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WO2011112191A1 - Composés utilisables pour le traitement de l'hépatite c - Google Patents

Composés utilisables pour le traitement de l'hépatite c Download PDF

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Publication number
WO2011112191A1
WO2011112191A1 PCT/US2010/026898 US2010026898W WO2011112191A1 WO 2011112191 A1 WO2011112191 A1 WO 2011112191A1 US 2010026898 W US2010026898 W US 2010026898W WO 2011112191 A1 WO2011112191 A1 WO 2011112191A1
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Prior art keywords
solvent
column
mmol
gradient
fluorophenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2010/026898
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English (en)
Inventor
Kap-Sun Yeung
Kyle E. Parcella
John A. Bender
Brett R. Beno
Katharine A. Grant-Young
Ying Han
Piyasena Hewawasam
John F. Kadow
Andrew Nickel
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Priority to PCT/US2010/026898 priority Critical patent/WO2011112191A1/fr
Priority to CN2010800667265A priority patent/CN102906080A/zh
Priority to EP10710487A priority patent/EP2545042A1/fr
Priority to JP2012557020A priority patent/JP2013522192A/ja
Publication of WO2011112191A1 publication Critical patent/WO2011112191A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the disclosure generally relates to the novel compounds of formula I, including their salts, which have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV.
  • HCV hepatitis C virus
  • the disclosure also relates to
  • compositions and methods of using these compounds are provided.
  • HCV Hepatitis C virus
  • HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5 '-untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.
  • the single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases.
  • ORF open reading frame
  • the first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (also referred to as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites.
  • the NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components.
  • NS5B (also referred to as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the replication of HCV.
  • the HCV NS5B protein is described in "Structural Analysis of the Hepatitis C Virus RNA Polymerase in Complex with Ribonucleotides
  • HCV-796 an HCV NS5B inhibitor
  • HCV-796 showed an ability to reduce HCV RNA levels in patients.
  • the viral RNA levels decreased transiently and then rebounded during dosing when treatment was with the compound as a single agent but levels dropped more robustly when combined with the standard of care which is a form of interferon and ribavirin.
  • the development of this compound was suspended due to hepatic toxicity observed during exteneded dosing of the combination regimens.
  • US patent 7,265, 152 and the corresponding PCT patent application WO2004/041201A2 describe compounds of the HCV-796 class.
  • the invention provides technical advantages, for example, the compounds are novel and are effective against hepatitis C. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.
  • One aspect of the invention is a compound of formula I
  • R 1 is R 5 R 6 N; alkoxy; (alkoxycarbonylamino)alkoxy; (alkylphenyl)alkoxy;
  • R 2 is hydrogen, halo, nitro, amino, phenyl, or R ⁇ 6 ] ⁇ ;
  • R 3 is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl, (alkylsulfonyl)aminocarbonyl, CONR n R 12 , (R n )(R 12 )NCONH, triazolyl, thiazolyl, or tetrazolyl;
  • R is phenyl substituted with 0-2 halo substituents
  • R 5 is hydrogen, alkyl, or alkylsulfonyl
  • R 6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or alkylsulfonyl
  • R 7 is hydrogen, alkyl, alkenyl, alkynyl, cyanoalkyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, alkoxyalkyl, oxoalkyl, aminoalkyl, (alkylamino)alkyl,
  • R 8 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; or R 7 R 8 N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, dihydroindolyl, or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, dialkylcarboxamido, alkylcarbonylamino, alkoxycarbonylamino, pyridinyl, and phenyl where said phenyl is substituted with 0-2 halo or alkyl substituents;
  • R 9 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl
  • R is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; or R 9 and R 10 taken together is ethylene, propylene, butylene, pentylene, or hexylene;
  • R 11 is hydrogen, alkyl, or cycloalkyl
  • R is hydrogen, alkyl, or cycloalkyl; or R 11 and R 12 taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R is hydrogen, alkyl, cyanoalkyl, haloalkyl, alkenyl, alkynyl, or thiazolyl;
  • R 14 is hydrogen or alkyl
  • R 15 is hydrogen, alkyl, hydroxyalkyl, cycloalkyl, or benzyl; R is hydrogen or alkyl; or R 15 and R 16 taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 17 is haloalkyl, cyanoalkyl, (cycloalkyl)alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (R 18 )alkyl, (Ar 4 )alkyl, alkynyl, or aminocycloalkyl;
  • R 18 is CONH 2 , H 2 NCONH, dibenzylamino, phthalimido, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl where azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl is substituted with 0- 3 alkyl or alkoxycarbonyl substituents;
  • R 19 is cyano, hydroxyalkyl, morpholinylalkyl, carboxy, alkoxycarbonyl,
  • R 20 is hydrogen, halo, alkyl, or alkoxy
  • R 21 is hydrogen, halo, alkyl, or alkoxy
  • Ar 1 is phenyl, naphthalenyl, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, oxadiathiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, or benzothiazolyl, and is substituted with 0-2 substituents selected from halo, alkyl, cycloalkyl, haloalkyl, alkoxyalkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aminocarbonyl, pyridinyl, phenyl, halophenyl, alkylphenyl, and alkoxyphenyl;
  • Ar 2 is phenyl, biphenyl, or pyridinyl and is substituted witlh 0-2 substituents selected from halo, alkyl, cyano, hydroxy, alkoxy, and carboxy;
  • Ar 3 is pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, oxathiadiazolyl, pyrimidinyl, or pyrizinyl and is substituted witlh 0-2 substituents selected from hydroxy, alkyl, hydroxyalkyl, and CONR 13 R 14 ;
  • Ar 4 is furanyl, thienyl, pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, indolyl, or phenyl and is substituted with 0-2 substituents selected from halo, alkyl, haloalkyl, hydroxyl, and alkoxy; and
  • Ar 5 is pyrrozolyl, imidazolyl, or oxadiazolyl and is substituted with 0-2 substituents selected from alkyl, carboxy, alkoxycarbonyl, benzyl, and phenyl; or a pharmaceutically acceptable salt thereof.
  • Another aspect of the inventon is a compound of formula I where R 20 and R 21 are hydrogen.
  • Another aspect of the invention is a compound of formula I where
  • R 1 is R 5 R 6 N; (carboxy)alkenyl; (alkoxycarbonyl)alkenyl;
  • R 2 is hydrogen, nitro, or R ⁇ N;
  • R 3 is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl, (alkylsulfonyl)aminocarbonyl, CONR n R 12 , (R n )(R 12 )NCONH, triazolyl, thiazolyl, or tetrazolyl;
  • R 4 is phenyl substituted with 0-2 halo substituents
  • R 5 is hydrogen, alkyl, or alkylsulfonyl
  • R 6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or alkylsulfonyl
  • R 7 is hydrogen, alkyl, alkenyl, alkynyl, cyanoalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, oxoalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl,
  • R 8 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; or R 7 R 8 N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or dihydroindolyl, and is substituted with 0-2 substituents selected from alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, dimethylcarboxamido, alkylcarbonylamino, alkoxycarbonylamino, pyridinyl, and phenyl where phenyl is substituted with 0-2 substituents selected from halo and alkyl;
  • R'R 8 N taken together is , (quinuclidinyl)(alkyl)amino, (methylpyrrolidinyl)(alkyl)amino, (alkylthiazolyl)amino, ((carboxamido)cyclopentanyl)amino, ((halophenyl)cyclopentanyl)amino, or (hydroxyindanyl)amino;
  • R 9 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl
  • R 10 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; or R 9 and R 10 taken together is ethylene, propylene, butylene, or pentylene;
  • R 11 is hydrogen, alkyl, or cycloalkyl
  • R 12 is hydrogen, alkyl, or cycloalkyl; or R 11 and R 12 taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 13 is hydrogen, alkyl, cyanoalkyl, alkenyl, or alkynyl;
  • R 14 is hydrogen or alkyl
  • R 15 is hydrogen or alkyl
  • R 16 is hydrogen or alkyl
  • R 17 is haloalkyl, hydroxyalkyl, alkoxyalkyl, alkynyl, (R 18 )alkyl or (Ar 4 )alkyl;
  • R 18 is CONH 2 , dibenzylamino, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl where azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-3 substituents selected from alkyl and alkoxycarbonyl;
  • R 19 is cyano, ((alkyl)pyrazolyl)amino, ((alkyl)isoxazolyl)amino (thiadiazolyl)amino, or (triazinyl)amino; R and R are hydrogen;
  • Ar 1 is phenyl, naphthalenyl, pyridinyl, thienyl, thiazolyl, or pyrazinyl and is substituted with 0-2 substituents selected from alkyl, halo, hydroxy, alkoxy, amino, alkylamino, and dialkylamino;
  • Ar 2 is phenyl, biphenyl, or pyridinyl and is substituted witlh 0-2 substituents selected from halo, alkyl, cyano, hydroxy, and alkoxy;
  • Ar 3 is pyrazolyl isoxazolyl, thiazolyl, pyrimidinyl, or pyrizinyl and is substituted witlh 0-2 substituents selected from alkyl and hydroxyalkyl;
  • Ar 4 is pyrrolyl, imidazolyl, pyridinyl, indolyl, or phenyl and is substituted with 0-2 substituents selected from halo, alkyl, hydroxyl, and alkoxy;
  • Ar 5 is pyrrozolyl, imidazolyl, or oxadiazolyl and is substituted with 0-2 substituents selected from alkyl, carboxy, alkoxycarbonyl, benzyl, and phenyl; or a pharmaceutically acceptable salt thereof.
  • R 1 is alkoxy; (alkoxycarbonylamino)alkoxy; (alkylphenyl)alkoxy; (carboxy)alkenyl; ((N- dimethylbenzyl)aminocarbonyl)alkenyl; or phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of halo, cyano, alkyl, haloalkyl, hydroxyalkyl, (carboxy)alkyl, alkoxy, hydroxyalkyloxy,
  • R 3 is CONR n R 12 ; phenyl substituted with 0-2 halo substituents;
  • R 5 is hydrogen or alkylsulfonyl
  • R 6 is hydrogen, alkyl, hydroxyalkyl, or alkylsulfonyl
  • R 7 is hydrogen, alkyl, alkynyl, cyanoalkyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, alkoxyalkyl, oxoalkyl, (dialkylamino)alkyl, (cycloalkyl)alkyl, cycloalkyl,
  • R 8 is hydrogen, alkyl, or alkoxyalkyl
  • R 7 R 8 N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, dihydroindolyl, or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxycarbonyl, dialkylcarboxamido, alkylcarbonylamino, pyridinyl, and phenyl where said phenyl is substituted with 0-2 halo or alkyl substituents; or where R 7 R 8 N taken together is "N" ' , (quinuclidinyl)amino, (quinuclidinyl)(alkyl)amino, (methylpyrrolidinyl)(alkyl)amino,
  • R 9 is hydrogen, alkyl, or hydroxyalkyl
  • R 10 is hydrogen or alkyl
  • R 9 and R 10 taken together is ethylene or propylene
  • R is alkyl
  • R is hydrogen
  • R 13 is hydrogen, alkyl, cyanoalkyl, haloalkyl, alkenyl, or thiazolyl;
  • R is hydrogen or alkyl
  • R 15 is alkyl, hydroxyalkyl, cycloalkyl, or benzyl
  • R 16 is hydrogen
  • R 15 and R 16 taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 17 is haloalkyl, cyanoalkyl, (cycloalkyl)alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (R 18 )alkyl, (Ar 4 )alkyl, alkynyl, or aminocycloalkyl;
  • R 18 is CONH 2 , H 2 NCONH, dibenzylamino, phthalimido, amino, dialkylamino, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl where azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl is substituted with 0-3 alkyl or
  • R 19 is cyano, hydroxyalkyl, morpholinylalkyl, carboxy, alkoxycarbonyl, cycloalkylsulfoxamido, ((alkyl)pyrazolyl)amino, ((alkyl)isoxazolyl)amino,
  • R 20 and R 21 are hydrogen
  • Ar 1 is phenyl, naphthalenyl, pyridinyl, furanyl, pyrazolyl, isoxazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, or benzothiazolyl, and is substituted with 0-2 substituents selected from halo, alkyl, cycloalkyl, haloalkyl, alkoxyalkyl, hydroxy, alkoxy, amino, aminocarbonyl, pyridinyl, phenyl, halophenyl, alkylphenyl, and alkoxyphenyl;
  • Ar 2 is phenyl, biphenyl, or pyridinyl and is substituted witlh 0-2 substituents selected from halo, alkyl, cyano, hydroxy, alkoxy, and carboxy;
  • Ar 3 is pyrazolyl, isoxazolyl, thiazolyl, triazolyl, pyrimidinyl, or pyrizinyl and is substituted witlh 0-2 substituents selected from hydroxy, alkyl, and CONR 13 R 14 ;
  • Ar 4 is furanyl, pyrrolyl, pyrazolyl, isoxazolyl, imidazolyl, oxadiazolyl, triazolyl, pyridinyl, indolyl, or phenyl and is substituted with 0-2 substituents selected from halo, alkyl, haloalkyl, and hydroxy; and
  • Ar 5 is pyrrozolyl, imidazolyl, or oxadiazolyl and is substituted with 0-2 substituents selected from alkyl, alkoxycarbonyl, benzyl, and phenyl; or a pharmaceutically acceptable salt thereof.
  • R 1 is phenyl substituted with 1 CONR 7 R 8 substituent and also substituted with 0-2 halo, alkyl, or alkoxy substituents
  • R 2 is hydrogen, halo, or R 5 R R 3 CONR n R 12
  • R 4 is monofluorophenyl
  • R 5 is alkylsulfonyl
  • R 6 is hydroxyalkyl
  • R 7 is ;
  • R 8 is hydrogen;
  • R 9 is alkyl;
  • R 10 is alkyl or R 9 and R 10 taken together is ethylene or
  • R is alkyl; R is hydrogen; R and R are hydrogen; Ar is phenyl, pyridinyl, pyrimidinyl, isoxazolyl, oxazolyl, or oxadiazolyl, and is substituted with 0- 1 halo or alkyl substituents; or a pharmaceutically acceptable salt thereof.
  • R 1 is phenyl substituted with 1-2 substituents selected from the group consisting of halo, cyano, alkyl, haloalkyl, hydroxyalkyl, (carboxy)alkyl, alkoxy, hydroxyalkyloxy, tetrahydropyranyloxy, carboxy, alkoxycarbonyl, (carboxy)alkenyl,
  • pyrimidinyl pyrimidinedionyl; aminopyrimidinyl; indolyl; isoquinolinyl; and phenyl substituted with 0-2 substituents selected from halo, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amino, carboxy, aminocarbonyl, alkylaminocarbonyl, alkylcarboxamido, and carboxyalkenyl.
  • R 1 is phenyl substituted with 1 CONR 7 R 8 substituent and also substituted with 0-2 halo, alkyl, or alkoxy substituents.
  • Another aspect of the invention is compound of formula I where R 7 is and at least one of R 9 and R 10 is not hydrogen.
  • Another aspect of the invention is compound of formula I where R 2 is R '
  • Another aspect of the invention is compound of formula I where R 3 is CONR n R 12 .
  • Another aspect of the invention is compound of formula I where R 4 is phenyl or monofluorophenyl.
  • Alkyl means a straight or branched alkyl group composed of 1 to 6 carbons.
  • Alkenyl means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond.
  • Cycloalkyl means a monocyclic ring system composed of 3 to 7 carbons.
  • Hydroxyl means a straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety.
  • Aryl includes carbocyclic and heterocyclic aromatic substituents. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.
  • Substituents which are illustrated by chemical drawing to bond at variable positions on a multiple ring system are intended to bond to the ring where they are drawn to append.
  • substituents R 1 and R 2 of formula I are intended to bond to the benzene ring of formula I and not to the furan ring.
  • Ethylene means ethanediyl or -CH 2 CH 2 -; propylene means propanediyl or -CH 2 CH 2 CH 2 -; butylene means butanediyl or -CH 2 CH 2 CH 2 CH 2 -; pentylene means pentanediyl or -CH2CH2CH2CH2CH2-.
  • Dioxothiazinyl means Any scope of any variable, including R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , Ar 1 , Ar 2 , Ar 3 , Ar 4 , or Ar 5 can be used independently with the scope of any other instance of a variable.
  • the invention includes all pharmaceutically acceptable salt forms of the compounds.
  • Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
  • Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
  • the invention includes all stereoisomeric forms, including enantiomers and diastereomers as well as mixtures of stereoisomers such as racemates. Some stereoisomers can be made using methods known in the art. Stereoisomeric mixtures of the compounds and related intermediates can be separated into individual isomers according to methods known in the art.
  • the invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
  • the compounds may be made by methods known in the art including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials.
  • the variables (e.g. numbered "R" substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the invention.
  • some compounds of the invention may be prepared by coupling a benzofuran triflate or halide to a substituted phenyl boronic acid that in some examples contains a carboxylic acid or carboxylic acid ester.
  • Other coupling techniques and conditions are also known in the art as are other carbon-carbon bond forming reactions. Acids and esters may be converted to amides by methods known in the art.
  • Scheme 2 depicts one specific example of Scheme 1.
  • a nitro group on the benzofuran ring may be reduced and the resulting amino group may be functionalized using known chemistry.
  • the amine may be converted to a monosulfonamide via reaction with a sulfonyl chloride or by preparation of a bis sulfonamide followed by selective hydrolysis.
  • the monosulfonamide may be alkylated again with either a simple or functionalized alkyl.
  • the hydroxyl ethyl group is unmasked via acidic removal of the silyl protecting group.
  • Scheme 3 depicts the preparation of two intermediates labelled as common intermediate 1 and 2 which can be used to prepare some compounds of the invention.
  • the isopropyl group is used to temporarily mask the C5 hydroxy group so the methyl amide can be constructed from the ethyl ester.
  • the more advanced common intermediate 2 allows functionalization of the sulfonamide, acid deprotection and formation of some amide compounds after coupling of amines to the acid as described earlier.
  • Scheme 4 depicts some conditions for preparing some of the compounds described and for accessing an alternate common intermediate 3 which allows amide formation prior to nitro reduction and amine functionalization.
  • Scheme 5 illustrates a method for preparing some compounds by preparing 2-(4- fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran- 3-carboxamide in which the boron is attached to the benozfuran and then coupling to triflates or halogen containing aryl moieties.
  • Scheme 6 shows a preparation of the functionalized benzofuran and Scheme 7 shows one method for installation of nitrogen functionality which can then functionalized as described in the previous schemes.
  • Scheme 8 illustrates that a free phenolic OH group can be used to form some ether compounds.
  • Scheme 9 provides an alkylation for forming ethers under mild or more extreme contions depending on the reactivity of the alkylating reagent.
  • Scheme 10 shows how an ether with a protected amine can be attached, and after subsequent deprotection of the pthalimide, a free amine is liberated which can be either incorporated into compounds of the invention or derivatized further via standard chemistry to provide secondary or tertiary amines or amides or sulfonamides.
  • HCVNS5B RdRp cloning, expression, and purification The cDNA encoding the NS5B protein of HCV, genotype lb, was cloned into the pET21a expression vector. The protein was expressed with an 18 amino acid C-terminal truncation to enhance the solubility.
  • the E. coli competent cell line BL21(DE3) was used for expression of the protein. Cultures were grown at 37 °C for ⁇ 4 hours until the cultures reached an optical density of 2.0 at 600 nm. The cultures were cooled to 20 °C and induced with 1 mM IPTG. Fresh ampicillin was added to a final concentration of 50 ⁇ g/ml and the cells were grown overnight at 20 °C.
  • Cell pellets (3L) were lysed for purification to yield 15-24 mgs of purified NS5B.
  • the lysis buffer consisted of 20 mM Tris-HCl, pH 7.4, 500 mM NaCl, 0.5% triton X-100, 1 mM DTT, ImM EDTA, 20% glycerol, 0.5 mg/ml lysozyme, 10 niM MgC12, 15 ug/ml deoxyribonuclease I, and Complete TM protease inhibitor tablets (Roche). After addition of the lysis buffer, frozen cell pellets were resuspended using a tissue homogenizer.
  • aliquots of the lysate were sonicated on ice using a microtip attached to a Branson sonicator.
  • the sonicated lysate was centrifuged at 100,000 x g for lhr at 4 °C and filtered through a 0.2 ⁇ filter unit (Corning).
  • the protein was purified using three sequential chromatography steps:
  • the chromatography buffers were identical to the lysis buffer but contained no lysozyme, deoxyribonuclease I, MgC12 or protease inhibitor and the NaCl concentration of the buffer was adjusted according to the requirements for charging the protein onto the column.
  • Each column was eluted with a NaCl gradient which varied in length from 5-50 column volumes depending on the column type.
  • the resulting purity of the enzyme is >90% based on SDS-PAGE analysis.
  • the enzyme was aliquoted and stored at -80 °C.
  • HCV RdRp genotype lb assays were run in a final volume of 60 ⁇ in 96 well plates (Costar 3912).
  • the assay buffer is composed of 20 mM Hepes, pH 7.5, 2.5 mM KC1, 2.5 mM MgC12, 1 mM DTT, 1.6 U RNAse inhibitor (Promega 2515), 0.1 mg/ml BSA (Promega R3961), and 2 % glycerol. All compounds were serially diluted (3 -fold) in DMSO and diluted further in water such that the final concentration of DMSO in the assay was 2%.
  • HCV RdRp genotype lb enzyme was used at a final concentration of 28 nM.
  • a polyA template was used at 6 nM, and a biotinylated oligo-dT12 primer was used at 180 nM final concentration. Template was obtained commercially (Amersham 27- 41 10).
  • Biotinylated primer was prepared by Sigma Genosys. 3H-UTP was used at 0.6 ⁇ (0.29 ⁇ total UTP). Reactions were initiated by the addition of enzyme, incubated at 30 °C for 60 min, and stopped by adding 25 ⁇ of 50 mM EDTA containing SPA beads (4 ⁇ g/ ⁇ l, Amersham RPNQ 0007).
  • Modified HCVNS5B RdRp enzyme assay was performed essentially as described for the standard enzyme assay except for the following: The biotinylated oligo dT12 primer was precaptured on streptavidin- coated SPA beads by mixing primer and beads in assay buffer and incubating at room temperature for one hour. Unbound primer was removed after centrifugation. The primer-bound beads were resuspended in 20 mM Hepes buffer, pH 7.5 and used in the assay at final concentrations of 20 nM primer and 0.67 ⁇ g/ ⁇ l beads.
  • enzyme 14 nM was added to diluted compound followed by the addition of a mixture of template (0.2 nM) , 3H-UTP (0.6 ⁇ , 0.29 ⁇ ), and primer-bound beads, to initiate the reaction; concentrations given are final. Reactions were allowed to proceed for 4 hours at 30° C.
  • FRET Assay Preparation. To perform the HCV FRET screening assay, 96- well cell culture plates were used.
  • the FRET peptide (Anaspec, Inc.) (Taliani et al, Anal. Biochem. 1996, 240, 60-67) contains a fluorescence donor, EDANS, near one end of the peptide and an acceptor, DABCYL, near the other end.
  • the fluorescence of the peptide is quenched by intermolecular resonance energy transfer (RET) between the donor and the acceptor, but as the NS3 protease cleaves the peptide the products are released from RET quenching and the fluorescence of the donor becomes apparent.
  • RET intermolecular resonance energy transfer
  • the assay reagent was made as follows: 5X cell Luciferase cell culture lysis reagent from Promega (#E153A) diluted to IX with dH 2 0, NaCl added to 150 mM final, the FRET peptide diluted to 20 ⁇ final from a 2 mM stock.
  • HCV replicon cells with or without a Renilla luciferase reporter gene, were trypsinized and placed into each well of a 96-well plate with titrated test compounds added in columns 3 through 12; columns 1 and 2 contained a control compound (HCV protease inhibitor), and the bottom row contained cells without compound.
  • the plates were then placed in a CO 2 incubator at 37 °C. Assays. Subsequent to addition of the test compounds described above (FRET Assay Preparation), at various times the plate was removed and Alamar blue solution (Trek Diagnostics, #00-100) was added per well as a measure of cellular toxicity.
  • Compound analysis was determined by quantification of the relative HCV replicon inhibition and the relative cytotoxicity values.
  • cytoxicity values the average Alamar Blue fluorescence signals from the control wells were set as 100% non-toxic. The individual signals in each of the compound test wells were then divided by the average control signal and multiplied by 100% to determine percent cytotoxicity.
  • HCV replicon inhibition values an average background value was obtained from the two wells containing the highest amount of HCV protease inhibitor at the end of the assay period. These numbers were similar to those obtained from naive Huh-7 cells.
  • the HCV replicon luciferase assay was developed to monitor the inhibitory effects of compounds described in the disclosure on HCV viral replication.
  • HUH-7 cells constitutively expressing the HCV replicon, were grown in Dulbecco's Modified Eagle Media (DMEM) (Gibco-BRL) containing 10% Fetal calf serum (FCS) (Sigma) and 1 mg/ml G418 (Gibco-BRL).
  • DMEM Dulbecco's Modified Eagle Media
  • FCS Fetal calf serum
  • the plates were incubated for 2 hrs at 37°C and then read immediately for 30 seconds with Viewlux Imager (PerkinElmer) using a luminescence program.
  • CC5 0 values were generated by multiplexing the EnduRen-containing plates with Cell Titer-Blue (Promega, cat # G8082). 3 ⁇ of Cell-Titer Blue was added to each well and incubated for 8 hrs at 37°C. The fluorescence signal from each well was read, with an excitation wavelength at 525/10 nm and an emission wavelength of 598/10 nm, using the Viewlux Imager.
  • compositions comprising a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions further comprising a compound having anti-HCV activity.
  • Another aspect of the invention is a composition where the compound having anti-HCV activity is an interferon.
  • the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.
  • compositions where the compound having anti-HCV activity is a cyclosporin.
  • cyclosporin is cyclosporin A.
  • compositions where the compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'- monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
  • Another aspect of the invention is a composition where the compound having anti-HCV activity is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.
  • a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.
  • compositions comprising a compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, an interferon and ribavirin.
  • Another aspect of the invention is a method of inhibiting the function of the HCV replicon comprising contacting the HCV replicon with a compound of formula I or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of inhibiting the function of the HCV NS5B protein comprising contacting the HCV NS5B protein with a compound of formula I or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in conjunction with (prior to, after, or concurrently) another compound having anti-HCV activity.
  • Another aspect of the invention is the method where the other compound having anti-HCV activity is an interferon.
  • interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.
  • interferon alpha 2B is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.
  • other compound having anti-HCV activity is a cyclosporin.
  • Another aspect of the invention is the method where the cyclosporin is cyclosporin A.
  • Another aspect of the invention is the method where the other compound having anti-HCV activity is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
  • Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.
  • a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.
  • Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of target in the HCV life cycle other than the HCV NS5B protein.
  • “Therapeutically effective” means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of hepatitis and HCV infection.
  • Patient means a person infected with the HCV virus and suitable for therapy as understood by practitioners in the field of hepatitis and HCV infection.
  • compositions comprised of a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients.
  • Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles.
  • Compositions encompass all common solid and liquid forms including for example capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example,
  • compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.
  • Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.
  • agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.
  • the invention encompasses all conventional modes of administration; oral and parenteral methods are preferred.
  • the dosing regimen will be similar to other agents used clinically.
  • the daily dose will be 1-100 mg/kg body weight daily.
  • more compound is required orally and less parenterally.
  • the specific dosing regime will be determined by a physician using sound medical judgment.
  • the invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating hepatitis and HCV infection.
  • the compound will generally be given in a daily dose of 1-100 mg kg body weight daily in conjunction with other agents.
  • the other agents generally will be given in the amounts used therapeutically.
  • the specific dosing regime will be determined by a physician using sound medical judgement.
  • HCV Inhibitors Arrow Therapeutics Ltd. From WO
  • N-(3-cyano-2-(4-fluorophenyl)-5-isopropoxybenzofuran-6- yl)methanesulfonamide Trifluoroacetic anhydride (375 ⁇ ,, 2.66 mmol) was added to a stirring solution of DIEA (928 ⁇ , 5.31 mmol), 2-(4-fluorophenyl)-5- isopropoxy-6 (methylsulfonamido) benzofuran-3-carboxamide (300 mg, 0.738 mmol) in CH2C12 (4 mL) and THF (4 mL) at 0 °C for 1 hour. The mixture was diluted with EtOAc and washed with sat NaHC03, and sat NaCl.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10%> MeOH / 90%> H20 / 0.1 % trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 niM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 1 Cesium carbonate (333 mg, 1.021 mmol) was added to Pd(Ph3P)4 (39 mg, 0.034 mmol), ethyl 2-(4-fluorophenyl)-4-nitro-5- (trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (325 mg, 0.681 mmol), 3- boronobenzoic acid (169 mg, 1.021 mmol).
  • Step 2 The crude m-acid was diluted with DMF (5 mL) and treated with HATU (388 mg, 1.021 mmol), 2-phenylpropan-2-amine (138 mg, 1.021 mmol), and DIEA (357 ⁇ , 2.043 mmol) and allowed to stir at rt for 1 hr. The mixture was diluted with EtOAc and washed with sat NaHC03, and sat NaCl.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Ethyl 2-(4-fluorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3- carboxylate Triethylamine (121 ⁇ , 0.869 mmol) was added to a stirring solution of 1 , 1 , 1 -trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (155 mg, 0.434 mmol) and ethyl 2-(4-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3- carboxylate (100 mg, 0.290 mmol) in DCM (3 mL). It was allowed to stir overnight.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 1 Methanamine (4.4 ml, 8.83 mmol) was added to a stirring solution of DIEA (3 ml, 17.65 mmol), BOP (2.9 g, 6.62 mmol), and 2-(4- fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylic acid (1.4 g, 4.41 mmol) in DMF (44 ml) at 0°C. It was allowed to warm to rt and stir for 1 hr. The mixture was concentrated and diluted with EtOAc and washed with 1M HC1, and sat NaCl.
  • Step 2 The hmpa-adduct (100 mg, 0.203 mmol) was taken up in EtOH and treated with 1M NaOH (609 ⁇ , 0.609 mmol) at 70 °C. It was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 1M HC1, and sat NaCl. The organic phase was dried over Na2S04, filtered and concentrated to give the nitro phenol (50 mg, 75%) as a brown solid.
  • LC-MS retention time 1.34 min; m/z (MH+): 331.
  • LC data was recorded on a Shimadzu LC- 10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 niM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 3 Triethylamine (422 ⁇ ,, 3.03 mmol) was added to a stirring solution of N-Phenylbis(trifluoromethane)sulfonimide (649 mg, 1.817 mmol) and 2-(4-fluorophenyl)-5-hydroxy-N-methyl-6-nitrobenzofuran-3 - carboxamide (400 mg, 1.211 mmol) in DCM (24 mL) at rt. The slurry was allowed to stir overnight. The mixture was diluted with EtOAc and washed with sat NaHC03, and sat NaCl.
  • LC-MS retention time 1.96 min; m/z (MH-): 461.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Methanesulfonyl chloride (146 ⁇ ,, 1.873 mmol) was added to a stirring solution of 6-amino-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Trimethylsilyldiazomethane 500 ⁇ ⁇ , 1.00 mmol, 2M in diethyl ether
  • 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5- yl)benzoic acid 100 mg, 0.257 mmol
  • diethyl ether 2.5 mL
  • the mixture was concentrated to afford the titled compound (100 mg, 97%).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Mi romass Platform for LC in electrospray mode.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 2.03 min; m/z (MH+) : parent does not ionize. 420 (-tBu) was observed.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 niM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 1 Methanesulfonyl chloride (16 ⁇ ,, 0.208 mmol) was added to a stirring solution of ethyl 6-amino-5-(3- (tert-butoxycarbonyl)phenyl)-2-(4-fluorophenyl)benzofuran-3 -carboxylate (90 mg, 0.189 mmol) in pyridine (2 mL) at rt.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 2 The crude residue was diluted with DMF (2mL) and treated with DIEA (99 ⁇ , 0.568 mmol) and Iodomethane (18 ⁇ , 0.284 mmol) followed by Na2C03 (20 mg). The reaction was allowed to stir for 3 days. The mixture was diluted with EtOAc and washed with sat NaHC03, and sat NaCl. The organic phase was dried over Na2S04, filtered and concentrated to give the titled compound (100 mg, 93%). LC-MS retention time: 1.96 min; m/z (MH+): the parent does not ionize.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 niM ammonium acetate.
  • MS data was determined u ing a Micromass Platform for LC in electrospray mode.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100%> solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 1 (2-bromoethoxy)(tert- butyl)dimethylsilane (189 ⁇ ,, 0.881 mmol) was added to a stirring suspension of Na2C03 (311 mg, 2.94 mmol) and ethyl 3-(6-(N-(2-(tert- butyldimethylsilyloxy)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-5-yl)benzoate in DMF (6 mL) at 100 °C.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 2 The residue was diluted with EtOH (10 mL) and treated with NaOH (2938 ⁇ , 2.94 mmol) and allowed to stir at 60°C for 4 hours. The mixture was diluted with EtOAc and washed with 1M HC1, and sat NaCl. The organic phase was dried over Na2S04, filtered and concentrated.
  • Step 3 The crude residue was taken up in THF and treated with 1M HC1 (making it 30% in THF). The reaction was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with 1M HC1, and sat NaCl. The organic phase was dried over Na2S04, filtered and concentrated to give the titled compound (300 mg, 97%).
  • LC-MS retention time 1.09 min; m/z (MH+): 527.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • N,N- Dimethylformamide dimethyl acetal (500 ⁇ , 3.76 mmol) and 2-(4-fluorophenyl)-5- isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.246 mmol) were combined and heated to 85 °C .
  • DMF (1 mL) was added. It was allowed to stir for 1 hr.
  • the mixture was concentrated and diluted with dioxane (200 ⁇ ), acetic acid (1 ml) and treated with hydrazine (154 ⁇ , 4.92 mmol) and heated at 85 °C for several hours.
  • the mixture was diluted with EtOAc and washed with sat NaHC03, and sat NaCl.
  • chromatograph equipped with a Waters XB ridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • LC-MS retention time 1.04 min; m/z (MH+): 432.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XB ridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 1.71 min; m/z (MH+): 459.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100%> solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 1.67 min; m/z (MH-): 509.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 1.66 min; m/z (MH-): 509.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XB ridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 1.72 min; m/z (MH-): 523.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 1.71 min; m/z (MH-): 505.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 1.63 min; m/z (MH-): 503.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% MeOH / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 1.70 min; m/z (MH+): 547.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • LC-MS retention time 1.45 min; m/z (MH+): 466.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 1.65 min; m/z (MH+): 459.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 2 EDC (128 mg, 0.668 mmol) was added to a stirring solution of the crude 2- (4-fluorophenyl)-4-nitro-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3- carboxylic acid (300 mg, 0.557 mmol), methanamine (306 ⁇ , 0.613 mmol),l- hydroxy-7-azabenzotriazole (83 mg, 0.613 mmol) , DIEA (204 ⁇ , 1.170 mmol)in DCM (5.5 mL) at rt.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • LC-MS retention time 2.33 min; m/z (MH+): 522.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10%> MeOH / 90%> H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • 4-acetamido-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl)benzofuran-3-carboxamide 4-amino-2-(4-fluorophenyl)-N- methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide (20 mg, 0.038 mmol) was diluted in pyridine (1 mL) and treated with excess acetyl chloride (10 ⁇ ). The reaction was allowed to stir for 2 hours. The mixture was concentrated and diluted with MeOH (lmL).
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 1 2-(4-fluorophenyl)-N-methyl-6-nitro-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl)benzofuran-3-carboxamide.
  • Step 1 cesium carbonate (143 mg, 0.440 mmol) was added to Pd(Ph3P)4 (17 mg, 0.015 mmol), ethyl 2-(4- fluorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (140 mg, 0.293 mmol), 3-boronobenzoic acid (73 mg, 0.440 mmol).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • Step 3 This material was treated with NaOH (1 mL, 1.000 mmol) in ethanol (2.93 mL) at 60°C for 2 hr then allowed to stir overnight while cooling to rt. The reaction was heated to 60° C for 3 hrs. The mixture was diluted with EtOAc and washed with 1M HC1, and sat NaCl. The organic phase was dried over Na2S04, filtered and concentrated.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10%> MeOH / 90%> H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • LC data was recorded on a Shimadzu LC- 10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • Step 1 DIEA (134 ⁇ _,, 0.765 mmol) was added to Pd(Ph3P)4 (30 mg, 0.025 mmol), 2-(4-fluorophenyl)-3- (methylcarbamoyl)-6-(N-(methylsulfonyl)methylsulfonamido)benzofuran-5-yl trifluoromethanesulfonate (150 mg, 0.255 mmol), 3-(ethoxycarbonyl)phenylboronic acid (74 mg, 0.382 mmol). Dioxane (5 mL) and water (1 mL) was added at rt. The reaction was degassed 3x and heated to 90 °C overnight.
  • Step 2 The mixture was concentrated and diluted with EtOH (5 mL) and treated with excess IN NaOH ( ⁇ 1 mL) and allowed to stir at rt overnight to give the meta-acid. The mixture was diluted with EtOAc and washed with 1M HC1, and 1M HC1. The organic phase was dried over Na2S04, filtered and concentrated.
  • Step 3 The crude residue was diluted with DMF (5 mL) and treated with HATU (145 mg, 0.382 mmol), 2-phenylpropan-2-amine (52 mg, 0.382 mmol) and DIEA (134 ⁇ ⁇ , 0.765 mmol) and allowed to stir at rt overnight.
  • HATU 145 mg, 0.382 mmol
  • 2-phenylpropan-2-amine 52 mg, 0.382 mmol
  • DIEA 134 ⁇ ⁇ , 0.765 mmol
  • the mixture was concentrated and purified by preparative reverse phase HPLC on a CI 8 column using a suitably buffered gradient, and concentrated.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H20 / 0.1% TFA and solvent B was 5% H20 / 95% acetonitrile / 0.1% TFA.
  • methanesulfonyl chloride (10 ⁇ ,, 0.128 mmol) was added to a stirring solution of 6- amino-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl)benzofuran-3-carboxamide (50 mg, 0.096 mmol) in pyridine (1 mL) at rt. It was allowed to stir for 2 hours and then concentrated and diluted with EtOAc and washed with sat NaHC03, and sat NaCl. The organic phase was dried over Na2S04, filtered and concentrated.
  • Step 2 The crude residue was dissolved in DMF (1 mL) and treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (102 ⁇ ⁇ , 0.479 mmol) and Na2C03 (31 mg, 0.288 mmol) at rt. It was heated to 100°C for 4 hours and then diluted with EtOAc and washed with sat NaHC03, and sat NaCl. The organic phase was dried over Na2S04, filtered and concentrated.
  • Step 3 The crude residue was taken up in THF (2 mL) and treated with 2 mL of IN HC1. and allowed to stir at rt for 1 hr.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method:
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10%> MeOH / 90%> H20 / 0.1%> trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • the reaction was concentrated and diluted with EtOH (3 mL) and treated with excess IN NaOH (500 ⁇ ) and stirred at 60°C for 2 hours to hydrolyze the acylated amide.
  • the mixture was filtered and the filtrate was diluted with EtOAc and washed with sat NaHC03, and sat NaCl.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10%> MeOH / 90%> H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 1.63 min; m/z (MH+): 457.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu CI 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10%> MeOH / 90%> H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 2.09 min; m/z (MH+): 470.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu CI 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • LC-MS retention time 2.02 min; m/z (MH+): 456.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu CI 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10%> MeOH / 90%> H20 / 0.1%> trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method:
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XB ridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XB ridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XB ridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 1.41 min; m/z (MH-): 426.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • the mixture was subjected to microwave irradiation for 5 min at 160 °C.
  • the mixture was concentrated and purified by preparative reverse phase HPLC on a C 18 column using a suitably buffered H 2 0/CH 3 CN gradient, and concentrated to give the titled compound (11 mg, 20%).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • LC-MS retention time 1.94 min; m/z (MH+) : 490 .
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XB ridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 niM ammonium acetate.
  • LC-MS retention time 2.00 min; m/z (MH+) : 502.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10%> MeOH / 90%> H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu CI 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10%> MeOH / 90%> H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method:
  • LC-MS retention time 1.69 min; m/z (MH+) : 555.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu CI 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • LC-MS retention time 1.69 min; m/z (MH+) : 555.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu CI 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10%> MeOH / 90%> H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 1.56 min; m/z (MH+): 553.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu CI 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • the reaction was heated to 90 °C overnight.
  • the mixture was diluted with ethyl acetate and washed with sat NaHC03, and sat NaCl.
  • LC-MS retention time 1.46 min; m/z (MH+): 498.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 1.60 min; m/z (MH+): 660.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC-MS retention time 1.66 min; m/z (MH+): 662.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu CI 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • LC-MS retention time 1.59 min; m/z (MH+): 508.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XB ridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • Lawesson's reagent (129 mg, 0.32 mmol) was added to a solution of 2- (4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxamide (125 mg, 0.31 mmol) in THF (3 mL) was stirred at r.t. for 1.5 h. The two batches were then combined and partitioned between EtOAc (50 mL) and water (10 mL). The organic phase was washed with sat'd aHC0 3 and brine, dried over Na 2 S0 4 , filtered, and concentrated to give a yellow oil.
  • LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.
  • Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm.
  • LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.
  • LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.

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Abstract

La présente invention concerne des composés de formule (I) et leurs sels, ainsi que des compositions en contenant et des méthodes d'utilisation desdits composés. Ces composés sont actifs contre le virus de l'hépatite C (VHC) et peuvent être utilisés dans le cadre du traitement de personnes infectées par le VHC.
PCT/US2010/026898 2010-03-11 2010-03-11 Composés utilisables pour le traitement de l'hépatite c Ceased WO2011112191A1 (fr)

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PCT/US2010/026898 WO2011112191A1 (fr) 2010-03-11 2010-03-11 Composés utilisables pour le traitement de l'hépatite c
CN2010800667265A CN102906080A (zh) 2010-03-11 2010-03-11 治疗丙型肝炎的化合物
EP10710487A EP2545042A1 (fr) 2010-03-11 2010-03-11 Composés utilisables pour le traitement de l'hépatite c
JP2012557020A JP2013522192A (ja) 2010-03-11 2010-03-11 Ｃ型肝炎の処置のための化合物

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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013148620A1 (fr) * 2012-03-27 2013-10-03 Bristol-Myers Squibb Company Dérivés de benzofuranne pour le traitement de l'hépatite c
US8614207B2 (en) 2010-10-26 2013-12-24 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
US8629274B2 (en) 2011-12-21 2014-01-14 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US8993771B2 (en) 2013-03-12 2015-03-31 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US9126944B2 (en) 2013-02-28 2015-09-08 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9169212B2 (en) 2014-01-16 2015-10-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9181288B2 (en) 2014-01-16 2015-11-10 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9400280B2 (en) 2014-03-27 2016-07-26 Novira Therapeutics, Inc. Piperidine derivatives and methods of treating hepatitis B infections
WO2016133948A1 (fr) * 2015-02-19 2016-08-25 Bristol-Myers Squibb Company Composés de benzofurane pour le traitement de l'hépatite c
WO2016133972A1 (fr) * 2015-02-19 2016-08-25 Bristol-Myers Squibb Company Composés de benzofurane substitués pour le traitement de l'hépatite c
US9549921B2 (en) * 2013-06-24 2017-01-24 Merck Sharp & Dohme Corp. Heterocyclic compounds and methods of use thereof for the treatment of hepatitis C
WO2017165233A1 (fr) * 2016-03-21 2017-09-28 Bristol-Myers Squibb Company Dérivés de benzofurane pour le traitement de l'hépatite c
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US20180030017A1 (en) * 2015-02-19 2018-02-01 Bristol-Myers Squibb Company Benzofurans substituted with primary benzamide as hcv inhibitors
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9884831B2 (en) 2015-03-19 2018-02-06 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10818850B2 (en) 2017-12-22 2020-10-27 Samsung Display Co., Ltd. Organic electroluminescence device and compound including nitrogen for organic electroluminescence device
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015143654A1 (fr) * 2014-03-26 2015-10-01 Merck Sharp & Dohme Corp. Inhibiteurs de la kinase trka, compositions et méthodes associées

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041201A2 (fr) 2002-11-01 2004-05-21 Viropharma Incorporated Composes de benzofurane, compositions et methodes utilisees pour le traitement et la prophylaxie des infections virales induites par l'hepatite c et des maladies associees
US20090208449A1 (en) * 2008-02-14 2009-08-20 Roche Palo Alto Llc Heterocyclic antiviral compounds

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2007000481A (es) * 2004-07-14 2007-03-29 Ptc Therapeutics Inc Metodos para tratar hepatitis c.
ZA200701235B (en) * 2004-07-14 2009-10-28 Ptc Therapeutics Inc Methods for treating hepatitis C
CN101541748A (zh) * 2006-01-13 2009-09-23 Ptc医疗公司 治疗丙型肝炎的方法
US8048887B2 (en) * 2008-09-11 2011-11-01 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041201A2 (fr) 2002-11-01 2004-05-21 Viropharma Incorporated Composes de benzofurane, compositions et methodes utilisees pour le traitement et la prophylaxie des infections virales induites par l'hepatite c et des maladies associees
US7265152B2 (en) 2002-11-01 2007-09-04 Viropharma Incorporated Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and associated diseases
US20090208449A1 (en) * 2008-02-14 2009-08-20 Roche Palo Alto Llc Heterocyclic antiviral compounds

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
BRESSANELLI; S. ET AL., JOURNAL OF VIROLOGY, 2002, pages 3482 - 3492
DEFRANCESCO; RICE, CLINICS IN LIVER DISEASE, vol. 7, 2003, pages 211 - 242
KRIEGER N; LOHMANN V; BARTENSCHLAGER R, J VIROL., vol. 75, no. 10, 2001, pages 4614 - 4624
LAUER, G. M.; WALKER, B. D., N. ENGL. J. MED., vol. 345, 2001, pages 41 - 52
POYNARD, T. ET AL., LANCET, vol. 352, 1998, pages 1426 - 1432
See also references of EP2545042A1
TALIANI ET AL., ANAL. BIOCHEM., vol. 240, 1996, pages 60 - 67
ZEUZEM, S. ET AL., N. ENGL. J. MED., vol. 343, 2000, pages 1666 - 1672

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US10570108B2 (en) 2015-02-19 2020-02-25 Bristol-Myers Squibb Company Substituted benzofuran compounds for the treatment of hepatitis C
US10131645B2 (en) * 2015-02-19 2018-11-20 Bristol-Myers Squibb Company Benzofurans substituted with primary benzamide as HCV inhibitors
US10537580B2 (en) 2015-03-19 2020-01-21 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US9884831B2 (en) 2015-03-19 2018-02-06 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
WO2017165233A1 (fr) * 2016-03-21 2017-09-28 Bristol-Myers Squibb Company Dérivés de benzofurane pour le traitement de l'hépatite c
US11161837B2 (en) 2016-03-21 2021-11-02 Bristol-Myers Squibb Company Benzofuran derivatives for the treatment of hepatitis C
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US11129834B2 (en) 2016-04-15 2021-09-28 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10818850B2 (en) 2017-12-22 2020-10-27 Samsung Display Co., Ltd. Organic electroluminescence device and compound including nitrogen for organic electroluminescence device
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases

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