CA2187932A1 - Substituted sulfonamides as selective .beta.3 agonists for the treatment of diabetes and obesity - Google Patents

Substituted sulfonamides as selective .beta.3 agonists for the treatment of diabetes and obesity

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Publication number
CA2187932A1
CA2187932A1 CA002187932A CA2187932A CA2187932A1 CA 2187932 A1 CA2187932 A1 CA 2187932A1 CA 002187932 A CA002187932 A CA 002187932A CA 2187932 A CA2187932 A CA 2187932A CA 2187932 A1 CA2187932 A1 CA 2187932A1
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Canada
Prior art keywords
ethyl
phenyl
amino
hydroxy
pyridinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002187932A
Other languages
French (fr)
Inventor
Michael H. Fisher
Elizabeth M. Naylor
Dong Ok
Ann E. Weber
Thomas Shih
Hyun Ok
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Merck and Co Inc
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Individual
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Filing date
Publication date
Priority claimed from US08/404,566 external-priority patent/US5541197A/en
Application filed by Individual filed Critical Individual
Publication of CA2187932A1 publication Critical patent/CA2187932A1/en
Abandoned legal-status Critical Current

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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    • 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
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    • 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
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    • 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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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • 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
    • C07D471/04—Ortho-condensed systems

Abstract

Substituted sulfonamides having formula (I), are selective .beta.3 adrenergic receptor agonists with very little .beta.1 and .beta.2 adrenergic receptor activity and as such the compounds are capable of increasing lipolysis and energy expenditure in cells. The compounds thus have potent activity in the treatment of Type II diabetes and obesity. The compounds can also be used to lower triglyceride levels and cholesterol levels or raise high density lipoprotein levels or to decrease gut motility. In addition, the compounds can be used to reduce neurogenic inflammation or as antidepressant agents. The compounds are prepared by coupling an aminoalkylphenyl-sulfonamide with an appropriately substituted epoxide. Compositions and methods for the use of the compounds in the treatment of diabetes and obesity and for lowering triglyceride levels and cholesterol levels or raising high density lipoprotein levels or for increasing gut motility are also disclosed.

Description

WO 95129159 P~ J~.S/O 19S6 . TITLE OF THE INVENTION
SUBSTITUTED SULFONAMIDES AS SELECTIVE ~3 AGONISTS
. ~Y FOR THE TREATMENT OF DIABETES AND OBESITY

This is a c.~ illu~lion-in-part of co-pending application U.S.S.N. 08/233,166 filed April 26, 1994, which is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
~ -Adrenoceptors have been ,~ c~ d as ~1 and ~2 since 1967. Increased heart rate is the primary congeq--~nl~e of ,131-receptor stimulation, while brnn~hn~ tion and smooth muscle relaxation typically result from ~2 stimlll~ltion Adipocyte lipolysis was initially 5 thought to be solely a ,~l-mediated process. However, more recent results indicate that the receptor-mP~ tin~ lipolysis is atypical in nature. These atypical receptors, later called ~3-adrenoceptors, are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis (breakdown of fat) and energy 20 ~ rlont1ifl1re.
Early developments in this area produced c~ ")~,u-,ds with greater agonist activity for the stimulation of lipolysis (,B3 activity) than for stimulation of atrial rate (,~1) and tracheal relaxation (~2)- These early developments disclosed in Ainsworth et al., U.S. Patents 4,478,849 and 4,396,627, were dGIiv~lLivGs of phenyl~th lnnl~min~g Such sel~,Livi~y for ~3-adrenoceptors could make ;v",l,(Jul,d~ of this type potentially useful as antiobesity agents. In addition, these C~JIII~OUIIdS have been reported to show antil,y~G,~;ly~G",ic effects in animal models of non-insulin-dG~!G.IdGllL
3 diabetes mellitus.
A major drawback in treatment of chronic diseases with ,133 agonists is the potential for stimulation of other ~-receptors and ~"l,se~lllr"l side effects. The most likely of these include muscle tremor (1~2) and increased heart rate (,~1)- Although these phenyleth~nnl~minf-W095/29159 ~ 2 ~ ~ 7932 ~ ol~sG

derivatives do possess some ~3 selectivity, side effects of this type have .
been observed in human volunteers. It is reasonable to expect that these side effects resulted from partial ~1 and/or ~2 agonism. ., More recent developments in this area are disclosed in 5Ainsworth et ~.~ U.~. Patent 5,153,210, Caulkett et al., U.S. Patent 4,999,377, Alig et al., U.S. Patent 5,017,619, Lecount et al., European Patent 427480 and Bloom et 1, European Patent 455006.
Even though these more recent developments purport to describe compounds with greater ~3 selectivity over the ¦31 and ,B2 activities, this sclc~livily was rlr~ cd using rodents, in particular, rats as the test animal. Because even the most highly selective compounds, as (1~l. . ",;". d by these assays, still show signs of side effects due to residual ~1 and ,B2 agonist activity when the compounds are tested in humans, it has become apparent that the rodent is not a 5good model for predicting human ~3 s~lc~livily.
Recently, assays have been developed which more ac, u-dl~ly predict the effects that can be expected in humans. These assays utilize cloned human ~3 receptors which have been expressed in Chinese hamster ovary cells. See Emorine et al, Science, 1989, 2245:1118-1121; and Liggett, Mol. Pharmacol.. 1992, 42:634-637. The agonist and antagonist effects of the various ~;UIII~JUUII~Lt on the cultivated cells provide an inrlir~tion of the amtiobesity and ~nti~ hetir effects of the ~ uul~ds in humans.
SUMM~R Y OF THF. T~VENTION
The instant invention is concerned with substituted sulfonamides which are useful as antiobesity and ~nti(li~hetic compounds. Thus, it is an object of this invention to describe such compounds. It is a further object to describe the specific preferred ,~
stereoisomers of the ~ub~lilul~d sulf~-n~nnifif ~ A still further object is to describe processes for the preparation of such compounds. Another , object is to describe methods and compositions which use the cu~ c.u.lds as the active ingredient thereof. Further objects will become apparent from reading the following description.

WO 95129159 r ~ . Q .~JG
~ 2~ 87932 DESCRIPTION OF THE INVENTION
.. The present invention provides compounds having the formula I:

. (R )n CHCH2N-C~~X)m~ ~ N-So2(CH2)r-R7 w here O to 5;
mis Oorl;
ris Oto3;
A is (1) a 5 or 6-1llclllb~l~,d heterocyclic ring with from 1 to 4 h~ ua~ullls selected from oxygen, sulfur and nitrogen, (2) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 h~,t~,lu~ selected from oxygen, sulfur and nitrogen, (3) a 5 or 6-1ll.,lllb~l-,d heterocyclic ring with from I to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from I
to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) phenyl, or (5) a benzene ring fused to a C3-Cg cycloalkyl ring;
R1 is (1) hydroxy, (2) oxo, (3) halogen, (4) cyano, (S) NR8R8~

WO 95/29159 r~ o :~56 ~1 8~3~
(6) SR8, (7) trifluoromethyl, (8) Cl-C1o alkyl, (9) oR8, (10) S02R9, (11) OCOR9, (12) NR8COR9, (13) COR9, (14) NR8S02R9, o (15) NR8C02R8, or (16) Cl-Clo alkyl s--hctit~ d by hydroxy, halogen, cyano, NR8R8, SR8, I-ifluulolllethyl, oR8, C3-Cg cycloalkyl, phenyl, NR8CoR9, CQR9, S02R9, OCOR9, NR8S02R9 or NR8C02R8;
5 R2 and R3 are independentlY
(1) hydrogen, (2) Cl-C1o alkyl or (3) C1-C1o alkyl with 1 to 4 c~lhstitllPntc selected from hydroxy, Cl-Clo alkoxy, and halogen;
X is (1) -CH2-, (2) -CH2-CH2-, (3) -CH=CH- or (4) -CH20-;
R4 and R5 are in~ .p~n~1~ntly (l)hydrogen, (2) C1-C1o alkyl, (3) halogen, (4) NHR8, (S) oR8, (6) S02R9 or (7) NHS02R9;
R6 is (1) hydrogen or (2) C1-C1o alkyl;
R7 is Z-(R 1 a)n;

wo951~91~i9 PU~ c:95G

.~ Rla is (1) Rl, with the proviso that when A is phenyl, Rla is not Cl-Clo alkyl, ,~ (2) C3-Cg cycloalkyl, (3) phenyl optionally substituted with up to 4 groups independently selected from R8, NR8R8, oR8, SR8 and halogen, or (4) S or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently o selected from oxo, R8, NR8R8, oR8, SR8, and halogen;
Z is (1) phenyl, (2) naphthyl, (3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) a benzene ring fused to a C3-Cg cycloalkyl ring, (5) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 hc;l~ludlollls selected from oxygen, sulfur and nitrogen, (6) a 5 o} 6-1llc;llll)el~,d heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and rlitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 h~,t~,lualullls selected from oxygen, sulfur and rlitrogen, or 2s (7) a S or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-Cg cycloalkyl ring;
R8 is (1) hydrogen, (2) Cl-Clo alkyl, (3) C3-Cg cycloalkyl, (4) Z optionally having 1 to 4 ~ub~lilut;lll~ selected from halogen, nitro, oxo, NRlOR10, Cl-clo alkyl, Cl-clo alkoxy, Cl-Clo alkylthio, and Cl-Clo alkyl having 1 to 4 sllhstitll.ont~ selected from hydroxy, halogen, Co2H~ Co2-Cl-Clo alkyl, So2-cl-clo alkyl, C3-c8 cycloalkyl, Cl-WO 95129159 2 1 8 7 9 3 ~ G

Clo alkoxy, and Z optionally substituted by from l to 3 of halogen, C1-Clo alkyl or C1-C1o alkoxy, or (5) C1-C1o alkyl having 1 to 4 substituents selected from hydroxy, halogen, Co2H~ Co2-cl-clo alkyl, S02-Cl-C10 alkyl, C3-Cg cycloalkyl, C1-C1o alkoxy, C1-Clo alkyl, and Z optionally s~lhstit~t~d by from 1 to 4 of halogen, Cl-C10 alkyl or C1-C1o alkoxy;
R9 is (1) R8 or (2) NR8R8;
lO is (1) Cl-Clo alkyl, or (2) two RlO groups together with the N to which they are attached formed a 5 or 6-membered ring optionally h..l,:,lilll~d with Cl-C10 alkyl; or a rh~rmsl~ellti~lly acceptable salt thereof.
In one embodiment of the instant invention A is a 5 or 6-membered heterocyclic ring with from I to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a 5 or 6~ lb~
heterocyclic ring with from 1 to 4 h~,t~,lu~l~.llls selected from oxygen, sulfur and nitrogen, or a 5 or 6-membered heterûcyclic ring with from 1 to 4 h~telu~L~llls selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from l to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
In another embodiment of the instant invention A is phenyl or benzene fused to a C3-Cg cycloalkyl ring.
Preferred cL)Ill~oul~ds of the instant invention are realized when in the above structural formula I:
R2 and R3 are hydrogen or methyl;
X is -CH2-;
nis Oto3;
30 m is 1;
r is O to 2; and R4, R5 and R6 are hydrogen.
Other preferred compounds of the instant invention are realized when in the above structural formula I:

wo 9S/~9lS9 2 1 ~ 7 9 3 ~ JV C :956 . A is phenyl or a 6-membered hete}ocyclic ring with I or 2 heteroatoms selected from nitrogen and sulfur;
Rl is hydroxy, halogen, cyano, trifluoromethyl, NR8R8, NR8SO2R9, NR8COR9, NR8CO2R8, Cl-C6 alkyl optionally substituted by hydroxy; and ris Oor2.
More preferred compounds are represented by the formula Ia:

(Rl)n ~ J CHcH2N-c-(x)m~ ;3NH=so2--Z (R1a)~
Ia wherein nis Oto3;
mis Rl is (1) halogen or (2) NR8R8;
R2, R3 are in-l.op~n~ nt1y hydrogen or methyl;
Rla is (1) halogen, (2) Cl-Clo alkyl, 2s (3) NR8R8, (4) NR8COR9, (S) NR8C02R8 (6) COR9, (7) OCOR9, or (8) a S or 6-membered heterocycle with from I to 4 het~,lua~ullls selected from oxygen, sulfur and nitrogen, optionally ~I-hstitllt~-rl with up to four groups independently selected from oxo, halogen, R8, NR8R8, oR8, and SR8;
Z is (1) phenyl, (2) naphthyl, WO 95/29159 r~ c 155G
21 87~32 (3) a 5 or 6-membered heterocyclic ring with from l to 4 , heteroatoms selected from oxygen, sulfur and nitrogen, (4) benzene ring fused to a S or 6-membered heterocyclic ring with from l to 3 heteroatoms selected from oxygen, sulfur and nitrogen, or (S) a S or 6-membered heterocyclic ring with from l to 4 hc~ s selected from oxygen, sulfur and nitrogen fused to a C3-Cg cycloalkyl ring;
X is -CH2-; and R8 and R9 are as defined under formula 1.
Even more preferred compounds are those ~l~,sc.-L~d by formula Id:

(R1)n--~ JCHCH2N- I cH2~NH-so2--~ (Rta)n Id nis Oorl;
Rl is NR8R8;
R2 and R3 are in~PpPn~ ntly (l) hydrogen, or (2) methyl;
B is (l) hydrogen, (2) benzene fused to the benzene ring to form naphthyl, or (3) a S or 6-membered heterocycle with l to 4 heteroatoms selected from oxygen, sulfur and nitrogen atom fused to the benzene ring;
Rla is (l) halogen, (2) Cl-Clo alkyl, (3) NR8R8~
(4) NR8CoR9, (S) NR8C02R8 WO95/29159 1~I/u~'C.~
2 1 8 7~32 g - (6) COR9~ or (7) a ~ or 6-membered heterocycle with from 1 to 4 - hcilel~,dt~,llls selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R8, SR8, o~8, arld NR8R8;
when B and the benzene ring form a fused ring system, Rla is attached to either ring;
R8 is (1) hydrogen, (2) Cl-Clo alkyl, (3) Z optionally having l to 4 sllhstitl-~nt~ selected from nitro, oxo, and NR10Rl0, or (5) Cl-Clo alkyl having 1 to 4 substituents selected from hydroxy, halogen, Cl-Clo alkyl, C3-Cg cycloalkyl, and Z
optionally sllbstitllt~-d by from l to 4 of halogen, Cl-clo alkyl or Cl-Clo alkoxy;
R9 is (1) R8 or (2) NR8R8;
R10 is (1) Cl-Clo aLkyl, or 0 (2) two R10 groups together with the N to which they are attached formed a 5 or 6-lll~.llb~ d ring optionally bub~ ul~d with Cl-Clo alkyl; and Z is (1) phenyl, (2) a 5 or 6-membered heterocyclic ring with from 1 to 4 L~JIlls selected from oxygen, sulfur and nitrogen, (3) a benzene ring fused to a 5 or 6-membered heterocyclic rirlg with from 1 to 4 h~ u~al~ulls selected from oxygen, sulfur and nitrogen, or (4) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and rlitrogen fused to a C3-Cg cycloalkyl ring.
.- Other more preferred compounds are l~ s~ t;d by formula Ib:

wo ssnslss P~ o ;9s6 OH H R2 .
(R1)n ~--CHCHzN- I (X)m~NH-soz-z-(R1a)n Ib wherein nis Oto3;
mis Rl is (1) hydroxy, (2) cyano, (3) NR8R8 or (4) halogen;
Rla is (1) halogen, (2~ NR8R8 (3) NR8COR9, (4) NR8CO2R8, (5) OCOR9, or (6) a S or 6-membered heterocycle with from 1 to 4 .,L~Iv~llullls selected from oxygen, sulfur and nitrogen, optionally substituted with up to three groups in~lPp~nrl~ntly selected from ûxo~ halogen, R8, NR8R8~ oR8 and SR8;
Z is (1) phenyl, (2) naphthyl or (3) benzene ring fused to a S or 6-membered heterocyclic rirlg with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrûgen;
X is -CH2-; and R2 and R3 are independently hydrogen or methyl.
Re~ live ~ntinb~ity and ~nti~ hetif~ compounds of the present invention include the following: .
~-[4-[2-[[2-hydroxy-2-(6-allfill~ylidin-3-yl)ethyl]amino]ethyl]phenyl]-4-(hexylamin~carbonylamino)l,~", r11~ 1 fO~ llidc WO 95/29159 2 1 8 7 q 3 2 ~ . ;.c ,jSf ~-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethy1]pheny1]-4-iodokçn7f nPsl-lfonamide N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-b~ lfonamide N-[4-[2-[[2-hyd}oxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-2-nslrhth~lPn~sl-lfonamide N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-3-quinolinesulfonamide N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-o 5-bt;~ vlc-s-ll rvllal~lide N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[(h~yl~ yl~minoc~rbonyl)amino]l~r.~.r.~ lfonamide N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[(dimethyl~minvc~rbonyl)amino]~.r.,,.r.~f.~,llfonamide 5 N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-2-imi~1 l7oli~10n-l-yl)br.~Y~ Ilfonamide N-[4-[3-[[2-hydroxy-2-(6-~.1illv~ylidin-3-yl)ethyl]amino]propyl]-phenyl]-4-~fhexyl:-minor~rbonylamino)~ .r"~jlllrollalllide ~[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]propyl]-20 phenyl]-4-iocl~ . ,,.=. ,. . j"lfonamide ~-[4-[3-[[2-hydroxy-2-(6-alllillo~ylidin-3-yl)ethyl]amino]propyl]
phenyl]l,- .,,...lf ClllfOnamide ~!:-t4-t3-t[2-hydrvxy-2-(6-alllillv~ylidin-3-yl)ethyl]amino]propyl]
phenyl]-2-n~rhth~ n.o.slll rvllalllidf 25 N-[4-[3-[[2-hydroxy-2-(6-~--illvl,y-idin-3-yl)ethyl]amino]propyl]-phenyl]-3-qllin~-lin~slllfonamide ~[-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(hexyl~minoc~rbonylamino)l,~ ul rvllalllide N-[4-t2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-30 isv~,lv~,ylll l~ ll]fonamide . N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-2-l ,r.l: .. ,..,. llfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-3-quinolinesuLfonamide WO 95/29159 1~ .'C ;~5G
93:2 ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(hexylmethylaminocarbonyl)amino]bf~n7~.n~s~1fonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-2-imidazolidinon- 1 -yl)b~ r . ,r.~. ll fonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-iodObr.,,...~P~Ilfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3-cyclopentylpropyl)-[1,2,4]-oxadiazol-3-yl]hPn7.~ .nc~1fonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(1 -oxoheptyl)amino]l ,..., ,.~ .. "~.clllfonamide ~!-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(1 -oxo-4-phenylbutyl)amino]l~r",...~ lfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(propoAyl,d,bo"yl)amino]~çn7~onPs--lfonamide 5 ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[[(fur-2-ylmethyl)amino]carbonyl]amino]bf~n7.l nPc--lfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[[(2-phenylethyl)amino]carbonyl]amino]b; ,,.., ,,llfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[[(2-20 indol-3-ylethyl)amino]carbonyl]amino]l,r"~i..,..,.llfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[(~ yl~~ lo)carbonyl]amino]~...,,.~., ~.Ilfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -[(h~ ylalllillo)carbonyl]-s-inllnlin~slllfonamide 25 N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[(octylamino)carbonyl]-S-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[(N-methyl-N-octylamino)carbonyl] -5-indolinesulfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1-( I -30 oxononyl)-s-inflnlinps~lfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -(4-ia~lol-2-yl)-s-inl1Qlin~s~llfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -(4-octylthiazol-2-yl)-S-in~lolin~s--lfonamide W0 95129159 r~ V' l~56 ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-ethyl-S-methylthiazol-2-yl)-5-in~lnlinP.s-llfonamide - N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-octyl-2-imidazolidinon-l-yl)bPn7PnPslllfonamide ~I-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(4,4,4-trifluorobutyl)-2-imitl~7nli~1innn-l-yl]br.,ll~.r.,f.i,.llfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-phenylpropyl)-2-imidazolidinon- l-yl]bF n7PnF s~llfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-o (4,4,5,5,5-pentafluoropentyl)-2-imidazolidinon-1-yl]b~ l,rllF~ lfonamide N-~4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(2-cyclohexylethyl)-2-imidazolidinon- 1 -yl]l,r", rl IF-SI llfonamide N-L4-[2-[[2-hydroxy-2-(3-pyridin~ ethyl]amino]ethyl]phenyl]-4-[3-[3-15 (4-chlorophenyl)propyl]-2-imidazolidinon-l-yl]hP,n7.enP.~ulfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-pentyl-2-imidazolidinon-1-yl)l~r",.~ P,~ fonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-cyclo~ lyl~lu~)yl)-2-imi~1~7n~ inon-l-yl]hl~ rllp~ fonamide 20 N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(2-~;y~.lU~ ylethyl)-2-im~ 7~n~ innn- 1 -yl]l I ,r.l l~.rl IF ~. Ilfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-cycloll~,AylL,Iu~yl)-2-imidazolidinon-l-yl]bFn7Pn~slllfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(2,2-25 dimethylhexyl)-2-imifl~7olil1inon-l-yl]l~"~r ~F~ lfonamide ~L-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-2-imidazolon- 1 -yl)~r~ I ~.f -1l'.~ lfonamide ~[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(4,4,4-trifluorobutyl)-2-imidazolon-1-yl]b~ .r"P.~"lfonamide 30 ~_[4_[2_[[2_hydroxy-2-(3-pyridinyl)ethyl]amillo]ethyl]phellyl]-4-(3-octyl-2-imitl~.nlnn-1-yl)l?r",F..~P,~,Ilfonamide ~I-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-cyclo~..,.llyl~1luL~yl)-2-imidazolon-l-yl]hpn7enpslllfonamide WO 95/29159 P~ .'C 1~6 N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-octyl-3-oxo-[1,2,4]-triazol-4-yl)ben7P,nPsl-lfonamide N-~4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-hexyl-S-tetrazolon- 1 -yl)bPn7PnP.sl-lfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-octyl-5-tetrazolon-1-yl)~ .17f 1If ~I llfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(3-cyclopentylpropyl)-5-tetrazolon- 1 -yl]bpn7pnpslllfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-10 pentyloxazol-5-yl)l, 1~ ~f ,~lfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-octyloxazol-5-yl)bPn7f nP.~IIlfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(2-cyclopentylethyl)oxazol-5-yl]~ lfonamide 5 ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(4-ethyl-5-".~ ylil.i~ol-2-yl)amino]l,~ fonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(4,5,6,7-tetrallyd.~ .zullli~ul-2-yl)amino]bPn7P.nPslllfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]arnino]ethyl]phenyl]-4-(2-20 hexylimidazol-4-yl)lr",. l- ~ llfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(1-methyl-2-octylimidazol-S-yl)l,~ - f D~ ~I ru--Oll ide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[1 -methyl-2-(2-cyclopentylethyl)imidazol-S-yl]b~ - '7~ ~ If slllfollamide 25 N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[l-methyl-2-[2-(4-flu~lu~ yl)ethyl]imidazol-5-yl]bPn7PnPsl~lfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-pentyl-[l ,2,4]-oxadiazol-3-yl)b,~", ~. ~f ~ Ilfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2-30 cyclopentylethyl)-[1~2~4]-oxadiazol-3-yl]l~ fD~Ilfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-heptyl-[1,2,4]-oxadiazol-3-yl)~ . If D~ llfonarnide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-octyl-[1,2,4]-oxadiazol-3-yl)~r",.~ .llfonamide WO 95/29159 P~, I/L~_,'U ~9~C

~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-hexylthio-[1,2,4]-triazol-3-yl)~.r",l~ ,llfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[4-(4-propylpiperidin- 1-yl)- 1,1 -dioxo-[ 1 ,2,5]-thi~ 7Ol-3-5 yl]amino]br~ f-~,llfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[4-(hexylmethylamino)- 1,1 -dioxo- [ 1,2 ,5] -thiadiazol-3 -yl]amino]~r~ . "~,clllfonamide N-[4-[2-t[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[4-(N-o heptyl, N-methylamino)- I ,1 -dioxo- [ 1,2,5] -thiadiazol-3-yl]amino]bf n7f.nf c-l1fonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]~(1 -octyl-2,4-imi-i~7~ 1inf ~ion-3-yl)bf. n7f~nr-~ ~1 rullalllide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl~phenyl]-4-[3-(3-5 llillu~ lyl)-s-pyrazolon-l-yl]b~ rllf~lllfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(1 -hydroxy-l-hexylheptyl)-5-methyl-[1,2,3]-triazol-2-yl]l,r..,,~.~f-.~..lrul~-amide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]~[4-( 1 -20 hydroxyheptyl)-5-methyl-[ 1 ,2,3]-triazol-2-yl]bf n7f nf s--1fonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]-2-1ll.,lllyl~l~",y~]-phenyl]-4-(3-hexyl-2-imi(1~7- lirlinon- 1 -yl)l: f n7f nf clllfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]-2-m~lllyll,luL~yl]-phenyl]~iodoh.~n7f nf s--1 rullallPidf 25 ~-l4-[2-[[2-hydrOXy-2-(3-pyridinyl)ethyl]amillo]-2~ lllyl~)lu~Jyl]-phenyl]-4-[[(he~ylalllillo)carbonyl]amino]b~n7rnf,s~lfonamide ~-[4-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-4-iodub~ llf;-sulfonamide N-[4-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-2-n~rh~h~lf n~

3 Sulfollamide N-14-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-3-quinoline-~ullullalllide N-[4-[2-[[2-hydroxy-2-(3-chlorophenyl)ethyl]amino]ethyl]phenyl]-3-isopropylhr. ., ~ .. If ~. .lfonamide woss/2slss ~1 ~3.7~32 P~,l/u~.~.~C l~s6 ~-[4-[2-[[2-hydroxy-2-(3-chlorophenyl)ethyl]amino]ethyl]phenyl]-2-n~rhth~lf n~slllfonamide ~-[4-[2-[[2-hydroxy-2-(3-chlorophenyl)ethyl]amino]ethyl]phenyl]-3-quinolinesulfonamide N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]ethyl]-phenyl]-4-(hexylaminocarbonylamino)b~n7f nf slllfonamide N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]ethyl]-phenyl]- I -[(octylamino)carbonyl]-S-inf1--1inPclllfonamide ~[-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlolu,~ lyl)ethyl]amino]ethyl]-10 phenyl]-4-(3-hexyl-2-imidazolidinon-l-yl)kf~n7fnpslllfonamide ~-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]ethyl]-phenyl]-4-(3-octyl-2-imi~1~7nli~1inrn- 1 -yl)~r~ l .1 rullalllide N-~4-[2-[[2-hydroxy-2-(4-llydlu~y~ llyl)ethyl]amino]ethyl]phenyl]-,- If ~ lfonamide 5 N-[4-[2-[[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino]ethyl]phenyl]-4-iodo~ 11 rullalllide ~-[4-[2-[[2-hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-4-(hexyl~lminor~rbonylamino)kf n7f nf cl~lfonamide ~-[4-[2-[[2-hydroxy-2-(3-~:yallu~h~ll,yl)ethyl]amino]ethyl]phenyl]-3-20 quin()linf.slllfollamide 4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4 hexyl-[1,2,4]-oxadiazol-3-yl)l,r.,i~ ,P~,llfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-heptyl-5-methyl-[1,2,3]-triazol-2-yl)~,....~.f ..f'~. lfonamide 25 ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-2,4-imidazoli~linf.-lit)n- 1 -yl)l,r., ,.... If.,"l rc,llalllide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-octyl-2,4-imidazolidinedion- 1 -yl)k~n7f.nf slllfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-3 ,ycl~ yl~-lul!yl)-2,4-imidazolidinedion- 1 -yl]~f n7f nf slllfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-pentyl-[1,2,4]-oxadiazol-S-yl)1~ lf~ fonamide ~[-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-[ 1 72,4]-oxadiazol-5-yl)ben7f nf c~l1fonamide W095129159 2 1 8 7 9 3 2 ~ u." ~04JsG
.~ ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-heptyl-[1,2,4]-oxadiazol-5-yl)br",.r,"P~lfonamide N-[~[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-octyl- [ 1,2 ,4] -oxadiazol-5-yl)benzenesulfonamide N-~4-[2-L[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(2-cyclopentylethyl)-[1,2,4]-oxadiazol-S-yl]b.qn7P.nf~s-llfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-cyclu~ yl~lul,yl)-[1,2,4]-oxadiazol-S-yl]ben7~n~-s--lfonamide N-[4-t2-tt2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]4-(3-pentyl-[1,2,4]-thiadiazol-5-yl)bf n7.~n~s--1fonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-[1,2,4]-thi~ 701-S-yl)l~r.~f "~.~lllfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-heptyl-[1,2,4]-thiadiazol-5-yl)ll. ~l~rll~lllfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-octyl-[1,2,4]-thi~ 7QI-S-yl)l~ zf .~e~ulfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(2-cyclopentylethyl)-[1,2,4]-thiadiazol-5-yl]l,r",r .,~.blllfonamide I!!.-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-20 cyclo~.,.l~yl~lu~yl)-[1,2,4]-thiadiazol-5-yl]b~ ,f ,~lfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]arnino]ethyl]phenyl]-4-(5-pentyl-[l,2,4]-thiq~ 7--1-3-yl)br",~ .llfonamide N-[4-[2-t[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]4-(5-hexyl-[1,2,4]-thi~ 7-1-3-yl)llr.,,.~."f-s~lfonamide 25 1!~4-~2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(S-heptyl-[1,2~4]-thiadiazol-3-yl)bf n7lonl~slllfonamide ~I-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(S-octyl-[ 1 ,2,4]-thiadiazol-3-yl)l.f . ~.f .~f~l llfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]e~hyl]phenyl]-4-[5-(2-3~ cyclopentylethyl)-[1,2,4]-thiadiazol-3-yl]hf n7f nf~s--lfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3-cyclu~ yl~lu~yl)-[1,2,4]-thiadiazol-3-yl]b~n71-nlocl-lfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-pentyl-3-oxo-[1,2,4] triazol-2-yl)l~PIl7r,~. ,lllfonamide WO 95/29159 1~,11 ~J.,,_10 I~SG
7~ ~7~3~ --~I-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- , hexyl-3-oxo-~1,2,4]-triazol-2-yl)iJc;."e~ ulfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-heptyl-3-oxo-[1,2,4]-triazol-2-yl)l: Pn7.3nf~sll1fonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-octyl-3-oxo-[1,2,4]-triazol-2-yl)ben7~nr,s~l1fonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(2-cyclopentylethyl)-3-oxo-[1,2,4]-triazol-2-yl]~,n7f~nl~.sll1fonamide ~-[4- [2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(3-10 cyclopentylpropyl)-3-oxo-[1,2,4]-triazol-2-yl]hPn7Pn~slllfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-pentyloxazol-2-yl)bPn7~n~.cll1fonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-hexyloxazol-2-yl)b~n7~n~sll1fonamide 15 ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]~(5-heptyloxazol-2-yl)bPn7f~,n~.cll1fonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-octyloxazol-2-yl)l,~ lfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2-20 cyclopentylethyl)oxazol-2-yl]l ~r~ ,lfonamide I!I-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3-;y-,lu~ yll~ullyl)oxazol-2-yl]b...~ lfonamide ~!-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-pentyloxazol-2-yl)b~.n7P,n~..c~lfonamide 25 N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-hexyloxazol-2-yl)k~,n7~nf~s~l1fonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-heptyloxazol-2-yl)~ P~Illfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]arnino]ethyl]phenyl]~(4-30 octyloxazol-2-yl)b~n7..onl~.sll1fonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(2-cyclopentylethyl)oxazol-2-yl]l-r- ~ ~.. "~ lfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclo~ yl~lu~yl)oxazol-2-yl]~n7~n~os~lfonamide WO 95/Z9159 F~
2 1 8 7932 ~ 556 I!~-L4-~2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2 hexyloxazol-S-yl)bf,n7enPslllfonamide . N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-heptyloxazol-5-yl)L r.",r,~e~,llfonamide 1~1-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3-cyclup~ yl~lu~yl)oxazol-5-yl]~ .rl l. .~. llfonamide N-L4-L2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(4-cycloll~hylL,ulyl)oxazol-5-yl]L.. .,,r~,f.i,,llfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-[2-(4-fluorophenyl)ethyl]oxazol-5-yl]L~r~ 17rl Ir~ lfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-pentyloxazol-4-yl)bf n7f nf-slllfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]~(2-hexyloxazûl-4-yl)L,~" ~r:J)f ~l llfonamide 5 N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-heptyloxazol-4-yl)Llrl 17f . If ~1 llfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-octyloxazol4-yl)L,r, I,rl .... Ilfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]4-[2-(2-2 0 cyclopentylethyl)oxazol-4-yl]L~r ~ ~ ~ r ~ Ir~l ~1 ru~ lide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3-cyclu~ yl~luL,yl)oxazol-4-yl]br,~ foll~lllide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-p~ ylllliaz~JI-2-yl)lJ...,,.r"e~ fonamide 25 N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-hehylllliaLul-2-yl)L~ .rl If.~. Ilfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]4-(5-yl~lli~ol-2-yl)bf n7f.nesll1fonamide ~-[4-12-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-( 30 o~yl~.lliazul-2-yl)L~r",r".,.llfonamide ~I-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2-cyclopentylethyl)thiazol-2-yl]L~r~ I~.r.l If ~- Ilfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3-cyclu~ yl~lu~l)thiazol-2-yl]~ 7r",~ lfonamide WO 95/29159 r~ 'C ;~6 21 ~932 N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyljphenyl]-4-(4-pentylthiazol-2-yl)L,r.,,r".~ lfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-hexylthiazol-2-yl)L ~",r"t-~llfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-heptylthiazol-2-yl)~.r.,,,~ lfonamide ~-[4-[2-~[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-octylthiazol-2-yl)L r.,,~.. .f.~"lfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(2-10 cyclopentylethyl)thiazol-2-yl]br~~~P ,p~lllfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclo~clllyllJluluyl)thiazol-2-yl]kpn7pnp~lllfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]~(2-pentylthiazol-4-yl)kP,n7PnP,slllfonamide 5 ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-hexylthiazol-4-yl)LP.~ f ,,llfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-heptylthiazol-4-yl)bPn7PnPslllfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-20 octylthiazol-4-yl)b .,~ ,lP~Illfonamide ~I-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(2-cyclopentylethyl)thiazol-4-yl]~ "1 rvll~llid~
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]arnino]ethyl]phenyl]-4-[2-(3-cyclopentylpropyl)thiazol-4-yl]l,r",~ .~lp~lllfonamide 25 ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-ylLllidL~)I-S-yl)l~ r lP~.llfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-hexylthiazol-5-yl)l,r.,, .... ,..1 r~ ide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-30 heptylthiazol-5-yl)l-,~..,..,f j..lfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-octylthiazol-S-yl)L,- ,~ lllfonamide ~I-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(2-cyclopentylethyl)thiazol-S-yl]hPn7P,nPslllfonamide WO95/2915g P~,I/u., ~ 35C
~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3-cyclopentylpropyl)thiazol-5-yl]ben7enes-llfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-methylthiazol-2-yl)-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-pentylthiazol-2-yl)-5-in~ lin~s--lfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-hexylthiazol-2-yl)-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-10 h~ yll~lia2c,l-2-yl)-5-in~ lin~slllfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -(5-octylthiazol-2-yl)-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[5-(2-cyclopentylethyl)thiazol-2-yl] -5-indolinesulfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[5-(3-cyclo~ lyl~lu~yl)thiazol-2-yl]-5-inrlnlines~lfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -(4-pentylthiazol-2-yl)-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-20 hexylthiazol-2-yl)-5-in,l,~lin~slllfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-h~;L)Iyllllia~1-2-yl)-5-indolinesulfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -[4-(2-cyclopentylethyl)thiazol-2-yl]-5-in-101inesl-1fonamide 25 ~[-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[4-(3-y~ ylpropyl)thiazol-2-yl]-5-infl~lineslllfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-methyloxazol-2-yl)-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1-(5-3 ~ pentyloxazol-2-yl)-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1-(5-hexyloxazol-2-yl)-5-in-loline~- Il rOIIalllide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -(5-heptyloxazol-2-yl)-5-in~ lin~s--lfonamide WO95/29159 r~~ ,5!019~G
~ ~7~3~ --N-~4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-octyloxazol-2-yl)-S-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1-[5-(2- - .
cyclopentylethyl)oxæol-2-yl] -5-indolinesulfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[5-(3-cycluy~ ylyluyyl)oxæol-2-yl]-S-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -(4-methyloxazol-2-yl)-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -(4-pentyloxazol-2-yl)-5-in~ lin~slllfonamide ~[-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -(4-hexyloxazol-2-yl)-5-inrl~lin~lllfonamide ;~-[4-[2-[[2-hydroxy-2-~3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -(4-heptyloxazol-2-yl)-5-indolinesulfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-octyloxazol-2-yl)-5-intll linf~.clllfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -[4-(2-cyclopentylethyl)oxazol-2-yl] -5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[4-(3-cycluy~ ylyluyyl)oxazol-2-yl]-5-in~ lin~oslllfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]arnino]ethyl]phenyl]- 1 -(3-methyl-[l ,2,4]-oxadiæol-5-yl)-5-indolinesulfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -(3-pentyl-[l ,2,4]-oxadiæol-5-yl)-5-in-lolin~slllfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]arnino]ethyl]phenyl]-1-(3-hexyl-[1,2,4]-oxadiæol-5-yl)-5-in~lolinf~.slllfonamide ![-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1-(3-heptyl-[l ,2,4]-oxadiazol-5-yl)-S-indolinesulfonarnide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1-(3-octyl-[1,2,4]-oxadiæol-5-yl)-5-in~ lin~slllfonamide ~[-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -[3-(2-cyclopentylethyl)-[1,2,4]-oxadiæol-5-yl]-5-inrl~linP~IIlfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[3-(3-cycloy~ ylyl~lyyl)-[l,2,4]-oxadiazol-5-yl]-5-in-lolin~slllfonamide WO 95/29159 r~ . v :556 8793~
N-L4-~2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -(5-methyl-[1,2,4]-oxadiazol-3-yl)-5-in~ linPslllfonamide ~-~4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -(5-pentyl-[1,2,4]-oxadiazol-3-yl)-5-in~ linPs-llfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-hexyl-[ 1 ,2,4]-oxadiazol-3-yl)-5-indolinesulfonamide ~-[4-[2-~[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-heptyl-[1,2,4]-oxadiazol-3-yl)-5-in~ linPsl-lfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1-(5-octyl- [ 1 ,2,4]-oxadiazol-5 -yl)-3 -indolinesulfonamide ~-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[5-(2-cyclopentylethyl)-[1,2,4]-oxadiazol-3-yl]-5-in~ lin~clllfonamide ~-[4-t2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 -[5-(3-cyclopentylpropyl)-[l ,2,4]-oxadiazol-3-yl]-5-in-lnlinPclllfonamide The CU~ JUUII~S of the instant invention all have at least one a~yll~"Gtlic center as noted by the asterisk in structural Formula I.
Additional a~yl,L~"~l~ic centers may be present on the molecule depending upon the nature of the various sllhstitllPntc on the molecule, in particular, R2 and R3. Each such a~yllull~llic center will produce 20 two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, be included within the ambit of the instant invention.
In the case of the ~yllllll~lfic center l~l.,~ d by the asterisk in Formula I, it has been found that the compound in which the hydroxy 2~ is above the plane of the structure, as seen in Formula Ic, is more active and thus more preferred over the compound in which the hydroxy sllhstitllPnt is below the plane of the structure.
The following stereospecific structure represents the preferred stere~i~nmPr.c of the instant invention:

WO 95~29159 ~ C 15~G
27~J93~ --~ C-CH2N-C-(X)~e ~ N-So2(CH2)r-R7 (R1)n R3 Rs R6 Ic where n, m, r, A, Rl, R2, R3, R4, RS, R6, R7 and X are as defined above under formula 1.
0 Throughout the instant application, the following terms have the indicated m~ningS
The alkyl groups specified above are intended to include those alkyl groups of the rll-ci~n~r-.cl Iength in either a straight or branched configuration. Exemplary of such alkyl groups are methyl, 5 ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
The alkoxy groups specified above are intended to include those alkoxy groups of the lP~i~n~r-d length in either a straight or branched configuration. Exemplary of such alkoxy groups are 20 methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The term "halogen" is intended to include the halogen atoms fluorirle, chlorine, bromine and iodine.
F-r~mrll~ of 5 and 6-~ llb~ ,d heterocycles and fused 25 h~,t~lu~,y~ of A, Z and Rla include pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl, thiazolyl, ben7.imi~ rr~lyl7 thiadiazolyl, benzu~ adidL~,lyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, b~llY.,rul~lyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahyr~ .d~ l-yl, dihydlol)t;llz~Jruldllyl, 30 tetrahydroquinolinyl, furopyridine and thienopyridine.
The preferred values of A and Z are phenyl, naphthyl, benzene ring fused to a S or 6-membered heterocyclic ring with from I
to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or W0 95129159 1~ s~a .,.,v 2 1 87q32 heterocycles with from 1 to 4 heteroatoms independently selected from one of oxygen or sulfur, and/or l to 4 nitrogen atoms.
The more preferred values of A are phenyl, pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl, and thiazolyl.
The more preferred values of Z are phenyl, naphthyl, quinolinyl, thienyl, kçn7imi~i~7olyl~ thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, b~,l.zuruldllyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, L~llahydlu~ JllLllyl, dihydrobenzofuranyl, triazûlyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazolyl, tetrahydroh~n7ofhi~7--lyl and tetrahydroquinolinyl. When Z is attached to -NSO2(CH2)r-, it is preferably phenyl, naphthyl or a benzene ring fused to a 5 or 6-~"llbelcd heterocyclic ring with from 1 to 4 heteroatoms selected from 5 oxygen, sulfur and nitrogen. When Z is part of the definition of R8, it is preferably phenyl, a S or 6-1llt;lllb~lc;d heterocyclic ring with from 1 to 4 h~,Lt;lu~ullls selected from ûxygen~ sulfur and nitrogen, a benzene ring fused to a S or 6-membered heterocyclic ring with from l to 4 h~,t1lu~1ullls selected frûm oxygen, sulfur and nitrogen, or a S or 6-20 membered heterocyclic ring with from 1 to 4 h.,L~u~lullls selected from oxygen, sulfur and nitrogen fused to a C3-Cg cycloaLkyl ring.
The preferred hc~l~-u-;ycles of Rla are thienyl, thiadiazolyl, triazolyl, tetrazolyl, ~IY~ 7.~lyl, imidazolyl, oxazolyl, thiazolyl, imi~iq7rtli-1inyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, and pyrazolyl.
Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other; thus for example, NR8R8 may represent NH2, NHCH3, N(CH3)CH2CH3, and the like.
The following abbreviations are used throughout the 30 srte~ifi~:lti~ln Boc : tert-butyloxycarbonyl Cbz : carbobenzyloxy DIP-CI : diisopinor:lmrhf ylchloroborane DMF : dimethylformamide WO 95/29159 1'~ .'0 ~5~
DMSO : dimethylsulfoxide HPLC : high pressure liquid chromatography Me : methyl MPLC : medium pressure liquid chromatography Ms : m~thAnPslllfonyl (mesyl) NBS : N-bromosuccinimide NCS : N-chlorosuccinimide nHex : n-hexyl TBAF : tetrabutylammonium fluoride TBS (TBDMS) : t-butyldimethylsilyl TFA : trifluoroacetic acid THF : tetrahydrofuran The compounds (I) of the present invention can be prepared from epoxide in~Prm~rliAtf~c such as those of formula Il and 5 amine intr- "-. ~ .t~ ~i such as those of formula III. The preparation of these i,,l~ .,,,P/l;AIrs is described in the following schemes.
~ H2N~C-(X)m{l~NI S2(CH2)r~R
(Rl)n D m where n, m, r, A, R1, R2, R3, R4, R~, R6, R7 and X are as dehned 25 aboYe.
Compounds II are known in the literature or may be ~ ,v~ ly prepared by a variety of methods familiar to those skilled in the art. One common route is illll~trAtrd in Scheme 1. Acid chloride 30 L which may be culll~ ially available or readily prepared from the corresponding acid by treatment with, for example, thionyl chloride or oxalyl chloride, is treated with did2011lc;~ lC in a solvent such as diethyl ether. The resultant diazoketone is then treated with hydrogen chloride to give chloroketone ~ (X = Cl). The haloketone ~ is then reduced with a reducing agent such as sodium borohydride. The resultant alcohol 3 is ,,, _ _ _ . . . . . .. .. .

WO 95/29159 r~.,u~ r, 21~7932 . treated with base such as pOt~i~iiUIII carbonate in refluxing acetone to provide the desired epoxide II. The enantiomerically enriched (R) and ,- (S) epoxides II are readily available by asymmetric reduction of haloketones 2 using chiral reducing agents such as (-) or (+)-DIP-Cl, 5 (R) or (S)-Alpine borane or (R) or (S)-tetrahydro-l-methyl-3,3-diphenyl-lH,3H-pyrrolo[1,2-c][1,3,2]oxazaborole-borane ((R) or (S)-OAB-BH3).
SCHEMF. 1 o ~CI 1) CH2N2 ~J~, (Rl)n 2) HCI (Rt)n~) ~ (X = Cl, Br) OH
[H] ~~X base 1 ~) (R )n 3 (X = Cl, Br) ,~
(R1)n II

An alternate route to the desired haloketones 2 is illustrated in Scheme 2. Methylketone 4 may be converted to the ~ ldillg haloketone using a variety of reagents known to those in the art and ,.", ~,;,. d in Larock Comprehensive Organic Transforfnations; VCH:
New York, 19~9, 369-372. Conveniently, methyLketone 4 is treated WO 95129159 r~ o 1~6 ~ ~7~32 with chlorine or N-chloros-lrrinimi(lr in acetic acid with an additional acid source such as hydrogen chloride or ~ lnninllm chloride. For the synthesis of ~ (X = Br), bromine, dibromobarbituric acid or NBS with hydrogen bromide or ~IIlminllm bromide may be used. In some cases, 5 the chloro or bromokPton~c ~ may be commercially available.
SCHF.Ml~ 2 (R )n CH3 Cl2 or Br2 ~ _~ X
(R1)n 2 (X = Cl, Br) Many of the methylketones _ are commercially available or readily prepared by methods described in the literature and known to those skilled irl the art. Rl substituents on the acid chlorides 1 or 20 methylketones 4 may need to be protected during the cllhseqll~nt procedures. A description of such protecting groups may be found in:
Protective Groups in Or~nir Synthesis. 2nd Ed., T. W. Greene and P.
G. M. Wuts, John Wiley and Sons, New York, l991.
Compounds m can be conveniently prepared by a variety 25 of methods familiar to those skilled in the art. A ;OII~GII1.,II~ route for their preparation when R6 is hydrogen is illustrated in Scheme 3.
Compound ~ is selectively protected as a suitable ~;~ub~lld~G derivative 6 with, for example, di-tert-butyl dicarbonate or ~;~I,ob~ yloxy chloride. This compound is then treated with a sulfonyl halide, 30 ~ Glably the sulfonyl chloride 7. and a base such as pyridine in an anhydrous solvent such as dichloromethane or chloroform for 0.5 to 24 hours at LGIIIIJGInLUIGS of -20 to 50C, preferably 0C, to provide the sulfonamide 8. The protecting group is then removed with, for WO9S/29159 r~ J. o 2 ~ ~7932 . example, trifluoracetic acid in the case of Boc or catalytic hydrogenation in the case of Cbz, to give the desired amine 9.
SCHEM~ 3.

H2N-C~(X)m{ ~NH2 Boc20 R3 F~5 orCbzCVbase GNH--C~X)m~l~ N H2 G=BocorCbz R7(CH2)rSO2cl CZ) GNH~C-(X)m~; ~Nso2(cH2)r-R7 pyridine, CH2CI2 R F;s H

TFA, CH2CI2 lR2 R
or H2/Pd catalyst F; Rs H

Cu~ uulld~ III where R6 is not hydrogen may be conveniently prepared as illllctr~t.od in Scheme 4. Sulfonamide ~
3O prepared as described above, is aLkylated with an d,U~IU~Iidl~ alkylating agent 10 in the presence of base to provide sulfonamide 1 1. Removal of the protecting ~roup as above gives the desired compound ~.

WO 95/29159 ~ 7 9~ ~ c ;956 R2 R4 Alk-Y
C~X)m{l~ INso2(cH2)r-R

~1~
GNH~Ç~X)m~ ~NSo2(CH2)r-R7 TFA, CH2CI2 10 R3 R5 Alk or H2/Pd catalyst 15 H2N~C~(X)m~NSO2(CH2)r~R G=BocorCbz R3 15 Alk Y = Cl, Br, or I
R Alk = Cl-C6 alkyl 20 The sulfonyl chlorides 7, many of which are cullu~ i2illy available, can also be readily prepared by a number of methods familiar to those skilled in the art. One suitable method involves the addition of an u~ lolillliulll reagent or a Grignard reagent to sulfuryl chloride following the procedure of S. N. Bhattacharya, et. al., J. Chem. Soc.
25 (C), 1265-1267 (1969). Another convenient method involves the treatment of a thiol with sulfuryl chloride and a metal nitrate according to the procedure of Y. J. Park, et. al., Chemistry Letters, 1483-1486 (1992). Sulfonic acids are also conveniently converted to the corresponding sulfonyl chloride by treatment with PC15, PC13 or SOC12 30 (J. March, Advanced Ore~ni~ (~hlomi~try~ 4th Ed., John Wiley and Sons, New York: 1992, pl297 and references sited therein). Aromatic and l;.,t~,lu~ullldLic compounds may be chlorosulfonylated directly by treatment with Vilsmeier's reagent or chorosulfonic acid (Organic Synthesis, I, 8).

WO95129159 P_ I/ u.. ,~ 56 The diamines 5 are commercially available or readily prepared by methods described in the literature or known to those skilled in the art. Compound 5 where R2 or R3 is methyl can be prepared from the co~ onding amino acid following the method of J.
D. Bloom, et. al., J. Med. Chem., 35, 3081-3084 (1992). As illustrated in Scheme 5 for R3 = methyl, the a~lup.i~ (R) amino acid 12 is cst~rifie-1 conveniently by treatment with methanolic hydrochloric acid, and then treated with di-tert-butyl dicarbonate to give compound 13.
The ester group is reduced with a hydride source such as lithium o borohydride and the resultant alcohol is converted to a leaving group such as a mesylate. Removal of the Boc protecting groups gives diamine 14. This compound is subjected to catalytic hydrogenation in the presence of base such as sodium acetate to give the desired o~-methyl amine 15. The other ~n~ntinmf-r is available through an analogous sequence starting with the corresponding (S) amino acid.

WO 95/Z91~i9 . .,~ .'C :~6 ~1 ~79~2 SCHEMF. 5 H2N (X)m~f/ 1) MeOH, HCI
2 R5~ NH2 BocNH (X)m ~ R4 1 ) LiBH
~ 2) MeSO2CI, Et3N
MeO2C Rs~ NHBoc 3) TFA, CH2C12 H2N (X)m ~ R4 ~ ~ H2, NaOAc ~ 2CF3CO2H cat. Pd H2N (x)m~¢~R4 Me /`~ NH

Diamines ~ or sulfonamide amines 2 where X is -cH2 and m is 1 are also readily prepared by methods described irl the literature or known to those skilled in the art. For example, as shown in Scheme 6, the sodium salt of 4-1liLIu~ ol 16 is alkylated with 1-bromo-2-chl:>lu~ c, conveninetly in refluxing 2-butanone with a base 30 such as potassium carbonate to give chloro derivative 17. The chloride is converted to the COll~ ulldillg amine by treatment with lithium azide followed by reduction with, for example, kiphenylph~srhinp in aqueous tekahydrofuran. Protection of the resultant amine, conveniently as its t-butyl ~ by keatment with di-tert-butyldicarbonate, gives derivative 18. The nitro group is then reduced, for example, by ... . . .. . ~

~O 951291S9 2 1 ~ 7 9 3 2 ~ c catalytic hydrogenation to provide amine 19. Acylation of i"l~""P.l;~t~
19 with sulfonyl chloride 7, followed by deprotection with acid such as trifluoroacetic acid gives the desired intermediate 20.
ScT IF~E 6 NaO~¢~ N2 KtCO ~, C1~~l3~ NO2 1. LiN3, DMF, 60 2. PPh3, THFIH2O, BocNH~ ~ H2, Pd/C
3. Boc annydride, 18 No2 BocNH~ `13~ 1. R7(CH2)rS02CI (~), pyridine, CH2CI2 19 NH2 2- TFAJCH2CI2 (1:3) H2N ~ ~
NHSo2(CH2)r-R7 Alternatively, diamine 5 where X is -CH2O- and m is 1 is available from i~ r~ lr 1~ by treatment with trifluoroacetic acid.
rhis diamine may then be modified as illustrated in Scheme 3.

wo 95/29159 , ~c 2 1 8 7 9 3 2 I ~ C ~
Diamines ~ and sulfonamide amines ~ where X is .
-CH2CH2- and m is 1 are also readily prepared by methods described in the literature or known to those skilled in the art. For example, as shown in Scheme 7, bromo derivative 21 is treated with sodium cyanide 5 to provide nitrile 22. The rlitro group is selectively reduced by treatment with hydrogen and catalytic pr~ lm to provide arnine 23.
Amine ~ is acylated with sulfonyl chloride ~Z to give the ~u~ ulldillg sulfonamide 24. Reduction of compound _ with cobalt chloride and sodium borohydride provides the desired amine 25.

St~TlF.l\/lF 7 Br 3~ NaCN N C ~
NO DMSO 22 ~ No2 H2, Pd/C N C R7(CH2)rSO2CI ( Z) ' ~ ~
MeOH ~ `NH2 pyridine,CH2CI2 NC 3~ CoCl2 6H20 NHSo2(CH2)r-R7 NaBH4, MeOH

H2N 3~
NHSO2(CH2)r~R

W0 95/29159 2 ~ 8 7 9 3 2 P~ .'C :SS6 Alternatively, diamine 5 where X is -CH2CH2- and m is 1 is available from intPnn~ t~ 23 by reduction of the nitrile group with, for example, cobalt chloride and sodium borohydride. This diamine may then be modified as illustrated in Scheme 3.
Tntf nn~ t.os Il and III are coupled by heating them neat or as a solution in a polar solvent such as methanol, ?,~etonitrilt~, tetrahydrofuran, dimethylsulfoxide or N-methyl pyrrolidinone for 1 to 24 hours at l~ aiulc;s of 30 to 150C to provide compounds I as shown in Scheme 8. The reaction is conveniently conducted in refluxing methanol. Alternatively, a salt of amine III, such as the trifluo.~,ac~,Lat~ or hydrochloride salt, may be used. In these cases, a base such as sodium bicarbonate or diethylisopropylamine is added to the reaction mixture. The product is purified from unwanted side products by recrystallization, trituration, lJIC~udtiV~ thin layer 5 chromatography, flash chromatography on silica gel as described by W.
C. Still, et. ~., J. Org. Chem. 43. 2923 (1978), medium pressure liquid L~ la~lly, or HPLC. Compounds which are purified by HPLC
may be isolated as the c~ ollding salt. Purification of int.onn is achieved in the same manner.

W095/291!i9 ~ 1 .8;~93~7 P~1/~ ~CI~5G
S(~F.l~IF 8 O .
(~ +
(R )n R3 ~I~ R6 III

~CHCH2N-C~X)m~l~NSo2(CH2),-R7 R
In some cases, the coupling product I from the reaction described in Scheme 8 may be further modified, for example, by the removal of protecting groups or the manipulation of ~ on, in particular, Rl and R7. These manipulations may include, but are not limited to, reduction, o~ AAtiO~ alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
An alternate method for the synthesis of compound I is illustrated in Scheme 9. Epoxide II is coupled to amine 5 as described above for coupling ill~ ,,.f~llA . ~ II and III (Scheme 8) to giYe aniline d~.liv~livt; ~Z. The secondary amine is selectively protected, for example, as a carbamate by treatrnent with di-tert-butyldicarbonate to provide C~llb~ 2. Alternatively, nitro amine 26 is used in the coupling reaction to provide 28. Following protection as described above, the nitro group is reduced, for example, by catalytic hydrogenation with pAAllArli~ catalyst or raney nickel, to provide i"l~ . ,,,f,liAIf. 29. In some cases, other group may be reduced con~;ullliL~l~ly. For example, if Rl is halogen in intermediate 28, it may wo 95129159 r~ 56 2 1 ~79~2 be converted to hydrogen in int~rm~ t~ 29. Treatment with a sulfonyl chloride in the presence of a base such as pyridine followed by removal of the protecting group with, in the case of a tert-butylcarbamate, acid such as trifluoroacetic acid or mt-th~noli~ hydrogen chloride, provides 5 the sulfonamide I.

~<1 l A ) (R1)n>~ Il H2N-C-(X)m{ ~Z
~i (Z = NH2) 2~ (Z = NO2) 20 (R )n R pS 2) H Pd/C
2:Z (Z = NH2) 2~ (Z = NO2) ,OH Boc R2 (R1)n R3 {¦~
- 30 1) R (CH2)r-s02cl~ base 2) TFA or HCI/MeOH
In some cases, compound I from the reaction sequence illustrated in ~heme 9 may be further modified, for example, by the WO95/291~9 2~ 87g3~ I~,J/I 3'/CI3~6 removal of protecting groups or the manipulation of sllhstitl-f nts on, in .
particular, Rl and R7, as described above. In addition, m:lnir~ tion of ~Ub~ U~ i on any of the intf~rmf ~ tfAs in the reaction sequence illustrated in Scheme 9 may occur. One such example is illustrated in 5 Scheme 10. Compound 30, which is prepared as outlined in Scheme 9 from the collc~l~ullding epoxide, is subjected to reduction using tin(II) chloride to provide compound ~1. Other examples of Sllhcfitll~ntc on compound I which may be reduced to the corr~.sron~lin~ amine by methods commonly known to those skilled in the art include nitro groups, nitriles, and azides N~ R6 ¦ SnCI
~ aq. HCI-MeOH
OH H ,=~, R
H2N~ R~ R~R6 The compounds (I) of the present invention can also be prepared from amine intf rrnf ~ tf c such as those of formula III and 30 haloketone i.,~.. ".f.1i,~rs such as those of formula 2, as shown in Scheme 11. Amine III is alkylated with haloketone derivative ~, ~.~llvclP~ y by treatment of a mixture of III and ~ with base such as polaS:~;ulll carbonate or triethylamine in a polar solvent such as :~retonitrilf~ ~etone or ~ llc~llylrllll~ . The resultant ~nnin~kfsone ~09S~29159 2 ~ 8 793~ r~.,.)~ ~c .)~G
. 32 is reduced wi~, for example, sodium borohydride in methanol to give the desir~d aminoalcohol I.
SCHE~E 1 1 ~X +
~R1~n ~ (X = Cl, Br) ~2 r~
H2N-~ (X)m~ NSo2(CH2)r-R7 m ~,4 ~ ~~ H ~S2 ~l~
(Rl)n CCH2N-C,-(X)m~ NSO2(CH2);R
~2 [H]
~ - I
In some cases, the product I from the reaction described in Scheme 11 may be further mc-~ifiçrl, for example, by the removal of protecting groups or the n~nirll~tinn of cllbstitllPnfc on, in particular, R1 and K7. These manipulations may include, but are not limited to, reduction, oxi~l~tinn, alkylation, acylation, and hydrolysis reactions 3 D which are commonly known to those skilled irl the aIt An alternate synthesis of key intPrm~ t~ 29 is shown is Scheme 12. The alcohol of i~ ~t~ 3 is protected, for examp~e, as its t-butyldimethylsilyl ether to give ll~S derivative 33. This compound is then treated with amine 5 and a base such as diisopropylethylamine in a solvent, typically polar aprotic such as ~c~tnnifril~, at temperatures of WO 95/29159 2 1 8 7 9 3 2 P~ 56 25 to 150 C for 1 to 72 hours. Typically, an iodide source such as .
sodium iodide is added to facilitate the reaction. The protecting group is then removed, in the case of silyl ether, by treatment of the resultant amine 34 with a fluoride source such as tetrabutylammonium fluoride.
5 Protection of the secondary amine as before gives key intermediate 29.
SCHF.l~F. 1?
OR
. ~X +
~J 3(R=H,X=Cl,Br) tR1)n 33 (R = SiMe2tBu) ~2 H2N-C (X)m~l ~ NH2 ~OTBS Hl R2 rl=\ 1 ) TBAF
(R )n CHCH2N-C, (X)m~ kNH2 OH Boc ~2 ~4 ~CHCH2N-CI ~X)m~l~ NH2 R

In some cases, compound I may be synthesized directly from int~.rrn~ t~ ~ Z without protection of the secondary amine. For example, when R2 and R3 are both methyl, aniline derivative 27 is treated with sulfonyl chloride :Z and a base such as pyridine in a solvent 0 9SI291S9 ~ U~ C
ff~f ~ ~ ;i'f~f3 such as dichloromethane at a le~ dlulfc of -30 to 50 C, typically O
C, to provide compound I.
In some cases, the product I from the reaction described in Scheme 13 may be further modified, for example, by the removal of 5 protecting groups or the manipulation of substituents on, in particular, Rl and R7, as described above.
SCHF.MF 13 (R )n OH H R2 2~ (R2,R3 = Me R7(CH2`f,-SO2CI (~,~f base 2 o The compounds (I) of the present invention where R2 and R3 are hydrogen can also be prepared from acid intff~nnfff~fi~tP.s of formula 36 and aTninf ff~lrohols of formula 37, as shown in Scheme 14.
Acid 36 is available from the Cullc"~full.lillg ester 35, typically a methyl or ethyl ester, by treatment with sulfonyl chloride 7 and a base such as 25 pyridine, followed by hydrolysis of the ester with aqueous acid or base.
Acid 36 is coupled to amine 37, which is known in the literature or readily prepared by methoff1s known to those skilled in the art, using a coupling agent such as benzotriazolyl-N-oxy-tris(dimef,llylalllillo)phosphonium hexdlluulu~ o~rh~tff~ or 1-(3-30 dimethyl~ulu~luL,lupyl)-3-ethylcarbodiimide methiodide to provide the amide 38. This is treated with a reducing agent, typically borane, to provide the desired compound I.

WO 95/29159 r~~ .'0155G
~ 8~3~ --S(~TTF~IF. 14 RO-C (X)m~ ~ NH 1 ) ClSO2(CH2)r-R~ (7), base Rs 2) aqueous acid or base ~R = Me orEt, etc.
H-C'(X)m{l~ INSO2(CH2)r~R
OH
~J NH2 (R1)n 3;7 (R )n CCH N~C~(X)m~ ~ INso2(cH2)r-R

[H]

Compounds of the general Formula I may be separated into ;lia~ oi~ ic pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for exarnple methanol or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained ~0 95129159 2 ~ 8 ~ 9 3 2 ~ 5~
. may be separated into individual sterer~ig~mer.s by conventional means, for example by the use of an optically active acid as a resolving agent.
.. Alternatively, any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using 5 optically pure starting materials of known configuration.
The instant compounds can be isolated in the form of their . rlllirRlly acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic trifluoroacetic, propionic, maleic, succinic, malonic and the like. In addition, certain COIII1JOUIId~ contRinin~ an acidic function such as a carboxy or tetrazole, can be isolated in the form of their inorganic salt in which the counterion can be selected from sodium, pot~iulll, lithium, calcium, Il~ l and the like, as well as from organic bases.
As previously inAirRt~.A the compounds of the present invention have valuable rhRrmRr~logirRl properties.
The present invention also provides a compound of the general Formula I or a pl~ UI;r Rlly acceptable salt thereof for use as an active Ill. .,.l.~.l~;r sllhgtRnrr In one aspect, the present invention provides a compound of the general Formula I or a 1~ ;rRlly acceptable ester thereof:
or a rhRrmRrelltirRlly acceptable salt thereof for use in the treatment of obesity in human or non-human animals.
The present invention further provides a cu---~Jou--d of the general Formula I, or a l,llR.lll~.-rlll;~RIly acceptable ester thereof; or ;eRlly acceptable salt thereof, for use in the treatment of hyperglycemia (diabetes) in human or non-human animals.
The disease diabetes mellitus is ~ ala~,t~ ,d by metabolic defects in production and utilization of glucose which result in the 30 failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia. Research on the treatment of diabetes has centered on attempts to nr)rrnRli7e fasting and pr~ 1 blood glucose levels. Tl~,a~ b have included parenteral WO 95129159 I ~ ,,.,.'C I~S6 2~ ~7932 administration of exogenous insulin, oral administration of drugs and dietary therapies.
Two major forms of diabetes mellitus are now recognized.
Type I diabetes, or insulin~ .p~.n(l~nt diabetes, is the result of an 5 absolute deficiency of insulin, the hormone which regulates glucose lltili7~tic)n. Type II diabetes, or insulin-independent diabetes, often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond ul~liat~ly to insulin. Most of the Type II diabetics are also obese.
In addition the ~,u~ uulld~ of the present invention lower triglyceride levels and cholesterol levels and raise high density i~U~lUlCill levels and are therefore of use in cOIll~à~lillg medical conditions wherein such lowering (and raising) is thought to be beneficial. Thus they may be used in the treatment of hyper-5 triglycP.ri~ mi~ hypercholesterolaemia and conditions of low HDL(high density li~u~u~ill) levels in addition to the treatment of uscl~lu~ic disease such as of coronary, cerebrovascular and peripheral arteries, cardiovascular disease and related conditions.
A-,~u~dil~ly, in another aspect the present invention 20 provides a method of lowering triglyceride and/or cholesterol levels and/or increasing high density li~u~,~u~ill levels which .. " . ,1-, ;c~s ~Amini~t~orjn~, to an animal in need thereof, a ~ ui~ y effective amount of a compound of the formula (I) or pharrn~e--ti~lly acceptable salt thereof. In a further aspect the present invention 25 provides a method of treating atherosclerosis which comprises ~minict~rin~, to an animal in need thereof; a th~r~relltirsllly effective amount of a compound of the formula (I) or phzlrmsl~ellti~ y acceptable salt thereof. The compositions are formlllAtPd and :~11mini~t~-.red in the same general manner as detailed below for treating 3 diabetes and obesity. They may also contain other active ingredients known for use in the treatrnent of atherosclerosis and related conditions, for example fibrates such as clofibrate, bezafibrate and gemfibrozil;
inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors for example lovastatin, ~ lva~la~ and pravastatin; inhibitors WO 95/291!i9 P~ 'C 19~i6 ~ ~ B7~
of cholesterol absorption for example beta-sitosterol and (acyl CoA:cholesterol a~yl~ldll~r~lase) inhibitors for example mrlin~mi~if;
anion exchange resins for example cholestyramine, colestipol or a dialkyl~mino~lkyl derivatives of a cross-linKed dextran; nicotinyl 5 alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimetics.
The compounds of the instant invention also have the effect of reducing intestinal motility and thus find utility as aiding in the treatment of various ga~Lluill~e~i"al disorders such as irritable bowel syndrome. It has been proposed that the motility of non-grhinrt~ric smooth muscle contraction is mediated by activity at ,~3 adrenu.~cc;~ol~. The availability of a ~3 specific agonist, with little activity at ~1 and ~2 receptors will assist in the plldlllla~OlOgiC control of intestinal motility without concurrent cardiovascular effects. The instant compounds are ~(l,,,i,,i~l~ .~d generally as described below with 5 dosages similar to those used for the treatment of diabetes and obesity.
It has also been found Illlr,~llç~ r11y that the compounds which act as agonists at J33 ~l~ Olt~ Ul~i may be useful in the treatment of ~5d~ i"lr,li"~l disorders, especially peptic ulcerations, ~su~ha~i~is, gastritis and duodenitis, (including that induced by ~.
20 ~Ls~, intestinal Illrrr~tionc (including i~ y bowel disease, ulcerative colitis, Crohn's disease and proctitis) and ~ Lluill~ ldl Illrrr~tir,ng In addition, ~3 receptors have been indicated to have an effect on the inhibition of the release of n~ulu~ ides in certain sensory 25 fibers in the lung. As sensory nerves may play an illlllOl~dll~ role in the nt;ulu~ ic infl~mm~tion of airways, including cough, the instant specific ,B3 agonists may be useful in the treatment of neurogenetic il~ll,.""",.lion, such as asthma, with minimal effects on the cardio-~UllllUllaly system.
,B3 al.~ o.c;c~ u.~ are also able to produce selective antid~ d..L effects by stimlll~tin~ the ~3 receptors in the brain and thus arl additional ~-)"lr."l.l,.lrd utility of the uu---lJou--ds of this invention are as antid~ s~a.ll agents.

WO 95/29159 P~ . 5'0 1~6 2 1 8 7~32 The active compounds of the present invention may be orally administered as a rh,-l ",~ l composition, for example, with an iner~ diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be c,u~ .c~sed into 5 tablets, or they may be incorporated directly with the food of the diet.
For oral Ih~r~lre~ltic ~-lmini~tr~tion, which includes sublingual administration, these active compounds may be iI~cul~ula~d with excipients and used in the form of tablets, pills, capsules, ampules, sachets, elixirs, suspensions, syrups, and the like. Such cornpositions and preparations should contain at least O. l percent of active compound.
The percentage of active c--mro~ln-1 in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such ~ lly useful compositions is such that an 5 effective dosage will be obtained. The active Co~ oUIldS can also be lmini~tl~.red intranasally as, for exarnple, liquid drops or spray.
The effective dosage of active ingredient employed may vary r1~pPn~lin~ on the particular compound employed, the mode of administration, the condition being treated and the severity of the 20 condition being treated.
When treating diabetes mellitus and/or hyL~ ly~lllià
generally soti~f~tory results are obtained when the culll~oulld~i of the present invention are ~-l",i"i~ d at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, 25 preferably given in divided doses two to six times a day, or in sustained release form For most large m~mm~lg the total daily dosage is from about 10 milligrams to about 1000 milligrams, preferably from about l milligr;lmc to about 50 milli~r~mc In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 30 350 milligrams This dosage regimen may be adjusted to provide the optimal thlqr~relltic response When treating obesity, in conjunction with diabetes and/or hyperglycemia, or alone, general!y ~ticf~t~ry results are obtained when the compounds of the present invention are ~lmini~t~red at a daily 951~9159 P~ u~ Jl~
21 87q32 dosage of from 1 milligram to about lO00 milli~rAmc per kilogram of animal body weight, preferably given in divided doses two to six times a . day, or in sustained release form. For most large mAmmAls, the total daily dosage is from about lO milligrams to about lO,000 milligrams, 5 preferably from about lO milligrams to about 500 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 70 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
The tablets, pills, capsules, and the like may also contain a binder such as gum ~ a~ , acacia, corn starch or gelatin; excipients such as ~lirAlrillm rhocrhAt~; a disiu.L~ i--g agent such as corn starch, potato starch, alginic acid; a lubricant such as mA~n~ m stearate; and a il.g agent such as sucrose, lactose or sArrh~rjn When a dosage unit form is a capsule, it may contain, in addition to materials of the 5 above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a b~vc;t;L~Ilillg agent, methyl 20 and ~ yllJalabens as ~ ,.v~livc;s, a dye and a flavoring such as cherry or orange flavor.
These active compounds may also be ~l",i";~ d parenterally. Solutions or s--~pPnci~m~ of these active ~ ou~d~ can ~e prepared in water suitably mixed with a $1lrfAr~An~ such as hydroxy-propylcellulose. Di~rrrsion~ can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary con~1ifi~-n~ of storage ar~a use, these preparations contain a plt;s~-v~liv~
to prevent the growth of microorganisms.
The rl~ ",;~ ir~l forms suitable for injectable use 30 include sterile aqueous solutions or dib~ i.,lls and sterile powders for the ~t~ ulcul~)us preparation of sterile injectable s~lutions or dispersions. In all cases, the form must be sterile anu must be fluid to the extent that easy syringability exists. It must be stable under the conditions of mAnllf~rtllre and storage and must be preserved against the WO 951291~9 r~ ''O ;~iG
cont~min~tin~ action of microorganisms such as bacteria and fungi.
The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and Iiquid polyethylene glycol), suitable mixtures thereof, and vegetable 5 oils.
The following examples are provided so that the invention might be more fully understood. They should not be construed as limiting the invention in any way.
F~xAMpLE 1 OH
N~ N~13`NH
N=N 2 [2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(tetrazolo[ 1 ,5-a]pyrid-6-yl)ethylamine A solution of 1.62 g (10 mmol) of (R)-2-(tetrazolo[l,S-a]pyrid-6-yl)oxirane (See Fisher and Wyvratt, European Patent Application 0 318 092 A2 for the synthesis of this compound.) and 4.1 g (30 mmol) of 2-(4-arninophenyl)ethylamine in 30 rnL of methanol was heated at reflux for Sh. The reaction rnixture was cullc~ t~d and the 25 residue chromatographed on silica gel (2% methanol/98% methylene chloride) to give 1.69 g (56%) of the title compound:lH NMR (400 MHz, CD30D) o 9.01 (d, lH, J =1.3 Hz), 8.02 (d,l H, J = 9.2 Hz), 7.82 (dd, lH, J = 1.3, 9.2 Hz), 6.94 (d, 2H, J = 6.3 Hz), 6.63 (d, 2H, J = 6.3 30 Hz), 4-91 (m, IH), 2.82 (m, 4H), 2.67 ~t,: H, J = 7.1Hz).

S'C4956 ~V0951~9159 2 ~ ~ 79 32 EXAMPT T~ 2 .
OH
Boc N ,N NH2 \N=N
ao-~-[2-[4-(a~ llyl)]ethyl]-2-hydroxy-2-(tetrazolo[l,5-a]pyrid-6-yl)ethvl~rl?~mic acid 1.~--limerllylethvl ester c . A solution of 1.69 g (56.7 mmol) of the amine from ~xample 1 and 1.23 g (56.7 mmol) of di-tert-butyl dicarbonate in 10 mL of t~tldl~ lluruldll (THF) at 0 C was stirred for 2 h. The reaction mixture was ~,u~ t~dl~d and the residue chromatographed on silica gel (4% methanoV96% methylene chloride) to afford 2.2 g (97%) of the title compound: 1H NMR (400 MHz, CD30D) Q 8.96 (s, lH), 8.05 (m, 2H),7.85(m,2H),6.93(dd,2H,J=7.7,8.3Hz),6.66(d,2H,J=8.3 Hz), 4.99 (m, lH), 3.49 (m, 4H), 2.70 (t, 2H~ J =6.5 Hz), 1.26 (s, 9H).
ExAMpT F 3 nHex-NH H~
2s 4-(Hexyl~minQcarbonyl~mino)~.f..7~ -f-~ fonyl chloride Hexylamine, 12.15 ml (9.2 mmol), was added dropwise to a solution of 10 ml (9.2 mmol) of phenyl isocyanate iD T~TF (150 ml) at 0C, and stirring was continued for 1 h. The solvent was removed in 30 vacuo, and the resultant hexyl phenyl urea was used without further purification.
A 6-g (2.7 mmol) portion was added over 20 min to chlorosulfonic acid at 0C, followed by heating at 60C for 2h. After cooling, the mixture was added to ice/water (lOOml) and the aqueous WO 95/29159 1 ~ .,'0 :~SG
- 2~87~32 phase extracted with EtOAc (3x100 ml). The combined organic phase was washed with brine (50 ml), dried with MgSO4, concentrated, and purified by flash chromatography (silica gel, 75% hexane/ 25% ethyl acetate) to give 6 g (70%) of the title compound: lH NMR (CDC13) o 7.85 (d, 2H, J = 9.6 Hz), 7.54 (d, 2H, J = 9.6 Hz), 6.79 (br.s, IH), 4.71(br. s, lH), 3.23 (t, 2H, J = 8 Hz), 1.54-1.44 (m, 2H), 1.33-1.20 (m, 6H), 0.91-0.79 (m, 3H).

OH Boc NH
N=N ~so2 nHex-NH NH~J
20 (O-N-[4-[2-[N-(l~l-dimethyleth~l~y~lb~llyl)-N-[2-hydroxy-2-(tetra zolo[l,5-a]pyrid-6-yl)]ethyl]amino]ethyl]phenyl]-4-(l~ y~ ;"n~
vlamino)benzenesulfonamide To a stirred solution of 0.200 g (0.502 rnmol) of the Boc-compound from Example 2 in 3 mL of methylene chloride was adde~
25 80 mg (1.00 mmol) of pyridine followed by 0.16 g (0.75 rnmol) of the sulfonyl chloride from Example 3. After being stirred for 5h, the reaction mixture was concentrated and the residue chrom~to~phl~d on silica gel (10% methanol/90% methylene chloride) to afford 0.303 g (88%) of the title compound: lH NMR (400 Hz, CD30D) o 8.95 (s, 30 lH), 8.0-8.08 (m, lH), 7.75-7.87 (m, lH), 7.40-7.62 (m, 4H), 7.00 (m, 4H), 4.95 (m, 2H), 3.47 (m, 2H), 3.15 (m, 2H), 2.75 (m, 2H), 1.52 (t, 2H, J = 6.0 Hz), 1.33 (m, 8H), 1.21 (s, 9H), 0.90 (t, 3H, J = 60 Hz).
\

~0 95129159 2 ~ 8 7 9 3 2 ~ 3'~ 5~5 . FX~PT F S
~ OH H
H2N~ ,N 3`NH
J~ ~
o nHex NH H
(O-N-l4-[2-[[2-hydroxy-2-(6-~lllilloL~ylidin-3-yl)ethyl]amino]ethyl]
phenyll-4-(hexyl~min~c~rbonylamino)~.~,.,7r.,e.~.11fonamide A mixture of 0.302 g (0.44 mmol) of the tetrazine from Example 4, 0.20 g (0.88mol) of tin(II) chloride dihydrate and 0.3 ml of c~,llL~ ed aqueous hydrochloric acid in 2 mL of methanol was heated at reffux for S h. The reaction mixture was col-c~ d and the residue purified by reverse-phase MPLC (C8, 47%methanol/53 0.1%
trifluoroacetic acid buffer) to give 0.32 g (78%) of the title compound 20 as its bistriflu~,loact;~c salt: lH NMR (400 MHz, CD30D) o 7.96 (dd, lH, J = 2.0, 9.2 Hz), 7.86 (d, lH, J = 2.0 Hz), 7.59 (d, 2H, J = 8.8 Hz), 7.43 (d, 2H, J = 8.8 Hz), 7.14 (d, 2H, J = 8.4 Hz), 7.07 (d, 2H, J = 8.4 Hz), 7.03 (d, lH, J = 9.2 Hz), 4.92 (m, lH), 3.23 (m, 2H), 3.15 (m, 2H), 2.93 (m, 2H, 4.0 Hz), 1.49 (t, 2H, J = 6.0Hz), 1.32 (m, 8H), 0.91 (t, 3H, 25 J = 6-0 Hz); CI MS m/z 555(M+l).
Following the procedures outlined for Fx~mrl.os l-S, the compounds listed in Table 1 were prepared.

WO 95/29159 . ~ 4~56 T.ART,F, 1 H2N ~ tl H O
Example R Selected lH NMR (CD30D) Data o 6 Ph, trifluoroacetate salt 7.74 (m,2H), 7.53 (m, lH), 7.45 (m, 2H).
7 2-naphthyl, 7.93 (m, 4H), 7.75 (d, IH, J = 1.7 trifluoroacetate salt Hz), 7.61 (m, 2H) 8 3-quinolinyl, 9.00 (d, lH, J = 2.3 Hz), 8.06 (m, trifluol~,act;~ salt 2H), 7.94 (m, 2H), 7.72 (t, lH, J =
7.2 Hz) 9 1,2-b.qn7i~o~ 7c)l-5-yl, 9.02 (s, lH), 8.30 (d, lH, J = 1.3 trifluoroacetate salt Hz), 7.90 (m, lH), 7.77 (m, lH) 4-iodophenyl, 7.83 (d, 2H, J = 8.6 Hz), 7.46 (d, Llinuoloac~iL ~ salt 2H, J = 8.6 Hz) 11 4-[(N-hexyl,N-methyl- 7.62 (d, 2H, J = 4.6 Hz), 7.48 (d, aminocarbonyl)amino]- 2H, J = 4.6Hz), 2.99 (s, 3H) phenyl, trifluc,l~,ace salt 25 12 4-[(N,N-dimethyl- 3.0 (s, 6H) arninocarbonyl)amino] -phenyl, Llinuol~,acetate salt 13 4-(3-hexyl-2- 3.88-3.83 (m, 2H), 3.57-3.50 (m, imidazolidinon-1- 2H), 2.89-2.95 (m, 2H), 1.61-1.52 yl)phenyl, (m, 2H), 1.37-1.30 (m, 6H), and trifluoroacetate salt 0.93-0.88 (m,3H) 95129159 r_l~u,,. _/0 :956 ~ ~793~
. E~;AMPLE 14 ~J~ CI
N HCI
3-(2-Chloroacetyl)pyridine hydrochloride To a solution of 12 g (11 mL, 100 mmol) of 3-a~lyl~ylidil.c in 100 mL of ethyl ether was added 100 mL of 1 M
ethereal hydrogen chloride. The resultant ~Iu.,i~ lc was filtered and 15.0 g (95.2 mmol) was collected and placed in a 500-mL round bottom flask equipped with a magnetic stir bar. To this was added 95 mL of 1 M hydrogen chloride in acetic acid. After the mixture was stirred until 5 all the solid had dissolved, 12.7 g (95.2 mmol) of N-chlol-,~uc~;illilllide (NCS) was added in one portion. The solution turned yellow and the NCS gradually di~solved. After 4 h, a white ~ iL~l~ had formed.
The mixture was allowed to stir for 2.5 days. It was then filtered. The solid collected was washed with 10 mL of acetic acid and 200 mL of 20 ethyl ether to give 15.2 g (83%) of the title compound as a white solid:
IH NMR (200 MHz, d6-DMSO) o 9.22 (t, lH, J = 1 Hz), 8.29 (dd, IH, J
= 1.6, 5.1 Hz), 8.55 (td, lH, J = 2, 8.1 Hz), 7.82 (ddd, lH, J = 0.8, 5.1, 8.1 Hz), 5.27 (s, 2H).

OH
~
(R)-a-Chloromethyl - 3-pyridinemethanol To a stirred solution of 3.67 g (11.5 mmol) of (-)-B-chlorodiisopin-~r~mrh~ylborane [(-)-DIP-CI] in 11 mL of THF at -25 C was added a slurry of 1.00 g (5.21 mmol) of the product from .

WO95/29159 ~` 11IJ~--'~j-'(i 2 1 8 7q32 Example 14 in S mL of THF via a cannula. Following the addition of 0.80 mL (5.79 mmol) of triethylamine, the reaction mixture was stirred at -25 C for 4 days. To the mixture was added 10 mL of water which was then allowed to warm to room ~ ;ld~UI~. To the mixture was 5 added 20 mL of ethyl acetate and the organic phase separated. The aqueous phase was neutralized with saturated NaHCO3 solution then extracted six times with ethyl acetate. The combined organic phase was ~,u", ~.,l...~. d in vacuo to afford a yellow oil. Flash chromatography (silica gel, 75 - 100% ethyl acetate-hexanes) afforded 561 mg (68~o) of the title compound as a pale yellow oil: IH NMR (400 MHz, CD30D) o 8.58 (d, IH, J = 1.8 Hz), 8.46 (dd, lH, J - 4.9, l.S Hz), 7.90 (d, lH, J =
7.9 Hz), 7.44 (dd, lH, J = 7.9, 4.9 Hz), 4.93 (m, lH), 3.75 (m, 2H).

[~

(R)-(Pyrid-3-yl)oxirane To a solution of 557 mg (3.55 mmol) of the product from Example lS in 16 mL of acetone was added 1.80 g of ~ iul--carbononate. The mixture was heated at reflux for 20 h then cooled to 25 room L~lllp~;ldlul~. The mixture was filtered and the filtrate evaporated in vacuo. Flash chromatography (silica gel, 2% methanol-methylene chloride) afforded 262 mg (61~o) of the title compound as a pale yellow oil: lH NMR ~200 MHz, CDC13) o 8.54 (m, 2H), 7.52 (m, lH), 7.24 (m, lH), 3.86 (dd, lH, J = 4.0, 2.5 Hz), 3.17 (dd, lH, J = 5.4, 4.0 Hz), 30 2-80 (dd, lH, J = 5.4, 2.5 Hz).

95129159 ~ u.,,~ 'C 1~5C.
OH
~ ,H NH2 (R)-N-r2-r4-(Aminophenvl)lethyll-2-hydroxy-2-(pyrid-3-yl)ethylamine To a stirred solution of 377 mg (2.44 mmol) of o 4-aminophenethylamine in 10 mL of methanol was added a solution of 300 mg (2.48 mmol) of the product from Example 16 in 15 mL of methanol. The mixture was heated at reflux for 16 h then cooled to room ~III~IdlUlC;. The methanol was removed in vacuo and the residue chromatographed (silica gel, 6 - 8% m.-th~n-)l, 1% ammonia-methylene 5 chloride) to afford 101 mg (16%) of the title compound together with 279 mg of a mixture that was l~ lu~ld~ ed (5% methanol, 1%
ammonia-methylene chloride) to give a further 54 mg (9%) of the title ~_ullll~uulld as an off-white solid: lH NMR (500 MHz, CD30D) o 8.52 (d, lH, J = 1.8 Hz), 8.43 (dd, lH, J = 4.8, 1.4 Hz), 7.81 (m, lH), 7.40 20 (m,lH),6.95(d,2H,J=8.3Hz),6.67(d,2H,J=8.3Hz),4.81(m, lH~, 2.90-2.65 (m, 6H).
FXAMPT.F 18 ~I` BNC NH2 ao-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(pyrid yl)ethylcarbamic acid l.l-dimethylethyl ester A solution of 386 mg (1.77 mmol) of di-tert-butyl dicarbonate in 3.5 mL of THF was added, via a cannula, to a stirred slurry of 456 mg (1.77 mmol) of the product from Example 17 in 3.6 WO 95/29159 P~ '0 :9~G
2~ 87932 mL of THF cooled to 0 C. The yellow solution was stirred at 0 C for 3 h, then the THF was removed in vacuo. Flash chromatography (silica gel, 10% ml-th~nol, 1% ammonia-methylene chloride) afforded 549 mg ~.
(87%) of the title compound as an off white solid: lH NMR (500 MHz, CD30D, mixture of rotomers) o 8.45 (m, 2H), 7.83 (d, 0.6H, J = 7.4 Hz), 7.78 (d, 0.4H, J = 6.9 Hz), 7.41 (m, lH), 6.94 (d, 0.8H, J = 8.0 Hz), 6.89 (d, 1.2H, J = 7.8 Hz), 6.66 (d, 2H, J = 7.3 Hz), 4.89 (m, lH), 3.42-3.21 (m, 4H), 2.67 (m, 2H), 1.39 (s, 5.4H), 1.36 (s, 3.6H).
o An alternative synthesis of the aniline derivative in Example 18 is illustrated in F.~ nnpl~ 19-23:
FX~ MPLE 19 O
CI~JI "Br 20 2-Chloro-5-(2-bromoacetyl)pyridine hydrochloride A solution of 784 mg of 2-chloro-5-a~yl~,y~ .e in 10 mL of THF was added via canula to a solution of 1.44 g of dibl.~lllo~ lic acid (DBBA) in 10 mL of THF. The resultan~
solution was heated at 50-55 C for 12 h, and then an additional 0.72 g 25 DBBA was added. After stirring at 50-S5 C for 2.5 more hours, 0.36 g DBBA was added. The mixture was allowed to stir for 2 h at which point NMR analysis of an aliquot indicated 87% conversion. The reaction mixture was cooled, diluted with ethyl acetate, washed with two portions of saturated aqueous sodium bicarbonate, water, and brine, 30 dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica gel, 15% ethyl acetate~exane) provided 0.86 g (73%) of the title compound as a white solid: lH NMR (400 MHz, CDCI3) o 8.96 (d, lH, J = 2.6 Hz), 8.21 (dd, lH, J = 2.5, 8.3 Hz), 7.46 (d, lH, J = 8.4 Hz), 4.37 (s, 2H). The NMR also indicated the presence ~095129159 21 87q32 .~ o U36 .. of the cu~ ul~dillg 2-bromo derivative. The ~4:1 mixture was carried on through the synthesis.

OH
Cl~ Br (R)-cc-Bromomethyl-3-(6-chloropyridine)methanol To a solution of 602 mg (1.88 mmol) of (-)-DIP-CI in 0.5 mL of THF at -25 C was added via canula 200 mg of ketone from Example 19 in 1.5 mL of THF at -25 C. The reaction mixture was 5 allowed to stir at -25 C for 17 h. It was then quenched by the addition of water and extracted with ether. The ether phase was diluted with ethyl acetate, washed with two portions of saturated aqueous sodium bicarbonate, water, and brine, dried over ", g~ sulfate and cull~t;ll~la~d. Purification by flash chromatography (silica gel, 15 and 20 25% ethyl acetate/hexane) gave 170 mg (84%) of the title cu---~-uu--d.
H NMR (400 MHz, CDC13) ~ 8.38 (d, lH), 7.70 (dd, lH), 7.32 (d, lH), 4.97 (m, IH), 3.61 (dd, lH), 3.50 (dd, lH), 2.85 (d, lH).

o CI
(R)-(2-chloropvrid-5-yl)oxir~ne - To a solution of 100 mg of bromoS~lr~-h- l from Example 20 in 2 mL of 1:1 THF:water was added 1 mL of 5 N aqueous sodium hydroxide solution. The mixture was allowed to stir for 10 min. It was then extract~d with three portions of dichlornmPth~n- The combined wo 95/29159 . ~ C ~6 ~7 8~3~ --organic phases were washed with two portions of water and brine, dried .
over m~n~ m sulfate, and concentrated to give 98 mg (93%) of the title compound which was used without further purification: IH NMR
(400 MHz, CDC13) o 8.34 (d, IH), 7.48 (dd, lH), 7.29 (d, lH), 3.86 (dd, IH), 3.18 (dd, lH), 2.78 (dd, lH).

Boc Cl J~ , N--3~ N2 -[2-[4-(Nitrophenyl)]ethyl]-2-hydroxy-2-(2-chloropyrid-5-5 yl)ethylcarbamic acid l.l-dimethylethyl ester Following the procedure outlined in F~slmrlf c 17 and 18, the title compound was prepared from the epoxide from Example 21 and 4-lliL~u~l~c;~ylethylamine: IH NMR (400 MHz, CDC13) o 8.32 (d, lH, J = 1.3 Hz), 8.13 (d, 2H, J - 8.6 Hz), 7.66 (br m, lH), 7.30 (d, 2H, 20 J = 8.1 Hz), 7.27 (br m, lH), 4.94 (br m), 3.38 (br m, 4H), 2.84 (br m, 2H), 1.40 (s, 9H).
FXAMP! F 23 ~1 ,N ¢~`NH2 3 ~-~-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(pyrid-3 yl)ethylcarbamic acid l.l-dimethylethyl ester To a solution of 80 mg (0.19 mmol) of the nitro compound from Example 22 in 2 mL of ethanol was added 0.114 mL (0.57 mmol) of S N aqueous sodium hydroxide solution and 20 mg of rarley nickel.

0 95/29159 1 ~, I /IJ.. _ .'0 1,~
2~ ~7q32 ~- The reaction mixture was shaken at room ~ laLul~ under 45 psi hydrogen for 16 h. The mixture was neutralized with saturated aqueous sodium phosphate monob~ir and extracted with three portions of ethyl acetate. The combined organic phases were washed with water and 5 brine, dried (m:l~n-~gillm sulfate), and concentrated to give 40 mg (59%) of the title compound which was identical to the sample prepared in Example 18.

o ~SO2CI
nHex~NJ~NJ~J

4-(3-Hexyl-2-imidazolon-1-yl)phenylsulphonvl chloride Hexyl iodide (SOmmol, 7.38ml) was added to a mixture of 2-amino acetaldehyde dimethyl acetal (lOOmmol, llml) and p~,l,.~;.....
carbonate (SOmmol, 6.9g) in DMF (lOml) at 0C. Stirring was 20 contin~ d for 16h before diluting with ethyl acetate (200ml), and filtering the solution through a plug of celite. C.~.l.~ ..~I.;.I;~n in vacuo was follwed by column chromatography (eluant ethyl acetate) to give N-hexyl 2-amino acetaldehyde dimethyl acetal (7.39g, 78%) as a colourless oil.
To the amine (38.6mmol, 7.3g) in methylene chloride (lOOml) at 0C was added 4-(chlorosulphonyl) phenyl isocyanate (38.6mmol, 8.4g). The reaction mixture was stirred for 20mins until a clear solution had formed, and 1:1 water: trifluoroacetic acid (lOOml total) was added. Vigorous stirring was continued for 16h., the layers 30 separated, the organic layer was diluted with ethyl acetate (SOOml) and washed with saturated sodium bi~,allJull~l~ solution (4xSOml), brine (SOml), dried with anhydrous mll~n.ocillm sulphate, and concentrated in vacuo. Column chromatrography (eluant 3 hexane/ I ethyl acetate) yielded the title compound as pale yellow crystals (8.8g, 67%).

WO9S/29159 r~~ o ~SG
2~87932 EX~MP! F 25 OH - .
~ "N NH
nHex-NH H)3,so2 (O-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-(hexylaminocarbonyl ~mino)benzenesulfonamide To a solution of 302 mg (0.845 mmol) of the product from Example 18 and 137 mL (1.69 mmol) of pyridine in 10 mL of methylene chloride was added 296 mg (0.928 mmol) of 4-(hexylaminoca~bonylamino)l,r .~.~"- ,.~lfonyl chloride from Example 3. The reaction was stirred for 12 h then the solvent removed in vacuo.
Flash chromatography (silica gel, 6% m~th~ l, 0.5% ammonia-20 methylene chloride) afforded 468 mg (87%) of the BOC-protected title co...~ ,ou..d.
A solution of 468 rng (0.731 mmol) of BOC-protected title compound in 5 mL of methylene chloride and 5 mL of trifluoroacetic acid was stirred for 30 min then the volatile c~".,~ lr~ removed in 2~ vacuo. The residue was a~oL~ ed twice with 10% methanol/toluene, twice with mP.th:ln(ll, then dried in vacuo to give 521 mg (93%) of the title compound as its L.inu.~lac"t~e salt: IH NMR (400 MHz, CD30D) 8.8g (s, IH), 8.79 (d, lH, J = 5.5 Hz), 8.53 (d, lH, J = 8.2 Hz), 7.99 (m, lH), 7.59 (dd, 2H, J = 6.9, 1.9 Hz), 7.43 (dd, 2H, J = 6.9, 1.9 Hz), 30 7.15 (dd, 2H, J = 8.6, 2.1 Hz ~, 7.08 (dd, 2H, J = 8.6, 2.1 Hz), 5.23 (m, lH), 3.40-3.10 (m, 6H), 2.94 (m, 2H), 1.49 (m, 2H), 1.32 (m, 6H), 0.90 (m, 2H).

~o 95/29159 , ~"I,.,,r~c :9s6 :~ 8~932 - CbzNH 13~
NH
NC J3' 10 ~ ~4 [2 ~(pl~ ly~ llo;~y~ llyl)amino]ethyl]phenyl]-4 cyanoben7f~n~ulfonamide Following the procedure outlined in Example 4, the title compound was prepared from 2-(4-dlllillu~llc;llyl)ethylcarbamic acid phenylmethyl ester (see Fisher, et. al., Eur. Pat. Appl. 0 611 003 Al, 15 1994) and 4-cy~n- b~ , -lfonyl chloride: IH NMR (400 MHz, CD30D) o lH ~MR (400 MHz, CDC13) o 7.81 (d, 2H, J=8.7Hz), 7.69 (d, 2H, J=8.7Hz), 7.32 (m, SH), 7.06 (d, 2H, J=8.4Hz), 6.96 (d, 2H, J=8.4Hz), 6.75 (s, lH), 5.06 (s, 2H), 4.71 (t, br, lH), 3.38 (q, 2H, J=6.9Hz), 2.74 (t, 2H, J=7.0Hz).

EXAMPT F. 27 CbZNH 3~
NH
~SO2 H2N ~l~
' 30 HO
(0-[4-[2-[(pll~,llyllll~ u~y.~ u''yl)amino]ethyl]phenyl]-4-~minoo,lrimidomethyl)benzensulfonamide A mixture of the nitrile from Example 26 (2.71g, 6.23mmol), absolute ethanol (65ml), finely divided K2co3 (5.17g, WO g5/29159 P~ .,G
2~7932 37.4mmol), and hydroxylamine hydrochloride (2.17g, 31.2mmol) was refluxed for 6 h. The ethanol was removed under reduced pressure.
The resulting solid was dissolved in ethyl acetate and washed with water 3 times. The organic phase was concentrated in vacuo to 2.87g (98%) of 5 the title ~u~ uulld as a white powder which was of sufficient purity to be used in subsequent steps: 1H NMR (400 MHz, CD30D) o 7.71 (s, 4H), 7.31 (m, 5H), 7.04 (d, 2H, J=8.4Hz), 6.99 (d, 2H, J=8.4Hz), 5.02 (s, 2H), 3.25 (t, 2H, J=6.8Hz), 2.67 (t, 2H, J=6.7Hz).
o FXAMPLE 28 CbzNH 3~
,NH
~SO2 N /~) , / o~N

(rD-[4-[2-[(L~ lyllll~ ycarbonyl)amino]ethyl]phenyl]-4-[s-(3 L~y~lv~ lylyl ~,~yl)-rl .2.41-oxadiazol-3-ylll,. .,~ for~mi(l~o To a solution of ~-)rnro--n~1 from Example 27 (0.468g, l.OOmmol) in dry pyridine (5.0ml) was added 4-cyclopentylbutyryl chloride (0.175g, l.OOmmol). The mixture was refluxed for 3.5 h. The pyridine was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (35% ethyl acetate in hexanes~ to give 0.152g (26%) of the title compound: 1H NMR (400 MHz, CDCL3) o 8.12 (d, 2H, J=8.7Hz), 7.81 (d, 2H, J=8.7Hz), 7.31 (m, SH), 7.03 (d, 2H, J=8.1Hz), 6.97 (d, 2H, J-8.4Hz), 6.67 (s, lH), 5.05 (s, 2H), 4.70 (t, br, lH), 3.37 (q, 2H, J=6.5Hz), 2.91 (t, 2H, J=7.6Hz), 2.72 (t, 2H, J=7.0), 1.90-1.70 (m, 5H), 1.65-1.30 (m, 6H), 1.06 (m, 2H).

-~0 95/79159 2 1 8 7 q 3 2 r~ 9~6 - l~XAMPLE 29 '- H2N 3~
NH
~SO2 N~
~</o~ N
N-[4-(2-aminoethyl)phenyl]-4-[5-(3-cycl~ lLyl~ l)-[1,2,4]-5 oxadiazol-3-yllbenzensulfonamide A mixture of Cbz amine from Example 28 (0.145g, 0.246mrnol), rq~ m hydroxide on carbon (0.02g), and glacial acetic acid (5.0ml) was hydrogenated for 2 h. The acetic acid was removed under reduced pressure. The residue was purified by silica gel 20 chromatography (1: 9 of 10% :~mm--ni--Tn hydroxide in methanol:
methylene chloride) to giYe 0.058g (52%) of the title l~ )UUlld. lH
NMR (400 MHz, CD30D) o 8.11 (d, 2H, J=8.6Hz), 7.87 (d, 2H, J=8.5Hz), 7.06 (d, 2H, J=8.6Hz), 7.02 (d, 2H, J=8.7Hz), 2.97 (t, 2H, J=7.5Hz)~ 2.84 (t, 2H, J=6.9Hz), 2.67 (t, 2H, J=7.5Hz), 1.90-1.75 (m, 25 5H), 1.70-1.40 (m, 6H), 1.12 (m, 2H).

WO 95/29159 r~ o l~SG
~ ~7~
-OH H NH
~q~S02 N
~/ 11 15 a~)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]~
[5-(3-cyclu~ yl~ ",yl)-rl.2.41-oxadiazol-3-ylll,...,~r..~.llfonamide To a solution of arnine from Example 29 (0.053g, 0.117mmol) in dry methanol (30.0ml) was added 3-pyridine epoxide from Example 16 (0.021g, 0.175rnmol). The resulting solution was 20 refluxed overnight. After c~ l;cn, the residue was purified by silica gel ~ )".~ Y (13% methanol in methylene chloride) to give O.Olg (15%) of ~e title CWII~OUU~. lH NMR (400 MHz, CD30D) o 8.52 (d, lH, J=1.9Hz), 8.42 (dd, lH, J=1.5, 4.8Hz), 8.13 (d, 2H, J=8.6Hz), 7.85 (m, 3H), 7.40 (dd, lH, J=4.8, 7.8Hz), 7.10 (d, lH, 25 J=8.6Hz), 7.03 (d, 2H, J=8.6Hz), 4.81 (dd, lH, J=4.9, 8.1Hz), 2.96 (t, 2H, J=7.5Hz), 2.93-2.70 (m, 6H), 1.90-1.72 (m, 5H), 1.68-2.48 (m, 4H), 1.42 (m, 2H), 1.11 (m, 2H).

0 95129159 ~ .'0 19~6 OH H NH
~SO2 HO\ N_ --/~N
R = nHex R=H Me (O-_-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(1 -hydroxy- 1 -hexylheptyl)-5-methyl-[ 1 ,2,3]-triazol-2-yl]br-I~.rl~r~l~1 ru~ lide and (O-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(1 -(R.S)-hydroxyheptyl)-5-methyl-rl.2~31-triazol-2-vllbcl,7~.,. .~lllfonamide To a solution of 180 mg of (O-~-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-(4-metho~yc~bvllyl-5-methyl-[1,2,3]-triazol-2-yl)l,~ ,,r~ lfonamide (prepared ac-,vl-lillg to the procedures outlined in examples 14-19) in 2 mL of distilled THF
under argon at OoC was added, dropwise, 2 mL of a 2.0M solution of n-hexylm~gn--cillrn bromide in ether. After S min, the reaction was quenched with cautious addition of 5 mL of aqueous ;1l,,,,,..,,;-,...
chloride followed by ethyl acetate extraction of the aqueous layer. The combined organic extracts were dried over sodium sulfate, filtered, and ~;vll.;~ l.,t~,d in vacuo to yield the crude products. ~ ~dliv~ layer chromatography (PLC) on 2X0.5 mm thick silica gel plates eluted in 9:1 (v/v) dichlol~",..~ ,- Illr~ l gave two bands A (20 mg) and B
(60mg). IH NMR (500 MHz, CD30D) of A: o 8.51 (d, lH, J=2 Hz), 8.41 (dd, lH, J=1.5, 5 Hz), 8.01 (dd, 2H, J=2.5, 6.5Hz), 7.81 (m, lH), 7.78 (dd, 2H, J=2.0, 9.0 Hz), 7.37 (m, lH), 7.07;7.02 (ABq, 4H, Jab=
8.5 Hz), 4.86 (s, CD30H), 4.79 (dd, lH, J= 7.5, 8 Hz), 2.9-2.7 (m, 6H), 2.44 (s, 3H), 1.85 (m, 4H), 1.40-1.15 (m, 16H), 0.83 (t, 6H, J=7 Hz) WOgS/29159 2 ~ 8 7932 1~ 56 in~lic~ting the dihexyl tertiary alcohol adduct, mass spec. expected 677 found 677. IH NMR (500 MHz, CD3~D) of B: 8.51 (d, lH, J=2 Hz), 8.41 (dd, lH, J=1.5, 5 Hz), 8.03 (d, 2H, J=9 Hz), 7.78 (d, 2H, J=9 Hz), 7.37 (dd, lH, J= 4.8, 7.7 Hz), 7.07;7.02 (ABq, 4H, Jab=8 Hz), 4.86 ~s, CD30H), 4.80 (m, 2H), 2.9-2.7 (m, 6H), 2.38 (s, 3H), 1.87 (m, 2H), 1.44 (m, lH), 1.4-1.2 (m, 7H), 0.87 (t, 3H, J=7 Hz) in~ir~ting the mono-hexyl adduct. Mass spec expected 591 (for the hexyl ketone) found 593 (hexyl alcohol, int~rmf~ t~ ketone reduced by Grignard reagent in situ).

Following the procedures outlined for F.x:lmpll~c 14-31, the compounds listed in Table 2 were prepared.
T~R! F 2 OH H
¢~, N `13` H ' lo~ R

Example R Selected 1H NMR (CD30D) Data 32 4-isc,~I~J~yllJhenyl 7.64 (d, 2H, J = 8.0 Hz), 7.33 (d, 2H, J = 8.0 Hz), 4.80 (m, lH), 2.95-2.70 (m, 7H), 1.22 (d, 6H, J = 6.7 Hz) 33 4-iodopheny1 7.84 (d, 2H, J = 8.6 Hz), 7.47 (d, 10.1, 3.0 Hz), 3.40-3.20 (m, 4H), 2.96 (m, 2H) 34 2-naphthyl 8.28 (s, lH), 7.94 (m, 3H), 7.72 (dd, lH, J = 8.7, 1.9 Hz), 7.60 (m, 2H) 3-quinolinyl, 9.01 (d, lH, J = 2.3 Hz), 8.76 (d, bistrifluoroacetate salt lH, 1 8 Hz), 8-08 (d, lH, J - 8j7 (m, lH), 7.73 (m, lH) 0 9S/29159 r~ r l,~G
2~ ~793~
-- 36 4-[(N-hexy1,N-methy1- 5-12 (d, IH, J - 8.7 Hz), 3.40-3.10 aminocarbonyl) (m, 6H) 2 99 (s, 3H), 2 95 (m, 2H), .- amino]phenyl, (m, 3H) bistrifluulu~;c;~ salt 37 4-(3-hexyl-2- S.lS (m, lH), 3.85 (m, 2H), 3.53 imi(i~7o~ inon-l- (m, 2H), 3.40-3.15 (m, 6H), 2.94 yl)phenyl, (m, 2H), 1.55 (m, 2H), 1.32 (m, bistrifluoroacetate salt 6H), 0.89 (m, 3H).
o 38 4-[(1-oxoheptyl)- 2.35 (tr, 2H, J=7.5 Hz), 1.65 amino]phenyl, (quint., 2H, J=7. 1 Hz), 1.32 (m, b~ inuuludc~l~t~ salt 6H), 0.892 (tr, 3H, J=6.8Hz).
39 4-[(1-oxo-4-phenyl- 7.34-7.25 (m, 4H), 7.15-7.05 (m, butyl)amino]phenyl, SH), 2.71 (tr, 2H, J=7.7Hz), 2.36 bi~LIinuulua~ salt (tr, 2H, J-7.4 Hz), 1.96 (m, 2H).
4-[(propoxycarbonyl)- 4.07 (tr, 2H, J=6.6 Hz), 1.67 amino]phenyl (sextet, 2H, J=7.0 Hz). 0.968 (tr, 3H, J=7.4 Hz).
41 4-[[[(fur-2- 7.40 (d, lH, J = 0.9 Hz), 6.32 (dd, ylmethyl)amino]car- lH, J = 2.9, 1.8 Hz), 6.23 (d, lH, J
bonyl]amino]phenyl, = 2.9 Hz), 4.34 (s, 2H) hi~rifl~ u~c~ salt 42 4-[[[(2- 7.38-7.02 (m, 9H), 3.50-3.15 (m, phenylethyl)amino]car- 6H), 2.80 (m, 2H) bonyl]amino]phenyl, bistrifluoroacetate salt 43 4-[[[(2-indol-3- 7.58-7.53 (m, 3 H), 7.42-7.30 (m, 4 ylethyl)amino]carbon- H), 7.08-6.94 (m, 7H), 3.48 (tr, 2 yl]amino]phenyl H, J=6.9 Hz) 2.94 (tr, 2H, J=6.8 3 o Hz).
44 4- 2.94 (m, 2H), 1.51 (tr, 2H, J=6.8 [[(octylamino)carbonyl] Hz), 1.30 (m, lOH), 0.884 (tr, 3H, amino]phenyl, J=6.9 Hz).
bistrifluoroacetate salt WO 95/~9 159 P~ I I ~1,,,~'0 1356 - 2 ~ ~ 7932 45 1- 7.83 (d, 2H, J = 9.2 Hz), 7.48 (m, .
[(hexylamino)carbonyl] 2H), 3.92 (t, 2H, J = 8.8 Hz), 3.1-indolin-5-yl 3.2 (two overlap-ping t, 4H), 1.54 (m, 2H), 1.30 (m, 6H), 0.90 (t, 3H, J=6.8Hz).
46 1- 7.83 (d, 2H, J = 9.2 Hz), 7.48 (m, [(octylamino)carbonyl]- 2H), 3.92 (t, 2H, J = 8.8 Hz), 3.1-indolin-5-yl 3.2 (two overlap-ping t, 4H), 1.63 (m, 2H), 1.30 (m, lOH), 0.89 (t, 3H, o J=6.9Hz) 47 1-[(N-methyl-N- 7.53 (m, 2H), 6.90 (d, lH, J = 8.3 octylamino)carbonyl]- Hz), 3.89 (t, 2H, J = 8.4 Hz), 3.26 indolin-5-yl (t, 2H, J = 7.6 Hz), 3.04 (t, 2H, J =
8.4 Hz), 2.91 (s, 3H), 1.60 (m, 2H), 1.27 (m, lOH), 0.87 (t, 3H, J = 6.8).
48 l-(1-oxononyl)indolin- 7.49 (m, 2H), 8.09 (d, lH, J=9.1), 5-yl 4.04 (t, 2H, J=8.5), 3.07 (t, 2H, J=8.5), 2.41 (t, 2H, J=7.5), 1.62 (m, 2H), 1.30 (m, lOH), 0.88 (t, 3H, J=6.8) 49 1-(4-mt;lllyl~ .Lvl-2- 7.87 (d, lH, J= 8.6 Hz), 7.58 (lH, yl)indolin-5-yl dd, J = 2.0, 8.6 ~z), 7.52 (d, lH, J
= 2.0 Hz), 6.48 (s, lH), 4.08 (t, 2H, J=8.7Hz),3.25(t,2H,J=8.7Hz), 2.30 (s, 3H).
1-(4-octylthiazol-2- 7.97 (d, lH, J= 8.6 Hz), 7.57 (lH, yl)indolin-5-yl dd, J = 2.0, 8.6 Hz), 7.53 (d, lH, J
= 2.0 Hz), 6.49 (s, lH), 4.06 ~t, 2H, J=8.8Hz),3.24(t,2H,J=8.8Hz), 2.62 (t, 2H, J = 7.5 Hz), 1.68 (m, 2H), 1.2-1.4 (m, lOH), 0.88 (t, 3H, J = 7.0 Hz).

95/29159 P~ l.. _.'C ~5~i 2 1 ~3~
. Sl 1-(4-ethyl-S- 7.87 (d, lH, J= 8.5 Hz), 7.54 (lH, methylthiazol-2- dd, J = 2.0, 8.5 Hz), 7.50 (d, lH, J
- yl)indolin-S-yl = 2.0 Hz), 4.02 (t, 2H, J = 8.7 Hz), 3.20 (t, 2H, J = 8.7 Hz), 2.56 (q, 2H, J = 7.7 Hz), 2.26 (s, 3H), 1.20 (t, 3H, J = 7.7 Hz).
52 4-(3-octyl-2- 4.78 (m, IH), 3.83 (m, 2H), 3.52 imi~l~7- 1i(1int-n-l- (m, 2H), 3.24 (t, 2H, 8Hz), 1.60-yl)phenyl l.S1 (m, 2H), 1.35-1.25 (m, lOH), o 0.88 (t, 2H, 8Hz).
53 4-[3-(4,4,4- 3.86 (m, 2H), 3.54 (m, 2H), 3.40-trifluorobutyl)-2- 3.20 (m, 6H), 2.19 (m, 2H), 1.82 imidazolidinon-l- (quin, J = 7.9 Hz, 2H) yl]phenyl, bistrifluoroacetate salt 54 4-[3-(3-phenylpropyl)- 7.20 (m, 4H), 7.10 (m, lH), 5.15 2-imi(l~7~ 1innn-1- (dd, IH, 9.6,4Hz), 3.75 (m, 2H), yl]phenyl, 3.46 (m, 2H), 3.36-3.20 (m, 6H), bistrifluoroacetate salt 2.95-2.91 (m, 2H), 2.65 (t, 2H, 8Hz), 1.90 (qu, 2H, 8Hz).
SS 4-[3-(4,4,5,5,5- 3.87 (m, 2H), 3.56 (m, 2H), 3.40-pentafluoropentyl)-2- 3.20 (m, 6H), 2.14 (m, 2H), 1.86 imit1~7--1itlinon-1- (quin, J = 7.8 Hz, 2H) yl]phenyl, bistrifluoroacetate salt 56 4-[3-(2- 3.82 (m, 2H), 3.50 (m, 2H), 2.87-cyclohexylethyl)-2- 2.70 (m, 6H), 1.78-1.63 (m, SH), imi~7oli(1in-)n-l- 1.41 (quartet, 2H, J=7.2 Hz), 1.30-30 yl]phenyl, 1.18 (m, 4H), 0.949 (m, 2H).
bistrifluoroacetate salt 57 4-[3-[3-(4- 7.19 (s, 4H), 4.79 (m, IH), 3.74 (m, chlo~ ;.lyl)propyl]- 2H), 3.47 (m, 2H), 3.30 (m, 2H), 2-imidazolidinon-1- 2.63 (t, 2H, 7.6Hz), 1.91-1.83 (m, yl]phenyl 2H).
.. . . . ..

woss/2slss i~l ~ 793~ r~ oi~c ~
58 4-(3-pentyl-2- 3.82 (m, 2 H), 3.53 (m, 2H), 2.94 imidazolidinon-l- (m, 2H), 1.57 (quintet, 2H, J=7.4 yl)phenyl, Hz), 1.39-1.28 (m, 4H), 0.916, (tr, -.
bistrifluoroacetate salt 3H, J=7.1 Hz).
S9 4-[3-(3- 3.81 (m, 2H), 3.51 (m, 2H), 3.23 (t, cyclopentylpropyl)-2- J = 7.3 Hz, 2H), 1.78 (m, 3H), 1.57 imidazolidinon-l- (m, 6H), 1.33 (m, 2H), 1.17 (m, yl]phenyl 2H) o 60 4-[3-(2- 3.83 (m. 2H), 3.53 (m, 2H), 2.94 cyclopentylethyl)-2- (m, 2H), 1.81 (m, 4H), 1.65-1.53 imi~l~7o~ in~-n-l- (m, SH), 1.16 (m, 2H).
yl]phenyl, bistrifluoroacetate salt 61 4_[3_(3_ 3.83 (m, 2H), 3.51 (m, 2H), 3.22 (t, cyclohe~yl~lu~yl)-2- J = 7.3 Hz, 2H), 1.71 (m, SH), 1.56 imi~l~7~-lidin~-n-l- (m, 2H), 1.20 (m, 6H), 0.88 (m, yl]phenyl 2H) 62 4-[3-(2,2- 3.82 (m, 2H), 3.60 (m, 2H), 3.03 (s, dimethylhexyl)-2- 2H), 1.28 (m, 6H), 0.93 (m, 3H), imidazolidinon-l- 0.91 (s, 6H) yl]phenyl 63 4-(3-hexyl-2- 6.93 (d, lH, 4Hz), 6.70 (d, lH, imida_olon-l-yl)phenyl 4Hz), 4.79 (m,lH), 3.64 (t, 2H, 8Hz), 1.71-1.64 (m, 2H), !.35-1.28 (m, 6H), 0.91-0.86 (m, 3H).
64 4-[3-(4,4,4- 6.97 (d, lH, 3Hz), 6.73 (d, lH, trifluorobutyl)-2- 3Hz), 3.73 (t, 2H, 7Hz), 2.23-2.19 imidazolon-l-yl]phenyl (m, 2H), 1.98-1.92 (m, 2H).
30 65 4-(3-octyl-2- 6.93 (d, lH, 4Hz), 6.69 (d, lH, imidazolon-l-yl)phenyl 4Hz), 3.64 (t, 2H, 7Hz), 1.70-1.63 (m, 2H), 1.33-1.23 (m, lOH), 0.90-0.85 (m, 3H).

0 95/29159 r~l~u . ~ 5 2~ ~37932 - 66 4-[3-(3- 6.93 ~d, IH, 3Hz), 6.69 (d, lH, cyclopentylpropyl)-2- 3Hz), 3.63 (t, 2H, 7Hz), 1.80-1.47 imidazolon- l -yl]phenyl (m, l l H), 1.35-1.29 (m, 2H), 1.13-1.02 (m, 2H).
67 4-(2-octyl-3-oxo- 8.25 (s, lH), 3.79 (t, 2H, 7Hz), [1,2,4]-triazol-4- 1.80-1.70 (m, 2H), 1.36-1.25 (m, yl)phenyl lOH), 0.91-0.86 (m, 3H).
68 4-(4-hexyl-5- 3.9~ (t, 2H, J=7.1Hz), 2.9-2.7 (m, 0 tetrazolon-l-yl)phenyl 6H), 1.82 (q, 2H, J=7 Hz), 1.4-1.27 (m, 6H), 0.89 (t, 3H, J=7Hz ) 69 4-(4-octyl-5-tetrazolon- 3.98 (t, 2H, J=7.1Hz), 2.9-2.7 (m, l-yl)phenyl 6H), 1.83 (m, 2H), 1.4-1.2 (m, lOH), 0.87 (t, 3H, J=7 Hz) 4_[(3_ 3.97 (t, 2H, J-7.1Hz), 2.9-2.7 (m, cyclopentylpropyl)-5- 9H), 1.9-1.7 (m, 5H), 1.6 (m, lH), tetrazolon-l-yl]phenyl 1.5 (m, lH), 1.37(m, 2H), 1.07(m, lH) 71 4-(2-pentyloxazol-5- 7.48 (s, lH), 4.82 (m, lH), 2.92-yl)phenyl 2.70 (m, 8H), 1.80 (m, 2H), 1.39 (m, 4H), 0.92 (m, 4H) 72 4-(2-octyloxazol-5- 7.52 (s, IH), 5.09 (m, IH), 3.01-yl)phenyl 2.82 (m, 8H), 1.77 (m, 2H), 1.37-1.27 (m, lOH), 0.87 (m, lH) 73 4-[2-(2- 7.52 (s, !H), 4.80 (m, lH), 2.94-cyclopentylethyl)oxazol 2.70 (m, 8H), 1.79 (m, 5H), 1.62 -5-yl]phenyl (m, 2H), 1.54 (m, 2H), 1.12 (m, 2H) 74 4-[(4-ethyl-5- 7.62 (d, 2H, J = 9 Hz), 7.58 (d, 2H, ~0 mc;lllylll.iaz~l-2- J = 9 Hz), 2.53 (q, 2H, J = 7.5 Hz), yl)amino]phenyl 2.23 (s, 3H), 1.18 (t, 3H, J = 7.5 ~h) WO95129159 I'~ J,, S'C:9~C
21 ~7932 75 4-[(4,5,6,7- 7.54 (d, 2H, J = 9 Hz), 7.48 (d, 2H, tetrahydrobenzo- J = 9 Hz), 2.54 (m, 2H), 2.50 (m, thiazol-2- 2H), 1.75 (m, 4H) ~.
yl)amino]phenyl 76 4-(2-hexylimidazol-4- 7.75 (s, lH), 5.04 (m, lH), 3.29-yl)phenyl 3.20 (m, 4H), 2.97-2.90 (m, 4H), 1.82 (m, 2H), 1.40-1.30 (m, 6H), 0.9 (m, 3H) 77 4-(1-methyl-2- 7.92 (s, lH), 5.30 (m, lH), 4.84 (s, o octylimidazol-S-yl)- 3H), 3.48-3.25 (m, 4H), 3.05-2.95 phenyl (m, 4H), 1.80 (m, 2H), 1.50-1.26 (m, lOH), 0.89 (m, 3H) 78 4-[1-methyl-2-(2- 7.41 (s, lH), 3.64 (s, 3H), 2.96-2.68 cyclopentylethyl)- (m, 8H), 1.90-1.79 (m, 9H), 1.16 imidazol-S-yl]phenyl (m, 2H) 79 4-[1-methyl-2-[2-(4- 7.40 (s, lH), 7.10-6.95 (m, 4H), nuvluL,ll~,~lyl)ethyl]- 4.91 (m, lH), 3.39 (s, 3H), 3.0 (bs, imidazol-S-yl]phenyl 4H) 20 80 4-(S-pentyl-[1,2,4]- 2.96 (t, 2H, J=7.6Hz), 1.84 (t, 2H, oxadiazol-3-yl)phenyl . J=7.4Hz), 1.39 (m, 4H), 0.92 (t, 3H, J=7.1) 81 4-[S-(2- 2.98 (t, 2H, J=7.5Hz), 1.84 (m, SH), cyclopentylethyl)- 1.70-l.S0 (m, 4H), 1.16 (m, 2H) 2s [1 ,2,4]-oxadiazol-3-yl]phenyl 82 4-(S-hexyl-[1,2,4]- 2.96 (t, 2H, J=7.5Hz), 1.84 (quin, oxadiazol-3-yl)phenyl 2H, J=7.4Hz), 1.48-1.28 (m, 6H), 0.90 (t, 3H, J=7.0Hz) 3D 83 4-(S-heptyl-[1,2,4]- 2.96 (t, 2H, J=7.5Hz), 1.84 (quin, oxadiazol-3-yl)phenyl 2H, J=7.0Hz), 1.46-1.26 (m, 8H), 0.89 (t, 3H, J=6.9Hz) j~095~291S9 71 B7~32 ~ 6 84 4-(5-hexylthio-[1,2,4]- 3.11(t,2H,J=7.3Hz), 2.98-2.84 triazol-3-yl)phenyl (m,4H), 2.76 (t,2H,J=7.3Hz), 1.65 ~ (q,2H,J=7.3Hz), 1.37 (q,2H,J=7.1Hz), 1.28-1.23 (m,4H), 0.84 (t,3H,J=6.9Hz) 4-[[4-(4- 8.84 (s, lH), 8.75(d, lH, J=5.07 ul~ylpi~eridin-l-yl)- Hz), 8.46(d, lH, J=8Hz), 7.15 &
1,1-dioxo-[1,2,5]- 7.08 each (d, 2H, J=8Hz), 0.92(t, thi~ 7~1-3- 3H, J=7Hz) o yl]amino]phenyl 86 4-[[4- 7.15(d, 2H, J=8.5Hz), 7.12(d, 2H, yl~ ylamino)- J=8.5Hz), 5.19(dd, lH, 3.1Hz, 9Hz), 1,1-dioxo-[1,2,5]- 2.93(m, 2H), O.90(t, 3H, 6.8Hz) thi~ 7-)l_3 yl]amino]phenyl 87 4-[[4- 7.16(d, 2H, J=8.8Hz), 7.11(d, 2H, (h~yllllc;lllylamino)- J=8.8 Hz), 5.01(dd, J=3.2Hz, 1,1-dioxo-[1,2,5]- 9.9Hz), 2.92(m, 2H), 1.68(m, 2H) thi~ 7~1-3-yl]amino]phenyl 88 4-(1-octyl-2,4- 4.09 (s, 2H), 3.41 (t, 2H, 7hz), imi-l~7~ iin~ n-3- 1.65-1.56 (m, 2H), 1.30-1.25 (m, yl)phenyl lOH), 0.91-0.86 (m, 3H).
25 89 4-[3-(3-l~ pll~llyl)-5- 8.55 (t,lH,J=1.9Hz), 8.47 (d, pyrazolon-l-yl]phenyl lH,J=2.0Hz), 8.37 (dd,lH, J=3.2Hz), 8.14 (d,2H,J=8.9Hz), 8.08 (t,2H,J=8.5Hz), 7.74(d, 3H,J=8.9Hz), 7.56 (t,lH,J=8.0 Hz), 3o 7.33 (dd,lH,J=4.8Hz), 7.04 (dd,4H,J=6.6Hz), 4.75 (t, lH,J=2.1Hz), 2.83-2.69 (m,6H) W095/291~9 ~1 87~3~ r ~ C~55G ~

Starting with commercially available (R)-styrene epoxide and following the procedures outlined for Examples 17,18 and 25, the compounds listed in Table 3 were prepared.
TAp~T F. 3 OH
~N N,SOI~R
H O
Example R Selected lH NMR (CD30D) Data 4-iodopheny1 7.84 (d, 2H, J = 8.6 Hz), 7.45 (d, trifluoroacetate salt 2H, J = 8.5 Hz) 91 2-naphthyl, 8.31 (s, lH), 7.96-7.90 (m, 3H), uoloac~ salt 7.74 (dd, lH, J = 1.8, 8.7 Hz), 7.63 (t, lH), 7.58 (t, lH) 92 3-quinolinyl, 9.01 (d, lH, J = 2.2 Hz), 8.75 (d, trifluoroacetate salt IH, J = 2.1 Hz), 8.07 (d, lH, J = 8.4 Hz), 8.03 (d, lH, J = 8.3 Hz), 7.92 (t, lH, J = 7.0 Hz), 7.72 (t, lH, J =
7.1 Hz) OH
3 o ~Me~` NH
nHex-N N~--S02 -I I

wo 95r~9159 1 ~ ~ 1936 21 87~32 (O-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]-2-methylpropyl]phenyl]-4-(3-hexvl-2-imidazolidinon- 1 -vl)benzenesulfonamide A solution of pyridine epoxide (160mg,1.32 mmol) from example 16 and 4-amino-a,a-dim~ yl~ ethylamine (1.2g, 7.3 mmol), prepared according to J. Biol. Chem. 1981, 256, 11944-50, in methanol (8 ml) was warmed at reflux for 16 hours. After cooling, the reaction mixture was c. ll. r~ lrd and purified by flash chromatography (silica gel, 95:5 CH2C12: 10% NH40H/CH3OH) to give 23 mg (0.080 mmol) o Of product as an oil.
The above product (18 mg, 0.063 mmol) was dissolved in CH2C12 (1 mL) and pyridine (0.05 mL). The resulting solution was cooled to 0C and treated with 4-(3-hexyl-2-imidazolidinon-1-yl)l,~"~r.l~ lfonyl chloride (22 mg, 0.063 mmol). The mixture was 5 allowed to stir at 0C for 20 hours and was then purified by flash chromatography (silica gel, 95:5 CH2C12: 10% NH40H/CH30H) to give the desired product (21 mg, 0.035mmol) as an oil: IHNMR (CD30D) o 8.53 (s, lH), 8.44 (d,lH, J=5.0), 7.83 (d~ lH~ J=7.9), 7.63 (m, 4H), 7.40 (dd, lH, J=5.0, 7.9), 6.98 (m, 4H), 4.72 (dd, lH, J=4.0, 8.4), 3.80 (m, 20 2H), 3.49 (m, 2H), 3.22 (t, 2H, J=7.2), 2.78 (m, 2H), 2.62 (m, 2H), 1.55 (m, 2H), 1.31 (m, 6H), 1.01 (s, 3H), 0.99 (s, 3H), 0.89 (m, 3H).
Following the ~loccdul~; outlined above, the compounds in Table 4 were prepared.

OH
¢~e~ NH'lo`R
Example ¦ R ¦ Selected IH NMR (CD30D) Data WO 9S/29159 1 ~ .'C 1~56 ~ ~793:2 94 4-iodophenyl 7.82 (d, 2H, J=8.6), 7.42 (d, 2H, J=8.6) 4-[[(ll~yl~ )car- 7.55 (d, 2H, J=8.8), 7.42 (d, 2H, bonyl]amino]phenyl J=8.8), 3.11 (t, 2H, J=7.0), 1.49 (m, 2H), 1.30 (m, 6H), .089~}n, 3H) F.XAMPLE 96 o-Si(tBU)Me2 Cl~,Br H2N ~
CI
(R)-4-amino-a-(l,lulllolll~,lllyl)-3 ,5-dichluluhr . 17r. Ir . "~th~lnoI, dimethyl-1,1--limPthylethylsilyl .othPr A solution of t-butyldimethylsilyl chloride (1.67 g, 11.1 mmol) in DMF (15 mL) was added slowly to a stirred solution of (R)-4-20 amino-a-(l,lulllu;llyl)-3,5-dichlu.~ ,r~,,r.II.,..,ol (2.1 g, 7.4 mmol, see Judkins, et. al, European Patent Arrlit~ )n 0 460 924) and imidazole (0.75 g, 11.1 mmol) in DMF (6 mL) with an ice-water bath cooling. After being stirred at RT for 3h, the reaction mixture was poured into water (300 mL) arld the product was extracted with ether.
25 The organic phase was washed with saturated aqueous sodium bicarbonate solution, brine, dried(MgSO4) and evaporated to dryness.
The crude product was purified on silica (95/5 hexane/ethyl acetate) to give the title culll~uulld (2.73 g, 93 %): IH NMR (400 MHz, CDC13) o 7.14 (s, 2H), 4.67 (dd, lH, J=2.1, 6.4 Hz), 3.33 (m, 2H), 0.87 (s, 9H), 30 0.89(s, 6U) WO 95129159 P~ '.556 O,Si(tBu)Me2 5 Cl~ N ~ 3~ NH2 Cl o !R)-N-[2-[4-(Alllillu~l~cllyl)]ethyl]-2-[(dimethyl- 1,1-dimethylethylsilyl)ûxy]-2-(4-amino-3.5-dichlorophenyl)ethylamine O-TBDMS bromo ;u~ uulld from Example 96 (2.73g, 6.86 mmol) was dissolved in CH3CN (50 mL) and 4-amino-phenethylamine (1.86 g, 13.72 mmol) was added, followed by the addition of N,N'-diisopropylethylamine (3.58 mL, 20. 6 mmol) and sodium iodide (1.03 g, 6.86 mmol). After being heated at reflux for 48 h, the reaction mixture was cullccllLIi~L~d and the residue ~luulllalu~,ld~llcd on silica (50/50 ethyl acetate/hexane) to provide the title compound (2.3 g, 75 %): lH NMR (400 MHz, CDC13) o 7.08 (s, 20 2H), 6.94 (AA', 2H, J=8.4 Hz), 6.60 (BB', 2H, J=8.4 Hz), 4.63 (m, lH), 4.37 (s, 2H), 3.53 (br s, 2H), 2.87-2.60 (m, 6H), 0.80 (s, 9H), -0.03 (s, 6H) FXAMPT F. 98 OH H
Cl~l`~ N--3~ NH2 . Cl (R)-N-[2-[4-(Aminophenyl)]ethyl]-2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethylamine To a stirred solution of silyl compound from Example 97 (2.2 g, 4.8 mmol) in THF (20 mL) at RT was added .

WO 9!;/291~9 . ~ .'0135G
~ 8193~ ~

tetrabutylammonium fluoride (10 mL of 1.0 M solution in THF) in one ..
portion. After being stirred at RT for 2h, the reaction mixture was ~ollc~llt,dl~d and chromatographed on silica (10/90 CH3OH~CH2C12) to give the title compound (1.59 g, 97 %): lH NMR (400 MHz, CD30D) o 7.15 (s, 2H), 6.92 (AA', 2H, J=8.3 Hz), 6.60 (BB', 2H, 8.3 Hz), 4.58 (m,lH), 2.83-2.65 (m, 6H) 01 I H ,NH
-NJ~N~J3'SO2 H H
(O-N-[4-[2-[[2-Hydroxy-2-(4-amino-3,5-20 dichlorophenyl)ethyl]amino]ethyl]-phenyll-4-(hexvlaminocarbonyl~mino)b~llz~ c~ulfon~mi~f~
Following the procedure outlined in Example 18 and 25, the title culll~uulld was prepared from the aniline dc;liva~iv~ from Example 98: NMR (400 MHz, CD30D) 7.57 (AA', 2H, J=2.7 Hz), 7.42 25 (BB', 2H, J=2.7 Hz), 7.16 (s, 2H), 7.04 (AA', 2H, J=2.0 Hz), 7.00 (BB', 2H, J=2.0 Hz), 4.58 (t, IH, j=7.1 Hz), 3.14 (t, lH, J=7.0 Hz), 2.80 (m, 2H), 2.73 (m, 4H), 1.49 (m, 2H), 1.32 (m, 6H), 0.90 (t, 3H, J=6.7 Hz).
ESI MS n~/z 622 (M).
Following the l~luccdult; outlined in Examples 96-99, the ~;c,lll~oullds in Table 5 were p ~,~ed.

W~951291~9 2 l ~7932 P._l"~

H2N~ N`^13~H'So~R
Cl Example R Selected 1H NMR (CD30D) Data o 100 1- 7.82 (d, lH, J=9.2 Hz), 7.47 (m, [(octylamino)carbonyl]- 2H), 3.93 (t, 2H, J=9.0 Hz), 3.18 indolin-5-yl (m, 4H), 1.53 (m, 2H), 1.31 (m, IOH), 0.88 (t, 3H, J=7.1 Hz) 101 4-(3-hexyl-2- 7.68-7.60 (AA'BB', 4H), 3.82 (t, imidazolidinon-1- 2H, J=6.2 Hz), 3.52 (t, 2H, J=6.2 yl)phenyl Hz), 3.30 (t, 2H, J=6.0 Hz), 1.54 (m, 2H), 1.31 (m, 6H), 0.89 (t, 3H
J=6.0 Hz) 102 4-(3-octyl-2- 7.65-7.60 (AA'BB', 4H), 3.82 (t, imi~iA7~ inon-1- 2H, J=6.2 Hz), 3.52 (t, 2H, J=6.2 yl)phenyl Hz), 3.29 (t, 2H, J=6.0 Hz), 1.54 (m, 2H), 1.30 (m, lOH), 0.87 (t, 3H, J=6.1 HZ) OH
HO~N 3`NH
[3,S2 , WO95/29159 `? ~ 3~ F~,l/.l ,. /01~56 (E~)-N-[4-[2-[[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]amino]ethyl]phenyl]-b~n7Pn~ -lfonamide A solution of 5 g of 4-aminophenethyl alcohol in 50 mL of DMF was silylated with 5.5 g of t-butyldimethylsilyl chloride (TBDMS-5 Cl) and 2.5 g of imidazole overnight at room ~ alulc. Extractionof the product following an aqueous ~mmonillm chloride workup afforded 6.6 g of the O-TBDMS ether. This aniline derivative was then coupled to bl~n7tont sl~lfonyl chloride in pyridine-dichlololll.,lllalle to give the sulfonamide in greater than gO% yield after chromatographic purification. The TBDMS group of the sulfonamide was removed with methanolic HCI at room t~ lalul~; for 30 min. The crude alcohol was oxidized to the corresponding carboxylic acid with Jones reagent in acetone (RT 30 min, ethyl acetate extraction).
To a solution of 180 mg of (R)-octoparnine and 300 mg of 5 the resultant 4-N-br~ ,llfonamidophenylacetic acid in 7 mL of DMF
was added 0.5 mL of triethylamine and 490 mg of b~ o~ lyl-N-oxy-tris(dimethylamino)rh--grh~ m hexafluororhosrh~t~ The reaction mixture was stirred at RT 2h, flash chromatography over silica gel eluting with 95:5 chloroform-methanol gave 322 mg of purified 20 amide.
A solution of 220 mg of this amide in 13 mL of 1.0 M
borane-THF was refluxed under argon for 2h followed by the addition of 3 mL of N,N-dimethyl~minoethsm~l and further reflux for another hour. The solvent and excess volatiles were removed in vacuo and the 2s residual solid was taken up in acetone and purified by PLC on silica gel (9:1 ethyl ;I(~t;~ ) to yield 61 mg of the title compound: IH
NMR (500 MHz, CD30D) o 7.73 (dt, 2H, J=2.1, 8.2Hz), 7.53 (tt, lH, J=1.4, 7.6Hz), 7.44 (t, 2H, J=8 Hz), 7.18 (d, 2H, J=8.4 Hz), 7.05 (ABq, 4H, Jab=8.5 Hz), 6.76 (d, 2H, J=8.4Hz), 4.75 (dd, lH, J=7.5, 7.6 Hz), 30 3.05-2.90 (m, 4H), 2.81 (t, 2H, J=7.6 Hz). Mass spec calcd. 412.5 found 413.2.

~ 2187932 r~ J. o .. JJC
OH H
HOJ~ N 3` NH

ao-N-[4-[2-[[2-Hydroxy-2-(4-h~dlu~y~ lyl)ethyl]amino]ethyl]phenyl]-4-iodob~ lfonamide Following the procedure outlined in Example 103, the title cu~ uulld was prepared: IH NMR (500 MHz, CD30D) o 7.77 (d, 2H, J=8.5 Hz), 7.43 (d, 2H, J=8.5 Hz), 7.15 (d, 2H, J=8.5 Hz), 7.02 (ABq, 4H, Jab=8.7 Hz), 6.75 (d, 2H, J=8.5 Hz), 4.67 (dd, lH, J=4.4, 6.6 Hz), 2.90-2.66 (m, 6H). Mass spec calcd. 538.4 found 538.9.

2s NC~ Br 3-(2-bromoacetyl)benzonitrile To a solution of 1.02 g (7.04 mmol) of 3-acetylb~,.lz~lliLIile in 70 mL of ethyl ether was added 1.02 g (3.52 mmol, 0.5 equiv) of 30 dibromobarbituric acid. The mixture was allowed to stir at room I~IlllJc;l~Lult; overnight. The resultant white slurry was filtered and the filtrate was concentrated. Purification by flash chromotography (silica gel, 20% ethyl acetate/hexane) gave 1.28 g (81%) of the title compound as a white solid: IH NMR (400 MHz, CDC13) o .8.26 (t, IH, J = 1.4 WO 95/29IS9 1 ~ .'C ~6 2~ 87q~2 ~
Hz), 8.20 (td, lH, J = 1.5, 8.0 Hz), 7.87 (dd, lH, J = 1.3, 7.8 Hz), 7.64 (t, lH, J = 7.9 Hz), 4.40 (s, 2H).

OH
NC ~ ~, Br (R)-a-Bromomelhyl-3-cyanophenylmethanol To a suspension of 181 mg (0.623 mmol) of (O-tetrahydro- l-methyl-3,3-diphenyl- lH,3~I-pyrrolo[l,2~[1,3,2]oxazaborole-borane (~OAB catalyst) in 6 mL of THF at 0 C was added dropwise 6.24 mL (6.24 mmol) of a I M
solution of borane in THF. The resultant clear solution was allowed to stir for 5 min, and then a solution of 1.27 g (5.67 mmol) of bromn~tot~nf from Example 105 in 6 mL of THF was added slowly over 1 h. After the reaction was allowed to stir for 30 min more, it was 20 quenched by the dropwise addition of 6 mL of methanol and cullccllLl~t~d~ pllrifir~ril~n by flash chromatography (silica gel, 20-25%
ethyl acetate/hexane) provided 944 mg (74%) of the title cu~ uul,d as a clear oil which crystaUized: IH NMR (400 MHz, CDC13) o 7.70 (d, lH, J = 1.5 Hz), 7.62-7.60 (m, 2H), 7.48 (t, lH, J = 7.7 Hz), 4.95 (dd, lH, J
25 = 3.4, 8.4 Hz), 3.63 (dd, lH, J = 3.4 Hz), 3.49 (dd, lH, J = 8.4 Hz).

NC~
1~
(R~-(3-cyano~henyl)oxirane ~ o 95129159 2 ~ ~ 7 9 3 2 P~ .'ûS~3u To a solution of 937 mg (4.14 mmol) of bromohydrin from Example 106 in 8 mL of methanol was added 601 mg (4.35 mmol, . 1.05 equiv) of potas~iu-l. carbonate. The reaction mixture was allowed to stir at room ~ pC;ldlUl~ for 7 h. It was then diluted with ethyl 5 acetate, washed with water, dried over m lgnPcillrn sulfate, and c-)nr~.ntr~t.--1 Purification by flash chromatography (silica gel, 20%
ethyl acetdte/hexane) provided 573 mg (95%) of the title compound: IH
NMR (400 MHz, CDCI3) o .7.59-7.55 (m, 2H), 7.49 (dd, lH, J = 1.6, 7.9 Hz), 7.44 (t, lH, J = 7.7 Hz), 3.87 (dd, lH, J = 2.5, 4.0 Hz), 3.17 (dd, lH, J = 4.1, 5.5 Hz), 2.74 (dd, lH, J = 2.5, 5.4 Hz).

OH
Boc NC ~, N ~¢~ NH2 a~)-N-[2-[4-(alllillo~hc;llyl)]ethyl]-2-hydroxy-2-(3-20 ~;yallu~ lyl)ethylcarbamic acid l.l-dim~thylethyl ester Following the ~luc~dulu~ outlirled in F.Y~mrlf-~ 17 and 18, the title culll~,uulld was prepared from the epoxide from Example 107:
IH NMR (400 MHz, CDC13) o 7.58-7.52 (br m, 3H), 7.41 (t, lH, J =
7.5 Hz), 6.89 (br d, 2H, J = 7.6 Hz), 6.65 (br d, 2H, J = 7.8 Hz), 4.82 25 (br dd, lH, J = 2.7, 7.9 Hz), 3.42-3.05 (br m, 4H), 2.75-2.55 (br m, 2H).

WO 95129159 P~ o Ij5C
~ 879~
EXAMPLE 109 r~
H
5 NO~ ,N ¢~ ~NH
nHex-NH NJ3,so2 H
(O-~-[4-[2-l[2-Hydroxy-2-(3-~;ydllo~ yl)ethyl]amino]ethyl]phenyl]-4-~h~xylaminocarbonylamino)benzenesulfonamide Following the procedure outlined in Example 25, the title compound was prepared from the Boc aniline derivative from Example 108: IH NMR (400 MHz, CD30D) o 7.70 (s, lEI), 7.63-7.57 (m, 4H), 7.48 (t, lH7 J - 7.7 Hz), 7.43 (d, 2H, J = 8.9 Hz), 7.06 (d, 2H, J = 8.5 Hz), 6.99 (d, 2H, J = 8.5 Hz), 4.77 (dd, lH, J = 3.9, 8.5 Hz), 3.15 (t, 2H, J = 7.0 Hz), 2.86-2.69 (m, 6H), 1.49 (br m, 2H), 1.31 (br m, 6H), 20 0-90 (br t, 3H).

OH
NC~ ~NH ~NH
~,SO2 (O-N-[4-[2-[[2-Hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-3-quinolinesulfonamide Following the ~lOce-lu-~ outlined in Example 25, the title compound was prepared from the Boc aniline derivative from Example .

wo gS/29159 r~ ) w~su 108 and 3-quinolinesulfonyl chloride: IH NMR (400 MHz, CD30D) o 9.02 (d, lH, J = 2.3 Hz), 8.68 (d, lH, J = 1.9 Hz), 8.06 (d, lH, J = 8.3 ,. Hz), 8.02 (d, lH, J = 7.9 Hz), 7.90 (ddd, lH, J = 1.4, 7.0, 8.4 Hz), 7.72-7.69 (m, 2H), 7.62-7.58 (m, 2H), 7.47 (t, lH, J = 7.7 Hz), 7.07 (d, 2H, J
= 8.7 Hz), 7.03 (d, 2H, J = 8.7 Hz), 4.76 (dd, lH, J = 4.0, 8.5 Hz), 2.85-2.68 (m, 6H).
Following the procedures outlined for F.~mrlf-.s 14-31, the compounds listed in Table 6 were prepared.

¢~ ~~ N 'o`R
Example R Selected IH NMR (CD30D) Data 111 4-(3-hexyl-2,4- 4.40 (s,2H), 3.54 (m, 2H), 1.68-imi~l~7~ 1in~-rlit)n-1- 1.59 (m, 2H), 1.37-1.28 (m, 6H), yl)phenyl 0.91 (m, 3H).
112 4-(3-octyl-2,4- 4.40 (s,2H), 3.52 (m, 2H), 1.68-imidazoli-lin~ inn-l- 1.59 (m, 2H), 1.38-1.23 (m, lOH), yl)phenyl 0.89 (m, 3H).
113 4-[2-(4- 7.66 (s, lH), 5.35 (m, lH), 3.22-cyclohexylbutyl)- 3.32 (m, SH), 2.95 (m, 2H), 2.90 (t, oxazol-S-yl]phenyl, J=6.5Hz, 2H), 1.8 (m, 2H), 1.69 (m, trihydrochloride SH), 1.45 (m, 2H), 1.24 (m, 6H), 0.89 (m. 2H) 114 4-[2-[2-(~ 7.49 (s, lH), 7.2 (m, 2H), 6.99 (m, fluorophenyl)ethyl]- 2H), 4.90 (m, lH), 3.05 (m, 4H), oxazol-5-yl]phenyl 2.70-2.85 (m, 6H) WO 95/291~9 A ~ .0 1~56 - 7 ~ 8793~ --115 4-[2-(3- 7.51 (s, lH), 4.90 (m, lH), 2.65-cyclopentylpropyl)- 2.90 (m, 8H), 1.80 (m, 5H), 1.46-oxazol-5-yllphenyl 1.62 (m, 4H), 1.05 (m, 2H) 116 4-(4-hexyl-3-oxo- 8.04 (s, lH), 3.69 (m, 2H), 1.78-[1,2,4]-triazol-2- 1.69 (m, 2H), 1.39-1.28 (m, 6H), yl)phenyl 0.90 (m, 3H).
117 4-(4-octyl-3-oxo- 8.03 (s, lH), 3.69 (m, 2H), 1.77-[1,2,4]-triazol-2- 1.69 (m, 2H), 1.38-1.25 (m, lOH), o yl)phenyl 0.89 (m, 3H).
118 4-(4-heptyl-5-methyl- 2.28 (s,3H), 1.67 (t, 2H, J=6.9 Hz), [1,2,3]-triazol-2- 1.36-1.34 (m, 4H), 1.31-1.29 (m, yl)phenyl 2H), 1.18 (d, 4H, J=2.5 Hz), 0.88 (t, 3H, J=7.0 Hz)

Claims (17)

WHAT IS CLAIMED IS:
1. A compound having the formula I:

I

where n is 0 to 5;
m is 0 or 1;
r is 0 to 3;
A is (1) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (2) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) phenyl, or (5) a benzene ring fused to a C3-C8 cycloalkyl ring;
R1 is (1) hydroxy, (2) oxo, (3) halogen, (4) cyano, (5) NR8R8, (6) SR8, (7) trifluoromethyl, (8) C1-C10 alkyl, (9) OR8, (10) SO2R9, (11) OCOR9, (12) NR8COR9, (13) COR9, (14) NR8SO2R9, (15) NR8CO2R8, or (16) C1-C10 alkyl substituted by hydroxy, halogen, cyano, NR8R8, SR8, trifluoromethyl, OR8, C3-C8 cycloalkyl, phenyl, NR8COR9, COR9, SO2R9, OCOR9, NR8SO2R9 or NR8CO2R8;
R2 and R3 are independently (1) hydrogen, (2) C1-C10 alkyl or (3) C1-C10 alkyl with 1 to 4 substituents selected from hydroxy, C1-C10 alkoxy, and halogen;
X is (1) -CH2-, (2) -CH2-CH2-, (3) -CH=CH- or (4) -CH2O-;
R4 and R5 are independently (1) hydrogen, (2) C1-C10 alkyl, (3) halogen, (4) NHR8, (5) OR8 (6) SO2R9 or (7) NHSO2R9;
R6 is (1) hydrogen or (2) C1-C10 alkyl;
R7 is Z-(R1a)n;
R1a is(1) R1, with the proviso that when A is phenyl, R1a is not C1-C10 alkyl, (2) C3-C8 cycloalkyl, (3) phenyl optionally substituted with up to 4 groups independently selected from R8, NR8R8, OR8, SR8 and halogen, or (4) 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R8, NR8R8, OR8, SR8, and halogen;
Z is (1) phenyl, (2) naphthyl, (3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) a benzene ring fused to a C3-C8 cycloalkyl ring, (5) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (6) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heterotoms selected from oxygen, sulfur and nitrogen, or (7) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring;
R8 is (1) hydrogen, (2) C1-C10 alkyl, (3) C3-C8 cycloalkyl, (4) Z optionally having 1 to 4 substituents selected from halogen, nitro, oxo, NR10R10, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, and C1-C10 alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO2H, CO2-C1-C10 alkyl, SO2-C1-C10 alkyl, C3-C8 cycloalkyl, C1-C10 alkoxy, and Z optionally substituted by from 1 to 3 of halogen, C1-C10 alkyl or C1-C10 alkoxy, or (5) C1-C10 alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO2H7, CO2-C1-C10 alkyl, SO2-C1-C10 alkyl, C3-C8 cycloalkyl, C1-C10 alkoxy, C1-C10 alkyl, and Z optionally substituted by from 1 to 4 of halogen, C1-C10 alkyl or C1-C10 alkoxy;
R9 is (1) R8 or (2) NR8R8;
R10 is (1) C1-C10 alkyl, or (2) two R10 groups together with the N to which they are attached formed a 5 or 6-membered ring optionally substituted with C1-C10 alkyl; or a pharmaceutically acceptable salt thereof.
2. A compound of Claim 1 where n is 0 to 3;
m is 1;
r is 0 to 2;
A is phenyl or a 5- or 6-membered heterocyclic ring with from 1 to 4 nitrogen atoms;
X is -CH2-;
R1 is (1) hydroxy, (2) halogen, (3) cyano, (4) trifluoromethyl, (5) NR8R8, (6) NR8SO2R9, (7) NR8COR9, (8) NR8CO2R8, or (9) C1-C10 alkyl optionally substituted by hydroxy;
R2, R3 are independently (1) hydrogen or (2) methyl;
R4, R5 and R6 are each hydrogen;
R7 is Z-(R1a)n; and R8, R9, Z and R1a are as defined in Claim 1, and when R1 is part of the definition of R1a has the meaning defined in Claim 1.
3. A compound of Claim 1 having the formula Ia:

Ia wherein n is 0 to 3;
m is 1 R1 is (1) halogen or (2) NR8R8;
R2, R3 are independently hydrogen or methyl;
R1a is (1) halogen, (2) C1-C10 alkyl, (3) NR8R8, (4) NR8COR9, (5) NR8CO2R8, (6) COR9, (7) OCOR9, or (8) a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, halogen, R8, NR8R8, OR8, and SR8;
Z is (1) phenyl, (2) naphthyl, (3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, or (5) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring;
X is -CH2-; and R8 and R9 are as defined in Claim 1.
4. A compound of Claim 3 wherein R2 and R3 are each hydrogen.
5. A compound of Claim 1 having the formula Ib:

Ib wherein n is 0 to 3;
m is 1 R1 is (1) hydroxy, (2) cyano, (3) NR8R8 or (4) halogen;
R1a is (1) halogen, (2) NR8R8, (3) NR8COR9, (4) NR8CO2R8, (5) OCOR9, or (6) a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to three groups independently selected from oxo, halogen, R8, NR8R8, OR8 and SR8;
Z is (1) phenyl, (2) naphthyl or (3) benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;
X is -CH2-; and R2 and R3 are independently hydrogen or methyl.
6. A compound of Claim 1 having the formula Id Id n is 0 or 1;
R1 is NR8R8;
R2 and R3 are independently (1) hydrogen, or (2) methyl;
B is (1) hydrogen, (2) benzene fused to the benzene ring to form naphthyl, or (3) a 5 or 6-membered heterocycle with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atom fused to the benzene ring;
R1a is (1) halogen, (2) C1-C10 alkyl, (3) NR8R8, (4) NR8COR9, (5) NR8CO2R8, (6) COR9, or (7) a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R8, SR8, OR8, and NR8R8;
when B and the benzene ring form a fused ring system, R1a is attached to either ring;
R8 is (1) hydrogen, (2) C1-C10 alkyl, (3) Z optionally having 1 to 4 substituents selected from nitro, oxo, and NR10R10, or (5) C1-C10 alkyl having 1 to 4 substituents selected from hydroxy, halogen, C1-C10 alkyl, C3-C8 cycloalkyl, and Z
optionally substituted by from 1 to 4 of halogen, C1-C10 alkyl or C1-C10 alkoxy;
R9 is (1) R8 or (2) NR8R8;
R10 is (1) C1-C10 alkyl, or (2) two R10 groups together with the N to which they are attached formed a 5 or 6-membered ring optionally substituted with C1-C10 alkyl; and Z is (1) phenyl, (2) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or (4) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring.
7. A compound of Claim 1 selected from the group consisting of:

N-[4-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-4-iodobenzenesulfonamide;
N-[4-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-2-naphthalenesulfonamide; and N-[4-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-3-quinolinesulfonamide.
N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]-ethyl]-phenyl]-4-(hexylaminocarbonylamino)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]-ethyl]-phenyl]-1-[(octylamino)carbonylamino]-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]-ethyl]-phenyl]-4-(3-hexyl-2-imidazolidon-1-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]-ethyl]-phenyl]-4-(3-octyl-2-imidazolidon-l-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino]-ethyl]phenyl]-benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino]-ethyl]phenyl]-4-iodobenzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-4-(hexylaminocarbonylamino)benzenesulfonamide, and N-[4-[2-[[2-hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-3-quinolinesulfonamide
8. A compound of Claim 1 selected from the group consisting of:
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-(hexylaminocarbonylamino)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-iodobenzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-2-naphthalenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-3-quinolinesulfonamide;

N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-5-benzisoxazolesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[(hexylmethylaminocarbonyl)amino]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[(dimethylaminocarbonyl)amino]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-2-imidazolidon-1-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(hexylaminocarbonylamino)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-isopropylbenzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-2-naphthalenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-3-quinolinesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(hexylmethylaminocarbonyl)amino]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-2-imidazolidon-1-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-iodobenzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-cyclopentylpropyl)-2-imidazolidon-1-yl]benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-octyl-2-imidazolidinon-1-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-2-imidazolon-1-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-octyl-2-imidazolon-1-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-cyclopentylpropyl)-2-imidazolon-1-yl]benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-octylthiazol-2-yl)-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-pentyl-[1,2,4]-oxadiazol-3-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-hexyl-[1,2,4]-oxadiazol-3-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-heptyl-[1,2,4]-oxadiazol-3-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-octyl-[1,2,4]-oxadiazol-3-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2-cyclopentylethyl)-[1,2,4]-oxadiazol-3-yl]benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3-cyclopentylpropyl)-[1,2,4]-oxadiazol-3-yl]benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-pentyloxazol-5-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-hexyloxazol-5-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-heptyloxazol-5-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-octyloxazol-5-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]4-[2-(2-cyclopentylethyl)oxazol-5-yl]benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3-cyclopentylpropyl)oxazol-5-yl]benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-hexyl-5-tetrazolon-1-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-octyl-5-tetrazolon-1-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(3-cyclopentylpropyl)-5-tetrazolon-1-yl]benzenesulfonamide
9. A compound of Claim 1 with the structural formula Ic:

Ic where n, m, r, A, R1, R, R3, R4, R5, R6, R7 and X are as defined in Claim 1.
10. A method for the treatment of diabetes which comprises administering to a diabetic patient an effective amount of a compound of Claim 1.
11. A method for the treatment of obesity which comprises administering to an obese patient an effective amount of a compound of Claim 1.
12. A method for lowering triglyceride levels and cholesterol levels or raising high density lipoprotein levels which comprises administering to a patient needing lower triglyceride and cholesterol levels or higher high density lipoprotein levels an effective amount of a compound of Claim 1.
13. A method for decreasing gut motility which comprises administering to a patient in need of decreased gut motility, an effective amount of a compound of Claim 1.
14. A method for reducing neurogenic inflammation of airways which comprises administering to a patient in need of reduced neurogenic inflammation, an effective amount of a compound of Claim 1.
15. A method for reducing depression which comprises administering to a depressed patient an effective amount of a compound of Claim 1.
16. A method for treating gastrointestinal disorders which comprises administering to a patient with gastrointestinal disorders an effective amount of a compound of Claim 1.
17. A composition for the treatment of diabetes or obesity or for lowering triglyceride or cholesterol levels or increasing high density liproprotein levels or for decreasing gut motility or for reducing neurogenic inflammation or for treating depression or for treating gastrointestinal disorders which comprises an inert carrier and an effective amount of a compound of Claim 1.
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