CA2213466C - Inhibitors of microsomal triglyceride transfer protein and method - Google Patents

Inhibitors of microsomal triglyceride transfer protein and method Download PDF

Info

Publication number
CA2213466C
CA2213466C CA002213466A CA2213466A CA2213466C CA 2213466 C CA2213466 C CA 2213466C CA 002213466 A CA002213466 A CA 002213466A CA 2213466 A CA2213466 A CA 2213466A CA 2213466 C CA2213466 C CA 2213466C
Authority
CA
Canada
Prior art keywords
mmol
compound
amino
aryl
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CA002213466A
Other languages
French (fr)
Other versions
CA2213466A1 (en
Inventor
John R. Ii Wetterau
Daru Young Sharp
Richard E. Gregg
Scott A. Biller
John K. Dickson
R. Michael Lawrence
David R. Magnin
Michael A. Poss
Jeffrey A. Robl
Richard B. Sulsky
Joseph A. Tino
John E. Lawson
Henry M. Holava
Richard A. Partyka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Pennsylvania Penn
Original Assignee
University of Pennsylvania Penn
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Pennsylvania Penn filed Critical University of Pennsylvania Penn
Publication of CA2213466A1 publication Critical patent/CA2213466A1/en
Application granted granted Critical
Publication of CA2213466C publication Critical patent/CA2213466C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D419/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/04—Endocrine or metabolic disorders
    • G01N2800/044—Hyperlipemia or hypolipemia, e.g. dyslipidaemia, obesity

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 R1 to R6, 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 tricilyceride transfer protein, and to methods for decreasing serum lipids and treating atherosclerosis employing such compounds.

The microsomal triglyc;eride transfer protein (MTP) catalyzes the transport: of triglyceride (TG),' cholesteryl ester (CE), and phosphatidylcholine (PC) between small unilamellar vesicles (SUV). Wetterau &
Zilversmit, Chem. Phys. Liipid~; , U, 205-22 (1985).
When transfer rates are expressed as the percent 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. Phvs.
Ligids U, 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 moletcular weiahts 58,000 and 88,000, since a single band was present when purified MTP was electrophoresed under nondenaturing condition, while two bands of apparent molecular weights 58,000 and 88,000 were identified when electrophoresis was performed in th(=_ 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, respeczively, or the low molecular weight SUBSTITUTE SHEET (RULE 26) 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. 265, 9800-7 (1990). The presence of PDI in the transfer protein is supported by evidence showing that (1) the amino 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 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. 262, 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 HC1), a chaotropic agent (sodium perchlorate), or a SUBSTITUTE SHEET (RULE 26) nondenaturing detergent (octyl glucoside) results in a loss of transfer activity. Wetterau -et a1., Biochemistry 3Q, 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. Bio hys, Acta 875, 610-7 (1986).
Lipid transfer activity was f`ound in liver and intestine. Little or no trarisfer activity was found in plasma, brain, heart, or kidney. Wit'hin the liver, MTP was a soluble protein located within the lumen of the microsomal fraction. Approximately equal concentrations were found in the sr,nooth and rough microsomes.
Abetalipoproteinemia is an autosomal recessive disease characterized by a virtual absence of plasma lipoproteins which contain apolipoprotein B (apoB).
Kane & Havel in The Metabolic Basis of T:^her;red 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 abnorinalities are the result of a genetic defec:t in the assembly and/or secretion of very low density lipoproteins (VLDL) in the liver and chylomicrons 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 at a1., Clin. Chem. 34, B9-12 (1988). A link between. the apoB gene and SUBSTITUTE SH EET (RULE 26) abetalipoproteinemia has been excluded in several families. Talmud et a1., J. Clin. Inv.sr_ aa, 1803-6 (1988) and Huang et al., Am. J. Hum. nPr. _4_E, 1141-8 (1990).
Subjects with abetalipoproteinemia are afflicted with numerous maladies. Kane & Havel, suVra. 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 retinopathv, and ceroid myopathy.
Treatment of abetalipoproteinemic subjects includes dietary restriction of fat intake and dietary supplementation with vitamins A, E and K.
.T,a 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. Biobhvs. 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.

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PC7."/US96/00824 Olofsson and colleagues have studied lipoprotein assembly in HepG2 cells. Bostrom E` al., J. Biol. Chem. 263, 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 tc) 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, ~9_2_, 833-45 (1982), isolated nascent lipoproteins from the hepatic Golgi fraction of rat liver. There was a spectrum off sizes of particles present with varying lipid and protein compositions. Particles of high density lipoprotein (HDL) density, yet containing apoB, were f ound.
Higgins and Hutson, J. Lipid Res 25, 129-li-1305 (1984), reported lipoproteins isolated from Golgi were consistently larger than those from t:he endoplasmic reticuluiri, 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 inciicate that MTP is required for the synthesis of apoB containing lipoproteins, such as VLDL, the precursor to LD:.. 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 mari.

SUBSTITUTE SHEET (RULE 26) -6-= =

Canadian Patent AppliCation No. 2,091,102 published Karch 2; 1994 (corresponding to U.S.
Patent No. 5,595,872, filed September 3, ' 1993 (file DC21b)) rc=ports.MTP inhibitors which also block the production of apCiH containing lipoproteins in a human hopatio 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 N N
= ~ ~
which has the name 3-diphenylpropyl)-4-piperidinyll-2, 3-dihydro-3-oxo-lii-isoindple hydrochloride and O l I `
ro~N
.F NJ OCH3 which has the name 1-(3-(6-fluoro-l-tetralanyl)methyl]-4-0-methoxyphenyl piperazine WO 96/26205 PCTlUS96/00824 In accordance with the present invention, novel compounds are provided which are inhibitors of MTP and have the structure I
R?
R3' N IV- R' =
~ / X= r =
R
or Ii R2 O R' N
R3 N-{ ~
X
R
or II

R Q, NN- R' =
I

or ITi R' ~ N
RS N
1 ;

where Gl Is - C- or - s-X Is: CHR8, - C- -CH- CH- or -Cc C- ;
0 Rs Rlo Rs Rlo R8, R9 and R10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkyl.alkyl;
R1 is a fluorenyl-type group of the structure SUBSTITUTE SHEET (RULE 26) R1s R15 z or z R12_ Z2 Het c Het 1 -R"-Z' or R12_ Z2 Z
Het 2 R13 R1a or c R1 is an indenyl-type group of the structure / I ~R14 R13 R14 = ~_~~
_R11-Z' -R"-Z' ` or \ / or R12_ Z2 I R16a 12- 2 R1sa R1sa (CH2 a R Z
R15a (a = 2,3 or 4) E R13 R13 R1a R1a Het Het - R"- Z' or _ R11 _ Z1 R12- Z2 / Rtsa R12_ Z2 R16a R15a (CH2)a -Ca H R15a Z1 and Z2 are the same or different and are independently a bond, 0, S, =
H
-NH-C- , S I ~~ ~ -N-C- , - 1C- or -C-O (0)2 alkyl O 0 OH

SUBSTITUTE SHEET (RULE 26) wo 9612620-5 PCTIUS96100824 with the proviso that with respect to,g, at least one of Z1 and Z2 will be other than a bond;
R11 is a bond, alkylene, alkenylerie or alkynylene of up to 10 carbon atoms, ary.lene (for example or mixed arylene-alkylene (for example r-;~
(CH2),r- ~
where n is 1 to 6;
R12 is hydrogen, alkyl, alkenyl, aryl, halo-alkyl, trihaloalkyl, trihaloalkylalkyl, :neteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl; with the provisos that (1) when R3=2 is H, aryl-oxy, alkoxy - Nli- C-or arylalkoxy, then Z2 is 0 - N C- - C-~
aikyl 0 0 or a bond;
and (2) when Z2 is a bond, R12 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;
R13, R14, R15, and R16 are indepenciently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, a:Lkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonvloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;
R15a and R16a are independently an./ of the R15 or R16 groups except hydroxy, nitro, amino or thio;
R2, R3, R4 are independentlv hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, SUBSTITUTE SHEET (RULE 261) alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
R5 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 R5 substituents and R6 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-SUBSTITUTE SHEET (RULE 26) sulfonyl, or alkylsulfinyl. Where R5 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;
R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl;

./~ ~ /~ fHet/~
Het Het 1 2 I
= and 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 IIi compounds, that is ^ ~o ~r N ~ Rl ; and 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 amr.nonium, choline, diethanolamine, ethylenediamine, t-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.

SUBSTITUTE SHEET (RULE 26) Thus, the compounds of formulae I and II of the invention encompass compounds of the structure O
I' R2 R3 l\ I N ~ ,N- R' ____~ \_/

o ' I i R\ N
' R3 ( N 0 R Re O
Ib R2 r\- I N

ly, R4 Rlo O Ri I i R\ N

r" N~
ly~
R4 Ry o Rs Ic R\
N~N- R' ly, /
R4 Rlo SUBSTITUTE SHEET (RULE 26) WO 96/2620-5 P(7T/US96/00824 0 R' \ N
1=

R4 Rio =a R2 R3 l~/ I N N- R' R
O

R' Ia R2 I
N N

R4 \

O
IIa RS "J~ N-{\,N- Rl R6 -l IIi RS J"' N N .
-I

i=b s R'` ~I I\ N-I~N- Rl IIb 11 N
w i RS~O'~i_ SUBSTITUTE SHEET (RULE 26)1 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 IIi 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 IIi 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 et al., 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.
SUBSTITUTE SHEET (RULE 26) WO 96126205 PCT'IUS96100824 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, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimet~hylpentyl, 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 CF3, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloallcyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, acyl, heteroaryl, heteroarylox.y, hetero-arylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanovlamino, arylcarbonylamino, nitro, cyano, thioi, haloalkyl, triha.loalkyl and/or alkylthio, as well as any of t.he other substituents as defined for R5 and R6.
Unless otherwise indicated, the term "cycloalkyl" as employed herein alone or as part of SUBSTiTUTE SH E1=T (RULE 26) 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, cc 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 R5 or R6. .
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 SUBSTITUTE SHEET (RULE 26) and 1 or 2 bridges. Exemplary polycycloalkyl groups include [3.3.0]-bicyclooctanyl, adamantariyl, [2.2.1]-bicycloheptanyl, [2.2.2]-bicyclooctanyl and the like and may be optionally substituted as defined for cycloalkyl.
The term polycycloal}:enyl as em;ployed 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 contairiing 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]-bicyclooctenvl and the like and n:iay 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 eis phenvl 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 se]-ected from hydrogen, halo, haloalkyl, alkyl, haloal}:yl, 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, SUBSTITUTE SHEET (RULE 26) arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonyl-amino, arylsulfinyl, arylsulfinylalkyl, arylsul-fonylamino or arylsulfonaminocarbonyl, or any of the substituents as defined for the RSor R6 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 "aralkoxy" 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.

SUBSTITUTE SHEET (RULE 26) The term "acyl" as employed herein by itself or part of another group as deEined herein., refers to an organic radical linked to a carbonyl group, examples of acyl groups include alk:anoyl, 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, c:yclohetero-alkyl, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol and/or alkylthio, as well as any of the other substituents as defined for F:5 or R6.
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 borid in the normal chain, such as 2-propynyl, 3-butynyl, 2-SUBSTITUTE SHEET (RULE 26) 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 R5 or R6.
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 (CH2) n or (CH2) p (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 SUBSTITUTE SHEET (RULE 26) WO 96/2620i -21 PC'ClUS96(0082-{
-as well as any of the substituents defineci for R5 or R6, 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)p groups include -CH =CH -CH2 -, -CH2CH =CH -, -C -C -CH2 -, I
-CH2C =CCH2 - , -C =CH -CIri2-+
-(CH2)2 -, -(CH2)3 - ~ -(CH2)4 - ~

-, -(CH2)2 -C -CHZCHZ - ~ -CH2CH -, -CH2CHCH2 -CHCH2 - ~ -CHCH2CH2 - -C;HCHCH2 - , I I I

- CH2CH2O- C- , -CH2CH2N- C- + -CH2CH2- N- C--CH2-C -CH2 - , -(CHZ)5 - , -(CH2)2 -C -CHZ - , I

ci CH3 CH3 CH2 - CH - CH2 , - (CH2)2 - CH-- , - CH2 - CH- i --CH2 -CH -CH -CH2 -, - CH2 --CH i -CH2 - i Fi -- , SUBSTITUTE SHEET (RULE 26) WO 96/26205 CA 02213466 1997-08-20 pCT/US96/00824 I I
-CH -CHZCH2 --CH-CH2CH2 ~ -CH2OCHf- ~ --OCH2CH2- ~ -CH2NHCH2- ~ --NHCH2CH2- ~
iHg -N-CHZCHZ--(CHZ)3-"CF2- , -CH2-N-CH4- ' CH3 -(CHZ)Z---C-CHZ- , -(CH2 )2""C-CH2--(CH2)3--C--CHZ- , -(CHZ)3"-C- or -(CH2 )3--C--H CH3 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 CF3, 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 (CH2)p (which is defined above), such as SUBSTITUTE SHEET (RULE 26) WO 96/2620i -23 P~CT/US96l0082~1 -O NO S~~

~) 9 ! ~ /
L~~
~
`

N~~ r O l~

and the like. The above groups may include 1 to 3 substituents such as any of the R1, R5 or R6 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 Hec Hec ~ or Hae 2 (also referred to as heteroaryl) as used herein alone or as part of another group refers to a`i- or 6-membered 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 (CH2)p (which is defined abov(a_), such as ~

SUBSTiTUTE SH EET (RULE 26) WO 96/26205 CA 02213466 1997-08-20 pCT/US96/00824 \ ~ O\ N%
/

S
/N I N~/O S
\ N ' L=1 ~! ~ % ~

and the like, and includes all possible N-oxide derivatives.

H t i~ and Hee 2 4 4 Het 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 T
SUBSTITUTE SHEET (RULE 26) 5 -25 P(CT(iJS96/0082-1 -I LZI i Z, LZI
N(~
-CID , rr ~ rr ,r ,r, `~ `ZI rr ~ ~ ~.

LZI
, ~
p, S S \~~ S S
S~ N ~ ~ N\ N=
S s ~
L2~ S S
cr4 wherein u is selected from 0, S, and NR7a;
R7a is H, lower alkyl, aryl, --C (O) R7b, -C (;O) OR7b%
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 R5 or R6 groups as = defined above. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

SUBSTITUTE SHEET (RULE 26) -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(CH2)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-(CH2)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:

R16 R1s ,/

- R11- Z1 _ - R11- Zi z or z R12- Zz / \ R12- ZZ
Het R13 `-' R14 13 R14 c R16 R1s Het 1 - R11- Z1 or R12_ Z2 z Het 2 P
The term "indenyl-type group" as emplyed herein refers to a group of the structure SUBSTITUTE SHEET (RULE 26) WO 96/26205 PC'T1US96100824 R1e ~-\ R14 F{ 14 R
Rõ-Z, or -R"-::' or R12- Z2 / RtBa 'Z- 2 R18a Rtsa (CH2 a R Z
Rtsa E
(a=2,3or4) E

R73 R14 Rla Het Het -R"-Z' or _R11 _Z' R12- Z2 ~ R16a R12_ Z2 R=iea Rtsa (CH2)a Si R1sa Z, Z1, Z2, R11, R12, R13, R14, R15, R16, R15a. and R16a as used in the above groups A 1=hrough H are as defined hereinbefore.
Preferred are compounds of formulae I and II
wherein R1 is /
\ z2 Z, R13 R's or O O
B, (including where Z1 is a bond and R11 is alkylene or NH-C- O ~ /lol\ or ~
alkenylene and Z2 is 0, )2 and R12 is C1-C3 alkyl or 1,1,1-trifluoroethyl, R13 is = H or F and R15 is H or F, and 2, is a bond or 0; and where R11 is alkylene or alkenylene or alkylene SUBSTiTUTE SHEIET (RULE 26) substituted with oxo, R12 is alkyl, alkenyl, aralkyl, aralkenyl, Z is 0, S or a bond).
In structure I, it is preferred that R2, R3 and R4 are each H and X is CH2, CH2CH2, or CH=CH.
In structure II, it is preferred that R6 is H
or CH3 and R5 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 -O-O-, -0-C-OH, N-C-OH and -S-C-OH linkages.
The compounds of formulae I, Ii, II, and IIi 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.

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PC'TlUS96100824 Scheme I. Routes to lsoindolinone Piperidines j R. 0 R3 I_ C O
H2NNR" R4 Y O R. 2 =~
wJ
LY Phthalimide R3 ~- / NR ls Rta is Rt or (CH3)3COCO [BOC] Formation Ra 0 Yl Reduction Zn, Acetic Acid Rs 0 or'finMCl p R3 O
Alkyl O
R~j Halo R?= ~\
Heat R3. ~- ~ N--{ NR"
Isoindolone Formation Rs ~/
la Scheme II. Additional Routes to Isoindolinone Piperidines I

R; \

O
/~~ R4 ~ R?= 1 NR"
H2N-( NR" Amide Formation R~ ~- H~J
~! (Heat or AI(CH3)3 promotion) 4 Iy R OH 21 Ria is R' or (CH3)3COCO [BOC]
(a) Mesylate Formation 2 0 followed by Base Cyclization R= or Amide R3 ~ ~ Halo (b) Mitsunobu Cyclization Formation Ra Halo X

Base R? ///-----~~~
Rz 0 Cyclization Ra ,: i NNR"
Ra. ~- ~ H--( \__/NR" ~ R

R~ iti Halo zi SUBSTITUTE SHEET (RULE 26) WO 96/26205', PCT/US96/00824 Scheme III. Introduction of R' by Alkylation or Arylation R2 - XN ~~ /~~ Deprotection R~
Ra - ( N-BOC R I- ~ N~NH
~/

R4 ~.` R4 Hydrogenolysis Amine R2 O Alkylation or Arylation R3- ~- / N--( N-CHzAryI
~/

R3 ~- N--CN-RI
X

~
Scheme IV. Routes to Starting Materials JV%b and jyg crZ 0 ~\
H2N-{ N-CH2Ph O (IN-(N..CH2Ph \-/ Phthalimide ly-a Formation 0 YJa Hydrogenolysis Amine 0 Alkylation or Arylation 0 cJN-_N.Rh (as in Scheme III) ()~N-CWH
O MQ o Vib Hydrazinolysis ~jol0' \
"BOC ANHYDRIDE"
/~
HsN-(~/N-R' Hydrazinolysis 0 /~ c H2N--( N-BOC ~_-_L1Ltti/ 0 Yjd, SUBSTITUTE SHEET (RULE 26) WO 96/2620i F'CT(LJS96100824 Scheme V. General Routes to Startinci Materials jVL
Protecting Group HZN-( N-CHZPh Formation PG-N N-CH2Ph ~/
~

Hydrogenolysis Amine Alkylation or Arylation PG-N N-R' PGN N-H
(as in Scheme III) J
2S11~ Xll~
Deprotection H2N---( N-R' ~J
lYb SUBSTITUTE SHEET (RULE 26) Schemes VI and VII. General Routes to jj ~\ Amide Formation 0 /'~~
H2N--( N-R' R5~ N-{ N-R' ~/ H ~/
Amine Alkylation Amide or Arylation N-Alkylation Amide Formation 0 Rg'~ N N-R, R5~ N-CN-Ri xm Ilb LiAIH4 Reduction Reductive s Amination (R = CH3) O==( N- R' alkyl- O~ H-{ N- R' ~/
~XXTI ~a SUBSTITUTE SHEET (RULE 26) WO 96/26205 Pi:.T1US96100824 Scheme VIII Preparation of Compounds IA1, IA2 R3= ~- / X

~ ~ Rg ~ \ \
H2N N- R R3. ' ~/ H-cN- R' X is halo or OH R4 IVb F39 XIA
amide formation base R10CON(OMe)Me acylation or DMF (Rlo is H) O
Z O N' tion R %
dehydra R3= R~o - R
~OH
b R4 Rg R4 RI; Rio IA' XIB
hydrogenation R' R ~~ \
R3=~-/ C
Rio .

SUBSTITUTE SHEET (RULE 26) WO 96/2620~ PCT/US96/00824 Scheme IX Preparation of Compounds IA3-1A6 =~ arylation R3- ~- N~NH IA3 O
R4 halo =-XXitI or le' R 31 R32 R33 XXIV base addition R3. ,N--( N~ XXIV
X ~_/ /L=\ R33 Rg R31 R32 IA4 (M=metal such as ~A3 Li, or Mg or Zn) = R3a R3.~_ N N OH
Y1=X R33 1Aa deoxygenation alkylation or R35 halo hydrogenolysis = R3 R3- :eN-CN X R33 IAS

. ~ R3a 3 ~-R31 and R32 are independently selected from any of the R2, R3, or P.4 radicals;
R33 and P.34 are independently selected from any of the R1 radicals as well as aryloxy, alkoxy, SUBSTITUTE SHEET (RULE 26) WO 96/2620i PCT'fUS96l0082-t arylalkoxy, heteroarylalkoxy arid heteroaryloxy, at least one of R33 and R34 being an R1 radical;
R35 can be any of the R1 radicals.
Schemes X and XI Preparation of Compound IA7 '~ ~ ~ alkylation % ~
Rao I_ N- R' --- R:-. N- R, '~ 1) Base R4 8 "J
R4 2) R8 halo R
IA (halo=l,Br,C1) IA7 reduction R2 O Zn, AcOH or . Et3SiH, trifluoroacetic ~ ~ X acid R3. I ., O
RA Rs R2 0 H2N-{ N- RI XB X is CI or OH R3 12 N-C
N- R' ~/
amide formation Ra OHI
lVb followed by intramolecular R8 cyclization xxv SUBSTITUTE SHEiET (RULE 26) Scheme XII Preparation of Compound II
(Robotic Amide Coupling) CI FizN N- R' free basing H N N- R' XXV I XXVI I
O
~ II O
XXV I I R- C- OH Rs_ C-N~N- R' I I

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.
SUBSTITUTE SHEET (RULE 26) WO 96/26205 -37 PCTlUS96/00824 -Scheme XIII - Preparation of Intermediates where Z2 is S, SO or SO2 ie y R's H Z XXXV

/ ~ .
R13 ~-' R1a acid treatment 16 R1s ~6 R15 '' XXXVI Sulfur -R12- S Z oxidation R Z XXXVII
S

~pl ~.-.\ \ /n Alkylation 1) strong base 1) strong base Alkylation 2) Xl- R11-Y' 2) .K1 - R'1 -Y' R16 Ris R18 R's Sutfur X'- R'1 - XXXVIII oxidation XZ- R'~
R12- S z R-- S` 'z OJ
13 R1a R 13 ' R1a XXXVIIIEI

Xl, YI are same or different halo or Osulfonate n = 1 or 2 SUBSTITUTE SHEET (RULE 26) $cheme XIV - Preparation of A (Intermediates where Z2 is NHCO) R16 RR1s R,\R1s O
HOOC Z amide formation 12_ R N Z
H

XXXIX

1) Z 2 equiv. base 1) a 2 equiv. base Alkylation Alkylation 2) z 1 equiv. Xl - R11-Y' 2) 1 equiv. Xl - R'1-Y~

R\R's R16R1s X1 11 amide formation Xl *0, XLI XXXIIIC
Xl, Y' are same or different halo or Osultonate SUBSTITUTE SHEET (RULE 26) Scheme XIVA

Alternative Procedure for Preparinci Intermediate XL
(Shown in Scheme XIV) 16 R's R16 R15 Base 0 ('z R12N=C-O R' \ Z
R13 R14 R13 1:04 XXXIXA XL
In carrying out the above reaction, bases such as n-butyllithiun, Iiihium bis(trimethylsilyl) amide and sodium bis(trimettiylsilyl) 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 (R12N=C-O) together in solvent, and then add the base, and optionally add further excess isocyanate subsequently.

SUBSTITUTE SHEET (RULE 26;1 Scheme XV - Preparation of Intermediate where ZI is - N- C--It O
16 ' R15 16 R15 ~T--~j 12 "- amide formation *12-XLII XLIII
R16 R1s halogenation or 12 _ XLIII H
Xl- R11- N Z
suffonation ~ ~

R13 ~ R14 XXXIIID
Xl is halo or Osutfonate SUBSTITUTE SHEET (RULE 26) WO 96/26205 -41 PC'TlLIS96l0082~t -Scheme XVI

R16R's R
R\ ~j 's Grignard iz , -~
Z addition Z
R12MgX HO ~

R13 R14 R13 ~_. R14 XLIV XLV

R~~) acid treatment ~
XLV Z
Y2- R'i- SIT Y2- R'l- S
Y2 = OPG or COOMe OPG is a protecting group R13 R14 (e.g. benzoate) XLVI
16 R1s ~./ acid treatment H Z XLVII
y2- R11- SH

Y2 = OPG or COOMe R~s R1a OPG is a protecting group xxxv (e.g. benzoate) 1sR's Alkylation z YZ- R"- S 1) strong base XLVI
2) Xl- R12 R~a R14 XLVII Xl = halo or Osulfonate SUBSTITUTE SHEET (RULE 26) 18 R15 R1s R15 -`\
<
Reduction R12 - (y2_ CO2Me) R12 -z z z 11- 11 Y- R Sor Deprotection HO- R- S ~\
R 13 R1a ~2 OPG) XLVI XLVIII

halogenation R12 Z
XLVIII X1_- R11- S
or sutfonation Xl is halo or Osulfonate XXXIIIE
R16 R1s Sulfur Oxidation R12 -XXXIIIE z X1-R1t- S
(O)n XXXIIIF (n=1) XXXIIIG (n=2) SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTi'US96f0082-f Scheme XVIA Preparation of Ketones 16 R15 ~e R,s 1) acid chl,oride ~16 formation for G = CI
alkylation HOOC (COCI)2 HOOC Z z base R,Z
R12Xl IN\ 2) amide f`ormation for G
R1a R14 R13 R1a = MeN-~IX X~ = halo or O~
Osuffonate XLII

~\~\\~ o \~\\~
Ketone formation halogenation G Z HO- R" Z
R1Z X'MgO- R"- MgX' R1Z
R13 R14 (Optional catalytic Cu(I)) R13 R14 XLIIA Xl = halo or XLIIB
G= CI or MeN- Osulfonate OMe Ris a chain of >2 carbons 1e R's iX_ R" Z

Rt2 XXXIIIH
Xl = halo or Osulfonate SUBSTITUTE SHEET (RULE 26) WO96/26205 CA 02213466 1997-08-20 pCT/US96/00824 Scheme XVIB. Preparation of Ketones (Preferred Route) R1s R's is Atkytation R~e R
1 base 2) PG-OR"X' HOOC I" Decarboxylation HOOC Z Z
Xl = halo or PG-O- R" - DMSO, RT
R13i ,=- R14 0-sulfonate R13~~ R14 XXXlX XLIIC
Ketone Formation R16 R's (Acylation) R' ^ R15 ~ 1) base O 1)Deprotection H 2) R12COCI R12 ~ ~
Z Z 2) Halide PG-O- R" PG-O- R" - Formation y R14 ~ R14 R1a R'a XLIID XLIIE
R'r--. R's PG is an appropiate protecting group:
O~ such as t-butyl(dimethyt)silyl or R1Z t-butyl(diphenyl)silyl, which can be Z deprotected with aqueous acid or Xl_ RO~ n-Bu NF.
~ Ri4 iaR~~

xxxiiii SUBSTITUTE SHEET (RULE 26) WO 96/2620:+ PC:T(US96/00824 Scheme XVIIA - Preparation of Amide Linked Compounds R16 R15 1) base 2) X'-R"-CO2AIkyl HO2C
Z
HO C Z where X' Is halo ,AlkyI02C- R"
s or 0-sulfonate ~ R13/~- R14 XLV
Ri3R'4 XXXIX Arnide Fcirmation ~~
R12, Saponification O - `) H Z R12~
N
HOZC- R" H
A.Iky1O2C- R"

..~ ,\
XLVII Rlj R14 XLVI
R'--C NH Amide Formation XLV~IIA/
R16 R1s *R11 R12 'H Ra~~ O R13 R14 R' Is s CL, N- or R3 N-~

SUBSTITUTE SHEET (RULE 26) Scheme XVIIB - Preparation of Carbamate and Urea Linked =
Compounds R16 r--~/ R15 R16 R's 1) base 2) -where XI Is halo Y- R'1 -or 0-sulfonate ~ , RY3 R1 Y= CN or CH=CH2 R13R14 xxxix and RI~~ Is defined as Is RII L
Amide Formation R16 R's R12NH2 o ~ Y=CN
R'Z_ Nitrlle 16 R~s H Z Reduction R
(e.g H2, Pd/C or Pt02, o H2NCH2- Rl" or NaBH4/Co(11) ) R12`
N
R13 R14 H z LII Y- Rl"
R13Rta LI
= yy vyl Where W and W' are leaving groups ~ such as Cl or OC6H4-p-N02 Y= CH=CH2 O or NI-imidazole, and L is 0 or NHCH2 1) Ozone LV 2) NaBH4 R16 R's Rys Ris R'Z` N LV O R'Z` N
*Rl"- w ~W' O ~! `
H H Z
WYL- CH2- HO- CH2- R~~' -O R13 ~ R14 t3%u\

LVI
Where L Is 0 or HN Llil ~/ R1e R's XLVIIA o `
Ri2 \/ThH
`N
H Z
RaNv L- CH2- R~~' -~~~~~/// (O~ R13 ~`:'~ R14 LIV

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PC']C(US96(00824 Scheme XVIIIA - Formation of Sulfonamides H ~\ R5S02CI O
R tJ-( N- R' ~ R5- S O - N~/N- R' ~/
R
lVb. XIII LXI

(Reaction in a variety of solvents (CH2CI2, THF, pyridine) optionally in the presence of a tertiary amine base, such as pyridine or triethyl amine).
Scheme XVIIIB - Formation of Ureas (R5 is Amino) O
H. R5'-N_C_O
N N- R' N NC%N- R' R6 H Rs 1 IVb. XIII
LXII
(1 to 10 equiv of R-C=N=O, in aprotic solvent such as toluene, frorr- 0 C to 150 C).
(R5'is alkyl, aryl, heteroaryl or arylalkyl).

Scheme XIXA - General Route to Final Product R'--\( N- H

XLV-I I /A i' Rl- Xl or (where Rl is as in Amine Alkylation XXXIII A-K or any other Rl as defined herein) SUBSTITUTE SHEET (RULE 26) Scheme XIXB General Route to Final Products (I or II) /"'~ R' - X1 ~\
PG-N-{ NH PG-N--( N- R' ~/ Amine Alkylation ~/
~ IVb (where RI is as in XXXIII A-I or any of the other Rlas Deprotection defined herein) As in Schemes 1, li, VI, VIII, X, Xi, Final Products -(I or II) XVIIIA, XVIIB H2N N- R' -C
2Slltz (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 HCI In dioxane or neat trifluoroacetic acid).

SUBSTITUTE SHEET (RULE 26) WO 96/2620'i PC;T(US96f0082-1 Scheme XX - Oxidation of sulfur at the end of the reaction sequence R's `16 ,-\y R12 - 1) HCI' or CF3CO2H' /~~ 110 Z r R'-{ N- R'l- S 2) Selective sulfur ~/ oxidation /.-.\ 3) base *Acid pretreatment protects 19 baisic piperidine from oxidation R' N- R"
n0~

n=1or2 (Ra is defined as in ,Scheme XVIIA) SUBSTITUTE SHEET (RULE 261, Scheme KXI - Preparation of Halide Intermediates R1\~\/ R's R16 Ris ` PG-O Ox (Alkyl or aryl) /%
- ~-' C_ C~ HO2C
HO2C Z H H pG-O Z
Palladium Catalyst R13 ~~=,\ Base H H %
R14 Aprotic Solvent R13 `--~ R14 XXXIX LXV
All alkenes in this scheme may be cis or trans or a mixture. Amide Formation 16 R's PG-O O (Alkyl or aryl) ~s R~4-~~~ C= C--/ R1\r/ R
0 H H O .
72_ R H Z Palladium Catalyst PG-O R72' H Z
Base Aprotic Solvent H
R13 C_r R 14 H is14 XL LXVI R R
For exam{Zle: Palladium catalyst can be Pd(Ph3P)4, base can be NaH or bis(trimethyisilyl)acetamide, Deprotection aprotic solvent can be THF or DMF or mixtures.
PG- can be organosil , such as t-Bu(Ph)2St-, and deprotection con~tions can be n-Bu4NF, THF.
LXVII

SUBSTITUTE SHEET (RULE 26) WO 96126205 Pt~TlUS96/00824 116 R's ~~ O ~
o Hydrogenation 12 -R12 N (for example, H2-Pd/C) HO R H~ Z
H Z ~--H H . , ia HO R13 % R14 LXVII R 13/ R
u LXIX
Halide Halide Formation Formation R1s R75 R~e R~s O ~.....
O `\~

Z Halo H~ Z
- ~-I
Halo Is C1, Br, I H H
Halo R13/u R14 R13 `=J Ria XXXIIIJ XXXIIIK
SUBSTITUTE SHEET (RULE 26) Scheme XXII - Preparation of 3-Substituted Piperidine Starting Materials R1-X1 amine alkylation C02Et CO2Et Rl- N
Rl is as in XXIIIA to XXXIIIK
or is any other R' as defined HN
herein Xl = halo or Osulfonate Saponfication KOH, then HCI
O

HN OCH2Ph Ph2PON3, Et3N COOH
then PhCH2OH
Ri -N Rl-N

- HCI
deprotection H2, Pd(OH)2/ C

Rl- N
Intermediate S2 can be utilized as a starting material to prepare 3-substituted isomers Ii and IIi 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.

SUBSTITUTE SHEET (RULE 26) WO 96/26205 -53 PC:TIUS96(0082~t -Scheme XXIII - Preparation of N-Oxides of Formulae I and II
compounds N-Rl O -CR, Oxidation (for example, peracid such as meta-chloroperbenzoic acid) i 0 ~R N-R' r 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 piper=idine isomers to afford the corresponding compounds of the invention Ii or IIi 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 D, _Q and p or indenyl-type groups as set out in E, F, _Q and/or E to provide an intermediate compound for use in preparing a compound of formula I, I', II or II' of the invention as per Reaction Schenies I to XXIII.
Phthalimide formation (Reaction Schemes I, IV) may be carried out by heating to about 80 to 150 C in SUBSTITUTE SHEET (RULE 26) WO 96/26205 pCT/LTS96/00824 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--t-butylpyridine or triethylamine).
Amide formation (Reaction Schemes II, VI, VII, VIII, X, XI, XII, XIV, XIVA, 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 R5C(O)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 (R5CO2H) in`
the presence of a coupling agent such as dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide 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(CH3)3) in an aprotic solvent, followed by an ester (e.g., R5CO2alkyl or compound VIII) or (6) mixed anhydride formation, by reacting the acid with an SUBSTITUTE SHEET (RULE 26) WO 96/26205 -55 PCTYUS96I0082~3 -acid chloride (e.g., isobutyl chloroformate or bis-(2-oxo-3-oxazolidinyl)-phosphinic chloride (Bop-C1)) 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 anci triethylamine or pyridine or in an aprotic solvent, such as dichloromethane.
Base cyclization (Reaction Schemes II, VTII) may be carried out by treatment with a base (e.g., potassium t,-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. Ora. Chem., A2, 3527 (1984); Genin, M. J., E` al., J. Ora. Chem., U, 2334-7 (1993).
Alternatively, a mixture of compouncis IV and VIII can be converted to compound Ia 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 ceirried out by procedures generally known in the art. See, for example, T. W. Greene, Protecting Groups in Oraanic Synthesis, Second edition, 1991. PG in Scheme V
denotes a nitrogen-protecting group. One particuiarly useful group is tert-butoxy-carbonyl (BOC) whic^ can be derived from the associated anhydride as; shov.-n in Scheme IV. BOC-protected amines may typically be SUBSTITUTE SHEiET (RULE 26) 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 H2 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.
Chen. 31, 2242-2247 (1991). For example, the alkylation or arylation may be carried out by treating the amine substrate with a halide (e.g., R1-halo) or an oxytosylate (e.g., R1-O-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 carbonat e ) .
Reductive amination may be employed as an alternative to the foregoing amine alkylation and arylation procedures when R1, R6 or R7 is R9R10CH` and R9 and R10 are each independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl, or R9 and R10 together are alkylene (i.e., R9R10CH- forms a cycloalkyl group). Such reductive amination may be carried out by treating the amine with (a) a ketone or aldehyde (R9-C(O)-R10), (b) NaBH4, NaBH3CN or NaB(acetoxy)3H, (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 SUBSTITUTE SHEET (RULE 26) WO 96/26205 -57 PCTIUS9610082~i -isopropoxide). When R1 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. R8-halo) or alkyl sulfonate (e.g. R8-tosylate) in an inert solvent (e.g. tetrahydrofuran or dimethoxy-ethane).
Alternatively, as seen in Schemes X and X7:, 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 acqents as zinc in acetic acid or triethylsilane in trifluoroacetic acid to give IA7.
Hydrazinolysis of phthalimides may be carried out by standard means known in the art. See, e.g., T.
W. Greene, Protectina Groups in Oraanic Svnthesis, Second edition, 1991.
Amide N-alkylation (Reaction Scheme VI) may be carried out by base treatment (e.g., NaH, KH, KN[Si(CH3)3]2, K2C03, P4-phosphazene base, or butyl lithium) in an aprotic organic solvent, followed-by treatment with R6-halo or R6-O--tosylate. Use of P-phosphazene base is described in T. Pietzonka, D.
Seebach, Anaew. Chem. Int. Ed. Enal. _IL-. 1481, 1992.
Dehydration (Scheme VIII) may be carried out employing a strong acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid.

SUBSTITUTE SHEET (RULE 26) Hydrogenation (Scheme VIII) may be carried out in the presence of a conventional catalyst such as Pd/C or Pt or Rh under a H2 atmosphere.
The addition reaction shown in Scheme IX may be carried out by treating IA3 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 R12 in R12Q
may be any of the R12 groups as defined hereinbefore.
Alternatively, the alkylation in the above Schemes can be performed where either or both Z1 or Z2 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)-SUBSTITUTE SHEET (RULE 26) Wa 96I26205 -59 PC:T/i}S96/ 082-t -acetamide), a palladium catalyst (for exan:iple Pd ( Ph3 ) 4) and an allylic acetate (CH3CO2CH2-C,H-CH4 or CH3CO2CH-CH-CH2 ) in an inert solvent (for example THF). This reaction is to introduce either -R12 (Scheme XII) or -R11-X1 (Schemes XIII, XIV, XVI, XVIA) or -R11-OPG (Scheme XVIB, Scheme XXI). The product of this reaction contains either an -R12 group or an -R11-X1 group (or an -R11-OPG qroup) which begins with -CH2-CH=CH-~ . Saturation of the alkene in R11 or R12 can be accomplished by standard catalytic hydrogenation condit.:ions.
The sulfur oxidation in Schemes XIII, XVI and XVIII is carried out as follows.
Sulfides of structures XXXVI, XXXVIII, XXXIIIE
and Ig can be selectively oxid:_zed to sulfoxides by 1 molar equivalent of reagents known in the art, such as 30% H202, Na104, 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% H202, KMn04, 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%
H202 and peracids (e.g., meta-chloroperbenzoic acid).
In cases where an amine (such zis a piperidine in 19) is present during the oxidatiori, the basic nitrogen may be protected by pretreatmerit with an acid such as HC1 or CF3CO2H (see Scheme XIX).
To prepare examples where Z1 or Z2 is -CHOH, the compounds I, Ii, II and IIi where Z1 or Z2 is C=0 can be reduced with a hydride reagent, for example NaBH4.

SUBSTITUTE SH1=ET (RULE 261 WO 96l25205 PGTNS96IOQ824 The compounds of the invencion may. be employed in.preventing, stabilizing or causing-regression of atherosclerosis in a ma=-alian species by administering a therapeutically effective amount of a coMound to decrease the activity of MTP.
. The gompounds of the invention can be tested for MTP inhibitory activity employing the procedures set out in U.S. Patent No. 5,595,872 filed September 3, 1993, employing MTP isolated from one of the following sources:
(1) bovine liver microsomes, 12) HepG2 cells (human hepatoma cells) or (3) recombinant human MTP expressed in baculovirus.
i5 The compounds of'the'invention may also be employed in lowering serum lipid levels, such as cholesterol or triglyceride (TG) levels, in a mamralian species, by administering a therapeutically effective amount of a compound to decrease the activity of MTP.
' The compounds of -the ihvention may be employed in the treatment of various other conditions or diseaseg 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, hyper'triglyceridemia, 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 5pecies, such as monkeys, dogs, cats, rats, humans, etc., in need of WO 96/2620i -61 PI-T(LJS96/0082~t -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 incorporELted 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 cluite satisfactory as well.
The dose administered must be caref'.ully adjusted according to the age, weight, anci 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.

SUBSTITUTE SHEET (RULE 26) Example 1 9-[3-[4-(2,3-Dihydro-l-oxo-lH-isoindol-2-yl)-1-piperidinyl]propyl]-N-propyl-9H-fluorene-9- carboxamide Me H
O
/~\ ~
N }- N ~
~1 /
A.
I ~ O
Ni"" Me H

To a suspension of 10 g (47.57 mmol) of 9-fluorenecarboxylic acid (Aldrich) in 80 mL of CH2C12, under argon at 0 C, was added a catalytic amount of DMF (0.5 mL) followed by the dropwise addition of 36 mL (71.35 mmol ) of oxalyl chloride (2M in CH2C12 );
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 CH2C1~, 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 HC1. The reaction solidified and was treated with 1:1 CH2C12/water (200 mL) and allowed to stir until everything was in solution. The organics were washed with water (2x), dried (NaSO4) and evaporated to provide a yellow SUBSTITUTE SHEET (RULE 26) VVO 96/26205 P(CML3S96!(10824 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.

Ni=~ Me H
1 ~

OTB,S
B(1).
HO~~~ 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 stir-red fc= 18 h at which time the reaction was diluted with ether and washed with NH4C1, water, Na2CO3, brine and dried (MgSO4). The resulting colorless title compound in the form of a liquid, 50 g, contained approximately 15% of the disilylated compound.

B(2).
arsS
To a solution of 8.5 g (42 mmol) cf Part B(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 SUBSTITUTE SHEET (RULE 261) 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 1I1 sodium bisulfite, Na2CO3, brine and dried (Na2SO4). The resulting residue was triturated with ether (3x), filtered (to remove triphenylphosphine oxide) and evaporated to provided 10 g(610) of title compound as a pale yellow oil.

B(3).
o Me N
H
OTBS
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 (Na2SO4), 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.

SUBSTITUTE SHEET (RULE 26) WO 96/26205 -65 PCTlUS96100824 -' C.
~ O
Me N
H
OH
To 5.6 g (12.80 mmol) of Part B cornpound 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 whict-:. time it was diluted with ether and quenched with NH4C1. The organics were washed with water, brine, dried (Na2S04) and evaporated. Flash chromatography was performed on 250 g of silica gel eluting with 95:5 dichloro-methane/isopropanol to provide 4.09 g(994's) of title compound as a white solid.

mp 73-75 C.
D.

Me H

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
SUBSTITUTE SHEET (RULE 26) and was stirred for 1 h at which time it was diluted with hexanes and the organics were washed with sodium bisulfite, NaHCO3, brine and dried (Na2SO4). 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]-lH-isoindol-1,3(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-pirneridinvll-lH-isoindol-i-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 CeliteO, 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 MgSO4. Evaporation gave a crude oil. The resulting residue was azeotroped with SUBSTITUTE SHEET (RULE 26) WO 96/26205 PC7'lUS96/00824 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-l-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 Celitem and washed with ethanol. The filtrate was evaporated to dryness.
The resulting residue was dissolved in chloroform (100 mL) and washed with 1 I KOH saturated with sodium chloride (2 x 30 mL) and dried over IAgSO4.
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)-l-piperidinyl]propyl]-N-propyl--9H-#'1 unrPnP-q-carbn,ram; rle To a solution of 330 mg (0.76 mmol) of Part D
compound in 5 mL of DMF, under argon at RT, was added 210 mg (1.52 mmol) of K2C03 followed by 198 mg (0.76 mmol) of Part G compound. The m.ixture was stirred at RT for 72 h, at which time the reaction was diluted with ether and washed with water, brine, dried (Na2SO4) and evaporated. Recrys=:allization was SUBSTITUTE SHEET (RULE 26) Wa 96126205 PCTIUS96/00824 attained from hot hexanes to provide 270 mg (68%) of title compound as a white solid., mp 136-138 C.
Anal. Calcd. for C34H39N302:
C, 78.28; H, 7.53; N, 8.05 Found: C, 78.11; H, 7.62; N, 8.09.
FxAw~` P ~n, Alternate synthesis of Example 310 hydrochloride salt To a solution of Example 5 free amine (12 g, 23.1 mmol) in absolute EtOH (400 xnL) was added 10$.
palladium on activated carbon.(1.z g). The mixturs was hydrogenated on a Parr apparatus at 40 psi for 2 h, then filtered through Celite'". The filtrate was concentrated in vacua to provide a colorless oil.
The product was dissolved in MeOH (100 mL) and l.OM
HCl.i.n Et20 (20 mL, 20 mmol) was added dropwise. The reaction was stirred for 10 min then concentrated in vacuo. The residue was taken up in CH3CN (2 mL)'and water (25 3nL) was added. The slightly cloudy solution was lyophilized overnight to giv'e title compound (11.1 g, 86$) as a white lyophilate.
Analysis Calcd. for C34H39N3O2 = 1.3HC1 = 1.6H20:
C, 68.24; H, 7.33; N, 7.02; Cl, 7.76 Found: C, 58.27; H, 7.31; N, 6.99; C1, 7.77.

WO 96/26205 PC'lilUS96/00824 Examp1e 2 2,3-Dihydro-2-[1-[4-oxo-4-(9-propyl-9H-fluoren-9-yl)butyl]-4-piper-idinyl]-lH-isoindol-l-one:, m9nohvdrochloride o N--C N-'~~

= HCI

A.
CIMg--,-~ OMciCI
To a stirred solution of 28.55 g.(301.9 mmol) of 3-chloro-l-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.

O

CI

B(1). 9-Propyl-9H-fluorene-9-carboxylic acid SUBSTITUTE SHE1=T (RULE 26) Wo 96/26205 ' PCT/U896100824 HVCH2c1izC CoGH

A solution of 9-fluorenecarboxylic acid (12 g, 57 nunol) 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-m?, 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 Ãor 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 HC1. The reaction mixture was extracted with hexane (3x200=n1) and the hexane extract washed with water; brine and dried over 8rihy. sodium sulfate. The solvents were evaporated yielding the crude product as a yellow oil which was dissolved in -250 ml of ethanol and heaLed at reflux with Darcom G-60, filtered through Celitel' 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.120-122 C.

WO 96/26205 -71 PiCTIUS9610082-1 -B(2), X o 4_ \
(/I
A solution of oxalyl chloride (4.5 mL, 8.93 mmol) was added over 5 min. to a solution of Part B(1) compound in CH2C12 (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.
o OH
A solution of Part B compound (1.07 g, 3.97 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 NH4C1 (10 mL). The reaction was diluted with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with saturated NH4C1, water, and brine (10 mL
each), then dried over MgSOq. Evaporation gave 1.3 g of a yellow oil, which was purified by flash chromatography on silica gel (:L50 g), loading in 50%

SUBSTITUTE SHEET (RULE 26) -EtOAc/hexane, and eluting with 25% EtOAc/hexane to provide title compound (885 mg, 76%) as a colorless oil.

D.
o Br 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 CH2C12 (7 mL) at 0 C under argon. The reaction was stirred at 0 C for 1 h, diluted with CH2C12 (20 mL), and washed with 10% aqueous potassium sulfite (5 mL), water (5 mL), and brine (5 mL), then dried over MgSOq. 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% CH2C12/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-?-one. monohvdrochloride 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 SUBSTITUTE SHEET (RULE 26) WO 96/26205 -73 PC'TlUS96100824 -NaHCO3 (10 mL). The organic layer was washed with water (5 mL) and brine (5 mL), then dried over Na2SO4. Evaporation gave 415 mg of a colorless oil, which was purified by flash chromatography on silica gel (50 g) eluting with 25% acetone/CH2C12 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 1N HC1/Et20 (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 C33H37C1N2O2 - H20:
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.
Examole 3 (E)-9-[4-[4-(1,3-Dihydro-l-oxo-?H-isoindol-2-yl)-1-piperidinyl]-2-butenyl-2,7-difluoro-N-(2,2,2-trifluoroethvll-9H-fluorene-9-ciarboxamide H.
~ ~1/ C:F3 C - N
F / ( F
\

SUBSTITUTE SHEET (RULE 26) A.

F 0 p 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 HBF4 (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. HBF4, 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 (Si02, 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.
SUBSTITUTE SHEET (RULE 26) WO 96/26205 -75 PC^.C1US96/0082~1 -B.

F e C12~-- F

To a THF (15 ml) soluticn 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 CO2 ( excess ) was added, followed by Et20 (-5 m7; ), 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 HC1, and i:he aqueous layer extracted twice with EtOAc. The combined organics were dried over Na2SO4 and evaporated in vatcuo 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.

C.
Br COOH
F F

A solution of Part B compound (2,7-difluorofluorene-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-SUBSTITUTE SHEE'T (RULE 26) 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 HC1 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.
D.
Br O H

F F

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 mg, 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 SUBSTITUTE SHEET (RULE 26) WO 96126205 -77 PCT/US96/OOS2~l -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.

O H
C_ N\/ CF3 F / \ \ /}- F

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 ir¾nol) 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 C33H30N3F502 + 1.7 H20:
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.

SUBSTITUTE SHEET (RULE 26) Examnle 4 9-[4-[4-(1,3-Dihydro-l-oxo-2H-isoindol-2-yl)-i-piperidinyl]butyl]-2,7-difluoro-N-(2,2,2-trifluo-roethvl)-9H-fluorene-9-carboxamide O
N
\ -C
O H
C- N,-_-_/ CF3 F F
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. 150-1520C.
Anal Calc'd for C33H32N3F504 + 1.75 H20:
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.
SUBSTITUTE SHEET (RULE 26) Example _5 (Z)-9-[4-[4-(2,3-Dihydro-l-ox:o-1H-isoindol-2-yl)-1-piperidinyl]-2-butenyl]-N-propyl-9H-fluo:rene-9-carboxamide. monohvdrochlorid.e o g<LN

= HCI
N~\
~{J O
N
A.

O

H

cl Butyllithium (8.4 mL, 2.5M in hexane, 21.mmol) was added dropwise over 10 min to a solution of fluorenecarboxylic acid (Aldrich Chemica:L 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-butexie (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 1N HC1 (50 mL) and extracted with CH2C12 (3 x 50 mL). The combined SUBSTITUTE SHEET (RULE 26) organic layers were washed with brine (30 mL) then dried over MgSO4. 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 CH2C12 (15 mL) at RT under argon was added oxalyl chloride (3.6 mL, 2.OM in CH2C12, 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 CH2C12 (15 mL) and cooled to 0 C.
Propylamine (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 1N HC1 (2 x 20 mL) and brine (20 mL), then dried over MgSO4. Evaporation gave 1.7 g of an orange oil, which was purified by flash I
chromatography on silica gel (150 g) eluting with CH2C12 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-fluorene-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 SUBSTITUTE SHEET (RULE 26) "NO 96/26205 P'CT/US96/00824 was partitioned between CH2C12 (20 mL) ar.Ld saturated NaHCO3 (7 mL). The organic layer was washed with brine (5 mL) and dried over Na2SO4. Evaporation gave 900 mg of a pale yellow oil, which was piirified by flash chromatography on silica gel (75 g) eluting with 3% MeOH/CH2C12 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/Et20 (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 C34H38C1N3O2 = 0.7H2O:
C, 71.81; H, 6.98; N, 7.39; Cl, 6.23.
Found: C, 71.86; H, 7.34; N, 7.34; C1, 6.16.
Following the procedure of Examples 1 to 5, the following additional compounds were prepared.
6. 2,3-Dihydro-2-[1-[2-oxo-2-(9-propyl-9H- fluorene-9-yl)ethyl]-4-piperidinyl]-isoindol-l-one, monohydrochloride o MS (ES) 465 (M+H) mp 146-149 C

SUBSTITUTE SHEET (RULE 26) .
Anal. Calcd. for C31H33C1N202 = 0.95 H20:
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 O
N
H

O
. / ~
MS(Cl) 520 (M+H) mp 115-116.5 C

Anal. Calcd. for C34H37N302 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)-1-piperidinylJpropyl]-N-propyl-9H-fluorene-9-carboxamide SUBSTITUTE SHEET (RULE 26) a o / N Me H

N
b M.S. (ES, + ions) m/e 508 (M+H) mp 172-175 C

Calcd: C, 78.07; H, 7.34; N, 8.28 Found: C, 77.80; H, 7.50; N, 8.10.
ExamAle 9 S

~\ .

A.

C-H
The title compound was purchased i'rom Aldrich Chemical Co.

SUBSTITUTE SHEET (RULE 26) WO 96/26205 -84 PCT/US96/0082-t -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.
C.

S
,~ .
ci 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 1-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 NH4C1 solution and 30 mL of ethyl acetate. The organic fraction was dried (Na2SO4) and concentrated. The crude product was purified by SUBSTITUTE SHEET (RULE 26) WO 96126205 -85 PCT/US96/0082~i -column chromatography on si7-ica gel (50 g) with 2:98 acetone/dichloromethane (500 mL) followed by 15:85 dichloromethane/hexanes to cJive 1.00 (73%) of title compound as a colorless oil.
D.

Z O
$v \
O
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 FC2C03 (20 mL) and ether (30 mL). The organic fractiori was dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel (50 g) with 15:85 ethyl acetate/hexanes to crive 0.24 g of sulfone as a colorless oil. I
To a solution of the suifone chloride (0.24 g, 0.64 mmol) in2-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). Z'he organic fraction was dried (Na2SO4) 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.

SUBSTITUTE SH E:ET (RULE 26) E.
z o~~
S

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 NH
~ \
/
(prepared as described in Example 1 Part G) The reaction mixture was warmed to 550 and allowed to stir for 24 h. The mixture was diluted with NaHCO3 solution (50 mL) and ethyl acetate (50 mL). The layers were separated, the organics dried (Na2SO4) 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/NH3 (1L). Pure fractions were pooled and concentrated to give 0.70 g (85%) of title compound as a thick oil which solidified after standing.
m.p. 128-131 C.

SUBSTITUTE SHEET (RULE 26) `WO 96126205 -87 P'CI`/US96/00824 -Anal. calcd for C34H40N203S = 0.45 H20:
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.
Examu 1e 1Q
9-[4-[4-[[(1,1-Dimethylethoxy)carbonyl]am:ino]-1-piperidinyl]butyl]-N-gropyl-9E[-fluorene-9=-caarboxami de to CH3 N' O--~ CH3 A. [1-(Phenylmethyl)-4-piperidinyl.]carbamic acid. l.l-dimethylethyl ester To a solution of 4-amino-l-benzylpiperidine (20.0 g, 105 mmol) in dichloro:methane (150 mL) was added dropwise a solution of di-tert-butyl.dicar-bonate (25.2 g, 116 mmol) in dichlorometha.ne (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).

SUBSTITUTE SHEE'T (RULE 26) WO 96/26205 -88 PCT/US96/0082-t -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 LT 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).

SUBSTITUTE SHEET (RULE 26) ->
C.

I O
N
H
/ I
a \

H--~ ~KCH3 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 overnigY.Lt. 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 MgSO4. Purification was performed by flash chromatography on silica gel (300 cr), 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-Dimiethylethoxy)carbonyl)-amino]-1-piperidinyl)butyl]-N-propyl-9H-fluorene-9-carb xamide To a solution of Part C compound (3.0 g, 5.89 mmol) in methanol (10 mL) at lRT 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 cjive title compound (2.90 g, 97%) as a white solid.

SUBSTITUTE SHEET (RULE 26) -m.p. 118-120 OC.

Anal. Calc. for C31H43N303 = 2.4 H20:
C, 67.83; H, 8.78; N, 7.65 Found: C, 67.45; H, 8.33; N, 7.52 Example 11 N-[2-[4-.(1,3-Dihydro-l-oxo-2H-isoindol-2-yl)-1-piperidinyl]ethyl]-9-propyl-9H-fluorene-9-carboxamide O
~
D-O NN N I/
H

A.

2>~- O OH N
H
To a CH2C12 (30 ml) solution of Example 2 Part B(1) 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 NaHCO3 and the aqueous layer extracted twice with CH2C12. The combined organics were washed with H20, dried over SUBSTITUTE SHEET (RULE 26) ==
~
Na2SO4 and evaporated in vacuo to give an oily residue (2.55 g). The residue was purified by flash column chromatography (Si02, 350 mL), eluting with 30% EtOAc:CH2C12, to give title compound. (1.73 g, 74%
yield) as a colorless solid.
B.

O Br N
H
To a CH2C12 (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 irmol) and N-bromosuccinimide (0.930 g, 5.22 mmol) and the reaction allowed to stir for 2 h. The reaction mixture was diluted with CH2C12 and the poured into 10% aqueous sodium bisulfite. The aqueous layer was extracted 4 times with CH2C12, the combined organics dried over Na2SO4, and evaporated in vacuo to give an oily brown colored residuf. (3.4 g). The residue was purified by flash column chromatography (Si02, 5 by 18.5 cm), eluting with 4::L CH2C12:hexanes to give title compound (1.52 g, 89.5`, yield) as a colorless solid.

SUBSTITUTE SHEET (RULE 26) -C. N-[2-[4-(1,3-Dihydro-l-oxo-2H-isoindol-2-yl)-1-pineridinvllethv11-9-rproovl-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 1h, followed by the addition of K2C03 (200 mg, 1.45 mmol) and DMF (0.5 ml). After 24 h, the reaction was partitioned between saturated NaHCO3 and EtOAc. The aqueous layer was extracted with EtOAc, CHC13, and twice with CH2C12. The combined organics were dried over Na2SO4 and the volatiles were removed in vacuo to give an oily-solid residue (720 mg). The residue was purified by flash column chromatography (Si02, 5 by 8 cm), eluting with 1% MeOH:CH2C12 then 5%
MeOH:CH2C12, to give title compound (184 mg, 25%
yield) as a colorless solid. mp 219-221 C.
Anal. Calc. for C32H35N302 = 0.32 H20:
C, 76.97 H, 7.19; N 8.42 Found: C, 76.88; H, 7.16; N, 8.51.
SUBSTITUTE SHEET (RULE 26) -Examo 1 E12 9-[4-[4-[[2-(Phenoxyphenyl)carbonyl]amino]-1-piperidinyl]butyl]-N-propyl--9H-fluorene-9-a boxamide I ~ .

N
H
~\1 O
~1\H

O
A.

O
N ~/

` NH2 10 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 iri dioxane (4N, 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.

SUBSTITUTE SHE:ET (RULE 26) WO 96/26205 -94 PCT/US96/0082~t -Anal. Calc. for C26H37C12N30 = 1.1 H20:
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.OM, 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 H20 (2 x 30 mL), brine (2 x 30 mL) and dried over MgSO4. 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.

SUBSTITUTE SHEET (RULE 26) -Anal. Calc. for C39H43N303 = 0.2 H20:
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 procedureIs set out in Examples 1 to 12, the following compounds of the invention were prepared.

kHNCI O

c 9-[5-[4-(1,3-Dihydro-1-oxo-2H-isoindol-2-y1)-1-piperidinyljpentyl)-N-propyl-9H-fluorene-9-carboxamide.
m.p. 146-148 C
MS (ES, + ION): 536 (M+H) Anal. Calcd. for C35H42CIN302 = 1.8 H20: C, 69.76; H, 7.29; N, 6.97; CI, 5.88 Found: C, 69,70; H, 7.39; N, 7.00; Cl, 5.74.
14.

~

t c:L.o N
H I

SUBSTITUTE SHEE'T (RULE 26) -9-[4-[4-(Benzoylamino)-1-piperidinyl]butyl]-N-propyl-9H-fluorene-9-carboxamide.
m.p. 157-160 C
MS (Cl, + ion) (M+H) 510 Anal. Calcd. for C33H39N302 = 0.5 H20:
C, 76.41; H, 7.77; N, 8.10 Found: C, 76.37; H, 7.70; N, 8.02.
15.
~

NH

~ 10 9-[4-[4-(2,3-Dihydro-l-oxo-lH-isoindol-2-yl)-1-piperidinyl)butyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide m. p . 143 -146 C
MS (ES, + ions) m/z 562 (M+H) Anal. Calcd. for C33H34N3F302:
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.

o N *'~ Me H

1 ~ N p 9-[2-[4-(2,3- Dihydro - 1 -oxo- 1 H-isoindol-2-yl)-1-piperidinyl]ethyl]-N-propyl-9H-f1uorene-9-carboxamide, monohydrochloride.

SUBSTITUTE SHEET (RULE 26) WO 96(2620S -97 PCTlUS96/0082~t -~ 17.

. / C

H

Co 9-[4-[4-(Acetylamino)-1-piperidinyf]butyl]-N-propyl-9H-fluorene-9-carboxamide.
m.p. 133-135 C
MS (Cl, + ion) (M+H) 448 Anal. Calcd. for C28H37N302 - -1.0 H20:
C, 72.23; H, 8.44; N, 9.02 Found: C, 71.94; H, 7.90; N, 8.88.
18.

kH

N ~
~

N-Ethyl-9-[4-[4-(2,3-dihydro-l-oxo-lH-isoindol-2-yl)- piperidinyl]butyl]-9H-f luore ne-9-carboxamide m.p. 137-140 C
MS (Cl, M+H+) m/z 508+
Anal. Calcd. for C33H37N302 = 0.29 H20:
C, 77.27; H, 7.39; N, 8.19 Found: C, 77.05; N, 7.38; N, 8.41.
SUBSTITUTE SHEET (RULE 26) -19.
O
O
NH
~ O

9-[4-[4-(2,3-Dihydro-l-oxo-lH-isoindol-2-yl)-1-pipe 'irdinyl]butyl]-N-2,2,2-trif luoroethyl-9H-xanthe ne-9-carboxamide.

m.p. 164-166 C (dec) M.S. (FAB) m/z 578 (M+H) 20.
O
O
NH
O
N

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 C34H3903N3+O.5 H20:
C, 74.70; H, 7.37; N, 7.69 Found: C, 74.45; H, 7.32; N, 7.56 SUBSTITUTE SHEET (RULE 26) WO 96/26205 -99 PCTlUS96/00824 -Examnl e~ 21 9-[4-[4-(2,3-Dihydro-1,3-dioxo-lH-isoindol-2-yl)-1-piperidinyl]butyl]-N-propyl--9H-fluorene-9-carbox-amide, monohvdrochloride f ~ .
t i N ^~
O
N
= HCI / \
O
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, 1õ15 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 niL), brine (2 x 30 mL) and dried over MgSO4. Purification was performed by flash chromatography on silica gel (50 g), loaded and eluted with 2.5% methanol. in dichloromethane. Pure fractions were conibined 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

SUBSTITUTE SHEET (RULE 26) WO 96/26205 -100 PCT/US96/0082~3 -Anal. Calc. for C34H38C1N303 = 1.3 H20: 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. 5 Examnle 22 9-[4-[4-(2,3-Dihydro-l-oxo-lH-isoindol-2-yl)-1-piperidinyl]butyl]-N-propyl-9H-indeno[2,1-b]-pvridine-9-carboxamide o N
H

I /N
1- N \
I /
A.
O

N
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. Heterocycles, 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 SUBSTITUTE SHEET (RULE 26) 'WO 96/26205 - 101 PCT/US96100824 -a further 15 min with saturated NH4C1. The aqueous layer was extracted with EtOAc, the organics washed = with brine, dried over Na2SO4 and evaporated in vacuo to give a red colored oily-solid residue (535 mg).
The residue was purified by flash column chromatography (SilicARu buffered silica gel, 5 by 7 cm), eluting with 20% EtOAc:CH2C12, and f:Lushing with 5% MeOH:CH2Cl2 to give title compound (202 mg, 58%
yield) as an orange colored solid. mp 131-133 C.
HO
B . O-StP62tBu 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 H20 and the aqueous layer was ext:racted with hexanes. The organic layer was dried over Na2SO4 and evaporated to an oil (33 g). The residue was purified by flash column chromatography (silica gel, 10 by 26 cm), eluting with CH21--12, 5, 7.5, and then 10% EtOAc:CH2C12 to give title compound (24.5 g, 74%) as a colorless oil.

C. O-SiPh2tBu 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 SUBSTITUTE SHEET (RULE 26) -quenched with 5% aqueous sodium bisulfite. The mixture was diluted with H20 and hexanes, the organic layer washed with H20, saturated NaHCO3, and brine.
The organic layer was dried over Na2SO4 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 (SilicARM buffered silica gel, 5 by 10 cm), eluting with 30% CH2C12:hexanes to give title compound (6.2 g, 84%) as a colorless oil.

D.
N O O-SiPh2tBu N

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 NH4C1. The aqueous layer was extracted twice with EtOAc, the organics dried over Na2SO4, 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:CH2C12 to give title compound (817 mg, 92%) as a colorless oil.

SUBSTITUTE SHEET (RULE 26) `WO 96126205 -103 I)CT)US96)0082.~
-E
N O OH

To a THF (3.5 ml) solution under argon of Part D compound (800 mg, 1.42 mmol) was added dropwise tetrabutylammonium fluoride (:L.5 ml, 1 M in THF).
After 2 h, a second portion oi= 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 part_Ltioned between H20 and EtOAc. The aqueous layer was extracted 3 times with EtOAc, and the organics washeci with brine. The first organic layer contained less eimmonium salts and was dried over Na2SO4, and evaporated in vacuo to give an oil (885 mg). The residue was purified by flash column chromatography (SilicAFt" buffered silica gel, 90 g), eluting with 4.5% MeOH:;CH2Cl2 to give title compound (437 mg, 95%) as a colorless oil.

SUBSTITUTE SHEET (RULE 26) -F.
N ~ Br =
N

To a CH2C12 (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 CH2C12.
The combined organics were washed with brine, dried over Na2SO4, 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%
EtOAc:CH2C12 to give the unstable title compound (217 mg, 78%) as a colorless oil.
G.
. I ` 00 N
H
O
N N

To a DMF (1.6 ml) solution of Part F compound (180 mg, 0.465 mmol) and Example 1 Part G compound SUBSTITUTE SHEET (RULE 26) -(135 :ag, 0.624 mmol ) under argon was added K2C03 (65 mg, 0.47 mmol). After 18.15 h, the purple colored reaction was partitioned between dilute NaHCO3 and EtOAc. The aqueous layer was extracted twice with EtOAc, the combined organics were washed with H20, brine, dried over Na2SO4, 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% MeOH:CH2C12, 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+.
Examn 1 e 2 3 2,3-Dihydro-2-[1-[4-hydroxy--4-(9-propyl-9H-fluoren-9-vl)butvll -4-ni.beridinvll -1H=-isoindol-l-one A solution of Example 2 Part D free amine (300 mg, 0.61 mmol) in 12 ml of iriethanol was cooled to 0 C
under an argon atmosphere and 2 equiv. of sodium borohydride (48.5 mg, 1.28 rnmol) was adcied. The reaction mixture was stirred at 0 C for 45 min. The reaction was quenched with 1 N hydrochloric acid and SUBSTITUTE SHEET (RULE 26) WO 96/26205 + 106 _ PCT/US96/0082 3 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(CI) m/z 495 (M+H) ExamBle 24 2,3-Dihydro-2-[1-[3-[(9-propyl-9H-fluoren-9-yl)-thiolpror)vll-4-8igeridinvll-lH-isoindol-Z-on I
N N
~ 20 A.

OH
To a THF (100 ml) solution of fluoren-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). After 1.15 h, the orange colored reaction mixture was quenched with saturated NH4C1. The SUBSTITUTE SHEET (RULE 26) WO 96/26205 -107 PCTIUS96100S2-f -aqueous layer was extracted twice with EtOAc, the organics washed with brine, dried over Na2SO4 and evaporated in vacuo to give an oily-solid residue (11.1 g). The residue was purified by crystallization from EtOH:H2:O to give title compound contaminated with 14% by weight 9-hydroxyfluorene (4 g, 30% yield) as a colorless; solid. Mati=_rial was sufficiently pure for the subsequent reaction.
B.

S

, To an AcOH (25 ml) solution of Part A compound (3.64 g, 0.014 mol) and methyl 3-mercapt.opropionate (1.62 ml, 0.015 mol) under argon is added concentrated H2SO4 (7 drops). After stirring at room temperature for 24 h, the reaction was concentrated to 1/3 the original volume and diluted with H20. The aqueous layer was extracted laith EtOAc and the`
organic layer washed with 1 N NaOH. The basic wash was extracted 3 times with EtOAc, the combined organics extracted with brinia, dried over Na2SO4 and evaporated to an oily-solid of the structure (B1) SOMe o (5.55 g) . (Compound 13(1) was sufficiently pure for the subsequent reaction.
Rf = 0.49 (25% EtOAc:hexanes).

SUBSTITUTE SHEET (RULE 26) WO 96126705 PCT/US96ro0S24 To an EtOH (15 ml) solution of compound 8(1) (385 mg, 0.956 =anol) was added Na8x4 (470 mg, 0.012 mol). After stiriing overna.ght, the reaction mixture was cooled to 0 C and quenched with saturated NH4Cl.
The aqueous layer was extracted with EtOAc, the organic layer washed with brine, dried over Na2SO4 and evaporated to an oily residue (390 mq). This residue was purified by flash column chromatography (siZica gel, 3 by 10 cm), eluting with 3%
EtOAc:CH2C12 to give title compound (110 mg, 38%
yield from Part A campound) as a colorless oil.
C.

aTs 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 imnol) and the reaction slowly allowed to come to room tempez'attire.
After 4 h and 7.5 h, more p-toluenesuZfanyl chloride (60 and then 40 mg, 0.52 nano2) was added at room tesnperature 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 NaHCO3. The aqueous layer was -extracted 3 times with EtOAC, the organic layer washed with brine, dried bver Na2SO4 and evaporated to an oily-solid (200 mg) . This reszdue was preabsorbed onto Celitel 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.
D.

`
S N N

A mixture of Part C coi.pound (102 mg, 0.227 mmol), Example 1 Part G compound (64 mg, 0.296 mmol), and K2C03 (34 mg, 0.246 mmol) in isopropanol (1.5 ml) under argon was refluxed for 6 h. Af`ter cooling, the reaction was partitioned between saturated NaHCO3 and EtOAc. The aqueous layer was extracted twice with EtOAc, the combined orgainics were dried over Na2SO4 and the volatiles were removed in vacuo to give an oil (126 mg). The residue was conibined 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:CH2C12 to give intpure title icompound (108 mg). The mixture was further purified by flash column chromatography (silica gel, 12 g), eluting with 4% MeOH:CH2C12 to give title compound (101 mg, 74% yield) as an oily foam.

SUBSTITUTE SHEI"cT (RULE 26) -MS: (electrospray, M+H+) : m/z 497+.
Anal. Calcd. for C32H36N20S=0.26 H20:
C, 76.64; H, 7.34; N, 5.59 Found: C, 76.73; H, 7.27; N, 5.51.
Examnle 25 2,3-Dihydro-2-[1-[3-[(9-propyl-9H-fluoren-9-yl)-sulfonvllTpronv11-4- iA ridinvll-1H-i oindol-1-one O
Oo A.

S~! OMe , ?~I( 0-Do 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 H2SO4 (7 drops). After stirring at room temperature for 24 h, the reaction was concentrated to 1/3 the original volume and diluted with H20. 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 Na2SO4 and evaporated to an oily-solid (5.55 g, > 100% recovery). SUBSTITUTE SHEET (RULE 26) IJVO 9612620-5, P'CTlUS96100824 -~11-To a CH2C12 (25 ml) solution of crude compound prepared above (1 g, 2.63 mmol) at 0 C under argon was added 3-chloroperoxybenzo:ic 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 briize, dried over Na2SO4 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 C20H22S04 = 0.29 H20:
C, 66.04; H, 6.26; S, 8.81 Found: C, 66.04; H, 6.11; S, 8.45.
B.

~/ OH
OS

~ \
1 / ~
~
To an EtOH (14 ml) suspension of Part A
compound (559 mg, 1.56 mmol )zit 0 C under argon was added NaBH4 (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 NaBH4 (80 mg, 3.36 mmol) was aLdded. After 5 h at room temperature, the reactiori mixture was quenched SUBSTITUTE SHEET (RULE 26) WO 96126245 .PGTlUS46JUDM
at 0 C with saturated NHaCl 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 Ce].ite", the residue was purified by flash column.
chromatography (silica ge].; 5 by 7 czn), eluting with 3% MeDH:CH2Cl2 to give title compound (328 mg, 64%
yield) as a colorless solid. mp 111.5-112.5 C.
C.

To a CH2Cl2 (5 ml) solution of Paxt B compound (308 mg. 0.933 mrnol) and Lriphenylphosphine (490 mg, 1.87 mnol) at 0 C under argon was added N-bromosuccinimide (210 mg, 1.18 mmol). After 2 h, a second portiori of N-bromosuccinimide (40 mg, 0.34 stmnoi) 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 H20, brine, dried over NaaSOa, and evaporated in vacuo to give an oily-solid residue. The residue was purified by flash column chroQnatography (SilicAR' buffered silica gei;
5 by 9 ca-), eluting with 6.7% liexanes:CH2C12, then MC12 to give the unstable Compound C(1) of the 0X8Br structure (283 mg, 775; yield) as a colorless solid. mp 83-86 C.
A DMF (2 ml) solution of Compour.Ld C(1) (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 iri 4 h by K2C03 (33 mg, 0.239 mmol). After 24 h, the cooled reaction mixture was partitioned between saturated NaHCO3 and EtOAc. The aqueous layer was extracted with EtOAc, the organics were washed with brine, dried over Na2SO4 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:CH2C12 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:hE:xanes to give title compound (39 mg) as a colorless solid. The impure title compound was further purif:ied by flash column chromatography (silica gel, 24 cr), 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+.

SUBSTITUTE SHEET (RULE 26) Anal. Calcd. for C32H36N203S=1.01 H20:
C, 70.29; H, 7.01; N, 5.12 Found: C, 70.45; H, 6.60; N, 4.96.
Example 26 N rN
HN O ~___/ , 2,3-Dihydro-l-[4-[4-(2,3-dihydro-l-oxo-lH-isoindol-2-yl)-1-piperidinyl]butyl]-N-propyl-lH-indene-l-carboxamide A.

I \ ~
/
To a stirred slurry of 0:~ (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, 2M in dichloromethane) and then 0.1 rnL 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 SUBSTITUTE SHEET (RULE 26) between ethyl acetate and 10$ citric acid solution.
The.orgnnic extract was dr=ied'(MgS04) and evaporated.
Purification by flash chromatography on silica gel (5 x 20 cm,co3umn, 1:2 ethyl acetate/hexanes as elutant) provided title compound as a yellow solid, 2.36 g, 59$ yield, mp 123-125 C.' g.
CoHHl~CH~CFI9 Cb 10 A degassed slurxy of Part A compound (1.10 g, 5.47 iranol) 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 Celites" and evaporated to give title compound as a white solid, 894 mg, 81% mp 61-63 C.

C. ~`~~ QS88v~
To a solution of 49 m:, (0.55 mol) of 1,4.-butanediol in 25 mL of DMF, under argon at 0 C, was added 10.5 g (0.15 mal) of imidazole followed by 20.7 g(0.14 mol) of t-butyldimethylsilyl chloride. The reaction was slowly warmed to RT and stirred for 1.$ h at which tilr-e -the reaction was diluted with Gther and washed with NH4C1, water, Na2CO3, brine and dried (MgSO4). The resulting colorless liquid H~~~~ OSitauMe=
50 g, contained appXoximate}.v 15$
-_of the disilylated compflund.
To a solution of .8 . 5 g ( 42 'aanol ) of the -above alcohol in 50 mL of THF, under argon at 0 C, was added 7.3 g(108 nanol) of imidazqle 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, Na2CO3, brine and dried (Na2SO4). 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.
D.
NHPr OSitBuMe2 O

To a stirred solution of diisopropylamine (0.95 mL, 6.8 mmoi) 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 1-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 (Na2SO4) and evaporated. Purification by flash chromatography on silica gel gave title compound as a colorless oil, 680 mg, 58%.
SUBSTITUTE SHEET (RULE 26) E.
NHPr OH

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 tetra.butylammonium fluoride (3 mL, 3 mmol, 1Z in THF). After 1 h, the reaction mixture was partitioned between ethyl acetate and 10%
citric acid solution. The organic extract was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (2.5 x 15 cm column, 1:4 hexanes/ethyl acetate) provided title coinpound as a colorless oil, 380 mg, 80%.

F.
NHPr To a solution of Part E compound 1;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 iociine (360 mg, 1.39 mmol) in 5 mL of THF. After 15 min, the reaction was quenched with 5% NaHSO3 solution and extracted with ether. The organic extract was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (5 x 15 cm column, 5:7 ethyl acetate/hexanes) gave title compourid as a colorless oil, 442 mg, 83%.

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlUS96/00824 G. 2,3-Dihydro-l-[4-[4-(2,3-dihydro-l-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-r)rnpvl-lH-indene-l- arboxamidP
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% NaHSO3 solution and extracted with ethyl acetate. The organic extract was dried (MgSO4), 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-i.

Calculated for C30H39N302=0.94 H20:
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).
1H NMR (CDC13, 300 MHz) S 7.83 (d, 1H, J = 7.3 Hz) 7.52-7.44 (m, 3H) 7.30-7.23 (m, 4H) 5.53 (t, 1H, J = 5.5 Hz) 4.35 (s, 2H) 4.30 (5-plet, 1H, J 5.3 Hz) 4.01 (dd, 1H, J 7.2, 7.8 Hz) 3.13 (m, 2H) 3.04 (d, 2H, J 9.8 Hz) SUBSTITUTE SHEET (RULE 26) 2.92 (t, 2H, J = 6.7 Hz) 2.50 (5-plet, 1H, J 5.5 Hz) 2.38 (t, 4H, J = 7.7 Hz) 2.18-1.84 (m, 9H) 1.56-1.35 (m, 6H) 0.81 (t, 3H, J = 7.4 Hz) ppm.
Examg~ e 27 NP

I O

1-[4-[4-(2,3-Dihydro-l-oxo-lH-isoindol--2-yl)-1-piperidinyl]butyl]-2-phenyl-N-propyl-lFi-indene-l-carboxamide A. HO--'r OSiPh2tBu To a slurry of sodium hydride (6.975 g; 60%
mineral oil dispersion, 0.174 mo1) in 200 mL of THF
at room temperature under argon was adcied 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 rapicily 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, t:he reaction was quenched with water and extracted t:wice with = hexanes. The organic layers were combined, dried (Na2SO4) and evaporated. Piarification by flash chromatography on silica gel (12 x 30 cm column, SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlUS96/00824 dichloromethane) gave title compound as a colorless oil, 46.6 g, 82%.

B. AcO~ OSiPh2tBu 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 (NaiSO4) and evaporated. The isolated colorless oil, (7.02 g, 95%), was used without further purification in Part F.

C.
~ 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, 3M 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 SUBSTITUTE SHEET (RULE 26) and extracted twice with ether. The organic extracts were dried (MgSO4) and evaporated. Purification by flash chromatography on sil:Lca gel (5 x 20 cm column, 17:3 dichloromethane/hexanes) gave title compound as a colorless oil, 6.66 g, 77";.
D.

To neat Part C compound (6.40 g, 30.4 mmol) was added potassium bisulfat:e (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 dichioromethane and water. The organic laye:r was dried (MgSO4) and evaporated to provide title compound (5.84 g, 100%) as a white solid, mp 163-164 C.

E.
co21H

To a solution of Part D compound (1.481 g, 7.70 mmol) in 20 mL of THF eLt 0 C under argon was added n-butyllithium (3.0 mL, 7.50 mmol, 2.5 M in hexanes) over 10 min. The resulting deep orange solution was stirred for lh. The reaction was quenched with several small pieces of THF-washed dry ice. The resulting thick ye:llow 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 3Ll sulfuric acid. The mixture was SUBSTITUTE SHI:ET (RULE 261 extracted three times with ethyl acetate, the extracts combined, dried (MgSO4) and evaporated to give title compound as a light yellow powder (1.50 g, 82%) , mp 212-215 C.
F.
NHPr OSiPh2tBu O ~
I \ -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%a citric acid. The organic extract was dried (MgSO4), evaporated and re-evaporated once from toluene.
To-a stirred solution of this product in 10 mL
of dichioromethane 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%

SUBSTITUTE SHEET (RULE 26) WO 96126205 PCT/U596MOw24 - i 23 -citric acid. The.organic extract was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (5 x 20 tzn column, dichloromethane) gave title compound as an orange oi1,.1.50 g, 77%.
b G.
wmwpr oH

~ ~ ~ . .
To a stirred solution of Part F compound (2.15 g. 4.18 aanol) in 15 mL'of THF at room temperature under argon was added tetrabutylam'noniurn fluoride (10 mL,. 10 mmol, 1 1K in THP). Aftex'lh, the reaction was quenched with brine and extracted three times with ethyl acetate. The organic extract was dried (1vIgSO4) and evaporated. Puriiication by flash chromatography on silica gel (5 x 15 cm column, 3:2 hexanes/ethyl acetate) gave title compQund as a colorl'ess glass, 1.09 g, 75%.

H_ =
NHPr 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 5t 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%.

NHPr O

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 triphenyiphosphine (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% NaHSO3 solution and extracted with ether. The organic extract was dried (MgSO4) 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)-1-piperidinyl]butyl]-2-phenyl-N-nropyl-lH-indene-l-carboxamide To a stirred solution of Part I compound (74 mg, 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% NaHSO3 solution and extracted with ethyl acetate. The organic extract was dried (MgSO4), evaporated and re-evaporated twice from toluene. Purification bv 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.

SUBSTITUTE SHEET (RULE 26) WO 96/262"-- l'CT/US96100824 IR (KBr pellet) 3326, 2942, 2863, 1678, 1622, 1512, 1454, 1302, 737 cm-1.

MICROANALYSIS Calculated for C36H41N3O? -1 .17 H20:
C, 76.02; H, 7.68; N 7.39 Found: C, 76.02; H, 7.43; N 7.30.

MS (electrospray, + ions) m/e 548 (M+H).
1H NMR (CDC13, 300 MHz) 7.83 (d, 1H, J= 7.6 Hz) 7.56 (d, 2H, J= 7.6 Hz) 7.40 (s, 1H) 7.54-7.2 (m, 9H) 5.32 (t, 1H, J= 5.8 Hz) 4.30 (d, 1H, J= 7.3 Hz) 3.05 (m, 2H) 2.85 (d, 2H) 2.62 (dt, 1H, J= 4.2, 9.2 Hz) 2.31 (dt, 1H, J= 4.5, 9.2 Hz) 2.06 (m, 2H) 1.94 (m, 2H) 1.71 (m, 4H) 1.26 (m, 4H) 0.59 (t, 3H, J= 7.3 Hz) 0.6 (m, 1H) 0.43 (m, 1H) ppm.
SUBSTITUTE SHEET (RULE 26) Example 28 HN O

trans-2,3-Dihydro-l-[4-[4-(2,3-dihydro-l-oxo-lH-isoindol-2-yl)-1-piperidinyl]butyl]-2-phenyl-N-t)robvl-lH-indene-l-carboxamid A.

NiPhcfHPrOs2tBt1 H
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 (MgSO4) 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%. SUBSTITUTE SHEET (RULE 26) WO 96126205 PCT(US96100824 B.
NHPr OH
H

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 tetra)outylammonium fluoride (1.0 mL, 1.0 mmol, 1,~,I in Ti:iF). After lh, the reaction was quenched with ]orine and extracted three times with ethyl acetate. `Phe organic extract was dried (MgSO4) 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%.

C.
NHPr 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 tripheinylphosphine (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% NaHSO3 solution and extracted with ether. The organic extract was dried (MgSO4) and evaporated.
Purification by flash chromatography (2.5 x 15 cm = column, dichloromethane) gave title compound as a colorless glass, 101 mg, 6110.

SUBSTITUTE SHEET (RULE 26), D. trans-2,3-Dihydro-l-[4-[4-(2,3-dihydro-1-oxo-lH-isoindol-2-yl)-1-piperidinyl]-butyl]-2-phenyl-N-propyl-lH-indene-l-carboxamide 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% NaHSO3 solution and extracted with ethyl acetate. The organic extract was dried (MgSO4), 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 jbH43N302 = 1. 54 H20:
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).
'H NMR (CDC13, 300 MHz) 7.82 (d, 1H, J = 7.3 Hz) 7.51-7.14 (m, 12H) 5.66 (t, 1H, J 5.2 Hz) 4.33 (m, 2H) 4.26 (dd, 1H, J 0.7, 3.6 Hz) 4.01 (dd, 1H, J 7.2, 7.8 Hz) 3.28 (m, 4H) 2.95 (d, 2H, J 10.7 Hz) SUBSTITUTE SHEET (RULE 26) WO 96/26205 ]PCT/US9610082-3 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, .7' = 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.

SUBSTITUTE SHEE1' (RULE 26) Exal:)1es Table A
Rd O
R`
( N N- RlX
Rb Ra where RlX is H
R -(a) O
(Re_C3H7 or CF3CH2) 0 0 0 ~
s (b) p' or (c) R - H
O O
, Ra Rb Rc Rd H H H F

H H H o H H F Cl k- CH2 ~ i H H H

H H H H H

H
F Cl H H
~-s H H H

SUBSTITUTE SHEET (RULE 26) `NO 96126205 P'CT1US96/00824 Table A (continued) Ra Rb Rc' Ftd H H Cl. H

CI
H H H
H H H H
H H H c:i H H CF1:3 F,t s H H H Et H H H ~- CM2 = H

H H H
H H H CH2 <

SUBSTITUTE SHEET (RULE 26) Table B

R'x where RiX is (a), (b) or (c) as in Table A

Examples of Q

CHsO O CI O' O
N N N
H I

C~,P~ O O
H3C c-71 O O
NH3C N~
H CH3 H e N
H
N

r0crY I\ N H

H
butylS O cyclohexylO 0 0 Ni`Z-, I/ H I/ H
SUBSTITUTE SHEET (RULE 26) - 133 -, Table B (continued) Rtx Examples af Q

( o .
N~`Z, N~`~-, N

0 0 o N O__z3 IV ~N N
/ H CH3 H Cf{3 H
(J1s O CF3CH2 O CF3(CH2)2 OH
Ll H C, /
CF3CF2CH2 0 CH3 \ I O 0 F3C,~ CF3 .`Z, 'k N I`Z, H H (~I H
SUBSTITUTE SHEET (RULE 26) Tab'! e C
0 0 0 /~~
! \ / N N- RI N-(~,/N- R' [:::I N--CN- R' Examples of R1 x 0 X ~
O S O X
~.
Ol S
X X x X
OH\ I X1 X~

"

0 x O x x x x x l~ ~\ \
S \ X
xS
HO x Z z=o,s R HN O N R HN Re=propyl, CF3CH2-R =propyi, CF3CH2- 0 15 X for Table C H or F

SUBSTITUTE SHEET (RULE 26) Tab1E-. D
x R- N O i C!-( 0 x O 0 a= ~ N-~ or or a~ c H
X=HorF 0 Example of R

F3C F3C F~~ H O~~~
F
OMe "O
a-.---F3C' 0O~~ HOO"~, CI Me CI
. ~ O ~O
F3C H;zN- S
It O N O
z N~ O N HO ( ~ MeO" v v `~
Et N4O
,,0~~~ H~~ N`~
N F
MeO~ H F3C ~~ CF3 F ~
Cr N Y
p , CF3 F3C ^ F (~ F
F
SUBSTITUTE SHEET (RULE 26) Iab1e E
x x Oi F3C~ Oi H ~ H \ ~
H/ H~
~
X=HorF -X X
Example of R
~ ~
HO~ HOj~ Br S
uy--O HO Br N N~ HO~, "
~
p MeO~~ ' O~f HO~
OH

cL FsC~~ S-N~ HN, O
O O
O
N N" N
H O
O=g,O C\ C\3 y S cr&

S S 5 ~ O
J
o SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlUS9610082-1 - 137 ..

Table E (Cant=dl o,ss o OLOH H CO
~ N~~ N~ ~i= N`t, N
H H
IPHa H
NCr N N
NCH3 ~ H

H
\ O' o~' If H~' ~== H

SUBSTITUTE SHEET (RULE 26) Table F Y

Z <===== Fluorenyl-Type Compounds X= N"~ or o H
0j 0 0 Y R' H' \s,s- or R,-s or R,,,S" ~ R= propyl or CF3CH2 Fluorenyl-Type Rings: Z =

G
G
- - ~ ` ~
G= CH2, O, S, SO, S02 CF3 F

Et-W Et F F3C
N
N~~

F F3C , F

N/ N 1-13C, S /

G
\ ~ \
N
~ ~ -F F F
G=CH2,O,S,SO,SO2 SUBSTITUTE SHEET (RULE 26) -139=-IakIe C'a Y
~'\
X-( N---~~Z ~ Indenyi-Type Compounds X or N-~ or C\ H cir ~
~ I le~ H

Y= R. H~~ or Ror R. S11 ~~ R piropyl or CF3CH2 O

indenyl-Type Rings: Z ~
F F

F3C F3C CI Ci F F

F

x SUBSTITUTE SHEET (RULE 26) Table G (cont'd1 Indenyl-Type Rings: Z -N N Ph Ph N_ Me Me Me Me ~

F \ / F

N F F l=\
N N

SUBSTITUTE SHEET (RULE 26) I~L~tI
X X
O F3C-'1 0 $-C' 0 x XisHorF x Exampio of R

N

~

H3C'O F O
i~ iN' F

IN

i~ -H3C ci `L. lliz:t ~ &\S s SUBSTITUTE SHEET (RULE 26) x 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 IIi, 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-propyl-9H-fluorene-9-carboxamide, N-oxide A slurry of 3-chloroperoxybenzoic acid (approx. 50%) (341 mg, 0.99 mmol) in CH2C12 (1 mL) was added dropwise to a solution of Example 1 compound (524 mg, 0.99 mmol) in CH2C12 (1 mL) at 0 C
under argon. The reaction was stirred at 0'C for 20 min, diluted with CH2C12 (15 mL), washed with saturated NaHCO3 (5 mL) and brine (5 mL), then dried over MgSO4. 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/CH2C12 to give title compound (308 mg, 58%) as a white foam.

MS (ES): 538 [M+H]

.
Anal. Calcd. for C34H39N303 = 1.5 H20:
C, 72.29; H, 7.50; N, 7.44 Found: C, 72.32; H, 7.28; N, 7.41.
SUBSTITUTE SHEET (RULE 26) WO 96126205 PCTlUS96/00824 Examole 3Q
2-[1-[4-[9-(Butylsulfonyl)-9H-fluoren-9-yl]butyl]-4-niperidinvll-2,3-dihydro-lH-isoindol-1--one A.

CC
Bus H

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 stira_ing 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.

BuS Ci A solution of Part A 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 1-chloro-4-bromo-butane (0.81 g, 4.70 rnmol). 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 mL of aqueous NH4C1 solution and 30 SUBSTITUTE SHEE'T (RULE 26) mL of ethyl acetate. The organic fraction was dried (Na2SO4) 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.

ci o= I I

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 mixture was stirred for 1 h when it was diluted with 0.1 M
K2C03 (20 mL) and ether (30 mL). The organic fraction was dried (Na2SO4) 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(750) of title compound as a colorless oil.

TLC Silica gel (2:8 dichloromethane/hexanes) Rf= 0.07.

SUBSTITUTE SHEET (RULE 26) W O 9612620-55 PCqYUS96/00824 D.
~ i ~ ~ -~
~
-~, -h To a solution of Part. C compound (0.24 g, 0.64 mmol) in 2-butanone (10 mL) at RT was added NaI (1.00 g, 6.66 mmol) in one portiori. The mixture was refluxed for 30 h when it wEis diluted with water (20 mL) and ether (30 mL). The organic fraction was dried (Na2SO4) and concentrated. The remainder was purified by column chromatocfraphy 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-[1-[4-[9-(Butylsulfonyl)-9]i-fluoren-9-yl]butyl]-4-piperidir.,yl]-2,3-dihvdro-lH-isoindol-l-one To a stirred solutior.~. 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 NaHCO3 solution (50 mL) and ethyl acetate (50 mL). The layers were separated, the organics dried (Na2SO4) 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 (1L). Pure fractions were pooled and concentrated to , give 0.70 g (85%) of title compound as a thick oil which solidified after standing.

SUBSTITUTE SHEET (RULE 26) mp: 130-132 C.
TLC Silica gel (5:95:1 methanol/dichloromethane/NH3) Rf= 0.35.

Anal. Calcd. for C34H40N2S03 + 0.5 H20:
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 31 9-[4-[[4-[(1,1-Dimethylethoxy)carbonyl]amino]-1-piperidinyl]butyl]-2,7-difluoro-N-(2,2,2-trifluoro-ethvl)-9H-fluorene-9-carboxamide A.
Br F
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. . A
After an additional 14 h, the reaction mixture was poured into 1M hydrochloric acid (70 mL) and extracted twice with ethyl acetate. The combined organic extracts were dried (Na2SO4) and evaporated.

SUBSTITUTE SHEET (RULE 26) WO 96126205 7?CTIUS96/0092-1 The semi-solid residue was triturated wiith 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 temperaturta_ under argon was added a solution of oxalyl chloride (25 mL, 2.0,U
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% cit:ric acid solution and extracted twice with ethyl acetate. The organic extract was dried (Na2SO4) and evaporated.
Purfication by flash chromatography (12 }: 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 .
.

SUBSTITUTE SHEET (RULE 26) WO 96/26205 -148 PCT/US96/0082~1 -B= 9-[4-[[4-[(1,1-Dimethylethoxy)carbonyl]-amino]-1-piperidinyl]butyl]-2,7-difluoro-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-car-boxamide 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%
NaHSO3 solution and extracted with ethyl acetate.
The organic extract was dried (MgS04), 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.
Examnle 32 9-[4-[4-[(2-Phenoxybenzoyl)amino]-1-piperidinyl]-butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide. monohvdrochloride 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 HC1 in ethyl ether (15 mL) was added. The solution was evaporated and heated in a vacuum oven (550C) overnight to give title compound (5.1 g, 82%) as a white solid. m.p. 123-127 C.

MS (ES, + ion): 656 (M+H).

SUBSTITUTE SHEET (RULE 26) Anal. Calc. for C38H39C1F3N302 = 0.7 H20:
C, 66.07; H, 5.90; N, 6.08; F, 8.25 Found: C, 66.05; H, 5.97; N, E5.96; F, 8.21.
Examp 1 e 9-[4-[[4-(Benzoylamino)-1-piperidinyl]butyl1-2,7-difluoro-N-(2,2,2-trifluoroethyl)-9H-fluo:rene-9-carboxamide A solution of Example 31 compound (2.07 g, 3.56 mmol) in 10 mL of 4 I hycirogen 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 bicarbor.iate solution and extracted twice with ethyl ace!tate. The organic extract was dried (Na2SO4) and evaporated.
Purfication by flash chromatocrraphy on silica gel (5 x 20 cm column, 1:19 methanoliethylacetat(R as elutant) provided, after recrystallization from ethyl acetate/hexanes, title compour.Ld as a white solid, 1.83 g, 87% yield, mp 177-179 C.

Anal. Calc'd for C32H32F5N302=0.25 H20:
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).

SUBSTITUTE SHEET (RULE 26) Examnle 34 9-[4-[[4-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1- piperidinyl]butyl]-2,7-difluoro-N-(2,2,2-tri-fluoroethvl)-9H-fluorene-9-carboxamide A solution of Example 31 compound (2.02 g, 3.47 mmol) in 10 mL of 4 N 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 (Na2SO4) 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 1500C 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 C38H36F5N'303=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-9-carboxamide To a solution of 565 mg (2.64 mmol) of 2-acid (Aldrich) in 10 mL of dichloro-phenoxybenzoic methane under argon, was added 2 mL of oxalyl SUBSTITUTE SHEET (RULE 26) chloride (2.0 Z in dichlorome:thane, 4.0 mmol) and then 0.1 mL of DMF. After 1 h, the reaction was evaporated and the residue, 2-phenoxyben:zoyl 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,I hydrogen chlo3-ide 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, t.he reaction was quenched with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The organic extract was dried (Na;2SO4) 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 C38H36F5N303:
C, 67.35; H, 5.35; F, 1-1-4.02; 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).

SUBSTITUTE SHEIET (RULE 26) WO 96/26205 -152 PCT/US96/0082-i -Example 36 9-[4-[4-(Benzoylamino)-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohvdrochloride A.

Z_- 0 OH

Br To a solution of 9-fluorenecarboxylic acid (50 g, 240 mmol) in THF (1200 mL) at 0OC 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 0oC 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 HC1 solution (1N, 500 mL), then extracted with dichloromethane (3 x 750 mL). The combined organic layers were dried over MgSO4.
Evaporation gave title compound (71 g, 85%) as a white solid.

B.

H ^CF3 / ~ -Br SUBSTITUTE SHEET (RULE 26) To a solution of Part A acid (60 g, 173 mmol) and DMF (100 L) in CH2C12 (1500 mL) under argon at ti 0'C was added oxalyl chloride (104 mL, 2.OM in CH2C12, 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-trifluoroethylamine hydrochloride (25.9 g, 191 mmol) in CH2C12 (500 mL) at 0oC under argon was added triethylamine (73 mL, 521 mmol) followed by dropwise addition of a solution of the crude acid chloride in CH2C12 (15 mL). The reaction was stirred at 0 C for 1 h, diluted with CH2C12 (500 mL), and washed with water (2 x 300 mL), iN HC1 (2 x 300 mL), saturated NaHCO3 (2 x 300 mL), and brine (2 x 300 mL), then'dried over MgSO4. 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 mixtiire of CH2C12 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.
O

H CI=3 NHBOC
SUBSTITUTE SHE:ET (RULE 26) -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 CH2C12 (500 mL). The solution was washed with saturated NaHCO3 (3 x 80 mL) and brine (2 x 80 mL), then dried over MgSO4. Evaporation gave a yellow oil which was purified by flash chromatography on silica gel (600 g), loaded in CH2C12, and eluted with a step gradient of 2% MeOH/CH2C12 (3L) to 3% MeOH/CH2C12 (4L). Pure fractions were combined and evaporated to give title compound (30 g, 86%) as a white foamy gum.

D.
o ~ \ = 2 HCI
~

Za NH2 To a solution of Part C compound (30.5 g, 60.4 mmol) in dioxane (120 mL) was added 4N HC1 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-9-carboxamide. monohvdrochloride SUBSTITUTE SHEET (RULE 26) 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 MgSO4.
Purification was performed by flash chromatography on silica gel (100 g), loaded and eluted wit:h 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 HC1 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 obt.ained (1.3 g, 72%) as a white solid.

m.p. 132-137 C.
MS (Cl, +ion): 550 (M+H).

Anal. Calc. for C32H35C1F3N302 = 0.2 H20:
C, 65.18; H, 6.05; N, 7.13; Cl, 6.01;
F, 9.66 Found: C, 65.45; H, 6.06; N, E5.88; Cl, 5.16;
F, 9.30.

ExamBl e ~7 2,3-Dihydro-2-[1-[4-[9-(1-oxopentyl)-9H-fluoren-9-yl]butyl]-4-piperidinyl]-1H-isoindol-l-one, mono-hyclroc-h_ oride A.
O'TBS
A(1) .

SUBSTITUTE SHEET (RULE 26) OTBS (TBS Is Si(CH3)2t-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 NH4C1, water, Na2CO3, brine and dried (MgSO4). 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(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 triphenyiphosphine. 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 1,M sodium bisulfite, Na2CO3, brine and dried (Na2SO4). The resulting residue was triturated with ether (3x), filtered (to remove triphenylphosphine oxide) and evaporated to provided 10 g(610) of title compound as a pale yellow oil.
TLC Silica gel (4:1 hexanes/ethyl acetate) Rf = 0.60.

SUBSTITUTE SHEET (RULE 26) WO 96126205-t iPCT/LIS96/00824 B.
I ~ O
O H
OTBS
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 mL (52.32 mmor.) of n-butyllithium (2.5 M in hexaiies) dropwise. The orange-red anion was stirred :Eor 0.5 h, at which time 7.5 g (23.78 mmol) of ~~~'OTBS (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 di:Luted with a 1:1 mixture of ethyl acetate/H20 (250 mL). The organics were washed with NaHCO3, brine, dr:Led (Na2SO4) and evaporated. Flash chromatography was performed on 250 g of silica gel eluting with 9:1 dichloromethane/
isopropanol to provide 4.9 g~;520) of title compound as a yellow oil. `

TLC: Silica gel (9:1 dichloromethane/isop:ropanol) Rf = 0.50.

C.
-OT B S
_ SUBSTITUTE SHEET (RULE 26) 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.
I ~ O
Me 1 / .

OTBS
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 M 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 (NaSO4) 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.

SUBSTITUTE SHEET (RULE 26) MS (CI-NH3, + ions) m/e 397 (M+H).

Anal. Calcd. for C24H32O3Si + 0.15 mol H20:
C, 72.20; H, 8.15 Found: C, 72.20; H, 7.88.
E.

Me OH
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 NaHCO3, water (3x), brine, dried (MgSO4) 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. 20 TLC: Silica gel (8:2 hexanes/ethyl acetate) Rf = 0.15.

SUBSTiTUTE SHEiET (RULE 26) F.

O
Me 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, NaHCO3, water, brine, dried (MgSO4) 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-[l-[4-[9-(1-oxopentyl)-9H-fluoren-9-yl]butyl]-4-piperidinyl]-1H-isoindol-l-one, monohvdrochloride 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 K2C03 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 (Na2SO4) and evaporarted to provide a SUBSTITUTE SHEET (RULE 26) pale yellow solid. The solid was dissolved in ether and treated with 305 mL (0.30 mmol) of HC1 (1 Z 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 tit1El compound as a pale yellow solid.

mp 96-100 C.
TLC: Silica gel (95:5 dichlor=omethane/is(Dpropanol +
1% NH4OH) Rf = 0.46.
MS (ES; NH4OH, + ions) m/e 521 (M+H).

Anal. Calcd. for C35H40N202 HC1 + 0.5 moa H20:
C, 74.25; H, 7.48; N, 4.95 Found: C, 74.24; H, 7.45; N, 4.98.
Examole .U
2,3-Dihydro-2-[1-(1-oxo-3,3-diphenylpropyl)-4-8iiperidinyll-lH-isoindol-l-one To a solution of 3,3-dipheny1propi.onic 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.OM, 1.66 mL, 3.32 mmo1). Bubbling of escapincr 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 cr=ude 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 dichlorometl:zane (2 mL). The reaction was stirred at 0 C for 10 min.
Dichloromethane (100 mL) was added to dilute the SUBSTITUTE SHEIET (RULE 26) reaction and the resulting solution was washed with H20 (40 mL), saturated sodium bicarbonate solution (40 mL), brine (40 mL) and dried over MgSO4.
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. 166-1690C.
MS (FAB, +ion): 425 (M+H) Anal. Calc. for C28H28N202 = 1.1 H20:
C, 75.68; H, 6.85; N, 6.30 Found: C, 75.50; H, 6.45; N, 6.24.

Example 39 [1-[4-[9-[(Propylamino)carbonyl]-9H-fluoren-9-yl]-butyl]-3-piperidinyl]carbamic acid, phenylmethyl ester.monohydrochloride A.

Z / O
N
H
CO2Et 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 CH2C12 (50 mL), washed with SUBSTITUTE SHEET (RULE 26) WO 96/26205 .PCT/11596100824 saturated NaHCO3 (2 x 15 mI,) and brine (20 mL), then dried over Na2SO4. L"vaporatiort gave 3.6 g of an orange gum, which was dissolved.in a minimal amount of CH2Cl2 and purified by flash chromatography on silica gel (175 g) eluting wit4 2% MeOH/CH2C12 to provide 2.65 g of product,contanninated with approximately 20 inolt DMF. The product was dissolved in EtOAc (60 mI,), washed with water (3 x 20 mL) and brine (20 mL), then dried over Na2S04. Evaporation gave title compound (2.35 g, 75%) as an amber oil.

B. ..
0 ~' . .

H f , Palladi,um on carbon (10V (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 EtOPi.(ZS
mL). The mixture was hydrogenated (balloon) at RT
for 1.5 h, filtered through Celite ', and washed with EGOAc (3 x 20 mL). The filtrate was concentrated in vacuo to.give title compound (2.42 g, 100%) as a pale yellow oil.

C.

Z O N
H
cc Aqueous KOH (5.6 mL, 1N, 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 HC1. The cloudy reaction was diluted with water (30 mL) and extracted with CHC13 (3 x 100 mL), then dried over Na2SO4. Evaporation afforded title compound (2.2 g, 100% crude) as a foamy white solid.
D. [1-[4-[9-[(Propylamino)carbonyl]-9H-fluoren-9-yl]-butyl]-3-piperidinyl]carbamic acid phenvlmethyl ester, monohydrochlor;de To a cloudy suspension of Part C compoundA(336 mg, 0.714 mmol) and triethylamine (238 L, 1.71 mmol) in dioxane under argon was added diphenylphosphoryl azide (184 L, 0.857 mmol). The mixture was heated at 80'C for 2 h(N2 evolution observed soon after heating commenced). Benzyl alcohol (367 L, 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 CH2C12 (20 mL) and saturated NaHCO3 (5 mL). The organic layer was washed with brine (5 mL) and dried over Na2SO4. Evaporation gave 760 mg of a yellow oil, SUBSTITUTE SHEET (RULE 26) which was purified by flash chromatography on silica gel (50 g) eluting with 3% MeOH/CH2C12 to give 215 mg of a colorless oil.
The free amine was dissolved in Et20 (3 mL) and treated with 0.77N HC1 in Et20 (3 mI,). The white precipitate was filtered, washed with Et.20 (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 C34H42C1N303 = 0.3 H20:
C, 70.22; H, 7.38; N, 7.23.
Found: C, 70.11; H, 7.24; N, 7.09.
Example 4Q
9-[4-[4-(2,3-Dihydro-l-oxo-lH-isoindol-2-yl)-1-piperidinyl]butyl]-N-(2,2,2-t:rifluoroethyl)-9H-fluorene-9-carboxamide. hvdre)chloride sa.It A.

o H~ ci To a stirred solution of 10.0 g (33.5 mmol) of compound prepared in Example 5 Part A first paraaraph 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 SUBSTITUTE SHEET (RULE 26) 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 (Na2SO4) 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 (1L). Pure fractions were pooled and concentrated to give 9.25 g(730) of title compound as a white solid.

mp: 87-89 C
B.

H N O

N
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 K2C03. 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 rrmL 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.

SUBSTITUTE SHEET (RULE 26) wo 46r26208 rcrrcJS96/00324 -167 '-C. 9-[4-[4-(2,3-Dihydro-'1-oxo-lH-isoindol-2- yl) -l-piperidiny],]butyl] -N- (2, 2, 2--tri-f, uoroethcv;.1 - H-f? ~dren .-9-carboxamidy9 ,_ A suspension of 10.00 g,(- 17 mmol) of Part B
costpound in 80 YaL of ethanol was. treated with 0.5 g of 10% Pd/caxbon 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 retqa=inder was triturated with warm water to give 9.0 g(93$) of title compound as a white solid.

mp: 143-146 C. =
TLC Silica gel (5:95:1 methanol/dichloromethane/NH3) Rf= 0.35-D. 9-[4-[4-(2,3-Di]aydro-l-oxo-lH-isoindol-2-yl)-l-piperidinylJbtttyl3-N-(2.2,2-triflu-oroethyl)-9H-fluorene-9-carboxamide, ~drnr}~1 nri d~ isa] t A suspension of 9.00 g (d 16 marol ) of Part B
compound in 200 mL of ethyl ether was treated with 8 ri. (32 mml) of 4Z4 HCl in dioxane and the reaction mixture stirred for lh under.'an atmmosphexe of N2.
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.
mp: 139-141 C.
TLC Silica gel (5:95:1 :nethanol/dichlorometha3ne/NH3) Rf= 0.35. .
MS (ES, + ions) m/z 562 (M+H).

Anal. Calcd. for C33H35N3O2F3C1:

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.

Exam,ple 41 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.

I ~ ?

N-\

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 K2C03. 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=11). The white solids were collected by filtration and dried to give 4.50 g of title compound.

SUBSTITUTE SHEET (RULE 26) VJO 96/26205 .PCT/iTS961QQ824 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 HC1 in dioxane and the reaction mixture stirred for lh under an atmosphere of N2.
The reaction mixture was filtered and th(=_ cream colored solid collected. The solid was dried at 40 C
under vacuum to give 3.8 g(730) of title compound.
mp: 139-141 C.
MS (ES, + ions) m/z 562 (M+H).
Anal. Calcd. for C33H35N302F3C1:
C, 66.27; H, 5.90; N, 7.03 Found: C, 65.87; H, 6.14; N, 6.71.

Examvles 42-50 Following the procedures set out herein, the following compounds were prepared.

Examnle 42 9-[4-[3-(Benzoylamino)-1-piperidinyl]butyl]-N-propyl-9H-1`luorene-9-carboxamide.

MS (ES) 510 (M+H) Anal. Calcd. for C33H39N302 = 0.2 H20:
= 30 C, 77.22; H, 7.74; N, 8.19 Found: C, 77.12; H, 7.58; N, 8.16.
SUBST[TUTE SHEET (RULE 26) Example 43 9-[4-[3-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-piperidinyljbutyl]-N-propyl-9H-fluorene-9-carboxamide.

MS (ES) 536 (M+H) Anal. Calcd. for C34H37N303 = 0.2 H20:
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-Dihydro-1-oxo-1 H-isoindol-2-yl)-1-piperidinyl]butyl]-N-(2,2,3,3,4,4,4-heptafluorobutyl)-9H-fluorene-9-carboxamide, monohydrochioride.

mp: 122-132 C
MS (ES, + ions) m/z 662 (M+H) Anal. Calcd. for C35H3502N3F7C1 = 0.8 H20:
C, 59.04; H, 5.17; N, 5.90 Found: C, 59.04; H, 5.04; N, 5.90.
Examiple 45 9-[4-[[4-[(1,1-Dimethylethoxy)carbonyl]amino]-1-piperidinyl]butyl]-3,6-dif16oro-N-(2,2,2-trifluo ro ethyl)-9H-ftuo rene-9-carboxamide.

mp: 59-64 C
MS (FAB, M+H)+= m/z 582+
Anal. Calcd. for C30H36F5N303 = 0.2 equiv. hexane:
C, 62.58; H, 6.53; N, 7.02 Found: C, 62.41; H, 6.55; N, 6.84.
ExamplP 46 1-[4-[4-(1,3-Dihydro-1-oxo-2H-isoindo1-2-y1)-1-piperidinyl]butyl]-2-methyl-N-(2,2,2-trff1uoroethyl)-1 H-indene-1-carboxamide.

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlUS96/00824 mp: 124-126 C
MS m/z (ES, + ions) 526.3 (M+H) .
- Anal. Calcd. for C30H34F3N302=
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.
Example 47 9-[4-[4-(1,3-Dihydro-1-oxo-2H-isoindol-2-ji1)-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 C34H35N302F5C1 + 1.2 H~;O:
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.
Example48 1-[4-[4-(1,3-Dihydro-l-oxo-2H-isoin,dol-2-yl)-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-1 H-indene-l-carboxamide.
mp: 62-65 C
MS m/z (ES, - ions) 510 (M-H), 556 (M+HC:O2-) Anal. Calcd. for C29H32F3N302 = 0.16 H20:
C, 67.70; H, 6.33; N, 8.17; F, 11.08 Found: C, 67.70; H, 6.26; N, 7.94; F, 1C).62.
Examn1e 4 9 9-[4-[4-(Benzoylamino)-1-pipe ridinyl]butyl] -3,6-difluo ro-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide.
- MS (FAB, M+H)+ m/z 586+
Anal. Calcd. for C32H32F5N302=H20=0.15 CH2C12:
C, 62.65; H, 5.61; N, 6.82 Found: C, 62.52; H, 5.56; N, 6.67.
SUBSTITUTE SHIEET (RULE 26) Exam e 50 3,6-Difluoro-9-[4-[4-[(2-phenoxybenzoyl)amino]-1-piperidinyl]butyi]-N-(2,2,2-trifiuoroethyl)-9H-f1uorene-9-carboxamide.
mp: 124-26 C
MS (FAB, M+H) m/z 678+
Anal. Calcd. for C38H36F5N303:
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 p r CF3 A. Aqueous KOH/CHC13 ~ H B. RSC02H, DIC, HOBT, DMF
~ C. Optional HPLC Purification bis HCI salt ~ r CF3 N
H
O

H
I
y A. Preparation of the diamine starting material:
A solution of the diamine bishydrochloride salt (compound X) (10 g, 19.3 mmol) in chloroform SUBSTITUTE SHEET (RULE 26) -(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 drie(i over MgSO4. Evaporation gave the free diamine (8.8 g, 100%) as a colorless oil.

B. General Experiment:al for Robotics Compounds:
The following is a general procedure for the synthesis of amides according to the above equation via the coupling of carboxy:Lic 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 run the operating program and to write the Benchmate procedures.
A 16 mm x 100 mm tubea was charged with 1.6 mmol, 4 eq R5CO2H 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) of a 81 mg/niL 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 CH2C12.
3) Added 1 mL (178 mg, 0.4 mmol, 1 eq) of a 178 mg/mL solution of diamine in CH2C12.
4) Washed syringe with 3 mL of CH2C12 5) Mixed tube contents by vortexing at speed 3 for 15 sec.

SUBSTITUTE SHEET (RULE 26) WO 96/26205 CA 02213466 1997-08-20 pCT[US96/00824 After 12-48 h the reaction was complete (no starting amine remained as determined by TLC; 10%
MeOH + 1% NH40H in CH2C12, 12) 5 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 Benchmatee:
1) Condition a Varian solid phase extraction 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 Z 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 inL 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 SUBSTITUTE SHEET (RULE 26) WO 96/26205 -175 I'CTlUS96f0082~t -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 + i:i) C. Preparative HPLC Purification In cases where the coupling reaction is carried out with carboxylic acids bearing basic substituents (for example, pyridyl or amin.o), the product Y isolated as above in Part B, is contam-inated with the starting acid. These materials were further purified by preparativ(B 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% H20, 0.1% TFA
Solvent B: 90% MeOH, 10% H20, 0.1% TFA
Column: YMC ODS-A, SH-363-5, :30 x 250 mm I.D. S-5 p1m, 120 A, No. 3025356A. 25 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.

SUBSTITUTE SHEf:T (RULE 26) WO 96/2620~ PCT/US96/00824 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 in 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 o F
~ F
~ N F
m/z 585 51 (M+H) Q
N
O
H
a o \
52 N a m/z 585 C~N (M+H) F
F-'~N
F
O

SUBSTITUTE SHEET (RULE 26) WO 96/26205 -177 PCT(US96/0082~t -~ o F

= 53 N F m/2:585 - ` ~
N (M-i-H) ~ O
~ ~
CI

O p N
54 a m/z 619 (M+H) F
,N
F
O
CI
O
\ -N ~ ~ a 55 bN m/z619 (M+H) F F
FN ) O

SUBSTITUTE SHEET (RULE 26) WO 96/26205 -178 PCT/iJS96/0082=1 -/
0 o-`
56 ~--~ % m/z 580 (M+H) N

F
Fti1 N
F,/
O
i O

57 m/z 580 ~ (M+H) F
F/N
F O
! O F
N F
58 m/z 580 N----, ( M+H ) ~
QN
Ir \`' O
JI~
o, SUBSTITUTE SHEET (RULE 26) WO 96/26205 -179 PCT(US96l0082~i -F
59 N F m/z 563 (M-_ ~ ~ H) N\N
~ O
~ ~
O
F
60 FF m/z 618 O N
N
N- o (MiH) F-FF
O~ F
61 N F F m/z 618 ~ (M-t=H) F N ~
F~ O

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlUS96/00824 O\ F
F
N
F
62 m/z 618 N (M+H) F F
F>~'N
O
O~~ Q
O
63 N m/z 642 ~ON (M+H) i F N
F --4~
F O
O

N/~~
64 b m/z 642 N (M+H) F F
F
N
~

o F
F

m/z 564 (M+H) N

N

O

SUBSTITUTE SHEET (RULE 26) 'WO 96/26205 PCT/US96100824 ~ NZ O F
F' 66 N F m/z !564 (M+H) i ~4 N
_ \O
O

67 ~ m/z !5 64 N (M+fi) F ~(F
F" ~N
O

F
F
afN --F
68 m/z !i78 (M+Fi) N~~
-N

O
O

N
69 m/z 606 N ( M+fi) F~N
F

O
c \ /

SUBSTiTUTE SHEIET (RULE 26) o F
F
N F
70 m/z 595 (M+H) N

N
O O
1 _ O F F
N F
71 m/z 595 a (M+H) N

O~
Nr0 O

O

72 N N m/z 563 / (M-H) N
F~ O
F'/
F
O~
73 N/ m/z 591 N (M-H) N F / F F

SUBSTITUTE SHEET (RULE 26) WO 96126205 -183 ]PCT/US96100824 -Pt-~N
74 m/z 540 N l0 -3 (M+I-I) F~
F F

F F
O r F
75 N m/z ;556 ND- n1 S ( M+fi ) j o F
j~ F
O F
76 N m/z 539 NN N (M+H) ./
O

N F
77 m/z554 (M+H) N-) O
~.
O

SUBSTITUTE SHEiET (RULE 26) gLN F F F
78 m/z 590 (M+H) O~

O F

m/z 570 (M+H) v N
O
S

O F
\
80 F m/z 591 (M+H) N

a ~O

81 N-C m/z 569 N (M+H) F~ O
F F

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTfUS96f00824 F m/z:631 82 (M +H) a~~f ~
NN

O O
~
o F
N F
83 m/z 684 (Mi-H) F, N
a o f N
-O
F F m/z 567 ~F (M-f H) o~

o -ND-N N
O
O

85 0 N~N_ ^ ~ \ m/z 56; (M-~ H
F N":~
'%LJ O
F
F

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlUS96/00824 gL FF
86 F m/z 565 (M-a H) N
O
~ ~ -F
o~
~ N F
87 m/z 619 (M+H) N
0 \ C!
~

CI
O F
N--f-F
F
88 0 m/z 629 e (M+H) F
89 F F m/z 568 (M+H) N F

~

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCT/[JS96100824 .
. F
~F

90 N m/z 540 (M+H) N

O F
F
91 m/z 583 (M+IH) ~ N
a N :5 O
N
o ~
N F

92 m/z 567 / (M+I-i) ~ N
a N O~ `
~ N
,J
F
-F
93 N ~r m/z 1301 N ~ N (M+H) ~

SUBSTITUTE SHEET (RULE 26) O ~fF
N' TF

94 m/z 586 X (M+H) ~ N
a N CI
O~
N
F F

O ?,~ N O
95 N m/z 603 N_ (M+H) O / F
N'-~TF
F
96 m/z 643 (M+H) N

N
O F

F
97 m/z 625 (M+H) N
O

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlUS96100824 . p F
F
N
F
98 m/z :587 (M+H) N

Saz~,-o F

OiYNF N-`~~ 0 99 m/z 610 N ( M+fi) l ~ ~=
0 F' N' ^T"' F
F
100 ~ -~ m/z 581 (M+H) N

O F
Nl-~-F
F
101 m/z 5 91 (M+hi) O ! -'ZZZJ.5 SUBSTITUTE SHEET (RULE 26) F
F
O F N O
102 N ~ m/z 621 \ N/ (M+H) F
F
r---~F
O N ~\ - O
103 ~-~ NJ m/z 617 (M+H) N
O
N
F
104 m/z 676 N (M+H) ~ O
N /
F
F ~ ~ O I
F F

F
k0i F
105 m/z 649 ~, (M+H) ~ =
N
' \
O
O
< .f =
x f F

SUBSTITUTE SHEET (RULE 26) WO 96126205 -191 I'CT/US9610082~i -o N
106 . F m/z 594 - F (M+H) N

O
N

O /
O
N
107 ~FF m/z 641 ( M+H ) o N

1 ~ O
N
108 1-4 m/z 626 F ( M+H ) N

O
cLN
109 ~F m/z 640 ( M+H) o SUBSTITUTE SHEl=T (RULE 26) gkN
110 m/z 655 F (M+H) QN

~
g kN
111 F m/z 656 F (M+H) \ F

o O

o N
112 m/z 528 F (M+H) ~-l o N-, O

113 m/z 556 (M+H) N

N

SUBSTITUTE SHEET (RULE 26) ~ O F
N' I-F
F
114 m/2:570 (M=+-H) Cz N
O
o N
115 F m/z.544 F (M-EH) N

o F m/z 544 F (M+H) , ~ .
O
N
117 ~F m/z 594 (Mi-H) N ~

-O \ /

SUBSTiTUTE SHIEET (RULE 26;) o m/z 578 (M+H) F
N

O
klN

F m/z 544 F (M+H) N /
o - I
1120 m/z 600 - ~ F (M+H) Q I
N _ O
O
N
121 ~ m/z 600 F (M+H) N~

N
O/

SUBSTITUTE SHEET (RULE 26) W O 96126205 .PCT/CTS96/00824 - ' N
122 F m/z a30 F (M+ti) N

Nl O F N---- F

123 -~ m/z f340 (M+H) ~
N
O

N F
124 ~F m/z !i 80 (M+H) o ~

125 N'--- / F m/z 5 18 FF (M+H) = N
IJ
N ~
; ~~

SUBSTITUTE SHEET (RULE 26) o 126 N F m/z 532 ~F (M+H) N~

Ol O
O
N
127 F m/z 564 (M+H) N

N
O

kN,N
128 F F m/z 592 ( M+H ) F
N

~ N

O
gkN

F m/z 530 F (M+H) F

Q.o N ~ .
SUBSTITUTE SHEET (RULE 26) WO 9612620+ PCT/1JS96/0082-1 o N
F
130 ~F m/z 606 N (M+H) (~() o N

N
131 F m/z 544 F (M+H) v o 132 N m/z 654 F (M+H) N F
O~ N

\ I\ I
O
O F
I
N F
F
133 m/z 545 (M+H) N
a-'0 SUBSTITUTE SHEf:T (RULE 26) O
N F

F m/z 615 F (M+H) ~
O

N

F
135 -- F m/z 544 F (M+H) N

O

N
136 F m/z 656 ~ (M+H) N ~ i .
p p r \ p N
137 ~F m/z 656 (M+H) O~N
~
i Cp ~
~~

SUBSTITUTE SHEET (RULE 26) WO 96126205 -199 PCT/US96/0082~3 -o 138 N~ F/ m/z 532 F (IM+H) Examples 1 S, to 167 In the following Examples, the coinpounds prepared were purified by preparative HPLC (Method C) and isolated as trifluoroacetic acid salts.

F
N
F
139 - m/z 565 ~ i (NA+H) ~
ra N O
O F

F m/;z 593 140 - (Ni+H) N

SUBSTITUTE SHEET (RULE 26) O F
NFF
141 m/z 551 (M+H) O

N
0 ~[ F
N',/`F
F
142 m/z 551 (M+H) N

NO

N~ F
F
143 m/z 567 N--", ~, (M+H) N/ `

N F
F
144 m/z 566 (M+H) N

N N
O~

N
~~ .
SUBSTITUTE SHEET (RULE 26) WO 96/26205 :PCT/US96/00824 F
t 145 m/;z 597 (M+H) N
/ o N S

O F
N~ F m/z 609 146 \ _ ~ o 0 0 (M+H) N ~~

O F
N F
F
147 m/2: 565 (M+H) N
x ' , G) Q ~(F
N' /-F
F
148 m/z 616 (M+H) N
. G~ o SUBSTITUTE SHEET (RULE 26) O F
N---~F
149 m/z 611 (M+H) o O N O
F
F
rl<F
O\ N ^ / N O
150 - ( I7 m/z 601 N~ N (M+H) F
F
O N NY O
151 - ~ ( m/z 601 N~ 501 (M+H) F F
?`~ F
152 0 N m/z 552 N (M+H) . .
, \ N/

SUBSTITUTE SHEET (RULE 26) F
- - F
F
153 0 N m/z 552 N. ~ (M+H) N_NJ
F
F
F
154 o N N~O
I m/z 567 N"
Y N Y N (M+H) N

F
F
r-,<F
O~ N N 0 155 m/z 602 N--- (M+H) H
N`
F
F
F

156 N N~ m/z 592 N (M+H) N

SUBSTITUTE SHIEET (RULE 26) WO 96/26205 PC1'/US96/0082-1 F
~F
F
N O
157 N N N m/z 555 (M+H) N-N
<
F

~ F N O
158 0~~N m/z 589 N~ (M+H) N
F
F
F
N N
159 ~ N~ ~ m/z 613 S ~ (M+H) `_~ O

F
~F
'O
160 N,- m/z 670 ~ S (M+NH4) SUBSTITUTE SHEET (RULE 26) .
F
-F
O N
= 161 m/z 634 (M+H) nr-S

162 " F
F m/z 654 0 N (M+H) o =~~

N F
163 m/z 650 (M+H) 0 N- ~
O
/ \
gkN F

m/z 636 (M+H) o N-(D\

SUBSTITUTE SHEET (RULE 26) i qo N
~F
165 F F m/z 684 N (M+H) o N
N__~N

o 166 F m/z 596 F F (M+H) / ~ Chiral N
167 '--4F m/z 557 F (M+H) N

U
Examnle 168 9-[4-[4-[(Phenoxycarbonyl)amino]-1-piperidinyl]-butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide. monohvdrochloride To a solution of Example 36 Part D amine (500 mg, 0.96 mrnol) and triethylamine (0.33 mL, 2.4 mmol) SUBSTITUTE SHEET (RULE 26) -in dichloromethane (5 mL) at 0OC was added dropwise phenyl chloroformate (0.14 niG, 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 sodiuun bicarbonate (2 x 30 mL) , water (2 x 30 mm:,) , brine (2 x 30 mL) and dried over MgSO4. 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 g:Lve 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 C32H35C1F3N3O3 = 0.6 H20:
C, 62.71; H, 5.95; N, 6.86; F, 9.30 Found: C, 62.79; H, 5.88; N, 6.50; F, 9.1.0 Examole 169 9-[4-[4-[[(Phenylamino)carbonyl]amino]-1-piper-idinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene--~-carboxamide. monohvdrochloride 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 0OC 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 MgSO4. 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 (CI, + ion): 565 (M+H) Anal. Calc. for C32H36C1F3N4O2 = 0.6 H20:
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 Exam8le 170 9-[4-[4-[(Phenylsulfonyl)amino]-i-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 (0.46 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 SUBSTITUTE SHEET (RULE 26) dried over MgSO4. Evaporation gave a yellow oil.
Purification was performed by flash chr=omatography 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 vacu'um oven (550C, 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 C31H35C1F3N3S03 = 0.8 H20:
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 . NHCO2tBu O

SUBSTITUTE SHEET (RULE 261 A. 0 OEt 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 N 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 (Na2SO4) 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 L). 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 (MgSO4) and evaporated. Purfication by flash chromatography on silica gel (5 x 15 cm column, 3:97 ether/dichloromethane as elutant) SUBSTITUTE SH EET (RULE 26) -211:-provided title compound as a white solid, 956 mg, 47%
yield , mp 108-110 C.

B-O OH

/ ,/

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 ......,~~; - L
ica~~ioii iiixture was 5tir=e~ Q Lor 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 (MgSO4) and evaporated to give title compound as a white solid, 540 mg. It was used in the next step without further purification.

C.
NHCOZtBu O cr x To a solution of Part B compound (530 mg, 1.41 mmol), Example 10 Part B ami,ne (280 mg, 1.41 mmol) and HOAt (210 mg, 1.5 mmol) in 5 mL of T:HF at room temperature under argon, was added DCC (.295 mg, 1.43 SUBSTITUTE SHEET (RULE 26) 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 (Na2SO4) 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 C30H36F'3N304 =H,O:
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).
ExamBle 172 cis-9-[4-[4[(2-Phenoxybenzoyl)amino]-1-piperidinyl]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 CH2C12 (5 mL) at 0'C under argon was added a solution of 3-chloroperoxybenzoic acid (80-85%) (82 mg, 0.407 mmol) in CH2C12 (1.5 mL) slowly over 5 min. The reaction mixture was stirred at 0'C for 10 min, then saturated aqueous NaHCO3 (1 mL) was added. The reaction mixture was stirred at 0'C vigorously for 1 h, diluted with CH2C12 (10 mL), washed with brine (5 mL), and then dried over Na2SO4.
Evaporation gave 320 mg of a SUBSTITUTE SHEET (RULE 26) white foam, which was purified by flash chromatography on silica gel (50 g) eluting with step gradient of 3% to 5% MeOH/CH;2C12 to provide title compound (74 mg, 25%) as a white foamy solid.
MS (ES, + ions) m/z 658 (M+H) Anal. Calcd for C38H38F3N304 + H20:
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-trifluoro(athyl)-9H-fluorene-9-carboxamide A solution of Example 171 compound (2.00 g, 3.59 mmol) in 10 mL of 4tj 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 imnol) 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 extracce3 twice with ethyl acetate. The organic iBxtract was dried (Na2SO4) 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.

SUBSTITUTE SHEET (RULE 26) Anal. Calcd for C38H36F3N304 + H20:
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+NH4 ) .

Examnle 174 NHCOPh A solution of Example 171 compound (2.00 g, 3.59 mmol) in 10 mL of 4 N 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 rrL 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 (Na2SO4) 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 -v::ite solid, 725 mg, 71% yield, mp 204-206 C.

SUBSTITUTE SHEET (RULE 26) WO 96/26205 ]PCT/US96/00824 Anal. Calcd for C32H32F3N303:
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/=r. 437 (M-CF;;CH-)NHCO), 562 (M-H).

Fxample :175 9-[4-[4-[[(l,l-Dimethylethoxy)carbonylJaminoJ-1-piperidinylJpentylJ-N-(2,2,2-t:rifluoroethyl)-9H-fluorene-9-carboxamide A.
Br COpH
To a solution of 2.50 cq (11.9 mmol) of 9-fluorenecarboxylic acid in 25 mL of THF under argon (evacuated and purged with ar5-on three tinies) 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 mriol ) 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 (MgSO4) and evaporated.
Trituration of the residue in ethyl acetate/hexanes gave title compound as a white solid, 3.72 g, 87%.

SUBSTITUTE SHEET (RULE 26) B.

To HCH2CF3 C%C-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 L).
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 (MgSO4) 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 (MgSO4) 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.

SUBSTITUTE SHEET (RULE 26) C.
NHCO2tBu R~/

A solution of Part B -compound (1.27 g, 2.60 mrnol), 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 undei- argon was heated to 50 C. After 15 h, the reaction was quenched with water, decanted and the oily residue ext:racted twice with ethyl acetate. The extracts were combined, washed once with water, once with saturaited sodium bicarbonate solution, dried (Na)S04) and evaporated.
Purification by flash chromatography on silica gel (5 x 15 cm column, 1:99 methano:L/ethyl acetate as elutant) provided title compound as a white solid, 1.20 g, 82% yield, mp 58-60 C.

Anal. Calcd for C31H40F3N303 + 0.25 H=,O:
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--1-piper-idinyl]butyl]-N-(2,2,2-trifluoroethyl)-9li-fluorene-9-carboxamide, monohvdrochlox-ide To a solution of 2-phenoxyaniline (5.0 g, 27.0 mmol) in conc. hydrochloric eicid (20 mL) and glacial acetic acid (6 mL) at -10 C, a solution of sodium SUBSTITUTE SHEET (RULE 26) nitrite (2.01 g, 29.2 mznol) 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 rnL), brine (2 x 100 mL) and dried over MgSO4. Evaporation gave a mixture containing 0'O0 õs- cl O
ctr (2.5 g, 36%) as a brown oil. 20 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 HC1 to give title compound (210 mg, 26%) as a white solid.
m.p. 142 -146 C
MS ( ES, + ions ): 678 (M + H) SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlLJS96f0flS24 Anal. Calc. for C37H39C1F3N3SO4 + 0.4 H20::
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.

Examnle 177 [1-[[[2-[9-[[(2,2,2-Trifluoroethyl)amino)carbonyl]-9H-fluoren-9-yl]ethyl]amino]c:arbonyl]-4-piperidin-yllcarbamic acid, 1.1-dimethvlethvl ester A.
( \ .C02H
O"CN To a solution of 9-flu;orenecarboxylic 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 mrnol,) over 15 min under argon. The dark yellow solution was stirred at 0 C
for 30 min, and then chloroacetonitrile (3.8 mL, 60 manol) 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 H20 (250 mL) and Et20 (250 mL), and concentrated in vacuo to 300 mL.
Water (200 mL) and CH2C12 (500 mL) were added. The mixture was acidified to pH 1.85 with iN HC1 and extracted with CH2C12 (6 x 250 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give crude solid title compound (10.45 g, 76.7%).

SUBSTITUTE SHEET (RULE 26) B.

H

CN

To a solution of Part A compound (6.7 g, 26.9 mmol, dried by concentration with THF/toluene) and DMF (102 l, 1.36 mmol) in CH2C12 (80 mL) under N2 was added oxalyl chloride (20.5 mL of a 2.OM solution in CH2C12, 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 CH2C12 (50 mL) at 0 C under N2. The resulting thick slurry was stirred at 0 C for 5 min and then a solution of the crude acid chloride in CH2C12 (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 HC1 (2 x 80 mL) and saturated NaHCO3 (80 mL), dried over Na2SO4, 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 CH2C12, to give title compound (10.5 g, 83.3 %) as a solid.

SUBSTITUTE SHEET (RULE 26) C.

~ \ fi^

~ INH2.HC1 A solution of Part B compound (4.5 g, 13.6 mmol) in absolute ethanol (400:nL)/CHC13 (7 mL) was hydrogenated at 50 psi over 1.0% 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.

O
H/

/ I -\ N~ N02 H

0 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 = 20 diluted with EtOAc (700 mL). The EtOAc was washed with 5% NaHCO3 (4 x 50 mL), H20 (4 x 50 mL), 0.2N HC1 (5 x 50 mL), H20 (2 x 40 mL), and brine (40mL) and then dried over Na2SO4. Evaporation gave 3.1 g of a foam, which was purified by f:lash chromatography on SUBSTiTUTE SHIEET (RULE 26) 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. [1-[[[2-[9-[[(2,2,2-Trifluoroethyl)-amino)carbonyl]-9H-fluoren-9-yl]ethyl]-amino]carbonyl]-4-piperidinyl]carbamic acid, l.l-dimethylethvl ester To a solution of Part D compound (1.59 g, 3.18 irnnol) in CH2C12 (30 mL) under N2 was added a soluzion of Example 10 Part B ester (1.27 g, 6.36 mmol) ir.
CH2C12 (20 mL), followed by 4-dimethylaminopyridine (56 mg, 0.46 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with CH2C12 (50 mL), washed with 0.1 N NaOH (3 x 40 ml), H20 (2 x 40 mL), 1% KHSO4 (2 x 40 ml), H20 (40 mL), 5% NaHCO3 (2 x 40 mL), H20 (40 mL) and brine 40 mL) and then dried over Na2SO4. Evaporation of the CH2C12 gave 1.8 g of a foam, which was purified by flash chromatography on silica gel (100 mL), eluting with EtOAc/hexane (60:40 to 100:0), to give title compound (1.43 g, 80.1% ) as a white solid. mp 77-8 0 C . 25 MS (ESI, + ions) m/z 561 (M + H), 1121 (2M + H) (-ion) 559 (M - H).
Anal. Calcd for C29H35N404F3 + 0.15CH2C12 +
0.4CH3C02C2H5:
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. {
SUBSTITUTE SHEET (RULE 26) WO 96/2620-ci PC"Tfi3S96100824 Examole 178 9-[2-[[[4-(Benzoylamino)-1-piperidinyl]c:arbonyl]-amino]ethyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide A.

O
H
N CF;3 N NH2=1HC1 ~ HY

To a solution of Exantple 177 compound (1.1 g, 1.97 mmol) in THF (4 mL) was added 4N HC:1 in dioxane (9 mL, 36.4 mmol). The reaction mixture was stirred at room temperature for 3 h and concentrated ',~n vacuo and then from dioxane (3 x 10 mL) to give crude title compound (1.46 g) as a white foamy solicl.

B. 9-[2-[[[4-(Benzoylamino)-1-piperidinyl]-carbonyl]amino]ethyl]-N-(2,2,2-trifluoro-ethvl)-9H-fluorene-9-carboxamide To a solution of crud.e Part A conipound (730 mg, 0.98 mmol) and triethylamine (615 L, 4.41 mmol) in CH2C12 (10 mL) at 0 C was added dropwise benzoyl chloride (172 L,_1.47 mmol). The reaction was stirred at 0 C for 30 minutes and diluted with CH2C12 (30 mL). The solution was washed with 0.1N NaOH (2 x 40 mL), H20 (40 mL), 0.2N HC1 (2 x 40 mL), H20 (40 = 25 mL) and brine (40 ml),then dried over MgSO4 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.

SUBSTITUTE SHEET (RULE 26) m.p. 220-222 C.
MS (ESI, + ions) m/z 565 (M + H), 582 (M + NH4) ;
(-ion) 563 (M - H).
Anal. Calcd For C31H31N4 03F3:
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 179 4-[[(1,1-Dimethylethoxy)carbonyl]amino]-1-piper-idinecarboxylic acid, 2-[9-[[(2,2,2-trifluoro-ethvl)aminolcarbonvll-9H-flu ren-Q-yllethvl ester A.

COOH

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-C1- (150 mL) and then acidified with iN HC1 (pH < 2). After extraction, the aqueous was extracted with additional CH-)C1i (2 x 100 mL), and the combined CH7C1, extracts were washed with water, dried (MgSO4) and SUBSTITUTE SHEET (RULE 26) concentrated to give 9.41 g (94%) of title compound as an amorphous solid.

B.

'N
H
~ -~
1 ~ \\

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-)C12 and 1.43 mL of DMF' under nitrogen was added cautiously 28 mL of 2.0 M oxalyl chloride in CH-)Cl- (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-)Cl-) 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-)C1, was added over 10 min keeping the internal temperature <12 C. The reaction was stirred at 0 C for 15 mi;a and at room temperature for 1 h and then diluted with 150 mL of CH;C1,. The CH-)C1? was washed with 1N HC]"_(2 x 75 mL), water (180 mL), 5% NaHCO3 (120 mL), and water (2 x:L80 mL), dried (Na~SO4), and concentrated to a residue (12.67 g). Chromatography of this residue over 500 g of silica gel provided 10.74 g(870) of title compound as an amorphous white solid, mp 84-86 C.
SUBSTITUTE SHEET (RULE 26) C.

N
H
OH

Ozone (in oxygen) was passed into a stirred solution of 5.30 g of Part B compound in 80 mL, of dry CH30H 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 NaBFi_ (908 mg, 24 mmol) in 20 mL of 50% aqueous CHzOH
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 HC1), and the reaction was concentrated to remove CH3OH. The residue was partitioned between EtOAc and water, and the EtOAc was washed with water (4 x), dried (Na:SO4), 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-EtOAc (1:1) afforded 2.77 g(490) of title compound as an amorphous solid. An earlier eluting fraction provided 1.97 g of compound N

OH

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCT1LIS96l40824 D.
r CF3 O
N
- ~ \ H O
Ox 0 a N02 4-Nitrophenyl chloroformate (1.2 g, 6 mmol) was added to a stirred solution of 1.34 q(4 mmol) of Part C compound and 0.97 mL (12 mmol) of dry pyridine in 15 mL of dry CH)C1-) at roorn temperature under argon. The reaction was stiY=red for 20 r:iin at room temperature and then diluted with CH)C12. The CH,)C12 solution was washed with 5% NaHCO; (4x), water, dilute HC1 (2x), and water (3x), dried (Na,S04), and concentrated to give crude title compounci in the form of a foamy residue (2.30 g).

E. 4-[ [ (1,1-Dimethylethoxy)carboriyl]amino] -1-piperidinecarboxylic acid, 2-[9--[[(2,2,2-trifluoroethyl)amino]carbonyl]-9H--fluoren-a-vllethvl ester 4-Boc-aminopiperidine (1.58 g, 7.90 mrnoL), was added to a stirred solution of 2.29 g of the above preparation of Part D compound in 30 mL of dry CH-)C1-) at room temperature under argon. The reaction was stirred at room temperature for 2 h and then diluted with CH-)C12. The CH)C1-2 solution was washed with dilute NaOH (2x), water (2x), dilute KHSG4 (2x), and water (3x), dried (Na-)SO4), arid 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 subseauent crystallization from. EtOAc-hexane provided 2.07 g(940) of title compound as a white solid having mp 120-122 C.

SUBSTITUTE SHE:ET (RULE 26) Anal. Calcd for C)QH34F?N3O5 + 0.5 CH-iCO>C2H5:
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 (ESI-NH3, + ions) 562 (M+H), 579 (M+NH4);
(- ions) 560.
Exam8le 180 4-[(2-Phenoxybenzoyl)amino]-l-piperidinecarboxylic acid, 2-[9-[[(2,2,2-trifluoroethyl)amino]carbonyl]-9H-fluoren-9-vll_t-.hvl ester A.
r CF3 O
N
H O
Ox N :/ }-- NH2 - HCI

To a solution of 898 mg (1.6 mmol) of Example 179 compound in 3 n1L of dry THF under argon at room temperature was added 6 mL of 4N HC1 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.

B.
O Cr Ph CI

To 428 mg (2.0 mmol) of 2-phenoxvbenzoic acid and 10 L of DMF in 4 mL of dry CH_Cl: at 0 C under nitrogen was added 1.5 mL of 2.0 M oxalyl chloride in SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlUS96100824 - 229 =-CH2C12 (3.0 mmoL) . The reaction was stirred at room temperature for 1.5 h and cor.icentrated 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 CH2C12 .

C. 4-[(2-Phenoxybenzoyl)amino]-1--piper-idinecarboxylic acid, 2-[9-[[(2,2,2-tri-fluoroethyl)amino]carbonyl]-9H-fluoren-9-vllethvl 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-)C1- at 0 C under argon was added 0.46 mL (4 mmol) of triethyle.mine. 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 CH2C12 (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 CH->Cl~. The CH)Cl, was washed with dilute NaOH (2x), water (2x), dilute HC1 (2x), and water (3x), dried (Na2SO4), and concentrated to a thick oil (577 mg). Chromatography of this oil over 45 g of silica gel using hexane-EtOAc (1:1) provicied 414 mg of title compound (79%) as a foam having mp 68-73 C.

Anal. Calcd for C3,7H34F3N305 + 0.2 CH:CO~C-)H5:
C, 67 . 23 ; H, 5. 31 ; N, 6. 22 ; F, 8.414 Found: C, 67.04; H, 5.20; N, 6.18; F, 8.70.

SUBSTITUTE SHIEET (RULE 26) MS (ESI-NH;, + ions) 658 (M+H), 675 (M+NH4).
Example 181 9-[4-[4-[(2-Phenoxybenzoyl)amino]-1-piperidinyl]-pentyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohvdrochloride A solution of Example 175 compound (1.25 g, 2.23 mmol) in 10 mL of 4 N hydrogen chloride in dioxane was stirred, protected by a calcium chlcride 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 of dichloromethane 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-ISO;) 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 mL of 4 N 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, mc 136-138 C.
Anal. Calcd for C;aH4;,F3N-iO +HC1+H-)O:
C, 65.95; H, 6.10; Cl, 4.99; F, 8.02;
N, 5.92 SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCT([IS9610082-1 Found: C, 65.87; H, 6.08; Cl, 5.13; F, 7.96;
N, 5.92.
MS (electrospray, + ions) m/e 654 (M + H).

Examnles 182 to 187 Following the procedures set out herein-before and in the working Examples, the following additional compounds were prepared.

Example 182 9-[2-[[[4-[(2-Phenoxybenzoyl)amino]-1-pipe ridinyl)carbonyl]amino]ethyl]-N-(2,2,2-trif luoro ethyl)-9 H-fluorene-9-c:arboxamide.

MS (ESI, + ion): 657 (M+H) Anal. Calcd for C37H35N404F3+0.2 CH2C12+0.1 CH3CO2C2H5, 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.

Examnle 183 4-(Benzoylamino)-1-piperidinecarboxylic acid, 2-[9-[[(2,2,2-trifluoroethyl)amino]carbonyl]-9hi-fluoren-9-yi]ethyl ester.

MS (ESI-NH3, + ions) 566 (M+lH) Anal. Calcd for C31H30F3N304+0.2 CH3C0>C?11K5+0.25 H20:

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-(Benzoylamino)-1-piperidiny!I]pentyl]-N-(2,2, 2-trifluoroethyi)-9H-fluorene-9-carboxamide, monohydrochloride.
_ MS (electrospray, + ions) m/z 564 (M+H) = Anal. Calcd for C33H36F3N302 + HC1 + H20:

SUBSTITUTE SHEET (RULE 26) 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.

Examole_ 185 9-[4-[4-[[(1,1-Dimethylethoxy)carbonyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-thioxanthene-9-carboxamide.
mp 76-79 C.
MS (ES, + ions, NH3) m/z 578 (M+H).
Example 186 9-[4-[4-(Benzoyiamino)-1-piperidinylJbutyl]-N-(2,2,2-trifluoroethyl)-9H-thioxanthene-9-carboxamide.
mp 167-169 C.
MS (ES, + ions, NH3) rn/z 582 (M+H).
Exam-ple 187 9-[4-[4-[[(2-Phenoxyphe nyl)carbonyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-thioxanthene-9-carboxamide.
mp 164-166 C.
MS (ES, + ions, NH3) m/z 674 (M+H) SUBSTITUTE SHEET (RULE 26) In accordance with the present invention, another class of preferred compounds is provided which are inhibitors of MTP and have the structure I*
Xl o II H
C- N- CH2- +CF3 z (CHy)= N N-C-R5' H I I
\ / 0 Xz wherein Z is a bond, 0 or S;
X1 and X2 are independently H or halo, preferably F;
x is an integer from ? to 6, preferably from 3 to 5, and (CH2)x may be optionally substituted with 1, 2 or 3 substituents which are the same or different and are alkyl or halo; and R5* is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R5* group being optionally substituted with 1, 2, 3 or 4 substituent:s which may be the same or different as ciefined hereinafter; and including piperidine T1-oxides of the formula I
compound, that is ~o S r N~ R.L and 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 amrnonium, choline, diethanolamine, ethylenediamine, t-butyl--amine, t-octylamine, dehydroabietylam:-ne, as well as pharmaceutically acceptable einions such as chloride, bromide, iodide, tartrate, acetate, methanesulfonate, SUBSTITUTE SHIEET (RULE 26) WO 96/2620-zi PCT/US96/00824 maleate, succinate, glutarate, and salts of naturallv 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 rina system, such as s N s S \ N ( N ~
, / \ O

CH3 S N ~ N CH3 CH3 CH3 N=N
OH N_ N = N .
H C= O
cH3 I - ~ ~
N N
` = ~ ( ~ J :
N N

(3) heteroarylalkyl wherein heteroaryl is as - (CHZ)p / I
defined above such as s SUBSTITUTE SHEET (RULE 26) (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 O
C:). ~ ~ I

(5) alkyl;
(6) aryl such as phenyl, phenyl substituted with (a) halo, (b) alkyl, (c) CF3O, (d) alkoxy (e) CF3 ( f ) CF3, 3, or (g) phenyl;
H
(7) alkylamino such as -N-(CH2)pCF3-(8) alkyl(aryl)amino such as -N(C'H3)C6H5;
-S _<CF3 (9) alkythio such as -S-(CH2)pCF3, CF3, -S- (CH2 ) p-S- C6H5 -S-alkyl, 0 ~CF3 -O

(10) alkoxy such as -O-(CH2)p-CF3, cF3, OCH3;
(11) cycloalkyl such as cyclohexyl;

- C - o -~~- C 1 (12) aryloxy such as ~J =
(13) amino;
, H O
N
(14) arylamino such as CF3 SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCT(US96/00824 --S-{ n }- c1 (15) arylthio such as NC
--S-~ OCH3 -S O
(16) acyl such as (a) alkanoyl, such as II II
CCH3 , (b) alkoxycarbonyl, such as c- O- CF3 0 0 II c Q F
(c) aroyl, such as - c- c6H5 - c- Nx - CHZ
(d) heteroarylaminocarbonyl, such as II H N~o C-N-~~
CH3 ~(e) arylalkyloxycarbonyl, such as if - C-- o- CH2C6H5 (17) arylthioalkyl, such as -CH2-S-C6H5;
H HN-N
-N \ I
(18) heteroarylamino, such as CF3 N
-N(CH3)-CH2 ~ ~

- O- CHZ-( ( ) }- F
(19) arylalkyloxy, such as N
(20) heteroarylthio, such as N
O
(21) heteroaryloxy, such as C1 ; and ' =
J_ _Cl 5 (22) arylsulfinyl, such as Thus, the compounds of formula I* of the invention encompass compounds of the structure SUBSTITUTE SHEET (RULE 26) _= =a* Xl - ~ ~
fl H

(CH2)x_N H- II_lD s * t O

Ib` Xi O

C- N- G:H2CF3 S
i / (CHZ)x- N H -'i-R5* , and O

Ic* XI

O
- " H

(CH2)x-N }--~-"-RS*
~___/ O
x2 In addition, in accordance with the present invention, a method for previ=_nting, inhibiting or treating atherosclerosis, pancreatitis or obesity is provided, wherein a compound of formula I* as defined hereinbefore is administered in an amoun;: which decreases the activity of mi(zrosomal triglyceride transfer protein.

SUBSTITUTE SHEET (RULE 26) 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 prczeir..
Suitable (CH2)X groups (were x is 2 to 6, preferably 3 to 5) (which may include alkvlene, 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-a;kyl or N-aryl.
Examples of (CH2)x groups include -CH =CH -CH2 -, -CH2CH =CH -, -C =-C -CH2 --, - CHZ- C- , - CHZ- CHZ- CH2- C--CH2C =CCH2 -- ~ -C =CH -CH2 -(CH2)2 - 1 -(CH2)3 -, -(CH2)4 - ~

I
-(CH2)2 --C -CH2CH2 -CH2CH --, -CH2CHCH2 -CHCH2 '- ~ -CHCH2CH2 '-, -CHCHCH2 - , SUBSTITUTE SHEET (RULE 26) WO 9Gl26205 PCTIUS96100824 o 0 0 - CH2CH2O- C- CH2CH2N- C- ,- CH2CH2- N- C-H

CH3 -CH2-C -CH2 - , -(CH2)s -' , -(CH2)2 -(:1 -CH2 - , ci CH3 CH3 ' - CHZ - CH - CH2 , - (CH2)2 - CI4 - , - CH2 CH- i -Jr CIH3 CH3 -- , -CH2 -CH -CH -CH2 - ~ -CH2 -CH -CH2--CH
I I I I

-CH -CH2CH2 - ~ CH-CH2CiH2 -CH2IOCHr--OCH2CH2- ~ -CH2NHCH2- -NHCH2CH2-; H3 - i- CH2CH2--(CH2 ) 3- CF2- , - CH2- N- CH2- ~ CH3 -(CH2)2--C-CH2- , -(CH2)2"'_C-CH2--(CH2)2-i-CH2- , -(CH2)3--i- or -(CH2)3-C-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.

N/N .I
LN", N ' N~~N
SUBSTITUTE SHIEET (RULE 26) N N=N /-N ~

S O N ,O N
I
and the like, and includes all possible N-oxide derivatives.
Preferred are compounds of formula I*
where Z is a bond;
X1 and X2 are H;
R5* is aryl such as phenyl substituted with (1) aryl such as phenyl, , cl, S11-~ N

(2) heteroaryl such as (3) halo such as Cl 5* is S I or S/
R heteroaryl such as substituted with (1) aroyl such as -{ nr -s ci (2) arylthio such as wherein the R5* substituent is preferably in the u position adjacent to the carbon linked to C.

(CH2) X is - (CH2) 4- or 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,l-Biphenyl]-4-ylcarbonyl)amino]-1-Niper-idinyl]-3,3-difluorobutyl]-[J-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohvdrochlori.de NNG~, 2~F
F
F
HN

O
A.
F OEt O
O
OH
F OH
O
F
O
A mixture of OH (5.18 g, 33.6 mmol), acetyl chloride (5.2 mL) and acetic anhydride (55.2 mL) was heated to 50 C under argon for 1 h. The SUBSTITUTE SHEET (RULE 26) reaction was cooled and evaporated. The residue was dissolved in EtOH (20 mL) and stirred at room temperature (RT) under argon. After 16 h, the solution was evaporated, the residue redissolved in Et->O and the solution dried (Na-2SO4) to give title compound as a colorless oil, 5.91 g, 97% material balance. The compound was used without further purification.

B.
F OEt F O
OH
To a stirred solution of Part A compound (1.82 g, 10.0 irnnol ) 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%.

C.
OEt F O
OSiPh2tBu To a stirred solution of Part B compound (1.40 g, 8.33 mmol) in DMF (10 mL) at room temperature under argon was added Ph)tBuSiCl (2.6 mL, 9.2 mmol) SUBSTITUTE SHEET (RULE 26) WO 96/26205 I'CTILTS96J00824 - 24'1t -.
~ 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 (Na2SO4) and evaporated to give a brown oil. Purification by f'lash chromatography on silica gel (5 x 20 cm column, 2:7 dichloromethane/
hexanes) gave title compound as a colorless oil, 1.83 g, 54%.

D.
OH
F

OSiPhZtBu To a stirred solutiori 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, 2M 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 (Na2)SO4) and evaporated to give title conipound as a colorless oil, 1.51 g, 97%. The compound was used in subsequent reactions without further pLirification.

E.
OCH2OCH2Ph OSiPh2tBu To a stirred solutiori of Part D compound (1.50 g, 4.12 mmol) in diisopropy:Lethylamine (5 mL) at 10 C
under argon was added benzy].oxymethyl chloride (BomCl) (0.7 mL, 4.9 mmol) in one portion. A
SUBSTITUTE SHEET (RULE 26) 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 (MgSO4) 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.
OBom 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 fl,uoride 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 (Na2S04) 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.
- OBom F

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 SUBSTITUTE SHEET (RULE 26) 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 5o NaHSO3). The organic extract was dried (Na2SO4) 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.

CO2NHCF~CF3 OBom / \ F F

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 mQnol, 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 48h, the reaction was quenched with 10% citric acid solution and extracted twice with EtOAc. The organic extracts were combined, dried (MgSO4) 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) iand DMF (0.1 mL). After 1 h, the reaction was evaporated and then redissolved in dichloromethane (5 mL). 'I'his solution was added, dropwise over 10 min, to a stirred slurry of trifluoroethylamine hydrochloride (502 mg, 3.70 m:nol) and Et3N (1.12 mL, 8 mmol) in dichloromethane (10 mL) at 0 C under argon. After 1 h, the reaction was SUBSTiTUTE SHE1=T (RULE 26) quenched with 10% citric acid solution and extracted twice with EtOAc. The organic extgracts were combined, dried (MgSO4) and evaporated. Purification by flash chromatography (5 x 20 cm column, 1 L
dichloromethane, then 5:95 ether/dichloromethane) to F F
provide OBom , 375 mg, 47% and then title compound, 120 mg, 9% as colorless oils.

I.

OH

A stirred slurry of Part H compound (108 mg, 0.208 mmol) and 20% Pd(OH)2-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 (MgSO4) and filtered through a 0.75 m nylon filter. Evaporation provided title compound as a colorless oil, 53 mg, 640. 20 J.

OTf F F
F
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 quencned with 1 M

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlUS96109S24 hydrochloric acid and extracted twice with EtOAc.
The organic extracts were ccmbined, dried (MgSO4) and evaporated to give title compound as an orange crystalline solid, 68 mg, 100%.
K.

HCI=HN~ O
I\/I` H
K(1) .

o 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 iri vacuo. at less than C, and the residue was dissolved in m.ethylene chloride (250 ml). This solution was added dropwise 20 to a solution of 4-aminobenzyl piperidine (Aldrich, 25.0g, 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 25 with water and once with brine. The organic layer was dried (Na2SO4), and the solvent was removed in vacuo to give title comnound as a light vellow solid (56.6 g, 95.4% yield).

SUBSTITUTE SHIEET (RULE 26) ~
K(2) HCL O
H
To a solution of Part K(1) 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).
L.

()CO2NHCu2CF3 H
N I ~
O
F F

T o a stirred solution of Part J compound (68 mgØ126 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 (Na2SO4) and evaporated. Purification by flash chromatography on silica gel (1 x 10 cm column, EtOAc) provided title compound as the free base as a SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTfUS96100824 white foam, 57 mg, 68%. The foam was diluted with dichloromethane and 0.1 mL of 4Ll hydrochloric acid.
Evaporation provided the HC1 salt of the title compound, 59 mg, mp 115-118 C.
TLC: Rf = 0.20 (free base, E-tOAc, Silica gel 60) Mass Spectrometry: (electrospray, + ions) m/z 662 (M+H) Exam~~ 2 *
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 \ ( I /

NH NH
O N~

O
CI

HCI salt A.

CI

\OH
The title compound was prepared by the me-::hod of Meyers by Grignard addition of p-chlorophenylr:ag-nesium bromide to o-methoxy-phenyl-l,l-dimethyl-isoxazole and hvdrolysis with 6 N HC1.
SUBSTITUTE SHEET (RULE 26) B. 9-[4-[4-[[(4'-Chloro-[l,1'-biphenyl]-2-yl)carbonyl]-amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, 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 in 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 in 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 (MgSO4), 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 1M HC1 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.

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTfUS96/00824 Anal Calcd. for C38H37N302F3C1 + HC1:
C, 63.07; H, 5.71; N, 5.81 Found: C, 62.79; H, 5.62; N, 6.05.
Example 3*
9-[4-[-4[[[1-(Phenylmethyl)-2-piperidinyl]carbonyl]-amino]-l-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, dihvdrochloride O

H

\ I /
o ~= N
N
FI
= 2HC;1 A.
~ Ph 0- COOEt Benzyl bromide (700m1, 5.7 mmol) was added dropwise to a slurry of ethyl pipecolinate hydro-chloride (1.0 g, 5.2 mmol) and potassiuit 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 mL). The combined organic layers were dried over sodium sulfate, then concentrated in vacuo to give a cloudy cil, which was SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCT/iJS96/00824 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 c:x COOH
= HCI

A biphasic mixture of Part A compound (600 mg, 2.4 mmol) and 1N KOH (7.2 mL) in dioxane was stirred at RT overnight, then the reaction was heated at 500C
for 2 days. The reaction was cooled to RT then adjusted to pH 2 with 1N HC1. The cloudv 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 ir vacuo to give title compound (411 mg, 67%) as a yellow foam.

C.
o H

N
= 2HCI

Ethyl 3-(3-dimethylamino)propyl carbodiimide (164 mg, 0.86 mmol) was added to a mixture of Example 11* Part C compound (404 mg, 0.78 mmol), Part B

compound (200 mg, 0.78 mmol), hydroxybenzotriazole (105 mg, 0.78 mmol), and 4-methyl morpholine (300 ml, SUBSTITUTE SHEET (RULE 26) - 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. Evaporstion gave a yellow gum.
Purification was performed by flash chromatography (4% methanol in dichloromethiane) on silica gel (50 g). Pure fractions were comlDined and evaporated to give a colorless oil. The rEasulting 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 ivas driea in a vacuum oven (55 C, 24 h) ta give title compound (302 mg, 54%) as a white solid.

m.p. 161-165 C
MS (ESI, +ion): 647 (M+H) Anal. Calc. for C38H47C12F;P14C)12 = 1.5 H20:
C, 61.12; H, 6.75; 1:, 7.50; Cl, 9.50; F, 7.63 Found: C, 60.97; H, 6.77; N, 7.40; Cl, 9,.18; F, 7.34 SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlUS96/00824 ExamnlP 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, monohvdrochloride F3C-, NH Na N O
O
I \ ~

A.

F3C <\/ OCONEtZ
OH
c To a stirred solution of CF3 (3.08 g, 19.0 mmol) in THF (20 mL) at room temperature under argon was added triethylamine (2.80 mL, 20.0 mmol), diethyl 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 (MgS04). 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.

F3C OCONEt2 COZH

SUBSTITUTE SHEET (RULE 26) WO 9612620~ PCT/US9G/00824 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 rnL, 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, dr~,, carbon dioxide gas was bubbled through the solution for 30 mir.. The cold bath was removed and the reaction was al]-owed 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%.
C.

F3C <~/ f- OH
COzH
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 (MgSO4) and evaporated to give title compound as a white solid, 1.52 g, 99%, mp 148-149 C.

D.

F3C z~- OMe coZH
SUBSTITUTE SHEET (RULE 26) -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 (MgSO4) 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 M
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 1M
hydrochloric acid and extracted twice with dichloromethane. The extracts were combined, dried (MgSO4) and evaporated to give title compound as a white solid, 1.45 g, 91%, mp 105-107 C.

E.

F3C ~ ~ OMe H
N
O
X~OH
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 Et3N (1.02 mL, 7.33 mmol) and then 2-amino-2-methyl-1-propanol (0.70 mL, 7.33 iranol). An exotherm results in an orange solution. After 13 h, the reaction SUBSTITUTE SHEET (RULE 26) mixture was diluted with dichloromethane, washed twice with 10% citric acid solution, dried (MgSO4) and evaporated to give title compound as; a white foam, 2.08 g, >100% material balance.
F.

F3C C/ OMe ~h-N
G

To a solution of- Part E compound (2.08 g) in 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'S04) and evaporated. Purification by flash chromatoaraphy on silica gel (5 x 10 cm column, 1:9 EtOAc/dichloro-methane) provided title compound as a white solid, 1.56 g, 90% yield starting from Part D compound, mp 55-57 C .

G.

F3C ~ 0 N
To a stirred solution of Part F compound (1.17 g, 4.28 mmol ) in THF (10 in; ) at 0 C under argon c=.-=s SUBSTITUTE SHIEET (RULE 26;) added a solution of phenylmagnesium bromide (1.7 mL, 3 M in ether, 5.1 mnol) 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 (Na2SO4) 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.

F3C ~ ~ O
COZH
A slurry of Part G compound (1.25 g, 3.91 mmol) in 6 M 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 chromatograph_v on silica gel (5 x 15 cm column, EtOAc) provided title compound as a white solid, 395 mg, 38%, mp 120-122 C.

z.

=HCl H
N
NHCHZCFs cr 0 O

SUBSTITUTE SHEET (RULE 26) WO 96/2620i -259 PCTf[JS9610(i824 -A solution of Part H compound (380 mg, 1.43 mmol) in thionyl chloride (3 mL) was stix=red at room = temperature, protected by a Drierite-fill.ed tube.
After 2 h, the reaction was evaporated and then re-evaporated from dichloromethane. The senti-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), Et3N
(0.7 mL, 5 nmol) 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-.SO4) and evaporated. Purification by flash chromatography on silica gel (5 x 15 cm colu:nn, 3:17 hexanes/EtOAc) provided title compound (as t:he free base) as a white foam, 640 mg, 65%. The foam was dissolved in dichloromethane (5 mL) and tr?ated with 4 M hydrogen chloride in dioxane (0.3 mL). Evaporation provided title compound as the hydroge;-i chloride salt, 670 mg, mp 129-134 C.

Mass Spectrometry: (electrospray, + ions) m/z 694 (M+H).

SUBSTITUTE SHEET (RULE 26) Examnle 5* 9-[4-[4-[[2-Chloro-5-(trifluoromethyl)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide. N-oxide o 0 Nla N-H
N' H CI

o 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 in 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 mL) and the contents stripped. The residue was pumped to constant weight.
The colorless remainder was diluted with CHC13/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 com.bined to give 6.5 g (75%) of title compound as a white solid.

mp:131-136 C; material then resolidified:
mp: 198-200 C decomp.
SUBSTITUTE SHEET (RULE 26) MS (ES, + ions) m/z 668 (M+H). monochloro isotope pattern.

Anal Calcd. for C33H32N3O3F6C:1 + H20:
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'-(trifluoromethyl)[ 1,1-biphenyl)-2-yl]carbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide, N-oxide.

CF
O N~CF3 3 H
N+
-0. N
H I~

A CH2C12 (5 ml) solution of Example 10A*
compound (200 mg, 0.274 mmol) was added to a 0 C
solution of saturated NaHCO3 (5 ml). After several minutes, a CH2C12 (2 ml) solution of meta-chloroperbenzoic acid (63 mg, 80%, 0.292 mmol) v:ac-z added. A further amount of ineta-chloroperbenzoi`c 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 CH2C12 and saturated NaHCO3 after 1.45 h. The aqueous layer was extracted twice with CH2C12, the organics dried over Na2SO4, 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:CH2C12, then 10% MeOH:CH~.Cl2 with 1% NH4OH, zio give title compound (151 mg, 77.6o yield) as a colorless solid. mp 136-142 C [shrinks 115 C) SUBSTITUTE SHEET (RULE 26) Rf = 0.38 (10% MeOH:CH2C12). MS: (electrospray, +
ions) m/z 710+(M+H).

Example 6B*
N-(2,2,2-Trifluoroethyl)-9-[4-[4-[[[4'-(trifluoromethyl)[1,1-biphenyl]-2-yl]carbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide, N-oxide.
(io CF3 : CF3 + ~
N
O' ' ' N
H
(Alternative Preparation) To a CH2C12 (20 ml) solution of Example l0A*
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 CH2C12 and 1N KOH, the aqueous layer extracted twice with CH2C12, the combined organics washed with H20-dried over Na2SO4, and concentrated in vacuo to a foam (4.95 g). The residue was crystalized from hot EtOH
and H20 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:CH2C12 to give the title compound (3.5 g, 57% yield) as a colorless solid.

SUBSTITUTE SHEET (RULE 26) Example 7*
9- [4- [4- [ [2- (2-Benzothiazolyl) benzoyl] am:ino] -1-piperidinyl]butyl]-N-(2,2,2-trifluoroethy1)-9H-f1 nnrPne-Q-rarbnsrami dc TT-w_Lde X O ~- CF3 N
H
O"
\ / +W--\
C S
N -N
H

A solution Example 9* compound (free base, 14.589 g, 21.3 mmol) in CH2C12 (= 300 mL) at room temperature was treated with 4.40 mL 32% peracetic acid in dilute HOAc. After 2 hours, add:Ltional peracetic acid solution (1.2 mL) was added and stirring continued for 1 hour. The mixture was quenched with saturated NaHCO3 and the CH2C12 layer was separated. The organic extract was washed with half-saturated NaCl, dried (Na2SO4), and filtered.
The solution was diluted with EtOAc (= 200 mL) ahd let stand to give a white precipitate which was collected by filtration, washed with EtOAc and Et20, and dried in vacuo to give title compound (8.582 g, 55% corrected for-solvent) : inp 189-191 C., MS: ESI (M+H)+ 699; (M-H)- 697.
SUBSTITUTE SHIEET (RULE 26) Example 8*
9-[4-[4-[(5-Chloro-2-methylbenzoyl)amino]-1-piper-idinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, N'-oxide.
CI
H
N
-O ~
NHCHzCF3 N O
O

A.
ci -HCI H
N
NHCHZCF3 Cr O
O

cl To a stirred slurry of cOZH (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-H20 (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 (Na2SO4) and evaporated. The resulting solid was recrystallized from EtOAc/hexanes to give the free base of the title compound, 6.56 g, SUBSTITUTE SHEET (RULE 26) 91%, mp 201-202 C. The free base was dissolved in dichloromethane (25 mL) and treated with 4M hydrogen chloride in dioxane (3 mL). Evaporation provided title compound as the hydrogen chloride salt, an amorphous solid, 7.15 g, 1009,s MICROAnal. Calcd for C33H35C1F3N3O-1 + HC1 + 0.4 H-)O +
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.
ci H
( N
_Q
NHCH2CF3 N ~ O
O

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 dichloromet:hane and washed twice with saturated sodium bicarbonate = solution. The organic layer was dried (rZgSO.;) and evaporated. Purification by flash chromatography or_ silica gel (5 x 15 cm column, 3:17 methanol/EtOAc) followed by redissolving the evaporated residue ir:
dichloromethane and filtration through a 2 mM nylor.

SUBSTITUTE SHI:ET (RULE 26) filter provided title compound as a white solid, 450 mg, 73%, mp 124-127 C.

MICROAnal. Calcd for C33H35C1F3N303 1.5 H~O + 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, + ions) m/z 614 (M+H) ExamtJle 9*
9-[4-[4-[[2-(2-Benzothiazolyl)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride.
~ 0 N/'- CF3 H

+ HCI N
H
A.

0 S,i N
HO

A slurry of phthalic anhydride (7.1 g, 47.9 mmol) and 2-aminothiophenol (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 gumrny precipitate. The mixture was extracted with EtOAc SUBSTITUTE SHEET (RULE 26) WO 96/2620i PCTI[JS96100824 and the EtOAc extract was washed with 1 N HC1 and H20. The organic layer was extracted three times with saturated NaHCO3 and the pooled bicarbonate extracts were acidified with 6 N HC1 to give a precipitate which was collected by filtration, washed with H20, and dried in vacuo i:o give title compound (11.27 g, 92%) as a white solid: mp 188-189 C.

B.
~ 0 H / \
~ ~ N^ O S N
N
H

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 CH2C12 (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/Et2O and saturated NaHCO3. The organic layer was separated, washed twice with H,O and brine, then dried (Na2SO4), filtered, and stripped. Flash chromatography (Merck Si02, 8/92-MeOH/CH2C12) gave title compound (5.369 g, 103% of theory, 96%
corrected for solvent) as a white foam.
SUBSTITUTE SHEET (RULE 26) WO 96/26205 PC'T/US96/00824 C .
~ 0 /.-- CF3 H

O s ~ N
+HCI N
H
Part B compound (the free base, 5.254 g, 7.16 mmol corrected for solvent) was dissolved in = 25 mL
of 1,4-dioxane and treated with 2.2 mL of 4 N HC1 in 1,4-dioxane at room temperature. The resulting homogeneous mixture was added via canula to = 350 mL
of Et20 with rapid swirling. The precipitate was collected by filtration, washed with Et20, 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.
ExamplG 103*
9-[4-[4-[[2-(2,2,2-Trif1uoroethoxy)benzoy!]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fiuorene-9-carboxamide, monohydrochloride.
O

cHc1g SUBSTITUTE SHEET (RULE 26) - 269 =-HOO(;
To a solution of the acid F3C
(3.2g, 12 inmol) in methylene chloride (35 ml) was added oxalyl chloride (1.8ml, 21 mmol) fallowed by a few drops of DMF. The reaction bubbled vigorously and stirred under argon at room temp 2h. The soivent 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.Og, 9.6 mmol) and triethylamine (6.7m1, 48 mmol) in methylene chloride (50 ml) at -5 C. The reactiorz stirred in a melting ice bath lh. The reaction mixture was diluted with MeCl2 and washed once with water. The organic laver was dried (Na-)SO.;), and the solvent was removed in vacuo to give an off-white solid foam which was purified by flash column chromatography (SiO;;, 800g) eluted with 5% MeOH: 0. S %NH,OH;, MeC1- to gi.ve 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~.40 yield). This oil (4.07g) was dissolved in MeOH
(25ml) and 1.1 N ethereal HC1 (8.Om1) was added. The solvent was removed ji-n- vacuo I_o 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. H:-F.:N=.O-=HC1 + 1H-)O:
C, 62.61; H, 5.39; P:, 5.62 Found: C, 62.48; H, 5.19; .=:, 5.60 SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlUS96/00824 Example 10B*
9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride.
O

CL o ~
H

A.

N O

H . ~ \

To a slurry of 4'-(trifluoromett-iyl)-2-biphenyl carboxylic acid (50.0 g, 190 mmol) in methylene chloride (500 ml) was added the oxalvl 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 dissoived 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 NH2 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 SUBSTITUTE SHEET (RULE 26) 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 1N KpH. The oXganic layer was dried with Na25041 and the solvent, removed in vacuo to give a white solid. 'I'his solid was recxystallized froir-hot EtOH (1 L) and washed with heptane to give title compound as a white solid (59.11 gj=75.6% yield). The mother liquor was concentrated to dryness and recrystallized from hot EtOH (300 ml) and washed with hepcane to give a second crop of title compound as a white solid (12.7 g, 16.2% yield).

B.

I ~ .
~NH

H

To a solution of Part A compound (59.0 g, 130 nntol) in methanol (300 ml) and ethanol (300 ml) was added the cyclohexene (150 ml, 1.5 mo.l) and 20%
palladium hydroxide on carbon (11.8 g). The reactiori was heated in an argon atmosphere to ref lux (80 C) and stirred at that teniperature 2.5 h. The hot.
mixture was filtered through Celite'r', washed with methanol and the solvent removed in vacuo to give title compound as a white solid (46.*7 g, 99.6%
yield).

C.

Z o 1 ~ H 3 =HCI
O
H

To a stirred solution of Part B compound (18.Og, 49 mmol) in DMF (100 ml) at room temperature under argon was added potassium carbonate (12.6g, 49 O
N^ CF3 H

mmol) followed by Br compound (prepared as described in Example 11* Part C(2)) (21.0g, 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 (Na.)SO.;) and the solvent removed in vacua 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.
SUBSTITUTE SHEET (RULE 26) -Examt~le 1 1 *
=
9-[4-[4-[(2-Pyridinylbenzoyl)amino]-1-piperidinyl]-butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, dihvdrochloride z O
N~ CF3 H

iN
U,N C

- 2HC1 H ( /
A.

N
To a degassed solution of 2-bromopyridine (1.9 ml, 20 mmol) in ethylene glycol. dimethyl ether (60 ml) under argon, tetrakis(triprLenylphospharie) palladium (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-IS0~4), 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.
SUBSTITUTE SHEET(RULE 26) B .

iN

COOH
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.

Z /' O
N~ CF3 ti H

- 2HC1 lNH2 C(1) .
O
g0H

Br SUBSTITUTE SHEET (RULE 26) WO 96/2620; PCT/US96/00824 To a solution of 9-fluorenecarbox.ylic acid (50 g, 240 mmol) in THF (1200 mL) at 0 C was added dropwise a solution of n-but;Yllithium (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 miii, 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 etiaer (800 mL). The aqueous layer was made acidic- with HC1 solution (1N, 500 mL), then extracted with dichloromethane (3 x 750 mL). The combined organic layers were dried over MgSO4. Evaporation gave title compound ('71 g, 85%) as a white solid.

C(2).
~ o li CF3 Br To a solution of Part C(1) acid (60 g, 173 mmol) and DMF (100 L) in CH,2C12 (600 mL) under argon at 0'C was added oxalyl chloride (104 mL, 2.OM in CH2C12, 208 nunol) 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-trifluoroethylamine hydrochloride (25.9 g, 191 mmol) in CH2C12 (500 mL) at 0 C under argon was added triethylamine (73 mL, 521 mmol) followed by dropwise addition of a solution of the SUBSTITUTE SHIEET (RULE 26) WO 96/26205 PCT?U596100824 crude acid chloride in CH2Cl2(15 mL). The reaction was stirred at 0'C for 1 h, diluted with CH7Cl2 (500 mL), and washed with water (2 x 300 mL), 1N HC1 (2, x 300 mL), saturated NaHCO3 (2 x 300 mL), and brine (2 x 300 mL), then dried over Mg8O4. 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 CH2C12 and hexane, and eluted with'a step gradient of 10% Et4Ac/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 (rnp 88-92'C) .

CM-HN,}- MHedC

To a solution of 4-aminobenzylpiperidine (20 g, 105 mmol) iri diGhloromethane (200 mL) at 0aC was added dropwise (about 30 min) a solution of di-tert-butyldicarbonate (25.2 g, 115 mmol) in dichloro-methane (50 inL). 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 rimL, 177 mnol) 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'r" and the filtrate was concentrated to dryness. The residue was dissolved in chloroform (500mL) and washed with 1N
KOH saturated with sodium chloride (3 x 100 mL).

The aqueous layers were combined and extracted with chloroform (3 x 80 mL). Corrbined organics were dried over sodium sulfate and evaporated to give title compound (16 g, 90%) as a white solid (m.p. 157-159 C) .

C(4).
o NHBOC
A mixture of Part C(2) compound (29.5 g, 69.2 mmol ), Part C(3) compound (14.5 g, 72.7 nunol ), 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 CH2C12 (500 mL). The solution was washed with saturated NaHCO3 (3 x 80 mL) and brine (2 x 80 mL), then dried over MgSO4. Evaporation gave a yellow oil which was purified by flash chromatography on silica gel (600 g), loaded in CH2C12, and eluted with a;step gradient of 2% MeOH/CH2C12 (3L) to 3% MeOH/CH2C12 (4L). Pure fractions were combined and evaporated to give title compound (30 g, 86%) as a white foamy gum.

SUBSTITUTE SHIEET (RULE 26) WO 96/2620-i PCT/US96/00824 C(5) . '.

=2HCI CLNH2 To a solution of Part C(4) compound (30.5 g, 60.4 mmol) in dioxane (120 mL) was added 4N HC1 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. dihvdrochloride To a solution of the Part B acid (145 mg, 0.7 mmol) in methylene chloride (2 ml) was added oxalyl chloride (110 l, 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 l, 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 MeCli and washed once with water. The organic layer was extracted twice with iN HC1. The combined acid extractions were made basic with 1N
NaOH and extracted twice with EtOAc. The combined SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlUS96100824 = EtOAc layers were dried (Na25O4), and the solvent was removed in vacuo to give a brown oil which was purified by flash column chromatography (Si02, 90g) eluted with 5% MeOH: 0.5% NH4OH:MeC1--) to give a clear oil (170 mg, 46.8% yield). 3.60 mg of this oil was dissolved in MeOH (2 ml) and 1.1 N ethereal HC1 (800 l) was added. The solvent was removed -i_n vacuo to give title compound as a light yellow so].id (173 mg).
mp 146-50 C (dec.) MS (ESI, + ions) m/z 627 (M+Ft) Anal. calc'd for C37H37F3N4O--2=2HC1 + 2H20:
C, 60.41; H, 5.89; N, 7.62 Found: C, 60.38; H, 5.86; N, 7.50 The following additiortal compounds were prepared employing procedures as set out herein-bef ore .

Examrple 11a*
s C 1,^ H

NH
N

. ~ ~
1:1 HCI Salt 9-[4-[4=(Benzoylamino)-1-piperidinyliibutyl]-N-(2,2,2-trifluoroethyl)-9H-thioxanthene-9-carboxamide, monohydrochloride.
M.P. 145-150 C
MS (ES, + ions) m/z 582 (M+H) SUBSTITUTE SHEET (RULE 26) Elemental Anal. Calc'd for C32H34N302F3S + 1.0 HC1 +
0.75 H20:
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.
Examipl e 12*
S

\ I I /
O NlD H
NH
N

& O
1:1 HCI Salt 9-[4-[4-[(2-Phenoxybe nzoyl)amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-thioxanthene-9-carboxamide, monohydrochioride.
M.P. 204-208 C
MS (ES, + ions) m/z 578 (M+H) Elemental Anal. Calc'd for C38H3803SF3N3 + 1 HC1+0.5 H20:

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.

Examr)le 13*

HN

O
SUBSTITUTE SHEET (RULE 26) WO 96/26205% PCT/US96100824 9-[4-[4-[([1,1-Biphenyl]-4-ylcarbonyl)amino]-1-piperidinyl]-3,3-dimethylbutyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohycirochloride.
M.P. 95-101 C
MS (electrospray, - ions) m/z 654 (M+H) Examole 14*
i o ~ ~- CF3 N
H
N o N
H
N
dihydrochloride salt 9-[4-[4-[[(3-Phenyl-2-pyridinyl)carbonyl]amino]-1-pipe ridinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, dihydrochloride salt.

MS (ESI, + ions) m/z 627 (M+E[)+; (ESI, - ions) m/z 625 (M-H)-ExamplP 15*
o O HNJ
-N
/~\
N }- 2 HI'I
N-[ 1-[4-[9-[[(2,2,2-Trifluoroe'thyl)amino]carbonyt]-9H-fluorene-9-yl]but-1-yl]pip,eridin-l-yl]-2-[N-(2,2,2-trif luoroethyl)amino]pyridine-3-carbox-amide, hydrochloride.

MS (ESI, + ions) m/z 648 (M+H); (ESI, -:Lons) m/z 646 (M-H) SUBSTITUTE SHIEET (RULE 26) Example 16*
rCF3 I
p H o , ~\
N }-H ~ N-2HCI
~/
\ ' .
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.

MS (ESI-NH3, + ions) 627 (M+H) Examnle 17*
GONN

OH
HN

O

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) SUBSTITUTE SHEET (RULE 26) WO 96/2620-i PCT1US96100824 Example 18*

H ME:
N-"- O ~
N I
H N
dihydrochloride salt 9-[4-[4-[[[3-(4-Fluoro-3-methyiphenyl)-2-pyridinyl]-carbonyl]aminoJ-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-ca rboxamide, dihydrochloride.
MS (ESI, + ions) m/z 659 (M+H)+; (ESI, - ions) m/z 657 (M-H)-Elemental Anal. Calc'd for C3BH38F4N402+2 HCI + 1.5 H20 + 0.2 Et20 + 0.2 dioxane C, 60.12; H, 5.94; N, 7.08; F, 9.61; CI, 8.96 Found: C, 60.17; H, 5.89; N, 7.24; F, 10.48; CI, 8.91 Examnle 19 /- CFs N
H

N O S N

H
dihydrochloride salt 9-[4-[4-[[[3-(2-Thienyl)-2-pyridinyl]carbonyl]amino]-1-pipe 6dinyl]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)-. 20 SUBSTITUTE SHEET (RULE 26) Example 20*
r CF3 CF3 O N O
H S
N~ H N 2HCI
contains 0.15 mole of ethyl ether N-(2,2,2-Trifluoroethyl)-9-[4-[4-[[[2-[(2,2,2-trifluoroethyl)thio]-3-pyridinyl]carb-onyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide, dihydrochloride.
MS (ESI-NH3, + ions) 665 (M+H); 663 [M-H]
Examiple 21 *

gLH /'' C
O Or CF3 N
' HCI I H
9-[4-[4-[[2-(2,2,2 -Trif luoroethoxy) benzoyl] amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride.
MS (electrospray, + ions) m/z 648 (M+H) Example 22*
o N
H

N O
N
H
dihydrochloride salt 9-[4-[4-[[(3-Cyclohexyl-2-pyridinyl )carbonyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-tr'rfluoroethyl)-9H-fluorene-9-carboxamide, dihydrochloride.

SUBSTITUTE SHEET (RULE 26) WO 96/2620a PCT/i3S96100824 MS (ESI, + ions) m/z 633 (M+F[)+; (ESI, - ions) m/z 631 (M-H)-Elemental Anal. Calc'd for C17H42F3N402+2 HC1 + 1.5 H20 + 0.25 Et20:
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 Examble 2 *

O
/ Nl' CF3 O
H
O
~ aH
I ' 9-[4-[4-[[2-(4-Morpho linyl)benzoyl) amino]-1-piperid iny1]buty1]-N-(2, 2,2-triftuoroethy!)-9H-fluorene-9-carboxamide, monohydroch lo ride.

MS (electrospray, + ions) m/:: 635 (M+H) Examle 24*
O

N

N, O CI

H
N
9-[4-[4-[(4-Chloro-3-pyridinyi)carbonyl]amino)-1-piperidinyl]butyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, dihydr'ochloride.
M.P. 165-73 C
MS (ESI, + ions) m/z 585 (M+l-i) SUBSTITUTE SHEET (RULE 26) Examnl e 25* gLH

~ C

= 2 HCI H
9-[4-[4-[[2-(4-Methy!-1-piperazinyl)benzoyl]amino]-1-piperidiny!]butyl]-N-(2,2,2-trif!uoroethyl)-9H-fluorene-9-carboxamide, dihydroch!oride.
MS (electrospray, + ions) m/z 648 (M+H) Example 26*

F3C--~ N }- N O
NH ~_/
O H/r I H
/ /

trans-9-[4-[4-[[(1-Phenyl-3-cyc!ohexen-1-yl)carbonyl]aminoJ-l-pir)eridinylJbutylJ-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydroc:hioride.

M.P. 160-163 C
MS (electrospray, + ions) m/z 630 (M+H) Examole 27*
F3C--~ N~ N O
NH
O H//
~ ~ H
/ / / \ -trans-9-[4-[4-[[(2-Pheny!cyc!ohexyl)carbony!]amino]-1-piperidinyl]butylJ-N-(2,2,2-trif!uoroethyl)-9H-f!uorene-9-carboxamide, nionohydroch!oride.

SUBSTITUTE SHEET (RULE 26) M.P. 156-159 C
MS (electrospray, + ions) m/,z 632 (M+H) Exarnole 28*
O

~ = HCq q:~

N H 5 9-[4-[4-[[(2-Phenyl-3-thienyl)carbony[lamino]-1-piperidinyf]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-ca rboxamide, monohydrochloride.
MS (ES, + ions) m/z 632 (M+H) Example 29kH *

o N
H
N
9-[4-[4-[(4-Phenyl-3-pyridinyl)carbon yl] amino]-1-piperidinyi]butyl]-N-(2,2,2-tr=rfluoroethyl)-9H-fluorene-9-carboxamide, dihydrochloride.
M.P. 144-50 C
MS (ESI, + ions) m/z 627 (M+Ii) Elemental Anal. Calc'd for C:37H37F3N402 + 2 HC1 + 1.2 H20:
C, 61.62; H, 5.79; N, 7.77 Found: C, 61.64; H, 5.80; N, 7.32 SUBSTITUTE SHI:ET (RULE 26) Examole 30*
O
/ N/~ CF3 H
O
N

9-[4-[4-[[2-(1-Piperidinyl)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-tr'rfluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride.

MS (electrospray, + ions) m/z 633 (M+H) Example 31*

O

O CI
H
CI
= TFA
MS (ESI, + ions) m/z 618 (M+H) SUBSTITUTE SHEET (RULE 26) WO 96126205 PCTlUS96100824 Example, 32*
O
. ~ \
H~ CF3 O.

H
O
H O N ~ \J
= TFA

MS (ESI, + ions) m/z 754 (M+H) Example 33*

F3C--\ NH N N O CI
~
O
ci 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) miz 694 (M+H) Examole~ 34*
cHID&C
\

9-[4-[4-[[(6-Phenyl-1-cyclohexen-1-yl)carbonyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, moncihydrochloride.
SUBSTITUTE SHEET (RULE 26) ~
M.P. 110-114 C
MS (electrospray, - ions) m/z 630 (M+H) Example 35*
' / O
N~ CF3 ,H HCl O F
H

F
9-[4-[4-[(2,5-Difluorobenzoyl)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 C32H32F5N302 + 1 HC1 + 1.2 H20:
C, 59.71; H, 5.54; N, 6.53 Found: C, 59.68; H, 5.53; N, 6.44 Exam-ple 36*
I \

H N
ND-~ =2HCI
9-[4-[4-[[[2-[2,2,2-Trifluoro-l-(2,2,2-trifluoromethyl)ethoxy]-3-pyridinyl]carbonyl]-amino]-1-piperid inyl]butyl]-N-(2,2,2-trif luoroethyl) -9H-f luo rene-9-carboxamide, dihydrochloride.

SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTIiJS9610(182a MS (ESI, + ions) 717 (M+H); (.-ions) 715 (M-H) Example 7*
/ O

H

QLcH4iOo dihydrochtoride sal';
9-[4-[4-[[(4-Phenyl-2-pyridinyl)carbonj+,I]amino]-1-piperidinyl]butyl]-N-(2,2,2-tr'rffuoroethyl)-9H-fiuorene-9-carboxamide, dihycirochloride.

MS (ESI, + ions) m/z 627 (M+H)+; (ESI, - ions) m/z 625 (M-H)-Elemental Anal. Calc'd for C3'7H37F3N402 + 2 HC1 + 0.44 Et20 + 3.0 H20:
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 Examole 38*
/"-\
F3C~ N r N 0 NH `-~/
O F;IC CF3 s / \

9-[4-[4-[[2, 6-Bis(trif luoro methyl)benzoyl]amino]-1-pipe ridinyl]butyl]-N-(2,2,2-tr'rfluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride.
M.P. 145-150 C
MS (electrospray, - ions) m/z 686 (M+H) SUBSTITUTE SHEET (RULE 26) Example 39*
CI
~CF3 , ~ -O

H i \ f .
contains 0.05 mole of ethyl ether 9-[4-[4-[[[2-(4-Chlorophenyl)-3-pyridinyl]carbonyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyt)-9H-fluorene-9-carboxamide, dihydrochioride.
MS (ESI-NH3, + ions) (M+H) 661 Example 40*

r CF3 f O N 0 S ~\
N }--H N N=HCI
~J

contains 0.12 mole of ethyl ether N-(2,2,2-Trifluoroethyl)-9-[4-[4-[[[2-[(3,3,3-trifluoropropyl)thio]-3-pyridinyl]carbonyl]amino]-1-pipe rid inyl]butyl]-9H-f luorene-9-carboxamide, monohydrochloride.

MS (ESI-NH3, + ions) (M+H) 679 Examole 41*
VH N~ CF3 N
` C
= 2HCI
N
H

SUBSTITUTE SHEET (RULE 26) WO 96/26205 I'CT/US96J00824 9-[4-[4-[[2-(4-Pyridinyl)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxzimide, dihydrochior'ide.

M.P. 140-150 C (shrinking corrunencing at 115 C) MS (electrospray, - ions) m/z 627 (M+H)+
Elemental Anal. Calc'd for C-37H37F3N402=2 HC1=2.14 H20:
C, 60.21; H, 5.91; N, 7.59; Cl, 9.60; F, 7.72 Found: C, 60.21; H, 6.08; N, 8.01; Cl, 9.23; F, 7.37 Example 42*

~ F3 F
kH C
=HC1 1 ~ N-"
l o N
H

F
9-[4-[4-[[(4,4'-Difiuoro[1,1'-biphenyl]-2-y1)carbonyi]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride.
M.P. 131-34 C
MS (ESI, + ions) m/z 662 (M+H) Elemental Anal. Calc'd for C:38H36F5N302 + HC1 + 1.7 H20:
C, 62.63; H, 5.59; N, 5.77 Found: C, 62.59; H, 5.29; N, 5.82 ~

SUBSTITUTE SH,EET (RULE 26) Example 43*
gLH ~ CF a 71O
O N

' 1 HCI H
9-[4-[4-[[2-(2-Oxo-1-pyrrofidinyl)benzoyljamino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride.
MS (electrospray, + ions) m/z 633 (M+H) Examole 44*

o ^ CF3 CF3 H

O O
_N
Na~ =HCI

Contains: 1.25H20=0.12H5C20C2H5 N-(2,2,2-Trifluoroethyl)-9-[4-[4-[[[2-(3,3,3-trifluoropropoxy)-3-pyridinyl]carbanyl]-amino]-1-piperidinyl]butylj-9H-fluorene-9-carboxamide, monohydrochloride.
MS (ESI, + ion) m/z 663 (M+H); (-ion) 661 (M-H) Elemental Anal. Calc'd for C34H36N403F6 = HC1 = 1.25 H20 = 0.12 H5C20C2H5 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 SUBSTITUTE SHEET (RULE 26) WO 96/26205 -295 PCTlUS96f00824 -Examn l e 115*
~\ H
F3C--\ NH ~/ N }-- N 0 O
\ \ ~
CI' 9-[4-[4-[[(4-Chloro[ 1,1-biphenyl]-2-y1)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) Examnle 46*
o ("CF3 H3C CH3 \ ~ o /~\ ~ -N
N }-1 HCI
Contains: 0.8H20 9-[4-[4-[[[2-(1-Methylethoxy)-3-pyridinyl]carbonyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohyclrochloride.
MS (ESI, + ion) m/z 609 (M+H) ; (-ion) 607 (M-H) Elemental Anal. Ca1c' d for C34H39N403F3 =:HC1 = 0.8 H20:
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 SUBSTITUTE SHEET (RULE 26) Example 47*
Q

O S
_N
-1.65 HCI N ~ /
Contains: 1.5H20 9-[4-[4-[[[2-[(1-Methylethyl)thio]-3-pyridinyl]carbonyljamino]-1-piperidinyljbutyl]-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 C34H39N402SF3 = 1.65 HC1 =
1.5 H20:
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*
o CF3 ~ N
O ` /
_ ~ = 2HCI
~ \
H /
contains 2.14 moles H20 Eff. Mol Wt. = 738.105 9-[4-[4-[[2-(3-Pyridinyl)benzoyl]amino]-1-piperidinyljbutyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-cartioxamide, dihydrochloride.

M.P. 120-130 C (shrinking commencing at 110 C) MS (electrospray, - ions) m/z (M+H)+ = 627 SUBSTITUTE SHEET (RULE 26) Elemental Anal. Calc'd for C37H37F3N402 = 2 HC1=2.14 H20:
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 Examrple 49*
O' F3C--\ N
NH NH O
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*

g ( \ LH / /~ CF3 \ ~O CF3 I N ~
/ = 1 HCI

9-[4-[4-[[2,5-Bis(tr'rfluoromethyl)benzoyl]amino]-1-piperidiny1]buty1]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride.
MS (electrospray, + ions) m/z 686 (M+H) SUBSTITUTE SHEET (RULE 26) Example 51*
g O
N~ CF3 H

N
= 1 HCI H

CI
9-[4-[4-[(5-Chloro-2-methylbenzoyl) amino]-1-piperidinyl)butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride.
MS (electrospray, + ions) m/z 598 (M+H) Example 52*

N~ CF3 H
O CI
N
= 1 HCI H

CI
9-[4-[4-[[(3,6-Dichloro-2-pyrid inyl)carbonyl] amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochioride.

MS (electrospray, + ions) m/z 619 (M+H) [2 Cl isotope pattern]
Example 53*
gLH /'- C F3 O
O N~O

SUBSTITUTE SHEET (RULE 26) 9-[4-[4-[[2-(Tetrahydro-2-oxo-2H-1,3-oxazin-3-yl)benzoyil]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochioride.

Example 54*
O

O
~- ZHJL"~ S CI
'HCI N ~

Contains: 0.6 H20-0.2 H5C2OC2H5 9-[4-[4-[[(5-Chloro-2-thienyl)carbonyl]Eimino]-1 -piperidinyl]butyl]-N-(2,2,2-trifluo ro ethyl) -9 H-f luorene-9-carboxamide, mo nohydrochlo ride.
MS (ESI, + ion) m/z 590 (M+H) 1C1 Isotope Pattern Elemental Anal. Calc'd for C30H31N302C1SF3 = HC1 = 0.6 H20 = 0.2 H5C20C2H5:
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 F

SUBSTITUTE SHEET (RULE 26) Examrple 55*
N^ CF3 H =HCI

N F
H

9-[4-[4-[[2-Fiuoro-5-(trifluoromethyl)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trnfluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride.
(M+H)+ 636; (M-H)' 634 Example 56*
F3C--\ N~ H
C

cN
~~
CI

9-[4-[4-[(5-Chloro-2-methoxybenzoyl)amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochioride.
M.P. 108-113 C -MS (electrospray, - ions) m/z 615 (M+H) SUBSTITUTE SHEET (RULE 26) WO 96/26205 -301 PCTlUS96100824 -Examble 57*
= ( \
O

O S
'HCI No-N

Contains: H20= 0.15 H$C20C2H5 9-[4-[4-[[(2:2'-Bithiophen-5-yl)carbonyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-cart)oxamide, monohydrochloride.
MS (ESI, + ion) m/z 638 (M+H) Elemental Anal. Calc'd for C3,jH34N3O2S2F3 = HC1 = H20 = 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*
/~ C

gLH

9-[
4-[4-[[2-(Phenylmethylamino)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohyJrochloride.
ESI (M+H)+ 655 SUBSTITUTE SHEET (RULE 26) Example 59*
O

/
O
/~''~ H S
'HCI N }-N
~ -/ CI
9-[4-[4-[[(3-Chlorobenzo[b]thiophen-2-yt)carbonylJamino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohyd ro chloride.
MS (ESI, + ions) m/z 640 (M+H) 1 Cl Isotope pattern Example 60*
O
N " CF3 ~ 1 = HCI
O CI
CI
/ I
H g 9-[4-[4-[[(3,4-Dichtoro-2-thienyt)carbonyl]amino)-1-piperidinylJbutyl)-N-(2,2,2-trifluoroethyl)-9H-ftuorene-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 Examnle 61*
F3C-\ N }- N O
NH ~-/ / I
O f{1 \
H

SUBSTITUTE SHEET (RULE 26) trans-9-[4-[4-[[(2-Phenylcyclopropyl)carioonyl]amino]-1-piperidinyi]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-ca,rboxamide, monohydrochloride.
M.P. 118-126 C
MS (electrospray, - ions) m/z 590 (M+H) Elemental Anal. Calc'd for C35H38F3N302 + HC1 + 0.82 H20 + 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 ExamAle 2*
H
F3C--\ N N 0 CF3 NH
O / \ I
I \ ~
CI~
9-[4-[4-[[[4-Chloro-4'-(trifluoromethyl)[1,'I -biphenyl]-2-yi]-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 C39H36C1F6N302+HC1+0.5`H20:
,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 Examole 63*
H
F3C-\ N 0 CFs NH 'Or I
O / \
CI, SUBSTITUTE SHIEET (RULE 26) 9-[4-[4-[[[4-Chioro-4'-(trifluoromethyl)[1,1'-biphenyl]-2-yljcarbonyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, N-oxide.

M. P . 142 -144 C
MS (electrospray, - ions) m/z 743 (M-H) Elemental Anal. Calc'd for C39H36C1F6N303+0.88 H20:
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 Examole 64*
-~ 0 ~- CF3 N
H
O' F-N
N O =2HCI H

9N-oxide, d ihydrochlo ride.
MS (M+H)+ 643; (M-H)- 641 Elemental Anal. Calc'd for C37H37F3N403+2 HC1 + 1,94 H20:
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 SUBSTITUTE SHEET (RULE 26) -Example 65*
O

H

~ = 2 HCI / CF3 CL
N~
H

N-(2,2,2-Trifluoroethyl)-9-[4-[4-[[[1-[[4-(trifluoromethyl)phenyl)methyl]-2-piperidinyl]carbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide,dihydrochtoride.
MS (ES, + ions) m/z 715 [M+H]
Elemental Anal. Calc'd for C39H,E4F6N402+2 H20 + 2 HC1:
C, 56.87; H, 6.12; N, 6.80 Found: C, 57.01; H, 6.01; N, 6.74 ExamplA 66*
~ O ~

~ / N
H
O' /
~ ~ ~
O
N
=2HCI H N ~
N-[1-[4-[9-[[(2,2,2-Trifluoroethyi)amino]carbonyi]-9H-f1uoren-9-y1]buty1]-4-piperidinyl]-2-pyridinecarboxamide, N-oxide, dihydrochioride.
MS (M+H)+ @ 567; (M-H)' @ 565; ;2M+H)+ @ 1133 = Elemental Anal. Calc'd for C31H_S3F3N403+2 HC1+1.7 H20:
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 SUBSTITUTE SHEE:T (RULE 26) Exam-o le 67*
W0~H f-- CF3 N

O' `
+
C S
N N
H

trans-9-[4-[4-[[2-(2-Benzothiazolyl)benzoyl]amino]-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 C39H37F3N403S+1.5 H20+0.3 C6H14:
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 Examnle 68*
o N = 2 HCI
N
H
9-[4-[4-[[[1-(Cyclohexytmethyl)-2-piperidinyl]carbonyl]amino]-1-piperidinyl]-butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, dihydrochloride.
MS (ES, + ions) m/z 653 [M+H]
Elemental Anal. Calc'd for C38H53C1?F3N402+1.5 H20:
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 SUBSTITUTE SHEET (RULE 26) WO 96/2620i -307 PCTiUS96100824 -Examp l e E;9*
O

H~ CF3 =2HC:1 la O ~ CF3 N N
H

N-(2,2,2-Trifluoroethyl)-9-[4-[4-[[[ i -(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 C34H44C12F6N402+1.5 H20:
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 Examo l e 'Q*
F
~ ~N- O /'_+ F
H F

O
ND_ O/
H

MS (ESI + ions) m/z 551 (M+H) SUBSTITUTE SHEET (RULE 26) Examble 71*
I \ ~

~ = HCI

CL O I
H I
I
N-(2,2,2-Trifluoroethyl)-9-[4-[4-[(2,3,5-triiodobe nzoyl) aminoJ-1-piperidinylJbutylJ-9H-fluorene-9-carboxamide, monohydrochloride.
M.P. 178-182 C
MS (ES, + ions) m/z 928 (M+H) Elemental Anal. Calc'd for C?2H32C1F3I3N302+0.5 H20:
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 Examole 72*
S

\ I ~ /
C
NH I
`
N

1:1 HCI Salt 9-[4-[4-(Benzoylamino)-1-piperidinylJbutylJ-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 C32H34N302F3S + 1.0 HC1 +
0.75 H20:
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.
SUBSTITUTE SHEET (RULE 26) -Exambles 73* to 159*
The following compounds were prepared by robotics procedures as described below.

ROBOTICS PROCEDURES

Robotic Method for the Preparation of Amides 0 r CF3 A. Aqueous KOH/CHC13 ~ H B. R$C02H, DIC, 1=IOBT, DMF
(C. Optional HPLC Purification bis HCi salt (Example 11 Part C) 0 j N
H
O
a R5' IH
y Please note that in the Examples 7:3* to 159*, for structures bearing only two single borided 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 bearirig oxygens and sulfurs with only one sincrle bonded substituent, the second substituent is alwaiys hydrogen, but is not shown explicitly in the struct.ures.

=

SUBSTITUTE SHEET (RULE 26), Example 73*

O

NF F FF
1 ~ F

ZO
m/z 694 (M+H) Example 74*
O
F
~
F
F
1 , N S ~
~ ~
N ~
m/z 672 (M+H) Example 75*
o F

HaC. ~N
N~ lo \ CH, if m/z 659 (M+H) SUBSTITUTE SHEET (RULE 26) -ExamA l e 76*

F
F
F
1 ~
O,NO
Can/z 595 (M+H) Example 77*
p F
F
F

N---) p p ~I I` \
I I
m/z 654 (M+H) Examp l e 78*
F
F
F
- N O F
b F
m/z 586 (M+H) SUBSTITUTE SHEET (RULE 26) Examrple 79*

N--'-~ F
F F

O
N ( CI
CI
m/z 619 (M+H) Examrnle 80*
O
F
N -~ O O- CH3 ! O- CH3 m/z 610 (M+H) Example 81*

F
NF
F

~~ II
N

C
m/z 579 (M+H) SUBSTITUTE SHEET (RULE 26) Examnle 2*

gtN'--~l ~

~~.

N
O "O
m/z 609 (M+H) Examiple 83*
F f 9tN- f:

~ ~ O

H, C
m/z 565 (M+H) Examole 84*
O
N----T< F
F F

0 S' CH3 y v i~Y \ N

m/z 611 (M+H) SUBSTITUTE SHEET (RULE 26) Example 85*

O
F
F
F

F
`N O N ~ ~ FF
I N
i m/z 710 (M+H) Exam-ole 86*

F
NF

N N
m/z 553 (M+H) Examle 87*

~F
N
F F

\/~ I
c m/z 556 (M+H) SUBSTITUTE SHEET (RULE 26) :i -Example, 88*
O
F
N---T,-F F

N O CH, NO S
m/z 598 (M+H) Example, 89*
O
F
F
F

\ \ J
I\ ~ if N
S
m/z 660 (M+H) Exa=l(?90 *_ O

N~F
F

m/z 618 (M+H) SUBSTITUTE SHEET (RULE 26) WO 96/26205 ' PCT/US96/00824 Example 91*
I ~ p ~F
F
F

p 0N ! \ _ m/z 675 (M+H) 6 Example 92*
O
F
N--')<
F F

O ON
N F
m/z 693 (M+H) Example 93*

F
N--~
F F
~ -/

I

m/z 570 (M+H) SUBSTITUTE SHEET (RULE 26) Examble 94*

O
F
N~
F F

o O~,o N
N

m/z 677 (M+H) Example 95*
O
F
N
F F
1 ~

O O yO
N/',.l N
~
,j m/z 677 (M+H) Example 96*
O
F
F F

O
0 O~CFI3 m/z 643 (M+H) SUBSTITUTE SHEET (RULE 26) Examnle 97*
O

N F
F
Na p oyO~CH3 I /
N N> H3C CH3 S
m/z 661 (M+H) Example 98*

11 ~
O
F
~
N F
F
~ / .

N/\ O p~0 CH3 N\H3CCH3 S/
m/z 661 (M+H) Examrple 99*
O

W--- ! F
OLF
F j II

m/z 644 (M+H) r SUBSTITUTE SHEET (RULE 26) -31(9-Exa=le 100*

O
F
F
N H3Ci Ci H, N I ~ \
m/z 592 (M+H) Exam-ple 101*
O
F

CI
N 0 m/z 675 (M+H) Examnle 102*
O
F
F
F
O

l~/i\ I , m/z 688 (M+H) SUBSTITUTE SHE'ET (RULE 26) Examole 103*
o F
F~

o s N

m/z 660 (M+H) Examrple 104*
O
~ -^ F
F
m/z 709 (M+H) Example 105*
O
F
N- F F

F
F
N", Ii O,_t,F
m/z 634 (M+H) SUBSTITUTE SHEET (RULE 26) WO 96/26205 PCTlUS96/00824 ExamAle 106*
F
O

N
"-~
F
F

m/z 683 (M+H) ExamT)le 107*

F
N ~F
F
O',CH3 i I
N----' iD S
~\ ~I I
m/z 688 (M+H) Examrple 108*
O

N~GF F~F~F
F H
N'~ 0 tf v m/z 709 (M+H) SUBSTITUTE SH1=ET (RULE 261) Example 109*

F
F

O CI
l\/~\

m/z 619 (M+H) Exam nle 110*

N F
F
F

N li CI
N
I I

Br m/z 663 (M+H) Example 111*
O
II F
N--,<
F
F
N O CI
N

F"'kF
F
m/z 653 (M+H) SUBSTITUTE SHEET (RULE 26) Examn le 1 12 O
I N ,~ F.
F
F

N O F
FTF
F
m/z 686 (M+H) ~ ExamBle.113*
O
N
~ ~f=
F
1 ~

`/
m/z 678 (M+H

SUBSTITUTE SHE1=T (RULE 26) Example 114*
O
N F
F
F
~ / .
0 O' CH3 O
i m/z 610 (M+H) Example 115*
O
N F

F F

Ni~ O O' CH3 ~

m/z 610 (M+H) Examole 116*
O
F
/
~F
F
~ , .
N~~ O
N - CH
O
H'C0 m/z 610 (M+H) SUBSTITUTE SHEET (RULE 26) Example 117*
N~
~ f=
F

O -O
N~"N

O If ~

m/z 638 (M+H) Examiple 118*
O
~F
F
I

o- O
m/z 723 (M+H) Example :119*
O
F
F
F
Y 1 ~

. ~/~. N
N
m/z 589 (M+H) SUBSTITUTE SHEET (RULE 26) Exam-ple 120*
~ ~ -O
1 N--r F
F
F

N O
I
m/z 638 (M+H) Example 121*
O
F
N--,<F
F

O
m/z 638 (M+H) Example 122*
O
F
N
F

~ ~ I N / ~i~"3 \/ ~ N Y
m/z 565 (M+H) SUBSTITUTE SHEET (RULE 26) ExamAle 123*
O
.~/F
F
F

i O
'N N,C) m/z 596 (M+H) Exarnple 124*
F
F
~
~

N
~I 3 N
m/z 565 (M+H) Example 125*
g O
A~F
N F

F N 1 C) C:H3 ~N~ Iv`N
m/z 653 (M+H) SUBSTITUTE SHEIET (RULE 26) Examtple 126*
O
F
N --,)<F
~ F
/ O`
N O S S
O
N I jN

m/z 751 (M+H) Examble 127*

F
N ~F
~ F
CI
N~ O O ~
WAV l N
m/z 678 (M+H) Examiple 128*
O
F
F
F
CI
O s I;
N
m/z 694 (M+H) SUBSTITUTE SHEET (RULE 26) Examiple 129*
O
- - ~ F
F CH, F
O
I
O S O
~ N CFI3 I
~
m/z 719 (M+H) Examn 1 e =130*
O
F
F
F

N^ F
I F
V
F
CI
m/z 654 (M+H) Examole 131*
F
F
g O
F

G O

/ F
m/z 680 (M+H) SUBSTITUTE SHE1:T (RULE 26) Example 132*
o N~F
F F

N. O H,C~
I\/I\ S N -N
N
I ~ F
F
F
m/z 704 (M+H) Exa=le 133*
o F
F
F

CI
Ni~ 0 S O

S
m/z 699 (M+H) Example 134*
o F
F
F
F
N- F
Ni~i O F
S

S
m/z 733 (M+H) SUBSTITUTE SHEET (RULE 26) Examr)le 135*
O

N~
F
N O
N
N
m/z 617 (M+H) Example 136*
O
- I F, N
~ F CI
N~~
O
m/z 652 (M+H) Examp l e :i 3 7*
O

N ~F
F
1 ~
N<N

H, ~
m/z 653 (M+H) SUBSTITUTE SHEET (RULE 26) Example 138*
N -----]< F
F
F

N--i O

S
m/z 668 (M+H) Example 139*
O
F
NF
F

N\/~~

m/z 634 (M+H) Examiple 140*
N F
F
F

,K, N
N
N

~-S
m/z 634 (M+H) SUBSTITUTE SHEET (RULE 26) Example 141*
O

N--)< F
F F
Na C
N
S` "' m/z 635 (M+H) Examx)l e 14E 2*

F
NF

C) Ha N
N
I
L~-S S-N
m/z 655 (M+H) Example 143*
O
F
F
F
\ /- \
~
N~~ ~
O
\/\ ~~ N
, N
N
m/z 617 (M+H) SUBSTITUTE SHEET (RULE 26) Example 144*
F
F
gt0N F

II

N~N
S-N
m/z 572 (M+H) Example 145*
O
F
N,~
F
N O
N
N
S

m/z 558 (M+H) Example 146*
/ pl F
F
\ , ~ ~vF

N p (\ ^ I
v 'N \
m/z 672 (M+H) SUBSTITUTE SHEET (RULE 26) T;`xamnl e 147 *

^ x F
F
F

O
N

N 0 m/z 673 (M+H) Example 14"

I F
N
F

O\\/
N O
N I ~ i 1 m/z 759 (M+H) Examble 1<<*

I ^ F
N/ (u\

1 CN~ N'~ 1 ~ ' \ I

m/z 698 (M+H) SUBSTITUTE SHEE T (RULE 26) WO 96/26205 PCT/US96/0082~1 Examrp le 150*

1 ~
, i -N __~ F
F
F

O CH.
~ II ~ CH~
N[a O N/\ O CH.
N I

m/z 665 (M+H) ExamBle 151*
O

N X
F
F
Oi ^ O ^\ /
Nt/ ~ 0 ~\5' v I f (~
m/z 709 (M+H) Example 152*
O

F
1 ~ tJ-N
N ~ O

~
O C N, m/z 674 (M+H) SUBSTITUTE SHEET (RULE 26) -33?-Example 153*

N ,-~ F
F
F
N -N

H'O \ CH, ~/ \N \

CH~
m/z 688 (M+H) ExamAle154*

p F
F

N ` p O Y N YiN \ O
N
II CH~
N_ /J

m/z 675 (M+H) Example 155*

I I F
F
\ F ' I
HO

H IN
N/\ O

N\/
m/z 695 (M+H) SUBSTITUTE SHE:ET (RULE 261) Example 156*

I ^ F
N
F
F o 1 N Cl%
N
N CHS
a O
N
m/z 679 (M+H) Examr)le 157*

II F
N

CN~
a N O O
\
m/z 609 (M+H) Example 158*

F
F
F

O O /CH~
N C Y ( \
CNa H, m/z 657 (M+H) SUBSTITUTE SHEET (RULE 26) ExamA 1, e 159*

F
N X
F
II\
F
1 ~

O\ O CN;
\7 ' 'r~CK
1 ' . , . N CK
m/z 657 (M+H) SUBSTiTUTE SHE;ET (RULE 26)

Claims (32)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A compound which has the structure where Q is R1 is a fluorenyl-type group of the structure Z1 and Z2 are the same or different and are independently a bond, O, S, with the proviso that with respect to B, at least one of Z1 and Z2 will be other than a bond; R11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms; arylene or mixed arylenealkylene; R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the provisos that (1) when R12 is H, aryloxy, alkoxy or arylalkoxy, then Z2 is or a bond and (2) when Z2 is a bond, R12 cannot be heteroaryl or heteroarylalkyl;
Z is bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene from 1 to 5 carbon atoms;
R13, R14, R15, and R16 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;
R5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, 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, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl;
R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl; all optionally substituted with 1, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R5 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, wherein, the term "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, in the normal chain, as well as such groups including 1 to 4 substituents selected from halo, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, 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 R5 and R6, the term "cycloalkyl" as employed herein alone or as part of another group defines saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, selected from monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, and which may be fused to 1 or 2 aromatic rings as described for aryl, which may be optionally substituted with 1 to 4 substituents selected from 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 R5 or R6, the term "cycloalkenyl" as employed herein alone or as part of another group refers to cyclic hydrocarbons containing 5 to 20 carbons, and 1 or 2 double bonds, 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, 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, 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 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, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, 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, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl, or any of the substituents as defined for the R5 or R6 groups set out above, the term "amino" as employed herein alone or as part of another group may optionally be substituted with one or two substituents selected from alkyl and/or aryl, the term "alkenyl" as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, in the normal chain, which include 1 to 6 double bonds in the normal chain, and which may be optionally substituted with 1 to 4 substituents, selecting from halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol and/or alkylthio, as well as any of the other substituents as defined for R5 or R6, the term "alkynyl" as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, which include one triple bond in the normal chain, and which may be optionally substituted with 1 to 4 substituents, selected from, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, as well as any of the other substituents as defined for R5 or R6, 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 (CH2)p (which is defined above), selected from which may include 1 to 3 substituents selected from any of the R1, R5 or R6 groups as defined above, additionally, 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-membered 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, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)p (which is defined above), selected from and comprises all possible-N-oxide derivatives and 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) and are selected from wherein u is selected from O, S, and NR7a; R7a is H, lower alkyl, aryl, -C(O)R7b, -C,(O)OR7b; R7b is alkyl or aryl, and comprises all possible N-oxide derivatives, whereby the heteroaryl groups comprising the above groups may optionally include 1 to 4 substituents selected from any of the substituents listed for aryl, or those substituents indicated for R5 or R6 groups as defined above and additionally any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
2. The compound as defined in claim 1 having the formula
3. The compound as defined in Claim 1 having the formula
4. The compound as defined in Claim 1 wherein R1 is Z is a bond, O or S;
R13, R14, R15 and R16 are each H or one of R15 and R16 and one of R13 and R14 are halogen;
Z1 is a bond or C=O;

R11 is alkylene or alkenylene;
R12 - Z2 is R12a is alkyl, fluorinated lower alkyl or polyfluorinated lower alkyl.
5. The compound as defined in Claim 1 having the structure where Q is Z is a bond, O or S;
where R5 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;
R6 is H or CH3;
R13 and R15 are independently H or F;
Z1 is a bond;
R11 is alkylene;
R12 - Z2 is or Z2 is a bond and R12 is alkyl.
6. The compound as defined in Claim 5 wherein R11 is -(CH2)4-, Z1 is a bond, and R12-Z2 is
7. The compound as defined in Claim 5 having the structure where Q is Z is a bond, O or S;
where R5 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;
R6 is H or CH3;
R13 and R15 are independently H or F;
Z1 is a bond;
R11 is alkylene;
R12 - Z2 is or Z2 is a bond and R12 is alkyl and R12 is trifluoromethylalkyl or alkyl.
8. The compound as defined in Claim 1 having the structure where Q is Z is a bond, O or S;
where R5 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;

R6 is H or CH3;
R13 and R15 are independently H or F;
Z1 is a bond;
R11 is alkylene;
R12 - Z2 is R12a is alkyl, fluorinated lower alkyl or polyfluorinated lower alkyl, or Z2 is a bond and R12 is alkyl.
9. The compound as defined in Claim 1 which is:
9-[4-(4-[[(1,1-dimethylethoxy)carbonyl]-amino]-1-piperidinyl]butyl]-N-propyl-9H-fluorene-9-carboxamide;
9-[4-[4-[[2-(phenoxyphenyl)carbonyl]amino]-1-piperidinyl]butyl]-N-propyl-9H-fluorene-9-carboxamide;
9-[4-[4-(benzoylamino)-1-piperidinyl]-butyl]-N-propyl-9H-fluorene-9-carboxamide;
9-[4-[4-(acetylamino)-1-piperidinyl]butyl]-N-propyl-9H-fluorene-9-carboxamide;
9-[4-[[4-[(1,1-dimethylethoxy)carbonyl]-amino]-1-piperidinyl]butyl]-2,7-difluoro-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide;
9-[4-[4-[(2-phenoxybenzoyl)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;

2,7-difluoro-9-[4-[[4-(2-phenoxybenzoyl)-amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide;
9-[4-[4-(benzoylamino)-1-piperidinyl]-butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide;
[1-[4-[9-[(propylamino)carbonyl]-9H-fluorene-9-yl]butyl]-3-piperidinyl]carbamic acid, phenylmethyl ester;
9-[4-[3-(benzoylamino)-1-piperidinyl]-butyl]-N-propyl-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;
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)-amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide;

9-(4-[4-[(phenoxycarbonyl)amino]-1-piperidinyl]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-fluorone-9-carboxamide;
9-[4-(4-[(phenylsulfonyl)amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide;

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-piperxdinyl]-4-oxobutyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxa-mide;

9-[4-[4-[((1,1-dimethylethoxy)carbonyl]-amino]-1-piperidinyl]pentyl]-N-(2,2,2-trifluoroethyl)-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;
[1-[[[2-[9-[[(2,2,2-trifluoroethyl)-amino]-carbonyl]-9H-fluorene-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-fluorene-9-yl] ethyl ester;
4-[[(1,1-dimethylethoxy)carbonyl]amino]-1-piperidine-carboxylic acid, 2-[9-[[(2,2,2-trifluoroethyl)amino]carbonyl]-9H-fluorene-9-yl]ethyl ester;
9-[4-[4-[(2-phenoxybenzoyl)amino]-1-piperidinyl]pentyl]-N-(2,2,2-trifluoroethyl)y-9H-fluorene-9-carboxamide;
9-[2-[[[4-[(2-phenoxybenzoyl)amino]-1-pipezidinyl]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-fluorene-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-trifluoroethyl)-9H-thioxanthene-9-carboxamide;
9-[4-[4-(benzoylamino)-1-piperidinyl]-butyl]-N-(2,2,2-trifluoroethyl)-9H-thioxanthene-9-carboxamide;
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.
10. A compound having the structure comprising the piperidine N-oxide thereof or a pharmaceutically acceptable salt thereof, wherein Z is a bond, O or S;
X1 and X2 are independently selected from H or halo;
x is an integer from 2 to 6;
R5* is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R5* group being optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different.
11. The compound as defined in Claim 10 wherein Z
is a bond, each of X1 and X2 is H.
12. The compound as defined in Claim 10 which is a piperidine N-oxide.
13. The compound as defined in Claim 10 wherein the substituent on R5* is adjacent to the carbon attached to the group.
14. The compound as defined in Claim 10 wherein R5*
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.
15. The compound as defined in Claim 14 wherein R5*
is substituted with 1, 2, 3 or 4 of one or more of the following I, Cl, F, CF3 where x is 1 to 5 alkyl, phenyl, phenyl substituted with halo, alkyl, CF3O, alkoxy, CF3, or phenyl;
where p is 1 to 5, -N(CH3)C6H5; -S-(CH2)p CF3 where p is 1 to 5, -S-alkyl, , -O- (CH2)o-CF3, , OCH3;
cyclohexyl, amino, alkanoyl, alkoxycarbonyl, aroyl, heteroarylaminocarbonyl, arylalkyloxycarbonyl, -CH2-S-C6H6,
16. The compound as defined in Claim 15 wherein (CH2)x is (CH2)4 or Z is a bond;
X1 and X2 are H;
R5* is aryl, which is substituted with trifluoromethylphenyl, heteroaryl, halo and/or aryl or R5*
is heteroaryl;
wherein the R5* includes a substituent attached to a carbon adjacent to the carbon linked to
17. The compound as defined in Claim 10 which is the monohydrochloride thereof, the dihydrochloride thereof or the pharmaceutically acceptable salt thereof.
18. The compound as defined in Claim 10 which is the monohydrochloride thereof, the dihydrochloride thereof or other pharmaceutically acceptable salt thereof.
19. A compound having the structure comprising the piperidine N-oxide thereof or a pharmaceutically acceptable salt thereof, wherein R5* is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R5* group being optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different.
20. The compound as defined in Claim 19 wherein the substituent on R5* is adjacent to the carbon attached to the group.
21. The compound as defined in Claim 19 wherein R5*
is phenyl substituted with haloalkylphenyl or heteroaryl.
22. The compound as defined in Claim 21 wherein R5*
is
23. The compound as defined in Claim 19 which is
24. A compound which has the structure R1 is an indenyl-type group of the structure Z1 and Z2 are the same or different and are independently a bond, O, S, with the proviso that with respect to B, at least one of Z1 and Z2 will be other than a bond; R11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms; arylene or mixed arylenealkylene; R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the provisos that (1) when R12 is H, aryloxy, alkoxy or arylalkoxy, then Z2 is or a bond and (2) when Z2 is a bond, R12 cannot be heteroaryl or heteroarylalkyl;
(3) in the third and fourth formulae, where R1 is indenyl E, if Z1 is a bond, then R12-Z2 is other than alkyl or H;
(4) in the third and fourth formulae, where R1 is indenyl F then Z2 is where Z2 is other than alkoxy, or where R12 is other than alkyl;
z is bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene containing from 1 to 5 carbon atoms;
R13 and R14 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;
R155, and R16a are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;
R5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, 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, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heleroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl;
R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl; all optionally substituted with 1, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R5 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.
25. The compound as defined in Claim 24 having the formula
26. The compound as defined in Claim 24 having the formula
27. The compound as defined in Claim 1 which is:
9-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-propyl-9H-indeno[2,1-b]pyridine-9-carboxamide;

2,3-dihydro-1-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-propyl-1H-indene-1-carboxamide;
trans-2,3-dihydro-1-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-2-phenyl-N-propyl-1H-indene-1-carboxamide;
1-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-2-phenyl-N-propyl-1H-indene-1-carboxamide;
1-[4-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-1-piperidinyl]butyl]-2-methyl-N-(2,2,2-trifluoroethyl)-1H-indene-1-carboxamide; or 1-[4-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-1H-indene-1-carboxamide.
28. A pharmaceutical composition comprising a compound as defined in any one of claims 1-27 and a physiologically acceptable carrier.
29. Use of a compound as defined in any one of claims 1-9, 11, 24-27 for the preparation of a pharmaceutical composition for preventing, inhibiting or treating atherosclerosis, pancreatitis, hyperglycemia or obesity in a mammalian species.
30. Use of a compound as defined in any one of claims 1-27 for the preparation of a pharmaceutical composition for lowering serum lipid levels, cholesterol and/or triglycerides, or inhibiting and/or treating hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia.
31. Use of a compound as defined in any one of claims 1-9, 11, 24-27 for preventing, inhibiting or treating atherosclerosis, pancreatitis, hyperglycemia or obesity in a mammalian species.
32. Use of a compound as defined in any one of claims 1-27 for lowering serum lipid levels, cholesterol and/or triglycerides, or inhibiting and/or treating hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia.
CA002213466A 1995-02-21 1996-02-01 Inhibitors of microsomal triglyceride transfer protein and method Expired - Lifetime CA2213466C (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US39190195A 1995-02-21 1995-02-21
US08/391,901 1995-02-21
US08/472,067 US5739135A (en) 1993-09-03 1995-06-06 Inhibitors of microsomal triglyceride transfer protein and method
US08/472,067 1995-06-06
PCT/US1996/000824 WO1996026205A1 (en) 1995-02-21 1996-02-01 Inhibitors of microsomal triglyceride transfer protein and method

Publications (2)

Publication Number Publication Date
CA2213466A1 CA2213466A1 (en) 1996-08-29
CA2213466C true CA2213466C (en) 2009-09-08

Family

ID=27013673

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002213466A Expired - Lifetime CA2213466C (en) 1995-02-21 1996-02-01 Inhibitors of microsomal triglyceride transfer protein and method

Country Status (27)

Country Link
US (5) US5739135A (en)
EP (1) EP0886637B9 (en)
JP (1) JP4036244B2 (en)
KR (1) KR19980703598A (en)
CN (1) CN1108301C (en)
AR (1) AR001795A1 (en)
AT (1) ATE283851T1 (en)
AU (1) AU699865B2 (en)
BG (1) BG101717A (en)
CA (1) CA2213466C (en)
CZ (1) CZ261797A3 (en)
DE (1) DE69633983T2 (en)
EE (1) EE9700182A (en)
ES (1) ES2233961T3 (en)
FI (1) FI973416A (en)
GE (1) GEP20001916B (en)
HU (1) HUP9801278A3 (en)
IL (1) IL116917A (en)
LV (1) LV11951B (en)
MX (1) MX9705005A (en)
NO (1) NO973821D0 (en)
NZ (1) NZ302055A (en)
PL (1) PL185443B1 (en)
SK (1) SK113597A3 (en)
TW (1) TW486469B (en)
UY (1) UY24165A1 (en)
WO (1) WO1996026205A1 (en)

Families Citing this family (205)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6214994B1 (en) * 1997-04-21 2001-04-10 Molecular Geriatrics Corporation Certain substituted 1-aryl-3-piperazin-1′-yl propanones
PL328094A1 (en) * 1996-01-16 1999-01-04 Bristol Myers Squibb Co Conformingly restricted aromatic inhibitors triglycerides carrying chromosome protein and method of obtaining such inhibitors
US5948917A (en) * 1996-03-26 1999-09-07 Nippon Soda Co., Ltd. 3-(isoxazol-5-yl)-substituted benzoic acid derivative and method for production thereof
US6057339A (en) * 1996-05-09 2000-05-02 Bristol-Myers Squibb Company Method of inhibiting or treating phytosterolemia with an MTP inhibitor
DE19631244A1 (en) * 1996-08-02 1998-02-12 Clariant Gmbh New light stabilizers based on sterically hindered amines
JP3270764B2 (en) * 1996-11-27 2002-04-02 ファイザー・インク Apo B-secretion / MTP inhibitory amide
US5760246A (en) 1996-12-17 1998-06-02 Biller; Scott A. Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method
WO1998027979A1 (en) * 1996-12-20 1998-07-02 Bristol-Myers Squibb Company Heterocyclic inhibitors of microsomal triglyceride transfer protein and method
US6066653A (en) * 1997-01-17 2000-05-23 Bristol-Myers Squibb Co. Method of treating acid lipase deficiency diseases with an MTP inhibitor and cholesterol lowering drugs
WO1998031225A1 (en) * 1997-01-17 1998-07-23 Bristol-Myers Squibb Company A method of inhibiting or treating phytosterolemia with an mtp inhibitor
CA2286341A1 (en) * 1997-05-01 1998-11-12 John R. Ii Wetterau Mtp inhibitors and fat soluble vitamin therapeutic combinations to lower serum lipid levels
US5968950A (en) * 1997-06-23 1999-10-19 Pfizer Inc Apo B-secretion/MTP inhibitor hydrochloride salt
US5990110A (en) * 1997-07-15 1999-11-23 Bristol-Meyers Squibb Company Method for treating tumors having high LDL requirements employing MTP inhibitors
AU751139B2 (en) * 1997-10-13 2002-08-08 Astellas Pharma Inc. Amide derivative
JP2959765B2 (en) 1997-12-12 1999-10-06 日本たばこ産業株式会社 3-piperidyl-4-oxoquinazoline derivative and pharmaceutical composition containing the same
WO1999063929A2 (en) 1998-06-08 1999-12-16 Advanced Medicine, Inc. Multibinding inhibitors of microsomal triglyceride transferase protein
EE200100155A (en) 1998-09-17 2002-08-15 Bristol-Myers Squibb Company A method of treating atherosclerosis using an a2 inhibitor and a combination thereof
US6780883B2 (en) 1998-11-05 2004-08-24 Warner-Lambert Company Amide inhibitors of microsomal triglyceride transfer protein
FR2788270B1 (en) * 1999-01-08 2001-03-16 Atochem Elf Sa PROCESS FOR THE PREPARATION OF BETA-PHOSPHORUS NITROXIDE RADIALS
US6548529B1 (en) 1999-04-05 2003-04-15 Bristol-Myers Squibb Company Heterocyclic containing biphenyl aP2 inhibitors and method
AU779550B2 (en) * 1999-04-09 2005-01-27 Meiji Seika Kaisha Ltd. Nitrogen-containing heterocyclic compounds and benamide compounds and drugs containing the same
US6472410B1 (en) 1999-06-11 2002-10-29 Merck & Co., Inc. N-cyclopentyl modulators of chemokine receptor activity
AU5473800A (en) 1999-06-11 2001-01-02 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6538002B1 (en) 1999-06-11 2003-03-25 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6358979B1 (en) 1999-06-11 2002-03-19 Merck & Co., Inc. N-cyclopentyl modulators of chemokine receptor activity
WO2000076512A1 (en) * 1999-06-11 2000-12-21 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6432981B1 (en) 1999-06-11 2002-08-13 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
SE9902987D0 (en) 1999-08-24 1999-08-24 Astra Pharma Prod Novel compounds
DE19945594A1 (en) * 1999-09-23 2001-03-29 Boehringer Ingelheim Pharma Substituted piperazine derivatives, their preparation and their use as medicines
DE19963235A1 (en) * 1999-12-27 2001-07-05 Boehringer Ingelheim Pharma Substituted piperazine derivatives, their manufacture and their use as pharmaceuticals
DE19963234A1 (en) * 1999-12-27 2002-01-24 Boehringer Ingelheim Pharma New N,N-disubstituted piperazine and diazacycloheptane derivatives useful in treatment of hyperlipidemia, atherosclerosis, diabetes mellitus, adiposity and pancreatitis
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
GB0013346D0 (en) * 2000-06-01 2000-07-26 Glaxo Group Ltd Therapeutic benzamide derivatives
GB0013383D0 (en) * 2000-06-01 2000-07-26 Glaxo Group Ltd Therapeutic benzamide derivatives
DE10030375A1 (en) * 2000-06-21 2002-01-03 Bayer Ag Use of MTP inhibitors to lower ppTRL
CA2417727C (en) 2000-07-31 2009-09-01 Nycomed Danmark A/S Fentanyl composition for nasal administration
DE10040051A1 (en) * 2000-08-11 2002-02-21 Basf Ag Derivatives of 4- (trifluoromethyl) phenol and derivatives of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether and process for their preparation
JO2654B1 (en) 2000-09-04 2012-06-17 شركة جانسين فارماسوتيكا ان. في Polyarylcarboxamides useful as lipid lowering agents
JO2409B1 (en) 2000-11-21 2007-06-17 شركة جانسين فارماسوتيكا ان. في Biphenylcarboxamides useful as lipid lowering agents
GB0104050D0 (en) 2001-02-19 2001-04-04 Astrazeneca Ab Chemical compounds
GB0107228D0 (en) 2001-03-22 2001-05-16 Astrazeneca Ab Chemical compounds
JO2390B1 (en) 2001-04-06 2007-06-17 شركة جانسين فارماسوتيكا ان. في Lipid lowering biphenulcarboxamides
US6774112B2 (en) 2001-04-11 2004-08-10 Bristol-Myers Squibb Company Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
US20020193403A1 (en) * 2001-05-03 2002-12-19 Allergan Sales, Inc. Methods of treating hyperlipidemia
JP4366081B2 (en) 2001-05-22 2009-11-18 エーザイ・アール・アンド・ディー・マネジメント株式会社 Highly purified anti-endotoxin compounds
GEP20063720B (en) * 2001-06-28 2006-01-10 Pfizer Prod Inc Triamide-Substituted Indoles, Benzofuranes and Benzothiophenes as Inhibitors of Microsomal Triglyceride Transfer Protein (MTP) and/or Apolipoprotein B (Apo B) Secretion
US7238671B2 (en) * 2001-10-18 2007-07-03 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
WO2003033671A2 (en) * 2001-10-18 2003-04-24 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US6806381B2 (en) * 2001-11-02 2004-10-19 Bristol-Myers Squibb Company Process for the preparation of aniline-derived thyroid receptor ligands
SE0103818D0 (en) 2001-11-15 2001-11-15 Astrazeneca Ab Chemical compounds
WO2003043624A1 (en) 2001-11-16 2003-05-30 Bristol-Myers Squibb Company Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein
US6831102B2 (en) * 2001-12-07 2004-12-14 Bristol-Myers Squibb Company Phenyl naphthol ligands for thyroid hormone receptor
WO2003094845A2 (en) 2002-05-08 2003-11-20 Bristol-Myers Squibb Company Pyridine-based thyroid receptor ligands
KR101069781B1 (en) * 2002-05-14 2011-10-05 프라샌트 인베스트먼츠, 엘엘씨 Method for producing a transmission signal
US7057046B2 (en) * 2002-05-20 2006-06-06 Bristol-Myers Squibb Company Lactam glycogen phosphorylase inhibitors and method of use
WO2003106628A2 (en) * 2002-06-17 2003-12-24 Bristol-Myers Squibb Company Benzodiazepine inhibitors of mitochondial f1f0 atp hydrolase and methods of inhibiting f1f0 atp hydrolase
TW200409637A (en) 2002-06-26 2004-06-16 Glaxo Group Ltd Compounds
AU2003282983A1 (en) * 2002-10-23 2004-05-13 Bristol-Myers Squibb Company Glycinenitrile-based inhibitors of dipeptidyl peptidase iv and methods
US7098235B2 (en) 2002-11-14 2006-08-29 Bristol-Myers Squibb Co. Triglyceride and triglyceride-like prodrugs of glycogen phosphorylase inhibiting compounds
MXPA05006744A (en) * 2002-12-20 2005-09-08 Pfizer Prod Inc Microsomal triglyceride transfer protein inhibitors.
BR0317426A (en) * 2002-12-20 2005-11-16 Pfizer Prod Inc Microsomal triglyceride transfer protein inhibitors
TW200504021A (en) * 2003-01-24 2005-02-01 Bristol Myers Squibb Co Substituted anilide ligands for the thyroid receptor
US20040176425A1 (en) * 2003-01-24 2004-09-09 Washburn William N. Cycloalkyl containing anilide ligands for the thyroid receptor
ATE479667T1 (en) 2003-02-06 2010-09-15 Bristol Myers Squibb Co THIAZOLYL-BASED COMPOUNDS SUITABLE AS KINASE INHIBITORS
US20050090426A1 (en) * 2003-03-24 2005-04-28 Blumberg Richard S. Methods of inhibiting inflammation
US6846836B2 (en) * 2003-04-18 2005-01-25 Bristol-Myers Squibb Company N-substituted phenylurea inhibitors of mitochondrial F1F0 ATP hydrolase
US7557143B2 (en) 2003-04-18 2009-07-07 Bristol-Myers Squibb Company Thyroid receptor ligands
DK1618092T3 (en) 2003-05-01 2011-01-31 Bristol Myers Squibb Co Aryl-substituted pyrazole-amide compounds useful as kinase inhibitors
SE0301369D0 (en) 2003-05-09 2003-05-09 Astrazeneca Ab Chemical compounds
US7459474B2 (en) 2003-06-11 2008-12-02 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor and method
US7129252B2 (en) * 2003-06-16 2006-10-31 Guoqing P Chen Six membered amino-amide derivatives an angiogenisis inhibitors
US6995183B2 (en) * 2003-08-01 2006-02-07 Bristol Myers Squibb Company Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
TW200526626A (en) * 2003-09-13 2005-08-16 Astrazeneca Ab Chemical compounds
US7371759B2 (en) * 2003-09-25 2008-05-13 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US7317109B2 (en) * 2003-11-12 2008-01-08 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7576121B2 (en) * 2003-11-12 2009-08-18 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
KR20070054762A (en) * 2003-11-12 2007-05-29 페노믹스 코포레이션 Heterocyclic boronic acid compounds
US7767828B2 (en) 2003-11-12 2010-08-03 Phenomix Corporation Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7420059B2 (en) * 2003-11-20 2008-09-02 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US7273881B2 (en) 2004-01-16 2007-09-25 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7253283B2 (en) 2004-01-16 2007-08-07 Bristol-Myers Squibb Company Tricyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
DE102004005172A1 (en) * 2004-02-02 2005-08-18 Aventis Pharma Deutschland Gmbh Indazole derivatives as inhibitors of the hormone sensitive lipase
JP2007520543A (en) 2004-02-04 2007-07-26 ファイザー・プロダクツ・インク Substituted quinoline compounds
JP5697296B2 (en) 2004-03-05 2015-04-08 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア Method for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia with minimal side effects
WO2005097131A2 (en) * 2004-04-09 2005-10-20 Janssen Pharmaceutica N.V. Intermittent dosing regimen for the treatment of overweight with mtp-inhibitors
US7314875B2 (en) * 2004-04-13 2008-01-01 Cephalon, Inc. Tricyclic aromatic and bis-phenyl sulfinyl derivatives
NZ550441A (en) * 2004-05-05 2009-07-31 Hoffmann La Roche Arylsulfonyl benzodioxanes useful for modulating the 5-HT6 receptor, the 5-HT2A receptor or both
US7253167B2 (en) * 2004-06-30 2007-08-07 Bristol-Myers Squibb Company Tricyclic-heteroaryl compounds useful as kinase inhibitors
US7534763B2 (en) 2004-07-02 2009-05-19 Bristol-Myers Squibb Company Sustained release GLP-1 receptor modulators
TW200611704A (en) * 2004-07-02 2006-04-16 Bristol Myers Squibb Co Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions
US7145040B2 (en) * 2004-07-02 2006-12-05 Bristol-Myers Squibb Co. Process for the preparation of amino acids useful in the preparation of peptide receptor modulators
CA2573848A1 (en) * 2004-07-12 2006-02-16 Phenomix Corporation Constrained cyano compounds
US7429611B2 (en) * 2004-09-23 2008-09-30 Bristol-Myers Squibb Company Indole inhibitors of 15-lipoxygenase
US7754755B2 (en) * 2004-09-23 2010-07-13 Bristol-Myers Squibb Company Inhibitors of 15-lipoxygenase
AR051446A1 (en) * 2004-09-23 2007-01-17 Bristol Myers Squibb Co C-ARYL GLUCOSIDS AS SELECTIVE INHIBITORS OF GLUCOSE CONVEYORS (SGLT2)
TW200630337A (en) 2004-10-14 2006-09-01 Euro Celtique Sa Piperidinyl compounds and the use thereof
WO2006050999A2 (en) * 2004-11-15 2006-05-18 Obe Therapy Biotechnology S.A.S Methods of reducing body fat
SA05260357B1 (en) 2004-11-19 2008-09-08 ارينا فارماسيتو تيكالز ، أنك 3-phenyle-pyrazole derivatives as modulators of the 5-ht 2a serotonin receptor useful for the treatment of disorders related thereto
RU2388748C2 (en) * 2004-12-21 2010-05-10 Ф. Хоффманн-Ля Рош Аг Tetralin and indane derivatives and use thereof as 5-ht antagonists
AU2005318550B2 (en) * 2004-12-21 2011-04-07 F. Hoffmann-La Roche Ag Tetralin and indane derivatives and uses thereof
WO2006066745A1 (en) * 2004-12-21 2006-06-29 F.Hoffmann-La Roche Ag Tetralin and indane derivatives and uses thereof
BRPI0515830A (en) 2004-12-21 2008-08-05 F Hoffmann La Roche chroman derivatives and their use in the treatment of central nervous system disorders
KR20070088798A (en) * 2004-12-21 2007-08-29 에프. 호프만-라 로슈 아게 Chroman derivatives and their use as 5-ht receptor ligands
US7635699B2 (en) * 2004-12-29 2009-12-22 Bristol-Myers Squibb Company Azolopyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US7589088B2 (en) * 2004-12-29 2009-09-15 Bristol-Myers Squibb Company Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US7317024B2 (en) 2005-01-13 2008-01-08 Bristol-Myers Squibb Co. Heterocyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
TW200637869A (en) 2005-01-28 2006-11-01 Chugai Pharmaceutical Co Ltd The spiroketal derivatives and the use as therapeutical agent for diabetes of the same
US20060178388A1 (en) * 2005-02-04 2006-08-10 Wrobleski Stephen T Phenyl-substituted pyrimidine compounds useful as kinase inhibitors
WO2006087543A1 (en) * 2005-02-18 2006-08-24 Astrazeneca Ab Antibacterial piperidine derivatives
EP1856044A2 (en) * 2005-02-18 2007-11-21 AstraZeneca AB Pyrrole derivatives as dna gyrase and topoisomerase inhibitors
EP1861396A1 (en) * 2005-03-04 2007-12-05 AstraZeneca AB Tricyclic derivatives of azetidine and pyrrole with antibacterial activity
JP2008531671A (en) * 2005-03-04 2008-08-14 アストラゼネカ アクチボラグ Compound
US20130082232A1 (en) 2011-09-30 2013-04-04 Unity Semiconductor Corporation Multi Layered Conductive Metal Oxide Structures And Methods For Facilitating Enhanced Performance Characteristics Of Two Terminal Memory Cells
EP2527337A1 (en) 2005-04-14 2012-11-28 Bristol-Myers Squibb Company Inhibitors of 11-beta hydroxysteroid dehydrogenase type I
GEP20104878B (en) 2005-04-19 2010-01-11 Surface Logix Inc Inhibitors of microsomal triglyceride transfer protein and apo-b secretion
US7521557B2 (en) 2005-05-20 2009-04-21 Bristol-Myers Squibb Company Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods
US7825139B2 (en) 2005-05-25 2010-11-02 Forest Laboratories Holdings Limited (BM) Compounds and methods for selective inhibition of dipeptidyl peptidase-IV
AR053495A1 (en) * 2005-05-26 2007-05-09 Bristol Myers Squibb Co PEPTIDE MODULATORS 1 SIMILAR TO HUMAN GLUCAGON AND ITS USE IN THE TREATMENT OF DIABETES AND RELATED CONDITIONS
WO2006129193A2 (en) * 2005-05-27 2006-12-07 Pfizer Products Inc. Combination of a cannabinoid-1- receptor-antagonist and a microsomal triglyceride transfer protein inhibitor for treating obesity or mainataining weight loss
US7888381B2 (en) 2005-06-14 2011-02-15 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity, and use thereof
US7473784B2 (en) * 2005-08-01 2009-01-06 Bristol-Myers Squibb Company Benzothiazole and azabenzothiazole compounds useful as kinase inhibitors
US7534804B2 (en) * 2005-08-24 2009-05-19 Bristol-Myers Squibb Company Benzoxazole inhibitors of 15-lipoxygenase
EP1951224A2 (en) * 2005-10-18 2008-08-06 Aegerion Pharmaceuticals Methods for treating disorders associated with hyperlipidemia in a mammal
WO2007053819A2 (en) 2005-10-31 2007-05-10 Bristol-Myers Squibb Company Pyrrolidinyl beta-amino amide-based inhibitors of dipeptidyl peptidase iv and methods
ES2359735T3 (en) * 2005-11-03 2011-05-26 F. Hoffmann-La Roche Ag ARYLSULPHONYL CHROMANES AS 5-HT6 INHIBITORS.
US7592461B2 (en) 2005-12-21 2009-09-22 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
EP1976873A2 (en) * 2006-01-11 2008-10-08 Brystol-Myers Squibb Company Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions
US8110681B2 (en) 2006-03-17 2012-02-07 The United States Of America As Represented By The Secretary, Department Of Health And Human Services Compounds for the treatment of spinal muscular atrophy and other uses
US8247442B2 (en) * 2006-03-29 2012-08-21 Purdue Pharma L.P. Benzenesulfonamide compounds and their use
US20070238770A1 (en) * 2006-04-05 2007-10-11 Bristol-Myers Squibb Company Process for preparing novel crystalline forms of peliglitazar, novel stable forms produced therein and formulations
TW200815353A (en) * 2006-04-13 2008-04-01 Euro Celtique Sa Benzenesulfonamide compounds and their use
TW200812963A (en) * 2006-04-13 2008-03-16 Euro Celtique Sa Benzenesulfonamide compounds and the use thereof
US8481535B2 (en) 2006-05-18 2013-07-09 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
CN103396412A (en) 2006-05-18 2013-11-20 艾尼纳制药公司 Modifier of 5-HT2A serotonin receptor
ES2536762T3 (en) 2006-05-18 2015-05-28 Arena Pharmaceuticals, Inc. Primary amines and their derivatives as 5-HT2A serotonin receptor modulators useful for the treatment of disorders related to this
WO2007140191A2 (en) 2006-05-23 2007-12-06 Theracos, Inc. Glucose transport inhibitors and methods of use
EP2021014A1 (en) * 2006-05-26 2009-02-11 Brystol-Myers Squibb Company Sustained release glp-1 receptor modulators
CN101472884A (en) * 2006-06-20 2009-07-01 弗·哈夫曼-拉罗切有限公司 1 2 3 4-tetralin and indane derivatives and uses thereof
BRPI0713742A2 (en) * 2006-06-20 2013-02-13 Hoffmann La Roche arylsulfonyl naphthalene derivatives and uses of these
EP2076489A1 (en) * 2006-06-20 2009-07-08 F. Hoffmann-Roche AG Arylsulfonamidyl tetralin derivatives and uses thereof
US7919598B2 (en) 2006-06-28 2011-04-05 Bristol-Myers Squibb Company Crystal structures of SGLT2 inhibitors and processes for preparing same
US20080044326A1 (en) * 2006-07-04 2008-02-21 Esencia Co., Ltd. Sterilizer for baby products
EP2046753A2 (en) 2006-07-06 2009-04-15 Brystol-Myers Squibb Company Pyridone/hydroxypyridine 11-beta hydroxysteroid dehydrogenase type i inhibitors
US7795291B2 (en) 2006-07-07 2010-09-14 Bristol-Myers Squibb Company Substituted acid derivatives useful as anti-atherosclerotic, anti-dyslipidemic, anti-diabetic and anti-obesity agents and method
TWI403516B (en) 2006-07-27 2013-08-01 Chugai Pharmaceutical Co Ltd To replace spirocyclic alcohol derivatives, and its use as a therapeutic agent for diabetes
TWI432446B (en) 2006-07-27 2014-04-01 Chugai Pharmaceutical Co Ltd Fused ring spiroketal derivative and use thereof as anti-diabetic drug
US7727978B2 (en) 2006-08-24 2010-06-01 Bristol-Myers Squibb Company Cyclic 11-beta hydroxysteroid dehydrogenase type I inhibitors
EP2072522A4 (en) 2006-10-13 2010-01-06 Chugai Pharmaceutical Co Ltd Thioglucose spiroketal derivative and use thereof as therapeutic agent for diabetes
ATE469122T1 (en) * 2006-10-24 2010-06-15 Janssen Pharmaceutica Nv MTP-INHIBITING TETRAHYDRONAPHTHALINE-1 CARBOXYLIC ACID DERIVATIVES
JO2653B1 (en) * 2006-10-24 2012-06-17 شركة جانسين فارماسوتيكا ان. في Piperidine Or Piperazine Substituted Tetrahydro-Naphthalene-1-Carboxylic Acid Mtp Inhibiting Compounds.apoB
WO2008057856A2 (en) 2006-11-01 2008-05-15 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, ap-1 and/or nf-kappab activity and use thereof
WO2008057862A2 (en) 2006-11-01 2008-05-15 Bristol-Myers Squibb Company MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-&kappav;B ACTIVITY AND USE THEREOF
EP2089389A2 (en) 2006-11-01 2009-08-19 Bristol-Myers Squibb Company Heterocyclic compounds as modulators of glucocorticoid receptor, ap-1, and/or nf-kappa-b activity
JP2010508358A (en) 2006-11-01 2010-03-18 ブリストル−マイヤーズ スクイブ カンパニー Glucocorticoid receptor, AP-1 and / or modulator of NF-κB activity, and use thereof
WO2008079398A1 (en) * 2006-12-21 2008-07-03 Aegerion Pharmaceuticals, Inc. Methods for treating obesity with a combination comprising a mtp inhibitor and a cholesterol absorption inhibitor
WO2008090198A1 (en) * 2007-01-25 2008-07-31 Janssen Pharmaceutica Nv Use of mtp inhibitors for increasing levels of satiety hormones
UY30892A1 (en) * 2007-02-07 2008-09-02 Smithkline Beckman Corp AKT ACTIVITY INHIBITORS
PE20090185A1 (en) 2007-03-22 2009-02-28 Bristol Myers Squibb Co PHARMACEUTICAL FORMULATIONS CONTAINING AN SGLT2 INHIBITOR
WO2008124384A2 (en) * 2007-04-03 2008-10-16 Aegerion Pharmaceuticals, Inc. Combinations of mtp inhibitors with cholesterol absorption inhibitors or interferon for treating hepatitis c
US8399486B2 (en) * 2007-04-09 2013-03-19 Purdue Pharma L.P. Benzenesulfonyl compounds and the use thereof
EP2474549A1 (en) 2007-04-17 2012-07-11 Bristol-Myers Squibb Company Fused heterocyclic 11-beta-hydroxysteroid dehydrogenase type I inhibitors
PE20090696A1 (en) * 2007-04-20 2009-06-20 Bristol Myers Squibb Co CRYSTALLINE FORMS OF SAXAGLIPTIN AND PROCESSES FOR PREPARING THEM
JP2010528023A (en) * 2007-05-18 2010-08-19 ブリストル−マイヤーズ スクイブ カンパニー Crystal structure of SGLT2 inhibitor and method for producing the same
TW200906412A (en) * 2007-06-12 2009-02-16 Astrazeneca Ab Piperidine compounds and uses thereof
WO2009018065A2 (en) * 2007-07-27 2009-02-05 Bristol-Myers Squibb Company Novel glucokinase activators and methods of using same
JP4809931B2 (en) 2007-08-23 2011-11-09 セラコス・インコーポレイテッド Benzylbenzene derivatives and methods of use thereof
TW200918062A (en) * 2007-09-12 2009-05-01 Wyeth Corp Azacyclylisoquinolinone and-isoindolinone derivatives as histamine-3 antagonists
EP2573080A1 (en) * 2007-09-27 2013-03-27 The United States of America, as Represented by the Secretary, Department of Health and Human Services Isoindoline compounds for the treatment of spinal muscular atrophy and other uses
US8765736B2 (en) * 2007-09-28 2014-07-01 Purdue Pharma L.P. Benzenesulfonamide compounds and the use thereof
CN101910171A (en) 2007-11-01 2010-12-08 百时美施贵宝公司 Nonsteroidal compounds useful as modulators of glucocorticoid receptor AP-1 and/or NF-kappa B activity and use thereof
ES2575131T3 (en) 2007-12-03 2016-06-24 Obe Therapy Biotechnology Enteropeptidase boropeptide inhibitors and their uses in treatments of obesity, overweight and / or diseases associated with an abnormal fat metabolism
CN101990541A (en) 2008-02-07 2011-03-23 百时美施贵宝公司 Fused heteroaryl modulators of glucocorticoid receptor, ap-1, and/or nf-kb activity and use thereof
EP2334671A1 (en) 2008-06-24 2011-06-22 Bristol-Myers Squibb Company Cyclopentathiophene modulators of the glucocorticoid receptor, ap-1, and/or nf-kappa b activity and use thereof
EP2312944B1 (en) * 2008-07-15 2018-09-05 Theracos, Inc. Deuterated benzylbenzene derivatives and methods of use
US20100215635A1 (en) * 2009-02-23 2010-08-26 Zoltan Kiss Small molecules to induce weight loss or to reduce weight gain
MY198422A (en) 2009-04-29 2023-08-29 Amarin Pharmaceuticals Ie Ltd Pharmaceutical compositions comprising epa and a cardiovascular agent and methods of using the same
HUE040486T2 (en) 2009-11-13 2019-03-28 Astrazeneca Ab Bilayer tablet formulations
MX2012005425A (en) 2009-11-13 2012-06-14 Astrazeneca Uk Ltd Reduced mass metformin formulations.
MX2012005365A (en) 2009-11-13 2012-05-29 Bristol Myers Squibb Co Immediate release tablet formulations.
WO2011075596A1 (en) 2009-12-18 2011-06-23 Arena Pharmaceuticals, Inc. Crystalline forms of certain 3-phenyl-pyrazole derivatives as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto
TWI562775B (en) 2010-03-02 2016-12-21 Lexicon Pharmaceuticals Inc Methods of using inhibitors of sodium-glucose cotransporters 1 and 2
US8592396B2 (en) 2010-04-14 2013-11-26 Bristol-Myers Squibb Company Glucokinase activators and methods of using same
WO2011153712A1 (en) 2010-06-12 2011-12-15 Theracos, Inc. Crystalline form of benzylbenzene sglt2 inhibitor
RU2016125229A (en) 2010-07-09 2018-12-04 БиЭйчВи ФАРМА, ИНК. COMBINED DELIVERY SYSTEM WITH IMMEDIATE / SLOW-DELIVERY FOR MEDICINES WITH A SHORT HALF-HOUR, INCLUDING REMOGLYPHLOSIN
WO2012018950A1 (en) 2010-08-03 2012-02-09 Beth Israel Deaconess Medical Center Methods and compositions for treatment of metabolic disorders
TWI631963B (en) 2011-01-05 2018-08-11 雷西肯製藥股份有限公司 Compositions comprising and methods of using inhibitors of sodium-glucose cotransporters 1 and 2
PL395470A1 (en) 2011-06-29 2013-01-07 Adamed Spólka Z Ograniczona Odpowiedzialnoscia Alicyclic amines sulfonamide derivatives for the treatment of diseases of the central nervous system
EP2925735B1 (en) 2012-11-20 2019-03-13 Lexicon Pharmaceuticals, Inc. Inhibitors of sodium glucose cotransporter 1
WO2015027021A1 (en) 2013-08-22 2015-02-26 Bristol-Myers Squibb Company Imide and acylurea derivatives as modulators of the glucocorticoid receptor
CN105764498A (en) 2013-11-20 2016-07-13 西玛贝医药公司 Treatment of homozygous familial hypercholesterolemia
BR112016018062B1 (en) 2014-02-07 2022-11-16 Exithera Pharmaceuticals Inc THERAPEUTIC COMPOUNDS, PHARMACEUTICAL COMPOSITION AND USES
US9624172B2 (en) 2014-02-17 2017-04-18 Hetero Research Foundation Polymorphs of lomitapide and its salts
US10272058B2 (en) 2014-03-20 2019-04-30 Cymabay Therapeutics, Inc. Treatment of intrahepatic cholestatic diseases
EP3119384B1 (en) 2014-03-20 2018-09-12 CymaBay Therapeutics, Inc. Treatment of intrahepatic cholestatic diseases
LT3129018T (en) 2014-04-11 2020-01-10 Cymabay Therapeutics, Inc. Treatment of nafld and nash
TW201623321A (en) 2014-05-13 2016-07-01 韓美藥品股份有限公司 Bicyclic derivatives and pharmaceutical composition including the same
WO2016012934A1 (en) 2014-07-21 2016-01-28 Mylan Laboratories Ltd Process for making lomitapide mesylate
US20160083345A1 (en) * 2014-09-19 2016-03-24 Cadila Healthcare Limited Polymorphic forms of lomitapide and its salts and processes for their preparation
EP3215490A1 (en) * 2014-11-05 2017-09-13 Hetero Research Foundation Process for the preparation of lomitapide
CN106146385A (en) * 2015-04-03 2016-11-23 天津药物研究院有限公司 A kind of synthetic method of triglyceride transfer protein enzyme inhibitor
BR102015025502B1 (en) * 2015-04-30 2022-06-21 Aegerion Pharmaceuticals, Inc Composition of lomitapide, tablet, lomitapide product, methods for analyzing a sample composition of lomitapide and for determining an amount of an impurity in a sample of the composition
WO2017098522A1 (en) * 2015-12-08 2017-06-15 Msn Laboratories Private Limited Crystalline polymorph of n-(2,2,2-trifluoroethyl-9-[4-[r4-r[[[i4'- (trifluoromethyl) [ 1,1 ' -biphenyl] -2-yl] carbonyl] amino] -1 -piperidinyl] butyl] -9h- fluorene-9-carboxamide methanesulfonate and process for preparation thereof
CN105481758A (en) * 2016-01-13 2016-04-13 天津药物研究院有限公司 Lomitapide crystal form I as well as preparation method and application thereof
CA3113037A1 (en) 2018-09-26 2020-04-02 Lexicon Pharmaceuticals, Inc. Crystalline forms of n-(1-((2-(dimethylamino)ethyl)amino)-2-methyl-1-oopropan-2-yl)-4-(4-(2-methyl-5-(2s,3r,4r,5s,6r)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2h-pyran-2-yl)benzyl)phenl)butanamide and methods of their synthesis
CN111187200A (en) * 2020-04-09 2020-05-22 南京昊绿生物科技有限公司 Synthesis method of lomitapide-D8

Family Cites Families (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1404868A (en) * 1972-12-21 1975-09-03 Wyeth John & Brother Ltd Pyridine tetrahydropyridine and piperidine derivatives
US3910931A (en) * 1970-09-03 1975-10-07 Wyeth John & Brother Ltd 1-(Naphthylalkyl- or indenylalkyl)-piperidines
GB1425578A (en) * 1972-10-21 1976-02-18 Wyeth John & Brother Ltd Piperidine derivatives
US4053615A (en) * 1972-10-21 1977-10-11 John Wyeth & Brother Limited Phthalimidopiperidines and anti-convulsant compositions thereof
US4000287A (en) * 1974-12-16 1976-12-28 Ciba-Geigy Corporation Isoindolinopiperidines
CH605914A5 (en) * 1974-07-31 1978-10-13 Ciba Geigy Ag
GB1586468A (en) * 1976-10-29 1981-03-18 Anphar Sa Piperidine derivatives
GB1574418A (en) * 1976-11-16 1980-09-03 Anphar Sa Piperidine derivatives
US4291042A (en) * 1979-01-26 1981-09-22 John Wyeth & Brother Limited Antidepressant piperidine derivatives
MA18763A1 (en) * 1979-03-12 1980-10-01 Lilly Co Eli PROCESS FOR THE PREPARATION OF 9-AMINOALKYLFLUORENES
SE7907121L (en) * 1979-08-27 1981-02-28 Astra Laekemedel Ab FTALIMIDINDERIVAT
GB2061932B (en) * 1979-11-01 1983-07-13 Wyeth John & Brother Ltd Piperidine derivatives
PL135545B1 (en) * 1980-03-01 1985-11-30 Wyeth John & Brother Ltd Process for preparing novel derivatives of piperidine
JPS6084281A (en) * 1983-09-14 1985-05-13 Yoshitomi Pharmaceut Ind Ltd 3-indolecarboxamide
JPS60142981A (en) * 1983-12-28 1985-07-29 Yoshitomi Pharmaceut Ind Ltd 3-indolecarboxamide derivative
GB8406089D0 (en) * 1984-03-08 1984-04-11 Wyeth John & Brother Ltd Treatment/prevention of atherosclerotic disorders &c
GB8615560D0 (en) * 1986-06-25 1986-07-30 Maggioni Farma Aminoalcohols
DE3600390A1 (en) * 1986-01-09 1987-07-16 Hoechst Ag DIARYLALKYL-SUBSTITUTED ALKYLAMINE, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND MEDICINAL PRODUCTS CONTAINING THE SAME
US5053413A (en) * 1989-09-05 1991-10-01 G. D. Searle & Co. N-benzylpiperidineisoindolinones
US5028616A (en) * 1989-09-05 1991-07-02 G. D. Searle & Co. N-benzylpiperidine amides
US5098915A (en) * 1989-09-05 1992-03-24 G. D. Searle & Co. Substituted N-benzylpiperidine amides
US5356906A (en) * 1989-10-27 1994-10-18 The Du Pont Merck Pharmaceutical Company (N-phthalimidoalkyl) piperidines useful as treatments for psychosis
US5032598A (en) * 1989-12-08 1991-07-16 Merck & Co., Inc. Nitrogens containing heterocyclic compounds as class III antiarrhythmic agents
US5215989A (en) * 1989-12-08 1993-06-01 Merck & Co., Inc. Nitrogen-containing heterocyclic compounds as class III antiarrhythmic agents
GB9005014D0 (en) * 1990-03-06 1990-05-02 Janssen Pharmaceutica Nv N.(4.piperidinyl)(dihydrobenzofuran or dihydro.2h.benzopyran)carboxamide derivatives
FR2662162B1 (en) * 1990-05-18 1995-01-20 Adir NOVEL DERIVATIVES OF AMINO PIPERIDINE, AMINO PYRROLIDINE AND AMINO PERHYDROAZEPINE, PROCESSES FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
US5229517A (en) * 1990-09-27 1993-07-20 Hoechst-Roussel Pharmaceuticals Incorporated 2-(4-Piperindinyl)-1H-pyrido[4,3-B]indol-1-ones and related compounds
US5212182A (en) * 1990-10-03 1993-05-18 American Home Products Corpooration Substituted quinolinyl- and naphthalenylbenzamides or benzylamines and related compounds useful as analgesics
US5130333A (en) * 1990-10-19 1992-07-14 E. R. Squibb & Sons, Inc. Method for treating type II diabetes employing a cholesterol lowering drug
FR2679906B1 (en) * 1991-07-31 1995-01-20 Adir NOVELS (ISOQUINOLEIN-5 YL) SULFONAMIDES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
US5527801A (en) * 1991-09-24 1996-06-18 Dainippon Pharmaceutical Co., Ltd. Ameliorant for blood lipid metabolism
CA2091102C (en) * 1992-03-06 2009-05-26 John R. Ii Wetterau Microsomal triglyceride transfer protein
US5595872A (en) * 1992-03-06 1997-01-21 Bristol-Myers Squibb Company Nucleic acids encoding microsomal trigyceride transfer protein
US5578611A (en) * 1992-11-13 1996-11-26 Synaptic Pharmaceutical Corporation Use of α-1C specific compounds to treat benign prostatic hyperplasia
US5571832A (en) * 1992-11-13 1996-11-05 The United States Of America As Represented By The Department Of Health And Human Services Nitrogen-containing cyclohetero alkylamino aryl derivatives for CNS disorders
WO1994022826A1 (en) * 1993-04-07 1994-10-13 Otsuka Pharmaceutical Co., Ltd. Peripheral vasodilating agent containing n-acylated 4-amino piperidine derivatives as active ingredients
EP0832069B1 (en) * 1995-06-07 2003-03-05 Pfizer Inc. BIPHENYL-2-CARBOXYLIC ACID-TETRAHYDRO-ISOQUINOLIN-6-YL AMIDE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS INHIBITORS OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN AND/OR APOLIPOPROTEIN B (Apo B) SECRETION

Also Published As

Publication number Publication date
NO973821L (en) 1997-08-20
KR19980703598A (en) 1998-12-05
FI973416A0 (en) 1997-08-20
NZ302055A (en) 2000-02-28
CN1176640A (en) 1998-03-18
EP0886637A4 (en) 1998-12-30
IL116917A0 (en) 1996-05-14
TW486469B (en) 2002-05-11
SK113597A3 (en) 1998-09-09
US5883099A (en) 1999-03-16
EP0886637A1 (en) 1998-12-30
LV11951B (en) 1998-11-20
ES2233961T3 (en) 2005-06-16
CZ261797A3 (en) 1998-01-14
US5712279A (en) 1998-01-27
NO973821D0 (en) 1997-08-20
FI973416A (en) 1997-08-20
US5739135A (en) 1998-04-14
CN1108301C (en) 2003-05-14
WO1996026205A1 (en) 1996-08-29
AR001795A1 (en) 1997-12-10
AU4763196A (en) 1996-09-11
EE9700182A (en) 1998-02-16
US6066650A (en) 2000-05-23
HUP9801278A2 (en) 1999-06-28
PL322003A1 (en) 1998-01-05
BG101717A (en) 1998-02-27
EP0886637B9 (en) 2005-05-04
HUP9801278A3 (en) 2001-12-28
CA2213466A1 (en) 1996-08-29
ATE283851T1 (en) 2004-12-15
AU699865B2 (en) 1998-12-17
UY24165A1 (en) 2001-07-31
JPH11500442A (en) 1999-01-12
JP4036244B2 (en) 2008-01-23
EP0886637B1 (en) 2004-12-01
LV11951A (en) 1998-01-20
MX9705005A (en) 1998-07-31
GEP20001916B (en) 2000-01-05
DE69633983D1 (en) 2005-01-05
US6034098A (en) 2000-03-07
IL116917A (en) 2000-08-31
PL185443B1 (en) 2003-05-30
DE69633983T2 (en) 2005-12-22

Similar Documents

Publication Publication Date Title
CA2213466C (en) Inhibitors of microsomal triglyceride transfer protein and method
US6472414B1 (en) Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method
AU716729B2 (en) Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method
AU2007212236B2 (en) Piperidinyl derivatives as modulators of chemokine receptor activity
NZ264372A (en) N-(piperidin-4-yl)isoindolone and-1-oxoquinoline, n-(piperdin-4-yl)carboxamide and n-(piperazinyl)(alkyl or carbonyl)-1-oxo-tetrahydronaphthalene derivatives; pharmaceutical compositions
US5885983A (en) Inhibitors of microsomal triglyceride transfer protein and method
CA2341678C (en) Potassium channel inhibitors and method
WO1997043257A1 (en) Inhibitors of microsomal triglyceride transfer protein and method
WO2004037817A1 (en) N-oxide compounds
CA2730793A1 (en) Azole compound
UA60368C2 (en) Fkbp inhibitors
CA3034108A1 (en) Cxcr3 receptor agonists
LT4367B (en) Inhibitors of microsomal tryglyceride transfer protein and method
KR19990077338A (en) Morphologically restricted aromatic inhibitors and methods of microsomal triglyceride transport proteins
CZ2001236A3 (en) Heterocyclic compounds functioning as rotamase inhibitors

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry

Effective date: 20160201

MKEX Expiry

Effective date: 20160201