WO2011156543A2 - Inhibitors of hcv ns5a protein - Google Patents

Inhibitors of hcv ns5a protein Download PDF

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Publication number
WO2011156543A2
WO2011156543A2 PCT/US2011/039707 US2011039707W WO2011156543A2 WO 2011156543 A2 WO2011156543 A2 WO 2011156543A2 US 2011039707 W US2011039707 W US 2011039707W WO 2011156543 A2 WO2011156543 A2 WO 2011156543A2
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compound
group
mmol
independently
methyl
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PCT/US2011/039707
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French (fr)
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WO2011156543A3 (en
Inventor
Leping Li
Min Zhong
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Presidio Pharmaceuticals, Inc.
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Priority to US13/703,004 priority Critical patent/US20130310427A1/en
Priority to EP11793132.9A priority patent/EP2580209A4/en
Priority to CA2802067A priority patent/CA2802067A1/en
Publication of WO2011156543A2 publication Critical patent/WO2011156543A2/en
Publication of WO2011156543A3 publication Critical patent/WO2011156543A3/en

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    • 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
    • C07D403/14—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 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D405/14—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 three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to compounds useful for inhibiting hepatitis C virus (“HCV”) replication, particularly functions of the non-structural 5A (“NS5A”) protein of HCV.
  • HCV hepatitis C virus
  • NS5A non-structural 5A
  • HCV is a single-stranded RNA virus that is a member of the Flaviviridae family.
  • the virus shows extensive genetic heterogeneity as there are currently seven identified genotypes and more than 50 identified subtypes.
  • viral RNA is translated into a polyprotein that is cleaved into ten individual proteins.
  • NS2, NS3, NS4A, NS4B, NS5A and NS5B which play a functional role in the HCV life cycle, (see, for example, Lindenbach, B.D. and CM. Rice, Nature. 436:933- 938, 2005).
  • HCV infection is a serious health issue. It is estimated that 170 million people worldwide are chronically infected with HCV. HCV infection can lead to chronic hepatitis, cirrhosis, liver failure and hepatocellular carcinoma. Chronic HCV infection is thus a major worldwide cause of liver-related premature mortality.
  • the present standard of care treatment regimen for HCV infection involves interferon-alpha, alone, or in combination with ribavirin.
  • the treatment is cumbersome and sometimes has debilitating and severe side effects and many patients do not durably respond to treatment. New and effective methods of treating HCV infection are urgently needed.
  • a a ' are independently selected from the group consisting of s
  • R is selected from the group consisting of C1-C4 alkyl, aryl, a halogen, -CN, -N0 2 , -
  • R 2 , R 3 , and R 4 are each independently chosen from the group consisting of hydrogen, Ci to C 4 alkyl, Ci to C 4 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl, and wherein for each A and A', B may be attached to either side of A and ' so that in the
  • X a , X b , X a' , and X b' are each independently selected from the group consisting of C 2 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 heteroalkyl, and C 2 to C 6 heteroalkenyl,wherein:
  • each hetero atom if present, is independently N, O or S, and
  • X a -X b and X a -X b together with the atoms to which they are attached, optionally form a 4- to 9-membered ring which may be cycloalkyl and heterocycle and which may optionally be fused to another 3-5 membered ring;
  • R a , R b , R a and R b are each independently hydrogen, d to C 8 alkyl or Ci to C 8 heteroalkyl, wherein: each hetero atom, if present, is independently N, O or S,
  • R a and R b are optionally joined, together with the atom to which they are attached, to form a 3- to 6-membered ring, and
  • R a' and R b' are optionally joined, together with the atom to which they are attached, to form a 3- to 6-membered ring;
  • Y and Y' are each independently N or CH;
  • Z and Z' are each independently selected from the group consisting of hydrogen, Ci to C 8 alkyl, Ci to Cg heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, 1-3 amino acids,
  • U is selected from the group consisting of -C(O)-, -C(S)- and -S(0) 2 -, each R 4 R 5 and R 7 is independently selected from the group consisting of
  • Ci to Cg alkyl
  • Ci Ci to Cg heteroalkyl
  • cycloalkyl heterocycle
  • aryl heteroaryl and aralkyl
  • R 8 is selected from the group consisting of hydrogen, Ci to Cg alkyl, Ci to Cg heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, -C(0)-R 81 , -C(S)-R 81 , -C(0)-0-R 81 , -C(0)-N-R 81 2, -S(0) 2 -R 81 and -S(0) 2 -N-R 81 2 , wherein each R 81 is independently chosen from the group consisting of hydrogen, Ci to Cg alkyl, Ci to Cg heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl, optionally, R 7 and R 8 together form a 4-7 membered ring, each t is independently 0, 1, 2, 3, or 4, and u is 0, 1, or 2.
  • a and A' are selected from the group
  • D is independently selected from
  • Group 1 consists of
  • R 1 is independently selected from the group consisting of hydrogen, -OH, Ci to C 12 alkyl, Ci to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.
  • Group 2 consists of: wherein R e , R f , R g , and
  • R h are each independently hydrogen, Ci to Cg alkyl or Ci to Cg heteroalkyl, each hetero atom, if present, is independently N, O or S.
  • R e and R f are optionally joined, together with the atom to which they are attached, to form a 5- to 8-membered ring, and R g and R h are optionally joined, together with the atom to which they are attached, to form a 3- to 8-membered ring.
  • D' is independently selected from group
  • R is independently selected from the group consisting of hydrogen
  • Ci to Ci 2 alkyl Ci to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
  • Group 2' consists of , ,
  • Ci to C 8 alkyl or Ci to C 8 heteroalkyl are each independently hydrogen, Ci to C 8 alkyl or Ci to C 8 heteroalkyl, each hetero atom, if present, is
  • R e and R f are optionally joined, together with the atom to which they are attached, to form a 5- to 8-membered ring
  • R g and R h are optionally joined, together with the atom to which they are attached, to form a 3- to 8-membered ring.
  • D is selected from Group 1
  • D' is selected from Group 2'.
  • D is selected from Group 2.
  • A-B-A' is selected from the group of:
  • Z and Z' in any of the previous aspects are each 1-3 amino acids.
  • the amino acids are all in the D or all in the L configuration.
  • Z and Z' are each independently selected from the group consisting of
  • one or both of Z and Z' are -C(0)-(CR 4 2 ) n -NR 7 -(CR 4 2 ) n -C(0)-R 81 .
  • one or both of Z and Z' are -C(0)-(CR 4 2 ) n -NR 7 -(CR 4 2 ) n -C(0)-0-R 81 .
  • one or both of Z and Z' are -C(0)-(CR 4 2 ) n -NR 7 -C(0)-0-R 81 .
  • one or both of Z and Z' are -C(0)-(CR 4 2 ) t -0-(CR 4 2 ) t -R 8 .
  • Z and Z' are - C(0)-(CR 4 2 ) admir-NR 7 -R 8 wherein R 7 and R 8 together form a 4-7 membered ring.
  • a fourth aspect of the invention provides a pharmaceutical composition comprising the compounds of the invention.
  • a fifth aspect of the invention provides use of the compounds of the invention in the manufacture of a medicament.
  • the medicament is for the treatment of hepatitis C.
  • a sixth aspect of the invention provides a method of treating hepatitis C comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention.
  • alkanoyl as used herein contemplates a carbonyl group with a lower alkyl group as a substituent.
  • alkenyl as used herein contemplates substituted or unsubstituted, straight and branched chain alkene radicals, including both the E- and Z-forms, containing from two to eight carbon atoms.
  • the alkenyl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -N0 2 , -C0 2 R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N ) 2 , -OC(0)R, -OC(0)N(R N ) 2 , -S(0)R, -S0 2 R, -S0 3 R, -S(0) 2 N(R N ) 2 , phosphate, phosphonate, cycloalkyl, cycloalkenyl, ary
  • alkoxy contemplates an oxygen with a lower alkyl group as a substituent and includes methoxy, ethoxy, butoxy, trifiuromethoxy and the like. It also includes divalent substituents linked to two separated oxygen atoms such as, without limitation, -0-(CH 2 )i_ 4 -0-, -0-CF 2 -0-, -0-(CH 2 )i_ 4 -0-(CH 2 CH 2 -0)i_ 4 - and
  • alkoxycarbonyl as used herein contemplates a carbonyl group with an alkoxy group as a substituent.
  • alkyl as used herein contemplates substituted or unsubstituted, straight and branched chain alkyl radicals containing from one to fifteen carbon atoms.
  • lower alkyl as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl and the like.
  • the alkyl group may be optionally substituted with one or more substituents selected from halogen, -CN, -N0 2 , -C(0) 2 R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N ) 2 , -OC(0)R, -OC(0)N(R N ) 2 , -SOR, -S0 2 R, -S0 3 R, -S(0) 2 N(R N ) 2 , phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halogen, -CN, -N0 2 , -C(0) 2 R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R
  • alkylene alkenylene and alkynylene as used herein refers to the groups “alkyl,” “alkenyl” and “alkynyl” respectively, when they are divalent, ie, attached to two atoms.
  • alkylsulfonyl as used herein contemplates a sulfonyl group which has a lower alkyl group as a substituent.
  • alkynyl as used herein contemplates substituted or unsubstituted, straight and branched carbon chain containing from two to eight carbon atoms and having at least one carbon-carbon triple bond.
  • alkynyl includes, for example ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 3 -methyl- 1-butynyl and the like.
  • the alkynyl group may be optionally substituted with one or more substituents selected from halo, -CN, -N0 2 , -C0 2 R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N ) 2 , -OC(0)R, -OC(0)N(R N ) 2 , -SOR, -S0 2 R, -S0 3 R, -S(0) 2 N(R N ) 2 , phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halo, -CN, -N0 2 , -C0 2 R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C
  • amino as used herein contemplates a group of the structure -NR N 2 .
  • amino acid as used herein contemplates a group of the structure
  • the present invention also includes, without limitation, D-configuration amino acids, beta-amino acids, amino acids having side chains as well as all non-natural amino acids known to one skilled in the art.
  • aralkyl as used herein contemplates a lower alkyl group which has as a substituent an aromatic group, which aromatic group may be substituted or unsubstituted.
  • the aralkyl group may be optionally substituted with one or more substituents selected from halogen, -CN, -N0 2 , -C0 2 R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N ) 2 , -OC(0)R, -OC(0)N(R N ) 2 , -SOR, -S0 2 R, -S0 3 R, -S(0) 2 N(R N ) 2 , phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • aryl as used herein contemplates substituted or unsubstituted single-ring and multiple aromatic groups (for example, phenyl, pyridyl and pyrazole, etc.) and polycyclic ring systems (naphthyl and quinolinyl, etc.).
  • the polycyclic rings may have two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is aromatic, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls.
  • the aryl group may be optionally substituted with one or more substituents selected from halogen, alkyl, -CN, -N0 2 , -C0 2 R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N ) 2 , -OC(0)R, -OC(0)N(R N ) 2 , -SOR, -S0 2 R, -S0 3 R,
  • arylsulfonyl as used herein contemplates a sulfonyl group which has as a substituent an aryl group.
  • the term is meant to include, without limitation, monovalent as well as multiply valent aryls (eg, divalent aryls).
  • carbonyl as used herein contemplates a group of the structure
  • cycloalkyl as used herein contemplates substituted or unsubstituted cyclic alkyl radicals containing from three to twelve carbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl and the like.
  • cycloalkyl also includes polycyclic systems having two rings in which two or more atoms are common to two adjoining rings (the rings are "fused").
  • the cycloalkyl group may be optionally substituted with one or more substituents selected from halo, -CN, -N0 2 , -C0 2 R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N ) 2 , -OC(0)R, -OC(0)N(R N ) 2 , -SOR, -S0 2 R, -S(0) 2 N(R N ) 2 , phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halo, -CN, -N0 2 , -C0 2 R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, -N(R N
  • cycloalkenyl as used herein contemplates substituted or unsubstituted cyclic alkenyl radicals containing from four to twelve carbon atoms in which there is at least one double bond between two of the ring carbons and includes cyclopentenyl, cyclohexenyl and the like.
  • cycloalkenyl also includes polycyclic systems having two rings in which two or more atoms are common to two adjoining rings (the rings are "fused").
  • the cycloalkenyl group may be optionally substituted with one or more substituents selected from halo, -CN, -NO 2 , -C0 2 R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N ) 2 , -OC(0)R, -OC(0)N(R N ) 2 , -SOR, -S0 2 R, -S(0) 2 N(R N ) 2 , phosphate,
  • halo or halogen as used herein includes fluorine, chlorine, bromine and iodine.
  • heteroalkyl as used herein contemplates an alkyl with one or more heteroatoms.
  • heteroatom particularly within a ring system, refers to N, O and S.
  • heterocyclic group contemplates substituted or unsubstituted aromatic and non-aromatic cyclic radicals having at least one heteroatom as a ring member.
  • Preferred heterocyclic groups are those containing five or six ring atoms which includes at least one hetero atom and includes cyclic amines such as morpholino, piperidino, pyrrolidino and the like and cyclic ethers, such as tetrahydrofuran, tetrahydropyran and the like.
  • Aromatic heterocyclic groups also termed "heteroaryl” groups, contemplates single-ring hetero-aromatic groups that may include from one to three heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, oxodiazole, thiadiazole, pyridine, pyrazine, pyridazine, pyrimidine and the like.
  • heteroaryl also includes polycyclic hetero-aromatic systems having two or more rings in which two or more atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is a heteroaryl, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls.
  • polycyclic heteroaromatic systems examples include quinoline, isoquinoline, cinnoline, tetrahydroisoquinoline, quinoxaline, quinazoline, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, indazole, purine, benzotriazole, pyrrolepyridine, pyrrazolopyridine and the like.
  • the heterocyclic group may be optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, -CN, -N0 2 , -C0 2 R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N ) 2 , -OC(0)R, -OC(0)N(R N ) 2 , -SOR, -S0 2 R, -SO 3 R, -S(0) 2 N(R ) 2 , -S1R 3 , -P(0)R, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from the group consisting of halo, alkyl, -CN, -N0 2 , -C0 2 R, -C(0)
  • oxo as used herein contemplates an oxygen atom attached with a double bond.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is made with counterions understood in the art to be generally acceptable for pharmaceutical uses and which possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid,
  • cyclopentanepropionic acid glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
  • salts of amino acids such as arginates and the like, and salts of organic acids like glucurmic or galactunoric acids and the like (see, e.g., Berge et al., 1977, J. Pharm. Sci. 66: 1-19).
  • phosphate and “phosphonate” as used herein refer to the moieties having the following structures, respectively: O o
  • salts and “hydrates” refers to the hydrated forms of the compound that would favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion.
  • Other factors, more practical in nature, which those skilled in the art may take into account in the selection include the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity, flowability and manufacturability of the resulting bulk drug.
  • sulfonamide as used herein contemplates a group having the structure
  • R s is selected from the group consisting of hydrogen, Ci-Cio alkyl,
  • alkylsulfonyl including, but not limited to alkylsulfonyl and arylsulfonyl.
  • thiocarbonyl means a carbonyl wherein an oxygen atom has been replaced with a sulfur.
  • Each R is independently selected from hydrogen, -OH, -CN, -N0 2 , halogen, Ci to Ci 2 alkyl, Ci to C 12 heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide, amino and oxo.
  • Each R N is independently selected from the group consisting of hydrogen, -OH, Ci to Ci 2 alkyl, Ci to C 12 heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.
  • Two R N may be taken together with C, O, N or S to which they are attached to form a five to seven membered ring which may optionally contain a further heteroatom.
  • the compounds of the present invention may be used to inhibit or reduce the activity of HCV, particularly HCV's NS5A protein.
  • inhibition and reduction of activity of the NS5A protein refers to a lower level of the measured activity relative to a control experiment in which the cells or the subjects are not treated with the test compound.
  • the inhibition or reduction in the measured activity is at least a 10% reduction or inhibition.
  • reduction or inhibition of the measured activity of at least 20%>, 50%>, 75%, 90% or 100% or any number in between, may be preferred for particular applications.
  • DIPEA Diisopropylethylamine DIBAL Diisobutylaluminium hydride
  • Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 1 FiNMR spectra were recorded on a Bruker 400 MHz or 500 MHz NMR spectrometer. Significant peaks are tabulated in the order: chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz) and number of protons.
  • LC-MS Liquid chromatography mass spectra
  • ESI electrospray ionization
  • Step 1 to 3 N-protected 2,5- dihydro-lH-pyrrole-2-carboxylic acids bearing various types of 4-substituents, including those represented by compounds l-2a, l-2b, l-2c, and l-2d.
  • Other dihydropyrrole compounds bearing different substituents and substitution patterns may also be prepared similarly.
  • Step 1 To a stirred solution of sodium bis(trimethylsilyl)amide (1 N in THF, 45.2 mL, 45.2 mmol) was added dropwise a solution of (S)-l-tert-butyl 2-methyl 4- oxopyrrolidine-l,2-dicarboxylate (10 g, 41.1 mmol, prepared as described in Tetrahedron, 57(14), 4195-212; 1995) in THF (50 mL) at -78 °C. After 20 mins, N-phenyl- bis(trifluoromethanesulfonimide) (15.4 g, 43.2 mmol) was added, and the reaction mixture was stirred at -78 °C for another 3 hrs.
  • Step 3 To a solution of (S)- 1 -tert-butyl 2-methyl 4-methyl- lH-pyrrole- l,2(2H,5H)-dicarboxylate (3.76 g, 15.6 mmol) in THF (20 mL), MeOH (15 mL) and H 2 0 (15 mL) was added LiOH H 2 0 (1.30 g, 31.2 mmol). The reaction was stirred at rt overnight. The mixture was concentrated in vacuo and water (15 mL) was added. The solution was washed with Et 2 0, acidified with 6 N HC1 to pH 3 and extracted with DCM (2 x 100 niL).
  • Step a To a solution of ⁇ S)- ⁇ -tert- vXy ⁇ 2-methyl 4-(trifluoromethylsulfonyloxy)- lH-pyrrole-l,2(2H,5H)-dicarboxylate (15 g, 40 mmol) in dioxane (250 mL) was added cyclopropylboronic acid (5.15 g, 60 mmol), Pd(PPh 3 ) 4 (2.31 g, 2.0 mmol) and Na 2 C0 3 (2 N in H 2 0, 45 mL). The flask was degassed and heated at 100 °C for 3 hr under N 2 atmosphere. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was diluted in EtOAc and washed with H 2 0, brine. The organic layer was dried with anhydrous Na 2 S0 4 and concentrated. The resulting residue was purified by flash column chromatography
  • Step b To a solution of ( ⁇ S)-l-ierf-butyl 2-methyl 4-methyl-lH-pyrrole- l,2(2H,5H)-dicarboxylate from above (3.70 g, 13.8 mmol) in THF (20 mL), MeOH (15 mL) and H 2 0 (15 mL) was added LiOH H 2 0 (1.30 g, 30.9 mmol). The reaction was stirred at rt overnight. The mixture was concentrated in vacuo and water (15 mL) was added. The solution was washed with Et 2 0, acidified with 6 N HC1 to pH 3. The aqueous phase was extracted with DCM. The combined organic phase was dried with anhydrous Na 2 S0 4 and concentrated to give 25 (3.5 g, quantitative yield) as a colorless oil.
  • Step 1 A solution of 2-bromo-l-(4-bromophenyl)ethanone (1-1) (2.27 g, 10.0 mmol) in CH3CN (30 mL) was added (5)-l-(fert-butoxycarbonyl)-4-methyl-2,5-dihydro-lH- pyrrole-2-carboxylic acid (l-2b) (3.05 g, 11.0 mmol) and DIPEA (3.30 mL, 20 mmol). The resulting mixture was stirred at rt overnight. The volatile components were removed in vacuo, and the residue was partitioned between water and DCM. The organic layer was dried over anhydrous Na 2 S0 4 , filtered, and concentrated.
  • Step 2 To a solution of (5)-2-(2-(4-bromophenyl)-2-oxoethyl) 1 -tert-butyl 4- methyl-lH-pyrrole-l,2(2H,5H)-dicarboxylate (3.65 g, 8.6 mmol) in xylene (90 mL) in a sealed tube was added ammonium acetate (10.4 g, 135 mmol) and triethylamine (18.8 mL, 135 mmol). The resulting mixture was stirred at 140 °C for 2 hrs. Analysis by LC-MS showed the reaction was completed. The solvent was removed in vacuo, and the residue was partitioned between water and DCM.
  • Step 1 To a solution of l-3b (10.0 g, 24.8 mmol) in anhydrous THF (100 mL) was added PPh 3 (1.34 g, 5.11 mmol), Pd[PPh 3 ] 2 Cl 2 (1.79 g, 2.56 mmol), Cul (0.24 g, 1.28 mmol), DIPEA (7.75 g, 76.8 mmol), and TMS-acetylene (5.02 g, 51.2 mmol). The mixture was refluxed under argon overnight. At the completion of the reaction, volatile solvents were removed under reduced pressure; the residue was treated with water, extracted with EtOAc (2 x 100 mL).
  • Step 1 Again referring to route outlined in Scheme 1, (General Procedure A) a solution of l-(6-bromonaphthalen-2-yl)-2-chloroethanone (1-8) (1.18 g, 4.15 mmol, prepared from 2-bromo-naphthalene via a Friedel-Craft reaction with chloroacetyl chloride) in CH 3 CN (40 mL) was added (5)-4-methyl-2,5-dihydro-pyrrole-l,2-dicarboxylic acid 1-tert-butyl ester (940 mg, 4.15 mmol) and N,N-diisopropylethylamine (0.73 mL, 4.15 mmol). The mixture was stirred overnight.
  • Step 2 In a sealed tube, (5)-2-(2-(6-bromonaphthalen-2-yl)-2-oxoethyl) 1-tert- butyl 4-methyl- lH-pyrrole-l,2(2H,5H)-dicarboxylate (1.2 g, 2.53 mmol), ammonium acetate (2.92 g, 38 mmol) and triethylamine (0.7 mL, 5.06 mmol) were added in xylene (30 mL). The resulting mixture was stirred at 140 °C for 2 hrs. LC-MS showed the reaction was completed. The solvent was removed in vacuo, and the residue was partitioned between water and DCM.
  • Step 2 The mixture of the product from above (230 mg, 0.488 mmol) potassium carbonate (540 mg, 3.91 mmol) in methanol (6 mL) was warmed up to 80 °C and stirred overnight. The reaction was cooled to rt, diluted with ethyl acetate (100 mL) and washed with water and brine.
  • Step 2 To a solution of (S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1 -tert-butyl pyrrolidine- 1,2-dicarboxylate (159 g, 0.39 mol) in xylene (250 mL) was added NH 4 OAc (300 g, 3.90 mol), the mixture was stirred at 140 °C for overnight.
  • Step 1 To a solution of N-Boc-L-Pro-OH (29 g, 135 mmol) and DIPEA (29 g, 225 mmol) in THF (500 mL) was added HATU (51 g, 135 mmol) at rt. After stirring at rt for 10 min, 4-bromobenzene-l,2-diamine (1-5) (25 g, 135 mmol) was added and the resulting solution was stirred at rt for another several hours. Subsequently, the reaction mixture was concentrated and the residue was diluted with EtOAc (500 mL).
  • Step 2 A mixture of acylated products from above in AcOH (1000 mL) was stirred at 40 °C for 12 hrs. After cooling, the reaction mixture was carefully neutralized by adding saturated aqueous sodium bicarbonate solution to adjust the pH value to 8. The resulting mixture was extracted with EtOAc (250 mL x 3). The combined extract was washed with water, and dried with anhydrous Na 2 S0 4 .
  • Step 1 To a solution of 2-bromonaphthalene (1-7) (62 g, 0.3 mol) in DCM (1000 mL) was added A1C1 3 (44 g, 0.33 mol), followed by 2-chloroacetyl chloride (34 g, 0.3 mmol) at 0 °C. After stirring at 0 °C for 1 hr, the reaction mixture was quenched by adding water (500 mL). The organic layer was separated, washed with brine, and dried with anhydrous Na 2 S0 4 . The solvent was removed and the residue was re-crystallized in 10% of EtOAc in hexane to give compound 1-8 (28 g, 33% yield) as a white solid.
  • Step 1 Referring to Scheme 2b, to a solution of 2b-l (20.6 g, 0.128 mol) in 45 mL of 48% hydrobromic acid and 10 mL of water was added a solution of 9.72 g (0.141 mol) of sodium nitrite in 18 mL of water, maintaining a temperature below 5 °C. After stirring at 5 °C for 1 hr, CuBr (0.128 mol) was added and the resulting mixture was stirred at rt for 3 hrs. Subsequently, the mixture was extracted with EtOAc (2 x 200 mL). The extracts were combined, washed with brine, and dried with anhydrous Na 2 S0 4 .
  • Step 2 To a solution of 2b-2 (12.49 g, 55.5 mmol) in 300 mL of methylene chloride and 0.30 mL of 48% hydrobromic acid was slowly added 3.1 mL of bromine at 0 °C. The reaction mixture was gradually warmed up to rt, and kept stirring for another 2 hrs. The organic solution was washed with saturated NaHC0 3 twice, and then with water. The crude product was purified by silica gel column chromatography to afford 2b-3 (11.9 g, 71% yield).
  • Step 4 A mixture of 2b-4 (11.09 g, 25.3 mmol), ammonium acetate (29.25 g, 38.0 mmol) and triethylamine (38.45 g, 38.0 mmol) in xylenes (600 mL) in a sealed tube was stirred at 140 °C for 2 hrs. After being cooled, the reaction mixture was transferred into a flask and concentrated to dryness. The residue was partitioned between chloroform and water, and the organic layer was washed with water, and concentrated.
  • Step 5 (S)-ieri-butyl 2-(7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-4,5- dihydro- lH-naphtho[ 1 ,2-d]imidazol-2-yl)pyrrolidine- 1 -carboxylate (2b-6).
  • Compound 2b-6 was prepared from 2b-5 using the conditions described in General Procedure D.
  • Step 6 N-Boc deprotection and reacylation (Step 6 and 7). Trifluoroacetic acid (20 mL) was slowly added into a solution of 2b-5 (4.80 g, 11.4 mmol) in methylene chloride (40 mL) at rt. After stirring at rt for 2 hrs, the reaction mixture was concentrated and the residue was dried in vacuo to give a TFA salt 2b-7, which was used for the next step without further purification.
  • Step 8 To a mixture of compound 2b-8 (2.5 g, 5.27 mmol),
  • Step 2 To a solution of ⁇ S)-tert-bvXy ⁇ 2-(lH-imidazol-2-yl)pyrrolidine-l- carboxylate (2c-l) (10.0 g, 42.2 mmol) in DCM (300 mL) was added NIS (19.0 g, 84.4 mmol) slowly at 0 °C, the reaction mixture was stirred for 1 hr at this temperature.
  • Step 1 A mixture of compound 2c-3 (54.5 g, 0.15 mol), trimethylsilylacetylene (17.7 g, 0.18 mol), P(t-Bu) 3 (121.4 g, 0.6 mol), piperidine (51.0 g, 0.6 mol), and Pd[PPh 3 ] 2 Cl 2 (10.5 g, 15 mmol) in DMF (300 mL) was stirred at 70 °C overnight under an atmosphere of N 2 . Subsequently, the reaction mixture was concentrated and the residue was diluted with EtOAc (500 mL). The resulting mixture was washed with water for several times (100 mL x 3) and dried with anhydrous Na 2 S0 4 . The solvent was removed and the residue was purified by silica gel column chromatography to give the TMS-acetylene compound (27.5 g, 55% yield). LC-MS (ESI): m/z 334.2 [M+H] + .
  • Step 2 A mixture of the TMS-acetlyene product obtained from the above reaction (25 g, 75 mmol) and K 2 C0 3 (41.5 g, 300 mmol) in MeOH (250 mL) and THF (250 mL) was stirred at rt for 2 hrs. Subsequently, the reaction mixture was filtered through pad of
  • compound 3-4 was obtained by treating a sample of compound la-4 under the procedures described in General Procedure G.
  • analogs of compound 3-3 in which the dihydropyrrole moiety is functionalized with different amino acid residues can be readily prepared by reacting intermediate 3-6 with the chosen amino acids under standard peptide coupling conditions. Applying the procedures and conditions described in the above examples, analogs of 3-3 which the pyrrolidine and the dihydropyrrole moieties are substituted by other ring structures may be obtained, such as compounds 3-12 and 3-13 etc.
  • Step 1 General Procedure E. To a solution of l-6b (180 mg, 0.47 mmol) in DMF (6.0 mL) in a sealed tube was added 3-4 (224 mg, 0.57 mmol),
  • Step 2 To a solution of 4a-l (100 mg, 0.14 mmol) in DCM (2 mL) was added TFA (1.0 mL). The resulting solution was stirred at rt for 2 hrs. The solvent was removed. The residue was dried on vacuum for 1 hr. The crude 4a-2 was directly used in the next step without purification.
  • Step 3 To a solution of N-Moc-L-Val-OH (30 mg, 0.17 mmol) in DMF (1 mL) was added HATU (82 mg, 0.21 mmol) and DIPEA (0.24 mL, 1.45 mmol). The resulting mixture was stirred at room temperature for 20 min, then poured into the solution of the crude 4a-2 (0.14 mmol) in DMF (1 mL). The solution was stirred at rt for another 2 hrs. The reaction mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic phase was dried with anhydrous Na 2 S0 4 , filtered, and concentrated.
  • Step 1 To a solution of 4-bromo-2-chlorobenzoic acid (18.4 g, 83.9 mmol) and 4-bromophenol (24 g, 109 mmol) in nitrobenzene was added cesium carbonate (82 g, 251.7 mmol). The resulting solution was heated at 170 °C with a condenser for 1 day. The reaction mixture was cooled to 70 °C and filtered at this temperature. The residue was washed with toluene. The organic layer was removed by vacuum distillation till a thick dark residue remained. To the dark residue was added aqueous HC1 (I N, 400 mL) and DCM (200 mL). The resulting solution was stirred until dark oil dispersed into DCM solution. The mixture was filtered. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated to afford the crude product. The residue was purified by column
  • Step 3 Trimethylaluminum (2.4 mL, 2 M in hexanes, 4.80 mmol) was added dropwise to a degassed stirred solution of 2,6-dibromo-9H-xanthen-9-one (8-2) (500 mg, 1.412 mmol) in toluene (8 mL) at 0 °C. The resulting solution was allowed to warm up to rt and left to stir for 16 hrs. The crude reaction mixture was poured into ice-cold 1 N HC1 aq.
  • Step 4 A seal tube was charged with Pd 2 (dba) 3 (55 mg, 0.06 mmol),
  • Step 5 General Procedure H (Steps 5 and 6). To a suspension of 8-4 (180 mg, 0.40 mmol) in CH 3 CN (6 mL) was added l-2b (210 mg, 0.83 mmol) and N,N- Diisopropylethylamine (0.144 mL, 0.826 mmol). The mixture was stirred overnight. The volatile component was removed in vacuo, and the residue was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic phases were washed by brine, saturated sodium carbonate, and water, and dried over anhydrous Na 2 S04. After concentration, the crude mixture was purified by flash column chromatography
  • Step 6 A mixture of 8-5 (230 mg, 0.289 mmol), ammonium acetate (445 mg, 5.78 mmol) and N,N-Diisopropylethylamine (1.00 mL, 5.78 mmol) in xylene (4 mL) in a sealed tube was stirred at 140 °C for 2 hrs. LC-MS showed the reaction was completed. The solvent was removed in vacuo, and the residue was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic phase was washed by brine, water, and dried over anhydrous Na 2 S04.
  • Step 7 To a stirred solution of 8-6 (60 mg) in dichloromethane (5 mL) was added trifluoro acetic acid (1 mL). After 3 hrs, the reaction was concentrated to dryness. The de- Boced intermediate was dissolved in DMF (1 mL). To the solution were added DIPEA (0.139 mL), N-Moc-L-Val-OH (28 mg) and HATU (61 mg) subsequently. After 1 hr stirring, the reaction was diluted with water. The reaction was extracted by dichloromethane. The combined organic solution was washed with brine and water, dried over anhydrous Na 2 S0 4 , filtered, and concentrated. The resulting crude product was purified by prep-HPLC
  • Biological activity of the compounds of the invention was determined using an HCV replicon assay.
  • the lb_Huh-Luc/Neo-ET cell line persistently expressing a bicistronic genotype lb replicon in Huh 7 cells was obtained from ReBLikon GMBH. This cell line was used to test compound inhibition using luciferase enzyme activity readout as a measurement of compound inhibition of replicon levels.
  • each compound is added in triplicate to the cells. Plates incubated for 72 h prior to running the luciferase assay. Enzyme activity was measured using a Bright-Glo Kit (cat. number E2620) manufactured by Promega Corporation. The following equation was used to generate a percent control value for each compound.
  • a fourth aspect of the invention provides a pharmaceutical composition comprising the compounds of the invention.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients.
  • excipients are known to those of skill in the art.
  • the compounds of the present invention include, without limitation, basic compounds such as free bases and pharmaceutically acceptable salts of these compounds. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington's Pharmaceutical Sciences, 18th Edition (Easton,
  • the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • the compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, may include other pharmaceutical agents, adjuvants, diluents, buffers, etc.
  • the invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention including isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof together with one or more
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate and the like.
  • the composition will generally take the form of a tablet, capsule, a softgel capsule nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use will generally include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent may be combined with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents may be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents and the like.
  • a fifth aspect of the invention provides use of the compounds of the invention in the manufacture of a medicament.
  • the medicament is for the treatment of hepatitis C.
  • a sixth aspect of the invention provides a method of treating hepatitis C comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention, optionally in a pharmaceutical composition.
  • a pharmaceutically or therapeutically effective amount of the composition will be delivered to the subject.
  • the precise effective amount will vary from subject to subject and will depend upon the species, age, the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. Thus, the effective amount for a given situation can be determined by routine experimentation.
  • the subject may be administered as many doses as is required to reduce and/or alleviate the signs, symptoms or causes of the disorder in question, or bring about any other desired alteration of a biological system.
  • One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of this invention for a given disease.
  • pharmaceutically acceptable salts thereof are useful in treating and preventing HCV infection alone or when used in combination with other compounds targeting viral or cellular elements or functions involved in the HCV lifecycle.
  • Classes of compounds useful in the invention may include, without limitation, all classes of HCV antivirals.
  • mechanistic classes of agents that may be useful when combined with the compounds of the present invention include, for example, nucleoside and non-nucleoside inhibitors of the HCV polymerase, protease inhibitors, helicase inhibitors, NS4B inhibitors and medicinal agents that functionally inhibit the internal ribosomal entry site (IRES) and other medicaments that inhibit HCV cell attachment or virus entry, HCV RNA translation, HCV RNA transcription, replication or HCV maturation, assembly or virus release.
  • IRS internal ribosomal entry site
  • telaprevir VX-950
  • boceprevir SCH-503034
  • narlaprevir SCH-9005178
  • ITMN-191 R-7227
  • TMC-435350 a.k.a.
  • Nucleosidic HCV polymerase (replicase) inhibitors useful in the invention include, but are not limited to, R7128, PSI-7851, IDX-184, IDX-102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879 and PSI-7977 and various other nucleoside and nucleotide analogs and HCV inhibitors including (but not limited to) those derived as 2'-C-methyl modified nucleos(t)ides, 4'-aza modified
  • Non-nuclosidic HCV polymerase (replicase) inhibitors useful in the invention include, but are not limited to , HCV-796, HCV- 371, VCH-759, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF- 00868554, BI-207127, GS-9190, A-837093, JKT-109, GL-59728 and GL-60667.
  • NS5A inhibitors of the present invention may be used in combination with cyclophyllin and immunophyllin antagonists (eg, without limitation, DEBIO), cyclophyllin and immunophyllin antagonists (eg, without limitation, DEBIO), cyclophyllin and immunophyllin antagonists (eg, without limitation, DEBIO), cyclophyllin and immunophyllin antagonists (eg, without limitation, DEBIO), cyclophyllin and immunophyllin antagonists (eg, without limitation, DEBIO), cyclophyllin and immunophyllin antagonists (eg, without limitation, DEBIO), cyclophyllin and immunophyllin antagonists (eg, without limitation, DEBIO), cyclophyllin and immunophyllin antagonists (eg, without limitation, DEBIO), cyclophyllin and immunophyllin antagonists (eg, without limitation, DEBIO), cyclophyllin and immunophyllin antagonists (eg, without limitation, DEB
  • kinase inhibitors kinase inhibitors
  • inhibitors of heat shock proteins e.g., HSP90 and HSP70
  • other immunomodulatory agents may include, without limitation, interferons (-alpha, -beta, -omega, -gamma, -lambda or synthetic) such as Intron ATM, Roferon-ATM, Canferon-A300TM, AdvaferonTM, InfergenTM,
  • HumoferonTM Sumiferon MPTM, AlfaferoneTM, IFN- ⁇ TM, FeronTM and the like; polyethylene glycol derivatized (pegylated) interferon compounds, such as PEG interferon-a-2a
  • PegasysTM PEG interferon-a-2b (PEGIntronTM), pegylated IFN-a-conl and the like
  • long acting formulations and derivatizations of interferon compounds such as the albumin- fused interferon, AlbuferonTM , LocteronTM and the like
  • interferons with various types of controlled delivery systems e.g.
  • ITCA-638 omega-interferon delivered by the DUROSTM subcutaneous delivery system
  • compounds that stimulate the synthesis of interferon in cells such as resiquimod and the like
  • interleukins compounds that enhance the development of type 1 helper T cell response, such as SCV-07 and the like
  • TOLL-like receptor agonists such as CpG-10101 (actilon), isotorabine, ANA773 and the like
  • thymosin a -1 ANA-245 and ANA-246
  • histamine dihydrochloride propagermanium; tetrachlorodecaoxide; ampligen; IMP-321; KRN-7000
  • antibodies such as civacir, XTL-6865 and the like and prophylactic and therapeutic vaccines such as InnoVac C, HCV E1E2/MF59 and the like.
  • any of the above-described methods involving administering an NS5A inhibitor, a Type I interferon receptor agonist (e.g., an IFN-a) and a Type II interferon receptor agonist (e.g., an IFN- ⁇ ) can be augmented by administration of an effective amount of a TNF-a antagonist.
  • a Type I interferon receptor agonist e.g., an IFN-a
  • a Type II interferon receptor agonist e.g., an IFN- ⁇
  • exemplary, non-limiting TNF-a antagonists that are suitable for use in such combination therapies include ENBRELTM, REMICADETM and HUMIRATM.
  • NS5A inhibitors of the present invention may be used in combination with antiprotozoans and other antivirals thought to be effective in the treatment of HCV infection, such as, without limitation, the prodrug nitazoxanide.
  • Nitazoxanide can be used as an agent in combination the compounds disclosed in this invention as well as in combination with other agents useful in treating HCV infection such as peginterferon alfa-2a and ribavarin (see, for example,_Rossignol, JF and Keeffe, EB, Future Microbiol. 3:539-545, 2008).
  • NS5A inhibitors of the present invention may also be used with alternative forms of interferons and pegylated interferons, ribavirin or its analogs (e.g., tarabavarin, levoviron), microRNA, small interfering RNA compounds (e.g., SIRPLEX-140-N and the like), nucleotide or nucleoside analogs, immunoglobulins, hepatoprotectants, anti-inflammatory agents and other inhibitors of NS5A.
  • interferons and pegylated interferons e.g., tarabavarin, levoviron
  • microRNA e.g., small interfering RNA compounds
  • nucleotide or nucleoside analogs e.g., immunoglobulins, hepatoprotectants, anti-inflammatory agents and other inhibitors of NS5A.
  • Inhibitors of other targets in the HCV lifecycle include NS3 helicase inhibitors; NS4A co-factor inhibitors; antisense oligonucleotide inhibitors, such as ISIS- 14803, AVI-4065 and the like; vector-encoded short hairpin RNA (shRNA); HCV specific ribozymes such as heptazyme, RPI, 13919 and the like; entry inhibitors such as HepeX-C, HuMax-HepC and the like; alpha glucosidase inhibitors such as celgosivir, UT- 23 IB and the like; KPE-02003002 and BIVN 401 and IMPDH inhibitors.
  • NS3 helicase inhibitors such as ISIS- 14803, AVI-4065 and the like
  • antisense oligonucleotide inhibitors such as ISIS- 14803, AVI-4065 and the like
  • HCV inhibitor compounds include those disclosed in the following publications: U.S. Pat. No. 5,807,876; U.S. Pat. No. 6,498,178; U.S. Pat. No. 6,344,465; U.S. Pat. No.
  • combinations of, for example, ribavirin and interferon may be administered as multiple combination therapy with at least one of the compounds of the present invention.
  • the present invention is not limited to the aforementioned classes or compounds and contemplates known and new compounds and combinations of biologically active agents (see, Strader, D.B., Wright, T., Thomas, D.L. and Seeff, L.B., AASLD Practice Guidelines. 1-22, 2009 and Manns, M.P., Foster, G.R., Rockstroh, J.K., Zeuzem, S., Zoulim, F. and Houghton, M., Nature Reviews Drug Discovery . 6:991-1000, 2007, Pawlotsky, J-M., Chevaliez, S.
  • Combination therapy can be sequential, that is treatment with one agent first and then a second agent (for example, where each treatment comprises a different compound of the invention or where one treatment comprises a compound of the invention and the other comprises one or more biologically active agents) or it can be treatment with both agents at the same time (concurrently).
  • Sequential therapy can include a reasonable time after the completion of the first therapy before beginning the second therapy. Treatment with both agents at the same time can be in the same daily dose or in separate doses.
  • Combination therapy need not be limited to two agents and may include three or more agents. The dosages for both concurrent and sequential combination therapy will depend on absorption, distribution, metabolism and excretion rates of the components of the combination therapy as well as other factors known to one of skill in the art.
  • Dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules may be adjusted over time according to the individual's need and the professional judgment of the person administering or supervising the administration of the combination therapy.

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Abstract

Antiviral compounds may be used to inhibit or reduce the activity of Hepatitis C virus (HCV), particularly HCV's NS5A protein. In these contexts, inhibition and reduction of activity of the NS5A protein refers to a lower level of the measured activity relative to a control experiment in which the cells or the subjects are not treated with the test compound. The inhibition or reduction in the measured activity is at least a 10% reduction or inhibition. The compounds and their isomeric forms and pharmaceutically acceptable salts thereof are useful in treating and preventing HCV infection alone or when used in combination with other compounds targeting viral or cellular elements or functions involved in the HCV lifecycle.

Description

INHIBITORS OF HCV NS5A PROTEIN
Inventors: Leping Li and Min Zhong
This application claims priority to and the benefit of prior filed U.S. Provisional Application 61/353,166 filed on June 9, 2010, which is hereby incorporated by reference for all purposes.
Field of the Invention
[0001] The invention relates to compounds useful for inhibiting hepatitis C virus ("HCV") replication, particularly functions of the non-structural 5A ("NS5A") protein of HCV.
Background of the Invention
[0002] HCV is a single-stranded RNA virus that is a member of the Flaviviridae family. The virus shows extensive genetic heterogeneity as there are currently seven identified genotypes and more than 50 identified subtypes. In HCV infected cells, viral RNA is translated into a polyprotein that is cleaved into ten individual proteins. At the amino terminus are structural proteins: the core (C) protein and the envelope glycoproteins, El and E2. p7, an integral membrane protein, follows El and E2. Additionally, there are six nonstructural proteins, NS2, NS3, NS4A, NS4B, NS5A and NS5B, which play a functional role in the HCV life cycle, (see, for example, Lindenbach, B.D. and CM. Rice, Nature. 436:933- 938, 2005).
[0003] Infection by HCV is a serious health issue. It is estimated that 170 million people worldwide are chronically infected with HCV. HCV infection can lead to chronic hepatitis, cirrhosis, liver failure and hepatocellular carcinoma. Chronic HCV infection is thus a major worldwide cause of liver-related premature mortality.
[0004] The present standard of care treatment regimen for HCV infection involves interferon-alpha, alone, or in combination with ribavirin. The treatment is cumbersome and sometimes has debilitating and severe side effects and many patients do not durably respond to treatment. New and effective methods of treating HCV infection are urgently needed.
Detailed Description of the Invention
[0005] Essential features of the NS5A protein of HCV make it an ideal target for inhibitors. The present disclosure describes a class of compounds targeting the NS5A protein and methods of their use to treat HCV infection in humans. 6] In a first aspect, compounds of formula I are provided:
D A B A' D' wherein:
A a ' are independently selected from the group consisting of
Figure imgf000003_0001
s
Figure imgf000003_0002
, and wherein
* indicates attachment points to the reminder of the compound,
R is selected from the group consisting of C1-C4 alkyl, aryl, a halogen, -CN, -N02, -
OR1, -CF3, -OCF3, -OCHF2, -C02R2, -C(0)R3, -C(0)NR3R4, -NR3R4 ,
-S(0)2R2, and -S(0)2NR3R4, m is 0, 1, or 3,
V is -CH2-CH2-, -CH=CH-, -N=CH-, (CH2)a-N(R3)-(CH2)b- or
-(CH2)a-0-(CH2)b-, wherein a and b are independently 0, 1, 2, or 3 with the proviso that a and b are not both 0,
R2, R3, and R4 are each independently chosen from the group consisting of hydrogen, Ci to C4 alkyl, Ci to C4 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl, and wherein for each A and A', B may be attached to either side of A and ' so that in the
example can be any of:
Figure imgf000003_0003
B is selected from the group consisting of a single bond, triple bond,^^= w , W == =^Ξ W Ξ^ΞΞ W == W W— W == and W-W, wherein each W is independently selected from the group consisting of a cycloalkyl group, cycloalkenyl group, heterocyclic group, aryl group or heteroaryl group, with the proviso that when B is W-W, only one W is a six-membered aromatic ring;
Figure imgf000004_0001
Xa, Xb, Xa', and Xb' are each independently selected from the group consisting of C2 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 heteroalkyl, and C2 to C6 heteroalkenyl,wherein:
each hetero atom, if present, is independently N, O or S, and
either or both of Xa-Xb and Xa-Xb , together with the atoms to which they are attached, optionally form a 4- to 9-membered ring which may be cycloalkyl and heterocycle and which may optionally be fused to another 3-5 membered ring;
Ra, Rb, Ra and Rb are each independently hydrogen, d to C8 alkyl or Ci to C8 heteroalkyl, wherein: each hetero atom, if present, is independently N, O or S,
Raand Rb are optionally joined, together with the atom to which they are attached, to form a 3- to 6-membered ring, and
Ra' and Rb' are optionally joined, together with the atom to which they are attached, to form a 3- to 6-membered ring;
Y and Y' are each independently N or CH; and
Z and Z' are each independently selected from the group consisting of hydrogen, Ci to C8 alkyl, Ci to Cg heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, 1-3 amino acids,
-[U-(CR4 2),-NR5-(CR4 2),]U-U-(CR4 2),-NR7-(CR4 2),-R8, -U-(CR4 2),-R8 and -[U-(CR4 2)t-NR5-(CR4 2)t]u-U-(CR4 2)t-0-(CR4 2)t-R8, wherein,
U is selected from the group consisting of -C(O)-, -C(S)- and -S(0)2-, each R4 R5 and R7 is independently selected from the group consisting of
hydrogen, Ci to Cg alkyl, Ci to Cg heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl,
R8 is selected from the group consisting of hydrogen, Ci to Cg alkyl, Ci to Cg heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, -C(0)-R81, -C(S)-R81, -C(0)-0-R81, -C(0)-N-R812, -S(0)2-R81 and -S(0)2-N-R81 2, wherein each R81 is independently chosen from the group consisting of hydrogen, Ci to Cg alkyl, Ci to Cg heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl, optionally, R7 and R8 together form a 4-7 membered ring, each t is independently 0, 1, 2, 3, or 4, and u is 0, 1, or 2.
In a first embodiment of the first aspect, A and A' are selected from the group
Figure imgf000005_0001
Figure imgf000006_0001
[0008] In a second embodiment of the first aspect, D is independently selected from
group 1 and group 2. Group 1 consists of
Figure imgf000006_0002
Figure imgf000006_0003
, and wherein
R1 is independently selected from the group consisting of hydrogen, -OH, Ci to C12 alkyl, Ci to C12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide. Group 2 consists of:
Figure imgf000006_0004
Figure imgf000006_0005
wherein Re, Rf, Rg, and
Rh are each independently hydrogen, Ci to Cg alkyl or Ci to Cg heteroalkyl, each hetero atom, if present, is independently N, O or S. Re and Rf are optionally joined, together with the atom to which they are attached, to form a 5- to 8-membered ring, and Rg and Rh are optionally joined, together with the atom to which they are attached, to form a 3- to 8-membered ring..
[0009] In a third embodiment of th first aspect, D' is independently selected from group
Figure imgf000006_0006
Figure imgf000007_0001
Figure imgf000007_0002
R is independently selected from the group consisting of hydrogen,
-OH, Ci to Ci2 alkyl, Ci to C12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and
sulfonamide. And Group 2' consists of
Figure imgf000007_0003
, ,
Figure imgf000007_0004
are each independently hydrogen, Ci to C8 alkyl or Ci to C8 heteroalkyl, each hetero atom, if present, is
independently N, O or S. Re and Rf are optionally joined, together with the atom to which they are attached, to form a 5- to 8-membered ring, and Rg and Rh are optionally joined, together with the atom to which they are attached, to form a 3- to 8-membered ring.
[0010] In a fourth embodiment of the first aspect, if D is selected from Group 1, D' is selected from Group 2'.
[0011] In a fifth embodiment of the first aspect, if D' is selected from Group , D is selected from Group 2.
In a sixth embodiment of the first aspect, A-B-A' is selected from the group of:
Figure imgf000008_0001
wherein * indicates attachment points to the reminder of the compound. [0013] In a second aspect one or both of Y and Y' in any of the previous aspects are -N-.
[0014] In a third aspect Z and Z' in any of the previous aspects are each 1-3 amino acids.
[0015] In a first embodiment of the third aspect, the amino acids are all in the D or all in the L configuration.
[0016] In a second embodiment of the third aspect, Z and Z' are each independently selected from the group consisting of
-[U-(CR4 2)t-NR5-(CR4 2)t]u-U-(CR4 2)t-NR7-(CR4 2)t-R8,
-U-(CR4 2)t-R8 and -[U-(CR4 2)t-NR5-(CR4 2)t]u-U-(CR4 2)t-0-(CR4 2)t-R8.
[0017] In a third embodiment of the third aspect, one or both of Z and Z' are
-[U-(CR4 2)t-NR5-(CR4 2)t]u-U-(CR4 2)t-NR7-(CR4 2)t-R8.
[0018] In a fourth embodiment of the third aspect, one or both of Z and Z' are
-U-(CR4 2)t-NR5-(CR4 2)t-U-(CR4 2)t-NR7-(CR4 2)t-R8.
[0019] In a fifth embodiment of the third aspect, one or both of Z and Z' are
-U-(CR4 2),-NR7-(CR4 2),-R8.
[0020] In a sixth embodiment of the third aspect, one or both of Z and Z' are
-[C(0)-(CR4 2)t-NR5-(CR4 2)t]u-U-(CR4 2)t-NR7-(CR4 2)t-R8.
[0021] In a seventh embodiment of the third aspect, one or both of Z and Z' are
-C(0)-(CR4 2),-NR5-(CR4 2),-U-(CR4 2),-NR7-(CR4 2),-R8.
[0022] In an eighth embodiment of the third aspect, one or both of Z and Z' are
-[C(0)-(CR4 2)t-NR5-(CR4 2)t]u-C(0)-(CR4 2)t-NR7-(CR4 2)t-R8.
[0023] In a ninth embodiment of the third aspect, one or both of Z and Z' are
-C(0)-(CR4 2),-NR5-(CR4 2),-C(0)-(CR4 2),-NR7-(CR4 2),-R8.
[0024] In a tenth embodiment of the third aspect, one or both of Z and Z' are
-C(0)-(CR4 2),-NR7-(CR4 2),-R8.
[0025] In an eleventh embodiment of the third aspect, one or both of Z and Z' are -C(0)-(CR4 2)n-NR7-(CR4 2)n-C(0)-R81.
[0026] In a twelfth embodiment of the third aspect, one or both of Z and Z' are
-C(0)-(CR4 2)n-NR7-C(0)-R81.
[0027] In a thirteenth embodiment of the third aspect, one or both of Z and Z' are -C(0)-(CR4 2)n-NR7-(CR4 2)n-C(0)-0-R81. [0028] In a fourteenth embodiment of the third aspect, one or both of Z and Z' are -C(0)-(CR4 2)n-NR7-C(0)-0-R81.
[0029] In a fifteenth embodiment of the third aspect, one or both of Z and Z' are
-U-(CR4 2)t-R8.
[0030] In a sixteenth embodiment of the third aspect, one or both of Z and Z' are
Figure imgf000010_0001
[0031] In a seventeenth embodiment of the third aspect, one or both of Z and Z' are
-[U-(CR4 2)t-NR5-(CR4 2)t]u-U-(CR4 2)t-0-(CR4 2)t-R8.
[0032] In an eighteenth embodiment of the third aspect, one or both of Z and Z' are
-U-(CR4 2),-NR5-(CR4 2),-U-(CR4 2),-0-(CR4 2),-R8.
[0033] In a nineteenth embodiment of the third aspect, one or both of Z and Z' are
-C(0)-(CR4 2)t-NR5-(CR4 2)t-C(0)-(CR4 2)t-0-(CR4 2)t-R8.
[0034] In a twentieth embodiment of the third aspect, one or both of Z and Z' are
-U-(CR4 2)t-0-(CR4 2)t-R8.
[0035] In a twenty-first embodiment of the third aspect, one or both of Z and Z' are -C(0)-(CR4 2)t-0-(CR4 2)t-R8.
[0036] In a twenty-second embodiment of the third aspect, one or both of Z and Z' are - C(0)-(CR4 2)„-NR7-R8 wherein R7 and R8 together form a 4-7 membered ring.
[0037] A fourth aspect of the invention provides a pharmaceutical composition comprising the compounds of the invention.
[0038] A fifth aspect of the invention provides use of the compounds of the invention in the manufacture of a medicament.
[0039] In a first embodiment of the fifth aspect the medicament is for the treatment of hepatitis C.
[0040] A sixth aspect of the invention provides a method of treating hepatitis C comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention.
Detailed Description
[0041] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Definition of standard chemistry terms may be found in reference works, including Carey and Sundberg (2007) "Advanced Organic Chemistry 5th Ed." Vols. A and B, Springer Science+Business Media LLC, New York. The practice of the present invention will employ, unless otherwise indicated, conventional methods of synthetic organic chemistry, mass spectroscopy, preparative and analytical methods of chromatography, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology.
[0042] The term "alkanoyl" as used herein contemplates a carbonyl group with a lower alkyl group as a substituent.
[0043] The term "alkenyl" as used herein contemplates substituted or unsubstituted, straight and branched chain alkene radicals, including both the E- and Z-forms, containing from two to eight carbon atoms. The alkenyl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -N02, -C02R, -C(0)R, -O-R, -N(RN)2, -N(RN)C(0)R, -N(RN)S(0)2R, -SR, -C(0)N(RN)2, -OC(0)R, -OC(0)N(RN)2, -S(0)R, -S02R, -S03R, -S(0)2N(RN)2, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0044] The term "alkoxy" as used herein contemplates an oxygen with a lower alkyl group as a substituent and includes methoxy, ethoxy, butoxy, trifiuromethoxy and the like. It also includes divalent substituents linked to two separated oxygen atoms such as, without limitation, -0-(CH2)i_4-0-, -0-CF2-0-, -0-(CH2)i_4-0-(CH2CH2-0)i_4- and
Figure imgf000011_0001
[0045] The term "alkoxycarbonyl" as used herein contemplates a carbonyl group with an alkoxy group as a substituent.
[0046] The term "alkyl" as used herein contemplates substituted or unsubstituted, straight and branched chain alkyl radicals containing from one to fifteen carbon atoms. The term "lower alkyl" as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl and the like. The alkyl group may be optionally substituted with one or more substituents selected from halogen, -CN, -N02, -C(0)2R, -C(0)R, -O-R, -N(RN)2, -N(RN)C(0)R, -N(RN)S(0)2R, -SR, -C(0)N(RN)2, -OC(0)R, -OC(0)N(RN)2, -SOR, -S02R, -S03R, -S(0)2N(RN)2, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl. [0047] The term "alkylene," "alkenylene" and "alkynylene" as used herein refers to the groups "alkyl," "alkenyl" and "alkynyl" respectively, when they are divalent, ie, attached to two atoms.
[0048] The term "alkylsulfonyl" as used herein contemplates a sulfonyl group which has a lower alkyl group as a substituent.
[0049] The term "alkynyl" as used herein contemplates substituted or unsubstituted, straight and branched carbon chain containing from two to eight carbon atoms and having at least one carbon-carbon triple bond. The term alkynyl includes, for example ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 3 -methyl- 1-butynyl and the like. The alkynyl group may be optionally substituted with one or more substituents selected from halo, -CN, -N02, -C02R, -C(0)R, -O-R, -N(RN)2, -N(RN)C(0)R, -N(RN)S(0)2R, -SR, -C(0)N(RN)2, -OC(0)R, -OC(0)N(RN)2, -SOR, -S02R, -S03R, -S(0)2N(RN)2, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0050] The term "amino" as used herein contemplates a group of the structure -NRN 2.
[0051] The term "amino acid" as used herein contemplates a group of the structure
Figure imgf000012_0001
in either the D or the L
configuration and includes but is not limited to the twenty "standard" amino acids: isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine and histidine. The present invention also includes, without limitation, D-configuration amino acids, beta-amino acids, amino acids having side chains as well as all non-natural amino acids known to one skilled in the art.
[0052] The term "aralkyl" as used herein contemplates a lower alkyl group which has as a substituent an aromatic group, which aromatic group may be substituted or unsubstituted. The aralkyl group may be optionally substituted with one or more substituents selected from halogen, -CN, -N02, -C02R, -C(0)R, -O-R, -N(RN)2, -N(RN)C(0)R, -N(RN)S(0)2R, -SR, -C(0)N(RN)2, -OC(0)R, -OC(0)N(RN)2, -SOR, -S02R, -S03R, -S(0)2N(RN)2, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl. [0053] The terms "aryl," "aromatic group" or "aromatic ring" as used herein contemplates substituted or unsubstituted single-ring and multiple aromatic groups (for example, phenyl, pyridyl and pyrazole, etc.) and polycyclic ring systems (naphthyl and quinolinyl, etc.). The polycyclic rings may have two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is aromatic, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls. The aryl group may be optionally substituted with one or more substituents selected from halogen, alkyl, -CN, -N02, -C02R, -C(0)R, -O-R, -N(RN)2, -N(RN)C(0)R, -N(RN)S(0)2R, -SR, -C(0)N(RN)2, -OC(0)R, -OC(0)N(RN)2, -SOR, -S02R, -S03R,
-S(0)2N(RN)2, -SiR3, -P(0)R, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0054] The term "arylsulfonyl" as used herein contemplates a sulfonyl group which has as a substituent an aryl group. The term is meant to include, without limitation, monovalent as well as multiply valent aryls (eg, divalent aryls).
[0055] The term "carbamoyl" as used herein contemplates a group of the structure
O C NRN2
[0056] The term "carbonyl" as used herein contemplates a group of the structure
Figure imgf000013_0001
[0057] The term "carboxyl" as used herein contemplates a group of the structure
Figure imgf000013_0002
[0058] The term "cycloalkyl" as used herein contemplates substituted or unsubstituted cyclic alkyl radicals containing from three to twelve carbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl and the like. The term "cycloalkyl" also includes polycyclic systems having two rings in which two or more atoms are common to two adjoining rings (the rings are "fused"). The cycloalkyl group may be optionally substituted with one or more substituents selected from halo, -CN, -N02, -C02R, -C(0)R, -O-R, -N(RN)2, -N(RN)C(0)R, -N(RN)S(0)2R, -SR, -C(0)N(RN)2, -OC(0)R, -OC(0)N(RN)2, -SOR, -S02R, -S(0)2N(RN)2, phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl. [0059] The term "cycloalkenyl" as used herein contemplates substituted or unsubstituted cyclic alkenyl radicals containing from four to twelve carbon atoms in which there is at least one double bond between two of the ring carbons and includes cyclopentenyl, cyclohexenyl and the like. The term "cycloalkenyl" also includes polycyclic systems having two rings in which two or more atoms are common to two adjoining rings (the rings are "fused"). The cycloalkenyl group may be optionally substituted with one or more substituents selected from halo, -CN, -NO2, -C02R, -C(0)R, -O-R, -N(RN)2, -N(RN)C(0)R, -N(RN)S(0)2R, -SR, -C(0)N(RN)2, -OC(0)R, -OC(0)N(RN)2, -SOR, -S02R, -S(0)2N(RN)2, phosphate,
phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.
[0060] The term "halo" or "halogen" as used herein includes fluorine, chlorine, bromine and iodine.
[0061] The term "heteroalkyl" as used herein contemplates an alkyl with one or more heteroatoms.
[0062] The term "heteroatom", particularly within a ring system, refers to N, O and S.
[0063] The term "heterocyclic group," "heterocycle" or "heterocyclic ring" as used herein contemplates substituted or unsubstituted aromatic and non-aromatic cyclic radicals having at least one heteroatom as a ring member. Preferred heterocyclic groups are those containing five or six ring atoms which includes at least one hetero atom and includes cyclic amines such as morpholino, piperidino, pyrrolidino and the like and cyclic ethers, such as tetrahydrofuran, tetrahydropyran and the like. Aromatic heterocyclic groups, also termed "heteroaryl" groups, contemplates single-ring hetero-aromatic groups that may include from one to three heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, oxodiazole, thiadiazole, pyridine, pyrazine, pyridazine, pyrimidine and the like. The term heteroaryl also includes polycyclic hetero-aromatic systems having two or more rings in which two or more atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is a heteroaryl, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls. Examples of polycyclic heteroaromatic systems include quinoline, isoquinoline, cinnoline, tetrahydroisoquinoline, quinoxaline, quinazoline, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, indazole, purine, benzotriazole, pyrrolepyridine, pyrrazolopyridine and the like. The heterocyclic group may be optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, -CN, -N02, -C02R, -C(0)R, -O-R, -N(RN)2, -N(RN)C(0)R, -N(RN)S(0)2R, -SR, -C(0)N(RN)2, -OC(0)R, -OC(0)N(RN)2, -SOR, -S02R, -SO3R, -S(0)2N(R )2, -S1R3, -P(0)R, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0064] The term "oxo" as used herein contemplates an oxygen atom attached with a double bond.
[0065] By "pharmaceutically acceptable" or "pharmacologically acceptable" is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
[0066] "Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is made with counterions understood in the art to be generally acceptable for pharmaceutical uses and which possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4- toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion or an aluminum ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine,
dimethylamine, diethylamine and the like. Also included are salts of amino acids such as arginates and the like, and salts of organic acids like glucurmic or galactunoric acids and the like (see, e.g., Berge et al., 1977, J. Pharm. Sci. 66: 1-19).
[0067] The terms "phosphate" and "phosphonate" as used herein refer to the moieties having the following structures, respectively: O o
— O-P-OR — P-OR
I
OR OR
[0068] The terms "salts" and "hydrates" refers to the hydrated forms of the compound that would favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which those skilled in the art may take into account in the selection include the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity, flowability and manufacturability of the resulting bulk drug.
[0069] The term sulfonamide as used herein contemplates a group having the structure
Figure imgf000016_0001
[0070] The term "sulfonate" as used herein contemplates a group having the structure
Figure imgf000016_0002
wherein Rs is selected from the group consisting of hydrogen, Ci-Cio alkyl,
C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkanoyl or C1-C10 alkoxycarbonyl.
[0071] The term "sulfonyl" as used herein contemplates a group having the structure
Figure imgf000016_0003
[0072] "Substituted sulfonyl" as used herein contemplates a group having the structure
Figure imgf000016_0004
including, but not limited to alkylsulfonyl and arylsulfonyl.
[0073] The term "thiocarbonyl," as used herein, means a carbonyl wherein an oxygen atom has been replaced with a sulfur. [0074] Each R is independently selected from hydrogen, -OH, -CN, -N02, halogen, Ci to Ci2 alkyl, Ci to C12 heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide, amino and oxo.
[0075] Each RN is independently selected from the group consisting of hydrogen, -OH, Ci to Ci2 alkyl, Ci to C12 heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide. Two RN may be taken together with C, O, N or S to which they are attached to form a five to seven membered ring which may optionally contain a further heteroatom.
[0076] The compounds of the present invention may be used to inhibit or reduce the activity of HCV, particularly HCV's NS5A protein. In these contexts, inhibition and reduction of activity of the NS5A protein refers to a lower level of the measured activity relative to a control experiment in which the cells or the subjects are not treated with the test compound. In particular aspects, the inhibition or reduction in the measured activity is at least a 10% reduction or inhibition. One of skill in the art will appreciate that reduction or inhibition of the measured activity of at least 20%>, 50%>, 75%, 90% or 100% or any number in between, may be preferred for particular applications.
General Synthesis
[0077] The following abbreviations are used throughout this application:
ACN Acetonitrile
AcOH Acetic acid
aq Aqueous
Bn Benzyl
BnOH Benzyl alcohol
Boc t-Butoxycarbonyl
Cbz Benzoxylcarbonoyl
DCE Dichloroethane
DCM Dichloromethane
DEAD Diethyl azodicarboxylate
DEPBT 3-(Diethoxy-phosphoryloxy)-3H-benzo[d][l ,2,3] triazin-4-one
DIEA (DIPEA) Diisopropylethylamine DIBAL Diisobutylaluminium hydride
DMA NN-Dimethylacetamide
DME 1 ,2-Dimethoxyethane
DMF N,N-Dimethylformamide
DMSO Dimethylsulfoxide
DMTMM 4-(4,6-Dimethoxy- 1 ,3 ,5-triazin-2-yl)-4-methylmorpholinium chloride
DPPA Diphenylphosphoryl azide
dppp 1 ,3-Bis(diphenylphosphino)propane
dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene
DTT Dithiothreitol
EDCI l-Ethyl-3-[3-(dimethylamino) propyl]carbodiimide hydrochloride
EDTA Ethylene diamine tetraacetic acid
EC50 Effective concentration to produce 50% of the maximal effect
ESI Electrospray Ionization
Et3N, TEA Triethylamine
EtOAc, EtAc Ethyl acetate
EtOH Ethanol
g Gram(s)
h or hr Hour(s)
HATU 2-(7- Aza- 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium
hexafluorophosphate
HBTU 0-Benzotriazol-l-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate
Hex Hexanes
HOBt 1-Hydroxybenzotriazole
IC50 The concentration of an inhibitor that causes a 50 % reduction in a measured activity
LAH Lithium aluminum hydride
LDA Lithium diisopropylamide
LC-MS Liquid Chramatography Mass Spectrometry
mCPBA m-Chloroperoxybenzoic acid
Mel Methyl Iodide
MeOH Methanol
min Minute(s) mmol Millimole(s)
Moc Methoxylcarbonyl
NMM 4-Methylmorpholine
NMP N-methylpyrrolidinone
PG Protective Group
PTT Phenyl trimethyl tribromide
Py, Pyr Pyridine
rt Room temperature
TEA Triethylamine
Tf Trifluoromethanesulfonate
TFA Trifluoroacetic acid
TFAA Trifluoroacetic anhydride
THF Tetrahydrofuran
TLC Thin Layer Chromatography
TMSOTf Trimethylsilyl trifluoromethanesulfonate
[0078] Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 1FiNMR spectra were recorded on a Bruker 400 MHz or 500 MHz NMR spectrometer. Significant peaks are tabulated in the order: chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz) and number of protons.
[0079] The following examples are provided by way of illustration only and not by way of limitation. Those skilled in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts,
temperatures, etc.), but some experimental errors and deviations should, of course, be allowed for.
[0080] Liquid chromatography mass spectra (LC-MS) were typically obtained using an electrospray ionization (ESI) source in either the positive or negative mode.
[0081] The compounds were named using ChemDraw program from CambridgeSoft Inc.
[0082] The compounds and processes of the present invention will be better understood through the following examples. The schemes and procedures exemplify some of the synthetic routes that can be used for the preparation of compounds and their analogs in this invention. The examples are provided by way of illustration only and not by way of limitation. Those skilled in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results. Alternative reagents for a given transformation are also possible. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should, of course, be allowed for.
Preparation of key building blocks:
Figure imgf000020_0001
Scheme 1
(S)-l-(tert-butoxycarbonyl)-4-methyl-2,5-dihydro-lH-pyrrole-2-carboxylic acid (l-2b):
Figure imgf000020_0002
[0083] The following procedures (Step 1 to 3) were utilized to prepare N-protected 2,5- dihydro-lH-pyrrole-2-carboxylic acids bearing various types of 4-substituents, including those represented by compounds l-2a, l-2b, l-2c, and l-2d. Other dihydropyrrole compounds bearing different substituents and substitution patterns may also be prepared similarly.
[0084] Step 1. To a stirred solution of sodium bis(trimethylsilyl)amide (1 N in THF, 45.2 mL, 45.2 mmol) was added dropwise a solution of (S)-l-tert-butyl 2-methyl 4- oxopyrrolidine-l,2-dicarboxylate (10 g, 41.1 mmol, prepared as described in Tetrahedron, 57(14), 4195-212; 1995) in THF (50 mL) at -78 °C. After 20 mins, N-phenyl- bis(trifluoromethanesulfonimide) (15.4 g, 43.2 mmol) was added, and the reaction mixture was stirred at -78 °C for another 3 hrs. After being quenched with aqueous NaHC03 the reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by flash column chromatography (Hex/EtOAc = 9/1 (v/v)) to afford (5)-l-tert-butyl 2-methyl 4- (trifluoromethylsulfonyloxy)-lH-pyrrole-l,2(2H,5H)-dicarboxylate (14.8 g, 96% yield) as a yellow oil. 1H NMR (300 MHz, CDC13): δ 5.72 (dd, 1H), 5.02 (m, 1H), 4.28-4.42 (m, 2H), 3.77 (s, 3H), 1.42-1.47 (m, 9H) ppm.
[0085] Step 2. To a solution of (S)-l-(tert-butoxycarbonyl)-4-
(trifluoromethylsulfonyloxy)-2,5-dihydro-lH-pyrrole-2-carboxylic acid (5.00 g, 13.3 mmol) in dioxane (75 mL) was added methylboronic acid (1.0 g, 16.6 mmol), Pd[PPh3]4 (0.465 g, 0.402 mmol) and Na2C03 (2 M in H20, 15 mL). After being thoroughly degassed the reaction mixture was heated at 95 °C for 2.5 hrs under a N2 atmosphere. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was diluted in EtOAc and washed with H20 and brine, respectively. The organic layer was dried over anhydrous Na2S04, filtered and concentrated in vacuo. The ramaining residue was purified by flash column
chromatography (Hex/EtOAc = 5/1 (v/v)) to afford (5)-l-tert-butyl 2-methyl 4-methyl-lH- pyrrole-l,2(2H,5H)-dicarboxylate (2.25 g, 70% yield) as a colorless oil. 1H NMR (300 MHz, CDC13): δ 5.36 (dd, 1H), 4.90 (m, 1H), 4.04-4.16 (m, 2H), 3.72 (m, 3H), 1.79 (m, 3H), 1.42- 1.47 (m, 9H) ppm.
[0086] Step 3. To a solution of (S)- 1 -tert-butyl 2-methyl 4-methyl- lH-pyrrole- l,2(2H,5H)-dicarboxylate (3.76 g, 15.6 mmol) in THF (20 mL), MeOH (15 mL) and H20 (15 mL) was added LiOH H20 (1.30 g, 31.2 mmol). The reaction was stirred at rt overnight. The mixture was concentrated in vacuo and water (15 mL) was added. The solution was washed with Et20, acidified with 6 N HC1 to pH 3 and extracted with DCM (2 x 100 niL). The combined DCM extracts were dried over anhydrous Na2S04, filtered and concentrated to give (5)-l-(fert-butoxycarbonyl)-4-methyl-2,5-dihydro-lH-pyrrole-2-carboxylic acid (l-2b) (3.5 g, quantitative yield) as a colorless oil. LC-MS (ESI): m/z 226 [M-H]~.
(S)-l-(tert-butoxycarbonyl)-4-cyclopropyl-2, 5-dihydro-lH-pyrrole-2-carboxylic acid (l-2d) :
Figure imgf000022_0001
[0087] Compound l-2d was prepared by using the conditions described above and substituting cyclopropylboronic acid for methylboronic acid in Step 2.
[0088] Step a. To a solution of {S)-\-tert- vXy\ 2-methyl 4-(trifluoromethylsulfonyloxy)- lH-pyrrole-l,2(2H,5H)-dicarboxylate (15 g, 40 mmol) in dioxane (250 mL) was added cyclopropylboronic acid (5.15 g, 60 mmol), Pd(PPh3)4 (2.31 g, 2.0 mmol) and Na2C03 (2 N in H20, 45 mL). The flask was degassed and heated at 100 °C for 3 hr under N2 atmosphere. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was diluted in EtOAc and washed with H20, brine. The organic layer was dried with anhydrous Na2S04 and concentrated. The resulting residue was purified by flash column chromatography
(Hex/EtOAc = 5/1 (v/v)) to afford (S)-l-ierf-butyl 2-methyl 4-methyl-lH-pyrrole- l,2(2H,5H)-dicarboxylate(4.0 g) as a colorless oil. 1H NMR (300 MHz, CDC13): δ 5.30 (m, 1H), 4.90 (m, 1H), 4.13-3.95 (m, 2H), 3.72-3.70 (m, 3H), 1.47-1.42 (m, 9H), 1.32-1.25 (m, 1H), 0.77-0.73 (m, 2H), 0.55-0.53 (m, 2H) ppm.
[0089] Step b. To a solution of (<S)-l-ierf-butyl 2-methyl 4-methyl-lH-pyrrole- l,2(2H,5H)-dicarboxylate from above (3.70 g, 13.8 mmol) in THF (20 mL), MeOH (15 mL) and H20 (15 mL) was added LiOH H20 (1.30 g, 30.9 mmol). The reaction was stirred at rt overnight. The mixture was concentrated in vacuo and water (15 mL) was added. The solution was washed with Et20, acidified with 6 N HC1 to pH 3. The aqueous phase was extracted with DCM. The combined organic phase was dried with anhydrous Na2S04 and concentrated to give 25 (3.5 g, quantitative yield) as a colorless oil. LC-MS (ESI): m/z 252
[M-H]".
(S)-tert-butyl 2-(5-(4-bromophenyl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH-pyrrole-l- carboxylate (l-3b):
Figure imgf000023_0001
[0090] General Procedure A: Steps 1 and 2, synthesis of a 2,5-disubstitued imidazole from an a-bromoketone (or a-chloroketone) and a carboxylic acid.
[0091] Step 1. A solution of 2-bromo-l-(4-bromophenyl)ethanone (1-1) (2.27 g, 10.0 mmol) in CH3CN (30 mL) was added (5)-l-(fert-butoxycarbonyl)-4-methyl-2,5-dihydro-lH- pyrrole-2-carboxylic acid (l-2b) (3.05 g, 11.0 mmol) and DIPEA (3.30 mL, 20 mmol). The resulting mixture was stirred at rt overnight. The volatile components were removed in vacuo, and the residue was partitioned between water and DCM. The organic layer was dried over anhydrous Na2S04, filtered, and concentrated. The crude product was purified by flash column chromatography (Hex/EtOAc = 4/1 (v/v)) to afford (5)-2-(2-(4-bromophenyl)-2- oxoethyl) \-tert-bvXy\ 4-methyl-lH-pyrrole-l,2(2H,5H)-dicarboxylate (3.65 g, 86% yield). LC-MS (ESI): m/z 426 [M+H]+.
[0092] Step 2. To a solution of (5)-2-(2-(4-bromophenyl)-2-oxoethyl) 1 -tert-butyl 4- methyl-lH-pyrrole-l,2(2H,5H)-dicarboxylate (3.65 g, 8.6 mmol) in xylene (90 mL) in a sealed tube was added ammonium acetate (10.4 g, 135 mmol) and triethylamine (18.8 mL, 135 mmol). The resulting mixture was stirred at 140 °C for 2 hrs. Analysis by LC-MS showed the reaction was completed. The solvent was removed in vacuo, and the residue was partitioned between water and DCM. The aqueous layer was back extracted with DCM. The combined organic phase was dried with anhydrous Na2S04, filtered, and concentrated. The crude mixture was purified by flash column chromatography (Hex/EtOAc = 1/1 (v/v)) to afford the compound l-3b (2.5 g, 72% yield). LC-MS (ESI): m/z 406 [M+H]+.
Synthesis of (S)-tert-butyl 2-(5-(4-ethynylphenyl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro- lH-pyrrole-l-carboxylate (l-4b):
Figure imgf000023_0002
[0093] General Procedure B: Steps 1 and 2, synthesis of an arylacetylyne by
Sonogoshira Reaction. [0094] Step 1. To a solution of l-3b (10.0 g, 24.8 mmol) in anhydrous THF (100 mL) was added PPh3 (1.34 g, 5.11 mmol), Pd[PPh3]2 Cl2 (1.79 g, 2.56 mmol), Cul (0.24 g, 1.28 mmol), DIPEA (7.75 g, 76.8 mmol), and TMS-acetylene (5.02 g, 51.2 mmol). The mixture was refluxed under argon overnight. At the completion of the reaction, volatile solvents were removed under reduced pressure; the residue was treated with water, extracted with EtOAc (2 x 100 mL). The combined organic phases were dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 3/1 (v/v)) to afford (S)-tert-butyl 4-methyl-2-(5-(4-((trimethylsilyl)ethynyl)phenyl)- lH-imidazol-2-yl)- 2,5-dihydro-lH-pyrrole-l-carboxylate (5.80 g, 55% yield) as a yellow solid. LC-MS (ESI): m/z 427 [M+H]+.
[0095] Step 2. A solution of (S)-tert-butyl 4-methyl-2-(5-(4-
((trimethylsilyl)ethynyl)phenyl)-lH-imidazol-2-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate (5.80 g, 13.6 mmol) in THF (100 mL) and MeOH (100 mL) was treated with K2C03 (5.85 g, 42.4 mmol) at rt for 3 hrs. The mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM / MeOH = 40/1 (v/v)) to afford (S)-ierf-butyl 2-(5-(4-ethynylphenyl)-lH-imidazol-2-yl)-4- methyl-2,5-dihydro-lH-pyrrole-l-carboxylate (l-4b) (3.80g, 80% yield) as a yellow solid. LC-MS (ESI): m/z 450 [M+H]+.
(S)-tert-butyl 2-(5-(4-bromophenyl)-lH-imidazol-2-yl)-4-cyclopropyl-2,5-dihydro-lH- pyrrole-l-carboxylate (l-3d): LC-MS (ESI): m/z 430 [M+H]+.
Figure imgf000024_0001
(S)-tert-butyl 4-cyclopropyl-2-(5-(4-ethynylphenyl)-lH-imidazol-2-yl)-2,5-dihydro pyrrole- 1-carboxylate (l-4d): LC-MS (ESI): m/z 376 [M+H]+.
Figure imgf000024_0002
(S)-tert-butyl 2-(6-bromo- lH-benzo [ d]imidazol-2-yl)-4-methyl-2, 5-dihydro-lH-pyrrole-l- carboxylate (l-6b):
Figure imgf000024_0003
[0096] General Procedure C: synthesis of benzoimidazole from 1,2-benzenediamine. To a solution of (5)-l-(tert-butoxycarbonyl)-4-methyl-2,5-dihydro-lH-pyrrole-2-carboxylic acid (l-2b) (0.95 g, 4.19 mmol) in THF (15 mL) was added DIPEA (2.0 mL, 12.1 mmol). The mixture was stirred at room temperature for 10 min. ED AC (0.80 g, 4.19 mmol) was added to the solution. The resulting solution was stirred for another 1 hr, 4-bromobenzene- 1,2-diamine (1-5) (0.87 g, 4.65 mmol) was added. The mixture was stirred at 30 °C overnight. The solvent was removed in vacuo, and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic phases were dried (Na2S04), filtered, and concentrated. The crude acylated product was dissolved in AcOH (15 mL), and the mixture was stirred at 40 °C overnight. The solvent was concentrated in vacuo. The residue was re-dissolved in EtOAc and washed with NaHC03, H20 and brine. The organic phase was dried with anhydrous Na2S04, filtered, and concentrated. The crude mixture was purified by flash column chromatography (EtOAc/DCM = 1/20 to 1/10 (v/v)) to afford compound l-6b (420 mg). LC-MS (ESI): m/z 378 [M+H]+.
(S)-tert-butyl 2-(6-ethynyl-lH-benzo[d]imidazol-2-yl)-4-methyl-2,5-dihydro-lH-pyrrole-l- carboxylate (l-7b):
Figure imgf000025_0001
[0097] Prepared by following General Procedure B. LC-MS (ESI): m/z 324 [M+H] .
(S)-tert-butyl 2-(6-bromo-lH-benzo[ d]imidazol-2-yl)-4-cyclopropyl-2, 5-dihydro-lH-pyrrole- 1 -carboxylate (l-6d):
Figure imgf000025_0002
[0098] Prepared by following General Procedure C. LC-MS (ESI): m/z 404 [M+H]+
(S)-tert-butyl 2-( 6-ethynyl-lH-benzof d]imidazol-2-yl)-4-cyclopropyl-2, 5-dihydro-lH-pyrrole- 1 -carboxylate (1-7 d):
Figure imgf000025_0003
[0099] Prepared by following General Procedure B. LC-MS (ESI): m/z 350 [M+H] (S)-tert-butyl 2-(5-(6-bromonaphthalen-2-yl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro pyrrole- 1 -carboxylate (l-9b):
Figure imgf000026_0001
[0100] Step 1. Again referring to route outlined in Scheme 1, (General Procedure A) a solution of l-(6-bromonaphthalen-2-yl)-2-chloroethanone (1-8) (1.18 g, 4.15 mmol, prepared from 2-bromo-naphthalene via a Friedel-Craft reaction with chloroacetyl chloride) in CH3CN (40 mL) was added (5)-4-methyl-2,5-dihydro-pyrrole-l,2-dicarboxylic acid 1-tert-butyl ester (940 mg, 4.15 mmol) and N,N-diisopropylethylamine (0.73 mL, 4.15 mmol). The mixture was stirred overnight. The volatile component was removed in vacuo, and the residue was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic phase was washed by brine, saturated sodium carbonate, and water, and dried over anhydrous Na2S04. After concentration, the crude mixture was purified by flash column chromatography (Hex/Ethyl acetate = 4/1 (v/v)) to afford (5)-2-(2-(6- bromonaphthalen-2-yl)-2-oxoethyl) 1 -tert-butyl 4-methyl- lH-pyrrole- 1 ,2(2H,5H)- dicarboxylate (1.2 g). LC-MS (ESI): m/z 496.2 [M+Na]+.
[0101] Step 2. In a sealed tube, (5)-2-(2-(6-bromonaphthalen-2-yl)-2-oxoethyl) 1-tert- butyl 4-methyl- lH-pyrrole-l,2(2H,5H)-dicarboxylate (1.2 g, 2.53 mmol), ammonium acetate (2.92 g, 38 mmol) and triethylamine (0.7 mL, 5.06 mmol) were added in xylene (30 mL). The resulting mixture was stirred at 140 °C for 2 hrs. LC-MS showed the reaction was completed. The solvent was removed in vacuo, and the residue was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic phase was washed by brine, water, and dried over Na2S04. After removing the solvents, the crude mixture was purified by flash column chromatography (Hex/EtOAc = 1/1 (v/v)) to afford (S)-tert-butyl 2- (5-(6-bromonaphthalen-2-yl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH-pyrrole-l- carboxylate (l-9b) (1.0 g). LC-MS (ESI): m/z 454.2 [M+H]+.
(S)-tert-butyl 2-(5-(6-ethynylnaphthalen-2-yl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH- pyrrole-1 -carboxylate (1-lOb):
Figure imgf000026_0002
[0102] Step 1. General Procedure B. To a solution of (S)-ieri-butyl 2-(5-(6- bromonaphthalen-2-yl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH-pyrrole-l-carboxylate (l-9b) (300 mg, 0.66 mmol) and trimethylsilylacetylene (0.44 mL, 3.09 mmol) in
triethylamine (3 mL) was added copper iodide (8.3 mg) and Pd(PPh3)2Cl2 (31 mg) at room temperature. After through degassing, the reaction was warmed up to 80 °C and stirred overnight while under nitrogen gas protection. The reaction was cooled to rt and diluted with ethyl acetate (100 mL) and washed with brine and water and then dried over anhydrous Na2S04. After removal of solvents, the crude mixture was purified by flash column chromatography (Hexane/Ethyl acetate = 2/1 (v v)) to afford (S)-tert-butyl 4-methyl-2-(5-(6- ((trimethylsilyl)ethynyl)naphthalen-2-yl)-lH-imidazol-2-yl)-2,5-dihydro-lH-pyrrole-l- carboxylate (230 mg). LC-MS (ESI): m/z 472.3 [M+H]+.
[0103] Step 2. The mixture of the product from above (230 mg, 0.488 mmol) potassium carbonate (540 mg, 3.91 mmol) in methanol (6 mL) was warmed up to 80 °C and stirred overnight. The reaction was cooled to rt, diluted with ethyl acetate (100 mL) and washed with water and brine. The organic payer was dried over anhydrous Na2S04, filtered, and concentrated to afford (S)-tert-butyl 2-(5-(6-ethynylnaphthalen-2-yl)-lH-imidazol-2-yl)-4- methyl-2,5-dihydro-lH-pyrrole-l-carboxylate (1-lOb) (190 mg). LC-MS (ESI): m/z 400.30
[M+Hf.
(S)-tert-butyl 2-(5-(6-bromonaphthalen-2-yl)-lH-imidazol-2-yl)-4-cyclopropyl-2,5-dihydro- lH-pyrrole-l-carboxylate (l-9d) :
Figure imgf000027_0001
[0104] Prepared similarly as compound l-9b, LC-MS (ESI): m/z 480 [M+H]+.
(S)-tert-butyl 4-cyclopropyl-2-(5-(6-ethynylnaphthalen-2-yl)-lH-imidazol-2-yl)-2,5-dihydro- lH-pyrrole-l-carboxylate (1-lOd): LC-MS (ESI): m/z 426 [M+H]+.
Figure imgf000027_0002
Figure imgf000028_0001
Figure imgf000028_0002
[0105] Referring to Scheme la, compound la-3 was prepared according to conditions described in General Procedure A. Step 1. To a solution of 2-bromo-l-(4- bromophenyl)ethanone 1-1 (120 g, 0.43 mol) in CH3CN (300 mL) was added (5)-N-Boc-Pro- OH (97.0 g, 0.45 mol) and Et3N (130 g, 1.29 mol), the mixture was stirred at room
temperature for 2 h. The mixture was concentrated under reduced pressure to afford (S)-2-(2- (4-bromophenyl)-2-oxoethyl) 1-tert-butyl pyrrolidine- 1,2-dicarboxylate. The crude product was used for next step without further purification.
[0106] Step 2. To a solution of (S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1 -tert-butyl pyrrolidine- 1,2-dicarboxylate (159 g, 0.39 mol) in xylene (250 mL) was added NH4OAc (300 g, 3.90 mol), the mixture was stirred at 140 °C for overnight. The mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 10/1 (v/v)) to afford (S)-tert-butyl 2-(4-(4-bromophenyl)-lH- imidazol-2-yl)pyrrolidine-l-carboxylate la-3 (105 g, 70% yield) as a white solid: 1H NMR (500 MHz, CDC13) :δ 1.48 (s, 9H), 1.96 (m, 1H), 2.16 (m, 2H), 3.01 (m, 1H), 3.42 (m, 2H), 4.96 (d, 1H, J= 5.5Hz), 7.22 (s, 1H), 7.46-7.55 (m, 4H) ppm; LCMS (ESI) m/z 392.1 (M+H)+. [0107] Compound la-4, prepared according to General Procedure B, was obtained as a yellow solid in 80% yield in 2 steps from la-3. 1H NMR (500 MHz, CDC13): δ 1.49 (s, 9H), 1.97 (m, 1H), 2.15 (m, 2H), 3.01 (brs, 1H), 3.40 (m, 2H), 4.96 (d, 1H, J= 5.0Hz), 7.24 (s, 1H), 7.47 - 7.52 (m, 4H) ppm; LC-MS (ESI): m/z 338 [M+H]+.
(S)-tert-butyl 2-(6-ethynyl-lH-benzo[d]imidazol-2-yl)pyrrolidine-l-carboxylate (la-6):
Figure imgf000029_0001
[0108] Step 1. To a solution of N-Boc-L-Pro-OH (29 g, 135 mmol) and DIPEA (29 g, 225 mmol) in THF (500 mL) was added HATU (51 g, 135 mmol) at rt. After stirring at rt for 10 min, 4-bromobenzene-l,2-diamine (1-5) (25 g, 135 mmol) was added and the resulting solution was stirred at rt for another several hours. Subsequently, the reaction mixture was concentrated and the residue was diluted with EtOAc (500 mL). The resulting mixture was washed with water for several times (100 mL x 3) and dried with anhydrous Na2S04. The solvent was removed and the residue was dried in vacuo to give a mixture of acylated products, which were used for the next step without further purification.
[0109] Step 2. A mixture of acylated products from above in AcOH (1000 mL) was stirred at 40 °C for 12 hrs. After cooling, the reaction mixture was carefully neutralized by adding saturated aqueous sodium bicarbonate solution to adjust the pH value to 8. The resulting mixture was extracted with EtOAc (250 mL x 3). The combined extract was washed with water, and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 4/1 (v/v)) to give (S)-tert- butyl 2-(6-bromo-lH-benzo[d]imidazol-2-yl)pyrrolidine-l-carboxylate (la-6) (35 g, 71% yield in 2 steps) as a yellow solid. LC-MS (ESI): m/z 366.1 [M+H]+.
(S)-tert-butyl 2-(6-ethynyl-lH-benzo[d]imidazol-2-yl)pyrrolidine-l-carboxylate (la-7):
Figure imgf000029_0002
[0110] Compound la-7 was prepared following General Procedure B, and was obtained in 75% overall yield for 2 steps. LC-MS (ESI): m/z 312.2 [M+H]+. (S)-tert-butyl 2-(5-(6-bromonaphthalen-2-yl)-lH-imidazol-2-yl)pyrrolidine-l-carboxylate
(la-8):
Figure imgf000030_0001
[0111] Step 1. To a solution of 2-bromonaphthalene (1-7) (62 g, 0.3 mol) in DCM (1000 mL) was added A1C13 (44 g, 0.33 mol), followed by 2-chloroacetyl chloride (34 g, 0.3 mmol) at 0 °C. After stirring at 0 °C for 1 hr, the reaction mixture was quenched by adding water (500 mL). The organic layer was separated, washed with brine, and dried with anhydrous Na2S04. The solvent was removed and the residue was re-crystallized in 10% of EtOAc in hexane to give compound 1-8 (28 g, 33% yield) as a white solid. 1H NMR (500 MHz, CDCI3): δ 8.44 (s, 1H), 8.07 (s, 1H), 8.04 (d, J= 11.0 Hz, 1H), 7.84 (d, J= 8.5 Hz, 2H), 7.66 (d, J= 8.5 Hz, 1H), 4.81 (s, 2H) ppm; LC-MS (ESI): m/z 282.9 [M+H]+.
[0112] Starting from l-(6-bromonaphthalen-2-yl)-2-chloroethanone (1-8) (28 g, 99 mmol) and following General Procedure A, compound la-8 was obtained as a yellow solid (30 g, 68% yield). LC-MS (ESI): m/z 442.1 [M+H]+.
(S)-tert-butyl 2-(5-(6-ethynylnaphthalen-2-yl)-lH-imidazol-2-yl)pyrrolidine-l-carboxylate
(la-9):
Figure imgf000030_0002
[0113] Treatment of compound la-8 under the conditions described in General Procedure B yielded compound la-9 (1.3 g, 77% yield) as a yellow solid. LC-MS (ESI): m/z 388.2 [M+H]+.
Figure imgf000031_0001
Scheme 2a
(S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-lH-imidazol-2- yl)pyrrolidine-l -carboxylate (2a-l ) :
Figure imgf000031_0002
[0114] General Procedure D: preparation of arylboronate (or boronic acid) from aryl halide by a Suzuki Reaction. To a mixture of la-3 (4.90 g, 12.5 mmol),
bis(pinacolato)diboron (7.10 g, 26.3 mmol), potassium acetate (3.20 g, 32.5 mmol) in 1,4- dioxane (100 mL) was added Pd[dppf]Cl2 (400 mg, 0.500 mmol). After stirring at 80 °C for 3 hrs, the reaction mixture was filtered and concentrated in vacuo. The residue was purified with silica gel column chromatography (Petroleum ether/EtOAc = 2/1 (v v)) to provide 2a- 1 (3.0 g, 53% yield) as a gray solid: LC-MS (ESI) m/z 440 [M+H]+. (S)-tert-butyl 2-(6-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)- lH-benzo [d] imidazol-2- yl)pyrrolidine-l -carboxylate (2a-2).
Figure imgf000032_0001
[0115] Compound 2a-2 was prepared from la-6 by following General Procedure D. (3.3 g, 58% yield). LC-MS (ESI): m/z 414.2 [M+H]+.
(S)-tert-butyl 2-(5-(6-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)naphthalen-2-yl)-lH- imidazol-2-yl)pyrrolidine-l -carboxylate (2a-3):
Figure imgf000032_0002
[0116] Compound 2a-3 was prepared from la-8 by following General Procedure D. LC- MS (ESI): m/z 490.3 [M+H]+.
[0117] Other boronate building blocks represented by 2-la to 2-ld, 2-2a to 2-2d, and 2- 3a to 3-3d may be prepared similarly.
Figure imgf000033_0001
Figure imgf000033_0002
Scheme 2b
(S)-tert-butyl 2-(7-bromo-4,5-dihydro-lH-naphtho[2,l-d]imidazol-2-yl)pyrrolidine-l- carboxylate (2b-3):
[0118] Step 1. Referring to Scheme 2b, to a solution of 2b-l (20.6 g, 0.128 mol) in 45 mL of 48% hydrobromic acid and 10 mL of water was added a solution of 9.72 g (0.141 mol) of sodium nitrite in 18 mL of water, maintaining a temperature below 5 °C. After stirring at 5 °C for 1 hr, CuBr (0.128 mol) was added and the resulting mixture was stirred at rt for 3 hrs. Subsequently, the mixture was extracted with EtOAc (2 x 200 mL). The extracts were combined, washed with brine, and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel column chromatography (Hex/EtOAc= 12/1 (v/v)) to afford 2b-2 (13.3 g, 46% yield) as a powder. 1H NMR (CDC13, 400 MHz): δ 7.90 (d, 1H), 7.44 (m, 2H), 2.96 (t, 2H), 2.64 (t, 2H), 2.15 (m, 2H) ppm.
[0119] Step 2. To a solution of 2b-2 (12.49 g, 55.5 mmol) in 300 mL of methylene chloride and 0.30 mL of 48% hydrobromic acid was slowly added 3.1 mL of bromine at 0 °C. The reaction mixture was gradually warmed up to rt, and kept stirring for another 2 hrs. The organic solution was washed with saturated NaHC03 twice, and then with water. The crude product was purified by silica gel column chromatography to afford 2b-3 (11.9 g, 71% yield). 1H NMR (CDCI3, 400 MHz): δ 7.94 (d, 2H), 7.52 (m, 2H), 4.72 (t, 1H), 3.32 (m, 1H), 2.92 (m, 1H), 2.48 (m, 2H) ppm.
[0120] Step 3. A mixture of 2b-3 (11.80 g, 38.8 mmol), N-Boc-L-Pro-OH (10.02 g, 46.6 mmol), and diisopropylethylamine (7.02 g, 54.3 mmol) in acetonitrile (200 mL) was stirred at 50 °C for 10 hrs. The solvent was evaporated and the residue was partitioned between methylene chloride and water. The organic layer was separated and concentrated to dryness. The crude product was purified by silica gel column chromatography (hexanes/ethyl acetate = 1/7 to 1/4 (v/v)) to provide 2b-4 (11.53 g, 68% yield) as a white solid. 1H NMR (CDC13, 400 MHz): δ 7.84 (m, 1H), 7.48 (m, 2H), 5.58 (m, 1H), 4.40 (m, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 3.18 (m, 1H), 3.04 (m, 1H), 2.37 (m, 2H), 2.04 (m, 1H), 1.96 (m, 1H), 1.46 (ds, 9H) ppm.
[0121] Step 4. A mixture of 2b-4 (11.09 g, 25.3 mmol), ammonium acetate (29.25 g, 38.0 mmol) and triethylamine (38.45 g, 38.0 mmol) in xylenes (600 mL) in a sealed tube was stirred at 140 °C for 2 hrs. After being cooled, the reaction mixture was transferred into a flask and concentrated to dryness. The residue was partitioned between chloroform and water, and the organic layer was washed with water, and concentrated. The crude product was purified by silica gel column chromatography (NH4OH/ACN/EtOAc = 1/8/100 (v/v/v)) to afford 2b-5 (8.22 g, 75% yield) as a white solid. LC-MS (ESI): m/z 420.1 [M+H]+.
[0122] Step 5. (S)-ieri-butyl 2-(7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-4,5- dihydro- lH-naphtho[ 1 ,2-d]imidazol-2-yl)pyrrolidine- 1 -carboxylate (2b-6).
[0123] Compound 2b-6 was prepared from 2b-5 using the conditions described in General Procedure D.
[0124] Step 6. General Procedure G: N-Boc deprotection and reacylation (Step 6 and 7). Trifluoroacetic acid (20 mL) was slowly added into a solution of 2b-5 (4.80 g, 11.4 mmol) in methylene chloride (40 mL) at rt. After stirring at rt for 2 hrs, the reaction mixture was concentrated and the residue was dried in vacuo to give a TFA salt 2b-7, which was used for the next step without further purification. LC-MS (ESI): m/z 318.1 [M+H]+.
[0125] Step 7. To a mixture of the TFA salt 2b-7 (6.28 g, 11.5 mmol) in DMF (23 mL) was added DIPEA (22.8 mL, 138 mmol), followed by N-Moc-L-Val-OH (2.42 g, 13.8 mmol) and HATU (5.25 g, 13.8 mmol). After stirring at rt for 2 hrs, the reaction mixture was slowly dropped into water while stirring. The resulting precipitate was collected by filtration. The crude product was purified by silica gel column chromatography (Hex/EtOAc = 1/4 (v/v) to pure EtOAc) to afford 2b-8 (4.43 g, 81% yield). LC-MS (ESI): m/z 475.3 [M+H]+.
[0126] Step 8. To a mixture of compound 2b-8 (2.5 g, 5.27 mmol),
bis(pinacolato)diboron (2.6 g, 10.5 mmol), potassium acetate (2.2 g, 15.8 mmol) in 1,4- dioxane (50 mL) was added Pd[dppf]Cl2 (260 mg, 0.3 mmol) at rt under an atmosphere of N2. After stirring at 80 °C for 3 hrs under an atmosphere of N2, the reaction mixture was filtered through Celite™545 and the filter cake was washed with EtOAc for several times (30 mL x 3). The filtrate was washed with brine and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 2/1 (v/v)) to give compound 2b-9 (1.6 g, 58% yield). LC-MS (ESI): m/z 522.3 [M+H]+.
Figure imgf000035_0001
Scheme 2c
(S)-tert-butyl 2-(5-iodo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (2c-3):
[0127] Referring to Scheme 2c, Step 1. To a solution of freshly prepared N-Boc-L- prolinaldehyde (20.0 g, 0.10 mol) in MeOH (200 mL) was added glyoxal (20.0 g, 0.34 mol) and NH4OH (68.0 g, 1.90 mol), the mixture was stirred at rt overnight. The organic solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc = 1/1 (v/v)) to afford (S)-tert-butyl 2-(lH-imidazol-2- yl)pyrrolidine-l-carboxylate (10.7 g, 45% yield) as a white solid. lU NMR (500 MHz, CDCI3): δ 1.48 (s, 9H), 1.96 - 2.12 (m, 3H), 2.91 - 2.92 (m, 1H), 3.38 (m, 2H), 4.93 (d, 1H, J = 7.0 Hz), 6.96 (s, 2H) ppm. LC-MS (ESI): m/z 238.2 [M+H]+.
[0128] Step 2. To a solution of {S)-tert-bvXy\ 2-(lH-imidazol-2-yl)pyrrolidine-l- carboxylate (2c-l) (10.0 g, 42.2 mmol) in DCM (300 mL) was added NIS (19.0 g, 84.4 mmol) slowly at 0 °C, the reaction mixture was stirred for 1 hr at this temperature. The organic solvent was removed and the residue purified by silica gel column chromatography (Petroleum ether/EtOAc = 3/1 (v/v)) to afford (S)-tert-bvAy\ 2-(4,5-diiodo-lH-imidazol-2- yl)pyrrolidine-l-carboxylate (18.2 g, 88% yield) as a yellow solid. LC-MS (ESI): m/z 490 [M+H]+.
[0129] Step 3. To a suspension of (5)-tert-butyl 2-(4,5-diiodo-lH-imidazol-2- yl)pyrrolidine-l-carboxylate (2c-2) (18.0 g, 36.8 mmol) in 800 mL EtOH / H20 (v/v = 30:70) solution was added Na2S03 (39.4 g, 312.9 mmol), the mixture was refluxed for 17 hrs. EtOH was evaporated under reduced pressure, and the residue was diluted with EtOAc, the organic layer was washed with brine and dried over Na2S04, then concentrated to dryness, the residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 3/1 (v/v)) to afford {S)-tert-bvXy\ 2-(4-iodo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (2c-3) (10.5 g, 80% yield) as a white solid. 1H NMR (500 MHz, DMSO): 5 1.16 (s, 5H), 1.38 (s, 4H), 1.80 - 1.91 (m, 3H), 2.08 - 2.18 (m, 1H), 3.30 - 3.46 (m, 2H), 4.66 - 4.76 (m, 1H), 7.16 (d, 1H, J = 14 Hz), 12.04 - 12.09 (m, 1H) ppm; LC-MS (ESI): m/z 364.0 [M+H]+.
(S)-tert-butyl 2-(5-ethynyl-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (2c-4).
[0130] Step 1. A mixture of compound 2c-3 (54.5 g, 0.15 mol), trimethylsilylacetylene (17.7 g, 0.18 mol), P(t-Bu)3 (121.4 g, 0.6 mol), piperidine (51.0 g, 0.6 mol), and Pd[PPh3]2Cl2 (10.5 g, 15 mmol) in DMF (300 mL) was stirred at 70 °C overnight under an atmosphere of N2. Subsequently, the reaction mixture was concentrated and the residue was diluted with EtOAc (500 mL). The resulting mixture was washed with water for several times (100 mL x 3) and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel column chromatography to give the TMS-acetylene compound (27.5 g, 55% yield). LC-MS (ESI): m/z 334.2 [M+H]+.
[0131] Step 2. A mixture of the TMS-acetlyene product obtained from the above reaction (25 g, 75 mmol) and K2C03 (41.5 g, 300 mmol) in MeOH (250 mL) and THF (250 mL) was stirred at rt for 2 hrs. Subsequently, the reaction mixture was filtered through pad of
Celite®545 and the filter cake was washed with EtOAc several times (100 mL x 3). The filtrate was concentrated and the residue was diluted with EtOAc (500 mL). The resulting mixture was washed with water for several times (100 mL x 3) and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel column chromatography to give (S)-tert-butyl 2-(5-ethynyl-lH-imidazol-2-yl)pyrrolidine-l- carboxylate (2c-4) (12.3 g, 63% yield). LC-MS (ESI): m/z 262.1 [M+H]+.
Methyl (S)-l-((S)-2-(5-ethynyl-lH-imidazol-2-yl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2- ylcarbamate (2c- 5):
[0132] General Procedure G. A mixture of compound 2c-4 (10 g, 38.3 mmol) in 4 N HCl/dioxane (100 mL) was stirred at rt for 2 hrs. The reaction mixture was concentrated and the residue was dried in vacuo to give an HCl salt, which was used for the next step without further purification. LC-MS (ESI): m/z 162.1 [M+H]+.
[0133] Subsequently, the HCl salt was dissolved in DMF (120 mL) and the resulting mixture was sequentially added Et3N (19.3 g, 191 mmol), N-Moc-L-Val-OH (7.4 g, 42 mmol), and HATU (16 g, 42 mmol). After stirring at rt for 1 hr, the reaction mixture was concentrated and the residue was diluted with DCM (150 mL). The resulting mixture was washed with water several times (100 mL x 3) and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel column chromatography
(DCM/EtOAc = 4/1 (v/v)) to give compound 2c-5 (7.0 g, 57% yield). LC-MS (ESI): m/z 319.2 [M+H]+.
Figure imgf000038_0001
Figure imgf000038_0002
Scheme 3
[0134] General Procedure E: Sonogashira cross coupling of an arylacetylene and an arylhalide. To a solution of l-4b (200 mg, 0.50 mmol) in DMF (6.0 mL) in a sealed tube was added la-4 (187 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol), Cul (19 mg, 0.1 mmol) and triethylamine (0.2 mL, 1.5 mmol). The resulting solution was degassed and heated at 110°C overnight. After cooled to rt, the reaction mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic layer was dried with anhydrous Na2S04, filtered, and concentrated. The crude mixture was purified by flash column chromatography (EtOAc/ACN/NH4OH =
100/7/1 (v/v/v)) to afford (S)-ieri-butyl 2-(5-(4-((4-(2-((5)-l-(tert-butoxycarbonyl)pyrrolidin-
2- yl)-lH-imidazol-5-yl)phenyl)ethynyl)phenyl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH- pyrrole-l-carboxylate (3-1) (150 mg, 47% yield). LC-MS (ESI): m/z 661 [M+H]+.
[0135] Compound 3-1 is alternatively obtained by reacting la-4 and l-4b under the same set of conditions described in General Procedure E.
Methyl N-[(2S)-l-[(2S)-2-(5-{4-[2-(4-{2-[(2S)-l-[(2S)-2-[(methox
methylbutanoylj ' -4-methyl-2 ,5-dihydro-lH-pyrrol-2-yl] '-lH-imidazol-5- yl}phenyl)ethynylj 'phenyl}- lH-imidazol-2-yl)pyrrolidin-l -ylj -3-methyl-l -oxobutan-2- yl] carbamate (3-3).
[0136] Compound 3-3 was obtained via compound 3-2 following General Procedure G described previously. LC-MS (ESI): m/z 775.4 [M+H]+.
[0137] One of the alternative routes to prepare compound 3-3 was outlined Scheme 3, via
3- 4, 3-5, and 3-6. More specifically, compound 3-4 was obtained by treating a sample of compound la-4 under the procedures described in General Procedure G.
[0138] Under General Procedure E described previously, to a solution of l-3b (200 mg, 0.50 mmol) in DMF (6.0 mL) in a sealed tube was added 3-4 (187 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol), Cul (19 mg, 0.1 mmol) and triethylamine (0.2 mL, 1.5 mmol). The resulting solution was degassed, sealed and heated at 110 °C overnight. The reaction mixture was cooled to rt, and then partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic layer was dried with anhydrous Na2S04, filtered, and concentrated. The crude mixture was purified by flash column chromatography (EtOAc/ACN/NH4OH = 100/7/1 (v/v/v)) to afford compound 3-5 (150 mg, 47% yield). LC-MS (ESI): m/z 718.4 [M+H]+.
[0139] Treatment of a sample of 3-5 under the conditions detailed in Geneal Procedure G, compound 3-3 was obtained via intermediate 3-6.
[0140] Those skilled in the art will understand that analogs of compound 3-3 in which the dihydropyrrole moiety is functionalized with different amino acid residues (in addition to the substituted valine shown) can be readily prepared by reacting intermediate 3-6 with the chosen amino acids under standard peptide coupling conditions. Applying the procedures and conditions described in the above examples, analogs of 3-3 which the pyrrolidine and the dihydropyrrole moieties are substituted by other ring structures may be obtained, such as compounds 3-12 and 3-13 etc.
Methyl N-[(2S)-l-[(2S)-2-(5-{4-[2-(4-{2-[(2S)-4-cyclopropyl-l-[(2S)-2- [(methoxycarbonyl) amino] ' -3-methylbutanoylj ' -2,5-dihydro-lH-pyrrol-2-yl] '-lH-imidazol-5- yl}phenyl)ethynyl] phenyl}- lH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2- yl] carbamate (3-12).
Figure imgf000040_0001
[0141] LC-MS (ESI): m/z 801.4 [M+H]+.
Methyl N-f(2S)-l-f(2S)-2-(5-{4-[2-(4-{2-f(2S)-l-f(2S)-2-f(methoxy
methylbutanoyl]-4-methyl-2,5-dihydro-lH-pyrrol-2-yl]-lH-imidazol-5- yl}phenyl)ethynyl] phenyl}- lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH-pyrrol-l-yl] -3- methyl-1 -oxobutan-2-ylj 'carbamate (3-13).
Figure imgf000040_0002
[0142] LC-MS (ESI): m/z 787.4 [M+H]+.
Figure imgf000041_0001
Scheme 3a
Methyl N-[(2S)-l-[(2S)-2-{7-[2-(4-{2-[(2S)-l-[(2S)-2-[(methoxycarbonyl)a
methylbutanoyl] -4-methyl-2,5-dihydro-lH-pyrrol-2-yl] -lH-imidazol-5-yl}phenyl)ethynyl] - 1H, 4H, 5H-naphtho[ 1, 2-d]imidazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2- yl] carbamate (3-11).
[0143] Referring to the synthetic Scheme 3a, a Sonogoshira coupling reaction between compound l-4b and compound 2b-5 under the conditions described in General Procedure B led to 3-14, which in turn was converted to compound 3-15 under the same procedures and conditions described in General Procedure G. LC-MS (ESI): m/z 801.4 [M+H]+.
Methyl N-[(2S)-l-[(2S)-2-{7-[2-(4-{2-[(2S)-l-[(2S)-2-[(methox
methylbutanoyl] -4-methyl-2,5-dihydro-lH-pyrrol-2-yl] -lH-imidazol-5-yl}phenyl)ethynyl] - IH-naphthof 1, 2-d]imidazol-2-yl}pyrrolidin-l -yl]- 3 -methyl- 1 -oxobutan-2-ylJ carbamate (3- 16).
[0144] Compound 3-15 was readily converted by treating with DDQ to 3-16. LC-MS (ESI): m/z 799.4 [M+H]+.
Figure imgf000042_0001
Scheme 4
(S)-tert-butyl 2-(5-(4-((2-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)-lH-benzofdJimidazol- 6-yl)ethynyl)phenyl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH^yrrole-l-carboxylate (4-1)
[0145] General Procedure E -Sonogashira coupling of an arylacetylene and an arylhalide. To a solution of l-3b (200 mg, 0.50 mmol) in DMF (6.0 mL) in a sealed tube was added la- 7 (187 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol), Cul (19 mg, 0.1 mmol) and triethylamine (0.2 mL, 1.5 mmol). The resulting solution was degassed, sealed and heated at 110 °C overnight. After cooled to rt, the reaction mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic phases were dried with anhydrous Na2S04, filtered, and concentrated. The crude mixture was purified by flash column chromatography (EtOAc/Acetonitrile/NH4OH= 100/7/1 (v/v/v)) to afford compound 4-1 (150 mg, 47% yield). LCMS (ESI): m/z 635 [M+H]+.
[0146] As outlined in Scheme 4, compound 4-1 is alternatively prepared by reacting la-6 and l-4b under the conditions described in General Procedure E.
6-((4-(2-((S)-4-methyl-2,5-dihydro-lH^yrrol-2-yl)-lH-imidazol-5-yl)phenyl)ethynyl) pyrrolidin-2-yl)-lH-benzo [d] imidazole (4-2).
[0147] To a solution of 4-1 (150 mg, 0.24 mmol) in DCM (3 mL) was added TFA (1.5 mL). The resulting solution was stirred at rt for 2 hrs. The solvent and reagent were removed. The Boc-deprotected product 4-2 was used in the next acylation step. Methyl N-[(2S)-l-[(2S)-2-{6-[2-(4-{2-[(2S)-l-[(2S)-2-[(methoxycarbonyl)am
methylbutanoyl]-4-methyl-2,5-dihydro-lH-pyrrol-2-yl]-lH mid
lH-l,3-benzodiazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl] carbamate (4-3).
[0148] To a solution of N-Moc-L-Val-OH (91 mg, 0.29 mmol) in DMF (2 mL) was added HATU (269 mg, 0.71 mmoL) and DIPEA (0.47 mL, 2.83 mmol). The resulting mixture was stirred at rt for 20 min, then transfered into a solution of 4-2 (0.24 mmol) in DMF (2 mL). The misture was stirred at rt for another 2 hrs. The reaction mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic phase was dried with anhydrous Na2S04, filtered, and concentrated. The crude mixture was purified by prep HPLC to afford 4-3 (40 mg). 1H NMR (300 MHz, CD3OD): δ 7.64 (m, 2H), 7.48 (m, 3H), 7.37 (m, 2H), 7.06 (dd, 1H), 5.82 (s, 1H), 5.51 (s, 1H), 5.13 (t, 1H), 4.63 (dd, 2H), 4.25 (t, 1H), 4.14 (t, 1H), 4.04 (m, 1H), 3.92 (m, 1H), 3.62 (s, 6H), 2.42-2.25 (m, 2H), 2.21-2.16 (m, 1H), 2.10-1.98 (m, 3H), 1.92 (s, 3H), 0.98-0.82 (m, 12H) ppm. LC-MS (ESI): m/z 749.6 [M+H]+, 375.5 (M+2)/22+, 747.5 [M-H]~.
Figure imgf000043_0001
Scheme 4a
(S)-tert-butyl 2-(6-((4-(2-((S)-l-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin- 2-yl)-lH-imidazol-5-yl)phenyl)ethynyl)-lH-benzofdJimidazol-2-yl)-4-methyl-2,5-d^ pyrrole- 1 -carboxylate (4a-l).
[0149] Step 1. General Procedure E. To a solution of l-6b (180 mg, 0.47 mmol) in DMF (6.0 mL) in a sealed tube was added 3-4 (224 mg, 0.57 mmol),
tetrakis(triphenylphosphine)palladium (55 mg, 0.047 mmol), Cul (18 mg, 0.09 mmol) and triethylamine (0.2 mL, 1.5 mmol). The resulting solution was degassed and heated at 110 °C overnight. After cooled to rt, the mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic phase was dried with anhydrous Na2S04, filtered, and concentrated. The crude mixture was purified by flash column chromatography (EtOAc/ACN/NH4OH = 100/7/1 (v/v/v)) to afford 4a-l (150 mg, 46% yield). LC-MS (ESI): m/z 692 [M+H]+.
Methyl (S)-3-methyl-l-((S)-2-(5-(4-((2-((S)-4-methyl-2,5-dih^
benzofdJimidazol-6-yl)ethynyl)phenyl)-lH-imidazol-2-yl)pyrrolidin-l-yl)
ylcarbamate (4a-2).
[0150] Step 2. To a solution of 4a-l (100 mg, 0.14 mmol) in DCM (2 mL) was added TFA (1.0 mL). The resulting solution was stirred at rt for 2 hrs. The solvent was removed. The residue was dried on vacuum for 1 hr. The crude 4a-2 was directly used in the next step without purification.
Methyl N-[(2S)-l-[(2S)-2-{5-[4-(2-{2-[(2S)-l-[(2S)-2-[(methoxycarbonyl)aminoJ-3- methylbutanoyl]-4-methyl-2,5-dihydro-lH-pyrrol-2-yl]-lH-l,3-benzodiazol-6- yl}ethynyl)phenylJ-lH-imidazol-2-yl}pyrrolidin-l-ylJ-3-methyl-l-oxobutan-2-ylJcarbam
(4a-3).
[0151] Step 3. To a solution of N-Moc-L-Val-OH (30 mg, 0.17 mmol) in DMF (1 mL) was added HATU (82 mg, 0.21 mmol) and DIPEA (0.24 mL, 1.45 mmol). The resulting mixture was stirred at room temperature for 20 min, then poured into the solution of the crude 4a-2 (0.14 mmol) in DMF (1 mL). The solution was stirred at rt for another 2 hrs. The reaction mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic phase was dried with anhydrous Na2S04, filtered, and concentrated. The crude mixture was purified by prep HPLC to afford 4a-3 (23 mg). 1H NMR (300 MHz, CD3OD): δ 7.76 (m, 1H), 7.64 (m, 2H), 7.50-7.46 (m, 3H), 7.35 (m, 2H), 5.90 (s, 1H), 5.57 (s, 1H), 5.17 (t, 1H), 4.66 (dd, 2H), 4.19 (dd, 2H), 4.01 (m, 1H), 3.88 (m, 1H), 3.62 (s, 6H), 2.38-2.18 (m, 3H), 2.12-1.98 (m, 3H), 1.92 (s, 3H), 0.98-0.82 (m, 12H) ppm. LC-MS (ESI): m/z 749.5 [M+H]+, 375.4 [M+2H]2+.
Methyl N-[(2S)-l-[(2S)-2-{5-[4-(2-{2-[(2S)-4-cyclopropyl-l-[(2S)-2- [(methoxycarbonyl)amino] -3-methylbutanoyl] -2,5-dihydro- lH-pyrrol-2-yl] - 1H- 1 ,3- benzodiazol-6-yl}ethynyl)phenyl]-lH-imidazol-2-yl}pyrrolidin-l-yl]-3-m
yl] carbamate (4a-5). [0152] The title compound was prepared following procedures described for the synthesis of 4a-3 and substituting l-6d for l-6b in Step 1. LC-MS (ESI): m/z 775.4 [M+H]+.
Figure imgf000045_0001
Methyl N-[(2S)-l-[(2S)-2-{6-[2-(4-{2-[(2S)-4-cyclopropyl-l-[(2S)-2- [(methoxycarbonyl) amino] ' -3-methylbutanoylj ' -2,5-dihydro-lH-pyrrol-2-yl] '-lH-imidazol-5- yl}phenyl)ethynyl]-lH-l,3-benzodiazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2- yl] carbamate (4a-6).
[0153] LC-MS (ESI): m/z 775.4 [M+H]+.
Figure imgf000045_0002
Figure imgf000046_0001
Scheme 5
(S)-tert-butyl 2-(5-(6-((2-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)-lH-imidazol-5- yl)ethynyl)naphthalen-2-yl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH-pyrrole-l- carboxylate (5-1).
[0154] Referring to Scheme 5. General Procedure E: Sonogashira coupling between an acetylene and an aryl bromide, chloride or triflate. To a solution of 1-lOb (100 mg, 0.25 mmol) and 2c-3 (136 mg, 0.375 mmol) in triethylamine (2 mL) was added copper iodide (9.5 mg) and Pd(PPli3)2Cl2 (18 mg) at rt. The reaction mixture after being thoroughly degassed was warmed up to 80 °C under the protection of nitrogen atmosphere and stirred overnight. After cooled to rt, the mixture was diluted with ethyl acetate (100 mL), washed with water and brine, and the organic phase was dried over anhydrous Na2S04. After removing the solvents, the crude mixture was purified by flash column chromatography (Hex/EtOAc = 1/2 (v/v)) to afford 5-1 (50 mg). LC-MS (ESI): m/z 636.4 [M+H]+.
Methyl N-((2S)-l-((2S)-2-(5-(6-(2-(2-(l-((2S)-2-((methoxy
methylbutanoyl)pyrrolidin-2-yl)-lH-imidazole-5-yl)ethynyl)naphthalene-2-yl)-lH-M
2-yl)-4-methyl)-2, 5-dihydro-lH-pyrrol-l-yl)-3-methyl-l-oxobutan-2-yl)carbamate ( 5-3). [0155] Deprotection of the Boc groups of 5-1 in the presence of a strong acid, such as TFA or HCl, followed amide formation with N-Moc-L-Val-OH gave 5-3. LC-MS (ESI): m/z 749.4 [M+H]+.
Figure imgf000047_0001
Scheme 6
(S)-tert-butyl 2-(5-(6-(2-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)-lH-benzo[d]imidazol-6- yl)naphthalen-2-yl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH-pyrrole-l-carboxylate (6-1).
[0156] Referring to Scheme 6. Following General Procedure F, 2-3b coupled with la-6 to give 6-1. LC-MS (ESI): m/z 661.3 [M+H]+.
6-(6-(2-((S)-4-methyl-2,5-dihydro-lH-pyrrol-2-yl)-lH-imidazol-5-yl)naphthalen-2-yl)-2 pyrrolidin-2-yl)-lH-benzo[ d] imidazole ( 6-2).
[0157] Treatment of 6-1 with a strong acid, such as TFA or HCl gave 6-2. LC-MS (ESI): m/z 461.2 [M+H]+.
Methyl N-((2S)-l-((2S)-2-(6-(6-(2-(2-(l-((2S)-2-((methoxylcarbonyl)am^
methylbutanoyl)-4-methyl-2,5-dihydro-lH-pyrrol-2-yl)-lH-imidazole-5-yl)
1, 3-benzodiazol-2-yl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)carbamate ( 6-3). [0158] Amide formation of 6-2 with N-Moc-Val-OH (General Procedure G) gave 6-3. LC-MS (ESI): m/z 775.4 [M+H]+.
(S)-tert-butyl 2-(5-(6-(2-((S)-l-(tert-butoxycarbonyl)-4-cyclopropyl-2,5-dihydro-lH-pyrrol-2- yl)-lH-benzo[d]imidazol-6-yl)naphthalen-2-yl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH- pyrrole- 1 -carboxylate (6-4).
[0159] Following General Procedure F, 2-3b coupled with l-6d to give 6-4. LC-MS (ESI): m/z 699.4 [M+H]+.
2- ((S)-4-cyclopropyl-2,5-dihydro-lH-pyrrol-2-yl)-6-(6-(2-((S)-4-methyl-2,5-dihydro-lH- pyrrol-2-yl)-lH-imidazol-5-yl)naphthalen-2-yl)-lH-benzo[ d] imidazole ( 6-5).
[0160] Treatment of 6-1 with a strong acid, such as TFA or HC1 gave 6-5. LC-MS (ESI): m/z 499.3 [M+H]+.
Methyl N-((2S)-l-((2S)-4-cyclopropyl-2-(6-(6-(2-((2S)-l-((2S)-2-((methoxylcarbonyl)amino)-
3- methylbutanoyl)-4-methyl-2,5-dihydro-lH-pyrrol-2-yl)-lH-imidazole-5-yl)naphthalen-2-yl- 1, 3-benzodiazol-2-yl)-2, 5-dihydro-lH-pyrrol-l-yl)-3-methyl-l-oxobutan-2-yl)carbamate ( 6-
6).
[0161] Amide formation of 6-5 with N-Moc-Val-OH (General Procedure G) gave 6-6. LC-MS (ESI): m/z 813.4 [M+H]+.
Methyl N-((2S)-l-((2S)-2-(5-(6-(2-((2S)-l-((2S)-2-((methoxycarbonyl)aminoJ-3- methylbutanoyl)-4-methyl-2,5-dihydro-lH-pyrrol-2-yl)-lH-l,3-benzodiazol-6-yl)naphthalen- 2-yl)-lH-imidazol-2-yl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl] carbamate (6-7).
[0162] Following the procedure described in Scheme 6, 6-7 was obtained. LC-MS (ESI): m/z 775.4 [M+H]+.
Figure imgf000048_0001
Methyl N-((2S)-l-((2S)-2-(5-(6-(2-((2S)-l-((2S)-2-((methoxycarbonyl)am^
methylbutanoyl)-4-cyclopropyl-2,5-dihydro-lH-pyrrol-2-yl)-lH-l,3-benzodiazol-6- yl)naphthalen-2-yl)-lH-imidazol-2-yl)pyrrolidin-l-yl)- (6-8).
[0163] Following the procedure described in Scheme 6, compound 6-8 was obtained. LC-MS (ESI): m/z 801.4 [M+H]+.
Figure imgf000049_0001
Scheme 7
(S)-tert-butyl 2-(5-(4-(6-(2-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)-lH-imidazol-5- yl)naphthalen-2-yl)phenyl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH-pyrrole-l- carboxylate (7-1).
[0164] Referring to Scheme 7. General Procedure F: To a solution of 2-lb (200 mg, 0.50 mmol) in DMSO (5.0 mL) and H20 (1.5 mL) was added l-3b (245 mg, 0.5 mmol), tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) and potassium carbonate (207 mg, 1.5 mmol). The resulting solution was degassed and heated at 100 °C for 2 hrs. The reaction mixture was cooled to room temperature and poured into water (100 mL). The precipitate was collected through filtration. The crude mixture was purified by flash column
chromatography (EtOAc/Acetonitrile/NH4OH = 100/7/1 (v/v/v)) to afford the compound 7-1 (240 mg, 70% yield). LC-MS (ESI): m/z 688 [M+H]+. 2-((S)-4-methyl-2,5-dihydro-lH-pyrrol-2-yl)-5-(4-(6-(2-((S)-pyrrolidin-2-yl)-lH-imidazol-5- yl)naphthalen-2-yl)phenyl)-lH-imidazole (7-2).
[0165] To a solution of 7-1 (100 mg, 0.146 mmol) in DCM (2 niL) was added TFA (1 mL). The resulting solution was stirred at rt for 2 hrs. The solvent was removed. The residue was dried on vacuum for 1 hr. The deprotected product 7-2 was directly used in the next step. LC-MS (ESI): m/z 487 [M+H]+.
Methyl N-[(2S)-l-[(2S)-2-{5-[6-(4-{2-[(2S)-l-[(2S)-2-[(methoxycarbonyl)aminoJ-3- methylbutanoyl]-4-methyl-2,5-dihydro-lH-pyrrol-2-yl]-lH-imidazol-5-yl}phenyl)naphthalen- 2-ylJ -1 H-imidazol-2-yljpyrrolidin-l -ylj -3-methyl-l -oxobutan-2-ylJ carbamate (7-3).
[0166] General Procedure G. To a solution of N-Moc-L-Val-OH (51.2 mg, 0.29 mmol) in DMF (1.5 mL) was added HATU (167 mg, 0.44 mmol) and DIPEA (0.29 mL, 1.75 mmol). The resulting mixture was stirred at rt for 20 min, the mixture was then transferred to a solution of the crude 7-2 (0.146 mmol) in DMF (1.5 mL). The entire mixture was stirred at rt for another 2 hrs. The reaction mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic phase was dried with anhydrous Na2S04, filtered, and concentrated. The crude mixture was purified by prep HPLC to afford 7-3 (30 mg). 1H NMR (300 MHz, CD3OD): δ 8.30 (s, 1H), 8.26 (s, 1H), 8.12 (d, 1H), 8.08 (d, 1H), 7.99-7.84 (m, 8H), 6.04 (bs, 1H), 5.65 (s, 1H), 5.28 (t, 1H), 4.80-4.59 (dd, 2H), 4.25 (d, 1H), 4.15-4.06 (m, 2H), 3.92 (m, 1H), 3.66 (s, 6H), 2.60 (m, 1H), 2.35-2.18 (m, 3H), 2.14-2.04 (m, 2H), 2.03 (s, 3H), 0.98-0.82 (m, 12H) ppm. LC-MS (ESI): m/z 801.6
[M+H]+, 799.5 [M-H]~.
Methyl N-[(2S)-l-[(2S)-2-{5-[6-(4-{2-[(2S)-4-cyclopropyl-l-[(2S)-2- [(methoxycarbonyl) amino) ' -3-methylbutanoylj ' -2,5-dihydro-lH-pyrrol-2-yl] '-lH-imidazol-5- yl}phenyl)naphthalen-2-yl]-lH-imidazol-2-yl}pyrrolidin-l-yl] -3-methyl-l -oxobutan-2- yl] carbamate (7-4).
[0167] Following the same procedure as described for thr synthesis of 7-3 by replacing 1- 3b with l-3d, 7-4 was obtained. LC-MS (ESI): m/z 827.4 [M+H]+.
Figure imgf000050_0001
Figure imgf000051_0001
Scheme 7a
(S)-tert-butyl 2-(5-(6-(4-(2-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)-lH-imid
yl)phenyl)naphthalen-2-yl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH-pyrrole-l- carboxylate (7a-l).
[0168] Referring to Scheme 7a. Following General Procedure F, either la-3 coupled with 2-3b or 2a-l coupled with l-9b gave 7a-l. LC-MS (ESI): m/z 687.4 [M+H]+.
Methyl N-((2S)-l-((2S)-2-(5-(4-(6-(2-((2S)-l-((2S)-((me^
methylbutanoyl)-4-methyl-2,5-dihydron-lH-imidazole-5-yl)naphtha^
imidazole-2-yl)-pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)carbamate (7a-2).
[0169] Treatment of compound 7a-l with either TFA or 4 N HC1 in dioxane, followed by Procedure G gave compound 7a-2. LC-MS (ESI): m/z 801.4 [M+H]+.
(S)-tert-butyl 2-(5-(4-(6-(2-((S)-l-(tert-butoxycarbonyl)-4-methyl-2,5-dihydro-lH-pyrrol-2- yl)-lH-imidazol-5-yl)naphthalen-2-yl)phenyl)-lH-imidazol-2-yl)-4-meth^
pyrrole- 1-carboxylate (7a-3).
[0170] Following General Procedure F, either compound l-3b coupled with compound 2- 3b or compound l-9b coupled with compound 2-lb gave compound 7a-3. LC-MS (ESI): m/z 699.4 [M+H]+. Methyl N-((2S)-l-((2S)-2-(5-(4-(6-(2-((2S)-l-((2S)-2-((methox
methylbutanoyl)-4-methyl-2,5-dihydro-lH^yrrol-2-yl)-lH-imidazole-5-yl)naphthalene-2- yl)phenyl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH-pyrrol-l-yl)-3-methyl-l-oxobutan-2- yl)carbamate (7a-4).
[0171] Treatment of compound 7a-3 with either TFA or 4 N HC1 in dioxane, followed by Procedure G gave compound 7a-4. LC-MS (ESI): m/z 813.4 [M+H]+,
Methyl N-((2S)-l-((2S)-2-(5-(4-(6-(2-((2S)-l-((2S)-2-((methoxy
methylbutanoyl)-4-methyl-2,5-dihydro-lH^yrrol-2-yl)-lH-imidazole-5-yl)naphthalene-2- yl)phenyl)-lH-imidazol-2-yl)-4-cyclopropyl-2,5-dihydro-lH-pyrrol-l-yl)-3-methyl-l- oxobutan-2-yl) carbamate (7a-5).
[0172] Following the procedure described in Scheme 7a by replacing compound la-3 with l-3d or compound 2a-l with 2-ld, compound 7a-5 was obtained. LC-MS (ESI): m/z
839.4 [M+Hf.
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000053_0002
Scheme 8
[0173] Referring to Scheme 8, Step 1. To a solution of 4-bromo-2-chlorobenzoic acid (18.4 g, 83.9 mmol) and 4-bromophenol (24 g, 109 mmol) in nitrobenzene was added cesium carbonate (82 g, 251.7 mmol). The resulting solution was heated at 170 °C with a condenser for 1 day. The reaction mixture was cooled to 70 °C and filtered at this temperature. The residue was washed with toluene. The organic layer was removed by vacuum distillation till a thick dark residue remained. To the dark residue was added aqueous HC1 (I N, 400 mL) and DCM (200 mL). The resulting solution was stirred until dark oil dispersed into DCM solution. The mixture was filtered. The organic layer was dried over anhydrous Na2S04 and concentrated to afford the crude product. The residue was purified by column
chromatography on silica gel, eluted first with DCM and then with a mixture of DCM and MeOH to give 8-1.
[0174] Step 2. Compound 8-1 (16 g, 5:3 ratio, 44.3 mmol) was treated with concentrated sulfuric acid (95 mL). The solution was heated at 105 °C for 2 hrs. The reaction mixture was cooled and poured into ice water. The product precipitated out and was collected by filtration, washed with Et20 and H20. The solid was dried and further purified by flash column chromatography on silica gel (eluents: Hex/EtOAc = 9/1 (v/v) to pure EtOAc and to pure DCM) to afford 8-2 (12 g).
[0175] Step 3. Trimethylaluminum (2.4 mL, 2 M in hexanes, 4.80 mmol) was added dropwise to a degassed stirred solution of 2,6-dibromo-9H-xanthen-9-one (8-2) (500 mg, 1.412 mmol) in toluene (8 mL) at 0 °C. The resulting solution was allowed to warm up to rt and left to stir for 16 hrs. The crude reaction mixture was poured into ice-cold 1 N HC1 aq. (200 mL), and the aqueous layer was washed with DCM (2 x 150 mL), dried over anhydrous MgS04, filtered and solvents were removed in vacuo to give 2,6-dibromo-9,9-dimethyl-9H- xanthene (8-3) (482 mg, 93 % yield) as a white solid. 1H NMR (CDC13): δ 7.77-7.74 (1H, m), 7.55-7.51 (1H, m), 7.44-7.40 (1H, m), 7.33-7.29 (2H, m), 7.06-7.02 (1H, m), 1.58 (6H, s) ppm.
[0176] Step 4. A seal tube was charged with Pd2(dba)3 (55 mg, 0.06 mmol),
tricyclohexylphosphine (34 mg, 0.12 mmol) and dioxane (20 mL). The resulting solution was bubbled with N2 for 5 mins and stirred for 30 mins at rt. Compound 8-3 (1.0 g, 2.71 mmol), tri-ft-butyl(l-ethoxyvinyl)stannane (2.1 mL, 6.20 mmol) and cesium fluoride (1.8 g, 11.9 mmol) were added while being protected under an atmosphere of N2. After stirring 30 hrs at 145 °C, the reaction mixture was cooled to rt and filtered through a pad of Celite®545, which was rinsed with dioxane (20 mL).
[0177] The combined dioxane solution from above was diluted with H20 (10 mL) and cooled to 0 °C. NBS (l .OOg, 5.62 mmol) was then added in portions over 15 mins. After about 30 mins stirring, the volatile component was removed in vacuo, and the residue was partitioned between DCM (100 mL) and water. The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic phases were washed by brine, water, dried over Na2S04. After concentration to remove all solvents, the crude residue was triturated by DCM (3 x 15 mL) to remove most of stannane derivative to afford l,l'-(9,9-dimethyl-9H-xanthene-2,6- diyl)bis(2-bromoethanone) (8-4) (1.1 g). 1H NMR (300 MHz, CDC13): δ 8.14 (d, J= 2.2 Hz, 1H), 7.86 (dd, J; = 8.5 Hz, J2 = 2.2 Hz, 1H), 7.75 (dd, J; = 8.1 Hz, J2 = 1.7 Hz, 1H), 7.70 (d, J= 1.7 Hz), 7.56 (d, J= 8.0 Hz), 7.16 (d, J = 8.5 Hz), 4.44 (s, 2H), 4.42 (s, 2H), 1.70 (s, 6H) ppm.
[0178] Step 5. General Procedure H (Steps 5 and 6). To a suspension of 8-4 (180 mg, 0.40 mmol) in CH3CN (6 mL) was added l-2b (210 mg, 0.83 mmol) and N,N- Diisopropylethylamine (0.144 mL, 0.826 mmol). The mixture was stirred overnight. The volatile component was removed in vacuo, and the residue was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic phases were washed by brine, saturated sodium carbonate, and water, and dried over anhydrous Na2S04. After concentration, the crude mixture was purified by flash column chromatography
(hexanes/ethyl acetate = 2/1 (v/v)) to afford compound 8-5 (230 mg). LC-MS (ESI): m/z 819.5 [M+Na]+.
[0179] Step 6. A mixture of 8-5 (230 mg, 0.289 mmol), ammonium acetate (445 mg, 5.78 mmol) and N,N-Diisopropylethylamine (1.00 mL, 5.78 mmol) in xylene (4 mL) in a sealed tube was stirred at 140 °C for 2 hrs. LC-MS showed the reaction was completed. The solvent was removed in vacuo, and the residue was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic phase was washed by brine, water, and dried over anhydrous Na2S04. After removing the solvents, the crude mixture was purified by flash column chromatography (Hex/EtOAc =1/2 (v/v)) to afford compound 8-6 (120 mg). LC-MS (ESI): m/z 757.4 [M+H]+.
[0180] Step 7. To a stirred solution of 8-6 (60 mg) in dichloromethane (5 mL) was added trifluoro acetic acid (1 mL). After 3 hrs, the reaction was concentrated to dryness. The de- Boced intermediate was dissolved in DMF (1 mL). To the solution were added DIPEA (0.139 mL), N-Moc-L-Val-OH (28 mg) and HATU (61 mg) subsequently. After 1 hr stirring, the reaction was diluted with water. The reaction was extracted by dichloromethane. The combined organic solution was washed with brine and water, dried over anhydrous Na2S04, filtered, and concentrated. The resulting crude product was purified by prep-HPLC
(Phenomenex, C18-Luna column, FL -ACN, 0.1% HC02H) to give compound 8-7 (17 mg). 1H NMR (300 MHz, CDC13): δ 8.29 (s, 2H), 7.47 (br s, 1H), 7.19-7.14 (m, 4H), 7.08-7.05 (m, 1H), 6.98-6.94 (m, 1H), 6.79-6.72 (m, 1H), 5.92 (br s, 2H), 5.56 (br s, 2H), 4.53 (br s, 4H), 4.29 (t, J= 8.0 Hz, 2H), 3.68 (br s, 6H), 2.00 (s, 6H), 1.60-1.40 (m, 6H), 0.95-0.80 (m, 14H), 0.80-0.60 (m, 4H) ppm; LC-MS (ESI): m/z 871.4 [M+H]+.
Methyl N-[(2S)-l-[(2S)-2-[5-(7-{2-[(2S)-l-[(2S)-2-[(methoxycarbonyl)am^
methylbutanoyl]-4-methyl-2,5-dihydro-lH-pyrrol-2-yl]-lH mida
xanthen-3-yl)-lH midazol-2-yl]-4-methyl-2,5-dihydro-lH-pyrrol-l-yl]-3-methyl-l
2 -yl] carbamate (8-8).
[0181] Following the procedure described in Scheme 8 by replacing l-2d with l-2b, 8-8 was obtained. LC-MS (ESI): m/z 819.4 [M+H]+.
Figure imgf000056_0001
Figure imgf000056_0002
Scheme 9
Methyl N-((2S)-l-((2S)-2-(5-(7-(2-((2S)-l-((2S)-2-((methoxy
methylbutanoyl)-4-methyl-2,5-dihydro-lH^yrrol-2-yl)-lH-imidazol-5-yl)-9-oxo-9H-xanthen- 3-yl)-lH-imidazol-2-yl)-4-methyl-2,5-dihydro-lH-pyrrol-l-yl)-3-methyl-l-oxobutan-2- yl)carbamate (9-5).
[0182] Following the procedure described in Scheme 8 by replacing both 8-3 with 8-2 and l-2d with l-2b, 9-5 was obtained. LC-MS (ESI): m/z 805.4 [M+H]+.
Methyl N-((2S)-l-((2S)-4-cyclopropyl-2-(5-(7-(2-((2S)-4-cyclopropyl-l-((2S)-2- ((methoxycarbonyl)amino)-3-methylbutanoyl)-2,5-dihydro-lH-pyrrol-2-yl)-lH-imidazol-5- yl)-9-oxo-9H-xanthen-3-yl)-lH-imidazol-2-yl)-2,5-dihydro-lH-pyrrol-l-yl)-3-methyl-l- oxobutan-2-yl) carbamate (9-6).
[0183] Following the procedure described in Scheme 8 by replacing 8-3 with 8-2, 9-6 was obtained. LC-MS (ESI): m/z 857.4 [M+H]+.
Figure imgf000057_0001
Additional Synthetic Schemes
[0184] Provided below are additional synthetic schemes useful in making the disclosed compounds. All compound numbering is restarted in this section, "Additional Synthetic Schemes."
Figure imgf000057_0002
R = H, Me, Et, c-Pr
Figure imgf000057_0003
Scheme Al
Figure imgf000058_0001
Scheme A2
Figure imgf000058_0002
Scheme A3
Figure imgf000059_0001
piperidine, DMF, 60°C 4-7 R = H, Me, Et, cPr
Figure imgf000059_0002
Scheme A4
Figure imgf000060_0001
Figure imgf000060_0002
/ 6-2 R = H, Me, Et, cPr \
Scheme A6
Figure imgf000060_0003
Scheme A7
Figure imgf000061_0001
Scheme A8
Example Compounds
Below are representative examples of the invention.
Figure imgf000061_0002
Figure imgf000062_0001
61
Figure imgf000063_0001
62
Figure imgf000064_0001
63
Figure imgf000065_0001
64
Figure imgf000066_0001
65 Biological Activity
[0186] Biological activity of the compounds of the invention was determined using an HCV replicon assay. The lb_Huh-Luc/Neo-ET cell line persistently expressing a bicistronic genotype lb replicon in Huh 7 cells was obtained from ReBLikon GMBH. This cell line was used to test compound inhibition using luciferase enzyme activity readout as a measurement of compound inhibition of replicon levels.
[0187] On Day 1 (the day after plating), each compound is added in triplicate to the cells. Plates incubated for 72 h prior to running the luciferase assay. Enzyme activity was measured using a Bright-Glo Kit (cat. number E2620) manufactured by Promega Corporation. The following equation was used to generate a percent control value for each compound.
% Control = (Average Compound Value/ Average Control)* 100
[0188] The EC50 value was determined using GraphPad Prism and the following equation:
Y = Bottom + (Top-Bottom)/ (1+10Λ ((LogIC50-X)*HillSlope))
[0189] EC50 values of compounds are repeated several times in the replicon assay.
[0190] Synthesized compounds of the disclosed invention along with inhibitory activity and mass spectrometry results are illustrated in Table 1 below. The biological activity is indicated as being *, ** , ***? or ****? which corresponds to EC50 ranges of >1000 nM, 999 nM to 10 nM, 9.9 nM to 1 nM, or <1 nM respectively.
Table 1.
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Pharmaceutical Compositions
[0191] A fourth aspect of the invention provides a pharmaceutical composition comprising the compounds of the invention. In a first embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients. Such excipients are known to those of skill in the art. The compounds of the present invention include, without limitation, basic compounds such as free bases and pharmaceutically acceptable salts of these compounds. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington's Pharmaceutical Sciences, 18th Edition (Easton,
Pennsylvania: Mack Publishing Company, 1990).
[0192] Depending on the intended mode of administration, the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, may include other pharmaceutical agents, adjuvants, diluents, buffers, etc.
[0193] The invention includes a pharmaceutical composition comprising a compound of the present invention including isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof together with one or more
pharmaceutically acceptable carriers and optionally other therapeutic and/or prophylactic ingredients. [0194] For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate and the like.
[0195] For oral administration, the composition will generally take the form of a tablet, capsule, a softgel capsule nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use will generally include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent may be combined with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents may be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents and the like.
[0196] A fifth aspect of the invention provides use of the compounds of the invention in the manufacture of a medicament.
[0197] In a first embodiment of the fifth aspect the medicament is for the treatment of hepatitis C.
[0198] A sixth aspect of the invention provides a method of treating hepatitis C comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention, optionally in a pharmaceutical composition. A pharmaceutically or therapeutically effective amount of the composition will be delivered to the subject. The precise effective amount will vary from subject to subject and will depend upon the species, age, the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. Thus, the effective amount for a given situation can be determined by routine experimentation. The subject may be administered as many doses as is required to reduce and/or alleviate the signs, symptoms or causes of the disorder in question, or bring about any other desired alteration of a biological system. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of this invention for a given disease. Combination Therapy
[0199] The compounds of the present invention and their isomeric forms and
pharmaceutically acceptable salts thereof are useful in treating and preventing HCV infection alone or when used in combination with other compounds targeting viral or cellular elements or functions involved in the HCV lifecycle. Classes of compounds useful in the invention may include, without limitation, all classes of HCV antivirals. For combination therapies, mechanistic classes of agents that may be useful when combined with the compounds of the present invention include, for example, nucleoside and non-nucleoside inhibitors of the HCV polymerase, protease inhibitors, helicase inhibitors, NS4B inhibitors and medicinal agents that functionally inhibit the internal ribosomal entry site (IRES) and other medicaments that inhibit HCV cell attachment or virus entry, HCV RNA translation, HCV RNA transcription, replication or HCV maturation, assembly or virus release. Specific compounds in these classes and useful in the invention include, but are not limited to, macrocyclic, heterocyclic and linear HCV protease inhibitors such as telaprevir (VX-950), boceprevir (SCH-503034), narlaprevir (SCH-900518), ITMN-191 (R-7227), TMC-435350 (a.k.a. TMC-435), MK- 7009, BI-201335, BI-2061 (ciluprevir), BMS-650032, ACH-1625, ACH-1095 (HCV NS4A protease co-factor inhibitor), VX-500, VX-813, PHX-1766, PHX2054, IDX-136, IDX-316, ABT-450 EP-013420 (and congeners) and VBY-376; the Nucleosidic HCV polymerase (replicase) inhibitors useful in the invention include, but are not limited to, R7128, PSI-7851, IDX-184, IDX-102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879 and PSI-7977 and various other nucleoside and nucleotide analogs and HCV inhibitors including (but not limited to) those derived as 2'-C-methyl modified nucleos(t)ides, 4'-aza modified
nucleos(t)ides, and 7'-deaza modified nucleos(t)ides. Non-nuclosidic HCV polymerase (replicase) inhibitors useful in the invention, include, but are not limited to , HCV-796, HCV- 371, VCH-759, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF- 00868554, BI-207127, GS-9190, A-837093, JKT-109, GL-59728 and GL-60667.
[0200] In addition, NS5A inhibitors of the present invention may be used in combination with cyclophyllin and immunophyllin antagonists (eg, without limitation, DEBIO
compounds, NM-811 as well as cyclosporine and its derivatives), kinase inhibitors, inhibitors of heat shock proteins (e.g., HSP90 and HSP70), other immunomodulatory agents that may include, without limitation, interferons (-alpha, -beta, -omega, -gamma, -lambda or synthetic) such as Intron A™, Roferon-A™, Canferon-A300™, Advaferon™, Infergen™,
Humoferon™, Sumiferon MP™, Alfaferone™, IFN-β™, Feron™ and the like; polyethylene glycol derivatized (pegylated) interferon compounds, such as PEG interferon-a-2a
(Pegasys™), PEG interferon-a-2b (PEGIntron™), pegylated IFN-a-conl and the like; long acting formulations and derivatizations of interferon compounds such as the albumin- fused interferon, Albuferon™ , Locteron™ and the like; interferons with various types of controlled delivery systems (e.g. ITCA-638, omega-interferon delivered by the DUROS™ subcutaneous delivery system); compounds that stimulate the synthesis of interferon in cells, such as resiquimod and the like; interleukins; compounds that enhance the development of type 1 helper T cell response, such as SCV-07 and the like; TOLL-like receptor agonists such as CpG-10101 (actilon), isotorabine, ANA773 and the like; thymosin a -1; ANA-245 and ANA-246; histamine dihydrochloride; propagermanium; tetrachlorodecaoxide; ampligen; IMP-321; KRN-7000; antibodies, such as civacir, XTL-6865 and the like and prophylactic and therapeutic vaccines such as InnoVac C, HCV E1E2/MF59 and the like. In addition, any of the above-described methods involving administering an NS5A inhibitor, a Type I interferon receptor agonist (e.g., an IFN-a) and a Type II interferon receptor agonist (e.g., an IFN-γ) can be augmented by administration of an effective amount of a TNF-a antagonist. Exemplary, non-limiting TNF-a antagonists that are suitable for use in such combination therapies include ENBREL™, REMICADE™ and HUMIRA™.
[0201] In addition, NS5A inhibitors of the present invention may be used in combination with antiprotozoans and other antivirals thought to be effective in the treatment of HCV infection, such as, without limitation, the prodrug nitazoxanide. Nitazoxanide can be used as an agent in combination the compounds disclosed in this invention as well as in combination with other agents useful in treating HCV infection such as peginterferon alfa-2a and ribavarin (see, for example,_Rossignol, JF and Keeffe, EB, Future Microbiol. 3:539-545, 2008).
[0202] NS5A inhibitors of the present invention may also be used with alternative forms of interferons and pegylated interferons, ribavirin or its analogs (e.g., tarabavarin, levoviron), microRNA, small interfering RNA compounds (e.g., SIRPLEX-140-N and the like), nucleotide or nucleoside analogs, immunoglobulins, hepatoprotectants, anti-inflammatory agents and other inhibitors of NS5A. Inhibitors of other targets in the HCV lifecycle include NS3 helicase inhibitors; NS4A co-factor inhibitors; antisense oligonucleotide inhibitors, such as ISIS- 14803, AVI-4065 and the like; vector-encoded short hairpin RNA (shRNA); HCV specific ribozymes such as heptazyme, RPI, 13919 and the like; entry inhibitors such as HepeX-C, HuMax-HepC and the like; alpha glucosidase inhibitors such as celgosivir, UT- 23 IB and the like; KPE-02003002 and BIVN 401 and IMPDH inhibitors. Other illustrative HCV inhibitor compounds include those disclosed in the following publications: U.S. Pat. No. 5,807,876; U.S. Pat. No. 6,498,178; U.S. Pat. No. 6,344,465; U.S. Pat. No. 6,054,472; WO97/40028; WO98/40381; WO00/56331, WO 02/04425; WO 03/007945; WO 03/010141; WO 03/000254; WO 01/32153; WO 00/06529; WO 00/18231; WO 00/10573; WO 00/13708; WO 01/85172; WO 03/037893; WO 03/037894; WO 03/037895; WO 02/100851; WO 02/100846; EP 1256628; WO 99/01582; WO 00/09543; WO02/18369; W098/17679,
WO00/056331; WO 98/22496; WO 99/07734; WO 05/073216, WO 05/073195 and WO 08/021927.
[0203] Additionally, combinations of, for example, ribavirin and interferon, may be administered as multiple combination therapy with at least one of the compounds of the present invention. The present invention is not limited to the aforementioned classes or compounds and contemplates known and new compounds and combinations of biologically active agents (see, Strader, D.B., Wright, T., Thomas, D.L. and Seeff, L.B., AASLD Practice Guidelines. 1-22, 2009 and Manns, M.P., Foster, G.R., Rockstroh, J.K., Zeuzem, S., Zoulim, F. and Houghton, M., Nature Reviews Drug Discovery . 6:991-1000, 2007, Pawlotsky, J-M., Chevaliez, S. and McHutchinson, J.G., Gastroenterology. 132: 179-1998, 2007 , Lindenbach, B.D. and Rice, CM., Nature 436:933-938, 2005, Klebl, B.M., Kurtenbach, A., Salassidis, K., Daub, H. and Herget, T., Antiviral Chemistry & Chemotherapy. 16:69-90, 2005, Beaulieu, P.L., Current Opinion in Investigational Drugs. 8:614-634, 2007, Kim, S-J., Kim, J-H., Kim, Y-G., Lim, H-S. and Oh, W-J., The Journal of Biological Chemistry. 48:50031-50041, 2004, Okamoto, T., Nishimura, Y., Ichimura, T., Suzuki, K., Miyamura, T., Suzuki, T., Moriishi, K. and Matsuura, Y., The EMBO Journal. 1-11, 2006, Soriano, V., Peters, M.G. and Zeuzem, S. Clinical Infectious Diseases. 48:313-320, 2009, Huang, Z., Murray, M.G. and Secrist, J.A., Antiviral Research. 71 :351-362, 2006 and Neyts, J ., Antiviral Research. 71 :363-371, 2006, each of which is incorporated by reference in their entirety herein). It is intended that combination therapies of the present invention include any chemically compatible
combination of a compound of this inventive group with other compounds of the inventive group or other compounds outside of the inventive group, as long as the combination does not eliminate the anti-viral activity of the compound of this inventive group or the anti-viral activity of the pharmaceutical composition itself.
[0204] Combination therapy can be sequential, that is treatment with one agent first and then a second agent (for example, where each treatment comprises a different compound of the invention or where one treatment comprises a compound of the invention and the other comprises one or more biologically active agents) or it can be treatment with both agents at the same time (concurrently). Sequential therapy can include a reasonable time after the completion of the first therapy before beginning the second therapy. Treatment with both agents at the same time can be in the same daily dose or in separate doses. Combination therapy need not be limited to two agents and may include three or more agents. The dosages for both concurrent and sequential combination therapy will depend on absorption, distribution, metabolism and excretion rates of the components of the combination therapy as well as other factors known to one of skill in the art. Dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules may be adjusted over time according to the individual's need and the professional judgment of the person administering or supervising the administration of the combination therapy.
[0205] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.
[0206] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the invention as defined in the appended claims.

Claims

We claim:
1. A compound of formula I,
Figure imgf000078_0001
* indicates attachment points to the reminder of the compound,
R1 is selected from the group consisting of C1-C4 alkyl, aryl, a halogen, -CN, -N02, -OR1, -CF3, -OCF3, -OCHF2, -C02R2, -C(0)R3, -C(0)NR3R4, -NR3R4 , -S(0)2R2, and -S(0)2NR3R4, m is 0, 1, or 3,
V is -CH2-CH2-, -CH=CH-, -N=CH-, (CH2)a-N(R3)-(CH2)b- or
-(CH2)a-0-(CH2)b-, wherein a and b are independently 0, 1, 2, or 3 with the proviso that a and b are not both 0,
R2, R3, and R4 are each independently chosen from the group consisting of hydrogen, Ci to C4 alkyl, Ci to C4 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl, and wherein for each A and A', B may be attached to either side of A and A' so that in
the example of A or A' be
Figure imgf000078_0002
the A-B-A' can be any of:
Figure imgf000079_0001
B is selected from the group consisting of a single bond, triple bond, W
W EE^≡ ΞΞΞΞΞ W ≡Ξ≡ W == W
w w = , and W-W, wherein each W is independently selected from the group consisting of a cycloalkyl group, cycloalkenyl group, heterocyclic group, aryl group or heteroaryl group, with the proviso that when B is W-W, only one W is a six-member aromatic ring;
Figure imgf000079_0002
Xa-Xb and Xa-Xb are each independently selected from the group consisting of C2 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 heteroalkyl, and C2 to C6 heteroalkenyl,wherein: each hetero atom, if present, is independently N, O or S, and
either or both of Xa-Xb and Xa-Xb , together with the atoms to which they are attached, optionally form a 4- to 9-membered ring which may be cycloalkyl and heterocycle and which may optionally be fused to another 3-5 membered ring; Ra, Rb, Ra and Rb are each independently hydrogen, d to C8 alkyl or Ci to C8 heteroalkyl, wherein: each hetero atom, if present, is independently N, O or S,
Ra and Rb are optionally joined, together with the atom to which they are attached, to form a 3- to 6-membered ring, and
Ra' and Rb' are optionally joined, together with the atom to which they are attached, to form a 3- to 6-membered ring; Y and Y' are each independently N or CH; and
Z and Z' are each independently selected from the group consisting of hydrogen, Ci to Cg alkyl, Ci to Cg heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, 1-3 amino acids,
-[U-(CR4 2),-NR5-(CR4 2),]U-U-(CR4 2),-NR7-(CR4 2),-R8, -U-(CR4 2),-R8 and -[U-(CR4 2),-NR5-(CR4 2),]u-U-(CR4 2),-0-(CR4 2),-R8, wherein,
U is selected from the group consisting of -C(O)-, -C(S)- and -S(0)2-, each R4 R5 and R7 is independently selected from the group consisting of hydrogen, Ci to Cg alkyl, Ci to Cg heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl,
R8 is selected from the group consisting of hydrogen, Ci to Cg alkyl, Ci to Cg heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, -C(0)-R81,
-C(S)-R81, -C(0)-0-R81, -C(0)-N-R812, -S(0)2-R81 and -S(0)2-N-R81 2, wherein each R81 is independently chosen from the group consisting of hydrogen, Ci to Cg alkyl, Ci to Cg heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl, optionally, R7 and R8 together form a 4-7 membered ring, each t is independently 0, 1, 2, 3, or 4, and u is 0, 1, or 2.
2. The compound of claim 1 wherein A and A' are selected from the group consisting of:
Figure imgf000081_0001
3. The compound of any previous claim wherein D is independently selected from group 1 and group 2 wherein:
Group 1 consists of
Figure imgf000081_0002
Figure imgf000081_0003
wherein R is independently selected from the group consisting of hydrogen, -OH, Ci to Ci2 alkyl, Ci to C12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide; and
Figure imgf000081_0004
wherein Re, Rf, Rg, and Rh are each independently hydrogen, Ci to Cs alkyl or Ci to Cs heteroalkyl, each hetero atom, if present, is independently N, O or S; Re and Rf are optionally joined, together with the atom to which they are attached, to form a 5- to 8- membered ring, and Rg and Rh are optionally joined, together with the atom to which they are attached, to form a 3- to 8-membered ring.
4. The compound of any previous claim wherein D' is independently selected from group an group 2' wherein:
Figure imgf000082_0001
hydrogen, -OH, Ci to C12 alkyl, Ci to C12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide; and
Figure imgf000082_0002
independently hydrogen, Ci to Cg alkyl or Ci to Cg heteroalkyl, each hetero atom, if present, is independently N, O or S; Re and Rf are optionally joined, together with the atom to which they are attached, to form a 5- to 8-membered ring, and Rg and Rh are optionally joined, together with the atom to which they are attached, to form a 3- to 8- membered ring.
The compound of any previous claim wherein if D is selected from Group 1, D' is selected from Group 2'.
The compound of any one of claims 1-4 wherein if D' is selected from Group , D is selected from Group 2.
The compound of any previous claim wherein A-B-A' is selected from the consisting of:
Figure imgf000084_0001
wherein * indicates attachment points to the reminder of the compound.
8. The compound of any previous claim wherein one or both of Y and Y' are -N-.
9. The compound of any previous claim wherein Z and Z' are each 1-3 amino acids.
10. The compound of claim 9 wherein the amino acids are all in the D or all in the L
configuration.
11. The compound of any one of claims 1-8 wherein Z and Z' are each independently selected from the group consisting of
-[U-(CR4 2)t-NR5-(CR4 2)t]u-U-(CR4 2)t-NR7-(CR4 2)t-R8,
-U-(CR4 2)t-R8 and -[U-(CR4 2)t-NR5-(CR4 2)t]u-U-(CR4 2)t-0-(CR4 2)t-R8.
12. The compound of claim 11 wherein one or both of Z and Z' are
-[U-(CR4 2)t-NR5-(CR4 2)t]u-U-(CR4 2)t-NR7-(CR4 2)t-R8.
13. The compound °f claim 12 wherein one or both of Z and Z' are
-U-(CR4 2),-NR5-(CR4 2)t-U (CR4 2)t-NR7-(CR4 2)t-R8.
14. The compound of claim 12 wherein one or both of Z and Z' are
-U-(CR4 2),-NR7-(CR4 2),-R8.
15. The compound of claim 12 wherein one or both of Z and Z' are
-[C(0)-(CR4 2)t-NR5-(CR4 2)t]u-U-(CR4 2)t-NR7-(CR4 2)t-R8.
16. The compound of claim 15 wherein one or both of Z and Z' are
-C(0)-(cR4 2)t NR5-(CR4 2)t-U-(CR42)t-NR7-(CR4 2)t-R8.
17. The compound of claim 15 wherein one or both of Z and Z' are
-[C(0)-(CR4 2)t-NR5-(CR4 2)t]u-C(0)-(CR4 2)t-NR7-(CR4 2)t-R8.
18. The compound of claim 17 wherein one or both of Z and Z' are
-C(0)-(CR4 2),-NR5-(CR4 2),-C(0)-(CR4 2),-NR7-(CR4 2),-R8.
19. The compound of claim 11 wherein one or both of Z and Z' are
-C(0)-(cR4 2)t NR7-(CR4 2)t-R8.
20. The compound of claim 11 wherein one or both of Z and Z' are
-C(0)-(CR4 2)n-NR7-(CR4 2)n-C(0)-R81.
21. The compound of claim 11 wherein one or both of Z and Z' are
-C(0)-(CR4 2)n-NR7-C(0)-R81.
22. The compound of claim 11 wherein one or both of Z and Z' are
-C(0)-(CR4 2)n-NR7-(CR4 2)n-C(0)-0-R81.
23. The compound of claim 11 wherein one or both of Z and Z' are
-C(0)-(CR4 2)n-NR7-C(0)-0-R81.
24. The compound of claim 11 wherein one or both of Z and Z' are
-U-(CR4 2)t-R8.
25. IThe compound of claim 11 wherein one or both of Z and Z' are
Figure imgf000086_0001
26. The compound of claim 11 wherein one or both of Z and Z' are
-[U-(CR4 2)t-NR5-(CR4 2)t]u-U-(CR4 2)t-0-(CR4 2)t-R8.
27. The compound of claim 11 wherein one or both of Z and Z' are
-U-(CR4 2),-NR5-(CR4 2),-U-(CR4 2),-0-(CR4 2),-R8.
28. The compound of claim 11 wherein one or both of Z and Z' are
-C(0)-(CR4 2)t-NR5-(CR4 2)t-C(0)-(CR4 2)t-0-(CR4 2)t-R8.
29. The compound of claim 11 wherein one or both of Z and Z' are
-U-(CR4 2)t-0-(CR4 2)t-R8.
30. The compound of claim 11 wherein one or both of Z and Z' are
-C(0)-(CR4 2)t-0-(CR4 2)t-R8.
31. The compound of claim 11 wherein one or both of Z and Z' are
-C(0)-(CR4 2)„-NR7-R8 wherein R7 and R8 together form a 4-7 membered ring.
32. A pharmaceutical composition comprising any one of the previous claims.
33. The use of a compound according to any one of claims 1-31 in the manufacture of a medicament.
34. The use of claim 33 wherein the medicament is for the treatment of hepatitis C.
35. A method of treating hepatitis C comprising administering to a subject in need thereof, a therapeutically effective amount of any one of the compounds of claims 1-32.
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