CA2346933A1 - N-ureidoalkyl-piperidines as modulators of chemokine receptor activity - Google Patents

N-ureidoalkyl-piperidines as modulators of chemokine receptor activity Download PDF

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CA2346933A1
CA2346933A1 CA002346933A CA2346933A CA2346933A1 CA 2346933 A1 CA2346933 A1 CA 2346933A1 CA 002346933 A CA002346933 A CA 002346933A CA 2346933 A CA2346933 A CA 2346933A CA 2346933 A1 CA2346933 A1 CA 2346933A1
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alkyl
occurrence
substituted
cycloalkyl
phenyl
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Daniel S. Gardner
George V. Delucca
John V. Duncia
Soo S. Ko
Joseph B. Santella, Iii
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Bristol Myers Squibb Pharma Co
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring 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
    • C07D401/06—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
    • 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
    • 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
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Abstract

The present application describes modulators of CCR3 of formula (I) or pharmaceutical acceptable salt forms thereof, useful for the prevention of asthma and other allergic diseases.

Description

DEMANDES OU BREVETS VOLUMlNEUX
L.~4 PRESENTS PARTIE DE CETTE DEMANDS OU CE BREVET
COMPAEND PLUS D'UN TOME.
CECt EST LE TOME ~ DE
NOTE. Pour les tomes additionels, veuiilez contacter le Bureau canadien des brevets Tl~ ilS SECTION OF THE APPLICATIONIPATENT CONTAINS MORE
T1HAN ONE VOLUME , , . THIS !S VOLI~ME ~ ~_ OI= 2_ PdOTE: For additional volumes-plE,ase.contact the Canadian Patent Office TITLE
N-UREIDOALKYL-PIPERIDINES AS MODULATORS OF CHEMOKINE
RECEPTOR ACTIVITY
S FIELD OF THE INVENTION
This invention rel,~tes generally to modulators of chemokine receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of inflammatcry diseases such as asthma and allergic diseases, as well as autoimmune pathologies ::>uch as rheumatoid arthritis and atherosclerosi:~.
BACKGROT.JIsTD OF THE INVENTION
Chemokines are chemotactic cytokines, of molecular weight 6-25 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in Luster, New ~ng. ~ Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)).
There are two major cla~~s~e~; of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The C;~C chemokines, such as interleukin-8 (IL-8), neuv~rophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T
lymphocytes, whereas the CC chemokines, such as RANTES, MIP-loC, MIP-1~, the monocvte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and. MCP-5) and the eotaxins (-1,-2, and -3) are chemotactic for, among other cell types, :macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotact:in-2 (both C chemokines), and fractalkine (a CXX.XC chemokine) that do not fall into .either of the major chemol~:ine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed "chemokine receptors." On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC
chemokines with the following characteristic patterns: CCR-1 (or "CKR-1" or "CC-CKR-1") [MIP-la, MCP-3, MCP-4, RANTES]
(Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or "CKR-2A"/"CKR-2B" or "CC-CKR-2A"/"CC-CKR-2B") [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad.
Sci. USA, 91, 2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3 (or "CKR-3" or "CC-CKR-3") [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4J (Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or "CKR-4"
or "CC-CKR-4") [TARC, MIP-la, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270, 19495-19500 (1995), Luster, New Eng.
J. Med., 338, 436-445 (1998)); CCR-5 (or "CKR-5" OR "CC-CKR-5") [MIP-1a, RANTES, MIP-1(3] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or "CKR-6" or "CC-CKR-6") [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898 (1997)); CCR-7 (or "CKR-7" or "CC-CKR-7") [ELC]
(Yoshie et al., J. Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or "CKR-8" or "CC-CKR-8") [I-309, TARO, MIP-1~3J
(Napolitano et al., J. Immunol., 157, 2759-2763 (1996), .
Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998));
and CCR-10 (or "CKR-10" or "CC-CKR-10") [MCP-1, MCP-3]
(Bonini et al, DNA and Cell Biol., 16, 1249-1256 (1997)).

In addition to the mammalian chemokine receptors, mammalian cytomegaloviru;~es, herpesviruses and poxviruses have been shown to expre=ss, in infected cells, proteins with the binding properties of chemokine receptors (reviewed by Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748 (1997)). Human C'C chemokines, such as RANTES and MCP-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection. Additionally, human chemokine receptors, such as CXCR4, CCR2, CCR3, CCRS and CCR8, can act as co-receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV) .
Chemokine receptors :have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorder, and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation and in subsequently activating these cells. The chemokine ligands for CCR-3 induce a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, ce:Llu7_ar degranulation, and the promotion of eosinophil migration. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. I:n addition, agents which modulate ~hemokine receptors would also be useful in infectious diseases such as by blocking infection of CCR3 expressing ~~ells by HIV or in preventing the manipulation of immune ~~ellular responses by viruses such as cytomegaloviruses.
A substantial body of art has accumulated over the . 35 past several decades with respect to substituted piperidines and pyrrolidines. These compounds have :implicated in the treatment of a variety of disorders.
4 describes spiro-substituted azacycles which are useful as modulators of chemokine receptors:
RS ('C H?Jm R N
(C H2)i R (C N~k wherein R1 is C1-6 alkyl, optionally substituted with functional groups such as -NR6CONHR~, wherein R6 and R~ may be phenyl further substituted with hydroxy, alkyl, cyano, halo and haloalkyl. Such spiro compounds are not considered part of the present invention.
WO 95/13069 is directed to certain piperidine, pyrrolidine, and hexahydro-1H-azepine compounds of general formula:
H

R1--~-NHC O-A-f~
=O R5 N W
X
(CH2~

wherein A may be substituted alkyl or Z-substituted alkyl, with Z=NR6a or O. Compounds of this type are claimed to promote the release of growth hormone in humans and animals.
WO 93/06108 discloses pyrrolobenzoxazine derivatives as 5-hydroxytryptamine (5-HT) agonists and antagonists:
R5 ~-N

y Rs CONH-(A)~ R4 wherein A is lower alkylene and R4 may be phenyl optionally substituted with halogen.

U.S. Pat. No. 5,66$,251 discloses Neuropeptide Y (NPY) antagonists comprising 1,4-dihydropyridines with a piperidinyl or tetrahydropyridinyl-containing moiety attached to the 3-position of the 4-phenyl ring:

. HN \ Ra R~
R2 \ / NHCO-B-(CH~~ N\ X 6 .~J ~w R~02C \ I~ R
Rs wherein B may be NH, NR1, 0, or a bond, and R? may be substituted phenyl, benzyl, phenethyl and the like.
These reference compounds are readily distinguished structurally by either the nature of the urea functionality, the attacrunent chain, or the possible substitution of the present invention. The prior art does not disclose nor suggest the unique combination of structural fragments which embody these novel piperidines and pyrrolidines as having activity toward the chemokine receptors.
SUMMARY.' OF THE INVENTION
Accordingly, one object of the present invention is to provide novel agonists or antagonists of CCR-3, or pharmaceutically acceptable salts or prodrugs thereof.
It is another objects of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at lf~ast one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory diseases and allergic disorders comprising administering to a host in . need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel N-ureidoal:kyl-piperidines for use in therapy It is another object of the present invention to provide the use of novel N-ureidoalkyl-piperidines for the manufacture of a medicament for the treatment of allergic disorders.
In another embodiment, the present invention provides novel N-ureidoalkyl-piperidines for use in therapy.
In another embodiment, the present invention provides the use of novel N-ureidoalkyl-piperidines for the manufacture of a medicame=nt for the treatment of allergic disorders.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):
-iV~-R3 i 2 0 L-(~ R~ R2 (I) or stereoisomers or pharir~aceutically acceptable salts thereof, wherein E, Z, M, J, K, L, Q, Rl, R', R3, and R4 are defined below, are effective modulators of chemokine activity.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[1] Thus, in a first embodimenr_, the present invention provides novel compounds of formula (I):
n 4 hi 1~ ~E-N~-R
L-C~ R ~ R2 (I) or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
M is absent or selected from CH2, CHRS, CHR13, CR13R13, and CRSR13 ;
Q is selected from CHR~3, CR13R13 and CR5R13;
J, K, and L are independently selected from CH2, CHRS, CHR6, CR6R6 and CR5R6;
with the provisos:
1) at least one of M, J, K, L, or Q contains an R5;
and 2) when M is absent, J is selected from CH2, CHRS, CHR13 , and CR5RI3 ;
Z is selected from O, >, NRla, CHCN, CHN02, and C(CN)2;
Rla is selected from H, C1_6 alkyl, C3-6 cycloalkyl, CONRIbRib ORib NOz, CN, and(CH2)wphenyl;
Rlb is independently selE_cted from H, C1_3 alkyl, C3_6 cycloalkyl, and phenyl;
E is -(CR~Rg)-(CR9Rlo)~--(CR~1R12)_;
R1 and R2 are independent=ly selected from H, C1-8 alkyl, C2_a alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl, and a (CH2)r-C3-1o carbocyclic residue substituted with 0-5 Ra;
Ra, at each occurrence, is selected from C1_4 alkyl, C2_g alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl, C1, Br, I, F, (CF2)rCF3, N02, C'N, (CH2)rNRbRb, (CH2)rOH, (CH2)rOR~, ( CH2 ) rSH , ( CH2 ) rSR~= , ( CH2 ) rC ( O ) Rb ( CH2 ) rC ( 0 ) NRbRb, ( CHZ ) rNRbC: ( O ) Rb, ( CH:2 ) rC ( O ) ORS', ( CH2 ) rOC ( O ) Rc , ( CH2 ) rCH ( ==NRb ) NRbRb, ( CH2 ) rNHC ( =NRb ) NRbRb, ( CH2 ) rS ( O ) pRc , (CH2)rS(0;2NRbRb, (CH2)rNRbS(0)2Rc, and (CH2)rphenyl;
Rb, at each occurrence, is selected from H, C1_6 alkyl, C3-6 cycloalkyl, and phenyl;
Rc, at each occurrence, is selected from Cy-6 alkyl, C3-6 cycloalky:l, and phenyl;
alternatively, R2 and R3 join to form a 5, 6, or 7-membered ring subs~ituted with 0-3 Ra;
R3 is selected from a (CR3'R3")r-C3-to carbocyclic residue substituted with 0--5~ R1' and a (CR3'R3") r-5-10 membered heterocyc:lic system containing 1-4 heteroatoms selected :from N, O, and S, substituted with 0-3 R15;
R3' and R3", at each occui:rence, are selected from H, C1_s alkyl, (CH2)rC3-6 cYcloalkyl, and phenyl;
R4 is absent, taken with the nitrogen to which it is attached too form an N-oxide, or selected from C1_8 alkyl, C2-8 alkenyl, C2_~ alkynyl, (CH2)rC3-6 cycloalky:L, (CH2 ) qC (O) R4b, (CHZ ) qC (0) NR4aR4a~ , (CHZ) qC (O) OR4b, and a (CHZ ) r-C3_lo carbocyclic residue substituted with 0-3 R4c;
R4a and R4a' , at each occurrence, are selected from H, C1_6 alkyl, (CFi2)rC3-5 cYcloalkyl, and phenyl;
R4b, at each occurrence, is selected from C1_6 alkyl, C2_8 alkenyl, ~;CHZ)rC3-5 c'Ycloalkyl, C2_g alkynyl, and phenyl;
R9c, at each occurrence, :is selected from C1-6 alkyl, C2_g alkenyl, C:2_8 alkyny:L, C3_6 cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CHZ)rOC1_5 alkyl, (CH2)rOH, (CHz)rSCl_5 alkyl, (CHZ)rNR4aR4a' and (CH2)rphenyl;
alternatively, R4 joins with R~, R5, or R1I to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle substituted with 0-3 Ra;
R5 is selected from a (C1~5'RS" ) t-C3-1o carbocyclic residue substituted with 0-5 R16 and a (CRS'RS")t-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, C), and S, substituted with 0-3 R16;
RS' and R5", at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R6, at each occurrence, .is selected from C1_6 alkyl, C2_g alkenyl, C2_8 alkyny7., (CH2)rC3-6 cYcloalkyl, (CF2)rCF3, CN, (CH2)rNR6aR6a'. (CH2)rOH, (CH2)rOR6b, (CH2)rSH, (CH2)rSR6D, (CH2)rC(0)OH, (CH2)rC(O)R6b, (CH2)rC(O)NR6aR6a', (CH2)rNR6dC(O)R6a (CH2)rC(O)OR6b, (CH2)rOC(0)R6b, (CH2)rS(O)pR6b (CH2)rS(0)2NR6aR6a'.
(CH2)rNR6dS(O)2R6b, and (CH2)tphenyl substituted with 0-3 R6c;
R6a and R6a' , at each occurrence, are selected from H, C, _6 alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6b, at each occurrence, is selected from Cz_~ alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is selected from C1_5 alkyl, C3-6 cycloalkyl, C1, F, ~3r, I, CN, N02, (CFZ)rCF3, (CHZ)rOCl_ 5 alkyl, (CH2)rOH, (~~H2)rSCl_5 alkyl, and (CH2)rNR6dR6d;

R6d, at each occurrence, is selected from H, C1_6 alkyl, and C3-6 cycloalkyl;
with the proviso that when any of J, K, or L is CR6R6 and R6 is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, the other R6 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R~, is selected from H, C1_6 alkyl, CZ_g alkenyl, C2_ alkynyl, (CH2}qOH, (CH2)qSH, (CH2)qOR~d, (CHZ)qSR~d, (CH2)qNR~aR7a', (CH2)rC(O)OH, (CH2)rC(O)R7b (CH2)rC(O)NR~aR7a', (CH2)qNR~aC(O)R7a, (CH2)~NR~aC(0)H, ( CH2 ) rC ( O ) OR~b , ( CHZ ) qOC ( O ) Rib , ( CH2 ) qS ( O ) pR~ b , (CH2)qS(O)zNR~aR7a', (CH2}qNR~aS(O)2R7b, C1_6 haloalkyl, a (CH2)r-C3-to carbocyclic residue substituted with 0-3 R~~, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 R~~;
Rya and Rya', at each occurrence, are selected from H, C1 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2)r-C3-to carbocyclic residue substituted with 0-5 Rye, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rye;
Rib, at each occurrence, is selected from Cl_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2)r-C3-s carbocyclic residue substituted with 0-2 Rye, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 Rye;
R~~, at each occurrence, is selected from C1_6 alkyl, C2_a alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl, C1, Br, I, F, (CF2)rCF3, N02, CN, (CHZ)rNR~fR7f, (CH2)rOH, (CH2)rOCl_4 alkyl, (CH2)rSCl_4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R7b (CH~)rC(O)NR~fR7f, (CH2)rNR~fC(0)R7a (CHZ ) rC (O) OC1_4 alkyl, (CH2 ) rOC (O) Rib, ( CHZ ) rC ( =NR~ f ) NR~ f R7 f ~ ( CH2 ) rS ( O ) pR7b (CH2)rNHC(=NR~f)NR';~fr~7f~ (CH2)rS(0)2NR~fR7f~
(CH2)rNR~fS(O)2R~b, and (CH2)rphenyl substituted with 0-3 Rye;
Rid, at each occurrence, is selected from C~_~ alkyl substituted with CD-3 Rye, alkenyl, alkynyl, and a C3_1o carbocyclic residue substituted with 0-3 R~~;
Rye, at each occurrence, is selected from C1_b alkyl, C2_g alkenyl, C2_g alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2}rCF3, (CH4)rOC1_5 alkyl, OH, SH, (CH2)rSCl_ ~ alkyl, (CH2)rNR~fR~-', and (CH2)rphenyl;
Ref, at each occurrence, is selected from H, C1-6 alkyl, and C3_6 cycloalkyl;
R8 is selected from H, C_~_6 alkyl, C3__6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 RBa;
R8a, at each occurrence, is selected from C1_~ alkyl, C2_8 alkenyl, C2_a alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CFZ)rCF3, (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_ alkyl , ( CH2 ) rNR~ f R'7 f and ( CH2 ) rphenyl ;
alternatively, R~ and R8 join to form C3_~ cycloalkyl, or -NR$b;
R8b is selected from H, C_'~-5 alkyl, C3_6 cycloalkyl, OH, CN, and (CH2)r-phenyl;
R9, is selected from H, C_Z_s alkyl, C2_8 alkenyl, C2_a alkynyl, F, C1, Br, I, N02, CN, (CH2)rOH, (CH2)rSH, (CH2 ) rOR93, (CH2 ) rSR'.3d~ (CH2 ) rNR~aR9a' , (CH2 ) rC (0) OH, (CH2)rC(O)R9b, (CH;r)rC(0)NR9aR9a', (CH2)rNR9aC(O)R9a (CH2)rNR9aC(O)H, (CH2)rNR9aC(O)NHR9a, (CH2)rC(O)OR9b, (CH2)rOC(0)R9b (CH2)rOC(O)NHR9a, (CH2)rS(O)pR9b, (CH2)rS(0)zNR9aR9a', (CH2)rNR9aS(0)ZR9b, C1_6 haloalkyl, a (CH2)r-C3-1o carbocyclic residue substituted with 0-5 R9~, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9~;
R9a and R9a', at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2_8 alkynyl, a (CH2)r-C3-1o carbocyclic residue substituted with 0-5 R9e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 R9e;
R9b, at each occurrence, is selected from C1-6 alkyl, C2_g alkenyl, C2_8 alkynyl, a (CH2)r-C3-5 carbocyclic residue substituted with 0-2 R9e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
R9~, at each occurrence, is selected from C1_6 alkyl, C2_a alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl, C1, Br, I, F, (CF2)rCF3, N02, CN, (CH2)rNR9fR9f (CH2)rOH, (CH2)rOCl_4 alkyl, (CH2)rSCl-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R9b (CH2)rC(0)NR9fR9f (CH2)rNR9fC(O)R9a (CH2)rC(O)OC1_4 alkyl, (CHZ)rOC(O)R9b, (CH2 ) rC (=NR9f ) NR9fR9f (CH2 ) rS (0) pR9b (CH2)rNHC(=NR9f)NR9fR9f (CH2)rS(O)2NR9fR9f~
(CH2)rNR9fS(0)ZR9b, and (CH2)rphenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1_6 alkyl, C2-5 alkenyl, C2-6 alkynyl, a C3-to carbocyclic residue substituted with 0-3 R9~, and a S-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R9c;
_ R9e, at each occurrence, is selected from C1_6 alkyl, C2-8 alkenyl, C2_8 a7_kynyl, (CH2)rC3-5 cYcloalkyl, C1, F, Br, I, CN, N02, (CF~)rCF3, (CHZ)rOC1_5 alkyl, OH, SH, (CH2)rSC1_S alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl;
R9f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
Rlo, is selected fronn H, C1_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, F, C1, Br, I, NO?, CN, (CH2)rOH, (CH2)rORlOd~
( CH2 ) rSRlOd ( C_'H2 ) r.NR10aR10a' , ( CHZ ) rC ( O ) OH, ( CH2 ) rC ( 0 ) RlOb r ( CH2 ) rC ( O ) NR1 OaRlOa' ~ ( CHZ ) rNRlOaC ( O ) RlOa (CH2)rNRlOaC(O)H, (CH2)rC(O)ORlOb (CH2)rOC(O)RlOb ( CH2 ) rS ( O ) pRlOb ( CH2 ) rS ( O ) 2NR10aR10a' (CH2) rNRloaS (O) Z,Rlob, C1-6 haloalkyl, a (CH2) r-C3-10 carbocyclic residue substituted with 0-5 Rloc, and a (CHZ)r-5-10 mernbered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rloc;
Rloa and Rloa' , at each occurrence, are selected from H, C1_6 alkyl, C2_8 alkenyl, C2_g alkynyl, a (CH2)r-C3-10 carbacyclic residue substituted with 0-5 Rloe, and a (CHZ)r-5-10 membered heterocyclic system containing 1-4 heteroatoms sel~scted from N, O, and S, substituted with 0-3 RlOe;
Rlob at each occurrence, is selected from C1_6 alkyl, C2_g alkenyl, C2_g alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 Rloe, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rloe;

WO 00/35449 PCf/US99/30292 F;loc~ at each occurrence, .is selected from C1_6 alkyl, C2_8 alkenyl, C~>_g alkynyl, (CHZ) rC3-6 cycloalkyl, C1, Br, I, F, (CF2)rCF'3, N02, CN, (CH2)rNRl~'fRlOf~ (CH2)rOH, (CH2)rOCl-4 alkyl, (CH2)rSCl_4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)RlOb~ (CH2)rC(0)NR10fR10f, (CH2)rNRlOfC(0)RlOa~
(CH2)rC(O)OC1_q alkyl, (CH2)i.OC(O)Rlob~
(CH2)rC(=NRlOf)~lOfRlOf~ (CH~,)rS(0)pRlOb~
(CH2 ) rNHC (=NRlOf ) NRlOf~~lOf (CH2 } rS (O) 2NR10fR10f (CHZ ) rNRlOf;~ (0) 2R10b~ ~~nd (CHa ) rphenyl substituted with 0-3 RlOe;
Rlod, at each oc~~urrence, is selected from C1_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, a C3-1.o carbocyclic residue substituteoi with 0-3 Rloc, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, 0, and S
substituted. with 0-3 Bloc;
R:loe~ at each occurrence, i.s selected from C1_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2)rC3-s cYcloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCl_~ alkyl, OH, SH, (CH2)rSCl_5 alkyl, (CHO)rNRlOfRlOf and (CH2)rphenyl;
R:LOf ~ at each occurrence, is seler_ted from H, C1-6 alkyl, and C3_6 cycloalkyl;
a:Lternatively, R9 and R10 join to form C3_~ cycloalkyl, 5-6-membered cyclic ketal" or =O;
wuth the proviso that when Rlo is halogen, cyano, nitro, or bonded to t:he carbon too which it is attached through d heteroatom, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R11, is selected from H, C1_~ alkyl, C2_g alkenyl, C2_8 alkynyl , (Cl~z ) qOH, (CH2 ) qSH, (CH2 ) qORlld (CH2 ) qSRlld, (CHZ}qNR11aR11a'~ (CH2)rC(0)OH, (CH2)rC(O)Rllb ( CHz ) rC ( O ) NRilaRl la" ( CH2 ) qNRllaC ( O ) Rlla (CH2)qNRllaC(0)NHRlla~ (CH2)rC(0)ORllb (CHZ)qOC(O)Rllb (CH2)qS(O)pRllb, (CH;~)qS(0)2NR11aR11a' (CH2)qNRllaS(O)2Rllb C1-6 haloalkyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 Rllc, and a (CH2)r-5-10 memberec~ heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 Rllc;
Rlla and Rlla', at each occurrence, are selected from H, C1-s alkyl, Cz_g alkenyl, C2_g alkynyl, a (CH2)r-C3-to carbocyclic residue substituted with 0-5 Rlle, and a (CH2)r-5-10 memberec) heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 Rlle;
Rllb~ at each occurrence, is selected from C1_6 alkyl, C2_g alkenyl, C2_g alkynyl, a (CH2)r-C3-s carbocyclic residue substituted with G-:2 Rlle and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Riles Rllc~ at each occurrence, is selected from C1_6 alkyl, C2_8 alkenyl, Cz_8 alkynyl, (CH2)rCz_6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3% NO?, CN, (CH2)rNRllfRllf (CH2)rOH, (CH2)rOCl._4 alkyl, (CH~)rSCI_4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)Rllb (CHZ)rC(O)NRllfRllf~ (CH2)rNRllfC(O)Rlla (CH2)rC(O)OC1_q alkyl, (CH2)rOC(O)Rllb (CH2)rC(=NRllf)NRIIfFZIlf (CH2)rNHC(=NRllf)NRllfRllf (CH2 ) rS ,(O) pRllb (C,HZ ) rS (0) 2NR11fRllf (CH2)rNRllfS(0)2Rllb and (CH2)rphenyl substituted with 0-3 Rlle Rlld, at each occurrence, is selected from C1_6 alkyl substituted with 0-3 Rlle, C2_e alkenyl, CZ_6 alkynyl, and a C3-to carbocyclic residue substituted with 0-3 Rllc.

Rlle, at each occurrence, is selected from C1_6 alkyl, Cz_g alkenyl, Cz_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, NOz, (CFZ)rCF3, (CHZ)rOCI_5 alkyl, OH, SH, (CHZ)rSCl_ 5 alkyl, (CHz)rNRIIfRW f, and (CHZ)rphenyl;
Rlif, at each occurrence, is selected from H, C1_6 alkyl, and C3_6 cycloalkyl;
R1z is selected from H, C~_6 alkyl, (CHZ)qOH, (CH2)rC3-6 cycloalkyl, and (CHz)tphenyl substituted with 0-3 Rl2a;
Rlza~ at each occurrence, is selected from C1_6 alkyl, C2_g alkenyl, Cz_8 alkynyl, C3_6 cycloalkyl, C1, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_ 5 alkyl, (CHz)rNR9fR9f, and (CHZ)rphenyl;
alternatively, R11 and R1z join to form C3_~ cycloalkyl;
R13, at each occurrence, is selec'~-~ from (CHR"°) OH, ( CHRl3a ) ORl3b ! C:ri;;m~ ) SH , (CHRlsa) SRl3b, (CHRl3a)NR1%eC (p) ~t='F, and (CHRl3a)NRl3eS (O) 2R13f;
Rl3a is selected from C1_~ alkyl;
Rl3b, at each occurrence, is selected from C(O)RI3d, C(O)NHRl3d Cl_E alkyl, C3_6 cycloalkyl, and phenyl 13c.
substituted with 0-3 R
Rl3c, at each occurrence, is selected from C1_6 alkyl, Cz-g alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I, CN, NOZ, (CFZ)rCF3, (CHz)rOCl_5 alkyl, OH, SH, (CHZ)rSCl_ 5 alkyl, (CHZ)rNR9fR9f, and (CHZ)rphenyl;
Rl3a, at each occurrence, is selected from C1_6 alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3 R6c;

Ri3e, at each occurrence, is selected from H, C1_6 alkyl, (CH2)rC3-5 cyc:loalkyl, and phenyl where phenyl is substituted from G-3 R13~
Rl3f, at each occurrence, is selected from C1_s alkyl, (CH2)rC3-5 cycloalkyl, CF3, and phenyl where phenyl is substituted from 0-3 Rl3c R15, at each occurrence, :is independently selected from C1_g alkyl, (CH2)rC3-s cycl.oalkyl, C1, Br, I, F, N02, CN, ( CHR' ) rNRl 5aR15a' , ( C~iR' ) rOH, ( CHR' ) r.0 ( CHR' ) rRlSd, (CHR')rSH, (CHR')rC(0)H, (CHR')xS(CHR~)rRlSd, (CHR')rC(O)OH, (CHR')rC(O)(CHR')rRlSb, (CHR' ) rC (0)NR15aR15a' , (CHR' ) rNRlSfC (O) (CHR' ) rRlSb, (CHR' ) rNRlSfC (0) NRlSfFt~iSf, (CHR' ) rC (O) O (CHR' ) rRlSd, ( CHR' ) rOC (O) (CHR' ) ~RlSb, (CHR' ) rC (=NRlSf ) NR15aR15a' , (CHR' ) rNHC (=NRlSf ) NRlSfRlsf, (CHR' ) rS (O) p (CHR' ) rRlSb, (CHR' ) rS (O) 2NR15aR15a' ~ (CHR' ) rNRl5fS (O) 2 (CHR' ) rRlSb, C1-6 haloalkyl, C2_g alkenyl substituted with 0-3 R', C2_s alkynyl substituted with 0-3 R', (CHR')rphenyl substituted with 0-3 R,lse, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 RlSe.
R', at each occurrence, i;~ selected from H, C1_6 alkyl, C2-g alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with RlSe;
RlSa and RlSa', at each occurrence, are selected from H, C1_6 alkyl, C2_g alkenyl, C2_g alkynyl, a (CH2)r-C3-to carbocyclic residue ssubstituted with 0-5 Rl5e, and a (CH2)r-5-10 rnembered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 RlSe Rlsb at each occurrence, is selected from C1_6 alkyl, C2_8 alkenyl, C2_g alkynyl, a (CH2)Y-C3_6 carbocyclic residue substituted with 0-3 Rlse, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 RlSe;
Risd~ at each occurrence, is selected from CZ_8 alkenyl, C2_8 alkynyl, C1_6 alkyl substituted with 0-3 RlSe, a (CH2)r-C3-to carbocyclic residue substituted with 0-3 RlSe~ and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rlse_ Rise at each occurrence, is selected from C1_6 alkyl, C2_g alkenyl, C2_8 alkynyl, (CH2)rC3-6 cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)YOC1_5 alkyl, OH, SH, (CH2)rSCl_s alkyl, (CH2)rNRlSfRlsf and (CHZ)rphenyl;
Rlsf, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R16, at each occurrence, is selected from C1_g alkyl, CZ_g alkenyl, C2_g alkynyl, (CHz)rC3-6 cycloalkyl, Cl, Br, I, F, N02, CN, (CHR')rNR16aR16a' (CHR')rOH, (CHR')r0(CHR')rRl6d (CHR')rSH, (CHR')rC(O)H, (CHR')rS(CHR')rRl6d (CHR')rC(O}OH, ( CHR' ) rC ( 0 ) ( CHR' ) rRl6b , ( CHR' ) y C ( O ) NR16aR16a' (CHR')rNRl6fC(O)(CHR')rRl6b (CHR')rC(0)0(CHR')rRl6d ( CHR' ) rOC ( O ) ( CHR' ) rRl 6b , ( CHR' ) rC ( =NR16 f ) NR16aR16a' (CHR')rNHC(=NRl6f}NR16fR16f (CHR')rS(0)D(CHR')rRl6b (CHR')rS(O)2NR16aR16a' (CHR')rNRl6fS(0)2(CHR')rRl6b C1_6 haloalkyl, C2-8 alkenyl substituted with 0-3 R', C2_8 alkynyl substituted with 0-3 R', and (CHR')rphenyl substituted with 0-3 Rl6e;
Rl6a and Rl6a', at each occurrence, are selected from H, C1_6 alkyl, C2_g alkenyl, C2_g alkynyl, a (CH2)r-C3-1o carbocyclic residue ~~ubstituted with 0-5 Rl6e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 Rl6e;
,~16b~ at each occurrence, is selected from C1_6 alkyl, C2_g alkenyl, C2_e alkynyl, a (CH2)rC3-6 carbocyclic residue substituted with 0-.3 Rl6e, and a (CH2)r-5-6 membered heterocyclic system containing 2-4 heteroatoms selected from N, 0, a.nd S, substituted with 0-2 Rl6e;
FZl6d~ at each occurrence, .is selected from C2_8 alkenyl, C2_g alkynyl, C;1_6 alkyl substituted with 0-3 Rl6e~ a (CH2)r-C3-1o carbocyclic residue substituted with 0-3 Rl6e and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rl6e_ F;l6e, at each occurrence, is selected from C1_6 alkyl, C2_g alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCI_5 alkyl, OH, SH, (CH2)~SC1-5 alkyl, (CHZ)rNR16fR16f, and (CHZ)rphenyl;
R,l6f~ at each occurrence, i.s selected from H, C1_5 alkyl, and C3-6 cycloalkyl, a.nd phenyl;
v is selected from 0, 1, and 2;
t is selected from 1 and 2;
w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4, and 5;
q is selected from 1, 2, 3, 4, and 5; and p is selected from 0, 1, 2, and 3.

[2] In a preferred embodiment, the present invention provides novel compounds of formula (I), wherein:
R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1_g alkyl, (CH2)rC3-6 cycloalkyl, and (CHz)r-phenyl substituted with 0-3 R4c.
R4c, at each occurrence, is selected from CI_6 alkyl, Cz_8 alkenyl, C2_s alkynyl, C3_6 cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, (CH2)rOH, (CHZ)rSCl_5 alkyl, (CH2)rNR4aR4a', and (CH2)rphenyl;
alternatively, R4 joins with R~, R9, or R11 to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle substituted with 0-3 Ra;
R1 and R2 are independently selected from H and C1_4 alkyl;
R6, at each occurrence, is selected from C1_4 alkyl, C2_8 alkenyl, Cz_8 alkynyl, (CH2)rC3-6 cycloalkyl, (CF2)rCF3, CN, (CH2 ) rOH, (CH2 ) rOR6b, (CH2 ) rC (O) R6b, (CHZ)rC(O)NR6aR6a', (CH2)rNR6dC(0)R6a, and (CH2)tphenyl substituted with 0-3 R6c;
R6a and R6a', at each occurrence, are selected from H, C1_6 alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3 R6c .
R6b, at each occurrence, is selected from C1_6 alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is selected from C1_6 alkyl, C3-5 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CHZ)rOH, (CH2)rSCl_5 alkyl, and (CHZ)rNR6dR6d;

R6~, at each occurrence, :is selected from H, C1_6 alkyl, and C3-6 cycloalkyl;
R~, is selected from H, C.L_3 alkyl, (CH2)rC3-6 cYcloalkyl, (CH2)qOH, (CH2)qOR~d, (CH2)qNR~aR7a', (CH2)rC(0)R~b, (CH2 ) rC (O) NR~aR7a' , (CH2 ) qNR~aC (O) Rya, Cl_6 haloalkyl, (CH2)rphenyl with 0-2 R~~;
IQ Rya and Rya', at each occurrence, are selected from H, C1-6 alkyl, (CHZ)rC3-5 cycloalkyl, a (CH2)rphenyl substituted with 0-3 Rye;
Rib, at each occurrence, i.s selected from C1_6 alkyl, C2_8 alkenyl, C.2_g alkynyl, (CH2)rC3-6 cycloalkYl, (CH2)rphenyl substitLaed with 0-3 Rye;
R~~, at each occurrence, is selected from C1_4 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2)rC3-6 cYcloalkyl, C1, Br, I, F, (CFZ)rCF3, N02, CN, (CH2)rNR~fR7f, (CHZ)rOH, (CH2)rOCl_q alkyl, (CH2)rC(O)R~b, (CH2)rC(O)NR~fR7f (CHZ)rNR~fC(O)R~a, (CH2)rS(O)pR7b (CHZ)rS(O)2NR~fR7f~
(CH2)rNR~fS(O)2R~b, and (CH2)rphenyl substituted with 0-2 Rye;
Rid, at each occurrence, is selected from C1_6 alkyl, (CH2)rC3-6 CYcloalkyl, (CH2)rphenyl substituted with 0-3 Rye;
3E~ l~~e, at each occurrence, is selected from C1_6 alkyl, Cz_8 alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I, CN, N02 , (CF2 ) rCF3 , (CH2 ) rOCl_5 alkyl , OH, SH, (CH2 ) rSCz_ 5 alkyl , ( CH2 ) rNR~ f R~~ f , and ( CH2 ) phenyl ;
~z~f, at each occurrence, is selected from H, C1_5 alkyl, and C3-6 cycloalkyl;

R8 is H or joins with R? to form C3_~ cycloalkyl or =NR8b;
R11, is selected from H, C1_6 alkyl, (CH2)rC3-5 cycloalkyl (CH2)qOH, (CH2)qORlld tCH2)qNRllaRlla', (CH2)rC(0)Rllb (CH2)rC(O)NRllaRlla' (CH2)qNRllaC(O)Rlla C1-6 haloalkyl, (CH2)rphenyl with 0-2 Rllc, (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
Rlla and Rlla' , at each occurrence, are selected from H, C1_6 alkyl, (CH2)rC3-s cycloalkyl, a (CH2)rphenyl substituted with 0-3 Rlle.
Rllb, at each occurrence, is selected from C1_6 alkyl, alkenyl, C2_8 alkynyl, (CH2)rC3-5 cycloalkyl, (CHZ)rphenyl substituted with 0-3 Rlle;
Rllc at each occurrence, is selected from C1_4 alkyl, C2_g alkenyl, C2_8 alkynyl, (CH2)rC3-6 cycloalkyl, C1, Br, I, F, (CF2)rCF3, N02, CN, (CHZ)rNRllfRllf (CH2)rOH, (CH2)rOCl_4 alkyl, (CH2)rC(O)Rllb (CH~)rC(O)NRllfRllf (CHZ)rNRllfC(O)Rlla~ (CH2)rS(O)pRllb (CHZ ) rS (O) 2NR11fRllf (CH2 ) r~llfS (O) 2Rllb arid (CH2)rphenyl substituted with 0-2 Rlle;
Rlld, at each occurrence, is selected from C1_6 alkyl, (CH2)rC3-6 cycloalkyl, (CHZ)rphenyl substituted with 0-3 Rlle.
Rlle, at each occurrence, is selected from C1_6 alkyl, CZ_8 alkenyl, Cz_8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CHz)rOCl_5 alkyl, OH, SH, (CHZ)rSCl_ 5 alkyl, (CH2)rNR11fR11f, and (CH2)rphenyl;
Rllf at each occurrence, is selected from H, C1_S alkyl and C3-6 cycloalkyl;

R12 is H or joins with R11 to form C3_7 cycloalkyl;
v is selected from 1 and 2;
q is selected from 1, 2, and 3; and r is selected from 0, 1, 2, and 3.
[3] In a more preferred Esmbodiment, the present invention ;..provides novel compounds of formula (I), wherein:
:R3 is selected from a (CR'''H)r-carbocyclic residue substituted with 0-5 R15, wherein the carbocyclic residue is selected ,From phenyl, C3_6 cycloalkyl, naphthyl, and adamant=yl; and a (CR3'H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system .is selected from pyridinyl, thiophenyl, furanyl, :indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiad_Lazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-tr_~azolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazo:lyl, thiazolyl, oxazolyl, pyrazinyl, and pyrim_Ldinyl; and l~5 is selected from (CR''H)t-phenyl substituted with 0-5 R16; and a (CRS'H)t-h~aterocyclic system substituted with 0-3 R16, wherein. the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothia::olyl, benzimidazolyl, benzothiophenyl, ben::ofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.

[4) In an even more preferred embodiment, the present invention provides novel compounds of formula (I-i), wherein the compound of formula (I-i) is:
Z
J II
K ~N-E-N~N-R3 - L-~ H H
(I-i) R16, at each occurrence, is selected from C1_8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, C1, Br, I, F, (CH2)r~16aR16a' N02 CN, OH,, (CHZ)rORl6d (CH2)rC(O)Rl6b, (CH2)rC(O)NR16aR16a', (CH2)rNRl6fC(O)Rl6b (CH2)rS(0)pRl6b (CH2)rS(0)2NR16aR16a', (CH2)rNRl6fS(O)2R16b and (CH2)rphenyl substituted with 0-3 Rl6e-Rl6a and Rl6a' at each occurrence, are selected from H, C1_6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 Rl6e;
Rl6b at each occurrence, is selected from H, C1_6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 Rl6e;
Rl6d at each occurrence, is selected from C1_6 alkyl and phenyl;
Rl6e, at each occurrence, is selected from C1_6 alkyl, C1, F, Br, I, CN, N02, (CFZ)rCF3, OH, and (CH2)rOCl_5 alkyl;
and Rl6f, at each occurrence, is selected from H, and C1-5 alkyl.
[5) In another even more preferred embodiment, the present invention provides novel compounds of formula (I-ii), wherein the compound formula (I-ii) is:

z ~K ~N-E-N~N-R3 H H
, (I-ii) R16, at each occurrence, is selected from C1_g alkyl, (CH2)rC:3-6 cYcloalkyl, CF3, C1, Br, I, F, (CH2)rNR16aR16a', NO~, CN, OH, (CH2)rORl6d~
(CH2)rC:(0)Rl6b, (CH2)=C(O)NR16aR16a', (C:HZ)rNRl6fC(0)Rl6b~
(CH2)rS(O)pRl6b, (CH2)rS(O)2NR16aR16a', (CH2)rNRl6fs(O)2R16b, and (CH2)rphenyl substituted with 0-3 RlE~e;
Rl6a and Rl6a', at each occurrence, are selected from H, C1_6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0--3 Rl6e;
Rl6b, at each occurrence, is selected from H, C1_6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 Rl6e;
Rl6d, at each occurrence, is selected from C1-6 alkyl and phenyl;
Rl6e, at each occurrence, is selected from C1-6 alkyl, C1, 2'.~ F , Br , I , CN , N02 , ( CF2 ) rCF3 , OH , and ( CH2 ) rOC1-5 alkyl ;
and Rl6f, at each occurrence, is selected from H, and C1-5 alkyl.
[6] In a preferred embodiment, the present invention provides no~~el compounds of formula (I-i) wherein:
R5 is CH2phenyl substituted with 0-3 R16 3 ~i E is -CH2- (CR9R1~ ) - ( CR11R12 ) ;

R9, is selected from H, C1_6 alkyl, (CH2)rC3-6 cycloalkyl, F, Cl, CN, (CH2)rOH, (CH2)rOR9d, (CH2)rNR9aR9a', (CH2)rOC(O)NHR9a, (CH2)rphenyl substituted with 0-5 R9e, and a heterocyclic system substituted with 0-2 R9e, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a~ , at each occurrence, are selected from H, Cl_6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R9e;
R9a, at each occurrence, is selected from C1_6 alkyl and phenyl;
R9e, at each occurrence, is selected from C1_6 alkyl, C1, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOCl-5 alkyl;
R1~ is selected from H, C1_5 alkyl, OH, and CH20H;
alternatively, R9 and R1~ join to form C3_~ cycloalkyl, 5-6-membered cyclic ketal or =O;
with the proviso that when R1~ is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R11 is selected from H, C1_g alkyl, (CHZ)rphenyl substituted with 0-5 Rlle, and a (CH2)r-heterocyclic system substituted with 0-2 Rlie, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and _ Rlle~ at each occurrence, is selected from C1_6 alkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
R12 is H;
alternatively, R11 ancL R12 join to form C3_~ cycloalkyl; and :L 0 r is selected from 0, :L, and 2.
[7]. In another preferred embodiment, the present invention provides novel compounds of formula (I-ii), :L5 wherein:
R5 is CH2phenyl substituted with 0-3 Rls;
E is -CH2- (CR9Rlo) - (CR:L1R12 ) ;
R9, is selected from H, C1_6 alkyl, (CH2)rC3-6 cYcloalkyl, F, C1, CN, (CH2)rOH, (CH2)rOR9d, (CH2)rNR9aR9a'.
(CH2)rOC(O)NHR9a, (CH2)rphenyl substituted with 0-5 R9e, and a heterocyc:li.c system substituted with 0-2 R9e, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a', at each occurrence, are selected from H, C,_6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted 3 0 with 0-3 R9e;
R9d, at each occurrence, is selected from C1_6 alkyl and phenyl;
R9e, at each occurrence, is selected from C1_6 alkyl, Cl, F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_S alkyl;

R1~ is selected from H, C1_g alkyl, OH, and CH20H;
alternatively, R9 and R1~ join to form C3_~ cycloalkyl, 5-6-membered cyclic ketal or =0;
with the proviso that when R1~ is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R11 is selected from H, CI_8 alkyl, (CH2)rphenyl substituted with 0-5 Rlle, and a (CH2)r-heterocyclic system substituted with 0-2 Rlle, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and Rlle, at each occurrence, is selected from C1_6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
R12 is H;
alternatively, R11 and R12 join to form C3_~ cycloalkyi; and r is selected from 0, 1, and 2.
[8] In a more preferred embodiment, the present invention provides novel compounds of formula (I-i), wherein:
J is selected from CH2 and CHRS;
K is selected from CH2 and CHRS;

L is selected from CHZ and CHRS;
R3 is a C3_lU carbocycl:ic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3'H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl_, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, c~.~inolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl., isoindolyl, isothiadiazolyl, isoxazolyl, pipe.ri.dinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-t:riazolyl, t.etrazolyl, thiadiazolyl, thiazolyl, oxazoly:l, pyrazinyl, and pyrimidinyl; and R15, at each occurrence, is selected from C1_g alkyl, (CH2)rC3-6 cycloalk:yl, CF3, C1, Br, I, F, ( CH2 ) rNR15aR15a ~ ~ ~~~2 CN , OH , ( CHZ ) rORlSd (CH2)rC(O)RlSb~ {~~~H,;~)rC(O)NR15aR15a'. {CH2)rNRlSfC(O)RlSb~
{ CH2 ) rS ( O ) pRlSb C CH2 ) rS ( O ) 2NR=5aR15a' (CH2)rNR.lSfS(O)2RlSb, (CH2)rphenyl substituted with 0-3 RlSe~ and a (CH2).~-S-5 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 RlSe;
RlSa and Rlsa~ , at each occurrence, are selected from H, C1_s alkyl, C3_6 cycloal.kyl, and (CH2)rphenyl substituted with 0-3 RlSe;
RlSb~ at each occurrence, is selected from H, C1_6 alkyl, C3_6 cyc:loalkyl, and (CH2)rphenyl substituted with 0-3 RlSe;
RlSd, at each occurrence, is selected from C1_6 alkyl and phenyl;

Rl5e, at each occurrence, is selected from C1_6 alkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOC1_5 alkyl;
and RlSf, at each occurrence, is selected from H, and C1-5 alkyl.
[9] In another more preferred embodiment, the present invention provides novel compounds of formula (I-ii), wherein:
K is selected from CHZ and CHRS;
L is selected from CH2 and CHRS;
R3 is a C3-to carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3'H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R15~ at each occurrence, is selected from C1_8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR15aR15a' N02 CN, OH,, (CH2)rpRlSd (CH2)rC(0)RlSbWCH2)rC(0)NR15aR15a', (CH2)rNRlSfC(O)RlSb 3 5 (CH2)rS(O)pRlSb (CH2)rS(0)ZNR15aR15a', (CH2)rNRlSfS(O)zRlSb, (CH2)rphenyl substituted with 0-3 RlSe, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 RlSe;
RlSa and RlSa~, at each. occurrence, are selected from H, Cz_6 alkyl, C3_6 cyclo~alkyl, and (CH2)rphenyl substituted with 0-3 RlSe;
RlSb~ at each occurrence, is selected from H, C1_6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 1.0 RlSe;
RlSd at each occurrence, is selected from C1_6 alkyl and phenyl;
RlSe, at each occurrence, is selected from C1_6 alkyl, C1, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CHZ)rOCl_5 alkyl;
and RlSf, at each occurrence, is selected from H, and C1-5 alkyl.
[10] In another more preferred embodiment, the present invention provides novel compounds of formula (I-ii), wherein:
Rl3a is selected from H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isobutyl, isopentyl and isohexyl.
[11] In a further even more preferred embodiment, the present invention provides novel compounds of formula (I) and pharmaceutically acceptable salt forms thereof, wherein the compound of formula (I) is selected from:
erythro-cis~-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop 1-yl)-~~-benzyl-cx-methyl-2-piperidinemethanol;

erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-a-ethyl-2-piperidinemethanol;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-a-(n-prop-1-yl)-2-piperidinemethanol;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-a-(n-but-1-yl)-2-piperidinemethanol;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-a-(n-prop-2-yl)-2-piperidinemethanol;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-a-(3-methyl-n-prop-1-yl)-2-piperidinemethanol;
(+)-erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-a-(n-but-1-yl)-2-piperidinemethanol;
erythro-cis-1-[3-(indazol-5-yl)aminocarbonylamino)-n-prop-1-yl]-4-benzyl-a-(n-but-1-yl)-2-piperidinemethanol;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-2-[1-(3-acetylphenylaminocarbonyloxy)-n-prop-1-yl]-4-benzylpiperidine;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-2-[1-(3-acetylphenylaminocarbonyloxy)-n-but-1-yl]-4-benzylpiperidine;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-2-[1-(3-acetylphenylaminocarbonyloxy)-n-pent-1-yl]-4-benzylpiperidine;

erythro-cis-1-[3-(3-acE_tylphenylaminocarbonylamino)-n-prop-1-yl]-2-[1-(3-aces:ylphenylaminocarbonyloxy)-2-methyl-n-prop-1-yl]-4-benzylpiperidine; and erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-2-[1-(3-acet:ylphenylaminocarbonyloxy)-3-methyl-n-but-1-ylJ-4-benzylpiperidine.
[12] In a second embodiment, the present invention provides novel compounds of formula (I):
Z
,E-M R4 I~ ~ E-iV~-R3 l.-Q R 1 R2 (I) or stereoisomers or pharmaceutically acceptable salts 1_'i thereof, wherein:.
M is absent or selected from CH2, CHRS, CHR13, CR13R13, and CR'R13 ;
Q is selected from CHR13 , CR13R13 , and CR5R13 ;
J, K, and L are independently selected from CH2, CHRS, CHR6, CR6R6 and CR5R6;
with the provisos:
1) at least one of M, J, K, L, or Q contains an R5;
and 2) when M is absewt, J is selected from CH2, CHRS, and CRSR13 ;
Z is selected from 4, S; NRla, CHCN, CHNOz, and C(CN)2;

Rla is selected from H, C1-6 alkyl, C3_6 cycloalkyl, CONRIbRib OR>.b , N02 , CN , and ( CH2 ) Wphenyl ;
R1b is independently selected from H, C1_3 alkyl, C3_s S cycloalkyl, and phenyl;
E is selected from:

R' 8 ~ R8 A A A
~R 14)9 ' (R 14)9 ' R9 ~Rlo ~R 14)9 ' R9 ~Rlo (R 14)9 IO
11 12 Rg 10 7 R8 9 10 A ~ A R1i R12 A - R~R12 (R 14)9 (R 14)9 (R 14) 9 , 7 8 11 R12 7 8 Rs 1o R a Rs R1o A A R~R12 1o A
R R
(R 14)9 , R R 1 ° (R 14)9 ' (R 14)9 , and R~ R8 R9 R10 11 R12 R ~Rto 15 (R 14)9 ring A is a C3_6 carbocyclic residue;
with the proviso that when A is phenyl, R14 20 is not ortho to CR~Ra;
R1 and R2 are independently selected from H, C1_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2)rC3-6 cycloalkyl, and a (CH2)r-C3-1o carbocyclic residue substituted with 0-5 25 Ra;

Ra, at each occurrence', is selected from C1_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CHZ)rC3_6 cycloalkyl, C1, Br, I, F, (CF2)rCF3, N02. CN, (CH2)rNRbRb. (CH2)rOH, (CH2)rORc.
( CH2 ) rSH, ( CH2 ) L.S:Rc , ( CH2 ) rC ( 0 ) Rb, ( CH2 ) rC ( 0 ) NRbRb , ( CH2 ) rNRbC ( O ) Rb, ( CH2 ) rC ( 0 ) ORb, ( CHZ ) rOC ( 0 ) Rc , (CH2)rCH(=NRb)NRbl~b, (CH2)rNHC(=NRb)NRbRb, (CH2)rS(0)pRc, (CH2)rS(O)2NRbRb, (CHZ)rNRbS(0)ZRc, and (CH2)rphenyl;
Rb, at each occurrence, is selected from H, C1_6 alkyl, C3-5 cycloalkyl, and phenyl;
Rc, at each occurrence, is selected from C1_6 alkyl, C3-6 cycloalkyl, and phenyl;
alternatively, R2 and 1~3 join to form a 5, 6, or 7-membered ring substituted with 0-3 Ra;
R3 is selected from a (CR3'R3") r-C3-1o carbocyclic residue substituted with 0-5 R15 and a (CR3'R3")r-5-10 membered 2~~ heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
R3' and R3", at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3_ti cycloalkyl, and phenyl;
2 _'i R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1_s alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2)rC3-6 cycloalkyl, (CH2)~~C(0)R4b, {CH2)qC(0)NR4aR4a~, 3 Ci (CH2 ) qC (O) OR4b, and a (CHZ ) =-C3_1o carbocyclic residue substituted with 0-3 R4c;
R4a and R4a', at each occurrence, are selected from H, C1-s alkyl, (CH2)rC3-5 c=ycloalkyl, and phenyl;

WO 00/35449 PC'T/US99/30292 R4b, at each occurrence, is selected from C~_6 alkyl, C2_8 alkenyl, (CHZ)rC3-6 cycloalkyl, C2_g alkynyl, and phenyl;
R4c, at each occurrence, is selected from C1_6 alkyl, C2_g alkenyl, C2_g alkynyl, C3-6 cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, (CHZ)rOH, (CHZ)rSCl_5 alkyl, (CH2)rNR4aR4a', and (CH2)rphenyl;
alternatively, R4 joins with R~, R9, or R11 to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle substituted with 0-3 Ra;
R5 is selected from a (CR5'R5°)t-C3-1o carbocyclic residue substituted with 0-5 R16 and a (CRS'RS'~)t-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16;
R5' and R5", at each occurrence, are selected from H, C1_6 alkyl, (CHZ)rC3-6 cycloalkyl, and phenyl;
R6, at each occurrence, is selected from C1_6 alkyl, CZ_8 alkenyl, C2_8 alkynyl, (CH2)rC3-6 cycloalkyl, (CFZ)~CF3, CN, (CH2)rNR6aR6a', (CH2)rOH, (CH2)rOR6b, (CHZ)rSH, (CH2 ) rSR6b, (CHZ ) rC (O) OH, (CH2 ) rC (O) R6b, (CH2)rC(O)NR6aR6a', (CH2)rNR6dC(O)R6a, (CH2)rC(O)OR6b, (CH2)rOC(O)R6b, (CH2)rS(0)pR6b, (CH2)rS(O)2NR6aR6a'.
(CH2)rNR6aS(O)2R6b, and (CH2)tphenyl substituted with 0-3 R6c;
R6a and R6a', at each occurrence, are selected from H, C1_6 alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3 R6c.
R6b, at each occurrence, is selected from Ci_o alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;

R6~, at each occurrence, is selected from C1_6 alkyl, C3-6 cycloalkyl, CI, F, Br, I, CN, N02, (CFZ)rCF3, (CH2)rOCl-alkyl, (CH2)rOH, (CH2)rSCl_5 alkyl, and (CHZ)rNR6dR6d;
5 R6d, at each occurrence, is selected from H, C1_6 alkyl, and C3-6 cycloalkyl;
with the proviso that.when any of J, K, or L is CR6R6 and R6 is halogen, cyano,, nitro, or bonded to the carbon to which it is attached through a heteroatom, the other R6 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R~, is selected from H, C1-6 alkyl, C2_g alkenyl, C2_8 alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qOR~d, (CH2)qSR~d, (CH2 ) qNR~aR7a' , (CH:2 ) rC (O) OH, (CHZ ) rC (O) R7b (CH2)rC(O)NR~aR7a", (CH2)qNR~aC(O)R~a, (CH2)qNR~aC(O)H, (CH2)rC(O)OR~b, (CHZ)qOC(O)R~b, (CH2)qS(O)pR7b (CH2)qS(O)2NR~aR7a', (CH2)qNR~aS(O)2R7b, C1_6 haloalkyl, 2« a (CH2),_-C3_1o carbocyclic residue substituted with 0-3 R~~, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 R~~;
Rya and Rya' , at each occurrence, are selected from H, C1-6 alkyl, (:2_g alkeny7., C2_8 alkynyl, (CH2) rC3-5 cycloalkyl, a (CH2)r-C3-1o carbocyclic residue substituted with 0-5 Rye, and a (CH2)r-5-10 membered heterocyclic system containing i-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rye;
Rib, at each occurrence,. is selected from C1_6 alkyl, C2_$
alkenyl, C2_$ alkynyl, a (CH2)r-C3_6 carbocyclic residue substituted with 0-2 Rye, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rye;

R~~, at each occurrence, is selected from C1_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CHZ)rC3-6 cYcloalkyl, C1, Br, I, F, (CF2)rCF3, N02, CN, (CH2)rNR~fR7f, (CH2)rOH, (CH2)rOCl_q alkyl, (CH2)rSCl_4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R~b, (CH2)rC(O)NR~fR7f, (CHZ)rNR~fC(0)R~a, (CH2)rC(O)OC1_q alkyl, (CH2)rOC(O)R7b (CH2)rC(=NR~f)NR~fR7f, (CH2)rS(O)pR~b, (CH2 ) rNHC (=NR~f ) NR~fR7f, (CHZ ) rS (O) 2NR7fR7f (CH2)rNR~fS(0)zR~b, and (CH2)rphenyl substituted with 0-3 Rye;
Rid, at each occurrence, is selected from C1_6 alkyl substituted with 0-3 Rye, alkenyl, alkynyl, and a C3-1o carbocyclic residue substituted with 0-3 R~~;
Rye, at each occurrence, is selected from C1_6 alkyl, CZ_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_ 5 alkyl, (CH2}rNR~fR~f, and (CHZ)rphenyl;
Ref, at each occurrence, is selected from H, C1_6 alkyl, and C3-6 cycloalkyl;
R8 is selected from H, C1_6 alkyl, C3_5 cycloalkyl, and (CH2)tphenyl substituted with 0-3 RBa;
RBa, at each occurrence, is selected from C1_6 alkyl, CZ_8 alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I, CN, N02, (CF2);CF3, (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_ 5 alkyl, (CH2)rNR~fR~f, and (CH2)rphenyl;
alternatively, R~ and R8 join to form C3_~ cycloalkyl, or =NRBb;
R8b is selected from H, C1_6 alkyl, C3_6 cycloalkyl, OH, CN, and (CH2)r-phenyl;

R9, is selected from H, C1_6 alkyl, C2-8 alkenyl, C2_g alkynyl, F, C1, Br, I, N02, CN, (CH2)rOH, (CH2)rSH, (CH2)rC~R9d, (CH2)rSR9d, (CHZ)rNR9aR9a', (CH2)rC(0)OH, (CH2)rG(0)R9b, (C~C~;)rC(0)NR9aR9a'~ (CH2)rNR9aC(O)R9a, ( CH2 ) rNR9aC ( 0 ) H , ( CHZ ) rNR9aC ( O ) NHR9a , ( CHZ ) rC ( 0 ) OR9b, (CH2)rOC(0)R9b, (C.'H2)rOC(O)NHR9a, (CH2)rS(O)pR9b~
(CH2)rS(O)2NR9aR9a'. (CH2)rNR9aS(O)ZR9b, C.'1_6 haloalkyl, a (CHZ)r-C3-1o carbocyclic residue substituted with 0-5 1() R9c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c R9a and R9a' , at each occurrence, are selected from H, C1-s 1'. alkyl, C2_8 alkenyl., C2_8 alkynyl, a (CH2) r-C3-1o carbocyclic residue substituted with 0-5 R9e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 R9e;
R9b, at each occurrence, is selected from C1_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CHZ)~-C3-E carbocyclic residue substituted with 0-G R9e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
R9c, at each occurrence, is selected from C1_6 alkyl, C2_8 alkenyl, C2-8 alkynyl, (CHZ)rC3-6 cycloalkyl, C1, Br, I, F, (CF2)rCF3, N0~7, CN, (CH2)rNR9fR9f (CH2)rOH, (CH2)rOCl-4 alkyl, (CH2)rSCl_.~ alkyl, (CHZ)rC(O)OH, (CH2)rC(0)R9b, (CH2)rC(0)NR9fR9f (CH2)rNR9fC(0)R9a (CHZ)rC(O)OC1_4 alkyl, (CH2)rOC(O)R9b, (CH2)rC(=NR9f)NR9fR~f, (CH2)rS(O)pR9b (CH2 ) rNHC (=NR9f ) NR9fR9f , (CH2 ) rS (O) ZNR9fR9f, (CH2)rNR9fS(0)2R9b, and (CH2)rphenyl substituted with 0-3 R9e.

R9d, at each occurrence, is selected from C1_6 alkyl, C2-5 alkenyl, C2_6 alkynyl, a C3_1o carbocyclic residue substituted with 0-3 R9c, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R9c;
R9e, at each occurrence, is selected from C1_6 alkyl, C2_g alkenyl, C2_8 alkynyl, (CH2)rC3-6 cYcloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH, (CHZ)rSCl_5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl;
R9f, at each occurrence, is selected from H, C1_6 alkyl, and C3-o cycloalkyl;
Rlo, is selected from H, C1_6 alkyl, Cz_e alkenyl, C2_8 alkynyl, F, Cl, Br, I, N02, CN, (CH2)rOH, (CH2)rORlod, (CH2)rSRlOd (CH2)rNRl0aR10a', (CH2)rC(O)OH, (CH2 ) rC (O) R20b. (CH2 ) rC (O) NR10aR10a' , (CH2 ) rNRlOaC (O) RlOa 2 0 ( CH2 ) rNRl OaC ( O ) H , ( CH2 ) rC ( O ) OR1 Ob , ( CHZ ) rOC ( O ) R1 Ob (CH2)rS(O)pRlOb (CH2)rS(O)2NR10aR10a', (CH2) rNRloaS (0) 2RIOb C1-6 haloalkyl, a (CH2 ) r-C3-10 carbocyclic residue substituted with 0-5 Rloc, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 Rloc;
Rloa and Rloa' , at each occurrence, are selected from H, C1-5 alkyl, C2_g alkenyl, C2_g alkynyl, a (CH2)r-C3-to carbocyclic residue substituted with 0-5 Rloe, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 RlOe.
RlOb, at each occurrence, is selected from C~_6 alkyl, C2_g alkenyl, C2_g alkynyl, a (CH2)r-C3-s carbocyclic residue substituted with 0-2 R2oe, and a (CHZ)~-5-6 membered WO 00/35449 PCTlUS99/30292 heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 RlOe;
Rloc~ at each occurrence, is selected from C1_6 alkyl, C2_g alkenyl, C2_8 alkynyl, (CH2)rC3_6 cycloalkyl, C1, Br, I, F, (CF2)rCF3, NO~, CN, (CH2)rNR10fR10f (CH2)rOH, (CH2)r0(:1-4 alkyl, (CH2)rSCI_4 alkyl, (CH2)rC(O)OH, (CH2)rC(0)RlOb~ (CH~)rC(0)NR10fR10r~ (CH2)rNRlOfC(O)RlOa~
(CHZ)rC(0)OC1_q al)cYl, (CH2)rOC(0)RlOb~
(CH2)rC(=NRlOf)NR.lffRlOf~ (CH2)rS(0)pRlOb~
(CH2 ) rNHC (=NRlOf ) NRxOfRlOf (CH2 ) rS (0) zNR10fR10f (CH2 ) rNRlofS (0) ZR:LOb and (CH2 ) rphenyl substituted with 0-3 Rloe .
Rlod, at each occurrences, is selected from C1_6 alkyl, C2-6 alkenyl, C2_6 alky:nYl, a C3_1o carbocyclic residue substituted with f--3 Rloc, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S
substituted with G-3 Rloc;
RlOe, at each. occurrence., is selected from Cl_6 alkyl, C2_8 alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, PJO2, (CF2)rCF3, (CH2)rOC1_5 alkyl, OH, SH, (CH2 ) rSC'1_5 alkyl , (CH2 ) rNR10fR10f and (CHZ) rphenyl;
Rlof at each occurrence, is selected from H, Cl_5 alkyl, and C3_E cycloalkyl;
alternatively, R9 and Rlo join to form C3_~ cycloalkyl, 5-6-membered cyclic ketal or =0;
with the proviso that when Rlo is -OH, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;

R11, is selected from H, C1_6 alkyl, C2_g alkenyl, C2_~
alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qORlld, (CH2)qSRlld (CH2)qNR11aR11a~ (CH2)rC(0)OH, (CHZ)rC(O)Rllb ( CH2 ) rC ( O ) NR11aR11a' , ( CH2 ) qNRllaC ( O ) Rlla ( CHZ ) qNRllaC ( O ) NHRlla ( CH2 ) rC ( O ) ORllb ( CH2 ) qOC ( 0 ) Rllb (CH2)qS(O)pRllb (CH2)qS(O)2NR11aRlla' (CH2)qNRllaS(O)2R11b C1-6 haloalkyl, a (CH2)r-C3-1o carbocyclic residue substituted with 0-5 Rllc, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rllc;
Rlla and Rlla', at each occurrence, are selected from H, C1_6 alkyl, Cz_~ alkenyl, C2_8 alkynyl, a (CHZ)r-C3-lc carbocyclic residue substituted with 0-5 Rlle, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 Rlle;
Rllb, at each occurrence, is selected from C1_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 Rlle, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rlle.
Rllc at each occurrence, is selected from C1_6 alkyl, C2-8 alkenyl, C2_g alkynyl, (CH2)rC3-5 cycloalkyl, C1, Br, I, F, (CF2)rCF3, N02, CN, (CH2)rNRllfRllf (CH2)rpH, (CH2)rOCl_4 alkyl, (CH2)rSCl_4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)Rllb (CH2)rC(0)NRllfRllf (CH2)rNRIIfC(0)Rlla (CH2)rC(O)OC1_q alkyl, (CHZ)rOC(O)Rllb (CH2)rC(=NRllf)NRllfRllf (CHZ)rNHC(=NRllf)NRllfRllf (CH2)rS(O)pRllb WCH2)rS(O)2NR11fR11f (CHZ)rNRllfS(0)2R11b and (CH2)rphenyl substituted with 0-3 Rlle.

Rlld~ at each occurrence, is selected from Cl_6 alkyl substituted with 0-3 Rlle, C2-5 alkenyl, C2_6 alkynyl, and a C3_1o carboc_yclic residue substituted with 0-3 Rllc;
Rlle~ at each occurrence, is selected from C1_6 alkyl, C2 alkenyl, C2_8 alky:nyl, C3_6 cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3,, (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_ alkyl,. (CH2)rNRll.f:Rllf~ and (CH2)rphenyl;
Rllf at each occurrencE=_, is selected from H, C1-6 alkyl, and C3_E; cycloalkyl;
R12 is selected from H, C1_6 alkyl, (CH2)qOH, (CH2)rC3-5 1'. cycloalkyl, and (CH2)tphenyl substituted with 0-3 Rl2a;
Rl2a, at each occurrence, is selected from C1_6 alkyl, C2_8 alkenyl,, C2_8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_ 2 0 5 alkyl , ( CH2 ) rNR'3 f R9 f , and ( CH2 ) rphenyl ;
alternatively, R1i and R12 join to form C3_~ cycloalkyl;
R13, at each occurrence, is selected from (CHRl'a)OH, 25 (CHRl3a)O:Rl3b (CHRla") SH, (CHRl'a) SRl3b, (CHRl3a) ~l3eC (O) Rl3f and (CHRl3a)PJRI3eS (O) 2R13f;
Rl3a is selected from C1_~ alkyl;
Rl3b~ at each occurrence, is selected from C(O)Rl3d~
C(0)NHRl3d, C1-6 alkyl, C3_6cycloalkyl, and phenyl substituted with 0--3 Rl3c;
Rl3c, at each occurrence, is selected from C~_6 alkyl, C2_g alkenyl, C2_~ alkynyl, C3-s cYcloalkyl, Cl, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_ alkyl, (CHZ)rNR9fR9f, and (CH2)rphenyl;
Rl3d at each occurrence, is selected from C1_6 alkyl, C3_6 5 cycloalkyl, and phenyl substituted with 0-3 R6c;
Rl3e~ at each occurrence, is selected from H, C1_s alkyl, (CH2)rC3-5 cycloalkyl, and phenyl where phenyl is substituted from 0-3 Rz3c;
Rl3f, at each occurrence, is selected from C1-5 alkyl, (CH2)rC3-5 cycloalkyl, CFA, and phenyl where phenyl is substituted from 0-3 R13~;
alternatively, R14 joins with R4 to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle fused to ring A, the spirocycle substituted with 0-3 Ra:
R14, at each occurrence, is selected from C1_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2)rC3-s cycloalkyl, C1, Br, I, F, N02, CN, (CHR')rIVR14aR14a' (CHR')rOH, (CHR')r0(CHR')rRl4d (CHR')rSH, (CHR')rC(0)H, (CHR')rS(CHR~)rRl4d, (CHR')rC(O)OH, ( CHR' ) rC { O ) ( CHR' ) rRl4b , ( CHR' ) rC ( O ) NR14aR14a' (CHR' ) rNRl4fC (O) (CHR~ ) rRl4b {CHR' ) rC (0) O (CHR' ) rRl4d~
( CHR' ) rOC ( O ) ( CHR' ) rRl4b , ( CHR' ) rC ( =NR14 f ) NR14aR14a' (CHR' ) rNHC (=NRl4f ) NR14fR14f (CHR' ) rS (0) p (CHR' ) rRl4b (CHR')rS(O)2NR14aR14a', {CHR')rNRl4fS(O)2(CHR')rRl4b Ci_6 haloalkyl, C2_g alkenyl substituted with 0-3 R', C2_g alkynyl substituted with 0-3 R', (CHR')rphenyl substituted with 0-3 Rl4e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 RlSe.

R', at each occurrence, is selected from H, C1_6 alkyl, C2_8 alkenyl, C2_8 alk:ynyl, (CHZ)rC3_o cycloalkyl, and (CH2)rphenyl substituted with Rl4e;
Rl4a and Rl4a', at each occurrence, are selected from H, C1_s alkyl, C2_g alkenyl, C2_g alkynyl, a (CHZ)r-C3-1o carbocyclic residue substituted with 0-5 Rl4e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted ~-0 with 0-2 Rl4e;
Rl4b, at each occurrence, is selected from C1-6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2)~-C3-6 carbocyclic residue substituted with I7-3 Rl4e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 Rl4e;
Rl4d at each occurrence, is selected from Cz-8 alkenyl, C2_g alkynyl, C,_6 alkyl substituted with 0-3 Rl4e~ a (CH2)r--C3-so carbocyclic residue substituted with 0-3 Rl4e~ and a (CH2),~'~-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rl4e;
Rl4e, at each occurrence, is selected from C1_6 alkyl, C2_8 alkeny:l, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOC1_5 alkyl, OH, SH, (CH2 ) r=>C1-5 alkyl, (CH2 ) rNR14fR14f ~ and (CH2 ) rphenyl;
Rl4f, at each occurrence, is selected from H, C1_6 alkyl, C3-6cyc:loalkyl, and phenyl;
R15, at each occurrence, is selected from C1_6 alkyl, C2_8 alkenyl, CZ_8 alk5myl, (CH2)rC3-6 cycloalkyl, C1, Br, I, 3!i F, N02, CN, (CHR')rNR15aR15a'~ (CHR')rOH, (CHR' ) r0 (CHR' ) rRlSd, (CHR' ) rSH, (CHR' ) rC (O) H, (CHR')rS(CHR~)rRl5d, (CHR')rC(O)OH, WO 00!35449 PCT/US99/30292 (CHR')rC(O)(CHR')rRlSb, (CHR')rC(O)NR15aR15a', (CHR' ) rNRlSfC (0) (CHR' ) rRlSb, (CHR' ) rC (O) O (CHR' ) ,.RlSd, (CHR')rOC(O)(CHR')rRlSb, (CHR')rC(O)NR15aR15a' (CHR')rC(=NRlSf)NR15aR15a', (CHR')rNHC(=NRlSf)NR15fR15f, (CHR')rS(0)p(CHR')rRl5b, (CHR')rS(0)2NR15aR15a~~
(CHR')rNRlSfS(0)2(CHR')rRlSb, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 R', C2_8 alkynyl substituted with 0-3 R', (CHR')rphenyl substituted with 0-3 RlSe, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 R~Se;
RlSa and RlSa' , at each occurrence, are selected from H, Cl-6 alkyl, C2-a alkenyl, C2_g alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 RlSe, and a (CHZ)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 RlSe;
RlSb, at each occurrence, is selected from C1-6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CHZ)r-C3-s carbocyclic residue substituted with 0-3 RlSe, and (CHZ)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 RlSe RlSd, at each occurrence, is selected from C2_8 alkenyl, C2-g alkynyl, C1-6 alkyl substituted with 0-3 R~Se, a (CH2)r-C3-1o carbocyclic residue substituted with 0-3 R25e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 RlSe;
RlSe~ at each occurrence, is selected from C1_6 alkyl, alkenyl, C2_8 alkynyl, (CH2)rC3_6 cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CHZ)rOCl_5 alkyl, OH, SH, (CH2)rSCl_5 alkyl, (CH2)rNR15fR15f, and (CH2)rphenyl;

RlSf, at each occurrence, is selected from H, C1_6 alkyl, C3_6 cycloalkyl, and phenyl;
R16, at each occurrence, is selected from C1_6 alkyl, CZ_8 alkenyl, C2_g alk:ynyl, (CH2)rC3-6 cycloalkyl, C1, Br, I, F , N0;> , CN, ( CHR' ) rNR16aR16a' ~ ( CHR' ) rOH, ( CHR' ) r0 ( CHR' ) rRl'S d , ( CHR' ) rSH , ( CHR' ) rC ( O ) H , (CHR')rS(CHR')rRlnd, (CHR')=C(O)OH, (CHR')rC(0)(CHR°)rRl6b, (CHR')rC(0)NR16aR16a'~
( CHR' ) rNRl6 fC { O ) ( CHR' ) rRl6b, ( CHR' ) rC ( 0 ) O ( CHR' ) rRl6d ( CHR' ) rOC ( O ) ( CHR' ) rRl 6b , ( CHR' ) rC ( =NR16 f ) ~16aR16a' ( CHR' ) rNHC ( =NR16 f ) NR16 f R16 f ( CHR' ) r S ( 0 ) p ( CHR' ) rRl6b (CHR' ) rS (0) 2NR16aF~16a' ~ (CHR' ) rNRl6fS {O) 2 (CHR' ) rRl6b~ C1-6 haloalkyl, CZ_8 a:lkenyl substituted with 0-3 R', C2_8 :L5 alkynyl substituted with 0-3 R', and (CHR')rphenyl substituted with 0-3 Rl6e;
Rl6a and Rl6a' at each occurrence, are selected from H, C1_6 alkyl, C2_g alken5rl, C2_8 alkynyl, a (CH2 ) r-C3_lo ?0 carbocyclic residue substituted with 0-5 Rl6e, and a (CHZ)r~-5-10 membe:red heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 Rl6e;
c.5 Rl6b at each occurrence, is selected from C1_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2)rC3-6 carbocyclic residue substituted with 0-3 Rl6e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 Rl6e.
Rl6d, at each occurrence, is selected from C2_g alkenyl, C2_8 alkyny:L, C1_6 alkyl substituted with 0-3 Rl6e, a (CH2)r-~C3-1o carbo~~yclic residue substituted with 0-3 Rl6e~ and a (CH2)r-5-6 membered heterocyclic system containing 1-4 he~teroatoms selected from N, O, and S, substituted with 0-3 Rise;

Rl6e at each occurrence, is selected from C1_6 alkyl, C2_8 alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl, Ci, F, Br, I, CN, NO~, (CF2)rCF3, (CH2)rOCl_7 alkyl, OH, SH, (CH2)rSCl_S alkyl, (CH2)rNR16fR16f, and (CH2)rphenyl;
Rl6f at each occurrence, is selected from H, C1_6 alkyl, and C3_6 cycloalkyl, and phenyl;
g is selected from 0, 1, 2, 3, and 4;
v is selected from 0, 1, and 2;
t is selected from 1 and 2;
w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4, and 5;
q is selected from 1, 2, 3, 4, and 5; and p is selected from 1, 2, and 3.
[13] In a preferred embodiment, the present invention provides novel compounds of formula (I), wherein:
E is selected from:
R8 ~i ~2 R~ a ~ a _ A A A
(R~4~9 Rs Rya (R~a)9 Rs Rio (R'4)9 i~ i2 ~ ~ ' A
3 0 (R ~a)s Rs ~o F ~ Rg 9 10 ~ 8 ~ ~ Ri2 R~R12 ~ ~ R~.R12 (R ia)9 ' (R ~a)9 and R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1_8 alkyl, (CH2)rC3-6 cycloalkyl, and (CHZ)r-phenyl substituted with 0-3 R4c;
R4c, at each occurrence, is selected from C1_6 alkyl, C2_8 .LO alkenyl, C2_g alk:ynyl, C3-6 cycloalkyl, C1, F, Br, I, CN, NG2, (CF2)rCF'3, (CH2)rOCl_5 alkyl, (CH2)rOH, (CHz)rSC~_5 alkyl, (CH2)rNR4aR4a', arid (CH2)rphenyl;
alternatively, R4 joins with R~ or R9 to form a 5, 6 or 7 J.5 membered piperid:inium spirocycle substituted with 0-3 Ra_ R1 and R2 are independently selected from H and C1_4 alkyl;
c.0 R6, at each occurrence',. is selected from C1_4 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2)rC3_6 cycloalkyl, (CFZ)rCF3, CN, (CH2 ) rOH, (CH:2 ) ~OR6b, (CH2 ) rC (O) R6b, (CH2)rC(O)NR6aR6a'', (CH2)rNR6dC(O)R6a, arid (CH2)tphenyl substituted with 0-3 R6c;
R6a and R6a' , at each occurrence, are selected from H, C1_6 alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3 R6c R6b, at each occurrence, is selected from C1_6 alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3 R6c;

R6~, at each occurrence, is selected from Ci_6 alkyl, C3_E
cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOC1-alkyl, (CH2)rOH, (CH2)rSCl_5 alkyl, and (CH2)rNR6aR6d;
5 R6d, at each occurrence, is selected from H, C1_6 alkyl, and C3_6 cycloalkyl;
R~, is selected from H, C1_3 alkyl, (CH2)rC3-6 cycloalkyl, (CHZ)qOH, (CH2)qOR~d, (CH2)qNR~aR7a', (CH?)rC(O)R~b, (CH2)rC(O)NR~aR~a', (CH2)qNR~aC(O)R~a, C1_6 haloalkyl, (CH2)rphenyl with 0-2 R~~;
Rya and Rya', at each occurrence, are selected from H, C1_6 alkyl, (CH2)rC3-5 cycloalkyl, a (CH2)rphenyl substituted with 0-3 Rye;
Rib, at each occurrence, is selected from C1_6 alkyl, C
alkenyl, C2_8 alkynyl, (CH2)rC3-6 cycloalkyl, (CH2)rphenyl substituted with 0-3 Rye;
R~~, at each occurrence, is selected from C1_4 alkyl, C
alkenyl, C2_8 alkynyl, (CH2)rC3-5 cYcloalkyl, C1, Br, I, F, (CF2)rCF3, N02, CN, (CH2)rNR~fR7f, (CH2)rOH, (CH2)rOCl_4 alkyl, (CH2)rC(0)R~b, (CH2)rC(O)NR~fR7f (CH2)rNR~fC(O)R7a, (CH2)rS(0)pR7b, (CHZ)rS(O)2NR7fR7f (CH2)rNR~fS(O)2R~b, and (CH2)rphenyl substituted with 0-2 Rye;
Rid, at each occurrence, is selected from C1_6 alkyl, (CH2)rC3_6 cycloalkyl, (CH2)rphenyl substituted with 0-3 Rye;
Rye, at each occurrence, is selected from C1_6 alkyl, C2_g alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, C1, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_ 5 alkyl, (CH2)rNR~fR~f, and (CH2)rphenyl;

Ref, at each occurrence, is selected from H, C1-5 alkyl, and C3_6 cycloalkyl;
R8 is H or joins with R~ to form C3_~ cycloalkyl or =NReb;
R11, is selected from H, C1_6 alkyl, (CH2)rC3-6 cycloalkyl, (CH2)qOH, (CH2)q01211d, (CH2)qNRllaRlla', (CHZ)rC(0)Rllb~
(CH2 ) rC (O) NR11aR11.a' ~ (CH2 ) q~llaC (0) Rlla C1-6 haloalkyl, (CH2)rphenyl with 0-2 Rllc, (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 Rls;
Rlla and Rlla' , at each occurrence, are selected from H, C1_6 alkyl, (CH2)rC3_6 cycloalkyl, a (CHZ)rphenyl LS substituted with 0-3 Rlle;
Rllb at each occurrence, is selected from C1_6 alkyl, C2_8 alkenYl, C2_8 alkynyl, (CH2)rC3-s cYcloalkyl, (CH2)rphenyl substituted with 0-3 Rlle;
Rllc, at each occurrence, is selected from C1_4 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2)rC3-6 cYcloalkyl, C1, Br, I, F, (CF'2)rCF3, N02, CN, (CH2)rNRllfRllf~ (CH2)rOH.
(CH2)rOCl-4 alkyl, (CH2)rC(O)Rllb~ (CH2)rC(0)NRllfRllf~
:25 (CH2 ) rNRllfC (O) Rll.a (CH2 ) rS (O) pRllb~
(CHZ ) rS (0) 2NR11fRl.l.f ~ (CH2 ) rNRllfS (O) ZRllb, and (CH2)rphenyl substituted with 0-2 Rlle;
Rlld~ at each occurrence, is selected from C1_6 alkyl, :30 (CH2)rC3-s cYcloa:Lkyl, (CH2)rphenyl substituted with 0-3 Rlle Rlle, at each occurrence, is selected from C1_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, C1, F, Br, I, :35 CN, NC>2, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_ alkyl, (CH2)rNRl:1fR11f~ and (CH2)rphenyl;

Rllf, at each occurrence, is selected from H, C1-5 alkyl and C3_5 cycloalkyl;
R12 is H or joins with R11 to form C3_~ cycloalkyl;
v is selected from 1 and 2;
q is selected from 1, 2, and 3; and r is selected from 0, 1, 2, and 3.
[14] In a more preferred embodiment, the present invention provides novel compounds of formula (I), wherein:
ring A is selected from:
(R 14)9 (R 14)9 (R 14)9 (R 14)9 (R 14)9 .r' ~'i (R )9 , and (R )9 ;
R3 is selected from a (CR3'H)r-carbocyclic residue substituted with 0-5 R15, wherein the carbocyclic residue is selected from phenyl, C3_6 cycloalkyl, naphthyl, and adamantyl; and a (CR3'H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoqui.nolinyl, i:midazolyl, indolyl, indolinyl, isoindolyl, isot.hiadiazolyl, isoxa;:olyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and p:yrimidinyl; and R5 is selected from (C:R~'H)t-phenyl substituted with 0-5 R16; and a (CR5'H)t-heterocyclic system substituted with 0-3 R16, wherein the heterocyclic system is J_0 selected from pYridinyl, thiophenyl, furanyl, indazolyl, benzot:hiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolYl, indolyl, isoindo7_yl, piperidinyl, pyrrazolyl, 1,2,4-25 triazolyl, 1,2,3--triazolyl, tetrazolyl, thiazolyl, oxazol:yl, pyrazinyl, and pyrimidinyl.
[15). In an even more' preferred embodiment, the present invention provides novel compounds of formula (I-i), 20 wherein the compound of= formula (I-i) is:
Z
K~ N-E-N~N-R3 H H
(I-i) 25 R16, at each occurrence, is selected from C1_8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, C1, Br, I, F, (CH2)rNR16aR16a'~ N02, CN, OH, (CH2)rORl6d~
(CH2 ) rC (O) Rl6b~ (CH2 ) rC (O) NR16aR16a' , (CH2 ) rNRl6fC (O) Rl6b (CH2)rS(O)pRl6b~ (CH2)rS(O)2NR16aR16a'~
31) (CH2 ) rNRl6fS (O) 2R16b, and (CH2 ) rphenyl substituted with 0-3 Rl6e Rl6a and Rl6a~~ at each occurrence, are selected from H, C1-6 alkyl, C3_6 cycloa~lkyl, and (CH2)rphenyl substituted 3-''~ with 0-3 Rl6e Rl6b at each occurrence, is selected from H, C1_6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 Rl6e;
Rl6d, at each occurrence, is selected from Cl_6 alkyl and phenyl;
Rl6e, at each occurrence, is selected from C1_6 alkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_~ alkyl;
and Rl6f at each occurrence, is selected from H, and C1-5 alkyl.
[16] In an another even more preferred embodiment, the present invention provides novel compounds of formula (I-ii), wherein (I-ii) is:
Z
K ~N-E-N ~ N-R3 H H
2 0 R's (I-ii) R16, at each occurrence, is selected from C1_a alkyl, (CH2)rC3-6 cycloalkyl, CF3, C1, Br, I, F, (CH2)rNR16aR16a', NO2, CN, OH, (CH2)rORl6d (CH2 ) rC (O) Rl6b (CH2 ) rC (O) NR16aR16a' , (CH2 ) rNRl6fC (O) Rl6b (CH2)rS(p)pRl6b tCH2)rS(O)2NR16aR16a', (CH2)rNRl6fS(O)2R16b and (CH2)rphenyl substituted with 0-3 Rl6e;
Rl6a and Rl6a' , at each occurrence, are selected from H, C1_6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 Rl6e;

Rl6b, at each occurrence, is selected from H, C1_6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 Rl6e;
Rl6d, at each occurrence, is selected from C1_6 alkyl and phenyl;
Rl6e at each occurrence, is selected from C1_6 alkyl, C1, F, Br, I, CN, NO~, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
and Rl6f~ at each occurrence, is selected from H, and C1-5 alkyl.
[17] In a preferred embodiment, the present invention provides navel compounds of formula (I-i), wherein:
R5 is CH2phenyl substituted with 0-3 R16;
:~0 R9, is selected from H, C~_6 alkyl, (CH2)rC3-6 cYcloalkyl, F, C1, Cnf, (CH2)rOH, (CH2)rOR9d, (CH2)rNR9aR9a'.
(CH2)rOC(O)NHR9a, (CH2)rphenyl substituted with 0-5 R9e, and a heterocycl_LG System substituted with 0-2 R9e, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a'~, at each occurrence, are selected from H, C1-6 alkyl, C3_6 cycloalkyl, and (CHZ)rphenyl substituted with 0-3 R9e;
:30 R9d, at each occurrence, is selected from C1_6 alkyl and phenyl;
R9e, at each occurrence, is selected from C1_6 alkyl, C1, F, a5 Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCZ_5 alkyl;
R1~ is selected from H, C1_5 alkyl, OH, and CH20H;

alternatively, R9 and R1~ join to form C3_~ cycloalkyl, 5-6-membered cyclic ketal or =0;
with the proviso that when R1~ is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R11 is selected from H, C1_g alkyl, (CH2)rphenyl substituted with 0-5 Rlle, and a (CHZ)r-heterocyclic system substituted with 0-2 Rlle, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and Rlle at each occurrence, is selected from C1_6 alkyl, Cl, F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)_OC1_5 alkyl;
R12 is H;
alternatively, R11 and R12 join to form C3_~ cycloalkyl;
R14, at each occurrence, is selected from C1_8 alkyl, (CH2 ) rC3-6 cYcloalkyl , CF3 , C1, Br, I, F, (CHZ)rNR14aR14a~ NOZ CN, OH, (CH2)rORl4d (CH2)rC(O)Rl4b~ (CH2)rC(O)NR14aR14a' (CH2)rNRl4fC(0)Rl4b (CH2)rS(0)pRl4b~ (CH2)rS(O)2NR14aR14a'~
(CHz)rNRl4fS(O)2R14b (CH2)rphenyl substituted with 0-3 Rl4e~ and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 RlSe;

Rl4a and R14~~' , at each occurrence, are selected from H, Cz_6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0~-3 Rl4e, anti a (CHZ)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 RlSe;
Rl4b~ at each occurrence, is selected from H, C1-6 alkyl, C3_6 cycloalkyl, and (CHZ)rphenyl substituted with 0-3 Rl4e Rl4d, at each occurrence, is selected from C1_6 alkyl and phenyl ;~
Rl4e, at each occurrence, is selected from C1_6 alkyl, C1, F, Br, I, CN, N02; (CF2)rCF3, OH, and (CH2)rOCl-5 alkyl;
and Rl4f, at each occurrence, is selected from H, and C1-5 alkyl;
and r is selected from 0, :1, and 2.
[18) In a preferred embodiment, the present invention provides novel compounds of formula (I-ii), wherein:
R5 is CH2phenyl substituted with 0-3 R16 R9, is selected from H,. C1_6 alkyl, (CH2)rC3-5 cycloalkyl, F, C1, CN, (CH2)rOH, (CH2)rOR9d, (CH2)rNR9aR9a', (CH2)rOC(0)NHR9a, (CH2)rphenyl substituted with 0-5 R9e, and a heterocyclic system substituted with 0-2 R9e, wherein the heterocyclic system is selected from pyridy7., thiophenyl, furanyl, oxazolyl, and thiazolyl;
3'.~

R9a and R9a' , at each occurrence, are selected from H, Cl-5 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1_6 alkyl and phenyl;
R9e, at each occurrence, is selected from C1_6 alkyl, C1, F, Br, I, CN, N02, (CFZ)rCF3, OH, and (CHz)rOCl_S alkyl;
RIB is selected from H, C1_8 alkyl, OH, and CH20H;
alternatively, R9 and R1~ join to form C3_~ cycloalkyl, 5-6-membered cyclic ketal or =O;
with the proviso that when R1~ is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R11 is selected from H, C1_g alkyl, (CH2)rphenyl substituted with 0-5 Rile, and a (CH2)r-heterocyclic system substituted with 0-2 Rlle, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and Rlle~ at each occurrence, is selected from Cl_6 alkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
R12 is H;
alternatively, R11 and R12 join to form C3_~ cycloalkyl;

R14, at each occurrence, is selected from C1_8 alkyl, (CH2)rC3-6 cyclaalkyl, CF3, Cl, Br, I, F, (CH2)rNR14aR14a' NO2~ CN, OH, (CH2)rORl4d~
(CH2)r~(O)Rl4b~ (CH')rC(O)NR14aR14a', (CH2)rNRl4fC(O}Rl4b~
(CH2)rS(O)pRl4b, (CH2)rS(0}2NR14aR14a'~
(CH2 ) r;.'~3R14fS (O) 2R:L4b (CH2 ) rphenyl substituted with 0-3 Rl4e ~~nd a (CH~)r-S-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 RlSe;
Rl4a and Rl4a~, at each occurrence, are selected from H, C1_6 alkyl, C3_6 cycloa.lkyl, and (CH2)rphenyl substituted with 0-3 Rl4e Rl4b at each occurrence, is selected from H, C1_6 alkyl, C3_6 cycloalkyl, .and (CH2)rphenyl substituted with 0-3 Rl4e.
Rl4d at each occurrence, is selected from C1_6 alkyl and phenyl ,;
Rl4e, at each occurrence, is selected from C1_6 alkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2}rOCl_5 alkyl;
Rl4f~ at each occurrence, is selected from H, and C1-5 alkyl;
and 31) r is selected from 0, 1, and 2.
[19] In a more preferred embodiment, the present invention provides novel compounds of formula (I-i), wherein:
J is selected from CH2 and CHRS;
K is selected from CH2 and CHRS;

WO 00/35449 PCT/L'S99/30292 L is selected from CH2 and CHRS;
R3 is a C3_to carbocyclic residue substituted with 0-3 R1J, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3'H}r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R15, at each occurrence, is selected from C1-g alkyl, (CH2)rC3-6 cYcloalkyl, CF3, C1, Br, I, F, 2 0 (CHZ)rNR15aR15a'. N02, CN, OH, (CH2)rORlSd (CH2)rC(0)RlSb. (CH2)rC(O)NR15aR15a', (CH2)rNRlSfC(O)RlSb (CHZ)rS(O)pRlSb. (CHZ)rS(0)2NR15aR15a'.
(CH2)rNRlSfS(O)2R15b (CH2)rphenyl substituted with 0-3 RlSe. and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 RlSe;
RlSa and RlSa', at each occurrence, are selected from H, C1-6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 RlSe;
Rl5b. at each occurrence, is selected from H, C1_6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 RlSe;
RlSd. at each occurrence, is selected from C1_6 alkyl and phenyl;

RlSe, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NC)~;, (CF2)rCF3, OH, and (CHZ)rOCl_S alkyl;
and RlSf, at each occurrence, is selected from H, and C1-5 alkyl.
[20] In a more preferred embodiment, the present invention provides novel compounds of formula (I-ii), wherein:
K is selected from CH4 and CHRS;
L is selected from CHI; and CHRS;
R3 is a C3_.lo carbocyc;lic residue substituted with 0-3 R15, wherein the cark>ocyclic residue is selected from cyclopropyl, cyc:lopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3'H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazo7.yl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, pipE:ridinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R15, at each occurrence, is selected from C1_g alkyl, (CH2):rC3-~ cycloalkyl, CF3, Cl, Br, I, F, (CH2):rNR15aR15a' ~ N02, CN, OH, (CH2)rORlSd (CH2):rC(0)RlSb~ (CH2)rC(O)NR15aR15a'. (CH2)rNRlSfC(O)RlSb~
(CH2).rS(0)pRlSb~ (CHZ)rS(0)2NR15aR15a'.
(CH2)rNRl5tS(O)2FZ15b, and (CH2)rphenyl substituted with 0-3 RlSe, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 RlSe.
RlSa and RlSa', at each occurrence, are selected from H, C1-5 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 RlSe;
RlSb, at each occurrence, is selected from H, C1_6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 RlSe;
RlSd at each occurrence, is selected from C1-6 alkyl and phenyl;
RlSe, at each occurrence, is selected from C1_6 alkyl, C1, F, Br, I , CN, N02 , ( CF2 ) rCF3 , OH , and ( CH2 ) rOCl-5 alkyl ;
and RlSf~ at each occurrence, is selected from H and Cz-5 alkyl.
[21] In another embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention.
[22] In another embodiment, the present invention provides a method for modulation of chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of the compounds of the present invention.
[23] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.
[24) In a fifth embodiment, the present invention provides a method for treating or preventing asthma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.
In another embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount :10 of a compound of the present invention.
In another embodiment, the present invention provides a method for modulation of chemokine receptor activity comprising administering to a patient in need thereof a J_5 therapeutically effective amount of a compound of the present invention.
In another embodiment, the present invention provides a method fo:r treating inflammatory disorders comprising 20 administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention In anot=her embodiment, the present invention provides 25 a method for treating or preventing disorders selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplantation, familial 31) eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinoph~l.ic fasciitis, eosinophilic gastroenteritis, drug :induced eosinophilia, HIV infection, cystic fibrosis, Churg~-Strauss syndrome, lymphoma, Hodgkin's disease, and colonic carcinoma.
3 ~~

DEFINITIONS
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., =O), then 2 hydrogens on the atom are replaced.
When any variable (e. g., Ra) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 Ra, then said group may optionally be substituted with up to two Ra groups and Ra at each occurrence is selected independently from the definition of Ra. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in :table compounds.
As used herein, "C1-g alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-prop:yl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. C1_8 alkyl, is intended to include C1, Cz, C3, C4, C~, C6, C~, and Cg alkyl groups.
"Alkenyl" i.s intended to include hydrocarbon chains of .15 either a straight or branched configuration and one or more unsaturateo. carbon-cao~bon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. "Alkyny:l" is intended to include hydrocarbon chains of either a straight or branched configuration and a:0 one or more unsaturated triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, and the like. "C3_6 cycloalkyl" is intended to include saturated ring groups having the specified number of carbon atoms in the ring, including 25 mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl in the case of C~ cycloalkyl. C3_6 cycloalkyl, is intended to include C3, C4, C5, and C6 cycloalkyl groups "Halo" or "halogen" as used herein refers to fluoro, 30 chloro, bromo, and iod.o; and "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, for example CF3, having the specified niunber of carbon atoms, substituted with 1 or more halogen (for example -C~FW where v = 1 to 3 and w = 1 3:5 to ( 2v+1 ) ) .
The compounds of Formula I can also be quaternized by standard techniques such as alkylation of the piperidine or WO 00/35449 PCT/US99l30292 pyrrolidine with an alkyl halide to yield quaternary piperidinium salt products of Formula I. Such quaternary piperidinium salts would include a counterion. As used herein, "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, the term "piperidinium spirocycle or pyrrolidinium spirocycle" is intented to mean a stable spirocycle ring system, in which the two rings form a quarternary nitrogene at the ring junction.
As used herein, the term "5-6-membered cyclic ketal"
is intended to mean 2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane and their derivatives.
As used herein, "carbocycle" or "carbocyclic residue"
is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings . WO 00/35449 YCT/US99/30292 described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to ?- membered monocyclic or bicyclic ox- 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indol.yl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazol;yl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzi.midazalonyl, carbazolyl, 4aH-carbazo:lyl, p-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-8)tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinoli;nyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazoly:l, oxazo-~idinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxaz:ale, pyridoimidazole, WO 00135449 PCT/1JS99/3v292 pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, 25 isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts"
refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or arganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, malefic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-:10 acetoxyben~:oic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention c:an be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical .l5 methods. Gienerally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiomet:ric amount of the appropriate base or acid in water or in an organi~~ solvent, or in a mixture of the two;
generally, nonaqueous media like ether, ethyl acetate, ~.'0 ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, l.7th ed., Mack Publishing Company, Easton, PA, 1985, p. 1918, the disclosure of which is hereby incorporated by refer=_nce.
25 Since prodrugs a:re known to enhance numerous desirable qualities of pharmaceuticals (e. g., solubility, bioavailability, manufacturing, etc...) the compounds of the present invention may be delivered in prodrug form.
Thus, the present invention is intended to cover prodrugs ?.0 of the presently claimed compounds, methods of delivering the same and compositions containing the same. "Prodrugs"
are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a 35 mammalian subject. P:rodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present S invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
SYNTHESIS
The compounds of Formula I can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

Generally, compounds described in the scope of this patent application can be synthesized by the route described in Scheme 1. The appropriately substituted pyrrolidine (n=0) or piperidine (n=1) 1 is alkylated by a N-protected alkylhalide (halide = C1, Br, I), mesylate, tosylate or triflate, 2, (where E represents a linkage described within the scope of this application in its fully elaborated form with the appropriate protecting groups as understood by one skilled in the art or in a precursor form which can be later elaborated into its final form by methods familiar to one skilled in the art) with or without base or an acid scavenger to yield the piperidinyl- or pyrrolidinylalkyl protected amine 3. If the halide is not I, then KI car. also loe added to facilitate the displacement, provided the solvent is suitable, such as an alcohol, 2-butanone, DMF or DMSO, amongst others. The displacement can be performed at room temperature to the reflux temperature o:E the solvent. The protecting group is subsequently removed to yield amine _4. Protecting groups include phthalimide ~Nhich can be removed by hydrazine, a reaction familiar to one skilled in the art; bis-BOC which can be removed by eit=her TFA or HC1 dissolved in a suitable solvent, both procedures being familiar to one skilled in the art; a nitro group instead of an amine which can be reduced to yield an amine by conditions familiar to one skilled in the art; :?,4-dimethyl pyrrole (S. P. Breukelman, et al. J. Chem. Soc. Perkin Trans. I, 1984, 2801); N-1,1,4,4-Tetramethyl-<iisilylazacyclopentane (STABASE) (S.
Djuric, J. Venit, and P. Magnus Tet. Lett 1981, 22, 1787) and other protecting groups. Reaction with an isocyanate or isothiocyanate 5 (Z =- O,S) yields urea ~r thiourea 6.
Reaction with a chloroformate or chlorothioformate 7 (Z=O,S) such as o-, p-nitrophenyl-chloroformate or phenylchloroformate (ar their thiocarbonyl equivalents), followed by diplacement with an amine 9, also yields the corresponding urea or thiourea 6. Likewise, reaction of carbamate _8 (X = H, c>r 2- or 4-N02) with disubstituted amine 10 yields trisubstituted urea or thiourea 12.
Reaction of the amine 4 with an N,N-disubstituted carbamoyl chloride 11 (or its thiocarbonyl equivalent) yields the corresponding N,N-disubstituted urea or thiourea 12.
Amine 4 can also be reductively aminated to yield 13 by conditions familiar to one skilled in the art and by the following conditions: Abdel-Magid, A. F., et al. Tet. Lett.
1990, 31, (39) 5595-5598. This secondary amine can subsequently be reacted with isocyanates or isothiocyanates to yield trisubstituted ureas 14 or with carbamoyl chlorides to yield tetrasubstituted ureas 15.

H
1V~ H--.~- P
+ X/,L~N_ P ~ wN~

R5 n 1 P=protecting grow 5 ri P
X=leaving group: CI,Br,I, R 3 n=0, 1 OTs, OMs, OTf, etc E=linker y (C'=Z ) -NR2R3 E"~~2 ~ Cl- (C=Z) -NR2R3 11 n R5 :n 12 R5 4 2 3 C1- ( C=Z ) -OPh R3N=C=Z

~-NH- ( C=Z ) -OPh- Y ,~NH- ( C=Z ) -NH-R3 R5 l:n 8 --.-~ R~ Jn 6 Y = H, o- or p-N02 Na (Ac0) 38H /
'~R2- (C=Z ~ -~3 R3N=C=Z
~,z--NHR 2 s R5 n 14 R5 n 13 ~r---NR2- (C=Z ) -NRzR3 C1- (C=Z) -NR2R3 Z=0 or S 11 R5 n 15 One can also convert amine 4 into an isocyanate, isothiocyanate, carbamoyl chloride or its thiocarbonyl 5 equivalent (isocyanate~: Nowakowski, J. J Prakt. Chem/Chem-Ztg 1996, 3.38 (7), 667-671; Knoelker, H.-J. et al., Angew.
Chem. 1995, 107 (22), 2746-2749; Nowick, J. S.et al., J.
Org. Chem. :1996, 61 (11), 3929-3934; Staab, H. A.; Benz, W.; Angew Chem 1961, 73; isothiocyanate: Strekowski L.et al., J. Heterocycl. Chem. 1996, 33 (6), 1685-1688;
Kutschy, Pet al., Synlett. 1997, (3), 289-290) carbamoyl chloride: Hintze, F.; Hoppe, D.; Synthesis (1992) 12, 1216-1218; thiocarbamoyl chloride: Ried, W.; Hillenbrand, H.;
Oertel, G.; Justus Liebigs Ann Chem 1954, 590) (these reactions are not shown in Scheme 1). These isocyanates, isothiocyantes, carbamoyl chlorides or thiocarbamoyl chlorides can then be reacted with R2R3NH to yield di- or trisubstituted ureas or thioureas 12. An additional urea forming reaction involves the reaction of carbonyldiimidazole (CDI) (Romine, J. L.; Martin, S. W.;
Meanwell, N. A.; Epperson, J. R.; Synthesis 1994 (8), 846-850) with 4 followed by reaction of the intermediate imidazolide with 9 or in the reversed sequence (9 + CDI, followed by 4). Activation of imidazolide intermediates also facilitates urea formation (Bailey, R. A., et al., Tet. Lett. 1998, 39, 6267-6270). One can also use 13 and 10 with CDI. The urea forming reactions are done in a non-hydroxylic inert solvent such as THF, toluene, DMF, etc., at room temperature to the reflux temperature of the solvent and can employ the use of an acid scavenger or base when necessary such as carbonate and bicarbonate salts, triethylamine, DBU, Hunigs base, DMAP, etc.
Substituted pyrrolidines and piperidines 1 can either be obtained commercially or be prepared as shown in Scheme 2. Commercially available N-benzylpiperid-3-one 16 can be debenzylated and protected with a BOC group employing reactions familiar to one skilled in the art. Subsequent Wittig reaction followed by reduction and deprotection yields piperidine 20 employing reactions familiar to one skilled in the art. Substituted pyrrolidines may be made by a similar reaction sequence. Other isomers and analogs around the piperidine ring can also be made by a similar reaction sequence. Chiral pyrrolidines/piperidines can be synthesized via asymmetric hydrogenation of 18 using chiral catalysts (see Parshall, G.W. Homogeneous Catalysis, John Wiley and Sons, New 'York: 1980, pp. 43-45; Collman, J.P., Hegedus, h.S. Principles and Applications of Organotransition Met,ai Chemistry, University Science gooks, Mill Valley, CA, 1980, pp. 341-348).

Hz/Pd Wittig H2/Pd _--s s -:.
BOC:2 0 R~
BOC BOC

H+

H
The ~~yanoguanidines (Z = N-CN) can be synthesized by the method of K. S. Atwal, et al. and references contained therein (.J. Med. Chem. (1998) 41, 217-275). The nitroethylene analog (Z - C-N02) can be synthesized by the method of F. Moimas, et al. (Synthesis 1985, 509-510) and references contained therein. The malononitrile analog (Z
- C(CN)2) may be synthesized by the method of S. Sasho, et al. (J. Med. Chem. 1993, 36, 572-579).
Guanidines (Z=NRla) can be synthesized by the methods outlined in Scheme 3. Compound ~1 where Z=S can be methylated -to yield the methylisothiourea 22. Displacement of the SMe group with amines yields substituted guanidines ?L3 (see H. King and T. M. Tonkin J. Chem. Soc. 1946, 1063 and references therein). Alternatively, reaction of thiourea ,21 with amines in the presence of triethanolamine and "lac sulfur" which facilitates the removal of H2S
yields substituted g~uanidines 23 (K. Ramadas, Tet. Lett.
1996, 37, 5161 and references therein). Finally, the use of carbonimidoyldichloride 24, or 25 followed by sequential displacements by amines yields the corresponding substituted guanidine 23 (S. Nagarajan, et al., Syn. Comm.
1992, 22, 1191-8 and references therein). In a similar manner, carbonimidoyldichlorides, R2-N=C(CI)2 (not shown in Scheme 3) and R3-N=C(C1)2 (not shown) can also be reacted sequentially with amines to yield di- and trisubstituted guanidine 23.

E-NR' - ( C=S ) -NHR la ~~1 _ ( C=NHRla ) -SMe R5 n 21 ~ /n n=0,1 N ( CH20H ) 3 , "lac sulfur" , F-NR1- (C=NHRla) -NR2R3 ~i I.H2NR", Et3N R5 n 23 2 . HNR2R3 or 1 . HNR2R3 , Et3N 1 . HNR2R3 , Et3N
2 . HZNR" 2 . 13 or 1 . 13 , Et3N
2 . HNR2R3 N=C (C1) 2 Rla-N=C ( C1 ) 2 ~n 24 25 R
A method for introducing substituents in linkage E is that of A. Chesney et al. (Syn. Comm. 1990, 20 (20), 3167-3180) as shown in Scheme 4. Michael reaction of pyrrolidine or piperidine 1 with Michael acceptor 26 yields intermediate 27 which can undergo subsequent reactions in the same pot. For example, reduction yields alcohol 28 which can be elaborated to the amine 29 by standard procedures familiar to one skilled in the art. Some of these include mesylation or tosylation followed by d:.splacement with NaN3 followed by reduction to yield amine 29. Another route as depicted in Scheme 4 involves reaction with diphenylphosphoryl azide followed by reduction of the azide to yield amine 29.
SCHEME 9.
g 9 ~H 9 + ~ ~ O Michael R5 n Rxn iz Re R11 R5 n R
n=0, 1 Rl2Li or Rl2MgBr NaBH4 31 a Old R~ n R1 i 2 8 1~
(Ph0)2(P=O):N3 32 (ph0)2(P=O)N3 .H2, Pd/C
H2, Pd/C

h n 33 29 as described as described previously previously 1- ( C=~~ ) -NR2 R3 1 _ ( C=Z ) -NR2 R3 The mesylate or tosylate can also be displaced by other nucleophiles such as NH3, BOC2N-, potassium phthalimide, etc., with subsequent deprotection where necessary to yield amines 29. Finally, 29 can be converted to urea or thiourea 30 by procedures discussed for Scheme 1 or to the compounds of this invention by procedures previously discussed. Similarly, aldehyde 27 may be reacted with a lithium or a Grignard reagent 31 to yield alcohol adduct 32. This in turn can be converted to urea or thiourea 34 in the same way as discussed for the conversion of 28 to 30.
Scheme 5 shows that intermediate 36 can be extended via a Wittig reaction (A. Chesney, et al. Syn. Comm. 1990, (20), 3167-3180) to yield 37. This adduct can be 15 reduced catalytically to yield 38 or by other procedures familiar to one skilled in the art. Alkylation yields 39, followed by saponification and Curtius rearrangement (T. L.
Capson and C. D. Poulter, Tet. Lett., (1984) 25, 3515-3518) followed by reduction of the benzyl protecting group yields 20 amine 40 which can be elaborated further as was described earlier in Scheme 1 and elsewhere in this application to make the compounds of this invention. Dialkyllithium cuprate, organocopper, or copper-catalyzed Grignard addition (for a review, see G. H. Posner, "An Introduction to Synthesis Using Organocopper Reagents", J. Wiley, New York, 1980; Organic Reactions, 19, 1 (1972)) to alpha,beta-unsaturated ester 37 yields 41 which can undergo subsequent transformations just discussed to yield amine 43 which can be elaborated further to the compounds of this invention as was described earlier. The intermediate enolate ion obtained upon cuprate addition to 37 can also be trapped by an electrophile to yield 42 (for a review, see R. J. K.
Taylor, Synthesis 1985, 364). Likewise, another 2-carbon homologation is reported by A. Chesney et al. (ibid.) on intermediate 36 which involves reacting 36 with an enolate anion to yield aldol condensation product 42 where R~2-OH.
The OH group can undergo synthetic transformations which are familiar to one skilled in the art and which will be discussed in much detail later on in the application.
Chiral au:xilliaries can also be used to introduce stereo-and enantioselectivi.ty in these aldol condensations, procedures which are familiar to one skilled in the art.

i SCHEME S
7 8 Rg H g O Michael Rxn ~ ~0 R
R5 ~r_ / > R5 Jn Rg 1 R8 Rg 3 6 n=0 , 1 35 R11 Wittig ~ pph~( \'OMe Hz Pd/C
1.LDA '°
2 . RlzX 37 1 . -OH
2 . ( Ph0 ) z ( P=O ) N3 5 n Rg R ,~ ~ 2 3.BnOH
39 4.Hz Pd/C 40 to compounds by methods 8 g 7 8 g previously discussed 11 as above 11 ~n R9~NH2 g OMe R R R~ wn R Rlo 44 41 ~ (Rlo)zCuLi 1.LDA
to compounds by methods ~ 8 9 2 ' R12X 8 g 2 . RlzX
previously discussed ~ R11 12 ag R 11 above ~ Rlz R~ 'n Rg Rlo NHz R~ ~n Rg Rlo OMe Examples of such methods are taught in D. A. Evans, et al., J. Am. Chem. Soc. 1981, 103, 2127; D. A. Evans, J. Am.
5 Chem.Soc. 1982, 104, 1737; D. A. Evans, J. Am. Chem. Soc.

WO 00/35449 PCT/iJS99/30292 1986, 108, 2476; D. A. Evans. et al., J. Am. Chem. Soc.
1986, 108, 657; D. A. Evans, J. Am. Chem. Soc. 1986, 108, 6395; D. A. Evans, J. Am. Chem. Soc. 1985, 107, 4346; A.
G. Myers, et al., J. Am. Chem. Soc. 1997, 119, 6496. One can also perform an enantioselective alkylation on esters 38 or 41 with Ri2X where X is a leaving group as described in Scheme 1, provided the ester is first attached to a chiral auxiliary (see above references of Evans, Myers and Mauricio de L. Vander..lei, J. et al., Synth. Commum. 1998, 1.0 28, 3047} .
One ca:n also react alpha,beta-unsaturated ester 37 (Scheme 6) with Corey's dimethyloxosulfonium methylide (E.J. Corey and M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1345) to foam a cyclopropane which can undergo eventual Curtius rearrangement and subsequent elaboration to the compounds of this invention wherein the carbon containing R9R1~ is tied up in a cyclopropane ring with the carbon containing ;R11R12. In addition, compound 48 can also undergo the analogous reactions just described to form cyclopropylamine 50 which can be further elaborated into the compounds of this invention as described previously.
Compound 48 may be synthesized by an alkylation,reaction of pyrrolidine/piperidine 1 with bromide 47 in an inert solvent employing the conditions as described for the alkylation of 2 onto 1 in Scheme 1.
Another way to synthesize the compounds in the scope of this application is shown in Scheme 7. Michael reaction of amine 1 with an acrylonitrile 51 (as described by I.
Roufos in J. Med. Chem. 1996, 39, 1514-1520) followed by Raney-Nicke:i hydrogenation yields amine 53 which can be elaborated to the compounds of this invention as previously described.

I-OMe OMe NaH, THF
37 '*o 1 . - OH
2 . ( Ph0 ) 2 ( P=O ) N3 3.BnOH
4.H2 Pd/C
~ ~s 9 to compounds by methods ~ +
previously discussed R5 ~n R9 NH2 C02 Me --~ +
C02 Me ~n Rli NaH, R 48 THF R~ ~n R11 s R9 1.-OH
1 + 2 . ( Ph0 ) 2 ( P=O ) N3 Br ~ 3.BnOH
47 C02Me 4. H2 Pd/C

g 9 to compounds by methods ~ ~ +
previously discussed R5 n R11 In Schemes 4,5, and 6, we see that there is no gem-substitution on the alpha-carbon to the electron-s withdrawing group of what used to be the Michael acceptor.
In other words, in Scheme 4, there is no R~0 gem to R9; in Scheme 5, there is no R10 gem to one of the R9s and in Scheme 7 there is no R10 gem to R9. Gem-substitution can be introduced by :~eact:ing pyrrolidine or piperidine 1 with the epoxide of Michael acceptors 26, 35, and 51 to yield the corresponding alcohols (for amines reacting with epoxides of Michael acceptors, see Charvillon, F. B.;
Amouroux, R.; Tet. Lett. 1996, 37, 5103-5106; Chong, J.
M.; SharplE~ss, K. B.; J Org Chem 1985, 50, 1560). These alcohols a«entually can be further elaborated into R10 by one skilled in the art, as, for example, by tosylation of .LO the alcohol. and cuprate displacement (Hanessian, S.;
Thavonekham, B.; DeHoff, B.; J Org. Chem. 1989, 54, 5831), etc., and by other displacement reactions which will be discussed in great detail later on in this application.
SCHEME '1 R Re H ~3 V
+ R CN Ra_Ni/H2 ~CN --~ ' R9 Rs n 1 R8 R5 ~n 5~
n=0,1 51 R~
C:H2 -NH2 '' ~ to compounds g by methods previously discussed Jn 1'S 5 :3 Further_ use of epoxides to synthesize compounds of this invention are shown in Scheme 8. Reaction of pyrrole or piperidine 1 with epoxide 54 yields protected- - amino-2() alcohol 55. This reaction works- exceptionaly well when R~
and R8 are H but is not limited thereto. The reaction is performed in an inert solvent at room temperature to the reflux temperature of the solvent. Protecting groups on the nitrogen atom of 54 include BOC and CBZ but are not 25~ limited thereto. The :hydroxyl group can be optionally protected by a variety of protecting groups familiar to one skilled in the art.

H ~ 9or10 R
+ Rg NH- P
R5 n R1 Rlz - P

h n=0,1 55 fO] -P
( R9or10=H ) "-7 ~8 p9or10 _P
7 ' ~mnz R9or10-M R5 n R-11 \R12 where M=Li,MgBr, MgCl, ZnCl, etc.
_P
-7 a R9or10 to compounds OH by methods previously discussed _P
R5" ~ ~n R11 'Rlz S
Deprotection of the nitrogen by methods familiar to one skilled in the art yields 56 which can be elaborated to the compounds of this invention by the procedures previously discussed. If R9=H, then oxidation, for example, by using PCC (Corey E.J. and Suggs, J.W., Tet. Lett. 1975, 31, 2647-2650) or with the Dess-Martin periodinane (Dess, D.B. and Martin, J.C., J. Org. Chem. 1983, 48, 4155-4156) yields ketone 57 which may undergo nucleophilic 1,2-addition with organometallic reagents such as alkyl- or aryllithiums, Grignards, or zinc reagents, with or without CeCl3 (T.
Imamoto, et al., Tet. I~ett. 1985, 26, 4763-4766; T.
Imamoto, et al., Tet. Lett. 1984, 25, 4233-4236) in aprotic solvents s,ich as ether, dioxane, or THF to yield alcohol 58. The hydroxyl group can be optionally protected by a variety of protecting groups familiar to one skilled in the art. Deprotection of the nitrogen yields 56 which can be finally el<~borated to the compounds of this invention as previously discussed. Epoxides disclosed by structure _54 may be synt=hesized enantio-selectively from amino acid starting materials by the methods of Dellaria, et al. J Med Chem 1987, 30 (11), 2:L37, and Luly, et al. J Org Chem 1987, 52 (fi) , 1487.
The carbonyl group of ketone 57 in Scheme 8 may :L5 undergo Wit:tig reactions followed by reduction of the double bond to yield alkyl, arylalkyl, heterocyclic-alkyl, cycloalkyl, cycloalky7Lalkyl, etc. substitution at that position, reactions that are familiar to one skilled in the art. Wittig reagents can also contain functional groups :?0 which after reduction of the double bond yield the following functionality: esters (Buddrus, J. Angew Chem., 1968, 80), nitriles (C:ativiela, C.et al., Tetrahedron 1996, 52 (16), 5881-5E~88.), ketone (Stork, G.et al., J Am Chem Soc 1996, 118 (43), 10660-10661), aldehyde and ~;5 methoxymethyl (Bertram, G.et al., Tetrahedron Lett 1996, 37 (44), 7955-7958.), gamma-butyrolactone Vidari, G.et al.,Tetrahedron: Asymmetry 1996, 7 (10), 3009-3020.), carboxylic acids (Svoboda, J.et al., Collect Czech Chem Commun 1996, 61 (10), 1509-1519), ethers (Hamada, Y.et 30 al., Tetrahedron Lett 1984, 25 (47), 5413), alcohols (after hydrogenation and deprotection--Schonauer, K.; Zbiral, E.;
Tetrahedron Lett 1983, 24 (6), 573), amines (Marxer, A.;
Leutert, T. Helv Chim Acta, 1978, 61) etc., all of which may further undergo transformations familiar to one skilled 35 in the art 'to form a wide variety of functionality at this position.

Scheme 9 summarizes the displacement chemistry and subsequent elaborations that can be used to synthesize the R9 groups. In Scheme 9 we see that alcohol 55 or 58 may be tosylated, mesylated, triflated, or converted to a halogen by methods familiar to one skilled in the art to produce compound 59. (Note that all of the following reactions in this paragraph can be also performed on the compounds, henceforth called carbon homologs of 55 or 58 where OH can be (CH2)rOH and it is also understood that these carbon homologs may have substituents on the methylene groups as well). For example, a hydroxyl group may be converted to a bromide by CBr4 and Ph3P (Takano, S. Heterocycles 1991, 32, 1587). For other methods of converting an alcohol to a bromide or to a chloride or to an iodide see R.C. Larock, Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp. 354-360. Compound 59 in turn may be displaced by a wide variety of nucieophiles as shown in Scheme 9 including but not limited to azide, cyano, malonate, cuprates, potassium thioacetate, thiols, amines, etc., all nucleophilic displacement reactions being familiar to one skilled in the art. Displacement by nitrile yields a one-carbon homologation product. Nitrile 60 can be reduced with DIBAL to yield aldehyde 61. This aldehyde can undergo reduction to alcohol 62 with, for example, NaBH4 which in turn can undergo all of the SN2 displacement reactions mentioned for alcohol 55 or 58.
Alcohol 62 is a one carbon homolog of alcohol 55 or 58.
Thus one can envision taking alcohol 62, converting it to a leaving group X as discussed above for compound 55 or 58, and reacting it with NaCN or KCN to form a nitrile, subsequent DIBAL reduction to the aldehyde and subsequent NaBH4 reduction to the alcohol resulting in a two carbon homologation product. This alcohol can undergo activation followed by the same SN2 displacement reactions discussed previously, ad infinitum, to result in 3,4,5...etc. carbon homologation products. Aldehyde 61 can also be reacted with a lithium or Grignard reagent to form an alcohol 61a V~10 00/35449 PCT/US99/30292 which can also undergo the above displacement reactions.
Oxidation f>y methods famili~.r to one skilled in the art yields ketone 61b. Displacement by malonate yields malonic ester 63 which can be saponified and decarboxylated to yield carboxylic acid 64, a two carbon homologation product. Conversion to ester 65 (A. Hassner and V.
Alexanian, Tet. Lett., 1978, 46, 4475-8) and reduction with LAH yields alcohol 68 which can undergo all of the displacemer_t reactions discussed for alcohol 55 or 58.
:LO Alcohols may be converted to the corresponding fluoride 70 by DAST (diethylaminosulfur trifluoride) (Middleton, W. J.;
Bingham, E. M.; Org. Synth. 1988, VI, pg. 835). Sulfides 71 can be converted to the corresponding sulfoxides 72 (p=1) by sodium metaperiodate oxidation (N. J. Leonard, C.
.L5 R. Johnson J. Org. Chem. 1962, 27, 282-4) and to sulfones 72 (p=2) by Oxone~ (A. Castro, T.A. Spencer J. Org. Chem.
1992, 57, 3496-9). Sulfones 72 can be converted to the corresponding sulfonamides 73 by the method of H.-C. Huang, E. et al., Tet. Lett.. (1994) 35, 7201-7204 which involves :?0 first, treatment with base followed by reaction with a trialkylborane yielding a sulfinic acid salt which can be reacted with hydroxyl,amine-O-sulfonic acid to yield a sulfonamide. Another mute to sulfonamides involves reaction of amines with a sulfonyl chloride (G. Hilgetag 25 and A. Martini, Preparative Organic Chemistry, New York:
John Wiley and Sons, 1972, p.679). This sulfonyl chloride (not shown in Scheme 9) can be obtained from the corresponding sulfide (71, where R9d=H in Scheme 9, the hydrolysis product after thioacetate displacement), _s0 disulfide, or isothiouronium salt by simply reacting with chlorine in water. The isothiouronium salt may be synthesized from the corresponding halide, mesylate or tosylate 5~ via reaction with thiourea (for a discussion on the synthesis of sulfonyl chlorides see G. Hilgetag and A.
a5 Martini, ibid., p. 6'70). Carbaxylic acid 64 can be converted to amides 6~6_ by standard coupling procedures or via an acid chloride by Schotten-Baumann chemistry or to a Weinreb amide (66: R9a=OMe, R9a'= Me in Scheme 9) (S. Nahm and S. M. Weinreb, Tet. Lett., 1981, 22, 3815-3818) which can undergo reduction to an aldehyde 67 (R9b=H in Scheme 9) with LAH (S. Nahm and S. M. Weinreb, ibid.) or reactions with Grignard reagents to form ketones 67 (S. Nahm and S.
M. Weinreb, ibid.). The aldehyde 67 obtained from the Weinreb amide reduction can be reduced to the alcohol with NaBH4. The aldehyde or ketone 67 (or 61 or 61b for that matter) can undergo Wittig reactions as discussed previously followed by optional catalytic hydrogenation of the olefin. This Wittig sequence is one method for synthesizing the carbocyclic and heterocyclic substituted systems at R9 employing the appropriate carbocyclic or heterocyclic Wittig (or Horner-Emmons) reagents. Of course, the Wittig reaction may also be used to synthesize alkenes at R9 and other functionality as well. Ester 65 can also form amides 66 by the method of Weinreb (A. Basha, M.
Lipton, and S.M. Weinreb, Tet. Lett. 1977, 48, 4171-74) (J.
I. Levin, E. Turos, S. M. Weinreb, Syn. Comm. 1982, 12, 989-993). Alcohol 68 can be converted to ether 69 by procedures familiar to one skilled in the art, for example, NaH, followed by an alkyliodide or by Mitsunobu chemistry (Mitsunobu, O. Synthesis, 1981, 1-28). Alcohol 55 or 58, 62, or 68, can be acylated by procedures familiar to one skilled in the art, for example, by Schotten-Baumann conditions with an acid chloride or by an anhydride with a base such as pyridine to yield 78. Halide, mesylate, tosylate or triflate 59 can undergo displacement with azide followed by reduction to yield amine 74 a procedure familiar to one skilled in the art. This amine can undergo optional reductive amination and acylation to yield 75 or reaction with ethyl formate (usually refluxing ethyl formate) to yield formamide 75. Amine 74 can again undergo optional reductive amination followed by reaction with a sulfonyl chloride to yield 76, for example under Schotten-Baumann conditions as discussed previously. This same sequence may be employed for amine 60a, the reduction product of nitrile 60. Tosylate 59 can undergo displacement with cuprates to yield 77 (Hanessian, S.;
Thavonekham, B.; DeHoff, B.; J Org. Chem. 1989, 54, 5831).
Aldehyde 61 or its homologous extensions can be reacted with a carbon anion of an aryl (phenyl, naphthalene, etc.) or heterocyclic group to yield an aryl alcohol or a heterocyclic alcohol. If necessary, CeCl3 may be added (T.
Imamoto, et al., Tet. Lett. 1985, 26, 4763-4766; T.
Imamoto, et al., Tet. Lett. 1984, 25, 4233-4236). This alcohol may be reduced with Et3SiH and TFA (J. Org. Chem.
1969, 34, 4; J. Org. Chem. 1987, 52, 2226) (see discussion of aryl and heterocyclic anions for Schemes 20-22). These aryl and heterocyclic anions may also be alkylated by 59 (or its carbon homology to yield compounds where R9 contains an aryl or laeterocyclic group. Compound 59 or its carbon homologs may be alkylated by an alkyne anion to produce alkynes at R'-3 (see R.C. Larock, Comprehensive Organic Transformations, New York, 1989, VCH Publishers, p 297). In addition, carboxaldehyde 61 or its carbon homologs can undergo 1,2-addition by an alkyne anion (Johnson, A.W. The Chemistry of Acetylenic Compounds. V.
1. "Acetylenic Alcohols," Edward Arnold and Co., London (1946)). Nitro groups can be introduced by displacing bromide 59 (or its carbon homologs) with sodium nitrite in DMF (J.K. Stille and E.D. Vessel J. Org. Chem. 1960, 25, 478-490) or by the action of silver nitrite on iodide 59 or its carbon homologs (Org. Syntheses 34, 37-39).

ZO
10 ~ 1 9d R ~O~ ~ (O)pR9d O(CO)R9b 7 8 ,,~,,. 7 0 ~ 71 7 2 1 . KSAc 10 2.-OH ~ (O)2~9a DAST
3 . R9dX ~,, R9a or KSR9a /~ ~ 73 OH ~ a to NH _ P
R5 n R11 R12 ~ 59 NH-P
55 or 58 R5 n Rll R12 If an anion is made of the pyrrolidine/piperidine 1 5 with LDA or n-BuLi, etc., then that anion in a suitable nonhydroxylic solvent such as THF, ether, dioxane, etc., can react in a Michael-type fashion (1,4-addition) with an alpha, beta-unsaturated ester to yield an intermediate enolate which can be quenched with an electrophile (R9X) 10 (where X is as described in Scheme 1) (Uyehara, T.; Asao, N.; Yamamoto, Y.; J Chem Soc, Chem Commun 1987, 1410) as shown in Scheme 10.

SCHEME 9 (con~t) -P ~ -P
1, 1, 55 or 58 , 59 X=O~cs ; ( R9 ) 2cuLi ~ KCN , Et OEt - Na 9 to Rlo ~ CN OE
1 . N ~ g to \ 2 . [H 60 '~'' ~~C OEt _lo to l0 63 t CHO
74 ~
62 ~ LAH
1 . R 9'CHO
Na (Ac0) gBH 1 .R9aCH0, 61 1 . -OH
2 . R9bSO2C1 Na (Ac0) gBH 2 -H+.
i0 2 . R9aC:OC.1 or R 10 CO
Et0(C=C>)H,0 ~OH
i~ R CHZNH2 'NRaS02Rb 61a 76 l0 60a NHR9aC ( O) R9a g H
( or -NHCHO ) ~ Rlo ..w~- 7 cp to 7 g b R:LO _ reductive ~'OR9d ~ Cj O ainination + v R acylation 64 i 69 ~ if desired 61b g OH Rgb R9aR9a' R9b 1(1 /
// 7 g 10 7 g 10 7 g 10 LAH ~

6g ~ ~ ~ ''~ 65 ~
66 , It is to be understood that R9 is either in its final form or in a suitable protected precursor form. This electrophile can be a carbon-based electrophile, some examples being formaldehyde to introduce a CH20H group, an aldehyde or a ketone which also introduces a one-carbon homologated alcohol, ethylene oxide (or other epoxides) which introduces a -CH2CHZOH group (a two-carbon homologated alcohol), an alkyl halide, etc., all of which can be later elaborated into R9. It can also be an oxygen-based electrophile such as MCPBA, Davis' reagent (Davis, F. A.;
Haque, M. S.; J Org Chem 1986, 51 (21),4083; Davis, F. A.;
Vishwaskarma, L. C.; Billmers, J. M.; Finn, J.; J Org Chem 1984, 49, 3241) or MoO~ (Martin, T. et al., J Org Chem 1996, 61 (18), 6450-6453) which introduces an OH group.
These OH groups can undergo the displacement reactions discussed previously in Scheme 9 or protected by suitable protecting groups and deprotected at a later stage when the displacement reactions decribed in Scheme 9 can be performed. In addition, these OH groups can also undergo displacement reactions with heterocycles as described for Schemes 19-22 to introduce N- or C-substituted heterocycles at this position. Ester 80 can be converted into its Weinreb amide 82 (S. Nahm and S. M. Weinreb, Tet. Lett., 1981, 22, 3815-3818) or Weinreb amide 82 can be synthesized via Michael-type addition of 1 to alpha, beta-unsaturated Weinreb amide 83. Subsequent reaction with a Grignard reagent forms ketone 85. This ketone can also be synthesized in one step directly from 1 and alpha,beta-unsaturated ketone 84 using the same procedure. This ketone may be reduced with LAH, NaBH4 or other reducing agents to form alcohol 86. Or else, ketone 85 can be reacted with an organolithium or Grignard reagents to form tertiary alcohol 87 . Or else, ester 80 can be directly reduced with LiBH4 or LAH to yield primary alcohol 88.

SCHEME: 10 R~ Ra H ~ 1c R ~ 1. BuLi 0 'OMe R s~ w --;- ~
n 2 . R9X ) R' y -Rlo R
OMe 5 'n n:=0,1 1.
R ~ Rio R7 s R~ io 84 O p ~ 'OH
R$ Rllorl2 R'9 'R10 N (CH3 ) OMe 2 . R9X R5 'n l.BuLi 81 2 . R9X ~ 83 R~ s R a ~ ~N(CH,3)OMe ~ Rllorl2 R9 'R10 R11 9 10 ' MgBr or ~ R R
RS 'n 82 Ri2MgBr R5 n R~ a _ p Rll or12 R11or12MgBr R9 R1o R~ s H
R5 n 89 R~ s H

'j ~Rllorl2 Rllor 12M Br ~j~10 Rll 9 R~~~o R5 rin ) Rs /n 1 -p ss ~ 87 R12 ~1 r 9 'R1~ -~ OH -~ NH2 R~ s ' w 9 0 to compounds .~ ~ OH
by ;methods ~ ' R9 'R10 prewioiusly ~ R5 'ri des~~ribed Alcohols 85, 87 , arid $8 can all be tosylated, mesylated, triflated, or converted to a halogen by methods discussed 5 previously and displaced with an amine nucleophile such as azide, diphenylphosphoryl azide (with or without DEAD and Ph3P), phthalimide, etc. as discussed previously (and which are familiar to one skilled in the art) and after reduction (azide) or deprotection with hydrazine (phthalimide), for example, yield the corresponding amines. These can then be elaborated into the compounds of this invention as discussed previously. Ketone 85 can also be converted into imine 89 which can be reacted with a Grignard reagent or lithium reagent, etc., to form a protected amine 90 which can be deprotected and elaborated into the compounds of this invention as discussed previously. Some protecting groups include benzyl and substituted benzyl which can be removed by hydrogenation, and cyanoethyl, which can be removed with aqueous base, etc. It is to be understood that R~-12 in Scheme 10 can be in their final form or in precursor form which can be elaborated into final form by procedures familiar to one skilled in the art.
Magnesium amides of amines have been used to add in a Michael-type manner to alpha, beta-unsaturated esters where the substituents at the beta position of the unsaturated ester are tied together to form a cyclopentane ring (for example, compound 79 where R~ and Rs are taken together to be -(CH2)4-) (Kobayashi, K. et al., Bull Chem Soc Jpn, 1997, 70 (7), 1697-1699). Thus reaction of pyrrolidine or piperidine -1 with cycloalkylidine esters 79 as in Scheme 10 yields esters 80 where R~ and Ra are taken together to form a cycloalkyl ring. Subsequent elaboration yields compounds of this invention where R~ and R8 are taken together to form a cycloalkyl ring.
Compounds of structure 95a may also be synthesized from epoxyalcohols which are shown in Scheme 11. Allylic alcohol 91 can be epoxidized either stereoselectively using VO(acac)2 catalyst (for a review, see Evans: Chem.
Rev. 1993, 93, 1307) or enantioselectively (Sharpless: J.
Am. Chem. Soc. 1987, 109, 5765) to epoxyalcohol 92. SN2 displacement of the alcohol using zinc azide and triphenylphosphine (Yoshida, A. J. Org. Chem. 57, 1992, 1321-1322) or diphenylphosphoryl azide, DEAD, and triphenylphosphine (;3aito, A. et al., Tet. Lett. 1997, 38 (22), 3955-3958) yie:Lds azidoalcohol 93. Hydrogen~3tion over a Pd catalyst yields aminoalcohol 94. This can be protected in situ or :in a subsequent step with BOC20 to put on a BOC protecting croup, or with CBZ-C1 and base to put on a CBZ-group or other protecting groups. Alternatively, the amino group can be reacted with an isocyanate, an isothiocyanate, a carbamoyl chloride, or any reagent depicted in Scheme 1 to form 95 which can be alkylated with 1 to form the compounds of this invention.

R R
s OH Rs OH
R

R7 9 ~ 9 R
s Rg 2 Rs N3 R R12 R1 Ri2 R R
RB NH- P Rs NH- ( C=Z ) NR2R3 H
as in Scheme 8 R~ 'n n=0,1 _ ( C=Z ) NR2R3 95a Sometimes amine 1 might have to be activated with Lewis acids in order to open the epoxide ring (Fujiwara, M.; Imada, M.; Baba, A.; Matsuda, H.;Tetrahedron Lett 1989, 30, 739; Caron, M.; Sharpless, K. B.; J Org Chem 1985, 50, 1557) or 1 has to be deprotonated and used as a metal amide, for example the lithium amide (Gorzynski-Smith, J.;
Synthesis 1984 (8), 629) or MgBr amide (Carre, M. C.;

Houmounou, J. P.; Cau:bere, P.; Tetrahedron Lett 1985, 26, 3107) or aluminum amide (Overman, L. E.; Flippin, L. A.;
Tetrahedron Lett 1981, 22, 195).
The quaternary salts (where R4 is present as a substituent) of pyrro:Lidines and piperidines can be synthesized by simply reacting the amine with an alkylating agent, such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, ethyl or methyl bromoacetate, bromoacetonitrile, allyl iodide, allylbromide, benzyl 7.0 bromide, et~~. in a suitable solvent such as THF, DMF, DMSO, etc. at room temperature to the reflux temperature of the solvent. Spiroquaternary salts can be synthesized in a similar manner, the orally difference being that the alkylating agent is located intramolecularly as shown in Scheme 12. It is understood by one skilled in the art that functional groups might: not be in their final form to permit cycl~_zation to the quaternary ammonium salt and might have t:o be in precursor form or in protected form to be elaborated to their final form at a later stage. For example, the' NR1(C=Z)NR2R3 group on the rightmost phenyl ring of compound 104 might exist as a nitro group precursor for ease of manipulation during quaternary salt formation.
Subsequent reduction a:nd NR1(C=Z)NR2R3 group formation yields product 105. T:he leaving groups represented by X in 2!i Scheme 12 may equal those represented in Scheme 1, but are not limited thereto. lV-oxides of pyrrolidines and piperidines can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514). This simply entails reacting the pyrrolidine or piperidine with MCPBA, for 3Cl example, in an inert solvent such as methylene chloride.

11812 ~ a 11812 NRl(C=Z)NR2R3 X 1(C=Z)NR2R3 R9 Rlo X=leaving ~ 9 to ) R
R5 n group R~ 'n n=0,1 96 97 R7 fi 11 812 ~ Rg 11 812 X- R
NR1 ( C=Z ) NR2R3 NR1 ( C=Z ) NR2R3 /9 ~Rlo ~ ~ to R
Rs n ~ 4_X ~~ R~R9 Rs n n=0,1 99 R~ 8 ~11 12 4/R 1 ( C=Z ) NR2R 3 X_ R _._ _ NR1 ( C=Z ) NR2R 3 ' + R1o R9 R1o ~ ~~~~R9 R5 n 10 0 Rs n R~ Rg 1 O l R~ 8 g 10 ~ 11 1 (C=z) ~2R3 1 (C=Z) NR2R3 X R
w +
R ~ lo~ _ R
11 812 ~ 810 Rs n ~4_X Rs n R~ R8 1 (C=Z) NR2R3 X- R4-R1 ~ ~ ~1 ( C=Z ) NR2R 3 R4~R1 '+
Rlo ~ to R5 n 104 R~ ~n R9 R 105 Multisubstituted pyrrolidines and piperidines may be synthesized by the methods outlined in Scheme 13.
Monoalkylation of 106 via an enolate using LDA or potassium hexamethyldisilazane, or converting 106 first to an enamine, or by using other bases, all of which can be done in THF, ether, dioxane, benzene, or an appropriate non-hydroxylic solvent at -78 oC to room temperature with an alkylating agent such as methyl iodide, benzyl bromide, etc. where :X is as defined in Scheme 1, yields product 107.
This product can subsequently undergo alkylation again under thermodynamic or kinetic conditions and afterwards, if need be, can underg~a two more alkylations to produce tri- and tetrasubstitu.ted analogs of 107. The thermodynamic or kinetic conditions yield regioselectively alkylated products (for a discussion on thermodynamic vs.
kinetic alk:~rlations see H. House Modern Synthetic Reactions, Via. A. Benjamin, Inc. (Menlo Park, CA: 1972) chapter 9).

~Ph 1. Base R R
~Ph ~Ph --n 2. R5-X
206 107n RSP 108 n=0,1 X = leaving group R5p=precursor to R5 HZ / Pd or Pd(OH)z R H
to compounds by methods previously described s R5 n cis and trans C02Et COZEt C02Et 1 . Base ~Rb -> --2 . R 6X
H BOC BOC
110 111 X=leaving group as defined in 1_[H]
Scheme 1 2.Swern 5x CHzR CH ( OH) R5* RS*MgBr or CHO
~R6 ~ R6 ~ Rs RSxLi Wittig CH2 R5 * CH2 CH2R 5 CH= CHRSx R6 Rs H2 Pd/C
R

H+ ~ * ~ H+ 5 CHz CH2R 5 CH= CHR
R6 ~Rs H 11~ H 115 x RS =R5 or a precursor thereof to products by methods previously described Subsequent Wittig olefination yields compound 108.
Hydrogenation (asymmetric hydrogenation is an option here:
Parshall, G.W. Homogeneous Catalysis, John Wiley and Sons, New York: 1980, pp. 43-45; Collman, J.P., Hegedus, L.S.
Principles and Applications of Organotransition Metal Chemistry, University Science Books, Mill Valley, CA, 1980, pp. 341-348) yields pyrrolidine or piperidine 109 which can be resolved :into its relative and/or absolute isomers at this stage or later on in the synthesis either by crystallizat_~on, chromatographic techniques, or other methods familiar to one skilled in the art. The amine 109 an then be ei.aborated into the compounds of this invention by methods discussed pr.=viousl.y (Scheme 1). The carbonyl-containing intermediate 107 in Scheme 13 can also be reduced to the methylene analog via a Wolff-Kishner reduction and. modifications thereof, or by other methods familiar to one skilled in the art. The carbonyl group can also be reduced to an OH group, which can undergo all of the reactions described in Scheme 9 to synthesize the R6 groups. This piperidine~ or pyrrolidine can be deprotected and elaborated to the compounds of this invention by methods discussed earlier. Thus, mono-, di-, tri-, or tetraalkylated carbonyl-containing pyrrolidines or piperidines can be synthesized, which in turn can be reduced to thES corresponding -CH2- analogs employing the Wolff-Kishner reduction or other methods.
Another method for synthesizing gem-substituted pyrrolidines and piperidines is shown in Scheme 14. It is understood by one skilled in the art that some of the steps in this scheme can be rearranged. It is also understood that gem-disubstitution :is only shown at only one position on the piperidine ring and that similar transformations may be performed on other carbon atoms as well, both for piperidine and pyrrolidine. Thus, 3-carboethoxypiperidi.ne 110 may be BOC-protected and alkylated employing a base such as LDA, KHMDS, LHDM:>, etc., in THF, ether, dioxane, etc. at -78 °C to room temperature, and an alkylating agent R6X where X is a halide (halide = C1, Br, I), mesylate, tosylate or triflate, to yield 1~. Reduction using DIBAL, for example, and if necessary followed by oxidation such as a Swern oxidation (S. L. Huang, K. Omura, D. Swern J. Org.
Chem. 1976, 41, 3329-32) yields aldehyde 113. Wittig olefination (114) followed by deprotection yields 115 which may be elaborated as described previously into the compounds of this invention. Reduction of the Wittig adduct 114 yields 116 which may be deprotected to yield 117 which may be in turn elaborated as described previously into the compounds of this invention. Reaction of S aldehyde 113 with an alkyllithium or Grignard reagent yields alcohol 118 which may be reduced catalytically or with Et3SiH/TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem.
1987, 52, 2226) if R5* (R5* - R5 or a precursor thereof) is aromatic to yield 119. If R5* is not aromatic, then the OH
may be reduced by the method of Barton (Barton, D. H. R.;
Jaszberenyi, J. C. Tet. Lett. 1989, 30, 2619 and other references therein). Once tosylated, the alcohol can also be displaced with dialkyllithium cuprates (not shown) (Hanessian, S.; Thavonekham, B.; DeHoff, B.; J Org. Chem.
1989, 54, 5831). Deprotection if necessary yields 120 which may be elaborated as described previously into the compounds of this invention.

R R
1. s-BuLi )n n RSOrRI3 TMEDA
BOC
BOC 2. vR5_ or R13-X 122 X-as defined n=0, 1 i~z Scheme 1 1. s-BuLi TMEDA
2. R~- or R13-X
R~ ~ n R
1. s-BuLi R50 r R13 s RSOrRl~ R5orR13 TMEDA
BOC 5_ 5~ 5 13 2. R R -R orR
124 or R13-X or R13 BOC

1. s-BuLi TMEDA
2. R.5- or R13-X
R
a ~ /n R r- o )Z5o rRl3 RSOr:Rl3 ~F;~orRl3 BOC

A method for the alkylation of alkyl groups, arylalkyl groups, all:ylic groups, propargylic groups, etc., and a variety of other electrophiles onto the pyrrolidinyl and/or piperidinyl alpha-carbons (alpha to the ring nitrogen atom) is represented by the work of Peter Beak, et al. as shown in Scheme 1':5. It is understood by one skilled in the art that the R5 and R13 groups are either in their precursor, protected, or final form. Only one RS group is shown to be substituted on piperidine/pyrrolidine 121. However it is understood by one skilled in the art that additional functionality may be present on the ring in either precursor, protected, or final form. Thus lithiation with an alkyllithium reagent such as n-BuLi or s-BuLi as shown, followed by quenching with an electrophilic species such as R5X or R13X where X is as defined in Scheme 1 and RS and R13 are in their precursor, protected, or final form, yields monoalkylated piperidine/pyrrolidine 122. This alkylation may occur either stereoselectively (P. Beak and W.K. Lee J. Org. Chem. 1990, 55, 2578-2580) or enantioselectively if sparteine is included as a source of chirality (P. Beak, et al., J. Am. Chem. Soc. 1994, 116, 3231-3239). The alkylation process may be repeated up to three more times as shown in Scheme 15 to result in di-, tri-, and tetrasubstitution at the alpha-positions.
Compounds where R9 and R1~ form a cyclic 3,4,5,6, or 7-membered ring can be synthesized by the methods disclosed in Scheme 16. These same methods may also be used to synthesize gem-disubstituted compounds in which R9 can be different from R1~ by step-wise alkylation of the malonate derivative. Of course, this scheme may be used to synthesize compounds where Rla=H also. For example, a cyclohexyl-fused malonate may be synthesized by Michael addition and alkylation of I(CH2)4CH=CC02Me with dimethyl malonate employing NaH/DMF (Desmaele, D.; Louvet, J.-M.;
Tet Lett 1994, 35 (16), 2549-2552) or by a double Michael addition (Reddy, D. B., et al., Org. Prep. Proced. Int. 24 (1992) 1, 21 -26) (Downes, A. M.; Gill, N. S.; Lions, F.; J
Am Chem or by an alkylation followed by a second intromolecular alkylation employing an iodoaldehyde (Suami, T.; Tadano, K.; Kameda, Y.; Iimura, Y.; Chem Lett 1984, 1919), or by an alkylation followed by a second intramolecular alkylation employing an alkyl dihalide (Kohnz, H.; Dull, B.; Mullen, K.; Angew Chem 1989, 101 (10), 1375), etc.

SCHEME. 16 R9 Rlo R9 Rlo diethyl _~ OF,t OEt > H OEt malonate O

H
R5 n n=0,1 OEt ~H~
h R9 Rlp ~-OH
.\
R5 n 13 0 to compounds by methods previous;ly described Subsequent monosa.ponification (Pallai, P.V., Richman, S., Struthe:rs, R.S., G'~c>odman, M. Int. J. Peptide Protein Res. 1983, 21, 84-92; M. Goodman Int. J. Peptide Protein Res. 19831, 17, 72-88), standard coupling with pyrrolidine/
piperidine L yields 12g. Reduction with borane yields 129 followed by reduction with LAH yields 130 which can be then converted to amine X31. and then to the compounds of this invention by procedures as discussed previously. Ester 1~
can also be converted to a Weinreb amide and elaborated to the compounds of this invention as described in Scheme 10 for ester 80 which would introduce substituents R11 and R12.

Scheme 17 describes another method for the synthesis of compounds where R9 and R1~ are taken together to form cycloalkyl groups. Aminoalcohols 132 are found in the literature (CAS Registry Nos. for n = 0,1,2,3, respectively: 45434-02-4, 2041-56-7, 2239-31-8, 2041-57-8).
They can easily be protected, as with a BOC group (or CBZ, or any other compatible protecting group) by known procedures familiar to one skilled in the art to yield alcohols 133. The alcohols can then be activated either by conversion to a halide or to a mesylate, tosylate or triflate by methods familiar to one skilled in the art and as discussed previously, and then alkylated with pyrrolidine/piperidine 1 by the conditions described in Scheme 1 to yield 135. Subsequent deprotection yields amine 136 which can be elaborated to the compounds of this invention as described previously. Of course, alcohol 133 can be oxidized to the aldehyde and then reacted with R~°r8MgBr or R~°rBLi with or without CeCl3 to yield the corresponding alcohol 133 where instead of -CHzOH, we would have -CHR~°rgOH. This oxidation-1,2-addition sequence may be repeated to yield a tertiary alcohol. The alcohol may then be tosylated, mesylated, triflated, or converted to C1, Br, or I by procedures familiar to one skilled in the art to yield 134 and then displaced with pyrrolidine/piperidine 1 to yield 135. Subsequent deprotection yields 136 which may undergo elaboration to the compounds of this invention as discussed previously.

(CH2)n (CH2)n (CH2)n H N-CH ~ -'' BOC--NH-CH2 -~BOC-NH-CH2 OH OH X
n=0,1,2,3 133 H 134 R5 n n=0,1 .,...
- BOC
CH+) to compounds by previously described A method to introduce cycloalkyl groups at R11R12 is shown in Scheme 18. Protection of the nitrogen of compounds 13'7 which are commercially available yields 138 (the protecting group m.ay be BOC, CBZ, or any other compatible p~.~otecting group) by procedures familiar to one skilled in the art. Esterification by any one of a number procedures familiar to one skilled in the art (for example A. Hassner and V. Alexar~ian, Tet. Lett, 1978, 46, 4475-8) followed by :reduction with DIBAL (or alternatively reduction to the alcohol. with, for example, LiBH4, followed by Swern oxidation (op. cit.)) yields aldehyde 139. One carbon homologation via the Wittig reaction followed by hydrolysis o:E the vinyl ether yields aldehyde 141.
Reductive am:ination (Ab~del-Magid, A. F., et al. Tet. Lett.
1990, 31, (39) 5595-5598) yields 142 followed by deprotection yields amine 143 which can be elaborated to the compounds of this invention by the methods previously discussed. Of course, aldehyde 139 can be reacted with R9orloMggr or R9orloLi with or without CeCl3 to yield an alcohol which can be oxidized to a ketone. Wittig one-carbon homologation on this ketone as described above followed by hydrolysis yields 141 where the -CHZCHO is substituted with one R9orlo group (-CHR9orlo CHO) .

(CH2)n BOC20 (CHZ)n (CHZ)n H 2 '' BOC ---1 BOC
2.ROH C02R CHO
COO H DCC
n=0,1,2,3 DAP 138 139 (CH2)n H+ (CHz)n ~-.-- BOC
BOC CH2CHO H=CHOMe 1' 140 Na(Ac0)3BH 141 ~ ~u_ v -BOC to compounds ~ H+ ~ -~ by methods ' ~. described previously Aldehyde 141 (-CH2CH0) or its monosubstituted analog synthesized above (-CHR9or1oCH0) can undergo alkylation with R9orloX where X is as defined in Scheme 1 to yield compound 141 containing one or both of the R9 and Rlo substituents alpha to the aldehyde group. Alkylation can be.performed using LDA or lithium bistrimethylsilyl amide amongst other bases in an inert solvent such as ether, THF, etc., at -78 °C to room temperatur~L. Aldehyde 141 (-CH2CH0)or its substituted analogs synthesized above (i.e., -CHR9R1~CH0) can undergo reductive amination with 1 and subsequent elaboration to the compounds of this invention. Aldehyde 141 (-CH2CH0)or its substituted analogs synthesized above (i.e., -CHR.9R1~CH0) ca.n also undergo 2,2-addition with R~°rBMgBr or. R~°reLi to yield the corresponding alcohol -CH2CHR~°r80H or -CHR9R~LOCHR~°r80H . The alcohol may then be tosylated, mesylated, triflated, or converted to Cl, Br, or 1.0 I by procedures familiar to one skilled in the art and displaced with pyrrol:ldine/piperidine 2 to yield, after subsequent deprotection and elaboration, the compounds of this invention. Or else alcohol -CHZCHR~°r80H or -CR9R1~CHR~°r80H can be oxidized (i.e., Swern, op. cit.) to the ketone and reductively aminated with 1 and subsequently elaborated to the compounds of this invention. Or else alcohol -CH2CHR~°r80H or -CR9R1~CHR~°rgOH can be oxidized (i.e., Swer:n, op. cit.) to the ketone and reacted once more with R~°r8MgBr or R~°~8Li to yield the corresponding alcohol -CH2CR~R80H or -CR9R1~C'.R~R80H. If the ketone enolizes easily, CeCl3 may beg used together with the Grignard or lithium reagent. The alcohol can again be tosylated, mesylated, triflated, or converted to C1, Br, or I by procedures familiar to one skilled in the art and displaced with 2:~ pyrrolidine! piperidin.e 1 to yield, after subsequent deprotection and elaboration, the compounds of this invention. Thus each one of the R~, Rg, R9, and R1~ groups may be introduced into compounds 141, ~ and 143 and and, of course, un the compounds of this invention, by the methods discussed above.
A method for the synthesis of N-substituted heterocycles at RS is .shown in Scheme 19. The heterocycle can be deprc>tonated with NaH or by other bases familiar to one skilled in the art, in a solvent such as DMF, THF, or 3'. another appropriate non-hydroxylic solvent and reacted with piperidine or pyrrolidine 143 at room temperature to the reflux temperature of the solvent. Deprotection and elaboration as described before yields compounds where R5 contains an N-substituted heterocycle. If the nitrogen atom of the heterocycle is sufficiently nucleophilic, then an acid scavenger, such as K2C03, KHC03, Na2C03, NaHC03, amongst others, can be used in place of NaH, employing THF, DMF, or methyl ethyl ketone as solvents. In this case hydroxylic solvents may be used as well, such as methanol, ethanol, etc. from room temperature to the reflux temperature of the solvent. Compound 143 as well as its other positional isomers are available, for example, from commercially available 4-hydroxymethylpiperidine, 2-, 3-, and 4-carboethoxypiperidine, L- or D-proline ethyl ester, or from methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate by methods familiar to one skilled in the art and as discussed previously in this application.

heterocycle heterocycle BOC
H
n NaH or KzC03 X

1~~ 11 n=0, 1 deprotect X = leaving group to compounds by methods described previously A method for the synthesis of C-substituted heterocycles at R5 is shown in Scheme 20. Many heterocycles such as the ones shown in Scheme 20, but not limited thereto, can be metallated with strong bases such as LDA, n-BuLi, sec-BuLi, t-BuLi, etc. to yield the corresponding anionic species. These anions may also be generated via halogen-metal exchange employing n-BuLi, or other alkyllithium reagents. These reactions may be performed in THF, ether, dioxane, DME, benzene, etc. at -?8 °C to room temperature.

\ (-) (_.) R
(_) (_) ~ (-) heterocycle ,BO(. C
N C \, N N
(CH )m In ~ \ ( - ) \
X
I 4 3 ~ ( ) ( - ) ~'BOC
1~N 14 5 j n n= 0 , 1 X = leaving m=1,2 \
descpibed ~ / \, (-) in Scheme 1 (_) C02Li C02Li to compounds \ by methods described ,(-) (-) previously R=suitable protecting (-) I (_) group or functional C
N N group etc.
For reviews of these metallations and halogen-metal exchange reactions see Organometallics in Organic Synthesis, FMC Corp., Lithium Division, 1993, pp. 17-39;
Lithium Link,. FMC Corp., Spring 1993, pp. 2-17; n-Butyllithium in Organic Synthesis, Lithium Corp. of America, 1982, pp. 8-16; G. Heinisch, T. Langer, P.
Lukavsky, J. Het. Chem. 1997, 34, 17-19. The anions can then be quenched with e:lectrophile 143 or its positional isomers to yield the co=rresponding C-alkylated heterocyclic pyrrolidine or piperidine 145.

\ (-) (-) ( i heterocycle BOC I ~( ) (-) (-) C
N N H
s ''n ~ ( _ ) \ \ BOC
H I _ 146 ~( ) / ( ) ..
n=0, 1 NON
\ \ \ CH) I \ (_) I
C02Li ) C02 L i ecc . net R=suitable protecting group or functional group to compounds by methods described ,.
previously Another method for the synthesis of C-substituted heterocyclic-methylpyrrolidines or piperidines is shown in Scheme 21. The protected aldehyde 146 is reacted with the anion of the heterocycle (its generation as described previously) at -78 °C to room temperature with or without CeCl3 in an inert solvent such as THF, ether, dioxane, DME, benzene, etc. to yield carbinol 147. Catalytic hydrogenation of the alcohol yields the corresponding methylene compound 145. Other reduction methods include Et3SiH/TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem. 1987, 52, 2226} amongst others familiar to one skilled in the art. It is understood by one skilled in the art that the aldehyde group can be located in other positions instead of, for example, the 4-position of piperidine in compound 146 as depicted in Scheme 21. It is to be understood that other heterocycles may also be used besides the ones shown in Scheme 20 and 21.
The anions of the methyl-substituted heterocycles may also be reacted with a BOC-protected piperidone or pyrrolidone (148) to yield alcohols 149 as shown in Scheme 22 (see above reviews an metallations for references).
These alcohols may be reduced using Pt02 and TFA (P. E.
Peterson and C. Casey, J. Org. Chem. 1964, 29, 2325-9) to yield piper.idines and pyrrolidines 150. These can subsequentl:~ be taken an to the compounds of this invention as described previously. It is understood by one skilled in the art that the carbonyl group can be located in other positions instead of, for example, the 4-position of piperidine _-in compound 148, as depicted in Scheme 22. It is to be understood that ather heterocycles may also be used besides the ones shown in Scheme 22.

heterocycle Boc~ ~ ~ ( _ ) ~ ~.-- ( - ) C
N
d~ n (_) 148 - (-) n=0,1 et_c. TFA, Et3SiH
R=suitable protecting group o:r functional het \ ~ycle group to compounds of by methods described ' N.
previously 150 n One may also react: aryl (phenyl, naphthyl, etc.) anions, generated either by halogen-metal exchange or by ortho-directed metallat:ion (Snieckus, V. Chem. Rev. 1990, 90, 879-933) using n- or s- or t-BuLi in a non-hydroxylic solvent such as THF, ether, etc., with or without TMEDA and allow them to react with compounds 143, 146, and 148 with subsequent elaboration to yield the compounds of this invention by the methods depicted in Schemes 19-22.
Another method for the preparation of C-substituted heterocycles is shown in Scheme 23. Protected piperidone 148 undergoes a Wittig reaction with heterocyclic phosphorous ylides to yield 151. Hydrogenation over a noble metal catalyst such as Pd in an alcoholic solvent or with an optically active transition metal catalyst (see asymmetric hydrogenation references of Parshall and Coleman, op. cit.) yields 152 which can be further elaborated into the compounds of this invention by the procedures described previously. It will be appreciated by one skilled in the art that the carbonyl group can be located in other positions instead of, for example, the 4-position of piperidine in compound 148 as depicted in Scheme 23. It is to be understood that other heterocycles may also be used besides the ones shown in Scheme 23.

Scheme 23 Ph3 heterocycle Boc ~ ~, ~Ph3 N
C~ n 148 PPh3 n=0,1 \
N PPh3 etc.
R=suitable protecting group or functional group nets to compounds by methods described previously Syntha_ses of amines _9, 10, and the amines which are precursors to isocyanates or isothiocyanates 5 will now be discussed. For example, 3-nitrobenzeneboronic acid (153:
Scheme 24) is commerically available and can undergo Suzuki couplings (Suzuki, A. Pure Appl. Chem. 1991, 63, 419) with a wide variety of substituted iodo- or bromo aryls (aryls such as phenyl, naphthalene, etc.), heterocycles, alkyls, akenyls (Moreno-manas, M., et al., J. Org. Chem., 1995, 60, 2396), or alkynes. It can also undergo coupling with triflates of aryls, h~eterocycles, etc. (Fu, J.-m, Snieckus, V. Tet. Lett. 1990, 31, 1665-1668). Both of the above reactions can also undergo carbonyl insertion in the presence o:F an atmosphere of carbon monoxide (Ishiyama, et al., Tet. Lett. 1993, 34, 7595). These nitro-containing compounds (155 and X5'7) can then be reduced to the corresponding amines ,either via catalytic hydrogenation, or via a number of chemical methods such as ~n/CaCl2 (Sawicki, E. J Org Chem 1956, 21). The carbonyl insertion compounds (158) can also undergo reduction of the carbonyl group to either the CHOH or CH2 linkages by methods already discussed (NaBHq or Et3SiH, TFA, etc.). These amines can then be converted to isocyanate 5 via the following methods (Nowakowski, J. J Prakt Chem/Chem-Ztg 1996, 338 (7), 667-671; Knoelker, H.-J. et al., Angew Chem 1995, 107 (22), 2746-2749; Nowick, J. S.et al., J Org Chem 1996, 61 (11), 3929-3934; Staab, H. A.; Benz, W.; Angew Chem 1961, 73); to isothiocyanate 5 via the following methods (Strekowski L.et al., J Heterocycl Chem 1996, 33 (6), 1685-1688; Kutschy, Pet al., Synlett 1997, (3), 289-290); to carbamoyl chloride 11 (after 156 or 158 is reductively aminated with an R2 group) (Hintze, F.; Hoppe, D.;
Synthesis (1992) 12, 1216-1218); to thiocarbamoyl chloride 11 (after 156 or 158 is reductively- aminated with an R2 group) (Ried, W.; Hillenbrand, H.; Oertel, G.; Justus Liebigs Ann Chem 1954, 590); or just used as 9, or 10 (after 156 or 158 is reductively aminated with an R2 group), in synthesizing the compounds of this invention by the methods depicted in Scheme 1.

Suzuki-type O2 \ X--O coupling / ~B
(OH) 2 X=Br, I, OTf 1~~3 154 155 Suzuki -type coupling, CO (g) ~H~
~n2 p n2 ~H) ~ / \
O /

make isocyanate or isothiocyanate 5, or carbamoyl chlorides 11, or used as 9_ or 10 to make the compounds of this invention as described for the compounds of Scheme 1 Likewise, pro tected aminobromobenzenes or triflates or protected. aminobromoheterocycles or triflates 159 (Scheme 25) may undergo Suzuki-type couplings with arylboronic acids or heterocycl.ic boronic acids (160) These same bromides or triflates 159 may also undergo Stifle-type coupling (Echavarren, A. M., Stifle, J.K. J. Am. Chem.
Soc., 1987, 109, 54'78-5486) with aryl, vinyl, or heterocyclic stannanes 163. Bromides or triflates 159 may also undergo Negish:L-type coupling with other aryl or heterocyclic bromides 164 (Negishi E. Accts. Chem. Res.
1982, 15, 340; M. Sletzinger, et al., Tet. Lett. 1985, 26, 2951). Deprotection of the amino group yields an amine with can ;be coupled to make a urea and other linkers containing Z as described above and for Scheme ~. Amino protecting groups include phthalimide, 2,4-dimethyl pyrrole (S. P. Breukelman, et al. J. Chem. Soc. Perkin Trans. I, 1984, 2801); N-1,1,4,4-Tetramethyldisilyl-azacyclopentane (STABASE) (S. Djuric, J. Venit, and P. Magnus Tet. Lett 1981, 22, 1787) and others familiar to one skilled in the art.

_P
Suzuki-type -P
coupling + (HO) 2 Br,I,OTf 160 Stille-type 161 coupliing 159 + Bu3 Sn~-163 Negishi-type P
coupling 159 + Br or vn2 make isocyanate or isothiocyanate ~, or carbamoyl chlorides or used as 9 or IO to make 1 62 the compounds of this invention as described for the compounds of Scheme 1 Compounds where R7 and R8 are taken together to form =NRBb can be synthesized by the methods in Scheme 25a.
Reacting _1 with nitrite a with CuCl catalysis forms amidine b where R8b is H (Rousselet, G.; Capdevielle, P.; Maumy, M.; Tetrahedron Lett. 1993, 34 (40), 6395-6398). Note that the urea portion may be in final form or in precursor form (for example, a protected nitrogen atom; P = protecting group such as STABASE, bis-BOC, etc., as was discussed previously) which may be subsequently elaborated into the compounds of this invention. Compounds b may be also synthesized by reacting iminoyl chloride c with pyrrolidine/piperidine 1 to yield b where R8b is not H
(Povazanec, F., et al., J. J. Heterocycl. Chem., 1992, 29, 6, 1507-1512). Iminoyi chlorides are readily available from the corresponding amide via PC15 or S CC14/PPh3 (l~uncia, J.V. et al., J. Org. Chem., 1991, 56, 2395-2400). Again, the urea portion may be in final form or in precuwsor form.
Scheme 25a H 1~~ R1o R~ NRl ( C=Z ) NR2R 3 or N-P
R5 n ~ ~R12 --1 NC' R° 1i -----!~

n=0,1 a R 1(C=Z)NR2R3 JR1 ( C=Z ) NR2R 3 or N-P
RS Jn C ~ 1 b n=0.1 c Many amines are commercially available and can be used as 9_, 10, or used as precursors to isocyanates or isothiocyanat:es 5. There are numerous methods for the synthesis of non-commercially available amines familiar to one skilled in the art. For example, aldehydes and ketones may be converted to their O-benzyl oximes and then reduced with LAH to form an amine (Yamazaki, S.; Ukaji, Y.;
Navasaka, K.; Bull Chem Soc Jpn 19$6, 59, 525). Ketones and trifluoromethylketones undergo reductive amination in the presence of TiCl4 followed by NaCNBH4 to yield amines (Barney, C.L., Huber, E.W., McCarthy, J.R. Tet. Lett. 1990, 31, 5547-5550). Aldehydes and ketones undergo reductive amination with Na(Ac0)3BH as mentioned previously to yield amines (Abdel-Magid, A. F., et al. Tet. Lett. 1990, 31, (39) 5595-5598). Amines may also be synthesized from aromatic and heterocyclic OH groups (for example, phenols) via the Smiles rearrangement (Weidner, J.J., Peet, N.P. J.
Het. Chem., 1997, 34, 1857-1860). Azide and nitrile displacements of halides, tosylates, mesylates, triflates, etc. followed by LAH or other types or reduction methods yield amines. Sodium diformyl amide (Yinglin, H., Hongwen, H. Synthesis 2989 122), potassium phthalimide, and bis-BOC-amine anion can all displace halides, tosylates, mesylates, etc., followed by standard deprotection methods to yield amines, procedures which are familiar to one skilled in the art. Other methods to synthesize more elaborate amines involve the Pictet-Spengler reaction, imine/immonium ion Diels-Alder reaction (Larsen, S.D.; Grieco, P.A. J. Am.
Chem. Soc. 1985, 107, 1768-69; Grieco, P.A., et al., J.
Org. Chem. 1988, 53, 3658-3662; Cabral, J. Laszlo, P. Tet.
Lett. 1989, 30, 7237-7238; amide reduction (with LAH or diborane, for example), organometallic addition to imines (Bocoum, A. et al., J. Chem. Soc. Chem. Comm. 1993, 1542-4) and others all of which are familiar to one skilled in the art.
Compounds containing an alcohol side-chain alpha to the nitrogen of the piperidine/pyrrolidine ring can be synthesized as shown in Scheme 25b. Only the piperidine case is exemplified, and it is to be understood by one skilled in the art that the alpha-substituted pyrrolidines may be synthesized by a similar route. It is also understood that appropriate substituents may be present on the piperidine/pyrrolidine ring. A 4-benzylpiperidine 196 is protected with a BOC group. The BOC-piperidine 197 is then metallated under conditions similar to those Beak, et al. (P. Beak and W.-K. Lee, J. Org. Chem. 1990, S5, 2578-2580, and references therein) and quenched with an aldehyde to yield alcohol 198. The metallation may also be done enantioselectively using sparteine (P. Beak, S.T. Kerrick, S. Wu, J. Chu J. Am. Chem. Soc. 1994, 116, 3231-3239).
This alcohol can be deprotonated with NaH and cyclized to carbamate 198a which permits structural assignments of the erythro and threo isomers. Deprotection with base yields aminoalcohol 199. Subsequent N-alkylation yields phthalimidoa.lkylpiperidine 201. It is to be understood 14 that the alkyl chain does not necessarily have to be n-propyl, but that n-propyl was chosen for demonstration purposes only. Deprote:ction of the phthalimido group with hydrazine yields amine 202. Finally, reaction with an isocyanate or via any of the previously described 1'i conditions described in Scheme 1 yields urea 203. If an isocyanate is used, the isocyanate can add twice to yield urea-carbamate 204.
l21 i Scheme 25b N.H N~O
Di-t-butyl Bicarbonate I T~', 0 C to 25 C I

19 6 O 1 ) Et2o, ~, -~o °c 2) sec-BuLi, N O -70 °C to -30 °C ~
OH
1' again to -70 °C
I R N 3 ) RCFiO, 1 9 8 ~ O -70 °C to -30 °C then v=
H R quench with water NaOH, EtOH, /
reflex, 3h ~ 195a + threo erythro NH o OH K2Cpj, ~, 2_butanone N~~N
R OH
o R o 19 9 Br~N ~ ~ ~ I 2 O 1 2 0 0 N2H4 , EtOH
O
N~N~NHR3 i R 203 y I + O THF', 25 °C N ~2 OH
N~N~NHR3 O~ H ~ R
O~/'NHR3 Compounds where Z = N-CN, CHN02, and C(CN)2 can be synthesized by the methods shown in Scheme 25c. Thus amine 208 reacts with malononitrile 207 neat or in an inert solvent at room temperature to the reflex temperature of the solvent, or at the melting point of the solidJsolid mixture, to yield malononitrile 206. This in turn can undergo reaction with amine 205 under similar conditions stated just above to yield molononitrile 209. Likewise, a similar reaction sequence may be used to make 212 and 21S

[for Z = C(CN) 2], see for example P. Traxler, et al., J.
Med. Chem. {1997), 40, 3601-3616; for Z = N-CN, see K. S.
Atwal, J. Med. Chem. (1998) 41, 271; for Z = CHN02, see J.
M. Hoffman, et al., J. Med. Chem. (1983) 26, 140-144).
Scheme 25c.
NC CN
+ R2R3NH
\S S/

1 ~7 NC CN
NC CN
/F~~ . /E~ ( /R3 ~N ~ ~N N N
R ~ Rl + ~S N'/R2 ~ R5 ~ Rl RZ
i3 OZN

/Ew /Ew ~ iR3 RS ~N ~ + 3 5 ~N N N
Rl \;S I N/R ~ R ~ Rl + RzR3~
\S S ~~

1 ~~

f.rCN
N
E
R5 ~Ni y + ~ N,,.rCN N/E\ ~ /R3 R3 ~ R5 ~ i N
1 ~2 0 N ~ R R

RCN
I N
+ R2R3NH
O O

EXAMPLES
The compounds of this invention and their preparation can be understood further by the following working examples. These examples are meant to be illustrative of the present invention, and are not to be taken as limiting thereof.

Part A: Preparation of 4-benzyl-1-(3-N-phthalimido-n-prop-1-yl)piperidine ~~N
4-benzylpiperidine (8.0 g , 45.6 mmol, leq), N-(3-bromopropyl)-phthalimide (13.5 g, 50.2 mmol, 1.1 eq), potassium iodide (7.6 g, 45.6 mmol, 1 eq) and potassium carbonate (2.6 g, 91.3 mmol, 2 eq) were refluxed in 125 mL
of 2-butanone. The reaction was worked up after 5 hours by filtering off the inorganic solids then adding EtOAc and rinsing the organic layer 2X with water. The organic layer was dried over magnesium sulfate then the solvent removed in vacuo to obtain an amber oil. The oil was purified bar flash chromatography in 100 EtOAc to remove impurities then 8:2 chloroformJmethanol to isolate 3.67 g of the product as a light amber oil. NMR(300 MHz. CDC13) 8 8.00-7.80 (m, 2H); 7.80-7.60 (m, 2H);7.35-7.10 (m, 3H); 7.08 (d, 2H, J=7 Hz.); 3.76 (t, 2H, J = 7 Hz); 2.83 (d, 2H, J=10 Hz);
2.45-2.30 (m, 4H); 1.95-1.30 (m, 7H); 1.20-0.90 (m, 2H)-Part B: Preparaton of 4-benzyl-1-(3-wino-n-prop-1-yl)piperidine rf " Nf'I2 4-benzyl-1-(3-r~-phthalimido-n-prop-1-yl)piperidine (13.72 g, 37.9 mmo:l, 1 eq.) was dissoved in 200 mL of EtOH
at 25 oC under N2, t:he anhydrous hydrazine (2.38 mL, 75.7 mmol, 2 eq.) was added. The solution was then refluxed during which time a white precipitate formed. The reaction was worked up after refluxing 4 hours by filtering off the solids. The solvent was removed in vacuo to obtain an oil which was re-rotovapped from toluene to remove excess hydrazine. Obtained an oil which was stirred in Et20.
Insoluble material was filtered then the solvent removed in vacuo to obtain 5.55g of an amber oil as product. NMR
(300 MHz, CDC13) b 7.40-7.21 (m, 2H); 7.21-7.05 (m, 3H):
2 .92 (d, 2H, J=10 F(z) ; 2 .73 (t, 2H, J=7 Hz) ; 2 .53 (d, 2H, J=7 Hz); 2.40-2.20 (m, 2H); 1.84 (t of t, 2H, J=7,7 Hz);
1.75-1.10 (m, 9H).
Part C: N-(3-cyanophenyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl]propyl]'urea PCT/US99/3029~
N~
/ H H ~N
4-benzyl-1-(3-amino-n-prop_1_yl)piperidine (300 mg, 1.29 mmol, 1 eq) was dissoved in THF at 25 oC under N2 then 3-cyanophenyl isocyanate (186 mg, 1.29 mmol, 1 eq) was added. TLC after 30 minutes shows the reaction complete.
The solvent was removed in vacuo then the residue was purified over silica gel in 100$ EtOAc to 8:2 chloroform/MeOHto yield 437 mg of an amber oil as product.
1VI~ (300 MHz, DMSO-d6) $ 9.90-9.50 (m, 1H) ; 9.32 (s 1H) ;
7.93 (s, 1H) ; 7.59 (d, 1H, J= 7Hz) ; 7.43 (t, 1H, J= 7Hz) .
7.40-7.24 (m, 3H); 7.24-7.10 (m, 3H
6 . 68 ( t , IH, J=7 Hz ) ;
3.50-3.25 (m, 2H); 3.25-3.07 (m, 2H); 3.07-2.90 (m, 2H);
2.90-2.60 (m, 2H); 2.60-2.40 (m, 2H); 2.00-1.60 (m, SH);
1.60-1.30 (m, 2H).

Part A: Preparation of 4-benzyl-1-carbomethoxymethyl-1-[3-(3-cyanophenylaminocarbonylamino)prop-1_yl]piperidinium bromide Br~
4-benzyl-1-[3-(3-cyanophenylaminocarbonylamino)prop-1-yl]piperidine (50mg, 0.133 mmol, I a q), was dissoved in acetone at 25 oC under N2 then methyl bromoacetate (l3uL, 0.133 mmol, 1 eq),was added. After 16 hours, the solven t ' was removed in vacuo and the residue was purified over silica gel in 100$ EtOAc to 8:2 chloroform/MeOH to yield m 50 g of white solids as product. NMR (300MHz, CD30D) $ 8.00-7.80 (m, 1H) ; 7.65-7.45 (m, IH); 7.45-7.33 (m, 1H); 7.33-7.05 (m, 6H); 4.50--4.25 (m, 2H); 4.00-3.60 (m, 5H); 3.50-3.20 (m, 6H); 2.70--2.50 (m, 2H); 2.10-1.60 (m, 7H).

Part A: Preparation of 1-(t-Butoxycarbonyl)-3-piperidone i. H2, Pd/C, CH30H, - / 23 °C

ii. (Boc)20, NaHC03, THF, 23 °C
86~
To a deep yellow solution of 1-benzyl-3-piperidone hydrochloride (3.0() g, 1.33 mmol, 1 equiv) in methanol (100 mL) was added 10 wt.. ~ (dry basis) palladium on activated carbon (600 mg) under a stream of nitrogen. The resulting black suspension was deoxygenated by alternate evacuation and flushing with nitrogen (3x) followed by alternate evacuation and flu:~hing with hydrogen (3x). The reaction suspension was then shaken vigorously under a hydrogen atmosphere of 55 p:~i. After 12 hours, gravity filtration of the supsension and concentration of the resulting filtrate in vacuo ~r:ielded crude 3-piperidone as a viscous light green oil. '.Che oil was immediately treated with tetrahydrofuran (150 mL) and di-t-butyldicarbonate (4.73 g, 21.7 mmol, 0.98 equiv). Upon addition of saturated aqueous sodium bicarbonate (25 mL), the oil completely dissolved to give a light yellow suspension. After stirring the suspension vigorou:~ly for 2 hours, the now white suspension was poured into aqueous hydrogen chloride (1N, 100 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 70 mL), and the combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, and filtered.
Concentration of the resulting filtrate in vacuo yielded 1-(t-butoxycarbonyl)--3-piperidone (3.79 g, 86~) as a white oily solid. 1H NM~Z (300 MHz, CDC13), 8:3.94 (s, 2H), 3.53 (t, 2H, J = 6 Hz), 2.41 (t, 2H, J = 7 Hz), 1.92 (m, 2H), 1.41 (s, 9H) Part B: Preparation of 1',3-(2H)-Dehydro-3-benzyl-1-(t-butoxycarbonyl)piperidine NaH, Bn(0)P(OEt)2 DME, 23-80 °C
O
23~
To a flame-dried 100-mL flask charged with sodium hydride (60~ wt. dispersion in mineral oil; 601 mg, 15.0 mmol, 2.3 equiv)) and 1,2-dimethoxyethane (20 mL) was added benzyl diethylphosphite (3.42 g, 3.13 mL, 15.0 mmol, 2.3 equiv) dropwise over a period of 5 min. After 10 min, 1-(t-butoxycarbonyl)-3-piperidone was added in one portion to the pale yellow suspension. The flask was fitted with a relfux condensor, and the resulting yellow-gray suspension at heated under reflux conditions for 2 hrs. Upon cooling to 23 °C, the reaction was poured into aqueous hydrogen chloride (0.20 N, 100 mL) and diethyl ether (75 mL). The layers were separated and the aqueous layer was basified with saturated aqueous sodium bicarbonate to pH 9. The aqueous layer was extracted with diethyl ether (4 x 75 mL), and the combined organic layers were dried over sodium sulfate. Filtration, concentration in vacuo, and purification of the resulting residue by flash column chromatography (5~ ethyl acetate in hexanes) afforded a mixture of the desired olefin (410 mg, 23~) and the corresponding ethoxycarbamate (550 mg, 34~) as a clear oil.
The ethoxycarbamate was removed in the subsequent step by flash column chromatography. 1H NMR (300 MHz, CDC13), $:
7.30 (m, 2H), 7.18 (m, 3H), 6.42 (s, 1H), 4.02 (s, 2H), 3.50 (t, 2H, J = 6 Hz), 2.51 (t, 2H, J = 5 Hz), 1.61 (m, 2H), 1.49 (s, 9H). MS (CI), m+/z: (M+H)+ = 274, [(M+H)+ -(-C(0)OC(CH3)3)] 174.
Part C: Preparation of 1-(t-Butoxycarbonyl)-3-benzylpi~peridine H2, Pd/C
CH30H, 23 °C
99~
To a solution of impure product (410 mg, 1.50 mmol) obtained in the previous step in methanol (100 mL) was added 10 wt. ~ (dry basis) palladium on activated carbon (200 mg) under a stream of nitrogen. The resulting black suspension was deoxygenated by alternate evacuation and flushing with nitrogen (3x) followed by alternate evacuation and flu~~hing with hydrogen (3x). The reaction suspension was then shaken vigorously under a hydrogen atmosphere of 55 ps~i . After 12 hours, gravity filtration of the supsension and concentration of the resulting filtrate in vacuo resulted in a pale yellow residue.
Purification of this residue by flash column chromatography afforded 1-(t-butoacycarbonyl)-3-benzyl-piperidine (407 mg, 99~) as .a clear oi7_. 1H NMR (300 MHz, CDC13), 8: 7.23 (m, 2H), 7.14 (m, 3H), 3.86 (m, 2H), 2.75 (br m, 1H), 2.51 (m, 3H), 1.70 (br. m, 2H), 1.64 (br. m, 1H), 1.41 (s, 9H), 1.34 (br. m, 1H), 1.09 (br. m, 1H). MS (CI), m+/z: (M+ + 1) 276, I(M+H)+ - (-C'(0)OC(CH3)3)] - 176.
Part D: 3-Benzylp~_peridine hydrochloride ~ HC 1 To a solution of 1-(t-butoxycarbonyl)-3-benzylpiperidine (400 mg, 1.45 mmol) in methanol (5 mL) was added hydrogen chloride in dioxane (4M, 15 mL). The resulting yellow solution was stirred for 1 hr, at which time the reaction was concentrated in vacuo to provide 3-benzylpiperidine hydrochloride (308 mg, 1000 as an amorphous solid. 1H NMR (300 MHz, CD30D), b: 7.27 (m, 2H,), 7.19 (m, 3H), 3.29 (br. d, 1H, J = l2Hz), 3.20 (br.
d, 1H, J = 12 Hz), 2.87 (br. t, 1H, J = 12 Hz), 2.67 (m, IH), 2.60 (d, 2H, J = 7Hz), 2.08 (m, 1H) 1.70-1.87 (m, 3H), 1.26 (m, 1H). MS (CI), m+/z: (M+H)+ = 176.
Part E: Preparation of N-(3-methoxyphenyl)-N'-[3-[3-[(phenyl)methyl]-1-piperidinyl]propyl]urea The above compound was prepared by the methods similar to the ones employed in Example 1, part C.
1H NMR (300 MHz, CD30D), 8:7.29-7.13 (m, 4H); 7/07 (d, 1H, J=9 Hz); 7.02 (m, 1H); 6.78 (d, 1H, J = 9 Hz); 6.60 (d, 1H, J = 9 Hz); 3.77 (s, 3H); 3.30 (m, 2H); 2.80 (m, 2H);
2.53-2.32 (m, 4H); 1.85-1.55 (m, 7H); 1.44-0.78 (m, 2H).
MS (ESI), m+/z: (M+H)+ - 382.

Part A: 3?reparation of a,a'-Dibromo-3-nitro-o-xylene B _ p+
B ~ o 3-Nitro-o-xylene (lO.Og, 66.14 mmol, 1.00 eq), N-bromosuccinimide (24.14 g, 135.6 mmol, 2.05 eq), and benzoyl peroxide (0.8 g, 3.30 mmol, 0.5 eq) were refluxed under N2 .in 200 ml of carbon tetrachloride. The reaction was worked up after two days by washing with 3 x 100 ml of water. The organic phase was dried over sodium sulfate, then the :solvent was removed in vacuo to obtain an amber oil. The oil was purified by flash chromatography on a 8 cm x 20 crn quartz column, eluting with 7.5'k EtOAc/Hexanes to yield 4.46 g of product as a sticky solid. NMR (300 MHz, CDC1;; ) 8 7 . 88 (d, 1H, J=7 Hz) , 7 .64 (d, 1H, J=7 Hz) , 7.48 dd, :LH, J=8 Hz), 4.86 (s, 2H), 4.69(s, 2H).
Part B: Preparation of 1,3-Dihydro-4'-[4-fluorophenylmethyl]-4-nitro-spiro[2H-isoindole-2,1'-piperidinium] bromide + ~+ O

Br-~--~~
4-Fluorobenzylp~iperidine (0.94 g, 4.86 mmol, 1.0 eq), a,a'-dibromo-3-nitro~-o-xylene (1.50 g, 4.86 mmol, 1.0 eq), and sodium carbonate: (2.57 g, 24.3 mmol, 5.0 eq) were combined :in 20 ml TH:F and stirred at 25~ C under N2, during which time a white solid precipitated from the reaction mixture. The reaction was worked up after 22 hours by filtering the solids and rinsing with THF. The solids were dissolved in methanol and applied to a 3.5 cm x 5 cm quartz column via silica plug. The product was eluted with 200 MeOH/CHC13 to yield 1.04 g of a white foam. NMR (300 MHz, CD30D) 8 8.27 (d, 1H, J=8 Hz), 7.84 -7.80 (m, 1H), 7.75-7.69 (m, 1H), 7.23 (m, 2H), 7.01 (dd, 2H, J=8 Hz, 8 Hz), 5.38-5.37 (m, 2H), 5.09 (s, IH), 5.04 (s, 1H), 3.80-3.72 (m, 2H), 3.65-3.54 (m, 2H), 2.71-2.68 (m, 2H), 2.05-1.75 (m, 5H) .
Part C: Preparation of 4-Amino-1, 3-dihydro-4'-[4-fluorophenylmethyl]-spiro[2H-isoindole-2,1'-piperidinium]
bromide I ~l-~- 2 1,3-Dihydro-4'-[4-fluorophenylmethyl]-4-nitro-spiro[2H-isoindole-2,1'-piperidinium] bromide (1.03 g, 2_46 mmol, 1.0 eq), zinc (5.32 g, 81.5 mmol, 33.0 eq), and calcium chloride (0.18 g, 1.60 mmol, 0.65 eq) were refluxed under N2 in 25 ml of a 78~ ethanol/water solution. The reaction was worked up after 5 hours by filtering through Celite~ and rinsing the cake with methanol. The filtrate was concentrated in vacuo to a mixture of water and an amber oil. The mixture was dissolved in 50 ml of 2-propanol, and concentrated in vacuo to remove excess water.
The resulting yellow foam was dissolved in methanol and applied to a 3.5 cm x 5 cm quartz column via silica plug.
The product was eluted with 20~ MeOH/CHC13 to yield 0.81g of a yellow foam. NMR (300 MHz, DMSO) 8 7.27-7.05 (m, 5H), 6.61-6.53 (m, 2H}, 5.43-5.42 (m, 2H), 4.80 (bs, 1H), 4.74 (bs, 2H}, 4.63 (bs, 1H), 3.62-3.43 (m, 4H), 2.60 (bd, 2H, J=7 Hz), 1.98-1.59 (m, 5H).

Part D: Preparation of N-[1,3-Dihydro-4'-[4-fluorophenyl-methyl]spiro(2H-isoindole-2,1'-piperdinium-4-yl]-N'-4-f luorophen~~lurea bromide 4-Amino-1, 3-dihydro-4'-[4-fluorophenylmethyl]-spiro(2H-isoindole-2, 1'-piperidinium] bromide (0.33 g, 0.84 mmol, 1.0 eg), and 4-fluorophenyl isocyanate (0.23 g, J.0 1.69 mmol, 2.0 eq) were combined in 3 ml DMF and stirred at 25~ C under N2 . They reaction was worked up after 22 hours by removing the solvent in vacuo, dissolving the residue in methanol, and applying the mixture to a 3.5 cm x cm quartz column via silica plug. The product was 15 eluted with 10~ MeOH/CHC13 to yield 65 mg of a yellow foam.
NMR (300 MHz, DMSO) b 9.18 (s, 1H), 9.00 (s, 1H), 7.49-7.43 (m, 2H), 7.41-7.34 (m, 2H), 7.26-7.21 (m, 2H), 7.17-7.10 (m, 5H), 4.94 (s, 2H), 4.80 (s, 2H), 3.63-3.45 (m, 4H), 2.61 (bd, j=7 Hz), 1.91-1.62 (m, 5H) Part A. Preparation c>f 4-benzyl-1-(3-hydroxy-3-phenylprop-1-yl)piperidine , 25 To a flame-dried 3-neck flask under a N2 atmosphere with a magnetic stirring bar, 4-benzylpiperidine (5.00 mL, 28 mmol, 1 eq), DBU (42 uL, 0.28 mmol, 0.01 eq), and THF
(100 mL) were added, mixed, and cooled to -15 °C using a CC14/C02(s) bath. Acrolein (1.87 mL, 28 mmol, 1 eq) was then syringed in slowly during 10 minutes maintaining the temp. at -15 °C. After 0.5 hours at -15 °C, phenylmagnesium chloride (2.0 M, 14.0 mL, 28 mmol, 1 eq) was syringed in slowly and the contents allowed to slowly warm to room temperature and then stirred for 48 h. The reaction was worked up by adding 0.1 N NaOH and EtOAc (200 mL each).
1D The viscous magnesium salts were suction filtered through fiberglass filter paper. The layers were separated and the aqueous layer was extracted again with ethyl acetate (2 x 200 mL). The organic layers were combined, washed with brine (1 x 200 mL), dried (MgS04) and the solvent removed in vacuo to yield 7.39 g of an amber oil. Flash chromatography in 100 ethyl actetate yielded 2.48 g of an orange oil. NMR (CDC13) 8 7.40-7.10 (m, lOH); 4.93 (d of d, 1H, J=3,7 Hz); 3.12-2.96 (m, 2H); 2.68-2.46 (m, 4H);
2.01 (t of d, 1H, J=2, 10 Hz); 1.86-1.26 (m, 8H). ESI MS
detects (M+H)+ = 310.
Part B: Preparation of 4-benzyl-1-(3-azido-3-phenylprop-1-yl)piperidine The product from part A (209 mg, 0.675 mmol, 1 eq), DBU (123 mg, 0.810 mmol, 1.2 eq), diphenylphosphoryl azide (0.175 mL, 0.810 mmol, 1.2 eq), and toluene (1.0 mL) were mixed and stirred overnight at room temperature under a N2 atmosphere. The reaction was then worked up by adding ethyl acetate (50 mL), washing with water (3 x 25 mL), followed by washing with brine (1 x 25 mL), drying (MgS04) and removing the solvent in vacuo to yield 277 mg of an WO 00/35449 PCT/US99/3029.".".
amber oil. Flash chromatography in 1:I hexane/ethyl acetate yiE:lded 84 mg of product as an oil. NMR (CDC13) 8 7.41-7.09 (m, 10 H); 4.56 (t, 1H, J=7 Hz); 3.83 (m, 2H);
2.52 (d, 2Fi, J=7 Hz) ; 2.32 (t, 2H, J=7 Hz) ; 2.30-1.77 (m, 5H); 2.59 (m, 2H); 1.98 (m, 1H); 1.39-1.26 (m, 4H). IR
(neat) 2095 cm'1.
Part C: Preparation of 4-benzyl-1-(3-amino-3-phenylprop-1-yl ) piperid:ine The compound from part B (100 mg), 10~ Pd on carbon (120 mg), and methanol (100 mL) were carefully combined in a flask under a N2 atmosphere. The contents were then submitted to 1 atm of H2 being delivered via a sparge tube for 0.5 h at room temperature. Filtration of the contents through Celite~ and removal of the solvent in vacuo yielded 70 mg of product. NriR (CDC13) (key peak only) 53.94 (t, 1, J = 7 Hz) . NH4-CI M~; detects (M+H) + = 309 .
Part D: N-(3-cyanophenyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl]-1-pheny7_propyl]urea The compound from Part C (57 mg, 0.185 mmol, 1 eq) was mixed and stirred with 3-cyanophenylisocyanate 26.6 mg, 0.185 mmol, 1 eq) in T'HF (1 mL) overnight at room temperature under a N2 atmosphere. The solvent was removed in vacuo and the residue flash chromatographed on silica gel in 3:1 to 1:1 hexane/ethyl acetate to 100 ethyl acetate to yield 44.3 mg of a yellow oil. NMR (CDC13) 87.58 (s, 1H); 7.52 (d, 1H, J = 9 Hz); 7.42 (s, 1H);
7.30-7.27 9m, 8H); 7.12 (m, 3H); 4.82 (m, 1H); 2.97-2.80 (m, 3H); 2.52 (d, 2H, J=7 Hz); 2.35 (m, 2H); 2.05-1.85 (m, 4H); 1.81-1.60 (m, 2H); 1.54 (m, 1H); 1.25 (m, 1H).
ESI MS detects (M+H)+ = 453.

Part A: Preparation of 2-benzyloxycarbonylamino-1-phenyl-3-butene.
To a stirred suspension of methyltriphenylphosphonium bromide (10.72 g, 0.03 moles) in 100 mL of dry tetrahydofuran at -78°C was added dropwise 1.6M n-butyl lithium (17.5 mL, 0.028 moles), and the mixture was stirred for 0.5 hrs at -78 ~ -20°C. Then was added a solution of N-Cbz-phenylalaninal (5.67 g, 0.02 moles) in 50 rnL of dry tetrahydrofuran, and the mixture was stirred for 16 hrs at room temperature. After addition of saturated NH4C1 (50 mL) the mixture was extracted with EtOAc, and the extract was washed with water and brine. It was dried over Na2S04 and evaporated to give an oily residue. The crude product was purified by column chrornatograpy on silica gel with elution by 5:95 EtOAc-hexane to give pure 2-benzyloxycarbonylamino-1-phenyl-3-butene. , Part B: Preparation of 2-benzyloxycarbonylamino-1-phenyl-3,4-epoxy-butane.

H
To a stirred solution of 2-benzyloxycarbonylamino-1-phenyl-3-butene (1.43 g, 5.08 mmoles) in 20 mL of CH2C12 was added 3-chloroperoxybenzoic acid (2.19 g, 60~, 7.62 mmoles) in ;several portions, and the mixture was stirred at room temperature for 30 hrs. After addition of EtOAc (60 mL), the mixture was washed with saturated NaHC03 and brine, and ~he organic layer was dried over Na2S04.
Evaporation of the solvent afforded an oily residue. The crude product was purified by column chromatography on silica gel with elution by 2:8 EtOAc-hexane to give pure 2-benzyloxyca~_bonylamino-1-phenyl-3,4-epoxy-butane.
1'S Part C: Preparation of 2-benzyloxycarbonylamino-4-[4-(4-fluoropheny:L)methyl-1-piperidinyl]-1-phenyl-butan-3-ol.
F~'~U ~ "~°~
21) A solution of 4-(4-fluorophenyl)methyl-piperidine (0.515 g, 2..314 mmoles) and 2-benzyloxycarbonylamino-1-phenyl-3,4-epoxy-butane (0.688 g, 2.314 mmoles) in 5 mL of DMF was stirred for 4 hours at 100°C and cooled to room temperature.. After addition of EtOAc (30 mL), the mixture 2!i was washed with water (2x) and brine. The oranic solution was dried over Na2S04, and evaporated to give an oily residue. It was then purified by passing through a plug of silica gel with elution by EtOAc to give pure product.

Part D: Preparation of 2-amino-4-[4-(4-fluorophenyl)methyl-1-piperidinyl]-1-phenyl-butan-3-ol.
~z The above product was dissolved in 10 mL of ethanol, and was added 0.1 g of 10~ Pd on carbon. The mixture was stirred under hydrogen (1 atm) for 8 hours, and filtered through Celite. Evaporation of the solvent gave the titled product as solid (0.662 g).
Part E: Preparation of N-(3-cyanophenyl)-N'-[1-benzyl-2-hydroxy-3-[4-(4-fluorophenylmethyl)-1-piperidinyl]propyl]urea H H ~N
~H
To a solution of 2-amino-4-[4-(4-fluorophenyl)methyl-1-piperidinyl]-1-phenyl-butan-3-of (50 mg, 0.14 mmoles) in 2.5 mL of dry THF was added 3-cyanophenyl isocyanate (20.2 mg, 0.14 mmoles) and the mixture was stirred for 15 minutes at room temperature. Then the solvent was evaporated off to give an oily residue. It was purified by column chromatography on silica gel with elution by EtOAc to give pure titled compound as an amorphous solid.
MS (ES+) for C3pH33FN4O2 - 501.
The following examples were prepared by the procedures previously described in Schemes 1-25 , Examples 1-6 and/or by procedures familiar to one skilled in the art.

TABLE 1*
H H
C/~~ N~ NR3 ~~ ~ H
R~ ~~~~ R
H. H
a b C 0 Q H H
C~~~ N~ NR3 ~N\/~,~ ~ G H H N.
G R3 /~\~~ R
H H

f H H H H H H
Ks i~ N.R G~~ IS
3 ~ R3 0 Ph 0 Ph h i G H H ~..~ ~ H H H G H H
~N ~ N N.R G N N N. N N N.
3 Y R3 ~ R
~ ~ 3 P~ O PYl 0 ~ 0 j k 1 Ex Core_ G ' M+1 # R3 7 a Ph _ 410 3-C02Et-Ph 8 a Ph 3_.I_p~- 464 9 a Ph 1-adamant 1 396 a Ph 3-OCH3-Ph 368 11 a Ph Ph 338 12 a Ph 4-F-Ph 356 13 a Ph 4-C02Et-Ph 410 14 a Ph 4-CN-Ph 363 b Ph 1-adamant 1 410 _16 b Ph 2-F-5-CF3-Ph 438 17 b Ph 2-na hth 1 402 ~

18 b Ph 2-F-5-N02-Ph 415 19 b Ph 4-N(CH3)2-Ph 395 _20 b Ph 2-N02-Ph 397 21 b Ph 2-C2H5-Ph 380 22 b Ph 4-CF4-Ph 420 23 b Ph 3,5-diCF3-Ph 488 --_24 b Ph 3-C02Et-Ph 424 b Ph 3-CN-Ph 377 26 b Ph 4-OBn-Ph 458 27 b Ph 2-Ph-Ph 428 28 b Ph 2-BrPh 431 29 b Ph 4-I-Ph 478 b Ph 3-I-Ph 478 31 b Ph 4-OEt-Ph 396 32 b Ph 4-nBu-Ph 408 33 b Ph 4-nBuO-Ph 424 34 b Ph CH(Bn)C02Et 452 35 b Ph CH(iPr)C02Et 404 36 b Ph nC8H17 3gg 37 b Ph 3-OCH3-Ph 382 38 b Ph Ph 352 39 b Ph 4-C02Et-Ph 424 40 b Ph 4-F-Ph 370 41 b Ph 2-Phenyl- 392 cyclo ro 1 42 b Ph 2-OCH3-Ph 382 43 b Ph 4-OCH3-Ph 382 44 b 4-F-Ph 3-CN-Ph 395 45 b 4-F-Ph 4-F-Ph 3gg 46 b 4-F-Ph 4-C02Et-Ph 442 47 b 3,4-OCH20-Ph 3-CN-Ph 421 48 b 4-F-Ph 3-OCH3-Ph 400 49 b 3,4-OCH20-Ph 3-C02Et-Ph 468 50 b 3,4-OCH20-Ph 3-OCH3-Ph 426 51 b 4-OCH3-Ph 3-OCH3-Ph 412 52 b 4-OCH3-Ph 4-F-Ph 400 53 b Ph 4-CN-Ph 377 54 b 3,4-OCH20-Ph 4-F-Ph 414 55 b 4-OCH3-Ph 4-CN-Ph 407 56 b 2,4-diF-Ph 4-F-Ph 406 57 b 2,4-diF-Ph 3-OCH3-Ph 418 58 b 2,4-diF-Ph 3-CN-Ph 413 59 b 3-CF3-Ph 4-F-Ph 438 60 b 3-CF3-Ph 3-OCH3-Ph 450 61 b 4-F-Ph CH2Ph 384 62 b 4-F-Ph CH2CH2Ph 398 63 b 4-F-Ph 2-F-Ph 388 64 b 4-F-Ph 3-F-ph 3gg 65 b 4-F-Ph c clohexyl 376 66 b 4-F-Ph iPr 336 67 b 4-F-Ph 2-phenyl- 410 c clo ro 1 68 b 4-CF3-Ph 3-CN-Ph 445 69 b 3-CF3-Ph 3-CN-Ph 445 70 b 4-CH3-Ph 3-OCH3-Ph 396 71 b 4-CH3-Ph 3-CN-Ph 391 72 b 4-C1-Ph 3-CN-Ph 411 73 b 4-CF3-Ph 4-C02Et-Ph 492 74 b 3-OCH3-Ph 3-OCH3-Ph 412 75 b 3-OCH3-Ph 3-CN-Ph 407 76 b 4-C02CH3-Ph 3-OCH3-Ph 440 77 b 4-C02CH3-Ph 3-CN-Ph 435 78 b 4-C02CH3-Ph 4-F-Ph 428 79 b 4-C02CH3-Ph 4-C02CH3-Ph 482 80 b 4-CF3-Ph 4-F-Ph 438 81 b 4-CF3-Ph 3-OCH3-Ph 450 82 b 3-OCH3-Ph 4-F-Ph 400 83 b 3-OCH3-Ph 4-C02Et-Ph _ 454 84 b 2-F-Ph 3-CN-Ph 395 85 b 3-OCH3-Ph 3-F-Ph _ 400 86 b 2-F-~?h 3-OCH3-Ph 400_ 87 b 3-OCH3-Ph 3-C02Et-Ph 454 88 b 2-F-~?h 3-F-Ph 388_ 89 b 2-F-1?h 4-F-Ph 388 90 b 2-F-1?h 3-C02Et-Ph __442_ 91 b 3-F-1?h 3-CN-Ph 395 92 b 3 , 4-diF~-Ph 3-CN-Ph 413 93 b 3,4-diF-Ph 3-OCH3-Ph 418 94 b 4-C1-Ph 4-F-Ph 409 95 b 4-Cl.-Ph 3-OCH3-Ph 416 96 b 2-F-lPh 4-C02Et-Ph 442 97 b 3-F-1Ph 3-OCH3-Ph 400 98 b 3-F-lPh 4-F-Ph 388 99 b 3-F-1Ph 4-C02Et-Ph 442 100 b 3 , 4-di1?-Ph 4-F-Ph 406 101 b 3-Cl-Ph 3-CN-Ph 411 102 b 4-F-lPh 3-COCH3-Ph 412 103 b 3,5-dih-Ph 3-CN-Ph 413 104 b 3,5-dil=-Ph 3-OCH3-Ph 418 105 b 4-F-:Ph 4-COCH3-Ph 412 106 b 1-na h~th 1 3-CN-Ph 427 107 b 1-na hth 1 4-F-Ph 420 108 _ 1-na ht:h 1 3-OCH3-Ph 432 b 109 b 3-CH3-Ph 3-CN-Ph 391 110 b 3-CH3-Ph 4-F-Ph 384_ 111 b 3-CH3-Ph 3-OCH3-Ph 396 112 b 4-F-Ph 2-iPr-Ph 412 113 b 4-F-Ph 2-CF3-Ph 438 114 b 4-F-P 3-C1-Ph 404 h 115 b _ 3-CF3-Ph 438 4-F-Ph 116 b 4-F-Ph 4-Ph-Ph 446 117 b 4-F-Ph 2-C1-Ph 404 118 b 4-F-Ph 2,4-diF-Ph 406 119 c Ph_ 3-C02Et-Ph 424 120 c Ph 3-CN-Ph 377 121 c Ph 4-F-Ph _ _370 _ 122 c Ph Ph _352 123 c Ph 1-adamant 1 410 124 c- Ph 4-C02Et-Ph 424 125 c 4-F-Ph Ph 370 126 c 4-F-Ph 3-CN-Ph 39_5 127 c 4-F-Ph 1-adamant 1 428 128 c 4-F-Ph 3-OCH3-Ph 400 129 c 4-F-Ph 3-C02Et-Ph 442 130 c 4-F-Ph 4-F-Ph 388 130a c 4-F-Ph 3-COCH3-Ph 412 131 c 2-F-Ph Ph 370 132 c 2-F-Ph 3-CN-Ph 395 _ 133 c 2-F-Ph 3-OCH3-Ph 400 134 c 2-F-Ph 4-F-Ph 388 135 c 3-F-Ph 3-OCH3-Ph 400 136 c 3-F-Ph 3-CN-Ph 395 137 c 2,4-diF-Ph 3-CN-Ph 413 138 c 2,4-diF-Ph 3-OCH3-Ph 418 139 c 2,4-diF-Ph Ph 388 140 c 2,4-diF-Ph 4-F-Ph 406 141 c 2,4-diF-Ph 3-COCH3-Ph 430 142 d Ph 3-CN-Ph 391 143 d Ph 3-C02Et-Ph 438 144 d Ph 3-I-Ph 492 145 d Ph 4-OCH2Ph-Ph 472 146 d Ph 1-adamant 1 424 147 d Ph 3-OCH3-Ph 396 148 d Ph Ph 366 149 d Ph 4-F-Ph 384 150 d Ph 4-C02Et-Ph 438 151 d Ph 4-CN-Ph 391 152 a 4-F-Ph Ph 356 153 a 4-F-Ph 3-CN-Ph 381 154 a 4-F-Ph 3-OCH3-Ph 386 155 a 4-F-Ph 4-F-Ph 374 156 a 4-F-Ph 3-C02Et-Ph 428 157 a 4-F-Ph 4-C02Et-Ph 428 158 a 4-F-Ph 1-adamant 1 414 159 f 4-F-Ph 3-CN-Ph 411 160 f 4-F-Ph 3-OCH3-Ph 416 161 j Ph Ph 458 162 j Ph 3-CN-Ph 483 163 Ph 3-OCH3-Ph 488 _164 j 4-F-Ph 3-OCH3-Ph 506 165 j 4-F-Ph 4-F-Ph 494 166 j 4-F-Ph 1-adamant 1 534 167 1 Ph 3-OCH3-Ph 458 168 1 Ph 1-adamant 1 486 169 c imidazol-1- 1 3-OCH3-Ph 372 * All stereocenters are (+/-) unless otherwise indicated TABLE 2**
RS a Sb R5C ~1 ~2 R~ N O ~~ Z

X
m Ex Y Z R4 X R5a R5b R5c R1 R2 #

170 H H - - H H H H Ph 172 H 3-OCH3 CH2Ph Br H H H H H

WO 00/35449 PCTlUS99/30292 t 176 H 3-CN CH2Ph Br H H H H H

h 178 H 3-CN - - H H H Et H

180 H 4-F CH2Ph Br H H H H H

181 H 4-F CH2C02CH Br H H H H H

182 H 3-CN CH2CN Br H H H H H

183 H 3-CN CH2COPh Br H H H H H

188 H 3-OCH3 _ - H H H H H
O

h 191 F 3- _ - H CH2P H H H

_ 192 F 4-F-Ph - - H CH2P H H H
h h h h **All compounds are amorphous unless otherwise indicted.
TABLE 3**
X ~~ Z Y + X ~H~~ Z
Y~ + L ~O N O
n o Ex # Core Y Z X

196 n H 3-CN Br 197 n -- H 3-~ Br 198 n H _ 4-F Br 199 n H 4-F Br _ __ 2 0 0 n F 3 -~ Br 2 01 n F 3 -~ $r 202 n F 3-OCH3 Br 203 n F 3-OCH3 Br 204 o F 4-F gr 205 o F 4-F Br 206 o F 3-OCH3 Br 207 o F 3-OCH3 Br 208 o F 3-CN Br 209 o F 3-CN Br r~~l compounas are amorphous unless otherwise indicted.
The compounds of the present invention in which E
contains ring A can be prepared in a number of ways well known to one skilled in the art of organic synthesis. As shown in Scheme 26, 4-benzyl piperidine is N-alkylated with an alkylating agent, such as 165 (2-vitro-benzyl bromide (X
- Br, R14 = H), Scheme 26) to give the N-benzyl compound 166. The vitro group of 166 is then reduced using catalytic hydrogenation to give the corresponding aniline 167. The aniline can be converted to the carbamate 168 using chloro-phenyl formate. The carbamate 168 can then be reacted with various amines to give the urea 169.
Alternatively, the aniline 167 can be reacted with the appropriate isocyanates to give the urea 169 directly. The saturated ring analogs can also be used. For example, 4-benzyl piperidine can be alkylated with the urea mesylate 185 (Scheme 30) to give corresponding cyclohexyl derivative 186.
As shown in Scheme 27, 4-benzyl piperidine can also be N-alkylated with the phenacyl bromide 170 to give the vitro ketone 171. The vitro group of 171 is then reduced using catalytic hydrogenation to give the corresponding aniline 172. The aniline 172 can be reacted with the appropriate isocyanates to give the ketone urea 173. The ketone of 173 can be reduced with NaBH4 to give the alcohol 1?4.

Alternatively, the epoxide ,~5 (R - H) can be opened with the 4-benzyl piperidine to give the corresponding vitro benzyl alcohol which is hydrogenated to give the aniline alcohol 176. The aniline 176 may be treated with various isocyanates to give the urea alcohols 174.

The 4-benzyl piperidine can also be N-alkylated with 3-cyanobenzyl bramide (177, Scheme 28) to give the cyano analog 178. The cyano group is reduced using Raney nickel to give the <:orresponding benzyl amine 179. Treatment of 179 with isoc:yanates gives the urea 180.
As shown in Scheme 29, treatment of 3-cyano aniline with phenylisocyanate gives the urea 182. The cyano group of 182 is converted to the imidate ~ by HC1/ethanol.
Reaction with 4-benzyl piperidine in ethanol then gives the amidine 184.
The saturated ring analogs can also be synthesized using analogous procedures as outlined in Schemes 30 and 31. For example, 4-benzyl piperidine can be alkylated with the urea mesylate 185 (Scheme 29) to give corresponding cyclohexyl derivative 186. Alternatively, starting with the enantiomerically pure amino alcohol 187 [J. Am. Chem. Soc.
1996, 118, 5502-5503 and references therein) one can protect the nitrogen to give the N-Cbz alcohol ~. Swern oxidation of the alcohol gives the aldehyde 18~. Reductive amination with piperidine analogs gives the cyclohexyl methyl-1-piperidinyl analogue ~. The Cbz group is removed by catalytic hydrogenation to give the free amine 191, which is treated with a phenylisocyanate to give the desired urea analogue 192. Several examples using these synthetic methods are listed in Table 3a and Table 3.1.

X
R14 i / + w NOa A .-.~ R1~ \

NOZ
X = C1, Br, MsO, etc. 166 R1~ \ _ / \
I/
H ~ ~ Ri4 I /
NHz R14= \
I/
~~R

A: DMF/KzC03/RT or THF/RT. H:10%Pd/C, H z 50 psi.
C: THF/Et3N/chlorophenylformate. D:NHR/DMF/50°C.
E: R-N=C=O/THF

r \ ~ /
v R14 i + Rla NO.
/ '~ ' / NOZ 171 i B

C Ri4.

D D

\ H (~.~/ ~/
R1~ C R1~. \ ~/
~~~R .,.-_~ / NHy 176 fIO
A, B

R +
/ NOZ
r A: DMF/KzCO~/RT or DMF/50°C. B:10$Pd/C, ~I50 psi. C: R-~N=C=O/THF. D:NaBF~/MeOH/RT
sct~a~ z a Br ~ A

CN CN
177 , 1 B
W
N.-I~ 17 s N- R
NHZ

A: DMF/K 2C0~/RT B:Raney nickel, H 2 50 psi.
C: R-N=C=0/THF.

VH
CN A' ~ \ CN B' ~ \ pEt C ~ ~ \
/ / /
~2 o -.~~ '~' ~ \ '~' , \
/ o / o A: R-N=C=O/THF. B:EtOH/HC1/RT
C: 4-benzylpiperidine/EtOH/RT

OH OMs A,B
C
~~ N~ \ OMe ' y N~ ~ ~ OMe O
O

A: R-N=C=O/DMF. B:Ms-C1/THF
C:4-benzylpiperidine/DMF/RT

.WO 00/35449 PCT/US99/30292 OH
a OH
----..
NH-CB Z
'187 188 H N
__ I
.'~NH-CBZ ~ ---~..
C 1V -C: t3G

B
..~~nNH2 , ----.-____ a:Benzyl chloroformate:/Na2C03/CH2C12. b.Swern Ox.
c:NaBH(OAc)3 d:Hz/10~ F?d/C e:R-N=C=O/THF.

SCHEME 31a OH
a OH
b ~2 ~NH-CB Z

/ \ F / \
O F
H N
N
d NH-CBZ -~~~~'N-CBz / \ F / \
F
N- ) N-~/a ...~~~NH2 -,-~. ...,.~N N O

a:Benzyl chloroformate/Na2C03/CHzCl2. b.Swern Ox.
c:NaBH(OAc)3 d:Hz/10$ Pd/C e:R-N=C=O/THF.
The following examples were synthesized using the methods outlined in Schemes 26-31a. These examples are meant to be illustrative of the present invention, and are not to be limiting thereof.

N-[1-(phenylmethyl)4-piperidinyl]-N'-[2-[[4-(phenylmethyl)-1-piperidinyl]-methyl]phenyl]urea.
A solution of 4--benzylpiperidine (1.75 g, 10 mmol) in 25 mL of DMF was treat=ed with 2-nitrobenzyl bromide (2.16 g, 10 mmol ) and KZC03 ( 1 . 3 8 g, 10 mmol ) and the reaction mixture stirred at room temperature for 2 h. The mixture was diluted with water and extracted into ethyl acetate.
The organic extracts were washed successively with water and brine, and the organic solvent removed und4r vacuum on a rotary evaporator t:o give 1 6 (Scheme 26, R - H) as a yellow oil.
The oil was re-dissolved in ethyl acetate (50 ml) and treated with 10~ Pd/C: and hydrogenated at 50 psi hydrogen at room temperature f:or 40 min. The solution was then filtered and the solvent removed under vacuum to give the aniline 167 as a white solid. The aniline was purified by chromatography (MPLC, 40~ ethyl acetate/ hexane; silica gel) to give 2.0 g oi_ aniline X67 as a white solid.
A solution of aniline ~ (1.2 g, 4.3 mmol) in THF was treated with Et3N (1.0 g, 10 mmol) and cooled in an ice bath to °0 C. Chlorophenyl formate (0.71 g, 4.5 mmol) was added to the mixture and stirred for 1 h. The mixture was diluted with water and extracted into ethyl acetate. The extracts were washed with water and brine, and the solvent removed under vacuum to give the phenyl carbamate 168 as an off-white solid. ThE_ crude product was used without further purification.
A solution of phenylcarbamate ~ (0.2 g, 0.5 mmol) in DMF is treated with 4-amino-1-benzylpiperidine (95 mg, 0.5 mmol) and K2C03 (138 mg, 1 mmol) and the mixture was heated at 50 °C for 2 h. The mixture was diluted with water and extracted into ethyl acetate. The extracts were washed with water' and brine, and the solvent removed under vacuum.
The residue was puri:Eied by chromatography (MPLC, 0-25 $
MeOH/ethyl acetate; ailica gel) to give 200 mg of the target compound as a white solid. esi mss (M+H)' - 497.

N-(2,5-difluorophenyl)-N'-[2-[[4-(phenylmethyl)-1 piperidinyl]-methyl]phenyl]urea.

A solution of aniline 167 (Scheme 26; (R - H)) (140 mg, 0.5 mmol) in THF is treated with 2,5-difluoro-isocyanate (80 mg, 0.5 mmol) at room temperature for 1 h.
The solvent is removed under vacuum and the residue was purified by chromatography (MPLC, 20~ EtOAc/Hexane, silica gel) to give the desired urea as a white solid. esi ms:
(M+H)~ - 436.

N-(2,5-difluorophenyl)-N'-[[3-[[4-(phenylmethyl)-1-piperidinyl]methyl)phenyl]methyl]urea.
A solution of 4-benzylpiperidine (1.75 g, 10 mmol) in mL of DMF was treated with 3-cyanobenzyl bromide 277 20 (1.96 g, 10 mmol) and KzC03 (2.76 g, 20 mmol) and the reaction mixture stirred at room temperature for 2 h. The mixture was diluted with water and extracted into ethyl acetate. The organic extracts were washed successively with water and brine, and the organic solvent removed under 25 vacuum on a rotary evaporator to give 178 (Scheme 28) as a . yellow oil.
To a suspension of Raney nickel (2.0 g) in EtOH
(saturated with NH3~gas) ) was added crude 178 (Scheme 28) (1.45 g, 5 mmol) and hydrogenated at 50 psi for 3 days.
The solution was then filtered and the solvent removed under vacuum to give the amine 179 as a yellow oil. A
solution of amine 179 (200 mg, 0.68 mmol) in THF is treated with 2,5-difluoroisocyanate (I15 mg, 0.74 mmol) at room temperature for 1 hour. The solvent is removed under vacuum and the residue is washed with 1 NaOH and water to give the desired urea as a white solid. esi ms: (M+H)+ - 450.

. WO 00/35449 PCTNS99/30292 N-(2,5-difluoroph.enyl)-N'-[2-~[[4-(phenylmethyl)-1-pigeridinyl)acetylJphenyl]urea To an ice cold solution of 2-bromo-2'-nitro-acetophenone 170 (2.4 g, 10 mmol) in DMF is added 4-benzylpiperidine (1.75 g, 10 mmol) and stirred for 30 min.
The solution was poured into a mixture of K2C03 (1.38 g, 10 mmol) in water/ice and. extracted into ethyl acetate. The .LO ethyl acetate extract was washed several times with water.
The resultant ethyl acetate solution of crude nitroketone 171 is treated with 10~ Pd/C and hydrogenated at 50 psi hydrogen at room temperature for 40 min. The solution was then filter, the solvent removed under vacuum, and the J.5 residue purified by chromatography (MPLC, 30~ ethyl acetate/hexane; silica. gel) to give 1.8 g of aniline 172 as a tan/brown solid.
A solution of aniline 172 (Scheme 27) (310 mg, 1.0 mmol) in THF is treated with 2,5-difluoroisocyanate (160 ~:0 mg, 1.0 mmol) at room temperature for 1 h. The solvent is removed under vacuum a.nd the residue is purified by chromatography (MPLC, 20~ EtOAc/Hexane, silica gel) to give 420 mg of the desired urea-ketone 173 as a white solid. esi ms: (M+H)' - 464.
~! 5 EX~MgLE 222 N-(2,5-difluorophenyl)-N~-[2-[2-[4-(phenylmethyl)-1-piperidinyl]-1-hydroxyethyl)phenyl]urea .!0 A solution of the urea-ketone 17 (260 mg, 0.56 mmol) in MeOH is treated with NaBHg (400 mg, 11 mmol) at room temp for 1 hour. The solvent is removed under vacuum and the residue is treated with 1 N NaOH and extracted into EtOAc.
The extracts are washed with water, brine and the solvent .15 removed under vacuum t:o give the desired alcohol 174 as a white solid. esi ms: LM+H)+ - 466.

N-[3-[imino-[4-(phenylmethyl)-1-piperidinyl]methyl]
phenyl]-N'-phenylurea A solution of 3-cyanoaniline (3.54 g, 30 mmol) in THF
is treated with phenylisocyanate (3.58 g, 30 mmol) at room temperature for 1 h. The solvent is removed under vacuum and the residue is titurated with hexane to give 7 grams of urea 182 (Scheme 29) as a white solid. Urea 182 (1.0 g, 4.2 mmol) is dissolved in EtOH, cooled in an ice bath while HC1 is bubbled-in for 20 min. The solution is left standing at room temperature for 24 h. The solvent is removed under vacuum to give 1.1 g of the imidate 183 as a white solid. The crude imidate (0.5 g, 1.8 mmol) was dissolved in EtOH and treated with 4-benzyl-piperidine (1.8 g, 10 mmol) at room temperature for 2 days. The solvent was removed under vacuum and the residue was purified by chromatography (MPLC, 0 to 30~ MeOH/EtOAc, silica gel) to give 200 mg of the desired amidine 184 (Scheme 29) as a white solid. esi ms: (M+H)' - 413.

N-(3-methoxyphenyl)-N'-[(1R,2S)-2-[[(4-phenylmethyl) piperidinyl]methyl]cyclohexyl]urea.
Step a: To a solution of (R,R) amino alcohol 187 [~T. Am.
Chem. Soc. 1996, 118, 5502-5503 and references therein]
( 1 . 9 g, 14 . 7 mmol ) in CHzCl~ ( 50 mL) is added 50 ml of an aqueous solution of Na2C03 (2.4 g, 28.9 mmol)_ While stirring, benzyl chloroformate (2.51 g, 14.7 mmol) is added and the mixture is stirred at room temperature for 1 h. The organic layer is separated and washed with water and brine.
The solution is concentrated on a rotary evaporator and the residue is chromatographed on silica gel (30~ ethyl acetate/hexane) to give 3.1 g (12 mmol) of 188 as a white solid. 1H NMR (300 MHz, CDC13) 8 7.40-7.29 (m, 5 H) , 5.11 (s, 2 H) , 4.71 (bd, 1 H) , 3 . 76-3 .71 (m, 1 H) , 3 . 53-3 .28 (m, 3 H) , 2 . 00-1 .95 (m, 1 H) , 1.90-1.09 (m, 8 H) . MS AP' (M+H)' - 264.3 (100 Step b: A solution of DMSO (2.52 g, 30 mmol) in CHZC12 (50 mL) is cooled to -'78°C. To this solution is added drop-wise oxalyl chloride (:L.81 g, 14 mmol) and the resulting solution is stirred fo:r an additional 10 min. Then a solution of alcohol 18.3 ( 2 . 5 g, 9 . 5 mmol ) in CH~C1~ ( 7 0 ml ) is added via an addition funnel and stirred for 10 min.
Then Et3N (_'>.0 g, 50 rcumol) is added and the solution is allowed to warm to room temperature. The solution is diluted with water and the organic layer washed with water, 1 N HC1, and brine. The organic layer is dried over Na2S0,, filtered, and concentrated to give 2.5 g (9.5 mmol) of the aldehyde 183 as a white solid. 1H NMR (300 MHz, CDC1,) b 9.59 (d, 3.6 Hz, 1 H), 7.38-7.28 (m, 5 H), 5.07 (m, 2 H), 4.69 (m, 1 H), 3.84 (m, 21 H), 2.19-2.11 (m,l H), 2.09-2.01 ( m, 1 H) , :L . 86-1. 75 (m, 3 H) , 1. 54-1.17 (m, 4 H) .
2 iJ
Step c: A solution of aldehyde ,~89 (2.0 g, 7.7 mmol), 4-(4-fluorophenylmethyl)piperidine hydrochloride (1.8 g, 7.8 mmol) in dichloroe~thane (80 ml) was treated with Na(OAc),BH (3.23 g, 15 mmol) and 1 ml AcOH and stirred overnight at room temperature. The resulting solution was diluted with methylene chloride and washed with 1 n NaOH, water, andbrine. The organic solvents were removed under vacuum and the residue' chromatographed on silica gel (50$
EtOAc/hex - 100 EtOAc:) to give 3.0 g (6.8 mmol) of ~ as an oil.
Step d: A solution of 190 (3.0 g, 6.8 mmol) in MeOH
was treated with 1.5 g of 10~ Pd/C and hydrogenated at 50 psi overnight in a Parr apparatus. The mixture was filtered and the filtrate concentrated on a rotary evaporator to give 1.8 g (5.9 mmol) of the amine 191 as an oil.

Step e: A solution of amine 191 (200 mg, 0.67 mmol) in THF is treated with 3-methoxyphenyl isocyanate (110 mg, 0.75 mmol) and the mixture is stirred for 30 min. The solvent is removed on a rotary evaporator and the residue is chromatographed on silica gel (50~ EtOAc/hex - 100 EtOAc) to give 250 mg of urea 192 as a solid. MS esi:
(M+H)' - 454.4 (1000 , HRMS (M+H)' - 454.2875.

N-(3-acetvlphenyl)-N'-f(1R 2S)-2 ff(3S) 3 (4 fluorophenvl)methvlloiraeridinyllmethyllcyclohexyllurea Step a: To a solution of (R, R) amino alcohol 187 [J.Org.
Chem. 1996, 51, 5557-5563; J. Am. Chem. Soc. 1996, 118, 1S 5502-5503] (9.5 g, 73.8 mmol) in CH=C12 (200 mL) is added 200 ml of an aqueous solution of Na~CO, (15 g, 141 mmol).
While stirring, benzyl chloroformate (12.6 g, 73.8 mmol) is added slowly and the mixture is stirred at room temperature for 1 h. The organic layer is separated and washed with 2D water and brine. The organic solvent is removed on a rotary evaporator to give a white solid. The solid is recrystallized from hexane to give 16.3 g (62 mmol) of the alcohol 188 (Scheme 31a)as a white solid. 1H NMR (300 MHz, CDCI~} $ 7.40-7.29 (m, 5 H), 5.11 (s, 2 H), 4.71 (bd, 1 H), 25 3.76-3.71 (m, 1 H), 3.53-3.28 (m, 3 H), 2.00-1.95 (m, 1 H), 1.90-1.09 (m, 8 H) . MS AP' (M+H)' - 264.3 (100 Step b: A solution of DMSO (36 g, 430 mmol) in CHzClz (200 mL) is cooled to -78°C. To this solution is added drop-wise 30 oxalyl chloride (27.41 g, 216 mmol) and the resulting solution is stirred for an additional 10 min. A solution of alcohol 188 (38 g, 144 mmol) in CH,C12 (150 ml) is added via an addition funnel and stirred for 10 min. Then, Et~N (58 g, 570 mmol) is added and the solution is stirred for 20 35 min and the ice bath removed and stirred for an additional 30 min. The solution is diluted with water and the organic layer separated and washed with water, 1 N HC1, and brine.
The organic layer is dried over NazSO', filtered, and concentrated to give ?.8 g of aldehyde 189 as a white solid.
The solid is recrystal.lized from hexane to dive 19.7 grams of a first crop of alc~ehyde 189 as white needles. A second crop gave an additional 11 grams. 1H NMR (300 MHz, CDClj) b 9.59 (d, 3.6 Hz, 1 H), 7.38-7.28 (m, 5 H), 5.07 (m, 2 H), 4.69 (m, 1 H), 3.84 (m, 21 H), 2.19-2.11 (m,l H), 2.09-2.01 ( m, 1 H), 1.86-1.75 (m, 3 H), 1.54-1.17 (m, 4 H).
Step c: A solution of aldehyde 189 (19.6 g, 75 mmol) and J.0 ( 3 S) -3 - ( 4- f luorophenyl.methyl ) piperidine ( 14 . 5 g, 75 mmol ) in dichloroethane (40Cr ml) was treated with Na(OAc)3BH (32 g, 152 mmol) and stirred overnight at room temperature. The resulting solution was. poured slowly into a stirred mixture of ice/water/1 N NaOH and stirred for 20 min. The organic 1.5 layer was separated and washed water, and brine. The solution was dried over MgSOa and the organic solvent was removed under vacuum a.nd the residue chromatographed on basic alumina (50~ EtC>Ac/hexane) to give 32.1 g (73 mmol) of amine ~3- as mixture of (15~)cis and traps isomers. 1H
f.0 NMR (300 MHz, CDC1,) b '7 .79 (bs, 1 H) , 7.38-7.29 (m, 5 H) , 6.95-6.84 (m, 4 H), 5.08 (m, 2 H), 3.71 (m, 1 H, cis isomer ), 3.06 (m, 1 H, trans~ isomer), 2.80 (m, 1 H), 2.55-2.36 (m, 2 H), 2.30 (dd, J ~ 9 Hz, J = 13 Hz, 1 H, traps isomer), 2.05 (dd, J = 2 Hz, J = 13 Hz , 1 H, traps 25 isomer), 1.81-0.90 (m, 16 H).
Step d: A solution of 193 (32 g, 73 mmol) in MeOH was treated with 8 g of 10~~ Pd/C and hydrogenated at 50 psi overnight in a Parr aF~paratus. The mixture was filtered and 30 the filtrate concentrated on a rotary evaporator to give 20 g (65 mmol) of the amine 1~4, which was used without further purification.
Step e: A solution of amine 1_~ (10 g, 32.8 mmol) in THF is 35 treated with 3-acetylyphenyl isocyanate (5.3 g, 32.8 mmol) and the mixture is stirred for 30 min. The solvent is removed on a rotary evaporator and the residue is WO 00!35449 PCT/US99/30292 chromatographed on silica gel (0.5:4.5:95 NHaOH/MeOH/CH2Clz) to give 11 g of urea 295 (Example 415) as a solid. Also obtained 2 g of cis isomer (Example 416a). The urea Example 415 was further purified by a second chromatography on silica gel (40:60:1 EtAc/Hex/TEA) and final recrystallization from ether to give crystalline solid. mp 115-117 °C, [a]DZS - +16.8° (CH30H, c = 0.23 g/dL) . 1H NMR
(300 MHz, CDC1~) 87.86 (m, 1 H), 7.78 (bs, 1 H), 7.68-7.64 (m, 1 H), 7.62-7.59(m, 1 H), 7.38 (t, J = 8 Hz, 1 H), 6.95 6_90 (m, 2 H), 6.79-6.72 (m, 2 H), 6.25 (s, 1 H), 3.21 (dt, J = 3 Hz, 11 Hz, 1 H), 3.00-2.97 (m, 1 H), 2.66-2.56 (m, 1 H), 2.61 (s, 3 H), 2.44-2.32 (m, 4 H), 2.06 (dd, J = 2 Hz, J = 13 Hz, 1 H), 1.80-0.86 (m, 15 H). MS esi: (M+H)' - 466.3 (1000 . Anal. Calcd for C28H~6N~OZF: C, 72.23; H 7.70; N, 9.02. Found: C, 72.33; H, 7.91; N, 9.00.
EXAMPLE 415a N-(3-acetylphenvl)-N~-f(1R,2S)-2-ft(3S)-3-(4 fluorophenyl)methvllpiperidinvllmethyllcyclohexvllurea Hydrochloride.
A solution of example 415 (15 g, 32 mmol) in 300 ml of THF
was cooled in an ice bath and treated drop-wise with 36 ml of a 1 M HC1/ether solution. The resulting solution was stirred for 30 min and concentrated in vacuo. The resulting solid was titurated with ether and the resulting white solid dried under high vacuum overnight to give 16 g of the hydrochloride salt. mp 58-60 °C. [a]DZ5 - +20.0 ° (CH,OH, c =
0.23 g/dL). 1H NMR (400 MHz, DMSO-D6) 8 9.61 (s, 1 H), 9.15 (s, 1 H), 8.00 (m, 1 H), 7.63-7.61 (m, 1 H), 7.51-7.49(m, 1 H), 7.39-7.34 (m, 1 H), 7.22-7.17 (m, 2 H), 7.09-7.04 (m, 2 H), 6.86 (d, J = 8 Hz, 1 H), 3.47-3.31 (m, 4 H), 3.11 (m, 1 H), 2.98-2.82 (m, 2 H), 2.67-2.62 (dd, J = 5 Hz, J = 13 Hz, 1 H), 2.58-2.50 (m, 2 H), 2.52 (s, 3 H), 2.39 (dd, J = 8 Hz, J = 13 Hz, 1 H), 2.16-2.06 (m, 2 H), 1.84-1.556 (m, 7 H), 1.30-1.00 (m, 4 H)_ Anal. Calcd for CZBH~7N;02FC1 ~H20 ~THFo.25 : C, 64 .73 ; H 7 . 68 ; N, 7 . 81 . Found: C, 64.89; H, 7.41; N, 7.81.
EXAMPLE 415b N~(3-acetylphenyl)-N'-f (1R.2S)-. 2-f f (3S)-3-(4-fluorophenyl)methv7.lpiperidinvllmethyllcvclohexyllurea Benzenesulfonate.
1.0 Bezenesulfonic acid monohydrate (1.06 g, 6 mmol) was dried by azeotroping off they water of a benzene solution (twice) and adding 'the dried acid solution to a solution of example (2.81 g, 6 mmol) in toluene (40 ml). The solvents were removed in vacuo (twice) and the resulting residue recrystallized twice from toluene and dried under high vacuum overnight give 'x.77 g of benzenesulfonic acid salt as a white aolid. mp 157-159 °C. [oc]°zs - +16.9 °
(CHlOH, c =
0.23 g/dL) . Anal. Ca7.cd for C~aH4~N~O5FS: C, 65.47; 'H 6.80;
N, 6.75; S, 5.14. Found: C, 65.48; H, 6.80; N, 6.70; S, 5.35.
The compounds of Table 3a and Table 3.1 were prepared by procedures described in Schemes 26-31A, other examples and methods taught herein, and procedures familiar to one skilled in the~art.
TABLE 3a R~s w Ras w i N.E i N.E
0 5~ 1 0 Rya ~ 2 ~N-R3 Rya ~,/IZ~CN-Rs H 4~ 2 H
P
R~s ~ ~ ~s ~ H
N.E R -~ +N E s i ~ Z 0 5f li 0 Rya 4~ Z ~N.R3 R'4 /ZEN-Rs a H 4~ 2 H
r s Ex Core RI6 E Z R14 R3 S
#

M+H~

p H CHZ (1) (phenylmethyl) 497 NH H _4-i eridin 1) 2,5-219 p H CHZ (1) difluorophenyl 436 NH H

2,5-220 p H CHZ (2) difluorophenyl 450 CHZNH H

2, 5-221 p H .~ (1) difluorophenyl 464 ~, ~ NH H

O

2,5-222 p H ,~ (1) difluorophenyl 466 ~

~ NH H

OH

2 2 p H C=~ ( 2 phenyl 3 ) NH H

224 p H CH2 (2) (phenylmethyl) 497 NH H -4_ i eridin 1]

2_(4_ 225 p H CHZ (1) fluorophenyl)- 446 H ethyl 226 p H CHl (1) H hydroxypropyl 382 NH

_ 2-{1-227 p H CHI {1) H piperidinyl)- 435 NH eth 1 228 p H CHa (1) H (dimethylamino 395 j eth 1 229 p H CH2 (1) H (phenylmethyl) 483 NH -1-piperazine 230 p H CH2 (1) H (phenylmethyl) 482 NH -1-piperidine (l, 3-231 p H CH2 (1) H benzodioxol-5- 458 NH ylmethyl) 2,2-232 p H CH2 (1) H (diphenyl)ethy 504 4-(4-233 p H CHz (1) H chlorophenyl)- 518 NH 4-hydroxy-1-piperidine 4-phenyl-4-234 p H CHZ (1) H hydroxy-1- 484 NH piperidine 4-phenyl-1-235 p H CH2 (1) H piperidine 468 NH

(1H)-indazol-236 p H CH2 (1) H 5-yl 440 NH

(1H)-indazol-237 p H CH2 (1) H 6-yl 440 NH

phenylmethyl 238 p H CH2 (1) H 414 NH

_ 1, 3-239 p H CH2 (1) H benzodioxol-5- 444 i 240 (3 4) 1-P H CH (1) z (phenylmethyl) NH o _4_ ~ piperidinyl]

(3-4) 2-(4-p CHZ (1) fluorophenyl)- 490 o ethyl 'O

242 (3-4) 4- ( (2-H

P CH2 (1) phenyl)ethyl) 541 NH
'O -1-piperazine 243 (3-4) (1H)-indazol-H

P CH2 (1) 5-yl 484 NH
~O

244 (3-4) (1H)-indazol-H

p CH2 ( 1 6-yl 484 ) NH
'O

245 (3-4) benzothiazol-P H CH2 (1) 6-yl 501 NH
'O

246 f2- (4-p H CHz (1) (4) fluorophenyl)- 462 OH ethyl 247 p H CH2 (1) (4) (phenylmethyl) 513 NH OH _4-i eridin 1]

(3-4) 3-phenylpropyl p H CH2 (1) 486 NH
'O

249 (1H)-indazol-Z ( H 5-yl 440 ) NH

250 f 2- (4-p H CH (2) z H fluorophenyl)- 446 ethyl 2 ~ 5 - _ 251 p H bond (1) H difluorophenyl 422 NH

Phenyl 252 p H CHI (1) H 400 NH

_ 4-253 p H CHz (1) H methoxyphenyl 430 3_ 254 p H CH2 (1) H methoxyphenyl 430 NH

3_ 255 q 4-F CH2 (2) H methoxyphenyl 454 NH

3-acetylphenyl 256 q 4-F CHz (2) H 466 NH

257 r H CHZ (1) H methoxyphenyl 430 NH

3-cyanophenyl 258 p H CHz (2) H 425 NH

3-cyanophenyl 259 p H CH2 (3) H 425 NH

260 p H CH2 (3) H methoxyphenyl 430 NH

2-phenylethyl 261 p H CHz (3) H 428 NH

3-carboethoxy-2 62 p H CHZ ( 1 H phenyl 472 ) NH

3-cyanophenyl 263 p H CH2 (1) H 425 NH

phenyl 264 p 4-F CHZ (1) H 418 NH

phenyl 265 p H CHz (1) H 490 N-Benzyl 3-cyanophenyl 266 p CHz (1) H 515 H

N_ Benzyl 267 2-Phenylethyl p H CHz (1) H 428 NH

(3-4) 3-cyanophenyl 268 p H CH2 (1) 469 NH
O

(3-4) 3-carboethoxy-269 p H CH2 (1) phenyl 516 NH
'O

270 ~ (3-4) 4-carboethoxy-P H CHz (1) phenyl 516 NH
'O

271 phenyl p H CHz (1) (4) NH OH

3-cyanophenyl p H CH2 (1) (4) NH OH

273 (4 ) 3-P H CHz (1) methoxyphenyl 524 274 (4) Trans-2-P H CH2 (1) phenyl- 534 cyclopropyl 275 (3) 3-cyanophenyl P H CH2 ( 1 483 ) NH COZMe 276 (3 ) 3-p H CH2 (1) methoxyphenyl 488 NH COZMe (4) 3-cyanophenyl 277 p H CHz (1) 519 NH O~~
O

S

-O~ CHa (3) 3-278 p H CHz (1) methoxyphenyl 460 NH ~H

(3) 3-cyanophenyl ~

279 p H CHz (1) 455 NH ~H

(4) 3-cyanophenyl 280 p 4-F CHZ (1) 501 NH CO~Me (5) 3-cyanophenyl 280a p 4-F CHz (1) 501 NH COzMe (5) 3-cyanophenyl 280b p 4-F CH2 (1) NH CONMe (5) 3-cyanophenyl 280c p 4-F CHI (1) 486 NH CONHz (5) 3- (1-280d P 4-F CH2 (1) hydroxyethyl)- 520 NH COzMe phenyl (5) phenyl 280e r H CHz (1) 458 NH C02Me ( 5 ) phenyl 280f P 4-F CHl (1) 462 NH COZH

(5) 3-cyanophenyl 280g r H ~H2 (1) 483 NH CO~Me (5) ~ 3_ 280h r H CHz (1) methoxyphenyl 488 NH COzMe f (5) 3-acetylphenyl 2801 r H CHZ (1) 500 NH COzMe (5) 3-acetylphenyl 280j p 4-F CH2 (1) 518 HC1 NH COzMe ( sa lt) (5) 3-cyanophenyl 280k p 4-F CHZ (1) 501 HC1 NH CO.Me ( sa ' 1 r.
) (4) phenyl 281 p 4-F CHz (1) 476 NH COZMe (5) phenyl 281a p 4-F CHZ (1) 476 NH COzMe (5) phenyl 281b p 4-F CHz (1) 475 NH CONMe (5) phenyl 281c p 4-F CH2 (1) 461 NH CONHz 282 p 4-F CHz (1) (4) metho xyphenyl 506 NH

CO Me 282a p 4-F CH2 (1) (5) methoxyphenyl 506 NH

CO Me (5) 3-282b p 4-F CH2 (1) methoxyphenyl 505 NH CONMe (5) 3-acetylphenyl 282c p 4-F CHz (1) 518 NH COzMe (5) 3-acetylphenyl 282d p 4-F CHz (1) 517 NH CONMe (5) 3-acetylphenyl 282e p 4-F CHZ (1) 503 NH CONHZ

(4) 3-cyanophenyl 283 p 4-F CHz (1) 473 NH OOH

3-cyanophenyl 284 p 4-F CHz (1) (3-4) 493 fused Phenyl 285 p 4-F CHz (1) (3-4) methoxyphenyl 498 fused Phenyl 3-cyanophenyl 286 p 4-F CHz (1) (4) 562 NH

-CONPh 3-cyanophenyl 286a p 4-F CHz (1) (5) 562 NH

-CONPh 3-acetylphenyl 286b p 4-F CHz (1) (5) 579 NH

-CONPh (4) 3-287 p 4-F CHz (1) methoxyphenyl 478 NH w,\,~OH

(4) 3-cyanophenyl 288 p 4-F CHz (1) NH CONMe (4) 3-cyanophenyl 288a p 4-F CHz (1) 500 HC 1 NH CONMe ( s.
a lt) (5) 3-acetylphenyl 288b p 4-F CHz (1) HC1 ( NH CONMe s,a lt) (5) 3-acetylphenyl 288c p 4-F CHz (1) 574 NH CON

( CHz ) z NMez (5) 3-acetylphenyl 288d p 4-F CHz (1) 557 NH CON

(CHz)z NMez (5) 3-acetylphenyl 288e p 4-F CHz (1) 453 NH CON

C3Hs (5) 3-acetylphenyl 288f p 4-F CH2 (1) NH CON

C3Hs (5) 3 2888 p 4-F CH2 ~ (1) metho 519 xyphenyl NH CONMe2 (5) 3-acetylphenyl 288h p 4-F CH2 (1}

NH CONMe2 (5) 3-acetylphenyl 2881 p 4-F CHZ (1) NH CON ( pyridi nyl) (5) 3-288j p 4-F CHz (1) methoxyphenyl 568 NH CONMez 2,5-289 p H CHz (1) H difluorophenyl 450 3-cyanophenyl 290 p H CH2 (1) H 439 3-carboethoxy-291 p H CHz (I) H phenyl 486 292 p H CHz (1) H metho xyphenyl 444 CHzNH

293 p H CH2 (1} methoxyphenyl 444 294 p H ~,~ (1) H methoxyphenyl 460 ~

~ NH

OH

295 r H ,~ (1) H methoxyphenyl 460 ~

~ NH

OH

3-cyanophenyl 296 p H ,~ (1) H 455 ~~ NH

Ohl 3-carboethoxy-297 p H ,~ (1) H phenyl 502 ~

~ NH

Oh-I

phenyl 298 p H .~ (1) H 430 ~

~ NH

C~h-I

(5) phenyl 299 p 4-F CHz (1) 448 LVH OOH

S 3 phenyl ~~
r 3 00 p H ~- ( 1 443 ) NOH NH H

phenyl 301 p H .~ (2) H 428 ~.

~ NH

O

phenyl 302 p H ,~ (2) H 430 ~.~ NH

OH

phenyl 3 03 p 4-F .~ ( 1 H 448 ) ~.~ NH

Oti 3 04 p 4-F ,~ ( 1 H methoxyphenyl 478 ~ ) ~I NH
S ~'-a-~

3-cyanophenyl 3 05 p 4-F ,~ ( 1 H 473 ) ~r~ NH

a-~

( 3-4 3 -cyanophenyl ) 306 p H ,~ (1) O 499 ~,~ NH

OIH p 3-cyanophenyl 307 p H CHz- (1) H 439 3-cyanophenyl 308 p 4-F CH2- (1) H 457 CHZ NH

309 p H CHZ- (1) H methoxyphenyl 444 CHZ NH

310 p 4-F CH2CH~ ~ ( H methoxyphenyl 462 ) NH

311 r H CH2- (1) H methoxyphenyl 444 CHz NH

3-acetylphenyl 312 p 4-F CH2- (1) H

4-fluorophenyl 313 p 4-F CH2- (1) H 450 1-adamantyl 314 p 4-F CHZ- (1) H 490 CHz NH

( 3-4 3 -cyanophenyl ) 315 s H CHZ (1) ~ 483 NH
(M+) 3-cyanophenyl 316 s H CH2 (1) (4) 455 NH OH (M+) 3-cyanophenyl 317 s H CH2 (1) (4) 539 o- ( M+
) (2-THP) TABLE 3.1 R~s Rts / %~ / /
2 ~N Z N
a HN~NH R3 HN-~-NH R3 R~s -,.
y --N
HN~-NH R3 b Ex Core R16 Stereo- Salt MS
# 3 f R M+H

chemistry Form 400 a H 1,2 traps - 3-methoxylphenyl 436 racemic 401 a 4-F 1,2 traps - 3-methoxylphenyl 454 racemic 402 a H 1,2 cis - 3-methoxylphenyl 436 racemic 403 a 4-F 1,2 traps - 3-cyanophenyl 449 rac emi c 403a a 4-F 1,2 traps - 3-acetylphenyl 466 racemic 403b a 4-F _ - 3-nitrophenyl 469 1,2 traps racemic 403c a 4-F 1,2 traps - 4-nitrophenyl 469 racemic 403d a 4-F 1,2 t.rans - 4-pyridinyl 425 racemic 403e a 4-F 1,2 t.rans HC1 ~ 3-acetylphenyl 466 racemic 403f a 4-F 2,2 t,rans - (1H)-indazol-5-yl 464 racemic 404 a 4-F _ - 3-acetylphenyl 466 1S,2R

405 a 4-F 1.S,2R - 3-cyanophenyl 449 406 a 4-F 1S,2R - 3-methoxylphenyl 454 407 a 4-F 1S,2R - phenyl 424 408 a 4-F 1R,2S - 3-acetylphenyl 466 409 a 4-F 1R,2S - 3-cyanophenyl 449 410 a 4-F 1R,2S - 3-methoxyphenyl 454 411 a 4-F 1R,2S - phenyl 424 412 a 4-F 1R,2S - phenylmethyl 438 413 a 4-F 1R,2S - (1H)-indazol-5-yl 464 414 a 4-F 1R,2S - (1H)-indol-5-yl 463 414a b H 1,2 traps - 3-methoxyphenyl 464 (3RS) racemic 414b b H 1,2 traps - 3-cyanophenyl 431 (3RS) racemic 414c b H 1,2 traps - 3-acetylphenyl 448 (3RS) racemic 414d b 4-F 1,2 traps - 3-acetylphenyl 466 (3RS) racemic 414e b 4-F 1,2 traps - 3-cyanophenyl 449 (3RS) racemic 414f b 4-F 1,2 traps - 3-methoxyphenyl 454 (3RS) racemic 414g b 4-F 1,2 traps - 3-nitrophenyl 469 (3RS) racemic 415 b 4-F 1R,2S,3S - 3-acetylphenyl 466 415a b 4-F 1R,2S,3S HC1 3-acetylphenyl 466 415b b 4-F 1R,2S,3S Besyl 3-acetylphenyl 466 416 b 4-F 1R,2S,3R - 3-acetylphenyl 466 416a b 4-F 1R,2R,3S - 3-acetylphenyl 466 416b b 4-F 1R,2S,3R HC1 3-acetylphenyl 466 417 b 4-F 1R,2S,3S - 3-cyanophenyl 449 418 b 1 4-FI1R,2S,3R - 3-cyanophenyl 449 ~

419 b 4-F 1R,2S,3S - 3-methoxylphenyl 454 420 b 4-F 1R,25,3R - 3-methoxylphenyl 454 421 b 4-F 1R,2S,3S - 4-fluorohenyl 442 422 b 4-F 1R,2S,3R - 4-fluorohenyl 442 423 b 4-F 1R,2S,3S - phenyl 424 424 b 4-F 1R,2S,3S - (1H)-indazol-5-yl 464 425 b 4-F 1R,2S,3S - (1H)-indazol-6-yl 464 426 b 4-F 1R,2S,3S - benzthiazol-6-yl 481 427 b 4-F 1R,2S,3S - (1H)-indol-5-yl 463 428 b 4-F 1R,2S,3S - (1H)-indol-6-yl 463 429 b 4-F 1R,2S,3S - (1H)-2,3- 491 dimethylindol-5-1 430 b 4-F 1R,2S,3S - benzimidazol-5-yl 464 431 b 4.-F 1R,2S,3S - indolin-S-yl 465 432 b 4-F 1R,2S,3S - 3-cyano-4- 467 fluoro hen 1 433 b 9:-F 1R,2S,3S - 3-acetyl-4- 484 fluoro hen 1 434 b 9:-F 1R,2S,3S - 3,5-diacetylphenyl 508 435 b 4-F 1R,2S,3S - 3-(1- 468 hydroxyethyl)-hen 1 436 b 4.-F 1R,2S,3S - 4-methyl-thiazol- 445 437 b 4-F 1R,2S,3S - 4-methyl-5-acetyl- 487 thiazol-2-yl 438 b 9:-F 1R,2S,3S - 1,3,4-thiadiazol- 432 439 b 4-F 1R,2S,3S - 4-chlorol- 515 benzthiazol-2- 1 440 b 4-F 1R,2S,3S - thiazol-2-yl 431 441 b 4:-F 1R,2S,3S - 5-methyl-isoxazol- 429 3-yl 442 b 4-F 1R,2S,3S - 1-methyl-pyrazol- 428 443 b 4-F 1R,2S,3S - 4-(1,2,4-triazol- 491 1- 1) hen 1 443a b 9-F 1R,2R,3S - 4-(1,2,4-triazol- 491 1- 1) hen 1 444 b 4-F 1R,2S,3S - (1H)-3-chloro- 499 indazol-5- 1 445 b 4-F 1R,2S,3S - 4-fluorophenyl 492 446 b 4-F 1R,2S,3S - 4-chlorophenyl 458 447 b 4-F 1R,2S,3S - 4-bromophenyl 502 448 b 4-F 1R,2S,3S - 3-bromophenyl 502 449 b 4-F 1R,2S,3S - 3-fluorophenyl 442 450 b 4-F 1R,2S,3S - 3,4-difluorophenyl 460 451 b. 4-F 1R,2S,3S - 3-chloro-4- 476 fluoro hen 1 452 b 4-F 1R,2S,3S - 3,5-dichiorophenyl 492 453 c 4-F 1R,2S,3S - 3-acetylphenyl 452 454 c 4-F 1R,2S,3R - 3-acetylphenyl 452 455 c 4-F 1R,2R,3S - 3-acetylphenyl 452 456 c 4-F 1R,2S,3S - 3-cyanophenyl 435 457 c 4-F 1R,2S,3R - 3-cyanophenyl 435 458 c 4-F 1R,2R,3S - 3-cyanophenyl 435 458a c 4-F 1R,2R,3R - 3-cyanophenyl 435 459 c 4-F 1R,2S,3S - phenyl 410 460 c 4-F 1R,2S,3R - phenyl 410 461 c 4-F 1R,2R,3S - phenyl 4I0 462 b 4-F 1R,2S,3S - (1H)-5-amino- 464 indazol-1- 1 463 b 4-F 1R,2S,3S - 3-chlorophenyl 458 464 b 4-F 1R,2S,3S - 3-fluoro-4- 456 meth 1 hen 1 465 b 4-F 1R,2S,3S - 3-cyano-4-(1- 515 razol 1) hen 1 466 b 4-F 1R,2S,3S - 2-methylphenyl 454 467 b 4-F 1R,2S,3S - 2-methylphenyl 438 468 b 4-F 1R,2S,3S - 2,4-dimethylphenyl 452 469 b 4-F ~R,2S,3S - 2,4- 484 dimetho hen 1 470 b 4-F 1R,2S,3S - 2,5- 484 dimetho henyl PCTNS99l30292 ~WO 00/35449 X71 b 4-F 1R,2S,3S - 2-methoxy-5- 468 me thy lphen. 1 472 b 4-F 1R,2S,3S - fluoro hen 1 456 473 b 4-F 1R,2S,3S~ - 3,5-bis((1H)-1- 588 methyltetrazol-5 yl ) phen 1 474 b 4-F 1R,2S,3S - (3-((1H)-1- 506 methyltetrazol-5-yl ) hen 1 475 b 4-F 1R,2S,3S - (4- 517 (carboethoxymethYl )thiazol-2- 1 476 b 4--F 1R,2S,3S - 5-bromothiazol-2- 509 477 b 4--F 1R, 2S , 3 S -- 4 , 5-di ( 4- 619 fluorophenyl)thiaz 0l-2- 1 478 b 4-F 1R,2S,3S - 2-fluorophenyl 442 479 b 4-F 1R.2S, 3S - 2-chloroplzenyl 458 480 b 4-F 1R, 2S, 3S CF.,CO,H indanon-6-Y1 478 i 481 b 4-F 1R,2S,3S CF,CO,H indanon-4-yl 478 482 b 4-F 1R, 2S, 3S CF,CO,H 4- 466 (iso ro 1) hen 1 483 b 4-F 1R, 25, 3S CF,CO,H 3-vitro-4- 483 ~eth 1 hen 1 484 b 4-F 1R, 2S, 3S CF,CO,H trans-2- - ~ 464 phenylcycioprop-1 485 b 4-F 1R,2S,3S CF,CO,H 2,4-difluorophenyl 460 486 b 4-F 1R,2S,3S CF,CO,H 2,5-difluorophenyl 460 487 b 4-F 1R.2S,3S CF,CO,H 2,4-dichlorophenyl 492 488 b 4-F 1R. 2S, 3S CF,CO,H 2, 5-dichlorophenyl 492 489 b 4-F 1R, 2S, 3S CF,CO,H 2-methoxyphenyl 454 490 b 4-F 1R.2S,3S CF,CO,H 2,4-dimethoxy- 484 her~~~
491 b 4-F 1R,2S.3S CF,CO,H 2,5- 484 dimetho henyl 492 b 4-F 1R, 2S, 3S CF,CO,H 2- 492 trifluoromethylyph en 1 493 b 4-F 1R,2S,3S CF,CO,H 2-methylphenyl 438 494 b 4-F 1R, 2S, 3S CF,CO,H trifluoromethyly- 492 I I 1 I r,henvl i 495 b 4-F 1R,2S,3S CF,CO,H 3-methylphenyl 43 496 b 4-F 1R, 2S, 3S CF CO H 4-methoxyphenyl 4 497 b 4-F 1R, 2S, 3S CF~CO,H 4-carboethoxy-henyl 498 b 4-F 1R, 2S, 3S CF,CO,H 4- 4 trifluoromethyly-hen 1 499 b 4-F 1R,2S,3S CF CO H 4-methylphenyl S00 b 4-F 1R,2S,3S CF CO H 2-fluorophenyl SO1 b 4-F 1R, 2S, 3S CFzCO,H 2-chloropheny 4 502 b 4-F 1R, 2S, 3S CF,CO,H 2-nitrophen 1 503 b 4-F 1R, 2S, 3S CF~CO,H 2, 4-dichlorophenyl 5 504 b 4-F 1R, 2S, 3S CFtCO,H 3-nitrophenyl 505 b 4-F 1R, 2S, 3S CF~CO,H 3 , 5-di ltrifluoromethyly) 506 -phenyl b 4-F 1R, 2S, 3S CF~CO,H 2, 4- 452 dimeth 1 henyl 507 b 4-F 1R,2S,3S CF~CO,H 2,4-dimethoxy-5_ chloro hen 1 508 b 4-F 1R, 2S, 3S CF CO H 3, 4, 5-trimetho hen 1 509 b 4-F 1R,2S,3S CF CO H 3,5-dimethylphen 1 510 b 4-F 1R,2S,3S CF,CO,H 3-trifluoromethyl-4-chloro hen 1 511 b 4-F 1R, 2S, 3S CF,CO,H 4-phenoxyphen 1 512 b 4-F 1R,2S,3S CF~CO,H 4-ethoxyphen 1 513 b 4-F 1R, 2S, 3S CF,CO,H 4-thiomethylphen 1 5I4 b 4-F 1R, 2S, 3S CF~CO,H 2-naphthyl 515 b 4-F 1R, 2S, 3S CF~CO,fi 4-acetylphenyl 516 b 4-F 1R,2S,3S CF CO H 2,6-dichloro-ridin-4-yl 517 b 4-F 1R,2S,3S CF CO H 5-indan-4-yl 518 b 4-F 1R, 2S, 3S CF1CO,H 4-chloronaphth-1-519 b 4-F 1R, 2S, 3S CF,CO,H 3-fluoro-4-methoxvwhenyl 520 b 4-F 1R, 2S, 3S CF,CO,H 4-fmethylsulfonyl)-phenvl) 521 b 4-F 1R, 2 S, CF,CO,H 3- 502 (methylsulfonyl)-hen 1 522 b 4-F 1R, 2S, CF,CO,H 2- ( ( 1H) -pyrrol-1-489 ) 523 b 4-F 1R, 2S, CF,CO,H 1, 3-ben 468 3S zodioxol-5-524 b 4-F 1R,2S,3S CF,CO,H 1-acetylindolin-6- 507 525 b 4-F 1R, 2S, CF,CO,H 4- (6- 571 rnethylbenzothiazol -2- 1) hen 1 526 b 4-F 1R, 2S, CF,CO,H 4- ( (2, 2- 523 dimethylpropanoyl) amino) hen 1 527 b 4-F 1R, 2S, CF,CO,H 4- (1- 506 methyltetrazol-5-1)phen 1 528 b 4-F 1R, 2S, CF.,CO,H4- ( 1- 509 mo holino) hen 1 529 b 4-F 1R, 2S, CF.,CO,Hquinolin-8-yl 475 3S c 530 b 4-F 1R, 2S, CF.,CO,H3-hydroxyphenyl 440 531 b 4-F 1R, 2S, CF.,CO,H4- (acetylamino) 481 hen 1 532 b 4-F 1R, 2S, CF.,CO,H4-hydroxyphenyl 440 533 b 4-F 1R,2S,3S CF,CO,H 3-hydroxy-4- 470 metho hen 1 534 b 4-F 1R, 2S, CF,CO,H 3- (acetylamino) 48I

hen 1 535 b 4-F 1R,2S,:3S CF,CO,H 4-fluoro-3- 456 meth 1 hen 1 536 b 4-F 1R,25,:3S CF,CO,H 3-methoxy-4- 468 meth 1 hen 1 537 b 4-F 1R, 2S, CF,CO,H 4-chloro-3- 472 :3S

meth 1 hen 1 538 b 4-F 1R, 2S, CF,CO,H 4- (N- 4g1 methylcarboxamide) hen 1 539 b 9-F 1R,2S,:3S CF,CO,H 1-adamantyl 482 540 b 4-F 1R, 2S, CF,CO,H quinolin-5-yl 475 541 b 4-F 1R, 25, CF,CO,H quinolin-6-yl 475 542 b 4-F 1R, 2S, CF,CO,H 1, 4-benzodioxan-6- 482 _ 543 b 4-F 1R,2S,3S CF,CO,H isoquinolin-5-yl 475 544 b 4-F 1R, 25, CF,CO,H 4- (sulfonamide) 503 ~S -hen 1 545 b 4-F 1R, 2S, CF,CO,H benzotriazol-5-yl 465 WO 00!35449 PCT/US99/30292 546 b 4-F 1R,2S,3S CF.~CO~H2-hydroxy-4- 454 methylphenyl 547 b 4-F 1R,2S,3S CF.~CO~H3-hydroxy-4- 454 methyl henyl 548 b 4-F 1R,2S,3S CF~CO~H 2-methyl- 495 benzothiazol-5-yl 549 b 4-F 1R, 2S, CF.~CO~H(4- 468 methoxylphenyl)-methyl 550 b 4-F 1R,2S,3S CF.~CO~H(4-fluorophenyl)- 456 methyl 551 b 4-F 18,25,35 CF.~CO~H(4-methylphenyl)- 452 meth 1 552 b 4-F 1R,2S,3S (1R)-1- 452 CF~CO~H

( henyl)eth 1 553 b 4-F 1R,2S,3S CF~CO~H 1-acetylindolin-5- 507 554 b 4-F 1R,2S,3S CF~CO~H 5,6,7,8- 478 tetrahydronaphth-555 b 4-F 1R,2S,3S CF~CO~H 3-acetyl-4- 482 h dro hen 1 556 b 4-F 1R,2S,3S CF~CO~H 4-(PiPeridin-1- 507 1) henyl 557 b 4-F 1R,2S,3S CF~CO~H cyclohexyl 430 558 b 4-F 1R,2S,3S CF.~CO~H2-methoxyphenyl 468 559 b 4-F 1R,2S,3S CF.~CO~H2.6-dimethylphenyl 452 560 b 4-F 1R,2S,3S CF~CO~H 2-ethylphenyl 452 561 b 4-F 1R, 2S, CF,~CO~H2, 4, 6- 466 trimeth 1 hen 1 562 b 4-F 1R, 2S, CF.~CO~H, 2, 5- 484 dimetho hen 1 563 b 4-F 1R, 2S, CF.~CO~Ht-butyl 404 564 b 4-F 1R,2S,3S CF~CO~H i-Propyl 390 565 b 4-F 1R,2S,3S CF.~CO~HEthoxycarbonyl- 434 meth 1 ) 566 b 4-F 1R,2S,3S CF~CO~H ~ 2- 508 trifluoromethoxy-henyl 567 b 4-F 1R,2S,3S CF~CO~H (1R,S)-1-- 462 (methoxycarbonyl)-2-meth 1- ro 1 568 b 4-F 1R,2S,3S [(1S)-1- 510 CF.~CO~H

(methoxycarbonyl)-2-phen leth 1 569 b 4-F 1R,2S,3S CF~CO~H 24,4-trimethyl-2- 460 ent 1 570 b 4-F 1R,2S,3S CF~CO~H 2-Phenylethyl 452 571 b 4-F 1R,2S,3S CF~CO~H 3-acetylphenyl 466 572 b 4-F 1R,2S,3S CF.~CO~H2-carbomethoxy- 482 hen 1 573 b 4-F _ (1S)-1- 452 1R,2S,3S CF.~CO~H

(rhenyl)ethyl 574 b 4-F 1R,2S,3S CFiCO~H 4-(Phenyl)phenyl 500 575 b 4-F 1R,2S,3S CF~CO~H 1-naphthyl 474 576 b 4-F 1R,2S,3S CF.~CO~H2-(Phenyl)phenyl 500 577 b 4-F 1R,2S,3S CF.~CO~HPhenylmethoxy 454 578 b 4-F 1R, 2S, CF~CO.,H3. 4- 484 dimethoxyphenyl 579 b 4-F 1R, 2S, CF (3H) -2- 520 3S CO~H

~ ethylquinazolin-4-on-3- 1 580 b 4-F 1R,2S,3S CF~CO,,H3-PYridinyl 425 581 b 4-F 1R,2S,3S CF 6-methoxy-3- 455 CO~H

~ ridin 1 582 b 4-F 1R,2S,3S CF~C07H 2-methylquinolin- 489 8-yl 583 b 4-F 1R,2S,3S CF.~CO?H2-methylnaphth-1- 488 584 b 4-F 1R,2S,3S CF. 4-((1H)-1-propyl- 534 CO~H

~ tetrazol-5-1) hen 1 585 b 4-F 1R,2S,3S CF~CO~H 3-aminophenyl 439 586 b 4-F 1R,2S,3S - 3-(acetylamino)- 481 phenyl 587 b 4-F 1R, 2S, CF.~CO~H3- (N- 481 methylcarbamoyl)-hen 1 588 b 4-F 1R,2S,3S CF, 2-nitro-4- 499 CO~H

~ metho hen 1 589 b 4-F 1R,2S,3S CF.~CO~H8-hydroxyquinolin- 491 590 b 4-F 1R,2S,3S CFzCO~H 3-methylpyridin-2- 439 591 b 4-F ~ 1R, 2S, ~ CF.~CO~H~ isoquinolin-1-yl ~ 475 Ex mple 318 O
N ~0~
~1 Part A: Preparation of 1-t-butvloxycarbonvl 4 benzvlpiperidine 4-benzylpiperidine (10.0 g, 57.1 mmol, 1.0 eq.) was dissolved in 100 mL of THF under Nz and subsequently cooled to 0 °C. Di-tert-butyl dicarbonate (11.21 g, 51.3 mmol, 0.9 eq.) dissolved in 50 mL of THF, was added dropwise. Gas 20 evolution was observed. Once gas evolution ceased, the ice bath was removed. After 20 hours, the THF was removed in vacuo then the residue was dissolved in EtOAc and rinsed 3X
with 1N citric acid, IX with brine. The organic was dried over magnesium sulfate and stripped to yield 15.4 g of colorless oil as product. Yield = 97.9. NMR (300 MHz, CDC13)8 7.35-7.17 (m,3H); 7.14 (d, 2H, J = 7 Hz); 4.20-3.90 (m, 2H); 2.75-2.55 (m, 2H); 2.54 (d, 2H, J = 7 Hz); 1.70-1.50 (m, 3H);
1_46 (s, 9H); 1.20-1.00 (m, 2H).

II Ij N~O
+ ~~,OH
er_ythro threo Part B: Preparation of erythro-and threo-cis-4-benzyl-1-t-butoxycarbonyl-a-ethylpiperidinemethanol 1-t-butyloxycarbonyl-4-benzylpiperidine (5.0 g, 18.2 mmol; 1.0 eq. ) was dissolved in EtzO at 25 °C under N, and cooled to -'78 °C. N,N,Td',N'-Tetramethylethylenediamine (TMEDA) (3.29 mL, 21.8 mmol, 1.2 eq.) was added followed by the dropwise addition of sec--butyllithium (16.?6 mL, 2;1.8 mmol, 1.2 eq.). The reaction was allowed to warm and stir 1.5 at -30 °C for 30 minutes then again cooled to -78 °C. Once cool, propionaldehyde (1.31 mL, 20.0 mmol, 1.1 eq.) was added neat. The reaction was allowed warmed to warm t=o -30 °C then imme:diateiy quenched with 10 mL of water and the organic layer was separated. The aqueous layer was extracted 2X more with Et~O. The organic layers were combined, dried over magnesium sulfate and the solvenr_ removed in vacuo to y.i_eld a colorless oil which was purified by flash chromatography in 4 . 1 to 1 . 1 hexane/
EtOAc: Obtained 0.68 g of a colorless oil as isomer A, yield = 11.2% and -0.91 g of a colorless oil as isomer B, yield = lS.Oo.
Isomer A NMR (300 MHz,, CDC13)b7.40-7.25 (m, 2H); 7.21 (d, 1H, J = 7 Hz); 7.16 (d, 2H, J = 7 Hz); 3.60-3.30 (m, 2H);
2.56 (d, 2H J = 7 Hz); 1.90-1.00 (m, 7H); 1.46 (s, 9H);
1.00-0.70 (m, 5H).
Isomer B NMR (300 MHz, CDC13)8 7.30-7.23 (m, 2H); 7.20 (d, 1H, J = 7 Hz); 7.14 (d, 2H, J = 7 Hz.); 3.60-3.20 (m, 2H);

2.60-2.40 (m, 2H); 1.90-1.00 (m, 9H); 1.44 (s, 9H); 0.96 (t, 3H, J = 7 Hz) .
O
N-O

erythro Part C: Structure determination of Isomer B via cyclization to 4a,6a,7a-4-benzyl-7-ethyl-8-oxa-1-azabicyclo[4.3.0]nonane-9-one Isomer B (60 mg, 0.18 mmol, 1 eq.) was dissolved in DMF at 2 5 °C under N2 then NaH ( 7 . 9 mg , 0 .19 8 mmal , 1 eq _ ) was added. After 20 hours, 2 mL of water was added followed by EtOAc. The layers were separated. The aqueous layer was extracted 2X more with EtOAc. The organic layers were combined, dried over magnesium sulfate, and the solvent removed in vacuo to yield an oil which was purified over silica gel in 9:1 to 1:1 hexane/EtOAc. Obtained 30 mg.
Yield = 64~. Product structure confirmed by N.O.E. NMR
(300 MHz, CDCl~) 8 7.40-7.20 (m, 3H); 7.16 (d, 2H, J = 7 Hz); 4.45-4.25 (m, 1H); 4.00-3.80 (m, 1H); 3.65-3.45 (m, 1H); 2.95-2.70 (m, 1H); 2.65-2.45 (m, 2H); 1.85-1.40 (m, 4H) ; 1.40-1 . 00 (m, 6H) .

Part D: Preparation of erythro-cis-4-benzyl-a-ethylpiperidinemethanol Erythro-cis-4-benzyl-1-t-butoxycarbonyl-a-ethylpiperidinemethano:l(isomer B from part B)(815 mg, 2.44 mmol, 1 eq.) was dissolved in 8 mL of ethanol at 25 °C under N2. NaOH (391 mg, 9.78 mmol, 4 eq.) was added and the mixture ref:luxed for 4 hours. The solvent was removed .in vacuo to yield an oil. Water was added followed by EtOAc.
The layers were separated. The aqueous layer was extracted 2X more with EtOAc. The organic layers were combined dried over magnesium sulfate, and the solvent removed in vacuo to yield 390 mg of an oil. Yield = 68~. NMR (300 MHz, CDC13) S 7 . 35-7 .20 (m, 2H) ; 7 .23-7 . 00 (m, 3H) ; 3 .75-3 . 65 (m, l.H) ;
3.20-3.00 (m, 1H); 2.90-2.40 (m, 4H); 1.70-1.50 (m, 2H);
1.50-1.30 (m, 1H); 1.20-0.80 (m, 5H).
2 ~D
O . , '_ /~'N ~ \
i ~a )H O
Part E: Preparation of erythro-cis-4-benzyl-ot-ethyl-1-(3-N-phthalimido-n-prop-1-yl)piperidinemethanol 2 ~i Erythro-cis-4-benzyl-ot-ethylpiperidinemethanol (195 mg, 0.84 mmol, 1 eq.), N-(3-bromopropyl)phthalimide (224 mg, 0.84 mmol, 1 eq.), potassium iodide (139 mg, 0.84 mmol, 1 eq.), and potassium carbonate (231 mg, 0.84 mmol, 1 eq.) were refluxed in 10 mL of 2-butanone for 3 hours. The reaction was worked up by filtering off the inorganic solids. The filtrate solvent was removed in vacuo to yield an oil. Purified by flash chromatography in 100 EtOAc then 4:1 chloroform/MeOH. Obtained 200 mg. Yield = 57$.
NMR (300 MHz, CDClj) 8 7.95-7.80 (m, 2H); 7.80-7.65 (m, 2H); 7.35-7.00 (m, 5H); 3.90-3.60 (m, 3H); 3.20-2.90 (m, 2H); 2.65-2.30 (m, 3H); 2.20-2.00 (m, 2H); 2.00-1.75 (m, 2H); 1.70-1.40 (m, 4H); 1.35-0.90 (m, 3H); 0.96 (t, 3H, J =
7 Hz).
.~ ~NH., )H
Part F. Preparation of erythro-cis-1-(3-amino-n-prop-1-yl)-4-benzyl-a-ethylpiperidinemethanol Erythro-cis-4-benzyl-a-ethyl-1-(3-N-phthalimido-n-prop-1-yl)piperidinemethanol(200 mg, 0.48 mmol, 1 eq.) was dissolved in 5 mL of ethanol at 25 °C under N2. Anhydrous hydrazine (0.03mL, 0.95 mmol, 2 eq.) was added and the reaction refluxed for 3 hours during which time a white precipitate (phthalhydrazide) formed. Once cool, The solids were filtered. The filtrate solvent was removed in vacuo to yield an oil which was stirred in EtzO. The triturated solids were filtered and the filtrate solvent was removed in vacuo to yield 120 rng of an oil. Yield =
87~. NMR (300 MHz, CDC1,) ~ 7 (t, 2H, J = 7 Hz) ; 7.17 .27 (d, 1H, J Hz); 7.13 (d, 2H, J 7 Hz); 3.70-3.30 (m, 2H);
= 7 =

3.20-3.00(m, 2H); 3.00-2.70 2H); 2.70-2.40 (m, 2H);
(m, 2.30-2.10 (m., 1H); 2.10-1.90 (m, 2H); 1.90-1.40 (m, 5H);
1.40-1.00 (m, 3H); 0.96 (t, 3H, J = 7 Hz).
O ~ , O
~N ~,~ + .~/~.N~N O
.~ ~ H H H\ H H
)H ~~N I
COI /
O
Part G: preparation of erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-a-ethylpiperidinemethano:L and erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-2-(1-(3-acetylphenylaminocarbonyloxy)-n-prop-1-yl)-4-benzylpiperidine Erythro-cis-1-(3-amino-n-prop-1-yl)-4-benzyl-oc-ethylpiperidinemethanol (120 mg, 0.41 mmol, 1 eq.) was dissolved in 5 mL of THF at 25 °C under N2 then 3-acetylphenyl isocyanate added neat. After 1 hour the solvent was removed in vacuo to yield an oil. Purified by flash chromatography in 100$ EtOAc to 4:1 chloroform/MeOH.
Isolated mono-addition product (product A) along with an additional bis-addition product (product B). Prouct A
yielded 81 mg of an oil. Yield = 43~. Product B yielded 43 mg of an oil.
Product A NMR (300 MHz, CDC1,) 8 7.86 (bs, 1H) ; 7.73 (d, 1H, J = 7 Hz); 7.60 (s, 1H); 7.56 (d, 1H, J = 7 Hz); 7.40-7.15 (m, 4H) ; 7.12 (d, 2H, ;7 = 7 Hz) ; 6.30-6.05 (m, 1H) ; 4.00-3.80 (m, 1H); 3.50-3.30 (m, 1H); 3.30-2.90 (m, 5H); 2.60-2.40 (m, 2H); 2.57 (s, 3H); 2.30-2.10 (m, 1H); 2.10-1.90 (m. 2H); 1.80-1.40 (m, 5H); 1.30-1.05 (m, 2H); 0.94 (t, 3H, J = 7 Hz) .
Product B NMR (300 MHz,CDC13) $ 10.80-10.60 (m, 1H);8.20-8.00 (m, 1H); 7.9I (bs,1H); 7.80-7.18 (m, 9H); 7.11 (d, 2H, J = 7 Hz); 6.20 -6.00(m, 1H); 5.20-5.00 (m, 1H); 3.50-3.00 (m, 4H); 2.57 (s, H); 2.56 (s, 3H); 2.55-2.00 (m, 5H); 2.00-1.00 (m, lOH);1.00-0.80 (m, 3H) Product A was separated into its enantiomers employing a Daicel Chiral Pack AD column, eluting with 0.1~
diethylamine in methanol. (-)-isomer [a]p5 (c - 0.300 g/dL, MeOH) - -I4.9°. (+)-isomer [a]p5 (c = 0.290 g/dL, MeOH) -+20.2°.
The following compounds can be synthesized by the methods discussed previously:

TABLE 3b.

6 / ~ 6 / . 4 R3 3 O 1 ~3 N
~ ~ ~N 2 N~ H H ~D' H
OH H
OH
R1 _~ Ri a b 5 ~ R 6 /
C' R3 /~3 3 O 1 a ~ 3 1~
~N 2 ~N~N 2 ._ f'N' Ii N/'~ H H H
OH O ~ NH

/ v R R2b O ( / R3 Ri RZ m c d 6 / ~ R3 O 1 ~ ~ 3 ~N~N 2 H
H
O~~
O ~ R3 R~ /
a Cores R1 R2 R2a, R2b R3 M+1 319 a,b H CH3 -- 3-COCH3 438 320 a,b H CH3 --- 4-N02 441 321 a,b H CH3CH2 --- 3-COCH3 452 322 c H -- CH3, CH3 3-COCH3 452 323 a,b H CH3CH2CH2 ~ --- ~ 3-COCH3 466 324 ' a,b H (CH3)2CH --- 3-COCH3 466 325 a,b H CH3CH2CH2CH2 --- 3-COCH3 480 326 a,b H (CH3)2CHCH2 --- 3-COCH3 480 327 d,e H CH3CH2 --- 3-COCH3 613 328 d,e H CH3CH2CH2 --- 3-COCH3 627 329 d,e H (CH3)2CH --- 3-COCH3 627 330 d,e H CH3CH2CH2CH2 --- 3-COCH3 641 331 d,e H (CH3)2CHCH2 --- 3-COCH3 641 Example 332 Part A Prebaration of N-cvano-N'-3-methoxvnhenylcarbamimidic acid phenyl ester /N
N/
\ ~ \
O N O
m-Anisidine (4.56 mL, 4.06 mmol, 1 eq.), and diphenylcyanocarbonimidate (967 mg, 4.06 mmol, 1 eq.) were mixed and refluxed in acetonitrile under N2 for 1 hour.
Solids precipitated. The reaction was worked up by filtering off the solids. Obtained 580 mg as product.
M.P. - 170.0 - I71.0 °C. NMR (300 MHz, DMSO-d6) 8 8.70 -8.50 (m, 1H); 7.43 (t, 2H, J = 7 Hz); 7.40 - 7.20 (m, 2H);
7.14 (d, 2H, J = 7 Hz); 7.00 - 6.80 (m, 2H); 6.80 - 6.70 (m, 1H); 3.80 (s, 3H).
Part B Preparation of N " -cyano-N'-(3-(4-(4 2 0 f_luorobenzvl ) piperidine 1 propyl-N- ( 3 -methoxvt~henyl ) cruanidine ~N
F

3-(4-(4-fluorophenylmethyl)piperidin-1-yl)propylamine, (synthesized in a similar fashion to the previously described des-fluoro compound} (53 mg, 0.20 mmol, 1 eq.) and the product from Part A (50 mg, 0.20 mmol, 1 eq..) were mixed and refluxed :in 2-propanol under N2 for 1 hour. The reaction was stripped and the residue then purified over silica gel in 100 ~ ethyl acetate followed by 8:2 chloroform/methanol. Obtained 55 mg of off-white solids as product. NMR (300 MHz, CDC1~) 8 7.33 (t, 1H, J = 7 Hz);
7.10 - 6.90 (m, 4H); 6.90 - 6.80 (m, 3H); 3.83 (s, :3H);
3.50 - 3.35 (m, 2H); 2.90 - 2.70 (m, 2H); 1.50 - 1.20 (m, 3H). Mass Spec detects 424 (M+H).
Example 334 art A Preparation of ((Methvlthiol(3-acetylnhenvl amino)lmethylenebroganedinitrile N~~ ~ N
~S N
O
[Bis(methylthio)methylene]propanedinitrile 3.00 g, 17.6 mmol, 1 eq.), and 3'amino-acetophenone (2.38 g, 17.6 mmol, 1 eq.), were mixed and refluxed under Nz in ethanol for 16 hours. Solids precipitated while cooling to 25 °C.
The solids were filtered. Obtained 1.86 g of tan solids.
M.P. - 165.0 - 166.5 °C. NMR (300 MHz, DMSO-db) S 10.66 (m, 1H); 7.90 - 7.80 (m, 2H); 7.60 - 7.50 (m, 2H); 2.60 (s, 3H) ; 2 . 54 (s, 3H) .

Part B: Preparation of 2-[(3-acetylanilino)({3-[4-(4-fluorobenzyl)-1-piperidinyl]propyl~
amino)methylene]malononitrile N\ / N
F ~ \
NON N
O
3-(4-(4-fluorophenylmethyl)piperidin-1-yl)propylamine, 49 mg, 0_194 mmol, 1 eq.) and the product from Part A (50 mg, 0.194 mmol, 1 eq.) were mixed then stirred under N2 overnight. The reaction was stripped and the residue purified over chloroform/methanol. Obtained 17 mg of a white amphorphous solid. NMR (300 MHz, CDC1,) S 7.82 (d, 1H, J = 7 Hz); 7.73(s, 1H); 7.51 (t, 1H, J= 7 Hz); 7.34 (d, 1H, J = 7Hz); 7.10-6.80 (m, 4H); 3.28 (m, 2H); 2.62 (s, 3H); 2.64-2.40 (m,2H); 2.40-2.25 (m, 2H); 2.05-1.70 (m, 2H); 1.70-1.35 (m, 3H); 1.20-0.80 (m, 2H).
Mass Spec detects 460 (M+H).
Example 335 Part A: Preparation of N-[1-(methylthio)-2-nitroethenyl]-3-acetylbenzenamine O
H
S N
OZN
A neat mixture of 1,1-bismethylthio-2-nitroethylene (6.5 g, 38.5 mmol, 10 eq) and 3-aminoacetophenone (0.5 g, 3.85 mmol, leq) was melted together and heated at 140° C for four hours. The mixture was cooled to room temperature, WO 00/35449 PCT~'US99/30292 then subjected to flash chromatography, eluting with 50°s ethyl acetate/hexanes, to yield 0.63 g of a yellow powder as product. Yiel~3 = 65~. NMR (300 MHz, CDCl~) b 12_82 (bs, 1H), 7.95-7.91 (m, 2H), 7..59-7.48 (m, 2H), 6.73 (s, 1H), 2.65 (s, 3H), 2.41 (s, 3H).
Part B: Preparation of 1-(3-{[(E)-1-(t-[4-(4-fluorobenzyl)-1-piperidinyl]propyl}amino)-2-nitroethylenyl)amino}phenyl)ethanone O
H H
F ~ ~\/N\.~\,/N N ~ _ To a suspension of N-[1-(methylthio)-2-nitroethenyl]-3-acetylbenzenamine (0.30 g, 1.19 mmol, 1.00 eq) in 20 ml of methanol was added 3-(4-fluorobenzyl)piperidin-1--yl)propyl.amine (0.3:L g, 1.25 mmol, 1.05 eq), and the mixture was stirred at room temperature. After three days, a colorless solution was observed. The solvent was removed in-vacuo, and the re=sidue was subjected to flash chromatography, eluting with 10~ methanol/chloroform, to yield 0.38 g of an orange glass as product. Yield = 70~.
NMR (300 MHz, CDCla) 8 10.51 (bs, 1H) , 7.92 (d, 1H, .j - 8 Hz), 7.72 (bs, 1H), 7.54 (dd, 1H, j - 8 Hz, 8 Hz), 7.35 (bd, 1H), 6.90-6.88 (m, 5H), 6.17 (s, 1H), 3.54 (bs, 2H), 2.92-2.84 (m, 2H), 2.63 (s. 3H), 2.51 (m, 2H), 1.99--1.91 (m, 4H), 1.55-1.50 (m, 3H), 0.88-0.85 (m, 2H). MS (ESI) detects (M+H)' - 455.
The following compounds can be prepared by procedures described previously:

Table 3c H H ,..~ H H
F i N~N~N~R F i N~.N~N~R3 F ~ ~ Z
~,.~-rN H F~,.~'~N..~N~N~Rs H H H
~'N Z N~R3 d F i ,~. ~N
H H
i I..~N Z N~R3 Core Z R3 Mass Spec M+1 332 a N-CN 3-methoxyphenyl 424 333 a N-CN 3-acetylphenyl 460 334 a C(CN)2 3-acetylphenyl 460 335 a CHN02 3-acetylphenyl 455 336 b N-CN 3-acetylphenyl 436 337 b C(CN)2 3-acetylphenyl 460 338 b NCONH2 3-acetylphenyl 454 339 b CHN02 3-acetylphenyl 455 340 b N-CN 3,5-diacetylphenyl 478 341 b NCONH2 3,5-diacetylphenyl 496 342 b NC02CH3 3,5-diacetylphenyl 511 343 b C(CN)2 3,5-diacetylphenyl 344 b N-CN 3-(1-methyl-1H- 476 tetrazol-5-yl)phenyl 345 b C(CN)2 3-(1-methyl-1H- 500 tetrazol-5-yl)phenyl 346 b NCONH2 3-(1-methyl-1H- 494 tetrazol-5-yl)phenyl 347 b N-CN 2,4-dimethoxy-phenyl 454 348 b N-CN 5-acetyl-2-methoxy- 466 phenyl 349 d N-CN 3-(1-methyl-1H- 488 tetrazol-5-yl)phenyl 350 c N-CN phenyl 448 351 c N-CN :3-acetylphenyl 490 352 c N-CN 3-cyanopneyl 473 353 c N-CN 2,4-dimethoxyphenyl 508 354 c N-CN 2,5-dimethoxyphenyl 508 355 c N-CN 5-acetyl-2-methoxy- 520 phenyl 356 c N-CN 2,4-dimethylphenyl 476 357 c N-CN 4-(1-methyl-1H- 530 tetrazol-5-yl)phenyl 358 c N-CN 4-(1-propyl-1H- 558 tetrazol-5-yl)phenyl 359 c N-CN 5,6,?,8-tetrahydro- 502 naphthy-2-yl-phenyl 360 c N-CN 4-(4-morpholinyl)- 533 phenyl 361 C N-CN 2,5-dimethylphenyl 362 c N-CN 4-hydroxy-2-methylphenyl 363 c N-CN 2-methylphenyl 364 c N-CN 2-phenylethyl 365 c N-CN 1-adamantyl 366 c N-CN 2-adamantyl 367 c C(CN)2 3-acetylphenyl 514 368 c C(CN)2 5-acetyl-2-methoxy- 544 phenyl 369 c CHN02 3-acetylphenyl 509 370 a CHN02 3-acetylphenyl 560 371 a N-CN 3,5-diacetylphenyl 583 372 a N-CN 3-acetylphenyl 541 373 a N-CN 4-(1-propyl-1H- 581 tetrazol-5-yl)phenyl The following tables contain representative examples of the present invention, and may be prepared by procedures described above, or methods familiar to one skilled in the art. Each entry in each table is intended to be paired with each formulae at the start of the table. For example, Entry 1 in Table 4 is intended to be paired with each of formulae la-44.

WO 00!35449 PCT/US99/30292 SABLE 4*
G/~N~ ~ R3 G/~J~N N.R G~N~N~N,R3 H H p 3 H H
la 2a 3a ~;~~N~ ,~ Rz G~,~N~N N.R ~N~/~N~N~R3 H H p 3 H H
lb 2b 3b H H ~
G~N~'~N~NR3 G~N~'N~N R3 G~N~N~N'R3 H H p H H
G~~N~ G~N G~N
1 H a H
~N.R3 ~'~R3 Hl~'/'N.R3 8a a 9a p 10 G~,~N~ ~~N G~N
a H ~ H H
~~R3 ~N.R3 ~'N:R3 8b p 9b p 11 p 1 H ~ H
HNYN,R3 HNY~R3 12a p 13a O
H ~ H
HN~I~L R3 HN~N'R3 12b p 13b p G~N.~ G~N
H ~ H
HNYN: R3 HNY1~I. R3 14 p 15 p G'~~ G
HN N- HN N-R3 ~ R3 16a O 17a O
. H ~ H
HN N. HN N_ R3 ~ R3 16b O 17b O
N N
G~~ H R~ _ 1 H
~~R3 ~N.R3 G~N~ ~ R3 G~N~'r7~NR3 H H H H
20a 21a ~~I~l~ N~. NR3 ~~1~ N~ NR3 H H H H
20b 21b ~n!\~/~N~N_RZ R~N~/~N~N.R2 G~N~N N.R3 ~;~~N~N N_R ~N~N N.R

O O O

G~N H N N_ R G~.,~N H N N_ R3 G~N~ NY N-R 3 Me O Me O Me O

H
H H
G~N H N N. Nw/~.NYN-R3 G N N~N_R3 iPrO iPrO iPrO

G~'~ H H H C~ n H H H ~ H H H
N~N~N_R3 ,,/~N~N~N-R3 G N~NYN R3 iBuO iBuO iBuO

G~N H N N. R G~.~N H N N_ R ~N H N N_ Ph O Ph O Ph O

H H N, G~ H H ~ /""~N H H N.
R3 ~ R3 G ~ R3 P O Ph 0 P O

H ~ G'~ H H N, R ~~N H H ~ R
R ~ 3 G 3 Ph Entry G R3 1 4-F-Ph Ph 2 4-F-Ph 3-CN-Ph 3 4-F-Ph 3-COCH3-Ph 4 _ 4-F-Ph 3-C02Me_-Ph ~~ ~

4-F-Ph 3-C02Et-Ph 6 4-F-Ph 3-C02H-Ph 7 4-F-Ph 3-CONH2-Ph 8 4 -F-Ph 3 -CONHMe-~?h 9 4-F-Ph 3-F-Ph 4-F-Ph 3-C1-Ph 11 4-F-Ph 3-Br-Ph 12 4-F-Ph 3-N02-Ph 13 4-F-Ph 3-NH2-Ph 14 4-F-Ph 3-NHMe-Ph 4-F-Ph 3-NMe2-Ph 16 4-F-Ph 3-NHCOCH3-Ph 1? 4-F-Ph 3-S02NH2-Ph 18 4-F-Ph 3-S02NHMe-Ph 19 4-F-Ph 3-CF3-Ph.

~ 4-F-Ph 3-OCH3-Ph 21 4-F-Ph 3-OPh-Ph 22 4-F-Ph 3-OCF3-Ph 23 4-F-Ph 3-SCH3-Ph 24 4-F-Ph 3-SOCH3-Ph 4-F-Ph 3-S02CH3-Ph 26 4-F-Ph 3-OH-Ph 27 4-F-Ph 3-CH20H-Ph 28 4-F-Ph 3-CHOHCH3-Ph 29 4-F-P:h 3-COH(CH3)2-Ph 4-F-Ph 3-CHOHPh-Ph 31 4-F-Ph 3-CH3-Ph 32 4-F-Ph 3-C2H5-Ph 33 4-F-Ph 3-iPr-Pra 34 4-F-Ph 3-tBu-Ph 4-F-Ph 3-Ph-Ph 36 4-F-Ph 3-CH2Ph-Ph 37 4-F-Ph 3-CH2C02Me-Ph 38 4-F-Ph 3-(1- i eridin 1)-Ph 39 4-F-Ph 3-(1- rrolidin 1)-Ph 40 4-F-Ph 3-(2-imidazolyl)-Ph 41 4-F-Ph 3-(1-imidazol 1)-Ph 42 4-F-Ph 3-t2-thiazolyl)-Ph 43 4-F-Ph 3-(3- yrazol 1)-Ph 44 4-F-Ph 3-(1- razolyl)-Ph 45 4-F-Ph 3-(1-tetrazol 1)-Ph 46 4-F-Ph 3-(5-tetrazolyl)-~Ph 47 4-F-Ph 3-(2- ridyl)-Ph 48 4-F-Ph 3-(2-thien 1)-Ph 49 4-F-Ph 3-(2-furan 1)-Ph 50 4-F-Ph 4-CN-Ph 51 4-F-Ph 4-COCH3-Ph 52 4-F-Ph 4-C02Me-Ph 53 4-F-Ph 4-C02Et-Ph 54 4-F-Ph 4-C02H-Ph 55 4-F-Ph 4-CONH2-Ph 56 4-F-Ph 4-CONHMe-Ph 57 4-F-Ph 4-CONHPh-Ph 58 4-F-Ph 4-NHCONH2-Ph 59 4-F-Ph 4-F-Ph 60 4-F-Ph 4-Cl-Ph 61 4-F-Ph 4-Br-Ph 62 4-F-Ph 4-N02-Ph 63 4-F-Ph 4-NH2-Ph 64 4-F-Ph 4-NHMe-Ph 65 4-F-Ph 4-NMe2-Ph 66 4-F-Ph 4-NHCOCH3-Ph 67 4-F-Ph 4-S02NH2-Ph 68 4-F-Ph 4-S02NHMe-Ph 69 4-F-Ph 4-CF3-Ph 70 4-F-Ph 4-OCH3-Ph 71 4-F-Ph 4-OPh-Ph 72 4-F-Ph 4-OCF3-Ph 73 4-F-Ph 4-SCH3-Ph 74 4-F-Ph 4-SOCH3-Ph 75 4-F-Ph 4-S02CH3-Ph 76 4-F-Ph 4-OH-Ph 77 4-F-Ph 4-CH20H-Ph 78 4-F-Ph 4-CHOHCH3-Ph 79 4-F-Ph 4-COH(CH3)2-Ph 80 4-F-Ph 4-CH3-Ph 81 4-F-Ph 4-C2H5-Ph 82 4-F-Ph 4-iPr-Ph 83 4-F-Ph 4-tBu-Ph 84 4-F-Ph 4-Ph-Ph 85 4-F-Ph 4-CH2Ph-Ph 86 4-F-Ph 4-CH2C02Me-Ph 87 4-F-Ph 4-(1- i eridin 1)-Ph 88 4-F-Ph 4-(1- rrolidin 1)-Ph 89 4-F-Ph 4-(2-imidazol 1)-Ph 90 4-F-Ph 4-(1-imidazolyl)-Ph 91 4-F-Ph 4-(2-thiazol 1)-Ph 92 4-F-Ph 4-(3-pyrazol 1)-Ph WO 00/35449 PCTlUS99/30292 93 4-F--Ph 4- (1-pyrazolyl) -Ph 94 4 -F--Ph 4- ( 1-_tetrazolyl ) -Ph 95 4 -F--Ph 4- ( 5-tetrazol 1 ) -Ph 96 4-F--Ph 4-(2- rid 1)-Ph 97 4-F-Ph 4-(2-thien 1)-Ph 98 _ 4-(2-furanyl)-Ph 4-F--Ph 99 4-F--Ph 2-CN-Ph 0 4 - F--Ph 2 -COCH3 --Ph 101 4-F-Ph 2-C02Me-Ph 102 4-F-Ph 2-C02Et-Ph 103 4-F-Ph 2-C02H-Ph 104 _ 2-CONH2-Ph 4-F--Ph 105 4-F--Ph 2-CONHMe-Ph 106 4-F--Ph 2-F-Ph 107 4-F--Ph 2-C1-Ph 108 4 -F--Ph 2-Br-Ph 109 4-F-Ph 2-N02-Ph 110 4-F-Ph 2-NH2-Ph 111 4-F--Ph 2-NHMe-Ph 212 4-F-Ph 2-NMe2-Ph 113 ~ 4-F-Ph 2-NHCOCH:3-Ph 114 4-F--Ph 2-S02NH2-Ph 115 4-F-Ph 2-S02NHMe-Ph 116 4-F--Ph 2-CF3-Ph 117 4-F--Ph 2-OCH3_-Ph 118 _ 2-OPh-Ph - 4-F--Ph 119 4-F--Ph 2-OCF3-Ph 120 4-F--Ph 2-SCH3-Ph 121 4 -F-- Ph 2 - SOCH3 - Ph 122 4-F-Ph 2-S02CH3-Ph 123 h 2-OH-F'h P

124 _ 2-CH20H-Ph _ 4-F--Ph 125 4-F-Ph 2-CHOHCH3-Ph 126 ' 4-F-Ph 2-COH(CH3)2-Ph 127 4-F-Ph 2-CHOHPh-Ph 128 4-F~-Ph 2-CH3-Ph 129 4-F-Ph 2-C2H5--Ph 130 4-F-Ph 2-iPr-Ph 131 4-F-Ph 2-tBu-Ph 132 4-F-Ph 2-Ph-Ph 133 4-F-Ph 2-CH2Ph-Ph 134 4-F-Ph 2-CH2C02Me-Ph 135 4-F-Ph 2-(1-piperidin 1)-Ph 136 4-F-Ph 2-(1- rrolidin 1)-Ph 137 4-F-Ph 2-(2-imidazol 1)-Ph 138 4-F-Ph 2- (1-imidazal 1) -Ph _ 4-F-Ph 2-(2-thiazol 1)-Ph 140 4-F-Ph 2-(3-_ razol 1)-Ph 141 _ 2-(1- razo~l 1)-Ph 4-F-Ph 142 4-F-Ph 2-(1-tetrazol 1)-Ph 143 4-F-Ph 2-(5-tetrazo_lyl)-Ph 144 4-F-Ph 2-(2- rid 1)-Ph 145 4-F-Ph 2- (2-thien 1) -Ph 146 4-F-Ph ~~ 2-(2-furanyl)-Ph 147 4-F-Ph 2,4-diF-Ph 148 4-F-Ph 2,5-diF-Ph 149 4-F-Ph 2,6-diF-Ph 150 4-F-Ph 3,4-diF-Ph 151 4-F-Ph 3,5-diF-Ph 152 4-F-Ph 2,4-diCl-Ph 153 4-F-Ph 2,5-diCl-Ph 154 4-F-Ph 2,6-diCl-Ph 155 4-F-Ph 3,4-diCl-Ph 156 4-F-Ph 3,5-diCl-Ph 157 4-F-Ph 3,4-diCF3-Ph 158 4-F-Ph 3,5-diCF3-Ph 159 4-F-Ph 5-C1-2-Me0-Ph 160 4-F-Ph 5-C1-2-Me-Ph 161 4-F-Ph 2-F-5-Me-Ph 162 4-F-Ph 2-F-5-N02-Ph 163 4-F-Ph 3,4-OCH20-Ph 164 4-F-Ph 3,4-OCH2CH20-Ph 165 4-F-Ph 2-Me0-4-Me-Ph 166 4-F-Ph 2-Me0-5-Me-Ph 167 4-F-Ph 1-na hth 1 168 4-F-Ph 2-na hth 1 169 4-F-Ph 2-thienyl 1?0 4-F-Ph 3-thien 1 171 4-F-Ph 2-furanyl 172 4-F-Ph 3-furanyl 173 4-F-Ph 2- rid 1 174 4-F-Ph 3- rid 1 175 4-F-Ph 4- ridyl 176 4-F-Ph 2-indolyl 177 4-F-Ph 3-indol 1 178 4-F-Ph 5-indol 1 179 4-F-Ph 6-indol 1 180 4-F-Ph 3-indazolyl 181 4-F-Ph 5-indazol 1 182 4-F-Ph 6-indazol 1 183 4-F-Ph 2-imidazol 1 184 4-F-Ph 3- yrazolyl 185 4-F-Ph 2-thiazol 1 186 4-F-Ph 5-tetrazol 1 187 4-F-Ph 2-benzimidazolyl 188 4-F-Ph 5-benzimidazolyl 189 4-F-Ph 2-benzothiazol 1 190 4-F-Ph 5-benzothiazol 1 191 4-F-Ph 2-benzoxazol 1 192 4-F-Ph 5-benzoxazolyl 193 4-F-Ph 1-adamant 1 194 4-F-Ph 2-adamant 1 195 4-F-Ph t-Bu 196 2-F-Ph 3-CN-Ph 197 2-F-Ph 3-COCH3-Ph 198 2-F-Ph 3-C02Me-Ph 199 2-F-Ph 3-C02Et-Ph 200 2-F-Ph 3-C02H-Ph 201 _ 3-CONH2-Ph 2-F-Ph 202 2-F-Ph 3-F-Ph 203 _ 3-C1-Ph 2-F-Ph 204 2-F-Ph 3-NH2-Ph 205 2-F-Ph 3-S02NH2-Ph 2 0 6 2 -F- Ph 3 -CF3 - Ph 207 2-F-Ph 3-OCH3-Ph 208 2-F-Ph 3-OEt-Ph 209 2-F-Ph 3-OCF3-Ph 210 2-F-Ph 3-S02CH3--Ph 211 2-F-Ph 3-OH-Ph 212 2-F-Ph 3-CH3-Ph 213 _ 3-C2H5-Ph 2-F-:Ph 214 2 -F-:Ph 4 -CN- Ph 215 2-F-Ph 4-COCH3-Ph 216 2-F-Ph 4-C02Me-Ph 217 2-F-Ph 4-C02Et-Ph 218 2-F-Ph 4-C02H-Ph 219 2 -F-l?h 4 -CONH2 -Ph 220 2-F-Ph 4-F-Ph 221 2-F-Ph ~ 4-C1-Ph 222 2-F-Ph 4-NH2-Ph 223 2-F-Ph 4-S02NH2--Ph 224 2-F-Ph ~ _ _ 4-CF3-Ph 225 2-F-Ph 4-OCH3-Ph 226 2-F-Ph 4-OEt-Ph 227 2-F-Ph _ h 228 2-F-Ph _ 4-S02CH3-Ph 229 2-F-Ph _ 4-OH-Ph _ 230 2-F-Ph 4-CH3-Ph 231 2-F-F>h 4-C2H5-Ph 232 _ 2,4-diF-Ph 2-F-Ph 233 2-F-Ph 2,5-diF-Ph 234 2-F-Ph 3,4-diF-Ph 235 2-F-Ph 3,5-diF-Ph 236 2-F-Ph 2,4-diCl-Ph 237 2-F-Ph 2,5-diCl-Ph 238 2-F-Ph 3,4-diCl-Ph 239 2-F-Ph 3,5-diCl-Ph 240 2-F-Ph 3,4-OCH20-Ph 241 2-F-Ph 3,4-OCH2CH20-Ph 242 2-F-Ph 2-thien '1 243 2-F-Ph 2-furan l 244 2-F-Ph 2- rid 1 245 2-F-Ph 4- rid 246 2-F-Ph _ 2-imidazol 1 247 2-F-Ph 3- yrazolLrl 248 2-F-Ph 2-thiazol 1 249 2-F-Ph 5-tetrazol 1 250 2-F-Ph 1-adamant 1 251 2,4-diF-Ph 3-CN-Ph 252 _ 2,4-diF-Ph 3-COCH3-Ph ~ ~

253 2, 4-_di_F-Ph 3-C02Me-Ph .

254 2,4- 3-C02Et-Ph diF-Ph 255 2,4-diF-Ph 3-C02H-Ph 256 2,4-diF-Ph 3-CONH2-Ph 257 2,4-diF-Ph 3-F-Ph 258 2,4-diF-Ph 3-Cl-Ph 259 2,4-diF-Ph 3-NH2-Ph 260 2,4-diF-Ph 3-S02NH2-Ph 261 2,4-diF-Ph 3-CF3-Ph 262 2,4-diF-Ph 3-OCH3-Ph 263 2,4-diF-Ph 3-OEt-Ph 264 2,4-diF-Ph 3-OCF3-Ph 265 2,4-diF-Ph 3-S02CH3-Ph 266 2,4-diF-Ph 3-OH-Ph 267 2,4-diF-Ph 3-CH3-Ph 268 2,4-diF-Ph 3-C2H5-Ph 269 2,4-diF-Ph 4-CN-Ph 270 2,4-diF-Ph 4-COCH3-Ph 271 2,4-diF-Ph 4-C02Me-Ph 272 2,4-diF-Ph 4-C02Et-Ph 273 2,4-diF-Ph 4-C02H-Ph 274 2,4-diF-Ph 4-CONH2-Ph 275 2,4-diF-Ph 4-F-Ph 276 2,4-diF-Ph 4-Cl-Ph 277 2,4-diF-Ph 4-NH2-Ph 2?8 2,4-diF-Ph 4-S02NH2-Ph 279 2,4-diF-Ph 4-CF3-Ph 280 2,4-diF-Ph 4-OCH3-Ph 281 2,4-diF-Ph 4-OEt-Ph 282 2,4-diF-Ph 4-OCF3-Ph 283 2,4-diF-Ph 4-S02CH3-Ph 284 2,4-diF-Ph 4-OH-Ph 285 2,4-diF-Ph 4-CH3-Ph 286 2,4-diF-Ph 4-C2H5-Ph 287 2,4-diF-Ph 2,4-diF-Ph 288 2,4-diF-Ph 2,5-diF-Ph 289 2,4-diF-Ph 3,4-diF-Ph 290 2,4-diF-Ph 3,5-diF-Ph 291 2,4-diF-Ph 2,4-diCl-Ph .

292 2,4-diF-Ph 2,5-diCl-Ph 293 2,4-diF-Ph 3,4-diCl-Ph 294 2,4-diF-Ph 3,5-diCl-Ph 295 2,4-diF-Ph 3,4-OCH20-Ph 296 2,4-diF-Ph 3,4-OCH2CH20-Ph 297 2,4-diF-Ph 2-thien 1 298 2,4-diF-Ph 2-furan 1 299 2,4-diF-Ph 2- rid 1 300 2,4-diF-Ph 4- rid 1 301 2,4-diF-Ph 2-imidazolyl 302 2,4-diF-Ph 3- razolyl 303 2,4-diF-Ph 2-thiazolyl 304 2,4-diF-Ph 5-tetrazolyl 305 2,4-diF-Ph 1-adamant 1 306 _ 4-Cl-Ph Ph 307 4-Cl-Ph 3-CN-Ph .__ 308 4-Cl-Ph 3-COCH3-P
h 309 4-C1-Ph _ 3-C02Me-Ph 310 4-C1-Ph 3-C02Et-Ph 311 4-C1-Ph 3-C02H-Fh 312 4-Cl-Ph 3-CONH2-Ph 313 4-C1-:Ph _ 3-CONHMe-Ph 314 4 -C1-:Ph 3 -F-Ph 315 4- 3-C1-Ph Cl-Ph 316 _ 3-Br-Ph 4-Cl-Ph 317 4-C1-Ph 3-N02-Ph 318 4-C1-Ph 3-NH2-Ph 319 4-C1-Ph 3-NHMe-Ph 320 4-C1-Ph 3-NMe2-Ph 321 4-C1-Ph 3-NHCOCH3--Ph 322 4-Cl-Ph _ 3-S02NH2-Ph 323 4-C1-Ph 3-S02NHMe-Ph 324 4~C1-P_h 3-CF3-Pry 325 4-Cl-Ph 3-OCH3-Ph 326 4-C1-Ph 3-OPh-Ph 327 4-C1-Ph 3-OCF3-Ph _ 328 4-C1-Ph 3-SCH3-Ph 329 4-C1-Ph 3-SOCH3-Fh 330 4-C1-Ph 3-S02CH3-Ph 331 4- 3-OH-Ph C1-Ph 332 _ 3-CH20H-Ph 4-C1-Ph 333 4-C1-Ph _ ~ 3-CHOHCH3-Ph 334 4-C1-F'h 3-COH(CH3)2-Ph 335 4-C1-Ph 3-CHOHPh-Ph 336 4-C:L-Ph 3-CH3-Ph.

337 4-C1-Ph 3-C2H5-Ph 338 4-Cl-Ph 3-iPr-Ph 339 4-Cl 3-tBu-Ph -Ph 340 _ 3-Ph-Ph 4-C1-Ph 341 4-C1-Ph 3-CH2Ph-Ph 342 4-Cl-Ph 3-CH2C02Me-Ph 343 4-Cl-Ph 3-(1- i eridin 1)-Ph 344 4-Cl-Ph 3-(1- rrolidin I)-Ph 345 4-C1-Ph _3-(2-imidazolrl)-Ph 346 4-C1-Ph 3-(1-imidazolyl)-Ph 347 4-C1-Ph 3-(2-thiazolyl)-Ph 348 4-C1-Ph 3-(3-pyrazolyl}-Ph 349 4-Cl-Ph 3-(1-pyrazolyl}-Ph 350 4-C1-Ph 3-(1-tetrazol 1)-Ph 351 4-C1-Ph 3-(5-tetrazol 1)-Ph 352 4-C1-Ph 3-(2- rid 1)-Ph 353 4-C1-Ph 3-(2-thien 1)-Ph 354 4-Cl-Ph 3-(2-furanyl)-Ph 355 4-C:1-Ph 4-CN-Ph 356 4-C:1-P:h 4-COCH3-Ph 357 4-Cl-Ph 4-C02Me-Ph WO 00/35449 PCT/iJS99I30292 358 4-C1-Ph _ 4-C02Et-Ph ~

359 __ 4-C02H-Ph 4-CI-Ph 360 4-CI-Ph 4-CONH2-Ph 361 4-CI-Ph 4-CONHMe-Ph 362 4-Cl-Ph 4-CONHPh-Ph 363 4-C1-Ph 4-NHCONH2-Ph 364 4-C1-Ph 4-F-Ph 365 4-C1-Ph 4-C1-Ph 366 4-CI-Ph 4-Br-Ph 367 4-C1-Ph 4-N02-Ph 368 4-C1-Ph 4-NH2-Ph 369 4-C1-Ph 4-NHMe-Ph 370 4-C1-Ph 4-NMe2-Ph 371 4-C1-Ph 4-NHCOCH3-Ph 372 4-C1-Ph 4-S02NH2-Ph 373 4-C1-Ph 4-S02NHMe-Ph 374 4-C1-Ph 4-CF3-Ph 375 4-Cl-Ph 4-OCH3-Ph 376 4-Cl-Ph 4-OPh-Ph 377 4-Cl-Ph 4-OCF3-Ph 378 4-C1-Ph 4-SCH3-Ph 379 4-C1-Ph 4-SOCH3-Ph 380 4-Cl-Ph 4-S02CH3-Ph 381 4-C1-Ph 4-OH-Ph 382 4-C1-Ph 4-CH20H-Ph 383 4-C1-Ph 4-CHOHCH3-Ph 384 4-Cl-Ph 4-COH(CH3)2-Ph 385 4-C1-Ph 4-CH3-Ph 386 4-C1-Ph 4-C2H5-Ph 387 4-C1-Ph 4-iPr-Ph 388 4-C1-Ph 4-tBu-Ph 389 4-C1-Ph 4-Ph-Ph 390 4-C1-Ph 4-CH2Ph-Ph 391 4-C1-Ph 4-CH2C02Me-Ph 392 4-Cl-Ph 4-(1-piperidin 1)-Ph 393 4-C1-Ph 4-(1- rrolidinyl)-Ph 394 4-C1-Ph 4-(2-imidazol 1)-Ph 395 4-C1-Ph 4-(1-imidazol 1)-Ph 396 4-C1-Ph 4-(2-thiazol 1)-Ph 397 4-C1-Ph 4-(3- razol 1)-Ph 398 4-CI-Ph 4-(1- razol 1)-Ph 399 4-CI-Ph 4-(1-tetrazol 1)-Ph 400 4-C1-Ph 4-(5-tetrazol 1)-Ph 401 4-C1-Ph 4-(2- rid 1)-Ph 402 4-C1-Ph 4-(2-thien I)-Ph 403 4-C1-Ph 4-(2-furan 1)-Ph 404 4-Cl-Ph 2-CN-Ph 405 4-C1-Ph 2-COCH3-Ph 406 4-C1-Ph 2-C02Me-Ph 407 4-C1-Ph 2-C02Et-Ph 408 4-Ci-Ph 2-C02H-Ph 409 4-C1-Ph 2-CONH2-Ph 410 4-Cl-Ph 2-CONHMe-Ph 411 4-C1--Ph 2-F-Ph 412 4-~C1--Ph 2-C1-Ph 413_ 4-C1-Ph 2-Br-Ph 414 4-C1-Ph 2-N02-Ph 415 4-CI-Ph 2-NH2-Ph 416 4-C1-~Ph 2-NHMe-Ph 417 4-C1--Ph 2-NMe2-P
h 418 4-C1-Ph _ Ph 419 4-C1-Ph _ 2-S02NH2-~Ph 420 4-C1-Ph 2-S02NHMe-Ph 421 4-C1-Ph 2-CF3-Ph 422 4-C1-Ph 2-OCH3-Ph 423 4-C1-Ph 2-OPh-Ph 424 4-C1-Ph _ 2-OCF3-Ph 425 4-Cl-Ph 2-SCH3-Ph 426 4-C1-Ph 2-SOCH3-Ph 427 ~ 4-C1-Ph 2-S02CH3-Ph 428 4~C1-Ph 2-OH-Ph 429 4-C1-Ph 2-CH20H-Ph 430 4-C1-Ph 2-CHOHCH3~-Ph 431 4-C1-Ph 2-COH(CH3)2-Ph 432 4-Cl-Ph 2-CHOHPh-Ph 433 4-C1-Ph _ 2-CH3-Ph 434 4-C1-Ph 2-C2H5-Ph 435 4-Cl-Ph 2-iPr-Ph 436 4-C1-Ph 2-tBu-Ph 437 4-C1-Ph 2-Ph-Ph -438 4-C1-Ph 2-CH2Ph-Ph 439 4-C1-ph 2-CH2C02Me-Ph 440 4-C1-:Ph _ 441 4-C1-Ph ~ 2- ( 1- i eridiri 1 442 4-C1-:Ph ) -Ph 443 4-C1-Ph 2-(1-pyrrolidin 1)-Ph 444 4-C1-Ph 2- (2-imidazoh I) -Ph 445 4-C1-P_h _2-(1-imidazol:yl)-Ph 446 4-Cl-Ph 2-(2-thiazol1)-Ph 447 4-Cl-Ph 2- (3-pyrazol~I ) -Ph 448 4-C1-Ph 2-(1- razol~1)-Ph 449 4-C1-Ph _2-(1-tetrazoh l)-Ph 450 4-C1-Ph ~2-(5-tetrazol~l)-Ph 451 4-Cl-Ph _2-(2-pyridyl)-Ph 2-(2-thien 1)-Ph 2-(2-furanyl)-Ph 452 4-C1-1?h 2, 4-diF-Ph 453 4-C1-Ph 2,5-diF-Ph 454 4-C1-Ph 2,6-diF-Ph 455 4-C1-~?h 3 , 4-diF-Ph 456 4 _ -C1-F?h 3, 5-diF-Ph 457 _ 2 , 4-diCl-Ph 4-C1-F'h 458 4-C1-Ph 2,5-diCl-Ph 459 _4-C1-Ph 2,6-diCl-Ph 460 4-CI-Ph 3 , 4-diCl-Ph 461 4-C1-Ph _ 3,5-diCl-Ph 462 _ 3,4-4-~1-Ph T iCF3-Ph d 463 4-C1-F'h 3, 5-diCF3-Ph 464 4-C1-Ph 5-C1-2-Me0-Ph 465 4-C1-Ph 5-C1-2-Me-Ph 466 _ 2-F-5-Me-Ph 4-C1-Ph 467 4-C1-Ph 2-F-5-N02-Ph 468 4-C1-Ph 3,4-OCH20-Ph 469 4-C1-Ph 3,4-OCH2CH20-Ph 470 4-C1-Ph 2-Me0-4-Me-Ph 471 4-C1-Ph 2-Me0-5-Me-Ph 472 4-C1-Ph 1-na hth 1 473 4-C1-Ph 2-na hthyl 474 4-C1-Ph 2-thienyl 475 4-C1-Ph 3-thien 1 476 4-Cl-Ph 2-furan 1 477 4-C1-Ph 3-furan 1 478 4-C1-Ph 2- rid 1 479 4-C1-Ph 3- rid 1 480 4-C1-Ph 4- ridyl 481 4-C1-Ph 2-indol 1 482 4-C1-Ph 3-indol 1 483 4-Cl-Ph 5-indol 1 484 4-Cl-Ph 6-indol 1 485 4-C1-Ph 3-indazol 1 486 4-Cl-Ph 5-indazol 1 487 4-C1-Ph 6-indazol 1 488 4-Cl-Ph 2-imidazolyl 489 4-Cl-Ph 3- razol 1 490 4-Cl-Ph 2-thiazol 1 491 4-C1-Ph 5-tetrazolyl 492 4-Cl-Ph 2-benzimidazolyl 493 4-C1-Ph 5-benzimidazol 1 494 4-Cl-Ph 2-benzothiazolyl 495 4-C1-Ph 5-benzothiazolyl 496 4-Cl-Ph 2-benzoxazol 1 497 4-C1-Ph 5-benzoxazolyl 498 4-C1-Ph 1-adamant 1 499 4-C1-Ph 2-adamant 1 500 4-Cl-Ph t-Bu 501 2-C1-Ph 3-CN-Ph 502 2-C1-Ph 3-COCH3-Ph 503 2-Cl-Ph 3-C02Me-Ph 504 2-C1-Ph 3-C02Et-Ph 505 2-C1-Ph 3-C02H-Ph 506 2-C1-Ph 3-CONH2-Ph __5_07_ 2-C1-Ph 3-F-Ph 2-C1-Ph 3-C1-Ph 08__ _ 2-C1-Ph 3-NH2-Ph 510 2-C1-Ph 3-S02NH2-Ph 51 2-C1-Ph 3-CF3-Ph _ 2-C1-Ph 3-OCH3-Ph _ 513 2-C1-Ph 3-OEt-Ph 514 2-C1-Ph 3-OCF3-Ph 515 2-C1-Ph 3-S02CH3-Ph 516 2-Cl-Ph 3-OH-Ph 517 2~C1-Ph 3-CH3-Ph 518 2-C1-Ph __ 3-C2H5-Ph 519 2-C1-Ph 4-CN-Ph 520 __ 2-C1-Ph 4-COCH3-Ph 521 2-C1-Ph 4-C02Me-Ph 522 _ 2-C1-Ph 4-C02Et-Ph 523 2-C1-Ph 4-C02H-Ph 524 2-C1-Ph 4-CONH2-Ph 525 __ 2-C1-Ph _ 4-F-Ph 526 2-C1-Ph 4-C1-Ph -527 2-C1-Ph 4-NH2-Ph 528 2-CI-Ph 4-S02NH2-Ph 529 _ 2-C1-:Ph 4-CF3-Ph ~

530 2-C1-Ph 4-OCH3-Ph 531 2-C1-:Ph 4-OEt-Ph 532 __ 2-C1-Ph 4-OCF3-Ph 533 _ _ 2-C1-Ph 4-S02CH3-Ph 534 2-C1-Ph 4-OH-Ph 535 _ 2-C1-Ph 4-CH3-Ph 536 2-C1-Ph 4-C2H5-Ph 537 _ 2-Cl-Ph 2, 4-diF-Ph 538 2-C1-Ph 2,5-diF-Ph 539 2-C1-I?h 3, 4-diF-Ph 540 2-C1-Ph 3,5-diF-Ph 541 __ 2-C1-Ph 2, 4-diCl-Ph 542 2-CI-Ph 2,5-diCl-Ph 543 2 -C1-Ph 3 , 4 -diCl-:Ph 544 2-C1-Ph 3, 5-diCl-:Ph 545 2-C1-Ph 3,4-OCH20-~Ph ~

546 _ 2-C1-Ph 3 , 4-OCH2CH20-Ph 547 2-C1-Ph 2-thien I

548 2-C1-Ph 2-furan :1 __-549 2-C1-Ph 2- rid 1 550 _ l 551 _ 2-C1-Ph 2 irnidazol ~ l 552 2-C1-Ph 3- razor 1 553 _ 2-C1-Ph 2-thiazol 1 ~

554 2-C1-Fh 5-tetrazol 1 555 2-C1-Ph 1-adamant 1 556 2,4-diCl-Ph 3-CN-Ph 557 2,4-diCl-Ph 3-COCH3-Ph 558 2,4-diCl-Ph 3-C02Me-Ph 559 2,4-diCl-Ph 3-C02Et-Ph 560 2_, 4-diCl-Ph 3-C02H-Ph 561 2,4-diCl-Ph 3-CONH2-Ph 562 _ 3-F-Ph 2,4-diCl-Ph 563 2,4-diCl-Ph 3-C1-Ph 564 2,4-diCl-Ph 3-NH2-Ph 565 2,4-diCl-Ph 3-S02NH2-Ph 566 2,4-diCl-Ph 3-CF3-Ph 567 2,4-diCl-Ph 3-OCH3-Ph 568 _ 3-OEt-Ph 2,4-diCl-Ph 569 2,4-diCl-Ph ~ 3-OCF3-Ph 570 2,4-diCl-Ph 3-S02CH3-Ph 5?1 2,4-diCl-Ph 3-OH-Ph 572 2,4-diCl-Ph 3-CH3-Ph 573 2,4-diCl-Ph 3-C2H5-Ph 574 2,4-diCl-Ph 4-CN-Ph 575 2,4-diCl-Ph 4-COCH3-Ph 576 2,4-diCl-Ph 4-C02Me-Ph 577 2,4-diCl-Ph 4-C02Et-Ph 578 2,4-diCl-Ph 4-C02H-Ph 579 2,4-diCl-Ph 4-CONH2-Ph 580 2,4-diCl-Ph 4-F-Ph 581 2,4-diCl-Ph 4-C1-Ph 582 2,4-diCl-Ph 4-NH2-Ph 583 2,4-diCl-Ph 4-S02NH2-Ph 584 2,4-diCl-Ph 4-CF3-Ph 585 2,4-diCl-Ph 4-OCH3-Ph 586 2,4-diCl-Ph 4-OEt-Ph 587 2,4-diCl-Ph 4-OCF3-Ph 588 2,4-diCl-Ph 4-S02CH3-Ph 589 2,4-diCl-Ph 4-OH-Ph 590 2,4-diCl-Ph 4-CH3-Ph 591 2,4-diCl-Ph 4-C2H5-Ph 592 2,4-diCl-Ph 2,4-diF-Ph 593 2,4-diCl-Ph 2,5-diF-Ph 594 2,4-diCl-Ph 3,4-diF-Ph 595 2,4-diCl-Ph 3,5-diF-Ph 596 2,4-diCl-Ph 2,4-diCl-Ph 597 2,4-diCl-Ph 2,5-diCl-Ph 598 2,4-diCl-Ph 3,4-diCl-Ph 599 2,4-diCl-Ph 3,5-diCl-Ph 600 2,4-diCl-Ph 3,4-OCH20-Ph 601 2,4-diCl-Ph 3,4-OCH2CH20-Ph 602 2,4-diCl-Ph 2-thien 1 603 2,4-diCl-Ph 2-furanyl 604 2,4-diCl-Ph 2-p ridyl 605 2,4-diCl-Ph 4- rid 1 606 2,4-diCl-Ph 2-imidazol 1 607 2,4-diCl-Ph 3- razolyl 608 2,4-diCl-Ph 2-thiazolyl 609 2,4-diCl-Ph 5-tetrazol 1 610 2,4-diCl-Ph 1-adamant 1 611 3-OCH3-Ph 3-CN-Ph 612 3-OCH3-Ph 3-COCH3-Ph 613 3-OCH3-Ph 3-C02Me-Ph 614 3-OCH3-Ph 3-C02Et-Ph 615 3-OCH3-Ph 3-C02H-Ph 616 3-OCH3-Ph 3-CONH2-Ph 617 3-OCH3-Ph 3-F-Ph 618 3-OCH3-Ph 3-C1-Ph 619 3-OCH3-Ph 3-NH2-Ph 620 3-OCH3-Ph 3-S02NH2-Ph 621 3-OCH3-Ph 3-CF3-Ph 622 3-OCH3-Ph 3-OCH3-Ph 623 3-OCH3--Ph 3-OEt-Ph 624 _3 -OCH3--Ph 3 -OCF3-Ph ~

625 3-OCH3--Ph 3-S02CH3-Ph 626 3-OCH3-Ph 3-OH-Ph 627 3-OCH3-Ph 3-CH3-Ph 628 3-OCH3-Ph 3-C2H5-Ph 629 3-OCH3-Ph 4-CN-Ph 630 3-OCH3--Ph 4-COCH3-Ph 631 3-OCH3-Ph 4-C02Me-Ph 632 3-OCH3-Ph 4-C02Et-Ph 633 3-OCH3-Ph 4-C02H-Ph 634 3-OCH3--Ph 4-CONH2-Ph 635 3-OCH3--Ph 4-F-Ph 636 3-OCH3-Ph 4-C1-Ph 637 3-OCH3-Ph 4-NH2-Ph 638 3-OCH3-Ph 4-S02NH2-Ph 639 3-OCH3-Ph 4-CF3-Ph 64 0 3 -OCH3 --Ph 4 -OCH3 -Ph 641 3-OCH3-Ph 4-OEt-Ph 642 3-OCH3-Ph 4-OCF3-Ph 643 3-OCH3-Ph 4-S02CH3-Ph ~

644 3-OCH3-Ph 4-OH-Ph 645 3-OCH3-Ph 4-CH3-Ph 646 3-OCH3-Ph 4-C2H5-Ph 647 3-OCH3--Ph 2, 4-diF-Ph 648 3-OCH3-Ph 2,5-diF-Ph 649 3-OCH3-Ph 3,4-diF-Ph 650 3-OCH3-Ph 3,5-diF-Ph 651 3-OCH3-Ph 2, 4-diCl-1?h 652 3-OCH3--Ph 2, 5-diCl-~?h 653 3-OCH3-Ph 3,4-diCl-Ph ~

654 3-OCH3-Ph 3 , 5-diCl-l?h 655 3-OCH3-Ph 3,4-OCH20-Ph 656 3-OCH3--Ph 3, 4-OCH2CH20-Ph 657 3-OCH3--Ph 2-thien :L

658 3-OCH3--Ph 2-furan :L

659 3-OCH3-Ph 2- rid :L

660 3-OCH3-Ph 4- rid :L

661 3-OCH3-Ph 2-imidazolyl 662 3-OCH3-Ph 3- razol 1 663 _ 2-thiazolyl 3-OCH3--Ph 664 3-OCH3--Ph 5-tetrazol 1 665 3-OCH3-Ph 1-adamantyl 666 2-thien~l -_ 3-CN-Ph 667 2-thien l1 3-COCH3-Ph 668 2-thien 1 3-F-Ph 669 2-thien 1 3-C1-Ph 670 2-thienyl -, 3-NH2-Ph 671 2-thienyl 3-OCH3-Ph 672 2-thien 1 3-OH-Ph 673 2-thien 1 ~ 4-CN-Ph 674 2-thien 1 4-COCH3-Ph 675 2-thien 1 4-F-Ph _676 2-thien 1 ~ 4-C1-Ph 677 2-thien 1 _ 4-NH2-Ph 678 2-thienyl 4-OCH3-Ph 679 2-thien 1 4-OH-Ph 680 2-thien 1 3,4-diF-Ph 681 2-thienyl 3,5-diF-Ph 682 2-thien 1 3,4-diCl-Ph 683 2-thien 1 3,5-diCl-Ph 684 2-thien 1 3,4-OCH20-Ph 685 2-thien 1 3,4-OCH2CH20-Ph 686 3-thien 1 3-CN-Ph 687 3-thien 1 3-COCH3-Ph 688 3-thien 1 3-F-Ph 689 3-thien 1 3-C1-Ph 690 3-thien 1 3-NH2-Ph 691 3-thien 1 3-OCH3-Ph 692 3-thien 1 3-OH-Ph 693 3-thien 1 4-CN-Ph 694 3-thienyl 4-COCH3-Ph 695 3-thien 1 4-F-Ph 696 3-thien 1 4-C1-Ph 697 3-thien 1 4-NH2-Ph 698 3-thien 1 4-OCH3-Ph 699 3-thien 1 4-OH-Ph 700 3-thien 1 3,4-diF-Ph 701 3-thien 1 3,5-diF-Ph 702 3-thien 1 3,4-diCl-Ph 703 3-thien 1 3,5-diCl-Ph 704 3-thien 1 3,4-OCH20-Ph 705 3-thien 1 3,4-OCH2CH20-Ph 706 2-furanyl 3-CN-Ph 707 2-furan 1 3-COCH3-Ph 708 2-furan 1 3-F-Ph 709 2-furan 1 3-C1-Ph 710 2-furan 1 3-NH2-Ph 711 2-furan 1 3-OCH3-Ph 712 2-furan 1 3-OH-Ph 713 2-furan 1 4-CN-Ph 714 2-furan 1 4-COCH3-Ph 715 2-furan 1 4-F-Ph 716 2-furan 1 4-C1-Ph 717 2-furan 1 4-NH2-Ph 718 2-furan 1 4-OCH3-Ph 719 2-furan 1 4-OH-Ph 720 2-furan 1 3,4-diF-Ph 721 2-furan 1 3,5-diF-Ph 722 2-furan 1 3,4-diCl-Ph 723 2-furan 1 3,5-diCl-Ph ?24 2-furan 1 3,4-OCH20-Ph 725 2-furan 1 3,4-OCH2CH20-Ph 726 3-furan 1 3-CN-Ph 727 3-furan 1 3-COCH3-Ph 728 3-furan 1 3-F-Ph 729 =i-furan 1 3-C1-Ph 730 3-furanyl _ ~ ~
3-NH2-Ph 731 3-furan 1 _ 3-OCH3-Ph 732 3-furan 1 3-OH-Ph 733 :3-furanyl 4-CN-Ph 734 3-furanyl 4-COCH3-Ph 735 _ 4-F-Ph 3-furan 1 736 3-furan 1 4-C1-Ph 737 3-furan 1 4-NH2-Ph 738 ~~-furan 1 4-OCH3-Ph.

739 3-furan 1 4-OH-Ph 740 3-furanyl 3,4-diF-Ph 741 =~-furanyl 3,5-diF-Ph _742 _ 3,4-diCl-Ph 3-furan 1 ~

743 _ ?I-furan 1 3,5-diCl-Ph 744 ~-furan 1 3,4-OCH20-Ph 745 ?.-furan 1 3,4-OCH2CH20-Ph ?46 2.-pyrid 1 3-CN-Ph 747 2-pyridyl 3-COCH3-Ph ?48 ~ - rid' 1 3-F-Ph 749 2- rid 1 3-Cl-Ph 750 2- rid 1 3-NH2-Ph 751 ~,- .rid 1 3-OCH3-Ph _ 752 2- rid 1 3-OH-Ph 753 2 - .rid 1 4-CN-Ph 754 2- rid I 4-COCH3-P h _ 755 2- rid 1 4-F-Ph _ 756 e:- rid 1 4-C1-Ph 757 __ 2- rid 1 4-NH2-Ph -758 _2;-pyridyl 4-OCH3-Ph 759 2- id 1 _ 4-OH-Ph 760 2- rid 1 3,4-diF-Ph 761 2-pyrid 1 3,5-diF-Ph 762 2-pyridyl 3,4-diCl-Ph 763 2;- rid 1 3,5-diCl-Ph 764 ~- rid I 3,4-OCH20-Ph 765 2- rid I 3,4-OCH2CH20-Ph 766 3.- rid 1 3-CN-Ph 7 67 _3. -pyridyl 3 -COCH3 -Ph 768 3- rid' 1 3-F-Ph 769 3- rid 1 3-C1-Ph 770 _3.- rid 1 3-NH2-Ph 771 3- rid 1 3-OCH3-Ph 772 3- rid 1 3-OH-Ph _773 3- rid 1 4-CN-Ph 774 3-pyrid 1 4-COCH3-Ph 775 3.- rid 1 4-F-Ph 776 3- rid 1 4-C1-Ph 777 3-pyridyl 4-NH2-Ph 778 3-pyridyl 4-OCH3-Ph 779 3- rid 1 4-OH-Ph 780 3~- rid 1 3,4-diF-Ph 781 3-pyridyl 3,5-diF-Ph 782 3- ridyl 3,4-diCl-Ph 783 3-p rid 1 3,5-diCl-Ph 784 3-pyridyl 3,4-OCH20-Ph 785 3- rid 1 3,4-OCH2CH20-Ph 786 4- rid 1 3-CN-Ph 787 4-pyrid 1 3-COCH3-Ph 788 4- rid 1 3-F-Ph 789 4- rid 1 3-C1-Ph 790 4- rid 1 3-NH2-Ph 791 4- yrid 1 3-OCH3-Ph 792 4- yrid 1 3-OH-Ph 793 4- rid 1 4-CN-Ph 794 4- rid 1 4-COCH3-Ph 795 4- yrid 1 4-F-Ph 4-pyrid 1 4-C1-Ph 4- rid 1 4-NH2-Ph 798 4- rid 1 4-OCH3-Ph 799 4- rid 1 4-OH-Ph 800 4- rid 1 3,4-diF-Ph 801 4- rid 1 3,5-diF-Ph 802 4- rid 1 3,4-diCl-Ph 803 4-p rid 1 3,5-diCl-Ph 804 4- rid 1 3,4-OCH20-Ph 805 4-p rid 1 3,4-OCH2CH20-Ph 806 3-indol 1 3-CN-Ph 807 3-indolyl 3-COCH3-Ph 808 3-indol 1 3-F-Ph 809 3-indol 1 3-C1-Ph 810 3-indol 1 3-NH2-Ph 811 3-indol 1 3-OCH3-Ph 812 3-indol 1 3-OH-Ph 813 3-indol 1 4-CN-Ph 814 3-indol 1 4-COCH3-Ph 815 3-indolyl 4-F-Ph 816 3-indolyl 4-C1-Ph 817 3-indol 1 4-NH2-Ph 818 3-indol 1 4-OCH3-Ph 819 3-indol 1 4-OH-Ph 820 3-indol 1 3,4-diF-Ph 821 3-indol 1 3,5-diF-Ph 822 3-indol 1 3,4-diCl-Ph 823 3-indol 1 3,5-diCl-Ph 824 3-indol 1 3,4-OCH20-Ph 825 3-indol l 3,4-OCH2CH20-Ph 826 5-indolyl 3-CN-Ph 827 5-indol 1 3-COCH3-Ph 828 5-indolyl 3-F-Ph 829 5-indol 1 3-C1-Ph 830 5-indol 1 3-NH2-Ph 831 5-indol 1 3-OCH3-Ph 832 5-indol 1 3-OH-Ph 833 5-indol 1 4-CN-Ph 834 5-indol 1 4-COCH3-Ph WO 00;35449 PCT/US99/30292 835 5-indol 1 4-F-Ph 836 5-indol 1 4-Cl-Ph 837 5-indol 4-NH2-Ph 838 _ 4-OCH3-Ph 5-indol 1 839 5-indol 1 _ 4-OH-Ph 840 5-indol 1 3,4-diF-Ph 841 __ 5-indol 1 3,5-diF-Ph _ 842 5-indo~ 3,4-diCl-P
h 843 5-indolyl _ 3,5-diCl-Ph 8_44 5-indol 1 3,4-OCH20-Ph 845 5-indolyl 3,4-OCH2CH20-Ph 846 5-indazol 1 3-CN-Ph .

847 5-indazol 3-COCH3-Ph l 848 _5-indazolyl _ 3-F-Ph 849 5-indazolyl 3-C1-Ph 850 5-indazol 1 _ 3-NH2-Ph 851 5-indazol 1 3-OCH3-Ph.

852 5-indazol 1 3-OH-Ph 853 5~-indazol 1 4-CN-Ph 854 5-indazol 1 4-COCH3-Ph 855 5-indazol 1 4-F-Ph 856 _5-indazol 1 4-C1-Ph 857 5-indazol 1 _ ~ 4-NH2-Ph 858 5-indazol 1 4-OCH3-Ph.

859 5-indazol 1 4-OH-Ph 860 5-indazolyl 3,4-diF-Ph 861 _ 5-indazol 1 3,5-diF-Ph 862 5-indazol 1 _ 3,4-diCl-Ph 863 5-indazol 1 3,5-diCl-Ph 864 5-indazol 1 3,4-OCH20-Ph 865 5-indazolyl 3,4-OCH2CH20-Ph 866 5-benzimidazol 1 3-CN-Ph 867 5-benzimidazol 1 ___ - ~ 3-COCH3-Ph 868 5-benzimidazol 1 3-F-Ph 869 5-benzimidazolyl 3-C1-Ph 870 5-benzimidazol 1 3-NH2-Ph 8_7_1 5-benzimidazolyl 3-OCH3-Ph 872 _ _ 5-be_nzimidazol 1 3-OH-Ph 873 5-benzimidazolyl 4-CN-Ph 874 5-benzimidazol 1 4-COCH3-Ph 875 5-benzimidazol~ 4-F-Ph 876 5-benzimidazolyl 4-C1-Ph 877 5-benzimidazolyl 4-NH2-Ph 878 5-benzimidazol 1 4-OCH3-Ph 879 5-benzimidazol 1 4-OH-Ph 880 5-benzimidazol 1 3,4-diF-Ph 881 5-benzimidazolyl 3,5-diF-Ph 882 5-benzimidazolyl 3,4-diCl-Ph 883 5-benzimidazol 1 3,5-diCl-Ph 884 5-benzimidazol l 3,4-OCH20-Ph 885 5-benzimidazolyl 3,4-OCH2CH20-Ph 886 5-benzothiazol l _ 3-CN-Ph 887 5-benzothiazolyl 3-COCH3-Ph 888 5-benzothiazolyl 3-F-Ph 889 5-benzothiazolyl 3-C1-Ph 890 5-benzothiazol 1 3-NH2-Ph 891 5-benzothiazolyl 3-OCH3-Ph 892 5-benzothiazol 1 3-OH-Ph 893 5-benzothiazol 1 4-CN-Ph 894 5-benzothiazolyl 4-COCH3-Ph 895 5-benzothiazol 1 4-F-Ph 896 5-benzothiazol 1 4-C1-Ph 897 5-benzothiazol 1 4-NH2-Ph 898 5-benzothiazolyl 4-OCH3-Ph 899 5-benzothiazol 1 4-OH-Ph 900 5-benzothiazol 1 3,4-diF-Ph 901 5-benzothiazol 1 3,5-diF-Ph 902 5-benzothiazol 1 3,4-diCl-Ph 903 5-benzothiazol 1 3,5-diCl-Ph 904 5-benzothiazol 1 3,4-OCH20-Ph 905 5-benzothiazol 1 3,4-OCH2CH20-Ph 906 5-benzoxazolyl 3-CN-Ph 5-benzoxazolyl 3-COCH3-Ph 908 5-benzoxazol 1 3-F-Ph 909 5-benzoxazal 1 3-C1-Ph 910 5-benzoxazol 1 3-NH2-Ph 911 5-benzoxazol 1 3-OCH3-Ph 912 5-benzoxazol I 3-OH-Ph 913 5 -benzoxazol 1 4 -CN-Ph 914 5-benzoxazol 1 4-COCH3-Ph 915 5-benzoxazol 1 4-F-Ph 916 5-benzoxazol 1 4-C1-Ph 91~ 5-benzoxazol 1 4-NH2-Ph 918 5-benzoxazolyl 4-OCH3-Ph 919 5-benzoxazolyl 4-OH-Ph 920 5-benzoxazol 1 3,4-diF-Ph 921 5-benzoxazol 1 3 5-diF-Ph 922 S-benzoxazol 1 , 3,4-diCl-Ph 923 5-benzoxazol 1 3,5-diCl-Ph 924 5-benzoxazol 1 3,4-OCH20-Ph 925 5-benzoxazol 1 3,4-OCH2CH20-Ph 'TABLE 6 ~~N'R ~~N'R ~ _R3 H F J~ 'v H Iv HN H
R a R a R a O

C HN~H.R HN~H_R3 HN~N.R3 H
F
1a C1 ~ HN~N~R~
H

O O
F ~ HN~N~R~ a HN~L "Rs H 8 ~.. H

is O is HN~N~R3 9 ~~..// ~~'~~'' H
O
~~ R3 0 HN'°'H~ a HN~ ~R3 F 1:1 H
a 1~

~~N.R
F H
F

N N.R ~ R3 F~~~t~ H R ~~~/~ ~ H

R a 8 Ria 13 Cl ~~N.R3 1 S
C1 ~ H C
~ 17 ~ 3 N H~N'R3 HN N-R
CI~~~f~ H R C H

Rla R a 16 lg ~~N_R
H

F O
3 Rla k .R3 _R
HN N

F
Rla Rla ~ 3 HN" H R
F

HN I3'R Rla ~~N_R
H 23 C1 ~ H
Rla 24 Rla H ~ _R'; H ~ .R3 HIV H HN N
H H p N 3 C1 H
~j_ R
Rla H Rla F

Rla ~~H.R3 26 CI R~H R3 F' HN~NR3 30 la la R ~./~ H R

Rla N\ H ~~N.R-~ 29 C1 Fi 1NR3 H HIS ~H
R1a F H ~ 3 Rla HN_ 'NR 3 3 ~~N.R-~ 32 C1 1 NR3 H FiN~ ~H

Rla Rla NR

H ~ .R3 H Rla CI H ~ R3 35 ~ ~ H
Rla F H~ NR3 R1a 37 ~H 39 R'"

HN_ _N'R3 HN~NR3 Cl.~~\~~~ HN~NR3 H H I~/~ H
Ria Hla Rla 40 4~ 42 p O
11 R3 F ~.
t ~w . N ~- HN N
H ~;, N .. ~ . .. N i~. HN N
Ri 4 ; ~_ ' ~' 1~=y H =- , H
F 1a is i R R -;:
__ _ "~:~ O
O
/ ~,.N HN N-R3 C1 ~~~"-1'y, ~ R3 F ~\~ ~,~ O
~.N~ HN N ~ i C 1 14 ~ v H ''~ ~ ~ I-I 1' ' ~ N ~ ~ N

R ~~~ Rl a--~'' J/i F R14~!-'~ H
\~

/~,/~ ~, O 3 F ~~, ~- N 1 HN ~ N R C 1 %~ ~'~, ~4 ' ~ 3 ~~-~i O
v H ~; ' 14 ~-.- 'w~ . N'~~ HN y\N R C1 '~~ ' N~., HN!'~1V R
F R ~;s /' \' 1a j=~ H ~ ~-_. 1 C I R -~~~~~~ C 1 R i a~ ~~~ , H
4 9 _,%
F ~ O 51 J~ R3 ~ ,,~-''~, O
F ~~ ~~ ~,. N ~ HN N C 1 , ~, , 3 ~-~ =- O .
H ~,i, ' N \ ~'~. N R C 1 ~(- Y ~ a R.
i4 '-=- ~ ~L~ wN~ HN~ ~N
R ~~~ Ria H F ~% J
Ria_~% H
5 2 \'''~/, _ ~ O
N, J:- R3 _..I O
HN N F , ~ JL R3 ~ r'~ O

i 4 ~~ H ~ ~ ~ ~ N 1 ~ H ~ , _ ~ ~-- '~~.. N __ ~ J~ N R
R ~,~ / R i a~ F ~' l a ~-. H
R -F ~ y ~ 3 F ~~ ~, W O 3 ~N1 ~hN R ~~ iw.~'"N1 ~~N R /~~~ ; W.
CI~ 14 ~ H F 14 ~ H ~~ /~-- ,~,- N ~ ~ N R
R ~~ R ~/, F 1 a ~r---1, H
F R --!;
5g 59 ~~~N HN N R ~I ,~ -''~~N1 HN N R C1 ~ ~~\, ~ R3 R14 \- H CI~ R14 H ~~ ~''~'Nw HN N
C1 ~ la ~-~ H
R --~ /ri Entry R3 R14 CN

2 - Ph - F
_ Ph Cl -4 Ph CH2OH

Ph OH

6 Ph _. _ NH2 7 Ph C02Me 8 Ph C02Et _ 9 Ph CONH2 __.

Ph NHPh 11 Ph NHMe 12 Ph OMe 13 Ph C(O)(2-imidazolyl) 14 Ph C(0)(4-imidazolyl) Ph ~ C(0)(2-thiazolyl) 16 Ph C(O)(4-thiazolyl) 17 Ph C(O)(2-oxazolyl) 18 Ph C(O)(4-oxazolyl) 19 Ph C(O)C3-pyrazolyl) Ph C(O)(4-pyrazolyl) 21 Ph C(O)(5-tetrazolyl) 22 Ph C(O)(2-pyridyl) 23 Ph C(O)(3-pyridyl) 24 Ph _ C(O)(4-pyridyl) Ph C(O)(2-thienyl) 26 Ph C(O)(3-thienyl) 27 Ph C(O)(2-furanyl) 28 Ph C(O)(3-furanyl) 29 Ph 2-thienyl Ph 3-thienyl 31 Ph 2-furanyl 32 Ph 3-furanyl 33 Ph 2-pyridyl _ 34 Ph 3-pyridyl Ph 4-pyridyl _ 36 Ph 1-imidazolyl 37 Ph 2-imidazolyl 38 Ph 4-imidazolyl 39 Ph 1-pyrazolyl Ph 3-pyrazolyl 41 Ph 4-pyrazolyl 42 Ph 2-thiazolyl 43 Ph 4-thi,azolyl 44 Ph 5-tetrazolyl Ph 2-oxazolyl 46 Ph 4-oxazolyl 47 Ph C(O)N(2-imidazolyl) 48 Ph C(O)N(4-imidazolyl) 49 Ph C(O)N(2-thiazolyl) ~ Ph ~ C(O)N(4-thiazolyl) 51 Ph C (O) N (2-oxazolyl) 52 ___ C(O)N(4-oxazolyl) Ph 53 _ C(O)N(3-pyrazolyl) Ph 54 Ph C(O)N(4-pyrazolyl) 55 Ph C(O)N(2-pyridyl) 56 Ph C(O)N(3-pyridyl) 57 Ph C(O)N(4-pyridyl) 58 Ph C(O)N(2-thienyl) 59 Ph C(O)N(3-thienyl) 60 Ph C (O)N(2-furanyl) 61 Ph C(O)N(3-furanyl) 62 Ph C ( O ) N ( 2 -pyrro lyl ) 63 Ph C(O)N(3-pyrrolyl) 64 Ph CH2(1-imidazolyl) 65 Ph CH2(1-(1,2,3-triazolyl)) 66 Ph CH2(2-(1,2,3-triazolyl)) 67 Ph CH2 (1- ( 1, 2, 4-triazolyl) ) 68 Ph CH2(1-pyrazolyl) 69 3-CN-Ph CN

70 3-CN-Ph F

71 3-CN-Ph C1 72 3-CN-Ph CH20H

73 3-CN-Ph OH

74 3-CN-Ph NH2 75 3-CN-Ph C02Me 76 3-CN-Ph C02Et 77 3-CN-Ph CONH2 78 3-CN-Ph NHPh 79 3-CN-Ph NHMe 80 3-CN-Ph OMe 81 3-CN-Ph C(O)(2-imidazolyl) 82 3-CN-Ph C(O)(4-imidazolyl) 83 3-CN-Ph C(O)(2-thiazolyl) 84 3-CN-Ph C(O)(4-thiazolyl) 85 3-CN-Ph C(O)(2-oxazolyl) 86 3-CN-Ph C(O)(4-oxazolyl) 87 3-CN-Ph C(O)(3-pyrazolyl) 88 3-CN-Ph C(O)(4-pyrazolyl) 89 3-CN-Ph C(O)(5-tetrazolyl) 90 3-CN-Ph C(O)(2-pyridyl) 91 3-CN-Ph C(O)(3-pyridyl) 92 3-CN-Ph C(O)(4-pyridyl) 93 3-CN-Ph C(O)(2-thienyl) 94 3-CN-Ph C(O)(3-thienyl) 95 3-CN-Ph C(O)(2-furanyl) 96 3-CN-Ph C(O)(3-furanyl) 97 3-CN-Ph 2-thienyl 98 3-CN-Ph 3-thienyl 99 3-CN-Ph 2-furanyl 100 3-CN-Ph 3-furanyl 101 3-CN-Ph 2-pyridyl 102 3-CN-Ph 3-pyridyl 103 3-CN-Ph 4-pyridyl 104 3-CN-Ph 1-imidazolyl 105 3-CN-Ph 2-imidazolyl 106 3-CN-Ph 4-imidazolyl 107 3-CN-Ph 1-pyrazolyl 108 3-CN-Ph 3-pyrazolyl 109 3-CN-Ph 4-pyrazolyl 110 3-CN-Ph 2-thiazolyl 111 3-CN-Ph 4-thiazolyl 112 3-CN-Ph 5-tetrazolyl 113 3-CN-Ph 2-oxazolyl 114 3-CN-Ph 4-oxazolyl 115 3-CN-Ph C(O)N(2-imidazolyl) 116 3-CN-Ph C(O)N(4-imidazolyl) 117 3-CN-Ph C(O)N(2-thiazolyl) 118 3-CN-Ph C(O)N(4-thiazolyl) 119 3-CN-Ph C(O)N(2-oxazolyl) 120 3-CN-Ph C(O)N(4-oxazolyl) 121 3-CN-Ph C(O)N(3-pyrazolyl) 122 3-CN-Ph C(O)N(4-pyrazolyl) 123 3-CN-Ph C(O)N(2-pyridyl) 124 3-CN-Ph C(O)N(3-pyridyl) 125 3-CN-Ph C(O)N(4-pyridyl) 126 3-CN-Ph C(O)N(2-thienyl) 127 3-CN-Ph C(O)N(3-thienyl) 128 3-CN-Ph C(O)N(2-furanyl) 129 3-CN-Ph C(O)N(3-furanyl) 130 3-CN-Ph C(O)N(2-pyrrolyl) 131 3-CN-Ph C(O)N(3-pyrrolyl) 132 3-CN-Ph CH2(1-imidazolyl) 133 3-CN-Ph CH2(1-(1,2,3-triazolyl.)) 134 3-CN-Ph CH2(2-(1,2,3-triazolyl)) 135 3-CN-Ph CH2(1-(1,2,4-triazolyl.)) 136 3-CN-Ph CH2(:1-pyrazolyl) 137 3-OMe-Ph ~ CN

138 3-OMe-Ph ' F

139 3-OMe-Ph C1 1 ~'= 3 -OMe- Ph CH2 141 3-OMe-Ph OH

142 3-OMe-Ph NH2 143 3-OMe-Ph C02Me 144 3-OMe-Ph ~ C02Et 145 3-OMe-Ph ) CONH2 146 3-OMe-Ph NHPh 147 3-OMe-Ph ~e 148 3-OMe-Ph OMe _149 3-OMe-Ph C(O)(2-imidazolyl) 150 3-OMe-Ph ~~~~ C(0)(4-imidazolyl) 151 3-OMe-Ph C(O)(2-thiazolyl) 152 3-OMe-Ph C(O)(4-thiazolyl) 153 3-OMe-Ph C(0)(2-oxazolyl) 154 3-OMe-Ph C(0)(4-oxazolyl) 155 3-OMe-Ph C{O)(3-pyrazolyl) 156 3-OMe-Ph C(O)(4-pyrazolyl) 157 3-OMe-Ph C(O)(5-tetrazolyl) 158 3-OMe-Ph C(0)(2-pyridyl) 159 3-OMe-Ph C(O)(3-pyridyl) 160 3-OMe-Ph C(O)(4-pyridyl) 161 3-OMe-Ph C(0)(2-thienyl) 162 3-OMe-Ph C(O)(3-thienyl) 163 3-OMe-Ph C(O)(2-furanyl) 164 3-OMe-Ph C(0)(3-furanyl) 165 3-OMe-Ph 2-thienyl 166 3-OMe-Ph 3-thienyl 167 3-OMe-Ph 2-furanyl 168 3-OMe-Ph 3-furanyl 169 3-OMe-Ph 2-PYridyl 170 3-OMe-Ph 3-PYridyl 171 3-OMe-Ph 4-pYridyl 172 3-OMe-Ph 1-imidazolyl 173 3-OMe-Ph 2-imidazolyl 174 3-OMe-Ph 4-imidazolyl 175 3-OMe-Ph 1-pYrazolyl 176 3-OMe-Ph 3-PYrazolyl 177 3-OMe-Ph 4-PYrazolyl 178 3-OMe-Ph 2-thiazolyl 179 3-OMe-Ph 4-thiazolyl 180 3-OMe-Ph 5-tetrazolyl 181 3-OMe-Ph 2-oxazolyl 182 3-OMe-Ph 4-oxazolyl 183 3-OMe-Ph C(O)N(2-imidazolyl) 184 3-OMe-Ph C(O)N(4-imidazolyl) 185 3-OMe-Ph C(O)N(2-thiazolyl) 186 3-OMe-Ph C(O)N(4-thiazolyl) 187 3-OMe-Ph C(O)N(2-oxazolyl) 188 3-OMe-Ph C(0)N(4-oxazolyl) 189 3-OMe-Ph C(O)N(3-pyrazolyl) 190 3-OMe-Ph C(O)N(4-pyrazolyl) 191 3-OMe-Ph C(0)N(2-pyridyl) 192 3-OMe-Ph C(0)N(3-pyridyl) 193 3-OMe-Ph C(0)N(4-pyridyl) 194 3-OMe-Ph C(O)N(2-thienyl) 195 3-OMe-Ph C(O)N(3-thienyl) 196 3-OMe-Ph C(0)N(2-furanyl) 197 3-OMe-Ph C(0)N(3-furanyl) 19 8 3 -OMe-~ Ph C ( O ) N ( 2 -pyrro lyl ) 199 3 -OMe-~Ph C ( O ) N ( 3 -pyrrolyl ) 200 3-OMe-Ph CH2(1-imidazolyl) 201 3-OMe-Ph CH2(1-(1,2,3-triazolyl)) 202 3-OMe-Ph CH2(2-(1,2,3-triazolyl)) 203 3-OMe-Ph CH_2(1-(1,2,4-triazolyl)) 204 3-OMe-_Ph ~ CH2(1-pyrazolyl) 205 3-C(O)Me-Ph CN

206 3-C(O)MES-Ph g 207 3-C(O)Me-Ph C1 208 3-C(OjMe-Ph CH20H

209 3-C(O)Me-Ph OH

210 3-C(0)ME~-Ph ~2 211 _ C02Me 3-C(0)Me-Ph 212 3-C(O)Me-Ph C02Et 213 3~-C(O)Me-Ph CONH2 214 3 -C ( O) Me-Ph kph 215 3-C(O)M
e-Ph 216 _ OMe 3-~C(O)Me-Ph 217 3-~C(O)Me-Ph C(O)(2-imidazolyl) 218 3-C(O)Me-Ph C(O)(4-imidazolyl) 219 3-C (O)Me-Ph C (O) (2-thiazolyl) 220 3-C(O)Me-Ph C(O)(4-thiazolyl) 221 3-C(O)Me~-Ph C(O) (2-oxazolyl) 222 3-C(O)Nte-ph C(0) (4-oxazolyl) 223 3-C(O)Me-Ph C(O)(3-pyrazolyl) 224 3-C(O)Me-Ph C(O)(4-pyrazolyl) 225 3-C(O)Me-Ph C(O)(5-tetrazolyl) 226 3-C(O)Me-Ph C(O)(2-pyridyl) 227 3-C(O)Me-Ph C(O)(3-pyridyl) 228 3-C(O)Me-Ph C(O)(4-pyridyl) 229 3-C(O)Me-Ph C(O)(2-thienyl) 230 3-C(O)Me-Ph C(O)(3-thienyl) 231 3-C(O)Me-Ph C(0)(2-furanyl) 232 3-C(O)Me-Ph C(O) (3-furanyl) 233 3-C(O)Me-Ph 2-thienyl 234 3-C(O)Me-Ph 3-thienyl 235 3-C(O)Me-Ph 2-furanyl 236 3-C(O)Me-Ph 3-furanyl 237 3-C(O)Me-Ph 2-PYridyl 238 3-C(O)Me-Ph 3-pyridyl 239 _ 4-pyridyl 3-C(O)Me-Ph 240 3-C(O)Me~-Ph 1-imidazolyl 241 3-C(O)Me~-Ph 2-imidazolyl 242 3-C(O)Me-Ph 4-imidazolyl 243 3-C(O)Me~-Ph 1-pyrazolyl 244 3-C(O)Me--Ph 3-pyrazolyl 245 3-~ (O)Me--Ph 4-PYrazolyl 246 3-C(O)Me--Ph 2-thiazolyl 247 3-C(O)Me-Ph 4-thiazolyl 248 3-C(O)Me-Ph 5-tetrazolyl 249 3-C(0)Me-Ph 2-oxazolyl 250 3-C(O)Me-Ph 4-oxazolyl 252 3-C(O)Me-Ph C(O)N(2-imidazolyl) 252 3-C(O)Me-Ph C(O)N(4-imidazolyl) 253 3-C(O)Me-Ph C(O)N(2-thiazolyl) 254 3-C(0)Me-Ph C(O)N(4-thiazolyl) 255 3-C(0)Me-Ph C(O)N(2-oxazolyl) 256 3-C(O)Me-Ph C(O)N(4-oxazolyl) 257 3-C(O)Me-Ph C(O)N(3-pyrazolyl) 258 3-C(O)Me-Ph C(O)N(4-pyrazolyl) 259 3-C(O)Me-Ph C(O)N(2-pyridyl) 260 3-C(O)Me-Ph C(0)N(3-pyridyl) 261 3-C(O)Me-Ph C(O)N(4-pyridyl) 262 3-C(O)Me-Ph C(O)N(2-thienyl) 263 3-C(O)Me-Ph C(O)N(3-thienyl) 264 3-C(O)Me-Ph C(O)N(2-furanyl) 265 3-C(O)Me-Ph C(0)N(3-furanyl}

266 3-C(O)Me-Ph C(O)N(2-pyrrolyl) 267 3-C(O)Me-Ph C(O)N(3-pyrrolyl) 268 3-C(O)Me-Ph CH2(I-imidazolyl) 269 3-C(O)Me-Ph CH2(1-(1,2,3-triazolyl)) 270 3-C(O)Me-Ph CH2(2-(1,2,3-triazolyl)) 271 3-C(O)Me-Ph CH2(1-(1,2,4-triazolyl)) 272 3-C(O)Me-Ph CH2(1-pyrazolyl) 273 4-F-Ph CN

274 4-F-Ph F

275 4-F-Ph C1 276 4-F-Ph CH20H

277 4-F-Ph OH

278 4-F-Ph ~2 279 4-F-Ph C02Me 280 4-F-Ph C02Et 281 4-F-Ph CONH2 282 4-F-Ph NHPh 283 4-F-Ph 284 4-F-Ph OMe 285 4-F-Ph C(O)(2-imidazolyl) 286 4-F-Ph C(O)(4-imidazolyl) 287 4-F-Ph C(O)(2-thiazolyl) 288 4-F-Ph C(O)(4-thiazolyl) 289 4-F-Ph C(0)(2-oxazolyl) 290 4-F-Ph C(O)(4-oxazolyl) 291 4-F-Ph C(O)(3-pyrazolyl) 292 4-F-Ph C(O)(4-pyrazolyl) 293 4-F-Ph C(O)(5-tetrazolyl) 294 4-F-Ph C(O)(2-pyridyl) 295 4-F-Ph C(O)(3-pyridyl) 296 4-F-Ph C(0)(4-pyridyl) 297 4-F-Ph C(0)(2-thienyl) 298 4-F-Ph C(0) (3-thienyl) 299 4-F-Ph C (0) (2-furanyl ) 300 4-F-Ph C(O) (3-furanyl) 301 4-F-Ph 2-thienyl 302 4-F-Ph 3-thienyl 303 4-F-Ph 2-furanyl 304 4-F--Ph 3-furanyl 305 4-F-Ph 2-pyridyl 306 4-F-Pla 3-pyridyl 307 4-F-Plz 4-pyridyl 308 4-F-Ph 1-imidazolyl 309 4-F-Plz 2-imidazolyl 310 4-F-Plz 4-imidazolyl 311 4-F-Ph 1-pyrazolyl 312 4-F-Ph 3-pyrazolyl 313 4-F-Ph 4-pyrazolyl 314 4-F-Ph 2-thiazolyl 315 4-F-Ph 4-thiazolyl 316 4-F-Ph 5-tetrazolyl 317 4-F-_Ph 2-oxazolyl 318 4-F-Ph 4-oxazolyl 319 4-F-Ph C(O)N(2-imidazolyl) 320 4-F-Ph C(O)N(4-imidazolyl) 321 4-F-Ph C(O)N(2-thiazolyl) 322 4-F-Ph C(O)N(4-thiazolyl) 323 4-F-Ph C(O)N(2-oxazolyl) 324 4-F-Ph C(O)N(4-oxazolyl) 325 4-F-Ph C(O)N(3-pyrazolyl) 326 4-F-Ph C(O)N(4-pyrazolyl) 327 4-F-Ph_ (O)N(2-pyridyl) C

328 4-F-Ph _ C(O~)N(3-pyridyl) _ 329 4-F-Ph_ C(0)N(4-pyridyl) 330 4-F-Ph C(O)N(2-thienyl) 331 4-F-Ph C (O) N (3-thienyl ) 332 4-F-Ph C(O)N(2-furanyl) 333 4-F-Ph C(O)N(3-furanyl) 334 4-F-Ph C(0)N(2-pyrrolyl) 335 4-F-Ph C(0)N(3-pyrrolyl) 336 4'-F-Ph CH2(1-imidazolyl) 337 4-F-Ph CH2(1-(1,2,3-triazolyl)) 338 4-F-Ph CH2(2-(1,2,3-triazolyl)) 339 4-F-Ph CH2(1-(1,2,4-triazolyl)) 340 4-F-Ph CH2(1-pyrazolyl) Table 7.

G'~;~ 0 G~ ~ ~~ H H G"~~~'~~. O
I

w-Y-N,.- ~ N N R ~,~N v~-y, N=~ N R
N-, N N R _If 3 3 Ri OH H H Ri \~OH 0 R1 '\OH H H

2a 3a la '~i H H 0 0 N ~
G ~
%' ~~.~ N N
~ N. _N
' ~,~
N '~~ J~ R G ~,, ~ N ~~
~ R3 R3 Y N N z Ri OH H H _~ Ri OOH H H
Rl ~OH O

lb 2b 3b O .;~: H H /~ 0 ~ .-~, G ~~ N '.;~,.~ N ~ G i N ~~~J N N R3 ~'.,~ N ~~

N Ri ~A.\OH O Ri OH H H
G
Ri ~
H H

~ ~ ~'\
G N~ ~
~l I N~
/

Y _~ H
N (~ G
H H ~
i ' ~~
R ~
R
HN
N

OH HN,~N R OH HN~N R i ~

8a O 3 9a /~1 y, /,~ ~~ ~ ~I
~
J

.~ ~N~J G~. G YN~~ H
-~N~
H
~

H _ RnOH ~ ~N R3 R ~OH HN.-N R R1 OH HN ~N R3 8b O 9b O 11 O

-, '~ N .~ % H : ~
, ~' ~ N ~ ~ N
G

, ~ , Ri OH HN H ~.
N 1 '/
Ri j.~OH HN H
N ~

~ ~ Ri R3 R3 OH HN~N R

12a O 13a O 12b O

G ~~~N'~ H
Ri ~OH H,N ~N R3 13b O

v G ,r N .~ : H G , .~ N ~: H
Ri ~~OH ~T~N R3 Ri OH ~~N R3 G '~ ~
N ~ H G '~ N
~~ H
R1 \OH ~~N R3 R1 OH ~yN R3 16a O 17a O
G~~N./~ H G~N~ H

Rl 'OH ~ j~N R3 Ri OH ~~~N R3 16b O 17b O
~1 ~~1 ~~N ~/'~ H ~ '~ , N .~ H
R ~OH ~~N R~ Ri OH ~ N R

G ~~I ~ O G ~~ ~.,, O
N,/ N~ N R3 N ,N.~N R3 R1 OH 20a H H Ri \OH 21a H H
I ~'\ O ~\1 O
N~~N~N R3 G. ~ N~w~N~N R3 R1 OH H H R~ H H H
20b 21b ~N~N~IN R2, ~~ N~",N~N.R2 R1 ~ G ~
R H H Ri 0H H H

G ~'~~~ OH H H OH H H OH H H
N,~~~,N,~~N G : N _ - _~N, : N ,N _. ',N, ,N
R3 - ~ R3 G~ ~ R3 R1 OH 24 Ri ~OH 25 0 Ri -v_OH 26 0 G ~~~~ OH H H '~ 1 -; OH H H ~~, OH H H
N~~wN N G~,~~ ,N'.-~ ,N N ' N~ N N
R3 ~' ~ Y R3 G \~ Y ~ R3 Ri OH Me O Ri ~~ OH Me 0 R ~~OH Me 0 G ~~~ OH H H ~ ~\; OH H H ~ OH H H
G,~yN,~~, ,N ,N '~'YN~1~N~N 3 N ~~ N , N ~l ~1 R 3 G ~ ~ R
' 1i R3 iPrO
R1~OH 1P~ Ri OH ipr0 R1 OH

G ~~i OH H H ~ ~~ ~'; OH H H ~ '~, OH H H
N~~,~N,~N G "r~,N_ ;~~ N N ~ v,,N_ -~, N N
~~ R3 _ ~~ Y R3 G _. i ~! R3 Ri OH iBuO Ri~~~OH iBuO Ri OH iBuO

Gy OH H H ~-~~ ~ OH H H /y OH H H
~N~~N~N R3 G~-'y~N_v.-~,~N~,N R3 G ,~N~N~N
' R
Ri OH Ph O Ri ~~OH Ph 0 Rig OH Ph O

G~ "~~ OH H H ~'; OH H H /~~ OH H H
N~-NON 3 G ~-~N~~~-NON R3 G~' N ~~N,i N R3 R
Rl 'OH ph ~ O Ri~~ OH phi 0 Ri OHphJ O

G H H i ,~ OH H H /'~ OH H H
~N~- N NR G~'~yNJ~N~NR3 ~ ,1V~N NR
3 ~ J ' G ~ ~ ~i 3 R OH ph O Ri OH ph O R1 OH ph O

G N y H G~N w ~ H ~ N
H
R ~ HN N G
R1 OH ~ ~ N R3 1 \OH ~! R3 Ri ' OH ~ ~ N R3 R1 = a) H, b) methyl, c) ethyl, d) n-propyl, e) allyl., f) n-butyl, g) n-penty:l, and h) n-hexyl.
Entry G R3 1 4-F-Ph Ph 2 4-F-Ph 3-CN-Ph 3 4-F-Ph 3-COCH3-Ph 4 4-F-Ph 3-C02Me-Ph 4-F-Ph 3-C02Et-Ph 6 4-_F-Ph 3-C02H-Ph 7 4-F-Ph 3-CONH2-Ph 8 4-F-Ph 3-CONHMe-Ph 9 4-F-Ph 3-F-Ph 4-F-Ph 3-C1-Ph 11 4-F-Ph 3-Br-Ph 12 4-F-Ph 3-N02-Ph 13 4-F-Ph 3-NH2-Ph 14 4--F-Ph 3-NHMe-Ph 4--F-Ph 3-NMe2-Ph 16 4--F-Ph _ 3-NHCOCH3-Ph 17 4-F-Ph 3-S02NH2-Ph 18 4-F-Ph 3-S02NHMe-Ph 19 4-F-Ph 3-CF3-Ph 4-F-Ph 3-OCH3-Ph 21 4--F-Ph _ 3-OPh-Ph 22 4-F-Ph 3-OCF3-Ph 23 4-F-Ph 3-SCH3-Ph 24 4-F-Ph 3-SOCH3-Ph 4-F-Ph 3-S02CH3-Ph 26 4-F-Ph 3-OH-Ph 27 4-F-Ph 3-CH20H-Ph 28 4-F-Ph 3-CHOHCH3-Ph 29 4-F-Ph 3-COH(CH3)2-Ph 3 0 4 --F-Ph 3 -CHOHPh-Ph 31 4-F-Ph 3-CH3-Ph 32 4-F-Ph 3-C2H5-Ph 33 4-F-Ph 3-iPr-Ph 34 4-F-Ph 3-tBu-Ph 4-F-Ph 3-Ph-Ph 3 6 4 -F'- Ph 3 -CH2 Ph-Ph 37 4~-F'-Ph 3-CH2C02Me-Ph 38 4-F-Ph 3-(1- i eridin 1)-Ph 39 4~-F-Ph 3-(1- rrolidinyl)-Ph 4-F'-Ph 3-(2-imidazolyl)-Ph 41 4-F-Ph 3-(1-imidazol 1)-Ph 42 4-F'-Ph 3-(2-thiazol 1)-Ph 43 4-F'-Ph 3- (3- razol 1) -Ph 44 4-F'-Ph 3- ( 1-pyrazol 1 ) -Ph 4-F'-Ph 3- ( 1-tetrazol 1 ) -Ph 46 4-F-Ph 3- ( 5-tetrazol 1 ) -Ph 47- 4-F-Ph 3-(2- rid 1)-Ph 48 4-F'-Ph 3-(2-thien 1)-Ph 49 4-F-Ph 3-(2-furanyl)-Ph 50 4-F-Ph 4-CN-Ph 51 4-F-Ph _ 4-COCH3-Ph 52 4-F-Ph 4-C02Me-Ph 53 4-F-Ph 4-C02Et-Ph 54 4-F-Ph 4-C02H-Ph 55 4-F-Ph 4-CONH2-Ph 56 4-F-Ph 4-CONHMe-Ph 57 4-F-Ph 4-CONHPh-Ph 58 4-F-Ph 4-NHCONH2-Ph 59 4-F-Ph 4-F-Ph 60 4-F-Ph 4-C1-Ph 61 4-F-Ph 4-Br-Ph 62 4-F-Ph 4-N02-Ph 63 4-F-Ph 4-NH2-Ph 64 4-F-Ph 4-NHMe-Ph 65 4-F-Ph 4-NMe2-Ph 66 4-F-Ph 4-NHCOCH3-Ph 67 4-F-Ph 4-S02NH2-Ph 68 4-F-Ph 4-S02NHMe-Ph 69 4-F-Ph 4-CF3-Ph 70 4-F-Ph 4-OCH3-Ph 71 4-F-Ph 4-OPh-Ph 72 4-F-Ph 4-OCF3-Ph 73 4-F-Ph 4-SCH3-Ph 74 4-F-Ph 4-SOCH3-Ph 75 4-F-Ph 4-S02CH3-Ph 76 4-F-Ph 4-OH-Ph 77 4-F-Ph 4-CH20H-Ph 78 4-F-Ph 4-CHOHCH3-Ph 79 4-F-Ph 4-COH(CH3)2-Ph 80 4-F-Ph 4-CH3-Ph 81 4-F-Ph 4-C2H5-Ph 82 4-F-Ph 4-iPr-Ph 83 4-F-Ph 4-tBu-Ph 84 4-F-Ph 4-Ph-Ph 85 4-F-Ph 4-CH2Ph-Ph 86 4-F-Ph 4-CH2C02Me-Ph 87 4-F-Ph 4-(1- i eridin 1)-Ph 88 4-F-Ph 4-(1- rrolidin 1)-Ph 89 4-F-Ph 4-(2-imidazol 1)-Ph 90 4-F-Ph 4-(1-imidazol 1)-Ph 91 4-F-Ph 4-(2-thiazolyl)-Ph 92 4-F-Ph 4-(3- razolyl)-Ph 93 4-F-Ph 4-(1- razol 1)-Ph 94 4-F-Ph 4-(1-tetrazol 1)-Ph 95 4-F-Ph 4-(5-tetrazolyl)-Ph 96 4-F-Ph 4-(2- rid 1)-Ph 97 4-F-Ph 4-(2-thienyl)-Ph 98 4-F-Ph 4-(2-furan 1)-Ph 99 4-F-Ph 2-CN-Ph 100 4-F-Ph 2-COCH3-Ph 101 4-F-Ph 2-C02Me-Ph 102 4-F-Ph 2-C02Et-Ph 103 4-F--Ph 2-C02H-Ph 104 4-F--Ph 2-CONH2-Ph 105 4-F--Ph 2-CONHMe-Ph 106 4-F--Ph 2-F-Ph 107 4-F--Ph 2-Cl-Ph 108 4-F--Ph 2-Br-Ph 109 4-F~-Ph 2-N02-Ph 110 4 -F ~- Ph 2 -NH2 - Ph 111 4 - F ~-Ph 2 -NF~ie-Ph 112 4-F~-Ph 2-NMe2-Ph 113 4-F-Ph 2-NHCOCH3-Ph 114 4-_F-Ph 2-SO2NH2-Ph I15 4-F-Ph 2-S02NHMe-Ph 116 4-F-Ph 2-CF3-Ph 117 4-F-Ph 2-OCH3-Ph 118 4-F-Ph 2-OPh-Ph 119 4-F-Ph 2-OCF3-Ph 120 4-F-Ph 2-SCH3-Ph 121 4-F-Ph 2-SOCH3-Ph 122 4-F-Ph 2-S02CH3-Ph 123 4-F-Ph 2-OH-Ph 124 4-F-Ph 2-CH20H-Ph 125 4-F-Ph 2-CHOHCH3-Ph 126 4-F-Ph 2-COH(CH3)2-Ph 127 4-F-Ph 2-CHOHPh-Ph 128 4-F-Ph 2-CH3-Ph 129 F-Ph 2-C2H5-Ph 130 _ 2-iPr-Ph 4-F-Ph 131 F-Ph 2-tBu-Ph I32 _ 2-Ph-Ph_ 4-F-Ph 133 4-F-Ph 2-CH2Ph-Ph 134 4-F-Ph 2-CH2C02Me-Ph 135 4--F-Ph 2- ( 1- i eridin 1) -Ph 136 4-F-Ph 2-(1-p rrolidinyl)-Ph 137 4--F-Ph 2- (2-imidazol 1) -Ph 138 4-F-Ph 2-(1-imidazol 1)-Ph 139 4-F-Ph 2-(2-thiazol 1)-Ph 140 4-F-Ph 2-(3-pyrazolyl)-Ph 141 4--F-Ph 2- ( 1- razol 1 ) -Ph 142 4-F-Ph 2-(1-tetrazol 1)-Ph 143 4-F-Ph 2-(5-tetrazolyl)-Ph 144 4-F-Ph 2-pyrid 1)-Ph 2-( 145 4-F-Ph -~-~(2-thien 1)-Ph 146 4--F-Ph 2- (2-furan 1) -Ph 147 4-F-Ph 2,4-diF-Ph 148 4-F-Ph _ 2,5-diF-Ph 149 4-F-Ph 2,6-diF-Ph 150 4-F-Ph ___ 3,4-diF_-Ph ~~

151 4-F-Ph 3,5-diF-Ph 152 4-F-Ph 2,4-diCl-Ph 153 4-~F-Ph 2,5-diCl-Ph 154 4-F-Ph 2,6-diCl-Ph 155 4-F-Ph 3,4-diCl-Ph 156 4_-F-Ph 3,5-diCl-Ph 157 4-F-Ph 3,4-diCF3-Ph 158 4-F-Ph 3,5-diCF3-Ph 159 4-F-Ph 5-C1-2-Me0-Ph 160 4-F-Ph 5-C1-2-Me-Ph 161 4-F-Ph 2-F-5-Me-Ph 162 4-F-Ph 2-F-5-N02-Ph 163 4-F-Ph 3,4-OCH20-Ph 164 4-F-Ph 3,4-OCH2CH20-Ph 165 4-F-Ph 2-Me0-4-Me-Ph 166 4-F-Ph 2-Me0-5-Me-Ph 167 4-F-Ph 1-na hth 1 168 4-F-Ph 2-na hthyl 169 4-F-Ph 2-thien 1 170 4-F-Ph 3-thien 1 171 4-F-Ph 2-furan 1 172 4-F-Ph 3-furan 1 173 4-F-Ph 2- ridyl 174 4-F-Ph 3- rid 1 175 4-F-Ph 4- rid 1 176 4-F-Ph 2-indol 1 177 4-F-Ph 3-indol 1 178 4-F-Ph 5-indol 1 179 4-F-Ph 6-indol 1 180 4-F-Ph 3-indazol 1 181 4-F-Ph 5-indazol 1 182 4-F-Ph 6-indazolyl 183 4-F-Ph 2-imidazol 1 184 4-F-Ph 3-p razol 1 185 4-F-Ph 2-thiazol 1 186 4-F-Ph 5-tetrazol 1 187 4-F-Ph 2-benzimidazol 1 188 4-F-Ph 5-benzimidazol 1 189 4-F-Ph 2-benzothiazolyl 190 4-F-Ph 5-benzothiazol 1 191 4-F-Ph 2-benzoxazal 1 192 4-F-Ph 5-benzoxazol 1 193 4-F-Ph 1-adamantyl 194 4-F-Ph 2-adamant 1 295 4-F-Ph t-Bu 196 2-F-Ph 3-CN-Ph 197 2-F-Ph 3-COCH3-Ph 198 2-F-Ph 3-C02Me-Ph 199 2-F-Ph 3-C02Et-Ph 200 2-F-Ph 3-C02H-Ph 201 2-F-Ph 3-CONH2-Ph 202 2-F-Ph 3-F-Ph 203 2-F-Ph 3-C1-Ph 204 2-F-Ph 3-NH2-Ph 205 2-F-Ph 3-S02NH2-Ph 206 2-F-Ph 3-CF3-Ph 207 2-F-Ph 3-OCH3-Ph 208 2-F-Ph 3-OEt-Ph 209 2-F-Ph 3-OCF3-Ph 210 2-F-Ph 3-S02CH3-Ph 211 2-F-Ph 3-OH-Ph 212 2-F-Ph 3-CH3-Ph 213 2-F-Ph 3-C2H5-Ph 214 2-F-Ph 4-CN-Ph 215 2-F-Ph 4-COCH3-Ph 216 2-F-Ph 4-C02Me-Ph 217 2-F-Ph 4-C02Et-Ph 218 2-F-Ph 4-C02H-Ph 219 2-F-Ph 4-CONH2-Ph 220 2-F-Ph 4-F-Ph 221 2-F-Ph 4-C1-Ph 222 2-F-Ph 4-NH2-Ph 223 _ 4-S02NH2-Ph 2--F-Ph 224 2--F-Ph _ _ ~~ 4-CF3-Ph 225 2-F-Ph 4-OCH3-Ph 226 2-F-Ph 4-OEt-Ph 227 2-F-Ph 4-OCF3-Ph 228 2-F-Ph 4-S02CH3-Ph 229 2 --F'-Ph 4-OH-Ph 230 2-F-Ph 4-CH3-Ph 231 2-F-Ph 4-C2H5-Ph 232 _ 2,4-diF-Ph 2-F-Ph 233 2--F'-Ph 2, 5-diF-Ph 234 2-F-Ph 3,4-diF-Ph 235 2-F-Ph 3,5-diF-Ph 236 2-F-Ph 2,4-diCl-Ph 237 2-F-Ph 2,5-diCl-Ph 238 2-F-Ph 3,4-diCl-Ph 239 2-F-Ph 3,5-diCl-Ph 240 2-F-Ph 3,4-OCH20-Ph 241 2-F-Ph 3,4-OCH2CH20-Ph 242 _ 2-thien 1 2--F-Ph 243 2-F-Ph 2-furan 1 244 2-F-Ph _ 2-p~yridyl 245 _ 4- rid 1 2-F-Ph 246 2--F-Ph 2-imidazol 1 247 2--F-Ph 3- razol 1 248 2-F-Ph 2-thiazol 1 249 2-F-Ph 5-tetrazol 1 250 2-F-Ph 1-adamant 1 251 2 , 4 --diF-Ph 3 -CN-Ph 252 2,4-diF-Ph 3-COCH3-Ph 253 2,4-diF-Ph 3-C02Me-Ph 254 2,4-diF-Ph 3-C02Et-Ph 255 2,4-diF-Ph 3-C02H-Ph 256 2,4-d_iF-Ph 3-C
ONH2-Ph 257 2,4-d.iF-Ph _ F-Ph 258 2, 4-d:iF-Ph _ 3-C1-Ph 259 2,4-diF-Ph _ 3-NH2-Ph 260 2,4-d:iF-Ph 3-S02NH2-Ph 261 2,4-diF-Ph 3-CF3-Ph 262 2,4-diF-Ph 3-OCH3-Ph 263 2,4-diF-Ph 3-OEt-Ph 264 2,4-diF-Ph 3-OCF3-Ph 265 2,4-diF-Ph 3-S02CH3-Ph 266 2,4-diF-Ph 3-OH-Ph 267 2,4-diF-Ph 3-CH3-Ph 268 2,4-diF-Ph 3-C2H5-Ph 269 2,4-diF-Ph 4-CN-Ph 270 2,4-diF-Ph 4-COCH3-Ph 271 2,4-diF-Ph 4-C02Me-Ph 272 2,4-diF-Ph 4-C02Et-Ph 273 2,4-diF-Ph 4-C02H-Ph 274 2 , 4-diF-Ph 4-CONFi2-Ph 275 2,4-diF-Ph 4-F-Ph 276 2,4-diF-Ph 4-C1-Ph 277 2,4-diF-Ph 4-NH2-Ph 278 2,4-diF-Ph 4-S02NH2-Ph 279 2,4-diF-Ph 4-CF3-Ph 280 2,4-diF-Ph 4-OCH3-Ph 281 2,4-diF-Ph 4-OEt-Ph 282 2,4-diF-Ph 4-OCF3-Ph 283 2,4-diF-Ph 4-S02CH3-Ph 284 2,4-diF-Ph 4-OH-Ph 285 2,4-diF-Ph 4-CH3-Ph 286 2,4-diF-Ph 4-C2H5-Ph 287 2,4-diF-Ph 2,4-diF-Ph 288 2,4-diF-Ph 2,5-diF-Ph 289 2,4-diF-Ph 3,4-diF-Ph 290 2,4-diF-Ph 3,5-diF-Ph 291 2,4-diF-Ph 2,4-diCl-Ph 292 2,4-diF-Ph 2,5-diCl-Ph 293 2,4-diF-Ph 3,4-diCl-Ph 294 2,4-diF-Ph 3,5-diCl-Ph 295 2,4-diF-Ph 3,4-OCH20-Ph 296 2,4-diF-Ph 3,4-OCH2CH20-Ph 297 2,4-diF-Ph 2-thien 1 298 2,4-diF-Ph 2-furan 1 299 2,4-diF-Ph 2- rid 1 300 2,4-diF-Ph 4- rid 1 301 2,4-diF-Ph 2-imidazol 1 302 2,4-diF-Ph 3- razol 1 303 2,4-diF-Ph 2-thiazolyl 304 2,4-diF-Ph 5-tetrazol 1 305 2,4-diF-Ph 1-adamant 1 306 4-C1-Ph Ph 307 4-Cl-Ph 3-CN-Ph 308 4-C1-Ph 3-COCH3-Ph 309 4-C1-Ph 3-C02Me-Ph 310 4-C1-Ph 3-C02Et-Ph 311 4-C1-Ph 3-C02H-Ph 312 4-C1-Ph 3-CONH2-Ph 313 4-Cl-Ph 3-CONHMe-Ph 314 4-C1-Ph 3-F-Ph 315 4-C1-Ph 3-Cl-Ph 316 4-C1-Ph 3-Hr-Ph 317 4-C1-Ph 3-N02-Ph 318 4-C1-Ph 3-NH2-Ph 319 4-C1-Ph 3-NHMe-Ph 320 4-C1-Ph 3-NMe2-Ph 321 4-C1-Ph _ 3-NHCOCH3-Ph 322 4-C1-Ph 3-S02NH2-Ph 323 4-C1-Ph 3-S02NHMe-Ph 324 4-C1-Ph 3-CF3-Ph 325 4-C1-Ph 3-OCH3-Ph 326 4-C1-Ph 3-OPh-Ph 327 4-C1-Ph 3-OCF3-Ph 328 4-C1-Ph 3-SCH3-Ph 329 4-C1-Ph 3-SOCH3-Ph 330 4-C1-Ph 3-S02CH3-Ph 331 4-C1-Ph 3-OH-Ph 332 4-C1-Ph 3-CH20H-Ph 333 4-C1-Ph 3-CHOHCH3-Ph 334 4-C1-Ph 3-COH(CH3)2-Ph 335 4-C1-Ph 3-CHOHPh-Ph 336 4-C1-Ph 3-CH3-Ph 337 4-C1-Ph 3-C2H5-Ph 338 4-C1-Ph 3-iPr-Ph 339 4-C1-Ph 3-tBu-Ph 340 4-C1-Ph 3-Ph-Ph 341 4-C1-Ph 3-CH2Ph-Ph 342 4-C1-Ph 3-CH2C02Me-Ph 343 4-C1-Ph 3-(1- i eridin 1)-Ph 344 4-C1-Ph 3-(1- yrrolidin 1)-Ph 345 4-Cl-Ph 3-(2-imidazol 1)-Ph 346 4-C1-Ph 3-(1-imidazol 1)-Ph 347 4-Cl-Ph 3-(2-thiazol 1)-Ph 348 4-C1-Ph 3-(3- razolyl)-Ph 349 4-C1-Ph 3-(1-pyrazol 1)-Ph 350 4-C1-Ph 3-(1-tetrazol 1)-Ph 351 4-C1-Ph 3-(5-tetrazol 1)-Ph 352 4-C1-Ph 3-(2- rid 1)-Ph 353 4-C1-Ph 3-(2-thien 1)-Ph 354 4-C1-Ph 3-(2-furan 1)-Ph 355 4-C1-Ph 4-CN-Ph 356 4-Cl-Ph 4-COCH3-Ph 357 4-C1-Ph 4-C02Me-i~h 358 4-Cl-Ph 4-C02Et-Ph 359 4-C1-Ph 4-C02H-Ph 360 4-C1.-Ph 4-CONH2-Ph 361 4-C1.-Ph 4-CONHMe-Ph 362 4-C1.-Ph 4-CONHPh-Ph 363 4-C~.-Ph 4-NHCONH2-Ph 3 64 4-C1.-Ph 4-F-Ph 365 4-C~.-Ph 4-Cl-Ph 366 4-C1.-Ph 4-Br-Ph 367 4-Cl-Ph 4-N02-Ph 368 4-Cl-Ph 4-NH2-Ph ~

369 4-Cl-Ph 4-NHMe-Ph 370 4-Cl-Ph 4-NMe2-Ph 371 4-CI-Ph 4-NHCOCH3-Ph 372 4-CI-Ph 4-S02NH2-Ph 373 4-Cl-Ph 4-S02NHMe-Ph 374 4-C1-Ph 4-CF3-Ph 375 4-Cl-Ph 4-OCH3-Ph 376 4-C1-Ph 4-OPh-Ph 377 4-C1-Ph 4-OCF3-Ph 378 4-Cl-Ph 4-SCH3-Ph 379 4-CI-Ph 4-SOCH3-Ph 380 4-C1-Ph 4-S02CH3-Ph 381 4-CI-Ph 4-OH-Ph 382 4-Cl-Ph 4-CH20H-Ph 383 4-Cl-Ph 4-CHOHCH3-Ph 384 4-C1-Ph 4-COH(CH3)2-Ph 385 4-C1-Ph 4-CH3-Ph 386 4-C1-Ph 4-C2H5-Ph 387 4-Cl-Ph 4-iPr-Ph 388 4-C1-Ph 4-tBu-Ph 389 4-C1-Ph 4-Ph-Ph 390 4-C1-Ph 4-CH2Ph-Ph 391 4-Cl-Ph 4-CH2C02Me-Ph 392 4-Cl-Ph 4-(1- i eridin 1)-Ph 393 4-C1-Ph 4-(1-p rrolidinyl)-Ph 394 4-C1-Ph 4-(2-imidazol 1)-Ph 395 4-Cl-Ph 4-(1-imidazolyl)-Ph 396 4-Cl-Ph 4-(2-thiazol 1)-Ph 397 4-Cl-Ph 4-(3-p azol 1)-Ph 398 4-Cl-Ph 4-(1- razol 1)-Ph 399 4-C1-Ph 4-(1-tetrazol 1)-Ph 400 4-C1-Ph 4-(5-tetrazol 1)-Ph 401 4-Cl-Ph 4-(2- rid 1)-Ph 402 4-Cl-Ph 4-(2-thien 1)-Ph 403 4-Cl-Ph 4-(2-furan 1)-Ph 404 4-CI-Ph 2-CN-Ph 405 4-Cl-Ph 2-COCH3-Ph 406 4-C1-Ph 2-C02Me-Ph 407 4-C1-Ph 2-C02Et-Ph 408 4-Cl-Ph 2-C02H-Ph 409 4-CI-Ph 2-CONH2-Ph 410 4-C1-Ph 2-CONHMe-Ph 411 4-Cl-Ph 2-F-Ph 412 4-C1-Ph 2-C1-Ph 413 4-CI-Ph 2-Br-Ph 414 4-C1-Ph 2-N02-Ph 415 4-Cl-Ph 2-NH2-Ph 416 4-C1-Ph 2-NHMe-Ph 417 4-C1-Ph 2-NMe2-Ph 418 4-Cl-Ph 2-NHCOCH3-Ph 419 4-CI-Ph 2-S02NH2-Ph 420 4-C1-Ph 2-S02NHMe-Ph 421 4-C~-Ph 2-CF3-Ph 422 4-Cl-Ph 2-OCH3-Ph 423 4-Cl-Ph 2-OPh-Ph 424 4-C1-Ph 2-OCF3-Ph 425 4-Cl-Ph 2-SCH3-Ph 426 4-C1-Ph 2-SOCH3-Ph 427 _ 4-C1-Ph 2-S02CH3-Ph 428 4-C1-Ph 2-OH-Ph 429 4-C1-Ph 2-CH20H-Ph 430 4-C1-Ph 2-CHOHCH3-Ph 431_ 4-C1-Ph 2-COH(CH3)2-Ph 432 ~ 4-C1-Ph 2-CHOHPh-Ph 433 4-C1-Ph _ 2-CH3-Ph 434 4-C1-Ph 2-C2H5-Ph ~

435 4-C1-Ph 2-iPr-Ph 436 4-C1-Ph 2-tBu-Ph _ _ _ 437 4-C1-Ph _ 2-Ph-Ph 438 4-C1-Ph 2-CH2Ph-Ph 439 4-C1-Ph 2-CH2C02Me-Ph 440 4-C1-Ph 2-(1- i eridin 1)-Ph 441 4-C1-Ph 2-(1- rrolidin 1)-Ph 442 4-C1-Ph 2-(2-imidazol 1)-Ph 443 4-C1-Ph 2-(1-imidazol 1)-Ph 444 4-C1-Ph 2-(2-thiazol 1)-Ph 445 4-C1-Ph 2-(3-p razol 1)-Ph 446 4-C1-Ph 2-(1- azol I)-Ph 447 4-C1-Ph 2-(1-tetraaol 1)-Ph 448 4-C1-Ph 2-(5-tetrazol 1)-Ph 449 4-C1-Ph 2-(2- rid 1)-Ph 450 4-C1-Ph 2-(2-thien 1)-Ph 451 4-C1-Ph 2-t2-furan 1)-Ph 452 4-C1-Ph 2,4-diF-Ph 453 4-C1-Ph 2,5-diF-Ph 454 4-C1-Ph 2,6-diF-Ph 455 4-Cl-Ph 3,4-diF-Ph 456 4-Cl-Ph 3,5-diF-Ph 457 4-C1-Ph 2,4-diCl-Ph 458 _ _ 4-C1-Ph 2,5-diCl-Ph 459 4-C1-Ph 2,6-diCl-Ph 460 4-C1-Ph 3,4-diCl-Ph 461 4-C1-Ph 3,5-diCl-Ph 462 4-C1-Ph 3,4-diCF3=Ph 463 4-C1-Ph 3,5-diCF3-Ph 464 4-C1-Ph 5-C1-2-Me0-Ph 465 4-C1-Ph 5-C1-2-Me-Ph 466 4-C1-Ph 2-F-5-Me-Ph 467 4-C1-Ph 2-F-5-N02-Ph 468 4-C1-Ph 3,4-OCH20-Ph 469 4-C1-Ph 3,4-OCH2CH20-Ph 470 4-C1-Ph 2-Me0-4-Me-Ph 471 4-C1-Ph 2-Me0-5-Me-Ph 472 4-C1-Ph 1-na hth 1 WO 00!35449 PCT/US99/30292 473 4-C1-Ph 2-naphth 1 474 4-Cl-Ph 2-thien 1 475 4-C1-Ph 3-thienyl 476 4-C1-Ph 2-furan 1 477 4-C1-Ph 3-furanyl 478 4-Cl-Ph 2- rid 1 479 4-Cl-Ph 3- ridyl 480 4-C1-Ph 4- ridyl 481 4-C1-Ph 2-indol 1 482 4-Cl-Ph 3-indol 1 483 4-C1-Ph 5-indol 1 484 4-C1-Ph 6-indol 1 485 4-C1-Ph 3-indazol 1 486 4-C1-Ph 5-indazol 1 487 4-C1-Ph 6-indazol 1 488 4-C1-Ph 2-imidazol 1 489 4-C1-Ph 3- yrazolyl 490 4-Cl-Ph 2-thiazol 1 491 4-C1-Ph 5-tetrazol 1 492 4-C1-Ph 2-benzimidazol 1 493 4-C1-Ph 5-benzimidazol 1 494 4-C1-Ph 2-benzothiazol 1 495 4-C1-Ph 5-benzothiazolyl 496 4-C1-Ph 2-benzoxazol 1 497 4-Cl-Ph 5-benzoxazol 1 498 4-C1-Ph 1-adamant 1 499 4-C1-Ph 2-adamant 1 500 4-C1-Ph t-Bu 501 2-C1-Ph 3-CN-Ph 502 2-C1-Ph 3-COCH3-Ph 503 2-C1-Ph 3-C02Me-Ph 504 2-C1-Ph 3-C02Et-Ph 505 2-C1-Ph 3-C02H-Ph 506 2-C1-Ph 3-CONH2-Ph 507 2-C1-Ph 3-F-Ph 508 2-C1-Ph 3-C1-Ph 509 2-C1-Ph 3-NH2-Ph 510 2-C1-Ph 3-S02NH2-Ph 511 2-C1-Ph 3-CF3-Ph 512 2-C1-Ph 3-OCH3-Ph 513 2-C1-Ph 3-OEt-Ph 514 2-C1-Ph 3-OCF3-Ph 515 2-Cl-Ph 3-S02CH3-Ph 516 2-C1-Ph 3-OH-Ph 527 2-C1-Ph 3-CH3-Ph 518 2-C1-Ph 3-C2H5-Ph 519 2-Cl-Ph 4-CN-Ph 520 2-C1-Ph 4-COCH3-Ph 521 2-Cl-Ph 4-C02Me-Ph 522 2-C1-Ph 4-C02Et-Ph 523 2-C1-Ph 4-C02H-Ph 524 2-C1-Ph 4-CONH2-Ph 525 2-Cl-Ph 4-F-Ph . WO 00/35449 PCT/US99/30292 526 2-C1-Ph 4-C1-Ph 527 2-Cl-Ph 4-NH2-Ph 528 2-C1-Ph 4-S02NH2-Ph 529 2-C3.-Ph 4-CF3-Ph 530 2-C1-Ph 4-OCH3-Ph 531 2-C1-Ph 4-OEt-Ph 532 2-C1-Ph 4-OCF3-Ph 533 2-C1-Ph 4-S02CH3-Ph 534 2-C1-Ph 4-OH-Ph 535 2-C1-Ph 4-CH3-Ph 536 2-C1-Ph 4-C2H5-Ph 537 2-C1-Ph 2,4-diF-Ph 538 2-C1-Ph 2,5-diF-Ph 539 2-Cl-Ph 3,4-diF-Ph 540 2-C1-Ph 3,5-diF-Ph 541 2-C1-Ph 2,4-diCl-Ph 542 2-C1-Ph 2,5-diCl-Ph 543 2-Cl-Ph 3,4-diCl-Ph 544 2-C1-Ph 3,5-diCl-Ph 545 2-C1-Ph 3,4-OCH20-Ph 546 2-C1-Ph 3,4-OCH2CH20-Ph 547 2-C1-Ph 2-thien 1 548 2-C1-Ph 2-furan 1 549 2-C1-Ph 2- id 1 550 2-C1-Ph 4- rid 1 551 2-C_1-Ph 2-imidazol 1 552 2-C1-Ph 3-p razol 1 553 2-C1-Ph 2-thiazol 1 554 2-C1-Ph 5-tetrazol 1 555 2-C1-Ph 1-adamant 1 556 2,4-diCl-Ph 3-CN-Ph 557 2,4-diCl-Ph 3-COCH3-Ph 558 2,4-diCl-Ph 3-C02Me-Ph 559 2,4-diCl-Ph 3-C02Et-Ph 560 2,4-diCl-Ph 3-C02H-Ph 561 2,4-diCl-Ph 3-CONH2-Ph 562 2,4-diCl-Ph 3-F-Ph 563 2,4-diCl-Ph 3-C1-Ph 564 2,4-diCl-Ph 3-NH2-Ph 565 2,4-diCl-Ph 3-S02NH2-Ph 566 2,4-diCl-Ph 3-CF3-Ph 567 2,4-diCl-Ph 3-OCH3-Ph 568 2,4-diCl-Ph 3-OEt-Ph 569 2,4-diCl-Ph 3-OCF3-Ph 570 2,4-diCl-Ph 3-S02CH3-Ph 571 2,4-diCl-Ph 3-OH-Ph 572 2,4-diC1-Ph 3-CH3-Ph 573 2,4-di.Cl-Ph 3-C2H5-Ph 574 2,4-diCl-Ph 4-CN-Ph 575 2,4-diCl-Ph 4-COCH3-Ph 576 2,4-diCl-Ph 4-C02Me-Ph 577 2,4-diCl-Ph 4-C02Et-Ph 578 2,4-diCl-Ph ~
4-C02H-Ph WO OOI35449 PCT/US99/3~7292 579 2,4-diCl-Ph 4-CONH2-Ph 580 2,4-diCl-Ph _ 4-F-Ph 581 2,4-diCl-Ph 4-C1-Ph 582 2,4-diCl-Ph 4-NH2-Ph 583 2,4-diCl-Ph 4-S02NH2-Ph 584 2,4-diCl-Ph 4-CF3-Ph 585 2,4-diCl-Ph 4-OCH3-Ph 586 2,4-diCl-Ph 4-OEt-Ph 587 2,4-diCl-Ph 4-OCF3-Ph 588 2,4-diCl-Ph 4-S02CH3-Ph 589 2,4-diCl-Ph 4-OH-Ph 590 2,4-diCl-Ph 4-CH3-Ph 591 2,4-diCl-Ph 4-C2H5-Ph 592 2,4-diCl-Ph 2,4-diF-Ph 593 2,4-diCl-Ph 2,5-diF-Ph 594 2,4-diCl-Ph 3,4-diF-Ph 595 2,4-diCl-Ph 3,5-diF-Ph 596 2,4-diCl-Ph 2,4-diCl-Ph 597 2,4-diCl-Ph 2,5-diCl-Ph 598 2,4-diCl-Ph 3,4-diCl-Ph 599 2,4-diCl-Ph 3,5-diCl-Ph 600 2,4-diCl-Ph 3,4-OCH20-Ph 601 2,4-diCl-Ph 3,4-OCH2CH20-Ph 602 2,4-diCl-Ph 2-thien 1 603 2,4-diCl-Ph 2-furan 1 604 2,4-diCl-Ph 2- rid 1 605 2,4-diCl-Ph 4- ridyl 606 2,4-diCl-Ph 2-imidazol 1 607 2,4-diCl-Ph 3- razal 1 608 2,4-diCl-Ph 2-thiazol 1 609 2,4-diCl-Ph 5-tetrazolyl 610 2,4-diCl-Ph 1-adamant 1 611 3-OCH3-Ph 3-CN-Ph 612 3-OCH3-Ph 3-COCH3-Ph 613 3-OCH3-Ph 3-C02Me-Ph 614 3-OCH3-Ph 3-C02Et-Ph 615 3-OCH3-Ph 3-C02H-Ph 616 3-OCH3-Ph 3-CONH2-Ph 617 3-OCH3-Ph 3-F-Ph 618 3-OCH3-Ph 3-C1-Ph 619 3-OCH3-Ph 3-NH2-Ph 620 3-OCH3-Ph 3-S02NH2-Ph 621 3-OCH3-Ph 3-CF3-Ph 622 3-OCH3-Ph 3-OCH3-Ph 623 3-OCH3-Ph 3-OEt-Ph 624 3-OCH3-Ph 3-OCF3-Ph 625 3-OCH3-Ph 3-S02CH3-Ph 626 3-OCH3-Ph 3-OH-Ph 627 3-OCH3-Ph 3-CH3-Ph 628 3-OCH3-Ph 3-C2H5-Ph 629 3-OCH3-Ph 4-CN-Ph 630 3-OCH3-Ph 4-COCH3-Ph 631 3-OCH3-Ph 4-C02Me-Ph 632 3-OCH3-Ph 4-C02Et-Ph 633 3-OCH3-Ph 4-C02H-Ph 634 3-OCH3-Ph 4-CONH2-Ph 635 3-OCH.3-ph 4-F-Ph 636 3-OCH3-Ph 4-C1-Ph 637 3-OCH3-Ph 4-NH2-Ph 638 3-OCH3-Ph 4-S02NH2-Ph 639 3-OCH3-Ph 4-CF3-Ph 640 3-OCH3-Ph 4-OCH3-Ph 641 3-OCH3-Ph 4-OEt-Ph 642 3-OCH3-Ph 4-OCF3-Ph 643 3-OCH3-Ph 4-S02CH3-Ph 644 3-OCH3-P 4-OH-Ph h 645 _ 4-CH3-Ph 3-OCH3-Ph 646 3-OCH3-Ph- 4-C2H5-Ph 647 3-OCH3-Ph 2,4-diF-Ph 648 3-OCH3-Ph 2,5-diF-Ph 649 3-OCH3-Ph 3,4-diF-Ph 650 3-OCH3-Ph 3,5-diF-Ph 651 3-OCH3-Ph 2,4-diCl-Ph 652 3-OCH3-Ph 2,5-diCl-Ph 653 _3-OCH3-Ph 3,4-diCl-Ph 654 3-OCH3-Ph _ ~ 3,5-diCl-Ph 655 3-OCH3-Ph 3,4-OCH20-Ph 656 3-OCH3-Ph 3,4-OCH2CH20-Ph 657 3-OCH3-Ph 2-thien 1 658 3-OCH3-Ph 2-furanyl 659 3-OCH3-Ph 2- rid 1 660 3-OCH3-Ph 4- rid 1 661 3-OCH3-Ph 2-imidazol 1 662 3-OCH3-Ph 3- razol 1 663 3-OCH3-Ph 2-thiazol 1 664 3-OCH3-Ph 5-tetrazol 1 665 3-OCH3-Ph 1-adamant 1 666 2-thien 1 3-CN-Ph 667 2-thien 1 3-COCH3-Ph 668 2-thien 1 3-F-Ph 669 2-thien 1 3-C1-Ph 670 2-thienyl 3-NH2-Ph 671 2-thien 1 3-OCH3-Ph 672 2-thien 1 3-OH-Ph 673 2-thien1 4-CN-Ph 674 2-thien 1 4-COCH3-Ph 675 2-thien 1 4-F-Ph 676 2-thien l 4-C1-Ph 677 2-thien 1 4-NH2-Ph 678 2-thien1 4-OCH3-Ph 679 2-thien 1 4-OH-Ph 680 2-thienyl 3,4-diF-Ph 681 2-thien 1 3,5-diF-Ph 682 2-thienyl.- 3,4-diCl-Ph 683 2-thienyl ~ 3,5-diCl-Ph 684 2-thien 1 3,4-OCH20-Ph WO 00135449 PCT/US99C,i0292 685 2-thien 1 3,4-OCH2CH20-Ph 686 3-thien 1 3-CN-Ph 687 3-thien 1 ~ 3-COCH3-Ph 688 3-thienyl 3-F-Ph 689 3-thien 1 3-C1-Ph 690 3-thienyl 3-NH2-Ph 691 3-thienyl 3-OCH3-Ph 692 3-thien I 3-OH-Ph 693 3-thien 1 4-CN-Ph 694 3-thien 1 4-COCH3-Ph 695 3-thien 1 4-F-Ph 696 3-thienyl 4-CI-Ph 697 3-thien 1 4-NH2-Ph 698 3-thien 1 4-OCH3-Ph 699 3-thien 1 4-OH-Ph 700 3-thien 1 3,4-diF-Ph 701 3-thien 1 3,5-diF-Ph 702 3-thien 1 3,4-diCl-Ph 703 3-thienyl 3,5-diCl-Ph 704 3-thien 1 3,4-OCH20-Ph 705 3-thien 1 3,4-OCH2CH20-Ph 706 2-furan 1 3-CN-Ph 707 2-furan 1 3-COCH3-Ph 708 2-furan 1 3-F-Ph 709 2-furan 1 3-C1-Ph 710 2-furan 1 3-NH2-Ph 711 2-furanyl 3-OCH3-Ph 712 2-furan 1 3-OH-Ph 713 2-furan 1 4-CN-Ph 714 2-furan 1 4-COCH3-Ph 715 2-furanyl 4-F-Ph 716 2-furan 1 4-Cl-Ph 717 2-furanyl 4-NH2-Ph 718 2-furan 1 4-OCH3-Ph 719 2-furanyl 4-OH-Ph 720 2-furan 1 3,4-diF-Ph 721 2-furan 1 3,5-diF-Ph 722 2-furan 1 3,4-diCl-Ph 723 2-furan 1 3,5-diCl-Ph 724 2-furan 1 3,4-OCH20-Ph 725 2-furan 1 3,4-OCH2CH20-Ph 726 3-furan 1 3-CN-Ph 727 3-furan 1 3-COCH3-Ph 728 3-furan 1 3-F-Ph 729 3-furan 1 3-CI-Ph 730 3-furan 1 3-NH2-Ph 731 3-furan 1 3-OCH3-Ph 732 3-furan 1 3-OH-Ph 733 3-furan 1 4-CN-Ph 734 3-furan 1 4-COCH3-Ph 735 3-furan 1 4-F-Ph 736 3-furan 1 4-C1-Ph 737 3-furanyl 4-NH2-Ph 738 3-furan l 4-OCH3-Ph 739 3-furanyl 4-OH-Ph 740_ 3-furan 1 3,4-diF-Ph 741 3-furan 1 3,5-diF-Ph 742 3-furan 1 3,4-diCl-Ph 743 3-furan 1 3,5-diCl-Ph 744 3-furan 1 3,4-OCH20-Ph 745 3-furan 1 3,4-OCH2CH20-Ph 746 2- rid 1 3-CN-Ph 747 2- rid 1 3-COCH3-Ph 748 2- rid 1 3-F-Ph 749 2- ~ridyl 3-C1-Ph 750 2- rid 1 3-NH2-Ph 751 2- rid 1 3-OCH3-Ph 752 2- ridyl 3-OH-ph 753 2- ridyl _ - _ 4-CN-Ph 754 2-p rid 4-COCH3-Ph 755 2-pyrid 1 4-F-Ph 756 2- rid 1 4-C1-Ph 757 2- ~ridyl 4-NH2-Ph 758 2- yridyl 4-OCH3-Ph 759 2 =
_ridyl 4-OH-Ph 760 2-p 'rid 1 3, 4--diF-Ph 761 2- rid 1 3,5-diF-Ph 762 2- rid 1 3,4-diCl-Ph 763 2- rid 1 3,5-diCl-Ph 764 2- ridyl 3,4-OCH20-Ph 765 2- ridyl 3,4-OCH2CH20-Ph 766 3- ridyl _ 3-CN-Ph 767 _ 3- ridyl 3-COCH3-Ph 768 3- yridyl 3--F-Ph 769_ 3- rid l 3-C1-Ph 770 3- grid 1 3-NH2-Ph 771 3- rid 1 3-OCH3-Ph 772_ 3- ridyl _ 3-OH-Ph 773 3- rid 1 4-CN-Ph 774 3- rid 1 4-COCH3-Ph 775 3- _rid 1 4-F-Ph 776 3-pyridyl _ 4-C1-Ph 777 3- y:ridyl _ '4-NH2-Ph 778 3- rid 1 4-OCH3-Ph 779 3- ridyl 4-OH-Ph 780 3- y:rid 1 3,4-diF-Ph 781 3- rid 1 3,5-diF-Ph 782 3- riayl 3,4-di C1-Ph 783 3- ridyl _ 3,5-diCl-Ph 784 3- rid 1 3,4-OCH20-Ph 785 3- rid l 3,4-OCH2CH20-Ph 786 4- xidyl 3-CN-Ph 787 4- rid 1 3-COCH3-Ph 788 4- ridyl 3-F-Ph 789 4- ridyl 3-C1-Ph 790 4-p~rridyl 3-NH2-Ph WO 00/35449 PCT/US99/i0292 791 4- ridyl 3-OCH3-Ph 792 4- yrid 1 3-OH-Ph 793 4- yridyl _ __ ~~ 4-CN-Ph 794 4- rid 1 4-COCH3-Ph 795 4- rid 1 4-F-Ph 796 4- rid 1 4-C1-Ph 797 4- rid 1 4-NH2-Ph 798 4- ridyl 4-OCH3-Ph 799 4- rid 1 4-OH-Ph 800 4- yrid 1 3,4-diF-Ph 80I 4- grid 1 3,5-diF-Ph 802 4- rid 1 3,4-diCl-Ph 803 4- yrid 1 3,5-diCl-Ph 804 4- yridyl 3,4-OCH20-Ph 805 4- yrid 1 3,4-OCH2CH20-Ph 806 3-indol 1 3-CN-Ph 807 3-indol 1 3-COCH3-Ph 808 3-indol 1 3-F-Ph 809 3-indolyl 3-C1-Ph 810 3-indol 1 3-NH2-Ph 811 3-indol 1 3-OCH3-Ph 812 3-indol 1 3-OH-Ph 813 3-indol 1 4-CN-Ph 814 3-indolyl 4-COCH3-Ph 815 3-indol 1 4-F-Ph 816 3-indolyl 4-C1-Ph 817 3-indol 1 4-NH2-Ph 818 3-indolyl 4-OCH3-Ph 819 3-indol 1 4-OH-Ph 820 3-indol 1 3,4-diF-Ph 821 3-indol 1 3,5-diF-Ph 822 3-indol 1 3,4-diCl-Ph 823 3-indol 1 3,5-diCl-Ph 824 3-indol 1 3,4-OCH20-Ph 825 3-indol 1 3,4-OCH2CH20-Ph 826 5-indol 1 3-CN-Ph 827 5-indol 1 3-COCH3-Ph 828 5-indol 1 3-F-Ph 829 5-indolyl 3-C1-Ph 830 5-indol 1 3-NH2-Ph 831 5-indol 1 3-OCH3-Ph 832 5-indol 1 3-OH-Ph 833 5-indolyl 4-CN-Ph 834 5-indol 1 4-COCH3-Ph 835 5-indol 1 4-F-Ph 836 5-indol 1 4-C1-Ph 837 5-indol 1 4-NH2-Ph 838 5-indol 1 4-OCH3-Ph 839 5-indol 1 4-OH-Ph 840 5-indol 1 3,4-diF-Ph 841 5-indol 1 3,5-diF-Ph 842 5-indol 1 3,4-diCl-Ph 843 5-indol 1 3,5-diCl-Ph 844 5-indol 1 3,4-OCH20-Ph 845 5-indol 1 3,4-OCH2CH20-Ph 846 5-indazol 1 3-CN-Ph 847 5-indazol 1 3-COCH3-Ph 848 5-indazolyl 3-F-Ph 849 5-indazol 1 3-C1-Ph 850 5-indazol 1 3-NH2-Ph 851 5-indazol 1 3-OCH3-Ph 852 5-indazol 1 3-OH-Ph 853 5-indazol 1 4-CN-Ph 854 5-indazolyl 4-COCH3-Ph 855 5-indazol 1 4-F-Ph 856 5-indazolyl 4-C1-Ph 857 5-indazol 1 4-NH2-Ph 858 5-indazolyl 4-OCH3-Ph 859 5-indazol 1 4-OH-Ph 860 S-indazol 1 3,4-diF-Ph 861 5-indazol 1 3,5-diF-Ph 862 5-indazol I. 3,4-diCl-Ph 863 5-indazol 1 3,5-diCl-Ph 864 5-indazol 1 3,4-OCH20-Ph 865 5-indazol 1 _ ,4 -OCH2CH20-Ph 866 5- _ benzimidazol _ 1 3-CN-Ph 867 5- 3-COCH3-Ph benzimidazolyl 868 S- 3-F-Ph benzimidazol 869 5~- 3-C1-Ph benzimidazol 87 0 5 ~- 3 -NH2 -Ph benzimidazolyl 871 5-- 3 -OCH3 -Ph benzimidazol 872 5-- 3-OH-Ph benzimidazol 87 3 5 ~- 4 -CN-Ph benzimidazol 874 5~- 4-COCH3-Ph benzimidazolyl 8?5 5~- 4-F-Ph benzimidazol 876 5~- 4-C1-Ph benzimid_azolyl 877 5~- 4-NH2-Ph benzimidazol 878 5- 4-OCH3-Ph benzimidazolyl 879 5 ~- 4 -OH-Ph benzimidazol 880 5~- 3, 4-diF-Ph benzimidazol 881 5~- 3, 5-diF-Ph benzimidazol 882 5- 3,4-diCl-Ph i benzimidazolyl 883 5- 3,5-diCl-Ph benzimidazol 884 5- 3,4-OCH20-Ph benzimidazolyl 885 5- 3,4-OCH2CH20-Ph benzimidazol 886 5- 3-CN-Ph benzothiazol 887 5- 3-COCH3-Ph benzothiazol 888 5- 3-F-Ph benzothiazolyl 889 5- 3-C1-Ph benzothiazolyl 890 5- 3-~2-Ph benzothiazolyl 891 5- 3-OCH3-Ph benzothiazolyl 892 5- 3-OH-Ph benzothiazolyl 893 5- 4-CN-Ph benzothiazol 894 5- 4-COCH3-Ph benzothiazol 895 5- 4-F-Ph benzothiazol 896 5- 4-Cl-Ph benzothiazol 897 5- 4_~2_Ph benzothiazolyl 898 5- 4-OCH3-Ph benzothiazol 899 5- 4-OH-Ph benzothiazolyl 900 5- 3,4-diF-Ph benzothiazol 901 5- 3,5-diF-Ph benzothiazol1 902 5- 3,4-diCl-Ph benzothiazolyl 903 5- 3,5-diCl-Ph benzothiazol 904 5- 3,4-OCH20-Ph benzothiazolyl 905 5- 3,4-OCH2CH20-Ph benzothiazol 906 5-benzoxazol 3-CN-Ph 907 5-benzoxazol 3-COCH3-Ph 908 5-benzoxazol 3-F-Ph 909 5-benzoxazol 3-C1-Ph 910 5-benzoxazol 3-NH2-Ph 921 5-benzoxazolyl 3-OCH3-Ph ,WO 00/35449 PCT/US99/30292 912 5-benzoxazol 3-OH-Ph 913 5-benzoxazol~rl 4-CN-Ph 914 5-benzoxazolyl 4-COCH3-Ph 915 5-benzoxazol ~ 4-F-Ph 916 5-benzoxazol _ 1 4-C1-Ph 917 5-benzoxazo1 4-NH2-Ph 918 5-benzoxazo1 4-OCH3-Ph 919 5-ben~:oxazol 4-OH-Ph 920 5-benzoxazol 3,4-diF-Ph 921 5-benzoxazol 3,5-diF-Ph 922 5-ben~:oxazol 3,4-diCl-Ph 923 5-benzaxazoh 3,5-diCl 1 -Ph 924 5-benz;oxazol;yl_ 3 , 4-OCH20-Ph 925 5-benzoxazolyl~ 3,4-OCH2CH20-Ph Utilitv The utility of the compounds in accordance with the present invention as modulators of chemokine receptor activity may be demonstrated by methodology known in the art, such as the assays for CCR-2 and CCR-3 ligand binding, as disclosed by Ponath et al., J. Exp. Med., 183, 2437-2448 (1996) and Uguccioni et al., J. Clin. :Invest., 100, 1137-1143 (1997). Cell lines for expressing the receptor of interest include those naturally expressing the chemokine receptor, such as EOL-3 or THP-1, those induced to express the chemokine receptor by the addition of chemical or protein agents, such as HL-60 or AML14.3D10 cells treated with, for example, butyric acid with interleukin-5 present, or a cell engineered to express a recombinant chemokine receptor, such as CHO ~or HEK-293. Finally, blood or tissue cells, for example human peripheral blood eosinophils, isolated using methods as described by Hansel et al., J. Immunol.
Methods, 145, 105- 110 (1991), can be utilized in such assays. In particular, the compound of the present invention have activity in binding to the CCR-3 receptor in then aforementioned assays. As used herein, "activi.ty" is intended to mean a compound demonstrating an IC50 of 10 ).1M or lower in concentration when measured in the aforementioned assays. Such a result is indicative of the intrinsic activity of the compounds as modulators of chemokine receptor activity. A general binding protocol is described below.
CCR3-Receptor Binding Protocol Millipore filter plates (#MABVN1250) are treated with 5 ~lg/ml protamine in phosphate buffered saline, pH 7.2, for ten minutes at room temperature. Plates are washed three times with phosphate buffered saline and incubated with phosphate buffered saline for thirty minutes at room temperature. For binding, 50 X11 of binding buffer (0.5~
bovine serum albumen, 20 mM HEPES buffer and 5 mM magnesium chloride in RPMI 1640 media) with or without a test concentration of a compound present at a known concentration is combined with 50 X11 of I25-I labeled human eotaxin (to give a final concentration of 150 pM
radioligand) and 50 ~1 of cell suspension in binding buffer containing 5x105 total cells. Cells used for such binding assays can include cell lines transfected with a gene expressing CCR3 such as that described by Daugherty et al.
(1996), isolated human eosinophils such as described by Hansel et al. (1991) or the AML14.3D10 cell line after differentiation with butyric acid as described by Tiffany et al. (1998). The mixture of compound, cells and radioligand are incubated at room temperature for thirty minutes. Plates are placed onto a vacuum manifold, vacuum applied, and plates washed three times with binding buffer with 0.5M NaCl added. The plastic skirt is removed from the plate, the plate allowed to air dry, the wells punch out and CPM counted. The percent inhibition of binding is calculated using the total count obtained in the absence of any competing compound or chemokine ligand and the background binding determined by addition of 100 nM eotaxin in place of the test compound.

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Claims (29)

What is Claimed is:
1. A compound of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
M is absent or selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
Q is selected from CHR13, CR13R13, and CR5R13;
J, K, and L are independently selected from CH2, CHR5, CHR6, CR6R6 and CR5R6;
with the provisos:
1) ate least one of M, J, K, L, or Q contains an R5;
and 2) when M is absent, J is selected from CH2, CHR5, CHR13, and CR5R13;
Z is selected from O, S, NR1a, CHCN, CHNO2, and C(CN)2;
R1a is selected from H, C1-6 alkyl, C3-6 cycloalkyl, CONR1b R1b, OR1b, NO2 , CN, and (CH2)w phenyl;
R1b is independently selected from H, C1-3 alkyl, C3-6 cycloalkyl, and phenyl;
E is -(CR7R8)-(CR9R10)v-(CR11R12)-;

R1 and R2 are independently selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-5 cycloalkyl, and a (CH2)r-C3-to carbocyclic residue substituted with 0-5 R a.
R a, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-s cycloalkyl, Cl, Br, I, F, (CF2)r CF3, NO2, CN, (CH2)r NR b R b, (CH2)r OH, (CH2)r OR c, (CH2)r SH, (CH2)r SR c, (CH2)r C(O)R b, (CH2)r C(O)NR b R b, (CH2)r NR b C(O)R b, (CH2)r C(O)OR b, (CH2)r OC(O)R c, (CH2)r CH(=NR b)NR b R b, (CH2)r NHC(=NR b)NR b R b, (CH2)r S(O)p R c, (CH2)r S(O)2NR b R b, (CH2)r NR b S(O)2R c, and (CH2)r phenyl;
R b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
alternatively, R2 and R3 join to form a 5, 6, or 7-membered ring substituted with 0-3 R a;
R3 is selected from a (CR3'R3")r-C3-10 carbocyclic residue substituted with 0-5 R15 and a (CR3'R3")r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
R3' and R3", at each occurrence, are selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, and phenyl;
R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CH2)q C(O)R4b, (CH2)q C(O)NR4aR4a' (CH2)q C(O)OR4b, and a (CH2)r-C3-10 carbocyclic residue substituted with 0-3 R4c;

R4a and R4a' , at each occurrence, are selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, and phenyl;
R4b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, (CH2)r C3-6 cycloalkyl, C2-8 alkynyl, and phenyl;
R4c , at each occurrence, is selected from C1-6- alkyl , C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, (CH2)r NR4aR4a', and (CH2)r phenyl;
alternatively, R4 joins with R7, R9, or R11 to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle substituted with 0-3 R a;
R5 is selected from a (CR5'R5")t-C3-10 carbocyclic residue substituted with 0-5 R16 and a (CR5'R5")t-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16;
R5' and R5", at each occurrence, are selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, and phenyl;
R6, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CF2)r CF3, CN, (CH2)r NR6a R6a', (CH2)r OH, (CH2)r OR6b, (CH2)r SH.
(CH2)r SR6b, (CH2)r C(O)OH, (CH2)r C(O)R6b, (CH2)r C(O)NR6a R6a', (CH2)r NR6d C(O)R6a, (CH2)r C(O)OR6b.
(CH2)r OC(O)R6b, (CH2)r S(O)p R6b, (CH2)r S(O)2NR6a R6a', (CH2)r NR6d S(O)2R6b, and (CH2)t phenyl substituted with 0-3 R6c;
R6a and R6a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c.

R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, and (CH2)r NR6d R6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
with the proviso that when any of J, K, or L is CR6R6 and R6 is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, the other R6 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R7, is selected from H, C1-6 alkyl, C2-* alkenyl, C2-8 alkynyl, (CH2)q OH, (CH2)q SH, (CH2)q OR7d, (CH2)q SR7d, (CH2)q NR7a R7a', (CH2)r C(O)OH, (CH2)r C(O)R7b, (CH2)r C(O)NR7a R7a', (CH2)q NR7a C(O)R7a, (CH2)q NR7a C(O)H, (CH2)r C(O)OR7b, (CH2)q OC(O)R7b, (CH2)q S(O)p R7b, (CH2)q S(O)2NR7a R7a', (CH2)q NR7a S(O)2R7b, C1-6 haloalkyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-3 R7c, and a (CH2)r-5-10 membered heterocyclic system containing 2-4 heteroatoms selected from N, O, and S, substituted with 0-2 R7c;
R7a and R7a', at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R7e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7e;
R7b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 R7e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7e;
R7c, at each occurrence, is selected from C1-6 alkyl, alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, (CF2)r CF3, NO2, CN, (CH2)r NR7f R7f, (CH2)r OH, (CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH, (CH2)r C(O)R7b, (CH2)r C(O)NR7f R7f, (CH2)r NR7f C(O)R7a, (CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R7b, (CH2)r C(=NR7f)NR7f R7f, (CH2)r S(O)p R7b, (CH2)r NHC(=NR7f)NR7f R7f, (CH2)r S(O)2NR7f R7f, (CH2)r NR7f S(O)2R7b, and (CH2)r phenyl substituted with 0-3 R7e;
R7d, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 Rye, alkenyl, alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R7c;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-alkyl, (CH2)r NR7f R7f, and (CH2)r phenyl;
R7f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R8 is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R8a;
R8a, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-5 alkyl, (CH2)r NR7f R7f, and (CH2)r phenyl;
alternatively, R7 and R8 join to form C3-7 cycloalkyl, or =NR8b;

R8b is selected from H, C1-6 alkyl, C3-6 cycloalkyl, OH, CN, and (CH2)r-phenyl;
R9, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, NO2, CN, (CH2)r OH, (CH2)r SH, (CH2)r OR9d, (CH2)r SR9d, (CH2)r NR9a R9a', (CH2)r C(O)OH, (CH2)r C(O)R9b, (CH2)r C(O)NR9a R9a', (CH2)r NR9a C(O)R9a, (CH2)r NR9a C(O)H, (CH2)r NR9a C(O)NHR9a, (CH2)r C(O)OR9b, (CH2)r OC(O)R9b, (CH2)r OC(O)NHR9a, (CH2)r S(O)p R9b, (CH2)r S(O)2NR9a R9a', (CH2)r NR9a S(O)2R9b, C1-6 haloalkyl, a (CH2)r-C3-to carbocyclic residue substituted with 0-5 R9c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c.
R9a and R9a', at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-to carbocyclic residue substituted with 0-5 R9e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
R9b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-5 carbocyclic residue substituted with 0-2 R9e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
R9c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-5 cycloalkyl, Cl, Br, I, F, (CF2)r CF3, NO2, CN, (CH2)r NR9f R9f, (CH2)r OH, (CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH, (CH2)r C(O)R9b, (CH2)r C(O)NR9f R9f, (CH2)r NR9f C(O)R9a, (CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R9b, (CH2)r C(=NR9f)NR9f R9f, (CH2)r S(O)p R9b, (CH2)r NHC(=NR9f)NR9f R9f, (CH2)r S(O)2NR9f R9f, (CH2)r NR9f S(O)2R9b, and (CH2)r phenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, a C3-10 carbocyclic residue substituted with 0-3 R9c, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R9c;
R9e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-5 alkyl, (CH2)r NR9f R9f, and (CH2)r phenyl;
R9f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R10, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, NO2, CN, (CH2)r OH, (CH2)r OR10d, (CH2)r SR10d, (CH2)r NR10a R10a', (CH2)r C(O)OH, (CH2)r C(p)R10b, (CH2)r C(O)NR10a R10a', (CH2)r NR10a C(O)R10a, (CH2)r NR10a C(O)H, (CH2)r C(O)OR10b, (CH2)r OC(O)R10b, (CH2)r S(O)p R10b, (CH2)r S(O)2NR10a R20a', (CH2)r NR10a S(O)2R10b, C1-6 haloalkyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R10c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10c;
R10a and R10a, at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R10e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;

R10b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3_6 carbocyclic residue substituted with 0-2 R10e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
R10c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, (CF2)r CF3, NO2, CN, (CH2)r NR10f R10f, (CH2)r OH, (CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH, (CH2)r C(O)R10b, (CH2)r C(O)NR10f R10f, (CH2)r NR10f C(O)R10a, (CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R10b, (CH2)r C(=NR10f)NR10f R10f, (CH2)r S(O)p R10b, (CH2)r NHC(=NR10f)NR10f R10f, (CH2)r S(O)2NR10f R10f, (CH2)r NR10f S(O)2R10b and (CH2)r phenyl substituted with 0-3 R10e;
R10d, at each occurrence, is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, a C3-10 carbocyclic residue substituted with 0-3 R10c, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R10c;
R10e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-5 alkyl, (CH2)r NR10f R10f, and (CH2)r phenyl;
R10f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
alternatively, R9 and R10 join to form C3-7 cycloalkyl, 5-6-membered cyclic ketal, or =O;
with the proviso that when R10 is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;.
R11, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)q OH, (CH2)q SH, (CH2)q OR11d, (CH2)q SR11d, (CH2)q NR11a R11a', (CH2)r C(O)OH, (CH2)r C(O)R11b, (CH2)r C(O)NR11a R11a', (CH2)q NR11a C(O)R11a, (CH2)q NR11a C(O)NHR11a, (CH2)r C(O)OR11b, (CH2)q OC(O)R11b, (CH2)q S(O)p R11b, (CH2)q S(O)2NR11a R11a', (CH2)q NR11a S(O)2R11b, C1-6 haloalkyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R11c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11c;
R11a and R11a', at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R11e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 R11e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, (CF2)r CF3, NO2, CN, (CH2)r NR11f R11f, (CH2)r OH, (CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH, (CH2)r C(O)R11b, (CH2)r C(O)NR11f R11f, (CH2)r NR11C(O)R11a, (CH2)r C(O)OC1-4 alkyl, (CH2)=OC(O)R11b, (CH2)r C(=NR11f)NR11f R11f, (CH2)r NHC(=NR11f)NR11f R11f, (CH2)r S(O)p R11b, (CH2)r S(O)2NR11f R11f, (CH2)r NR11S(O)2R11b and (CH2)r phenyl substituted with 0-3 R11e;
R11d, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 R11e C2-6 alkenyl, C2-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R11c;
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-alkyl, (CH2)r NR11f R11f, and (CH2)r phenyl;
R11f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R12 is selected from H, C1-6 alkyl, (CH2)q OH, (CH2)r C3-6 cycloalkyl, and (CH2)t phenyl substituted with 0-3 R12a;
R12a, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2. (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-5 alkyl, (CH2)r NR9f R9f, and (CH2)r phenyl;
alternatively, R11 and R12 join to form C3-7 cycloalkyl;
R13, at each occurrence, is selected from (CHR13a)OH, (CHR13a) OR13b, (CHR13a) SH, (CHR13a) SR13b, (CHR13a) NR13e C(O)R13f, and (CHR13a)NR13e S(O)2R13f;
R13a is selected from C1-7 alkyl;
R13b at each occurrence, is selected from C(O)R13d C(O)NHR13d, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;

R13c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl , OH, SH, (CH2)r SC1-alkyl, (CH2)r NR9f R9f, and (CH2)r phenyl;
R13d, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c.
R13e, at each occurrence, is selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, and phenyl where phenyl is substituted from 0-3 R13c R13f, at each occurrence, is selected from C1-6 alkyl, (CH2)r C3-6 cYcloalkyl, CF3, and phenyl where phenyl is substituted from 0-3 R13c;
R15, at each occurrence, is independently selected from C1-8 alkyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHR')r NR15a R15a', (CHR')r OH, (CHR')r O(CHR')r R15d, (CHR')r SH, (CHR')r C(O)H, (CHR')r S(CHR')r R15d, (CHR')Cr (O)OH, (CHR')r C(O)(CHR')r R15b, (CHR')r C(O)NR15a R15a', (CHR')r NR15f C(O)(CHR')r R15b, (CHR')r NR15f C(O)NR15f R15f, (CHR')r C(O)O(CHR')r R15d, (CHR')r OC(O)(CHR')r R15b, (CHR')r C(=NR15f)NR15a R15a, (CHR')r NHC(=NR15f)NR15f R15f, (CHR')r S(O)p(CHR')r R15b, (CHR')r S(O)2NR15a R15a', (CHR')r NR15f S(O)2(CHR')r R15b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 R', C2-8 alkynyl substituted with 0-3 R', (CHR')r phenyl substituted with 0-3 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R', at each occurrence, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, and (CH2)r phenyl substituted with R15e;

R15a and R15a', at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R15e and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e R15b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-3 R15e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15d, at each occurrence, is selected from C2-8 alkenyl, C2-8 alkynyl, C1-6 alkyl substituted with 0-3 R15e, a (CH2)r-C3-10 carbocyclic residue substituted with 0-3 R15e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15e;
R15e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-5 alkyl, (CH2)r NR15f R15f, and (CH2)r phenyl;
R15f, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R16, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHR')r NR16a R16a', (CHR')r OH, (CHR')r O(CHR')r R16d, (CHR')r SH, (CHR')r C(O)H, (CHR')r S(CHR')r R16d, (CHR')r C(O)OH, (CHR')r C(O)(CHR')r R16b, (CHR')r C(O)NR16a R16a', (CHR')r NR16f C(O)(CHR')r R16b, (CHR')r C(O)O(CHR')r R16d, (CHR')r OC(O)(CHR')r R16b, (CHR')r C(=NR16f)NR16a R16a', (CHR')r NHC(=NR16f)NR16f R16f, (CHR')r S(O)p (CHR')r R16b, (CHR')r S(O)2NR16a R16a', (CHR')r NR16f S(O)2(CHR')r R16b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 R', C2-8 alkynyl substituted with 0-3 R', and (CHR')r phenyl substituted with 0-3 R16e;
R16a and R16a', at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r -C3-10 carbocyclic residue substituted with 0-5 R16e, and a (CH~)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
R16b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r C3-6 carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
R16d, at each occurrence, is selected from C2-8 alkenyl, C2-8 alkynyl, C1-6 alkyl substituted with 0-3 R16e, a (CH2)r-C3-to carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16e;
R16e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-5 alkyl, (CH2)r NR16f R16f, and (CH2)r phenyl;
R16f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl, and phenyl;
v is selected from 0, 1, and 2;
t is selected from 1 and 2;

w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4, and 5;
q is selected from 1, 2, 3, 4, and 5; and p is selected from 0, 1, 2, and 3.
2. The compound of claim 1, wherein:
R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1-8 alkyl, (CH2)r C3-6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 R4c;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, (CH2)r NR4a R4a', and (CH2)r phenyl;
alternatively, R4 joins with R7, R9, or R11 to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle substituted with 0-3 R a;
R1 and R2 are independently selected from H and C1-4 alkyl;
R6, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CF2)r CF3, CN, (CH2)r OH, (CH2)r OR6b, (CH2)r C(O)R6b, (CH2)r C(O)NR6a R6a', (CH2)r NR6d C(O)R6a, and (CH2)t phenyl substituted with 0-3 R6c;
R6a and R6a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;

R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrences is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, and (CH2)r NR6d R6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R7, is selected from H, C1-3 alkyl, (CH2)r C3-6 cycloalkyl, (CH2)q OH, (CH2)q OR7d. (CH2)q NR7a R7a', (CH2)r C(O)R7b, (CH2)r C(O)NR7aR7a', (CH2)q NR7a C(O)R7a, C1-6 haloalkyl, (CH2)r phenyl with 0-2 R7c;
R7a and R7a, at each occurrence, are selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, a (CH2)r phenyl substituted with 0-3 R7e;
R7b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CH2)r phenyl substituted with 0-3 R7e;
R7c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, (CF2)r CF3, NO2, CN, (CH2)r NR7f R7f, (CH2)r OH, (CH2) r OC1-4 alkyl, (CH2)r C (O) R7b, (CH2)r C(O)NR7f R7f (CH2)r NR7f C(O)R7a, (CH2)r S(O)p R7b. (CH2)r S(O)2NR7f R7f, (CH2)r NR7f S(O)2R7b, and (CH2)r phenyl substituted with 0-2 R7e;
R7d, at each occurrence, is selected from C1-6 alkyl, (CH2)r C3-6 cycloalkyl, (CH2)r phenyl substituted with 0-3 R7e.
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-alkyl, (CH2)r NR7f R7f, and (CH2)r phenyl;
R7f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl;
R8 is H or joins with R7 to form C3-7 cycloalkyl or =NR8b;
R11, is selected from H, C1-6 alkyl, (CH2)r C3-5 cycloalkyl, (CH2)q OH, (CH2)q OR11d, (CH2)q NR11a R11a', (CH2)r C(O)R11b, (CH2)r C(O)NR11a R11a', (CH2)q NR11a C(O)R11a, C1-6 haloalkyl, (CH2)r phenyl with 0-2 R11c, (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
R11a and R11a', at each occurrence, are selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, a (CH2)r phenyl substituted with 0-3 R11e;
R11b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CH2)r phenyl substituted with 0-3 R11e R11c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, (CF2)r CF3, NO2. CN, (CH2)r NR11f R11f, (CH2)r OH, (CH2)r OC1-4 alkyl, (CH2)r C(O)R11b, (CH2)r C(O)NR11f R11f, (CH2)r NR11f C(O)R11a, (CH2)r S(O)p R11b, (CH2)r S(O)2NR11f R11f, (CH2)r NR11f S(O)2R11b, and (CH2)r phenyl substituted with 0-2 R11e;
R11d, at each occurrence, is selected from C1-6 alkyl, (CH2)r C3-6 cycloalkyl, (CH2)r phenyl substituted with 0-3 R11e;
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)=CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-alkyl, (CH2)r NR11f R11f, and (CH2)r phenyl;
R11f, at each occurrence, is selected from H, C1-5 alkyl and C3-6 cycloalkyl;
R12 is H or joins with R11 to form C3-7 cycloalkyl;
v is selected from 1 and 2;
q is selected from 1, 2, and 3; and r is selected from 0, 1, 2, and 3.
3. The compound of claim 2, wherein:
R3 is selected from a (CR3'H)r-carbocyclic residue substituted with 0-5 R15, wherein the carbocyclic residue is selected from phenyl, C3-6 cycloalkyl, naphthyl, and adamantyl; and a (CR3'H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazalyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R5 is selected from (CR5'H)t-phenyl substituted with 0-5 R16; and a (CR5'H)t-heterocyclic system substituted with 0-3 R16, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
4. The compound of claim 3, wherein the compound of formula (I) is:
;
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)r NR16a R16a', NO2, CN, OH, (CH2)r OR16d, (CH2)r C(O)R16b, (CH2)r C(O)NR16a R16a', (CH2)r NR16f C(O)R16b, (CH2)r S(O)p R16b, (CH2)r S(O)2NR16a R16a', (CH2)r NR16f S(O)2R16b, and (CH2)r phenyl substituted with 0-3 R16e;
R16a and R16a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R16e.
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and R16f, at each occurrence, is selected from H, and C1-5 alkyl.
5. The compound of claim 3, wherein the compound formula (I) is:
;
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)r NR16a R16a', NO2, CN, OH, (CH2)r OR16d, (CH2)r C(O)R16b, (CH2)r C(O)NR16a R16a', (CH2)r NR16f C(O)R16b (CH2)r S(O)p R16b, (CH2)r S(O)2NR16a R16a', (CH2)r NR16f S(O)2R16b, and (CH2)r phenyl substituted with 0-3 R16e;
R16a and R16a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R16e R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and R16f, at each occurrence, is selected from H, and C1-5 alkyl.
6. The compound of claim 4, wherein:
R5 is CH2phenyl substituted with 0-3 R16;
E is -CH2-(CR9R10)-(CR11R12);

R9, is selected from H, C1-6 alkyl, (CH2)r C3-5 cycloalkyl, F, Cl, CN, (CH2)r OH, (CH2)r OR9d, (CH2)r NR9a R9a', (CH2)r OC(O)NHR9a, (CH2)r phenyl substituted with 0-5 R9e, and a heterocyclic system substituted with 0-2 R9e, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R9e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
R10 is selected from H, C1-5 alkyl, OH, and CH2OH;
alternatively, R9 and R10 join to form C3-7 cycloalkyl, 5-6-membered cyclic ketal or =O;
with the proviso that when R10 is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R11 is selected from H, C1-8 alkyl, (CH2)r phenyl substituted with 0-5 R11e, and a (CH2)r-heterocyclic system substituted with 0-2 R11e, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazalyl, pyrazinyl, and pyrimidinyl; and R11e at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
R12 is H;
alternatively, R11 and R12 join to form C3-7 cycloalkyl; and r is selected from 0, 1, and 2.
7. The compound of claim 5, wherein:
R5 is CH2phenyl substituted with 0-3 R16;
E is -CH2- (CR9R10) - (CR11R12);
R9, is selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, F, Cl, CN, (CH2)r OH, (CH2)r OR9d, (CH2)r NR9a R9a', (CH2)r OC(O)NHR9a, (CH2)r phenyl substituted with 0-5 R9e, and a heterocyclic system substituted with 0-2 R9e wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R9e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
R10 is selected from H, C1-8 alkyl, OH, and CH2OH;

alternatively, R9 and R10 join to form C3-7 cycloalkyl, 5-6-membered cyclic ketal or =O;
with the proviso that when R10 is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R11 is selected from H, C1-8 alkyl, (CH2)r phenyl substituted with 0-5 R11e, and a (CH2)r-heterocyclic system substituted with 0-2 R11e, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R11e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
R12 is H;
alternatively, R11 and R12 join to form C3-7 cycloalkyl; and r is selected from 0, 1, and 2.
8. The compound of claim 6, wherein:
J is selected from CH2 and CHR5;
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;

R3 is a C3-to carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3'H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R15, at each occurrence, is selected from C1-8 alkyl, (CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)r NR15a R15a', NO2, CN, OH, (CH2)r OR15d, (CH2)r C(O)R15b, (CH2)r C(O)NR15a R15a', (CH2)r NR15f C(O)R15b, (CH2)r S(O)p R15b, (CH2)r S(O)2NR15a R15a', (CH2)r NR15f S(O)2R15b, (CH2)r phenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15a and R15a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and phenyl;

R15e at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and R15f, at each occurrence, is selected from H, and C1-5 alkyl.
9. The compound of claim 7, wherein:
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3'H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R15, at each occurrence, is selected from C1-8 alkyl, (CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)r NR15a R15a', NO2, CN, OH, (CH2)r OR15d, (CH2)r C(O)R15b, (CH2)r C(O)NR15a R15a', (CH2)r NR15f C(O)R15b, (CH2)r S(O)p R15b, (CH2)r S(O)2NR15a R15a', (CH2)r NR15f S(O)2R15b, (CH2)r phenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;

R15a and R15a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and R15f, at each occurrence, is selected from H, and C1-5 alkyl.
10. The compound of claim 9, wherein:
R13a is selected from H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isobutyl, isopentyl and isohexyl.
11. The compound of claim 1 and pharmaceutically acceptable salt forms thereof, wherein the compound of formula (I) is selected from:
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl)-4-benzyl-.alpha.-methyl-2-piperidinemethanol;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl)-4-benzyl-.alpha.-ethyl-2-piperidinemethanol;
erythro-cis-1-(3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl)-4-benzyl-.alpha.-(n-prop-1-yl)-2-piperidinemethanol;

erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-.alpha.-(n-but-1-yl)-2-piperidinemethanol;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-.alpha.-(n-prop-2-yl)-2-piperidinemethanol;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-.alpha.-(3-methyl-n-prop-1-yl)-2-piperidinemethanol;
(+)-erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-.alpha.-(n-but-1-yl)-2-piperidinemethanol;
erythro-cis-1-[3-(indazol-5-yl)aminocarbonylamino)-n-prop-1-yl]-4-benzyl-.alpha.-(n-but-1-yl)-2-piperidinemethanol;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-2-[1-(3-acetylphenylaminocarbonyloxy)-n-prop-1-yl]-4-benzylpiperidine;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-2-[1-(3-acetylphenylaminocarbonyloxy)-n-but-1-yl]-4-benzylpiperidine;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-2-[1-(3-acetylphenylaminocarbonyloxy)-n-pent-1-yl]-4-benzylpiperidine;
erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl}-2-[1-(3-acetylphenylaminocarbonyloxy)-2-methyl-n-prop-1-yl]-4-benzylpiperidine; and erythro-cis-1-[3-(3-acetylphenylaminocarbonylamino)-n-prop-1-yl]-2-[1-(3-acetylphenylaminocarbonyloxy)-3-methyl-n-but-1-yl]-4-benzylpiperidine.
12. A compound of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
M is absent or selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
Q is selected from CHR13, CR13R13, and CR5R13;
J, K, and L are independently selected from CH2, CHR5, CHR6, CR6R6 and CR5R6;
with the provisos:
1) at least one of M, J, K, L, or Q contains an R5;
and 2) when M is absent, J is selected from CH2, CHR5, CHR13, and CR5R13;
Z is selected from O, S, NR1a, CHCN, CHNO2, and C(CN)2;
R1a is selected from H, C1-6 alkyl, C3-6 cycloalkyl, CONR1b R1b, OR1b, NO2, CN, and (C2)w phenyl;
R1b is independently selected from H, C1-3 alkyl, C3-6 cycloalkyl, and phenyl;
E is selected from:

ring A is a C3-6 carbocyclic residue;
with the proviso that when A is phenyl, R14 is not ortho to CR7R8;
R1 and R2 are independently selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, and a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R a:
R a, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, C1, Br, I, F, (CF2)r CF3. NO2, CN, (CH2)r NR b R b, (CH2)r OH, (CH2)r OR c, (CH2)r SH, (CH2)r SR c, (CH2)r C(O)R b, (CH2)r C(O)NR b R b, (CH2)r NR b C(O)R b, (CH2)r C (O)R b, (CH2)r OC (O) R c, (CH2)r CH (=NR b)NR b R b, (CH2)r NHC (=NR b)NR b R b, (CH2)r S (O)p R c, (CH2)r S(O)2NR b R b, (CH2)r NR b S(O)2R c, and (CH2)r phenyl;

R b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl R c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
alternatively, R2 and R3 join to form a 5, 6, or 7-membered ring substituted with 0-3 R a;
R3 is selected from a (CR3'R3")r-C3-10 carbocyclic residue substituted with 0-5 R15 and a (CR3'R3")r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
R3' and R3", at each occurrence, are selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, and phenyl;
R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CH2)q C(O)R4b, (CH2)q C(O)NR4a R4a' (CH2)q C(O)OR4b, and a (CH2)r-C3-10 carbocyclic residue substituted with 0-3 R4c;
R4a and R4a', at each occurrence, are selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, and phenyl;
R4b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, (CH2)r C3-6 cycloalkyl, C2-8 alkynyl, and phenyl;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, (CH2)r NR4a R4a', and (CH2)r phenyl;

alternatively, R4 joins with R7, R9, or R11 to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle substituted with 0-3 R a;
R5 is selected from a (CR5'R5")t-C3-10 carbocyclic residue substituted with 0-5 R16 and a (CR5'R5")t-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16;
R5' and R5", at each occurrence, are selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, and phenyl;
R6, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CF2)r CF3, CN, (CH2)r NR6a R6a', (CH2)r OH, (CH2)r OR 6b, (CH2)r SH, (CH2)r SR6b, (CH2)r C(O)OH, (CH2)r C(O)R6b, (CH2)r C(O)NR6a R6a', (CH2)r NR6d C(O)R6a, (CH2)r C(O)OR6b, (CH2)r OC(O)R6b, (CH2 )r S(O)p R6b, (CH2)r S(O)2NR6a R6a', (CH2)r NR6d S(O)2R6b, and (CH2)t phenyl substituted with 0-3 R6c;
R6a and R6a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, C1, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1_ alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, and (CH2)r NR6d R6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-5 cycloalkyl;
with the proviso that when any of J, K, or L is CR6 R6 and R6 is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, the other R6 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R7, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)q OH, (CH2)q SH, (CH2)q OR7d, (CH2)q SR7d, (CH2)q NR7a R7a' , (CH2)r C(O)OH, (CH2)r C(O) R7b (CH2)r C(O)NR7a R7a', (CH2)q NR7a C(O)R7a, (CH2)q NR7a C(O)H.
(CH2)r C(O)OR7b (CH2)q OC(O)R7b, (CH2)q S(p)p R7b, (CH2)q S(O)2NR7a R7a', (CH2)q NR7a S(O)2R7b. C1-6 haloalkyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-3 R7c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R7c;
R7a and R7a', at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R7e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7e;
R7b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 R7e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7e;
R7c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, C1, Br, I, F, (CF2)r CF3, NO2, CN, (CH2)r NR7f R7f, (CH2)r OH, (CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH, (CH2)r C(O)R7b. (CH2)r C(O)NR7fR7f, (CH2)r NR7fC(O)R7a, (CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R7b, (CH2)r C(=NR7f)NR7fR7f, (CH2)r S(O)p R7b, (CH2)r NHC(=NR7f)NR7f R7E, (CH2)r S(O)2NR7f R7f (CH2)r NR7f S(O)2R7b, and (CH2)r phenyl substituted with 0-3 R7e;
R7d, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 R7e, alkenyl, alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R7c;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-alkyl, (CH2)r NR7f R7f, and (CH2)r phenyl;
R7f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R8 is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)t phenyl substituted with 0-3 R8a;
R8a, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-5 alkyl, (CH2)r NR7fR7f, and (CH2)r phenyl;
alternatively, R7 and R8 join to form C3-7 cycloalkyl, or =NR8b;
R8b is selected from H, C1-6 alkyl, C3-6 cycloalkyl, OH, CN, and (CH2)r-phenyl;
R9, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, C1, Br, I, NO2, CN, (CH2)r OH, (CH2)r SH, (CH2)r OR9d, (CH2)r SR9d, (CH2)r NR9a R9a', (CH2)r C(O)OH, (CH2)r C(O)R9b, (CH2)r C(O)NR9a R9a', (CH2)r NR9a C(O)R9a, (CH2)r NR9a C(O)H, (CH2)r NR9a C(O)NHR9a, (CH2)r C(O)OR9b, (CH2)r OC(O)R9b, (CH2)r OC(O)NHR9a, (CH2)r S(O)p R9b, (CH2)r S(O)2NR9a R9a', (CH2)r NR9a S(O)2R9b, C1-6 haloalkyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R9c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c;
R9a and R9a', at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C1-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R9e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
R9b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 R9e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
R9c, at each occurrence, is selected from C2-6 alkyl, alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, (CF2)r CF3, NO2, CN, (CH2)r NR9f R9f, (CH2)r OH, (CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH, (CH2)r C(O)R9b, (CH2)r C(O)NR9f R9f, (CH2)r NR9f C(O)R9a, (CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R9b, (CH2)r C(=NR9f)NR9f R9f, (CH2)r S(O)p R9b, (CH2)r NHC(=NR9f)NR9f R9f, (CH2)r S(O)2NR9f R9f, (CH2)r NR9f S(O)2R9b, and (CH2)r phenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, a C3-10 carbocyclic residue substituted with 0-3 R9c, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, 0, and S
substituted with 0-3 R9c;

R9e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-5 alkyl, (CH2)r NR9f R9f, and (CH2)r phenyl;
R9f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R10, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, NO2, CN, (CH2)r OH, (CH2)r OR10d.
(CH2)r SR10d. (CH2)r NR10aR10a', (CH2)r C(O)OH, (CH2)r C(O)R10b, (CH2)r C(O)NR10a R10a', (CH2)r NR10aC(O)R10a, (CH2)r NR10a C(O)H, (CH2)r C(O)OR10b, (CH2)r OC(O)R10b.
(CH2)r S(O)p R10b, (CH2)r S(O)2NR10a R10a'.
(CH2)r NR10a S(O)2R10b, C1-6 haloalkyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R10c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 R10c;
R10a and R10a', at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R10e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
R10b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 R10e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e R10c. at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, (CF2)r CF3. NO2, CN, (CH2)r NR10f R10f, (CH2)r OH, (CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH, (CH2)r C(O)R10b, (CH2)r C(O)NR10f R10f, (CH2)r NR10f C(O)R10a, (CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R10b, (CH2)r C(=NR10f)NR10f R10f, (CH2)r S(O)p R10b, (CH2)r NHC(=NR10f)10f R10f, (CH2)r S(O)2NR10f R10f, (CH2)r NR10f S(O)2R10b and (CH2)r phenyl substituted with 0-3 R10e;
R10d, at each occurrence, is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, a C3-10 carbocyclic residue substituted with 0-3 R10c, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R10c R10e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-5 alkyl, (CH2)r NR10f R10f, and (CH2)r phenyl;
R10f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl;
alternatively, R9 and R10 join to form C3-7 cycloalkyl, 5-6-membered cyclic ketal or =O;
with the proviso that when R10 is -OH, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R11, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)q OH, (CH2)q SH, (CH2)q OR11d, (CH2)q SR11d, (CH2)q NR11a R11a', (CH2)r C(O)OH, (CH2)r C(O)R11b, (CH2)r C(O)NR11a R11a', (CH2)q NRa C(O)R11a, (CH2)q NR11a C(O)NHR11a', (CH2)r C(O)OR11b, (CH2)q OC(O)R11b, (CH2)q S(O)p R11b, (CH2)q S(O)2NR11a R11a', (CH2)q NR11a S(O)2R11b, C1-6 haloalkyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R11c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11c;
R11a and R11a', at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R11e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e R11b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 R11e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e.
R11c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, (CF2)r CF3. NO2. CN, (CH2)r NR11f R11f, (CH2)r OH, (CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH, (CH2)r C(O)R11b, (CH2)r C(O)NR11f R11f, (CH2)r NR11f C(O)R11a, (CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R11b, (CH2)r C(=NR11f)NR1f R11f, (CH2)r NHC(=NR11f)NR11f R11f, (CH2)r S(O)p R11b, (CH2)r S(O)2NR11f R11f, (CH2)r NR11f S(O)2R11b, and (CH2)r phenyl substituted with 0-3 R11e;
R11d, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 R11e, C2-6 alkenyl, C2-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R11c;
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-alkyl, (CH2)r NR11f R11f, and (CH2)r phenyl;

R11f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R12 is selected from H, C1-6 alkyl, (CH2)q OH, (CH2)r C3-6 cycloalkyl, and (CH2)t phenyl substituted with 0-3 R12a;
R12a, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3; (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-alkyl, (CH2)r NR9f R9f, and (CH2)r phenyl;
alternatively, R11 and R12 join to form C3-7 cycloalkyl;
R13, at each occurrence, is selected from (CHR13a) OH, (CHR13a)OR13b, (CHR13a)SH, (CHR13a)SR13b, (CHR13a)NR13e C(O)R13f, and (CHR13a)NR13e S(O)2R13f;
R13a is selected from C1-7 alkyl:
R13b, at each occurrence, is selected from C(O)R13d, C(O)NHR13d, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-alkyl, (CH2)r NR9f R9f, and (CH2)r phenyl;
R13d, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c R13e, at each occurrence, is selected from H, C1-6 alkyl, (CH2)r C3-s cycloalkyl, and phenyl where phenyl is substituted from 0-3 R13c;

R13f, at each occurrence, is selected from C1-6 alkyl, (CH2)r C3-5 cycloalkyl, CF3, and phenyl where phenyl is substituted from 0-3 R13c;
alternatively, R14 joins with R4 to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle fused to ring A, the spirocycle substituted with 0-3 R a;
R14, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHR')r NR14a R14a', (CHR')r OH, (CHR')r O(CHR')r R14d, (CHR')r SH, (CHR')r C(O)H, (CHR')r S(CHR')r R14d, (CHR')r C(O)OH, (CHR')r C(O)(CHR')r R14b, (CHR')r C(O)NR14a R14a', (CHR')r NR14f C(O)(CHR')r R14b, (CHR')r C(O)O(CHR')r R14d', (CHR')r OC(O)(CHR')r R14b, (CHR')r C(=NR14f)NR14a R14a', (CHR')r NHC (=NR14f)NR14f R14f, (CHR')r S(O)p(CHR')r R14b, (CHR')r S(O)2NR14a R14a', (CHR')r NR14f S(O)2(CHR')r R14b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 R', C2-8 alkynyl substituted with 0-3 R', (CHR')r phenyl substituted with 0-3 R14e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R', at each occurrence, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, and (CH2)r phenyl substituted with R14e;
R14a and R14a', at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R14e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14e;

R14b~ at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-3 R14e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14e;
R14d, at each occurrence, is selected from C2-8 alkenyl, C2-8 alkynyl, C1-6 alkyl substituted with 0-3 R14e, a (CH2)r-C3-10 carbocyclic residue substituted with 0-3 R14e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R14e;
R14e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl. OH, SH, (CH2)r SC1-5 alkyl, (CH2)r NR14f R14f, and (CH2)r phenyl;
R14f, at each occurrence, is selected from H, C1-6 alkyl, C3-6cycloalkyl, and phenyl;
R15, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-s cycloalkyl, Cl, Br, I, F, NO2, CN, (CHR')r NR15a R15a', (CHR')r OH, (CHR')r O(CHR')r R15d, (CHR')r SH, (CHR')r C(O)H, (CHR')r S(CHR')r R15d, (CHR')r C(O)OH, (CHR')r C(O)(CHR')r R15b, (CHR')r C(O)NR15a R15a', (CHR')r NR15f C(O)(CHR')r R15b, (CHR')r C(O)O(CHR')r R15d, (CHR')r OC(O)(CHR')r R15b, (CHR')r C(O)NR15a R15a', (CHR')r C (=NR15f) NR15a R15a', (CHR)r NHC(=NR15f)NR15f R1 5f, (CHR')r S(O)p(CHR')r R15b, (CHR')r S(O)2NR15a R15a', (CHR')r NR15f S(O)2(CHR')r R15b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 R', C2-8 alkynyl substituted with 0-3 R', (CHR')r phenyl substituted with 0-3 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;

R15a and R15a', at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-3 R15e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15d, at each occurrence, is selected from C2-8 alkenyl, C2-8 alkynyl, C1-6 alkyl substituted with 0-3 R15e a (CH2)r-C3-10 carbocyclic residue substituted with 0-3 R15e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15e.
R15e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-5 alkyl, (CH2)r NR15f R15f, and (CH2)r phenyl;
R15f, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R16, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHR')r NR16a R16a', (CHR')r OH, (CHR')r O(CHR')r R16d, (CHR')r SH, (CHR)r C(O)H, (CHR')r S(CHR')r R16d, (CHR')r C(O)OH, (CHR')r C(O)(CHR')r R16b, (CHR')r C(O)NR16a R16a', (CHR')r NR16f C(O)(CHR')r R16b, (CHR')r C(O)O(CHR')r R16d, (CHR')r OC(O)(CHR')r R16b, (CHR')r C(=NR16f)NR16a R16a', (CHR')r NHC(=NR16f)NR16f R16f, (CHR')r S(O)p(CHR')r R16b, (CHR')r S(O)2NR16a R16a', (CHR')r NR16f S(O)2(CHR')r R16b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 R', C2-8 alkynyl substituted with 0-3 R', and (CHR')r phenyl substituted with 0-3 R16e;
R16a and R16a', at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2) r-C3-to carbocyclic residue substituted with 0-5 R16e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
R16b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r C3-6 carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
R16d, at each occurrence, is selected from C2-8 alkenyl, C2-8 alkynyl, C1-6 alkyl substituted with 0-3 R16e, a (CH2)r-C3-10 carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16e;
R16e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-5 alkyl, (CH2)r NR16f R16f, and (CH2)r phenyl;
R16f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl, and phenyl;
g is selected from 0, 1, 2, 3, and 4;
v is selected from 0, 1, and 2;

t is selected from 1 and 2;
w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4, and 5;
q is selected from 1, 2, 3, 4, and 5; and p is selected from 1, 2, and 3.
13. The compound of claim 12, wherein:
E is selected from:
R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1-8 alkyl, (CH2)r C3-6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 R4c;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, (CH2)r NR4a R4a', and (CH2)r phenyl;
alternatively, R4 joins with R7 or R9 to form a 5, 6 or 7 membered piperidinium spirocycle substituted with 0-3 R a;0 R1 and R2 are independently selected from H and C1-4 alkyl;
R6, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CF2)r CF3, CN, (CH2)r OH, (CH2)r OR6b, (CH2)r C(O)R6b, (CH2)r C(O)NR6a R6a', (CH2)r NR6d C(O)R6a, and (CH2)t phenyl substituted with 0-3 R6c;
R6a and R6a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c R6c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, and (CH2)r NR6d R6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R7, is selected from H, C1-3 alkyl, (CH2)r C3-6 cycloalkyl, (CH2)q OH, (CH2)q OR7d, (CH2)q NR7a R7a', (CH2)r C(O)R7b, (CH2)r C(O)NR7a R7a', (CH2)q NR7a C(O)R7a, C1-6 haloalkyl, (CH2)r phenyl with 0-2 R7c;
R7a and R7a', at each occurrence, are selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, a (CH2)r phenyl substituted with 0-3 R7e;

R7b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CH2)r phenyl substituted with 0-3 R7e;
R7c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, (CF2)r CF3, NO2. CN, (CH2)r NR7f R7f, (CH2)r OH, (CH2)r OC1-4 alkyl, (CH2)r C(O)R7b, (CH2)r C(O)NR7f R7f, (CH2)r NR7f C(O)R7a, (CH2)r S(O)p R7b, (CH2)r S(O)2NR7f R7f, (CH2)r NR7f S(O)2R7b, and (CH2)r phenyl substituted with 0-2 R7e;
R7d, at each occurrence, is selected from C1-6 alkyl, (CH2)r C3-6 cycloalkyl, (CH2)r phenyl Substituted with 0-3 R7e;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-alkyl. (CH2)r NR7f R7f, and (CH2)r phenyl;
R7f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl;
R8 is H or joins with R7 to form C3-7 cycloalkyl or =NR8b;
R11, is selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, (CH2)q OH, (CH2)q OR11d, (CH2)q NR11a R11a', (CH2)r C(O)R11b, (CH2)r C(O)NR11a R11a', (CH2)q NR11a C(O)R11a, C1-6 haloalkyl, (CH2)r phenyl with 0-2 R11c, (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
R11a and R11a', at each occurrence, are selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, a (CH2)r phenyl substituted with 0-3 R11e;

R11b at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CH2)r phenyl substituted with 0-3 R11e R11c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I, F, (CF2)r CF3, NO2, CN, (CH2)r NR11f R11f, (CH2)r OH, (CH2)r OC1-4 alkyl, (CH2)r C(O)R11b, (CH2)r C(O)NR11f R11f, (CH2)r NR11f C(0)R11a, (CH2)r S(O)p R11b, (CH2)r S(O)2NR11f R11f, (CH2)r NR11f S(O)2R11b, and (CH2)r phenyl substituted with 0-2 R11e;
R11d, at each occurrence, is selected from C1-6 alkyl, (CH2)r C3-6 cycloalkyl, (CH2)r phenyl substituted with 0-3 R11e;
R11e, at each occurrence, is selected from C1-6 alkyl, C:2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-alkyl, (CH2)r NR11f R11f, and (CH2)r phenyl;
R11f, at each occurrence, is selected from H, C1-5 alkyl. and C3-6 cycloalkyl;
R12 is H or joins with R11 to form C3-7 cycloalkyl;
v is selected from 1 and 2;
q is selected from 1, 2, and 3; and r is selected from 0, 1, 2, and 3.
14. The compound of claim 13, wherein:
ring A is selected from:

R3 is selected from a (CR3'H)r-carbocyclic residue substituted with 0-5 R15, wherein the carbocyclic residue is selected from phenyl, C3-6 cycloalkyl, naphthyl, and adamantyl; and a (CR3'H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R5 is selected from (CR5'H)t-phenyl substituted with 0-5 R16; and a (CR5'H)t-heterocyclic system substituted with 0-3 R16, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
15. The compound of claim 14, wherein the compound of formula (I) is:

R16, at each occurrence, is selected from C1-8 alkyl, (CH2)r C3-6 cycloalkyl, CF3, C1, Br, I, F, (CH2)r NR16a R16a', NO2, CN, OH, (CH2)r OR16d, (CH2)r C(O)R16b, (CH2)r C(O)NR16a R16a'. (CH2)r NR16f C(O)r16b, (CH2)r S(O)p R16b, (CH2)r S(O)2NR16a R16a'.
(CH2)r NR16f S(O)2R16b, and (CH2)r phenyl substituted with 0-3 R16e;
R16a and R16a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, C1, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and R16f, at each occurrence, is selected from H, and C1-5 alkyl.
16. The compound of claim 14, wherein the compound of formula (I) is:

R16, at each occurrence, is selected from C1-8 alkyl, (CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)r NR16a R16a', NO2 CN, OH, (CH2)r OR16d, (CH2)r C(O)r16b, (CH2)r C(O)NR16a R16a'. (CH2)r NR16f C(O)r16b, (CH2)r S(O)p R16b, (CH2)r S(O)2NR16a R16a', (CH2)r NR16f S(O)2R16b, and (CH2)r phenyl substituted with 0-3 R16e;
R16a and R16a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R16e.
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and R16f, at each occurrence, is selected from H, and C1-5 alkyl.
17. The compound of claim 15, wherein:
R5 is CH2phenyl substituted with 0-3 R16;
R9, is selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, F, Cl, CN, (CH2)r OH, (CH2)r OR9d, (CH2)r NR9a R9a'.
(CH2)r OC(O)NHR9a, (CH2)r phenyl substituted with 0-5 R9e, and a heterocyclic system substituted with 0-2 R9e, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R9e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
R10 is selected from H, C1-5 alkyl, OH, and CH2OH;
alternatively, R9 and R10 join to form C3-7 cycloalkyl, 5-6-membered cyclic ketal or =O;
with the proviso that. when R10 is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R11 is selected from H, C1-8 alkyl, (CH2)r phenyl substituted with 0-5 R11e, and a (CH2)r-heterocyclic system substituted with 0-2 R11e, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R11e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;

R12 is H;
alternatively, R11 and R12 join to form C3-7 cycloalkyl;
R14, at each occurrence, is selected from C1-8 alkyl, (CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)r NR14a R14a'. NO2, CN, OH, (CH2)r OR14d.
(CH2)r C(O)r14b. (CH2)r C(O)NR14a R14a', (CH2)r NR14f C(O)r14b.
(CH2)r S(O)p R14b. (CH2)r S(O)2NR14a R14a'.
(CH2)r NR14f S(O)2R14b. (CH2)r phenyl substituted with 0-3 R14e. and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R14a and R14a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R14e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R14b. at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R14e;
R14d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R14e. at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and R14f, at each occurrence, is selected from H, and C1-5 alkyl;
and r is selected from 0, 1, and 2.
18. The compound of claim 16, wherein:
R5 is CH2phenyl substituted with 0-3 R16;
R9, is selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, F, Cl, CN, (CH2)r OH, (CH2)r OR9d. (CH2)=NR9a R9a', (CH2)r OC(O)NHR9a, (CH2)r phenyl substituted with 0-5 R9e, and a heterocyclic system substituted with 0-2 R9e, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R9e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
R10 is selected from H, C1-8 alkyl, OH, and CH2OH;
alternatively, R9 and R10 join to form C3-7 cycloalkyl, 5-6-membered cyclic ketal or =O;
with the proviso that when R10 is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R11 is selected from H, C1-8 alkyl, (CH2)r phenyl substituted with 0-5 R11e, and a (CH2)r-heterocyclic system substituted with 0-2 R11e, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R11e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
R12 is H;
alternatively, R11 and R12 join to form C3-7 cycloalkyl;
R14, at each occurrence, is selected from C1-8 alkyl, (CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)r NR14a R19a', NO2, CN, OH, (CH2)r OR14d, (CH2)r C(O)r14b, (CH2)r C(O)NR14a R14a', (CH2)r NR14f C(O)r14b, (CH2)r S(O)p R14b, (CH2)r S(O)2NR14a R14a', (CH2)r NR14f S(O)2R14b, (CH2)r phenyl substituted with 0-3 R14e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R14a and R14a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R14e;
R14b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R14e;
R14d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R14e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;

R14f at each occurrence, is selected from H, and C1-5 alkyl;
and r is selected from 0, 1, and 2.
19. The compound of claim 17, wherein:
J is selected from CH2 and CHR5;
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3'H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R15, at each occurrence, is selected from C1-8 alkyl, (CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)r NR15a R15a', NO2, CN, OH, (CH2)r OR15d, (CH2)r C(O)R15b, (CH2)r C(O)NR15a R15a'. (CH2)r NR15f C(O)R15b, (CH2)r S(O)p R15b, (CH2)r S(O)2NR15a R15a', (CH2)r NR15f S(O)2R15b, (CH2)r phenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;

R15a and R15a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R15e.
R15d at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and R15f, at each occurrence, is selected from H, and C1-5 alkyl.
20. The compound of claim 18, wherein:
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3'H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R15, at each occurrence, is selected from C1-8 alkyl, (CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)r NR15a R15a', NO2, CN, OH, (CH2)r OR15d, (CH2)r C(O)r 15b, (CH2)r C(O)NR15a R15a', (CH2)r NR15f C(O)r15b, (CH2)r S(O)p R15b, (CH2)r S(O)2NR15a R15a', (CH2)r NR15f S(O)2R15b, and (CH2)r phenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic :system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15a and R15a', at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3 R15e;
R15d at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and R15f, at each occurrence, is selected from H and C1-5 alkyl.
21. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1-20.
22. A method for modulation of chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1-20.
23. A method for treating or preventing inflammatory diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1-20.
24. A method for treating or preventing asthma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1-20.
25. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 12.
26. A method for modulation of chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 12.
27. A method for treating or preventing inflammatory diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 12.
28. A method for treating or preventing asthma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 12.
29. A method for treating or preventing disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1-20, said disorders being selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplantation, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, eosinophilic: gastroenteritis, drug induced eosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin's disease, and colonic carcinoma.
CA002346933A 1998-12-18 1999-12-17 N-ureidoalkyl-piperidines as modulators of chemokine receptor activity Abandoned CA2346933A1 (en)

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