Abstract:
The invention is directed to methods of treating, preventing, or inhibiting a Hepatitis C viral infection in a mammal comprising contacting the mammal with an effective amount of a compound of the formula:  
                         
 
     Wherein substitutions at R 1 , R 2  , R 3 -R 12 , and Y are set forth in the specification.

Description:
[0001]    This application claims the benefit of U.S. Provisional Application No. 60/382,154, filed on May 21, 2002, and U.S. Provisional Application No. 60/458,706, filed Mar. 28, 2003. These applications are hereby incorporated by reference. 
     
    
     
       BACKGROUND OF THE INVENTION  
         [0002]    1. Field of the Invention  
           [0003]    This invention is directed to pyranoindole derivatives, pharmaceutical compositions containing them, and to their use in the treatment of Hepatitis C viral infections, either alone or in conjunction with one or more biologically active agents, either concurrently or sequentially.  
           [0004]    2. Related Background Art  
           [0005]    Hepatitis C is a common viral infection that can lead to chronic Hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma. Infection with the Hepatitis C virus (HCV) leads to chronic Hepatitis in at least 85% of cases, is the leading reason for liver transplantation, and is responsible for at least 10,000 deaths annually in the United States (Hepatology, 1997, 26 (Suppl. 1), 2S-10S).  
           [0006]    The Hepatitis C virus is a member of the Flaviviridae family, and the genome of HCV is a single-stranded linear RNA of positive sense (Hepatology, 1997, 26 (Suppl. 1), 11S-14S). HCV displays extensive genetic heterogeneity; at least 6 genotypes and more than 50 subtypes have been identified.  
           [0007]    There is no effective vaccine to prevent HCV infection. The only therapy currently available is treatment with interferon-α (INF-α or combination therapy of INF-α with the nucleoside analog ribavirin (Antiviral Chemistry and Chemotherapy, 1997, 8, 281-301). However, only about 40% of treated patients develop a sustained response, so there is a need for more effective anti-HCV therapeutic agents.  
           [0008]    The HCV genome contains a number of non-structural proteins: NS2, NS3, NS4A, NS4B, NS5A, and NS5B (J. General Virology, 2000, 81, 1631-1648). NS5B is an RNA-dependent RNA polymerase which is essential for viral replication, and therefore, the inhibition of NS5B is a suitable target for the development of therapeutic agents.  
           [0009]    In the following U.S. patents, pyranoindole derivatives are disclosed and the compounds are stated to have antidepressant and antiulcer activity: U.S. Pat. Nos. 3,880,853 (Apr. 29, 1975), 4,118,394 (Oct. 3, 1978). In U.S. Pat. No. 4,179,503 (Dec. 18, 1979) pyranoindoles are disclosed and stated to have diuretic activity. In the following U.S. patents, pyranoindole derivatives are disclosed and the compounds are stated to have antiinflammatory, analgesic, antibacterial, and antifungal activity: U.S. Pat. Nos. 3,843,681 (Oct. 22, 1974), 3,939,178 (Feb. 17, 1976), 3,974,179 (Aug. 10, 1976), 4,070,371 (Jan. 24, 1979), 4,076,831 (Feb. 28, 1978). In the following U.S. patents, pyranoindole derivatives are disclosed and the compounds are stated to have antiinflammatory and analgesic activity: U.S. Pat. Nos. 4,670,462 (Jun. 2, 1987), 4,686,213 (Aug. 11, 1987), 4,785,015 (Nov. 15, 1988), 4,810,699 (Mar. 7, 1989), 4,822,781 (Apr. 18, 1989), 4,960,902 (Oct. 2, 1990). In U.S. Pat. No. 5,776,967 (Jul. 7, 1998) and U.S. Pat. No. 5,830,911 (Nov. 3, 1998), pyranoindole derivatives are disclosed and the compounds are said to inhibit cyclooxegenase-2 and be useful for treating arthritic disorders, colorectal cancer, and Alzheimer&#39;s disease.  
           [0010]    Also, in the following U.S. patents, processes for preparing pyranoindole derivatives are disclosed: U.S. Pat. Nos. 4,012,417 (Mar. 15, 1977), 4,036,842 (Jul. 19, 1977), 4,585,877 (Apr. 29, 1986), 4,822,893 (Apr. 18, 1989). Processes for the resolution of racemic pyranoindole derivatives are disclosed in the following U.S. Pat. Nos.: 4,501,899 (Feb. 26, 1985), 4,515,961 (May 7, 1985), 4,520,203 (May 28, 1985), 4,544,757 (Oct. 1, 1985).  
           [0011]    Other aspects of the instant invention are described in applicant&#39;s U.S. provisional patent application No. 60/382,148, filed concurrently with the instant application, and which is hereby incorporated by reference in its entirety.  
         BRIEF SUMMARY OF THE INVENTION  
         [0012]    This invention relates to pyranoindole derivatives, processes for their preparation and pharmaceutical compositions containing them, and to their use in the treatment of Hepatitis C viral infection. This invention further relates to methods of treating or preventing a Hepatitis C viral infection in a mammal, said methods comprising providing the mammal with an effective amount of at least one pharmaceutical composition, wherein the pharmaceutical composition includes a compound of the invention which is a pyranoindole derivative and further comprising providing the mammal with at least one biologically active agent, either concurrently or sequentially with the pharmaceutical composition. This invention also relates to methods of inhibiting replication of a Hepatitis C virus, said methods comprising contacting the virus with an effective amount of at least one pharmaceutical composition, wherein the pharmaceutical composition includes a compound of the invention which is a pyranoindole derivative and further comprising providing the mammal with at least one biologically active agent, either concurrently or sequentially with the pharmaceutical composition.  
           [0013]    In accordance with this invention there is provided a group of compounds represented by formula (I):  
                         
 
           [0014]    wherein:  
           [0015]    R 1  is H, a straight chain alkyl of 1 to 8 carbon atoms, a branched alkyl of 3 to 12 carbon atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an alkynyl of 2 to 7 carbon atoms, or an arylalkyl or an alkylaryl of 7 to 12 carbon atoms;  
           [0016]    R 2  is H, a straight chain alkyl of 1 to 12 carbon atoms, a branched alkyl of 3 to 12 carbon atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an alkynyl of 2 to 7 carbon atoms, an alkoxyalkyl of 2 to 12 carbon atoms, an arylalkyl or alkylaryl of 7 to 12 carbon atoms, a cyanoalkyl of 1 to 8 carbon atoms, an alkylthioalkyl of 2 to 16 carbon atoms, a cycloalkyl-alkyl of 4 to 24 carbon atoms, a substituted or unsubstituted aryl, or a heteroaryl;  
           [0017]    R 3 -R 6  are independently H, a straight chain alkyl of 1 to 8 carbon atoms, a branched alkyl of 3 to 12 carbon atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, a substituted or unsubstituted aryl, furanylmethyl, arylalkyl or alkylaryl of 7 to 12 carbon atoms, alkynyl of 2 to 7 carbon atoms, or R 5  and R 6  together with the ring carbon atom to which they are attached form a carbonyl group;  
           [0018]    R 7 -R 10  are independently H, a straight chain alkyl of 1 to 8 carbon atoms, a branched alkyl of 3 to 12 carbons atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, furanylmethyl, arylalkyl or alkylaryl of 7 to 12 carbon atoms, alkynyl of 2 to 7 carbon atoms, phenylalkynyl, alkoxy of 1 to 8 carbon atoms, arylalkoxy of 7 to 12 carbon atoms, fluoroalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to 8 carbon atoms, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, trifluoroethylthio, acyl of 1 to 7 carbon atoms, COOH, COO-alkyl, CONR 11 R 12 , F, Cl, Br, I, CN, CF 3 , NO 2 , alkylsulfinyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, pyrrolidinyl, or thiazolidinyl;  
           [0019]    R 11 -R 12  are independently H, straight chain alkyl of 1 to 8 carbon atoms, branched alkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, a substituted or unsubstituted aryl or heteroaryl;  
           [0020]    Y is a bond, CH 2 , CH 2 CH 2 , aryl, or R 2  and Y together with the ring carbon atom to which they are attached may additionally form a spirocyclic cycloalkyl ring of 3 to 8 carbon atoms; or  
           [0021]    a crystalline form or a pharmaceutically acceptable salt thereof.  
           [0022]    For purposes of this invention the term “alkyl” includes both straight and branched alkyl moieties, preferably of 1 to 8 carbon atoms. The term “alkenyl” refers to a radical aliphatic hydrocarbon containing one double bond and includes both straight and branched alkenyl moieties of 2 to 7 carbon atoms. Such alkenyl moieties may exist in the E or Z configurations; the compounds of this invention include both configurations. The term “alkynyl” includes both straight chain and branched moieties containing 2 to 7 carbon atoms having at least one triple bond. The term “cycloalkyl” refers to alicyclic hydrocarbon groups having 3 to 12 carbon atoms and includes but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, or adamantyl.  
           [0023]    For purposes of this invention the term “aryl” is defined as an aromatic hydrocarbon moiety and may be substituted or unsubstituted. An aryl may be selected from but not limited to, the group: phenyl, α-naphthyl, β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl, or phenanthrenyl groups. In one embodiment the substituted aryl may be optionally mono-, di-, tri- or tetra-substituted with substituents selected from, but not limited to, the group consisting of alkyl, acyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, cyano, halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, trifluoropropyl, amino, alkylamino, dialkylamino, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, —SO 3 H, —SO 2 NH 2 , —SO 2 NHalkyl, —SO 2 N(alkyl) 2 , —CO 2 H, CO 2 NH 2 , CO 2 NHalkyl, and —CO 2 N(alkyl) 2 . Preferred substituents for aryl and heteroaryl include: alkyl, halogen, amino, alkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy, arylalkyl, and alkylaryl.  
           [0024]    For purposes of this invention the term “heteroaryl” is defined as an aromatic heterocyclic ring system (monocyclic or bicyclic) where the heteroaryl moieties are five or six membered rings containing 1 to 4 heteroatoms selected from the group consisting of S, N, and O, and include but is not limited to: (1) furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, pyrrolidinyl; (2) a bicyclic aromatic heterocycle where a phenyl, pyridine, pyrimidine or pyridizine ring is: (i) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (ii) fused to a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (iii) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (iv) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S.  
           [0025]    For the purposes of this invention the term “alkoxy” is defined as C1-C12-alkyl-O—; the term “aryloxy” is defined as aryl-O—; the term “heteroaryloxy” is defined as heteroaryl-O—; wherein alkyl, aryl, and heteroaryl are as defined above.  
           [0026]    For purposes of this invention the term “arylalkyl” is defined as aryl-C1-C6-alkyl-; arylalkyl moieties include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.  
           [0027]    For purposes of this invention the term “alkylaryl” is defined as C1-C6-alkyl-aryl-.  
           [0028]    For purposes of this invention the term “alkylthio” is defined as C1-C6alkyl-S—.  
           [0029]    For purposes of this invention “alkoxyalkyl,” “cycloalkyl-alkyl,” “alkylthioalkyl,” “aryloxyalkyl,” and “heteroaryloxyalkyl” denote an alkyl group as defined above that is further substituted with an alkoxy, cycloalkyl, alkylthio, aryloxy, or heteroaryloxy group as defined above.  
           [0030]    For purposes of this invention “arylalkoxy,” “alkoxyalkoxy,” “fluoroalkoxy,” “alkylthioalkoxy,” and “heteroarylalkoxy” denote an alkoxy group as defined above that is further substituted with an aryl, alkoxy, fluoro, alkylthio, or heteroaryl group as defined above.  
           [0031]    For purposes of this invention “arylthio” and “heteroarylthio,” denote a thio group that is further substituted with an aryl or heteroaryl group as defined above.  
           [0032]    For purposes of this invention “arylthioalkyl” and “heteroarylthioalkyl” denote an alkyl group as defined above that is further substituted with an arylthio or heteroarylthio group as defined above.  
           [0033]    For purposes of this invention the term “arylalkylthio” is defined as aryl-C1-C8-alkyl-S—; “heteroarylalkylthio” is defined as heteroaryl-C1-C8-alkyl-S—, where aryl and heteroaryl are as defined above.  
           [0034]    For purposes of this invention “aryloxyalkylthio” is defined as aryloxy-C1-C8-alkyl-S; “heteroaryloxyalkylthio” is defined as heteroaryloxy-C1-C8alkyl-S—; where aryloxy, heteroaryloxy, and alkyl are defined above.  
           [0035]    For purposes of this invention “phenylalkynyl” is an alkynyl group further substituted with a phenyl group.  
           [0036]    In the most preferred embodiment of this invention a substituted methyl comprises a methyl substituent further substituted with for example a furanyl group. In another embodiment of this invention a furanyl substituent is further substituted with a methyl group.  
           [0037]    In a preferred embodiment of this invention trifluoromethoxy is CF3O—. In another embodiment of this invention trifluoromethylthio is CF3S—.  
           [0038]    In one embodiment of this invention trifluoroethoxy includes but is not limited to CF3CH2O—. In another embodiment of this invention trifluoroethylthio includes but is not limited to CF3CH2S—.  
           [0039]    The terms “monoalkylamino” and “dialkylamino” refer to moieties with one or two alkyl groups wherein the alkyl chain is 1 to 8 carbons and the groups may be the same or different. The terms monoalkylaminoalkyl and dialkylaminoalkyl refer to monoalkylamino and dialkylamino moieties with one or two alkyl groups (the same or different) bonded to the nitrogen atom which is attached to an alkyl group of 1 to 8 carbon atoms.  
           [0040]    “Acyl” is a radical of the formula —(C═O)-alkyl or —(C═O)-perfluoroalkyl wherein the alkyl radical or perfluoroalkyl radical is 1 to 7 carbon atoms; preferred examples include but are not limited to, acetyl, propionyl, butyryl, trifluoroacetyl.  
           [0041]    For purposes of this invention the term “alkylsulfinyl” is defined as a R′SO— radical, where R′ is an alkyl radical of 1 to 8 carbon atoms. Alkylsulfonyl is a R′SO2-radical, where R′ is an alkyl radical of 1 to 8 carbon atoms. Alkylsulfonamido, alkenylsulfonamido, alkynylsulfonamido are R′SO2NH-radicals, where R′ is an alkyl radical of 1 to 8 carbon atoms, an alkenyl radical of 2 to 8 carbon atoms, or an alkynyl radical of 2 to 8 carbon atoms, respectively.  
           [0042]    Saturated or partially saturated heteroaryl groups are defined in this invention as heterocyclic rings selected from but not limited to the moieties: azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dihydro-1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl .  
           [0043]    For purposes of this invention, the term “BB7” denotes an RNA-dependent RNA polymerase hepatitis C virus protein sequence which is derived from HCV replicon. A discussion of BB7 and related technology can be found in Blight, K. et al. (2000) Science 290:1972-1974. BB7 can be licensed from Apath, LLC (893 North Warson Road, Saint Louis Mo. 63141, USA). BB7 is also referred to as Con1 HCV sequence and discussions of Con1 can be found in the following references: Lohmann, V. et al. (1999) Science 285:110-113; Pietschmann, T. et al. (2001) J. Virol. 75:1252-1264; Lohmann, V. et al. (2001) J. Virol. 75:1437-1449.  
           [0044]    The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to stereoisomers, such as enantiomers and diastereomers. The stereoisomers of the instant invention are named according to the Cahn-Ingold-Prelog System. While shown without respect to stereochemistry in Formula (I), the present invention includes all the individual possible stereoisomers; as well as the racemic mixtures and other mixtures of R and S stereoisomers (scalemic mixtures which are mixtures of unequal amounts of enantiomers) and pharmaceutically acceptable salts thereof. It should be noted that stereoisomers of the invention having the same relative configuration at a chiral center may nevertheless have different R and S designations depending on the substitution at the indicated chiral center.  
           [0045]    For compounds of this invention containing two chiral centers, four possible stereoisomers are possible; these four stereoisomers are classified as two racemic pairs of diastereomers. These compounds of the invention may be present as racemic diastereomers which would be designated following the convention described in the 1997 Chemical Abstracts Index Guide, Appendix IV (Columbus, Ohio) whereas the first cited chiral atom is designated R* and the next cited chiral atom is designated R* if it possesses the same chirality as the first cited stereocenter or S* if it possesses opposite chirality to the first cited stereocenter. Alternatively, these compounds of the invention may be present as non-racemic mixtures of two diastereomers owing to the existence of a predefined stereocenter. In these instances, the predefined stereocenter is assigned based on the Cahn-Ingold-Prelog System and the undefined stereocenter is designated R* to denote a mixture of both R and S stereoisomers at this center. Compounds of this invention which possess two chiral centers but which are present as single stereoisomers are described using the Cahn-Ingold-Prelog System.  
           [0046]    To further clarify, the following examples of naming possibilities are provided below:  
                                                       Designation   Possible stereoisomers   See example                           1R* 10S   1R 10S and 1S 10S   261           1R* 10S*   1R 10S and 1S 10R   289           1R* 10R*   1R 10R and 1S 10S   290                      
 
           [0047]    Based on the chiral center at the C 1  carbon position in formula (1), a preferred embodiment of the instant invention is the compound of formula (Ia) shown below:  
                         
 
           [0048]    The configuration at C 1  in Formula (Ia) for purposes of this invention is also referred to as “Isomer A”, and the opposite configuration at C 1  is herein  
                         
 
           [0049]    defined as “Isomer B” and has the formula (1b) shown below:  
         (1b)  
         [0050]    In one embodiment of this invention the compound of the invention is comprised of a ratio of Isomer A to Isomer B of greater than 1:1. In the most preferred embodiment the compound is comprised of 100% Isomer A. In further embodiments the compound is comprised of a ratio of Isomer A to Isomer B of at least about 9:1. In another embodiment the compound is comprised of a ratio of Isomer A to Isomer B of at least about 8:1. Additionally the compound is comprised of a ratio of Isomer A to Isomer B of at least about 7:1.  
           [0051]    Another embodiment of this invention is where R 2  of formula (I) is a sec-butyl group. In a preferred embodiment, the chiral carbon of the sec-butyl group has an S to R configuration ratio of 1:1. In further embodiments, the chiral carbon of the sec-butyl group has an S to R configuration ratio selected from the group consisting of at least 7:1, at least 8:1, and at least 9:1. In a most preferred embodiment of the invention, the chiral carbon of the sec-butyl group has 100% S configuration.  
           [0052]    Pharmaceutically acceptable salts of the compounds of formula (I) having acidic moieties at R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , or R 10  may be formed from organic and inorganic bases. For example alkali metal salts: sodium, lithium, or potassium and N-tetraalkylammonium salts such as N-tetrabutylammonium salts. Similarly, when a compound of this invention contains a basic moiety at R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , or R 10  salts can be formed from organic and inorganic acids. For example salts can be formed from acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids.  
           [0053]    In one embodiment, the present invention provides for a method of inhibiting the Hepatitis C RNA-dependent RNA polymerase NS5B. The method comprises contacting a cell with an amount of a compound effective to decrease or prevent NS5B function. The cell may be a mammalian cell and more specifically a human cell. The cell may also be a bacterial cell such as for example  E coli.  The cell may include but is not limited to, a neuronal cell, an endothelial cell, a glial cell, a microglial cell, a smooth muscle cell, a somatic cell, a bone marrow cell, a liver cell, an intestinal cell, a germ cell, a myocyte, a mononuclear phagocyte, an endothelial cell, a tumor cell, a lymphocyte cell, a mesangial cell, a retinal epithelial cell, a retinal vascular cell, a ganglion cell or a stem cell. The cell may be a normal cell, an activated cell, a neoplastic cell, a diseased cell, or an infected cell.  
           [0054]    In another embodiment, the present invention provides for a method of inhibiting the Hepatitis C RNA-dependent RNA polymerase NS5B, comprising contacting a cell with an amount of a pharmaceutical composition, that comprises a compound of this invention, in combination or association with a pharmaceutically acceptable carrier in an amount effective to decrease or prevent NS5B function. The cell may be a mammalian cell and more specifically a human cell. The cell may also be a bacterial cell such as for example  E coli.  The cell may include but is not limited to, a neuronal cell, an endothelial cell, a glial cell, a microglial cell, a smooth muscle cell, a somatic cell, a bone marrow cell, a liver cell, an intestinal cell, a germ cell, a myocyte, a mononuclear phagocyte, an endothelial cell, a tumor cell, a lymphocyte cell, a mesangial cell, a retinal epithelial cell, a retinal vascular cell, a ganglion cell or a stem cell. The cell may be a normal cell, an activated cell, a neoplastic cell, a diseased cell, or an infected cell.  
           [0055]    In another embodiment, the present invention provides a method for the treatment or prevention of Hepatitis C infection in a mammal. The present invention accordingly provides to a mammal, a pharmaceutical composition that comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. The compound of this invention may be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or prevention of Hepatitis C viral infection in a mammal.  
           [0056]    The compounds and pharmaceutical compositions of the present invention are preferably provided orally or subcutaneously. The compounds may be provided by intralesional, intraperitoneal, intramuscular or intravenous injection; infusion; liposome-mediated delivery; topical, nasal, anal, vaginal, sublingual, uretheral, transdermal, intrathecal, ocular or otic delivery. In order to obtain consistency in providing the compound of this invention it is preferred that a compound of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg. Such compounds may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day. The effective amount will be known to one of skill in the art; it will also be dependent upon the form of the compound. One of skill in the art could routinely perform empirical activity tests to determine the bioactivity of the compound in bioassays and thus determine what dosage to administer.  
           [0057]    The compounds and pharmaceutical compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent, a color additive, or a carrier. The carrier may be for example a diluent, an aerosol, a topical carrier, an aqueous solution, a nonaqueous solution or a solid carrier. The carrier may be a polymer or a toothpaste. A carrier in this invention encompasses any of the standard pharmaceutically accepted carriers, such as phosphate buffered saline solution, acetate buffered saline solution, water, emulsions such as an oil/water emulsion or a triglyceride emulsion, various types of wetting agents, tablets, coated tablets and capsules.  
           [0058]    When provided orally or topically, such compounds would be provided to a subject by delivery in different carriers. Typically, such carriers contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid, talc, vegetable fats or oils, gums, or glycols. The specific carrier would need to be selected based upon the desired method of delivery, for example, phosphate buffered saline (PBS) could be used for intravenous or systemic delivery and vegetable fats, creams, salves, ointments or gels may be used for topical delivery.  
           [0059]    The compounds and pharmaceutical compositions of the present invention may be delivered together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers useful in treatment or prevention of Hepatitis C viral infection. Such compositions are liquids or lyophilized or otherwise dried formulations and include diluents of various buffer content (for example, Tris-HCl, acetate, phosphate), pH and ionic strength, additives such as albumins or gelatin to prevent absorption to surfaces, detergents (for example, TWEEN 20, TWEEN 80, PLURONIC F68, bile acid salts), solubilizing agents (for example, glycerol, polyethylene glycerol), anti-oxidants (for example ascorbic acid, sodium metabisulfate), preservatives (for example, thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (for example, lactose, mannitol), covalent attachment of polymers such as polyethylene glycol, complexation with metal ions, or incorporation of the compound into or onto particulate preparations of hydrogels or liposomes, micro-emulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance of the compound or composition. The choice of compositions will depend on the physical and chemical properties of the compound capable of treating or preventing a Hepatitis C viral infection.  
           [0060]    The compound and pharmaceutical compositions of the present invention may be delivered locally via a capsule that allows a sustained release of the compound over a period of time. Controlled or sustained release compositions include formulation in lipophilic depots (for example, fatty acids, waxes, oils).  
           [0061]    The present invention further provides controlled-release therapeutic dosage forms for the pharmaceutical composition in which the composition is incorporated into a delivery system. The dosage form controls release of the pharmaceutical composition in such a manner that an effective concentration of the composition in the blood can be maintained over an extended period of time, but also the release of the composition should be such that the concentration in the blood remains relatively constant over the extended period of time to improve therapeutic results and/or minimize side effects. Additionally, a controlled release system would affect minimal peak to trough fluctuations in blood plasma levels of the pharmaceutical composition.  
           [0062]    The present invention further provides a compound of the invention for use as an active therapeutic substance for preventing Hepatitis C infection. Compounds of formula (I) are of particular use for the treatment of infection with Hepatitis C virus.  
           [0063]    The present invention further provides a method of treating Hepatitis C infection in humans, which comprises administering to the infected individual an effective amount of a compound or a pharmaceutical composition of the invention.  
           [0064]    The present invention provides a method of treating or preventing a Hepatitis C viral infection in a mammal comprising providing the mammal with an effective amount of at least one pharmaceutical composition, wherein the at least one pharmaceutical composition includes a compound of a formula:  
                         
 
           [0065]    wherein:  
           [0066]    R 1  is H, a straight chain alkyl of 1 to 8 carbon atoms, a branched alkyl of 3 to 12 carbon atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an alkynyl of 2 to 7 carbon atoms, or an arylalkyl or an alkylaryl of 7 to 12 carbon atoms;  
           [0067]    R 2  is H, a straight chain alkyl of 1 to 12 carbon atoms, a branched alkyl of 3 to 12 carbon atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an alkynyl of 2 to 7 carbon atoms, an alkoxyalkyl of 2 to 12 carbon atoms, an arylalkyl or alkylaryl of 7 to 12 carbon atoms, a cyanoalkyl of 1 to 8 carbon atoms, an alkylthioalkyl of 2 to 16 carbon atoms, a cycloalkyl-alkyl of 4 to 24 carbon atoms, a substituted or unsubstituted aryl, or a heteroaryl;  
           [0068]    R 3 -R 6  are independently H, a straight chain alkyl of 1 to 8 carbon atoms, a branched alkyl of 3 to 12 carbon atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, a substituted or unsubstituted aryl, furanylmethyl, arylalkyl or alkylaryl of 7 to 12 carbon atoms, alkynyl of 2 to 7 carbon atoms, or R 5  and R 6  together with the ring carbon atom to which they are attached form a carbonyl group;  
           [0069]    R 7 -R 10  are independently H, a straight chain alkyl of 1 to 8 carbon atoms, a branched alkyl of 3 to 12 carbons atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, furanylmethyl, arylalkyl or alkylaryl of 7 to 12 carbon atoms, alkynyl of 2 to 7 carbon atoms, phenylalkynyl, alkoxy of 1 to 8 carbon atoms, arylalkoxy of 7 to 12 carbon atoms, fluoroalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to 8 carbon atoms, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, trifluoroethylthio, acyl of 1 to 7 carbon atoms, COOH, COO-alkyl, CONR 11 R 12 , F, Cl, Br, I, CN, CF 3 , NO 2 , alkylsulfinyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, pyrrolidinyl, or thiazolidinyl;  
           [0070]    R 11 -R 12  are independently H, straight chain alkyl of 1 to 8 carbon atoms, branched alkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, a substituted or unsubstituted aryl or heteroaryl;  
           [0071]    Y is a bond, CH 2 , CH 2 CH 2 , aryl, or R 2  and Y together with the ring carbon atom to which they are attached form a spirocyclic cycloalkyl ring of 3 to 8 carbon atoms and  
           [0072]    a pharmaceutically acceptable carrier.  
           [0073]    The method of the present invention further comprises providing the mammal with an effective amount of at least one biologically active agent.  
           [0074]    In an embodiment of the method of the present invention, the at least one biologically active agent is provided prior to the at least one pharmaceutical composition, concurrently with the at least one pharmaceutical composition or after the at least one pharmaceutical composition. In a further embodiment of the method of the present invention, the compound is a crystalline form or a pharmaceutically acceptable salt thereof.  
           [0075]    In a further embodiment of the method of the present invention, the at least one biologically active agent is selected from the group consisting of interferon, a pegylated interferon, ribavirin, protease inhibitors, polymerase inhibitors, small interfering RNA compounds, anti-sense compounds, nucleotide analogs, nucleoside analogs, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-infective compounds. In a further embodiment the at least one biologically active agent is a pegylated interferon. In a yet further embodiment the pegylated interferon is a pegylated interferon-alpha and the compound is  
           [0076]    [(R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid. In a yet further embodiment the pegylated interferon is a pegylated interferon-alpha and the compound is [(R)-5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid.  
           [0077]    The present invention also provides a method of treating or preventing a Hepatitis C viral infection in a mammal comprising providing the mammal with an effective amount of at least one pharmaceutical composition, wherein the at least one pharmaceutical composition includes a compound of a formula:  
                         
 
           [0078]    wherein:  
           [0079]    R 1  is H, a straight chain alkyl of 1 to 6 carbon atoms, a branched alkyl of 3 to 10 carbon atoms, a cycloalkyl of 3 to 10 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an alkynyl of 2 to 7 carbon atoms, or an arylalkyl of 7 to 12 carbon atoms;  
           [0080]    R 2  is H, a straight chain alkyl of 1 to 12 carbon atoms, a branched alkyl of 3 to 10 carbon atoms, a cycloalkyl of 3 to 10 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an alkynyl of 2 to 7 carbon atoms, an alkoxyalkyl of 2 to 12 carbon atoms, an arylalkyl of 7 to 12 carbon atoms, an unsubstituted aryl or an aryl substituted with one to four groups, or heteroaryl;  
           [0081]    R 3 -R 6  are independently H, a straight chain alkyl of 1 to 6 carbon atoms, a branched alkyl of 3 to 10 carbons atoms, a cycloalkyl of 3 to 10 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an unsubstituted aryl or an aryl substituted with one to four groups, furanylmethyl, an arylalkyl of 7 to 12 carbon atoms, an alkynyl of 2 to 7 carbon atoms, or R 5  and R 6  together with the ring carbon atom to which they are attached form a carbonyl group;  
           [0082]    R 7 -R 10  are independently H, a straight chain alkyl of 1 to 6 carbon atoms, a branched alkyl of 3 to 10 carbons atoms, a cycloalkyl of 3 to 10 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an unsubstituted aryl or an aryl substituted with one to four groups, an unsubstituted heteroaryl or a heteroaryl substituted with one to three groups, furanylmethyl, an arylalkyl of 7 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, phenylalkynyl, an alkoxy of 1 to 6 carbon atoms, an arylalkoxy of 7 to 12 carbon atoms, a fluoroalkoxy of 1 to 12 carbon atoms, an alkylthio of 1 to 6 carbon atoms, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, trifluoroethylthio, an acyl of 1 to 7 carbon atoms, a carboxy group, CONR 11 R 12 , F, Cl, Br, I, CN, CF 3 , NO 2 , an alkylsulfinyl of 1 to 6 carbon atoms, an alkylsulfonyl of 1 to 6 carbon atoms;  
           [0083]    R 11 -R 12  are independently H, a straight chain alkyl of 1 to 6 carbon atoms, a branched alkyl of 3 to 10 carbon atoms, a cycloalkyl of 3 to 10 carbon atoms, an aryl substituted with one to four groups, an unsubstituted heteroaryl or a heteroaryl substituted with one to three groups;  
           [0084]    Y is CH 2 , CH 2 CH 2 , or aryl; and  
           [0085]    a pharmaceutically acceptable carrier.  
           [0086]    The method of the present invention further comprises providing the mammal with an effective amount of at least one biologically active agent.  
           [0087]    In an embodiment of the method of the present invention, the at least one biologically active agent is provided prior to the at least one pharmaceutical composition, concurrently with the at least one pharmaceutical composition or after the at least one pharmaceutical composition. In a further embodiment of the method of the present invention, the compound is a crystalline form or a pharmaceutically acceptable salt thereof.  
           [0088]    In a further embodiment of the method of the present invention, the at least one biologically active agent is selected from the group consisting of interferon, a pegylated interferon, ribavirin, protease inhibitors, polymerase inhibitors, small interfering RNA compounds, anti-sense compounds, nucleotide analogs, nucleoside analogs, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-infective compounds. In a further embodiment, the at least one biologically active agent is a pegylated interferon. In a yet further embodiment the pegylated interferon is a pegylated interferon-alpha and the compound is  
           [0089]    [(R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid. In a yet further embodiment the pegylated interferon is a pegylated interferon-alpha and the compound is [(R)-5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9tetrahydropyrano[3,4-b]indol-1-yl]acetic acid.  
           [0090]    The present invention further provides a method of treating or preventing a Hepatitis C viral infection in a mammal comprising providing the mammal with an effective amount of at least one pharmaceutical composition, wherein the at least one pharmaceutical composition includes a compound of a formula:  
                         
 
           [0091]    R 1  is H;  
           [0092]    R 2  is H, or a straight chain alkyl of 1 to 4 carbon atoms;  
           [0093]    R 3 -R 6  are H;  
           [0094]    R 7 -R 10  are independently H, a straight chain alkyl of 1 to 3 carbon, F, Cl, or CN;  
           [0095]    Y is CH 2 ; and  
           [0096]    a pharmaceutically acceptable carrier.  
           [0097]    The method of the present invention further comprises providing the mammal with an effective amount of at least one biologically active agent.  
           [0098]    In an embodiment of the method of the present invention, the at least one biologically active agent is provided prior to the at least one pharmaceutical composition, concurrently with the at least one pharmaceutical composition or after the at least one pharmaceutical composition. In a further embodiment of the method of the present invention, the compound is a crystalline form or a pharmaceutically acceptable salt thereof.  
           [0099]    In a further embodiment the at least one biologically active agent is selected from the group consisting of interferon, a pegylated interferon, ribavirin, protease inhibitors, polymerase inhibitors, small interfering RNA compounds, anti-sense compounds, nucleotide analogs, nucleoside analogs, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-infective compounds. In a further embodiment the at least one biologically active agent is a pegylated interferon. In a yet further embodiment the pegylated interferon is a pegylated interferon-alpha and the compound is  
           [0100]    [(R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid. In a yet further embodiment the pegylated interferon is a pegylated interferon-alpha and the compound is [(R)-5-cyano-6-fluoro-8methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid.  
           [0101]    The present invention also provides a method of inhibiting replication of a Hepatitis C virus comprising contacting the Hepatitis C virus with an effective amount of at least one pharmaceutical composition, wherein the at least one pharmaceutical composition includes a compound of a formula:  
                         
 
           [0102]    wherein:  
           [0103]    R 1  is H, a straight chain alkyl of 1 to 8 carbon atoms, a branched alkyl of 3 to 12 carbon atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an alkynyl of 2 to 7 carbon atoms, or an arylalkyl or an alkylaryl of 7 to 12 carbon atoms;  
           [0104]    R 2  is H, a straight chain alkyl of 1 to 12 carbon atoms, a branched alkyl of 3 to 12 carbon atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an alkynyl of 2 to 7 carbon atoms, an alkoxyalkyl of 2 to 12 carbon atoms, an arylalkyl or alkylaryl of 7 to 12 carbon atoms, a cyanoalkyl of 1 to 8 carbon atoms, an alkylthioalkyl of 2 to 16 carbon atoms, a cycloalkyl-alkyl of 4 to 24 carbon atoms, a substituted or unsubstituted aryl, or a heteroaryl;  
           [0105]    R 3 -R 6  are independently H, a straight chain alkyl of 1 to 8 carbon atoms, a branched alkyl of 3 to 12 carbon atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, a substituted or unsubstituted aryl, furanylmethyl, arylalkyl or alkylaryl of 7 to 12 carbon atoms, alkynyl of 2 to 7 carbon atoms, or R 5  and R 6  together with the ring carbon atom to which they are attached form a carbonyl group;  
           [0106]    R 7 -R 10  are independently H, a straight chain alkyl of 1 to 8 carbon atoms, a branched alkyl of 3 to 12 carbons atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, furanylmethyl, arylalkyl or alkylaryl of 7 to 12 carbon atoms, alkynyl of 2 to 7 carbon atoms, phenylalkynyl, alkoxy of 1 to 8 carbon atoms, arylalkoxy of 7 to 12 carbon atoms, fluoroalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to 8 carbon atoms, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, trifluoroethylthio, acyl of 1 to 7 carbon atoms, COOH, COO-alkyl, CONR 11 R 12 , F, Cl, Br, I, CN, CF 3 , NO 2 , alkylsulfinyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, pyrrolidinyl, or thiazolidinyl;  
           [0107]    R 11 -R 12  are independently H, straight chain alkyl of 1 to 8 carbon atoms, branched alkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, a substituted or unsubstituted aryl or heteroaryl;  
           [0108]    Y is a bond, CH 2 , CH 2 CH 2 , aryl, or R 2  and Y together with the ring carbon atom to which they are attached may additionally form a spirocyclic cycloalkyl ring of 3 to 8 carbon atoms; and  
           [0109]    a pharmaceutically acceptable carrier.  
           [0110]    The method of the present invention further comprises providing the mammal with an effective amount of at least one biologically active agent.  
           [0111]    In an embodiment of the method of the present invention, the at least one biologically active agent is provided prior to the at least one pharmaceutical composition, concurrently with the at least one pharmaceutical composition or after the at least one pharmaceutical composition. In a further embodiment of the method of the present invention, the compound is a crystalline form or a pharmaceutically acceptable salt thereof.  
           [0112]    In a further embodiment the at least one biologically active agent is selected from the group consisting of interferon, a pegylated interferon, ribavirin, protease inhibitors, polymerase inhibitors, small interfering RNA compounds, anti-sense compounds, nucleotide analogs, nucleoside analogs, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-infective compounds. In a further embodiment the at least one biologically active agent is a pegylated interferon. In a yet further embodiment the pegylated interferon is a pegylated interferon-alpha and the compound is  
           [0113]    [(R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid. In a yet further embodiment the pegylated interferon is a pegylated interferon-alpha and the compound is [(R)-5-cyano-6-fluoro-8methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid.  
           [0114]    The present invention further provides a method of inhibiting replication of a Hepatitis C virus comprising contacting the Hepatitis C virus with an effective amount of at least one pharmaceutical composition, wherein the at least one pharmaceutical composition includes a compound of a formula:  
                         
 
           [0115]    wherein:  
           [0116]    R 1  is H, a straight chain alkyl of 1 to 6 carbon atoms, a branched alkyl of 3 to 10 carbon atoms, a cycloalkyl of 3 to 10 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an alkynyl of 2 to 7 carbon atoms, or an arylalkyl of 7 to 12 carbon atoms;  
           [0117]    R 2  is H, a straight chain alkyl of 1 to 12 carbon atoms, a branched alkyl of 3 to 10 carbon atoms, a cycloalkyl of 3 to 10 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an alkynyl of 2 to 7 carbon atoms, an alkoxyalkyl of 2 to 12 carbon atoms, an arylalkyl of 7 to 12 carbon atoms, an unsubstituted aryl or an aryl substituted with one to four groups, or heteroaryl;  
           [0118]    R 3 -R 6  are independently H, a straight chain alkyl of 1 to 6 carbon atoms, a branched alkyl of 3 to 10 carbons atoms, a cycloalkyl of 3 to 10 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an unsubstituted aryl or an aryl substituted with one to four groups, furanylmethyl, an arylalkyl of 7 to 12 carbon atoms, an alkynyl of 2 to 7 carbon atoms, or R 5  and R 6  together with the ring carbon atom to which they are attached form a carbonyl group;  
           [0119]    R 7 -R 10  are independently H, a straight chain alkyl of 1 to 6 carbon atoms, a branched alkyl of 3 to 10 carbons atoms, a cycloalkyl of 3 to 10 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an unsubstituted aryl or an aryl substituted with one to four groups, an unsubstituted heteroaryl or a heteroaryl substituted with one to three groups, furanylmethyl, an arylalkyl of 7 to 12 carbon atoms, an alkynyl of 2 to 7 carbon atoms, phenylalkynyl, an alkoxy of 1 to 6 carbon atoms, an arylalkoxy of 7 to 12 carbon atoms, a fluoroalkoxy of 1 to 12 carbon atoms, an alkylthio of 1 to 6 carbon atoms, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, trifluoroethylthio, an acyl of 1 to 7 carbon atoms, a carboxy group, CONR 11 R 12 , F, Cl, Br, I, CN, CF 3 , NO 2 , an alkylsulfinyl of 1 to 6 carbon atoms, an alkylsulfonyl of 1 to 6 carbon atoms;  
           [0120]    R 11 -R 12  are independently H, a straight chain alkyl of 1 to 6 carbon atoms, a branched alkyl of 3 to 10 carbon atoms, a cycloalkyl of 3 to 10 carbon atoms, an aryl substituted with one to four groups, an unsubstituted heteroaryl or a heteroaryl substituted with one to three groups;  
           [0121]    Y is CH 2 , CH 2 CH 2 , or aryl; and  
           [0122]    a pharmaceutically acceptable carrier.  
           [0123]    The method of the present invention further comprises providing the mammal with an effective amount of at least one biologically active agent.  
           [0124]    In an embodiment of the method of the present invention, the at least one biologically active agent is provided prior to the at least one pharmaceutical composition, concurrently with the at least one pharmaceutical composition or after the at least one pharmaceutical composition. In a further embodiment of the method of the present invention, the compound is a crystalline form or a pharmaceutically acceptable salt thereof.  
           [0125]    In a further embodiment of the method of the present invention, the at least one biologically active agent is selected from the group consisting of interferon, a pegylated interferon, ribavirin, protease inhibitors, polymerase inhibitors, small interfering RNA compounds, anti-sense compounds, nucleotide analogs, nucleoside analogs, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-infective compounds. In a further embodiment, the at least one biologically active agent is a pegylated interferon. In a yet further embodiment, the pegylated interferon is a pegylated interferon-alpha and the compound is  
           [0126]    [(R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid. In a yet further embodiment the pegylated interferon is a pegylated interferon-alpha and the compound is [(R)-5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid.  
           [0127]    The compounds of the present invention or precursors thereof and their isomers and pharmaceutically acceptable salts thereof are also useful in treating and preventing viral infections, in particular hepatitis C infection, and diseases in living hosts when used in combination with each other (i.e. pharmaceutical compositions comprising the compounds are administered concurrently with each or sequentially, in either order). The combination of compounds provided herein may further be provided to a subject in respective pharmaceutical compositions, concurrently with or sequentially to other biologically active agents, including but not limited to the group consisting of interferon, a pegylated interferon, ribavirin, protease inhibitors, polymerase inhibitors, small interfering RNA compounds, anti-sense compounds, nucleotide analogs, nucleoside analogs, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-infective compounds. The present invention further provides combination therapy with one or more pyranoindole derivatives, i.e., at least two pharmaceutical compositions, each comprising a different compound of the present invention, are provided to a subject in need thereof either concurrently with each other or sequentially, and such therapy may further comprise providing concurrently or sequentially other medicinal agents or potentiators, such as acyclovir, famicyclovir, valgancyclovir and related compounds, ribavirin and related compounds, amantadine and related compounds, various interferons such as, for example, interferon-alpha, interferon-beta, interferon-gamma and the like, as well as alternative forms of interferons such as pegylated interferons. Additionally, combinations of, for example ribavirin and interferon, may be administered as an additional combination for a multiple combination therapy with at least one of the compounds of the present invention.  
           [0128]    The combination therapy with any of the above-described biologically active agents may also be sequential, that is the treatment with a first pharmaceutical composition comprising a compound of the invention followed by treatment with a second pharmaceutical composition comprising a second compound of the invention, wherein the second compound is different than the first compound; alternatively, treatment may be with both two or more pharmaceutical compositions, wherein each pharmaceutical composition comprises a different compound of the invention, at the same time. The sequential therapy can be within a reasonable time after the completion of the first therapy with the pharmaceutical composition. Treatment with the respective pharmaceutical compositions, each comprising a different compound of the present invention, at the same time may be provided in the same daily dose or in separate doses. Combination therapy may also be provided wherein a pharmaceutical composition comprising at least one compound of the present invention is administered in a composition further comprising at least one biologically active agent, i.e. in a single dose. The dosages for both concurrent and sequential combination therapy (for combined pharmaceutical compositions comprising at least two compounds of the invention or compositions comprising at least one compound of the invention and at least one biologically active agent), will depend on absorption, distribution, metabolism and excretion rates of the components of the pharmaceutical composition as well as other factors known to one of skill in the art. Dosage values of the pharmaceutical composition will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules may be adjusted over time according to the individual&#39;s need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions.  
           [0129]    In a further embodiment, the compounds of the invention may be used for the treatment of HCV in humans in combination therapy mode with other inhibitors of the HCV polymerase.  
           [0130]    In yet a further embodiment, the compounds of the present invention may be used for the treatment of HCV in humans in combination therapy mode with other inhibitors of the HCV life cycle such as, for example, inhibitors of HCV cell attachment or virus entry, HCV translation, HCV RNA transcription or replication, HCV maturation, assembly or virus release, or inhibitors of HCV enzyme activities such as the HCV nucleotidyl transferase, helicase, protease or polymerase.  
           [0131]    It is intended that combination therapies of the pharmaceutical compositions include any chemically compatible combination of a compound of this inventive group with other compounds of the inventive group or other compounds outside of the inventive group, as long as the combination does not eliminate the antiviral activity of the compound of this inventive group or the anti-viral activity of the pharmaceutical composition itself.  
           [0132]    The term “interferon-alpha” as used herein means the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response. Typical suitable interferon-alphas include, but are not limited to, recombinant interferon alpha-2b such as INTRON-A INTERFERON available from Schering Corporation, Kenilworth, N.J., recombinant interferon alpha-2a such as Roferon interferon available from Hofman-La Roche, Nutley, N.J., a recombinant interferon alpha-2C, such as BEROFOR ALPHA 2 INTERFERON available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn., interferon alpha-n1, a purified blend of natural alpha interferons such as SUMIFERON available from Sumitomo, Japan or as Wellferon interferon alpha-n1 (INS) available from Glaxo-Wellcome Ltd., London, Great Britain, or a consensus alpha interferon such as those described in U.S. Pat. Nos. 4,897,471 and 4,695,623 (the contents of which are hereby incorporated by reference in their entireties, specifically examples 7, 8 or 9 thereof) and the specific product available from Amgen, Inc., Newbury Park, Calif., or interferon alpha-n3 a mixture of natural interferons made by Interferon Sciences and available from the Purdue Frederick Co., Norwalk, Conn., under the ALFERON trademark. The use of interferon alpha-2a or alpha 2b is preferred. Since interferon alpha 2b, among all interferons, has the broadest approval throughout the world for treating chronic hepatitis C infection, it is most preferred. The manufacture of interferon alpha 2b is described in U.S. Pat. No. 4,503,901.  
           [0133]    The term “pegylated interferon” as used herein means polyethylene glycol modified conjugates of interferon, preferably interferon alpha-2a and alpha-2b. The preferred polyethylene-glycol-interferon alpha-2b conjugate is PEG.sub.12000-interferon alpha 2b. The phrase “PEG.sub.12000-IFN alpha” as used herein means conjugates such as are prepared according to the methods of International Application No. WO 95/13090 and containing urethane linkages between the interferon alpha-2a or alpha-2b amino groups and polyethylene glycol having an average molecular weight of 12000.  
           [0134]    The following experimental details are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims that follow thereafter.  
         DETAILED DESCRIPTION OF THE INVENTION  
         [0135]    The compounds of the present invention can be readily prepared according to the following reaction schemes or modification thereof. In the following reaction schemes R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , or R 10 , R 11 , R 12  and Y are selected from the groups defined above.  
           [0136]    Preferred compounds of the present invention can be synthesized as described in the schemes below (Scheme 1 to 10). Starting material in Scheme 3 is readily available from a commercial source (Lancaster Synthesis Inc., Lancaster, U.K., product no. 15472).  
                         
 
                         
 
                         
 
                         
 
                         
 
                         
 
                         
 
                         
 
                         
 
                         
 
                         
 
                         
 
           [0137]    The ability of the compounds of the present invention to inhibit Hepatitis C Polymerase was established by the following experimental procedure:  
           [0138]    NS5B from the BK strain (genotype 1b) is expressed in  E. coli  as a protein in which the 21 C-terminal amino acids are replaced with a short linker and a hexahistidine tag (GSHHHHHH). The purified protein is mixed with radioactive nucleotides and allowed to replicate a heteropolymeric RNA substrate, primed by an endogenous short hairpin, resulting in an approximately 760 nt product. The radioactive product is captured on a filter and quantitated after removal of the unincorporated nucleotides.  
           [0139]    Reagents:  
           [0140]    10 mM uridine 5′-triphosphate (UTP) (Promega #p116B)  
           [0141]    10 mM adenine 5′-triphosphate (ATP) (Promega #p113B)  
           [0142]    10 mM cytidine 5′-triphosphate (CTP) (Promega #p114B)  
           [0143]    10 mM guanine 5′-triphosphate (GTP) (Promega #p115B)  
           [0144]    Bovine Serum Albumin (BSA) 10 mg/ml NEB (100× at 10 mg/ml) #007-BSA RNasein (Promega #N251X) 40 U/μl  
           [0145]    A-[33P]-GTP (NEN-easytides NEG/606H 3000 Ci/mmol, 370 MBq/ml, 10 mCi/ml)  
           [0146]    Falcon polypropylene 96 well plates (Becton Dickinson #351190)  
           [0147]    Millipore Multiscreen assasy system-96 well-filtration plate #MADE NOB 50  
           [0148]    Optiphase Supermix (Wallac) formulated by Fisher  
           [0149]    Millipore Multiscreen liner for use in microbeta 1450-106 casette [(Wallac) Perkin Elmer #1450-433] 
           [0150]    1 M(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]) (HEPES), pH 7.3  
           [0151]    Amersham Pharmacia Biotec (US16924-500 ml)  
           [0152]    1 M MgCl 2  (SIGMA #M1028)  
           [0153]    Dithiothreitol (DTT) (solid) (SIGMA #D9779)  
           [0154]    RNase free water (GIBCO-BRL #10977-023)  
           [0155]    Dimethyl sulfoxide (Aldrich #27685-5)  
           [0156]    Basilen Blue (Sigma, B5520)  
           [0157]    0.5M ethylenediaminetetraacetic acid (EDTA), pH 8 (GIBCO-BRL #15575-020)  
           [0158]    Dibasic sodium phosphate (7-hydrate) (Na 2 HPO 4 .7H 2 O; Baker#3824-07)  
           [0159]    Phosphoric acid (Baker, #0262.02)  
           [0160]    Further reagent preparation:  
           [0161]    0.5 M Na Phosphate buffer. Per liter, weigh 134 gr Na 2 HPO 4 .7H 2 O, add water to 900 ml. Adjust pH to 7.0 with phosphoric acid. Top off with water to 1 L.  
           [0162]    Dilute nucleotides 1:1000 to 10 μM (GTP and CTP) or 1:100 to 100 μM (ATP and UTP) into RNase free water.  
           [0163]    Procedure:  
           [0164]    (1) Compounds 10 μl at 10 μg/ml in 15 % dimethylsulfoxide (DMSO)  
           [0165]    When starting from 100 jig/ml compound stock in 1% DMSO:  
           [0166]    Dispense 5 μl 30 % DMSO per well  
           [0167]    Dispense 5 μl compound (100 μg/ml) per well.  
           [0168]    When starting from 50 μg/ml compound stock in 15 % DMSO:  
           [0169]    Add 10 μl compound per well.  
           [0170]    (2) Enzyme Mix:  
                                                                             Final Conc (in 50 μl   Per 20 μl mix (1           Stock   assay volume)   reaction)   Per 600 reactions                                DEPC H 2 0           17.06   μl   10236   μl       1 M HEPES,   20   Mm   0.5   μl   300   μl       pH 7.5       1 M   5   mM   0.25   μl   150   μl       MgCl 2         100 mM   1   mM   0.5   μl   300   μl       DTT       100 μM   0.5   μM   0.25   μl   150   μl       UTP       100 μM   1   μM   0.5   μl   300   μl       ATP        10 μM   0.08   μM   0.4   μl   240   μl       CTP        10 μM   0.025   μM   0.125   μl   75   μl       GTP       BSA,   0.05   mg/ml   0.25   μl   150   μl       10 mg/ml       HCV RdRp   24   nM   0.16   μl   96   μl       NS5B       d21BK       (500 μg/ml       or ˜7.5μM)       Total:           20   μl   12   ml                  
 
           [0171]    Add 20 [l enzyme mix into each well of the assay plate. Incubate compound and enzyme at room temperature for 15 minutes  
           [0172]    (3) Template mix—prepare ahead  
           [0173]    Spin down a tube of RNA (5 μg/tube stored in 75% ethanol and 0.3 M sodium acetate) in a microcentrifuge for 20 minutes at 4° C. One tube is enough for 1-1.5 plates. Remove as much ethanol from the tube as possible by inverting the tube. Be gentle, pellet RNA may not adhere to the tube. Vacuum dry the RNA. Resuspend the RNA by adding 1 ml of DEPC water, close the cap of the tube tightly. To dissolve RNA, incubate RNA solution on ice for ˜60 minutes and gently vortex. Spin briefly to ensure all RNA solution is down to the bottom of the tube before opening cap. Gently transfer RNA solution into a 5 ml or larger tube. Add another 3 ml of DEPC water (total 4 ml of volume).  
           [0174]    Add the following volumes of reagents  
                                                                             Final   Per 20 μl mix (1   Per       Stock   concentration   reaction)   600 reactions                                RNAse-free water           2.98   μl   1788   μl       HEPES, 1M   20   mM   0.5   μl   300   μl       RNase Inhibitor   0.4   μ/μl   0.5   μl   300   μl       (40 U/μl)       33P-GTP 3000   0.025   μM   0.0125   μl   7.5   μl       Ci/mmol, 10 μCi/μl       (3.3 μM)       POF RNA template   3   nM   16   μl   9600   μl                  
 
           [0175]    Add 20 μl template mix per reaction (i.e. 20 ng of pOF per reaction or ˜3 nM)  
           [0176]    (4) Incubate reaction at room temperature (22-25° C.) for 2 hours.  
           [0177]    (5) Stop reaction by adding 50 μl of 170 mM EDTA.  
           [0178]    Final concentration of EDTA is 85 mM.  
           [0179]    (6) Prewet filters of Millipore multiscreen assay plate by adding 200 μl of 0.5 M sodium phosphate buffer, pH 7.0 into each well. Let stand at room temperature for 2-3 minutes.  
           [0180]    (7) Place the multiscreen filter plate onto a Millipore Manifold and turn on vacuum to allow buffer to flow through. Turn off vacuum. Transfer 80 μl of the reaction product into each well of the filter plate. Let stand for 2-3 minutes. Turn on vacuum to filter reaction product.  
           [0181]    (8) Turn off vacuum. Add 200 μl of 0.5 M sodium phosphate buffer, pH 7.0 into each well to wash filter. Turn on vacuum.  
           [0182]    Repeat step (8) three more times.  
           [0183]    (9) Remove polypropylene bottom. Spot dry filter at the bottom with paper towel. Air dry filter plate on a bench for 1 hour. Add 40 μl Super Mix scintillant. Seal top of the plate with a tape. Place plate into a Packard carrier or microbeta carrier.  
           [0184]    (10) Count plate using a Packard Topcount or micro-beta counter. Count (for example using Program 10) for  33 P in Top count or  33 P program in micro-beta.  
           [0185]    Percent inhibition is calculated after background subtraction as a percent reduction of activity relative to the positive control (average value of the plate excluding the negative controls). For the primary screen hits were chosen as showing &gt;75% inhibition.  
           [0186]    See, Ferrari et al. 1999. J. Virology 73:1649-1654: “Characterization of soluble Hepatitis C virus RNA-dependent RNA polymerase expressed in  E. coli  and Takamizawa et al 1991” and J. Virology 65:1105-1113: “Structure and characterization of the Hepatitis C virus genome isolated from human carriers,” both references are hereby incorporated by reference.  
           [0187]    The compounds of the present invention inhibited Hepatitis C polymerase as summarized in Table 1 A and B:  
                                     TABLE 1A                           HCV pol   HCV pol           BK   % inh at       Example   IC 50  (μM)   20 μM                                1   0.5   —       2   0.33   —       3   2.4   —       4   1.0   —       5   0.44   —       6   5.7   —       7   0.2   —       8   0.06   —       9   1.1   —       10   0.08   —       11   0.08   —       12   0.6   —       13   &gt;20   23       14   11   75       15   &gt;20   7       16   &gt;20   &lt;5       17   &gt;20   &lt;5       18   &gt;20   &lt;5       19   &gt;20   6       20   &gt;20   21       21   &gt;20   58       22   5   70       23   &gt;20   12       24   &gt;20   &lt;5       25   &gt;20   33       26   &gt;20   &lt;5       27   &gt;20   3       28   &gt;20   &lt;5       29   &gt;20   &lt;5       30   &gt;20   &lt;5       31   &gt;20   12       32   &gt;20   &lt;5       33   &gt;20   &lt;5       34   &gt;20   5       35   &gt;20   35       36   &gt;20   4       37   &gt;20   28       38   &gt;20   11       39   &gt;20   7       40   &gt;20   27       41   &gt;20   13       42   &gt;20   31       43   &gt;20   83       44   &gt;20   41       45   &gt;20   14       46   &gt;20   15       47   &gt;20   15       48   &gt;20   18       49   &gt;20   &lt;5       50   &gt;20   34       51   7   84       52   &gt;20   11       53   13   62       54   &gt;20   6       55   &gt;20   &lt;5       56   &gt;20   3       57   3   56       58   6.9   78       59   &gt;20   23       60   &gt;20   15       61   &gt;20   18       62   &gt;20   32       63   &gt;20   30       64   &gt;20   18       65   &gt;20   27       66   &gt;20   28       67   0.76   78       68   10.3   61       69   5.5   —       70   &gt;5   22       71   &gt;5   45       72   &gt;20   45       73   &gt;20   22       74   17.9   69       75   &gt;20   17       76   &gt;20   29       77   &gt;20   16       78   &gt;20   26       79   &gt;20   40       80   &gt;20   35       81   &gt;20   27       82   9.2   73       83   &gt;20   41       84   19.7   46       85   &gt;20   18       86   &gt;20   20       87   &gt;20   42       88   &gt;20   30       89   &gt;20   36       90   &gt;20   2       91   &gt;20   &lt;5       92   &gt;20   35       93   &gt;20   64       94   &gt;20   33       95   14.4   68       96   &gt;20   37       97   &gt;20   21       98   &gt;20   44       99   &gt;20   32       100   &gt;20   54       101   1.5   89       102   21.7   51       103   14.4   60       104   &gt;20   &lt;5       105   &gt;5   57       106   2.3   71       107   19.1   50       108   11.2   66       109   0.18   87       110   6.4   63       111   4.1   66       112   &gt;20   34       113   0.26   35       114   &gt;20   57       115   &gt;20   40       116   &gt;20   34       117   9.6   39       118   &gt;20   10       119   &gt;20   31       120   &gt;20   33       121   &gt;20   &lt;5       122   &gt;20   5       123   &gt;20   51       124   6.7   61       125   &gt;20   73       126   &gt;20   35       127   &gt;20   24       128   &gt;20   70       129   &gt;20   45       130   5.5   77       131   0.32   93       132   9.5   78       133   0.7   88       134   &gt;20   28       135   &gt;20   55       136   4.3   81       137   &gt;20   5       138   &gt;20   38       139   8.3   40       140   &gt;20   28       141   1.4   79       142   19.8   39       143   16.5   56       144   6.0   73       145   &gt;20   20       146   &gt;20   45       147   10   34       148   &gt;20   47       149   16   &lt;11       150   9   &lt;37       151   &gt;20   34       152   1.0   87       153   0.3   93       154   22.4   22       155   0.47   84       156   0.08   88       157   0.6   89       158   0.28   91       159   &gt;20   36       160   &gt;20   15       161   0.3   74       162   2.4   73       163   &gt;10   28       164   2   77       165   0.6   89       166   3.7   55       167   3   80       168   &gt;10   4       169   0.22   82       170   1   53       171   &gt;10   3       172   1.7   74       173   &gt;5   19       174   &gt;5   70       175   0.5   84       176   &gt;5   49       177   4   70       178   &gt;5   &lt;32       179   &gt;5   15       180   0.81   92       181   &gt;5   14       182   &gt;5   55       183   0.59   88       184   &gt;5   39       185   4   69       186   &gt;5   2       187   &gt;5   61       188   &gt;5   76       189   4.2   74       190   0.2   94       191   0.4   93       192   &gt;5   74       193   4.5   69       194   &gt;5   50       195   0.27   90       196   1.2   77       197   &gt;5   55       198   &gt;5   82       199   &gt;5   52       200   2.1   83       201   0.15   82       202   2.9   82       203   0.19   94       204   1.2   87       205   &gt;20   34       206   1.1   84       207   0.58   76       208   0.23   88       209   17.9   63       210   0.43   87       211   0.13   89       212   0.4   81       213   0.28   87       214   0.74   82       215   0.32   86       216   0.26   86       217   0.63   88       218   0.29   92       219   &gt;5   30       220   &gt;5   43       221   0.43   81       222   &gt;5   45       223   &gt;5   37       224   &gt;20   —       225   &gt;20   —       226   &gt;20   —       227   &gt;20   —       228   8.9   —       229   7.0   —       230   3.1   —       231   7.2   —       232   7.6   —       233   &gt;20   —       234   13   —                  
 
           [0188]    [0188]                                     TABLE 1B                           BK   BB7       Example   IC 50  (μM)   IC 50  (μM)                                235   5.2   5.4       236   10   9.6       237   &gt;27   &gt;24       238   19   &gt;30       239   4.6   5.4       240   8.9   18       241   27   &gt;30       242   27   18       243   6.3   10       244   0.3   1.8       245   0.4   0.74       246   &gt;30   &gt;30       247   &gt;24   18       248   &gt;30   &gt;30       249   7   12       250   3.7   3.9       251   1.7   3.5       252   7.3   19       253   0.35   0.7       254   3.3   5.8       255   &gt;30   15       256   0.15   0.34       257   1.9   2.9       258   9.4   14       259   0.5   1.6       260   0.4   1.2       261   0.4   0.9       262   2.7   8.3       263   1.3   3.2       264   &gt;30   27       265   20   22       266   14   17       267   0.66   2.3       268   4.6   6.1       269   9.4   9.4       270   20   17       271   2.7   3.5       272   0.5   1.5       273   1.4   6.5       274   9.3   &gt;26       275   1.2   3.5       276   1.3   1.7       277   2.6   6.2       278   15   23       279   2   2.4       280   0.8   2       281   &gt;30   &gt;30       282   13   22       283   15   &gt;27       284   1   2.3       285   0.4   1.1       286   &gt;30   &gt;30       287   5.1   6.5       288   22   18       289   0.12   0.23       290   3.2   4.9       291   0.23   0.5       292   0.13   0.26       293   &gt;30   &gt;30       294   &gt;30   &gt;30       295   3.6   3.1       296   7.2   6.3       297   1.8   2.8       298   0.3   0.5       299   0.5   0.9       300   0.14   0.25       301   5.4   11.3       302   4   18       303   &gt;30   &gt;30       304   &gt;30   &gt;30       305   &gt;30   &gt;30       306   &gt;30   &gt;30       307   5.8   9.6       308   &gt;30   &gt;30       309   26   27       310   &gt;25   &gt;25       311   &gt;30   &gt;30       312   16   &gt;30       313   1.8   1.5       314   1.4   3.1       315   0.4   2.1       316   &gt;30   &gt;30       317   0.6   0.9       318   0.14   0.25       319   0.06   0.08       320   2.9   6.0       321   0.3   0.6       322   0.04   0.16       323   4.9   11       324   0.2   0.35       325   0.08   0.19       326   6.5   9.4       327   0.8   1.7       328   4.3   3.9       329   0.6   1.5       330   1.6   8.4       331   0.5   2.5       332   6.4   14       333   1.3   7.6       334   3   5       335   &gt;30   &gt;30       336   4.7   8.7       337   19   &gt;30       338   3.3   3.9       339   0.49   2.8       340   &gt;30   &gt;28       341   1.7   3.6       342   1.7   10       343   &gt;30   &gt;30       344   0.7   —       345   3.4   6.2       346   6.1   8       347   &gt;29   &gt;30       348   &gt;30   &gt;30       349   4.4   &gt;24       350   &gt;30   &gt;30       351   &gt;30   &gt;30       352   0.9   2.8       353   2   .81       354   3   2       355   5.1   2.9       356   1.8   1.4       357   1.3   .97       358   16   20       359   .07   .07       360   .09   .04       361   1.8   .77       362   .11   .07       363   .36   .13       364   .48   .22       365   .1   .06       366   1.7   .55       367   .08   .09       368   .11   .13       369   0.004   0.01       370   0.04   0.03                    
           [0189]    The ability of the compounds of the present invention to inhibit Hepatitis C virus replicon constitutively expressed in a human liver cell line was established by the following experimental procedure:  
           [0190]    Clone A cells (licensed from Apath, LLC) are derived from Huh-7 cells (human hepatoma cell line) and constitutively express the HCV replication proteins with concomitant amplification the HCV replicon (1b) genome. Cells are maintained and passaged in DMEM/10% FCS/1 mg/ml G418 (Geneticin from Gibco #11811-023; other media components as described below in “elisa media”). Care should be taken to maintain cell monolayers at a subconfluent state by 1:3 or 1:4 passages every 3-4 days. The replicon is extremely sensitive to the cellular metabolism/proliferation state and replicon copy number will rapidly decline in confluent monolayers (resting cells). Under ideal conditions each cell has, on average, 1000 copies of the HCV replicon genome.  
           [0191]    Reagents:  
           [0192]    Elisa media:  
           [0193]    Dulbecco&#39;s Modified Eagle Media (DMEM) (Gibco #12430-047)  
           [0194]    2% Fetal Calf Serum (FCS) (HyClone #SH30070.03)  
           [0195]    1× pen/strep (Gibco #15140-122)  
           [0196]    1× Non-essential amino acids (NEAA) (Gibco #11140-050)  
           [0197]    no G418  
           [0198]    Glutaraldehyde (Fisher #02957-4)  
           [0199]    TWEEN-20, 10% (Roche #1332465)  
           [0200]    TRITON X-100 (Sigma #T-8787)  
           [0201]    Superblock in Phosphate Buffered Saline (PBS) (Pierce #37515)  
           [0202]    NS5a monoclonal antibody (Virostat #1873)  
           [0203]    Goat antimouse-HRP monoclonal antibody (BioRad #172-1011)  
           [0204]    3,3′,5,5′ tetramethylbenzidine (TMB) substrate (Sigma #T-0440)  
           [0205]    Compound Dilution/Cell Plating:  
           [0206]    Drug Plate Preparation (Mother Plate)  
           [0207]    10 μl of compounds (in DMSO) are added to column 3 of the mother plate. 5 μl of DMSO are added to the remaining columns. Mother plates are set aside until ready for serial dilution to be performed.  
           [0208]    Control Drugs  
           [0209]    Drug and Cell Addition:  
           [0210]    The process for each plate involves:  
           [0211]    Prepare cell plates (daughter plates) by adding 52 μl of Elisa media to each well.  
           [0212]    In Mother plates, serially transfer 50 μl/well from column 3 through column 12.  
           [0213]    Transfer 8 μl from mother plate to daughter plates (all 96 wells).  
           [0214]    Place daughter plates in incubator until cells are prepared.  
           [0215]    Harvest Clone A cells and plate directly into daughter plates at 0.7×10 5  cells/ml, 100 μl/well.  
           [0216]    All plates are incubated at 37° C. in 5% CO 2  for 3 days.  
           [0217]    Elisa Assay:  
           [0218]    Remove media from 96-well plates (cells should be ca 80% confluent) by flicking into sink.  
           [0219]    Add 130 μl/well 1× PBS+0.05% glutaraldehyde.  
           [0220]    Incubate 37° C. for 1 hour.  
           [0221]    Remove by flicking into sink.  
           [0222]    Wash 3× with 300 μl/well PBS, shaking 5 min each wash. Remove by into sink.  
           [0223]    Add 130 μl/well PBS+0.05% TWEEN-20+0.1% TRITON X-100.  
           [0224]    Incubate 37° C. for 10 minutes.  
           [0225]    Remove by flicking into sink.  
           [0226]    Add 300 μl/well Superblock in PBS.  
           [0227]    Incubate 37° C. for 1 hour.  
           [0228]    Remove by flicking into sink.  
           [0229]    Wash 3× with 300 μl/well PBS, shaking 5 minutes each wash. Remove by flicking into sink.  
           [0230]    During last wash, make a 1:100 dilution of NS5a Monoclonal-antibody (Mab) in Superblock+0.02% TWEEN-20.  
           [0231]    After last wash, add 50 μL/well diluted Mab.  
           [0232]    Incubate 37° C. for 1 hour.  
           [0233]    Remove by flicking into sink.  
           [0234]    Wash 3× with 300 μl/well PBS+0.02% TWEEN-20, shaking 5 minutes each wash.  
           [0235]    Remove by flicking into sink.  
           [0236]    During last wash, make a 1:500 dilution of goat antimouse-HRP Mab in Superblock+0.02% TWEEN-20.  
           [0237]    After last wash, add 50 μl/well diluted Mab.  
           [0238]    Incubate 37° C. for 1 hour.  
           [0239]    Remove by flicking into sink.  
           [0240]    Wash 5× with 300 μl/well PBS+0.02% TWEEN-20, shaking 5 minutes each wash. Remove by flicking into sink.  
           [0241]    Wash 3× with 300 μl/well PBS, shaking 5 minutes each wash. Remove by flicking into sink.  
           [0242]    After last wash, add 130 μl/well room temperature TMB substrate.  
           [0243]    Incubate until blue color develops.  
           [0244]    Add 130 μl/well 1N HCl to stop reaction (color turns from blue to yellow).  
           [0245]    Read plates with optical density (O.D.) 450 filter.  
           [0246]    ANALYSIS OF RESULTS: IC 50  (μM); IC 50  (μg/ml); % Inhibition  
           [0247]    REFERENCE COMPOUNDS: Interferon-a 2 ; 4-30 U/ml IC50  
           [0248]    The following non-limiting specific examples are included to illustrate the synthetic procedures used for preparing compounds of the formula (I). In these examples, all chemicals and intermediates are either commercially available or can be prepared by standard procedures found in the literature or are known to those skilled in the art of organic synthesis. 
       
    
    
     EXAMPLE 1  
     (5-Cyano-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)acetic acid  
     5-Bromo-2-methylaniline  
       [0249]    The mixture of Fe powder (9.31 g, 167 mmol) and NH 4 Cl (2.48 g, 46.3 mmol) in water (50 mL) was refluxed for 30 minutes. To this hot mixture was added 4-bromo-2-nitrotoluene (10 g, 46.3 mmol) slowly and then the reaction mixture was refluxed for 48 hours. The mixture was cooled to room temperature and extracted with EtOAc (3×100 mL). The organic solution was washed with H 2 O (3×200 mL) and brine (200 mL), dried (Na 2 SO 4 ), and concentrated. The residue was purified by flash chromatography (silica, 15% EtOAc in hexanes) to give 7.9 g (92%) of title compound as a pale yellow oil. 1H nuclear magnetic resonance (NMR) (CDCl 3 ): 300 MHz δ6.88 (m, 1H), 6.81 (m, 2H), 3.63 (bs, 2H), 2.09 (s, 3H).  
       5-Bromo-2-methylphenylhydrazine Hydrochloride  
       [0250]    To a suspension of 5-bromo-2-methylaniline (4.80 g, 25.8 mmol) in concentrated HCl (16 mL) was added dropwise a solution of sodium nitrite (1.96 g, 28.4 mmol) in water (10 mL) over 30 minutes at 0° C. To the mixture was added dropwise a solution of SnCl 2 .2H 2 O (17.46 g, 77.4 mmol) in concentrated HCl (15 mL) over 50 minutes. After stirring for 1 hour at 0° C., the reaction mixture was basified with 50% NaOH (30 mL). The mixture was further diluted with water (20 mL) and treated with another 50% NaOH (10 mL) and then crushed ice (100 g). The reaction mixture was extracted with ether (3×100 mL) and the combined organic phases were washed with brine, dried over Na 2 SO 4 , and filtered. The filtrate was acidified by adding an anhydrous solution of HCl in ether (1 N in ether, 31 mL, 31 mmol). The precipitate was collected and dried under reduced pressure to give 4.57 g (75%) of title compound as a white amorphous solid. 1H NMR (DMSO): 300 MHz δ 10.31 (bs, 3H), 8.11 (bs, 1H), 7.12 (s, 1H), 7.06 (m, 2H), 2.14 (s, 3H).  
       4-Bromo-7-methyl Tryptophol  
       [0251]    To a solution of 5-bromo-2-methylphenylhydrazine hydrochloride (4.57 g, 19.2 mmol) in 30% aqueous tetrahydrofuran (THF) (100 mL) at 0° C. was added dropwise a solution of 2,3-dihydrofuran (1.60 mL, 21.2 mmol) in THF (10 mL). After stirring for 2 hours at 0° C. and 12 hours at room temperature, the reaction mixture was diluted with ether (100 mL). The organic solution was washed with saturated NaHCO 3  (2×100 mL) and brine (100 mL), dried (Na 2 SO 4 ) and concentrated. The residue was dissolved in ethylene glycol (30 mL), treated with ZnCl 2  (5.76 g, 42.2 mmol), and heated at 170° C. for 4 hours. The reaction mixture was cooled down to room temperature and 6 N HCl (100 mL) was added. The mixture was extracted with ether (3×100 mL) and washed with water (200 mL) and brine (200 mL). The organic solution was dried over Na 2 SO 4  and concentrated. The residue was purified by flash chromatography (silica, 40% EtOAc in hexanes) to give 1.22 g (25%) of title compound as a light brown oil. 1H NMR (CDCl 3 ): 300 MHz δ 8.23 (bs, 1H), 7.18 (d, J=7.65 Hz, 1H), 7.08 (d, J=2.16 Hz, 1H), 6.81 (d, J=7.65 Hz, 1H), 3.95 (t, J=6.42 Hz, 2H), 3.27 (t, J=6.42 Hz, 2H), 2.40 (s, 3H), 1.69 (bs, 1H)  
       5-Bromo-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic Acid Ethyl Ester  
       [0252]    To a solution of 4-bromo-7-methyl tryptophol (1.12 g, 4.41 mmol) and ethyl butyrylacetate (0.71 mL, 4.41 mmol) in CH 2 Cl 2  (20 mL) was added BF 3 .OEt 2  (0.56 mL, 4.41 mmol) dropwise at room temperature. The solution was stirred for 2 hours and then washed with saturated aqueous NaHCO 3  (15 mL) and brine (15 mL). The organic phase was dried (Na 2 SO 4 ) and filtered through a pad of silica gel. The filter cake was washed with additional CH 2 Cl 2  and the combined organic layer was evaporated to provide 1.62 g (93%) of title compound as a white solid. 1H NMR (CDCl 3 ): 300 MHz δ 9.33 (bs, 1H), 7.11 (d, J=7.65 Hz, 1H), 6.76 (d, J=7.65 Hz, 1H), 4.19 (m, 2H), 4.03 (m, 1H), 3.90 (m, 1H), 3.15 (m, 2H), 3.03 (d, J=16.6 Hz, 1H), 2.89 (d, J=16.6 Hz, 1H), 2.43 (s, 3H), 2.08 (m, 1H), 1.96 (m, 1H), 1.38 (m, 1H), 1.27 (t, J=7.14 Hz, 3H), 1.18 (m, 1H), 0.87 (t, J=7.29 Hz, 3H).  
       5-Cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid Ethyl Ester  
       [0253]    5-Bromo-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (1.27 g, 3.22 mmol) and CuCN (0.433 g, 4.83 mmol) was dissolved in N-methyl-2-pyrrolidinone (15 mL) and the solution was divided into the 4 microwave reaction vessels (3.75 mL each). The reaction vessels were heated in microwave at 220° C. for 15 minutes. The reaction mixtures in 4 vessels were combined and then diluted with water (30 mL). The crude mixture was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (100 mL), dried over Na 2 SO 4  and concentrated. The residue was purified by flash chromatography (silica, 20% EtOAc in hexanes) to give 0.959 g (88%) of title compound as a white solid. 1H NMR (CDCl 3 ): 300 MHz δ 9.75 (bs, 1H), 7.33 (d, J=7.52 Hz, 1H), 6.93 (d, J=7.52 Hz, 1H), 4.21 (m, 2H), 4.11 (m, 1H), 4.03 (m, 1H), 3.08 (t, J=5.52, 2H), 2.99 (d, J=4.17 Hz, 2H), 2.57 (s, 3H), 2.06 (m, 2H), 1.42 (m, 1H), 1.26 (t, J=7.16 Hz, 3H), 1.18 (m, 1H), 0.88 (t, J=7.3 Hz, 3H).  
       5-Cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid  
       [0254]    To a solution of 5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4b]indole-1-acetic acid ethyl ester (0.959 g, 2.82 mmol) in THF/MeOH (7 mL/15 mL) was added 1 N NaOH (5.64 mL, 5.64 mmol). The reaction mixture was stirred at ambient temperature overnight. The most of THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (60 mL), dried over Na 2 SO 4  and concentrated to provide 0.868 g (99%) of title compound as a white solid. 1H NMR (acetone-d6): 300 MHz δ 10.37 (bs, 1H), 7.35 (d, J=7.50 Hz, 1H), 7.03 (d, J=7.50 Hz, 1H), 4.05 (m, 2H), 3.08−2.91 (m, 4H), 2.54 (s, 3H), 2.09 (m, 2H), 1.45 (m, 1H), 1.03 (m, 1H), 0.84 (t, J=7.26 Hz, 3H).  
       EXAMPLE 2 AND EXAMPLE 3  
     [(R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     [(S)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     Resolution of (±)-5-Cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid  
       [0255]    Preparative high pressure liquid chromatography (HPLC) using CHIRALPACK-AD (250×20 mm) and 10% isopropyl alcohol in heptane (0.1% trifluoroacetic acid (TFA)) as eluant gave (R) and (S) enantiomers of 5-cyano-8methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid as white solids. HRMS (ESI) [M+H] +  calculated for C 18 H 21 N 2 O 3  313.1547, found 313.1545 (R enantiomer) and 313.1547 (S enantiomer); Chiral HPLC HP 1100 with spiderlink CHIRALPACK-AD, 250×4.6 mm, isopropyl alcohol/heptane containing 0.1% TFA (10:90), 1.0 mL/minutes, DAD 215 nm; t R =6.98 minutes (R enantiomer), 9.37 minutes (S enantiomer).  
         [0256]    Alternatively, [(R)-5-cyano-8-methyl-1-propyl-1,3,4,9tetrahydropyrano[b  3 , 4 -b]indol-1-yl]acetic acid can be obtained by resolution with cinchonine according to the following procedure. (±)-5-Cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (6.4 g, 20.5 mmol) and cinchonine (5.9 g, 20.0 mmol) were dissolved in a mixture of 2-butanone (125 mL) and water (5 mL) with heating. The clear solution was stirred and allowed to cool to room temperature overnight. The resulting solid was isolated, washed with 10 mL of 2-butanone, and dried to give 2.4 g (20% yield, &gt;98% e.e.). The mother liquor was concentrated and dissolved again in a mixture of 2butanone (100 mL) and water (1.5 mL) with heating. The solution was stirred and allowed to cool to room temperature overnight. The resulting solid was isolated, washed with 10 mL of 2-butanone, and dried to give a second crop of salt: 2.3 g (18% yield, &gt;98% e.e.). The two crops (total 4.7 g) were combined and treated with 50 mL of 1N HCl and 100 mL of ethyl acetate. The ethyl acetate layer was washed with 1N HCl (30 mL) and water (50 mL). The aqueous layers were combined and extracted with ethyl acetate (50 mL). This ethyl acetate layer was washed with water (50 mL). The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 2.25 g. This material was triturated with 10 mL of ethyl acetate and the precipitate was collected, rinsed with 5 mL of ethyl acetate, and dried to give 1.27 g (e.e. &gt;98%). The mother liquor was concentrated to a volume of 5 mL and the new formed precipitate was collected, rinsed with 2 mL of ethyl acetate and dried. A second crop of 0.4 g was obtained with an e.e. of &gt;99%. The mother liquor was concentrated and gave a third crop of 0.5 g with an e.e. of &gt;99%.  
         [0257]    The absolute configuration of the compound of Example 2 was determined by single crystal X-ray crystallography of the 4-bromobenzyl amide derivative, which was prepared as described below.  
       1-(R)—N-(4-Bromo-benzyl)-2-(5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)-acetamide  
       [0258]    To a solution of 1-(R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-3,4-b]indole-1-acetic acid (20.0 mg, 0.064 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 15.0 mg, 0.077 mmol) and 1-hydroxybenzotriazole (10.4 mg, 0.077 mmol) in DMF (4 mL) was added N,N-diisopropylethylamine (67 μl, 0.384 mmol) followed by 4-bromobenzylamine hydrochloride (17.1 mg, 0.077 mmol) at room temperature. The reaction mixture was stirred for 20 hours at ambient temperature. Water (5 mL) was added to the mixture and the resulting mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na 2 SO 4  and concentrated. The residue was purified by flash chromatography (silica, 40% EtOAc in hexanes) to give 27 mg (88%) of title compound as a white solid. The solid was crystallized from EtOAc for X-ray crystallography. Mp=173-175° C.; 1H NMR (CDCl 3 ): 300 MHz δ 10.15 (bs, 1H), 7.33 (m, 3H), 6.97 (m, 2H), 6.88 (m, 1H), 4.42 (dd, J=11.2, 4.6 Hz, 1H), 4.29 (dd, J=11.2, 4.6 Hz, 1H), 4.03 (m, 2H), 3.11−2.95 (m, 4H), 2.24 (s, 3H), 2.07 (m, 1H), 1.91 (m, 1H), 1.35 (m, 2H), 0.89 (t, J=5.4 Hz, 3H); HRMS (ESI) [M+H] +  calculated for C 25 H 27 BrN 3 O 2  480.1281, found 480.1285.  
         [0259]    The absolute configuration of the compound of Example 3 was determined by single crystal X-ray crystallography of the 4-bromobenzyl amide derivative.  
       1-(S)—N-(4-Bromo-benzyl)-2-(5-cyano-8-methyl-1-propyl-1,3,4,9tetrahydropyrano[3,4-b]indol-1-yl)-acetamide  
       [0260]    The above procedure was followed starting from 1-(S)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid. Mp=173-175° C.; 1H NMR (CDCl 3 ): 300 MHz δ 9.99 (bs, 1H), 7.36 (m, 3H), 6.95 (m, 3H), 6.71 (bs, 1H), 4.42 (dd, J=11.4, 4.6 Hz, 1H), 4.28 (dd, J=11.4, 4.6 Hz, 1H), 4.03 (m, 2H), 3.10−2.92 (m, 4H), 2.34 (s, 3H), 2.05 (m, 1H), 1.91 (m, 1H), 1.34 (m, 2H), 0.89 (t, J=5.4 Hz, 3H); HRMS (ESI) [M+H] +  calculated for C 25 H 27 BrN 3 O 2  480.1281, found 480.1274.  
       EXAMPLE 4  
     (5-Cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)acetic acid  
     5-Bromo-2-fluoroaniline  
       [0261]    Iron powder (9.3 g, 0.166 mM) and ammonium chloride (1.7 g, 0.032 mM) were stirred in water (42 ml) at 100° C. for 30 minutes. Commercially available 2-nitro 4-bromo fluorobenzene (9.2 g, 0.42 mM) was added drop wise to the above solution over a period of 45 minutes. The reaction was stirred at 100° C. for an additional five hours. Water was removed in vacuo. The resultant crude solution was stirred in ethyl acetate (100 mL) for 20 minutes and the organic solution was decanted off. This wash was repeated two more times. The organic layers were combined, dried (MgSO 4 ), passed through a plug of SiO 2 , and concentrated to afford 4.2 g (53% yield) of the desired product as a red oil. The product was used without further purification. NMR (CHCl 3 ) δ 3.78 (bs, 2H); 6.65-7.07(m, 3H).  
         [0262]    See, Courtin, A. Helv. Chim. Acta. 66, 1, (1983), hereby incorporated by reference.  
       5-Bromo-2-fluorophenylhydrazine  
       [0263]    A solution of sodium nitrate (0.49 g, 0.007 mM) in water (1.5 ml) was added drop wise to a vigorously stirred heterogeneous solution of 5-bromo-2-fluoroaniline (1.4 g) in concentrated HCl(aq) (3.5 ml) over a 30 minutes period at 0° C. Tin (II) chloride dihydrate (4.5 g, 0.02 mM) in concentrated HCl(aq) (3.5 ml) was added drop wise to the above solution over a period of 30 minutes. After the addition, the solution was allowed to stir at 0° C. for one hour. The reaction solution was basified (pH&gt;7) by slowly adding a solution of 50% aqueous NaOH to the reaction mixture. The water layer was washed with diethyl ether (3×). The organic layers were combined, dried (MgSO 4 ), and concentrated. The resultant solid was thoroughly washed with hexanes. The undissolved solid was captured on filter and further washed with hexanes to afford 0.8 1 g (54% yield) of the desired product as an off-white solid. NMR (CHCl 3 ) δ 5.45 (bs, 1H); 6.80-6.86(m, 2H); 7.25-7.28 (m, 1H).  
         [0264]    See, McKittrick, B. et al., J. Heterocyclic Chem. 27, 2151 (1990), hereby incorporated by reference.  
       4-Bromo-7-fluoro Tryptophol  
       [0265]    2,3-Dihydrofuran (2.0 ml, 0.026 mM) was added to a solution of 5-bromo2-fluorophenyl hydrazine (4.43 g, 0.21 mM) in dry THF (40 ml) at 0° C. Concentrated HCl(aq) (2.0 ml) was added to the mixture and the reaction was allowed to warm to room temperature and stirred overnight. THF was removed in vacuo. The crude residue was taken up in water and washed with ethyl acetate (3×). The organic layers were combined, dried (MgSO 4 ), and concentrated to afford 4.2 g of a mixture of the mono and di-adducts as a red oil. This crude mixture was used without further purification in the next step.  
         [0266]    Zinc chloride (5.4 g, 0.39 mM) and the crude mixture were stirred in ethylene glycol at 160° C. for three hours. The reaction was cooled and diluted with 10% HCl (aq) (50 ml). The aqueous layer was washed with ethyl acetate (3×). The organic layers were combined, dried (MgSO 4 ), and concentrated. The product was purified by using silica gel flash chromatography (mobile phase: 3:2/hexanes:ethyl acetate) to afford 1.2 g (yield: 21%) of the desired product as an off-white solid. NMR(CHCl 3 ) δ 3.26 (t, 2H, 6.3 Hz); 3.96(t, 2H, 6.4 Hz); 6.75 (m, 1H); 7.15(m, 2H); 8.54(bs, 1H).  
       5-Bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid Ethyl Ester  
       [0267]    BF 3 -etherate (0.74 ml, 0.0059 mM) was added to a solution of 4-bromo-7-fluorotryptophol (1.0 g, 0.0039 mM) and ethyl butyrylacetate (0.93 ml, 0.0059 mM) in dry dichloromethane (15 ml). This reaction was stirred for three hours at room temperature. Sat. NaHCO 3  (aq) (15 ml) was added to quench the reaction. The solution was washed with DCM (2×). The organic layers were combined, dried (MgSO 4 ), passed through a plug of SiO 2 , and concentrated to afford 1.02 g (66% yield) of the desired product as an off-white solid. NMR (CHCl 3 ) δ 0.87 (t, 3H, 7.38Hz); 1.44(m, 1H); 1.28(t, 3H, 7.14Hz); 1.39(m, 1H); 1.93(m, 1H); 2.03(m, 1H); 2.91m(m, 1H); 3.06(m 1H); 3.15(m, 2H), 3.91(m, 1H); 4.03(m, 1H), 4.22(m, 2H); 6.72(m, 1H); 7.09(m, 1H); 9.50(s, 1H).  
       5-Cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid Ethyl Ester  
       [0268]    The above ester (1.02 g, 0.026 mM) was dissolved in N-Methyl pyrrolidinone (12 ml). This solution was distributed equally into four Personal Chemistry microwave reaction vessels. CuCN (0.085 g, 0.0096 mM) was added into each reaction vessel. The reaction vessels were heated, under microwave conditions, at 220° C. for 15 minutes. The reaction solutions were combined and diluted with water (30 ml). The aqueous layer was washed with ethyl acetate (3×). The organic layers were combined, dried (MgSO 4 ), and concentrated. The product was purified by SiO 2  flash chromatography to afford 0.81 g (92% yield) of the desired product as an off-white solid. NMR (d 6 -DMSO) δ 0.78 (t, 3H); 0.86(m, 2H); 1.0(t, 3H); 1.29(m, 2H); 1.92(m, 2H); 2.76(d, 1H); 2.86(t, 2H); 3.02(d, 1H); 3.9(m, 4H); 7.07(m, 1H); 7.5(m, 1H); 11.94(s, 1H).  
       5-Cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid  
       [0269]    1N NaOH(aq) (4.6 ml) was added to a solution of the above ester (0.8 g, 0.0023 mM) in 1:1/MeOH:THF (10 ml) and stirred at room temperature overnight. THF and MeOH were removed in vacuo. The residue was diluted with brine (10 ml), acidified with (pH&lt;2) concentrated HCl (aq), and washed with ethyl acetate (3×). The organic layers were combined, dried (MgSO 4 ), and concentrated to afford 0.61 g (82% yield) of the desired product as a white solid. NMR (d 6 -DMSO) δ 0.95 (t, 3H, 5.4 Hz); 1.23(m, 1H); 1.42(m, 1H); 2.05(m, 1H); 2.99-3.13 (m, 4H); 3.99(m, 1H), 4.11(m, 2H); 6.90(m, 1H); 7.39(m, 1H) 9.45(s, 1H).  
       EXAMPLE 5 AND EXAMPLE 6  
     [(R)-5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     [(S)-5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     Resolution of (±)-5-Cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4b]indole-1-acetic acid  
       [0270]    Preparative HPLC using CHIRALPACK-AD (250×20 mm) and 10% isopropyl alcohol in heptane (0.1 % TFA) as eluant gave (R) and (S) enantiomers of 5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid as white solids. Chiral HPLC HP 1100 with spiderlink CHIRALPACK-AD, 250×4.6 mm, isopropyl alcohol/heptane containing 0.1% TFA (10:90), 1.0 mL/minutes, DAD 215 nm; tR=6.1 minutes (R enantiomer), 8.3 minutes (S enantiomer).  
         [0271]    Alternatively, [(S)-5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-acetic acid can be obtained by resolution with (+) (1S,2R) ephedrine according to the following procedure. (±)-5-Cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (27.75 g, 87.8 mmol) and (+) (1S,2R) ephedrine hemihydrate (15.28 g, 87.8 mmol) were dissolved in a mixture of isopropyl alcohol (730 mL) and water (43 mL) with heating. The clear solution was seeded with 98% e.e. ephedrine salt and allowed to cool to room temperature overnight. The resulting solid was isolated and washed with isopropyl alcohol (20 mL) to give 18.82 g of salt (44% yield, &gt;98% e.e.). Liberation of the salt was accomplished by addition of 1N HCl and ethylacetate to afford 12.4 g of acid. This material was combined with 0.9 g of acid obtained from previous experiments and recrystallized from ethyl acetate (30 mL) to afford 7.4 g in the first crop (&gt;99.8% e.e.) and another 3.8 g in the second crop (99.3-99.6% e.e.). These two crops were combined to give 11.1 g of resolved (S) acid (40% yield, &gt;99.5% e.e.). Concentration of the mother liquor afforded 2.4 g of (S) acid (98% e.e.).  
         [0272]    The absolute configuration of the compound of Example 5 was determined by single crystal X-ray crystallography of the 4-bromobenzyl amide derivative.  
       1-(R)—N-(4-Bromo-benzyl)-2-(5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)-acetamide  
       [0273]    The procedure described for Example 3 was followed starting from 1-(R)5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid. 1H NMR (d 6 -DMSO) δ 0.79 (t, 3H, 5.4 Hz); 0.94(m, 1H); 1.31(m, 1H); 1.96(m, 2H); 2.75 (d, 1H, 10.2 Hz); 2.91(m, 3H), 4.03(m, 2H); 4.21(d, 2H, 4.5 Hz); 7.09(m, 3H); 7.37(d, 2H, 6.0 Hz); 7.52(m, 1H); 8.22(t, 1H, 6.0 Hz); 11.93(s, 1H); MS: M−H: 482.1; CHN for C 24 H 23 BrFN 3 O 2 — Theory: C, 59.51; H, 4.79; N, 8.68; Found: C, 59.53; H, 4.86; N, 8.66.  
       EXAMPLE 7  
     5,8-Dichloro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)acetic acid  
     4,7-Dichloro-Tryptophol  
       [0274]    To a solution of 2,5 dichlorophenylhydrazine hydrochloride (20.4 g 0.11 mol) in THF (80 mL) at 0° C. was added dropwise a solution of 2,3-dihydrofuran (10.5 mL, 0.14 mol), water (15 mL) and HCl concentrated (5 mL). After stirring for 4 hours, the reaction mixture was diluted with ether (100 mL). The organic solution was washed with saturated NaCl (2×50 mL) and dried (Na 2 SO 4 ) and concentrated. The residue was dissolved in ethylene glycol (60 mL), treated with ZnCl 2  (34.6 g, 0.25 mol), and heated at 140° C. for 8 hours. The reaction mixture was cooled down to room temperature and 10% HCl was added. The mixture was extracted with ethyl actetate (3×75 mL) and washed with brine. The organic solution was dried over Na 2 SO 4  and concentrated. The residue was purified by flash chromatography (silica gel 60, EtOAc:Hexane 3:1) to give 10.4 g (39%) of title compound as a light brown oil. 1H NMR (CDCl 3 ): 300 MHz δ8.35 (bs, 1H), 7.16 (d, J=2.1 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 3.95 (t, J=6.3 Hz, 2H), 3.25 (t, J=6.3 Hz, 2H), 1.49 (bs, 1H).  
       5,8-Dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic Acid Ethyl Ester  
       [0275]    To a solution of 5,8 dichloro tryptophol (4.25 g, 18.55 mmol) and ethyl butyrylacetate (4.37 mL, 27.63 mmol) in CH 2 Cl 2  (40 mL) was added BF 3 ×OEt 2  (3.50 mL, 27.63 mmol) dropwise at room temperature. The solution was stirred for 2 hours and then washed with saturated aqueous NaHCO 3  (30 mL) and brine and concentrated. The oil was then purified by flash chromatography (silica gel 60, EtOAc:Hexane 4:1) to yield 1.5 g (32%). 1H NMR (CDCl 3 ): 300 MHz δ 9.55 (bs, 1H), 7.03 (d, J=8.10 Hz, 1H), 6.95 (d, J=8.10 Hz, 1H), 4.3 (m, 2H), 4.02 (m, 1H), 3.89 (m, 1H), 3.01 (m, 2H), 2.99 (m, 1H), 2.92(m, 1H), 2.01 (m, 2H), 1.28 (m, 5H), 0.88 (t, J=7.30 Hz, 3H).  
       5,8-Dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid  
       [0276]    To a solution of 5,8 dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4b]indole-1-acetic acid ethyl ester (1.2 g, 3.24 mmol) in EtOH (35 mL) was added 1 N NaOH (7 mL). The reaction mixture was stirred at 50° C. for 6 hours. The most of EtOH/NaOH was removed under reduced pressure and the resulting mixture was purified on HPLC to yield a white solid 0.730 g (66%). 1H NMR (CDCl 3 ): 300 MHz δ 9.12 (bs, 1H), 7.03 (d, J=8.26 Hz, 1H), 6.96 (d, J=8.26 Hz, 1H), 4.04 (m, 2H), 3.14(m, 2H), 3.06(m, 2H), 2.03 (m, 2H), 1.42 (m, 1H), 1.21(m, 1H), 0.89 (t, J=7.34 Hz, 3H).  
       EXAMPLE 8 AND EXAMPLE 9  
     [(R)-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     [(S)-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     Resolution of (±)-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic Acid  
       [0277]    Preparative HPLC using CHIRALCEL OJ (250×20 mm) and 3% isopropyl alcohol in heptane (0.1% TFA) as eluant gave (S) and (R) enantiomer of 5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid as a white solid. Chiral HPLC-HP 1100 with spiderlink; CHIRALCEL OJ, 250×4.6 mm, isopropyl alcohol/heptane (containing 0.1% TFA)=3:97, 1.0 mL/minutes, DAD 215 nm; t R =10.2 minutes (S enantiomer), 15.7 minutes (R enantiomer).  
       EXAMPLE 10  
     (5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano [3,4-b]indol1yl)acetic acid  
     4-Bromo-3-fluoro-6-nitrotoluene  
       [0278]    To a stirred solution of 4-bromo-3-fluorotoluene (10 g, 52.9 mmol) in H 2 SO 4  (100 mL) was added KNO 3  (5.34 g, 52.9 mmol) at 0° C. After stirring overnight at room temperature, the reaction mixture was poured into ice (200 g) and extracted with EtOAc (3×300 mL). The organic solution was washed with brine (200 mL), dried (Na 2 SO 4 ), and concentrated to give 12.35 g (100%) of title compound as a pale yellow oil. 1H NMR (CDCl 3 ): 300 MHz δ 8.29 (d, J=6.30 Hz, 1H), 7.12 (d, J=8.61 Hz, 1H), 2.60 (s, 3H).  
       5-Bromo-4-fluoro-2-methylaniline  
       [0279]    The mixture of iron powder (17.8 g, 318 mmol) and NH 4 Cl (5.10 g, 95.4 mmol) in water (100 mL) was refluxed for 30 minutes. To this hot mixture was added 4-bromo-3-fluoro-6-nitrotoluene (18.6 g, 79.5 mmol) slowly and then the reaction mixture was refluxed for 48 hours. The mixture was cooled to room temperature and extracted with EtOAc (3×200 mL). The organic solution was washed with H 2 O (3×300 mL) and brine (300 mL), dried (Na 2 SO 4 ), and concentrated. The residue was purified by flash chromatography (silica, 20% EtOAc in hexanes) to give 11.7 g (72%) of title compound as a pale yellow solid. 1H NMR (CDCl 3 ): 300 MHz δ 6.82 (m, 2H), 3.49 (bs, 2H), 2.11 (s, 3H).  
       5-Bromo-4-fluoro-2-methylphenylhydrazine Hydrochloride  
       [0280]    To a suspension of 5-bromo-4-fluoro-2-methylaniline (11.2 g, 54.9 mmol) in concentrated HCl (35 mL) was added dropwise a solution of sodium nitrite (4.17 g, 60.4 mmol) in water (20 mL) over 30 minutes at 0° C. To the mixture was added dropwise a solution of SnCl 2 .2H 2 O (37.2 g, 165 mmol) in concentrated HCl (45 mL) over 1 hour. After stirring for 2 hours at 0° C., the reaction mixture was basified with 50% NaOH (50 mL). The mixture was further diluted with water (50 mL) and treated with another 50% NaOH (20 mL) and then crushed ice (200 g). The reaction mixture was extracted with ether (3×200 mL) and the combined organic phases were washed with brine, dried over Na 2 SO 4 , and filtered. The filtrate was acidified by adding an anhydrous solution of HCl in ether (2 N in ether, 42 mL, 82.5 mmol). The precipitate was collected and dried under reduced pressure to give 9.92 g (71 %) of title compound as a pale yellow solid. 1H NMR (DMSO): 300 MHz δ 10.18 (bs, 3H), 7.98 (bs, 1H), 7.21 (m, 2H), 2.16 (s, 3H).  
       4-Bromo-5-fluoro-7-methyl Tryptophol  
       [0281]    To a solution of 5-bromo-4-fluoro-2-methylphenylhydrazine hydrochloride (4.75 g, 18.6 mmol) in 20% aqueous THF (100 mL) at 0° C. was added dropwise a solution of 2,3-dihydrofuran (1.55 mL, 20.4 mmol) in THF (10 mL). After stirring for 2 hours at 0° C. and 12 hours at room temperature, the reaction mixture was diluted with ether (100 mL). The organic solution was washed with saturated NaHCO 3  (2×100 mL) and brine (100 mL), dried (Na 2 SO 4 ) and concentrated. The residue was dissolved in ethylene glycol (50 mL), treated with ZnCl 2  (5.58 g, 40.9 mmol), and heated at 170° C. for 4 hours. The reaction mixture was cooled down to room temperature and 6 N HCl (100 mL) was added. The mixture was extracted with ether (3×100 mL) and washed with water (200 mL) and brine (200 mL). The organic solution was dried over Na 2 SO 4  and concentrated. The residue was purified by flash chromatography (silica, 40% EtOAc in hexanes) to give 1.52 g (30%) of title compound containing inseparable impurities (&lt;20%) as a light brown oil. 1H NMR (CDCl 3 ): 300 MHz δ 8.68 (bs, 1H), 7.06 (d, J=2.4 Hz, 1H), 6.76 (d, J=9.63 Hz, 1H), 3.92 (t, J=6.48 Hz, 2H), 3.21 (t, J=6.48 Hz, 2H), 2.35 (s, 3H), 2.27 (bs, 1H).  
       5-Bromo-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic Acid Ethyl Ester  
       [0282]    To a solution of 4-bromo-7-methyl tryptophol (400 mg g, 1.47 mmol) and ethyl butyrylacetate (0.28 mL, 1.76 mmol) in CH 2 Cl 2  (5 mL) was added BF 3 .OEt 2  (0.22 mL, 1.76 mmol) dropwise at room temperature. The solution was stirred for 2 hours and then washed with saturated aqueous NaHCO 3  (5 mL) and brine (5 mL). The organic phase was dried (Na 2 SO 4 ) and concentrated. The residue was purified by flash chromatography (silica, 15% EtOAc in hexanes) to give 496 mg (82%) of title compound as a pale yellow solid. Mp=137-138° C.; 1H NMR (CDCl 3 ): 300 MHz δ 9.73 (bs, 1H), 6.76 (d, J=10.1 Hz, 1H), 4.21 (m, 2H), 4.05 (m, 1H), 3.91 (m, 1H), 3.05−2.89 (m, 4H), 2.53 (s, 3H), 2.07 (m, 1H), 1.92 (m, 1H), 1.38 (m, 1H), 1.30 (t, J=6.98 Hz, 3H), 1.21 (m, 1H), 0.89 (t, J=7.08 Hz, 3H).  
       5-Cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano [3,4-b]indole-1-acetic Acid Ethyl Ester  
       [0283]    5-Bromo-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4b]indole-1-acetic acid ethyl ester (496 mg, 1.20 mmol) and CuCN (162 mg, 1.81 mmol) was dissolved in N-methyl-2-pyrrolidinone (6 mL) and the solution was divided into the 2 microwave reaction vessels (3.0 mL each). The reaction vessels were heated in microwave at 220° C. for 15 minutes. The reaction mixtures in 2 vessels were combined and then diluted with water (10 mL). The crude mixture was extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (50 mL), dried over Na 2 SO 4  and concentrated. The residue was purified by flash chromatography (silica, 25% EtOAc in hexanes) to give 404 mg (94%) of title compound as a white solid. 1H NMR (DMSO): 300 MHz δ 12.02 (bs, 1H), 11.33 (bs, 1H), 7.00 (d, J=9.00 Hz, 1H), 3.96 (m, 2H), 2.95 (d, J=10.3 Hz, 1H), 2.83 (t, J=3.9 Hz, 1H), 2.72 (d, J=10.3 Hz, 1H), 2.54 (s, 3H), 1.99 (m, 2H), 1.28 (m, 1H), 0.85 (m, 1H), 0.79 (t, J=5.41 Hz, 3H).  
       5-Cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic Acid  
       [0284]    To a solution of 5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (404 mg, 1.13 mmol) in THF/MeOH (2.5 mL/5 mL) was added 1 N NaOH (2.26 mL, 2.26 mmol). The reaction mixture was stirred at ambient temperature overnight. Most of the THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na 2 SO 4  and concentrated to provide 341 mg (91%) of title compound as a white solid. 1H NMR (DMSO): 300 MHz δ 12.02 (bs, 1H), 11.33 (bs, 1H), 7.00 (d, J=9.00 Hz, 1H), 3.96 (m, 2H), 2.95 (d, J=10.3 Hz, 1H), 2.83 (t, J=3.9 Hz, 1H), 2.72 (d, J=10.3 Hz, 1H), 2.54 (s, 3H), 1.99 (m, 2H), 1.28 (m, 1H), 0.85 (m, 1H), 0.79 (t, J=5.41 Hz, 3H).  
       EXAMPLE 11 AND EXAMPLE 12  
     [(R)-5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4b]indol-1-yl]acetic acid  
     [(S)-5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano [3,4b]indol-1-yl]acetic acid  
     Resolution of (±)-5-Cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic Acid  
       [0285]    Preparative HPLC using CHIRALPACK-AD (250×20 mm) and 10% isopropyl alcohol in heptane (0.1% TFA) as eluant gave (R) and (S) enantiomers of 5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid as white solids. HRMS (ESI) [M+H] +  calculated for C 18 H 20 FN 2 O 3  331.1453, found 331.1447 (R enantiomer) and 331.1452 (S enantiomer); Chiral HPLC HP 1100 with spiderlink CHIRALPACK-AD, 250×4.6 mm, isopropyl alcohol/heptane containing 0.1% TFA (10:90), 1.0 mL/minutes, DAD 215 nm; tR=7.19 minutes (R enantiomer), 9.27 minutes (S enantiomer).  
         [0286]    Example 13-30 were synthesized following the above mentioned procedure for example 1 using the intermediates 4-Chloro or 4-Bromotryptophol and reacting with β-ketoesters like methylacetoacetate, ethylpropionyl acetate, ethylbutyryl acetate, ethylisobutyryl acetate, methyl-3-oxo-6-octenoate, ethylbenzoyl acetate, methyl-4-methoxycarbonyl benzoyl acetate, ethyl 3 or 4-nitrobenzoyl acetate, ethyl 2-fluorobenzoyl acetate, ethyl β-oxo-3-furan propionate or ethyl-3,4,5-trimethoxybenzoyl acetate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0287]    Examples 31-49 were synthesized following Suzuki reaction conditions using 5-bromo-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic Acid Ethyl Ester (1 eq), corresponding boronic acids (1.2 eq), Pd(Ph 3 P) 4  (0.1 eq) and 2M Na 2 CO 3  in dimethoxy ethane as solvent at 65° C. (overnight). The resulting esters were hydrolyzed using 1N (aq.) NaOH in THF/MeOH.  
         [0288]    Examples 50-57 were synthesized following the above mentioned procedure for example 1 using the intermediate 4,7-dichlorotryptophol and reacting with β-ketoesters like methyl-3-oxo-6-octenoate, ethylisobutyryl acetate, ethylbenzoyl acetate, ethyl β-oxo-3-furan propionate, ethylisoamyl acetoacetate, ethyl-3,4,5-trimethoxybenzoyl acetate, ethyl 2-fluorobenzoyl acetate or methyl-4-methoxycarbonyl benzoyl acetate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0289]    Examples 58-66 were synthesized following the above mentioned procedure for example 1 using the intermediates 4-Bromotryptophol and reacting with β-ketoesters like ethylbutyryl acetate, ethylisobutyryl acetate, methyl-3-oxo-6-octenoate, ethyl β-oxo-3-furan propionate, ethylbenzoyl acetate, ehtyl-3,4,5-trimethoxybenzoyl acetate, ethyl 4 or 3-nitrobenzoyl acetate or ethyl 2-fluorobenzoyl acetate. The product was converted to the corresponding 5-cyano-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic Acid Ethyl Ester derivatives using CuCN in NMP using the microwave conditions provided in the Example 1. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0290]    Examples 67-69 were synthesized following the above mentioned procedure for example 1 using the intermediates 4,7-dichloro or 4-bromo or 4-chlorortryptophol and reacting with 3-oxoenanthic acid methyl ester. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0291]    Examples 70 and 71 were synthesized following the above mentioned procedure for example 1 using the intermediates 4-chlorortryptophol and reacting with dimethyl 1,3-acetonedicarboxylate. The resulting ester was hydrolyzed using 1N (aq) NaOH in THF/MeOH to give both 70 and 71.  
         [0292]    Examples 72-88 were synthesized following the above mentioned procedure for example 1 using the intermediates 7-Chloro or 7-Bromotryptophol and reacting with β-ketoesters like methylacetoacetate, ethylpropionyl acetate, ethylbutyryl acetate, ethylisobutyryl acetate, 3-oxoenanthic acid methyl ester, methyl-3-oxo-6-octenoate, ethylbenzoyl acetate, ethyl β-oxo-3-furan propionate or methyl-4-methoxycarbonyl benzoyl acetate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0293]    Examples 89-97 were synthesized following Suzuki reaction conditions using 8-bromo-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic Acid Ethyl Ester (1 eq), corresponding boronic acids (1.2 eq), Pd(Ph 3 P) 4  (0.1 eq) and 2M Na2CO3 in dimethoxy ethane as solvent at 650° C. (overnight). The resulting ester was hydrolyzed using 1N aq. NaOH in THF/MeOH.  
         [0294]    Example 98 was synthesized using 8-bromo-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic Acid Ethyl Ester using CuCN in NMP using the microwave conditions provided in the Example 1. The resulting ester was hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0295]    Examples 99-114 were synthesized following the above mentioned procedure for example 1 using the intermediates 5,7-dichloro or 6,7-dichloro or 4,6-dichlorotryptophol and reacting with β-ketoesters like methylacetoacetate, ethylpropionyl acetate, ethylbutyryl acetate, ethylisobutyryl acetate, 3-oxoenanthic acid methyl ester, methyl-3-oxo-6-octenoate, ethylbenzoyl acetate, methyl-4-methoxycarbonyl benzoyl acetate, ethyl 3 or 4-nitrobenzoyl acetate, ethyl 2-fluorobenzoyl acetate, ethyl β-oxo-3-furan propionate or ethyl-3,4,5-trimethoxybenzoyl acetate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0296]    Examples 115-121 were synthesized following the above mentioned procedure for example 1 using the intermediate 7-trifluoromethyltryptophol and reacting with β-ketoesters like methylacetoacetate, ethylpropionyl acetate, ethylbutyryl acetate, ethylisobutyryl acetate, 3-oxoenanthic acid methyl ester, methyl-3-oxo-6-octenoate, ethylbenzoyl acetate. The resulting esters were hydrolyzed using 1N(aq) NaOH in THF/MeOH.  
         [0297]    Examples 122-128 were synthesized following the above mentioned procedure for example 1 using the intermediate 4,7-difluorotryptophol and reacting with β-ketoesters like methylacetoacetate, ethylpropionyl acetate, ethylbutyryl acetate, ethylisobutyryl acetate, 3-oxoenanthic acid methyl ester, methyl-3-oxo-6-octenoate or methyl-4-methoxycarbonyl benzoyl acetate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0298]    Examples 129-136 were synthesized following the above mentioned procedure for example 1 using the intermediate 7-chloro-4-trifluoromethyltryptophol and reacting with β-ketoesters like methylacetoacetate, ethylpropionyl acetate, ethylbutyryl acetate, ethylisobutyryl acetate, 3-oxoenanthic acid methyl ester, methyl-3-oxo-6-octenoate ethylbenzoyl acetate or ethyl β-oxo-3-furan propionate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0299]    Examples 137-139 were synthesized following the above mentioned procedure for example 1 using the intermediate 4,7dimethyltrytophot and reacting with β-ketoesters like methylacetoacetate, ethylpropionyl acetate or ethylbutyryl acetate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0300]    Examples 140-146 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-fluoro-7-methyltryptophol and reacting with β-ketoesters like methylacetoacetate, ethylpropionyl acetate, ethylbutyryl acetate, ethylisobutyryl acetate, 3-oxoenanthic acid methyl ester, methyl-3-oxo-6-octenoate or ethylbenzoyl acetate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0301]    Examples 147-151 were synthesized following Suzuki reaction conditions using 5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic Acid Ethyl Ester (1 eq), corresponding boronic acids (1.2 eq), Pd(Ph 3 P) 4  (0.1 eq) and 2M Na 2 CO 3  in dimethoxy ethane as solvent at 650 C (overnight). The resulting ester was hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0302]    Example 152 was synthesized by hydrolyzing the intermediate 5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester in example 4 using 1N (aq) NaOH in THF/MeOH.  
         [0303]    Example 153 was synthesized by hydrolyzing the intermediate 5-bromo-8-methyl-1-propyl-1,3,4,9-acetic acid ethyl ester in example 1 using 1N (aq) NaOH in THF/MeOH.  
         [0304]    Examples 154-162 were synthesized following the above mentioned procedure for example 1 using the intermediate 4,5,7-trichlorotryptophol and reacting with β-ketoesters like methylacetoacetate, ethylpropionyl acetate, ethylbutyryl acetate, ethylisobutyryl acetate, 3-oxoenanthic acid methyl ester, methyl-3-oxo-6-octenoate or ethylbenzoyl acetate or ethyl [3-oxo-3-furan propionate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0305]    Examples 163-169 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-7-fluoro-5-methyltryptophol and reacting with β-ketoesters like methylacetoacetate, ethylpropionyl acetate, ethylbutyryl acetate, ethylisobutyryl acetate, 3-oxoenanthic acid methyl ester, ethylbenzoyl acetate, methyl-3-oxo-6-octenoate or methyl-4-methoxycarbonyl benzoyl acetate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0306]    Examples 170-172 were synthesized using 1-butyl-5-bromo-8-fluoro-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester or 5-bromo-8-fluoro-6-methyl-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester or 5-bromo-1-(4′carbonylethoxyphenyl)-8-fluoro-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1acetic acid ethyl ester using CuCN in NMP using the microwave conditions provided in the Example 1. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0307]    Examples 173-180 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-7-chloro-5-methyltryptophol and reacting with β-ketoesters like methylacetoacetate, ethylpropionyl acetate, ethylbutyryl acetate, ethylisobutyryl acetate, 3-oxoenanthic acid methyl ester, methyl-3-oxo-6-octenoate, ethylbenzoyl acetate, or methyl-4-methoxycarbonyl benzoyl acetate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0308]    Examples 181-188 were synthesized from the intermediate esters from the examples 173-180 using CuCN in NMP using the microwave conditions provided in the Example 1. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0309]    Examples 189-193 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-5,7-difluorotryptophol and reacting with β-ketoesters like ethylpropionyl acetate, ethylbutyryl acetate, 3-oxoenanthic acid methyl ester, ethyl β-oxo-3-furan propionate or ethylisobutyryl acetate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0310]    Examples 194-198 were synthesized from the intermediate esters from the examples 189-193 using CuCN in NMP using the microwave conditions provided in the Example 1. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0311]    Examples 199-204 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-5-fluoro-7-methyltryptophol and reacting with β-ketoesters like ethylpropionyl acetate, ethylbutyryl acetate, ethylisobutyryl acetate, 3-oxoenanthic acid methyl ester or methyl-4-methoxycarbonyl benzoyl acetate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0312]    Examples 205-209 were synthesized from the intermediate esters from the examples 199-204 using CuCN in NMP using the microwave conditions provided in the Example 1. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0313]    Examples 210-213 were synthesized following the above mentioned procedure for example 1 using the intermediate 4,7-dibromotryptophol and reacting with β-ketoesters like ethylpropionyl acetate, ethylbutyryl acetate, ethylisobutyryl acetate or 3-oxoenanthic acid methyl ester. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0314]    Example 214-218 were synthesized using the ethyl ester of examples 152, 175 and 165 as intermediates using CuCl or CuI in NMP using the microwave conditions provided in the Example 1. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
         [0315]    Examples 219-223 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-5-methyl-7-fluorotryptophol and reacting with P-ketoesters like methylacetoacetate, ethylpropionyl acetate, ethylisobutyryl acetate or methyl-3-oxo-6-octenoate. The intermediate esters were converted to the cyano compounds using CuCN in NMP using the microwave conditions provided in the Example 1. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.  
       EXAMPLE 224  
     (8-Methyl-5-methylcarbamoyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic Acid  
     4-Bromo-3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methyl-1H-indole  
       [0316]    A mixture of 2-(4-bromo-7-methyl-1H-indol-3-yl)-ethanol (2.51 g, 9.89 mmol), imidazole (1.68 g, 24.7 mmol) and tert-butyldimethylsilyl chloride (1.79 g, 11.9 mmol) in DMF (30 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (200 mL). The organic solution was washed with H 2 O (5×200 mL) and brine (200 mL), dried (Na 2 SO 4 ), and concentrated to give 3.49 g (96%) of title compound as yellow oil. 1H NMR (CDCl 3 ): 300 MHz δ 8.14 (bs, 1H), 7.11 (d, J=7.59 Hz, 1H), 6.99 (s, 1H), 6.72 (d, J=7.59 Hz, 1H), 3.90 (t, J=7.17 Hz, 2H), 3.19 (t, J=7.17 Hz, 2H), 2.31 (s, 3H), 0.87 (s, 9H), −0.08 (s, 6H).  
       3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-7-methyl-1H-indole-4-carboxylic acid  
       [0317]    To a suspension of KH (1.85 g of 30 wt % in oil, 13.85 mmol) in THF (100 mL) was added a solution of 4-bromo-3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methyl-1H-indole (3.40 g, 9.24 mmol) in THF (10 mL) at 0° C. After stirring for 40 minutes, the solution was cooled to −78° C. and tert-BuLi (10.9 mL of 1.7 M in pentane, 18.47 mmol), precooled to −78° C., was added. After stirring for 1 hour at −78° C., the reaction mixture was transferred to the flask containing anhydrous CO 2  (dry ice, 100 g) via cannula under N 2  atmosphere at −78° C. The suspension was warmed to room temperature very slowly using cold bath. The mixture was diluted with EtOAc (200 mL) and the organic solution was washed with 1 N HCl (2×200 mL), H 2 O (200 mL) and brine (200 mL). The organic phase was dried (Na 2 SO 4 ) and concentrated. The residue was purified by flash chromatography (silica, 15% EtOAc in hexanes) to give 0.74 g (41% based on the recovered SM) of title compound as a white solid. 1H NMR (CDCl 3 ): 300 MHz δ 8.26 (bs, 1H), 7.84 (d, J=7.56 Hz, 1H), 7.32 (d, J=2.46 Hz, 1H), 7.12 (d, J=7.56 Hz, 1H), 3.98 (t, J=6.39 Hz, 2H), 3.33 (t, J=6.39 Hz, 2H), 2.63 (s, 3H), 0.89 (s, 9H), −0.08 (s, 6H).  
       3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-7-methyl-1H-indole-4-carboxylic acid methylamide  
       [0318]    To a solution of 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methyl-1H-indole-4-carboxylic acid (150 mg, 0.45 mmol), EDCI (104 mg, 0.54 mmol) and HOBt (91.2 mg, 0.68 mmol) in DMF (3 mL) was added diisopropylethylamine (0.39 mL, 2.25 mmol) at room temperature. A solution of methylamine (0.45 mL of 2.0 M in THF, 0.90 mmol) was added to the mixture and the mixture was stirred overnight at room temperature. The solution was diluted with H 2 O (5 mL) and extracted with EtOAc (3×10 mL). The organic solution was washed brine (20 mL), dried (Na 2 SO 4 ) and concentrated. The residue was purified by flash chromatography (silica, 40% EtOAc in hexanes) to give 140 mg (90%) of title compound as a pale yellow solid. 1H NMR (CDCl 3 ): 300 MHz δ 8.28 (bs, 1H), 7.20 (m, 2H), 7.00 (d, J=7.35 Hz, 1H), 6.40 (bs, 1H), 3.91 (t, J=6.41 Hz, 2H), 3.08 (m, 5H), 2.54 (s, 3H), 0.88 (s, 9H), −0.08 (s, 6H).  
       (8-Methyl-5-methylcarbamoyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic Acid Ethyl Ester  
       [0319]    To a solution of 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methyl-1H-indole-4-carboxylic acid methylamide (100 mg, 0.289 mmol) and ethyl butyrylacetate (92 mL, 0.578 mmol) in CH 2 Cl 2  (2 mL) was added BF 3 .OEt2 (0.11 mL, 0.867 mmol) dropwise at room temperature. After stirring overnight, the solution was diluted with CH 2 Cl 2  (10 mL) and then washed with saturated aqueous NaHCO 3  (10 mL) and brine (10 mL). The organic phase was dried (Na 2 SO 4 ) and concentrated. The residue was purified by flash chromatography (silica, 50% EtOAc in hexanes) to give 88 mg (82%) of title compound as a yellow solid. 1H NMR (CDCl 3 ): 300 MHz δ 9.54 (bs, 1H), 7.12 (d, J=7.38 Hz, 1H), 6.89 (d, J=7.38 Hz, 1H), 6.05 (d, J=4.71 Hz, 1H), 4.15 (m, 2H), 3.96 (m, 1H), 3.86 (m, 1H), 3.03-2.83 (m, 7H), 2.48 (s, 3H), 2.00 (m, 2H), 1.37 (m, 1H), 1.25 (t, J=6.84 Hz, 3H), 1.22 (m, 1H), 0.87 (t, J=7.17 Hz, 3H).  
       (8-Methyl-5-methylcarbamoyl-1-propyl-1,3,4,9-tetrahydro-pyrano [3,4-b]indol-1-yl)-acetic Acid  
       [0320]    To a solution of (8-methyl-5-methylcarbamoyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (87 mg, 0.234 mmol) in THF/MeOH (1.5 mL/1.5 mL) was added 1 N NaOH (0.468 mL, 0.468 mmol). The reaction mixture was stirred at ambient temperature overnight. The most of THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na 2 SO 4  and concentrated. The residue was purified by preparative HPLC to give 67 mg (84%) of title compound as a white solid. Mp=89-91° C.; HRMS (ESI) [M+H] +  calculated for C 19 H 25 N 2 O 4  345.1809, found 345.1807; 1H NMR (DMSO-d 6 ): 300 MHz δ 10.63 (s, 1H), 8.00 (s, 1H), 6.97 (d, J=6.00 Hz, 1H), 6.84 (d, J=6.00 Hz, 1H), 3.89 (m, 1H), 3.81 (m, 1H), 2.93-2.46 (m, 10H), 2.01 (m, 2H), 1.29 (m, 1H), 0.82 (m, 1H), 0.78 (t, J=5.10 Hz, 3H). LCMS retention time: 1.936 minutes.  
       EXAMPLE 225  
     [8-Fluoro-5-(morpholine-4-carbonyl)-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-acetic Acid  
     5-Bromo-1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole  
       [0321]    To a solution of (5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acid ethyl ester (2.0 g, 5.02 mmol) in THF (10 mL) was added LAH (5.27 mL of 1.0 M in THF, 5.27 mmol) slowly at room temperature. The mixture was stirred for 30 minutes at room temperature. The reaction mixture was quenched by the addition of H 2 O (0.5 mL) and then 10% NaOH (0.5 mL) was added to the mixture. Na 2 SO 4  was added to the mixture and the resulting mixture was filtered. The filtrate was concentrated to give 1.79 g (100%) of 2-(5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol as yellow oil. A mixture of 2-(5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol (1.79 g, 5.02 mmol), imidazole (0.854 g, 12.55 mmol) and tert-butyldimethylsilyl chloride (0.909 g, 6.03 mmol) in DMF (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (100 mL). The organic solution was washed with H 2 O (5×100 mL) and brine (100 mL), dried (Na 2 SO 4 ), and concentrated. The residue was purified by flash chromatography (silica, 7% EtOAc in hexanes) to give 2.29 g (97%) of title compound as a white solid. 1H NMR (CDCl 3 ): 300 MHz δ 8.97 (bs, 1H), 6.95 (dd, J=8.37, 4.17 Hz, 1H), 6.57 (d, J=10.41, 8.37 Hz, 1H), 3.98-3.54 (m, 4H), 3.00 (m, 2H), 2.00-0.90 (m, 6H), 0.80 (s, 9H), 0.74 (d, J=7.32 Hz, 3H), 0.06 (s, 3H), 0.03 (s, 3H).  
       1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-5-carboxcylic acid  
       [0322]    To a suspension of KH (0.36 g of 30 wt % in oil, 2.70 mmol) in THF (20 mL) was added a solution of 5-bromo-1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole (0.845 g, 1.80 mmol) in THF (2 mL) at 0° C. After stirring for 30 minutes, the solution was cooled to −78° C. and tert-BuLi (2.18 mL of 1.7 M in pentane, 3.60 mmol), precooled to −78° C., was added. After stirring for 30 minutes at −78° C., the reaction mixture was transferred to the flask containing anhydrous CO 2  (dry ice, 8 g) via cannula under N 2  atmosphere at −78° C. The suspension was warmed to room temperature very slowly using cold bath. The mixture was diluted with EtOAc (100 mL) and the organic solution was washed with 1 N HCl (2×100 mL), H 2 O (100 mL) and brine (100 mL). The organic phase was dried (Na 2 SO 4 ) and concentrated. The residue was purified by flash chromatography (silica, 40% EtOAc in hexanes) to give 0.60 g (77%) of title compound as a white solid. 1H NMR (CDCl 3 ): 300 MHz δ 11.55 (bs, 1H), 9.37 (s, 1H), 7.75 (dd, J=8.50, 5.04 Hz, 1H), 6.74 (dd, J=10.05, 8.50 Hz, 1H), 3.89 (m, 1H), 3.80 (m, 2H), 3.61 (m, 1H), 3.03 (m, 1H), 2.05 (m, 2H), 1.74 (m, 1H), 1.31 (m, 1H), 1.14 (m, 1H), 1.01 (m, 1H), 0.80 (s, 9H), 0.75 (t, J=7.38 Hz, 3H), 0.06 (s, 3H), 0.03 (s, 3H).  
       {1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-5-yl}-morpholin-4-yl-methanone  
       [0323]    To a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-5-carboxylic acid (6) (400 mg, 0.918 mmol), EDCI (211 mg, 1.10 mmol) and HOBt (186 mg, 1.38 mmol) in DMF ( 5 mL) was added diisopropylethylamine (0.80 mL, 4.59 mmol) at room temperature. Morpholine (0.12 mL, 1.38 mmol) was added to the mixture and the mixture was stirred overnight at room temperature. The solution was diluted with H 2 O (10 mL) and extracted with EtOAc (3×15 mL). The organic solution was brine washed (30 mL), dried (Na 2 SO 4 ) and concentrated. The residue was purified by flash chromatography (silica, 50% EtOAc in hexanes) to give 415 mg (90%) of title compound as a colorless oil. 1H NMR (CDCl 3 ): 300 MHz δ 9.38 (s, 1H), 6.77 (m, 2H), 3.86-3.20 (m, 12 H), 2.67 (m, 2H), 1.97-b  1 . 15  (m, 6H), 0.81 (s, 9H), 0.76 (t, J=7.34 Hz, 3H), 0.06 (s, 3H), 0.03 (s, 3H). [8-Fluoro-5-(morpholine-4-carbonyl)-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-acetaldehyde  
         [0324]    To a solution of {1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-5-yl}-morpholin-4-yl-methanone (350 mg, 0.693 mmol) in THF (5 mL) was added TBAF (0.832 mL of 1.0 M in THF, 0.832 mmol) at room temperature. After stirring for 4 hours at room temperature, the reaction mixture was diluted with EtOAc (20 mL). The organic solution was washed with 0.5 N HCl (20 mL) and brine (20 mL), dried (Na 2 SO 4 ) and concentrated. The residue was purified by flash chromatography (silica, 50% EtOAc in hexanes) to give 254 mg (94%) of [8-fluoro-1-(2-hydroxy-ethyl)-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-5-yl]-morpholin-4-yl-methanone as white solid.  
         [0325]    The mixture of [8-fluoro-1-(2-hydroxy-ethyl)-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-5-yl]-morpholin-4-yl-methanone (100 mg, 0.256 mmol) and o-iodoxybenzoic acid (IBX, 430 mg, 1.54 mmol) in DMSO (3.5 mL) was stirred overnight at room temperature. The solution was diluted with H 2 O (7 mL) and the precipitates were filtered and the filter cake was rinsed with EtOAc. The filtrate was extracted with EtOAc (3×10 mL) and the combined organic solution was washed with brine (20 mL), dried (Na 2 SO 4 ) and concentrated. The residue was purified by flash chromatography (silica, 60% EtOAc in hexanes) to give 89 mg (90%) of the title compound as a pale yellow solid. 1H NMR (CDCl 3 ): 300 MHz δ 9.75 (bs, 1H), 9.05 (bs, 1H), 6.89 (m, 2H), 4.00-2.64 (m, 14H), 1.89 (m, 1H), 1.63 (s, 1H), 1.26 (m, 2H), 0.88 (t, J=5.49 Hz, 3H).  
       [8-Fluoro-5-(morpholine-4-carbonyl)-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-acetic Acid  
       [0326]    To a solution of [8-fluoro-5-(morpholine-4-carbonyl)-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-acetaldehyde (8) (99 mg, 0.255 mmol) in DMSO (3.5 mL) was added a solution of NaH 2 PO 4  in H 2 O (0.36 mL of 0.7 M in H 2 O, 0.255 mmol) at room temperature. To the mixture was added a solution of NaClO 2  in H 2 O (1.52 mL of 0.5 M in H 2 O, 0.765 mmol). After stirring for 20 hours at room temperature, the mixture was acidified with HCl. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na 2 SO 4  and concentrated. The residue was purified by preparative HPLC to give 77 mg (75%) of title compound as a white solid. Mp=98-100° C.; HRMS (ESI) [M+H] +  calculated for C 21 H 26 FN 2 O 5  405.1820, found 405.1821; 1H NMR (DMSO-d 6 ): 300 MHz δ 12.30 (bs, 1H), 11.45 (s, 1H), 6.95-6.85 (m, 2H), 3.92 (m, 2H), 3.66 (m, 2H), 3.45 (m, 1H), 3.15 (m, 1H), 2.94 (d, J=10.2 Hz, 2H), 2.70 (d, J=10.2 Hz, 2H), 2.59 (m, 1H), 2.57 (s, 1H), 2.51 (m, 2H), 1.99 (t, J=5.10 Hz, 2H), 1.31 (m, 1H), 0.86 (m, 1H), 0.08 (t, J=5.10 Hz, 3H). LCMS retention time: 2.073 minutes.  
       EXAMPLE 226  
     (5-Carbamoyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
       [0327]    The compound was synthesized by using the same procedures that were used for the synthesis of Example 224 except using ammonium chloride and PyBop instead of methylamine and EDCI. LCMS retention time: 1.756 minutes, [M+H] +  calculated for C 18 H 23 N 2 O 4  331.39, found 331.10; [M−1] +  calculated for C 18 H 21 N 2 O 4  329.39, found 329.10.  
       EXAMPLE 227  
     (5-Dimethylcarbamoyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic Acid  
       [0328]    The compound was synthesized by using the same procedures that were used for the synthesis of Example 224 except using dimethylamine instead of methylamine. LCMS retention time: 2.127 minutes, [M+H] +  calculated for C 20 H 27 N 2 O 4  359.44, found 359.10; [M−1] +  calculated for C 20 H 25 N 2 O 4  357.44, found 357.10.  
       EXAMPLE 228  
     (5-Cyano-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic Acid  
     (4-Bromo-7-fluoro-1H-indol-3-yl)-acetaldehyde  
       [0329]    The mixture of 2-(4-bromo-7-fluoro-1H-indol-3-yl)-ethanol (3.00 g, 11.6 mmol) and o-iodoxybenzoic acid (IBX, 9.76 g, 34.9 mmol) in DMSO (60 mL) was stirred overnight at room temperature. The solution was diluted with H 2 O (100 mL) and the precipitates were filtered and the filter cake was rinsed with EtOAc. The filtrate was extracted with EtOAc (3×150 mL) and the combined organic solution was washed with brine (300 mL), dried (Na 2 SO 4 ) and concentrated. The residue was purified by flash chromatography (silica, 25% EtOAc in hexanes) to give 2.48 g (83%) of the title compound as a pale yellow solid. 1H NMR (CDCl 3 ): 300 MHz δ 9.93 (s, 1H), 8.44 (bs, 1H), 7.20 (m, 1H), 7.17 (dd, J=8.40, 4.32 Hz, 1H), 6.80 (dd, J=10.2, 8.40 Hz, 1H), 4.12 (s, 2H).  
       1-(4-Bromo-7-fluoro-1H-indol-3-yl)-propan-2-ol  
       [0330]    To a solution of (4-bromo-7-fluoro-1H-indol-3-yl)-acetaldehyde (358 mg, 1.40 mmol) in THF (10 mL) was added a solution of MeMgBr (4.0 mL of 1.4 M in toluene-THF (75:25), 5.59 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with H 2 O and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (50 mL), dried over Na 2 SO 4  and concentrated. The residue was purified by flash chromatography (silica, 30% EtOAc in hexanes) to give 158 mg (42%) of the title compound as a white solid. 1H NMR (CDCl 3 ): 300 MHz δ 8.97 (bs, 1H), 7.11 (dd, J=8.10, 4.20 Hz, 1H), 6.70 (dd, J=10.2, 8.10 Hz, 1H), 4.18 (m, 1H), 3.29(dd, J=14.5, 3.93 Hz, 1H), 2.87 (dd, J=14.5, 8.43 Hz, 1H), 2.16 (bs, 1H), 1.29 (d, J=6.18 Hz, 3H).  
       (5-Cyano-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic Acid Ethyl Ester  
       [0331]    To a solution of 1-(4-bromo-7-fluoro-1H-indol-3-yl)-propan-2-ol (155 mg, 0.570 mmol) and ethyl butyrylacetate (0.137 mL, 0.854 mmol) in CH 2 Cl 2  (3 mL) was added BF 3 .OEt 2  (0.11 mL, 0.854 mmol) dropwise at room temperature. After stirring for 3 hours, the mixture was diluted with CH 2 Cl 2  (15 mL) and then washed with saturated aqueous NaHCO 3  (15 mL) and brine (15 mL). The organic phase was dried (Na 2 SO 4 ) and concentrated. The residue was purified by flash chromatography (silica, 10% EtOAc in hexanes) to give (5-bromo-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as a pale yellow solid (this sample contains ethyl butyrylacetate).  
         [0332]    (5-Bromo-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acid ethyl ester (235 mg, 0.570 mmol) and CuCN (77 mg, 0.854 mmol) was dissolved in N-methyl-2-pyrrolidinone (3 mL). The reaction vessels were heated in microwave at 220° C. for 15 minutes. The reaction mixtures was diluted with water (3 mL). The crude mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (30 mL), dried over Na 2 SO 4  and concentrated. The residue was purified by flash chromatography (silica, 10% EtOAc in hexanes) to give 156 mg (76% in two steps) oftitle compound as a yellow oil. 1H NMR (CDCl 3 ): 300 MHz δ 10.16 (bs, 1H), 7.37 (m, 1H), 6.88 (m, 1H), 4.27 (m, 2H), 4.04 (m, 1H), 3.14 (m, 2H), 2.73 (m, 2H), 2.00 (m, 2H), 1.57 (m, 1H), 1.40 (d, J=6.12 Hz, 3H), 1.29 (m, 4H), 0.95 (t, J=7.32 Hz, 3H).  
       (5-Cyano-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic Acid  
       [0333]    To a solution of (5-cyano-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic Acid Ethyl Ester (156 mg, 0.435 mmol) in THF/MeOH (1.5 mL/1.5 mL) was added 1 N NaOH (0.871 mL, 0.871 mmol). The reaction mixture was stirred at ambient temperature overnight. The most of THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na 2 SO 4  and concentrated. The residue was purified by preparative HPLC to give 125 mg (87%) of title compound as a white solid. LCMS retention time: 2.775 minutes, [M+H] +  calculated for C 18 H 20 FN 2 O 3  331.36, found 331.10, [M−1] +  calculated for C 18 H 18 FN 2 O 329.36, found 329.10.  
       EXAMPLE 229  
     (5,8-Dichloro-4-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
       [0334]    To a solution of [2-(4,7-dichloro1H-indol-3-yl)-propan-1-ol] (500 mg) (prepared following the procedure described in EP 0238226) in DCM (50 mL) was added ethyl butyrylacetate (488 mg, 3.08 mmol), BF 3 .Et 2 O (437 mg, 3.08 mmol) and stirred at room temperature overnight. The solution was then washed with saturated aqueous NaHCO 3  and brine. Dried over Na 2 SO 4  and flashed over silica gel (hexane: EtOAc 4:1) to yield white/blue crystals 700 mg (88%).  
         [0335]    To a solution of above ester (700 mg, 1.83 mmol) in EtOH was added 1 N NaOH and heated in oil bath at 60° C. for 4 hours. The resulting mixture was then concentrated down where 35 mg was purified on HPLC to yield white solid 25 mg. LCMS retention time: 3.308 minutes, 355 [M−H] + .  
         [0336]    Example 230-231 were prepared following the above mentioned procedure for example 229 starting from [2-(4,7-dichloro1H-indol3-yl)-2-methylpropan-1-ol] and [2-(4,7-dichloro-1-indol-3-yl)cyclobutylmethanol].  
       EXAMPLE 232  
     (5,8-Dichloro-9-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
       [0337]    To a solution of (5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (160 mg, 0.432 mmol) in N,N, dimethylformamide (4.5 mL) was added sodium hydride (20.7 mg, 0.866 mmol). The reaction was stirred for 30 minutes and then added iodomethane (184 mg, 1.30 mmol). The reaction mixture was microwaved at 170° C. for 12 minutes. The resulting mixture was concentrated down and purified by flash column. The ester was dissolved in EtOH (4 ml) and 1 N NaOH (1 mL) and stirred at 50° C. for 3 hours. The EtOH/NaOH was removed under reduced pressure and the resulting mixture was purified on HPLC to yield a white solid.  
         [0338]    Examples 233-234 were prepared following the above mentioned procedure for example 232 starting using allyl bromide and benzyl bromide in the place of methyl iodide.  
         [0339]    Examples 235-239 were synthesized following the above mentioned procedure for example 1 using the intermediate 4,5-dichlorotryptophol and reacting with β-ketoesters like ethyl 3-cyclobutyl-3-oxopropionate, ethyl 3-cyclopentyl-3-oxopropionate, methyl 4-methoxy-3-oxobutyrate, methyl 5-methoxy-3-oxopentanoate, or ethyl 6,6,6-trifluoro-3-oxohexanoate. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0340]    Examples 240 and 241 were synthesized following the above mentioned procedure for example 1 using the intermediate 5,6-dichlorotryptophol and reacting with β-ketoesters like ethyl butyrylacetate or ethyl 4-ethoxy-3-oxobutyrate. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0341]    Examples 242-258 were synthesized following the above mentioned procedure for example 1 using the intermediate 4,7-dichlorotryptophol and reacting with β-ketoesters like methyl acetoacetate, ethyl propionylacetate, ethyl 5-cyano-3-oxopentanoate, ethyl 3-oxo-6-butenoate, ethyl 3-cyclopropyl-3-oxopropionate, ethyl 3-cyclobutyl-3-oxopropionate, ethyl 3-cyclopentyl-3-oxopropionate, ethyl 3-cyclohexyl-3-oxopropionate, ethyl 4-cyclopropyl-3-oxobutyrate, ethyl 4-cyclopentyl-3-oxobutyrate, (±)-ethyl 4-methyl-3-oxopentanoate, methyl 4-methoxy-3-oxobutyrate, methyl 5-methoxy-3-oxopentanoate, ethyl 4-ethoxy-3-oxobutyrate, methyl 3-oxo-4-thiomethylbutyrate, methyl 3-oxo-4-thioethylbutyrate, or ethyl 6,6,6-trifluoro-3-oxohexanoate. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0342]    Examples 259 and 260 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-chloro-7-methyltryptophol and reacting with β-ketoesters like ethyl 3-cyclobutyl-3-oxopropionate, or ethyl butyrylacetate. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0343]    Example 262 was synthesized following the above mentioned procedure for example 1 using the intermediate 7-chloro-4-methyltryptophol and reacting with β-ketoesters like ethyl butyrylacetate. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0344]    Examples 263-267 were synthesized following the above mentioned procedure for example 1 using the intermediate 7-chloro-4-trifluoromethyltryptophol and reacting with β-ketoesters like ethyl 3-cyclobutyl-3-oxopropionate, methyl 4-methoxy-3-oxobutyrate, methyl 5-methoxy-3-oxopentanoate, ethyl 4-ethoxy-3-oxobutyrate, or ethyl 6,6,6-trifluoro-3-oxohexanoate. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0345]    Examples 268-270 were synthesized following the above mentioned procedure for example 1 using the intermediate 7-fluoro-4-trifluoromethyltryptophol and reacting with β-ketoesters like ethyl butyrylacetate, ethyl 3-cyclobutyl-3-oxopropionate, or ethyl 3-cyclopentyl-3-oxopropionate. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0346]    Example 271 was synthesized following the above mentioned procedure for example 1 using the intermediate 4,7-bis(trifluoromethyl)tryptophol and reacting with β-ketoesters like ethyl butyrylacetate. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0347]    Examples 272-275 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-trifluoromethyl-7-methyltryptophol and reacting with β-ketoesters like ethyl butyrylacetate, ethyl 3-oxoheptanoate, ethyl 3-cyclobutyl-3-oxopropionate, or ethyl 3-cyclopropyl-3-oxopropionate. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0348]    Examples 276 and 277 were synthesized following the above mentioned procedure for example 1 using the intermediate 7-bromo-4-trifluoromethyltryptophol and reacting with β-ketoesters like ethyl butyrylacetate, or ethyl 3-cyclobutyl-3-oxopropionate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 1. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0349]    Examples 280-284, 287, 288, and 294 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-7-methyltryptophol and reacting with β-ketoesters like ethyl 3-cyclobutyl-3-oxopropionate, ethyl 3-cyclopentyl-3-oxopropionate, ethyl 4-cyclopropyl-3-oxobutyrate, ethyl 4-cyclopentyl-3-oxobutyrate, ethyl 4-ethyl-3-oxohexanoate, methyl 4-methoxy-3-oxobutyrate, methyl 3-oxo-4-thiomethylbutyrate, or ethyl 6,6,6-trifluoro-3-oxohexanoate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 1. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
       EXAMPLE 285 AND EXAMPLE 286  
     (1R)-(5-Cyano-1-cyclobutyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     (1S)-(5-Cyano-1-cyclobutyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     Resolution of (±)-(5-Cyano-1-cyclobutyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
       [0350]    Preparative HPLC using a CHIRALPAK-AS (250×20 mm) and 10% ethyl alcohol in heptane (0.1% TFA) as eluant gave (R)- and (S)-enantiomers of 1-cyclobutyl-5-cyano-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid as white solids. MS (API-ES) [M−] calculated for C 19 H 20 N 2 O 3  324.3, found 323.1 (R-enantiomer) and 323.1 (S-enantiomer); Chiral HPLC HP 1100 with CHIRALPAK-AS, 250×4.6 mm, ethyl alcohol/heptane containing 0.1% TFA (10:90), 0.6 mL/minutes, DAD 215 nm; tR=12.97 minutes (R-enantiomer), 15.46 minutes (S-enantiomer).  
         [0351]    Examples 295 and 296 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-7-ethyltryptophol and reacting with β-ketoesters like ethyl butyrylacetate, or ethyl 3-oxoheptanoate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 1. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0352]    Example 297 was synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-7-isopropyltryptophol and reacting with β-ketoesters like ethyl butyrylacetate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 1. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0353]    Examples 298 and 299 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-nitro-7-methyltryptophol and reacting with β-ketoesters like ethyl butyrylacetate, or ethyl 3-cyclobutyl-3-oxopropionate. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0354]    Examples 301-311 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-7-fluorotryptophol and reacting with β-ketoesters like ethyl 3-cyclobutyl-3-oxopropionate, ethyl 3-cyclopentyl-3-oxopropionate, ethyl 4-cyclopropyl-3-oxobutyrate, ethyl 3-cyclohexyl-3-oxopropionate, ethyl 4-cyclopentyl-3-oxobutyrate, ethyl 4-ethyl-3-oxohexanoate, ethyl 3-oxo-6-butenoate, methyl 4-methoxy-3-oxobutyrate, 5-methoxy-3-oxopentanoate, methyl 3-oxo-4-thiomethylbutyrate, or ethyl 6,6,6-trifluoro-3-oxohexanoate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 1. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0355]    Example 317 was synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-5-fluoro-7-methyltryptophol and reacting with β-ketoesters like ethyl 3-cyclobutyl-3-oxopropionate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 1. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0356]    Examples 321 and 327 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-7-chlorotryptophol and reacting with β-ketoesters like ethyl butyrylacetate, or ethyl 3-cyclobutyl-3-oxopropionate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 1. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
       EXAMPLE 322 AND EXAMPLE 323  
     (1R)-(8-Chloro-5-cyano-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     (1S)-(8-Chloro-5-cyano-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     Resolution of (±)-(8-Chloro-5-cyano-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
       [0357]    Preparative HPLC using a CHIRALPAK-AS (250×20 mm) and 10% isopropyl alcohol in heptane as eluant gave (R)- and (S)-enantiomers of 8-chloro-5-cyano-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid as white solids. MS (API-ES) [M−H] −  calculated for C 17 H 17 ClN 2 O 3  332.7, found 330.9 (R-enantiomer) and 330.9 (S-enantiomer); Chiral HPLC HP 1100 with CHIRALPAK-AS, 250×4.6 mm, isopropyl alcohol/heptane (10:90) containing 0.1% TFA, 0.6 mL/minutes, DAD 215 nm; tR=10.9 minutes (R-enantiomer), 12.22 minutes (S-enantiomer).  
       EXAMPLES 289 AND 290  
     (±)-(1R*,10S*)-5-Bromo-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid Ethyl Ester and (±)-(1R*,10R*)-5-Bromo-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid Ethyl Ester  
       [0358]    To a solution of 4-bromo-7-methyl tryptophol (2.04 g, 8.03 mmol) and (±)-ethyl 4-methyl-3-oxohexanate (1.52 g, 8.83 mmol) in CH 2 Cl 2  (10 mL) was added BF 3 .OEt 2  (1.12 mL, 8.83 mmol) dropwise at room temperature. The solution was stirred for 16 h then quenched by the addition of saturated aqueous Na 2 CO 3  (2 mL). The reaction mixture was diluted with water and extracted three times with diethyl ether (150 mL). The combined organic layer was washed with brine then dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness. The crude product was purified by normal phase HPLC (isocratic, 5% EtOAc/hexane) to afford 1.4 g (43%) of esters as a mixture of 4 stereoisomers. Mass spectrum (APCI-): m/z 408 [M−].  
       (±)-(1R*,10S*)-5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester and (±)-(1R*,10R*)-5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester  
       [0359]    A mixture of (±)-(1R*,10S*)-5-bromo-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester and (±)-(1R*,10R*)-5-bromo-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (1.4 g, 3.43 mmol) and CuCN (1.54 g, 17.1 mmol) was dissolved in N-methyl-2-pyrrolidinone (20 mL) and the solution was warmed to 160° C. After 5.5 h, the reaction was complete by TLC analysis and cooled to ambient temperature. The reaction mixture was diluted with water (25 mL) and extracted three times with diethyl ether (150 mL). The combined organic layer was washed once with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude product was purified by normal phase HPLC (isocratic, 5% EtOAc/hexanes) to afford a mixture of diastereomers. The two racemic diastereomers were separated by repeated normal phase HPLC (isocratic, 5% EtOAc/hexanes) combining only those fractions which contained diastereomer in &gt;3:1 ratio. The enriched, separated diastereomers were resubjected to HPLC conditions (isocratic, 5% EtOAc/hexanes) until &gt;10:1 diastereomeric ratio ( 1 H NMR analysis) was obtained. This material was used directly in the next step.  
       (±)-(1R*,10S*)-5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid  
       [0360]    To a solution of (±)-(1R*,10S*)-5-cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (0.04 g, 0.12 mmol) in EtOH (1 mL) was added 1.0 M LiOH (2 mL). The reaction mixture was stirred 16 h at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and diethyl ether. The mixture was acidified with dilute aqueous HCl and the layers were separated. The aqueous phase was extracted once with ether and the combined ether extracts were washed once with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford 25 mg (68%) of (±)-(1R*,10S*)-5-cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid as a white solid.  1 H NMR (CDCl 3 , 300 MHz) δ 9.61 (br s, 1H), 7.34 (d, J=8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 4.28-4.09 (m, 2H), 3.82-3.73 (m, 1H), 3.17−2.98 (m, 3H), 2.55 (s, 3H), 2.23-2.15 (in, 1H), 1.29 (dt, J=7 Hz, J=2 Hz, 3H), 1.21-1.08 (m, 1H), 1.05 (d, J=7 Hz, 3 H), 0.75 (d, J=7 Hz, 3H) ppm. Mass spectrum (API-ES): m/z 325 [M−H] − .  
       (±)-(1R*,10R*)-5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid  
       [0361]    To a solution of (±)-(1R*,10R*)-5-cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (0.12 g, 0.36 mmol) in EtOH (1 mL) was added 1.0 M LiOH (2 mL). The reaction mixture was stirred 16 h at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and diethyl ether. The mixture was acidified with dilute aqueous HCl and the layers were separated. The aqueous phase was extracted once with ether and the combined ether extracts were washed once with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford 110 mg (99%) of (±)-(1R*,10R*)-5-cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid as a white solid.  1 H NMR (CDCl 3 , 300 MHz) δ 9.08 (br s, 1H), 7.34 (d, J=8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 4.19 (dt, J=5 Hz, 1H), 3.96-3.87 (m,  1 H), 3.17-3.10 (m, 4H), 2.41 (s, 3H), 2.27-2.17 (m, 1H), 1.74-1.64 (m, 1H), 1.39-1.26 (m, 1H), 0.95 (t, J=7 Hz, 3H), 0.78 (d, J=6 Hz, 3H) ppm. Mass spectrum (API-ES): m/z 325 [M−H] − .  
         [0362]    Examples 312 and 313 were synthesized following the above mentioned procedure for examples 289 and 290 using the intermediate 4-bromo-7-fluorotryptophol and reacting with (±)-ethyl 4-methyl-3-oxohexanate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in examples 289 and 290. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
       EXAMPLE 291  
     (1R*,10S)-[5-Bromo-8-methyl-1-(1-methylpropyl)-1,3,4,9 tetrahydropyrano[3,4-b]indol-1-yl]acetic acid ethyl ester  
       [0363]    To a solution of 4-bromo-7-methyl tryptophol (2.66 g, 10.4 mmol) and (S)-ethyl 4-methyl-3-oxohexanate (1.8 g, 10.4 mmol) in CH 2 Cl 2  (50 mL) was added BF 3 .OEt 2  (1.33 mL, 10.4 mmol) dropwise at room temperature. The solution was stirred for 48 h then quenched by the addition of saturated aqueous Na 2 CO 3  (10 mL). The reaction mixture was diluted with water and extracted three times with diethyl ether (250 mL). The combined organic layer was washed with brine then dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness. The crude product was purified by normal phase HPLC (3% to 7% EtOAc/hexane, 70 minutes, 40 mL/minutes) to afford 1.85 g (43%) of esters as a mixture of 2 diastereomers.  1 H NMR (CDCl 3 , 300 MHz): ˜1:1 mixture of 2 diastereomers, δ 9.32 (br s, 1H), 7.12 (d, J=7 Hz, 1H), 6.78 (d, J 7 Hz, 1H), 4.22-4.15 (m, 2H), 4.10-4.05 (m, 1H), 3.81-3.71 (m, 1H), 3.17-2.95 (m, 4H), 2.44 (s, 3H), 2.41-2.17 (m, 1H), 1.81-1.61 (m, 1H), 1.53-1.51 (m, 1H), 1.30-1.22 (m, 1H), 1.14-1.11 (m, 4H), 1.10-1.02 (m, 1H), 0.97-0.87 (m, 1H), 0.74 (t, J=7 Hz, 3H), 0.65 (d, j=7 Hz, 3H) ppm.  
       (1R*,10S)-[5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid Ethyl Ester  
       [0364]    A mixture of (1R,10S)-5-bromo-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester and (1S,10S)-5-bromo-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (1.8 g, 4.41 mmol) and CuCN (1.98 g, 22.06 mmol) was dissolved in N-methyl-2-pyrrolidinone (20 mL) and the solution was warmed to 175° C. After 4 h, the reaction was complete by TLC analysis and cooled to ambient temperature. The reaction mixture was diluted with water (30 mL) and diethyl ether (30 mL) and filtered through a pad of celite. The filtrate was extracted three times with diethyl ether (150 mL). The combined organic layer was washed five times with water, once with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude product was purified by normal phase HPLC (3% to 7% EtOAc/hexane, 70 minutes, 40 mL/minutes) to afford 1.0 g (64%) of esters as a mixture of 2 diastereomers.  1 H NMR (CDCl 3 , 300 MHz): ˜1:1 mixture of 2 diastereomers, δ 9.58 (br s, 1H), 7.34 (d, J=8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 4.27-4.09 (m, 3H), 3.82-3.73 (m, 1H), 3.17-2.84 (m, 4H), 2.55 (s, 3H), 2.51-2.14 (m, 1H), 1.72-1.64 (m, 1H), 1.40-1.23 (m, 1H), 1.28 (t, J=7 Hz, 3H), 1.21-1.10 (m, 1H), 1.05 (d, J=6 Hz, 1H), 0.94 (t, J=8 Hz, 3H), 0.75 (t, J=7 Hz, 3H), 0.65 (d, J=6 Hz, 1H) ppm.  
       (1R*,10S)-[5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
       [0365]    To a solution of (1R,10S)-5-cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester and (1S,10S)-5-cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (0.95 g, 2.68 mmol) in EtOH (10 mL) was added 2.0 M LiOH (5 mL). After 2 h, an additional portion of 2.0 M LiOH (2 mL) was added. The reaction mixture was stirred 16 h at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (25 mL) and diethyl ether (25 mL). The mixture was acidified with dilute aqueous HCl and the layers were separated. The aqueous phase was extracted once with ether (15 mL) and the combined ether extracts were washed once with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford 0.8 g (92%) of the mixture of 2 diastereomeric acids as a white solid.  1 H NMR (CDCl 3 , 300 MHz) δ 9.16-9.12 (m, 1H), 7.34 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 4.22-4.14 (m, 1H), 3.96-3.88 (m, 1H), 3.17-3.09 (m, 4H), 2.38 (s, 3H), 2.25-2.15 (m, 1H), 1.74-1.67 (m, 1H), 1.36-1.12 (m, 2H), 1.08 (d, J=7 Hz, 1H), 0.95 (t, J=8 Hz, 3H), 0.84-0.77 (m, 6H) ppm. Mass spectrum (API-ES + ): m/z 327 [M+H] + .  
         [0366]    Example 261 was synthesized following the above mentioned procedure for example 291 using the intermediate 4-chloro-7-methyltryptophol and reacting with (S)-ethyl 4-methyl-3-oxohexanate. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0367]    Example 279 was synthesized following the above mentioned procedure for example 291 using the intermediate 7-bromo-4-trifluoromethyltryptophol and reacting with (S)-ethyl 4-methyl-3-oxohexanate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 291. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0368]    Example 278 was formed as a by-product during the base-mediated saponification of the ester described in example 279.  
         [0369]    Example 300 was synthesized following the above mentioned procedure for example 291 using the intermediate 7-methyl-4-nitrotryptophol and reacting with (S)-ethyl 4-methyl-3-oxohexanate. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0370]    Example 314 was synthesized following the above mentioned procedure for example 291 using the intermediate 4-bromo-7-fluorotryptophol and reacting with (S)-ethyl 4-methyl-3-oxohexanate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 291. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0371]    Example 318 was synthesized following the above mentioned procedure for example 291 using the intermediate 4-bromo-5-fluoro-7-methyltryptophol and reacting with (S)-ethyl 4-methyl-3-oxohexanate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 291. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0372]    Example 324 was synthesized following the above mentioned procedure for example 291 using the intermediate 4-bromo7-chlorotryptophol and reacting with (S)-ethyl 4-methyl-3-oxohexanate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 291. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
       EXAMPLE 292 AND EXAMPLE 293  
     (1R,10S)-[5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano [3,4-b]indol-1-yl]acetic acid  
     (1S,10S)-[5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     Separation of (1R*,10S)-5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid  
       [0373]    Preparative HPLC using a CHIRALPAK-AS (250×20 mm) and 10% isopropyl alcohol in heptane (0.1% TFA) as eluant gave the (1R, 10S)- and (1S,10S)-diastereomers of 5-cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid as white solids. MS (API-ES) [M−] calculated for C 19 H 22 N 2 O 3  326.4, found 325.1 {(1R,10S)-diastereomer, [M−H] − } and 327.0 {(1S,10S)-diastereomer, [M+H] + }; Chiral HPLC HP 1100 with CHIRALPAK-AS, 250×4.6 mm, isopropyl alcohol/heptane (10:90), 0.6 mL/minutes, DAD 215 nm; tR=8.12 minutes [(1R,10S)-diastereomer], 16.41 minutes [(1S,10S)-diastereomer].  
       EXAMPLE 315 AND 316  
     (1R,10S)-[5-Cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     (1S,10S)-[5-Cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     Separation of (1R*,10S)-5-Cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid  
       [0374]    Preparative HPLC using a CHIRALPAK-AS (250×20 mm) and 10% isopropyl alcohol in heptane (0.1% TFA) as eluant gave the (1R,10S)- and (1S,10S)-diastereomers of 5-cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid as white solids. MS (API-ES) [M−] calculated for C 18 H 19 N 2 O 3  330.3, found 329.2 {(1R,10S)-diastereomer, [M−H] −} and  329.2 {(1S,10S)-diastereomer, [M−H] − }; Chiral HPLC HP 1100 with CHIRALCEL OD, 250×4.6 mm, isopropyl alcohol/heptane (10:90) containing 0.1% TFA, 0.6 mL/minute, DAD 215 nm; tR=6.10 minutes [(1R,10S)-diastereomer], 7.20 minutes [(1S,10S)-diastereomer].  
       EXAMPLE 319 AND 320  
     (1R,10S)-[5-Cyano-6-fluoro-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     (1S,10S)-[5-Cyano-6-fluoro-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     Separation of (1R*,10S)-5-Cyano-6-fluoro-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid  
       [0375]    Preparative HPLC using a CHIRALPAK-AS (250×20 mm) and 10% isopropyl alcohol in heptane as eluant gave the (1R,10S)- and (1S,10S)-diastereomers of 5-cyano-6-fluoro-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid as white solids. MS (API-ES) [M−] calculated for C 19 H 21 FN 2 O 3  344.3, found 345.1 {(1R,10S)-diastereomer, [M+H] + } and 342.9 {(1S,10S)-diastereomer, [M−H] − }; Chiral HPLC HP 1100 with CHIRALPAK-AS, 250×4.6 mm, isopropyl alcohol/heptane (10:90), 0.6 mL/minute, DAD 215 nm; tR=20.21 minutes [(1R,10S)-diastereomer], 9.28 minutes [(1S,10S)-diastereomer].  
       EXAMPLE 325 AND 326  
     (1R,10S)-[8-Chloro-5-cyano-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1yl]acetic acid  
     (1S,10S)-[8-Chloro-5-cyano-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     Separation of (1R*,10S)-8-Chloro-5-cyano-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid  
       [0376]    Preparative HPLC using a CHIRALPAK-AS (250×20 mm) and 10% isopropyl alcohol in heptane containing 0.1% TFA as eluant gave the (1R,10S)- and (1S,10S)-diastereomers of 8-chloro-5-cyano-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid as white solids. MS (API-ES) [M−] calculated for C 18 H 19 ClN 2 O 3  346.8, found 345.0 {(1R,10S)-diastereomer, [M−H−]} and 345.0 {(1S,10S)-diastereomer, [M−H] − }; Chiral HPLC HP 1100 with CHIRALPAK-AS, 250×4.6 mm, isopropyl alcohol/heptane (10:90) containing 0.1% TFA, 0.6 mL/minutes, DAD 215 nm; tR=7.24 minutes [(1R,10S)-diastereomer], 9.89 minutes [(1S,10S)-diastereomer].  
         [0377]    Example 328 was synthesized following the above mentioned procedure for example 1 using the intermediate 4,5-dichlorotryptophol and reacting with α-ketoesters like ethyl-2-oxopentanoate. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0378]    Example 329 was synthesized following the above mentioned procedure for example 1 using the intermediate 4,7-dichlorotryptophol and reacting with α-ketoesters like ethyl-2-oxopentanoate. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0379]    Example 330 was synthesized following the above mentioned procedure for example 1 using the intermediate 4-chloro-7-methyltryptophol and reacting with a-ketoesters like ethyl-2oxopentanoate. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0380]    Example 331 was synthesized following the above mentioned procedure for example 1 using the intermediate 7-chloro-4-trifluoromethyltryptophol and reacting with a-ketoesters like ethyl-2-oxopentanoate. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0381]    Example 332 was synthesized following the above mentioned procedure for example 1 using the intermediate 7-fluoro-4-trifluoromethyltryptophol and reacting with α-ketoesters like ethyl-2-oxopentanoate. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0382]    Example 333 was synthesized following the above mentioned procedure for example 1 using the intermediate 7-methyl-4-trifluoromcthyltryptophol and reacting with α-ketoesters like ethyl-2-oxopentanoate. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0383]    Examples 334, 337, and 338 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-7-methyltryptophol and reacting with α-ketoesters like ethyl-2-oxopentanoate, methyl 4-methyl-2-oxopentanoate, methyl 2-cyclobutyl-2-oxoacetate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 1. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0384]    Examples 335 and 336 were synthesized following the above mentioned procedure for example 291 using the intermediate 4-bromo-7-methyltryptophol and reacting with (S)-methyl 3-methyl-2-oxopentanoate. The resulting esters were separated by normal phase HPLC and the hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0385]    Example 339 was synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-5-fluoro-7-methyltryptophol and reacting with α-ketoesters like ethyl-2-oxopentanoate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 1. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0386]    Example 340 was synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-7-ethyltryptophol and reacting with α-ketoesters like ethyl-2-oxopentanoate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 1. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0387]    Example 341 was synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-7-chlorotryptophol and reacting with α-ketoesters like ethyl-2-oxopentanoate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 1. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0388]    Example 342 was synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-7-fluorotryptophol and reacting with a-ketoesters like ethyl-2-oxopentanoate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 1. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.  
       EXAMPLE 343 AND EXAMPLE 344  
     Resolution of (±)-(5-Cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
       [0389]    Preparative HPLC using a CHIRALPAK-AS (250×20 mm) and 10% ethyl alcohol in heptane (0.1% TFA) as eluant gave (R)- and (S)-enantiomers of 5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxylic acid as white solids. MS (API-ES) [M−] calculated for C16H15FN2O3 302.3, found 301.1 (R-enantiomer) and 301.0 (S-enantiomer); Chiral HPLC HP 1100 with CHIRALPAK-AS, 250×4.6 mm, ethyl alcohol/heptane containing 0.1% TFA (10:90), 0.6 mL/minute, DAD 215 nm; tR=7.07 minutes (R-enantiomer), 10.5 minutes (S-enantiomer).  
         [0390]    Examples 345-347, 350, and 351 were synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-7-fluorotryotophol and reacting with c-ketoesters like methyl 2-oxohexanoate, methyl 2-oxohex-5-enoate, methyl 4-methyl-2-oxopentanoate, methyl 2-cyclopentyl-2-oxoacetate, and methyl 2-cyclohexyl-2-oxoacetate. The bromo substituent was converted to a cyano group using CuCN in N-methyl-2-pyrrolidinone as described in example 1. The resulting esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0391]    Examples 348 and 349 were synthesized following the above mentioned procedure for example 291 using the intermediate 4-bromo-7-methyltryptophol and reacting with (S)-methyl 3-methyl-2-oxopentanoate. The resulting esters were separated by normal phase HPLC and the esters were hydrolyzed using aqueous NaOH in THF/EtOH.  
         [0392]    Example 352 was synthesized following the above mentioned procedure for example 291 using the intermediate 7-methyl-4-nitrotryptophol and reacting with ethyl-2-oxopentanoate. The resulting ester was separated by normal phase HPLC and the hydrolyzed using aqueous NaOH in THF/EtOH.  
       EXAMPLE 353  
     1-Carboxymethyl-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid  
     5-Bromo-2-methyl-3-nitrobenzoic acid  
       [0393]    A 5000 mL, three neck round bottom flask (RBF) equipped with an overhead stirrer was charged with 2-methyl-3-nitro benzoic acid (150.0 g, 0.82 mol) and concentrated H 2 SO 4  (600 mL). To this solution was added 1,3-dibromo-5,5 dimethylhydantoin (130.7 g, 0.455 mol) over ten minutes with vigorous stirring. The reaction was vigorously stirred at ambient temperature for 5 hours. The reaction mixture was then added to water (4000 mL), and the mixture was cooled in an ice bath over 30 minutes. This mixture was then filtered, and the solids were washed twice with water and further dried under vacuum to yield 217.7 g (99.8%) of an off-white solid.  1 H NMR (CDCl 3 ) δ 8.18 (s, 1H), 7.95 (s, 1H), 2.59 (s, 3H).  
       5-bromo-2-methyl-3-nitrobenzole acid benzyl ester  
       [0394]    A 5000 mL three neck RBF equipped with an overhead stirrer and thermometer was charged with 5-bromo-2-methyl-3-nitro benzoic acid (116.2 g, 0.45 mol), THF (1L), and benzyl bromide (BnBr) (84.90 mL, 0.715 mol). To the stirring solution was added diisopropyl ethylamine (DIEA) (78 mL, 0.450 mol). The reaction was then brought to reflux. After 5.5 hours at reflux, the reaction was cooled to 40° C., and pyrrolidine (83 mL, 1.00 mol) was added. The reaction was stirred for 10 minutes at 40° C., then allowed to cool to ambient temperature over approximately 20 minutes. The reaction mixture was diluted with EtOAc and washed with 3% HCl (2×), water (1×), and saturated NaCl (1×), dried (MgSO4), and concentrated. The brown oil was taken up in DCM and slurried with approximately 300 g of silica gel. The slurry was filtered, solids were washed with EtOAc, and the filtrate was concentrated to afford a yellow oil. Upon trituration with hexanes, 244.9 g (83.8%) of an off white powder was obtained. 1H NMR (CDCl3) δ 8.10 (s, 1H), 7.96 (s, 1H), 7.41 (m, 5H), 5.37 (s, 2H), 2.55 (s, 3H).  
       3-Amino-5-bromo-2-methylbenzoic acid benzyl ester  
       [0395]    A 1000 mL RBF equipped with an overhead stirrer was charged with 5-bromo-2-methyl-3-nitro benzoic acid benzyl ester (75.0 g, 0.214 mol) and water (200 mL). While stirring vigorously, Fe powder (−325 mesh, 47.81g, 0.857 mol) and NH 4 Cl (13.88g, 0.257 mol) were added. The mixture was heated to reflux for 4.5 hours. The reaction mixture was then allowed to cool to room temperature, diluted with EtOAc and filtered through a pad of Celite. The filtrate was washed with water (2×), saturated NaCl (1×), dried (MgSO 4 ), and concentrated. Upon trituration with hexanes, 63.2 g (92.1%) of an off-white powder was obtained.  1 H NMR (CDCl 3 ) δ 7.38 (m, 6H), 6.90 (s, 1H), 5.31 (s, 2H), 3.76 (br s, 2H), 2.25 (s, 3H).  
       5-Bromo-3-hydrazino-2-methyl benzoic acid benzyl ester hydrochloride  
       [0396]    A 1000 mL three neck RBF equipped with an overhead stirrer was charged with 3-amino-5-bromo-2-methyl benzoic acid benzyl ester (25.0 g, 0.078 mol), water (150 mL), and concentrated HCl (150 mL). This mixture was stirred vigorously while cooling to −10° C. in a MeOH/ice bath. A solution of NaNO 2  (8.08g, 0.120 mol) in water (150 mL) was cooled to −10° C. and then added to the reaction mixture dropwise over 15 minutes. The reaction was vigorously stirred at &lt;10° C. for 1.5 hours, then a solution of SnCl 2 .2H 2 O (73.99 g, 0.330 mol) at −10° C. in concentrated HCl (150 mL) was added to the reaction mixture dropwise over 20 minutes. The resulting mixture was allowed to react for 1.5 hours at −with very vigorous stirring. The reaction mixture was then added to 6N NaOH (600 mL) and extracted with EtOAc. The organic layer was separated and washed with saturated NaCl (1×), dried over MgSO 4 , and concentrated. The yellow solid was taken up in THF (100 mL), and 4N HCl (30 mL) in dioxane was added. The solvents were removed under vacuum. Trituration with DCM/hexanes yielded 27.1 g (93.5%) of a white powder.  1 H NMR (d 6 -DMSO) δ 10.47(br s, 2H), 8.39 (br s, 1H), 7.40 (m, 7H), 5.33 (s, 2H), 2.26 (s, 3H).  
       4-Bromo-3-(2-hydroxy-ethyl)-7-methyl-1H-indole-6-carboxylic acid benzyl ester  
       [0397]    A 1000 mL RBF was charged with 5-bromo-3-hydrazino-2-methyl benzoic acid benzyl ester hydrochloride (30.0 g, 0.081 mol), ethylene glycol (350 mL), and water (60 mL). This mixture was heated to 40° C., and dihydrofuran (7.63 mL, 0.101 mol) was added. The reaction mixture was next heated to 100-105° C. with stirring for 2.25 hours. The reaction was then cooled to ambient temperature, diluted with EtOAc, washed with saturated NaCl (2×), dried (MgSO 4 ), and concentrated. The resulting oil was chromatographed on SiO 2 , eluting with a 10% EtOAc/DCM to 50% EtOAc/DCM gradient. Isolation of the product as an impure solid, followed by trituration with DCM and hexanes, afforded 8.45 g (27.0%) of a pale yellow solid.  1 H NMR (CDCl 3 ) δ 8.28 (br s, 1 H), 7.94 (s, 1H), 7.40 (m, 6H), 5.36 (s, 2H), 3.96 (q, J=6.4 Hz, 2H), 3.28 (t, J=6.4 Hz, 2H), 2.72 (s, 3H).  
       5-Bromo-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxy acid benzyl ester  
       [0398]    A 1000 mL RBF was charged with of 4-bromo-3-(2-hydroxy-ethyl)-7-methyl-1H-indole-6-carboxylic acid benzyl ester (12,03 g, 0.031 mol), ethyl butyrylacetate (5.45 mL, 0.034 mol), and DCM (500 mL). This mixture was cooled to 0° C. with stirring. Over approximately 5 minutes, BF 3 .Et 2 O (9.82 mL, 0.078 mol) was added to the stirring mixture. The reaction was allowed to warm to ambient temperature and was stirred for 1 hour. The mixture was then diluted with EtOAc, washed with saturated NaHCQ 3  (2×) and saturated NaCl (1×), dried (MgSO 4 ), and concentrated. The resulting oil was purified by flash chromatography on SiO 2  eluting with a 10% EtOAc/hexanes to 20% EtOAc/hexanes gradient. Trituration with hexanes yielded 13.71 g (84.0%) of a white powder.  1 H NMR (CDCl 3 ) δ 9.81 (br s, 1H), 7.89 (s, 1H), 7.40 (m, 5H), 5.35 (s, 2H), 4.21 (m, 2H), 3.95 (m, 2H), 3.15 (t, J=4.7 Hz, 2H), 3.03 (d, J=16.7 Hz, 1H), 2.91 (d, J=16.7 Hz, 1H), 2.73 (s, 3H), 2.00 (m, 2H), 1.29 (m, 5H), 0.88 (t, J=7.6 Hz, 3H).  
       5-Cyano-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid benzyl ester  
       [0399]    A 500 mL RBF was charged with 5-bromo-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid benzyl ester (12.00 g, 23 mmol), NMP (100 mL), and CuCN (20.34 g, 0.227 mol). The reaction was heated to 190° C. with vigorous stirring for 45 minutes. The reaction was then cooled to ambient temperature, diluted with EtOAc followed by water (300 mL). A 1:1 mixture of Celite/silica gel were added to the mixture. This suspension was stirred for several minutes and filtered through a pad of Celite. The Celite pad was washed with EtOAc, and the filtrate was washed with water (5×) and saturated NaCl (1×), dried over MgSO 4 , and concentrated. Upon trituration with hexanes, 8.82 g (81.8%) of a light tan solid was obtained.  1 H NMR (CDCl 3 ) δ 10.11 (br s, 1H), 8.12 (s, 1H), 7.40 (m, 5H), 5.37 (s, 2H), 4.22 (m, 2H), 3.95 (m, 2H), 3.00 (m, 4H), 2.83 (s, 3H), 2.00 (m, 2H), 1.30 (m, 5H), 0.89 (t, J=7.6 Hz, 3H).  
       5-Cyano-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid  
       [0400]    A 500 mL Parr flask was charged with 5-cyano-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid benzyl ester (14.24 g, 0.030 mol), 1:1 MeOH/EtOAc (180 mL), and Pd(OH) 2  (20% on C, 3.02 g). The flask was shaken on a Parr shaker at 5 psi above ambient pressure for 30 minutes. The reaction mixture was filtered through a pad of Celite, washed with methanol and concentrated. Trituration with hexanes yielded 1.11 g (96.4%) of an off-white powder.  1 H NMR (CDCl 3 ) δ 10.21 (br s, 1H), 8.22 (s, 1H), 4.22 (m, 2H), 4.00 (m, 2H), 3.09 (m, 4H), 2.89 (s, 3H), 2,00 (m, 2H), 1.30 (m, 5H), 0.90 (t, J=7.6 Hz, 3H).  
       1-Carboxymethyl-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid  
       [0401]    To a solution of 5-Cyano-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid (27.9 mg, 0.073 mmol) in EtOH (2 mL) was added 10% NaOH (200 μL). The solution was stirred for 18 hours, acidified with 3% HCl, and extracted with EtOAc (2×). The organic layers were combined, washed with brine, dried (Na 2 SO 4 ) and concentrated in vacuo to afford 25.6 mg (99%) of the title compound as an off-white solid.  1 H NMR (d 6 -DMSO) δ 11.42 (br s,1H), 7.93 (s, 1H), 3.97 (m, 2H), 3.00 (d, J=13.8 Hz, 1H), 2.88 (m, 2H), 2.81 (s, 3H), 2.76 (d, J=13.8 Hz, 1H), 2.04 (m, 2H), 1.30 (m,1H), 0.80 (m, 4H). ESI MS m/z 355 (M−H).  
       EXAMPLE 354  
     (5-Cyano-8-methyl-1-propyl-7-propylcarbamoyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
       [0402]    To a solution of 5-cyano-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b ]indole-7-carboxylic acid (36.3 mg, 0.09 mmol) in methylene chloride (2 mL) was added N-methylmorpholine (NMM) (31 μL, 0.2 mmol), propylamine (15 μL, 0.19 mmol), and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (54 mg, 0.14 mmol). After 21 hours, the solution was diluted with EtOAc, and then water was added. The layers were separated, and the organic layer was washed with 3% HCL (2×), 5% NaHCO 3  (2×), water (1×), and brine (1×), dried (Na 2 SO 4 ), and concentrated in vacuo to afford 37.1 mg (92%) of crude product which was carried on to the next step.  
         [0403]    EtOH (2 mL) and 10% NaOH (aq, 125 μL) were added to the crude propylamide. The solution was stirred for 16 hours, acidified with 3% HCl, and extracted with DCM. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated in vacuo to afford 30.3 mg (88%) of the title compound as a pale yellow solid. 1H NMR (CDCl3) δ 10.10 (br s, 1H), 7.40 (s, 1H), 6.11 (t, J=5.9 Hz, 1H), 4.04 (m, 1H), 3.92 (m, 1H), 3.44 (m, 2H), 3.05 (t, J=5.6 Hz, 2H), 2.97 (br s, 2H), 2.53 (s, 3H), 2.0 (m, 2H), 1.68 (m, 2H), 1.43 (m, 1H), 1.20 (m,1H), 1.03 (m, 3H), 0.87 (t, J=7.3 Hz, 3H). ESI MS m/z 398 (MH)+.  
         [0404]    Examples 355-358 were synthesized following the above mentioned procedure for example 354 using the intermediate 5-cyano-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid and coupling it with the following amines: isopropylamine, 3,3-dimethylbutylamine, methylamine, and dimethylamine. The resulting esters were hydrolyzed using 10% NaOH (aq) in EtOH. In most instances the final products required no chromatographic purification.  
       EXAMPLE 359  
     (5-Cyano-8-methyl-7-propoxy-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)acetic acid  
     (5-Cyano-7-hydroxymethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyranol3,4-b]indol-1-yl)-acetic acid ethyl ester  
       [0405]    To a solution of 5-cyano-l-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7carboxylic acid (11.1 g, 29.0 mmol) in THF (150 mL) at 0° C. was added BH 3 .THF (1.0M in THF, 72.2 mL, 72.2 mmol). The cooling bath was removed, and the solution was stirred for 1.5 hours. The reaction was quenched with 3% HCl, diluted with EtOAc, and the layers separated. The organic layer was washed with saturated NaHCO 3 , water and brine, dried (MgSO 4 ), and concentrated in vacuo. Purification via flash chromatography on SiO 2  using 20% EtOAc/DCM as eluent afforded 8.28 g (77%) of a pale green foam. ESI-MS m/z 369 (M−H) − .  1 HNMR (CDCl 3 ) δ 9.72 (bs, 1H), 7.43 (s, 1H), 4.80 (d, J=5.5, 2H), 4.25 (m, 2H), 4.15 (m, 1H), 3.93 (m, 1H), 3.02 (m, 3H), 2.92 (d, J=17.0 Hz, 1H), 2.57 (s, 3H), 2.00 (m, 2H), 1.30 (m, 5H), 0.88 (t, J=7.6 Hz, 3H).  
       (5-Cyano-7-formyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester  
       [0406]    To a solution of (5-cyano-7-hydroxymethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (8.28 g, 22 mmol) in dichloroethane/benzene (85 mL/85 mL) was added a homogeneous mixture of activated MnO 2  (19.4 g, 223 mmol) and Celite (19.4 g). The solution was heated to 40° C. and agitated vigorously for 1.3 hours. The reaction was cooled, diluted with EtOAc and filtered through Celite. Concentration of the filtrate in vacuo afforded 7.88 g (96%) of a pale yellow foam.  1 H NMR (CDCl 3 ) δ 10.31 (bs, 1 H), 10.27 (s, 1H), 7.90 (s, 1H), 4.27 (m, 2H), 4.11 (m, 1H),, 3.95 (m, 1H), 3.09 (m, 2H), 3.04 (d, J=17.0 Hz, 1H), 2.95 (d, J=7.6 Hz, 1H), 2.57 (s, 3H), 2.00 (m, 2H), 1.30 (m, 4H), 0.90 (t, J=7.62 Hz, 2H).  
       (5-Cyano-7-hydroxy-8-methyl-7-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester  
       [0407]    To a solution of (5-cyano-7-formyl-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]-acetic acid (7.88 g, 21 mmol) in tert-butanol (150 mL) was added SeO 2  (0.90 g, 6.4 mmol) followed by 30% H 2 O 2  (75 mL) and trifluoroacetic acid (0.23 mL). The solution was stirred at ambient temperature for 1 hour. The reaction was diluted with EtOAc, washed with saturated NaHCO 3  (2×), water and brine, dried (MgSO 4 ), and concentrated in vacuo to afford a brown foam. ESI-MS m/z 383 (M−H)−,  1 H NMR CDCl 3  (300 MHz) δ 9.86 (bs, 1H), 8.35 (s, 1H), 7.16 (s, 1H), 4.20 (m, 2H), 4.00 (m, 2H), 3.01 (m, 4H), 2.57 (s, 3H), 2.00 (m, 2H), 1.30 (m, 5H), 0.89 (t, J=7.6 Hz, 3H).  
         [0408]    The residue was dissolved in MeOH (145 mL), and to this was added 10% K 2 CO 3  (aq., 14.5 mL). After stirring for 30 minutes, the reaction was diluted with EtOAc, washed with water (2×) and brine, dried (MgSO 4 ) and concentrated in vacuo. Trituration with DCM/hexane afforded 5.59 g (73%) of the title compound as an off-white solid. ESI-MS m/z 355 (M−H).  1 HNMR (CD 3 OD) δ 6.90 (s,1H), 4.01 (m, 4H), 3.03 (d, J=13.5 Hz, 1H), 2.91 (m, 2H), 2.82 (d, J=13.5 Hz, 1H), 2.39 (s, 3H), 2.00 (m, 2H), 1.42 (m, 1H), 1.06 (m, 4H), 0.87 (t, J=7.0 Hz, 3H).  
       (5-Cyano-8-methyl-7-propoxy-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
       [0409]    To a solution of (5-cyano-7-hydroxy-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (41.5 mg, 0.12 mmol) in dry THF (2 mL) was added triphenyl phosphine (52.2 mg, 0.20 mmol) and n-propanol (14.7 μL, 0.20 mmol). To this solution was added diisopropylazodicarboxylate (DIAD, 39 μL, 0.20 mmol). After 20 minutes, additional portions of triphenyl phosphine (5 mg) and DIAD (5 μL) were added. The reaction mixture was stirred for 10 minutes and quenched with water. The mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed with water and brine, dried (Na 2 SO 4 ), and concentrated in vacuo. Flash chromatography on SiO 2  using 5% EtOAc/hexanes as eluent afforded 30.9 mg (67%) of the ester intermediate as a white solid.  
         [0410]    To the ester intermediate was added EtOH (2 mL) and 10% NaOH (aq., 150 μL). The solution was stirred for 20 hours, acidified with 3% HCl, and extracted with EtOAc. The organic layer was washed with water and brine, dried (Na 2 SO 4 ), and concentrated in vacuo to afford 28.9 mg (quant.) of the title compound as a white solid. ESI-MS m/z 371 (MH) + .  1 H NMR (d 6 -DMSO) δ 11.95 (br s, 1H), 10.85 (s, 1H), 7.18 (s, 1H), 3.96 (m, 4H), 2.93 (d, J=13.9 Hz, 1H), 2.82 (m, 2H), 2.71 (d, J=13.9 Hz, 1H), 2.38 (s, 3H), 1.98 (m, 2H),1.74 (m, 2H), 1.25 (m, 1H), 1.01 (t, J=7.3 Hz, 3H), 0.85 (m, 4H).  
       EXAMPLE 360 AND 361  
     (1R)-(5-cyano-8-methyl-7-propoxy-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
     (1S)-(5-Cyano-8-methyl-7-propoxy-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
       [0411]    Preparative HPLC using CHIRALPAK AS (250×20mm) and 5% ethanol in hexane as eluant gave the (R) and (S) enantiomers of (5-cyano-8-methyl-7-propoxy-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as white solids. ESI-MS m/z 371 (MH + , R isomer) and m/z 371 (MH + , S isomer). Chiral HPLC HP 100 with CHIRALPAK AS, 250×4.6 mm, ethanol/hexane (7/93), 1.0 mL/min, 235 nm UV detection; tR=8.46 min (R enantiomer), 13.42 min (broad peak, S enantiomer).  
         [0412]    Examples 362-368 were synthesized following the above mentioned procedure for example 359 using the intermediate (5-cyano-7-hydroxy-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester and coupling it with the following alcohols: ethanol, methanol, isopropanol, n-butyl alcohol, 3,3-dimethyl-1-butanol, 3-fluorobenzyl alcohol, and benzyl alcohol. The resulting esters were hydrolyzed using 10% NaOH (aq) in EtOH.  
       EXAMPLE 369  
     [5-Cyano-7-(2-fluoro-ethoxy)-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-acetic acid  
       [0413]    To a solution of (R)-[5-cyano-7-hydroxy-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4]indol-1-yl-]-acetic acid methyl ester (35 mg, 0.10 mmol) in anhydrous dichloromethane (1 mL) was added 2-fluoroethanol (40 mg, 0.62 mmol), 1,1′-(azodicarbonyl)dipiperidine (39 mg, 0.15 mmol), and triphenylphosphine (40 mg, 0.15 mmol) at ambient temperature. After 48 h, the reaction mixture was absorbed onto silica gel and the product was eluted with hexane/EtOAc (4:1). The ester was used directly in the next reaction.  
         [0414]    The crude ester was dissolved in EtOH (2 mL) and THF (1 mL). At ambient temperature, 3 N NaOH (2 mL) was added and the reaction mixture was stirred for 3 h. The reaction mixture was then acidified with 1 M HCl and the aqueous solution was extracted with ethyl ether. The organic phase was washed once with 1 M HCl, once with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude acid was triturated with ethyl ether/hexanes and the solid was collected on a Hirsch funnel and washed several times with hexane to afford 21 mg of the title compound as an off-white solid. ESI-MS m/z 373 (M−H) − .  1 H NMR (CDCl 3 ) δ 8.99 (br s, 1H), 6.99 (s, 1H), 4.77 (dt, J=47.4, 3.5 Hz, 2 H), 4.03-4.27 (m, 4H), 3.12 (m, 4H), 2.15 (s, 3H), 1.89-2.11 (m, 4H),1.19-1.61 (m, 2H), 0.91 (t, J=7.0 Hz, 3H) ppm.  
       EXAMPLE 370  
     [5-Cyano-7-(3-fluoro-propoxy)-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-acetic acid  
       [0415]    To a solution of (R)-[5-cyano-7-hydroxy-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[[3,4-b]indol-1 0 yl]-acetic acid methyl ester (32 mg, 0.09 mmol) in anhydrous N-methyl-2-pyrrolidinone (2 mL) was added Cs 2 CO 3  (76 mg, 0.23 mmol), KI (2 mg, 10 mol %), and 1-bromo-3-fluoropropane (26 mg, 0.18 mmol) at ambient temperature. After 6 h, the reaction mixture was diluted with water (50 mL) and ethyl ether (50 mL). Aquesous HCl (1 M) was added and the layers were separated. The organic phase was washed 5 times with water, once with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to provide the crude ester which was used directly in the next reaction.  
         [0416]    The crude ester was dissolved in EtOH (2 mL) and THF (1 mL). At ambient temperature, 3 N NaOH (2 mL) was added and the reaction mixutre was stirred for 3 h. The reaction mixture was then acidified with 1 M HCl and the aqueous solution was extracted with ethyl ether. The organic phase was washed once with 1 M HCl, once with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude acid was triturated with ethyl ether/hexanes and the solid was collected on a Hirsch funnel and washed several times with hexane to afford 25 mg of the title compound as a yellow solid. ESI-MS m/z 387 (M−H) − . 1H NMR (CDCl 3 ) δ 8.91 (br s, 1H), 6.99 (s, 1H), 4.69 (dt, J=46.8, 5.8 Hz, 2 H), 4.09 (m, 4H), 3.11 (m, 4H), 1.89-2.35 (m, 4H), 2.09 (s, 3H), 1.23-1.59 (m, 2H), 0.91. (t, J=7.0 Hz, 3H) ppm.  
                                                   TABLE 2                           Pyranoindole derivatives                    LC@254               EX   minutes   MS                            1   2.61   311 (M − H)           2   6.98*           3   9.37*           4   2.58   315 (M − H)           5   6.18*           6   8.32*           7   3.15   340 (M − H)           8   15.1*           9   10.2*           10   2.803   329 (M − H)           11   7.19*           12   9.27*           13   2.663   316 (M + Na)           14   2.849   330 (M + Na)           15   2.892   330 (M + Na)           16   3.096   356 (M + Na)           17   3.010   364 (M + Na)           18   3.113   409 (M + Na)           19   3.031   409 (M + Na)           20   3.029   382 (M + Na)           21   2.716   362 (M + Na)           22   2.919   376 (M + Na)           23   2.947   376 (M + Na)           24   3.157   400 (M + Na)           25   2.825   399 (M + Na)           26   3.067   410 (M + Na)           27   2.930   500 (M + Na)           28   3.136   453 (M + Na)           29   3.082   453 (M + Na)           30   3.093   428 (M + Na)           31   3.103   372 (M + Na)           32   3.27   386 (M + Na)           33   3.039   402 (M + Na)           34   3.352   406 (M + Na)           35   3.44   440 (M + Na)           36   3.411   440 (M + Na)           37   3.047   378 (M + Na)           38   3.401   422 (M + Na)           39   3.569   448 (M + Na)           40   2.884   362 (M + Na)           41   3.407   452 (M + Na)           42   3.227   386 (M + Na)           43   2.991   402 (M + Na)           44   3.158   406 (M + Na)           45   3.199   440 (M + Na)           46   3.259   418 (M + Na)           47   3.051   402 (M + Na)           48   3.157   390 (M + Na)           49   3.327   406 (M + Na)           50   3.364   390 (M + Na)           51   3.217   364 (M + Na)           52   2.741   398 (M + Na)           53   3.708   388 (M + Na)           54   3.999   406 (M + Na)           55   3.74   488 (M + Na)           56   3.806   416 (M + Na)           57   3.549   442 (M + Na)           58   2.472   321 (M + Na)           59   2.470   321 (M + Na)           60   2.723   347 (M + Na)           61   2.364   345 (M + Na)           62   2.614   355 (M + Na)           63   2.489   423 (M + H)           64   2.673   400 (M + Na)           65   2.636   400 (M + Na)           66   2.625   373 (M + Na)           67   3.321   378 (M + Na)           68   3.067   388 (M + Na)           69   3.017   344 (M + Na)           70   2.242   360 (M + Na)           71   2.035   346 (M + Na)           72   2.346   302 (M + Na)           73   2.540   316 (M + Na)           74   2.744   330 (M + Na)           75   2.792   330 (M + Na)           76   2.926   344 (M + Na)           77   2.982   356 (M + Na)           78   2.880   342 (M + H)           79   2.629   354 (M + Na)           80   2.409   346 (M + Na)           81   2.606   360 (M + Na)           82   2.794   374 (M + Na)           83   2.845   374 (M + Na)           84   2.965   388 (M + Na)           85   3.025   400 (M + Na)           86   2.931   408 (M + Na)           87   2.585   452 (M + Na)           88   2.690   398 (M + Na)           89   3.125   350 (M + H)           90   3.274   364 (M + H)           91   3.129   380 (M + H)           92   3.339   384 (M + H)           93   3.355   440 (M + Na)           94   3.443   418 (M + H)           95   2.813   374 (M + Na)           96   2.816   452 (M + Na)           97   2.586   365 (M + H)           98   2.521   321 (M + Na)           99   2.783   312 (M − H)           100   2.952   326 (M − H)           101   3.138   340 (M − H)           102   3.204   340 (M − H)           103   3.302   354 (M − H)           104   3.376   366 (M − H)           105   2.792   374 (M − H)           106   2.877   418 (M − H)           107   2.703   312 (M − H)           108   2.877   326 (M − H)           109   3.049   340 (M − H)           110   3.088   340 (M − H)           111   3.210   354 (M − H)           112   3.289   366 (M − H)           113   2.826   418 (M − H)           114   2.818   312 (M − H)           115   2.564   314 (M + H)           116   2.759   328 (M + H)           117   2.944   364 (M + Na)           118   3.013   363 (M + Na)           119   3.101   378 (M + Na)           120   3.160   368 (M + H)           121   3.062   376 (M + H)           122   2.283   304 (M + Na)           123   2.468   318 (M + Na)           124   2.684   332 (M + Na)           125   2.693   332 (M + Na)           126   2.862   324 (M + H)           127   2.917   358 M + Na)           128   2.451   410 (M + Na)           129   2.852   346 (M − H)           130   3.013   360 (M − H)           131   3.198   374 (M − H)           132   3.269   374 (M − H)           133   3.341   388 (M − H)           134   3.404   400 (M − H)           135   3.332   408 (M − H)           136   3.079   398 (M − H)           137   2.413   296 (M + Na)           138   2.556   310 (M + Na)           139   2.794   324 (M + Na)           140   2.506   276 (M − H)           141   2.852   304 (M − H)           142   2.653   290 (M − H)           143   2.881   304 (M − H)           144   3.018   318 (M − H)           145   3.093   330 (M − H)           146   3.583   338 (M − H)           147   3.202   366 (M − H)           148   3.378   380 (M − H)           149   3.140   396 (M − H)           150   3.478   434 (M − H)           151   2.393   381 (M − H)           152   2.897   368 (M − H)           153   3.064   364 (M − H)           154   3.002   346 (M − H)           155   3.170   360 (M − H)           156   3.362   374 (M − H)           157   3.432   374 (M − H)           158   3.528   388 (M − H)           159   3.575   402 (M − H)           160   3.492   408 (M − H)           161   3.088   452 (M − H)           162   3.236   398 (M − H)           163   2.827   254 (M − H)           164   3.043   368 (M − H)           165   3.237   382 (M − H)           166   3.277   382 (M − H)           167   3.397   396 (M − H)           168   3.377   416 (M − H)           169   2.963   461 (M − H)           170   2.939   343 (M − H)           171   2.876   363 (M − H)           172   2.484   407 (M − H)           173   3.148   370 (M − H)           174   3.337   384 (M − H)           175   3.519   398 (M − H)           176   3.600   398 (M − H)           177   3.683   412 (M − H)           178   3.735   424 (M − H)           179   3.643   432 (M − H)           180   3.284   476 (M − H)           181   2.572   317 (M − H)           182   2.767   331 (M − H)           183   2.967   345 (M − H)           184   3.041   345 (M − H)           185   3.135   359 (M − H)           186   3.187   371 (M − H)           187   3.097   379 (M − H)           188   2.682   423 (M − H)           189   2.907   372 (M − H)           190   3.090   388 (M − H)           191   3.252   402 (M − H)           192   2.977   412 (M − H)           193   3.129   388 (M − H)           194   2.524   319 (M − H)           195   2.725   333 (M − H)           196   2.907   347           197   2.604   357 (M − H)           198   2.739   333 (M − H)           199   2.799   356 (M − H)           200   2.953   370 (M − H)           201   3.137   384 (M − H)           202   3.181   384 (M − H)           203   3.287   398 (M − H)           204   2.862   462 (M − H)           205   2.481   301 (M − H)           206   2.598   315 (M − H)           207   2.820   329 (M − H)           208   2.964   343 (M − H)           209   2.514   407 (M − H)           210   3.117   416 (M − H)           211   3.314   430 (M − H)           212   3.397   430 (M − H)           213   3.478   444 (M − H)           214   3.006   324 (M − H)           215   3.125   416 (M − H)           216   3.354   354 (M − H)           217   3.491   446 (M − H)           218   3.222   338 (M − H)           219   2.391   301 (M − H)           220   2.561   315 (M − H)           221   2.758   315 (M − H)           222   2.768   329 (M − H)           223   2.996   355 (M − H)           224   1.936   345 (M + H)           225   2.073   405 (M − H)           226   1.756   329 (M − H)           227   2.127   357 (M − 1)           228   2.775   329 (M + H)           229   3.308   355 ((M − 1)           230   3.431   369 (M − 1)           231   3.524   381 (M − 1)           232   3.313   355 ((M − 1)           233   3.457   381 (M − 1)           234   3.066   431 (M − 1)           235       353 (M − H)           236       368 (M+)           237       344 (M+)           238       356 (M − H)           239       395 (M − H)           240       342 (M)           241       358 (M)           242       313 (M − H)           243       327 (M − H)           244           245       396 (M+)           246       344 (M+)           247       256 (M − 2H)           248       358 (M+)           249       360 (M+)           250       374 (M+)           251       354 (M+)           252       340 (M+)           253       354 (M+)           254       368 (M+)           255       382 (M+)           256       354 (M − 2H)           257       352 (M − 2H)           258       381 (M − H)           259       332 (M − H)           260       321 (M+)           261       334 (M − H)           262       320 (M − H)           263       428 (M − H)           264       376 (M − H)           265       392 (M + H)           266       392 (M + H)           267       388 (M+)           268       358 (M − H)           269       370 (M − H)           270       384 (M − H)           271       408 (M − H)           272       354 (M − H)           273       368 (M − H)           274       354 (M + H)           275       368 (M + H)           276       365 (M − H)           277       577 (M − H)           278       397 (M − H)           279       379 (M − H)           280       365 (M − H)           281       313 (M − H)           282       329 (M − H)           283       309 (M − H)           284       323 (M − H)           285       323 (M − H)           286           287       339 (M + H)           288       351 (M − H)           289       325 (M − H)           290       325 (M − H)           291       327 (M + H)           292       325 (M − H)           293       327 (M + H)           294       339 (M − H)           295       325 (M − H)           296       339 (M − H)           297       341 (M + H)           298       331 (M − H)           299       343 (M − H)           300       347 (M + H)           301       369 (M − H)           302       327 (M − H)           303       317 (M − H)           304       331 (M − H)           305       333 (M − H)           306       313 (M − H)           307       327 (M − H)           308       341 (M − H)           309       355 (M − H)           310       355 (M − H)           311       343 (M − H)           312       329 (M − H)           313           314           315           316           317       341 (M − H)           318       343 (M − H)           319       343 (M − H)           320       343 (M − H)           321       331 (M − H)           322       331 (M − H)           323       331 (M − H)           324       345 (M − H)           325       345 (M − H)           326       345 (M − H)           327       343 (M − H)           328           329       328 (M+)           330       306 (M − H)           331       362 (M+)           332       344 (M − H)           333       340 (M − H)           334       297 (M − H)           335       312 (M+)           336       312 (M+)           337       313 (M + H)           338       309 (M − H)           339       315 (M − H)           340       311 (M − H)           341       317 (M − H)           342       302 (M−)           343           344       301 (M − H)           345       315 (M − H)           346       314 (M+)           347       317 (M + H)           348       315 (M − H)           349           350       328 (M+)           351       342 (M+)           352       317 (M − H)           353       355 (M − H)           354       398 (M + H)           355       398 (M + H)           356       440 (M + H)           357       368 (M − H)           358       384 (M + H)           359       371 (M + H)           360       371 (M + H)           361       371 (M + H)           362       357 (M − H)           363       341 (M − H)           364       369 (M − H)           365       383 (M + H)           366       411 (M − H)           367       435 (M − H)           368       419 (M + H)                      
 
       EXAMPLE 1  
     (5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 2  
     [(R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 3  
     [(S)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 4  
     (5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 5  
     [(R)-5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 6  
     [(S)-5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 7  
     (5,8-dichloro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 8  
     [(R)-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 9  
     [(S)-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 10  
     (5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 11  
     [(R)-5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 12  
     [(S)-5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 13  
     (5-Chloro-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 14  
     (5-Chloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 15  
     (5-chloro-1-isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 16  
     {5-chloro-1-[(3E)-pent-3-enyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 17  
     (5-chloro-1-phenyl-1,3,4,9-tetrahydropyrano [3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 18  
     [5-chloro-1-(4-nitrophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 19  
     [5-chloro-1-(3-nitrophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 20  
     [5-chloro-1-(2-fluorophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 21  
     (5-bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 22  
     (5-bromo-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 23  
     (5-bromo-1-isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 24  
     {5-bromo-1-[(3E)-pent-3-enyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 25  
     [5-bromo-1-(3-furyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 26  
     (5-bromo-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 27  
     [5-bromo-1-(3,4,5-trimethoxyphenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 28  
     [5-bromo-1-(4-nitrophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 29  
     [5-bromo-1-(3-nitrophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 30  
     [5-bromo-1-(2-fluorophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 31  
     (5-phenyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 32  
     [5-(4-methylphenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 33  
     [5-(4-methoxyphenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 34  
     (5-(4-chlorophenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 35  
     [5-(2,4-dichlorophenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 36  
     {1-propyl-5-[4-(trifluoromethyl)phenyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 37  
     (1-propyl-5-thien-2-yl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 38  
     [5-(2-naphthyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 39  
     [5-(1,1′-biphenyl-4-yl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 40  
     [5-(2-furyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 41  
     [5-(4-bromophenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 42  
     [5-(2-methylphenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 43  
     [5-(2-methoxyphenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 44  
     [5-(2-chlorophenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 45  
     (1-propyl-5-[2-(trifluoromethyl)phenyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 46  
     (5-[4-(methylthio)phenyl]-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 47  
     [5-(3-methoxyphenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 48  
     [5-(4-fluorophenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 49  
     [5-(3-chlorophenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 50  
     (5,8-dichloro-1-[(3E)-pent-3-enyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 51  
     (5,8-dichloro-1-isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 52  
     (5,8-dichloro-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 53  
     [5,8-dichloro-1-(3-furyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 54  
     [5,8-dichloro-1-(4-methylpentyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 55  
     [5,8-dichloro-1-(3,4,5-trimethoxyphenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 56  
     [5,8-dichloro-1-(2-fluorophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 57  
     4-[1-(carboxymethyl)-5,8-dichloro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]benzoic acid  
     EXAMPLE 58  
     (5-cyano-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 59  
     (5-cyano-1-isopropyl-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl)acetic acid  
     EXAMPLE 60  
     {5-cyano-1-[(3E)-pent-3-enyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 61  
     [5-cyano-1-(3-furyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 62  
     (5-cyano-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 63  
     [5-cyano-1-(3,4,5-trimethoxyphenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 64  
     [5-cyano-1-(4-nitrophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 65  
     [5-cyano-1-(3-nitrophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 66  
     [5-cyano-1-(2-fluorophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 67  
     (1-butyl-5,8-dichloro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 68  
     (5-bromo-1-butyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 69  
     (1-butyl-5-chloro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 70  
     [5-chloro-1-(2-methoxy-2-oxoethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 71  
     [1-(carboxymethyl)-5-chloro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 72  
     (8-chloro-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 73  
     (8-chloro-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 74  
     (8-chloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 75  
     (8-chloro-1-isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 76  
     (1-butyl-8-chloro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 77  
     {8-chloro-1-[(3E)-pent-3-enyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 78  
     (8-chloro-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 79  
     [8-chloro-1-(3-furyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 80  
     (8-bromo-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 81  
     (8-bromo-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 82  
     (8-bromo-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 83  
     (8-bromo-1-isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 84  
     (8-bromo-1-butyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 85  
     {8-bromo-1-[(3E)-pent-3-enyl] -1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 86  
     (8-bromo-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 87  
     4-[8-bromo-1-(carboxymethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]benzoic acid  
     EXAMPLE 88  
     [8-bromo-1-(3-furyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 89  
     (8-phenyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 90  
     [8-(4-methylphenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 91  
     [8-(4-methoxyphenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 92  
     [8-(4-chlorophenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 93  
     [8-(2,4-dichlorophenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 94  
     {1-propyl-8-[4-(trifluoromethyl)phenyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 95  
     (1-propyl-8-thien-2-yl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 96  
     [8-(3-bromophenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 97  
     [8-(3-aminophenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 98  
     (8-cyano-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 99  
     (6,8-dichloro-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 100  
     (6,8-dichloro-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 101  
     (6,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 102  
     (6,8-dichloro-1-isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 103  
     (1-butyl-6,8-dichloro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 104  
     {6,8-dichloro-1-[(3E)-pent-3-enyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 105  
     (6,8-dichloro-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 106  
     4-[1-(carboxymethyl)-6,8-dichloro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]benzoic acid  
     EXAMPLE 107  
     (5,6-dichloro-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 108  
     (5,6-dichloro-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 109  
     (5,6-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 110  
     (5,6-dichloro-1-isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 111  
     (1-butyl-5,6-dichloro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 112  
     {5,6-dichloro-1-[(3E)-pent-3-enyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 113  
     4-[1-(carboxymethyl)-5,6-dichloro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]benzoic acid  
     EXAMPLE 114  
     (5,7-dichloro-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 115  
     [1-methyl-8-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 116  
     [1-ethyl-8-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 117  
     [1-propyl-8-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 118  
     [1-isopropyl-8-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 119  
     [1-butyl-8-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 120  
     [1-[(3E)-pent-3-enyl]-8-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 121  
     [1-phenyl-8-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 122  
     (5,8-difluoro-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 123  
     (1-ethyl-5,8-difluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 124  
     (5,8-difluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 125  
     (5,8-difluoro-1-isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 126  
     (1-butyl-5,8-difluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 127  
     {5,8-difluoro-1-[(3E)-pent-3-enyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 128  
     4-[1-(carboxymethyl)-5,8-difluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]benzoic acid  
     EXAMPLE 129  
     [8-chloro-1-methyl-5-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 130  
     [8-chloro-1-ethyl-5-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 131  
     [8-chloro-1-propyl-5-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 132  
     [8-chloro-1-isopropyl-5-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 133  
     [1-butyl-8-chloro-5-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 134  
     [8-chloro-1-[(3E)-pent-3-enyl]-5-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 135  
     [8-chloro-1-phenyl-5-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 136  
     [8-chloro-1-(3-furyl)-5-(trifluoromethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 137  
     (1,5,8-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 138  
     (1-ethyl-5,8-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 139  
     (5,8-dimethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 140  
     (5-fluoro-1,8-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 141  
     (5-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 142  
     (1-ethyl-5-fluoro-1,3,4,9-tetrahydro-8-methyl-pyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 143  
     (5-fluoro-1-isopropyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 144  
     (1-butyl-5-fluoro-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 145  
     {5-fluoro-8-methyl-1-[(3E)-pent-3-enyl] -1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 146  
     (5-fluoro-8-methyl-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 147  
     (8-fluoro-5-phenyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 148  
     [8-fluoro-5-(4-methylphenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 149  
     [8-fluoro-5-(4-methoxyphenyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 150  
     {8-fluoro-1-propyl-5-[4-(trifluoromethyl)phenyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 151  
     [5-(3-aminophenyl)-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 152  
     (5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 153  
     (5-bromo-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 154  
     (5,6,8-trichloro-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 155  
     (5,6,8-trichloro-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 156  
     (5,6,8-trichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 157  
     (5,6,8-trichloro-1-isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 158  
     (1-butyl-5,6,8-trichloro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 159  
     {5,6,8-trichloro-1-[(3E)-pent-3-enyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 160  
     (5,6,8-trichloro-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 161  
     4-[1-(carboxymethyl)-5,6,8-trichloro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]benzoic acid  
     EXAMPLE 162  
     [5,6,8-trichloro-1-(3-furyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 163  
     (5-bromo-8-fluoro-1,6-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 164  
     (5-bromo-1-ethyl-8-fluoro-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 165  
     (5-bromo-8-fluoro-6-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 166  
     (5-bromo-8-fluoro-1-isopropyl-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 167  
     (5-bromo-1-butyl-8-fluoro-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 168  
     (5-bromo-8-fluoro-6-methyl-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 169  
     4-[5-bromo-1-(carboxymethyl)-8-fluoro-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]benzoic acid  
     EXAMPLE 170  
     (1-butyl-5-cyano-8-fluoro-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 171  
     (5-cyano-8-fluoro-6-methyl-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 172  
     4-[1-(carboxymethyl)-5-cyano-8-fluoro-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]benzoic acid  
     EXAMPLE 173  
     (5-bromo-8-chloro-1,6-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 174  
     (5-bromo-8-chloro-1-ethyl-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 175  
     (5-bromo-8-chloro-6-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 176  
     (5-bromo-8-chloro-1-isopropyl-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 177  
     (5-bromo-1-butyl-8-chloro-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 178  
     {5-bromo-8-chloro-6-methyl-1-[(3E)-pent-3-enyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 179  
     (5-bromo-8-chloro-6-methyl-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 180  
     4-[5-bromo-1-(carboxymethyl)-8-chloro-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]benzoic acid  
     EXAMPLE 181  
     (8-chloro-5-cyano-1,6-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 182  
     (8-chloro-5-cyano-1-ethyl-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 183  
     (8-chloro-5-cyano-6-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 184  
     (8-chloro-5-cyano-1-isopropyl-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 185  
     (1-butyl-8-chloro-5-cyano-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 186  
     {8-chloro-5-cyano-6-methyl-1-[(3E)-pent-3-enyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 187  
     (8-chloro-5-cyano-6-methyl-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 188  
     4-[1-(carboxymethyl)-8-chloro-5-cyano-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]benzoic acid  
     EXAMPLE 189  
     (5-bromo-1-ethyl-6,8-difluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 190  
     (5-bromo-6,8-difluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 191  
     (5-bromo-1-butyl-6,8-difluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 192  
     [5-bromo-6,8-difluoro-1-(3-furyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 193  
     (5-bromo-6,8-difluoro-1-isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 194  
     (5-cyano-1-ethyl-6,8-difluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 195  
     (5-cyano-6,8-difluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 196  
     (1-butyl-5-cyano-6,8-difluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 197  
     [5-cyano-6,8-difluoro-1-(3-furyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 198  
     (5-cyano-6,8-difluoro-1-isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 199  
     (5-bromo-6-fluoro-1,8-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 200  
     (5-bromo-1-ethyl-6-fluoro-8-methyl-1,3,4,9-tetrahydropyrano [3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 201  
     (5-bromo-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano [3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 202  
     (5-bromo-6-fluoro-1-isopropyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 203  
     (5-bromo-1-butyl-6-fluoro-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 204  
     4-[5-bromo-1-(carboxymethyl)-6-fluoro-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]benzoic acid  
     EXAMPLE 205  
     (5-cyano-6-fluoro-1,8-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 206  
     (5-cyano-1-ethyl-6-fluoro-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 207  
     (5-cyano-6-fluoro-1-isopropyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 208  
     (1-butyl-5-cyano-6-fluoro-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 209  
     4-[1-(carboxymethyl)-5-cyano-6-fluoro-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]benzoic acid  
     EXAMPLE 210  
     (5,8-dibromo-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 211  
     (5,8-dibromo-1-propyl-1,3,4,9-tetrahydropyrano [3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 212  
     (5,8-dibromo-1-isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 213  
     (5,8-dibromo-1-butyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 214  
     (5-chloro-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 215  
     (8-fluoro-5-iodo-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 216  
     (5,8-dichloro-6-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 217  
     (8-chloro-5-iodo-6-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 218  
     (8-fluoro-5-iodo-6-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 219  
     (5-cyano-8-fluoro-1,6-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 220  
     (5-cyano-1-ethyl-8-fluoro-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 221  
     (5-cyano-8-fluoro-6-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 222  
     (5-cyano-8-fluoro-1-isopropyl-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)aceti acid  
     EXAMPLE 223  
     {5-cyano-8-fluoro-6-methyl-1-[(3E)-pent-3-enyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid  
     EXAMPLE 224  
     (8-methyl-5-methylcarbamoyl-1-propyl-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl)acetic acid  
     EXAMPLE 225  
     [8-methyl-5-(morpholine-4-carbonyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 226  
     (5-carbamoyl-8-Methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 227  
     (5-dimethylcarbamoyl-8-Methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 228  
     (5-cyano-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 229  
     (5,8-dichloro-4-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 230  
     (5,8-dichloro-4,4-dimethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 231  
     (4-cyclobutyl-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 232  
     (5,8-dichloro-9-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 233  
     (9-allyl-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 234  
     (9-benzyl-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 235  
     (5,6-dichloro-1-cyclobutyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 236  
     (5,6-dichloro-1-cyclopentyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 237  
     (5,6-Dichloro-1-methoxymethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 238  
     [5,6-dichloro-1-(2-methoxyethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 239  
     [5,6-dichloro-1-(3,3,3-trifluoropropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 240  
     (6,7-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 241  
     (6,7-dichloro-1-ethoxymethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 242  
     (5,8-dichloro-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 243  
     (5,8-dichloro-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 244  
     [5,8-dichloro-1-(3-cyanopropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 245  
     [5,8-dichloro-1-(3,3,3-trifluoropropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 246  
     (5,8-dichloro-1-methoxymethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 247  
     [5,8-dichloro-1-(2-methoxyethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 248  
     (5,8-dichloro-1-ethoxymethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 249  
     (5,8-dichloro-1-methylthiomethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 250  
     (5,8-dichloro-1-ethylthiomethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 251  
     [5,8-dichloro-1-(3-butenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 252  
     (5,8-dichloro-1-cyclopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 253  
     (5,8-dichloro-1-cyclobutyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 254  
     (5,8-dichloro-1-cyclopentyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 255  
     (5,8-dichloro-1-cyclohexyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 256  
     [5,8-dichloro-1-(1-methylpropyl) -1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 257  
     (5,8-dichloro-1-cyclopropylmethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 258  
     (5,8-dichloro-1-cyclopentylmethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 259  
     (5-chloro-1-cyclobutyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 260  
     (5-chloro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 261  
     (1R*,10S)-[5-chloro-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 262  
     (8-chloro-5-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 263  
     [8-chloro-5-trifluoromethyl-1-(3,3,3-trifluoropropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-acid  
     EXAMPLE 264  
     (8-chloro-1-methoxymethyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 265  
     [8-chloro-1-(2-methoxyethyl)-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4b]indol-1-yl]acetic acid  
     EXAMPLE 266  
     (8-chloro-1-ethoxymethyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 267  
     (8-chloro-1-cyclobutyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 268  
     (8-fluoro-1-propyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 269  
     (1-cyclobutyl-8-fluoro-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 270  
     (1-cyclopentyl-8-fluoro-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 271  
     [5,8-bis(trifluoromethyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 272  
     (8-methyl-1-propyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 273  
     (8-methyl-1-butyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 274  
     (1-cyclopropyl-8-methyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 275  
     (1-cyclobutyl-8-methyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 276  
     (8-cyano-1-propyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 277  
     (8-cyano-1-cyclobutyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 278  
     (1R*,10S)-[8-aminocarbonyl-1-(1-methylpropyl)-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 279  
     (1R*,10S)-[8-cyano-1-(1-methylpropyl)-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 280  
     [5-cyano-8-methyl-1-(3,3,3-trifluoropropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 281  
     (5-cyano-1-methoxymethyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 282  
     (5-cyano-1-methylthiomethyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 283  
     (5-cyano-1-cyclopropyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 284  
     (5-cyano-1-cyclobutyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 285  
     (1 R)-(5-cyano-1-cyclobutyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 286  
     (1S)-(5-cyano-1-cyclobutyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 287  
     (5-cyano-1-cyclopentyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 288  
     (5-cyano-1-cyclopentylmethyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 289  
     (1R*,10S*)-[5-cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 290  
     (1R*,10R*)-[5-cyano-8-methyl 1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 291  
     (1R*,10S)-[5-cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 292  
     (1R,10S)-[5-cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 293  
     (1S,10S)-[5-cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 294  
     [5-cyano-1-(1-ethylethyl)-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 295  
     (5-cyano-8-ethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 296  
     (1-butyl-5-cyano-8-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 297  
     [5-cyano-8-(1-methylethyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 298  
     (8-methyl-5-nitro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 299  
     (1-cyclobutyl-8-methyl-5-nitro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 300  
     (1R*,10S)-[8-methyl-1-(1-methylpropyl)-5-nitro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl acetic acid  
     EXAMPLE 301  
     [5-cyano-8-fluoro-1-(3,3,3-trifluoropropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 302  
     [1-(3-butenyl)-5-cyano-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 303  
     (5-cyano-8-fluoro-1-methoxymethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 304  
     [5-cyano-8-fluoro-1-(2-methoxyethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 305  
     (5-cyano-8-fluoro-1-methylthiomethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 306  
     (5-cyano-1-cyclopropyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 307  
     (5-cyano-1-cyclobutyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 308  
     (5-cyano-1-cyclopentyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 309  
     (5-cyano-1-cyclohexyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 310  
     (5-cyano-1-cyclopentylmethyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 311  
     [5-cyano-1-(1-ethylethyl)-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 312  
     (1R*,10R*)-[5-cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 313  
     (1R*,10S*)-[5-cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 314  
     (1R*,10S)-[5-cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 315  
     (1R, 10S)-[5-cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 316  
     (1S, 10S)-[5-cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 317  
     (5-cyano-1-cyclobutyl-6-fluoro-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 318  
     (1R*,10S)-[5-cyano-6-fluoro-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 319  
     (1R,10S)-[5-cyano-6-fluoro-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 320  
     (1S,10S)-[5-cyano-6-fluoro-8-methyl-1-(1-methylpropyl)-1,3,4,9tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 321  
     (8-chloro-5-cyano-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 322  
     (1R)-(8-chloro-5-cyano-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 323  
     (1S)-(8-chloro-5-cyano-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 324  
     (1R*,10S)-[8-chloro-5-cyano-1-(1-methylethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 325  
     (1R,10S)-[8-chloro-5-cyano-1-(1-methylethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 326  
     (1S,10S)-[8-chloro-5-cyano-1-(1-methylethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 327  
     (8-chloro-5-cyano-1-cyclobutyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid  
     EXAMPLE 328  
     (5,6-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 329  
     (5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 330  
     (5-chloro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 331  
     (8-chloro-5-trifluoromethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 332  
     (8-fluoro-5-trifluoromethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 333  
     (5-trifluoromethyl-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 334  
     (5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 335  
     (1R*,10S*)-[5-cyano-8-methyl-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1yl]carboxylic acid  
     EXAMPLE 336  
     (1R*,10R*)-[5-cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]carboxylic acid  
     EXAMPLE 337  
     [5-cyano-8-methyl-1-(3-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]carboxylic acid  
     EXAMPLE 338  
     (5-cyano-1-cyclobutyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 339  
     (5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 340  
     (5-cyano-8-ethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 341  
     (8-chloro-5-cyano-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 342  
     (5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 343  
     (1R)-(5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol 1-yl)carboxylic acid  
     EXAMPLE 344  
     (1S)-(5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 345  
     (1-butyl-5-cyano-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 346  
     [1-(3-butenyl)-5-cyano-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]carboxylic acid  
     EXAMPLE 347  
     [5-cyano-8-fluoro-1-(3-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol 1-yl]carboxylic acid  
     EXAMPLE 348  
     (1R*,10S*)-[5-cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]carboxylic acid  
     EXAMPLE 349  
     (1R*,10R*)-[5-cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol--1-yl]carboxylic acid  
     EXAMPLE 350  
     (5-cyano-1-cyclopentyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 351  
     (5-cyano-1-cyclohexyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 352  
     (8-fluoro-5-nitro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid  
     EXAMPLE 353  
     1-carboxymethyl-5-cyano-8-methyl-1-propyl-1,3,4,9 tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid  
     EXAMPLE 354  
     (5-cyano-8-methyl-1-propyl-7-propylcarbamoyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
     EXAMPLE 355  
     (5-cyano-7-isopropylcarbamoyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
     EXAMPLE 356  
     [5-cyano-7-(4,4-dimethyl-butylcarbamoyl)-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1yl]acetic acid  
     EXAMPLE 357  
     (5-cyano-8-methyl-7-methylcarbamoyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
     EXAMPLE 358  
     (5-cyano-8-methyl-7-dimethylcarbamoyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
     EXAMPLE 359  
     (5-cyano-8-methyl-7-propoxy-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
     EXAMPLE 360  
     (1R)-(5-cyano-8-methyl-7-propoxy-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
     EXAMPLE 361  
     (1S)-(5-cyano-8-methyl-7-propoxy-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
     EXAMPLE 362  
     (5-cyano-7-ethoxy-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
     EXAMPLE 363  
     (5-cyano-7-methoxy-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
     EXAMPLE 364  
     (5-cyano-7-isopropoxy-8-methyl-l-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
     EXAMPLE 365  
     (7-butoxy-5-cyano-8-methyl-l-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
     EXAMPLE 366  
     [5-cyano-7-(3,3-dimethyl-butoxy)-8-methyl-1-propy-1,3,4,9-tetrahydro-pyrano[3,4-b)indol-1-yl]-acetic acid  
     EXAMPLE 367  
     [5-cyano-7-(3-fluoro-benzyloxy)-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 368  
     (7-benzyloxy-5-cyano-8-methyl-l-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid  
     EXAMPLE 369  
     [5-cyano-7-(2-fluoro-ethoxy)-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]acetic acid  
     EXAMPLE 370  
     [5-cyano-7-(3-fluoro-propoxy)-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]acetic acid