llllllllllllllllllllllllllllllll||l||llllllllllllllllllllllllllllllllllllll
`US005561142A
`
`[19]
`
`[11] Patent Number:
`
`5,561,142
`
`United States Patent
`Fisher et a].
`[45] Date of Patent: Oct. 1, 1996
`
`
`
`[54] SUBSTITUTED SULFONAMIDES AS
`SELECTIVE [33 AGONISTS FOR THE
`TREATNIENT OF DIABETES AND OBESITY
`
`[75]
`
`Inventors: Michael H. Fisher, Ringoes; Elizabeth
`M. Naylor, Scotch Plains; Dong 0k,
`Edison; Ann E. Weber, Scotch Plains;
`Thomas Shih; Hyun 0k, both of
`Edison, all of NJ.
`
`[73] Assignee: Merck & Co., Inc., Rahway, NJ.
`
`[21] Appl. No.: 445,630
`
`[22]
`
`Filed:
`
`May 22, 1995
`
`FOREIGN PATENT DOCUMENTS
`
`0091749 10/1983
`.
`European Pat. OE.
`0007206
`l/l989
`European Pat. OE. .
`0427480
`5/1991
`European Pat. OE.
`.
`0455006
`11/1991
`European Pat. OE.
`.
`0516350 12/1992
`European Pat. OE. .
`0516349 12/1992
`European Pat. OE. .
`0068669
`1/1993
`European Pat. 0E. .
`0565317 10/1993
`European Pat. OE.
`.
`0611003
`8/1994
`European Pat. OE. .
`1108577
`4/1968
`United Kingdom .
`1565080
`4/1990
`United Kingdom .
`WIPO .
`WO93/10074
`5/1993
`WO93/22277
`11/1993
`WIPO .
`WO94/02493
`2/1994 WIPO.
`WO94/29290 l2/l994 WIPO.
`
`Related US. Application Data
`
`OTHER PUBLICATIONS
`
`[63]
`
`Continuation—impart of Ser. No. 404,565, Mar. 21, 1995,
`abandoned, which is a continuation-in—part of Ser. No.
`233,166, Apr. 26, 1994, abandoned.
`
`[51]
`
`Int. Cl.6 ...................... C07D 413/12; C07D 213/30;
`A61K 31/44; A61K 31/47
`.......................... 514/312; 546/153; 546/194;
`[52] US. Cl.
`546/269; 546/271; 546/275; 546/276; 546/277;
`546/286; 546/338; 514/318; 514/337; 514/338;
`514/340; 514/342
`[58] Field of Search ..................................... 546/153, 194,
`546/269, 271, 275, 276, 277, 280, 338;
`514/312, 318, 337, 338, 340, 342
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,452,037
`3,816,516
`4,000,193
`4,396,627
`4,478,849
`4,999,377
`5,017,619
`5,153,210
`5,321,036
`
`.......................... 514/365
`6/1969 Santilli et a1.
`6/1974 Cox et a1.
`.......................
`514/653
`12/1976 Lunts et a1.
`............................. 546/344
`8/1983 Ainsworth et a1.
`.
`424/309
`10/1984 Ainsworth et a1.
`.
`424/285
`3/1991 Ainsworth et a1.
`424/285
`5/1991 Alig et al.
`........
`514/653
`10/1992 Ainsworth et a1.
`546/344
`6/1994 Sher ........................................ 514/366
`
`
`
`A. A. Larsen, et al, Journal of Medicinal Chemistry, vol. 10,
`(3) pp. 462—472, 1967.
`
`Primary Examiner—Zinna Northington Davis
`Attorney, Agent, or FirmwMollie M. Yang; David L. Rose
`[57]
`ABSTRACT
`
`Substituted sulfonamides are selective [33 adrenergic recep—
`tor agonists with very little [3, and [32 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 den-
`sity lipoprotein levels or to decrease gut motility. In addi-
`tion,
`the compounds can be used to reduced 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.
`
`18 Claims, N0 Drawings
`
`SAWAI EX. 1014
`
`Page 1 of 35
`
`SAWAI EX. 1014
`Page 1 of 35
`
`

`

`1
`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. patent application Ser. No. 08/404,565 filed Mar. 21,
`1995, now abandoned, which is a continuation—in—part of
`U.S. patent application Ser. No. 08/233,166 filed Apr. 26,
`1994, now abandoned these applications are hereby incor-
`porated by reference in their entirety.
`
`BACKGROUND OF THE INVENTION
`
`B—Adrenoceptors have been subclassified as [51 and [52
`since 1967. Increased heart rate is the primary consequence
`of Bl-receptor
`stimulation, while bronchodilation and
`smooth muscle relaxation typically result from B2 stimula-
`tion. 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 Bs-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 (B1) and
`tracheal relaxation ([52). These early developments disclosed
`in Ainsworth et al., U.S. Pat. Nos. 4,478,849 and 4,396,627,
`were derivatives of phenylethanolamines.
`Such selectivity for 133-adrenoceptors could make com-
`pounds 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 diabetes mellitus.
`A major drawback in treatment of chronic diseases with
`[33 agonists is the potential for stimulation of other B-recep—
`tors and subsequent side effects. The most likely of these
`include muscle tremor (B2) and increased heart rate ([31).
`Although these phenylethanolamine derivatives do possess
`some B3 selectivity, side effects of this type have been
`observed in human volunteers. It is reasonable to expect that
`these side effects resulted from partial [31 and/or [32 agonism.
`More recent developments in this area are disclosed in
`Ainsworth et al., U.S. Pat. No. 5,153,210, Caulkett et al.,
`U.S. Pat. No. 4,999,377, Alig et al., U.S. Pat. No. 5,017,619,
`Lecount et al., European Patent 427480 and Bloom et al.,
`European Patent 455006.
`Even though these more recent developments purport to
`describe compounds with greater B3 selectivity over the BI
`and [32 activities,
`this selectivity was determined using
`rodents, in particular, 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 are tested in
`humans, it has become apparent that the rodent is not a good
`model for predicting human [33 selectivity.
`Recently, assays have been developed which more accu-
`rately predict the effects that can be expected in humans.
`These assays utilize cloned human {33 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
`
`5,561,142
`
`2
`
`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 sul-
`fonamides 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 prepara-
`tion 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.
`
`10
`
`15
`
`DESCRIPTION OF THE INVENTION
`
`20
`
`The present invention provides compounds having the
`formula I:
`
`25
`
`30
`
`35
`
`4o
`
`45
`
`50
`
`55
`
`60
`
`65
`
`H R2
`|
`|
`
`R3
`
`1
`
`R4
`
`R5
`
`Iy—soz(cng),—R7
`
`R6
`
`Q} CHCHgN—IC—(XM
`
`OH
`l
`*
`
`(RI),l
`where
`n is
`
`m is Oto 5;
`Cor l;
`r is Oto 3;
`
`A is (l) 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 het-
`eroatoms 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) 0x0, (3) halogen, (4) cyano, (5)
`NR8R8, (6) SRS, (7) trifluoromethyl, (8) Cl—C10 alkyl,
`(9) ORS, (10) SOZRQ, (ll) OCORQ, (12) NRBCORQ,
`(l3) COR9, (14) NR8S02R9, (15) NRSCOZRg, or (16)
`C1—C10 alkyl substituted by hydroxy, halogen, cyano,
`NRSRS, SR8, trifluoromethyl, 0R8, C3—C3 cycloalkyl,
`phenyl,
`NRSCORQ,
`COR9,
`S02R9,
`OCOR",
`NR8302R9 or NR8C02R8;
`R2 and R3 are independently (1) hydrogen, (2) Cl—Clo
`alkyl or (3) Cl—C10 alkyl with 1
`to 4 substituents
`selected from hydroxy, C1—C10 alkoxy, and halogen;
`
`X is (1)
`CH2
`, (2)
`CH;1 CH2
`, (3)
`CH—CH—-
`or (4) —CH20—;
`R4 and R5 are independently (l)hydrogen, (2) C1—C10
`alkyl, (3) halogen, (4) NHRs, (5) ORS, (6) SOZR9 or (7)
`NHSOZR9;
`R6 is (1) hydrogen or (2) C1—C10 alkyl;
`R7 is Z-(R1”)n;
`R1‘1 is (1) R1, with the proviso that when A is phenyl, R1“
`is not C1—C10 alkyl, (2) C3—C8 cycloalkyl, 3) phenyl
`optionally substituted with up to 4 groups indepen-
`dently selected from R8, NR8R8, ORS, SR8 and halo-
`gen, or (4) 5 or 6-membered heterocycle with from 1 to
`
`SAWAI EX. 1014
`
`Page 2 of 35
`
`SAWAI EX. 1014
`Page 2 of 35
`
`

`

`3
`
`5,561,142
`
`4 heteroatoms selected from oxygen, sulfur and nitro-
`gen, optionally substituted with up to four groups
`independently selected from oxo, R8, NRBRS, 0R8,
`SR8, and halogen;
`Z is (l) phenyl, (2) naphthyl, (3) a 5 or 6—membered
`heterocyelic 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-mcmbered heterocyelic ring with from
`1
`to 4 heteroatoms selected from oxygen, sulfur and
`nitrogen, (6) a 5 or 6—membered heterocyelic ring with
`from I
`to 4 heteroatoms selected from oxygen, sulfur
`and nitrogen fused to a 5 or 6-membered heterocyelic
`ring with from I to 4 heteroatoms selected from oxy-
`gen, sulfur and nitrogen, or (7) a 5 or 6—membered
`heterocyelic ring with from 1 to 4 heteroatoms selected
`from oxygen, sulfur and nitrogen fused to a C3—C8
`cycloalkyl ring;
`
`nisOto3;
`
`misl;
`
`risOto2;and
`
`R4, R5 and R6 are hydrogen.
`Other preferred compounds of the instant invention are
`realized when in the above structural formula I:
`
`10
`
`15
`
`A is phenyl or a 6-membered heterocyelic ring with 1 or
`2 heteroatoms selected from nitrogen and sulfur;
`
`R1 is hydroxy, halogen, cyano, trifluoromethyl, NR8R8,
`NRSSOZRQ, NRSCORQ, NRSCOZRX, C1—C6
`alkyl
`optionally substituted by hydroxy; and
`r is 0 or 2.
`
`More preferred compounds are represented by the for-
`mula Ia:
`
`(RI)"
`
`H R2
`1
`I
`/ (3“
`CHCHzN—C—(X)m
`\
`*
`I
`R3
`
`N
`
`la
`
`NH—SOz—Z——(R1“)n
`
`30
`
`35
`
`(3) C3—C8 25
`(2) C1~Clo alkyl,
`(1) hydrogen,
`R8 is
`eycloalkyl, (4) Z optionally having 1 to 4 substituents
`selected from halogen, nitro, 0x0, NRIORIO, C1—C10
`alkyl, Cl—C10 aIkoxy, C1—C10 alkylthio, and C1”C10
`alkyl having 1 to 4 substituents selected from hydroxy,
`halogen, COZH, COZ—C1~C10 alkyl, SOZ~C1—C10
`alkyl, C3—C8 cycloalkyl, Cl—C10 alkoxy, and Z option—
`ally substituted by from 1 to 3 of halogen, C1—C10 alkyl
`or C1—C10 alkoxy, or (5) CrC10 alkyl having I to 4
`substituents selected from hydroxy, halogen, COZH,
`COz—Cl—C10 alkyl, SOz—CluC10 alkyl, C3—C8
`cycloalkyl, C1—C10 alkoxy, Cl—C1O alkyl, and Z option-
`ally substituted by from 1 to 4 of halogen, C1—C10 alkyl
`01' C1—Cm 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.
`In one embodiment of the instant invention A is a 5 or
`6-membered heterocyelic ring with from 1 to 4 heteroatoms
`selected from oxygen, sulfur and nitrogen, a benzene ring
`fused to a 5 or 6-membered heterocyelic ring with from 1 to
`4 heteroatoms selected from oxygen, sulfur and nitrogen, or
`a 5 or 6-membered heterocyelic ring with from 1
`to 4
`
`40
`
`45
`
`wherein
`
`n is 0to 3;
`m is 1
`
`R1 is (l) halogen or (2) NRSRS;
`R2, R3 are independently hydrogen or methyl;
`R1“ is (1) halogen,
`(2) C1—C10 alkyl, (3) NRBRS, (4)
`NRSCORg, (5) NR8C02R8, (6) CORQ, (7) OCOR9, or
`(8) a 5 or 6—membered heteroeycle with from 1
`to 4
`heteroatoms selected from oxygen, sulfur and nitrogen,
`optionally substituted with up to four groups indepen—
`dently selected from oxo, halogen, R8, NRSRS, 0R8,
`and SR8;
`is (l) phenyl, (2) naphthyl, (3) a 5 or 6—membered
`heterocyelic ring with from 1 t0 4 heteroatoms selected
`from oxygen, sulfur and nitrogen,
`(4) benzene ring
`fused to a 5 or 6-membered heterocyelic ring with from
`1
`to 3 heteroatoms selected from oxygen, sulfur and
`nitrogen, or (5) a 5 or 6—membered heterocyelic ring
`with from I
`to 4 heteroatoms selected from oxygen,
`sulfur and nitrogen fused to a C3—C8 eyeloalkyl ting;
`X is —-CH2—; and
`R8 and R9 are as defined in claim 1.
`Even more preferred compounds are those represented by
`formula Id:
`
`Id
`
`(Rm
`
`/
`\
`
`N
`
`H R2
`OH
`l
`|
`|
`CHCH:N——C-—CH3
`*
`[
`R3
`
`NH—SOZ
`
`(R‘m
`
`heteroatoms selected from oxygen, sulfur and nitrogen fused
`to a 5 or 6-membered heterocyelic ring with from 1
`to 4
`heteroatoms selected from oxygen, sulfur and nitrogen.
`In another embodiment of the instant
`invention A is
`h
`1
`b
`f
`d
`C C
`1 alk 1
`,
`_
`p eny or enzene use
`to a .3" 8 eye 0 . y ring.
`Preferred compounds of the instant 1nvention are realized
`when 1n the above structural formula I:
`R2 and R3 are hydrogen or methyl;
`X is —CH2——;
`
`60
`
`65
`
`n is 0 or 1;
`R1 is NRSRB;
`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) a5 or 6-membered heterocycle
`with 1
`to 4 heteroatoms selected from oxygen sulfur
`and nitrogen atom fused to the benzene ring;
`R1” is (1) halogen,
`(2) C,—c10 alkyl, (3) NRSRS, (4)
`NRSCORQ, (5) NR8C02R8, (6) COR9, or (7) a 5 or
`
`SAWAI EX. 1014
`
`Page 3 of 35
`
`SAWAI EX. 1014
`Page 3 of 35
`
`

`

`5
`
`6
`
`5,561,142
`
`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 0x0, R8, SR8, 0R8, and NRSRB; when B
`and the benzene ring form a fused ring system, R1” is
`attached to either ring;
`
`R8 is (1) hydrogen, (2) C1—C10 alkyl, (3) Z optionally.
`having 1 to 4 substituents selected from nitro, 0x0, and
`NRIOR”), 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—Cro alkoxy;
`R9 is (l) R8 or (2) NRSRS;
`R10 is (l) 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 substi-
`tuted 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 het-
`eroatoms 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 nitro-
`gen fused to a C3—C8 cycloalkyl ring. Most preferred
`compounds are those having the formula Ie
`
`1’0
`
`15
`
`20
`
`25
`
`Z is (l) 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.
`Representative antiobesity and antidiabetic compounds of
`the present invention include the following:
`N-[4-[2-[[2—hydroxy-2-(6-aminopyridin—3—yl)ethyl]amino]
`ethyl]phenyl]-
`4-(hexylaminocarbonylamino)ben-
`zenesulfonamide
`'
`
`N-[4-[2—[[2-hydroxy-2-(6—arriinopyridin—3-yl)ethyl]amino]
`ethyl]phenyl]— 4-iodobenzenesulfonarnide
`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)ethyllarnino]
`ethyl]phenyl]— 2—naphthalenesulfonamide
`N—[4-[2-[[2-hydroxy—2v(6-aminopyridin-3-yl)ethyl]amino]
`ethyl]phenyl]- 3—quinolinesulfonamide N-[4-[2—[[2-hy-
`droxy-2—(6—aminopyridin-3-yl)ethyl]amino]ethyllphe-
`nyl]- 5-benzisoxazolesulfonamide
`N—[4—[2-[[2—hydroxy-2—(6—aminopyridin-3-yl)ethyllamino]
`ethyl]phenyl]— 4-[(hexylmethylaminocarbonyl)amino]
`benzenesulfonamide
`
`N-[4-[2-[[2-hydroxy-2-(6—aminopyridin—3-yl)ethyl]amino]
`ethyl]phenyl]- 4—[(dimethylaminocarbonyl)amino]benze—
`nesulfonamide
`
`NH—SOz
`
`(R191.
`
`Ie
`
`H
`OH
`1
`/ l
`CHCHzN—CHz—CHz
`\
`*
`
`N
`
`n is Oor 1;
`
`R1” is (l) halogen, (2) NRSCORS’, or (3) a 5—membered
`heterocycle substituted with 0 or 1 oxo selected from
`irnidazolidinone,
`imidazolone, oxadiazole, oxazole,
`triazole and tetrazolone, optionally substituted with up
`to three groups independently selected from R8;
`R8 is (1) hydrogen, (2) C1—C10 alkyl, or (3) C1—C10 alkyl
`having 1
`to 4 substituents selected from hydroxy,
`halogen, Cl—Clo alkyl, C3—C8 cycloalkyl, and Z
`optionally substituted by from 1
`to 4 of halogen,
`Cl—C10 alkyl or C1—C10 alkoxy;
`R9 is NRSRS;
`Z is phenyl.
`Other more preferred compounds are represented by
`formula Ib:
`
`T2
`‘f
`?“
`*
`(111),.GCHCHZN—c+x)m@NH—sorz+R1a)n
`R3
`
`1b
`
`wherein
`n is
`
`0to 3;
`m is
`
`R” is (1) hydroxy, (2) cyano, (3) NRgR8 or (4) halogen;
`R1“ is
`(1) halogen,
`(2) NR8R8,
`(3) NRSCORg,
`(4)
`NRSCOZRS, (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, NRSRS, OR8 and SR8;
`
`35
`
`N-[4—[2-[[2-hydroxy-2-(6-aminopyridin—3-yl)ethyl]amino]
`ethyl]phenyl]— 4-(3-hexyl—2-imidazolidon- l-yl)benzene-
`sulfonamide
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`N—[4-[ 3-[[2-hydroxy-2-(6-arninopyridin—3-yl)ethyl]amino]
`propyl]-phenyl]—
`4-(hexylaminocarbonylamino)ben-
`zenesulfonamide
`
`N-[4-[3-[[2-hydroxy-2-(6—arninopyridin—3-yl)ethyl]amino]
`propyl]~phenyl]— 4-iodobenzenesulfonamide
`N-[4-[3-[[2-hydroxy—2-(6-aminopyridin-3—yl)ethyl]amino]
`propyl]—phenyl]benzcnesulfonamide
`N-[4-[ 3-[[2—hydroxy-2—(6-aminopyridin-3-yl)ethyl]amino]
`propyl]-phenyl]- 2-naphthalenesulfonamide
`N—[4—[3-[[2—hydroxy-2-(6-arninopy1idin—3-yl)ethyl]amin0]
`propyl]—phenyl]— 3-quinolinesulf0namide
`N-[4-[2-[[2-hydroxy—2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]- 4—(hexylaminocarbonylamino)benzenesulfonamide
`N-[4—[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]- 4-isopropylbenzenesulfonamide
`N-[4-[2—[[2-hydr0xy—2-(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]- 2-naphthalenesulfonamide
`N—[4-[2-[[2—hydroxy-2-(3—pyridinyl)ethyl]amino]ethyl]phe—
`nyl]- 3-quinolinesulfonamide
`N—[4-[
`2—[[ 2-hydroxy-2-(3—pyridinyl)ethyl]amino ]ethyl]
`phenyl]- 4—[(hexylmethylaminocarbonyl)amino]benzene-
`sulfonamide
`
`N-[4-[2—[[2-hydroxy—2-(3-pyridinyl)ethyl]an1ino]ethyl]phe-
`nyl]-4-( 3—hexyl-2-imidazolidinon—l-yl)benzenesulfona—
`Inide
`
`N—[4—[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phe—
`nyl]— 4-iodobenzenesulfonamide
`N-[4-[2—[[2-hydroxy—2-(3-pyridinyl)ethyl]an1ino]ethyl]phe-
`nyl]-4—[5-( 3-cyclopentylpropyl)-[l,2,4]—oxadiazol-3-yl]
`benzensulfonamide
`
`N—[4-[2-[[2—hydroxy-2—(3—pyridinyl)ethyl]amino]ethyl]phe-
`nyl]-4-[( l—oxoheptyl)amino]benzenesulfonamide
`
`SAWAI EX. 1014
`
`Page 4 of 35
`
`SAWAI EX. 1014
`Page 4 of 35
`
`

`

`5,561,142
`
`7
`
`N—[4-[2-[[2—hydroxy-2-(3-pyn’dinyl)clhyl]amino]ethyl]phc-
`ny1]—4—[(l—ox0-
`4—phcny1bulyl)amino]bcnzcncsu1f0na-
`midc
`N—[4—[2—[[2—hydroxy—2—(3—pyridiny1)cthyl]amino]c1hyl]phe-
`ny1]- 4—[(propoxycarbonyl)amino]bcnzcncsulfonanfidc
`N-[4—[2-[[2-hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phc—
`ny1]—4—[[[(fur— 2—y1methyl)amin0]carbony1]amino]benzc—
`ncsulfonamidc
`N—[4—[2—[[2—hydroxy-2—(3-pyridiny1)elhy1]amino]cthyl]phc-
`11y1]—4—[[[( 2—phcnylclhyDamino]carbonyl]amin0]bcnzc-
`ncsulfonamidc
`N-[4—[2—[[2—hydroxy—2—(3—pyridiny1)cthyl]amino]cthy1]phc—
`nyl]-4-[[[( 2-ind01—3—ylcLhyl)amino]carb0nyl]amino]bcn—
`zcncsulfonamidc
`N—[4-[2-[[2-hydr0xy-2-(3-pyridinyl)elhy1]arnino]ethy1]phe-
`ny1]v
`4-[[(0cty1amin0)carb0ny1]amin0]benzenesulfona—
`mide
`N-[4—[2-[[2—hydroxy—2-(3—pyridiny1)ethyl]amino]cthyl]phc—
`ny1]— 1—[(hcxylamino)carbony1]-5—indolincsu1fonamide
`N—[4—[2-[[2—hydroxy-2-(3-pyridiny1)elhyl]amino]ethyl]phc-
`ny1]- 1-[(octylamino)carbonyl]-5—indolinesulfonamide
`N—[4—[2-[[2—hydroxy—2—(3—pyridiny1)cthyl]amino]ethy1]phc—
`ny1]-
`1-[(N—mcthyl—N—octylamino)carbonyl]—5—indolinc-
`sulfonamide
`N-[4—[2-[[2—hydroxy—2—(3—pyridinyl)ethy1]amino]ethy1]phc—
`ny1]-1-( 1-oxononyl)-5-indolincsulfonamidc
`N-[4-[2—[[2-hydroxy-2-(3-pyridiny1)ethyl]amino]ethy1]phe-
`ny1]— 1-( 4-methylthiazo-1-2-y1)-5-ind01incsulfonamidc
`N-[4-[2-[[2—hydroxy—2—(3—pyridinyl)cthyl]amino]ethy1]phe-
`ny1]- 1-( 4-octyllhiazol—2Ay1)—5—indolinesulfonamide
`N-[4-[2-[[2-hydroxy-2—(3—pyridinyl)cthy1]amino]ethyl]phe—
`ny1]— 1 —( 4-ethyl—5—methylthiazol—2—yl)—5—ind01inesulfona—
`midc
`
`10
`
`15
`
`20
`
`25
`
`30
`
`)ethyl]amino]ethyl]
`N-[4-[2-[[2—hydroxy—2—(3—pyridiny1
`phenyl]-4—(
`3—octy1—2imidazolidinon—1—y1)bcnzene—
`sulfonamjdc
`
`35
`
`N-[4—[2-[[2—hydroxy—2—(3-pyridinyl)cthyl]amino]ethy1]phc-
`ny1]-4—[3—(
`4,4,4-trifiuorobuty1)—2-imidazolidinon-1-y1]
`benzenesulfonamidc
`N-[4—[2-[[2—hydroxy—2—(3-pyridiny1)ethy1]arrlino]ethyl]phe-
`nyl]—4—[3-( 3-pheny1propy1)-2-imidazolidinon— 1—y1]ben—
`zcncsulfonamidc
`N-[4—[2-[[2-hydroxy—2-(3-pyridiny1)ethy1]amino]cthyl]phe—
`ny1]-4-[3-(4,4,5,5,5—pcntafluoropcnly1)—2-imidazolidi—
`men 1 —yl]benzenesu1fonamidc
`N—[4-[2-[[2-hydr0xy-2-(3vpyridiny1)cthy1]amino]ethyl]phe-
`nyl]-4-[3-(
`2-cyclohexylethy1)—2—imidazolidinon-
`1-yl]
`benzcncsulfonamide
`N—[4—[2-[[2—hydroxy-2-(3-pyridinyl)cthy1]amino]cthyl]phc—
`ny]]—4-[3—[3—(4-chlor0phcny1)pr0pyl]—2—imidazolidinon-
`1 -y1]benzcnesu1fonamidc
`N—[4-[2-[[2—hydroxy-2-(3-pyridinyl)cthyl]amino]elhyl]phe-
`ny1]—4-( 3—pen1yl—2-imidazolidinon-1-yl)bcnzcnesulf0na—
`mide
`
`)eLhyl]amino]clhyl]
`2-hydroxy—2-(3—pyridiny1
`N-[4-[2-[[
`phenyl]—4-[ 3-( 3-cyc10pentylpr0py1)—2-imidazolidinon-
`1—y1]benzencsu1fonamidc
`N—[4-[2-[[2—hydroxy—2—(3—pyridiny1)ethyl]amino]ethyl]phc-
`ny1]— 4-[cyclopcntylclhyb-2—imidazolidinon— 1~yl]benze—
`ncsulfonamidc
`
`N—[4-[2—[[2-hydroxy—2-(3—pyn‘dinyl)ethy1]amino]ethyl]phe-
`nyl]—4—[3-( 3-cyclohcxylpropyl)—2-imidazolidinon-
`1—yl]
`benzenesulfonamidc
`
`40
`
`45
`
`50
`
`55
`
`60
`
`N—[4-[2-[[2—hydroxy—2~(3—pyridiny1)ethyl]amino]ethy1]phc-
`ny1]-4-[3-( 2,2—dimethylhexy1)-2-imidazolidinon— 1—yl]
`benzenesulfonamide
`
`65
`
`N—[4-[2—[[Z-hydroxy—2—(3-pyridinyl)ethyl]amino]ethyl]phe-
`nyl]—4-( 3-hcxy1-2—imidazolon-1—y1)benzenesulfonamidc
`
`8
`N—[4—[2—[[2-hydr0xy—2—(3—pyridinyl)cthyl]amino]elhyl]phc—
`ny1]-4-[3-( 4,4,4—[1‘ifluorobuly1)-2-imidazolon- 1-y1]bcn-
`zcnesulfonamidc
`N-[4-[2-[[2-hydroxy-2-(3—pyridinyl)cthy1]amino]cthy1]phc—
`nyl]—4-(3-octy1- 2-imidazolon—1-y1)bcn2cncsu1fonamidc
`N—[4-[
`2—[[
`2—hydroxy-Z-(3-pyridinyl)ethyl]amino]cthy1]
`phenyI]-4-[3-( 3-cyclopenlylpropyl)—2-imidazolon— 1—y1]
`benzenesulfonamidc
`N-[4—[2—[[2-hydroxy—2—(3—pyridiny1)elhyl]amino]ethyl]phc—
`ny1]—4-(2-octyl-
`3-oxo-[1,2,4]—triazol—4—y1)benzenc—
`sulfonamidc
`N—[4-[2-[[2-hydr0xy-2-(3—pyridinyl)eLhy1]amino]ethy1]phe—
`nyl]—4-( 4-hcxy1-5-tctrazolon-1—y1)bcnzcnesulfonamidc
`N-[4-[2-[[2—hydroxy—2-(3—pyridiny1)ethyl]amino]c1hy1]phc-
`ny1]-4-(4-octy1- 5-tetrazolon-1-yl)benzencsulfonamidc
`N—[4-[2—[[2-hydr0xy—2—(3—pyridinyl)cLhyl]amino]cthyl]phc-
`nyl]-4—[4—( 3—cyclopenty1propy1)—5~1e1razolon- 1-yl]bcn-
`zcncsulfonamidc
`N—[4-[2-[[2-hydroxy—2-(3-pyridiny1)clhyl]amino]cthy1]phc-
`ny1]-4—( 2—pentyloxazol-5-y1)benzcnesulfonamidc
`N—[4-[2-[[2-hydroxy-2-(3-pyridiny1)cthyl]amino]cthyl]phe—
`ny1]-4-( 2-octyloxazol-5-y1)bcnzcncsulfonamidc
`N—[4—[2-[[2-hydroxy-2-(3—pyridiny1)cthy1]amin0]clhyl]phe-
`ny1]-4-[2-(
`2—cyclopentylethy1)oxazol—5-y1]bcnzene—
`sulfonamide
`N—[4—[2—[[2—hydroxy—2-(3—pyridiny1)elhy1]amino]cthy1]phc-
`nyl]—4-[(
`4—cthy1—5—mcthylthiazol—Z—y1)amino]benzcnc-
`sulfonamidc
`N—[4-[2-[[2-hydroxy-2-(3-pyn‘diny1)cthyl]amino]cthyl]phc—
`ny1]—4—[( 4,5,6,7-tchahydrobenzothiazol-2-y1)amino]bcn-
`zenesulfonamide
`
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)cthy1]amino]elhy1]phe-
`nyl]-4-( 2-hcxylimidazo1—4—yl)benzenesu1fonamidc
`N-[4—[2—[[2—hydroxy—2-(3—pyridiny1)ethyl]arnino]cthyl]phe-
`nyl]~4—(
`1—mcthyl—2—octylimidazol-5-y1)benzcncsu1fona-
`mide
`‘
`N-[4-[2-[[2-hydroxy-2-(3—pyridinyl)ethyl]amino]cthyl]phc-
`ny1]—4-[
`1-methy1-2-(2—cyClopemylelhylfimidazol-5-y1]
`benzcncsulfonamidc
`N—[4—[2-[[2-hydr0xy-2-(3-pyridiny1)cthyl]amino]elhyl]phc-
`nyl]—4—[ 1-mcthyl—2-[2-(4—fluorophenyl)ethyl]imida201-5-
`yl]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phc-
`nyl]—4—( 5—pentyl-[1,2,4]—oxadiazol-3-y1)bcnzcnesulfona—
`mide
`
`N—[4-[2—[[2-hydroxy-2-(3-pyridinyl)cthyl]amino]elhyl]phc-
`ny1]-4-[5—(
`2-cyc10pemylcthy1)—[1,2,4]-oxadiazoI—3—yl]
`benzencsulfonamide
`
`N-[4—[2-[[2-hydr0xy—2—(3—pyridiny1)ethy1]amin0]ethy1]phe—
`nyl]—4—( 5-hepty1-[1,2,4]—oxadiazol—3—yl)benzencsulfona—
`mide
`
`N-[4-[2-[[2-hydroxy-2—(3—pyridiny1)ethyl]amino]cthy1]phe—
`ny1]-4-(
`5-octyl-[1,2,4]-oxadiazol—3—yl)benzcncsulfona—
`mide
`
`N-[4-[2-[[2-hydroxy—2—(3—pyridiny1)cthyl]amin0]ethyl]phe-
`nyl]—4—( 5—hcxyllhio-[1,2,4]-Lriazol-3-y1)benzenesu1fona-
`midc
`
`N-[4-[2-[[2-hydroxy-2—(3—pyridiny1)ethyl]amin0]cthyl]phe~
`ny1]-4-[[4—(4—propylpiperidin-1-y1)-1,1-di0x0—[1,2,5]—
`thiadiazol- 3—y1]amin0]benzenesulfonamidc
`N—[4-[2-[[2—hydroxy~2v(3—pyridiny1)clhyl]amin0]elhyl]phc-
`nyl]—4-[[4-(hexylmethylamino)-1,1-diox0—[1,2,5]—lhia-
`diazol- 3—y1]amino]benzencsulfonamide
`N-[4-[2-[[2-hydroxy-2—(3—pyridiny1)cthyl]amino]ethy1]phe-
`ny1]-4—[[4-(hepty1mcthy1amino)—1,1—dioxo-[1,2,5]-thia—
`diazol- 3-y1]anfino]bcnzenesulf0namide
`N—[4-[2-[[2-hydr0xy-2-(3-pyridiny1)ethyl]amino]cthy1]phe—
`nyl]—4—(
`1-octy1-2,4—imidazolidinedion-3-y1)bcnzene—
`sulfonamide
`
`SAWAI EX. 1014
`
`Page 5 of 35
`
`SAWAI EX. 1014
`Page 5 of 35
`
`

`

`9
`
`10
`
`5,561,142
`
`N—[4—[2—[[2—hydroxy-2—(3—pyridinyl)cthy1]amin0]ethyl]phe-
`nyl]—4—[3—(3—nitropheny1)-5—pyrazolon—
`1-y1]benzene—
`sulfonamide
`
`N—[4-[2—[[2—hydroxy-2-(3—pyridiny1)ethy1]amino]ethy1]phe-
`nyl]—4-[4—(
`1—hydroxy-1-hexy1hcpty1)-5-methy1-[1,2,3]—
`lriazol-2—y1]benzenesulf0namide
`N-[4-[2-[[Z—hydroxy-Z—(3-pyridiny1)ethyl]amino]ethyl]phc—
`ny1]—4-[4—( 1—hydroxyheptyl)-5—methyl—[1,2,3 ]-triazol—2—
`y1]benzenesu1fonamide
`N-[4—[2—[[2—hydroxy-2-(3-pyridiny1)ethy1]amino]—2-methyl-
`propy1]-phenyl]— 4-(3—hexyl-2-imidazolidinon- 1-yl)ben—
`zenesulfonamide
`
`N-[4-[2-[[2-hydroxy—2—(3—pyridiny1)ethy1]amino]~2-methy1-
`propy1]-pheny1]- 4—iodobenzenesulfonamide
`N-[4-[2—[[2-hydr0xy—2—(3—pyridinyl)ethy1]amino]—2-methy1-
`propyl]—pheny1]-
`4—[[(hexy1amino)carbony1]amino]ben—
`zenesulfonamide
`
`N-[4—[2—[(Z-hydroxy-2-phenylethy1)amino]ethy1]pheny1]-4-
`iodobenzene-sulfonamide
`
`N—[4-[2—[(2-hydroxy-Z-phenylethy1)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-ch10ropheny1)ethyl]amino]ethyl]
`pheny1]~ 3—isopropylbenzenesulfonanfide
`N-[4-[2-[[2-hydroxy-2-(3-chlor0pheny1)ethy1]amino]ethy1]
`pheny1]— Z-naphthalenesulfonamide
`N—[4-[2-[[2-hydr0xy-2-(3—ch10ropheny1)ethyl]amino]ethy1]
`pheny1]— 3-quinolinesulfonamide
`N-[4-[2—[[2—hydroxy-2-(4-amino-3,5-dichlorophenyl)ethy1]
`amino]ethy1]-pheny1]-
`4—(hexylaminocarbony1ami-
`no)benzenesulfonamide
`N-[4-[2—[[2-hydroxy—2-(4—amino—3,5—dichlorophenyl)ethy1]
`amino]ethy1]—pheny1]— 1-[(octylamino)carbonyl]—5—indo-
`linesulfonamide
`
`~
`
`N-[4-[2-[[2—hydroxy—2-(4-amino-3,5-dichlor0pheny1)ethy1]
`amino]ethyl]—pheny1]— 4-(3-hexy1-2-imidazolidinon-1-y1—
`)benzenesulfonamide
`N-[4—[2—[[2-hydr0xy—2-(4-amino—3,5-dich10ropheny1)ethy1]
`amino]ethy1]—phenyl]— 4-(3-octy1-2-imidazolidinon- 1-y1—
`)benzenesulfonamide
`N-[4-[2-[[Z-hydroxy-2-(4-hydroxyphenyl)ethyl]amino]
`ethyl]phenyl]vbenzenesulfonamide
`N-[4-[2—[[2—hydroxy-2-(4-hydroxypheny1)ethy1]amino]
`ethy1]pheny1]- 4-iodobenzenesulfonanfide
`N—[4-[2-[[2—hydroxy-2-(3-cyanopheny1)ethy1]amino]ethy1]
`phenyl}
`4-(hexy1aminocarbonylamino)ben—
`zenesulfonamide
`
`N—[4—[2—[[2—hydr0xy-2-(3-cyanopheny1)ethy1]amin0]ethy1]
`pheny1]- 3-quinolinesu1fonamide
`N-[4—[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethy1]phe—
`ny1]-4—( 5—hexy1—[1,2,4]—oxadiazol-3-y1)benzenesulfona—
`mide
`N—[4-[2—[[2-hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe-
`nyl]—4-(
`4-hepty1-5-methyl-[1,2,3]—tfiazol—2—y1)benzene-
`sulfonamide
`
`N—[4—[2—[[2—hydroxy—2-(3-pyfidiny1)ethy1]amino]ethyl]phe-
`ny1]-4-(
`3-hexy1-2,4-imidazolidinedion— 1-y1)benzene-
`sulfonamide
`
`N-[4-[2-[[2—hydroxy-2—(3—pyfldinyl)ethyl]amino]ethyl]phe-
`ny1]-4-( 2,4-imidazolidinedion-1-y1)benzenesu1fonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyfidiny1)ethy1]amino]ethy1]phe-
`ny1]-4-[3-( 3-cyclopentylpropy1)-2,4—imidazolidinedion-
`1-y1]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyfidiny1)ethyl]amino]ethyl]phe-
`nyl] [1 ,2,4] —oxadiazol—5-y1)benzenesu1fonamide
`N-[4-[2—[[2-hydroxy-2-(3-pyridiny1)ethyl]amino]ethy1]phe-
`ny1]-4-( 3—hexy1—[1,2,4]-oxadiazol-5-y1)benzenesulfona-
`mide
`
`N-[4—[2—[[2—hydroxy-2-(3-pyfidiny1)ethy1]amino]ethy1]phe~
`nyl]—4—( 3—heptyl—[1,2,4]-0xadiazol—5-y1)benzenesulfona—
`rnide
`N—[4-[2—[[2—hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe—
`ny1]-4—(
`3—octy1—[1,2,4]—0xadiazol-5—y1)benzenesulfona—
`mide
`N-[4-[2-[[2-hydr0xy—2—(3—pyfidiny1)ethy1]amino]elhy1]phe-
`ny1]—4-[3-(
`2—cyclopentylethy1)-[1,2,4]-oxadiaz01-5—y1]
`benzenesulfonamide
`N-[4-[
`2—[[2—hydroxy-2-(3-pyfidiny1)ethy1]amino]ethyl]
`pheny1]—4-[3-( 3-cyclopenty1propyl)—[1,2,4]—oxadiaz01-5-
`y1]benzenesulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]arnino]ethy1]phe-
`ny1]-4-( 3-penty1-[1,2,4]-thiadiazol—S-y1)benzenesu1fona—
`mide
`
`N-[4-[2-[[2-hydroxy-2-(3—pyfidiny1)ethy1]amino]ethy1]phe-
`ny1]-4-( 3-hexy1-[1,2,4]—thiadiazol—5-yl)benzenesu1f0na—
`mide
`
`5
`
`10
`
`15
`
`N-[4-[2-[[2—hydroxy-2—(3-pyridinyl)ethyl]amino]ethyl]phe-
`ny1]-4-( 3-hepty1-[1,2,4]-thiadiazol-5~y1)benzenesu1fona-
`mide
`
`20
`
`N—[4—[2—[[2—hydroxy-2-(3-pyridinyl)ethy1]amino]ethy1]phe—
`nyl]-4-(
`3-octy1-[1,2,4]—thiadiazol—5—yl)benzenesulfona-
`mide
`
`N-[4-[2-[[2-hydroxy-2-(3—pyridinyl)ethyl]amino]ethy1]phe-
`ny1]-4-[3-(2—cyclopentylethy1)-[1,2,4]—thiadiazol-5-y1]
`benzenesulfonamide
`
`N-[4-[2-[[2-hydroxy-2—(3-pyfidiny1)ethy1]amino]ethy1]phe-
`ny1]—4—[3—(3-cyclopentylpr0pyl)—[1,2,4]—thiadiazol-5—y1]
`benzenesulfonamide
`
`N-[4-[2—[[2-hydroxy-2—(3—pyridiny1)ethy1]amino]ethyl]phe-
`ny1]-4—( 5—penty1-[1,2,4]-thiadiazol-3-y1)benzenesu1fona-
`mide
`
`N—[4-[2—[[2—hydr0xy-2-(3-pyridiny1)ethy1]amino]ethy1]phe-
`ny1]-4—( 5—hexy1-[1,2,4]—Lhiadiazol-3-y1)benzenesulfona—
`mide
`
`N-[4—[2—[[2—hydroxy—2-(3-pyridiny1)ethyl]amino]ethy1]phe-
`nyl]-4-( 5—hepty1-[1,2,4]-thiadiazol-3-yl)benzenesu1fona-
`mide
`
`N—[4-[2—[[2-hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe-
`ny1]-4-(
`5-octy1-[1,2,4]-thiadiazol-3-y1)benzenesulfona—
`nfide
`
`N—[4-[2—[[2-hydroxy-2-(3-pyridiny1)ethyl]amino]ethy1]phe-
`ny1]-4-[5-( 2-cyclopentylethyl)-[1,2,4 ]—thiadiazol-3-y1]
`benzencsulfonamide
`N-[4-[2-[[2—hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe-
`nyl]—4—[ 5-( 3-cyclopentylpropyl)-[1,2,4]—thiadiazol-3-yl]
`benzenesulfonamide
`N—[4-[2—[[2—hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe-
`ny1]-4-(
`4-penty1-3-oxo-[1,2,4]-tfiazol-2-yl)benzene-
`sulfonamide
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny1)ethyl]amino]ethy1]phe-
`ny1]-4-(
`4-hexy1-3-oxo-[1,2,4]—triazol—2—y1)benzene—
`sulfonamide
`
`N-[4-[2-[[2-hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe-
`ny1]-4-(
`4-hepty1—3-oxo—[1,2,4]-triazol-2-y1)benzene-
`sulfonamide
`
`N-[4-[2-[[2—hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe-
`nyl]-4—(4—octy1—
`3-oxo-[1,2,4]—tn'azol—2—yl)benzene-
`sulfonamide
`
`N-[4-[2-[[2—hydr0xy-2—(3—pyridiny1)ethy1]arnino]ethyl]phe-
`ny1]—4-[4-(
`2-cyclopentylethy1)—3—oxo-[1,2,4]—triazol-2-
`yl]benzenesulfonamide
`N—[4-[2-[[2-hydroxy-2-(3-pyridiny1)ethy1]amino]ethy1]phe-
`ny1]-4-[4-( 3-cyclopentylpropyl)-3-oxo-[ 1,2,4]—triazol-2—
`y1]benzenesu1fonamide
`N-[4-[2-[[2-hydroxy-2—(3-pyridiny1)ethy1]amino]ethy1]phe-
`nyl]—4-( 5-penty10xazol-2—y1)benzenesulfonamide
`
`25
`
`30
`
`35
`
`4o
`
`45
`
`50
`
`55
`
`60
`
`65
`
`SAWAI EX. 1014
`
`Page 6 of 35
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`SAWAI EX. 1014
`Page 6 of 35
`
`

`

`11
`
`12
`
`5,561,142
`
`N—[4—[2—[[2—hydroxy-2—(3-pyridiny1)cthy1]amino]cthy1]phc—
`ny1]-4-( 5-hcxy10xazol—2—yl)benzencsulfonamidc
`N-[4-[2-[[2—hydr0xy—2—(3-pyridiny1)elhy1]amino]ethy]]phe-
`ny1]—4—( 5—hcp1y1oxaz01-2-y1)bcnzcncsulfonamidc
`N-[4-[2-[[2-hydr0xy—2-(3-pyridinyl)Clhyl]amino]elhy1]phe— 5
`nyl]—4—( 5—octy10xaz01~2—y1)bcnzencsulfonamidc
`N-[4-[2-[[2—hydroxy—2—(3—pyn'dinyl)ethyl]amino]cthyl]phc—
`ny1]v4—[5-(
`2-cyclopcntylcthyl)oxazol~2—y1]bcnzcne—
`sulfonamidc
`
`N—[4-[2—[[2-hydroxy—2-(3-pyridinyl)cthy11amino]elhyl]phe-
`ny1]-4-[5-(
`3-cyclopcntylpropy1)oxazol—2—yl]benzene-
`sulfonamide
`
`10
`
`N-[4-[2-[[2-hydroxy-2—(3—pyridiny1)ethy1]arnir10]c1hy1]phe-
`ny1]—4-( 4—pcnlyl0xa201-2—y1)bcnzcncsu1f0namide
`N-[4-[2-[[2—hydr0xy-2—(3-py1‘idinyl)clhy1]amino]cthy1]phc— 15
`ny1]-4-( 4—hcxyloxazol—2—yl)benzenesulfonamidc
`N-[4-[2—[[2—hydroxy-2-(3—pyridiny1)cthyl]amino]ethyl]phe-
`ny1]-4—( 4-hcptyloxazol-2-y1)bcnzenesu1fonamidc
`N-[4—[2—[[2-hydr0xy-