WO2011106929A1 - Inhibitors of hepatitis c virus ns5b polymerase - Google Patents

Inhibitors of hepatitis c virus ns5b polymerase Download PDF

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Publication number
WO2011106929A1
WO2011106929A1 PCT/CN2010/070831 CN2010070831W WO2011106929A1 WO 2011106929 A1 WO2011106929 A1 WO 2011106929A1 CN 2010070831 W CN2010070831 W CN 2010070831W WO 2011106929 A1 WO2011106929 A1 WO 2011106929A1
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Prior art keywords
alkyl
group
independently selected
methyl
mmol
Prior art date
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Ceased
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PCT/CN2010/070831
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French (fr)
Inventor
Casey Cameron Mccomas
Nigel J. Liverton
Joerg Habermann
Uwe Koch
Frank Narjes
Peng Li
Xuanjia Peng
Richard Soll
Hao Wu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon Pharma UK Ltd
Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme Ltd
Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
Merck Sharp and Dohme LLC
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Application filed by Merck Sharp and Dohme Ltd, Istituto di Ricerche di Biologia Molecolare P Angeletti SpA, Merck Sharp and Dohme LLC filed Critical Merck Sharp and Dohme Ltd
Priority to PCT/CN2010/070831 priority Critical patent/WO2011106929A1/en
Priority to PCT/CN2010/080332 priority patent/WO2011106986A1/en
Priority to ARP110100621A priority patent/AR080433A1/en
Priority to TW100106743A priority patent/TW201136919A/en
Priority to US13/582,240 priority patent/US20120328569A1/en
Priority to CA2791426A priority patent/CA2791426A1/en
Priority to JP2012555284A priority patent/JP2013521237A/en
Priority to AU2011223394A priority patent/AU2011223394A1/en
Priority to PCT/CN2011/000332 priority patent/WO2011106992A1/en
Priority to EP11750145.2A priority patent/EP2542545A4/en
Publication of WO2011106929A1 publication Critical patent/WO2011106929A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D513/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to antiviral compounds that are useful as inhibitors of the hepatitis C virus (HCV) NS5B (non-structural protein 5B) polymerase, compositions comprising such compounds, the use of such compounds for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection, methods for inhibiting the function of the NS5B polymerase, and methods for inhibiting HCV viral replication and/or viral production.
  • HCV hepatitis C virus
  • NS5B non-structural protein 5B
  • HCV infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals.
  • Current treatments for HCV infection include immunotherapy with recombinant interferon-a alone or in combination with the nucleoside analog ribavirin.
  • RNA-dependent RNA polymerase RNA-dependent RNA polymerase
  • HCV NS5B polymerase Sven-Erik Behrens et al , Identification and properties of the RNA-dependent RNA polymerase of heptatitis C virus, 15(1) EMBO J. 12-22 (1996). Antagonists of NS5B activity are inhibitors of HCV replication. Steven S. Carroll et al, Inhibition of Hepatitis C Virus RNA Replication by 2'- Modified Nucleoside Analogs, 278(14) J. BIOL. CHEM. 1 1979-84 (2003).
  • novel compounds of formula I and/or pharmaceutically acceptable salts thereof are useful, either as compounds or their pharmaceutically acceptable salts (when appropriate), in the inhibition of HCV (hepatitis C virus) NS5B (non- structural 5B) polymerase, the prevention or treatment of one or more of the symptoms of HCV infection, the inhibition of HCV viral replication and/or HCV viral production, and/or as pharmaceutical composition ingredients.
  • these compounds and their salts may be the primary active therapeutic agent, and, when appropriate, may be combined with other therapeutic agents including but not limited to other HCV antivirals, anti-infectives, immunomodulators, antibiotics or vaccines, as well as the present Standard of Care treatment options for HCV
  • each R 1 is independently selected from the group consisting of halogens
  • n 0, 1, 2 or 3;
  • R 2 is C(0)NR A R B ;
  • R A and R B are independently selected from the group consisting of hydrogen, Ci-Ce alkyl and 0(Ci-C 6 alkyl);
  • R 3 is ArA, wherein ArA is an aromatic ring system selected from the group consisting of:
  • ArA is substituted by 0, 1, 2 or 3 substitutents R c ;
  • each R c is independently selected from the group consisting of:
  • each ArB is an independently selected aromatic ring system selected from the group consisting of:
  • each R c c) d-C 6 alkyl, d) 0(d-C 6 alkyl), and f) (CH 2 )o- 3 -ArB is substituted by 0, 1, 2 or 3 substituents R F ;
  • each R D is independently selected from the group consisting of hydrogen and Ci- 6 alkyl
  • each R E is independently selected from the group consisting of hydrogen, Ci- 6 alkyl, OCi_ 6 alkyl and 5- or 6-membered monocyclic rings with 0, 1 , 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, wherein each R E OCi- 6 alkyl and 5- or 6-membered monocyclic rings is substituted by 0, 1, 2, 3 substituents independently selected from the group consisting of Ci-Ce alkyl, 0(Ci-C6 alkyl), halogen and OH;
  • each R F is independently selected from the group consisting of:
  • each ArC is an independently selected aromatic ring system selected from the group consisting of:
  • each R G is independently selected from the group consisting of halogen, CN, Ci-ealkyl, 0(Ci-C 6 alkyl), CF 3 and C(0)OH;
  • R 4 is selected from the group consisting of NR H R : ;
  • R H is selected from the group consisting of:
  • R J is selected from the group consisting of and R X R Y , where R x and R Y are independently selected from the group consisting of hydrogen and Ci-ealkyl;
  • R 1 is selected from the group consisting of:
  • R 1 is substituted by 0, 1, 2, 3 or 4 R ;
  • each R K is independently selected from the group consisting of: a) OR L ,
  • each ArD is an independently selected aromatic ring system selected from the group consisting of: i) 5- or 6-membered monocyclic rings with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, and
  • R L is selected from the group consisting of hydrogen, and phenyl
  • R M is selected from the group consisting of hydrogen, Ci. 6 alkyl and (CH 2 ) 0 -3(phenyl);
  • R N is selected from the group consisting of hydrogen
  • R M and R N are taken together with the N to which they are attached to form a 5- to 7-membered ring substituted by 0, 1, 2 or 3 R p ;
  • each R° is independently selected from the group consisting of halogen, Ci -6 alkyl, OCi -6 alkyl and C(0)0(Ci -6 alkyl);
  • each R p is independently selected from the group consisting of halogen, Ci-ealkyl, OCi-ealkyl, oxo and C(0)0(Ci_ 6 alkyl);
  • R H and R 1 are taken together with the N to which they are attached to form a 5- to 7-membered ring.
  • the present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions.
  • the present invention further includes methods of treating or reducing the likelihood or severity of HCV infection, methods for inhibiting the activity of the NS5B polymerase, and methods for inhibiting HCV viral replication and/or viral production.
  • the present invention includes compounds of formula I above, and pharmaceutically acceptable salts thereof.
  • the compounds of formula I are HCV NS5B polymerase inhibitors
  • n is 1. In this embodiment, all other groups are as provided in the general formula above.
  • the compound is a compound of formula la:
  • R is selected from the group consisting of fluorine, bromine and chlorine.
  • R 1 is fluorine.
  • all other groups are as provided in the general formula above and/or in the first or second embodiments.
  • R A is hydrogen.
  • all other groups are as provided in the general formula above and/or in the first through third embodiments.
  • R B is selected from the group consisting of -CH 3 and -OCH 3
  • all other groups are as provided in the general formula above and/or in the first through fourth embodiments.
  • ArA is phenyl.
  • all other groups are as provided in the general formula above and/or in the first through fifth embodiments.
  • each R c is independently selected from the group consisting of a) fluorine, b) OH, c) C ⁇ alkyl, d) Od_ 3 alky
  • each R c is
  • R H is selected from hydrogen, CH 3 and S0 2 CH 3 .
  • R H is S0 2 CH 3 .
  • all other groups are as provided in the general formula above and/or in the first through seventh embodiments.
  • R 1 is selected from the group consisting of Ci-6alkyl and C 2 _6alkenyl.
  • all other groups are as provided in the general formula above and/or in the first through eighth embodiments.
  • R K is selected from the group consisting of a) OR L , b) halogen, c) CN, d) NR M R N , e) OC(0)Ci. 6 alkyl, and f) C(0)OCi. 6 alkyl.
  • all other groups are as provided in the general formula above and/or in the first through ninth embodiments.
  • R L is selected from the group consisting of Ci-ealkyl.
  • all other groups are as provided in the general formula above and/or in the first through tenth embodiments.
  • R M is selected from the group consisting of hydrogen and Ci_ 6 alkyl.
  • all other groups are as provided in the general formula above and/or in the first through eleveth embodiments.
  • Ci_ 6 alkyl is selected from the group consisting of Ci_ 6 alkyl and S0 2 (Ci_ 6 alkyl). In this embodiment, all other groups are as provided in the general formula above and/or in the first through twelfth embodiments.
  • the compound of the invention is selected from the exemplary species depicted in Examples 1 through 154 shown below, and pharmaceutically acceptable salts thereof.
  • composition comprising an effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
  • HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
  • a pharmaceutical combination that is (i) a compound of formula I and (ii) a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents; wherein the compound of formula I and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HCV NS5B activity, or for inhibiting HCV viral replication, or for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
  • HCV antiviral agents are one or more antiviral agents selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
  • HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
  • (k) A method of inhibiting HCV viral replication and/ or HCV viral production in a cell-based system, which comprises administering to the subject an effective amount of a compound of formula I in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HCV antiviral agents,
  • HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
  • a method of inhibiting HCV NS5B activity in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
  • a method of treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
  • each embodiment may be combined with one or more other embodiments, to the extent that such a combination provides a stable compound or salt and is consistent with the description of the embodiments.
  • the embodiments of compositions and methods provided as (a) through (n) above are understood to include all embodiments of the compounds and/or salts, including such embodiments as result from combinations of embodiments.
  • Additional embodiments of the invention include the pharmaceutical compositions, combinations, uses and methods set forth in (a) through (n) above, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.
  • the present invention also includes a compound of the present invention for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) inhibiting HCV NS5B activity, or (b) inhibiting HCV viral replication, or (c) treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection, or (d) use in medicine.
  • the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from HCV antiviral agents, anti-infective agents, and immunomodulators.
  • alkyl refers to any linear or branched chain alkyl group having a number of carbon atoms in the specified range.
  • Ci_6 alkyl (or “Ci-Ce alkyl”) refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • C1.4 alkyl refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. Alkyl groups may be substituted as indicated.
  • halogenated refers to a group or molecule in which a hydrogen atom has been replaced by a halogen.
  • haloalkyl refers to a halogenated alkyl group.
  • halogen refers to atoms of fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
  • alkoxy refers to an "alkyl-O-" group. Alkoxy groups may be substituted as indicated.
  • cycloalkyl refers to any cyclic ring of an alkane or alkene having a number of carbon atoms in the specified range.
  • C3-8 cycloalkyl (or “C3-C cycloalkyl”) refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, and cyclooctenyl.
  • cycloalkoxy refers to a "cycloalkyl-O-" group. Cycloalkyl groups may be substituted as indicated.
  • aryl refers to aromatic mono- and poly- carbocyclic ring systems wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond.
  • aryl includes aromatic mono- and poly-carbocyclic ring systems that include from 0 to 4 heteroatoms (non-carbon atoms) that are independently chosen from N, O and S.
  • Suitable aryl groups include phenyl, naphthyl, biphenylenyl, pyridinyl, pyrimidinyl and pyrrolyl, as well as those discussed below.
  • Aryl groups may be substituted as indicated.
  • Aryl ring systems may include, where appropriate, an indication of the variable to which a particular ring atom is attached. Unless otherwise indicated, substituents to the aryl ring systems can be attached to any ring atom, provided that such attachment results in formation of a stable ring system.
  • carbocycle (and variations thereof such as “carbocyclic”) as used herein, unless otherwise indicated, refers to (i) a C5 to C7 monocyclic, saturated or unsaturated ring, or (ii) a Cg to C 10 bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated. Carbocycle groups may be substituted as indicated. When the carbocycles contain one or more heteroatoms independently chosen from N, O and S, the carbocycles may also be referred to as
  • heterocycles as defined below.
  • the carbocycle may be attached to the rest of the molecule at any carbon or nitrogen atom that results in a stable compound.
  • the fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term "fused bicyclic carbocycle” generally refers to a Cs to Cio bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system.
  • a fused bicyclic carbocycle in which both rings are saturated is a saturated bicyclic ring system.
  • Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc.
  • a fused bicyclic carbocycle in which one or both rings are unsaturated is an unsaturated bicyclic ring system.
  • Carbocycle ring systems may include, where appropriate, an indication of the variable to which a particular ring atom is attached. Unless otherwise indicated, substituents to the ring systems can be attached to any ring atom, provided that such attachment results in formation of a stable ring system.
  • heterocycle broadly refers to (i) a stable 5- to 7-membered, saturated or unsaturated monocyclic ring, or (ii) a stable 8- to 10-membered bicyclic ring system, wherein each ring in (ii) is independent of, or fused to, the other ring or rings and each ring is saturated or unsaturated, and the monocyclic ring or bicyclic ring system contains one or more heteroatoms (e.g ., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) independently selected from N, O and S and a balance of carbon atoms (the monocyclic ring typically contains at least one carbon atom and the bicyclic ring systems typically contain at least two carbon atoms); and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally oxidized, and any one or more of the nitrogen heteroatoms is optionally qua
  • heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure.
  • Heterocycle groups may be substituted as indicated, and unless otherwise specified, the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
  • Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl).
  • heteroaryl ring system refers to aryl ring systems, as defined above, that include from 1 to 4 heteroatoms (non-carbon atoms) that are independently chosen from N, O and S.
  • heteroatoms non-carbon atoms
  • substitutions can be those resulting in N-oxide formation.
  • heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
  • bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo- 1,4-dioxinyl and benzo-l,3-dioxolyl.
  • alkyl, cycloalkyl, and aryl groups are not substituted.
  • the substituents are selected from the group which includes, but is not limited to, halo, C1-C20 alkyl, -CF 3 , -NH 2 , -N(Ci-C6 alkyl) 2 , -NO2, oxo, - CN, -N 3 , -OH, -0(Ci-C 6 alkyl), C3-C10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 6 alkyl) S(0)o-2-, aryl-S(O) 0.2 -, (C 0 -C 6 alkyl)S(0)o-2(Co-C 6 alkyl)-, (C 0 -C 6 alkyl)C(0)NH-, H 2 N-C(NH)-
  • the term “compound” is intended to encompass chemical agents described by generic formula I in all forms, including hydrates and solvates of such chemical agents.
  • the term “compound” is intended to encompass prodrugs of the chemical agents described by generic formula I.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of formula I.
  • different isotopic forms of hydrogen (H) include protium ( ⁇ ) and deuterium ( 2 H or D).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • heteroaryl ring described as containing from “0 to 3 heteroatoms” means the ring can contain 0, 1, 2, or 3 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. The oxidized forms of the heteroatoms N and S are also included within the scope of the present invention.
  • any variable for example, R 1 or R 3
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • a “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g. , therapeutic or prophylactic administration to a subject).
  • certain of the compounds of the present invention can have asymmetric centers and can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether isolated or in mixtures, are within the scope of the present invention.
  • a reference to a compound of formula I is a reference to the compound per se, or to any one of its tautomers per se, or to mixtures of two or more tautomers.
  • the compounds of the present inventions are useful in the inhibition of HCV replication (e.g., HCV NS5B activity), the treatment of HCV infection and/or reduction of the likelihood or severity of symptoms of HCV infection.
  • HCV replication e.g., HCV NS5B activity
  • the compounds of this invention are useful in treating infection by HCV after suspected past exposure to HCV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • the compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds.
  • the compounds of this invention are useful for identifying resistant HCV replicon cell lines harboring mutations within NS5B, which are excellent screening tools for more powerful antiviral compounds.
  • the compounds of this invention are useful in establishing or determining the binding site of other antivirals to the HCV replicase.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to a salt that possesses the effectiveness of the parent compound and that is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof).
  • Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid.
  • suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts.
  • suitable pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
  • administration and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention mean providing the compound or a prodrug of the compound to the individual in need of treatment.
  • administration and its variants are each understood to include concurrent and sequential provision of the compound or salt and other agents.
  • composition is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.
  • pharmaceutically acceptable is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • the term "effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the effective amount is a "therapeutically effective amount” for the alleviation of one or more symptoms of the disease or condition being treated.
  • the effective amount is a "prophylactically effective amount” for reduction of the severity or likelihood of one or more symptoms of the disease or condition.
  • the effective amount is a "therapeutically effective amount” for inhibition of HCV viral replication and/or HCV viral production.
  • the term also includes herein the amount of active compound sufficient to inhibit HCV NS5B activity and thereby elicit the response being sought (i.e., an "inhibition effective amount").
  • active compound i.e., active ingredient
  • references to the amount of active ingredient are to the free acid or free base form of the compound.
  • the compounds of the present invention optionally in the form of a salt, can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by one or more
  • Liquid preparations suitable for oral administration can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like.
  • Solid preparations suitable for oral administration e.g., powders, pills, capsules and tablets
  • solid excipients as starches, sugars, kaolin, lubricants, binders,
  • Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as solubility aids.
  • injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions of the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18 th edition (ed. A. R. Gennaro, Mack Publishing Co., 1990).
  • the compounds of this invention can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses.
  • mammal e.g., human
  • One dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses.
  • Another dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses.
  • the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 mg of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, HCV viral genotype, viral resistance, and the host undergoing therapy.
  • the present invention also relates to a method of inhibiting HCV NS5B activity, inhibiting HCV viral replication and/or HCV viral production, treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection with a compound of the present invention in combination with one or more therapeutic agents and a pharmaceutical composition comprising a compound of the present invention and one or more therapeutic agents selected from the group consisting of a HCV antiviral agent, an
  • Such therapeutic agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha- 1, R7025 (an enhanced interferon (Roche)), interferon- ⁇ , interferon- ⁇ , pegylated interferon- ⁇ (peginterferon-a), a combination of interferon- ⁇ and ribavirin, a combination of peginterferon- ⁇ and ribavirin, a combination of interferon- ⁇ and levovirin, and a combination of peginterferon- ⁇ and levovirin.
  • Interferon- ⁇ includes, but is not limited to, recombinant interferon-a2a (such as ROFERON interferon available from Hoffmann- LaRoche, Nutley, NX), pegylated interferon-a2a (PEGASYS), interferon-a2b (such as INTRON-A interferon available from Schering Corp., Kenilworth, NJ), pegylated interferon-a2b
  • interferon-a2a such as ROFERON interferon available from Hoffmann- LaRoche, Nutley, NX
  • PGASYS pegylated interferon-a2a
  • interferon-a2b such as INTRON-A interferon available from Schering Corp., Kenilworth, NJ
  • the compounds of the invention may also be administered in combination with the antiviral agent NS5B polymerase inhibitor R7128 (Roche)
  • the compounds of the present invention also may be combined for the treatment of HCV infection with antiviral 2'-C-branched ribonucleosides disclosed in Rogers E. Harry-O'Kuru et al., A Short, Flexible Route toward 2 '-C-Branched Ribonucleosides, 62 J. ORG. CHEM. 1754-59 (1997); Michael S. Wolfe & Rogers E. Harry-O'Kuru, A Concise Synthesis of2'-C- Methylribonucleosides, 36(42) TETRAHEDRON LETTERS 7611-14 (1995); U.S. Patent
  • Such 2'-C-branched ribonucleosides include, but are not limited to, 2'-C-methyl-cytidine, 2'-C-methyl-uridine, 2'-C-methyl-adenosine, 2'-C-methyl- guanosine, and 9-(2-C-methyl-P-D-ribofuranosyl)-2,6-diaminopurine, and the corresponding amino acid ester of the ribose C-2', C-3 ', and C-5' hydroxyls and the corresponding optionally substituted cyclic 1,3-propanediol esters of the 5'-phosphate derivatives.
  • the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS3 serine protease.
  • HCV NS3 serine protease is an essential viral enzyme and has been described to be an excellent target for inhibition of HCV replication.
  • Exemplary substrate and non-substrate based inhibitors of HCV NS3 protease inhibitors are disclosed in International Patent Application Publications WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, WO 02/48116, WO 02/48172, WO 2008/057208 and WO 2008/057209, in British Patent No. GB 2 337 262, and in U. S. Patent Nos. 6,323, 180 and 7,470,664.
  • the compounds of the present invention may also be combined for the treatment of HCV infection with nucleosides having anti-HCV properties, such as those disclosed in International Patent Application Publications WO 02/51425, WO 01/79246, WO 02/32920, WO 02/48165 and WO 2005/003147 (including R1656, (2'i?)-2'-deoxy-2'-fluoro-2'-C- methylcytidine, shown as compounds on page 77); WO 01/68663; WO 99/43691;
  • WO 02/18404 and WO 2006/021341 and U.S. Patent Application Publication US 2005/0038240, including 4'-azido nucleosides such as R1626, 4'-azidocytidine; U.S. Patent Application Publications US 2002/0019363, US 2003/0236216, US 2004/0006007, US 2004/0063658 and US 2004/0110717; U.S. Patent Nos.
  • the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS5B polymerase.
  • HCV NS5B polymerase inhibitors that may be used as combination therapy include, but are not limited to, those disclosed in International Patent Application Publications
  • HCV polymerase inhibitors include, but are not limited to, valopicitabine (NM-283; Idenix) and 2' -F-2' -beta- methyl cytidine (see also WO 2005/003147).
  • additional nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS5B inhibitors are selected from the following compounds: 4-amino-7-(2-C-methyl-p-D-arabinofuranosyl)-7H-pyrrolo[2,3-tf]pyrimidine; 4- amino-7-(2-C-methyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-i ]pyrimidine; 4-methylamino-7-(2-C- methyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-i/
  • the compounds of the present invention may also be combined for the treatment of HCV infection with non-nucleoside inhibitors of HCV polymerase such as those disclosed in U.S. Patent Applciation Publications US 2006/0100262 and US 2009/0048239; International Patent Application Publications WO 01/77091, WO 01/47883, WO 02/04425, WO 02/06246, WO 02/20497, WO 2005/016927 (in particular JTK003), WO 2004/041201, WO 2006/066079, WO 2006/066080, WO 2008/075103, WO 2009/010783 and WO 2009/010785; the content of each is incorporated herein by reference in its entirety.
  • additional non-nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS5B inhibitors are selected from the following compounds: 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5, 6,7,8- tetrahydroindolo[2, l- ][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-(2-morpholin- 4-ylethyl)-5,6,7,8-tetrahydroindolo[2, l-a][2,5]benzodiazocine-l l-carboxylic acid; 14- cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-5,6,7,8-tetrahydroindolo[2, l-a]
  • [2, 5 ]benzodiazocine-l 1-carboxylic acid 6-allyl-14-cyclohexyl-3-methoxy-5, 6,7,8- tetrahydroindolo[2, 1 -a] [2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclopentyl-6-[2- (dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,l- ][2,5]benzodiazocine- 11-carboxylic acid; 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2, l- ][2,5]benzodiazocine- 11-carboxylic acid; 13-cyclohexyl-5-methyl-4,5,6,7-tetrahydrofuro[3',2':6,7][l,4]diazocino[l
  • HCV NS5B polymerase inhibitors are used in combination with non-nucleoside HCV NS5A inhibitors and pharmaceutically acceptable salts thereof.
  • the HCV NS5B inhibitory activity of the present compounds may be tested using assays known in the art.
  • the HCV NS5B polymerase inhibitors described herein have activities in a genotype lb replicon assay as described in the Examples.
  • the assay is performed by incubating a replicon harboring cell-line in the presence of inhibitor for a set period of time and measuring the effect of the inhibitor on HCV replicon replication either directly by quantifying replicon RNA level, or indirectly by measuring enzymatic activity of a co-encoded reporter enzyme such as luciferase or ⁇ -lactamase. By performing a series of such measurements at different inhibitor concentrations, the effective inhibitory concentration of the inhibitor (EC50 or EC90) is determined.
  • the present invention also includes processes for making compounds of formula I.
  • the compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. The following reaction schemes and examples serve only to illustrate the invention and its practice.
  • This scheme describes the preparation of compounds with the general structure of G and H.
  • compound A obtained according to procedure in WO 2004/041201 A2
  • coupling with a substituted or unsubstituted phenylboronic acid catalyzed by a transition metal, in this case Pd(dppf)Cl2 furnishes compounds of the general structure B.
  • Pd(dppf)Cl2 a transition metal
  • This type of transition- metal-mediated cross-coupling is common and there are numerous conditions that one skilled in the art can use to execute such a transformation.
  • Compounds of type C are next generated by reduction of the nitro group in compound B, which can be accomplished by exposure to common reducing conditions, in this case treatment by Fe in NH 4 CI solution under reflux.
  • the amino group in compounds C is then sulfonylated with a sulphonyl chloride to give compounds of type D.
  • the sulfonamide D can be coupled with an alkylating agent (an alkyl halide for example) in the presence of a suitable base, such as potassium carbonate, to provide compounds E.
  • a suitable base such as potassium carbonate
  • the ester functionality in compounds E is readily hydrolyzed by aqueous base to afford compounds F.
  • the carboxylic acid of compound F was condensed with methanamine or
  • Compound C can be coupled with an alkylating agent (an alkyl halide for example) in the presence of a suitable base, such as potassium carbonate, to provide compounds I where Z represents an alkylated aniline.
  • C may be condensed with substituted carboxylic acid in the presence of coupling reagents, such as EDCI and HOBT, to afford compounds I where Z represents a substituted amide.
  • Compounds J may be obtained from compounds I by further N-alkylation or N-acylation reaction.
  • Compounds of general structure I or J are hydrolyzed by aqueous hydroxide to provide compounds F.
  • the carboxylic acid of compound F may be condensed with an amine as shown in Scheme 1 to provide target compounds of general structure G and H.
  • Compound A may be reduced by a catalyst in the presence of a hydrogen source (for example, Pd in the presence of formic acid) to afford compound K. Further reduction of K provides aniline L. The amino group of compound L is reacted with sulfonyl chloride to afford compound M, which can be further N-alkylated with a wide variety of alkylating agents in the presence of a suitable base, such as potassium carbonate, to provide compound ⁇ . Halogenation of compound ⁇ , in this case bromination with FeCl 3 and Br2 in anhydrous CCU gives compound O. Compounds of general structure O are hydrolyzed by aqueous hydroxide to provide compounds P.
  • a hydrogen source for example, Pd in the presence of formic acid
  • the carboxylic acid of compound P may be condensed with an amine as shown in Scheme 1 to provide compounds of general structure Q.
  • Transition metal mediated coupling of compounds Q with a boronic acid (alternatively alkyl tin, silicon, or other types of coupling partners may be used) provides the target compounds of general structure G.
  • Compounds E that possess a hydroxyl group may be obtained from compounds D by reacting with 2-bromo ethanol.
  • the hydroxyl group E can be converted to a leaving group (by reaction with MsCl for example) to afford compound R.
  • Compound R may be treated with nucleophilic reagents such as an amine in the presence of a suitable base, such as triethylamine, to afford compound S.
  • Compounds T can then be obtained from compound S by further N-alkylation or N-acylation.
  • Compounds of structure T are readily converted to the target structures G following the general procedure described in Scheme 1.
  • Compound F' can be converted to compound G' by treated with fuming HNO 3 .
  • Compound H' is generated by reduction of the nitro group in compound G', and the amino group in compound H' is then sulfonylated with MsCl to furnish compound I'.
  • the sulfonamide I' can be coupled with Mel in the presence of potassium carbonate to provide compound J' .
  • the ester functionality in compound J' is readily hydro lyzed by aqueous base to afford compound K'.
  • the carboxylic acid of compound K' was condensed with methanamine using common amide forming reagents such as EDCI and HOBT to give compound L'.
  • Transition metal mediated coupling of compound L' with a meta-heterocycle-substituted phenyl boronic ester provides the target compounds of general structure M'.
  • Coupling compound L' with a substituted or unsubstituted 3-formylphenylboronic acid catalyzed by a transition metal, in this case Pd(dppf)Cl 2 furnishes compounds of the general structure N ⁇
  • Compounds of type N' were cyclized with ortho-amino anilines or ortho-amino thiophenols to provide the target compounds of general structure O' or P'.
  • LiHMDS Lithium bis(trimethylsilyl) amide
  • Example 1 2- 4-fluorophenvn-A r -methyl-6-[methyl(methylsulfonYnaminol-5-phenyl-l- benzofuran-3-carboxamide
  • Step 1 ethyl 2-(4-fluorophenyl)-6-nitro-5-phenyl-l-benzofuran-3-carboxylate
  • Phenylboronic acid 100 mg, 0.8 mmol
  • K 3 P0 4 -3H 2 0 119 mg, 0.8 mmol
  • ethyl 2-(4-fluorophenyl)-6-nitro-5- ⁇ [(trifluoromethyl)sulfonyl] oxy ⁇ -l-benzofuran-3-carboxylate obtained according to procedure in WO 2004/041201 A2, 200 mg, 0.4 mmol
  • dioxane 2 mL
  • DMF 2 mL
  • Pd(dppf)Cl 2 5 mg, 0.08 mmol
  • Step 3 ethyl 2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-5 ⁇ henyl-l-benzofuran-3- carboxylate
  • Step 4 ethyl 2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-5-phenyl-l-bem
  • Step 5 2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-5 ⁇ henyl-l-benzofuran- carboxylic acid
  • Step 4 The product of Step 4 (78 mg, 0.17 mmol) was dissolved in THF (2 mL) and H 2 0 (2 mL) Then, Li OH (71 mg, 1.7 mmol) was added to the solution, and the mixture was stirred at RT overnight. After acidification with HC1 (1 N) and extraction with EtOAc, the combined organic phases were washed with brine, dried over Na 2 S0 4 , filtered and evaporated to give the product of 2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-5-phenyl- 1 -benzofuran-3- carboxylic acid (50 mg, yield: 67%). It was used for the next step without further purification. Step 6: 2-(4-fluorophenyl)-N-methyl-6-[methyl(methylsulfonyl)amino
  • Steps 1-5 were performed in accordance with Example 1, Steps 1-5.
  • Step 6 2-(4-fluorophenyl)-N-methoxy-6-[meth l(methylsulfonvUamino]-5- ⁇
  • Examples 8- 12 were prepared according to the general procedures of Example 7.
  • Example 13 6-[icYclohexYlmethvnimethylsulfonyl aininol-2-(4-fluorophenYn-jV-inethyl-5-
  • Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
  • Step 6 6-[(cyclohexylmethyl)(methylsulfonyl)amino]-2-(4-fluoropheny
  • Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
  • Step 5 2-(4-fluorophenyl)-5-phenyl-6-[(l ⁇ henylethyl)amino]-l-benzofuran-3-carboxylic acid
  • Example 69 (20 mg, yield: 48.6%) was prepared according to the general procedure in Example 1, Step 6.
  • Example 70 2-f4-fluorQphenyl)-A-methyl-6-( ⁇ 2-[methyl(phenyl)aminolethyl ⁇ amino)-5- phenyl-l-benzofuran-3-carboxamide
  • Example 70 was prepared according to the general procedures of Example 69.
  • Steps 1-4 were performed in accordance with Example 69, Steps 1-4.
  • Step 5 ethyl 2-(4-fluorophenyl)-6-[methyl(l ⁇ henylethyl)amino]
  • Step 6 2-(4 ⁇ uoropheriyl)-6-[methyl(l ⁇ heriylethyl)amino]-5 ⁇ heny
  • the carboxylic acid (75 mg, yield: 90 %) was prepared in an analogous manner to Example 13 using the general procedure in Example 13, Step 4. The carboxylic acid was used in the next step without further purification.
  • Step 7 2-(4-fluorophenyl)-N-methyl-6-[methyl(l-phenylethyl)ammo]-5- ⁇
  • Example 72 ethyl [2-(4-fluorophenv0-3-(methylcarbamov0-5-phenyl-l-benzofuran-6-
  • Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
  • Step 4 ethyl 6-[(ethoxycarbonyl)amino]-2-(4-fluorophenyl)-5-phen l-l-benzofuran-3- carboxylate
  • DCM 3 mL
  • Step 5 ethyl 6-[ (ethoxycarbonyl) ⁇ 2-[methyl(phenyl)ammo]ethyl ⁇ amino]-2-(4-fluorophenyl)-5-
  • Step 4 The product of Step 4 (474 mg, 1.06 mmol), 2-(methyl(phenyl)amino)ethyl methanesulfonate (243 mg, 1.06 mmol) and Cs 2 C0 3 (7.8 g, 24 mmol) in dry DMF (100 mL) was stirred at 140°C for 4 hours. After the mixture was concentrated, the residue was diluted with DCM, washed with water, dried over Na 2 S0 4 and concentrated. The residue was purified by prep-TLC to give the desired amino carbamate (335 mg, yield: 54.6%). MS (M+H) + : 581. Step 6: 6-[(ethoxycarbonyl) ⁇ 2-[methyl(phenyl)amino]ethyl ⁇ amino]-2-(4-fl orophenyl)-5-
  • Step 5 The product of Step 5 (25 mg, yield: 90%) was prepared in an analogous manner to Example 13 using the general procedure in Example 13, Step 4. The carboxylic acid was used directly in the next step without further purification.
  • Step 7 ethyl [2-(4-fluorophenyl)-3-(methylcarbamoyl)-5-phenyl-l-benzofuran-6-yl] ⁇ 2- [methyHphenyl)ammo]ethyl ⁇ carbamate
  • Example 72 (15 mg, yield: 48.7%) was prepared according to the general procedure in Example 1, Step 6.
  • Steps 1-2 were performed in accordance with Example 1, Steps 1-2.
  • Step 3 ethyl 2-(4-fluorophenyl)-6-[ (N-methyl-N-phenylglycyl)amino]-5-phenyl-l-benzofuran-3- carboxylate
  • the amide (75 mg, yield: 50%) was prepared from the product of Step 2 according to the general procedure in Example 1, Step 6.
  • Step 4 2-(4-fluorophenyl)-6-[ (N-methyl-N-phenylglvcyl)amino]-5-phenyl-l-benzofuran-3- carboxylic acid
  • the carboxylic acid (50 mg, yield: 75%) was prepared in an analogous manner to Example 13 using the general procedure in Example 13, Step 4. The carboxylic acid was used in the next step without further purification.
  • Step 5 2-(4-fluorophenyl)-N-methyl-6-[ (N-methyl-N-phenylglycyl)amino]-5-phenyl-l-
  • Steps 1-3 were performed in accordance with Example 73, Steps 1-3.
  • Step 4 ethyl 2-(4-fluorophenyl)-6-[methyl( -methyl-N ⁇ henylglycyl)amino]-5-phenyl-l- benzofuran-3-carboxylate
  • the alkylated amide (90 mg, yield: 90%) was prepared in an analogous manner to the compound prepared in Example 1, Step 4.
  • the carboxylic acid (85 mg, yield: 95%o) was prepared in an analogous manner to
  • Example 13 using the general procedure in Example 13, Step 4. The carboxylic acid was used in the next step without further purification.
  • Step 6 2-(4-fluorophenyl)-N-methyl-6-[methyl(N-methyl-N ⁇ henylglvcyl)amin ⁇
  • Examples 75 and 76 were prepared according to the general procedures of
  • Example 77 2- 4-fluorophenyl)-A-methyl-6-[(4 t y,5 J RV4-methyl-2-oxo-5-phenyl-l,3- oxazolidin-3-yl1-5-phenyl-l-benzofuran-3-carboxamide
  • Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
  • Step 6 2-(4-fluorophenyl)-6-[(4S, 5R)-4-methyl-2-oxo-5-phenyl-l , 3-oxazolidin-3-yl]-5-phenyl-l-
  • Step 7 2-(4-fluorophenyl)-N-methyl-6-[(4S, 5R)-4-methyl-2-oxo-5 -phenyl- 1, 3-oxazolidin-3-yl]- 5-phenyl-l-benzofuran-3-carboxamide
  • Step 1 ethyl 5-(2-fluorophenyl)-2-(4-fluorophenyl)-6-nitro-l-benzofuran-3-carboxylate
  • Step 4 ethyl 5-(2-fluorophenyl)-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)ammo]-l- benzofuran-3-carboxylate
  • Steps 1-5 were performed in accordance with Example 78, Steps 1-5.
  • Example 90 was prepared using conditions analogous to the coupling reaction described in Example 7, Step 6 (40 mg, yield: 51%).
  • Steps 1-4 ethyl 5-(3-cyanophenyl)-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-l- benzofuran-3-carboxylate
  • Steps 1-4 were performed in an analogous manner to Example 1, Steps 1-4.
  • the ester (450 mg, 0.92 mmol) was dissolved in dioxane (5 mL). Then LiOH (96 mg, 4 mmol) was added to the solution, and the mixture was stirred at RT overnight. After acidifmg with HCl (I N) and extracting with EtOAc, the combined organic phases were washed with brine, dried over Na 2 SC1 ⁇ 4, filtered and evaporated to give the cyano carboxylic acid (300 mg, yield: 50%) and dicarboxylic acid (100 mg, yield: 30%). The crude mixture was used for the next step without further purification.
  • Step 6 2-(4-fluorophenyl)-N-methoxy-5-[ 3-(methoxycarbamoyl)phenyl]-6-
  • Example 99 was prepared using condition analogous to the coupling reaction described in Example 7, Step 6 (55 mg, yield: 73%).
  • Example 100 2-f4-fluorophenvn-A f -methyl-5-[3-(methYlcarbamoYnphenyll-6-
  • Steps 1-5 5-(3-carboxyphenyl)-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)a
  • Steps 1-5 were performed according to the general procedures in Example 99, Steps 1-5.
  • Step 6 2-(4-fluorophenyl)-N-methyl-5-[ 3-(methylcarbamoyl)phenyl]-6- [methyl(methylsulforiyl)amino]-l-benzofuran-3-carboxamide
  • Example 100 was prepared according to the general procedure in Example 1, Step 6.
  • Step 1 5-f 3-(aminomethyl)phenyl]-2-(4-fluorophenyl)-N-methyl-6- [methyl(methylsulfonyl)amino]-l-benzofuran-3-carboxamide
  • Example 102 2- 4-fluorophenvn-A r -methyl-6-[methvirmethylsulfonvnamino1-5- 3- i[(methylsulfonvnaminolmethyl ⁇ phenvn-l-benzofuran-3-carboxamide
  • Steps 1-2 were performed according to the general procedures in Example 1, Steps 1-2.
  • Example 102 was prepared in an analogous manner to the sulfonamide synthesis described in Example 1, Step 3 (20 mg, yield: 60%).
  • Example 103 was prepared according to the general procedures of Example 102.
  • Example 104 2- 4-fluorophenvn-A r -methyl-6-[methvirmethylsulfonvnamino1-5- 4-
  • Step 1 5-f 4-(aminomethyl)phenyl]-2-(4-fluorophenyl)-N-methyl-6-
  • Step 2 2-(4-fluorophenyl)-N-methyl-6-[methy methylsulfonyl)amino]-5-(4- ⁇ [(methylsulfonyl)amino]methyl ⁇ phenyl)-l-benzofuran-3-carboxamide
  • Example 104 was prepared in an analogous manner to the sulfonamide prepared in Example 1, Step 3 (20 mg, yield: 60%).
  • Examples 105-107 were prepared according to the general procedures of
  • Example 108 2-(4-fluorophenvn-A-meth ⁇ l-6-[niethylfinethylsulfonvnaininol-5-[4- (trifluoromethvQphenyll-l-benzofuran-3-carboxamide
  • Step 1 ethyl 2-(4-fluorophenyl)-6-nitro-l-benzofuran-3-carboxylate
  • Step 2 ethyl 6-amino-2-(4-fluorophenyl)-l-benzofuran-3-carboxylate
  • Step 4 ethyl 2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-l-benzofuran-3-carboxylate
  • Step 5 ethyl 5-bromo-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-l- ⁇
  • the ester (210 mg, yield: 80%) was hydrolysed in an analogous manner to the general procedure of Example 78, Step 5.
  • the carboxylic acid was used in the next step without further purification.
  • Step 7 5-bromo-2-(4-fluorophenyl)-N-methyl-6-[methyl(methylsulfonyl)a
  • Step 8 2-(4-fluoropheriyl)-N-methyl-6-[methyl(methylsulfonyl)amino]-5-[4-
  • Steps 1-4 were performed in an analogous manner to Example 1, Steps 1-4.
  • Step 5 ethyl 2-(4-fluorophenyl)-6-[(methylmlfonyl) ⁇ 2-[(methylsulfony
  • Step 6 ethyl 6- ⁇ [2-(benzylamino)ethyl](methylsnlfonyl)ammo ⁇ -2-(4-fluorophenyl)-5-phenyl-l-
  • Benzylamine (0.5 mL, 0.27 mmol) was added to a solution of mesylate (50 mg, 0.09 mmol) in Ets (1 mL) and MeCN (1 mL). The reaction mixture was stirred overnight at 60°C. After dilution with 3 ⁇ 40 and extraction with EtOAc, the mixture was washed with brine, dried over Na 2 SC>4 and filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by prep-TLC to give the benzylic amine (30 mg, yield: 58%).
  • Step 7 6-if2-(benzylamino)ethyllfmethylsulfonyl)amino ⁇ -2-(4-flnorophenyl)-5-phenyl-l-
  • the ester (30 mg, 0.05 mmol) was dissolved in 1,4-dioxane (1 mL) and 3 ⁇ 40 (1 mL). Then LiOH (21 mg, 0.5 mmol) was added to the solution, and the mixture was refluxed for 2 hours. After being acidified with HC1 (1 N) and extracted with EtOAc, the combined organic phases were washed with brine, dried over Na 2 SC>4, filtered and evaporated to give the carboxylic acid (22 mg, yield: 79%). The acid was used in the next step without further purification.
  • Step 8 6- ⁇ [2-(benzylamino)ethyl](methylsulfonyl)amino ⁇ -2-(4-fluorophe
  • Examples 124-132 were prepared according to the general procedures of
  • Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
  • Step 4 ethyl 2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amm ⁇
  • Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
  • Step 4 ethyl 2-(4-fluorophenyl)-6-[ ⁇ 2-[methyl(phenyl)amino]ethyll(methylsulfonyl)amino
  • Step 4 was performed in an an analogouos manner to Example 133, Step 4.
  • the crude product was purified by prep-TLC to give pure ethyl 2-(4-fluorophenyl)-6-[ ⁇ 2-
  • Step 5 2-(4-fluorophenyl)-6-[ ⁇ 2-[methyl(phenyl)amino]ethyl ⁇ (methylsulfonyl) amino5-phenyl-
  • Step 5 was performed in an analogous manner to Example 133, Step 5.
  • the crude product was purified by prep-TLC to give pure 2-(4-fluorophenyl)-6-[ ⁇ 2-[methyl(phenyl)amino] ethyl ⁇ (methyl sulfonyl) amino5-phenyl-l-benzofuran-3-carboxylic acid (50 mg, yield: 87%).
  • Step 6 was performed in an analogous manner to Example 133, Step 6.
  • the crude product was purified by prep-TLC to give pure 2-(4-fluorophenyl)-N-methyl-6-[ ⁇ 2- [methyl(phenyl)amino]ethyl ⁇ (methylsulfonyl)amino]-5-phenyl- 1 -benzofuran-3-carboxamide (13 mg, yield: 42%).
  • Step 2 Methyl 2-(5-bromo-2- tert-butyldimethylsilyl acetate
  • imidazole 0.56 g, 8.23 mmol
  • TBSC1 0.93 g, 6.17 mmol
  • the reaction mixture was washed with H 2 0, brine and concentrated in vacuo, the residue was purified by column chromatography to furnish the pure product of methyl 2-(5- bromo-2-(tert-butyldimethylsilyloxy)phenyl)acetate (1.4 g, yield: 95%).
  • Step 3 Methyl 2-(5-bromo-2-(tert-butyldimethylsilyloxy)phenyl)-3-(4-fluorophenyl)-3- oxopropanoate
  • Step 7 Methyl 6-amin -5-bromo-2-(4-fluorophenyl)-l-benzofuran-3-carboxylate
  • Step 8 Methyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)-l-benzofuran-3-carboxylate
  • Step 9 Methyl 5-bromo-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-l-benzofuran-3- carboxylate
  • Step 10 5-bromo-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-l-benzofuran-3- carboxylic acid
  • Step 12 5-(3-(benzo[d]thiazol-2-yl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(N-
  • Examples 136-142 were prepared according to the general procedures
  • Steps 1-11 were performed in an analogous manner to Example 135, Steps 1-11.
  • Step 12 2-(4-fluorophenyl)-5-(3-formylphenyl)-N-methyl-6-[methyl(methyl)
  • the aryl aldehyde (45 mg, yield: 73%) was prepared in an analogous manner to Example 136, Step 12.
  • Step 13 2-(4-fluorophenyl)-N-methyl-5-[ 3-( 5-methyl-l.3-benzothiazol-2-yl)phenyl]-6-
  • Examples 144-149 were prepared according to the general procedures of
  • Steps 1-12 were performed in an analogous manner to Example 143, Steps 1-12.
  • Step 13 5-[3-(5-fluoro-lH-benzimidazol-2-yl)phenyl]-2-(4-fluorophenyl)-N-m
  • Examples 151-154 were prepared according to the general procedures of Example 150.
  • Stable neomycin phosphotransferase encoding replicons-harboring cell lines were used, so all cell lines were maintained under G418 selection prior to the assay. Potency was deteremined using a cell ELISA assay with an antibody to the replicons encoded NS3/4a protease. See Caterina Trozzi et al , In Vitro Selection and Characterization of Hepatitis C Virus Serine Protease Variants Resistant to an Active-Site Peptide Inhibitor, 77(6) J. Virol. 3669 (2003). To initiate an assay, replicon cells were plated in the presence of a dilution series of test compound in the absence of G418.
  • the assays were performed in a 96-well plate formate for manual operation, or a 384-well plate format for automated assay. Replicon cells and compound were incubated for 96 hours. At the end of the assay, cells were washed free of media and compound, and the cells were then lysed. RNA was quantified indirectly through detection of replicon-encoded NS3/4A protein levels, through an ELISA-based assay with an antibody specific for NS3/4A. EC50 determinations were calculated as a percentage of a DMSO control by fitting the data to a four-parameter fit function.

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Abstract

Compounds of formula I that are used as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infection and for inhibiting HCV viral replication and /or viral production in a cell-based system.

Description

INHIBITORS OF HEPATITIS C VIRUS NS5B POLYMERASE
FIELD OF THE INVENTION
The present disclosure relates to antiviral compounds that are useful as inhibitors of the hepatitis C virus (HCV) NS5B (non-structural protein 5B) polymerase, compositions comprising such compounds, the use of such compounds for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection, methods for inhibiting the function of the NS5B polymerase, and methods for inhibiting HCV viral replication and/or viral production.
BACKGROUND OF THE INVENTION
Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals. Current treatments for HCV infection include immunotherapy with recombinant interferon-a alone or in combination with the nucleoside analog ribavirin.
Several virally-encoded enzymes are putative targets for therapeutic intervention, including a metalloprotease (NS2-3), a serine protease (NS3, amino acid residues 1-180), a helicase (NS3, full length), an S3 protease cofactor (NS4A), a membrane protein (NS4B), a zinc metalloprotein (NS5A) and an RNA-dependent RNA polymerase (NS5B).
One identified target for therapeutic intervention is HCV NS5B polymerase. Sven-Erik Behrens et al , Identification and properties of the RNA-dependent RNA polymerase of heptatitis C virus, 15(1) EMBO J. 12-22 (1996). Antagonists of NS5B activity are inhibitors of HCV replication. Steven S. Carroll et al, Inhibition of Hepatitis C Virus RNA Replication by 2'- Modified Nucleoside Analogs, 278(14) J. BIOL. CHEM. 1 1979-84 (2003).
There is a clear and long-felt need to develop effective therapeutics for treatment of HCV infection. Specifically, there is a need to develop compounds that selectively inhibit HCV viral replication and that would be useful for treating HCV-infected patients.
SUMMARY OF THE INVENTION
The present disclosure relates to novel compounds of formula I and/or pharmaceutically acceptable salts thereof. These compounds are useful, either as compounds or their pharmaceutically acceptable salts (when appropriate), in the inhibition of HCV (hepatitis C virus) NS5B (non- structural 5B) polymerase, the prevention or treatment of one or more of the symptoms of HCV infection, the inhibition of HCV viral replication and/or HCV viral production, and/or as pharmaceutical composition ingredients. As pharmaceutical composition ingredients, these compounds and their salts may be the primary active therapeutic agent, and, when appropriate, may be combined with other therapeutic agents including but not limited to other HCV antivirals, anti-infectives, immunomodulators, antibiotics or vaccines, as well as the present Standard of Care treatment options for HCV
to a compound of formula I:
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein:
each R1 is independently selected from the group consisting of halogens;
n is 0, 1, 2 or 3;
R2 is C(0)NRARB;
RA and RB are independently selected from the group consisting of hydrogen, Ci-Ce alkyl and 0(Ci-C6 alkyl);
R3 is ArA, wherein ArA is an aromatic ring system selected from the group consisting of:
i) 5- or 6-membered monocyclic rings, and
ii) 8-, 9- or 10-membered bicyclic rings, and
wherein said ArA is substituted by 0, 1, 2 or 3 substitutents Rc;
each Rc is independently selected from the group consisting of:
a) halogen,
b) OH
c) Ci-C6 alkyl,
d) 0(d-C6 alkyl),
e) CN, f) (CH2)o-3-ArB, wherein each ArB is an independently selected aromatic ring system selected from the group consisting of:
i) 5- or 6-membered monocyclic rings with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, and ii) 8-, 9- or 10-membered bicyclic rings with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, g) (CH2)o-3NRDC(0)RE,
h) (CH2)0-3NRDSO2RE,
i) (CH2)o-3C(0)NRDRE, and
j) (CH2)0-3SO2RE,
wherein each Rc c) d-C6 alkyl, d) 0(d-C6 alkyl), and f) (CH2)o-3-ArB is substituted by 0, 1, 2 or 3 substituents RF;
each RD is independently selected from the group consisting of hydrogen and Ci-6alkyl;
each RE is independently selected from the group consisting of hydrogen, Ci-6alkyl, OCi_6alkyl and 5- or 6-membered monocyclic rings with 0, 1 , 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, wherein each RE
Figure imgf000004_0001
OCi-6alkyl and 5- or 6-membered monocyclic rings is substituted by 0, 1, 2, 3 substituents independently selected from the group consisting of Ci-Ce alkyl, 0(Ci-C6 alkyl), halogen and OH;
each RF is independently selected from the group consisting of:
a) halogen,
b) Ci-C6 alkyl,
c) 0(Ci-C6 alkyl),
d) CN,
e) NH2,
f) (CH2)0-3-ArC, wherein each ArC is an independently selected aromatic ring system selected from the group consisting of:
i) 5- or 6-membered monocyclic rings with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, and ii) 8-, 9- or 10-membered bicyclic rings with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, wherein each RF b) C1-C6 alkyl, c) 0(Ci-C6 alkyl), and f) (CH2)o-3-ArC is substituted by 0, 1, 2 or 3 substituents RG;
each RG is independently selected from the group consisting of halogen, CN, Ci-ealkyl, 0(Ci-C6 alkyl), CF3 and C(0)OH;
R4 is selected from the group consisting of NRHR:;
RH is selected from the group consisting of:
a) hydrogen,
b) Ci.6alkyl,
c) C(0)0(C1-6alkyl), and
d) S02RJ;
RJ is selected from the group consisting of
Figure imgf000005_0001
and RXRY, where Rx and RY are independently selected from the group consisting of hydrogen and Ci-ealkyl;
R1 is selected from the group consisting of:
a) Ci_6alkyl,
b) C2-6alkenyl,
c) C2-6alkynyl,
d) (CH2)o-3(C3-8cycloalkyl),
e) (CH2)o-3(C3-gcycloalkenyl), and
f) C(0)Ci.6alkyl,
wherein R1 is substituted by 0, 1, 2, 3 or 4 R ;
each RK is independently selected from the group consisting of: a) ORL,
b) halogen,
c) CN,
d) NRMRN,
e) OC(0)Ci.6alkyl,
f) C(0)OCi.6alkyl,
g) (CH2)o-3-ArD, wherein each ArD is an independently selected aromatic ring system selected from the group consisting of: i) 5- or 6-membered monocyclic rings with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, and
ii) 8-, 9- or 10-membered bicyclic rings with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, wherein each RK e) OC(0)Ci.6alkyl, 1) C(0)OCi-6alkyL and g) (CH2)o-3-ArD is substituted by 0, 1, 2 or 3 substituents R°,
RL is selected from the group consisting of hydrogen,
Figure imgf000006_0001
and phenyl;
RM is selected from the group consisting of hydrogen, Ci.6alkyl and (CH2)0-3(phenyl);
RN is selected from the group consisting of hydrogen,
Figure imgf000006_0002
S02(Ci.6alkyl) and C(0)(C1.6alkyl);
or RM and RN are taken together with the N to which they are attached to form a 5- to 7-membered ring substituted by 0, 1, 2 or 3 Rp;
each R° is independently selected from the group consisting of halogen, Ci-6alkyl, OCi-6alkyl and C(0)0(Ci-6alkyl);
each Rp is independently selected from the group consisting of halogen, Ci-ealkyl, OCi-ealkyl, oxo and C(0)0(Ci_6alkyl);
or RH and R1 are taken together with the N to which they are attached to form a 5- to 7-membered ring.
The present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions. The present invention further includes methods of treating or reducing the likelihood or severity of HCV infection, methods for inhibiting the activity of the NS5B polymerase, and methods for inhibiting HCV viral replication and/or viral production.
Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims. DETAILED DESCRIPTION OF THE INVENTION
The present invention includes compounds of formula I above, and pharmaceutically acceptable salts thereof. The compounds of formula I are HCV NS5B polymerase inhibitors
In a first embodiment of the invention, n is 1. In this embodiment, all other groups are as provided in the general formula above.
In a second embodiment of the invention, the compound is a compound of formula la:
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof. In this embodiment, all other groups are as provided in the general formula above and/or in the first embodiment.
In a third embodiment of the invention, R is selected from the group consisting of fluorine, bromine and chlorine. In a first aspect of this third embodiment, R1 is fluorine. In all aspects of this embodiment, all other groups are as provided in the general formula above and/or in the first or second embodiments.
In a fourth embodiment of the invention, RA is hydrogen. In this embodiment, all other groups are as provided in the general formula above and/or in the first through third embodiments.
In a fifth embodiment of the invention, RB is selected from the group consisting of -CH3 and -OCH3 In this embodiment, all other groups are as provided in the general formula above and/or in the first through fourth embodiments.
In a sixth embodiment of the invention, ArA is phenyl. In this embodiment, all other groups are as provided in the general formula above and/or in the first through fifth embodiments.
In a seventh embodiment of the invention, each Rc is independently selected from the group consisting of a) fluorine, b) OH, c) C^alkyl, d) Od_3alky
Figure imgf000007_0002
Figure imgf000008_0001
g) (CH2)0.iN(CH3)SO2CH3, h) (CH2)o-iN(H)S02CH3, i) (CH2)o- iN(CH3)S02phenyl, j) C(0)NHCH3, k) (CH2)0-iN(H)C(O)CH3, and
1) (CH2)0-iN(H)C(O)phenyl. In a first aspect of this seventh embodiment each Rc is
Figure imgf000008_0002
Figure imgf000008_0003
. In all aspects of this embodiment, all other groups are as provided in the general formula above and/or in the first through sixth embodiments.
In an eighth embodiment of the invention, RH is selected from hydrogen, CH3 and S02CH3. In a first aspect of this eighth embodiment, RH is S02CH3. In all aspects of this embodiment, all other groups are as provided in the general formula above and/or in the first through seventh embodiments.
In a ninth embodiment of the invention, R1 is selected from the group consisting of Ci-6alkyl and C2_6alkenyl. In this embodiment, all other groups are as provided in the general formula above and/or in the first through eighth embodiments.
In a tenth embodiment of the invention, RK is selected from the group consisting of a) ORL, b) halogen, c) CN, d) NRMRN, e) OC(0)Ci.6alkyl, and f) C(0)OCi.6alkyl. In this embodiment, all other groups are as provided in the general formula above and/or in the first through ninth embodiments.
In an eleventh embodiment of the invention, RL is selected from the group consisting of Ci-ealkyl. In this embodiment, all other groups are as provided in the general formula above and/or in the first through tenth embodiments.
In a twelfth embodiment of the invention, RM is selected from the group consisting of hydrogen and Ci_6alkyl. In this embodiment, all other groups are as provided in the general formula above and/or in the first through eleveth embodiments. In a thirteenth embodiment of the invention, is selected from the group consisting of Ci_6alkyl and S02(Ci_6alkyl). In this embodiment, all other groups are as provided in the general formula above and/or in the first through twelfth embodiments.
In another embodiment of the invention, the compound of the invention is selected from the exemplary species depicted in Examples 1 through 154 shown below, and pharmaceutically acceptable salts thereof.
Other embodiments of the present invention include the following:
(a) A pharmaceutical composition comprising an effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
(b) The pharmaceutical composition of (a), further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents,
immunomodulators, and anti-infective agents.
(c) The pharmaceutical composition of (b), wherein the HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
(d) A pharmaceutical combination that is (i) a compound of formula I and (ii) a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents; wherein the compound of formula I and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HCV NS5B activity, or for inhibiting HCV viral replication, or for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
(e) The combination of (d), wherein the HCV antiviral agents are one or more antiviral agents selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
(f) A use of a compound of formula I in the preparation of a medicament for inhibiting HCV NS5B activity in a subject in need thereof.
(g) A use of a compound of formula I in the preparation of a medicament for preventing and/or treating infection by HCV in a subject in need thereof. (h) A method of treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula I.
(i) The method of (h), wherein the compound of formula I is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
(j) The method of (i), wherein the HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
(k) A method of inhibiting HCV viral replication and/ or HCV viral production in a cell-based system, which comprises administering to the subject an effective amount of a compound of formula I in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HCV antiviral agents,
immunomodulators, and anti-infective agents.
(1) The method of (k), wherein the HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
(m) A method of inhibiting HCV NS5B activity in a subject in need thereof, which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
(n) A method of treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection in a subject in need thereof, which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
In the embodiments of the compounds and salts provided above, it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination provides a stable compound or salt and is consistent with the description of the embodiments. It is further to be understood that the embodiments of compositions and methods provided as (a) through (n) above are understood to include all embodiments of the compounds and/or salts, including such embodiments as result from combinations of embodiments. Additional embodiments of the invention include the pharmaceutical compositions, combinations, uses and methods set forth in (a) through (n) above, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.
The present invention also includes a compound of the present invention for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) inhibiting HCV NS5B activity, or (b) inhibiting HCV viral replication, or (c) treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection, or (d) use in medicine. In these uses, the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from HCV antiviral agents, anti-infective agents, and immunomodulators.
As used herein, all ranges are inclusive, and all sub-ranges are included within such ranges, although not necessarily explicitly set forth. In addition, the term "or," as used herein, denotes alternatives that may, where appropriate, be combined; that is, the term "or" includes each listed alternative separately as well as their combination.
As used herein, the term "alkyl" refers to any linear or branched chain alkyl group having a number of carbon atoms in the specified range. Thus, for example, "Ci_6 alkyl" (or "Ci-Ce alkyl") refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. As another example, "C1.4 alkyl" refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. Alkyl groups may be substituted as indicated.
The term "halogenated" refers to a group or molecule in which a hydrogen atom has been replaced by a halogen. Similarly, the term "haloalkyl" refers to a halogenated alkyl group. The term "halogen" (or "halo") refers to atoms of fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
The term "alkoxy" refers to an "alkyl-O-" group. Alkoxy groups may be substituted as indicated.
The term "cycloalkyl" refers to any cyclic ring of an alkane or alkene having a number of carbon atoms in the specified range. Thus, for example, "C3-8 cycloalkyl" (or "C3-C cycloalkyl") refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, and cyclooctenyl. The term "cycloalkoxy" refers to a "cycloalkyl-O-" group. Cycloalkyl groups may be substituted as indicated.
The term "aryl" (or "aryl ring system") refers to aromatic mono- and poly- carbocyclic ring systems wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond. As used herein, the term aryl includes aromatic mono- and poly-carbocyclic ring systems that include from 0 to 4 heteroatoms (non-carbon atoms) that are independently chosen from N, O and S. Suitable aryl groups include phenyl, naphthyl, biphenylenyl, pyridinyl, pyrimidinyl and pyrrolyl, as well as those discussed below. Aryl groups may be substituted as indicated. Aryl ring systems may include, where appropriate, an indication of the variable to which a particular ring atom is attached. Unless otherwise indicated, substituents to the aryl ring systems can be attached to any ring atom, provided that such attachment results in formation of a stable ring system.
The term "carbocycle" (and variations thereof such as "carbocyclic") as used herein, unless otherwise indicated, refers to (i) a C5 to C7 monocyclic, saturated or unsaturated ring, or (ii) a Cg to C10 bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated. Carbocycle groups may be substituted as indicated. When the carbocycles contain one or more heteroatoms independently chosen from N, O and S, the carbocycles may also be referred to as
"heterocycles," as defined below. The carbocycle may be attached to the rest of the molecule at any carbon or nitrogen atom that results in a stable compound. The fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term "fused bicyclic carbocycle" generally refers to a Cs to Cio bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system. A fused bicyclic carbocycle in which both rings are saturated is a saturated bicyclic ring system. Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc. A fused bicyclic carbocycle in which one or both rings are unsaturated is an unsaturated bicyclic ring system. Carbocycle ring systems may include, where appropriate, an indication of the variable to which a particular ring atom is attached. Unless otherwise indicated, substituents to the ring systems can be attached to any ring atom, provided that such attachment results in formation of a stable ring system.
Unless indicated otherwise, the term "heterocycle" (and variations thereof such as "heterocyclic" or "heterocyclyl") broadly refers to (i) a stable 5- to 7-membered, saturated or unsaturated monocyclic ring, or (ii) a stable 8- to 10-membered bicyclic ring system, wherein each ring in (ii) is independent of, or fused to, the other ring or rings and each ring is saturated or unsaturated, and the monocyclic ring or bicyclic ring system contains one or more heteroatoms (e.g ., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) independently selected from N, O and S and a balance of carbon atoms (the monocyclic ring typically contains at least one carbon atom and the bicyclic ring systems typically contain at least two carbon atoms); and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally oxidized, and any one or more of the nitrogen heteroatoms is optionally quaternized. Unless otherwise specified, the heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure. Heterocycle groups may be substituted as indicated, and unless otherwise specified, the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results. Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl). Unless expressly stated to the contrary, the term
"heteroaryl ring system" refers to aryl ring systems, as defined above, that include from 1 to 4 heteroatoms (non-carbon atoms) that are independently chosen from N, O and S. In the case of substituted heteraromatic rings containing at least one nitrogen atom {e.g., pyridine), such substitutions can be those resulting in N-oxide formation. Representative examples of heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Representative examples of bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo- 1,4-dioxinyl and benzo-l,3-dioxolyl.
Unless otherwise specifically noted as only "substituted", alkyl, cycloalkyl, and aryl groups are not substituted. Preferably, the substituents are selected from the group which includes, but is not limited to, halo, C1-C20 alkyl, -CF3, -NH2, -N(Ci-C6 alkyl)2, -NO2, oxo, - CN, -N3, -OH, -0(Ci-C6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C6 alkyl) S(0)o-2-, aryl-S(O)0.2-, (C0-C6 alkyl)S(0)o-2(Co-C6 alkyl)-, (C0-C6 alkyl)C(0)NH-, H2N-C(NH)- , -0(Ci-C6 alkyl)CF3, (C0-C6 alkyl)C(O)-, (C0-C6 alkyl)OC(O)-, (Co-Qalky C d-Cs alkyl)-, (Co-C6 alkyl)C(0)i_2(Co-C6 alkyl)-, (C0-C6 alkyl)OC(0)NH-, aryl, aralkyl, heteroaryl, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle and halo-heterocyclylalkyl.
As used herein, the term "compound" is intended to encompass chemical agents described by generic formula I in all forms, including hydrates and solvates of such chemical agents. In addition, the term "compound" is intended to encompass prodrugs of the chemical agents described by generic formula I.
In the compounds of formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of formula I. For example, different isotopic forms of hydrogen (H) include protium (Ή) and deuterium (2H or D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
Isotopically-enriched compounds within formula I can be prepared without undue
experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heteroaryl ring described as containing from "0 to 3 heteroatoms" means the ring can contain 0, 1, 2, or 3 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. The oxidized forms of the heteroatoms N and S are also included within the scope of the present invention.
When any variable (for example, R1 or R3) occurs more than one time in any constituent or in formula I or in any other formula depicting and describing compounds of the invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom provided such substitution is chemically allowed and results in a stable compound. A "stable" compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g. , therapeutic or prophylactic administration to a subject).
As a result of the selection of substituents and substituent patterns, certain of the compounds of the present invention can have asymmetric centers and can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether isolated or in mixtures, are within the scope of the present invention.
As would be recognized by one of ordinary skill in the art, certain of the compounds of the present invention can exist as tautomers. For the purposes of the present invention a reference to a compound of formula I is a reference to the compound per se, or to any one of its tautomers per se, or to mixtures of two or more tautomers.
The compounds of the present inventions are useful in the inhibition of HCV replication (e.g., HCV NS5B activity), the treatment of HCV infection and/or reduction of the likelihood or severity of symptoms of HCV infection. For example, the compounds of this invention are useful in treating infection by HCV after suspected past exposure to HCV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for identifying resistant HCV replicon cell lines harboring mutations within NS5B, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to the HCV replicase.
The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt that possesses the effectiveness of the parent compound and that is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Many of the compounds of the invention carry an acidic moiety, in which case suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention mean providing the compound or a prodrug of the compound to the individual in need of treatment. When a compound of the invention is provided in combination with one or more other active agents (e.g., antiviral agents useful for treating HCV infection), "administration" and its variants are each understood to include concurrent and sequential provision of the compound or salt and other agents.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.
By "pharmaceutically acceptable" is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.
The term "subject" (alternatively referred to herein as "patient"), as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term "effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In one embodiment, the effective amount is a "therapeutically effective amount" for the alleviation of one or more symptoms of the disease or condition being treated. In another embodiment, the effective amount is a "prophylactically effective amount" for reduction of the severity or likelihood of one or more symptoms of the disease or condition. In another embodiment, the effective amount is a "therapeutically effective amount" for inhibition of HCV viral replication and/or HCV viral production. The term also includes herein the amount of active compound sufficient to inhibit HCV NS5B activity and thereby elicit the response being sought (i.e., an "inhibition effective amount"). When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free acid or free base form of the compound. For the purposes of inhibiting HCV NS5B polymerase, treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection and inhibiting HCV viral replication and/or HCV viral production, the compounds of the present invention, optionally in the form of a salt, can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by one or more
conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of the invention can, for example, be administered by one or more of the following: orally, parenterally
(including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation (such as in a spray form), or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like. Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders,
disintegrating agents and the like. Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as solubility aids. Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions of the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18th edition (ed. A. R. Gennaro, Mack Publishing Co., 1990).
The compounds of this invention can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses. One dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses. Another dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses. For oral administration, the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 mg of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, HCV viral genotype, viral resistance, and the host undergoing therapy.
As noted above, the present invention also relates to a method of inhibiting HCV NS5B activity, inhibiting HCV viral replication and/or HCV viral production, treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection with a compound of the present invention in combination with one or more therapeutic agents and a pharmaceutical composition comprising a compound of the present invention and one or more therapeutic agents selected from the group consisting of a HCV antiviral agent, an
immunomodulator, and an anti-infective agent. Such therapeutic agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha- 1, R7025 (an enhanced interferon (Roche)), interferon-β, interferon-α, pegylated interferon-α (peginterferon-a), a combination of interferon-α and ribavirin, a combination of peginterferon-α and ribavirin, a combination of interferon-α and levovirin, and a combination of peginterferon-α and levovirin. The combination of pegylated-interferon and ribaviron represents the current Standard of Care for HCV treatment. The combination of one or more compounds of the present invention with the Standard of Care for HCV treatment, pegylated-interferon and ribaviron is specifically contemplated as being encompassed by the present invention. Interferon-α includes, but is not limited to, recombinant interferon-a2a (such as ROFERON interferon available from Hoffmann- LaRoche, Nutley, NX), pegylated interferon-a2a (PEGASYS), interferon-a2b (such as INTRON-A interferon available from Schering Corp., Kenilworth, NJ), pegylated interferon-a2b
(PEGlNTRON), a recombinant consensus interferon (such as interferon alphacon-1), albuferon (interferon-α bound to human serum albumin (Human Genome Sciences)), and a purified interferon-α product. Amgen' s recombinant consensus interferon has the brand name INEERGEN. Levovirin is the L-enantiomer of ribavirin which has shown immunomodulatory activity similar to ribavirin. Viramidine represents an analog of ribavirin disclosed in International Patent Application Publication WO 01/60379. In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
For the treatment of HCV infection, the compounds of the invention may also be administered in combination with the antiviral agent NS5B polymerase inhibitor R7128 (Roche) The compounds of the present invention also may be combined for the treatment of HCV infection with antiviral 2'-C-branched ribonucleosides disclosed in Rogers E. Harry-O'Kuru et al., A Short, Flexible Route toward 2 '-C-Branched Ribonucleosides, 62 J. ORG. CHEM. 1754-59 (1997); Michael S. Wolfe & Rogers E. Harry-O'Kuru, A Concise Synthesis of2'-C- Methylribonucleosides, 36(42) TETRAHEDRON LETTERS 7611-14 (1995); U.S. Patent
No. 3,480,613; and International Patent Application Publications WO 01/90121, WO 01/92282, WO 02/32920, WO 04/002999, WO 04/003000 and WO 04/002422; the entire contents of each of which are incorporated by reference. Such 2'-C-branched ribonucleosides include, but are not limited to, 2'-C-methyl-cytidine, 2'-C-methyl-uridine, 2'-C-methyl-adenosine, 2'-C-methyl- guanosine, and 9-(2-C-methyl-P-D-ribofuranosyl)-2,6-diaminopurine, and the corresponding amino acid ester of the ribose C-2', C-3 ', and C-5' hydroxyls and the corresponding optionally substituted cyclic 1,3-propanediol esters of the 5'-phosphate derivatives.
For the treatment of HCV infection, the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS3 serine protease. HCV NS3 serine protease is an essential viral enzyme and has been described to be an excellent target for inhibition of HCV replication. Exemplary substrate and non-substrate based inhibitors of HCV NS3 protease inhibitors are disclosed in International Patent Application Publications WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, WO 02/48116, WO 02/48172, WO 2008/057208 and WO 2008/057209, in British Patent No. GB 2 337 262, and in U. S. Patent Nos. 6,323, 180 and 7,470,664.
The compounds of the present invention may also be combined for the treatment of HCV infection with nucleosides having anti-HCV properties, such as those disclosed in International Patent Application Publications WO 02/51425, WO 01/79246, WO 02/32920, WO 02/48165 and WO 2005/003147 (including R1656, (2'i?)-2'-deoxy-2'-fluoro-2'-C- methylcytidine, shown as compounds on page 77); WO 01/68663; WO 99/43691;
WO 02/18404 and WO 2006/021341, and U.S. Patent Application Publication US 2005/0038240, including 4'-azido nucleosides such as R1626, 4'-azidocytidine; U.S. Patent Application Publications US 2002/0019363, US 2003/0236216, US 2004/0006007, US 2004/0063658 and US 2004/0110717; U.S. Patent Nos. 7, 105,499, 7, 125,855, 7,202,224; and International Patent Application Publications WO 02/100415, WO 03/026589, WO 03/026675, WO 03/093290, WO 04/01 1478, WO 04/013300 and WO 04/028481 ; the content of each is incorporated herein by reference in its entirety.
For the treatment of HCV infection, the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS5B polymerase. Such HCV NS5B polymerase inhibitors that may be used as combination therapy include, but are not limited to, those disclosed in International Patent Application Publications
WO 02/057287, WO 02/057425, WO 03/068244, WO 2004/000858, WO 04/003138 and
WO 2004/007512; U. S. Patent Nos. 6,777,392, 7, 105,499, 7,125,855, 7,202,224 and U. S. Patent Application Publications US 2004/0067901 and US 2004/01 10717; the content of each is incorporated herein by reference in its entirety. Other such HCV polymerase inhibitors include, but are not limited to, valopicitabine (NM-283; Idenix) and 2' -F-2' -beta- methyl cytidine (see also WO 2005/003147).
In one embodiment, additional nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS5B inhibitors are selected from the following compounds: 4-amino-7-(2-C-methyl-p-D-arabinofuranosyl)-7H-pyrrolo[2,3-tf]pyrimidine; 4- amino-7-(2-C-methyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-i ]pyrimidine; 4-methylamino-7-(2-C- methyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-i/|pyrimidine; 4-dimethylamino-7-(2-C-methyl4 -D- ribofuranosyl)-7H-pyrrolo[2,3-c ]pyrimidine; 4-cyclopropylamino-7-(2-C-methyl- -D- ribofuranosyl)-7H-pyrrolo[2,3-c ]pyrimidine; 4-amino-7-(2-C-vinyl-p-D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine; 4-amino-7-(2-C-hydroxymethyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-c ]pyrimidine; 4-amino-7-(2-C-fluoromethyl-P-D-ribo ranosyl)-7H- pyrrolo[2,3-c ]pyrimidine; 4-amino-5-methyl-7-(2-C-methyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine; 4-amino-7-(2-C-methyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine-5-carboxylic acid; 4-amino-5-bromo-7-(2-C-methyl-P-D- ribofuranosyl)-7H-pyrrolo[2,3-cif]pyrimidine; 4-amino-5-chloro-7-(2-C-methyl-P-D- ribofuranosyl)-7H-pyrrolo[2,3-i/]pyrimidine; 4-amino-5-fluoro-7-(2-C-methyl-P-D- ribofuranosyl)-7H-pyrrolo[2,3-ci ]pyrimidine; 2,4-diamino-7-(2-C-methyl-P-D-ribofuranosyl)- 7H-pyrrolo[2,3-c¾pyrimidine; 2-amino-7-(2-C-methyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-^pyrimidine; 2-amino-4-cyclopropylamino-7-(2-C-methyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-c/]pyrimidine; 2-amino-7-(2-C-methyl- -D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidin-4(3H)-one; 4-amino-7-(2-C-ethyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-i/]pyrimidine; 4-amino-7-(2-C,2-0-dimethyl- -D-ribofuranosyl)-7H- pyrrolo[2,3-c/]pyrimidine; 7-(2-C-methyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-c/]pyrimidin-4(3H)- one; 2-amino-5-methyl-7-(2-C, 2-0-dimethyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-c ]pyrimidin- 4(3H)-one; 4-amino-7-(3-deoxy-2-C-methyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-cirjpyrimidine; 4-amino-7-(3-deoxy-2-C-methyl-P-D-arabinofuranosyl)-7H-pyrrolo[2,3-i ]pyrimidine; 4-amino- 2-fluoro-7-(2-C-methyl-P-D-ribofnranosyl)-7H-pyrrolo[2,3-i ]pyrimidine; 4-amino-7-(3-C- methyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-i/jpyrimidine; 4-amino-7-(3-C-methyl-P-D- xylofuranosyl)-7H-pyrrolo[2,3-^pyrimidine; 4-amino-7-(2,4-di-C-methyl-P-D-ribofuranosyl)- 7H-pyrrolo[2,3-t/|pyrimidine; 4-amino-7-(3-deoxy-3-fluoro-2-C-methyl- -D-ribofuranosyl)-7H- pyrrolo[2,3-c/]pyrimidine; and the corresponding 5'-triphosphates; or a pharmaceutically acceptable salt thereof.
The compounds of the present invention may also be combined for the treatment of HCV infection with non-nucleoside inhibitors of HCV polymerase such as those disclosed in U.S. Patent Applciation Publications US 2006/0100262 and US 2009/0048239; International Patent Application Publications WO 01/77091, WO 01/47883, WO 02/04425, WO 02/06246, WO 02/20497, WO 2005/016927 (in particular JTK003), WO 2004/041201, WO 2006/066079, WO 2006/066080, WO 2008/075103, WO 2009/010783 and WO 2009/010785; the content of each is incorporated herein by reference in its entirety.
In one embodiment, additional non-nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS5B inhibitors are selected from the following compounds: 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5, 6,7,8- tetrahydroindolo[2, l- ][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-(2-morpholin- 4-ylethyl)-5,6,7,8-tetrahydroindolo[2, l-a][2,5]benzodiazocine-l l-carboxylic acid; 14- cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-5,6,7,8-tetrahydroindolo[2, l-a]
[2, 5 ]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-3-methoxy-6-methyl-5, 6,7,8- tetrahydroindolo[2, 1 -a] [2,5]benzodiazocine-l 1-carboxylic acid; methyl ({[(14-cyclohexyl-3- methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2, l-a][2,5]benzodiazocin-l 1- yl)carbonyl]amino}sulfonyl)acetate; ({ [(14-cyclohexyl-3-methoxy-6-methyl-5, 6,7,8- tetrahydroindolo[2, l-a][2,5]benzodiazocin-l l-yl)carbonyl] amino } sulfonyl)acetic acid; 14- cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,l-a] [2, 5 ]benzodiazocine- 11 -carboxamide; 3 -chloro- 14-cyclohexyl-6-[2-(dimethylamino)ethyl] -7- oxo-5,6,7,8-tetrahydroindolo[2, l-a][2,5]benzodiazocine 11-carboxylic acid; N-(l l-carboxy-14- cyclohexyl-7,8-dihydro-6H-indolo[l,2-e][l,5]benzoxazocin-7-yl)-N,N-dimethylethane-l,2- diaminium bis(trifluoroacetate); 14-cyclohexyl-7,8-dihydro-6H-indolo[l,2-e][l,5]
benzoxazocine-11-carboxylic acid; 14-cyclohexyl-6-methyl-7-oxo-5,6,7,8-tetrahydroindolo [2, l- ][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-3-methoxy-6-methyl-7-oxo- 5,6,7,8-tetrahydroindolo[2,l- ][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-[2- (dimethylamino)ethyl] -3 -methoxy-7-oxo-5, 6, 7,8-tetrahydroindolo[2, 1 -a] [2, 5 ]benzodiazocine- 11-carboxylic acid; 14-cyclohexyl-6-[3-(dimethylamino)propyl]-7-oxo-5,6,7,8-tetrahydroindolo [2, l- ][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-7-oxo-6-(2-piperidin-l-ylethyl)- 5,6,7,8-tetrahydroindolo[2,l- ][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-(2- morpholin-4-ylethyl)-7-oxo-5,6,7,8-tetrahydroindolo[2, l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-[2-(diethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2, l-a]
[2, 5 ]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-(l-methylpiperidin-4-yl)-7-oxo-
5.6.7.8- tetrahydroindolo[2,l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-N- [(dimethylamino)sulfonyl]-7-oxo-6-(2-piperidin-l-ylethyl)-5,6,7,8-tetrahydroindolo[2, l- ] [2, 5 ]benzodiazocine- 11 -carboxamide; 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-N- [(dimethylamino)sulfonyl] -7-0X0-5, 6,7, 8-tetrahydroindolo [2, 1 -a] [2, 5]benzodiazocine- 1 1 - carboxamide; 14-cyclopentyl-6-[2-(dimethylamino)ethyl] -7-oxo-5 , 6, 7, 8-tetrahydroindolo [2, 1 -a] [2, 5 ]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-5,6,7,8-tetrahydroindolo[2, l-a]
[2, 5 ]benzodiazocine-l 1-carboxylic acid; 6-allyl-14-cyclohexyl-3-methoxy-5, 6,7,8- tetrahydroindolo[2, 1 -a] [2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclopentyl-6-[2- (dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,l- ][2,5]benzodiazocine- 11-carboxylic acid; 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2, l- ][2,5]benzodiazocine- 11-carboxylic acid; 13-cyclohexyl-5-methyl-4,5,6,7-tetrahydrofuro[3',2':6,7][l,4]diazocino[l,8- a]indole-10-carboxylic acid; 15-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-6,7,8,9- tetrahydro-5H-indolo[2,l-a][2,6]benzodiazonine-12-carboxylic acid; 15-cyclohexyl-8-oxo-
6.7.8.9- tetrahydro-5H-indolo[2, l- ][2,5]benzodiazonine-12-carboxylic acid; 13-cyclohexyl-6- oxo-6,7-dihydro-5H-indolo[l,2-i ][l,4]benzodiazepine-10-carboxylic acid; and pharmaceutically acceptable salts thereof. In another embodiment, the present HCV NS5B polymerase inhibitors are used in combination with non-nucleoside HCV NS5A inhibitors and pharmaceutically acceptable salts thereof.
The HCV NS5B inhibitory activity of the present compounds may be tested using assays known in the art. The HCV NS5B polymerase inhibitors described herein have activities in a genotype lb replicon assay as described in the Examples. The assay is performed by incubating a replicon harboring cell-line in the presence of inhibitor for a set period of time and measuring the effect of the inhibitor on HCV replicon replication either directly by quantifying replicon RNA level, or indirectly by measuring enzymatic activity of a co-encoded reporter enzyme such as luciferase or β-lactamase. By performing a series of such measurements at different inhibitor concentrations, the effective inhibitory concentration of the inhibitor (EC50 or EC90) is determined. See Jan M. Vrolijk et al. , A replicons-based bioassay for the measurement of interferons in patients with chronic hepatitis C, 1 10 J. ViROLOGiCAL METHODS 201 (2003). Such assays may also be run in an automated format for high through-put screening. See Paul Zuck et al. , A cell-based β-lactamase reporter gene assay for the identification of inhibitors of hepatitis C virus replication, 334 ANALYTICAL BIOCHEMISTRY 344 (2004).
The present invention also includes processes for making compounds of formula I. The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. The following reaction schemes and examples serve only to illustrate the invention and its practice.
General Schemes
Sch
Figure imgf000024_0001
This scheme describes the preparation of compounds with the general structure of G and H. Starting from compound A (obtained according to procedure in WO 2004/041201 A2), coupling with a substituted or unsubstituted phenylboronic acid catalyzed by a transition metal, in this case Pd(dppf)Cl2, furnishes compounds of the general structure B. This type of transition- metal-mediated cross-coupling is common and there are numerous conditions that one skilled in the art can use to execute such a transformation. Compounds of type C are next generated by reduction of the nitro group in compound B, which can be accomplished by exposure to common reducing conditions, in this case treatment by Fe in NH4CI solution under reflux. The amino group in compounds C is then sulfonylated with a sulphonyl chloride to give compounds of type D. The sulfonamide D can be coupled with an alkylating agent (an alkyl halide for example) in the presence of a suitable base, such as potassium carbonate, to provide compounds E. The ester functionality in compounds E is readily hydrolyzed by aqueous base to afford compounds F. The carboxylic acid of compound F was condensed with methanamine or
( -methylhydroxylamine using common amide-forming reagents such as EDCI and HOBT to give compounds G or compounds H. Sche
Figure imgf000025_0001
Compound C can be coupled with an alkylating agent (an alkyl halide for example) in the presence of a suitable base, such as potassium carbonate, to provide compounds I where Z represents an alkylated aniline. Alternatively C may be condensed with substituted carboxylic acid in the presence of coupling reagents, such as EDCI and HOBT, to afford compounds I where Z represents a substituted amide. Compounds J may be obtained from compounds I by further N-alkylation or N-acylation reaction. Compounds of general structure I or J are hydrolyzed by aqueous hydroxide to provide compounds F. The carboxylic acid of compound F may be condensed with an amine as shown in Scheme 1 to provide target compounds of general structure G and H.
Scheme
Figure imgf000025_0002
Compound A may be reduced by a catalyst in the presence of a hydrogen source (for example, Pd in the presence of formic acid) to afford compound K. Further reduction of K provides aniline L. The amino group of compound L is reacted with sulfonyl chloride to afford compound M, which can be further N-alkylated with a wide variety of alkylating agents in the presence of a suitable base, such as potassium carbonate, to provide compound Ν. Halogenation of compound Ν, in this case bromination with FeCl3 and Br2 in anhydrous CCU gives compound O. Compounds of general structure O are hydrolyzed by aqueous hydroxide to provide compounds P. The carboxylic acid of compound P may be condensed with an amine as shown in Scheme 1 to provide compounds of general structure Q. Transition metal mediated coupling of compounds Q with a boronic acid (alternatively alkyl tin, silicon, or other types of coupling partners may be used) provides the target compounds of general structure G.
Scheme 4
Figure imgf000026_0001
Compounds E that possess a hydroxyl group may be obtained from compounds D by reacting with 2-bromo ethanol. The hydroxyl group E can be converted to a leaving group (by reaction with MsCl for example) to afford compound R. Compound R may be treated with nucleophilic reagents such as an amine in the presence of a suitable base, such as triethylamine, to afford compound S. Compounds T can then be obtained from compound S by further N-alkylation or N-acylation. Compounds of structure T are readily converted to the target structures G following the general procedure described in Scheme 1.
Sche
Figure imgf000027_0001
This scheme describes the preparation of compounds with the general structure of M'. Starting from compound A', bromating and esterifying with TBATB in MeOH to afford compound BV Protecting the phenol group of B' with TBSC1 provides compound C, which can be C-acylated with 4-fluorobenzoyl chloride to give compound D'. After de-protection with TBAF and cyclizing by concentrated HC1, compound D' affords compound E' and F
sequentially. Compound F' can be converted to compound G' by treated with fuming HNO3. Compound H' is generated by reduction of the nitro group in compound G', and the amino group in compound H' is then sulfonylated with MsCl to furnish compound I'. The sulfonamide I' can be coupled with Mel in the presence of potassium carbonate to provide compound J' . The ester functionality in compound J' is readily hydro lyzed by aqueous base to afford compound K'. The carboxylic acid of compound K' was condensed with methanamine using common amide forming reagents such as EDCI and HOBT to give compound L'. Transition metal mediated coupling of compound L' with a meta-heterocycle-substituted phenyl boronic ester (alternatively boronic acid, alkyl tin, silicon, or other types of coupling partners may be used) provides the target compounds of general structure M'. Scheme 6
Figure imgf000028_0001
P'
Coupling compound L' with a substituted or unsubstituted 3-formylphenylboronic acid catalyzed by a transition metal, in this case Pd(dppf)Cl2, furnishes compounds of the general structure N\ Compounds of type N' were cyclized with ortho-amino anilines or ortho-amino thiophenols to provide the target compounds of general structure O' or P'.
List of Abbreviations
AcOH Acetic acid
Br2 Bromine
Bu3N N,N-dibutylbutan- 1 -amine
CC14 Carbon tetrachloride or tetrachloromethane
CDC13 Trichloro(2H)methane or deuterio-trichloromethane
CH3I Methyl iodide
Cs2C03 Cesium carbonate
Cul Copper iodide
DCM Dichloromethane
DMF Dimethylformamide
DMSO Dimethylsulfoxide
EDCI N-(3-Dimethylaminopropyl)-N'-ethylcarbodhmide (also EDC)
Et3N Triethylamine EtOAc Ethyl acetate
EtOH Ethanol
EtOOCCl, CICOOEt Ethyl chloroformate
Fe Iron
FeCl3 Ferric chloride or Iron(III) chloride
HC1 Hydrochloric acid
¾ Hydrogen gas or atmosphere
H20 Water
HCOOH Formic Acid
HOBT 1 -Hydroxy benzotriazole
XH-NMR Proton Nuclear Magnetic Resonance
HPLC High Performance Liquid Chromatography
K2C03 Potassium carbonate
KI Potassium iodide
K3PO4 Potassium Phosphate
LiHMDS Lithium bis(trimethylsilyl) amide
LiOH Lithium hydroxide
MeM¾, CH3NH2 Methanamine
MeCN, CH3CN Acetonitrile
MeOD Methan(2H)ol
MeOH Methanol
MeONH2, CH3ONH2 Methoxy amine
MS Mass spectroscopy
Ms Methanesulfonyl (or mesyl) group
MsCl Methanesulfonyl chloride
N2 Nitrogen gas or atmosphere
Ni Nickel
Na2S03 Sodium sulfite
Na2S04 Sodium sulfate (anhydrous)
NaH Sodium hydride
NaN02 Sodium nitrate
NH4CI Ammonium chloride Pd Palladium
Pd(dppf)Cl2 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
Pd(PPh3)2Cl2 1 , 1 '-bis(tetrakis(triphenylphosphine))palladium(II)dichloride
Ph Phenyl
PhB(OH)2 Phenylboronic acid
PhN02 Nitrobenzene
Py Pyridine
RT Room temperature, approximately 25 °C
S0C12 Thionyl chloride
TBAF Tetrabutyl ammonium fluoride
TBATB Tetrabutylammonium tribromide
TBS Tert-butyldimethylsilyl
TBSC1 Tert-butyldimethylsilylchloride
Tf Triflate
THF Tetrahydrofuran
TLC Thin layer chromatography
EXAMPLES
Example 1: 2- 4-fluorophenvn-Ar-methyl-6-[methyl(methylsulfonYnaminol-5-phenyl-l- benzofuran-3-carboxamide
Figure imgf000030_0001
Step 1: ethyl 2-(4-fluorophenyl)-6-nitro-5-phenyl-l-benzofuran-3-carboxylate
Figure imgf000030_0002
Phenylboronic acid (100 mg, 0.8 mmol) and K3P04-3H20 (119 mg, 0.8 mmol) were added to a suspension of ethyl 2-(4-fluorophenyl)-6-nitro-5-{[(trifluoromethyl)sulfonyl] oxy}-l-benzofuran-3-carboxylate (obtained according to procedure in WO 2004/041201 A2, 200 mg, 0.4 mmol) in dioxane (2 mL) and DMF (2 mL) under N2 protection. Then, Pd(dppf)Cl2 (5 mg, 0.08 mmol) was added to the mixture under N2 protection. The reaction mixture was heated to 90°C for 30 minutes. After cooling, the mixture was diluted with H20 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and evaporated. The crude product was purified by prep-TLC to give pure ethyl 2-(4- fluorophenyl)-6-nitro-5-phenyl-l-benzofuran-3-carboxylate (35 mg, yield: 23%).
'H-NMR (400 MHz, CDC13) δ 7.88-7.98 (m, 2H), 7.62 (s, 1H), 7.44-7.48 (m, 4H), 7.32-7.38 (m, 1H), 7.06-7.12 (m, 2H), 6.78 (s, IK), 4.29-4.35 (m, 2H), 1.27-1.30 (m, 3H) Step 2: ethyl 6-amino-2-(4-fluorophenyl)-5-phenyl-l-benzofuran-3-carboxylate
Figure imgf000031_0001
A mixture of ethyl 2-(4-fluorophenyl)-6-nitro-5-phenyl-l-benzofuran-3- carboxylate (110 mg, 0.27 mmol), Fe (120 mg, 2.16 mmol) and NH4C1 (217 mg, 4.05 mmol) in H20 MeOH /THF (l mL /l mL /l mL) was refluxed for 4 hours. Then, H20 was added to quench the reaction, and the mixture was extracted with EtOAc. After washing with brine and dried, the solvent was removed by distillation. The pure product of ethyl 6-amino-2-(4- fluorophenyl)-5-phenyl-l-benzofiiran-3 -carboxylate was obtained (85 mg, yield: 85%) by prep- TLC.
'H-NMR (400 MHz, CDCI3) δ 8.00-8 03 (m, 2H), 7.85 (d, J= 7 2 Hz, 2H), 7.45-7.49 (m, 3H), 7.29-7.32 (m, 2H), 7.10-7.14 (m, 2H), 4.29-4.35 (m, 2H), 1.27-1.30 (m, 3H).
Step 3: ethyl 2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-5^henyl-l-benzofuran-3- carboxylate
Figure imgf000031_0002
MsCI (66 mg, 0.6 mmol) was added to a solution of the product of Step 2 (85 mg, 0.23 mmol) and pyridine (73 mg, 0.92 mmol) in dry DCM (2 mL). The reaction mixture was stirred overnight at RT. After dilution with H20 and extraction with DCM, the organic layer was washed with brine, dried over Na2S04 and filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by prep-TLC to give ethyl 2-(4-fluorophenyl)- 6-[(methylsulfonyl)amino]-5-phenyl-l-benzofuran-3-carboxylate (90 mg, yield: 86%). 'H-NMR (400 MHz, CDCI3) δ 8.00-8 03 (m, 2H), 7.85 (d, J= 7.2 Hz, 2H), 7.45-7.49 (m; 3H), 7.29-7.32 (m, 2H), 7.10-7.14 (m, 2H), 6.50 (s, 1H), 4.29-4.35 (m, 2H), 2.80 (s, 3H), 1.27-1.30 (m, 3H).
Step 4: ethyl 2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-5-phenyl-l-bem
carboxylate
Figure imgf000032_0001
NaH (60% in oil, 20 mg, 0.5 mmol) and CH3I (85 mg, 0.6 mmol) were added to a solution of the product of Step 3 (90 mg, 0.2 mmol) in dry DMF under N2 protection. The mixture was stirred overnight at RT, and then ice-cold diluted AcOH was added to the mixture. After extraction with EtOAc, the organic solvent was washed with brine, dried over Na2SC>4, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by prep-TLC to give ethyl 2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-5-phenyl-l- benzofuran-3 -carboxylate (78 mg, yield: 84%).
'H-NMR (400 MHz, CDCI3) δ 8.00-8.02 (m, 2H), 7.97-7.98 (m, 1H), 7.55-7.56 (m, 1H), 7.39-7.40 (m, 4H), 7.32-7.34 (m, 1H), 7.11-7.15 (m, 2H), 4.32 (q, J= 7.2 Hz, 2H), 3.11 (s, 3H), 2.45 (s, 3H), 1.26-1.30 (t, J= 6.8 Hz, 3H).
Step 5: 2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-5^henyl-l-benzofuran- carboxylic acid
Figure imgf000032_0002
The product of Step 4 (78 mg, 0.17 mmol) was dissolved in THF (2 mL) and H20 (2 mL) Then, Li OH (71 mg, 1.7 mmol) was added to the solution, and the mixture was stirred at RT overnight. After acidification with HC1 (1 N) and extraction with EtOAc, the combined organic phases were washed with brine, dried over Na2S04, filtered and evaporated to give the product of 2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-5-phenyl- 1 -benzofuran-3- carboxylic acid (50 mg, yield: 67%). It was used for the next step without further purification. Step 6: 2-(4-fluorophenyl)-N-methyl-6-[methyl(methylsulfonyl)amino
3-carboxamide
Figure imgf000033_0001
The product of Step 5 (50 mg, 0. 1 1 mmol), HOBT (24.5 mg, 0.16 mmol) and EDCI (52 mg, 0.27 mmol) were dissolved in dry DMF (2 mL). The resulting solution was stirred for 30 minutes. Then, methanamine (HCl salt, 14 mg, 0.44 mmol) and Et3 (50 mg, 0.47 mmol) were added to the mixture. After stirring overnight, the mixture was diluted with ¾0 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SC>4, filtered and evaporated. The crude product was purified by prep-TLC to give pure 2-(4-fluorophenyl)-N-methyl-6-[methyl(methylsulfonyl)amino]-5-phenyl-l-benzofuran-3- carboxamide (20 mg, yield: 40%).
'H-NMR (400 MHz, CDC13) δ 7.92-7.96 (m, 2H), 7.59 (s, 1H), 7.52-7.54 (m, 1H), 7.29-7.47 (m, 5H), 7. 11-7.18 (m, 2H), 5.84 (s, 1H), 3.25 (s, 3H), 2.98 (d, J= 7.2 Hz, 3H), 2.61 (s, 3H).
Examples 2-6
Examples 2 through 6 were prepared according to the general procedures
Example 1.
Figure imgf000033_0002
Figure imgf000034_0001
Example 7: 2-f4-fluorophenvn-7Y-methoxy-6-[inethyl(methylsulfonvnaininol-5-phenyl-l- bcnzofuran-3-carboxamidc
Figure imgf000034_0002
Steps 1-5
Steps 1-5 were performed in accordance with Example 1, Steps 1-5.
Step 6: 2-(4-fluorophenyl)-N-methoxy-6-[meth l(methylsulfonvUamino]-5-^
3-carboxamide
Figure imgf000034_0003
The product of Step 5 (50 mg, 0.11 mmol), HOBT (24.5 mg, 0.16 mmol) and EDCI (52 mg, 0.27 mmol) were dissolved in dry DMF (2 mL). The resulting solution was stirred for 30 minutes. Then, O-methylhydroxylamine (HC1 salt, 36 mg, 0 44 mmol) and Et3N (50 mg, 0.47 mmol) were added to the mixture. After stirred overnight, the mixture was diluted with H20 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SC>4, filtered and evaporated. The crude product was purified by prep-TLC to give pure product (20 mg, yield: 40%). ^-NMR (400 MHz, CDC13) δ 8.26-8.27 (m, 1H), 7.70-7.87 (m, 2H), 7.56 ( 1H), 7.41 (s, 1H), 7.34-7.39 (m, 5H), 7.12-7. 16 (m, 2H), 3.78 (s, 3H), 3.10 (s, 3H), 2.45 (s, MS (M+H)+: 469.
Examples 8-12
Examples 8- 12 were prepared according to the general procedures of Example 7.
Figure imgf000035_0001
Example 13: 6-[icYclohexYlmethvnimethylsulfonyl aininol-2-(4-fluorophenYn-jV-inethyl-5-
Figure imgf000036_0001
Steps 1-3
Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
Step 4: 2-(4-fluorophenyl)-6-[{methylsulfonyl)amino]-5^henyl-l-benz acid
Figure imgf000036_0002
The compound prepared in Step 3 (1.3 g, 2.74 mmol) was dissolved in 1,4- dioxane (7 mL) and H20 (7 mL). Then, LiOH (1.14, 27.4 mmol) was added to the solution, and the mixture was refluxed for 2 hours. After acidified with HCl (1 N) and extracted with EtOAc, the combined organic phases were washed with brine, dried over Na2S04, filtered and evaporated to give the carboxylic acid (990 mg, yield: 85%). It was used for the next step without further purification.
Step 5: 2-(4-fluorophenyl)-N-methyl-6-[ (methylsuIfonyl)amino]-5-phenyl-l-benzofuran-3- carboxamide
Figure imgf000036_0003
The carboxylic acid prepared in Step 4 (990 mg, 2.34 mmol), HOBT (631 mg, 4.7 mmol) and EDCI (900 mg, 4.7 mmol) were dissolved in dry DMF (10 mL). The resulting solution was stirred for 30 minutes. Then, methanamine (HCl salt, 640 mg, 9.4 mmol) and Et3N (2 mL) were added to the mixture. After stirred overnight, the mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and evaporated. The crude product was purified by column to give pure 2-(4- fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-5-phenyl-l-benzofuran-3-carboxamide (900 mg, yield: 88%). 'H-NMR (400 MHz, CDCI3) δ 7.82-7.86 (m, 2H), 7.79 (s, 1H), 7.63 (s, 1H), 7.41-7.46 (m, 3H), 7.27-7.33 (m, 2H), 7.10-7.44 (m, 2H), 6.51 (br, lH), 5.84 (br, 1H), 2.91 (d, J = 4.8 Hz, 3H), 2.80 (s, 3H). MS (M+H)+: 439.
Step 6: 6-[(cyclohexylmethyl)(methylsulfonyl)amino]-2-(4-fluoropheny
Figure imgf000037_0001
The compound prepared in Step 5 (35 mg, 0.08 mmol), (bromomethyl) cyclohexane (21 mg, 0.12 mmol), K2C03 (22 mg, 0.16 mmol), KI (2 mg) in DMF (2 mL) was stirred at 90°C for 16 hours under N2. The mixture was concentrated, diluted with DCM, washed with brine, dried over Na2SC>4, filtered and the solvent was evaporated. The residue was purified by prep-HPLC to give pure product (15 mg, yield: 35%).
'H-NMR (400 MHz, CDCI3) δ 7.97-7 93 (m, 2H), 7.73 (s, 1H), 7.58 (s, 1H), 7.52-7.50 (m, 2H), 7.44-7.37 (m, 3H), 7.24-7.16 (m, 2H), 5.84 (s, 1H), 3.18-3.13 (m, 1H), 2.99-2.97 (m, 4H), 2.95 (s, 3H), 1.74-1.58 (m, 1H),1.54~1.51 (m, 2H), 1.43-1.41 (m, 2H), 1.04-0.91 (m, 4H), 0.89-0.79 (m, 2H), 0.76-0.56 (m, 1H). MS (M+H)+: 535.
Examples 14-68
Examples 14-68 were prepared according to the general procedures of
Example 13.
Figure imgf000037_0002
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
carboxamide
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
carboxylate
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Example 69: 2-r4-fluorophenyl)-ALmethyl-5-phenyl-6-[ i-phenylethyl)aminol-l- benzofuran-3-carboxamide
Figure imgf000047_0002
Steps 1-3
Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
Figure imgf000047_0003
A mixture of the product of Step 3 (400 mg, 1.06 mmol), (1-bromoethyl) benzene (197 mg, 1.06 mmol) and Cs2C03 (7.8 g, 24 mmol) in dry DMF (100 mL) was stirred at 140°C for 4 hours. After the mixture was concentrated, the residue was diluted with DCM, washed with water, dried over a2S04 and concentrated. The residue was purified by prep-TLC to give the product (200 mg, yield: 39%).
^-NM (400 MHz, CDC13) δ 7.90-7.88 (m, 2H), 7.62 (s, 1H), 7.47-7.45 (m, 2H), 7.45-7.44 (m, 1H), 7.26-7.25 (m, 5H), 7.18-7.17 (m, 2H), 7.04-7.03 (m, 2H), 6.45 (s, 1H), 4. 42-4.41 (m, 1H), 4 28-4.26 (q, J= 8.0 Hz, 2H), 1.36-1.34 (d, J= 8.0 Hz, 3H), 1.26-1.24 (t, J = 8.0 Hz, 3H). MS (M+H)+: 480.
Step 5: 2-(4-fluorophenyl)-5-phenyl-6-[(l^henylethyl)amino]-l-benzofuran-3-carboxylic acid
Figure imgf000048_0001
The product (1 10 mg, yield: 58.4%) was prepared in an analogous manner to Example 13 using the general procedure in Example 13, Step 4. The crude product was used in the next step without further purification.
'H-NMR (400 MHz, CDC13) δ 7.93-7.89 (m, 2H), 7.70 (s, 1H), 7.46-7.45 (m,
4H), 7.42-7.40 (m, 1H), 7.38-7.35 (m, 4H), 7.07-7.03 (m, 3H), 6.50 (s, 1H), 4.44-4.39 (m, 1H), 1.37-1.36 (d, J= 4.0 Hz, 3H). MS (M+H)+: 452.
Step 6: 2-(4^uorophenyl)-N-methyl-5-phenyl-6-[(l-phenylethyl)ammo]- carboxamide
Figure imgf000048_0002
Example 69 (20 mg, yield: 48.6%) was prepared according to the general procedure in Example 1, Step 6.
'H-NMR (400 MHz, CDCI3) δ 7.82-7.78 (m, 2H), 7.45-7.44 (m, 4H),
7.36-7.35(m, 2H), 7.27-7.25 (m, 4H), 7.18-7.16 (m, 2H), 7.05-7.01 (m, 2H), 6.48 (s, 1H), 5.72 (s, 1H), 4.44-4.39 (m, 1H), 2.89-2.87 (s, 3H), 1.37-1.35 (d, J= 8.0 Hz, 3H). MS (M+H)+: 465.
Example 70: 2-f4-fluorQphenyl)-A-methyl-6-({2-[methyl(phenyl)aminolethyl}amino)-5- phenyl-l-benzofuran-3-carboxamide
Example 70 was prepared according to the general procedures of Example 69.
Example 71: 2-r4-fluorophenyl)-A-inethyl-6-[methylfl-phenYlethvnaminol-5-phenyl-l- benzofuran-3-carboxamide
Figure imgf000049_0001
Steps 1-4
Steps 1-4 were performed in accordance with Example 69, Steps 1-4.
Step 5: ethyl 2-(4-fluorophenyl)-6-[methyl(l^henylethyl)amino]
carboxylate
The product of Step 4 (62 mg, 0.13 mmol), CH3I (29 mg, 0.20 mmol), K2C03 (37 mg, 0.27 mmol) in DMF (2 mL) was stirred at 90°C for 16 hours. The mixture was quenched with water, diluted with DCM, dried over Na2SC>4, filtered, and the solvent was evaporated. The residue was purified by prep-TLC to give pure compound product (49 mg, yield: 77.7%) as a yellow solid.
¾-NMR (400 MHz, CDC13) δ 7.90 7.88 (m, 2H), 7.62 (s, lH), 7.47-7.45 (m, 2H), 7.45-7.44 (m, 1H), 7.26-7.25 (m, 5H), 7.18-7.17 (m, 2H), 7.04-7.03 (m, 2H), 6.45 (s, 1H), 4.33-4.28 (q, J= 2.0 Hz, 2H), 4.17-4.12 (m, 1H), 2.50 (s, 3H), 1.32-1.27 (t, J= 2.0 Hz, 3H), 1.32-1.34 (d, J= 0.8 Hz, 3H). MS (M+H)+: 494.
Step 6: 2-(4^uoropheriyl)-6-[methyl(l^heriylethyl)amino]-5^heny
acid
Figure imgf000049_0003
The carboxylic acid (75 mg, yield: 90 %) was prepared in an analogous manner to Example 13 using the general procedure in Example 13, Step 4. The carboxylic acid was used in the next step without further purification.
'H-NMR (400 MHz, CDC13) δ 7.90-7.88 (m, 2H), 7.62 (s, 1H), 7.47-7.45 (m, 2H), 7.45-7.44 (m, 1H), 7.26-7.25 (m, 5H), 7.18-7.17 (m, 2H), 7.04-7.03 (m, 2H), 6.45 (s, 1H), 4. 17-4.12 (m, 1H), 2.50 (s, 3H), 1.32-1.34 (d, J= 0.8 Hz, 3H). MS (M+H)+: 466.
Step 7: 2-(4-fluorophenyl)-N-methyl-6-[methyl(l-phenylethyl)ammo]-5-^
carboxamide
Figure imgf000050_0001
The product (30 mg, yield: 38.9%) was prepared according to the general procedure in Example 1, Step 6.
^-NMR (400 MHz, CDC13) δ 7.86-7.83 (m, 2H), 7.66 (s, IH), 7.50-7.45 (m 4H), 7.34-7.33 (m, 2H), 7.25-7.20 (m, 2H), 7.17-7.13 (m, 2H), 6.95-6.93 (m, 2H), 6.96 (s, 4.55 (m, IH), 2.93 (s, 3H), 2.85 (s, 3H), 1.35 (s, 3H). MS (M+H)+: 479.
Example 72: ethyl [2-(4-fluorophenv0-3-(methylcarbamov0-5-phenyl-l-benzofuran-6-
Figure imgf000050_0002
Steps 1-3
Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
Step 4: ethyl 6-[(ethoxycarbonyl)amino]-2-(4-fluorophenyl)-5-phen l-l-benzofuran-3- carboxylate
Figure imgf000050_0003
A mixture of the product of Step 3 (64 mg, 0.17 mmol), EtOOCCl (22 mg, 0.21 mmol), Py (23 mg, 0.31 mmol) in DCM (3 mL) was stirred at RT for 2 hours. The mixture was quenched with H20, diluted with DCM, dried over Na2SC>4, filtered, and the solvent was evaporated The residue was purified by prep-TLC to give pure carbamate (63 mg, yield: 83.3%) as a white solid.
'H-NMR (400 MHz, CDC13) δ 8.02-8.00 (m, 2H), 7.78 (s, 1H), 7.49-7.47 (m, 2H), 7.45-7.34 (m, 3H), 7.14-7.09 (m, 2H), 6.67 (m, 1H), 4.34-4.30 (q, J= 1.6 Hz, 2H), 4.16-4.1 1 (q, J= 2.0 Hz, 2H), 2.18-2.14 (t, J= 1.6 Hz, 3H), 2.13-1.98 (t, J= 2.0 Hz, 3H). MS (M+H)+: 448.
Step 5: ethyl 6-[ (ethoxycarbonyl) {2-[methyl(phenyl)ammo]ethyl}amino]-2-(4-fluorophenyl)-5-
Figure imgf000051_0001
The product of Step 4 (474 mg, 1.06 mmol), 2-(methyl(phenyl)amino)ethyl methanesulfonate (243 mg, 1.06 mmol) and Cs2C03 (7.8 g, 24 mmol) in dry DMF (100 mL) was stirred at 140°C for 4 hours. After the mixture was concentrated, the residue was diluted with DCM, washed with water, dried over Na2S04 and concentrated. The residue was purified by prep-TLC to give the desired amino carbamate (335 mg, yield: 54.6%). MS (M+H)+: 581. Step 6: 6-[(ethoxycarbonyl){2-[methyl(phenyl)amino]ethyl}amino]-2-(4-fl orophenyl)-5-
Figure imgf000051_0002
The product of Step 5 (25 mg, yield: 90%) was prepared in an analogous manner to Example 13 using the general procedure in Example 13, Step 4. The carboxylic acid was used directly in the next step without further purification.
Step 7: ethyl [2-(4-fluorophenyl)-3-(methylcarbamoyl)-5-phenyl-l-benzofuran-6-yl]{2- [methyHphenyl)ammo]ethyl}carbamate
Figure imgf000052_0001
Example 72 (15 mg, yield: 48.7%) was prepared according to the general procedure in Example 1, Step 6.
'H-NMR (400 MHz, CDCls) δ 7.89 7.87 (m, 2H), 7.65 (s, lH), 7.40-7.36 (m, 2H), 7.32-7.20 (m, 6H), 7.19-7.18 (m, 3H), 7.15-7.10 (m, 2H), 6.09 (m, 1H), 4.09-4.04 (m, 2H), 3.35-3.36 (m, 2H), 3.19-3.07 (m, 2H), 2.97-2.89 (m, 6H), 1.21-1.10 (m, 3H). MS (M+H)+: 566.
Example 73: 2-f4-fluoroDhenyl)-ALmethyl-6-[(jV-methyl-ALphenylglvcvnaminol-5-phenyl- l-benzofuran-3-carboxamide
Figure imgf000052_0002
Steps 1-2
Steps 1-2 were performed in accordance with Example 1, Steps 1-2.
Step 3: ethyl 2-(4-fluorophenyl)-6-[ (N-methyl-N-phenylglycyl)amino]-5-phenyl-l-benzofuran-3- carboxylate
Figure imgf000052_0003
The amide (75 mg, yield: 50%) was prepared from the product of Step 2 according to the general procedure in Example 1, Step 6.
'H-NMR (400 MHz, CDCI3) δ 8.41-8.48 (m, 2H), 8.01-8.09 (m, 2H), 7.78 (s, 1H), 7.01-7.15 (m, 8H), 6.71-6.75 (m, 1H), 6.50 (t, J= 12.0 Hz, 2H), 4.31-4.35 (m, 2H), 3.24 (s, 3H), 2.61 (m, 2H), 1.30-1.33 (t, J= 12.0 Hz, 3H). MS (M+H)+: 523.
Step 4: 2-(4-fluorophenyl)-6-[ (N-methyl-N-phenylglvcyl)amino]-5-phenyl-l-benzofuran-3- carboxylic acid
Figure imgf000053_0001
The carboxylic acid (50 mg, yield: 75%) was prepared in an analogous manner to Example 13 using the general procedure in Example 13, Step 4. The carboxylic acid was used in the next step without further purification.
Step 5: 2-(4-fluorophenyl)-N-methyl-6-[ (N-methyl-N-phenylglycyl)amino]-5-phenyl-l-
Figure imgf000053_0002
The amide (35 mg, yield: 78%) was prepared according to the general procedure in Example 1, Step 6.
'H-NMR (400 MHz, CDCls) δ 8.85 (s, 3H), 8.71 (s, 3H), 7.81-7.89 (m, 2H), 7.55 (s, 1H), 7.23-7.25 (m, 5H), 7.01-7.12 (m, 2H), 6.71-6.75 (m, 1H), 6.50 (d, J= 12.0 Hz, 2H), 5.71-5.75 (m, 2H), 3.78 (s, 3H), 2.58 (s, 3H). MS (M+H)+: 508.
Example 74: 2-(4-fluorophenyl)-N-methyl-6- [methyliN-methyl-N-phenylglvcyl)aminol-5-
Figure imgf000053_0003
Steps 1-3
Steps 1-3 were performed in accordance with Example 73, Steps 1-3.
Step 4: ethyl 2-(4-fluorophenyl)-6-[methyl( -methyl-N^henylglycyl)amino]-5-phenyl-l- benzofuran-3-carboxylate
Figure imgf000053_0004
The alkylated amide (90 mg, yield: 90%) was prepared in an analogous manner to the compound prepared in Example 1, Step 4.
'H-NMR (400 MHz, CDC13) δ 8.09 (s, 1H), 8.01-8.05 (m, 2H), 7.36-7.45 (m, 6H), 7.13-7.18 (m, 2H), 6.96-7.02 (m, 2H), 6.53-6.61 (m, 1H), 6.53-6.61 (t, J= 4.0 Hz, 2H), 4.31-4.39 (m, 2H), 3.58-3.66 (m, 2H), 3.24 (s, 3H), 2.70 (s, 3H), 1.30-1.33 (t, J= 12.0 Hz, 3H). MS (M+H)+: 537.
Step 5: 2-(4-fluorophenyl)-6-[methyl(N-methyl-N^henylglycyl)am
Figure imgf000054_0001
The carboxylic acid (85 mg, yield: 95%o) was prepared in an analogous manner to
Example 13 using the general procedure in Example 13, Step 4. The carboxylic acid was used in the next step without further purification.
Step 6: 2-(4-fluorophenyl)-N-methyl-6-[methyl(N-methyl-N^henylglvcyl)amin^
benzofuran-3-carboxamide
Figure imgf000054_0002
The amide was prepared in an analogous manner to Example 1, Step 6 (25 mg, yield: 68%).
'H-NMR (400 MHz, CDCI3) δ 7.89-7 91 (m, 2H), 7.86 (s, 1H), 7.39-7.42 (m, 4H), 7.34-7.38 (m, 2H), 7.13-7.18 (m, 2H), 7.00-7.09 (m, 2H), 6.55-6.57 (m, 1H), 6.16 (d, J= 4.0 Hz, 2H), 5.71-5.73 (m, 1H), 3.48-3.56 (m, 2H), 3.24 (s, 3H), 2.94 (d, J = 8.0 Hz, 3H), 2.69 (s, 3H). MS (M+H)+: 522.
Examples 75-76
Examples 75 and 76 were prepared according to the general procedures of
Example 74.
Figure imgf000055_0001
Example 77: 2- 4-fluorophenyl)-A-methyl-6-[(4ty,5JRV4-methyl-2-oxo-5-phenyl-l,3- oxazolidin-3-yl1-5-phenyl-l-benzofuran-3-carboxamide
Figure imgf000055_0002
Steps 1-3
Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
Figure imgf000055_0003
A solution of the product of Step 3 (100 mg, 0.27 mmol) in 30% H2SO4 aqueous solution was cooled at 0°C. Then the solution of NaN02 in 1 mL H20 was added dropwise to amine solution over a period of 1 minute with keeping the temperature at 0°C. The resulting mixture was stirred for an additional 30 minutes at 0°C. An aqueous solution of KI was added dropwise over 5 minutes. The reaction mixture was stirred for 3 hours at RT, giving a dark brown solution. The solution was extracted with EtOAc. The organic layer was washed with Na2SC>3 solution and concentrated to give the crude iodide (40 mg, yield: 31%).
'H-NMR (400 MHz, CDCI3) δ 8.12 (s, 1H), 8.06-8.10 (m, 2H), 7.99 (s, 1H), 7.38-7.48 (m, 5H), 7.17-7.22 (m, 2H), 4.39 (q, J= 7.2 Hz, 2H), 1.35(t, J= 7.2 Hz, 3H). MS (M+H)+: 487. Step 5: ethyl 2-(4-fluorophenyl)-6-[(4S.5R)-4-methyl-2-oxo-5-phenyl-l.3-oxazolidin-3-yl]-5-
Figure imgf000056_0001
The iodide (30 mg, 0.06 mmol), (4S, 5R)-4-methyl-5-phenyloxazolidin-2-one (17 mg, 0.9 mmol), Cul (15 mg, 0.08 mmol) and K2C(¾ (20 mg, 0.14 mmol) in dry nitrobenzene (1 mL) was heated to 180°C for 6 hours. When TLC showed the reaction was completed, H20 was added to the mixture and the aqueous phase was extracted by EtOAc. The combined organic phase was washed with brine, dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by prep-TLC to give the N-aryl oxizohdinone (10 mg, yield: 30%).
'H-NMR (400 MHz, CDC13) δ 8.00-8 02 (m, 3H), 7.99 (s, 1H), 7.39-7.55 (m, 5H), 7.07-7.27 (m, 7H), 5.26 (d, J = 8.0 Hz, 1H), 4.33 (q, J= 7.2 Hz, 2H), 3.61 (br s, 1H), 1.31 (t, J= 7.2 Hz, 3H), 0.45 (d, J= 6.8 Hz, 3H). MS (M+H)+: 536.
Step 6: 2-(4-fluorophenyl)-6-[(4S, 5R)-4-methyl-2-oxo-5-phenyl-l , 3-oxazolidin-3-yl]-5-phenyl-l-
Figure imgf000056_0002
To a stirred solution of ester (40 mg, 0.07 mmol) in dioxane/H20 (1 : 1, 2 mL) was added LiOH (20 mg, 0.48 mmol), and the mixture was stirred at 100°C for 3 hours. The mixture was concentrated in vacuo. The residue was dissolved in H20, IN HC1 was added until pH to 3, and the mixture was extracted with EtOAc. The organic solvent was washed with brine, dried over Na2SC>4 and filtered, and the solvent was evaporated. The solvent was removed by distillation to provide the crude carboxylic acid (35 mg, yield: 92%). It was used for the next step without further purification.
Step 7: 2-(4-fluorophenyl)-N-methyl-6-[(4S, 5R)-4-methyl-2-oxo-5 -phenyl- 1, 3-oxazolidin-3-yl]- 5-phenyl-l-benzofuran-3-carboxamide
Figure imgf000057_0001
A solution of carboxylic acid (35 mg, 0.07 mmol), HOBT (40 mg, 0.30 mmol) and EDCI (50 mg, 0.32 mmol) in dry DMF (2 mL) was stirred at RT. After 30 minutes, Et3N (0.2 mL) and CH3NH2 (HCl salt, 40 mg, 0.59 mmol) was added to the mixture, and the mixture was stirred overnight. After the solvent was removed, H20 was added, and the mixture was extracted with EtOAc The combined organic layer was washed with H20, brine and concentrated. The residue was purified by prep-TLC to give the product of Example 77 (20 mg, yield: 56%).
^-NMR (400 MHz, CDC13) δ 7.86-7.89 (m, 2H), 7.74 (s, 1H), 7.52 (s, 1H), 7.40-7.42 (m, 5H), 7.25-7.26 (m, 3H), 7.06-7.14 (m, 4H), 5.84 (br s, 1H), 5.25 (d, J = 8.0 Hz, 1H), 3.62 (br s, 1H), 2.91 (d, J = 4.8 Hz, 3H), 0.44 (d, J= 6.8 Hz, 3H). MS (M+H)+: 521.
Example 78: S-f -fluorophenvD-l-^-fluorophenYn-A'-methYl^-
Figure imgf000057_0002
Step 1: ethyl 5-(2-fluorophenyl)-2-(4-fluorophenyl)-6-nitro-l-benzofuran-3-carboxylate
Figure imgf000057_0003
2-Fluorophenylboronic acid (obtained according to procedure in WO 2004/041201 A2; 283 mg, 2.10 mmol) and K3P04 3H20 (556 mg, 2.10 mmol) were added to a suspension of triflate (described in Example 1) (500 mg, 1.05 mmol) in dry DMF (2 mL) under N2. Then Pd(dppf)Cl2 (5 mg, 0.08 mmol) was added to the mixture under N2. The reaction mixture was heated to 80°C for 6 hours. The mixture was cooled, diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and evaporated. The crude product was purified by column to give pure aryl fluoride (250 mg, yield: 55%). 'H-NMR (400 MHz, CDCI3) δ 8.02 (s, 1H), 8.00-8.01 (m, 3H), 7.3 1-7.35 (m, 2H), 7.20-7.22 (m, 3H), 7.03-7.05 (m, 1H), 4.30-4.36 (dd, J= 8.0 Hz, 2H), 1.27-1.31 (m, 3H). MS (M+H)+: 424.
Figure imgf000058_0001
A mixture of nitro arene (250 mg, 0.59 mmol), Fe (264 mg, 4.70 mmol) and H4CI (475 mg, 8.85 mmol) in H20/MeOH7THF (2 niL/2 mL/2 mL) was refluxed for 3 hours. Then, H2O was added to quench the reaction, which was filtered and extracted with EtOAc, washed with brine and dried over Na2SC>4. The solvent was removed by distillation. After purification by column, the desired aninline was obtained (180 mg, yield: 77%).
'H-NMR (400 MHz, CDCI3) δ 7.94-7.97 (m, 2H), 7.74 (s, 1H), 7.32-7.35 (m, 2H), 7.05-7.20 (m, 4H), 6.67 (s, 1H), 4.26-4.30 (dd, J = 8.0 Hz, 2H), 1.18-1.27 (m, 3H). MS (M+H)+: 394.
Step 3: ethyl 5-(2-fluorophenyl)-2-(4-fluorophenyl)-6-[(m
carboxylate
Figure imgf000058_0002
MsCl (65 mg, 0.60 mmol) was added to a solution of aniline (180 mg, 0 50 mmol) and pyridine (79 mg, 1.00 mmol) in dry DCM (2 mL). The reaction mixture was stirred overnight at RT. After diluted with H20 and extracted with DCM, the mixture was washed with brine, dried over Na2SC>4 and filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by prep-TLC to give sulfonamide (150 mg, yield: 75%).
'H-NMR (400 MHz, CDCI3) δ 7.94-7.97 (m, 2H), 7.74 (s, 1H), 7.71 (s, 1H), 7.32-7.35 (m, 2H), 7.05-7.20 (m, 4H), 4.26-4.30 (dd, J= 8.0 Hz, 2H), 2.95 (s, 3H), 1.18-1.27 (m, 3H). MS (M+H)+: 472.
Step 4: ethyl 5-(2-fluorophenyl)-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)ammo]-l- benzofuran-3-carboxylate
Figure imgf000059_0001
KI (4 mg, 0.02 mmol), K2C03 (60 mg, 0.40 mmol), and CH3I (113 mg, 0.80 mmol) were added to a solution of sulfonamide (100 mg, 0.20 mmol) in dry DMF (5 mL) under N2. The mixture was heated to 80°C overnight. The mixture was cooled, diluted with H2O, and extracted with EtOAc; the organic solvent was washed with brine, dried over Na2SC>4 and filtered; and the solvent was evaporated under reduced pressure. The crude was purified by prep-TLC and the desired alkyl sulfonamide was obtained (90 mg, yield: 87%).
TT-NMR (400 MHz, CDC13) δ ppm 8.03-8.05 (m, 2H), 8.01 (s, 1H), 7.63 (s, 1H), 7.37-7.44 (m, 2H), 7.12-7.27 (m, 4H), 4.34-4.40 (dd, J= 8.0 Hz, 2H), 3.23 (s, 3H), 2.48 (s, 3H), 1.34-1 36 (m, 3H). MS (M+H)+: 486.
Step 5: 5-(2-fluorophenyl)-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)am
carboxylic acid
Figure imgf000059_0002
The ester (90 mg, 0.20 mmol) was dissolved in 1,4-dioxane (2 mL) and ¾0 (2 mL) Then LiOH (84 mg, 2.00 mmol) was added to the solution, and the mixture was refluxed for 2 hours. After acidified with HC1 (1 N) and extracted with EtOAc, the combined organic phases were washed with brine, dried over Na2S04, filtered and evaporated to give the carboxylic acid (80 mg, yield: 90%). It was used for the next step without further purification. Step 6: 5-(2-fluorophenyl)-2-(4-fluorophenyl)-N-methyl-6-[methyl(methylsulfom
benzofuran-3-carboxamide
Figure imgf000059_0003
The carboxylic acid (75 mg, 0.16 mmol), HOBT (37 mg, 0.24 mmol) and EDCI (77 mg, 0.40 mmol) were dissolved in dry DMF (2 mL). The resulting solution was stirred for 30 minutes. Then, methanamine HC1 salt (43 mg, 0.64 mmol) and Et3N (73 mg, 0.72 mmol) was added to the mixture. After stirred overnight, the mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and evaporated. The crude product was purified by prep-TLC to give pure Example 78 (35 mg, yield: 47%).
'H-NMR (400 MHz, CDC13) δ 7.88-7.92 (m, 2H), 7.74 (s, 1H), 7.60 (s, 1H), 7.34-7 40 (m, 2H), 7.10-7.24 (m, 4H), 5.92 (s, 1H), 3.20 (s, 3H), 2.94-2.95 (d, J= 4.0 Hz, 3H), 2.47 (s, 3H). MS (M+H)+: 471
Examples 79-89
Examples 79-89 were prepared according to the general procedures of
Example 78.
Figure imgf000060_0001
Figure imgf000061_0001
carboxamide
Example 90: 5-(2-fluorophenyl)-2-i4-fluorophenYn-ALmethoxy-6-
Figure imgf000061_0002
Steps 1-5
Steps 1-5 were performed in accordance with Example 78, Steps 1-5.
Step 6: 5-(2-fluorophen\l)-2-(4-fluorophenyl)-N-methoxy-6-[methyl(methy
Figure imgf000062_0001
Example 90 was prepared using conditions analogous to the coupling reaction described in Example 7, Step 6 (40 mg, yield: 51%).
'H- MR (400 MHz, CDCI3) δ 8.43 (s, 1H), 7.90-7.93 (m, 2H), 7.74 (s, 1H), 7.62 (s, 1H), 7.36-7.38 (m, 2H), 7.13-7.25 (m, 4H), 3.83 (s, 3H), 3.21 (s, 3H), 2.46 (s, 3H). MS (M+H)+: 487.
Examples 91-98
Examples 91-98 were prepared according to the general procedures of
Example 90.
Figure imgf000062_0002
'H-NMR (400 MHz, CDC13) MS
Example Structure Name
δ (M+H)+
N 8.37 (s, 1H), 7.84-7.88 (m,
5 -(3 -cyanophenyl)-2- 2H), 7.72 (s, 1H), 7.62-7.68 (4-fluorophenyl)-iV- (m, 3H), 7.56 (s,
94 methoxy-6-[methyl
1H),.7.48~7.54 (m, 1H), 494 (met ylsulfonyl)amino]
7.13-7.17 (m, 2H), 3.80 (s, -l-benzofuran-3- o=s=o 3H), 3.09 (s, 3H), 2.68 (s,
1 carboxamide
3H).
F 5 -(3 -fluorophenyl)-2- 8.29 (s, 1H), 7.91-7.95 (m,
(4-fluorophenyl)-iV- 2H), 7.76 (s, US), 7.61 (s,
95 methoxy-6-[methyl 1H), 7.38-7.44 (m, 1H),
487 (methylsulfonyl)amino] 7.07-7.23 (m, 5H), 3.85 (s,
1
o=s=o -l-benzofuran-3- 3H), 3.14 (s, 3H), 2.63 (s,
1 carboxamide 3H).
2,5-bis(4- 8.25 (s, US), 7.85-7.89 (m, fluorophenyl) -N- 2H), 7.69 (s, 1H), 7.54 (s,
96 methoxy-6-[methyl US), 7.33-7.37 (m, 2H),
487 (methylsulfonyl)amino] 7.06-7.17 (m, 4H), 3.80 (s,
1
o=s=o -l-benzofuran-3- 3H), 3.07 (d, J = 4.0 Hz,
1 carboxamide 3H), 2.59 (s, 3H).
8.49 (s, US), 7.89-7.93 (m,
2-(4-fluorophenyl)-iV- 2H), 7.72 (s, lH), 7.57 (s, methoxy-5-(3- US), 7.31-7.35 (m, 1H), methoxyphenyl)-6-
97 7.15-7.19 (m, 2H),
[methyl 499
6.97-6.99 (m, 2H),
(methylsulfonyl)amino]
6.91-6.93 (m, 1H), 3.83 (s,
1 -l-benzofuran-3- o=s=o 6H), 3 10 (s, 3H), 2 60 (s,
carboxamide
1 3H).
2 -(4 -fluorophenyl) -N- 8.29 (s, US), 7.91-7.89 (m, methoxy-5-(4- 2H), 7.87 (s, lH), 7.53 (s, methoxyphenyl)-6- 1H), 7.32-7.29 (m, 2H),
98
[methyl 7.19~7.10(m, 2H), 6.93-6.90 499 (methylsulfonyl)amino] (m, 2H), 3.80 (s, 3H), 3.09 o=s=o -l-benzofuran-3- (s, 3H), 2.93 (s, 3H), 2.53 (s,
1 carboxamide 3H).
Example 99: 2-(4-fluorophenyl)-ALmethoxY-5-[3-(methoxycarbamovQphenyll-6-
Steps 1-4: ethyl 5-(3-cyanophenyl)-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-l- benzofuran-3-carboxylate
Figure imgf000064_0001
Steps 1-4 were performed in an analogous manner to Example 1, Steps 1-4.
Step 5: 5-(3-cyanophenyl)-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]
carboxylic acid and 5-(3-carboxyphenyl)-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-l- benzofuran-3-carboxylic acid
Figure imgf000064_0002
The ester (450 mg, 0.92 mmol) was dissolved in dioxane (5 mL). Then LiOH (96 mg, 4 mmol) was added to the solution, and the mixture was stirred at RT overnight. After acidifmg with HCl (I N) and extracting with EtOAc, the combined organic phases were washed with brine, dried over Na2SC¼, filtered and evaporated to give the cyano carboxylic acid (300 mg, yield: 50%) and dicarboxylic acid (100 mg, yield: 30%). The crude mixture was used for the next step without further purification.
Step 6: 2-(4-fluorophenyl)-N-methoxy-5-[ 3-(methoxycarbamoyl)phenyl]-6-
Figure imgf000064_0003
Example 99 was prepared using condition analogous to the coupling reaction described in Example 7, Step 6 (55 mg, yield: 73%).
'H-NMR (400 MHz, CDC13) δ 9.49-9.54 (m, 1H), 8.39 (s, 1H), 7.86-7.89 (m, 2H), 7.83-7.85 (m, 2H), 7.79 (s, 1H), 7.45-7.51 (m, 3H), 7.13-7.17 (m, 2H), 3.81-3.82 (m, 6H), 2.99 (s, 3H), 2.78 (s, 3H). MS (M+H)+: 542.
Example 100: 2-f4-fluorophenvn-Af-methyl-5-[3-(methYlcarbamoYnphenyll-6-
[methyl(niethYlsulfonvnaminol-l-benzofuran-3-carboxamide
Figure imgf000065_0001
Steps 1-5: 5-(3-carboxyphenyl)-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)a
benzofuran-3-carboxylic acid
Steps 1-5 were performed according to the general procedures in Example 99, Steps 1-5.
Step 6: 2-(4-fluorophenyl)-N-methyl-5-[ 3-(methylcarbamoyl)phenyl]-6- [methyl(methylsulforiyl)amino]-l-benzofuran-3-carboxamide
Figure imgf000065_0002
Example 100 was prepared according to the general procedure in Example 1, Step 6.
'H-NMR (400 MHz, CDC13) δ 7.86-7.89 (m, 2H), 7.78-7.81 (m, 2H), 7.44-7.51 (m, 3H), 7.12-7.16 (t, J= 12.0 Hz, 2H), 6.72-6.73 (m, 1H), 5.81-5.82 (m, 1H), 2.92-2.95 (m, 6H), 2.90 (s, 3H), 2.84 (s, 3H). MS (M+H)+: 510. Example 101: 5-[3-(aminomethvnphenyll-2- 4-fluorophenyl)-jV-methYl-6- [methylimethylsulfonvnaminol-l-benzofuran-3-carboxamide
Figure imgf000065_0003
Step 1: 5-f 3-(aminomethyl)phenyl]-2-(4-fluorophenyl)-N-methyl-6- [methyl(methylsulfonyl)amino]-l-benzofuran-3-carboxamide
Figure imgf000066_0001
Raney-Ni (100 mg) and ammonia (cone. 0.5 mL) were added to a solution of the compound of Example 84 (58 mg, 0.13 mmol) in MeOH (20 mL). And then the mixture was degassed and stirred under 30 psi of H2 overnight at RT. After filtered through CELITE, the filtrate was concentrated to give the desired benzylic amine (50 mg, yield: 85%).
'H-NMR (400 MHz, CDCls) δ 7.79 7.82 (m, 2H), 7.57 (s, 1H), 7.29 (d, J= 8.0 Hz, 2H), 7.06-7.10 (t, J= 16.0 Hz, 2H), 6.58-6.59 (m, 3H), 3.98 (s, 2H), 2.93 (s, 3H), 2.71 (d, J = 4.0 Hz, 3H), 2.49 (s, 3H) MS (M+H)+: 482. Example 102: 2- 4-fluorophenvn-Ar-methyl-6-[methvirmethylsulfonvnamino1-5- 3- i[(methylsulfonvnaminolmethyl}phenvn-l-benzofuran-3-carboxamide
Figure imgf000066_0002
Steps 1-2
Steps 1-2 were performed according to the general procedures in Example 1, Steps 1-2.
Step 3: 2-(4-fluorophenyl)-N-methyl-6-[methyl(methylsulfonyl)amino]-5-(3-
Figure imgf000066_0003
Example 102 was prepared in an analogous manner to the sulfonamide synthesis described in Example 1, Step 3 (20 mg, yield: 60%).
'H-NMR (400 MHz, CDCI3) δ 7.85-7.88 (m, 2H), 7.76 (s, lH), 7.52 (s, 1H), 7.46 (s, 1H), 7.36-7.38 (m, 1H), 7.28-7.32 (m, 2H), 7.12-7.16 (m, 2H), 5.78-5.79 (m, 1H), 4.95-4 96 (m, 1H), 4.31 (d, J = 8.0 Hz, 2H), 2.91-2 93 (m, 6H), 2.86 (s, 3H), 2.79 (s, 3H). MS (M+H)+: 560.
Example 103
Example 103 was prepared according to the general procedures of Example 102.
Figure imgf000067_0003
Example 104: 2- 4-fluorophenvn-Ar-methyl-6-[methvirmethylsulfonvnamino1-5- 4-
Figure imgf000067_0001
Step 1: 5-f 4-(aminomethyl)phenyl]-2-(4-fluorophenyl)-N-methyl-6-
Figure imgf000067_0002
To a solution of the compound of Example 85 (400 mg, 83.8 mmol) in MeOH (10 mL), and aney-Ni (30 mg) was added. The reaction was degassed and then was shaken under 30 psi H2 overnight. The reaction mixture was filtered, washed with MeOH. The solvent was evaporated to give the desired benzylic amine (350 mg, yield: 87%).
¾- MR (400 MHz, CDC13) 7.82-7.85 (m, 2H), 7.47-7.52 (m, 3H), 7.45 (s, 1H), 7.31-7.37 (m, 2H), 6.99-7.1 1 (m, 2H), 6.41 (s, 1H), 4.12 (s, 2H), 2.88 (s, 3H), 2.72 (d, J= 4.0 Hz, 3H), 2.52 (s, 3H). MS (M+H)+: 482.
Step 2: 2-(4-fluorophenyl)-N-methyl-6-[methy methylsulfonyl)amino]-5-(4- {[(methylsulfonyl)amino]methyl}phenyl)-l-benzofuran-3-carboxamide
Figure imgf000068_0001
Example 104 was prepared in an analogous manner to the sulfonamide prepared in Example 1, Step 3 (20 mg, yield: 60%).
'H- MR (400 MHz, CDC13) 7.85-7.88 (m, 2H), 7.69 (s, 1H), 7.51 (s, 1H), 7.37 (s, 4H), 7.14-7.19 (m, 2H), 4.21 (s, 2H), 3.04 (s, 3H), 2.83 (s, 3H), 2.75 (s, 3H) 2.70 (s, 3H). MS (M+H)+: 560.
Examples 105-107
Examples 105-107 were prepared according to the general procedures of
Example 104.
Figure imgf000068_0002
Example 108: 2-(4-fluorophenvn-A-meth\l-6-[niethylfinethylsulfonvnaininol-5-[4- (trifluoromethvQphenyll-l-benzofuran-3-carboxamide
Figure imgf000069_0001
Step 1: ethyl 2-(4-fluorophenyl)-6-nitro-l-benzofuran-3-carboxylate
Figure imgf000069_0002
HCOOH (2.4 g, 71.23 mmol), Bu3N (11.6 g, 85.47 mmol) and Pd(PPh3)2Cl2 (197 mg, 0.28 mmol) were added to a solution of triflate (obtained according to procedure in WO 2004/041201 A2, 9 g, 28.49 mmol) in DMF (90 mL). The mixture was heated to 110°C under N2 protection. After stirred for 0.5 hour, the mixture was diluted with ¾0 and extracted with ether. The combined organic layers were washed with brine, dried over Na2S04, filtered and the solvent was evaporated The crude product was purified by column to give pure nitro arene (4.78 g, yield: 51%).
'H-NMR (400 MHz, CDCI3) δ 8.36 (d, J= 2 Hz, 1H), 8.20-8.23 (m, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.03-8.07 (m, 2H), 7.13-7.18 (m, 2H), 4.36-4.41 (m, 2H), 1.37 (t, J= 7.2 Hz, 3H). MS (M+H)+: 330.
Step 2: ethyl 6-amino-2-(4-fluorophenyl)-l-benzofuran-3-carboxylate
Figure imgf000069_0003
A mixture of the product of Step 1 (4.78 g, 14.5 mmol), Fe (4.06 g, 72.6 mmol) and H4CI (6.20 g, 116 mmol) in H20/MeOH/THF (50 mL /50 mL /50 mL) was refluxed for 4 hours. Then, ¾0 was added to quench the reaction, and the mixture was extracted with EtOAc. After washing with brine and dried, the solvent was removed by distillation. The pure aniline was obtained (3.47 g, yield: 80%) by prep-TLC.
'H-NMR (400 MHz, CDCI3) δ 7.94-7.98 (m, 2H), 7.73 (d, J= 8 Hz, 1H), 7.08 (t, J = 8.8 Hz, 2H), 6.77 (s, 1H), 6.68 (d, J= 6.8 Hz, 1H), 4.30-4.35 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H). MS (M+H)+: 300.
Figure imgf000069_0004
MsCl (122 mg, 1.06 mmol) was added to a solution of aniline (200 mg,
0.67 mmol) and pyridine (107 mg, 1.35 mmol) in dry DCM (2 mL). After stirred overnight at RT, the mixture was diluted with H20 and extracted with DCM. The organic layer was washed with brine, dried over Na2S04 and filtered, and the solvent was evaporated. The crude product was purified by prep-TLC to give the desired sulfonamide (200 mg, yield: 78.5%).
'H-NMR (400 MHz, CDC13) δ 7.97-8.06 (m, 3H), 7.53-7.54 (m, 1H), 7.11-7.19 (m, 3H), 6.74 (s, 1H), 4.30-4.35 (m, 2H), 3.93 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H). MS (M+H)+: 378.
Step 4: ethyl 2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-l-benzofuran-3-carboxylate
Figure imgf000070_0001
NaH (60 % in oil, 111 mg, 2.78 mmol) and CH3I (395 mg, 2.78 mmol) were added to a solution of sulfonamide (211 mg, 0.56 mmol) in dry DMF (4 mL) under N2. After stirred overnight at RT, ice cold diluted AcOH was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and filtered, and the solvent was evaporated under reduced pressure. The crude product was used for the next step without further purification (210 mg, yield: 96%).
Step 5: ethyl 5-bromo-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-l-^^
carboxylate
Figure imgf000070_0002
A stirred solution of sulfonamide (500 mg, 1.3 mmol) and FeCl3 (210 mg, 0.78 mmol) in dry CCI4 (5 mL) was added Br2 (210 mg, 1.3 mmol) in dry CCI4 (2 mL). The mixture was allowed to stir at 50°C for 4 hours. The mixture was cooled, diluted with ¾0, and extracted with DCM; the organic solvent was washed with brine, dried over Na2SC>4 and filtered; and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography to give aryl bromide (240 mg, yield: 30%).
TT-NMR (400 MHz, CDC13) δ 8.25 (s, 1H), 7.91-8.05 (m, 2H), 7.62 (s, 1H), 7.02-7.15 (m, 2H), 4.32-4.46 (m, 2H), 3.37 (s, 3H), 3.02 (s, 3H), 1.35 (t, J= 4.4 Hz, 3H). MS (M+H)+: 470. Step 6: 5-bromo-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]
carboxylic acid
Figure imgf000071_0001
The ester (210 mg, yield: 80%) was hydrolysed in an analogous manner to the general procedure of Example 78, Step 5. The carboxylic acid was used in the next step without further purification.
Step 7: 5-bromo-2-(4-fluorophenyl)-N-methyl-6-[methyl(methylsulfonyl)a
carboxamide
Figure imgf000071_0002
The amide was prepared according to the general procedure in Example 1 , Step 6
(180 mg, yield: 75%).
TT-NMR (400 MHz, CDC13) δ 8.09 (s, 1H), 7.81-7.85 (m, 2H), 7.63 (s, 1H), 7.12-7.19 (m, 2H), 5.71 (br, 1H), 3.27 (s, 3H), 3.02 (s, 3H), 2.93 (d, J= 4.4 Hz, 3H). MS (M+H)+: 455.
Step 8: 2-(4-fluoropheriyl)-N-methyl-6-[methyl(methylsulfonyl)amino]-5-[4-
Figure imgf000071_0003
To a solution of 5-bromo-2-(4-fluorophenyl)-N-methyl-6- [methyl(methylsulfonyl)amino]-l-benzofuran-3 -carboxamide (30 mg, 0.066 mmol) in DMF (2 mL) were added 4-hydroxy-phenyl boronic acid (21 mg, 0.13 mmol) and K3P04-3H20 (36.5 mg, 0.13 mmol). Then, Pd(dppf)Ci2 (3.4 mg, 0.004 mmol) was added under N2. The resulting mixture was heated to 90°C for 12 hours. The mixture was cooled to RT, then filtered and purified by prep-HPLC to give 2-(4-fluorophenyl)-5-(4-hydroxyphenyl)-N-methyl-6- [methyl(methylsulfonyl)amino]-l-benzofuran-3 -carboxamide. (4.8 mg, Yield; 15.5%).
MS (M+H)+: 469. Examples 109-122
Examples 109-122 were prepared according to the general procedures of
Example 108.
Figure imgf000072_0001
Figure imgf000073_0001
Example 123: 6-{[2-(benzYlamino)ethYllfmethYlsulfonvnamino}-2-(4-fluorophcnylVN- methyl-5-phenYl-l-benzofura -3-carboxamide
Figure imgf000073_0002
Steps 1-4
Steps 1-4 were performed in an analogous manner to Example 1, Steps 1-4. Step 5: ethyl 2-(4-fluorophenyl)-6-[(methylmlfonyl){2-[(methylsulfony
Figure imgf000073_0003
MsCl (0.2 mL, 3.0 mmol) was added to a solution of alcohol (1 g, 2.0 mmol) and
Et3N (0.6 mL, 4 0 mmol) in dry DCM (10 mL), in a manner similar to that of Example 1, Step 4. The reaction mixture was stirred overnight at RT. After dilution with H20 and extraction with DCM, the mixture was washed with brine, dried over Na2SC<4 and filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by column to give the mesylate (800 mg, yield: 75%).
'H-NMR (400 MHz, CDCI3) δ 8.00 8.03 (m, 2H), 7.99 (s, 1H), 7.57 (s, 1H), 7.48-7.50 (m, 2H), 7.35-7.43 (m, 3H), 7.11-7.16 (m, 2H), 4.30-4.35 (dd, J = 8.0 Hz, 2H), 4.02-4 05 (m, 2H), 3.21-3.83 (m, 2H), 2.98 (s, 3H), 2.90 (s, 3H), 1.27-1.30 (m, 3H) MS (M+H)+: 576.
Step 6: ethyl 6-{[2-(benzylamino)ethyl](methylsnlfonyl)ammo}-2-(4-fluorophenyl)-5-phenyl-l-
Figure imgf000074_0001
Benzylamine (0.5 mL, 0.27 mmol)) was added to a solution of mesylate (50 mg, 0.09 mmol) in Ets (1 mL) and MeCN (1 mL). The reaction mixture was stirred overnight at 60°C. After dilution with ¾0 and extraction with EtOAc, the mixture was washed with brine, dried over Na2SC>4 and filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by prep-TLC to give the benzylic amine (30 mg, yield: 58%).
'H-NMR (400 MHz, CDC13) δ 8.00-8.03 (m, 2H), 7.99 (s, 1H), 7.57 (s, 1H), 7.48-7.50 (m, 2H), 7.35-7.43 (m, 7H), 7.11-7.16 (m, 3H), 4.30-4.35 (dd, J= 8.0 Hz, 2H), 4.02-4.05 (m, 2H), 3.21-3.83 (m, 2H), 2.98 (s, 3H), 2.32 (d, J= 8.0 Hz, 2H), 1.27-1.30 (m, 3H). MS (M+H)+: 587.
Step 7: 6-if2-(benzylamino)ethyllfmethylsulfonyl)amino}-2-(4-flnorophenyl)-5-phenyl-l-
Figure imgf000074_0002
The ester (30 mg, 0.05 mmol) was dissolved in 1,4-dioxane (1 mL) and ¾0 (1 mL). Then LiOH (21 mg, 0.5 mmol) was added to the solution, and the mixture was refluxed for 2 hours. After being acidified with HC1 (1 N) and extracted with EtOAc, the combined organic phases were washed with brine, dried over Na2SC>4, filtered and evaporated to give the carboxylic acid (22 mg, yield: 79%). The acid was used in the next step without further purification.
Step 8: 6-{[2-(benzylamino)ethyl](methylsulfonyl)amino}-2-(4-fluorophe
Figure imgf000074_0003
Carboxylic acid (22 mg, 0.04 mmol), HOBT (10 mg, 0 06 mmol) and EDCI (19 mg, 0.10 mmol) were dissolved in dry DMF (1 mL). The resulting solution was stirred for 30 minutes. Then, methanamine HC1 salt (11 mg, 0.16 mmol) and Et3N (18 mg, 0.18 mmol) was added to the mixture. After stirred overnight, the mixture was diluted with I¾0 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SC>4, fdtered and evaporated. The crude product was purified by prep-HPLC to give pure amide (Example 124) (20 mg, yield: 70%).
'H-NMR (400 MHz, CDC13) δ 7.87-7.88 (m, 2H), 7.68 (s, 1H), 7.44 (s, 1H), 7.38-7.42 (m, 2H), 7.23-7.25 (m, 6H), 7.13-7.19 (m, 4H), 5.87 (s, 1H), 3.58-3.61 (m, 2H), 3.51-3.52 (m, 2H), 3.06 (s, 3H), 2.91 (s, 3H), 2.53-2.59 (m, 2H). MS (M+H)+: 572.
Examples 124-132
Examples 124-132 were prepared according to the general procedures of
Example 123.
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Example 133: 2-(4-fluorophenvn-6-[ 2-hvdroxYethvnimethylsulfonvnaminol-A-methyl-5-
Figure imgf000077_0002
Steps 1-3
Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
Step 4: ethyl 2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amm^
Figure imgf000077_0003
KI (6 mg, 0.036 mmol), K2C03 (46 mg, 0.33 mmol), and 2-bromo ethanol (80 mg, 0.563 mmol) were added to a solution of ethyl 2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-5- phenyl-l-benzofuran-3-carboxylate (50 mg, 0.131 mmol) in dry DMF under N2 protection. The mixture was stirred at 60°C overnight. After dilution with H20 and extraction with EtOAc, the organic solvent was washed with brine, dried over Na2SC>4 and filtered, and the solvent was evaporated under reduced pressure. The crude was purified by prep-TLC to give the desired product of ethyl 2-(4-fluorophenyl)-6-[(2-hydroxyethyl) (methylsulfonyl)amino]-5-phenyl-l- benzofuran-3-carboxylate (60 mg, yield: 91%).
'H-NMR (400 MHz, CDCI3) δ 8.00-8.03 (m, 3H), 7.61 (s, 1H), 7. 1-7.52 (m, 2H), 7.35-7.44 (m, 3H), 7.11-7.16 (m, 2H), 4.30-4.36 (m, 2H), 3.21-3.56 (m, 4H), 2.91 (s, 3H), 1.29 (t, J= 7.2 Hz, 3H). Step 5: 2-(4-fluorophertyl)-6-[(2-hydroxyethyl)(methylsulfony
3-carboxylic aci
Figure imgf000078_0001
To a solution of the product of Step 4 (60 mg, 0 12 mmol) in dioxane (1 mL) was added LiOH H20 (40 mg, 0.952 mmol) and H20 (1 mL), and the resultant solution was stirred for 2 hours at 60°C. H20 was added, and then 2N aqueous HC1 was added to adjust pH = 4-5. After extraction with EtOAc, the combined organic layer was washed with brine, dried over Na2S04, and evaporated to provide the crude product. The crude was purified by prep-TLC. The desired product of 2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-5-phenyl- l-benzofuran-3-carboxylic acid was obtained (50 mg, yield: 88%).
'H-NMR (400 MHz, CDC13) δ 8.05 (s, 1H), 7.99-8.03 (m, 2H), 7.62 (s, 1H), 7.48-7.49 (m, 2H), 7.38-7.43 (m, 3H), 7.11-7.15 (m, 2H), 3.19-3.59 (m, 4H), 2.90 (s, 3H).
Figure imgf000078_0002
benzofuran-3-carboxamide
Figure imgf000078_0003
The product of Step 5 (20 mg, 0.043 mmol), HOBT (12 mg, 0.08 mmol) and EDCI (26 mg, 0.13 mmol) were dissolved in dry DMF (1 mL). The resulting solution was stirred for 30 minutes. Then, methanamine (HC1 salt, 7 mg, 0.22 mmol) and Et3N (25 mg, 0.24 mmol) were added to the mixture. After stirring overnight, the mixture was diluted with H20 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and evaporated. The crude product was purified by prep-TLC to give pure 2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-N-methyl-5-phenyl-l- benzofuran-3-carboxamide (10 mg, yield: 48%).
'H-NMR (400 MHz, CDCI3) δ 7.86-7.90 (m, 2H), 7.72 (s, 1H), 7.59 (s, 1H), 7.47-7.50 (m, 2H), 7.32-7.40 (m, 3H), 7.10-7.16 (m, 2H), 5.80 (s, 1H), 3.28-3.47 (m, 4H), 2.90 (s, 6H). Example 134: 2-(4-fluorophenvn-Ar-methyl-6-[{2-[methvi phenYnaminolethyl}
(methylsulfonvnaminol-5-phen -l-benzofuran-3-carboxaniide
Figure imgf000079_0001
Steps 1-3
Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
Step 4: ethyl 2-(4-fluorophenyl)-6-[{2-[methyl(phenyl)amino]ethyll(methylsulfonyl)amino
Figure imgf000079_0002
Step 4 was performed in an an analogouos manner to Example 133, Step 4. The crude product was purified by prep-TLC to give pure ethyl 2-(4-fluorophenyl)-6-[{2-
[methyl(phenyl)amino]ethyl}(methylsulfonyl)amino]-5-phenyl-l-benzofuran-3-carboxylate (60 mg, yield: 77%).
'H-NMR (400 MHz, CDC13) δ 8.06-8.10 (m, 3H), 7.59 (s, 1H), 7.49-7.51 (m, 2H), 7.39-7.46 (m, 3H), 7.14-7.22 (m, 4H), 6.66-6.70 (m, 1H), 6.54-6.56 (m, 2H), 4.37-4.42 (m, 2H), 3.23-3.67 (m, 4H), 2.81 (s, 3H), 2.75 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H).
Step 5: 2-(4-fluorophenyl)-6-[ {2-[methyl(phenyl)amino]ethyl}(methylsulfonyl) amino5-phenyl-
Figure imgf000079_0003
Step 5 was performed in an analogous manner to Example 133, Step 5. The crude product was purified by prep-TLC to give pure 2-(4-fluorophenyl)-6-[{2-[methyl(phenyl)amino] ethyl} (methyl sulfonyl) amino5-phenyl-l-benzofuran-3-carboxylic acid (50 mg, yield: 87%).
'H-NMR (400 MHz, CDC13) δ 7.80-7.89 (m, 3H), 7.50 (s, 1H), 7.07-7.42 (m, 10H), 6.97-7.01 (m, 2H), 3.41-3.67 (m, 4H), 2.94 (s, 3H), 2.71 (s, 3H).
Step 6: 2-(4-fluoropheriyl)-N-methyl-6-[{2-[methyl(phenyl)amino]ethyl}(m
5-phenyl-l-benzofuran-3-carboxamide
Figure imgf000080_0001
Step 6 was performed in an analogous manner to Example 133, Step 6. The crude product was purified by prep-TLC to give pure 2-(4-fluorophenyl)-N-methyl-6-[{2- [methyl(phenyl)amino]ethyl} (methylsulfonyl)amino]-5-phenyl- 1 -benzofuran-3-carboxamide (13 mg, yield: 42%).
'H-NMR (400 MHz, CDC13) δ 7.90-7.91 (m, 2H), 7.74 (s, 1H), 7.51 (s, 1H), 7.31-7 43 (m, 5H), 7.08-7.18 (m, 4H), 6.60-6.63 (m, 1H), 6.48-6.50 (m, 2H), 5.78 (s, 1H), 3.24-3.41 (m, 4H), 2.92 (d, J = 4.8 Hz, 3H), 2.74 (s, 3H), 2.70 (s, 3H). Example 135 : 5-f 3-f benzo Tdl thiazol-2-vnphenyl)-2-f 4-flu 0 r op h en vD-N- m ethyl-6-f Ν-
Figure imgf000080_0002
Step 1: Methyl 2-(5-bromo-2-hydroxyphenyl)aceta
Figure imgf000080_0003
2-(2-hydroxyphenyl)acetic acid (100 g, 0.66 mol) was dissolved in MeOH, and then TBATB (320 g, 0.66 mmol) was added to the solution. The resulting mixture was stirred at RT for 18 hours. After evaporation of solvent, the residue was dissolved in diethyl ether. The organic layer was washed with 1 N HC1, 2 M sodium bisulfate, H20 and brine, dried and evaporated to yield methyl 2-(5-bromo-2-hydroxyphenyl)acetate (145 g, yield: 90%).
'H- MR (400 MHz, CDC13) δ 7.48 (br s, 1H), 7.20-7.25 (m, 2H), 6.75-6.78 (m, 1H), 3.74 (s, 3H), 3.62 (s, 2H). MS (M+H)+: 245.
Step 2: Methyl 2-(5-bromo-2- tert-butyldimethylsilyl acetate
Figure imgf000080_0004
To a stirred solution of the product of Step 1 (1 g, 4.1 mmol) in DCM (5 mL) was added imidazole (0.56 g, 8.23 mmol) and TBSC1 (0.93 g, 6.17 mmol) at 0°C. After stirred overnight at RT, the reaction mixture was washed with H20, brine and concentrated in vacuo, the residue was purified by column chromatography to furnish the pure product of methyl 2-(5- bromo-2-(tert-butyldimethylsilyloxy)phenyl)acetate (1.4 g, yield: 95%).
'H-NMR (400 MHz, CDC13) δ 7.23 (d, J = 2.4 Hz, 1H), 7.17 (dd, Ji = 8.4 Hz, J2 = 2.4 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 3.61 (s, 3H), 3.50 (s, 2H), 0.91 (s, 9H), 0.15 (s, 6H). MS (M+H)+: 359.
Step 3: Methyl 2-(5-bromo-2-(tert-butyldimethylsilyloxy)phenyl)-3-(4-fluorophenyl)-3- oxopropanoate
Figure imgf000081_0001
A solution of the product of Step 2 (500 mg, 1.4 mmol) in THF (10 mL) at -78°C was treated dropwise with lithium bis(trimethylsilyl)amide (1.7 mL, 1.7 mmol, 1 N in THF). After stirred 30 minutes, a solution of 4-fluorobenzoyl chloride (250 mg, 1.6 mmol) in THF was added dropwise. The reaction mixture was stirred at -78°C for 1 hour and at 0°C for another 1 hour. The mixture was quenched with 1 N HCl, THF was removed in vacuo, and the residue was extracted with EtOAc. The organic layer was concentrated and purified by column chromatography to afford the pure product of methyl 2-(5-bromo-2-(tert- butyldimethylsilyloxy)phenyl)-3-(4-fluorophenyl)-3-oxopropanoate (550 mg, yield: 82%).
'H-NMR (400 MHz, CDCI3) δ 7.83 7.87 (m, 2H), 7.28 (d, J = 2.4 Hz, 1H), 7.16 (dd, Ji = 8.4 Hz, h = 2.4 Hz, 1H), 6.93-6.98 (m, 2H), 6.63 (d, J = 8.4 Hz, 1H), 5.86 (s, 1H), 3.65 (s, 3H), 0.91 (s, 9H), 0.18 (s, 3H), 0.10 (s, 3H). MS (M+H)+: 481.
Figure imgf000081_0002
To a solution of the product of Step 3 (300 mg, 0.6 mmol) in THF (10 mL), TBAF (500 mg, 1.9 mmol) was added and the mixture was stirred at 0°C for 1 hour. After concentrated in vacuo, the mixture was suspended in H20 and extracted with EtOAc. The organic layer was washed with H20, brine and concentrated. The residue was purified by column chromatography to give the product of methyl 2-(5-bromo-2-hydroxyphenyl)-3-(4- fluorophenyl)-3-oxopropanoate (200 mg, yield: 87%).
'H-NMR (400 MHz, CDC13) δ 7.99 (m, 2H), 7.33 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.07 (m, 2H), 6.68 (d, J = 8.0 Hz, 1H), 5.93 (s, 1H), 3.77 (s, 3H). MS (M+H)+: 367.
Figure imgf000082_0001
To a solution of the product of Step 4 (100 mg, 0.3 mmol) in acetone (4 mL) was added concentrated HC1, and the mixture was heated under reflux for 30 minutes. Then, the reaction mixture was concentrated in vacuo, suspended in ¾0 and extracted with EtOAc. The organic layer was washed with H20, brine and concentrated. The residue was purified by prep- TLC to give pure methyl 5-bromo-2-(4-fluorophenyl)-l-benzofuran-3-carboxylate (70 mg, yield: 73%).
TT-NMR (400 MHz, CDC13) δ 8.15 (s, 1H), 8.05 (m, 2H), 7.43 (m, 1H), 7.37 (m, 1H), 7.16 (m, 2H), 3.94 (s, 3H). MS (M+H)+: 349.
Figure imgf000082_0002
To a solution of the product of Step 5 (0.5 g, 1.4 mmol) in CHCI3 (4 mL), fuming HNO3 (1 mL) was added dropwise at RT, and the mixture was stirred for 4 hours. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with NaHCC and brine. The solvent was removed by concentration to provide the crude product of methyl 5-bromo-2-(4-fluorophenyl)-6-nitro-l-benzofuran-3-carboxylate (0.4 g, yield: 70%). It was used for the next step without further purification.
Step 7: Methyl 6-amin -5-bromo-2-(4-fluorophenyl)-l-benzofuran-3-carboxylate
Figure imgf000082_0003
A mixture of the product of Step 6 (200 mg, 0.5 mmol), iron filings (200 mg, 3.58 mmol) and NH4C1 (300 mg, 5.61 mmol) in MeOH: THF:H20 (1 : 1 : 1 , 20 mL) was stirred at reflux for 3 hours. After filtered and concentrated in vacuo, the residue was purified by column chromatography to furnish the pure methyl 6-amino-5-bromo-2-(4-fluorophenyl)-l-benzofuran- 3-carboxylate (150 mg, yield: 81%).
'H-NMR (400 MHz, CDC13) δ 7.99 (s, 1H), 7.96 (m, 2H), 7.05-7.10 (m, 2H), 6.82 (s, 1H), 4.18 (br s, 2H), 3.86 (s, 3H). MS (M+H)+: 364.
Step 8: Methyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)-l-benzofuran-3-carboxylate
Figure imgf000083_0001
MsCI (60 μΐ,, 0.77 mmol) was added to a solution of the product of Step 7 (150 mg, 0.41 mmol) and pyridine (0.34 mL) in dry DCM (10 mL) at 0°C. After stirring overnight at RT, the mixture was diluted with water, and extracted with DCM. The organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated in vacuo, and the residue was purified by prep-TLC to afford the pure product of methyl 5-bromo-2-(4-fiuorophenyl)-6- (methylsulfonamido)-l-benzofuran-3-carboxylate (150 mg, yield: 82%).
^-NMR (400 MHz, CDC13) δ 8.21 (s, 1H), 7.99-8.03 (m, 2H), 7.83 (s, 1H), 7.11-7.16 (m, 2H), 6.82 (br s, 1H), 3.90 (s, 3H), 2.96 (s, 3H). MS (M+H)+: 442.
Step 9: Methyl 5-bromo-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-l-benzofuran-3- carboxylate
Figure imgf000083_0002
CH3I (0.8 mL, 12.85 mmol) was added to a mixture of the product of Step 8 (5.0 g, 11.31 mmol), K2C03 (3.2 g, 23.15 mmol) and KI (1.9 mg, 11.45 mmol) in DMF (40 mL) under N2 protection. The mixture was stirred at reflux overnight. After filtered and concentrated in vacuo, the residue was purified by column chromatography to give the product of methyl 5- bromo-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)- 1 -benzofuran-3-carboxylate (5 g, yield: 96%).
ΊΤ-NMR (400 MHz, CDC13) δ 8.32 (s, 1H), 8.05-8.09 (m, 2H), 7.72 (s, 1H), 7.17-7.22 (m, 2H), 3.96 (s, 3H), 3.35 (s, 3H), 3.10 (s, 3H). MS (M+H)+: 456.
Step 10: 5-bromo-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-l-benzofuran-3- carboxylic acid
Figure imgf000084_0001
To a solution of the product of Step 9 (5 g, 0.11 mol) in dioxane / H20 (1: 1, 100 mL) was added LiOH-H20 (4.6 g, 0.11 mol), and the mixture was stirred at 100°C for 2 hours. After concentration, the residue was dissolved in H20, 1 N HC1 was added until pH reached 3, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SC>4 and filtered. The solvent was removed by distillation to provide the crude product of 5-bromo-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-l-benzofuran-3- carboxylic acid (4.5 g, yield: 97%). It was used for the next step without further purification. Step 11: 5-bromo-2-(4^uorophenyl)-N-methyl-6-(N-methylmethylsulform
carboxamide
Figure imgf000084_0002
A solution of the product of Step 10 (5 g, 11.31 mmol), HOBT (3.2 g, 23.7 mmol) and EDCI (5.0 g, 26.1 mmol) in dry DMF (100 mL) was stirred at RT. After 30 minutes, Et3N (16 mL) and CH3M¾ (HC1 salt, 3.7 g, 56.5 mmol) was added to the mixture, and the mixture was stirred overnight. After the solvent was removed, H2O was added, and the mixture was extracted with EtOAc. The combined organic layer was washed with H20 and brine and concentrated. The residue was purified by column chromatography to give the product of 5- bromo-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-l-benzofuran-3- carboxamide (4.8 g, yield: 93%).
^-NMR (400 MHz, CDC13) δ 8.16 (s, 1H), 7.88-7.92 (m, 2H), 7.70 (s, 1H), 7.18-7 23 (m, 2H), 5.78 (br s, 1H), 3.34 (s, 3H), 3.09 (s, 3H), 3.00 (d, J = 4 8 Hz, 3H) MS (M+H)+: 455.
Step 12: 5-(3-(benzo[d]thiazol-2-yl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(N-
Figure imgf000084_0003
A mixture of Pd(dppf)Cl2 (10 mg), the product of Step 11 (50 mg, O i l mmol), K3PO4 (60 mg, 0.28 mmol) and 2-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)benzo[d]thiazole (100 mg, 0.30 mmol) in DMF (2 mL) was stirred at 100°C under N2 protection overnight. Then, the solvent was removed, and ¾0 was added. After extracted with EtOAc, the combined organic layer was dried over Na SC and evaporated. The residue was purified by prep-HPLC to give the product of 5-(3-(benzo[d]thiazol-2-yl)phenyl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)- 1 -benzofuran-3 -carboxamide (20 mg, yield: 31%).
TT-NMR (400 MHz, CDC13) δ 8.19 (s, 1H), 8.12 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.91-7.96 (m, 3H), 7.86 (s, 1H), 7.58-7. 64 (m, 3H), 7.48-7.53 (m, 1H), 7.38-7.42 (m, 1H), 7.17-7.22 (m, 2H), 6.03 (br s, 1H), 3.17 (s, 3H), 2.99 (d, J = 4.8 Hz, 3H), 2.71 (s, 3H). MS (M+H)+: 586.
Examples 136-142
Examples 136-142 were prepared according to the general procedures
Example 135.
Figure imgf000085_0001
Figure imgf000086_0001
Example 143: 2-(4-fluorophenvn-Ar-methyl-5-[3-(6-methYl-l,3-benzothiazol-2-Ynphenyll-6-
Figure imgf000087_0001
Steps 1-11
Steps 1-11 were performed in an analogous manner to Example 135, Steps 1-11.
Step 12: 2-(4-fluorophenyl)-5-(3-formylphenyl)-N-methyl-6-[methyl(methy
benzofuran-3-carboxamide
Figure imgf000087_0002
The aryl aldehyde (45 mg, yield: 73%) was prepared in an analogous manner to Example 136, Step 12.
Step 13: 2-(4-fluorophenyl)-N-methyl-5-[ 3-( 5-methyl-l.3-benzothiazol-2-yl)phenyl]-6-
Figure imgf000087_0003
A mixture of 2-amino-5-methylbenzenethiol (50 mg, 0.10 mmol) and the aryl aldehyde (50 mg, 0.36 mmol) in DMSO was stirred at 200°C for 1 hour. After cooling, 20 mL H20 was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and filtered. The solvent was removed, and the crude product was purified by prep-TLC to give pure 2-(4-fluorophenyl)-N-methyl-5-[3-(6-methyl-l,3- benzothiazol-2-yl)phenyl]-6-[methyl(methylsulfonyl)amino]- 1 -benzofuran-3-carboxamide (50 mg, yield: 82%).
'H-NMR (400 MHz, CDCl3) 8 8.19 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 7.94-7.99 (m, 3H), 7.87 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.57-7.61 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.19-7.24 (m, 2H), 6.05 (br s, 1H), 3.19 (s, 3H), 3.01 (d, J = 4.8 Hz, 3H), 2.72 (s, 3H), 2.53 (s, 3H). MS (M+H)+: 600. Examples 144-149
Examples 144-149 were prepared according to the general procedures of
Example 143.
Figure imgf000088_0001
Figure imgf000089_0001
Example 150: 5-[3-(5-fluoro-lH-benzimidazol-2-vnphenYll-2-i4-fluorophenvn-N-methyl-6-
Figure imgf000089_0002
Steps 1-12
Steps 1-12 were performed in an analogous manner to Example 143, Steps 1-12. Step 13: 5-[3-(5-fluoro-lH-benzimidazol-2-yl)phenyl]-2-(4-fluorophenyl)-N-m
Figure imgf000089_0003
The aryl aldehyde of Example 143, Step 12 (100 mg, 0.21 mmol) and 4- fluorobenzene-l,2-diamine (32 mg, 0.25 mmol) were added in PI1NO2 (4 mL) and the mixture was heated to 120°C and stirred overnight. The mixture was concentrated, and H20 (30 mL) was added. After extraction with EtOAc, the organic layer was washed with brine and concentrated. The residue was purified by prep-HPLC to give pure 5-[3-(5-fluoro-lH-benzimidazol-2- yl)phenyl]-2-(4-fluorophenyl)-N-methyl-6-[me
carboxamide (30 mg, yield: 41.5%).
'H-NMR: (400 MHz, CDC13) δ 8.16 (s, 1H), 8.00 (d, J = 6.8 Hz, 1H), 7.87 (m, 2H), 7.72 (s, 1H), 7.56-7.58 (m, 1H), 7.48-7.50 (m, 1H), 7.41(s,lH), 7.28-7.35 (m, 2H), 7.04-7.14 (m, 3H), 6.62-6.68 (m, 1H), 2.93-2.96 (m, 9H). MS (M+H)+: 587.
Examples 151-154
Examples 151-154 were prepared according to the general procedures of Example 150.
Figure imgf000090_0001
Example 155: Measuring Compound Inhibitory Potency
Measurement of inhibition by compounds was performed using the HCV replicon system. Several different replicons encoding different HCV genotypes or mutations were used. In addition, potency measurements were made using different formats of the replicon assay, including different ways of measurements and different plating formats. See Jan M. Vrolijk et al., A replicons-based bioassay for the measurement of interferons in patients with chronic hepatitis C, 110 J. ViROLOGiCAL METHODS 201 (2003); Steven S. Carroll et al, Inhibition of Hepatitis C Virus KNA Replication by 2' -Modified Nucleoside Analogs, 278(14) J. BIOLOGICAL CHEMISTRY 11979 (2003). However, the underlying principles are common to all of these determinations, and are outlined below.
Stable neomycin phosphotransferase encoding replicons-harboring cell lines were used, so all cell lines were maintained under G418 selection prior to the assay. Potency was deteremined using a cell ELISA assay with an antibody to the replicons encoded NS3/4a protease. See Caterina Trozzi et al , In Vitro Selection and Characterization of Hepatitis C Virus Serine Protease Variants Resistant to an Active-Site Peptide Inhibitor, 77(6) J. Virol. 3669 (2003). To initiate an assay, replicon cells were plated in the presence of a dilution series of test compound in the absence of G418. Typically, the assays were performed in a 96-well plate formate for manual operation, or a 384-well plate format for automated assay. Replicon cells and compound were incubated for 96 hours. At the end of the assay, cells were washed free of media and compound, and the cells were then lysed. RNA was quantified indirectly through detection of replicon-encoded NS3/4A protein levels, through an ELISA-based assay with an antibody specific for NS3/4A. EC50 determinations were calculated as a percentage of a DMSO control by fitting the data to a four-parameter fit function.
The activity table provided below illustrates the observed activity:
Example Replicon lb (nM) Example Replicon lb (nM)
1 120 87 39
2 114 88 52
3 80 89 23
4 703 90 197
5 47 91 342
6 118 92 252
7 ND 93 54
Figure imgf000092_0001
Example Replicon lb (nM) Example Replicon lb (nM)
80 241 149 11
81 117 150 1
82 53 151 5
83 232 152 4
84 107 153 4
85 43 154 4
86 28
It will be appreciated that various of the above-discussed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. Also that various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequently made by those skilled in the art which are also intended to be encompassed by the following claims.

Claims

A compound having structural formula I:
Figure imgf000094_0001
or a pharmaceutically acceptable salt thereof, wherein:
each R1 is independently selected from the group consisting of halogens;
n is 0, 1, 2 or 3;
R2 is C(0)NRARB;
RA and RB are independently selected from the group consisting of hydrogen, Ci-Ce alkyl and 0(Ci-C6 alkyl);
R3 is ArA, wherein ArA is an aromatic ring system selected from the group consisting of:
i) 5- or 6-membered monocyclic rings, and
ii) 8-, 9- or 10-membered bicyclic rings, and wherein said ArA is substituted by 0, 1, 2 or 3 substitutents Rc;
each Rc is independently selected from the group consisting of:
a) halogen,
b) OH
c) Ci-Ce alkyl,
d) 0(Ci-C6 alkyl),
e) CN,
f) (CH2)o-3-ArB, wherein each ArB is an independently selected aromatic ring system selected from the group consisting of:
i) 5- or 6-membered monocyclic rings with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, and ii) 8-, 9- or 10-membered bicyclic rings with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S,
Figure imgf000094_0002
i) (CH2)o-3C(0)NRDRE, and j) (CH2)o-3S02RE,
wherein each Rc c) Ci-C6 alkyl, d) 0(d-C6 alkyl), and f) (CH2)o-3-ArB is substituted by 0, 1, 2 or 3 substituents RF;
each RD is independently selected from the group consisting of hydrogen and Ci-6alkyl;
each RE is independently selected from the group consisting of hydrogen, Ci-6alkyl, OCi_6alkyl and 5- or 6-membered monocyclic rings with 0, 1 , 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, wherein each RE
Figure imgf000095_0001
OCi-6alkyl and 5- or 6-membered monocyclic rings is substituted by 0, 1, 2, 3 substituents independently selected from the group consisting of Ci-Ce alkyl, 0(Ci-C6 alkyl), halogen and OH;
each RF is independently selected from the group consisting of:
a) halogen,
b) Ci-C6 alkyl,
c) 0(Ci-C6 alkyl),
d) CN,
e) NH2,
f) (CH2)o-3-ArC, wherein each ArC is an independently selected aromatic ring system selected from the group consisting of:
i) 5- or 6-membered monocyclic rings with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, and ii) 8-, 9- or 10-membered bicyclic rings with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, wherein each RF b) Ci- alkyl, c) 0(Ci-C6 alkyl), and f) (CH2)o-3-ArC is substituted by 0, 1, 2 or 3 substituents RG;
each RG is independently selected from the group consisting of halogen, CN, Chalky., 0(d-C6 alkyl), CF3 and C(0)OH;
R4 is selected from the group consisting of NRHR!;
RH is selected from the group consisting of:
a) hydrogen,
b) Ci.6alkyl,
c) C(0)0(Ci_6alkyl), and d) S02RJ;
RJ is selected from the group consisting of Ci-ealkyl and RXRY, where Rx and RY are independently selected from the group consisting of hydrogen and
Ci_6alkyl;
R1 is selected from the group consisting of:
a) Ci_6alkyl,
b) C2-6alkenyl,
c) C2-6alkynyl,
d) (CH2)0-3(C3-8cycloalkyl),
e) (CH2)o-3(C3-gcycloalkenyl), and
f) C(0)Ci.6alkyl,
wherein R1 is substituted by 0, 1, 2, 3 or 4 RK;
each RK is independently selected from the group consisting of: a) ORL,
b) halogen,
c) CN,
d) NRMRN,
e) OC(0)Ci.6alkyl,
f) C(0)OCi.6alkyl,
g) (CH2)o-3-ArD, wherein each ArD is an
independently selected aromatic ring system selected from the group consisting of:
i) 5- or 6-membered monocyclic rings with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, and
ii) 8-, 9- or 10-membered bicyclic rings with 0,
1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, wherein each RK e) OC(0)Ci.6alkyl, f) C(0)OCi-6alkyl, and g) (CH2)o-3-ArD is substituted by 0, 1, 2 or 3 substituents R°,
RL is selected from the group consisting of hydrogen,
Figure imgf000096_0001
and phenyl;
RM is selected from the group consisting of hydrogen, Ci_6alkyl and (CH2)o-3(phenyl); R is selected from the group consisting of hydrogen, Ci_6alkyl, S02(Ci-6alkyl) and C(0)(C1.6alkyl);
or RM and RN are taken together with the N to which they are attached to form a 5- to 7-membered ring substituted by 0, 1, 2 or 3 RF;
each R° is independently selected from the group consisting of halogen, d-6alkyl, OCi-6alkyl and C(0)0(Ci.6alkyl),
each Rp is independently selected from the group consisting of halogen,
Figure imgf000097_0001
oxo and C(0)0(Ci_6alkyl);
or RH and R1 are taken together with the N to which they are attached to form a 5- to 7-membered ring.
2. The compound according to claim 1 , wherein n is 1.
3. The compound according to any one of claims 1 -2, wherein the compound is a compound of formula la:
Figure imgf000097_0002
or a pharmaceutically acceptable salt thereof.
4. The compound according to any one of claims 1 -3, wherein R1 is selected from the group consisting of fluorine, bromine and chlorine.
5. The compound according to any one of claims 1 -4, wherein R1 is fluorine.
6. The compound according to any one of claims 1 -5, wherein RA is hydrogen.
7. The compound according to any one of claims 1 -6, wherein RB is selected from the group consisting of -C¾ and -OCH3.
8. The compound according to any one of claims 1-7, wherein said ArA is phenyl.
9. The compound according to any one of claims 1-8, wherein each said Rc is independently selected from the group consisting of:
a) fluorine,
b) OH,
c) Ci.3alkyl,
d) OC1-3alkyl,
e) CN,
f) (CH2)o-i-ArB, wherein ArB is independently selected from the group
Figure imgf000098_0001
(CH2)o-1N(CH3)S02CH3,
(CH2)o.1N(H)S02CH3,
(CH2)o-iN(CH3)S02phenyl,
C(0)NHCH3,
(CH2)o.1N(H)C(0)CH3, and
(CH2)0-iN(H)C(O)phenyl.
10. The compound according to any one of claims 1-9, wherein each said Rc
Figure imgf000098_0002
11. The compound according to any one of claims 1-10, wherein R is selected from hydrogen, CH3 and SO2CH3.
12. The compound according to any one of claims 1-1 1, wherein RH is
13. The compound according to any one of claims 1-12, wherein R1 is selected from the group consisting of Ci-6alkyl and C2-6alkenyl.
14. The compound according to any one of claims 1-13, wherein RK is selected from the group consisting of
a) ORL,
b) halogen,
c) CN,
d) R RN,
e) OC(0)Ci.6alkyl, and
f) C(0)OCi.6alkyl. 15. The compound according to any one of claims 1-14, wherein RL is selected from the group consisting of Ci-6alkyl.
16. The compound according to any one of claims 1-15, wherein RM is selected from the group consisting of hydrogen and
Figure imgf000099_0001
17. The compound according to any one of claims 1-16, wherein RN is selected from the group consisting of
Figure imgf000099_0002
and S02(Ci_6alkyl).
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
101
Figure imgf000103_0001
102
Figure imgf000104_0001
Figure imgf000105_0001
104
Figure imgf000106_0001
19. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1-18, and a pharmaceutically acceptable carrier. 20. The pharmaceutical composition according to claim 19, further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
21. The pharmaceutical composition according to claim 20, further comprising a second therapeutic agent selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.
22. A use of the compound according to any one of claims 1-18 in the preparation of a medicament for inhibiting HCV NS5B activity or for preventing and/or treating infection by HCV in a subject in need thereof. 23 A method of treating a patient infected with HCV comprising the step of administering an amount of the compound according to any one of claims 1-18 effective to prevent and/or treat infection by HCV in a subject in need thereof. 24. A method according to claim 24, further comprising the step of administering pegylated-interferon alpha and ribovirin.
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