WO2009103022A1 - Derivatives of substituted fused ring cycloindoles and methods of their use - Google Patents

Derivatives of substituted fused ring cycloindoles and methods of their use Download PDF

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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
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Prior art keywords
substituted
unsubstituted
tetrahydro
compound
carbazole
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PCT/US2009/034148
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French (fr)
Inventor
James E. Macdonald
Andrew Jeremiah Jackson
Gopi Kumar Mittapalli
Fang Zhao
Cornelis A. Rijnbrand
Haekyung Lee
Jing Zhang
Flossie Wong-Staal
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Itherx Pharmaceuticals, Inc.
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Publication of WO2009103022A1 publication Critical patent/WO2009103022A1/en

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    • 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.

Abstract

Disclosed herein are derivatives of substituted fused ring cycloindole useful, inter alia, in combating Hepatitis C infection and entry into cells.

Description

DERIVATIVES OF SUBSTITUTED FUSED RING CYCLOINDOLES AND METHODS OF THEIR USE
BACKGROUND OF THE INVENTION
[0001] Hepatitis C is caused by infection with Hepatitis C Virus (HCV), which is carried by more than 100 million people worldwide. 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.
[0002] There are currently four FDA approved Hepatitis C combination therapies: Intron A and Rebetol (Interferon Alpha-2b and ribavirin, respectively); Roferon A (Interferon Alpha-2a) and Ribavirin ; Pegasys and Copegus (PEGylated Interferon Alpha-2a and ribavirin, respectively); and PEG-Intron and Rebetol (PEGylated Interferon Alpha-2b and ribavirin, respectively). These are in addition to the five FDA approved monotherapies: Infergen (Interferon alfacon-1), Roferon A, Intron A, PEG-Intron, and Pegasys. Generally, 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.
[0003] The currently FDA approved Hepatitis C treatments are generally accepted to be effective in less than half of HCV infections. If not cured, 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.
[0004] Despite significant efforts, no efficacious vaccine has been developed that can protect against HCV. During infection, the host produces a wide array of antibodies targeting viral structural and nonstructural proteins. However, these antibodies fail to clear the virus. In addition, the E2 outer membrane protein contains two hyper- variable regions that most likely contribute to the virus's ability to escape clearance by the immune system.
[0005] Thus, a need clearly exists to develop more effective treatments against HCV. Provided herein are compounds useful for these and other purposes. BRIEF SUMMARY OF THE INVENTION
[0006] In one aspect, derivatives of 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. In some embodiments, the substituted fused ring cycloindole derivative has the formula:
Figure imgf000003_0001
[0007] In Formula (I), ring A is a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. L1 is substituted or unsubstituted alkylene. L2 is a bond, - O-L3-, -S(O)n-L3-, -NR6-L3-, -NR6C(O)-L3-, -C(O)N(R6)-L3-, -NR6S(O)2-L3-, or -S(O)2NR6- L3-, L3 is a bond, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene and n is an integer from 0 to 2. R1, R2, R3 and R4 are independently hydrogen, halogen, -CN, -S(O)2N(R7)(R8), -C(O)R9, -NR10-C(O)Rn, -NR12-C(O)-OR13, - C(O)NR14R15, -NR16S(O)2R17, -S(O)1R19, -NR20R21, -OR22, -C(NR20)-N(R21)-OR22, -C(O)OR23, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. The symbol t is an integer from 0 to 2. R5 is hydrogen, -CN, halogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and R23 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.
[0008] In another aspect, a method of inhibiting the entry of a Hepatitis C virus into a cell 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. [0009] In another aspect, 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.
[0010] In another aspect, a method of treating a disease in a subject caused by a Hepatitis C viral infection is provided. The method includes administering to the subject an effective amount of a substituted fused ring cycloindole derivative disclosed above.
DETAILED DESCRIPTION OF THE INVENTION I. Definitions
[0011] The abbreviations used herein have their conventional meaning within the chemical and biological arts.
[0012] Where 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., -CH2O- is equivalent to -OCH2-.
[0013] The term "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-C10 means one to ten carbons). Examples of 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. Examples of 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.
[0014] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH2CH2CH2CH2-. Typically, 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.
[0015] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, 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. Examples include, but are not limited to, -CH2-CH2-O-CH3, - CH2-CH2-NH-CH3, -CH2-CH2-N(CHa)-CH3, -CH2-S-CH2-CH3, -CH2-CH25-S(O)-CH3, - CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)- CH3, 0-CH3, -0-CH2-CH3, and -CN. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2- . For heteroalkylene groups, 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)2R'- represents both -C(O)2R'- and -R1C(O)2-. As described above, heteroalkyl groups, as used herein, 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 -SO2R'. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR1R 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.
[0016] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and
"heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3- cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl 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.
[0017] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(Ci-C4)alkyl" is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
[0018] The term "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. The term "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-isoquinolyl, 5- isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted 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.
[0019] For brevity, the term "aryl" when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "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).
[0020] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom. [0021] Each of the above terms (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.
[0022] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to: -OR', =0, =NR', =N-OR', -NR1R", -SR', -halogen, - SiR'R"R'", -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR1R", -NR11C(O)R', -NR'-C(O)NR"R"', -NR11C(O)2R1, -NR-C(NR1R11R11O=NR"", -NR-C(NR'R")=NR'", -S(O)R1, -S(O)2R1, -S(O)2NR1R", -NRSO2R', -CN and -NO2 in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R', R", R1" 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. When a compound of the invention includes more than one R group, for example, 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. When R1 and R11 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. For example, -NR1R" is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).
[0023] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: halogen, -OR1, -NR'R", -SR1, -halogen, -SiR1R11R"1, -OC(O)R1, -C(O)R1, -CO2R1, -CONR'R", -OC(O)NR1R", -NR11C(O)R1, -NR^C(O)NR11R"1, -NR11C(O)2R', -NR-C(NR'R"R'")=NR"", -NR-C(NR1R1O=NR"1, -S(O)R', -S(O)2R', -S(O)2NR1R", -NRSO2R1, -CN and -NO2, -R1, -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(C]-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R1, R", R1" and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R1" and R"1' groups when more than one of these groups is present.
[0024] 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. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR1-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- 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. Alternatively, 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-X1-(C'1R'")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)2NR1-. The substituents R, R1, R" and R1" 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.
[0025] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
[0026] A "substituent group," as used herein, means a group selected from the following moieties:
[0027] (A) -OH, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
[0028] (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from: [0029] (i) oxo, -OH, -NH2, -SH, -CN, -CF3, -NO2, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
[0030] (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from:
[0031] (a) oxo, -OH, -NH2, -SH, -CN, -CF3, -NO2, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
[0032] (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, substituted with at least one substituent selected from oxo, -OH, -NH2, -SH, -CN, -CF3, -NO2, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.
[0033] 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 C1- C20 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 C4-C8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4 to 8 membered heterocycloalkyl.
[0034] 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-C8 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 C5- C7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7 membered heterocycloalkyl.
[0035] The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or 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.
[0036] Thus, 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.
[0037] 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.
[0038] In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
[0039] 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.
[0040] 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.
[0041] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
[0042] The terms "a" or "an," as used in herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted Ci-C2O alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
[0043] The symbol * denotes a point of attachment of a moiety to the remainder of a compound. [0044] 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. Generally 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.
[0045] The terms "treat," "treating" or "treatment," and other grammatical equivalents as used herein, 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. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the 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.
II. Derivatives of Substituted Fused Ring Cycloindoles
[0046] In one aspect, derivatives of substituted fused ring cycloindoles (also referred to herein as a 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. In some embodiments, the substituted fused ring cycloindole derivative has the formula:
Figure imgf000013_0001
[0047] In Formula (I), ring A is a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. L1 is substituted or unsubstituted alkylene. L2 is a bond, - O-L3-, -S(O)n-L3-, -NR6-L3-, -NR6C(O)-L3-, -C(O)N(R6)-L3-, -NR6S(O)2-L3-, or -S(O)2NR6- L -. L is a bond, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene and n is an integer from 0 to 2. In some embodiments, ring A is a substituted or unsubstituted C3-C8 (e.g. C5 to C7) cycloalkyl, or substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl. L1 may be a substituted or unsubstituted Ci-C]0 alkylene. L3 may be a bond, substituted or unsubstituted C1-C1O 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.
[0048] R1, R2, R3 and R4 are independently hydrogen, halogen, -CN, -S(O)2N(R7)(R8), -C(O)R9, -NR10-C(O)Rπ, -NR12-C(O)-OR13, -C(O)NR14R15, -NR16S(O)2R17, -S(O)1R19, -NR20R21, -OR22, -C(NR20)-N(R21)-OR22, -C(O)OR23, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. The symbol t is an integer from 0 to 2.
[0049] In some embodiments, R1, R2, R3 and R4 are independently hydrogen, halogen, - CN, -S(O)2N(R7XR8), -C(O)R9, -NR^-C(O)R1 \ -NR12-C(O)-OR13, -C(O)NR14R15, - NR16S(O)2R17, -S(O)tR19, -NR20R21, -OR22, -C(NR20)-N(R21)-OR22, -C(O)OR23, substituted or unsubstituted Ci-C1O alkyl, or substituted or unsubstituted 2 to 10 membered heteroalkyl. In some embodiments, R3 is not hydrogen.
[0050] In some embodiments, R3 is halogen, -CN, -NR1 ^C(O)R1 ' , -C(O)NR14R15, -NR16S(O)2R17, -S(O)1R19, -C(N)-N-OR22, or -C(O)OR23. R1, R2 and R4 may independently be hydrogen. In certain embodiments, R1, R2 and R4 are hydrogen.
[0051] R5 is hydrogen, -CN, halogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R5 may also be hydrogen, CN, halogen, substituted or unsubstituted C3-C8 (e.g. C5 to C7) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C6 or C10 aryl, or substituted or unsubstituted 5, 6, 8, or 10 membered heteroaryl.
[0052] R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and R23 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. R6, R7, R8, R9, R10, R", R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and R23 may also independently be hydrogen, substituted or unsubstituted CI-C10 alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C3-C8 (e.g. C5 to C7) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C6 or Ci0 aryl, or substituted or unsubstituted 5 or 6 membered heteroaryl.
[0053] In some embodiments, ring A has the formula:
Figure imgf000014_0001
In Formula (II), X, Y and Z are independently a bond, substituted or unsubstituted C1-C3 alkylene, -N(R24)-, -O-, -S(O)n-, -S(O)2-N(R24)-, -N(R24)-S(O)2-N(R25)-, -C(O)-N(R24)-, - N(R24)-C(O)-,-C(O)-, or -C(R26R27)-. X, Y and Z do not combine, however, to form a substituted or unsubstituted phenyl.
[0054] R24 and R25 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. R24 and R25 may also independently be hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C3-C8 (e.g. C5 to C7) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C6 or Cio aryl, or substituted or unsubstituted 5 or 6 membered heteroaryl. [0055] R26 and R27 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. R26 and R27 may also independently be hydrogen, - CN, halogen, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C3-C8 (e.g. C5 to C7) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C6 or C 10 aryl, or substituted or unsubstituted 5 or 6 membered heteroaryl. In some embodiments, R26 is halogen. In other embodiments, R26 is F.
[0056] In some embodiments, at least two of X, Y and Z are not a bond. X and Z may independently be a bond, or substituted or unsubstituted C1-C3 alkylene. Y may be a bond, -N(R24)-, -O-, -S(O)n-, -S(O)2-N(R24)-, -N(R24)-S(O)2-N(R25)-, -C(O)-N(R24)-, -N(R24)- C(O)-, -C(O)-, or -C(R26R27)-. In some embodiments, Y is not a bond. Y may also be - CH(F)-,
-CF2-, -C(O)-, -C(O)-N(R24)-, -S(O)2-, -S(O)2-N(R24)-, or -N(R24)-S(O)2-N(R25)-.
[0057] In other embodiments, Ring A is a substituted or unsubstituted C5 to C7 cycloalkyl, or substituted or unsubstituted 5 to 7 membered heterocycloalkyl.
[0058] Ring A may also have the formula:
Figure imgf000016_0001
The formulae above are herein referred to as "ring A subgeneric formulae." In the ring A subgeneric formulae set forth above, 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.
[0059] R28 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. R28 may also be -CN, halogen, hydroxyl, substituted or unsubstituted C1-CiO alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C3-C8 (e.g. C5 to C7) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C6 or C10 aryl, or substituted or unsubstituted 5 or 6 membered heteroaryl. In some embodiments, when R28 is a substituent of a nitrogen atom (e.g. attached to a nitrogen atom of a ring), R28 is not halogen. In some embodiments, R28 is halogen. In other embodiments, R28 is F.
[0060] In some embodiments, ring A has the formula:
Figure imgf000017_0001
, wherein v, k, m, and R 28 are as defined above.
[0061] In other embodiments, ring A has the formula:
Figure imgf000017_0002
, wherein v, k, m, and R28 are as defined above.
[0062] In some embodiments of Formula (I), L1 is substituted or unsubstituted Ci to C12 alkylene. L1 may also be substituted or unsubstituted C1 to C8 alkylene. In other embodiments, L1 is substituted or unsubstituted C1 to C6 alkylene. L1 may also be C2 to C4 substituted or unsubstituted alkylene. In still other embodiments, L1 is substituted or unsubstituted Ci to C3 alkylene. L1 may also simply be unsubstituted alkylene.
[0063] L2 may be -O-L3-, -S(O)n-L3-, -NR6-L3, -S(O)2NR6-L3-, or -NR6S(O)2-L3-. In certain embodiments, L2 is -O-L3-, -S(O)n-L3-, or -NR6-L3. The symbol n may represent the integer 2. And in some embodiments, L3 is a bond.
[0064] R5 may be hydrogen, R29-substituted or unsubstituted cycloalkyl, R29-substituted or unsubstituted heterocycloalkyl, R29-substituted or unsubstituted aryl, or R29-substituted or unsubstituted heteroaryl, unsubstituted Ci to Ci o alkyl or unsubstituted 2 to 10 membered heteroalkyl. R29 is oxo, -CN, halogen, -OR30, -C(O)OR31, -NR32R33, R34-substituted or unsubstituted alkyl, R34-substituted or unsubstituted heteroalkyl, R34-substituted or unsubstituted cycloalkyl, R34-substituted or unsubstituted heterocycloalkyl, R34-substituted or unsubstituted aryl, or R34-substituted or unsubstituted heteroaryl. In some embodiments, R5 is substituted or unsubstituted aryl. In other embodiments, R5 is substituted or unsubstituted heteroaryl. In still other embodiments, R5 is substituted or unsubstituted heterocycloalkyl.
[0065] R30, R31, R32 and R33 are independently R35-substituted or unsubstituted alkyl, R35- substituted or unsubstituted heteroalkyl, R35-substituted or unsubstituted cycloalkyl, R35- substituted or unsubstituted heterocycloalkyl, R35-substituted or unsubstituted aryl, or R35- substituted or unsubstituted heteroaryl. R34 and R35 are independently unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
[0066] In some embodiments, R5 is hydrogen, R29-substituted or unsubstituted C3-C8 (e.g. C5 to C7) cycloalkyl, R29-substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, R29-substituted or unsubstituted C6 or C10 aryl, or R29- substituted or unsubstituted 5 to 10 membered (e.g. 5 or 6) membered heteroaryl.
[0067] R29 may be -CN, halogen, -OR30, -C(O)OR31, -NR32R33, R34-substituted or unsubstituted Ci-Cio alkyl, R34-substituted or unsubstituted 2 to 10 membered heteroalkyl, R34-substituted or unsubstituted C3-Cs (e.g. C5 to C7) cycloalkyl, R34substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, R34-substituted or unsubstituted Ce or C1O aryl, or R34-substituted or unsubstituted 5 or 6 membered heteroaryl. R30, R31, R32 and R33 may independently be R35-substituted or unsubstituted C1-C10 alkyl, R35-substituted or unsubstituted 2 to 10 membered heteroalkyl, R35-substituted or unsubstituted C3-C8 (e.g. C5 to C7) cycloalkyl, R35-substituted or unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, R35-substituted or unsubstituted C6 or Cio aryl, or R35-substituted or unsubstituted 5 or 6 membered heteroaryl.
[0068] R34 and R35 may independently be unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. R34 and R35 may also independently be unsubstituted Ci-C10 alkyl, unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C3-C8 (e.g. C5 to C7) cycloalkyl, unsubstituted 3 to 8 membered (e.g. 3 to 6 membered) heterocycloalkyl, unsubstituted C6 or Cio aryl, or unsubstituted 5 or 6 membered heteroaryl.
[0069] In other embodiments, R5 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 piperidinyl, or substituted or unsubstituted piperazinyl. In other embodiments, R5 is R34-substituted or unsubstituted pyridinyl, R34-substituted or unsubstituted pyrimidinyl, R34-substituted or unsubstituted imidazolyl, R34-substituted or unsubstituted pyrazolyl, R34-substituted or unsubstituted oxazolyl, R34-substituted or unsubstituted pyrazinyl, R34-substituted or unsubstituted triazolyl, R34-substituted or unsubstituted tetrazolyl, R34-substituted or unsubstituted morpholino, R34-substituted or unsubstituted purinyl, R34-substituted or unsubstituted phenyl, R34-substituted or unsubstituted benzoimidazolyl, R34-substituted or unsubstituted pyrrolidine-2,5-dionyl, R34- substituted or unsubstituted thieno-imidazol-onyl, R34-substituted or unsubstituted piperidinyl, or R34-substituted or unsubstituted piperazinyl. [0070] In some embodiments, R29 is -0-CH3, halogen (e.g. F or Cl), methyl, ethyl, propyl, butyl, -C(O)CH3, -CF3, -NH2, -N(CH3)2, or oxo.
[0071] In some embodiments, R5 is substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, L is -O-L -, and L is a bond.
[0072] In some embodiments R2 is hydrogen. In certain embodiments, R4 is hydrogen. And in some embodiments, R1 is hydrogen.
[0073] In some embodiments, 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
R2 and R4 are hydrogen.
Table 1
Figure imgf000019_0001
Figure imgf000020_0001
[0074] In some embodiments, 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.
[0075] In other embodiments of the compounds of Formulae (I), (II), and the ring A subgeneric formulae, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C2O 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 C3-C8 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-C20 alkylene, and each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene. [0076] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C8 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 C5-C7 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 C1-C8 alkylene, and/or each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0077] In another embodiment, 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.
III. Chemical Synthesis
[0078] Following the guidance set forth in the general synthesis methods below, in the synthesis methods set forth in the Examples, and synthetic methods generally known in the art (e.g. Anderson et al., Angew Chem, Int Ed 2006, 45 (39), 6523-6527; Poindexter et al., Bioorganic & Medicinal Chemistry 12 (2004) 507-521; Altaian et al., OrgLett 2007, 9 (4), 643-646; Altaian, et al., J Org Chem 2007, 72 (16), 6190-6199; and AIy, et al., Synthesis 2007, (13), 1955-1960), one of skill would be able to synthesis the compounds set forth in Formula (I), Formula (II), the ring A subgeneric formulae, Table 3, Table 4, Table 5, and or the Examples provided below.
[0079] Alkylation of the nitrogen of the cycloindole with X'-L'-IAR5 provides compounds disclosed herein. The group X1 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. The reactions may be run at elevated temperatures to reduce the time required for completion.
Figure imgf000022_0001
[0080] An alternate alkylation route involves the reaction of a cycloindole-L'-X2 with H- L2-R5 and base to generate the disclosed compounds. The group X2 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. The reactions may be run at elevated temperatures to reduce the time required for completion.
Figure imgf000022_0002
[0081] Preparation of certain compounds can also be achieved by activating a carboxylate at the site of the R3 position, and coupling with H-O-R23 or H2NR15 to provide certain R3 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-R23 or H2NR15 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.
Figure imgf000023_0001
[0082] 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. 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.
R5
Figure imgf000023_0002
IV. Methods
[0083] In another aspect, a method of inhibiting the entry of a Hepatitis C virus into a cell is provided. In some embodiments, the method 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. Thus, the sample may contain the cell, the Hepatitis C virus, or both. In other embodiments, 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. The terms "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.
[0084] The cell may be, or derive from, a mammalian cell such as a primate cell (e.g. a human cell). The cell may be in vitro, in situ, or in vivo. In some embodiments, the cell forms part or a tissue, organ, or organism.
[0085] "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. Typically, 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. For example, where the method is performed with a population of cells and a population of Hepatitis C viruses, 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.
[0086] In another aspect, 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. 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.
[0087] In another aspect, a method of treating a disease in a subject caused by a Hepatitis C viral infection is provided. The method 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.
[0088] In some embodiments, the disease caused by Hepatitis C viral infection is
Hepatitis C. 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. In some embodiments, the Hepatitis C is Acute Hepatitis C. Acute Hepatitis C refers to the first 6 months after infection with HCV. In other embodiments, the Hepatitis C is Chronic Hepatitis C. Chronic hepatitis C refers to infection with the hepatitis C virus persisting for more than six months.
[0089] In some embodiments, the substituted fused ring cycloindole derivative is provided in a pharmaceutical formulation (see below). In therapeutic use for the treatment of disease states recited above, 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, however, 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.
V. Assays
[0090] 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. [0091] After assessing the ability of test compounds to inhibit viral entry and/or infection in a cellular based assay, 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).
VI. Pharmaceutical Formulations
[0092] In another aspect, pharmaceutical compositions are provided including a substituted fused ring cycloindole derivative in admixture with a pharmaceutically acceptable excipient. One of skill in the art will recognize that the pharmaceutical compositions include the pharmaceutically acceptable salts of the substituted fused ring cycloindole derivatives described above.
[0093] In therapeutic and/or diagnostic applications, 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 (20th ed.) Lippincott, Williams & Wilkins (2000).
[0094] 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.
[0095] Pharmaceutically acceptable 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, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Other pharmaceutically acceptable salts may be found in, for example, Remington: The Science and Practice of Pharmacy (20th 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.
[0096] Depending on the specific conditions being treated, such 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 (20th 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.
[0097] For injection, 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. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
[0098] Use of pharmaceutically acceptable inert carriers to formulate the compounds herein disclosed for the practice of the invention into dosages suitable for systemic administration is within the scope of the invention. With proper choice of carrier and suitable manufacturing practice, the 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.
[0099] For nasal or inhalation delivery, 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.
[0100] Pharmaceutical 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.
[0101] In addition to the active ingredients, 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. The preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
[0102] Pharmaceutical preparations 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). If desired, disintegrating agents may be added, such as the cross- linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
[0103] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions 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.
[0104] Pharmaceutical preparations 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. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added.
[0105] Depending upon the particular condition, or disease state, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention. For example, chemotherapeutic agents or other antiproliferative agents may be combined with the inhibitors of this invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.
[0106] Other examples of agents the compounds of this invention may also be combined with include, without limitation, anti-inflammatory agents such as corticosteroids, TNF blockers, IL-I RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; agents for treating diabetes such as insulin, insulin analogues, alpha glucosidase inhibitors, biguanides, and insulin sensitizers; and agents for treating immunodeficiency disorders such as gamma globulin.
[0107] These additional agents may be administered separately, as part of a multiple dosage regimen, from the composition. Alternatively, these agents may be part of a single dosage form, mixed together with the compound in a single composition.
[0108] The present invention is not to be limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the invention. Indeed, various modifications of the invention in addition to those described herein will become apparent to those having skill in the art from the foregoing description. Such modifications are intended to fall within the scope of the invention. Moreover, any one or more features of any embodiment of the invention may be combined with any one or more other features of any other embodiment of the invention, without departing from the scope of the invention. For example, the substituted fused ring cycloindole derivatives described above are equally applicable to the methods of treatment and the methods of inhibiting Hepatitis C entry and infection described herein. References cited throughout this application are examples of the level of skill in the art and are hereby incorporated by reference herein in their entirety for all purposes, whether previously specifically incorporated or not.
VIL Examples
[0109] In addition to the methods of synthesis described in the examples below, methods for the preparation of 1 ,2,3,4,-tetrahydrocarbazoles from hydrazines and cyclohexanones are well known (see, for example, U.S. Pat. Nos. 3,642,816; 3,931,222; 3,948,939; 4,057,559;
4,146,542 and 4,172,834). 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.
2007/0276009). Compounds containing a ketone such as 1,2,3,4,-tetrahydrocarbazol-l- ones can be converted to the corresponding l,l-difluoro-l,2,3,4,-tetrahydrocarbazole species (see G. S. LaI et al., J. Org. Chem., 1999, 7048-7054).
[0110] Diverse compounds of the present invention were shown both by a pseudoparticle /luciferase assay and by an infectious clone/luciferase assay to inhibit HCV entry into cells (see Examples 38 and 39).
[0111] The following examples are provided to illustrate but not limit the present invention.
Example 1 9-[3-(3,5-Dimethyl-piperazin-l-yl)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester a) δJ^^-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 solidified mixture was suspended in CH2Cl2, filtered and washed with CH2Cl2 to obtain 5.5 g of the product. b) ό^^^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester
[0113] A sample of 6,7,8, 9-tetrahydro carbazole-S-carboxylic acid (2 g, 9.3 mmol) in 80 ml of MeOH, 8 ml of conc.H2SO4, was refluxed overnight. The solvents were removed in vacuo, the residue treated with sat. NaHCO3 and the mixture was extracted with EtOAc. The organic layer was separated, washed with H2O and sat. brine solution. The organic layer was dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 1.6 g of the product. 1H NMR 500 MHz CDCl3: 8.22, d, J = 0.7, IH, 7.9, brs, IH, 7.83, dd, J = 1.7, 8.6, IH, 7.27, d (merged with CHCl3), IH, 3.92, s, 3H, 2.73, t, J = 6, 4H, 1.96-1.84, m, 4H.
c) 9-(3-Chloro-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester
[0114] To a stirred solution of όJ^^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester (1.6 g, 7.2 mmol), in 20 ml of dry DMF, NaH (60%, 0.86 g, 21.6 mmol) was added portion wise, followed by the addition of l-bromo-2-chloro propane (2.136 ml, 21.6 mmol). The reaction mixture was stirred for 3 hrs at r.t, under N2. The TLC of mixture showed completion of starting material and a new spot with higher Rf value. The solvents were removed in vacuo, the residue treated with H2O and the mixture was extracted with EtOAc (2x100 ml). The organic layer was separated, washed with H2O (50 ml) and sat.brine solution (50 ml). The organic layer was dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 1.5 g of the product. The 1H NMR showed a 2: 1 mixture of 9-(3-chloro- propy^-δ^jδ^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester and 9-(3-bromo- ρropyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester, which was used for next step without separation. 1H NMR 500 MHz CDCl3: 8.23, d, J = 1.2, IH, 7.86, dd, J - 1.6, 8.8, IH, 7.31, d, J - 8.6, 0.33H, 7.3, d, J = 8.6, 0.66H, 4.22, m, (two triplets merged), 2H, 3.92, s, 3H, 3.51, t, J = 6, 1.33H, 3.37, t, J = 6, 0.66H, 2.77-2.71, m, 4H, 2.3, q, J = 6.5, 0.66H, 2.22, q, J = 6.3, 1.33H, 1.99-1.93, m, 2H, 1.9-1.84, m, 2H.
d) 9-[3-(3,5-Dimethyl-piperazin-l-yl)-proρyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0115] To a solution of 9-(3-chloro-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester (0.2 g, 0.654 mmol) in 2 ml of dry DMF, tetra-Η-butyl ammonium iodide (0.362 g, 0.98 mmol) was added followed by the addition of m-2,6-dimethyl piperazine (0.298 g, 2.62 mmol) and the reaction mixture was heated to 37 0C for 3 days. The TLC of mixture showed complete consumption of starting material and a new spot with lower Rf value. The mixture was diluted with EtOAc (50 ml), washed with H2O (20 ml) and satbrine solution (20 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using CH2Cl2MeOH as eluents, to obtain 0.17 g of the product. 1H NMR 500 MHz CDCl3: 8.21, s, IH, 7.82, dd, J = 1.3, 8.5, IH, 7.29, d, J = 8.7, IH, 4.08, t, J = 6.9, 2H, 3.92, s, 3H, 3.02- 2.94, m, 2H, 2.76-2.69, m, 6H, 2.28, t, J = 6.9, 2H, 1.97-1.82, m, 6H, 1.65, brt, J = 9, 2H, 1.11, d, J = 6.2, 6H.
Example 2
9-(3-Moφholin-4-yl-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0116] The compound was prepared, as described for example Id, from 9-(3-chloro- propy^-ό^jδ^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester and morpholine. 1H NMR 500 MHz CDCl3: 8.22, d, J = 1.5, IH, 7.83, dd, J = 1.5, 8.5, IH, 7.31, d, J = 8.5, IH, 4.11, t, J = 6.9, 2H, 3.92, s, 3H, 3.72, t, J = 4.6, 4H, 2.76-2.69, m, 4H, 2.38, brs, 4H, 2.28, t, J = 6.8, 2H, 1.98-1.83, m, 6H.
Example 3
9-Ethyl-6,6-dimethyl-6,7,8,9-tetrahydro carbazole-3-carboxylic acid (2-morpholin-4-yl- ethyl)-amide. a) 6,6-Dimethyl-6,7,8,9-tetrahydro carbazole-3-carboxylic acid
[0117] A sample of 4-hydrazino benzoic acid hydrochloride (0.75g, 4 mmol), 4,4- dimethyl cyclohexanone (0.505g, 4 mmol), were taken in 6 ml of AcOH and the mixture was refluxed overnight. The mixture was cooled to room temperature and kept in refrigerator for 2 hrs. The solidified mixture was suspended in CH2Cl2 (10 ml), filtered and washed with CH2Cl2 to obtain 0.85 g of the product. 1H NMR 500 MHz D6DMSO: 12.21, s, IH, 11.08, s, IH, 7.98, d, J=0.9, IH, 7.62, dd, J=I.6, 8.5, IH, 7.28, d, J=8.4, IH, 2.69, t, J=6.3, 2H, 2.45, s, 2H, 1.61, t, 3=6 Λ, 2H, 1.01, s, 6H.
b) 6,6-Dimethyl-6,7,8,9-tetrahydro carbazole-3-carboxylic acid methyl ester
[0118] A sample of 6,6-Dimethyl-6,7,8,9-tetrahydro carbazole-3-carboxylic acid (1.7 g,
6.94 mmol) in 40 ml of MeOH, 4 ml of cone. H2SO4, was refluxed overnight. The solvents were removed in vacuo, the residue treated with sat. NaHCO3, and the mixture was extracted with EtOAc. The organic layer was separated, washed with H2O and sat. brine solution. The organic layer was dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 1.3 g of pure product. 1H NMR 500 MHz CDCl3: 8.2, s, IH, 8.03, s, IH, 7.82, dd, J=I.2, 8.6, IH, 7.27, d, J=8.7, IH, 3.91, s, 3H, 2.72, t, J=6.3, 2H, 2.52, s, 2H, 1.67, t, 3=6 A, 2H, 1.05, s, 6H.
c) 9-Ethyl-6,6-dimethyl-6,7,8,9-tetrahydro carbazole-3 -carboxylic acid methyl ester [0119] To a stirred suspension of 6,6-dimethyl-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester (0.15 g, 0.58 mmol) and Cs2CO3 (0.293 g, 0.9 mmol), in 2 ml of dry DMF, diethyl sulfate (0.118 ml, 0.9 mmol) was added and the mixture was stirred at r.t., for 6 hrs. The mixture was diluted with EtOAc (50 ml), washed with H2O (20 ml), and sat.brine solution (20 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.15 g of the product. 1H NMR 500 MHz CDCl3: 8.21 , d, J=1.3, IH, 7.85, dd, J=1.7, 10.4, IH, 7.26, d. J=8.6, IH, 4.1, q, J=7.25, 2H, 3.92, s, 3H, 2.7, t, J=6.4, 2H, 2.55, s, 2H, 1.7, t, J=6.4, 2H, 1.33, t, J=6.4, 3H, 1.05, s, 6H. d) 9-Ethyl-6,6-dimethyl-6,7,8,9-tetrahydro carbazole-3 -carboxylic acid
[0120] To a stirred suspension of 9-Ethyl-6,6-dimethyl-6,7,8,9-tetrahydro carbazole-3- carboxylic acid methyl ester (0.5 g, 1.753 mmol) in 2 ml of MeOH, 1.8 ml of 2N NaOH was added at r.t., and the mixture was refluxed for 3 hrs. The solvents were removed in vacuo, acidified with IN HCl, the resulting solids were collected and dried under high vacuo to obtain 0.42 g of the product. e) 9-Ethyl-6,6-dimethyl-6,7,8,9-tetrahydro carbazole-3 -carboxylic acid (2-morpholin-4-yl- ethyl)-amide.
[0121] A sample of 9-Ethyl-6,6-dimethyl-6,7,8,9-tetrahydro carbazole-3 -carboxylic acid
(0.108 g, 0.4 mmol) was taken in 2 ml of dry DMF. To this solution, NEt3 (0.112 ml, 0.8 mmol) was added followed by the addition of HATU (0.152 g, 0.4 mmol). After stirring for 5 min., 2-aminoethyl morpholine (0.057 ml, 0.44 mmol) was added and the reaction mixture was stirred at room temperature for overnight. The DMF was removed in vacuo, the residue was taken into EtOAc (50 ml), washed with H2O (20 ml) and sat. NaHCO3 (20 ml). The organic layer was separated, dried over anhyd. MgSO4, the solvents were removed in vacuo and the residue was purified by column chromatography to obtain 0.138 g of the product. 1H NMR 500 MHz CDCl3: 7.93, d, J = 1.5, IH, 7.56, dd, J = 1.6, 8.5, IH, 7.27, d, J = 8.5, IH, 6.75, bit, IH, 4.1, q, J = 7.2, 2H, 3.73, t, J = 4.5, 4H, 3.59, q, J = 5.7, 2H, 2.7, t, J = 6.4, 2H, 2.62, t, J = 6.1, 2H, 2.55-2.49, m, 6H, 1.74, s, 2H, 1.7, t, J = 6.4, 2H, 1.33, t, J = 7.2, 3H. Example 4
4-[9-Ethyl-6,6-dimethyl-6,7,8,9-tetrahydro carbazole-3-carbonyl)-amino] -butyric acid ethyl ester [0122] The compound was prepared as described for example 3e, from 9-Ethyl-6,6- dimethyl-6,7,8,9-tetrahydro carbazole-3-carboxylic acid and 4-amino-butyric acid ethyl ester. 1H NMR 500 MH D6DMSO: 8.27, t, IH, 7.94, d, IH, 7.60, dd, IH, 7.39, d, IH, 4.13, q, 2H, 4.06-4.02, m, 2H, 3.28, q, 2H, 2.73, t, 4H, 2.37, t, 2H, 1.82-1.75, m, 2H, 1.65, t, 2H, 1.23, t, 3H, 1.18, t, 3H, 1.01, s, 6H.
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. 1H NMR 500 MHz CDCl3: 8.22, d, J = 1.5, IH, 7.83, d, J = 1.5, 8.5, IH, 7.31, d, J = 8.6, IH, 4.13, q, J = 7.0, 2H, 4.11, t, J = 6.8, 2H, 3.92, s, 3H, 3.48, brt, 4H3 2.76-2.70, m, 4H, 2.33, brs, 4H, 2.28, t, J = 6.7, 2H, 1.98-1.83, m, 6H, 1.26, t, J = 3, 3H.
Example 6
9-[3-(3,5-Dimethyl-piperazin-l-yl)-propyl]-6,6-dimethyl-6,7,8,9-tetrahydro-5H-carbazole-
3-carboxylic acid methyl ester [0124] The compound was prepared, as described for example Id, from 9-(3-chloro- propy^-ό^-dimethyl-δJjδ^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester and cώ-3,5-dimethyl piperzine. 1H NMR 500 MHz CDCl3: 8.2, d, J = 1.4, IH, 7.83, dd, J = 1.5, 8.5, IH, 7.3, d, J = 8.7, IH, 4.10, t, J = 7, 2H, 3.91, s, 3H, 2.97-2.89, m, 2H, 2.74-2.68, m, 4H, 2.54, s, 2H, 2.26, t, J = 7, 2H, 1.92, q, J = 7, 2H, 1.69, t, J = 6.4, 2H, 1.54, brt, J = IO, 2H, 1.05, d, J = 6.1 , 6H, 1.04, s, 6H (doublet, singlet merged together).
Example 7
5-Ethyl-l,3,4,5-tetrahydro-pyrido[4,3-δ]indole-2,8-dicarboxylic acid 2-tert-butyl ester 8- methyl ester a) l,3,4,5-Tetrahydro-pyrido[4,3-έ]indole-2,8-dicarboxylic acid 2-benzyl ester: [0125] The compound was prepared, as described for example 3a, from 4-hydrazino benzoic acid hydrochloride and 4-oxo-piperidine-l-carboxylic acid benzyl ester. 1H NMR 500 MHz D6DMSO: 11.31,s, IH, 8.07, s, IH, 7.68, dd, J=I.5, 8.5, IH, 7.42-7.30, m, 6H, 5.14, s, 2H, 4.69, brs, IH, 4.64, brs, IH, 3.79, brs, 2H, 2.82, t, J=5.4, 2H. b) l,3,4,5-Tetrahydro-pyrido[4,3-δ]indole-2,8-dicarboxylic acid 2-benzyl ester-8 -methyl ester [0126] A sample of l,3,4,5-Tetrahydro-pyrido[4,3-ό]indole-2,8-dicarboxylic acid 2- benzyl ester (0.89g, 2.54 mmol) and HATU (0.95g, 2.5 mmol) were taken in 10 ml of dry DMF. To this stirred solution, NEt3 (0.7ml, 5 mmol) was added, stirred for 5 min and then 1 ml of MeOH containing DMAP (0.3g, 2.54 mmol) was added. The reaction mixture was heated to 50 0C overnight and the solvents were removed in vacuo. The residue was taken into EtOAc (100 ml), washed sequentially with IN HCl (40 ml), H2O (40 ml), and sat. NaHCO3 (40 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents were concentrated in vacuo and the crude was purified by column chromatography to obtain
0.53g of the pure product. 1H NMR 500 MHz CDCl3: 8.19, brs, IH, 8.1, brs, IH, 7.88, dd, J=I.5, 8.5, IH, 7.42-7.37, m, 4H, 7.37-7.29, m, 2H, 5.2, s, 2H, 4.75, brs, 2H, 3.93, s, 3H, 3.91, brs, 2H, 2.87, brs, 2H. c) 5-Ethyl-l,3,4,5-tetrahydro-pyrido[4,3-6]indole-2,8-dicarboxylic acid 2-benzyl ester-8- methyl ester
[0127] The compound was prepared, as described for example 3c, from 1,3,4,5-
Tetrahydro-pyrido[4,3-δ]indole-2,8-dicarboxylic acid 2-benzyl ester-8-methyl ester and diethyl sulfate. 1H NMR 500 MHz CDCl3: 8.2, brs, IH, 7.89, dd, J=I.6, 8.7, IH, 7.42-7.36, m, 4H, 7.35-7.32, m, IH, 7.29, d, J=8.6, IH, 5.19, s, 2H, 4.76, brs, 2H, 4.10, q, J=6.9, 2H, 3.92, s, 3H, 2.85, brs, 2H, 1.34, t, J=7.2, 3H.
d) 5-Ethyl-2,3,4,5-tetrahydro-pyrido[4,3-£]indole-8-carboxylic acid methyl ester
[0128] A sample of 5-Ethyl-l,3,4,5-tetrahydro-pyrido[4,3-έ]indole-2,8-dicarboxylic acid
2-benzyl ester-8-methyl ester (0.72g, 1.83 mmol) and 10% Pd-C (0.36 g) were taken in 8 ml of dry MeOH. To this mixture, 2 ml of 1,4-cyclohexadiene was added and the mixture was stirred at room temperature for 4 hrs. The TLC of mixture showed complete consumption of starting material and a new spot with lower Rf value. The reaction mixture was filtered over celite through sintered funnel, washed with MeOH, filtrates were concentrated in vacuo and the crude was purified by colum chromatography, using CH2Cl2/Me0H as eluents, to obtain 0.33 g of the pure product. 1H NMR 500 MHz CDCl3: 8.18, d, J=1.5, IH, 7.87, dd, J=I-O, 8.5, IH, 7.29, d, J=8.7, IH, 4.11, t, J=1.5, 2H, 4.09, q, J=7.2, 2H, 3.92, s, 3H, 3.28, t, J=5.8, 2H, 2.77, t, J=5.7, 2H, 1.34, t, J=7.3, 3H. e) 5-Ethyl-l,3,4,5-tetrahydro-pyrido[4,3-ό]indole-2,8-dicarboxylic acid 2-tert-bntyl ester 8- methyl ester [0129] To a stirred solution of 5-Ethyl-2,3,4,5-tetrahydro-pyrido[4,3-6]indole-8- carboxylic acid methyl ester (0.103 g, 0.4 mmol), in dry CH2Cl2, NEt3 (0.17 ml, 1.2 mmol) was added followed by the addition of di-tert-butyl dicarbonate (0.261 g, 1.2 mmol) and the reaction mixture was stirred at r.t, overnight. The reaction mixture was diluted with CH2Cl2 (50 ml), washed with 0.5 N HCl (20 ml), H2O (20 ml) and sat.NaCHO3 (20 ml). The organic layer was separated, dried over anhyd. MgSO4, the solvents were removed in vacuo and the residue was purified by column chromatography to obtain 0.033 g of the product. 1H NMR 500 MHz CDCl3: 8.22, s, IH, 7.89, dd, J = 1.4, 8.6, IH, 7.29, d, J = 8.6, IH, 4.66, s, IH, 4.1, q, J = 7.2, 2H, 3.93, s, 3H, 3.85, brt, 2H, 2.81, brt, 2H, 1.5. s. 9H, 1.34, t, J = 7.2, 3H.
Example 8 5-Ethyl-2-(propane-l-sulfonyl)-2,3,4,5-tetrahydro-pyrido[4,3-έ]indole-8-carboxylic acid methyl ester [0130] The compound was prepared as described for example 7e, using 1 -propane sulfonyl chloride. 1H NMR 500 MHz CDCl3: 8.2, d, J = 1.4, IH, 7.91, dd, J = 1.7, 8.7, IH, 7.31, d, J = 8.7, IH, 4.61, s, IH, 4.11, q, J = 7.3, 2H, 3.92, s, 3H, 3.78, t, J = 5.7, 2H, 3.1- 2.94, m, 2H, 2.91, t, J = 5.7, 2H, 1.92-1.83, m, 2H, 1.35, t, J = 7.2, 3H, 1.05, t, J = 7.4, 3H.
Example 9
5-Ethyl-2-(3-phenyl-propionyl)-2,3,4,5-tetrahydro-pyrido[4,3-Z)]indole-8-carboxylic acid methyl ester [0131] The compound was prepared as described for example 7e, using hydrocinnmoyl chloride. 1H NMR 500 MHz CDCl3: 8.25, dd, J = 1.2, 0.3H, 8.15, dd, J = 1.3, 0.7H, 7.33- 7.11, m, 6H, 4.86, s, 0.6H, 4.64, s, 1.4H, 4.11, q, J = 7.3, 2H, 3.93, s (two singlets merged), 3H, 3.07-2.9, m (two triplets merged), 2H, 2.84-2.7, m, 4H, 1.35, t, J - 7.3, 3H.
Example 10
9-[3-(3-Oxo-piperazin-l-yl)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester
[0132] 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. 1H NMR 500 MHz CDCl3: 8.22, d, J = 1.4, IH, 7.83, dd, J = 1.5, 8.5, IH, 7.29, d, J = 8.5, IH, 6.11, brs, IH, 4.13, t, J = 6.8, 2H, 3.92, s, 3H, 3.39-3.35, m, 2H, 3.12, s, 2H, 2.72-2.68, m, 4H, 2.58, t, J = 5.5, 2H, 2.36, t, J = 6.6, 2H, 1.98-1.82, m, 6H. Example 11
9-[3-(2,6-Dimethyl-morpholin-4-yl)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0133] The compound was prepared, as described for example Id, from 9-(3-chloro-
5 propyO-βJjδ^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester and cis-2,6- dimethyl morpholine. 1H NMR 500 MHz CDCl3: 8.22, d, J = 1.4, IH, 7.82, dd, J = 1.5, 8.6, IH, 7.30, d, J = 8.6, IH, 4.10, t, J = 6.9, 2H, 3.92, s, 3H, 3.7-3.6, m, 2H, 2.77-2.7, m, 4H, 2.65, d, J = 10.4, 2H, 2.25, t, J = 6.9, 2H, 1.98-1.83, m, 6H, 1.66, t, J = 10.6, 2H, 1.5, d, J = 6.3, 6H.
[0 Example 12
9-(3-Cyano-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0134] To a stirred solution of 6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester (0.206 g, 0.9 mmol), in 4 ml of dry DMF, NaH (60%, 0.108 g, 2.7 mmol) was added portion wise, followed by the addition 4-bromobutyronitrile (0.27 ml, 2.7 mmol). The
[5 reaction mixture was stirred for 3 hrs at r.t, under N2. The TLC of mixture showed completion of starting material and a new spot with lower Rf value. The solvents were removed in vacuo, the residue treated with H2O and the mixture was extracted with EtOAc (60 ml). The organic layer was separated, washed with H2O (25 ml) and sat.brine solution (25 ml). The organic layer was dried over anhyd.MgSO4, solvents removed in vacuo and
.0 the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.21 g of the product. 1H NMR 500 MHz CDCl3: 8.23, d, J = 1.4, IH, 7.87, dd, J = 1.6, 8.6, IH, 7.26, d, J = 8.6, IH, 4.19, t, J = 7, 2H, 3.92, s, 3H, 2.76-2.69, m, 4H, 2.31, t, J = 7, 2H, 2.12, q, J = 6.8, 2H5 2.0-1.96, m, 2H, 1.9-1.84, m, 2H.
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- ό^δ^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester and l-bromo-3-chloro propane. 1H NMR 500 MHz CDCl3: 8.21, d, J = 1.3, IH, 7.86, dd, J = 1.6, 8.7, IH, 7.3, d, J0 = 8.7, 0.66H, 7.29, d, J = 8.5, 1.33H, 4.25-4.20, m (two triplets merged), 2H, 3.5, t, J = 6, 1.33H, 3.36, t, J = 6.1, 0.66H, 2.74-2.71, m, 2H, 2.54, s, 2H, 2.3, q, J = 6.5, 0.66H, 2.21, q, J = 6.3, 1.33H, 1.71, t, J = 6.4, 2H, 1.05, s, 6H. Example 14
6-Chloro-9-ethyl-3 ,3 -dimethyl-2,3 ,4,9-tetrahydro- 1 H-carbazole a) 6-Chloro-3,3-dimethyl-2,3,4,9-tetrahydro carbazole
[0136] A sample of 4-chloro phenylhydrazine hydrochloride (0.268 g, 1.5 mmol) and 4,4- dimethyl cyclohexanone (0.19 g, 1.5 mmol) were taken in 4 ml of AcOH and the mixture was refluxed overnight. The solvents were removed in vacuo, the residue taken in EtOAc (60 ml), washed with sat. NaHCO3 (25 ml), H2O (25 ml), and sat.brine solution (25 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.21 g of the product.
^ δ-Chloro-P-ethyl-S^-dimethyl^^^^-tetrahydro-lH-carbazole
[0137] The compound was prepared, as described for example 3c, from 6-chloro-3,3- dimethyl-2,3,4:9-tetrahydro carbazole and ethyl iodide. 1H NMR 500 MHz CDCl3: 7.4, d, J = 2, IH, 7.16, d, J = 8.6, IH, 7.07, dd, J = 2, 8.6, IH, 4.05, q, J = 7.3, 2H, 2.68, t, J = 6.4, 2H, 2.47, s, 2H, 1.69, t, J = 6.4, 2H, 1.3, t, J = 7.2, 3H, 1.04, s, 6H.
Example 15
4-Chloro-9-ethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester a) 2-Chloro-4-hydrazino benzoic acid hydrochloride
[0138] A sample of 4-amino-2-chloro benzoic acid (1.715 g, 10 mmol) was taken in 20 ml of conc.ΗCl and cooled to 0 °C. To this stirred suspension, at 0 0C, ice cold solution of NaNO2 (0.828 g, 12 mmol) in 8 ml OfH2O was added dropwise through addition funnel over 30 min, the mixture stirred further 30 min at 0 0C and then, ice cold solution of SnCl2.2H2O (6.77 g, 30 mmol) in 10 ml of conc.HCl was added dropwise. The mixture was stirred at 0 0C 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.
b) 4-Chloro-6,7,8,9-tetrahydro carbazole-3-carboxylic acid methyl ester
[0139] A sample of 2-chloro-4-hydrazino benzoic acid hydrochloride (3.5 g, ca. 10 mmol), cyclo hexanone (1.03 ml, 10 mmol), were taken in 15 ml of AcOH and the mixture was refluxed overnight. The mixture was cooled to room temperature and solids were filtered off. The filtrates were evaporated, residue taken into EtOAc, washed with H2O and sat. brine solution. The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo to obtain 1.7 g of a crude mixture of 4-chloro-6,7,8,9-tetrahydro carbazole-3-carboxylic acid and 2-chloro-6,7,8,9-tetrahydro carbazole-3-carboxylic acid. The crude mixture was suspended in CH2Cl2, solids collected by filtration and washed with CH2Cl2 to obtain 0.95 g of mixture. The mixture (0.94 g) ) was taken in 30 ml of MeOH, 3 ml of conc.H2Sθ4 and refluxed overnight. The solvents were removed in vacuo, the residue treated with sat. NaHCO3, and the mixture was extracted with EtOAc. The organic layer was separated, washed with H2O and sat. brine solution. The organic layer was dried over anhyd.MgSO4, solvents removed in vacuo to obtain 0.9 g of pure 1:1 mixture, by 1H NMR, of 4-Chloro-6,7,8,9-tetrahydro carbazole-3-carboxylic acid methyl ester (lower Rf, TLC system: 30:70 EtOAc :Hexane), and 2-Chloro-6,7,8,9-tetrahydro carbazole-3-carboxylic acid methyl ester (higher Rf). The mixture was suspended in 10 ml OfCH2Cl2, solids collected and washed with 2 ml of CH2Cl2 to obtain 0.38 g of pure 4-Chloro-6,7,8,9-tetrahydro carbazole-3-carboxylic acid methyl ester. 1H NMR 500 MHz D6DMSO: 11.33, s, IH, 7.44, d, J = 8.4, IH, 7.24, d, J = 8.4, IH, 3.81, s, 3H, 2.99, brt, 2H, 2.7, brt, 2H, 1.82-1.74, m, 4H. c) 4-Chloro-9-ethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0140] The compound was prepared, as described for example 3c, from 4-chloro-6,7,8,9- tetrahydro-5H-carbazole-3-carboxylic acid methyl ester and ethyl iodide. 1H NMR 500
MHz CDCl3: 7.62, d, J = 8.5, IH, 7.13, d, J = 8.6, IH, 4.06, q, J = 7.2, 2H, 3.92, s, 3H, 3.14, t, J = 6.2, 2H, 2.69, t, J = 6, 2H, 1.94-1.88, m, 2H, 1.88-1.81, m, 2H, 1.31, t, J = 7.2, 3H.
Example 16
9-[2-(l-rerr-Butoxycarbonyl-piperidin-4-yl)-ethyl]-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester
[0141] 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 [0142] 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 K2CO3 as a base. 1H NMR 500 MHz CDCl3: 8.23, d, J = 1.5, IH, 7.85, dd, J = 1.7, 8.7, IH, 7.45, s, IH, 7.11, t, J = 4.6, 2H, 6.9, s, IH, 4.04, t, J = 7.1, 2H, 3.95, t, J = 7, 2H, 3.92, s, 3H, 2.73, t, J = 6.1, 2H, 2.58, t, J = 5.9, 2H, 2.26, q, J = 7.2, 2H, 1.96-1.9, m, 2H, 1.89-1.83, m, 2H. Example 18
9-Ethyl-6-methoxy-3,3-dimethyl-2,3,4,9-tetrahydro-lH-carbazole a) 6-Methoxy-3,3-dimethyl-2,3 ,4,9-tetrahydro carbazole
[0143] The compound was prepared, as described for example 14a, from 4-methoxy phenylhydrazine hydrochloride and 4,4-dimethyl cyclohexanone.
b) 9-Ethyl-6-methoxy-3,3-dimethyl-2,3,4,9-tetrahydro-lH-carbazole
[0144] The compound was prepared, as described for example 3c, from 6-methoxy-3,3- dimethyl-2,3,4,9-tetrahydro carbazole and ethyl iodide. 1H NMR 500 MHz CDCl3: 7.16, d, J - 8.7, IH, 6.92, d, J = 2.4, IH, 6.79, dd, J = 2.4, 8.8, IH, 4.04, q, J = 7.2, 2H, 3.85, s, 3H, 2.68, t, J = 6.4, 2H, 2.49, s, 2H, 1.69, t, J = 6.4, 2H, 1.3, t, J = 7.3, 3H, 1.05, s, 6H.
Example 19
9-[3-tert-Butoxycarbonylamino-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0145] To a stirred solution of ό^S^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester (0.458 g, 2 mmol), in 4 ml of dry DMF, NaH (60%, 0.096 g, 2.4 mmol) was added portion wise. After stirring the reaction mixture for 15 min at r.t, toluene-4-sulfonic acid-3- tert-butoxycarbonylamino-propyl ester (0.987 g, 3 mmol), in 4 ml of dry DMF, was added and the reaction mixture was stirred, under N2, at r.t., for 24 hrs. The DMF was removed in vacuo, the residue taken into EtOAc (60 ml), washed with H2O (25 ml), sat. NaHCO3 (25 ml) and sat.brine solution (25 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.55 g of the product. 1H NMR 500 MHz CDCl3: 8.22, d, J = 1.4, IH, 7.84, dd, J = 1.6, 8.6, IH, 7.22, d, J = 8.6, IH, 4.5, brs, IH, 4.07, t, J = 7.2, 2H, 3.92, s, 3H, 3.14, q, J = 6.1, 2H, 2.73, t, J = 6.1, 2H, 2.69, t, J =6, 2H, 1.98-1.9, m, 4H, 1.88-1.82, m, 2H, 1.43, s, 9H.
Example 20
9-[3-(2-Methyl Imidazol-l-yl)-proρyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0146] The compound was prepared, as described for example Id, from 9-(3-chloro- propy^-δJjδ^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester and 2- methyl imidazole, using 3 equiv. OfK2CO3 as a base. 1H NMR 500 MHz CDCl3: 8.23, d, J = 1.3, IH, 7.85, dd, J = 1.6, 8.6, IH, 7.1, d, J = 8.6, IH, 6.95, d, J = 0.6, IH, 6.81, d, J = 0.8, IH, 4.05, t, J = 7.2, 2H, 3.92, s, 3H, 3.81, t, J = 7.1, 2H, 2.74, t, J = 6, 2H, 2.58, t, J = 5.8, 2H, 2.25, s, 3H, 2.2, t, J = 7, 2H, 1.96-1.9, m, 2H, 1.89-1.82, m, 2H. Example 21
9-(3-Imidazol-l-yl-propyl)-6,6-dimethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0147] The compound was prepared, as described for example Id, from 9-(3-chloro- propyO-όjό-dimethyl-β^^^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester and Imidazole, using 3 equiv. OfK2CO3 as a base. 1H NMR 500 MHz CDCl3: 8.21,d, J = 1.3, IH, 7.85, dd, J = 1.6, 8.6, IH, 7.46, brs, IH, 7.12, d, J = 8.5, IH, 7.11, s (merged with doublet), IH, 6.9, brs, IH, 4.06, t, J = 7.2, 2H, 3.95, t, J = 7, 2H, 3.92, s, 3H, 2.57, t, J = 6.3, 2H, 2.54, s, 2H, 2.27, q, J = 7.2, 2H, 1.68, t, J = 6.3, 2H, 1.03, s, 6H.
Example 22
9-(3-Cyano-propyl)-6,7,859-tetrahydro-5H-carbazole-3-carboxylic acid amide a) 9-(3-Cyano-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid
[0148] To a stirred suspension of 9-(3-Cyano-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester (0.12 g, 0.4 mmol) in 1 ml of MeOH, 0.4 ml of 2N NaOH was added at r.t, and the mixture was refluxed for 3 hrs. The solvents were removed in vacuo, neutralized with IN HCl and the mixture was extracted with EtOAc. The organic layer was separated, washed with H2O, and sat.brine solution. The organic layer was dried over anhyd.MgSO4, solvents removed in vacuo and the residue was dried under high vacuo to obtain 0.11 g of the product, which was used further without purification. b) 9-(3-Cyano-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid amide
[0149] A sample of 9-(3-cyano-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid (0.1 g, 0.35 mmol) was taken in 2 ml of dry DMF. To this solution, NEt3 (0.15 ml, 1.06 mmol) was added followed by the addition of ΗATU (0.13 g, 0.34 mmol). The reaction mixture was stirred for 5 min., solid NH4Cl (0.056 g, 1.06 mmol) was added and the reaction mixture was stirred at room temperature for overnight. The reaction mixture was diluted with EtOAc (50 ml) washed with H2O (2 x 20 ml), and sat.NaHCO3 solution (20 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using CH2Cl2/Me0H as eluents, to obtain 0.06 g of the product. 1U NMR 500 MHz D6DMSO: 8.0, d, J = 1.4, IH, 7.81, brs, IH, 7.65, dd, J = 1.6, 8.5, IH, 7.41, d, J = 8.5, IH, 7.05, brs, IH, 4.13, t, J = 7.2, 2H, 2.72, t, J = 5.5, 2H, 2.66, t, J = 6, 2H, 2.52-2.48, m (merged with DMSO), 2H, 1.94, q, J = 7.3, 2H, 1.9-1.87, m, 2H, 1.87-1.76, m, 2H. Example 23
9-[3-(6-Chloro-pyrimidin-4-ylamino)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester a) 9-(3-Amino-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester. 5 [0150] To a stirred solution of 9-[3-tert-butoxycarbonylamino-propyl]-6,7,8,9-tetrahydro-
5H-carbazole-3-carboxylic acid methyl ester (0.32 g, 0.828 mmol), in 2 ml of dry CH2Cl2, 2 ml of TFA was added at 0 0C, and the reactiom mixture was stirred for 2 hrs. The solvents were removed in vacuo, co-evaporated with toluene (3x) and the residue was dried under high vacuo to obtain 0.33 g of TFA salt of 9-(3-amino-propyl)-6,7,8,9-tetrahydro-5H- 10 carbazole-3-carboxylic acid methyl ester, which was used further without purification.
b) 9-[3-(6-Chloro-pyrimidin-4-ylamino)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester [0151] To a suspension of TFA salt of 9-(3-amino-propyl)-6,7,8,9-tetrahydro-5H- carbazole-3-carboxylic acid methyl ester (0.114 g, 0.4 mmol), in 2 ml of dioxane, at 0 0C, 15 DIPEA (0.28 ml, 1.6 mmol) was added. After stirring for 5 min, 4,6-dichloro pyrimidine (0.12 g, 0.8 mmol) was added and the mixture was stirred at r.t. overnight. The solvents were removed in vacuo, the residue taken into EtOAc (50 ml), washed with H2O (20 ml) and sat.brine solution (20 ml). The organic layer was separated, dried over anhyd.MgS04, solvents removed in vacuo and the crude was purified by column chromatography, using >0 using CH2Cl2MeOH as eluents, to obtain 0.08 g of the product. 1H NMR 500 MHz CDCl3: 8.33, s, IH, 8.25, d, J = 1.4, IH, 7.85, dd, J = 1.5, 8.6, IH, 7.22, d, J = 8.7, IH, 6.1, d, J = 0.6, IH, 4.16, t, J = 6.8, 2H, 3.93, s, 3H, 3.32, brs, 2H, 2.74, t, J = 6.1, 2H, 2.66, t, J = 5.9, 2H, 2.09, q, J = 6.8, 2H, 1.94-1.89, m, 2H, 1.87-1.81, m, 2H.
Example 24
15 9-(3-hydroxy-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0152] The compound was prepared, as described for example 12, from 6,7,8,9- tetrahydro-5H-carbazole-3-carboxylic acid methyl ester and 3-bromo propanol. 1H NMR 500 MHz D6DMSO: 8.05, d, IH, 7.70, dd, IH, 7.46, d, IH, 4.63, t, IH, 4.15, t, 2H, 3.83, s, 3H, 3.41, q, 2H, 2.73, t, 2H, 2.67, t, 2H, 1.88-1.85, m, 2H, 1.81-1.76, m, 4H.
50 Example 25
9-[3-(6-Chloro-2-methyl-pyrimidin-4-ylamino)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester [0153] The compound was prepared, as described for example 23b, from 4,6-dichloro-2- methyl pyrimidine. 1H NMR 500 MHz CDCl3: 8.24, d, J = 1.2, IH, 7.85, dd, J = 1.4, 8.5, IH, 7.22, d, J = 8.5, IH, 5.97, s, IH, 4.15, t, J = 6.9, 2H, 3.93, s, 3H, 3.29, brs, 2H, 2.72, t, J = 6, 2H, 2.67, t, J = 5.8, 2H, 2.46, s, 3H, 2.08, q, J = 6.8, 2H, 1.96-1.9, m, 2H, 1,89-1.82, m, 2H.
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-
6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester and 2-bromo propane, except the reaction was carried out at 50 0C overnight. 1H NMR 500 MHz CDCl3: 8.19, d, J = 1.5, IH, 7.8, dd, J = 1.6, 8.7, IH, 7.4, d, J - 8.8, IH, 4.63, m, IH, 3.92, s, 3H, 2.74, t, J = 6.4, 2H, 2.54, s, 2H, 1.69, t, J = 6.4, 2H, 1.59, d, J = 7, 6H, 1.04, s, 6H.
Example 27
9-[3-(4,6-Dimethoxy-[l,3,5]triazine-2-ylamino)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester [0155] The compound was prepared, as described for example 23b, from 2-Chloro-4,6- dimethoxy-l,3,5-triazine. The reaction was carried out at 80 0C for overnight in DMF solvent. 1H NMR 500 MHz CDCl3: 8.22, d, J = 1.4, IH, 7.83, dd, J = 1.7, 8.6, IH, 7.22, d, J = 8.64, IH, 5.55, t, J = 5.8, IH, 4.11, t, J = 7.1, 2H, 3.92, s, 3H, 3.9, s, 3H, 3.89, s, 3H, 3.45, q, J = 6.7, 2H, 2.73, t, J = 6, 2H, 2.68, t, J = 5.8, 2H, 2.07, q, J = 7, 2H, 1.96-1.9, m, 2H, 1.89-1.82, m, 2H.
Example 28
9-[3-(4,6-Dimethoxy-pyrimidin-4-ylamino)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester [0156] The compound was prepared, as described for example 23b, from 2-Chloro-4,6- dimethoxy pyrimidine, except the reaction was carried out at 80 °C overnight in DMF solvent. 1U NMR 500 MHz CDCl3: 8.22, d, J = 1.5, IH, 7.83, dd, J = 1.6, 8.5, IH, 7.24, d, J = 8.5, IH, 5.4, s, IH, 4.89, t, J = 5.8, IH, 4.13, t, J = 7, 2H, 3.92, s, 3H, 3.77, s, 6H, 3.41, q, J = 6.7, 2H, 2.74, t, J = 6.1, 2H, 2.69, t, J = 5.9, 2H, 2.07, q, J = 7, 2H, 1.96-1.9, m, 2H, 1.89-1.82, m, 2H.
Example 29 9-Ethyl-6,6-dimethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile. a) όjό-Dimethyl-ό^^^-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.
b) 9-Ethyl-6,6-dimethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile.
[0158] The compound was prepared, as described for example 3c, from 6,6-Dimethyl- 6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile and ethyl iodide. 1H NMR 500 MHz CDCl3:
7.6, d, J = 1.2, IH, 7.36, dd, J = 1.5, 8.4, IH, 7.28, d, J = 8.6, IH, 4.1, q, J = 7.2, 2H, 2.7, t, J = 6.4, 2H, 2.5, s, 2H, 1.71, t, J = 6.4, 2H, 1.33, t, J = 7.3, 3H, 1.05, s, 6H.
Example 30
4-Chloro-9-[3-(2,6-Dimethyl-moφholin-4-yl)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester
[0159] The compound was prepared, as described for example Id, from 4-chloro-9-(3- chloro-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester and cis-2,6- dimethyl morpholine. 1H NMR 500 MHz CDCl3: 7.59, d, J = 8.5, IH, 7.19, d, J = 8.6, IH,
4.07, t, J = 6.9, 2H, 3.92, s, 3H, 3.71-3.64, m, 2H, 3.14, t, J = 6.1, 2H, 2.71, t, J = 5.9, 2H, 2.64, d, J = 10.5, 2H, 2.23, t, J = 6.84, 2H, 1.92-1.80, m, 6H, 1.66, t, J = 10.8, 2H, 1.5, d, J =
6.3, 6H.
Example 31
9-(3-Purin-7-yl-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0160] The compound was prepared, as described for example Id, from 9-(3-chloro- propyty-όJ^^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester and purine (2 equiv.), using 2 equiv. OfK2CO3 as a base. 1H NMR 500 MHz CDCl3: 9.15, s, IH, 8.99, s, IH, 8.23, d, J = 1.3, IH, 7.9, s, IH, 7.85, dd, J = 1.6, 8.6, IH, 7.16, d, J = 8.7, IH, 4.29, t, J = 7.2, 2H, 4.17, t, J = 7, 2H, 3.92, s, 3H, 2.72, t, J = 6, 2H, 2.6, t, J = 5.8, 2H, 2.48, q, J = 7.2, 2H, 1.93-1.87, m, 2H, 1.86-1.79, m, 2H.
Example 32
9-{3-[5-(2-Oxo-hexahydro-thieno[3;4-d]imidazol-4-yl)-pentanoylamino]-propyl}-6,7,8,9- tetra-5H-carbzole-3-carboxylic acid methyl ester [0161] To a stirred solution of TFA salt of 9-(3-amino-propyl)-6,7,8,9-tetrahydro-5H- carbazole-3 -carboxylic acid methyl ester (0.070g, 0.183mmol) in 2 ml of dry DMF, triethylamine (52.7μl, 0.366mmol) was added followed by the addition of N- hydroxysuccinimido-biotin (125mg, 0.366mmol) and the reaction mixture was stirred at room temperature for over night. 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 H2O (20 ml) and sat. brine solution (20 ml). The organic layer was separated, dried over anhyd. MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using CH2Cl2/Me0H as eluents, to obtain 0.1 g of the product. 1H NMR 500 MHz CD3OD: 8.13, d, J = 1.5, IH; 7.78, dd, J = 9.0, 2.0, IH; 7.36, d, J = 8.5, IH; 4.48-4.45, m, IH; 4.29-4.26, m, IH; 4.14, t, J = 7.5, 2H; 3.89, s, 3H; 3.22-3.19, m, 3H; 2.91-2.88, m, IH; 2.77-2.69, m, 6H; 2.19, t, J = 7.4, 2H; 1.97-1.87, m, 6H, 1.63- 1.59,m, 4H; 1.44-1.40, m, 2H.
Example 33 2-Chloro-9-ethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester a) 2-Chloro-6,7,8,9-tetrahydro carbazole-3-carboxylic acid methyl ester [0162] The compound was prepared as described for example 15b. 1H NMR 500 MHz
CDCl3: 8.02, s, IH, 7.89, brs, IH, 7.31, s, IH, 3.93, s, 3H, 2.73-2.65, m, 4H, 1.94-1.82, m, 4H. b) 2-Chloro-9-ethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester
[0163] The compound was prepared, as described for example 3c, from 2-chloro-6,7,8,9- tetrahydro-5H-carbazole-3-carboxylic acid methyl ester and ethyl iodide. 1H NMR 500 MHz CDCl3: 8.05, s, IH, 7.3, s, IH, 4.03, q, J = 7.3, 2H, 3.93, s, 3H, 2.72-2.66, m, 4H, 1.98-1.91, m, 2H, 1.89-1.82, m, 2H, 1.32, t, J = 7.2, 3H.
Example 34
4-Chloro-9-(3-cyano-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0164] 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 4-bromobutyronitrile. 1H NMR 500 MHz CDCl3: 7.63, d, J = 8.5, IH, 7.15, d, J = 8.6, IH, 4.17, t, J = 6.9, 2H, 3.92, s, 3H, 3.13, t, J = 6.2, 2H, 2.69, t, J = 6, 2H, 2.31, t, J = 6.9, 2H, 2.1, q, J = 6.9, 2H, 1.96-1.89, m, 2H, 1.88-1.81, m, 2H.
Example 35
4-Chloro-9-(3-hydroxy-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester
[0165] 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 3-bromo propanol. 1H NMR 500 MHz CDCl3: 7.61, d, J = 8.6, IH, 7.19, d, J = 8.6, IH, 4.16, t, J = 6.9, 2H, 3.92, s, 3H, 3.61, t, J = 5, 2H, 3.14, t, J = 6.1, 2H, 2.71, t, J = 6.2, 2H, 1.95, q, J = 6.2, 2H, 1.92-1.87, m, 2H, 1.87-1.81, m, 2H.
Example 36
4-Chloro-9-(3-chloro-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester
[0166] 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. 1H NMR 500 MHz CDCl3: 7.62, d, J = 8.6, IH, 7.19, d, J = 8.6, IH, 4.2, t, J = 6.8, 2H, 3.92, s, 3H, 3.49, t, J = 5.9, 2H, 3.14, t, J = 6.2, 2H, 2.71, t, J = 6, 2H, 2.18, q, J = 6.4, 2H, 1.94- 1.88, m, 2H, 1.88-1.81, m, 2H.
Example 37
4-Chloro-9-[3-(3-oxo-piperazin-l-yl)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0167] The compound was prepared, as described for example Id, from 4-chloro-9-(3- piperazine. 1H NMR 500 MHz CDCl3: 7.59, d, J = 8.5, IH, 7.18, d, J = 8.5, IH, 6.02, brs, IH, 4.10, t, J = 6.8, 2H, 3.92, s, 3H, 3.4-3.34, m, 2H, 3.13, t (merged with singlet), J = 6.2, 2H, 3.12, s, 2H, 2.69, t, J = 8, 2H, 2.57, t, J = 5.5, 2H, 2.34, t, J = 6.5, 2H, 1.92-1.8, m, 6H.
Example 38
[0168] This example shows that the compounds of the invention inhibit entry of HCV, as measured by an HCV pseudoparticle/luciferase assay.
[0169] 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. Compounds that were able to reduce viral entry limited the amount of HCV pseudoparticle that was transduced into the host cells and thus reduced the luciferase levels and resulting luminescence. The most efficacious compounds induced the most significant reduction in luminescence. Specificity of the compounds was tested by evaluating the inhibitory effect on 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.
Example 39
[0170] This example shows that the compounds of the invention prevent entry of HCV into cells based upon an infectious clone/luciferase assay.
[0171] A. Construction of HCV2aCh-Rluc virus: 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.
[0172] 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 5x106 cells/ml. Five μg of HCV2aCh-Rluc RNA was mixed with 0.4 ml of cells in a 2 mm gap cuvette and electroporated (27OkV, 960 μF). [0173] Electroporated cells were plated in T75 cell culture flasks. Twenty-four hours post electroporation, the media was replaced with fresh media. When the cells reached 80-90% confluency, 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.
[0174] 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 μl of passive lysis buffer (Promega). 50 μl of lysate was mixed with 100 μl 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.
Table 2
Figure imgf000048_0001
Table 3
Figure imgf000048_0002
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Structure Structure
Figure imgf000056_0001
[0175] All references cited herein are incorporated in their entirety. It is appreciated that the detailed description above is intended only to illustrate certain preferred embodiments of the present invention. It is in no way intended to limit the scope of the invention, as set out in the claims.
Example 40
Figure imgf000056_0002
Methyl 9-{3-[(4,6-dimethoxypyrimidin-2-yl)oxy]propyl}-2,3,4,9-tetrahydro-lH-carbazole-
6-carboxylate [0176] To a solution of methyl 9-(3-hydroxypropyl)-2,3,4,9-tetrahydro-lH-carbazole-6- carboxylate (30 mg, 0.10 mmol) in DMF (2 ml) was added NaH (60% in mineral oil, 5 mg, 0.13 mmol). The resulting mixture was stirred at room temperature for 10 min and followed by addition of 2-chloro-4,6-dimethoxypyrimidine (15 mg, 0.09 mmol). The reaction mixture was kept stirring at room temperature for 4 h, poured into H2O (20 ml), and extracted with EtOAc (3 x 20 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 0-20%) to give the title compound (white solid, 17.0 mg). The yield: 45.9%. Example 41
Figure imgf000057_0001
a) Methyl 9-{3-[(terf-butoxycarbonyl)(methyl)amino]propyl}-2,3,4,9-tetrahydro-lH- carbazole-6-carboxylate [0177] To a solution of methyl 9-{3-[(te^butoxycarbonyl)amino]propyl}-2,3,4,9- tetrahydro-lH-carbazole-6-carboxylate (500 mg, 1.29 mmol) in DMF (10 ml) was added NaH (60% in mineral oil, 57 mg, 1.42 mmol). The resulting mixture was stirred at room temperature for 10 min and followed by addition of iodomethane (202 mg, 1.42 mmol). The reaction mixture was heated to 40 0C for 3 h, poured into H2O (30 ml), and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 10-60%) to give the title compound (colorless oil, 430 mg). The yield: 83.2%.
Figure imgf000057_0002
b) Methyl 9-[3-(methylamino)propyl]-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate [0178] To a solution of methyl 9-{3-[(terr-butoxycarbonyl)(methyl)amino]propyl}-
2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate (420 mg, 1.05 mmol) in DCM (6 ml) was added trifluoroacetic acid (6 ml). The resulting solution was stirred at room temperature for 2 h, cone, in vacuo to give the title compound (colorless oil, 300 mg). The yield: 99.9%.
Figure imgf000058_0001
c) Methyl 9- { 3 - [(4,6-dimethoxypyrimidin-2-yl)(methyl)amino]propyl } -2,3 ,4,9-tetrahydro-
1 H-carbazole-6-carboxylate [0179] To a solution of methyl 9-[3-(methylamino)propyl]-2,3,4,9-tetrahydro-lH- carbazole-6-carboxylate (200 mg, 0.67 mmol) in DMF (10 ml) was added /-Pr2NEt (0.15 ml, 0.83 mmol). The resulting solution was stirred at room temperature for 10 min and followed by addition of 2-chloro-4,6-dimethoxypyrimidine (97 mg, 0.56 mmol).. The reaction mixture was heated to 80 0C overnight, poured into H2O (30 ml), and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 0-40%) to give the title compound (colorless oil, 163 mg). The yield: 67.0%.
Example 42
Figure imgf000058_0002
Methyl 9- { 3 - [(6-chloro-2-methylpyrimidin-4-yl)oxy]propyl }-2,3 ,4,9-tetrahydro- 1 H- carbazole-6-carboxylate [0180] To a solution of methyl 9-(3-hydroxypropyl)-2,3,4,9-tetrahydro-lH-carbazole-6- carboxylate (50 mg, 0.17 mmol) in DMF (3 ml) was added NaH (60% in mineral oil, 9 mg, 0.22 mmol). The resulting mixture was stirred at room temperature for 10 min and followed by addition of 4,6-dichloro-2-methylpyrimidine (24 mg, 0.15 mmol). The reaction mixture was kept stirring at room temperature for 2 h, poured into H2O (20 ml), and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 0-50%) to give the title compound (colorless oil, 20 mg). The yield: 33.4%.
Example 43
Figure imgf000059_0001
Methyl 9- { 3 - [(6-chloropyrimidin-4-yl)oxy]propyl} -2,3 ,4,9-tetrahydro- 1 H-carbazole-6- carboxylate [0181] To a solution of methyl 9-(3-hydroxypropyl)-2,3,4,9-tetrahydro-lH-carbazole-6- carboxylate (50 mg, 0.17 mmol) in DMF (3 ml) was added NaH (60% in mineral oil, 9 mg, 0.22 mmol). The resulting mixture was stirred at room temperature for 10 min and followed by addition of 4,6-dichloropyrimidine (22 mg, 0.15 mmol). The reaction mixture was kept stirring at room temperature for 2 h, poured into H2O (20 ml), and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 0-50%) to give the title compound (colorless oil, 20 mg). The yield: 34.6%.
Example 44
Figure imgf000059_0002
a) 6-(Methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole
[0182] To a solution of 4-(methylsulfonyl)phenylhydrazine hydrochloride (1.00 g, 4.49 mmol) in ΗOAc (7 ml) was added cyclohexanone (0.47 ml, 4.49 mmol). The resulting mixture was heated to reflux for 5 h and then cone, in vacuo. The crude product was dissolved in EtOAc (50 ml), washed with H2O, sat.NaHCO3, dried over MgSO4, filtered and cone, in vacuo to give the title compound (brown solid, 1.10 g). The yield: 98.3%.
Figure imgf000060_0001
b) 3 -[6-(Methylsulfonyl)- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl]propan- 1 -ol
[0183] To a solution of 6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole (1.00 g, 4.01 mmol) in DMF (10 ml) was added NaH (60% in mineral oil, 192 mg, 8.02 mmol). The resulting mixture was stirred at room temperature for 10 min and followed by addition of 3- bromo-1-propanol (0.54 ml, 6.02 mmol). The reaction mixture was stirred at room temperature overnight, poured into H2O (50 ml), and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 50-100%) to give the title compound (white solid, 860 mg). The yield: 69.8%.
Figure imgf000060_0002
c) 9-{3-[(6-Chloro-2-methylpyrimidin-4-yl)oxy]propyl}-6-(methylsulfonyl)-2,3,4,9- tetrahydro- 1 H-carbazole [0184] To a solution of 3-[6-(methylsulfonyl)-l ,2,3,4-tetrahydro-9H-carbazol-9- yl]propan-l-ol (300 mg, 0.98 mmol) in DMF (4 ml) was added NaH (60% in mineral oil, 30 mg, 1.23 mmol). The resulting mixture was stirred at room temperature for 10 min and followed by addition of 4,6-dichloro-2-methylpyriniidine (1.34 ml, 0.82 mmol). The reaction mixture was stirred at room temperature overnight, poured into H2O (30 ml), and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 40-70%) to give the title compound (light yellow solid, 240 mg). The yield: 56.4%.
Example 45
Figure imgf000061_0001
a) 1 -(3-Chloropropoxy)-3,5-difluorobenzene
[0185] To a solution of 3,5-difluorophenol (500 mg, 3.84 mmol) and l-bromo-3- chlorpropane (0.76 ml, 7.68 mmol) in DMF (5 ml) was added cesium carbonate (3.12 g, 9.6 mmol). The resulting mixture was heated to 80 0C and kept stirring overnight and then poured into H2O (50 ml) and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 0-20%) to give the title compound (colorless oil, 118 mg). The yield: 14.9%.
Figure imgf000061_0002
b) 9-[3-(3,5-Difluorophenoxy)propyl]-6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole [0186] To a solution of 6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole (67 mg, 0.27 mmol) in DMF (3 ml) was added NaH (60% in mineral oil, 16 mg, 0.41 mmol) and tetrabutylammonium iodide (151 mg, 0.41 mmol). The resulting mixture was stirred at room temperature for 10 min and followed by addition of l-(3-chloropropoxy)-3,5- difluorobenzene (55 mg, 0.27 mmol). The reaction mixture was stirred at room temperature overnight, poured into H2O (30 ml), and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 30-80%) to give the title compound (white solid, 57 mg). The yield: 50.3%.
Example 46
Figure imgf000062_0001
a) 1 -(3-Chloropropoxy)-3,5-dimethylbenzene
[0187] To a solution of 3,3-dimethylphenol (469 mg, 3.84 mmol) and l-bromo-3- chlorpropane (0.76 ml, 7.68 mmol) in DMF (5 ml) was added cesium carbonate (3.12 g, 9.6 mmol). The resulting mixture was heated to 80 0C and kept stirring overnight and then poured into H2O (50 ml) and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 0-20%) to give the title compound (colorless oil, 446 mg). The yield: 58.5%
Figure imgf000062_0002
b) 9-[3-(3,5-Dimethylphenoxy)propyl]-6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole [0188] To a solution of 6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole (150 mg, 0.60 mmol) in DMF (5 ml) was added NaH (60% in mineral oil, 36 mg, 0.90 mmol) and tetrabutylammonium iodide (332 mg, 0.90 mmol). The resulting mixture was stirred at room temperature for 10 min and followed by addition of l-(3-chloropropoxy)-3,5- dimethylbenzene (119 mg, 0.60 mmol). The reaction mixture was stirred at room temperature overnight, poured into H2O (30 ml), and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 20-60%) to give the title compound (white solid, 164 mg). The yield: 66.4%.
Example 47
Figure imgf000063_0001
a) 6-Bromo-2,3,4,9-tetrahydro-lH-carbazole
[0189] To a solution of 4-bromophenylhydrazine hydrochloride (2.00 g, 8.95 mmol) in
ΗOAc (13 ml) was added cyclohexanone (0.93 ml, 8.95 mmol). The resulting mixture was heated to reflux for 7 h and then cone, in vacuo. The crude product was dissolved in EtOAc (50 ml), washed with H2O, sat.NaHCO3, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 0-30%) to give the title compound (brown solid, 1.63 g). The yield: 74.0%.
Figure imgf000063_0002
b) 6-Bromo-9-[3-(3,5-dimethylphenoxy)propyl]-2,3,4,9-tetrahydro-lH-carbazole
[0190] To a solution of 6-bromo-2,3,4,9-tetrahydro-lH-carbazole (150 mg, 0.61 mmol) in
DMF (5 ml) was added NaH (60% in mineral oil, 37 mg, 0.92 mmol) and tetrabutylammonium iodide (340 mg, 0.92 mmol). The resulting mixture was stirred at room temperature for 10 min and followed by addition of l-(3-chloropropoxy)-3,5- dimethylbenzene (121 mg, 0.61 mmol). The reaction mixture was stirred at room temperature overnight, poured into H2O (30 ml), and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 0-20%) to give the title compound (colorless oil, 182 mg). The yield: 72.4%. Example 48
Figure imgf000064_0001
6-Bromo-9- [3 -(3 ,5-difluorophenoxy)propyl]-2,3 ,4,9-tetrahydro- 1 H-carbazole
[0191] To a solution of 6-bromo-2,3,4,9-tetrahydro-lH-carbazole (66 mg, 0.27 mmol) in
DMF (3 ml) was added NaH (60% in mineral oil, 16 mg, 0.41 mmol) and tetrabutylammonium iodide (151 mg, 0.41 mmol). The resulting mixture was stirred at room temperature for 10 min and followed by addition of l-(3-chloropropoxy)-3,5- difluorobenzene (55 mg, 0.27 mmol). The reaction mixture was stirred at room temperature overnight, poured into H2O (30 ml), and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 0-20%) to give the title compound (colorless oil, 53 mg). The yield: 46.7%.
Example 49
Figure imgf000064_0002
9-[3-(3,5-Dimethylphenoxy)propyl]-2,3,4,9-tetrahydro-lH-carbazole-6-carbonitrile [0192] To a solution of 2,3,4,9-tetrahydro-lH-carbazole-6-carbonitrile (93 mg, 0.47 mmol) in DMF (3 ml) was added NaH (60% in mineral oil, 28 mg, 0.71 mmol) and tetrabutylammonium iodide (262 mg, 0.71 mmol). The resulting mixture was stirred at room temperature for 10 min and followed by addition of l-(3-chloropropoxy)-3,5- dimethylbenzene (93 mg, 0.47 mmol). The reaction mixture was stirred at room temperature overnight, poured into H2O (30 ml), and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 0-20%) to give the title compound (white solid, 118 mg). The yield: 68.5%.
Example 50
Figure imgf000065_0001
a) 4-(3-Chloropropoxy)-l ,2-difluorobenzene
[0193] To a solution of 3,4-difluorophenol (2.50 g, 19.22 mmol) and l-bromo-3- chlorpropane (3.80 ml, 38.44 mmol) in DMF (15 ml) was added cesium carbonate (12.52 g, 38.44 mmol). The resulting mixture was heated to 80 0C and kept stirring overnight and then poured into H2O (50 ml) and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSθ4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 0-10%) to give the title compound (colorless oil, 3.00 g). The yield: 75.5%
Figure imgf000065_0002
b) 9-[3-(3,4-Difluorophenoxy)propyl]-6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole [0194] To a solution of 6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole (117 mg, 0.47 mmol) in DMF (3 ml) was added NaH (60% in mineral oil, 28 mg, 0.71 mmol) and tetrabutylammonium iodide (262 mg, 0.71 mmol). The resulting mixture was stirred at room temperature for 10 min and followed by addition of 4-(3-chloropropoxy)-l,2- difluorobenzene (97 mg, 0.47 mmol). The reaction mixture was stirred at room temperature overnight, poured into H2O (30 ml), and extracted with EtOAc (3 x 30 ml). The organic layers were combined, dried over MgSO4, filtered and cone, in vacuo. The crude product was purified by silica gel flash chromatography (EtOAc/hexane, 30-60%) to give the title compound (white solid, 149 mg). The yield: 75.6%.
Example 51
6-bromo-9-{3-[(4,6-diethylpyrimidin-2-yl)oxy]propyl}-2,3,4,9-tetrahydro-lH-carbazole
Figure imgf000066_0001
a) 6-bromo-9- { 3-chloropropyl } -2,3 ,4,9-tetrahydro- 1 H-carbazole [0195] Following example 1 c, 6-bromo-2,3,4,9-tetrahydro-l H-carbazole was converted to 6-bromo-9- {3-chloropropyl } -2,3 ,4,9-tetrahydro- 1 H-carbazole b) 6-bromo-9- { 3 -[(4,6-diethylpyrimidin-2-yl)oxy]propyl } -2,3 ,4,9-tetrahydro-l Η-carbazole [0196] A sample of 6-bromo-9-{3-chloropropyl}-2,3,4,9-tetrahydro-lH-carbazole (64mg,
0.24mmol) was dissolved in 2ml of DMF, followed by addition of 4,6-dimethyl-2- hydroxypyrimidine hydrochloride (91.4mg, 0.50mmol) and potassium carbonate (168mg, 1.2mmol). The reaction mixture was stired at 80 degree for 16 hours. The TLC of reaction mixture, with 1 :3 ethyl acetate/hexane, showed a new spot with lower Rf. The mixture was partitioned between IM NaHCO3 aq.(150ml) and EtOAc (2 x 150 ml), the organic layers combined, washed with brine and dried over anhyd.MgSO4. The solvents were evaporated in vacuo and the residue was purified by column chromatography to obtain 50mg of the product
Example 52
6-bromo-9-{ 3 -[(4,6-dimethylpyrimidin-2-yl)oxy]propyl} -2,3, 4,9-tetrahydro-l H-carbazole
Figure imgf000067_0001
[0197] Following Example 51b, 6-bromo-9-{3-chloropropyl}-2,3,4,9-tetrahydro-lH- carbazole was converted to 6-bromo-9-{3-[(4,6-dimethylpyrimidin-2-yl)oxy]propyl}- 2,3,4,9-tetrahydro-lΗ-carbazole.
Example S3
6-Bromo-9-(3 -morpholin-4-yl-propyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole
Figure imgf000067_0002
[0198] Following Example Id, 6-bromo-9-{3-chloropropyl}-2,3,4,9-tetrahydro-lH- carbazole was converted to 6-Brorno-9-(3-morpholin-4-yl-propyl)-2,3,4,9-tetrahydro-lΗ- carbazole
Example 54
9-[4-(4,6-Dimethoxy-pyrimidin-2-ylamino)-butyl]-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester
Figure imgf000068_0001
a) 9-[3-tert-Butoxycarbonylamino-butyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester [0199] Following example 19, β^δ^-Tetrahydro-SH-carbazole-S-carboxylic acid methyl ester was converted 9-[3-tert-Butoxycarbonylamino-butyl]-6,7,8,9-tetrahydro-5H- carbazole-3-carboxylic acid methyl ester
b) 9-(3-Amino-butyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester. [0200] Following Example 23 a, 9-[3-tert-Butoxycarbonylamino-butyl]-6,7,8,9- tetrahydro-SΗ-carbazole-S-carboxylic acid methyl ester was converted to 9-(3-amino- buty^-όJjδ^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester c) 9-[4-(4,6-Dimethoxy-pyrimidin-2-ylamino)-butyl]-6,7,8,9-tetrahydro-5Η-carbazole-3- carboxylic acid methyl ester [0201] Following Example 23 b, 9-(4-Amino-butyl)-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester was converted to 9-[4-(4,6-Dimethoxy-pyrimidin-2-ylamino)- butylJ-β^jδ^-tetrahydro-SΗ-carbazole-S-carboxylic acid methyl ester
Example 55
9-[3-(6-Methylamino-7Η-purin-2-ylamino)-propyl]-6,7,8,9-tetrahydro-5Η-carbazole-3- carboxylic acid methyl ester
Figure imgf000069_0001
[0202] Following Example 23 b, 9-(3-Amino-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester was converted to 9-[3-(6-Methylamino-7Η-purin-2-ylamino)- propy^-όJjδ^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester using (2-Chloro- 9H-purin-6-yl)-methyl-amine.
Example 56
9-[3-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester
Figure imgf000069_0002
[0203] Following example 1 c, όJ^^-Tetrahydro-SH-carbazole-S-carboxylic acid methyl ester was converted to 9-[3-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-propyl]-6,7,8,9- tetrahydro-5H-carbazole-3-carboxylic acid methyl ester using 2-(3-Bromo-propyl)- isoindole-l,3-di one Example 57
[3 -(6-Bromo- 1 ,2,3 ,4-tetrahydro-carbazol-9-yl)-propyl] -(4,6-dimethoxy-pyrimidin-2-yl)- amine
Figure imgf000070_0001
a) [3-(6-Bromo-l,2,3,4-tetrahydro-carbazol-9-yl)-propyl]-carbamic acid tert-butyl ester [0204] Following example 19, 6-bromo-2,3,4,9-tetrahydro-lH-carbazole was converted to
[3 -(6-Bromo- 1, 2,3, 4-tetrahydro-carbazol-9-yl)-propyl]-carbamic acid tert-butyl ester b) 3 -(6-Bromo- 1, 2,3, 4-tetrahydro-carbazol-9-yl)-propylamine. [0205] Following Example 23 a, [3 -(6-Bromo- 1,2,3, 4-tetrahydro-carbazol-9-yl)-propyl]- carbamic acid tert-butyl ester was converted to 3 -(6-Bromo- 1,2,3, 4-tetrahydro-carbazol-9- yl)-propylamine. c) [3 -(6-Bromo- 1 ,2,3 ,4-tetrahydro-carbazol-9-yl)-propyl] -(4,6-dimethoxy-pyrimidin-2-yl)- amine. [0206] Following Example 23 b, 3 -(6-Bromo- 1 ,2,3,4-tetrahydro-carbazol-9-yl)- propylamine was converted to [3 -(6-Bromo- 1, 2,3, 4-tetrahydro-carbazol-9-yl)-propyl] -(4,6- dimethoxy-pyrimidin-2-yl)-amine.
Example 58
9-[3-(4,6-Dimethyl-pyrimidin-2-yloxy)-propyl]-6,7,8,9-tetrahydro-5Η-carbazole-3- carboxylic acid methyl ester
Figure imgf000071_0001
[0207] Following Example 51b, 9-(3-Chloro-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester was converted to 9-[3-(4,6-Dirnethyl-pyrirnidin-2-yloxy)- propy^-β^δ^-tetrahydro-SΗ-carbazole-S-carboxylic acid methyl ester.
Example 59
9-[3-(4,6-Diethyl-pyrimidin-2-yloxy)-propyl]-6,7,8,9-tetrahydro-5Η-carbazole-3-carboxylic acid methyl ester
Figure imgf000071_0002
[0208] Following Example 51b, 9-(3-Chloro-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester was converted to 9-[3-(4,6-Diethyl-pyrimidin-2-yloxy)- propy^-β^S^-tetrahydro-SΗ-carbazole-S-carboxylic acid methyl ester.
Example 60 9-[3-(4-tert-Butyl-6-trifluoromethyl-pyrimidin-2-yloxy)-propyl]-6,7,8,9-tetrahydro-5Η- carbazole-3-carboxylic acid methyl ester
Figure imgf000072_0001
[0209] Following Example 51b, 9-(3-Chloro-propyl)-6,7,8,9-tetrahydro-5H-carbazole-3- carboxylic acid methyl ester was converted to 9-[3-(4-tert-Butyl-6-trifluoromethyl- pyrimidin-2-yloxy)-propyl]-6,7,8,9-tetrahydro-5Η-carbazole-3-carboxylic acid methyl ester.
Example 61
6-Bromo-9-[3-(3,4-difluoro-phenoxy)-propyl]-2,3,4,9-tetrahydro-lH-carbazole
Figure imgf000072_0002
[0210] Following Example 51b, 6-bromo-9-{3-chloropropyl}-2,3,4,9-tetrahydro-lH- carbazole was converted to 6-Bromo-9-[3-(3,4-difluoro-phenoxy)-propyl]-2,3,4,9- tetrahydro- 1 Η-carbazole.
Example 62
6-cyano-9-[3 -(3 ,4-difluoro-phenoxy)-propyl]-2,3 ,4,9-tetrahydro- 1 Η-carbazole
Figure imgf000073_0001
[0211] Following Example 51b, 6-cyano-9-{3-chloropropyl}-2,3,4,9-tetrahydro-lH- carbazole was converted to 6-cyano-9-[3-(3,4-difluoro-phenoxy)-propyl]-2,3,4,9- tetrahydro-lΗ-carbazole.
Example 63
9- [3 -(3 ,4-Difluoro-phenoxy)-propyl] -N-hydroxy-6,7,8,9-tetrahydro-5Η-carbazole-3 - carboxamidine
Figure imgf000073_0002
[0212] Sodium (117mg, 5.1mmol) was completely dissolved in 2ml of methanol, followed by the addition of 6-cyano-9-[3-(3,4-difluoro-phenoxy)-propyl]-2,3,4,9- tetrahydro-lH-carbazole (400mg, 1.02mmol) and hydroxy lamine hydrochloride (340mg, 4.9mmol). The mixtures was refluxed for two days and the TLC showed all starting material was consumed and a new spot with lower Rf with 10% methanol/dichloromethane and. The mixture was evaporated in vacuo and partitioned between water (150ml) and EtOAc (2 x 150 ml), the organic layers combined, washed with brine and dried over anhyd.MgSO4. The solvents were evaporated in vacuo and the residue was purified by column chromatography to obtain 300mg of the product.
Example 64 ulfonyl)propyl]-2,3,4,9-tetrahydro-lH-carbazole-6-
Figure imgf000074_0001
Example 64a 4-[(3-chloropropyl)sulfonyl]morpholine
Figure imgf000074_0002
[0213] To a stirred solution of piperidine (0.395 ml, 4.0 mmol) in 8 ml of dry CH2Cl2, NEt3 (0.584 ml, 4.2 mmol) was added, at 0 0C, followed by the slow addition of 3- chloropropane sulfonylchloride (0.51 ml, 4.2 mmol) in 8 ml of dry CH2Cl2. The reaction mixture was stirred at 0 0C for 15 min, ice bath was removed, and then mixture was stirred at r.t., overnight. The mixture was diluted with 100 ml Of CH2Cl2, washed with IN HCl (2x25 ml), H2O (2x25 ml) and sat. NaHCO3 solution (2x25 ml). The organic layer was separated, dried over anhyd.MgSO4, 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. 1H NMR 500 MHz CDCl3: 3.75, t, J = 4.7, 4H, 3.68, t, J = 6.2, 2H, 3.27, t, J = 4.7, 4H, 3.07, t, J = 7.3, 2H, 2.31-2.26, m, 2H.
Example 64b [0214] To a stirred solution of, example Ib, όJ^^-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 N2, at 60 0C, overnight. The DMF was removed in vacuo, the residue taken into EtOAc (60 ml), washed with H2O (25 ml), sat. NaHCO3 (25 ml) and sat.brine solution (25 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.065 g of the product. 1H NMR 500 MHz CDCl3: 8.23, d, J = 1.3, IH, 7.86, dd, J = 1.6,
8.6, IH, 7.28, d, J = 8.6, IH, 4.23, t, J = 6.9, 2H, 3.93, s, 3H, 3.77, t, J = 4.7, 4H, 3.17, t, J =
4.7, 4H, 2.84, t, J = 7.1, 2H, 2.74, t, J = 6.1, 2H, 2.71, t, J = 6.1, 2H, 2.28, q, J = 7.1, 2H, 1.99-1.93, m, 2H, 1.90-1.85, m, 2H.
Example 65
9-{3-[(2/?,6S)-2,6-Dimethylmorpholin-4-yl]propyl}-2,3,4,9-tetrahydro-lH-carbazole-6- carbonitrile
Figure imgf000075_0001
carbazole-6-carbonitrile
Figure imgf000075_0002
[0215] A sample of 4-cyanophenylhydrazine hydrochloride (0.848 g, 5 mmol), cyclo hexanone (0.518 ml, 5 mmol), were taken in 8 ml of AcOH and the mixture was refluxed for 4 hrs. The mixture was cooled to room temperature, the solids were filtered off and washed with CH2Cl2. The filtrates were concentrated in vacuo, the residue taken into EtOAc (100 ml), washed with H2O (40 ml), sat. NaHCO3 (40 ml) and sat.brine solution (40 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.95 g of the product. ,4,9-tetrahydro-lH-carbazole-6-carbonitrile
Figure imgf000076_0001
[0216] The compound was prepared, as described for example 9-(3-chloro-propyl)- όJjδ^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester, from 2,3,4,9-tetrahydro- lH-carbazole-6-carbonitrile and l-bromo-3-chloropropane. 1H NMR 500 MHz CDCl3: 7.79, s, IH, 7.38, dd, J = 1.4, 8.4, IH, 7.35, d, J = 8.3, IH, 4.23, t, J = 6.8, 2H, 3.5, t, J = 5.9, 2H, 2.74, t, J = 6.0, 2H, 2.70, t, J = 6.2, 2H, 2.20, q, J = 6.4, 2H, 1.99-1.93, m, 2H, 1.90- 1.83, m, 2H.
Example 65c 9-{3-[(2i?,65)-2,6-Dimethylmoφholin-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^-ό^δ^-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. 1H NMR 500 MHz CDCl3: 7.78, s, IH, 7.36-7.32, m (dd and d merged), 2H, 4.11, t, J = 6.9, 2H, 3.69-3.65, m, 2H, 2.74-2.61, m, 4H, 2.62, brd, 2H, 2.23, t, J = 6.8, 2H, 1.96-1.83, m, 6H, 1.66, brt, 2H, 1.15, d, J = 6.3, 6H.
Example 66
9-{3-[(4,6-Dimethoxypyrimidin-2-yl)amino]propyl}-N-methyl-2,3,4,9-tetrahydro-lH- carbazole-6-carboxamide
Figure imgf000076_0002
Example 66a -yl)amino]propyl } -2,3 ,4,9-tetrahydro- 1 H-carbazole-6-
Figure imgf000077_0001
[0218] To a stirred solution of, example 27, methyl 9-{3-[(4,6-dimethoxypyrimidin-2- yl)amino]propyl}-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate (0.254 g, 0.6 mmol), in 1.5 ml of MeOH, 0.6 ml of aq. 2N NaOH was added and the mixture was refluxed for 6 hrs. The solvents were removed in vacuo, the residue taken into H2O, acidified to pH 4.5 with IN HCl and the mixture was extracted with EtOAc (2x). The organic layers were combined, washed with H2O and sat. brine solution. The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the residue was suspended in EtOAc, solids were collected by filtration, washed with EtOAc and dried under high vacuo to obtain 150 mg of pure product. The filtrates were concentrated to obtain another 50 mg of product, which was used for next step without purification. 1H NMR 500 MHz D6DMSO: 12.3, brs, IH, 8.02, d, J = 1.4, IH, 7.65, dd, J = 1.6, 8.6, IH, 7.44, d, J = 8.6, IH, 7.2, t, J = 5.5, IH, 5.31, s, IH, 4.14, t, J = 7, 2H, 3.75, brs, 3H, 3.61, brs, 3H, 3.24, q, J = 6.6, 2H, 2.72-2.68, m, 2H, 2.67-2.64, m, 2H, 1.92, q, J = 6.8, 2H, 1.87-1.82, m, 2H, 1.8-1.75, m, 2H.
Example 66b
9- {3 - [(4,6-Dimethoxypyrirnidin-2-yl)amino]propyl } -N-methyl-2,3 ,4,9-tetrahydro- 1 H- carbazole-6-carboxamide
[0219] The compound was prepared, as described for example 9-(3-cyano-propyl)-
6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid amide, from 9-{3-[(4,6- dimethoxypyrimidin-2-yl)amino]propyl } -2,3 ,4,9-tetrahydro- 1 H-carbazole-6-carboxylic acid and methylamine hydrochloride. 1H ΝMR 500 MHz CDCl3: 7.92, d, J = 1.5, IH, 7.54, dd, J = 1.7, 8.5, IH, 7.24, d, J = 8.6, IH, 6.17-6.14, m, IH, 5.4, s, IH, 5.02, brs, IH, 4.13, t, J = 7, 2H, 3.78, s, 6H, 3.4, q, J = 6.7, 2H, 3.04, d, J = 5.54, 3H, 2.74-2.67, m, 4H, 2.06, q, J = 7, 2H, 1.95-1.9, m, 2H, 1.88-1.84, m, 2H. Example 67 idin-2-yl)amino]propyl}-2,3,4,9-tetrahydro-lH-
Figure imgf000078_0001
[0220] 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- 1 H-carbazole-6- carboxylic acid, 2-propanol and DMAP. 1H ΝMR 500 MHz CDCl3: 8.21, d, J = 1.5, IH, 7.83, dd, J = 1.6, 8.6, IH, 7.23, d, J = 8.6, IH, 5.4, s, IH, 5.27, q, J = 6.3, IH, 4.94, brs, IH, 4.13, t, J = 7.1, 2H, 3.78, s, 6H, 3.4, q, J = 6.7, 2H, 2.75, t, J = 6.1, 2H, 2.69, t, J = 5.9, 2H, 2.06, q, J = 7, 2H, 1.95-1.9, m, 2H; 1.88-1.83, m, 2H, 1.39, d, J = 6.3, 6H.
Example 68
9-{3-[(4,6-Dimethoxypyrimidin-2-yl)amino]propyl}-N,iV-dimethyl-2,3,4,9-tetrahydro-lH- carbazole-6-carboxamide
Figure imgf000078_0002
[0221] 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. 1H ΝMR 500 MHz D6DMSO: 7.42, d, J = 1.3, IH, 7.38, d, J = 8.4, IH, 7.2, t, J = 5.4, IH, 7.08, dd, J = 1.6, 8.4, IH, 5.31, s, IH, 4.13, t, J = 7, 2H, 3.75, brs, 3H, 3.61, brs, 3H, 3.24, q, J = 6.5, 2H, 2.96, s, 6H, 2.7, t, J = 6.4, 2H, 2.62, t, J - 6, 2H, 1.92, q, J = 7, 2H, 1.88-1.81, m, 2H, 1.81-1.71, m, 2H.
Example 69 l)propyl]-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate
Figure imgf000079_0001
propane- 1 -sulfonamide
Figure imgf000079_0002
[0222] 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. 1H ΝMR 500 MHz CDCl3: 8.23, d, J = 1.4, IH, 7.86, dd, J = 1.6, 8.6, IH, 7.29, d, J = 8.5, IH, 4.23, t, J = 7, 2H, 3.93, s, 3H, 2.85, t, J = 7.2, 2H, 2.8, s, 6H, 2.77-2.7, m, 4H, 2.27, q, J = 7.1, 2H, 1.98-1.93, m, 2H, 1.90-1.86, m, 2H.
Example 70
Methyl 9-(3-{[4-(methoxycarbonyl)-6-methylpyrimidin-2-yl]amino}propyl)-2,3,4,9- tetrahydro- 1 H-carbazole-6-carboxylate
Figure imgf000080_0001
[0224] The compound was prepared, as described for example 9-[3-(6-chloro-pyrimidin- 4-ylamino)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester from methyl-2-chloro-6-methylpyrimidine-4-carboxylate. 1H NMR 500 MHz CDCl3: 8.22, d, J = 1.4, IH, 7.81, dd, J = 1.7, 8.7, IH, 7.24, d, J = 8.6, IH, 7.11, s, IH, 5.48, brs, IH, 4.13, t, J =
7.3, 2H, 3.96, s, 3H, 3.92, s, 3H, 3.5, q, J = 6.6, 2H, 2.74, t, J = 6.1, 2H, 2.69, t, J - 6.1, 2H,
2.4, s, 3H, 2.07, q, J = 7.2, 2H, 1.95-1.9, m, 2H, 1.88-1.83, m, 2H.
Example 71 9-[3-(Dimethylsulfamoyl)propyl]-N-methyl-2!3,4,9-tetrahydro-lH-carbazole-6- carboxamide
Figure imgf000080_0002
[0225] 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. 1H ΝMR 500 MHz CDCl3: 7.92, d, J = 1.3, IH, 7.57, dd, J = 1.6, 8.5, IH, 7.3, d, J = 8.6, lH, 6.19, brq, IH, 4.22, t, J = 7, 2H, 3.04, d, J = 4.9, 3H, 2.84, t, J = 7.1, 2H, 2.8, s, 6H, 2.74-2.7, m, 4H, 2.26, q, J = 7.1, 2H, 1.98-1.93, m, 2H, 1.90-1.83, m, 2H. Example 72
4,6-Dimethoxy-N- { 3 -[6-(methylsulfonyl)- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-
Figure imgf000081_0001
Example 72a -tetrahydro- 1 H-carbazole
Figure imgf000081_0002
[0226] A sample of 4-(methylsulfonyl) phenyl hydrazine hydrochloride (0.445 g, 2 mmol), cyclohexanone (0.207 ml, 2 mmol) was taken in 4ml of AcOH and the mixture was refluxed for 5 hrs. The solvents were removed in vacuo, the residue taken in EtOAc, washed with sat.ΝaHCO3, H2O and sat.brine solution. The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the solids were dried under high vacuo to obtain 0.5 g of the product which was used for next step without purification. l)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]propyl}carbamate
Figure imgf000081_0003
[0227] To a stirred solution of 6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole (0.373 g, 1.5 mmol), in 2 ml of dry DMF, NaH (60% suspension in oil, 0.072 g, 1.8 mmol) was added portion wise. After stirring the reaction mixture for 15 min at r.t, toluene-4-sulfonic acid-3-terf-butoxycarbonylamino-propyl ester (0.592 g, 1.8 mmol), in 2 ml of dry DMF, was added and the reaction mixture was stirred, under N2, at r.t., for 24 hrs. The DMF was removed in vacuo, the residue taken into EtOAc (60 ml), washed with H2O (25 ml), sat. NaHCO3 (25 ml) and sat.brine solution (25 ml). The organic layer was separated, dried over anhyd.MgS04, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.34 g of the product. 1H NMR 500 MHz CDCl3: 8.09, d, J = 1.6, IH, 7.66, dd, J = 1.7, 8.5, IH, 7.34, d, J = 8.7, IH, 4.53, brs, IH, 4.12, t, J = 8, 2H, 3.15, brq, 2H, 3.06, s, 3H, 2.75-2.7, m, 4H, 1.98-1.92, m, 4H, 1.90-1.83, m, 2H, 1.44, s, 9H.
,2,3 ,4-tetrahydro-9H-carbazol-9-yl]propan- 1 -amine
Figure imgf000082_0001
[0228] The compound was prepared, as described for example 9-(3-amino-propyl)- 6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester.
Example 72d
4,6-Dimethoxy-N- { 3 - [6-(methylsulfonyl)- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9- yl]propyl}pyrimidin-2-amine [0229] The compound was prepared, as described for example 9-[3-(4,6-dimethoxy-
[l,3,5]triazine-2-ylamino)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester, from TFA salt of 3-[6-(methylsulfonyl)-l,2,3,4-tetrahydro-9H-carbazol-9- yl]propan-l -amine and 2-chloro-4,6-dimethoxy pyrimidine. 1H NMR 500 MHz CDCl3: 8.08, d, J = 1.6, IH, 7.64, dd, J = 1.8, 8.6, IH, 7.34, d, J = 8.7, IH, 5.4, s, IH, 4.9, t, J = 5.8, IH, 4.16, t, J = 7.2, 2H, 3.77, s, 6H, 3.42, q, J = 6.6, 2H, 3.06, s, 3H, 2.75-2.7, m, 4H, 2.07, q, J = 6.9, 2H, 1.97-1.91, m, 2H, 1.89-1.84, m, 2H.
Example 73 Methyl 9-(3-{[(3,5-difluorophenyl)sulfonyl]amino}propyl)-2,3,4,9-tetrahydro-lH- carbazole-6-carboxylate
Figure imgf000083_0001
[0230] To a stirred suspension of TFA salt of 9-(3-amino-propyl)-6,7,8,9-tetrahydro-5H- carbazole-3-carboxylic acid methyl ester (0.2 g, 0.5 mmol), in 2 ml of dry CH2Cl2, NEt3 (0.208 ml, 1.5 mmol) was added at 0 °C. After stirring for 5 min, 3,5-difluorobenzene sulfonylchloride (0.106 g, 0.5 mmol), in 1 ml of dry CH2Cl2 was added and the mixture was stirred for 3 hrs. The reaction mixture was diluted with CH2Cl2, washed sequentially with IN HCl (25 ml), H2O (25 ml) and sat. NaHCO3 (25 ml) solution. The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.14g of the product. 1H NMR 500 MHz CDCl3: 8.2, d, J = 1.4, IH, 7.8, dd, J = 1.6, 8.7, IH, 7.3-7.24, m, 2H, 7.15, d, J = 8.7, IH, 7.04-6.97, m, IH, 4.48, t, J = 5.9, IH, 4.1, t, J = 7, 2H, 3.92, s, 3H, 2.98, q, J = 6.6, 2H, 2.73, t, J = 6.2, 2H, 2.66, t, J = 5.9, 2H, 2.05-1.89, m, 4H, 1.88-1.82, m, 2H.
Example 74
Methyl 9-(3-{[(3,5-dimethylphenyl)sulfonyl]amino}propyl)-2,3,4,9-tetrahydro-lH-
Figure imgf000083_0002
[0231] 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. 1H NMR 500 MHz CDCl3: 8.2, d, J = 1.2, IH, 7.81, dd, J = 1.7, 8.7, IH, 7.4, s, 2H, 7.18, s, IH, 7.16, d, J = 8.7, IH, 4.37, t, J = 6, IH, 4.09, t, J = 7.1, 2H, 3.92, s, 3H, 2.94, q, J = 6.5, 2H, 2.72, t, J = 6, 2H, 2.65, t, J = 5.8, 2H, 2.35, s, 6H, 1.96-1.9, m, 4H, 1.87-1.82, m, 2H.
Example 75
Methyl 9- [3 -(azetidin- 1 -ylsulfonyl)propyl] -2,3 ,4,9-tetrahydro- 1 H-carbazole-6-carboxylate
Figure imgf000084_0001
Example 75a
Figure imgf000084_0002
[0232] The compound was prepared, as described for example 3-chloro-N,N- dimethylpropane-1 -sulfonamide, from azetidine.
Example 75b
[0233] The compound was prepared, as described for example methyl 9-[3-
(dimethylsulfamoyl)propyl]-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate.
Example 76
Methyl 9- { 3 - [(4,6-dimethoxypyrimidin-2-yl)amino]butyl } -2,3 ,4,9-tetrahydro- lH-carbazole- 6-carboxylate mino]butyl }-2,3 ,4,9-tetrahydro- 1 H-carbazole-6-
Figure imgf000085_0001
[0234] 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.
Example 76b ,4,9-tetrahydro-lH-carbazole-6-carboxylate
Figure imgf000085_0002
[0235] The compound was prepared, as described for example 9-(3-amino-propyl)- β^δ^-tetrahydro-SH-carbazole-S-carboxylic acid methyl ester.
Example 76c
[0236] The compound was prepared, as described for example 9-[3-(4,6-dimethoxy-
[l,3,5]triazine-2-ylamino)-propyl]-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester, from TFA salt of methyl 9-(3-aminobutyl)-2,3,4,9-tetrahydro-lH-carbazole-6- carboxylate and 2-chloro-4,6-dimethoxy pyrimidine. Example 77
9-{3-[(4,6-Diethylpyrimidin-2-yl)oxy]propyl}-6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH- carbazole
Figure imgf000086_0001
thylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole
Figure imgf000086_0002
[0237] To a stirred solution of 6-(m,ethylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole (0.3 g, 1.2 mmol), in 3 ml of dry DMF, NaH (60% suspension in oil, 0.06 g, 1.5 mmol) was added portion wise, followed by the addition of l-bromo-3-chloro propane (0.356 ml, 3.6 mmol). The reaction mixture was stirred overnight, under N2. The mixture was diluted with EtOAc (75 ml), washed with H2O (30 ml) and sat.brine solution (30 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.28 g of the product.
Example 77b
9-{3-[(4,6-Diethylpyrimidin-2-yl)oxy]propyl}-6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH- carbazole
[0238] A sample of 9-(3-chloropropyl)-6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH- carbazole (0.13 g, 0.4 mmol), 2-oxo-4,6-diethyl pyrimidine hydrochloride (0.226 g, 1.2 mmol), Cs2CO3 (1.3 g, 4 mmol) was taken in 2ml of dry DMF and the mixture was heated to 80 0C overnight. The mixture was diluted with EtOAc (50 ml), washed with H2O (25 ml) and sat.brine solution (25 ml). The organic layer was separated, dried over anhyd.MgS04, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.09 g of the product.
Example 78
Methyl 9-[2-(lH-benzimidazol-2-yl)ethyl]-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate
-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate
Figure imgf000087_0001
[0239] To a stirred solution of 6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester (0.916 g, 4 mmol), in 12 ml of dry DMF, NaH (60% suspension in oil, 0.192 g, 4.8 mmol) was added portion wise. After stirring the reaction mixture for 15 min at r.t., 3- chloropropionaldehyde diethylacetal (1.01 ml, 6 mmol), in 4 ml of dry DMF, was added followed by the addition of TBAI (2.21 g, 6 mmol) and the reaction mixture was heated to 50 0C for 24 hrs. The DMF was removed in vacuo, the residue taken into EtOAc (100 ml), washed with H2O (40 ml) and sat.brine solution (40 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude product was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.75 g of the product.
Example 78b
Methyl 9-(3-oxopropyl)-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate
Figure imgf000088_0001
[0240] To a stirred solution of methyl 9-(3,3-diethoxypropyl)-2,3,4,9-tetrahydro-lH- carbazole-6-carboxylate (0.359 g, 1 mmol), in 1 ml of AcOH, 0.5 ml of IN aq.ΗCl was added at 0 0C and the mixture was stirred for 3 hrs. The TLC of mixture showed completion of starting material and a new spot with lower R/ value. The mixture was slowly added to sat. NaHCO3 solution and was extracted with CH2Cl2 (2x50 ml). The organic layers were combined, washed with H2O (40 ml) and sat.brine solution (40 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the residue was dried under high vacuo to obtain 0.28 g of the product, which was used for next step without purification.
Example 78c
Methyl 9-[2-(lH-benzimidazol-2-yl)ethyl]-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate
[0241] A sample of methyl 9-(3-oxopropyl)-2,3,4,9-tetrahydro-lH-carbazole-6- carboxylate (0.256 g, 0.9 mmol), ørf/zø-phenylenediamine (0.097 g, 0.9 mmol), was taken in 3 ml of dry DMF and the mixture was heated to 150 °C overnight. The solvents were removed in vacuo, the residue taken in EtOAc (60 ml), washed with H2O (25 ml) and sat.brine solution (25 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.07 g of the product. 1H NMR 500 MHz CDCl3: 8.12, d, J = 0.8, IH, 7.7, dd, J = 1.4, 8.5, IH, 7.51-7.48, m, 2H, 7.27-7.2, m, 3H, 7.21, d, J = 8.6, IH, 4.53, t, J = 6.9, IH, 3.9, s, 3H, 3.33, t, J = 6.8, 2H, 2.59, brs, 2H, 2.34, brs, 2H, 1.66, brs, 4H.
Example 79 9-{3-[(4,6-Dimethylpyrimidin-2-yl)oxy]propyl}-2,3,4,9-tetrahydro-lH-carbazole-6- carbonitrile
Figure imgf000089_0001
[0242] 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. 1H NMR 500 MHz CDCl3: 7.76, d, J = 1, IH, 7.32, d, J = 8.5, IH, 7.26, dd (merged with CHCl3) IH, 6.69, s, IH, 4.3-4.42, m (two t merged together), 4H, 2.73-2.67, m (two t merged together), 4H, 2.39, s, 6H, 2.2, q, J = 6, 2H, 1.94- 1.90, m, 2H, 1.89-1.81, m, 2H.
Example 80 dro-9H-carbazol-9-yl)-N,N-dimethylpropane- 1 -sulfonamide
Figure imgf000089_0002
[0243] 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. 1H NMR 500 MHz CDCl3: 7.79, s, IH, 7.39-7.34, m (dd and d merged), 2H, 4.25, t, J = 7.2, 2H, 2.85, t, J = 7, 2H, 2.83, s, 6H, 2.74-2.68, m (two t merged together), 4H, 2.25, q, J = 7.1, 2H, 1.99-1.93, m, 2H, 1.90-1.84, m, 2H.
Example 81
9- [3 -(Morpholin-4-ylsulfonyl)propyl]-2,3 ,4,9-tetrahydro- 1 H-carbazole-6-carbonitrile
Figure imgf000090_0001
[0244] 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. 1H NMR 500 MHz CDCl3: 7.79, d, J = 0.7, IH, 7.38, dd, J = 1.4, 8.6, IH, 7.34, d, J = 8.4, IH, 4.25, t, J = 7.1, 2H, 3.74-3.71, m (two t merged together), 4H, 3.21-3.18, m (two t merged together), 4H, 2.85, t, J = 7.1, 2H, 2.74-2.68, m (two t merged together), 4H, 2.27, q, J = 7.1, 2H, 1.99- 1.93, m, 2H, 1.90-1.85, m, 2H.
Example 82
9- {3 - [(4,6-Dimethoxypyrimidin-2-yl)amino]propyl} -2,3 ,4,9-tetrahydro- 1 H-carbazole-6- carbonitrile
Figure imgf000090_0002
[0245] 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. 1H NMR 500 MHz CDCl3: 7.78, d, J = 1.1, IH, 7.34, dd, J = 1.5, 8.4, IH, 7.27, d, J = 8.1, IH, 5.4, s, IH, 4.9, t, J = 5.8, IH, 4.14, t, J = 7.1, 2H, 3.77, s, 6H, 3.41, q, J = 6.7, 2H, 2.7, t, J = 5.7, 4H, 2.06, q, J = 7, 2H, 1.95-1.90, m, 2H, 1.88-1.83, m, 2H. Example 83
9. {3. [(4,6-Dimethylpyrimidin-2-yl)oxy]propyl} -6-(methylsulfonyl)-2,3 ,4,9-tetrahydro- 1 H- carbazole
Figure imgf000091_0001
[0246] 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. 1H NMR 500 MHz CDCl3: 8.06, d, J = 1.2, IH, 7.57, dd, J = I .6, 8.6, IH, 7.41, d, J = 8.6, IH, 6.7, s, IH, 4.32, t, J = 6.9, 2H, 4.27, t, J = 5.7, 2H, 3.05, s, 3H, 2.73, brs, 4H, 2.41, s, 6H, 2.22, q, J = 6.5, 2H, 1.93-1.89, m, 2H, 1.88-1.83, m, 2H.
Example 84 enzimidazol-2-yl)ethyl]-2,3,4,9-tetrahydro-lH-carbazole-6-
Figure imgf000091_0002
[0247] 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. 1H NMR 500 MHz CDCl3: 8.11, d, J = 1.2, IH, 7.69, dd, J = 1.6, 8.6, IH, 7.24, s, 2H, 7.18, d, J = 7.5, IH, 4.5, t, J = 6.9, 2H, 3.89, s, 3H, 3.28, t, J = 6.9, 2H, 2.59, m, 2H, 2.35, m, 2H, 2.32, s, 6H, 1.68, m, 4H.
Example 85 2-yl)oxy]propyl } -2,3 ,4,9-tetrahydro- 1 H-carbazol-6-
Figure imgf000092_0001
Example 85a
6-Nitro-2,3,4,9-tetrahydro-lH-carbazole
Figure imgf000092_0002
[0248] A sample of 4-nitro phenylhydrazine hydrochloride (1.89 g, 10 mmol), cyclohexanone (1.03 ml, 10 mmol) was taken in 15 ml of AcOH and the mixture was refluxed for 6 hrs. The reaction mixture was cooled to room temperature, filtered and washed with EtOAc. The filtrates were concentrated, suspended in EtOAc, filtered and washed with EtOAc. The filtrates were concentrated and the residue was purified by column chromatography using EtOAc/hexane as eluents, to obtain 1.1 g of the product.
Example 85b 9-(3-Chloropropyl)-6-nitro-2,3,4,9-tetrahydro-lH-carbazole
Figure imgf000092_0003
[0249] To a stirred solution of 6-nitro-2,3,4,9-tetrahydro-lH-carbazole (0.8 g, 3.7 mmol), in 10 ml of dry DMF, NaH (60% suspension in oil, 0.18 g, 4.5 mmol) was added portion wise, followed by the addition of l-bromo-3-chloro propane (1.08 ml, 11 mmol). The reaction mixture was stirred at r.t, overnight, under N2. The solvents were removed in vacuo, the residue taken in EtOAc (100 ml), washed with H2O (40 ml) and sat.brine solution (40 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.7 g of the product.
Example 85c 9-{3-[(4,6-Dimethylpyrimidin-2-yl)oxy]propyl}-6-nitro-2,3,4,9-tetrahydro-lH-carbazole
Figure imgf000093_0001
[0250] A sample of 9-(3-chloropropyl)-6-nitro-2,3,4,9-tetrahydro-lH-carbazole (0.7 g,
2.39 mmol), 2-oxo-4,6-diethyl pyrimidine hydrochloride (1.15 g, 7.17 mmol), Cs2CO3 (3.89 g, 11.95 mmol) was taken in 10 ml of dry DMF and the mixture was heated to 80 °C overnight. The solvents were removed in vacuo, the residue taken in EtOAc (100 ml), washed with H2O (40 ml) and sat.brine solution (40 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.7 g of the product. -2-yl)oxy]propy 1 }-2,3 ,4,9-tetrahydro- 1 H-carbazol-6-amine
Figure imgf000093_0002
[0251] To a stirred solution of 9-{3-[(4,6-dimethylpyrimidin-2-yl)oxy]propyl}-6-nitro- 2,3,4,9-tetrahydro-lH-carbazole (0.2 g, 0.525 mmol) in 4/1 ml of MeOΗ/AcOΗ, Zn powder (0.2 g) was added and the mixture was stirred at r.t, for 4 hrs. The TLC of mixture showed completion of starting material and a new spot with lower R/ value. The mixture was filtered off, the filtrates concentrated in vacuo, the residue suspended in EtOAc and the insoluble solids were filtered off. The filtrates were diluted with EtOAc, washed with sat.NaΗCO3 (25 ml), H2O (25 ml) and sat.brine solution (25 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude product was dried under high vacuo, which was used for next step without purification. Example 85e
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 CH2Cl2, NEt3 was added, at 0 °C, followed by addition of methanesulfonyl chloride (0.049 ml, 0.63 mmol). The ice bath was removed after 30 min and the mixture was stirred overnight. The solvents were removed in vacuo, the residue taken in EtOAc (60 ml), washed with sat.NaHCO3 (25 ml), H2O (25 ml) and sat.brine solution (25 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents, to obtain 0.07 g of the product. 1H NMR 500 MHz CDCl3: 7.34, d, J = 2 , IH, 7.26, d, J = 8.5, IH, 6.96, dd, J = 2.1, 8.6, IH, 6.68, s, IH, 6.24, brs, IH, 4.28, t, J = 5.8, 2H, 4.25, t, J = 7, 2H, 2.92, s, 3H, 2.72-2.65, m, 4H, 2.39, s, 6H, 2.21, q, J = 6.1, 2H, 1.93-1.85, m, 2H, 1.85-1.79, m, 2H.
Example 86 -yl)oxy]propyl}-2,3,4,9-tetrahydro-lH-carbazol-6-
Figure imgf000094_0001
[0253] 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 Ac2O and pyridine. 1H ΝMR 500 MHz CDCl3: 7.59, d, J = 1.8, IH, 7.21, d, J = 8.6, IH, 7.17, brs, IH, 7.08, dd, J = 1.9, 8.7, IH, 6.67, s, IH, 4.28, t, J = 5.7, 2H, 4.22, t, J = 6.9, 2H, 2.7-2.65, m, 4H, 2.39, s, 6H, 2.19, q, J = 6.2, 2H, 2.17, s, 3H, 1.91-1.78, m, 4H.
Example 87
Figure imgf000095_0001
Example 87a 9-(3,3-Diethoxypropyl)-6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH-carbazole
Figure imgf000095_0002
[0254] 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
Figure imgf000095_0003
[0255] 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. 1H NMR 500 MHz CDCl3: 9.24, brs, IH, 8.04, d, J = 1.5, IH, 7.71, brs, IH, 7.52, dd, J = 1.6, 8.5, IH, 7.28, d, J = 8.6, IH, 7.23, brs, 2H, 4.54, t, J = 7, 2H, 3.23, t, J = 7, 2H, 3.06, s, 3H, 2.63, brs, 2H, 2.43, brs, 2H, 1.73, brs, 4H.
Example 88 9-[2-(lH-Benzimidazol-2-yl)ethyl]-6-bromo-2,3,4,9-tetrahydro-lH-carbazole
Figure imgf000096_0001
[0257] 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. 1H NMR 500 MHz CDCl3: 8.48, brs, IH, 7.72, brs, IH, 7.59, d, J = 1.7, IH, 7.22, brs, 2H, 7.18, dd, J = 1.6, 8.6, IH, 7.11, d, J = 8.6, IH, 4.48, t, J = 6.7, 2H, 3.25, t, J = 6.7, 2H, 2.58, t, J = 5.7, 2H, 2.26, t, J = 5.9, 2H, 1.67-1.55, m ,6H.
Example 89
Benzyl 5 - { 3 - [(4,6-dimethylpyrimidin-2-yl)oxy]propyl } - 1 ,3 ,4,5-tetrahydro-2H-pyrido [4,3 - έ]indole-2-carboxylate
Figure imgf000097_0001
Η
[0258] A sample of phenylhydrazine hydrochloride (0.984 ml, 10 mmol), cyclohexanone (1.03 ml, 10 mmol) was taken in 15 ml of AcOH and the mixture was refluxed for 6 hrs. The reaction mixture was cooled to room temperature, solvents removed in vacuo, the residue taken into EtOAc, washed with IN HCl, H2O, and sat. NaHCO3 solution. The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the crude was purified by column chromatography, using EtOAc/hexane as eluents. The purifided product was crystallized from EtOAc/hexane to obtain 1.1 g of pure product. ahydro-2H-pyrido[4,3-δ]indole-2-carboxylate
Figure imgf000097_0002
[0259] 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.
Example 89c
Benzyl 5 - { 3 - [(4,6-dimethylpyrimidin-2-yl)oxy]propyl } - 1 ,3 ,4,5-tetrahydro-2H-pyrido [4,3- 6]indole-2-carboxylate [0260] The compound was prepared, as described for example 9-{3-[(4,6- diethylpyrimidin-2-yl)oxy]propyl }-6-(methylsulfonyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole, from benzyl 5-(3-chloropropyl)-l,3,4,5-tetrahydro-2H-pyrido[4,3-ό]indole-2-carboxylate and 2-oxo-4,6-dimethoxypyrimidine. 1H NMR 500 MHz CDCl3: 7.48-7.34, m, 5H, 7.33, brd, J = 8.7, 2H, 7.15-7.1, m, IH, 7.07, t, J = 7.5, IH, 6.67, s, IH, 5.18, s, 2H, 4.72, brs, 2H, 4.33-4.22, m, 4H, 3.84, brs, 2H, 2.82, brs, 2H, 2.38, s, 6H, 2.22, q, J = 6.4, 2H.
Example 90
Figure imgf000098_0001
Example 90a ]cyclohex-2-en-l-one
Figure imgf000098_0002
[0261] To a stirring solution of 1,3-cyclohexane dione in 5 ml/15 ml of EtOH/H2O, 4- bromo phenylhydrazine hydrochloride was added portion wise and the reaction mixture (clear solution) was stirred at r.t., overnight. The resulting solids were collected by filtration, washed with H2O and the solids were dried under high vacuo to obtain 2.1 g of the product, which was used for next step without purification.
Example 90b
6-Bromo- 1 ,2,3,9-tetrahydro-4H-carbazol-4-one
Figure imgf000098_0003
[0262] A sample of 3-[2-(4-bromophenyl)hydrazinyl]cyclohex-2-en-l-one (0.56 g, 2 mmol) was taken in 6 ml of TFA and the mixture was refluxed overnight. The solvents were removed in vacuo, the residue suspended in MeOH, the insoluble product was collected by filtration, washed with MeOH and the solids were dried under high vacuo to obtain 115 mg of pure product. lfanyl]-3,5-difluorobenzene 3-chloropropyl 3,5-difluorophenyl sulfide
Figure imgf000099_0001
[0263] To a stirred solution of 3,5-difluoro thiophenol (1.48 ml, 15 mmol), in 5 ml of
MeOH, sodium hydroxide (600 mg, 15 mmol), in 20 ml of H2O, was added and the mixture was strirred at room temperature for 30 min. Then, l-bromo-3-chloro propane, in 5 ml of MeOH, was added and the mixture was stirred for 18 hrs. The reaction mixture was diluted with EtOAc (200 ml), the organic layer separated, washed sequentially with IN NaOH (75 ml), sat.NH4Cl (75 ml) and sat.brine (75 ml) solution. The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the residual oil was dried under high vacuo to obtain 2.4 g of the product, which was used for next step without purification. 1H NMR 500 MHz CDCl3: 6.9-6.75, m, 2H, 6.65-6.57, m, IH, 3.66, t, J = 6.2, 2H, 3.10, t, J = 6.96, 2H, 2.11, q, J = 6.67, 2H.
Example 9Od
6-Bromo-9- { 3 -[(3 ,5 -difluoroρhenyl)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. After stirring for 30 min at r.t., l-(3-chloro-propylsulfanyl)-3,5-difluoro benzene (0.334 g, 1.5 mmol), in 1 ml of dry DMF, was added followed by the addition of tetra-«-butyl ammonium iodide (0.554 g, 1.5 mmol). The reaction mixture was heated to 70 °C, under N2, overnight. The DMF was removed in vacuo, the residue treated with H2O and the mixture was extracted with EtOAc (2x40 ml). The organic layer was separated, washed with H2O (30 ml), sat.brine (30 ml) solution, was dried over anhyd.MgSO4, solvents removed in vacuo and the crude product was purified by column chromatography to obtain 0.18g of pure product. 1H NMR 500 MHz CDCl3: 8.41, d, J = 1.9, IH, 7.34, dd, J = 1.9, 8.7, IH, 7.16, d, J = 8.7, IH, 6.79-6.73, m, 2H, 6.68-6.59, m , IH, 4.24, t, J = 7, 2H, 2.91, t, J = 6.5, 4H, 2.57, t, J = 6, 2H, 2.24, q, J = 6.4, 2H, 2.15, q, J = 6.9, 2H.
Example 91
9-{3-[(3,5-Difluorophenyl)sulfanyl]propyl}-6-(methylsulfonyl)-2,3,4,9-tetrahydro-lH- carbazole
Figure imgf000100_0001
[0265] 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. 1H NMR 500 MHz CDCl3: 8.1, d, J = 1.6, IH, 7.65, dd, J = 1.7, 8.6, IH, 7.35, d, J = 8.6, IH, 6.76-6.64, m, 2H, 6.63-6.56, m, IH, 4.21 t, J = 6.9, 2H, 3.06, s, 3H, 2.87, t, J = 6.9, 2H, 2.77-2.65, m, 4H, 2.1, q, J = 6.9, 2H, 1.98-1.92, m, 2H, 1.91-1.84, m, 2H.
Example 92 uorophenyl)sulfanyl]propyl}-3,4,5,6-tetrahydroazepino[4,3-
Figure imgf000100_0002
Example 92a (4£/Z)-6-bromo-N-hydroxy-l,2,3,9-tetrahydro-4H-carbazol-4-imine
Figure imgf000101_0001
[0266] A sample of 6-bromo-l,2,3,9-tetrahydro-4H-carbazol-4-one (0.528 g, 2 mmol) was taken in 5 ml of pyridine, 5 ml of EtOH and was added hydroxy lamine hydrochloride (2.78 g, 40 mmol). The reaction mixture was refluxed overnight, solvents removed in vacuo, the residue was treated with H2O and the mixture was extracted with EtOAc (2x40 ml). The combined organic layers were combined, washed with with H2O (30 ml) and sat.brine (30 ml) solution. The organic layer was dried over anhyd.MgSO4, solvents removed in vacuo and the residue was dried under high vacuo to obtain 0.5 g of crude product, which was used for next step.
Example 92b
9-Bromo-3,4,5,6-tetrahydroazepino[4,3-&]indol-l(2H)-one
Figure imgf000101_0002
[0267] To a sample of polyphosphoric acid (20 g), (4£/Z)-6-bromo-N-hydroxy-l,2,3,9- tetrahydro-4H-carbazol-4-imine (0.5 g, 1.75 mmol), in 10 ml of dioxane, was added and the mixture was refluxed for 3 hrs. The mixture was cooled to r.t, slowly added to ice cold sat. NaHCO3 solution (300 ml), the resulting solids were collected by filtration, washed with H2O and the solids were dried under high vacuo to obtain 0.3 g of crude product, which was used for next step without purification. opyl)-3,4,5,6-tetrahydroazepino[4,3-έ]indol-l(2H)-one
Figure imgf000101_0003
[0268] To a sample of 9-bromo-3;4,5,6-tetrahydroazepino[4,3-έ]indol-l(2H)-one (0.15g, 0.53 mmol) in 2 ml of dry DMF, Cs2CO3 (0.21 g, 0.645 mmol) was added followed by the addition of l-bromo-3-chloro propane (0.064ml, 0.645 mmol). After stirring at r.t., overnight, Cs2CO3 (0.21 g, 0.645 mmol) and l-bromo-3-chloro propane (0.064ml, 0.645 mmol) was added and the mixture was stirred for 6 hrs. 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 H2O (25 ml) and sat.brine (25 ml) solution. The organic layer was dried over anhyd. MgSO4, solvents removed in vacuo and the crude product was purified by column chromatography to obtain 0.12 g of pure product.
Example 92d
9-Bromo-6- {3- [(3 ,5 -difluorophenyl)sulfanyl]propyl } -3 ,4,5 ,6-tetrahydroazepino[4,3 - 6]indol-l(2H)-one
[0269] A sample of 9-bromo-6-(3-chloropropyl)-3,4,5,6-tetrahydroazepino[4,3-δ]indol- l(2H)-one (0.11 g, 0.31 mmol), 3,5-difluorothiophenol (0.135 g, 0.927 mmol), Cs2CO3 (0.302 g, 0.927 mmol) and the mixture was stirred at r.t., overnight. 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 H2O (25 ml) and sat.brine (25 ml) solution. The organic layer was dried over anhyd.MgSO4, solvents removed in vacuo and the crude product was purified by column chromatography to obtain 0.088 g of pure product. 1B. NMR 500 MHz D6DMSO: 8.42 d, J = 1.8 IH, 7.6, t, J = 5, IH, 7.46, d, J = 8.7, IH, 7.26, dd, J = 1.8, 8.6, IH, 7.1-6.98, m, 3H, 4.27, t, J = 7.4, 2H, 3.18, q, J = 4.9, 2H, 3.11, t, J = 7.2, 2H, 3.07, t, J = 6.5, 2H, 2.05-1.98, m, 2H, 1.95, q, J - 7.2, 2H.
Example 93
2-methoxyethyl 9- [3 -(dimethylsulfamoyl)propyl]-2,3 ,4,9-tetrahydro- 1 H-carbazole-6- carboxylate
Figure imgf000102_0001
[0270] 2-methoxyethyl-2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate, 200 mg, Dimethyl formamide, 2 ml, sodium hydride, 19.3 mg, were combined in a 20 ml vial. The mix was stirred 15 minutes, the N^-dimethyl-S-chloropropylsulfonamide, 163 mg, and tetrabutylammonium iodide, 1.Ig, was added. The mixture was stirred over night at room temperature. The reaction was portioned between dichloromethane, 20 ml and water, 20 ml. The dichloromethane layer was dried and evaporated. The residue was purified by chromatography on silicia with dichloromethane and ethyl acetate to provide 2- methoxy ethyl 9- [3 -(dimethylsulfamoyl)propyl] -2,3 ,4,9-tetrahydro- 1 H-carbazole-6- carboxylate, a yellow oil.
Example 94
6-bromo-9- { 3 - [(4,6-diethylpyrimidin-2-yl)oxy]propyl } -2,3 ,4,9-tetrahydro- 1 H-carbazol- 1 - one
Figure imgf000103_0001
a) 6-bromo-9-{ 3 -chloropropyl} -2,3, 4,9-tetrahydro-l H-carbazol- 1 -one
[0271] Following example 1 c, 6-bromo-2,3,4,9-tetrahydro-lH-carbazol-l-one was converted to 6-bromo-9-{3-chloropropyl}-2,3,4,9-tetrahydro-lH-carbazol-l-one
b) 6-bromo-9- { 3-[(4,6-diethylpyrimidin-2-yl)oxy]propyl} -2,3,4,9-tetrahydro- 1 Η-carbazol-
1-one [0272] Following Example 1 d, 6-bromo-9-{3-chloropropyl}-2,3,4,9-tetrahydro-lH- carbazol-1-one was converted to 6-bromo-9-{3-[(4,6-diethylpyrimidin-2-yl)oxy]propyl}- 2,3,4,9-tetrahydro- lΗ-carbazol-1 -one.
Example 95 l-(6-bromo-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-3-[(4,6-diethylpyrimidin-2- yl)oxy]propan-2-ol
Figure imgf000104_0001
a) 6-bromo-9-(oxiran-2-ylmethyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole
[0273] Prepared following the method of example Ic using 6-bromo-2,3,4,9-tetrahydro-
1 H-carbazole and epichlorhydrin.
[0274] b) 6-bromo-9-(oxiran-2-ylmethyl)-2,3,4,9-tetrahydro-l H-carbazole, 132 mg, Cesium carbonate, 423 mg, and DMF, 1.5 ml, were combined in a 20 ml vial, and 2- hydroxy-4,6-dimethylpyrimidine hydrochloride, 139 mg, was added. The mix was heated at 80 0C over night. The mix was cooled to room temperature, diluted with dichloromethane, 10 ml, and washed3 X 10 ml water. The combine water washes were back extracted wit hlO ml dichloromethane. The combined dichloromethane extracts were washed with brine and dried with magnesium sulfate. The mix was evaporated to a yellow oil. The yellow oil was crystalised from dichlomethane to provide 45 mg of l-(6-bromo- 1,2,3, 4-tetrahydro-9H- carbazol-9-yl)-3-[(4,6-diethylpyrimidin-2-yl)oxy]propan-2-ol
Example 96
9-{3-[(4,6-dimethoxypyrimidin-2-yl)amino]propyl}-2,3,4,9-tetrahydro-lH-carbazole-6- carboxamide
Figure imgf000104_0002
a) 9-{3-[(4,6-dimethoxypyrimidin-2-yl)amino]propyl}-2,3,4,9-tetrahydro-lH-carbazole-6- carboxylic acid [0275] A sample of the compound of Example 28, 200 mg, in methanol, 1.5 ml, was treated with aqueous 2N sodium hydroxide, 0.6 ml. When TLC indicated consumption of the starting material, the mix was diluted wit hlO ml of water, and acidified with IM hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and air dried to give the 9-{3-[(4,6-dimethoxypyrimidin-2-yl)amino]propyl}-2,3,4,9- tetrahydro- 1 H-carbazole-6-carboxylic acid.
b) 9- { 3 - [(4,6-dimethoxypyrimidin-2-yl)amino]propyl } -2,3 ,4,9-tetrahydro- 1 H-carbazole-6- carboxamide [0276] 9-[3-(4,6-Dimethoxy-pyrimidin-4-ylamino)-propyl]-6,7,8,9-tetrahydro-5H- carbazole-3-carboxcylic acid, 100 mg, was combined with DMF, 2 ml, PIATU, 92mg, in a 20 ml vial with a stirring bar. Then triethylamine, 106 uL, was added. The mix was stirred 10 minutes, and then ammonium chloride, 40 mg, was added. The mixture was stirred over night. The mixture was diluted wit h20 ml water and extracted 2 X 10 ml dichloromethane. The combined dichloromethane extracts were washed with brine and dried with magnesium sulfate. The mix was evaporated to a yellow oil. 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-lΗ-carbazole-6-carboxamide, RF 0.2 on silica with 2:1 dichloromethane/ethyl acetate.
Example 97 (9- { 3 -[(4,6-dimethoxypyrimidin-2-yl)amino]propyl } -2,3 ,4,9-tetrahydro- 1 H-carbazol-6-
Figure imgf000105_0001
[0277] Following the method of 96b, except add 1 -(trimethylsiliyl)pyrrolidine to provide (9- { 3 -[(4,6-dimethoxypyrimidin-2-yl)amino]propyl } -2,3 ,4,9-tetrahydro- 1 H-carbazol-6- yl)(pyrrolidin- 1 -yl)methanone Example 98
2-methoxyethyl 9- { 3- [(4,6-dimethoxypyrimidin-2-yl)amino]propyl} -2,3 ,4,9-tetrahydro- 1 H- carbazole-6-carboxylate
Figure imgf000106_0001
[0278] A sample of the compound of example 28, 150 mg, in methoxyethanol, 2 ml, and sulfuric acid, 0.2 ml, was warmed to 90 0C for 18 hours. The mix was treated with 1 ml of water and evaporated in vacuo. The residue was taken up in ethyl acetate and washed with water X3, then brine, and dried over magnesium sulfate. The organic layer was evaporated and purified by column chromatography on silica to provide 2-methoxyethyl 9-{3-[(4,6- dimethoxypyrimidin-2-yl)amino]propyl } -2,3 ,4,9-tetrahydro- 1 H-carbazole-6-carboxylate, 10 mg.
Example 99
(9- { 3 -[(4,6-dimethoxypyrimidin-2-yl)amino]propyl } -2,3 ,4,9-tetrahydro- 1 Η-carbazol-6- yl)(3 -hydroxypiperidin- 1 -yl)methanone
Figure imgf000106_0002
[0279] Following the method of 96b, except add 3-hydroxypiperidine to provide (9-{3- [(4,6-dimethoxypyrimidin-2-yl)amino]propyl}-2,3,4,9-tetrahydro-lH-carbazol-6-yl)(3- hydroxypiperidin- 1 -yl)methanone
Example 100 methyl 9- { 3 - [(4,6-dimethylpyrimidin-2-yl)oxy]propyl } -2,3 ,4,9-tetrahydro- 1 H-carbazole-6- carboxylate
Figure imgf000107_0001
[0280] In a 25 ml round bottom flask with stirring bar was combined 2-hydroxy-4,6- dimethylpyrimidine hydrochloride, 2.05 g, cesium carbonate, 5.5g, and dimethyl formamide, 8.5 ml. The mix was stirred 30 minutes, then intermediate 1 c, 1.3g, was added. The resulting mix was heated at 80 0C overnight. TLC with 1 : 1 ethyl acetate/hexanes on silica showed complete conversion to new lower RF spot. The reaction was diluted with water, and extracted with ethyl acetate. The organic layer was washed twice with water. The combined aqueous layers were back extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated in vacuo to provide methyl 9-{3-[(4,6-dimethylpyrimidin-2-yl)oxy]propyl}- 2,3,4,9-tetrahydro-lH-carbazole-6-carboxylate as an orange oil.
Example 101
9-{3-[(4,6-dimethylpyrimidin-2-yl)oxy]propyl}-N-(2-methoxyethyl)-2,3,4,9-tetrahydro-lH- carbazole-6-carboxamide
Figure imgf000107_0002
a) 9- { 3 - [(4,6-dimethylpyrimidin-2-yl)oxy]propyl } -2,3 ,4,9-tetrahydro- 1 H-carbazole-6- carboxylic acid
Figure imgf000108_0001
[0281] In a 50 ml round bottom with stirring bar, a sample or example 100, 1.0 g, and methanol, 10 ml, was treated with aqueous 2 N sodium hydroxide, 3 ml. The mix was heated 18 hours at 85 0C. TLC showed conversion to product with lower RF. The solvents were removed in vacuo. The residue was suspended in ethyl acetate and washed with water, brine then HCl aqueous. The resulting suspention of solids was filtered and wahed with 1/1 ethyl acetate/hexanes and dried to provide 9-{3-[(4,6-dimethylpyrimidin-2-yl)oxy]propyl}- 2,3,4,9-tetrahydro-lH-carbazole-6-carboxylic acid, an off white solid. b) 9-{3-[(4,6-dimethylpyrimidin-2-yl)oxy]propyl}-N-(2-methoxyethyl)-2,3,4,9-tetrahydro- lH-carbazole-6-carboxamide
b) 9- { 3 - [(4,6-dimethylpyrimidin-2-yl)oxy]propyl} -N-(2-methoxyethyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole-6-carboxamide
[0282] Following the method of 96b, 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.
Table 4
Figure imgf000108_0002
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Table 5
Figure imgf000115_0001
Figure imgf000116_0001

Claims

WHAT IS CLAIMED IS:
1. A compound having the formula:
Figure imgf000117_0001
wherein, ring A is a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
L1 is substituted or unsubstituted alkylene;
L2 is a bond, -O-L3-, -S(O)n-L3-, -NR6-L3-, -NR6C(O)-L3-, -C(O)N(R6)-L3-, -NR6S(O)2-L3-, or -S(O)2NR6-L3-, wherein L3 is a bond, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene and n is an integer from 0 to 2; R1, R2, R3 and R4 are independently hydrogen, halogen, -CN, - S(O)2N(R7XR8), -C(O)R9, -NR10-C(O)R' \ -NR12-C(O)-OR13, -C(O)NR14R15, - NR16S(O)2R17, -S(O)1R19, -NR20R21, -OR22, -C(NR20)-N(R21)-OR22, -C(O)OR23, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, wherein t is an integer from O to 2;
R5 is hydrogen, -CN, halogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
J RtI6, R IS.7, J RtV8, J RtV9, R JK.10 , RIv11 , RJΛ.12 , RJtV13 , RIv14 , RIv15 , RJtV16 , RIv17 , R1V18 , RJtV19 , RJtV20 , R1V21 , R1V22 , and R23 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.
2. The compound of claim 1, wherein ring A has the formula:
Figure imgf000118_0001
wherein, X, Y and Z are independently a bond, substituted or unsubstituted C1-C3 alkylene, -N(R24)-, -O-, -S(O)n-, -S(O)2-N(R24)-, -N(R24)-S(O)2-N(R25)-, -C(O)-N(R24)-, - N(R24)-C(O)-, -C(O)-, or -C(R26R27)-; R24 and R25 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; and R26 and R27 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; wherein at least two of X, Y and Z are not a bond.
3. The compound of claim 2, wherein Y is not a bond.
4. The compound of claim 3, wherein Y is -CH(F)-, -CF2-, -C(O)-, -C(O)-N(R24)-, -S(O)2-, -S(O)2-N(R24)-, or -N(R24)-S(O)2-N(R25)-.
5. The compound of claim 1 , wherein ring A is a substituted or unsubstituted C5 to C7 cycloalkyl, or substituted or unsubstituted 5 to 7 membered heterocycloalkyl.
6. The compound of claim 1 , wherein ring A has the formula:
Figure imgf000119_0001
wherein, k is an integer from 0 to 2; m is in integer from 0 to 3 ; v is an integer from 0 to 4; and R28 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, wherein if R28 is attached to nitrogen then R28 is not halogen.
7. The compound of claim 6, wherein k, m and v are 0.
8. The compound of claim 1 , wherein ring A has the formula:
Figure imgf000119_0002
9. The compound of claim 1 , wherein ring A has the formula:
Figure imgf000120_0001
10. The compound of claim 9, wherein R 28 is hydrogen.
11. The compound of claim 1, wherein L1 is substituted or unsubstituted Ci to Ci2 alkylene.
12. The compound of claim 1, wherein L1 is substituted or unsubstituted C1 to C8 alkylene.
13. The compound of claim 1, wherein L1 is substituted or unsubstituted Ci to Ce alkylene.
14. The compound of claim 1, wherein L1 is substituted or unsubstituted C2 to C4 alkylene.
15. The compound of claim 1 , wherein L2 is -O-L3-, -S(O)n-L3-, -NR6-L3-
, -S(O)2NR ,6°-τIΛ3 , or -NR0S(O)2-L -.
16. The compound of claim I5 wherein L is -O-L -, -S(O)n-L -, or -NR -
L , wherein n is 2.
17. The compound of one of claims 15 or 16, wherein L3 is a bond.
18. The compound of claim 17, wherein L1 is substituted or unsubstituted C1 to C6 alkylene.
19. The compound of claim 1, wherein R5 is hydrogen, R29-substituted or unsubstituted cycloalkyl, R29-substituted or unsubstituted heterocycloalkyl, R29-substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl, wherein R29 is -CN, oxo, halogen, -OR30, -C(O)OR31, -NR32R33, R34-substituted or unsubstituted alkyl, R34-substituted or unsubstituted heteroalkyl, R34-substituted or unsubstituted cycloalkyl, R34-substituted or unsubstituted heterocycloalkyl, R34-substituted or unsubstituted aryl, or R34-substituted or unsubstituted heteroaryl, R30, R3 ! , R32 and R33 are independently R35-substituted or unsubstituted alkyl, R35-substituted or unsubstituted heteroalkyl, R35-substituted or unsubstituted cycloalkyl, R35 -substituted or unsubstituted heterocycloalkyl, R35-substituted or unsubstituted aryl, or R3D-substituted or unsubstituted heteroaryl, and R34 and R35 are independently unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
20. The compound of claim 1, wherein R5 is substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.
21. The compound of claim 1 , wherein R5 is substituted or unsubstituted aryl.
22. The compound of claim 1, wherein R5 is substituted or unsubstituted heteroaryl.
23. The compound of claim 1 , wherein R5 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted imidizolyl, 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 piperidinyl, or substituted or unsubstituted piperazinyl.
24. The compound of claim 1 , wherein R3 is halogen, -CN, -NR10- C(O)R", -C(O)NR14R15, -NR16S(O)2R17, -S(O)1R19, -C(N)-N-OR22, or -C(O)OR23.
25. The compound of claim 1, wherein R2 is hydrogen.
26. The compound of claim 1 , wherein R4 is hydrogen.
27. The compound of claim 1, wherein R1 is hydrogen.
28. A pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a compound of one of claims 1 to 27.
29. A method of inhibiting the entry of a Hepatitis C virus into a cell, said method comprising contacting said cell and/or said Hepatitis C virus with an effective amount of the compound of one of claims 1 to 27.
30. A method of treating a disease in a subject caused by a Hepatitis C viral infection, said method comprising administering to said subject an effective amount of the compound of one of claims 1 to 27.
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