WO2004002940A1 - Inhibitors of hcv ns5b polymerase - Google Patents

Inhibitors of hcv ns5b polymerase Download PDF

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Publication number
WO2004002940A1
WO2004002940A1 PCT/US2003/020486 US0320486W WO2004002940A1 WO 2004002940 A1 WO2004002940 A1 WO 2004002940A1 US 0320486 W US0320486 W US 0320486W WO 2004002940 A1 WO2004002940 A1 WO 2004002940A1
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WIPO (PCT)
Prior art keywords
amino
alkyl
phenyl
carboxyphenyl
trifluoromethyl
Prior art date
Application number
PCT/US2003/020486
Other languages
French (fr)
Other versions
WO2004002940A8 (en
Inventor
Carlo Battistini
Francesco Casuscelli
Robert C. Kelly
Linda L. Maggiora
Mark A. Mitchell
Claudia Piutti
Matthew T. Reding
Original Assignee
Pharmacia & Upjohn Company
Pharmacia Italia S.P.A
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia & Upjohn Company, Pharmacia Italia S.P.A filed Critical Pharmacia & Upjohn Company
Priority to CA002491156A priority Critical patent/CA2491156A1/en
Priority to EP03762206A priority patent/EP1525183A1/en
Priority to MXPA05000255A priority patent/MXPA05000255A/en
Priority to AU2003256334A priority patent/AU2003256334A1/en
Priority to BR0305259-1A priority patent/BR0305259A/en
Priority to JP2004518076A priority patent/JP2005531638A/en
Publication of WO2004002940A1 publication Critical patent/WO2004002940A1/en
Publication of WO2004002940A8 publication Critical patent/WO2004002940A8/en

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    • C07—ORGANIC CHEMISTRY
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
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    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
    • C07C229/58—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of a six-membered aromatic ring, e.g. N-phenyl-anthranilic acids
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    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
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    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/57—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton
    • C07C309/59—Nitrogen analogues of carboxyl groups
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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
    • C07C317/36—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 atoms of the amino groups bound to hydrogen atoms or to carbon atoms
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    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to compounds, process for their synthesis, compositions and methods for the treatment and prevention of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • the present invention provides novel compounds, pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment or prevention of HCV infection.
  • the present invention also provides processes and intermediates for the synthesis of these compounds.
  • Hepatitis C virus is the major etiological agent of post- transfusion and community-acquired non-A non-B hepatitis worldwide. It is estimated that over 150 million people worldwide are infected by the virus. A high percentage of carriers become chronically infected and many progress to chronic liver disease, so-called chronic hepatitis C. This group is in turn at high risk for serious liver disease such as liver cirrhosis, hepatocellular carcinoma and terminal liver disease leading to death. The mechanism by which HCV establishes viral persistence and causes a high rate of chronic liver disease has not been thoroughly elucidated. It is not known how HCV interacts with and evades the host immune system.
  • interferon was the only available therapy of proven benefit approved in the clinic for patients with chronic hepatitis C.
  • the sustained response rate is low, and interferon treatment also induces severe side- effects (i.e. retinopathy, thyroiditis, acute pancreatitis, depression) that diminish the quality of life of treated patients.
  • interferon in combination with ribavirin has been approved for patients non-responsive to IFN alone.
  • the side effects caused by IFN are not alleviated with this combination therapy. Therefore, a need exists for the development of effective antiviral agents for treatment of HCV infection that overcomes the limitations of existing pharmaceutical therapies.
  • Viral polymerases are attractive targets for antiviral drug development.
  • inhibitors of Viral RNA polymerase activity have been described; see, for example, JAEN, Juan, et.al., WO 0177091, Altamura et. al., WO 00/06529 and Bailey et. al., WO 00/10573, which references are incorporated by reference herein.
  • the HCV protein NS5B is an RNA dependent RNA polymerase, see, e.g., Lohmann et al. (1997) J Virol. 71:8416-8428, Behrens et al. (1996) EMBO J 15:12-22 and Ishido et al. (1998) Biochem. Biophys. Res. Comm. 244:35-40, which references are incorporated by reference herein.
  • the sequence of various genotypes of HCV NS5B are known (Kato et al. (1990) Proc. Natl. Acad. Sci. USA. 87:9524-9528; Webster, G., et al.
  • NS5B contains sequence motifs that are highly conserved among all the RNA-dependent RNA polymerases characterized to date.
  • the present invention provides compounds, compositions and methods that are useful for treating viral infections and associated diseases, particularly HCV infections and associated diseases.
  • the compounds of the invention inhibit viral replication, preferably HCV replication.
  • the methods of the invention comprise administering to an infected or susceptible host a therapeutically or prophylactically effective amount of a compound as represented by Formula 1, or a pharmaceutically acceptable salt or prodrug thereof.
  • treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • prevent refers to a method of 'barring a subject from acquiring a disease.
  • prevention refers to a method of 'barring a subject from acquiring a disease.
  • prevention also include reducing a subject's risk of acquiring a disease.
  • viral infection refers to the introduction of a virus into cells or tissues, e.g., hepatitis C virus (HCV). In general, the introduction of a virus is also associated with replication. Viral infection may be determined by measuring virus antibody titer in samples of a biological fluid, such as blood, using, e.g., enzyme immunoassay. Other suitable diagnostic methods include molecular based techniques, such as RT-PCR, direct hybrid capture assay, nucleic acid sequence based amplification, and the like. A virus may infect an organ, e.g., liver, and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease and hepatocellular carcinoma.
  • HCV hepatitis C virus
  • Flaviviridae virus refers to a virus of the family Flaviviridae, which family includes the Flavivirus, Pestivirus and Hepacivirus or hepatitis C-like virus genera. Representative species of the genus Flavivirus include yellow fever virus, tick-bome encephalitis virus, Rio Bravo virus, Japanese encephalitis virus,
  • Tyuleniy virus Ntaya virus, Uganda S virus, Dengue virus and Modoc virus.
  • Pestivirus Representative species of the genus Pestivirus include bovine diarrhea virus, border disease virus and hog cholera virus.
  • a representative species of the genus of hepatitis C- like viruses is hepatitis C virus. Unassigned viruses in the family Flaviviridae are included in the meaning of Flaviviridae virus.
  • modulate refers to the ability of a compound to increase or decrease the catalytic activity of a viral polymerase, e.g. a viral RNA polymerase.
  • a modulator preferably activates the catalytic activity of a viral polymerase or more preferably activates or inhibits the catalytic activity of a viral polymerase depending on the concentration of the compound exposed to the viral polymerase or most preferably inhibits the catalytic activity of a viral polymerase.
  • modify refers to the act of altering, in whole or in part, the structure of a molecule, e.g., a protein.
  • Modification may be covalent or noncovalent, and includes, but is not limited to, aggregation, association, substitution, conjugation and/or elimination of a chemical group. Modification may alter the function or other properties (e.g., chemical, physical) of the molecule.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C ⁇ -C 8 means 1-8 eight carbons).
  • saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)ethyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-
  • butadienyl 2,4-pentadienyl, 3 -(1,4- pentadienyl), ethynyl, I - and 3 -propynyl, 3 - butynyl, and the higher homologs and isomers.
  • a "lower alkyl” is a shorter chain alkyl having eight or fewer carbon atoms.
  • alkoxy alkylcylamino and “alkylthio” refer to those groups having an alkyl group attached to the remainder of the molecule through an oxygen, nitrogen or sulfur atom, respectively.
  • dialkylamino is used in a conventional sense to refer to -NRR' wherein the R groups can be the same or different alkyl groups.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized.
  • the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 .
  • heteroalkyl those radicals described in more detail below as "heterocycloalkyl”.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • halo or halogen
  • Fluoroalkyl are meant to include monofluoroalkyl and polyfluoroalkyl, including perfluoroalkyl.
  • aryl employed alone or in combination with other terms (e.g., aryloxy, arylthioxy, aralkyl) means, unless otherwise stated, an aromatic substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • heteroaryl is meant to include those aryl rings which contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized.
  • the "heteroaryl” groups can be attached to the remainder of the molecule through a heteroatom.
  • Non- limiting examples of aryl and heteroaryl groups include phenyl, 1- naphthyl, 2-napthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3- pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzothiazolyl, purinyl, 2- benzimidazolyl, 1-indolyl, 5-
  • aryl ring systems are selected from the group of acceptable substituents described below.
  • aralkyl is meant to include those radicals in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) or a heteroalkyl group (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
  • alkyl group e.g., benzyl, phenethyl, pyridylmethyl and the like
  • a heteroalkyl group e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like.
  • alkyl group e.g., benzyl, phenethyl, pyridylmethyl and the like
  • R, R" and X each independently refer to hydrogen, unsubstituted Cl-COalkyl and heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(Cl-C4)alkyl groups.
  • R and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-7 membered ring.
  • -NR'R is meant to include 1- pyrrolidinyl and 4- morpholinyl.
  • alkyl is meant to include groups such as haloalkyl (e.g., - CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
  • Two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula -S-C(O)-(CH 2 )q-R-, wherein S and R are independently -NH-, -O-, -CH 2 - or a single bond, and the subscript q is an integer of from 0 to 2.
  • two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) W -B-, wherein A and B are independently -CH 2 -, -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR- or a single bond, and w is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula -(CH 2 ) W -G-(CH 2 ) W -, where w and w' are independently integers of from 0 to 3, and G is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • the substituent R in -NR'- and - S(O) NR'- is selected from hydrogen or unsubstituted (Cl-C6)alkyl.
  • heteroatom is meant to include oxygen (O), nitrogen (N), ) and sulfur(S).
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactouronic acids and the like (see, for example, Berge, S.M., et. al. (1977) J. Pharm. Sci., 66:1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex- vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity.
  • Additional examples include peptidyl derivatives of a compound of the invention.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • Viral RNA polymerase is required for the transcription of genomic RNA, which process is required for replication of the genome of an RNA virus. Therefore, inhibition of viral RNA polymerase will inhibit viral replication.
  • the present invention provides compounds having antiviral activity.
  • the compounds of the invention block viral replication by specifically inhibiting the activity of a viral polymerase.
  • the compounds useful for modification of a viral RNA-dependent RNA polymerase protein are of Formula I
  • X is selected from the group consisting of NH, O, and S;
  • Z is -COOH or 5-tetrazolyl
  • R 2 , R 3 and P represent 1 to three substituents independently selected from the group consisting of halogen, -CN, N(R)(R'), NO 2 , fluoroalkyl, fluroalkyloxy, alkyl, aryl, aralkyl, arlyoxy, aralkyloxy, alkylthio, arylthio, and heteroalkyl;
  • R and R are independently H or -C O alkyl
  • R and R' may be taken together to form a 3 to 7 membered ring optionally containing an additional heteroatom of -O-, -NR-, -S- or -SO-;
  • Ri is selected from the group consisting of H, -CN, and -(CH ) n -N(R 5 )R 6 ;
  • R 5 is H or C.-C 6 alkyl
  • A is selected from the group consisting of C ⁇ -C 6 alkyl, aryl, substituted aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalkyl and substituted heteroalkyl;
  • R 5 and R 6 may be joined together to form a 5 to 7 membered ring optionally containing an additional heteroatom of -NR-, -O-, -S- or -SO n -;
  • n is independently 0, 1 or 2.
  • Non-limiting examples of the invention are shown in Table 1.
  • the subject compounds and compositions may be demonstrated to have pharmacological activity, e.g, antiviral activity, in in vitro and in vivo assays, as known in the art. See for example Behrens, S.E., et.al EMBO J. 15:12-22; Lohmann, V., et.al., 1997, J. Virol. 71:8416-8428; Ferrari, E., et al., 1999. J. Virol. 73:1649-1654; Bealieu, P.L. et.al., WO0204425 A2; Perni, R.B. et. al., WO9833501; which references are incorporated by reference herein.
  • pharmacological activity e.g, antiviral activity
  • the subject compounds and compositions are capable of specifically inhibiting or suppressing a viral infection, e.g., an HCV infection.
  • An in vivo assessment of the antiviral activity of the compounds of the invention may be made using an animal model of viral infection, e.g., a primate model.
  • Cell-based assays may be performed using, e.g, a cell line directly infected with a virus.
  • Cell-based assays for activity against a specific viral component, e.g., a polymerase may also be performed.
  • biochemical or mechanism-based assays e.g., transcription assays using a purified protein, Northern blot, RT-PCR, etc., may be performed.
  • the above-described assays are exemplary and not intended to limit the scope of the invention. The skilled practitioner can appreciate that modifications can be made to conventional assays to develop equivalent assays that obtain the same result.
  • High throughput assays for the presence, absence, quantification, or other properties of particular compounds are well known to those of skill in the art. Such assays may be adapted to identify compounds capable of modifying a viral RNA dependent RNA polymerase protein, e.g., NS5B using functional protein. Preferred assays thus detect enhancement or inhibition of HCV RNA-dependent RNA activity.
  • the present invention further provides pharmaceutical compositions comprising one or more of the above compounds in combination with a pharmaceutically acceptable excipient.
  • the invention provides the subject compounds combined with a pharmaceutically acceptable excipient such as sterile saline or other medium, water, gelatin, an oil, etc. to form pharmaceutically acceptable compositions.
  • a pharmaceutically acceptable excipient such as sterile saline or other medium, water, gelatin, an oil, etc.
  • the compositions and/or compounds may be administered alone or in combination with any convenient carrier, diluent, etc. and such administration may be provided in single or multiple dosages.
  • Useful carriers include solid, semi-solid or liquid media including water and.non-toxic organic solvents.
  • the invention provides the subject compounds in the form of a prodrug, which can be metabolically or chemically converted to the subject compound by the recipient host.
  • prodrug derivatives are known in the art such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • compositions may be provided in any convenient form, including tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, suppositories, etc.
  • the compositions in pharmaceutically acceptable dosage units or in bulk, may be incorporated into a wide variety of containers.
  • dosage units may be included in a variety of containers including capsules, pills, etc.
  • Methods of Use the present invention provides novel methods for the use of the foregoing compounds and compositions.
  • the invention provides novel methods for treating or preventing viral infections, e.g., HCV infection.
  • the invention also provides novel methods for treating or preventing diseases resulting from, in whole or in part, viral infections, preferably diseases resulting from, in whole or in part, infection, such as hepatitis C, cirrhosis, chronic liver disease and hepatocellular carcinoma.
  • the methods typically involve administering to a patient an effective amount of one or more of the subject compounds or compositions.
  • the compositions may be advantageously combined and/or used in combination with other antiviral agents which are either therapeutic or prophylactic agents, and different from the subject compounds.
  • the compositions may also be advantageously combined and/or used in combination with agents that treat conditions often associated with the viral infections that are sensitive to the present compounds, such as anti-HJN agents or immunosuppressive agents.
  • hepatitis C hepatitis C
  • interferons e.g., interferon alfa-2b, interferon alfa-2a, and interferon alfacon-1.
  • pegylated interferon interferon attached to a polyethylene glycol moiety which significantly improves its pharmacokinetic profile.
  • Combination therapy with interferon alfa-2b (pegylated and unpegylated) and ribavarin has also been shown to be efficacious for some patient populations.
  • Other agents currently being developed include interferon alfa-2b, interferon alfa-2a, and interferon alfa-2a, and interferon alfacon-1.
  • R ⁇ A replication inhibitors antisense agents, therapeutic vaccines, protease ihibitors, helicase inhibitors and antibody therapy (monoclonal and polyclonal).
  • compositions of the present invention may also be used with agents that enhance the body's immune system, including low-dose cyclophosphamide, thymostimulin, vitamins and nutritional supplements (e. g., antioxidants, including vitamins A, C, E, beta-carotene, zinc, selenium, glutathione, coenzyme Q-10 and echinacea), and vaccines, e.g., the immunostimulating complex (ISCOM), which comprises a vaccine formulation that combines a multimeric 5 presentation of antigen and an adjuvant.
  • ICOM immunostimulating complex
  • the compositions and compounds of the invention and the pharmaceutically acceptable salts thereof can be administered in any effective way such as via oral, parenteral or topical routes.
  • the compounds are administered in dosages ranging from about 2 mg up to about 2,000 mg per day, although variations will necessarily occur depending on the disease target, the patient, and the route of administration.
  • Preferred dosages are administered orally in the range of about 0.05 mg/kg to about 20 mg/kg, more preferably in the range of about 0.05 mg/kg to about 2 mg/kg, most preferably in the range of about 0.05 mg/kg to about 0.2 mg per kg of body weight per day.
  • Preparation of the Compounds Some of compounds of this invention are commercially available. For example, 2,2'-
  • the compounds of this invention can also be prepared by methods described in the chemical literature. For example, methods for the preparation of compounds are described by Sudhakar, K., U.S. pat. 6,177,551, R. Nagar et. al., Proc. Natl. Acad. Sci., India, Sect. A
  • the compounds of this invention can also be prepared by one or more of the following schemes described below.
  • the preparation of the various diaryl amine products and intermediates of this invention is based on variations of the palladium catalysed amine coupling reaction methodology described in the literature (See for example Buchwald, S.L., et.al., U.S. pat. 6,307,087; Buchwald, S.L. et.al., J. Org. Chem. (2000) 65, 1144; Buchwald, S.L. et. al., J. Organomet. Chem. (1988) 348, 95; Amatore, C, Coord. Chem. Rev., (1998) 178-80, 511; Buchwald, S.L., et.al., Angew. Chem. Int. Ed.,
  • R groups are as defined infra.
  • M, Ml and M2 are independently chosen from the group CI, Br, I or OSO 2 CF 3 with the proviso that, in Scheme 3, when M2 is CI, Ml is Br, I or OSO 2 CF 3 and when M2 is Br, Ml is I .
  • Suitable sources of palladium include tris(dibenzylideneacetone)dipalladium(O) (Pd 2 dba 3 ), palladium acetate bis[ ⁇ -(acetato- ⁇ O: ⁇ O')]bis[[2-[bis(2-methylphenyl)phosphino- ⁇ P]phenyl]methyl- ⁇ C]di-palladium, bis[l ,2- bis(diphenylphosphino)ethane]palladium (0), bis(2-methylallyl)palladium chloride dimer,bis(tri-t-butylphosphine)palladium (0), bis(tricyclohexylphosphine)palladium (0), chloro(di-2-norbornylphosphino)(2'-imethylamino- 1 , 1 '-biphenyl-2-yl)palladium (II), diacetatobis(triphenylphosphine)palladium (
  • Suitable ligands include tri-o-tolylphosphine, 2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl (BINAP), l,l'-bis(diphenylphosphino)ferrocene, 2-(di-t-butylphosphino)biphenyl, tri-2- furylphosphine, tris(2,4-di-t-butylphenyl) phosphite, dicyclohexyl 2-(2'-N,N- dimethylamino)biphenylphosphine, 1 -[( 1 S)- 1 -(dimethylamino)ethyl]-2-(diphenylphosphino)- Ferrocene (PPFA), bis[2-(diphenylphosphino)phenyl] ether (DPEphos) and the like.
  • BINAP 2,2'-Bis(diphenyl
  • Bases suitable for the reactions include Cs CO , lithium di-o-tolylamide, sodium t-butoxide, potassium t-butoxide, lithium bis-trimethylsilylamide, lithium diisopropylamide, potassium phosphate, sodium 2,4,6-tri-t-butylphenoxide, sodium carbonate, lithium carbonate, potassium carbonate, rubidium carbonate, triethylamine, diazabicycloundecane, Hunig's base, pyridine, and the like.
  • Suitable solvents include toluene, xylene, acetonitrile, dimethoxyethane, tetrahydrofuran, dioxane, dimethylformamide and the like. It is obvious to one of ordinary skill in the art that further transformations of the products and intermediates of Schemes 1-7 are readily achieved using methods common in the art. These transformations include for example, ester, nitrile and amide hydrolysis; ester, amide and nitrile reduction; primary and secondary amine alkylation, acylation, aroylation; alcohol acylation, aroylation and alkylation; and the like.
  • Methyl 2- ⁇ [2-nitro-4-(trifluoromethyl)phenyl]amino ⁇ benzoate (505 mg, 1.48 mmol) is suspended in a solution of methanol (10 mL)and THF (20 mL), the resulting solution is cooled to 0°C. NiCl 2 (192 mg, 1.48 mmol), is added followed by NaBFL (280 mg, 7.4 mmol), which is slowly added with vigorous effervescence. The solution is warmed to room temperature and after 2 h, the reaction mixture is concentrate and then saturated NaHCO 3 (40 mL), and EtOAc (30 mL), are added. The organic phase is separated, dried (Na 2 SO ), and evaporated.
  • Cs CO (668 mg, 2.05 mmol), Pd 2 (dba) 3 (15 mg, 0.016 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (19 mg, 0.049 mmol), anhydrous toluene (5 mL), methyl 2-iodobenzoate (0.334 mL, 2.05 mmol), 1,2- diamino-3-methylbenzene (100 mg, 0.82 mmol).
  • the mixture is heated with efficient stirring at 100°C for 36 h.
  • the resulting mixture is cooled to room temperature and filtered through Celite®.
  • 1-N, 2-N-bis(2-(Methylcarboxy)phenyl)-l,2-diamino-3-methylbenzene (135 mg, 0.35 mmol) is suspended in a solution of ethanol (5 mL), 1 ⁇ aqueous sodium hydroxide (5 mL) and THF (5 mL). The mixture is stirred at 55°C for 4 h. The mixture is cooled on an ice bath and acidified with 6 N aqueous HCl. The resulting precipitate is collected on a filter and washed with water. Drying under a vacuum affords 1-N, 2-N-bis(2-carboxyphenyl)-l,2-diamino-3- methylbenzene. The yield is 112 mg, 88%.
  • Methyl 2-[2-nitro-4-(trifluoromethyl)phenoxy]benzoate (5.8 g, 18.6 mM) is dissolved in 50ml of EtOH 95 % and SnCl 2 (37.3mM, 7.07g) is added with 1-2 ml of HCl cone. The reaction is stirred at r.t. until there is no more starting material ( about 24 hr), then evaporated down and worked up with NaOH 2M and ethyl acetate. Water phase is extracted twice before a heavy white precipitate forms. Organic layer is dried over Na 2 SO 4 , filtered and concentrated. The product is isolated in 80 % yield after chromatography.
  • Pd 2 dba 3 54 mg, 0.06 mM
  • PCy 2 dmab 47 mg, 0.12mM
  • Cs 2 CO 3 733 mg, 2.25 mM
  • Methyl-2-[2-amino-4- trifluoromethyl)phenoxy]benzoate (466 mg, 1.5 mM)
  • methyl 5-cyano-2-iodobenzoate (434 mg, 1.5 mM) are dissolved in anhydrous toluene (already degassed with argon for 20 minutes) and afterwards added into the flask.
  • the final solution is heated to 100 °C with an oil bath.
  • Methyl-5-cyano-2- ⁇ [2-[2-(methoxycarbonyl)phenoxy]-5-trifluoromethyl) phenyl]amino ⁇ benzoate (340 mg, 0.78 mM) are dissolved in THF-MeOH (1:1) and the solution is cooled in an ice bath. NiCl 2 (0.7 mM, 94 mg) is added and finally portions of NaBJL (53 mg, 1.4 mM) are added every half an hour until no more starting material is present. Meanwhile the mixture has turned black. The reaction is worked up with water and ethyl acetate while organic residues are removed by filtration. The organic layer is dried over Na 2 SO 4 , filtered and evaporated down.
  • the pu le mixture is capped with septum and heated at ⁇ 100°C under nitrogen, which turns from purple to almost colorless within 10 minutes. Heating and stirring are continued for overnight.
  • the resulting brown mixture is cooled to room temperature, filtered through celite and washed with THF (20ml).
  • the filtrate solution is concentrated and chromatographed through a silica gel column with 10-20% EtOAc/hexanes to yield methyl 5- ⁇ [(tert-butoxycarbonyl)amino]methyl ⁇ -2- ⁇ [2- ⁇ [2-(methoxycarbonyl)phenyl]amino ⁇ -5-(trifluoromethyl)phenyl]amino ⁇ benzoate as a light yellow oil. Yield: ⁇ 70mg (67%).
  • Precipitates are filtered, washed with H 2 O, dried in vacuo, to afford 60mg of gray powder (the di-acid), which is dissolved in lml of 1,4-dioxane, treated with 4M HCl solution in 1,4-dioxane (2ml) for 1 hour.
  • the clear solution is concentrated to dryness, redissolved in 2ml of EtOH and added dropwise into 100ml of hexanes with vigorous stirring.
  • Compounds of the present invention are evaluated for inhibition of HCV NS5b RNA dependent RNA polymerase activity in assays comprised of a suitable buffer (e.g. 20 mM Tris-HCl pH 7.6), primed or unprimed RNA templates, GTP, ATP, CTP, and UTP, MnCl or MgCl 2 , and reducing agent such as 10 mM dithiothreitol or 2- mercaptoethanol.
  • the assay buffer may contain salts such as ammonium acetate, KC1, or NaCl, and nonionic or zwitterionic detergents such as Tween or CHAPS.
  • RNA templates for de novo initiation in the presence of 20-50 ⁇ M GTP or ATP are the homopolymers poly rC and poly rU, respectively.
  • Heteropolymer RNA templates with 1-3 cytidine (C) bases or 1-3 uridine (U) bases at the 3' terminus of the template may also be used for de novo initiation.
  • Primed RNA templates such as poly rC primed with oligo rG or oligo dG, and poly rA primed with oligo rU may also be used to detect polymerase activity.
  • the primers may be any length greater than 10 bases.
  • a biotin residue may be added to the 5' end of the template or the 5' end of the primer to capture the template and the newly synthesized, complementary strand on avidin coated spheres.
  • One embodiment of this technology consists of a mixture of NS5b polymerase, a poly rC RNA template primed with 5' biotinylated oligo rG, 20 mM Tris HCl pH 7.6, 100 mM ammonium acetate, 10 mM dithiothreitol, 2 mM CHAPS, 1 mM MgCl 2 , and 150-200 nM 3 H labeled GTP.
  • Test compounds may be inco ⁇ orated in the reaction mixture with up to 10% DMSO. The reaction is run for various times (1-180 minutes) at 22-37°C, and stopped by the addition of 10-140 mM EDTA. Scintillation Proximity Assay avidin-coated beads (Amersham Pharmacia Biotech) are added to capture the ds RNA product; or the reaction mixtures may be transferred to avidin coated Flash Plates (Perkin Elmer Life Sciences). The inco ⁇ oration of radiolabeled GTP into the complementary strand is measured in 96, 384, or 1536 well plates in scintillation counters such as the Wallac Microbeta and Packard TopCount.
  • IC50 values ranging from less than 1 to about 30 ⁇ M or more.
  • Table 2 the inhibitory activity of representative examples is provided. Activity is listed in Table 2 as +++ if the concentration for 50% inhibition is ⁇ l ⁇ M, ++ if activity is l-20 ⁇ M and + if activity is >20 ⁇ M.

Abstract

The present invention provides compounds of Formula I, compositions and methods that are useful for treating viral infections and associated diseases, particularly HCV infections and associated diseases.

Description

INHIBITORS OF HCV NS5B POLYMERASE
FIELD OF THE INVENTION
The present invention relates to compounds, process for their synthesis, compositions and methods for the treatment and prevention of hepatitis C virus (HCV) infection. In particular, the present invention provides novel compounds, pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment or prevention of HCV infection. The present invention also provides processes and intermediates for the synthesis of these compounds.
BACKGROUND OF THE INVENTION Hepatitis C virus (HCV) is the major etiological agent of post- transfusion and community-acquired non-A non-B hepatitis worldwide. It is estimated that over 150 million people worldwide are infected by the virus. A high percentage of carriers become chronically infected and many progress to chronic liver disease, so-called chronic hepatitis C. This group is in turn at high risk for serious liver disease such as liver cirrhosis, hepatocellular carcinoma and terminal liver disease leading to death. The mechanism by which HCV establishes viral persistence and causes a high rate of chronic liver disease has not been thoroughly elucidated. It is not known how HCV interacts with and evades the host immune system. In addition, the roles of cellular and humoral immune responses in protection against HCV infection and disease have yet to be established. Immunoglobulins have been reported for prophylaxis of transfusion- associated viral hepatitis, however, the Center for Disease Control does not presently recommend immunoglobulins treatment for this purpose. The lack of an effective protective immune response is hampering the development of a vaccine or adequate post-exposure prophylaxis measures, so in the near-term, hopes are firmly pinned on antiviral interventions.
Various clinical studies have been conducted with the goal of identifying pharmaceutical agents capable of effectively treating HCV infection in patients afflicted with chronic hepatitis C. These studies have involved the use of interferon-alpha, alone and in combination with other antiviral agents. Such studies have shown that a substantial number of the participants do not respond to these therapies, and of those that do respond favorably, a large proportion were found to relapse after termination of treatment.
Until recently, interferon (IFN) was the only available therapy of proven benefit approved in the clinic for patients with chronic hepatitis C. However the sustained response rate is low, and interferon treatment also induces severe side- effects (i.e. retinopathy, thyroiditis, acute pancreatitis, depression) that diminish the quality of life of treated patients. Recently, interferon in combination with ribavirin has been approved for patients non-responsive to IFN alone. However, the side effects caused by IFN are not alleviated with this combination therapy. Therefore, a need exists for the development of effective antiviral agents for treatment of HCV infection that overcomes the limitations of existing pharmaceutical therapies.
General Viral polymerases are attractive targets for antiviral drug development. For example, inhibitors of Viral RNA polymerase activity have been described; see, for example, JAEN, Juan, et.al., WO 0177091, Altamura et. al., WO 00/06529 and Bailey et. al., WO 00/10573, which references are incorporated by reference herein.
The HCV protein NS5B is an RNA dependent RNA polymerase, see, e.g., Lohmann et al. (1997) J Virol. 71:8416-8428, Behrens et al. (1996) EMBO J 15:12-22 and Ishido et al. (1998) Biochem. Biophys. Res. Comm. 244:35-40, which references are incorporated by reference herein. The sequence of various genotypes of HCV NS5B are known (Kato et al. (1990) Proc. Natl. Acad. Sci. USA. 87:9524-9528; Webster, G., et al. (2000) Balliere's Clinical Gastroenterology 14, 229-240; van Doom, L.J. (1994) J. of Medical Virology 43, 345-356; Houghton, M. (1996) Hepatitis C viruses Fields Virology: Third Edition, edited by B.N. Fields, D.M. Knipe, P.M. Howley, et al. Lippincott-Raven Publishers, Philadelphia, pp. 1035-1058; Lau, J.Y. et.al., J Infect Dis. 1995, 171(2), 281-9). However, NS5B contains sequence motifs that are highly conserved among all the RNA-dependent RNA polymerases characterized to date.
SUMMARY OF THE INVENTION The present invention provides compounds, compositions and methods that are useful for treating viral infections and associated diseases, particularly HCV infections and associated diseases. The compounds of the invention inhibit viral replication, preferably HCV replication. The methods of the invention comprise administering to an infected or susceptible host a therapeutically or prophylactically effective amount of a compound as represented by Formula 1, or a pharmaceutically acceptable salt or prodrug thereof.
Figure imgf000004_0001
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions The abbreviations used herein are conventional, unless otherwise defined.
The terms "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.
The terms "prevent", "preventing" and "prevention" refer to a method of 'barring a subject from acquiring a disease. As used herein, "prevent", "preventing" and
"prevention" also include reducing a subject's risk of acquiring a disease.
The term "therapeutically effective amount" refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the disease being treated. The term "viral infection" refers to the introduction of a virus into cells or tissues, e.g., hepatitis C virus (HCV). In general, the introduction of a virus is also associated with replication. Viral infection may be determined by measuring virus antibody titer in samples of a biological fluid, such as blood, using, e.g., enzyme immunoassay. Other suitable diagnostic methods include molecular based techniques, such as RT-PCR, direct hybrid capture assay, nucleic acid sequence based amplification, and the like. A virus may infect an organ, e.g., liver, and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease and hepatocellular carcinoma.
"Flaviviridae virus", as used herein, refers to a virus of the family Flaviviridae, which family includes the Flavivirus, Pestivirus and Hepacivirus or hepatitis C-like virus genera. Representative species of the genus Flavivirus include yellow fever virus, tick-bome encephalitis virus, Rio Bravo virus, Japanese encephalitis virus,
Tyuleniy virus, Ntaya virus, Uganda S virus, Dengue virus and Modoc virus.
Representative species of the genus Pestivirus include bovine diarrhea virus, border disease virus and hog cholera virus. A representative species of the genus of hepatitis C- like viruses is hepatitis C virus. Unassigned viruses in the family Flaviviridae are included in the meaning of Flaviviridae virus.
The term "modulate" refers to the ability of a compound to increase or decrease the catalytic activity of a viral polymerase, e.g. a viral RNA polymerase. A modulator preferably activates the catalytic activity of a viral polymerase or more preferably activates or inhibits the catalytic activity of a viral polymerase depending on the concentration of the compound exposed to the viral polymerase or most preferably inhibits the catalytic activity of a viral polymerase. The term "modify" refers to the act of altering, in whole or in part, the structure of a molecule, e.g., a protein. Modification may be covalent or noncovalent, and includes, but is not limited to, aggregation, association, substitution, conjugation and/or elimination of a chemical group. Modification may alter the function or other properties (e.g., chemical, physical) of the molecule.
The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. Cι-C8 means 1-8 eight carbons). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)ethyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-
(butadienyl), 2,4-pentadienyl, 3 -(1,4- pentadienyl), ethynyl, I - and 3 -propynyl, 3 - butynyl, and the higher homologs and isomers. A "lower alkyl" is a shorter chain alkyl having eight or fewer carbon atoms.
The terms "alkoxy alkylcylamino" and "alkylthio" refer to those groups having an alkyl group attached to the remainder of the molecule through an oxygen, nitrogen or sulfur atom, respectively. Similarly, the term "dialkylamino" is used in a conventional sense to refer to -NRR' wherein the R groups can be the same or different alkyl groups.
The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Examples include -CH2-CH -O-CH3, -CH2- CH2-NH- CH3, - CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, - CH2-CH -S(O)2-CH3, - CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and - CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3. Also included in the term "heteroalkyl" are those radicals described in more detail below as "heterocycloalkyl".
The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "Fluoroalkyl," are meant to include monofluoroalkyl and polyfluoroalkyl, including perfluoroalkyl.
The term "aryl," employed alone or in combination with other terms (e.g., aryloxy, arylthioxy, aralkyl) means, unless otherwise stated, an aromatic substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. The term "heteroaryl" is meant to include those aryl rings which contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. The "heteroaryl" groups can be attached to the remainder of the molecule through a heteroatom. Non- limiting examples of aryl and heteroaryl groups include phenyl, 1- naphthyl, 2-napthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3- pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzothiazolyl, purinyl, 2- benzimidazolyl, 1-indolyl, 5-indolyl, 1-isoquinolyl, 5- isoquinolyl, 2-quinoxalinyl, 5- quinoxalinyl, 3-quinolyl, and 6-quinolyl.
Substituents for each of the above noted aryl ring systems are selected from the group of acceptable substituents described below. The term "aralkyl" is meant to include those radicals in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) or a heteroalkyl group (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like). Each of the above terms (e.g., "alkyl heteroalkyl" and "aryl") are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be a variety of groups selected from: -OR', =O, =NR, =N-OR', -NR'R" -SR', -halogen, - SiR'R"R, - OC(O)R, -C(O)R, -CO2R', CONR'R", -OC(O)NR'R" -NR'C(O)R, - NR- C(O)NR"R'", -NR'COOR", -NH-C(NH2)=NH, -NR'C(NH2)=N-H, -NH- C(NH2)=NR, -S(O)R, S(O)2R, -S(O)2NR'R", -CN and -NO2 in a number ranging from zero to (2N+ 1), where N is the total number of carbon atoms in such radical. R, R" and X" each independently refer to hydrogen, unsubstituted Cl-COalkyl and heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(Cl-C4)alkyl groups. When R and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-7 membered ring. For example, -NR'R" is meant to include 1- pyrrolidinyl and 4- morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as haloalkyl (e.g., - CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).
Similarly, substituents for the aryl groups are varied and are selected from: halogen, -OR, -OC(O)R, -NR'R", -SR, -R', -CN, -NO2, -CO2R', -CONR'R:', -C(O)R', - OC(O)NR'R", -NR"C(O)R, -NR"C(O)2R, -NR'-C(O)NR"R'", -NH-C(NH2)=NH, - NR'C(NH2)=NH, -NH-C(NH2)=NR, -S(O)R', -S(O)2R, -S(O)2NR'R", -N3, - CH(Ph)2, perfluoro(CI-C4)alkoxy, and perfluoro(CI-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R" and R'" are independently selected from hydrogen, (Cl-C8)alkyl and heteroalkyl, unsubstituted aryl, (unsubstituted aryl)-(Cl-C4)alkyl, and (unsubstituted aryloxy-(Cr C4)alkyl. Two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula -S-C(O)-(CH2)q-R-, wherein S and R are independently -NH-, -O-, -CH2- or a single bond, and the subscript q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula -A-(CH2)W-B-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR- or a single bond, and w is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula -(CH2)W-G-(CH2)W-, where w and w' are independently integers of from 0 to 3, and G is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R in -NR'- and - S(O) NR'- is selected from hydrogen or unsubstituted (Cl-C6)alkyl.
As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), ) and sulfur(S).
The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactouronic acids and the like (see, for example, Berge, S.M., et. al. (1977) J. Pharm. Sci., 66:1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex- vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmacological compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound of the invention.
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
Certain compounds of the present invention possess asymmetric carbon atoms
(optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention unless otherwise stated.
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
Description of the Embodiments
Viral RNA polymerase is required for the transcription of genomic RNA, which process is required for replication of the genome of an RNA virus. Therefore, inhibition of viral RNA polymerase will inhibit viral replication. The present invention provides compounds having antiviral activity. The compounds of the invention block viral replication by specifically inhibiting the activity of a viral polymerase. In a first group of preferred embodiments, the compounds useful for modification of a viral RNA-dependent RNA polymerase protein are of Formula I
Figure imgf000011_0001
wherein:
X is selected from the group consisting of NH, O, and S;
Z is -COOH or 5-tetrazolyl;
R2, R3 and P represent 1 to three substituents independently selected from the group consisting of halogen, -CN, N(R)(R'), NO2, fluoroalkyl, fluroalkyloxy, alkyl, aryl, aralkyl, arlyoxy, aralkyloxy, alkylthio, arylthio, and heteroalkyl;
R and R are independently H or -CO alkyl;
R and R' may be taken together to form a 3 to 7 membered ring optionally containing an additional heteroatom of -O-, -NR-, -S- or -SO-; Ri is selected from the group consisting of H, -CN, and -(CH )n-N(R5)R6;
R5 is H or C.-C6 alkyl;
R6 is selected from the group consisting of H, -Cδ alkyl, -CN, -C(=NH)NH2, aryl, substituted aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalkyl, substituted heteroalkyl, and C(O)A; A is selected from the group consisting of Cτ-C6 alkyl, aryl, substituted aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalkyl and substituted heteroalkyl;
R5 and R6 may be joined together to form a 5 to 7 membered ring optionally containing an additional heteroatom of -NR-, -O-, -S- or -SOn-;
Each n is independently 0, 1 or 2. Non-limiting examples of the invention are shown in Table 1.
Figure imgf000012_0001
Figure imgf000013_0001
IV.
Figure imgf000013_0002
Vlll.
Figure imgf000013_0003
IX.
Figure imgf000013_0004
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000015_0001
Figure imgf000015_0002
xxvu.
Figure imgf000015_0003
Figure imgf000015_0004
XXlll. XXVIU.
Figure imgf000016_0001
XXXll.
Figure imgf000016_0002
XXXlll.
Figure imgf000016_0003
Figure imgf000016_0004
XXXIV.
XXX.
Figure imgf000016_0005
XXXVI.
xxxvu.
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000018_0001
xlix.
Figure imgf000018_0002
xlv.
Figure imgf000018_0003
xlvi.
Figure imgf000018_0004
Figure imgf000018_0005
Figure imgf000018_0006
xlvii.
Figure imgf000018_0007
xlviii.
Figure imgf000018_0008
liii.
Figure imgf000018_0009
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0003
lvi.
Figure imgf000019_0004
Figure imgf000019_0005
lvii.
Figure imgf000019_0006
Ixii.
Figure imgf000019_0007
lviii.
Figure imgf000020_0001
lxiii.
Figure imgf000020_0002
lxvi.
lxiv.
Figure imgf000020_0003
lxvii
Figure imgf000020_0004
Analysis of the Compounds
The subject compounds and compositions may be demonstrated to have pharmacological activity, e.g, antiviral activity, in in vitro and in vivo assays, as known in the art. See for example Behrens, S.E., et.al EMBO J. 15:12-22; Lohmann, V., et.al., 1997, J. Virol. 71:8416-8428; Ferrari, E., et al., 1999. J. Virol. 73:1649-1654; Bealieu, P.L. et.al., WO0204425 A2; Perni, R.B. et. al., WO9833501; which references are incorporated by reference herein.
The subject compounds and compositions are capable of specifically inhibiting or suppressing a viral infection, e.g., an HCV infection. An in vivo assessment of the antiviral activity of the compounds of the invention may be made using an animal model of viral infection, e.g., a primate model. Cell-based assays may be performed using, e.g, a cell line directly infected with a virus. Cell-based assays for activity against a specific viral component, e.g., a polymerase, may also be performed. Additionally, biochemical or mechanism-based assays, e.g., transcription assays using a purified protein, Northern blot, RT-PCR, etc., may be performed. The above-described assays are exemplary and not intended to limit the scope of the invention. The skilled practitioner can appreciate that modifications can be made to conventional assays to develop equivalent assays that obtain the same result.
High throughput assays for the presence, absence, quantification, or other properties of particular compounds are well known to those of skill in the art. Such assays may be adapted to identify compounds capable of modifying a viral RNA dependent RNA polymerase protein, e.g., NS5B using functional protein. Preferred assays thus detect enhancement or inhibition of HCV RNA-dependent RNA activity. Compositions
In view of the antiviral activity associated with the compounds described above, the present invention further provides pharmaceutical compositions comprising one or more of the above compounds in combination with a pharmaceutically acceptable excipient.
In one embodiment, the invention provides the subject compounds combined with a pharmaceutically acceptable excipient such as sterile saline or other medium, water, gelatin, an oil, etc. to form pharmaceutically acceptable compositions. The compositions and/or compounds may be administered alone or in combination with any convenient carrier, diluent, etc. and such administration may be provided in single or multiple dosages. Useful carriers include solid, semi-solid or liquid media including water and.non-toxic organic solvents. In another embodiment, the invention provides the subject compounds in the form of a prodrug, which can be metabolically or chemically converted to the subject compound by the recipient host. A wide variety of prodrug derivatives are known in the art such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
The compositions may be provided in any convenient form, including tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, suppositories, etc. As such, the compositions, in pharmaceutically acceptable dosage units or in bulk, may be incorporated into a wide variety of containers. For example, dosage units may be included in a variety of containers including capsules, pills, etc. Methods of Use In yet another aspect, the present invention provides novel methods for the use of the foregoing compounds and compositions. In particular, the invention provides novel methods for treating or preventing viral infections, e.g., HCV infection. The invention also provides novel methods for treating or preventing diseases resulting from, in whole or in part, viral infections, preferably diseases resulting from, in whole or in part, infection, such as hepatitis C, cirrhosis, chronic liver disease and hepatocellular carcinoma. The methods typically involve administering to a patient an effective amount of one or more of the subject compounds or compositions. The compositions may be advantageously combined and/or used in combination with other antiviral agents which are either therapeutic or prophylactic agents, and different from the subject compounds. The compositions may also be advantageously combined and/or used in combination with agents that treat conditions often associated with the viral infections that are sensitive to the present compounds, such as anti-HJN agents or immunosuppressive agents. In many instances, administration in conjunction with the subject compositions enhances the efficacy of such agents. Accordingly, the present compounds, when combined or administered in combination with other antiviral agents, can be used in dosages which are less than the expected amounts when used alone, or less than the calculated amounts for combination therapy. Exemplary treatment options for hepatitis C (HCV) include interferons, e.g., interferon alfa-2b, interferon alfa-2a, and interferon alfacon-1. Less frequent interferon dosing can be achieved using pegylated interferon (interferon attached to a polyethylene glycol moiety which significantly improves its pharmacokinetic profile). Combination therapy with interferon alfa-2b (pegylated and unpegylated) and ribavarin has also been shown to be efficacious for some patient populations. Other agents currently being developed include
RΝA replication inhibitors, antisense agents, therapeutic vaccines, protease ihibitors, helicase inhibitors and antibody therapy (monoclonal and polyclonal).
The compounds and compositions of the present invention may also be used with agents that enhance the body's immune system, including low-dose cyclophosphamide, thymostimulin, vitamins and nutritional supplements (e. g., antioxidants, including vitamins A, C, E, beta-carotene, zinc, selenium, glutathione, coenzyme Q-10 and echinacea), and vaccines, e.g., the immunostimulating complex (ISCOM), which comprises a vaccine formulation that combines a multimeric 5 presentation of antigen and an adjuvant. The compositions and compounds of the invention and the pharmaceutically acceptable salts thereof can be administered in any effective way such as via oral, parenteral or topical routes. Generally, the compounds are administered in dosages ranging from about 2 mg up to about 2,000 mg per day, although variations will necessarily occur depending on the disease target, the patient, and the route of administration. Preferred dosages are administered orally in the range of about 0.05 mg/kg to about 20 mg/kg, more preferably in the range of about 0.05 mg/kg to about 2 mg/kg, most preferably in the range of about 0.05 mg/kg to about 0.2 mg per kg of body weight per day. Preparation of the Compounds Some of compounds of this invention are commercially available. For example, 2,2'-
(l,2-phenylenediimino)bis-benzoic acid is available from Oak Samples Ltd., Str. Ak. Krymsky 4A, Kiev- 142, 03680, Ukraine.
The compounds of this invention can also be prepared by methods described in the chemical literature. For example, methods for the preparation of compounds are described by Sudhakar, K., U.S. pat. 6,177,551, R. Nagar et. al., Proc. Natl. Acad. Sci., India, Sect. A
(1993), 63(4), 617-22, Black, D. S., Aust. J. Chem. (1983), 36(12), 2395-406. Bourson, J., Bull. Soc. Chim. Fr. (1970), (5), 1867-72 and Baudoin, O., J. Org. Chem. (1997), 62(16), 5458-5470.
To the advantage of the practitioner, the compounds of this invention can also be prepared by one or more of the following schemes described below. The preparation of the various diaryl amine products and intermediates of this invention is based on variations of the palladium catalysed amine coupling reaction methodology described in the literature (See for example Buchwald, S.L., et.al., U.S. pat. 6,307,087; Buchwald, S.L. et.al., J. Org. Chem. (2000) 65, 1144; Buchwald, S.L. et. al., J. Organomet. Chem. (1988) 348, 95; Amatore, C, Coord. Chem. Rev., (1998) 178-80, 511; Buchwald, S.L., et.al., Angew. Chem. Int. Ed.,
(1999) 38, 2413; Buchwald, S.L, et.al., J.Amer.Chem.Soc, (1996) 118, 7215; Hartwig, J.F., et.al., JAmer.Chem.Soc, (1996) 118, 7217; Hartwig, J.F., et.al., J.Amer.Chem.Soc, (1997) 119, 11695; Hartwig, J.F., et.al., J.Amer.Chem.Soc, (1996) 118, 7217; Hartwig, J.F., et.al., J.Amer.Chem.Soc. , (1998) 118, 827). In general, the methodolgy provides the diaryl amine products and intermediates of the invention under mild reaction conditions tolerant of a wide variety of substituents. Scheme 1
reduction
Figure imgf000024_0001
IX
Figure imgf000024_0002
III
Scheme 2a:
Figure imgf000024_0003
hydrolysis
Figure imgf000024_0004
Scheme 2b:
Figure imgf000025_0001
deprotection
Figure imgf000025_0002
Scheme 2c:
Coupling agent
Figure imgf000025_0005
Figure imgf000025_0004
Figure imgf000025_0003
deprotection
Figure imgf000025_0006
Scheme 3:
Figure imgf000026_0001
III
Scheme 4:
Figure imgf000026_0002
Scheme 5:
Pd source
Figure imgf000027_0001
πι
Scheme 6:
Figure imgf000027_0002
III
Scheme 7:
Pd source
R4 *%_-NHR15 /=*/ ligand base solvent
VIII II reduction
OR R4
R3"Θ 2 + R15HN~^
Figure imgf000028_0001
IX
Figure imgf000028_0002
III
In the schemes R groups are as defined infra. M, Ml and M2 are independently chosen from the group CI, Br, I or OSO2CF3 with the proviso that, in Scheme 3, when M2 is CI, Ml is Br, I or OSO2CF3 and when M2 is Br, Ml is I . Suitable sources of palladium include tris(dibenzylideneacetone)dipalladium(O) (Pd2dba3), palladium acetate bis[μ-(acetato-κO: κO')]bis[[2-[bis(2-methylphenyl)phosphino-κP]phenyl]methyl-κC]di-palladium, bis[l ,2- bis(diphenylphosphino)ethane]palladium (0), bis(2-methylallyl)palladium chloride dimer,bis(tri-t-butylphosphine)palladium (0), bis(tricyclohexylphosphine)palladium (0), chloro(di-2-norbornylphosphino)(2'-imethylamino- 1 , 1 '-biphenyl-2-yl)palladium (II), diacetatobis(triphenylphosphine)palladium (JJ), dichlorobis(acetonitrile)palladium (JJ), dichlorobis(benzonitrile)palladium (IT), dichloro(l ,2-bis(diphenylphosphino)ethane)palladium (JJ), dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium (JJ) dichloromethane adduct, trans-dichlorobis(tricyclohexylphosphine)palladium (IT), trans- dichlorobis(triphenylphosphine)palladium (JJ), trans-dichlorobis(tri-o- tolylphosphine)palladium (JJ), dichloro(l,5-cyclooctadiene)palladium (II), trans- dichlorodiammine palladium (JJ), palladium (IT) acetate, palladium (JJ) acetylacetonate, palladium (JJ) bromide, palladium (IJ) chloride, palladium (JJ) cyanide, palladium (JJ) iodide, palladium (IT) nitrate hydrate, palladium (JJ) oxide, palladium (JJ) sulfate dihydrate, palladium (JJ) trifluoroacetate, tetraammine palladium (JJ) tetrachloropalladate (JJ), tetrakis(acetonitrile)palladium (II) tetrafluoroborate, tetrakis(triphenylphosphine)palladium (0) and the like.
Suitable ligands include tri-o-tolylphosphine, 2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl (BINAP), l,l'-bis(diphenylphosphino)ferrocene, 2-(di-t-butylphosphino)biphenyl, tri-2- furylphosphine, tris(2,4-di-t-butylphenyl) phosphite, dicyclohexyl 2-(2'-N,N- dimethylamino)biphenylphosphine, 1 -[( 1 S)- 1 -(dimethylamino)ethyl]-2-(diphenylphosphino)- Ferrocene (PPFA), bis[2-(diphenylphosphino)phenyl] ether (DPEphos) and the like. Bases suitable for the reactions include Cs CO , lithium di-o-tolylamide, sodium t-butoxide, potassium t-butoxide, lithium bis-trimethylsilylamide, lithium diisopropylamide, potassium phosphate, sodium 2,4,6-tri-t-butylphenoxide, sodium carbonate, lithium carbonate, potassium carbonate, rubidium carbonate, triethylamine, diazabicycloundecane, Hunig's base, pyridine, and the like.
Suitable solvents include toluene, xylene, acetonitrile, dimethoxyethane, tetrahydrofuran, dioxane, dimethylformamide and the like. It is obvious to one of ordinary skill in the art that further transformations of the products and intermediates of Schemes 1-7 are readily achieved using methods common in the art. These transformations include for example, ester, nitrile and amide hydrolysis; ester, amide and nitrile reduction; primary and secondary amine alkylation, acylation, aroylation; alcohol acylation, aroylation and alkylation; and the like. EXAMPLES
The following examples further illustrate the preparation and analysis of compounds of the invention. The examples are illustrative only and not intended to limit the scope of the invention in any way. Reagents and solvents can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). All commercially obtained reagents are used as received without further purification. Solvents are used as received or dried over appropriate drying agents and distilled. Proton NMR experiments are carried out on a Bruker 400 MHz spectrometer, and chemical shifts are reported in ppm downfield from internal TMS. Carbon NMR experiments are carried out on a Bruker 500 MHz spectrometer, and chemical shifts are reported in ppm relative to the central line of deuteriochloroform at 77.0 ppm. Low resolution mass spectra (ESI) are obtained on a Micromass Platform C spectrograph. Low resolution mass spectra (El) and high resolution mass spectra (FAB), as well as JR spectra and elemental analyses are conducted by the Pharmacia analytical laboratory. Flash column chromatography is carried out on Biotage 40 prepacked columns, while preparative TLC is carried out on Merck silica gel F 54-coated plates with 0.25 mm or 0.5 mm silica layers. Unless otherwise noted, reactions are carried out in dry glassware under a nitrogen atmosphere.
Example 1 according to Scheme 1:
5-(Aminomethyl)-2-{[2-[(2-carboxyphenyl)amino]-4-(trifluoromethyl)- phenyl]amino}benzoic acid hydrochloride [xxiv.]
Figure imgf000030_0001
xxiv.
Combine 3-amino-4-nitrobenzotrifluoride (0.5 g), dicyclohexyphosphino-2'- (N, N- dimethylamino)biphenyl (76 mg) and cesium carbonate (2.0 g). Charge and evacuate system 3X with argon, add tris(dibenzylideneacetone)-dipalladium(0) (0.11 g). Charge system again with argon 3X and then add methyl 2-iodobenzoate (0.64 g) argon dissolved in argon sparged toluene (13 mL). The mixture is stirred mechanically at 100°C for 24 hrs under argon. The reaction mixture is cooled and filtered through celite®. Concentration of filtrate under reduced pressure yields crude product, which is purified by silica gel chromatography to give methyl 2-{ [2-nitro-5-(trifluoromethyl)phenyl]amino}benzoate (0.64 g). 1H NMR (400 MHz, DMSO-cfc) δ 3.88 (s, 3 H), 7.20-7.25 (m, 1 H), 7.36 (dd, J = 4.4, 4.4 Hz, 1 H), 7.58-7.67 (m, 2 H), 7.79 (s, 1 H), 8.01 (dd, 7 = 4.0, 3.9 Hz, 1 H), 8.35 (d, J = 4.4 Hz, 1 H), 10.94 (s, 1 H); MS (ESI+) for 5H11F3N2O4 m/z 341.1 (M+H)+. MS (ESI-) for C15HπF3N2O4 /z 339.0 (M-HV.
Blanket Parr flask with argon and 10% palladium/carbon (0.11 g), wet with MeOH (13 mL) and then add methyl 2-{ [2-nitro-5-(trifluoromethyl)phenyl]amino}benzoate (0.62 g) in
MeOH (40 mL). Hydrogenate at 45 psi for 4.0 hrs. At this time another 10% Pd C (0.11 g) is added and mixture hydrogenated for an additional 1.5 hours. The mixture is filtered through celite® and filtrate concentrated to dryness under reduced pressure. The crude residue is purifiedy by silica gel chromatography to methyl 2-{ [2-amino-5- (trifluoromethyl)phenyl]amino}benzoate yield (0.41 g). Η NMR (400 MHz, OMSO-d6) δ 3.86 (s, 3 H), 5.69 (s, 2 H), 6.53 (d, J = 4.2 Hz, 1 H), 6.74 (t, J = 7.5 Hz, 1 H), 6.90 (d, J = 4.1 Hz, 1 H), 7.27-7.38 (m, 3 H), 7.89 (dd, J = 4.0, 4.0 Hz, 1 H), 8.77 (s, 1 H); MS (ESI+) for C,5H13F3N2O2 m/z 311.1 (M+H)+. MS (ESI-) for Cι5H13F3N2O2 m/z 309.1 (M-HV.
A mixture of Cs2CO3 (0.814 g, 2.49 mmol), Pd2(dba)3 (0.046 g, 0.050 mmol), 2- dicyclohexyl 2-(2'-N,N-dimethylamino)biphenylphosphine (0.031 g, 0.078 mmol), acetonitrile (6 mL, sparged with argon), methyl 5-cyano-2-iodobenzoate (0.287 g, 1.0 mmol) and methyl 2-{ [2- amino-5-(trifluoromethyl)phenyl]amino}benzoate (0.310 g, 1.0 mmol) is heated with efficient stirring at 100°C for 1 h, cooled to room temperature and filtered through Celite®. The filtrate is concentrated and purified by column chromatography to give 0.090 g of methyl 5- cyano-2-{[2-{ [2-(methoxycarbonyl)-phenyl]amino}-4-(trifluoromethyl)- phenyl]amino}benzoate as a yellow solid. MS (ESI+) for C24H18F3N3O4 m/z 470.1340 (M+H)+. 1H NMR (400 MHz, CDC13) δ 3.76 (s, 3 H), 3.81 (s, 3 H), 6.75 (dd, 1 H), 6.96 (m, 2 H), 7.27 (m, 2 H), 7.40 (m, 2 H), 7.66 (s, 1 H), 7.86 (dd, 1 H), 8.17 (d, 1 H), 9.35 (s, 1 H), 9.83 (s, 1 H).
A mixture of methyl 5-cyano-2-{ [2-{[2-(methoxycarbonyl)-phenyl]amino}-4- (trifluoromethyl)-phenyl] amino }benzoate (0.15 g, 0.319 mmol), platinum oxide (0.03 g) and HC1 (0.160 mL, 4 N) in a mixture of methanol (5 mL) and THF (2 mL) is hydrogenated (40 lb initial hydrogen pressure) for 1-1/2 h. The reaction is filtered through Celite®, rinsed with methanol and evaporated to give 0.175 g solid, which is purified by column chromatography to give 0.064 g of methyl 5-(aminomethyl)-2-{ [2-{[2-(methoxycarbonyl)phenyl]amino}-4- (trifluoromethyl)phenyl] amino jbenzoate as a yellow oil. A portion of the product is treated with saturated HCl/EtOAc solution to give 0.018 g of product as the HCl salt. MS (ESI+) for C24H22F3N3O4 m/z 474.1659 (M+H)+. Η NMR (400 MHz, DMSO-< ) δ 3.78 (s, 3 H), 3.82 (s, 3 H), 3.90 (m, 2 H), 6.84 (dd, 1 H), 6.89 (d, 1 H), 7.34-7.40 (m, 2 H), 7.51 (d, 1 H), 7.56- 7.62 (m, 2 H), 7.67 (s, 1 H), 7.88 (dd, 1 H), 8.01 (d, 1 H), 8.23 (br s, 3 H), 9.20 (s, 1 H), 9.45 (s, 1H).
Methyl 5-(aminomethyl)-2-{ [2-{ [2-(methoxycarbonyl)phenyl]amino}-4- (trifluoromethyl)phenyl]amino}benzoate (0.046, 0.097 mmol) and 1 N sodium hydroxide solution (0.500 mL, 0.5 mmol) are heated in methanol (1 mL) at 60 °C for 5 h. The reaction is cooled, concentrated to remove the methanol and acidified using IN HCl (0.550 mL). The resulting solid is filtered, washed with water (2 mL) and air-dried to give 0.038 g of 5- (aminomethyl)-2-{[2-[(2-carboxyphenyl)amino]-4-(trifluoromethyl)-phenyl]amino}benzoic acid hydrochloride as a tan solid (80% yield). MS (ESI+) for C22H18F3N3O4 m/z 445.1251 (M+H)+. Η NMR (400 MHz, OMSO-d6) δ 3.92 (s, 2 H), 6.79 (dd, 1 H), 6.95 (d, 1 H), 7.29- 7.36 (m, 2 H), 7.40-7.46 (m, 2 H), 7.59 (d, 1 H), 7.64 (s, 1 H), 7.90 (dd, 1 H), 8.06 (dd, 1 H), 8.33 (br s, 2 H) 9.95 (s, 1 H), 10.6 (s, 1 H).
Example 2a according to Scheme 2a:
2-{[2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-
[(dibenzylamino)methyl]benzoic acid [xlviii.]
Figure imgf000032_0001
A mixture of Cs2CO3 (1.9 g, 5.85 mmol), bromo[tris(triphenylphosphine)]cuprate (725 mg, 0.78 mmol), anhydrous toluene (10 mL), methyl 2-iodobenzoate (1.04 g, 3.9 mmol) 2-nitro-4- (trifluoromethyl)aniline (818 rhg, 3.9 mmol) is heated with efficient stirring at 100°C for 24 h, cooled to room temperature and filtered through Celite®. The filtrate is concentrated and purified by flash chromatography to give 1.07 g of methyl 2-{ [2-nitro-4-
(trifluoromethyl)phenyl]amino}benzoate, 75%. MS (ESI+) for C15HπF3N2O4 m/z 341 (M+H)+. Η NMR (300 MHz, DMSO d6) δ 11.02 (s, IH), 8.40 (s, IH), 8.01 (m, IH), 7.81 (m, IH), 7.60 (m, 2H), 7.46 (s, IH), 7.25 (m, IH), 3.85 (s, 3H).
Methyl 2-{ [2-nitro-4-(trifluoromethyl)phenyl]amino}benzoate (505 mg, 1.48 mmol) is suspended in a solution of methanol (10 mL)and THF (20 mL), the resulting solution is cooled to 0°C. NiCl2 (192 mg, 1.48 mmol), is added followed by NaBFL (280 mg, 7.4 mmol), which is slowly added with vigorous effervescence. The solution is warmed to room temperature and after 2 h, the reaction mixture is concentrate and then saturated NaHCO3 (40 mL), and EtOAc (30 mL), are added. The organic phase is separated, dried (Na2SO ), and evaporated. The crude residue is purified by flash chromatography to give methyl 2-{ [2- amino-4-(trifluoromethyl)phenyl] amino }-benzoate, 368 mg, 80%. MS (ESI+) for C15H13N2O2 m/z 311 (M+H)+. 1H NMR (400 MHz, DMSO d6) δ 8.86 (s, IH), 7.93 (m, IH), 7.40 (m, IH), 7.26 (m, IH), 7.12 (m, IH), 6.90 (m, IH), 6.82 (m, 2H), 5.38 (bs, 2H), 3.88 (s, 3H).
A mixture of Cs2CO3 (885 mg, 2.7 mmol), Pd2(dba)3 (41 mg, 0.045 mmol), 2- dicyclohexyl 2-(2'-N,N-dimethylamino)biphenylphosphine (35 mg, 0.09 mmol), anhydrous toluene (10 mL), methyl 2-iodo-5-cyano-benzoate[PHA-741105] (520 mg, 1.81 mmol) and methyl 2- { [2-amino-4-(trifluoromethyl)phenyl] amino }-benzoate [PHA-727080] (561 mg, 1.81 mmol) is heated with efficient stirring at 100°C for 18 h, cooled to room temperature and filtered through Celite®. The filtrate is concentrated and purified by flash chromatography to give 286 mg of methyl 5-cyano-2-{[2-{[2-(methoxycarbonyl)phenyl]amino-5- (trifluoromethyl)phenyl]amino}-benzoate, 34%. MS (ESI+) for C24H18 F3 N3 O4 m/z 470 (M+H)+. Η NMR (400 MHz, DMSO d6) δ 9.95 (m, 2H), 8.19 (s, IH), 7.86 (s, IH), 7.70 (m, 2H), 7.61 (m, 2H), 7.45 (m, 3H), 6.90 (s, 2H), 6.67 (IH), 3.92 (s, 3H), 3.89 (s, 3H). Methyl 5-cyano-2-{ [2-{ [2-(methoxycarbonyl)ρhenyl]amino-5-
(trifluoromethyl)phenyl]amino}-benzoate (57 mg, 0.12 mmol), is dissolved in methanol (2 mL), and THF (3 mL) the resulting solution is cooled to 0°C. NiCl2 (15 mg, 0.12 mmol), is added followed by NaBH4 (90 mg, 2.4 mmol), which is slowly added with vigorous effervescence. The solution is warmed to room temperature and after 2 h, the reaction mixture is concentrate and then saturated NaHCO (20 mL), and EtOAc (20 mL), are added. The organic phase is separated, dried (Na2SO4), and evaporated. The crude residue is purified by flash chromatography to give methyl 5-(aminomethyl)-2-{ [2-{[2- (methoxycarbonyl)phenyl] amino-5-(trifluoromethyl)phenyl] amino } -benzoate which is dissolved in 2M HCl/ Et2O, after 2 hr the solution is added to n-hexane for crystallization, the resulting precipitate is collected on a filter. Drying under vacuum to afford 25 mg of methyl 5-(aminomethyl)-2-{ [2-{ [2-(methoxycarbonyl)phenyl]amino-5-
(trifluoromethyl)phenyl]amino} -benzoate hydrochloride 41%. MS (ESI+) for C24 H22 F3 N O4 m/z 474 (M+H)+. 1H NMR (400 MHz, DMSO d6) δ 9.49 (s, IH), 9.18 (s, IH), 8.00 (m, 4H), 7.85 (m, IH), 7.68 (m, 2H), 7.46 (m, 3H), 7.29 (m, IH), 6.90 (m, 2H), 3.92 (s, 2H), 3.83 (s, 3H), 3.74 (3H).
Methyl 2-{[2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5- [(dibenzylamino)methyl]benzoate (35 mg, 0.053 mmol) is suspended in a solution of THF (8 mL), MeOH (1 mL) and water (1 mL) with lithium hydroxide (12 mg, 0.5 mmol). The mixture is stirred at room temperature for 4 h, then is acidified with 1 N aqueous HCl and portioned with EtOAc, the organic phase is concentrated to give 24 mg of 2-{ [2-[(2- carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-[(dibenzylamino)methyl]benzoic acid, 72%. MS (ESI+) for C36 H30F3 N3 O4 m/z 626 (M+H)+. 1H NMR (400 MHz, DMSO d6) δ 13.05 (bs, IH), 10.23 (s, IH), 9.89 (s, IH), 9.68 (s, IH), 8.00 (s, IH), 7.79 (m, IH), 7.65 (m, 2H), 7.30 (m, 14H), 6.78 (m, 2H), 4.20 (s, 4H), 3.39 (s, 2H).
Example 2b according to Scheme 2b:
N-(3-carboxy-4-{[2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl]amino}benzyl)-L-phenylalaninamide chloride [xviii.]
Figure imgf000035_0001
Methyl 5-(aminomethyl)-2-{ [2-{ [2-(methoxycarbonyl)phenyl]amino}-5- (trifluoromethyl)phenyl]amino} benzoate (100 mg, 0.21 mmol) is suspended in DCM (6 mL), with N-(tert-butoxycarbonyl)-L-phenylalanine (64 mg, 0.24 mmol), and PS-DCC (N-
Cyclohexylcarbodiimide, N-methyl polystyrene HL 1.93 mmol/g), (200 mg, 0.38 mmol). The mixture is stirred at room temperature for 24 h. The resin is filter off and washed. The solution is dried and the residue is purified by flash chromatography to give 131 mg of methyl 5-({ [N-(tert-butoxycarbonyl)-L-phenylalanyl]amino}methyl)-2-{ [2-{ [2- (methoxycarbonyl)phenyl]amino}-5-(trifluoromethyl)phenyl]amino}benzoate, 90%. MS (ESI+) for C38H39F3N4O7 /z 721 (M+H)+. 1H NMR (400 MHz, DMSO d6) δ 9.83 (s, IH), 9.50 (s, IH), 8.70 (s, 2H), 7.93 (m, IH), 7.82 (m, IH), 7.65 (m, IH), 7. 62 (m, IH), 7.46 (m, 2H), 7.25 (m, 6H), 7.03 (m, IH), 6.77 (m, 2H), 4.1 1 (m, 2H), 4.05 (m, IH), 3.84 (s, 3H), 3.80 (s, 3H), 3.10 (m, 2H), 1.35 (s, 9H).
Methyl 5-( { [N-(tert-butoxycarbonyl)-L-phenylalanyl] amino } methyl)-2- { [2- { [2- (methoxycarbonyl)phenyl]amino}-5-(trifluoromethyl)phenyl]amino}benzoate (131 mg, 0.18 mmol) is suspended in a solution of THF (8 mL), MeOH (1 mL) and water (1 mL) with lithium hydroxide (24 mg, 1 mmol). The mixture is stirred at room temperature for 18 h, then is acidified with IN aqueous HCl and portioned with EtOAc, the organic phase is concentrated to give 120 mg of 5-({[N-(tert-butoxycarbonyl)-L-phenylalanyl]amino}methyl)- 2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}benzoic acid,96%. MS (ESI+) for C36H35F3N4O7 m/z 693 (M+H)+. 1H NMR (400 MHz, DMSO d6) δ 13.00 (bs, 2H), 9.86 (s, IH), 9.52 (s, IH), 8.75 (s, IH), 8.03 (s, IH), 7.92 (m, IH), 7.83 (m, IH), 7.66 (m, IH), 7. 64 (m, IH), 7.49 (m, 2H), 7.24 (m, 6H), 7.04 (m, IH), 6.78 (m, 2H), 4.10 (m, 2H), 4.03 (m, IH), 3.04 (m, 2H), 1.35 (s, 9H).
5-( { [N-(tert-butoxycarbonyl)-L-phenylalanyl] amino } methyl)-2- { [2- [(2- carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}benzoic acid (120 mg, 0.17 mmol) is dissolved with 2M HCl in diethylether (5 mL). The mixture is stirred for 1 h and then the solution is added dropwise in n-hexane (30 mL), the resulting precipitate is collected on a filter. Drying under vacuum affords 105 mg of 1. N-(3-carboxy-4-{[2-[(2- carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}benzyl)-L-phenylalaninamide chloride 98%. MS (ESI+) for C31H27F3N4O5 HCl m/z 593 (M+H)+. 1H NMR (400 MHz, DMSO d6) δ 13.02 (bs, 2H), 9.87 (s, IH), 9.53 (s, IH), 8.75 (s, IH), 8.23 (bs, 3H), 7.91 (m, IH), 7.81 (m, IH), 7.68 (m, IH), 7. 63 (m, IH), 7.47 (m, 2H), 7.27 (m, 6H), 7.06 (m, IH), 6.79 (m, 2H), 4.15 (m, 2H), 3.97 (m, IH), 3.03 (m, 2H).
Example 2c according to Scheme 2c:
5-({[amino(imino)methyl]amino}methyl)-2-{[2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl]amino}benzoic acid [xxxii.]
Figure imgf000036_0001
Methyl 5-(aminomethyl)-2-{ [2-{ [2-(methoxycarbonyl)phenyl]amino}-5- (trifluoromethyl)phenyl] amino} benzoate (74 mg, 0.15 mmol) is suspended in EtOH (6 mL), with (3,5-dimethyl-lH-pyrazol-l-yl)(imino)methanaminium nitrate (62 mL, 0.3 mmol) and triethylamine (105 DL, 0.75 mmol). The mixture is stirred at room temperature for 4 h. The solvent is removed and the residue is purified by flash chromatography to give 60 mg of methyl 5-({ [amino(imino)methyl]amino}methyl)-2-{ [2-{ [2-
(methoxycarbonyl)phenyl]amino }-5-(trifluoromethyl)phenyl]amino } benzoate, 78%. MS (ESI+) for C25 H24F3 N5 O4 m/z 516 (M+H)+. 1H NMR (400 MHz, DMSO d6) δ 10.18 (bs, IH), 9.58 (bs, IH), 9.11 (bs, 2H), 7.85 (m, 2H), 7.60 (m, IH), 7.45 (s, IH), 7.40(bs, IH), 7.23 (m, 3H), 7.10 (m, IH), 6.71 (m, 2H), 4.04 (m, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 3.31 (bs, 3H). Methyl 5-({ [amino(imino)methyl]amino}methyl)-2-{ [2-{ [2-
(methoxycarbonyl)phenyl]amino}-5-(trifluoromethyl)phenyl]amino}benzoate (60 mg, 0.11 mmol) is suspended in a solution of THF (8 mL), MeOH (1 mL) and water (1 mL) with lithium hydroxide (24 mg, 1 mmol). The mixture is stirred at room temperature for 4 h, then is acidified with IN aqueous HCl and portioned with EtOAc, the organic phase is concentrated. The resulting residue is purified by C18 cartridge with water acetonitrile as eluent to afford 13 mg of 5-({ [amino(imino)methyl]amino}methyl)-2-{[2-[(2- carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}benzoic acid, 23%. MS (ESI+) for C23 H20F3 N3 O4 m/z 488 (M+H)+. 1H NMR (400 MHz, DMSO d6) δ 10.78 (bs, IH), 10.18 (bs, IH), 9.31 (bs, 2H), 7.87 (m, 2H), 7.61 (m, IH), 7.51 (s, IH), 7.48 (bs, IH), 7.29 (m, 3H), 7.10 (m, IH), 6.75 (m, 2H), 4.04 (m, 2H), 3.41 (bs, 3H).
Example 3 according to Scheme 3: 1-N, 2-N-bis(2-carboxyphenyl)-l,2-diamino-3-methylbenzene. [xlvii.]
Figure imgf000037_0001
xlvii.
Into a round-bottomed flask are placed Cs CO (668 mg, 2.05 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (19 mg, 0.049 mmol), anhydrous toluene (5 mL), methyl 2-iodobenzoate (0.334 mL, 2.05 mmol), 1,2- diamino-3-methylbenzene (100 mg, 0.82 mmol). The mixture is heated with efficient stirring at 100°C for 36 h. The resulting mixture is cooled to room temperature and filtered through Celite®. The filtrate is concentrated and purified by flash chromatography. The yield is 265 mg of 1-N, 2-N-bis(2-(methylcarboxy)phenyl)-l,2-diamino-3-methylbenzene, 83%. MS (ESI+) for C23H22Ν2O4 m/z 391 (M+H)+. Η NMR (400 MHz, CDC13) δ 9.19 (s, 1 H), 8.91 (s, 1 H), 7.86 (dd, 7 = 23, 8 Hz, 2 H), 7.36 (d, 7= 8 Hz, 1 H), 7.24 (m, 2 H), 7.16 (m, 2 H), 7.00 (d, 7 = 7 Hz, 1 H), 6.69 (dt, 7 = 28, 3 Hz, 2 H), 6.32 (d, 7 = 8 Hz, 1 H), 3.88 (s, 3 H), 3.68 (s, 3 H), 2.24 (s, 3 H).
1-N, 2-N-bis(2-(Methylcarboxy)phenyl)-l,2-diamino-3-methylbenzene (135 mg, 0.35 mmol) is suspended in a solution of ethanol (5 mL), 1 Ν aqueous sodium hydroxide (5 mL) and THF (5 mL). The mixture is stirred at 55°C for 4 h. The mixture is cooled on an ice bath and acidified with 6 N aqueous HCl. The resulting precipitate is collected on a filter and washed with water. Drying under a vacuum affords 1-N, 2-N-bis(2-carboxyphenyl)-l,2-diamino-3- methylbenzene. The yield is 112 mg, 88%. MS (ESI+) for C2ιH18Ν2O4m/z 363 (M+H)+. 1H NMR (400 MHz, DMSO-^) δ 12.89 (br s, 2 H), 9.80 (s, 1 H), 9.07 (s, 1 H), 7.82 (m, 2 H), 7.38 (m, 3 H), 7.21 (m, 2 H), 7.03 (d, 7 = 7 Hz, 1 H), 6.76 (t, 7 = 8 Hz, 1 H), 6.63 (t, 7 = 8 Hz, l H), 2.15 (s, 3 H).
Example 4 according to Scheme 4: 5-(aminomethyl)-2-{[2-(2-carboxyphenoxy)-5-(trifluoromethyl)phenyl]amino}benzoic acid hydrochloride [xxv.]
Figure imgf000038_0001
A solution of methyl salicylate (4.1g, 27 mM) in about 25 ml of anhydrous DMF is cooled in an ice bath and NaH (50 % in hexane, 27 mM, 1.00 g) is added portion wise. All is kept under stirring for 30 minutes and a white sponge forms. 4 bromo-3-nitro benzene trifluoride (22.5 mM, 6.07 g), diluted in 5 ml of DMF, is added. The ice bath is removed and the mixture is heated to 80°C with an oil bath. The brownish solution turns into dark green. After two hours the solution is cooled to r.t. and poured into a conical flask containing about 200 ml of water and ethyl acetate. The organic layer is washed several times with water, dried over Na2SO4, filtered and concentrated under vacuum. Purification of the crude material by chromatography gives the product as yellow crystals in 78 % yield. MS (ESI+) for C15H10 F3NO5 m/z 342 (M+H)+. Η NMR (400 MHz, DMSO) D 8.45 (m, 1 H), 8.00 (m, 1 H), 7.91 (m, 1 H), 7.77 (m, 1 H), 7.51 (m, 1 H), 7.42 (m, 1 H), 6.95 (m, 1 H), 3.65 (s, 3 H). Methyl 2-[2-nitro-4-(trifluoromethyl)phenoxy]benzoate (5.8 g, 18.6 mM) is dissolved in 50ml of EtOH 95 % and SnCl2 (37.3mM, 7.07g) is added with 1-2 ml of HCl cone. The reaction is stirred at r.t. until there is no more starting material ( about 24 hr), then evaporated down and worked up with NaOH 2M and ethyl acetate. Water phase is extracted twice before a heavy white precipitate forms. Organic layer is dried over Na2SO4, filtered and concentrated. The product is isolated in 80 % yield after chromatography. MS (ESI+) for C15H12F3NO3 m z 312 (M+l)+. 1H NMR (400 MHz, DMSO) D7.82 (m, 1 H), 7.56(m, 1 H), 7.25 (m, 1 H) 7.08 (m, 1 H), 6.97 (m, 1 H), 6.79 (m, 1 H), 6.71 (m, 1 H), 5.29 (bs, 2 H), 3.74 (s, 3 H).
Pd2dba3 (54 mg, 0.06 mM), PCy2dmab (47 mg, 0.12mM) and Cs2CO3 (733 mg, 2.25 mM) are put together in a two necked flask previously filled with argon. Methyl-2-[2-amino-4- trifluoromethyl)phenoxy]benzoate (466 mg, 1.5 mM) and methyl 5-cyano-2-iodobenzoate (434 mg, 1.5 mM) are dissolved in anhydrous toluene (already degassed with argon for 20 minutes) and afterwards added into the flask. The final solution is heated to 100 °C with an oil bath. After 18 hr the reaction is cooled to r.t. and worked up with HCl 1 M and ethyl acetate. The organic layer is washed with brine, dried over Na2SO4 and concentrated under vacuum. Chromatography provided 425 mg of clean product (60 % yield). MS (ESI+) for C24Hι7F3N2O5 m/z 471(M+1)+. 1H NMR (400 MHz, DMSO) ) D 9.58 (s, 1 H), 7.85 (m, 2 H), 7.60 (m, 2 H), 7.47 (m, 1 H), 7.32 (m, 2 H), 7.22 (m, 2 H), 6.8 (m, 1 H), 3.78 (s, 3 H), 3.65 (s, 3H).
Methyl-5-cyano-2-{[2-[2-(methoxycarbonyl)phenoxy]-5-trifluoromethyl) phenyl]amino}benzoate (340 mg, 0.78 mM) are dissolved in THF-MeOH (1:1) and the solution is cooled in an ice bath. NiCl2 (0.7 mM, 94 mg) is added and finally portions of NaBJL (53 mg, 1.4 mM) are added every half an hour until no more starting material is present. Meanwhile the mixture has turned black. The reaction is worked up with water and ethyl acetate while organic residues are removed by filtration. The organic layer is dried over Na2SO4, filtered and evaporated down. The crude material was purified by chromatography providing the clean product in 50 % yield. MS (ESI+) for C2 H21F3N2O5 m/z 475(M+1)+. 1H NMR (300 MHz, DMSO) D 9.54 (s, 1 H), 7.90 (m, 2 H), 7.65 (m, 2 H), 7.52 (m, 1 H), 7.38 (m, 2 H), 7.27 (m, 2 H), 6.8 (m, 1 H), 3.82 (s, 3 H), 3.71 (s, 2 H), 3.65 (s, 3H). Methyl-5-(aminomethyl)-2- { [2- [2-(methoxycarbonyl)phenoxy] -5-
(trifluoromethyl)phenyl]amino} benzoate (180 mg, 38 mM) is dissolved in MeOH (3 ml) and THF (3 ml). 2 ml of 3M NaOH 3M are added and the mixture is heated in oil bath @ 70 °C for 2 hr. The reaction is cooled to room temperature and then acidified with 2N HCl until pH <3 and a precipitate forms. The organic solvent is removed under vacuum and the residue is dissolved in 1-4 dioxane and 4M HCl in dioxane (2 ml) is added. All is stirred for 1 hr. After evaporation to dryness, the residue is dissolved in absolute EtOH and the addition of hexane makes the product precipitate. The white product is filtered through a sintered funnel and dried @ 60 °C under vacuum. Yield : 35%. MS (ESI+) for C22H17F3N2O5 m/z 447 (M+l)+. 1H NMR (400 MHz, DMSO) D 13.06 (bs, 2 H), 10.00 (s, 1 H), 8.11 (bs, 2 H), 8.04 (m, 1 H), 7.91 (m, 1 H), 7.71 (m, 1 H), 7.64 (m, 1 H), 7.54 (m, 1 H), 7.38 (m, 3 H), 7.29 (m, 1 H), 7.21 (m, 1 H), 3.95 (m 2 H).
Example 5 according to Scheme 5: l-N-carboxyphenyl-2-N-(2-carboxy-3-nitrophenyl)-l,2-diaminobenzene. [xlix.]
Figure imgf000040_0001
Figure imgf000040_0002
Into a round-bottomed flask are placed sodium t-butoxide (249 mg, 2.59 mmol), Pd2(dba)3 (34 mg, 0.037 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (44 mg, 0.11 1 mmol), anhydrous toluene (5 mL), t-butyl anthranilate (500 mg, 2.59 mmol), 1-bromo- 2-iodobenzene (0.236 mL, 1.85 mmol). The mixture is stirred efficiently at room temperature for 12 h. The resulting mixture is filtered through Celite®, and the filtrate is concentrated and purified by flash chromatography. The yield is 381 mg of N-(2-(t-butylcarboxy)phenyl)- amino-2-bromobenzene, 60%. MS (ESI+) for C17Hι8BrΝO2 m/z 348/350 (M+H)+. 1H NMR (400 MHz, CDC13) δ 9.52 (s, 1 H), 7.94 (d, 7 = 8 Hz, 1 H), 7.61 (d, 7 = 8 Hz, 1 H), 7.47 (d, 7 = 8 Hz, 1 H), 7.24 (m, 3 H), 6.91 (t, 7 = 8 Hz, 1 H), 6.79 (t, 7 = 8 Hz, 1 H), 1.62 (s, 9 H). Into a round-bottomed flask are placed Cs2CO3 (147 mg, 0.45 mmol), Pd2(dba)3 (5 mg, 0.006 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (84 mg, 0.019 mmol), anhydrous toluene (5 mL), methyl 2-amino-5-nitrobenzoate (86 mg, 0.45 mmol), N-(2-(t- butylcarboxy)phenyl)-amino-2-bromobenzene (111 mg, 0.32 mmol). The mixture is heated with efficient stirring at 100°C for 12 h. The resulting mixture is filtered through Celite®, and the filtrate is concentrated and purified by flash chromatography. The yield is 65 mg of 1 -N-(2-(methylcarboxy)-4-nitrophenyl)-2-N-(2-(t-butylcarboxy)phenyl)- 1 ,2-diaminobenzene, 44%. MS (ESI-) for C25H25Ν3O6 m/z 462 (M-H)-. 1H NMR (400 MHz, CDC13) δ 9.92 (s, 1 H), 9.54 (s, 1 H), 8.84 (s, 1 H), 8.04 (d, 7 = 9 Hz, 1 H), 7.80 (d, 7 = 6 Hz, 1 H), 7.53 (d, 7 = 8 Hz, 1 H), 7.36 (d, 7 = 8 Hz, 1 H), 7.26 (m, 2 H), 7.16 (t, 7 = 8 Hz, 1 H), 7.07 (d, 7 = 8 Hz, 1 H), 6.77 (d, 7= 9 Hz, 1 H), 6.71 (t, 7= 8 Hz, 1 H), 3.90 (s, 3 H), 1.47 (s, 9 H).
1 -N-(2-(Methylcarboxy)-4-nitrophenyl)-2-N-(2-(t-butylcarboxy)phenyl)- 1 ,2-diaminobenzene is dissolved in CH2C12 (5 mL). Trifluoroacetic acid (5 mL) is added and the mixture is stirred at room temperature for 12 h. The solvent is removed and the residue is suspended in a solution of methanol (10 mL), 1 Ν aqueous sodium hydroxide (105 mL) and THF (10 mL). The mixture is stirred at room temperature for 12 h. The mixture is concentrated by rotary evaporation, and the residue is cooled on an ice bath and acidified with 6 Ν aqueous HCl. The resulting precipitate is collected on a filter and washed with water. Drying under a vacuum affords l-N-carboxyphenyl-2-N-(2-carboxy-3-nitrophenyl)-l,2-diaminobenzene. The yield is 44 mg, 77%. MS (ESI+) for C20H15Ν3O6 m/z 408 (M+H)+. 1H NMR (400 MHz, OMSO-d6) δ 13.78 (br s, 1 H), 12.99 (br s, 1 H), 10.21 (s, 1 H), 9.66 (s, 1 H), 8.66 (s, 1 H), 8.12 (d, 7 = 9 Hz, 1 H), 7.85 (d, 7 = 8 Hz, 1 H), 7.57 (d, 7 = 8 Hz, 1 H), 7.48 (d, 7 = 8 Hz, 1 H), 7.36 (br m, 2 H), 7.23 (t, 7 = 8 Hz, 1 H), 7.09 (d, 7 = 8 Hz, 1 H), 6.76 (t, 7 = 7 Hz, 1 H). Example 6 according to Scheme 6:
2-{[2-[(2-carboxy-4-cyanophenyl)amino]-4-(trifluoromethyl)phenyl]amino}-5- cyanobenzoic acid [xiv.]
Figure imgf000042_0001
Cs2CO3 (926 mg, 2.84 mmol), Pd2(dba)3 (104 mg, 0.114 mmol), 2-dicyclohexylphosphino-2'- (N,N-dimethylamino)biphenyl (36 mg, 0.091 mmol), anhydrous toluene (5 mL), methyl 2- amino-5-cyanobenzoate [PHA-522499] (200 mg, 1.136 mmol), l-iodo-2-bromo-5- trifluoromethylbenzene [PHA-738728] (400 mg, 1.136 mmol). The mixture is heated at 65 °C for 66 h. The resulting mixture is cooled to room temperature and filtered through Celite®. The filtrate is concentrated and purified by flash chromatography. The yield is 65mg of methyl 5-cyano-2-{ [2-{ [4-cyano-2-(methoxycarbonyl)phenyl]amino}-4- (trifluoromethyl)phenyl] amino} benzoate, 13%. MS (ESI-) for C25Hι7F3N4O4 m/z 493 (M-H)~. 1H NMR (400 MHz, CDC13) δ 9.93 (bs, 1 H), 9.83 (bs, 1 H), 8.22 (m, 2 H), 7.69 (bs, 1 H), 7.52 (m, 4 H), 7.05 (m, 1 H), 6.81 (m, 1 H), 3.84 (s, 3 H), 3.86 (s, 3 H).
Methyl 5-cyano-2- { [2- { [4-cyano-2-(methoxycarbonyl)phenyl]amino } -4- (trifluoromethyl)phenyl]amino} benzoate (60mg, 0.121 mmol) is dissolved in a 1:1 mixture of THF/H2O and stirred at rt. LiOH H2O (excess) is then added; after 3h THF is evaporated, aqueous layer is acidified to pH=3 with conc.HCl., then washed with EtOAc (three times), dried (Na SO4), and concentrated. Crude is purified by preparative HPLC, to give 25 mg of 2- { [2-[(2-carboxy-4-cyanophenyl)amino]-4-(trifluoromethyl)phenyl]amino } -5-cyanobenzoic acid, 45%. mp: 235-240°C. MS (ESI-) for C23H13F3N4O4 m/z 465 (M-H)\ 1H NMR (400 MHz, DMSO) δ 10.24 (bs, 1 H), 9.99 (bs, 1 H), 8.14 (m, 2 H), 7.79 (m, 1 H), 7.74 (m, 1 H), 7.65 (m, 5 H), 7.19 (d, 1 H), 6.75 (d, 1 H).
Example 7 according to Scheme 7: 5-Aminomethyl-2-[2-(2-carboxy-phenylamino)-5-trifluoromethyl-phenylamino]- benzoic acid hydrochloride [xv.]
Figure imgf000043_0001
A mixture of methyl 2-amino-5-bromobenzoate (50g, 217mmol) and CuCN (19.7g, 220mmol) in 200ml of N-methyl-2-pyrrolidinone are stirred at reflux (~200°C) for overnight, and cooled to room temperature. The dark mixture is slowly added to 1800ml of Et2O with vigorous stirring. Dark sticky oil at the bottom is discarded and the upper cloudy solution (2000ml) is washed consecutively with brine (200ml), 1M NaOH (200ml) and brine (2x200ml), dried over Na2SO4, then evaporated to dryness to give ~20g of yellow solids, methyl 2-amino-5-cyanobenzoate. Yield for crude product: 52%.
A mixture of methyl 2-amino-5-cyanobenzoate (8.2g), PtO2 (400mg) and 20ml of concentrated HCl in 50ml of MeOH is shaken under 45psi of hydrogen for overnight. The mixture is filtered through celite, then evaporated under high vacuum. The resulting semi- solid residue is dissolved in 200ml of MeOH and cooled to 0°C. Et3N (20ml, 144mmol) and Boc2O (20g, 92mmol) are added. The mixture is allowed to warm to room temperature and heated to 45°C. Stirring is continued at 45°C for 0.5 hour. The clear solution is cooled to room temperature, concentrated, partitioned between ethyl acetate (250ml) and water (100ml). Organic layer is washed again with water (100ml), dried over Na2SO4, concentrated and purified by chromatography on a silica gel column. Elution with 10-20% ethyl acetate/hexanes and evaporation yields methyl 2-amino-5-(Boc-aminomethyl)benzoate, as a light yellow oil. Yield: 7.0g, 54%. 1H NMR (300MHz, CDC13): 7.78ppm (d, IH, J=1.87Hz, Ar-H), 7.24 (bd, IH. J=7.47Hz, Ar-H), 6.66 (d, IH, J=8.50Hz, Ar-H), 5.72 (br, 2H, -NH2), 4.75 (br, IH, Boc-NH-), 4.20 (d, 2H, J=5.39Hz, -CH2-), 3.89 (s, 3H, -OCH3), 1.48 (s, 9H, - C(CH3)3).
Under nitrogen flow, reagents and solvents are added into a flame-dried 100ml two-neck round bottom flask in the following order: Cs2CO3 (812mg, 2.49mmol), Pd2(dba)3 (20.4mg, 0.022mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (26.4mg, 0.067mmol), 20ml of anhydrous toluene, 3-bromo-4-nitrobenzotrifluoride (500mg, 1.85mmol), and methyl 2-amino-5-(Boc-aminomethyl)benzoate (500mg, 1.78mmol). The purple mixture is capped with septum and heated at ~100°C under nitrogen, which turns from purple to light yellow within 10 minutes. Heating and stirring are continued for overnight. The resulting brown mixture is cooled to room temperature, filtered through celite and washed with THF (~20ml). The filtrate solution is concentrated and chromatographed through a silica gel column with 10-15% EtOAc/hexanes. Orange yellow band is collected and concentrated to give orange crystals of methyl 5-{ [(tert-butoxycarbonyl)amino]methyl}-2- { [2-nitro-5-(trifluoromethyl)phenyl]amino}benzoate. Yield: ~180mg (22%). ESI-: 468.0 (M-H)-. 1H NMR (300MHz, CDC13): 11.22ppm (s, IH, Ar-NH-Ar), 8.30 (d, IH, J=8.67Hz, Ar-H), 8.01 (s, IH, Ar-H), 7.84 (s, IH, Ar-H), 7.48 (s, 2H, Ar-H), 7.15 (dd, IH, J-l=8.66Hz, J-2=1.69Hz, Ar-H), 4.95 (br, IH, Boc-NH-), 4.35 (d, 2H, J=5.46Hz, -CH2-), 3.98 (s, 3H, - OCH3), 1.50 (s, 9H, -C(CH3)3).
A mixture of methyl 5-{ [(tert-butoxycarbonyl)amino]methyl}-2-{[2-nitro-5-
(trifluoromethyl)phenyljamino} benzoate (90mg, 0.19mmol), PtO2 (lOmg) in 10ml of MeOH is shaken under 30psi of hydrogen for 1 hour. The colorless mixture is filtered through celite, evaporated, dried in vacuo to give methyl 2-{ [2-amino-5-(trifluoromethyl)phenyl]amino}-5- { [(tert-butoxycarbonyl)amino] methyl} benzoate as a light purple solid. Yield: 84mg, -100%. ESI+: 384.1 (M+H-(CH3)3CH)+. Η NMR (300MHz, CDC13): 8.98ppm (s, IH, Ar-NH-Ar), 7.91 (d, IH, J=1.88Hz, Ar-H), 7.40 (s, IH, Ar-H), 7.35 (d, IH, J=9.79Hz, Ar-H), 7.25 (br, 2H, -NH2), 6.86 (d, IH, J=8.66Hz, Ar-H), 6.60 (d, IH, J=8.66Hz, Ar-H), 4.79 (br, IH, Boc- NH-), 4.23 (d, 2H, J=5.65Hz, -CH2-), 3.94 (s, 3H, -OCH3), 1.48 (s, 9H, -C(CH3)3).
Under nitrogen flow, reagents and solvents are added into a flame-dried 100ml two-neck round bottom flask in the following order: Cs2CO3 (83mg, 0.25mmol), Pd2(dba)3 (2.0mg, 0.0022mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (2.7mg, 0.0069mmol), 10ml of anhydrous toluene, methyl 2-bromobenzoate (47mg, 0.22mmol), and methyl 2-{ [2-amino-5-(trifluoromethyl)phenyl]amino}-5-{ [(tert- butoxycarbonyl)amino]methyl}benzoate (80mg, O.lδm ol). The pu le mixture is capped with septum and heated at ~100°C under nitrogen, which turns from purple to almost colorless within 10 minutes. Heating and stirring are continued for overnight. The resulting brown mixture is cooled to room temperature, filtered through celite and washed with THF (20ml). The filtrate solution is concentrated and chromatographed through a silica gel column with 10-20% EtOAc/hexanes to yield methyl 5-{ [(tert-butoxycarbonyl)amino]methyl}-2-{ [2- {[2-(methoxycarbonyl)phenyl]amino}-5-(trifluoromethyl)phenyl]amino}benzoate as a light yellow oil. Yield: ~70mg (67%). ESI-: 572.0 (M - H)-. 1H NMR (300MHz, CDC13): 9.47ppm (s, IH, NH), 9.30 (s, IH, NH), 7.96 (dd, IH, J-l=7.91Hz, J-2=1.51Hz, Ar-H), 7.89 (d, IH, J=2.07Hz, Ar-H), 7.64 (d, IH, J=1.51Hz, Ar-H), 7.56 (d, IH, J=8.48Hz, Ar-H), 7.40- 7.26 (m, 4H, Ar-H), 6.99 (d, IH, J=8.67Hz, Ar-H), 6.85 (t, IH, J=7.54Hz, Ar-H), 4.80 (br, IH, Boc-NH-), 4.23 (d, 2H, J=5.65Hz, -CH2-), 3.87 (s, 3H, -OCH3), 3.83 (s, 3H, -OCH3), 1.48 (s, 9H, -C(CH3)3).
To a stirred solution of methyl 5-{ [(tert-butoxycarbonyl)amino]methyl}-2-{[2-{ [2- (methoxycarbonyl)phenyl]amino}-5-(trifluoromethyl)phenyl]amino}benzoate (70mg, 0.122mmol) in a mixture of THF (2ml) and MeOH (2ml), is added 1ml of 3N NaOH solution. The mixture is heated at reflux for one hour, cooled to room temperature, and evaporated under reduced pressure until no organic solvents are left. The resulting mixture is diluted with 5ml of water, acidified with concentrated HCl until pH < 3. Precipitates are filtered, washed with H2O, dried in vacuo, to afford 60mg of gray powder (the di-acid), which is dissolved in lml of 1,4-dioxane, treated with 4M HCl solution in 1,4-dioxane (2ml) for 1 hour. The clear solution is concentrated to dryness, redissolved in 2ml of EtOH and added dropwise into 100ml of hexanes with vigorous stirring. The resulting precipitates are filtered, washed with hexanes and dried in vacuo to yield 5-aminomethyl-2-[2-(2-carboxy-phenylamino)-5- trifluoromethyl-phenylamino]- benzoic acid hydrochloride as a light brown powder. Yield: 42mg, 71%. ESI-: 443.9 (M - H )-. 1H NMR (300MHz, d6-DMSO): 13.19ppm (br, 2H, -COOH), 9.96 (s, IH, NH), 9.63 (s, IH, NH), 8.09 (br, 3H, -NH3 +), 8.03 (d, IH, J=2.07Hz, Ar-H), 7.90 (dd, IH, J-l=7.91Hz, J- 2=1.32Hz, Ar-H), 7.70 (d, IH, J=8.48Hz, Ar-H), 7.63 (s, IH, Ar-H), 7.53-7.37 (m, 4H, Ar- H), 6.93-6.87 (m, 2H, Ar-H), 3.93 (q, 2H, J=4.90Hz, -CH2-).
Example 7
Other non-limiting examples of compounds of this invention include: i. 5-(aminomethyl)-2-{ [2-[(2-carboxyphenyl)amino]-4-chloro-5-
(trifluoromethyl)phenyl] amino} benzoic acid hydrochloride; ii. (3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl]amino}phenyl)-N-(4-hydroxybenzyl)methanaminium chloride; iii. (3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl] amino } phenyl)-N- [4-
(dimethylamino)benzyl]methanaminium chloride; iv. (3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl] amino } phenyl)-N-(4-chlorobenzyl)methanaminium chloride; v. (3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl] amino } phenyl)-N-(pyridin-3-ylmethyl)methanaminium chloride hydrochloride; vi. (3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl] amino } phenyl)-N-[( 1 -methyl- 1 H-pyrrol-2- yl)methyl]methanaminium chloride; vii. 2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-({ [(2,4- dioxo-1 ,2,3,4-tetrahydropyrimidin-5-yl)methyl]amino }methyl)benzoic acid; Vlll. (3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl]amino}phenyl)-N-(4-methoxybenzyl)methanaminium chloride;
IX. 2-{[2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-{ [(2- furylmethyl)amino] methyl } benzoic acid;
X. (2S)-l-[(3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl] amino } benzyl)amino] -4-(methylsulf inyl)- 1 -oxobutan-2 - aminium chloride;
XI. 2-{[2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-
[(isobutylamino)methyl]benzoic acid;
Xll. 5-(aminomethyl)-2-{ [2-[(2-carboxyphenyl)thio]-5-
(trifluoromethyl)phenyl] amino } benzoic acid;
Xlll. 2-{[2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-[(l,3- dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)methyl]benzoic acid;
XIV. 2-{[2-[(2-carboxy-4-cyanophenyl)amino]-4-(trifluoromethyl)phenyl]amino}-5- cyanobenzoic acid;
XV. (3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl]amino}phenyl)methanaminium;
XVI. 2-{[2-[(2-carboxyphenyl)amino]-4-(trifluoromethyl)phenyl]amino}-5- cyanobenzoic acid;
XV11. 2-{[2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5- cyanobenzoic acid;
XVUl. N-(3-carboxy-4-{[2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl]amino}benzyl)-L-phenylalaninamide chloride;
XIX. 2-{ [2-[(2-carboxyphenyl)amino]-4-chloro-5-
(trifluoromethyl)phenyl] amino} benzoic acid;
XX. 2-{[2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-
(morpholin-4-ylmethyl)benzoic acid;
XXI. 2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-
({ [(ethylamino)carbonyl]amino}methyl)benzoic acid; xxu. 2- { [2- [(2-carboxyphenyl)amino] -5-(trifluoromethyl)phenyl]amino } -5-( { [(2S)-2- amino-3-thien-2-ylpropanoyl]amino }methyl)benzoic acid; XUl. 4-[(3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5- (trifluoromethyl)phenyl]amino}benzyl)ammonio]piperidinium dichloride; xxiv. 5-(aminomethyl)-2-{ [2-[(2-carboxyphenyl)amino]-4- (trifluoromethyl)phenyl] amino} benzoic acid hydrochloride; xxv. 5-(aminomethyl)-2- { [2-(2-carboxyphenoxy)-5- (trifluoromethyl)phenyl] amino} benzoic acid hydrochloride; xxvi. 1 2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-[(l- oxidothiomoφholin-4-yl)methyl]benzoic acid; xxvii. 5-(2-aminoethyl)-2-{[2-[(2-carboxyphenyl)amino]-4- (trifluoromethyl)phenyl] amino} benzoic acid hydrochloride; xxviii. 2-{[2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5- (piperazin-l-ylmethyl)benzoic acid hydrochloride; xxix. N-(3-carboxy-4- { [2-[(2-carboxyphenyl)amino]-5- (trifluoromethyl)phenyl]amino}benzyl)-L-tryptophanamide chloride; xxx. 2- { [2- [(2-carboxyphenyl)amino] -5-(trifluoromethyl)phenyl] amino } -5- (pyrrolidin-l-ylmethyl)benzoic acid; xxxi. 2-{ [2-[(2-carboxyphenyl)amino]-4-(trifluoromethyl)phenyl]amino Jbenzoic acid; xxxii. 5-({ [amino(imino)methyl]amino}methyl)-2-{ [2-[(2-carboxyphenyl)amino]-5- (trifluoromethyl)phenyl] amino Jbenzoic acid; xxxiii. 2-( { 2-[(2-carboxyphenyl)amino]-4,5-dimethylphenyl } amino)benzoic acid; xxxiv. 2-({4-tert-butyl-2-[(2-carboxyphenyl)amino]phenyl}amino)benzoic acid; xxxv. 2-({2-[(2-carboxyphenyl)amino]-4,5-dichlorophenyl}amino)benzoic acid; xxxvi. 2- { [2-[(2-carboxyphenyl)amino]-4-(propylthio)phenyl]amino Jbenzoic acid; xxxvii. (3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]- amino}phenyl)-N,N-bis(cyclopropylmethyl)methanaminium chloride;
(xxviii. 5-(2-aminoethyl)-2-{ [2-[(2-carboxyphenyl)amino]-5- (trifluoromethyl)phenyl]amino}benzoic acid hydrochloride; xxxix. 2-{[2-[(2-carboxyphenyl)amino]-4-(trifluoromethoxy)phenyl]amino Jbenzoic acid; xl. 2-({2-[(2-carboxyphenyl)amino]-4-methylphenyl}amino)benzoic acid; xli. N-(3-carboxy-4-{[2-[(2-carboxyphenyl)amino]-5- (trifluoromethyl)phenyl] amino }benzyl)-L-tyrosinamide chloride; xlϋ. 2-( { 2-[(2-carboxyphenyl)amino]-4-chlorophenyl } amino)benzoic acid; xliii. (3-carboxy-4-{[2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]- amino } phenyl)-N-(4-hydroxy-3-methoxybenzyl)methanaminium chloride; xliv. N,N'-bis[2-(lH-tetrazol-5-yl)phenyl]benzene-l,2-diamine xlv. [3-carboxy-4-( { 2-[(2-carboxyphenyl)amino]phenyl } amino)- phenyl]methanaminium chloride; xlvi. 2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-{ [(3- furylmethyl)amino] methyl Jbenzoic acid; xlvii. 2-({2-[(2-carboxyphenyl)amino]-3-methylphenyl}amino)benzoic acid; xlviii. 2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5- [(dibenzylamino)methyl]benzoic acid; xlix. 2-({2-[(2-carboxyphenyl)amino]phenyl}amino)-5-nitrobenzoic acid; 1. 2-({2-[(2-carboxyphenyl)amino]-3,5-dichlorophenyl}amino)benzoic acid; li. 2-({2-[(2-carboxyphenyl)amino]phenyl}amino)-5-cyanobenzoic acid; Iii. 2-({2-[(2-carboxyphenyl)amino]-4-fluorophenyl}amino)benzoic acid; liii. 5-(Benzylamino-methyl)-2-[2-(2-carboxy-phenylamino)-5-trifluoromethyl- phenylamino] -benzoic acid; liv. 3-carboxy-4-( { 2-[(2-carboxyphenyl)amino]phenyl } amino)benzenaminium chloride; lv. N,N'-bis[2-(lH-tetrazol-5-yl)phenyl]benzene-l,2-diamine, disodium salt; lvi. 2-({2-[(2-carboxyphenyl)amino]-4-cyanophenyl}amino)benzoic acid; lvii. 2-({2-[(2-carboxyphenyl)amino]phenyl}amino)-4,5-difluorobenzoic acid; lviii. N,N'-bis[2-(carboxyphenyl]benzene-l,2-diamine lix. 2-({2-[(2-carboxyphenyl)amino]phenyl}amino)-4-fluorobenzoic acid; lx. 2-({2-[(2-carboxyphenyl)amino]phenyl}amino)-5-methoxybenzoic acid; lxi. 2-( { 2-[(2-carboxyphenyl)amino]-4-methoxyphenyl } amino)benzoic acid; lxii. 2-{ [2-[(2-carboxyphenyl)amino]-4-(propylsulfinyl)phenyl]amino}benzoic acid; lxiii. 2- { [2-[(2-carboxyphenyl)amino]-4-(propylsulfonyl)phenyl]amino }benzoic acid; lxiv. 5-({ [(benzylamino)carbonyl] amino }methyl)-2-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl]amino Jbenzoic acid; lxv. 2-{ [2-(2-carboxyphenoxy)-5-(trifluoromethyl)phenyl]amino}benzoic acid; lxvi. 2- { [2-(2-carboxyphenoxy)phenyl]amino Jbenzoic acid; lxvii. 2-({ [2-{ [4-(aminomethyl)phenyl]amino}-5-
(trifluoromethyl)phenyl]amino}carbonyl)-4,5-dichlorobenzoic acid hydrochloride
Compound Method 1H NMR
No. LRMS HRMS Ion
Η NMR (300MHz, d8-THF): 12-1 lppm, (br, 2H), 10.03 (s, 1H), 9.77 (s, IH), 8.20 (d, IH), 7.89 (dd, IH), 7.54 (dd,
444 (M-H)- IH), 7.46-7.36 (m, 2H), 7.29-7.23 (m, 2H), 7.16-7.11 (m, 2H), 6.82 (d, 1H), 6.69 (t, IH).
IH NMR (300MHz, d6-DMSO): 12.23ppm (br, 2H), 9.66 (s, IH), 9.61 (br, IH), 8.1-7.9 (overlapping (bs,), (d, ), xlv. combined integration 4H), 7.85 (dd, IH), 7.49-7.30 (m, 377.1396 M+ 4H), 7.21-7.17 (m, 2H), 7.02 (t, 2H), 6.74 (t, 1H), 3.92 (q, 2H).
IH NMR (300MHz, d8-THF): 11.35ppm, (br, 2H), 9.82 (s, lix. IH), 9.72 (s, IH), 7.88-7.96 (m, 2H), 7.7.39-7.50 (m, 2H), 367 (M+H)+ 7.05-7.24 (m, 4H); 6.55-6.69 (m, 2H), 6.34 - 6.40 (m, IH)
IH NMR (300MHz, d8-THF): 11.50ppm, (br, 2H), 9.69 (s, IH), 9.58 (s, IH), 7.87-7.90 (m, IH), 7.70-7.77 (m, IH), lvii. 385 (M+H)+ 7.47-7.49 (d, I H), 7.36-7.39 (d, IH), 7.05-7.27 (m, 4H); 6.63-6.70 (m, 2H)
Η NMR (400 MHz, DMSO-^) G 6.82 (t, J = 5.7 Hz, 2 H), xxxv. 7.06 (d, J = 6.3 Hz, 2 H), 7.39 (m, 2 H), 7.65 (s, 2 H), 7.86 415 (M-H)" (dd, J = 1.3, 7.9 Hz, 2 H), 9.65 (s, 2 H), 13.09 (s, 2 H).
Η NMR (400 MHz, OMSO-d6) D 6.28 (d, J = 8.0 Hz, 1 H), 6.72 (m, 1 H), 6.91 (m, 1 H), 7.23 (m, 1 H), 7.34 (d, J =
417 (M+H)+
2.2 Hz, 1 H), 7.50 (m, 3 H), 7.85 (m, 2 H), 9.31 (s, 1 H), 10.01 (s, l H), 13.10 (m, 2 H).
Η NMR (400 MHz, DMSO-d6) D 0.99 (t, J = 7.3 Hz, 3 H), 1.61 (m, 2 H), 2.93 (t, J = 7.3 Hz, 2 H), 6.74 (m, 2 H), 6.96- xxxvi. 7.03 (m, 2 H), 7.11 (dd, J = 1.9, 8.3 Hz, 1 H), 7.36 (m, 4 421 (M-H)" H), 7.84 (m, 2 H), 9.54 (s, 1 H), 9.59 (s, 1 H), 12.97 (bs, 2 H).
Η NMR (400 MHz, DMSO-^) D 6.77 (m, 1 H), 6.83 (m, 1 H), 6.94 (d, J = 8.5 Hz, 1 H), 7.12 (m, 2 H), 7.35 (m, 1 xxxix. 433 (M+H)+ H), 7.41 (m, 2 H), 7.52 (d, J = 8.7 Hz, 1 H), 7.87 (m, 2 H), 9.56 (s, 1 H), 9.78 (s, 1 H), 13.05 (bs, 2 H).
Η NMR (400 MHz, CD3OD) D 6.81 (m, 1 H), 6.90 (d, J = 8.3 Hz, 1 H), 6.95 (m, 1 H), 7.34 (m, 1 H), 7.42 (d, J = 8.3
XIX. 449 (M-H)" Hz, 1 H), 7.49 (m, 1 H), 7.66 (s, 1 H), 7.69 (s, 1 H), 8.00 (m, 2 H). Η NMR (400 MHz, DMSO-^) D 6.77 (m, 2 H), 6.99 (d, J xliv. = 8.3 Hz, 2 H), 7.35 (m, 2 H), 7.45 (m, 2 H), 7.84 (d, J = 383 (M-H)" 7.1 Hz, 2 H), 9.56 (s, 2 H), 13.02 (bs, 2 H).
IH NMR (400 MHz, DMSO-d6)0.94 (t, J = 7.4 Hz, 3 H), 1.59 (m, 2 H), 3.26 (m, 2 H), 6.82 (m, 1 H), 6.88 (d, J = 8.3 Hz, 1 H), 6.95 (m, 1 H), 7.38 (m, 1 H), 7.49 (m, 2 H), 7.61
Ixiii. 453 (M-H)" (dd, J = 2.0, 8.5 Hz, 1 H), 7.72 (d, J = 8.6 Hz, 1 H), 7.78 (d, J = 2.0 Hz, 1 H), 7.91 (m, 2 H), 9.62 (s, 1 H), 10.08 (s, 1 H), 13.19 (bs, 2 H).
IH NMR (400 MHz, DMSO-d6) D 0.98 (t, J = 7.4 Hz, 3 H), 1.54 (m, 1 H), 1.66 (m, 1 H), 2.80 (m, 1 H), 2.93 (m, 1 lxii. H), 6.82 (m, 2 H), 7.00 (d, J = 8.2 Hz, 1 H), 7.21 (d, J = 8.3 439 (M+H)+ Hz, 1 H), 7.40 (m, 3 H), 7.67 (m, 2 H), 7.89 (m, 2 H), 9.70 (s, 1 H), 9.83 (s, 1 H), 13.10 (bs, 2 H)
Η NMR (400 MHz, OMSO-d6) D 1.30 (s, 9 H), 6.70 (m, 2 H), 6.95 (m, 2 H), 7.21 (dd, 7 = 2.1 , 8.4 Hz, 1 H), 7.31 (m,
XXXIV. 405 (M+H)+ 2 H), 7.38 (d, J = 8.2 Hz, 1 H), 7.44 (d, J = 2.1 Hz, 1 H), 7.83 (m, 2 H), 9.49 (s, 1 H), 9.55 (s, 1 H), 12.90 (bs, 2 H).
Η NMR (400 MHz, OMSO-d6) d 2.78 (t, 2 H), 2.98 (m, 2 H), 6.89 (m, 2 H), 7.30 (m, 2 H), 7.45 (m, 2 H), 7.66 (m, 2
460.1502 (M+H)+ H), 7.78 (m, 1 H), 7.85-7.91 (m, 4 H), 9.55 (s, 1 H), 9.90 (s, I H), 13.14 (br s, 2 H).
Η NMR (400 MHz, DMSO-d6) D 3.92 (s, 2 H), 6.79 (dd, 1 H), 6.95 (d, 1 H), 7.29-7.36 (m, 2 H), 7.40-7.46 (m, 2 H),
XXIV. 445.1251 (M+H)+ 7.59 (d, 1 H), 7.64 (s, 1 H), 7.90 (dd, 1 H), 8.06 (dd, 1 H), 8.33 (br s, 2 H) 9.95 (s, 1 H), 10.6 (s, 1 H).
Η NMR (400 MHz, DMSO d6) G 12.93 (bs, 2H), 10.30 (s, IH), 9.76 (s, IH), 8.04 (s, IH), 7.86 (m, IH) 7.64 (m, 3H),
XXX. 500 (M+H)+ 7.41 (m, 2H), 7.29 (m, IH), 6.84 (m, 2H), 4.18 (s, 2H), 3.30 (bs, 2H), 3.12 (bs, 2H), 1.89 (s, 4H).
Η NMR (400 MHz, DMSO-^s) d 2.83 (t, 2 H), 2.99 (m, 2 H), 6.81 (m, 2 H), 7.37 (m, 3 H), 7.49 (d, 1 H), 7.65 (m, 2 xvu. 460.1483 (M+H)+ H), 7.78 (s, 1 H), 7.90 (dd, 1 H), 8.02 (br s, 3 H) 9.55 (s, 1 H), 9.90 (s, 1 H), 13.10 (br s, 1 H), 13.3 (br s, 1 H).
Η NMR (400 MHz, CDC13) D 6.84 (dd, 1 H), 7.06 (m, 2 H), 7.35-7.43 (m, 2 H), 7.52 (m, 2 H), 7.77 (s, 1 H), 7.93 440 (M-H)- (dd, 1 H), 8.22 (d, 1 H), 9.45 (s, 1 H), 9.88 (s, 1 H)
Η NMR (400 MHz, DMSO d6) D 13.17 (bs, 2H), 9.95 (m, xvu 2H), 8.19 (s, IH), 7.86 (s, IH), 7.70 (m, 2H), 7.61 (m, 2H), 442 (M+H)+ 7.45 (m, 2H), 6.90 (s, IH), 6.67 (IH)
Η NMR (400 MHz, DMSO d6) G 13.29 (bs, IH), 10.05 (bs, IH), 9.88 (s, IH), 9.68 (s, IH), 8.03 (s, IH), 7.85 (m,
516 (M+H)+ IH), 7.66 (m, 2H), 7.43 (m, 4H), 6.84 (m, 2H), 4.20 (s, 2H), 3.90 (bs, 2H), 3.62 (bs, 2H), 3.26 (bs, 2H), 3.02 (bs, 2H) Η NMR (400 MHz, DMSO d6) G 13.30 (bs, IH), 11.25 (bs, IH), 9.89 (s, IH), 9.66 (s, IH), 9.27 (s, IH), 8.03 (s, Vlll. IH), 7.86 (m, IH), 7.66 (m, IH), 7.63 (m, IH), 7.44 (m, 515 (M+H)+ 4H), 6.85 (m, 2H), 4.24 (m, 2H), 3.55 (bs, 4H), 3.37 (bs, 4H).
Η NMR (400 MHz, DMSO d6) D 13.00 (s, 3H), 9.90 (s,
Xlll. 1 IH), 9.51 (s, IH), 8.74 (m, IH), 7.87 (m, IH), 7.70 (m, IH), 594 (M+H)+ 7.62 (m, 2H), 7.41 (m, 8H), 6.89 (m, 2H), 4.30 (m, 2H).
Η NMR (400 MHz, OMSO-d6) D 3.92 (d, 2 H), 6.98 (t, 1 I H), 7.40-7.58 (m, 3), 7.69 (d, 2 H), 7.90 (dd, 1 H), 8.03 (d, 481 (M+H)+ 1 H), 8.20(s, 3 H).
Η NMR (400 MHz, DMSO d6) G 10.63 (bs, 2H), 9.89 (s, IH), 9.42 (s, IH), 8.08 (s, IH), 7.86 (m, IH), 7.67 (m, 2H),
548 (M+H)+ 7.47 (m, 3H), 7.35 (m, 1 H), 6.88 (m, IH), 6.81 (m, IH), 4.29 (bs, 2H), 3.40 (bs, 8H)
Η NMR (400 MHz, DMSO d6) D 13.05 (bs, I H), 10.23 (s, IH), 9.89 (s, IH), 9.68 (s, IH), 8.00 (s, IH), 7.79 (m, IH), xlviii. 2a 626 (M+H)+
7.65 (m, 2H), 7.30 (m, 14H), 6.78 (m, 2H), 4.20 (s, 4H), 3.39 (s, 2H).
Η NMR (400 MHz, DMSO d6) G 13.11 (bs, 2H), 9.92 (s, IH), 9.66 (s, IH), 9.18 (bs, 2H), 8.08 (s, IH), 7.89 (m, IH), liii. 2a 536 (M+H)+ 7.68 (m, 2H), 7.43 (m, 8H), 6.90 (m, 2H), 4.14 (s, 2H), 4.10 (s, 2H).
Η NMR (400 MHz, DMSO d6) D 13.14 (bs, 2H), 9.89 (s, IH), 9.62 (s, IH), 8.56 (m, IH), 8.05 (s, IH), 7.86 (m, IH),
XI. 2a 7.66 (m, IH), 7.62 (m, IH), 7.47 (m, 3H), 7.36 (m, 2H), 502 (M+H)+ 6.86 (m, 2H), 4.02 (m, 2H), 2.68 (m, 2H), 1.92 (m, IH), 0.90 (m, 3H).
Η NMR (400 MHz, DMSO d6) D 13.05 (bs, 2H), 11.37 (bs, IH), 11.25 (bs, IH), 10.10 (bs, IH), 9.71 (s, IH), 8.03 vii. 2a (s, IH), 7.86 (m, IH), 7.65 (m, IH), 7.60 (m, IH), 7.47 (m, 570 (M+H)+
IH), 7.40 (m, 2H), 7.33 (m, IH), 6.85 (m, 2H), 6.48 (s, IH), 4.00 (m, 3H), 3.67 (s, 2H)
Η NMR (400 MHz, DMSO d6) G 13.78 (bs, IH), 12.53 (bs, IH), 9.97 (s, IH), 9.63 (s, IH), 8.07 (s, IH), 7.87 (m, xxiii. 2a IH), 7.66 (m, IH), 7.66 (m, IH), 7.61 (s, IH), 7.47 (m, 4H), 529 (M+H)+
7.36 (m, 2H), 6.87 (m, 2H), 4.05 (s, 2H), 3.29 (m, 2H), 2.77 (m, 3H), 2.19 (m, 2H), 1.71 (m, 2H).
IH NMR (400 MHz, DMSO d6) d IH NMR (400 MHz, DMSO d6) d 13.02 (bs, 2H), 9.92 (s, IH), 9.69 (s, IH), 2a 9.65 (s, IH), 9.00 (bs, 2H), 8.06 (s, IH), 7.89 (m, IH), 7.70 552 (M+H)+ (m, 2H), 7.47 (m, 3H), 7.27 (m, 2H), 6.89 (m, 2H), 6.81 (m, 2H), 4.01 (m, 4H). IH NMR (400 MHz, DMSO d6) d IH NMR (400 MHz, DMSO d6) d 13.11 (bs, 2H), 9.92 (s, IH), 9.66 (s, IH), 9.26 (bs, IH), 8.07 (s, IH), 7.89 (m, IH), 7.79 (s, IH), 7.70
IX. 2a 526 (M+H)+ (m, IH), 7.60 (s, IH), 7.50 (m, 3H), 7.39 (m, IH), 6.92 (m, 2H), 6.61 (m, IH), 6.54 (m, IH), 4.21 (bs, 2H), 4.07 (bs, 2H).
IH NMR (400 MHz, DMSO d6) d 13.14 (bs, 2H), 9.92 (s, IH), 9.66 (s, IH), 9.18 (s, 2H), 8.07 (s, IH), 7.89 (m, IH), iv. 2a 570 (M+H)+ 7.67 (m, 2H), 7.49 (m, 7H), 7.39 (m, IH), 6.89 (m, 2H), 4.15 (m, 2H), 4.09 (m, 2H).
IH NMR (400 MHz, DMSO d6) d 13.17 (bs, 2H), 9.92 (s, IH), 9.65 (s, IH), 8.97 (s, 2H), 8.08 (s, IH), 7.89 (m, IH), 2a 7.67 (m, 2H), 7.49 (m, 3H), 7.39 (m, IH), 6.89 (m, 3H), 539 (M+H)+ 6.24 (s, IH), 6.02 (s, IH), 4.14 (m, 2H), 4.10 (m, 2H), 3.61 (s, 3H).
IH NMR (400 MHz, DMSO d6) d 13.19 (bs, 2H), 9.93 (s, IH), 9.65 (s, IH), 9.07 (s, 2H), 8.06 (s, IH), 7.89 (m, IH), 2a 7.70 (m, IH), 7.67 (m, IH), 7.49 (m, 3H), 7.39 (m, IH), 579 (M+H)+ 7.31 (m, 2H), 6.87 (m, 2H), 6.80 (bs, 2H), 4.00 (m, 4H), 2.93 (s, 6H).
IH NMR (400 MHz, DMSO d6) d 13.18 (bs, 2H), 9.97 (s, IH), 9.66 (s, IH), 9.24 (s, IH), 9.07 (s, 2H), 8.07 (s, IH), xliii 2a 7.89 (m, IH), 7.70 (m, IH), 7.65 (m, IH), 7.51 (m, 2H), 582 (M+H)+
7.37 (m, IH), 7.10 (m, IH), 6.85 (m, 3H), 4.02 (m, 4H), 3.79 (s, 3H).
IH NMR (400 MHz, DMSO d6) d 13.15 (bs, 2H), 9.97 (s, IH), 9.70 (s, IH), 9.49 (bs, IH), 8.10 (s, IH), 7.88 (m, IH), xxxvii. 2a 7.71 (m, 2H), 7.51 (m, 3H), 7.45 (m, IH), 6.91 (m, IH), 554 (M+H)+
6.81 (m, IH), 4.33 (m, 2H), 2.94 (m, 4H), 1.10 (m, 2H), 0.64 (m, 4H), 0.30 (m, 4H).
IH NMR (400 MHz, DMSO d6) d 13.26 (bs, 2H), 9.94 (s, IH), 9.67 (s, IH), 9.54 (bs, 2H), 8.81 (s, IH), 8.70 (m, IH), 2a 8.18 (bs, IH), 8.09 (s, IH), 7.89 (m, IH), 7.70 (m, IH), 537 (M+H)+
7.67 (m, 3H), 7.51 (m, 3H), 7.39 (m, I H), 6.90 (m, 2H), 4.26 (m, 2H), 4.13 (m, 2H).
IH NMR (400 MHz, DMSO d6) d 13.15 (bs, 2H), 9.93 (s, IH), 9.66 (s, IH), 9.08 (bs, IH), 8.07 (s, IH), 7.90 (m, IH), xlvi. 2a 7.81 (s, IH), 7.70 (m, 3H), 7.65 (s, IH), 7.50 (m, 2H), 7.39 526 (M+H)+
(m, IH), 6.92 (m, 2H), 6.65 (m, IH), 4.06 (bs, 2H), 4.01 (bs, 2H).
IH NMR (400 MHz, DMSO d6) d 13.05 (bs, 2H), 9.95 (s, IH), 9.65 (s, IH), 9.06 (bs, 2H), 8.06 (s, IH), 7.89 (m, IH),
VIH. 2a 566 (M+H)+ 7.70 (m, IH), 7.65 (m, IH), 7.47 (m, 6H), 7.00 (m, 2H), 6.89 (m, 2H), 4.07 (m, 4H), 3.78 (s, 3H). IH NMR (400 MHz, DMSO d6) d 13.02 (bs, 2H), 9.87 (s, IH), 9.53 (s, IH), 8.75 (s, IH), 8.23 (bs, 3H), 7.91 (m, IH), xviii. 2b 7.81 (m, IH), 7.68 (m, IH), 7. 63 (m, IH), 7.47 (m, 2H), 593 (M+H)+
7.27 (m, 6H), 7.06 (m, IH), 6.79 (m, 2H), 4.15 (m, 2H), 3.97 (m, IH), 3.03 (m, 2H).
IH NMR (400 MHz, DMSO d6) d 13.02 (bs, 2H), 9.91 (s, IH), 9.54 (s, IH), 8.77 (s, IH), 8.26 (bs, 3H), 7.91 (m, IH), 2b 7.84 (s, IH), 7.68 (m, IH), 7. 63 (m, IH), 7.47 (m, 2H), 599 (M+H)+ 7.35 (m, 2H), 7.19 (m, IH), 6.92 (m, 4H), 4.24 (m, 2H), 3.97 (m, IH), 3.33 (m, 2H).
IH NMR (400 MHz, DMSO d6) d 13.12 (bs, 2H), 10.99 (s, IH), 9.91 (s, IH), 9.55 (s, IH), 8.88 (s, IH), 8.11 (bs, 3H),
7.90 (m, IH), 7.84 (s, IH), 7.68 (m, 2H), 7. 63 (m, IH),
XXIX. 2b 632 (M+H)+ 7.47 (m, 2H), 7.34 (m, 2H), 7.20 (m, IH), 7.03 (m, 3H),
6.91 (m, IH), 6.85 (m, IH), 4.23 (m, 2H), 3.97 (m, IH), 3.31 (m, 2H).
IH NMR (400 MHz, DMSO d6) d 13.07 (bs, 2H), 9.90 (s, IH), 9.56 (s, IH), 9.32 (bs, IH), 8.79 (s, IH), 8.12 (bs, 3H), 7.90 (m, IH), 7.85 (s, IH), 7.67 (m, IH), 7. 64 (s, IH), xli. 2b 609 (M+H)+ 7.47 (m, 2H), 7.35 (m, IH), 7.16 (m, IH), 7.00 (m, 2H), 6.92 (m, 2H), 6.70 (m, 2H), 4.23 (m, 2H), 3.88 (m, IH), 2.96 (m, 2H).
IH NMR (400 MHz, DMSO d6) d 13.17 (bs, 2H), 9.92 (s, IH), 9.55 (s, IH), 8.95 (s, IH), 8.29 (bs, 3H), 7.91 (m, IH), x. 2b 7.87 (m, IH), 7.68 (m, IH), 7. 64 (m, IH), 7.51 (m, 2H), 593 (M+H)+
7.35 (m, 2H), 6.90 (m, 2H), 4.27 (m, 2H), 3.93 (m, IH), 2.85 (m, IH), 2.69 (m, IH), 2.54 (s, 3H), 2.17 (m, 2H).
Η NMR (400 MHz, DMSO d6) G 10.78 (bs, IH), 10.18 (bs, IH), 9.31 (bs, 2H), 7.87 (m, 2H), 7.61 (m, IH), 7.51 (s,
XXXII. 2c 488 (M+H)+ IH), 7.48 (bs, IH), 7.29 (m, 3H), 7.10 (m, IH), 6.75 (m, 2H), 4.04 (m, 2H), 3.41 (bs, 3H).
Η NMR (400 MHz, DMSO d6) G 13.02 (s, 2H), 9.88 (s, IH), 9.47 (s, IH), 7.87 (m, IH), 7.77 (s, IH), 7.61 (m, 2H),
XXI. 2c 517 (M+H)+ 7.41 (m, 2H), 7.28 (m, 2H) 6.87 (m, 2H), 6.21 (bs, IH), 5.81 (bs, IH), 4.06 (s, IH), 3.00 (m, 2H), 0.96 (m, 3H).
IH NMR (400 MHz, DMSO d6) d 13.11 (bs, 2H), 9.93 (s, IH), 9.52 (s, IH), 7.91 (m, IH), 7.84 (s,lH), 7.66 (m, 2H),
Ixiv. 2c 579 (M+H)+ 7.49 (m, IH), 7.31 (m, 8H), 6.89 (m, 2H), 6.41 (m, 2H), 4.25 (m, 2H), 4.16 (m, 2H).
Η NMR (400 MHz, OMSO-d6) G 6.88 (t, 2 H), 7.12 (d, 2 lv. H), 7.18 (m, 2 H), 7.27 (m, 2 H), 7.48 (m, 2 H), 7.80 (d, 2 397 (M+H)+ H), 9.25 (s, 2 H).
Η NMR (400 MHz, CD3OD) G 7.95 (m, 2 H), 7.36-7.41 xlii. (m, 4 H), 7.11-7.14 (m, 2 H), 6.98 (m, 1 H), 6.74-6.80 (m, 2 381 (M-H)" H) Η NMR (400 MHz, CD3OD) D 7.95 (m, 2 H), 7.36-7.41
Hi. (m, 4 H), 7.11-7.14 (m, 2 H), 6.98 (m, 1 H), 6.74-6.80 (m, 2 365 (M-H)" H)
Η NMR (400 MHz, OMSO-d6) G 9.71 (s, 1 H), 9.24 (s, 1 lxi. H), 7.82 (m, 2 H), 7.24-7.29 (m, 4 H), 7.06 (s, 1 H), 6.61- 379 (M+H)+ 6.79 (m, 4 H), 3.78 (s, 3 H)
Η NMR (400 MHz, DMSO-rf6) G 9.58 (s, 1 H), 9.44 (s, 1 H), 7.83 (d, J = 8 Hz, 2 H), 7.30 (m, 4 H), 7.06 (d, J = 8 Hz, xl. 363 (M+H)+ 1 H), 6.99 (d, J = 8 Hz, 1 H), 6.86 (d, f = 8 Hz, 1 H), 6.70 (m, 2 H), 2.32 (s, 3 H)
IH NMR (400 MHz, DMSO d6) d 6.80 (m, 1 H), 6.86 (m,
XXXI. 1 H), 6.96 (d, J = 7.8 Hz, 1 H), 7.33 (m, 2 H), 7.41 (m, 2 415 (M-H)" H), 7.65 (m, 2 H), 7.99 (m, 2 H).
Η NMR (400 MHz, CDC13) D 9.19 (s, 1 H), 8.91 (s, 1 H), 7.86 (dd, J = 23, 8 Hz, 2 H), 7.36 (d, J = 8 Hz, 1 H), 7.24 xlvii. (m, 2 H), 7.16 (m, 2 H), 7.00 (d, J = 1 Hz, 1 H), 6.69 (dt, J 391 (M+H)+ = 28, 3 Hz, 2 H), 6.32 (d, J = 8 Hz, 1 H), 3.88 (s, 3 H), 3.68 (s, 3 H), 2.24 (s, 3 H).
Η NMR (400 MHz, DMSO- s) G 8.20 (s, 2 H), 7.92 (s, 1 H), 7.90 (s, 1 H), 7.58 (s, 1 H), 7.49 (d, J = 8.09 Hz, 1 H), lvi. 372 (M-H)" 7.29 (m, 4 H), 7.05 (d, 1 H), 6.84 (m, 1 H), 6.75 (t, J = 7.67 Hz, 1 H)
Η NMR (400 MHz, OMSO-d6) G 12.86 (br s, 2 H), 9.44
XXXll. (s, 2 H), 7.81 (d, J = 6 Hz, 2 H), 7.29 (m, 2 H), 7.23 (s, 2 377.1501 (M+H)+ H), 6.91 (d, J = 8 Hz, 2 H), 6.68 (m, 2 H), 2.22 (s, 6 H)
Η NMR (400 MHz, DMSO) Q 12.95 (bs, 2 H), 9.94 (s, 1 H), 7.93 (m, 1 H), 7.91 (m, 1 ), 7.74 (m, 1 H), 7.61 (m, 1
Ixv. 418 (M+H)+ H), 7.52 (m, 1 H), 7.36 (m, 1 H), 7.35 (m, 1 H), 7.27 (m, 1 H), 7.19 (m, 1 H), 6.87 (m, 1 H), 6.73 (m, 1 H)
Η NMR (400 MHz, DMSO) D 12.80 (bs, 2 H), 9,73 (s, 1 H), 7.83 (m, 2 H), 7.50 (m, 2 H), 7.39 (m, 1 H), 7.29 (m, 1 lxvi. 350 (M+H)+ H), 7.20 (m, 1 H), 7.10 (m, 1 H), 7.0 (m, 1 H), 6.92 (m, 1 H), 6.76 (m, 1 H).
Η NMR (400 MHz, DMSO) D 13.06 (bs, 2 H), 10.00 (s, 1 H), 8.11 (bs, 2 H), 8.04 (m, 1 H), 7.91 (m, 1 H), 7.71 (m, 1
447 (M+H)+ H), 7.64 (m, 1 H), 7.54 (m, 1 H), 7.38 (m, 3 H), 7.29 (m, 1 H), 7.21 (m, 1 H), 3.95 (m 2 H)
IH NMR (400 MHz, DMSO d6) d 8.03 (s, IH), 7.79 (d,
XII. 561 (M+H)+ IH), 7.70 (m, 2H), 7.32 (m, 5H), 6.82 (d, IH), 3.92 (s, IH) Η NMR (400 MHz, DMSO-^) D 13.78 (br s, 1 H), 12.99 (br s, 1 H), 10.21 (s, 1 H), 9.66 (s, 1 H), 8.66 (s, 1 H), 8.12 (d, J = 9 Hz, 1 H), 7.85 (d, J = 8 Hz, 1 H), 7.57 (d, 7 = 8 xlix. 408 (M+H)+ Hz, 1 H), 7.48 (d, 7 = 8 Hz, 1 H), 7.36 (br m, 2 H), 7.23 (t, 7 = 8 Hz, 1 H), 7.09 (d, 7 = 8 Hz, 1 H), 6.76 (t, 7 = 7 Hz, 1 H)
Η NMR (400 MHz, DMSO-< ) D 10.00 (br s, 2 H), 9.68 (s, 1 H), 9.54 (s, 1 H), 7.84 (m, 2 H), 7.49 (d, 7 = 8 Hz, 1 liv. 364.1292 M+ H), 7.44 (d, 7 = 7 Hz, 1 H), 7.31 (m, 2 H), 7.19 (m, 2 H), 7.02 (m, 2 H), 6.75 (t, 7 = 7 Hz, 1 H)
Η NMR (400 MHz, OMSO-d6) D 12.95 (br s, 2 H), 9.58 (s, 2 H), 7.85 (d, 7 = 8 Hz, 2 H), 7.46 (m, 2 H), 7.33 (m, 2
Iviii. 349 (M+H)+ H), 7.17 (m, 2 H), 7.00 (d, 7 = 8 Hz, 2 H), 6.73 (t, 7 = 8 Hz, 2 H)
Η NMR (400 MHz, CDC13) G 9.93 (bs, 1 H), 9.83 (bs, 1 xiv. H), 8.22 (m, 2 H), 7.69 (bs, 1 H), 7.52 (m, 4 H), 7.05 (m, 1 493 (M-H)- H), 6.81 (m, 1 H), 3.84 (s, 3 H), 3.86 (s, 3 H).
IH NMR (300MHz, d8-THF): 11.33ppm, (br, 2H), 9.58 (s, IH) 9.30 (s, IH) 7.89-7.92 (m, IH), 7.35-7.45 (m, 3H), lx. 379 (M+H)+ 7.18-7.23 (m, IH); 6.91-7.11 (m, 5H), 6.61 - 6.66 (m, IH), 3.72 (s, 3H)
Η NMR (300MHz, d6-DMSO): 13.19ppm (br, 2H), 9.96 (s, IH), 9.63 (s, IH), 8.09 (br, 3H), 8.03 (d, IH), 7.90 (dd,
XV. 444 (M-H)" IH), 7.70 (d, IH), 7.63 (s, IH), 7.53-7.37 (m, 4H), 6.93- 6.87 (m, 2H), 3.93 (q, 2H).
Example 8 Evaluation of Polymerase Activity
Compounds of the present invention are evaluated for inhibition of HCV NS5b RNA dependent RNA polymerase activity in assays comprised of a suitable buffer (e.g. 20 mM Tris-HCl pH 7.6), primed or unprimed RNA templates, GTP, ATP, CTP, and UTP, MnCl or MgCl2, and reducing agent such as 10 mM dithiothreitol or 2- mercaptoethanol. The assay buffer may contain salts such as ammonium acetate, KC1, or NaCl, and nonionic or zwitterionic detergents such as Tween or CHAPS. The incorporation of nucleotides into the complementary RNA strand may be monitored by the incorporation of radiolabeled NTP (e.g. 3H labeled GTP). Suitable RNA templates for de novo initiation in the presence of 20-50 μM GTP or ATP are the homopolymers poly rC and poly rU, respectively. Heteropolymer RNA templates with 1-3 cytidine (C) bases or 1-3 uridine (U) bases at the 3' terminus of the template may also be used for de novo initiation. Primed RNA templates such as poly rC primed with oligo rG or oligo dG, and poly rA primed with oligo rU may also be used to detect polymerase activity. The primers may be any length greater than 10 bases. A biotin residue may be added to the 5' end of the template or the 5' end of the primer to capture the template and the newly synthesized, complementary strand on avidin coated spheres. One embodiment of this technology consists of a mixture of NS5b polymerase, a poly rC RNA template primed with 5' biotinylated oligo rG, 20 mM Tris HCl pH 7.6, 100 mM ammonium acetate, 10 mM dithiothreitol, 2 mM CHAPS, 1 mM MgCl2, and 150-200 nM 3H labeled GTP. Test compounds (inhibitors) may be incoφorated in the reaction mixture with up to 10% DMSO. The reaction is run for various times (1-180 minutes) at 22-37°C, and stopped by the addition of 10-140 mM EDTA. Scintillation Proximity Assay avidin-coated beads (Amersham Pharmacia Biotech) are added to capture the ds RNA product; or the reaction mixtures may be transferred to avidin coated Flash Plates (Perkin Elmer Life Sciences). The incoφoration of radiolabeled GTP into the complementary strand is measured in 96, 384, or 1536 well plates in scintillation counters such as the Wallac Microbeta and Packard TopCount.
A substantial number of the compounds exhibited IC50 values ranging from less than 1 to about 30 μM or more. In Table 2, the inhibitory activity of representative examples is provided. Activity is listed in Table 2 as +++ if the concentration for 50% inhibition is <lμM, ++ if activity is l-20μM and + if activity is >20μM.
xv. +++
xxiv. +++
XXXI. +++
xxvii. +++
xlviii. +++
txxviii. +++
xl. xlii. ++
XXX. ++
li. ++
lv. ++
xvi. ++
lxv. ++
lvii. ++
xlv. ++
Hi. ++
lix. +
lx. +
lviii. +
xii ++
xlii + xv +
xlv +
XXV +
xlviii +
xviii +
Table 2
All publications and patent applications cited in this specification are herein incoφorated by reference as if each individual publication or patent application were specifically and individually indicated to be incoφorated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for puφoses of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

What is claimed is:
1. A method for treating a viral infection comprising administering to an animal in need thereof an effective amount of a compound of Formula I:
Figure imgf000060_0001
wherein:
X is selected from the group consisting of NH, O, and S;
Z is -COOH or 5-tetrazolyl;
R2, R3 and Rt represent 1 to three substituents independently selected from the group consisting of halogen, -CN, N(R)(R'), NO2, fluoro-C.-Cg-alkyl, fluoro-Cι-C8- alkyloxy, Cι-C8-alkyl, aryl, ara-Cι-C8-alkyl, arlyoxy, ara- - -alkyloxy, -Cι-C8- alkylthio, arylthio, and hetero-Cι-C8-alkyl;
R and R' are independently H or Cτ-C8 alkyl;
R and R' may be taken together to form a 3 to 7 membered ring optionally containing an additional heteroatom of -O-, -NR-, -S- or -SO-; Ri is selected from the group consisting of H, -CN, and -(CH2)n-N(R5)R6;
R5 is H or Cι-C6 alkyl;
R6 is selected from the group consisting of H, Cι-C alkyl, -CN, -C(=NH)NH2, aryl, substituted aryl, ara-Cr -alkyl, heteroaryl, heteroara-Cι-C8-alkyl, hetero-Cι-C8- alkyl, substituted hetero-Cτ-C8-alkyl, and C(O)A; A is selected from the group consisting of Cι-C8 alkyl, aryl, substituted aryl, ara-Ci-
Cg-alkyl, heteroaryl, heteroara-Cι-C8-alkyl, hetero-Cj-C8-alkyl and substituted hetero-
CrC8-alkyl; R5 and R6 may be joined together to form a 5 to 7 membered ring optionally containing an additional heteroatom of -NR-, -O-, -S- or -SOn-; Each n is independently 0, 1 or 2.
2. The method of Claim 1, wherein said viral infection is hepatitis infection.
3. The method of Claim 1, wherein said viral infection is hepatitis C virus infection.
4. The method of Claim 1, wherein: X is NH;
Z is -COOH;
R2 is H;
R3 and Rt represent 1 to three substituents independently selected from the group consisting of halogen, -CN, N(R)(R'), -NO2, fluoro-Cι-C8-alkyl, fluoro-Q-Cg- alkyloxy, -Cι-C8-alkyl, aryl, ara-C] -C8-alkyl, - -Cg-alkoxy, arlyoxy, ara-Ct-Cg- alkyloxy, -Cι-C8-alkylthio, arylthio, and hetero-CrC8-alkyl;
R and R' are independently H or -Cg alkyl;
R and R' may be taken together to form a 3 to 7 membered ring optionally containing an additional heteroatom of -O-, -NR-, -S- or -SO-; R] is selected from the group consisting of H, -CN, and -(CH2)n-N(R5)R6;
R5 is H or CrC8 alkyl;
Rό is selected from the group consisting of H, Cι-C8 alkyl, -CN, -C(=NH)NH2, aryl, substituted aryl, ara- - -alkyl, heteroaryl, heteroara- -Cg-alkyl, hetero- -Cr alkyl, substituted hetero-Cι-C8-alkyl, and C(O)A; A is selected from the group consisting of Cι-C8 alkyl, aryl, substituted aryl, ara- -
C8-alkyl, heteroaryl, heteroara- -Cs-alkyl, substituted heteroara-Cτ-C8-alkyl, hetero-
C Cg-alkyl and substituted hetero- -Cg-alkyl;
R5 and R6 may be joined together to form a 5 to 7 membered ring optionally containing an additional heteroatom of -NR-, -O-, -S- or -SO„-; Each n is independently 0, 1 or 2.
5. The method of Claim 4 wherein: R2 is H; R3 and Rt represent 1 to three substituents independently selected from the group consisting of halogen, fluoro-Cι-C8-alkyl, -Cι-C8-alkyl, -Cι-C8-alkyloxy, ara-Cι-C8- alkyloxy, -CpCg-alkylthio, arylthio, and hetero-Ci-Cg-alkyl; Ri is selected from the group consisting of -(CH2)n-N(R5)R6; R5 is H or Q-Cg alkyl;
R6 is selected from the group consisting of H, C Cg alkyl, -CN, -C(=NH)NH , aryl, substituted aryl, ara-Ci-Cg-alkyl, heteroaryl, heteroara- -Cg-alkyl, hetero-Cι-C8- alkyl, substituted hetero- -Cs-alkyl, and C(O)A; A is selected from the group consisting of Q-Cg alkyl, aryl, substituted aryl, ara- - Cg-alkyl, heteroaryl, hetero- -Cg-aralkyl, substituted heteroara-Ci -Cg-alkyl, hetero- CrC8-alkyl and substituted hetero- -Cg-alkyl;
R5 and R may be joined together to form a 5 to 7 membered ring optionally containing an additional heteroatom of -NR-, -O-, -S- or -SOn-; Each n is independently 0, 1 or 2.
6. A method for treating a viral infection comprising administering, to an animal in need thereof, an effective amount of 1-3 compounds of Formula 1 in combination with other antiviral agents which are either therapeutic or prophylactic agents.
7. The method of Claim 6, wherein the other antiviral agents are interferon alfa-2b, interferon alfa-2a, interferon alfacon-1 and ribavarin.
8. The method of Claim 6, wherein the other antiviral agent is interferon alfa-2b, interferon alfa-2a, or interferon alfacon-1.
9. The method of Claim 6, wherein the other antiviral agent is ribavarin.
10. A compound of Formula 1 wherein:
Figure imgf000063_0001
wherein:
X is selected from the group consisting of NH, O, and S;
Z is -COOH or 5-tetrazolyl;
R2, R3 and * represent 1 to three substituents independently selected from the group consisting of halogen, -CN, N(R)(R), NO2, fluoro-CrC8-alkyl, fluro-C C8-alkyloxy, Cι-C8-alkyl, aryl, ara-Ci -Cg-alkyl, arlyoxy, ara-Ci-Cg-alkyloxy, -Ci -Cg-alkyl thio, arylthio, and hetero-Ci -Cg-alkyl;
R and R are independently H or Q-Cg alkyl;
R and R may be taken together to form a 3 to 7 membered ring optionally containing an additional heteroatom of -O-, -NR-, -S- or -SO-; Rι is selected from the group consisting of H, -CN, and -(CH2)n-N(Rs)R6;
R5 is H or d-Cg alkyl;
R6 is selected from the group consisting of H, Ci-Cg alkyl, -CN, -C(=NH)NH2, aryl, substituted aryl, ara-Q -Cg-alkyl, heteroaryl, heteroara-Cι-C8- alkyl, hetero-Cτ-C8- alkyl, substituted hetero-Ci-Cg-alkyl, and C(O)A; A is selected from the group consisting of Q-Cg alkyl, aryl, substituted aryl, ara-C
Cg- alkyl, heteroaryl, heteroara-Ci -Cg-alkyl, hetero-Ci -Cg-alkyl and substituted hetero-Ci -Cg-alkyl;
R5 and R6 may be joined together to form a 5 to 7 membered ring optionally containing an additional heteroatom of -NR-, -O-, -S- or -SOn-; Each n is independently 0, 1 or 2.
11. A compound of Claim 10, wherein: X is NH;
Z is -COOH;
R2 is H;
R3 and t represent 1 to three substituents independently selected from the group consisting of halogen, -CN, N(R)(R'), -NO2, fluoro-Ci -Cg-alkyl, fluoro-Q-Cg- alkyloxy, -Ci-C8-alkyl, aryl, ara-Ci -Cg-alkyl, arlyoxy, ara-Q-Cg-alkyloxy, Q-Cg- alkylthio, arylthio, and hetero-Ci -C8-alkyl;
R and R' are independently H or Q-Cg alkyl;
R and R' may be taken together to form a 3 to 7 membered ring optionally containing an additional heteroatom of -O-, -NR-, -S- or -SO-;
Ri is selected from the group consisting of H, -CN, and -(CH )n-N(R5)R6;
R5 is H or Q-Cg alkyl;
Re is selected from the group consisting of H, Q-Cg alkyl, -CN, -C(=NH)NH2, aryl, substituted aryl, ara-Ci -C8-alkyl, heteroaryl, heteroara-Q-C8-alkyl, hetero-Q-Cg- alkyl, substituted hetero-Q -Cg-alkyl, and C(O)A;
A is selected from the group consisting of Q-Cg alkyl, aryl, substituted aryl, ara-Q-
Cg-alkyl, heteroaryl, heteroara-Q-Cg-alkyl, hetero-Ci -Cg-alkyl and substituted hetero-
Q-Cg-alkyl;
R5 and R6 may be joined together to form a 5 to 7 membered ring optionally containing an additional heteroatom of -NR-, -O-, -S- or -SOn-;
Each n is independently 0, 1 or 2.
12. A compound of Claim 11 wherein:
R2 is H; R and P represent 1 to three substituents independently selected from the group consisting of halogen, fluoro-Q -Cg-alkyl, alkyl, -Q-Cg-alkyloxy, ara-Q-Cg-alkyloxy,
-Q-Cg-alkylthio, arylthio, and hetero-Q -Cg-alkyl;
Ri is selected from the group consisting of -(CH )n-N(R5)R6;
R5 is H or Q-C8 alkyl; R6 is selected from the group consisting of H, Q-C8 alkyl, aryl, substituted aryl, ara-
Q-Cg-alkyl, heteroaryl, heteroara-Q-C8-alkyl optionally substituted with NH2 and hetero-Ci -Cg-alkyl, optionally substituted with NH ;
Each n is independently 0, 1 or 2.
13. A compound according to Claim 11 wherein: X is NH; Z is -COOH;
R2 is H;
R3 and represent 1 to three substituents independently selected from the group consisting of halogen, -CN, N(R)(R'), -NO2, fluoro-Q -Cg-alkyl, fluoro-Q-Cg- alkyloxy, Q-C8-alkyl, aryl, ara-C i -Cg-alkyl, Q-Cg-alkoxy, arlyoxy, ara-Q-Cg- alkyloxy, Ci -Cg-alkyl thio, arylthio, and hetero-Q -C8-alkyl;
R and R' are independently H or Ci-Cg alkyl;
R and R' may be taken together to form a 3 to 7 membered ring optionally containing an additional heteroatom of -O-, -NR-, -S- or -SO-;
Figure imgf000065_0001
R5 is H or Q-C8 alkyl;
R6 is -C(O)A;
A is selected from the group consisting of Q-C8 alkyl, aryl, substituted aryl, ara-Q-
C8-alkyl, heteroaryl, heteroara-Q -Cg-alkyl optionally substituted with NH2, and hetero-Ci -C8-alkyl optionally substituted with NH . Each n is independently 0, 1 or 2.
14. A compound according to Claim 11 wherein: X is NH;
Z is -COOH; R2 is H;
R3 and R4 represent 1 to three substituents independently selected from the group consisting of halogen, -CN, N(R)(R'), -NO2, fluoro-Q-C8-alkyl, fluoro-Q-Cg- alkyloxy, -Q-C8-alkyl, aryl, ara-Q -Cg-alkyl, arlyoxy, ara-C i-Cg-alkyloxy, -Q-Cg- alkylthio, arylthio, and hetero-Ci -Cg-alkyl; R and R are independently H or Q-Cg alkyl;
R and R' may be taken together to form a 3 to 7 membered ring optionally containing an additional heteroatom of -O-, -NR-, -S- or -S(O)n-; Ri is -(CH2)n-N(R5)R6 where R5 and R6 are joined together to form a 5 to 7 membered ring optionally containing an additional heteroatom of -NR-, -O-, -S- or - SOn-;
Each n is independently 0, 1 or 2.
15. A compound according to Claim 1 1 selected from the group comprised of:
2-{ [2-[(2-carboxy-4-cyanophenyl)amino]-4-(trifluoromethyl)phenyl]aminoJ-5- cyanobenzoic acid;
2-{ [2-[(2-carboxyphenyl)amino]-4-(trifluoromethyl)phenyl]amino}-5- cyanobenzoic acid;
2- { [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino } -5- cyanobenzoic acid;
2- { [2-[(2-carboxyphenyl)amino]-4-chloro-5-
(trifluoromethyl)phenyl] amino } benzoic acid; 2-{ [2-[(2-carboxyphenyl)amino]-4-(trifluoromethyl)phenyl]amino Jbenzoic acid;
5-( { [amino(imino)methyl]amino } methyl)-2- { [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl] amino Jbenzoic acid;
2-({2-[(2-carboxyphenyl)amino]-4,5-dimethylphenylJamino)benzoic acid; 2-({4-tert-butyl-2-[(2-carboxyphenyl)amino]phenyl}amino)benzoic acid;
2-({2-[(2-carboxyphenyl)amino]-4,5-dichlorophenyl}amino)benzoic acid;
2-{ [2-[(2-carboxyphenyl)amino]-4-(propylthio)phenyl]amino}benzoic acid;
2-{ [2-[(2-carboxyphenyl)amino]-4-(trifluoromethoxy)phenyl]amino}benzoic acid; 2-({2-[(2-carboxyphenyl)amino]-4-methylphenyl}amino)benzoic acid;
2-( { 2-[(2-carboxyphenyl)amino]-4-chlorophenyl } amino)benzoic acid;
N,N'-bis[(2-carboxy)phenyl]-3,4-difluorobenzene-l,2-diamine;
2-({2-[(2-carboxyphenyl)amino]-3-methylphenyl}amino)benzoic acid;
2-({2-[(2-carboxyphenyl)amino]phenyl}amino)-5-nitrobenzoic acid; 2-( { 2-[(2-carboxyphenyl)amino] -3 ,5-dichlorόphenyl } amino)benzoic acid;
2-({2-[(2-carboxyphenyl)amino]phenyl}amino)-5-cyanobenzoic acid;
2-({2-[(2-carboxyphenyl)amino]-4-fluorophenyl}amino)benzoic acid;
2-({2-[(2-carboxyphenyl)amino]-4-cyanophenyl }amino)benzoic acid; 2-({2-[(2-carboxyphenyl)amino]phenyl}amino)-4,5-difluorobenzoic acid;
N,N'-bis[2-(carboxyphenyl]benzene-l,2-diamine
2-( { 2-[(2-carboxyphenyl)amino]phenyl } amino)-4-fluorobenzoic acid;
2-( { 2-[(2-carboxyphenyl)amino]phenyl } amino)-5-methoxybenzoic acid; 2-( { 2-[(2-carboxyphenyl)amino]-4-methoxyphenyl } amino)benzoic acid;
2-{ [2-[(2-carboxyphenyl)amino]-4-(trifluoromethoxy)phenyl]amino Jbenzoic acid;
2-({2-[(2-carboxyphenyl)amino]-4-methylphenyl}amino)benzoic acid;
(3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]- amino }phenyl)-N-(4-hydroxy-3-methoxybenzyl)methanaminium chloride;
2- { [2- [(2-carboxyphenyl)amino] -4-(propylsulfinyl)phenyl] amino } benzoic acid and
2- { [2-[(2-carboxyphenyl)amino]-4-(propylsulfonyl)phenyl]amino Jbenzoic acid.
16. A compound according to Claim 12 selected from the group comprised of:
5-(aminomethyl)-2- { [2-[(2-carboxyphenyl)amino]-4-chloro-5-
(trifluoromethyl)phenyl] amino Jbenzoic acid hydrochloride; (3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl]amino}phenyl)-N-(4-hydroxybenzyl)methanaminium chloride;
(3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl]amino}phenyl)-N-[4- (dimethylamino)benzyl]methanaminium chloride;
(3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl]amino}phenyl)-N-(4-chlorobenzyl)methanaminium chloride;
(3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5- (trifluoromethyl)phenyl] amino }phenyl)-N-(pyridin-3- ylmethyl)methanaminium chloride hydrochloride; (3-carboxy-4-{[2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl] amino }phenyl)-N-[( 1 -methyl- 1 H-pyrrol-2- yl)methyl]methanaminium chloride;
2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-({[(2,4- dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)methyl]amino}methyl)benzoic acid;
(3-carboxy-4-{[2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl]amino}phenyl)-N-(4-methoxybenzyl)methanaminium chloride;
2-{[2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-{[(2- furylmethyl)amino] methyl Jbenzoic acid;
2-{[2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-
[(isobutylamino)methyl]benzoic acid;
(3-carboxy-4-{[2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl]amino}phenyl)methanaminium; 4-[(3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl]amino } benzyl)-ammonio]piperidinium dichloride;
5-(aminomethyl)-2- { [2-[(2-carboxyphenyl)amino]-4-
(trifluoromethyl)phenyl] amino Jbenzoic acid hydrochloride;
5-(aminomethyl)-2- { [2-(2-carboxyphenoxy)-5- (trifluoromethyl)phenyl] amino Jbenzoic acid hydrochloride;
5-(2-aminoethyl)-2-{ [2-[(2-carboxyphenyl)amino]-4-
(trifluoromethyl)phenyl] amino Jbenzoic acid hydrochloride;
2-{[2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-
(pyrrolidin- 1 -ylmethyl)benzoic acid; (3-carboxy-4-{[2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]- amino}phenyl)-N,N-bis(cyclopropylmethyl)methanaminium chloride;
5-(2-aminoethyl)-2-{[2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl] amino Jbenzoic acid hydrochloride;
2-( { 2-[(2-carboxyphenyl)amino]-4-chlorophenyl } amino)benzoic acid; [3-carboxy-4-({2-[(2-carboxyphenyl)amino]phenyl}amino)- phenyl]methanaminium chloride;
2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-{[(3- furylmethyl)amino]methyl Jbenzoic acid; 2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-
[(dibenzylamino)methyl]benzoic acid;
5-(Benzylamino-methyl)-2-[2-(2-carboxy-phenylamino)-5-trifluoromethyl- phenylamino]-benzoic acid; 3-carboxy-4-({2-[(2-carboxyphenyl)amino]phenylJamino)benzenaminium chloride;
2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-
[(isobutylamino)methyl]benzoic acid; and
2-( { [2- { [4-(aminomethyl)phenyl] amino } -5- (trifluoromethyl)phenyl] amino } - carbonyl)-4,5-dichlorobenzoic acid hydrochloride.
17. A compound according to Claim 13 selected from the group comprised of:
2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino }-5-[(l ,3- dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl]benzoic acid; N-(3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl] amino }benzyl)-L-phenylalaninamide chloride;
2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-
({ [(ethylamino)carbonyl] amino }methyl)benzoic acid;
2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-({ [(2S)- 2-amino-3-thien-2-ylpropanoyl]amino}methyl)benzoic acid;
N-(3-carboxy-4- { [2- [(2-carboxyphenyl)amino] -5-
(trifluoromethyl)phenyl] amino }benzyl)-L-tryptophanamide chloride;
N-(3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-
(trifluoromethyl)phenyl] amino }benzyl)-L-tyrosinamide chloride; (2S)-l-[(3-carboxy-4-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)- phenyljamino } benzyl)amino] -4-(methylsulf inyl)- 1 -oxobutan-2-aminium chloride; and
5-({ [(benzylamino)carbonyl]amino}methyl)-2-{ [2-[(2-carboxyphenyl)amino]-
5-(trifluoromethyl)phenyl]amino Jbenzoic acid.
18. A compound according to Claim 14 selected from the group comprised of: 2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5- (moφholin-4-ylmethyl)benzoic acid;
2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-[(l- oxidothiomoφholin-4-yl)methyl]benzoic acid; and 2-{ [2-[(2-carboxyphenyl)amino]-5-(trifluoromethyl)phenyl]amino}-5-
(piperazin-l-ylmethyl)benzoic acid hydrochloride.
19. A compound according to Claim 10 selected from the group comprised of: 5-(aminomethyl)-2- { [2-[(2-carboxyphenyl)thio]-5- (trifluoromethyl)phenyl]aminoJ -benzoic acid;
N,N'-bis[2-( 1 H-tetrazol-5-yl)phenyl] benzene- 1 ,2-diamine, disodium salt;
2- { [2-(2-carboxyphenoxy)-5-(trifluoromethyl)phenyl]amino Jbenzoic acid; and
2- { [2-(2-carboxyphenoxy)phenyl] amino Jbenzoic acid.
20. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically or prophylactically effective amount of a compound of any one of claims 10-20.
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WO2004002944A1 (en) 2004-01-08
JP2005531638A (en) 2005-10-20
BR0305259A (en) 2004-10-05
AU2003256334A1 (en) 2004-01-19
BR0305258A (en) 2004-10-05
EP1525183A1 (en) 2005-04-27

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