PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`Intematronal Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 6 =
`53;? 333(1): giggflggzl’z’zgggg’
`
`233/36, 215/36, A61K 31/44, 31/47, 31/18
`
`(11) International Publication Number:
`(43) International Publication Date:
`
`WO 95/29159
`2 November 1995 (02.11.95)
`
`1A 1‘
`ti N
`21 It
`t‘
`pp rca on
`) nerna “ma
`(
`--
`.
`.
`(22) International Frhng Date.
`
`b :
`um er
`
`-
`21 April 1995 (21.04.95)
`
`PCT/US95/O4956 ”WWW“; 3“"
`(75) Inventors/Applicants (for US only): FISHER, Michael, H.
`[US/US]; 126 East Lincoln Avenue, Rahway, NJ 07065
`(US). NAYLOR, Elisabeth, M. [GB/US]; 126 East Lincoln
`Avenue, Rahway, NJ 07065 (US). OK, Dong [US/US]; 126
`East Lincoln Avenue, Rahway, NJ 07065 (US). WEBER,
`Ann, E. [US/US]; 126 East Lincoln Avenue, Rahway, NJ
`
`triglyceride levels and cholesterol levels or raising high density lipoprotein levels or for increasing gut motility are also disclosed.
`
`-
`-
`.
`(30) P";';§f,2g“a-
`
`26 Apfi11994(26_04_94)
`
`US
`
`ts
`
`(
`
`60 P
`t A li
`ti
`G
`)(6Srfitlatépbfcgfinfigfiogan
`US
`Filed on
`US
`Filed on
`US
`Filed on
`
`404,565 (CIP)
`21 March 1995 (21.03.95)
`404,566 (Cl?)
`21 March 1995 (21.03.95)
`233,166 (CIP)
`26 April 1994 (26.04.94)
`
`(71) Applicant (forall designated States except US): MERCK &
`CO., INC. [US/US]; 126 East Lincoln Avenue, Rahway, NJ
`07065 (US).
`
`East Lincoln Avenue, Rahway, NJ 07065 (US).
`
`(74) Common Representative: MERCK & CO.,
`INC.; Patent
`Dept, 126 East Lincoln Avenue, Rahway, NJ 07065 (US).
`
`(81) Designated States: AM, AU, BB, BG, BR, BY, CA, CN, CZ,
`EE, Fl, GE, HU, IS, JP, KG, KR, KZ, LK, LR, LT, LV,
`MD, MG, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK,
`TI, TT, UA, US, UZ, European patent (AT, BE,
`DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, E),
`patent (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE,
`SN, TD, TG), ARIPO patent (KE, MW, S
`.
`
`Published
`
`With international search report.
`
`(54) Title: SUBSTITUTED SULFONAMIDES AS SELECTIVE £3 AGONISTS FOR THE TREATMENT OF DIABETES AND
`OBESITY
`
`Fl"
`H n2
`OH
`ll
`I
`@CHCHzN-C-(X)m—</:
`'—
`in
`‘
`R5
`
`(R‘)n
`
`p-sogcngrw
`86'
`
`(I)
`
`I
`
`(57) Abstract
`
`Substituted sulfonamides having formula (I), are selective 63 adrenergic receptor agonists with very little £1 and 62 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 levelsand 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
`
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`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`Gabon
`
`AT
`AU
`BB
`BE
`BF
`BG
`3.]
`BR
`BY
`CA
`CF
`CG
`CH '
`CI
`CM
`CN
`CS
`CZ
`DE
`DK
`ES
`H
`FR
`GA
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`_
`Canada
`Central African Republic
`Congo
`Switzerland
`care d'Ivoire '
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Spain
`Finland
`France
`
`_
`
`I
`
`'
`
`'
`
`'
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`-
`
`Mauritania
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`United States of America
`Uzbekistan
`Viet Nam
`
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`WO 95/29159
`
`A
`
`PCT/US95/04956
`
`-1-
`
`TITLE OF THE INVENTION
`
`SUBSTITUTED SULFONAMIDES AS SELECTIVE [33 AGONISTS
`
`FOR THE TREATMENT OF DIABETES AND OBESITY
`
`CROSS REFERENCE
`
`This is a continuation-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.
`
`10
`
`15
`
`20
`
`25
`
`BACKGROUND OF THE INVENTION
`
`B-Adrenoceptors have been subclassified as [31 and B2 since
`Increased heart rate is the primary consequence of Bl-receptor
`
`1967.
`
`stimulation, while bronchodilation and smooth muscle relaxation
`
`typically result from [32 stimulation. Adipocyte lipolysis was initially
`
`thought to be solely a Bl—mediated process. However, more recent
`
`results indicate that the receptor-mediating lipolysis is atypical in
`nature. These atypical receptors, later called B3—adrenoceptors, are
`
`found on the cell surface of both white and brown adipocytes where
`
`their stimulation promotes both lipolysis (breakdown of fat) and energy
`
`expenditure.
`
`Early developments in this area produced compounds with
`greater agonist activity for the stimulation of lipolysis ([33 activity) than
`for stimulation of atrial rate ([3]) and tracheal relaxation ([32). These
`
`early developments disclosed in Ainsworth e_t_ _al., US. Patents 4,478,849
`
`and 4,396,627, were derivatives of phenylethanolamines.
`Such selectivity for B3-adrenoceptors could make
`
`compounds of this type potentially useful as antiobesity agents.‘ In
`
`addition, these compounds have been reported to show
`antihyperglycemic effects in animal models of non-insulin-dependent
`
`30.
`
`diabetes mellitus.
`A major drawback in treatment of chronic diseases with [33
`agonists is the potential for stimulation of other B-receptors and ‘
`I
`subsequent side-effects. The most likely of these include muscle tremor
`(I32) and increased heart rate (B1). Although these phenylethanolamine
`
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`WO 95/29159
`
`PCT/US95/04956
`
`-2-
`
`derivatives do possess some [33 selectivity, side effects of this type have
`
`It is reasonable to expect that these
`been observed in human volunteers.
`side effects resulted from partial [31 and/or [32 agonism.
`
`More recent developments in this area are disclosed in
`
`Ainsworth gt a_l., US. Patent 5,153,210, Caulkett e_t a_l., US. Patent
`
`4,999,377, Alig e_t al, US. Patent 5,017,619, Lecount 91 a_l., European
`
`Patent 427480 and Bloom gt a_l., European Patent 455006.
`
`Even though these more recent developments purport to
`describe compounds with greater [33 selectivity over the B1 and [32
`
`activities, this selectivity was determined using rodents, in particular,
`
`10
`
`rats as the test animal. Because even the most highly selective
`
`compounds, as determined by these assays, still show signs of side
`effects due to residual [31 and B2 agonist activity when the compounds
`
`15
`
`are tested in humans, it has become apparent that the, rodent is not a
`good model for predicting human [33 selectivity.
`
`20
`
`25
`
`'
`
`3'0
`
`Recently, assays have been developed which more
`
`accurately predict the effects that can be expected in humans. These
`assays utilize cloned human B3 receptors which have been expressed in
`
`Chinese hamster ovary cells. See Emorine et al, Science, 1989,
`
`245:1118-1121; and Liggett, Mol. Pharmacol., 1992, 42:634-637. The
`
`agonist and antagonist effects of the various compounds on the
`
`cultivated cells provide an indication of the antiobesity and antidiabetic
`
`effects of the compounds in humans.
`
`SUMMARY OF THE INVENTION
`
`The instant invention is concerned with substituted
`
`sulfonamides which are Useful as antiobesity and antidiabetic
`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 substituted sulfonamides. 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
`compounds as the active ingredient thereof. Further objects will
`
`become apparent from reading the following description.
`
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`W0 95/29159
`
`PCT/US95/04956
`
`-3-
`
`DESCRIPTION OF THE INVENTION
`
`The present invention provides compounds having the
`
`formula I:
`
`HR2
`
`@(IDHCHzN'LaC(X){Z:\>—RN--so2(CH2)-R
`
`(R1)n
`
`0 to 5;
`
`O or 1;
`
`0 to 3;
`
`(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;
`
`10
`
`where
`
`15
`
`n is
`
`m is
`
`r is
`
`A is
`
`20
`
`25
`
`30
`
`Rlis- '
`
`(1) hydroxy,
`
`(2) oxo,
`
`—
`
`(3) halogen,
`
`(4) cyano,
`(5) NR8R8,
`
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`

`WO 95/29159
`
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`
`(6) SR8,
`
`(7) trifluoromethyl,
`
`(8) Cl-CIO alkyl,
`(9) 0R8,
`(10) SOzR9,
`(11) OCOR9,
`(12) NR8C0R9,
`(13) COR9,
`(14) NR8302R9,
`(15) NR8c02R8, or
`
`(16) C1-C10 alkyl substituted by hydroxy, halogen, cyano,
`NR8R8, SR8, trifluoromethyl, 0R8, C3-C8 cycloalkyl,
`phenyl, NR8c0R9, COR9, 302129, OCOR9, NR8802R9 or
`NR8C02R8;
`
`R2 and R3 are independently
`
`(1) hydrogen,
`
`(2) C1-C10 alkyl or
`
`(3) C1-C10 alkyl with 1 to 4 substituents selected from
`
`hydroxy, C 1 -C 10 alkoxy, and halogen;
`
`10
`
`15
`
`20
`
`X is
`
`(1) -CH2-,
`
`(2) -CH2-CH2- ,
`
`(3) -CH=CH- or
`
`(4) -CH20-;
`
`R4 and R5 are independently
`
`25
`
`(1)hydrogen,
`
`(2) Cl-CIO alkyl,
`
`(3) halogen,
`(4) NHR8,
`(5) 0R8,
`(6) SOzR9 or
`(7) NHSOZR9;
`(1) hydrogen or
`(2) C1-C10 alkyl;
`z—(Rla)n;
`
`30
`
`R6 is
`
`R7 is
`
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`

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`
`PCT/US95/04956
`
`-5-
`
`Rlais
`
`(1) R1, with the proviso that when A is phenyl, R12:1 is not
`C1-C10 alkyl,
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Z is
`
`(2) C3—C8 cycloalkyl,
`
`(3) phenyl optionally substituted with up to 4 groups
`independently selected from R8, NR8R8, 0R8, 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, 0R8, SR8, and halogen;
`(l) 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 heteroatoms 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, NRIORIO, Cv1-C10 alkyl, C1-C10
`alkoxy, C1-C10 alkylthio, and C1-C10 alkyl having 1 to 4
`substituents selected from hydroxy, halogen, COzH, C02—
`C1-C10 alkyl, SOz-C1-C10 alkyl, C3-C8 cycloalkyl, C1—
`
`SAWAI EX. 1013'
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`WO 95/29159
`
`PCT/US95/04956
`
`-6—
`
`C10 alkoxy, and Z optionally substituted by from 1 to 3 of
`
`halogen, C1-C1() alkyl or C1-C1() alkoxy, or
`
`(5) C1—C1() alkyl having 1 to 4 substituents selected from
`
`hydroxy, halogen, COzH, COz-C1-C10 alkyl, SOz-Cl-Clo
`
`alkyl, C3-C8 cycloalkyl, C1—C10 alkoxy, C1—C1() alkyl, and
`
`Z optionally substituted by from 1 to 4 of halogen, C1—C10
`
`alkyl or C1—C10 alkoxy;
`(1) R8 or
`(2) NR8R8;
`(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
`
`R9 is
`
`10
`
`R10 is
`
`substituted with C1-C10 alkyl; or
`
`a pharmaceutically acceptable salt thereof.
`
`In one embodiment of the instant invention A is a 5 or 6-
`
`membered heterocyclic ring with from 1 to 4 heteroatoms selected from
`
`oxygen, sulfur and nitrogen, 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 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.
`
`In another embodiment of the instant invention A is phenyl
`or benzene fused to a C3—C8 cycloalkyl ring.
`
`Preferred compounds of the instant invention arerealized
`
`15
`
`20
`
`25
`
`when in the above structural formula I:
`
`R2 and R3 are hydrogen or methyl;
`X is
`—CH2-;
`
`30
`
`n is
`
`m is
`
`0 to 3;
`
`1;.
`
`0 to 2; and
`r is
`.
`R4, R5 and R6 are hydrogen.
`> Other preferred compounds of the instant invention are
`realized whenin the above structural formula I:
`
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`

`WO 95/29159
`
`PCTfUS95/04956
`
`-7-
`
`Ais
`
`phenyl or a 6-membered heterocyclic ring with 1 or 2
`
`R1 is
`
`heteroatoms selected from nitrogen and sulfur;
`hydroxy, halogen, cyano, trifluoromethyl, NR8R8,
`NR3802R9, NR8COR9, NR8C02R8, C1-C6 alkyl
`
`optionally substituted by hydroxy; and
`
`ris
`
`O or 2.
`
`More preferred compounds are represented by the formula
`
`Ia:
`
`T T2
` A CI)H
`\ j-C*HCH2N-Cl-(X)m_©‘NH—SO2-Z-(R“"‘)n
`(R1)n
`
`/K
`
`N
`
`R3
`
`10
`
`15
`
`20
`
`25
`
`30'
`
`la
`
`0 to 3;
`
`1 (
`
`wherein
`
`n is
`
`m is
`
`R1 is
`
`1) halogen or
`(2) NR3R8;
`R2, R3 are independently hydrogen or methyl;
`R1&1 is
`(l) halogen,
`(2) C1-C10 alkyl,
`(3) NR8R8,
`(4) NR8C0R9,
`(5) NR8C02R3,
`(6) COR9,
`(7) 0C0R9, or
`(8) a 5 or 6-membered heterocycle with from 1 to 4 I
`heteroatoms selected from oxygen, sulfur and nitrogen,
`
`optionally substituted with up to four groups independently
`selected from oxo, halogen, R8, NR8R8, 0R8, and SR8;
`
`Zis'
`
`(1) phenyl,
`
`(2) naphthyl,
`
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`
`-8-
`
`(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 under formula 1.
`
`Even more preferred compounds are those represented by
`
`formula Id:
`
`f/DB
`I
`1
`)Al
`nKN Cl-l-CHZNCHCHg-QVNH802—2V (R )
`
`OH
`
`HR2
`
`R3
`
`n— _
`
`_ 1a
`
`5
`
`10
`
`15
`
`20
`
`Id
`
`0 or 1;
`n is
`NR8R8;
`R1 is
`R2 and R3 are independently
`(1) hydrogen, or
`
`25
`
`(2) methyl;
`
`B is
`
`'
`
`(1) hydrogen,
`
`g
`
`H30
`
`_
`
`,
`
`R121 is
`
`(2) benzene fused to the benzene ring to form naphthyl, or
`
`‘
`
`(3) a 5 or 6—membered heterocycle with l to 4 heteroatoms
`selected from oxygen, sulfur and nitrogen atom fused to the
`benzene ring;
`(l) halogen,
`(2) C1-C10 alkyl,
`(3) NR8R8,
`(4) NR8c0R9,
`(5) NR8C02R8,
`
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`WO 95/29159
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`
`(6) C0R9, 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, 0R8, and NR8R8;
`when B and the benzene ring form a fused ring system, R1a
`
`is attached to either ring;
`
`(1) hydrogen,
`
`(2)C1-C10 alkyl,
`
`(3) Z optionally having 1 to 4 substituents selected from
`nitro, 0x0, 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;
`(1) R8 or
`(2) NR3R8;
`
`(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
`
`R9 is
`
`Rlois
`
`Zis
`
`(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.
`Other more preferred compounds are represented by
`
`formula Ib:
`
`10
`
`15
`
`20
`
`25
`
`"30
`
`SAWAI EX. 1013
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`Page 11 of 103
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`SAWAI EX. 1013
`Page 11 of 103
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`

`

`WO 95/29159
`
`PCTfUS95/04956
`
`-10-
`
`HR2
`
`
`
`l—CHCH N-lo- x
`)nv 2
`| '( )m
`R3
`
`NH—so —Z-(R a)n
`2
`
`lb
`
`0 to 3;
`
`1 (
`
`1) hydroxy,
`
`(2) cyano,
`(3) NR8R8 or
`
`(4) halogen;
`
`(1) halogen,
`(2) NR8R8,
`(3) NR8COR9,
`(4) NR8C02R8,
`(5) OCOR9, or
`
`10
`
`wherein
`
`n is
`
`m is
`
`R1 is
`
`15
`
`Rlais
`
`20
`
`(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;
`
`Zis
`
`25
`
`(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;
`
`30
`
`Xis
`
`—CH2-; and
`' ’Rz-and R3 are independently hydrogen or methyl.
`Representative antiobesity and antidiabetic compounds of
`
`the present invention include the following:
`N;[4-[2-[[2--hydroxy——2-(6--arninopyridin——3-y-l)ethyl]amino]ethy1]phenyl]—
`4--(hexylaminocarbonylamino)benzenesulfonamide
`
`. SAWAI EX. 1013
`
`Page 12 of 103 '
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`SAWAI EX. 1013
`Page 12 of 103
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`

`

`WO 95/29159
`
`PCT/US95/04956
`
`-11-
`
`N-[4-[2-[[2-hydroxy—2-(6-aminopyridin—3—y1)ethy1]amino]ethyl]phenyl]—
`4-iodobenzenesulfonamide
`
`_I\_I—[4—[2-[[2—hydroxy—2-(6-aminopyridin—3-y1)ethy1]amino]ethyl]phenyl]—
`
`benzenesulfonamide
`
`N-[4-[2—[[2—hydr0xy-2-(6-aminopyridin—3—y1)ethy1]amino]ethy1]phenyl]-
`
`2-naphthalenesulf0namide
`
`N—[4-[2-[[2—hydroxy-2-(6-aminopyridin-3-y1)ethy1]amino]ethy1]phenyl]—
`
`3—quinolinesulfonamide
`
`10
`
`N—[4—[2-[[2-hydr0xy-2—(6-aminopyridin-3—y1)ethy1]amino]ethy1]pheny1]-
`5—benzisoxazolesulfonamide
`
`N—[4—[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethy1]amino]ethyl]phenyl]-
`4—[(hexylmethylaminocarbonyl)amino]benzenesulfonamide
`
`15
`
`N—[4—[2-[[2—hydroxy-2-(6-aminopyridin-3-y1)ethy1]amino]cthyl]phenyl]—
`4-[(dimethylaminocarbony1)amino]benzenesulfonamide
`N—[4-[2-[[2-hydroxy-2-(6-amin0pyridin-3-y1)ethy1]amino]ethyl]pheny1]—
`4-(3-hexy1—2-imidazolidon- 1 —y1)benzenesulfonamide
`
`N—[4-[3-[[2-hydroxy—2-(6-aminopyridin-3-y1)ethyl]amino]propyl]-
`pheny1]-4-(hexylaminocarbonylamino)benzenesulfonamide
`
`20
`
`N—[4—[3—[[2-hydroxy-2—(6-aminopyridin—3—y1)ethyl]amino]propyl]—
`phenyl]-4-iod0benzenesu1fonamide
`
`N-[4-[3—[[2-hydroxy-2—(6—aminopyridin-3—y1)ethy1]amino]propyl]-
`pheny1]bcnzencsulfonamidc
`
`25
`
`N—[4—[3-[[2-hydroxy-2-(6-aminopyridin-3-y1)ethy1]amino]propyl]—
`phenyl]—2-naphthalenesulfonamide
`
`N—[4—[3-[[2-hydroxy-2-(6—aminopyridin-3-y1)ethy1]amino]propyl]-
`phenyl]-3-quinolinesulfonamide
`
`N-[4-[2-[[2-hydroxy—2—(3'—pyridinyl)ethy1]amino]ethy1]pheny1]-4—
`(hexylaminocarbonylamino)benzenesulfonamide
`
`-30
`
`N-[4-[2-[[2—hydroxy—2—(3-pyridiny1)ethy1]amino]ethy1]pheny1]-4-
`isopropylbenzenesulfonamide
`
`N— [4— [2- [[2--hydroxy--2- (3-p—yridiny1)ethyl]amino]ethy1]pheny1]-2—
`naphthalenesulfonamide
`-
`
`N-[4[2-[[2-hydroxy—2--(3-pyridiny1)ethyl]amino]ethyl]pheny1]~3-
`quinolinesulfonamide
`
`SAWAI EX. 1013
`
`Page 13 of 103
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`SAWAI EX. 1013
`Page 13 of 103
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`

`WO 95/29159
`
`PCT/US95/04956
`
`-12-
`
`_N_— [4—[2— [[2-hydroxy—2—(3-pyridiny1)ethyl]amino]ethyl]pheny1]—4-
`
`[(hexylmethylaminocarbonyl)amino]benzenesulfonamide
`
`N; [4- [2- [[2—hydroxy—2- (3-pyridinyl)ethyl] amino] ethyl] pheny1]~4-(3-
`
`hexyl—2-imidazolidinon— 1 -y1)benzenesu1fonamide
`
`'
`
`li- [4— [2— [[2-hydroxy-2—(3 -pyridiny1)ethyl] amino] ethy1]pheny1]—4-
`
`iodobenzenesulfonamide
`
`_N_- [4— [2— [ [2-hydroxy—2— (3-pyridinyl)ethy1] amino] ethyl] pheny1]-4- [5—(3 -
`
`cyclopentylpropyl)-[1,2,4]-oxadiazol-3-yl]benzensulfonamide
`
`N;[4-[2-[[2—hydroxy-2-(3-pyridinyl)ethyl]amino]ethy1]pheny1]-4—[( 1-
`
`oxohcptyl)amino]bcnzenesulfonamide
`
`H—[4-[2-[[2-hydroxy-2—(3-pyridinyl)ethy1]amino]ethy1]phenyl]—4-[( l—
`
`oxo—4-phenylbutyl)amino]benzenesulf0namide
`
`fl-[4-[2—[[2-hydr0xy-2-(3-pyridiny1)ethy1]amino]ethyl]phenyl]-4-
`
`[(propoxycarbonyl)amino]benzenesulfonamide
`
`fl- [4- [2-[[2-hydroxy-2-(3—pyridinyl)ethyl] amino] ethyl]pheny1]-4— [ [ [(fur—
`
`2—ylmethy1)amino]carbony1]amino]benzenesulfonamide
`
`N; [4- [2—[[2-hydroxy-2-(3-pyridiny1)ethyl]amino] ethyl]pheny1]-4— [[[(2-
`
`phenylethy1)amino]carbonyl]amino]benzenesulfonamide
`
`fl—[4—[2—[[2-hydroxy-2-(3—pyridiny1)ethyl]amin0]ethyl]pheny1]-4—[[[(2-
`ind01-3-y1ethy1)amino] carbonyl]amino]benzenesulforiamide
`_I_\l-[4— [2-[[2-hydroxy-2—(3-pyridinyl)éthyl]amino] ethyl]phenyl]—4-
`
`[[(octylamino)carbonyl]amin0]benzenesulfonamide
`
`N; [4- [2-[[2-hydroxy-2-(3-pyridinyl)ethy1]amino]ethy1]phenyl]— 1 -
`
`[(hexylamino)carbonyl]-5—indolinesulfonamide
`
`bl—[4—[2-[[2-hydroxy—2—(3-pyridiny1)ethy1]amino]ethyl]phenyl]- 1-
`
`[(octylamino)carbonyl]—5—indolinesulfonamide
`
`fl- [4- [2- [ [2-hydroxy-2-(3-pyridinyl)ethyl] amino]ethyl]phenyl]- 1 -[(N—
`
`methyl—N-octylamino)carb0ny1]-5-ind01inesulfonamide
`
`M—[4— [2—[[2-hydroxy~2—(3—pyridinyl)ethy1]amino]ethyl]phenyl]-1 -( 1-
`
`oxonony1)—5—indolinesu1fonamide
`
`M—[4-[2-[[2-hydr0xy—2-(3-pyridiny1)ethyl]amin0]ethy1]phenyl]-1-(4-
`
`methylthiazol—Z-y1)-5-indolinesulfonamide
`. E¥[4—[2-[[2-hydroxy—2—(3-pyridiny1)ethy1]amino]ethyl]phenyl]—1-(4-
`octylthiazol—Z—y1)-5-indolinesu1fonamide
`
`_
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`SAWAI EX. 1013
`
`Page 14 of 103
`
`SAWAI EX. 1013
`Page 14 of 103
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`

`

`WO 95/29159
`
`PCT[U895/04956
`
`-13-
`
`N-[4—[2—[[2-hydroxy-2—(3—pyridinyl)ethyl]amino]ethy1]phenyl]- 1-(4—
`
`ethyl—5-Hmethylthiazol-2——yl)——5-indolinesulfonamide
`
`N- [4— [2— [[2-hydroxy-2-(3--pyridiny1)ethyl]amino]ethyl]pheny1]-4-(3-
`octy1—2—imidazolidinon- 1--yl)benzenesulfonamide
`
`_N-[4- [2— [[2-hydroxy-2—(3-p—yridiny1)ethyl]amino]ethyl]phenyl]-4-[3—
`(4,4,4—trifluorobutyl)-2-imidazolidinon-1-y1]benzenesulf0namide
`
`ill—[4-[2-[[2—hydroxy-2—(3—pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3—
`phenylpropyl)-2-imidazolidinon—1—y1]benzenesulfonamide
`
`10
`
`N-[4—[2-[[2—hydroxy-2-(3—pyridinyl)ethy1]amino]ethyl]phenyl]-4-[3-
`(4,4,5,5,5—pentaflu0ropentyl)-2-imidazolidinon— 1—
`
`yl]benzenesulf0namide
`
`N—[4-[2-[[2—hydroxy—2—(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4—[3-(2-
`cyclohexylethyl)-2-imidazolidinon- l—yl]benzenesulf0namide
`N-[4—[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4—[3-[3—
`(4-chlorophenyl)propyl]-2-imidazolidinon-1-y1]benzenesulf0namide
`N—[4—[2-[[2-hydroxy-2—(3—pyridiny1)ethyl]amin0]ethyl]phenyl]-4-(3—
`pentyl-2—imidazolidinon— 1 -yl)benzenesu1fonamide
`N-[4—[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-
`cyclopentylpropyl)-2-imidazolidinon— 1-y1]benzenesulfonamide
`N—[4—[2-[[2-hydroxy-2—(3-pyridinyl)ethyl]amino]ethyl]phenyl]—4—[3-(2—
`cyclopentylethyl)-2-imidazolidinon—I-yl]benzenesulfonamide
`N—[4—[2-[[2—hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-
`cyclohexylpropyl)-2-imidazolidinon-1-y1]benzenesulfonamide
`N—[4-[2-[[2-hydroxy-2—(3-pyridiny1)ethyl]amino]ethyl]phenyl]-4—[3-(2,2—
`dimethylhexy1)-2-imidazolidinon-1-y1]benzenesulfonamide
`N-[4—[2-[[2-hydroxy—2—(3-pyridiny1)ethyl]amino]ethyl]phenyl]—4—(3-
`hexyl—2-imidazolon— 1—y1)benzenesulfonamide
`N-[4—[2-[[2-hydroxy—2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]—4-[3-
`(4,4,4--trifluorobuty1)-2—imidazolon- 1 —yl]benzenesulfonamide
`N-[4- [2- [[2-hydroxy—2—(3——pyridiny1)ethy1]amino]ethy1]pheny1] 4—-(3-
`octy1-2—imidazolon—1-yl)benzenesu1fonamide
`
`15
`
`20
`
`25
`
`30
`
`N-[4- [2—[[2--hydroxy-2-(3——pyridinyl)ethyl]amino]ethyl]phenyl]~4—[3-(3-
`cyclopentylpropyl)—2-imidazolon—1—yl]benzenesulfonamide
`
`.
`
`SAWAI EX. 1013
`
`Page 15 of 103
`
`SAWAI EX. 1013
`Page 15 of 103
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`

`

`WO 95/29159
`
`PCT/US95I04956
`
`-14-
`
`fl-[4- [2— [[2-hydr0xy—2-(3-pyridiny1)ethy1]amino]ethyl]phenyl]-4-(2-
`
`octy1—3-ox0—[1,2,4]-triazol-4—y1)benzenesulfonamide
`
`fl— [4— [2— [ [2—hydroxy—2—(3-pyridiny1)ethyl]amino] ethyl]pheny1] -4—(4-
`
`hexyl-S-tetrazolon- 1 -yl)benzenesulfonamide
`
`fl- [4- [2- [ [2-hydr0xy—2—(3 —pyridiny1)ethyl]amino] ethyl] phenyl] -4- (4-
`
`octyl-S-tetrazolon-1—y1)benzenesulfonamide
`
`E- [4- [2— [ [2-hydroxy-2-(3 -pyridiny1)ethy1] amino] ethyl]phenyl] -4— [(3—
`
`cyclopentylpropyl)-5 —tetrazolon— 1 -y1]benzenesulfonamide
`
`M- [4— [2— [ [2-hydroxy-2-(3-pyridiny1)ethyl]amino]ethy1]phenyl]—4— (2-
`
`pentyloxazol-5-yl)benzenesulfonamide
`
`fl- [4- [2- [ [2—hydroxy-2-(3-pyridiny1)ethyl]amino] ethyl] pheny1]-4- (2-
`
`octyloxazol-S-yl)benzenesulfonamide
`
`E [4— [2- [ [2-hydroxy—2-(3-pyridiny1)ethy1]amino]ethyl]pheny1]-4- [2—(2—
`
`cyclopentylethyl)oxazol—5-y1]benzenesulfonamide
`
`M— [4- [2- [[2-hydroxy-2-(3-pyridinyl)ethy1]amino]ethyl]pheny1]-4- [(4-
`
`ethyl-5—methylthiazol-2—yl)amino]benzenesulf0namide
`
`fl- [4- [2-[[2-hydroxy—2— (3—pyridiny1)ethy1]amino]ethy1]phenyl] -4-
`
`[(4,5,6,7-tetrahydr0benzothiazol-2—yl) amino]benzenesulfonamide
`
`fl- [4- [2—[[2-hydroxy-2-(3-pyridiny1)ethyl]amin0] ethyl]pheny1] -4-(2-
`
`hexylimidazol-4-yl)benzenesulfonamide
`
`E— [4- [2-[[2—hydroxy-2—(3-pyridinyl)ethyl]amino]ethy1]phenyl]-4—( 1 -
`
`methyl-2-octylimidazol-S-y1)benzenesu1f0namide
`
`L1- [4- [2— [[2-hydroxy-2—(3-pyridiny1)ethy1]amino]ethy1]phenyl]-4— [ 1 ~
`
`methyl-2-(2-cyclopentylethyl)imidazol-5-y1]benzenesulfonamide
`
`_1_\1—[4-[2-[[2-hydroxy-2-(3—pyridiny1)ethy1]amino]ethy1]phenyl]-4— [ 1 -
`methyl-2-[2-(4-fluoropheny1)ethyl]imidazol-5-yl]benzenésu1f0namide
`M— [4— [2-[[2-hydroxy—2- (3-pyn'diny1)ethyl]amino]ethy1] pheny1]—4-(5—
`
`pentyl- [1 ,2,4]-oxadiaz01—3—y1)benzcnesu1fonamide
`fl- [4-[2-[[2—hydroxy-2-(3 —pyridinyl)ethy1]amin0]ethy1]pheny1] -4-[5—(2-
`
`cyclopentylethy1)-[ 1 ,2,4] -oxadiazol-3—yl]benzenesu1fonamide
`
`E- [4- [2— [[2-hydroxy-2—(3-pyridiny1)ethyl] amino] ethyl] pheny1]-4- (5—
`
`heptyl- [1 ,2,4]-oxadiazol—3-yl)benzenesu1fonamide
`. fl-[4—[2—[[2-hydroxy—2—(3—pyridinyl)ethy1]amino]ethy1]phenyl]¥4-(5—
`octyl-[1I,2,4]-oxadiazol-3—yl)benzenesu1f0namide
`
`10
`
`15
`
`20
`
`25
`
`30
`
`SAWAI EX. 1013
`
`Page 16 of 103
`
`SAWAI EX. 1013
`Page 16 of 103
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`

`

`W0 95/29159
`
`PCT/US95/04956
`
`-15-
`
`N—[4—[2-[[2—hydroxy-2-(3-pyridinyl)ethy1]amino]ethyl]pheny1]-4—(5-
`
`hexylthio—[1,2,4]—triazol—3-yl)benzenesulfonamide
`
`N—[4-[2—[[2—hydroxy-2-(3-pyridiny1)ethyl]amino]ethyl]pheny1]-4—[[4-(4-
`
`propylpiperidin-l-y1)-1,1—di0xo-[1,2,5]—thiadiazol-3-
`
`yl]amino]benzenesulfonamide
`
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny1)ethyl]amin0]ethyl]phenyl]-4-[[4-
`
`(hexylmethylamino)-1,1—dioxo-[1,2,5]—thiadiazol—3-
`
`yl]amin0]benzenesu1fonamide
`
`10
`
`15
`
`N—[4-[2—[[2—hydroxy—2—(3-pyridiny1)ethy1]amino]ethyl]phenyl]—4—[[4—(N-
`
`heptyl, N—methylamino)— 1, 1-dioxo-[l,2,5]-thiadiazol-3—
`
`yl]amino]benzenesulfonamide
`N—[4— [2-[[2—hydroxy-2-(3-—pyridiny1)ethy1]amin0]ethyl]phenyl]-4-(1-
`octyl—2,4-imidazolidinedion— 3--yl)bcnzenesulfonamide
`
`N-[4-[2—[[2-hydroxy—2—(3-pyridinyl)ethy1]an‘1ino]ethyl]phenyl]-4—[3-(3-
`
`nitropheny1)-5—pyrazolon- 1-y1]benzenesulfonamide
`
`N-[4-[2-[[2-hydroxy—2-(3-pyridinyl)ethy1]amino]ethyl]pheny1]-4-[4-(1-
`hydroxy-1-hexy1heptyl)-5-methyl-[1 ,2,3]-triazol-2-y1]benzenesulfon-
`amide
`
`20
`
`N; [4— [2- [ [2-hydroxy-2-(3-pyridiny1)ethyl]amino]ethy1]pheny1] -4— [4—( 1-
`hydroxyheptyl)—5-methyl-[1,2,3]-triazol-2—y1]benzenesulfonamide
`
`N—[4-[2—[[2-hydroxy-2-(3-pyridinyl)ethy1]amino]—2-methy1propyl]-
`pheny1]-4-(3—hexyl—2-imidazolidinon-1-y1)benzenesulfonamide
`
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethy1]amino]—2-methy1propyl]--
`phenyl]-4-iodobenzenesu1fonamide
`
`25
`
`N-[4-[2-[[2-hydroxy—2-(3—pyridiny1)ethy1]amino]—2-methy1propyl]-
`phenyl]-4—[[(hexylamino)ca1bonyl]a111ino]benzeneqsulfonamide
`N—[4—[2—[(2-hydroxy-2-phenylethyl)amino]ethyl]pheny1]-4-iodobenzene-
`sulfonamide
`I
`I
`
`30
`
`N—[4-[2-[(2-hydroxy—2-phenylethyl)amino]ethyl]pheny1]-2-naphthalene-
`sulfonamide
`"
`
`N—[4-[2—[(2-hydroxy-2-phenylethy1)amino]ethy1]pheny1]—3-quinoline-
`sulfonamide
`
`‘
`
`N-[4-[2-[[2--hydroxy——2-(3--chlorophenyl)ethyl]amino]ethy1]phe11y1]—3-
`
`isopropylbenzenesulfonamide
`
`SAWAI EX. 1013
`
`Page 17 of 103
`
`SAWAI EX. 1013
`Page 17 of 103
`
`

`

`WO 95/29159
`
`PCT/US95/04956
`
`—16-
`
`fl— [4- [2— [[2-hydroxy—2-(3-chlorophenyl)ethyl] amino]ethyl]phenyl]—2-
`
`naphthalenesulfonamide
`
`li— [4-[2— [[2-hydroxy-2-(3-chlorophenyl)ethyl] amino]ethy1]phenyl]—3-
`
`quinolinesulfonamide
`
`N; [4- [2- [[2-hydroxy-2- (4—amino-3 ,5—dich10rophenyl)ethyl] amino] ethyl]-
`phenyl]-4-(hexylaminocarbonylamino)benzenesulfonamide
`
`_1\_I- [4— [2— [[2-hydroxy-2- (4-amino-3 ,5—dichlorophenyl)ethy1] amino] ethyl]—
`
`phenyl]—1-[(0cty1amin0)carbonyl]-5 -indolinesulf0namide
`
`10
`
`_I\_I— [4— [2- [[2-hydroxy-2- (4-amino—3 ,5—dichloropheny1)ethyl] amino] ethyl]-
`pheny1]-4—(3-hexyl—2-imidazolidinon- 1-yl)benzenesulfonamide
`.
`
`N; [4- [2- [[2-hydroxy-2-(4-amino-3 ,5—dichlorophenyl)ethyl] amino] ethyl]-
`phenyl]-4-(3-octyl-2-imidazolidinon- 1 -yl)benzenesulfonamide
`
`E— [4-[2- [[2-hydroxy-2-(4-hydroxypheny1)ethyl] amino] ethyl]pheny1]-
`benzenesulfonamide
`
`E- [4— [2-[[2-hydroxy-2—(4-hydroxyphenyl)ethyl] amino]ethy1]phenyl]-4—
`iodobcnzenesulfonamide
`
`15
`
`fl- [4—[2-[[2-hydroxy-2-(3-cyanophenyl)ethy1] amino]ethy1]pheny1]—4-
`(hexylaminocarbonylamino)benzenesulfonamide
`
`20
`
`E- [4— [2-[[2-hydr0xy-2-(3—cyanopheny1)ethyl] amino] ethyl]phenyl]-3-
`quinolinesulfonamide
`
`25
`
`30
`
`E- [4-[2— [[2—hydroxy-2—(3-pyridinyl)ethyl]amino]ethy1]pheny1]~4-(5-
`hexyl- [ 1 ,2,4]-oxadiazol-3-y1)benzenesulfonamide
`fl- [4—[2- [[2-hydroxy-2— (3-pyridinyl)ethyl]amino]ethy1]pheny1]-4-(4-
`heptyl-S-methy1—[1,2,3]—triazol-2—yl)benzenesulfonamide
`
`M— [4- [2- [[2-hydroxy-2—(3-pyridinyl)ethy1]amino] ethyl]pheny1] -4—(3-
`hexyl—Z,4—imidazolidinedion— 1 -y1)benzenesulfonamide
`M— [4- [2-[[2—hydroxy-2—(3—pyridinyl)ethy1]amino] ethyl] phenyl] -4-(3-
`octyl-2,4-imidazolidinedion— 1 -y1)benzenesulfonamide
`_ M—[4-[2—[[2-hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phenyl]-4-[3-(3-
`cyclopentylpropyl)-2,4—imidazolidinedion—l—y1]benzenesulfonamide
`H- [4—[2-[[2-hydroxy-2-(3-pyridiny1)ethyl]amino]ethyl]phenyl]—4-(3-
`pentyl- [1 ,2,4]-oxadiazol-5-yl)benzenesul_fonamide
`- E—[4—[2—[[2—hydroxy-2-(3—pyridinyl)ethyl]amiho]ethyl]phenyl]-4-(3-
`hexy1-[1,2,4]-oxadiazol—5-y1)benzenesulfonamide
`
`SAWAI EX. 1013
`
`Page 18 of 103
`
`SAWAI EX. 1013
`Page 18 of 103
`
`

`

`WO 95/29159
`
`PCT/US95/04956
`
`-17-
`
`E-[4—[2-[[2-hydroxy-2—(3—pyridiny1)ethy1]amino]ethyl]phenyl]—4—(3—
`
`heptyl-[l,2,4]-oxadiazol—5-yl)benzenesu1fonamide
`
`_N_-[4-[2-[[2-hydroxy—2-(3—pyridinyl)ethy1]amino]ethyl]phenyl]—4—(3—
`octyl—[l,2,4]-oxadiazol-5-y1)benzenesulfdnamide
`
`E-[4-[2-[[2-hydroxy—2—(3—pyridinyl)ethy1]amin0]ethy1]phenyl]—4—[3-(2-
`
`cyclopentylethy1)—[1,2,4]-oxadiazol-S-yl]benzenesulfonamide
`
`E-[4—[2—[[2-hydroxy—2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]—4-[3-(3—
`
`cyclopentylpropyl)-[1,2,4]-oxadiazol-5-yl]benzenesulfonamide
`
`fl-[4-[2—[[2-hydroxy-2-(3-pyridiny1)ethyl]amino]ethyl]phenyl]-4—(3—
`
`pentyl-[1,2,4]-thiadiazol-5—y1)bcnzenesulfonamide
`
`LI-[4-[2—[[2-hydroxy-2-(3—pyridinyl)ethyl]amino]ethyl]phenyl]-4—(3-
`
`hexy1-[ 1 ,2,4]-thiadiazol—5-y1)benzenesulfonamide
`
`b1-[4-[2-[[2—hydroxy-2—(3-pyridinyl)ethyl]amin0]ethyl]phenyl]-4—(3-
`heptyl-[l,2,4]-thiadiazol—5-yl)benzenesulfonamide
`
`M-[4-[2—[[2-hydroxy—2-(3—pyridinyl)ethyl]amino]ethyl]phenyl]—4—(3-
`
`octyl—[l,2,4]~thiadiazol-5—yl)benzenesulf0namide
`
`10
`
`15
`
`_N_—[4-[2-[[2-hydroxy-2-(3—pyridinyl)ethyl]amino]ethy1]phenyl]-4-[3-(2-
`cyclopentylethy1)— [1 ,2,4]-thiadiazol—5—yl]benzenesulfonamide
`
`20
`
`_N_-[4-[2—[[2-hydroxy-2—(3—pyridiny1)ethyl]amino]ethyl]pheny1]—4-[3-(3-
`cyclopentylpropyl)-[1,2,4]-thiadiazol-5-y1]benzenesu1fonamide
`
`25
`
`30
`
`N; [4-[2—[[2-hydroxy-2-(3-pyridiny1)ethyl]amino]ethyl]phenyl]-4—(5—
`pentyl-[1,2,4]-thiadiazol-3-yl)benzenesu1fonamide
`fl— [4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethy1]phenyl]-4—(5—
`hexyl- [ 1 ,2,4]-thiadiazol—3-yl)benzenesu1fonamide
`
`fl-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethy1]amin0]ethyl]phenyl]-4-(5-
`heptyl-[1,2,4]-thiadiazol-3-yl)benzenesulfonamide
`
`M-[4-[2—[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4—_(5-
`octyl-[l,2,4]-thiadiazol—3-yl)benzenesulfonamide
`V H— [4— [2-[[2-hydroxy—2—(3-pyridinyl)ethy1]amino]ethyl]phenyl]-_4—[5-,(2-
`cyclopentylethyl)-[-1,2,4]-thiadiazol—3—y1]benzenesulfonamide
`
`M-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]—4—[5-(3-
`cyclopentylpropy1)—[1,2,4]-thiadiazol—3—yl]benzenesulf0namide
`fl-[4—[2—[[2—hydroxy-2-(3—pyridinyl)ethyl]amino]ethyl]phenyl]~4-(4-
`penty1-3—oxo— [1 ,2,4]—triazol-2-yl)benzenesu1fonamide
`
`SAWAI EX. 1013
`Page 19 of 103
`
`SAWAI EX. 1013
`Page 19 of 103
`
`

`

`WO 95/29159
`
`PCT/US95/04956
`
`—18-
`
`N—[4-[2-[[2—hydr0xy-2-(3—pyridiny1)ethyl]amino]ethyl]pheny1]