[go: up one dir, main page]

WO2009103022A1 - Dérivés de cycloindoles à cycle condensé substitué et leurs procédés d’utilisation - Google Patents

Dérivés de cycloindoles à cycle condensé substitué et leurs procédés d’utilisation Download PDF

Info

Publication number
WO2009103022A1
WO2009103022A1 PCT/US2009/034148 US2009034148W WO2009103022A1 WO 2009103022 A1 WO2009103022 A1 WO 2009103022A1 US 2009034148 W US2009034148 W US 2009034148W WO 2009103022 A1 WO2009103022 A1 WO 2009103022A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
tetrahydro
compound
carbazole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2009/034148
Other languages
English (en)
Inventor
James E. Macdonald
Andrew Jeremiah Jackson
Gopi Kumar Mittapalli
Fang Zhao
Cornelis A. Rijnbrand
Haekyung Lee
Jing Zhang
Flossie Wong-Staal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
iTherX Pharmaceuticals Inc
Original Assignee
iTherX Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by iTherX Pharmaceuticals Inc filed Critical iTherX Pharmaceuticals Inc
Publication of WO2009103022A1 publication Critical patent/WO2009103022A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • Hepatitis C is caused by infection with Hepatitis C Virus (HCV), which is carried by more than 100 million people worldwide.
  • HCV Hepatitis C Virus
  • the currently FDA-approved Hepatitis C therapies for example, non-specific antiviral substances that boost the host's antiviral responses and target virus replication, are only moderately efficacious and cause significant adverse reactions.
  • interferons and PEGylated interferons are non-specific antiviral and antineoplastic proteins that act by inhibiting viral replication.
  • Ribavirin is a non-specific, antiviral, nucleotide analog prodrug that interferes with RNA metabolism and is not effective in monotherapy for the treatment of HCV infection.
  • HCV infection leads to chronic Hepatitis in up to 85% of patients, and is responsible for an estimated 10,000 deaths per year in the United States.
  • substituted fused ring cycloindole derivatives are provided that are useful, inter alia, in inhibiting the entry of a Hepatitis C virus into a cell and treating a disease caused by a Hepatitis C viral infection.
  • the substituted fused ring cycloindole derivative has the formula:
  • ring A is a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
  • L 1 is substituted or unsubstituted alkylene.
  • L 2 is a bond, - O-L 3 -, -S(O) n -L 3 -, -NR 6 -L 3 -, -NR 6 C(O)-L 3 -, -C(O)N(R 6 )-L 3 -, -NR 6 S(O) 2 -L 3 -, or -S(O) 2 NR 6 - L 3 -, L 3 is a bond, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene and n is an integer from 0 to 2.
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen, halogen, -CN, -S(O) 2 N(R 7 )(R 8 ), -C(O)R 9 , -NR 10 -C(O)R n , -NR 12 -C(O)-OR 13 , - C(O)NR 14 R 15 , -NR 16 S(O) 2 R 17 , -S(O) 1 R 19 , -NR 20 R 21 , -OR 22 , -C(NR 20 )-N(R 21 )-OR 22 , -C(O)OR 23 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 5 is hydrogen, -CN, halogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • a method of inhibiting the entry of a Hepatitis C virus into a cell includes contacting the cell and/or the Hepatitis C virus with an effective amount of a substituted fused ring cycloindole derivative disclosed above.
  • a method of inhibiting infection of a cell by a Hepatitis C virus is provided. The method includes contacting the cell and/or the Hepatitis C virus with an effective amount of a substituted fused ring cycloindole derivative disclosed above.
  • a method of treating a disease in a subject caused by a Hepatitis C viral infection includes administering to the subject an effective amount of a substituted fused ring cycloindole derivative disclosed above.
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. Ci-C 10 means one to ten carbons).
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4- pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • alkylene by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH 2 CH 2 CH 2 CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 - .
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O) 2 R'- represents both -C(O) 2 R'- and -R 1 C(O) 2 -.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R " , -OR', -SR, and/or -SO 2 R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR 1 R or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R or the like.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl” and
  • heteroalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3- cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1 -(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2- yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
  • a "cycloalkylene” and “heterocycloalkylene” refer to a divalent radical derived from cycloalkyl and heterocycloalkyl, respectively.
  • halo or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C 4 )alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (preferably from 1 to 3 rings) which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-is
  • aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
  • “Arylene” and “heteroarylene” refers to a divalent radical derived from a aryl and heteroaryl, respectively.
  • aryl when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g. , phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like).
  • oxo as used herein means an oxygen that is double bonded to a carbon atom.
  • alkyl e.g., "alkyl,” “heteroalkyl,” “aryl” and “heteroaryl” are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
  • R', R", R 1 " and R" 1 ' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R', R", R'" and R' 1 " groups when more than one of these groups is present.
  • R 1 and R 11 are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring.
  • -NR 1 R is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
  • haloalkyl e.g., -CF 3 and -CH 2 CF 3
  • acyl e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR 1 -, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X 1 -(C' 1 R'")d-, where s and d are independently integers of from 0 to 3, and X' is - O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR 1 -.
  • R, R 1 , R" and R 1 " are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • heteroatom or "ring heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • a "substituent group,” as used herein, means a group selected from the following moieties:
  • a “size-limited substituent” or “ size-limited substituent group,” as used herein means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 - C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 4 -C 8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4 to 8 membered heterocycloalkyl.
  • a "lower substituent” or " lower substituent group,” as used herein means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 5 - C 7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7 membered heterocycloalkyl.
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al. , “Pharmaceutical Salts” ', Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the compounds of the present invention may exist as salts with pharmaceutically acceptable acids.
  • the present invention includes such salts.
  • Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (eg (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates and salts with amino acids such as glutamic acid.
  • These salts may be prepared by methods known to those skilled in the art.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • the present invention provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, tautomers, geometric isomers and individual isomers are encompassed within the scope of the present invention.
  • the compounds of the present invention do not include those which are known in the art to be too unstable to synthesize and/or isolate.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • a or “an,” as used in herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted Ci-C 2O alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • the symbol * denotes a point of attachment of a moiety to the remainder of a compound.
  • the phrase "effective amount” refers to an amount sufficient to attain the desired result.
  • the phrase "therapeutically effective amount” means an amount sufficient to produce the desired therapeutic result.
  • the therapeutic result is an objective or subjective improvement of a disease or condition, achieved by inducing or enhancing a physiological process, blocking or inhibiting a physiological process, or in general terms performing a biological function that helps in or contributes to the elimination or abatement of the disease or condition.
  • treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and prophylaxis.
  • the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • substituted fused ring cycloindoles also referred to herein as a substituted fused ring cycloindole derivatives
  • a substituted fused ring cycloindole derivative has the formula:
  • ring A is a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
  • L 1 is substituted or unsubstituted alkylene.
  • L 2 is a bond, - O-L 3 -, -S(O) n -L 3 -, -NR 6 -L 3 -, -NR 6 C(O)-L 3 -, -C(O)N(R 6 )-L 3 -, -NR 6 S(O) 2 -L 3 -, or -S(O) 2 NR 6 - L -.
  • L is a bond, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene and n is an integer from 0 to 2.
  • ring A is a substituted or unsubstituted C 3 -C 8 (e.g. C 5 to C 7 ) cycloalkyl, or substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl.
  • L 1 may be a substituted or unsubstituted Ci-C] 0 alkylene.
  • L 3 may be a bond, substituted or unsubstituted C 1 -C 1O alkylene or substituted or unsubstituted 2 to 10 membered heteroalkylene. Because ring A is a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl, ring A is not a substituted or unsubstituted aryl, such as phenyl.
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen, halogen, -CN, -S(O) 2 N(R 7 )(R 8 ), -C(O)R 9 , -NR 10 -C(O)R ⁇ , -NR 12 -C(O)-OR 13 , -C(O)NR 14 R 15 , -NR 16 S(O) 2 R 17 , -S(O) 1 R 19 , -NR 20 R 21 , -OR 22 , -C(NR 20 )-N(R 21 )-OR 22 , -C(O)OR 23 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • the symbol t is an integer from 0 to 2.
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen, halogen, - CN, -S(O) 2 N(R 7 XR 8 ), -C(O)R 9 , -NR ⁇ -C(O)R 1 ⁇ -NR 12 -C(O)-OR 13 , -C(O)NR 14 R 15 , - NR 16 S(O) 2 R 17 , -S(O) t R 19 , -NR 20 R 21 , -OR 22 , -C(NR 20 )-N(R 21 )-OR 22 , -C(O)OR 23 , substituted or unsubstituted Ci-C 1O alkyl, or substituted or unsubstituted 2 to 10 membered heteroalkyl.
  • R 3 is not hydrogen.
  • R 3 is halogen, -CN, -NR 1 ⁇ C(O)R 1 ' , -C(O)NR 14 R 15 , -NR 16 S(O) 2 R 17 , -S(O) 1 R 19 , -C(N)-N-OR 22 , or -C(O)OR 23 .
  • R 1 , R 2 and R 4 may independently be hydrogen. In certain embodiments, R 1 , R 2 and R 4 are hydrogen.
  • R 5 is hydrogen, -CN, halogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 5 may also be hydrogen, CN, halogen, substituted or unsubstituted C 3 -C 8 (e.g. C 5 to C 7 ) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C 6 or C 10 aryl, or substituted or unsubstituted 5, 6, 8, or 10 membered heteroaryl.
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 6 , R 7 , R 8 , R 9 , R 10 , R", R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 may also independently be hydrogen, substituted or unsubstituted CI-C 10 alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 (e.g. C 5 to C 7 ) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C 6 or Ci 0 aryl, or substituted or unsubstituted 5 or 6 membered heteroaryl.
  • substituted or unsubstituted CI-C 10 alkyl substituted or unsubstituted 2 to 10 membered heteroal
  • ring A has the formula:
  • X, Y and Z are independently a bond, substituted or unsubstituted C 1 -C 3 alkylene, -N(R 24 )-, -O-, -S(O) n -, -S(O) 2 -N(R 24 )-, -N(R 24 )-S(O) 2 -N(R 25 )-, -C(O)-N(R 24 )-, - N(R 24 )-C(O)-,-C(O)-, or -C(R 26 R 27 )-.
  • X, Y and Z do not combine, however, to form a substituted or unsubstituted phenyl.
  • R 24 and R 25 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 24 and R 25 may also independently be hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 (e.g.
  • C 5 to C 7 cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C 6 or Cio aryl, or substituted or unsubstituted 5 or 6 membered heteroaryl.
  • R 26 and R 27 are independently hydrogen, -CN, halogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 26 and R 27 may also independently be hydrogen, - CN, halogen, hydroxyl, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 (e.g.
  • R 26 is halogen. In other embodiments, R 26 is F.
  • X and Z are not a bond.
  • X and Z may independently be a bond, or substituted or unsubstituted C 1 -C 3 alkylene.
  • Y may be a bond, -N(R 24 )-, -O-, -S(O) n -, -S(O) 2 -N(R 24 )-, -N(R 24 )-S(O) 2 -N(R 25 )-, -C(O)-N(R 24 )-, -N(R 24 )- C(O)-, -C(O)-, or -C(R 26 R 27 )-.
  • Y is not a bond.
  • Y may also be - CH(F)-,
  • Ring A is a substituted or unsubstituted C 5 to C 7 cycloalkyl, or substituted or unsubstituted 5 to 7 membered heterocycloalkyl.
  • Ring A may also have the formula:
  • ring A subgeneric formulae The formulae above are herein referred to as "ring A subgeneric formulae.”
  • the symbol k is an integer from 0 to 2.
  • the symbol m is in integer from 0 to 3.
  • the symbol v is an integer from 0 to 4. In some embodiments, k, m and v are 0.
  • R 28 is -CN, halogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 28 may also be -CN, halogen, hydroxyl, substituted or unsubstituted C 1 -Ci O alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 (e.g.
  • R 28 is a substituent of a nitrogen atom (e.g. attached to a nitrogen atom of a ring), R 28 is not halogen. In some embodiments, R 28 is halogen. In other embodiments, R 28 is F.
  • ring A has the formula: , wherein v, k, m, and R 28 are as defined above.
  • ring A has the formula:
  • L 1 is substituted or unsubstituted Ci to C 12 alkylene.
  • L 1 may also be substituted or unsubstituted C 1 to C 8 alkylene.
  • L 1 is substituted or unsubstituted C 1 to C 6 alkylene.
  • L 1 may also be C 2 to C 4 substituted or unsubstituted alkylene.
  • L 1 is substituted or unsubstituted Ci to C 3 alkylene. L 1 may also simply be unsubstituted alkylene.
  • L 2 may be -O-L 3 -, -S(O) n -L 3 -, -NR 6 -L 3 , -S(O) 2 NR 6 -L 3 -, or -NR 6 S(O) 2 -L 3 -.
  • L 2 is -O-L 3 -, -S(O) n -L 3 -, or -NR 6 -L 3 .
  • the symbol n may represent the integer 2.
  • L 3 is a bond.
  • R 5 may be hydrogen, R 29 -substituted or unsubstituted cycloalkyl, R 29 -substituted or unsubstituted heterocycloalkyl, R 29 -substituted or unsubstituted aryl, or R 29 -substituted or unsubstituted heteroaryl, unsubstituted Ci to Ci o alkyl or unsubstituted 2 to 10 membered heteroalkyl.
  • R 29 is oxo, -CN, halogen, -OR 30 , -C(O)OR 31 , -NR 32 R 33 , R 34 -substituted or unsubstituted alkyl, R 34 -substituted or unsubstituted heteroalkyl, R 34 -substituted or unsubstituted cycloalkyl, R 34 -substituted or unsubstituted heterocycloalkyl, R 34 -substituted or unsubstituted aryl, or R 34 -substituted or unsubstituted heteroaryl.
  • R 5 is substituted or unsubstituted aryl.
  • R 5 is substituted or unsubstituted heteroaryl.
  • R 5 is substituted or unsubstituted heterocycloalkyl.
  • R 30 , R 31 , R 32 and R 33 are independently R 35 -substituted or unsubstituted alkyl, R 35 - substituted or unsubstituted heteroalkyl, R 35 -substituted or unsubstituted cycloalkyl, R 35 - substituted or unsubstituted heterocycloalkyl, R 35 -substituted or unsubstituted aryl, or R 35 - substituted or unsubstituted heteroaryl.
  • R 34 and R 35 are independently unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 5 is hydrogen, R 29 -substituted or unsubstituted C 3 -C 8 (e.g. C 5 to C 7 ) cycloalkyl, R 29 -substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, R 29 -substituted or unsubstituted C 6 or C 10 aryl, or R 29 - substituted or unsubstituted 5 to 10 membered (e.g. 5 or 6) membered heteroaryl.
  • R 29 may be -CN, halogen, -OR 30 , -C(O)OR 31 , -NR 32 R 33 , R 34 -substituted or unsubstituted Ci-Cio alkyl, R 34 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 34 -substituted or unsubstituted C 3 -Cs (e.g. C 5 to C 7 ) cycloalkyl, R 34 substituted or unsubstituted 3 to 8 membered (e.g.
  • R 34 -substituted or unsubstituted Ce or C 1O aryl may independently be R 35 -substituted or unsubstituted C 1 -C 10 alkyl, R 35 -substituted or unsubstituted 2 to 10 membered heteroalkyl, R 35 -substituted or unsubstituted C 3 -C 8 (e.g.
  • R 34 and R 35 may independently be unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 34 and R 35 may also independently be unsubstituted Ci-C 10 alkyl, unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C 3 -C 8 (e.g. C 5 to C 7 ) cycloalkyl, unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, unsubstituted C 6 or Cio aryl, or unsubstituted 5 or 6 membered heteroaryl.
  • R 5 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted morpholino, substituted or unsubstituted purinyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzoimidazolyl, substituted or unsubstituted pyrrolidine-2,5-dionyl, substituted or unsubstituted thieno-imidazol-onyl, substituted or unsubstituted piperidiny
  • R 5 is R 34 -substituted or unsubstituted pyridinyl, R 34 -substituted or unsubstituted pyrimidinyl, R 34 -substituted or unsubstituted imidazolyl, R 34 -substituted or unsubstituted pyrazolyl, R 34 -substituted or unsubstituted oxazolyl, R 34 -substituted or unsubstituted pyrazinyl, R 34 -substituted or unsubstituted triazolyl, R 34 -substituted or unsubstituted tetrazolyl, R 34 -substituted or unsubstituted morpholino, R 34 -substituted or unsubstituted purinyl, R 34 -substituted or unsubstituted phenyl, R 34 -substit
  • R 29 is -0-CH 3 , halogen (e.g. F or Cl), methyl, ethyl, propyl, butyl, -C(O)CH 3 , -CF 3 , -NH 2 , -N(CH 3 ) 2 , or oxo.
  • halogen e.g. F or Cl
  • methyl e.g. methyl, ethyl, propyl, butyl, -C(O)CH 3 , -CF 3 , -NH 2 , -N(CH 3 ) 2 , or oxo.
  • R 5 is substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, L is -O-L -, and L is a bond.
  • R 2 is hydrogen.
  • R 4 is hydrogen.
  • R 1 is hydrogen.
  • the compounds of Formula (I) do not include one or all of the compounds with the combination of substituent groups listed in Table 1 below, in which
  • R 2 and R 4 are hydrogen.
  • each substituted group described above in the compounds of Formulae (I), (II), and the ring A subgeneric formulae is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, and/or substituted heteroalkylene described above in the compounds of Formulae (I), (II), and the ring A subgeneric formulae are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. Alternatively, at least one or all of these groups are substituted with at least one lower substituent group.
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 2O alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-C 20 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalky
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 5 -C 7 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7 membered heterocycloalkyl
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 8 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • the compounds of the present invention include any one or all of the compounds set forth in Table 3, Table 4, Table 5, and or the Examples provided below.
  • Alkylation of the nitrogen of the cycloindole with X'-L'-IAR 5 provides compounds disclosed herein.
  • the group X 1 may be a halogen, sulfate, sulfonate or other leaving group useful in nucleophilic displacements.
  • the reaction requires base, and useful bases for this reaction include sodium hydride, potassium tert-butoxide, or more generally alkali alkoxides, Lithium, sodium or potassium hexamethyldisilizane or more generally akali amide bases.
  • Acceptable solvents for this reaction include ethers such as tetrahydrofuran and dioxane, or other ether solvents, and polar aprotic solvents such as dimethyl formamide, dimethyl acetamide and dimethylsulfoxide.
  • ethers such as tetrahydrofuran and dioxane, or other ether solvents
  • polar aprotic solvents such as dimethyl formamide, dimethyl acetamide and dimethylsulfoxide.
  • the reactions may be run at elevated temperatures to reduce the time required for completion.
  • An alternate alkylation route involves the reaction of a cycloindole-L'-X 2 with H- L 2 -R 5 and base to generate the disclosed compounds.
  • the group X 2 may be a halogen, sulfate, sulfonate or other leaving group useful in nucleophilic displacements.
  • the reaction requires a base such as sodium hydride, potassium tert-butoxide, or more generally alkali alkoxides, Lithium, sodium or potassium hexamethyldisilizane or more generally akali amide bases.
  • Acceptable solvents for this reaction include ethers such as tetrahydrofuran and dioxane, or other ether solvents, and polar aprotic solvents such as dimethyl formamide, dimethyl acetamide and dimethylsulf oxide.
  • ethers such as tetrahydrofuran and dioxane, or other ether solvents
  • polar aprotic solvents such as dimethyl formamide, dimethyl acetamide and dimethylsulf oxide.
  • the reactions may be run at elevated temperatures to reduce the time required for completion.
  • Preparation of certain compounds can also be achieved by activating a carboxylate at the site of the R 3 position, and coupling with H-O-R 23 or H 2 NR 15 to provide certain R 3 groups in the final product.
  • the activation of the acid group can be by appropriate coupling reagents, such as carbodiimides and HOBT, or HATU, or by first converting the acid to the acid chloride.
  • Reaction of the activated acid with H-O-R 23 or H 2 NR 15 group can be completed in hydrocarbon solvents such as toluene, halocarbons such as dichloromethane, ethers such as THF or polar aprotic solvents such as DMF, and may require the addition of a base such as triethylamine, methylmorpholine or diisopropylethylamine, or as well as a catalyst such as DMAP.
  • hydrocarbon solvents such as toluene, halocarbons such as dichloromethane, ethers such as THF or polar aprotic solvents such as DMF
  • the desired products may alternately be prepared through formation of the X-Y-Z ring from two substituents that can be cyclized.
  • the bond X-Y or Y-Z may be formed through displacement of a leaving group LG from X, Y or Z under thermal, acidic or basic conditions.
  • the group LG may be a halogen, sulfate, sulfonate, hydroxyl, alkoxy or other leaving group useful in ring closures.
  • the ring closure can be achieved in hydrocarbon solvents such as toluene, halocarbons such as dichloromethane or dichlorobenzene, ethers such as THF or polar aprotic solvents such as DMF.
  • Cyclization may require the addition of a base such as triethylamine, methylmorpholine or diisopropylethylamine, or acids such as sulfuric acid, hydrochloric acid, or boron trifluoride, or dehydrating agents such as thionyl chloride or polyphosphoric acid.
  • a base such as triethylamine, methylmorpholine or diisopropylethylamine
  • acids such as sulfuric acid, hydrochloric acid, or boron trifluoride
  • dehydrating agents such as thionyl chloride or polyphosphoric acid.
  • the cyclization reaction may also include a catalyst such as DMAP. The reactions may be run at elevated temperatures to reduce the time required for completion.
  • a method of inhibiting the entry of a Hepatitis C virus into a cell includes contacting a sample containing the cell and/or Hepatitis C virus with an effective amount of a substituted fused ring cycloindole derivative disclosed above.
  • the sample may contain the cell, the Hepatitis C virus, or both.
  • the method includes contacting the cell and/or the Hepatitis C virus with an effective amount of a substituted fused ring cycloindole derivative disclosed above.
  • hepatitis C virus or “HCV” are used in their conventional manner to refer to the small (approximately 55-65 nm in size), enveloped, positive sense single strand RNA virus in the family Flaviviridae generally referred to using those terms.
  • the cell may be, or derive from, a mammalian cell such as a primate cell (e.g. a human cell).
  • a mammalian cell such as a primate cell (e.g. a human cell).
  • the cell may be in vitro, in situ, or in vivo.
  • the cell forms part or a tissue, organ, or organism.
  • “Inhibiting the entry of a Hepatitis C virus into a cell,” as used herein, includes arresting, decreasing (relative to the absence of administration of a substituted fused ring cycloindole derivative), and/or preventing entry of the Hepatitis C virus into a cell.
  • the entry of the Hepatitis C virus is sufficiently antagonized to result in prevention of, decreased amount of, or arrest of viral infection of the cell.
  • inhibiting the entry of a Hepatitis C virus into a cell may include decreasing the number of viral entries into the population of cells relative to the absence of an effective amount of a substituted fused ring cycloindole derivative.
  • a method of inhibiting infection of a cell by a Hepatitis C virus includes contacting the cell and/or the Hepatitis C virus with an effective amount of a substituted fused ring cycloindole derivative disclosed above.
  • the cell may be in vitro, in situ, or in vivo. In some embodiments, the cell forms part or a tissue, organ, or organism.
  • the cell may be, or derive from, a mammalian cell such as a primate cell (e.g. a human cell).
  • “Inhibiting infection in a cell by a Hepatitis C virus,” as used herein, includes preventing infection of a cell, arresting infection of a cell, or decreasing the number of infections in a population of cells relative to the absence of an effective amount of a substituted fused ring cycloindole derivative.
  • a method of treating a disease in a subject caused by a Hepatitis C viral infection includes administering to the subject an effective amount of a substituted fused ring cycloindole derivative disclosed above.
  • the effective amount in the context of treating a disease is a therapeutically effective amount.
  • the disease caused by Hepatitis C viral infection is a cell
  • Hepatitis C is a disease caused by the hepatitis C virus (HCV) affecting the liver. Chronic infection may cause inflammation of the liver, also referred to as chronic hepatitis. Chronic hepatitis can cause scarring of the liver (fibrosis), and advanced scarring (cirrhosis). In some instances, liver failure or other complications of cirrhosis may develop such as liver cancer.
  • HCV hepatitis C virus
  • the Hepatitis C is Acute Hepatitis C. Acute Hepatitis C refers to the first 6 months after infection with HCV.
  • the Hepatitis C is Chronic Hepatitis C. Chronic hepatitis C refers to infection with the hepatitis C virus persisting for more than six months.
  • the substituted fused ring cycloindole derivative is provided in a pharmaceutical formulation (see below).
  • the substituted fused ring cycloindole derivatives utilized in the pharmaceutical method of the invention are administered at an initial dosage of about 0.001 mg/kg to about 1000 mg/kg daily.
  • a daily dose range of about 0.1 mg/kg to about 100 mg/kg is more typical.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the modulator being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the modulator. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day.
  • Compounds useful in inhibiting the entry of a Hepatitis C virus into a cell or inhibiting infection of Hepatitis C virus in a cell may be tested using any appropriate assay system.
  • One useful system includes the use of an infectious Hepatitis C viral clone or Hepatitis C pseudoparticle containing a detection gene that produces a detectable gene product.
  • the gene product may be detectable, for example, using a nucleic acid detection technique (e.g. detectable probes or PCR), light detection (e.g. luciferase or green fluorescent protein), or the like.
  • One particularly useful detection system includes a luciferase gene.
  • the ability of the Hepatitis C viral clone or Hepatitis C pseudoparticle may be tested in the presence and the absence of the test compound to determine the effect of the compound on viral entry into the cell. See, for example, Examples 38 and 39 below.
  • certain compounds may be further evaluated for their ability to treat Hepatitis C in animal (e.g. human) models in need of such treatment. Animal models may be constructed by infecting an animal with the Hepatitis C virus. The test compound may be administered to the animal before, after, or simultaneous with Hepatitis C viral (or appropriate model) contact.
  • Animal models containing cDNA derived from hepatitis C are generally known in the art and may also be used to evaluate test compounds. See, for example, U.S. Patent no. 6,429,355 and Guha et al., J. Hepatology, vol. 36, pp. 447-449 (2002).
  • compositions including a substituted fused ring cycloindole derivative in admixture with a pharmaceutically acceptable excipient.
  • pharmaceutical compositions include the pharmaceutically acceptable salts of the substituted fused ring cycloindole derivatives described above.
  • the compounds of the invention can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy (20 th ed.) Lippincott, Williams & Wilkins (2000).
  • the compounds disclosed herein are effective over a wide dosage range.
  • the exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • salts are generally well known to those of ordinary skill in the art, and may include, by way of example but not limitation, acetate, benzenesulfonate, besylate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carnsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicy
  • compositions may be found in, for example, Remington: The Science and Practice of Pharmacy (20 th ed.) Lippincott, Williams & Wilkins (2000).
  • Preferred pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, pamoate (embonate), phosphate, salicylate, succinate, sulfate, or tartrate.
  • agents may be formulated into liquid or solid dosage forms and administered systemically or locally.
  • the agents may be delivered, for example, in a timed- or sustained- low release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20 th ed.) Lippincott, Williams & Wilkins (2000).
  • Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articullar, intrasternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.
  • the agents of the invention may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • compositions of the present invention in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection.
  • the compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject (e.g. patient) to be treated.
  • the agents of the invention may also be formulated by methods known to those of skill in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances such as, saline, preservatives, such as benzyl alcohol, absorption promoters, and fluorocarbons.
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
  • compositions for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl-cellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone).
  • disintegrating agents may be added, such as the cross- linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs).
  • PEGs liquid polyethylene glycols
  • stabilizers may be added.
  • additional therapeutic agents which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention.
  • chemotherapeutic agents or other antiproliferative agents may be combined with the inhibitors of this invention to treat proliferative diseases and cancer.
  • known chemotherapeutic agents include, but are not limited to, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.
  • these additional agents may be administered separately, as part of a multiple dosage regimen, from the composition.
  • these agents may be part of a single dosage form, mixed together with the compound in a single composition.
  • 1,2,3,4,-tetrahydrocarbazoles may also be prepared from anilines and 2-halocylohexanones (see, for example, U.S. Pat. Nos. 3,752,823 and 3,687,969).
  • 1,2,3,4,-tetrahydrocarbazol-l-ones may be prepared by the condensation of 2- (hydroxymethylene)cylohexenones with diazotized anilines (see U.S. Pat. App.
  • Example 1 9-[3-(3,5-Dimethyl-piperazin-l-yl)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester a) ⁇ J ⁇ -tetrahydro-SH-carbazole-S-carboxylic acid [0112]
  • a sample of 4-hydrazino benzoic acid hydrochloride (5 g, 26.5 mmol), cyclo hexanone (2.74 ml, 26.5 mmol), were taken in 40 ml of AcOH and the mixture was refluxed overnight. The mixture was cooled to room temperature and kept in refrigerator for 2 hrs.
  • the 1 H NMR showed a 2: 1 mixture of 9-(3-chloro- propy ⁇ - ⁇ j ⁇ -tetrahydro-SH-carbazole-S-carboxylic acid methyl ester and 9-(3-bromo- ⁇ ropyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester, which was used for next step without separation.
  • the TLC of mixture showed complete consumption of starting material and a new spot with lower R f value.
  • the mixture was diluted with EtOAc (50 ml), washed with H 2 O (20 ml) and satbrine solution (20 ml).
  • the organic layer was separated, dried over anhyd.MgSO 4 , solvents removed in vacuo and the crude was purified by column chromatography, using CH 2 Cl 2 MeOH as eluents, to obtain 0.17 g of the product.
  • Example 5 9-[3-(4-Ethoxycarbonyl-piperazin-l -yl)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester [0123]
  • the compound was prepared, as described for example Id, from 9-(3-chloro- propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester and piperazine-1- carboxylic acid ethyl ester.
  • 3-carboxylic acid methyl ester [0124] The compound was prepared, as described for example Id, from 9-(3-chloro- propy ⁇ - ⁇ -dimethyl- ⁇ Jj ⁇ -tetrahydro-SH-carbazole-S-carboxylic acid methyl ester and c ⁇ -3,5-dimethyl piperzine.
  • the reaction mixture was diluted with CH 2 Cl 2 (50 ml), washed with 0.5 N HCl (20 ml), H 2 O (20 ml) and sat.NaCHO 3 (20 ml).
  • the organic layer was separated, dried over anhyd. MgSO 4 , the solvents were removed in vacuo and the residue was purified by column chromatography to obtain 0.033 g of the product.
  • Example 8 5-Ethyl-2-(propane-l-sulfonyl)-2,3,4,5-tetrahydro-pyrido[4,3- ⁇ ]indole-8-carboxylic acid methyl ester [0130] The compound was prepared as described for example 7e, using 1 -propane sulfonyl chloride.
  • the compound was prepared, as described for example Id, from 9-(3-chloro- propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester and 2-oxo piperazine.
  • Example 13 5 9-(3-Chloro-propyl)-6,6-diemthyl-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0135] The reaction was carried out, as described for example 12, using 6,6-diemthyl- ⁇ -tetrahydro-SH-carbazole-S-carboxylic acid methyl ester and l-bromo-3-chloro propane.
  • the mixture was stirred at 0 0 C for 1 hr, brought to r.t, in about 3 hrs, filtered and air-dried overnight.
  • the solids were broken up and dried further under high vacuo to obtain 3.5 g of product, contaminated with tin salts, which was used further without purification.
  • the compound was prepared, as described for example 12, from 6,7,8,9- tetrahydro-5H-carbazole-3-carboxylic acid methyl ester and 4-[2-(toluene-4sulfonyloxy)- ethyl]-piperidine-l -carboxylic acid tetr-butyl ester.
  • Example 17 9-(3-Imidazol-l-yl-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester
  • the compound was prepared, as described for example Id, from 9-(3-chloro- propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester and Imidazole, using 3 equiv. Of K 2 CO 3 as a base.
  • the compound was prepared, as described for example 14a, from 4-methoxy phenylhydrazine hydrochloride and 4,4-dimethyl cyclohexanone.
  • reaction mixture was diluted with EtOAc (50 ml) washed with H 2 O (2 x 20 ml), and sat.NaHCO 3 solution (20 ml).
  • the organic layer was separated, dried over anhyd.MgSO 4 , solvents removed in vacuo and the crude was purified by column chromatography, using CH 2 Cl 2 /Me0H as eluents, to obtain 0.06 g of the product.
  • Example 26 9-Isopropyl-6,6-diemthyl-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0154] The compound was prepared, as described for example 3c, from 6,6-diemthyl-
  • Example 29 9-Ethyl-6,6-dimethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile. a) ⁇ j ⁇ -Dimethyl- ⁇ -tetrahydro-SH-carbazole-S-carbonitrile. [0157] The compound was prepared, as described for example 14a, from 4-cyano phenylhydrazine hydrochloride and 4,4-dimethyl cyclohexanone.
  • the TLC of mixture showed complete consumption of starting material and a new spot with higher Rf value.
  • the mixture was diluted with EtOAc (50 ml), washed with H 2 O (20 ml) and sat. brine solution (20 ml).
  • the organic layer was separated, dried over anhyd. MgSO 4 , solvents removed in vacuo and the crude was purified by column chromatography, using CH 2 Cl 2 /Me0H as eluents, to obtain 0.1 g of the product.
  • the compound was prepared, as described for example 12, from 4-chloro-6,7,8,9- tetrahydro-5H-carbazole-3-carboxylic acid methyl ester and l-bromo-3-chloro propane.
  • HCV pseudoparticles (see Voisset, C, and Dubuisson, J, Biology of the Cell, 96, (2004) 413-420) incorporating a lentiviral backbone harboring the luciferase gene were used to assay for HCV entry as follows. Huh7 cells seeded in 96-well plates were incubated with a concentration range of the tested compounds in the presence of 2% DMSO for 1 hour prior to infection by HCV or VSV pseudoparticles. Three days post infection, luciferase was evaluated by a standard luminescence assay.
  • VSV-pseudoparticles Compounds that inhibit HCV pseudoparticle entry and did not block infections mediated by VSV pseudoparticles were judged to be specific. Compounds that reduced luciferase values for VSV-pseudoparticles are considered not specific for HCV and most likely affect a general viral entry pathway or act on the HIV backbone. All the compounds listed in Table 1 were found to significantly reduce viral entry as measured by the pseuodoparticle/luciferase assay, and they were also found to be specific when assayed against the inhibitory effect on VSV pseudoparticles.
  • HCV2aCh-Rluc is a monocistronic, full- length HCV2a genome that expresses Renilla luciferase (Rluc).
  • the HCV2a genome was derived from an infectious HCV2a J6/JFH chimeric virus.
  • FMDV 2A and ubiquitin monomer (Ubi) sequences were fused to the C-terminus of Rluc while the C-terminus of Ubi was fused to the start of the HCV polyprotein.
  • HCV2aCh-Rluc RNA was generated by in vitro transcription of Xbal-linealized DNA templates using the T7 MEGAscript kit (Ambion), followed by DNase treatment and column purification. Subconfiuent Huh7 cells were trypsinized, harvested by centrifugation, washed twice with PBS and resuspended in cytomix at 5x10 6 cells/ml. Five ⁇ g of HCV2aCh-Rluc RNA was mixed with 0.4 ml of cells in a 2 mm gap cuvette and electroporated (27OkV, 960 ⁇ F). [0173] Electroporated cells were plated in T75 cell culture flasks.
  • the media was replaced with fresh media.
  • the supernatant was harvested and the cells were trypsinized and replated. After every 3-4 days of incubation, the supernatants were harvested and cells were replated.
  • B. Luciferase assay (Infection assay): Huh7 cells were incubated with HCV2aCh- Rluc viral supernatant in the presence of a compound of the invention or a control compound for 3 days. The supernatants were removed from the cells. The cells were washed with PBS twice prior to the addition of 100 ⁇ l of passive lysis buffer (Promega). 50 ⁇ l of lysate was mixed with 100 ⁇ l of Renilla luciferase substrate (Promega). Luciferase activity was measured within 10 minutes using a luminometer. Table 2 below shows selected compounds of the invention that prevented entry of HCV into cells with an IC50 of less than 35OnM. Table 3 shows additional compounds that exhibited inhibition of HCV entry.
  • the mixture was diluted with 100 ml Of CH 2 Cl 2 , washed with IN HCl (2x25 ml), H 2 O (2x25 ml) and sat. NaHCO 3 solution (2x25 ml).
  • the organic layer was separated, dried over anhyd.MgSO 4 , solvents removed in vacuo and the residue was dried under high vacuo to obtain 0.8 g of the product which was used for next step without purification.
  • Example 64b To a stirred solution of, example Ib, ⁇ J ⁇ -tetrahydro-SH-carbazole-S-carboxylic acid methyl ester (0.137 g, 0.6 mmol), in 2 ml of dry DMF, NaH (60% suspension in oil, 0.036 g, 0.9 mmol) was added portion wise. After stirring the reaction mixture for 15 min at r.t, 4-[(3-chloropropyl)sulfonyl]morpholine (0.0.273 g, 1.2 mmol), was added followed by the addition of TBAI (0.664 g, 1.8 mmol) and the reaction mixture was stirred, under N 2 , at 60 0 C, overnight.
  • TBAI 0.664 g, 1.8 mmol
  • the compound was prepared, as described for example 9-(3-chloro-propyl)- ⁇ Jj ⁇ -tetrahydro-SH-carbazole-S-carboxylic acid methyl ester, from 2,3,4,9-tetrahydro- lH-carbazole-6-carbonitrile and l-bromo-3-chloropropane.
  • Example 65c 9- ⁇ 3-[(2i?,65)-2,6-Dimethylmo ⁇ holin-4-yl]propyl ⁇ -2,3,4,9-tetrahydro-lH-carbazole-6- carbonitrile [0217]
  • the compound was prepared, as described for example 9-[3-(3,5-dimethyl- piperazin-l-yrj-propy ⁇ - ⁇ -tetrahydro-SH-carbazole-S-carboxylic acid methyl ester, from 9-(3-chloropropyl)-2,3,4,9-tetrahydro-lH-carbazole-6-carbonitrile and cis-2,6- dimethyl morpholine.
  • the compound was prepared, as described for 9- ⁇ 3-[(4,6-dimethoxypyrimidin-2- yl)amino]propyl ⁇ -N-methyl-2,3,4,9-tetrahydro-lH-carbazole-6-carboxamide, from 9- ⁇ 3- [(4,6-dimethoxypyrimidin-2-yl)amino]propyl ⁇ -2,3,4,9-tetrahydro-lH-carbazole-6- carboxylic acid and dimethylamine hydrochloride.
  • the compound was prepared, as described for example 4-[(3- chloropropyl)sulfonyl]morpholine from 3-chloropropane sulfonylchloride and dimethylamine hydrochloride.
  • Example 69b Methyl 9-[3-(dimethylsulfamoyl)propyl]-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate [0223] The compound was prepared, as described for example methyl 9-[3-(morpholin-4- ylsulfonyl)propyl]-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate, from 6,7,8,9-tetrahydro- 5H-carbazole-3-carboxylic acid methyl ester and 3-chloro-N,N-dimethylpropane-l- sulfonamide.
  • the compound was prepared, as described for example 9- ⁇ 3-[(4,6- dimethoxypyrimidin-2-yl)amino]propyl ⁇ -N-methyl-2,3,4,9-tetrahydro-lH-carbazole-6- carboxamide, from methyl 9-[3-(dimethylsulfamoyl)propyl]-2,3,4,9-tetrahydro-lH- carbazole-6-carboxylate and methylamine hydrochloride.
  • reaction mixture was diluted with CH 2 Cl 2 , washed sequentially with IN HCl (25 ml), H 2 O (25 ml) and sat. NaHCO 3 (25 ml) solution.
  • the organic layer was separated, dried over anhyd.MgSO 4 , solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.14g of the product.
  • the compound was prepared, as described for example methyl 9-(3- ⁇ [(3,5- difluorophenyl)sulfonyl]amino ⁇ propyl)-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate, from 2,5-dimethylbenzene sulfonylchloride.
  • the compound was prepared, as described for example 3-chloro-N,N- dimethylpropane-1 -sulfonamide, from azetidine.
  • the compound was prepared, as described for example 9-[3-tert- butoxycarbonylamino-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester, from 3 - [(terr-butoxycarbonyl)amino]butyl 4-methylbenzenesulfonate.
  • the compound was prepared, as described for example 9- ⁇ 3-[(4,6- diethylpyrimidin-2-yl)oxy]propyl ⁇ -6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole, from 9-(3-chloropropyl)-2,3,4,9-tetrahydro-lH-carbazole-6-carbonitrile and 2-oxo-4,6- dimethylpyrimidine hydrochloride.
  • the compound was prepared, as described for example methyl 9-[3-(morpholin-4- ylsulfonyl)propyl]-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate, from 2,3,4,9-tetrahydro- 1 H-carbazole-6-carbonitrile and 3 -chloro-NJV-dimethylpropane- 1 -sulfonamide.
  • the compound was prepared, as described for example methyl 9-[3-(morpholin-4- ylsulfonyl)propyl]-2,3 ,4,9-tetrahydro- 1 H-carbazole-6-carboxylate, from 2,3 ,4,9-tetrahydro- lH-carbazole-6-carbonitrile and 4-[(3-chloropropyl)sulfbnyl]morpholine.
  • the compound was prepared, as described for example 9- ⁇ 3-[(4,6- diethylpyrimidin-2-yl)oxy]propyl ⁇ -6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole, from 2,3,4,9-tetrahydro-lH-carbazole-6-carbonitrile and 2-amino-4,6-dimethoxypyrimidine.
  • the compound was prepared, as described for example 9- ⁇ 3-[(4,6- diethylpyrimidin-2-yl)oxy]propyl ⁇ -6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole, from 9-(3-chloropropyl)-6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole and 2-oxo-4,6- dimethoxypyrimidine.
  • the compound was prepared, as described for example methyl 9- [2 -(I H- benzimidazol-2-yl)ethyl]-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate, from methyl 9-(3- oxopropyl)-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate and 4,5-dimethyl-l,2- phenylenediamine.
  • N-(9- ⁇ 3-[(4,6-Dimethylpyrimidin-2-yl)oxy]propyl ⁇ -2,3,4,9-tetrahydro-lH-carbazol-6- yl)methanesulfonamide [0252] To a stirred solution of 9- ⁇ 3-[(4,6-dimethylpyrimidin-2-yl)oxy]propyl ⁇ -2,3,4,9- tetrahydro-lH-carbazol-6-amine (0.525 mmol), in 2ml of dry CH 2 Cl 2 , NEt 3 was added, at 0 °C, followed by addition of methanesulfonyl chloride (0.049 ml, 0.63 mmol).
  • the compound was prepared, as described for example N-(9- ⁇ 3-[(4,6- dimethylpyrimidin-2-yl)oxy]propyl ⁇ -2,3 ,4,9-tetrahydro- 1 H-carbazol-6- yl)methanesulfonamide, using Ac 2 O and pyridine.
  • the compound was prepared, as described for example methyl 9-(3,3- diethoxypropyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-6-carboxylate, from 6-(methylsulfonyl)- 2,3 ,4,9-tetrahydro- 1 H-carbazole. ,3,4-tetrahydro-9H-carbazol-9-yl]propanal
  • the compound was prepared, as described for example methyl 9-(3-oxopropyl)- 2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate , from 9-(3,3-diethoxypropyl)-6- (methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole.
  • Example 87c 9-[2-(lH-Benzimidazol-2-yl)ethyl]-6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole [0256]
  • the compound was prepared, as described for example methyl 9-[2-(1H- benzimidazol-2-yl)ethyl]-2,3 ,4,9-tetrahydro- 1 H-carbazole-6-carboxylate, from 3-[6- (methylsulfonyl)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]propanal.
  • the compound was prepared, as described for example methyl 9-[2-(1H- benzimidazol-2-yl)ethyl]-2,3,4,9-tetrahydro-l H-carbazole-6-carboxylate, starting from 6- bromo-2,3,4,9-tetrahydro-lH-carbazole.
  • the compound was prepared, as described for example 9-(3-chloro-propyl)- 6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester, from benzyl 1,3,4,5- tetrahydro-2H-pyrido[4,3-&]indole-2-carboxylate and l-bromo-3-chloropropane.
  • 6-Bromo-9- ⁇ 3 -[(3 ,5 -difluoro ⁇ henyl)sulfanyl]propyl ⁇ - 1 ,2,3 ,9-tetrahydro-4H-carbazol-4-one [0264] To a stirred solution of 6-bromo- 1 ,2,3 ,9-tetrahydro-4H-carbazol-4-one (0.264 g, 1 mmol), in 2 ml of dry DMF, NaH (60% suspension in oil, 0.05 g, 1.2 mmol) was added portion wise.
  • the compound was prepared, as described for example 6-bromo-9- ⁇ 3-[(3,5- difluorophenyl)sulfanyl]propyl ⁇ - 1 ,2,3 ,9-tetrahydro-4H-carbazol-4-one, from 6- (methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole.
  • the TLC of mixture showed completion of starting material and a new spot with higher R/ value.
  • the mixture was diluted with EtOAc (50 ml), washed with with H 2 O (25 ml) and sat.brine (25 ml) solution.
  • the organic layer was dried over anhyd. MgSO 4 , solvents removed in vacuo and the crude product was purified by column chromatography to obtain 0.12 g of pure product.
  • the yellow oil was column purified on silica with dichloromethane wit h 1% methanol to give 9- ⁇ 3-[(4,6-dimethoxypyrimidin-2- yl)amino]propyl ⁇ -2,3,4,9-tetrahydro-l ⁇ -carbazole-6-carboxamide, RF 0.2 on silica with 2:1 dichloromethane/ethyl acetate.
  • intermediate 101a 100 mg was reacted with 2- methoxyethylamine, 45 ul, to provide 9- ⁇ 3-[(4,6-dimethylpyrimidin-2-yl)oxy]propyl ⁇ -N- (2-methoxyethyl)-2, 3, 4,9-tetrahydro-l H-carbazole-6-carboxamide.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés de cycloindole à cycle condensé substitué utiles, entre autre, dans la lutte contre l’infection par l’hépatite C et contre son entrée dans les cellules.
PCT/US2009/034148 2008-02-13 2009-02-13 Dérivés de cycloindoles à cycle condensé substitué et leurs procédés d’utilisation Ceased WO2009103022A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2824608P 2008-02-13 2008-02-13
US61/028,246 2008-02-13

Publications (1)

Publication Number Publication Date
WO2009103022A1 true WO2009103022A1 (fr) 2009-08-20

Family

ID=40957290

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/034148 Ceased WO2009103022A1 (fr) 2008-02-13 2009-02-13 Dérivés de cycloindoles à cycle condensé substitué et leurs procédés d’utilisation

Country Status (1)

Country Link
WO (1) WO2009103022A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014524448A (ja) * 2011-08-24 2014-09-22 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃ型肝炎阻害化合物
JP2014524447A (ja) * 2011-08-24 2014-09-22 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃ型肝炎阻害化合物
US9056877B2 (en) 2011-07-19 2015-06-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9181221B2 (en) 2010-05-21 2015-11-10 Infinity Pharmaceuticals, Inc. Chemical compounds, compositions and methods for kinase modulation
US9206182B2 (en) 2009-07-15 2015-12-08 Intellikine Llc Substituted isoquinolin-1(2H)-one compounds, compositions, and methods thereof
US9481667B2 (en) 2013-03-15 2016-11-01 Infinity Pharmaceuticals, Inc. Salts and solid forms of isoquinolinones and composition comprising and methods of using the same
US9527847B2 (en) 2012-06-25 2016-12-27 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
US9546180B2 (en) 2011-08-29 2017-01-17 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9822131B2 (en) 2008-01-04 2017-11-21 Intellikine Llc Certain chemical entities, compositions and methods
USRE46621E1 (en) 2011-01-10 2017-12-05 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US11110096B2 (en) 2014-04-16 2021-09-07 Infinity Pharmaceuticals, Inc. Combination therapies
US11147818B2 (en) 2016-06-24 2021-10-19 Infinity Pharmaceuticals, Inc. Combination therapies
US11414423B1 (en) 2019-02-27 2022-08-16 The Regents Of The University Of California Substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles for treating brain disorders
CN114957293A (zh) * 2022-05-30 2022-08-30 常州大学 用于特异性识别胰岛素的基于鸟嘌呤的花菁探针及其制备方法
US12213983B2 (en) 2012-11-01 2025-02-04 Infinity Pharmaceuticals, Inc. Treatment of cancers using PI3 kinase isoform modulators
US12295959B2 (en) 2021-12-15 2025-05-13 Delix Therapeutics, Inc. Phenoxy and benzyloxy substituted psychoplastogens and uses thereof
US12343337B2 (en) 2016-09-29 2025-07-01 The Regents Of The University Of California Compounds for increasing neural plasticity

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004060308A2 (fr) * 2002-12-27 2004-07-22 Chiron Corporation Thiosemicarbazones antiviraux et immunostimulants
WO2005037791A1 (fr) * 2003-10-15 2005-04-28 Chiron Corporation Compositions et procedes d'inhibition virale
WO2006121466A2 (fr) * 2004-11-22 2006-11-16 Smithkline Beecham Corporation Inhibiteurs du virus de l'hepatite c

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004060308A2 (fr) * 2002-12-27 2004-07-22 Chiron Corporation Thiosemicarbazones antiviraux et immunostimulants
WO2005037791A1 (fr) * 2003-10-15 2005-04-28 Chiron Corporation Compositions et procedes d'inhibition virale
WO2006121466A2 (fr) * 2004-11-22 2006-11-16 Smithkline Beecham Corporation Inhibiteurs du virus de l'hepatite c

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11433065B2 (en) 2008-01-04 2022-09-06 Intellikine Llc Certain chemical entities, compositions and methods
US9822131B2 (en) 2008-01-04 2017-11-21 Intellikine Llc Certain chemical entities, compositions and methods
US9216982B2 (en) 2008-01-04 2015-12-22 Intellikine Llc Certain chemical entities, compositions and methods
US9655892B2 (en) 2008-01-04 2017-05-23 Intellikine Llc Certain chemical entities, compositions and methods
US9522146B2 (en) 2009-07-15 2016-12-20 Intellikine Llc Substituted Isoquinolin-1(2H)-one compounds, compositions, and methods thereof
US9206182B2 (en) 2009-07-15 2015-12-08 Intellikine Llc Substituted isoquinolin-1(2H)-one compounds, compositions, and methods thereof
US9738644B2 (en) 2010-05-21 2017-08-22 Infinity Pharmaceuticals, Inc. Chemical compounds, compositions and methods for kinase modulation
US9181221B2 (en) 2010-05-21 2015-11-10 Infinity Pharmaceuticals, Inc. Chemical compounds, compositions and methods for kinase modulation
USRE46621E1 (en) 2011-01-10 2017-12-05 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US11312718B2 (en) 2011-01-10 2022-04-26 Infinity Pharmaceuticals, Inc. Formulations of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one
US9840505B2 (en) 2011-01-10 2017-12-12 Infinity Pharmaceuticals, Inc. Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1 (2H)-one and methods of use thereof
US10550122B2 (en) 2011-01-10 2020-02-04 Infinity Pharmaceuticals, Inc. Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one and methods of use thereof
US9605003B2 (en) 2011-07-19 2017-03-28 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9056877B2 (en) 2011-07-19 2015-06-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
JP2014524448A (ja) * 2011-08-24 2014-09-22 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃ型肝炎阻害化合物
EP2748167A4 (fr) * 2011-08-24 2015-01-14 Boehringer Ingelheim Int Composés inhibiteurs de l'hépatite c
JP2014524447A (ja) * 2011-08-24 2014-09-22 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃ型肝炎阻害化合物
US9546180B2 (en) 2011-08-29 2017-01-17 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9527847B2 (en) 2012-06-25 2016-12-27 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
US12213983B2 (en) 2012-11-01 2025-02-04 Infinity Pharmaceuticals, Inc. Treatment of cancers using PI3 kinase isoform modulators
US9481667B2 (en) 2013-03-15 2016-11-01 Infinity Pharmaceuticals, Inc. Salts and solid forms of isoquinolinones and composition comprising and methods of using the same
US11944631B2 (en) 2014-04-16 2024-04-02 Infinity Pharmaceuticals, Inc. Combination therapies
US11110096B2 (en) 2014-04-16 2021-09-07 Infinity Pharmaceuticals, Inc. Combination therapies
US11147818B2 (en) 2016-06-24 2021-10-19 Infinity Pharmaceuticals, Inc. Combination therapies
US12343337B2 (en) 2016-09-29 2025-07-01 The Regents Of The University Of California Compounds for increasing neural plasticity
US11414423B1 (en) 2019-02-27 2022-08-16 The Regents Of The University Of California Substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles for treating brain disorders
US12325710B2 (en) 2019-02-27 2025-06-10 The Regents Of The University Of California Substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles for treating brain disorders
US12295959B2 (en) 2021-12-15 2025-05-13 Delix Therapeutics, Inc. Phenoxy and benzyloxy substituted psychoplastogens and uses thereof
CN114957293A (zh) * 2022-05-30 2022-08-30 常州大学 用于特异性识别胰岛素的基于鸟嘌呤的花菁探针及其制备方法

Similar Documents

Publication Publication Date Title
WO2009103022A1 (fr) Dérivés de cycloindoles à cycle condensé substitué et leurs procédés d’utilisation
AU2018203354B2 (en) Hepatitis B antiviral agents
CN103562208B (zh) 三环促旋酶抑制剂
CS413791A3 (en) Pyrrole-amidine antitumor preparations
CN102216279B (zh) 一类含有嘧啶酮苯基的化合物、其药物组合物及其制备方法和用途
KR20100081294A (ko) 간염과 같은 바이러스성 감염 치료용 이미다조[1,2-ａ] 피라진 화합물
JP6306035B2 (ja) 医薬組成物のためのスルホキシミン置換キナゾリン
WO2006135383A2 (fr) Indazoles
JP2009513640A (ja) Ｈｉｖインテグラーゼインヒビター
JP7717704B2 (ja) Ｂ型肝炎ウイルスのスピロ環式阻害剤
EP3985010A1 (fr) Inhibiteurs spirocycliques du virus de l'hépatite b
NZ724493B2 (en) Hepatitis B Antiviral Agents
HK1197550B (en) Hepatitis b antiviral agents
HK1197550A (en) Hepatitis b antiviral agents

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09710921

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC EPO F1205A DATED 01/02/2011

122 Ep: pct application non-entry in european phase

Ref document number: 09710921

Country of ref document: EP

Kind code of ref document: A1