INHIBITORS OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN AND METHOD

Abstract: Compounds are provided which inhibit microsomal triglyceride transfer protein and thus are useful for lowering serum lipids and treating atherosclerosis and related diseases. The compounds have the structure (a, b, c or d) wherein R<1> to R<6>, Q, and X are as defined herein.

Description: INHIBITORS OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN AND METHOD This invention relates to novel compounds which inhibit microsomal triglyceride transfer protein, and to methods for decreasing serum lipids and treating atherosclerosis employing such compounds. The microsomal triglyceride transfer protein (MTP) catalyzes the transport of triglyceride (TG) , cholesteryl ester (CE) , and phosphatidylcholine (PC) between small unilamellar vesicles (SUV) . Wetterau & Zilversmit, Chem. Phvs . Lipids 33. 205-22 (1985) . When transfer rates are expressed as the percen of the donor lipid transferred per time, MTP expresses a distinct preference for neutral lipid transport (TG and CE) , relative to phospholipid transport. The protein from bovine liver has been isolated and characterized. Wetterau & Zilversmit, Chem. Phys . Lipids 38. 205-22 (1985) . Polyacrylamide gel electrophoresis (PAGE) analysis of the purified protein suggests that the transfer protein is a complex of two subunits of apparent molecular weights 58,000 and 88,000, since a single band was present when purified MTP was electrop oresed under nondenaturing condition, while two bands of apparent molecular weights 58,000 and 88,000 were identified when electrophoresis was performed in the presence of sodium dodecyl sulfate (SDS) . These two polypeptides are hereinafter referred to as 58 kDa and 88 kDa, respectively, or the 58 kDa and the 88 kDa component of MTP, respectively, or the low molecular weight subunit and the high molecular weight subunit of MTP, respectively. Characterization of the 58,000 molecular weight component of bovine MTP indicates that it is the previously characterized multifunctional protein, protein disulfide isomerase (PDI) . Wetterau et al.. J. Biol. Chem. Z H , 9800-7 (1990). The presence of PDI in the transfer protein is supported by evidence showing that (1) the ammo terminal 25 amino acids of the bovine 58,000 kDa component of MTP is identical to that of bovine PDI, and (2) disulfide isomerase activity was expressed by bovine MTP following the dissociation of the 58 kDa - 88 kDa protein complex. In addition, antibodies raised against bovine PDI, a protein which by itself has no TG transfer activity, were able to immunoprecipitate bovine TG transfer activity from a solution containing purified bovine MTP. PDI normally plays a role in the folding and assembly of newly synthesized disulfide bonded proteins within the lumen of the endoplasmic reticulum. Bulleid & Freedman, Nature 335. 649-51 (1988) . It catalyzes the proper pairing of cysteine residues into disulfide bonds, thus catalyzing the proper folding of disulfide bonded proteins. In addition, PDI has been reported to be identical to the beta subunit of human prolyl 4-hydroxylase. Koivu et al .. J. Biol. Chem. 2^1 , 6447-9 (1987) . The role of PDI in the bovine transfer protein is not clear. It does appear to be an essential component of the transfer protein as dissociation of PDI from the 88 kDa component of bovine MTP by either low concentrations of a denaturant (guanidine HCl), a chaotropic agent (sodium perchlorate) , or a nondenaturing detergent (octyl glucoside) results in a loss of transfer activity. Wetterau et al.. Biochemistry ifi, 9728-35 (1991). Isolated bovine PDI has no apparent lipid transfer activity, suggesting that either the 88 kDa polypeptide is the transfer protein or that it confers transfer activity to the protein complex. The tissue and subcellular distribution of MTP activity in rats has been investigated. Wetterau & Zilversmit, Biochem. Biophvs. Acta 875. 610-7 (1986) . Lipid transfer activity was found in liver and intestine. Little or no transfer activity was found in plasma, brain, heart, or kidney. Within the liver, MTP was a soluble protein located within the lumen of the microsomal fraction. Approximately equal concentrations were found in the smooth and rough microsomes. Abetalipoproteinemia is an autosomal recessive disease characterized by a virtual absence of plasma lipoproteins which contain apolipoprotein B (apoB) . Kane s. Havel in The Metabolic βasis of inherited Disease. Sixth edition, 1139-64 (1989) . Plasma TG levels may be as low as a few mg/dL, and they fail to rise after fat ingestion. Plasma cholesterol levels are often only 20-45 mg/dL. These abnormalities are the result of a genetic defect in the assembly and/or secretion of very low density lipoproteins (VLDL) in the liver and chylo icrons in the intestine. The molecular basis for this defect has not been previously determined. In subjects examined, triglyceride, phospholipid, and cholesterol synthesis appear normal. At autopsy, subjects are free of atherosclerosis. Schaefer et al .. Clin. Chem. 2A , B9-12 (1988) . A link between the apoB gene and abetalipoproteinemia has been excluded in several families. Talmud et al.. J. Clin. Invest. £2, 1803-6 (1988) and Huang et al .. Am. J. Hum. Genet. ££, 1141- 8 (1990) . Subjects with abetalipoproteinemia are afflicted with numerous maladies. Kane & Havel, supra. Subjects have fat malabsorption and TG accumulation in their enterocytes and hepatocytes. Due to the absence of TG-rich plasma lipoproteins, there is a defect in the transport of fat-soluble vitamins such as vitamin E. This results in acanthocytosis of erythrocytes, spinocerebellar ataxia with degeneration of the fasciculus cuneatus and gracilis, peripheral neuropathy, degenerative pigmentary retinopathy, and ceroid myopathy. Treatment of abetalipoproteinemic subjects includes dietary restriction of fat intake and dietary supplementation with vitamins A, E and K. In vitro. MTP catalyzes the transport of lipid molecules between phospholipid membranes. Presumably, it plays a similar role in vivo, and thus plays some role in lipid metabolism. The subcellular (lumen of the microsomal fraction) and tissue distribution (liver and intestine) of MTP have led to speculation that it plays a role in the assembly of plasma lipoproteins, as these are the sites of plasma lipoprotein assembly. Wetterau _ * Zilversmit, Biochem. Bionhvs. Acta 875. 610-7 (1986) . The ability of MTP to catalyze the transport of TG between membranes is consistent with this hypothesis, and suggests that MTP may catalyze the transport of TG from its site of synthesis in the endoplasmic reticulum (ER) membrane to nascent lipoprotein particles within the lumen of the ER. Olofsson and colleagues have studied lipoprotein assembly in HepG2 cells. Bostro et al .. J. Biol. Chem. 231, 4434-42 (1988) . Their results suggest small precursor lipoproteins become larger with time. This would be consistent with the addition or transfer of lipid molecules to nascent lipoproteins as they are assembled. MTP may play a role in this process. In support of this hypothesis, Howell and Palade, J. Cell Biol . 22 , 833-45 (1982), isolated nascent lipoproteins from the hepatic Golgi fraction of rat liver. There was a spectrum of sizes of particles present with varying lipid and protein compositions. Particles of high density lipoprotein (HDL) density, yet containing apoB, were found. Higgins and Hutson, J. Lipid Res. 23 , 1295-1305 (1984) , reported lipoproteins isolated from Golgi were consistently larger than those from the endoplasmic reticulum, again suggesting the assembly of lipoproteins is a progressive event. Recent reports (Science, Vol. 258, page 999, 1992; D. Sharp et . al . , Nature, Vol. 365, page 65, 1993) demonstrate that the defect causing abetalipoproteinemia is in the MTP gene, and as " a result, the MTP protein. Individuals with abetalipoproteinemia have no MTP activity, as a result of mutations in the MTP gene, some of which have been characterized. These results indicate that MTP is required for the synthesis of apoB containing lipoproteins, such as VLDL, the precursor to LDL. It therefore follows that inhibitors of MTP would inhibit the synthesis of VLDL and LDL, thereby lowering VLDL levels, LDL levels, cholesterol levels, and triglyceride levels in animals and man. Canadian Patent Application No. 2,091,102 published March 2, 1994 (corresponding to U.S. application Serial No. 117,362, filed September 3, 1993 (file DC21b) ) reports MTP inhibitors which also block the production of apoB containing lipoproteins in a human hepatic cell line (HepG2 cells) . This provides further support for the proposal that an MTP inhibitor would lower apoB containing lipoprotein and lipid levels in vivo. This Canadian patent application discloses a method for identifying the MTP inhibitors which has the name 2-[l-(3, 3-diphenylpropyl) -4* piperidinyl] -2, 3-dihydro-3-oxo-lH-isoindole hydrochloride and which has the name 1 - [ 3 - ( 6- f luoro-1 - tetralanyl ) methyl ] -4 -O-methoxyphenyl piperazine In accordance with the present invention, novel compounds are provided which are inhibitors of MTP and have the structure I or Ii or II or Hi R 8 , R 9 and R 10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl; R 1 is a fluorenyl-type group of the structure 1 R 1 is an indenyl-type group of the structure Z 1 and Z 2 are the same or different and are independently a bond, O, S, , with the proviso that with respect to £, at least one of Z 1 and Z 2 will be other than a bond; R 11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms, arylene (for example AA > or mixed arylene-alkylene (for example where n is 1 to 6; R 12 is hydrogen, alkyl, alkenyl, aryl, halo- alkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl; with the provisos that (1) when R 12 is H, aryloxy, alkoxy —NH-C— . or arylalkoxy, then Z 2 is ° or a bond; and (2) when Z 2 is a bond, R 12 cannot be heteroaryl or heteroarylalkyl; Z is a bond, 0, S, N-alkyl, N-aryl, or alkylene or alkenylene of from 1 to 5 carbon atoms; R 13 , R 14 , R 15 , and R 16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy; R 15a and R 16a are independently any of the R 15 or R 16 groups except hydroxy, nitro, amino or thio; R 2 , R 3 , R 4 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; R 5 is alkyl , alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryloxy, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkenyl- alkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all of the R 5 substituents and R 6 substituents (set out hereinafter) being optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroaryl-alkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino (wherein the amino includes 1 or 2 substituents which are alkyl, aryl or heteroaryl, or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylamino-carbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylamino-carbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkyl¬ carbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroaryl- sulfonyl, or alkylsulfinyl. Where R 5 is phenyl, aryl, heteroaryl or cycloalkyl; this group preferably includes an ortho hydrophobic substituent such as alkyl, haloalkyl (with up to 5 halo groups), alkoxy, haloalkoxy (with up to 5 halo groups), aryl, aryloxy or arylalkyl; R 6 is hydrogen or C 1 -C alkyl or C 1 -C 4 alkenyl; are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members; and including N-oxides of the formulae I, Ii, II and Hi compounds, that is including pharmaceutically acceptable salts thereof such as alkali metal salts such as lithium sodium or potassium, alkaline earth metal salts ' such as calcium or magnesium, as well as zinc or aluminum and other cations such as ammonium, choline, diethanolamine, ethylenedia ine, -butyl-amine, t- octylamine, dehydroabietylamine, as well as pharmaceutically acceptable anions such as chloride, bromide, iodide, tartrate, acetate, methanesulfonate, maleate, succinate, glutarate, and salts of naturally occurring amino acids such as arginine, lysine, alanine and the like, and prodrug esters thereof. Thus, the compounds of formulae I and II of the invention encompass compounds of the structure 10 In addition, in accordance with the present invention, a method for preventing, inhibiting or treating atherosclerosis, pancreatitis or obesity is provided, wherein a compound of formula I, Ii, II, or Hi as defined hereinbefore, is administered in an amount which decreases the activity of microsomal triglyceride transfer protein. Furthermore, in accordance with the present invention, a method is provided for lowering serum lipid levels, cholesterol and/or triglycerides, or inhibiting and/or treating hyperlipemia, hyper- lipidemia, hyperlipoproteinemia, hypercholes- terolemia and/or hypertriglyceridemia, wherein a compound of formula I, Ii, II, or Hi as defined hereinbefore, is administered in an amount which decreases the activity of microsomal triglyceride transfer protein. The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances. The term "MTP" refers to a polypeptide or protein complex that (1) if obtained from an organism (e. g., cows, humans, etc. ) . can be isolated from the microsomal fraction of homogenized tissue; and (2) stimulates the transport of triglycerides, cholesterol esters, or phospholipids from synthetic phospholipid vesicles, membranes or lipoproteins to synthetic vesicles, membranes, or lipoproteins and which is distinct from the cholesterol ester transfer protein [Drayna £l_a_ , Nature 327. 632-634 (1987)] which may have similar catalytic properties. However, the MTP molecules of the present invention do not necessarily need to be catalytically active. For example, catalytically inactive MTP or fragments thereof may be useful in raising antibodies to the protein. The phrase "stabilizing" atherosclerosis as used in the present application refers to slowing down the development of and/or inhibiting the formation of new atherosclerotic lesions. The phrase "causing the regression of" atherosclerosis as used in the present application refers to reducing and/or eliminating atherosclerotic lesions. Unless otherwise indicated, the term "lower alkyl", "alkyl" or "alk" as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons, more preferably 1 to 12 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, -butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4, 4-dimethylpentyl, octyl, 2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1 to 4 substituents such as halo, for example F, Br, Cl ' or I or CF 3 , alkoxy, aryl, aryloxy, aryl (aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, acyl, heteroaryl, heteroaryloxy, hetero-arylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/or alkylthio, as well as any of the other substituents as defined for R 5 and R 6 . Unless otherwise indicated, the term "cycloalkyl" as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 4 to 12 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, any of which groups may be optionally substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio, as well as any of the other substituents as defined for R 5 or R 6 . The term "cycloalkenyl" as employed herein alone or as part of another group refers to cyclic hydrocarbons containing 5 to 20 carbons, preferably 6 to 12 carbons and 1 or 2 double bonds. Exemplary cycloalkenyl groups include cyclopentenyl, cyclo¬ hexenyl, cycloheptenyl, cyclooctenyl, cyclohexa- dienyl, and cycloheptadienyl, which may be optionally substituted as defined for cycloalkyl. The term "polycycloalkyl" as employed herein alone or as part of another group refers to a bridged multicyclic group containing 5 to 20 carbons and containing 0 to 3 bridges, preferably 6 to 12 carbons and 1 or 2 bridges. Exemplary polycycloalkyl groups include [3.3.0] -bicyclooctanyl, adamantanyl, [2.2.1]- bicycloheptanyl, [2.2.2] -bicyclooctanyl and the like and may be optionally substituted as defined for cycloalkyl. The term "polycycloalkenyl" as employed herein alone or as part of another group refers to a bridged multicyclic group containing 5 to 20 carbons and containing 0 to 3 bridges and containing 1 or 2 double bonds, preferably 6 to 12 carbons and 1 or 2 bridges. Exemplary polycycloalkyl groups include [3.3.0] -bicyclooctenyl, [2.2.1] -bicycloheptenyl, [2.2.2]-bicyclooctenyl and the like and may be optionally substituted as defined for cycloalkyl. The term "aryl" or "Ar" as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl) and may optionally include one to three additional rings fused to Ar (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings) and may be optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, cyclo¬ heteroalkyl, cycloheteroalkylalkyl, aryl, hetero¬ aryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroaryl- alkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio. arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, aryla inocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonyl- a ino, arylsulfinyl, arylsulfinylalkyl, arylsul- fonylamino or arylsulfonaminocarbonyl, or any of the substituents as defined for the R 5 or R 6 groups set out above. The term "aralkyl", "aryl-alkyl" or "aryllower alkyl" as used herein alone or as part of another group refers to alkyl groups as discussed above having an aryl substituent, such as benzyl or phenethyl, or naphthylpropyl, or an aryl as defined above. The term "lower alkoxy", "alkoxy", "aryloxy" or "aral oxy" as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom. The term "amino" as employed herein alone or as part of another group may optionally be substituted with one or two substituents such as alkyl and/or aryl. The term "lower alkylthio", alkylthio", "arylthio" or "aralkylthio" as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom. The term "lower alkylamino", "alkylamino", "arylamino", or "arylalkylamino" as employed herein alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom. The term "acyl" as employed herein by itself or part of another group as defined herein, refers to an organic radical linked to a carbonyl c ' group, examples of acyl groups include alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl and the like. The term "alkanoyl" as used herein alone or as part of another group refers to alkyl linked to a carbonyl group. Unless otherwise indicated, the term "lower alkenyl" or "alkenyl" as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 3 to 12 carbons, and more preferably 1 to 8 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3- butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2- hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4- heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3- undecenyl, 4-dodecenyl, 4, 8, 12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cyclo-alkyl, amino, hydroxy, heteroaryl, cyclohetero- alkyl, alkanoylaminc, alkylamido, arylcarbonylamino, nitro, cyano, thiol and/or alkylthio, as well as any of the other substituents as defined for R 5 or R 6 . Unless otherwise indicated, the term "lower alkynyl" or "alkynyl" as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2- butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3- hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3- octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4- dodecynyl and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonyl-amino, nitro, cyano, thiol, and/or alkylthio, as well as any of the other substituents as defined for R 5 or R 6 . The term "alkylene" as employed herein alone or as part of another group (which also encompasses "alkyl" as part of another group such as arylalkyl or heteroarylalkyl) refers to alkyl groups as defined above having single bonds for attachment to other groups at two different carbon atoms and may optionally be substituted as defined above for "alkyl". The definition of alkylene applies to an alkyl group which links one function to another, such as an arylalkyl substituent. Ther terms "alkenylene" and "alkynylene" as employed herein alone or as part of another group (which also encompass "alkenyl" or "alkynyl" as part of another group such as arylalkenyl or arylalkynyl), refer to alkenyl groups as defined above and alkynyl groups as defined above, respectively, having single bonds for attachment at two different carbon atoms. Suitable alkylene, alkenylene or alkynylene groups or (CH 2 ) n or (CH2) (which may include alkylene, alkenylene or alkynylene groups) as defined herein, may optionally include 1,2, or 3 alkyl, alkoxy, aryl, heteroaryl, cycloheteroalkyl, alkenyl, alkynyl, oxo, aryloxy, hydroxy, halogen substituents as well as any of the substituents defined for R 5 or R 6 , and in addition, may have one of the carbon atoms in the chain replaced with an oxygen atom, N-H, N- alkyl or N-aryl. Examples of alkylene, alkenylene, alkynylene, (CH2)n and (CH2)ρ groups include — CH =CH — CH 2 1 — CH 2 CH =CH — , — C ≡C — CH 2 — , - CH 2 — C- CH CH? CH? C— ~ II O O CH, — CH 2 C SCCH 2 - — C =CH — CH, — (CH2) 2 . (CH 2 ) 3 , — (CH 2 ) 4 — , CH 3 — (CH 2 ) 2 — C — CH 2 CH 2 . — CH 2 CH — , — CH 2 CHCH 2 — CH 3 CH ' C 2 H 5 — CHCH 2 » — CHCH 2 CH 2 . — CHCHCH 2 — , I I I I CH 3 C H 5 I CH 3 CH 3 O O O II II II - CH 2 CH 2 0- C— , — CH 2 CH 2 - C— . - CH 2 CH 2 - N- C— , H CH 3 CH 3 — CH 2 — C — CH 2 — , — (CH 2 ) 5 — , — (CH 2 ) 2 — C — CH 2 - , CH 3 F Cl CH 3 CH 3 I ' ' - CH 2 - CH - CH 2 . — (CH 2 ) 2 - CH— , - CH 2 - CH- C— CH 3 CH 3 ~CH 2 - — , OH OCH 3 I I ■ CH ■ CH 2 CH 2 t -CH-CH 2 CH 2 — CH 2 OCH j — OCH 2 CH 2 ♦ CH 2 NHCH 2 — — NHCH 2 CH 2 — CH 3 — N-CH_,CH 2 - I -(CH a ) 3 — CF a - , — CH 2 -N— CH 2 - CH 3 CH 3 I (CH 2 ) 2 C— CH 2 - (CH 2 ) 2 c— CH 2 - H CH 3 CH, CH 3 CH 3 (CH 2 ) 2 C— CH 3 - (CH 2 ) 3 — C -(CH 2 ) 3 C I I H CH, H The term "halogen" or "halo" as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF 3 , with chlorine or fluorine being preferred. The term "metal ion" refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum. The term "cycloheteroalkyl" as used herein alone or as part of another group refers to a 5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH 2 ) p (which is defined above), such as and the like. The above groups may include 1 to 3 substituents such as any of the R 1 , R 5 or R 6 groups as defined above. In addition, any of the above rings can be fused to 1 or 2 cycloalkyl, aryl, heteroaryl or cycloheteroalkyl rings. The term "heteroaryl" or (also referred to as heteroaryl) as used herein alone or as part of another group refers to a 5- or 6- me bered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH 2 ) p (which is defined above), such as and the like, and includes all possible N-oxide derivatives. are the same or different as defined hereinbefore and are attached to the central ring of the indenyl or fluorenyl type group at adjacent positions (that is ortho or 1,2-positions) . Examples of such groups include wherein u is selected from 0, S, and NR 7a ; R 7a is H, lower alkyl, aryl, -C(0)R 7 , -C(0)OR 7b *' R7b is alkyl or aryl, and includes all possible N- oxide derivatives. The heteroaryl groups including the above groups may optionally include 1 to 4 substituents such as any of the substituents listed for aryl, or those substituents indicated for R 5 or R 6 groups as defined above. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring. The term cycloheteroalkylalkyl" as used herein alone or as part of another group refers to cycloheteroalkyl groups as defined above linked through a C atom or heteroatom to a (CH 2 ) P chain. The term "heteroarylalkyl" or "heteroarylalkenyl" as used herein alone or as part of another group refers to a heteroaryl group as defined above linked through a C atom or heteroatom to a -(CH 2 )p- chain, alkylene or alkenylene as defined above. The term "fluorenyl" or "fluorenyl analog" or "fluorenyl-type group" as employed herein refers to a group of the structure: £ The term " indenyl -type group " as emplyed herein refers to a group of the structure Z, Z 1 , Z 2 , R 11 , R 12 , R 13 , Rl , R 15 , Rl6, Rl5a and R 16a as used in the above groups _ m through ϋ are as defined hereinbefore. Preferred are compounds of formulae I and II wherein R 1 is £1 (including where Z 1 is a bond and R 11 is alkylene or s s c — NH — c- " /ιi\ or " ' O ' (θ) 2 O . alkenylene and Z Δ is ° , ' and R 12 is Cι-C 3 alkyl or 1 , 1 , 1-trif luoroethyl, R 13 is H or F and R 15 is H or F, and Z is a bond or 0; and where R 11 is alkylene or alkenylene or alkylene substituted with oxo, R 12 is alkyl, alkenyl, aralkyl, aralkenyl, Z is 0, S or a bond) . In structure I, it is preferred that R 2 , R 3 and R 4 are each H and X is CH 2 , CH 2 CH 2 , or CH=CH. In structure II, it is preferred that R 6 is H or CH 3 and R 5 is cycloalkyl, phenyl, aryl or heteroaryl, or cycloalkyl, phenyl, aryl heteroaryl having an ortho hydrophobic substituent which is alkyl, alkoxy, haloalkyl (containing up to five halo groups), trifluoromethyl, aryl, aryloxy, arylalkyl, arylalkoxy, haloalkoxy (containing up to five halo groups) . It is to be understood that combinations of substituents which lead to chemically unstable molecules are not included within the scope of the present invention; for example, compounds of the invention will not include -0-0-, -0-C-OH, N-C-OH and -S-C-OH linkages. The compounds of formulae I, Ii, II, and Hi may be prepared by the exemplary processes described in the following reaction schemes. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples. Scheme I. Routes to Isoindolinone Piperidines 1 R ιa Scheme II. Additional Routes to Isoindolinone Piperidines 1 R ιa n Scheme III. Introduction of R 1 by Alkylation or Arylation Dβprotection Hydrogenolysis Amine Alkylation or Arylation Scheme IV. Routes to Starting Materials Mi an ~ lYc is Hydrazinolysis -^o^o-^o^ "BOC ANHYDRIDE" Scheme V. General Routes to Starting Materials IVb Protecting Group Formation H 2 N— N I -CH j Ph PG-N - — ( N-CH j Ph Hydrogenolysis Amine Dβprotection H 2 N— N-R 1 Schemes VI and VII. General Routes to U XXII XXI Ia Scheme VIII Preparation of Compounds IA 1 1 , I IAA : 2 base R 10 CON(OMe)Me acylation or DMF (R 10 is H) dehydration IA 1 XIB hydrogenation Scheme IX Preparation of Compounds IA 3 -IA 6 XXIV base IA 6 R 31 and R 32 are independently selected from any of the R 2 , R 3 , or R 4 radicals; R 33 and R 34 are independently selected from any of the R 1 radicals as well as aryloxy, alkoxy, arylalkoxy, heteroarylalkoxy and heteroaryloxy, at least one of R 33 and R 34 being an R 1 radical; R 35 can be any of the R 1 radicals. Schemes X and XI Preparation of Compound IA 7 XXV Scheme XII Preparation of Compound II (Robotic Amide Coupling) XXVI XXVII In the following Schemes XII et al, in the fluorenyl rings or fluorenyl analogs, the fused aryl groups: may each optionally be replaced by a 5- or 6-membered heteroaryl ring as defined herein. Scheme XIII - Preparation of Intermediates where Z z is S, SO or S0 2 acid treatment R 12 SH Sulfur oxidation Alkylation 1) strong base 1 ) strong base Alkylation 2) X 1 -R"-Y 1 2)X 1 -R 11 -Y 1 Sulfur oxidation XXXVIIIB X 1 , Y 1 are same or different halo or Osulfonate n = 1 or 2 Scheme XIV - Preparation of A (Intermediates where Z 2 is NHCO) amide formation XXXIX 1 ) ≥ 2 equiv. base 1 ) ≥ 2 equiv. base Alkylation Alkylation 2)≥.1 equiv. X^R^-Y 1 2)2.1 equiv. X 1 - R^-Y 1 amide formation XLI XXXIIIC X 1 , Y 1 are same or different halo or Osulfonate S heme XJYA Alternative Procedure for Preparing Intermediate XL (Shown in Scheme XIV) XXXIXA In carrying out the above reaction, bases such as n-butyllithiun, lithium bis(trimethylsilyl) amide and sodium bis(trimethylsilyl) amide may be employed in an aprotic solvent such as THF, at between -78°C and 35°C. It is preferable to have the starting material and isocyanate (R 12 N=C-0) together in solvent, and then add the base, and optionally add further excess isocyanate subsequently. H Scheme XV - Preparation of Intermediate where Z 1 is — N- C- o XLII XLIII halogenation or XLIII sutfonation XXXIIID X 1 is halo or Osulfonate Scheme XVI XLV XLIV XLVII OPG is a protecting group XXXV (e.g. benzoate) XLVII X 1 = halo or Osulfonate XLVI XLVIII halogenation XLVII I or sulfonation X 1 is halo or Osulfonate XXXIIIE Sulfur Oxidation XXXIIIE XXXIIIF (n=1) XXXIIIG (n=2) Scheme XVIA Preparation of Ketones XXXIIIH X 1 _= halo or Osulfonate Scheme XVIB. Preparation of Ketones (Preferred Route) XXXIX XLIIC Ketone Formation 1)Deprotectlon 2) Hallde Formation XLIID XLIIE p: XXXIIII Scheme XVIIA - Preparation of Amide Linked Compounds XLVII Scheme XVIIB - Preparation of Carbamate and Urea Linked Scheme XVTIIA - Formation of Sulfonamides N- R 1 (Reaction in a variety of solvents (CH2CI2, THF, pyridine) optionally in the presence of a tertiary amine base, such as pyridine ortriethyl amine). Scheme XVTIIB - Formation of Ureas (R- is Amino) (1 to 10 equiv of R-C=N=0, in aprotic solvent such as toluene, from 0°C to 150°C). (R 5 ' is alkyl , aryl , heteroaryl or arylalkyl ) . Scheme XIXA - General Route to Final Product R'- X 1 or (where R 1 is as in Amine Alkylation II XXXIII A-K or any other R 1 as defined herein) l (Example of a protected nitrogen (PG-N) Is the t-BuOC=ONH (BOC amino) group, which can be deprotected under mild conditions, such as anhydrous HCl in dioxane or neat trlfluoroacetic acid). Scheme XX - Oxidation of sulfur at the end of the reaction sequence 'Acid pretreatment protects basic piperidine from oxidation ,10 n = 1 or 2 (R a is defined as in Scheme XVIIA) Sche e XXI - Preparat ion of Hal ide Intermediates For example: Palladium catalyst can be Pd(Ph 3 P) 4p base can be NaH or bis(trimethylsilyl)acetamlde, Deprotection aprotic solvent can be THF or DMF or mixtures. PG- can be organosiM, such as t-Bu(Ph) 2 SI-, and deprotection conmtions can be n-Bu 4 NF, THF. LXVII XXXIIIJ XXXIIIK Scheme XXII - Preparation of 3-Substituted Piperidine Starting Materials R 1 is as in or is any o herein X 1 = halo or Osulfonate Saponfication KOH, then HCl HCl deprotection H 2 , Pd(OH) 2 / C Intermediate Ω can be utilized as a starting material to prepare 3-substituted isomers Ii and.Hi via the same methodology as outlined in the Schemes herein, specifically Schemes I, II, IV, V, VI, VII, VIII, X, XI, XII, XVIIIA, XVIIIB, XIXB, XX, XXIII. Scheme XXTTT - Preparation of N-Oxides of Formulae I and II compounds Oxidation s-O (for example, peracid such as meta-chloroperbenzoic acid) It is to be understood that in Schemes I to VI, VIII to XII, XVIIA, XVIIB, XVIIIA, XVIIIB, XIXA, XIXB, XX and XXI (which relate to preparation of compounds of the invention of formula I or II), the starting materials which are depicted as the 4- substituted piperidine isomers may be substituted with the corresponding 3-substituted piperidine isomers to afford the corresponding compounds of the invention Ii or Hi which include the 3-substituted piperidine isomer. In the above Reaction Schemes XII through XXI, the starting fluorenyl-type acid XXVIII, alcohol XXXV, acids XXXIX and XLII, ketone XLIV, hydride XXXIXA, and amide XL groups may be substituted with corresponding acid, alcohol, ketone, hydride and amide containing fluorenyl type groups as set out in £, £ and U or indenyl-type groups as set out in £, ∑ , Q and/or U to provide an intermediate compound for use in preparing a compound of formula I, I', II or II' of the invention as per Reaction Schemes I to XXIII. Phthalimide formation (Reaction Schemes I, IV) may be carried out by heating to about 80 to 150°C in an oil bath optionally in an inert solvent or by various other procedures known in the art. Reduction (Reaction Scheme I) may be carried out by treatment with such reducing agents as zinc in the presence of acetic acid or tin in the presence of hydrochloric acid under an inert atmoshphere (e.g., argon) . Isoindolone formation (Reaction Scheme I) may be carried out by heating in the range of about 50 to 150°C in an organic solvent (e.g., toluene, ethanol, dimethylformamide) optionally in the presence of a salt (e.g., potassium carbonate) or a tertiary amine base (e.g., 2, 6-di-JL-butylpyridine or triethylamine) . Amide formation (Reaction Schemes II, VI, VII, VIII, X, XI, XII, XIV, IVA, XV, XVI, XVI, XVIA, XVIIA, XVIIB) , XXI may be carried out by a number of methods known in the art. For example, an amine substrate may be treated with (1) an acid halide R 5 C(0)halo or compound X or XA in an aprotic solvent, optionally in the presence of a tertiary amine base (e.g., triethylamine); (2) the acid halide in the presence of an aqueous base under Schotten-Baumann conditions; (3) a free carboxylic acid (R 5 C0 2 H) in- the presence of a coupling agent such as dicyclohexylcarbodiimide (DCC) , diisopropyl carbodiimide (DIC) or 1- (3-dimethylamino-propyl) -3- ethylcarbodii ide hydrochloride (WSC) , optionally in the presence of 1-hydroxybenzotriazole (HOBT); (4) the free acid in the presence of N, N-carbonyl- diimidazole in an aprotic organic solvent followed by the amine substrate; (5) trialkylaluminum (e.g., Al(CH 3 > 3 ) in an aprotic solvent, followed by an ester (e.g., R 5 Cθ 2 alkyl or compound VIII) or (6) mixed anhydride formation, by reacting the acid with an acid chloride (e.g., isobutyl chlorofor ate or bis- (2-oxo-3-oxazolidinyl) -phosphinic chloride (Bop-CD) in the presence of a tertiary amine base (e.g., triethylamine) followed by treatment with the amine substrate. Mesylate formation (Reaction Scheme II) may be carried out by treatment of the amine-alcohol substrate with methanesulfonyl chloride and triethylamine or pyridine or in an aprotic solvent, such as dichloromethane. Base cyclization (Reaction Schemes II, VIII) may be carried out by treatment with a base (e.g., potassium £.-butoxide or sodium hydride) in an inert solvent (e.g., dimethylformamide, tetrahydrofuran, dimethoxymethane, or toluene) . Mitsunobu cyclization (Reaction Scheme II) may be carried out by procedures generally known in the art. See, e.g., R. K. Olsen, J. Pro. Chem.. 12, 3527 (1984); Genin, M. J., et al.. J. Pro. Chem.. ££, 2334-7 (1993) . Alternatively, a mixture of compounds IV and VIII can be converted to compound la in a single pot by heating the mixture in a protic solvent (e.g., water, methanol, ethenyl or isopropanol or mixtures thereof) at 100 to 200 °C. See, e.g., European patent application 81 / 26,749, FR 2, 548,666 (1983). Protection and deprotection (Reaction Schemes III, IV, V, XVI, XVIB, XIXB, XXI) may be carried out by procedures generally known in the art. See, for example, T. W. Greene, Protecting Groups in Ora.--.n-ir Synthesis. Second edition, 1991. PG in Scheme V denotes a nitrogen-protecting group. One particularly useful group is tert-butoxv-carbonvl (BOC) which can be derived from the associated anhydride as shown in Scheme IV. BOC-protected amines may typically be deprotected by treatment with acid (e.g., trifluoroacetic acid or hydrochloric acid) in procedures well understood by those having ordinary skill in the art. Hydrogenolysis (Reaction Schemes III, IV, V) may be carried out with H 2 using a balloon apparatus or a Parr Shaker in the presence of a catalyst (e.g., pallladium on activated carbon) . Amine alkylation and arylation (Reaction Schemes III, IV, V, IX, XII, XIXA, XIXB) may be carried out by methods known in the art. Suitable procedures are described in Cortizo, L., J. Med. Chem. 2 L A , 2242-2247 (1991) . For example, the alkylation or arylation may be carried out by treating the amine substrate with a halide (e.g., R 1 - halo) or an oxytosylate (e.g., R 1 -0-tosylate) in an aprotic solvent (e.g., dimethylformamide) , optionally in the presence of a tertiary amine (e.g., triethylamine) or an inorganic base (e.g., potassium carbonate) . Reductive amination may be employed as an alternative to the foregoing amine alkylation and arylation procedures when R 1 , R 6 or R 7 is R 9 R 10 CH- and R 9 and R 10 are each independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl, or R 9 and R 10 together are alkylene (i.e., R 9 R 10 CH- forms a cycloalkyl group) . Such reductive amination may be carried out by treating the amine with (a) a ketone or aldehyde (R 9 -C(0) -R 10 ) , (b) NaBH , NaBH 3 CN or NaB(acetoxy) 3 H, (c) a protic solvent (e.g., methanol) or a dipolar aprotic solvent (e.g., acetonitrile) , and, optionally, (d) an acid (e.g., acetic acid, trifluoroacetic acid, hydrochloric acid, or titanium isopropoxide) . When R 1 is aryl or heteroaryl, transition metals (e. g., palladium or copper salts or complexes) may be used to promote the arylation reaction. Alkylation of the isoindolone (Reaction Scheme X) may be carried out by treatment of the isoindolone with a strong base (i.e. sodium bis (trimethylsilyl) amide or lithium diisopropyl- amide) followed by an alkyl halide (e.g. R 8 -halo) or alkyl sulfonate (e.g. R 8 -tosylate) in an inert solvent (e.g. tetrahydrofuran or dimethoxy-ethane) . Alternatively, as seen in Schemes X and XI, amine IVb can be treated under amide formation conditions with a ketone with the structure XB to provide a hydroxylactam XXV, which could be subjected to reduction conditions with such reducing agents as zinc in acetic acid or triethylsilane in trifluoroacetic acid to give IA 7 . Hydrazinolysis of phthalimides may be carried out by standard means known in the art. See, e.g., T. W. Greene, Protecting Groups in Organic Synthesis. Second edition, 1991. Amide N-alkylation (Reaction Scheme VI) may be carried out by base treatment (e.g., NaH, KH, KN[Si (CH ) 3 . 2 , K2C0 3 , P4-phosphazene base, or butyl lithium) in an aprotic organic solvent, followed -by treatment with R 6 -halo or R 6 -0-tosylate. Use of P- phosphazene base is described in T. Pietzonka, D. Seebach, Anαew. Chem. Int. Ed. Enαl . 2_ . 1481, 1992. Dehydration (Scheme VIII) may be carried out employing a strong acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid. Hydrogenation (Scheme VIII) may be carried out in the presence of a conventional catalyst such as Pd/C or Pt or Rh under a H 2 atmosphere. The addition reaction shown in Scheme IX may be carried out by treating IA 3 with an organometallic reagent XXIV, such as an organolithium or organic magnesium compound where organo is alkyl or aryl. The deoxygenation or hydrogenation reaction (Scheme IX) is carried out in the presence of a strong acid such as trifluoroacetic acid or boron trifluoride etherate, in the presence of a hydride source such as triethyl silane or tris (trimethylsilyl)silane. The alkylation in Schemes XIII, XIV, XVI, XVIA, XVIB is carried out in the presence of base such as butyllithium or sodium bis (trimethyl¬ silyl)amide. It will be appreciated that R 12 in R 12 Q may be any of the R 12 groups as defined hereinbefore. Alternatively, the alkylation in the above Schemes can be performed where either or both Z 1 or Z 2 is a bond, using a palladium catalyzed allylic alkylation procedure. In this reaction, the fluorenyl-type or indenyl-type precursors (compounds XXVIII, XXXVI, XXXVII, XXXIX, XL, XLVII) are reacted with a base (sodium hydride, sodium bis (trimethylsilyl)amide or bis (trimethylsilyl) - acetamide) , a palladium catalyst (for example Pd(Ph 3 ) ) and an allylic acetate (CH3C ° 2CH2 ' CH = CH ^ or T CH 3 C0 2 CH-CH=CH ) -j_ n an i ner t solvent (for example THF) . This reaction is to introduce either -R 12 (Scheme XII) or -R-^-X 1 (Schemes XIII, XIV, XVI, XVIA) or -R H -OPG (Scheme XVIB, Scheme XXI) . The product of this reaction contains either an -R 12 group or an -R 11 -X 1 group (or an -R l l -OPG group) which begins with -CH 2 - C H__CH- . _ Saturation of the alkene in R 11 or R 12 can be accomplished by standard catalytic hydrogenation conditions. The sulfur oxidation in Schemes XIII, XVI and XVIII is carried out as follows. Sulfides of structures XXXVI, XXXVIII, XXXIIIE and I 9 can be selectively oxidized to sulfoxides by 1 molar equivalent of reagents known in the art, such as 30% H 2 O 2 , NaI0 4 , and peracids (e.g., meta- chloroperbenzoic acid) . The resulting sulfoxides can be further transformed to corresponding sulfones by another molar equivalent or excess of 30% H 2 O 2 , KMnθ , KHSO5, or peracids (e.g., meta- chloroperbenzoic acid) . Alternatively, the sulfones can be directly prepared from sulfides with 2 molar equivalents or more of oxidizing agents, such as 30% H 2 O 2 and peracids (e.g., meta-chloroperbenzoic acid). In cases where an amine (such as a piperidine in I 9 ) is present during the oxidation, the basic nitrogen may be protected by pretreatment with an acid such as HCl or CF 3 CO 2 H (see Scheme XIX) . To prepare examples where Z 1 or Z 2 is -CHOH, the compounds I, Ii, II and Hi where Z 1 or Z 2 is C=0 can be reduced with a hydride reagent, for example NaBH 4 . The compounds of the invention may be employed in preventing, stabilizing or causing regression of atherosclerosis in a mammalian species by administering a therapeutically effective amount of a compound to decrease the activity of MTP. The compounds of the invention can be tested for MTP inhibitory activity employing the procedures set out in U.S. application Serial No. 117,362 filed September 3, 1993, employing MTP isolated from one of the following sources: (1) bovine liver microsomes, (2) HepG 2 cells (human hepatoma cells) or (3) recombinant human MTP expressed in baculovirus . The compounds of the invention may also be employed in lowering serum lipid levels, such as cholesterol or triglyceride (TG) levels, in a mammalian species, by administering a therapeutically effective amount of a compound to decrease the activity of MTP. The compounds of the invention may be employed in the treatment of various other conditions or diseases using agents which decrease activity of MTP. For example, compounds of the invention decrease the amount or activity of MTP and therefore decrease serum cholesterol and TG levels, and TG, fatty acid and cholesterol absorption and thus are useful in treating hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, pancreatitis, hyperglycemia and obesity. The compounds of the present invention are agents that decrease the activity of MTP and can be administered to various mammalian species, such as monkeys, dogs, cats, rats, humans, etc.. in need of such treatment. These agents can be administered systemically, such as orally or parenterally. The agents that decrease the activity or amount of MTP can be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable formulation. The above dosage forms will also include the necessary physiologically acceptable carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol) , anti-oxidants (ascorbic acid or sodium bisulfite) or the like. Oral dosage forms are preferred, although parenteral forms are quite satisfactory as well. The dose administered must be carefully adjusted according to the age, weight, and condition of the patient, as well as the route of administration, dosage form and regimen, and the desired result. In general, the dosage forms described above may be administered in amounts of from about 5 to about 500 mg per day in single or divided doses of one to four times daily. The following Examples represent preferred embodiments of the invention. All temperatures are in °C unless indicated otherwise. Example 1 9- [3- [4- (2, 3-Dihydro-l-oxo-lH-isoindol-2-yl) -1* piperidinyl.propyl] -N-propyl-9H-fluorene-9- carboxa ide A. To a suspension of 10 g (47.57 mmol) of 9- fluorenecarboxylic acid (Aldrich) in 80 mL of CH 2 CI 2 , under argon at 0°C, was added a catalytic amount of DMF (0.5 mL) followed by the dropwise addition of 36 L (71.35 mmol) of oxalyl chloride {2M in CH Cl 2 ) . i The reaction was warmed to RT and was stirred for 45 min (the reaction becomes a clear yellow solution) at which time it was evaporated to dryness and pumped on under high vacuum for 0.5 h. The yellow residue was dissolved in 50 mL of CH 2 CI , cooled to 0°C, and treated dropwise with 7.8 mL (95.14 mmol) of propylamine(very exothermic) followed by 7 mL of pyridine to sponge up excess HCl. The reaction solidified and was treated with 1:1 CH 2 Cl 2 /water (200 mL) and allowed to stir until everything was in solution. The organics were washed with water (2x) , dried (NaS0 ) and evaporated to provide a yellow solid. Purification by crystallization from hot methanol resulted in 4.0 g (33%) of title compound as a pale yellow solid. mp 198-200°C. B. B(l) . OTBS To a solution of 49 mL (0.55 mol) of 1,4- butanediol in 25 mL of DMF, under argon at 0°C, was added 10.5 g (0.15 mol) of imidazole followed by 20.7 g (0.14 mol) of t-butyldimethylsilyl chloride. The reaction was slowly warmed to RT and stirred fcr 18 h at which time the reaction was diluted with ether and washed with NH 4 CI, water, Na 2 C0 3 , brine and dried (MgS0 4 ) . The resulting colorless title compound in the form of a liquid, 50 g, contained approximately 15% of the disilylated compound. B(2) . OTBS To a solution of 8.5 g (42 mmol) of Part 3(1] compound in 50 mL of THF, under argon at 0°C, was added 7.3 g (108 mmol) of imidazole and 16.7 g (64 mmol) of triphenylphosphine. This mixture was stirred for 45 min (solution became homogeneous, at which time 16.2 g (64 mmol) of iodine in 50 mL of THF was added dropwise over 20 min. The reaction was stirred for 1 h, diluted with hexanes and washed with 1M sodium bisulfite, Na 2 C0 3 , brine and dried (Na 2 S0 4 ) . The resulting residue was triturated with ether (3x) , filtered (to remove triphenylphosphine oxide) and evaporated to provided 10 g (61%) of title compound as a pale yellow oil. B(3) . To a mixture of 300 mg (1.20 mmol) of Part A compound in 10 mL of THF, under argon at 0°C, was added dropwise 960 mL (2.40 mmol) of n-BuLi (2.5 M in hexanes) . The resulting orange dianion was stirred at 0°C for 0.5 h at which time 452 mg (1.44 mmol) of Part B(2) compound was added dropwise. The reaction was warmed to RT and was stirred for 18 h at which time it was treated with a 1:1 mixture of ethyl acetate/water. The organics were dried (Na 2 S0 4 ), evaporated and flash chromatographed on 50 g of silica gel eluting with 4:1 hexanes/ ethyl acetate to provide 460 mg (87%) of title compound as a pale yellow solid. To 5.6 g (12.80 mmol) of Part B compound was added 14.1 mL (14.10 mmol) of 1M tetrabutylammonium fluoride in THF. The reaction was stirred, under argon at RT, for 18 h at which time it was diluted with ether and quenched with NH 4 C1. The organics were washed with water, brine, dried ( a 2 S0 4 ) and evaporated. Flash chromatography was performed on 250 g of silica gel eluting with 95:5 dichloro- methane/isopropanol to provide 4.09 g (99%) of title compound as a white solid. mp 73-75°C. To a solution of 1 g (3.10 mmol) Part C compound in 20 mL of THF, under argon at 0°C, was added 463 mg (6.81 mmol) of imidazole followed by 1.0 g (4.03 mmol) of triphenylphosphine. The mixture became homogeneous after 15 min at which time 1.0 g ( 4.03 mmol) of iodine in 20 mL of THF was added dropwise over 20 min. The reaction was warmed to RT and was stirred for 1 h at which time it was diluted with hexanes and the organics were washed with sodium bisulfite, NaHC0 3 , brine and dried ( a 2 S0 4 ) . Flash chromatography was performed on 100 g of silica gel eluting with 1:1 hexanes/ethyl acetate to provide 1.1 g (85%) of title compound as a colorless oil. E. 2- [1- (Phenylmethyl) -4-piperidinyl] -1H- isoinriol-I . (2H. -dione A mixture of phthalic anhydride (15.0 g, 101 mmol) and 4-amino-l-benzylpiperidine (19.3 g. 101 mmol) was heated with stirring in an oil bath until the mixture melted (about 125°C) . The reaction was kept at this temperature until the mixture solidified again (about 30 minutes) . The reaction was cooled to room temperature. Purification was performed by flash chromatography on 1 kg silica gel, loaded and eluted with 30% ethyl acetate in hexane. Pure fractions were combined and evaporated to give compound A (25 g, 77%) as a white solid, melting point 151-154°C. F. 2, 3-Dihydro-2- [1- (phenylmethyl) -4- jperidinvl . -lH-isoindol-1-one To a solution of compound E (20.0 g, 62.5 mmol) in acetic acid (248 mL) was added zinc dust (28.6 g, 438 mmol) under argon. With mechanical stirring, the reaction was refluxed overnight. The reaction was filtered through Celite®, then evaporated to dryness. Dichloromethane (500 mL) was added, and the organic layer was washed with saturated sodium bicarbonate (2 x 100 mL) , brine (100 mL) and dried ^ over MgS0 4 . Evaporation gave a crude oil. The resulting residue was azeotroped with toluene (2 x 30 mL) to afford a white solid. The product was recrystallized from isopropanol to give compound B (16 g, 80%) as a white solid (melting point 130-133°C) . G. 2- (4-Piperidinyl) -2, 3-dihydro-lH- isoindol-1-one To a solution of Part F compound (8.5 g, 26.4 mmol) in ethanol (65 mL) was added acetic acid (3.5 mL, 52.8 mmol) , followed by 10% palladium on activated carbon (0.7 g) under argon. The slurry was purged with nitrogen and agitated under a pressure of 45 psi of hydrogen gas for 48 hours. The reaction mixture was filtered through Celite® and washed with ethanol. The filtrate was evaporated to dryness. The resulting residue was dissolved in chloroform (100 mL) and washed with 1 E OH saturated with sodium chloride (2 x 30 mL) and dried over MgS0 4 . The resulting clear solution was evaporated to dryness and azeotroped with toluene (2 x 30 mL) to give compound G (5.0 g, 77%) as a white solid, melting point 137-140°C. H. 9- [3- [4- (2, 3-Dihydro-l-oxo-lH-isoindol- 2-yl) -1-piperidinyl . propyl] -N-propyl-9H- fluorene-9-carboxamide To a solution of 330 mg (0.76 mmol) of Part D compound in 5 L of DMF, under argon at RT, was added 210 mg (1.52 mmol) of K 2 C0 3 followed by 198 mg (0.76 mmol) of Part G compound. The mixture was stirred at RT for 72 h, at which time the reaction was diluted with ether and washed with water, brine, dried (Na 2 S0 4 ) and evaporated. Recrystallization was attained from hot hexanes to provide 270 mg (68%) of title compound as a white solid. mp 136-138°C. Anal. Calcd. for C 34 H 3 9N 3 θ 2 : C, 78.28; H, 7.53; N, 8.05 Found: C, 78.11; H, 7.62; N, 8.09. Example 1A Alternate synthesis of Example 310 hydrochloride salt To a solution of Example 5 free amine (12 g, 23.1 mmol) in absolute EtOH (400 mL) was added 10% palladium on activated carbon (1.2 g) . The mixture was hydrogenated on a Parr apparatus at 40 psi for 2 h, then filtered through Celite. The filtrate was concentrated in vacuo to provide a colorless oil. The product was dissolved in MeOH (100 mL) and 1.0M HCl in Et 2 θ (20 mL, 20 mmol) was added dropwise. The reaction was stirred for 10 min then concentrated in vacuo. The residue was taken up in CH 3 CN (2 mL and water (25 mL) was added. The slightly cloudy solution was lyophilized overnight to give title compound (11.1 g, 86%) as a white lyophilate. Analysis Calcd. for C34H39N3O2 • 1.3HC1 • 1.6H 2 0: C, 68.24; H, 7.33; N, 7.02; Cl, 7.76 Found: C, 68.27; H, 7.31; N, 6.99; Cl, 7.77. E c--r. le 2 2, 3-Dihydro-2- [1- [4-oxo-4- (9-propyl-9H-fluoren-9* yl)butyl] -4-piper-idinyl] -lH-isoindol-1-one, monohvdrochloride A . CI g' ^-^ ' OMgCI To a stirred solution of 28.55 g (301.9 mmol) of 3-chloro-1-propane (Aldrich) in 300 mL of THF at -20°C under argon was added 101 mL (303 mmol) of 3.0 M methyl magnesium chloride in THF dropwise over 20 min. After 0.5 h at -20°C, the reaction was allowed to warm to room temperature and 11.0 g (452.8 mmol) of magnesium turnings were added and the reaction was heated to reflux. At the start of reflux, 0.60 mL (6.94 mmol) of 1, 2-dibromoethane was added and after 1 h at reflux another 0.60 mL was added. After 2 h at reflux the reaction was allowed to cool to room temperature. B. B ( l ) . 9 - Propyl - 9H- f luorene- 9 -carboxylic acid A solution of 9-fluorenecarboxylic acid (12 g, 57 mmol) in 250 ml of THF was cooled to 0°C under an argon atmosphere and 2 equiv. (71.25 ml) of a 1.6 M n-butyl lithium solution in hexane was added followed by the addition of n-propyl iodide (7.5 ml, 13.1 g, 77 mmol) . The reaction mixture was stirred at 0°C for 6 hrs . An additional 1 ml of n-propyl iodide was added and the reaction stirred for 4 hrs at 0°C . The reaction was quenched by adding 75 ml of water and the pH was adjusted to pH 1 with 3 N HCl. The reaction mixture was extracted with hexane (3x200ml) and the hexane extract washed with water, brine and dried over anhy. sodium sulfate. The solvents were evaporated yielding the crude product as a yellow oil which was dissolved in -250 ml of ethanol and heated at reflux with Darco G-60, filtered through Celite and concentrated to approximately one half of the. original volume. Water was slowly added until the mixture became cloudy. The mixture was reheated and slowly allowed to cool to room temperature yielding 10.5 grams (73%) of title compound as colorless crystals. m.p.l20-122°C. B(2) . A solution of oxalyl chloride (4.5 mL, 8.93 mmol) was added over 5 min. to a solution of Part B(l) compound in CH 2 CI 2 (10 mL) containing 2 drops of DMF. The reaction was stirred at RT for 2 h, then concentrated in vacuo to give 1.6 g of the crude acid chloride as a dark yellow solid. C. A solution of Part B compound (1.07 g, 2.97 mmol) in THF (10 mL) under argon was cooled to 0°C. Copper (I) iodide (38 mg, 0.20 mmol) was added followed by dropwise addition of Part A compound (14.5 mL, 0.3M in THF, 4.37 mmol) over 10 min. Upon addition, a deep red color appeared but quickly dissipated with stirring. The opaque yellow reaction was stirred at 0°C for 45 min, then quenched by addition of saturated NH 4 C1 (10 L) . The reaction was diluted with water (10 mL) and extracted with EtOAc (3 x 30 mL) . The combined organic layers were washed with saturated NH 4 C1, water, and brine (10 mL each), then dried over MgS0 4 . Evaporation gave 1.3 g of a yellow oil, which was purified by flash chromatography on silica gel (150 g) , loading in 50% EtOAc/hexane, and eluting with 25% EtOAc/hexane to provide title compound (885 mg, 76%) as a colorless oil. D. N-Bromosuccinimide (431 mg, 2.42 mmol) was added to a solution of Part C compound (647 mg, 2.20 mmol) and triphenylphosphine (634 mg, 2.42 mmol) in CH2CI2 (7 mL) at 0°C under argon. The reaction was stirred at 0°C for 1 h, diluted with CH2CI2 (20 mL) , and washed with 10% aqueous potassium sulfite (5 mL) , water (5 mL) , and brine (5 mL) , then dried over MgS0 4 . The mixture was filtered, and to the filtrate was added silica gel (3 g) . Evaporation gave a green powder, which was purified by flash chromatography on silica gel (50 g) eluting with 30% CH2CI2/hexane to provide title compound (733 mg, 93%) as a colorless oil. E. 2,3-Dihydro-2- [1- [4-oxo-4- (9-propyl-9H- fluoren-9-yl)butyl] -4-piperidinyl] -1H- isoindol-1-one. rnonohvdrochloride A solution of Part D compound (336 mg, 0.941 mmol) and Example 1 Part G compound (225 mg, 1.04 mmol) in absolute ethanol (3 mL) was refluxed under argon overnight (20 h) and cooled to RT, at which time a white solid precipitated. The mixture was concentrated in vacuo. and the resulting residue was partitioned between EtOAc (20 mL) and saturated NaHC0 3 (10 mL) . The organic layer was washed with water (5 mL) and brine (5 mL) , then dried over Na 2 S0 4 . Evaporation gave 415 mg of a colorless oil, which was purified by flash chromatography on silica gel (50 g) eluting with 25% acetone/CH2Cl2 to give 205 mg of the desired free amine as a colorless oil. To a solution of the amine prepared above in Et20 (3 mL) was added IN HCl/Et2θ (3 mL, 3 mmol) . The mixture containing a gummy solid was concentrated in vacuo to give a gummy glass. The product was dissolved in isopropanol (2 mL) and hexane (15 mL) was added to precipitate the product . The mixture was concentrated in vacuo to give a foamy solid, which was dried at 60°C overnight under high vacuum to give title compound (206 mg, 41%) as a white foam. Anal. Calcd. for C33H37CIN2O2 • H2O: C, 72.27; H, 7.19; N, 5.11; Cl, 6.46 Found: C, 72.36; H, 7.21; N, 5.02; Cl, 6.59. Ex mple 3 (E)-9-[4-[4-(l, 3-Dihydro-l-oxo-2H-isoindol-2-yl) -1* piperidinyl] -2-butenyl-2,7-difluoro-N- (2,2,2- ri luoroethyl . -9H-fluorene-9-carboxamide A. To a THF (25 ml) supension of 2,7-diamino- fluorene (Aldrich) (7.17 g, 0.036 mol) at -10°C under argon was added aqueous HBF 4 (71 mL, 1.13 mol, 48- 50%) . Near the end of addition stirring became difficult due to solid formation, although most of the solid went into solution upon complete addition of acid. A saturated aqueous solution of sodium nitrite (7.1 g in 11 mL, 0.103 mol) was added and after 1.5 h the mixture was filtered, washing with 5% aq. HBF 4 , MeOH, then ether, and the collected solid dried briefly on the fliter flask. The resulting brown solid (9.7 g) was used in the subsequent reaction. The above solid was suspended in xylenes (100 ml) and heated to 110°C for 2 h, with gas evolution observed, then brought to reflux for an additional 2 h. The solution was decanted from a black tar in the reaction flask and the volatiles removed under high vacuum to give a dark tan solid (7.5 g) . The solid was crystallized from hot EtOH to give title compound (1.4 g) as a colorless solid. An ether wash of the black tar was combined with the mother liquor and concentrated in vacuo. The oily-solid residue (4.3 g) was purified by flash column chromatography (Siθ 2 , 9 by 16 cm) , eluting with hexanes then 2.5% EtOAc:hexanes, to give title compound (2.44 g, total 3.84 g, 52% yield) as a colorless solid. B. To a THF (15 ml) solution of Part A compound (1.38 g, 6.82 mmol) at -5°C (ice/brine bath) under argon was added dropwise n-BuLi (3.4 ml, 8.50 mmol, 2.5 M in hexanes). After 1.15 h, crushed solid CO 2 (excess) was added, followed by Et 2 θ (-5 ml) , and the reaction allowed to stir at room temperature for 19 h. The brown colored reaction mixture was cooled to 0°C, quenched with 2N HCl, and the aqueous layer extracted twice with EtOAc. The combined organics were dried over Na 2 S0 4 and evaporated in vacuo to give crude title compound (1.64 g) , as a colorless solid suitable for the next reaction. Trituration with hexanes can remove unreacted starting material Part A compound. A solution of Part B compound (2,7- difluorofluσrene-9-carboxylic acid) (500mg, 2.05 mmol) in 5 ml of THF was cooled to -30°C under an argon atmosphere and 2 equiv. of a 2.5 M solution of n-butyl lithium in hexane (1.64 ml, 4.1 mmol) was added. The mixture was stirred for 5 min. at -30°C and was then added to a cold (-30°C) solution of 1,4- dibromo-2-butene (2.14 g, 10 mmol) in 4 ml of THF. The reaction mixture was stirred at -30°C for 30 min and was then quenched with 1 N HCl and extracted with ethyl acetate (3x10 ml) . The ethyl acetate extract was washed with water, brine and dried over anhy. sodium sulfate. The crude material was purified on a Merck EM silica column eluting with 5% isopropanol/dichloromethane yielding 480 mg (62%) of title compound as a colorless solid, m.p. 142-146°C. The Part C carboxylic acid (465 mg, 1.23 mmol) was dissolved in 10 ml of dichloromethane and DMF (50 ml) was added. The mixture was cooled to 0°C under an argon atmosphere and oxalyl chloride (165 mg, 1.3 mmol) was added and the mixture allowed to warm to ambient temperature and stir for 2.5 hrs. The mixture was evaporated several times from dichlormethane yielding the crude acid chloride as a pale yellow solid. The acid chloride was dissolved in 5 ml of THF and cooled to 0°C under an argon atmosphere. Triethylamine (142 mg, 1.4 mmol) was added followed by the addition of 2,2,2-trifluoroethyl-amine (139 g, 1.4 mmol). The reaction was allowed to warm to ambient temperature and stir overnight. The reaction was quenched by adding sat. sodium bicarbonate and extracted with ethyl acetate (3x20 ml) . The crude product was purified on a Merck EM silica column eluting wiith 10% ethyl acetate / hexane yielding 230 mg (38%) of title compound as a pale yellow solid. E. A solution of Part D compound (184 mg, 0.4 mmol) in dimethylformamide (3 ml) was stirred under an argon atmosphere and potasssium carbonate (55 mg, 0.4 mmol) was added, followed by the addition of Example 1 Part G compound (95 mg, 0.44 mmol) and the resulting mixture was stirred overnight at ambient temper-ature. The reaction was diluted with ethyl acetate and washed with water, brine and dried over anhy. sodium sulfate. The solvents were evaporated and the crude residue was purified on a Merck EM silica column eluting with 5% isopropanol/dichloromethane yielding 230 mg (96%) of title compound as a colorless solid. Anal Calc'd for C33H30N3F5O2 + 1.7 H 2 0: C, 63.35; H, 5.37; N, 6.72; F, 15.18 Found : C , 63 .24 ; H, 5 . 34 ; N, 6 .45 ; F, 15 .14 m.p . 168-170°C . Example 4 9-[4- [4- (1,3-Dihydro-l-oxo-2H-isoindol-2-yl) -1- piperidinyl] utyl]-2,7-difluoro-N-(2,2,2-trifluo¬ roethyl) -9H-fluorene-9-carboxamidfr A solution of Example 3 compound (100 mg, 0.17 mmol) in 2 ml of DMF and 2 ml of methanol containing 30 mg of 10% palladium on carbon was stirred under a hydrogen atmosphere (balloon) for 18 hrs. The reaction was filtered through a 0.2 mm nylon filter to remove the catalyst and the solvent evaporated yielding the crude product as a colorless oil. The product was purified on a Merck EM silica column eluting 5% IPA / dichloromethane yielding 91 mg (90%) of title compound as a colorless solid. m.p. 150-152°C. Anal Calc'd for C 3 3H32N3Fs0 4 + 1.75 H 2 0: C, 63.01; H, 5.69; N, 6.68; F, 15.10 Found: C, 63.05; H, 5.50; N, 6.48; F, 14.99 Example 5 (Z)-9- [4- [4- (2,3-Dihydro-l-oxo-lH-isoindol-2-yl)-1* piperidinyl] -2-butenyl] -N-propyl-9H-fluorene-9- rarboxamide. monohvdrochloride Butyllithium (8.4 mL, 2.5M in hexane, 21 mmol) was added dropwise over 10 min to a solution of fluorenecarboxylic acid (Aldrich Chemical Co.) (2.10 g, 10 mmol) in THF (50 mL) at 0°C under argon. During addition of the first equivalent of BuLi, the reaction became thick with a white precipitate which became yellow and cleared after addition of the second equivalent. The reaction was stirred at 0°C for 20 min, then cis-1,4-dichloro-2-butene (1.2 mL, 11 mmol) was added dropwise over 5 min. The reaction lightened in color during addition and was stirred at 0°C for 3 h, then poured into IN HCl (50 mL) and extracted with CH 2 CI 2 (3 x 50 mL) . The combined organic layers were washed with brine (30 mL) then dried over MgS0 4 . Evaporation provided 3.5 g of a yellow oil containing crystalline solid. The crude residue was triturated with hexane (20 mL) . The supernatant was decanted, and the residue pumped under high vacuum to give 2.93 g of a tan solid. To a suspension of the crude acid prepared above (1.42g, 4.77 mmol) and N,N-dimethylformamide (5 drops) in CH 2 CI 2 (15 mL) at RT under argon was added oxalyl chloride (3.6 mL, 2.0M in CH 2 C1 2 , 7.16 mmol). The reaction bubbled for 10 min, then the reaction was stirred at RT for 1.5 h, at which time all solids had dissolved. The reaction was concentrated in vacuo to give an orange oil. The crude acid chloride was dissolved in CH 2 CI 2 (15 mL) and cooled to 0°C. Propyla ine (1.2 mL, 14.3 mmol) was added dropwise over 1 min, and the reaction was stirred at 0°C for 10 min. The reaction was partitioned between EtOAc (50 mL) and water (20 mL) . The organic layer was washed with IN HCl (2 x 20 mL) and brine (20 mL) , then dried over MgSθ4. Evaporation gave 1.7 g of an orange oil, which was purified by flash chromatography on silica gel (150 g) eluting with CH 2 CI 2 to give title compound (1.38 g, 84%) as a pale yellow oil. B. 9-[4-[4- (2,3-Dihydro-l-oxo-lH-isoindol- 2-yl) -1-piperidinyl] -2-butenyl] -N-propyl-9H- fl.ιorene-9-carboxamide. monohvdrochloride A mixture of Part A compound (440 mg, 1.30 mmol) and Example 1 Part G compound (337 mg, 1.56 mmol) in DMF (3 mL) under argon was heated at 50°C overnight, cooled to RT, then the solvent was distilled off under high vacuum at RT. The residue was partitioned between CH 2 CI 2 (20 mL) and saturated NaHC03 (7 mL) . The organic layer was washed with brine (5 mL) and dried over Na2S04. Evaporation gave 900 mg of a pale yellow oil, which was purified by flash chromatography on silica gel (75 g) eluting with 3% Me0H CH2Cl 2 to afford 467 mg of the free base as a white foam. The free amine prepared above was dissolved in MeOH (3 mL) and treated with IN HCl/Et2θ (3 mL) , then concentrated in vacuo. The resulting foam was heated at 50°C under high vacuum overnight then for 6 h further at 60°C to give title compound (420 mg, 58%) as a white foamy solid. Anal. Calcd. for C34H38CIN3O2 • 0.7H2O: C, 71.81; H, 6.98; N, 7.39; Cl, 6.23. Found: C, 71.86; H, 7.34; N, 7.34; Cl, 6.16. Following the procedure of Examples 1 to 5, the following additional compounds were prepared. 6. 2,3-Dihydro-2-[l- [2-OXO-2- (9-propyl-9H- fluorene-9-yl)ethyl]-4-piperidinyl]-1H- isoindol-1-one, monohydrochloride MS (ES) 465 (M+H) mp 146-149°C Anal. Calcd. for C31H33CIN2O2 • 0.95 H2O: Calcd: C, 71.85; H, 6.79; N, 5.41 Found: C, 72.29; H, 7.22; N, 5.37. 7. (E)-9- [4-[4- (2,3-Dihydro-l-oxo-lH-isoindol- 2-yl)-1-piperidinyl]-2-butenyl] -N-propyl-9H- fluorene-9-carboxamide, monohydrochloride MS(C1) 520 (M+H) mp 115-116.5°C Anal. Calcd. for C34H37N3O2 Calcd: C, 78.58; H, 7.18; N, 8.09 Found: C, 78.49; H, 7.26; N, 8.06. 8. 9- [3-[4- (2, 3-Dihydro-l-oxo-lH-isoindol-2* yl) -l-piperidinyl]propyl] -N-propyl-9H- fluorene-9-carboxamide M.S. (ES, + ions) m/e 508 (M+H) mp 172-175°C Calcd: C, 78.07; H, 7.34; N, 8.28 Foun : C, 77.80; H, 7.50; N, 8.10, Example 9 The title compound was purchased from Aldrich Chemical Co. B. A solution of Part A alcohol (1.58 g, 10.0 mmol) and butanethiol (0.72 g, 8.00 mmol) in 10 mL of dichloromethane at -20°C was treated with boron triflouride etherate (1.28 g, 9.00 mmol). The reaction was stirred for 1 h at -20°C and warmed to room temperature. After stirring for 18 h the reaction was concentrated in vacuo, and the crude product was purified by column chromatography on silica gel (100 g) with hexanes followed by 1:9 dichloromethane/hexanes to give 1.54 g (75%) of title compound as a colorless oil. A solution of Part B compound (1.0 g, 3.93 mmol) in 10 mL of THF at -78°C was treated with n- butyllithium in hexanes (1.75 mL, 4.40 mmol) followed by l-chloro-4-bromo-butane (0.81 g, 4.70 mmol) . The reaction was stirred for 0.5 h and warmed to room temperature for 18 h. The reaction was diluted with 30 mL of aqueous NH C1 solution and 30 mL of ethyl acetate. The organic fraction was dried (Na 2 S0 ) and concentrated. The crude product was purified by column chromatography on silica gel (50 g) with 2:98 acetone/dichloromethane (500 mL) followed by 15:85 dichloromethane/hexanes to give 1.00 (73%) of title compound as a colorless oil. To a solution of Part C sulfide (0.30 g, 0.86 mmol) in dichloromethane (5 mL) at 0°C was added 3- chloroperoxybenzoic acid (0.37 g, 80% by weight = 0.1.72 mmol) in one portion. The mixture was stirred for 1 h then partitioned between 0.1 M K 2 C0 3 (20 mL) and ether (30 mL) . The organic fraction was dried (Na2S04) and concentrated. The crude product was purified by column chromatography on silica gel (50 g) with 15:85 ethyl acetate/hexanes to give 0.24 g of sulfone as a colorless oil. To a solution of the sulfone chloride (0.24 g, 0.64 mmol) in 2-butanone (10 mL) at RT was added sodium iodide (1.00 g, 6.66 mmol) in one portion. The mixture was refluxed for 30 h when it was diluted with water (20 mL) and ether (30 mL) . The organic fraction was dried ( a2S04) and concentrated. The crude product was purified by column chromatography on silica gel (50 g) with 15:85 ethyl acetate/hexanes to give 0.24 g (81%) of title compound as a colorless oil. E. To a stirred solution of 0.70 g (1.49 mmol) of Part D compound in 6 mL of DMF at RT was added 0.38 g (1.80 mmol) of (prepared as described in Example 1 Part G) . The reaction mixture was warmed to 55° and allowed to stir for 24 h. The mixture was diluted with NaHC0 3 solution (50 mL) and ethyl acetate (50 mL) . The layers were separated, the organics dried (Na 2 S0 ) and concentrated. The remainder was purified by flash column chromatography on silica gel (100 g) eluting with 5:95 methanol/dichloromethane (700 mL) followed by 5:95:0.5 methanol/di- chloromethane/NH 3 (IL) . Pure fractions were pooled and concentrated to give 0.70 g (85%) of title compound as a thick oil which solidified after standing. .p. 128-131°C. _ __ Anal, calcd for C3 4 H 4 oN2θ3S • 0.45 H2O: C, 72.29; H, 7.30; N, 4.96; S, 5.76 Found: C, 72.25; H, 7.15; N, 5.00; S, 5.69. Example 10 9-[4-[4-[ [ (1,1-Dimethylethoxy)carbonyl]amino] piperidinyl] utyl] -N-£>ropyl-9H-fluorene-9- carboxamide H CH, A. [1- (Phenylmethyl) -4-piperidinyl]carbamic acid, l.-t-dimethYlethYl ester To a solution of 4-amino-l-benzylpiperidine (20.0 g, 105 mmol) in dichloromethane (150 mL) was added dropwise a solution of di-j≤ϋ-butyldicar- bonate (25.2 g, 116 mmol) in dichloromethane (50 mL) at 0°C. After addition, the reaction was warmed to room temperature. The reaction was maintained at this temperature for 2 hours. The reaction was evaporated to dryness. The resulting residue was recrystallized from ethyl ether to give compound A (23.5 g, 76%) as a white solid (melting point 119- 121°C) . B. 4-Piperidinylcarbamic acid, 1,1-di- methvlethvl ester A suspension of 64.94 g (0.224 mol) of compound A and 25.6 mL (0.447 mol) of acetic acid in 500 mL of absolute ethanol was warmed to dissolve all solids. After cooling, 6.5 g (1 wt %) of 10% palladium on charcoal was added and the mixture was shaken on a Parr apparatus under initial hydrogen pressure of 40 psi for 23 hours. The catalyst was removed by filtration and the solution was concentrated to a clear oil which was dissolved in 1.5 L of chloroform. The organics were washed with a 3 U KOH solution saturates with NaCl (2 x 75 mL) . The aqueous layer was back extracted with chloroform (5 x 200 mL) . The combined organics were dried (sodium sulfate) and concentrated to provide 65 g of a white solid which was redissolved in 1.5 L of chloroform and washed with brine (2 x 200 mL) to remove residual acetate. The combined aqueous layers were back extracted and the combined organics were dried (sodium sulfate) and concentrated to provide 40.15 g (90%) of compound B as a white solid (melting point 156-159°C) . The solution of Example 5 Part A compound (6.0 g, 17.6 mmol) and Part B compound (2.88 g, 16.0 mmol) in DMF (3mL) was stirred at 50°C overnight. Ethyl acetate (150 mL) was added and the organic layer was washed with saturated sodium bicarbonate solution (2 x30 mL) , water (2 x 50 mL) , brine (2 x 50 mL) and dried over MgS0 4 . Purification was performed by flash chromatography on silica gel (300 g) , loaded and eluted with 2.5% methanol in dichloromethane. Pure fractions were combined and evaporated to give title compound(3.0 g, 34%) as a colorless oil. D. 9-[4-[4-[ [ (1,1-Dimethylethoxy)carbonyl] - amino] -1-piperidinyl]butyl] -N-propyl-9H- fluorene-9-carboxa ide To a solution of Part C compound (3.0 g, 5.89 mmol) in methanol (10 mL) at RT was added palladium on activated carbon (10%, 300 mg) . The reaction was hydrogenated (balloon) at RT for 18 h. The reaction was filtered and the filtrate was evaporated to give a white solid. The resulting solid was recrystallized from ethyl acetate/hexane to give title compound (2.90 g, 97%) as a white solid. m.p. 118-120 °C . Anal. Calc. for C3iH 4 3N3θ3 • 2.4 H2O: C, 67.83; H, 8.78; N, 7.65 Found: C, 67.45; H, 8.33; N, 7.52 Example 11 N- [2- [4-.(l, 3-Dihydro-l-oxo-2H-isoindol-2-yl) -1* piperidinyl]ethyl] -9-propyl-9H-fluorene-9- carboxamide To a CH 2 CI 2 (30 ml) solution of Example 2 Part B(l) compound (2 g, 7.93 mmol) under nitrogen was added 1, 1 ' -carbonyldiimidazole (1.35 g, 8.32 mmol) . After 1 h, ethanolamine (0.486 g, 7.95 mmol) was added, followed by DMF (1.5 mL) to aid solubility of the amine, and the reaction allowed to stir at room temperature overnight. After 24 h, the reaction mixture was diluted with saturated NaHCθ3 and the aqueous layer extracted twice with CH 2 CI 2 . The combined organics were washed with H 2 O, dried over Na 2 S0 4 and evaporated in vacuo to give an oily residue (2.55 g) . The residue was purified by flash column chromatography (Siθ 2 , 350 mL) , eluting with 30% EtOAc:CH 2 Cl2, to give title compound (1.73 g, 74% yield) as a colorless solid. B, To a CH 2 CI2 (30 ml) solution of Part A compound (1.4 g, 4.74 mmol) at 0°C under argon was added triphenylphosphine (1.39 g, 5.30 mmol) and Ν- bromosuccinimide (0.930 g, 5.22 mmol) and the reaction allowed to stir for 2 h. The reaction mixture was diluted with CH 2 CI 2 and the poured into 10% aqueous sodium bisulfite. The aqueous layer was extracted 4 times with CH 2 CI 2 , the combined organics dried over Νa 2 S0 4 , and evaporated in vacuo to give an oily brown colored residue (3.4 g) . The residue was purified by flash column chromatography (Si0 2 , 5 by 18.5 cm), eluting with 4:1 CH 2 CI 2 :hexanes to give title compound (1.52 g, 89.5% yield) as a colorless solid. C. N-[2-{4- (l,3-Dihydro-l-oxo-2H-isoindol- 2-yl) -l-pioeridinvllethvl1 -9-propvl-9H- fluorene-9-carboxamide A DMF (1.5 ml) solution of Part B compound (520 mg, 1.45 mmol) and Example 1 Part G compound (315 mg, 1.45 mmol) under argon was stirred for lh, followed by the addition of K 2 CO3 (200 mg, 1.45 mmol) and DMF (0.5 ml). After 24 h, the reaction was partitioned between saturated NaHCθ 3 and EtOAc. The aqueous layer was extracted with EtOAc, CHCI 3 , and twice with CH 2 CI 2 . The combined organics were dried over a 2 S0 4 and the volatiles were removed in vacuo to give an oily-solid residue (720 mg) . The residue was purified by flash column chromatography (Siθ 2 , 5 by 8 cm), eluting with 1% MeOH:CH Cl 2 then 5% MeOH:CH 2 Cl 2 , to give title compound (184 mg, 25% yield) as a colorless solid, mp 219-221°C. Anal. Calc. for C3 2 H35N3O 2 • 0.32 H 2 0: C, 76.97 H, 7.19; N 8.42 Found: C, 76.88; H, 7.16; N, 8.51. Example 12 9-[4-[4-[[2-(Phenoxypheny1) carbonyl]amino] -1 ■ piperidinyl]butyl] -N-propyl-9H-fluorene-9- carbgxaπύtie A. To a solution of Example 10 Part A compound (2.65 g, 5.20 mmol) in dioxane (10 mL) at RT was added a solution of hydrochloric acid in dioxane (4N, 10 mL, 40 mmol) . The reaction was stirred at RT for 3.5 h. The reaction was evaporated to give a white solid. The resulting solid was recrystallized from methanol/water to give title compound (2.4 g, 97%) as a white solid. m.p. 156-160°C. Anal. Calc. for C26H37CI2 3O • 1.1 H 0: C, 62.67; H, 7.93; N, 8.43 Found: C, 62.63; H, 7.87; N, 8.46. B. 9-[4-[4-[ [2-(Phenoxyphenyl)carbonyl] - amino] -1-piperidinyl]butyl] -N-propyl-9H- fluorene-9-carboxamide To a solution of 2-phenoxybenzoic acid (purchased from Aldrich) (500 mg, 2.33 mmol) and DMF (1 drop) in dichloromethane (10 mL) at RT was added dropwise a solution of oxalyl chloride in dichloromethane (2.0M, 1.28 mL, 2.56 mmol). Bubbling of escaping gasses continued for 10 min after addition. The reaction was stirred at RT for 60 min, then concentrated in vacuo to give a crude oil. To a solution of crude acid chloride and triethylamine (1.14 mL, 8.16 mmol) in dichloromethane (10 mL) at 0 °C under argon was added dropwise a solution of Part A compound (1.12 g, 2.33 mmol) in dichloromethane (2 mL) . The reaction was stirred at 0 °C for 30 min. Ethyl acetate (100 mL) was added to dilute the reaction and the resulting solution was washed with H 2 O (2 x 30 mL) , brine (2 x 30 mL) and dried over MgSθ4. Evaporation gave a crude gum. Purification was performed by flash chromatography on silica gel (100 g) , loaded and eluted with 2.5% methanol in dichloromethane. Pure fractions were combined and evaporated to give a coloress gum. The resulting product was triturated with ethyl ether to give title compound (720 mg, 51%) as a white solid. m.p. 149-152°C. Anal. Calc. for C39H43N3O3 • 0.2 H2O: C, 77.38; H, 7.23; N, 6.94 Found: C, 77.37; H, 7.39; N, 6.89. Examples 13 to 20 Following the procedures set out in Examples 1 to 12, the following compounds of the invention were prepared. 13. 9-[5-[4-(1,3-Dihydro-1-oxo-2H-isoiπdol-2-yl)-1-piperidinyl]pentyl]-N-propyl- 9H-fluorene-9-carboxamide. m.p. 146-148°C MS (ES, + ION) : 536 (M+H) Anal. Calcd. for C35H 4 2CIN3θ2 C, 69.76; H, 7.29; N, Found: C, 69,70; H, 7.39; N, 14 - - 9-[4-[4-(Benzoylamino)-1-pipβridinyl]butyl]-N-propyl-9H-fluorβnβ- 9-carboxamide. m.p. 157-160°C MS (Cl, + ion) (M+H) 510 Anal. Calcd. for C 33 H 39 N 3 O 2 • 0.5 H 0: C, 76.41; H, 7.77; N, 8.10 Found: C, 76.37; H, 7.70; N, 8.02. 15 9-[4-(4-(2,3-Dihydro-l-oxo-lH-isoindol-2-yl) -1- piperidinyl] butyl] -N-(2, 2, 2 -trif luoroethyl) -9H- f luorene-9-carboxamide m.p. 143-146°C MS (ES, + ions) m/z 562 (M+H) Anal. Calcd. for C33H3 4 N3F3O 2 : C, 70.57; H, 6.10; N, 7.48; F, 10.15 Found: C, 70.04; H, 6.18; N, 7.34; F, 9.87. 16 9-[2-[4-(2,3-Dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]ethyl]-N-propyl- 9H-fluorene-9-carboxamide, monohydrochloride. 17 9-[4-[4-(Acetylamino)-1-piperidinyl]butyl]-N-propyl-9H-fluorβnβ- 9-carbcxamide. m.p. 133-135°C MS (Cl, + ion) (M+H) 448 Anal. Calcd. for C28H37N3O2 • 1.0 H 2 0: C, 72.23; H, 8.44; N, 9.02 Found: C, 71.94; H, 7.90; N, 8.88. 18 N-Ethyl-9-[4-[4-(2,3-dihydro-1 -oxo-1 H-isoindo • lC-2-y-Ul)-1-piperidinyl]bulyl]-9H- fluorene-9-carboxamide m.p. 137-140°C MS (Cl, M+H + ) m/z 508 + Anal. Calcd. for C33H37N3O2 • 0.29 H 2 0: C, 77.27; H, 7.39; N, 8.19 Found: C, 77.05; N, 7.38; N, 8.41. 9-[4-[4-(2,3-Dihydro-1 -oxo-1 H-isoindol-2-yl)-1-piperidinyl]butyl]-N-2,2,2- trifluoroethyl-9H-xanthene-9-carboxamide. m.p. 164-166°C (dec) M.S. (FAB) m/z 578 (M+H) 20 9-[4-[4-(2,3-Dihydro-1 -oxo-1 H-isoindol-2-yl)-1-piperidinyl]butyl]-N-propyl- 9H-xanthene-9-carboxamide. m.p. 62-65°C Anal. Calcd. for C 34 H 39 θ 3 N 3 + 0.5 H 2 0: C, 74.70; H, 7.37; N, 7.69 Found: C, 74.45; H, 7.32; N, 7.56 Example 21 9- [4- [4- (2 , 3 -Dihydro-l , 3 -dioxo-lH-isoindol-2 -yl ) -1* piperidinyl] butyl ] -N-propyl -9H-f luorene- 9- carbox- amide . monohydrochloride A solution of Example 12 Part A compound (500 mg, 1.05 mmol), diisopropylethylamine (0.4 mL, 2.31 mmol) and phthalic anhydride (170 mg, 1.15 mmol) in toluene (3 mL) was refluxed for 5 h, then cooled to RT. Dichloromethane (80 mL) was added and the solution was washed with water (2 x 30 mL) , brine (2 x 30 mL) and dried over MgS0 4 . Purification was performed by flash chromatography on silica gel (50 g) , loaded and eluted with 2.5% methanol in dichloromethane. Pure fractions were combined and evaporated to give a white solid. The resulting product was dissolved in ethyl ether (5 mL) and a solution of hydrochloric acid in ethyl ether (0.77M, 2.0 mL) was added. The reaction was stirred at RT for 10 min, then evaporated to dryness. The product was dried in a vacuum oven (50 °C, 18 h) to give title compound (440 mg, 73%) as a white solid. m.p. 125-130°C Anal. Calc. for C 34 H 3 8CIN 3 O 3 • 1.3 H 2 O: C, 68.57; H, 6.87; N, 7.06; Cl, 5.95 Found: C, 68.71; H, 6.66; N, 7.01; Cl, 5.82. Exampl 22 9- [ 4- [4- ( 2 , 3 -Dihydro-l -oxo-lH-isoindol-2 -yl ) -1 * piperidinyl ] butyl ] -N-propyl-9H-indeno [2 , 1-b] - r>vr . riing-9 -carboxamide A THF (5 ml) solution of 1-aza-fluorene (233 mg, 1.39 mmol; prepared from benzo(f)quinoline by known procedures, Kloc, K. Journal f . prakt . Chemie, 319, 959-967 (1977) and Kloc, K. Heterocycleε , 9, 849-852 (1978)) and n-propyliso-cyanate (0.13 ml, 1.39 mmol) was degassed three times by cooling to -78°C, evacuating, and allowing to warm to room temperature, and finally purging with argon. To the degassed solution at -10°C was added dropwise sodium bis (trimethylsilyl)amide (1.4 ml, 1 M in THF). After 5 min, a second portion of n-propylisocyanate (0.13 ml, 1.39 mmol) was added to the red solution. The now green colored reaction mixture was quenched after a further 15 min with saturated NH 4 C1. The aqueous layer was extracted with EtOAc, the organics washed with brine, dried over Na2S0 4 and evaporated in vacuo to give a red colored oily-solid residue (535 mg) . The residue was purified by flash column chromatography (SilicAR" buffered silica gel, 5 by 7 cm), eluting with 20% EtOAc:CH 2 Cl 2 , and flushing with 5% MeOH:CH2Cl2 to give title compound (202 mg, 58% yield) as an orange colored solid, mp 131-133°C. HO. ^ ^ ^^ B ^^ ^^ O-SIPhjtBu To a THF (100 ml) suspension of sodium hydride (4 g, 60% oil dispersion, 0.10 mol) at 18°C (cool water bath) under argon is added 1, 4-butane-diol. After stirring at room temperature for 14 h, t- butylchlorodiphenylsilane (26 mL, 0.1 mol) was added in rapid drops. The reaction was quenched after 30 min with H2O and the aqueous layer was extracted with hexanes. The organic layer was dried over Na 2 ≤0 4 and evaporated to an oil (33 g) . The residue was purified by flash column chromatography (silica gel, 10 by 26 cm), eluting with CH 2 CI 2 , 5, 7.5, and then 10% EtOAc:CH 2 Cl 2 to give title compound (24.5 g, 74%) as a colorless oil. 0-SIPh 2 tBu To a THF ( 70 ml ) solution of Part B compound ( 5.48 g, 0 . 0167 mol ) , triphenylphosphine ( 4 . 3 g, 0 . 0164 mol ) , and imidazole (2 .49g , 0 . 0366 mol ) at 0°C was added a THF ( 15 ml ) solution of iodine (4 .23 g , 0 . 0167 mol ) over 10 min . After 1 h at room temperature , the reaction was cooled to 0°C and quenched with 5% aqueous sodium bisulfite. The mixture was diluted with H 2 O and hexanes, the organic layer washed with H 2 O, saturated NaHCθ 3 , and brine. The organic layer was dried over Na 2 S0 4 and evaporated to an oily-solid. The residue was triturated with hexanes, cooled to 0°C, filtered and the volatiles removed in vacuo to give an oil (7.35 g) . This residue was purified by flash column chromatography (SilicAR" buffered silica gel, 5 by 10 cm), eluting with 30% CH2CI 2 :hexanes to give title compound (6.2 g, 84%) as a colorless oil. A THF (9 ml) solution of Part A compound (400 mg, 1.58 mmol) was degassed three times by cooling to -78°C, evacuating, and allowing to warm to room temperature, and finally purging with argon. To the degassed solution at 0°C was added dropwise n-BuLi (1.3 ml, 2.5 M in hexanes). After several minutes, Part C compound (0.63 ml, 1.82 mmol) was added to the red solution. The now brown colored reaction mixture was quenched after a further 1 h with saturated NH 4 CI. The aqueous layer was extracted twice with EtOAc, the organics dried over Na 2 S0 4 , and evaporated in vacuo to give an orange colored oil (1.07 g) . The residue was purified by flash column chromatography (SilicAR" buffered silica gel, 5 by 8.5 cm), eluting with 8% EtOAc:CH 2 Cl 2 to give title compound (817 mg, 92%) as a colorless oil. To a THF (3.5 ml) solution under argon of Part D compound (800 mg, 1.42 mmol) was added dropwise tetrabutylammonium fluoride (1.5 ml, 1 M in THF). After 2 h, a second portion of tetra-butylammonium fluoride (0.15 ml, 1 M in THF) was added and the reaction mixture was allowed to stir a further 1 h. The reaction mixture was partitioned between H 2 O and EtOAc. The aqueous layer was extracted 3 times with EtOAc, and the organics washed with brine. The first organic layer contained less ammonium salts and was dried over a 2 S0 4 , and evaporated in vacuo to give an oil (885 mg) . The residue was purified by flash column chromatography (SilicAR" buffered silica gel, 90 g) , eluting with 4.5% MeOH:CH 2 Cl 2 to give title compound (437 mg, 95%) as a colorless oil. To a CH 2 CI 2 (5 ml) solution of Part E compound (231 mg, 0.712 mmol) and triphenylphos-phine (285 mg, 1.09 mmol) at 0°C under argon was added N- bromosuccinimide (153 mg, 0.860 mmol). After 2.15 h, a second portion of N-bromosuccinimide (18 mg, 0.101 mmol) was added and the reaction stirred 45 min at 0°C and 15 min at room temperature. The reaction mixture was then quenched with 10% sodium bisulfite and the aqueous layer extracted twice with CH 2 CI 2 . The combined organics were washed with brine, dried over Na 2 S0 4 , and evaporated in vacuo to give an oily-solid residue (653 mg) . The residue was purified by flash column chromatography (SilicAR * buffered silica gel, 68 g) , eluting with 10.5% E OAc:CH 2 Cl 2 to give the unstable title compound (217 mg, 78%) as a colorless oil. To a DMF (1.6 ml) solution of Part F compound (180 mg, 0.465 mmol) and Example 1 Part G compound . . (135 iiig, 0.624 mmol) under argon was added K 2 C0 3 (65 mg, 0.47 mmol). After 18.15 h, the purple colored reaction was partitioned between dilute NaHC0 3 and EtOAc. The aqueous layer was extracted twice with EtOAc, the combined organics were washed with H 2 O, brine, dried over Na 2 S0 , and the volatiles were removed in vacuo to give a purple colored oil (230 mg) . The residue was purified by flash column chromatography (SilicAR" buffered silica gel, 26.5 g) , eluting with 5 then 6% Me0H:CH 2 Cl 2 , to give title compound (83 mg, 34% yield) as a colorless foam. Additional title compound was obtained as a mixture (96 mg, 92% pure by HPLC, 72% yield) mp 52-54°C. MS: (electrospray, M+H + ) : m/z 523 + . Example 23 2,3-Dihydro-2-[1- [4-hydroxy-4-(9-propyl-9H-fluoren-9- vl.hutvl1 -4-pjperidinvl1 -lH-isoindol-1-one A solution of Example 2 Part D free amine (300 mg, 0.61 mmol) in 12 ml of methanol was cooled to 0°C under an argon atmosphere and 2 equiv. of sodium borohydride (48.5 mg, 1.28 mmol) was added. The reaction mixture was stirred at 0°C for 45 min. The reaction was quenched with 1 N hydrochloric acid and extracted with ethyl acetate (3 x 20 ml) . The extract was washed with brine and dried over sodium sulfate. Evaporation yielded an oily residue which was dissolved in dichloromethane, dried over sodium sulfate and evaporated to yield 550 mg of a colorless solid. The crude product was purified on a Merck EM silica column eluting with 5% methanol/dichloromethane yielding 290mg (96%) of title compound as colorless solid. m.p. 75 - 78°C. MS(CD m/z 495 (M+H) . Example 24 2,3-Dihydro-2-[1-[3-[ (9-propyl-9H-fluoren-9-yl) t-h-iolnropvn -4-pjperidinvlI -lH-isoindol-1-one A. To a THF ( 100 ml ) solution of f luoren-9 -one ( 9 .12 g , 0 . 051 mol ) at - 10°C under argon was added dropwise n-propylmagnesium chloride ( 25 .4 ml , 2 M in ether) . Af ter 1 .15 h, the orange colored reaction mixture was quenched with saturated NH 4 C1 . The aqueous layer was extracted twice with EtOAc, the organics washed with brine, dried over Na 2 S0 4 and evaporated in vacuo to give an oily-solid residue (11.1 g) . The residue was purified by crystallization from EtOH:H 2 θ to give title compound contaminated with 14% by weight 9-hydroxyfluorene (4 g, 30% yield) as a colorless solid. Material was sufficiently pure for the subsequent reaction. B. To an AcOH (25 ml) solution of Part A compound (3.64 g, 0.014 mol) and methyl 3-mercaptopropionate (1.62 ml, 0.015 mol) under argon is added concentrated H 2 SO 4 (7 drops) . After stirring at room temperature for 24 h, the reaction was concentrated to 1/3 the original volume and diluted with H 2 O. The aqueous layer was extracted with EtOAc and the " organic layer washed with 1 N NaOH. The basic wash was extracted 3 times with EtOAc, the combined organics extracted with brine, dried over Na 2 S0 4 and evaporated to an oily-solid of the structure (Bl) (5.55 g) . (Compound B(l) was sufficiently pure for the subsequent reaction. Rf = 0.49 (25% EtOAc:hexanes) . To an EtOH (15 ml) solution of compound B(l) (385 mg, 0.956 mmol) was added NaBH (470 mg, 0.012 mol) . After stirring overnight, the reaction mixture was cooled to 0°C and quenched with saturated NH4C1. The aqueous layer was extracted with EtOAc, the organic layer washed with brine, dried over Na 2 S0 4 and evaporated to an oily residue (390 mg) . This residue was purified by flash column chromatography (silica gel, 3 by 10 cm) , eluting with 3% EtOAc:CH 2 Cl2 to give title compound (110 mg, 38% yield from Part A compound) as a colorless oil. To a pyridine (0.75 ml) solution of Part B compound (110 mg, 0.369 mmol) at 0°C was added p- toluenesulfonyl chloride (80 mg, 0.42 mmol) and the reaction slowly allowed to come to room temperature. After 4 h and 7.5 h, more p-toluenesulfonyl chloride (60 and then 40 mg, 0.52 mmol) was added at room temperature and the reaction was stirred at 5°C overnight. A final portion of p-toluenesulfonyl chloride (40 mg, total 1.15 mmol) was then added and the reaction stirred at room temperature for 8 h. The reaction mixture was partitioned between EtOAc and saturated NaHC0 3 . The aqueous layer was extracted 3 times with EtOAc, the organic layer washed with brine, dried over Na 2 S0 4 and evaporated to an oily-solid (200 mg) . This residue was preabsorbed onto Celite and purified by flash column - - chromatography (silica gel, 3 by 8 cm), eluting with 15% EtOAc:hexanes to give title compound (110 mg, 66% yield) as a colorless oil. A mixture of Part C compound (102 mg, 0.227 mmol), Example 1 Part G compound (64 mg, 0.296 mmol), and K 2 CO 3 (34 mg, 0.246 mmol) in isopropanol (1.5 ml) under argon was refluxed for 6 h. After cooling, the reaction was partitioned between saturated NaHCC> 3 and EtOAc. The aqueous layer was extracted twice with EtOAc, the combined organics were dried over a 2 S0 and the volatiles were removed in vacuo to give an oil (126 mg) . The residue was combined with another crude residue from an identical reaction using 48.6 mmol of Part C compound (146 mg total). The mixture was purified by flash column chromatography (silica gel, 3 by 5.5 cm), eluting with 4% MeOH:CH2Cl 2 to give impure title compound (108 mg) . The mixture was further purified by flash column chromatography (silica gel, 12 g) , eluting with 4% MeOH:CH 2 Cl 2 to give title compound (101 mg, 74% yield) as an oily foam. MS: (electrospray, M+H + ) : m/z 497 + . Anal. Calcd. for C 32 H 36 N 2 OSO.26 H 2 O: C, 76.64; H, 7.34; N, 5.59 Found: C, 76.73; H, 7.27; N, 5.51. Ex mple 5 2,3-Dihydro-2-[1-[3- [ (9-propyl-9H-fluoren-9-yl) - sulfonvllpropvll -4-piperidinyl1 -lH-isoindol-1-one To an AcOH (25 ml) solution of Example 24 Part A compound (3.64 g, 0.014 mol) and methyl 3- mercaptopropionate (1.62 ml, 0.015 mol) under argon is added concentrated H 2 S0 4 (7 drops) . After stirring at room temperature for 24 h, the reaction was concentrated to 1/3 the original volume and diluted with H 2 O. The aqueous layer was extracted with EtOAc and the organic layer washed with 1 N NaOH. The basic wash was extracted 3 times with EtOAc, the combined organics extracted with brine, dried over Na 2 S0 and evaporated to an oily-solid (5.55 g, > 100% recovery). To a CH 2 CI2 (25 ml) solution of crude compound prepared above (1 g, 2.63 mmol) at 0°C under argon was added 3-chloroperoxybenzoic acid (1.41 g, 6.13 mmol, 75%) and the reaction brought to room temperature. After 1.45, 4.1, and 6 h, more 3- chloroperoxybenzoic acid (0.25, 0.3, and 0.2 g, total 9.39 mmol) was added. The reaction was stored at -80°C after 8 h. After warming, the reaction mixture was partitioned between 1 N NaOH and EtOAc. The aqueous layer was extracted twice with EtOAc, the organic layer washed with brine, dried over Na 2 ≤0 4 and evaporated to an oily-solid residue. This residue was purified by flash column chromatography (silica gel, 5 by 9 cm), eluting with 18% EtOAc:hexanes to give title compound (630 mg, 67% yield from Example 24 Part A compound) as a colorless solid, mp 74-77°C. Anal. Calc. for C 20 H 22 SO- 1 • 0.29 H 2 O: C, 66.04; H, 6.26; S, 8.81 Found: C, 66.04; H, 6.11; S, 8.45. B. To an EtOH (14 ml) suspension of Part A compound (559 mg, 1.56 mmol) at 0°C under argon was added NaBH 4 (80 mg, 3.36 mmol) and the mixture brought to room temperature. After 1 h, the reaction mixture was cooled to 0°C and a second portion of NaBH 4 (80 mg, 3.36 mmol) was added. After 5 h at room temperature, the reaction mixture was quenched at 0°C with saturated NH 4 C1 and the mixture stirred at room temperature for 30 min. The aqueous layer was extracted twice with EtOAc and the combined organic layers were evaporated to an oily residue. This residue was co-evaporated 3 times with MeOH to give 500 mg of oily-solid. After pre-absorbing onto Celite, the residue was purified by flash column chromatography (silica gel, 5 by 7 cm) , eluting with 3% MeOH:CH 2 Cl 2 to give title compound (328 mg, 64% yield) as a colorless solid, mp 111.5-112.5°C. To a CH 2 CI 2 (5 ml) solution of Part B compound (308 mg, 0.933 mmol) and triphenylphosphine (490 mg, 1.87 mmol) at 0°C under argon was added N- bromosuccinimide (210 mg, 1.18 mmol) . After 2 h, a second portion of N-bromosuccinimide (40 mg, 0..34 mmol) was added and the reaction stirred an additional 1 h. The reaction mixture was then quenched with 10% sodium bisulfite and the aqueous layer extracted twice with EtOAc. The combined organics were washed with H 2 O, brine, dried over Na 2 S0 4 , and evaporated in vacuo to give an oily- solid residue. The residue was purified by flash column chromatography (SilicAR" buffered silica gel, 5 by 9 cm), eluting with 6.7% hexanes:CH 2 Cl 2 , then CH 2 CI 2 to give the unstable Compound C(l) of the structure (283 mg, 77% yield) as a colorless solid, mp 83-86°C. A DMF (2 ml) solution of Compound C(l) (234 mg, 0.595 mmol) and Example 1 Part G compound (155 mg, 0.717 mmol) under argon was stirred for 15 h. A second portion of Example 1 Part G compound (17 mg, 0.078 mmol) was then added, followed in 4 h by K 2 CO 3 (33 mg, 0.239 mmol) . After 24 h, the cooled reaction mixture was partitioned between saturated NaHC0 3 and EtOAc. The aqueous layer was extracted with EtOAc, the organics were washed with brine, dried over Na 2 S0 4 and the volatiles were removed in vacuo to give an oil (357 mg) . The mixture was purified by flash column chromatography (silica gel, 3 by 12.5 cm) , eluting with 5% MeOH:CH 2 Cl 2 to give impure title compound (222 mg) , as well as pure title compound (76 mg, contaminated with 10% DMF) . The pure title compound was crystallized from EtOAc:hexanes to give title compound (39 mg) as a colorless solid. The impure title compound was further purified by flash column chromatography (silica gel, 24 g) , eluting with 5% MeOH:CH2Cl2 to give title compound (153 mg, 192 mg total, 61% yield), mp dec. 138-141°C. MS: (electrospray, M+H + ) : m/z 529 + . Anal. Calcd. for C 32 H 3 6N 2 θ3S-l.01 H 2 0: C, 70.29; H, 7.01; N, 5.12 Found: C, 70.45; H, 6.60; N, 4.96. Ex mp 6 2,3-Dihydro-l- [4- [4- (2, 3-dihydro-l-oxo-lH-isoindol-2* yl) -1-piperidinyl]butyl] -N-propyl-lH-indene-1- carhoxamide A. To a stirred slurry of 2 H (Aldrich) (3.20 g, 20.0 mmol) in 20 mL of dichloromethane at room temperature under argon was added 15.0 mL of oxalyl chloride solution (30.0 mmol, 2 U in dichloromethane) and then 0.1 mL of DMF. Vigorous gas evolution results in a light yellow solution. After 1 h, the reaction mixture was evaporated at less than 25°C and the residue was dissolved in 10 mL of THF. This solution was then added dropwise over 15 minutes to a solution of 3.5 mL of n-propylamine (46 mmol) in 25 mL of THF at -10°C under argon. After one hour, the reaction mixture was partitioned between ethyl acetate and 10% citric acid solution. The organic extract was dried (MgS0 4 ) and evaporated. Purification by flash chromatography on silica gel (5 x 20 cm column, 1:2 ethyl acetate/hexanes as elutant) provided title compound as a yellow solid, 2.36 g, 59% yield, mp 123-125°C. B. A degassed slurry of Part A compound (1.10 g, 5.47 mmol) and 330 mg of 10% palladium-on-carbon in 25 mL of ethyl acetate at room temperature was stirred under atmospheric pressure hydrogen for 16 h. The reaction was filtered through Celite and evaporated to give title compound as a white solid, 894 mg, 81% mp 61-63°C. OSitBuMβj To a solution of 49 mL (0.55 mol) of 1,4-- butanediol in 25 mL of DMF, under argon at 0°C, was added 10.5 g (0.15 mol) of imidazole followed by 20.7 g (0.14 mol) of t-butyldimethylsilyl chloride. The reaction was slowly warmed to RT and stirred for 18 h at which time the reaction was diluted with ether and washed with NH 4 C1, water, Na 2 Cθ3, brine and dried (MgS0 4 ) . The resulting colorless liquid OSi l BuM β 2 ^ go g, contained approximately 15% of the disilylated compound. To a solution of 8.5 g (42 mmol) of the above alcohol in 50 mL of THF, under argon at 0°C, was added 7.3 g (108 mmol) of imidazole and 16.7 g (64 mmol) of triphenylphosphine. This mixture was stirred for 45 min (solution became homogeneous) at which time 16.2 g (64 mmol) of iodine in 50 mL of THF was added dropwise over 20 min. The reaction was stirred for 1 h, diluted with hexanes and washed with 1U sodium bisulfite, N 2 Cθ 3 , brine and dried ( a 2 S0 4 ) . The resulting residue was triturated with ether (3x) , filtered (to remove triphenylphosphine oxide) and evaporated to provided 10 g (61%) of title iodobutane as a pale yellow oil. To a stirred solution of diisopropy1amine (0.95 L, 6.8 mmol) in 10 mL of THF at -5°C under argon was added n-butyllithium solution (2.70 mL, 6.75 mmol, 2.5 M in hexane) and stirred for 15 min. A solution of Part B compound (593 mg, 3.38 mmol) in 5 mL of THF was added over 10 min. The resulting deep orange solution was stirred for 30 min and a solution of Part C l-t-butyldimethyl-silyloxy-4- iodobutane (1.03 g, 3.31 mmol) in 5 mL of THF was added. A light yellow solution forms within 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The organic extracts were combined, dried (Na S0 4 ) and evaporated. Purification by flash chromatography on silica gel gave title compound as a colorless oil, 680 mg, 58%. To a solution of Part D compound (675 mg, 1.73 mmol) in 5 mL of THF at room temperature under argon was added a solution of tetrabutylammonium fluoride (3 mL, 3 mmol, 1 fcj in THF) . After 1 h, the reaction mixture was partitioned between ethyl acetate and 10% citric acid solution. The organic extract was dried (MgS0 4 ) and evaporated. Purification by flash chromatography on silica gel (2.5 x 15 cm column, 1:4 hexanes/ethyl acetate) provided title compound as a colorless oil, 380 mg, 80%. F. To a solution of Part E compound (380 mg, 1.38 mmol) in 5 mL of THF under argon at room temperature was added triphenylphosphine (365 mg, 1.39 mmol) and imidazole (210 mg, 3.0 mmol) and then iodine (360 mg, 1.39 mmol) in 5 mL of THF. After 15 min, the reaction was quenched with 5% NaHS0 3 solution and extracted with ether. The organic extract was dried (MgS0 ) and evaporated. Purification by flash chromatography on silica gel (5 x 15 cm column, 5:7 ethyl acetate/hexanes) gave title compound as a colorless oil, 442 mg, 83%. G. 2,3-Dihydro-l- [4- [4- (2,3-dihydro-l-oxo- lH-isoindol-2-y.l) -1-piperidinyl]butyl] -N- nronvl-lH-indene-l-carboxamidp To a stirred solution of Part F compound (430 mg, 1.12 mmol) in 5 mL of DMF at room temperature under argon was added Example 1 Part G compound (265 mg, 1.23 mmol). The reaction was heated to 50°C. After 14 h, the reaction was quenched with 10% NaHS0 3 solution and extracted with ethyl acetate. The organic extract was dried (MgS0 ) , evaporated and re- evaporated twice from toluene. Purification by flash chromatography on silica gel (2.5 x 15 cm column, 1:9 methanol/ethyl acetate) gave title compound as a colorless amorphous solid, 425 mg, 88%. IR (thin film) 3470, 2940, 1680, 1660, 1530, 1510, 1470, 1455, 740 cm" 1 . Calculated for C 3 oH 3 9 3 0 2 -»0.94 H 2 0: C, 73.45; H, 8.30; N 8.57 Found: C, 73.44; H, 8.11; N 8.47. MS (electrospray, + ions) m/e 474 (M+H) . λ H NMR (CDC1 3 , 300 MHz) δ 7.83 (d, IH, J = 7.3 Hz) 7.52-7.44 (m, 3H) 7.30-7.23 (m, 4H) 5.53 (t, IH, J = 5.5 Hz) 4.35 (s, 2H) 4.30 (5-plet, IH, J = 5.3 Hz) 4.01 (dd, IH, J = 7.2, 7.8 Hz) 3.13 (m, 2H) 3.04 (d, 2H, J = 9.8 Hz) 2.92 (t, 2H, J = 6.7 Hz) 2.50 (5-plet, IH, J = 5.5 Hz) 2.38 (t, 4H, J = 7.7 Hz) 2.18-1.84 (m, 9H) 1.56-1.35 ( , 6H) 0.81 (t, 3H, J = 7.4 Hz) ppm. Example 27 l-[4-[4-(2,3-Dihydro-l-oxo-lH-isoindol-2-yl) -1- piperidinyl]butyl] -2-phenyl-N-propyl-lH-indene-1• carboxamide OSiPh 2 tBu To a slurry of sodium hydride (6.975 g, 60% mineral oil dispersion, 0.174 mol) in 200 mL of THF at room temperature under argon was added 2-butene- 1,4-diol (15.36 g, 0.174 mol) over 20 minutes. Gas evolved and a thick precipitate formed. The slurry was stirred for 16 h and then was rapidly treated with t-butyl diphenylchlorosilane (47.82 g, 0.174 mol) . The reaction warms to 40°C autogenously and a clear solution formed. After 15 min, the reaction was quenched with water and extracted twice with hexanes. The organic layers were combined, dried (Na 2 S0 4 ) and evaporated. Purification by flash chromatography on silica gel (12 x 30 cm column, dichloromethane) gave title compound as a colorless oil, 46.6 g, 82%. B AcO— — OSiPh 2 tBu To a stirred solution of Part A compound (6.53 g, 20.0 mmol) and triethylamine (3.53 mL, 25.3 mmol) in 50 mL of dichloromethane at room temperature under argon was added acetic anhydride (2.4 mL, 22.5 mmol) and DMAP (20 mg, 0.16 mmol). The reaction was evaporated at less than 30°C and the residue partitioned between 10% citric acid and hexanes. The organic layer was washed with water and saturated sodium bicarbonate solution, dried (Na 2 S0 4 ) and evaporated. The isolated colorless oil, (7.02 g, 95%) , was used without further purification in Part F. Anhydrous cerium chloride (16.00 g, 64.9 mmol) was stirred in an evacuated flask heated in an oil bath to 145°C for 2 h. The flask is flooded with argon, cooled to room temperature and then to 0°C in an ice bath. To this powder was added 150 mL of THF. The stirred slurry was warmed to room temperature. After 14 h, the flask was again cooled to 0°C and phenylmagnesium chloride solution (21.2 mL, 63.6 mmol, 3 H in ether) was added. The resulting yellow slurry was stirred for 1.5 h and then a solution of 2-indanone (5.45 g, 41.2 mmol, freshly chromatographed) was added. After 30 min, the reaction mixture was quenched with 10% citric acid and extracted twice with ether. The organic extracts were dried (MgS0 4 ) and evaporated. Purification by flash chromatography on silica gel (5 x 20 cm column, 17:3 dichloromethane/hexanes) gave title compound as a colorless oil, 6.66 g, 77%. To neat Part C compound (6.40 g, 30.4 mmol) was added potassium bisulfate (6.4 g, 47 mmol) . The mixture was stirred under argon and placed in an oil bath heated to 160°C for 20 min. The resulting solid mass was cooled, partitioned between dichloromethane and water. The organic layer was dried (MgS0_*) and evaporated to provide title compound (5.84 g, 100%) as a white solid, mp 163-164°C. To a solution of Part D compound (1.481 g, 7.70 mmol) in 20 mL of THF at 0°C under argon was added n-butyllithium (3.0 mL, 7.50 mmol, 2.5 ϋ in hexanes) over 10 min. The resulting deep orange solution was stirred for Ih. The reaction was quenched with several small pieces of THF-washed dry ice. The resulting thick yellow slurry was stirred for 1 h and then treated with 20 mL of 2 M potassium hydroxide solution. This solution was extracted twice with ether and the aqueous residue was brought to pH 2 with 3 sulfuric acid. The mixture was extracted three times with ethyl acetate, the extracts combined, dried (MgS0 4 ) and evaporated to give title compound as a light yellow powder (1.50 g, 82%) , mp 212-215°C. F . A mixture of Part E compound (890 mg, 3.77 mmol), Part B compound (2.55 g, 3.77 mmol) and triphenylphosphine (190 mg, 0.724 mmol) was evaporated twice from toluene. The mixture was dissolved in 20 mL of THF, stirred under argon and treated with bis (trimethylsilyl)acetamide (BSA) (3.7 mL, 15 mmol). After 30 min, tetrakis (tri¬ phenylphosphine)palladium(0) (430 mg, 0.39 mmol) was added and the reaction set to reflux. After 16h, the orange solution was cooled, evaporated and re- evaporated twice from methanol. The gummy residue was dissolved in ether and washed once with 10% - citric acid. The organic extract was dried (MgS0 ) , evaporated and re-evaporated once from toluene. To a stirred solution of this product in 10 mL of dichloromethane under argon at room temperature was added oxalyl chloride (0.9 mL, 7.0 mmol) and then DMF (0.05 mL) . After 1 h, the reaction was evaporated to give an orange oil which was dissolved in 10 mL of THF. This solution was added to a stirred solution of n-propylamine (1.4 mmol, 16 mmol) in 10 mL of THF at 0°C over 10 min. After lh, the reaction mixture was diluted with ether and washed once with 10% citric acid. The organic extract was dried (MgS0 4 ) and evaporated. Purification by flash chromatography on silica gel (5 x 20 cm column, dichloromethane) gave title compound as an orange oil, 1.50 g, 77%. To a stirred solution of Part F compound (2.15 g, 4.18 mmol) in 15 mL of THF at room temperature under argon was added tetrabutylammonium fluoride (10 mL, 10 mmol, 1 M in THF) . After lh, the reaction was quenched with brine and extracted three times with ethyl acetate. The organic extract was dried (MgS0 4 ) and evaporated. Purification by flash chromatography on silica gel (5 x 15 cm column, 3:2 hexanes/ethyl acetate) gave title compound as a colorless glass, 1.09 g, 75%. H. To a solution of Part G compound (209 mg, 0.60 mmol) in 10 mL of ethanol at room temperature purged with argon was added 5% Pd-C (45 mg) . The flask is evacuated and purged with argon twice and with hydrogen from a baloon and stirred under a hydrogen atmosphere for 30 min. The reaction was filtered through Celite and the filtrate evaporated. Purification by flash chromatography (2.5 x 15 cm column, 1:1 hexanes/ethyl acetate) gave title compound as a white foam, 92 mg, 44%. To a stirred solution of Part H compound (90 mg, 0.26 mmol) in 2 mL of THF at room temperature under argon was added triphenylphosphine (68 mg, 0.26 mmol) and imidazole (40 mg, 0.57 mmol) and then iodine (65 mg, 0.26 mmol) in 2 mL of THF. After 10 min, the reaction was quenched with 10% NaHS0 3 solution and extracted with ether. The organic extract was dried (MgS0 4 ) and evaporated. Purification by flash chromatography on silica gel (2.5 x 15 cm column, dichloromethane) gave title compound as a white solid, 87 mg, 73%, mp 125-127°C. J. 1- [4- [4- (2, 3-Dihydro-l-oxo-lH-isoindol- 2-yl) -l-piperidinyl]butyl] -2-phenyl-N- ropyl-lH-indene-1-carboxamide To a stirred solution of Part I compound (74 g, 0.161 mmol) in 2 mL of DMF at room temperature under argon was added Example 1 Part G compound (40 mg, 0.181 mmol). The reaction was heated to 50°C. After 14 h, the reaction was quenched with 10% NaHS0 3 solution and extracted with ethyl acetate. The organic extract was dried (MgS0 4 ) , evaporated and re- evaporated twice from toluene. Purification by flash chromatography on silica gel (2.5 x 15 cm column, 1:12 methanol/ethylacetate) gave title compound as a white solid, 80 mg, 91%, mp 156-57°C. IR (KBr pellet) 3326, 2942, 2863, 1678, 1622, 1512, 1454, 1302, 737 cm' 1 . MICROANALYSIS Calculated for C 36 H 4 ιN 3 0 -1.17 H 2 0: C, 76.02; H, 7.68; N 7.39 Found: C, 76.02; H, 7.43; N 7.30. Example 28 trans-2,3-Dihydro-1- [4- [4- (2,3-dihydro-l-oxo-lH- isoindol-2-yl) -1-piperidinyl]butyl] -2-phenyl-N- propvl-lH-indene-l-carboxamide To a solution of 682 mg (1.34 mmol) of compound Example 27 Part F in 10 mL of ethanol at room temperature was added 2 g (32 mmol) of ammonium formate. The slurry was stirred and purged with nitrogen for 20 min. After adding 10% palladium-on- carbon (1 g) , the reaction was stirred under argon for 16 h. The reaction mixture was filtered through Celite ® , washing with ethyl acetate. The filtrate was washed twice with water and once with brine, dried (MgS0 4 ) and evaporated. Purification by flash chromatography on silica gel (5 x 15 cm column, 1:99 ether/dichloromethane) gave title compound as a colorless oil, 354 mg, 52%. B . To a stirred solution of Part A compound (315 mg, 0.534 mmol) in 3 mL of THF at room temperature under argon was added tetrabutylammonium fluoride (1.0 mL, 1.0 mmol, 1 M in THF). After lh, the reaction was quenched with brine and extracted three times with ethyl acetate. The organic extract was dried (MgS0 ) and evaporated. Purification by flash chromatography (2.5 x 15 cm column, 3:5 hexanes/ethyl acetate) gave title compound as a white foam, 135 mg, 72%. To a stirred solution of Part B compound (127 mg, 0.361 mmol) in 2 mL of THF at room temperature under argon was added triphenylphosphine (95 mg, 0.36 mmol) and imidazole (60 mg, 0.86 mmol) and then iodine (92 mg, 0.36 mmol) in 1 mL of THF. After 15 min, the reaction was quenched with 5% NaHS0 3 solution and extracted with ether. The organic extract was dried (MgS0 ) and evaporated. Purification by flash chromatography (2.5 x 15 cm column, dichloromethane) gave title compound as a colorless glass, 101 mg, 61%. D. trans-2, 3-Dihydro-l- [4- [4- (2, 3-dihydro- l-oxo-lH-isoindol-2-yl) -1-piperidinyl] - butyl] -2-phenyl-N-propyl-lH-indene-1- carbQxamid, To a stirred solution of Part C compound (100 mg, 0.217 mmol) in 3 mL of DMF at room temperature under argon was added Example 1 Part G compound (54 mg, 0.244 mmol) . The reaction was heated to 50 °C. After 14 h, the reaction was quenched with 10% NaHS0 3 solution and extracted with ethyl acetate. The organic extract was dried (MgS0 4 ), evaporated and re- evaporated twice from toluene. Purification by flash chromatography on silica gel (2.5 x 15 cm column, 1:9 hexane/ethyl-acetate) gave title compound as a light yellow amorphous glass, 105 mg, 88%. IR (KBr pellet) 3432, 2934, 2872, 1676, 1516, 1470, 1454, 766, 737 cm" 1 . MICROANALYSIS Calculated for C 36 H 43 N 3 0 2 •1.54 H 2 0: C, 74.87; H, 8.04; N 7.64 Found: C, 74.88; H, 7.82; N 7.33. MS (electrospray, + ions) m/e 550.5 (M+H) 1 H NMR (CDC1 3 , 300 MHz) δ 7.82 (d, IH, J = 7.3 Hz) 7.51-7.14 ( , 12H) 5.66 (t, IH, J = 5.2 Hz) 4.33 (m, 2H) 4.26 (dd, IH, J = 0.7, 3.6 Hz) 4.01 (dd, IH, J = 7.2, 7.8 Hz) 3.28 ( , 4H) 2.95 (d, 2H, J = 10.7 Hz) 2.24 (m, 2H) 2.12 (t, 2H, J = 11.1 Hz) 1.80 (m, 4H) 1.53-1.16 (m, 8H) 0.88 (t, 3H, J = 7.3 Hz) ppm. Additional compounds falling within the scope of the present invention are described by the following structures. Substituents for each example are identified in the table following each structure. Examples Table A where R lx is (R"=C 3 H7 or CF3CH2) R» R H H -o " Cl H H H H .-o H P ci H H .-•-o -131 - Table A (continued) Table B where R lx is (a) , (b) or (c) as in Table A Examples of Q cyclohexylO 0 Table B (continued) Examples of Q Examples of R 1 pyl, CF 3 CH 2 - X for Table C = H or F Example of R OMe lable_E Example of R X Table E (Conr d_ Tab \. F <- .z <~ Fluorenyl-Type Compounds = R = propyl or CF 3 CH 2 Fluorenyl-Type Rings: Z = G = CH 2 , O, S, SO, S0 2 Table G <-o Indenyl-Type Compounds R = propyl or CF 3 CH 2 Indenyl-Type Rings: Z = Table G . conf d. Indenyl-Type Rings: Z = Table H Example of R In the foregoing Tables which set out compounds of the invention of formulae I and II, that is compounds which include the 4-substituted piperidine isomers, it will be understood that the formulae I and II compounds may be substituted with compounds of the invention of formulae Ii and Hi, that is compounds which include the 3-substituted piperidine isomers. Example 29 cis-9- [4- [4- (2, 3-Dihydro-lH-isoindol-2-yl) -1-piper- idinyl]butyl] -N-propy1-9H-fluorene-9-carboxamide, N-oxide A slurry of 3-chloroperoxybenzoic acid (approx. 50%) (341 mg, 0.99 mmol) in CH2CI2 (1 mL) was added dropwise to a solution of Example 1 compound (524 mg, 0.99 mmol) in CH2CI2 (1 mL) at 0°C under argon. The reaction was stirred at 0'C for 20 min, diluted with CH2CI2 (15 mL) , washed with saturated NaHCC-3 (5 mL) and brine (5 mL) , then dried over MgS04. Evaporation gave 612 mg of a white foam, which was purified by flash chromatography on silica gel (75 g) eluting with a step gradient of 4% to 5% to 7% to 10% MeOH/CH2Cl2 to give title compound (308 mg, 58%) as a white foam. MS (ES) : 538 [M+H] Anal. Calcd. for C34H39N3O3 • 1.5 H2O: C, 72.29; H, 7.50; N, 7.44 Found: C, 72.32; H, 7.28; N, 7.41. Example 30 2-[1-[4-[9-(Butylsulfonyl)-9H-fluoren-9-yl]butyl] 4-piperidinvll -2.3-dihvdro-lH-isoindol-l-one A. A solution of 9-hydroxy- (9H) -flourene (1.58 g, 10.0 mmol) and butanethiol (0.72 g, 8.00 mmol) in 10 mL of dichloromethane at -20°C was treated with borontrifluoride etherate (1.28 g, 9.00 mmol) . The reaction was stirred for 1 h at -20°C and warmed to room temperature. After stirring for 18 h the contents of the flask were purified by column chromatography on silica gel (100 g) with hexanes followed by 1:9 dichloromethane/hexanes to give 1.54 g (75%) of title compound as a colorless oil. TLC Silica gel (1:9 dichloromethane/hexanes) Rf= 0.5. B_ A solution of Part A compound (1.0 g, 3.93 mmol) in 10 mL of THF at -78°C was treated with n- butyllithiu in hexanes (1.75 mL, 4.40 mmol) followed by l-chloro-4-bromo-butane (0.81 g, 4.70 mmol). The reaction was stirred for 0.5 h and warmed to room temperature for 18 h. The contents of the flask were diluted with 30 L of aqueous H4CI solution and 30 mL of ethyl acetate. The organic fraction was dried (Na2Sθ4) and concentrated. The remainder was purified by column chromatography on silica gel (50 g) with 2:98 acetone/dichloromethane (500 mL) followed by 15:85 dichloromethane/hexanes to give 1.00 (73%) of title compound as a colorless oil. TLC Silica gel (2:8 dichloromethane/hexanes) Rf= 0.4. Mass Spec. (ES, + ions) m/e 255 (M-SC4H9). C. To a solution of Part B compound (0.30 g, 0.86 mmol) in dichloromethane (5 mL) at 0°C was added 3- chloroperoxybenzoic acid (m-CPBA) (0.37 g, 80% by weight - 0.1.72 mmol) in one portion. The mixcure was stirred for 1 h when it was diluted with 0.L M K2CO3 (20 mL) and ether (30 mL) . The organic fraction was dried (Na2Sθ4) and concentrated. The remainder was purified by column chromatography on silica gel (50 g) with 15:85 ethyl acetate/hexanes to give 0.24 g (75%) of title compound as a colorless oil. TLC Silica gel (2:8 dichloromethane/hexanes) Rf= 0.07. To a solution of Part C compound (0.24 g, 0.64 mmol) in 2-butanone (10 mL) at RT was added Nal (1.00 g, 6.66 mmol) in one portion. The mixture was refluxed for 30 h when it was diluted with water (20 mL) and ether (30 mL) . The organic fraction was dried (Na2Sθ4) and concentrated. The remainder was purified by column chromatography on silica gel (50 g) with 15:85 ethyl acetate/hexanes to give 0.24 g (81%) of title compound as a colorless oil. E. 2-[l-[4-[9- (Butylsulfonyl) -9H-fluoren-9- yl]butyl]-4-piperidinyl]-2,3-dihydro-1H- isojndQi-i-pne To a stirred solution of 0.70 g (1.49 mmol) of Part D compound in 6 mL of DMF at RT was added 0.38 g (1.80 mmol) of Example 1 Part G compound. The. reaction mixture was warmed to 55°C and allowed to stir for 24 h. The mixture was diluted with NaHCθ3 solution (50 mL) and ethyl acetate (50 mL) . The layers were separated, the organics dried (Na2S04) and concentrated. The remainder was purified by flash column chromatography on silica gel (100 g) eluting with 5:95 methanol/dichloromethane (700 mL) followed by 5:95:0.5 methanol/dichloromethane/NH3 (IL) . Pure fractions were pooled and concentrated to give 0.70 g (85%) of title compound as a thick oil which solidified after standing. mp : 130 -132°C . TLC Silica gel (5:95:1 methanol/dichloromethane/NH3) Rf= 0.35. Anal. Calcd. for C34H40N2SO3 + 0.5 H2O: C, 72.79; H, 7.30; N, 4.96; S, 5.68 Found: C, 72.25; H, 7.15; N, 5.00; S, 5.69. Example 1 9- [4- [ [4- [ (1, 1-Dimethylethoxy)carbonyl]amino] -1- piperidinyl]butyl] -2,7-difluoro-N- (2, 2,2-trifluoro- ethyl) -9H-f uorene-9-carboxamide A Solution of Example 3 Part B compound (8.00 g, 32.5 mmol) in 100 mL of THF at room temperature was carefully evacuated and then purged with argon four times. The stirred solution was cooled to -25°C and a solution of n-butyllithium (26.5 mL, 2.5 M in hexanes, 66.3 mmol) was added over 15 min. The resulting slurry was stirred for 1 h and cooled to -78°C. Neat dibromobutane (6.0 mL, 50.0 mmol) was added in one portion and the reaction was allowed to warm to room temperature over the course of 6 h. After an additional 14 h, the reaction mixture was poured into 1 E hydrochloric acid (70 mL) and extracted twice with ethyl acetate. The combined organic extracts were dried (Na2Sθ4) and evaporated. The semi-solid residue was triturated with hexanes and filtered to give 11.32 g of an off-white solid. To a slurry of the above solid (11.0 g) in 25 mL of dichloromethane at room temperature under argon was added a solution of oxalyl chloride (25 mL, 2.0 M in dichloromethane, 50 mmol) followed by 0.5 mL (6.0 mmol) of DMF. After 1 h, the reaction was evaporated at less than 25°C and the residue redissolved in 30 mL of THF. This solution was added over 20 min to a solution of 2,2,2-trifluoroethyl amine (6.10 g, 61.5 mmol) in 25 mL of THF at -10 ' °C under argon. After 2 h, the reaction was quenched with 10% citric acid solution and extracted twice with ethyl acetate. The organic extract was dried (Na2Sθ4) and evaporated. Purfication by flash chromatography (12 x 20 cm column, 7:3 dichloromethane/hexanes as elutant) on silica gel provided title compound as a white solid, 9.03 g, 60% yield from Example 3 Part B compound, mp 147-148°C. B. 9-[4- [ [4- [ (1, 1-Dimethylethoxy)carbonyl] - amino] -1-piperidinyl]butyl] -2,7-difluoro-N- (2,2,2-trifluoroethyl) -9H-fluorene-9- c fl rbp;xaiT_ide To a stirred solution of Part A compound (5.48 g, 11.9 mmol) in 20 mL of DMF at room temperature under argon was added Example 10 Part B compound (2.85 g, 14.2 mmol). The reaction was heated to 50°C. After 14 h, the reaction was quenched with 10% NaHS03 solution and extracted with ethyl acetate. The organic extract was dried (MgSθ4) , evaporated and re-evaporated twice from toluene. Purification by flash chromatography on silica gel (2.5 x 15 cm column, ethyl acetate elutant) gave title compound, as a white solid, 6.23 g, 90%, mp 152-154°C. Example 32 9- [4- [4- [ (2-Phenoxybenzoyl)amino] -1-piperidinyl] - butyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9- carboxamide. monohydrochloride Following the procedure in Example 12 Part B, 2-phenoxybenzoic acid (2.0 g, 9.34 mmol) was transformed into the acid chloride then reacted with Example 36 Part D compound (4.84 g, 9.34 mmol) to give a white solid (5.0 g) . The product was dissolved in MeOH (5 mL) , then 0.77M HCl in ethyl ether (15 mL) was added. The solution was evaporated and heated in a vacuum oven (55°C) overnight to give title compound (5.1 g, 82%) as a white solid. m.p. 123-127°C. MS (ES, + ion) : 656 (M+H) . Anal. Calc. for C38H39CIF3N3O2 • 0.7 H2O: C, 66.07; H, 5.90; N, 6.08; F, 8.25 Found: C, 66.05; H, 5.97; N, 5.96; F, 8.21. Example 33 9- [4- [ [4- (Benzoylamino)-1-piperidinyl]butyl] -2,7- difluoro-N-(2,2,2-trifluoroethyl) -9H-fluorene-9- carbgκaιr.i<ae A solution of Example 31 compound (2.07 g, 3.56 mmol) in 10 mL of 4 U hydrogen chloride in dioxane was stirred, protected by a calcium chloride drying tube, for 3 h. The solution was evaporated at 30°C and the resulting solid was re-dissolved in 20 mL of THF. To this stirred solution, cooled to -10°C under argon, was added triethylamine (1.24 mL, 8.9 mmol) and then benzoyl chloride (0.46 mmol, 4.0 mmol) over 10 min. After 1 h, the reaction was quenched with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The organic extract was dried (Na2Sθ4) and evaporated. Purfication by flash chromatography on silica gel (5 x 20 cm column, 1:19 methanol/ethylacetate as elutant) provided, after recrystallization from ethyl acetate/hexanes, title compound as a white solid, 1.83 g, 87% yield, mp 177-179°C. Anal. Calc'd for C32H32F5N3O2»0.25 H2O: C, 65.13; H, 5.55; F, 16.10; N, 7.12 Found: C, 65.10; H, 5.49; F, 15.85; N, 7.12. MA ( electrospray, + ions ) m/e 586 (M+H) . Examole 34 9-[4- [ [4-(l,3-Dihydro-l,3-dioxo-2H-isoindol-2-yl) -1- piperidinyl] butyl] -2 , 7-dif luoro-N- (2, 2 2-tri- luoroethyl -9H-f luorene-9-carboxaπ.idg A solution of Example 31 compound (2.02 g, 3.47 mmol) in 10 mL of 4 £1 hydrogen chloride in dioxane was stirred, protected by a calcium chloride drying tube, for 3 h. The solution was evaporated at 30 °C and partitioned between saturated sodium bicarbonate solution and dichloromethane. The organic layer was separated, dried (Na2S04) and evaporated to give a white solid. To this residue was added 550 mg (3.71 mmol) of phthalic anhydride under an argon atmosphere. The solids were melted together at 150°C for 6 h. On cooling, the resulting solid was recrystallized from ethyl acetate/hexanes to give title compound as a white solid, 1.71 g, 80% yield, mp 186-188°C. Anal. Calc'd for C38H36F5N3O3-0.13 H2O: C, 64.56; H, 4.94; N 6.87 Found: C, 64.56; H, 5.03; N 6.81. MS (electrospray, + ions) m/e 612.2 (M+H) . Example 35 2,7-Difluoro-9- [4- [ [4-[ (2-phenoxybenzoyl)amino]-1- piperidinyl]butyl] -N- (2,2,2-trifluoroethyl) -9H- fluorene- -carboxamide To a solution of 565 mg (2.64 mmol) of 2- phenoxybenzoic acid (Aldrich) in 10 mL of dichloro¬ methane under argon, was added 2 mL of oxalyl chloride (2.0 M in dichloromethane, 4.0 mmol) and then 0.1 mL of DMF. After 1 h, the reaction was evaporated and the residue, 2-phenoxybenzoyl chloride, was redissolved in 10 mL of THF. A solution of Example 31 compound (1.00 g, 1.76 mmol) in 10 mL of 4 ϋ hydrogen chloride in dioxane was stirred, protected by a calcium chloride drying tube, for 3 h. The solution was evaporated at 30°C and the resulting solid was re-dissolved in 10 mL of THF. To this stirred solution, cooled to -10°C under argon was added triethylamine (0.95 mL, 6.5 mmol) and then the 2-phenoxybenzoyl chloride solution prepared above over 10 min. After 1 h, the reaction was quenched with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The organic extract was dried ( a2S04) and evaporated. Purfication by flash chromatography on silica gel (5 x 20 cm column, 1:19 methanol/ethylacetate as elutant) provided, after recrystallization from ethyl acetate/hexanes, title compound as a white solid, 1.01 g, 85% yield, mp 168-69°C. Anal. Calc'd for C38H36F5N3O3 : C, 67.35; H, 5.35; F, 14.02; N 6.20 Found: C, 67.20; H, 5.35; F, 14.33; N 6.08. MS (electrospray, - ions) m/e 676.3 (M-H) . Example 36 9-[4-[4-(Benzoylamino) -l-piperidinyl]butyl] -N- (2,2, 2-trifluoroethyl) -9H-fluorene-9-carboxamide, monohydrochloride A. To a solution of 9-fluorenecarboxylic acid (50 g, 240 mmol) in THF (1200 mL) at 0°C was added dropwise a solution of n-butyllithium (2.5M, 211 mL, 530 mmol) in THF. The yellow reaction was stirred at 0°C for 1 h, then 1,4-dibromobutane (31.3 mL, 260 mmol) was added dropwise over 30 min. The reaction was stirred at 0°C for 30 min, then the reaction was warmed to RT for 30 h. The reaction was extracted with water (3 x 750 mL) . The combined aqueous layers were extracted with ethyl ether (800 mL) . The aqueous layer was made acidic with HCl solution (IN, 500 mL) , then extracted with dichloromethane (3 x 750 mL) . The combined organic layers were dried over MgSθ4. Evaporation gave title compound (71 g, 85%) as a white solid. B. To a solution of Part A acid (60 g, 173 mmol) and DMF (100 μL) in CH2CI2 (600 mL) under argon at 0 * C was added oxalyl chloride (104 mL, 2.0M in CH2CI2 208 mmol) dropwise. The reaction was stirred at O'C for 10 min, then warmed to RT and stirred for 1.5 h. The reaction was concentrated in vacuo to give the crude acid chloride as a yellow oil . To a suspension of 2,2,2-trifluoroethylamine hydrochloride (25.9 g, 191 mmol) in CH2CI2 (500 mL) at 0°C under argon was added triethylamine (73 L, 521 mmol) followed by dropwise addition of a solution of the crude acid chloride in CH2CI2 (15 mL) . The reaction was stirred at 0°C for 1 h, diluted with CH2CI2 (500 mL) , and washed with water (2 x 300 mL) , IN HCl (2 x 300 mL) , saturated NaHCθ3 (2 x 300 mL) , and brine (2 x 300 mL) , then dried over MgSθ4. Evaporation gave 80 g of a oil which was purified by flash chromatography on silica gel (2.5 kg) . The crude product was loaded in a mixture of CH2CI2 and hexane, and eluted with a step gradient of 10% EtOAc/hexane (4L) to 15% EtOAc/hexane (2L) to 20% EtOAc/hexane (4L) . Pure fractions were combined and evaporated to give title compound (52.5 g, 71%) as a white solid (mp 88-92°C) . A mixture of Part B compound (29.5 g, 69.2 mmol), Example 10 Part B compound (14.5 g, 72.7 mmol), and anhydrous potassium carbonate (11.5 g, 83.0 mmol) in DMF (100 mL) was stirred at 50 * C for 48 h, concentrated to dryness, and taken up in CH2CI2 (500 mL) . The solution was washed with saturated NaHC03 (3 x 80 mL) and brine (2 x 80 mL) , then dried over MgS04. Evaporation gave a yellow oil which was purified by flash chromatography on silica gel (600 g) , loaded in CH2CI2, and eluted with a step gradient of 2% MeOH/CH2Cl2 (3L) to 3% MeOH/CH2Cl2 (4L) . Pure fractions were combined and evaporated to give title compound (30 g, 86%) as a white foamy gum. To a solution of Part C compound (30.5 g, 60.4 mmol) in dioxane (120 mL) was added 4N HCl in dioxane (121 mL, 483 mmol) . The reaction was stirred at RT for 4 h, then concentrated in vacuo to provide title compound (30 g) as a white foamy solid, containing a residual amount of dioxane. E. 9- [4- [4- (Benzoylamino) -1-piperidinyl] - butyl] -N-(2, 2,2-trifluoroethyl) -9H-fluorene- -carboxamide. monohydrochloride To a solution of Part D compound (1.6 g, 3.08 mmol) and triethylamine (1.5 mL, 10.8 mmol) in dichloromethane (10 mL) at 0°C was added dropwise benzoyl chloride (0.4 mL, 3.40 mmol). The reaction was stirred at 0°C for 30 min. Dichloromethane (200 mL) was added and the solution was washed with water (2 x 50 mL) , brine (2 x 50 mL) and dried over MgSθ4. Purification was performed by flash chromatography on silica gel (100 g) , loaded and eluted with 2.5% methanol in dichloromethane. Pure fractions were combined and evaporated to give a white solid. The product was dissolved in methanol (5 mL) and a solution of HCl in ethyl ether (0.77N, 5.19 mL) was added. The reaction was stirred at RT for 10 min, then evaporated to dryness. After drying in a vacuum oven (65°C, 72 h) , title compound was obtained (1.3 g, 72%) as a white solid. m.p. 132-137°C. MS (Cl, +ion) : 550 (M+H). Anal. Calc. for C32H35CIF3N3O2 • 0.2 H2O: C, 65.18; H, 6.05; N, 7.13; Cl, 6.01; F, 9.66 Found: C, 65.45; H, 6.06; N, 6.88; Cl, 5.16; F, 9.30. Example 37 2 , 3 -Dihydro-2- [1- [4- [ 9- (1 -oxopentyl ) -9H-f luoren-9- yl ] butyl ] -4-piperidinyl ] -lH-isoindol-1-one , mono- hvrirochloride A. OTBS A ( l ) __ __ OTBζ HO^^^^ (TBS IS SI(CH 3 ) t-Bu) To a solution of 49 mL (0.55 mol) of 1,4- butanediol in 25 mL of DMF, under argon at 0°C, was added 10.5 g (0.15 mol) of imidazole followed by 20.7 g (0.14 mol) of t-butyldimethylsilyl chloride. The reaction was slowly warmed to RT and stirred for 18 h at which time the reaction was diluted with ether and washed with NH4CI, water, Na2C03, brine and dried (MgS04) . The resulting title compound in the form of a colorless liquid, 50 g, contained approximately 15% of the disilylated compound. A(2) . OTBS To a solution of 8.5 g (42 mmol) of Part A(l) compound in 50 mL of THF, under argon at 0°C, was added 7.3 g (108 mmol) of imidazole and 16.7 g (64 mmol) of triphenylphosphine. This mixture was stirred for 45 min (solution became homogeneous) at which time 16.2 g (64 mmol) of iodine in 50 mL of THF was added dropwise over 20 min. The reaction was stirred for 1 h, diluted with hexanes and washed with 1M sodium bisulfite, Na2C03, brine and dried (Na2S04) . The resulting residue was triturated with ether (3x) , filtered (to remove triphenylphosphine oxide) and evaporated to provided 10 g (61%) of title compound as a pale yellow oil. TLC Silica gel (4:1 hexanes/ethyl acetate) Rf = 0.60. B. To a solution of 5 g (23.78 mmol) of 9- fluorenecarboxylic acid (Aldrich) in 20 mL of THF, under argon at 0°C, was added 20.6 L (52.32 mmol) of n-butyllithium (2.5 $2 in hexanes) dropwise. The orange-red anion was stirred for 0.5 h, at which time _^_^ _ _.OTBS 7.5 g (23.78 mmol) of ' (prepared as described in Part A) was added dropwise. The reaction gradually warmed to RT and was stirred for 36 h, at which time it was diluted with a 1:1 mixture of ethyl acetate/H2θ (250 mL) . The organics were washed with NaHC03, brine, dried (Na2Sθ4) and evaporated. Flash chromatography was performed on 250 g of silica gel eluting with 9:1 dichloromethane/ isopropanol to provide 4.9 g (52%) of title compound as a yellow oil. TLC: Silica gel (9:1 dichloromethane/isopropanol) Rf = 0.50. To 550 mg (1.38 mmol) of Part B compound was added 5 mL of DMSO. The reaction was stirred for 18 h, under argon at RT, at which time it was diluted with ether and washed with water (3x) . Flash chromatography was performed on 100 g of silica gel eluting with 95:5 hexanes/ethyl acetate to provide 340 mg (70%) of title compound as a pale yellow oil. TLC: Silica gel (95:5 hexanes/ethylacetate) Rf = 0.31. D. To a solution of 340 mg (0.96 mmol) of Part C compound in 3 mL of THF, under argon at 0°C, was added dropwise 462 mL (1.16 mmol) of n-butyllithium (2.5 U in hexanes). The resulting anion was stirred for 0.5 h, at which time 140 mL (1.16 mmol) of freshly distilled valeryl chloride (Aldrich) was added dropwise. The reaction was stirred for 2 h, at which time it was diluted with ether and quenched with NaHC03. The organics were washed with water, brine, dried (NaS04) and evaporated. Flash chromatography was performed on 100 g of silica gel eluting with 95:5 hexanes/dichloromethane to provide 290 mg (69%) of title compound as a pale yellow oil. TLC: Silica gel (95:5 hexanes/ethyl acetate) Rf = 0.36. MS ( CI -NH3 , + ions ) m/ e 397 (M+H ) . Anal. Calcd. for C24H32θ3≤i + 0.15 mol H2O: C, 72.20; H, 8.15 Found: C, 72.20; H, 7.88. To 200 mg (0.46 mmol) of Part D compound was added 1 mL of 5:95 aqueous HF/acetonitrile. The reaction was stirred under argon at RT, for 3 h, at which time it was diluted with ether and washed with NaHCθ3, water (3x) , brine, dried (MgSθ4) and evaporated. Flash chromatography was performed on 50 g of silica gel eluting with 7:3 hexanes/ethyl acetate to provide 120 mg (81%) of title compound as a pale yellow oil. TLC: Silica gel (8:2 hexanes/ethyl acetate) Rf = 0.15. To a solution of 120 mg (0.37 mmol) of Part E compound in 1.5 mL of THF, under argon at 0°C, was added 55 mg (0.81 mmol) of imidazole followed by 126 mg (0.48 mmol) of triphenylphosphine. The mixture was stirred for 0.5 h, at which time 122 mg (0.48 mmol) of iodine in 1 mL of THF was added dropwise. The reaction was stirred for 1 h at 0°C, 1 h at RT, then diluted with hexanes and washed with fresh sodium bisulfite solution, NaHC03, water, brine, dried (MgS04) and evaporated. Flash chromatography was performed on 25 g of silica gel eluting with 9:1 hexanes/ethyl acetate to provide 130 mg (81%) of title compound as a colorless oil. TLC: Silica gel (9:1 hexanes/ethyl acetate) Rf = 0.40. G. 2,3-Dihydro-2- [1- [4- [9- (1-oxopentyl) -9H- fluoren-9-yl]butyl] -4-piperidinyl] -1H- isoindol-1-one. monohydrochloride To a solution of 130 mg (0.30 mmol) of Part F compound in 1.5 mL of DMF, under argon at RT, was added 20 mg (0.15 mmol) of K2CO3 and 84 mg (0.39 mmol) of Example 1 Part G compound. The reaction was stirred for 18 h, at which time it was poured into water. The precipitate was collected, dissolved into ether, dried (Na2Sθ ) and evaporarted to provide a pale yellow solid. The solid was dissolved in ether and treated with 305 mL (0.30 mmol) of HCl (I B in ether) . The ether was decanted off, the solids collected and dried for 18 h (50°C under vacuum) to provide 115 mg (74%) of title compound as a pale yellow solid. mp 96-100°C. TLC: Silica gel (95:5 dichloromethane/isopropanol + 1% NH4OH) Rf = 0.46. MS (ES; NH4OH, + ions) m/e 521 (M+H) . Anal. Calcd. for C35H40N2O2 HCl + 0.5 mol H2O: C, 74.25; H, 7.48; N, 4.95 Found: C, 74.24; H, 7.45; N, 4.98. Example 3ft 2,3-Dihydro-2-[1- (1-oxo-3, 3-diphenylpropy1) -4- piperidinyl] -lH-isoindol-1-on To a solution of 3, 3-diphenylpropionic acid (500 mg, 2.21 mmol) and DMF (1 drop) in dichloromethane (5 mL) at RT was added dropwise a solution of oxalyl chloride in dichloromethane (2.0M, 1.66 mL, 3.32 mmol). Bubbling of escaping gasses continued for 10 min after addition. The reaction was stirred at RT for 60 min, then concentrated in vacuo to give a crude oil. To a solution of crude acid chloride and triethylamine (1.4 mL, 10.0 mmol) in dichloromethane (10 mL) at 0°C under argon was added dropwise a solution of Example 1 Part G compound (434 mg, 2.00 mmol) in dichloromethane (2 mL) . The reaction was stirred at 0°C for 10 min. Dichloromethane (100 mL) was added to dilute the reaction and the resulting solution was washed with H2θ (40 mL) , saturated sodium bicarbonate solution (40 mL) , brine (40 mL) and dried over MgSθ4. Evaporation gave a crude gum. Purification was performed by flash chromatography on silica gel (100 g) , loaded and eluted with 2.5% methanol in dichloromethane. Pure fractions were combined and evaporated to give title compound (610 mg, 72%) as a off-white solid. m.p. 166-169°C. MS (FAB, +ion) : 425 (M+H) Anal. Calc. for C28H28N2O2 • 1.1 H2O: C, 75.68; H, 6.85; N, 6.30 Found: C, 75.50; H, 6.45; N, 6.24. Exampl 39 [1-[4-[9-[ (Propylamino)carbonyl] -9H-fluoren-9-yl] butyl] -3-piperidinyl]carbamic acid, phenylmethyl ester, monohydrochloride A. A mixture of Example 5 Part A compound (2.34 g, 6.90 mmol) and ethyl nipecotate (1.3 mL, 8.28 mmol) in DMF (3.5 mL) under argon was heated at 60 * C for 22 h, then cooled to RT. The solvent was removed under reduced pressure. The resulting orange residue was dissolved in CH2CI2 (50 mL) , washed with saturated NaHC03 (2 x 15 mL) and brine (20 mL) , then dried over Na2Sθ4. Evaporation gave 3.6 g of an orange gum, which was dissolved in a minimal amount of CH2CI2 and purified by flash chromatography on silica gel (175 g) eluting with 2% MeOH/CH2Cl2 to provide 2.65 g of product contaminated with approximately 20 mol% DMF. The product was dissolved in EtOAc (60 mL) , washed with water (3 x 20 mL) and brine (20 mL) , then dried over Na2Sθ4. Evaporation gave title compound (2.38 g, 75%) as an amber oil. B. Palladium on carbon (10%) (273 mg, 0.258 mmol) was added to a solution of Part A compound (2.37 g, 5.15 mmol) in a mixture of EtOAc (10 mL) and EtOH (15 mL) . The mixture was hydrogenated (balloon) at RT for 1.5 h, filtered through Celite, and washed with EtOAc (3 x 20 mL) . The filtrate was concentrated in vacuo to give title compound (2.42 g, 100%) as a pale yellow oil. Aqueous KOH (5.6 mL, IN, 5.6 mmol) was added to a solution of Part B compound (2.17 g, 4.70 mmol) in THF (10 mL) under argon. The biphasic mixture was stirred at RT for 4 h, then heated at 50 * C for 48 h. The reaction was cooled to RT and acidified to pH 1.5 with IN HCl. The cloudy reaction was diluted with water (30 mL) and extracted with CHCI3 (3 x 100 mL) , then dried over Na2S04. Evaporation afforded title compound (2.2 g, 100% crude) as a foamy white solid. D. [l-[4-[9-[ (Propylamino)carbonyl] -9H- fluoren-9-yl] -butyl] -3-piperidinyl]carbamic arid, nhenvl ethvl ester, monohydrochloride To a cloudy suspension of Part C compound -(336 g, 0.714 mmol) and triethylamine (238 μL, 1.71 mmol) in dioxane under argon was added diphenylphosphoryl azide (184 μL, 0.857 mmol) . The mixture was heated at 80 * C for 2 h (N2 evolution observed soon after heating commenced). Benzyl alcohol (367 μL, 3.57 mmol) was added, and the reaction was heated at 80 * C overnight. The reaction was cooled to RT and the solvent was distilled off under reduced pressure. The resulting residue was partitioned between CH2CI2 (20 mL) and saturated NaHCθ3 (5 mL) . The organic layer was washed with brine (5 mL) and dried over Na2S04. Evaporation gave 760 mg of a yellow oil, which was purified by flash chromatography on silica gel (50 g) eluting with 3% MeOH/CH2Cl2 to give 215 mg of a colorless oil. The free amine was dissolved in Et2θ (3 mL) and treated with 0.77N HCl in Et2θ (3 mL) . The white precipitate was filtered, washed with Et2θ (2 x 3 mL) , then dried under high vacuum at 50 * C overnight to give title comound (173 mg, 42%) as a white foamy solid. MS (ES) 540 [M+H] Anal. Calcd. for C34H42CIN3O3 • 0.3 H2O: C, 70.22; H, 7.38; N, 7.23. Found: C, 70.11; H, 7.24; N, 7.09. Example Q 9-[4-[4- (2,3-Dihydro-l-oxo-lH-isoindol-2-yl) -1- piperidinyl]butyl]-N-(2,2,2-trifluoroethyl) -9H- fluorene-9-carboxamide. hydrochloride salt A. To a stirred solution of 10.0 g (33.5 mmol) of compound prepared in Example 5 Part A first paragraph in 100 mL of dichloromethane at RT was added 20.0 mL (40 mmol) of 2M oxalyl chloride in dichloromethane followed by 30 mL of DMF. The reaction was allowed to stir at RT for 2 h when the solvent was evaporated and the semisolid residue pumped (= 1 mm pressure) for 0.5 h. The residue was dissolved by adding 300 mL of ether and cooled to 0°C. The mixture was treated with 7.30 g (67 mmol) of 2,2,2- trifluoroethylamine and warmed to room temperature. The mixture was diluted with 150 mL of ethyl acetate and 100 mL of 0.5 M HCL. The layers were separated, the organics dried ( a2Sθ4) and concentrated. The remainder was purified by flash column chromatography on silica gel (250 g) eluting with 1:9 ethyl acetate/hexanes (800 mL) followed by 1:5 ethyl acetate/hexanes (IL) . Pure fractions were pooled and concentrated to give 9.25 g (73%) of title compound as a white solid. mp: 87-89°C B. To a stirred solution of 6.54 g (17.22 mmol) of Part A compound in 6 mL of DMF at RT was added 4.00 g (18.51 mmol) of Example 1 Part G compound and 2.41 g (17.50 mmol) of K2CO3. The reaction mixture was warmed to 40° and allowed to stir for 20 h. The mixture was diluted with 200 mL of water and 2 mL of 1M NaOH solution (pH = 11) . The white solids were collected by filtration and dried to give 10.0 g (100%) of title compound. TLC Silica gel (5:95:1 methanol/dichloromethane/NH3) Rf= 0.35. ,. β _, - 167- C. 9-[4-[4-(2,3-Dihydro-l-oxo-lH-isoindol- 2- yl)-1-piperidinyl]butyl]-N-(2,2,2-tri- fluoroethvl)-9H-fluorene-9-carboxamide A suspension of 10.00 g (= 17 mmol) of Part B compound in 80 mL of ethanol was treated with 0.5 g of 10% Pd/carbon and placed under an atmosphere of H2 (balloon pressure) . The reaction mixture was stirred for 25 h when it was filtered through a pad of Celite and concentrated. The remainder was triturated with warm water to give 9.0 g (93%) of title compound as a white solid. p: 143-146°C. TLC Silica gel (5:95:1 methanol/dichloromethane/NH3) Rf= 0.35. D. 9-[4-[4- (2,3-Dihydro-l-oxo-lH-isoindol- 2-yl) -1-piperidinyl]butyl] -N- (2,2,2-triflu- oroethyl)-9H-fluorene-9-carboxamide, hydrochloride salt A suspension of 9.00 g (= 16 mmol) of Part B compound in 200 mL of ethyl ether was treated with 8 mL (32 mmol) of 4M HCl in dioxane and the reaction mixture stirred for lh under an atmmosphere of 2. The reaction mixture was filtered and the white solid collected. The solid was dried at 40°C under vaccuum to give 9.0 g (93%) of title compound as a white solid. p: 139-141°C. TLC Silica gel (5:95:1 methanol/dichloromethane/NH3 Rf= 0.35. MS (ES, + ions) m/z 562 (M+H) . - - Anal. Calcd. for C33H35N3O2F3CI: C, 66.27; H, 5.90; N, 7.03; F, 9.53 Found: C, 66.53; H, 5.82; N, 6.78, F, 8.99. Example 9- [4- [4- (2,3-Dihydro-l-oxo-lH-isoindol-2-yl) -1- piperidinyl]butyl] -N- (2,2,2-trifluoroethyl) -9H- fluorene-9-carboxamide. hydrochloride salt A. To a stirred solution of 4.00 g (9.38 mmol) of Example 36 Part B compound in 6 mL of DMF at RT was added 2.44 g (18.51 mmol) of Example 2 Part A compound and 1.59 g (11.30 mmol) of K2CO3. The reaction mixture was warmed to 50°C and allowed- to stir for 18 h. The mixture was diluted with 200 mL of water and 2 mL of 1M NaOH solution (pH=ll) . The white solids were collected by filtration and dried to give 4.50 g of title compound. B. 9- [4- [4- (2,3-Dihydro-l-oxo-lH-isoindol- 2-yl)-1-piperidinyl]butyl] -N- (2,2,2-triflu¬ oroethyl) -9H-fluorene-9-carboxamide, hydrochloride salt A suspension of 4.00 g (= 9.00 mmol) of Part A compound in 200 mL of ethyl ether was treated with 8 mL (32 mmol) of 4M HCl in dioxane and the reaction mixture stirred for lh under an atmosphere of 2. The reaction mixture was filtered and the cream colored solid collected. The solid was dried at 40°C under vacuum to give 3.8 g (73%) of title compound. mp: 139-141°C. MS (ES, + ions) m/z 562 (M+H) . Anal. Calcd. for C33H35N3O2F3CI: C, 66.27; H, 5.90; N, 7.03 Found: C, 65.87; H, 6.14; N, 6.71. Examples 42-50 Following the procedures set out herein, the following compounds were prepared. Example 42 9-[4-[3-(Benzoylamino)-1-piperidinyl]butyl]-N-propyl-9H-fluorene- 9-carboxamide. MS (ES) 510 (M+H) Anal. Calcd. for C33H39N3O2 • 0.2 H2O: C, 77.22; H, 7.74; N, 8.19 Found: C, 77.12; H, 7.58; N, 8.16. Examole 43 9-[4-[3-( 1 ,3-Dihydro- 1 ,3-dioxo-2H-isoindol-2-yl)- 1 -piperidinyl]butyl]-N-propyl- 9H-fluorene-9-carboxamide. MS (ES ) 536 (M+H) Anal. Calcd. for C34H37N3O3 • 0.2 H2O: C, 75.72; H, 6.99; N, 7.79 Found: C, 75.68; H, 6.78; N, 7.68. Example 44 9-[4-[4-(2,3-Di ydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]- N-(2,2,3,3,4,4,4- eptafluorobutyl)-9H-fluorene-9-carboxamide, monohydrochloride. mp: 122-132°C MS (ES, + ions) m/z 662 (M+H) Anal. Calcd. for C35H35O2N3F7CI • 0.8 H2O: C, 59.04; H, 5.17; N, 5.90 Found: C, 59.04; H, 5.04; N, 5.90. Example 45 9-[4-[[4-[(1 ,1-Dimethylethoxy)carbonyl]amino]-1-piperidinyl]butyl]-3,6-difluoι : o- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide. p: 59-64°C MS (FAB, M+H) + = m/z 582 + Anal. Calcd. for C30H36F5N3O3 • 0.2 equiv. hexane: C, 62.58; H, 6.53; N, 7.02 Found: C, 62.41; H, 6.55; N, 6.84. Example 46 1-[4-[4-(1 ,3-Dihydro-1-oxo-2H-isoindol-2-yl)-1-piperidinyl]butyl]-2-methyl- N-(2,2,2-trif luoroethyl)- . H-indene-1-carboxamide. mp : 124-126°C MS m/z (ES, + ions) 526.3 (M+H) Anal. Calcd. for C30H34F3N3O2: C, 67.55; H, 6.52; N, 7.99; F, 10.84 Found: C, 67.80; H, 6.53; N, 7.89; F, 10.75. Examp e 7 9-[4-[4-(1 ,3-Dihydro-1-oxo-2H-isoindol-2-yl)-1-piperidinyl]butyl]-N-(2,2,3,3,3- pentafluoropropyl)-9H-fluorene-9-carboxamide, monohydrochloride. mp : 130-144°C MS (ES, + ions) m/z 578 (M+H) Anal. Calcd. for C34H35N3O2F5CI + 1.2 H2O: C, 60.98; H, 5.63; N, 6.27; F, 14.18 Found: C, 61.34; H, 5.48; N, 6.08; F, 13.69. Example 48 1 -[4-[4-( 1 ,3-Dihydro- 1 -oxo-2H-isoindol-2-yl)-1 -piperidinyljbutyl]- N-(2,2,2-trifluoroethyl)- 1 H-indene-1 -carboxamide. mp: 62-65°C MS m/z (ES, - ions) 510 (M-H) , 556 (M+HCO2-) Anal. Calcd. for C29H32F3N3O2 • 0.16 H2O: C, 67.70; H, 6.33; N, 8.17; F, 11.08 Found: C, 67.70; H, 6.26; N, 7.94; F, 10.62. Example 49 9-[4-[4-(Benzoylamino)-1-piperidinyl]butyl]-3,6-difluoro-N-(2,2,2-trifluoroethyl)- 9H-.luorene-9-carboxamide. MS (FAB, M+H) + m/z 586 + Anal. Calcd. for C32H32F5N3θ2*H2θ-0.15 CH2CI2 C, 62.65; H, 5.61; N, 6.82 Found: C, 62.52; H, 5.56; N, 6.67. Examole 50 3,6-Difluoro-9-[4-[4-[(2-phenoxybenzoyl)amino]-1-piperidinyl]butyl]-N-(2,2,2- trifluoroethyl)-9H-liuorene-9-carboxamide. mp: 124-26°C MS (FAB, M+H) m/z 678 + Anal. Calcd. for C38H36F5N3O3 : C, 67.35; H, 5.35; N, 6.20 Found: C, 67.38; H, 5.62; N, 5.92 Examples 51 to 167 The following compounds were prepared by robotics procedures as described below. ROBOTICS PROCEDURES Robotic Method for the Preparation of Amides A. Aqueous KOH/CHCI3 B. R 5 C0 2 H, DIC, HOBT, DMF C. Optional HPLC Purification A. Preparation of the diamine starting material: A solution of the diamine bishydrochloride salt (compound X) (10 g, 19.3 mmol) in chloroform (400 mL) was washed with IN KOH solution (3 x 100 mL) . The organic layer was washed H20 (2 x 100 mL) , brine (2 x 100 mL) and dried over MgSθ4. Evaporation gave the free diamine (8.8 g, 100%) as a colorless oil. B. General Experimental for Robotics Compounds: The following is a general procedure for the synthesis of amides according to the above equation via the coupling of carboxylic acids with the diamine. These acid-amine couplings and subsequent purifications were carried out using a Zymark Benchmate® Robotic system using an IBM PC to ru the operating program and to write the Benchmate procedures. A 16 mm x 100 mm tube was charged with 1.6 mmol, 4 eq R 5 C0 2 H acid and capped loosely with a plastic cap/column holder. The Benchmate® then carried out the following steps on the tube: 1) Added 1 mL (81 mg, 0.6 mmol, 1.5 eq) cf a 81 mg/mL solution of 1-hydroxybenzotriazole hydrate in DMF. 2) Added 1 mL (75 mg, 0.6 mmol, 1.5 eq) of a 75 mg/mL solution of diisopropylcarbodiimide in CH2CI2. 3) Added 1 mL (178 mg, 0.4 mmol, 1 eq) of a 178 mg/mL solution of diamine in CH2CI2. 4) Washed syringe with 3 mL of CH2CI2 5) Mixed tube contents by vortexing at speed 3 for 15 sec. After 12-48 h the reaction was complete (no starting amine remained as determined by TLC; 10% MeOH + 1% NH4OH in CH2CI2, 12) • The reaction mixture contents were then purified by ion exchange chromatography mediated by the Benchmate® Robot. The following is the standard procedure developed for purification of the coupled products by the Benchmate®: 1) Condition a Varian solid phase extraccion column (1.5 g, SCX cation exchange) with 10 mL of MeOH at 0.25 ml/sec 2) Load reaction contents onto column at 0.05 mL/sec 3) Wash column with 2 x 10 mL of MeOH at 0.1 ml/sec 4) Wash column with 10 mL of 0.1 M ammonia in MeOH at 0.1 ml/sec 5) Elute column with 4 mL of 2 M ammonia in MeOH and collect into a tared receiving tube at 0.1 ml/sec 6) Elute column with 1 mL of 2 M ammonia in MeOH and collect into same tared receiving tube at 0.1 ml/sec 7) Rinse syringe with 5 mL of MeOH All solution/solvent deliveries were followed by 1.8 mL of air and 10 sec push delay was used after loading reaction contents onto the ion exchange column. The product solution was concentrated on a Savant Speed Vac (approx. 2 mm Hg for 5 h) and final solvent remnants were removed by further exposure to high vac (0.015 mm Hg, 14 h) to afford product Y, which was characterized by HPLC and MS. MS (ES, + ions) m/z 619 (M + H) C. Preparative HPLC Purification In cases where the coupling reaction is carried out with carboxylic acids bearing basic substituents (for example, pyridyl or amino), the product Y isolated as above in Part B, is contam¬ inated with the starting acid. These materials were further purified by preparative HPLC. The samples after elution from the SCX column and speed vac concentration were reconstituted in MeOH and a small amount of trifluoroacetic acid (1 drop) was added to each. The products Y were purified by preparative chromatography using the following conditions: Solvent A: 10% MeOH, 90% H2θ, 0.1% TFA Solvent B: 90% MeOH, 10% H2O, 0.1% TFA Column: YMC ODS-A, SH-363-5, 30 x 250 mm I.D. S-5 μm, 120 A, No. 3025356A. Starting % B: 0% Final % B: 100% Gradient time: 30 min Flow rate: 25 mL/min Wavelength: 220 nm Attenuation: 9 (1.28 AUFS) Pure fractions were combined and concentrated to afford purified product Y, which was characterized by HPLC + MS. Please note that in the Examples 51 to 167, for structures bearing only two single bonded substituents to nitrogen, the third substituent is always hydrogen, but it is not shown explicitly n the structures. Also, please note that in the Examples 51 to 167 for structures bearing oxygens and sulfurs with only one single bonded substituent, the second substituent is always hydrogen, but is not shown explicitly in the structures. Example No. Molecular Structure Analytical Data 193- Examples 139 to 167 In the following Examples, the compounds prepared were purified by preparative HPLC (Method C) and isolated as trifluoroacetic acid salts. -203 Example 168 9-[4-[4-[ (Phenoxycarbonyl)amino] -1-piperidinyl] - butyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9- carboxamide. monohydrochloride To a solution of Example 36 Part D amine (500 mg, 0.96 mmol) and triethylamine (0.33 mL, 2.4 mmol) in dichloromethane (5 mL) at 0°C was added dropwise phenyl chloroformate (0.14 mL, 1.06 mmol). The reaction was warmed to RT and stirring was continued for 1 h. Dichloromethane (100 mL) was added and the solution was washed with saturated sodium bicarbonate (2 x 30 mL) , water (2 x 30 mL) , brine (2 x 30 mL) and dried over MgSθ4. Evaporation gave a yellow oil. Purification was performed by flash chromatography on silica gel (100 g) , loaded and eluted with 5% methanol in dichloromethane. Pure fractions were combined and evaporated to give a colorless oil. The resulting product was dissolved in methanol (1 mL) and a solution of hydrochloric acid in ethyl ether (1.1M, 1.1 mL) was added. The reaction was stirred at RT for 10 min, then evaporated to dryness. The product was dried in a vacuum oven (50°C, 24 h) to give title compound (300 mg, 53%) as a white solid. m.p. 197-200°C MS (ES, +ion) : 566 (M+H) Anal. Calc. for C 32 H 35 C1F 3 N 3 0 3 • 0.6 H 0: C, 62.71; H, 5.95; N, 6.86; F, 9.30 Found: C, 62.79; H, 5.88; N, 6.50; F, 9.10 Example iξ ~ 9-[4-[4-[ [ (Phenylamino)carbonyl]amino] -1-piper¬ idinyl]butyl]-N-(2,2,2-trifluoroethyl) -9H-fluorene-9- carboxamide. monohydrochloride To a solution of Example 36 Part D amine (500 mg, 0.96 mmol) and triethylamine (0.33 mL, 2.4 mmol) in dichloromethane (5 mL) at 0 °C was added dropwise phenyl isocyanate (0.10 mL, 1.06 mmol). The reaction was warmed to RT and stirring was continued for 1 h. Dichloromethane (100 mL) was added and the solution was washed with saturated sodium bicarbonate (2 x 30 mL) , water (2 x 30 mL) , brine (2 x 30 mL) and dried over MgSC- 4 . Evaporation gave a yellow oil. Purification was performed by flash chromatography on silica gel (100 g) , loaded and eluted with 5% methanol in dichloromethane. Pure fractions were combined and evaporated to give a colorless oil. The resulting product was dissolved in methanol (2 mL) and a solution of hydrochloric acid in ethyl ether (1.1M, 1.1 mL) was added. The reaction was stirred at RT for 10 min, then evaporated to dryness. The product was dried in a vacuum oven (55°C, 24 h) to give title compound (200 mg, 40%) as a white solid. m.p. 145-150°C MS (Cl, + ion) : 565 (M+H) Anal. Calc. for C 32 H 36 C1F 3 4 0 2 • 0.6 H 2 0: C, 62.81; H, 6.13; N, 9.16; F, 9.31 Found: C, 62.83; H, 6.05; N, 9.20; F, 9.27 Example 170 9-[4-[4-[ (Phenylsulfonyl)amino] -1-piperidinyl] - butyl] -N-(2,2,2-trifluoroethyl) -9H-fluorene-9- carhoxamidf.. monohydrochloride To a solution of Example 36 Part D amine (500 mg, 0.96 mmol) and triethylamine (0.46 mL, 3.36 mmol) in dichloromethane (5 mL) at 0°C was added dropwise benzenesulfonyl chloride (0.13 mL, 1.06 mmol). The reaction was warmed to RT and stirring was continued for 1 h. Dichloromethane (100 mL) was added and the solution was washed with saturated sodium bicarbonate (2 x 30 mL) , water (2 x 30 mL) , brine (2 x 30 mL) and dried over MgSθ . Evaporation gave a yellow oil. Purification was performed by flash chromatography on silica gel (100 g) , loaded and eluted with 5% methanol in dichloromethane. Pure fractions were combined and evaporated to give a colorless oil. The resulting product was dissolved in methanol (2 mL) and a solution of hydrochloric acid in ethyl ether (1.1M, 1.1 mL) was added. The reaction was stirred at RT for 10 min, then evaporated to dryness. The product was dried in a vacuum oven (55°C, 24 h) to give title compound (400 mg, 71%) as a white solid. m.p. 130-134°C MS (ES, + ion) : 586 (M+H) Anal. Calc. for C 31 H 35 CIF 3 N 3 SO 3 • 0.8 H 2 O: C, 58.59; H, 5.65; N, 6.61; Cl, 5.58; F, 8.97 Found: C, 58.77; H, 5.66; N, 6.40; Cl, 5.95; F, 9.03. Example 171 To a solution of 1.05 g (5.00 mmol) of 9- fluorenecarboxylic acid in 15 mL of THF under argon (evacuated and purged with argon three times) at -10°C, was added 4.0 mL of n-butyllithium (10.0 mmol, 2.5 M in hexanes) over 10 min. A thick slurry formed initially followed by a yellow solution. After 30 min, 0.75 mL (7.0 mmol) of ethyl bromobutyrate was added. The reaction was allowed to warm to room temperature. After 24 h, the reaction was quenched with 10% citric acid solution and extracted twice with ethyl acetate. The organic extract was dried (Na S0 4 ) and evaporated. The residue was dissolved in 15 mL of dichloromethane and stirred at room temperature under argon while 7.5 mL of oxalyl chloride solution (2 M in dichloromethane, 15 mmol) was added, followed by DMF (100 μL) . After 1 h, the resulting solution was evaporated at less than 30°C and the residue was then redissolved in 15 mL of THF. This solution was added to a solution of 2,2,2- trifluoroethylamine (1.1 g, 11 mmol) in 10 mL of THF under argon at 0°C. After 1 h, the reaction was quenched with 10% citric acid solution and extracted twice with ethyl acetate. The extracts were combined, dried (MgS0 4 ) and evaporated. Purfication by flash chromatography on silica gel (5 x 15 cm column, 3:97 ether/dichloromethane as elutant) provided title compound as a white solid, 956 mg, 47% yield , mp 108-110°C. B. To a solution of Part A compound (580 mg, 1.43 mmol) in 5 mL of methanol at room temperature under argon was added a solution of lithium hydroxide hydrate (130 mg, 3.0 mmol) in 5 mL of water. The reaction mixture was stirred for 14 h and then partially evaporated to remove methanol. The reaction was quenched with 10% citric acid solution and extracted twice with ethyl acetate. The extracts were combined, dried (MgS0 4 ) and evaporated to give title compound as a white solid, 540 mg. It was used in the next step without further purification. To a solution of Part B compound ( 530 mg , 1 .41 mmol ) , Example 10 Part B amine (280 mg , 1 .41 mmol ) and HOAt (210 mg, 1 . 5 mmol ) in 5 mL of THF at room temperature under argon , was added DCC ( 295 mg, 1 . 43 mmol) . After 15 h, the reaction was quenched with 10% citric acid and extracted twice with ethyl acetate. The extracts were combined, washed once with water, once with saturated sodium bicarbonate solution, dried (Na S0 4 ) and evaporated. Purification by flash chromatography on silica gel (5 x 15 cm column, 1:2 ethyl acetate/dichloromethane as elutant) provided title compound as a white solid, 625 mg, 79% yield, mp 90-92°C. Anal. Calc. for C 3 oH 36 F 3 N 3 θ 4 -H 2 θ: C, 62.38; H, 6.63; F, 9.87; N 7.27 Found: C, 62.41; H, 6.24; F, 9.78; N 7.14. MS (electrospray, - ions) m/e 558 (M-H) . Example 172 cis-9-[4-[4[ (2-Phenoxybenzoyl)amino] -1- piperidiny1]butyl]-N-(2,2,2-trifluoroethyl) -9H- fluorene-9-carboxamide. N-oxide To a solution of Example 32 free amine (290 mg, 0.452 mmol) in CH2CI2 (5 mL) at 0"C under argon was added a solution of 3-chloroperoxybenzoic acid (80-85%) (82 mg, 0.407 mmol) in CH2CI2 (1.5 mL) slowly over 5 min. The reaction mixture was stirred at O'C for 10 min, then saturated aqueous NaHCθ3 (1 mL) was added. The reaction mixture was stirred at O'C vigorously for 1 h, diluted with CH2CI2 (10 mL) , washed with brine (5 mL) , and then dried over a2Sθ4 Evaporation gave 320 mg of a white foam, which was purified by flash chromatography on silica gel (50 g) eluting with step gradient of 3% to 5% MeOH/CH2Cl2 to provide title compound (74 mg, 25%) as a white foamy solid. MS (ES, + ions) m/z 658 (M+H) Anal. Calcd for C38H38F3N3O4 + H2O: C, 67.54; H, 5.97; N, 6.22; F, 8.43 Found: C, 67.61; H, 5.65; N, 6.18; F, 8.21. Example 173 9-[4-[4-[ (2-Phenoxybenzoyl)amino] -1-piperidinyl] -4- oxobutyl]-N- (2,2,2-trifluoroethyl) -9H-fluorene-9- carboxaπύd A solution of Example 171 compound (2.00 g, 3.59 mmol) in 10 mL of 4 hydrogen chloride in dioxane was stirred, protected by a calcium chloride drying tube, for 3 h. The solution was evaporated at 30°C and the resulting solid was re-dissolved in 10 mL of dichloromethane. To one-half of this solution (by weight) , cooled to -10°C under argon, was added triethylamine (0.75 mL, 5.4 mmol) and then 500 mg of 2-phenoxybenzoyl chloride (2.15 mmol) over 10 min. After 1 h, the reaction was quenched with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The organic extract was dried (Na 2 S0 4 ) and evaporated. Purfication by flash chromatography on silica gel (5 x 15 cm column, 1:9 hexanes/ethyl acetate as elutant) provided, after recrystal-lization from ethyl acetate/hexanes, title compound as a white solid, 745 mg, 63% yield , mp 96- 98°C. Anal. Calcd for C 38 H 36 F 3 N 3 0 + H 2 0: C, 67.74; H, 5.69; F, 8.46; N, 6.24. Found: C, 67.84; H, 5.61; F, 8.63; N, 6.00. MS (electrospray, + ions) m/z 656.3 (M+H) , 673.3 (M+NH 4 ) . Example 174 A solution of Example 171 compound (2.00 g, 3.59 mmol) in 10 mL of 4 hydrogen chloride in dioxane was stirred, protected by a calcium chloride drying tube, for 3 h. The solution was evaporated at 30°C and the resulting solid was re-dissolved in 10 mL of dichloromethane. To one-half of this solution (by weight) , cooled to -10°C under argon, was added triethylamine (0.75 mL, 5.4 mmol) and then 0.25 ir of benzoyl chloride (2.2 mmol) over 10 min. After 1 h, the reaction was quenched with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The organic extract was dried (Na 2 S0 ) and evaporated. Purfication by flash chromatography on silica gel (5 x 15 cm column, 1:9 hexanes/ethyl acetate as elutant) provided, after recrystalliza-ion from ethyl acetate/hexanes, title compound as a white solid, 725 mg, 71% yield, mp 204-206°C. Anal. Calcd for C 32 H 32 F 3 N 3 0 3 : C, 68.19; H, 5.72; F, 10.11; N, 7.46. Found: C, 68.14; H, 5.73; F, 10.33; N, 7.40. MS (electrospray, - ions) m/z 437 (M-CF 3 CH 2 MHCO) , 562 (M-H) . Example l ~~ 9-[4-[4-[ [ (1,1-Dimethylethoxy)carbonyl]amino]-1- piperidinyl]pentyl]-N- (2,2,2-trifluoroethyl) -9H- fluorene-9-carboxamide A. To a solution of 2.50 g (11.9 mmol) of 9- fluorenecarboxylic acid in 25 mL of THF under argon (evacuated and purged with argon three times) at -10°C, was added 10.0 mL of n-butyllithium (25.0 mmol, 2.5 M in hexanes) over 10 min. A thick slurry formed initially followed by a yellow solution. After 40 min, 2.05 mL (15.0 mmol) of 1,4- dibromopentane was added. The reaction was allowed to warm to room temperature. After 60 h, the reaction was quenched with 10% citric acid solution and extracted twice with ethyl acetate. The organic extract was dried (MgS0 4 ) and evaporated. Trituration of the residue in ethyl acetate/hexanes gave title compound as a white solid, 3.72 g, 87%. B . To a stirred solution of 1.80 g ( ca . 5.0 mmol) of Part A compound in 10 mL of dichloromethane at room temperature under argon was added 0.65 mL of oxalyl chloride (7.5 mmol) followed by DMF (100 μL) . After 1 h, the resulting solution was evaporated at less than 30 °C and the residue was then redissolved in 15 mL of dichloromethane. This solution was added to a solution of 2,2,2-trifluoroethylamine hydrochloride (820 mg, 6.0 mmol) and 2.1 mL of triethylamine (15 mmol) in 20 mL of dichloromethane under argon at 0°C. After 1 h, the reaction was quenched with 10% citric acid solution and extracted twice with ethyl acetate. The extracts were combined, dried (MgS0 ) and evaporated. The crude product was dissolved in 25 mL of 2-butanone, 7.7 g (52 mmol) of sodium iodide was added and the reaction mixture was set to reflux for 48 h under argon. The solution was cooled, evaporated and the residue partitioned between ethyl acetate and 10% sodium bisulfite solution. The organic extract was dried (MgS0 4 ) and evaporated. Purfication by flash chromatography on silica gel (5 x 15 cm column, 3:7 hexanes/dichloromethane as elutant) provided title compound as a white solid, 1.42 g, 58% yield , mp 102-106°C. A solution of Part B compound (1.27 g, 2.60 mmol), Example 10 Part B amine (680 mg, 3.38 mmol) and potassium carbonate (420 mg, 3.0 mmol) in 5 mL of DMF at room temperature under argon was heated to 50°C. After 15 h, the reaction was quenched with water, decanted and the oily residue extracted twice with ethyl acetate. The extracts were combined, washed once with water, once with saturated sodium bicarbonate solution, dried (Na 2 S0 4 ) and evaporated. Purification by flash chromatography on silica gel (5 x 15 cm column, 1:99 methanol/ethyl acetate as elutant) provided title compound as a white solid, 1.20 g, 82% yield, mp 58-60°C. Anal. Calcd for C 31 H 40 F 3 N 3 O 3 + 0.25 H 2 0: C, 66.00; H, 7.24; F, 10.18; N, 7.45. Found: C, 66.00; H, 7.14; F, 10.39; N, 7.60. MS (electrospray, + ions) m/e 560.3 (M+H). Example 176 9-[4-[4-[ [ (2-Phenoxyphenyl)sulfonyl]amino] -1-piper- idinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene- 9-carboxamide. monohydrochloride To a solution of 2-phenoxyaniline (5.0 g, 27.0 mmol) in cone, hydrochloric acid (20 mL) and glacial acetic acid (6 mL) at -10°C, a solution of sodium nitrite (2.01 g, 29.2 mmol) in water (3.5 mL) was added dropwise at such a rate that the reaction temperature did not exceed -5°C. The reaction was stirred at -5°C for 1 h. While the diazotization was being completed, sulfur dioxide was bubbled through glacial acetic acid (15 mL) until it was saturated. Cuprous chloride (0.75 g) was then added and the introduction of sulfur dioxide was continued until the yellow-green suspension became blue-green (30 min) . The mixture was then cooled to 10°C and the solution containing the diazonium salt was added dropwise over 15 min. The green reaction mixture was warmed to RT and stirred for an additional 30 min, then poured into ice water (300 mL) . Ethyl ether (200 mL) was added and the organic layer was washed with water (2 x 100 mL) , saturated sodium bicarbonate solution (6 x 100 mL) , brine (2 x 100 mL) and dried over MgSθ . Evaporation gave a mixture containing (2.5 g, 36%) as a brown oil. Following the procedure in Example 480 the above sulfonyl chloride (2.5 g, 9.3 mmol) was reacted with Example 36 Part D amine (0.62 g, 1.2 mmol) followed by treatment with HCl to give title compound (210 mg, 26%) as a white solid. m.p . 142 - 146°C MS ( ES , + ions ) : 678 (M + H ) Anal. Calc. for C37H39CIF3N3SO4 + 0.4 H 0: C, 61.60; H, 5.56; N, 5.82; Cl , 4.91; S, 4.44; F, 7.90. Found: C, 61.67; H, 5.55; N, 5.62; Cl , 4.66; S, 4.31; F, 7.95. Example 177 [l-[ [ .2-[9-[ [ (2,2,2-Trifluoroethyl)amino)carbonyl] ■ 9H-fluoren-9-yl]ethyl]amino]carbonyl] -4-piperidin- vl.carbamic acid. 1.1-dimethvlethvl ester A. To a solution of 9-fluorenecarboxylic acid (10.5 g, 50 mmol) in THF (500 mL) at 0°C was added dropwise a solution of n-butyllithium (44 mL of a 2.5 M solution in hexanes, 110 mmol,) over 15 min under argon. The dark yellow solution was stirred at 0°C for 30 min, and then chlσroacetonitrile (3.8 mL, 60 mmol) was added dropwise over 3 min. The dark orange reaction mixture was stirred at 0°C for 10 min, warmed to room temperature and stirred for 3h. The reaction mixture was diluted with H2O (250 mL) and Et2θ (250 mL) , and concentrated in vacuo to 300 mL. Water (200 mL) and CH2CI2 (500 mL) were added. The mixture was acidified to pH 1.85 with IN HCl and extracted with CH2CI2 (6 x 250 mL) . The combined organic extracts were dried over MgSCj, filtered, and concentrated in vacuo to give crude solid title compound (10.45 g, 76.7%). B . To a solution of Part A compound (6.7 g, 26.9 mmol, dried by concentration with THF/toluene) and DMF (102 μl, 1.36 mmol) in CH2CI2 (80 mL) under N2 was added oxalyl chloride (20.5 mL of a 2.0M solution in CH2CI2, 40.6 mmol). The reaction was stirred at room temperature for 1.5 h and concentrated in vacuo and then dried under high vacuum to give the crude acid chloride. Triethylamine (11.3 mL, 81.0 mmol) was added to a suspension of 2,2,2- trifluoroethylamine hydrochloride (4.38 g, 32.4 mmol) in CH2CI2 (50 mL) at 0°C under N2. The resulting thick slurry was stirred at 0°C for 5 mm and then a solution of the crude acid chloride in CH2CI2 (30 mL) was added dropwise over 5 min. The reaction mixture was stirred at 0°C for 10 min. Dichloromethane (100 mL) was added and the solution was washed with IN HCl (2 x 80 mL) and saturated NaHCθ3 (80 mL) , dried over Na2S04, filtered and concentrated in vacuo to give foamy solid 8.3 g. This material was combined with another batch of crude solid (4.4 g) and the combined mixture was purified by flash chromatography on silica gel (1200 mL) , eluting with CH2CI2, to give title compound (10.5 g, 83.3 %) as a solid. C. A solution of Part B compound (4.5 g, 13.6 mmol) in absolute ethanol (400mL) /CHCI3 (7 mL) was hydrogenated at 50 psi over 10% Pd/C (2.1 g) for 3 days. The catalyst was removed by filtration through a nylon 66 filter, and the filtrate was concentrated in vacuo to give crude solid title compound (4.8 g) . D. To a solution of the crude Part C compound (4.0 g) in THF (80 mL) and pyridine (3.5 mL, 43.4 mmol) at room temperature was added a solution of 4- nitrophenyl chloroformate (1.46 g, 7.22 mmol) in THF (25 mL) . The mixture was stirred at room temperature overnight, concentrated in vacuo to remove THF, and diluted with EtOAc (700 mL) . The EtOAc was washed with 5% NaHC03 (4 x 50 mL) , H2O (4 x 50 mL) , 0.2N HCl (5 x 50 mL) , H2O (2 x 40 mL) , and brine (40mL) and then dried over Na2S0 . Evaporation gave 3.1 g of a foam, which was purified by flash chromatography on silica gel (500 mL) , eluting with EtOAc/hexane (20:80 to 35:75) to give title compound (1.59 g, 41.6 %) as pale yellow solid (mp 138-140°C) . E. [l-[[[2-[9-[[(2,2,2-Trifluoroethyl)- amino)carbonyl]-9H-fluoren-9-yl]ethyl] - amino]carbonyl]-4-piperidinyl]carbamic acid. 1.1-dimethvlethvl ester To a solution of Part D compound (1.59 g, 2.18 mmol) in CH2CI2 (30 mL) under N2 was added a solution of Example 10 Part B ester (1.27 g, 6.36 mmol) in CH2CI2 (20 mL) , followed by 4-dimethylaminopyridine (56 mg, 0.46 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with CH2CI2 (50 mL) , washed with 0.1 N NaOH (3 x 40 ml), H2O (2 x 40 mL) , 1% KHSO4 (2 x 40 ml), H2O (40 mL) , 5% NaHC03 (2 x 40 mL) , H2O (40 mL) and brine 40 mL) and then dried over a2S04. Evaporation of the CH2CI2 gave 1.8 g of a foam, which was purified by flash chromatography on silica gel (100 mL) , elutmg with EtOAc/hexane (60:40 to 100:0), to give title compound (1.43 g, 80.1% ) as a white solid, mp 1 ~ - 80°C. MS (ESI, + ions) m/z 561 (M + H), 1121 (2M + H) ; (-ion) 559 (M - H) . Anal. Calcd for C29H35N4O4F3 + 0.15CH2C12 + O.4CH3CO2C2H5: C, 60.69; H, 6.38; N, 9.21; F, 9.36 Found C, 60.83; H, 6.36; N, 9.29; F, 9.61. Exai ple 1 ? 9- [2- [ [ [4-(Benzoylamino)-1-piperidinyl]carbonyl]- amino]ethyl] -N-(2,2,2-trifluoroethyl) -9H-fluorene- 9-carboxamide To a solution of Example 177 compound (1.1 g, 1.97 mmol) in THF (4 mL) was added 4N HCl in dioxane (9 L, 36.4 mmol). The reaction mixture was stirred at room temperature for 3 h and concentrated in vacuo and then from dioxane (3 x 10 mL) to give crude title compound (1.46 g) as a white foamy solid. B. 9-[2-[ [[4-(Benzoylamino) -1-piperidinyl] - carbonyl]amino]ethyl] -N-(2,2,2~trifluoro- ethγl?-9H-fluorene-9-carboxamide __ To a solution of crude Part A compound (730 mg, 0.98 mmol) and triethylamine (615 μL, 4.41 mmol) in CH2CI2 (10 mL) at 0°C was added dropwise benzoyl chloride (172 μL, 1.47 mmol). The reaction was stirred at 0°C for 30 minutes and diluted with CH2CI2 (30 mL) . The solution was washed with 0.1N NaOH (2 x 40 mL) , H20 (40 mL) , 0.2N HCl (2 x 40 mL) , H2O (40 mL) and brine (40 ml),then dried over MgSθ4 and concentrated to a white solid (1.6 g) . Purification of this solid over silica gel (100 mL) by eluting with 5% methanol in dichloromethane gave title comopund (427 mg, 77.2%) as white solid. m.p. 220-222°C. MS (ESI, + ions) m/z 565 (M + H), 582 (M + NH4; (-ion) 563 (M - H) . Anal. Calcd For C31H31N4 O3F3: C, 65.95; H, 5.53; N, 9.92; F, 10.09. Found: C, 65.80; H, 5.41; N, 9.84; F, 9.98. Example 1 ? 4- [ [ (1, 1-Dimethylethoxy)carbonyl]amino] -1-pιper- idinecarboxylic acid, 2-[9- [[ (2,2,2-trifluoro¬ ethyl . minolcarbonyl1 -9H-fluoren-P-yl1ethyl ester A. To a stirred solution of 8.41 g (40 mmol) of 9-fluorenecarboxylic acid in 400 mL of dry THF at 0°C under argon was added, over 15 min, 35.2 mL of 2.5 M n-butyllithium in hexane (88 mmol) . The reaction was stirred at 0°C for 30 min and then 4.2 mL (48.5 mmol) of allyl bromide was added over 15 min. The reaction was stirred at 0°C for 15 min and at room temperature for 1 h and then quenched by addition of water (80 mL) . The THF was removed in vacuo and the aqueous mixture was extracted with ether (2 x 100 mL) . The aqueous layer was layered with CH^Cl ^ (150 mL) and then acidified with IN HCl (pH < 2) . After extraction, the aqueous was extracted with additional CH 2 C1; (2 x 100 mL) , and the combined CH;C1; extracts were washed with water, dried (MgSO^) and concentrated to give 9.41 g (94%) of title compound as an amorphous solid. B. Part A compound (9.30 g) was dried by concentration in vacuo from a mixture of dry THF and dry toluene (2x) . To a stirred solution of this acid in 100 mL of dry CH 2 C1 and 143 mL of DMF under nitrogen was added cautiously 28 mL of 2.0 M oxalyl chloride in CH 2 C1_ (55.8 mmol) . The reaction was stirred at room temperature for 1.5 h and concentrated in vacuo and then dried at 0.5 mm for 1 h to give the crude acid chloride of Part A acid. Triethylamine (15.6 mL, 112 mmol) was added to a stirred suspension of 6.04 g (44.6 mmol) of 2,2,2- trifluoroethylamine hydrochloride in 75 mL of dry CH 2 C1 2 at 0°C under argon. The slurry was stirred at 0°C for 10 min and then a solution of the crude acid chloride in 35 mL of CH 2 C1_* was added over 10 min keeping the internal temperature <12°C. The reaction was stirred at 0°C for 15 mm and at room temperature for 1 h and then diluted with 150 mL of CH 2 C1; . The CH 2 C1 2 was washed with IN HCl (2 x 75 mL) , water (180 mL) , 5% NaHC0 3 (120 mL) , and water (2 x 180 mL) , dried (Na 2 S0 ), and concentrated to a residue (12.67 g) . Chromatography of this residue over 500 g of silica gel provided 10.74 g (87%) of title compound as an amorphous white solid, mp 84-86°C. Ozone (in oxygen) was passed into a stirred solution of 5.30 g of Part B compound in 80 πiL of dry CH 3 OH at -55°C for 1 h. Nitrogen was bubbled through the reaction for 10 min at -55°C and then the reaction was warmed to -30°C. A solution of NaBH, (908 mg, 24 mmol) in 20 mL of 50% aqueous CH 3 OH cooled to 0°C was added and the reaction was stirred at -30°C for 70 min. The cooling bath was removed, the pH was adjusted to < pH 2 (3N HCl) , and the reaction was concentrated to remove CH 3 OH. The residue was partitioned between EtOAc and water, and the EtOAc was washed with water (4 x) , dried (Na;S0 ) , and concentrated to a residue (6.67 g) . Chromatography of this residue over 475 g of silica gel using hexane-EtOAc (6:4) and then hexane-EtOA (1:1) afforded 2.77 g (49%) of title compound as an amorphous solid. An earlier eluting fraction provided 1.97 g of compound 4-Nitrophenyl chloroformate (1.2 g, 6 mmol) was added to a stirred solution of 1.34 g (4 mmol) of Part C compound and 0.97 mL (12 mmol) of dry pyridine in 15 mL of dry CH 2 CI 2 at room temperature under argon. The reaction was stirred for 20 min at room temperature and then diluted with CH 2 C1; . The CH 2 CI 2 solution was washed with 5% NaHCO- (4x) , water, dilute HCl (2x) , and water (3x) , dried (Na;>SO_*) , and concentrated to give crude title compound in the form of a foamy residue (2.30 g) . E. 4- [[ (1, 1-Dimethylethoxy) carbonyl]amino] - 1-piperidinecarboxylic acid, 2- [9- [ [ (2,2,2- trifluoroethyl)amino] carbonyl] -9H-fluoren-9- vll ethvl ester 4-Boc-aminopiperidine (1.58 g, 7.90 mmoL) was added to a stirred solution of 2.29 g of the above preparation of Part D compound in 30 mL of dry CH 2 CI 2 at room temperature under argon. The reaction was stirred at room temperature for 2 h and then diluted with CH 2 C1 2 . The CH 2 C1 solution was washed with dilute NaOH (2x) , water (2x) , dilute KHS0 4 (2x) , and water (3x) , dried (Na 2 S0 ) , and concentrated to give 2.63 g of an oily residue. Chromatography of this residue over 230 g of silica gel using hexane-EtOAc (6:4) and subsequent crystallization from EtOAc- hexane provided 2.07 g (94%) of title compound as a white solid having mp 120-122°C. Anal. Calcd for C20H34F3N3O5 + 0.5 CH . CO C 2 H s : C, 61.48; H, 6.32; N, 6.94; F, 9.41 Found: C, 61.25; H, 6.39; N, 6.85; F, 9.42. MS (EΞI-NH 3 , + ions) 562 (M+H), 579 (M+NH 4 ) ; (- ions) 560. Example 180 4- [ (2-Phenoxybenzoyl)amino] -1-pιperidmecarboxylic acid, 2-[9-[ [ (2,2, 2-trifluoroethyl) ammo] carbonyl] - 9H-fluoren- Q -vl. ethvl ester To a solution of 898 mg (1.6 mmol) of Example 179 compound in 3 mL of dry THF under argon at room temperature was added 6 mL of 4N HCl in dioxane (24 mmol) . The reaction was stirred at room temperature for 2 h and then stored overnight at 5°C. The reaction was concentrated in vacuo and then concentrated from dry dioxane (2 x 5 mL) and then dried at 0.5 mm for 2h to afford crude title compound as an amorphous residue. To 428 mg ( 2 . 0 mmol ) of 2 -phenoxybenzoιc acid and 10 μL of DMF in 4 mL of dry CH C1_ at 0°C under nitrogen was added 1 . 5 rnL of 2 . 0 M oxalyl chloride in CHC1 2 (3.0 mmoL) . The reaction was stirred at room temperature for 1.5 h and concentrated in vacuo and then dried at 0.5 mm for 1 h to give the crude title acid chloride as a pale yellow oil. This oil was dissolved in 3.2 mL of . C. 4-[ (2-Phenoxybenzoyl)amino]-1-piper- idinecarboxylic acid, 2-[9-[ [ (2,2,2-tri- fluoroethyl)amino]carbonyl] -9H-fluoren-9- vl.ethvl ester To a stirred solution of one-half of the crude preparation of Part A compound above (ca. 0.8 mmoL) in 4 mL of dry CH 2 C1_ at 0°C under argon was added 0.46 mL (4 mmol) of triethylamine. The solution was stirred at 0°C for 5 min and then a 2.0 mL aliquot of the above solution of Part B compound in 3.2 mL of CHC1 2 (ca. 1.2 mmoL of crude Part B compound) was added. The reaction was stirred at 0°C for 2.5 h and then diluted with CH2CI . The CH 2 CI was washed with dilute NaOH (2x) , water (2x) , dilute HCl (2x) , and water (3x) , dried (Na 2 S0 4 ), and concentrated to a thick oil (577 mg) . Chromatography of this oil over 45 g of silica gel using hexane-EtOAc (1:1) provided 414 mg of title compound (79%) as a foam having mp 68-73°C. Anal. Calcd for C37H34F3N3O5 + 0.2 CH . .CO 2 C 2 H 5 : C, 67.23; H, 5.31; N, 6.22; F, 8.44 Found: C, 67.04; H, 5.20; N, 6.18; F, 8.70. MS (EΞI-NH 3 , + ions) 658 (M+H), 675 (M+NH 4 ) . Exa le 181 9- [4- [4- [ (2-Phenoxybenzoyl)amino] -1-piperidinyl] - pentyl]-N- (2 , 2, 2-trifluoroethyl) -9H-fluorene-9- arboxa ide. monohydrochloride A solution of Example 175 compound (1.25 g, 2.23 mmol) in 10 mL of 4 hydrogen chloride m dioxane was stirred, protected by a calcium chloride drying tube, for 3 h. The solution was evaporated at 30°C and the resulting solid was re-dissolved to a total volume of 20.0 mL with dichloromethane. To 10.0 mL of this stirred solution (ca. 1.12 mmol), cooled to -10°C under argon, was added triethylamine (0.4 mL, 2.9 mmol) and then the 2-phenoxybenzoyl chloride (320 mg, 1.38 mmol) solution in 10 mL cf dichloromethane over 10 mm. After 1 h, the reaction was quenched with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The organic extract was dried (l.a;SO_,) and evaporated. Purfication by flash chromatography (5 x 20 cm column, ethyl acetate as elutant) provided a colorless oil, 603 mg, 77%. The oil was dissolved in 5 mL of ethyl acetate and then 0.25 L of 4 HCl in dioxane was added. Ether was added until a gummy precipitate formed. Decanting and drying in vacuo gave title compound as a white solid, 650 mg, mp 136- 138°C. Anal. Calcd for C, 65.95; H, 6.10; Cl, 4.99; F, 8.02; N, 5.92 Found: C, 65.87; H, 6.08; Cl, 5.13; F, 7.96; N, 5.92. MS (electrospray, + ions) m/e 654 (M + H) . Examples 182 to 187 Following the procedures set out herem-before and in the working Examples, the following additional compounds were prepared. Example 182 9-[2-[[[4-[(2-P enoxybenzoyl)aπ.ιπo]-1-pιperιdιnyl]carbonyl]amιno]ethyl]- N-(2,2,2-trιfluoroethyl)-9H-fluorene-9-carboxamιde MS (ESI, + ion) : 657 (M+H) Anal. Calcd for C2.7H35N4O4F3 + O .2 CH2CI2 + O.I CH 3 CO2C2H5. C, 66.17; H, 5.35; N, 8.21; F, 8.35 Found: C, 66.14; H, 5.29; N, 8.13; F, 8.47. mp 84-87°C. Example 183 4-(Benzoyiamιno)-1-pιperιdιnecarboxylιc acid, 2-[9-[[(2,2,2- tπfluoroethyl)amιno]carbonyl]-9H-fluoren-9-yl]ethyl ester MS (ESI-NH3, + ions) 566 (M+H) Anal. Calcd for C31H30F3N3O4 + 0.2 CH.CO_C 2 H 5 +0.25 H 0 : C, 64.99; H, 5.51; N, 7.04; F, 9.70 Found: C, 64.77; H, 5.45; N, 7.15; F, 10.10. mp 75-85°C. Example 184 9-[4-[4-(Benzoylamιno)-1-pιperιdιnyl]pentyl]-N-(2,2,2-trιfluoroethyl)- 9H-flι_ιorene-9-carboxamιde, monohydrochloride MS (electrospray, + ions) m/z 564 (M+H) Anal. Calcd for C 33 H 3 6F 3 N 3 θ2 + HCl + H2O C, 64.12; H, 6.36; Cl, 5.74; F, 9.22; N, 6,80 Found: C, 64.17; H, 6.27; Cl, 5.65; F, 9.65; N, 6.60. mp 130-132°C. Example 185 9-[4-[4-[[( 1 , 1 -Dimethylethoxy)carbonyl]amino]- 1 -piperidinyljbutyl]- N-(2,2.2-trifluoroethyl)-9H-thioxanthene-9-cartoxamide. p 76-79°C. MS (ES, + ions, NH 3 ) m/z 578 (M+H) Example 186 9-[4-[4-(Benzoylamino)-1-piperidinyl]butyl]-N-(2,2,2-triluoroethyl)- 9H-thioxanthene-9-carboxamide. mp 167-169°C. MS (ES, + ions, NH 3 ) m/z 582 (M+H! Example 187 9-[4-[4-[[(2-Phenoxyphenyl)carbonyl]amino]-1-piperidinyl]butyl]- N-(2,2,2-trifluoroethyl)-9H-thioxanthene-9-carboxamide. mp 164-166°C. MS (ES, + ions, NH 3 ) m/z 674 (M+H) In accordance with the present invention, another class of preferred compounds is provided which are inhibitors of MTP and have the structure I* wherein Z is a bond, 0 or S; X 1 and X- are independently H or halo, preferably F; x is an integer from 2 to 6, preferably from 3 to 5, and (CH2)χ may be optionally substituted with 1, 2 or 3 substituents which are the same or different and are alkyl or halo; and R 5* is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R^ * group being optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different as defined hereinafter; and including piperidine N-oxides of the formula I compound, that is A^»: and AJ including pharmaceutically acceptable salts thereof such as alkali metal salts such as lithium sodium or potassium, alkaline earth metal salts such as calcium or magnesium, as well as zmc or aluminum and other cations such as ammonium, choline, diethanolamine, ethylenediamme, -butyl-am e, t- octylamine, dehydroabietylamme, as well as pharmaceutically acceptable anions such as chloride, bromide, iodide, tartrate, acetate, methanesulfonate, maleate, succinate, glutarate, and salts of naturally occurring amino acids such as arginine, lysine, alanine and the like, and prodrug esters thereof. The R5* group may be substituted with 1, 2, 3 or 4 substituents, including (1) halogen such as Cl, F, CF3 , and I, (2) heteroaryl, including monocyclic or bicyclic ring systems, which includes 1, 2 or 3 heteroatoms which are S, N and/or 0, and which includes from 2 to 10 carbons in the ring or ring system, such as 3) heteroarylalkyl wherein heteroaryl is as def ined above such as (4) cycloheteroalkyl which includes 1, 2 or 3 hetero atoms which are N, S or 0 in a monocyclic or bicyclic ring system such as (5) alkyl; (6) aryl such as phenyl, phenyl substituted with (a) halo, (b) alkyl, (c) CF3O, (d) alkoxy (e) - CFI c?3 , (f) CF3, or (g) phenyl; H (7) alkylamino such as N < CH2 > P cι ?3 - . (8) alkyl (aryl) amino such as -N(CH3)C6Hs; / C?3 ■ s- (9) alkythio such as -S- (CH2) p CF3 , CP 3 o II -S-(CH 2 ) p -S-C β H 5 -S-alkyl, o .CF*, (10) alkoxy such as -0- (CH2) p-CF , cp 3 , OCH3; (11) cycloalkyl such as cyclohexyl; (12) aryloxy such as (13) amino; (14) arylamino such as CF3 ; (15) arylthio such as (16) acy o II CCH 3 t (j-. * . al (c) aroyl, such (d) heteroarylam inocarbonyl , such as - ~ II—H ,**._ CIi3 , (e) arylalkyloxycarbonyl, such as o II — C— 0-CH s C β H s . (17) arylthioalkyl, such as -CH2-S-C6H5; H ™*~fΛ (18) heteroarylamino, such as ■ " Λ cp s , -N(CH 3 >-CH 2 — (_ (19) arylalkyloxy, such as (20) heteroarylthio, such as (21) heteroaryloxy, such as -°-Q cl ; and (22) arylsulfinyl, such as -"- N —oV ' cι Thus, the compounds of formula I* of the invention encompass compounds of the structure In addition, in accordance with the present invention, a method for preventing, inhibiting or treating atherosclerosis, pancreatitis or obesity is provided, wherein a compound of formula I* as defined hereinbefore is administered in an amount which decreases the activity of microsomal triglyceride transfer protein. Furthermore, in accordance with the present invention, a method is provided for lowering serum lipid levels, cholesterol and/or triglycerides, cr inhibiting and/or treating hyperlipemia, hyper- lipidemia, hyperlipoproteinemia, hypercholes- terolemia and/or hypertriglyceridemia, wherein a compound of formula I* as defined hereinbefore is administered in an amount which decreases the activity of microsomal triglyceride transfer protein, Suitable (CH 2 )χ groups (were x is 2 to 6, preferably 3 to 5) (which may include alkylene, alkenylene or alkynylene groups) as defined herein, may optionally include 1, 2, or 3 alkyl or halogen and in addition, may have one of the carbon atoms in the chain replaced with an oxygen atom, N-H, N-alkyl or N-aryl. Examples of (CH 2 ) groups include —CH =CH —CH 2 — —CH 2 CH —CH » —C =C —CH, . CH 3 I ■-— CHC -__-_CCH 2 ~" " —C =CH —CH 2 —- —(CH 2 ) 2 —, —(CH 2 ) 3 , —(CH 2 ) 4 —, CH 3 I —(CH 2 ) 2 -C -CH 2 CH 2 — . -CH 2 CH —, -CH 2 CHCH 2 — < CH 3 CH ' C = H 5 -CHCH 2 — . -CHCH 2 CH 2 — , -CHCHCH 2 — , I I I I CH 3 C 2 H 5 | CH 3 CH 3 O O o II II n -CH 2 CH,0-C— , — CH 2 CH,N-C— . - CH 2 CH 2 - N- C— , H CH 3 CH 3 — CH 2 — C— CH 2 , — (CH 2 ) 5 — , — (CH 2 ) 2 — C — CH 2 - , I I CH 3 F Cl CH 3 CH 3 I 1 1 -CH 2 -CH -CH 2 . — (CH 2 ) 2 -CH— , -CH 2 -CH-C- . CH 3 CH 3 — CH 2 — CH — CH —CH 2 , — CH 2 — CH — CH 2 — CH , I I I I CH 3 CH 3 CH 3 CH 3 OH OCH 3 I I — CH — CH 2 CH 2 , — CH-CH 2 CH 2 # — CH 2 OCH 5 — — OCH 2 CH 2 . CH 2 NHCH 2 — . — NHCH 2 CH 2 — » CH 3 — N-CH 2 CH 2 - , I I -(CH 2 ) 3 — CF 2 - , — CH 2 -N— CH 2 - ' CH 3 F CH3 I I -(CH 2 ) 2 — C— CH 2 - - -(CH 2 ) 2 — C— CH 2 - • I ' H CH 3 CH 3 CH 3 CH 3 -(CH 2 )2~C— CH j - > -<CH 2 ) 3 — C or _(CH 2 ) 3 — c H CH 3 i The term "heteroaryl" as used herein alone or as part of another group is defined above. Additional examples of "heteroaryl" groups are set out below. NN NN n——IM N——NN M k —N and the l ■ ike, and in • cludes all possible N --Xoxide ) derivatives. Preferred are compounds of formula I* where Z is a bond; X 1 and X 2 are H; R 5* is aryl such as phenyl substituted with (1) aryl such as phenyl (2) heteroaryl such as (3) halo such as Cl R 5* is heteroaryl such as ώs ' . or Ω s " substituted with (1) aroyl such as ^^ (2) arylthio such as wherein the R 5* substituent is preferably in the position adjacent to the carbon linked to . (CH 2 ) X is -(CH 2 ) 4 - or F —CH 2 -CH 2 —C-CH 2 - F The following Examples represent additional preferred embodiments of the invention. All temperatures are in °C unless indicated otherwise. NOTE: The phrase "flash chromatography" as employed in the following examples refers to chromatography performed on EM Industries Silica Gel 60, 230-400 mesh under 10-20 psi of nitrogen pressure. Example 1* 9-[4-[4-[([l,1-Biphenyl] -4-ylcarbonyl)ammo] -1-piper¬ idinyl] -3,3-difluorobutyl] -N- (2,2,2-trifluoroethyl) - 9H-fluorene-9-carboxamide. monohydrochloride A mixture of OM (5.18 g, 33.6 mmol), acetyl chloride (5.2 mL) and acetic anhydride (5.2 mL) was heated to 50°C under argon for 1 h. The reaction was cooled and evaporated. The residue was dissolved in EtOH (20 L) and stirred at room temperature (RT) under argon. After 16 h, the solution was evaporated, the residue redissolved in Et 2 0 and the solution dried (Na 2 S0 4 ) to give title compound as a colorless oil, 5.91 g, 97% material balance. The compound was used without further purification. To a stirred solution of Part A compound (1.82 g, 10.0 mmol) in THF (10 mL) at room temperature under argon was added a solution of borane-methyl sulfide complex (1.25 mL, 13.2 mmol) in dichloro¬ methane (14 mL) . The reaction was set to reflux. After 24 h, the reaction was cooled, methanol (20 mL) was added and the reaction again set to reflux. After 1 h, the excess solvents were distilled at atmospheric pressure. The residue was bulb-to-bulb distilled at reduced pressure to provide title compound as a colorless oil, 1.45 g, 86%. OSiPh 2 tBu To a stirred solution of Part B compound (1.40 g, 8.33 mmol) m DMF (10 mL) at room temperature under argon was added Ph_tBuSιCl (2.6 mL, 9.2 mmol) and imidazole (1.4 g, 21 mmol) . After 2 h, the reaction was quenched with water and extracted three times with ether. The organic extracts were combined, dried (Na S0 ) and evaporated to give a brown oil. Purification by flash chromatography on silica gel (5 x 20 cm column, 2:7 dichloromethane/ hexanes) gave title compound as a colorless oil, 1.83 g, 54%. To a stirred solution of Part C compound (1.73 g, 4.26 mmol) in THF (5 mL) at room temperature under argon was added lithium borohydride solution (1.2 mL, 2.4 mmol, 2 H in THF) . After 16 h, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted three times with EtOAc. The organic extracts were dried (Na 2 S0 4 ) and evaporated to give title compound as a colorless oil, 1.51 g, 97%. The compound was used in subsequent reactions without further purification. OSiPh tBu To a stirred solution of Part D compound (1.50 g, 4.12 mmol) in diisopropylethylamine (5 L) at 10°C under argon was added benzyloxymethyl chloride (BomCl) (0.7 mL, 4.9 mmol) in one portion. A precipitate began to form within 10 min. After 1 h, hexane was added to the reaction mixture and the resulting slurry washed with 10% hydrochloric acid (20 mL) and once with water. The organic layer was dried (MgS0 ) and evaporated to give a light yellow oil. Purification by flash chromatography on silica gel (5 x 20 cm column, 2:3 dichloromethane/hexane) gave title compound as a colorless oil, 1.77 g, 89%. F. OH To a stirred solution of Part E compound (1.72 g, 3.55 mmol) in THF (5 mL) at room temperature under argon was added tetrabutylammonium fluoride solution (TBAF, 7.5 mL, 7.5 mmol, 1 M in THF) . After 1 h, the reaction was quenched with brine and extracted twice with EtOAc. The combined extracts were dried (Na 2 SO-i) and evaporated. Purification by flash chromatography on silica gel (5 x 12 cm column, 1:9 EtOAc/dichloromethane) provided title compound as a colorless oil, 774 mg, 89%. G. To a stirred solution of Part F compound (770 mg, 3.13 mmol), triphenylphosphine (826 mg, 3.15 mmol) and imidazole (470 mg, 6.9 mmol) in THF (10 mL) at room temperature under argon was added a solution of iodine (800 mg, 3.15 mmol) in THF (5 mL) dropwise over 10 min. The reaction mixture was diluted with ether and washed once with saturated sodium bicarbonate (containing 5% NaHS0 3 ) . The organic extract was dried (Na 2 S0 4 ) and evaporated. Purification by flash chromatography on silica gel (5 x 10 cm column, dichloromethane) provided title compound as a colorless oil, 935 mg, 84%. H. To a solution of 9-fluorenecarboxylic acid (631 mg, 3.0 mmol) in THF (5 mL) under argon at -10°C was added a solution of sodium bis(trimethylsilyl) - amide (6.2 mL, 6.2 mmol, 1 M in THF) over 10 min. The resulting slurry was stirred 60 min and then a solution of Part G compound (930 mg, 2.61 mmol) in THF (5 mL) was added. The reaction was allowed to warm to room temperature and stirred. After 48 h " , the reaction was quenched with 10% citric acid solution and extracted twice with EtOAc. The organic extracts were combined, dried (MgS0 4 ) and evaporated. The oily residue was dissolved in dichloromethane (10 mL) and treated, at room temperature, with oxalyl chloride (0.52 mL, 6.0 mmol) and DMF (0.1 L) . After 1 h, the reaction was evaporated and then redissolved in dichloromethane (5 mL) . This solution was added, dropwise over 10 min, to a stirred slurry of trifluoroethylamine hydrochloride (502 mg, 3.70 mmol) and Et 3 N (1.12 mL, 8 mmol) in dichloromethane (10 L) at 0°C under argon. After 1 h, the reaction was quenched with 10% citric acid solution and extracted twice with EtOAc. The organic extgracts were combined, dried (MgS0 ) and evaporated. Purification by flash chromatography (5 x 20 cm column, 1 L dichloromethane, then 5:95 ether/dichloromethane) to 375 mg, 47% and then title compound, 120 mg, 9% as colorless oils. A stirred slurry of Part H compound (108 mg, 0.208 mmol) and 20% Pd(OH) -on-carbon (200 mg) in cyclohexene (2 mL) and ethanol (5 mL) was refluxed for 2 h under argon. The reaction was cooled, evaporated, diluted with EtOAc, dried (MgS0 4 ) and filtered through a 0.75 m nylon filter. Evaporation provided title compound as a colorless oil, 53 mg, 64%. To a solution of Part I compound (50.9 mg, 0.128 mmol) and pyridine (68 mL, 0.8 mmol) in dichloromethane (1 mL) at 0°C under argon was added triflic anhydride (40 mL, 0.15 mmol) over 2 min. After 1 h, the reaction was quenched with 1 M hydrochloric acid and extracted twice with EtOAc. The organic extracts were combined, dried (MgS0 4 ) and evaporated to give title compound as an orange crystalline solid, 68 mg, 100%. K. K(l) To a solution of 2-biphenyl carboxylic acid (31.2 g, 160 mmol) in methylene chloride (300 ml) was added the oxalyl chloride (21 ml, 280 mmol), followed by a few drops of DMF. The reaction bubbled vigorously and was stirred under argon at room temp 2h. The solvent was evaporated in vacuo at less than 25°C, and the residue was dissolved in methylene chloride (250 ml) . This solution was added dropwise to a solution of 4-aminobenzyl piperidine (Aldrich, 25.Og, 130 mmol) and triethylamine (46 ml, 330 mmol) in methylene chloride (200 ml) at -5°C. The reaction stirred 30 minutes at that temperature after addition was complete. The reaction mixture was washed twice with water and once with brine. The organic layer was dried (Na 2 S0 4 ) , and the solvent was removed in vacuo to give title compound as a light yellow solid (56.6 g, 95.4% yield) . K(2) . To a solution of Part K(l) compound (55.5 g, 150 mmol) in ethanol (500 ml) was added cyclohexene (167 ml, 1.6 mol) and 20% palladium hydroxide on carbon (11.1 g) . The reaction was heated to reflux and stirred at that temperature 2.75 h. The warm reaction was filtered through Celite ® and rinsed with ethanol and methanol. The filtrate was concentrated in vacuo to give a light yellow oil. This oil was triturated twice with ether to give a light yellow solid (30.1 g) . To a stirred solution of Part J compound (68 mg.0.126 mmol) in toluene (2 mL) at room temperature under argon was added Part K compound (84 mg, 0.3 mmol) in DMF (0.5 mL) . The solution was heated to 50°C. After 14 h, the reaction was cooled, diluted with ether and washed once with saturated sodium bicarbonate solution. The organic layer was dried (Na 2 S0 4 ) and evaporated. Purification by flash chromatography on silica gel (1 x 10 cm column, EtOAc) provided title compound as the free base as a white foam, 57 mg, 68%. The foam was diluted with dichloromethane and 0.1 mL of 4 hydrochloric acid. Evaporation provided the HCl salt of the title compound, 59 mg, mp 115-118°C. TLC: R f = 0.20 (free base, EtOAc, Silica gel 60) Mass Spectrometry: (electrospray, + ions) m/z 662 (M+H) Example 2* 9-[4-[4-[ [ (4 '-Chloro-tl, 1 ' -biphenyl] -2-yl ) carbonyl ] ■ amino] -1-piperidinyl]butyl] -N- (2,2, 2-trifluoroethyl! 9H-fluorene-9-carboxamide. monohydrochloride HCl salt The title compound was prepared by the method of Meyers by Grignard addition of p-chlorophenylrr.ag- nesium bromide to o-methoxy-phenyl-1, 1-dimethyl- isoxazole and hydrolysis with 6 N HCl . B. 9-[4-[4-[ [ (4'-Chloro-[l,l'-bιphenyl]-2- yl) carbonyl] -amino] -1-pιperidinyl]butyl] -N- (2,2, 2-trifluoroethyl) -9H-fluorene-9- rarboxamide. monohydrochloride To a solution of the Part A acid (2.0 g, 8.6 mmol) in methylene chloride (35 ml) was added a 2 M solution of oxalyl chloride (6.0 ml, 12 mmol) in dichloromethane followed by a 2 drops of DMF. The reaction bubbled vigorously and stirred under argon at RT for 2h. The solvent was evaporated m vacuo at less than 25°C, and the residue was dissolved in THF (50 ml) . This solution was added dropwise to a solution of the Example 11* Part C diamine (4.45 g, 8.6 mmol) and triethylamine (3.54 g, 35 mmol) in THF (150 ml) at 0°C. The reaction stirred m a melting ice bath lh and warmed to RT and stirred for 48 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed once with water. The organic layer was dried (MgSθ4) , and the solvent was removed in vacuo to give an off-white solid foam which was purified trituration with ethyl acetate to give a white solid. The solid was diluted with ether (100 mL) and treated with IM HCl in ether (10 mL, 10 mmol) in give a white powder which was filtered. The solid was collected and dried at 55°C (20 mm Hg) overnight to give 3.95 g (67%) of title compound as a white powder. mp:140-150°C MS (ES, + ions) m/z 660 (M + H) ; 1 Cl isotope pattern. Anal Calcd. for C38H37N3O2F3CI + HCl: C, 63.07; H, 5.71; N, 5.81 Found: C, 62.79; H, 5.62; N, 6.05. Exam le 2* 9-[4-[-4[[[l- (Phenylmethyl) -2-piperidinyl] carbonyl] • amino] -1-piperidinyl]butyl] -N- (2,2, 2-trifluoroethyl! 9H-fluorene-9-carboxamide. dihydrochloride A. hL COOEt Benzyl bromide (700ml, 5.7 mmol) was added dropwise to a slurry of ethyl pipecolinate hydro¬ chloride (1.0 g, 5.2 mmol) and potassium carbonate (1.5 g, 11.4 mmol) in DMF (10 mL) under argon. The reaction was stirred at RT for 2.5 h., then the solvent was removed in vacuo. The residue was partitionated between dichloromethane (10 mL) and water (10 mL) , and the aquous layer was extracted with dichloromethane (3 x 10 L) . The combined organic layers were dried over sodium sulfate, then concentrated in vacuo to give a cloudy oil, which was chromatographyed (10% ethyl acetate in hexane) on silica gel (60 g) . Pure fractions were combined and evaporated to give title compound (1.24 g, 97%) as a colorless oil. B. r Ph COOH HCl A biphasic mixture of Part A compound (600 mg, 2.4 mmol) and IN KOH (7.2 mL) in dioxane was stirred at RT overnight, then the reaction was heated at 50°C for 2 days. The reaction was cooled to RT then adjusted to pH 2 with IN HCl. The cloudy mixture was concentrated in vacuo then pumped under high vaccum overnight. The solid product was stirred with chloroform (10 mL) for 15 min. then filtered. The filtrate was concentrated j_r vacuo to give title compound (411 mg, 67%) as a yellow foam. Ethyl 3- (3-dimethylamino)propyl carbodiimide (164 mg, 0.86 mmol) was added to a mixture of Example 11* Part C compound (404 mg, C.78 mmol) , Part B compound (200 mg, 0.78 mmol), hydroxybenzotπazole (105 mg, 0.78 mmol) , and 4-methyl morpholine (300 ml, 2.7 mmol) in dichloromethane (3 mL) under argon. The reaction was stirred at RT for 24 h., diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate solution (5 mL) . The organic layer was washed with water (2 x 5 mL) then dried over sodium sulfate. Evaporation gave a yellow gum. Purification was performed by flash chromatography (4% methanol in dichloromethane) on silica gel (53 g) . Pure fractions were combined and evaporated to give a colorless oil. The resulting product was dissolved in methanol (1 mL) and a solution of hydrochloric acid in ethyl ether (1.1M, 1.1 mL) was added. The reaction was stirred at RT for 10 mm, then evaporated to dryness. The product was dried in a vacuum oven (55°C, 24 h) to give title compound (302 mg, 54%) as a white solid. m.p. 161-165°C MS (ESI, +ion) : 647 (M+H) Anal. Calc. for C38H47CI2F3N4O2 • 1.5 H 2 0: C, 61.12; H, 6.75; I.\ 7.50; Cl, 9.50; F, ".63 Found: C, 60.97; H, 6.77; K, 7.40; Cl, 9.18; F, ".34 Examole 4* N- (2,2,2-Trifluoroethyl) -9- [4- [4- [ [ [4- (trifluoro¬ methyl) [1, 1-biphenyl] -2-yl] carbonyl]amino] -1-piper¬ idinyl]butyl] -9H-fluorene-9-carboxamide, onohvdrochloride OCONE-2 To a stirred solution of (3.08 g, 19.0 mmol) in THF (20 mL) at room temperature under argon was added triethylamine (2.80 mL, 20.0 rnmol) , diethyi carbamyl chloride (2.50 mL, 19.5 mmol) and dimethylaminopyridine (100 mg) . The reaction was heated to 50°C for 18 h. The reaction was cooled, diluted with ether, washed with 10% citric acid solution, brine and dried (MgS0 4 ) . Purification by flash chromatography on silica gel (5x15 cm column, 55:45 hexane/dichloromethane) provided title compound as a colorless oil, 4.35 g, 89%. B. ONEt 2 To a flame-dried three-necked flask fitted with a dropping funnel and thermometer under an argon atmosphere was added THF (100 mL) and N,N,N,N- tetramethylethylene diamine (TMEDA, 4.4 mL, 29.2 mmol) . The resulting solution was cooled to -73°C and a solution of s-butyllithium in hexane (22.0 mL, 1.25 M 27.5 mmol) was added dropwise over 1 min. After 30 min, a solution of Part A compound (5.90 g, 22.6 mmol) in THF (20 mL) was added over 20 min. After an additional hour, dry carbon dioxide gas was bubbled through the solution for 30 mm. The cold bath was removed and the reaction was allowed to warm to 0°C. The turbid solution was immediately quenched with 10% citric acid solution, extracted twice with EtOAc, dried (MgSO_*) and evaporated to give title compound as a white solid, mp 124-126°C, 5.88 g, 85%. A slurry of Part B compound (2.28 g, 7.47 mmol) in 6 M hydrochloric acid (25 mL) under argon was heated to reflux for 1 h. The reaction was cooled, diluted with water, washed and filtered. The damp filter cake was dissolved in EtOAc, dried (MgS0 4 ) and evaporated to give title compound as a white solid, 1.52 g, 99%, p 148-149°C. To a stirred solution of Part C compound (1.50 g, 7.28 mmol) in DMF (20 mL) under argon at room temperature was added potassium carbonate (2.8 g, 20 mmol) . The slurry was heated to 50°C and then dimethyl sulfate (1.9 mL, 20 mmol) was added. After 1 h, the reaction mixture was quenched with 10% citric acid solution (20 mL) and extracted twice with ether. The combined extracts were washed with water, dried (MgS0 4 ) and evaporated to give the methyl ester of title compound as a colorless oil, 1.71 g, 100%. The oil was dissolved in THF (10 mL) , 3 tø sodium hydroxide solution (10 mL) was added and the mixture was heated to reflux under argon for 1 h. The solution was cooled, poured into cold 1 H hydrochloric acid and extracted twice with dichloromethane. The extracts were combined, dried (MgSO.;) and evaporated to give title compound as a white solid, 1.45 g, 91%, mp 105-107°C. E. To a stirred solution of Part D compound (1.40 g, 6.36 mmol) in dichloromethane (10 mL) protected by a Drierite-filled tube at room temperature was added oxalyl chloride (1.00 mL, 11.5 mmol) and DMF (50 mL) . After 2 h, the solution was evaporated and redissolved in dichloromethane (20 mL) . To this solution, under argon at room temperature, was added Et 3 N (1.02 mL, 7.33 mmol) and then 2-ammo-2-methyl- 1-propanol (0.70 mL, 7.33 mmol) . An exotherm results in an orange solution. After 13 h, the reaction mixture was diluted with dichloromethane, washed twice with 10% citric acid solution, dried (MgSO.* and evaporated to give title compound as a white foam, 2.08 g, >100% material balance. F. To a solution of Part E compound (2.08 g) m dichloromethane (20 mL) at room temperature and protected by a Drierite-filled tube was added thionyl chloride (1.9 mL, 23.6 mmol) . The solution was stirred for 2 h, then diluted with dichloromethane and poured into a 1:1 mixture of ice and saturated sodium bicarbonate solution. The aqueous layer was adjusted to pH 8 with 1 M potassium hydroxide solution and extracted twice with dichloromethane. The organic extracts were combined, dried (Na 2 S0 4 ) and evaporated. Purification by flash chromatography on silica gel (5 x 10 cm column, 1:9 EtOAc/dichϊoro- methane) provided title compound as a white solid, 1.56 g, 90% yield starting from Part D compound, mp 55-57°C. To a stirred solution of Part F compound ( 1 . 17 g, 4 .28 mmol ) in THF ( 10 mL ) at 0°C under argon was added a solution of phenylmagnesium bromide (1.7 mL, 3 U in ether, 5.1 mmol) over 5 min. After stirring an additional 10 min, the ice bath was removed and the reaction allowed to stir at room temperature. After 2 h, the reaction was quenched with saturated ammonium chloride solution and extracted twice with EtOAc. The extracts were combined, dried (Na 2 S0 4 ) and evaporated to give a brown oil. Purification by flash chromatography on silica gel (5 x 15 cm column, 0.5 L hexane and then dichloromethane) provided title compound as a colorless oil, 1.36 g, 100%. H. A slurry of Part G compound (1.25 g, 3.91 mmol) in 6 J hydrochloric acid (25 mL) was heated to reflux for 13 h. The reaction mixture was cooled and extracted twice with dichlormethane. The extracts were combined, dried (MgSO,) and evaporated. Purification by flash chromatography on silica gel (5 x 15 cm column, EtOAc) provided title compound as a white solid, 395 mg, 38%, mp 120-122°C. I. A solution of Part H compound (380 mg, 1.43 mmol) in thionyl chloride (3 mL) was stirred at room temperature, protected by a Drierite-filled tube. After 2 h, the reaction was evaporated and then re- evaporated from dichloromethane. The semi-solid residue was dissolved in dichloromethane (5 mL) and added dropwise to a solution, at 0°C under argon, of Example 11* Part C compound (816 mg, 1.57 mmol), Et 3 N (0.7 mL, 5 mmol) and DMAP (50 mg, 0.4 mmol) in 10 mL of dichloromethane. After the addition was completed, the reaction was warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with EtOAc, washed once with saturated sodium bicarbonate solution, dried (Na 2 S0 ) and evaporated. Purification by flash chromatography on silica gel (5 x 15 cm column, 3:17 hexanes/EtOAc) provided title compound (as the free base) as a white foam, 640 mg, 65%. The foam was dissolved in dichloromethane (5 mL) and treated with 4 £J hydrogen chloride in dioxane (0.3 mL) . Evaporation provided title compound as the hydrogen chloride salt, 670 mg, mp 129-134°C. Mass Spectrometry: (electrospray, + ions) m/z 694 (M+H) . Examole 5* 9- [4- [4- [ [2-Chloro-5- (trifluoromethyl)benzoyl]amino] 1-piperidinyl]butyl] -N- (2 , 2, 2-trifluoroethyl) -9H- fluorene- Q -carboxamide. N-oxide To a solution of the Example 111* amine free base (8.50 g, 13.0 mmol) in methylene chloride (35 ml) was added a 35% of peracetic acid solution m acetic acid (3.7 ml, 15 mmol) . An additional 3.7 mL of peracetic acid solution was added (15 mmol) after 1 h. The reaction mixture was stirred for 16 h at RT, diluted with toluene (200 L) and the contents stripped. The residue was pumped to constant weight. The colorless remainder was diluted with CHCI3/methanol (100 mL, 9:1) and concentrated to give an off-white solid foam which was recrystalized from a (10:1; 10 mL) dichloromethane/methanol solution. The yield of material was 2.3 g. The mother liquor was purified by flash column chromatography on silica gel with 7:93 methanol/dichloromethane to give 4.2 g of pure material. The solids were combined to give 6.5 g (75%) of title compound as a white solid. mp:131-136°C; material ther. resolidified: mp: 198-200°C decomp. MS (ES, + ions) m/z 668 (M+H) . monochloro isotope pattern. Anal Calcd. for C33H32N3O3F6CI + H2O: C, 57.77; H, 5.00; N, 5.78; Cl, 5.06 Found: C, 57.44; H, 5.11; N, 5.78; Cl, 5.06. Example 6A* N-(2,2,2-Trifluoroethyl)-9-(4-[4-[[[4'-(trilluoro et yl)[1 ,1 -bip enyl]-2- yl]carbonyl]amino]-1 -pιperidinyl]butyl]-9H-fluorene-9-carboxamide, N-oxide. A CH 2 CI 2 (5 ml) solution of Example 10A* compound (200 mg, 0.274 mmol) was added to a 0°C solution of saturated NaHC0 3 (5 ml) . After several minutes, a CH 2 CI 2 (2 ml) solution of meta- chloroperbenzoic acid (63 mg, 80%, 0.292 mmol) was added. A further amount of meta-chloroperbenzoic. acid (23 mg, 80%, 0.107 mmol) was added in three portions over the next 1 h while the reaction was allowed to come to room temperature. The reaction mixture was partitioned between CH 2 CI2 and saturated NaHC0 3 after 1.45 h. The aqueous layer was extracted twice with CH 2 CI 2 , the organics dried over Na 2 S0 4 , and concentrated in vacuo to a colorless foam (200 mg) . The residue was purified by flash column chromatography (silica gel, 50 ml), eluting with 5% MeOH:CH 2 Cl2, then 10% MeOH:CH 2 Cl 2 with 1% NH4OH, to give title compound (151 mg, 77.6% yield) as a colorless solid, mp 136-142°C (shrinks 115°C] . Rf = 0.38 (10% MeOH:CH 2 Cl 2 ) . MS: (electrospray, + ions) m/z 710 + (M+H) . Example 6B* N-(2,2,2-Trif luoroethyl)-9-[4-[4-[[[4'-(trilluoromet yl)[ 1 , 1 -biphenyl]-2- yl]carbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide, N-oxide. (Alternative Preparation) To a CH 2 CI 2 (20 ml) solution of Example 10A* compound (5.3 g, 7.64 mmol) in an adiabatic water bath was added peracetic acid (1.7 ml, 32% in AcOH, 8.08 mmol) . A further amount of peracetic acid (0.9 ml, 32% in AcOH, 4.28 mmol, 12.3 mmol total) was added in three portions over the next 1.5 h. The reaction mixture was partitioned between CH 2 CI 2 and IN KOH, the aqueous layer extracted twice with CH 2 CI 2 , the combined organics washed with H 2 O, .dried over Na 2 Sθ , and concentrated in vacuo to a foam (4.95 g) . The residue was crystalized from hot EtOH and H 2 O to give a colorless solid containing still impure solid. The crude material (5.5 g, combined with an identical reaction starting with 0.93 mmol Example 10A* compound) could be purified by flash column chromatography (silica gel, 200 g) , eluting with 10% MeOH:CH 2 Cl 2 to give the title compound (3.5 g, 57% yield) as a colorless solid. Examole 7 * 9-[4-[4-[[2- (2-Benzothiazolyl)benzoyl]amino] -1- piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H- fluorene-9-carboxamide, N-oxide A solution Example 9* compound (free base, 14.589 g, 21.3 mmol) in CH 2 C1 2 (= 300 mL) at room temperature was treated with 4.40 mL 32% peracetic acid in dilute HOAc. After 2 hours, additional peracetic acid solution (1.2 mL) was added and stirring continued for 1 hour. The mixture was quenched with saturated NaHC0 3 and the CH 2 CI 2 layer was separated. The organic extract was washed with half-saturated NaCl, dried (Na 2 S0 4 ), and filtered. The solution was diluted with EtOAc (= 200 mL) and let stand to give a white precipitate which was collected by filtration, washed with EtOAc and Et 2 θ, and dried in vacuo to give title compound (8.582 g, 55% corrected for solvent): mp 189-191°C. MS: ESI (M+H) + 699; (M-H)" 697. Example 8 * 9-[4-[4-[(5-Chloro-2-methylbenzoyl)amino]-1 -piper-idinyl]butyl]- N-(2,2,2-trilluoroet yl)-9H-lluorene-9-carboxamide, N -oxide. A . To a stirred slurry of C0 2 H (2.05 g, 12.0 mmol), Example 11* Part C compound (6.22 g, 12.0 mmol), N-methylmorpholine (3.30 mL, 30.0 mmol) and HOBt»H 2 0 (1.80 g, 12.0 mmol) in dichlormethane (100 mL) at room temperature under argon was added EDAC (2.61 g, 13.7 mmol) . Within 1 h, a clear yellow solution had formed. After 3 h, the reaction mixture was partitioned between EtOAc and saturated sodium bicarbonate solution. The organic extract was washed with brine, dried (Na 2 S0_)) and evaporated. The resulting solid was recrystallized from EtOAc/hexanes to give the free base of the title compound, 6.56 g, 91%, mp 201-202°C. The free base was dissolved in dichloromethane (25 mL) and treated with 4 H hydrogen chloride in dioxane (3 mL) . Evaporation provided title compound as the hydrogen chloride salt, an amorphous solid, 7.15 g, 100% MICROAnal. Calcd for C 33 H 35 CIF 3 N 3 O; + HCl + 0.4 H 0 + 0.22 dioxane: C, 61.55; H, 5.88; N, 6.36; Cl, 10.72 Found: C, 61.56; H, 5.86; N, 6.28; Cl, 10.95 B. To a rapidly stirring slurry of Part A compound (635 mg, 1.00 mmol) and sodium bicarbonate (100 mg, 1.2 mmol) in dichloromethane (20 mL) and saturated sodium bicarbonate solution (5 mL) at room temperature under argon, was added m-chloroperbenzoic acid (mCPBA, 220 mg, 80% purity, 1.05 mol) portionwise over the course of 20 min. After 1 h, the reaction was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The organic layer was dried (MgSO_j) and evaporated. Purification by flash chromatography or. silica gel (5 x 15 cm column, 3:17 methanol/EtOAc) followed by redissolving the evaporated residue m dichloromethane and filtration through a 2 mM nylon filter provided title compound as a white solid, 450 mg, 73%, mp 124-127°C. MICROAnal. Calcd for C 33 H 3 5CIF 3 N 3 O, 1.5 H : 0 + 0.6 EtOAc: C, 61.27; H, 6.22; N, 6.22; Cl, 5.11; F, 8.21 Found: C, 61.33; H, 6.38; N, 6.09; Cl, 5.19; F, 8.21 Mass Spectrometry: (electrospray, + ons) m/z 614 (M+H) Ex mple Q * 9-[4-[4-[[2-(2-Benzothιazolyl)benzoyl]amιno]-1 -pιperιdιnyl]butyl)-N- (2,2,2-trιlluoroethyl)-9H-fluorene-9-carboxamιde. monohydrochloride A . A slurry of phthalic anhydride (7.1 g, 47.9 mmol) and 2-ammothιophenol (7.0 mL, 8.2 g, 65.4 mmol) in glacial acetic acid (50 mL) was heated at reflux for 3 hours. The cooled reaction mixture was poured into = 400 mL ice water to give a gummy precipitate. The mixture was extracted with EtOAc and the EtOAc extract was washed with 1 N HCl and H 2 O. The organic layer was extracted three times with saturated NaHC0 3 and the pooled bicarbonate extracts were acidified with 6 N HCl to give a precipitate which was collected by filtration, washed with H 2 O, and dried in vacuo to give title compound (11.27 g, 92%) as a white solid: mp 188-189°C. B. A slurry of Part A acid (2.048 g, 8.0 mmol) and Example 11* Part C diamine (3.960 g, 7.64 mmol) in CH 2 CI 2 (80 mL) was treated with N-methyl morpholine (2.1 mL, 1.93 g, 19.1 mmol) and DMF (6 mL) . The slurry was then treated successively with HOBT hydrate (1.12 g, 8.3 mmol) and EDAC (1.630 g, * 8.5 mmol). The mixture became homogeneous within 3 hours. After 4 hours, the solution was partitioned between EtOAc/Et 2 θ and saturated NaHC0 3 . The organic layer was separated, washed twice with H 2 O and brine, then dried (Na 2 S0 4 ) , filtered, and stripped. Flash chromatography (Merck Siθ 2 , 8/92-MeOH/CH 2 Cl 2 ) gave title compound (5.369 g, 103% of theory, 96% corrected for solvent) as a white foam. C. Part B compound (the free base, 5.254 g, 7.16 mmol corrected for solvent) was dissolved in = 25 rnL of 1,4-dioxane and treated with 2.2 L of 4 N HCl m 1,4-dioxane at room temperature. The resulting homogeneous mixture was added via canula to = 350 mL of Et 2 θ with rapid swirling. The precipitate was collected by filtration, washed with Et 2 θ, and dried in vacuo at 45°C to give title compound (5.113 g, 95% corrected for solvent) as a white solid. MS (ESI) : (M+H) + 683; (M-H) " 681 Exampl e 10 A* 9-[4-[4-[[2-(2,2,2-Trilluoroethoxy)benzoyl]amιno]- 1 -pipeπdinyljbutyl]- . N-(2,2,2-trιlluoroethyl)-9H-lluorene-9-carboxamιde, monohydrochloride. To a solution of the acid (3.2g, 12 mmol) in methylene chloride (35 ml) was added oxalyl chloride (1.8ml, 21 mmol) followed by a fe drops of DMF. The reaction bubbled vigorously and stirred under argon at room temp 2h. The solvent was evaporated in vacuo at less than 25°C, and the residue was dissolved in methylene chloride (50 ml) . This solution was added dropwise to a solution of the Example 11* Part C diamine (5.0g, 9.6 mmol) and triethylamine (6.7ml, 48 mmol) in methylene chloride (50 ml) at -5°C. The reaction stirred in a melting ice bath lh. The reaction mixture was diluted with MeCl and washed once with water. The organic layer was dried (Na SO.;) , and the solvent was removed A vacuo to give an off-white solid foam which was purified by flash column chromatography (SiO;, 800g) eluted with 5% MeOH: 0.5%NH 4 OH: MeCl to give a clear oil (5.23g, 91.5% pure) . This oil was purified again by flash column chromatography (SiO , 500g) eluted with 3%MeOH: MeCl to give a clear oil (4.11g, 61.4% yield) . This oil (4.07g) was dissolved in MeOH (25ml) and 1.1 N ethereal HCl (8.0ml) was added. The solvent was removed in vacuo to give title compound as a white solid foam (4.17g) . mp 129-142°C MS (ESI, + ions) m/z 694 (M+H) Anal, calc'd for C 3 oH 3 -F.;N;0 -HCl -r* 1H 2 0: C, 62.61; H, 5.39; K, 5.62 Found: C, 62.48; H, 5.19; I.\ 5.60 Example 10B* 9-[4-[4-[[2-(2,2.2-Trilluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]- N-(2,2,2-tri.luoroethyl)-9H-lluorene-9-carboxamide, monohydrochloride. To a slurry of 4 '- (trifluoromethyl) -2-biphenyl carboxylic acid (50.0 g, 190 mmol) in methylene chloride (500 ml) was added the oxalyl chloride (28.7 ml, 330 mmol) followed by DMF (5 drops) . The reaction bubbled vigorously and stirred at room temperature under argon 2 h. All solid had dissolved and evolution of gas had ceased. The solvent was removed in vacuo , and the residue was dissolved in methylene chloride (400 ml) . This solution was added dropwise to a solution of compound NHz , 4-amino-l-benzylpiperidine (36.4 ml, 180 mmol) and triethylamine (65.4 ml, 470 mmol) in methylene chloride (300 ml) cooled in an ice/brine bath. After the addition was complete, a lot of solid had precipitated from solution. An additional 200 ml methvlene chloride was added. The reaction stirred at room temperature under argon 18h. The reaction was diluted with methylene chloride (600 ml) and washed twice with saturated NaHCO,, once with brine and once with IN KOH. The organic layer was dried with Na 2 S0 , and the solvent removed in vacuo to give a white solid. This solid was recrystallized from hot EtOH (1 L) and washed with heptane to give title compound as a white solid (59.1 g, 75.6% yield). The mother liquor was concentrated to dryness and recrystallized from hot EtOH (300 ml) and washed with heptane to give a second crop of title compound as a white solid (12.7 g, 16.2% yield) . B. To a solution of Part A compound (59.0 g, 130 mmol) in methanol (300 ml) and ethanol (300 ml) was added the cyclohexene (150 ml, 1.5 mol) and 20% palladium hydroxide on carbon (11.8 g) . The reaction was heated in an argon atmosphere to reflux (80°C) and stirred at that temperature 2.5 h. The hot mixture was filtered through Celite, washed with methanol and the solvent removed i vacuo to give title compound as a white solid (46.7 g, 99.6% yield) . To a stirred solution of Part B compound (18.0g, 49 mmol) in DMF (100 ml) at room temperature under argon was added potassium carbonate (12.6g, 49 mmol) followed by compound (prepared as described in Example 11* Part C(2)) (21.Og, 49 mmol) . The reaction was heated to 50°C and stirred at that temp under argon 24h. After cooling, the reaction was filtered to remove potassium carbonate, and the filter cake was rinsed with ethyl acetate. The filtrate was partitioned between 20% heptane .in ethyl acetate and water. The organic layer was washed five times with water and once with brine. The organic layer was dried (NaτSO.;) and the solvent removed in vacuo to give a beige solid (30 g) . This solid was recrystallized from 300 ml 25% EtOAc in heptane to give title compound as an off-white solid (27.0 g, 78.9% yield), mp 164-68°C. Example U * 9-[4-[4-[ (2-Pyridinylbenzoyl)amino] -1-piperidinyl] butyl] -N-(2,2,2-trifluoroethyl)-9H-fluorene-9- carboxamide. dihydrochloride A. To a degassed solution of 2-bromopyridine (1.9 ml, 20 mmol) in ethylene glycol dimethyl ether (60 ml) under argon, tetrakis(triphenylphosphane) palladium 0 (700 mg, 0.6 mmol) was added. After stirring for 10 min., 2-methylphenyl boronic acid ' (2.9 g, 22 mmol) was added followed by sodium bicarbonate (5.04 g, 60 mmol in 60 ml water) . The mixture was heated to reflux (~85°C) and stirred at that temp overnight. After cooling to room temp., the solvent was removed in vacuo, the residue was partitioned between water and ether, and the aqueous layer was extracted twice with ether. The combined organic layers were dried (Na S0 4 ), and the solvent was removed in vacuo to give a black oil. This oil was distilled under high vacuum at ~95°C to give title compound (2.75 g, 81.6% yield) as a clear oil. B. A solution of Part A compound (850 mg, 5.0 mmol) and potassium permanganate (1.9 g, 12.0 mmol) in water (25 ml) was heated to reflux (~100°C) and stirred at that temperature 1 h. The hot reaction mixture was filtered, and the filtrate was evaporated to dryness. The solid residue was dissolved in water (5 ml) and acidified with acetic acid to pH 4-5. The resulting precipitate was isolated by filtration and rinsed with water to give a white solid (800 mg) which was recrystallized from hot ethanol (12 ml) to give title compound as a white solid (453 mg, 45.3% yield) . C. C(l) To a solution of 9-fluorenecarboxylic acid (50 g, 240 mmol) in THF (1200 mL) at 0°C was added dropwise a solution of n-butyllithium (2.5M, 211 mL, 530 mmol) in THF. The yellow reaction was stirred at 0°C for 1 h, then 1,4-dibromobutane (31.3 L, 260 mmol) was added dropwise over 30 min. The reaction was stirred at 0°C for 30 min, then the reaction was warmed to RT for 30 h. The reaction was extracted with water (3 x 750 mL) . The combined aqueous layers were extracted with ethyl ether (800 mL) . The aqueous layer was made acidic with HCl solution (IN, 500 mL) , then extracted with dichloromethane (3 x 750 mL) . The combined organic layers were dried over MgS0 . Evaporation gave title compound (71 g, 85%) as a white solid. C(2) To a solution of Part C(l) acid (60 g, 173 mmol) and DMF (100 μL) in CH 2 CI 2 (600 mL) under argon at 0 * C was added oxalyl chloride (104 L, 2.0M in CH 2 CI 2 , 208 mmol) dropwise. The reaction was stirred at 0 * C for 10 min, then warmed to RT and stirred for 1.5 h. The reaction was concentrated in vacuo to give the crude acid chloride as a yellow oil. To a suspension of 2,2,2-trifluoroethyla ine hydrochloride (25.9 g, 191 mmol) in CH 2 C1 2 (500 mL) at 0°C under argon was added triethylamine (73 mL, 521 mmol) followed by dropwise addition of a solution of the crude acid chloride in CH 2 CI 2 (15 mL) . The reaction was stirred at O'C for 1 h, diluted with CH 2 CI 2 (500 mL) , and washed with water (2 x 300 mL) , IN HCl (2 x 300 mL) , saturated NaHC0 3 (2 x 300 mL) , and brine (2 x 300 mL) , then dried over MgS0 4 . Evaporation gave 80 g of a oil which was purified by flash chromatography on silica gel (2.5 kg). The crude product was loaded in a mixture of CH 2 CI 2 and hexane, and eluted with a step gradient of 10% EtOAc/hexane (4L) to 15% EtOAc/hexane (2L) to 20% EtOAc/hexane (4L) . Pure fractions were combined and evaporated to give title compound (52.5 g, 71%) as a white solid (mp 88-92 * C) . C(3). HN )—-N 1 HBOC To a solution of 4-amιnoben∑ylpιperidine (20 g, 105 mmol) in dichloromethane (200 mL) at 0°C was added dropwise (about 30 min) a solution of di-tert- butyldicarbonate (25.2 g, 115 mmol) m dichloro¬ methane (50 mL) . The reaction was stirred at RT for 2 h, then evaporated to give an off-white solid. The product was triturated with ethyl ether (2 X 20 mL) to give a white solid (26.5 g, 90%) . The product was dissolved in ethanol (200 mL) . To the resulting solution at RT was added glacial acetic acid (10 mL, 177 mmol) and 10% palladium on activated carbon (2.6 g) . Hydrogenation on a Parr apparatus (Initial pressure 40 psi) was maintained for 19 h. The reaction was filtered through Celite and the filtrate was concentrated to dryness. The residue was dissolved in chloroform (500 mL) and washed with IN KOH saturated with sodium chloride (3 x 100 mL) . The aqueous layers were combined and extracted with chloroform (3 x 80 mL) . Combined organics were cried over sodium sulfate and evaporated to give title compound (16 g, 90%) as a white solid (m.p. 157- 159°C) . C(4) NHBOC A mixture of Part C(2) compound (29.5 g, 69.2 mmol), Part C(3) compound (14.5 g, 72.7 mmol), and anhydrous potassium carbonate (11.5 g, 83.0 mmol) in DMF (100 mL) was stirred at 50'C for 48 h, concentrated to dryness, and taken up in CH 2 CI 2 (500 mL) . The solution was washed with saturated NaHC0 3 (3 x 80 mL) and brine (2 x 80 mL) , then dried over MgS0 4 . Evaporation gave a yellow oil which was ^ purified by flash chromatography on silica gel (600 g) , loaded in CH 2 CI 2 , and eluted with a step gradient of 2% MeOH/CH 2 Cl (3D to 3% MeOH/CH Cl 2 (4L) . Pure fractions were combined and evaporated to give title compound (30 g, 86%) as a white foamy gum. C(5) To a solution of Part C(4) compound (30.5 g, 60.4 mmol) in dioxane (120 mL) was added 4N HCl in dioxane (121 mL, 483 mmol) . The reaction was stirred at RT for 4 h, then concentrated in vacuo to provide title compound (30 g) as a white foamy solid, containing a residual amount of dioxane. D. 9- [4- [4- [ (2-Pyridinylbenzoyl)amino] -1- piperidinyl] -butyl] -N- (2,2, 2-trifluoroethyl) - 9H-fluorene-9-carboxamide. dihydrochloride To a solution of the Part B acid (145 mg, 0.7 mmol) in methylene chloride (2 ml) was added oxalyl chloride (110 μl, 1.3 mmol) followed by a few drops of DMF. The reaction bubbled vigorously, turned. yellow, and stirred under argon at room temp 2 h. The solvent was evaporated in vacuo at less than 25°C, and the residue was dissolved in methylene chloride (5 ml) . This solution was added dropwise to a solution of the Part C diamine (300 mg, 0.6 mmol) and triethylamine (400 μl, 2.9 mmol) in methylene chloride (5 ml) at -5°C. The reaction stirred in a melting ice bath overnight. The reaction mixture was diluted with MeCl^ and washed once with water. The organic layer was extracted twice with IN HCl. The combined acid extractions were made basic with IN NaOH and extracted twice with EtOAc. The combined EtOAc layers were dried (Na 2 S0 4 ) , and the solvent was removed n vacuo to give a brown oil which was purified by flash column chromatography (Si0 , 90g) eluted with 5% MeOH: 0.5% NH 4 OH:MeCl 2 to give a clear oil (170 mg, 46.8% yield) . 160 mg of this oil was dissolved in MeOH (2 ml) and 1.1 N ethereal HCl (800 μl) was added. The solvent was removed in vacuo to give title compound as a light yellow solid (173 mg) . mp 146-50 °C (dec.) MS (ESI, + ions) m/z 627 (M+H) Anal, calc'd for C37H 3 -F3N 4 O 2 -2HC1 + 2H 2 0: C, 60.41; H, 5.89; N, 7.62 Found: C, 60.38; H, 5.86; N, 7.50 The following additional compounds were prepared employing procedures as set out herein¬ before. Example ua* 1:1 HClSalt 9-[4-[4-(Benzoylamino)-1-piperidinyl]butyl]-N-(2,2, 2-trif luoroethyl)- 9H-thioxanthene-9-carboxamide, monohydrochloride. M . P . 145 -150°C MS (ES , + ions ) m/ z 582 (M+H) Elemental Anal. Calc'd for C 3 2H 34 N 3 θ2F 3 S + 1.0 HCl 0.75 H 2 0: C, 60.94; H, 5.67; N, 6.66; F, 9.04 Found: C, 60.97; H, 6.00; N, 6.26; F, 9.15. Example 12* 9-[4-[4-[(2-Phenoxybenzoyl)amino]-1 -piperidinyl]butyl]-N-(2,2, 2-trif luoroethyl)- 9H-thioxanthene-9-carboxamide, monohydrochloride. M.P. 204-208°C MS (ES, + ions) m/z 578 (M+H) Elemental Anal. Calc'd for C 3 8H 38 0 3 SF 3 N3 + 1 HC1+0.5 H 2 0: C, 63.46; H, 5.61; N, 5.84; S, 4.46 Found: C, 63.45; H, 5.51; N, 5.72; S, 4.15. Example 13* 9-[4-[4-[([1,1-Biphenyl]-4-ylcarbonyl)amino]-1-piperidinyl]-3,3-dimethylbutyl]- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. M.P. 95-101°C MS (electrospray, - ions) m/z 654 (M+H) Example 1 dihydrochloride salt 9-[4-[4-[[(3-Phenyl-2-pyridinyl)carbonyi]amino]- 1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)- 9H-fluorene-9-carboxamide, dihydrochloride salt. MS (ESI, + ions) m/z 627 (M+H) + ; (ESI, - ions) m/z 625 (M-H)- Example 15' N-[1-[4-[9-[[(2.2,2-Trifluoroethyl)amino]carbonyl]- 9H-lluorene-9-yl]but-.-yl]piperidin-1-yl]- 2-[N-(2,2,2-trifluoroethyl)amino]pyridine-3-carbox- a ide, hydrochloride. MS (ESI, + ions) m/z 648 (M+H); (ESI, - ions) m/z 646 (M-H) Example 16 * contains 0.1 mole of ethyl ether N-[1 -[4-[9-[[(2,2,2-Trifluoroethyl)amino]carbonyl]- 9H-fluoren-9-yl]but-1 -yl]piperidin-4-yl]-2-phenyl- pyridine-3-carboxamide, hydrochloride. S ( ESI-NH 3 , + ions ) 627 (M+H ) Example 17 * 9-[4-[4-[([1 ,1-Biphenyl]-4-ylcarbonyl)amino]-1-piper- idinyl]-3-hydroxybutyl]-N-(2,2,2-trifluoroethyl)- 9H-fluorene-9-carboxamide, monohydrochloride. M.P. 163-165°C MS (electrospray, + ions) m/z 642 (M+H) Example 18 1 dihydrochloride salt 9-[4-[4-[[[3-(4-Fluoro-3-methylphenyl)-2-pyridinyl]-carbonyl]amino]-1- piperidinyl]butyl]-N-(2 f 2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, dihydrochloride. MS (ESI, + ions) m/z 659 (M+H) + ; (ESI, - ions) m/z 657 (M-H)- Elemental Anal. Calc'd for C 38 H 38 F 4 N 4 O 2 +2 HCl + 1.5 H 2 O + 0.2 Et 2 θ + 0.2 dioxane C, 60.12; H, 5.94; N, 7.08; F, 9.61; Cl, 8.96 Found: C, 60.17; H, 5.89; N, 7.24; F, 10.48; Cl, 8.91 Ex m le 19* dihydrochloride salt 9-[4-[4-[[[3-(2-Thienyl)-2-pyridinyl]carbonyl)amino]-1-piperidinyi]butyl]- N-(2,2,2-trrfluoroetl.yl)-9H-fluorene-9-carboxamide, dihydrochloride. MS (ESI, + ions) m/z 633 (M+H) + ; (ESI, - ions) m/z 631 (M-H)- Example 20* contains 0.15 mole of ethyl ether N-(2 > 2,2-Trifluoroethy!)-9-[4-[4-[[[2-[(2,2,2-trifluoroethyl)thio]-3-pyridinyl]carb- onyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide, dihydrochloride. ( ESI -NH3 , + ions ) 665 (M+H ) ; 663 [M-H ] E xam le gr 9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1 -piperidinyl]butyl]- N-(2,2.2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. (electrospray, + ions) m/z 648 (M+H) Example 22* dihydrochloride salt 9-[4-[4-[[(3-Cyclohexyl-2-pyridinyl)carbonyl]amino]-1 -piperidinyl]butyl]- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, dihydrochloride. MS (ESI, + ions) m/z 633 (M+H) + ; (ESI, - ions) m/z 631 (M-H)- Elemental Anal. Calc'd for C 37 H 42 F 3 N θ 2 +2 HCl + 1.5 H 2 0 + 0.25 Et2θ: C, 60.69; H, 6.60; N, 7.45; F, 7.58; Cl, 9.43 Found: C, 60.89; H, 6.98; N, 7.51; F, 7.25; Cl, 9.83 Example 23 ' 9-[4-[4-[[2-(4-Mθ holinyl)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2- trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. MS (electrospray, + ions) m/z 635 (M+H) Example 2 ' 9-[4-[4-[{4-Chloro-3-pyridinyl)carbonyl]amino]-1-piperidinyl]butyl]-N- (2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, dihydrochloride. M. P . 165 -73°C MS (ESI , + ions ) m/ z 585 (M+H ) E? aτnP e 25 ' 9-[4-[4-[[2-(4-Methyl-1-pιperazιnyl)benzoyl]amιno]-1 -pιperιdιnyl]butyl]- N-(2,2,2-trιfluoroethyl)-9H-fluorene-9-carboxamιde. dihydrochloride S (electrospray, + ions) m/z 648 (M+H; Example 26* trans-9-[4-[4-[[(1-Phenyl-3-cyclohexen-1-yl)carbonyl]amιno]-1-pι eπdιnyl]butyl]- N-(2,2,2-tπfluoroethyl)-9H-fluorene-9-carboxamιde, monohydroi-hloride M.P. 160-163°C MS (electrospray, + ions) m/z 630 (M+H) Example 27 * trans-9-[4-[4-[[(2-Phenylcyclohexyl)carbonyl]amιno]-1-pιpendιnyl]butyl]- N-fΣ.Σ.Σ-trit'uoroethy -ΘH-fluorene-θ-carboxamide monohydrochloride M.P. 156-159°C MS (electrospray, + ions) m/z 632 (M+H) Example 28* 9-[4-[4-[[(2-Phenyl-3-thienyl)carbonyl]amino]-1-piperidinyl]butyl]-N- (2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. MS (ES, + ions) m/z 632 (M+H) Example 2 ' 9-[4-[4-[(4-Phenyl-3-pyridinyl)carbonyl]amino]-1-piperidinyl]butyl]- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, dihydrochloride. M.P. 144-50°C MS (ESI, + ions) m/z 627 (M+H) Elemental Anal. Calc'd for C37H37F3N4O2 + 2 HCl + 1.2 H 2 0: C, 61.62; H, 5.79; N, 7.77 Found: C, 61.64; H, 5.80; N, 7.32 Examole 30' 9-[4-[4-([2-(1-Piperidinyl)benzoyl]amino]-1-pιperidinyl]butyl]-N-(2,2,2- trifluoroethyl)-9H-fluorene-9-carboxamιde, monohydrochloride. lectrospray, + ions) m/z 633 (M+H) TFA SI, + ions) m/z 618 (M+H) Example 32' TFA MS (ESI, + ions) m/z 754 (M+H) Example 33* 9-[4-[4-[[2-(2,4-Dichlorophenyl)benzoyl]amino]-1 -piperidinyl]butyl]-N- (2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. M . P . 123 - 128°C MS (electrospray, - ions) m/z 694 (M+H) Example 34' 9_[4-[4-[[(6-Phenyl-1-cyclohexen-1-yl)carbonyl]amino]-1-piperidinyl]butyl]- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. M.P. 110-114°C MS (electrospray, - ions) m/z 630 (M+H) Example 35' 9-[4-[4-[(2,5-D ' ιfluorobenzoyl)amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)- 9H-fluorene-9-carboxamide, monohydrochloride. M.P. 80-84°C MS (ESI, + ions) m/z 586 (M+H) Elemental Anal. Calc'd for C3 2 H3 2 F5N3O 2 + 1 HCl + 1.2 H 2 0: C, 59.71; H, 5.54; N, 6.53 Found: C, 59.68; H, 5.53; N, 6.44 Exam l 26* 9-[4-[4-([[2-[2,2,2-Trifluoro-1-(2,2,2-trifluoromethyl)ethoxy]-3-pyridinyl]carbonyl]- amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-tluorene-9-carboxamide, dihydrochloride. MS (ESI, + ions) 717 (M+H) ; (-ions) 715 (M-H) Example 37* dihydrochloride salt 9-[4-[4-[[(4-Phenyl-2-pyridinyl)carbonyl]amino]-1-piperidinyl]butyl]- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamιde, dihydrochloride. MS (ESI, + ions) m/z 627 (M+H) + ; (ESI, - ions) m/z 625 (M-H)- Elemental Anal. Calc'd for C37H37F3N4O2 + 2 HCl + 0.44 Et2θ + 3.0 H 2 0: C, 59.21; H, 6.33; N, 7.13; F, 7.25; Cl. 9.02 Found: C, 59.59; H, 6.01; N, 6.97; F, 7.10; Cl, 9.17 Sa le 38* 9-[4.[4_[[2,6-Bis(trifluoromethyl)benzoyl]amino]-1-piperidinyl]butyl]-N- (2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. M.P. 145-150°C MS (electrospray, - ions) m/z 686 (M+H) Exampl e 3 9 * contains 0.05 mole of ethyl ether 9-[4-[4-[[[2-(4-Chlorophenyl)-3-pyridinyl]carbonyl]amino]-1-piperidinyl]butyl]- N-(2,2,2-triiluoroethyl)-9H-fluorene-9-carboxamide, dihydrochloride. (ESI-NH3, + ions) (M+H) 661 Example 40* contains 0.12 mole of ethyl ether N-(2,2,2-Trifluoroethyl)-9-[4-[4-[[[2-[(3,3,3-trifluoropropyl)thio]- 3-pyridinylJcarbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene- 9-carboxamide, monohydrochloride. (ESI-NH3, + ions) (M+H) 679 Example 41' 9-[4-[4-[[2-(4-Pyridinyl)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2- trifluoroethyl)-9H-fluorene-9-carboxamide, dihydrochloride. M.P. 140-150°C (shrinking commencing at 115°C) MS (electrospray, - ions) m/z 627 (M+H) + Elemental Anal. Calc'd for C 37 H 37 F 3 N θ 2 '2 HCl* 2.14 H 2 0: C, 60.21; H, 5.91; N, 7.59; Cl , 9.60; F, ".72 Found: C, 60.21; H, 6.08; N, 8.01; Cl , 9.23; F, 7.37 Example 42* 9-[4-[4-[[(4,4'-Difluoro[1,1'-biphenyl]-2-yl)carbonyl]amιno]-1-pιperidinyl]butyl]- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamιde, monohydrochloride. M.P. 131-34°C MS (ESI, + ions) m/z 662 (M+H) Elemental Anal. Calc'd for C38H36F5N3O 2 + HCl + 1.7 H 2 0: C, 62.63; H, 5.59; N, 5.77 Found: C, 62.59; H, 5.29; N, 5.82 Example 43* 9-[4-[4-[[2-(2-Oxo-1-pyrrolidinyl)benzoyl]amino]-1-piperidinyl]butyl]-N- (2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. S (electrospray, + ions) m/z 633 (M+H; Example 44* Contains: 1.25H 2 OO.12H 5 C 2 θC 2 H 5 N-(2,2,2-Trifluoroethyl)-9-[4-[4-[[[2-(3,3,3-trifluoropropoxy)-3-pyridinyl]carbonyl]- amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide. monohydrochloride. MS (ESI, + ion) m/z 663 (M+H) ; (-ion) 661 (M-H) Elemental Anal. Calc'd for C34H3 6 N 4 θ3F 6 • HCl • 1.25 H 2 0 • 0.12 H5C2OC2H5 C, 56.69; H, 5.62; N, 7.67; Cl, 4.85; F, 15.60 Found: C, 56.98; H, 5.52; N, 7.63; Cl, 4.74; F, 15.31 Example 45' 9-[4-[4-{[(4-Chloro[1 ,1-biphenyl]-2-yl)carbonyl]amino]-1-piperidinyl]butyl]- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. M . P . 123 -128°C MS ( electrospray, - ions ) m/ z 661 (M+H ) Example 46 ' Contains: 0.8H 2 O 9-(4-[4-[[[2-( 1 -Methylethoxy)-3-pyridinyl]carboπyl]amino]- 1 -piperidinyl]butyl]- N-(2,2.2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. MS (ESI, + ion) m/z 609 (M+H); (-ion) 607 (M-H) Elemental Anal. Calc'd for C 34 H3 9 N 4 O 3 F 3 • HCl • 0.8 H 2 0: C, 61.91; H, 6.36; N, 8.49; Cl, 5.38; F, 8.64 Found: C, 61.63; H, 6.45; N, 8.31; Cl, 5.80; F, 8.50 Example 47 * Contains: 1.5H 2 0 9-[4-[4-[[[2-[(1-Methylethyl)thio]-3-pyridinyl]carbonyl]amino]-1 -piperidinyl]butyl]- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, dihydrochloride. MS (ESI, + ion) m/z 625 (M+H); (-ion) 623 (M-H) Elemental Anal. Calc'd for C 34 H 3 9N 4 O 2 SF 3 • 1.65 HCl • 1.5 H 2 0: C, 57.36; H, 6.18; N, 7.87; Cl, 8.22; F, 8.01; S, 4.50 Found: C, 57.56; H, 6.37; N, 7.74; Cl , 8.12; F, 8.06 S. 4.47 Example 48* contains 2.14 moles H 2 0 Eft. Mol Wt. = 738.105 9-[4-[4-[[2-(3-Pyridinyl)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2- trifluoroethyl)-9H-fluorene-9-carboxamide, dihydrochloride. M. P . 120-130°C ( shrinking commencing at 110°c ; MS ( electrospray, - ions ) m/ z (M+H) + = 627 Elemental Anal. Calc'd for C37H37F3N4O2 • 2 HCl •2.14 H 2 0: C, 60.21; H, 5.91; N, 7.59; Cl, 9.60; F, 7.72; Found: C, 60.26; H, 6.26; N, 7.04; Cl , 9.09; F, 7.15 Example 49* o- 9-[4-[4-[([1,1-Biphenyl]-4-ylcarbonyl)amino]-1-piperidinyl]-3,3-difluorobutyl]- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, N-oxide. M.P. 185-188°C MS (electrospray) (M+H) + 642; (M-H) " 640 Example 50' 9-[4-[4-[[2,5-Bis(trifluoromethyl)benzoyl]amino]-1-piperidinyl]butyl]-N- (2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. MS (electrospray, + ions) m/z 686 (M+H) Example 51' 9-[4-[4-[(5-Chloro-2-methylbenzoyl)amιno]-1-pιperidιnyl]butyl]-N-(2,2,2- trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. MS ( electrospray, + ions ) m/ z 598 (M+H ) Example 52 * 9-[4-{4-[[(3,6-Dichloro-2-pyridinyl)carbonyl]amιno]-1 -pιperidinyl]butyl]-N- (2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamιde, monohydrochloride. MS (electrospray, + ions) m/z 619 (M+H) [2 Cl isotope pattern] Example 53* 9-[4-[4-[[2-(Tetrahydro-2-oxo-2H-1,3-oxazin-3-yl)benzoyl]amino]-1- piperidinyl]buty.]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. Contains: 0.6 H 2 O 0.2 H 5 C 2 OC2H5 9-{4-[4-[[(5-Chloro-2-thienyl)carbonyl]amino]-1-piperidinyl]butyl]-N- (2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. MS (ESI, + ion) m/z 590 (M+H) ICl Isotope Pattern Elemental Anal. Calc'd for C3 0 H 31 N 3 O 2 CISF 3 • HCl • 0.6 H 2 0 • 0.2 H5C 2 OC2H5: C, 56.72; H, 5.44; N, 6.44; Cl, 10.87; F, 8.74 S, 4.92 Found: C, 56.43; H, 5.37; N, 6.38; Cl, 10.70; F, 8.73 S, 5.36 9-[4-[4-f[2-Fluoro-5-(trifluoromethyl)benzoyl]amino]-1-piperidinyl]butyl]- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. (M+H) + 636; (M-H) " 634 Example 56* 9-[4-[4-[(5-Chloro-2-methoxybenzoyl)amino]-1-piperidinyl]butyl]-N- (2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide. monohydrochloride. M.P. 108-113°C MS (electrospray, - ions) m/z 615 (M+H) Example 57' Contains: H 2 0- 0.15 H5C2OC2H5 9-[4-[4-[[(2:2 , -Bithiophen-5-yl)carbonyl]amino]-1-piperidinyl]butyl]-N- (2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. MS (ESI, + ion) m/z 638 (M+H) Elemental Anal. Calc'd for C 34 H 34 N 3 θ 2 S 2 F 3 • HCl • H 2 O • 0.15 H5C2OC2H5: C, 59.08; H, 5.52; N, 5.97; Cl, 5.04; F, 8.10 S, 9.12 Found: C, 58.88; H, 5.41; N, 5.90; Cl, 4.97; F, 8.24 S, 9.22 Example 58* 9-[4-[4-[I2-(Phenylmethylamino)benzoyl]amino]-1-piperidinyl]butyl]-N- (2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. ESI (M+H) + 655 Examole 59* 9-{4-[4-([(3-Chlorobenzo[b]thiophen-2-yl)carbonyl]amino]-1 -piperidinyl]butyl]- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. S (ESI, + ions) m/z 640 (M+H) 1 Cl Isotope pattern Example 60' 9-[4-[4-[[(3,4-Dichloro-2-thienyl)carbonyl]amino]-1-piperidinyl]butyl]-N- (2,2,2-tri1luoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. M.P. 110-120°C (shrinking commencing at 95°C MS (electrospray, - ions) m/z (M+H) 624; 2 Cl isotope pattern Example 61* trans-9-[4-[4-[[(2-Phenylcyclopropyl)carbonyl]amino]-1-piperidinyl]butyl]- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride. M.P. 118-126°C MS (electrospray, - ions) m/z 590 (M+H) Elemental Anal. Calc'd for C35H38F3N3O2 + HCl + 0.82 H2O + 0.36 dioxane C, 65.07; H, 6.52; N, 6.25; Cl , 5.27; F, 8.47 Found: C, 65.07; H, 6.50; N, 6.12; Cl, 5.36; F, 8.25 Example $2* 9-[4-[4-[[[4-Chloro-4'-(trif luoromethyl)! 1 , 1 -biphenyl]-2-yl]-carbonyl]amino]- 1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride M.P. 123-128°C MS (electrospray, - ions) m/z 728 (M+H) Elemental Anal. Calc'd for C39H3 6 CIF6N 3 O 2 +HCI+0.5 H2O: •C, 60.55; H, 4.95; N, 5.43; Cl, 9.17 Found: C, 60.54; H, 4.84; N, 5.22; Cl, 8.91 Example 63* 9-[4-[4-{[[4-Chloro-4'-(trif luoromethyl)! 1 ,1 '-biphenyl]-2-yl]carbonyl]amino]- 1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fiuorene-9-carboxamide, N-oxide. M . P . 142 -144°C MS (electrospray, - ions) m/z 743 (M-H) Elemental Anal. Calc'd for C39H36CIF6N 3 O 3 +0.88 H 2 O: C, 61.63; H, 5.01; N, 5.53; Cl, 4.66 Found: C, 61.64; H, 5.05; N, 5.42; Cl, 5.02 Example 64' 9-l4-[4-I(2-Pyridinylbenzoyl)amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)- 9H-fluorene-9-carboxamide, N-oxide, dihydrochloride. MS (M+H) + 643; (M-H) " 641 Elemental Anal. Calc'd for C 3 7H37F3N 4 O3+2 HCl + 1.94 H 2 0: C, 59.21; H, 5.76; N, 7.46; F, 7.59; Cl, 9.45 Found: C, 59.61; H, 5.81; N, 7.25; F, 7.19; Cl, 9.05 Exampl e 65 ' Λ/-(2,2,2-Trifluoroethyl)-9-!4-!4-[!!1-f{4-(trifluoromethyl)phenyl]methyl]- 2-piperidinyl]carbonyl]aminoj-1 -piperidinyl]butyl]-9H-fluorene- 9-cart>oxamide,dihydrochloride. MS (ES, + ions) m/z 715 [M+H] Elemental Anal. Calc'd for C 39 H 44 F 6 N 4 O 2 +2 H 2 O + 2 HCl C, 56.87; H, 6.12; N, 6.80 Found: C, 57.01; H, 6.01; N, 6.74 Example 66* N-[1-{4-[9-[[(2,2,2-Trifluoroethyl)amino]carbonyl]-9H-fluoren-9-yl]butyl]- 4-piperidinylJ-2-pyridinecarboxamide, N-oxide, dihydrochloride. MS (M+H) + @ 567; (M-H)' @ 565; (2M+H) + @ 1133 Elemental Anal. Calc'd for C3 1 H3 3 F3N 4 O 3 +2 HC1+1.7 H 2 0: C, 55.56; H, 5.78; N, 8.36; F, 8.50; Cl, 10.58 Found: C, 55.89; H, 5.81; N, 8.18; F, 8.66; Cl, 10.18 Example 6 ' trans-9-[4-[4-[[2-{2-Benzothiazolyl)ber.zoyl]arnino]-1-piperidinyl]butyl]- N-(2,2,2-trifluorOethyl)-9H-fluorene-9-carboxamide, N-oxide. MS (M+H) + @ 699; (M-H)" ~ 697 Elemental Anal. Calc'd for C39H37F3N4O3S+1.5 H 2 O+0.3 C 6 H 1 : C, 65.19; H, 5.93; N, 7.45; F, 7.58; Cl, 4.27 Found: C, 65.12; H, 5.85; N, 7.29; F, 7.23; Cl, 4.29 Example 68* 9-[4-[4-[[[1-(Cyclohexylmethyl)-2-piperidinyl]carbonyl]amino]-1-piperidinyl]- butyl]-N-(2,2,2-trifluoroethyl)-9H-1luorene-9-carboxamide, dihydrochloride. MS (ES, + ions) m/z 653 [M+H] Elemental Anal. Calc'd for C38H53CI 2 F3N 4 O2+1.5 H 2 0: C, 60.63; H, 7.50; N, 7.44; F, 7.57; Cl, 9.42 Found: C, 60.73; H, 7.74; N, 7.65; F, 7.22; Cl, 9.85 N-(2,2.2-Trifluoroethyl)-9-[4-[4-[[[1-(3.3,3-trifluoropropyl)-2-piperidinyl]carb- onyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide, dihydrochloride. MS (ES, + ions) m/z 653 [M+H] Elemental Anal. Calc'd for C34H 44 CI 2 F 6 N 4 O 2 +1.5 H 2 O: C, 54.26; H, 6.29; N, 7.44; F, 15.14 Found: C, 54.40; H, 6.21; N, 7.38; F, 15.53 Example 70- MS (ESI + ions ) m/ z 551 (M+H) Example 71* N-(2,2,2-Trifluoroethyl)-9-[4-[4-[(2,3,5-triiodobenzoyl)amino]-1- piperidinyl]butyl]-9H-fluorene-9-carboxamide, monohydrochloride. M.P. 178-182°C MS (ES, + ions) m/z 928 (M+H) Elemental Anal. Calc'd for C32H32CIF3I3N3O2+0.5 H 2 0: C, 39.51; H, 3.42; N, 4.32; Cl , 3.64 Found: C, 39.40; "H, 3.25; N, 4.27; Cl, 3.61 Example 72* 1:1 HCl Salt 9-[4-[4-(Benzoylamino)-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)- 9H-thioxanthene-9-carboxamide, monohydrochloride. M.P. or B.P. 145-150°C MS (ES, + ions) m/z 582 (M+H) Elemental Anal. Calc'd for C32H34N3O2F3S + 1.0 HCl 0.75 H 2 0: C, 60.94; H, 5.67; N, 6.66; F, 9.04 Found: C, 60.97; H, 6.00; N, 6.26; F, 9.15. Examples 73 * to 159* The following compounds were prepared by robotics procedures as described below . ROBOTICS P QCEPVRES Robotic Method for the Preparation of Amides A. Aqueous KOH/CHCI 3 B. R 5 C0 2 H, DIC, HOBT, DMF C. Optional HPLC Purification (Example 11 PartC) Please note that in the Examples 73* to 159*, for structures bearing only two single bonded substituents to nitrogen, the third substituent is always hydrogen, but it is not shown explicitly in the structures. Also, please note that in the Examples 73* to 159* for structures bearing oxygens and sulfurs with only one single bonded substituent, the second substituent is always hydrogen, but is not shown explicitly in the structures. Example 7 - m/z 694 (M+H) Example 74 1 m/z 672 (M+H) Example 75* m/z 659 (M+H) m/z 595 (M+H) Example 77* m/z 654 (M+H) Example 7S* m/∑ 586 (M+H) Exa ple 79' m/z 619 (M+H) Example 80' m/z 610 (M+H) Example 8T m/z 579 (M+H) Example 8?* m/z 609 (M+H) Exam le 83* m/z 565 (M+H) Example 84* m/z 611 (M+H) Example 85* m/z 710 (M+H) Example 86' m/z 553 (M+H) m/z 556 (M+H) Example 88* m/z 598 (M+H) Exam le 89* m/z 660 (M+H) Example 90* m/z 618 (M+H) Example 91* m/z 675 (M+H) Example 92* m/z 693 (M+H) Example 93* m/z 570 (M+H) Example 94* m/z 677 (M+H) Exa plP 95* m/z 677 (M+H) Exa le ''• > m/z 643 (M+H) Example 97* m/z 661 (M+H) Example 98* m/z 661 (M+H) Example 99* m/z 644 (M+H) Example inn* m/z 592 (M+H) Exa plP 1 rη * m/z 675 (M+H) Examp.p in?' m/z 688 (M+H) Example 103* m/z 660 (M+H) Example 104' m/z 709 (M+H) m/z 634 (M+H) Example 106* m/z 683 (M+H) Example 107* m/z 688 (M+H) Example 108* m/z 709 (M+H) Example 109* m/z 619 (M+H) Example 110' Br m/z 663 (M+H) Example 111* F^F F m/z 653 (M+H) ExamplP 1] ' F^F m/z 686 (M+H) Examp.P 1 " * m/z 678 (M+H Example 114* m/z 610 (M+H) _o H.C m/z 610 (M+H) Example 116* .0 H 3 C m/z 610 (M+H) Example 117* m/z 638 (M+H) Example 118* m/z 723 (M+H) Example U9* x> m/z 589 (M+H) Example 120* m/z 638 (M+H) Exam le 12I 1 m/z 638 (M+H) Example 122' m/z 565 (M+H) Example 123* m/z 596 (M+H) Example 124 ' m/z 565 (M+H) Example 125* m/z 653 (M+H) Example 126* m/z 751 (M+H) Example 127* m/z 678 (M+H) Example 128* m/z 694 (M+H) Examplp 129* m/z 719 (M+H) Exa p.P T * Cl m/z 654 (M+H) Example 13V m/z 680 (M+H) Example 132* m/z 704 (M+H) Example 133* m/z 699 (M+H) Exam le 134* m/z 733 (M+H) m/z 617 (M+H) Example 136* m/z 652 (M+H) Example 137* m/z 653 (M+H) Example 138' m/z 668 (M+H) Example 139* m/z 634 (M+H) Example 140' m/z 634 (M+H) ExamolP 1 "|* m/z 635 (M+H) Exa nlP 14?* m/z 655 (M+H) Exa plP 1 ?* m/z 617 (M+H) Example 144* m/z 572 (M+H) Example 145' m/z 558 (M+H) Example 146* m/z 672 (M+H) Example 147* m/z 673 (M+H) Exa plp 14ft' m/z 759 (M+H) ExamplP 149* m/z 698 (M+H) Exa le 15Q* m/z 665 (M+H) Example 151* m/z 709 (M+H) Exampl p 152* m/z 674 (M+H) Example 153' m/z 688 (M+H) Example 154* m/z 675 (M+H) Example 155* m/z 695 (M+H) Example 156* m/z 679 (M+H) Example 157' m/z 609 (M+H) Example 158* m/z 657 (M+H) Example 159' m/z 657 (M+H)

Claims: What We Claimed Is: 1. A compound which has the structure or or ,5*Q. / y. N— ( N-R 1 R 6 \ f o where Q Is — c — or ■ s— II o XIS.CHR 8 , -C— ,-CH-CH- or -C = C- ; I R n 9 _ R . 1 10 R 9 R 10 R 8 , R 9 and R 10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl; R 1 is a fluorenyl-type group of the structure £ R 1 is an indenyl-type group of the structure Z 1 and Z 2 are the same or di f ferent and are independently a bond, 0, S , S . • " NH-c- , -N c- , - c- or - c- . O o alkyl 0 0 OH with the proviso that with respect to £, at least one of Z 1 and Z 2 will be other than a bond; R 11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms; arylene or mixed arylenealkylene; R 12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaio- alkyl, trihaloalkylalkyl, heteroaryl, heteroaryl- al yl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the provisos that (1) when R 12 is H, aryloxy, alkoxy or —NH-C— . —N C— —c— arylalkoxy, then Z 2 is © a-M ° ' o or a bond and (2) when Z 2 is a bond, R 12 cannot be heteroaryl or heteroarylalkyl; Z is bond, 0, S, N-alkyl, N-aryl, or alkylene or alkenylene from 1 to 5 carbon atoms; R 13 , R 14 , R 15 , and R 16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl or aryloxy; R 15a and R 16a are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cyclo- heteroalkyl, alkenyl, alkynyl, alkoxy, alkyl¬ sulfonyl, arylsulfonyl, alkylthio, arylthio, amino¬ carbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy; R 2 , R 3 , R 4 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkyl¬ alkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; R 5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkyl¬ alkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycyclo- alkenylalkyl, heteroarylcarbonyl, amino, alkylamino, aryla ino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cyclohetero- alkylalkyl, aryl, heteroaryl, arylalkyl, arylcyclo- alkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxy- alkyl, arylalkoxy, arylazo, heteroaryloxo, hetero¬ arylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcar¬ bonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl* R 6 is hydrogen or C 1 -C 4 alkyl or C 1 -C 4 alkenyl; all optionally substituted with 1, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R 5 set out above; are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members; and N-oxides thereof; and pharmaceutically acceptable salts thereof. 2. The compound as defined in Claim 1 having the formula or or or pharmaceutically acceptable salts thereof. 3. The compound as defined in Claim 1 having the formula 4. The compound as defined in Claim 1 having the formula R 1 The compound as defined in Claim 1 wherein R 1 is fi The compound as defined in Claim 5. wherein B Z is a bond, 0 or S ; R 13 , R 14 , R 15 and R 16 are each H or one of R 15 and R 16 and one of R 13 and R 14 are halogen ; Z 1 is a bond or C=0; R 11 is alkylene or alkenylene; p o R 12 __ Z 2 is R 12a -NH-C- ϊ or R 12 *C— . R 12 is alkyl, fluorinated lower alkyl or polyfluorinated lower alkyl . 7. The compound as defined in Claim 1 having the structrure o II o it where Q is — c — or — s 1 — o Z is a bond, 0 or S ; where R 5 is cycloalkyl, phenyl, aryl, heteroaryl, or cycloalkyl, phenyl, aryl or heteroaryl, independently substituted at the ortho position with alkyl, alkoxy, haloalkyl (optionally substituted with up to 5 halogens), trifluoromethyl, aryl, aryloxy, haloalkoxy (optionally substituted with up to 5 halogens) , arylalkyl or arylalkoxy; R 6 is H or CH 3 ; R 13 and R 15 are independently H or F; Z 1 is a bond; R 11 is alkylene ; o o R 12 _ z 2 is a'kyl- NH- C— or CF 3 alkylNHC— or Z 2 is a bond and R 12 is alkyl . 8. The compound as defined in Claim 7 wherein R 11 is -{CH2)4-. Z 1 is a bond, and R 12 -Z 2 is p p CH 3 (CH 2 ) 2 -N-C— CF 3 CH 2 -N-C— H or H 9. The compound as defined in Claim 7 having the structure and R 12 is trifluoromethylalkyl or alkyl. 10. The compound as defined in Claim 1 having the structrure whereQIs — Z is a bond, 0 or S; where R 5 is cycloalkyl, phenyl, aryl, heteroaryl, or cycloalkyl, phenyl, aryl or heteroaryl, independently substituted at the ortho position with alkyl, alkoxy, haloalkyl (optionally substituted with up to 5 halogens) , trifluoromethyl, aryl, aryloxy, haloalkoxy (optionally substituted with up to 5 halogens) , arylalkyl or arylalkoxy; R 6 is H or CH 3 ; R 13 and R 15 are independently H or F; Z 1 is a bond; R 11 is alkylene; o II alkyl— ! R 12a - S- R12 - z 2 is o ■ 0 0 0 alkyl— c— or R 12β — c— R 12a is alkyl, fluorinated lower alkyl or polyfluorinated lower alkyl, or Z 2 is a bond and R 12 is alkyl. 11. The compound as defined in Claim 1 which is: 9-[3-[4-(2,3-dihydro-l-oxo-lH-isoindol-2-yl) - 1-piperidinyl]-propyl] -N-propyl-9H-fluorene-9- carboxamide; 2,3-dihydro-2-[l- [4-oxo-4-( -propyl-9H- fluoren-9-yl)butyl]-4-piperidinyl] -lH-isoindol-1-one or its monohydrochloride salt; (E)-9-[4-[4-(l,3-dihydro-l-oxo-2H-isoindol-2- yl) -1-piperidinyl] -2-butenyl-2,7-difluoro-N- (2,2,2- trifluoroethyl)-9H-fluorene-9-carboxamide; 9-{4-[4-(1,3-dihydro-l-oxo-2H-isoindol-2-yl) - 1-piper-idinyl]butyl] -2,7-difluoro-N- (2,2,2- trifluoroethyl) -9H-fluorene-9-carboxamide; (Z)-9-[4-[4-(2,3-dihydro-l-oxo-lH-isoindol-2- yl)-1-piperidinyl] -2-butenyl]-N-propyl-9H-fluorene-9- carboxamide; 2,3-dihydro-2-[l-[2-oxo-2-(9-propyl-9H- fluoren-9-yl)ethyl] -4-piperidinyl] -lH-isoindol-1-one; (E) -9-[4-[4- (2,3-dihydro-l-oxo-lH-isoindol-2- yl)-1-piperidinyl]-2-butenyl]-N-propyl-9H-fluorene-9- carboxamide; 9-[3-[4-(2,3-dihydro-l-oxo-lH-isoindol-2-yl) - 1-piperidinyl]-propyl]-N-propyl-9H-fluorene-9- carboxamide; 9- [4- [4- [ [ (1, 1-dimethylethoxy) carbonyl] - amino] -1-piper-idinyl] -butyl] -N-propyl-9H-fluorene-9- carboxamide; N-[2-[4-(l,3-dihydro-l-oxo-2H-isoindol-2-yl) - 1-piperidinyl] -ethyl] -9-propyl-9H-fluorene-9- carboxa ide; 9-[4- [4- [ [2- (phenoxyphenyl) carbonyl] amino] -1- piperidinyl] -butyl] -N-propyl-9H-fluorene-9- carboxamide; 9- [5- [4- (1, 3-dihydro-l-oxo-2H-ιsoindol-2-yl) - 1-piperidinyl] -pentyl] -N-propyl-9H-fluorene-9- carboxamide; 9-[4-[4- (benzoylamino) -1-piperidinyl]butyl] -N- propy1-9H-fluorene-9-carboxamide; 9-[4-[4-(2,3-dihydro-l-oxo-lH-isoindol-2-yl) - 1-piperidinyl] -butyl] -N- (2,2, 2-trifluoroethyl) -9H- fluorene-9-carboxamide; 9- [ 2 - [4- (2, 3-dihydro-l-oxo-lH-isoιndol-2-yl ) - 1-piperidinyl] -ethyl] -N-propyl-9H-fluorene-9- carboxamide; 9- [4- [4- (acetylamino) -1-piperidinyl]butyl] -N- propy1-9H-fluorene-9-carboxamide; N-ethyl-9-[4-[ (4- (2, 3-dihydro-1-oxo-lH- isoindol-2-yl) -1-piperidinyl]butyl] -9H-fluorene-9- carboxamide; n F Λ - 351 - 9-[4-[4-(2,3-dihydro-l-oxo-lH-isoindol-2-yl) - 1-piperidiny1]butyl]-N-2,2,2-trifluoroethyl-9H- xanthene-9-carboxamide; 9-[4-[4-(2,3-dihydro-l-oxo-lH-isoindol-2-yl)- 1-piperidinyl] -butyl] -N-propyl-9H-xanthene-9- carboxamide; 9-[4-[4-(2, 3-dihydro-l, 3-dioxo-lH-isoindol-2- yl) -1-piperidinyl]butyl] -N-propyl-9H-fluorene-9- carboxamide; 9-[4-[4-(2,3-dihydro-l-oxo-lH-isoindol-2-yl) - 1-piperidinyl] -butyl] -N-propyl-9H-indeno[2,1- b]pyridine-9-carboxamide; 2,3-dihydro-2-[1- [4-hydroxy-4- (9-propyl- H- fluoren-9-yl)butyl] -4-piperidinyl] -lH-isoindol-1-one; 2,3-dihydro-2-[l-[3-[ (9-propyl-9H-fluoren-9- yl)thio]propyl]-4-piperidinyl]-lH-isoindol-1-one; 2,3-dihydro-2-[1-[3-[ (9-propyl-9H-fluoren-9- yl)sulfonyl]propyl] -4-piperidinyl] -lH-isoindol-1-one; cis-9-[4-[4-(2,3-dihydro-lH-isoindol-2-yl) -1- piperidinyl]butyl] -N-propyl-9H-fluorene-9- carboxamide; 2,3-dihydro-l-[4- [4- (2,3-dihydro-l-oxo-lH-. isoindol-2-yl) -1-piperidinyl]butyl] -N-propyl-1H- ■ indene-1-carboxamide; trans-2,3-dihydro-l-[4-[4-(2,3-dihydro-l-oxo- lH-isoindol-2-yl) -1-piperidinyl]butyl] -2-phenyl-N- propyl-lH-indene-1-carboxamide,• l-[4-[4-(2,3-dihydro-l-oxo-lH-isoindol-2-yl) - 1-piperidinyl]butyl]-2-phenyl-N-propyl-IH-indene-1- carboxamide; 2-[1-[4-[9- (butylsulfonyl) -9H-fluoren-9- yl]butyl] -4-piperidinyl] -2,3-dihydro-lH-isoindol-l- one; „ c „ -352- 9-[4-[[4-[(l, 1-dimethylethoxy) carbonyl] - amino] -1-piperidinyl]butyl] -2,7-difluoro-N- (2,2,2- trifluoroethyl) -9H-fluorene-9-carboxamide; 9- [4- {4- [ (2-phenoxybenzoy1)amino] -1- piperidinyl]butyl] -N- (2,2, 2-trifluoroethyl) -9H- fluorene-9-carboxamide; 9- [4- [ [4- (benzoylamino) -1-piperidinyl]butyl] - 2,7-difluoro-N- (2, 2, 2-trifluoroethyl) -9H-fluorene-9- carboxamide; 9-[4-[ [4-(l,3-dihydro-l,3-dioxo-2H-isoindol-2- yl) -1-piperidinyl]butyl] -2,7-difluoro-N- (2,2,2- trifluoroethyl) -9H-fluorene-9-carboxamide; 2, 7-difluoro-9- [4- [ [4- [ (2-phenoxybenzolyl) - amino] -1-piperidinyl]butyl] -N- (2,2, 2-trifluoro- ethyl) -9H-fluorene-9-carboxamide; 9- [4- [4- (benzoylamino) -1-piperidinyl]butyl] -N- (2,2, 2-trifluoroethyl) -9H-fluorene-9-carboxamide; 2,3-dihydro-2-[l-[4-[9- (1-oxopentyl) -9H- fluoren-9-yl]butyl] -4-piperidinyl] -lH-isoindol-1-one; 2 , 3-dihydro-2- [1- (l-oxo-3, 3-diphenylpropyl) -4- piperidinyl] -lH-isoindol-1-one; [1- [4- [9- [ (propylamino) carbonyl] -9H-fluoren-9- yl]butyl] -3-piperidinyl]carbamic acid, phenylmethyl ester; 9- [4- [4- (2, 3-dihydro-l-oxo-lH-isoindol-2-yl) - 1-piperidinyl]butyl] -N- (2,2,2-trifluoroethyl) -9H- fluorene-9-carboxamide; 9- [4- [4- (2, 3-dihydro-l-oxo-lH-isoindol-2-yl) - 1-piperidinyl]butyl] -N- (2,2, 2-trifluoroethyl) -9H- fluorene-9-carboxamide; 9- [4- [3- (benzoylamino) -1-piperidinyl]butyl] -N- propy1-9H-fluorene-9-carboxamide; 9-[4-[3-(1,3-dihydro-l,3-dioxo-2H-isoindol-2- yl) -1-piperidinyl]butyl] -N-propyl-9H-fluorene-9- carboxamide; 9-[4-[4-(2,3-dihydro-l-oxo-lH-isoindol-2-yl) • 1-piperidinyl]butyl] -N-(2,2,3,3,4,4,4-heptafluoro¬ butyl) -9H-fluorene-9-carboxamide; 9-[4-[ [4-[ (1,1-dimethylethoxy)carbonyl]- amino] -1-piperidinyl]butyl]-3,6-difluoro-N- (2,2,2- trifluoroethyl) -9H-fluorene-9-carboxamide; 1-[4-[4- (1,3-dihydro-l-oxo-2H-isoindol-2-yl)■ 1-piperidinyl]butyl] -2-methyl-N- (2,2,2-trifluoro¬ ethyl) -lH-indene-1-carboxamide; 9-[4-[4-(l,3-dihydro-l-oxo-2H-ιsoindol-2-yl)- 1-piperidinyl]butyl] -N- (2,2,3,3, 3-pentafluoro- propyl)-9H-fluorene-9-carboxamide; 1-[4-[4-(1,3-dihydro-l-oxo-2H-isoindol-2-yl) - 1-piperidinyl]butyl]-N- (2,2,2-trifluoroethyl) -1H- indene-1-carboxamide; 9- [4- [4-(benzoylamino) -1-piperidinyl]butyl] - 3,6-difluoro-N-(2,2,2-trifluoroethyl) -9H-fluorene-9- carboxamide; 3,6-difluoro-9-[4-[4- [ (2-phenoxybenzoyl) r amino] -1-piperidinyl]butyl] -N-(2,2,2-trifluoro¬ ethyl) -9H-fluorene-9-carboxamide; C iral 9-[4-[4-[ (phenoxycarbonyl)amino] -1-piper- idinyl]butyl]-N-(2,2,2-trifluoroethyl) -9H-fluorene-9- carboxamide; 9-[4-[4-[ [ (phenylamino)carbonyl]amino] -1- piperidinyl]butyl]-N-(2,2,2-trifluoroethyl) -9H- fluorene-9-carboxamide; 9- [4- [4-[ (phenylsulfonyl)amino] -1-piper- idinyl]butyl]-N-(2,2,2-trifluoroethyl) -9H-fluorene-9- carboxa ide; cis-9-[4-[4[ (2-phenoxybenzoyl)amino] -1- piperidinyl]butyl]-N-(2,2,2-trifluoroethyl) -9H- fluorene-9-carboxamide, N-oxide; 9-[4- [4-[ (2-phenoxybenzoyl)amino] -1-piper- idinyl]-4-oxobutyl]-N- (2,2,2-trifluoroethyl) -9H- fluorene-9-carboxamide; 9-[4-[4-[[(l,1-dimethylethoxy)carbonyl] - amino] -l-piperidinyl]pentyl] -N- (2,2,2-trifluoro¬ ethyl) -9H-fluorene-9-carboxamide; 9-[4-[4- [ [ (2-phenoxyphenyl) sulfonyl]amino . -1- piperidinyl]butyl]-N-(2,2,2-trifluoroethyl) -9H- fluorene-9-carboxamide; 9-[2-[ [ [4- (benzoylamino) -1-piperidinyl] - carbonyl]amino]ethyl] -N- (2,2,2-trifluoroethyl) -9H- fluorene-9-carboxamide; [l-[[[2-[9-[[ (2,2,2-trifluoroethyl)amino]- carbonyl]-9H-fluoren-9-yl]ethyl]amino]carbonyl] -4- piperidinyl]carbamic acid, 1, 1-dimethylethyl ester; 4-[ (2-phenoxybenzoyl)amino]-1-piperidine- carboxylic acid, 2- [9- [[ (2,2,2-trifluoroethyl) - amino]carbonyl]-9H-fluoren-9-yl]ethyl ester; 4-[ [ (1,1-dimethylethoxy)carbonyl]amino] -1- piperidinecarboxylic acid, 2-[9-[[ (2,2,2-trifluoro¬ ethyl)amino]carbonyl] -9H-fluoren-9-yl]ethyl ester; 9-[4-[4-[ (2-phenoxybenzoyl)amino] -1- piperidinyl]pentyl] -N-(2,2,2-trifluoroethyl) -9H- fluorene-9-carboxamide; 9-[2-[[[4-[(2-phenoxybenzoy1)amino] -1- piperidinyl]carbonyl]amino]ethyl] -N-(2,2,2- trifluoroethyl) -9H-fluorene-9-carboxamide; 4-(benzoylamino) -1-piperidinecarboxylic acid, 2-[9-[[(2,2,2-trifluoroethyl)amino]carbonyl] -9H- fluoren-9-yl]ethyl ester; 9- [4-[4- (benzoylamino) -1-piperidinyl]pentyl]- N- (2,2,2-trifluoroethyl) -9H-fluorene-9-carboxamide; 9-[4-[4-[ [ (1,1-dimethylethoxy) carbonyl] - amino] -1-piperidinyl]butyl]-N-(2,2,2-trifluoro- ethyl) -9H-thioxanthene-9-carboxamide; 9-[4-[4-(benzoylamino) -1-piperidinyl]butyl] -N- (2,2,2-trifluoroethyl) -9H-thioxanthene-9-carbσxamide; 9-[4-[4-[ [ (2-phenoxyphenyl)carbonyl]amino] -1- piperidinyl]butyl] -N-(2,2,2-trifluoroethyl) -9H- thioxanthene-9-carboxamide; and a pharmaceutically acceptable salt of any of the above and an N-oxide of any of the above. 12. A method for preventing, inhibiting or treating atherosclerosis, pancreatitis or obesity in a mammalian species, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in Claim 1 or 14. 13. A method of lowering serum lipid levels, cholesterol and/or triglycerides, or inhibiting and/or treating hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/Gr hypertriglyceridemia, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in Claim 1 or 14. 14. A compound having the structure including the piperidine N-oxide thereof or a pharmaceutically acceptable salt thereof, wherein Z is a bond, 0 or S; X 1 and X 2 are independently selected from H or halo; x is an integer from 2 to 6; R 5* is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R 5* group being optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different. 15. The compound as defined in Claim 14 wherein Z is a bond, each of X 1 and X 2 is H. 16. The compound as defined in Claim 14 which is a piperidine N-oxide. 17. The compound as defined in Claim 14 wherein the substituent on R 5* is adjacent to the carbon attached to the group. 18. The compound as defined in Claim 14 wherein R 5* is substituted with 1, 2, 3 or 4 substituents which may be the same or different and are halogen, monocyclic heteroaryl, bicyclic heteroaryl, heteroarylalkyl, cycloheteroalkyl, alkyl, alkoxy, cycloalkyl, aryl, aryloxy, substituted aryl, arylalkyloxy, heteroaryloxy, amino, alkylamino, alkyl(aryl)amino, heteroarylamino, arylamino, alkylthio, arylthio, arylthioalkyl, heteroarylthio, arylsulfinyl or acyl. 19. The compound as defined in Claim 18 wherein R 5* is substituted with 1, 2, 3 or 4 of one or more of the following I, Cl, F, CF 3 where x is 1 to 5 alkyl, phenyl, phenyl substituted with halo, alkyl, CF 3 0, alkoxy, c?3 , CF 3 , or phenyl; H N (CH 2 ) p CP 3 where p i s 1 o 5, -N(CH 3) C 6 H 5; -S-(CH 2 ) P CF 3 where p is 1 to 5, , -S-alkyl, -S-(CH a ) p -S-C β H 5 , -0-(CH 2 )p-CF 3 , -x CF 3 , OCH3; cyclohexyl, -°- o> . - -XQX Cl CH 3 alkanoyl, alkoxycarbonyl, aroyl, heteroarylaminocarbonyl, arylalkyloxycarbonyl, H N. N N(CH 3 ) -CH2-S-C6H5, C C F p 3 3 " CH2 " 20. The compound as defined in Claim 19 F I -CH 2 CH 2 -C-CH 2 - wherein (CH 2 ) X is (CH 2 U or P Z is a bond; X 1 and X 2 are H; R 5* is aryl, which is substituted with trifluoromethylphenyl, heteroaryl, halo and/or aryl or R 5* is heteroaryl wherein the R 5* includes a substituent attached to a carbon adjacent to the carbon linked to c . 21. The compound as defined in Claim 14 which is 10 10 O- Cl H 3 C' v. s- Cl Cl FXF F F _CH, 0 O 3 CH, H.C- -N; o o S-. the monohydrochloride thereof, the dihydrochloride thereof or the pharmaceutically acceptable salt thereof. 22. The compound as defined in Claim 14 which is Cl Cl the monohydrochloride thereof, the dihydrochloride thereof or other pharmaceutically acceptable salt thereof. 23. A compound having the structure including the piperidine N-oxide thereof or a pharmaceutically acceptable salt thereof, R 5* is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R 5* group being optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different. 24. The compound as defined in Claim 23 wherein the substituent on R 5* is adjacent to the carbon attached to the c group. 25. The compound as defined in Claim 23 wherein R 5* is phenyl substituted with haloalkyl- phenyl or heteroaryl. 26. The compound as defined in Claim 25 wherein R 5* is 27. The compound as defined in Claim 23 which

Inventors: BILLER SCOTT A, DICKSON JOHN A, GREGG RICHARD E, HOLAVA HENRY M, LAWRENCE R MICHAEL, LAWSON JOHN E, MAGNIN DAVID R, PARTYKA RICHARD A, POSS MICHAEL A, ROBL JEFFREY A, SHARP DARU YOUNG, SULSKY RICHARD B, TINO JOSEPH A, WETTERAU JOHN R II, BILLER, SCOTT, A., DICKSON, JOHN, A., GREGG, RICHARD, E., HOLAVA, HENRY, M., LAWRENCE, R., MICHAEL, LAWSON, JOHN, E., MAGNIN, DAVID, R., PARTYKA, RICHARD, A., POSS, MICHAEL, A., ROBL, JEFFREY, A., SHARP, DARU, YOUNG, SULSKY, RICHARD, B., TINO, JOSEPH, A., WETTERAU, JOHN, R. II
Applicants: SQUIBB BRISTOL MYERS CO, BRISTOL-MYERS SQUIBB COMPANY
Application year: 1996
Main classification: C07D401
IPC codes: A61K31, A61P3, A61P9, A61P43, C07D211, C07D401, C07D405, C07D409, C07D413, C07D417, C07D419