# Patent

## Title
Method for the use of pyranoindole derivatives to treat infection with Hepatitis C virus

## 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 R1, R2, R3—R12, and Y are set forth in the specification.

## Background
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
1. Field of the Invention
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.
2. Related Background Art
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).
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.
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.
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.
In the following U.S. patents, pyranoindole derivatives are disclosed and the compounds are stated to have antidepressant and antiulcer activity: U.S. Pat. No. 3,880,853 (Apr. 29, 1975), U.S. Pat. No. 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. No. 3,843,681 (Oct. 22, 1974), U.S. Pat. No. 3,939,178 (Feb. 17, 1976), U.S. Pat. No. 3,974,179 (Aug. 10, 1976), U.S. Pat. No. 4,070,371 (Jan. 24, 1979), U.S. Pat. No. 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. No. 4,670,462 (Jun. 2, 1987), U.S. Pat. No. 4,686,213 (Aug. 11, 1987), U.S. Pat. No. 4,785,015 (Nov. 15, 1988), U.S. Pat. No. 4,810,699 (Mar. 7, 1989), U.S. Pat. No. 4,822,781 (Apr. 18, 1989), U.S. Pat. No. 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's disease.
Also, in the following U.S. patents, processes for preparing pyranoindole derivatives are disclosed: U.S. Pat. No. 4,012,417 (Mar. 15, 1977), U.S. Pat. No. 4,036,842 (Jul. 19, 1977), U.S. Pat. No. 4,585,877 (Apr. 29, 1986), U.S. Pat. No. 4,822,893 (Apr. 18, 1989). Processes for the resolution of racemic pyranoindole derivatives are disclosed in the following US Patents: U.S. Pat. No.: 4,501,899 (Feb. 26, 1985), U.S. Pat. No. 4,515,961 (May 7, 1985), U.S. Pat. No. 4,520,203 (May 28, 1985), U.S. Pat. No. 4,544,757 (Oct. 1, 1985).
Other aspects of the instant invention are described in applicant'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
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.
In accordance with this invention there is provided a group of compounds represented by formula (I):




wherein:

    
    
        R1 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;
        R2 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;
        R3–R6 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 R5 and R6 together with the ring carbon atom to which they are attached form a carbonyl group;
        R7–R10 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, CONR11R12, F, Cl, Br, I, CN, CF3, NO2, alkylsulfinyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, pyrrolidinyl, or thiazolidinyl;
        R11–R12 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;
        Y is a bond, CH2, CH2CH2, aryl, or R2 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
        a crystalline form or a pharmaceutically acceptable salt thereof.
    
    


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.
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, —SO3H, —SO2NH2, —SO2NHalkyl, —SO2N(alkyl)2, —CO2H, CO2NH2, CO2NHalkyl, and —CO2N(alkyl)2. Preferred substituents for aryl and heteroaryl include: alkyl, halogen, amino, alkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy, arylalkyl, and alkylaryl.
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.
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.
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.
For purposes of this invention the term “alkylaryl” is defined as C1–C6-alkyl-aryl-.
For purposes of this invention the term “alkylthio” is defined as C1–C6alkyl-S—.
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.
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.
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.
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.
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.
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.
For purposes of this invention “phenylalkynyl” is an alkynyl group further substituted with a phenyl group.
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.
In a preferred embodiment of this invention trifluoromethoxy is CF3O—. In another embodiment of this invention trifluoromethylthio is CF3S—.
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—.
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.
“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.
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.
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 .
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.
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.
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.
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










Based on the chiral center at the C1 carbon position in formula (1), a preferred embodiment of the instant invention is the compound of formula (Ia) shown below:




The configuration at C1 in Formula (Ia) for purposes of this invention is also referred to as “Isomer A”, and the opposite configuration at C1 is herein




defined as “Isomer B” and has the formula (1b) shown below:

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.
Another embodiment of this invention is where R2 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.
Pharmaceutically acceptable salts of the compounds of formula (I) having acidic moieties at R3, R4, R5, R6, R7, R8, R9, or R10 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 R3, R4, R5, R6, R7, R8, R9, or R10 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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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:




wherein:

    
    
        R1 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;
        R2 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;
        R3–R6 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 R5 and R6 together with the ring carbon atom to which they are attached form a carbonyl group;
        R7–R10 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, CONR11R12, F, Cl, Br, I, CN, CF3, NO2, alkylsulfinyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, pyrrolidinyl, or thiazolidinyl;
        R11–R12 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;
        Y is a bond, CH2, CH2CH2, aryl, or R2 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
        a pharmaceutically acceptable carrier.
    
    


The method of the present invention further comprises providing the mammal with an effective amount of at least one biologically active agent.
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.
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

    
    
        [(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.
    
    


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:




wherein:

    
    
        R1 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;
        R2 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;
        R3–R6 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 R5 and R6 together with the ring carbon atom to which they are attached form a carbonyl group;
        R7–R10 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, CONR11R12, F, Cl, Br, I, CN, CF3, NO2, an alkylsulfinyl of 1 to 6 carbon atoms, an alkylsulfonyl of 1 to 6 carbon atoms;
        R11–R12 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;
        Y is CH2, CH2CH2, or aryl; and
        a pharmaceutically acceptable carrier.
    
    


The method of the present invention further comprises providing the mammal with an effective amount of at least one biologically active agent.
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.
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

    
    
        [(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.
    
    


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:




    R1 is H;
    R2 is H, or a straight chain alkyl of 1 to 4 carbon atoms;
    R3–R6 are H;
    R7–R10 are independently H, a straight chain alkyl of 1 to 3 carbon, F, Cl, or CN;
    Y is CH2; and
    a pharmaceutically acceptable carrier.


The method of the present invention further comprises providing the mammal with an effective amount of at least one biologically active agent.
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.
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

    
    
        [(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.
    
    


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:




wherein:

    
    
        R1 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;
        R2 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;
        R3–R6 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 R5 and R6 together with the ring carbon atom to which they are attached form a carbonyl group;
        R7–R10 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, CONR11R12, F, CI, Br, I, CN, CF3, NO2, alkylsulfinyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, pyrrolidinyl, or thiazolidinyl;
        R11–R12 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;
        Y is a bond, CH2, CH2CH2, aryl, or R2 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
        a pharmaceutically acceptable carrier.
    
    


The method of the present invention further comprises providing the mammal with an effective amount of at least one biologically active agent.
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.
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

    
    
        [(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.
    
    


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:




wherein:

    
    
        R1 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;
        R2 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;
        R3–R6 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 R5 and R6 together with the ring carbon atom to which they are attached form a carbonyl group;
        R7–R10 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, CONR11R12, F, Cl, Br, I, CN, CF3, NO2, an alkylsulfinyl of 1 to 6 carbon atoms, an alkylsulfonyl of 1 to 6 carbon atoms;
        R11–R12 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;
        Y is CH2, CH2CH2, or aryl; and
        a pharmaceutically acceptable carrier.
    
    


The method of the present invention further comprises providing the mammal with an effective amount of at least one biologically active agent.
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.
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

    
    
        [(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.
    
    


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.
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's need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions.
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.
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.
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.
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.
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.
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
The compounds of the present invention can be readily prepared according to the following reaction schemes or modification thereof. In the following reaction schemes R1, R2, R3, R4, R5, R6, R7, R8, R9, or R10, R11, R12 and Y are selected from the groups defined above.
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).
















































The ability of the compounds of the present invention to inhibit Hepatitis C Polymerase was established by the following experimental procedure:

    
    
        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.
    
    


Reagents:

    10 mM uridine 5′-triphosphate (UTP) (Promega # p116B)
    10 mM adenine 5′-triphosphate (ATP) (Promega # p113B)
    10 mM cytidine 5′-triphosphate (CTP) (Promega # p114B)
    10 mM guanine 5′-triphosphate (GTP) (Promega # p115B)
    Bovine Serum Albumin (BSA) 10 mg/ml NEB (100× at 10 mg/ml) #007-BSA
    RNasein (Promega #N251X) 40 U/μl
    A-[33P]-GTP (NEN-easytides NEG/606H 3000 Ci/mmol, 370 MBq/ml, 10 mCi/ml)
    Falcon polypropylene 96 well plates (Becton Dickinson # 351190)
    Millipore Multiscreen assasy system-96 well-filtration plate #MADE NOB 50
    Optiphase Supermix (Wallac) formulated by Fisher
    Millipore Multiscreen liner for use in microbeta 1450-106 casette [(Wallac) Perkin Elmer #1450-433]
    1 M(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]) (HEPES), pH 7.3
    Amersham Pharmacia Biotec (US16924-500 ml)
    1 M MgCl2 (SIGMA #M1028)
    Dithiothreitol (DTT) (solid) (SIGMA #D9779)
    RNase free water (GIBCO-BRL #10977-023)
    Dimethyl sulfoxide (Aldrich #27685-5)
    Basilen Blue (Sigma, B5520)
    0.5M ethylenediaminetetraacetic acid (EDTA), pH 8 (GIBCO-BRL #15575-020)
    Dibasic sodium phosphate (7-hydrate) (Na2HPO4.7H2O; Baker#3824-07)
    Phosphoric acid (Baker, #0262.02)


Further reagent preparation:

    
    
        0.5 M Na Phosphate buffer. Per liter, weigh 134 gr Na2HPO4.7H2O, add water to 900 ml. Adjust pH to 7.0 with phosphoric acid. Top off with water to 1 L.
        Dilute nucleotides 1:1000 to 10 μM (GTP and CTP) or 1:100 to 100 μM (ATP and UTP) into RNase free water.
    
    


Procedure:

    (1) Compounds 10 μl at 10 μg/ml in 15% dimethylsulfoxide (DMSO)


When starting from 100 μg/ml compound stock in 1% DMSO:

    Dispense 5 μl 30% DMSO per well
    Dispense 5 μl compound (100 μg/ml) per well.


When starting from 50 μg/ml compound stock in 15% DMSO:

    Add 10 μl compound per well.
    (2) Enzyme Mix:
















Final Conc (in 50 μl
Per 20 μl mix (1



Stock
assay volume)
reaction)
Per 600 reactions





















DEPC H2O


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


MgCl2


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









Add 20 μl enzyme mix into each well of the assay plate. Incubate compound and enzyme at room temperature for 15 minutes

    (3) Template mix—prepare ahead


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).
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









Add 20 μl template mix per reaction (i.e. 20 ng of pOF per reaction or  ̃3 nM)

    (4) Incubate reaction at room temperature (22–25° C.) for 2 hours.
    (5) Stop reaction by adding 50 μl of 170 mM EDTA.
    
        Final concentration of EDTA is 85 mM.
    
    
    (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.
    (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.
    (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.
    
        Repeat step (8) three more times.
    
    
    (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 micro-beta carrier.
    (10) Count plate using a Packard Topcount or micro-beta counter. Count (for example using Program 10) for 33P in Top count or 33P program in micro-beta.


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 >75% inhibition.
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.
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
IC50 (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
>20
23


14
11
75


15
>20
7


16
>20
<5


17
>20
<5


18
>20
<5


19
>20
6


20
>20
21


21
>20
58


22
5
70


23
>20
12


24
>20
<5


25
>20
33


26
>20
<5


27
>20
3


28
>20
<5


29
>20
<5


30
>20
<5


31
>20
12


32
>20
<5


33
>20
<5


34
>20
5


35
>20
35


36
>20
4


37
>20
28


38
>20
11


39
>20
7


40
>20
27


41
>20
13


42
>20
31


43
>20
83


44
>20
41


45
>20
14


46
>20
15


47
>20
15


48
>20
18


49
>20
<5


50
>20
34


51
7
84


52
>20
11


53
13
62


54
>20
6


55
>20
<5


56
>20
3


57
3
56


58
6.9
78


59
>20
23


60
>20
15


61
>20
18


62
>20
32


63
>20
30


64
>20
18


65
>20
27


66
>20
28


67
0.76
78


68
10.3
61


69
5.5
—


70
>5
22


71
>5
45


72
>20
45


73
>20
22


74
17.9
69


75
>20
17


76
>20
29


77
>20
16


78
>20
26


79
>20
40


80
>20
35


81
>20
27


82
9.2
73


83
>20
41


84
19.7
46


85
>20
18


86
>20
20


87
>20
42


88
>20
30


89
>20
36


90
>20
2


91
>20
<5


92
>20
35


93
>20
64


94
>20
33


95
14.4
68


96
>20
37


97
>20
21


98
>20
44


99
>20
32


100
>20
54


101
1.5
89


102
21.7
51


103
14.4
60


104
>20
<5


105
>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
>20
34


113
0.26
35


114
>20
57


115
>20
40


116
>20
34


117
9.6
39


118
>20
10


119
>20
31


120
>20
33


121
>20
<5


122
>20
5


123
>20
51


124
6.7
61


125
>20
73


126
>20
35


127
>20
24


128
>20
70


129
>20
45


130
5.5
77


131
0.32
93


132
9.5
78


133
0.7
88


134
>20
28


135
>20
55


136
4.3
81


137
>20
5


138
>20
38


139
8.3
40


140
>20
28


141
1.4
79


142
19.8
39


143
16.5
56


144
6.0
73


145
>20
20


146
>20
45


147
10
34


148
>20
47


149
16
<11


150
9
<37


151
>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
>20
36


160
>20
15


161
0.3
74


162
2.4
73


163
>10
28


164
2
77


165
0.6
89


166
3.7
55


167
3
80


168
>10
4


169
0.22
82


170
1
53


171
>10
3


172
1.7
74


173
>5
19


174
>5
70


175
0.5
84


176
>5
49


177
4
70


178
>5
<32


179
>5
15


180
0.81
92


181
>5
14


182
>5
55


183
0.59
88


184
>5
39


185
4
69


186
>5
2


187
>5
61


188
>5
76


189
4.2
74


190
0.2
94


191
0.4
93


192
>5
74


193
4.5
69


194
>5
50


195
0.27
90


196
1.2
77


197
>5
55


198
>5
82


199
>5
52


200
2.1
83


201
0.15
82


202
2.9
82


203
0.19
94


204
1.2
87


205
>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
>5
30


220
>5
43


221
0.43
81


222
>5
45


223
>5
37


224
>20
—


225
>20
—


226
>20
—


227
>20
—


228
8.9
—


229
7.0
—


230
3.1
—


231
7.2
—


232
7.6
—


233
>20
—


234
13
—


















TABLE 1B






BK
BB7


Example
IC50 (μM)
IC50 (μM)

















235
5.2
5.4


236
10
9.6


237
>27
>24


238
19
>30


239
4.6
5.4


240
8.9
18


241
27
>30


242
27
18


243
6.3
10


244
0.3
1.8


245
0.4
0.74


246
>30
>30


247
>24
18


248
>30
>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
>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
>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
>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
>30
>30


282
13
22


283
15
>27


284
1
2.3


285
0.4
1.1


286
>30
>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
>30
>30


294
>30
>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
>30
>30


304
>30
>30


305
>30
>30


306
>30
>30


307
5.8
9.6


308
>30
>30


309
26
27


310
>25
>25


311
>30
>30


312
16
>30


313
1.8
1.5


314
1.4
3.1


315
0.4
2.1


316
>30
>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
>30
>30


336
4.7
8.7


337
19
>30


338
3.3
3.9


339
0.49
2.8


340
>30
>28


341
1.7
3.6


342
1.7
10


343
>30
>30


344
0.7
—


345
3.4
6.2


346
6.1
8


347
>29
>30


348
>30
>30


349
4.4
>24


350
>30
>30


351
>30
>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









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:

    
    
        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.
    
    


Reagents:
Elisa media:
Dulbecco's Modified Eagle Media (DMEM) (Gibco #12430-047)
2% Fetal Calf Serum (FCS) (HyClone #SH30070.03)
1× pen/strep (Gibco #15140-122)
1× Non-essential amino acids (NEAA) (Gibco #11140-050)
no G418
Glutaraldehyde (Fisher #02957-4)
TWEEN-20, 10% (Roche #1332465)
TRITON X-100 (Sigma #T-8787)
Superblock in Phosphate Buffered Saline (PBS) (Pierce #37515)
NS5a monoclonal antibody (Virostat #1873)
Goat antimouse-HRP monoclonal antibody (BioRad #172-1011)
3,3′,5,5′ tetramethylbenzidine (TMB) substrate (Sigma #T-0440)
Compound Dilution/Cell Plating:
Drug Plate Preparation (Mother Plate)
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.
Control Drugs
Drug and Cell Addition:
The process for each plate involves:
Prepare cell plates (daughter plates) by adding 52 μl of Elisa media to each well.
In Mother plates, serially transfer 50 μl/well from column 3 through column 12.
Transfer 8 μl from mother plate to daughter plates (all 96 wells).
Place daughter plates in incubator until cells are prepared.
Harvest Clone A cells and plate directly into daughter plates at 0.7×105 cells/ml, 100 μl/well.
All plates are incubated at 37° C. in 5% CO2 for 3 days.
Elisa Assay:
Remove media from 96-well plates (cells should be ca 80% confluent) by flicking into sink.
Add 130 μl/well 1×PBS+0.05% glutaraldehyde.
Incubate 37° C. for 1 hour.
Remove by flicking into sink.
Wash 3× with 300 μl/well PBS, shaking 5 min each wash. Remove by flicking into sink.
Add 130 μl/well PBS+0.05% TWEEN-20+0.1% TRITON X-100.
Incubate 37° C. for 10 minutes.
Remove by flicking into sink.
Add 300 μl/well Superblock in PBS.
Incubate 37° C. for 1 hour.
Remove by flicking into sink.
Wash 3× with 300 μl/well PBS, shaking 5 minutes each wash. Remove by flicking into sink.
During last wash, make a 1:100 dilution of NS5a Monoclonal-antibody (Mab) in Superblock+0.02% TWEEN-20.
After last wash, add 50 μl/well diluted Mab.
Incubate 37° C. for 1 hour.
Remove by flicking into sink.
Wash 3× with 300 μl/well PBS+0.02% TWEEN-20, shaking 5 minutes each wash.
Remove by flicking into sink.
During last wash, make a 1:500 dilution of goat antimouse-HRP Mab in Superblock+0.02% TWEEN-20.
After last wash, add 50 μl/well diluted Mab.
Incubate 37° C. for 1 hour.
Remove by flicking into sink.
Wash 5× with 300 μl/well PBS+0.02% TWEEN-20, shaking 5 minutes each wash. Remove by flicking into sink.
Wash 3× with 300 μl/well PBS, shaking 5 minutes each wash. Remove by flicking into sink.
After last wash, add 130 μl/well room temperature TMB substrate.
Incubate until blue color develops.
Add 130 μl/well 1N HCl to stop reaction (color turns from blue to yellow).
Read plates with optical density (O.D.) 450 filter.
ANALYSIS OF RESULTS: IC50 (μM); IC50 (μg/ml); % Inhibition
REFERENCE COMPOUNDS: Interferon-a2; 4–30 U/ml IC50
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
The mixture of Fe powder (9.31 g, 167 mmol) and NH4Cl (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 H2O (3×200 mL) and brine (200 mL), dried (Na2SO4), 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) (CDCl3): 300 MHz δ 6.88 (m, 1H), 6.81 (m, 2H), 3.63 (bs, 2H), 2.09 (s, 3H).
5-Bromo-2-methylphenylhydrazine Hydrochloride
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 SnCl2.2H2O (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 Na2SO4, 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
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 NaHCO3 (2×100 mL) and brine (100 mL), dried (Na2SO4) and concentrated. The residue was dissolved in ethylene glycol (30 mL), treated with ZnCl2 (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 Na2SO4 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 (CDCl3): 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
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 CH2Cl2 (20 mL) was added BF3.OEt2 (0.56 mL, 4.41 mmol) dropwise at room temperature. The solution was stirred for 2 hours and then washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL). The organic phase was dried (Na2SO4) and filtered through a pad of silica gel. The filter cake was washed with additional CH2Cl2 and the combined organic layer was evaporated to provide 1.62 g (93%) of title compound as a white solid. 1H NMR (CDCl3): 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
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 Na2SO4 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 (CDCl3): 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=7.32 Hz, 3H).
5-Cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid
To a solution of 5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]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 Na2SO4 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
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-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 C18H21N2O3 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; tR=6.98 minutes (R enantiomer), 9.37 minutes (S enantiomer).
Alternatively, [(R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[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, >98% e.e.). The mother liquor was concentrated and dissolved again in a mixture of 2-butanone (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, >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. >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 >99%. The mother liquor was concentrated and gave a third crop of 0.5 g with an e.e. of >99%.
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 
To a solution of 1-(R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[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 Na2SO4 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 (CDCl3): 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 C25H27BrN3O2 480.1281, found 480.1285.
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-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)-acetamide
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 (CDCl3): 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 C25H27BrN3O2 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
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 (MgSO4), passed through a plug of SiO2, 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 (CHCl3) δ 3.78 (bs, 2H); 6.65–7.07(m, 3H).
See, Courtin, A. Helv. Chim. Acta. 66, 1, (1983), hereby incorporated by reference.
5-Bromo-2-fluorophenylhydrazine
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>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 (MgSO4), and concentrated. The resultant solid was thoroughly washed with hexanes. The undissolved solid was captured on filter and further washed with hexanes to afford 0.81 g (54% yield) of the desired product as an off-white solid. NMR (CHCl3) δ 5.45 (bs, 1H); 6.80–6.86(m, 2H); 7.25–7.28 (m, 1H).
See, McKittrick, B. et al., J. Heterocyclic Chem. 27, 2151 (1990), hereby incorporated by reference.
4-Bromo-7-fluoro Tryptophol
2,3-Dihydrofuran (2.0 ml, 0.026 mM) was added to a solution of 5-bromo-2-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 (MgSO4), 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.
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 (MgSO4), 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(CHCl3) 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
BF3-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. NaHCO3 (aq) (15 ml) was added to quench the reaction. The solution was washed with DCM (2×). The organic layers were combined, dried (MgSO4), passed through a plug of SiO2, and concentrated to afford 1.02 g (66% yield) of the desired product as an off-white solid. NMR (CHCl3) δ 0.87 (t, 3H, 7.38 Hz); 1.44(m, 1H); 1.28(t, 3H, 7.14 Hz); 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
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 (MgSO4), and concentrated. The product was purified by SiO2 flash chromatography to afford 0.81 g (92% yield) of the desired product as an off-white solid. NMR (d6-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
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<2) concentrated HCl (aq), and washed with ethyl acetate (3×). The organic layers were combined, dried (MgSO4), and concentrated to afford 0.61 g (82% yield) of the desired product as a white solid. NMR (d6-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[3,4-b]indole-1-acetic acid
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).
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, >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 (>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, >99.5% e.e.). Concentration of the mother liquor afforded 2.4 g of (S) acid (98% e.e.).
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
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 (d6-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 C24H23BrFN3O2— 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
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 (Na2SO4) and concentrated. The residue was dissolved in ethylene glycol (60 mL), treated with ZnCl2 (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 Na2SO4 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 (CDCl3): 300 MHz δ 8.35 (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
To a solution of 5,8 dichloro tryptophol (4.25 g, 18.55 mmol) and ethyl butyrylacetate (4.37 mL, 27.63 mmol) in CH2Cl2 (40 mL) was added BF3xOEt2 (3.50 mL, 27.63 mmol) dropwise at room temperature. The solution was stirred for 2 hours and then washed with saturated aqueous NaHCO3 (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 (CDCl3): 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
To a solution of 5,8 dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]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 (CDCl3): 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
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; tR=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]indol-1yl)acetic acid
4-Bromo-3-fluoro-6-nitrotoluene
To a stirred solution of 4-bromo-3-fluorotoluene (10 g, 52.9 mmol) in H2SO4 (100 mL) was added KNO3 (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 (Na2SO4), and concentrated to give 12.35 g (100%) of title compound as a pale yellow oil. 1H NMR (CDCl3): 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
The mixture of iron powder (17.8 g, 318 mmol) and NH4Cl (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 H2O (3×300 mL) and brine (300 mL), dried (Na2SO4), 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 (CDCl3): 300 MHz δ 6.82 (m, 2H), 3.49 (bs, 2H), 2.11 (s, 3H).
5-Bromo-4-fluoro-2-methylphenylhydrazine Hydrochloride
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 SnCl2.2H2O (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 Na2SO4, 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
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 NaHCO3 (2×100 mL) and brine (100 mL), dried (Na2SO4) and concentrated. The residue was dissolved in ethylene glycol (50 mL), treated with ZnCl2 (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 Na2SO4 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 (<20%) as a light brown oil. 1H NMR (CDCl3): 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
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 CH2Cl2 (5 mL) was added BF3.OEt2 (0.22 mL, 1.76 mmol) dropwise at room temperature. The solution was stirred for 2 hours and then washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic phase was dried (Na2SO4) 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 (CDCl3): 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
5-Bromo-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]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 Na2SO4 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
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 Na2SO4 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
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 C18H20FN2O3 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).
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.
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(Ph3P)4 (0.1 eq) and 2M Na2CO3 in dimethoxy ethane as solvent at 65° C. (overnight). The resulting esters were hydrolyzed using 1N (aq.) NaOH in THF/MeOH.
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.
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.
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.
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.
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.
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(Ph3P)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.
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.
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.
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.
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.
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.
Examples 137–139 were synthesized following the above mentioned procedure for example 1 using the intermediate 4,7dimethyltryptophol and reacting with β-ketoesters like methylacetoacetate, ethylpropionyl acetate or ethylbutyryl acetate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.
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.
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(Ph3P)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.
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.
Example 153 was synthesized by hydrolyzing the intermediate 5-bromo-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester in example 1 using 1N (aq) NaOH in THF/MeOH.
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 β-oxo-3-furan propionate. The resulting esters were hydrolyzed using 1N (aq) NaOH in THF/MeOH.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 β-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 
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 H2O (5×200 mL) and brine (200 mL), dried (Na2SO4), and concentrated to give 3.49 g (96%) of title compound as yellow oil. 1H NMR (CDCl3): 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
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 CO2 (dry ice, 100 g) via cannula under N2 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), H2O (200 mL) and brine (200 mL). The organic phase was dried (Na2SO4) 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 (CDCl3): 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
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 H2O (5 mL) and extracted with EtOAc (3×10 mL). The organic solution was washed brine (20 mL), dried (Na2SO4) 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 (CDCl3): 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
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 CH2Cl2 (2 mL) was added BF3.OEt2 (0.11 mL, 0.867 mmol) dropwise at room temperature. After stirring overnight, the solution was diluted with CH2Cl2 (10 mL) and then washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic phase was dried (Na2SO4) 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 (CDCl3): 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
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 Na2SO4 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 C19H25N2O4 345.1809, found 345.1807; 1H NMR (DMSO-d6): 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
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 H2O (0.5 mL) and then 10% NaOH (0.5 mL) was added to the mixture. Na2SO4 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 H2O (5×100 mL) and brine (100 mL), dried (Na2SO4), 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 (CDCl3): 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
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 CO2 (dry ice, 8 g) via cannula under N2 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), H2O (100 mL) and brine (100 mL). The organic phase was dried (Na2SO4) 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 (CDCl3): 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
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 H2O (10 mL) and extracted with EtOAc (3×15 mL). The organic solution was brine washed (30 mL), dried (Na2SO4) 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 (CDCl3): 300 MHz δ 9.38 (s, 1H), 6.77 (m, 2H), 3.86–3.20 (m, 12 H), 2.67 (m, 2H), 1.97–1.15 (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
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 (Na2SO4) 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.
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 H2O (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 (Na2SO4) 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 (CDCl3): 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
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 NaH2PO4 in H2O (0.36 mL of 0.7 M in H2O, 0.255 mmol) at room temperature. To the mixture was added a solution of NaClO2 in H2O (1.52 mL of 0.5 M in H2O, 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 Na2SO4 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 C21H26FN2O5 405.1820, found 405.1821; 1H NMR (DMSO-d6): 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
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 C18H23N2O4 331.39, found 331.10; [M−1]+ calculated for C18H21N2O4 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
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 C20H27N2O4 359.44, found 359.10; [M−1]+ calculated for C20H25N2O4 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
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 H2O (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 (Na2SO4) 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 (CDCl3): 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
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 H2O and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4 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 (CDCl3): 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
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 CH2Cl2 (3 mL) was added BF3.OEt2 (0.11 mL, 0.854 mmol) dropwise at room temperature. After stirring for 3 hours, the mixture was diluted with CH2Cl2 (15 mL) and then washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL). The organic phase was dried (Na2SO4) 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).
(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 Na2SO4 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 (CDCl3): 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
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 Na2SO4 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 C18H20FN2O3 331.36, found 331.10, [M−1]+ calculated for C18H18FN2O 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
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), BF3.Et2O (437 mg, 3.08 mmol) and stirred at room temperature overnight. The solution was then washed with saturated aqueous NaHCO3 and brine. Dried over Na2SO4 and flashed over silica gel (hexane: EtOAc 4:1) to yield white/blue crystals 700 mg (88%).
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]+.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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 C19H20N2O3 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).
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.
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.
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.
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.
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.
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
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 C17H17ClN2O3 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
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 CH2Cl2 (10 mL) was added BF3.OEt2 (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 Na2CO3 (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 Na2SO4, 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
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 Na2SO4, 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 >3:1 ratio. The enriched, separated diastereomers were resubjected to HPLC conditions (isocratic, 5% EtOAc/hexanes) until >10:1 diastereomeric ratio (1H 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
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 Na2SO4, 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. 1H NMR (CDCl3, 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 (m, 1H), 1.29 (dt, J=7 Hz, J=2 Hz, 3H), 1.21–1.08 (m, 1H), 1.05 (d, J=7 Hz, 3H), 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
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 Na2SO4, 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. 1H NMR (CDCl3, 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, 1H), 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]−.
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
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 CH2Cl2 (50 mL) was added BF3.OEt2 (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 Na2CO3 (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 Na2SO4, 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. 1H NMR (CDCl3, 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
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 Na2SO4, 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. 1H NMR (CDCl3, 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
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 Na2SO4, filtered and concentrated to afford 0.8 g (92%) of the mixture of 2 diastereomeric acids as a white solid. 1H NMR (CDCl3, 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]+.
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.
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.
Example 278 was formed as a by-product during the base-mediated saponification of the ester described in example 279.
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.
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.
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.
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
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 C19H22N2O3 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
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 C18H19N2O3 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
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 C19H21FN2O3 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
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 C18H19ClN2O3 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].
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.
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.
Example 330 was synthesized following the above mentioned procedure for example 1 using the intermediate 4-chloro-7-methyltryptophol and reacting with α-ketoesters like ethyl-2oxopentanoate. The resulting ester was hydrolyzed using aqueous NaOH in THF/EtOH.
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.
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.
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.
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.
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.
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.
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.
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.
Example 342 was synthesized following the above mentioned procedure for example 1 using the intermediate 4-bromo-7-fluorotryptophol 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.
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
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).
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 α-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.
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.
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
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 H2SO4 (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. 1H NMR (CDCl3) δ 8.18 (s, 1H), 7.95 (s, 1H), 2.59 (s, 3H).
5-bromo-2-methyl-3-nitrobenzole acid benzyl ester
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 (1 L), 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
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, 47.81 g, 0.857 mol) and NH4Cl (13.88 g, 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 (MgSO4), and concentrated. Upon trituration with hexanes, 63.2 g (92.1%) of an off-white powder was obtained. 1H NMR (CDCl3) 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
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 NaNO2 (8.08 g, 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 −10° C. for 1.5 hours, then a solution of SnCl2.2H2O (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 −10° C. 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 MgSO4, 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. 1H NMR (d6-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
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 (MgSO4), and concentrated. The resulting oil was chromatographed on SiO2, 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. 1H NMR (CDCl3) 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
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, BF3.Et2O (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 NaHCLO3 (2×) and saturated NaCl (1×), dried (MgSO4), and concentrated. The resulting oil was purified by flash chromatography on SiO2 eluting with a 10% EtOAc/hexanes to 20% EtOAc/hexanes gradient. Trituration with hexanes yielded 13.71 g (84.0%) of a white powder. 1H NMR (CDCl3) 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
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 MgSO4, and concentrated. Upon trituration with hexanes, 8.82 g (81.8%) of a light tan solid was obtained. 1H NMR (CDCl3) 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
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 11.11 g (96.4%) of an off-white powder. 1H NMR (CDCl3) 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
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 (Na2SO4) and concentrated in vacuo to afford 25.6 mg (99%) of the title compound as an off-white solid. 1H NMR (d6-DMSO) δ 11.42 (br s,1 H), 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
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% NaHCO3 (2×), water (1×), and brine (1×), dried (Na2SO4), and concentrated in vacuo to afford 37.1 mg (92%) of crude product which was carried on to the next step.
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)+.
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
To a solution of 5-cyano-1-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 BH3.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 NaHCO3, water and brine, dried (MgSO4), and concentrated in vacuo. Purification via flash chromatography on SiO2 using 20% EtOAc/DCM as eluent afforded 8.28 g (77%) of a pale green foam. ESI-MS m/z 369 (M−H)−. 1HNMR (CDCl3) 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
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 MnO2 (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. 1H NMR (CDCl3) 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
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 SeO2 (0.90 g, 6.4 mmol) followed by 30% H2O2 (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 NaHCO3 (2×), water and brine, dried (MgSO4), and concentrated in vacuo to afford a brown foam. ESI-MS m/z 383 (M−H)−, 1H NMR CDCl3 (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).
The residue was dissolved in MeOH (145 mL), and to this was added 10% K2CO3 (aq., 14.5 mL). After stirring for 30 minutes, the reaction was diluted with EtOAc, washed with water (2×) and brine, dried (MgSO4) 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). 1HNMR (CD3OD) 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
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 (Na2SO4), and concentrated in vacuo. Flash chromatography on SiO2 using 5% EtOAc/hexanes as eluent afforded 30.9 mg (67%) of the ester intermediate as a white solid.
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 (Na2SO4), and concentrated in vacuo to afford 28.9 mg (quant.) of the title compound as a white solid. ESI-MS m/z 371 (MH)+. 1H NMR (d6-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
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).
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
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.
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 Na2SO4, 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)−. 1H NMR (CDCl3) 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
To a solution of (R)-[5-cyano-7-hydroxy-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[[3,4-b]indol-1-yl]-acetic acid methyl ester (32 mg, 0.09 mmol) in anhydrous N-methyl-2-pyrrolidinone (2 mL) was added Cs2CO3 (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 Na2SO4, filtered and concentrated to provide the crude ester which was used directly in the next reaction.
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 Na2SO4, 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 (CDCl3) 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-yl ]acetic 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[3,4-b]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 
(1R)-(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-1-yl]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-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid
EXAMPLE 365 
(7-butoxy-5-cyano-8-methyl-1-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-1-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

## Claims

1. A method of treating a Hepatitis C viral infection in a mammal comprising providing the mammal with an effective amount of a compound of a formula:



wherein:
R1 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;
R2 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, or with the proviso that when Y is CH2 or CH2CH2, R2 and Y together form a cycloalkyl of 3 to 8 carbon atoms;
R3—R6 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 R5 and R6 together with the ring carbon atom to which they are attached form a carbonyl group;
R7—R10 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 6 carbon atoms, COOH, COO-alkyl, CONR11R12, F, Cl, Br, I, CN, CF3, NO2, alkylsulfinyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, pyrrolidinyl, or thiazolidinyl;
R11—R12 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;
Y is a bond, CH2, or CH2CH2; or
a crystalline form or a pharmaceutically acceptable salt thereof.

2. A method of treating a Hepatitis C viral infection in a mammal comprising providing the mammal with an effective amount of a compound of a formula:



wherein:
R1 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;
R2 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;
R3—R6 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 R5 and R6 together with the ring carbon atom to which they are attached form a carbonyl group;
R7—R10 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 6 carbon atoms, a carboxy group, CONR11R12, F, Cl, Br, I, CN, CF3, NO2, an alkylsulfinyl of 1 to 6 carbon atoms, an alkylsulfonyl of 1 to 6 carbon atoms;
R11—R12 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;
Y is CH2, or CH2CH2; or
a crystalline form or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 wherein the compound is selected from:
(5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol -1-yl)acetic acid;
[(R)-5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid; and
[(S)-5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid.

4. The method of claim 1 wherein the compound is selected from:
(5-cyano-1-ethyl-6,8-difluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-cyano-6,8-difluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(1-butyl-5-cyano-6,8-difluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[5-cyano-6,8-difluoro-1-(3-furyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(5-cyano-6,8-difluoro-1-isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
5-bromo-6-fluoro-1,8-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-bromo-1-ethyl-6-fluoro-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-bromo-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-bromo-6-fluoro-1-isopropyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-bromo-1-butyl-6-fluoro-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid; and
4-[5-bromo-1-(carboxymethyl)-6-fluoro-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]benzoic acid.

5. The method of claim 1 wherein the compound is selected from:
(5-cyano-8-fluoro-1,6-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-cyano-1-ethyl-8-fluoro-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-cyano-8-fluoro-6-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-cyano-8-fluoro-1-isopropyl-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid; and
{5-cyano-8-fluoro-6-methyl-1-[(3E)-pent-3-enyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetic acid.

6. The method of claim 1 wherein the compound is selected from:
(8-Methyl-5-methylcarbamoyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[8-Methyl-5-(morpholine-4-carbonyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-Carbamoyl-8-Methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-Dimethylcarbamoyl-8-Methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-cyano-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,8-Dichloro-4-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,8-Dichloro-4,4-dimethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(4-Cyclobutyl-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,8-Dichloro-9-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(9-Allyl-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid; and
(9-Benzyl-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid.

7. The method of claim 1 wherein the compound is selected from:
(5,8-Dichloro-4,4-dimethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(4-Cyclobutyl-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,8-Dichloro-9-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(9-Allyl-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(9-Benzyl-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,6-Dichloro-1-cyclobutyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,6-Dichloro-1-cyclopentyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,6-Dichloro-1-methoxymethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[5,6-Dichloro-1-(2-methoxyethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
[5,6-Dichloro-1-(3,3,3-trifluoropropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(6,7-Dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(6,7-Dichloro-1-ethoxymethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,8-Dichloro-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,8-Dichloro-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[5,8-Dichloro-1-(3-cyanopropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[5,8-Dichloro-1-(3,3,3-trifluoropropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(5,8-Dichloro-1-methoxymethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[5,8-Dichloro-1-(2-methoxyethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(5,8-Dichloro-1-ethoxymethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,8-Dichloro-1-methylthiomethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,8-Dichloro-1-ethylthiomethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[5,8-Dichloro-1-(3-butenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(5,8-Dichloro-1-cyclopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid
(5,8-Dichloro-1-cyclobutyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,8-Dichloro-1-cyclopentyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,8-Dichloro-1-cyclohexyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[5,8-Dichloro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(5,8-Dichloro-1-cyclopropylmethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,8-Dichloro-1-cyclopentylmethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-Chloro-1-cyclobutyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-Chloro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(1R*,10S)-[5-Chloro-8-methyl -1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(8-Chloro-5-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[8-Chloro-5-trifluoromethyl-1-(3,3,3-trifluoropropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(8-Chloro-1-methoxymethyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[8-Chloro-1-(2-methoxyethyl)-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(8-Chloro-1-ethoxymethyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(8-Chloro-1-cyclobutyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(8-Fluoro-1-propyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid
(1-Cyclobutyl-8-fluoro-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(1-Cyclopentyl-8-fluoro-5-trifluoromethyl -1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[5,8-bis(trifluoromethyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(8-Methyl-1-propyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(8-Methyl-1-butyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(1-Cyclopropyl-8-methyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(1-Cyclobutyl-8-methyl-5-trifluoromethyl -1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(8-Cyano-1-propyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(8-Cyano-1-cyclobutyl-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(1R*,10S)-[8-Aminocarbonyl-1-(1-methylpropyl)-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(1R*,10S)-[8-Cyano-1-(1-methylpropyl)-5-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
[5-Cyano-8-methyl-1-(3,3,3-trifluoropropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(5-Cyano-1-methoxymethyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-Cyano-1-methylthiomethyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-Cyano-1-cyclopropyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-Cyano-1-cyclobutyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(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;
(5-Cyano-1-cyclopentyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-Cyano-1-cyclopentylmethyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(1R*,10S*)-[5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(1R*,10S*)-[5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(1R*,10S)-[5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-y1]acetic acid;
(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;
[5-Cyano-1-(1-ethylethyl)-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(5-Cyano-8-ethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(1-Butyl-5-cyano-8-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[5-Cyano-8-( 1-methylethyl)-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(8-Methyl-5-nitro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(1-Cyclobutyl-8-methyl-5-nitro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(1R*,10S)-[8-Methyl-1-(1-methylpropyl)-5-nitro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
[5-Cyano-8-fluoro-1-(3,3,3-trifluoropropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
[1-(3-butenyl)-5-cyano-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(5-Cyano-8-fluoro-1-methoxymethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[5-Cyano-8-fluoro-1-(2-methoxyethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(5-Cyano-8-fluoro-1-methylthiomethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-Cyano-1-cyclopropyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-Cyano-1-cyclobutyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-Cyano-1-cyclopentyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-Cyano-1-cyclohexyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5-Cyano-1-cyclopentylmethyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[5-Cyano-1-(1-ethylethyl)-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(1R*,10R*)-[5-Cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(1R*,10S*)-[5-Cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(1R*,10S)-[5-Cyano-8-fluoro-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(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;
(5-Cyano-1-cyclobutyl-6-fluoro-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(1R*,10S)-[5-Cyano-6-fluoro-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(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;
(8-Chloro-5-cyano-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(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;
(1R*,10S)-[8-Chloro-5-cyano-1-(1-methylethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(1R,10S)-[8-Chloro-5-cyano-1-(1-methylethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(1S,10S)-[8-Chloro-5-cyano-1-(1-methylethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
(8-Chloro-5-cyano-1-cyclobutyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
(5,6-Dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid; and
(5,8-Dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid.

8. The method of claim 1 wherein the compound is selected from:
(5,6-Dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(5,8-Dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(5-Chloro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
8-Chloro-5-trifluoromethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(8-Fluoro-5-trifluoromethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(5-Trifluoromethyl-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(5-Cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(1R*,10S*)-[5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]carboxylic acid;
(1R*,10S*)-[5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]carboxylic acid;
[5-Cyano-8-methyl-1-(3-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]carboxylic acid;
(5-Cyano-1-cyclobutyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(5-Cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(5-Cyano-8-ethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(8-Chloro-5-cyano-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(5-Cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(1R)-(5-Cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(1S)-(5-Cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(1-Butyl-5-cyano-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
[1-(3-Butenyl)-5-cyano-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]carboxylic acid;
[5-Cyano-8-fluoro-1-(3-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]carboxylic acid;
(1R*,10S*)-[5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]carboxylic acid;
(1R*,10S*)-[5-Cyano-8-methyl-1-(1-methylpropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]carboxylic acid;
(5-Cyano-1-cyclopentyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(5-Cyano-1-cyclohexyl-8-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
(8-Fluoro-5-nitro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)carboxylic acid;
1-carboxymethyl-5-cyano-8-methyl-1-propyl-1,3,4,9 tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid;
(5-cyano-8-methyl-1-propyl-7-propylcarbamoyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid;
(5-cyano-7-isopropylcarbamoyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid;
[5-cyano-7-
(4,4-dimethyl-butylcarbamoyl)-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-acetic acid;
(5-cyano-8-methyl-7-methylcarbamoyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid;
(5-cyano-8-methyl-7-dimethylcarbamoyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid;
(5-cyano-8-methyl-7-propoxy-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid;
(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;
(5-cyano-7-ethoxy-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid;
(5-cyano-7-methoxy-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid;
(5-cyano-7-isopropoxy-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid;
(7-butoxy-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid;
[5-cyano-7-(3,3-dimethyl-butoxy)-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b)indol-1-yl]-acetic acid;
[5-cyano-7-(3-fluoro-benzyloxy)-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-acetic acid;
(7-benzyloxy-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid;
[5-cyano-7-(2-fluoro-ethoxy)-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-acetic acid; and
[5-cyano-7-(3-fluoro-propoxy)-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-acetic acid.

9. The method of claim 1 wherein R21 is n-propyl, (S)-sec-butyl, or cyclobutyl.

10. The method of claim 1 wherein the compound of the formula has a ratio of Isomer A to Isomer B of greater than 1:1.

11. The method of claim 1 wherein the compound of the formula is 100% Isomer A.

12. The method of claim 1 wherein the compound of the formula has a ratio of Isomer A to Isomer B of at least 9:1.

13. The method of claim 1 wherein the compound of the formula has a ratio of Isomer A to Isomer B of at least 8:1.

14. The method of claim 1 wherein the compound of the formula has a ratio of Isomer A to Isomer B of at least 7:1.

15. The method of claim 1 comprising a compound of a formula:



wherein:
R1 is H;
R2 is H, or a straight chain alkyl of 1 to 4 carbon atoms;
R3—R6 are H;
R7—R10 are independently H, a straight chain alkyl of 1 to 3 carbon, F, Cl, or CN;
Y is CH2; or
a crystalline form or a pharmaceutically acceptable salt thereof.

16. The method of claim 15 wherein the compound is selected from:
[(R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
[(R)-5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
[(R)-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid; and
[(R)-5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid.

17. A method of inhibiting replication of a Hepatitis C virus comprising contacting the Hepatitis C virus with a compound of a formula:



wherein:
R1 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;
R2 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, or with the proviso that when Y is CH2 or CH2CH2, R2 and Y together form a cycloalkyl of 3 to 8 carbon atoms;
R3—R6 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 R5 and R6 together with the ring carbon atom to which they are attached form a carbonyl group;
R7—R10 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, CONR11R12, F, Cl, Br, I, CN, CF3, NO2, alkylsulfinyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, pyrrolidinyl, or thiazolidinyl;
R11—R12 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;
Y is a bond, CH2, or CH2CH2; or
a crystalline form or a pharmaceutically acceptable salt thereof.

18. A method of inhibiting replication of a Hepatitis C virus comprising contacting the Hepatitis C virus with a compound of a formula:



wherein:
R1 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;
R2 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;
R3—R6 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 R5 and R6 together with the ring carbon atom to which they are attached form a carbonyl group;
R7—R10 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 6 carbon atoms, a carboxy group, CONR11R12, F, Cl, Br, I, CN, CF3, NO2, an alkylsulfinyl of 1 to 6 carbon atoms, an alkylsulfonyl of 1 to 6 carbon atoms;
R11—R12 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;
Y is CH2, or CH2CH2; or
a crystalline form or a pharmaceutically acceptable salt thereof.

19. The method of claim 17 wherein the compound is selected from:
(5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid;
[(R)-5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid; and
[(S)-5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid.

20. The method of claim 17 wherein R1 is n-propyl, (S)-sec-butyl, or cyclobutyl.

21. The method of claim 17 wherein the compound of the formula has a ratio of R-enantiomer to S-enantiomer of greater than 1:1.

22. The method of claim 17 wherein the compound of the formula is 100% R-enantiomer.

23. The method of claim 17 wherein the compound of the formula has a ratio of R-enantiomer to S-enantiomer of at least 9:1.

24. The method of claim 17 wherein the compound of the formula has a ratio of R-enantiomer to S-enantiomer of at least 8:1.

25. The method of claim 17 wherein the compound of the formula has a ratio of R-enantiomer to S-enantiomer of at least 7:1.

26. The method of claim 17 comprising a compound of the formula:



wherein
R1 is H;
R2 is H, a straight chain alkyl of 1 to 4 carbon atoms, or a sec-butyl;
R3—R6are H;
R7—R10 are independently H, a straight chain alkyl of 1 to 3 carbon, F, Cl, or CN;
Y is CH2; or
a crystalline form or a pharmaceutically acceptable salt thereof.

27. The method of claim 26 wherein the compound is selected from:
[(R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
[(R)-5-cyano-8-fluoro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid;
[(R)-5,8-dichloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid; and
[(R)-5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl]acetic acid.

28. A method of treating 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:



wherein:
R1 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;
R2 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;
R3—R6 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 R5 and R6 together with the ring carbon atom to which they are attached form a carbonyl group;
R7—R10 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, CONR11R12, F, Cl, Br, I, CN, CF3, NO2, alkylsulfinyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, pyrrolidinyl, or thiazolidinyl;
R11—R12 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;
Y is a bond, CH2, or CH2CH2; and
a pharmaceutically acceptable carrier.

29. The method of claim 28, further comprising providing the mammal with an effective amount of at least one biologically active agent.

30. The method of claim 29, wherein 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.

31. The method of claim 28, 29 or 30, wherein the compound is a crystalline form or a pharmaceutically acceptable salt thereof.

32. The method of claim 29, wherein 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.

33. The method of claim 32, wherein the at least one biologically active agent is a pegylated interferon.

34. The method of claim 33, wherein 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.

35. A method of treating 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:



wherein:
R1 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;
R2 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;
R3—R6 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 R5 and R6 together with the ring carbon atom to which they are attached form a carbonyl group;
R7—R10 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, CONR11R12, F, CI, Br, I, CN, CF3, NO2, an alkylsulfinyl of 1 to 6 carbon atoms, an alkylsulfonyl of 1 to 6 carbon atoms;
R11—R12 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;
Y is CH2, or CH2CH2; and
a pharmaceutically acceptable carrier.

36. The method of claim 35, further comprising providing the mammal with an effective amount of at least one biologically active agent.

37. The method of claim 36, wherein 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.

38. The method of claim 35, 36 or 37, wherein the compound is a crystalline form or a pharmaceutically acceptable salt thereof.

39. The method of claim 36, wherein 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.

40. The method of claim 39, wherein the at least one biologically active agent is a pegylated interferon.

41. The method of claim 40, wherein 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.

42. A method of treating 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



wherein:
R1 is H;
R2 is H, or a straight chain alkyl of 1 to 4 carbon atoms;
R3—R6are H;
R7—R10 are independently H, a straight chain alkyl of 1 to 3 carbon, F, Cl, or CN;
Y is CH2; and
a pharmaceutically acceptable carrier.

43. The method of claim 42, further comprising providing the mammal with an affective amount of at least one biologically active agent.

44. The method of claim 43, wherein 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.

45. The method of claims 42, 43 or 44, wherein the compound is a crystalline form or a pharmaceutically acceptable salt thereof.

46. The method of claim 43, wherein 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, immunoglobulin, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-infective compounds.

47. The method of claim 46, wherein the at least one biologically active agent is a pegylated interferon.

48. The method of claim 47, wherein 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.

49. 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:



wherein:
R1 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;
R2 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;
R3—R6 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 R5 and R6 together with the ring carbon atom to which they are attached form a carbonyl group;
R7—R10 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, CONR11R12, F, Cl, Br, I, CN, CF3, NO2, alkylsulfinyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, pyrrolidinyl, or thiazolidinyl;
R11—R12 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;
Y is a bond, CH2, or CH2CH2; and
a pharmaceutically acceptable carrier.

50. The method of claim 49, further comprising contacting the Hepatitis C virus with an affective amount of at least one biologically active agent.

51. The method of claim 50, wherein 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.

52. The method of claims 49, 50 or 51, wherein the compound is a crystalline form or a pharmaceutically acceptable salt thereof.

53. The method of claim 50, wherein 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, immunoglobulin, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-infective compounds.

54. The method of claim 53, wherein the at least one biologically active agent is a pegylated interferon.

55. The method of claim 54, wherein 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.

56. 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:



wherein:
R1 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;
R2 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;
R3—R6 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 R5 and R6 together with the ring carbon atom to which they are attached form a carbonyl group;
R7—R10 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, CONR11R12, F, Cl, Br, I, CN, CF3, NO2, an alkylsulfinyl of 1 to 6 carbon atoms, an alkylsulfonyl of 1 to 6 carbon atoms;
R11—R12 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;
Y is CH2, or CH2CH2; and
a pharmaceutically acceptable carrier.

57. The method of claim 56, further comprising contacting the Hepatitis C virus with an affective amount of at least one biologically active agent.

58. The method of claim 57, wherein the at least one biologically active agent is provided prior to the at leat one pharmaceutical composition, concurrently with the at least one pharmaceutical composition or after the at least one pharmaceutical composition.

59. The method of claims 56, 57 or 58, wherein the compound is a crystalline form or a pharmaceutically acceptable salt thereof.

60. The method of claim 57, wherein 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.

61. The method of claim 60, wherein the at least one biologically active agent is a pegylated interferon.

62. The method of claim 61, wherein 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.