MXPA06003756A - Indole derivatives - Google Patents

Abstract

Provided herein are indole derivatives, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.

Description

- to amend claims before expiration For two-letter codes and other abbreviations consult the time limit and before re-publication in case of receiving such amendments the notes "Guidelines on Codes and Abbreviations" that appear at the beginning of the PCT Gazette. (88) Date of publication of the international search report: June 30, 2005 INDOL DERIVATIVES This application claims priority to the provisional application in the USA. No. 60 / 508,592, filed on October 2, 2003, as well as the provisional application in the US. No. 60 / 556,599, filed March 26, 2004, which are incorporated herein by reference. Field of the Invention This invention relates to antineoplastic, antiinflammatory and analgesic indole derivatives, pharmaceutical compositions containing them, methods of use and methods of preparing these compounds. Background of the Invention Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat inflammation, pain, and chronic and acute inflammatory disorders, for example, osteoarthritis and rheumatoid arthritis. It is believed that these compounds work by inhibiting cyclooxygenase (COX) enzyme, which is also known as prostaglandin G / H synthase. COX catalyzes the conversion of arachidonic acid to prostaglandins. Several forms of COX enzymes have been reported. These include a constitutive form known as COX-1, an inducible form known as COX-2 and the newly discovered COX-3, a variant of COX-1 that is made through acetaminophen. COX-2 is inducible through mitogens, endotoxins, hormones, tumor promoters, and growth factors. COX-1 is responsible for the endogenous release of prostaglandins important for the maintenance of gastrointestinal integrity and blood flow in the kidneys. It is believed that the various side effects associated with NSAI D are due to the inhibition of COX-1. Because of this, the selective compounds for COX-2 have been developed and marketed. However, it has been reported that COX-2 inhibitors cause dyspepsia, gastropathy and cardiovascular problems. NSAI D have also been used for the prevention and treatment of cancer. The mechanism by which NSAI D functions in the prevention and treatment of cancer can be related to the over expression of COX. For example, some studies indicate a link between COX expression and carcinogenesis. For example, it is reported that cell lines that overexpress COX-2 are resistant to apoptosis, have an increased invasive capacity as well as an increased potential for angiogenesis. In addition, studies indicate that increased amounts of prostaglandins and COX-2 are commonly found in premalignant tissues as well as in your malignant mores.

Researchers have reported that COX-2 regulates various types of cancer in humans, including cancers of the colon, pancreas and breast. Other studies have reported that the chemoprotective and antineoplastic properties of NSAIDs can be presented in a mechanism independent of COX. For example, R-flurbiprofen is a chemopreventive agent in the mouse model of intestinal polyposis and prostate cancer, although it does not have COX inhibition activity. Similarly, sulfone sulindac, a metabolite of NSAID sulindac, inhibits azoxy-methane-induced colon tumors in rats, even though it does not have COX inhibition activity. Additionally, NSAIDs can induce apoptosis in cancer cells that do not express COX-2 (Baek et al., 2001 Mol.Pharmacol. 59: 901-908). The authors of these studies report that the chemoprotective and antineoplastic effects of NSAIDs are presented through COX-independent and COX-independent mechanisms. Β-catenin (also known as cadherin-associated protein) is a proto-oncogene path in the direction of the 3 'end of the "wingless / frizzled" (wnt / fzd) signaling path (wingless / coiled). The alterations in the pathways involved in the regulation of β-catenin are associated in the pathogenesis of many cancers in humans, including colorectal, desmoid fibroma (aggressive fibromatosis), endometrial, hepatocellular, leukemia, renal, medulloblastoma, melanoma, ovarian, pancreatic, prosthetic, thyroid and uterine (Polakis, 2000 Genes Dev. 14: 1837-1851; Chung er al. 2002 Blood 100: 982-990). It is reported that β-catenin exists in at least three forms: attached to the membranes (complex adhesions), cytosolic and nuclear. The nuclear accumulation of β-catenin, in conjunction with the TCF / LEF proteins, induces genes towards the 3 'end, including many genes involved in the generation of tumors, for example, cyclin D1 and c-myc. The literature also reports that ß-catenin is involved in the genetic regulation of the androgen receptor, providing evidence of a role for Wnt / ß-catenin-pathway TCF for neoplastic and normal growth of the prostate (Amir et al., 2003 , J. Biol. Chem. 278: 30828-30834). The literature reports in the same way that ß-catenin can improve COX-2 (Okamura er al., 2003, Cancer Res. 63: 728-34). It is reported that β-catenin levels are regulated post-translationally by the signaling path Wnt / fzd. In the absence of a Wnt signal, ß-catenins not bound to the adheins are labeled to be degraded by a complex of ß-catenin-binding proteins including glycogen synthase kinase-3β (GSK-3β), polyposis adenomatous protein coli (APC) and axina. This complex facilitates the phosphorylation of β-catenin by GSK-3β and the subsequent rapid degradation of β-catenin through the degradation of the proteasome. The transfer of Wnts to its receptors causes the disruption of the β-catenin complex and the inhibition of β-catenin degradation. This causes the accumulation of β-catenin in the cytoplasm and in the nucleus, where it interacts with TCF / LEF proteins to regulate gene expression. It has been reported that mutations in APC, β-catenin or axin increase the nuclear accumulation of β-catenin in cancers of epithelial origin. The accumulation of β-catenin in the cytoplasm and in the nucleus is reported in tumors with or without mutations in β-catenin. In colorectal cancers, APC has a measurement in 80% of all cases. In cases where there are no mutations in APC, β-catenin mutations are found in 50% of cases. It is reported that the accumulation of β-catenin occurs in a high percentage of cases in hepatoblastomas, au nq ue ß-catenin presents a mutation in only 34% of the samples (Blaker er a /., 1999 Genes Ch romosomes Cancer 25: 399-402). In hepatocellular carcinomas, the accumulation of β-catenin is the result of ß-catenin mutations or axiom mutations, and in rare cases due to APC mutations. Forty-two percent of anaplastic thyroid samples demonstrate a nuclear accumulation of β-catenin. Additionally, it has been reported that this high accumulation is correlated with a decrease in the survival rate (Garcia-Rostan et al., 1999, Cancer Res.59: 1811-5). Rubinfeld et al. reported abnormal regulation of β-catenin in 30% of melanoma cell lines (1997 Science 275: 1790-2). It is reported that the uterine endometrium is associated with the accumulation of β-catenin both in the samples containing ß-catenin mutations and in the samples without ß-catenin mutations (Fukuchi et al 1998 Cancer Res. 58: 3526-3528 ). Iwao et al. It reports that 63% of bone and soft tissue tumors that have a lack of specific β-catenin mutations continue to show the accumulation of β-catenin (1999 Jpn J. Cancer Res. 90: 205-209). Lin et al. reported that immunohistochemical analysis of cyclin D1 and β-catenin in breast tumors indicate that of 53 positive samples for cyclin D1, 49 of them were also positive for β-catenin observing β-catenin in both the nucleus and the cytoplasm (2000 Proc. Nati, Acad. Sci. USA 97: 4262-4266). A relationship between β-catenin and cyclin D1 has been reported for colon cancer and hepatocellular carcinoma (Tetsue et al., 1999 Nature 398: 422-426, Ueta et al., 2002 Oncology Reports 9: 1197-1203). It has been reported that Cyclin D1 is involved in the pathogenesis of squamous cell carcinoma (Xu et al.1994 I nt J. Cancer 59: 383-387). It has been reported that NSAI D affect the activity of β-catenin. For example, it has been reported that both aspirin and indomethacin in h iben transcription of β-catenin / TCF target cyclin D 1 (Dihlman nd al 2001 Oncogene 20: 645-53). It has been reported that Sulindac decreases ß-catenin in the intestinal lesions of Min / + mice (McEntee et al., 1999 Carcinogenesis 20: 635-640). Noda I went to. , reports that etodolac increases expression and accumulation in the cytoplasm of the cytoplasmic E-cadherin in Caco2 cells, but does not present quantitative changes in the expression of β-catenin (2002 J. Gastorenterol .37 (11): 896-904). It is reported that receptors activated by peroxisome proliferators (PPAR) are nuclear hormonal receptors that are involved in several cellular processes, including lipid metabolism and disease-related processes. PPARs form dimers with a retinoid-X receptor and regulate their effects after ligand binding through genetic transcription. To date, three isoforms of PPAR, a and y d, are known. PPARa has high expression in the liver and is reported to stimulate lipid metabolism. PPARy has a high expression in adipose tissue and is reported to be involved in the activation of adipogenesis. It is reported that PPARy is involved in insulin resistance and in various neoplastic processes, including colorectal cancer. Shimada I went to. They hypothesize that activation of PPARγ signaling may com-ment the dysregulated expression of c-myc in APC cells with mutations (2002 Gut 50: 658-664). Ohta, al. report that a PPARγ ligand can cause a change in β-catenin from the nucleus to the cytoplasm, as well as the induction of differentiation in pancreatic cancer cells (2002 I nt J. Oncol 21: 37-42 ). PPARd is expressed in various tissues and organs, and its major expression is in the brain, colon and skin. Researchers have involved PPARd in cholesterol effusion, colon cancer, embryo implantation, preadipocyte proliferation and epidermal maturation. Researchers report that PPARd is a target toward the 3 'end of the transcription complex of β-catenin / TCF-4 (He et al., 1 999 Cel l 99: 335-345). Equally, mRNA of PPARd is reported to be over expressed in many colorectal cancers. It has been reported that NSAI D activates PPAR receptors (Lehmann et al.1997 J Biol. Chem. 272: 3406-341 0). Researchers have also reported that NSAI D can inhibit PPARd, which may contribute to the chemoprotective effects of NSAIDs in the prevention of colorectal cancers (He et al., 1999). Epidemiological studies indicate that NSAIDs can reduce or prevent the occurrence of Alzheimer's disease. A connection between the COX path and Alzheimer's disease has been reported and is based mainly on epidemiological studies. Studies indicate that Cox-2 is sensitized in brain areas related to memory (Hinz et al., 2002 J Pharm. Exp. Ther. 300: 367-375). Weggen I went to. It reports that some NSAIDs can reduce the pathogenic β-amyloid β peptide, Aβ42, by 80% (2001 Nature 414: 212-216). It has been reported that this reduction occurs in a COX-independent mechanism (Eriksen et al., 2002 J. Clinical Invest., 112: 440-449). Eriksen has also reported that flurbiprofen and its enantiomers decrease Aß42 by targeting the β-secretase complex that produces Aβ from the β-amyloid protein precursor. U.S. Pat. No. 6,255,347 describes the use of R-ibuprofen for the treatment or prevention of Alzheimer's disease. Analogs of etodolac are known in the art, see, for example, U.S. Pat. Nos. 5,830,911; 5,824,699; 5,776,967; 5,420,289; 4,748,252; 4,686,213; 4,070,371; 3,939,178; and 3,843,681. The use of etodolac and etodolac enantiomers to treat cancer is described in U.S. Pat. Nos. 6,573,292; 6,545,034; and 5,955,504. The use of NSAIDs to treat inflammation, cancer and angiogenesis has been reported in the art, see, for example, U.S. Pat. Nos. 5,972,986; 6,025,353; 5,955,504; and 5,561,151. Summary of the Invention The compounds of Formula I, the pharmaceutical compositions containing them, and the methods for using them are provided herein: Formula I where: (a) X is C, S or O; (b) R-i is hydrogen; halogen; -CN; -OH; -SH; -N02 or a substituted or unsubstituted portion selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl; wherein the substituted groups are substituted with ono, two or three substituents each independently selected from the group consisting of: halogens, -CN, -N02, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl and - (CH 2) ZCN, wherein z is an integer from 0 to 6; (c) R2, R3, R4 and R5 are each independently hydrogen; halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl and heteroaryl; (d) R6, R7, Re and R9 are each independently hydrogen; halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from alkylene, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein at least one of R6, R7, Rs and R9 is an unsubstituted or substituted portion selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkenyl, and alkynyl; (e) R10 is hydrogen; or an unsubstituted or unsubstituted portion selected from lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl; (f) Y is an unsubstituted or substituted portion selected from alkyl, alkenyl and alkynyl; and (g) Z is a portion selected from -OH, -NH2, -SH, -S02OH, -S (0) H, -OCO (0) NH2, -S02NH2, -NHC (0) H, C (0) NH2, unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; wherein Ri and Y can form one or more rings to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group; or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof. In some embodiments, the groups substituted on R2, R3, R, R5, R6, R7, Rs, R9 and R10 of Formula I are substituted with one, two or three suitable substituents, each independently selected from the group consisting of in: halogens, groups = 0, = S, -CN, -N02, alkyl, alkenyl, heteroaryl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) ZCN where z is an integer from 0 to 6 , = NH, -NHOH, -OH, -C (0) H, -OC (0) H, -C (0) OH, -OC (0) OH, -OC (0) OC (0) H, - OOH, -C (NH) NH2, -NHC (NH) NH2I- C (S) NH2, -NHC (S) NH2, -NHC (0) NH2, -S (02) H, -S (0) H, -NH2, -C (0) NH2, -OC (0) NH2, -NHC (0) H, -NHC (0) OH, -C (0) NHC (0) H, -OS (02) H, - OS (0) H, -OSH, -SC (0) H, -S (0) C (0) OH, -S02C (0) 0H, -NHSH, -NHS (0) H, -NHS02H, -C ( 0) SH, -C (0) S (0) H, -C (0) S (02) H, -C (S) H, -C (S) OH, -C (SO) OH, -C ( S02) OH, -NHC (S) H, -OC (S) H, -OC (S) OH, -0C (S02) H, -S (02) NH2, -S (0) NH2, -SNH2, - NHCS (02) H, -NHC (SO) H, -NHC (S) H, and -SH unsubstituted or substituted with one, two or three suitable substituents selected i independently of the group consisting of halogens, = 0, -N02, -CN, -OH, -SH, - (CH2) Z-CN wherein z is an integer from 0 to 6, -ORc, -NRcORc, -NRcRc, -C (0) NRc, -C (0) ORc, -C (0) Rc, -NRcC (0) NRcRc, -NRcC (0) Rc, -OC (0) ORc, OC (0) NRCRc, -SRc, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls and unsubstituted heteroaryls, wherein Rc is hydrogen , unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together form one or more rings to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group. In other embodiments, the groups substituted on R2, R3, R4, Rs, Re, R7, Rs, R9 and R10 of Formula I are substituted with one, two or three suitable substituents, each independently selected from the group consisting of in: halogens, groups = 0, = S, -CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) zCN where z is an integer from 0 to 6 , = NH, -OH, -C (0) H, -OC (0) H, -C (0) OH, -OC (0) OH, -C (NH) NH2, -NHC (0) NH2, - S (0) H, -NH 2, -C (0) NH 2, -OC (0) NH 2, -NHC (0) H, -NHC (0) OH, -C (S) H, and -SH unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, = 0, -N02.-CN, -OH, -SH, - (CH2) z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls idos, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls. The compounds of Formula I, pharmaceutical compositions comprising them and methods for using them are provided herein, wherein X is S or O; R ^ is hydrogen; or an unsubstituted portion selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl; R2, R3, R4, and R5 are each independently hydrogen; or an unsubstituted portion selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl; R6, R7, Rs, and R9 are each independently hydrogen or an unsubstituted or substituted portion selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein at least one, but not more than two, of R6, R7, Rs, and R9 is an unsubstituted or substituted portion selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkenyl, and alkynyl; and R10 is hydrogen; or an unsubstituted portion selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, benzyl, heteroaryl, heterocycloalkyl, and cycloalkyl. The compounds of Formula I, pharmaceutical compositions comprising them and methods for using them are provided herein, wherein X is O; R-i is an unsubstituted alkyl group or an unsubstituted aryl group; R2, R3, R4, and R5 are each hydrogen; R7 is an unsubstituted or substituted portion selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and R10 is hydrogen. In some embodiments, R9 is an unsubstituted alkyl group. In other embodiments, Y is an unsubstituted alkyl group. In other embodiments Z is hydroxyl. In other embodiments, R is an aryl or heteroaryl group unsubstituted or substituted by one, two or three suitable substituents independently selected from the group consisting of: halogens, groups = 0, = S, -CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) zCN, wherein z is an integer from 0 to 6, = NH, -OH, -C (0) H, -OC (0 ) H, -C (0) OH, -OC (0) OH, -C (NH) NH2, -NHC (0) NH2, -S (0) H, -NH2, -C (0) NH2, -OC (0) NH2, -NHC (0) H, -NHC (0) OH, -C (S) H, and -SH not substituted or substituted with one, two or three suitable substituents each independently selected from the group that consists of halogens, = 0, -N02, -CN, -OH, -SH, - (CH2) z-CN, wherein z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyl, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls two and unsubstituted heteroaryls. The compounds of Formula I, pharmaceutical compositions comprising them and methods for using them are provided herein, wherein X is O; R i is an unsubstituted lower alkyl group or an unsubstituted aryl group; R2, R3, R4, and R5 are each hydrogen; R9 is an unsubstituted or substituted portion selected from alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; and R10 is hydrogen. In some embodiments, R7 is an unsubstituted lower alkyl group. In other embodiments, Y is an unsubstituted lower alkyl group. In other embodiments, Z is hydroxyl. In still other embodiments, R7 is an aryl or heteroaryl group unsubstituted or substituted with one, two or three suitable substituents selected independently from the group consisting of: halogens, groups = 0, = S, -CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) zCN wherein z is an integer from 0 to 6, = NH, -OH, -C (0) H, -OC ( 0) H, -C (0) OH, -OC (0) OH, -C (NH) NH2, -NHC (0) NH2, -S (0) H, -NH2, -C (0) NH2, - OC (0) NH2, -NHC (0) H, -NHC (0) OH, -C (S) H, and -SH are unsubstituted or substituted with one, two or three suitable substituents each selected independently from the group consisting of halogens, = 0, -N02.-CN, -OH, -SH, - (CH2) z-CN wherein z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls two, and unsubstituted heteroaryls. The compounds of Formula I, the pharmaceutical compositions containing them, and the methods for using them are provided herein, wherein X is O; R-i is a non-substituted portion selected from aryl, alkyl, and lower alkoxy; R2, R3, R4, and R5 each is hydrogen; R6 and R8 each is hydrogen or halogen; R7 is an unsubstituted or substituted portion selected from aryl and heteroaryl; R9 is selected from halogen; unsubstituted alkyl; and an unsubstituted or substituted portion selected from aryl, heteroaryl, cycloalkyl, alkenyl, and alkynyl; and R10 is hydrogen; wherein the substituted groups on R7 and R9 are substituted with one, two or three suitable substituents independently selected from the group consisting of: halogens, groups = 0, = S, -CN, -N0, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) zCN where z is an integer from 0 to 6, = NH, -OH, -C (0) H, -OC (0) H, -C (0) OH, -OC (0) OH, -C (NH) NH2, -NHC (0) NH2, -S (0) H, -NH2, -C (0) NH2, -OC (0) NH2, -NHC (0) H, -NHC (0) OH, -C (S) H, and -SH not substituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, = 0, -N02, -CN, -OH, -SH, - (CH2) z-CN, wherein z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, haloalkyls unsubstituted, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and heteroaryl unsubstituted uidos In some embodiments, Y is an unsubstituted lower alkyl group. In other embodiments Z is hydroxyl. Also provided herein are compounds of Formula I, pharmaceutical compositions comprising one or more compounds of Formula I, and methods for using them, wherein: Formula I (a) X is C, S or O; (b) R-] is hydrogen; halogen; -CN; -OH; -SH; -N02 or a substituted or unsubstituted portion selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl; wherein the substituted groups are substituted with ono, two or three substituents each independently selected from the group consisting of: halogens, -CN, -OH, -SH, -N02, unsubstituted alkyl, unsubstituted alkenyl, heteroalkyl, substituted, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl, and - (CH 2) z CN, wherein z is an integer from 0 to 6; (c) R2, R3, R4 and R5 are each independently hydrogen; halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl and heteroaryl; (d) R6, R8, R9 are each independently hydrogen; halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; (e) R7 is hydrogen; halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from alkyl, alkenyl, and alkynyl. (f) River is hydrogen; or an unsubstituted or unsubstituted portion selected from lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl; (g) Y is an unsubstituted or substituted portion selected from alkyl, alkenyl, and alkynyl; wherein the substituted portion is substituted with one, two or three substituents each independently selected from halogen; -CN; -OH; -SH; -N02; unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls; and (h) Z is a portion selected from -OH, -NH2, -SH, -OC (0) NH2, -S (0) 2NH2, -S02OH, -S (0) H, -NHC (0) H, C (0) NH2, unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; wherein R, and Y can form one or more rings to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group; and at least one of R6, R7, R8 and R9 is not hydrogen; or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof. In some embodiments, the IC50 of the compound is greater than 50 μM at least for one of COX-1 or COX-2. In other embodiments, the IC50 of the compound is greater than about 100 μM for at least one of COX-1 or COX-2. In still other embodiments, the IC50 of the compound is greater than about 200 μM for at least one of COX-1 or COX-2. In other embodiments, the IC 50 of the compound is greater than about 50 μM for both COX-1 and COX-2. In other embodiments, the IC 50 of the compound is greater than about 100 μM for both COX-1 and COX-2. In still other embodiments, the IC50 of the compound is greater than about 200 μM for both COX-1 and COX-2. The compounds of Formula I are described herein, wherein: (i) at least one of R6, R7, R8 and R9 is not hydrogen; (ii) when R 1 is propyl, Y-Z is ethoxy and R 9 is fluorine, R 6 is not substituted with a heterocycloalkyl group -C (O) -; (iii) when Y-Z is propoxy and R9 is ethyl, R1 is not CN; (iv) when R1 is ethyl and R9 is ethyl, YZ is not unsubstituted or substituted methoxyl or unsubstituted or substituted ethoxy; (v) when R1 is methyl and R9 is methyl, Y-Z is not methoxy or ethoxy; (vi) when Y-Z is ethoxy and R9 is ethyl, R1 is not ethoxy; and (vii) when Z is a substituted amide or a substituted amine; R6 is not methyl or chlorine; and R7 is not idroxyl, alkoxyl-phenyl or methoxy. In some embodiments Z is unsubstituted hydroxyl. Compounds of Formula I, pharmaceutical compositions comprising them and methods for using them are provided herein, wherein R 1 is hydrogen, or an unsubstituted portion selected from lower alkyl, lower hydroxyalkyl, lower alkenyl, lower hydroxyalkenyl, lower alkynyl , lower hydroxyalkynyl, aryl, heteroaryl, heterocycloalkyl and cycloalkyl. In some embodiments, R-i forms one ring or more with Y to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl group. The compounds of Formula I, the pharmaceutical compositions comprising them and the methods for using them are provided herein, wherein R 2, R 3, R 4 and R 5 each are independently hydrogen, or an unsubstituted portion selected from lower alkyl , lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl and heteroaryl. In some embodiments, R2, R3, R4 and R5 each are independently hydrogen. The compounds of Formula I, the pharmaceutical compositions containing them, and the methods for using them are provided herein, wherein R6, R8 and R9 are each independently hydrogen; or an unsubstituted or substituted portion selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein at least one of R6, R8 and R9 is not hydrogen. In some embodiments, the substituted portions are each independently selected from the group consisting of halogen, -CN, alkyl, alkoxy, -NH2, -O-haloalkyl, -CH (O), haloalkyl, aryl, heteroaryl, heterocycloalkyl , alkenyl, alkynyl, -OH, -C (0) 2 -alkyl, and -C (0) 2H. The compounds of Formula I, the pharmaceutical compositions containing them, and the methods for using them are provided herein, wherein R7 is hydrogen, halogen, or a substituted or unsubstituted portion selected from alkyl and alkoxy, wherein the substituted with one, two or three substituents is independently selected from the group consisting of -OH, -SH, -C (0) 2 -alkyl, -C (0) 2H, alkoxy, -O-haloalkyl, halogen, alkyl , haloalkyl, and NH2. In some embodiments, R7 is hydrogen; halogen; -CN; -OH; -SH; -N02; lower or substituted alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, lower alkyl-C (0) 2H, lower alkyl-C (O) 2-lower alkyl, or alkoxy. The compounds of Formula I, the pharmaceutical compositions containing them, and the methods for using them are provided herein, wherein R6 is hydrogen or halogen. The compounds of Formula I, the pharmaceutical compositions containing them, and the methods for using them are provided herein, wherein R8 is hydrogen or halogen. Compounds of Formula I, pharmaceutical compositions containing them, and methods for using them are provided herein, wherein R9 is hydrogen, halogen, or an unsubstituted or substituted portion selected from alkyl, aryl, heteroaryl, heterocycloalkyl, haloalkyl. , alkynyl, alkenyl, haloalkyl, wherein the substituted portion is substituted with one or two substituents independently selected from the group consisting of alkyl, -C (0) H, -CN, halogen, alkoxy, aryl and -C ( 0) 2H. The compounds of Formula I, the pharmaceutical compositions containing them, and the methods for using them are provided herein, wherein R 10 is hydrogen, alkyl, or alkyl-aryl. In some embodiments, X is O. In other embodiments, Y is lower alkyl. The compounds of Formula I, the pharmaceutical compositions containing them, and methods for using them are provided herein, wherein Z is hydroxyl. In some embodiments, Z is (C) (0) NH2 unsubstituted or substituted with one or two alkyl groups. In other embodiments, Z is hydroxyl, unsubstituted or substituted lower alkoxy, amino, lower alkylamino, di (lower) alkylamino, arylamino, lower (aryl) alkylamino, lower di (aryl) alkylamino, di (aryl) amino, (heterocycle) amino, (heterocycle) lower alkylamino, di (heterocycle) lower alkylamino and di (heterocycles) amino. The compounds of Formula I, the pharmaceutical compositions containing them, and the methods for using them are provided herein, wherein: (a) X is S or O; (b) Ri is hydrogen; or an unsubstituted portion selected from lower alkyl, lower hydroxyalkyl, lower alkenyl, lower hydroxyalkenyl, lower alkynyl, lower hydroxyalkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl; (c) R2, R3, R and R5 are each independently hydrogen; or an unsubstituted portion selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl; (d) R6, Rs and R9 each are independently hydrogen; or an unsubstituted or substituted portion selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein the substituted portions are each independently selected from the group consisting of halogen, CN, alkyl, alkoxy, NH 2, -O-haloalkyl, -CH (O), haloalkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, OH, C (0) 2 -alkyl, and C (0) 2H. (e) R7 is hydrogen; halogen; -CN; -OH; -SH; -N02; unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, lower alkyl-C (0) 2H, lower alkyl-C (O) 2-lower alkyl, or lower alkoxy; and (f) R10 is hydrogen; or an unsubstituted portion selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, benzyl, heteroaryl, heterocycloalkyl, and cycloalkyl.

The compounds of Formula I, the pharmaceutical compositions containing them, and the methods for using them are provided herein, wherein: (a) X is O; (b) R-i is an unsubstituted alkyl group or an unsubstituted aryl group; (c) R2, R3, R4 and R5 each are hydrogen. (d) R7 is hydrogen, halogen, unsubstituted lower alkyl, lower alkyl-C (0) 2H, lower alkyl-C (O) 2-lower alkyl, or alkoxy; (e) R9 is hydrogen, halogen or an unsubstituted lower alkyl group; (f) Y is an unsubstituted alkyl group; (g) R10 is hydrogen; and (h) Z is hydroxyl. The compounds of Formula I, the pharmaceutical compositions comprising them, and methods for using them are provided herein, wherein at least one of R6, R8 and R9 is an aryl group unsubstituted or substituted with one, two or three substituents each independently selected from the group consisting of halogens, groups = 0, = S, -CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) zCN where z is an integer from 0 to 6, = NH, -OH, -C (0) H, -OC (0) H, -C (0) OH, - OC (0) OH, -C (NH) NH2, -NHC (0) NH2, -S (0) H, -NH2, -C (0) NH2, -OC (0) NH2, -NHC (0) H, -NHC (0) OH, -C ( S) H, and -SH not substituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, = 0, -N02, -CN, -OH, -SH, - (CH2 ) z-CN where z is an integer from 0 to 6 unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, heteroalkyls not substituted, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls. In some embodiments, at least one of R6, R8 and R9 is a heteroaryl group unsubstituted or substituted with one, two or three suitable substituents selected independently from the group consisting of: halogens, groups = 0, = S, - CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) zCN wherein z is an integer from 0 to 6, = NH, -OH, -C (0) H, -OC (0) H, -C (0) OH, -OC (0) OH, -C (NH) NH 2, -NHC (0) NH 2, -S (0) H, -NH 2, -C ( 0) NH2, -OC (0) NH2, -NHC (0) H, -NHC (0) OH, -C (S) H, and -SH not substituted or substituted with one, two or three suitable substituents each selected independently of the group consisting of halogens, = 0, -N02, -CN, -OH, -SH, - (CH2) z-CN, wherein z is an integer from 0 to 6, unsubstituted alkyls, non-alkenyls substituted, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, heterocycloalkyl unsubstituted and unsubstituted heteroaryls. In other embodiments, at least one of R6, R8 and R9 is a heterocycloalkyl group unsubstituted or substituted with one, two or three suitable substituents selected independently from the group consisting of: halogens, groups = 0, = S, - CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) zCN wherein z is an integer from 0 to 6, = NH, -OH, -C (0) H, -OC (0) H, -C (0) OH, -OC (0) OH, -C (NH) NH 2, -NHC (0) NH 2, -S (0) H, -NH 2, -C ( 0) NH 2, OC (0) NH 2, -NHC (0) H, -NHC (0) OH, -C (S) H, and -SH not substituted or substituted with one, two or three suitable substituents each selected from independently from the group consisting of halogens, = 0, -N02.-CN, -OH, -SH, - (CH2) z-CN wherein z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, heterocycloal unsubstituted quinols, and unsubstituted heteroaryls. The compounds of Formula I, the pharmaceutical compositions containing them, and the methods for using them are provided herein, wherein: (a) X is O or S; (b) Ri is an unsubstituted lower alkyl group or an unsubstituted aryl group; (c) R2, R3, R and R5 each are hydrogen, (d) R6 is hydrogen or halogen; (d) R7 is hydrogen, halogen, unsubstituted lower alkyl, lower alkyl-C (0) 2H, lower alkyl-C (O) 2-lower alkyl, or alkoxy; (f) R8 is hydrogen or halogen; (g) R9 is hydrogen or an unsubstituted or substituted portion selected from alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; and (h) R-io is hydrogen. In some embodiments, Y is an unsubstituted lower alkyl group and Z is hydroxyl. In some embodiments, R9 is an unsubstituted alkyl group. In other embodiments, R is not hydrogen. In other embodiments, R7 is a small chemical group, where small is defined as taking less space than a phenyl group. In still other embodiments, Y-Z is an unsubstituted ethoxy group. In still other embodiments, R1 is an unsubstituted ethyl group. In still further embodiments, Z is a portion selected from -OH, -SS, and -OC (0) NH2. Pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier are provided herein. Exemplary compounds within Formulas I are shown below: or pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprising a therapeutically effective amount of a prodrug, active metabolite or a pharmaceutically acceptable salt of a compound of Formula I, as well as the pharmaceutically acceptable salts of said active metabolites, are also provided herein. Methods for treating a neoplasm are provided herein and these comprise administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound of Formula I. In some embodiments, the neoplasm is a hematologic cancer. In other modalities, neoplasia is selected among leukemias such as chronic lymphocytic leukemia, myelomas such as multiple myeloma and lymphomas. In yet other modalities, cancer is selected from cancer in the brain, cancer in the bones, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, cancer in the mouth, cancer in the esophagus, cancer in the intestine, thin, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, prostate cancer and carcinoma of renal cells. Herein methods are provided for treating cancer by administering a composition comprising a therapeutically effective amount of a composition of Formula I which is delivered in combination with another anti-neoplastic agent. In some embodiments, the antineoplastic agent is an alkylating agent. In other embodiments, the alkylating agent is selected from the group consisting of bendamustine, chlorambucil, cyclophosphamide and melphalan. In still other embodiments, the antineoplastic agent is a glucocorticoid. In other modalities, the glucocorticoid is prednisone. In other modalities, the glucocorticoid is administered in combination with additional antineoplastic agents. Herein methods are provided for treating a disease in which the mediator is β-catenin in a subject in need of such therapy, wherein a therapeutically effective amount of a compound of Formula I is administered to the subject. Herein methods are provided for treating a disease in which the mediator is Cyclin D1 in a subject in need of such therapy, wherein a therapeutically effective amount of a compound of the invention is administered.

Formula I to the subject. Methods for reducing or preventing the development of Alzheimer's disease are provided herein, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound of Formula I. In some embodiments, the method comprises administering to a mammal in need of such treatment a therapeutically effective amount of: (a) at least one compound, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug or a pharmaceutically active metabolite of Formula I; and (b) at least one agent selected from the group consisting of estrogen, risperidone, a thiobenzodiazepine, ampakine, [N- (2,6-dimethylphenyl) -2- (2-oxo-1-pyrrolidinyl) acetamide, DM9384, a cholinesterase inhibitor, donepezil hydrochloride, rivastigmine tartrate, galantamine, NGF, and metrifonate. The methods for treating a disease in a mammal that can be treated by administering a COX-1 and / or COX-2 inhibitor comprising administering to the mammal a therapeutically effective amount of a compound of Formula are provided herein. I that inhibits one or both of COX-1 or COX-2. In some modalities, the disease is an inflammatory disease. Methods for treating a hyperplastic disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I are provided herein. Methods for inhibiting or delaying the appearance of a neoplasia in a mammal in need are provided herein. such a treatment which comprises administering to the mammal a therapeutically effective amount of a compound of Formula I. In some embodiments, the neoplasm is selected from the group consisting of adenomatous polyps, gastrointestinal cancer, liver cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer and skin cancer. The present invention provides methods for treating, inhibiting or delaying the onset of uncontrolled angiogenesis or abnormal angiogenesis in a subject in need of such treatment, inhibition or delay, wherein uncontrolled or abnormal angiogenesis is selected from the group consisting of metastasis, corneal graft rejection, ocular neovascularization, retinal neovascularization, diabetic retinopathy, retrolental fibroplasia, neovascular laucoma, gastric ulcer, infantile hemangiomas, angiofibroma of the nasofariid nerve, avascular necrosis of the bones and endometriosis, as well as the method comprises the treatment of a subject with a therapeutically effective amount of a compound of Formula I. Herein are provided pharmaceutical compositions for the treatment of one or more conditions selected from the group consisting of arthritis, fever, common cold, disminorreas, menstrual cramps, inflammatory bowel disease, Crohn's disease, Crohn's disease, emphysema, breathing difficulties, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, hypersensitivity or allergic contact, persistency, cancer, tissue ulceration, peptic ulcer, gastritis, regional enteritis, ulcerative colitis, d iverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondiitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loose articular implants, atherosclerosis, aortic aneurysm , periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, brain trauma, spinal cord injuries, neuralgia, neurodegenerative disorders, autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathies, pain, gingivitis, cerebral amyloid angiopathy, cognition or nootropic improvement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint tension or strain, tendonitis, disorders of the skin, myasthenia gravis, polymyositis, myositis, bursitis, lesions, diabetes, tumor invasion, tumor growth, tumor metastasis, scars on the cornea, scleritis, immunodeficiency diseases, sepsis, preterm labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behecet syndrome, hypersensitivity, is schizophrenia, kidney diseases, rickettsial infection, diseases caused by protozoa, reproductive disorders, obesity and septic shock in a mammal, comprises an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof effective in such treatments and a pharmaceutically acceptable carrier . Methods for treating a neoplasm in a subject in need of treatment, wherein the subject is treated with a composition comprising a compound of Formula I. Neoplasms that can be treated include, but are not limited to, hematologic cancers, such as leukemias, myelomas and lymphomas, cancer of the brain, bone cancer, neoplasia derived from epithelial cells (epithelial carcinomas) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as cancer of the lips, cancer of the mouth, cancer of the esophagus , small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, cancer of the pancreas, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, such as squamous cell cancers and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that make epithelial cells throughout the body and cancer of the skin. the marrow Hereby methods are provided for the treatment of one or more conditions selected from the group consisting of arthritis, fever, common cold, disminorreas, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, respiratory difficulties, obesity, asthma, bronchitis. , chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, hypersensitivity or allergic contact, hypersensitivity, cancer, tissue ulceration, peptic ulcer, gastritis, regional enteritis, ulcerative colitis, diverticulitis, gastrointestinal injury recurrent, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loose artificial joint implants, atherosclerosis, aortic aneurysm, periarteritis nodosa, congestive heart failure, myocardial infarction gave, stroke, cerebral ischemia, brain trauma, spinal cord injuries, neuralgia, neurodegenerative disorders, autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathies, pain, gingivitis, cerebral amyloid angiopathy, Improvement of the cognition or nootropic, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal healing of wounds, muscle or joint tension or strain, tendonitis, skin disorders, myasthenia gravis, polymyositis, myositis, bursitis, lesions, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scars, scleritis, immunodeficiency diseases, sepsis, preterm labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, schizophrenia, kidney diseases, rickettsial infection, in diseases caused by protozoa, reproductive disorders and septic shock in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt of the same effective to treat such conditions. In some embodiments, methods for treating a hyperplastic disease in a mammal by administering to the mammal a therapeutically effective amount of a compound of Formula I. In other embodiments, methods are provided for treating, inhibiting or delaying the onset of uncontrolled or abnormal angiogenesis in a subject in need of such treatment, inhibition or delay by administration of a therapeutically effective amount of a compound of the Formula I. In one embodiment of this method, the uncontrolled or abnormal angiogenesis to be treated is selected from the group including, but not limited to, metastasis, corneal graft rejection, ocular neovascularization, retinal neovascularization, diabetic retinopathy, retrolental fibroplasia. , neovascu lar glaucoma, gastric ulcer, infantile hemangiomas, angiofi jokes of the nasopharynx, avascular necrosis of the bones and endometriosis. In still other embodiments, methods for selecting a subject to treat it for a disease or condition mediated by β-catenin, wherein the method involves obtaining a sample from the subject's tumor, to determine whether β-catenin is activated in the tumor and treat the subject with an agent that modulates the activity of β-catenin. In a related method, the activation of β-catenin is determined by immunohistochemical methods. In other embodiments, methods for selecting a subject to treat for a disease or condition mediated by Cyclin D1, wherein the method involves obtaining a sample of the subject's tumor, to determine if Cyclin D1 has an overexpression in the tumor and to treat the subject with agents that modulate the activity of Cyclin D1. The compounds that are preferred for use in the method are the compounds of Formula I. In a related method, overexpression of Cyclin D1 is determined using quantitative PCR. Brief Description of the Figures Figure 1 shows the inhibition of β-catenin: SUPERIOR by R-etodolac and the compounds of the invention; Figure 2 shows the inhibition of the expression of Cyclin D1 mRNA by R-etodolac and the compounds of the present invention. Detailed Description of the Invention To more readily provide an understanding of the present invention and its preferred embodiments, the meanings of the terms used herein will be apparent from the context of the present detailed description in light of the common usage of several. terms and the explicit definitions of other terms that are provided in the glossary below in the description presented below. Glossary of Terms As used herein, the terms, "comprises", "includes", and "how" are used in their open and non-limiting sense. As used herein and in the appended claims, the singular forms "a", "an", "the", "the" and "the" include a plural reference unless the context clearly indicates another way. In accordance with a conventionalism used in the art, * -,. it is used in the structural formulas herein to illustrate the binding which is the point where the portion or substituent is attached to the core or structure. In accordance with a conventionalism used in the art, the symbol y represents a methyl group, ^^ represents an ethyl group, represents a cyclopentyl group, etc. The term "alkyl" as used herein refers to a straight or branched chain alkyl group having from one to twelve carbon atoms. Exemplary alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tere-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like . The term "lower alkyl" denotes an alkyl having from 1 to 6 carbon atoms (a C? -6 alkyl). The term "heteroalkyl" as used herein refers to straight or branched chain alkyl groups having from one to twelve atoms containing one or more heteroatoms selected from S, O and N. The term "lower heteroalkyl" denotes a heteroalkyl having 1 to 6 carbon atoms (a heteroalkyl of C 1-6). The term "alkenyl" means an alkyl radical having one or more double bonds and from two to twelve carbon atoms. The alkenyl groups containing three or more carbon atoms may be straight or branched. Alkenyl groups as used herein include the cis or trans configurations. Exemplary alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like. The term "lower alkenyl" denotes an alkyl having 1 to 6 carbon atoms (a C 1-6 alkenyl). The term "allyloxy" refers to an alkenyloxy group that is CH2 = CHCH2-0-. The term "alkynyl" means an alkyl radical having one or more triple bonds and from two to twelve carbon atoms. Alkynyl groups containing three or more carbon atoms may be straight or branched. The alkynyl groups as used herein include the cis or trans configurations. Exemplary alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, 2-methylbut-2-ynyl, hex-2-ynyl, and the like. The term "lower alkynyl" denotes an alkyl having from 1 to 6 carbon atoms (an alkynyl of C? -6). The term "aryl" (Ar) refers to a carbocycle (ring structure that has atoms in the ring that are all carbon) aromatic, monocyclic or fused or polycyclic spiro, which has three to twelve atoms in the ring for each ring. Some illustrative examples of the aryl groups include the following portions: , and similar. The term "heteroaryl" (heteroAr) refers to a heterocycle (ring structure having ring atoms selected from carbon atoms, as well as nitrogen, oxygen and sulfur heteroatoms) aromatic, monocyclic or fused or polycyclic spiro, which has of three to twelve atoms in the ring for each ring. Some illustrative examples of heteroaryl groups include the following portions: , and similar. The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or fused or polycyclic spiro carbocycle having from three to twelve ring atoms per ring. Some illustrative examples of the cycloalkyl groups include the following portions: ox 0.0.0. X. o. , and similar. A "heterocycloalkyl" refers to a monocyclic, or fused or polycyclic spiro ring structure, which is saturated or partially saturated and has from three to twelve ring atoms per ring selected from C atoms and N, O, and S heteroatoms. Examples of heterocycloalkyl groups include: or. .or. . ^. ó.O. o.o.o.Q. ? and c ° co.y.c -c, - and the like. The term "alkoxy" refers to -O-alkyl. Illustrated examples include methoxy, ethoxy, propoxy and the like. The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chlorine, fluorine, bromine or iodine.

Unless defined otherwise, the term "substituted" as used herein means that at least one hydrogen atom is replaced with a suitable substituent. The term "unsubstituted" means that the specified group does not host substituents. The term "lower" when referring to a group such as alkyl, alkenyl, alkynyl, alkoxy or other group refers to such a group having up to 6 carbon atoms. As used herein, "tumors" or "neoplasms" include the growth of tissue cells in which the multiplication of cells is uncontrolled and progressive. Some of these growths are benign, but others are called malignant and can cause the death of the organism. Malignant neoplasms, or cancers, are distinguished from benign growths in that in addition to exhibiting aggressive cell proliferation, they can invade surrounding tissues and metastasize. Malignant neoplasms can be characterized by showing a greater loss of differentiation and relative organization between themselves and the surrounding tissues. The term "hyperplasia" refers to the abnormal multiplication or increase in the number of normal cells in a normal arrangement in a tissue.

The term "subject" for treatment reasons includes any animal or human subject having any of the known conditions or diseases described herein, for example, cancer, hyperplasia, inflammation, Alzheimer's and abnormal angiogenesis. For methods of prevention, the subject is any human or animal, and preferably is a human subject that is at risk for the disease or conditions described herein, for example, cancer. The subject may be at risk due to a genetic predisposition, and / or exposure to various agents, including chemical and viral agents. In addition to being useful for treatment in humans, the compounds described herein are also useful for the veterinary treatment of mammals, including companion animals and farm animals, such as horses, dogs, cows, sheep and pigs. Preferably, subject refers to a human. As used herein "a β-catenin-mediated disease" means a disease that is associated with changes in the regulation of β-catenin, as are its levels, distribution and / or association with other proteins in the cytoplasm and its nucleus differs from that found in normal cells. Changes in ß-catenin levels, their associations and / or distribution, for example, nuclear accumulation may cause mutations in ß-catenin, APC, axin or other proteins that are involved in ß-catenin trafficking. The accumulation of β-catenin, its levels and / or its distribution can also be affected by changes in the wnt / fzd signaling path. The accumulation of β-catenin in the nucleus can produce the transcription of genes involved in tumorigenesis, such as cyclin D1 and c-myc. As used herein "activated β-catenin" represents β-catenin which is not labeled for degradation. As used herein "a Cyclin D1-mediated disease" means a disease that is associated with changes in the expression of cyclin D1, such as its levels, distribution and / or association with other proteins in the cell that differ from those of the cyclin D1. that are found in normal cells. As used herein, "angiogenesis" is the development of new blood vessels in a tissue or organ. Under normal conditions, angiogenesis is observed in the healing of a wound and in embryonic development. Uncontrolled or abnormal angiogenesis is associated with neoplastic diseases, tumor metastasis and other diseases related to angiogenesis. "A pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound, and is not undesirable biologically or otherwise. As used herein a "pharmaceutically acceptable prodrug" is a compound that can be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of said compound. The term "a pharmaceutically active metabolite" is intended to refer to the pharmacologically active product produced through the metabolism within the body of a specified compound or a salt thereof. An "effective amount" means that an amount of an agent that, when administered to a subject requiring such treatment, is sufficient to perform the treatment of a disease and / or condition associated with β-catenin, COX, PPAR, cyclin D and / or Aß42. Thus, for example, a therapeutically effective amount of a compound of Formula I, salt, active metabolite or prodrug thereof is an amount sufficient to modulate, regulate, or inhibit the activity of β-catenin, COX, PPAR, Cyclin D and / or Aβ42 so that that disease and / or condition that is regulated by this activity is reduced or alleviated. The terms "treatment", "treating" and "treating" refer to any treatment of a disease and / or condition of a mammal mediated by COX, β-catenin, PPAR, or amyloid-β, particularly a human, and includes: (i) preventing the occurrence of the disease or condition in a subject who may be predisposed to the condition, eg, subjects with accumulated Aβ peptides, so that the treatment constitutes a prophylactic treatment for the pathological condition; (i) modulate or inhibit the disease or condition, that is, stop its development; (iii) alleviating the disease or condition, that is, causing the regression of the disease or condition; or (iv) relieving and / or relieving the disease or condition or symptoms caused by the disease or condition, for example, relieving an inflammatory response without addressing the underlying disease or condition. By "effective levels" is meant the levels at which the effects of the activity or amount of β-catenin, COX, PPAR, Cyclin D and / or Aβ42 are regulated to the minimum. The phrase "conjunctive therapy" (or "combination therapy"), is the definition of the use of a compound of the invention and another pharmaceutical agent, is intended to include the administration of each agent in sequence in a regimen that will provide beneficial effects. of the combination of the drugs, and is intended to include the co-administration of these agents substantially simultaneously, as in a single formulation having a fixed ratio of these active agents, or in multiple and separate formulations for each agent. COMPOUNDS Applicants have discovered compounds, such as those represented by Formulas I, which possess COX inhibitory activity, β-catenin inhibitory activity, cyclin D1 activity, and / or are cytotoxic to cancer cell lines. Hereby are provided compounds that are represented by Formulas I: Formula I or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof, wherein RrR10, X, Y, Z and n are as defined herein. The compounds of Formula I may exhibit the phenomenon of tautomerism. While Formulas I can not expressly illustrate all possible tautomeric forms, it should be understood that Formula I is intended to represent any tautomeric form of the compound illustrated and is not limited merely to a specific form of the compound illustrated by the drawings. of the formula. The compounds of Formula I may have one or more asymmetric centers depending on the nature of the various substituents of the molecule. As a consequence of these symmetric centers, the compounds of the Formulas I can exist as unique stereoisomers (ie, essentially without other stereoisomers), racemates and / or mixtures of enantiomers and / or diastereomers. All such stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Preferably, the compounds of the invention that are optically active are used in an optically pure form. As is generally understood by those skilled in the art, an optically pure compound having a chiral center (i.e., an asymmetric carbon atom) is that which consists essentially of one of two possible enantiomers (i.e., is enantiomerically pure) ), and a pro optically compound having more than one chiral center is one that is pure both diastereomerically and enantiomerically. The compounds of the present invention can be used in a form that is at least 90% pure optically, that is, a form containing at least 90% of a single isomer (80% enantiomeric excess ("ee") or diastereomeric excess ("from")). In some cases, for example to reduce toxicity, the compounds may be used in a form that contains at least 95% (90% ee or de), even more preferably at least 5% (95% ee or de), and very preferably at least 99% (98% ee or de) of an ee isomer or d.e. In addition, Formula I intends to cover the solvated forms, as well as the unsolvated forms of the structures identified. For example, Formula I includes compounds of the structure indicated both in the hydrated form and in the non-hydrated form. Other examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine. In addition to the compounds of Formula I, the invention includes pharmaceutically acceptable prodrugs, pharmaceutically active metabolites and pharmaceutically acceptable salts of such compounds and metabolites. Prodrugs and active metabolites of a compound can be identified using routine techniques known in the art. See, for example, Bertolini et al., J. Med. Chem., 40, 2011-2016 (1997); Shan, ei al., J. Pharm.

Sci., 86 (7), 765-767; Bagshawe, Drug Dev. Res., 34, 220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984); Bundgaard, Design of Prodrugs (Elsevier Press 1985); Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., Eds., Harwood Academic Publishers, 1991); Dear et al., J. Chromatogr. B, 748, 281-293 (2000); Spraul et al., J. Pharmaceutical & Biomedical Analysis, 10, 601-605 (1992); and Prox et al., Xenobiol., 3, 103-112 (1992). A compound of the invention may possess sufficient acidic, basic functional groups or both functional groups, and react accordingly with any of various inorganic or organic bases in addition to inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include salts prepared by reaction of the compounds of the present invention with a mineral or an organic acid or an inorganic base, such as salts that include sulphates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenated phosphates, dihydrogenated phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formats, isobutyrates, caproates, heptanes, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulphonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, g-hydroxybutyrates, glucolates, tartrates, methansulfonates, propansulfonates, naphthalene-1-hisphophonates, naphthalene-2-sulfonates and andelates. If the compound of the present invention is a base, the pharmaceutically acceptable salt that is desired can be prepared by any suitable method available in the art, for example, the treatment of the free base with an organic acid, such as hydrochloric acid, hydrobromic acid , sulfuric acid, nitric acid, phosphoric acid and the like or with an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid , such as glycononic acid or galacturonic acid, an alpha-hydroxyl acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. If the compound of the invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), a hydroxide of alkali metal or an alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glucine and arginine, ammonia, primary, secondary and tertiary amines and cyclic amines, such as piperidine, morpholine and piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium , manganese, iron, copper, zinc, aluminum and lithium. In the case of agents that are solid, those skilled in the art should understand that the compounds of the invention and their salts may exist in different forms of crystals or polymorphs, all of which are within the scope of the present invention and their formulas specified. Therapeutically effective amounts of the agents of the invention can be used to treat or prevent diseases and / or conditions mediated by the modulation or regulation of β-catenin, COX, Aβ42, and PPAR. The amount of a given agent that corresponds to that amount varies depending on factors such as the particular compound, condition of the disease, and its severity, the identity (eg, weight) of the subject in need of treatment, however it must be determined routinely by an expert in the art. The active agents of the invention can be formulated into pharmaceutical compositions as described below. The pharmaceutical compositions of this invention comprise an amount effective to modulate, regulate or inhibit a compound of Formula I and an inert and pharmaceutically acceptable carrier or diluent. In one embodiment of the pharmaceutical compositions, the effective levels of the agents of the invention are provided so as to provide therapeutic benefits involving the modulation of β-catenin, COX, PPAR, and / or Aβ42. These compositions are prepared in a dosage form per unit appropriate for the mode of administration, for example, for parenteral or oral administration. An agent of the invention can be administered in a conventional dosage form prepared by combining a therapeutically effective amount of an agent (e.g., a compound of Formula I) as an active ingredient with suitable pharmaceutical carriers or diluents in accordance with conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired preparation.

The pharmaceutical carrier that is used can be solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary liquid vehicles are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include material with time delay or release over time already known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methyl methacrylate and the like. A variety of pharmaceutical forms can be employed. In this way, if a solid vehicle is used, the preparation can be made into tablets, placed in hard gelatin capsules in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier may vary, but will generally be from about 25 mg to about 1 g. If a liquid vehicle is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in a vial or bottle or a non-aqueous liquid suspension. To obtain a stable water-soluble dosage form, a pharmaceutically acceptable salt of an agent of the invention is dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent can be dissolved in a suitable cosolvent or co-solvent combinations. Examples of suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume. In an exemplary embodiment, a compound of Formula I is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose. It will be apparent that the current dosages of the agents used in the compositions of the present invention will vary in accordance with the particular complex that is used, the particular composition formulated, the mode of administration and the site, host and disease and / or particular condition that be in treatment. Those skilled in the art will be able to determine optimum dosages for a given set of conditions using tests for conventional dosage determination in view of the experimental data of an agent. For oral administration, an exemplary daily dose that is generally employed is from about 0.001 to about 3000 mg / kg body weight, with courses of treatment repeated at appropriate intervals. In some embodiments, the daily dosage is about 1 to 3000 mg / kg of body weight. The common daily doses in a patient can be between about 500 mg to about 3000 mg, given once or twice a day, for example, you can give 3000 mg twice a day to have a total dose of 6000 mg. In one modality, the dose is between about 1000 to about 3000 mgs. In another modality, the dose is between about 1500 to about 2800 mgs. In other modalities, the dose is between about 2000 to about 3000 mgs. The plasma concentrations in the subjects can be between about 100 μM to about 1000 μM. In some embodiments, the plasma concentration may be between about 200 μM to about 800 μM. In other embodiments, the dose is between about 300 μM to about 600 μM. In some other embodiments, the plasma concentration may be between about 400 to about 800 μM. Prodrug administration is commonly dosed based on weight levels, which are chemically equivalent to the weight levels of the fully active form. The compositions of the invention can be manufactured using techniques generally known to prepare pharmaceutical compositions, for example, through conventional techniques such as mixing, dissolving, granulating, dragee-making, grinding, emulsifying, encapsulating, trapping or lyophilizing. The pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, which can be selected from the excipients and auxiliaries that facilitate the processing of the active compounds in the preparations, which can be used pharmaceutically. The appropriate formulation depends on the route of administration chosen. For injection, the agents of the invention can be formulated in aqueous solutions, preferably in compatible pH regulators such as Hanks solution, Ringer's solution or a pH regulator in physiological saline solution. For transmucosal administration, suitable penetrants are used in the formulation for the barrier that will be permeated. Such penetrants are generally known in the art. For oral administration, the compounds can be easily formulated by combining the active compounds with acceptable pharmaceutical carriers known in the art. Said vehicles allow the compounds of the invention to be formulated in the form of tablets, pills, dragees, capsules, liquids, jellies, syrups, slurries, suspensions and the like so that a patient undergoing treatment orally ingests them. Pharmaceutical preparations for oral use can be obtained by using a solid excipient in an admixture with the active ingredient (agent), optionally grinding the resulting mixture, and with processing the granule mixture after adding suitable auxiliaries, if desired, to obtain tablets or centers of dragees. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; in addition to cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). Disintegrating agents may be added, if desired, such as interlaced polyvinyl-pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee centers are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, polyvinylpyrrolidone, Carbopol jelly, polyethylene glycol, and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to tablets or dragee coatings for identification or to represent different combinations of active agents. Pharmaceutical preparations that can be used orally include snap-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Pressure-adjusting capsules may contain the active ingredients in a blend with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids such as fatty acids, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be given in dosages suitable for such administration. For buccal administration, the compositions may be in the form of tablets or troches formulated in conventional manner. For intranasal administration or by inhalation, the compounds for use in accordance with the present invention are conveniently delivered in the form of a sprayed aerosol presentation of pressurized packets or a nebulizer, with a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane , dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of the pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a measured quantity. Capsules and gelatin cartridges for use in an inhaler or insufflator and the like can be formulated with a powder mixture of the compound and a suitable powder base such as lactose or starch. The compounds can be formulated for parenteral administration by injection, for example, in bolus or continuous infusion. Formulations for injection may be presented in dosage form per unit, for example, in ampoules or in multiple dose containers with an added preservative. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulating agents as suspending, stabilizing and / or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compounds in water soluble form. In addition, suspensions of the active agents can be prepared as appropriate oil suspensions for injection. Suitable solvents or lipophilic vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspensions may also contain stabilizers or suitable agents, which increase the solubility of the compounds to allow the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form to be constituted with a suitable vehicle, for example, sterile, pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, for example, those containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described in the preceding paragraphs, the compounds can also be formulated as a depot preparation. Said long acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as soluble derivatives in small amounts, for example, as a salt soluble in small quantities. An exemplary pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a non-polar wetting agent, an organic water miscible polymer and an aqueous phase. The cosolvent system can be a VPD cosolvent system. VPD is a solution of 3% w / v of benzyl alcohol, 8% w / v of polysorbate of non-polar wetting agent 80, and 65% w / v of polyethylene glycol 300, made with volume in absolute ethanol. The VPD cosolvent system (VPD: 5W) contains VPD diluted 1: 1 with 5% dextrose in a water solution. This cosolvent system dissolves hydrophobic compounds well, and produces low toxicity during systemic administration. Naturally the proportions of a cosolvent system can vary considerably without destroying its solubility and toxicity characteristics. In addition, the identity of the cosolvent components can vary: for example, other non-polar, low-toxicity wetting agents can be used in place of the polysorbate 80; the size of the polyethylene glycol fraction may vary; polyethylene glycol can be replaced with other biocompatible polymers, for example, polyvinylpyrrolidone and other sugars; or polysaccharides can be replaced by dextrose. Alternatively, other delivery systems for the pharmaceutically hydrophobic compounds can be used. Liposomes and emulsions are known examples of delivery vehicles for hydrophobic drugs. Some organic solvents such as dimethylsulfoxide can also be used, although with a usual cost of higher toxicity. Additionally, the compounds can be delivered using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Several sustained release materials have been established and are known to those skilled in the art. Sustained-release capsules can release, depending on their chemical nature, the compounds for a few weeks and up to 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization can be used. The pharmaceutical compositions may further comprise vehicles or excipients with jelly phase or with solid phase. Examples of such carriers include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Some compounds of the present invention can be provided as salts with pharmaceutically compatible counterions. The pharmaceutically compatible salts can be formed with mucos acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. The salts tend to be more soluble in aqueous or protonic solvents than the corresponding free base forms. The administration of the present invention can be for prevention or treatment purposes. When used for the treatment and / or prevention of neoplasia, or Alzheimer's, or for the treatment of diseases that can be treated by inhibiting COX, the methods and compositions described herein may be used alone or in conjunction with additional therapies known to those skilled in the art. Alternatively, the methods and compositions described herein can be used as a whole therapy. By way of example, the compounds described herein may be administered alone or in conjunction with other antineoplastic agents, glucocorticoids or other growth inhibitory agents or other drugs or nutrients. There are a large number of antineoplastic agents available for commercial use, in clinical evaluation and in preclinical development, which could be chosen for the treatment of a neoplasm by the combination of chemotherapy with drugs. Said antineoplastic agents are located in several main categories, namely antibiotic agents, alkylating agents, antimetabolite agents, hormonal agents, including glucocorticoids such as prednisone and dexamethasone, immunological agents, agents of the interferon type and a category of agents miscellaneous Alternatively, other antineoplastic agents may be used, such as metallomatrix proteases (MMP), SOD mimic or alphav beta3 inhibitors. A family of antineoplastic agents that can be used in combination with the compounds of the inventions consists of anti-metabolite antineoplastic agents. Suitable antimetabolite antineoplastic agents can be selected from the group consisting of alanosine, AG2037 (Pfizer), 5-FU-fibrinogen, acantifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine stearate phosphate , conjugates of cytarabine, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck &; Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N- (2'-pharanidyl) -5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, Methobenzaprim, Methotrexate, Wellcome MZPES, Norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, Pentostatin, Piritrexime, Plicamycin, Asahi Chemical PL-AC, Takeda TAC-788 , thioguanine, thiazofurine, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT and uricitin.

A second family of antineoplastic agents that can be used in combination with the compounds of the invention consists of antineoplastic agents of the alkylator type. Appropriate alkylator-type antineoplastic agents can be selected from the group consisting of Shionogi 254-S, analogs of aldo-phosphamide, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bendamustine, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine. , Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cinamide CL-286558, Sanofi CY-233, cisyplatate, Degussa D-19-384, Sumimoto DACHP (Myr) 2, diphenylspiromustine, cytostatic diplatin, Erba derivatives distamycin, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine sodium phosphate, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, melphalan, Mylalactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, Oxaliplatin, Upjohn PCNU, Prednimustine, Proter PTT-119, Ranimustine, Semustine, SmithKline SK &F-101772, Yakult Honsha SN-22, Spiromustine, Tanabe Seiyaku TA-077, tauromustine, temozoly ida, teroxirone, tetraplatin and trimelamol. Another family of antineoplastic agents that can be used in combination with the compounds of the invention consists of antineoplastic agents of the antibiotic type. Suitable antineoplastic agents of the antibiotic type may be selected from the type consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, alanosine, Erbamont ADR-456, derivatives of aeroplisinin, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-micin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol -Myers BMY-28438, bleomycin sulfate, briostatin-1, Taiho C-1027, calichemycin, chromoximicin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1 , Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-AI, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin , Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudines, kazu samicina, kesarirrodinas, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamide LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone , SmithKIine M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalisin, oxaunomycin, peplomycin, pilatin, pirarubicin, porotramycin, prindamycin A, Tobishi RA-I, rapamycin, rhizoxin, RoboBubicin, Sibanomicin, Siwenmicin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, Sorangicin-A, Sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, Steffimicin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, trazine, tricrozarine A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorrubicin. A fourth family of antineoplastic agents that can be used in combination with the compounds of the invention include a miscellaneous family of antineoplastic agents selected from the group consisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin, arsenic trioxide, Avastin® (bevacizumab), Biotec AD-5, Kyorin AHC-52, alstonin, amonafide, amfetinil, amsacrine, Angiostat, ankinomycin, antineoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, afidicolin glucinate, asparaginase , Avarol, Baccharin, Batracilin, Benfluron, Benzotript, Ipsen-Beaufour BIM-23015, Bisantrene, Bristol-Myers BMY-40481, Vestar Boron-10, Bromophosphide, Wellcome BW-502, Wellcome BW-773, Caracemide, Carbohydrate Hydrochloride, Ajinomoto CDAF, Clorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, Clanfenur, Claviridenone, ICN Compound 1259, ICN Compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, dateliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, eliprabine, eliptinium acetate, epumiones Tsumura EPMTC, erbitux, ergotamine, erlotnib, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate , genkwadaphnin, Glivec® (imatnib), Chugai GLA-43, Glaxo GR-63178, gefitinib, grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, indanocin, ilmofosine, isoglutamine, isotretinoin , Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, maricine, mefloquine, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, Merocyanine derivatives, Methylanilinoacridine, Molecular Genetics MGI-136, Minactivine, Mitonafide, Mitochidone, Mopidamol, Motretinide, Zenyaku Kogyo MST-16, N- (retinoyl) amino acids, Nisshin Flour Milling N-021, N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, derived from nocodazole, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotide, Ono ONO-112, oquizanocin, Akzo Org-10172, paclitaxel, pancratistatin, pazeliptine , Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhematoporphyrin, polyprotein acid, Efamol porfirin, probimana, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, reteliptine, retinoic acid co, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, Rituxan® (and other anti-CD20 antibodies, eg, Bexxar®, Zevalin®), SmithKine SK & amp;; F-104864, Statins (Lipitor ® etc.), Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, Spray, Spirocyclopropane Derivatives, Spirogermanium, Unimed, SS Pharmaceutical SS-554, Strypoldinone, Stipoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Thalidomide, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, taliblastin, Eastman Kodak TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01 , Kyowa Hakko UCN-1028, ukraine, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides and Yamanouchi YM-534, zometa. Examples of radioprotective agents that can be used in combination with the chemotherapy of this invention are AD-5, adnchon, analogs of amifostine, detox, dimesna, 1-102, MM-159, N-acylated-dehydroalanines, TGF-Genentech, tiprotimoda , amifostine, WR-151327, FUT-187, transdermal ketoprofen, nabumetone, superoxide dismutase (Chiron) and superoxide dismutase Enzon. The methods of preparation of the antineoplastic agents described above can be found in the literature. Methods of preparation of doxorubicin, for example, are described in U.S. Pat. Nos. 3,590,028 and 4,012,448. Methods for preparing metallomatrix protease inhibitors are described in EP 780386. Methods for preparing SOD mimics are described in EP 524,101. Methods for preparing alphav, .beta3 inhibitors are described in WO97 / 08174. Additionally, the compounds of Formula I can be administered either alone or in combination with other effective compounds to treat Alzheimer's or dementia.

For example, the compounds of the invention can be administered in combination with other agents that are used to treat diseases or conditions mediated by amyloid-β, such as estrogen, risperidone, a thiobenzodiazepine, ampakine, [N- (2,6-dimethylphenyl) -2- (2-oxo-1-pyrrolidin i lo) acetamide, DM9384, a cholinesterase inhibitor, donepezil hydrochloride, rivastigmine tartrate, galantamine, NGF, and metrifonate. COX INHIBITORS The compounds of Formula I described herein or the pharmaceutically acceptable salts may possess an inhibitory activity of COX and possess anti-inflammatory, antipyretic, analgesic, antithrombotic and anticancer activities. The compounds of Formula 1 and the pharmaceutically acceptable salt thereof, in this manner, are useful for treating and / or avoiding diseases mediated by COX, inflammatory conditions, pain, fever, rheumatic fever, collagen diseases, autoimmune diseases, various immunological diseases, thrombosis, cancer and neurodegenerative diseases in humans or animals through systemic or topical administration. In particular, the compounds and pharmaceutically acceptable salts thereof are useful for the treatment and / or prevention of inflammation and muscular and chronic joint pain or acute [eg in rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, etc.], inflammatory skin condition [eg, solar dermatitis, burns, eczema, dermatitis, etc.], ocular inflammatory condition [eg, conjunctivitis, etc.], pulmonary disorders where inflammation is involved [eg, asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.], gastrointestinal tract conditions associated with inflammation [eg, aphthous ulcers, Crohn's disease, atopic gastritis, gastritis varialiforme, ulcerative colitis, celiac disease , regional ileitis, irritable bowel syndrome, etc.], gingivitis, inflammation, pain and tumescence after surgery or injury, pyrexia, pain and other conditions associated with inflammation, particularly those where the lipoxygenase and cyclooxygenase products are a factor, systemic lupus erythematosus, scleroderma, polymyositis, tendonitis, bursitis, periarteritis nodosa, rheumatic fever, Sjogren's syndrome, Behcet's disease, thyroiditis, type I diabetes, nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis due to contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimer's disease, Parkinson's disease, symptoms associated with influenza and other viral infections, common cold, lower back and neck pain, dysmenorrhea, headache, tooth pain, tension and distension, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint disease or osteoarthritis, gout , ankylosing spondolitis, bursitis, injuries after surgical procedures dental procedures and procedures, bone loss, or the like. In addition, the compounds described herein or a salt thereof are expected to be useful as therapeutic and / or preventive agents for cardiovascular or cerebrovascular diseases, diseases caused by hyperglycemia and hyperlipidemia. The anti-inflammatory activity of the compounds of the present invention can be evaluated by measuring the ability of the compounds to inhibit COX-1 and COX-2. The techniques for measuring COX inhibition are described herein and in the literature, for example see U.S. patent application Ser. No. 2002/0107280; Winter I went to. 1962 Proc. Soc. Exp. Biol. Med. 111: 544, both documents incorporated herein by reference. In other embodiments, the preferred compounds of Formula I are compounds with low or no COX activity. CANCER Neoplasms that can be treated by the present invention include solid tumors, that is, carcinomas and sarcomas. Carcinomas include malignant neoplasms derived from epithelial cells that infiltrate the surrounding tissues and cause metastasis. Adenocarcinomas are carcinomas derived from glandular tissue or tissues that form recognizable glandular structures. Another broad category of cancer includes sarcomas, which are tumors whose cells are embedded in a fibrillar or homogeneous substance, such as embryonic connective tissue. The invention also enables cancer treatments of the myeloid or lymphoid systems, including leukemias, such as chronic CLL lymphoid leukemia, myelomas, such as multiple myeloma, lymphomas and other types of cancer that are not commonly present in the form of tumors, nevertheless They are distributed in the vascular or linforreticular systems. Types of cancer that can be treated using the compounds described herein include, without limitation, cancer of the brain, bone cancer, neoplasms derived from epithelial cells (epithelial carcinoma) such as a basal cell carcinoma, adenocarcinomas , gastrointestinal cancer such as lip cancer, cancer of the mouth, esophageal cancer, cancer of the small intestine, stomach cancer, colon cancer, liver cancer, bladder cancer, cancer of the pancreas, ovarian cancer, cancer cervical cancer, lung cancer, breast cancer, skin cancer such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma and other known cancers that develops in epithelial cells in the body. The activity of the compounds of Formula I against various types of cancer can be tested using tests known in the art, for example, MTT test for in vitro cancer cell lines and animal tumor models, see for example, Romijn et al. ., 1988 Prostate 12: 99-110. The types of cancer that can be treated with the compounds of the invention include those mentioned above and those that are mediated by β-catenin. Some examples of cancer include those with mutations in APC, the signaling pathway wnt / fzd, axin and / or β-catenin that causes the deregulation of β-catenin and a subsequent increase in β-catenin in the cytoplasm and in the core. The identification of ß-catenin mediated cancer types can be determined using a variety of techniques already known in the art. For example, the expression of wnt and / or fzd RNA can be measured in cancer cells and purchased with normal cells as described in International Publication Nos. WO 02/092635 and WO 02/088081 (both of which are incorporated herein by reference). reference completely). Types of cancer that over-express wnt and / or fzd are expected to have a dysregulation of β-catenin. Deregulation of β-catenin can also be shown by analysis of the subcellular localization of β-catenin, eg, cytoplasmic, nuclear and / or plasma membrane in cancer cells compared to normal cells of the same type. Said representation can be made using techniques known in the art, including immunohistochemical analysis, confocal microscopy and immunoblot analysis. Samples for the analysis of β-catenin can be obtained using standard procedures known to those skilled in the art to generally include generally known biopsy methods including fine needle aspiration, surgical biopsy and hollow needle biopsy. Samples for analysis can also be fixed and embedded in materials such as paraffin. For a review of immunological procedures and immunological tests in general, see Stites et al. (eds.) (1991) Basic and Clinical Immunology (7th ed.). Immunoassays for detecting β-catenin can be performed in any of several configurations, which are reviewed to a large extent in Maggio (ed.) (1980) Enzyme Immunoassay CRC Press, Boca Raton, Fia.; Tijan (1985) "Practice and Theory of Enzyme Immunoassays", Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers B.V., Amsterdam; and Harlow and Lane, Antibodies, A Laboratory Manual, mentioned in preceding paragraphs, each of which is incorporated herein by reference. See also Chan (ed.) (1987) Immunoassay: A Practical Guide Academic Press, Orlando, Fia .; Price to al. (eds.) (1997) Principies and Practice of Immunoassay (2nd ed.), Groves Dictionaries, Inc .; Boenisch (ed.) (2001) Handbook Immunochemical Staining Methods DAKO Corp. Carpinteria, CA, USA and Ngo (ed.). (1988) Non-Isotopic Immunoassays Plenum Press, NY; all incorporated herein by reference. In general, the design considerations of the immunoprotes include the preparation of antibodies (e.g., monoclonal or polyclonal) that have a sufficient top binding specificity for their antigen so that the specifically bound antibody-antigen complex can be reliably distinguished. of non-specific interactions. Polyclonal and monoclonal antibodies that detect β-catenin are known in the art and are commercially available, for example, Upstate Cell Signaling Solutions, Charlottesville, VA-nos. 06-734; 05-601; and 05-482. Western blot analysis can be used to quantify the amount of the β-catenin protein in a sample. Electrophoresis develops, for example, in a sample of tissue that is suspected to contain the protein. After electrophoresis to separate the proteins, and transfer them to a suitable solid support such as a nitrocellulose filter, the solid support is incubated with a reagent for the antibody with the denatured protein. This antibody can be labeled or alternatively detected by subsequent incubation with a labeled second antibody that binds to a primary antibody. A preferred method to identify cancer that has unregulated ß-catenin in the immunohistochemistry (IHC). Immunohistochemistry allows the evaluation of microanatomic details and heterogeneity in tissues and tumors. Immunohistochemistry is useful over other methods of analysis because it is the only method that can locate proteins for individual cell types and specific cell locations, for example, in the plasma membrane, in the cytoplasm, and / or in the nucleus. The differences between the genetic expression of normal tissues and those of the tumor can be detected by observing simultaneous changes in the number and composition of the cells. In contrast, techniques such as Western blotting require the use of cellular extracts; therefore, there is the possibility of contamination of different types of cells. For IHC, a primary β-catenin antibody that recognizes the β-catenin protein is introduced into a biological sample. After incubation with the primary antibody, a wash can be performed to remove the free antibody. Then, a secondary antibody, directed against the primary antibody and labeled with an enzyme, can be incubated with the biological sample. During incubation, the secondary antibody binds to the primary antibody. Alternatively, it is possible that the second antibody does not have a label, but, in turn, is bound by a third antibody specific to the antibodies of the species from which the second antibody is derived. The primary antibody can be labeled with an enzyme in a manner that eliminates the need for a second antibody. Alternatively, the labeled ß-catenin antibody can be labeled with biotin instead of using an enzyme. Then, in a further step, the avidin or streptavidin labeled with the enzyme is introduced into the sample and allowed to bind to the biotinylated antibody. For immunohistochemistry, the tissue sample may be freshly obtained or frozen or it may be embedded, for example, in paraffin, or in other waxes, nitrocellulose, carbowax, also known as soluble polyethylene glycol (see, Gao ed. (1993) "Polyethylene Glycol as an Embedment for Microscopy and Histochemistry", CRC Press, Inc. Boca Raton, Fl.), Plastics, including resins such as acrylic and epoxy resins, frozen blocks embedded in OCT. Preferably, the samples are embedded in paraffin or other waxes, nitrocellulose, carbowax, or plastic. Samples can be fixed in a conservator, such as formalin, for example. Samples for immunohistochemistry can be obtained from surgical biopsies, fine needle biopsies, fine needle aspiration biopsies, hollow needle biopsies, body cavity effusions, for example from the abdominal cavity, the pleural cavities and the cavity. pericardial, and the cells can be collected from other body fluids, such as blood, urine and the like. Methods for obtaining such samples are known in the art. For example, a sample of 'effusion can be collected by puncturing the chest wall or the abdominal wall with a needle and evacuating the fluid. Samples of fine needle aspirations, effusions or other bodily fluids can be placed on slides using conventional centrifugation or Cytospin®; (Shandon, Runcom, R.U.) or by smears on a sheet suitable for staining and / or fixation. Cell blocks can also be prepared with said samples by concentrating the cells contained therein. For example, the cells can be concentrated by. example, by centrifugation. After concentration, the cells can be fixed in a suitable fixative agent, such as formalin or alcohol and then embedded in paraffin or other suitable material as is done for the tissues in the surgical pathology. The concentrated cells can also be processed for the ThinPrep® preparation using, for example, a Cytyc Thin Prep processor (Cytyc Corp Boxborough, MA). Another technique to detect ß-catenin is a flow cytometry (FACS). The theory of flow cytometry is analyzed in Ormerod (ed) Flow Cytometry: A Practical Approach (IRL Press, Oxford, 1994); Shapiro, Practical Flow Cytometry. 3rd Edition; (Alan R Liss, Inc.). Givan, Flow Cytometry. First Principies (Wiley-Liss, New York, 1992.); Robinson (ed.) Handbook of Flow Cytometry Methods. (Wiley-Liss, New York, 1993) FAC provides the mean of the examination of individual cells in search of the presence of deregulated β-catenin. Antibodies reactive with a particular protein can also be measured through a variety of immunoprotective methods, as discussed herein. To review the immunological and immunoprotective procedures applicable to the measurement of antibodies by immunoprotection techniques, see, for example, Stites and Terr (eds.) Basic and Clinical Immunology (7th ed.) Mentioned in preceding paragraphs; Maggio (ed.) Enzyme Immunoassay, mentioned in previous paragraphs; and Harlow and Lane, Antibodies, A Laboratory Manual, mentioned in previous paragraphs. Techniques for determining the location of β-catenin in cells using immunoprotes are known in the art, for example, see Wakita et al. 2001 Cancer Res. 61: 854-858; Carayol I went to. 2002 Am J. Respir Cell Mol Biol. 26: 341-347; Lim et al 2002 Oncology Reports 9: 915-928; and Sakai I went to. 2002 Int. J. Oncology 21: 547-552; all incorporated herein by reference. OTHER CONDITIONS AND DISEASES Other conditions and diseases that can be treated with the compounds described herein include, for example, benign prostatic hyperplasia, familial adenomatous polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, fibrosis that presents with radiotherapy, arthritis, psoriasis, glomerulonephritis, restenosis after angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplant rejection, endotoxic shock in addition to fungal infections; in addition to conditions associated with defective apoptosis, such as cancer (including, but not limited to, the types already mentioned in the preceding paragraphs herein), viral infections (including without limitation, HIV, human papillomavirus, herpesvirus, virus) of smallpox, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of the development of AIDS in HIV-infected individuals, autoimmune diseases (including, without limitation, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, mediated autoimmune glomerulonephritis, inflammatory bowel disease and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy, and cerebral degeneration), myelodysplastic syndromes , dysplastic anemia, ischemic lesions associated with myocardial infarction heartburn, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver diseases, hematological diseases (including, but not limited to, chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including, without limited to these, osteoporosis and arthritis), rhinosinusitis sensitive to aspirin, cystic fibrosis, multiple sclerosis, schizophrenia, renal diseases, abnormal angiogenesis and pain caused by cancer. Compounds that inhibit abnormal or uncontrolled angiogenesis are useful for the treatment of neoplasms, including metastasis; ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological conditions. More non-malignant, such as hemangiomas, including infantile hemangiomas, angiofibromas of the nasopharynx and avascular necrosis of the bones; as well as disorders of the female reproductive system, such as endometriosis. PREPARATION OF THE COMPOUNDS OF THE INVENTION The compounds of the present invention can be synthesized using standard synthesizing techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. See, for example, March, Advanced Organic Chemistry 4th ed. , (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 3rd ed., Volumes A and B (Plenu 1992), and Green and Wuts, Protective Groups in Organic Synthesis 2nd Ed. (Wiley 1991). General methods for the preparation of compounds as described herein may be derived from the reactions known in the art, and the reactions may be modified by the use of reagents and suitable conditions, as will be recognized by those skilled in the art, for the presentation of several portions found in the formulas provided herein. Selected examples of covalent bonds and functional groups of precursors that produce them are presented in the Table entitled "Examples of covalent bonds and precursors thereof". The functional groups of the precursors are shown as electrophilic groups and nucleophilic groups. The functional group in the organic substance can be directly annexed or can be attached through a useful separator or bonds as defined below. Examples of covalent bonds and precursors thereof In general, electrophilic carbons are susceptible to attack by complementary nucleophiles, including nucleophilic carbons, where an attacking nucleophile provides a pair of electrons to the electrophilic carbon to form a new bond between the nucleophile and the electrophilic carbon. Suitable nucleophilic carbons include, but are not limited to, alkyl, alkenyl, aryl and alkynyl of Grignard, organolithium reagents, organozinc, alkyl-, alkenyl, aryl- and alkynyl tin (organotins), alkyl-, alkenyl- reagents, aryl- and alkynylborane (organoborane and organoboronates); these nucleophilic carbons have the utility of being kinetically stable in water or in polar organic solvents. Other nucleophilic carbons include phosphorus iodides, enol and enolate reagents; these nucleophilic carbons have the utility that they can be easily generated from precursors already known to those skilled in the art of synthetic organic chemistry. Nucleophilic carbons when used in conjunction with electrophilic carbons, generate new carbon-carbon bonds between the nucleophilic carbon and the electrophilic carbon. Nucleophilic non-carbon suitable for coupling to electrophilic carbons include, without being limited to primary and secondary amines, thiols, thiolates and thioethers, alcohols, alkoxides, azides, semicarbazides, and the like. These non-nucleophilic carbon, when used in conjunction with electrophilic carbons, commonly generate heterogeneous atom bonds (C-X-C), where X is a heterogeneous atom, for example, oxygen or nitrogen. The term "protecting group" refers to the chemical portions that block some or all of the reactive portions and prevents said groups from participating in chemical reactions until the protective group is removed. It is preferred that each protecting group be removable through various means. The protective groups that are embedded under conditions of disparate reactions fill the differential removal requirement. The protecting groups can be removed by hydrogenolysis, acid and base. Groups such as trifyl, dimethoxytrityl, acetal and t-butyldimethylsilyl are unstable acids and can be used to protect the reactive carboxy and hydroxy moieties in the presence of protected amino groups with Cbz groups, which can be removed through hydrogenolysis, and Fmoc groups, which are unstable bases. The reactive portions of carboxylic acid and hydroxy can be blocked with unstable base groups such as, without limitation, methyl, ethyl, and acetyl in the presence of blocked amines with unstable acid groups such as t-butyl carbamate or with carbamates which are stable but hydrolytically removable acids and bases. Reactive portions of carboxylic acid and hydroxy can also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids can be blocked with unstable base groups such as Fmoc. Reactive carboxylic acid moieties can be protected by conversion to simple ester derivatives as exemplified herein, or they can be blocked with protective groups removable by oxidation such as 2-dimethoxybenzyl, while coexisting with amino groups that can be blocked with carbamates. of unstable fluoride silyl. The blocking groups of a I i I o are useful in the presence of acid or base protecting groups, since the former are stable and can be subsequently removed by pi-acid or metal catalysts. For example, a carboxylic acid blocked with I i o can be deprotected with a Pd0 catalyzed reaction in the presence of unstable amino acetate base or unstable t-butyl carbamate acid protecting groups. Another form of a protecting group is a resin to which a compound or intermediate can be attached. While the residue is attached to the resin, that functional group is blocked and can not react. Once it is released from the resin, the functional group is available to react. Common protective / blocking groups can be selected from: Atine Me Et t-butyl TBDMS Tcoc Other protective groups are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety. In various embodiments, the compounds of the present invention may be prepared in accordance with the following reaction schemes and examples, or modifications thereof. The raw material can be purchased or made with the methods known in the art or as illustrated. In these reactions, one skilled in the art may use variations that are not described in detail. Other methods for preparing the compounds of the invention will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. For example, the synthesis of non-exemplified compounds according to the invention can be performed in a satisfactory manner making the modifications obvious to one skilled in the art, for example, by adequate protection of the interference groups, making a change to other suitable reagents known in the art, or by making routine modifications of the reaction conditions. Alternatively, other reactions described herein or generally known in the art will be recognized with an ability to be applied to prepare other compounds of the invention. Unless stated otherwise, the variables are as defined in the preceding paragraphs. The abbreviations used in the application have the following meanings, unless otherwise indicated: EtOH: ethyl alcohol; NH2OH.HCl: hydroxylamine; CCI3CH (OH) 2: doral hydrate; H2SO4: sulfuric acid; LiBH 4: lithium borohydride; CICOCOCI: oxalyl chloride; HCl: hydrochloric acid; NaOH: sodium hydroxide; BF3. Et20: boron trifluoride etherate; CH2Cl2: methylene chloride; [R]: partial reduction. General Scheme 1A shows the preparation of pyranoindol-1-yl alcohols from raw material 1. General Scheme 1 1A.

In General Scheme 1, 1, 3,4,9-tetrahydro-pyrano [4-b] indole of this invention can be prepared by techniques known to those skilled in the art of organic synthesis. The substituted tryptopholes (VI) can be prepared by the appropriate segment of the path illustrated in General Scheme 1A, starting with an aniline (I), a satin (III), or an indole (IV). Suitable raw materials are commercially available anilines with desired R or can be easily prepared. The aniline can be converted into a corresponding satin (III) through the treatment of aniline with chloral hydrate and hydroxylamine, followed by heating with sulfuric acid. Indole (IV) can be obtained by reduction of satin with lithium borohydride or other reducing agents. Tryptofol (VI) can be prepared by acylation in the 3-position of indole (IV) with a suitable reagent, for example, oxalyl chloride, followed by reduction of gluoxylate (V) with lithium borohydride. The substituted triptopholes (VI) can be condensed with a suitable ketone or aldehyde, in the presence of an acid catalyst, to provide 1,3,4,9-tetradihydro-pyrano [3-b] indole (Vil). After the ester (VII) is reduced through a reducing reagent, for example lithium borohydride, the title compounds (IX) can be prepared from (HIV) by displacement of halogen with an appropriately activated Ar portion. For example, in the presence of a suitable Pd (L) m catalyst, Ar-boronic acids can be coupled through a Suzuki reaction to present the title compounds (IX). Compounds (X) and (XI) can be prepared, through a Heck reaction, starting from suitable alkyne precursors and alkenes in the presence of a Pd (L) m catalyst. The cis isomer of (XI) can also be prepared by a partial reduction of (X) by hydrogenation over palladium on activated carbon which was treated with quinoline. General Scheme 1B shows the preparation of alkynylphenamides piranoindoI-1-iio from raw material 6. Scheme 1B Scheme 1B illustrates the synthesis of the title compounds (XIII), (XIV), or (XV) wherein - (CH2) nS02Y is substituted at the 1-position of 1, 3,4,9-tetradihydro-pyran [3 , 4-b] indole. The compounds (XIII) can be prepared by the condensation of the tryptopholes (VI) with a suitable ketone or an aldehyde containing -S02Y in the presence of a suitable acid, followed by coupling reactions, which can be through the reaction of Suzuki with an Ar portion properly activated in the presence of an appropriate Pd (L) m catalyst. Analogously, compounds (XIV) and (XV) can be prepared, through a Heck reaction, starting from suitable alkynes and alkenes in the presence of an appropriate Pd (L) m catalyst.

General Scheme 2 illustrates the additional embodiment wherein R-io is a lower alkyl, lower alkenyl, lower alkynyl or aryl. The nitrogen of the compound (VII) can be alkylated with an appropriate alkyl halide in the presence of a suitable base. After the ester is reduced to alcohol (XVII) through a suitable reducing reagent, for example, lithium borohydride, the title compounds (XVIII), (XIX), or (XX) can be prepared through reactions of coupling, for example, the Suzuki reaction or the Heck reaction. General scheme 2 R10 = lower alkyl, lower alkenyl, lower alkynyl, benzyl, or aryl X = Br, l General Scheme 3 illustrates the synthesis of the compounds wherein R is substituted R 9 is an isopropyl group, R-i is ethyl, and Y-Z is ethylalcohol. Scheme 3 Br2 AcOH, heat General Scheme 4 illustrates the synthesis of pyranoindol-1-yl alcohols. General scheme 4 -OiMH-Q- - "-ex R2CO (CH2) nC02R R, r and f? J R ^ (CH2)" C02R EXAMPLES EXAMPLE 1: SYNTHESIS OF COMPOUNDS COMPOSED 1: 2-M .8-diethyl-6-phenyl-1.3.4.9-tetrahydro-pyran Í3.4- blindol-1-in-ethanol 1. A. Synthesis of N- (4-Bromo-2-etl-phenyl-2-hydroxy-acetoamide) To a suspension of 4-bromo-2-ethylaniline (50.0 g, 250 mmoi) in water (1000 mi) was added concentrated hydrochloric acid (25 ml), sodium sulfate (220 g), and hydroxylamine hydrochloride (26.25 g), followed by the addition of a doral hydrate (44.0 g). 90 ° C using an oil bath for 1 hour.After cooling to room temperature, it was extracted with ethyl acetate.The extract was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (31.1 g, 46% yield) 1 H NMR (DMSO-d 6) d 12.24 (s, 1 H), 9.56 (s, 1 H), 7.68 (s, 1 H), 7.41 (m, 3 H), 2.58 (q, 2 H), 1.11 (t, 3H) 1.B. Synthesis of 5-Bromo-7-ethyl-1 H-indole-2,3-dione To a solution of sulfuric acid (100 ml) and water (10 ml) at 80 ° C (oil bath) was added N- (4-bromo-2-ethyl-phenyl) -2-hydroximino-acetoamide (60.0 g, 225 mmol) in small portions during 20 minutes The reaction mixture was heated to 80 ° C (in an oil bath) for 15 minutes. After cooling to room temperature, ice water (500 ml) was added and the mixture was extracted with ethyl acetate. The extracts were washed with a solution of sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (42.3 g, yield 74%). 1 H NMR (DMSO-d 6) d 8.87 (s, 1 H), 7.75 (d, 1 H), 7.71 (d, 1 H), 2.75 (q, 2 H), 1.44 (t, 3 H). 1 C. Synthesis of ethyl ester of (5-Bromo-7-ethyl-1H-indol-3-iP-oxo-acetic acid) To a solution of 5-bromo-7-ethyl-1 H-indole-2,3-dione ( 36. g, 144 mmol) in tetrahydrofuran (120 ml) at room temperature was added dropwise a 2.0 M solution of lithium borohydride in tetrahydrofuran.The reaction mixture was stirred at 90 ° C (in oil bath) for 5 hours After cooling to room temperature, it was quenched with a 5% hydrochloric acid solution until the excess of lithium borohydride was destroyed, a solution of sodium bicarbonate (300 ml) was added to the mixture and it was extracted with acetate. The extracts were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product of 5-bromo-7-ethyl-1H-indole, which was taken to the next reaction without further purification. of 5-bromo-7-etiI-1 H-indole in ethyl ether (400 ml) at room temperature under nitrogen, a solution of 2.0 M oxalyl chloride in dichloromethane was added. After stirring the reaction mixture at room temperature for 6 hours, the solvents were removed under reduced pressure. To the residue was added ethyl alcohol (400 ml) and stirred at room temperature overnight. After removing the ethyl alcohol under reduced pressure, a solution of saturated sodium bicarbonate (300 ml) was added to the residue and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate 30-50%) to give the title compound (14.5 g, 31% yield). ES-MS (m / z) 324 [M + 1] +, 322 [M-1] \ 1.D. Synthesis of (6-bromo-1, 8-diethyl-1,3,4,9-tetrahydro-pyran [3,4-b] indol-1-yl) -acetic acid ethyl ester To an ester solution of Ethyl (5-bromo-7-ethyl-1 H-indol-3-yl) -oxo-acetic acid (1.55 g, 4.8 mmol) in tetrahydrofuran at room temperature under nitrogen was added dropwise a 2 M solution of sodium borohydride. lithium in tetrahydrofuran. The reaction mixture was heated at 90 ° C in an oil bath for 5 hours. After cooling to room temperature, it was quenched with a 5% hydrochloric acid solution until excess lithium borohydride was destroyed. A solution of saturated sodium bicarbonate was added to the mixture and extracted with ethyl acetate. The extracts were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product of 2- (5-bromo-7-ethyl-1 H-indoI-3-yl) -ethanol, which was taken to the next reaction without further purification. To a solution of 2- (5-bromo-7-etiI-1 H-indol-3-yl) -ethanol in dichloromethane at room temperature under nitrogen was added diethyl etherate boron trifluoride (0.809 g, 5.7 mmol), followed by ethyl propionylacetate (1.038 g, 7.2 mmol). The reaction mixture was stirred at room temperature for 5 hours. It was quenched with a saturated sodium bicarbonate solution and extracted with methylene chloride. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified through column chromatography (silica gel, hexane / ethyl acetate 15-20%) to give the title compound (0.994 g, 53% yield). ES-MS (m / z) 394 [M + 1] +, 392 [M-1] \ 1.E. Synthesis of 2- (6-bromo-1,8-d-ethyl-1, 3.4.9-tetrahydro-pyranof3.4-blindol-1-p-ethanol To a solution of ethyl ester of (6-bromo-1, 8-diethyl-l, 3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -acetic acid (5.2 g, 13.2 mmol) in tetrahydrofuran at room temperature under nitrogen was added dropwise 2.0 M solution of lithium borohydride in tetrahydrofuran.The reaction mixture was heated to 90 ° C (in an oil bath) for 5 hours.After cooling to room temperature, it was quenched with a 5% hydrochloric acid solution until it was destroyed. Excess lithium borohydride Water was added and the mixture was extracted with ethyl acetate The extracts were dried over magnesium sulfate and concentrated under reduced pressure The crude product was purified by column chromatography (silica gel hexane / ethyl acetate 50%) to give the title compound (3.80 g, 82% yield) -, H NMR (CDCl 3) d 8.07 (s, 1H), 7.64 (d, 1 H), 7.26 (d, 1H), 4.17 (m, 2H), 3.86 (m, 2H), 2.94 (m, 3H), 2.87 (dt, 1H), 2.76 (t, br, 1H), 2.36 (m , 1H), 2.24 (m, 1H), 2.13 (m, 2H), 1.49 (t, 3H), 1.08 (t, 3H). ES-MS (m / z) 352 [M + 1] +, 350 [M-1] \ 1. F. Synthesis of 2- (1,8-diethyl-6-phenyl-1, 3,4,9-tetrahydropyranof3, 4- blindol-1-ih- ethanol To a solution of 2- (6-bromo-1, 8-diethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) Ethanol (3.8 g, 10.8 mmol) in dimethyl ether ethylene glycol (50 ml) was added potassium phosphate (6.37 g, 30 mmol), phenylboronic acid (1.83 g, 15 mmol), and complex [1]., 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) with dichloromethane. The reaction mixture was heated to 90 ° C (in an oil bath) overnight. It was quenched with water and extracted with ethyl acetate. The extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 50% hexane / ethyl acetate, followed by chloroform / hexane Sephadex LH-20, 50%) to give the title compound (0.75 g, 20% yield) . 1 H NMR (CDCl 3) d 7. 77 (s, 1 H), 7.66 (d, 1 H), 7.63 (m, 1 H), 7.56 (d, 1 H), 7.44 (m, 3 H), 7.32 (m, 1 H), 4.06 (m, 2H), 3.72 (m, 3H), 2.91 (m, 3H), 2.81 (dt, 1H), 2.65 (d, 1H), 2.20 (m, 1H), 2.07 (m, 2H), 1.40 (t, 3H), 0.95 (t, 3H). ES-MS (m / z) 348 [M-1] \ COMPOUND 2: 2-M .8-diethyl-6- (4-methoxy-phenin-1.3.4.9-tetrahydro-pyrano f3.4-b1indol-1- N- ethanol The title compound was prepared in analogy to Example 1, with the exception of the use of 4-methoenylboronic acid in step 1.F. COMPOUND 3: 2-M .8-diethyl-6- (3-trifluoromethoxy-phenyl) -1, 3.4.9-tetrahydro-pyran-3,4-b] indole-1-yl-ethanol The title compound was prepared in analogy to Example 1, with the exception of the use of 3-fluoromethoenylboronic acid in step 1.F. COMPOUND 4: 2-I1.8-diethyl-6- (2-trifluoromethyl-phenan-1,3,4,9-tetrahydro-pyran [3,4-b1indol-1-yl] -ethanol The title compound was prepared as described in Example 1, with the exception of the use of 2-trifluoromethylphenylboronic acid in step 1.F. COMPOUND 5: 2-rß- (2,4-difluoro-phenin-1,3-diethyl-1,3,4,9-tetrahydropyran f 3 .4-b1indol-1-yl-ethanol The title compound was prepared in analogy to Example 1, with the exception of the use of 2,4-difluorophenylboronic acid in step 1.F. COMPOUND 6: 2-M .8-diethyl-6-pyridine-4-l-1.3.4.9-tetrahydro-pyranof3,4-blindol-1-ethanol The title compound was prepared in analogy to Example 1, with the exception of the use of the pyridine-4-boric acid in step 1.F. COMPOUND 8: 2- f6-f3-amino-phenin-1,8-diethyl-1.3.4.9-tetrahydro-pyranoí3. 4- blindol-1-ill-ethanol The title compound was prepared in a manner analogous to Example 1, with the exception of the use of 3-aminophenylboronic acid in step 1.F. COMPOUND 10: 2- rß-f3.4-difluoro-phenyl) -1,8-diethyl-1, 3,4,9-tetrahydro-pyrano [3, 4-b] indol-1-yl-1-ethanol The title compound was prepared in a manner analogous to Example 1, with the exception of the use of 3,4-difluorophenylboronic acid in step 1.F. COMPOUND 11: 2-r6- (5-Chloro-thiophen-2-n-1,8-diethyl-1, 3,4,9-tetrahydro-pyran [3, 4-blindol-1-ill-ethanol] The title compound was prepared in analogy to Example 1, with the exception of the use of 5-chloro-2-tlofenboric acid in step 1.F. COMPOUND 12: 2-M-ethyl-6-isopropyl-8-phenyl-1,3,4,9-tetrahydro-pyran [3,4-b1indol-1-yl] -ethanol 12. A. Synthesis of N- (2-Bromo-4-isopropyl-pheyp-2-hydroxyiminoacetoamide) The title compound was prepared in analogy to Example 1, with the exception of the use of 2-bromo-4-aminoaniline acid in the step 1.A. 12. B. Synthesis of 7-Bromo-5-isopropyl-1 H-indole-2,3-dione The title compound was prepared in a manner analogous to Example 1, with the exception of the use of N- (2-bromo-4-isopropyl-phenyl) -2-hydroximino-acetoamide in step 1.B. 12. C. Synthesis of (7-Bromo-5-isopropyl-1H-indol-3-p-oxoacetic acid ethyl ester) The title compound was prepared in analogy to Example 1, except for the use of 7-bromo-5-isopropyl-1 H-indole-2,3-dione in step 1.C. 12. D. Synthesis of ethyl ester of (8-Bromo-1-ethyl-6-isopropyl- 1, 3,4,9-tetrahydro-pyranof3,4-b1indol-1-ip-acetic acid The title compound was prepared in analogy to Example 1, with the exception of the use of ethyl ester of (7-bromo- 5-isopropyl-1H-indoI-3-yl) -oxo acetic acid in step 1.D. 12.E. Synthesis of 2- (8-Bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro- pyran [3,4-b] ndol-1-yl) -ethanol The title compound was prepared in analogy to Example 1, with the exception of the use of ethyl ester of (8-bromo-1-ethyl-6) acid. -isopropyl-1, 3,4,9-tetrahydro-pyrano [3-b] idol-1-yl) -acetic in step 1.E. 12.F. Synthesis of 2- (1-ethyl-6-) isopropyl-8-phenyl-1.3.4.9-tetrahydro-pyran [3.4-blindol-1- il) -ethanol The title compound was prepared in analogy to Example 1, with the exception of the use of 2- (8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyran [ 3-b] indol-1-yl) -ethanol in step 1.F. COMPOUND 13: 2-r8- (3- (cyano-phenin-1-ethyl-6-isopropyl-1, 3,4,9-tetrahydro-pyran [3,4-b1indol-1-yl] -ethanol) The title compound was prepared in analogy to Example 1, with the exception of the use of 2- (8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyran [3,4- b] indol-1-yl) -ethanol and 3-cyanophenylboronic acid in step 1.F. COMPOUND 14: 2- [8- (5-bromo-2-methoxy-phen-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-p-rano [3, 4-blindol-1-il ) - ethanol The title compound was prepared in analogy to Example 1, with the exception of the use of 2- (8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyran [3,4- b] indoI-1-yl) -ethanol and 2-bromo-3-methoxypheniolboric acid in step 1.F. COMPOUND 15: 2-M - (- ethyl-8- (2-fluoro-biphenyl-4-yn-6-isopropyl-1,3,4,9-tetrahydro-pyrano [3,4-b] indol-1-ill -ethanol The title compound was prepared in analogy to Example 1, with the exception of the use of 2- (8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyran [3,4- b] indole-1-yl) -ethanol and 2-fluorobiphenyl-4-boronic acid in step 1.F. COMPOUND 16: 4-M-ethyl-1- (2-hydroxy-ethyn-6-isopropyl-1, 3,4,9-tetrahydro-pyran [3,4-b] indol-8-ip-benzoic acid The title compound was prepared analogously to Example 1, except for the use of 2- (8-bromo-1-ethyl-6-isopropyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indole). 1-yl) -ethanol and 4-carboxylphenylboronic acid in step 1.F. COMPOSITE 17: 3-M-ethyl-1 - (2-hydroxy-ethylene-6-isopropyl-1, 3.4.9- tetrahydro-pyrano [3,4-bl indole-8-iH-benzaldehyde The title compound was prepared in analogy to Example 1, with the exception of the use of 2- (8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyran [3,4- b] indole-1-yl) -ethanol and 3-formylphenylboronic acid in step 1.F. COMPOUND 18: 2-r8- (3,5-dimethyl-phenin-1-ethyl-6-isopropyl-1,3.4.9-tetrahydro-pyran r3.4-blindol-1-h-ethanol The title compound was prepared in analogy to Example 1, with the exception of the use of 2- (8-bromo-1-ethyl-6-isopropyl-1, 3,4,9-tetrahydro-pyran [3,4-] b] indol-1-yl) -ethanol and 3,5-dimethylphenylboronic acid in step 1.F. COMPOUND 19: 2- (8-dibenzofuran-3-yl-1-ethyl-6-isopropyl-1, 3,4,9-tetrahydro-pyran [3,4-blindol-l-ih-ethanol] The title compound was prepared in analogy to Example 1, with the exception of the use of 2- (8-bromo-1-ethyl-6-isopropyl-1, 3,4,9-tetrahydro-pyran [3,4-] b] indol-1-yl) -ethanol and 4-dibenzofuranboric acid in step 1.F. COMPOUND 20: 2- (1-ethyl-6-isopropyl-8-styryl-1.3.4.9-tetrahydro-pyran [3,4- b] indole-1-iH-ethanol . A. Synthesis of 2- (1-ethyl-6-isopropyl-8-styryl-1.3.4.9-tetrahydro-pyran [3,4-blindol-1-yl) -ethanol The title compound was prepared in accordance with the following process. To a solution of 2- (8-bromo-1-ethyl-6-isopropyl-1, 3,4,9-tetrahydro-pyrano [3-b] indoI-1-yl) ethanol (1.0 mmol) in dry acetonitrile ( 10 mL) under nitrogen was added triethylamine (1.5 mL), tri-o-tolylphosphine (0.4 mmol), styrene (2.0 mmol), and tri (dibenzylideneacetone) dipalladium (0) (0.1 mmol). The reaction mixture was heated to 90 ° C (in an oil bath) overnight. It was quenched with water and extracted with ethyl acetate. The extracts were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography (silica gel) provided the title compound. COMPOUND 21: 2-M-ethyl-6-isopropyl-8-phenylethenyl-1.3.4.9-tetrahydro-pyran [3.4-blindol-1-iD-ethanol The title compound was prepared in analogy to Example 20. A, except that phenylacetylene was used. COMPOUND 22: (1-ethyl-1.3.4.9-tetrahydro-pyranor3.4-b1indol-1-yl) -ethanol The title compound was prepared in a manner analogous to the procedure outlined below: 22. A. Synthesis of ethyl ester of (1-ethyl-1,3,4,9-tetrahydro-pyrranof 3,4-bindole-1-p-acetic acid) A mixture of tryptophol (1,612 g, 10 mmol), ethyl propionylacetate ( 1730 g, 12 mmol), and p-toluenesulfonic acid mohydrate (20 g) in benzene (70 ml) was heated under reflux for 5 hours, quenched with ethyl acetate and washed with saturated sodium bicarbonate. dried over magnesium sulfate and evaporated to dryness, Flash chromatography over silica gel afforded 1943 g (68%) of the title compound as a solid, PF <80 ° C., 1 H NMR (300 MHz, CDCl 3) d 9.06 (br, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 7.14 (t, 1H), 7.12 (t, 1H), 4.18 (q, 2H), 4.03 (m, 1H), 3.94 (m, 1H), 2.99 (d, 1H), 2.88 (d, 1H), 2.78 (m, 2H), 2.14 (m, 1H), 2.01 (m, 1H), 1.25 (t, 3H), 0.82 ( t, 3H); ESI (+) MS m / e = 288 (MH +), ESI (-) MS m / e = 286 (Ml-T). 22.B. Synthesis of acid (1-ethyl-1, 3.4.9-tetrahydro-pyran [3,4-b1indol-1-yl) -acetic acid To a solution of ethyl ester of (1-ethyl-1-1, 3,4,9 -tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid (2.50 g, 8.7 mmol) in 1,4-dioxane was added a solution of lithium hydroxide monohydrate (1.50 g, 35.7 mmol) in water (5 mi). The mixture was stirred at room temperature overnight. It was neutralized with a 5% HCl solution and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography on silica gel afforded 0.954 g (42%) of the title compound as a solid. PF. 135-136 ° C. 1 H NMR (500 MHz, CDCl 3) d 10.0 (br, 1H), 8.55 (br, 1H), 7.51 (d, 1H), 7.34 (d, 1H), 7.18 (t, 1H), 7.12 (t, 1H) , 4.12 (m, 1H), 4.06 (m, 1H), 3.01 (d, 1H), 2.99 (d, 1H), 2.85 (m, 2H), 2.10 (m, 1H), 2.03 (m, 1H), 0.86 (t, 3H); ESI (+) MS m / e = 260 (MH +), ESI (-) MS m / e = 258 (MH ") 22. C. Synthesis of (-eti 1-1, 3,4,9-tetrahydro -piranor3,4-blindol-1-iO-ethanol To a solution of (1-ethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid (0.52) g, 2.0 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium aluminum hydride (0.114 g, 3.0 mmol) in several small portions, the mixture was stirred at room temperature for 6 hours, and was quenched with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated to dryness.Stop chromatography on silica gel gave 0.389 g (79%) of the title compound as an oil.1H NMR (500 MHz). , CDCI3) d 7.82 (br, 1H), 7.52 (d, 1H), 7.34 (d, 1H), 7.18 (td, 1H), 7.13 (td, 1H), 4.07 (m, 1H), 4.01 (m, 1H), 3.70 (m, 1H), 3.64 (m, 1H), 2.89 (m, 1H), 2.77 (dt, 1H), 2.71 (br, 1H), 2.20 (m, 1H), 2.05 (m, 1H) ), 2.00 (m, 1H), 1.90 (m, 1H), 0.94 (t, 3H), ESI (+ ) MS m / e = 246 (MH +), ESI (-) MS m / e = 244 (MH '). COMPOUND 23: 2- (1-ethyl-6-methoxy-1, 3,4,9-tetrahydro-pyran) 3,4-b1indol-1-in-ethanol 23. A. Synthesis of ethyl ester of M-ethyl-6-methoxy-1,3,4,9-tetrahydro-pyranor3,4-b1indol-1-P-acetic acid The title compound was synthesized in an analogical manner to step 22, using 5-methoxytryptophol as the 3-indoletanol component in step 22.A.1H NMR (300 MHz, CDCl3) d 8.93 (br, 1H), 7.25 (d, 1H), 6.95 (d, 1H) , 6.90 (dd, 1H), 4.17 (q, 2H), 4.03 (m, 1H), 3.94 (m, 1H), 3.86 (s, 3H), 2.99 (d, 1H), 2.90 (d, 1H), 2.74 (m, 2H), 2.12 (m, 1H), 2.00 (m, 1H), 1.27 (t, 3H), 0.82 (t, 3H); ESI (+) MS m / e = 318 (MH +), ESI (-) MS m / e = 316 (MH ") 23. B. Synthesis of acid (1-ethyl-6-methoxy-1, 3.4. 9-tetrahydro-pyran [3,4-b1indol-1-yl) -acetic The title compound was synthesized in an analog manner to step 22, using ethyl ester of (1-ethyl-6-methoxy-1, 3,4 , 9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid as the ester component in step 22. B, and gave the title compound as a solid, PF 169 ° C. (300 MHz, CDCl 3) d 8.38 (br, 1H), 7.22 (d, 1H), 6.94 (d, 1H), 6.84 (d, 1H), 4.08 (m, 2H), 3.85 (s, 3H), 2.97 (m, 2H), 2.81 (m, 2H), 2.02 (m, 2H), 0.85 (t, 3H), ESI (+) MS m / e = 290 (MH +), ESI (-) MS m / e = 288 (MH "). 23. C. Synthesis of 2- (1-ethyl-6-methoxy-1.3.4.9-tetrahydro-pyranor3.4-b] indol-1-yl) -ethanol The title compound was synthesized in an analog manner to step 22 , using (1-ethyl-6-methoxy-1, 3,4,9-tetrahydro-pyrano [3,4-b] indoI-1-yl) -acetic acid as the carboxylic acid component in step 22. C, and gave the title compound as a solid. 1 H NMR (500 MHz, CDCl 3) d 7.71 (br, 1 H), 7.22 (d, 1 H), 6.97 (d, 1 H), 6.83 (dd, 1 H), 4.08 (m, 1 H), 4.00 (m, 1 H) , 3.86 (s, 3H), 3.69 (m, 1H), 3.64 (m, 1H), 2.85 (m, 1H), 2.73 (dt, 1H), 2.19 (m, 1H), 2.05 (br, 1H), 2.03 (m, 1H), 1.98 (m, 1H), 1.89 (m, 1H), 0.93 (t, 3H); ESI (+) MS m / e = 276 (MH +), ESI (-) MS m / e = 274 (MH '). COMPOUND 24: 2- (1 -eti l-6-metí I-1, 3,4,9-tetrahydro-pyran Í3.4- blindol-1-in-ethanol 24. A. Synthesis of 2- (5-methyl-1 H-indol-3-ih-ethanol To a suspension of 4-methyl-phenylhydrazine hydrochloride (250 g, 15.7 mmol) in 1-dioxane (25 mL) and water (1.5 mL) was added dropwise pure 2,3-dihydrofuran (1.66 g, 23.6 mmol). After the addition, the mixture was heated at 95 ° C for 4 hours. After cooling to room temperature, it was poured into ethyl ether, dried over magnesium sulfate and evaporated to dryness. Chromatography on silica gel afforded 0.485 g (18%) of the title compound as a solid. 1 H NMR (500 MHz, CDCl 3) d 7.95 (br, 1 H), 7.41 (s, 1 H), 7.27 (d, 1 H), 7.05 (m, 2 H), 3.90 (dd, 2 H), 3.01 (t, 2 H) , 2.46 (s, 3H), 1.50 (t, br, 1H). 24.B. Synthesis of ethyl ester of d-ethyl-6-methyl-1, 3,4,9-tetrahydro-pyran [3,4-b1indol-1-h-acetic acid To a solution of 2- (5-methyl-1 H-indole -3-yl) -ethanol (0.48 g, 2.7 mmol) in dichloromethane (10 mL) was added diethyl etherate boron trifluoride (0.468 g, 3.3 mmol), followed by ethyl propionylacetate (0.649 g, 4.5 mmol). The mixture was stirred at room temperature for 5 hours. It was quenched with a saturated sodium bicarbonate solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel afforded 0.421 g (52%) of the title compound as an oil. 1 H NMR (500 MHz, CDCl 3) d 8.90 (br, 1 H), 7.28 (s, 1 H), 7.24 (d, 1 H), 6.99 (d, 1 H), 4.16 (m, 2 H), 4.03 (m, 1 H) , 3.94 (m, 1H), 2.98 (d, 1H), 2.88 (d, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 2.44 (s, 3H), 2.12 (m, 1H), 1.98 (m, 1H), 1.25 (t, 3H), 0.80 (t, 3H); ESI (-) MS m / e = 300 (MH ") 24. C. Synthesis of acid (1-ethyl-6-methyl-1, 3,4,9-tetrahydro-pyrranof-3,4-b1ndol -1-p-acetic The title compound was synthesized in an analog manner to step 22. B, using ethyl ester of (1-ethyl-6-methyl-1, 3,4,9-tetrahydro-pyran [ 3,4-b] indol-1-yl) -acetic as the ester component and the title compound was obtained as a solid, PF 158-159 ° C, 1 H NMR (500 MHz, CDCl 3) d 9.70 (br, 1H), 8.33 (br, 1H), 7.29 (s, 1H), 7.22 (d, 1H), 7.00 (d, 1H), 4.10 (m, 1H), 4.05 (m, 1H), 2.99 (d, 1H) ), 2.98 (d, 1H), 2.81 (q, 2H), 2.44 (s, 3H), 2.07 (m, 1H), 2.01 (m, 1H), 0.85 (t, 3H); ESI (+) MS m / e = 274 (MH +), ESI (-) MS m / e = 272 (MH ") 24. D. Synthesis of 2-M-ethyl-6-methyl-1, 3.4. 9-tetrahydro-pyran [3,4-b] indol-1-yl) -ethanol The title compound was synthesized in an analogue manner to step 22. B, using acid (1-ethyl-6-methyl-1, 3,4 , 9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid as the carboxylic acid component and the title compound was obtained as a solid PF 114-115 ° C. 1 H NMR (500 MHz , CDCI3) d 7.70 (br, 1H), 7.30 (s, 1H), 7.21 (d, 1H), 7.00 (dd, 1H), 4.06 (m, 1H), 3.97 (m, 1H), 3.67 (m, 1H), 3.62 (m, 1H), 2.84 (m, 1H), 2.73 (m, 1H), 2.71 (br, 1H), 2.45 (s, 3H), 2.17 (m, 1H), 2.04 (m, 1H) ), 1.96 (m, 1H), 1.86 (m, 1H), 0.92 (t, 3H), ESI (+) MS m / e = 260 (MH +), ESI (-) MS m / e = 258 (MH "). COMPOUND 25: 2- (1-ethyl-8-methyl-1, 3.4.9-tetrahydro-pyran [3.4-blindol-l-ih-ethanol . A. Synthesis of 2- (7-methyl-1 H-indol-3-ih-ethanol) Following the procedure of Example 24. A, except that 2-methylphenylhydrazine hydrochloride was used as the hydrazine component, the compound of titre as a solid.1H NMR (500 MHz, CDCl3) d 7.97 (br, 1H), 7.49 (d, 1H), 7.11 (d, 1H), 7.07 (t, 1H), 7.03 (d, 1H), 3.91 (t, 2H and br, 1H), 3.04 (t, 2H), 2.49 (s, 3H) 25. B. Synthesis of ethyl ester of acid (1-ethyl-8-methyl-1, 3.4.9- tetrahydro-pyran [3,4-b1indol-1-ip-acetic Following the procedure of Example 23. B. Except that 2- (7-methyI-1 H -indodo-3-yl) -ethanol was used as the 3-indoletanol component the title compound was obtained as a solid, PF 77-78 ° C, 1 H NMR (500 MHz, CDCl 3) d 9.04 (br, 1H), 7.36 (d, 1H), 7 02 (t, 1H), 6.97 (d, 1H), 4.19 (m, 2H), 4.04 (m, 1H), 3.94 (m, 1H), 2.98 (d, 1H), 2.90 (d, 1H), 2.81 (m, 1H) ), 2.75 (dt, 1H), 2.49 (s, 3H), 2.15 (m, 1H), 2.02 (m, 1H), 1.27 (t, 3H), 0.83 (t, 3H), ESI (-) MS m / e = 300 (MH ").

. C. Synthesis of 2- (1-ethyl-8-methyl-1, 3.4.9-tetrahydro-pyran [3.4-blindol-1-yl] -ethanol) Following the procedure of Example 22. C, except that it was used Ethyl ester of (1-ethyl-8-methyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indoI-1-yl) -acetic acid as the carboxylic acid component, the compound was obtained of the title as a solid. PF. 68 ° C. 1 H NMR (500 MHz, CDCl 3) d 7.68 (br, 1 H), 7.37 (d, 1 H), 7.05 (t, 1 H), 6.98 (d, 1 H), 4.06 (m, 1 H), 3.98 (m, 1 H) , 3.70 (m, 1H), 3.65 (m, 1H), 2.88 (m, 1H), 2.76 (t, 1H), 2.72 (m, 1H), 2.47 (s, 3H), 2.21 (m, 1H), 2.07 (m, 1H), 2.00 (m, 1H), 1.91 (m, 1H), 0.94 (t, 3H); ESI (+) MS m / e = 260 (MH +), ESI (-) MS m / e = 258 (MH "). COMPOUND 26: 2-M -eti l-8-f Ior- 1, 3.4. 9-tetrahydro-pyran r3.4-b1ndol-1-m-ethanol 26. A. Synthesis of 2- (7-Fluor-1 H-indol-3-yl) -ethanol Following the procedure of Example 24. A, except that 2-fluoro-phenylhydrazine hydrochloride was used as the hydrazine component, the compound was obtained of the title as an oil. 26.B. Synthesis of (1-ethyl-l-8-fl uor-1, 3,4,9-tetrahydro-pyran [3,4-b1indol-1-yl] -acetic acid ethyl ester Following the procedure of B. Except that 2- (7-fluoro-1 H-indol-3-yl) -ethanol was used as the 3-indoletanol component, the title compound was obtained as an oil. 26. C. Synthesis of 2-M-ethyl-8-fluoro-1, 3,4,9-tetrahydro-pyran [3,4-b1indol-1-p-ethanol] Following the procedure of Example 22. C, except that used ethyl ester of (1-ethyl-8-fluoro-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid as the carboxylic acid component and the composed of the title as a solid. 1 H NMR (500 MHz, CDCl 3) d 8.18 (br, 1H), 7.27 (d, 1H), 7.02 (m, 1H), 6.89 (dd, 1H), 4.07 (m, 1H), 3.99 (m, 1H) , 3.71 (m, 1H), 3.65 (m, 1H), 2.88 (m, 1H), 2.78 (dt, 1H), 2.76 (br, 1H), 2.22 (m, 1H), 2.07 (m, 1H), 1.99 (m, 1H), 1.91 (m, 1H), 0.94 (t, 3H); ESI (+) MS m / e = 264 (MH +), ESI (-) MS m / e = 262 (MH "). COMPOSITE 27: 2- (8-chloro-1-ethyl-1.3.4.9-tetrahydro- pyran [3.4-blindol-1-ih-ethanol 27. A. Synthesis of 2- (7-chloro-1 H-indol-3-in-ethanol Following the procedure of Example 24. A, except that 2-chlorophenylhydrazine hydrochloride was used as the hydrazine component, the compound was obtained 1H NMR (500 MHz, CDCl 3) d 8.26 (br, 1H), 7.52 (d, 1H), 7.21 (d, 1H), 7.15 (d, 1H), 7.06 (t, 1H), 3.91 (t, 2H), 3.02 (t, 2H), 1.48 (br, 1H) 27.B. Synthesis of ethyl ester of acid (8-chloro-1-ethyl-1,3,4,9-tetrah 3-piolol-3,4-b1indol-1-yl) -acetic acid Following the procedure of Example 24. B, except that 2- (7-chloro-1 H -indol-3-yl) -ethane was used as the 3-indoletanol component The title compound was obtained as a solid.1H NMR (500 MHz, CDCl3) d 9.28 (br, 1H), 7.39 (d, 1H), 7.16 (d, 1H), 7.02 (t, 1H) , 4.18 (m, 2H), 4.05 (m, 1H), 3.94 (m, 1H), 2.98 (d, 1H), 2.88 (d, 1H), 2.82 (m, 1H), 2.75 (dt, 1H), 2.15 (m, 1H), 2.03 (m, 1H), 1.27 (t, 3H), 0.84 (t, 3H), ESI (-) MS m / e = 230 (MH ") 27. C. Acid synthesis (8-chloro-1-ethyl-1.3 .4.9-tetrahydro-pyrranof.4.4-b] indol-1-yl) -acetic Following the procedure of Example 22. B, except that (8-chloro-1-ethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid ethyl ester was used as the component ester, the title compound was obtained as a solid. 1 H NMR (500 MHz, CDCl 3) d 8.81 (br, 1 H), 7.40 (d, 1 H), 7.17 (d, 1 H), 7.04 (t, 1 H), 4.09 (m, 1 H), 4.03 (m, 1 H) , 3.05 (d, 1H), 3.02 (d, 1H), 2.82 (m, 2H), 2.13 (m, 1H), 2.06 (m, 1H), 0.88 (t, 3H); ESI (+) MS m / e = 294 (MH +), ESI (-) MS m / e = 292 (MH ") 27. D. Synthesis of 2- (8-chloro-1-ethyl-1.3.4.9 -tetrahydro-pyran [3.4-b1indol-1-ip-ethanol] Following the procedure of Example 22. C, except that acid (8-chloro-1-ethyl-1, 3,4,9-tetrahydro-pyran was used [3,4-b] indol-1-l) -acetic as the carboxylic acid component, the title compound was obtained as a solid.1H NMR (500 MHz, CDCl3) d 8.05 (br, 1H), 7.41 (d , 1H), 7.17 (d, 1H), 7.05 (t, 1H), 4.07 (m, 1H), 4.00 (m, 1H), 3.72 (m, 1H), 3.67 (m, 1H), 2.87 (m, 1H), 2.76 (dt, 1H), 2.70 (br, 1H), 2.23 (m, 1H), 2.03 (m, 1H), 1.91 (m, 1H), 0.94 (t, 3H), ESI (+) MS m / e = 280 (MH +), ESI (-) MS m / e = 278 (MH '). COMPOUND 28: 2- (8-bromo-1-ethyl-1, 3,4.9-tetrahydro-pyran I3.4 - blindol-l-ih-ethanol 28. A. Synthesis of 2- (7-Bromo-1 H-indol-3-ih-ethanol Following the procedure of Example 24. A, except that bromophenylhydrazine 2-hydrochloride was used as the hydrazine component and the compound was obtained 28.B. Synthesis of ethyl ester of (8-bromo-1-ethyl-1,3,4,9-tetrahydro-pyranor 3,4-b) indole-1-p-acetic acid. Following the procedure of 24. B. except that 2- (7-bromo-1 H-indol-3-yl) -ethanol was used as the 3-indolean component, the title compound was obtained as an oil. C. Synthesis of 2- (8-bromo-1-ethyl-1, 3.4.9-tetrahydro-pyranof3.4-b1indol-1-yl) -ethanol To a solution of ethyl ester of (8-bromo) acid 1-ethyl-1,3,4,9-tetrahydropyrano [3-b] indol-1-yl) -acetic acid (1.03 g, 2.8 mmol) in tetrahydrofuran at room temperature was added a solution of 2.0 M lithium borohydride in tetrahydrofuran.

The mixture was refluxed for 5 hours. It was quenched with a 5% HCl solution, followed by saturated sodium bicarbonate. It was extracted with ethyl acetate, the extracts were dried over magnesium sulphate and evaporated to dryness. Crystallization with diethyl ether yielded 0.682 g (75%) of the title compound as a solid. 1H NMR (500 MHz, CDCI3) d 8.01 (br, 1H), 7.45 (d, 1H), 7.32 (d, 1H), 7.00 (t, 1H), 4.07 (m, 1H), 3.99 (m, 1H), 3.72 (m, 1H), 3.67 (m, 1H), 2.87 (m, 1H), 2.75 (dt, 1H), 2.68 (dd, 1H), 2.24 (m, 1H), 2.08 (m, 1H), 2.02 ( m, 1H), 1.93 (m, 1H), 0.94 (t, 3H); ESI (+) MS m / e = 324 (MH +), ESI (-) MS m / e = 322 (MH ') COMPOUND 29: 2- (8-ethyl-1-methyl-1, 3.4.9-tetrahydro) -pirano Í3.4- blindol-l-ih-ethanol 29. A. Synthesis of 2- (7-ethyl-1 H-indol-3-in-ethanol) Following the procedure of Example 24. A, except that 2-hydrochloride ethylphenylhydrazine was used as the hydrazine component, gave the title compound as a solid. 1 H NMR (500 MHz, CDCl 3) d 8.05 (br, 1H), 7.50 (d, 1H), 7.08 (m, 3H), 3.92 (m, 2H), 3.04 (m, 2H), 2.86 ( m, 2H), 2.06 (br, 1H), 1.35 (t, 3H), ESI (+) MS m / e = 190 (MH +), ESI (-) MS m / e = 188 (MH '). B) Synthesis of ethyl ester of (8-ethyl-1-methyl-1,3,4,9-tetrahydro-pyran [3,4-b1indol-1-yl] -acetic acid ester Following the procedure of Example 22. A. with Except that 2- (7-ethyl-1 H-indol-3-yl) -ethanol was used as the component 3-indoletanol and ethyl acetoacetate as the ketone component, the title compound was obtained as an oil. (500 MHz, CDCl 3) d 9.16 (br, 1H), 7.35 (d, 1H), 7.01 (m, 2H), 4.17 (m, 2H), 4.02 (m, 2H), 2.85 (m, 6H), 1.57 (t, 3H), 1.36 (t, 3H), 1.29 (t, 3H), ESI (+) MS m / e = 302 (MH +), ESI (-) MS m / e = 300 (MH '). 29. C. Synthesis of acid (β-ethyl-1-ethyl-1,3,4,9-tetrahydro-pyran [3,4-b] indol-1-i) -acetic Following the procedure of Example 1, step (b), except that (8-ethi I-1-methyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid ethyl ester was used as the component ester, the title compound was obtained as a solid. ESI (-) MS m / e = 272 (MH '). 29. D. Synthesis of 2- (8-ethyl-1-methyl-1, 3,4,9-tetrahydro-pyrano [3,4-b1indol-1-ip-ethanol] Following the procedure of Example 22. C , except that (8-ethyl-1-methyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid was used as the carboxylic acid component, obtained the title compound as a solid.1H NMR (500 MHz, CDCl3) d 7.74 (br, 1H), 7.37 (d, 1H), 7.09 (m, 1H), 7.03 (d, 1H), 4.12 (m, 1H), 3.98 (m, 1H), 3.70 (m, 2H), 2.92 (m, 1H), 2.85 (m, 2H), 2.74 (m, 2H), 2.15 (m, 2H), 1.56 (s, 3H ), 1.36 (t, 3H), ESI (+) MS m / e = 282 (MNa +), ESI (-) MS m / e = 258 (MH '). COMPOSITE 30: 2- (8-ethyl-1- propyl-1.3.4.9-tetrahydro-pyran Í3.4- blindol-1-in-ethanol . A. Synthesis of ethyl ester of (β-ethyl-1-1-propyl-1.3.4.9-tetrahydro-pyrranof.4.4-b1indol-1-p-acetic acid ester Following the procedure of Example 1, step (a) except that 2- (7-ethyl-1H-indol-3-yl) -ethanol was used as the 3-indoletanol component and the ethyl butyrylacetate as the ketone component and the title compound was obtained as a solid 1 H NMR (500 MHz, CDCl 3) d 9.10 (br, 1H), 7.34 (d, 1H), 7.03 (m, 2H), 4.17 (m, 2H), 4.02 (m, 1H), 3.92 (m, 1H ), 2.99 (d, 1H), 2.84 (m, 3H), 2.73 (dt, 1H), 2.09 (m, 1H), 1.96 (m, 1H), 1.35 (t, 3H), 1.26 (t, 3H) , 1.19 (m, 2H), 0.85 (t, 3H); ESI (+) MS m / e = 330 (MH +), ESI (-) MS m / e = 328 (MH '). 30.B. Synthesis of (8-ethyl-1-propyl-1.3.4.9-tetrahydro-pyran [3,4-b1indol-1-yl) -acetic acid Following the procedure of Example 22. C, except that ethyl ester was used of (8-ethyl-1-propyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid as the ester component, the title compound was obtained as a solid. 30. C. Synthesis of 2- (8-ethyl-1-propyl-1, 3,4,9-tetrahydro-pyranor3.4-b1indol-1-ethanol Following the procedure of Example 22. C, except that (8-etiI-1-propyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indoI-1-yl) -acetic acid was used as the carboxylic acid component, the compound was obtained of the title as a solid.1H NMR (500 MHz, CDCl3) d 7.73 (br, 1H), 7.36 (d, 1H), 7.09 (t, 1H), 7.02 (m, 1H), 4.05 (m, 1H), 4.01 (m, 1H), 3.72 (m, 1H), 3.67 (m, 1H), 2.85 (m, 2H), 2.76 (d, 1H), 2.68 (br, 1H), 2.20 (m, 1H), 2.09 (m, 1H), 1.90 (m, 2H), 1.48 (m, 1H), 1.36 (t, 3H), 1.32 (m, 1H), 0.91 (t, 3H), ESI (+) MS m / e = 288 (MH +), ESI (-) MS m / e = 286 (MH '). COMPOUND 31: 2- (8-Ethyl-1-isopropyl-1, 3.4.9-tetrahydro-pyran [3,4-b1indol-1] -il) -ethanol 31. A. Synthesis of ethyl ester of (8-ethyl-1-isopropyl-1, 3,4,9-tetrahydro-pyran [3,4-b1indol-1-h-acetic acid ester Following the procedure of Example 22. A. with Except that 2- (7-ethyl-1 H-indol-3-yl) -ethanol was used as the 3-indolean component and ethyl iso-butyrylacetate as the ketone component, the title compound was obtained as a solid. 1 H NMR (500 MHz, CDCl 3) d 9.12 (br, 1 H), 7.36 (d, 1 H), 7.07 (m, 2 H), 4.13 (m, 3 H), 3.81 (m, 1 H), 3.04 (q, 2 H). , 2.87 (m, 3H), 2.66 (m, 1H), 2.56 (m, 1H), 1.37 (t, 3H), 1.25 (t, 3H), 1.05 (d, 3H), 0.69 (d, 3H). 31.B. Synthesis of (8-ethyl-1-propyl-1,3,4,9-tetrahydro-pyran [3,4-b1indol-1-yl) -acetic acid Following the procedure of Example 24. B, except that ethyl ester was used of (8-ethyl-8-isopropyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) acetic acid as the ester component, the title compound was obtained as a solid 1 H NMR (500MHz, CDCl 3) d 9.70 (br, 1H), 8.55 (br, 1H), 7.36 (d, 1H), 7.07 (d d, 1H), 7.01 (d, 1H), 4.18 (m, 1H), 3.94 (m, 1H), 3.10 (q, 2H), 2.82 (m, 4H), 2.52 (m, 1H), 1.32 (t , 3H), 1.06 (d, 3H), 0.82 (d, 3H); ESI (+) MS m / e = 302 (MH +), ESI (-) MS m / e = 300 (MH '). 31. C. Synthesis of 2- (8-ethyl-1-isopropyl-1.3.4.9-tetrahydro-pyranof3.4-b1indol-1-yl) -ethanol Following the procedure of Example 22. C, except that it was used acid (8-ethi I-1-isopropyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid as the carboxylic acid component, the title compound was obtained as a solid. 1 H NMR (500 MHz, CDCl 3) d 7.68 (br, 1H), 7.38 (d, 1H), 7.09 (dd, 1H), 7.03 (d, 1H), 4.06 (m, 2H), 3.65 (m, 2H) , 2.87 (m, 3H), 2.77 (dt, 1H), 2.68 (br, 1H), 2.32 (m, 1H), 2.23 (m, 1H), 2.05 (m, 1H), 1.35 (t, 3H), 1.05 (d, 3H), 1.00 (d, 3H); ESI (+) MS m / e = 288 (MH +), ESI (-) MS m / e = 286 (MH '). COMPOUND 32: 2- (8-ethyl-1-phenyl-1,3,4,9-tetrahydro-pyran f3.4-b1indol-1-in-ethanol 32. A. Synthesis of ethyl ester of f-8-ethyl-1-phenyl-1, 3,4,9-tetrahydro-pyranof3,4-b1ndol-1-yl) -acetic acid Following the procedure of Example 22. A. with Except that 2- (7-ethyl-1-1H-indol-3-yl) -ethanol was used as the component 3-indoletanol and ethyl butyl acetate as the ketone component, the title compound was obtained as a solid. 1 H NMR (500 MHz, CDCl 3) d 10.05 (br, 1H), 7.42 (d, 1H), 7.28 (m, 5H), 7.12 (m, 2H), 3.96 (m, 3H), 3.60 (m, 1H) , 3.43 (d, 1H), 3.22 (d, 1H), 3.05 (m, 3H), 2.65 (dd, 1H), 1.42 (d, 3H), 1.03 (t, 3H); ESI (-) MS m / e = 362 (MH '). 32.B. Synthesis of C8-ethyl-1-phenyl-1,3,4,9-tetrahydro-pyror-3,4-b1ndol-1-yl) -acetic acid Following the procedure of Example 22. C, except that it was used ethyl ester of (8-ethyI-1-phenyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-y!) -acetic acid as the ester component, the compound was obtained of the title as a solid. 1 H NMR (500 MHz, CDCl 3) d 9.25 (br, 1 H), 7.41 (d, 1 H), 7.31 (m, 5 H), 7.10 (t, 1 H), 7.06 (d, 1 H), 4.08 (m, 1 H) , 3.70 (m, 1H), 3.42 (d, 1H), 3.22 (d, 1H), 3.03 (m, 1H), 2.83 (m, 2H), 2.68 (m, 1H), 1.33 (t, 3H); ESI (+) MS m / e = 358 (MNa +). ESI (-) MS m / e = 334 (MH '). 32. C. Synthesis of 2-f8-ethyl-1-phenyl-1.3.4.9-tetrahydro-pyran [3,4-b1indol-1-yl) -ethanol Following the procedure of Example 22. B, except that acid (8) was used. -ethyl-1-phenyl-1, 3,4,9-tetrahydro-pyrano [3,4- b] indol-1-yl) acetic acid as the carboxylic acid component, the title compound was obtained as a solid. 1 H NMR (500MHz, CDCl 3) d 8.27 (br, 1H), 7.38 (m, 3H), 7.32 (m, 3H), 7.12 (t, 1H), 7.08 (d, 1H), 4.12 (m, 2H), 3.99 (dd, 1H), 3.61 (ddd, 1H), 3.01 (m, 1H), 2.94 (q, 2H), 2.61 (m, 2H), 2.47 (m, 1H), 1.39 (t, 3H). COMPOUND 34: 8'-etl-4'.9'-dihydro-3'H-spiro (cyclohexane-1,1'-pyran [3,4- b] indop-4-ill-methanol 34. A. Synthesis of ethyl ester of 8'-ethyl-4'19'-dihydro-3'H-spiro acid (cyclohexan-1,1'-pyran [3,4-bl indole) -4-carboxylic Following the procedure of Example 24. A. Except that 2- (7-ethyl-1 H-indol-3-yl) -ethanol was used as the 3-indoletanol component and 4-oxo-cyclohexane carboxylic acid ethyl ester as the ketone component., the title compound was obtained as an oil. ESI (+) MS m / e = 342 (MH +), ESI (-) MS m / e = 340 (MH '). 34.B. Synthesis of 8'-etl-4'.9'-dihydro-3'H-spiro acid (cyclohexane-1,1'-pyran [3,4-indole) -4-carboxylic acid Following the procedure of Example 22. B except that (8'-ethyl-4 ', 9'-dihydro-3'H-spiro (cyclohexane-1,1'-pyran [3,4-b] indole) ethyl ester was used. 4-carboxylic acid as the ester component, the title compound was obtained as a solid ESI (+) MS m / e = 314 (MH +), ESI (-) MS m / e = 312 (MH ') 34. C Synthesis of [8'-ethyl-4 ', 9'-dihydro-3'H-spiro (cyclohexan-1,1'-pyran [3,4-bl indole) -4-iH-methanol Following the procedure of Example 22. C, except that 8'-ethyl-4 ', 9'-dihydro-3'H-spiro (cyclohexane-1,1'-pyran [3,4-b] indole) -4-carboxylic acid was used as the carboxylic acid component, the title compound was obtained as a solid.1H NMR (500MHz, CDCl3) d 7.51 (br, 1H), 7.33 (d, 1H), 7.06 (t, 1H), 7.00 (d, 1H) , 3.97 (t, 2H), 3.54 (t, 2H), 2.84 (q, 2H), 2.78 (t, 2H), 2.12 (br, 1H), 2.09 (m, t, 1H), 1.69 (m, 4H ), 1.60 (m, 1H), 1 .52 (m, 3H), 1.35 (t, 3H); ESI (+) MS m / e = 300 (MH +), ESI (-) MS m / e = 298 (MH "). COMPOUND 35: R-2-Í1.8-diethyl-1.3.4.9-tetrahydro-pyran [ 3.4-bl indole-1-ih-ethanol . A. Synthesis of R-2-M, 8-diethyl-1, 3,4,9-tetrahydro-pyranof3.4-b1ndol-1-p-ethanol Following the procedure of Example 22, except that acid R - (1, 8-di eti I-, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) acetic acid as the carboxylic component in step 22. C, the compound of title as a solid. 1 H NMR (500MHz, CDCl 3) d 7.74 (br, 1H), 7.37 (d, 1H), 7. 09 (t, 1H), 7.03 (d, 1H), 4.07 (m, 1H), 3.98 (m, 1H ), 3.68 (m, 2H), 2.86 (m, 3H), 2.76 (dt, 1H), 2.69 (br, t, 1H), 2.21 (m, 1H), 2.07 (m, 1H), 2.00 (m, 1H), 1.91 (m, 1H), 1.35 (t, 3H), 0.94 (t, 3H); ESI (+) MS m / e = 274 (MH +), ESI (-) MS m / e = 272 (MH '). COMPOUND 36: 2- (1-ethyl-8-isopropyl-1,3,4,9-tetrahydro-pyran T3.4- blindol-l-ill-ethanol 36. A. Synthesis of 2-hydroxyimino-N- (2-isopropyl-pheyp-acetamide) A mixture of 2-isopropylamine (4.7 g, 35 mmol), Na 2 SO 4 (30.0 g), concentrated hydrochloride (3 ml), doral hydrate (6.5 g), hydroxylamine hydrochloride, (8.00 g) in water (150 ml) was heated at 85 ° C. for 40 minutes, after cooling to room temperature, it was extracted with ethyl acetate, the extracts were dried over magnesium sulfate and they were evaporated to dryness, Flash chromatography on silica gel afforded 4.357 g (54%) of the title compound as a solid. 36. B. Synthesis of 7-isopropyl-1 H-indole-2,3-dione To concentrated sulfuric acid at 80 ° C was added 2-hydroxyimino-N- (2-isopropyl-phenyl) -acetamide in several small portions for 10 minutes . After the addition, it was heated at 80 ° C for 30 minutes, then poured on ice. Filtration, washing with water and drying in vacuo over P205 afforded 2,974 g (84%) of the title compound as a solid. ESI (-) MS m / e = 188 (MH '). 36. C. Synthesis of (7-isopropyl-1H-indol-3-p-oxoacetic acid ethyl ester) To a solution of 7-isopropyl-1 H-indole-2,3-dione (2.97 g) 15.7 mmol) in tetrahydrofuran (20 mL) was added dropwise a 2.0 M solution of lithium borohydride in tetrahydrofuran (15 mL, 30 mmol) The mixture was heated at 90 ° C for 4 hours. %, followed by saturated sodium bicarbonate, extracted with ethyl acetate.The extracts were dried over magnesium sulfate and evaporated to dryness to give crude 7-isopropyl-1 H-indole. To a solution of 7-isopropyl- 1 H-indole in diethyl ether (40 ml) was added dropwise a 2.0 M solution of oxalyl chloride in dichloromethane (15 ml, 30 mmol) After stirring at room temperature for 5 hours, it was evaporated to dryness Ethanol was added to the residue and stirred at room temperature overnight After evaporation of ethanol, flash chromatography silica gel afforded 0.972 g (24%) of the title compound as a solid. ESI (-) MS m / e = 258 (MH " ) • 36.D. Synthesis of ethyl ester of M-ethyl-8-isopropyl-1,3,4,9-tetrahydro-pyranor 3,4-b1indol-1-p-acetic acid ester To a solution of ethyl ester of (7-isopropyl) acid -1H-indol-3-ll) -oxo-acetic acid (0.97 g, 3.7 mmol) in tetrahydrofuran was added a 2 M solution of lithium borohydride in tetrahydrofuran. The mixture was heated at 90 ° C for 5 hours. It was quenched with 5% HCl, followed by saturated sodium bicarbonate. It was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness to give crude 2- (7-isopropyl-1H-indol-3-yl) -ethanol. ESI (+) MS m / e = 330 (MH +), ESI (-) MS m / e = 202 (MH ") Following the procedure of Example 24. B except that 2- (7-isopropyl -1H-indol-3-yl) -ethanol as the 3-indoletanol component, the title compound was obtained as an oil ESI (+) MS m / e = 330 (MH +), ESI (-) MS m / e = 328 (MH "). 36. E. Synthesis of (1-ethyl-8-isopropyl-1, 3,4,9-tetrahydro-pyran [3,4-b1indol-1-yl) -acetic acid Following the procedure of Example 22. B except that ethyl ester of (1-ethyl) I-8-isopropyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid was used as the ester component, the title compound was obtained as a solid. 1 H NMR (500 MHz, CDCl 3) d 9.50 (br, 1 H), 8.58 (br, 1 H), 7.36 (d, 1 H), 7.08 (m, 2 H), 4.09 (m, 1 H), 4.04 (m, 1 H) , 3.20 (m, 1H), 3.05 (d, 1H), 3.02 (d, 1H), 2.84 (m, 2H), 2.13 (m, 1H), 2.04 (m, 1H), 1.38 (d, 3H), 1.35 (d, 3H), 0.88 (t, 3H); ESI (+) MS m / e = 302 (MH +), ESI (-) MS m / e = 300 (MH "). 36. F. Synthesis of 2- (1-ethyl-8-isopropyl-1.3.4.9 -tetrahydro-pyror3,4-b1ndol-1-yl) -ethanol Following the procedure of Example 22. C, except that acid (1-ethyl-8-isopropyl-1, 3,4 was used, 9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic as the carboxylic acid component, the title compound was obtained as a solid.1H NMR (500 MHz, CDCl3) d 7.78 (br, 1H ), 7.36 (d, 1H), 7.11 (t, 1H), 7.07 (d, 1H), 4.07 (m, 1H), 3.99 (m, 1H), 3.71 (m, 2H), 3.20 (m, 1H) , 2.90 (m, 1H), 2.76 (dt, 1H), 2.65 (br, 1H), 2.22 (m, 1H), 2.06 (m, 1H), 2.03 (m, 1H), 1.92 (m, 1H), 1.38 (d, 6H), 0.88 (t, 3H), ESI (+) MS m / e = 288 (MH +), ESI (-) MS m / e = 286 (MH ') COMPOUND 37: 2-M -ethyl-8-trifluoromethyl-1,3,4,9-tetrahydro-pyran [3,4-blindol-1-iD-ethanol 37. A. Synthesis of 2-hydroxyimino-N- (2-trifluoromethyl-phenyD-acetamide Following the procedure of Example 36. A, except that 2-trifluoromethylamino was used as the aniline component, the title compound was obtained as a solid. 37. B. Synthesis of 7-trifluoromethyl-1 H-indol-2,3-dione Following the procedure of Example 36. B, except that 2-hydroxyimino-N- (2-trifluoromethyl-phenyl) -acetamide was used as the acetamide component gave the title compound as a solid ESI (-) MS m / e = 214 (MH '). 37.C. Synthesis of (7-trifluoromethyl-1H-indol-3-ip-oxoacetic acid ethyl ester) Following the procedure of Example 36. C, except that 7-trifluoromethyl-1H-indole-2 was used , 3-dione as the dione component, the title compound was obtained as a solid 37.D. Synthesis of 2- (1-ethyl-8-trifluoromethyl-1,3,4,9-tetrahydro-pyran [3,4-b] indol-1-yl) -ethanol Following the procedure of Example 28. C, except that ethyl (1-ethyl-8-trifluoromethyl-1, 3,4,9-tetrahydro-pyran [1-ethyl ester] was used [ 3,4-b] in do 1-1 -yl) -acetic as the ester component, the title compound was obtained as a solid.1H NMR (500 MHz, CDCl3) d 8.42 (br, 1H), 7.67 (d , 1H), 7.41 (d, 1H), 7.18 (t, 1H), 4.07 (m, 1H), 4.00 (m, 1H), 3.71 (m, 2H), 2.89 (m, 1H), 2.78 (dt, 1H), 2.64 (br, 1H), 2.23 (m, 1H), 2.07 (m, 1H), 2.02 (m, 1H), 1.93 (m, 1H), 0.93 (t, 3H), ESI (+) MS m / e = 314 (MH +), ESI (-) MS m / e = 312 (MH '). COMPOSITE 38: 2-f5-chloro-1-ethyl-1.3.4.9-tetrahydro -pirano Í3.4- blindol-1-in-ethanol 38. A. Synthesis of (4-chloro-1H-indol-3-yl) -oxo-acetic acid ethyl ester Following the procedure of Example 36.C, except that 4-chloro-1 H-indole was used as the indole component, the title compound was obtained as a solid. 38. B. Synthesis of ethyl ester of (5-chloro-1-ethyl-1, 3,4,9-tetrahydro-pyranof3,4-b1indol-1 -M) -acetic acid Following the procedure of Example 36. D with exception that ethyl ester of (4-chloro-1H-indol-3-yl) -oxo-acetic acid was used as the ester component, the title compound was obtained as an oil. 1 H NMR (008-08) MS. ESI (+) MS m / e = 322 (MH +), ESI (-) MS m / e = 320 (MH ") 38.C. Synthesis of acid (5-chloro-1-ethyl-1, 3, 4,9-tetrahydro-pyranof3.4-blindol-1-p-acetic Following the procedure of Example 22. B, except that (5-chloro-1-ethyl-1, 3-ethyl ester was used. , 4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid as the ester component, the title compound was obtained as a solid ESI (+) MS m / e = 294 (MH +), ESI (-) MS m / e = 292 (MH ") 38. D. Synthesis of 2- (5-chloro-1-ethyl-1, 3.4.9-tetrahydro-pyrano [3,4-b1indol -1-il) -ethanol Following the procedure of Example 22. C, except that (5-chloro-1-ethyl-1, 3,4,9-tetrahydro-pyran [3,4-] b) indol-1-yl) -acetic as the carboxylic acid component, the title compound was obtained as a solid.1H NMR (500 MHz, CDCl3) d 8.04 (br, 1H), 7.20 (dd, 1H), 7.04 (m, 2H), 4.05 (m, 1H), 3.97 (m, 1H), 3.68 (m, 2H), 3.16 (m, 2H), 2.19 (m, 1H), 2.04 (m, 1H), 1.98 ( m, 1H), 1.89 (m, 1H), 0.92 (t, 3H); ESI (-) MS m / e = 278 (MH '). COMPOUND 39: 2- (1-ethyl-5-fluoro-1.3.4.9-tetrahydro-pyran Í3.4- blindol-1-in-ethanol 39. A. Synthesis of (4-fluoro-1H-indol-3-yl) -oxo-acetic acid ethyl ester Following the procedure of Example 36. C, except that 4-fluoro-1 H-indole was used As the indole component, the title compound was obtained as a solid. 39.B. Synthesis of (1-ethyl-5-fluoro-1,3,4,9-tetrahydro-pYrano [3,4-b] indol-1-p-acetic acid ethyl ester Following the procedure of Example 36. D except that (4-fluoro-1H-indol-3-yl) -oxo-acetic acid ethyl ester was used as the ester component, the title compound was obtained as an oil. ) MS rp / e = 304 (MH '). 39. C. Synthesis of acid (1-ethyl-5-f I úor-1, 3.4.9-tetrahydro-pyran [3,4-blolndol-1-] il) -acetic Following the procedure of Example 22. B, except that ethyl ester of (1-ethyl) I-5-fluoro-1, 3,4,9-tetrahydro-pyran [3,4-] was used. b) indol-1-yl) -acetic as the ester component, the title compound was obtained as a solid.1H NMR (500 MHz, CDCl3) d 9.70 (br, 1H), 8.75 (br, 1H), 7.06 ( m, 2H), 6.73 (dd, 1H), 4.08 (m, 1H), 4.04 (m, 1H), 3.00 (m, 4H), 2.10 (m, 1H), 2.01 (m, 1H), 0.86 (t , 3H); ESI (+) MS m / e = 278 (MH +), ESI (-) MS m / e = 276 (MH '). 39.D. Synthesis of 2-f 1 -ethyl-5-ethyl-5-f-lluor-1.3.4.9-tetrahydro-pyran [3,4-blindol-1-yl] -ethanol Following the procedure of Example 22, except that the acid (1-ethyl-5-fluoro-1, 3,4,9-tetrahydro-pyrano [3,4- b] lndol-1-yl) acetic acid as the carboxylic acid component, the title compound was obtained as a solid . 1 H NMR (500MHz, CDCl 3) d 7.97 (br, 1H), 7.08 (d, 1H), 7.04 (ddd, 1H), 6.75 (dd, 1H), 4.04 (m, 1H), 3.98 (m, 1H), 3.67 (m, 2H), 3.04 (m, 1H), 2.93 (m, 1H), 2.61 (br, 1H), 2.19 (m, 1H), 2.03 (m, 1H), 2.01 (m, 1H), 1.89 (m, 1H), 0.92 (t, 3H); ESI (+) MS m / e = 264 (MH +), ESI (-) MS m / e = 262 (MH '). COMPOUND 40: 2- (1-ethyl-6-fluoro-1,3,4,9-tetrahydro-pyran) Í3.4- blindol-1-in-ethanol 40. A. Synthesis of (5-fluoro-1H-indol-3-yl) -oxo-acetic acid ethyl ester Following the procedure of Example 36. C, except that 5-fluoro-1 H-indole was used as the indole component, the title compound was obtained as a solid. 40.B. Synthesis of (1-ethyl-6-fl uor-1,3,4,9-tetrahydro-pyranof3,4-b1indol-1-ip-acetic acid ethyl ester) Following the procedure of Example 36. D except that ethyl ester of (5-fIuor-1H-indol-3-yl) -oxo-acetic acid was used as the ester component, the title compound was obtained as an oil 40.C. Synthesis of 2- (1 - ethyl-6-f lúor-1, 3.4.9-tetrahydropyranof 3.4-bl i ndol-1-iO-ethanol Following the procedure of Example 22. C, except that ethyl ester of the acid (1-) was used. ethyl-6-fluoro-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid as the carboxylic acid component and the title compound was obtained as a solid.1H NMR (500 MHz, CDCI3) d 7.91 (br, 1H), 7.22 (dd, 1H), 7.14 (dd, 1H), 6.90 (ddd, 1H), 4.05 (m, 1H), 4.00 (m, 1H), 3.68 (m, 2H), 2.71 (dt, 1H), 2.69 (br, 1H), 2.18 (m, 1H), 2.04 (m, 1H), 1.97 (m, 1H), 1.89 (m, 1H), 0.92 ( t, 3H); ESI (+) MS m / e = 264 (MH +), ESI (-) MS m / e = 262 (MH ') COMPOUND 41: 2- (6-cl gold-1-ethyl-1, 3.4.9-tetrahydro-pyran [3.4-blindol-1-m-ethanol] 41. A. Synthesis of (5-chloro-1H-yl! -3-yl) -oxo-acetic acid ethyl ester Following the procedure of Example 36. C, except that 5-chloro-1 H-indole was used As the indole component, the title compound was obtained as a solid. 1 H NMR (500 MHz, DMSO-d 6) d 12.54 (br, 1 H), 8.50 (d, 1 H), 8.12 (d, 1 H), 7.56 (d, 1 H), 7.30 (dd, 1 H), 4.36 (q, 2H), 2.48 (t, br, 1H), 1.32 (t, 3H); APCl (-) MS m / e = 250 (MH '). 41. B. Synthesis of (6-chloro-1-ethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid ethyl ester Following the procedure of Example 36 D except that (5-chloro-1H-indol-3-yl) -oxo-acetic acid ethyl ester was used as the ester component, the title compound was obtained as an oil. 1 H NMR (500 MHz, CDCl 3) d 9.18 (br, 1 H), 7.46 (d, 1 H), 7.26 (d, 1 H), 7.11 (dd, 1 H), 4.19 (m, 2 H), 4.03 (m, 1 H) , 3.93 (m, 1H), 2.99 (d, 1H), 2.90 (d, 1H), 2.77 (m, 1H), 2.72 (m, 1H), 2.11 (m, 1H), 1.98 (m, 1H), 1.27 (t, 3H), 0.81 (t, 3H); APCl (+) MS m / e = 322 (MH +), APCl (-) MS m / e = 320 (MH '). 41. C. Synthesis of (6-chloro-1-ethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid Following the procedure of Example 22. B, except that (6-chloro-1-ethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid ethyl ester was used as the ester component , the title compound was obtained as a solid. 1 H NMR (500 MHz, CDCl 3) d 9.50 (br, 1 H), 8.68 (br, 1 H), 7.46 (s, 1 H), 7.23 (d, 1 H), 7.12 (d, 1 H), 4.09 (m, 1 H) , 4.03 (m, 1H), 3.03 (d, 1H), 2.99 (d, 1H), 2.79 (m, 2H), 2.10 (m, 1H), 2.01 (m, 1H), 0.86 (t, 3H); ESI (+) MS m / e = 294 (MH +), ESI (-) MS m / e = 292 (MH '). 41. D. Synthesis of 2- (6-chloro-1-ethyl-1,3,4,9-tetrahydro-pyran [3,4-b1indol-1-ih-ethanol] Following the procedure of Example 22. C, except that used (6-chloro-1-ethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid as the carboxylic acid component, the title compound was obtained as a solid.1H NMR (500 MHz, CDCl3) d 8.01 (br, 1H), 7.46 (s, 1H), 7.22 (d, 1H), 7.12 (d, 1H), 4.05 (m, 1H), 3.99 (m , 1H), 3.67 (, 2H), 2.83 (m, 1H), 2.72 (m, 1H), 2.65 (br, 1H), 2.19 (m, 1H), 2.00 (m, 2H), 1.88 (m, 1H ), 0.92 (t, 3H), APCl (+) MS m / e = 280 (MH +), APCl (-) MS m / e = 278 (MH ") COMPOUND 42: 2- (6-bromo-1) -ethyl-1, 3,4,9-tetrahydro-pyran Í3.4- blindol-1-ih-ethanol 42. A. Synthesis of (5-bromo-1H-indol-3-ip-oxoacetic acid ethyl ester) Following the procedure of Example 36, step (c), except that 5-bromo-1 H- was used indole as the indole component, the title compound was obtained as a solid 42. B. Synthesis of ethyl ester of (6-bromo-1-ethyl-1) acid3,4,9-tetrahydro-pyrano [3,4-b1indol-1-yl] -acetic acid Following the procedure of Example 36. B except that (5-bromo-1H-indole-3) ethyl ester was used. -yl) -oxo-acetic acid as the ester component, the title compound was obtained as an oil. 42. C. Synthesis of 2- (6-bromo-1-ethyl-1, 3,4,9-tetrahydro-pyran [3,4-b1indol-1-yl) -ethanol Following the procedure of Example 28. B, except that (6-bromo-1-ethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid ethyl ester was used as the ester component, the title compound was obtained as a solid. 1 H NMR (500 MHz, CDCl 3) d 7.95 (br, 1 H), 7.62 (d, 1 H), 7.24 (dd, 1 H), 7.19 (d, 1 H), 4.05 (m, 1 H), 3.97 (m, 1 H) , 3.67 (m, 2H), 2.84 (m, 1H), 2.71 (m, 1H), 2.55 (br, 1H), 2.19 (m, 1H), 2.03 (m, 1H), 1.97 (m, 1H), 1.88 (m, 1H), 0.91 (t, 3H); ESI (+) MS m / e = 324 (MH +), ESI (-) MS m / e = 322 (MH "). COMPOUND 43: 2- (1-ethyl-7-f Ior- 1, 3, 4.9-tetrahydro-pyran [3.4-blindol-1-in-ethanol 43. A. Synthesis of (6-Fluor-1H-indol-3-ih-oxo-acetic acid ethyl ester) Following the procedure of Example 36. C, except that 6-fluoro-1 H-indole was used as the Indole component, the title compound was obtained as a solid.

NMR (500 MHz, CDCl 3) d 8.75 (br, 1H), 8.48 (d, 1H), 8.39 (dd, 1H), 7.12 (m, 2H), 4.41 (q, 2H), 1.43 (t, 3H); ESI (-) MS m / e = 234 (MH '). 43. B. Synthesis of (1-ethyl-7-fluoro-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-ip-acetic acid ethyl ester Following the procedure of Example 36. D except that (6-fluoro-1H-indol-3-yl) -oxo-acetic acid ethyl ester was used as the ester component, the title compound was obtained as an oil. Synthesis of acid (1-ethyl-7-f Ior-1, 3.4.9-tetrahydro-pyran [3,4-blindol-1-ip-acetic Following the procedure of Example 22. B, except that the Ethyl (1-ethyl-7-fluoro-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid as the ester component, the title compound was obtained as a solid. 1 H NMR (500 MHz, CDCl 3) d 11.8 (br, 1 H), 9.53 (br, 1 H), 7.29 (dd, 1 H), 6.93 (dd, 1 H), 6.74 (ddd, 1 H), 3.94 (m , 1H), 3.89 (m, 1H), 2.86 (d, 1H), 2.82 (d, 1H), 2.69 (m, 1H), 2.66 (m, 1H), 2.03 (m, 1H), 1.95 (m, 1H), 0.74 (t, 3H), ESI (+) MS m / e = 278 (MH +), ESI (-) MS m / e = 276 (MH ') 43. D. Synthesis of 2-f 1-ethyl-7-f lúor-1, 3.4.9-tetrahidro-p¡ rano [3.4-bl indo l-l-ih-ethanol Following the procedure of Example 22. C, except that acid (1) was used. -ethyl-7-fluoro-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid as the carboxylic acid component, the title compound was obtained as a solid. 1 H NMR (500 MHz, CDCl 3) d 7.95 (br, 1H), 7.40 (dd, 1H), 7.00 (dd, 1H), 6.88 (ddd, 1H), 4.06 (m, 1H), 3.99 (m, 1H), 3.65 (m, 2H), 2.85 (m, 1H), 2.71 (m, br, 2H), 2.18 (m, 1H), 2.02 (m, 1H), 1.98 (m, 1H), 1.88 (m, 1H), 0. 92 (t, 3H); ESI (+) MS m / e = 264 (MH +), ESI (-) MS m / e = 262 (MH '). COMPOUND 44: 2- (7-chloro-1-ethyl-1,3,4,9-tetrahydro-pyran Í3.4- blindol-1-in-ethanol 44. A. Synthesis of (6-chloro-1H-indol-3-ip-oxoacetic acid ethyl ester) Following the procedure of Example 36. C, except that 6-chloro-1 H-indole was used as the Indole component, the title compound was obtained as a solid.1H NMR (500 MHz, CDCl3) d 11.50 (br, 1H), 8.30 (d, 1H), 8.21 (d, 1H), 7.37 (d, 1H), 7.15 (dd, 1H), 4.31 (q, 2H), 1.33 (t, 3H), ESI (+) MS m / e = 252 (MH +), ESI (-) MS m / e = 250 (MH ') 44. B. Synthesis of ethyl ester of (7-chloro-1-ethyl-, 3,4,9-tetrahydro-pyrano [3,4-b1indol-1-yl-acetic acid] Following the procedure of Example 22. D with Except that (6-chloro-1H-indol-3-yl) -oxo-acetic acid ethyl ester was used as the ester component, the title compound was obtained as an oil 44. C. Synthesis of acid ( 7-chloro-1-ethyl-1, 3.4.9-tetrahydro-pyran [3,4-b1indol-1-H-acetic Following the procedure of Example 22. B, except that ethyl ester of the -chloro-1-ethyl-1, 3,4,9-t ehydro-pyrano [3,4-b] indol-1-yl) -acetic acid as the ester component, the title compound was obtained as a solid. 1 H NMR (500 MHz, CDCl 3) d 11.80 (br, 1H), 9.57 (br, 1H), 7.30 (d, 1H), 7.24 (d, 1H), 6.95 (dd, 1H), 3.97 (m, 1H) , 3.88 (m, 1H), 2.88 (d, 1H), 2.80 (d, 1H), 2.71 (m, 1H), 2.66 (dt, 1H), 2.04 (m, 1H), 1.96 (m, 1H), 0.74 (t, 3H); ESI (+) MS m / e = 294 (MH +), ESI (-) MS m / e = 292 (MH '). 44. D. Synthesis of 2- (7-chloro-1-ethyl-1, 3,4,9-tetrahydro-pyran [3,4-b1indol-1-ip-ethanol] Following the procedure of Example 22. C, except that used (7-chloro-1-ethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid as the carboxylic acid component, the title compound was obtained as a solid.1H NMR (500 MHz, CDCl3) d 8.02 (br, 1H), 7.40 (d, 1H), 7.30 (d, 1H), 7.08 (dd, 1H), 4.05 (m, 1H), 3.99 (m , 1H), 3.66 (m, 2H), 2.73 (dt, 1H), 2.71 (br, 1H), 2.11 (m, 1H), 2.02 (m, 1H), 1.96 (m, 1H), 1.88 (m, 1H), 0.91 (t, 3H), ESI (+) MS m / e = 280 (MH +), ESI (-) MS m / e = 278 (MH '). COMPOSITE 45: 2- (1 -ethyl- 6.8-dimethyl-1.3.4.9-tetrahydro-pyran [3.4-blindol-l-iH-ethanol 45. A. Synthesis of 5,7-dimethyl-1 H-indole To a solution of 5,7-dimethyl-1 H-indole-2,3-dione in tetrahydrofuran at 0 ° C was added a 1.0 M solution of borane tetrahydrofuran. tetrahydrofuran complex (40 ml). After stirring at room temperature overnight, a 5% HCl solution was added to the mixture and stirred 20 minutes. It was neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated until dried to give the title compound as an oil. 45.B. Synthesis of (5,7-dimethyl-1H-indol-3-yl) -oxo-acetic acid ethyl ester Following the procedure of Example 36. C, except that 5,7-dimethyl-1H was used -indole as the indole component, the title compound was obtained as a solid. ESI (+) MS m / e = 246 (MH +). 45. C. Synthesis of ethyl ester of (1-ethyl-6,8-di methyl-1, 3,4,9-tetrahydro-pyran [3,4-b1ndol-1-p-acetic acid Following the procedure of Example 36. D except that (5,7-dimethyl-1 H -indol-3-yl) -oxo-acetic acid ethyl ester was used as the ester component, the title compound was obtained as an oil 45. D. Synthesis of M-tyl-6,8-dimethyl-1,3,4,9-tetrahydro-pyran [3,4-b1indol-1-yl) -acetic acid Following the procedure of Example 22. B, except that ethyl (1-ethyl-6,8-dimethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid ethyl ester was used as the ester component, obtained the title compound as a solid. 1 H NMR (500 MHz, CDCl 3) d 9.50 (br, 1H), 8.28 (br, 1H), 7.14 (s, 1H), 6.82 (s, 1H), 4.10 (m, 1H), 4.06 (m, 1H) , 3.02 (d, 2H), 3.01 (d, 1H), 2.81 (m, 2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.10 (m, 1H), 2.03 (m, 1H), 0.87 (t, 3H); ESI (+) MS m / e = 288 (MH +), ESI (-) MS m / e = 286 (MH '). 45. E. Synthesis of 2-M-ethyl-6,8-dimethyl-1, 3,4,9-tetrahydro-pyruran-3,4-b] indol-1-yl) -ethanol Following the procedure of Example 22. C, except that (1-ethyl-6,8-dimethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid was used as the carboxylic acid component, the title compound was obtained as a solid. 1 H NMR (500 MHz, CDCl 3) d 7.51 (br, 1 H), 7.15 (s, 1 H), 6.83 (s, 1 H), 4.06 (m, 1 H), 3.98 (m, 1 H), 3.67 (m, 2 H) , 2.85 (m, 1H), 2.72 (dt, 1H), 2.69 (br, 1H), 2.43 (s, 3H), 2.42 (s, 3H), 2.20 (m, 1H), 2.06 (m, 1H), 2.03 (m, 1H), 1.89 (m, 1H), 0.95 (t, 3H); ESI (+) MS m / e = 274 (MH +), ESI (-) MS m / e = 272 (MH ').

COMPOUND 46: 2- (6-8-dichloro-1-ethyl-1, 3,4,9-tetrahydro-pyran [3,4-blindol-1-i-ethanol 46. A. Synthesis of 5,7-dichloro-1 H-indole Following the procedure of Example 45.A, except that 5,7-dichloro-1 H-indole-2,3-dione was used as the dione component, the title compound was obtained as an oil. 46.B. Synthesis of (5,7-dichloro-1 H-indol-3-yl) -oxo-acetic acid ethyl ester Following the procedure of Example 36. C, except that 5,7-dichloro- 1 H-indole as the indole component, the title compound was obtained as a solid. 46.C. Synthesis of (6,8-dichloro-1-ethyl-1, 3,4,9-tetrahydro-pyranof3,4-b1indol-1-yl) -acetic acid ethyl ester Following the procedure of Example 36. D except that it was used ethyl ester of (5,7-dichloro-1 H-indol-3-yl) -oxo-acetic acid as the ester component, the title compound was obtained as an oil. 46. D. Synthesis of acid (6,8-dichloro-1-ethyl-1,3,4,9-tetrahydro-pyran [3,4-b1indol-1-ip-acetic Following the procedure of Example 22. B, except that Ethyl (6,8-dichloro-1-ethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) acetic acid ethyl ester was used as the ester component, the title compound as a solid.1H NMR (500MHz, CDCl3) d 9.07 (ber, 1H), 7.03 (d, 1H), 6.97 (d, 1H), 4.07 (m, 1H), 4.01 (m, 1H) , 3.15 (t, 2H), 3.10 (d, 1H), 3.03 (d, 1H), 2.15 (m, 1H), 2.05 (m, 1H), 0.88 (t, 3H), ESI (+) MS m / e = 328 (MH +), ESI (-) MS m / e = 326 (MH '). 46.E. Synthesis of 2- (6, 8-dichloro-1-ethyl-1, 3.4.9-tetrahydro-pyran [3,4-b1ndol-1-yl) -ethanol Following the procedure of Example 22. C, except that acid was used ( 6,8-dichloro-1-ethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) acetic acid as the carboxylic acid component, the title compound was obtained as a solid . 1 H NMR (500MHz, CDCl 3) d 8.25 (br, 1H), 7.03 (d, 1H), 6.98 (d, 1H), 4.03 (m, 1H), 3.99 (m, 1H), 3.71 (m, 2H), 3.13 (m, 2H), 2.57 (br, 1H), 2.23 (m, 1H), 2.07 (m, 1H), 2.04 (m, 1H), 1.92 (m, 1H), 0.93 (t, 3H); ESI (+) MS m / e = 314 (MH +), ESI (-) MS m / e = 312 (MH '). COMPOUND 47: 2- (6-bromo-1, 8-diethyl-1, 3,4,9-tetrahydro-pyran T3,4-b1indol-1-yl) -ethanol 47. A. Synthesis of N- (4-bromo-2-ethyl-pheyp-2-hydroxyiminoacetoamide) Following the procedure of Example 36. A, except that 4-bromo-2-ethylaniline was used as the aniline component, provided the title compound as a solid ESI (-) MS m / e = 269 (MH ") 47.B. Synthesis of 5-Bromo-7-ethyl-1 H-indole-2,3-dione Following the procedure of Example 36. B, except that N- (4-bromo-2-ethyl-phenyl) -2-hydroxyiminoacetamide was used as the acetamide component, gave the title compound as a solid.

MS m / e = 252 (MH '). 47. C. Synthesis of (5-bromo-7-ethyl-1H-indol-3-yl) -ox-o-acetic acid ethyl ester Following the procedure of Example 36. C, except that used 5-bromo-7-ethyl-1 H-indole-2-dione as the dione component, the title compound was obtained as a solid ESI (+) MS m / e = 324 (MH +), ESI (-) MS m / e = 322 (MH ') 47.D. Synthesis of ethyl ester of (6-bromo-1,8-diethyl-3,4,9-tetrahydro-pyran [3,4-b-indole] -1-yl) -acetic Following the procedure of Example 36. D except that (5-bromo-7-ethyl-1 H-indol-3-yl) -oxo-acetic acid ethyl ester was used as the ester component, the title compound was obtained as a solid. 47. E. Synthesis of 2- (6-bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyran [3,4-b1indol-1-yl) -ethanol Following the procedure of Example 28. C, except that ethyl ester of (6-bromo-1, 8-diethyl-1, 3,4,9-tetrahydro-pyrano [3-b] indol-1-yl) -acetic acid was used as the ester component, the composed of the title as a solid. 1 H NMR (500 MHz, CDCl 3) d 7.89 (br, 1 H), 7.48 (d, 1 H), 7.11 (d, 1 H), 4.05 (m, 1 H), 3.99 (m, 1 H), 3.70 (m, 2 H) , 2.80 (m, 3H), 2.71 (dt, 1H), 2.55 (br, t, 1H), 2.19 (m, 1H), 2.05 (m, 1H), 2.01 (m, 1H), 1.90 (m, 1H) ), 1.33 (t, 3H), 0.92 (t, 3H); ESI (+) MS m / e = 352 (MH +), ESI (-) MS m / e = 350 (MH '). COMPOSITE 48: 2- (1,8-Diethyl-1, 3,4,9-tetrahydro-pyrano [3,4-b1indol-1-yl] -N, N-dimethyl-acetamida) 2- (1,8-Diethyl-1,3,4,9-tetrahydro-pyrano [3,4- b] indol-1-yl) -N, N-dimethyl-acetamide. Following the procedure of Example 27, except that dimethylamine was used as the amine component, the title compound was obtained as a solid. 1 H NMR (500 MHz, CDCl 3) d 9.39 (br, 1H), 7.35 (d, 1H), 7.05 (t, 1H), 6.99 (d, 1H), 6.19 (m, 1H), 4.06 (m, 1H) , 3.98 (m, 1H), 2.84 (s, m, 9H), 2.11 (m, 1H), 2.01 (m, 1H), 1.36 (t, 3H), 0.85 (t, 3H); ESI (-) MS m / e = 299 (MH ').

COMPOUND 49: 2- (9-benzyl-1,8-diethyl-1, 3,4,9-tetrahydro-pyran [3,4-b1ndol-1-yl] -ethanol) Compound 49 was synthesized according to the following scheme: 49. A. Synthesis of acid (9-benzyl-1,8-diethyl-1,3,4,9-tetrahydro-p-prano [3,4-b] indol-1-yl) -acetic acid To a solution of (1,8-diethyl- 1, 3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -acetic acid (0.51 g, 1.8 mmol) in tetrahydrofuran at room temperature was added sodium hydride (60% dispersion in mineral oil, 0.4 g). After heating at 50 ° C for 2 hours, benzyl bromide (6 g, 3.5 mmol) was added and the solution was stirred for another 2 hours. It was quenched with ethyl acetate and washed with water. The ethyl acetate layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel afforded 0.486 g (73%) of the title compound as a solid. 1 H NMR (500 MHz, CDCl 3) d 7.13 (m, 3 H), 6.97 (d, 1 H), 6.74 (d, 1 H), 6.68 (t, 1 H), 6.21 (d, 1 h), 3.90 (s, 1 h) , 3.63 (m, 1h), 3.35 (td, 1H), 3.18 (d, 1H), 3.00 (d, 1H), 2.67 (q, 2H), 2.44 (q, 2H), 2.10 (m, 1H), 1.85 (d, 1H), 1.52 (m, 1H), 1.41 (m, 1H), 1.16 (t, 3H), 0.75 (t, 3H); ESI (+) MS m / e = 278 (MH +). 49.B. Synthesis of 2- (9-benzyl-1, 8-diethyl-1,3,4,9-tetrahydro-pyranof3,4-b1indol-1-yl) -ethanol To a solution of (9-benzyl-1, 8-diethyl-1) acid 3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -acetic acid (0.45 g, 1.2 mmol) in tetrahydrofuran at room temperature was added a 1.0 M solution of borane-tetrahydrofuran complex in tetrahydrofuran and stirred at 90 ° C for 4 hours. The mixture was quenched with a 5% HCl solution and stirred at room temperature for 20 minutes. It was extracted with ethyl acetate and washed with saturated sodium bicarbonate. The extracts were dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0. 321 g (74%) of the title compound as a solid. 1 H NMR (500 MHz, CDCI3) d 7.17 (m, 3H), 6.94 (d, 1H), 6.84 (m, 2H), 6.70 (t, 1H), 6.56 (d, 1H), 3.87 (m, 1H), 3.79 (m, 1H), 3.68 (dt, 1H), 3.64 (br, 1H), 3.41 (td, 1H), 2.93 (q, 2H), 2.43 (q, 2H), 2.04 (m, 1H), 1.93 (dt, 1H) ), 1.86 (m, 1H), 1.77 (m, 1H), 1.49 (m, 1H), 1.38 (m, 1H), 1.17 (t, 3H), 0.70 (t, 3H).

COMPOUND 50: 2-M .8-diethyl-9-methyl-1,3,4,9-tetrahydro-pyrano [3,4-b1ndol-1-yl] -ethanol 50. A. Synthesis of 2-M-8-diethyl-9-methyl-1,3,4,9-tetrahydro-pyran [3,4-b1indol-1-p-acetic acid Following the procedure of Example 49. A, except that acid (1,8-diethyl-, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid was used as the indole component, the title compound was obtained as an oil. 50.B. Synthesis of 2- (1,8-diethyl-9-methyl-1, 3,4,9-tetrahydro-pyran [3,4-b1indol-1-yl] -ethanol) Following the procedure of Example 49. B., except for that 2- (1,8-diethyl-9-methyl-1, 3,4,9-tetrahydro-pyrano [3,4-b] indol-1-yl) -acetic acid was used as the carboxylic acid component, obtained the title compound as a solid. 1 H NMR (500 MHz, CDCl 3) d 7.35 (dd, 1 H), 7.03 (t, 1 H), 6.98 (d, 1 H), 4.04 (m, 1 H), 3.93 (m, 1 H), 3.91 (s, 3 H) , 3.75 (m, 1H), 3.63 (m, 1H), 3.11 (q, 2H), 2.87 (m, 1H), 2.76 (dt, 1H), 2.68 (br, 1H), 2.27 (m, 1H), 2.22 (m, 1H), 2.12 (m, 1H), 1.97 (m, 1H), 1.35 (t, 3H), 0.94 (t, 3H); ESI (+) MS m / e = 288 (MH +).

COMPOUND 51: 2- (7-bromo-1, 8-diethyl-1, 3,4,9-tetrahydro-pyran [3,4-blindol-l-iH-ethanol 51. A. Synthesis of ethyl 2- (7-bromo-1,8-diethyl-1, 3,4,9-tetrahydropyrano [3,4-b1indol-1-yl] -acetate) Ethyl ester (R, S) was dissolved Etodolac (5 g, 15.8 mmol) in chloroform (50 ml) and cooled to -60 ° C with a dry ice / acetone bath. To this solution was added dropwise a solution of bromine (2.53 g, 15.8 mmol) in chloroform (50 ml) for 2 hours. After the addition, the reaction mixture was allowed to warm to -20 ° C and triethylamine (5 ml) was added dropwise followed by silica gel (-20 g). The mixture was stirred for 10 minutes, filtered through silica gel (-10 g), and the filtrate was evaporated until dried. The crude product was recrystallized from hexane / dichloromethane (60 ml / 20 ml) to obtain (4.5 g, 72%) of the product. 1 H NMR (300 MHz, CDCl 3) d 9.23 (b, NH), 7.45 (d, 1 H), 7.15 (d, 1 H), 4.21 (qrt, 2 H), 4.15 (m, 1 H), 3.95 (m, 1 H) , 3.25 (dd, 2H), 2.94 (m, 2H), 2.25 (m, 1H), 2.1 (m, 1H), 1.45 (t, 3H), 1.15 (t, 3H), 0.85 (t, 3H). 51.B. Synthesis of 2- (7-bromo-1, 8-diethyl-1, 3,4,9-tetrahydropyrano [3,4-b1ndol-1-yl] -acetic acid To a stirred solution of ethyl acetate 2- (7-bromo-1,8-diethyl-1,3,4,9-tetrahydropyran [3,4-b] indol-1-yl) (2.8 g, 5 mmol) in dioxane (40 ml) was added hydroxide. lithium monohydrate (2.8 g, 67 mmol) and water (30 ml). The mixture was stirred at room temperature overnight. It was concentrated under reduced pressure, neutralized with 5% HCl, extracted with CH2Cl2, dried over MgSO4, and concentrated. The crude product was recrystallized from dichloromethane / hexane (60 ml / 20 ml) to give a white solid (980 mg, 53%). 1 H NMR (300 MHz, CDCl 3) d 8.68 (br, NH)), 7.27 (d, 1H), 7.19 (d, 1H), 4.06 (m, 2H), 3.04 (qrt, 2H), 2.95 (qrt, 2H ), 2.80 (m, 2H), 2.09 (m, 2H), 1.24 (t, 3H), 0.874 (t, 3H). 51.C. Synthesis of 2- (7-bromo-1, 8-diethyl-1, 3,4,9-tetrahydropyran [3,4-b1indol-1-yl] -ethanol To a stirred solution of 2- (7-bromo-1, 8-Diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) acetic acid (0.87 g, 2.4 mmol) in THF (5 mL) was added dropwise by borane syringe -tetrahydrofuran complex, 1.0 M solution in tetrahydrofuran (3.6 ml, 3.6 mmol) for 30 min. The mixture was stirred at 90 ° C for 8 hours, cooled, quenched with distilled water and 5% HCl, extracted with EtOAc. The organic phases were collected, washed with brine, dried over MgSO4, and evaporated to give a residue which was subjected to chromatography on silica gel. Elution with hexane-EtOAc (1: 1) afforded the product which was further recrystallized from hexane / dichloromethane to give the product (0.64g, 76%). 1 H NMR (300 MHz, CDCl 3) d 7.91 (b, NH), 7.28 (d, 1H), 7.20 (d, 1H), 4.02 (m, 2H), 3.71 (m, 2H), 2.95 (qrt, 1H) , 2.81 (m, 1H), 2.75 (t, 1H), 2.69 (t, 1H), 2.58 (t, 1H), 2.19 (m, 1H), 2.04 (m, 2H), 1.26 (t, 3H), 0.93 (t, 3H). COMPOUND 54: 2- (6-Bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano [3,4- b] indol-1-yl) -ethanol 54. A. Synthesis of 2- (hydroxyiminoyN- (2-isopropylphenip-acetamide) Water (1000 ml) was placed in a 2-1 round bottom flask, followed by doral hydrate (49 g, 0.30 mol), anhydrous sodium sulfate ( 225 g), 2-isopropylaniline (50 g, 0.37 mol), concentrated hydrochloric acid (22 ml, 0.26 mol), hydroxylamine hydrochloride (57 g, 0.81 mol), the solution was boiled for 3 hours, cooled, it was quenched with water, and extracted with ethyl acetate.The extracts were dried over MgSO4, and evaporated.The residue was purified by elution from a column of silica gel with hexane / EtOAc (7: 3) to obtain the product. (26.7g, 35%). 1 H NMR (300 MHz, CDCl 3) d 8.28 (br, NH), 7.88 (dd, 1H), 7.82 (b, NOH), 7.63 (s, .N = CH), 7.24 ( m, 3H), 3.04 (m, 1H), 1.27 (d, 6H), ESI (+) MS m / e = 207 (MH +), ESI (-) MS m / e = 205 (MH '). 54. B. Synthesis of 7-isopropylindoline-2,3, -dione To a stirred solution of H2SO4 (210 mL) and H20 (50 mL) was added over 20 minutes (26.7 g, 0.13 mol) of 2- (hydroxyimino) - N- (2-isopropyl) acetamide. The mixture was stirred at 75 ° C for 2 hours, cooled and poured into crushed ice. After standing for 15 minutes, it was extracted with EtOAc, washed with water, dried over MgSO, and concentrated. Air drying produced 23.8 g, 97% of the crude product. 1 H NMR (300 MHz, CDCl 3) d 8.15 (b, NH), 7.49 (d, 2 H), 7.11 (t, 1 H), 2.87 (m, 1 H), 1.30 (d, 6 H); ESI (+) MS m / e = 190 (MH +), ESI (-) MS m / e = 188 (MH '). 54. C. Synthesis of 5-bromo-7-isopropylindoline-2,3-dione 7-isopropylindoline-2,3-dione (23.8 g, 12 mol) was added to a stirred solution of glacial acetic acid (700 ml). To this solution was added, through a funnel, additional bromine (7.8 ml, 0.15 mol) in glacial acetic acid (300 ml) for 30 minutes. After the addition, the combined mixture was stirred at 75 ° C for 3 hours, cooled, and extracted with EtOAc. The organic extracts were washed with slurry, dried over MgSO, and evaporated in vacuo; they were air dried and 31.8 g, 94% crude product was obtained. 1 H NMR (300 MHz, CDCl 3) d 8.04 (b, NH), 7.59 (dd 2 H), 2.84 (m, 1 H), 1.31 (d, 6 H); ESI (+) MS m / e = 269 (MH +), ESI (-) MS m / e = 267 (MH ") 54. D. Synthesis of 5-bromo-7-isopropyl-1 H-indole A stirred solution of 5-bromo-7-isopropylindoline-2,3-dione (45.1 g, 0.17 mol) in THF (275 ml) at room temperature under a nitrogen atmosphere, a 2.0 M solution of LiBH 4 / was added via syringe. THF (215 mL) for 30 minutes The reaction mixture was stirred at 90 ° C for 1 hour, cooled, quenched with distilled water and 5% HCl, and extracted with EtOAc The extracts were washed with brine, dried over MgSO, and concentrated under reduced pressure The crude product was purified by elution from a column of silica gel with hexane / EtOAc (9: 1) to give 14.5 g, 36% of the product.1H NMR (300 MHz , CDCI3) d 8.18 (b, NH), 7.62 (d, 1H), 7.21 (t, 1H), 7.16 (d, 1H), 6.51 (dd, 1H), 3.20 (m, 1H), 1.38 (d, 6H); ESI (+) MS m / e = 239 (MH +), ESI (-) MS m / e = 237 (MH '). 54.EE Synthesis of 2- (5-bromo-7-isopopil-1) H-indol-3-yl) -2 ethyl -oxoacetate A 2.0 M solution of oxalyl dichloride in dichloromethane (60 ml, 0.12 mol) was added dropwise over 10 minutes to a solution of 5-bromo-7-isopropyl-1 H-indole (14.5 g, 0.061 mol). ) in Et20 (220 ml) at room temperature under a nitrogen atmosphere. The mixture was stirred for 4.5 hours. The Et20 was removed by evaporation and EtOH (220 ml) absolute was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere-overnight. The EtOH was evaporated, and EtOAc was added to the residue and washed with saturated NaHCO 3 and brine. The organic layers were dried over MgSO4, concentrated and dried under vacuum to give a crude product (13.8 g, 67%). 1 H NMR (300 MHz, CDCl 3) d 8.85 (b, NH), 8.46 (dd, 2H), 7.33 (d, 1H), 4.42 (qrt, 2H), 3.21 (m, 1H), 1.44 (t, 3 H ), 1.38 (d, 6H), ESI (+) MS m / e = 339 (MH +), ESI (-) MS m / e = 337 (MH '). 54. F. Synthesis of 2- (5-Bromo-7-isopropyl-1 H-indol-3-yl) -ethanol. It was reduced ethyl 2- (5-bromo-7-isopropyl-1 H-indole-3- il) -2- oxoacetate (13.8 g, 0.04 mol) in THF (300 ml) with a 2.0 M solution of LiBH in THF (50 ml, 0.1 mol) by refluxing under a nitrogen atmosphere for 5 hours, cooled, quenched with distilled water and 5% HCl , and extracted with EtOAc. The extracts were washed with brine, dried over MgSO4, and concentrated. The crude product was purified by elution from silica gel with hexane / EtOAc to obtain 4.5 g, 39% product. 1 H NMR (300 MHz, CDCl 3) d 8.05 (b, NH), 7.59 (d, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 3.89 (t, 2H), 3.18 (m, 1H) 2.98 (t, 2 H), 1.37 (d, 6H); ESI (+) MS m / e = 283 (MH +), ESI (-) MS m / e = 281 (MH '). 54. G. Synthesis of 2- (6-bromo-1-ethyl-1, 3,4,9-tetrahydro-8-propylpyranoside [3,4-b1indol-1-yl] ethyl acetate To a suspension of 2- ( 5-bromo-7-isopropyl-1 H-indol-3-yl) -ethanol (4.5 g, 0.016 mol) under a nitrogen atmosphere was added diethyl etherate boron trifluoride (2.2 ml, 0.18 mol), followed by addition by dripping ethyl propionylacetate (3.4 ml, 0.024 mol) for 10 minutes. The mixture was stirred at room temperature for 1.5 hours. Dichloromethane was added to the mixture and the organic layer was washed with saturated NaHCO3 and water, and dried over MgSO4. The solvent was dried and concentrated in air to give the crude product (6 g, 92%). ESI (+) MS m / e = 409 (MH +), ESI (-) MS m / e = 407 (MH '). 54. F. Synthesis of 2- (6-bromo-1-ethyl-1, 3,4,9-tetrahydro-8-isopropylpyrano [3,4-b1indol-1-yl] -ethanol To a stirred solution of ethyl acetate 2- ( 6-Bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano [3,4-b] indol-1-yl) (6.0 g, 0.015 mol) in THF (120 ml), was added a 2.0 M solution of LiBH4 / THF (20 ml, 0.30 mol) through a syringe for 30 minutes under a nitrogen atmosphere at room temperature. The mixture was refluxed for 10 hours, cooled, quenched with water and 5% HCl and extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO, and evaporated to give a residue which was subjected to chromatography on silica gel. It was eluted with hexane-EtOAc (7: 3) and the product was obtained (4.3 g, 80%). 1 H NMR (300 MHz, CDCl 3) d 8.18 (b, NH), 0.92 (t, 3 H), 1.35 (d, 6 H), 1.98 (m, 3 H), 2.19 (m, 1 H), 2.54 (t, 1 H) , 2.75 (m, 2H), 3.17 (m, 1H), 3.71 (t, 1H), 4.03 (m, 2H), 7.13 (dd, 1H), 7.45 (d, 1H), 7.96 (b, NH). ESI (+) MS m / e = 367 (MH +), ESI (-) MS m / e = 365 (MH '). COMPOUND 55: 3- (1-ethyl-1, 3.4.9-tetrahydro-1 - (2-hydroxyethyl-8-isopropylpiranoi3,4-bindole! -6-yl) -ethyl-propanoate 55. A. Synthesis of (E) -ethyl 3-M-ethyl-1, 3,4,9-tetrahydro-1- (2-hydroxyethyl-8-isopropylpiran [3,4-b1 indole-6- ipacrylate A suspension of Pd (OAc) 2 (0.2 g, 0.8 mmol), P (o-tolyl) 3 (0.25 g, 0.8 mmol), 2- (6-bromo-1-ethyl-1, 3.4.9 -tetrahydro-8-isopropylpyrano [3,4-b] indol-1-yl) ethanol (1.5 g, 4.1 mmol), triethylamine (1.5 mL, 11 mmol), and ethyl acrylate (1.8 mL, 16 mmol) in acetonitrile (45 ml) and stirred under a nitrogen atmosphere at 100 ° C for 24 hours, the mixture was allowed to cool, was quenched with water, worked with dichloromethane, and washed with brine.The organic layers were dried over MgSO4. and concentrated under reduced pressure The product was chromatographed on EtOAc / silica hexane (6: 4) to obtain the product (0.9 g, 56%).%). 1 H NMR (300 MHz, CDCl 3) d 8.07 (br, NH), 7.83 (d, 1 H), 7.53 (d, 1 H), 7.28 (d, 1 H), 6.43 (d, 1 H), 4.27 (m, 2 H) , 4.04 (m, 2H), 3.73 (m, 2H), 3.19 (m, 1H), 2.84 (m, 1), 2.77 (d, 1H), 2.52 (br, 1H), 2.20 (m, 1H), 2.09 (m, 1H), 1.92 (m, 1H), 1.38 (d, 6H), 1.35 (t, 3H), 0.95 (t, 3H); ESI (+) MS m / e = 386 (MH +), ESI (-) MS m / e = 384 (MH '). 55. B. Synthesis of ethyl 3-f 1 -eti 1-1, 3,4,9-tetrahydro-1 - (2-hydroxyethyl-8-isopropylpyrano [3,4-b1 indol-6-iDpropanoate To a suspension of (E ) -ethyl-3- (1-ethyl-1, 3,4, 9-tetrahydro-1- (2-hydroxyethyl) -8-isopropylpyrano [3,4-b] indol-6-yl) acrylate (0.8 g, 2.3 mmol) in 2% HCl in EtOH (80 ml) was added palladium on carbon (10%, 0.5 g) The mixture was stirred under a hydrogen atmosphere (1 am) at room temperature for 24 hours. The filtrate was evaporated under reduced pressure, the residue was neutralized with saturated NaHCO 3, extracted with EtOAc and dried over MgSO 4, The solvent was concentrated under reduced pressure and purified by column chromatography. Flash over silica gel hexane / EtOAc (6: 4) to obtain the product (0.33 g, 38%). 1 H NMR (300 MHz, CDCl 3) d 7.72 (br, NH), 7.18 (d, 1 H), 6.91 ( d, 1H), 4.15 (qrt, 2H), 4.02 (m, 2H), 3.70 (m, 2H), 3.17 (m, 1H), 3.04 (t, 2H), 2.83 (m, 1H), 2.68 (m , 3 H), 2.18 (m, 1H), 2.05 (m, 1H), 1.96 (m, 2H), 1.36 (d, 6H), 1.26 (t, 3H), 0.94 (t, 3H); ESI (+) MS m / e = 388 (MH +), ESI (-) MS m / e = 386 (MH ") COMPOUND 56: 3- (1-ethyl-1, 3,4,9-tetrahydro) acid -1- (2-hydroxyethyl) -8-isopropylpiran [3,4-b1 indol-6-ip propanoic 56. A. Synthesis of 3-M-ethyl-1, 3,4,9-tetrahydro-1- (2-hydroxyethyl) -8-isopropylpirano [3,4-b1dol-6-yl] propanoic acid To a stirred suspension of ethyl 3- (1-ethyl-1, 3,4,9-tetrahydro-1- (2-hydroxyethyl) -8-isopropylpyrano [3,4-b] indol-6-yl) propoanoate (0.28 g, 0.72 mmol ) in dioxane (6 mL) was added lithium hydroxide monohydrate (0.18 g, 4.3 mmol) and water (3 mL). The mixture was stirred at room temperature for 8 hours. Concentrate under reduced pressure, neutralize with 5% HCl, extract with EtOAc and dry over MgSO4. The solvent was concentrated and purified by flash column chromatography on silica gel dichloromethane / methanol (8: 2) to obtain the product (0.09 g, 35%). 1 H NMR (300 MHz, CDCl 3) d 7.77 (br, NH)), 7.19 (d, 1 H), 6.91 (d, 1 H), 4.04 (m, 2 H), 3.68 (m, 2 H), 3.16 (m, 1 H) ), 3.06 (t, 2H), 2.85 (m, 1H), 2.74 (m, 3H), 2.18 (m, 1H), 1.98 (m, 3H), 1.35 (d, 6H), 0.94 (t, 3H); ESI (+) MS m / e = 360 (MH +), ESI (-) MS m / e = 358 (MH '). COMPOUND 57: 3-M-ethyl-1.3.4.9-tetrahydro-1 - (2-hydroxyeti-8-isopropylpiranoi3,4-b1indol-6-p-propan-1-ol 57. A. Synthesis of 3- (1-ethyl-1, 3,4,9-tetrahydro-1-f2-hydroxy-p-p-8-isopropylprano [3,4-b] indol-6-yl) propan-1-ol A solution of ethyl 3- (1-ethyl) I-, 3,4,9-tetrahydro-1- (2-hydroxyethyl) -8-isopropylpyrano [3,4-b] indol-6-yl) Propoanoate (0.18 g, 0.46 mmol) in anhydrous diethyl ether (15 mL) was stirred at room temperature under a nitrogen atmosphere. LIA1H4 (0.09 g, 2.4 mmol) was slowly added to the solution. The mixture was stirred for 18 hours, quenched with water and 5% HCl, extracted with EtOAc, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel hexane / EtOAc (4: 6) twice to give (31 mg) of the product (0.031 g, 20%). 1 H NMR (300 MHz, CDCl 3) d 7.70 (br, NH), 7.18 (d, 1 H), 6.91 (d, 1 H), 4.03 (m, 2 H), 3.73 (m, 4 H), 3.17 (m, 1 H) , 2.80 (m, 6H), 2.18 (m, 1H), 1.98 (m, 3H), 1.37 (d, 6H), 1.26 (ber, 1H), 0.94 (t, 3H); ESI (+) MS m / e = 346 (MH +), ESI (-) MS m / e = 344 (MH ") EXAMPLE 2: BIOLOGICAL DATA Cox-1 The test compound and / or a vehicle is incubated with human platelets (108 / ml) containing the phospholipase inhibitor MLnFP (100 μM) for 15 minutes at 37 ° C. Then arachidonic acid (100 μM) was added for an additional incubation period of 15 minutes. addition of 1N HCl and neutralized with 1N NaOH The levels of PGE2 in the supernatant were determined using the Amersham EIA equipment The compounds were screened at 10 μM The tests are described in Chan er 1999. J. Pharmacol Exp Ther. 290: 551-560; and Swinney et al., 1997 J Biol. Chem. 272: 12393-12398, both of which are incorporated herein by reference Cox-2 Cyclooxygenase-2 (recombinant human, expressed in Sf9 cells, Cayman was used. 60122) The test compound and / or a vehicle was previously incubated with 0.11 U cyclooxygenase-2, reduced glutathione 1 mM (GSH), 500 μM phenol and 1 μM hematin for 15 minutes at 37 ° C. The reaction was initiated by the addition of 0.3 μM of arachidonic acid as the substrate in Tris-HCl, pH 7.7 and was terminated after a 5 minute incubation at 37 ° C by the addition of 1N HCl. After centrifugation, the conversion of the substrate to PGE2 was measured with a computer Amersham EIA. The compounds were screened at 10 μM. The COX-2 analyzes are described in Riendeau, D., er al., 1997 Dog. J. Physiol. Pharmacol. 75: 1088-1095; and Warner, J. D., et al. 199 Proc. Nati Acad. Sci. USA 96: 7563-7568, both documents incorporated herein by reference. Table 1 is presented below, showing exemplary results of COX-1 inhibition and COX-2 through the compounds described herein: TABLE I Inhibition of β-Catenin The inhibition of β-catenin was measured using an indicator analysis that is based on the assays described in Korinek et al. 1997 Science 275: 1784-1787 and the reporter plasmid TOPFLASH was used. On Day 1, 24-well HEK-293 cells (ATCC), 40,000 cells per well in 450 μl of a DMEM + 10X FBS medium were placed in slides (VWR) of 24 receptacles and incubated overnight at 37 ° C, with C02 to 5%. On Day 2, the plasmid TOPFLASH (Upstate Cell Signaling Solutions, VA), the control vector pGL3 (Promega), and a plasmid encoding constitutively expressed human β-catenin (Hans Clevers) were separately diluted to 0.1 μg / μL in a pH regulator TE. Transfections were performed using FuGene 6 transfection reagent (Roche). Transfection mixtures included 8 μl of 0.1 μg / μl of pGL3 in 40 μl of a serum-free medium (DMEM, Gibco) and 9.6 μl of FuGene, or 8 μl of 0.1 μg / μL TOPFLASH and 16 μl of β-plasmid catenin in 400μl of a serum-free medium (DMEM, Gibco) and 9. 6μl of FuGene. The transfection mixtures were mixed carefully and incubated for 15 to 30 minutes at room temperature. 50μl of the appropriate transfection mixture was added to the 293 cells and the cells were incubated overnight at 37 ° C., COa at 5%. On Day 3, the compounds under test were diluted to 0.25 M in dimethyl sulfoxide (DMSO). This solution was used to make a 3X dilution of the compound in DMEM + 10% FBS, eg, 100 μm to 300 μm. Two hundred fifty μl of the 3X diluted compound was added dropwise to a suitable receptacle containing 500 μl of the medium. This was rotated smoothly. After mixing, 250 μl of the diluted 3X compound was added to another receptacle and the procedure continued until the compound was diluted three more times. The lamellae were incubated for 24 hours at 37 ° C, 5% C02. Experiments were performed in duplicate. On day 4, Luciferaza activity was measured using a Promega Steady-Glo® luciferase assay system (Promega Cat. No. EC251) in accordance with the manufacturer's instructions. The cells and Glo Lysis pH regulator were equilibrated at room temperature. Ten of the Glo Lysis® pH regulator were added to reconstitute the Steady-Glo® reagent. Five hundred μl of the test reagent / Glo Lysis Buffer® were added to each receptacle. The reaction was incubated for 5 minutes on a shaker at room temperature. 100 μl of the lysate was transferred to a 96-well slide and read in a Tecan micro-lamella reader (Research Triangle Park, NC) using the luminescence configuration. Inhibition of β-Catenin In Figure 1 the TOPFLASH of some compounds of the invention is shown. Cellular toxicity Normal prostate cells (PREC, Cambrex East Rutherford New Jersey), a prostate cancer cell line (LNCaP, ATCC), PBL (peripheral blood leukocytes - yellow-coated blood from the San Diego blood bank), and cells Primary CLL were incubated for two days in RPMI-1640 and 10% FBS (fetal bovine serum). They were placed in 96-well lamellae, at 100,000 cells / receptacle. The titrated concentrations of the test compound were added to the culture medium. The cells were incubated for 3 days at 37 ° C, 5% C02. The viability of the cells was analyzed through a standard MTT analysis. Each drug concentration was performed in duplicate. MTT test: 10 μl of 12 mM bromide 3, [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium (MTT) (Sigma) was added to each receptacle. Cells were incubated at 37 ° C, C02 5% for 4 hours. 100 μl of 20% SDS, 0.015 M HCl was added to each well and the cells were incubated overnight. The lamellae were read with an absorbance of 595 nM. The cytotoxic results are shown in Table II and III.

TABLE II TABLE III Selected analogues were tested and compared in various tumor cell lines and their sub-lines resistant to several drugs (M DR). The M DR cell lines used in these experiments have been extensively characterized in the literature and are resistant to various widely used anticancer drugs, such as doxorubicin, paclitaxel, etoposide, and others. As shown in Table IV, Table V and Table VI, the selected analogues were found 10-20 times more potent compared to Etodolac. In addition, there was no perceptible loss of activity in the sub-lines resistant to several drugs, when compared with the precursor cells. TABLE IV TABLE V TABLE VI Antiangiogenic tests To determine the effects of COX inhibitors or angiogenesis in vivo, a test of the compounds will be made in micro pocket tests on corneas of rats and mice. The micro pocket model of corneal neovascularization in mouse is performed with materials, reagents and procedures essentially as described in Muth ukkau ppah er al. , 1 982 J. Nati Cancer I nst. , 69, 699-708. In this test, a pellet containing the basic fibroblast growth factor (FG F) is implanted in the stroma of the mouse cornea and the newly formed vessels are measured using a slit lamp. In this model, COX-2 is expressed in the endothelial cells of newly developed blood vessels. The ability of a compound of the invention to inhibit angiogenesis induced by FG F in the mouse will be tested using the method mentioned in the preceding paragraphs. The inhibitory effects of the compounds of the invention in the mouse cornea model will be tested using other angiogenic stimuli, vascular endothelial growth factor (VEGF). Cyclin D1 Cyclin transcript expression levels as measured by the quantitative PCR assay. LNCaP were cultured at 37 ° C, with 5% C02 for 24 hours without treatment or in the presence of R-etodolac (200, μM), compound 42 (50 μM), compound 36 (100 μM), or compound 1 (20 μM). , μM) (see Table II for structures). The cells were cultured by trypsinization, washed with PBS, and stored at -80 ° C. Total cellular RNA was prepared from cell pellets using the RNEasy® mini kit (Qiagen, Inc., Valencia, CA). The RNA was quantified by a spectrophotometer. Approximately 2 μg of RNA was used to prepare cDNA using the ThermoScript ™ RT-PCR system (Invitrogen, Carlsbad, CA). The levels of cyclin D1 transcripts in the cDNA samples were measured by a quantitative PCR specific assay (qPCR) for cyclin D1. The cyclin D1 transcript was amplified using the following primer pair: Cyclin D1 for: 5'-AATGACCCCGACCGATT-3 '(SEQUENCE ID NO: 1) Cyclin D1 rev: 5'-GCACAAGAGGCAACGAAG G-3' (SEQUENCE ID NO: 2) Cyclin D1 primers are described in a manuscript of Takayasu et al. (2001 Clin Cancer Res. 7: 901-908). All tests were done in duplicate. All qPCR tests were performed and analyzed using a Bio-Rad iCycler kit (Bio-Rad, Hercules, CA). The levels of cyclin D1 transcripts were normalized to a total cDNA entry by performing a separate test to detect the levels of a maintenance gene (18s) using the following primer pair: 18s for: 5'-CGCCGCTAGAGGTGAAATTC -3 '(SEQUENCE ID NO: 3) 18s rev: 5'-TTGGCAAATGCTTTCGCTC-3' (SEQUENCE ID NO: 4) Samples were normalized for 18s transcript levels using the Livak et al method. (2001) Methods 25: 402-408). The level of cyclin transcripts D1 in the control sample was set to 1. Figure 2 represents the average normalized cyclin D1 transcripts ± standard deviation for three independent experiments (two independent experiments for compound 1). The data shows that Compound 42, Compound 36 and Compound 1 inhibit the expression of cyclin D1 mRNA. Western blot analysis of the LNCaP cell lysates of the cells treated with R-etodolac, Compound 42, Compound 36, or Compound 1 using a monoclonal antibody specific for Cyclin D1 (BD Pharmingen) confirmed that the compounds reduced the expression of the protein Cyclin D1. Other proteins Cyclin D have been shown to be dependent on the Wnt / β-catenin pathway (eg, Cyclin D2-Briata et al., 2003 Mol.Cell 12: 1201-11) and are expected to be affected by the compounds of the invention. similar ways to the Ciclina D1. The inhibition of the expression of Cyclin D by the compounds of the invention can be used as a biomarker of the efficacy of these compounds. EXAMPLE 3: MICE STUDIES FOR A HETEROLOGOUS GRAFT MODEL IN MURINOS WITH DAUDI LYMPHOMA Materials SCID male mice, 6-8 weeks old, obtained from Simonsen Laboratories, Inc. (Gilroy, CA) were housed in groups of five. The human Burkitt lymphoma cells of Daudi were obtained from the American Type Culture Collection and inoculated subcutaneously (1.0 x 10 7 cells / mouse) on the sides of the SCID mice. After the tumors reached a size of approximately 100 mm3, treatment was started.

The body weight and tumor volume of all mice was measured and recorded twice a week. The tumors were measured in three dimensions and the volume was calculated using the formula: 4 37ttr3. The time (days) it took for the tumors to grow 4X and 8X of the initial volume with a dosage was evaluated. The compounds under study were administered orally at 125 or 250 mg / kg / day (M-F) orally with a tube feeding until the end of the study. Efficacy The efficacy of chlorambucil (2 and 3 mg / kg / d) was studied, (R-etodoalc) (400 mg / kg / d) and compound 47 (250 mg / kg / d), compound 26 (250 mg / kg / d), and compound 1 (125 mg / kg / d) against tumors derived from the Daudi cell line in male SCID mice. R-etodolac and compounds 1, 26 and 47 were prepared in sesame oil. Both chlorambucil (ip, 0.1 ml) and the compounds of the invention (per os [p.o.], 0.31 ml) were dosed daily (Monday to Friday) for two weeks. SDX-101 (0.31ml) was dosed p. or. daily until the end of the study. A slight weight loss (<3%) was observed at the beginning of the study in the groups treated with chlorambucil (2 mg / kg / d), compounds 47 and 36. However, all treated mice recovered and maintained their weight after of Day 2. No weight loss was observed in the other treatment groups. At the end of the study, the mean tumor volume of the control group was 1583 mm3. The mean tumor volume of the groups treated with chlorambucil was 864 and 766 mm3 with a treatment of 2 and 3 mg / kg / d of chlorambucil, respectively. The mean tumor volume of R-etodolac and compounds 1, 36 and 47 was 802, 996, 1011, and 1157 mm3 with the treatment with compounds 47, 36, 1 and R-etodolac, respectively. The analysis of the variance (ANOVA) of the tumor volume in the control and chlorambucil groups on Day 20 showed a p-value of 0.001 and 0.0003 between the control groups vs the chlorambucil treatment groups of 2 and 3 mg / kg / d, respectively. ANOVA also showed a p-value of 0.007 and 0.03 between the control group vs. the groups treated with compound 47 and the compounds, respectively. At the end of the study, samples of the tumors were collected, together with liver, kidney and spleen samples from each group and the samples were fixed in 10% formalin with pH regulation for histopathology. Histological analysis of all organs, liver, spleen and kidney, indicated that all tissues appeared normal. Table VII shows the time it took the tumors to grow at 4X and 8X of the initial volume when the mice received chlorambucil, R-etodolac and compounds 1, 36 and 47. These data indicate that the compounds of the invention inhibit the growth of the tumor in the Daudi mouse model.

TABLE VII All patents and documents referred to in this document will be incorporated into it by reference. The invention is not limited to those embodiments described in the present detailed description, but includes modifications and variations that do not depart from the spirit and scope of the invention. While the invention has been described in conjunction with specific embodiments thereof, those skilled in the art understand that further modifications are within the scope of the following claims. In addition, where features or aspects of the invention are described in terms of Ma rkush groups or other ag rumenting alternatives, those skilled in the art will recognize that the invention is also described in that way in terms of any individual member or group. subgroups of members of the Markush group or gender, and the exclusion of individual members as appropriate.

Claims (10)

1. CLAIMS 1. A compound of Formula I: Formula I where: (a) X is C, S or O; (b) R-i is halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substituted groups are substituted with one, two or three suitable substituents each selected independently from the group consisting of : halogens, -CN, -N02, -OH, -SH, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl , and - (CH2) ZCN where z is an integer from 0 to 6; (c) R2, R3, R and R5 are each independently hydrogen; halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl; (d) R6, Rs and 9 are each independently hydrogen; halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; (e) R7 is hydrogen, halogen, -N, -OH, -SH, N02 or an unsubstituted or substituted portion selected from alkyl, alkenyl and alkynyl; (f) R-io is hydrogen; or an unsubstituted lower alkyl group; (g) Y is an unsubstituted or substituted portion selected from alkyl, alkenyl, and alkynyl; wherein the substituted portion is substituted with one, two or three substituents each independently selected from halogen; -CN; -OH; -SH; -N02; unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, and unsubstituted heteroaryls; and (h) Z is an unsubstituted portion selected from -OH, and -SH, wherein R-i and Y can form one or more rings to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group; and wherein: (i) at least one of R6, R7, Re, and Rs is not hydrogen; (ii) wherein Ri is propyl, Y-Z is -CH2CH2OH- and Rg is fluoro, R6 is not substituted with a heterocycloalkyl group -C (O) -; (iii) wherein Y-Z is -CH2CH2CH2OH- and R9 is ethyl, Ri is not CN; (iv) wherein R-i is ethyl and R9 is ethyl, Y-Z is unsubstituted or substituted -CH20H or -CH2CH2OH-; (v) wherein R-y is methyl and R 9 is methyl, Y-Z is -CH 2 OH- or -CH 2 CH 2 OH; and (vi) wherein Y-Z is -CH2CH2OH- and R9 is not -CH2CH2OH; or a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt thereof.
2. 2. A compound or a pharmaceutically acceptable salt according to claim 1.
3. 3. A compound or a pharmaceutically acceptable salt according to claim 1, wherein the compound has an IC50 or greater than about 100 μm at least for one of COX -1 or COX-2.
4. 4. A compound according to claim 1, wherein the groups substituted in R2, R3, R4, R5? R6, R7? R8? and R9 are substituted with one, two or three suitable substituents each independently selected from the group consisting of: halogens, groups = 0, = S, -CN, -N02, alkyl, alkenyl, heteroalkylop, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) ZCN wherein z is an integer from 0 to 6, = NH, -NHOH, -OH, -C (0) H, -OC (0) H, -C ( 0) OH, -OC (0) OH, -OC (0) OC (0) H, -OOH, -C (NH) NH2, -NHC (NH) NH2I- C (S) NH2, -NHC (S) NH2, -NHC (0) NH2, -S (Oz) H, -S (0) H, -NH2, -C (0) NH2, -OC (0) NH2, -NHC (0) H, -NHC ( 0) OH, -C (0) NHC (0) H, -OS (Oz) H, -OS (0) H, -OSH, -SC (0) H, -S (0) C (0) OH, -S02C (0) OH, -NHSH, -NHS (0) H, -NHS02H, -C (0) SH, -C (0) S (0) H, -C (0) S (02) H, - C (S) H, -C (S) OH, -C (SO) OH, -C (S02) OH, -NHC (S) H, -OC (S) H, -OC (S) OH, -OC (S02) H, -S (02) NH2, -S (0) NH2, -SNH2, -NHCS (02) H, -NHC (SO) H, -NHC (S) H, and -SH unsubstituted or substituted with one, two or three suitable substituents selected independently of the group consisting of halogens, = 0, -N02, -CN, -OH, -SH, - (CH2) Z-CN, wherein z is an integer from 0 to 6, -ORCl- NRcORc, -NRCRC, - C (0) NRc, -C (0) ORc, -C (0) Rc, -NRcC (0) NRcRc, -NRcC (0) Rc, -OC (0) ORc, -OC (0) NRcRc, -SRC unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls and unsubstituted heteroaryls, wherein Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl , unsubstituted aikinyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together form one or more ani They are to be part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
5. 5. A compound or a pharmaceutically acceptable salt according to claim 1, wherein X is S or O.
6. 6. A compound or a pharmaceutically acceptable salt according to claim 1, wherein Ri is an unsubstituted portion selected from lower alkyl. , lower hydroxyalkyl, lower alkenyl, lower hydroxyalkenyl, lower alkynyl, lower hydroxyalkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl.
7. 7. A compound or a pharmaceutically acceptable salt according to claim 1, wherein R-i forms one or more rings with Y to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl group.
8. 8. A compound or a pharmaceutically acceptable salt according to claim 1, wherein R2, R3? R and Rs are each independently hydrogen; or an unsubstituted portion selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl.
9. 9. A compound or a pharmaceutically acceptable salt according to claim 1, wherein R2? R3? R4 and R5 are each independently hydrogen.
10. 10. A compound or a pharmaceutically acceptable salt according to claim 1, wherein R6, Rs and R9 are each independently hydrogen or an unsubstituted or substituted portion selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein at least one of R6, R8 and R9 is not hydrogen. A compound or a pharmaceutically acceptable salt according to claim 1, wherein R7 is hydrogen, halogen, or an unsubstituted or substituted portion selected from alkyl and alkoxy, wherein the substituted portion is substituted with one, two or three substituents independently selected from the group consisting of -OH, -C (0) 2-alkyl, -C (0) 2H, alkoxy, -O-haloalkyl, halogen, alkyl, haloalkyl, and NH2. 13. A compound or a pharmaceutically acceptable salt according to claim 1, wherein R7 is hydrogen, halogen -CN; -OH; -SH; -N02; unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, lower alkyl-C (0) 2H, lower alkyl-C (0) 2-lower alkyl, or lower alkoxy. 14. A compound or pharmaceutically acceptable salt according to claim 1, wherein R7 is not hydrogen. 15. A compound or pharmaceutically acceptable salt according to claim 1, wherein R6 is hydrogen or halogen. 16. A compound or pharmaceutically acceptable salt according to claim 1, wherein R8 is hydrogen or halogen. 17. A compound or a pharmaceutically acceptable salt according to claim 1, wherein R9 is hydrogen, halogen, or an unsubstituted or substituted portion selected from alkyl, aryl, heteroaryl, heterocycloalkyl, haloalkyl, alkynyl, alkenyl, haloalkyl, wherein the substituted portion is substituted with one or two substituents independently selected from the group it consists of alkyl, -C (0) H, -CN, halogen, alkoxy, aryl and -C (0) 2H. 18. A compound or pharmaceutically acceptable salt according to claim 1, wherein R-io is hydrogen. 19. A compound or a pharmaceutically acceptable salt according to claim 1, wherein X is O and R-? 0 is hydrogen. 20. A compound or pharmaceutically acceptable salt according to claim 1, wherein Y is lower alkyl. 21. A compound or pharmaceutically acceptable salt according to claim 1, wherein Z is hydroxyl. 23. A compound or a pharmaceutically acceptable salt according to claim 1, wherein Z is SH. 24. A compound or a pharmaceutically acceptable salt according to claim 1, wherein the groups substituted in R2, R3, R4, R5, R6, R, Rs and 9 are substituted with one, two or three suitable substituents each independently selected from the group consisting of: halogens, groups = 0, = S, -CN, -N02 , alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) zCN wherein z is an integer from 0 to 6, = NH, -OH, -C (0) H, -OC (0) H, -C (0) OH, -0C (0) 0H, -C (NH) NH2, -NHC (0) NH2, -S (0) H, -NH2, -C (0) NH2, -0C (0) NH2, -NHC (0) H, -NHC (0) OH, -C (S) H, and -SH not substituted or substituted with one, two or three suitable substituents each selected independently from the group consisting of halogens, = 0, -N02l-CN, -OH, -SH, - (CH2) z-CN, wherein z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls , unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls. 25. A compound or pharmaceutically acceptable salt according to claim 1, wherein: (a) X is S or O; (b) R-i is an unsubstituted portion selected from lower alkyl, lower hydroxyalkyl, lower alkenyl, lower hydroxyalkenyl, lower alkynyl, lower hydroxyalkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl; (c) R2, R3, R4 and R5 are each independently hydrogen; or an unsubstituted portion selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl; (d) R6, Rs and R9 each are independently hydrogen; or an unsubstituted or substituted portion selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein the substituted portions are each independently selected from the group consisting of halogen, -CN, alkyl , alkoxy, -NH2, -O-haloalkyl, -CH (O), haloalkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, -OH, -C (0) 2 -alkyl, and -C (0) 2H; (e) R7 is hydrogen; halogen; -CN; -OH; -SH; -N02; unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, C (0) 2H alkyl, C (0) 2-alkyl, or lower alkoxy; and (f) R-io is hydrogen. 26. A compound or pharmaceutically acceptable salt according to claim 1, wherein: (a) X is O; (b) Ri is an unsubstituted alkyl group or an unsubstituted aryl group; (c) R2, R3, R and R5 each are hydrogen; (d) R7 is hydrogen, halogen unsubstituted lower alkyl, lower alkyl-C (0) 2H, lower alkyl-C (0) 2-lower alkyl, or lower hydroxyalkyl; and (e) R-io is hydrogen. 27. A compound or pharmaceutically acceptable salt according to claim 1, wherein: (a) R9 is hydrogen, halogen or an unsubstituted alkyl group; (b) Y is an unsubstituted alkyl group; and (c) Z is hydroxyl. 28. A compound or a pharmaceutical salt according to claim 1, wherein at least one of R6, Rs and 9 is an aryl group unsubstituted or substituted with one, two or three suitable substituents selected independently from the group consists of: halogens, groups = 0, = S, -CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) ZCN wherein z is an integer from 0 to 6, = NH, -OH, -C (0) H, -OC (0) H, -C (0) OH, -OC (0) OH, -C (NH) NH2, -NHC (0) NH2, -S (0) H, -NH 2, -C (0) NH 2, -OC (0) NH 2, -NHC (0) H, -NHC (0) OH, -C (S) H, and unsubstituted -SH or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, = 0, -N02, - CN, OH, -SH, - (CH2) z-CN, wherein z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, aryls substituted, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls. 29. A pharmaceutical compound or salt according to claim 1, wherein at least one of R6, Rs and 9 is a heteroaryl group unsubstituted or substituted with one, two or three suitable substituents each selected independently from the group which consists of halogens, groups = 0, = S, -CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) 2CN wherein z is an integer from 0 to 6, = NH, -OH, -C (0) H, -OC (0) H, -C (0) 0H, -0C (0) 0H, -C (NH) NH2, -NHC (0) NH2, -S (0) H, -NH 2, -C (0) NH 2, -OC (0) NH 2, -NHC (0) H, -NHC (0) 0H, -C (S) H, and unsubstituted -SH or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, = 0, -N02l-CN, -OH, -SH, - (CH2) Z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, ary the unsubstituted, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls. 30. A compound or a pharmaceutical salt according to claim 1, wherein at least one of R6, R8 and Rg is a heterocycloalkyl group unsubstituted or substituted with one, two or three suitable substituents each selected independently from the group consisting of halogens, groups = 0, = S, -OH, -SH, -CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) ZCN wherein z is an integer from 0 to 6, = NH, -OH, -C (0) H, -OC (0) H, -C (0) OH, -OC (0) OH, -C (NH) NH2I -NHC (0) NH2, -S (0) H, -NH2, -C (0) NH2, -OC (0) NH2, -NHC (0) H, -NHC (0) OH, -C (S) H, and -SH not substituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, = 0, -N02, -OH, -SH, -CN, - (CH2) z-CN wherein z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, haloalkyls n or substituted, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls. 31. A pharmaceutical acceptable compound or salt according to claim 1, wherein: (a) X is O u S; (b) R-i is an unsubstituted lower alkyl group; (c) R2, R3, R4 and R5 each are hydrogen; (d) R6 is hydrogen or halogen; (e) R7 is halogen or unsubstituted lower alkyl, lower alkyl-C (0) 2H, lower alkyl-C (0) 2-lower alkyl or lower alkoxy; (f) R8 is hydrogen or halogen; (g) R9 is hydrogen or an unsubstituted or substituted portion selected from alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; and (h) R-io is hydrogen. 32. A pharmaceutical acceptable compound or salt according to claim 31, wherein Y is an unsubstituted lower alkyl group and Z is hydroxyl. 33. A compound or a pharmaceutically acceptable salt according to claim 1, wherein (a) X is O; (b) R-i is an unsubstituted portion selected from aryl, alkyl and lower alkoxy; (c) R2? R3? R4 and R5 each are hydrogen; (d) R6 and R8 each are hydrogen or halogen; (e) R7 is halogen, unsubstituted lower alkyl, lower alkyl-C (0) 2H, lower alkyl-C (0) 2-lower alkyl or lower alkoxy; (f) R9 is an unsubstituted branched alkyl group; and (g) R-io is hydrogen; wherein the substituted groups on R7 are substituted with one, two or three suitable substituents independently selected from the group consisting of: halogens, groups = 0, = S, -CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - (CH2) zCN where z is an integer from 0 to 6, = NH, -OH, -C (0) H, -OC (0) H, -C (0 ) OH, -OC (0) OH, -C (NH) NH2, -NHC (0) NH2, -S (0) H, -NH2, -C (0) NH2, -OC (0) NH2, -NHC (0) H, -NHC (0) OH, -C (S) H, and -SH unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, = 0, -N02l-CN, -OH, -SH, - (CH2) Z-CN wherein z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, aryls unsubstituted, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls . 34. A compound or pharmaceutically acceptable salt according to claim 33, wherein: (a) Y is an unsubstituted lower alkyl group; and (b) Z is hydroxyl. 35. A compound or pharmaceutically acceptable salt according to claim 1, wherein Rg is a branched alkyl. 36. A compound selected from the group consisting of: 25; a pharmaceutically acceptable salt thereof. 37. A compound that has the following structure: or an acceptable pharmaceutically acceptable salt thereof. 38. A compound that has the following structure: or a pharmaceutically acceptable salt thereof. 39. A compound that has the following structure: or a pharmaceutically acceptable salt thereof. 40. A compound that has the following structure: or a pharmaceutically acceptable salt thereof. 41. A pharmaceutical composition comprising a therapeutically effective amount of an agent selected from the group consisting of the compounds and salts as defined in claim 1, and a pharmaceutically acceptable carrier. 42. A pharmaceutical composition comprising a therapeutically effective amount of an agent selected from the group consisting of the compounds and salts as described in claim 36, and a pharmaceutically acceptable carrier. 43. A method for treating a neoplasm comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound according to claim 1. 44. A method as described in claim 43, in where the neoplasm is a hematologic cancer. 45. A method as described in claim 44, wherein the neoplasm is selected from leukemias, myelomas and lymphomas. 46. A method as described in claim 43, wherein the neoplasm is selected from cancer in the brain, bone cancer, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, cancer of the mouth, cancer in the esophagus, cancer in the small intestine, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, cancer skin, prostate cancer and renal cell carcinoma. 47. A method as described in claim 40, wherein the compound is administered in combination with another antineoplastic agent. 48. A method as described in claim 47, wherein the antineoplastic agent is an alkylating agent. 49. A method as described in claim 48, wherein the alkylating agent is selected from the group consisting of bendamustine, chlorambucil, cyclophosphamide and melphalan. 50. A method as described in claim 48, wherein the alkylating agent is bendamistine. 51. A method as described in claim 47, wherein the antineoplastic agent is a glucocorticoid. 52. A method as described in claim 51, wherein the glucocorticoid is predinisone or dexmetasone. 53. A method as described in claim 51, wherein the glucocorticoid is administered in combination with additional antineoplastic agents. 54. A method for reducing or preventing the development of Alzheimer's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound as described in claim 1. 55. A method of treatment for Alzheimer's disease in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of: (a) at least one compound, a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug or pharmaceutically active metabolite as defined in claim 1; and (b) at least one agent selected from the group consisting of estrogen, risperidone, a thiobenzodiazepine, ampakine, [N- (2,6-dimethylphenyl) -2- (2-oxo-1-pyrroidinyl) acetamide, DM9384, a cholinesterase inhibitor, donepezil hydrochloride, rivastigmine tartrate, galantamine, NGF, and metrifonate. 56. A method of treating a disease in a mammal mediated by β-catenin by administering to a mammal in need of such treatment a therapeutically effective amount of at least one compound, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug or pharmaceutically active metabolite as is defined in claim 1. 57. A method of treating a hyperplastic disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as described in claim 1. 58. A method for inhibiting or delaying the appearance of a neoplasm in a mammal in need of such treatment, which comprises administering to the mammal a therapeutically effective amount of a compound as described in claim 1. 59. A method as described in claim 58, wherein said neoplasm is selected from the group consisting of n adenomatous polyps, gastrointestinal cancer, liver cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer and skin cancer. 60. A method for treating, inhibiting or delaying the onset of uncontrolled angiogenesis or abnormal angiogenesis in a subject in need of such treatment, inhibition or delay, wherein uncontrolled or abnormal angiogenesis is selected from the group consisting of metastasis, graft rejection of cornea, ocular neovascularization, retinal neovascularization, diabetic retinopathy, retrolental fibroplasia, neovascular glaucoma, gastric ulcer, infantile hemangiomas, angiofibroma of the nasopharynx, avascular necrosis of the bones and endometriosis, and the method comprises treating a subject with an amount Therapeutically effective of a compound as described in claim 1. 62. A compound of Formula I: Formula I where: (a) X is S or O; (b) R-i is hydrogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substituted groups are substituted with one, two or three suitable substituents each selected independently from the group consisting of : halogens, -CN, -N02, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl, and - (CH2) ZCN where z is an integer from 0 to 6; (c) R2, R3? R4 and R5 are each independently hydrogen; halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl and heteroaryl; (d) R6, R8 and Rg are each independently hydrogen; halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; (e) R7 is hydrogen, halogen, -N, -OH, -SH, N02 or an unsubstituted or substituted portion selected from alkyl, alkenyl and alkynyl; (f) R-io is hydrogen; or an unsubstituted lower alkyl group; (g) Y is an unsubstituted or substituted portion selected from alkyl, alkenyl, and alkynyl; wherein the substituted portion is substituted with one, two or three substituents each independently selected from halogen; -CN; -OH; -SH; -N02; unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, and unsubstituted heteroaryls; and (h) Z is an unsubstituted portion selected from -OH, and -SH, wherein R-i and Y can form one or more rings to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group; and wherein: (i) at least one of R6, R, R8, and Rg is not hydrogen; (ii) wherein R-i is propyl, Y-Z is -CH2CH20H- and Rg is fluoro, R6 is not substituted with a heterocycloalkyl group -C (O) -; (iii) wherein Y-Z is -CH2CH2CH2OH- and R9 is ethyl, R-, is not CN; (iv) wherein Ri is ethyl and R9 is ethyl, YZ is unsubstituted or substituted -CH2OH or -CH2CH20H-; (v) wherein R is methyl and Rg is methyl, Y-Z is -CH2OH- or -CH2CH2OH; and (vi) wherein Y-Z is -CH2CH2OH- and R9 is not -CH2CH2OH; or a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt thereof. 63. A compound as described in claim 62, wherein: (a) X is S or O; (b) R-i is hydrogen or an unsubstituted portion selected from lower alkyl, lower hydroxyalkyl, lower alkenyl, lower hydroxyalkenyl, lower alkynyl, lower hydroxyalkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl; (c) R2, R3, R4 and R5 are each independently hydrogen; or an unsubstituted portion selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl; (d) R6, R8 and Rg are each independently hydrogen; or an unsubstituted or substituted portion selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the substituted portions are each independently selected from the group consisting of halogen, -CN, alkyl, alkoxy, NH 2, -O-haloalkyl, -CH (O), haloalkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, -OH, -C (0) 2 -alkyl, and C (0) 2H; (e) R7 is hydrogen, halogen, -CN, -OH, -SH, N02 or unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, C (0) 2H alkyl, C-alkyl ( 0) 2-alkyl, or hydroxyalkyl; and (f) R10 is hydrogen. 64. A compound as described in claim 62, wherein: (a) X is O; (b) R-i is an unsubstituted alkyl group; (c) R2, R3, R4 and R5 are each hydrogen; (d) R7 is hydrogen, halogen, unsubstituted lower alkyl, -C (0) 2H-alkyl, C (0) -2-alkyl or hydroxyalkyl; and (e) R-io is hydrogen. 65. A compound as described in claim 62, wherein: (a) R9 is hydrogen, halogen or an unsubstituted alkyl group; (b) Y is unsubstituted alkyl group; and (c) Z is hydroxyl. 66. A compound as described in claim 62, wherein: (a) X is O or S; (b) R-i is an unsubstituted lower alkyl group or an unsubstituted aryl group; (c) R2? R3? R4 and R5 are each hydrogen; (d) R6, is hydrogen or halogen; (e) R7 is hydrogen, halogen, unsubstituted lower alkyl, -C (0) 2H-alkyl, C (0) -2-alkyl or hydroxyalkyl; and (f) R8 is hydrogen or halogen; (g) R9 is hydrogen, an unsubstituted or substituted portion selected from alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, and (h) R-io is hydrogen. 67. A compound of Formula I: Formula I where: (a) X is S or O; (b) R-, is halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substituted groups are substituted with one, two or three suitable substituents each selected independently from the group consisting of : halogens, -CN, -N02, -OH, -SH, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl , and - (CH2) ZCN where z is an integer from 0 to 6; (c) R2, R3, R4 and R5 are each independently hydrogen; halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl and heteroaryl; (d) R6, R8 and Rg are each independently hydrogen; halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted portion selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; (e) R7 is hydrogen, halogen, -CN, -OH, -SH, N02 or an unsubstituted or substituted portion selected from alkyl, alkenyl and alkynyl; (f) R10 is hydrogen; (g) Y is an unsubstituted or substituted portion selected from alkyl, alkenyl, and alkynyl; and (h) Z is -OH, and -SH; wherein Ri and Y can form one or more rings to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group; and wherein: (i) at least one of R6, R, R8, and 9 is not hydrogen; (I) wherein R 1 is propyl, Y-Z is -CH 2 CH 2 OH- and R g is fluorine, R 6 is not substituted with a heterocycloalkyl group -C (O) -; (iii) wherein Y-Z is -CH2CH2CH2OH- and R9 is ethyl, R-, is not CN; (iv) wherein R1 is ethyl and Rg is ethyl, YZ is unsubstituted or substituted methoxy or unsubstituted or substituted ethoxy; (v) wherein R 1 is methyl and R 9 is methyl, Y-Z is not -CH 2 OH- or -CH 2 CH 2 OH; and (vi) wherein Y-Z is -CH2CH2OH- and R9 is ethyl, R1 is not -CH2CH2OH-; or a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt thereof. 68. A method to treat a disease mediated by PPAR in a mammal by administering to a mammal in need thereof said treatment a therapeutically effective amount of at least one compound, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug or pharmaceutically active metabolite as defined in claim 1.