7.90-8.16 (m, 2H), 6.73-7.60 (m, 4H), 4.40-4.52 (m, c.a. 0.6 H), 2.7-3.3 (m, c.a. 5.4H), 1.77 and 1.74 (s, 3H), 1.1-141 (m, 11H), 0.62-0.90 (m, 3H).
  • Example 40A 2-acetylamino-3 -(4-amino-3 -piperidin- 1 -yl-pheny l)-propionic acid
  • the desired product was prepared according to the procedure described in Example
  • Example 41 A 3 -Methyl- 1 -(2-nitro-phenyl)-piperidine
  • 3-methylpiperidine 0.848 mL, 7.22 mmol
  • 2-chloronitrobenzene (1.04g, 6.57 mmol)
  • diisopropylethylamine (1.26 mL, 7.22 mmol) in DMSO (5 mL)
  • the mixture was cooled to ambient temperature then partioned between a mixture of ethyl acetate :hexane (1:1) and water (1:1, 75 mL total).
  • Example 42 2- ⁇ (carboxycarbony 1)
  • Example 42A l-(4-Methoxymethoxy-2-nitro-phenyl)-piperidine To a mixture of 4-chloro-3-nitrophenol (l.Og, 5.8 mmol) and K 2 CO 3 (1.6g, 12 mmol)in N,N-dimethylformamide (5 mL) at ambient temperature was slowly added chloromethyl methylether. After 10 min, piperidine (1.2 mL, 5.8 mmol) was added, the mixture was heated to 80 °C for 2 days, cooled to ambient temperature, partitioned between ethyl acetate and water.
  • Example 42B 2- [(5 -methoxymethoxy-2-piperidin- 1 -yl-phenyl)-oxaly 1-amino] -benzoic acid
  • the titled compound was prepared according to the procedure described in Example 41B-C, substituting the l-(4-methoxymethoxy-2-nitro-phenyl)-piperidine for 3- methyl- l-(2-nitro-phenyl)-piperidine in Example 41 B.
  • MS (ESI+) m/e 429 (M+H) + MS (ESI+) m/e 429 (M+H) + .
  • Example 42C 2- ⁇ (carboxy carbonyl) [5 -hy droxy-2-( 1 -piperidiny Dphenyl] amino ⁇ benzoic acid
  • a solution containing 2-[(5-methoxymethoxy-2-piperidin-l-yl-phenyl)-oxalyl- amino] -benzoic acid (25mg, 0.058 mmol) in methylene chloride/trifluoroacetic acid (2 mL, 1 :1, v:v) was stined at ambient temperature for 2hours, concentrated under reduced pressure, taken up in diethyl ether and filtered. The filter cake was dried to constant weigh to provide the titled compound (15 mg, 67%).
  • Example 43B 2-methanesulfonylamino-3-(4-nitro-phenyl)-N-pentyl-propionamide
  • 2-amino-3-(4-nitro-phenyl)-N-pentyl-propionamide 368mg, 1.3 mmol
  • triethylamine 500 ⁇ L, 3.6 mmol
  • methane sulfonyl chloride 122 ⁇ L, 1.6 mmol
  • the reaction mixture was partitioned between ethyl acetate and aqueous 3N HCl.
  • the organic layer was washed with aqueous NaHCO 3 , brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to provide the titled compound.
  • the titled compound was prepared according to the procedure described for Example 5 OB, substituting 2-methanesulfonylamino-3-(4-nitro-phenyl)-N-pentyl- propionamide for [2-(4-nitro-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester.
  • Example 43 D 3-(4-amino-3-iodo-phenyl)-2-methanesulfonylamino-N-pentyl-propionamide
  • the titled compound was prepared according to the procedure described for Example 38B, substituting 3-(4-amino-phenyl)-2-methanesulfonylamino-N-pentyl- propionamide for [2-(4-amino-3-iodo-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester.
  • Example 43E 4- r (carboxycarbonyl)(2-carboxyphenyl)amino " l-3 - ⁇ (1 E)-3 -amino-3 -oxo- 1 -propenyl "
  • the titled compound was prepared according to the procedure described for Example 38 C-E, substituting 3-(4-amino-3-iodo-phenyl)-2-methanesulfonylamino- ⁇ - pentyl-propionamide for 2-[4-(2-tert-butoxycarbonylamino-2-pentylcarbamoyl-ethyl)-2- iodo-phenylaminoj-benzoic acid.
  • Example 44 4-f(carboxycarbonyl)(2-carboxyphenyl)amino1-3-(3-amino-3-oxopropyl)-N- r(isopropylamino)carbonyl1-N-pentyl-L-phenylalaninamide
  • the titled compound was prepared according to the procedure described for Example 43B, substituting i-propyl isocyanate for the methane sulfonyl chloride.
  • Example 46 A ri-(2-amino-phenyl)-piperidin-4-yl]-methanol
  • the titled compound was prepared according to the procedure described in Example 41 by substituting 3-methylpiperidine with piperidin-4-yl-methanol.
  • Example 46B 2-((carboxycarbonyl) ⁇ 2-[4-(hydroxymethyl)-l-piperidinynphenyl ⁇ amino)benzoic acid
  • the desired product was prepared according to the procedure described in Example 3 by substituting [l-(2-amino-phenyl)-piperidin-4-yl]-methanol for 4-methoxyaniline.
  • MS (ESI(+)) m/e 399 (M+H) + ; 1H ⁇ MR (500 MHz, DMSO-d 6 ) a mixture of rotamers: ⁇ 7.80
  • Example 48 E 2-(4- ⁇ 2-(R)-acetylamino-2-r(S)-l-methylcarbamoyl-2-(4-nifro-phenyl)-ethylcarbam ⁇ yijl ethyl ⁇ -2-ethyl-phenylamino)-benzoic acid and 2-(4- ⁇ 2-(S)-acetylamino-2-[YS -l- methylcarbamoyl-2-(4-nitro-phenyl)-ethylcarbamoyl]-ethyl ⁇ -2-ethyl-phenylamino)- benzoic acid To a mixture of 2-(S)-[2-(S)-acetylamino-3-(4-amino-3-ethyl-phenyl)- propionylamino]-N-methyl-3-(4-nitro-phenyl)-propionamide and 2-(S)-[2-(R)- acetylamino-3
  • the mixture was stined at 100 °C under N 2 for 17 hours, poured into 0.2M NaOH (lOmL) and extracted with hexanes (3x5mL), using methanol to break emulsions.
  • the aqueous layer was acidified to a pH ⁇ 3 with IM HCl and extracted with ethyl acetate (3 x 5mL).
  • the combined ethyl acetate layers were extracted with IM HCl (1 x 3mL), brine (1 x 3mL), dried (MgSO 4 ), filtered, and concentrated under reduced pressure.
  • the residue was precipitated from ethyl acetate to provide the titled compound as a mixture of both diastereomers (58mg, 19%).
  • Example 48 F 2-
  • the mixture was stined at ambient temperature for 2.5hours followed by the addition of 2M NaOH (2mL) and was stined for 10 min.
  • the mixture was diluted with water (3mL), acidified to a pH ⁇ 3 with IM HCl and extracted with ethyl acetate (3 x 5 mL).
  • the combined ethyl acetate layers were extracted with brine (1 x 5mL), dried (MgSO 4 ), filtered, and concentrated under reduced pressure. The residue was precipitated with ethyl acetate to provide the titled compound (14mg, 37%) !
  • Example 49A 2-amino-3-(4-amino-3-iodo-phenyl)-N-pentyl-propionamide
  • the titled compound was prepared according to the procedure described in Example 43A, substituting [2-(4-amino-3-iodo-phenyl)-l-pentylcarbamoyl-ethyl]- carbamic acid tert-butyl ester from 38B for [2-(4-nitro-phenyl)-l-pentylcarbamoyl-ethyl]- carbamic acid tert-butyl ester.
  • Example 49B ⁇ 1 - [2-(4-amino-3 -iodo-phenyl)- 1 -pentylcarbamoyl-ethylcarbamoyl] -2-phenyl-ethyl
  • the titled compound was prepared according to the procedure described for Example 35 D, substituting L-N-boc phenylalanine for 2-acetylamino-3-(4-amino- naphthalen-l-yl)-propionic acid from example 35C and substituting 2-amino-3-(4-amino- 3-iodo-phenyl)- ⁇ -pentyl-propionamide from Example 49A for the amylamine.
  • the titled compound was prepared according to the procedure described in Example 43 A and 35D respectively, substituting ⁇ l-[2-(4-amino-3-iodo-phenyl)-l- pentylcarbamoyl-ethylcarbamoyl]-2-phenyl-ethyl ⁇ -carbamic acid tert-butyl ester for [2-(4- nitro-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester in procedure 43A, and substituting the resulting amine for amylamine, and the methyl monosuccinate for 2- acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid in procedure 35D.
  • Example 38 C-E substituting the N- ⁇ l-[2-(4-Amino-3-iodo-phenyl)-l-pentylcarbamoyl- ethylcarbamoyl]-2-phenyl-ethyl ⁇ -succinamic acid methyl ester for the [2-(4-Amino-3- iodo-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester in Example 38C.
  • MS (ESI+) m/e 758 (M+H) + MS (ESI+) m/e 758 (M+H) + .
  • Example 50 A [2-(4-nitro-phenyl)-l-pentylcarbamoyl-ethyl] -carbamic acid tert-butyl ester A solution of N-(t-butoxycarbonyl)-4-nitro-L-phenylalanine (10.0 g, 32.2 mmol), amylamine (4.9 mL, 42 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.0 g, 42 mmol), and 3 -hydroxy- 1, 2,3 -benzotriazin-4(3H)-one (5.8 mg, 35 mmol) in ⁇ , ⁇ -dimethylformamide (20 mL) was adjusted to p ⁇ 7 with triethylamine and stined overnight.
  • Example 50B r2-(4-amino-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester
  • Example 50D 2-
  • Example 50G 2- ⁇ r4-(2-amino-2-pentylcarbamoyl-ethyl)-phenyl1-tert-butoxyoxalyl-amino ⁇ -benzoic acid benzhydryl ester
  • 2- ⁇ [4-(2-allyloxycarbonylamino-2-pentylcarbamoyl-ethyl)- phenyl]-tert-butoxyoxalyl-amino ⁇ -benzoic acid benzhydryl ester (2.50 g, 3.35 mmol) in methylene chloride (50 mL) was added tetrakis(triphenylphosphine)palladium(0) (193 mg,
  • the mixture was concentrated under reduced pressure and purified on silica using 1-3 %
  • Example 501 3-(4-benzoylphenyl)-N-(tert-butoxycarbonyl)-L-alanyl-3- ⁇ 4-[(carboxycarbonyl)(2- carboxyphenyl)amino]phenyll-N ⁇ l— pentyl-L-alaninamide
  • a solution of 2-[(4- ⁇ 2-[2-(3-benzoyl-phenyl)-2-tert-butoxycarbonylamino- acetylamino] -2 -pentylcarbamoyl-ethyl ⁇ -phenyl)-tert-butoxyoxalyl-amino] -benzoic acid benzhydryl ester (515 mg, 0.507 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (3 mL) was stined for 3 hours, concentrated to constant weight under reduced pressure.
  • Example 35 C-E substituting the 4-methanesulfonyl-benzylamine for the amylamine, and 2-acetylamino-3-[4-amino-3-(2-hydroxy-ethyl)-phenyl]-propionic acid for 2-acetylamino- 3-(4-amino-naphthalen-l-yl)-propionic acid used in Example 35D.
  • Example 52 A 8-nitro-naphthalene-2-carboxylic acid ethyl ester
  • a cold nitric acid solution [prepared by adding fuming nitric acid (5.15 mL, 12.0 mmol) dropwise over 15 minutes to cooled (-10 °C) Ac 2 O (25 mL)] was added dropwise over 10 minutes to a cooled (-10 °C) solution of 2-naphthoic acid (19.0 g, 11.0 mmol) in concentrated H 2 SO 4 (5 mL) and acetic anhydride (200 mL). The mixture was stirred at ambient temperature for 5 hours, poured into ice water (1 L) and filtered.
  • the precipitate was washed with H 2 O and methanol and dried under vacuum at 50 °C for 16 hours.
  • the residue was taken up in ethanol (250 mL) and concentrated H 2 SO 4 (2 mL) and the mixture was refluxed for 3 days.
  • the mixture was cooled, filtered, reduce in volume and filtered.
  • the filter cakes were combined and crystallized from ethyl acetate to provide the titled compound.
  • Example 52B 8-nitro-naphthalene-2-carboxylic acid A solution of 8-nitro-naphthalene-2-carboxylic acid ethyl ester (0.95g, 3.9 mmol) in 4:1 methanokTHF (60 mL) was treated with 2 M NaOH (10 mL) and stined for 16 hours. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate and aqueous 2 N HCl. The organic layer was washed with H O (2 x 30 mL), dried (MgSO 4 ), filtered and concentrated under reduced pressure to give the titled compound.
  • Example 52C 8-nitro-naphthalene-2-carboxylic acid amide
  • a mixture of 8-nitro-naphthalene-2-carboxylic acid (0.82 g, 3.8 mmol), pyridine (1 drop), N,N-dimethylformamide (3 drops) in methylene chloride (3 mL) was treated with thionyl chloride (303 ⁇ L, 4.2 mmol) and stined 2 days. The mixture was dried (Na SO 4 ), filtered and concentrated under reduced pressure. To a solution of the residue (650 mg, 2.76 mmol) in THF (150 mL) was added concentrated NH OH (0.5 mL) and stined 30 minutes.
  • Example 52D 8-amino-naphthalene-2-carboxylic acid amide
  • a solution of 8-nitro-naphthalene-2-carboxylic acid amide (330 mg, 1.53 mmol) and 5% Pd/C (30 mg) in methanol (3 mL) was stirred under an atmosphere of hydrogen.
  • the catalyst was filtered and the filtrate was concentrated under reduced pressure to provide the titled compound.
  • Example 52E 2-(7-carbamoyl-naphthalen- 1 -ylamino)-benzoic acid
  • the titled compound was prepared according to the procedure described in Example 50 C, substituting 8-amino-naphthalene-2-carboxylic acid amide for [2-(4- amino-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester.
  • the titled compound was prepared according to the method described by Example 50 E substituting 2-(7-carbamoyl-naphthalen-l-ylamino)-benzoic acid for 2-[4-(2- allyloxycarbonylamino-2-pentylcarbamoyl-ethyl)-phenylamino]-benzoic acid, and substitutuing ethyl oxalylchloride for t-butyloxalyl chloride.
  • the material was purified by reverse phase HPLC with 0% to 70% acetonitrile/(0.1% trifluoroacetic acid in H O).
  • the compound was a 3 :2 mixture of rotamers.
  • Example 52G 2-[[7-(aminocarbonyl)- 1 -naphthyl](carboxycarbonyl)amino]benzoic acid A solution of 2-[(7-carbamoyl-naphthalen-l-yl)-ethoxyoxalyl-amino]-benzoic acid (30 mg, 0.074 mmol) and aqueous 2 M NaOH (0.5 mL)in methanol (2 mL) was stirred for 3 hours, acidified with aqueous 2N HCl and purified by reverse phase HPLC eluting with
  • Example 54 A 2-bromo-4-nitrobenzoic acid To a solution of 2-bromo-4-nitrotoluene (7.0g, 32 mmol) that was dissolved in sulfuric acid (98%, 50mL) and placed in a water bath to maintain ambient temperature was added dropwise a solution of chromium trioxide (7.5g, 75 mmol) in water (8mL). Following addition, the mixture was poured onto 200mL of ice, the precipitate was collected and washed with water (1 x 100 mL). The crade product was taken up in diethyl ether (50mL), extracted with aqueous NaHCO 3 solution (2 x 25 mL). The combined bicarbonate layers were acidified by the addition of 12M HCl, extracted with diethyl ether
  • Example 54B methyl 2-bromo-4-nitrobenzoate To a solution containing 2-bromo-4-nitrobenzoic acid (l.Og, 4.06 mmol) and K 2 CO (560 mg) in N,N-dimethylformamide (5 mL) was added methyl iodide (500 ⁇ L,
  • Example 54C methyl-2-bromo-4-aminobenzoate
  • a solution of methyl 2-bromo-4-nitrobenzoate (970mg, 3.73 mmol), iron powder 1.25g (22.4 mmol) and ammonium chloride (239 mg, 4.48 mmol) in aqueous 2-propanol (20 %, 15mL) was heated to reflux for 30minutes, cooled, filtered, and concentrated under reduced pressure. The residue was partitioned between diethyl ether (20mL) and water (5mL). The organic layer was washed with brine (1 x 5mL), dried (MgSO 4 ), filtered, and concentrated to provide the titled compound (813mg, 95%).
  • Example 54D methyl-2-bromo-4-hydroxybenzoate To a mixture of methyl-2-bromo-4-aminobenzoate (813mg, 3.53 mmol) in water (lOmL) and 98% H 2 SO 4 (lmL) at 0 °C was added a solution of aqueous NaNO 2 (244mg,
  • Example 54F benzyl-2-bromo-4-benzyloxybenzoate To 2-bromo-4-hydroxybenzoic acid (1 62mg, 0.747mmol) was added IM KOH in methanol (1.5mL). The mixture was stined until all material had dissolved, then concentrated under reduced pressure. The residue was taken up in N,N- dimethylformamide (3mL) and methanol (0.5mL) followed by the addition of benzyl bromide (300 ⁇ L, 1.68 mmol) and K CO 3 (150mg, 1.08 mmol). The mixture was heated to 90 °C for lOmin, poured into H 2 O (lOmL) and extracted with diethyl ether (3 x 5mL). The combined organic layers were washed with water (1 x 5mL), brine (1 x 5mL), dried (MgSO 4 ), filtered, and concentrated under reduced pressure to provide the titled compound (285mg, 96%).
  • Example 54G 2-(tert-butyldimethylsilyloxy)-8-aminonaphthalene A mixture of 8-amino-2-naphthol (3.18g, 20.0 mmol), tert-butyl-dimethylsilyl chloride (3.6g, 24 mmol) and imidazole (2.8g, 41 mmol) in N,N-dimethylformamide(
  • Example 54H 4-benzyloxy-2-[7-(tert-butyl-dimethyl-silanyloxy)-naphthalen-l-ylamino]-benzoic acid benzyl ester
  • Example 541 4-hydroxy-2-(7-hydroxy-naphthalen- 1 -ylamino)-benzoic acid
  • Example 54J 4-hydroxy-2-[(7-hydroxy-naphthalen-l-yl)-oxalyl-amino]-benzoic acid
  • 4-hydroxy-2-(7-hydroxy-naphthalen-l-ylamino)-benzoic acid 134mg, 0.454 mmol
  • triethylamine 0.6 mL, 4.3 mmol
  • ethyl oxalyl chloride 0.3 mL, 2.7 mmol
  • the reaction was stined at ambient temperature for 25 minutes, 2M NaOH (5mL) was added, stined for an additional 30 minutes, then diluted with water (15 mL) and extracted with diethyl ether (2 x 5 mL).
  • the aqueous layer was acidifiedto a pH ⁇ 3 with IM HCl, extracted with diethyl ether (3 x 5 mL).
  • the aqueous layer was extracted with ethyl acetate (3 x 5mL).
  • the combined ethyl acetate layers were washed with brine (1 x 5 mL), dried (MgSO 4 ), filtered, and concentrated under reduced pressure to provide the titled compound (37mg, 22%).
  • Example 55C 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid A mixture of 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-acrylic acid benzyl ester
  • 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid allyl ester A mixture of 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid (2.0 g, 8.0 mmol), Cs 2 CO 3 (2.61 g, 8.0 mmol) and allyl bromide (692 ul, 8.0 mmol) in N,N- dimethylformamide (40 mL) was stined at room temperature for 3 hours, concentrated under reduce pressure and partitioned between ethyl acetate and water (1 OOmL, 1:1).
  • Example 55E 2- ⁇ [4-(2-acetylamino-2-allyloxycarbonyl-ethyl)-2-ethyl-phenyl]-tert-butoxyoxalyl- amino ⁇ -benzoic acid
  • the titled compound was prepared according to the method described in Example 3 by substituting 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid allyl ester for
  • -benzoic acid benzhydryl ester A mixture of 2- ⁇ [4-(2-acetylamino-2-allyloxycarbonyl-ethyl)-2-ethyl-phenyl]-tert- butoxyoxalyl-amino ⁇ -benzoic acid benzhydryl ester (3.4 g, 4.8 mmol), Pd(Ph 3 P) 4 (166 mg, 0.144 mmol) and mo ⁇ holine (0.5 ml, 5.8 mmol) in dichloromethane (25 mL) was stined under N 2 atmosphere for 2 hours, partitioned between ethyl acetate and water (75 mL, 1:1). The organic phase was washed with IN HCl (1 x 25 mL), brine
  • Example 551 2-[(4- ⁇ 2-acetylamino-2-[4-(2-trimethylsilanyl-ethoxycarbonyl -butylcarbamoyll-ethyl
  • Example 55J 2-( ⁇ 4-[2-acetylamino-2-(4-carboxy-butylcarbamoyl)-ethyl]-2-ethyl-phenyl ⁇ -tert- butoxyoxalyl-amino)-benzoic acid benzhydryl ester 2-[(4- ⁇ 2-acetylamino-2-[4-(2-trimethylsilanyl-ethoxycarbonyl)-butylcarbamoyl]- ethyl ⁇ -2-ethyl-phenyl)-tert-butoxyoxalyl-amino]-benzoic acid benzhydryl ester (356 mg,
  • Example 55L N-acetyl-4- [(carboxy carbonyl)(2-carboxyphenyl)amino] -3 -ethyl-N- ⁇ 5-oxo-5-[( 1 - phenylethyl)amino]pentyl ⁇ phenylalaninamide
  • the material from Example 55K was treated with trifluoroacetic acid/dichloromethane (10 mL, 1 : 1) at ambient temperature for 3 hours, concentrated under reduced pressure and purified by HPLC eluting with 5-100% acetonitrile/ aqueous 0.1% trifluoroacetic acid to provide the titled comound (8 mg).
  • Example 56C 2-methoxycarbonylamino-3-(4-nitro-naphthalen- 1 -yl)-propionic acid
  • a mixture of 3 -(4-nitro- l-naphthyl)alanine (0.65 g, 2.5 mmol), aqueous ⁇ aHCO 3 (5 mL) and methylchloro formate (230uL, 3 mmol, 1.2 eq) in dioxane (10 mL) was stined for 3 hours, acidified to a pH ⁇ 3 with aqueous 2N HCl and extracted with ethyl acetate.
  • Example 56E 3-(4-amino-naphthalen- 1 -yl)-2-methoxycarbonylamino-propionic acid 2-trimethylsilanyl- ethyl ester A mixture of 2-methoxycarbonylamino-3 -(4-nitro-naphthalen- 1 -yl)-propionic acid
  • the reaction mixture was filtered through the frit of the Robbins reaction block into a collection block and the resin was washed with 1,2-dichloroethane.
  • the filtrate in the collection block was concenfrated under vacuum.
  • the protecting groups were removed by treatment with a solution consisting of 1,2-dichloroethane: trifluoroacetic acid: anisole (50%, 45%, 5%, 1 mL) for 3 hours.
  • the mixtures were concenfrated under reduced pressure and the crade product was purified by preparative reverse-phase HPLC.
  • Example 57 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(cyclohexylmethyl)-N- (methoxycarbonyl)naphthylalaninamide
  • the titled compound was prepared according to the method described in Example 56 J by substituting cyclohexylmethylamine for 1-pentylamine.
  • Example 58 4- [(carboxycarbony l)(2-carboxyphenyl)amino1-N-(methoxycarbonyl)-N- [( 1 ?)- 1 -(4- nitrophenyl)ethyl]naphthylalaninamide
  • the titled compound was prepared according to the method described in Example 56 J by substituting (17?)-l-(4-nitrophenyl)ethylamine for 1-pentylamine.
  • Example 60 4-r(carboxycarbonyl)(2-carboxyphenyl)amino1-N-(methoxycarbonyl)-N-(3,4,5- trifluorobenzyl)naphthylalaninamide
  • the titled compound was prepared according to the method described in Example 56 J by substituting 3,4,5-trifluorobenzylamine for 1-pentylamine.
  • Example 64 methyl 3 - ⁇ 4- [(carboxy carbony l)(2-carboxyphenyl)amino] - 1 -naphthyl ⁇ -N- (methoxycarbonyl)alanyl-L-norleucinate
  • Example 66 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4-chlorobenzyl)-N- (methoxycarbonyl)naphthylalaninamide The titled compound was prepared according to the method described in Example
  • Example 67 4-r(carboxycarbonyl)(2-carboxyphenyl)aminol-N-(4-bromobenzyl)-N- (methoxycarbonyl)naphthylalaninamide The titled compound was prepared according to the method described in Example
  • N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-(2-hydroxyethyl)-N-(4 : nitrobenzyl)phenylalaninamide The titled compound was prepared according to the procedure described in Example 35 C-G, substituting the 4-nitro-benzylamine for the amylamine, and 2- acetylamino-3-[4-amino-3-(2-hydroxy-ethyl)-phenyl]-propionic acid for 2-acetylamino-3- (4-amino-naphthalen-l-yl)-propionic acid used in Example 35D.
  • Methyl 2-nitro-4-carboxybenzoate A solution of dimethyl nitroterephthalate (5.98g, 25.0 mmol) and aqueous IM NaOH. (25 mL) in dioxane (50mL) was stined at ambient temperature for 2hours, then concentrated under reduced pressure. The remaining solution was diluted with water (50mL) and extracted with diethyl ether (3 x 25mL). The aqueous layer was acidified to a pH ⁇ 3 with IM HCl, then extracted with diethyl ether (3 x 25 mL). The second set of ether layers was washed with brine (1 x lOmL), dried (MgSO ), filtered, and concentrated under reduced pressure.
  • Example 72C benzyl-3-amino-4-methoxycarbonylbenzoate
  • Example 72D 1 -Iodo-7-hydroxynaphthalene To 8-amino-2-naphthol (448g, 30 mmol) was added a solution of 98% H 2 SO 4 (4mL) in water (50mL). The mixture was cooled with an ice bath, then a solution of aqueous NaNO 2 (2.50g, 36.2 mmol) in a minimum amount of water was added slowly via pipette, expelling the nitrite solution below the surface of the reaction. After lOmin, a solution of KI (15g, 90 mmol) in a minimum amount of water was added slowly to control the evolution of N 2 . Diethyl ether was added to break the foamy emulsion that formed and the reaction was stined for 18 hour at ambient temperature. Additional diethyl ether
  • Example 72E l-Iodo-7-dimethyl-tert-butylsilyloxynaphthalene
  • l-iodo-7-hydroxynaphthalene (3.05g, 11.3 mmol) in N,N-dimethylformamide (27mL) was added tert-butyldimethylsilyl chloride (2.09g, 13.9 mmol) and imidazole (1.85g, 27 mmol).
  • the reaction was stined at ambient temperature for 2 hours, diluted with aqueous 0.3M HCl (150mL) and extracted with hexanes (2 x 50mL).
  • Example 72F 2-r7-(tert-butyl-dimethyl-silanyloxy)-naphthalen-l-ylamino1-terephthalic acid 4-benzyl ester 1 -methyl ester
  • Example 72G 2-(7-hydroxy-naphthalen-l-ylamino)-terephthalic acid 4-benzyl ester 1 -methyl ester.
  • Example 72J 2-[(carboxycarbonyl)(7-hydroxy-l-naphthyl amino1-4-cyanobenzoic acid
  • Example 73A 4-(l ,3-dioxo- 1 ,3-dihydro-isoindol-2-ylmethyl)-benzenesulfonyl chloride The titled compound was prepared according to the procedure described in
  • Example 73 C 4-[(ethylamino)sulfonyl]benzylamine
  • a solution containing 4-(l,3-dioxo-l,3-dihydro-isoindol-2-ylmethyl)-N-ethyl benzenesulfonamide (0.84 g, 2.44 mmol) and hydrazine (0.38 mL) in methanol (5 mL) was stined under nitrogen for 14 hours diluted with aqueous NaHCO 3 and extracted with ethyl acetate.
  • Example 38 C-E substituting- ⁇ l-[2-(4-amino-3-iodo-phenyl)-l-pentylcarbamoyl- ethylcarbamoyl]-2-phenyl-ethyl ⁇ carbamic acid tert-butyl ester from Example 49B for[2- (4-amino-3-iodo-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester from Example 38B.
  • MS (ESI+) m/e 780 (M+Na) + ; 758 (M+H); No NMR data available.
  • Example 35D-E The titled compound was prepared according to the procedure described in Example 35D-E, substituting 2-acetylamino-3-[4-amino-3-(2-hydroxy-ethyl)-phenyl]- propionic acid for 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid and substituting 4-chloro-benzylamine for the amylamine in Example 35D.
  • MS (ESI+) m/e 582, 584 (M+H) + ; ! H ⁇ MR (300 MHz, DMSO-d 6 ) (A mixture of rotamers) ⁇ 8.52 (t, J-
  • Example 77 N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino1-N-(4-bromobenzyl)-3-(2- hydroxyethyl)phenylalaninamide
  • the titled compound was prepared according to the procedure described in Example 35D-G, substituting 2-acetylamino-3-[4-amino-3-(2-hydroxy-ethyl)-phenyl]- propionic acid for 2-acetylamino-3-(4-amino-naphthalen-l-yl)- ⁇ ropionic acid and 4- bromobenzylamine for the amylamine in Example 35D.
  • Example 78A 2-[7-(tert-butyl-dimethyl-silanyloxy)-naphthalen- 1 -ylamino] -4-nitro-benzoic acid methyl ester
  • the HCl layer was extracted with diethyl ether (1 x 15 mL), and the ether layer washed with brine (1 x 10 mL).
  • the combined ether and toluene layers were dried (MgSO 4 ), filtered, and concentrated under reduced pressure and the residue purified on silica gel eluting with 5% ethyl acetate: hexanes to provide the titled compound (2.58g, 52%).
  • Example 78B 2-r7-(tert-butyl-dimethyl-silanyloxy)-naphthalen-l-ylamino]-4-amino-benzoic acid methyl ester
  • 2-[7-(tert-butyl-dimethyl-silanyloxy)-naphthalen- 1 -ylamino]-4-nitro- benzoic acid methyl ester (796mg, 1.76 mmol), iron powder (580mg, 10.5 mmol), ammonium chloride (116mg, 2.16 mmol) in 2-propanol: water (8mL of 5:1, (v/v)) was heated to reflux for 1.75 hour, diluted with ethyl acetate (50mL), filtered through diatomaceous earth, and concentrated under reduced pressure. The product was purified on silica gel eluting with 20% ethyl acetate: hexanes to provide the titled compound (653mg, 88%).
  • Example 79 N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-ethyl-N-(4- nitrobenzyl)phenylalaninamide
  • Example 79A 2-Acetylamino-acrylic acid benzyl ester To a mixture of 2-acetamidoacrylic acid (10.3 g, 80.0 mmol) and K 2 CO 3 (10 g,
  • 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid allyl ester A mixture of 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid (2.0 g, 8.0 mmol), Cs 2 CO 3 (2.61 g, 8.0 mmol) and allyl bromide (692 ul, 8.0 mmol) in N,N- dimethylformamide (40 mL) was stined at room temperature for 3 hours, concentrated under reduce pressure and partitioned between ethyl acetate and water (1 OOmL, 1:1).
  • Example 79E 2- ⁇ [4-(2-acetylamino-2-allyloxycarbonyl-ethyl)-2-ethyl-phenyl]-tert-butoxyoxalyl- amino ⁇ -benzoic acid
  • the titled compound was prepared according to the method described in Example 50E by substituting 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid allyl ester for 2- ⁇ [4-(2-allyloxycarbonylamino-2-pentylcarbamoyl-ethyl)-phenyl]-tert- butoxyoxalylamino ⁇ -benzoic acid.
  • MS (APC1 (+)) m/e 539 (M+H) .
  • Example 79H The material from Example 79H was treated with trifluoroacetic acid/dichloromethane (10 mL, 1 :1) at ambient temperature for 3 hours, concentrated under reduced pressure and purified by HPLC eluting with 5-100% acetonitrile/ aqueous 0.1 % trifluoroacetic acid to provide the titled comound (8 mg). MS (ESI(+)) m/e 577 (M+H) + ;
  • Example 82 N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4- nitrobenzyl)naphthylalaninamide
  • the titled compound was prepared according to the procedure described in Example 35 D-G, substituting 4-nitro-benzylamine for the amylamine used in Example 35
  • Example 83 N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino1-N-[(17-,)-l-(4- bromophenyl)ethyl]-3-(2-hydroxyethyl)phenylalaninamide
  • the titled compound was prepared according to the procedure described in Example 35D-G, by substituting 2-acetylamino-3-[4-amino-3-(2-hydroxy-ethyl)-phenyl]- propionic acid for 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid and 4- bromo-(R)- ⁇ -methylbenzylamine for the amylamine used in Example 35D.
  • the titled compound was prepared according to the procedure described in Example 72I-J substituting n-butylamine for the aqueous ammonia in Example 721.
  • the titled compound was purified on silica gel eluting with 40% ethyl acetate: hexanes.
  • Example 85B The titled compound was prepared according to the procedure described in Example 55B-J, substituting the 4-bromo-2-piperidin-l-yl-aniline for the 4-bromo-2-ethyl- aniline in Example 55B.
  • Example 85B
  • Example 55K substituting 2-( ⁇ 4-[2-acetylamino-2-(4-carboxy-butylcarbamoyl)-ethyl]-2- piperidin-l-yl-phenyl ⁇ -tert-butoxyoxalyl-amino)-benzoic acid benzliydryl ester for 2-( ⁇ 4- [2-acetylamino-2-(4-carboxy-butylcarbamoyl)-ethyl]-2-ethyl-phenyl ⁇ -tert-butoxyoxalyI- amino)-benzoic acid benzhydryl ester, and 3 -hydroxy aniline for the 1-phenyl-ethylamine used in Example 55K.
  • Example 86 A 1 -allyl-4-nitro-benzene The titled compound was prepared according to the procedure described in JOC, 22, p. 1418, 1957.
  • Example 86B 4-allyl-phenylamine A solution of l-allyl-4-nitro-benzene (1.92 g, 11.8 mmol), ⁇ H 4 C1 (1.89g, 35.3 mmol) and iron powder (4.60g, 82.4 mmol) in 3:1 ethanol:H 2 O (200 mL) was heated to reflux overnight. The reaction was cooled, concentrated under reduced pressure and purified on silica gel eluting with ethyl acetate to provide the titled compound. MS (ESI(+)) m/e 134 (M+H) +
  • Example 86C 2-(4-allyl-phenylamino)-benzoic acid The titled compound was prepared according to the procedure described in
  • the titled compound was prepared according to the procedure described in 50E by substituting 2-(4-allyl-phenylamino)-benzoic acid for 2-[4-(2-allyloxycarbonylamino-2- pentylcarbamoyl-ethyl)-phenylamino] -benzoic acid and by substituting benzyl oxalylchloride for t-butyloxalyl chloride.
  • the material was purified on silica gel eluting with methylene chloride, 1% methanol/methylene chloride). The material was obtained as a 1 :1 mixture of rotamers.
  • Example 86E 2-[(4-allyl-phenyl)-benzyloxyoxalyl-amino]-benzoic acid benzhydryl ester
  • the titled compound was prepared according to the procedure described in Example 50F by substituting 2-[(4-allyl-phenyl)-benzyloxyoxalyl-amino]-benzoic acid for 2- ⁇ [4-(2-allyloxy carbonylamino-2-pentylcarbamoyl-ethyl)-phenyl] -tert- butoxyoxalylamino ⁇ -benzoic acid.
  • the material was obtained as a lmixture of rotamers.
  • Example 87A 2-[(4-bromo-naphthalen-l-yl)-tert-butoxyoxalyl-amino]-benzoic acid
  • the titled compound was prepared according to the procedure described in Example 50C and 50E respectively, by substituting 4-bromo-naphthalen-l-yl-amine for [2-(4-amino-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester in procedure 50C followed by substituting the product for 2-[4-(2-allyloxycarbonylamino-2- pentylcarbamoyl-ethyl)-phenylamino]-benzoic acid in procedure 50E.
  • Example 87B 2-[(4-bromo-naphthalen-l-yl)-tert-butoxyoxalyl-amino]-benzoic acid benzhydryl ester
  • the titled compound was prepared according to the procedure described in
  • Example 50F substituting 2-[(4-bromo-naphthalen-l-yl)-tert-butoxyoxalyl-amino]- benzoic acid for 2- ⁇ [4-(2-allyloxycarbonylamino-2-pentylcarbamoyl-ethyl)-phenyl]-tert- butoxyoxalylamino ⁇ -benzoic acid.
  • MS (ESI(+)) m/e 653, 655 (M+NH 4 ) + .
  • Example 87 D 2-((carboxycarbonyl) ⁇ 4- [3 -(pentylamino)butyll - 1 -naphthyl ⁇ amino)benzoic acid
  • a mixture of 2- ⁇ tert-butoxyoxalyl-[4-(3-oxo-butyl)-naphthalen-l-yl]-amino ⁇ - benzoic acid benzhydryl ester (45mg, 0.072 mmol) and amylamine (13 ⁇ L, 0.11 mmol) in anhydrous methanol (1.0 mL) was stined at ambient temperature for 3 hours, NaBH 4 (30 mg) was added in portions over 30 minutes, stined for 2 hours and concentrated under reduced pressure.
  • Example 88 2-((carboxycarbonyl) ⁇ 4-r3-(pentylamino)propyl]-l-naphthyl ⁇ amino)benzoic acid
  • the titled compound was prepared according to the procedure described in
  • Example 87 substituting 3-buten-2-ol used in Example 87B with allyl alcohol.
  • A is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl
  • R is selected from the group consisting of alkoxy, alkyl, amino, aminosulfonyl, aryl, arylalkyl, aryloxy, hydroxy, perfluoroalkoxy, and perfluoroalkyl;
  • R , R , and R are independently selected from the group consisting of hydrogen, alkoxy, alkyl, amido, amino, aminosulfonyl, arylcarbonylamino, cyano, halo, hydroxy, nitro, perfluoroalkoxy, and perfluoroalkyl;
  • R is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and (heterocycloalkyl)alkyl.

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Abstract

Compound of formula (I) or therapeutically acceptable salts thereof, are protein tyrosine kinase PTP1B inhibitors. Preparation of the compounds, compositions containing the compounds, and treatment of diseases using the compounds are disclosed.

Description

AMINO(OXO)ACETIC ACID PROTEIN TYROSINE PHOSPHATASE INHIBITORS
Technical Field
The instant invention is directed to compounds useful for inhibiting protein tyrosine phosphatase PTPIB, preparation of the compounds, compositions containing the compounds, and treatment of diseases using the compounds.
Background of the Invention
PTPIB belongs to a family of protein tyrosine phosphatases involved in the regulation of the cellular signaling mechanisms which are implicated in metabolism, growth, proliferation, and differentiation (Science 1991, 253, 401-406). Overexpression or altered activity of tyrosine phosphatase PTPIB can contribute to the progression of various diseases (Ann. Rev. Biochem. 1985, 54, 897-930). Two independent studies have indicated that PTP IB knock-out mice have increased glucose tolerance, increased insulin sensitivity and decreased weight gain on a high fat diet. Furthermore, there is evidence which suggests inhibition of protein tyrosine phosphatase PTPIB is therapeutically beneficial for the treatment of diseases such as type I and II diabetes, obesity, autoimmune disease, acute and chronic inflammation, osteoporosis and various forms of cancer (J. Natl. Cancer Inst. 1994, 86, 372-378; Mol. Cell. Biol. 1994, 14, 6674-6682; The EMBO J. 1993, 12, 1937-1946; J. Biol. Chem. 1994, 269, 30659-30667; and Biochemical
Pharmacology 1997, 54, 703-711).
Because of the important role played by unregulated protein tyrosine phosphatase PTPIB in these diseases, agents which inhibit the enzyme have been the subject of active cunent research for their clinical potential. Reference is made to WO 99/46236, WO 99/46237, WO 99/46267 and WO 99/46268; and although each teaches certain heteroaryl and aryl amino(oxo)acetic acid protein tyrosine phosphatase PTPIB inhibitors, the potency of these compounds decreases drastically as pH levels increase from 5.5 (J. Biol. Chem. 2000, 275, 10300-10307; and J Biol. Chem. 2000, 275, 7101-7108). The instant invention provides PTPIB inhibitors which demonstrate potency at physiological pH levels, making them more suitable for drag development. Summary of the Invention
In the principle embodiment of the instant invention, therefore, is provided a protein tyrosine phosphatase PTPIB inhibitor of formula (I)
(I), or a therapeutically acceptable salt thereof, wherein
A is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl; R is selected from the group consisting of alkoxy, alkyl, amino, aminosulfonyl, aryl, arylalkyl, aryloxy, hydroxy, perfluoroalkoxy, and perfluoroalkyl;
R is selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, amido, amino, carboxy, cyano, nitro, SO3H, PO(OH)2, CH2PO(OH)2, CHFPO(OH)2, CF2(PO(OH)2, C(=NH)NH2, and the following 5-membered heterocycles:
wherein * denotes the point of attachment to the parent molecular moeity; R , R , and R are independently selected from the group consisting of hydrogen, alkoxy, alkyl, amido, amino, aminosulfonyl, arylcarbonylamino, cyano, halo, hydroxy, nitro, perfluoroalkoxy, and perfluoroalkyl; and
R is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and (heterocycloalkyl)alkyl. In another embodiment of the instant invention is provided a compound of formula
or a therapeutically acceptable salt thereof, wherein
3
R is selected from the group consisting of hydrogen, amido alkoxy, arylcarbonylamino, cyano and hydroxy;
R is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and (heterocycloalkyl)alkyl; and η each R is independently selected from the group consisting of hydrogen and alkyl.
In a preferred embodiment of the compounds of formula (I), A is aryl.
In another prefened embodiment of the compounds of formula (I), A is aryl; and R is hydroxy. In another prefened embodiment of the compounds of formula (I), A is aryl; R1 is hydroxy; and R is carboxy.
In another prefened embodiment of the compounds of formula (I), A is aryl; R1 is hydroxy; R is carboxy; and R , R , and R5 are independently selected from the group consisting of hydrogen and alkoxy. In another prefened embodiment of the compounds of formula (I), A is aryl; R1 is hydroxy; R" is carboxy; R , R , and R5 are independently selected from the group consisting of hydrogen and alkoxy; and R is aryl, cycloalkyl, or heteroaryl.
In another embodiment of the instant invention is provided a method for inhibiting protein tyrosine phosphatase at physiological pH comprising administering a therapeutically effective amount of a compound of formula (I).
In another embodiment of the instant invention is provided a method for treating type II diabetes, obesity, impaired glucose tolerance and insulin resistance in a patient in recognized need thereof comprising administering to the patient a therapeutically effective amount of a compound of formula (I). In another embodiment of the instant invention is provided a composition comprising a compound of formula (I) in combination with a therapeutically acceptable excipient. In another embodiment of the instant invention is provided a method for inhibiting protein tyrosine phosphatase at physiological pH comprising administering a therapeutically effective amount of a compound of formula (II).
In another embodiment of the instant invention is provided a method for treating type II diabetes, obesity, impaired glucose tolerance and insulin resistance in a patient in recognized need thereof comprising administering to the patient a therapeutically effective amount of a compound of formula (II).
In another embodiment of the instant invention is provided a composition comprising a compound of formula (II) in combination with a therapeutically acceptable excipient.
Detailed Description of the Invention
The instant invention provides a series of compounds which inhibit protein tyrosine phosphatase PTPIB. As used throughout the instant specification, the following terms have the meanings indicated:
The term "alkanoyl," as used herein, represents an alkyl group attached to the parent molecular moiety through a carbonyl group.
The term "alkenyl," as used herein, represents a monovalent straight or branched chain hydrocarbon radical having from two to six carbons and at least one carbon-carbon double bond.
The term "alkoxy," as used herein, represents an alkyl group attached to the parent molecular moiety through an oxygen atom.
The term "alkoxycarbonyl," as used herein, represents an alkoxy group attached to the parent molecular moiety through a carbonyl group.
The term " alkoxy carbonylalkenyl," as used herein, represents an alkoxycarbonyl group attached to the parent molecular moiety through an alkenyl group.
The term " alkoxy carbonylalkyl," as used herein, represents an alkoxycarbonyl group attached to the parent molecular moiety through an alkyl group. The term "alkyl," as used herein, represents a saturated, monovalent straight or branched chain hydrocarbon having from one to six carbons.
The term "alkylsufonyl," as used herein, represents an alkyl group attached to the parent molecular moiety through a sulfonyl group.
The term "amido," as used herein, represents an amino group attached to the parent molecular moiety through a carbonyl group.
The term "amidoalkenyl," as used herein, represents an amido group attached to the parent molecular moiety through an alkenyl group. The term "amidoalkyl," as used herein, represents an amido group attached to the parent molecular moiety through an alkyl group. The alkyl part of the amidoalkyl can be optionally substituted with one or two substituents independently selected from hydroxy, thioalkoxy, RARB -, wherein RA and RB are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylsulfonyl, amido, aryl, arylalkyl, arylalkylcarbonyl, carboxyalkylcarbonyl, or a nitrogen protecting group.
8 9 8 9
The term "amino," as used herein, represents -NR R , wherein R and R are independently selected from hydrogen, alkanoyl, alkenyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylsulfonyl, aryl, arylalkyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, hydroxy alkyl, a nitrogen protecting group, phenylsulfonyl, and
8 9
RARβNcarbonylalkyl, wherein RA and RB are previously defined or R and R , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of moφholinyl, oxazinanyl, piperazinyl, piperidinyl, and pyrrolidinyl.
The term "aminoalkenyl," as used herein, represents an amino group attached to the parent molecular moiety through an alkenyl group.
The term "aminoalkyl," as used herein, represents an amino group attached to the parent molecular moiety through an alkyl group. The alkyl part of the aminoalkyl can be optionally substituted with one or two substituents independently selected from halogen and hydroxy. The term "aminosulfonyl," as used herein, represents an amino group attached to the parent molecular moiety through a sulfonyl group.
The term "aryl," as used herein, represents dihydronaphthyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. Aryl groups having an unsaturated or partially saturated ring fused to an aromatic ring can be attached through the saturated or the unsaturated part of the group. The aryl groups of the instant invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkoxy carbonylalkenyl, alkoxycarbonylalkyl, alkyl, alkylsufonyl, amido, amidoalkenyl, amidoalkyl, amino, aminoalkenyl, aminoalkyl, aminosulfonyl, carboxy, carboxyalkenyl, carboxyalkyl, cyano, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, hydroxy, hydroxyalkyl, nitro, perfluoroalkoxy, perfluoroalkyl, phenyl, phenylalkoxy, phenylalkyl, phenylcarbonyl and thioalkoxy.
The term "arylalkyl," as used herein, represents an aryl group attached to the parent molecular moiety through an alkyl group, wherein the alkyl part of the arylalkyl can be optionally substituted with amido and NRARB, wherein RA and RB are previously defined.
The term "arylalkylcarbonyl" as used herein, represents an arylalkyl group attached to the parent molecular moiety through a carbonyl. The term "aryloxy," as used herein, represents an aryl group attached to the parent molecular moiety through an oxygen atom.
The term "carbonyl," as used herein, represents -C(O)-.
The term "carboxy," as used herein, represents -CO2H. The term "carboxyalkenyl," as used herein, represents a carboxy group attached to the parent molecular moiety through an alkenyl group.
The term "carboxyalkyl," as used herein, represents a carboxy group attached to the parent molecular moiety through an alkyl group.
The term" carboxy alky lcarbonyl," as used herein, represents a carboxyalkyl group attached to the parent molecular moiety through a carbonyl group.
The term "cyano," as used herein, represents -CN.
The term "cycloalkenyl," as used herein, represents a monovalent cyclic or bicyclic hydrocarbon of four to twelve carbons having at least one carbon-carbon double bond.
The term "cycloalkenylalkyl," as used herein, represents a cycloalkenyl group attached to the parent molecular moiety through an alkyl group.
The term "cycloalkyl," as used herein, represents a monovalent saturated cyclic or bicyclic hydrocarbon group of three to twelve carbons. The cycloalkyl groups of the invention can be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amido, carboxy, halo and hydroxy.
The term "cycloalkylalkyl," as used herein, represents a cycloalkyl group attached to the parent molecular moiety through an alkyl group.
The term "halo," represents to F, Cl, Br, or I.
The term "haloalkyl," represents a halo group attached to the parent molecular moiety through an alkyl group.
The term "heteroaryl," as used herein, represents cyclic, aromatic groups having five or six atoms, wherein at least one atom is selected from the group consisting of nitrogen, oxygen, and sulfur, and the remaining atoms are carbon. The five-membered rings have two double bonds, and the six-membered rings have three double bonds. Heteroaryls of the invention are exemplified by furanyl, thienyl, pynolyl, oxazolyl, thiazplyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazinyl, and the like. The heteroaryl groups of the instant invention are connected to the parent moleculai' group through a carbon atom in the ring or, as exemplified by imidazole, indole, and pyrazole, through either a carbon atom or nitrogen atom in the ring. The heteroaryl groups of the invention can also be fused to a second ring selected from the group consisting of heteroaryl, heterocycloalkyl, and phenyl, in which case the heteroaryl group can be connected to the parent molecular group through either the heteroaryl part, the heterocycloalkyl part, or the phenyl part of the fused ring system. Heteroaryl groups of this type are exemplified by quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, benzoisoxazolyl, benzthiazolyl, benzooxazolyl, indolyl, thienopyrazinyl, thienylfuranyl, thienylpyridinyl, 2,3-dihydrothienofuranyl, and the like. The heteroaryl groups of this invention can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkyl, amido, amidoalkenyl, amidoalkyl, amino, aminoalkenyl, aminoalkyl, carboxy, carboxyalkenyl, carboxyalkyl, cyano, halo, haloalkyl, heterocycloalkyl, hydroxy, hydroxyalkyl, nitro, perfluoroalkoxy, perfluoroalkyl, phenyl, phenylalkoxy, phenylalkyl, and thioalkoxy.
The term "heteroarylalkyl," as used herein, represents a heteroaryl group attached to the parent molecular moiety through an alkyl group.
The term "heterocycloalkyl," as used herein, represents cyclic, non-aromatic, four-, five-, or six-membered groups containing at least one atom selected from the group consisting of oxygen, nitrogen, and sulfur. The four-membered rings have zero double bonds, the five-membered rings have zero or one double bonds, and the six-membered rings have zero, one, or two double bonds. Heterocycloalkyl groups of the invention are exemplified by dihydropyridinyl, imidazolinyl, moφholinyl, piperazinyl, pynolidinyl, pyrazolidinyl, tetrahydropyridinyl, piperidinyl, thiomoφholinyl, 1,3-dioxolanyl, 1,4- dioxanyl, 1,3-dioxanyl, and the like. The heterocycloalkyls of the instant invention can be attached to the parent molecular group through a carbon atom or nitrogen atom in the ring. The heterocycloalkyl groups of the invention can also be fused to a phenyl ring, in which case the heterocycloalkyl group can be connected to the parent molecular group through either the heterocycloalkyl part or the phenyl part of the fused ring system.
Heterocycloalkyl groups of this type are exemplified by benzodioxolyl, indolinyl, tetrahydroquinolinyl, chromanyl, and the like. The heterocycloalkyl groups of this invention can be optionally substituted one, two, three, four or five substituents independently selected from the group consisting of alkanoyl, alkyl, alkoxy, alkoxycarbonyl, amido, amidoalkenyl, amidoalkyl, amino, aminoalkenyl, aminoalkyl, aryl, arylalkyl, carboxy, cyano, halo, hydroxy, hydroxyalkyl, nitro, oxo and thioalkoxy. The term "(heterocycloalkyl)alkyl," as used herein, represents a heterocycloalkyl group attached to the parent molecular moiety through an alkyl group. The term "hydroxy," as used herein, represents -OH. The term "hydroxyalkyl," as used herein, represents a hydroxy group attached the parent molecular moiety through an alkyl group.
The term "nitro," as used herein, represents -NO2. The term "nitrogen protecting group," as used herein, represents selectively introducible and removable groups which protect amino groups against undesirable side reactions during synthetic procedures. Examples of amino protecting groups include methoxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl (Cbz), chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-butoxycarbonyl
(Boc), para-methoxybenzyloxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, benzyl, diphenylmethyl, triphenylmethyl (trityl), methylsulfonyl, phenylsulfonyl, para- toluenesulfonyl, trimethylsilyl, triethylsilyl, triphenylsilyl, and the like. The term "oxo," as used herein, represents =O. The term "perfluoroalkoxy," as used herein, represents a perfluoroalkyl group attached to the parent molecular moiety through an oxygen atom.
The term "perfluoralkyl," as used herein, represents an alkyl group in which all of the hydrogen atoms have been replaced with fluoride atoms.
The term "phenyl," as used herein, represents a 6 membered aromatic ring that is unsubstituted.
The term "phenylalkoxy," as used herein, represents a phenyl group attached to the parent molecular moiety through an alkoxy group.
The term "phenylalkyl," as used herein, represents a phenyl group attached to the parent molecular moiety through an alkyl group. The term "phenylcarbonyl," as used herein, represents a phenyl group attached to the parent molecular moiety through a carbonyl group.
The term"phenylsulfonyl," as used herein, represents a phenyl group attached to the parent molecular moiety through a sulfonyl group.
The term "sulfonyl," as used herein, represents -SO2-. The term "thioalkoxy," as used herein, represents an alkyl group attached to the parent molecular moiety through a sulfur atom.
The instant compounds can exist as therapeutically acceptable salts. The term "therapeutically acceptable salt," refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of diseases without undue toxicity, initation, and allergic response, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fimiarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetic, trifluoroacetic, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. The amino groups of the compounds can also be quatemized with alkyl chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.
Basic addition salts can be prepared during the final isolation and purification of the instant compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts derived from methylamine, dimethylamine, frimethylamine, triethylamine, diethylamine, ethylamine, tributlyamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmoφholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like, are contemplated as being within the scope of the instant invention.
The instant compounds can also exist as therapeutically acceptable prodrugs. The term "therapeutically acceptable prodrag," refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, initation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The term "prodrag," refers to compounds which are rapidly transformed in vivo to the parent compounds of formula (I) for example, by hydrolysis in blood.
Asymmetric centers can exist in the instant compounds. Individual stereoisomers of the compounds are prepared by synthesis from chiral starting materials or by preparation of racemic mixtures and separation by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns. Starting materials of particular stereochemistry are either commercially available or are made by the methods described hereinbelow and resolved by techniques well-known in the art. Geometric isomers can exist in the instant compounds The invention contemplates the various geometric isomers and mixtures thereof resulting from the disposal of substituents around a carbon-carbon double bond, a cycloalkyl group, or a heterocycloalkyl group. Substituents around a carbon-carbon double bond are designated as being of Z or E configuration and substituents around a cycloalkyl or heterocycloalkyl are designated as being of cis or trans configuration.
Therapeutic compositions of the instant compounds comprise an effective amount of the same formulated with one or more therapeutically acceptable excipients. The term "therapeutically acceptable excipient," as used herein, represents a non-toxic, solid, semi- solid or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type. Examples of therapeutically acceptable excipients include sugars; cellulose and derivatives thereof; oils; glycols; solutions; buffering, coloring, releasing, coating, sweetening, flavoring, and perfuming agents; and the like. These therapeutic compositions can be administered parenterally, intracisternally, orally, rectally, or intraperitoneally.
Liquid dosage forms for oral administration of the instant compounds comprise formulations of the same as emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the compounds, the liquid dosage forms can contain diluents and/or solubilizing or emulsifying agents. Besides inert diluents, the oral compositions can include wetting, emulsifying, sweetening, flavoring, and perfuming agents.
Injectable preparations of the instant compounds comprise sterile, injectable, aqueous and oleaginous solutions, suspensions or emulsions, any of which can be optionally formulated with parenterally acceptable diluents, dispersing, wetting, or suspending agents. These injectable preparations can be sterilized by filtration through a bacterial-retaining filter or formulated with sterilizing agents which dissolve or disperse in the injectable media.
PTP inhibition by the instant compounds can be delayed by using a liquid suspension of crystalline or amoφhous material with poor water solubility. The rate of absoφtion of the compounds depends upon their rate of dissolution which, in turn, depends on their crystallinity. Delayed absoφtion of a parenterally administered compound can be accomplished by dissolving or suspending the compound in oil. Injectable depot forms of the compounds can also be prepared by microencapsulating the same in biodegradable polymers. Depending upon the ratio of compound to polymer and the nature of the polymer employed, the rate of release can be controlled. Depot injectable formulations are also prepared by entrapping the compounds in liposomes or microemulsions which are compatible with body tissues.
Solid dosage forms for oral administration of the instant compounds include capsules, tablets, pills, powders, and granules. In such forms, the compound is mixed with at least one inert, therapeutically acceptable excipient such as a carrier, filler, extender, disintegrating agent, solution retarding agent, wetting agent, absorbent, or lubricant. With capsules, tablets, and pills, the excipient can also contain buffering agents. Suppositories for rectal administration can be prepared by mixing the compounds with a suitable non- initating excipient which is solid at ordinary temperature but fluid in the rectum. The instant compounds can be micro-encapsulated with one or more of the excipients discussed previously. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric and release- controlling. In these forms, the compounds can be mixed with at least one inert diluent and can optionally comprise tableting lubricants and aids. Capsules can also optionally contain opacifying agents which delay release of the compounds in a desired part of the intestinal tract. Transdermal patches have the added advantage of providing controlled delivery of the instant compounds to the body. Such dosage forms are prepared by dissolving or dispensing the compounds in the proper medium. Absoφtion enhancers can also be used to increase the flux of the compounds across the skin, and the rate of absoφtion can be controlled by providing a rate controlling membrane or by dispersing the compounds in a polymer matrix or gel.
Diseases caused or exacerbated by protein tyrosine phosphatase PTPIB activity are treated or prevented in a patient by administering to the same a therapeutically effective amount of the instant compounds in such an amount and for such time as is necessary to achieve the desired result. The term "therapeutically effective amount," refers to a sufficient amount of the compound to treat protein tyrosine phosphatase PTPIB activity at a reasonable benefit/risk ratio applicable to any medical treatment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, rate of excretion; the duration of the treatment; and drags used in combination or coincidental therapy.
The total daily dose of the instant compounds in single or divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions can contain such amounts or submultiples thereof of the compounds to make up the daily dose. In general, treatment regimens comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compounds per day in single or multiple doses.
Specific compounds of formula (II) include, but are not limited to: 2-((carboxycarbonyl)(l-naphthyl)amino)benzoic acid;
2-((carboxycarbonyl)(2-naphthyl)amino)benzoic acid; 2-((carboxycarbonyl)-4-methoxyanilino)benzoic acid; 2-((carboxycarbonyl)(l-naphthyl)amino)-5-methoxybenzoic acid; 2-((carboxycarbonyl)-2-chloro-5 -methoxyanilino)benzoic acid; 2-((carboxycarbonyl)-2-((lE)-3-ethoxy-3-oxo-l-propenyl)anilino)benzoic acid; 2-(4-((2S)-2-((tert-butoxycarbonyl)amino)-3-(((4- (methoxycarbonyl)cyclohexyl)methyl)amino)-3- oxopropyl)(carboxycarbonyl)anilino)benzoic acid;
2-(4-((2S)-2-((tert-butoxycarbonyl)amino)-3-(((4-carboxycyclohexyl)methyl)amino)-3- oxopropyl)(carboxycarbonyl)anilino)benzoic acid;
2-((carboxycarbonyl)-2-iodoanilino)benzoic acid;
2-((carboxycarbonyl)-2-((l E)-3 -( 1 ,3 -oxazinan-3 -yl)-3 -oxo- 1 -propenyl)anilino)benzoic acid;
2-((carboxycarbonyl)-3-(trifluoromethyl)anilino)benzoic acid; 2-((carboxycarbonyl)(cyclobutyl)amino)benzoic acid;
2-((7-(benzyloxy)- 1 -naphthyl)(carboxy carbonyl)amino)benzoic acid; 2-((carboxycarbonyl)-2-(2-hydroxyethyl)anilino)benzoic acid; 2-((carboxycarbonyl)-2-methylanilino)benzoic acid; 2-((carboxycarbonyl)(2-methyl- 1 H-indol- 1 -yl)amino)benzoic acid; 2-((carboxycarbonyl)(7-hydroxy- 1 -naphthyl)amino)benzoic acid;
2-((carboxycarbonyl)(7-((6-phenylhexyl)oxy)- 1 -naphthyl)amino)benzoic acid; 2-((l , 1 '-biphenyl)-2-yl(carboxycarbonyl)amino)benzoic acid; 2-((l , 1 '-biphenyl)-4-yl(carboxycarbonyl)amino)benzoic acid; 2-((carboxycarbonyl)(5,6,7,8-tetrahydro-l-naphthalenyl)amino)benzoic acid; 2-((carboxycarbonyl)(cyclohexyl)amino)benzoic acid;
2-((carboxycarbonyl)(2,3 -dihydro- 1 ,4-benzodioxin-6-yl)amino)benzoic acid; 2-((carboxycarbonyl)(3 -methylcyclohexyl)amino)benzoic acid;
2-[(carboxycarbonyl)(2-hydroxy-l -naphthyl)amino]benzoic acid; N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-pentyl-l- naphthylalaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-pentyl-3-(2- hydroxyethane)-phenylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-6-{[N-acetyl-3-(l- naphthy l)alany 1] amino } hexanoic acid; 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-[(lE)-3-amino-3-oxo-l- propenyl]-N-(tert-butoxycarbonyl)-N-pentyI-L-phenylaIaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-isopropyl-N- pentylphenylalaninamide;
4- [(carboxycarbonyl)(2-carboxyphenyl)amino]-6- { [N-acetyl-3 -(1 - piperidinyl)phenylalanyl] amino} hexanoic acid;
2- { (carboxy carbonyl) [2-(3 -methyl- 1 -piperidinyl)phenyl] amino } benzoic acid; 2- { (carboxycarbonyl) [5 -hydroxy-2-( 1 -piperidinyl)phenyl] amino } benzoic acid; 4- [(carboxycarbonyl)(2-carboxyphenyl)amino]-3 - [( 1 E)-3-amino-3 -oxo- 1 - propenyl]-N-(methylsulfonyl)-N-pentyl-L-phenylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-(3-amino-3-oxopropyl)-N- [(isopropylamino)carbonyl]-N-pentyl-L-phenylalaninamide; 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-[(lE)-3-amino-3-oxo-l- propenyl]-N-[(isopropylamino)carbonyl]-N-pentyl-L-phenylalaninamide;
2-((carboxycarbonyl){2-[4-(hydroxymethyl)-l-piperidinyl]phenyl}amino)benzoic acid;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-pentyl-4-(l- piperidinyl)phenylalaninamide;
Ν-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-ethylphenylalanyl-Ν- methyl-4-nitro-L-phenylalaninamide;
N-(3-carboxypropanoyl)-L-phenylalanyl-3 -[( 1 Ε)-3 -amino-3 -oxo- 1 -propenyl]-4- [(carboxycarbonyl)(2-carboxyphenyl)amino]-N-pentyl-L-phenylalaninamide; 3-(4-benzoylphenyl)-N-(tert-butoxycarbonyl)-L-alanyl-3-{4-[(carboxycarbonyl)(2- carboxyphenyl)amino]phenyl} -N-l — entyl-L-alaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-(2-hydroxyethyl)-N-[4- (methylsulfonyl)benzyl]phenylalaninamide;
2-[[7-(aminocarbonyl)-l-naphthyl](carboxycarbonyl)amino]benzoic acid; Ν-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-isopropyl-Ν-[4-
(methylsulfonyl)benzyl]phenylalaninamide
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-l-acetyl-6-(3-isopropylbenzyl)-4- [4-(methylsulfonyl)benzyl]-2,3,5-piperazinetrione;
2- [(carboxycarbonyl)(7-hydroxy- 1 -naphthyl)amino]-4-hydroxybenzoic acid; N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-ethyl-N-{5-oxo-5-[(l- phenylethyl)amino]pentyl}phenylalaninamide;
N-(methoxycarbonyl)-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N- pentylnaphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(cyclohexylmethyl)-N- (methoxycarbonyl)naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(methoxycarbonyl)-N-[(li?)-l- (4-nitrophenyl)ethyl]naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(methoxycarbonyl)-N-[4- (methylsulfonyl)benzyl]naphthylalaninamide; 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(methoxycarbonyl)-N-(3,4,5- trifluorobenzyl)naphthylalaninamide; 4-[(caι-boxycarbonyl)(2-carboxyphenyl)amino]-N-(cyclooctylmethyl)-N- (methoxycarbonyl)naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-[(17?)-l-(4-bromophenyl)ethyl]- N-(methoxycarbonyl)naphthylalaninamide; 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(methoxycarbonyl)-N-(3- phenylpropyl)naphthylalaninamide; methyl 3-{4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-l-naphthyl}-Ν- (methoxycarbonyl)alanyl-L-norleucinate;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(2-fluorobenzyl)-N- (methoxycarbony l)naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4-chlorobenzyl)-N- (methoxycarbonyl)naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4-bromobenzyl)-N- (methoxycarbonyl)naphthylalaninamide; 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(methoxycarbonyl)-N-(4- nitrobenzyl)naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-[4-(aminosulfonyl)benzyl]-N- (methoxycarbonyl)naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(methoxycarbonyl)-N-({4- [(methylamino)carbonyl] cyclohexyl} methyl)naphthylalaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-(2-hydroxyethyl)-N-(4- nitrobenzyl)phenylalaninamide;
2-[(carboxycarbonyl)(7-hydroxy- 1 -naphthyl)amino]-4-cyanobenzoic acid;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-{4- [(ethylamino)sulfonyl]benzyl}-N-(methoxycarbonyl)naphthylalaninamide;
Ν-(tert-butoxycarbonyl)-L-phenylalanyl-3-[(lE)-3-amino-3-oxo-l-propenyl]-4- [(carboxycarbonyl)(2-carboxyphenyl)amino]-N-pentyl-L-phenylalaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-(2-hydroxyethyl)-N- [(lS)-l-(4-nitrophenyl)ethyl]phenylalaninamide; N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4-chlorobenzyl)-3-(2- hydroxyethyl)phenylalaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4-bromobenzyl)-3-(2- hydroxyefhyl)phenylalaninamide;
2-[(carboxycarbonyl)(7-hydroxy-l-naphthyl)amino]-4-{[4- (dimethylamino)benzoyl] amino} benzoic acid;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-ethyl-N-(4- nitrobenzyl)phenylalaninamide; N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-ethyl-N-[(17.)-l-(4- nitrophenyl)ethyl]phenylalaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4-chlorobenzyl)-3- ethylphenylalaninamide; N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4- nitrobenzyl)naphthy lalaninamide ;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-[(17?)-l-(4- bromophenyl)ethyl]-3-(2-hydroxyethyl)phenylalaninamide;
4-[(butylamino)carbonyl]-2-[(carboxycarbonyl)(7-hydroxy- 1 - naphthyl)amino]benzoic acid;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-{5-[(3- hydroxyphenyl)amino]-5-oxopentyl}-3-(l-piperidinyl)phenylalaninamide;
2-((carboxy carbonyl) { 4- [2-hydroxy-3 -(pentylamino)propyl]phenyl } amino)benzoic acid; 2-((carboxycarbonyl) {4- [3 -(pentylamino)butyl]- 1 -naphthyl} amino)benzoic acid; and
2-((carboxycarbonyl){4-[3-(pentylamino)propyl]-l-naphthyl}amino)benzoic acid.
The following additional compounds, representative of formula (II), may be prepared by one skilled in the art using known synthetic methodology or by using synthetic methodology described in the Schemes and Examples contained herein.
2-((carboxycarbonyl)-2-((E)-2-carboxyethenyl)anilino)benzoic acid;
2-(2-(( 1 E)-3 -((tert-butoxycarbonyl)amino)- 1 -propenyl)(carboxycarbonyl)anilino)benzoic acid; 2-((carboxycarbonyl)-2,3-dimethylanilino)benzoic acid;
2-((carboxycarbonyl)-4-chloro-3-methylanilino)benzoic acid;
2-(2-(aminocarbonyl)(carboxycarbonyl)anilino)benzoic acid;
2-((7-(aminomethyl)-5,6,7,8-tetrahydro-l-naphthalenyl)(carboxycarbonyl)amino)benzoic acid; 2-((6-(aminomethyl)-5,6,7,8-tetrahydro-l-naphthalenyl)(carboxycarbonyl)amino)benzoic acid;
2-((carboxycarbonyl)-4-(2,3 -diamino-3 -oxopropyl)anilino)benzoic acid; and
2-((carboxycarbony 1)(5 -(2,3 -diamino-3 -oxopropyl)-5 ,6,7,8-tetrahydro- 1 - naphthalenyl)amino)benzoic acid.
Determination of Biological Activity
Purification of Human protein tyrosine phosphatase IB from E. coli Human protein tyrosine phosphatase IB (PTPIB, amino acid residues 1-321) was expressed in E. coli BL21(DΕ3). The cell paste was resuspended in 4 cell paste volumes of lysis buffer containing 100 mM MES (pH 6.5), 100 mM NaCl, 1 mM EDTA, 1 mM DTT, 1 mM PMSF, 20 U/mL Benzonase, 0.5 mg/mL lysozyme, and 1 mM MgCl2 and incubated for 35 minutes at room temperature. The cells were lysed at 11,000 psi using a
Rannie homogenizer, and the homogenate was clarified in a Beckman GSA rotor at 10,000 x g for 30 minutes at 4 °C. The supernatant was loaded onto a 5 x 21 cm S-Sepharose-FF column (Amersham Pharmacia Biotech) pre-equilibrated with 5 column volumes of buffer containing 100 mM MES (pH 6.5), 100 mM NaCl, 1 mM EDTA, and 1 mM DTT and eluted with 10 column volumes of the same. The fractions (28 mL each) were assayed for protein by 10-20% Tris-Glycine SDS-PAGE. Fractions which contained >95% protein tyrosine phosphatase IB were combined.
Protein Tyrosine Phosphatase IB Activity Assay ' Protein tyrosine phosphatase IB activity was determined by measuring the phosphate release from triphosphorylated peptide which conesponds to residues 1135- 1156 of the β-subunit of the human insulin receptor (βIRK substrate) as described in Nature, 1985, 313, 756-761. Protein tyrosine phosphatase IB activity was determined in a final assay volume of 50 μL containing 50 mM Tris HC1, 50 mM Tris Base, 150 mM NaCl, 3 mM DTT, 2 nM protein tyrosine phosphatase 1B(1-321), and 20 μM βIRK substrate. Various concentrations of test compounds in 5 μL of 10% DMSO were incubated for 5 minutes at room temperature in assay buffer (25 μl) containing 20 μM βIRK substrate in a round-bottom microtiter plate(Costar) pre-coated with 1% bovine serum albumin. The assay was initiated by the addition of protein tyrosine phosphatase IB enzyme (20 μl )in assay buffer. After 10 minutes of incubation at room temperature, the reaction was terminated by the addition of 100 μL of malachite green (Upstate Biotechnology Inc.) containing 0.01% Tween-20. After a 5 minute incubation, quantitation of free phosphate released from the βIRK substrate was determined in a Victor II plate reader (Wallac; Turku, Finland) by measuring the absorbence of the malachite green at 620 nm.
The instant compounds were found to inhibit protein tyrosine phosphatase IB with inhibitory potencies in a range of about 0.05 μM to about 100 μM. In a preferred range, the compounds inhibited protein tyrosine phosphatase IB with inhibitory potencies in a range of about of about 0.05 μM to about 60 μM; and in a more prefened range, the compounds inhibited protein tyrosine phosphatase IB with inhibitory potencies in a range of about of about 0.05 μM to about 21 μM. As protein tyrosine phosphatase IB inhibitors, therefore, the instant compounds are useful for treating diseases caused by overexpressed or altered protein tyrosine phosphatase IB activity. These diseases include autoimmune diseases, acute and chronic inflammatory diseases, osteoporosis, obesity, cancer, malignant diseases, and type I and type II diabetes.
Synthetic Methods
Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: dba for dibenzylideneacetone; DMSO for dimethylsulfoxide; NMP for N-methylpynolidinone; DMF for N,N-dimethylformamide; TFA for trifluoroacetic acid; THF for tetrahydrofuran; ED AC for l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride; and HOBT for 1-hydroxybenzotriazole hydrate.
The compounds and processes of the instant invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared. The groups R are as defined above unless otherwise noted below.
Scheme 1
(I)
As shown in Scheme 1, compounds of formula (2) (R is alkyl; X is Br or I) can be reacted with compounds of formula (3) (R is aryl or heteroaryl) in the presence of a palladium catalyst and base to form compounds of formula (4). Representative palladium catalysts include Pd2 ba3 with 2-dicyclohexylphosphino-2'-(N,N- dimethyl)aminobiphenyl, Pd2dba3 with tricyclohexylphosphine, and Pd2dba3 with PPI13. Representative bases include sodium hydride, potassium hydride, and calcium hydride. Examples of solvents used in these reactions include benzene and toluene. The reaction temperature is about 60 °C to about 110 °C and depends on the method chosen. Reaction times are typically about 2 to about 8 hours.
Compounds of formula (4) can be converted to compounds of formula (I) (R is hydroxy, R is carboxy) by treatment with an oxidizing agent. Representative oxidizing agents include KM11O4, ozone and hydrogen peroxide, and Crθ3. Examples of solvents used in these reactions include pyridine, water, and mixtures thereof. The reaction temperature is about 0 °C to about 35 °C and depends on the method chosen. Reaction times are typically about 12 to about 24 hours.
1 2
Compounds of formula (I) (R is hydroxy and R is carboxy) can be intraconverted to compounds of formula (I) (R 1 is alkoxy and R 2 are alkoxycarbonyl) by methods well known to those skilled in the art.
Scheme 2
Cl O^/
(7)
(I) (8) An alternative synthesis of compounds of formula (I) is shown in Scheme 2.
Compounds of formula (5) (R is alkyl) can be reacted with compounds of formula (3) (R is alkyl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl to provide compounds of formula (6). Examples of solvents used in these reactions include DMSO, dioxane, and NMP. The reaction temperature is about 80 °C to about 120 °C. Reaction times are typically about 12 to about 24 hours.
Compounds of formula (6) can be reacted with ethyl chloro(oxo)acetate (7) in the presence of base to provide compounds of formula (8). Representative bases include pyridine, friethylamine, and diisopropylethylamine. Examples of solvents used in these reactions include diethyl ether, methyl tert-butyl ether, and dioxane. The reaction temperature is about 20 °C to about 30 °C. Reaction times are typically about 8 to about 18 hours.
Compounds of formula (8) can be hydrolyzed to compounds of formula (I) (R is
2 hydroxy and R is carboxy) by methods known to those skilled in the art.
Scheme 3
(I) (11)
Another synthesis of compounds of formula (I) is shown in Scheme 3. Compounds of formula (9) can be reacted with compounds of formula (3) (R is aryl or heteroaryl) in the presence of catalytic copper(II) acetate to provide compounds of formula
(10). Examples of solvents used in these reactions include isopropanol, n-propanol, butanol, and pentanol. The reaction temperature is about 70 °C to about 100 °C. Reaction times are typically about 4 to about 12 hours.
Compounds of formula (10) can be converted to compounds of formula (11) and
1 2 then to compounds of formula (I) (R is hydroxy and R is carboxy) by the methods described in Scheme 2.
The instant invention will now be described in connection with certain prefened embodiments which are not intended to limit its scope. On the contrary, the instant invention covers all alternatives, modifications, and equivalents as can be included within the scope of the claims. Thus, the following examples, which include prefened embodiments, will illustrate the preferred practice of the instant invention, it being understood that the examples are for the purposes of illustration of certain prefened embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects. Compounds of the invention were named by ACD/ChemSketch version 4.01 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names which appeared to be consistent with ACD nomenclature.
Example 1 2-((carboxycarbonyl)(l -naphthyl)amino)benzoic acid
Example 1A methyl (2E)-3 -(2-bromophenyl)-2-propenoate A solution of (2E)-3-(2-bromophenyl)-2-propenoic acid (1.53 g, 6.74 mmol) in N,N-dimethylformamide (10 mL) at room temperature was treated with K2CO3 (900 mg, 6.51 mmol) and iodomethane (0.5 mL, 8.0 mmol), stined for 3 hours, poured into H2O (50 mL) and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Example IB ethyl (2E)-3 -(2-bromophenyl)-2-propenoate A mixture of Example 1A (135 mg, 0.56 mmol), 1-aminonaphthalene (80 mg, 0.56 mmol), tris(dibenzylideneacetone)-dipalladium(0) (3 mg, 0.003 mmol), 2- dicyclohexylphosphino-2'-(N,N-dimethyl)aminobiphenyl (4 mg, 0.01 mmol), and 60% NaH dispersion in mineral oil (50 mg, 1.2 mmol) in toluene (2 mL) was heated to reflux for 5.5 hours diluted with water (10 mL) and IN HC1 (5 mL), and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1 : 1 ethyl acetate/hexanes to provide the desired product. MS (ESI(+)) m/e 272 (M+H)+; !HNMR (300 MHz, DMSO-d6) δ 8.16 (d, 2H), 8.12 (d, 1H), 7.84 (dd, 1H), 7.74 (dd, 1H), 7.60 (dd, 1H), 7.57 (dt, 1H), 7.46 (ddd, 1H), 7.32 (ddd, 1H), 7.25 (dd, 1H), 7.20 (dd, 1H), 6.78 (d, 1H), 6.30 (d, 1H).
Example IC 2-((carboxycarbonyl)( 1 -naphthyl)amino)benzoic acid A solution of Example IB (97 mg, 0.36 mmol) in pyridine (1.2 mL) at room temperature was treated with water (1.2 mL), cooled to 0 °C, treated with KMnO4 (210 mg, 1.3 mmol), warmed to room temperature, and stined for 17 hours. The mixture was treated with methanol (0.2 mL), stined for 5 minutes, treated with IN NaOH (4 mL), and filtered through diatomaceous earth (Celite ). The filter cake was washed with water (15 mL) and the combined filtrates were washed with diethyl ether, cooled to 0 °C, adjusted to pH <7 with 12N HO, and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by reverse-phase HPLC with 100 % acetonitrile to 70:30 (0.1% aqueous trifluoroacetic acid)/acetonitrile provide the desired product as a 3:2 mixture of rotamers. MS (ESI(+)) m/e 336 (M+H)+; *H NMR (500 MHz, DMSO-d6) δ 8.37 (d, 1H), 8.05-8.03 (m, 1H), 8.01-7.95 (m, 1H), 7.87 (dd, 1H), 7.73-7.68 (m, 1H), 7.63-7.59 (m, 1H), 7.57- 7.49 (m, 2H), 7.45-7.38 (m, 1H), 7.34 (dt, 1H), 7.21 (d, 1H), 6.89 (d, 1H).
Example 2 2-((carboxycarbonyl)(2-naphthyl)amino)benzoic acid
The titled compound was prepared by substituting 2-aminonaphthalene for 1 aminonaphthalene in Example 1. MS(ES(+)) m/e 336 (M+H)+; 1H NMR (300 MH2 DMSO-d6) δ 7.98-7.82 (m, 4H), 7.72-7.62 (m, 3H), 7.58-7.45 (m, 4H).
Example 3 2-((carboxycarbonyl)-4-methoxyanilino)benzoic acid A mixture of 4-methoxyaniline (246 mg, 2 mmol), diphenyliodonium-2- carboxylate monohydrate (821 mg, 2.4 mmol), copper(II) acetate (18.2 mg, 0.1 mmol), and isopropanol (4 ml) in a sealed tube under nitrogen atmosphere was heated to 80 °C for 8 hours, cooled to room temperature, treated with IN NaOH (3 mL), and extracted with diethyl ether. The aqueous phase was adjusted to pH 2 with IN HC1 and extracted with ethyl acetate. The combined extracts were filtered through a pad of silica gel, dried (Na2SO4), filtered, and concentrated. A solution of the concentrate (427 mg, 1.75 mmol) and diisopropylethylamine (762 μL, 4.38 mmol) in dichloromethane (5 mL) was cooled to 0 °C, treated slowly with ethyl oxalyl chloride (450 μL, 4.03 mmol), stined for 1 hour, warmed to room temperature, stined for 16 hours, treated with IN HC1 (4 mL), and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50:50:0.8 ethyl acetate/hexanes/acetic acid. A solution of the purified concentrate (86 mg, 0.25 mmol) in ethanol (2 mL) at room temperature was treated with IN NaOH.(l mL), stined for 30 minutes, treated with IN HC1 (2 mL), and purified by reverse-phase HPLC with acetonitrile to 95:5 (0.1% aqueous trifluoroacetic acid)/ acetonitrile provide the desired product. MS (ESI(-)) m/e 314 (M-H)"; H NMR (300 MHz, DMSO-d6 at 90
°C) δ 7.84 (dd, 1H), 7.57 (td, 1H), 7.25-7.48 (br m, 4H), 6.91 (d, 2H), 3.74 (s, 3H). Example 4 2-((carboxycarbonyl)(l-naphthyl)amino)-5-methoxybenzoic acid
Example 4A ethyl (2E)-3 -(2-bromo-5 -methoxyphenyl)-2-propenoate
A suspension of 60 % NaH dispersion in mineral oil (220 mg, 5.5 mmol) in THF (10 mL) at room temperature was treated dropwise with triethyl phosphonoacetate (1.14 mL, 5.75 mmol), stined for 5 minutes, treated dropwise with a mixture of 2-bromo-5- methoxybenzaldehyde (1.07 g, 5.0 mmol) in THF (2 mL), stirred for 16 hours, and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 90:10 hexanes/ethyl acetate to provide the titled compound.
Example 4B
2-((carboxycarbonyl)(l-naphthyl)amino)-5-methoxybenzoic acid The desired product was prepared according to the procedure described in Example IB-C as a mixture of rotamers by substituting ethyl (2E)-3-(2-bromo-5-methoxyphenyl)-2- propenoate for methyl (2E)-3-(2-bromophenyl)-2-propenoate. MS (ESI(-)) m/e 364 (M- H)"; !H NMR (400 MHz, DMSO-d6) δ 8.38-8.35 (m, 1H), 8.05-7.83 (m, 3H), 7.40 (d,
1H), 7.36 (d, 1H), 7.18 (d, 1H), 7.07 (dd, 1H), 6.96 (dd, 1H), 6.84 (d, 1H), 3.76( s,3H), 3.78 (s,3H).
Example 5
2-((carboxycarbonyl)-2-chloro-5-methoxyanilino)benzoic acid
Example 5A 2-(2-chloro-5-methoxyanilino)benzoic acid A mixture of 2-chloro-5-methoxyaniline (260 mg, 1.65 mmol), diphenyliodonium-
2-carboxylate monohydrate (684 mg, 2.0 mmol), and copper(II) acetate (15 mg, 0.83 mmol) in 2-propanol (4 mL) was heated to reflux for 1.5 hours, diluted with IN NaOH (10 mL), and extracted with hexanes. The aqueous phase was adjusted to pH <7 with IM HCl and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Example 5B 2-((carboxycarbonyl)-2-chloro-5-methoxyanilino benzoic acid A solution of Example 5A (354 mg, 1.27 mmol) and pyridine (0.5 mL) in ethyl acetate (5 mL) at 0 °C was treated with ethyl chloro(oxo)acetate (350 mL, 3.1 mmol), warmed to room temperature, stined for 2.5 hours, and poured into IN HCl (20 mL). The aqueous phase was extracted with diethyl ether and the combined extracts were washed with water and 2N NaOH. The combined NaOH washes were adjusted to pH <7 with IN HCl (20 mL), and extracted with ethyl acetate. This combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by reverse phase HPLC with acetonitrile to 70:30 (0.1% aqueous trifluoroacetic acid)/ acetonitrile to provide the desired product as a mixture of rotamers. MS (ESI(+)) m/e 350 (M+H) ; H
NMR (300 MHz, DMSO-d6) δ 7.90-7.84 (m, 1H), 7.62-7.40 (m, 3H), 7.35 (d, 1H), 7.25- 7.08 (m, 1H), 7.05-6.97 (m, 2H), 6.91 (s, 1H), 6.88-6.84 (m, 1H).
Example 6 2-((carboxycarbonyl)-2-((lE)-3-ethoxy-3-oxo-l-propenyl)anilino)benzoic acid
The desired product was prepared by substituting ethyl (2E)-3-(2-aminophenyl)-2- propenoate for 4-methoxyaniline in Example 3. MS (ESI(-)) m/e 382 (M-H)~; H NMR (300 MHz, DMSO-d6) δ 7.94 (d, 1H), 7.91-7.77 (m, 2H), 7.50-7.16 (m, 5H),
6.87 (d, 1H), 6.70 (d, 1H), 4.18 (q, 2H), 1.24 (t, 3H).
Example 7
2-(4-((2S)-2-fftert-butoxycarbonyl)amino)-3-(((4-
(methoxycarbonyl)cyclohexyl)methyl)amino)-3- oxopropyl)(carboxycarbonyl)anilino)benzoic acid
Example 7A methyl 4-((((2S)-3-(4-aminophenyl)-2-((tert- butoxycarbonyl)amino)propanoyl)amino)methyl)cyclohexane-carboxylate A solution of (2S)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (350 mg, 1.25 mmol), methyl 4-(aminomethyl)cyclohexanecarboxylate hydrochloride
(285 mg, 1.50 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (335 mg, 1.75 mmol), and 1-hydroxybenzotriazole hydrate (245 mg, 1.50 mmol) in N,N- dimethylformamide (6 mL) at room temperature was adjusted to pH 6 with triethylamine (250 μL, 1.78 mmol), stined for 16 hours, treated with water, and filtered. The solid was washed with water, concentrated under reduced pressure and dried under vacuum to provide the desired product. Example 7B
2-(4-((2S)-2-((tert-butoxycarbonyl)amino)-3-(((4-
(methoxycarbonyl)cyclohexyl)methyl)amino)-3- oxopropyl)(carboxycarbonyl)anilino)benzoic acid The desired product was prepared by substituting Example 7A for 4- methoxyaniline and substituting tert butyl oxalyl chloride for ethyl oxalyl chloride in Example 3. Purification by reverse-phase HPLC with 5%-100% acetonitrile/H2θ with 0.1%) trifluoracetic acid provided the desired product as a mixture of rotamers. MS (ESI(- )) m/e 624 (M-H)"; 1H NMR (300 MHz, DMSO-d6) δ 7.93-7.73 (m, 2H), 7.68-7.32 (m, 4H), 7.32-7.05 (m, 3H), 7.05-6.83 (m, IH), 4.18-4.01 (m, IH), 3.80 (s, 3H), 2.97-2.79 (m,
3H), 2.79-2.66 (m, IH), 2.08 (t, IH), 1.85 (br d, IH), 1.78 (br d, 2H), 142-1.20 (m, 9H), 0.88 (t, 2H), 0.85 (t, 2H).
Example 8 2-(4-((2S)-2-((tert-butoxycarbonyl)amino)-3-(((4-carboxycyclohexyl)methyl)amino)-3- oxopropyl)(carboxycarbonyl)anilino)benzoic acid The desired product was isolated in the HPLC purification of Example 7B as a mixture of rotamers. MS (ESI(+)) m/e 612 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.93-7.73 (m, 2H), 7.68-7.32 (m, 4H), 7.32-7.05 (m, 3H), 7.05-6.83 (m, IH), 4.18-4.01 (m, IH), 2.97-2.79 (m, 3H), 2.79-2.66 (m, IH), 2.08 (t, IH), 1.85 (br d, IH), 1.78 (br d,
2H), 1.42-1.20 (m, 9H), 0.88 (t, 2H), 0.85 (t, 2H).
Example 9 2-((carboxycarbonyl)-2-iodoanilino)benzoic acid ' The desired product was prepared by substituting 2-iodoaniline for 4- methoxyaniline in Example 3. MS (ESI(+)) m e 412 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.95 (dd, IH), 7.82 (dd, IH), 7.50-740 (m, 3H), 7.37 (dd, IH), 7.31 (d, IH), 7.04 (td, IH).
Example 10
2-((carboxycarbonyl)-2-(( 1 E)-3-( 1 ,3 -oxazinan-3 -yl)-3-oxo- 1 -propenyl)anilino)benzoic acid The desired product was prepared by substituting 2-((lE)-3-(4-moφholinyl)-3- oxo-1 -propenyl)phenylamine for 4-methoxyaniline in Example 3. MS (ESI(+)) m/e 425 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 7.93-7.87 (m, IH), 7.76 (d, IH), 7.48-7.20
(m, 7H), 7.16 (d, IH), 3.62 (br m, 8H). Example 11 2-((carboxycarbonyl)-3 -(trifluoromethyl)anilino)benzoic acid The desired product was prepared by substituting 3-trifluoromethylaniline for 4- methoxyaniline in Example 3. MS (ESI(-)) m/e 352 (M-H)"; 1H NMR (300 MHz, DMSO-d6) δ 7.93 (m, IH), 7.83-7.65 (m, 3H), 7.64-7.55 (m, 2H), 7.54-7.38 (m, 2H).
Example 12 2-((carboxycarbonyl)(cyclobutyl)amino)benzoic acid The desired product was prepared by substituting cyclobutylamine for cyclohexylamine in Example 22. MS (APCI(+)) m/e 264 (M+H)+; H NMR (500 MHz,
CD3CN) δ 8.00 (dd, IH), 7.66 (dt, IH), 7.53 (dt, IH), 7.32 (dd, IH), 4.86-4.79 (m, IH), 2.23-2.10 (m, IH), 1.95-1.90 (m, 2H), 1.70-1.64 (m, 2H), 1.64-1.60 (m, IH).
Example 13 2-((7-(benzyloxy)- 1 -naphthyl (carboxycarbonyl amino)benzoic acid
Example 13 A 7-(benzy loxy)- 1 -naphthalenamine A solution of 8-amino-2-naphthol (1.59 g, 10.0 mmol) in IN KOH in methanol (10 mL) was concentrated, dissolved in N,N-dimethylformamide (10 mL), treated with benzyl bromide (1.2 mL, 10.1 mmol), stined for two hours, poured into H2O (50 mL), and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 70:30 hexanes/ethyl acetate to provide the desired product.
Example 13B 2-((7-(benzyloxy)- 1 -naphthyl)(carboxycarbonyl)amino)benzoic acid The desired product was prepared as a mixture of rotamers by substituting Example 13A for 1-aminonaphthalene in Example 1. MS (ESI(+)) m/e 442 (M+H); H
NMR (300 MHz, DMSO-d6) δ 8.06 (br s, IH), 7.98-7.83 (m, 3H), 7.69 (dd, IH), 7.53-7.31 (m, 9H), 7.23 (dd, 2H), 6.86 (dd, IH), 5.23 (br s, IH), 5.10 (d, IH), 4.91 (d, IH).
Example 14 2-((carboxycarbonyl -2-(2-hydroxyethyl)anilino)benzoic acid
The desired product was prepared by substituting 2-(2-aminophenyl)ethanol for 4- methoxyaniline in Example 3. MS (ESI(+)) m/e 330 (M+H)+; !H NMR (300 MHz, DMSO-d6) δ 7.98 and 7.85 (2 dd, IH total ), 7.58-7.22 (m, 6H), 7.18 and 6.83 (2 d, IH total), 4.44 (t, 2H), 3.12-2.92 (m, 2H).
Example 15 2-((carboxycarbonyl)-2-methylanilino)benzoic acid The desired product was prepared by substituting ethyl (2E)-3-(2-bromophenyl)-2- propenoate and 2-methylaniline for Example 1 A and 2-aminonaphthalene, respectively, in
E Exxaammppllee 11.. MMSS((EESSII((++)))) mm//ee 330000 ((MM++HH))++;; HH NNMMRR ((330000 JΛ MHz, DMSO-d6) δ 7.55 (m, IH), 7.42 (m, 2H), 7.30 (m, 2H), 7.15 (m, 3H), 2.24 (s, 3H).
Example 16 2-((carboxycarbonyl)(2-methyl- 1 H-indol- 1 -yl)amino)benzoic acid The desired product was prepared by substituting 2-methyl-l H-indol- 1 -amine for 4-methoxyaniline in Example 3. MS (ESI(+)) m e 339 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.63-7.32 (m, 4H), 7.23-6.92 (m, 3H), 644-6.33 (m, IH), 6.26 (s, IH), 2.36
(s, 3H).
Example 17 2-((carboxycarbonyl)(7-hydroxy- 1 -naphthyl)amino)benzoic acid A solution of Example 13B (74 mg, 0.17 mmol) in dioxane (1 mL) at room temperature was treated with 10% Pd/C (10 mg) and 60% HClO4 (1 drop), stined under H2 (1 atmosphere) for 4 hours, and filtered through diatomaceous earth (Celite ). The filter cake was washed with ethyl acetate, and the combined filtrates were concentrated. The concentrate was purified by reverse-phase HPLC with acetonitrile to 70:30 (0.1% aqueous trifluoroacetic acid)/acetonitrile to provide the desired product as a 5:3 mixture of rotamers. MS (ESI(+)) m/e 374 (M+Na)+; 1H NMR (300 MHz, DMSO-d6) δ 10.04 (br s, IH), 9.91 (br s, IH), 7.87 (dd, 2H), 7.83 (d, 2H), 7.79 (d, IH), 7.61 (dd, IH), 7.55-7.21 (m, 5H), 7.16 (dd, IH), 7.12 (dd, IH), 6.92 (d, IH).
Example 18
2-((carboxycarbonyl)(7-((6-phenylhexyl)oxy)-l-naphthyl)amino)benzoic acid
Example 18A 1 -(7-(benzyloxy)- 1 -naphthyl)-2( 1 H)-quinolinone The desired product was prepared by substituting Example 13 A for 1- aminonaphthalene in Example IB. Example 18B 1 -(7-hydroxy- 1 -naphthyl)-2( 1 H)-quinolinone Example 18A (397 mg, 1.05 mmol) at room temperature was treated with 33% HBr in acetic acid (6 mL), stined for 1 hour, poured into water (30 mL), and extracted with ethyl acetate. The combined extracts were washed sequentially with water, saturated NaHCO3, and brine, dried (MgSO4), filtered, treated with silica gel (5 mL), and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with 75:25 ethyl acetate/hexanes to provide the desired product.
Example 18B l-(7-((6-phenylhexyl)oxy)-l-naphthyl)-2(lH)-quinolinone A solution of 6-phenyl- 1 - hexanol (31 mg, 0.17 mmol), Example 18A (50 mg, 0.17 mmol), and triphenylphosphine (46 mg, 0.17 mmol) in THF (1 mL) at room temperature was treated with diethylazodicarboxylate (30 mL, 0.19 mmol), stined for 54 hours, and concentrated. The concentrate was dissolved in 1 :1 ethyl acetate/hexanes, decanted, concentrated, and purified by flash column chromatography on silica gel with 1 : 1 ethyl acetate/hexanes to provide the desired product.
Example 18C
2-((carboxycarbonyl)(7-((6-phenylhexyl)oxy)- 1 -naphthyl)amino)benzoic acid The desired product was prepared by substituting Example 18B for Example IB in Example IC. MS (ESI(+)) m/e 512 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 7.96-7.81 (m, 3H), 7.65 (d, IH), 746-7.11 (m, 10H), 6.86 (d, IH), 3.99-3.81 (m, IH), 3.82-3.75 (m, IH), 2.56 (m, 2H), 1.56-143 (m, 4H), 142-1.20 (m, 4H).
Example 19 2-(( 1 , 1 '-biphenyl)-2-yl(carboxycarbonyl)amino)benzoic acid The desired product was prepared as a mixture of rotamers by substituting (1,1'- biphenyl)-2-amine for 4-methoxyaniline in Example 3. MS (ESI(-)) m/e 360 (M-H)"; H
NMR (300 MHz, DMSO-d6) δ 7.75 and 7.54 (m, IH total), 7.56-7.45 (m, 6H), 7.35-7.23 (m, 4H), 7.15 (m, IH), 6.68 and 6.44 (m, IH total); Anal. Calcd for C2iH15NO5-1.81H2O: C, 64.02; H, 4.76; N, 3.56. Found: C, 63.97; H, 4.41; N, 3.88.
Example 20
2-((l , 1 '-biphenyl)-4-yl(carboxycarbonyl)amino)benzoic acid The desired product was prepared by substituting (l,l'-biphenyl)-4-amine for 4- methoxyaniline in Example 3. MS (ESI(-)) m/e 360 (M-H)"; 1H NMR (300 MHz, DMSO- d6) δ 7.62 (m, 4H), 7.53 (m, IH), 7.48-741 (m, 5H), 7.36 (m, IH), 7.27 (d, 2H); Anal. Calcd for C2iHi5NO5-3.22H2O: C5 60.15; H, 5.15; N, 3.34. Found: C, 59.86; H, 4.43; N, 3.18.
Example 21 2-((carboxycarbonyl)(5,6,7,8-tetrahydro-l-naphthalenyl)amino)benzoic acid The desired product was prepared as a mixture of rotamers by substituting 5,6,7,8- tetrahydro-l-naphthalenarnine for 1-aminonaphfhalene in Example 1.
MS (ESI(+) m/e 340 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 7.92 (d, IH), 7.81 (dd, IH), 7.53 (dt, IH), 748 (dt, IH), 741 (dt, IH), 7.35 (dt, IH), 7.23-7.04 (m, 3H), 6.97 (m, IH), 6.84 (dd, IH), 3.11 (td, IH), 2.81 (br s, IH), 2.75 (m, IH), 2.63, (m, IH), 2.10 (m, IH), 1.83 (br s, IH), 1.71-1.63 (m, 2H), 1.62-1.51 (m, IH).
Example 22 2-((carboxycarbonyl)(cyclohexyl)amino)benzoic acid
Example 22A methyl 2-(cyclohexylamino)benzoate
A mixture of methyl-2-fluorobenzoate (158 mg, 1 mmol) and cyclohexylamine (210 mg, 2.05 mmol) in DMSO (1 mL) was heated to 100 °C for 18 hours, poured into water (10 mL), and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Example 22B methyl 2-(cyclohexyl(ethoxy(oxo)acetyl)amino)benzoate A solution of Example 22A (23 mg, 0.1 mmol) in diethyl ether (1 mL) at room temperature was treated with pyridine (15 mL) and ethyl chloro(oxo)acetate (15 mL), stined for 15 hours, diluted with IN HCl (5 mL), and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 70:30 ethyl acetate/hexanes to provide the desired product.
Example 22C
2-((carboxycarbonyl (cyclohexyl)amino)benzoic acid A mixture of Example 22B (18 mg, 0.054 mmol) in IN NaOH in 5:1 ethanokwater (1 mL) at room temperature was stined for 2.5 hours and concentrated. The concentrate was dissolved in water (5 mL), adjusted to pH <7 with IN HCl (2 mL), and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated provide the desired product. MS (ESI(+)) m/e 292 (M+H)+; 1H NMR
(300 MHz, CDC13) δ 8.06 (dd, IH), 7.64 (dt, IH), 7.50 (dt, IH), 7.32 (dd, IH), 4.50-4.42 (m, IH), 2.11-2.07 (m, IH), 1.85-1.75 (m, IH), 1.77-1.55 (m, 3H), 149-1.21 (m, 3H), 1.05-0.81 (m, IH).
Example 23
2-((carboxycarbonyl)(2,3 -dihydro- 1 -benzodioxin-6-yl)amino)benzoic acid The desired product was prepared by substituting 2,3 -dihydro- l,4-benzodioxin-6- amine for 4-methoxyaniline in Example 3.
MS (ESI(+)) m/e 344 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 7.52-7.38 (m, 4H), 6.78 (dd, IH), 6.72 (d, IH), 6.65 (dd, IH), 4.19 (s, 4H).
Example 24 2-((carboxycarbonyl)(3-methylcyclohexyl)amino)benzoic acid The desired product was prepared as mixtures of diastereomers and rotamers by substituting 3-methylcyclohexylamine for cyclohexylamine in Example 22.
MS (APCI(+)) m/e 323 (M+NH4)+; !H NMR (500 MHz,CD3Cl) δ 7.94 (m, 1H), 7.62 (m, IH), 7.51 (m, IH), 7.34 (m, IH), 4.65-4.57 (m, IH), 4.39-4.32 (m, IH), 2.10-1.97 (m, IH), 1.84-1.73 (m, IH), 1.70-1.20 (m, 4H), 1.19-1.05 (m, IH), 1.03-0.96 (m, 2H), 0.90 (d, IH), 0.78 (d, IH), 0.76-049 (m, IH).
Following Schemes 1, 2, and 3 and the examples described above, Example 25-33 can be prepared:
Example 25 2-((carboxycarbonyl)-2-((E)-2-carboxyethenyl)anilino)benzoic acid
Example 26 2-(2-(( 1 E -3 -((tert-butoxycarbonyl)amino)- 1 -propenyl)(carboxycarbonyl)anilino)benzoic acid
Example 27
2-((carboxycarbonyl)-2,3 -dimethylanilino)benzoic acid Example 28 2-((carboxycarbonyl)-4-chloro-3 -methylanilino)benzoic acid
Example 29 2-(2-(aminocarbonyl)(carboxycarbonyl)anilino)benzoic acid
Example 30 2-((7-(aminomethyl)-5,6,7,8-tetrahydro-l-naphthalenyl)(carboxycarbonyl)amino)benzoic acid
Example 31 2-((6-(aminomethyl)-5,6,7,8-tetrahydro-l-naphthalenyl)(carboxycarbonyl)amino)benzoic acid
Example 32
2-((carboxycarbonyl)(5-(2,3-diamino-3-oxopropyl)-5,6,7,8-tetrahydro-l- naphthalenyl)amino)benzoic acid
Example 33 2-((carboxycarbonyl)-4-(2,3-diamino-3-oxopropyl)anilino)benzoic acid
Example 34 2-r(carboxycarbonyl)(2-hydroxy-l-naphthyl)amino1benzoic acid
Example 34A toluene-4-sulfonic acid l-amino-naphthalen-2-yl ester A mixture of 1 -amino-2-naphthol hydrochloride (3g, 15 mmol), τ toluenesulfonyl chloride (2.9g, 15 mmol) and triethylamine (4.3mL, 31 mmol)in dichloromethane (150 mL) was stined at ambient temperature for 18hours, diluted with additional methylene chloride, washed with water, brine, dried (MgSO ), filtered, and concentrated under reduced pressure. The product was purified via silica gel chromatography, eluting with 3:1 methylene chloride hexanes to provide the titled compound (940mg, 20%). Example 34B 2- 2-(toluene-4-sulfonyloxy)-naphthalen- 1 -ylamino] -benzoic acid The desired product was prepared according to the method described in Example 48E using diphenyliodonium-2-carboxylate and toluene-4-sulfonic acid 1-amino- naphthalen-2-yl ester.
Example 34C 2- f(2-hy droxy-naphthalen- 1 -yl)-oxalyl-aminol -benzoic acid
To a solution of 2-[2-(toluene-4-sulfonyloxy)-naphthalen-l-ylamino]-benzoic acid (326mg, 0.752 mmol) and N,N-diisopropylethylamine (0.7mL, 3.8 mmol) in toluene (lOmL) was added ethyl oxalyl chloride (04mL, 3.8 mmol). The reaction was heated to reflux for lShours, cooled and extracted with IM NaOH. The aqueous layer was extracted with diethyl ether, the pH adjusted to 2 by the addition of IM HCl, and further extracted with ethyl acetate. The combined ethyl acetate layers were dried (MgSO4), filtered, concentrated under reduced pressure and purified via silica gel chromatography eluting with 1 :1 hexanes: ethyl acetate to provide the oxalamide ethyl ester 395mg (99%). The ester was taken up in a mixture of 1.39 M NaOH (8 mL) in 20% aqueous ethanol (20 mL) and stined at ambient temperature for 16 hours. The solvents were removed under reduced pressure, the residue was taken up in water, acidified to a pH of 2 with IM HCl, and extracted with ethyl acetate. The combined ethyl acetate was dried (MgSO4), filtered, and concentrated under reduced pressure to provide the title compound (253mg (96%). !H NMR (300MHz, d6-DMSO) δ 8.16 (d, IH, J = 8.1), 7.89-7.80 (m, 2H), 749-744 (m, IH), 7.39-7.24 (m, 4H), 7.11 (d, IH, J = 8.4), 6.84 (dd, IH, J = 1.0, 8.2); MS (ESI) m/z= 350
(M-H), 369 (M+NH4+), 374 (M+Na+).
Example 35 N-acetyl-4-r(carboxycarbonyl)(2-carboxyphenyl)aminol-N-pentyl-l-naphthylalaninamide
Example 35A 2-acetylamino-3-(4-amino-naphthalen-l-yl)-acrylic acid methyl ester To a mixture of 4-bromo-l-naphthylamine (2.5 g, 11.3 mmol), Pd(OAc)2 (140 mg,
0.63 mmol), P(o-tolyl)3 (570 mg, 1.87 mmol) in anhydrous N,N-dimethylformamide (10 mL) in a pressure tube was added methyl 2-acetamidoacrylate (2.1 g, 14.7 mmol) and triethylamine (5.3 mL, 37.5 mmol). The mixture was flushed with nitrogen for 3 min before it was sealed and heated to 110 °C for 4 hours. The reaction mixture was cool to ambient temperature, partitioned between ethyl acetate and water. The aqueous layer was extracted once with ethyl acetate and the combined organic layers were washed with brine, dried (Na SO4), filtered, concentrated under reduced pressure and purified on a silica gel to provide the titled compound (2.5 g, 76%).
Example 35B
2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid methyl ester To a solution containing 2-acetylamino-3-(4-amino-naphthalen-l-yl)-acrylic acid methyl ester (2.5 g, 8.8 mmol) in ethyl acetate/methanol (50 mL, 1:1 by volume) under N atmosphere was added Pd/C (10%, 250 mg). The reaction flask was capped with a H2 balloon and heated to 60 °C for 18 hours. The mixture was filtered through celite, the filtration bed washed with ethyl acetate/methanol (2 x 25 mL, 1:1). The combined filtrate was concentrated under reduced pressure to provide the titled compound (2.5 g, 100%).
Example 35C
2-acetylamino-3-(4-amino-naphthalen- 1 -yl)-propionic acid To a solution containing 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid methyl ester (2.5 g, 8.8 mmol) in methanol (50 mL) was added dropwise 3N NaOH (4.75 mL, 14.3 mmol) and stined for 3 hours. The mixture was reduced in volume under reduced pressure, acidified to pH ~ 4.5 with 3N HCl. The mixture was concentrated to dryness under reduced pressure, taken up in methanol/dichloromethane (10%, 25 mL), filtered through celite. The filter cake was washed with additional methanol/dichloromethane (10%, 25 mL). The filtrate was concentrated under reduced pressure to provide the titled compound (1.75 g, 74%).
Example 35D 2-acetylamino-3-(4-amino-naphfhalen- 1 -yl)-N-pentyl-propionamide A solution of 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid (500 mg, 1.84 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (493 mg, 2.57 mmol), 1-hydroxybenzotriazole hydrate (360 mg, 2.21 mmol), amylamine (320 μL,
2.75 mmol) in anhydrous N,N-dimethylformamide (10 mL) was adjusted to the pH~6 by the addition of triethylamine and stined for 5 hours. The reaction was diluted with water and extracted with ethyl acetate (3x 15mL). The combined ethyl acetate was washed with Water, brine, dried (Na SO4), concentrated under reduced pressure and purified on a silica gel to provide the titled compound (552 mg, 1.62 mmol, 88%).
Example 35E 2-r4-(2-acetylamino-2-pentylcarbamoyl-ethyl)-naphthalen-l-ylamino1-benzoic acid To a stirred suspension of 2-acetylamino-3-(4-amino-naphthalen-l-yl)-N-pentyl- propionamide (552mg, 1.62 mmol) and diphenyliodonium-2-carboxylate monohydrate (580mg, 1.78 mmol) in N,N-dimethylformamide (10 mL) was added anhydrous Cu(OAc)2
(14.6 mg, 0.081 mmol). The resulting mixture was heated to 95 °C for 1.5 hour. The reaction mixture concentrated under reduced pressure after which the N,N- dimethylformamide was distilled out. The residue was further concentrated to a constant weight on an oil pump (790 mg).
Example 35F 2- { r4-(2-acetylamino-2-pentylcarbamoyl-ethyl)-naphthalen- 1 -yll-ethoxyoxalyl-amino } - benzoic acid A stined solution of 2-[4-(2-acetylamino-2-pentylcarbamoyl-ethyl)-naphthalen- 1 - ylamino] -benzoic acid (790 mg, 1.71 mmol) and triethylamine (680 μL, 5.13 mmol) in dichloromethane (10 mL) was cooled to 0 °C, treated slowly with ethyl oxalyl chloride (452 μL, 4.04 mmol) over 30 min, warmed to room temperature, stined for 16 hours, treated with IN HCl (4 mL), and extracted with dichloromethane (2 x 20 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated. The concentrate was purified by a Gilson preparative HPLC to give 291 mg of the acylated product (0.52 mmol, 31% over two steps) as a light yellow foam.
Example 35G
N-acetyl-4-r(carboxycarbonyl)(2-carboxyphenyl)aminol-N-pentyl-l-naphthylalaninamide
A solution of 2-{[4-(2-acetylamino-2-pentylcarbamoyl-ethyl)-naphthalen-l-yl]- ethoxyoxalyl-amino} -benzoic acid (291 mg, 0.52 mmol) in methanol (5 mL) at room temperature was treated with IN NaOH (1.3 mL, 1.3 mmol), stined for 2 hours, treated with IN HCl (2 mL), and purified by reverse-phase HPLC with acetonitrile to 95:5 (0.1% aqueous trifluoroacetic acid)/acetonifrile to provide 200 mg of the desired product (0.37mmol, 72%). MS (ESI+) m/e 534 (M+H)+; 1H NMR (300 MHz,DMSO-d6) (A mixture of rotamers) δ 845-8.15 (m, 3H), 8.10-7.80 (m, 3H), 7.68 (brs, IH), 7.64-7.27 (m, 4H), 7.18 (brs, IH), 6.86-6.77 (m, IH), 4.58 (q, J= 7.4 Hz, IH), 3.67-2.82 (m, 6H), 1.85- 1.70 (three s, 3H in total), 1.37-1.00 (m, 4H), 0.92-0.69 (m, 3H).
Example 36 N-acetyl-4-r(carboxycarbonyl)(2-carboxyphenyl)amino1-N-pentyl-3-(2-hydroxyethane)- phenylalaninamide
Example 36A 2-(2-amino-5-bromo-phenyl)-ethanol To a solution of 2-aminophenethyl alcohol (10. Og, 72.9 mmol) in acetic acid (60 L) at 10 °C was added Br (3.8 mL, 72.9 mmol) in acetic acid (5 mL). Additional acetic acid (30 mL) was added and the reaction was stined for 1 hour. The mixture was filtered and the filter cake washed with diethyl ether. The solid was then partitioned between ethyl acetate and aqueous 3N NaOH. The organic layer was washed with brine, dried (Na SO4), filtered and concentrated under reduced pressure to provide the titled compound (15.8 g).
Example 36B 4-bromo-2-( 1 -methyl- 1 -trimethylsilany l-ethoxymethyl)-phenylamine To a solution of 2-(2-amino-5-bromo-phenyl)-ethanol (15.8 g, 72.8 mmol) in anhydrous N,N-dimethylformamide (50 mL) was added imidazole (6.0 g, 88.1 mmol) and tert-butyl dimethylsilyl chloride (12.0 g, 79.6 mmol) sequentially. The resulting mixture was stined at ambient temperature for 1.5 hour, partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO ), filtered, concentrated under reduced pressure and purified on silica gel with 10-15% ethyl acetate/hexanes to provide the titled compound (15.0 g, 62.3%). MS (ESI+) m/e 330, 332 (M+H)+.
Example 36C 2-acetylammo-3-r4-amino-3-(2-hydroxy-ethyl)-phenyll-propionic acid The titled compound was prepared according to the procedure described in
Example 79 B-C, substituting 4-bromo-2-(l -methyl- 1-trimethylsilanyl-ethoxymetbyl)- phenylamine for the 4-bromo-2-ethylalanine. The tert butyldimethyl silyl protecting group came off during the hydrogenation step as described in Example 79C. MS (ESI+) m/e 381 (M+H)+.
Example 36D N-acetyl-4-r(carboxycarbonyl)(2-carboxyphenyl)aminol-N-pentyl-3-(2-hydroxyethane)- phenylalaninamide The titled compound was prepared according to the procedure described in 35 C-G by substituting 2-acetylamino-3-[4-amino-3-(2-hydroxy-ethyl)-phenyl]-propionic acid for 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid. MS (ESI+) m e 528 (M+H) , 545 (M+NH4); 1H NMR (300 MHz,DMSO-d6) (A mixture of rotamers) δ 8.14-7.58 (m,
3H), 7.52-6.85 (m, 6H), 4.80-4.30 (m, 3H), 3.60-3.79 (m, 2H), 3.04-2.64 (m, 6H), 1.82- 1.73 (multiple s, 3H in total), 140-1.10 (m, 4H), 0.84 (t, J= 74 Hz, 3H).
Example 37 4-r(carboxycarbonyl)(2-carboxyphenyl)amino1-6-{[N-acetyl-3-(l- naphthyl)alany!1 amino } hexanoic acid The titled compound was prepared according to the procedure described in 35 D-G by substituting 6-amino-hexanoic acid methyl ester HCl salt for amylamine. MS (ESI+) m/e 578 (M+H)+; !H ΝMR (300 MHz,DMSO-d6) (A mixture of totamers) δ 8.45-8.15 (m, 3H), 8.10-7.80 (m, 3H), 7.68 (brs, IH), 7.65-7.28 (m, 4H), 7.17 (brs, IH), 6.78-6.85 (m,
IH), 4.65-4.50 (m, IH), 2.85-3.60 (m, 4H), 2.14 (q, J= 7.1 Hz, 2H), 1.83-1.70 (multiple s, 3H in total), 1.56-1.01 (m, 6H).
Example 38 4-r(carboxycarbonyl)(2-carboxyphenyl)amino]-3-r(lE)-3-amino-3-oxo-l-propenyl1-N-
(tert-butoxycarbonyl)-N-pentyl-L-phenylalaninamide
Example 38A r2-(4-amino-phenyl)-l-pentylcarbamoyl-ethyn-carbamic acid tert-butyl ester
The titled compound was prepared according to the procedure described in Example 35 D substituting Ν-boc p-amino phenylalanine for 2-acetylamino-3-(4-amino- naphthalen- 1 -yl)-propionic acid.
Example 38B r2-(4-amino-3-iodo-phenyl)-l-pentylcarbamoyl-ethyll-carbamic acid tert-butyl ester To a stined solution of [2-(4-amino-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester (1.2g, 3.4 mmol) in acetic acid (5 mL) was added Nal (0.59g, 3.9 mmol) followed by the addition of chloramines-T trihydrate (l.lg, 3.9 mmol). The solution was stined for one hour, concentrated under reduced pressure, diluted with aqueous Na2S2O4 solution, and partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure and purified on silica gel eluting with 20% ethyl acetate/hexanes to provide the titled compound 0.78g (46%). MS (ESI+) m/e 476 (M+H)+.
Example 38C 2-r4-(2-tert-butoxycarbonylamino-2-pentylcarbamoyl-ethyl)-2-iodo-phenylaminol- benzoic acid To a stined suspension of [2-(4-amino-3-iodo-phenyl)-l-pentylcarbamoyl-ethyl]- carbamic acid tert-butyl ester (222mg, 0.47 mmol) and diphenyliodonium-2-carboxylate monohydrate (168mg, 0.49 mmol) in N,N-dimethylformamide (5 mL) was added anhydrous Cu(OAc) (7.3 mg, 0.040 mmol). The resulting mixture was heated to 95 °C for 1.5 hour. The reaction mixture concentrated under reduced pressure after which the N,N- dimethylformamide was distilled out. The residue was further concentrated to a constant weight on an oil pump to give the titled compound as a light brown solid (306 mg). MS
(ESI+) m/e 534 (M+H)+.
Example 38D 2-r4-(2-tert-Butoxycarbonylamino-2-pentylcarbamoyl-ethyl)-2-r(lE)-3-amino-3-oxo-l- propenyl] -pheny lamino] -benzoic acid
To a mixture of 2-[4-(2-tert-butoxycarbonylamino-2-pentylcarbamoyl-ethyl)-2- iodo-phenylamino]-benzoic acid (306 mg, 0.51 mmol), Pd(OAc) (6 mg, 0.026 mmol), P(o-tolyl)3 (23 mg, 0.80 mmol) in anhydrous N,N-dimethylformamide (10 mL) in a pressure tube was added acrylamide (66 mg, 0.93 mmol) and triethylamine (0.25 mL, 1.79 mmol). The mixture was flushed with nitrogen for 3 minutes before it was sealed and heated to 90 °C for 16 hours. The reaction mixture was cool to ambient temperature, solvent was removed on a SpeedVac. The residue was taken up in methanol and purified on a Gilson preparative HPLC using acetonitrile:0.3 mM aqueous NH4OAc to provide the titled compound (153 mg, 0.28 mmol). MS (ΕSI+) m/e 539 (M+H)+. Example 38E 4-r(carboxycarbonyl)(2-carboxyphenyl)amino1-3-r(lE)-3-amino-3-oxo-l-propenyll-N- (tert-butoxycarbonyl)-N-pentyl-L-phenylalaninamide A stined solution of 2-[4-(2-tert-Butoxycarbonylamino-2-pentylcarbamoyl-ethyl)- 2- [(lE)-3-amino-3 -oxo- l-propenyl]-phenylamino] -benzoic acid (153 mg, 0.28 mmol) and triethylamine (119 μL, 0.85 mmol) in dichloromethane (3 mL) was cooled to 0 °C, treated slowly with ethyl oxalyl chloride (70 μL, 0.63 mmol) over 30 minutes, warmed to room temperature, stined for 16 hours, treated with aqueous IN HCl (4 mL), and extracted with dichloromethane (2 x 20 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated. The concentrate was purified by a Gilson preparative HPLC. The residue
(89 mg, 0.14 mmol) in methanol (2 mL) at room temperature was treated with aqueous IN NaOH (0.42 mL, 042 mmol), stined for 2 hours, treated with aqueous IN HCl (1 mL), and purified by reverse-phase HPLC eluting with acetonitrile: 3 mM aqueous NH4OAc ) to provide the titled compound (65 mg, 76%). MS (ΕSI+) m/e 628 (M+NH4)+; H NMR (300 MHz,DMSO-d6) (A mixture of totamers) δ 7.81 (dd, J= 2.1, 84 Hz, IH), 7.63 (d, J
= 84 Hz, 2H), 7.72-6.83 (m, 7H), 6.79 (t, J= 7.5 Hz, IH), 6.52 (d, J= 15.8 Hz, IH), 4.19- 4.01 (m, IH), 3.10-2.82 (m, 4H), 1.31-1.10 (m, 15H), 0.83 (t, J= 7.2 Hz, 3H).
Example 39
N-acetyl-4-r(carboxycarbonyl)(2-carboxyphenyl)aminol-3-isopropyl-N- pentylphenylalaninamide
Example 39A
2-acetylamino-3 -(4-amino-3 -isopropyl-phenyD-propionic acid The titled compound was prepared according to the procedure described in Example 35 A-C, substituting 4-bromo-2-isopropylaniline for the 4-bromo-l- naphthylamine in Example 35 A.
Example 39B N-acetyl-4- [(carboxy carbonyl)(2-carboxyphenyl)amino1 -3 -isopropyl-N- pentylphenylalaninamide The titled compound was prepared according to the procedure described in
Example 35 D-G, substituting 2-acetylamino-3-(4-amino-3-isopropyl-phenyl)-propionic acid from Example 39A for 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid in Example 35 D. MS (ESI(+)) m/e 526 (M+H)+, 543(M+NH4)+; 1H NMR (500 MHz, DMSO-d6) A mixture of rotamers: δ 7.90-8.16 (m, 2H), 6.73-7.60 (m, 4H), 4.40-4.52 (m, c.a. 0.6 H), 2.7-3.3 (m, c.a. 5.4H), 1.77 and 1.74 (s, 3H), 1.1-141 (m, 11H), 0.62-0.90 (m, 3H).
Example 40 4-r(carboxycarbonyl)(2-carboxyphenyl)amino]-6-{ N-acetyl-3-(l- piperidiny l)pheny lalanyll amino } hexanoic acid
Example 40A 2-acetylamino-3 -(4-amino-3 -piperidin- 1 -yl-pheny l)-propionic acid The desired product was prepared according to the procedure described in Example
35 A-C, substituting 4-bromo-2-piperidin-l-yl-aniline for. 4-bromo-l-naphthylamine in Example 35 A.
Example 40 B
4- r(carboxycarbonyl)(2-carboxyphenyl)amino1 -6- { [N-acetyl-3 -( 1 - piperidiny l)pheny lalanyll amino } hexanoic acid The desired product was prepared according to the procedure described in Example 35 D-G, substituting 2-acetylamino-3-(4-amino-3-piperidin-l-yl-phenyl)-propionic acid for 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid and substituting 6-amino- hexanoic acid methyl ester HCl salt for amylamine in Example 35D. MS (ESI(+)) m/e 611 (M+H)+, 633(M+Νa)+; 1H NMR (500 MHz, DMSO-d6) a mixture of rotamers: δ 7.90-8.16 (m, 2H), 6.73-7.60 (m, 4H), 440-4.52 (br m, c.a. 0.6 H), 2.7-3.3 (m, c.a. 8.4H), 1.77 and 1.74 (s, 3H), 1.19-1.62 (m, 18H).
Example 41 2- { (carboxycarbonyl) f2-(3 -methyl- 1 -piperidiny l)pheny 11 amino } benzoic acid
Example 41 A 3 -Methyl- 1 -(2-nitro-phenyl)-piperidine A solution of 3-methylpiperidine (0.848 mL, 7.22 mmol), 2-chloronitrobenzene (1.04g, 6.57 mmol) and diisopropylethylamine (1.26 mL, 7.22 mmol) in DMSO (5 mL) were heated to 90-95 °C under N2 overnight. The mixture was cooled to ambient temperature then partioned between a mixture of ethyl acetate :hexane (1:1) and water (1:1, 75 mL total). The organic phase separated, dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash column chromatography (5% to 8% ethyl acetate/hexane) to give 2-(3-methyl-piperidin-l-yl)-nitrobenzene (1.03 g).
Exmaple 41B
2-(3-methyl-piperidin- 1 -yl)-phenylamine A solution of 2-(3-methyl-piperidin-l-yl)-nitrobenzene (1.00 g, 4.54 mmol) and 10% Pd/C (0.24 g, 0.227 mmol) in ethanol/ethyl acetate (7/3 mL) was stined under an atmosphere of hydrogen for 24 hours. The mixture was filtered through Celite and the solids were washed thoroughly with ethyl acetate. The combined filtrate was concentrated to under reduced pressure to provide the titled compound (0.86 g).
Example 41 C 2- { (carboxycarbony 1) l~2-(3 -methyl- 1 -piperidiny l)phenyll amino } benzoic acid
The desired product was prepared according to the procedure described in Example 3 by substituting 2-(3-methyl-piperidin-l-yl)-phenylamine for 4-methoxyaniline. MS (ESI(+)) m/e 383 (M+H)+; H NMR (500 MHz, DMSO-d6) a mixture of rotamers: δ 7.80 (m, IH), 7.55 (m, IH), 7.22-7.38 (m, 3H), 6.9-7.18 (m, 3H), 2.6-3.3 (m, 3H), 2.1-2.4 (m, 2H), 1.2-1.8 (m, 4H), 0.8-1.0 (m, 4H).
Example 42 2- { (carboxycarbony 1) |~5 -hy droxy-2-( 1 -piperidiny Dpheny 11 amino } benzoic acid
Example 42A l-(4-Methoxymethoxy-2-nitro-phenyl)-piperidine To a mixture of 4-chloro-3-nitrophenol (l.Og, 5.8 mmol) and K2CO3 (1.6g, 12 mmol)in N,N-dimethylformamide (5 mL) at ambient temperature was slowly added chloromethyl methylether. After 10 min, piperidine (1.2 mL, 5.8 mmol) was added, the mixture was heated to 80 °C for 2 days, cooled to ambient temperature, partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na SO4), filtered, concentrated under reduced pressure and purified on a silica gel flash column eluting with 15 % EtOAc/hexanes to provide the titled compound (0.98g, 64%).
Example 42B 2- [(5 -methoxymethoxy-2-piperidin- 1 -yl-phenyl)-oxaly 1-amino] -benzoic acid The titled compound was prepared according to the procedure described in Example 41B-C, substituting the l-(4-methoxymethoxy-2-nitro-phenyl)-piperidine for 3- methyl- l-(2-nitro-phenyl)-piperidine in Example 41 B. MS (ESI+) m/e 429 (M+H)+.
Example 42C 2- { (carboxy carbonyl) [5 -hy droxy-2-( 1 -piperidiny Dphenyl] amino } benzoic acid A solution containing 2-[(5-methoxymethoxy-2-piperidin-l-yl-phenyl)-oxalyl- amino] -benzoic acid (25mg, 0.058 mmol) in methylene chloride/trifluoroacetic acid (2 mL, 1 :1, v:v) was stined at ambient temperature for 2hours, concentrated under reduced pressure, taken up in diethyl ether and filtered. The filter cake was dried to constant weigh to provide the titled compound (15 mg, 67%). MS (ESI+) m/e 385 (M+H)+; *H NMR (300 MHz,DMSO-d6) (A mixture of rotamers) δ 9.52 (brs, IH), 7.79 (dd, J= 2.1, 8.4 Hz, IH), 7.53 (td, J= 2.1, 8.4 Hz, IH), 7.37 (td, J= 0.9, 7.65 Hz, IH), 7.20 (brd, J= 7.5 Hz,
IH), 6.99 (brm, IH), 6.70 (brd, J= 7.5 Hz, IH), 6.55 (brm, IH), 2.83-2.56 (m, 4H), 1.69- 1.30 (m, 6H).
Example 43
4- Kcarboxycarbonyl) (2-carboxyphenyl)aminol -3 - 1~( 1 E)-3 -amino-3 -oxo- 1 -propenyl] -N- (methylsulfonyl)-N-pentyl-L-phenylalaninamide
Example 43A
2-amino-3-(4-nitro-phenyl)-Ν-pentyl-propionamide A solution containing [2-(4-nitro-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester from Example 50A (500mg, 1.3 mmol) in methylene chloride/trifluoroacetic acid (10 mL, 1 :1, v:v) was stined at ambient temperature for 2 hours, concentrated under reduced pressure to provide the titled compound as its trifluoroacetic acid salt. Example 43B 2-methanesulfonylamino-3-(4-nitro-phenyl)-N-pentyl-propionamide To a solution of 2-amino-3-(4-nitro-phenyl)-N-pentyl-propionamide (368mg, 1.3 mmol) in methylene chloride (10 mL) at 0 °C was added triethylamine (500 μL, 3.6 mmol), followed by methane sulfonyl chloride (122 μL, 1.6 mmol). After stining at ambient temperature for one hour, the reaction mixture was partitioned between ethyl acetate and aqueous 3N HCl. The organic layer was washed with aqueous NaHCO3, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound.
Example 43 C 3-(4-amino-phenyl)-2-methanesulfonylamino-N-pentyl-propionamide
The titled compound was prepared according to the procedure described for Example 5 OB, substituting 2-methanesulfonylamino-3-(4-nitro-phenyl)-N-pentyl- propionamide for [2-(4-nitro-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester.
Example 43 D 3-(4-amino-3-iodo-phenyl)-2-methanesulfonylamino-N-pentyl-propionamide The titled compound was prepared according to the procedure described for Example 38B, substituting 3-(4-amino-phenyl)-2-methanesulfonylamino-N-pentyl- propionamide for [2-(4-amino-3-iodo-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester.
Example 43E 4- r(carboxycarbonyl)(2-carboxyphenyl)amino"l-3 - \(1 E)-3 -amino-3 -oxo- 1 -propenyl"|-N- (methylsulfonyl)-N-pentyl-L-phenylalaninamide The titled compound was prepared according to the procedure described for Example 38 C-E, substituting 3-(4-amino-3-iodo-phenyl)-2-methanesulfonylamino-Ν- pentyl-propionamide for 2-[4-(2-tert-butoxycarbonylamino-2-pentylcarbamoyl-ethyl)-2- iodo-phenylaminoj-benzoic acid. MS (ESI+) m/e 589 (M+H)+, 606 (M+NH4); *H NMR (300 MHz,DMSO-d6) (A mixture of rotamers) δ 8.05-7.92 (m, IH), 7.79 (d, J= 15.6 Hz, IH), 7.86-7.23 (m, 7H), 7.17 (d, J= 7.8 Hz, IH), 7.05 and 6.79 (d, J= 8.4 Hz, IH in total), 6.74-6.53 (three sets of d, J= 15.6 Hz, IH in total), 4.38 (overlapping m, IH), 3.10- 2.69 (m, 4H), 2.43 (s, 3H), 1.11-1.42 (m, 6H), 0.90-0.77 (m, 3H).
Example 44 4-f(carboxycarbonyl)(2-carboxyphenyl)amino1-3-(3-amino-3-oxopropyl)-N- r(isopropylamino)carbonyl1-N-pentyl-L-phenylalaninamide A solution containing 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-[(lE)-3- amino-3 -oxo- 1 -propenyl] -N- [(isopropylamino)carbony 1] -N-pentyl-L-pheny lalaninamide (25mg, 43 mmol) and 10% Pd/C (lOmg) in methanol/ethyl acetate (2 mL, l :l/v:v) was stined under an atmosphere of hydrogen for 2 hours. The mixture was filtered through celite and concentrated under reduced pressure to provide the titled compound (20 mg, 80%). MS (ΕSI+) m/e 598 (M+H)+.
Example 45 4-r(carboxycarbonyl)(2-carboxyphenyl)amino1-3-r(lE)-3-amino-3-oxo-l-propenyl]-N- r(isopropylamino)carbonyl]-N-pentyl-L-phenylalaninamide
Example 45A 2-(3-isopropyl-ureido)-3-(4-nitro-phenyl)-Ν-pentyl-propionamide
The titled compound was prepared according to the procedure described for Example 43B, substituting i-propyl isocyanate for the methane sulfonyl chloride.
Example 45B
4-amino-N-r(isopropylamino)carbonyl]-N-pentyl-L-phenylalaninamide The titled compound was prepared according to the procedure described for Example 50B, substituting 2-(3-isopropyl-ureido)-3-(4-nitro-phenyl)-Ν-pentyl- propionamide for [2-(4-nitro-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester.. Example 45 C
4-r(carboxycarbonyl)(2-carboxyphenyl)amino]-3-[(lE)-3-amino-3-oxo-l-propenyl1-N- r(isopropylamino)carbonyl]-N-pentyl-L-phenylalaninamide
The titled compound was prepared according to the procedure described for Example 38B-E substituting 4-amino-N-[(isopropylamino)carbonyl]-N-pentyl-L- phenylalaninamide for [2-(4-amino-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert- butyl ester. MS (ESI+) m/e 596 (M+H)+; !H ΝMR (300 MHz,DMSO-d6) (A mixture of rotamers) δ 8.15-7.92 (m, IH), 7.79 (d, J= 15.6 Hz, IH), 7.86-7.23 (m, 7H), 7.17 (d, J= 7.8 Hz, IH), 7.05 and 6.79 (d, J= 84 Hz, IH in total), 6.74-6.53 (three sets of d, J= 15.6 Hz, IH in total), 4.35 (overlapping m, IH), 3.62 (qd, J= 12.6, 6.6 Hz, IH), 3.10-2.69 (m,
4H), 1.30 (t, J= 6.6 Hz, 6H), 1.11-142 (m, 6H), 0.90-0.77 (m, 3H).
Example 46 i 2-((carboxycarbonyl) |2-[4-(hydroxymethyl)- 1 -piperidinyl]phenyl} amino)benzoic acid
Example 46 A ri-(2-amino-phenyl)-piperidin-4-yl]-methanol The titled compound was prepared according to the procedure described in Example 41 by substituting 3-methylpiperidine with piperidin-4-yl-methanol.
Example 46B 2-((carboxycarbonyl){2-[4-(hydroxymethyl)-l-piperidinynphenyl}amino)benzoic acid The desired product was prepared according to the procedure described in Example 3 by substituting [l-(2-amino-phenyl)-piperidin-4-yl]-methanol for 4-methoxyaniline. MS (ESI(+)) m/e 399 (M+H)+; 1H ΝMR (500 MHz, DMSO-d6) a mixture of rotamers: δ 7.80
(m, IH), 7.55 (m, IH), 7.22-7.38 (m, 3H), 6.9-7.18 (m, 3H), 2.6-3.3 (m, 2H), 2.1-2.4 (m, 2H), 1.5-1.8 (m, 4H),1.25 (t, IH), 1.05 (t, IH), 0.9-1.0 (m, 2H).
Example 47
N-acetyl-4-r(carboxycarbonyl)(2-carboxyphenyl)amino]-N-pentyl-4-(l- piperidinyl)phenylalaninamide The desired product was prepared according to the procedure described in Example 35 D-G, substituting 2-acetylamino-3-(4-amino-3-piperidin-l-yl-phenyl)-propionic acid from Example 40 A for 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid in Example 35D. MS (ESI(+)) m/e 567 (M+H)+; 1H NMR (500 MHz, DMSO-d6) a mixture of rotamers: δ 6.9-8.0 (m, 7H), 4.4 (br m, IH), 3.3-4.1(br m, 6H), 2.6-3.0 (m, 6H), 1.1- 1.78 (m, 11H), 0.82 (m, 2H).
Example 48 N-acetyl-4-r(carboxycarbonyl)(2-carboxyphenyl)amino]-3-ethylphenylalanyl-N-methyl-4- nitro-L-phenylalaninamide
Example 48A (S)-N-boc-4-nitrophenylalanine
To a solution of (S)-4-nitrophenylalanine (2.00g, 9.51 mmol) in aqueous 2M NaOH (lOmL) and THF (5 mL), was added di-tertbutyldicarbonate (2.00g, 9.17 mmol) in THF (5mL). The reaction was stined at ambient temperature for lhour, diluted with H O (25mL) and IM HCl (25mL), extracted with ether (3 x 25 mL). The combined ether layers were extracted with brine (1 x 25mL), dried (MgSO4), filtered, and concentrated under reduced pressure to provide the titled compound (2.5 lg, 88%).
Example 48B (S)-ri-methylcarbamoyl-2-(4-nitro-phenyl)-ethyl]-carbamic acid tert-butyl ester
To a solution of (S)-N-boc-4-nitrophenylalanine (2.5g, 8.1 mmol) and triethylamine (1.3mL, 9.3 mmol) in THF (30 mL) at 0 °C, was slowly added isobutylchloroformate (l.OmL, 7.7 mmol) dropwise. After 10 min, methylamine (7mL, 2M in THF) was added. The reaction was stined for 0.5 hour, concentrated under reduced pressure. The residue was suspended in H O (25mL) and filtered. The filter cake was washed with cold H O, and left on the filter to dry. The solid was suspended in ethyl acetate and concentrated under reduced pressure to provide the titled compound (1.74g, 66%). 1H NMR (300MHz, d6-DMSO) δ 8.16 (d, IH, J = 8.5), 7.89 (q, IH, J = 44), 7.52 (d, 2H, J = 8.8), 7.01 (d, IH, J = 8.5), 4.16 (ddd, IH, J = 4.3, 9.6, 9.6), 3.08 (dd, IH, J = 4.6, 13.7), 2.85 (dd, IH, J - 10.3, 13.4), 2.59 (d, 3H, J = 4.4), 1.27 (s, 9H); MS (ESI) m/z=
324 (MH+). Example 48C (S)-2-amino-N-methyl-3-(4-nitro-phenyl)-propionamide (S)-[l-methylcarbamoyl-2-(4-nitro-phenyl)-ethyl]-carbamic acid tert-butyl ester (400mg, 1.24 mmol) was dissolved in trifluoroacetic acid. (2mL) and stirred for 1 hour then concentrated under reduced pressure. The residue was taken up in ethyl acetate (30 mL) and H O (5mL). Solid K2CO3 was added to the mixture until an aliquot of ethyl acetate mixed with H O was basic. The organic phase was seperated, dried (MgSO4), filtered, and concentrated under reduced pressure to provide the titled compound (900mg). . 1H NMR (300MHz, d6-DMSO) δ 8.14 (m, 2H), 7.88 (q, IH, J = 4.8), 7.48 (m, 2H), 3.43
(dd, 1, J = 5.1, 8.1), 3.03 (dd, 1, J = 5.1, 13.2), 2.78 (dd, 1, J = 8.5, 13.2), 2.57 (d, 3, J = 4.8), 2.40 (bs, 2); MS (ESI) m/z= 224 (MH+).
Example 48D
2-(S)- 2-(S)-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionylamino]-N-methyl-3-(4- nitro-phenyl)-propionamide and 2-(S)- r2-(R)-acetylamino-3 -(4-amino-3 -ethyl-phenyl)- propionylamino] -N-methy 1-3 -(4-nitro-phenyl)-propionamide To a solution of (±)2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid (310mg), (S)-2-amino-N-methyl-3-(4-nitro-phenyl)-propionamide (900mg, 1.2 mmol) and triethylamine (400μL) in N,N-dimethylformamide (3mL) at 0 °C was added PyBOP (980mg, 1.88 mmol). The mixture was stined at ambient temperature for 2 hours, diluted with water (lOmL) and extracted with ethyl acetate (3 x 35 mL). The combined organic layers were dried (MgSO4), filtered, concentrated under reduced pressure and crystallized from ethyl acetate to provide the titled compound (244mg, 45%). IH NMR (300MHz, d6-
DMSO) 8:5 mixture of diastereomers, δ 8.38 (d, IH, J = 8.8), 8.15-8.09 (m, 2H), 7.98-7.91 (m, 2H), 7.55 (q, IH, J = 4.7), 6.76-6.60 (m, 2H), 6.45 (t, 1H, J - 8.1), 4.66 (bs, 1H), 4.50- 4.45 (m, IH), 4.26-4.36 (m, IH), 3.18-3.07 (m, 1H), 3.04-2.99 (m, 3H). 2.99-2.85 (m, 2H), 2.73-2.67 (m, IH), 2.60 (d, 3H, J = 4.8), 2.56 (d, 3H, J = 4.4), 2.41-2.32 (m, 3H), 1.75- 1.71 (m, 6H), 1.09 (t, 3H, J - 7.5), 1.08 (t, 3H, J = 7.5); MS (ESI) m/z= 454 (M-H), 478
(M+Na).
Example 48 E 2-(4-{2-(R)-acetylamino-2-r(S)-l-methylcarbamoyl-2-(4-nifro-phenyl)-ethylcarbamσyijl ethyl}-2-ethyl-phenylamino)-benzoic acid and 2-(4-{2-(S)-acetylamino-2-[YS -l- methylcarbamoyl-2-(4-nitro-phenyl)-ethylcarbamoyl]-ethyl}-2-ethyl-phenylamino)- benzoic acid To a mixture of 2-(S)-[2-(S)-acetylamino-3-(4-amino-3-ethyl-phenyl)- propionylamino]-N-methyl-3-(4-nitro-phenyl)-propionamide and 2-(S)-[2-(R)- acetylamino-3-(4-amino-3-ethyl-phenyl)-propionylamino]-N-methyl-3-(4-nitro-phenyl)- propionamide (244mg, 0.536 mmol) in N,N-dimethylformamide (2mL) was added diphenyliodonium-2-carboxylate monohydrate (219mg (0.643 mmol), copper(II)acetate (14mg, 14 mol%). The mixture was stined at 100 °C under N2 for 17 hours, poured into 0.2M NaOH (lOmL) and extracted with hexanes (3x5mL), using methanol to break emulsions. The aqueous layer was acidified to a pH <3 with IM HCl and extracted with ethyl acetate (3 x 5mL). The combined ethyl acetate layers were extracted with IM HCl (1 x 3mL), brine (1 x 3mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was precipitated from ethyl acetate to provide the titled compound as a mixture of both diastereomers (58mg, 19%). 1H NMR (300MHz, d6-DMSO) mixture of diastereomers, δ 9.46 (s, 1), 8.49 (d, 1, J = 8.8), 8.18 (d, 1, J = 8.5), 8.12 (m, 2), 8.04-
7.98 (m, 2), 7.87 (dd, 1, J = 1.5, 8.0), 7.80-7.76 ( , 1), 7.55-7.53 (m, 1), 749-7.39 (m, 2), 7.34-7.26 (m, 1), 7.18-7.02 (m, 4), 6.93 (dd, 1, J = 1.7, 8.1), 6.78 (t, 1, J = 7.6), 4.54-443 (m, 3), 3.17-3.11 (m, 3), 3.04-2.96 (m, 2), 2.94-2.84 (m, 3), 2.73-2.63 (m, 2), 2.61 (d, 3, J = 4.8), 2.57 (d, 3, J = 4.4), 1.76-1.71 (m, 3), 1.11 (t, 3, J = 7.5), 1.10 (t, 3, J = 7.5); MS (ESI) m/z= 576 (MH+).
Example 48 F 2-|~(4- {2-(R)-acetylamino-2- |"(S)- 1 -methylcarbamoyl-2-(4-nitro-phenyl)-ethylcarbamoyl] - ethyl } -2-ethyl-phenyl)-oxalyl-amino] -benzoic acid and 2-r(4-{2-(S)-acetylamino-2-r(S)-l- methylcarbamoyl-2-(4-nifro-phenyl)-ethylcarbamoyl]-ethyl}-2-ethyl-phenyl)-oxalyl- amino]-benzoic acid To the mixture of 2-(4-{2-(R)-a cetylamino-2-[(S)-l-methylcarbamoyl-2-(4-nifro- phenyl)-ethylcarbamoyl] -ethyl }-2-ethyl-phenylamino)-benzoic acid and 2-(4-{2-(S)- acetylamino-2-[(S)-l-methylcarbamoyl-2-(4-nitro-phenyl)-ethylcarbamoyl]-ethyl}-2- ethyl-phenylamino)-benzoic acid (33mg, 0.057 mmol) in N,N-dimethylformamide (0.5mL) was added N,N-diisopropylethylamine (30μL, 0.17 mmol) and ethyl oxalyl chloride (120 μL, 1.08 mmol). The mixture was stined at ambient temperature for 2.5hours followed by the addition of 2M NaOH (2mL) and was stined for 10 min. The mixture was diluted with water (3mL), acidified to a pH <3 with IM HCl and extracted with ethyl acetate (3 x 5 mL). The combined ethyl acetate layers were extracted with brine (1 x 5mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was precipitated with ethyl acetate to provide the titled compound (14mg, 37%) !H NMR (300MHz, d6-DMSO) (Note: spectrum shows a complicated pattern of rotational isomers superimposed on a mixture of diastereomers) δ 8.50-8.42 (m,l), 8.30-8.09 (m, 4), 8.08-7.90 (m, 1), 7.89-7.76 (m, 1), 7.55-7.45 (m, 2), 7.45-7.25 (m, 1), 7.22-7.06 (m, 1), 7.04-6.95 (m, 1), 6.82-6.73 (m, 1), 4.58-440 (m, 2), 3.20-3.05 (m, 4), 3.02-2.90 (m, 2), 2.72-2.56 (m, 3), 1.74-1.71 (m, 2), 1.25-1.18 (m, 1), 1.00-0.90 (m, 1); MS (ESI) m/z= 648 (MH+), 670 (M+Na).
Example 49 N-(3-carboxypropanoyl)-L-phenylalanyl-3-[(lE)-3-amino-3-oxo-l-propenyll-4- [(carboxycarbonyl)(2-carboxyphenyl)amino1-N-pentyl-L-phenylalaninamide
Example 49A 2-amino-3-(4-amino-3-iodo-phenyl)-N-pentyl-propionamide The titled compound was prepared according to the procedure described in Example 43A, substituting [2-(4-amino-3-iodo-phenyl)-l-pentylcarbamoyl-ethyl]- carbamic acid tert-butyl ester from 38B for [2-(4-nitro-phenyl)-l-pentylcarbamoyl-ethyl]- carbamic acid tert-butyl ester.
Example 49B { 1 - [2-(4-amino-3 -iodo-phenyl)- 1 -pentylcarbamoyl-ethylcarbamoyl] -2-phenyl-ethyl| - carbamic acid tert-butyl ester The titled compound was prepared according to the procedure described for Example 35 D, substituting L-N-boc phenylalanine for 2-acetylamino-3-(4-amino- naphthalen-l-yl)-propionic acid from example 35C and substituting 2-amino-3-(4-amino- 3-iodo-phenyl)-Ν-pentyl-propionamide from Example 49A for the amylamine.
Example 49C N-{l-f2-(4-amino-3-iodo-phenyl)-l-pentylcarbamoyl-ethylcarbamoyll-2-phenyl-ethyl - succinamic acid methyl ester
The titled compound was prepared according to the procedure described in Example 43 A and 35D respectively, substituting {l-[2-(4-amino-3-iodo-phenyl)-l- pentylcarbamoyl-ethylcarbamoyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester for [2-(4- nitro-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester in procedure 43A, and substituting the resulting amine for amylamine, and the methyl monosuccinate for 2- acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid in procedure 35D.
Example 49D N-(3-carboxypropanoyl)-L-phenylalanyl-3-r(lE)-3-ammo-3-oxo-l-propenyl1-4- r(carboxycarbonyl)(2-carboxyphenyl)amino]-N-pentyl-L-phenylalaninamide The titled compound was prepared according to the procedure described in
Example 38 C-E, substituting the N-{l-[2-(4-Amino-3-iodo-phenyl)-l-pentylcarbamoyl- ethylcarbamoyl]-2-phenyl-ethyl}-succinamic acid methyl ester for the [2-(4-Amino-3- iodo-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester in Example 38C. MS (ESI+) m/e 758 (M+H)+.
Example 50
3-(4-benzoylphenyl)-N-(tert-butoxycarbonyl)-L-alanyl-3-{4-r(carboxycarbonyl)(2- carboxyphenyl)amino]phenyl}-N-l — pentyl-L-alaninamide
Example 50 A [2-(4-nitro-phenyl)-l-pentylcarbamoyl-ethyl] -carbamic acid tert-butyl ester A solution of N-(t-butoxycarbonyl)-4-nitro-L-phenylalanine (10.0 g, 32.2 mmol), amylamine (4.9 mL, 42 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.0 g, 42 mmol), and 3 -hydroxy- 1, 2,3 -benzotriazin-4(3H)-one (5.8 mg, 35 mmol) in Ν,Ν-dimethylformamide (20 mL) was adjusted to pΗ 7 with triethylamine and stined overnight. The reaction was taken up in ethyl acetate, washed with Η O (4 x 25 mL), 1 N HCl (1 x 25 mL) and aqueous sodium bicarbonate (1 x 25 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexanes to provide the titled compound. MS (ESI(+)) m/e 380 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.16 (d, 2H), 7.88 (t, IH), 7.53 (d, 2H), 6.99 (d, IH), 4.22-4.14 (m, IH), 3.09-2.97 (m, 3H), 2.92-2.83 (m, IH), 1.89-1.14 (m + s, 15H), 0.85 (t, 3H).
Example 50B r2-(4-amino-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester A solution of [2-(4-nifro-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert- butyl ester (18.8 g, 49.5 mmol) and 10% Pd/C (0.5g) in methanol (50 mL) under an atmosphere of hydrogen at 60 psi was shaken for 15 minutes. The mixture was filtered and the filtrate concentrated under reduced pressure to provide the titled compound. MS (ESI(+)) m/e 350 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 7.72 (t, IH), 6.86 (d, 2H), 6.63 (d, IH), 6.44 (d, 2H), 4.82 (s, 2H), 4.00-3.95 (m, IH), 3.08-2.96 (m, 2H), 2.72 (dd, IH), 2.58-2.53 (dd, IH), 1.37-1.18 (m + s, 15 H), 0.85 (t, 3H).
Example 5 PC
2-r4-(2-tert-butoxycarbonylamino-2-pentylcarbamoyl-ethyl)-phenylamino]-benzoic acid A mixture of [2-(4-amino-phenyl)-l-pentylcarbamoyl-ethyl] -carbamic acid tert- butyl ester (17.0 g, 48.6 mmol), diphenyliodonium-2-carboxylate monohydrate (20.0 g, 58.4 mmol), and copper(II) acetate (1.3 g, 7.3 mmol) in N,N-dimethylformamide (25 mL) was heated to 75 °C for 4 hours, cooled to room temperature and partitioned between aqueous IN HCl and ethyl acetate (200 mL. 1:1). The organic layer was washed with H O (4 times), dried (MgSO4), filtered, concentrated, and crystallized from ethyl acetate/hexanes to provide the titled compound. MS (ESI(+)) m/e 470 (M+H) ; H NMR (300 MHz, DMSO-d6) δ 9.60 (bs, IH), 7.88 (dd, IH), 7.70 (t, IH), 7.37-7.32 (m, IH), 7.22 (d, 2H), 7.14 (bs + d, 3H), 6.86 (d, IH), 6.78-6.72 (m, IH), 4.13-4.07 (m, IH), 3.11-
2.96 (m, 2H), 2.88 (dd, IH), 2.72 (dd, IH), 1.38-1.18 (m + s, 15H), 0.84 (t, 3H).
Example 50D 2- |4-(2-aUyloxy carbonylamino-2-pentylcarbamoyl-ethyl)-phenylamino] -benzoic acid A mixture of 2-[4-(2-tert-butoxycarbonylamino-2-pentylcarbamoyl-ethyl)- phenylamino] -benzoic acid (10.2g, 21.7 mmol) and trifluoroacetic acid (50 mL) in methylene chloride (200 mL) was stined for 3 hours, concentrated under reduced pressure. The residue (10.5 g, 21.7 mmol) and sodium bicarbonate (8.0 g, 95 mmol) were taken up in ethyl acetate/H2O (250 mL, 3:2) and treated with allyl chloroformate (2.4 mL, 22.6 mmol). The mixture was stined for 1 hour then diluted with ethyl acetate (100 mL). The organic layer was washed with H2O (2 x 50 mL), dried (MgSO4), filtered, concentrated under reduced pressure and crystallized from ethyl acetate/hexanes to provide the titled compound. MS (ESI(+)) m/e 454 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 13.01 (bs, IH), 9.58 (bs, IH), 7.92-7.90 (m, 2H), 7.38-7.34 (m, 2H), 2.27 (d, 2H), 7.19-7.16 (m, 3H), 6.76 (t, IH), 5.88-5.81 (m, IH), 5.23 (d, IH), 5.14 (d, IH), 4.42 (d, 2H), 4.22-4.17 (m,
IH), 3.12-2.97 (m, 2H), 2.94 (dd, IH), 2.68 (dd, IH), 1.40-1.34 (m, 2H), 1.29-1.17 (m, 4H), 0.85 (t, 3H). Example 50E 2-{[4-(2-allyloxycarbonylamino-2-pentylcarbamoyl-ethyl)-phenyl]-tert- butoxyoxalylamino} -benzoic acid
To a solution of 2-[4-(2-allyloxycarbonylamino-2-pentylcarbamoyl-ethyl)- phenylamino] -benzoic acid (7.0 g, 14.5 mmol), diisopropylethylamine (8.8 mL, 50.7 mmol) ) in dichloromethane (25 mL) was added t-butyloxalyl chloride (5.2 g, 31.9 mmol) and stined overnight. The reaction was partitioned between ethyl acetate (75 mL) and aqueous IN HC1( 50 mL). The organic layer was washed with H O (2 x 30 mL), dried
(MgSO4), filtered and concentrated. The crude material was precipitated from dichloromethane to provide the titled compound as a 1:1 mixture of rotamers. MS (ESI(-)) m/e 580 (M-H)+; 1H NMR (300 MHz, DMSO-d6) δ 13.17 (bs, IH), 8.05- 8.02 and 7.87-7.83 (2m, IH total), 7.96-7.89 (m, IH), 7.72-7.34 (m, 6H), 7.28-7.18 (m, 2H), 5.88-5.75 (m, IH), 5.24-5.08 (m, 2H), 443-4.28 (m, 2H), 4.17-4.08 (m, IH), 3.07-
2.99 (m, 2H), 2.96-2.87 (m, IH), 2.78-2.69 (m, IH), 1.43-1.32 (m, 2 H), 1.30-1.18 (m, 4H), 1.13 and 1.11 (2s, 9H total), 0.85 (t, 3H).
Example 50F
2- { [4-(2-allyloxycarbonylamino-2-pentylcarbamoyl-ethyl)-phenyl] -tert-butoxyoxalyl- amino } -benzoic acid benzhydryl ester To a solution of 2-{[4-(2-allyloxycarbonylamino-2-pentylcarbamoyl-ethyl)- phenyl]-tert-butoxyoxalylamino} -benzoic acid (6.46 g, 11.1 mmol) in acetone (25 mL) was added diphenylmethyldiazomethane (3.25 g, 16.6 mmol) and stined overnight. The solution was concentrated under reduced pressure and purified on silica using 0-10 % ethyl acetate/dichloromethane as eluent to provide the titled compound as a 1:1 mixture of rotamers. MS (ESI(+)) m/e 765 M+H2O, 748 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.27-8.24 and 8.08-8.05 (2m, IH total), 7.95-7.88 (m, IH), 7.81-7.27 (m, 16H), 7.18-7.14 (m, IH), 7.07-7.03 (m, IH), 6.99 and 6.44 (2s, IH total), 5.87-5.74 (m, IH), 5.23-5.15 (m,
IH), 5.11-5.07 (m, IH), 443-4.28 (m, 2H), 4.15-4.08 (m, IH), 3.07-2.98 (m, IH), 2.93- 2.85 (m, IH), 2.76-2.67 (m, IH), 1.41-1.29 (m, 2H), 1.27-1.15 (m, 4H), 1.11 and 0.99 (2s, 9H total), 0.84 (t, 3H).
Example 50G 2-{r4-(2-amino-2-pentylcarbamoyl-ethyl)-phenyl1-tert-butoxyoxalyl-amino}-benzoic acid benzhydryl ester To a solution of 2-{[4-(2-allyloxycarbonylamino-2-pentylcarbamoyl-ethyl)- phenyl]-tert-butoxyoxalyl-amino} -benzoic acid benzhydryl ester (2.50 g, 3.35 mmol) in methylene chloride (50 mL) was added tetrakis(triphenylphosphine)palladium(0) (193 mg,
0.167 mmol) followed by piperidine (0.829 mL, 8.37 mmol) and then stined for 1 hour.
The mixture was concentrated under reduced pressure and purified on silica using 1-3 %
2-propanol/dichloromethane to provide the titled compound as a 1:1 mixture of rotamers.
MS (ESI(+)) m/e 664 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 8.28-8.25 and 8.09- 8.06 (2m, IH total), 7.82-6.94 (m, 21H), 3.93-3.73 (m, IH), 3.03-2.97 (m, 2H), 2.90-2.82
(m, IH), 2.63-2.55 (m, IH), 1.35-1.28 (m, 2H), 1.23-1.14 (m, 4H), 1.16 and 0.99 (2s, 9H total), 0.85-0.78 (m, 3H).
Example 5 OH
2- [(4- {2-f2-(3 -benzoyl-phenyl)-2-tert-butoxycarbonylamino-acetylamino1 -2- pentylcarbamoyl-ethyl}-phenyl)-tert-butoxyoxalyl-amino] -benzoic acid benzhydryl ester A mixture of N-(t-butoxycarbonyl)-4-benzoyl-L-phenylalanine and 2-{[4-(2-amino-2- pentylcarbamoyl-ethyl)-phenyl]-tert-butoxyoxalyl-amino} -benzoic acid benzhydryl ester were processed as described in Example 50A to provided the titled compound obtained as a 1 :1 mixture of rotamers. MS (ESI(-)) m/e 1014 (M-H)+; 1HΝMR (300 MHz, DMSO- d6) δ 8.27-7.88 (m, 3H), 7.72-6.83 (m, 28 H), 4.52-443 (m, IH), 4.23-4.16 (m, IH), 3.12- 2.68 (m, 6H), 1.33-1.07 (m, 6H), 1.26 (s, 9H), 1.14 and 0.98 (2s, 9H total), 0.83-0.77 (m, 3H).
Example 501 3-(4-benzoylphenyl)-N-(tert-butoxycarbonyl)-L-alanyl-3-{4-[(carboxycarbonyl)(2- carboxyphenyl)amino]phenyll-N~l— pentyl-L-alaninamide A solution of 2-[(4-{2-[2-(3-benzoyl-phenyl)-2-tert-butoxycarbonylamino- acetylamino] -2 -pentylcarbamoyl-ethyl } -phenyl)-tert-butoxyoxalyl-amino] -benzoic acid benzhydryl ester (515 mg, 0.507 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (3 mL) was stined for 3 hours, concentrated to constant weight under reduced pressure. A solution of the residue (351 mg, 0.435 mmol), triethylamine (182 μL, 1.31 mmol) and di-t-butyl dicarbonate (101 μL, 0.439 mmol) in methylene chloride (3 mL) was stined overnight, concentrated under reduced pressure and purified by reverse phase HPLC eluting with 0-70 % acetonitrile/(10mM ammonium acetate in H2O) to provide the titled compound. MS (ESI(-)) m/e 791 (M-H)+; 1H NMR (300 MHz, DMSO- d6) δ 2.98 (d, IH), 2.89 (t, IH), 7.73-7.53 (m, 8H), 746-7.35 (m, 7H), 7.16-7.03 (m, 5H), 4.48-4.40 (m, IH), 4.23-4.15 (m, IH), 3.01-2.71 (m, 6H), 1.29 (s, 9H), 1.32-1.08 ( , 6H), 0.82 (t, 3H).
Example 51 N-acetyl-4-r(carboxycarbonyl)(2-carboxyphenyl)amino1-3-(2-hydroxyethyl)-N-[4- (methylsulfonyl)benzyllphenylalaninamide The titled compound was prepared according to the procedure described in
Example 35 C-E, substituting the 4-methanesulfonyl-benzylamine for the amylamine, and 2-acetylamino-3-[4-amino-3-(2-hydroxy-ethyl)-phenyl]-propionic acid for 2-acetylamino- 3-(4-amino-naphthalen-l-yl)-propionic acid used in Example 35D. MS (ESI+) m e 648 (M+Νa)+; 626 (M+H)"; 1H NMR (300 MHz,DMSO-d6) (A mixture of rotamers) δ 8.63 (brm, IH), 8.28-8.13 (m, 2H), 8.00-7.77 (m, 3H), 7.60-6.74 (m, 7H), 5.25-4.20 (m, 5H),
3.18 (s, 3H), 3.14-2.62 (m, 4H), 1.88-1.73 (m, 3H).
Example 52 2-rr7-(aminocarbonyl)- 1 -naphthyll(carboxycarbonyl)amino1benzoic acid
Example 52 A 8-nitro-naphthalene-2-carboxylic acid ethyl ester A cold nitric acid solution [prepared by adding fuming nitric acid (5.15 mL, 12.0 mmol) dropwise over 15 minutes to cooled (-10 °C) Ac2O (25 mL)] was added dropwise over 10 minutes to a cooled (-10 °C) solution of 2-naphthoic acid (19.0 g, 11.0 mmol) in concentrated H2SO4 (5 mL) and acetic anhydride (200 mL). The mixture was stirred at ambient temperature for 5 hours, poured into ice water (1 L) and filtered. The precipitate was washed with H2O and methanol and dried under vacuum at 50 °C for 16 hours. The residue was taken up in ethanol (250 mL) and concentrated H2SO4 (2 mL) and the mixture was refluxed for 3 days. The mixture was cooled, filtered, reduce in volume and filtered. The filter cakes were combined and crystallized from ethyl acetate to provide the titled compound. MS (ESI(-)) m/e 245 (M-H)+; H NMR (300 MHz, DMSO-d6) δ 9.05 (s, IH), 848-8.43 (m, 2H), 8.30 (d, IH), 8.16 (dd, IH), 7.86 (t, IH), 4.42 (q, 2H), 1.39 (t,
3H). Example 52B 8-nitro-naphthalene-2-carboxylic acid A solution of 8-nitro-naphthalene-2-carboxylic acid ethyl ester (0.95g, 3.9 mmol) in 4:1 methanokTHF (60 mL) was treated with 2 M NaOH (10 mL) and stined for 16 hours. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate and aqueous 2 N HCl. The organic layer was washed with H O (2 x 30 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the titled compound. MS (ESI(-)) m/e 216 (M-H)+; 1H NMR (300 MHz, DMSO-d6) δ 1 - IH), 9.05 (s, IH), 848-8.42 (m, 2H), 8.29 (d, IH), 8.17 (dd, IH), 7.85 (t, IH).
Example 52C 8-nitro-naphthalene-2-carboxylic acid amide A mixture of 8-nitro-naphthalene-2-carboxylic acid (0.82 g, 3.8 mmol), pyridine (1 drop), N,N-dimethylformamide (3 drops) in methylene chloride (3 mL) was treated with thionyl chloride (303 μL, 4.2 mmol) and stined 2 days. The mixture was dried (Na SO4), filtered and concentrated under reduced pressure. To a solution of the residue (650 mg, 2.76 mmol) in THF (150 mL) was added concentrated NH OH (0.5 mL) and stined 30 minutes. The reaction was concentrated under reduced pressure and the residue purified on silica eluting with 5% methanol/dichloromethane to give the titled compound. MS (ESI(+)) m/e 217 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.87 (m, IH), 8.42 (d, IH), 8.37 (dd, IH), 8.30 (bs, IH), 8.25 (d, IH), 8.13 (dd, IH), 7.80 (t, IH), 7.65 (bs, IH).
Example 52D 8-amino-naphthalene-2-carboxylic acid amide A solution of 8-nitro-naphthalene-2-carboxylic acid amide (330 mg, 1.53 mmol) and 5% Pd/C (30 mg) in methanol (3 mL) was stirred under an atmosphere of hydrogen. The catalyst was filtered and the filtrate was concentrated under reduced pressure to provide the titled compound. MS (ESI(+)) m/e 187 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, IH), 7.88 (bs, IH), 7.85 (dd, IH), 7.75 (d, IH), 7.35 (bs, IH), 7.38 (t, IH), 7.10 (d, IH) 6.72 (d, IH), 5.82 (bs, 2H).
Example 52E 2-(7-carbamoyl-naphthalen- 1 -ylamino)-benzoic acid The titled compound was prepared according to the procedure described in Example 50 C, substituting 8-amino-naphthalene-2-carboxylic acid amide for [2-(4- amino-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester. MS (ESI(+)) m/e 307 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 10.07 (s, IH), 8.62 (s, IH), 8.16 (bs, IH), 8.05-7.95 (m, 3H), 7.79 (dd, IH), 7.64-7.57 (m, 2H), 7.45 (bs, IH), 7.38-7.33 (m, IH), 6.99 (d, IH), 6.83-6.78 (m, IH).
Example 52F 2-[(7-carbamoyl-naphthalen-l-yl)-ethoxyoxalyl-amino]-benzoic acid
The titled compound was prepared according to the method described by Example 50 E substituting 2-(7-carbamoyl-naphthalen-l-ylamino)-benzoic acid for 2-[4-(2- allyloxycarbonylamino-2-pentylcarbamoyl-ethyl)-phenylamino]-benzoic acid, and substitutuing ethyl oxalylchloride for t-butyloxalyl chloride. The material was purified by reverse phase HPLC with 0% to 70% acetonitrile/(0.1% trifluoroacetic acid in H O). The compound was a 3 :2 mixture of rotamers. MS (ESI(+)) m/e 407 (M+H)+; !H NMR (300 MHz, DMSO-d6) δ 8.94 and 8.58 (2s, IH total), 8.13-7.38 (m, 10H), 7.26 and 7.04 (2d, IH total), 4.06 and 3.74 (2q, 2H total), 1.00 and 0.51 (2t, 3H total).
Example 52G 2-[[7-(aminocarbonyl)- 1 -naphthyl](carboxycarbonyl)amino]benzoic acid A solution of 2-[(7-carbamoyl-naphthalen-l-yl)-ethoxyoxalyl-amino]-benzoic acid (30 mg, 0.074 mmol) and aqueous 2 M NaOH (0.5 mL)in methanol (2 mL) was stirred for 3 hours, acidified with aqueous 2N HCl and purified by reverse phase HPLC eluting with
0-70% acetonitrile/(0.1% trifluoroacetic acid in H2O) to provide the titled compound as a 3:2 mixture of rotamers. MS (ESI(+)) m/e 396 M+H2O, 379 (M+H)+; !H NMR (300 MHz, DMSO-d6) δ 8.97 and 8.58 (2s, IH total), 8.16-7.99 (m, 4H), 7.89-7.24 (m, 7H), 7.26 and 6.98 (2d, IH total).
Example 53
N-acetyl-4-[(carboxycarbonyl (2-carboxyphenyl)amino]-3-isopropyl-N-[4-
(methylsulfonyl benzyl]phenylalaninamide and 4-r(carboxycarbonyl)(2-carboxyphenyl)aminol-l-acetyl-6-(3-isopropylbenzyl)-4-r4-
(methylsulfonyl benzyl1-2,3,5-piperazinetrione The titled mixture of compounds was prepared according to the method described in Example 35 D by substituting 4-methanesulfonyl-benzylamine HCl salt for the amylamine. MS (ESI(+)) m/e 624 (M+H)+ and 678 (M+H)+; !H NMR (500 MHz, DMSO-d6) δ 6.9-8.0 (m, 7H), 3.3-4.1(br m, 4H), 3.18 (s, 3H), 1.771.80 (two s, 3H), 1.10- 1.30 (m, 6H), 0.61 (m, 2H).
Example 54 2-[(carboxycarbonyl)(7-hydroxy-l-naphthyl)amino1-4-hydroxybenzoic acid
Example 54 A 2-bromo-4-nitrobenzoic acid To a solution of 2-bromo-4-nitrotoluene (7.0g, 32 mmol) that was dissolved in sulfuric acid (98%, 50mL) and placed in a water bath to maintain ambient temperature was added dropwise a solution of chromium trioxide (7.5g, 75 mmol) in water (8mL). Following addition, the mixture was poured onto 200mL of ice, the precipitate was collected and washed with water (1 x 100 mL). The crade product was taken up in diethyl ether (50mL), extracted with aqueous NaHCO3 solution (2 x 25 mL). The combined bicarbonate layers were acidified by the addition of 12M HCl, extracted with diethyl ether
(2 x 25 mL). The second set of diethyl ether layers was washed with brine (1 x 25 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to provide the titled compound 4.0g (51%). 1H NMR (300MHz, d6-DMSO) δ 8.48 (d, IH, J = 24), 8.28 (dd, IH, J = 2.0, 8.5), 7.95 (d, IH, J = 8.5); MS (ESI) m/z-244, 246 (M-H).
Example 54B methyl 2-bromo-4-nitrobenzoate To a solution containing 2-bromo-4-nitrobenzoic acid (l.Og, 4.06 mmol) and K2CO (560 mg) in N,N-dimethylformamide (5 mL) was added methyl iodide (500μL,
8.03 mmol). The mixture was stined at ambient temperature for lhour, poured into water (30mL) and extracted with diethyl ether (3 x lOmL). The combined ether layers were washed with water (1 x lOmL), brine (1 x 10 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to provide the titled compound (970 mg, 92%). 1H NMR (300MHz, CDC13) δ 8.52 (d, IH, J = 2.4), 8.21 (dd, 1, J = 2.0, 8.5), 7.92 (d, 1, J =
8.8), 3.99 (s, 3); MS (ESI) m/z= 259 (M-H). Example 54C methyl-2-bromo-4-aminobenzoate A solution of methyl 2-bromo-4-nitrobenzoate (970mg, 3.73 mmol), iron powder 1.25g (22.4 mmol) and ammonium chloride (239 mg, 4.48 mmol) in aqueous 2-propanol (20 %, 15mL) was heated to reflux for 30minutes, cooled, filtered, and concentrated under reduced pressure. The residue was partitioned between diethyl ether (20mL) and water (5mL). The organic layer was washed with brine (1 x 5mL), dried (MgSO4), filtered, and concentrated to provide the titled compound (813mg, 95%).
Example 54D methyl-2-bromo-4-hydroxybenzoate To a mixture of methyl-2-bromo-4-aminobenzoate (813mg, 3.53 mmol) in water (lOmL) and 98% H2SO4 (lmL) at 0 °C was added a solution of aqueous NaNO2 (244mg,
3.53 mmol) dissolved in a minimum amount of water, via pipette below the surface of the reaction. After 15minutes, the mixture was filtered, and the filter cake washed with H2O (lOmL). The combined filtrate was heated to reflux for 15minut.es, stined at ambient temperature for l δhours and extracted with diethyl ether (3 x lOmL). The combined organic layers were washed with brine (1 x 5mL), dried (MgSO4), filtered, and concentrated under reduced pressure to provide the titled compound (444mg, 54%).
Example 54E 2-bromo-4-hydroxybenzoic acid
To methyl 2-bromo-4-hydroxybenzoate (212mg, 0.918 mmol) was added 30% HBr (w/w) in acetic acid (3mL). The solution was heated to 100 °C for 5hours, poured into H2O (lOmL) and extracted with diethyl ether (3 x 5mL). The combined ether layers were washed with water (1 x 5mL), brine (1 x 5mL), dried (MgSO ), filtered, and concentrated under reduced pressure to provide the titled compound (162mg, 81%). 1H NMR
(500MHz, CDC13) δ 7.86 (d, IH, J = 8.7), 7.14 (d, IH, J = 2.5), 6.79 (d, IH, J = 2.5, 8.7); MS (ESI) m/z= 215, 217 (M-H).
Example 54F benzyl-2-bromo-4-benzyloxybenzoate To 2-bromo-4-hydroxybenzoic acid (1 62mg, 0.747mmol) was added IM KOH in methanol (1.5mL). The mixture was stined until all material had dissolved, then concentrated under reduced pressure. The residue was taken up in N,N- dimethylformamide (3mL) and methanol (0.5mL) followed by the addition of benzyl bromide (300μL, 1.68 mmol) and K CO3 (150mg, 1.08 mmol). The mixture was heated to 90 °C for lOmin, poured into H2O (lOmL) and extracted with diethyl ether (3 x 5mL). The combined organic layers were washed with water (1 x 5mL), brine (1 x 5mL), dried (MgSO4), filtered, and concentrated under reduced pressure to provide the titled compound (285mg, 96%).
Example 54G 2-(tert-butyldimethylsilyloxy)-8-aminonaphthalene A mixture of 8-amino-2-naphthol (3.18g, 20.0 mmol), tert-butyl-dimethylsilyl chloride (3.6g, 24 mmol) and imidazole (2.8g, 41 mmol) in N,N-dimethylformamide(
20mL) was stined at ambient temperature for 30minutes, poured into water (70mL) and aqueous IM HCl (30mL) and extracted with diethyl ether (3 x 30mL). The combined ether layers were washed with water (1 x 30mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The product was purified on silica using 15% ethyl acetate/hexanes as eluent to provide the titled compound (4.39g, 80%). !H NMR
(300MHz, CDC13) δ 7.68 (d, IH, J = 8.8), 7.27 (d, IH, J = 8.8), 7.17 (d, IH, J = 24), 7.15 (dd, IH, J = 7.1, 8.1), 7.05 (dd, IH, J = 2.4, 8.8), 6.76 (dd,lH, J = 1.0, 7.1), 4.11 (bs, 2H), 1.03 (s, 9H), 0.25 (s, 6H); MS (ESI) m/z= 274 (MH+).
Example 54H 4-benzyloxy-2-[7-(tert-butyl-dimethyl-silanyloxy)-naphthalen-l-ylamino]-benzoic acid benzyl ester A mixture of benzyl-2-bromo-4-benzyloxybenzoate (285mg, 0.717mmol), 2- (tertbutyldimethylsilyloxy)-8-aminonaphthalene (196mg, 0.717mmol), tris-
(dibenzylideneacetone)dipalladium (4mg, 0.004mmol), (2'-dicyclohexylphosphanyl- biphenyl-2-yl)-dimethyl-amine (6mg, 0.015mmol) and 60% NaH in mineral oil (45mg, 1.1 mmol) in toluene (3mL) was heated to reflux under N2 for lhour, poured into water (lOmL) acidified to a pH <3 with aqueous IM HCl and extracted with diethyl ether (3 x 5mL). The combined ether layers were washed with brine (1 x 5mL), dried (MgSO ), filtered, concentrated under reduced pressure and purified silica gel eluting with 10% ethyl acetate/hexanes to provide the titled compound. Example 541 4-hydroxy-2-(7-hydroxy-naphthalen- 1 -ylamino)-benzoic acid A mixture of 4-benzyloxy-2- [7-(tert-butyl-dimethyl-silanyloxy)-naphthalen- 1 - ylamino] -benzoic acid benzyl ester and tetrabutylammonium fluoride (90mg, 1.0 mmol) in THF (2mL) was stined for 5 minutes, then concentrated under reduced pressure. The residue was taken up in aqueous 0.2M HCl (lOmL) and extracted with diethyl ether (2 x 5mL). The combined ether layers were dried (MgSO4), filtered, concentrated under reduced pressure and purified on silica gel eluting with 20% ethyl acetate/hexanes. A mixture of the residue, 10% Pd/C (lOmg), 60% HClO4 (3 drops) in 2- propanol (2mL) was stined under 1 atmosphere of H for 18hours, filtered and concentrated under reduced pressure. The product was taken up in toluene and concentrated under reduced pressure to remove water to provide the titled compound (134mg, 45%). HPLC/MS analysis showed a peak corresponding to the conect mass, and a minor contaminant peak.
Example 54J 4-hydroxy-2-[(7-hydroxy-naphthalen-l-yl)-oxalyl-amino]-benzoic acid To 4-hydroxy-2-(7-hydroxy-naphthalen-l-ylamino)-benzoic acid (134mg, 0.454 mmol) in N,N-dimethylformamide (3mL) was added triethylamine (0.6 mL, 4.3 mmol) followed by ethyl oxalyl chloride (0.3 mL, 2.7 mmol). The reaction was stined at ambient temperature for 25 minutes, 2M NaOH (5mL) was added, stined for an additional 30 minutes, then diluted with water (15 mL) and extracted with diethyl ether (2 x 5 mL). The aqueous layer was acidifiedto a pH <3 with IM HCl, extracted with diethyl ether (3 x 5 mL). The aqueous layer was extracted with ethyl acetate (3 x 5mL). The combined ethyl acetate layers were washed with brine (1 x 5 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to provide the titled compound (37mg, 22%). 1H NMR (300MHz, d6-DMSO) mixture of rotamers δ 10.30 (s, IH), 10.10 (s, IH), 10.06 (s, IH), 9.94 (s, IH), 7.95-7.76 (m, 6H), 7.56 (d, IH, J = 7.5), 7.50 (d, IH, J = 1.4), 7.41-7.23
(m, 5H), 7.19-7.11 (m, 3H), 6.76 (dd, IH, J = 2.5, 8.7), 6.70 (dd, J = 24, 8.5), 6.61 (d, 1, J = 24), 6.33 (bs, 1); MS (ESI) m/z= 368 (MH+), 385 (M+NH4+).
Example 55
N-acetyl-4-r(carboxycarbonyl (2-carboxyphenyl amino]-3-ethyl-N-{5-oxo-5-r(l- phenylethyl)amino]pentyl}phenylalaninamide Example 55 A 2-Acetylamino-acrylic acid benzyl ester To a mixture of 2-acetamidoacrylic acid (10.3 g, 80.0 mmol) and K CO3 (10 g, 72.5 mmol) in N,N-dimethylformamide (50 mL) was added benzyl bromide (8.7 ml, 72.5 mmol) at room temperature then stined at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water (50mL, 1:1), the aqueous layer was extracted with ethyl acetate (2 x 45 mL). The combined organic layers was washed with brine (2 x 25 mL), dried (MgSO4), filtered and concentrated under reduced pressure to provide titled compound. MS (ESI(+)) m/e 220(M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s,
IH), 7.43-7.30 (m, 5H), 6.13 (s, IH), 5.70 (s, IH), 5.23 (s, 2H), 2.01 (s, 3H).
Example 55B 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-acrylic acid benzyl ester
To 2-acetylamino-acrylic acid benzyl ester (80.0 mmol) in acetonitrile (200 mL) was added Pd(OAc)2 (488 mg, 2.18 mmol), (o-Tol)3P (1.32 g, 4.35.mmol), Et3N (20 mL) followed by addition of 4-bromo-2-ethylaniline (14.5 g, 72.5 mmol). The reaction mixture was heated to reflux overnight, concentrated under reduce pressure, taken up in ethyl acetate, washed with aqueous NaHCO3, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was precipitated from ethyl acetate/hexane to provide the titled compound (6.3 g). The filtrate was precipitated a second time to provide and additional 5 g of the titled compound. MS (ESI(+)) m/e 339 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.31 (s, IH), 740-7.20 (m, 8H), 6.59 (d, IH), 5.52 (s, 2H), 5.16 (s, 2H), 2.42 (q, 2H), 1.98 (s, 3H), 1.13 (t, 3H).
Example 55C 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid A mixture of 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-acrylic acid benzyl ester
(5g) and 10% Pd-C (100 mg) in methanol (50 mL) was stined under an atmosphere of hydrogen (4 atmospheres) at ambient temperature overnight to provide the titled compound. MS (ESI(+)) m/e 251 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.02 (d, IH), 6.77-6.70 (m, 2H), 6.50 (d, IH), 4.31-4.21 (m, IH), 2.84 (dd, IH), 2.65 (dd, IH), 2.39 (q, 2H), 1.78 (s, 3H), 1.10 (t, 3H). Example 55D
2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid allyl ester A mixture of 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid (2.0 g, 8.0 mmol), Cs2CO3 (2.61 g, 8.0 mmol) and allyl bromide (692 ul, 8.0 mmol) in N,N- dimethylformamide (40 mL) was stined at room temperature for 3 hours, concentrated under reduce pressure and partitioned between ethyl acetate and water (1 OOmL, 1:1). The organic phase was washed with brine (1 x 50 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by on silica gel with ethyl acetate/hexane (5:3) to provide titled compound (1.44 g). MS (ESI(+)) m/e 291 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.23 (d, IH), 6.77-6.70 (m, 2H), 6.50 (d, IH), 5.90-5.76 (m, IH), 5.30-5.15 (m, 2H), 4.67 (s, 2H), 4.54-4.50 (m, 2H), 4.38-4.30 (m, IH), 2.77(dddd, 2H), 2.39 (q, 2H), 1.80 (s, 3H), 1.10 (t, 3H).
Example 55E 2-{[4-(2-acetylamino-2-allyloxycarbonyl-ethyl)-2-ethyl-phenyl]-tert-butoxyoxalyl- amino} -benzoic acid The titled compound was prepared according to the method described in Example 3 by substituting 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid allyl ester for
4-methoxyaniline and t-butyl oxalyl chloride for ethyl oxalyl chloride. MS (APCI (+)) m/e 539 (M+H)+.
Example 55F
2-{r4-(2-acetylamino-2-allyloxycarbonyl-ethyl)-2-ethyl-phenyll-tert-butoxyoxalyl- amino j -benzoic acid benzhydryl ester To 2- { [4-(2-acetylamino-2-allyloxycarbonyl-ethyl)-2-ethyl-phenyl] -tert- butoxyoxalyl-amino} -benzoic acid in acetone was added diphenyldiazomethane (until all starting material was consumed as evident by monitoring via TLC). The reaction mixture was concentrated under reduced pressure, purified on silica gel using ethyl acetate as eluent to provide the titled compound. MS (ESI(+)) m/e 705 (M+H)+ ; 1H NMR (300 MHz, DMSO-d6) δ 8.51-8.01 (m, 2H), 7.73-6.86 (m, 16H), 5.93-5.78 (m, IH), 5.34-5.10 (m, 2H), 4.57-440 (m, 3H), 3.10-2.84 (m, 2H), 2.58-242 (m, 2H), 1.82-1.77 (m, 3H), 1.22-0.78 (m, 3H), 1.07, 1.05, 1.00 (s, s, s, 9H). Example 55G 2- { [4-(2-acetylamino-2-carboxy-ethyl)-2-ethyl-phenyl1-tert-butoxyoxalyl-amino| -benzoic acid benzhydryl ester A mixture of 2-{[4-(2-acetylamino-2-allyloxycarbonyl-ethyl)-2-ethyl-phenyl]-tert- butoxyoxalyl-amino} -benzoic acid benzhydryl ester (3.4 g, 4.8 mmol), Pd(Ph3P)4 (166 mg, 0.144 mmol) and moφholine (0.5 ml, 5.8 mmol) in dichloromethane (25 mL) was stined under N2 atmosphere for 2 hours, partitioned between ethyl acetate and water (75 mL, 1:1). The organic phase was washed with IN HCl (1 x 25 mL), brine (1 x 25mL), dried (MgSO4), filtered and concenfrated under reduced pressure to provide the titled compound
(3.3 g). MS (ESI(+)) m/e 665 (M+H)+; !H NMR (300 MHz, DMSO-d6) δ 12.67 (s, IH), 8.51-7.98(m, 2H), 7.73-6.86 (m, 16H), 4.53-4.33 (m, IH), 3.12-2.76 (m, 2H), 2.58-242 (m, 2H), 1.82-1.77 (m, 3H), 1.22-0.78 (m, 3H), 1.06, 1.04, 1.00 (s, s, s, 9H).
Example 55H 5-tert-butoxycarbonylamino-pentanoic acid 2-trimethylsilanyl-ethyl ester A mixture of boc-d-aminovaleric acid (13.0 g, 59.5 mmol), pyridine (45 mL), (2- trimethylsilyl)ethanol (10.3 ml, 71.8 mmol) and dicyclohexylcarbodiimide (13.5 g, 65.4 mmol) in acetotnitrile (60 mL) was stirred cold (ice bath) for 1 hour and then kept in a refrigerator overnight. The suspension was filtered and the filtrate concentrated under reduced pressure to remove most of pyridine, diluted with ethyl acetate and washed -with IN HCl, saturated NaHCO3. The organic phase was dried (MgSO4), filtered and concenfrated. The concentrate was purified by flash column chromatography on silica gel with hexane/ethyl acetate (4:1) to provide the desired product (15.3g). MS (ESI(+)) m/e
318 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 6.77 (t, IH), 4.11-4.03 (m, 2H), 3.30 (m, 2H), 2.91-2.83 (m, 2H), 2.26-2.20 (m, 2H), 1.52-140 (m, 2H), 1.35 (s, 9H), 0.96-0.88 (m, 2H).
Example 551 2-[(4-{2-acetylamino-2-[4-(2-trimethylsilanyl-ethoxycarbonyl -butylcarbamoyll-ethyl|-2- ethyl-phenyl)-tert-butoxyoχalyl-aminol -benzoic acid benzhydryl ester 5-tert-butoxycarbonylamino-pentanoic acid 2-trimethylsilanyl-ethyl ester (317 mg, 1.0 mmol) was treated with 4N HCl in dioxane at room temperature for 30 minutes, then concentrated under reduced pressure. The residue, 2-{[4-(2-acetylamino-2-carboxy- ethyl)-2-ethyl-phenyl]-tert-butoxyoxalyl-amino}-benzoic acid benzhydryl ester (665 mg, 1.0 mmol), 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (321 mg, 1.0 mmol) and diisopropylethylamine (521 ul, 3.0 mmol) in N,N-dimethylformamide (2 mL) was stined at ambient temperature overnight, diluted with ethyl acetate and washed with aqueous NaHCO3 (1 x 30 mL), brine (1 x 30 mL), dried (MgSO4), filtered and concentrate under reduced pressure. The residue was purified on silica gel eluting with ethyl acetate to provide of titled compound 480 mg. MS (APCI(+)) m/e 864 (M+H)+.
Example 55J 2-({4-[2-acetylamino-2-(4-carboxy-butylcarbamoyl)-ethyl]-2-ethyl-phenyl}-tert- butoxyoxalyl-amino)-benzoic acid benzhydryl ester 2-[(4-{2-acetylamino-2-[4-(2-trimethylsilanyl-ethoxycarbonyl)-butylcarbamoyl]- ethyl}-2-ethyl-phenyl)-tert-butoxyoxalyl-amino]-benzoic acid benzhydryl ester (356 mg,
0.41 mmol) was treated with tetrabutylammonium fluoride- IM in THF (4 mL) at room temperature for 2 hours. The mixture was diluted with ethyl acetate and washed with IN HCl (3 x 25 mL), dried (MgSO4), filtered and concentrated under reduced pressure to provide the titled compound (305 mg). MS (APCI(+)) m/e 764 (M+H)+ ; 1H NMR (300 MHz, DMSO-d6) δ 8.31-7.90(m, 2H), 7.73-6.85 (m, 16H), 443-4.33 (m, IH), 3.22-248
(m, 6H), 2.22-2.15 (m, 2H), 1.80-1.72 (m, 3H), 1.62-1.25 (m, 4H), 1.05, 1.04, 1.00 (s, s, s, 9H), 1.25-0.78 (m, 3H).
Example 55K
2-[(4-{2-acetylamino-2-r4-(l-phenyl-ethylcarbamoyl)-butylcarbamoyll-ethyl}-2-ethyl- phenyl)-tert-butoxyoxalyl-amino"l-benzoic acid benzhydryl ester A mixture of 2-({4-[2-acetylamino-2-(4-carboxy-butylcarbamoyl)-ethyl]-2-ethyl- phenyl}-tert-butoxyoxalyl-amino)-benzoic acid benzhydryl ester (25 mg, 0.03 mmol), 1- phenyl-ethylamine (10 μL, 0.07 mmol), 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium tetrafluoroborate (12 mg, 0.036 mmol) and diisopropylethylamine (20 μL) in N,N-dimethylformamide (250 μL) was stined at ambient temperature overnight, concentrated under reduced pressure and the residue purified by reverse-phase HPLC eluting with 5-100% acetonitrile/ aqueous 0.1% TRIFLUOROACETIC ACID to provide the titled compound. Example 55L N-acetyl-4- [(carboxy carbonyl)(2-carboxyphenyl)amino] -3 -ethyl-N- { 5-oxo-5-[( 1 - phenylethyl)amino]pentyl}phenylalaninamide The material from Example 55K was treated with trifluoroacetic acid/dichloromethane (10 mL, 1 : 1) at ambient temperature for 3 hours, concentrated under reduced pressure and purified by HPLC eluting with 5-100% acetonitrile/ aqueous 0.1% trifluoroacetic acid to provide the titled comound (8 mg). MS (ESI(+)) m/e 645 (M+H) ; H ΝMR (500 MHz, DMSO-d6) δ 8.20-7.79 (m, 4H), 7.56-6.75 (m, 11H), 4.93-4.88 (m, IH), 4.50-4.40 (m, IH), 3.04-2.97 (m, 2H), 2.98-2.89 (m, IH), 2.80-2.71 (m, IH), 2.70- 2.55 (m, 2H), 2.12-2.06 (m, 2H), 1.77,1.75 (s, s, 3H), 148-141 (m, 2H), 1.38-1.28 (m,
4H), 1.07,0.93 (t, t, 3H).
Example 56 N-(methoxycarbonyl)-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N- pentylnaphthylalaninamide
Example 56 A 1 -methyl-4-nitro-naphthalene
The titled compound was prepared according to the procedure described in J Org. Chem. 1991, 56, 1739. Davalli, S., Lunazzi, L., Macciantelli, D.
Example 56B
3 -(4-nitro- 1 -naphthyl)alanine The titled compound was prepared from 1 -methyl- 8 -nitronaphthalene according to the procedure described in J. Med. Chem. 1967, 10, 293. Benigni, J. D., Minnis, R. L.
Example 56C 2-methoxycarbonylamino-3-(4-nitro-naphthalen- 1 -yl)-propionic acid A mixture of 3 -(4-nitro- l-naphthyl)alanine (0.65 g, 2.5 mmol), aqueous ΝaHCO3 (5 mL) and methylchloro formate (230uL, 3 mmol, 1.2 eq) in dioxane (10 mL) was stined for 3 hours, acidified to a pH <3 with aqueous 2N HCl and extracted with ethyl acetate.
The combined organic layers was washed with water (1 x 25 mL), brine(l x 25 mL), dried (MgSO4), filtered and concentrated under reduce pressure to provide the titled compound. MS (APCI(+)) m/e 319 (M+H)+.
Example 56D
2-methoxycarbonylamino-3 -(4-nitro-naphthalen- 1 -yl)-propionic acid 2-trimethylsilanyl- ethyl ester To a mixture of 2-methoxycarbonylamino-3 -(4-nitro-naphthalen- l-yl)-propionic acid (0.35 g, 1.1 mmol), pyridine (0.78 mL) and 2-trimethylsilylethanol (0.18 mL, 1.25 mmol, 1.1 eq) in acetonitrile (1.1 mL) cooled in an ice bath was added dicyclohexylcarbodiimide (0.25 g, 1.21 mmol). The mixture was stined cold for 1 hour, placed in the refrigerator for 14 hours. The reaction mixture was filtered, concentrated under reduced pressure and purified on silica gel eluting with heptane/ethyl acetate (4: 1) to provide the titled compound. MS (ESI(-)) m/e 417 (M-H)" .
Example 56E 3-(4-amino-naphthalen- 1 -yl)-2-methoxycarbonylamino-propionic acid 2-trimethylsilanyl- ethyl ester A mixture of 2-methoxycarbonylamino-3 -(4-nitro-naphthalen- 1 -yl)-propionic acid
2-trimethylsilanyl-ethyl ester (1.1 g, 2.64 mmol), 10% palladium on C (0.056 g) in methanol (5 mL) was stirred under an atmosphere of hydrogen for 4 hours. The mixture was filtered through diatomaceous earth and the filter cake washed with methanol (2 x 25 mL). The combined methanol was concenfrated under reduced pressure to provide the titled compound. MS (ESI(+)) m/e 389 (M+H)+
Example 56F 2-{4-[2-methoxycarbonylamino-2-(2-trimethylsilanyl-ethoxycarbonyl)-ethyl]-naphthalen- 1 -ylamino} -benzoic acid
A mixture of 3-(4-amino-naphthalen-l-yl)-2-methoxycarbonylamino-propionic acid 2-trimethylsilanyl-ethyl ester (0.93 g, 2.40 mmol), diphenyliodonium-2-carboxylate (1.22 g, 3.8 mmol, 1.5 eq) and copper(II) acetate (25 mg, 0.14 mmol, 0.06 eq) in N,N- dimethylformamide (25 mL) was heated to 100°C for 14 hours, then cooled to room temperature. The mixture was acidified to a pH <3 with IN HCl, extracted with ethyl acetate (3 x 35 mL). The combined organic layers were washed with IN HCl (1 x 25 mL), water (1 x 25 mL), brine (1 x 25 mL), and dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with 4:1 toluene/ethyl acetate to provide the titled compound. MS (ESI(-)) m/e 507 (M-H)".
Example 56G
2-(tert-butoxyoxalyl-{4-[2-methoxycarbonylamino-2-(2-trimethylsilanyl-ethoxycarbonyl)- ethyl]-naphthalen-l-yl}-amino)-benzoic acid To a mixture of 2-{4-[2-methoxycarbonylamino-2-(2-trimethylsilanyl- ethoxycarbonyl)-ethyl]-naphthalen-l-ylamino}-benzoic acid (0.7 g, 1.38 mmol) and diisopropylethylamine (0.57 mL) in methylene chloride (8 mL) at 0°C was slowly added tert-butyl oxalyl chloride (538 mg, 3.61 mmol, 2.6 eq). The reaction was allowed to warm to room temperature over 1 hour and 4-(dimethylamino)pyridine (10 mg, 0.08 mmol, 0.06 eq) was added. The reaction was stined for 14 hours, acidified to a pH <3 with IN HCl, extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with IN HCl (2 x 30 mL), water (1 x 20 mL), and brine (1 x 20 mL), dried (MgSO ), filtered and concentrated. The residue was purified on silica gel eluting with toluene/ethyl acetate (10:1 ) to provide the titled product. MS (APCI(+)) m/e 637 (M+H)+.
Example 56H
2-(tert-butoxyoxalyl-{4-[2-methoxycarbonylamino-2-(2-trimethylsilanyl-ethoxycarbonyl)- ethyl]-naphthalen-l-yl}-amino)-benzoic acid benzhydryl ester Diphenyldiazomethane was prepared according to the procedure described in J. Org Chem. 1959, 24, 560, Miller, j. B. To a mixture of 2-(tert-butoxyoxalyl-{4-[2-methoxycarbonylamino-2-(2- trimethylsilanyl-ethoxycarbonyl)-ethyl]-naphthalen-l-yl}-amino)-benzoic acid (0.3 g, 0.47 mmol) in acetone (3 mL) was added diphenyldiazomethane (134 mg, 0.69 mmol). The reaction mixture was stirred for 6 hours, acidified to a pH <3 with IN HCl and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with IN HCl (1 x 20 mL), water (2 x 15 mL), brine (1 x 30 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The concentrate was purified on silica gel eluting with 10:1 toluene/ethyl acetate to provide the titled product. MS (ESI(+)) m/e 820 (M+H2O+H)+
Example 561
2-{tert-butoxyoxalyl-[4-(2-carboxy-2-methoxycarbonylamino-ethyl)-naphthalen-l-yl]- amino} -benzoic acid benzhydryl ester To 2-(tert-butoxyoxalyl-{4-[2-methoxycarbonylamino-2-(2-trimethylsilanyl- ethoxycarbonyl)-ethyl]-naphthalen-l-yl}-amino)-benzoic acid benzhydryl ester (0.7 g, 0.87 mmol) in tetrahydrofuran (2.5 mL) cooled in an ice bath was added tetrabutylammonium fluoride (1.5 mL, IM in tetrahydrofuran). The mixture was stined at 0°C for 1 hour, ambient temperature for 1 hour, diluted with IN HCl (40 mL)and extracted with methylene chloride ( 3 x 30 mL). The combined organic layers were washed with IN HCl (2 x 20 mL), water (1 x 20 mL), brine ( 2 x 20 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with 10:1 toluene/ethyl acetate to provide the titled product. MS (ESI(+)) m/e 720 (M+H2O+H)+
Example 56 J N-(methoxycarbonyl)-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N- pentylnaphthylalaninamide
2- {tert-butoxyoxalyl- [4-(2-carboxy-2-methoxycarbonylamino-ethyl)-naphthalen- 1 - yl] -amino} -benzoic acid benzhydryl ester (1.053 g, 1.5 mmol) was dissolved in 1,2- dichloroethane (15 mL) to yield a 0.1 M stock solution, l-hydroxy-7-azabenzotriazole (0.23 g, 1.69 mmol) was dissolved in 20% N,N-dimethylacetamide in 1,2-dichloroethane (10 mL) to yield a 0.17 M stock solution. N-cyclohexylccarbodiimide, N-methyl polystyrene HL resin (Nova Biochem; 35 mg per well, f = 2 mmol/g, 0.070 mmol) was added to the wells of a Robbins reaction block, followed by 0.35 mL of the 0.17 M 1- hydroxy-7-azabenzotriazole solution (0.060 mmol) and 0.5 mL of the 0.1M compound 2- {tert-butoxyoxalyl-[4-(2-carboxy-2-methoxycarbonylamino-ethyl)-naphthalen-l-yl]- amino} -benzoic acid benzhydryl ester solution (0.050 mmol). After shaking the block for one hour, 0.35 mL of a 0.1 M stock solution of 1-pentylamine (0.035 mmol) in N,N- dimethylacetamide was added to the first well and the block was shaken for 14 hours. Unreacted acid (2-{tert-butoxyoxalyl-[4-(2-carboxy-2-methoxycarbonylamino-ethyl)- naphthalen-1-yl] -amino} -benzoic acid benzhydryl ester) was removed by addition of tris- (2-aminoethyl)-amine polystyrene HL resin (Nova Biochem; 35 mg per well, f = 2.3 mmol/g, 0.080 mmol). After shaking the block for 2 hours, the reaction mixture was filtered through the frit of the Robbins reaction block into a collection block and the resin was washed with 1,2-dichloroethane. The filtrate in the collection block was concenfrated under vacuum. The protecting groups were removed by treatment with a solution consisting of 1,2-dichloroethane: trifluoroacetic acid: anisole (50%, 45%, 5%, 1 mL) for 3 hours. The mixtures were concenfrated under reduced pressure and the crade product was purified by preparative reverse-phase HPLC. MS (APCI(+)) m/e 506 (M+H-CO2)+, 550 (M+H)+; 1H NMR (500MHz, DMSO-d6) δ 8.50-6.75 (m, 13H), 4.40-4.25 (m, IH), 3.10- 2.95 (m, 2H), 1.40-1.10 (m, 6H), 0.90-0.75 (m, 3H), (signals of methylcarbamate and benzylic protons appeared in H2O signal).
Example 57 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(cyclohexylmethyl)-N- (methoxycarbonyl)naphthylalaninamide The titled compound was prepared according to the method described in Example 56 J by substituting cyclohexylmethylamine for 1-pentylamine. MS (APCI(+)) m/e 532
(M+H-CO2)+, 576 (M+H)+; 1HΝMR (500MHz, DMSO-d6) δ 8.50-6.75 (m, 13H), 4.45- 4.25 (m, IH), 3.00-2.80 (m, 2H), 1.70-0.95 (m, 9H), 0.80 (m, 2H), (signals of methylcarbamate and benzylic protons appeared in H2O signal).
Example 58 4- [(carboxycarbony l)(2-carboxyphenyl)amino1-N-(methoxycarbonyl)-N- [( 1 ?)- 1 -(4- nitrophenyl)ethyl]naphthylalaninamide The titled compound was prepared according to the method described in Example 56 J by substituting (17?)-l-(4-nitrophenyl)ethylamine for 1-pentylamine. MS (APCI(+)) m/e 585 (M+H-CO2)+, 629 (M+H)+; 1H ΝMR (500MHz, DMSO-d6) δ 8.75-6.75 (m, 17H), 5.05-4.80 (m, IH), 4.50-4.35 (m, IH), 1.45-0.95 (m, 3H), (signals of methylcarbamate and benzylic protons appeared in H2O signal).
Example 59 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(methoxycarbonyl)-N-r4-
(methylsulfonyl)benzyl]naphthylalaninamide The titled compound was prepared according to the method described in Example 56 J by substituting 4-(methylsulfonyl)benzylamine for 1-pentylamine. MS (APCI(+)) m/e 604 (M+H-CO2)+, 648 (M+H)+;1H ΝMR (500MHz, DMSO-d6) δ 8.75-6.75 (m, 17H), 4.50-4.30 (m, 3H), 3.20-3.15 (m, 3H), (signals of methylcarbamate and benzylic protons appeared in H2O signal).
Example 60 4-r(carboxycarbonyl)(2-carboxyphenyl)amino1-N-(methoxycarbonyl)-N-(3,4,5- trifluorobenzyl)naphthylalaninamide The titled compound was prepared according to the method described in Example 56 J by substituting 3,4,5-trifluorobenzylamine for 1-pentylamine. MS (APCI(+)) m/e 580 (M+H-CO2)+, 624 (M+H)+; 1H ΝMR (500MHz, DMSO-d6) δ 8.75-6.75 (m, 15H), 4.45- 4.25 (m, 2H), 4.25-4.15 (m, IH), (signals of methylcarbamate and benzylic protons appeared in H2O signal).
Example 61
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(cyclooctylmethyl)-N- (methoxycarbonyl)naphthylalaninamide The titled compound was prepared according to the method described in Example 56 J by substituting cyclooctylmethylamine for 1-pentylamine. MS (APCI(+)) m/e 560 (M+H-CO2)+, 604 (M+H)+; 1H ΝMR (500MHz, DMSO-d6) δ 8.50-6.75 (m, 13H), 4.45-
4.25 (m, IH), 2.95-2.8 (m, 2H), 1.7-1.0 (m, 15H), (signals of methylcarbamate and benzylic protons appeared in H O signal)
Example 62
4-r(carboxycarbonyl)(2-carboxyphenyl)amino]-N-[(17?)-l-(4-bromophenyl)ethyl1-N-
(methoxycarbonyl)naphthylalaninamide The titled compound was prepared according to the method described in Example 56 J by substituting (17?)-l-(4-bromophenyl)ethylamine for 1-pentylamine. MS (APCI(+)) m/e 618 (M+H-CO2)+, 662 (M+H)+; 1H ΝMR (500MHz, DMSO-d6) δ 8.65-6.75 (m,
17H), 4.95-4.70 (m, IH), 445-4.30 (m, IH), 140-0.95 (m, 3H), (signals of methylcarbamate and benzylic protons appeared in H2O signal).
Example 63
4-[(carboxycarbonyl)(2-carboxyphenyl)amino1-N-(methoxycarbonyl)-N-(3- phenylpropyl)naphthylalaninamide The titled compound was prepared according to the method described in Example 56 J by substituting 3-phenylpropylamine for 1-pentylamine. MS (APCI(+)) m/e 554 (M+H-CO2)+, 598 (M+H)+; 1H ΝMR (500MHz, DMSO-d6) δ 8.50-6.75 (m, 18H), 4.4-
4.25 (m, IH), 3.15-3.00 (m, 2H), 1.75-1.5 (m, 2H), (signals of methylcarbamate and benzylic protons appeared in H2O signal). Example 64 methyl 3 - { 4- [(carboxy carbony l)(2-carboxyphenyl)amino] - 1 -naphthyl } -N- (methoxycarbonyl)alanyl-L-norleucinate
The titled compound was prepared according to the method described in Example 56 J by substituting L-methyl-norleucinate for 1-pentylamine. MS (APCI(+)) m/e 564 (M+H-CO2)+, 608 (M+H)+; 1H NMR (500MHz, DMSO-d6) δ 8.50-6.75 (m, 13H), 4.55- 4.40 (m, IH), 4.35-4.15 (m, IH), 3.65-3.55 (m, 3H), 1.8-1.0 (m, 6H), 0.85-0.65 (m, 3H), (signals of methylcarbamate and benzylic protons appeared in H2O signal).
Example 65 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(2-fluorobenzyl)-N- (methoxycarbonyl)naphthylalaninamide
The titled compound was prepared according to the method described in Example 56 J by substituting 2-fluorobenzylamine for 1-pentylamine. MS (APCI(+)) m/e 544 (M+H-CO2)+, 588 (M+H)+; 1H ΝMR (500MHz, DMSO-d6) δ 8.70-6.75 (m, 17H), 4.50- 4.20 (m, 3H), (signals of methylcarbamate and benzylic protons appeared in H O signal).
Example 66 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4-chlorobenzyl)-N- (methoxycarbonyl)naphthylalaninamide The titled compound was prepared according to the method described in Example
56 J by substituting 4-chlorobenzylamine for 1-pentylamine. MS (APCI(+)) m/e 560 (M+H-CO2)+, 604 (M+H)+; 1H ΝMR (500MHz, DMSO-d6) δ 8.75-6.75 (m, 17H), 4.50- 4.35 (m, IH), 4.35-4.15 (m, 2H), (signals of methylcarbamate and benzylic protons appeared in H O signal).
Example 67 4-r(carboxycarbonyl)(2-carboxyphenyl)aminol-N-(4-bromobenzyl)-N- (methoxycarbonyl)naphthylalaninamide The titled compound was prepared according to the method described in Example
56 J by substituting 4-bromobenzylamine for 1-pentylamine. MS (APCI(+)) m/e 604 (M+H-CO2)+, 648 (M+H)+; 1H ΝMR (500MHz, DMSO-d6) δ 8.70-6.75 (m, 17H), 4.50- 4.35 (m, IH), 4.35-4.15 (m, 2H), (signals of methylcarbamate and benzylic protons appeared in H2O signal).
Example 68
4-r(carboxycarbonyl)(2-carboxyphenyl)amino1-N-(methoxycarbonyl)-N-(4- nitrobenzyl)naphthylalaninamide The titled compound was prepared according to the method described in Example 56 J by substituting 4-nitrobenzylamine for 1-pentylamine. MS (APCI(+)) m/e 571 (M+H-CO2)+, 615 (M+H)+; 1H ΝMR (500MHz, DMSO-d6) δ 8.85-6.75 (m, 17H), 4.50-
4.30 (m, 3H), (signals of methylcarbamate and benzylic protons appeared in H2O signal).
Example 69 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-[4-(aminosulfonyl)benzyl1-N-
(methoxycarbonyl)naphthylalaninamide The titled compound was prepared according to the method described in Example 56 J by substituting 4-(aminosulfonyl)benzylamine for 1-pentylamine. MS (APCI(+)) m/e 605 (M+H-CO2)+, 649 (M+H)+; 1H ΝMR (500MHz, DMSO-d6) δ 8.90-6.75 (m, 19H), 4.50-4.25 (m, 3H), (signals of methylcarbamate and benzylic protons appeared in H2O signal).
Example 70 4-[(carboxycarbonyl)(2-carboxyphenyl)amino1-N-(mefhoxycarbonyl)-N-({4-
[(methylamino)carbonyl]cyclohexyl}methyl)naphthylalaninamide The titled compound was prepared according to the method described in Example 56 J by substituting trα«5'-4-[(methylamino)carbonyl]cyclohexylmethylamine for 1- pentylamine. MS (APCI(+)) m/e 589 (M+H-CO2)+, 633 (M+H)+; 1H ΝMR (500MHz, DMSO-d6) δ 8.50-6.75 (m, 13H), 4.45-4.25 (m, IH), 3.00-2.80 (m, 2H), 2.56-2.53 (m,
3H), 2.05-1.90 (m, IH), 1.75 -1.50 (m, 3H), 140-1.15 (m, 3H), 0.90-0.70 (m, 2H), (signals of methylcarbamate and benzylic protons appeared in H O signal).
Example 71
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-(2-hydroxyethyl)-N-(4: nitrobenzyl)phenylalaninamide The titled compound was prepared according to the procedure described in Example 35 C-G, substituting the 4-nitro-benzylamine for the amylamine, and 2- acetylamino-3-[4-amino-3-(2-hydroxy-ethyl)-phenyl]-propionic acid for 2-acetylamino-3- (4-amino-naphthalen-l-yl)-propionic acid used in Example 35D. MS (ESI+) m/e 593 (M+H)+; ]H NMR (300 MHz,DMSO-d6) (A mixture of rotamers) d 8.65 (brt, J= 5.7 Hz, IH), 8.26-8.07 (m, 2H), 7.91 and 7.82 (two sets of doublets, J= 7.2 Hz, IH in total), 7.60- 6.62 (m, 9H), 4.63-4.27 (m, 3H), 3.85-3.10 (m, 2H), 3.10-2.64 (m, 4H), 1.85-1.75 (multiple siglets, 3H in total).
Example 72 2-r(carboxycarbonyl)(7-hydroxy- 1 -naphthyl)amino1-4-cyanobenzoic acid
Example 72A
Methyl 2-nitro-4-carboxybenzoate A solution of dimethyl nitroterephthalate (5.98g, 25.0 mmol) and aqueous IM NaOH. (25 mL) in dioxane (50mL) was stined at ambient temperature for 2hours, then concentrated under reduced pressure. The remaining solution was diluted with water (50mL) and extracted with diethyl ether (3 x 25mL). The aqueous layer was acidified to a pH <3 with IM HCl, then extracted with diethyl ether (3 x 25 mL). The second set of ether layers was washed with brine (1 x lOmL), dried (MgSO ), filtered, and concentrated under reduced pressure. The residue was precipitated from methanol (25 mL) and water (25 mL) to provide the titled compound (2.0g, 36%). 1H NMR (300MHz, d6-DMSO) δ 8.46 (d, IH, J = 1.5), 8.33 (dd, IH, j = 1.7, 7.8), 7.99 (d, IH, J = 8.1), 3.89 (s, 3); MS
(ESI) m/z= 224 (M-H).
Example 72B benzyl 3 -nitro-4-methoxycarbonylbenzoate
To a solution of methyl 2-nitro-4-carboxybenzoate (1.13g, 5.00 mmol), K2CO3 (680 mg, 4.92 mmol) in N,N-dimethylformamide (5 mL) was added benzyl bromide (750 μL, 6.30 mmol). The mixture was heated at 100 °C for 15 minutes, cooled to ambient temperature, poured into water (30mL) and extracted with diethyl ether (3 x lOmL). The combined ether layers were washed with water (2 x 10 mL), brine (1 x 10 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure. The residue was crystallized from 20% ethyl acetate hexanes to provide the titled compound (1.0g, 63%). ]H NMR (300MHz, d6-DMSO) δ 8.52 (d, 1, J = 1.7), 8.39 (dd, 1, J = 1.7, 8.1), 8.01 (d, 1, J = 7.8), 7.53-7.35 (m, 5), 5.43 (s, 2), 3.89 (s, 3); MS (ESI) m/z= 333 (M+NH4 +).
Example 72C benzyl-3-amino-4-methoxycarbonylbenzoate A solution of benzyl-3-nitro-4-methoxycarbonylbenzoate (958mg, 3.04 mmol), iron powder (990mg, 18 mmol), ammonium chloride (200mg, 3.73 mmol) in 2-propanol (15mL) and water (3 mL) was heated to reflux for lhour, filtered and concentrated under reduced pressure. The residue was partitioned between water (lOmL) and diethyl ether
(lOmL). The ether layer was washed with brine (1 x 5mL), dried (MgSO4), filtered, and concentrated under reduced pressure to provide the titled compound (528mg, 61%). !H NMR (300MHz, d6-DMSO) δ 7.80 (d, IH, J = 8.1), 7.48-7.33 (m, 6H), 7.08 (dd, 1, J = 1.7, 8.1), 6.87 (bs, 2H), 5.33 (s, 2), 3.81 (s, 3); MS (ESI) m z= 286 (MH+).
Example 72D 1 -Iodo-7-hydroxynaphthalene To 8-amino-2-naphthol (448g, 30 mmol) was added a solution of 98% H2SO4 (4mL) in water (50mL). The mixture was cooled with an ice bath, then a solution of aqueous NaNO2 (2.50g, 36.2 mmol) in a minimum amount of water was added slowly via pipette, expelling the nitrite solution below the surface of the reaction. After lOmin, a solution of KI (15g, 90 mmol) in a minimum amount of water was added slowly to control the evolution of N2. Diethyl ether was added to break the foamy emulsion that formed and the reaction was stined for 18 hour at ambient temperature. Additional diethyl ether
(50mL) was added, followed by solid NaHSO3 to remove the I2 color from the reaction. The mixture was filtered and the filter cake washed with ethyl acetate (150mL). The ether layer was separated from the supernatant, and the aqueous layer was extracted with diethyl ether (1 x 50 mL). The combined ether and ethyl acetate layers were washed with brine (1 x 25 mL), dried (MgSO4), filtered, and concentrated under reduced pressure and the residue purified on silica gel eluting with 20% ethyl acetate/hexanes to provide the titled compound (3.2g, 40%). 1H NMR (300MHz, d6-DMSO) δ 10.12 (s, IH), 8.02 (dd, IH, J = 1.2, 7.3), 7.84 (d, IH, J = 8.1), 7.78 (d, IH, J = 8.8), 7.33 (d, IH, J = 24), 7.13 (dd, IH, J = 2.4, 8.8), 7.04 (dd, IH, J = 7.1, 8.1); MS (ESI) m/z= 269 (M-H).
Example 72E l-Iodo-7-dimethyl-tert-butylsilyloxynaphthalene To l-iodo-7-hydroxynaphthalene (3.05g, 11.3 mmol) in N,N-dimethylformamide (27mL) was added tert-butyldimethylsilyl chloride (2.09g, 13.9 mmol) and imidazole (1.85g, 27 mmol). The reaction was stined at ambient temperature for 2 hours, diluted with aqueous 0.3M HCl (150mL) and extracted with hexanes (2 x 50mL). The combined hexanes layers were washed with water (1 x 50mL), brine (1 x 50mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was heated at 110 °C for 2 min to remove most of the excess silicon containing byproducts to provide the titled compound (4.34g, 100%). 1H NMR (300MHz, d6-DMSO) δ 8.01 (dd, IH, J = 1.0, 7.1), 7.75 (d, IH, J = 8.1), 7.49 (d, IH, J = 2.4), 7.09 (dd, IH, J = 24, 8.8), 7.04 (dd, IH, J =
7.5, 7.8), 1.04 (s, 9H), 0.31 (s, 6H); MS (ESI) m/z= 269 (M-TBS).
Example 72F 2-r7-(tert-butyl-dimethyl-silanyloxy)-naphthalen-l-ylamino1-terephthalic acid 4-benzyl ester 1 -methyl ester A mixture of benzyl-3-amino-4-methoxycarbonylbenzoate (1.2g, 4.21 mmol), 1- iodo-7-dimethyl-tert-butylsilyloxynaphthalene (1.62g, 4.21 mmol), tris- (dibenzylideneacetone)dipalladium (19mg, 0.019 mmol), (2'-dicyclohexylphosphanyl- biphenyl-2-yl)-dimethyl-amine (25mg, .064 mmol), and 60% NaH in mineral oil (210mg,
5.25 mmol) in toluene (13mL) was stined under N2 for 17hours at 80 °C, cooled to ambient temperature and poured into aqueous 0.1M HCl (50mL). The mixture was extracted with diethyl ether (3 x 15mL), the combined ether layers were washed with brine (1 x 15mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 10% ethyl acetate: hexanes to provide the titled compound (1.26g, 55%). 1H NMR (300MHz, CDC13) δ 9.70 (bs, IH), 8.05 (d, IH, J = 8.5), 7.79 (d, IH, J = 8.8), 7.68 (d, IH, J = 8.1), 7.55 (d, IH, J = 1.7), 7.46 (d, IH, J = 7.5), 7.35-7.24 (m, 8), 7.10 (dd, IH, J = 2.4, 8.8), 5.23 (s, 2H), 3.98 (s, 3H), 1.04 (s, 9H), 0.12 (s, 6H); MS (ESI) m/z= 542 (MH+).
Example 72G 2-(7-hydroxy-naphthalen-l-ylamino)-terephthalic acid 4-benzyl ester 1 -methyl ester. To 2-[7-(tert-Butyl-dimethyl-silanyloxy)-naphthalen-l -ylamino] -terephthalic acid 4-benzyl ester 1 -methyl ester (1.26g) in dioxane (30mL) was added 15 drops of 60%
HClO4. After stining for 18 hours, aqueous NaHCO3 solution (2mL) was added, the mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (15mL) and water (5mL). The ethyl acetate layer was washed with brine (1 x 5mL), dried(MgSO4), filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with ethyl acetate hexanes to provide the titled compound (553mg, 56%). 1H NMR (300MHz, d6-DMSO) δ 9.84 (s, IH), 9.50 (s, IH), 8.05 (m, IH), 7.89 (m, IH), 7.78 (d, IH, J = 8.1), 7.45 (d, IH, J = 7.1), 7.37-7.24 (m, 8), 7.15-7.12 (m, 2H), 5.21 (s, 2H), 3.95 (s, 3H); MS (ESI) m/z= 426 (M-H).
Example 72H 2-(7-hydroxy-naphthalen-l-ylamino)-terephthalic acid 1 -methyl ester
A mixture containing 2-(7-hydroxy-naphthalen-l-ylamino)-terephthalic acid 4- benzyl ester 1 -methyl ester (545mg, 1.27 mmol), 10%Pd-C (90mg) and 60% HClO4 (2 drops) in dioxane (lOmL ) was stined at ambient temperature under 1 atmosphere hydrogen for 4 hours. The mixture was filtered, aqueous NaHCO3 solution (lmL) was added, and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (15mL ) and aqueous IM HCl (5 mL), and the layers separated. The organic layer was washed with brine (1 x 5mL), dried (MgSO4), filtered, and concentrated under reduced pressure to provide the titled compound (450mg). 1H NMR (300MHz, d6-DMSO) δ 13.1 (bs, IH), 9.84 (s, IH), 948 (s, IH), 8.02 (d, IH, J = 8.5), 7.87 (d, IH, J = 8.5), 7.75 (d, IH, J = 8.1), 7.43 (d, IH, J = 7.1), 7.34 (t, IH, J = 7.6), 7.24 (dd, IH, J = 1.7, 8.1), 7.21
(d, IH, J = 1.7), 7.16-7.11 (m, 2H), 3.95 (s, 3H); MS (ESI) m/z= 336 (M-H).
Example 721 2-(7-hydroxy-naphthalen-l-ylamino)-terephthalyl amide 1 -methyl ester
To a solution of 2-(7-hydroxy-naphthalen-l-ylamino)-terephthalic acid 1 -methyl ester (75mg, 0.22 mmol) in THF (2mL ) was added triethylamine (155 μL, 1.11 mmol) and isobutyl chloroformate (80μL, 0.62 mmol). The reaction was stined at ambient temperature for 30min, aqueous ammonia (lmL) was added, the reaction was stined for 5hours and concentrated under reduced pressure. The residue was taken up in ethyl acetate (3mL ), washed with IM HCl (3 x lmL), aqueous NaHCO3 solution (2 x 1 mL), brine (l x l mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with ethyl acetate: hexanes to provide the titled compound.
Example 72J 2-[(carboxycarbonyl)(7-hydroxy-l-naphthyl amino1-4-cyanobenzoic acid A mixture of 2-(7-hydroxy-naphthalen-l-ylamino)-terephthalyl amide 1 -methyl ester and 1.39M NaOH (lmL) in 5:1 ethanol: water was stined at ambient temperature for 2hours, and concentrated under reduced pressure. The residue was partitioned between water (1 mL) and ethyl acetate (2mL), the mixture was acidified to a pH <3 with aqueous IM HCl (2mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2mL). The combined ethyl acetate layers were washed with brine (1 x 2mL), dried (MgSO4), filtered, and concentrated under reduced pressure. A solution of the residue, triethylamine (200μL) and ethyl oxalyl chloride (lOOμL) in N,N-dimethylformamide (lmL) was stined at ambient temperature for 40minutes, then aqueous 2M NaOH (2mL) was added, followed by the addition of water (6mL). The resulting solution was stined for 10 minutes, then ethyl acetate (2mL) was added, followed by 12M HCl (0.5 mL).. The mixture was shaken, then separated, and the aqueous phase was extracted with ethyl acetate (2 x lmL). The combined ethyl acetate layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified on reverse phase HPLC, eluting with a 0.1 % aqueous trifuoroacetic acid:acetonitrile to provide the titled compound (18mg, 23%). 1H NMR (500MHz, d6- DMSO) mixture of rotamers, major rotamer resonances only, δ 9.93 (bs, IH), 8.03 (d, IH, J = 8.1), 7.92 (d, IH, J = 8.1), 7.89 (d, IH, J = 7.8), 7.87-7.83 (m, 2H), 7.64 (d, IH, J = 6.6), 7.48 (d, IH, J = 2.2), 7.36 (dd, IH, J = 7.5, 8.1), 7.28 (d, IH, J = 1.3), 7.13 (dd, IH, J = 2.3, 8.9); MS (ESI) m/z= 375 (M-H), 394 (M+ NH4+).
Example 73 4- [(carboxycarbony l)(2-carboxyphenyl)amino] -N- {4- [(ethylamino)sulfonyl]benzy 1 } -N- (methoxycarbonyl)naphthylalaninamide
Example 73A 4-(l ,3-dioxo- 1 ,3-dihydro-isoindol-2-ylmethyl)-benzenesulfonyl chloride The titled compound was prepared according to the procedure described in
Bergeim, F. H.; Braker, W. J. Am. Chem. Soc. 1944, 64, 1459.
Example 73B 4-(l,3-dioxo-l,3-dihydro-isoindol-2-ylmethyl)-Ν-ethyl benzenesulfonamide
To a mixture of 4-(l,3-dioxo-l,3-dihydro-isoindol-2-ylmethyl)-benzenesulfonyl chloride (1.68 g, 5 mmol) in dioxane (15 mL) at 0°C was added aqueous sodium bicarbonate (5 mL) followed by ethylamine (10 mmol, 5 mL of a 2M solution in tetrahydrofuran). The mixture was stined for 30 minutes at 0°C, then warmed to ambient temperature for 2 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with water (1 x 20 mL), aqueous IN HCl (2 x 20 mL), aqueous NaHCO3 (2 x 20 mL), and brine (1 x 20 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in a minimum of chloroform and precipitated by the addition of hexane. The mixture was filtered and the solid washed with hexane and chloroform to provide the titled product. MS (APCI(+)) m/e 345 (M+H)+.
Example 73 C 4-[(ethylamino)sulfonyl]benzylamine A solution containing 4-(l,3-dioxo-l,3-dihydro-isoindol-2-ylmethyl)-N-ethyl benzenesulfonamide (0.84 g, 2.44 mmol) and hydrazine (0.38 mL) in methanol (5 mL) was stined under nitrogen for 14 hours diluted with aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with aqueous NaHCO (1 x 35 mL), brine (1 x 30 mL), dried ( MgSO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with 1 : 1 toluene/ethyl acetate with a gradient of methanol to provide the titled compound. MS (APCI(+)) m/e 215 (M+H)+.
Example 73D 4-r(carboxycarbonyl)(2-carboxyphenyl)amino1-N-{4-r(ethylamino)sulfonyllbenzyl}-N-
(methoxycarbonyl)naphthylalaninamide The titled compound was prepared according to the procedure described in 56 J by substituting 4-[(ethylamino)sulfonyl]benzylamine for 1-pentylamine. MS (ESI(+)) m/e 676 (M)+; 1H ΝMR (500MHz, DMSO-d6) δ 8.80-6.75 (m, 18H), 4.55-4.25 (m, 3H), 2.85- 2.65 (m, 2H), 1.00-0.90 (m, 3H), (signals of methylcarbamate and benzylic protons appeared in H O signal).
Example 74 N-(tert-butoxycarbonyl)-L-phenylalanyl-3 - [( 1 E)-3 -amino-3 -oxo- 1 -propenyl]-^ [(carboxycarbonyl)(2-carboxyphenyl)aminol-N-pentyl-L-phenylalaninamide The titled compound was prepared according to the procedure described for
Example 38 C-E, substituting- {l-[2-(4-amino-3-iodo-phenyl)-l-pentylcarbamoyl- ethylcarbamoyl]-2-phenyl-ethyl}carbamic acid tert-butyl ester from Example 49B for[2- (4-amino-3-iodo-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester from Example 38B. MS (ESI+) m/e 780 (M+Na)+; 758 (M+H); No NMR data available.
Example 75
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-(2-hydroxyethyl)-N-[(lS)-l-(4- nitrophenyl)ethyllphenylalaninamide The titled compound was prepared according to the procedure described in Example 35D-G, substituting 2-acetylamino-3-[4-amino-3-(2-hydroxy-ethyl)-phenyl]- propionic acid for 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid and substituting 4-nitro-(S)-α-methyl-benzylamine for the amylamine in Example 35D. MS (ESI+) m/e 607 (M+H)+; 1H ΝMR (300 MHz, DMSO-d6) (A mixture of rotamers and 1 :1 mixture of diastereoisomers) δ 8.74-844 (m, 2H), 8.22-7.79 (m, 4H), 7.59-6.84 (m, 7H), 5.02-4.82 (m, IH), 4.67-4.44 (m, IH), 3.58-3.33 (m, 2H), 3.01-2.60 (m, 4H), 1.78 (multiple s, 3H), 1.43- 1.10 (m, 3H).
Example 76 N-acetyl-4-r(carboxycarbonyl)(2-carboxyphenyl)amino1-N-(4-chlorobenzyl)-3-(2- hydroxyethyl)phenylalaninamide
The titled compound was prepared according to the procedure described in Example 35D-E, substituting 2-acetylamino-3-[4-amino-3-(2-hydroxy-ethyl)-phenyl]- propionic acid for 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid and substituting 4-chloro-benzylamine for the amylamine in Example 35D. MS (ESI+) m/e 582, 584 (M+H)+; !H ΝMR (300 MHz, DMSO-d6) (A mixture of rotamers) δ 8.52 (t, J-
5.25 Hz, IH), 8.23-8.11 (m, IH), 8.01-7.92 (m, IH), 7.87-7.77 (m, IH), 7.59-6.72 (m, 9H), 4.60-441 (m, 2H), 4.10-4.28 (m, 2H), 3.82-3.70 (m, IH), 2.62-3.14 (m, 4H), 1.33- 1.23 (m, 3H).
Example 77 N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino1-N-(4-bromobenzyl)-3-(2- hydroxyethyl)phenylalaninamide The titled compound was prepared according to the procedure described in Example 35D-G, substituting 2-acetylamino-3-[4-amino-3-(2-hydroxy-ethyl)-phenyl]- propionic acid for 2-acetylamino-3-(4-amino-naphthalen-l-yl)-ρropionic acid and 4- bromobenzylamine for the amylamine in Example 35D. MS (ES1+) m/e 626, 628 (M+H)+; *HNMR (300 MHz, DMSO-d6) (A mixture of rotamers) δ 8.65 (t, J= 5.25 Hz, IH), 8.35-8.14 (m, IH), 8.11-7.97 (m, IH), 7.89-7.77 (m, IH), 7.65-6.82 (m, 9H), 4.60- 441 ( , 2H), 4.10-4.28 (m, 2H), 3.82-3.70 (m, IH), 2.62-3.14 (m, 4H), 1.33-1.23 (m, 3H).
Example 78
2-[(carboxycarbonyl)(7-hydroxy-l-naphthyl)amino]-4-{[4-
(dimethylamino)benzoyl] amino } benzoic acid
Example 78A 2-[7-(tert-butyl-dimethyl-silanyloxy)-naphthalen- 1 -ylamino] -4-nitro-benzoic acid methyl ester A mixture of methyl 2-bromo-4-nitrobenzoate (2.86g, l l.Ommol), 7-tert-butyl- dimethylsilanlyoxy- 1 -naphthylamine (3.01 g, 11.0 mmol), tris(dibenzylideneacetone)dipalladium (50mg, 0.051 mmol), (2'-dicyclohexylphosphanyl- biphenyl-2-yl)-dimethyl-amine (66mg, 17 mmol), and 60% NaH in mineral oil (660mg, 16.5 mmol) in toluene (35mL) was refluxed for 2 hours under N2, cooled and extracted with aqueous IM HCl (1 x 15mL), brine (1 x 15mL). The HCl layer was extracted with diethyl ether (1 x 15 mL), and the ether layer washed with brine (1 x 10 mL). The combined ether and toluene layers were dried (MgSO4), filtered, and concentrated under reduced pressure and the residue purified on silica gel eluting with 5% ethyl acetate: hexanes to provide the titled compound (2.58g, 52%). 1H NMR (300MHz, CDC13) δ 9.82 (bs, IH), 8.15 (d, IH, J = 8.8), 7.81 (d, IH, J = 8.8), 7.75 (d, IH, J - 7.8), 7.51 (d, IH, J = 24), 747-7.36 (m, 3H), 7.25 (d, IH, J = 24), 7.12 (dd, IH, J = 2.4, 8.8), 4.01 (s, 3H), 0.94
(s, 9H), 0.13 (s, 6H); MS (ESI) m/z= 451 (M-H).
Example 78B 2-r7-(tert-butyl-dimethyl-silanyloxy)-naphthalen-l-ylamino]-4-amino-benzoic acid methyl ester A mixture of 2-[7-(tert-butyl-dimethyl-silanyloxy)-naphthalen- 1 -ylamino]-4-nitro- benzoic acid methyl ester (796mg, 1.76 mmol), iron powder (580mg, 10.5 mmol), ammonium chloride (116mg, 2.16 mmol) in 2-propanol: water (8mL of 5:1, (v/v)) was heated to reflux for 1.75 hour, diluted with ethyl acetate (50mL), filtered through diatomaceous earth, and concentrated under reduced pressure. The product was purified on silica gel eluting with 20% ethyl acetate: hexanes to provide the titled compound (653mg, 88%).
Example 78C
2-[(carboxycarbonyl)(7-hydroxy-l-naphthyl)amino]-4-{[4- (dimethy lamino)benzoyl] amino } benzoic acid A solution of 2-[7-(tert-butyl-dimethyl-silanyloxy)-naphthalen- 1 -ylamino]-4- amino-benzoic acid methyl ester (73mg, 0.17 mmol), triethylamine (66μL, 0.47 mmol), 4- N,N-dimethylaminobenzoyl chloride (40mg , 0.22mmol) in ethyl acetate (lmL) was stined for 10 minutes, extracted with aqueous IM HCl (2 x lmL), aqueous NaHCO3 solution (2 x lmL), dried (MgSO4), filtered, concentrated under reduced pressure, and purified on silica gel eluting with 30% ethyl acetate: hexanes (37mg). The residue was taken up and stined in aqueous 1.39M NaOH (lmL) in 5:1 ethanol: water for 14 hours. The mixture was concentrated under reduced pressure, taken up in water (lmL) and extracted with diethyl ether (3 x lmL). The aqueous layer was stined with ethyl acetate (3mL), acidified by the addition of 2mL of aqueous IM HCl. The ethyl acetate layer was separated, dried (MgSO4), filtered, and concentrated under reduced pressure. A mixture of the residue, triethylamine (200μL), ethyl oxalyl chloride (lOOμL) in N,N- dimethylformamide (lmL) were stined at ambient temperature for 10 minutes, aqueous
2M NaOH (2mL) was added and the mixture allowed to stand for 10 minutes. Water was added until a homogenous solution was achieved and the mixture was allowed to stand for 1.5 hour. The mixture was acidified to pH=l by addition of 12M HCl, and extracted with ethyl acetate (4 x lmL). The combined ethyl acetate layers were washed with water (1 x lmL), brine (1 x lmL), dried (MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by reverse-phase HPLC, eluting with a 0.1% trifluoroacetic acid: acetonitrile to provide the titled compound. 1H NMR (300MHz, d6-DMSO) mixture of rotamers, δ 10.13(s, IH), 9.99 (s, IH), 7.99-7.95 (m, 2H), 7.89-7.86 (m, 2H), 7.83-7.79 (m, 2H), 7.75-7.70 (m, 2H), 7.65 (m, IH), 7.53 (m, IH), 745 (s, 1), 7.35 (m, IH), 7.29 (d, IH, J - 2.2), 7.26 (t, IH, J = 7.8), 7.17 (m, IH), 7.11 (dd, IH, J = 2.2, 8.7), 6.68 (m, 2H),
2.96 (s, 6H); MS (ESI) m/z= 514 (MH+).
Example 79 N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-ethyl-N-(4- nitrobenzyl)phenylalaninamide Example 79A 2-Acetylamino-acrylic acid benzyl ester To a mixture of 2-acetamidoacrylic acid (10.3 g, 80.0 mmol) and K2CO3 (10 g,
72.5 mmol) in N,N-dimethylformamide (50 mL) was added benzyl bromide (8.7 ml, 72.5 mmol) at room temperature then stined at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water (50mL, 1:1), the aqueous layer was extracted with ethyl acetate (2 x 45 mL). The combined organic layers was washed with brine (2 x 25 mL), dried (MgSO4), filtered and concentrated under reduced pressure to provide titled compound. MS (ESI(+)) m/e 220(M+H)+; 1HNMR (300 MHz, DMSO-d6) δ 9.37 (s, IH), 743-7.30 (m, 5H), 6.13 (s, IH), 5.70 (s, IH), 5.23 (s, 2H), 2.01 (s, 3H).
Example 79B
2-acetylamino-3-(4-amino-3-ethyl-phenyl)-acrylic acid benzyl ester To 2-acetylamino-acrylic acid benzyl ester (80.0 mmol) in acetonitrile (200 mL) was added Pd(OAc)2 (488 mg, 2.18 mmol), (o-Tol)3P (1.32 g, 4.35 mmol), Et3N (20 mL) followed by addition of 4-bromo-2-ethylaniline (14.5 g, 72.5 mmol). The reaction mixture was heated to reflux overnight, concentrated under reduce pressure, taken up in ethyl acetate, washed with aqueous NaHCO3, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was precipitated from ethyl acetate/hexane to provide the titled compound (6.3 g). The filtrate was precipitated a second time to provide and additional 5 g of the titled compound. MS (ESI(+)) m/e 339 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.31 (s, IH), 740-7.20 (m, 8H), 6.59 (d, IH), 5.52 (s, 2H), 5.16 (s,
2H), 2.42 (q, 2H), 1.98 (s, 3H), 1.13 (t, 3H).
Example 79C 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid
A mixture of 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-acrylic acid benzyl ester (5g) and 10% Pd-C (100 mg) in methanol (50 mL) was stined under an atmosphere of hydrogen (4 atmospheres) at ambient temperature overnight to provide the titled compound. MS (ESI(+)) m/e 251 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 8.02 (d, IH), 6.77-6.70 (m, 2H), 6.50 (d, IH), 4.31-4.21 (m, IH), 2.84 (dd, IH), 2.65 (dd, IH),
2.39 (q, 2H), 1.78 (s, 3H), 1.10 (t, 3H). Example 79D
2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid allyl ester A mixture of 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid (2.0 g, 8.0 mmol), Cs2CO3 (2.61 g, 8.0 mmol) and allyl bromide (692 ul, 8.0 mmol) in N,N- dimethylformamide (40 mL) was stined at room temperature for 3 hours, concentrated under reduce pressure and partitioned between ethyl acetate and water (1 OOmL, 1:1). The organic phase was washed with brine (1 x 50 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by on silica gel with ethyl acetate/hexane (5:3) to provide titled compound (144 g). MS (ESI(+)) m e 291 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 8.23 (d, IH), 6.77-6.70 (m, 2H), 6.50 (d, IH), 5.90-5.76 (m, IH), 5.30-5.15 (m, 2H), 4.67 (s, 2H), 4.54-4.50 (m, 2H), 4.38-4.30 (m, IH), 2.77(dddd, 2H), 2.39 (q, 2H), 1.80 (s, 3H), 1.10 (t, 3H).
Example 79E 2-{[4-(2-acetylamino-2-allyloxycarbonyl-ethyl)-2-ethyl-phenyl]-tert-butoxyoxalyl- amino} -benzoic acid The titled compound was prepared according to the method described in Example 50E by substituting 2-acetylamino-3-(4-amino-3-ethyl-phenyl)-propionic acid allyl ester for 2-{[4-(2-allyloxycarbonylamino-2-pentylcarbamoyl-ethyl)-phenyl]-tert- butoxyoxalylamino} -benzoic acid. MS (APC1 (+)) m/e 539 (M+H) .
Example 79F
2-{r4-(2-acetylamino-2-allyloxycarbonyl-ethyl)-2-ethyl-phenyl1-tert-butoxyoxalyl- amino} -benzoic acid benzhydryl ester To 2- { [4-(2-acetylamino-2-allyloxycarbonyl-ethyl)-2-ethyl-phenyl]-tert- butoxyoxalyl-amino} -benzoic acid in acetone was added diphenyldiazomethane (until all starting material was consumed as evident by monitoring via TLC). The reaction mixture was concentrated under reduced pressure, purified on silica gel using ethyl acetate as eluent to provide the titled compound. MS (ESI(+)) m/e 705 (M+H)+ ; 1H NMR (300 MHz, DMSO-d6) δ 8.51-8.01 (m, 2H), 7.73-6.86 (m, 16H), 5.93-5.78 (m, IH), 5.34-5.10 (m, 2H), 4.57-4.40 (m, 3H), 3.10-2.84 (m, 2H), 2.58-242 (m, 2H), 1.82-1.77 (m, 3H), 1.22-0.78 (m, 3H), 1.07, 1.05, 1.00 (s, s, s, 9H). Example 79G 2-{[4-(2-acetylamino-2-carboxy-ethyl)-2-ethyl-phenyl]-tert-butoxyoxalyl-amino}-benzoic acid benzhydryl ester A mixture of 2-{ [4-(2-acetylamino-2-allyloxycarbonyl-ethyl)-2-ethyl-phenyl]-tert- butoxyoxalyl-amino} -benzoic acid benzhydryl ester (3.4 g, 4.8 mmol), Pd(Ph3P)4 (166 mg, 0.144 mmol) and moφholine (0.5 ml, 5.8 mmol) in dichloromethane (25 mL) was stined under N2 atmosphere for 2 hours, partitioned between ethyl acetate and water (75 mL, 1 :1). The organic phase was washed with IN HCl (1 x 25 mL), brine (1 x 25mL), dried (MgSO4), filtered and concentrated under reduced pressure to provide the titled compound
(3.3 g). MS (ESI(+)) m/e 665 (M+H)+; !H NMR (300 MHz, DMSO-d6) δ 12.67 (s, IH), 8.51-7.98(m, 2H), 7.73-6.86 (m, 16H), 4.53-4.33 (m, IH), 3.12-2.76 (m, 2H), 2.58-242 (m, 2H), 1.82-1.77 (m, 3H), 1.22-0.78 (m, 3H), 1.06, 1.04, 1.00 (s, s, s, 9H).
Example 79H
2-{[4-(2-acetylamino-2-(4-nifro-benzylcarbamoyl)-ethyl1-2-ethyl-phenyl]-tert- butoxyoxalyl-amino} -benzoic acid benzhydryl ester A mixture of 2-{[4-(2-acetylamino-2-carboxy-ethyl)-2-ethyl-phenyl3-tert- butoxyoxalyl-amino} -benzoic acid benzhydryl ester (25 mg, 0.038 mmol), 4- nitrobenzylamine hydrochloride (15 mg, 0.08 mmol), 2-(lH-benzotriazole-l-yl)-l,l,3,3- tetramethyluronium tetrafluoroborate (16 mg, 0.048 mmol) and diisopropylethylamine (26 μL) in N,N-dimethylformamide (250 μL) was stined at ambient temperature overnight, concentrated under reduced pressure and the residue purified by reverse-phase HPLC eluting with 5-100% acetonitrile/ aqueous 0.1% TRIFLUOROACETIC ACID to provide the titled compound.
Example 791 N-acetyl-4-r(carboxycarbonyl)(2-carboxyphenyl)amino]-3-ethyl-N-(4- nitrobenzyl)phenylalaninamide
The material from Example 79H was treated with trifluoroacetic acid/dichloromethane (10 mL, 1 :1) at ambient temperature for 3 hours, concentrated under reduced pressure and purified by HPLC eluting with 5-100% acetonitrile/ aqueous 0.1 % trifluoroacetic acid to provide the titled comound (8 mg). MS (ESI(+)) m/e 577 (M+H)+;
1H ΝMR (500 MHz, DMSO-d6) δ 8.65 (t, IH), 8.24-8.10 (m, 3H), 7.96-7.81 (m, IH), 7.56-6.75 (m, 8H), 4.59-4.50 (m, IH), 4.45-4.32 (m, 2H), 3.10-2.97 (m, IH), 2.88-2.78 ( , IH), 2.72-2.55 (m, 2H), 1.81,1.79 (s, s, 3H), 1.22,0.94 (t, t, 3H).
Example 80
N-acetyl-4- [(carboxycarbonyl)(2-carboxyphenyl)amino1-3 -ethyl-N-r( 17?)- 1 -(4- nitrophenyl)ethyl]phenylalaninamide The titled compound was prepared according to the procedure described in Example 79 H-I by substituting l-(4-nitro-phenyl)-ethylamine for 4-nitrobenzylamine in Example 79 H. MS (ESI(+)) m/e 591 (M+H)+; !H ΝMR (500 MHz, DMSO-d6) δ 8.68-
8.46 (m, IH), 8.20-8.01 (m, 3H), 7.96-7.81 (m, IH), 7.59-6.75 (m, 8H), 5.02--4.88 (m, IH), 4.65-4.50 (m, IH), 3.00-2.78 (m, 4H), 1.83-1.75 (m, 3H), 140-0.86 (m, 6H).
Example 81
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4-chlorobenzyl)-3- ethylphenylalaninamide The desired product was prepared according to the procedure described in Example 79 H-I by substituting 4-chlorobenzylamine for 4-nitrobenzylamine in Example 79 H. MS (ESI(+)) m/e 566, 567 (M+H)+; H ΝMR (500 MHz, DMSO-d6) δ 8.51 (t, IH), 8.20-8.12
(m, IH), 7.96-7.80 (m, IH), 7.58-6.75 (m, 10H), 4.57-448 (m, IH), 4.30-4.16 (m, 2H), 3.10-2.97 (m, IH), 2.88-2.78 (m, IH), 2.72-2.55 (m, 2H), 1.79,1.77 (s, s, 3H), 1.22,0.93 (t, t, 3H).
Example 82 N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4- nitrobenzyl)naphthylalaninamide The titled compound was prepared according to the procedure described in Example 35 D-G, substituting 4-nitro-benzylamine for the amylamine used in Example 35
D. MS (ESI+) m/e 599 (M+H)+; H ΝMR (300 MHz, DMSO-d6) (A mixture of rotamers) δ 8.77-8.60 (m, IH), 849-7.77 (m, 5H), 7.77-7.25 (m, 5H), 6.97-6.68 (m, 2H), 4.81-4.60 (m, 2H), 443-4.29 (m, 2H), 3.71-3.13 (overlapping m, 5H), 1.88-1.72 (m, 3H).
Example 83 N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino1-N-[(17-,)-l-(4- bromophenyl)ethyl]-3-(2-hydroxyethyl)phenylalaninamide The titled compound was prepared according to the procedure described in Example 35D-G, by substituting 2-acetylamino-3-[4-amino-3-(2-hydroxy-ethyl)-phenyl]- propionic acid for 2-acetylamino-3-(4-amino-naphthalen-l-yl)-propionic acid and 4- bromo-(R)-α-methylbenzylamine for the amylamine used in Example 35D. MS (ESI+) m/e 640, 642 (M+H)+; 1H ΝMR (300 MHz, DMSO-d6) (A mixture of rotamers and 1 :1 mixture of diastereoisomers) δ 8.55-8.27 (m, 2H), 8.20-7.80 (m, 3H), 7.58-6.95 (m, 7H), 6.83-6.64 (m, IH), 4.93-4.70 (m, 2H), 4.65-4.24 (m, 3H), 3.09-2.63 (m, 4H), 1.84-1.72 (multiple s, 3H in total), 1.38-1.05 (m, 3H).
Example 84 4-[(butylamino)carbonyl]-2-r(carboxycarbonyl)(7-hydroxy-l-naphthyl)amino1benzoic acid
The titled compound was prepared according to the procedure described in Example 72I-J substituting n-butylamine for the aqueous ammonia in Example 721. The titled compound was purified on silica gel eluting with 40% ethyl acetate: hexanes. 1H ΝMR (500MHz, d6-DMSO) (A mixture of rotamers, major rotamer resonances only) δ 9.90 (bs, IH), 8.51 (t, IH, J = 5.6), 7.94 (d, IH, J = 8.1), 7.89 (d, IH, J = 8.1), 7.84 (d,
IH, J = 9.1), 7.77 (dd, IH, J = 1.6, 8.1), 7.60 (d, IH, J = 6.6), 7.50 (d, IH, J = 2.2), 7.36 (d, IH, J = 8.1), 7.34 (s, IH), 7.12 (dd, IH, J = 2.3, 8.9), 3.17-3.10 (m, 2H), 1.45-1.37 (m, 2H), 1.28-1.18 (m, 2H), 0.83 (t, 3H, J = 7.3 Hz); MS (ESI)" m/z= 449 (M-H).
Example 85
N-acetyl-4- [(carboxy carbonyl)(2-carboxyphenyl)amino] -N- { 5 - f(3 -hydroxyphenyl)amino] -
5 -oxopentyl } -3 -( 1 -piperidiny l)pheny lalaninamide
Example 85 A
2-({4-[2-acetylamino-2-(4-carboxy-butylcarbamoyl)-ethyl]-2-piρeridin-l-yl-phenyl -tert- butoxyoxalyl-amino)-benzoic acid benzhydryl ester
The titled compound was prepared according to the procedure described in Example 55B-J, substituting the 4-bromo-2-piperidin-l-yl-aniline for the 4-bromo-2-ethyl- aniline in Example 55B. Example 85B
N-acetyl-4- [(carboxy carbony l (2-carboxyphenyl)amino] -N- { 5 - [(3 -hy droxyphenyl)amino] -
5 -oxopentyl } -3 -(1 -piperidiny l)pheny lalaninamide The titled compound was prepared by following the procedure as described in
Example 55K, substituting 2-({4-[2-acetylamino-2-(4-carboxy-butylcarbamoyl)-ethyl]-2- piperidin-l-yl-phenyl}-tert-butoxyoxalyl-amino)-benzoic acid benzliydryl ester for 2-({4- [2-acetylamino-2-(4-carboxy-butylcarbamoyl)-ethyl]-2-ethyl-phenyl}-tert-butoxyoxalyI- amino)-benzoic acid benzhydryl ester, and 3 -hydroxy aniline for the 1-phenyl-ethylamine used in Example 55K. MS (ESI+) m/e 688 (M+H)+; !H ΝMR (300 MHz, DMSO-d6) (A mixture of rotamers) δ 9.79(s, 1H), 9.75(s, 1H), 8.06-6.40(m, 11H), 4.43-4.37(m, IH), 3.16(d, 2H), 3.10-2.9(m, 6H), 2.02(s, 3H), 1.6-1.4 (m, 6H).
Example 86 2-((carboxycarbonyl){4-[2-hydroxy-3-(pentylamino)propyl]phenyl}amino)benzoic acid
Example 86 A 1 -allyl-4-nitro-benzene The titled compound was prepared according to the procedure described in JOC, 22, p. 1418, 1957.
Example 86B 4-allyl-phenylamine A solution of l-allyl-4-nitro-benzene (1.92 g, 11.8 mmol), ΝH4C1 (1.89g, 35.3 mmol) and iron powder (4.60g, 82.4 mmol) in 3:1 ethanol:H2O (200 mL) was heated to reflux overnight. The reaction was cooled, concentrated under reduced pressure and purified on silica gel eluting with ethyl acetate to provide the titled compound. MS (ESI(+)) m/e 134 (M+H)+
Example 86C 2-(4-allyl-phenylamino)-benzoic acid The titled compound was prepared according to the procedure described in
Example 50C substituting 4-allyl-phenylamine for [2-(4-amino-phenyl)-l-
+ pentylcarbamoyl-ethyl] -carbamic acid tert-butyl ester. MS (ESI(+)) m/e 254 (M+H) ; H NMR (300 MHz, DMSO-d6) δ 13.02 (bs, IH), 9.58 (bs, IH), 7.89 (dd, IH), 7.39-7.34
(m, IH), 7.19-7.16 (m, 5H), 6.78-6.73 (m, IH), 6.03-5.90 (m, IH), 5.13-5.04 (m, 2H),
3.37-3.33 (m, 2H).
Example 86D 2-[(4-allyl-phenyl)-benzyloxyoxalyl-amino1-benzoic acid
The titled compound was prepared according to the procedure described in 50E by substituting 2-(4-allyl-phenylamino)-benzoic acid for 2-[4-(2-allyloxycarbonylamino-2- pentylcarbamoyl-ethyl)-phenylamino] -benzoic acid and by substituting benzyl oxalylchloride for t-butyloxalyl chloride. The material was purified on silica gel eluting with methylene chloride, 1% methanol/methylene chloride). The material was obtained as a 1 :1 mixture of rotamers. MS (ESI(-)) m/e 414 (M-H)+; 1H NMR (300 MHz, CDC13) δ 8.07 and 7.92 (2dd, IH total), 7.57-6.98 (m, 13H), 5.97-5.73 (m, IH), 5.32 (d, IH), 5.10- 5.02 (m, 2H), 5.02 (d, IH), 3.35-3.30 (m, 2H).
Example 86E 2-[(4-allyl-phenyl)-benzyloxyoxalyl-amino]-benzoic acid benzhydryl ester The titled compound was prepared according to the procedure described in Example 50F by substituting 2-[(4-allyl-phenyl)-benzyloxyoxalyl-amino]-benzoic acid for 2- { [4-(2-allyloxy carbonylamino-2-pentylcarbamoyl-ethyl)-phenyl] -tert- butoxyoxalylamino} -benzoic acid. The material was obtained as a lmixture of rotamers. MS (ESI(-)) m/e 581 (M-H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.10 and 8.06 (2dd, IH total), 7.72-6.89 (m, 23 H), 5.97-5.83 (m, IH), 5.12-4.85 (m, 4H), 3.28-3.13 (m, 2H).
Example 86F 2-[benzyloxyoxalyl-(4-oxiranylmethyl-phenyl)-amino]-benzoic acid benzhydryl ester A solution of 2-[(4-allyl-phenyl)-benzyloxyoxalyl-amino]-benzoic acid benzhydryl ester (142 g, 2.44 mmol) ) in methylene chloride (15 mL) was treated with 65% meta chloro peroxybenzoic acid (780 mg, 2.94 mmol) and stined overnight. Chromatography of the reaction mixture (25%-40% EtOAc/hexanes) gave the titled compound as a 1:1 mixture of rotamers. !H NMR (300 MHz, DMSO-d6) δ 8.12 and 8.06 (2dd, IH total), 7.93-7.87 (m, IH), 7.73-6.89 (m, 22H), 5.03 (s, IH), 4.96 and 4.84 (2d, IH total), 3.10- 3.03 (m, IH), 2.78-2.68 (m, 4H).
Example 86G 2- {benzyloxy oxalyl- [4-(2-hydroxy-3 -pentylamino-propyl)-phenyl1-amino } -benzoic acid benzhydryl ester A solution of 2-[benzyloxyoxalyl-(4-oxiranylmethyl-phenyl)-amino]-benzoic acid benzhydryl ester (256 mg, 0.428 mmol) and diisopropylethylamine (112 μL, 0.642 mmol) in 2-methyl-2-propanol (5 mL) was treated with amylamine (55 μL, 0.47 mmol) and refluxed overnight. The reaction was concentrated under reduced pressure and purified by reverse phase HPLC using 20% to 100% acetonitrile /aqueous 0.1% trifluoroacetic acid to provide the titled compound as a 1:1 mixture of rotamers. MS (ESI(+)) m/e 685 (M+H) ; H NMR (300 MHz, DMSO-d6) δ 8.10 and 8.05 (2dd, IH total), 7.71-6.88 (m, 23H), 4.98
(s, IH), 4.96 and 4.84 (2d, IH total), 3.68-3.64 (m, IH), 2.73-2.86 (m, 6H), 1.38-1.33 (m, 2H), 1.26-1.22 (m, 4H), 0.86-0.81 (m, 3H).
Example 86H
2- { [4-(2-Hydroxy-3 -pentylamino-propyl)-phenyl] -oxalyl-amino } -benzoic acid A solution of 2-{benzyloxyoxalyl-[4-(2 -hydroxy-3-pentylamino-propyl)-phenyl]- amino} -benzoic acid benzhydryl ester (60 mg, 0.93 mmol) and 10% Pd/C (lOOmg) in methanol (3 mL) was stirred under an atmosphere of hydrogen for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure and purified by reverse phase HPLC with 0% to 70% acetonitrile/ aqueous 0.1% trifluoracetic acid to provide the titled product. MS (ESI(+)) m/e 429 (M+H)+; H NMR (300 MHz, DMSO- d6) δ 8.30 (bs, IH), 7.88-7.39 (m, 5H), 7.29-7.19 (m, 3H), 5.53 (bs, IH), 3.93 (bs, IH), 2.94-2.66 (m, 6H), 1.61-1.53 (m, 2H), 1.28-1.23 (m, 4H), 0.89-0.83 (m, 3H).
Example 87 2-((carboxycarbonyl {4-[3-(pentylamino)butyl]- 1 -naphthyl} amino)benzoic acid
Example 87A 2-[(4-bromo-naphthalen-l-yl)-tert-butoxyoxalyl-amino]-benzoic acid The titled compound was prepared according to the procedure described in Example 50C and 50E respectively, by substituting 4-bromo-naphthalen-l-yl-amine for [2-(4-amino-phenyl)-l-pentylcarbamoyl-ethyl]-carbamic acid tert-butyl ester in procedure 50C followed by substituting the product for 2-[4-(2-allyloxycarbonylamino-2- pentylcarbamoyl-ethyl)-phenylamino]-benzoic acid in procedure 50E.
Example 87B 2-[(4-bromo-naphthalen-l-yl)-tert-butoxyoxalyl-amino]-benzoic acid benzhydryl ester The titled compound was prepared according to the procedure described in
Example 50F, substituting 2-[(4-bromo-naphthalen-l-yl)-tert-butoxyoxalyl-amino]- benzoic acid for 2-{[4-(2-allyloxycarbonylamino-2-pentylcarbamoyl-ethyl)-phenyl]-tert- butoxyoxalylamino} -benzoic acid. MS (ESI(+)) m/e 653, 655 (M+NH4)+.
Example 87 C 2- {tert-butoxyoxalyl-[4-(3-oxo-butyl)-naphthalen- 1 -yl] -amino} -benzoic acid benzhydryl ester To a mixture of 2- [(4-bromo-naphthalen-l-yl)-tert-butoxyoxalyl-amino] -benzoic acid benzhydryl ester (230mg, 0.36 mmol), Pd(OAc)2 (4.0 mg, 0.018 mmol), P(o-tolyl)3
(11 mg, 0.036 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) in a pressure tube was added 3-buten-2-ol (47 μL, 0.54 mmol) and triethylamine (127 μL, 0.90mmol). The mixture was flushed with nitrogen for 3 minutes, capped and heated to 100 °C for 30 min. The reaction mixture was allowed to cool to ambient temperature, partitioned between ethyl acetate and water (75 mL, 1 :1). The organic layer was washed with brine (2 x 25 mL), dried (Na2SO4), filtered, concentrated under reduced pressure and purified on an Alltech Sep-Pak eluting with 20-30% ethyl acetate/hexanes to provide the titled compound (180mg, 81%). MS (ESI(+)) m/e 645 (M+NH4)+.
Example 87 D 2-((carboxycarbonyl) {4- [3 -(pentylamino)butyll - 1 -naphthyl } amino)benzoic acid A mixture of 2-{tert-butoxyoxalyl-[4-(3-oxo-butyl)-naphthalen-l-yl]-amino}- benzoic acid benzhydryl ester (45mg, 0.072 mmol) and amylamine (13 μL, 0.11 mmol) in anhydrous methanol (1.0 mL) was stined at ambient temperature for 3 hours, NaBH4 (30 mg) was added in portions over 30 minutes, stined for 2 hours and concentrated under reduced pressure. The residue was dissolved in methylene chloride (1.0 mL) and stined for 5 hours with trifluoroacetic acid (1.0 mL) and resorcinol (30 mg) then concentrated under reduced pressure. The residue was purified on a Gilson preparative HPLC to provide (22mg, 0.046mmol, 63%). MS (ESI+) m/e 477 (M+H)+; 1H NMR (300 MHz, DMSO-d6) (A mixture of rotamers) δ 8.40-8.08 (m, 3H), 7.77-7.25 (m, 6H), 6.70-6.89 (m, IH), 3.24-2.98 (m, 3H), 2.98-2.80 (m, 2H), 2.20-2.00 (m, IH), 1.92-1.70 (m, IH), 1.55
(sixtet, J= 7.2 Hz, 2H), 1.37 (t, J= 6.9 Hz, 3H), 1.33-1.20 (m, 4H), 0.92-0.82 (m, 3H).
Example 88 2-((carboxycarbonyl){4-r3-(pentylamino)propyl]-l-naphthyl}amino)benzoic acid The titled compound was prepared according to the procedure described in
Example 87, substituting 3-buten-2-ol used in Example 87B with allyl alcohol. MS (ESI+) m/e 640, 642 (M+H)+; 1H NMR (300 MHz, DMSO-d6) (A mixture of rotamers) δ 8.50-8.10 (m, 3H), 7.80-7.27 (m, 6H), 6.90-6.77 (m, IH), 3.24-2.80 (m, 6H), 2.07-1.90 (m, 2H), 1.63-1.47 (m, 2H), 1.35-1.20 (m, 4H), 0.92-0.82 (m, 3H).
WHAT IS CLAIMED IS
1. A compound of formula (I)
(I), or a therapeutically acceptable salt thereof, wherein
A is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl; R is selected from the group consisting of alkoxy, alkyl, amino, aminosulfonyl, aryl, arylalkyl, aryloxy, hydroxy, perfluoroalkoxy, and perfluoroalkyl;
R is selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, amido, amino, carboxy, cyano, nitro, SO3H, PO(OH)2, CH2PO(OH)2, CHFPO(OH)2, CF2(PO(OH)2, C(=NH)NH2, and the following 5-membered heterocycles:
HN ° -v°
wherein * denotes the point of attachment to the parent molecular moeity ; R , R , and R are independently selected from the group consisting of hydrogen, alkoxy, alkyl, amido, amino, aminosulfonyl, arylcarbonylamino, cyano, halo, hydroxy, nitro, perfluoroalkoxy, and perfluoroalkyl; and
R is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and (heterocycloalkyl)alkyl.

Claims
2. A compound according to Claim 1 of formula (II),
(II), or a therapeutically acceptable salt thereof, wherein
R is selected from the group consisting of hydrogen, amido, alkoxy, arylcarbonylamino, cyano, hydroxy,
R is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and (heterocycloalkyl)alkyl; and η
Each R is independently selected from the group consisting of hydrogen and alkyl.
3. A compound according to Claim 1 wherein A is aryl.
4. A compound according to Claim 3 wherein R is hydroxy.
2
5. A compound according to Claim 4 wherein R is carboxy.
3 4 5
6. A compound according to Claim 5 wherein R , R , and R are independently selected from the group consisting of hydrogen, alkoxy, amido, arylcarbonylamino, cyano and hydroxy.
7. A compound according to Claim 6 wherein R is aryl.
8. A compound according to Claim 6 wherein R is cycloalkyl.
A compound according to Claim 6 wherein R is heteroaryl.
10. A method for inhibiting protein tyrosine phosphatase at physiological pH comprising administering a therapeutically effective amount of a compound of Claim 1.
11. A method for inhibiting protein tyrosine phosphatase at about pH 6.5 to about pH 8.5 comprising administering a therapeutically effective amount of a compund of Claim 1.
12. The method of Claim 11 wherein the pH is about 7.5.
13. A method for treating diseases in a patient in recognized need thereof comprising administering to the patient a therapeutically effective amount of a compound of Claim 1.
14. The method of Claim 13 wherein the disease is selected from the group consisting of type II diabetes, obesity, impaired glucose tolerance and insulin resistance.
15. A composition comprising a compound of Claim 1 in combination with a therapeutically acceptable excipient.
16. A method for inhibiting protein tyrosine phosphatase at physiological pH comprising administering a therapeutically effective amount of a compound of Claim 2.
17. A method for inhibiting protein tyrosine phosphatase at about pH 6.5 to about pH 8.5 comprising administering a therapeutically effective amount of a compund of Claim 2.
18. The method of Claim 17 wherein the pH is about 7.5.
19. A method for treating diseases in a patient in recognized need thereof comprising administering to the patient a therapeutically effective amount of a compound of Claim 2.
20. The method of Claim 19 wherein the disease is selected from the group consisting of type II diabetes and obesity, impaired glucose tolerance and insulin resistance.
21. A composition comprising a compound of Claim 2 in combination with a therapeutically acceptable excipient.
22. A compound selected from the group consisting of 2-((carboxycarbonyl)-2-((E)-2-carboxyethenyl)anilino)benzoic acid; 2-(2-((lE)-3-((tert-butoxycarbonyl)amino)-l-propenyl)(carboxycarbonyl)aniIino)benzoic acid;
2-((carboxycarbonyl)-2,3 -dimethylanilino)benzoic acid; 2-((carboxycarbonyl)-4-chloro-3 -methylanilino)benzoic acid; 2-(2-(aminocarbonyl)(carboxycarbonyl)anilino)benzoic acid;
2-((7-(aminomethyl)-5,6,7,8-tetrahydro-l-naphthalenyl)(carboxycarbonyl)amino)benzoic acid;
2-((6-(aminomethyl)-5,6,7,8-tetrahydro-l-naphthalenyl)(carboxycarbonyl)amino)benzoic acid;
2-((carboxycarbonyl)-4-(2,3-diamino-3-oxopropyl)anilino)benzoic acid; and 2-((carboxycarbonyl)(5-(2,3-diamino-3-oxopropyl)-5,6,7,8-tetrahydro-l- naphthalenyl)amino)benzoic acid.
23. A compound selected from the group consisting of
2-((carboxycarbonyl)(l -naphthyl)amino)benzoic acid;
2-((carboxycarbonyl)(2-naphthyl)amino)benzoic acid;
2-((carboxycarbonyl)-4-methoxyanilino)benzoic acid;
2-((carboxycarbonyl)(l -naphthyl)amino)-5-methoxybenzoic acid; 2-((carboxycarbonyl)-2-chloro-5-methoxyanilino)benzoic acid;
2-((carboxycarbonyl)-2-(( 1 E)-3 -ethoxy-3 -oxo- 1 -propenyl)anilino)benzoic acid;
2-(4-((2S)-2-((tert-butoxycarbonyl)amino)-3-(((4-
(methoxycarbonyl)cyclohexyl)methyl)amino)-3- oxopropyl)(carboxycarbonyl)anilino)benzoic acid; 2-(4-((2S)-2-((tert-butoxycarbonyl)amino)-3 -(((4-carboxycyclohexyl)methyl)amino)-3 - oxopropyl)(carboxycarbonyl)anilino)benzoic acid;
2-((carboxycarbonyl)-2-iodoanilino)benzoic acid;
2-((carboxycarbonyl)-2-((lE)-3-(l,3-oxazinan-3-yl)-3-oxo-l-propenyl)anilino)benzoic acid; 2-((carboxycarbonyl)-3-(trifluoromethyl)anilino)benzoic acid;
2-((carboxycarbonyl)(cyclobutyl)amino)benzoic acid;
2-((7-(benzyloxy)-l -naphthyl)(carboxycarbonyl)amino)benzoic acid;
2-((carboxycarbonyl)-2-(2-hydroxyethyl)anilino)benzoic acid;
2-((carboxycarbonyl)-2-methylanilino)benzoic acid; 2-((carboxycarbonyl)(2-methyl-l H-indol- l-yl)amino)benzoic acid;
2-((carboxycarbonyl)(7-hydroxy-l-naphthyl)amino)benzoic acid;
2-((carboxycarbonyl)(7-((6-phenylhexyl)oxy)- 1 -naphthyl)amino)benzoic acid;
2-((l , 1 '-biphenyl)-2-yl(carboxycarbonyl)amino)benzoic acid;
2-(( 1 , 1 '-biphenyl)-4-yl(carboxycarbonyl)amino)benzoic acid; 2-((carboxycarbonyl)(5,6,7,8-tetrahydro-l -naphthalenyl)amino)benzoic acid;
2-((carboxycarbonyl)(cyclohexyl)amino)benzoic acid;
2-((carboxycarbonyl)(2,3 -dihydro- 1 ,4-benzodioxin-6-yl)amino)benzoic acid; 2-((carboxycarbonyl)(3 -methylcyclohexyl)amino)benzoic acid;
2-[(carboxycarbonyl)(2-hydroxy- 1 -naphthyl)amino]benzoic acid;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-pentyl-l- naphthylalaninamide; N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-pentyl-3-(2- hydroxyethane)-phenylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-6-{[N-acetyl-3-(l- naphthy l)alanyl] amino } hexanoic acid;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-[(lE)-3-amino-3-oxo-l- propenyl]-N-(tert-butoxycarbonyl)-N-pentyl-L-phenylalaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-isopropyl-N- pentylphenylalaninamide;
4- [(carboxycarbony l)(2-carboxyphenyl)amino] -6- { [N-acetyl-3 -( 1 - piperidinyl)phenylalanyl] amino} hexanoic acid; 2- { (carboxycarbony 1) [2-(3 -methyl- 1 -piperidiny l)phenyl] amino } benzoic acid;
2- { (carboxycarbony 1) [5 -hydroxy-2-( 1 -piperidinyl)phenyl] amino } benzoic acid;
4- [(carboxycarbonyl)(2-carboxyphenyl)amino]-3 - [( 1 E)-3 -amino-3 -oxo- 1 - propenyl]-N-(methylsulfonyl)-N-pentyl-L-phenylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-(3-amino-3-oxopropyl)-N- [(isopropylamino)carbonyl] -N-pentyl-L-pheny lalaninamide ;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-[(lE)-3-amino-3-oxo-l- propenyl]-N-[(isopropylamino)carbonyl]-N-pentyl-L-phenylalaninamide;
2-((carboxycarbonyl){2-[4-(hydroxymethyl)-l-piperidinyl]phenyl}amino)benzoic acid; N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-pentyl-4-(l- piperidinyl)phenylalaninamide;
Ν-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-etlιylphenylalanyl-Ν- methyl-4-nitro-L-phenylalaninamide;
N-(3 -carboxypropanoyl)-L-phenylalanyl-3 - [( 1 Ε)-3 -amino-3 -oxo- 1 -propenyl] -4- [(carboxycarbonyl)(2-carboxyphenyl)amino]-N-pentyl-L-phenylalaninamide;
3-(4-benzoylphenyl)-N-(tert-butoxycarbonyl)-L-alanyl-3-{4-[(carboxycarbonyl)(2- carboxyphenyl)amino]phenyl}-N~l— pentyl-L-alaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-(2-hydroxyethyl)-N-[4- (methylsulfonyl)benzyl]phenylalaninamide; 2-[[7-(aminocarbonyl)-l -naphthyl](carboxycarbonyl)amino]benzoic acid;
Ν-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-isopropyl-Ν-[4- (methylsulfonyl)benzyl]phenylalaninamide 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-l-acetyl-6-(3-isopropylbenzyl)-4- [4-(methylsulfonyl)benzyl]-2,3,5-piperazinetrione;
2-[(carboxycarbonyl)(7-hydroxy-l-naphthyl)amino]-4-hydroxybenzoic acid;
N-acetyl-4- [(carboxy carbony l)(2-carboxyphenyl)amino] -3 -ethy 1-N- { 5-oxo- 5 - [( 1 - phenylethyl)amino]pentyl}phenylalaninamide;
N-(methoxycarbonyl)-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N- pentylnaphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(cyclohexylmethyl)-N- (methoxycarbonyl)naphthylalaninamide; 4- [(carboxycarbony l)(2-carboxyphenyl)amino]-N-(methoxycarbonyl)-N- [(1 ?)- 1 -
(4-nitrophenyl)ethyl]naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(methoxycarbonyl)-N-[4- (methylsulfonyl)benzyl]haphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(methoxycarbonyl)-N-(3,4,5- trifluorobenzyl)naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(cyclooctylmethyl)-N- (methoxycarbonyl)naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-[(17-)-l-(4-bromophenyl)ethyl]- N-(methoxycarbonyl)naphthylalaninamide; 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(methoxycarbonyl)-N-(3- phenylpropyl)naphthylalaninamide; methyl 3-{4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-l-naphthyl}-Ν- (methoxycarbonyl)alanyl-L-norleucinate;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(2-fluorobenzyl)-N- (methoxycarbonyl)naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4-chlorobenzyl)-N- (methoxycarbonyl)naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4-bromobenzyl)-N- (methoxycarbonyl)naphthylalaninamide; 4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(methoxycarbonyl)-N-(4- nitrobenzyl)naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-[4-(aminosulfonyl)benzyl]-N- (methoxycarbonyl)naphthylalaninamide;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(methoxycarbonyl)-N-({4- [(methylamino)carbonyl] cy clohexy 1 } methyl)naphthy lalaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-(2-hydroxyethyl)-N-(4- nifrobenzyl)phenylalaninamide; 2-[(carboxycarbonyl)(7-hydroxy-l-naphthyl)amino]-4-cyanobenzoic acid;
4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-{4- [(ethylamino)sulfonyl]benzyl}-N-(methoxycarbonyl)naphthylalaninamide;
Ν-(tert-butoxycarbony l)-L-pheny lalany 1-3 - [( 1 E)-3 -amino-3 -oxo- 1 -propenyl] -4- [(carboxycarbonyl)(2-carboxyphenyl)amino]-N-pentyl-L-phenylalaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-(2-hydroxyethyl)-N- [(lS)-l-(4-nitrophenyl)ethyl]phenylalaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4-chlorobenzyl)-3-(2- hydroxyethyl)phenylalaninamide; N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4-bromobenzyl)-3-(2- hydroxyethyl)phenylalaninamide;
2- [(carboxycarbony 1) (7-hydroxy- 1 -naphthyl)amino] -4- { [4- (dimethylamino)benzoyl]amino}benzoic acid;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-ethyl-N-(4- nitrobenzyl)phenylalaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-3-ethyl-N-[(17?)-l-(4- nitrophenyl)ethyl]phenylalaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4-chlorobenzyl)-3- ethylphenylalaninamide; N-acetyl-4- [(carboxycarbonyl)(2-carboxyphenyl)amino]-N-(4- nitrobenzyl)naphthylalaninamide;
N-acetyl-4-[(carboxycarbonyl)(2-carboxyphenyl)amino]-N-[(17-)-l-(4- bromophenyl)ethyl]-3-(2-hydroxyethyl)phenylalaninamide;
4-[(butylamino)carbonyl]-2-[(carboxycarbonyl)(7-hydroxy- 1 - naphthyl)amino]benzoic acid;
N-acetyl-4- [(carboxy carbonyl)(2-carboxyphenyl)amino]-N- { 5- [(3 - hy droxyphenyl)amino] - 5 -oxopentyl } -3 -( 1 -piperidiny l)phenylalaninamide;
2-((carboxycarbonyl){4-[2-hydroxy-3-(pentylamino)propyl]phenyl}amino)benzoic acid; 2-((carboxy carbonyl) { 4- [3 -(pentylamino)butyl] - 1 -naphthyl } amino)benzoic acid; and
2-((carboxycarbonyl){4-[3-(pentylamino)propyl]-l-naphthyl}amino)benzoic acid.
EP01964500A 2000-08-29 2001-08-29 Amino(oxo)acetic acid protein tyrosine phosphatase inhibitors Withdrawn EP1313696A2 (en)

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US22865100P 2000-08-29 2000-08-29
US65092200A 2000-08-29 2000-08-29
US228651P 2000-08-29
US650922 2000-08-29
US09/918,928 US20020035137A1 (en) 2000-08-29 2001-07-31 Amino (oxo) acetic acid protein tyrosine phosphatase inhibitors
PCT/US2001/026906 WO2002018323A2 (en) 2000-08-29 2001-08-29 Amino(oxo)acetic acid protein tyrosine phosphatase inhibitors

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WO2008044731A1 (en) 2006-10-12 2008-04-17 Institute Of Medicinal Molecular Design. Inc. N-phenyloxamidic acid derivative

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US6972340B2 (en) 2000-08-29 2005-12-06 Abbott Laboratories Selective protein tyrosine phosphatatase inhibitors
CN1750758B (en) 2003-02-13 2012-06-20 维尔斯达医疗公司 Compounds for the treatment of metabolic disorders
US7141596B2 (en) 2003-10-08 2006-11-28 Incyte Corporation Inhibitors of proteins that bind phosphorylated molecules
WO2007087505A2 (en) 2006-01-25 2007-08-02 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
NZ569728A (en) 2006-01-25 2010-11-26 Wellstat Therapeutics Corp Compounds for the treatment of metabolic disorders
US20090176885A1 (en) 2006-02-02 2009-07-09 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
EP2272817A4 (en) 2008-04-11 2011-12-14 Inst Med Molecular Design Inc INHIBITOR OF PAI-1
CN104870422B (en) 2012-10-31 2019-03-15 富士胶片富山化学株式会社 Amine derivatives or their salts

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US3987192A (en) * 1974-01-07 1976-10-19 The Upjohn Company Compositions and process of treatment
GB1572527A (en) * 1977-05-05 1980-07-30 Ici Ltd Method of controlling pollen formation
WO1999046236A1 (en) * 1998-03-12 1999-09-16 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (ptpases)

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